SINGLE IMMUNOGLOBULIN DOMAIN BISPECIFIC ANTIBODIES AGAINST IL 10R alpha AND beta SUBUNITS AND METHODS OF USE

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63/724,109, filed on Nov. 22, 2024, which is hereby incorporated herein by reference in its entirety for all purposes.

[0002] The instant application contains a Sequence Listing which has been submitted electronically in .XML format and is hereby incorporated by reference in its entirety. Said .XML copy, created on Nov. 7, 2025, is named 1569-US-WO_SL.xml and is 1,039,098 bytes in size.

[0003] Interleukin-10 (IL-10) is an immunoregulatory cytokine that plays a role in limiting excessive inflammation and maintaining tissue homeostasis. Despite its potent immunosuppressive effects on myeloid cells, high concentrations of IL-10 can paradoxically activate T-cells, B-cells, and natural killer (NK) cells, counterbalancing its immunosuppressive actions in inflammatory conditions. Additionally, the activation of T-cells and B-cells by IL-10 leads to the production of IFN-γ, increased levels of IgE, a rise in granulocyte-monocyte progenitor (GMP) cells, and a reduction in red blood cells and platelets. These adverse effects of recombinant IL-10 limit its therapeutic potential for treating inflammatory bowel disease (IBD) and psoriasis.

[0004] In one aspect, provided is a single domain antibody (sdAb) comprising a variable domain (VHH) that specifically binds to the extracellular domain of interleukin-10 receptor (IL-10R) alpha subunit (IL-10Rα). In some embodiments, the anti-IL-10Rα VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Kabat, respectively: SEQ ID NOs: 1, 2 and 3 (A01); SEQ ID NOs: 4, 5 and 6 (A06); SEQ ID NOs: 7, 8 and 9 (A09); SEQ ID NOs: 10, 11 and 12 (B07); SEQ ID NOs: 4, 13 and 14 (B08); SEQ ID NOs: 4, 15 and 16 (C09); SEQ ID NOs: 4, 17 and 18 (D08); SEQ ID NOs: 19, 20 and 21 (D14); SEQ ID NOs: 22, 23 and 24 (E07); SEQ ID NOs: 22, 25 and 27 (huE07); SEQ ID NOs: 22, 27 and 24 (huE07); SEQ ID NOs: 4, 28 and 29 (E15); SEQ ID NOs: 4, 30 and 31 (F09); SEQ ID NOs: 22, 23 and 32 (F10); SEQ ID NOs: 33, 34 and 35 (F11); SEQ ID NOs: 4, 36 and 29 (F21); SEQ ID NOs: 19, 37 and 38 (G22); SEQ ID NOs: 39, 40 and 41 (G23); SEQ ID NOs: 42, 43 and 44 (H22); SEQ ID NOs: 45, 46 and 47 (I04); SEQ ID NOs: 4, 48 and 6 (J13); SEQ ID NOs: 4, 49 and 50 (J24); SEQ ID NOs: 19, 51 and 52 (L05); SEQ ID NOs: 19, 37 and 53 (L11) or SEQ ID NOs: 54, 55 and 24 (N16). In some embodiments, the anti-IL-10Rα VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to IMGT, respectively: SEQ ID NOs: 56, 57 and 58 (A01); SEQ ID NOs: 59, 60 and 61 (A06); SEQ ID NOs: 62, 63 and 64 (A09); SEQ ID NOs: 65, 66 and 67 (B07); SEQ ID NOs: 59, 68 and 69 (B08); SEQ ID NOs: 59, 70 and 71 (C09); SEQ ID NOs: 59, 72 and 73 (D08) SEQ ID NOs: 74, 75 and 76 (D14); SEQ ID NOs: 77, 78 and 79 (E07) SEQ ID NOs: 77, 80 and 81 (huE07); SEQ ID NOs: 77, 82 and 79 (huE07); SEQ ID NOs: 59, 83 and 84 (E15); SEQ ID NOs: 59, 85 and 86 (F09); SEQ ID NOs: 77, 78 and 87 (F10); SEQ ID NOs: 88, 89 and 90 (F11); SEQ ID NOs: 59, 91 and 84 (F21); SEQ ID NOs: 92, 75 and 93 (G22); SEQ ID NOs: 94, 89 and 95 (G23); SEQ ID NOs: 96, 89 and 97 (H22); SEQ ID NOs: 98, 99 and 100 (I04); SEQ ID NOs: 59, 101 and 61 (J13); SEQ ID NOs: 59, 102 and 103 (J24); SEQ ID NOs: 74, 75 and 104 (L05); SEQ ID NOs: 74, 75 and 105 (L11) or SEQ ID NOs: 106, 107 and 79 (N16). In some embodiments, the anti-IL-10Rα VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Chothia, respectively: SEQ ID NOs: 108, 109 and 110 (A01); SEQ ID NOs: 111, 112 and 113 (A06); SEQ ID NOs: 114, 115 and 116 (A09); SEQ ID NOs: 117, 118 and 119 (B07); SEQ ID NOs: 111, 112 and 120 (B08); SEQ ID NOs: 111, 121 and 122 (C09); SEQ ID NOs: 111, 121 and 123 (D08); SEQ ID NOs: 124, 125 and 126 (D14); SEQ ID NOs: 127, 128 and 129 (E07); SEQ ID NOs: 127, 130 and 131 (huE07); SEQ ID NOs: 111, 132 and 133 (E15); SEQ ID NOs: 111, 134 and 135 (F09); SEQ ID NOs: 127, 128 and 136 (F10); SEQ ID NOs: 137, 138 and 139 (F11); SEQ ID NOs: 111, 132 and 133 (F21); SEQ ID NOs: 140, 125 and 141 (G22); SEQ ID NOs: 142, 138 and 143 (G23); SEQ ID NOs: 124, 138 and 144 (H22); SEQ ID NOs: 145, 146 and 147 (I04); SEQ ID NOs: 111, 112 and 113 (J13)); SEQ ID NOs: 111, 148 and 149 (J24); SEQ ID NOs: 124, 125 and 150; (L05); SEQ ID NOs: 124, 125 and 151; (L11) or; SEQ ID NOs: 152, 121 and 129 (N16). In some embodiments, the anti-IL-10Rα VHH comprising a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Honegger, respectively: SEQ ID NOs: 153, 154 and 155 (A01); SEQ ID NOs: 156, 157 and 158 (A06); SEQ ID NOs: 159, 160 and 161 (A09); SEQ ID NOs: 162, 163 and 164 (B07); SEQ ID NOs: 156, 165 and 166 (B08); SEQ ID NOs: 156, 167 and 168 (C09); SEQ ID NOs: 156, 169 and 170 (D08); SEQ ID NOs: 171, 172 and 173 (D14); SEQ ID NOs: 174, 175 and 176 (E07); SEQ ID NOs: 174, 177 and 178 (huE07); SEQ ID NOs: 174, 179 and 176 (huE07); SEQ ID NOs: 156, 180 and 181; (E15); SEQ ID NOs: 156, 182 and 183; (F09); SEQ ID NOs: 174, 175 and 184; (F10); SEQ ID NOs: 185, 186 and 187; (F11); SEQ ID NOs: 709, 186 and 187; (huF11); SEQ ID NOs: 156, 188 and 181; (F21); SEQ ID NOs: 189, 190 and 191; (G22); SEQ ID NOs: 192, 193 and 194; (G23); SEQ ID NOs: 195, 196 and 197; (H22); SEQ ID NOs: 198, 199 and 200; (I04); SEQ ID NOs: 156, 201 and 158; (J13); SEQ ID NOs: 156, 202 and 203; (J24); SEQ ID NOs: 204, 205 and 206; (L05); SEQ ID NOs: 204, 190 and 207; (L11) or; SEQ ID NOs: 208, 209 and 176 (N16). In some embodiments, the anti-IL-10Rα VHH comprises a VHH-CDR1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, respectively: SEQ ID NOs: 22, 23 and 24; (E07; according to Kabat); SEQ ID NOs: 22, 25 and 27; (huE07; according to Kabat); SEQ ID NOs: 22, 27 and 24; (huE07; according to Kabat); SEQ ID NOs: 77, 78 and 79; (E07; according to IMGT); SEQ ID NOs: 77, 80 and 81; (huE07; according to IMGT); SEQ ID NOs: 77, 82 and 79; (huE07; according to IMGT); SEQ ID NOs: 127, 128 and 129; (E07; according to Chothia); SEQ ID NOs: 127, 130 and 131; (huE07; according to Chothia); SEQ ID NOs: 174, 175 and 176; (E07; according to Honegger); SEQ ID NOs: 174, 177 and 178; (huE07; according to Honegger) or SEQ ID NOs: 174, 179 and 176; (huE07; according to Honegger). In some embodiments, the anti-IL-10Rα VHH comprises a VHH-CDR1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, respectively: SEQ ID NOs: 33, 34 and 35 (F11; according to Kabat); SEQ ID NOs: 88, 89 and 90 (F11; according to IMGT); SEQ ID NOs: 137, 138 and 139 (F11; according to Chothia); SEQ ID NOs: 185, 186 and 187 (F11; according to Honegger) or SEQ ID NOs: 709, 186 and 187 (huF11; according to Honegger). In some embodiments, the anti-IL-10Rα VHH comprises the amino acid sequence of any one of SEQ ID NOs: 212, 230, 233, 234, 249 and 710, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to one of the amino acid sequences of SEQ ID NOs: 212, 230, 233, 234, 249 and 710. In some embodiments, the anti-IL-10Rα VHH comprises the amino acid sequence of any one of 210-211, 213-229, 231-232, 235-248, 250-287 and 752-755, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to one of the amino acid sequences of SEQ ID NOs: 210-211, 213-229, 231-232, 235-248, 250-287 and 752-755. In some embodiments, the anti-IL-10Rα VHH comprises the amino acid sequence of any one of SEQ ID NOs: 233-240 and 724-725, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to one of the amino acid sequences of SEQ ID NOs: 233-240 and 724-725 (E07). In some embodiments, the anti-IL-10Rα VHH comprises the amino acid sequence of any one of SEQ ID NOs: 249-252 and 752-755, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to one of the amino acid sequences of SEQ ID NOs: 249-252 and 752-755 (F11). In some embodiments, the anti-IL-10Rα VHH is humanized. In some embodiments, the anti-IL-10Rα VHH binds to an epitope on IL 10Rα comprising contact amino acid residues W33, E35, E37, H40, 142, H44, T46, L79, S80, T124, A170, R172, F178, F180, H182, Q204, K215, M217, W218, K220 and E221, wherein the amino acid residue positions are with respect to SEQ ID NO: 711. In some embodiments, the anti-IL-10Rα VHH binds to an epitope on IL 10Rα comprising contact amino acid residues I169, I171, K173, F178, F180, T181, H182, K183, K186, F190, L192, L193, S195, E197 and F201, wherein the amino acid residue positions are with respect to SEQ ID NO: 711. In some embodiments, the anti-IL-10Rα VHH binds to IL 10Rα with an equilibrium dissociation constant (KD) of lower than or less than 5 nM, e.g., lower than 4 nM, 3 nM or 2 nM. In some embodiments, the VHH that binds to IL 10Rα binds to both human IL-10Rα and cynomolgus IL-10Rα. In some embodiments, the anti-IL-10Rα sdAb comprises a human fragment crystallizable (Fc) domain. In some embodiments, the Fc domain comprises a human IgG1 or a human IgG4.

[0005] In another aspect, provided is a single domain antibody (sdAb) comprising a variable domain (VHH) that specifically binds to the extracellular domain of interleukin-10 receptor (IL-10R) beta subunit (IL 10Rβ). In some embodiments, the anti-IL-10Rβ VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Kabat, respectively: SEQ ID NOs: 288, 289 and 290 (A02); SEQ ID NOs: 291, 292 and 293 (A05); SEQ ID NOs: 291, 294 and 295 (huA05); SEQ ID NOs: 296, 297 and 298 (huA05); SEQ ID NOs: 299, 300 and 301 (B10); SEQ ID NOs: 302, 303 and 304 (B12); SEQ ID NOs: 305, 306 and 307 (C01); SEQ ID NOs: 296, 308 and 309 (C04); SEQ ID NOs: 310, 311 and 312 (C10); SEQ ID NOs: 302, 303 and 313 (D01); SEQ ID NOs: 314, 315 and 316 (E08); SEQ ID NOs: 317, 318 and 319 (E10); SEQ ID NOs: 320, 321 and 322 (G01) or; SEQ ID NOs: 323, 324 and 325 (G02). In some embodiments, the anti-IL-10Rβ VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to IMGT, respectively: SEQ ID NOs: 326, 327 and 328 (A02); SEQ ID NOs: 329, 330 and 331 (A05); SEQ ID NOs: 329, 332 and 333 (huA05); SEQ ID NOs: 334, 335 and 336 (huA05); SEQ ID NOs: 337, 338 and 339 (B10); SEQ ID NOs: 340, 341 and 342 (B12); SEQ ID NOs: 343, 344 and 345 (C01); SEQ ID NOs: 346, 347 and 348 (C04); SEQ ID NOs: 349, 350 and 351 (C10); SEQ ID NOs: 352, 341 and 353 (D01); SEQ ID NOs: 354, 355 and 356 (E08); SEQ ID NOs: 357, 358 and 359 (E10); SEQ ID NOs: 360, 361 and 362 (G01) or SEQ ID NOs: 363, 364 and 365 (G02). In some embodiments, the anti-IL-10Rβ VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Chothia, respectively: SEQ ID NOs: 366, 367 and 368 (A02); SEQ ID NOs: 369, 370 and 371 (A05); SEQ ID NOs: 369, 372 and 373 (huA05); SEQ ID NOs: 374, 375 and 376 (huA05); SEQ ID NOs: 377, 378 and 379 (B10); SEQ ID NOs: 380, 381 and 382 (B12); SEQ ID NOs: 383, 384 and 385 (C01); SEQ ID NOs: 386, 387 and 388 (C04); SEQ ID NOs: 389, 390 and 391 (C10); SEQ ID NOs: 392, 381 and 393 (D01); SEQ ID NOs: 394, 395 and 396 (E08); SEQ ID NOs: 397, 398 and 399 (E10); SEQ ID NOs: 400, 401 and 402 (G01) or SEQ ID NOs: 403, 404 and 405 (G02). In some embodiments, the anti-IL-10Rβ VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Honegger, respectively: SEQ ID NOs: 406, 407 and 408 (A02); SEQ ID NOs: 409, 410 and 411 (A05); SEQ ID NOs: 409, 412 and 413 (huA05); SEQ ID NOs: 414, 415 and 416 (huA05); SEQ ID NOs: 417, 418 and 419 (B10); SEQ ID NOs: 420, 421 and 422 (B12); SEQ ID NOs: 423, 424 and 425 (C01); SEQ ID NOs: 426, 427 and 428 (C04); SEQ ID NOs: 429, 430 and 431 (C10); SEQ ID NOs: 432, 421 and 433 (D01); SEQ ID NOs: 434, 435 and 436 (E08); SEQ ID NOs: 437, 438 and 439 (E10); SEQ ID NOs: 440, 441 and 442 (G01) or; SEQ ID NOs: 443, 444 and 445 (G02). In some embodiments, the anti-IL-10Rβ VHH comprises a VHH-CDR1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, respectively: SEQ ID NOs: 291, 292 and 293 (A05; according to Kabat); SEQ ID NOs: 291, 294 and 295 (huA05; according to Kabat); SEQ ID NOs: 296, 297 and 298 (huA05; according to Kabat); SEQ ID NOs: 329, 330 and 331 (A05; according to IMGT); SEQ ID NOs: 329, 332 and 333 (huA05; according to IMGT); SEQ ID NOs: 334, 335 and 336 (huA05; according to IMGT); SEQ ID NOs: 369, 370 and 371 (A05; according to Chothia); SEQ ID NOs: 369, 372 and 373 (huA05; according to Chothia); SEQ ID NOs: 374, 375 and 376 (huA05; according to Chothia); SEQ ID NOs: 409, 410 and 411 (A05; according to Honegger); SEQ ID NOs: 409, 412 and 413 (huA05; according to Honegger) or SEQ ID NOs: 414, 415 and 416 (huA05; according to Honegger). In some embodiments, the anti-IL-10Rβ VHH comprises the amino acid sequence of any one of SEQ ID NOs: 448, 449, 455 and 460, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the full length of the amino acid sequence of any one of SEQ ID NOs: 448, 449, 455 and 460. In some embodiments, the anti-IL-10Rβ VHH comprises the amino acid sequence of any one of SEQ ID NOs: 446-447, 450-454, 456-459 and 461-474, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the full length of the amino acid sequence of any one of SEQ ID NOs: 446-447, 450-454, 456-459 and 461-474. In some embodiments, the anti-IL-10Rβ VHH comprises the amino acid sequence of any one of SEQ ID NOs: 448-452, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the full length of the amino acid sequence of any one of SEQ ID NOs: 448-452 (A05). In some embodiments, the anti-IL-10Rβ VHH comprises the amino acid sequence of any one of SEQ ID NOs: 460-462, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the full length of the amino acid sequence of any one of SEQ ID NOs: 460-462 (C04). In some embodiments, the anti-IL-10Rβ VHH is humanized. In some embodiments, the anti-IL-10Rβ VHH binds to an epitope on IL-10Rβ comprising contact amino acid residues S78, S80, K81, Y82, V108, N138, E139, Y140, E141, T142, W143, N147, V148 and N150, wherein the amino acid residue positions are with respect to SEQ ID NO: 712. In some embodiments, the anti-IL-10Rβ VHH binds to an epitope on IL-10Rβ comprising contact amino acid residues N26, R28, N30, V32, Q39, E41, T72, D84, 1103, T104, D110, 1112, P115, Q157, Q190, R192, F194, N199, A201, E203, W204 and E206, wherein the amino acid residue positions are with respect to SEQ ID NO: 712. In some embodiments, the anti-IL-10Rβ VHH binds to IL 10Rβ with an equilibrium dissociation constant (KD) of greater than 10 nM, e.g., greater than 20 nM, 30 nM, 40 nM or 50 nM. In some embodiments, the VHH that binds to IL 10Rβ binds to both human IL-10Rβ and cynomolgus IL-10Rβ. In some embodiments, the anti-IL-10Rβ sdAb comprises a human fragment crystallizable (Fc) domain. In some embodiments, the Fc domain comprises a human IgG1 or a human IgG4.

[0006] Further provided is a bispecific antibody comprising a first single immunoglobulin variable domain (VHH) and a second VHH, wherein the first VHH specifically binds to the extracellular domain of interleukin-10 receptor (IL-10R) alpha subunit (IL 10Rα) and the second VHH specifically binds to the extracellular domain of interleukin-10 receptor beta subunit (IL-10Rβ). In some embodiments, the bispecific antibody is an IL-10R agonist that selectively suppresses activation of myeloid cells and induces minimal or no direct activation of one or both of T cells and B cells. In some embodiments, the bispecific antibody is an IL-10R agonist that predominantly suppresses activation of myeloid cells and induces minimal or no direct activation of one or both of T cells and B cells. In some embodiments, the bispecific antibody induces a maximum effective (Emax) activation of one or both of T cells and B cells that is 15% or less, e.g., 10% or less, of wild-type IL-10. In some embodiments, the bispecific antibody is an IL-10R agonist that predominantly or selectively suppresses activation of myeloid cells and induces a maximum effect (Emax) activation of one or both of T cells and B cells that is 15% or less, e.g., 10% or less, of wild-type IL-10. In some embodiments, the bispecific antibody is an IL-10R agonist suppressing activation of myeloid cells with a half maximal effective concentration (EC50) less than 10 pM and activating one or both of T cells and B cells below a predetermined threshold level at a concentration above 1000 nM. In some embodiments, the bispecific antibody activates T cells or B cells with a maximum effect (Emax) that is 15% or less, e.g., 10% or less, of wild-type IL-10. In some embodiments, the activation of T cells is measured by at least one of Granzyme B secretion and interferon-γ (IFN-γ) production. In some embodiments, the myeloid cells are selected from macrophages, monocytes and dendritic cells. In some embodiments, the bispecific antibody does not induce detectable granzyme B secretion from CD8+ T cells. In some embodiments, the bispecific antibody induces interferon-γ (IFN-γ) from CD8+ T cells less than 15%, e.g., less than 10%, the level of IFN-γ induced by wild-type IL-10. In some embodiments, the bispecific antibody induces minimal (e.g., less than 25%, less than 20%, less than 15%, less than 10%, in comparison to wild-type IL-10) or no inhibition of IL 10Rβ dimerization with other IL-10 family cytokine receptor subunits, e.g., IL-10Rβ dimerization with IL-20Rα, IL-22R, IL-28R or IL-29R. In some embodiments, the bispecific antibody agonizes the IL-10 receptor in a tyrosine kinase 2 (TYK2; NCBI Gene ID: 7297) dependent manner. In some embodiments, the bispecific antibody induces minimal (e.g., less than 25%, less than 20%, less than 15%, less than 10%, in comparison to wild-type IL-10) or no inhibition of intracellular signaling of other IL 10Rβ-binding cytokines, e.g., minimal or no inhibition of IL-22, IL-26, IL-28A, IL-28B, or IL-29 intracellular signaling. In some embodiments, the second VHH binds to IL 10Rβ with an equilibrium dissociation constant (KD) that is at least 5-fold greater, e.g., at least 7-fold greater, e.g., at least 10-fold, 15-fold, 20-fold, 25-fold greater, or more, than the KD of the first VHH binding to IL 10Rα, e.g., wherein the binding affinity is determined by surface plasmon resonance (SPR). In some embodiments, the first VHH binds to IL 10Rα with affinity that is at least 5-fold greater, e.g., at least 7-fold greater, e.g., at least 10-fold, 15-fold, 20-fold, 25-fold greater, or more, than the binding affinity of the second VHH binding to IL 10Rβ, e.g., wherein the binding affinity is determined by surface plasmon resonance (SPR). In some embodiments, the first variable domain binds to IL 10Rα with an equilibrium dissociation constant (KD) of lower than 2 nM and the second variable domain binds to IL 10Rβ with a KD of greater than 10 nM, e.g., wherein the binding affinity is determined by surface plasmon resonance (SPR). In some embodiments, the first variable domain binds to IL 10Rα with an equilibrium dissociation constant (KD) of lower than 2 nM and the second variable domain binds to IL 10Rβ with a KD of greater than 50 nM, e.g., wherein the binding affinity is determined by surface plasmon resonance (SPR). In some embodiments, the first VHH binds to an epitope on IL 10Rα comprising contact amino acid residues W33, E35, E37, H40, 142, H44, T46, L79, 580, T124, A170, R172, F178, F180, H182, Q204, K215, M217, W218, K220 and E221, wherein the amino acid residue positions are with respect to SEQ ID NO: 711 and the second VHH binds to an epitope on IL-10Rβ comprising contact amino acid residues S78, S80, K81, Y82, V108, N138, E139, Y140, E141, T142, W143, N147, V148 and N150, wherein the amino acid residue positions are with respect to SEQ ID NO: 712. In some embodiments, the first VHH binds to an epitope on IL-10Rα comprising contact amino acid residues I169, I171, K173, F178, F180, T181, H182, K183, K186, F190, L192, L193, S195, E197, and F201, wherein the amino acid residue positions are with respect to SEQ ID NO: 711 and the second VHH binds to an epitope on IL-10Rβ comprising contact amino acid residues N26, R28, N30, V32, Q39, E41, T72, D84, 1103, T104, D110, I112, P115, Q157, Q190, R192, F194, N199, A201, E203, W204, and E206, wherein the amino acid residue positions are with respect to SEQ ID NO: 712. In some embodiments, the bispecific antibody comprises at least one polypeptide (e.g., two polypeptides) comprising the first VHH in tandem with the second VHH. In some embodiments, the bispecific antibody comprises at least one polypeptide comprising from N-terminus to C-terminus the first VHH that specifically binds to IL-10Rα and the second VHH that specifically binds to IL-10Rβ. In some embodiments, the bispecific antibody comprises at least one polypeptide comprising from N-terminus to C-terminus the second VHH that specifically binds to IL-10Rβ and the first VHH that specifically binds to IL-10Rα. In some embodiments, the first VHH and the second VHH are connected via a linker. In some embodiments, the linker is selected from the group consisting of: GS (SEQ ID NO: 713), GGS (SEQ ID NO: 714), GGGS (SEQ ID NO: 715), GGSGGS (SEQ ID NO: 716), GGGSGGGS (SEQ ID NO: 717) and GGSGGSGGS (SEQ ID NO: 718). In some embodiments, the linker comprises GGGS (SEQ ID NO: 715). In some embodiments, the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH1-complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH comprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, according to Kabat, respectively: SEQ ID NOs: 22, 23, 24, 291, 292 and 293 (877); SEQ ID NOs: 22, 25, 26, 291, 294 and 295 (647); SEQ ID NOs: 22, 27, 24, 291, 297 and 298 (195); SEQ ID NOs: 22, 23, 24, 288, 289 and 290 (048); SEQ ID NOs: 22, 25, 26, 288, 289 and 290 (049); SEQ ID NOs: 22, 27, 24, 288, 289 and 290 (050); SEQ ID NOs: 22, 23, 24, 296, 308 and 309 (274); SEQ ID NOs: 22, 25, 26, 296, 308 and 309 (771); SEQ ID NOs: 22, 27, 24, 296, 308 and 309 (772); SEQ ID NOs: 4, 28, 29, 288, 289 and 290 (054); SEQ ID NOs: 4, 28, 29, 291, 294 and 295 (883); SEQ ID NOs: 4, 28, 29, 291, 294 and 295 (784); SEQ ID NOs: 4, 28, 29, 291, 297 and 298 (785); SEQ ID NOs: 4, 5, 6, 288, 289 and 290 (046); SEQ ID NOs: 4, 5, 6, 291, 294 and 295 (875); SEQ ID NOs: 4, 5, 6, 291, 294 and 295 (776); SEQ ID NOs: 4, 5, 6, 291, 297 and 298 (777); SEQ ID NOs: 4, 5, 6, 296, 308 and 309 (272); SEQ ID NOs: 4, 15, 16, 288, 289 and 290 (052); SEQ ID NOs: 4, 15, 16, 296, 308 and 309 (278); SEQ ID NOs: 4, 17, 18, 288, 289 and 290 (047); SEQ ID NOs: 4, 17, 18, 291, 292 and 293 (876); SEQ ID NOs: 4, 17, 18, 291, 294 and 295 (778); SEQ ID NOs: 4, 17, 18, 291, 297 and 298 (779); SEQ ID NOs: 45, 46, 47, 288, 289 and 290; (062); SEQ ID NOs: 45, 46, 47, 291, 292 and 293 (891); SEQ ID NOs: 45, 46, 47, 291, 294 and 295 (780); SEQ ID NOs: 45, 46, 47, 291, 297 and 298 (781); SEQ ID NOs: 45, 46, 47, 296, 308 and 309 (290); SEQ ID NOs: 4, 48, 6, 291, 292 and 293 (892); SEQ ID NOs: 4, 48, 6, 291, 294 and 295 (793); SEQ ID NOs: 4, 48, 6, 291, 297 and 298 (794); SEQ ID NOs: 54, 55, 24, 291, 292 and 293 (894); SEQ ID NOs: 54, 55, 24, 291, 294 and 295 (795); SEQ ID NOs: 54, 55, 24, 291, 297 and 298 (796); SEQ ID NOs: 4, 30, 31, 291, 292 and 293 (884); SEQ ID NOs: 4, 30, 31, 291, 294 and 295 (786); SEQ ID NOs: 4, 30, 31, 291, 297 and 298 (787); SEQ ID NOs: 4, 36, 29, 288, 289 and 290 (058); SEQ ID NOs: 33, 34, 35, 296, 308 and 309 (284); SEQ ID NOs: 33, 34, 35, 296, 308 and 309 (183); SEQ ID NOs: 33, 34, 35, 296, 308 and 309 (184); SEQ ID NOs: 19, 37, 38, 302, 303 and 304 (239); SEQ ID NOs: 19, 37, 38, 296, 308 and 309 (286) or SEQ ID NOs: 19, 51, 52, 302, 303 and 304 (247). In some embodiments, the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH1-complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH comprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, according to IMGT, respectively: SEQ ID NOs: 77, 78, 79, 329, 330 and 331 (877); SEQ ID NOs: 77, 80, 81, 329, 332 and 333 (647); SEQ ID NOs: 77, 82, 79, 334, 335 and 336 (195); SEQ ID NOs: 77, 78, 79, 326, 327 and 328 (048); SEQ ID NOs: 77, 80, 81, 326, 327 and 328 (049); SEQ ID NOs: 77, 82, 79, 326, 327 and 328 (050); SEQ ID NOs: 77, 78, 79, 346, 347 and 348 (274); SEQ ID NOs: 77, 80, 81, 346, 347 and 348 (771); SEQ ID NOs: 77, 82, 79, 346, 347 and 348 (772); SEQ ID NOs: 59, 83, 84, 326, 327 and 328 (054); SEQ ID NOs: 59, 83, 84, 329, 330 and 331 (883); SEQ ID NOs: 59, 83, 84, 329, 332 and 333 (784); SEQ ID NOs: 59, 83, 84, 334, 335 and 336 (785); SEQ ID NOs: 59, 60, 61, 326, 327 and 328 (046); SEQ ID NOs: 59, 60, 61, 329, 330 and 331 (875); SEQ ID NOs: 59, 60, 61, 329, 332 and 333 (776); SEQ ID NOs: 59, 60, 61, 334, 335 and 336 (777); SEQ ID NOs: 59, 60, 61, 346, 347 and 348 (272); SEQ ID NOs: 59, 70, 71, 326, 327 and 328 (052); SEQ ID NOs: 59, 70, 71, 346, 347 and 348 (278); SEQ ID NOs: 59, 72, 73, 326, 327 and 328 (047); SEQ ID NOs: 59, 72, 73, 329, 330 and 331 (876); SEQ ID NOs: 59, 72, 73, 329, 332 and 333 (778); SEQ ID NOs: 59, 72, 73, 334, 335 and 336 (779); SEQ ID NOs: 98, 99, 100, 326, 327 and 328 (062); SEQ ID NOs: 98, 99, 100, 329, 330 and 331 (891); SEQ ID NOs: 98, 99, 100, 329, 332 and 333 (780); SEQ ID NOs: 98, 99, 100, 334, 335 and 336 (781); SEQ ID NOs: 98, 99, 100, 326, 327 and 328 (290); SEQ ID NOs: 59, 101, 61, 329, 330 and 331 (892); SEQ ID NOs: 59, 101, 61, 329, 332 and 333 (793); SEQ ID NOs: 59, 101, 61, 334, 335 and 336 (794); SEQ ID NOs: 106, 107, 79, 329, 330 and 331 (894); SEQ ID NOs: 106, 107, 79, 329, 332 and 333 (795); SEQ ID NOs: 106, 107, 79, 334, 335 and 336 (796); SEQ ID NOs: 59, 85, 86, 329, 330 and 331 (884); SEQ ID NOs: 59, 85, 86, 329, 332 and 333 (786); SEQ ID NOs: 59, 85, 86, 334, 335 and 336 (787); SEQ ID NOs: 59, 91, 84, 326, 327 and 328 (058); SEQ ID NOs: 88, 89, 90, 326, 327 and 328 (284); SEQ ID NOs: 88, 89, 90, 326, 327 and 328 (183); SEQ ID NOs: 88, 89, 90, 326, 327 and 328 (184); SEQ ID NOs: 92, 75, 93, 340, 341 and 342 (239); SEQ ID NOs: 92, 75, 93, 326, 327 and 328 (286) or SEQ ID NOs: 74, 75, 104, 340, 341 and 342 (247). In some embodiments, the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH1-complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH comprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, according to Chothia, respectively: SEQ ID NOs: 127, 128, 129, 369, 370 and 371 (877); SEQ ID NOs: 127, 130, 131, 369, 372 and 373 (647); SEQ ID NOs: 127, 130, 131, 374, 375 and 376 (195); SEQ ID NOs: 127, 128, 129, 366, 367 and 368 (048); SEQ ID NOs: 127, 130, 131, 366, 367 and 368 (049); SEQ ID NOs: 127, 130, 131, 366, 367 and 368 (050); SEQ ID NOs: 127, 128, 129, 386, 387 and 388 (274); SEQ ID NOs: 127, 130, 131, 386, 387 and 388 (771); SEQ ID NOs: 127, 130, 131, 386, 387 and 388 (772); SEQ ID NOs: 111, 132, 133, 366, 367 and 368 (054); SEQ ID NOs: 111, 132, 133, 369, 370 and 371 (883); SEQ ID NOs: 111, 132, 133, 369, 372 and 373 (784); SEQ ID NOs: 111, 132, 133, 374, 375 and 376 (785); SEQ ID NOs: 111, 112, 113, 366, 367 and 368 (046); SEQ ID NOs: 111, 112, 113, 369, 370 and 371 (875); SEQ ID NOs: 111, 112, 113, 369, 372 and 373 (776); SEQ ID NOs: 111, 112, 113, 374, 375 and 376 (777); SEQ ID NOs: 111, 112, 113, 386, 387 and 388 (272); SEQ ID NOs: 111, 121, 122, 366, 367 and 368 (052); SEQ ID NOs: 111, 121, 122, 386, 387 and 388 (278); SEQ ID NOs: 111, 121, 123, 366, 367 and 368 (047); SEQ ID NOs: 111, 121, 123, 369, 370 and 371 (876); SEQ ID NOs: 111, 121, 123, 369, 372 and 373 (778); SEQ ID NOs: 111, 121, 123, 374, 375 and 376 (779); SEQ ID NOs: 145, 146, 147, 366, 367 and 368 (062); SEQ ID NOs: 145, 146, 147, 369, 370 and 371 (891); SEQ ID NOs: 145, 146, 147, 369, 372 and 373 (780); SEQ ID NOs: 145, 146, 147, 374, 375 and 376 (781); SEQ ID NOs: 145, 146, 147, 386, 387 and 388 (290); SEQ ID NOs: 111, 112, 113, 369, 370 and 371 (892); SEQ ID NOs: 111, 112, 113, 369, 372 and 373 (793); SEQ ID NOs: 111, 112, 113, 374, 375 and 376 (794); SEQ ID NOs: 152, 121, 129, 369, 370 and 371 (894); SEQ ID NOs: 152, 121, 129, 369, 372 and 373 (795); SEQ ID NOs: 152, 121, 129, 374, 375 and 376 (796); SEQ ID NOs: 111, 134, 135, 369, 370 and 371 (884); SEQ ID NOs: 111, 134, 135, 369, 372 and 373 (786); SEQ ID NOs: 111, 134, 135, 374, 375 and 376 (787); SEQ ID NOs: 111, 132, 133, 366, 367 and 368 (058); SEQ ID NOs: 137, 138, 139, 386, 387 and 388 (284); SEQ ID NOs: 137, 138, 139, 386, 387 and 388 (183); SEQ ID NOs: 137, 138, 139, 386, 387 and 388 (184); SEQ ID NOs: 140, 125, 141, 380, 381 and 381 (239); SEQ ID NOs: 140, 125, 141, 386, 387 and 388 (286) or SEQ ID NOs: 124, 125, 126, 380, 381 and 381 (247). In some embodiments, the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH1-complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH comprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, according to Honegger, respectively: SEQ ID NOs: 174, 175, 176, 409, 410 and 411 (877); SEQ ID NOs: 174, 177, 178, 409, 412 and 413 (647); SEQ ID NOs: 174, 179, 176, 414, 415 and 416 (195); SEQ ID NOs: 174, 175, 176, 406, 407 and 408 (048); SEQ ID NOs: 174, 177, 178, 406, 407 and 408 (049); SEQ ID NOs: 174, 179, 176, 406, 407 and 408 (050); SEQ ID NOs: 174, 175, 176, 426, 427 and 428 (274); SEQ ID NOs: 174, 177, 178, 426, 427 and 428 (771); SEQ ID NOs: 174, 179, 176, 426, 427 and 428 (772); SEQ ID NOs: 156, 180, 181, 406, 407 and 408 (054); SEQ ID NOs: 156, 180, 181, 409, 410 and 411 (883); SEQ ID NOs: 156, 180, 181, 409, 412 and 413 (784); SEQ ID NOs: 156, 180, 181, 414, 415 and 416 (785); SEQ ID NOs: 156, 157, 158, 406, 407 and 408 (046); SEQ ID NOs: 156, 157, 158, 409, 410 and 411 (875); SEQ ID NOs: 156, 157, 158, 409, 412 and 413 (776); SEQ ID NOs: 156, 157, 158, 414, 415 and 416 (777); SEQ ID NOs: 156, 157, 158, 426, 427 and 428 (272); SEQ ID NOs: 156, 167, 168, 406, 407 and 408 (052); SEQ ID NOs: 156, 167, 168, 426, 427 and 428 (278); SEQ ID NOs: 156, 169, 170, 406, 407 and 408 (047); SEQ ID NOs: 156, 169, 170, 409, 410 and 411 (876); SEQ ID NOs: 156, 169, 170, 409, 412 and 413 (778); SEQ ID NOs: 156, 169, 170, 414, 415 and 416 (779); SEQ ID NOs: 198, 199, 200, 406, 407 and 408 (062); SEQ ID NOs: 198, 199, 200, 409, 410 and 411 (891); SEQ ID NOs: 198, 199, 200, 409, 412 and 413 (780); SEQ ID NOs: 198, 199, 200, 414, 415 and 416 (781); SEQ ID NOs: 198, 199, 200, 426, 427 and 428 (290); SEQ ID NOs: 156, 201, 158, 409, 410 and 411 (892); SEQ ID NOs: 156, 201, 158, 409, 412 and 413 (793); SEQ ID NOs: 156, 201, 158, 414, 415 and 416 (794); SEQ ID NOs: 208, 209, 176, 409, 410 and 411 (894); SEQ ID NOs: 208, 209, 176, 409, 412 and 413 (795); SEQ ID NOs: 208, 209, 176, 414, 415 and 416 (796); SEQ ID NOs: 156, 182, 183, 409, 410 and 411 (884); SEQ ID NOs: 156, 182, 183, 409, 412 and 413 (786); SEQ ID NOs: 156, 182, 183, 414, 415 and 416 (787); SEQ ID NOs: 156, 188, 181, 406, 407 and 408 (058); SEQ ID NOs: 185, 186, 187, 426, 427 and 428 (284); SEQ ID NOs: 709, 186, 187, 426, 427 and 428 (183); SEQ ID NOs: 709, 186, 187, 426, 427 and 428 (184); SEQ ID NOs: 189, 190, 191, 420, 421 and 422 (239); SEQ ID NOs: 189, 190, 191, 426, 427 and 428 (286) or SEQ ID NOs: 204, 205, 206, 420, 421 and 422 (247). In some embodiments, the bispecific antibody comprises a VHH1-CDR1, a VHH1-CDR2, and a VHH1-CDR3 and a VHH2-CDR1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, respectively (E07-A05): SEQ ID NOs: 22, 23, 24, 291, 292 and 293 (877; according to Kabat); SEQ ID NOs: 22, 25, 26, 291, 294 and 295 (647; according to Kabat); SEQ ID NOs: 22, 27, 24, 291, 297 and 298 (195; according to Kabat); SEQ ID NOs: 77, 78, 79, 329, 330 and 331 (877; according to IMGT); SEQ ID NOs: 77, 80, 81, 329, 332 and 333 (647; according to IMGT); SEQ ID NOs: 77, 82, 79, 334, 335 and 336 (195; according to IMGT); SEQ ID NOs: 127, 128, 129, 369, 370 and 371 (877; according to Chothia); SEQ ID NOs: 127, 130, 131, 369, 372 and 373 (647; according to Chothia); SEQ ID NOs: 127, 130, 131, 374, 375 and 376 (195; according to Chothia); SEQ ID NOs: 174, 175, 176, 409, 410 and 411 (877; according to Honegger); SEQ ID NOs: 174, 177, 178, 409, 412 and 413 (647; according to Honegger) or SEQ ID NOs: 174, 179, 176, 414, 415 and 416 (195; according to Honegger). In some embodiments, the bispecific antibodies comprise a VHH1-CDR1, a VHH1-CDR2, and a VHH1-CDR3 and a VHH2-CDR1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, respectively (F11-C04): SEQ ID NOs: 33, 34, 35, 296, 308 and 309 (284; according to Kabat); SEQ ID NOs: 33, 34, 35, 296, 308 and 309 (183; according to Kabat); SEQ ID NOs: 33, 34, 35, 296, 308 and 309 (184; according to Kabat); SEQ ID NOs: 88, 89, 90, 326, 327 and 328 (284; according to IMGT); SEQ ID NOs: 88, 89, 90, 326, 327 and 328 (183; according to IMGT); SEQ ID NOs: 88, 89, 90, 326, 327 and 328 (184; according to IMGT); SEQ ID NOs: 137, 138, 139, 386, 387 and 388 (284; according to Chothia); SEQ ID NOs: 137, 138, 139, 386, 387 and 388 (183; according to Chothia); SEQ ID NOs: 137, 138, 139, 386, 387 and 388 (184; according to Chothia); SEQ ID NOs: 185, 186, 187, 426, 427 and 428 (284; according to Honegger); SEQ ID NOs: 709, 186, 187, 426, 427 and 428 (183; according to Honegger) or; SEQ ID NOs: 709, 186, 187, 426, 427 and 428 (184; according to Honegger). In some embodiments, the first VHH that specifically binds to IL 10Rα and the second VHH that specifically binds to IL-10Rβ comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in: SEQ ID NOs: 212 and 448 [A06con-A05con]; SEQ ID NOs: 212 and 449 [A06con-A05con]; SEQ ID NOs: 212 and 460 [A06con-C04con]; SEQ ID NOs: 233 and 448 [E07con-A05con]; SEQ ID NOs: 234 and 449 [E07con-A05con]; SEQ ID NOs: 233 and 460 [E07con-C04con]; SEQ ID NOs: 234 and 460 [E07con-C04con]; SEQ ID NOs: 710 and 448 [C09con-A05con]; SEQ ID NOs: 710 and 449; [C09con-A05con]; SEQ ID NOs: 710 and 460; [C09con-C04con]; SEQ ID NOs: 230 and 460 [G22con-C04con] or SEQ ID NOs: 249 and 460 [F11con-C04con]. In some embodiments, the first VHH that specifically binds to IL 10Rα and the second VHH that specifically binds to IL-10Rβ comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in: SEQ ID NOs: 235 and 450 (877); SEQ ID NOs: 237 and 451 (647); SEQ ID NOs: 239 and 452 (195); SEQ ID NOs: 235 and 446 (048); SEQ ID NOs: 237 and 447 (049); SEQ ID NOs: 239 and 447 (050); SEQ ID NOs: 235 and 461 (274); SEQ ID NOs: 237 and 462 (771); SEQ ID NOs: 239 and 462 (772); SEQ ID NOs: 241 and 446 (054); SEQ ID NOs: 243 and 447 (755); SEQ ID NOs: 241 and 450 (883); SEQ ID NOs: 243 and 451 (784); SEQ ID NOs: 243 and 452 (785); SEQ ID NOs: 213 and 446 (046); SEQ ID NOs: 215 and 447 (747); SEQ ID NOs: 213 and 450 (875); SEQ ID NOs: 215 and 451 (776); SEQ ID NOs: 215 and 452 (777); SEQ ID NOs: 213 and 461 (272); SEQ ID NOs: 215 and 462 (773); SEQ ID NOs: 224 and 446 (052); SEQ ID NOs: 226 and 447 (753); SEQ ID NOs: 224 and 461 (278); SEQ ID NOs: 226 and 462 (769); SEQ ID NOs: 227 and 446 (047); SEQ ID NOs: 229 and 447 (748); SEQ ID NOs: 227 and 450 (876); SEQ ID NOs: 229 and 451 (778); SEQ ID NOs: 229 and 452 (779); SEQ ID NOs: 267 and 446 (062); SEQ ID NOs: 269 and 447 (763); SEQ ID NOs: 267 and 450 (891); SEQ ID NOs: 269 and 451 (780); SEQ ID NOs: 269 and 452 (781); SEQ ID NOs: 267 and 461 (290); SEQ ID NOs: 269 and 462 (791); SEQ ID NOs: 270 and 450 (892); SEQ ID NOs: 272 and 451 (793); SEQ ID NOs: 272 and 452 (794); SEQ ID NOs: 285 and 450 (894); SEQ ID NOs: 287 and 451 (795); SEQ ID NOs: 287 and 452 (796); SEQ ID NOs: 244 and 450 (884); SEQ ID NOs: 246 and 451 (786); SEQ ID NOs: 247 and 452 (787); SEQ ID NOs: 253 and 446 (058); SEQ ID NOs: 255 and 447 (759); SEQ ID NOs: 250 and 461 (284); SEQ ID NOs: 251 and 462 (183); SEQ ID NOs: 252 and 462 (184); SEQ ID NOs: 256 and 456 (239); SEQ ID NOs: 258 and 457 (740); SEQ ID NOs: 256 and 461 (286); SEQ ID NOs: 258 and 462 (788); SEQ ID NOs: 278 and 456 (247) SEQ ID NOs: 280 and 457 (749); SEQ ID NOs: 752 and 461; SEQ ID NOs: 752 and 462; SEQ ID NOs: 753 and 461; SEQ ID NOs: 753 and 462; SEQ ID NOs: 754 and 461; SEQ ID NOs: 754 and 462; SEQ ID NOs: 755 and 461; or SEQ ID NOs: 755 and 462. In some embodiments, the first VHH that specifically binds to IL 10Rα and the second VHH that specifically binds to IL-10Rβ comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in: SEQ ID NOs: 236 and 450 (877); SEQ ID NOs: 238 and 451 (647); SEQ ID NOs: 240 and 452 (195); SEQ ID NOs: 236 and 446 (048); SEQ ID NOs: 238 and 447 (049); SEQ ID NOs: 240 and 447 (050); SEQ ID NOs: 236 and 461 (274); SEQ ID NOs: 238 and 462 (771); SEQ ID NOs: 240 and 462 (772); SEQ ID NOs: 242 and 446 (054); SEQ ID NOs: 243 and 447 (755); SEQ ID NOs: 242 and 450 (883); SEQ ID NOs: 243 and 451 (784); SEQ ID NOs: 243 and 452 (785); SEQ ID NOs: 214 and 446 (046); SEQ ID NOs: 215 and 447 (747); SEQ ID NOs: 214 and 450 (875); SEQ ID NOs: 215 and 451 (776); SEQ ID NOs: 215 and 452 (777); SEQ ID NOs: 214 and 461 (272); SEQ ID NOs: 215 and 462 (773); SEQ ID NOs: 225 and 446 (052); SEQ ID NOs: 226 and 447 (753); SEQ ID NOs: 225 and 461 (278); SEQ ID NOs: 226 and 462 (769); SEQ ID NOs: 228 and 446 (047); SEQ ID NOs: 229 and 447 (748); SEQ ID NOs: 228 and 450 (876); SEQ ID NOs: 229 and 451 (778); SEQ ID NOs: 229 and 452 (779); SEQ ID NOs: 268 and 446 (062); SEQ ID NOs: 269 and 447 (763); SEQ ID NOs: 268 and 450 (891); SEQ ID NOs: 269 and 451 (780); SEQ ID NOs: 269 and 452 (781); SEQ ID NOs: 268 and 461 (290); SEQ ID NOs: 269 and 462 (791); SEQ ID NOs: 271 and 450 (892); SEQ ID NOs: 273 and 451 (793); SEQ ID NOs: 274 and 452 (794); SEQ ID NOs: 286 and 450 (894); SEQ ID NOs: 287 and 451 (795); SEQ ID NOs: 287 and 452 (796); SEQ ID NOs: 245 and 450 (884); SEQ ID NOs: 246 and 451 (786); SEQ ID NOs: 246 and 452 (787); SEQ ID NOs: 254 and 446 (058); SEQ ID NOs: 255 and 447 (759); SEQ ID NOs: 250 and 461 (284); SEQ ID NOs: 251 and 462 (183); SEQ ID NOs: 252 and 462 (184); SEQ ID NOs: 752 and 461; SEQ ID NOs: 752 and 462; SEQ ID NOs: 753 and 461; SEQ ID NOs: 753 and 462; SEQ ID NOs: 754 and 461; SEQ ID NOs: 754 and 462; SEQ ID NOs: 755 and 461; or SEQ ID NOs: 755 and 462; SEQ ID NOs: 257 and 456 (239); SEQ ID NOs: 259 and 457 (740); SEQ ID NOs: 257 and 461 (286); SEQ ID NOs: 259 and 462 (788); SEQ ID NOs: 279 and 456 (247) or SEQ ID NOs: 280 and 457 (749). In some embodiments, the first VHH that specifically binds to IL 10Rα and the second VHH that specifically binds to IL-10Rβ comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in: SEQ ID NOs: 233 and 448 [E07con-A05con]; SEQ ID NOs: 234 and 449 [E07con-A05con]; SEQ ID NOs: 235 and 450 (877); SEQ ID NOs: 237 and 451 (647); SEQ ID NOs: 239 and 452 (195); SEQ ID NOs: 236 and 450 (877); SEQ ID NOs: 238 and 451 (647); SEQ ID NOs: 240 and 452 (195); SEQ ID NOs: 724 and 450 (E07-A05); SEQ ID NOs: 724 and 451 (E07-A05); SEQ ID NOs: 724 and 452 (E07-A05); SEQ ID NOs: 725 and 450 (E07-A05); SEQ ID NOs: 725 and 451 (E07-A05) or SEQ ID NOs: 725 and 452 (E07-A05). In some embodiments, the first VHH that specifically binds to IL 10Rα and the second VHH that specifically binds to IL-10Rβ comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in: SEQ ID NOs: 249 and 460 [F11con-C04con]; SEQ ID NOs: 250 and 461 (284); SEQ ID NOs: 251 and 462 (183); SEQ ID NOs: 252 and 462 (184); SEQ ID NOs: 250 and 461 (284); SEQ ID NOs: 251 and 462 (183); SEQ ID NOs: 252 and 462 (184); SEQ ID NOs: 752 and 461; SEQ ID NOs: 752 and 462; SEQ ID NOs: 753 and 461; SEQ ID NOs: 753 and 462; SEQ ID NOs: 754 and 461; SEQ ID NOs: 754 and 462; SEQ ID NOs: 755 and 461; or SEQ ID NOs: 755 and 462 (F11-C04). In some embodiments, the bispecifc antibody comprises in tandem the first VHH that specifically binds to IL 10Rα and the second VHH that specifically binds to IL-10Rβ, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 475-476 and 573. In some embodiments, the bispecifc antibody comprises in tandem the first VHH that specifically binds to IL 10Rα and the second VHH that specifically binds to IL-10Rβ, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 477, 479, 481, 483, 485, 487, 489, 491, 493, 495, 497, 499, 501, 503, 505, 507, 509, 511, 513, 515, 517, 519, 521, 523, 525, 527, 529, 531, 533, 535, 537, 539, 541, 543, 545, 547, 549, 551, 553, 555, 557, 559, 561, 563, 565, 567, 569, 571, 574, 576, 578, 580, 582, 584, 586, 588 and 590. In some embodiments, the bispecifc antibody comprises in tandem the first VHH that specifically binds to IL-10Rα and the second VHH that specifically binds to IL-10Rβ, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 478, 480, 482, 484, 486, 488, 490, 492, 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564, 566, 568, 570, 572, 575, 577, 579, 581, 583, 585, 587, 589, 591, 737-751 and 757-758. In some embodiments, the bispecifc antibody comprises in tandem the first VHH that specifically binds to IL-10Rα and the second VHH that specifically binds to IL-10Rβ, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 475-482 and 737-751 (E07-A05). In some embodiments, the bispecifc antibody comprises in tandem the first VHH that specifically binds to IL-10Rα and the second VHH that specifically binds to IL-10Rβ, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 573-579 and 757-758 (F11-C04). In some embodiments of the bispecific antibody, the first VHH that specifically binds to IL 10Rα binds to both human IL 10Rα and cynomolgus IL 10Rα. In some embodiments of the bispecific antibody, the second VHH that specifically binds to IL 10Rβ binds to both human IL 10Rβ and cynomolgus IL 10Rβ. In some embodiments of the bispecific antibody, the first VHH that specifically binds to IL 10Rα binds to both human IL 10Rα and cynomolgus IL 10Rα and wherein the second VHH that specifically binds to IL 10Rβ binds to both human IL 10Rβ and cynomolgus IL 10Rβ. In some embodiments, the bispecifc antibody comprises a first fragment crystallizable (Fc) domain and a second Fc domain. In some embodiments, the first Fc domain and the second Fc domain are a human IgG1 or a human IgG4. In some embodiments, one or both of the first Fc domain and the second Fc domain comprises one or more amino acid substitutions that reduces or inhibits or eliminates antibody-dependent cell-mediated cytotoxicity (ADCC) effector function. In some embodiments, one or both of the first Fc domain and the second Fc domain comprises effector function reducing amino acid substitutions at Fe positions (EU numbering) selected from: alanine at position 234 and alanine at position 235 (234A and 235A); glutamic acid at position 235 (235E); proline at position 228 and glutamic acid at position 235 (228P, 235E); alanine at position 237 (237A); alanine at position 234 and glutamic acid at position 235 (234A and 235E); phenylalanine at position 234, glutamic acid at position 235 and alanine at position 265 (234F, 235E and 265A); phenylalanine at position 234, glutamic acid at position 235 and alanine at position 236 (234F, 235E and 236A); phenylalanine at position 234, glutamic acid at position 235 and arginine at position 236 (234F, 235E and 236R); serine at position 234, threonine at position 235 and arginine at position 236 (234S, 235T and 236R); alanine at position 234, alanine at position 235 and glycine at position 329 (234A, 235A and 329G); alanine at position 234, alanine at position 235 and alanine at position 237 (234A, 235A and 237A); proline at position 228 and glutamic acid at position 235 (228P and 235E); proline at position 228, glutamic acid in position 235 and glycine at position 329 (228P, 235E and 329G); phenylalanine at position 234, glutamic acid at position 235 and serine at position 331 (234F, 235E and 331S); phenylalanine at position 234, glutamine at position 235 and glutamine at position 322 (234F, 235Q and 322Q); alanine at position 233, arginine at position 234 and arginine at position 235 (233A, 234R and 235R); alanine at position 233, aspartic acid at position 234 and glutamic acid at position 235 (233A, 234D and 235E); lysine at position 233, arginine at position 234 and arginine at position 235 (233K, 234R and 235R); alanine at position 234, alanine at position 235, alanine at position 237, serine at position 238, alanine at position 268, serine at position 330 and serine at position 331 (234A, 235A, 237A, 238S, 268A, 330S and 3315); and proline at position 228, alanine at position 234, alanine at position 235, alanine at position 237 and serine at position 238 (228P, 234A, 235A, 237A and 238S). In some embodiments, one or both of the first Fc domain and the second Fc domain comprises effector function reducing amino acid substitutions at Fe positions (EU numbering) alanine at position 234, alanine at position 235 and alanine at position 237 (234A, 235A and 237A). In some embodiments, one or both of the first Fc domain and the second Fc domain comprises one or more amino acid substitutions that extend serum half-life. In some embodiments, one or both of the first Fc domain and the second Fc domain comprises serum half-life extending amino acid substitutions at Fe positions (EU numbering) selected from: tyrosine at position 252, threonine at position 254 and glutamic acid at position 256 (252Y, 254T and 256E); leucine at position 428 (428L); glutamine at position 250 and leucine at position 428 (250Q and 428L); leucine at position 428 and serine at position 434 (428L and 434S); leucine at position 428 and alanine at position 434 (428L and 434A); arginine at position 311 and leucine at position 428 (311R and 428L); glycine at position 309 and leucine at position 428 (309G and 428L); glutamine at position 307, valine at position 311 and valine at position 378 (307Q, 311V and 378V); and aspartic acid at position 256, aspartic acid at position 286, arginine at position 307, valine at position 311 and valine at position 378 (256D, 286D, 307R, 311V and 378V). In some embodiments, the bispecific antibody comprises at least one polypeptide comprising the following amino acid sequence, or amino acid sequences that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 592-593 and 690. In some embodiments, the bispecific antibody comprises at least one polypeptide comprising the following amino acid sequence, or amino acid sequences that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 594, 596, 598, 600, 602, 604, 606, 608, 610, 612, 614, 616, 618, 620, 622, 624, 626, 628, 630, 632, 634, 636, 638, 640, 642, 644, 646, 648, 650, 652, 654, 656, 658, 660, 662, 664, 666, 668, 670, 672, 674, 676, 678, 680, 682, 684, 686, 688, 691, 693, 695, 697, 699, 701, 703, 705, and 707. In some embodiments, the bispecific antibody comprises at least one polypeptide comprising the following amino acid sequence, or amino acid sequences that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 595, 597, 599, 601, 603, 605, 607, 609, 611, 613, 615, 617, 619, 621, 623, 625, 627, 629, 631, 633, 635, 637, 639, 641, 643, 645, 647, 649, 651, 653, 655, 657, 659, 661, 663, 665, 667, 669, 671, 673, 675, 677, 679, 681, 683, 685, 687, 689, 692, 694, 696, 698, 700, 702, 704, 706 and 708. In some embodiments, the bispecific antibody comprises at least one polypeptide comprising the following amino acid sequence, or amino acid sequences that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 592-599 (E07-A05). In some embodiments, the bispecific antibody comprises at least one polypeptide comprising the following amino acid sequence, or amino acid sequences that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 690-696 (F11-C04). In some embodiments, the first VHH that specifically binds to IL-10Rα and the second VHH that specifically binds to IL-10Rβ are both humanized. In some embodiments, the bispecific antibody has a serum half-life in a human of at least 3 days, e.g., at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, or longer.

[0007] Further provided are means for agonizing an IL-10 receptor that selectively suppresses activation of myeloid cells and induces minimal or no direct activation of T cells or B cells. Also provided are means for agonizing an IL-10 receptor that predominantly suppresses activation of myeloid cells and induces minimal or no direct activation of T cells or B cells. In some embodiments, the means induces a maximum effective (Emax) activation of T cells or B cells that is 15% or less of wild-type IL-10. Also provided are means for agonizing an IL-10 receptor that induces a maximum effective (Emax) activation of T cells or B cells that is 15% or less of wild-type IL-10. Also provided are means for agonizing an IL-10 receptor that suppresses activation of myeloid cells with a half maximal effective concentration (EC₅₀) less than 10 pM and activating T cells and B cells below a predetermined threshold level at a concentration above 1000 nM. In some embodiments, the means agonizes the IL-10 receptor in a tyrosine kinase 2 (TYK2; NCBI Gene ID: 7297) dependent manner. In some embodiments, the activation of T cells is measured by at least one of Granzyme B secretion and interferon-γ (IFN-γ) production. In some embodiments, the means does not induce detectable granzyme B the secretion from CD8+ T cells. In some embodiments, the means induces interferon-γ (IFN-γ) from CD8+ T cells less than 15% the level of IFN-γ induced by wild-type IL-10. In some embodiments, the myeloid cells are selected from macrophages, monocytes and dendritic cells. In some embodiments, the means induces minimal (e.g., less than 25% in comparison to wild-type IL-10) or no inhibition of IL-10Rβ dimerization with other IL-10 family cytokine receptor subunits, e.g., IL-10Rβ dimerization with IL-20Rα, IL-22R, IL-28R or IL-29R. In some embodiments, the means induces minimal (e.g., less than 25% in comparison to wild-type IL-10) or no inhibition of intracellular signaling of other IL-10Rβ-binding cytokines, e.g., minimal or no inhibition of IL-22, IL-26, IL-28A, IL-28B, or IL-29 intracellular signaling. In some embodiments, the means binds to IL-10Rβ with an equilibrium dissociation constant (K_D) that is at least 5-fold greater, e.g., at least 7-fold greater, e.g., at least 10-fold, 15-fold, 20-fold, 25-fold greater, or more, than the K_D of binding to IL-10Rα, e.g., wherein the binding affinity is determined by surface plasmon resonance (SPR). In some embodiments, the means binds to IL-10Rα with an equilibrium dissociation constant (K_D) of lower than 2 nM and binds to IL-10Rβ with a K_D of greater than 10 nM, e.g., greater than 50 nM, e.g., wherein the binding affinity is determined by surface plasmon resonance (SPR). In some embodiments, the means binds to IL-10Rα contact amino acid residues W33, E35, E37, H40, 142, H44, T46, L79, 580, T124, A170, R172, F178, F180, H182, Q204, K215, M217, W218, K220 and E221, wherein the amino acid residue positions are with respect to SEQ ID NO: 711 and binds to IL-10Rβ contact amino acid residues S78, S80, K81, Y82, V108, N138, E139, Y140, E141, T142, W143, N147, V148 and N150, wherein the amino acid residue positions are with respect to SEQ ID NO: 712. In some embodiments, the means binds to IL-10Rα contact amino acid residues 1169, I171, K173, F178, F180, T181, H182, K183, K186, F190, L192, L193, S195, E197, and F201, wherein the amino acid residue positions are with respect to SEQ ID NO: 711 and binds to IL-10Rβ contact amino acid residues N26, R28, N30, V32, Q39, E41, T72, D84, 1103, T104, D110, I112, P115, Q157, Q190, R192, F194, N199, A201, E203, W204, and E206, wherein the amino acid residue positions are with respect to SEQ ID NO: 712.

[0008] Further provided is a polynucleotide that encode the sdAb that binds to IL-10Rα; the sdAb that binds to IL-10Rβ or the bispecific antibody, as described above and herein. In some embodiments, the polynucleotide is DNA or RNA, e.g., cDNA or mRNA. Further provided is an expression cassette comprising one or more regulatory sequences operably linked to the polynucleotide, as described above and herein. In some embodiments, the one or more regulatory sequences comprise a constitutive promoter. Further provided in an expression vector comprising one or more regulatory sequences operably linked to the polynucleotide or polynucleotides or the expression cassette or expression cassettes as described above and herein. In some embodiments, the expression vector comprises a plasmid vector or a viral vector.

[0009] Further provided is a method of producing an IL-10R binding molecule, as described herein. In some embodiments, the method comprises: (a) culturing a cell or population of cells as described herein transformed with the polynucleotide as described herein, or the expression cassette as described herein in a cell culture under conditions sufficient to express the IL-10R binding molecule; and (b) isolating or purifying the antigen binding molecules from the cell culture. Further provided is cell or population of cells, comprising the polynucleotide or polynucleotides, the expression cassette, or the expression vector as described above and herein. In some embodiments, the cell or population of cells comprises a eukaryotic cell. In some embodiments, the cell or population of cells comprises a mammalian cell, an insect cell, a plant cell or a yeast cell. In some embodiments, the mammalian cell is a Chinese Hamster Ovary (CHO) cell.

[0010] Further provided is a method of preventing or treating an inflammatory disease in a subject in need thereof, comprising administering to the subject an effective amount of a bispecific antibody as described above and herein. Also provided is a method of reducing the severity of or mitigating on or more symptoms of an inflammatory disease in a subject in need thereof, comprising administering to the subject an effective amount of a bispecific antibody as described above and herein. In some embodiments, the inflammatory disease is mediated by an IL-10 deficiency or deficient signaling through the IL-10R. In some embodiments, the inflammatory disease is an autoimmune disease. In some embodiments, the inflammatory disease is an inflammatory bowel disease. In some embodiments, the inflammatory bowel disease is selected from ulcerative colitis, Crohn's disease, mucosal proctocolitis and celiac disease. In some embodiments, the inflammatory disease is an inflammatory dermatitis disease. In some embodiments, the inflammatory dermatitis disease is selected from atopic dermatitis (AD), hidradenitis suppurativa (HS), and psoriasis. In some embodiments, the inflammatory disease is selected from ulcerative colitis, Crohn's disease, mucosal proctocolitis and celiac disease, rheumatoid arthritis (RA), juvenile idiopathic arthritis, atopic dermatitis (AD), hidradenitis suppurativa (HS), psoriasis, systemic lupus erythematosus (SLE), Behget's disease, type 1 diabetes, primary sclerosing cholangitis, ankylosing spondylitis, and multiple sclerosis. In some embodiments, the inflammatory disease is acute or chronic. In some embodiments, the bispecific antibody is administered subcutaneously, intravenously or orally. In some embodiments, the bispecific antibody is administered via a device. In some embodiments, the device is configured for sustained delivery. In some embodiments, the device is configured for self-administration. In some embodiments, the device is a prefilled syringe. In some embodiments, the device is an ingestible device configured for local delivery to the intestine. In some embodiments, the bispecific antibody is combined or co-administered with one or more additional agents. In some embodiments, the one or more additional agents are selected from infliximab, adalimumab, golimumab, vedolizumab, tofacitinib, ustekinumab, natalizumab, mesalamine, diazo-bonded 5-ASA, sulfasalazine, balsalazide, olsalazine, a corticosteroid (e.g., budesonide, hydrocortisone, methylprednisolone, prednisone); an immunosuppressant (e.g., azathioprine, 6-mercaptopurine, cyclosporine, methotrexate), and combinations thereof. In some embodiments, the one or more additional agents are selected from a PPARδ inhibitor, an IRAK4 inhibitor, a TPL2 inhibitor, an α4β7 inhibitor, a BTLA agonist, a PD-1 agonist, a CD200R agonist, or a FXR agonist. In some embodiments, the one or more additional agents are selected from seladelpar, edecesertib, tilpisertib fosmecarbil, GS-1427, GS 0272, GS-0151, GS-6791 and cilofexor.

[0011] Further provided is a kit comprising one or more unitary doses of a bispecific antibody as described above and herein. In some embodiments, the one or more unitary doses are the same or different. In some embodiments, the one or more unitary doses are in one or more ampoules, vials, pre-loaded syringes or delivery devices. In some embodiments, the bispecific antibody is combined or co-administered with one or more additional agents. In some embodiments, the one or more additional agents are selected from infliximab, adalimumab, golimumab, vedolizumab, tofacitinib, ustekinumab, natalizumab, mesalamine, diazo-bonded 5-ASA, sulfasalazine, balsalazide, olsalazine, a corticosteroid (e.g., budesonide, hydrocortisone, methylprednisolone, prednisone); an immunosuppressant (e.g., azathioprine, 6-mercaptopurine, cyclosporine, methotrexate), and combinations thereof. In some embodiments, the one or more additional agents are selected from a PPARδ inhibitor, an IRAK4 inhibitor, a TPL2 inhibitor, an α4β7 inhibitor, a BTLA agonist, a PD-1 agonist, a CD200R agonist, or a FXR agonist. In some embodiments, the one or more additional agents are selected from seladelpar, edecesertib, tilpisertib fosmecarbil, GS-1427, GS 0272, GS-0151, GS-6791 and cilofexor.

[0044] In this study, we employed extensive protein engineering on single-domain antibodies to generate potent anti-IL-10 receptor alpha subunit and anti-IL-10 beta subunit (IL-10Rαβ) agonists that selectively target myeloid cells. These IL-10Rαβ agonists exhibit strong myeloid cell specific immunosuppressive functions without activating T-cells, B-cells, or NK cells.

[0045] Provided are single immunoglobulin variable domain (VHH) binders that specifically bind to the extracellular domain of interleukin-10 receptor (IL-10R) alpha subunit (IL-10Rα). Illustrative IL-10Rα single immunoglobulin variable domain (VHH) binders are provided in Tables A1-A4 and B, below. The IL-10Rα single immunoglobulin variable domain (VHH) binders can be humanized and incorporated into antibodies, including multispecific antibodies, e.g., bispecific antibodies, e.g., comprising a human Fc domain, e.g., a human IgG1 or a human IgG4. The IL-10Rα single immunoglobulin variable domain (VHH) binders described herein are suitable to use with an antigen binding domain that specifically binds to the extracellular domain of interleukin-10 receptor (IL-10R) beta subunit (IL 10Rβ), including the IL-10Rβ single immunoglobulin variable domain (VHH) binders described herein.

[0046] With regard to the binding of an antibody or antigen-binding fragment thereof to a target molecule, the terms “bind,” “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction (e.g., with a non-target molecule). Specific binding can be measured, for example, by measuring binding to a target molecule and comparing it to binding to a non-target molecule. Specific binding can also be determined by competition with a control molecule that mimics the epitope recognized on the target molecule. In that case, specific binding is indicated if the binding of the antibody to the target molecule is competitively inhibited by the control molecule. An antibody or antigen-binding fragment thereof that “specifically binds to” or is “specific for” a particular polypeptide or an epitope on a particular polypeptide is one that binds to that particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope. Affinities of antibodies can be readily determined using conventional techniques, for example, those described by Scatchard et al. (Ann. N. Y. Acad. Sci. USA 51: 660 (1949), ELISA assays, biolayer interferometry (BLI) assays, and surface plasmon resonance (SPR) assays). Binding properties of an antibody to antigens, cells or tissues thereof may generally be determined and assessed using immunodetection methods including, for example, immunofluorescence-based assays, such as immuno-histochemistry (IHC) and/or fluorescence-activated cell sorting (FACS).

[0047] In some embodiments, the VHH binds to IL 10Rα with an equilibrium dissociation constant (K_D) of lower than about 5 nM, e.g., lower than about 4 nM, lower than about 3 nM or lower than about 2 nM.

[0048] In some embodiments, the VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Kabat, respectively:

• • [0049] 1) SEQ ID NOs: 1, 2 and 3; (A01)
  • [0050] 2) SEQ ID NOs: 4, 5 and 6; (A06)
  • [0051] 3) SEQ ID NOs: 7, 8 and 9: (A09)
  • [0052] 4) SEQ ID NOs: 10, 11 and 12; (B07)
  • [0053] 5) SEQ ID NOs: 4, 13 and 14; (B08)
  • [0054] 6) SEQ ID NOs: 4, 15 and 16; (C09)
  • [0055] 7) SEQ ID NOs: 4, 17 and 18; (D08)
  • [0056] 8) SEQ ID NOs: 19, 20 and 21; (D14)
  • [0057] 9) SEQ ID NOs: 22, 23 and 24; (E07)
  • [0058] 10) SEQ ID NOs: 22, 25 and 27; (huE07)
  • [0059] 11) SEQ ID NOs: 22, 27 and 24; (huE07)
  • [0060] 12) SEQ ID NOs: 4, 28 and 29; (E15)
  • [0061] 13) SEQ ID NOs: 4, 30 and 31; (F09)
  • [0062] 14) SEQ ID NOs: 22, 23 and 32; (F10)
  • [0063] 15) SEQ ID NOs: 33, 34 and 35; (F11)
  • [0064] 16) SEQ ID NOs: 4, 36 and 29; (F21)
  • [0065] 17) SEQ ID NOs: 19, 37 and 38; (G22)
  • [0066] 18) SEQ ID NOs: 39, 40 and 41; (G23)
  • [0067] 19) SEQ ID NOs: 42, 43 and 44; (H22)
  • [0068] 20) SEQ ID NOs: 45, 46 and 47; (I04)
  • [0069] 21) SEQ ID NOs: 4, 48 and 6; (J13)
  • [0070] 22) SEQ ID NOs: 4, 49 and 50; (J24)
  • [0071] 23) SEQ ID NOs: 19, 51 and 52; (L05)
  • [0072] 24) SEQ ID NOs: 19, 37 and 53; (L11) or
  • [0073] 25) SEQ ID NOs: 54, 55 and 24 (N16).

[0074] In some embodiments, the VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to IMGT, respectively:

• • [0075] 1) SEQ ID NOs: 56, 57 and 58; (A01)
  • [0076] 2) SEQ ID NOs: 59, 60 and 61; (A06)
  • [0077] 3) SEQ ID NOs: 62, 63 and 64; (A09)
  • [0078] 4) SEQ ID NOs: 65, 66 and 67; (B07)
  • [0079] 5) SEQ ID NOs: 59, 68 and 69; (B08)
  • [0080] 6) SEQ ID NOs: 59, 70 and 71; (C09)
  • [0081] 7) SEQ ID NOs: 59, 72 and 73; (D08)
  • [0082] 8) SEQ ID NOs: 74, 75 and 76; (D14)
  • [0083] 9) SEQ ID NOs: 77, 78 and 79; (E07)
  • [0084] 10) SEQ ID NOs: 77, 80 and 81; (huE07)
  • [0085] 11) SEQ ID NOs: 77, 82 and 79; (huE07)
  • [0086] 12) SEQ ID NOs: 59, 83 and 84; (E15)
  • [0087] 13) SEQ ID NOs: 59, 85 and 86; (F09)
  • [0088] 14) SEQ ID NOs: 77, 78 and 87; (F10)
  • [0089] 15) SEQ ID NOs: 88, 89 and 90; (F11)
  • [0090] 16) SEQ ID NOs: 59, 91 and 84; (F21)
  • [0091] 17) SEQ ID NOs: 92, 75 and 93; (G22)
  • [0092] 18) SEQ ID NOs: 94, 89 and 95; (G23)
  • [0093] 19) SEQ ID NOs: 96, 89 and 97; (H22)
  • [0094] 20) SEQ ID NOs: 98, 99 and 100; (I04)
  • [0095] 21) SEQ ID NOs: 59, 101 and 61; (J13)
  • [0096] 22) SEQ ID NOs: 59, 102 and 103; (J24)
  • [0097] 23) SEQ ID NOs: 74, 75 and 104; (L05)
  • [0098] 24) SEQ ID NOs: 74, 75 and 105; (L11) or
  • [0099] 25) SEQ ID NOs: 106, 107 and 79 (N16).

[0100] In some embodiments, the VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Chothia, respectively:

• • [0101] 1) SEQ ID NOs: 108, 109 and 110; (A01)
  • [0102] 2) SEQ ID NOs: 111, 112 and 113; (A06)
  • [0103] 3) SEQ ID NOs: 114,115 and 116; (A09)
  • [0104] 4) SEQ ID NOs: 117,118 and 119; (B07)
  • [0105] 5) SEQ ID NOs: 111, 112 and 120; (B08)
  • [0106] 6) SEQ ID NOs: 111, 121 and 122; (C09)
  • [0107] 7) SEQ ID NOs: 111, 121 and 123; (D08)
  • [0108] 8) SEQ ID NOs: 124, 125 and 126; (D14)
  • [0109] 9) SEQ ID NOs: 127, 128 and 129; (E07)
  • [0110] 10) SEQ ID NOs: 127, 130 and 131; (huE07)
  • [0111] 11) SEQ ID NOs: 111, 132 and 133; (E15)
  • [0112] 12) SEQ ID NOs: 111, 134 and 135; (F09)
  • [0113] 13) SEQ ID NOs: 127, 128 and 136; (F10)
  • [0114] 14) SEQ ID NOs: 137, 138 and 139; (F11)
  • [0115] 15) SEQ ID NOs: 111, 132 and 133; (F21)
  • [0116] 16) SEQ ID NOs: 140, 125 and 141; (G22)
  • [0117] 17) SEQ ID NOs: 142, 138 and 143; (G23)
  • [0118] 18) SEQ ID NOs: 124, 138 and 144; (H22)
  • [0119] 19) SEQ ID NOs: 145, 146 and 147; (I04)
  • [0120] 20) SEQ ID NOs: 111, 112 and 113; (J13))
  • [0121] 21) SEQ ID NOs: 111, 148 and 149; (J24)
  • [0122] 22) SEQ ID NOs: 124, 125 and 150; (L05)
  • [0123] 23) SEQ ID NOs: 124, 125 and 151; (L11) or
  • [0124] 24) SEQ ID NOs: 152, 121 and 129 (N16).

[0125] In some embodiments, the VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Honegger, respectively:

• • [0126] 1) SEQ ID NOs: 153, 154 and 155; (A01)
  • [0127] 2) SEQ ID NOs: 156, 157 and 158; (A06)
  • [0128] 3) SEQ ID NOs: 159, 160 and 161; (A09)
  • [0129] 4) SEQ ID NOs: 162, 163 and 164; (B07)
  • [0130] 5) SEQ ID NOs: 156, 165 and 166; (B08)
  • [0131] 6) SEQ ID NOs: 156, 167 and 168; (C09)
  • [0132] 7) SEQ ID NOs: 156, 169 and 170; (D08)
  • [0133] 8) SEQ ID NOs: 171, 172 and 173; (D14)
  • [0134] 9) SEQ ID NOs: 174, 175 and 176; (E07)
  • [0135] 10) SEQ ID NOs: 174, 177 and 178; (huE07)
  • [0136] 11) SEQ ID NOs: 174, 179 and 176; (huE07)
  • [0137] 12) SEQ ID NOs: 156, 180 and 181; (E15)
  • [0138] 13) SEQ ID NOs: 156, 182 and 183; (F09)
  • [0139] 14) SEQ ID NOs: 174, 175 and 184; (F10)
  • [0140] 15) SEQ ID NOs: 185, 186 and 187; (F11)
  • [0141] 16) SEQ ID NOs: 709, 186 and 187; (huF11)
  • [0142] 17) SEQ ID NOs: 156, 188 and 181; (F21)
  • [0143] 18) SEQ ID NOs: 189, 190 and 191; (G22)
  • [0144] 19) SEQ ID NOs: 192, 193 and 194; (G23)
  • [0145] 20) SEQ ID NOs: 195, 196 and 197; (H22)
  • [0146] 21) SEQ ID NOs: 198, 199 and 200; (I04)
  • [0147] 22) SEQ ID NOs: 156, 201 and 158; (J13)
  • [0148] 23) SEQ ID NOs: 156, 202 and 203; (J24)
  • [0149] 24) SEQ ID NOs: 204, 205 and 206; (L05)
  • [0150] 25) SEQ ID NOs: 204, 190 and 207; (L11) or
  • [0151] 26) SEQ ID NOs: 208, 209 and 176 (N16).

[0152] In some embodiments, the VHH comprises the amino acid sequence, or an amino acid sequence of any one of SEQ ID NOs: 212, 230, 233, 234, 249, 710 and 724-725, or that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to one of the amino acid sequences of any one of SEQ ID NOs: 212, 230, 233, 234, 249, 710 and 724-725. In some embodiments, the VHH comprises the amino acid sequence of any one of SEQ ID NOs: 210-211, 213-229, 231-232, 235-248, 250-287, 710 and 724-725, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to one of the amino acid sequences of any one of SEQ ID NOs: 210-211, 213-229, 231-232, 235-248, 250-287, 710 and 724-725.

[0153] “Homology” or “identity” or “similarity” as used herein in the context of nucleic acids and polypeptides refers to the relationship between two polypeptides or two nucleic acid molecules based on an alignment of the amino acid sequences or nucleic acid sequences, respectively. Homology and identity can each be determined by comparing a position in each sequence which may be aligned for purposes of comparison. When an equivalent position in the compared sequences is occupied by the same base or amino acid, then the molecules are identical at that position; when the equivalent site occupied by the same or a similar amino acid residue (e.g., similar in steric and/or electronic nature), then the molecules can be referred to as homologous (similar) at that position. Expression as a percentage of homology/similarity or identity refers to a function of the number of identical or similar amino acids at positions shared by the compared sequences. In comparing two sequences, the absence of residues (amino acids or nucleic acids) or presence of extra residues also decreases the identity and homology/similarity.

[0154] As used herein, “identity” means the percentage of identical nucleotide or amino acid residues at corresponding positions in two or more sequences when the sequences are aligned to maximize sequence matching, i.e., taking into account gaps and insertions. Sequences are generally aligned for maximum correspondence over a designated region, e.g., a region at least 20, 25, 30, 35, 40, 45, 50, 55, 60, 65 or more amino acids or nucleotides in length, and can be up to the full length of the reference polypeptide or polynucleotide sequence. For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer program, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Otherwise, standard parameters can be used. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters.

[0155] When comparing polynucleotide and polypeptide sequences, two sequences are said to be “identical” if the sequence of nucleotides or amino acids in the two sequences is the same when aligned for maximum correspondence, as described below. Comparisons between two sequences are typically performed by comparing the sequences over a comparison window to identify and compare local regions of sequence similarity. A “comparison window” as used herein, refers to a segment of at least 20 contiguous positions, usually 30 to 75, 40 to 50, or the full length of a sequence, in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned.

[0156] Optimal alignment of sequences for comparison may be conducted by the local identity algorithm of Smith and Waterman (1981) Add. APL. Math 2:482, by the identity alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443, by the search for similarity methods of Pearson and Lipman (1988) Proc. Natl. Acad. Sci. USA 85: 2444, by computerized implementations of these algorithms (e.g., GAP, BESTFIT, BLAST, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group (GCG), 575 Science Dr., Madison, WI), or by inspection.

[0157] One example of algorithms that are suitable for determining percent sequence identity are the Basic Local Alignment Search Tool (BLAST), BLAST 2.0 and PSI-BLAST algorithms, which are described in Altschul, et al., J. Mol. Biol. (1990) 215: 403-410, Altschul, et al., Nucleic Acids Res. (1977) 25: 3389-3402, and Altschul, et al., Nucleic Acids Res. (1997) 25(17):3389-402, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (blast.ncbi.nlm.nih.gov/Blast.cgi).

[0158] In one illustrative example, cumulative scores can be calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatching residues; always <0). Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T and X determine the sensitivity and speed of the alignment. The BLASTP program (for polypeptide sequences) or the BLASTN program (for polynucleotide sequences) uses as defaults a word length (W) of 11, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89: 10915) alignments, (B) of 50, expectation (E) of 10, M=5, N=−4 and a comparison of both strands.

[0159] For amino acid sequences, a scoring matrix can be used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLASTP algorithm parameters W, T and X determine the sensitivity and speed of the alignment.

[0160] In one approach, the “percentage of sequence identity” is determined by comparing two optimally aligned sequences over a window of comparison of at least 20 positions, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) of 20 percent or less, usually 5 to 15 percent, or 10 to 12 percent, as compared to the reference sequences (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid bases or amino acid residues occur in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the reference sequence (i.e., the window size) and multiplying the results by 100 to yield the percentage of sequence identity.

[0161] Residue positions which are not identical can differ by conservative amino acid substitutions. Conservative amino acid substitutions refer to the interchangeability of residues having similar side chains. For example, a group of amino acids having aliphatic side chains is glycine (Gly, G), alanine (Ala, A), valine (Val, V), leucine (Leu, L), and isoleucine (Ile, I); a group of amino acids having aliphatic-hydroxyl side chains is serine (Ser, S) and threonine (Thr, T); a group of amino acids having amide-containing side chains is asparagine (Asn, N) and glutamine (Gln, Q); a group of amino acids having aromatic side chains is phenylalanine (Phe, F), tyrosine (Tyr, Y), and tryptophan (Trp, W); a group of amino acids having basic side chains is lysine (Lys, K), arginine (Arg, R), and histidine (His, H); and a group of amino acids having sulfur-containing side chains is cysteine (Cys, C) and methionine (Met, M). Further, glutamic acid (Glu, E) and aspartic acid (Asp, D) are conservative amino acid substitutions.

[0162] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0163] 1) SEQ ID NOs: 1, 2 and 3 (according to Kabat);
  • [0164] 2) SEQ ID NOs: 56, 57 and 58 (according to IMGT);
  • [0165] 3) SEQ ID NOs: 108, 109 and 110 (according to Chothia); or
  • [0166] 4) SEQ ID NOs: 153, 154 and 155 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 210-211, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 210-211 (VHH A01).

[0167] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0168] 1) SEQ ID NOs: 4, 5 and 6 (according to Kabat);
  • [0169] 2) SEQ ID NOs: 59, 60 and 61 (according to IMGT);
  • [0170] 3) SEQ ID NOs: 111, 112 and 113 (according to Chothia); or
  • [0171] 4) SEQ ID NOs: 156, 157 and 158 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 212-215, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 212-215 (VHH A06).

[0172] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0173] 1) SEQ ID NOs: 7, 8 and 9 (according to Kabat);
  • [0174] 2) SEQ ID NOs: 62, 63 and 64 (according to IMGT);
  • [0175] 3) SEQ ID NOs: 114, 115 and 116 (according to Chothia); or
  • [0176] 4) SEQ ID NOs: 159, 160 and 161 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 216-217, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 216-217 (VHH A09).

[0177] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0178] 1) SEQ ID NOs: 10, 11 and 12 (according to Kabat);
  • [0179] 2) SEQ ID NOs: 65, 66 and 67 (according to IMGT);
  • [0180] 3) SEQ ID NOs: 117, 118 and 119 (according to Chothia); or
  • [0181] 4) SEQ ID NOs: 162, 163 and 164 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 218-219, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 218-219 (VHH B07).

[0182] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0183] 1) SEQ ID NOs: 4, 13 and 14 (according to Kabat);
  • [0184] 2) SEQ ID NOs: 59, 68 and 69 (according to IMGT);
  • [0185] 3) SEQ ID NOs: 111, 112 and 120 (according to Chothia); or
  • [0186] 4) SEQ ID NOs: 156, 165 and 166 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 220-223, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 220-223 (VHH B08).

[0187] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0188] 1) SEQ ID NOs: 4, 15 and 16 (according to Kabat);
  • [0189] 2) SEQ ID NOs: 59, 70 and 71 (according to IMGT);
  • [0190] 3) SEQ ID NOs: 111, 121 and 122 (according to Chothia); or
  • [0191] 4) SEQ ID NOs: 156, 167 and 168 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 224-226 and 710, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 224-226 and 710 (VHH C09).

[0192] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0193] 1) SEQ ID NOs: 4, 17 and 18 (according to Kabat);
  • [0194] 2) SEQ ID NOs: 59, 72 and 73 (according to IMGT);
  • [0195] 3) SEQ ID NOs: 111, 121 and 123 (according to Chothia); or
  • [0196] 4) SEQ ID NOs: 156, 169 and 170 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 227-229 and 710, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 227-229 and 710 (VHH D08).

[0197] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0198] 1) SEQ ID NOs: 19, 20 and 21 (according to Kabat);
  • [0199] 2) SEQ ID NOs: 74, 75 and 76 (according to IMGT);
  • [0200] 3) SEQ ID NOs: 124, 125 and 126 (according to Chothia); or
  • [0201] 4) SEQ ID NOs: 171, 172 and 173 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 230-232, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 230-232 (VHH D14).

[0202] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0203] 1) SEQ ID NOs: 22, 23 and 24; or 22, 25 and 26; or 22, 27 and 24 (according to Kabat); 2) SEQ ID NOs: 77, 78 and 79; or 77, 80 and 81; or 77, 82 and 79 (according to IMGT); 3) SEQ ID NOs: 127, 128 and 129; or 127, 130 and 131 (according to Chothia); or 4) SEQ ID NOs: 174, 175 and 176; or 174, 177 and 178; or 174, 179 and 176 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 233-240 and 724-725, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 233-240 and 724-725. In some embodiments, the VHH binds to an epitope on IL 10Rα comprising contact amino acid residues W33, E35, E37, H40, 142, H44, T46, L79, S80, T124, A170, R172, F178, F180, H182, Q204, K215, M217, W218, K220 and E221, wherein the amino acid residue positions are with respect to SEQ ID NO: 711. (VHH E07).

[0204] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0205] 1) SEQ ID NOs: 4, 28 and 29 (according to Kabat);
  • [0206] 2) SEQ ID NOs: 59, 83 and 84 (according to IMGT);
  • [0207] 3) SEQ ID NOs: 111, 132 and 133 (according to Chothia); or
  • [0208] 4) SEQ ID NOs: 156, 180 and 181 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 241-243 and 710, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 241-243 and 710 (VHH E15).

[0209] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0210] 1) SEQ ID NOs: 4, 30 and 31 (according to Kabat);
  • [0211] 2) SEQ ID NOs: 59, 85 and 86 (according to IMGT);
  • [0212] 3) SEQ ID NOs: 111, 134 and 135 (according to Chothia); or
  • [0213] 4) SEQ ID NOs: 156, 182 and 183 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 244-246, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 244-246 (VHH F09).

[0214] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0215] 1) SEQ ID NOs: 22, 23 and 32 (according to Kabat);
  • [0216] 2) SEQ ID NOs: 77, 78 and 87 (according to IMGT);
  • [0217] 3) SEQ ID NOs: 127, 128 and 136 (according to Chothia); or
  • [0218] 4) SEQ ID NOs: 174, 175 and 184 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 247-248, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 247-248 (VHH F10).

[0219] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0220] 1) SEQ ID NOs: 33, 34 and 35 (according to Kabat);
  • [0221] 2) SEQ ID NOs: 88, 89 and 90 (according to IMGT);
  • [0222] 3) SEQ ID NOs: 137, 138 and 139 (according to Chothia); or
  • [0223] 4) SEQ ID NOs: 185, 186 and 187 or 709, 186 and 187 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 249-252 and 752-755, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 249-252 and 752-755. In some embodiments, the VHH binds to an epitope on IL 10Rα comprising contact amino acid residues I169, I171, K173, F178, F180, T181, H182, K183, K186, F190, L192, L193, S195, E197 and F201, wherein the amino acid residue positions are with respect to SEQ ID NO: 711. (VHH F11).

[0224] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0225] 1) SEQ ID NOs: 4, 36 and 29 (according to Kabat);
  • [0226] 2) SEQ ID NOs: 59, 91 and 84 (according to IMGT);
  • [0227] 3) SEQ ID NOs: 111, 132 and 133 (according to Chothia); or
  • [0228] 4) SEQ ID NOs: 156, 188 and 181 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 253-255 and 710, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 253-255 and 710 (VHH F21).

[0229] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0230] 1) SEQ ID NOs: 19, 37 and 38 (according to Kabat);
  • [0231] 2) SEQ ID NOs: 92, 75 and 93 (according to IMGT);
  • [0232] 3) SEQ ID NOs: 140, 125 and 141 (according to Chothia); or
  • [0233] 4) SEQ ID NOs: 189, 190 and 191 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 230 and 256-259, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 230 and 256-259 (VHH G22).

[0234] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0235] 1) SEQ ID NOs: 19, 37 and 38 (according to Kabat);
  • [0236] 2) SEQ ID NOs: 92, 75 and 93 (according to IMGT);
  • [0237] 3) SEQ ID NOs: 140, 125 and 141 (according to Chothia); or
  • [0238] 4) SEQ ID NOs: 189, 190 and 191 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 260-263, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 260-263 (VHH G23).

[0239] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0240] 1) SEQ ID NOs: 42, 43 and 44 (according to Kabat);
  • [0241] 2) SEQ ID NOs: 96, 89 and 97 (according to IMGT);
  • [0242] 3) SEQ ID NOs: 124, 138 and 144 (according to Chothia); or
  • [0243] 4) SEQ ID NOs: 195, 196 and 197 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 264-266, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 264-266 (VHH H22).

[0244] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0245] 1) SEQ ID NOs: 45, 46 and 47 (according to Kabat);
  • [0246] 2) SEQ ID NOs: 98, 99 and 100 (according to IMGT);
  • [0247] 3) SEQ ID NOs: 145, 146 and 147 (according to Chothia); or
  • [0248] 4) SEQ ID NOs: 198, 199 and 200 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any of SEQ ID NOs: 267-269, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any of SEQ ID NOs: 267-269 (VHH I04).

[0249] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0250] 1) SEQ ID NOs: 4, 48 and 6 (according to Kabat);
  • [0251] 2) SEQ ID NOs: 59, 101 and 61 (according to IMGT);
  • [0252] 3) SEQ ID NOs: 111, 112 and 113 (according to Chothia); or
  • [0253] 4) SEQ ID NOs: 156, 201 and 158 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 270-273, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 270-273 (VHH J13).

[0254] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0255] 1) SEQ ID NOs: 4, 49 and 50 (according to Kabat);
  • [0256] 2) SEQ ID NOs: 59, 102 and 103 (according to IMGT);
  • [0257] 3) SEQ ID NOs: 111, 148 and 149 (according to Chothia); or
  • [0258] 4) SEQ ID NOs: 156, 202 and 203 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 274-277, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 274-277 (VHH J24).

[0259] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0260] 1) SEQ ID NOs: 19, 51 and 52 (according to Kabat);
  • [0261] 2) SEQ ID NOs: 74, 75 and 104 (according to IMGT);
  • [0262] 3) SEQ ID NOs: 124, 125 and 150 (according to Chothia); or
  • [0263] 4) SEQ ID NOs: 204, 205 and 206 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 230 and 278-280, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 230 and 278-280 (VHH L05).

[0264] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0265] 1) SEQ ID NOs: 19, 37 and 53 (according to Kabat);
  • [0266] 2) SEQ ID NOs: 74, 75 and 105 (according to IMGT);
  • [0267] 3) SEQ ID NOs: 124, 125 and 151 (according to Chothia); or
  • [0268] 4) SEQ ID NOs: 204, 190 and 207 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 230 and 281-284, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 230 and 281-284 (VHH L11).

[0269] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0270] 1) SEQ ID NOs: 54, 55 and 24 (according to Kabat);
  • [0271] 2) SEQ ID NOs: 106, 107 and 79 (according to IMGT);
  • [0272] 3) SEQ ID NOs: 152, 121 and 129 (according to Chothia); or
  • [0273] 4) SEQ ID NOs: 208, 209 and 176 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rα, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 285-287, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of any one of the amino acid sequences set forth in any one of SEQ ID NOs: 285-287 (VHH N16).

[0274] Generally, the herein described VHH that bind to IL-10Rα bind to both human IL-10Rα and cynomolgus IL-10Rα, within a 10-fold affinity difference, e.g., within a 5-fold or within a 3-fold affinity difference (e.g., as determined by SPR and expressed as an equilibrium dissociation constant (KD)). Amino acid sequences of complementarity determining regions (CDRs) of illustrative VHH that bind to IL-10Rα are provided in Tables A1-A4. Amino acid sequences of variable regions of illustrative VHH that bind to IL-10Rα are provided in Table B.

TABLE A1
Illustrative IL-10Rα Single Immunoglobulin Variable
domain (VHH) Binder CDR amino acid sequences
(according to Kabat)
VHH name	VHH - CDR1	VHH - CDR2	VHH - CDR3
A01	NYWVD	AINKDGGSAYYADSVKG	DYGSGMHD
	SEQ ID NO: 1	SEQ ID NO: 2	SEQ ID NO: 3
A06	SYGMG	AINWIPGTTYYADSVKG	RRRIDNYYRASEYDY
	SEQ ID NO: 4	SEQ ID NO: 5	SEQ ID NO: 6
A09	SYAID	CISSSGISTTYADSVKG	AALCMSGTYYAGPGY
	SEQ ID NO: 7	SEQ ID NO: 8	SEQ ID NO: 9
B07	YYAIG	CISSSGGSTYYADSVKG	DAACMVVAGTLILPDDY
	SEQ ID NO: 10	SEQ ID NO: 11	SEQ ID NO: 12
B08	SYGMG	TINWIPGSTYYADSVKG	RRRIESYYRASEYDY
	SEQ ID NO: 4	SEQ ID NO: 13	SEQ ID NO: 14
C09	SYGMG	AISWIGGGTYYADSVKG	KYYPDSYFAAASYAY
	SEQ ID NO: 4	SEQ ID NO: 15	SEQ ID NO: 16
D08	SYGMG	AISWIGGSTYYADSVKG	KYYTDSYFAATSYAY
	SEQ ID NO: 4	SEQ ID NO: 17	SEQ ID NO: 18
D14	GYGMG	SINWIYGATYYTDSVKG	KINGGSYFNTGSFGF
	SEQ ID NO: 19	SEQ ID NO: 20	SEQ ID NO: 21
E07	AYGMG	AIRWIGDSTYYADSVKG	KTSVTSYLSEKSYNY
	SEQ ID NO: 22	SEQ ID NO: 23	SEQ ID NO: 24
huE07	AYGMG	AIRWYGEGTYYAESVKG	KTRPDSYLSEKSYGY
	SEQ ID NO: 22	SEQ ID NO: 25	SEQ ID NO: 26
huE07	AYGMG	AIRWIGDATYYAESVKG	KTSVTSYLSEKSYNY
	SEQ ID NO: 22	SEQ ID NO: 27	SEQ ID NO: 24
E15	SYGMG	AISWIGNSAYYADSVKG	KYYTDSYYAAASYAY
	SEQ ID NO: 4	SEQ ID NO: 28	SEQ ID NO: 29
F09	SYGMG	AISWIGSATDYADSVRG	RRSPMSRTSVLQYDY
	SEQ ID NO: 4	SEQ ID NO: 30	SEQ ID NO: 31
F10	AYGMG	AIRWIGDSTYYADSVKG	KTSVTSYLSEKAYNY
	SEQ ID NO: 22	SEQ ID NO: 23	SEQ ID NO: 32
F11	SHTVG	AITWNGDTTYFGDFVEG	ATGQVWSLQYLRESSYAY
	SEQ ID NO: 33	SEQ ID NO: 34	SEQ ID NO: 35
F21	SYGMG	AISWIGNSTYYADSVKG	KYYTDSYYAAASYAY
	SEQ ID NO: 4	SEQ ID NO: 36	SEQ ID NO: 29
G22	GYGMG	AINWIYGATYYADSVKG	KINAGSYFNIGSFGS
	SEQ ID NO: 19	SEQ ID NO: 37	SEQ ID NO: 38
G23	DDTVG	AITWNGDTTYYGDSVKG	AAGQDWSLGYLRESSYAY
	SEQ ID NO: 39	SEQ ID NO: 40	SEQ ID NO: 41
H22	GYTVG	AITWNGDTTYFGDSVKG	ATGQEWSLQYLRESSYAY
	SEQ ID NO: 42	SEQ ID NO: 43	SEQ ID NO: 44
I04	NYAMA	AINWFGRATEYADSVKD	RTKVTTGRRNQAEYDY
	SEQ ID NO: 45	SEQ ID NO: 46	SEQ ID NO: 47
J13	SYGMG	TINWIPGNTYYADSVKG	RRRIDNYYRASEYDY
	SEQ ID NO: 4	SEQ ID NO: 48	SEQ ID NO: 6
J24	SYGMG	TIIGWIPGNTYYADSVKG	RRRIDSYYRASEYDY
	SEQ ID NO: 4	SEQ ID NO: 49	SEQ ID NO: 50
L05	GYGMG	SINWIYGATYYSDSVKG	KINGESYFNTGSFGS
	SEQ ID NO: 19	SEQ ID NO: 51	SEQ ID NO: 52
L11	GYGMG	AINWIYGATYYADSVKG	KINGGSYFNIGSFGS
	SEQ ID NO: 19	SEQ ID NO: 37	SEQ ID NO: 53
N16	YYGMG	AIRWIGGDTYYADSVKG	KTSVTSYLSEKSYNY
	SEQ ID NO: 54	SEQ ID NO: 55	SEQ ID NO: 24

TABLE A2
Illustrative IL-10Rα Single Immunoglobulin
Variable domain (VHH) Binder CDR amino acid sequences
(according to IMGT)
VHH name	VHH - CDR1	VHH - CDR2	VHH - CDR3
A01	GFTFSNYW	INKDGGSA	AKDYGSGMHD
	SEQ ID NO: 56	SEQ ID NO: 57	SEQ ID NO: 58
A06	GRTFSSYG	INWIPGTT	AARRRIDNYYRASEYDY
	SEQ ID NO: 59	SEQ ID NO: 60	SEQ ID NO: 61
A09	GFTLDSYA	ISSSGIST	AAAALCMSGTYYAGPGY
	SEQ ID NO: 62	SEQ ID NO: 63	SEQ ID NO: 64
B07	DFTLDYYA	ISSSGGST	AADAACMVVAGTLILPDDY
	SEQ ID NO: 65	SEQ ID NO: 66	SEQ ID NO: 67
B08	GRTFSSYG	INWIPGST	AARRRIESYYRASEYDY
	SEQ ID NO: 59	SEQ ID NO: 68	SEQ ID NO: 69
C09	GRTFSSYG	ISWIGGGT	AAKYYPDSYFAAASYAY
	SEQ ID NO: 59	SEQ ID NO: 70	SEQ ID NO: 71
D08	GRTFSSYG	ISWIGGST	AAKYYTDSYFAATSYAY
	SEQ ID NO: 59	SEQ ID NO: 72	SEQ ID NO: 73
D14	GRTFSGYG	INWIYGAT	AAKINGGSYFNTGSFGF
	SEQ ID NO: 74	SEQ ID NO: 75	SEQ ID NO: 76
E07	GRTFSAYG	IRWIGDST	AAKTSVTSYLSEKSYNY
	SEQ ID NO: 77	SEQ ID NO: 78	SEQ ID NO: 79
huE07	GRTFSAYG	IRWYGEGT	AAKTRPDSYLSEKSYGY
	SEQ ID NO: 77	SEQ ID NO: 80	SEQ ID NO: 81
huE07	GRTFSAYG	IRWIGDAT	AAKTSVTSYLSEKSYNY
	SEQ ID NO: 77	SEQ ID NO: 82	SEQ ID NO: 79
E15	GRTFSSYG	ISWIGNSA	AAKYYTDSYYAAASYAY
	SEQ ID NO: 59	SEQ ID NO: 83	SEQ ID NO: 84
F09	GRTFSSYG	ISWIGSAT	AARRSPMSRTSVLQYDY
	SEQ ID NO: 59	SEQ ID NO: 85	SEQ ID NO: 86
F10	GRTFSAYG	IRWIGDST	AAKTSVTSYLSEKAYNY
	SEQ ID NO: 77	SEQ ID NO: 78	SEQ ID NO: 87
F11	GRTFSSHT	ITWNGDTT	AAATGQVWSLQYLRESSYAY
	SEQ ID NO: 88	SEQ ID NO: 89	SEQ ID NO: 90
F21	GRTFSSYG	ISWIGNST	AAKYYTDSYYAAASYAY
	SEQ ID NO: 59	SEQ ID NO: 91	SEQ ID NO: 84
G22	GRTFDGYG	INWIYGAT	AAKINAGSYFNIGSFGS
	SEQ ID NO: 92	SEQ ID NO: 75	SEQ ID NO: 93
G23	GRTFSDDT	ITWNGDTT	AAAAGQDWSLGYLRESSYAY
	SEQ ID NO: 94	SEQ ID NO: 89	SEQ ID NO: 95
H22	GRTFSGYT	ITWNGDTT	AAATGQEWSLQYLRESSYAY
	SEQ ID NO: 96	SEQ ID NO: 89	SEQ ID NO: 97
I04	GRTFSNYA	INWF GRAT	AARTKVTTGRRNQAEYDY
	SEQ ID NO: 98	SEQ ID NO: 99	SEQ ID NO: 100
J13	GRTFSSYG	INWIPGNT	AARRRIDNYYRASEYDY
	SEQ ID NO: 59	SEQ ID NO: 101	SEQ ID NO: 61
J24	GRTFSSYG	IIGWIPGNT	AARRRIDSYYRASEYDY
	SEQ ID NO: 59	SEQ ID NO: 102	SEQ ID NO: 103
L05	GRTFSGYG	INWIYGAT	AAKINGESYENTGSFGS
	SEQ ID NO: 74	SEQ ID NO: 75	SEQ ID NO: 104
L11	GRTFSGYG	INWIYGAT	AAKINGGSYFNIGSFGS
	SEQ ID NO: 74	SEQ ID NO: 75	SEQ ID NO: 105
N16	GGTFSYYG	IRWIGGDT	AAKTSVTSYLSEKSYNY
	SEQ ID NO: 106	SEQ ID NO: 107	SEQ ID NO: 79

TABLE A3
Illustrative IL-10Rα Single Immunoglobulin
Variable domain (VHH) Binder CDR amino acid sequences
(according to Chothia)
VHH name	VHH - CDR1	VHH - CDR2	VHH - CDR3
A01	GFTFSNY	KDGG	YGSGMH
	SEQ ID NO: 108	SEQ ID NO: 109	SEQ ID NO: 110
A06	GRIFSSY	WIPG	RRIDNYYRASEYD
	SEQ ID NO: 111	SEQ ID NO: 112	SEQ ID NO: 113
A09	GFTLDSY	SSGI	ALCMSGTYYAGPG
	SEQ ID NO: 114	SEQ ID NO: 115	SEQ ID NO: 116
B07	DFTLDYY	SSGG	AACMVVAGTLILPDD
	SEQ ID NO: 117	SEQ ID NO: 118	SEQ ID NO: 119
B08	GRTFSSY	WIPG	RRIESYYRASEYD
	SEQ ID NO: 111	SEQ ID NO: 112	SEQ ID NO: 120
C09	GRTFSSY	WIGG	YYPDSYFAAASYA
	SEQ ID NO: 111	SEQ ID NO: 121	SEQ ID NO: 122
D08	GRIFSSY	WIGG	YYTD SYFAATSYA
	SEQ ID NO: 111	SEQ ID NO: 121	SEQ ID NO: 123
D14	GRTFSGY	WIYG	INGGSYFNTGSFG
	SEQ ID NO: 124	SEQ ID NO: 125	SEQ ID NO: 126
E07	GRTFSAY	WIGD	TSVTSYLSEKSYN
	SEQ ID NO: 127	SEQ ID NO: 128	SEQ ID NO: 129
huE07	GRTFSAY	WYGE	TRPDSYLSEKSYG
	SEQ ID NO: 127	SEQ ID NO: 130	SEQ ID NO: 131
E15	GRTFSSY	WIGN	YYTDSYYAAASYA
	SEQ ID NO: 111	SEQ ID NO: 132	SEQ ID NO: 133
F09	GRTESSY	WIGS	RSPMSRTSVLQYD
	SEQ ID NO: 111	SEQ ID NO: 134	SEQ ID NO: 135
F10	GRTFSAY	WIGD	TSVTSYLSEKAYN
	SEQ ID NO: 127	SEQ ID NO: 128	SEQ ID NO: 136
F11	GRTFSSH	WNGD	TGQVWSLQYLRESSYA
	SEQ ID NO: 137	SEQ ID NO: 138	SEQ ID NO: 139
F21	GRTFSSY	WIGN	YYTDSYYAAASYA
	SEQ ID NO: 111	SEQ ID NO: 132	SEQ ID NO: 133
G22	GRTFDGY	WIYG	INAGSYFNIGSFG
	SEQ ID NO: 140	SEQ ID NO: 125	SEQ ID NO: 141
G23	GRTFSDD	WNGD	AGQDWSLGYLRESSYA
	SEQ ID NO: 142	SEQ ID NO: 138	SEQ ID NO: 143
H22	GRTFSGY	WNGD	TGQEWSLQYLRESSYA
	SEQ ID NO: 124	SEQ ID NO: 138	SEQ ID NO: 144
I04	GRTFSNY	WFGR	TKVTTGRRNQAEYD
	SEQ ID NO: 145	SEQ ID NO: 146	SEQ ID NO: 147
J13	GRTFSSY	WIPG	RRIDNYYRASEYD
	SEQ ID NO: 111	SEQ ID NO: 112	SEQ ID NO: 113
J24	GRTFSSY	GWIPG	RRIDSYYRASEYD
	SEQ ID NO: 111	SEQ ID NO: 148	SEQ ID NO: 149
L05	GRTFSGY	WIYG	INGESYFNTGSFG
	SEQ ID NO: 124	SEQ ID NO: 125	SEQ ID NO: 150
L11	GRTFSGY	WIYG	INGGSYFNIGSFG
	SEQ ID NO: 124	SEQ ID NO: 125	SEQ ID NO: 151
N16	GGTFSYY	WIGG	TSVTSYLSEKSYN
	SEQ ID NO: 152	SEQ ID NO: 121	SEQ ID NO: 129

TABLE A4
Illustrative IL-10Rα Single Immunoglobulin
Variable domain (VHH) Binder CDR amino acid sequences
(according to Honegger)
VHH
name	VHH - CDR1	VHH - CDR2	VHH - CDR3
A01	ASGFTF SNYW	INKDGGSAYYADSVKGR	DYGSGMH
	SEQ ID NO: 153	SEQ ID NO: 154	SEQ ID NO: 155
A06	ASGRTFSSYG	INWIPGTTYYADSVKGR	RRRIDNYYRASEYD
	SEQ ID NO: 156	SEQ ID NO: 157	SEQ ID NO: 158
A09	ASGFTLDSYA	ISSSGISTTYADSVKGR	AALCMSGTYYAGPG
	SEQ ID NO: 159	SEQ ID NO: 160	SEQ ID NO: 161
B07	ASDFTLDYYA	ISSSGGSTYYADSVKGR	DAACMVVAGTLILPDD
	SEQ ID NO: 162	SEQ ID NO: 163	SEQ ID NO: 164
B08	ASGRTFSSYG	INWIPGSTYYADSVKGR	RRRIESYYRASEYD
	SEQ ID NO: 156	SEQ ID NO: 165	SEQ ID NO: 166
C09	ASGRTFSSYG	ISWIGGGTYYADSVKGR	KYYPDSYFAAASYA
	SEQ ID NO: 156	SEQ ID NO: 167	SEQ ID NO: 168
D08	ASGRTFSSYG	ISWIGGSTYYADSVKGR	KYYTDSYFAATSYA
	SEQ ID NO: 156	SEQ ID NO: 169	SEQ ID NO: 170
D14	ASGRTFSGYG	INWIYGATYYTDSVKGR	KINGGSYFNTGSFG
	SEQ ID NO: 171	SEQ ID NO: 172	SEQ ID NO: 173
E07	ASGRTFSAYG	IRWIGDSTYYADSVKGR	KTSVTSYLSEKSYN
	SEQ ID NO: 174	SEQ ID NO: 175	SEQ ID NO: 176
huE07	ASGRTFSAYG	IRWYGEGTYYAESVKGR	KTRPDSYLSEKSYG
	SEQ ID NO: 174	SEQ ID NO: 177	SEQ ID NO: 178
huE07	ASGRTFSAYG	IRWIGDATYYAESVKGR	KTSVTSYLSEKSYN
	SEQ ID NO: 174	SEQ ID NO: 179	SEQ ID NO: 176
E15	ASGRTFSSYG	ISWIGNSAYYADSVKGR	KYYTDSYYAAASYA
	SEQ ID NO: 156	SEQ ID NO: 180	SEQ ID NO: 181
F09	ASGRTFSSYG	ISWIGSATDYADSVRGR	RRSPMSRTSVLQYD
	SEQ ID NO: 156	SEQ ID NO: 182	SEQ ID NO: 183
F10	ASGRTFSAYG	IRWIGDSTYYADSVKGR	KTSVTSYLSEKAYN
	SEQ ID NO: 174	SEQ ID NO: 175	SEQ ID NO: 184
F11	NSGRTFSSHT	ITWNGDTTYFGDFVEGR	ATGQVWSLQYLRESSYA
	SEQ ID NO: 185	SEQ ID NO: 186	SEQ ID NO: 187
huF11	ASGRTFSSHT	ITWNGDTTYFGDFVEGR	ATGQVWSLQYLRESSYA
	SEQ ID NO: 709	SEQ ID NO: 186	SEQ ID NO: 187
F21	ASGRTFSSYG	ISWIGNSTYYADSVKGR	KYYTDSYYAAASYA
	SEQ ID NO: 156	SEQ ID NO: 188	SEQ ID NO: 181
G22	ASGRTFDGYG	INWIYGATYYADSVKGR	KINAGSYFNIGSFG
	SEQ ID NO: 189	SEQ ID NO: 190	SEQ ID NO: 191
G23	ASGRTFSDDT	ITWNGDTTYYGDSVKGR	AAGQDWSLGYLRESSYA
	SEQ ID NO: 192	SEQ ID NO: 193	SEQ ID NO: 194
H22	ASGRTFSGYT	ITWNGDTTYFGDSVKGR	ATGQEWSLQYLRESSYA
	SEQ ID NO: 195	SEQ ID NO: 196	SEQ ID NO: 197
I04	ASGRTFSNYA	INWFGRATEYADSVKDR	RTKVTTGRRNQAEYD
	SEQ ID NO: 198	SEQ ID NO: 199	SEQ ID NO: 200
J13	ASGRTFSSYG	INWIPGNTYYADSVKGR	RRRIDNYYRASEYD
	SEQ ID NO: 156	SEQ ID NO: 201	SEQ ID NO: 158
J24	ASGRTFSSYG	IIGWIPGNTYYADSVKGR	RRRIDSYYRASEYD
	SEQ ID NO: 156	SEQ ID NO: 202	SEQ ID NO: 203
L05	NSGRTFSGYG	INWIYGATYYSDSVKGR	KINGESYFNTGSEG
	SEQ ID NO: 204	SEQ ID NO: 205	SEQ ID NO: 206
L11	NSGRTFSGYG	INWIYGATYYADSVKGR	KINGGSYFNIGSFG
	SEQ ID NO: 204	SEQ ID NO: 190	SEQ ID NO: 207
N16	ASGGTFSYYG	IRWIGGDTYYADSVKGR	KTSVTSYLSEKSYN
	SEQ ID NO: 208	SEQ ID NO: 209	SEQ ID NO: 176

TABLE B
Illustrative IL-10Rα Single Immunoglobulin Variable
Domain (VHH) amino acid sequences
VHH
name	VHH amino acid sequence
A01	SEQ ID NO: 210
	DVQLVESGGGVVQPGGSLRLSCAASGFTFSNYWVDWLRQAPGKGLEWVSAINKDG
	GSAYYADSVKGRFTISRDNAKNTLYLQMTSLKPEDTAVYYCAKDYGSGMHDWGKG
	TQVTVSS
huA01	SEQ ID NO: 211
	EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWVDWLRQAPGKGLEWVSAINKDG
	GSAYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDYGSGMHDWGQG
	TMVTVSS
A06	SEQ ID NO: 212
con	X1X2LQLVESGGGX3VQX4GGSLRLSCAASGRTFSSYGMGWFRQAPGKERX5X6VA
	X7IX8NWIPGX9TYYADSVKGRFTIX10GDKX11KNTLYLQMDX12LX13X14EDTAVYY
	CAARRRIX15X16YYRASEYDYWGQGTX17VTVSS
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	X2 is E or Q
	X3 is L, S or V
	X4 is A or P
	X5 is E or G
	X6 is F or L
	X7 is A or T
	X8 is I or absent
	X9 is N, S or T
	X10 is S or T
	X11 is D or S
	X12 is N or S
	X13 is K or R
	X14 is A or P
	X15 is D or E
	X16 is N or S
	X17 is L or Q
A06	SEQ ID NO: 213
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues )
	SEQ ID NO: 214
	X1 is AS
	X1QLQLVESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKERGLVAAINWI
	PGTTYYADSVKGRFTI SGDKDKNTLYLQMDNLKPEDTAVYYCAARRRIDNYYRAS
	EYDYWGQGTQVTVSS
huA06	SEQ ID NO: 215
	ELQLVESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKERELVAAINWIP
	GTTYYADSVKGRFTISGDKSKNTLYLQMNSLRAEDTAVYYCAARRRIDNYYRASE
	YDYWGQGTLVTVSS
A09	SEQ ID NO: 216
	DLQLVESGGGLVQPGGSLRLSCAASGFTLDSYAIDWFRQAPGKEREGVSCISSSG
	ISTTYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAAAALCMSGTYYAG
	PGYWGQGTQVTVSS
huA09	SEQ ID NO: 217
	ELQLVESGGGLVQPGGSLRLSCAASGFTLDSYAIDWFRQAPGKEREGVSCISSSG
	ISTTYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCAAAALCMSGTYYAG
	PGYWGQGTTVTVSS
B07	SEQ ID NO: 218
	DVQLVESGGGLVQPGGSLRLSCAASDFTLDYYAIGWFRQAPGKEREGVSCISSSG
	GSTYYADSVKGRFTISRDNAKNTVSLQMNSLKPEDTAVYYCAADAACMVVAGTLI
	LPDDYWGQGTQVTVSS
huB07	SEQ ID NO: 219
	EVQLVESGGGLVQPGGSLRLSCAASGFTLDYYAIGWFRQAPGKEREGVSCISSSG
	GSTYYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCAADAACMVVAGTLI
	LPDDYWGQGTLVTVSS
B08	SEQ ID NO: 220
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues )
	SEQ ID NO: 221
	X1 is AS
	X1QVQLVESGGGSVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKERGEVATINWI
	PGSTYYADSVKGRFTISGDKDNNTVYLQMDNLKPEDTAVYYCAARRRIESYYRAS
	EYDYWGQGTQVTVSS
huB08	SEQ ID NO: 222
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues )
	SEQ ID NO: 223
	X1 is AS
	X1QVQLVESGGGVVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVATINWI
	PGSTYYADSVKGRFTISGDKSKNTVYLQMNSLRAEDTAVYYCAARRRIESYYRAS
	EYDYWGQGTLVTVSS
C09	SEQ ID NO: 710
Con	X1X2VQLX3ESGGGLVQX4GGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAIS
w/	WIGX5X6X7YYADSVKGRFTLSX8DNX9KNX10X11X12LQMNSLX13X14EDTAVYYCA
D08,	AKYYX15DSYX16AAX17SYAYWGQGTX18VTVSS
E15,	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
F21	residues )
	X2 is E or Q
	X3 is L or Q
	X4 is A or P
	X5 is G or N
	X6 is G or S
	X7 is A or T
	X8 is G, R or S
	X9 is A or S
	X10 is M, R or T
	X11 is I, L or V
	X12 is A or Y
	X13 is K or R
	X14 is A or P
	X15 is P or T
	X16 is F or Y
	X17 is A or T
	X18 is L or Q
C09	SEQ ID NO: 224
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues )
	SEQ ID NO: 225
	X1 is AS
	X1QVQLQESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI
	GGGTYYADSVKGRFTLSRDNAKNMVYLQMNSLKPEDTAVYYCAAKYYPDSYFAAA
	SYAYWGQGTQVTVSS
huC09	SEQ ID NO: 226
	EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWIG
	GGTYYADSVKGRFTLSRDNSKNTVYLQMNSLRAEDTAVYYCAAKYYPDSYFAAAS
	YAYWGQGTLVTVSS
D08	SEQ ID NO: 227
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues )
	SEQ ID NO: 228
	X1 is AS
	X1QVQLQESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI
	GGSTYYADSVKGRFTLSSDNAKNRIALQMNSLKPEDTAVYYCAAKYYTDSYFAAT
	SYAYWGQGTQVTVSS
huD08	SEQ ID NO: 229
	EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWIG
	GGTYYADSVKGRFTLSRDNSKNTVYLQMNSLRAEDTAVYYCAAKYYPDSYFAAAS
	YAYWGQGTLVTVSS
G22	SEQ ID NO: 230
con	X1X2LQLX3ESGGGLVQX4GGSLX5LSCX6X7SGRTFSGYGMGWFRQX8PGKEREFVS
w/	X9INWIYGATYYX10DSVKGRFX11X12SX13DKX14KX15TX16YLQMX17SLX18X19ED
D14,	TAVYYCAAKINGX20SYFNX21GSFGFWGQGTX22VTVSS
L05,	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
L11	residues )
	X2 is E or Q
	X3 is L, Q or V
	X4 is A or P
	X5 is K or R
	X6 is A, S or T
	X7 is A or N
	X8 is A or P
	X9 is A or S
	X10 is A, S or T
	X11 is A or T
	X12 is L or V
	X13 is G or R
	X14 is A, D or S
	X15 is G or N
	X16 is L, M or V
	X17 is D, N or S
	X18 is K or R
	X19 is A or P
	X20 is E or G
	X21 is I or T
	X22 is L or Q
D14	SEQ ID NO: 231
	ELQLVESGGGLVQAGGSLKLSCTASGRTFSGYGMGWFRQAPGKEREFVSSINWIY
	GATYYTDSVKGRFAVSRDKDKNTMYLQMSSLKPEDTAVYYCAAKINGGSYENTGS
	FGFWGQGTQVTVSS
huD14	SEQ ID NO: 232
	ELQLVESGGGLVQPGGSLRLSCAASGRTFSGYGMGWFRQAPGKEREFVSSINWIY
	GATYYTDSVKGRFTVSRDKSKNTMYLQMNSLRAEDTAVYYCAAKINGGSYENTGS
	FGFWGQGTLVTVSS
E07	SEQ ID NO: 233
con1	X1X2LQLVESGGGLVX3X4GX5SLRLSCAASGRTFSAYGMGWFRQAPGKX6X7EFVX8
	AIRWX9GX10X11TYYAX12SVKGRFTISKDX13X14KNTLYLQMX15SLX16X17EDTAV
	YYCAAKTX18X19X20SYLSEKSYX21YWGQGTX22VTVSS
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues )
	X2 is E or Q
	X3 is Q or R
	X4 is A or P
	X5 is D or G
	X6 is E or G
	X7 is L or R
	X8 is A or S
	X9 is I or Y
	X10 is D or E
	X11 is A, G or S
	X12 is D or E
	X13 is N or S
	X14 is A or S
	X15 is N or S
	X16 is K or R
	X17 is A or P
	X18 is R or S
	X19 is P or V
	X20 is D or T
	X21 is G or N
	X22 is M or Q
E07	SEQ ID NO: 234
con2	X1QLQLVESGGGLVX3X4GGSLRLSCAASGRTFSAYGMGWFRQAPGKX6REFVX7AI
	RWX8GX9X10TYYAX11SVKGRFTISKDNX13KNTLYLQMX14SLX15X16EDTAVYYCA
	AKTX17X18X19SYLSEKSYX20YWGQGTX21VTVSS
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues )
	X3 is Q or R
	X4 is A or P
	X6 is E or G
	X7 is A or S
	X8 is I or Y
	X9 is D or E
	X10 is A, G or S
	X11 is D or E
	X13 is A or S
	X14 is N or S
	X15 is K or R
	X16 is A or P
	X17 is R or S
	X18 is P or V
	X19 is D or T
	X20 is G or N
	X21 is M or Q
E07	SEQ ID NO: 235
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	SEQ ID NO: 236
	X1 is AS
	X1QLQLVESGGGLVRAGGSLRLSCAASGRTFSAYGMGWFRQAPGKEREFVAAIRWI
	GDSTYYADSVKGRFTISKDNAKNTLYLQMSSLKPEDTAVYYCAAKTSVTSYLSEK
	SYNYWGQGTQVTVSS
huE07	SEQ ID NO: 724
	ELQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKEREFVAAIRWIG
	DSTYYADSVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTSVTSYLSEKS
	YNYWGQGTMVTVSS
huE07	SEQ ID NO: 725
	ELQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKGREFVSAIRWIG
	DSTYYADSVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTSVTSYLSEKS
	YNYWGQGTMVTVSS
huE07	SEQ ID NO: 237
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	SEQ ID NO: 238
	X1 is AS
	X1QLQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKGREFVSAIRWY
	GEGTYYAESVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTRPDSYLSEK
	SYGYWGQGTMVTVSS
huE07	SEQ ID NO: 239
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues )
	SEQ ID NO:240
	X1 is AS
	X1QLQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKGREFVSAIRWI
	GDATYYAESVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTSVTSYLSEK
	SYNYWGQGTMVTVSS
E15	SEQ ID NO: 241
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues )
	SEQ ID NO: 242
	X1 is AS
	X1QVQLQESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI
	GNSAYYADSVKGRFTLSGDNAKNTLYLQMNSLKPEDTAVYYCAAKYYTDSYYAAA
	SYAYWGQGTQVTVSS
huE15	SEQ ID NO: 243
	EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWIG
	NSAYYADSVKGRFTLSGDNSKNTLYLQMNSLRAEDTAVYYCAAKYYTDSYYAAAS
	YAYWGQGTLVTVSS
F09	SEQ ID NO: 244
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues )
	SEQ ID NO: 245
	X1 is AS
	X1QVQLQESGGGLVQAGGSLSLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI
	GSATDYADSVRGRFTISGDNAKNTVYLLMNNLKPEDTAVYYCAARRSPMSRTSVL
	QYDYWGQGTQVTVSS
huF09	SEQ ID NO: 246
	EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWIG
	SATDYADSVRGRFTISGDNSKNTVYLQMNSLRAEDTAVYYCAARRSPMSRTSVLQ
	YDYWGQGTLVTVSS
F10	SEQ ID NO: 247
	EVQLVESGGGLVQAGDSLRLSCAASGRTFSAYGMGWFRQAPGKEREFVAAIRWIG
	DSTYYADSVKGRFTISKDSAKNTLYLQMSSLKPEDTAVYYCAAKTSVTSYLSEKA
	YNYWGQGTQVTVSS
huF10	SEQ ID NO: 248
	EVQLVESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKEREFVAAIRWIG
	DSTYYADSVKGRFTISKDSSKNTLYLQMNSLRAEDTAVYYCAAKTSVTSYLSEKA
	YNYWGQGTMVTVSS
F11	SEQ ID NO: 249
con	EX1QLX2ESGGGLVQX3GGSLRLSCAX4SGRTFSSHTVGWFRQAPGKX5REFVX6AI
	TWNGDTTYFGDFVEGRFX7ISRDX8X9KNTLYLX10MNX11LX12X13EDTAVYYCAAA
	TGQVWSLQYLRESSYAYWGQGTX14VTVSS
	X1 is L or V
	X2 is L or V
	X3 is A or P
	X4 is A or N
	X5 is E or G
	X6 is A or E
	X7 is S or T
	X8 is N or S
	X9 is A or S
	X10 is E or Q
	X11 is K or S
	X12 is K or R
	X13 is A or P
	X14 is L or Q
F11	SEQ ID NO: 250
	ELQLVESGGGLVQAGGSLRLSCANSGRTFSSHTVGWFRQAPGKEREFVAAITWNG
	DTTYFGDFVEGRFSISRDSAKNTLYLEMNKLKPEDTAVYYCAAATGQVWSLQYLR
	ESSYAYWGQGTQVTVSS
huF11	SEQ ID NO: 251
	EVQLLESGGGLVQPGGSLRLSCAASGRTFSSHTVGWFRQAPGKGREFVAAITWNG
	DTTYFGDFVEGRETISRDNSKNTLYLQMNSLRAEDTAVYYCAAATGQVWSLQYLR
	ESSYAYWGQGTLVTVSS
huF11	SEQ ID NO: 252
	ELQLLESGGGLVQPGGSLRLSCAASGRTFSSHTVGWFRQAPGKGREFVSAITWNG
	DTTYFGDFVEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAATGQVWSLQYLR
	ESSYAYWGQGTLVTVSS
huF11	SEQ ID NO: 752
	EVQLLESGGGLVQPGGSLRLSCANSGRTFSSHTVGWFRQAPGKGREFVSAITWNG
	DTTYFGDFVEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAATGQVWSLQYLR
	ESSYAYWGQGTLVTVSS
huF11	SEQ ID NO: 753
	EVQLLESGGGLVQPGGSLRLSCAASGRTFSSHTVGWFRQAPGKGREFVSAITWNG
	DTTYFGDFVEGRFTISRDSSKNTLYLQMNSLRAEDTAVYYCAAATGQVWSLQYLR
	ESSYAYWGQGTLVTVSS
huF11	SEQ ID NO: 754
	EVQLLESGGGLVQPGGSLRLSCAASGRTFSSHTVGWFRQAPGKGREFVAAITWNG
	DTTYFGDFVEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAATGQVWSLQYLR
	ESSYAYWGQGTLVTVSS
huF11	SEQ ID NO: 755
	ELQLLESGGGLVQPGGSLRLSCAASGRTFSSHTVGWFRQAPGKGREFVSAITWNG
	DTTYFGDFVEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAATGQVWSLQYLR
	ESSYAYWGQGTLVTVSS
F21	SEQ ID NO: 253
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues )
	SEQ ID NO: 254
	X1 is AS
	X1QVQLVESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI
	GNSTYYADSVKGRFTLSGDNAKNTLYLQMNSLKPEDTAVYYCAAKYYTDSYYAAA
	SYAYWGQGTQVTVSS
huF21	SEQ ID NO: 255
	EVQLVESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWIG
	NSTYYADSVKGRFTLSGDNSKNTLYLQMNSLRAEDTAVYYCAAKYYTDSYYAAAS
	YAYWGQGTLVTVSS
G22	SEQ ID NO: 256
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	SEQ ID NO: 257
	X1 is AS
	X1QLQLVESGGGLVQAGGSLKLSCTASGRTEDGYGMGWFRQAPGKEREFVSAINWI
	YGATYYADSVKGRFAVSRDKAKGTMYLQMNSLKPEDTAVYYCAAKINAGSYENIG
	SFGSWGQGTQVTVSS
huG22	SEQ ID NO: 258
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues )
	SEQ ID NO: 259
	X1 is AS
	X1QLQLVESGGGLVQPGGSLRLSCSASGRTEDGYGMGWFRQAPGKEREFVSAINWI
	YGATYYADSVKGRFTVSRDKSKNTMYLQMNSLRAEDTAVYYCAAKINAGSYFNIG
	SFGSWGQGTLVTVSS
G23	SEQ ID NO: 260
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues )
	SEQ ID NO: 261
	X1 is AS
	X1QLQLVESGGGLVQAGGSLRLSCAASGRTFSDDTVGWFRQAPGKEREFVAAITWN
	GDTTYYGDSVKGRFTISRDSAKNTLYLDMNKLEPEDTAVYYCAAAAGQDWSLGYL
	RESSYAYWGQGTQVTVSS
huG23	SEQ ID NO: 262
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues )
	SEQ ID NO: 263
	X1 is AS
	X1QLQLVESGGGLVQPGGSLRLSCSASGRTFSDDTVGWFRQAPGKEREFVAAITWN
	GDTTYYGDSVKGRFTISRDSSKNTLYLQMNSLRAEDTAVYYCAAAAGQDWSLGYL
	RESSYAYWGQGTLVTVSS
H22	SEQ ID NO: 264
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues )
	SEQ ID NO: 265
	X1 is AS
	X1QVQLQESGGGLVQAGDSLRLSCAASGRTFSGYTVGWFRQAPGKEREFVAAITWN
	GDTTYFGDSVKGRFTISRDSAKNTLYLEMNKLKPEDTAVYYCAAATGQEWSLQYL
	RESSYAYWGQGTQVTVSS
huH22	SEQ ID NO: 266
	EVQLLESGGGLVQPGGSLRLSCAASGRTFSGYTVGWFRQAPGKEREFVAAITWNG
	DTTYFGDSVKGRFTISRDSSKNTLYLQMNSLRAEDTAVYYCAAATGQEWSLQYLR
	ESSYAYWGQGTLVTVSS
I04	SEQ ID NO: 267
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues )
	SEQ ID NO: 268
	X1 is AS
	X1QVQLVESGGGLVQAGGSLRLSCAASGRTFSNYAMAWFRQAPGKEREFVSAINWF
	GRATEYADSVKDRETTSGDSAKNTVYLQMNSLKPEDTAVYYCAARTKVITGRRNQ
	AEYDYWGQGTQVTVSS
huI04	SEQ ID NO: 269
	EVQLVESGGGLVQPGGSLRLSCAASGRTFSNYAMAWFRQAPGKEREFVSAINWEG
	RATEYADSVKDRFTTSGDSSKNTVYLQMNSLRAEDTAVYYCAARTKVTTGRRNQA
	EYDYWGQGTLVTVSS
J13	SEQ ID NO: 270
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues )
	SEQ ID NO: 271
	X1 is AS
	X1QVQLVESGGGSVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKERGFVATINWI
	PGNTYYADSVKGRFTISGEEDKNTVYLQMDNLKPEDTAVYYCAARRRIDNYYRAS
	EYDYWGQGTQVTVSS
huJ13	SEQ ID NO: 272
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues )
	SEQ ID NO: 273
	X1 is AS
	X1QVQLVESGGGVVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVATINWI
	PGNTYYADSVKGRFTISGDESKNTVYLQMNSLRAEDTAVYYCAARRRIDNYYRAS
	EYDYWGQGTLVTVSS
J24	SEQ ID NO: 274
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues )
	SEQ ID NO: 275
	X1 is AS
	X1QVQLQESGGGSVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKERGEVATIIGW
	IPGNTYYADSVKGRFTITGDKDKNTVYLQMDNLKPEDTAVYYCAARRRIDSYYRA
	SEYDYWGQGTQVTVSS
huJ24	SEQ ID NO: 276
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues )
	SEQ ID NO: 277
	X1 is AS
	X1QVQLVESGGGVVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVATIIGW
	IPGNTYYADSVKGRFTISGDKSKNTVYLQMNSLRAEDTAVYYCAARRRIDSYYRA
	SEYDYWGQGTLVTVSS
L05	SEQ ID NO: 278
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues )
	SEQ ID NO: 279
	X1 is AS
	X1QVQLLESGGGLVQAGGSLKLSCTNSGRTFSGYGMGWFRQPPGKEREFVSSINWI
	YGATYYSDSVKGRFALSRDKAKNTVYLQMDSLKPEDTAVYYCAAKINGESYENTG
	SFGSWGQGTQVTVSS
huL05	SEQ ID NO: 280
	EVQLLESGGGLVQPGGSLRLSCAASGRTFSGYGMGWFRQAPGKEREFVSSINWIY
	GATYYSDSVKGRFTLSRDKSKNTVYLQMNSLRAEDTAVYYCAAKINGESYENTGS
	FGSWGQGTLVTVSS
L11	SEQ ID NO: 281
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues )
	SEQ ID NO: 282
	X1 is AS
	X1QLQLQESGGGLVQAGGSLKLSCTNSGRTFSGYGMGWFRQAPGKEREFVSAINWI
	YGATYYADSVKGRFAVSGDKAKNTLYLQMNSLKPEDTAVYYCAAKINGGSYENIG
	SFGSWGQGTQVTVSS
huL11	SEQ ID NO: 283
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues )
	SEQ ID NO: 284
	X1 is AS
	X1QLQLVESGGGLVQPGGSLRLSCSASGRTFSGYGMGWFRQAPGKEREFVSAINWI
	YGATYYADSVKGRFTVSGDKSKNTLYLQMNSLRAEDTAVYYCAAKINGGSYFNIG
	SFGSWGQGTLVTVSS
N16	SEQ ID NO: 285
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues )
	SEQ ID NO: 286
	X1 is AS
	X1QVQLVESGGGLVQAGGSLRLSCAASGGTFSYYGMGWFRQAPGKEREFVAAIRWI
	GGDTYYADSVKGRFTISKDNAKNTLYLQMSSLKPEDTAVYYCAAKTSVTSYLSEK
	SYNYWGQGTQVTVSS
huN16	SEQ ID NO: 287
	EVQLVESGGGLVQPGGSLRLSCAASGGTFSYYGMGWFRQAPGKEREFVAAIRWIG
	GDTYYADSVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTSVTSYLSEKS
	YNYWGQGTLVTVSS

[0275] In some embodiments, the VHH binds to an epitope on IL 10Rα comprising contact amino acid residues W33, E35, E37, H40, 142, H44, T46, L79, S80, T124, A170, R172, F178, F180, H182, Q204, K215, M217, W218, K220 and E221, wherein the amino acid residue positions are with respect to SEQ ID NO: 711 (e.g., VHH E07). In some embodiments, the VHH binds to an epitope on IL 10Rα comprising contact amino acid residues I169, I171, K173, F178, F180, T181, H182, K183, K186, F190, L192, L193, S195, E197 and F201, wherein the amino acid residue positions are with respect to SEQ ID NO: 711 (e.g., VHH F11).

Human IL-10RA amino acid sequence - NP_001549.2/Uniprot Q13651
(SEQ ID NO: 711)
1	MLPCLVVLLA ALLSLRLGSD AHGTELPSPP SVWFEAEFFH HILHWTPIPN QSESTCYEVA
61	LLRYGIESWN SISNCSQTLS YDLTAVILDL YHSNGYRARV RAVDGSRHSN WTVINTRFSV
121	DEVTLTVGSV NLEIHNGFIL GKIQLPRPKM APANDTYESI FSHFREYEIA IRKVPGNFTF
181	THKKVKHENF SLLTSGEVGE FCVQVKPSVA SRSNKGMWSK EECISLTRQY FTVINVIIFF
241	AFVLLLSGAL AYCLALQLYV RRRKKLPSVL LFKKPSPFIF ISQRPSPETQ DTIHPLDEEA
301	FLKVSPELKN LDLHGSTDSG FGSTKPSLQT EEPQFLLPDP HPQADRILGN REPPVLGDSC
361	SSGSSNSTDS GICLQEPSLS PSTGPTWEQQ VGSNSRGQDD SGIDLVQNSE GRAGDTQGGS
421	ALGHHSPPEP EVPGEEDPAA VAFQGYLRQT RCAEEKATKT GCLEEESPLT DGLGPKFGRC
481	LVDEAGLHPP ALAKGYLKQD PLEMTLASSG APTGQWNQPT EEWSLLALSS CSDLGISDWS
541	FAHDLAPLGC VAAPGGLLGS FNSDLVTLPL ISSLQSSE

[0276] Provided are single immunoglobulin variable domain (VHH) binders that specifically binds to the extracellular domain of interleukin-10 receptor (IL-10R) beta subunit (IL-10Rβ). Illustrative IL-10Rβ single immunoglobulin variable domain (VHH) binders are provided in Tables C1-C4 and D, below. The IL-10Rβ single immunoglobulin variable domain (VHH) binders can be humanized and incorporated into antibodies, including multispecific antibodies, e.g., bispecific antibodies, e.g., comprising a human Fc domain, e.g., a human IgG1 or a human IgG4. The IL-10Rβ single immunoglobulin variable domain (VHH) binders described herein are suitable to use with an antigen binding domain that specifically binds to the extracellular domain of interleukin-10 receptor (IL-10R) alpha subunit (IL 10Rα), including the IL-10Rα single immunoglobulin variable domain (VHH) binders described herein.

[0277] In some embodiments, the VHH binds to IL 10Rβ with an equilibrium dissociation constant (K_D) of greater than of greater than about 10 nM, e.g., greater than about 20 nM, greater than about 30 nM, greater than about 40 nM or greater than about 50 nM.

[0278] In some embodiments, the VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Kabat, respectively:

• • [0279] 1) SEQ ID NOs: 288, 289 and 290; (A02)
  • [0280] 2) SEQ ID NOs: 291, 292 and 293; (A05)
  • [0281] 3) SEQ ID NOs: 291, 294 and 295; (huA05)
  • [0282] 4) SEQ ID NOs: 296, 297 and 298; (huA05)
  • [0283] 5) SEQ ID NOs: 299, 300 and 301; (B10)
  • [0284] 6) SEQ ID NOs: 302, 303 and 304; (B12)
  • [0285] 7) SEQ ID NOs: 305, 306 and 307; (C01)
  • [0286] 8) SEQ ID NOs: 296, 308 and 309; (C04)
  • [0287] 9) SEQ ID NOs: 310, 311 and 312; (C10)
  • [0288] 10) SEQ ID NOs: 302, 303 and 313; (D01)
  • [0289] 11) SEQ ID NOs: 314, 315 and 316; (E08)
  • [0290] 12) SEQ ID NOs: 317, 318 and 319; (E10)
  • [0291] 13) SEQ ID NOs: 320, 321 and 322; (G01) or
  • [0292] 14) SEQ ID NOs: 323, 324 and 325 (G02).

[0293] In some embodiments, the VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to IMGT, respectively:

• • [0294] 1) SEQ ID NOs: 326, 327 and 328; (A02)
  • [0295] 2) SEQ ID NOs: 329, 330 and 331; (A05)
  • [0296] 3) SEQ ID NOs: 329, 332 and 333; (huA05)
  • [0297] 4) SEQ ID NOs: 334, 335 and 336; (huA05)
  • [0298] 5) SEQ ID NOs: 337, 338 and 339; (B10)
  • [0299] 6) SEQ ID NOs: 340, 341 and 342; (B12)
  • [0300] 7) SEQ ID NOs: 343, 344 and 345; (C01)
  • [0301] 8) SEQ ID NOs: 346, 347 and 348; (C04)
  • [0302] 9) SEQ ID NOs: 349, 350 and 351; (C10)
  • [0303] 10) SEQ ID NOs: 352, 341 and 353; (D01)
  • [0304] 11) SEQ ID NOs: 354, 355 and 356; (E08)
  • [0305] 12) SEQ ID NOs: 357, 358 and 359; (E10)
  • [0306] 13) SEQ ID NOs: 360, 361 and 362; (G01) or
  • [0307] 14) SEQ ID NOs: 363, 364 and 365 (G02).

[0308] In some embodiments, the VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Chothia, respectively:

• • [0309] 1) SEQ ID NOs: 366, 367 and 368; (A02)
  • [0310] 2) SEQ ID NOs: 369, 370 and 371; (A05)
  • [0311] 3) SEQ ID NOs: 369, 372 and 373; (huA05)
  • [0312] 4) SEQ ID NOs: 374, 375 and 376; (huA05)
  • [0313] 5) SEQ ID NOs: 377, 378 and 379; (B10)
  • [0314] 6) SEQ ID NOs: 380, 381 and 382; (B12)
  • [0315] 7) SEQ ID NOs: 383, 384 and 385; (C01)
  • [0316] 8) SEQ ID NOs: 386, 387 and 388; (C04)
  • [0317] 9) SEQ ID NOs: 389, 390 and 391; (C10)
  • [0318] 10) SEQ ID NOs: 392, 381 and 393; (D01)
  • [0319] 11) SEQ ID NOs: 394, 395 and 396; (E08)
  • [0320] 12) SEQ ID NOs: 397, 398 and 399; (E10)
  • [0321] 13) SEQ ID NOs: 400, 401 and 402; (G01) or
  • [0322] 14) SEQ ID NOs: 403, 404 and 405 (G02).

[0323] In some embodiments, the VHH comprises a complementarity determining region (CDR) 1, a VHH-CDR2, and a VHH-CDR3 comprising the following amino acid sequences, according to Honegger, respectively:

• • [0324] 1) SEQ ID NOs: 406, 407 and 408; (A02)
  • [0325] 2) SEQ ID NOs: 409, 410 and 411; (A05)
  • [0326] 3) SEQ ID NOs: 409, 412 and 413; (huA05)
  • [0327] 4) SEQ ID NOs: 414, 415 and 416; (huA05)
  • [0328] 5) SEQ ID NOs: 417, 418 and 419; (B10)
  • [0329] 6) SEQ ID NOs: 420, 421 and 422; (B12)
  • [0330] 7) SEQ ID NOs: 423, 424 and 425; (C01)
  • [0331] 8) SEQ ID NOs: 426, 427 and 428; (C04)
  • [0332] 9) SEQ ID NOs: 429, 430 and 431; (C10)
  • [0333] 10) SEQ ID NOs: 432, 421 and 433; (D01)
  • [0334] 11) SEQ ID NOs: 434, 435 and 436; (E08)
  • [0335] 12) SEQ ID NOs: 437, 438 and 439; (E10)
  • [0336] 13) SEQ ID NOs: 440, 441 and 442; (G01) or
  • [0337] 14) SEQ ID NOs: 443, 444 and 445 (G02).

[0338] In some embodiments, the VHH comprises the amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the full length of the amino acid sequence of any one of SEQ ID NOs: 448, 449, 455 and 460. In some embodiments, the VHH comprises the amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the full length of the amino acid sequence of any one of SEQ ID NOs: 446-447, 450-454, 456-459 and 461-474.

[0339] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rβ comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0340] 1) SEQ ID NOs: 288, 289 and 290 (according to Kabat);
  • [0341] 2) SEQ ID NOs: 326, 327 and 328 (according to IMGT);
  • [0342] 3) SEQ ID NOs: 366, 367 and 368 (according to Chothia); or
  • [0343] 4) SEQ ID NOs: 406, 407 and 408 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rβ, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 446-447 (VHH A02).

[0344] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rβ comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0345] 1) SEQ ID NOs: 291, 292 and 293; or 291, 294 and 295; or 296, 297 and 298 (according to Kabat);
  • [0346] 2) SEQ ID NOs: 329, 330 and 331; or 329, 332 and 333; or 334, 335 and 336 (according to IMGT);
  • [0347] 3) SEQ ID NOs: 369, 370 and 371; or 369, 372 and 373; or 374, 375 and 376 (according to Chothia); or
  • [0348] 4) SEQ ID NOs: 409, 410 and 411; 409, 412 and 413; or 414, 415 and 416 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rβ, wherein the VH and VL comprise, respectively, the amino acid sequences set forth below, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 448-452 (VHH A05).

[0349] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rβ comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0350] 1) SEQ ID NOs: 299, 300 and 301 (according to Kabat);
  • [0351] 2) SEQ ID NOs: 337, 338 and 339 (according to IMGT);
  • [0352] 3) SEQ ID NOs: 377, 378 and 379 (according to Chothia); or
  • [0353] 4) SEQ ID NOs: 417, 418 and 419 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rβ, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 453-454, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 453-454 (VHH B10).

[0354] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rβ comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0355] 1) SEQ ID NOs: 302, 303 and 304 (according to Kabat);
  • [0356] 2) SEQ ID NOs: 340, 341 and 342 (according to IMGT);
  • [0357] 3) SEQ ID NOs: 380, 381 and 382 (according to Chothia); or
  • [0358] 4) SEQ ID NOs: 420, 421 and 422 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rβ, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 455-457, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 455-457 (VHH B12).

[0359] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rβ comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0360] 1) SEQ ID NOs: 305, 306 and 307 (according to Kabat);
  • [0361] 2) SEQ ID NOs: 343, 344 and 345 (according to IMGT);
  • [0362] 3) SEQ ID NOs: 383, 384 and 385 (according to Chothia); or
  • [0363] 4) SEQ ID NOs: 423, 424 and 425 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rβ, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 458-459, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 458-459 (VHH C01).

[0364] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rβ comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0365] 1) SEQ ID NOs: 296, 308 and 309 (according to Kabat);
  • [0366] 2) SEQ ID NOs: 346, 347 and 348 (according to IMGT);
  • [0367] 3) SEQ ID NOs: 386, 387 and 388 (according to Chothia); or
  • [0368] 4) SEQ ID NOs: 426, 427 and 428 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rβ, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 460-462, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 460-462 (VHH C04).

[0369] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rβ comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0370] 1) SEQ ID NOs: 310, 311 and 312 (according to Kabat);
  • [0371] 2) SEQ ID NOs: 349, 350 and 351 (according to IMGT);
  • [0372] 3) SEQ ID NOs: 389, 390 and 391 (according to Chothia); or
  • [0373] 4) SEQ ID NOs: 429, 430 and 431 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rβ, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 463-464, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 463-464 (VHH C10).

[0374] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rβ comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0375] 1) SEQ ID NOs: 302, 303 and 313 (according to Kabat);
  • [0376] 2) SEQ ID NOs: 352, 341 and 353 (according to IMGT);
  • [0377] 3) SEQ ID NOs: 392, 381 and 393 (according to Chothia); or
  • [0378] 4) SEQ ID NOs: 432, 421 and 433 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rβ, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 455 and 465-466, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 455 and 465-466 (VHH D01).

[0379] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rβ comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0380] 1) SEQ ID NOs: 314, 315 and 316 (according to Kabat);
  • [0381] 2) SEQ ID NOs: 354, 355 and 356 (according to IMGT);
  • [0382] 3) SEQ ID NOs: 394, 395 and 396 (according to Chothia); or
  • [0383] 4) SEQ ID NOs: 434, 435 and 436 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rβ, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 467-468, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 467-468 (VHH E08).

[0384] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rβ comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0385] 1) SEQ ID NOs: 317, 318 and 319 (according to Kabat);
  • [0386] 2) SEQ ID NOs: 357, 358 and 359 (according to IMGT);
  • [0387] 3) SEQ ID NOs: 397, 398 and 399 (according to Chothia); or
  • [0388] 4) SEQ ID NOs: 437, 438 and 439 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rβ, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 469-470, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 469-470 (VHH E10).

[0389] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rβ comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0390] 1) SEQ ID NOs: 320, 321 and 322 (according to Kabat);
  • [0391] 2) SEQ ID NOs: 360, 361 and 362 (according to IMGT);
  • [0392] 3) SEQ ID NOs: 400, 401 and 402 (according to Chothia); or
  • [0393] 4) SEQ ID NOs: 440, 441 and 442 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rβ, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 471-472, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 471-472 (VHH G01).

[0394] In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rβ comprising a heavy chain variable region (VH)-complementarity determining region (CDR) 1; a VH-CDR2, a VH-CDR3, a light chain variable region (VL)-CDR1, a VL-CDR2, and a VL-CDR3 comprising, respectively, the amino acid sequences of:

• • [0395] 1) SEQ ID NOs: 323, 324 and 325 (according to Kabat);
  • [0396] 2) SEQ ID NOs: 363, 364 and 365 (according to IMGT);
  • [0397] 3) SEQ ID NOs: 403, 404 and 405 (according to Chothia); or
  • [0398] 4) SEQ ID NOs: 443, 444 and 445 (according to Honegger).
    In some embodiments, provided is a single domain antibody (sdAb) or antigen-binding fragment thereof (VHH) that specifically binds to IL-10Rβ, wherein the VH and VL comprise, respectively, the amino acid sequences set forth in any one of SEQ ID NOs: 473-474, or an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to, respectively, the full length of the amino acid sequence set forth in any one of SEQ ID NOs: 473-474 (VHH G02).

[0399] Generally, the herein described VHH that bind to IL-10Rβ bind to both human IL-10Rβ and cynomolgus IL-10Rβ, within a 10-fold affinity difference, e.g., within a 5-fold or within a 3-fold affinity difference (e.g., as determined by SPR and expressed as an equilibrium dissociation constant (KD)). Amino acid sequences of complementarity determining regions (CDRs) of illustrative VHH that bind to IL-10Rβ are provided in Tables C1-C4. Amino acid sequences of variable regions of illustrative VHH that bind to IL-10Rβ are provided in Table D.

TABLE C1
Illustrative IL-10Rβ Single Immunoglobulin Variable
domain (VHH) Binder CDR amino acid sequences
(according to Kabat)
VHH
name	VHH - CDR1	VHH - CDR2	VHH - CDR3
A02	EGVIG	CISARDGSTHYANAVKG	SLWGLGCKREEDYDY
	SEQ ID NO: 288	SEQ ID NO: 289	SEQ ID NO: 290
A05	YPTIG	CISASDGSTHYADSVKG	SLWGLGCKSEADYDY
	SEQ ID NO: 291	SEQ ID NO: 292	SEQ ID NO: 293
huA05	YPTIG	AISASDASTHYADAVKG	SLHGLGAKSEADYDY
	SEQ ID NO: 291	SEQ ID NO: 294	SEQ ID NO: 295
huA05	YSTIG	CISASEGSTHYADAVKG	SLHGLGCKSEADYDY
	SEQ ID NO: 296	SEQ ID NO: 297	SEQ ID NO: 298
B10	LDHMG	YMFTDGRTQYGEPVKG	QGI
	SEQ ID NO: 299	SEQ ID NO: 300	SEQ ID NO: 301
B12	ISTMA	RIIWSSGATNYADSVKG	AISQTRGTFWTY
	SEQ ID NO: 302	SEQ ID NO: 303	SEQ ID NO: 304
C01	SYGMS	QINTGGGSTSYADSVKG	SSRLYSSSWYGSREYDY
	SEQ ID NO: 305	SEQ ID NO: 306	SEQ ID NO: 307
C04	YSTIG	CISSSGRGVNANYIDSVRG	NCWRLTSPAADN
	SEQ ID NO: 296	SEQ ID NO: 308	SEQ ID NO: 309
C10	YYSIS	CISRSGGRINYADSVKG	TRLPLSGLCVIGSSDNAL
	SEQ ID NO: 310	SEQ ID NO: 311	SEQ ID NO: 312
D01	ISTMA	RIIWSSGATNYADSVKG	AISQRSGTFWTY
	SEQ ID NO: 302	SEQ ID NO: 303	SEQ ID NO: 313
E08	GYAVA	SISSSGIRTNYKDSVKG	KRGPILFGTYTH
	SEQ ID NO: 314	SEQ ID NO: 315	SEQ ID NO: 316
E10	IFAMG	AVTLRSGITSYLDSVKG	RDYRSRDY
	SEQ ID NO: 317	SEQ ID NO: 318	SEQ ID NO: 319
G01	RYAIG	CITTSGGGSNYADSVKG	TP LNYYCGIDENPDKYDY
	SEQ ID NO: 320	SEQ ID NO: 321	SEQ ID NO: 322
G02	FAPMG	AINRDFSTYYANSVKG	SPGRIWSGTILPPAPDRVVS
	SEQ ID NO: 323	SEQ ID NO: 324	SEQ ID NO: 325

TABLE C2
Illustrative IL-10Rβ Single Immunoglobulin
Variable domain (VHH) Binder CDR amino acid sequences
(according to IMGT)
VHH
name	VHH - CDR1	VHH - CDR2	VHH - CDR3
A02	GISLDEGV	ISARDGST	AASLWGLGCKREEDYDY
	SEQ ID NO: 326	SEQ ID NO: 327	SEQ ID NO: 328
A05	GNSLDYPT	ISASDGST	AASLWGLGCKSEADYDY
	SEQ ID NO: 329	SEQ ID NO: 330	SEQ ID NO: 331
huA05	GNSLDYPT	ISASDAST	AASLHGLGAKSEADYDY
	SEQ ID NO: 329	SEQ ID NO: 332	SEQ ID NO: 333
huA05	GNSLDYST	ISASEGST	AASLHGLGCKSEADYDY
	SEQ ID NO: 334	SEQ ID NO: 335	SEQ ID NO: 336
B10	GSTSTLDH	MFTDGRT	GAQGI
	SEQ ID NO: 337	SEQ ID NO: 338	SEQ ID NO: 339
B12	GSFSSIST	IIWSSGAT	SGAISQTRGTFWTY
	SEQ ID NO: 340	SEQ ID NO: 341	SEQ ID NO: 342
C01	GFAFSSYG	INTGGGST	AASSRLYSSSWYGSREYDY
	SEQ ID NO: 343	SEQ ID NO: 344	SEQ ID NO: 345
C04	GFTSPYST	ISSSGRGVNA	ATNCWRLTSPAADN
	SEQ ID NO: 346	SEQ ID NO: 347	SEQ ID NO: 348
C10	GLTLDYYS	ISRSGGRI	AATRLPLSGLCVIGSSDNAL
	SEQ ID NO: 349	SEQ ID NO: 350	SEQ ID NO: 351
D01	GNFSSIST	IIWSSGAT	AGAISQRSGTFWTY
	SEQ ID NO: 352	SEQ ID NO: 341	SEQ ID NO: 353
E08	ISTLNGYA	ISSSGIRT	AAKRGP ILFGTYTH
	SEQ ID NO: 354	SEQ ID NO: 355	SEQ ID NO: 356
E10	GSALSIFA	VTLRSGIT	NVRDYRSRDY
	SEQ ID NO: 357	SEQ ID NO: 358	SEQ ID NO: 359
G01	GFTVDRYA	ITTSGGGS	AATPLNYYCGIDENPDKYDY
	SEQ ID NO: 360	SEQ ID NO: 361	SEQ ID NO: 362
G02	ETIINFAP	INRDEST	AASPGRIWSGTILPPAPDRVVS
	SEQ ID NO: 363	SEQ ID NO: 364	SEQ ID NO: 365

TABLE C3
Illustrative IL-10Rβ Single Immunoglobulin
Variable domain (VHH) Binder CDR amino acid sequences
(according to Chothia)
VHH
name	VHH - CDR1	VHH - CDR2	VHH - CDR3
A02	GISLDEG	ARDG	LWGLGCKREEDYD
	SEQ ID NO: 366	SEQ ID NO: 367	SEQ ID NO: 368
A05	GNSLDYP	ASDG	LWGLGCKSEADYD
	SEQ ID NO: 369	SEQ ID NO: 370	SEQ ID NO: 371
huA05	GNSLDYP	ASDA	LHGLGAKSEADYD
	SEQ ID NO: 369	SEQ ID NO: 372	SEQ ID NO: 373
huA05	GNSLDYS	ASEG	LHGLGCKSEADYD
	SEQ ID NO: 374	SEQ ID NO: 375	SEQ ID NO: 376
B10	GSTSTLD	TDG	G
	SEQ ID NO: 377	SEQ ID NO: 378	SEQ ID NO: 379
B12	GSFSSIS	WSSG	ISQTRGTFWT
	SEQ ID NO: 380	SEQ ID NO: 381	SEQ ID NO: 382
C01	GFAFSSY	TGGG	SRLYSSSWYGSREYD
	SEQ ID NO: 383	SEQ ID NO: 384	SEQ ID NO: 385
C04	GFTSPYS	SSGRGV	CWRLTSPAAD
	SEQ ID NO: 386	SEQ ID NO: 387	SEQ ID NO: 388
C10	GLTLDYY	RSGG	RLPLSGLCVIGSSDNA
	SEQ ID NO: 389	SEQ ID NO: 390	SEQ ID NO: 391
D01	GNESSIS	WSSG	ISQRSGTFWT
	SEQ ID NO: 392	SEQ ID NO: 381	SEQ ID NO: 393
E08	ISTLNGY	SSGI	RGP ILFGTYT
	SEQ ID NO: 394	SEQ ID NO: 395	SEQ ID NO: 396
E10	GSALSIF	LRSG	DYRSRD
	SEQ ID NO: 397	SEQ ID NO: 398	SEQ ID NO: 399
G01	GFTVDRY	TSGG	PLNYYCGIDENPDKYD
	SEQ ID NO: 400	SEQ ID NO: 401	SEQ ID NO: 402
G02	ETIINFA	RDF	PGRIWSGTILPPAPDRVV
	SEQ ID NO: 403	SEQ ID NO: 404	SEQ ID NO: 405

TABLE C4
Illustrative IL-10Rβ Single Immunoglobulin Variable
domain (VHH) Binder CDR amino acid sequences
(according to Honegger)
VHH
name	VHH - CDR1	VHH - CDR2	VHH - CDR3
A02	ASGISLDEGV	ISARDGSTHYANAVKGR	SLWGLGCKREEDYD
	SEQ ID NO: 406	SEQ ID NO: 407	SEQ ID NO: 408
A05	ASGNSLDYPT	ISASDGSTHYADSVKGR	SLWGLGCKSEADYD
	SEQ ID NO: 409	SEQ ID NO: 410	SEQ ID NO: 411
huA05	ASGNSLDYPT	ISASDASTHYADAVKGR	SLHGLGAKSEADYD
	SEQ ID NO: 409	SEQ ID NO: 412	SEQ ID NO: 413
huA05	ASGNSLDYST	ISASEGSTHYADAVKGR	SLHGLGCKSEADYD
	SEQ ID NO: 414	SEQ ID NO: 415	SEQ ID NO: 416
B10	ASGSTSTLDH	MFTDGRTQYGEPVKGR	QG
	SEQ ID NO: 417	SEQ ID NO: 418	SEQ ID NO: 419
B12	ASGSFSSIST	IIWSSGATNYADSVKGR	AISQTRGTFWT
	SEQ ID NO: 420	SEQ ID NO: 421	SEQ ID NO: 422
C01	ASGFAFSSYG	INTGGGSTSYADSVKGR	SSRLYSSSWYGSREYD
	SEQ ID NO: 423	SEQ ID NO: 424	SEQ ID NO: 425
C04	ASGFTSPYST	ISSSGRGVNANYIDSVRGR	NCWRLTSPAAD
	SEQ ID NO: 426	SEQ ID NO: 427	SEQ ID NO: 428
C10	ASGLTLDYYS	ISRSGGRINYADSVKGR	TRLPLSGLCVIGSSDNA
	SEQ ID NO: 429	SEQ ID NO: 430	SEQ ID NO: 431
D01	ASGNESSIST	IIWSSGATNYADSVKGR	AISQRSGTFWT
	SEQ ID NO: 432	SEQ ID NO: 421	SEQ ID NO: 433
E08	SSISTLNGYA	ISSSGIRTNYKDSVKGR	KRGP ILFGTYT
	SEQ ID NO: 434	SEQ ID NO: 435	SEQ ID NO: 436
E10	ASGSALSIFA	VTLRSGITSYLDSVKGR	RDYRSRD
	SEQ ID NO: 437	SEQ ID NO: 438	SEQ ID NO: 439
G01	ASGFTVDRYA	ITTSGGGSNYADSVKGR	TPLNYYCGIDENPDKYD
	SEQ ID NO: 440	SEQ ID NO: 441	SEQ ID NO: 442
G02	ASETIINFAP	INRDFSTYYANSVKGR	SPGRIWSGTILPPAPDRVV
	SEQ ID NO: 443	SEQ ID NO: 444	SEQ ID NO: 445

TABLE D
Illustrative IL-10Rβ Single Immunoglobulin Variable
Domain (VHH) amino acid sequences
VHH
name	VHH amino acid sequence
A02	SEQ ID NO: 446
	QVQLQESGGGLVQPGGSLKLSCAASGISLDEGVIGWERRAPGKEREGVSCISARDG
	STHYANAVKGRFTISRDNTKNTVDLQMNNLEPEDAGRYYCAASLWGLGCKREEDYD
	YWGQGTQVTVSS
huA02	SEQ ID NO: 447
	EVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGWFRQAPGKEREGVSCISARDG
	STHYANAVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCAASLWGLGCKREEDYD
	YWGQGTLVTVSS
A05	SEQ ID NO: 448
con1	X1VQLX2ESGGGLVQPGGSLX3LSCAASGX4SLDX5X6X7IGWFRX8APGKX9X10EGVS
	X11ISAX12DX13STHYAX14X15VKGRFTISRDNX16KNTVX17LQMNX18LX19X20ED
	X21X22X23YYCAASLX24GLGX25KX26EX27DYDYWGQGTX28VTVSS
	X1 is E or Q
	X2 is L or Q
	X3 is K or R
	X4 is I or N
	X5 is E or Y
	X6 is G, P or S
	X7 is V or T
	X8 is Q or R
	X9 is E or G
	X10 is L or R
	X11 is A or C
	X12 is R or S
	X13 is A or G
	X14 is D or N
	X15 is A or S
	X16 is S or T
	X17 is D or Y
	X18 is N or S
	X19 is K or R
	X20 is A or P
	X21 is A or T
	X22 is A or G
	X23 is H or V
	X24 is H or W
	X25 is A or C
	X26 is R or S
	X27 is A or E
	X28 is L, M or Q
A05	SEQ ID NO: 449
con2	X1VQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGWFRQAPGKX2X3EGVSX4ISA
	SDX5STHYADX6VKGRFTISRDNX7KNTVX8LQMNX9LX10X11EDTX12X13YYCAASL
	X14GLGX15KSEADYDYWGQGTX16VTVSS
	X1 is E or Q
	X2 is E or G
	X3 is L or R
	X4 is A or C
	X5 is A or G
	X6 is A or S
	X7 is S or T
	X8 is D or Y
	X9 is N or S
	X10 is K or R
	X11 is A or P
	X12 is A or G
	X13 is H or V
	X14 is H or W
	X15 is A or C
	X16 is M or Q
A05	SEQ ID NO: 450
	QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGWFRQAPGKEREGVSCISASDG
	STHYADSVKGRFTISRDNTKNTVDLQMNNLKPEDTGHYYCAASLWGLGCKSEADYD
	YWGQGTQVTVSS
huA05	SEQ ID NO: 451
	EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGWFRQAPGKGLEGVSAISASDA
	STHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCAASLHGLGAKSEADYD
	YWGQGTMVTVSS
huA05	SEQ ID NO: 452
	EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGWFRQAPGKGLEGVSCISASEG
	STHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCAASLHGLGCKSEADYD
	YWGQGTMVTVSS
B10	SEQ ID NO: 453
	QVQLVESGGGVVQAGGSLRLSCAASGSTSTLDHMGWYRQAPGKSRELVGYMFTDGR
	TQYGEPVKGRFTVSRDNGRNTIFLQMNNLKLEDTAVYYCGAQGIWGQGTQVTVSS
huB10	SEQ ID NO: 454
	QVQLVESGGGVVQPGGSLRLSCAASGSTSTLDHMGWYRQAPGKSRELVGYMFTDGR
	TQYGEPVKGRFTVSRDNSKNTIYLQMNSLRAEDTAVYYCGAQGIWGQGTMVTVSS
B12	SEQ ID NO: 455
Con	X1VQLX2ESGGGLVX3X4GGSLRLSCAASGX5FSSISTMAWYRQX6PGKQREWX7ARI
w /	IWSSGATNYADSVKGRFTX8SRDNX9KNTMYLQMX10X11LX12X13EDTAAYX14CSGA
D01	ISQX15RGTFWTYX16SQGTX17VTVSS
	X1 is E or Q
	X2 is L, Q or V
	X3 is K or Q
	X4 is A or P
	X5 is N or S
	X6 is A or V
	X7 is L or V
	X8 is A or I
	X9 is A, S or T
	X10 is D or N
	X11 is R or S
	X12 is R or T
	X13 is A or P
	X14 is L or Y
	X15 is R or T
	X16 is K or W
	X17 is L or Q
B12	SEQ ID NO: 456
	EVQLVESGGGLVQAGGSLRLSCAASGSFSSISTMAWYRQVPGKQREWLARIIWSSG
	ATNYADSVKGRFTISRDNTKNTMYLQMDRLTPEDTAAYLCSGAISQTRGTFWTYKS
	QGTQVTVSS
huB12	SEQ ID NO: 457
	EVQLVESGGGLVQPGGSLRLSCAASGSFSSISTMAWYRQAPGKQREWLARIIWSSG
	ATNYADSVKGRFTISRDNSKNTMYLQMNSLRAEDTAVYYCSGAISQTRGTFWTYKG
	QGTLVTVSS
C01	SEQ ID NO: 458
	QVQLQESGGGLVQPGGSLRLSCAASGFAFSSYGMSWVRQAPGKGLEWVSQINTGGG
	STSYADSVKGRFTISRDNAKNTLYLQMNSLKPEDTAVYYCAASSRLYSSSWYGSRE
	YDYWGQGTQVTVSS
huC01	SEQ ID NO: 459
	EVQLLESGGGLVQPGGSLRLSCAASGFAFSSYGMSWVRQAPGKGLEWVSQINTGGG
	STSYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAASSRLYSSSWYGSRE
	YDYWGQGTLVTVSS
C04	SEQ ID NO: 460
con	X1VQLVESGGGLVQX2GGSLRLSCX3ASGFTSPYSTIGWFRQAPGKX4REGVACISS
	SGRGVNANYIDSVRGRFTISRDNX5NTVYLQMNX6LKX7X8DTAX9YYCATNCWRLT
	SPAADNWGQGTX10VTVSS
	X1 is E or Q
	X2 is P or S
	X3 is S or V
	X4 is E or G
	X5 is A or S
	X6 is K or S
	X7 is A or P
	X8 is D or E
	X9 is I or V
	X10 is M or Q
C04	SEQ ID NO: 461
	QVQLVESGGGLVQSGGSLRLSCVASGFTSPYSTIGWFRQAPGKEREGVACISSSGR
	GVNANYIDSVRGRFTISRDNAKNTVYLQMNKLKPDDTAIYYCATNCWRLTSPAADN
	WGQGTQVTVSS
huC04	SEQ ID NO: 462
	EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTIGWFRQAPGKGREGVACISSSGR
	GVNANYIDSVRGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCATNCWRLTSPAADN
	WGQGTMVTVSS
C10	SEQ ID NO: 463
	DLQLVESGGGLVQPGGSLRLSCAASGLTLDYYSISWFRQGPGNEREAVSCISRSGG
	RINYADSVKGRFTISRDSAKNTVYLQMNSLKPEDTAVYYCAATRLPLSGLCVIGSS
	DNALWGQGTQVTVSS
huC10	SEQ ID NO: 464
	ELQLVESGGGLVQPGGSLRLSCAASGLTLDYYSISWFRQAPGKEREAVSCISRSGG
	RINYADSVKGRFTISRDSSKNTVYLQMNSLRAEDTAVYYCAATRLPLSGLCVIGSS
	DNALWGQGTLVTVSS
D01	SEQ ID NO: 465
	QVQLQESGGGLVQAGGSLRLSCAASGNFSSISTMAWYRQVPGKQREWVARIIWSSG
	ATNYADSVKGRFTASRDNTKNTMYLQMDRLTPEDTAVYLCAGAISQRSGTFWTYWG
	QGTQVTVSS
huD01	SEQ ID NO: 466
	QVQLLESGGGLVKPGGSLRLSCAASGNFSSISTMAWYRQAPGKQREWVARIIWSSG
	ATNYADSVKGRFTASRDNAKNSMYLQMNSLRAEDTAVYYCAGAISQRSGTFWTYWG
	QGTLVTVSS
E08	SEQ ID NO: 467
	QLQLVESGGGLVQPGGSLTLSCASSISTINGYAVAWFRQAPGKERSAVSSISSSGI
	RTNYKDSVKGRFTIWRDNAKAAVYLQLNNLEPEDTAMYYCAAKRGPILFGTYTHWG
	QGTQVTVSS
huE08	SEQ ID NO: 468
	QLQLVESGGGLVKPGGSLRLSCAASGSTLNGYAVAWFRQAPGKEREAVSSISSSGI
	RTNYKDSVKGRFTISRDNAKNSVYLQMNSLRAEDTAVYYCAAKRGPILFGTYTHWG
	QGTLVTVSS
E10	SEQ ID NO: 469
	EVQLVESGGGLVQAGGSLRLSCAASGSALSIFAMGWYRQTPGKQSVSVAAVTLRSG
	ITSYLDSVKGRFIISIDRAKNTMYLEMNDLKPEDTAIYYCNVRDYRSRDYWGQGTQ
	VTVSS
huE10	SEQ ID NO: 470
	EVQLVESGGGLVQPGGSLRLSCAASGSALSIFAMGWYRQAPGKQSESVAAVTLRSG
	ITSYLDSVKGRFTISIDRSKNTMYLQMNSLRAEDTAVYYCNVRDYRSRDYWGQGTL
	VTVSS
G01	SEQ ID NO: 471
	QVQLQESGGGLVQPGGSLRLSCAASGFTVDRYAIGWFRQAPGKEREGVQCITTSGG
	GSNYADSVKGRFTIARDNAKNTVYLQMDSLKPEDTAIYYCAATPLNYYCGIDFNPD
	KYDYWGQGTQVTVSS
huG01	SEQ ID NO: 472
	EVQLLESGGGLVQPGGSLRLSCAASGFTVDRYAIGWFRQAPGKEREGVQCITTSGG
	GSNYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCAATPLNYYCGIDFNPD
	KYDYWGQGTMVTVSS
G02	SEQ ID NO: 473
	QVQLVESGGGLVQPGGSLRLSCVASETIINFAPMGWYRQAPGTERELVAAINRDFS
	TYYANSVKGRFTISRDNAKKMLSLQMNSLNPEDTAMYYCAASPGRIWSGTILPPAP
	DRVVSWGQGTQVTVSS
huG02	SEQ ID NO: 474
	QVQLVESGGGLVQPGGSLRLSCSASGTIINFAPMGWYRQAPGKERELVAAINRDFS
	TYYANSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAASPGRIWSGTILPPAP
	DRVVSWGQGTMVTVSS

[0400] In some embodiments, the VHH binds to an epitope on IL-10Rβ comprising contact amino acid residues S78, S80, K81, Y82, V108, N138, E139, Y140, E141, T142, W143, N147, V148 and N150, wherein the amino acid residue positions are with respect to SEQ ID NO: 712 (e.g., VHH A05). In some embodiments, the VHH binds to an epitope on IL-10Rβ comprising contact amino acid residues N26, R28, N30, V32, Q39, E41, T72, D84, 1103, T104, D110, I112, P115, Q157, Q190, R192, F194, N199, A201, E203, W204 and E206, wherein the amino acid residue positions are with respect to SEQ ID NO: 712 (e.g., VHH C04).

Human IL-10Rβ amino acid sequence - NP_000619.3 /
Uniprot Q08334
(SEQ ID NO: 712)
1	MAWSLGSWLG GCLLVSALGM VPPPENVRMN SVNFKNILQW
	ESPAFAKGNL TFTAQYLSYR
61	IFQDKCMNTT LTECDFSSLS KYGDHTLRVR AEFADEHSDW
	VNITFCPVDD TIIGPPGMQV
121	EVLADSLHMR FLAPKIENEY ETWTMKNVYN SWTYNVQYWK
	NGTDEKFQIT PQYDFEVLRN
181	LEPWTTYCVQ VRGFLPDRNK AGEWSEPVCE QTTHDETVPS
	WMVAVILMAS VEMVCLALLG
241	CFALLWCVYK KTKYAFSPRN SLPQHLKEFL GHPHHNTLLF
	FSFPLSDEND VFDKLSVIAE
301	DSESGKQNPG DSCSLGTPPG QGPQS

[0401] Provided are bispecific antibodies comprising a first immunoglobulin variable domain (VHH) and a second VHH, wherein the first VHH specifically binds to the extracellular domain of interleukin-10 receptor (IL-R) alpha subunit (IL-10Rα) and the second VHH specifically binds to the extracellular domain of interleukin-10 receptor beta subunit (IL-10Rβ). With respect to function, in some embodiments, the bispecific antibody is an IL-10R agonist that selectively suppresses activation of myeloid cells and induces minimal or no direct activation of T cells or B cells. In some embodiments, the bispecific antibody is an IL-10R agonist that predominantly suppresses activation of myeloid cells and induces minimal or no direct activation of T cells or B cells. In some embodiments, the bispecific antibody is an IL-10R agonist suppressing activation of myeloid cells (e.g., macrophages, monocytes and dendritic cells) with a half maximal effective concentration (EC50) less than about 10 pM and activating T cells and B cells below a predetermined threshold level at a concentration above about 1000 nM, e.g., above about 1500 nM, e.g., above about 2000 nM, e.g., above about 2500 nM, e.g., above about 3000 nM, e.g., above about 3500 nM, e.g., above about 4000 nM, e.g., above about 4500 nM, e.g., above about 5000 nM. In some embodiments, the bispecific antibody activates T cells or B cells with a maximum effect (Emax) that is 15% or less, e.g., 10% or less, e.g., 5% or less, in comparison to wild-type IL 10. In some embodiments, the activation of T cells is measured by at least one of Granzyme B secretion and interferon-γ (IFN-γ) production. In some embodiments, the bispecific antibody does not induce detectable granzyme B secretion from CD8+ T cells. In some embodiments, the bispecific antibody induces interferon-γ (IFN-γ) from CD8+ T cells less than 15%, e.g., less than 10%, e.g., less than 5%, the level of IFN-γ induced by wild-type IL-10. In some embodiments, the bispecific antibody agonizes the IL-10 receptor in a tyrosine kinase 2 (TYK2; NCBI Gene ID: 7297) dependent manner (i.e., requiring a functional TYK2, e.g., requiring the phosphorylation activity of TYK2). In some embodiments, the bispecific antibody induces minimal (e.g., less than 25% in comparison to wild-type IL-10) or no inhibition of IL 10Rβ dimerization with other IL-10 family cytokine receptor subunits, e.g., IL-10Rβ dimerization with IL-20Rα, IL-22R, IL-28R or IL-29R. In some embodiments, the bispecific antibody induces minimal (e.g., less than 25% in comparison to wild-type IL-10) or no inhibition of intracellular signaling of other IL-10Rβ-binding cytokines, e.g., minimal or no inhibition of IL-22, IL-26, IL-28A, IL-28B, or IL-29 intracellular signaling. In some embodiments, the second VHH binds to IL 10Rβ with an equilibrium dissociation constant (K_D) that is at least 5-fold greater, e.g., at least 7-fold greater, e.g., at least 10-fold greater, 15-fold greater, 20-fold greater, 25-fold greater, or more, than the K_D of the first VHH binding to IL 10Rα, e.g., wherein the binding affinity is determined by surface plasmon resonance (SPR). In some embodiments, the first VHH binds to IL 10Rα with affinity that is at least 5-fold greater, e.g., at least 7-fold greater, e.g., at least 10-fold, 15-fold, 20-fold, 25-fold greater, or more, than the binding affinity of the second VHH binding to IL 10Rβ, e.g., wherein the binding affinity is determined by surface plasmon resonance (SPR). In some embodiments, the first variable domain binds to IL 10Rα with an equilibrium dissociation constant (K_D) of lower than 2 nM and the second variable domain binds to IL 10Rβ with a K_D of greater than 10 nM, e.g., greater than 20 nM, e.g., greater than 30 nM, e.g., greater than 40 nM, e.g., greater than 50 nM, e.g., wherein the binding affinity is determined by surface plasmon resonance (SPR).

[0402] In some embodiments, the first VHH binds to an epitope on IL 10Rα comprising contact amino acid residues W33, E35, E37, H40, 142, H44, T46, L79, S80, T124, A170, R172, F178, F180, H182, Q204, K215, M217, W218, K220 and E221, wherein the amino acid residue positions are with respect to SEQ ID NO: 711 and the second VHH binds to an epitope on IL-10Rβ comprising contact amino acid residues S78, S80, K81, Y82, V108, N138, E139, Y140, E141, T142, W143, N147, V148 and N150, wherein the amino acid residue positions are with respect to SEQ ID NO: 712 (e.g., E07-A05). In some embodiments, the first VHH binds to an epitope on IL 10Rα comprising contact amino acid residues I169, I171, K173, F178, F180, T181, H182, K183, K186, F190, L192, L193, S195, E197, and F201, wherein the amino acid residue positions are with respect to SEQ ID NO: 711 and the second VHH binds to an epitope on IL-10Rβ comprising contact amino acid residues N26, R28, N30, V32, Q39, E41, T72, D84, I103, T104, D110, I112, P115, Q157, Q190, R192, F194, N199, A201, E203, W204, and E206, wherein the amino acid residue positions are with respect to SEQ ID NO: 712 (e.g., F11-C04).

[0403] With respect to structure, in some embodiments, the bispecific antibody comprises at least one polypeptide comprising the first VHH in tandem with the second VHH (e.g., in a single fusion protein). In some embodiments, the polypeptide comprises from N-terminus to C-terminus the first VHH that specifically binds to IL 10Rα and the second VHH that specifically binds to IL 10Rβ. In some embodiments, the polypeptide comprises from N-terminus to C-terminus the second VHH that specifically binds to IL 10Rβ and the first VHH that specifically binds to IL 10Rα. In some embodiments, the first VHH and the second VHH are connected or fused via a linker. In some embodiments, the linker is selected from the group consisting of: GS (SEQ ID NO: 713), GGS (SEQ ID NO: 714), GGGS (SEQ ID NO: 715), GGSGGS (SEQ ID NO: 716), GGGSGGGS (SEQ ID NO: 717) and GGSGGSGGS (SEQ ID NO: 718). In some embodiments, the linker comprises GGGS (SEQ ID NO: 715). The amino acid sequences of illustrative bispecific antibodies described herein are provided in Tables E and F, below.

[0404] In some embodiments of the bispecific antibody, the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH1-complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH comprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, according to Kabat, respectively:

• • [0405] 1) SEQ ID NOs: 22, 23, 24, 291, 292 and 293; (877)
  • [0406] 2) SEQ ID NOs: 22, 25, 26, 291, 294 and 295; (647)
  • [0407] 3) SEQ ID NOs: 22, 27, 24, 291, 297 and 298; (195)
  • [0408] 4) SEQ ID NOs: 22, 23, 24, 288, 289 and 290; (048)
  • [0409] 5) SEQ ID NOs: 22, 25, 26, 288, 289 and 290; (049)
  • [0410] 6) SEQ ID NOs: 22, 27, 24, 288, 289 and 290; (050)
  • [0411] 7) SEQ ID NOs: 22, 23, 24, 296, 308 and 309; (274)
  • [0412] 8) SEQ ID NOs: 22, 25, 26, 296, 308 and 309; (771)
  • [0413] 9) SEQ ID NOs: 22, 27, 24, 296, 308 and 309; (772)
  • [0414] 10) SEQ ID NOs: 4, 28, 29, 288, 289 and 290; (054)
  • [0415] 11) SEQ ID NOs: 4, 28, 29, 291, 294 and 295; (883)
  • [0416] 12) SEQ ID NOs: 4, 28, 29, 291, 294 and 295; (784)
  • [0417] 13) SEQ ID NOs: 4, 28, 29, 291, 297 and 298; (785)
  • [0418] 14) SEQ ID NOs: 4, 5, 6, 288, 289 and 290; (046)
  • [0419] 15) SEQ ID NOs: 4, 5, 6, 291, 294 and 295; (875)
  • [0420] 16) SEQ ID NOs: 4, 5, 6, 291, 294 and 295; (776)
  • [0421] 17) SEQ ID NOs: 4, 5, 6, 291, 297 and 298; (777)
  • [0422] 18) SEQ ID NOs: 4, 5, 6, 296, 308 and 309; (272)
  • [0423] 19) SEQ ID NOs: 4, 15, 16, 288, 289 and 290; (052)
  • [0424] 20) SEQ ID NOs: 4, 15, 16, 296, 308 and 309; (278)
  • [0425] 21) SEQ ID NOs: 4, 17, 18, 288, 289 and 290; (047)
  • [0426] 22) SEQ ID NOs: 4, 17, 18, 291, 292 and 293; (876)
  • [0427] 23) SEQ ID NOs: 4, 17, 18, 291, 294 and 295; (778)
  • [0428] 24) SEQ ID NOs: 4, 17, 18, 291, 297 and 298; (779)
  • [0429] 25) SEQ ID NOs: 45, 46, 47, 288, 289 and 290; (062)
  • [0430] 26) SEQ ID NOs: 45, 46, 47, 291, 292 and 293; (891)
  • [0431] 27) SEQ ID NOs: 45, 46, 47, 291, 294 and 295; (780)
  • [0432] 28) SEQ ID NOs: 45, 46, 47, 291, 297 and 298; (781)
  • [0433] 29) SEQ ID NOs: 45, 46, 47, 296, 308 and 309; (290)
  • [0434] 30) SEQ ID NOs: 4, 48, 6, 291, 292 and 293; (892)
  • [0435] 31) SEQ ID NOs: 4, 48, 6, 291, 294 and 295; (793)
  • [0436] 32) SEQ ID NOs: 4, 48, 6, 291, 297 and 298; (794)
  • [0437] 33) SEQ ID NOs: 54, 55, 24, 291, 292 and 293; (894)
  • [0438] 34) SEQ ID NOs: 54, 55, 24, 291, 294 and 295; (795)
  • [0439] 35) SEQ ID NOs: 54, 55, 24, 291, 297 and 298; (796)
  • [0440] 36) SEQ ID NOs: 4, 30, 31, 291, 292 and 293; (884)
  • [0441] 37) SEQ ID NOs: 4, 30, 31, 291, 294 and 295; (786)
  • [0442] 38) SEQ ID NOs: 4, 30, 31, 291, 297 and 298; (787)
  • [0443] 39) SEQ ID NOs: 4, 36, 29, 288, 289 and 290; (058)
  • [0444] 40) SEQ ID NOs: 33, 34, 35, 296, 308 and 309; (284)
  • [0445] 41) SEQ ID NOs: 33, 34, 35, 296, 308 and 309; (183)
  • [0446] 42) SEQ ID NOs: 33, 34, 35, 296, 308 and 309; (184)
  • [0447] 43) SEQ ID NOs: 19, 37, 38, 302, 303 and 304; (239)
  • [0448] 44) SEQ ID NOs: 19, 37, 38, 296, 308 and 309; (286) or
  • [0449] 45) SEQ ID NOs: 19, 51, 52, 302, 303 and 304; (247)

[0450] In some embodiments of the bispecific antibody, the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH1-complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH comprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, according to IMGT, respectively:

• • [0451] 1) SEQ ID NOs: 77, 78, 79, 329, 330 and 331; (877)
  • [0452] 2) SEQ ID NOs: 77, 80, 81, 329, 332 and 333; (647)
  • [0453] 3) SEQ ID NOs: 77, 82, 79, 334, 335 and 336; (195)
  • [0454] 4) SEQ ID NOs: 77, 78, 79, 326, 327 and 328; (048)
  • [0455] 5) SEQ ID NOs: 77, 80, 81, 326, 327 and 328; (049)
  • [0456] 6) SEQ ID NOs: 77, 82, 79, 326, 327 and 328; (050)
  • [0457] 7) SEQ ID NOs: 77, 78, 79, 346, 347 and 348; (274)
  • [0458] 8) SEQ ID NOs: 77, 80, 81, 346, 347 and 348; (771)
  • [0459] 9) SEQ ID NOs: 77, 82, 79, 346, 347 and 348; (772)
  • [0460] 10) SEQ ID NOs: 59, 83, 84, 326, 327 and 328; (054)
  • [0461] 11) SEQ ID NOs: 59, 83, 84, 329, 330 and 331; (883)
  • [0462] 12) SEQ ID NOs: 59, 83, 84, 329, 332 and 333; (784)
  • [0463] 13) SEQ ID NOs: 59, 83, 84, 334, 335 and 336; (785)
  • [0464] 14) SEQ ID NOs: 59, 60, 61, 326, 327 and 328; (046)
  • [0465] 15) SEQ ID NOs: 59, 60, 61, 329, 330 and 331; (875)
  • [0466] 16) SEQ ID NOs: 59, 60, 61, 329, 332 and 333; (776)
  • [0467] 17) SEQ ID NOs: 59, 60, 61, 334, 335 and 336; (777)
  • [0468] 18) SEQ ID NOs: 59, 60, 61, 346, 347 and 348; (272)
  • [0469] 19) SEQ ID NOs: 59, 70, 71, 326, 327 and 328; (052)
  • [0470] 20) SEQ ID NOs: 59, 70, 71, 346, 347 and 348; (278)
  • [0471] 21) SEQ ID NOs: 59, 72, 73, 326, 327 and 328; (047)
  • [0472] 22) SEQ ID NOs: 59, 72, 73, 329, 330 and 331; (876)
  • [0473] 23) SEQ ID NOs: 59, 72, 73, 329, 332 and 333; (778)
  • [0474] 24) SEQ ID NOs: 59, 72, 73, 334, 335 and 336; (779)
  • [0475] 25) SEQ ID NOs: 98, 99, 100, 326, 327 and 328; (062)
  • [0476] 26) SEQ ID NOs: 98, 99, 100, 329, 330 and 331; (891)
  • [0477] 27) SEQ ID NOs: 98, 99, 100, 329, 332 and 333; (780)
  • [0478] 28) SEQ ID NOs: 98, 99, 100, 334, 335 and 336; (781)
  • [0479] 29) SEQ ID NOs: 98, 99, 100, 326, 327 and 328; (290)
  • [0480] 30) SEQ ID NOs: 59, 101, 61, 329, 330 and 331; (892)
  • [0481] 31) SEQ ID NOs: 59, 101, 61, 329, 332 and 333; (793)
  • [0482] 32) SEQ ID NOs: 59, 101, 61, 334, 335 and 336; (794)
  • [0483] 33) SEQ ID NOs: 106, 107, 79, 329, 330 and 331; (894)
  • [0484] 34) SEQ ID NOs: 106, 107, 79, 329, 332 and 333; (795)
  • [0485] 35) SEQ ID NOs: 106, 107, 79, 334, 335 and 336; (796)
  • [0486] 36) SEQ ID NOs: 59, 85, 86, 329, 330 and 331; (884)
  • [0487] 37) SEQ ID NOs: 59, 85, 86, 329, 332 and 333; (786)
  • [0488] 38) SEQ ID NOs: 59, 85, 86, 334, 335 and 336; (787)
  • [0489] 39) SEQ ID NOs: 59, 91, 84, 326, 327 and 328; (058)
  • [0490] 40) SEQ ID NOs: 88, 89, 90, 326, 327 and 328; (284)
  • [0491] 41) SEQ ID NOs: 88, 89, 90, 326, 327 and 328; (183)
  • [0492] 42) SEQ ID NOs: 88, 89, 90, 326, 327 and 328; (184)
  • [0493] 43) SEQ ID NOs: 92, 75, 93, 340, 341 and 342; (239)
  • [0494] 44) SEQ ID NOs: 92, 75, 93, 326, 327 and 328; (286) or
  • [0495] 45) SEQ ID NOs: 74, 75, 104, 340, 341 and 342; (247).

[0496] In some embodiments of the bispecific antibody, the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH1-complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH comprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR) 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, according to Chothia, respectively:

• • [0497] 1) SEQ ID NOs: 127, 128, 129, 369, 370 and 371; (877)
  • [0498] 2) SEQ ID NOs: 127, 130, 131, 369, 372 and 373; (647)
  • [0499] 3) SEQ ID NOs: 127, 130, 131, 374, 375 and 376; (195)
  • [0500] 4) SEQ ID NOs: 127, 128, 129, 366, 367 and 368; (048)
  • [0501] 5) SEQ ID NOs: 127, 130, 131, 366, 367 and 368; (049)
  • [0502] 6) SEQ ID NOs: 127, 130, 131, 366, 367 and 368; (050)
  • [0503] 7) SEQ ID NOs: 127, 128, 129, 386, 387 and 388; (274)
  • [0504] 8) SEQ ID NOs: 127, 130, 131, 386, 387 and 388; (771)
  • [0505] 9) SEQ ID NOs: 127, 130, 131, 386, 387 and 388; (772)
  • [0506] 10) SEQ ID NOs: 111, 132, 133, 366, 367 and 368; (054)
  • [0507] 11) SEQ ID NOs: 111, 132, 133, 369, 370 and 371; (883)
  • [0508] 12) SEQ ID NOs: 111, 132, 133, 369, 372 and 373; (784)
  • [0509] 13) SEQ ID NOs: 111, 132, 133, 374, 375 and 376; (785)
  • [0510] 14) SEQ ID NOs: 111, 112, 113, 366, 367 and 368; (046)
  • [0511] 15) SEQ ID NOs: 111, 112, 113, 369, 370 and 371; (875)
  • [0512] 16) SEQ ID NOs: 111, 112, 113, 369, 372 and 373; (776)
  • [0513] 17) SEQ ID NOs: 111, 112, 113, 374, 375 and 376; (777)
  • [0514] 18) SEQ ID NOs: 111, 112, 113, 386, 387 and 388; (272)
  • [0515] 19) SEQ ID NOs: 111, 121, 122, 366, 367 and 368; (052)
  • [0516] 20) SEQ ID NOs: 111, 121, 122, 386, 387 and 388; (278)
  • [0517] 21) SEQ ID NOs: 111, 121, 123, 366, 367 and 368; (047)
  • [0518] 22) SEQ ID NOs: 111, 121, 123, 369, 370 and 371; (876)
  • [0519] 23) SEQ ID NOs: 111, 121, 123, 369, 372 and 373; (778)
  • [0520] 24) SEQ ID NOs: 111, 121, 123, 374, 375 and 376; (779)
  • [0521] 25) SEQ ID NOs: 145, 146, 147, 366, 367 and 368; (062)
  • [0522] 26) SEQ ID NOs: 145, 146, 147, 369, 370 and 371; (891)
  • [0523] 27) SEQ ID NOs: 145, 146, 147, 369, 372 and 373; (780)
  • [0524] 28) SEQ ID NOs: 145, 146, 147, 374, 375 and 376; (781)
  • [0525] 29) SEQ ID NOs: 145, 146, 147, 386, 387 and 388; (290)
  • [0526] 30) SEQ ID NOs: 111, 112, 113, 369, 370 and 371; (892)
  • [0527] 31) SEQ ID NOs: 111, 112, 113, 369, 372 and 373; (793)
  • [0528] 32) SEQ ID NOs: 111, 112, 113, 374, 375 and 376; (794)
  • [0529] 33) SEQ ID NOs: 152, 121, 129, 369, 370 and 371; (894)
  • [0530] 34) SEQ ID NOs: 152, 121, 129, 369, 372 and 373; (795)
  • [0531] 35) SEQ ID NOs: 152, 121, 129, 374, 375 and 376; (796)
  • [0532] 36) SEQ ID NOs: 111, 134, 135, 369, 370 and 371; (884)
  • [0533] 37) SEQ ID NOs: 111, 134, 135, 369, 372 and 373; (786)
  • [0534] 38) SEQ ID NOs: 111, 134, 135, 374, 375 and 376; (787)
  • [0535] 39) SEQ ID NOs: 111, 132, 133, 366, 367 and 368; (058)
  • [0536] 40) SEQ ID NOs: 137, 138, 139, 386, 387 and 388; (284)
  • [0537] 41) SEQ ID NOs: 137, 138, 139, 386, 387 and 388; (183)
  • [0538] 42) SEQ ID NOs: 137, 138, 139, 386, 387 and 388; (184)
  • [0539] 43) SEQ ID NOs: 140, 125, 141, 380, 381 and 381; (239)
  • [0540] 44) SEQ ID NOs: 140, 125, 141, 386, 387 and 388; (286) or
  • [0541] 45) SEQ ID NOs: 124, 125, 126, 380, 381 and 381 (247).

[0542] In some embodiments of the bispecific antibody, the first VHH comprises a first heavy chain variable domain (VHH1) comprising a VHH1-complementarity determining region (CDR) 1, a VHH1-CDR2, and a VHH1-CDR3 and the second VHH comprises a second heavy chain variable domain (VHH2) comprising a VHH2-complementarity determining region (CDR)

• • [0543] 1, a VHH2-CDR2, and a VHH2-CDR3, comprising the following amino acid sequences, according to Honegger, respectively:
  • [0544] 1) SEQ ID NOs: 174, 175, 176, 409, 410 and 411; (877)
  • [0545] 2) SEQ ID NOs: 174, 177, 178, 409, 412 and 413; (647)
  • [0546] 3) SEQ ID NOs: 174, 179, 176, 414, 415 and 416; (195)
  • [0547] 4) SEQ ID NOs: 174, 175, 176, 406, 407 and 408; (048)
  • [0548] 5) SEQ ID NOs: 174, 177, 178, 406, 407 and 408; (049)
  • [0549] 6) SEQ ID NOs: 174, 179, 176, 406, 407 and 408; (050)
  • [0550] 7) SEQ ID NOs: 174, 175, 176, 426, 427 and 428; (274)
  • [0551] 8) SEQ ID NOs: 174, 177, 178, 426, 427 and 428; (771)
  • [0552] 9) SEQ ID NOs: 174, 179, 176, 426, 427 and 428; (772)
  • [0553] 10) SEQ ID NOs: 156, 180, 181, 406, 407 and 408; (054)
  • [0554] 11) SEQ ID NOs: 156, 180, 181, 409, 410 and 411; (883)
  • [0555] 12) SEQ ID NOs: 156, 180, 181, 409, 412 and 413; (784)
  • [0556] 13) SEQ ID NOs: 156, 180, 181, 414, 415 and 416; (785)
  • [0557] 14) SEQ ID NOs: 156, 157, 158, 406, 407 and 408; (046)
  • [0558] 15) SEQ ID NOs: 156, 157, 158, 409, 410 and 411; (875)
  • [0559] 16) SEQ ID NOs: 156, 157, 158, 409, 412 and 413; (776)
  • [0560] 17) SEQ ID NOs: 156, 157, 158, 414, 415 and 416; (777)
  • [0561] 18) SEQ ID NOs: 156, 157, 158, 426, 427 and 428; (272)
  • [0562] 19) SEQ ID NOs: 156, 167, 168, 406, 407 and 408; (052)
  • [0563] 20) SEQ ID NOs: 156, 167, 168, 426, 427 and 428; (278)
  • [0564] 21) SEQ ID NOs: 156, 169, 170, 406, 407 and 408; (047)
  • [0565] 22) SEQ ID NOs: 156, 169, 170, 409, 410 and 411; (876)
  • [0566] 23) SEQ ID NOs: 156, 169, 170, 409, 412 and 413; (778)
  • [0567] 24) SEQ ID NOs: 156, 169, 170, 414, 415 and 416; (779)
  • [0568] 25) SEQ ID NOs: 198, 199, 200, 406, 407 and 408; (062)
  • [0569] 26) SEQ ID NOs: 198, 199, 200, 409, 410 and 411; (891)
  • [0570] 27) SEQ ID NOs: 198, 199, 200, 409, 412 and 413; (780)
  • [0571] 28) SEQ ID NOs: 198, 199, 200, 414, 415 and 416; (781)
  • [0572] 29) SEQ ID NOs: 198, 199, 200, 426, 427 and 428; (290)
  • [0573] 30) SEQ ID NOs: 156, 201, 158, 409, 410 and 411; (892)
  • [0574] 31) SEQ ID NOs: 156, 201, 158, 409, 412 and 413; (793)
  • [0575] 32) SEQ ID NOs: 156, 201, 158, 414, 415 and 416; (794)
  • [0576] 33) SEQ ID NOs: 208, 209, 176, 409, 410 and 411; (894)
  • [0577] 34) SEQ ID NOs: 208, 209, 176, 409, 412 and 413; (795)
  • [0578] 35) SEQ ID NOs: 208, 209, 176, 414, 415 and 416; (796)
  • [0579] 36) SEQ ID NOs: 156, 182, 183, 409, 410 and 411; (884)
  • [0580] 37) SEQ ID NOs: 156, 182, 183, 409, 412 and 413; (786)
  • [0581] 38) SEQ ID NOs: 156, 182, 183, 414, 415 and 416; (787)
  • [0582] 39) SEQ ID NOs: 156, 188, 181, 406, 407 and 408; (058)
  • [0583] 40) SEQ ID NOs: 185, 186, 187, 426, 427 and 428; (284)
  • [0584] 41) SEQ ID NOs: 709, 186, 187, 426, 427 and 428; (183)
  • [0585] 42) SEQ ID NOs: 709, 186, 187, 426, 427 and 428; (184)
  • [0586] 43) SEQ ID NOs: 189, 190, 191, 420, 421 and 422; (239)
  • [0587] 44) SEQ ID NOs: 189, 190, 191, 426, 427 and 428; (286) or
  • [0588] 45) SEQ ID NOs: 204, 205, 206, 420, 421 and 422; (247).

[0589] In some embodiments of the bispecific antibody, the first VHH that specifically binds to IL 10Rα and the second VHH that specifically binds to IL-10Rβ comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in:

• • [0590] 1) SEQ ID NOs: 212 and 448; [A06con-A05con]
  • [0591] 2) SEQ ID NOs: 212 and 449; [A06con-A05con]
  • [0592] 3) SEQ ID NOs: 212 and 460; [A06con-C04con]
  • [0593] 4) SEQ ID NOs: 233 and 448; [E07con-A05con]
  • [0594] 5) SEQ ID NOs: 234 and 449; [E07con-A05con]
  • [0595] 6) SEQ ID NOs: 233 and 460; [E07con-C04con]
  • [0596] 7) SEQ ID NOs: 234 and 460; [E07con-C04con]
  • [0597] 8) SEQ ID NOs: 710 and 448; [C09con-A05con]
  • [0598] 9) SEQ ID NOs: 710 and 449; [C09con-A05con]10) SEQ ID NOs: 710 and 460; [C09con-C04con]11) SEQ ID NOs: 230 and 460 [G22con-C04con] or 12) SEQ ID NOs: 249 and 460 [F11con-C04con].

[0599] In some embodiments of the bispecific antibody, the first VHH that specifically binds to IL 10Rα and the second VHH that specifically binds to IL-10Rβ comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in:

• • [0600] 1) SEQ ID NOs: 235 and 450; (877)
  • [0601] 2) SEQ ID NOs: 237 and 451; (647)
  • [0602] 3) SEQ ID NOs: 239 and 452; (195)
  • [0603] 4) SEQ ID NOs: 235 and 446; (048)
  • [0604] 5) SEQ ID NOs: 237 and 447; (049)
  • [0605] 6) SEQ ID NOs: 239 and 447; (050)
  • [0606] 7) SEQ ID NOs: 235 and 461; (274)
  • [0607] 8) SEQ ID NOs: 237 and 462; (771)
  • [0608] 9) SEQ ID NOs: 239 and 462; (772)
  • [0609] 10) SEQ ID NOs: 241 and 446; (054)
  • [0610] 11) SEQ ID NOs: 243 and 447; (755)
  • [0611] 12) SEQ ID NOs: 241 and 450; (883)
  • [0612] 13) SEQ ID NOs: 243 and 451; (784)
  • [0613] 14) SEQ ID NOs: 243 and 452; (785)
  • [0614] 15) SEQ ID NOs: 213 and 446; (046)
  • [0615] 16) SEQ ID NOs: 215 and 447; (747)
  • [0616] 17) SEQ ID NOs: 213 and 450; (875)
  • [0617] 18) SEQ ID NOs: 215 and 451; (776)
  • [0618] 19) SEQ ID NOs: 215 and 452; (777)
  • [0619] 20) SEQ ID NOs: 213 and 461; (272)
  • [0620] 21) SEQ ID NOs: 215 and 462; (773)
  • [0621] 22) SEQ ID NOs: 224 and 446; (052)
  • [0622] 23) SEQ ID NOs: 226 and 447; (753)
  • [0623] 24) SEQ ID NOs: 224 and 461; (278)
  • [0624] 25) SEQ ID NOs: 226 and 462; (769)
  • [0625] 26) SEQ ID NOs: 227 and 446; (047)
  • [0626] 27) SEQ ID NOs: 229 and 447; (748)
  • [0627] 28) SEQ ID NOs: 227 and 450; (876)
  • [0628] 29) SEQ ID NOs: 229 and 451; (778)
  • [0629] 30) SEQ ID NOs: 229 and 452; (779)
  • [0630] 31) SEQ ID NOs: 267 and 446; (062)
  • [0631] 32) SEQ ID NOs: 269 and 447; (763)
  • [0632] 33) SEQ ID NOs: 267 and 450; (891)
  • [0633] 34) SEQ ID NOs: 269 and 451; (780)
  • [0634] 35) SEQ ID NOs: 269 and 452; (781)
  • [0635] 36) SEQ ID NOs: 267 and 461; (290)
  • [0636] 37) SEQ ID NOs: 269 and 462; (791)
  • [0637] 38) SEQ ID NOs: 270 and 450; (892)
  • [0638] 39) SEQ ID NOs: 272 and 451; (793)
  • [0639] 40) SEQ ID NOs: 272 and 452; (794)
  • [0640] 41) SEQ ID NOs: 285 and 450; (894)
  • [0641] 42) SEQ ID NOs: 287 and 451; (795)
  • [0642] 43) SEQ ID NOs: 287 and 452; (796)
  • [0643] 44) SEQ ID NOs: 244 and 450; (884)
  • [0644] 45) SEQ ID NOs: 246 and 451; (786)
  • [0645] 46) SEQ ID NOs: 247 and 452; (787)
  • [0646] 47) SEQ ID NOs: 253 and 446; (058)
  • [0647] 48) SEQ ID NOs: 255 and 447; (759)
  • [0648] 49) SEQ ID NOs: 250 and 461; (284)
  • [0649] 50) SEQ ID NOs: 251 and 462; (183)
  • [0650] 51) SEQ ID NOs: 252 and 462; (184)
  • [0651] 52) SEQ ID NOs: 256 and 456; (239)
  • [0652] 53) SEQ ID NOs: 258 and 457; (740)
  • [0653] 54) SEQ ID NOs: 256 and 461; (286)
  • [0654] 55) SEQ ID NOs: 258 and 462; (788)
  • [0655] 56) SEQ ID NOs: 278 and 456; (247) or
  • [0656] 57) SEQ ID NOs: 280 and 457; (749).

[0657] In some embodiments of the bispecific antibody, the first VHH that specifically binds to IL 10Rα and the second VHH that specifically binds to IL-10Rβ comprise the following amino acid sequences, respectively, or amino acid sequences that are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequences set forth, respectively, in:

• • [0658] 1) SEQ ID NOs: 236 and 450; (877)
  • [0659] 2) SEQ ID NOs: 238 and 451; (647)
  • [0660] 3) SEQ ID NOs: 240 and 452; (195)
  • [0661] 4) SEQ ID NOs: 236 and 446; (048)
  • [0662] 5) SEQ ID NOs: 238 and 447; (049)
  • [0663] 6) SEQ ID NOs: 240 and 447; (050)
  • [0664] 7) SEQ ID NOs: 236 and 461; (274)
  • [0665] 8) SEQ ID NOs: 238 and 462; (771)
  • [0666] 9) SEQ ID NOs: 240 and 462; (772)
  • [0667] 10) SEQ ID NOs: 242 and 446; (054)
  • [0668] 11) SEQ ID NOs: 243 and 447; (755)
  • [0669] 12) SEQ ID NOs: 242 and 450; (883)
  • [0670] 13) SEQ ID NOs: 243 and 451; (784)
  • [0671] 14) SEQ ID NOs: 243 and 452; (785)
  • [0672] 15) SEQ ID NOs: 214 and 446; (046)
  • [0673] 16) SEQ ID NOs: 215 and 447; (747)
  • [0674] 17) SEQ ID NOs: 214 and 450; (875)
  • [0675] 18) SEQ ID NOs: 215 and 451; (776)
  • [0676] 19) SEQ ID NOs: 215 and 452; (777)
  • [0677] 20) SEQ ID NOs: 214 and 461; (272)
  • [0678] 21) SEQ ID NOs: 215 and 462; (773)
  • [0679] 22) SEQ ID NOs: 225 and 446; (052)
  • [0680] 23) SEQ ID NOs: 226 and 447; (753)
  • [0681] 24) SEQ ID NOs: 225 and 461; (278)
  • [0682] 25) SEQ ID NOs: 226 and 462; (769)
  • [0683] 26) SEQ ID NOs: 228 and 446; (047)
  • [0684] 27) SEQ ID NOs: 229 and 447; (748)
  • [0685] 28) SEQ ID NOs: 228 and 450; (876)
  • [0686] 29) SEQ ID NOs: 229 and 451; (778)
  • [0687] 30) SEQ ID NOs: 229 and 452; (779)
  • [0688] 31) SEQ ID NOs: 268 and 446; (062)
  • [0689] 32) SEQ ID NOs: 269 and 447; (763)
  • [0690] 33) SEQ ID NOs: 268 and 450; (891)
  • [0691] 34) SEQ ID NOs: 269 and 451; (780)
  • [0692] 35) SEQ ID NOs: 269 and 452; (781)
  • [0693] 36) SEQ ID NOs: 268 and 461; (290)
  • [0694] 37) SEQ ID NOs: 269 and 462; (791)
  • [0695] 38) SEQ ID NOs: 271 and 450; (892)
  • [0696] 39) SEQ ID NOs: 273 and 451; (793)
  • [0697] 40) SEQ ID NOs: 274 and 452; (794)
  • [0698] 41) SEQ ID NOs: 286 and 450; (894)
  • [0699] 42) SEQ ID NOs: 287 and 451; (795)
  • [0700] 43) SEQ ID NOs: 287 and 452; (796)
  • [0701] 44) SEQ ID NOs: 245 and 450; (884)
  • [0702] 45) SEQ ID NOs: 246 and 451; (786)
  • [0703] 46) SEQ ID NOs: 246 and 452; (787)
  • [0704] 47) SEQ ID NOs: 254 and 446; (058)
  • [0705] 48) SEQ ID NOs: 255 and 447; (759)
  • [0706] 49) SEQ ID NOs: 250 and 461; (284)
  • [0707] 50) SEQ ID NOs: 251 and 462; (183)
  • [0708] 51) SEQ ID NOs: 252 and 462; (184)
  • [0709] 52) SEQ ID NOs: 257 and 456; (239)
  • [0710] 53) SEQ ID NOs: 259 and 457; (740)
  • [0711] 54) SEQ ID NOs: 257 and 461; (286)
  • [0712] 55) SEQ ID NOs: 259 and 462; (788)
  • [0713] 56) SEQ ID NOs: 279 and 456; (247) or
  • [0714] 57) SEQ ID NOs: 280 and 457; (749).

[0715] In some embodiments, the bispecific antibody comprises a polypeptide comprising in tandem the first VHH that specifically binds to IL 10Rα and the second VHH that specifically binds to IL-10Rβ, comprising the following amino acid sequence, or an amino acid sequences that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 475-476 and 573.

[0716] In some embodiments, the bispecific antibody comprises a polypeptide comprising in tandem the first VHH that specifically binds to IL 10Rα and the second VHH that specifically binds to IL-10Rβ, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 477, 479, 481, 483, 485, 487, 489, 491, 493, 495, 497, 499, 501, 503, 505, 507, 509, 511, 513, 515, 517, 519, 521, 523, 525, 527, 529, 531, 533, 535, 537, 539, 541, 543, 545, 547, 549, 551, 553, 555, 557, 559, 561, 563, 565, 567, 569, 571, 574, 576, 578, 580, 582, 584, 586, 588 and 590.

[0717] In some embodiments, the bispecific antibody comprises a polypeptide comprising in tandem the first VHH that specifically binds to IL 10Rα and the second VHH that specifically binds to IL-10Rβ, comprising the following amino acid sequence, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical, to the amino acid sequence selected from SEQ ID NOs: 478, 480, 482, 484, 486, 488, 490, 492, 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564, 566, 568, 570, 572, 575, 577, 579, 581, 583, 585, 587, 589, 591, 737-751 and 757-758.

[0718] In some embodiments, the first VHH that specifically binds to IL 10Rα and the second VHH that specifically binds to IL-10Rβ are humanized. Illustrative humanized VHH sequences provided herein are designated with an “hu” prefix.

[0719] Amino acid sequence of illustrative αIL-10Rα/αIL-10Rβ Tandem Single Immunoglobulin Domain (VHH-VHH) are provided in Table E, below.

TABLE E
Illustrative αIL-10Rα / αIL-10Rβ Tandem Single
Immunoglobulin Domain (VHH-VHH) amino acid sequences
αIL-10Rα-αIL-10Rβ Tandem Single Immunoglobulin Domain (VHH-VHH)
VHH-VHH
name	VHH-VHH amino acid sequence
774	SEQ ID NO: 475
E07-A05	X1X2LQLVESGGGLVX3X4GX5SLRLSCAASGRTFSAYGMGWFRQAPGKX6REFVX7
con1	AIRWX8GX9X10TYYAX11SVKGRFTISKDX12X13KNTLYLQMX14SLX15X16EDTAV
	YYCAAKTX17X18X19SYLSEKSYX20YWGQGTX21VTVSSX22X23VQLX24ESGGGLV
	QPGGSLX25LSCAASGX26SLDX27X28X29IGWFRX30APGKX31X32EGVSX33ISA
	X34DX35STHYAX36X37VKGRFTISRDNX38KNTVX39LQMNX40LX41X42EDX43X44
	X45YYCAASLX46GLGX47KX48EX49DYDYWGQGTX50VTVSS
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	X2 is E or Q
	X3 is Q or R
	X4 is A or P
	X5 is D or G
	X6 is E or G
	X7 is A or S
	X8 is I or Y
	X9 is D or E
	X10 is A, G or S
	X11 is D or E
	X12 is N or S
	X13 is A or S
	X14 is N or S
	X15 is K or R
	X16 is A or P
	X17 is R or S
	X18 is P or V
	X19 is D or T
	X20 is G or N
	X21 is M or Q
	X22 is GGGS, GGGGS, or GGGSGGGS
	X23 is E or Q
	X24 is L or Q
	X25 is K or R
	X26 is I or N
	X27 is E or Y
	X28 is G, P or S
	X29 is V or T
	X30 is Q or R
	X31 is E or G
	X32 is L or R
	X33 is A or C
	X34 is R or S
	X35 is A or G
	X36 is D or N
	X37 is A or S
	X38 is S or T
	X39 is D or Y
	X40 is N or S
	X41 is K or R
	X42 is A or P
	X43 is A or T
	X44 is A or G
	X45 is H or V
	X46 is H or W
	X47 is A or C
	X48 is R or S
	X49 is A or E
	X50 is L, M or Q
775	SEQ ID NO: 476
E07-A05	X1QLQLVESGGGLVX3X4GGSLRLSCAASGRTFSAYGMGWFRQAPGKX6REFVX7A
con2	IRWX8GX9X10TYYAX11SVKGRFTISKDNX13KNTLYLQMX14SLX15X16EDTAVYY
	CAAKTX17X18X19SYLSEKSYX20YWGQGTX21VTVSSX22X23VQLVESGGGLVQPG
	GSLRLSCAASGNSLDYPTIGWFRQAPGKX24X25EGVSX26ISASDX27STHYADX28
	VKGRFTISRDNX29KNTVX30LQMNX31LX32X33EDTX34X35YYCAASLX36GLGX37
	KSEADYDYWGQGTX38VTVSS
	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	X3 is Q or R
	X4 is A or P
	X6 is E or G
	X7 is A or S
	X8 is I or Y
	X9 is D or E
	X10 is A, G or S
	X11 is D or E
	X13 is A or S
	X14 is N or S
	X15 is K or R
	X16 is A or P
	X17 is R or S
	X18 is P or V
	X19 is D or T
	X20 is G or N
	X21 is M or Q
	X22 is GGGS, GGGGS, or GGGSGGGS
	X23 is E or Q
	X24 is E or G
	X25 is L or R
	X26 is A or C
	X27 is A or G
	X28 is A or S
	X29 is S or T
	X30 is D or Y
	X31 is N or S
	X32 is K or R
	X33 is A or P
	X34 is A or G
	X35 is H or V
	X36 is H or W
	X37 is A or C
	X38 is M or Q
877	SEQ ID NO: 477
E07-A05	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 478
	X1 is AS; X2 is GGGS
	X1QLQLVESGGGLVRAGGSLRLSCAASGRTFSAYGMGWFRQAPGKEREFVAAIRW
	IGDSTYYADSVKGRFTISKDNAKNTLYLQMSSLKPEDTAVYYCAAKTSVTSYLS
	EKSYNYWGQGTQVTVSSX2QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW
	FRQAPGKEREGVSCISASDGSTHYADSVKGRFTISRDNTKNTVDLQMNNLKPED
	TGHYYCAASLWGLGCKSEADYDYWGQGTQVTVSS
647	SEQ ID NO: 479
huE07-	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
huA05	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 480
	X1 is AS; X2 is GGGS
	X1QLQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKGREFVSAIRW
	YGEGTYYAESVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTRPDSYLS
	EKSYGYWGQGTMVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW
	FRQAPGKGLEGVSAISASDASTHYADAVKGRFTISRDNSKNTVYLQMNSLRAED
	TAVYYCAASLHGLGAKSEADYDYWGQGTMVTVSS
195	SEQ ID NO: 481
huE07-	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
huA05	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 482
	X1 is AS; X2 is GGGS
	X1QLQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKGREFVSAIRW
	IGDATYYAESVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTSVTSYLS
	EKSYNYWGQGTMVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGW
	FRQAPGKGLEGVSCISASEGSTHYADAVKGRFTISRDNSKNTVYLQMNSLRAED
	TAVYYCAASLHGLGCKSEADYDYWGQGTMVTVSS
048	SEQ ID NO: 483
E07-A02	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 484
	X1 is AS; X2 is GGGS
	X1QLQLVESGGGLVRAGGSLRLSCAASGRTFSAYGMGWFRQAPGKEREFVAAIRW
	IGDSTYYADSVKGRFTISKDNAKNTLYLQMSSLKPEDTAVYYCAAKTSVTSYLS
	EKSYNYWGQGTQVTVSSX2QVQLQESGGGLVQPGGSLKLSCAASGISLDEGVIGW
	FRRAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNTKNTVDLQMNNLEPED
	AGRYYCAASLWGLGCKREEDYDYWGQGTQVTVSS
049	SEQ ID NO: 485
huE07-	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
huA02	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 486
	X1 is AS; X2 is GGGS
	X1QLQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKGREFVSAIRW
	YGEGTYYAESVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTRPDSYLS
	EKSYGYWGQGTMVTVSSX2EVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGW
	FRQAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNSKNTVYLQMNSLRAED
	TAVYYCAASLWGLGCKREEDYDYWGQGTLVTVSS
050	SEQ ID NO: 487
huE07-	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
huA02	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 488
	X1 is AS; X2 is GGGS
	X1QLQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKGREFVSAIRW
	IGDATYYAESVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTSVTSYLS
	EKSYNYWGQGTMVTVSSX2EVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGW
	FRQAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNSKNTVYLQMNSLRAED
	TAVYYCAASLWGLGCKREEDYDYWGQGTLVTVSS
274	SEQ ID NO: 489
E07-C04	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 490
	X1 is AS; X2 is GGGS
	X1QLQLVESGGGLVRAGGSLRLSCAASGRTFSAYGMGWFRQAPGKEREFVAAIRW
	IGDSTYYADSVKGRFTISKDNAKNTLYLQMSSLKPEDTAVYYCAAKTSVTSYLS
	EKSYNYWGQGTQVTVSSX2QVQLVESGGGLVQSGGSLRLSCVASGFTSPYSTIGW
	FRQAPGKEREGVACISSSGRGVNANYIDSVRGRFTISRDNAKNTVYLQMNKLKP
	DDTAIYYCATNCWRLTSPAADNWGQGTQVTVSS
771	SEQ ID NO: 491
huE07-	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
huC04	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 492
	X1 is AS; X2 is GGGS
	X1QLQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKGREFVSAIRW
	YGEGTYYAESVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTRPDSYLS
	EKSYGYWGQGTMVTVSSX2EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTIGW
	FRQAPGKGREGVACISSSGRGVNANYIDSVRGRFTISRDNSKNTVYLQMNSLRA
	EDTAVYYCATNCWRLTSPAADNWGQGTMVTVSS
772	SEQ ID NO: 493
huE07-	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
huC04	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 494
	X1 is AS; X2 is GGGS
	X1QLQLLESGGGLVQPGGSLRLSCAASGRTFSAYGMGWFRQAPGKGREFVSAIRW
	IGDATYYAESVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTSVTSYLS
	EKSYNYWGQGTMVTVSSX2EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTIGW
	FRQAPGKGREGVACISSSGRGVNANYIDSVRGRFTISRDNSKNTVYLQMNSLRA
	EDTAVYYCATNCWRLTSPAADNWGQGTMVTVSS
054	SEQ ID NO: 495
E15-A02	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 496
	X1 is AS; X2 is GGGS
	X1QVQLQESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISW
	IGNSAYYADSVKGRFTLSGDNAKNTLYLQMNSLKPEDTAVYYCAAKYYTDSYYA
	AASYAYWGQGTQVTVSSX2QVQLQESGGGLVQPGGSLKLSCAASGISLDEGVIGW
	FRRAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNTKNTVDLQMNNLEPED
	AGRYYCAASLWGLGCKREEDYDYWGQGTQVTVSS
755	SEQ ID NO: 497
huE15-	X2 is GGGS, GGGGS, or GGGSGGGS
huA02	SEQ ID NO: 498
	X2 is GGGS
	EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI
	GNSAYYADSVKGRFTLSGDNSKNTLYLQMNSLRAEDTAVYYCAAKYYTDSYYAA
	ASYAYWGQGTLVTVSSX2EVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGWF
	RQAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNSKNTVYLQMNSLRAEDT
	AVYYCAASLWGLGCKREEDYDYWGQGTLVTVSS
883	SEQ ID NO: 499
E15-A05	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 500
	X1 is AS; X2 is GGGS
	X1QVQLQESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISW
	IGNSAYYADSVKGRFTLSGDNAKNTLYLQMNSLKPEDTAVYYCAAKYYTDSYYA
	AASYAYWGQGTQVTVSSX2QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW
	FRQAPGKEREGVSCISASDGSTHYADSVKGRFTISRDNTKNTVDLQMNNLKPED
	TGHYYCAASLWGLGCKSEADYDYWGQGTQVTVSS
784	SEQ ID NO: 501
huE15-	X2 is GGGS, GGGGS, or GGGSGGGS
huA05	SEQ ID NO: 502
	X2 is GGGS
	EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI
	GNSAYYADSVKGRFTLSGDNSKNTLYLQMNSLRAEDTAVYYCAAKYYTDSYYAA
	ASYAYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGWF
	RQAPGKGLEGVSAISASDASTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT
	AVYYCAASLHGLGAKSEADYDYWGQGTMVTVSS
785	SEQ ID NO: 503
huE15-	X2 is GGGS, GGGGS, or GGGSGGGS
huA05	SEQ ID NO: 504
	X2 is GGGS
	EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI
	GNSAYYADSVKGRFTLSGDNSKNTLYLQMNSLRAEDTAVYYCAAKYYTDSYYAA
	ASYAYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGWF
	RQAPGKGLEGVSCISASEGSTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT
	AVYYCAASLHGLGCKSEADYDYWGQGTMVTVSS
046	SEQ ID NO: 505
A06-A02	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 506
	X1 is AS; X2 is GGGS
	X1QLQLVESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKERGLVAAINW
	IPGTTYYADSVKGRFTISGDKDKNTLYLQMDNLKPEDTAVYYCAARRRIDNYYR
	ASEYDYWGQGTQVTVSSX2QVQLQESGGGLVQPGGSLKLSCAASGISLDEGVIGW
	FRRAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNTKNTVDLQMNNLEPED
	AGRYYCAASLWGLGCKREEDYDYWGQGTQVTVSS
747	SEQ ID NO: 507
huA06-	X2 is GGGS, GGGGS, or GGGSGGGS
huA02	SEQ ID NO: 508
	X2 is GGGS
	ELQLVESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKERELVAAINWI
	PGTTYYADSVKGRFTISGDKSKNTLYLQMNSLRAEDTAVYYCAARRRIDNYYRA
	SEYDYWGQGTLVTVSSX2EVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGWF
	RQAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNSKNTVYLQMNSLRAEDT
	AVYYCAASLWGLGCKREEDYDYWGQGTLVTVSS
875	SEQ ID NO: 509
A06-A05	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 510
	X1 is AS; X2 is GGGS
	X1QLQLVESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKERGLVAAINW
	IPGTTYYADSVKGRFTISGDKDKNTLYLQMDNLKPEDTAVYYCAARRRIDNYYR
	ASEYDYWGQGTQVTVSSX2QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW
	FRQAPGKEREGVSCISASDGSTHYADSVKGRFTISRDNTKNTVDLQMNNLKPED
	TGHYYCAASLWGLGCKSEADYDYWGQGTQVTVSS
776	SEQ ID NO: 511
huA06-	X2 is GGGS, GGGGS, or GGGSGGGS
huA05	SEQ ID NO: 512
	X2 is GGGS
	ELQLVESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKERELVAAINWI
	PGTTYYADSVKGRFTISGDKSKNTLYLQMNSLRAEDTAVYYCAARRRIDNYYRA
	SEYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGWF
	RQAPGKGLEGVSAISASDASTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT
	AVYYCAASLHGLGAKSEADYDYWGQGTMVTVSS
777	SEQ ID NO: 513
huA06-	X2 is GGGS, GGGGS, or GGGSGGGS
huA05	SEQ ID NO: 514
	X2 is GGGS
	ELQLVESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKERELVAAINWI
	PGTTYYADSVKGRFTISGDKSKNTLYLQMNSLRAEDTAVYYCAARRRIDNYYRA
	SEYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGWF
	RQAPGKGLEGVSCISASEGSTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT
	AVYYCAASLHGLGCKSEADYDYWGQGTMVTVSS
272	SEQ ID NO: 515
A06-C04	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 516
	X1 is AS; X2 is GGGS
	X1QLQLVESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKERGLVAAINW
	IPGTTYYADSVKGRFTISGDKDKNTLYLQMDNLKPEDTAVYYCAARRRIDNYYR
	ASEYDYWGQGTQVTVSSX2QVQLVESGGGLVQSGGSLRLSCVASGFTSPYSTIGW
	FRQAPGKEREGVACISSSGRGVNANYIDSVRGRFTISRDNAKNTVYLQMNKLKP
	DDTAIYYCATNCWRLTSPAADNWGQGTQVTVSS
773	SEQ ID NO: 517
huA06-	X2 is GGGS, GGGGS, or GGGSGGGS
huC04	SEQ ID NO: 518
	X2 is GGGS
	ELQLVESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKERELVAAINWI
	PGTTYYADSVKGRFTISGDKSKNTLYLQMNSLRAEDTAVYYCAARRRIDNYYRA
	SEYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTIGWF
	RQAPGKGREGVACISSSGRGVNANYIDSVRGRFTISRDNSKNTVYLQMNSLRAE
	DTAVYYCATNCWRLTSPAADNWGQGTMVTVSS
052	SEQ ID NO: 519
C09-A02	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 520
	X1 is AS; X2 is GGGS
	X1QVQLQESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISW
	IGGGTYYADSVKGRFTLSRDNAKNMVYLQMNSLKPEDTAVYYCAAKYYPDSYFA
	AASYAYWGQGTQVTVSSX2QVQLQESGGGLVQPGGSLKLSCAASGISLDEGVIGW
	FRRAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNTKNTVDLQMNNLEPED
	AGRYYCAASLWGLGCKREEDYDYWGQGTQVTVSS
753	SEQ ID NO: 521
huC09-	X2 is GGGS, GGGGS, or GGGSGGGS
huA02	SEQ ID NO: 522
	X2 is GGGS
	EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI
	GGGTYYADSVKGRFTLSRDNSKNTVYLQMNSLRAEDTAVYYCAAKYYPDSYFAA
	ASYAYWGQGTLVTVSSX2EVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGWF
	RQAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNSKNTVYLQMNSLRAEDT
	AVYYCAASLWGLGCKREEDYDYWGQGTLVTVSS
278	SEQ ID NO: 523
C09-C04	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 524
	X1 is AS; X2 is GGGS
	X1QVQLQESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISW
	IGGGTYYADSVKGRFTLSRDNAKNMVYLQMNSLKPEDTAVYYCAAKYYPDSYFA
	AASYAYWGQGTQVTVSSX2QVQLVESGGGLVQSGGSLRLSCVASGFTSPYSTIGW
	FRQAPGKEREGVACISSSGRGVNANYIDSVRGRFTISRDNAKNTVYLQMNKLKP
	DDTAIYYCATNCWRLTSPAADNWGQGTQVTVSS
769	SEQ ID NO: 525
huC09-	X2 is GGGS, GGGGS, or GGGSGGGS
huC04	SEQ ID NO: 526
	X2 is GGGS
	EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI
	GGGTYYADSVKGRFTLSRDNSKNTVYLQMNSLRAEDTAVYYCAAKYYPDSYFAA
	ASYAYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTIGWF
	RQAPGKGREGVACISSSGRGVNANYIDSVRGRFTISRDNSKNTVYLQMNSLRAE
	DTAVYYCATNCWRLTSPAADNWGQGTMVTVSS
047	SEQ ID NO: 527
D08-A02	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 528
	X1 is AS; X2 is GGGS
	X1QVQLQESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISW
	IGGSTYYADSVKGRFTLSSDNAKNRIALQMNSLKPEDTAVYYCAAKYYTDSYFA
	ATSYAYWGQGTQVTVSSX2QVQLQESGGGLVQPGGSLKLSCAASGISLDEGVIGW
	FRRAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNTKNTVDLQMNNLEPED
	AGRYYCAASLWGLGCKREEDYDYWGQGTQVTVSS
748	SEQ ID NO: 529
huD08-	X2 is GGGS, GGGGS, or GGGSGGGS
huA02	SEQ ID NO: 530
	X2 is GGGS
	EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI
	GGGTYYADSVKGRFTLSRDNSKNTVYLQMNSLRAEDTAVYYCAAKYYPDSYFAA
	ASYAYWGQGTLVTVSSX2EVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGWF
	RQAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNSKNTVYLQMNSLRAEDT
	AVYYCAASLWGLGCKREEDYDYWGQGTLVTVSS
876	SEQ ID NO: 531
D08-A05	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 532
	X1 is AS; X2 is GGGS
	X1QVQLQESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISW
	IGGSTYYADSVKGRFTLSSDNAKNRIALQMNSLKPEDTAVYYCAAKYYTDSYFA
	ATSYAYWGQGTQVTVSSX2QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW
	FRQAPGKEREGVSCISASDGSTHYADSVKGRFTISRDNTKNTVDLQMNNLKPED
	TGHYYCAASLWGLGCKSEADYDYWGQGTQVTVSS
778	SEQ ID NO: 533
huD08-	X2 is GGGS, GGGGS, or GGGSGGGS
huA05	SEQ ID NO: 534
	X2 is GGGS
	EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI
	GGGTYYADSVKGRFTLSRDNSKNTVYLQMNSLRAEDTAVYYCAAKYYPDSYFAA
	ASYAYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGWF
	RQAPGKGLEGVSAISASDASTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT
	AVYYCAASLHGLGAKSEADYDYWGQGTMVTVSS
779	SEQ ID NO: 535
huD08-	X2 is GGGS, GGGGS, or GGGSGGGS
huA05	SEQ ID NO: 536
	X2 is GGGS
	EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI
	GGGTYYADSVKGRFTLSRDNSKNTVYLQMNSLRAEDTAVYYCAAKYYPDSYFAA
	ASYAYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGWF
	RQAPGKGLEGVSCISASEGSTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT
	AVYYCAASLHGLGCKSEADYDYWGQGTMVTVSS
062	SEQ ID NO: 537
I04-A02	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 538
	X1 is AS; X2 is GGGS
	X1QVQLVESGGGLVQAGGSLRLSCAASGRTFSNYAMAWFRQAPGKEREFVSAINW
	FGRATEYADSVKDRETTSGDSAKNTVYLQMNSLKPEDTAVYYCAARTKVITGRR
	NQAEYDYWGQGTQVTVSSX2QVQLQESGGGLVQPGGSLKLSCAASGISLDEGVIG
	WFRRAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNTKNTVDLQMNNLEPE
	DAGRYYCAASLWGLGCKREEDYDYWGQGTQVTVSS
763	SEQ ID NO: 539
huI04-	X2 is GGGS, GGGGS, or GGGSGGGS
huA02	SEQ ID NO: 540
	X2 is GGGS
	EVQLVESGGGLVQPGGSLRLSCAASGRTFSNYAMAWFRQAPGKEREFVSAINWE
	GRATEYADSVKDRFTTSGDSSKNTVYLQMNSLRAEDTAVYYCAARTKVTTGRRN
	QAEYDYWGQGTLVTVSSX2EVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGW
	FRQAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNSKNTVYLQMNSLRAED
	TAVYYCAASLWGLGCKREEDYDYWGQGTLVTVSS
891	SEQ ID NO: 541
I04-A05	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 542
	X1 is AS; X2 is GGGS
	X1QVQLVESGGGLVQAGGSLRLSCAASGRTFSNYAMAWFRQAPGKEREFVSAINW
	FGRATEYADSVKDRFTTSGDSAKNTVYLQMNSLKPEDTAVYYCAARTKVTTGRR
	NQAEYDYWGQGTQVTVSSX2QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIG
	WFRQAPGKEREGVSCISASDGSTHYADSVKGRFTISRDNTKNTVDLQMNNLKPE
	DTGHYYCAASLWGLGCKSEADYDYWGQGTQVTVSS
780	SEQ ID NO: 543
huI04-	X2 is GGGS, GGGGS, or GGGSGGGS
huA05	SEQ ID NO: 544
	X2 is GGGS
	EVQLVESGGGLVQPGGSLRLSCAASGRTFSNYAMAWFRQAPGKEREFVSAINWE
	GRATEYADSVKDRFTTSGDSSKNTVYLQMNSLRAEDTAVYYCAARTKVTTGRRN
	QAEYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW
	FRQAPGKGLEGVSAISASDASTHYADAVKGRFTISRDNSKNTVYLQMNSLRAED
	TAVYYCAASLHGLGAKSEADYDYWGQGTMVTVSS
781	SEQ ID NO: 545
huI04-	X2 is GGGS, GGGGS, or GGGSGGGS
huA05	SEQ ID NO: 546
	X2 is GGGS
	EVQLVESGGGLVQPGGSLRLSCAASGRTFSNYAMAWFRQAPGKEREFVSAINWE
	GRATEYADSVKDRETTSGDSSKNTVYLQMNSLRAEDTAVYYCAARTKVTTGRRN
	QAEYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGW
	FRQAPGKGLEGVSCISASEGSTHYADAVKGRFTISRDNSKNTVYLQMNSLRAED
	TAVYYCAASLHGLGCKSEADYDYWGQGTMVTVSS
290	SEQ ID NO: 547
I04-C04	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 548
	X1 is AS; X2 is GGGS
	X1QVQLVESGGGLVQAGGSLRLSCAASGRTFSNYAMAWFRQAPGKEREFVSAINW
	FGRATEYADSVKDRFTTSGDSAKNTVYLQMNSLKPEDTAVYYCAARTKVTTGRR
	NQAEYDYWGQGTQVTVSSX2QVQLVESGGGLVQSGGSLRLSCVASGFTSPYSTIG
	WFRQAPGKEREGVACISSSGRGVNANYIDSVRGRFTISRDNAKNTVYLQMNKLK
	PDDTAIYYCATNCWRLTSPAADNWGQGTQVTVSS
791	SEQ ID NO: 549
huI04-	X2 is GGGS, GGGGS, or GGGSGGGS
huC04	SEQ ID NO: 550
	X2 is GGGS
	EVQLVESGGGLVQPGGSLRLSCAASGRTFSNYAMAWFRQAPGKEREFVSAINWF
	GRATEYADSVKDRETTSGDSSKNTVYLQMNSLRAEDTAVYYCAARTKVTTGRRN
	QAEYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTIGW
	FRQAPGKGREGVACISSSGRGVNANYIDSVRGRFTISRDNSKNTVYLQMNSLRA
	EDTAVYYCATNCWRLTSPAADNWGQGTMVTVSS
892	SEQ ID NO: 551
J13-A05	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 552
	X1 is AS; X2 is GGGS
	X1QVQLVESGGGSVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKERGEVATINW
	IPGNTYYADSVKGRFTISGEEDKNTVYLQMDNLKPEDTAVYYCAARRRIDNYYR
	ASEYDYWGQGTQVTVSSX2QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW
	FRQAPGKEREGVSCISASDGSTHYADSVKGRFTISRDNTKNTVDLQMNNLKPED
	TGHYYCAASLWGLGCKSEADYDYWGQGTQVTVSS
793	SEQ ID NO: 553
huJ13-	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
huA05	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 554
	X1 is AS; X2 is GGGS
	X1QVQLVESGGGVVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVATINW
	IPGNTYYADSVKGRFTISGDESKNTVYLQMNSLRAEDTAVYYCAARRRIDNYYR
	ASEYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW
	FRQAPGKGLEGVSAISASDASTHYADAVKGRFTISRDNSKNTVYLQMNSLRAED
	TAVYYCAASLHGLGAKSEADYDYWGQGTMVTVSS
794	SEQ ID NO: 555
huJ13-	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
huA05	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 556
	X1 is AS; X2 is GGGS
	X1QVQLVESGGGVVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVATINW
	IPGNTYYADSVKGRFTISGDESKNTVYLQMNSLRAEDTAVYYCAARRRIDNYYR
	ASEYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGW
	FRQAPGKGLEGVSCISASEGSTHYADAVKGRFTISRDNSKNTVYLQMNSLRAED
	TAVYYCAASLHGLGCKSEADYDYWGQGTMVTVSS
894	SEQ ID NO: 557
N16-A05	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 558
	X1 is AS; X2 is GGGS
	X1QVQLVESGGGLVQAGGSLRLSCAASGGTFSYYGMGWFRQAPGKEREFVAAIRW
	IGGDTYYADSVKGRFTISKDNAKNTLYLQMSSLKPEDTAVYYCAAKTSVTSYLS
	EKSYNYWGQGTQVTVSSX2QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW
	FRQAPGKEREGVSCISASDGSTHYADSVKGRFTISRDNTKNTVDLQMNNLKPED
	TGHYYCAASLWGLGCKSEADYDYWGQGTQVTVSS
795	SEQ ID NO: 559
huN16-	X2 is GGGS, GGGGS, or GGGSGGGS
huA05	SEQ ID NO: 560
	X2 is GGGS
	EVQLVESGGGLVQPGGSLRLSCAASGGTFSYYGMGWFRQAPGKEREFVAAIRWI
	GGDTYYADSVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTSVTSYLSE
	KSYNYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGWF
	RQAPGKGLEGVSAISASDASTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT
	AVYYCAASLHGLGAKSEADYDYWGQGTMVTVSS
796	SEQ ID NO: 561
huN16-	X2 is GGGS, GGGGS, or GGGSGGGS
huA05	SEQ ID NO: 562
	X2 is GGGS
	EVQLVESGGGLVQPGGSLRLSCAASGGTFSYYGMGWFRQAPGKEREFVAAIRWI
	GGDTYYADSVKGRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAAKTSVTSYLSE
	KSYNYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGWF
	RQAPGKGLEGVSCISASEGSTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT
	AVYYCAASLHGLGCKSEADYDYWGQGTMVTVSS
884	SEQ ID NO: 563
F09-A05	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 564
	X1 is AS; X2 is GGGS
	X1QVQLQESGGGLVQAGGSLSLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISW
	IGSATDYADSVRGRFTISGDNAKNTVYLLMNNLKPEDTAVYYCAARRSPMSRTS
	VLQYDYWGQGTQVTVSSX2QVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGW
	FRQAPGKEREGVSCISASDGSTHYADSVKGRFTISRDNTKNTVDLQMNNLKPED
	TGHYYCAASLWGLGCKSEADYDYWGQGTQVTVSS
786	SEQ ID NO: 565
huF09-	X2 is GGGS, GGGGS, or GGGSGGGS
huA05	SEQ ID NO: 566
	X2 is GGGS
	EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI
	GSATDYADSVRGRFTISGDNSKNTVYLQMNSLRAEDTAVYYCAARRSPMSRTSV
	LQYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYPTIGWF
	RQAPGKGLEGVSAISASDASTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT
	AVYYCAASLHGLGAKSEADYDYWGQGTMVTVSS
787	SEQ ID NO: 567
huF09-	X2 is GGGS, GGGGS, or GGGSGGGS
huA05	SEQ ID NO: 568
	X2 is GGGS
	EVQLLESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI
	GSATDYADSVRGRFTISGDNSKNTVYLQMNSLRAEDTAVYYCAARRSPMSRTSV
	LQYDYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGNSLDYSTIGWF
	RQAPGKGLEGVSCISASEGSTHYADAVKGRFTISRDNSKNTVYLQMNSLRAEDT
	AVYYCAASLHGLGCKSEADYDYWGQGTMVTVSS
058	SEQ ID NO: 569
F21-A02	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 570
	X1 is AS; X2 is GGGS
	X1QVQLVESGGGLVQAGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISW
	IGNSTYYADSVKGRFTLSGDNAKNTLYLQMNSLKPEDTAVYYCAAKYYTDSYYA
	AASYAYWGQGTQVTVSSX2QVQLQESGGGLVQPGGSLKLSCAASGISLDEGVIGW
	FRRAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNTKNTVDLQMNNLEPED
	AGRYYCAASLWGLGCKREEDYDYWGQGTQVTVSS
759	SEQ ID NO: 571
huF21-	X2 is GGGS, GGGGS, or GGGSGGGS
huA02	SEQ ID NO: 572
	X2 is GGGS
	EVQLVESGGGLVQPGGSLRLSCAASGRTFSSYGMGWFRQAPGKEREFVAAISWI
	GNSTYYADSVKGRFTLSGDNSKNTLYLQMNSLRAEDTAVYYCAAKYYTDSYYAA
	ASYAYWGQGTLVTVSSX2EVQLLESGGGLVQPGGSLRLSCAASGISLDEGVIGWF
	RQAPGKEREGVSCISARDGSTHYANAVKGRFTISRDNSKNTVYLQMNSLRAEDT
	AVYYCAASLWGLGCKREEDYDYWGQGTLVTVSS
767	SEQ ID NO: 573
F11-C04	EX1QLX2ESGGGLVQX3GGSLRLSCAX4SGRTFSSHTVGWFRQAPGKX5REFVX6A
con	ITWNGDTTYFGDFVEGRFX7ISRDX8X9KNTLYLX10MNX11LX12X13EDTAVYYCA
	AATGQVWSLQYLRESSYAYWGQGTX14VTVSSX15X16VQLVESGGGLVQX17GGSL
	RLSCX18ASGFTSPYSTIGWFRQAPGKX19REGVACISSSGRGVNANYIDSVRGRF
	TISRDNX20KNTVYLQMNX21LKX22X23DTAX24YYCATNCWRLTSPAADNWGQGT
	X25VTVSS
	X1 is L or V
	X2 is L or V
	X3 is A or P
	X4 is A or N
	X5 is E or G
	X6 is A or E
	X7 is S or T
	X8 is N or S
	X9 is A or S
	X10 is E or Q
	X11 is K or S
	X12 is K or R
	X13 is A or P
	X14 is L or Q
	X15 is GGGS, GGGGS, or GGGSGGGS
	X16 is E or Q
	X17 is P or S
	X18 is S or V
	X19 is E or G
	X20 is A or S
	X21 is K or S
	X22 is A or P
	X23 is D or E
	X24 is I or V
	X25 is M or Q
284	SEQ ID NO: 574
F11-C04	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 575
	X2 is GGGS
	ELQLVESGGGLVQAGGSLRLSCANSGRTFSSHTVGWFRQAPGKEREFVAAITWN
	GDTTYFGDFVEGRESISRDSAKNTLYLEMNKLKPEDTAVYYCAAATGQVWSLQY
	LRESSYAYWGQGTQVTVSSX2QVQLVESGGGLVQSGGSLRLSCVASGFTSPYSTI
	GWFRQAPGKEREGVACISSSGRGVNANYIDSVRGRFTISRDNAKNTVYLQMNKL
	KPDDTAIYYCATNCWRLTSPAADNWGQGTQVTVSS
183	SEQ ID NO: 576
huF11-	X2 is GGGS, GGGGS, or GGGSGGGS
huC04	SEQ ID NO: 577
	X2 is GGGS
	EVQLLESGGGLVQPGGSLRLSCAASGRTFSSHTVGWFRQAPGKGREFVAAITWN
	GDTTYFGDFVEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAATGQVWSLQY
	LRESSYAYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTI
	GWFRQAPGKGREGVACISSSGRGVNANYIDSVRGRFTISRDNSKNTVYLQMNSL
	RAEDTAVYYCATNCWRLTSPAADNWGQGTMVTVSS
184	SEQ ID NO: 578
huF11-	X2 is GGGS, GGGGS, or GGGSGGGS
huC04	SEQ ID NO: 579
	X2 is GGGS
	ELQLLESGGGLVQPGGSLRLSCAASGRTFSSHTVGWFRQAPGKGREFVSAITWN
	GDTTYFGDFVEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAATGQVWSLQY
	LRESSYAYWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTI
	GWFRQAPGKGREGVACISSSGRGVNANYIDSVRGRFTISRDNSKNTVYLQMNSL
	RAEDTAVYYCATNCWRLTSPAADNWGQGTMVTVSS
239	SEQ ID NO: 580
G22-B12	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 581
	X1 is AS; X2 is GGGS
	X1QLQLVESGGGLVQAGGSLKLSCTASGRTFDGYGMGWFRQAPGKEREFVSAINW
	IYGATYYADSVKGRFAVSRDKAKGTMYLQMNSLKPEDTAVYYCAAKINAGSYFN
	IGSFGSWGQGTQVTVSSX2EVQLVESGGGLVQAGGSLRLSCAASGSFSSISTMAW
	YRQVPGKQREWLARIIWSSGATNYADSVKGRFTISRDNTKNTMYLQMDRLTPED
	TAAYLCSGAISQTRGTFWTYKSQGTQVTVSS
740	SEQ ID NO: 582
huG22-	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
huB12	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 583
	X1 is AS; X2 is GGGS
	X1QLQLVESGGGLVQPGGSLRLSCSASGRTFDGYGMGWFRQAPGKEREFVSAINW
	IYGATYYADSVKGRFTVSRDKSKNTMYLQMNSLRAEDTAVYYCAAKINAGSYFN
	IGSFGSWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGSESSISTMAW
	YRQAPGKQREWLARIIWSSGATNYADSVKGRFTISRDNSKNTMYLQMNSLRAED
	TAVYYCSGAISQTRGTFWTYKGQGTLVTVSS
286	SEQ ID NO: 584
G22-C04	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 585
	X1 is AS; X2 is GGGS
	X1QLQLVESGGGLVQAGGSLKLSCTASGRTFDGYGMGWFRQAPGKEREFVSAINW
	IYGATYYADSVKGRFAVSRDKAKGTMYLQMNSLKPEDTAVYYCAAKINAGSYFN
	IGSFGSWGQGTQVTVSSX2QVQLVESGGGLVQSGGSLRLSCVASGFTSPYSTIGW
	FRQAPGKEREGVACISSSGRGVNANYIDSVRGRFTISRDNAKNTVYLQMNKLKP
	DDTAIYYCATNCWRLTSPAADNWGQGTQVTVSS
788	SEQ ID NO: 586
huG22-	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
huC04	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 587
	X1 is AS; X2 is GGGS
	X1QLQLVESGGGLVQPGGSLRLSCSASGRTFDGYGMGWFRQAPGKEREFVSAINW
	IYGATYYADSVKGRFTVSRDKSKNTMYLQMNSLRAEDTAVYYCAAKINAGSYFN
	IGSFGSWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCSASGFTSPYSTIGW
	FRQAPGKGREGVACISSSGRGVNANYIDSVRGRFTISRDNSKNTVYLQMNSLRA
	EDTAVYYCATNCWRLTSPAADNWGQGTMVTVSS
247	SEQ ID NO: 588
L05-B12	X1 is S, GG, AS, ASS or absent (i.e., no amino acid
	residues)
	X2 is GGGS, GGGGS, or GGGSGGGS
	SEQ ID NO: 589
	X1 is AS; X2 is GGGS
	X1QVQLLESGGGLVQAGGSLKLSCTNSGRTFSGYGMGWFRQPPGKEREFVSSINW
	IYGATYYSDSVKGRFALSRDKAKNTVYLQMDSLKPEDTAVYYCAAKINGESYFN
	TGSFGSWGQGTQVTVSSX2EVQLVESGGGLVQAGGSLRLSCAASGSFSSISTMAW
	YRQVPGKQREWLARIIWSSGATNYADSVKGRFTISRDNTKNTMYLQMDRLTPED
	TAAYLCSGAISQTRGTFWTYKSQGTQVTVSS
749	SEQ ID NO: 590
huL05-	X2 is GGGS, GGGGS, or GGGSGGGS
huB12	SEQ ID NO: 591
	X2 is GGGS
	EVQLLESGGGLVQPGGSLRLSCAASGRTFSGYGMGWFRQAPGKEREFVSSINWI
	YGATYYSDSVKGRFTLSRDKSKNTVYLQMNSLRAEDTAVYYCAAKINGESYFNT
	GSFGSWGQGTLVTVSSX2EVQLVESGGGLVQPGGSLRLSCAASGSFSSISTMAWY
	RQAPGKQREWLARIIWSSGATNYADSVKGRFTISRDNSKNTMYLQMNSLRAEDT
	AVYYCSGAISQTRGTFWTYKGQGTLVTVSS