COMPOSITION FOR MODIFYING A T CELL

[0001] This disclosure claims the priority of U.S. provisional application No. 63/397,150 filed on Aug. 11, 2022 and incorporated herein by reference in its entirety.

[0002] This disclosure relates to the field of T cell genetic modifications, particularly the production of chimeric antigen receptor T cells (CAR-T) and vectors for performing the CAR gene editing.

[0003] Chimeric antigen receptors (CARs) typically include an extracellular target-binding domain, a hinge region, a transmembrane domain that anchors the CAR to the cell membrane, and one or more intracellular domains that transmit activation signals, by signal cascade. The transmembrane domain is generally a hydrophobic helix that spans the thickness of the cell membrane. CARs are generally classified based on their number of costimulatory domains: first generation (CD3z only), second generation (one costimulatory domain and CD3z), and third generation (more than one costimulatory domain and CD3z). The purpose of introducing CAR molecules into a T cell is to redirect the T cell to a desired specificity and provide the necessary signals to drive full T cell activation. For example, a T cell can be genetically modified into a CAR-T cell that has specificity to an antigen presented by specific cancer cells. One particular area of clinical interest for CAR-T cells is the treatment of blood cancer types. The recognition of an antigen by a CAR-T cell is driven by the binding of the target-binding single-chain variable fragment (scFv) to surface antigens.

[0004] The hinge, which can also be referred to as a spacer, is the extracellular structural region of the CAR that separates the binding units from the transmembrane domain. The majority of CAR T cells are designed with immunoglobulin (Ig)-like domain hinges. These spacers generally supply stability for efficient CAR expression and activity. The hinge also provides flexibility to access the targeted antigen. The length of the hinge affects the binding efficiency of the CAR. For example, long spacers provide flexibility and therefore improved access to membrane-proximal epitopes or complex glycosylated antigens, whereas short spaces are more effective at binding distal epitopes. The length of the spacer provides adequate intercellular distance for immunological synapse formation. Accordingly, hinges can affect the overall performance of CAR-T cells.

[0005] Cellular therapies utilizing CAR-T cells are immunotherapeutic tools for combating conditions such as hematological diseases. Natural killer (NK) cells are a type of T cell that can also be modified into a CAR-T cell with a specific target. CD8 T cells, similarly to NK cells, have the capacity to target and kill a specific cell whereas CD4 T cells generally mediate the immune response to direct other killer cells. NK and CD8 T cells have the capacity to target and kill a cell based on the specificity of the CAR inserted therein. The use of CAR-T cells can greatly improve cancer treatment and patient outcomes. An allogeneic setting requires universal CAR T cells that can kill target tumor cells, avoid depletion by the host immune system, and proliferate without attacking host tissues. On the other hand an autologous therapy harvests the patient's own T cells that are then genetically modified into CAR-T cells and administered to the patient.

[0006] The modification of a T cell into a CAR-T cell requires a delivery means to provide the gene editing tools as well as the genetic material encoding the CAR. Viral vectors have been used for producing CAR-T cells. Examples of viral vectors include lentiviral vectors, gamma-retroviral vectors, recombinant adeno-associated virus vectors, and the like. In the case of retroviral transduction, the insertional mutagenesis has deleterious impact on the viability of primary T cells which is a major limitation for the application of retrovirus clinically. Lentivirus-based transduction represents a safer option because of a lower genotoxicity and insertional mutagenesis. Unfortunately, the efficiency of lentiviral transduction in primary T cells is low, often requiring multiple rounds of transduction, therefore also limiting its capacity in the clinical setting. Further disadvantages of retroviruses include the fact that they can only integrate into dividing cells in the mitosis stage and that the genetic integration is non-targeted. An additional disadvantage of lentiviral vectors is that they are non-integrative. In general, viral vectors present a mutagenesis risk which is a major concern in the clinical setting.

[0007] Electroporation has also been used to deliver the gene editing material and CAR construct to the T cells. However, electroporation leads to a high cell death rate and a difficult genomic integration. Overall, the electroporation technique has low efficacy and is not desirable in the clinical setting particularly when primary cells are involved. Moreover, the gene-transduction approaches usually lead to random integration of DNA into the target cell genome, resulting in the potential risk for off-target effects, such as the silencing of essential genes or tumour suppressor genes that may trigger cell apoptosis or malignant transformation.

[0008] Accordingly, improvements in transduction efficiency and targeting are desired particularly for primary cells. This would greatly improve the use of CAR-T cell therapies involving primary T cells for example in the treatment of cancer.

[0009] In one aspect, there is provided a composition for modifying a T cell, the composition comprising: a protein complex comprising a polynucleotide-modifying enzyme domain, a T cell membrane binding domain and an endosome escape domain; a guide oligonucleotide specific to a T cell receptor a constant (TRAC) gene of the T cell; and a donor DNA comprising two homology arms at each end of the donor DNA homologous to exon1 of the TRAC gene and encoding therebetween a chimeric antigen T cell receptor comprising: a translocation signal for translocation to a cell membrane of the T cell; a transmembrane domain; an intracellular signaling domain; and an extracellular antigen binding domain. In some embodiments, the protein complex further comprises a hapten binding domain, preferably the donor DNA is conjugated to a hapten and the hapten binds the hapten binding domain. In some embodiments, the protein complex further comprises a nuclear localisation sequence. In some embodiments, the chimeric antigen T cell receptor further comprises a CD8 hinge region. In some embodiments, the chimeric antigen T cell receptor further comprises a B cell lymphoma recognition domain. In some embodiments, the guide oligonucleotide is complementary to a sequence located between 250 nucleotides before the start codon of the exon 1 of the TRAC gene to 250 nucleotides after the start codon of the exon 1 of the TRAC gene. In some embodiments, the polynucleotide-modifying enzyme domain is covalently linked to the endosome escape domain. In some embodiments, the T cell membrane binding domain is a cationic peptide. In some embodiments, the T cell membrane binding domain is a cell recognition domain. In some embodiments, the cell recognition domain targets CD4, CD8, CD16 or CD56. In some embodiments, the cell recognition domain is covalently coupled to the endosome escape domain. In some embodiments, the cell recognition domain is a display domain being a peptidic recognition sequence of from 3 to 20 amino acids in length positioned in a loop or alpha helix on an external surface of the polynucleotide-modifying enzyme domain. In some embodiments, the peptidic recognition sequence is a complementarity-determining region (CDR). In some embodiments, the cell recognition domain is an antigen binding domain selected from Fab, single-domain antibody (sdAb), V_HH, or camelid antibody domain, positioned in a loop on an external surface of the polynucleotide-modifying enzyme. In some embodiments, the polynucleotide-modifying domain is a type II Cas, a functional analog thereof, a variant thereof or a derivative thereof. In some embodiments, the type II Cas is Cas9, a functional analog thereof, a variant thereof or a derivative thereof. In some embodiments, the polynucleotide-modifying domain is a type V Cas, a functional analog thereof, a variant thereof or a derivative thereof. In some embodiments, the extracellular antigen binding domain is specific to a cancer specific antigen.

[0010] In one aspect, the composition of the present disclosure is provided for use in cellular therapy, such as in the treatment of cancer.

[0011] In one aspect, there is provided the use of the composition of the present disclosure in cellular therapy, such as in the treatment of cancer.

[0012] In one aspect, there is provided a method of performing cellular therapy for a subject in need thereof, the method comprising providing ex vivo allogenic T cells, modifying the genome of the T cells with the composition of the present disclosure to obtain chimeric antigen receptor (CAR) T cells, and administering the CAR T cells to the subject.

[0013] In one aspect, there is provided a method of performing cellular therapy for a subject in need thereof, the method comprising providing ex vivo allogenic T cells, modifying the genome of the T cells with the composition of the present disclosure by having the composition bind to the cell membrane of the T cells and undergo cell internalization to obtain CAR-T cells, and administering the CAR T cells to the subject.

[0014] In one aspect, there is provided a method of treating cancer for a subject in need thereof, the method comprising providing allogenic T cells, modifying the genome of the T cells with the composition of the present disclosure to obtain CAR T cells, and administering the CAR T cells to the subject.

[0015] In one aspect, there is provided a method of performing cellular therapy for a subject in need thereof, the method comprising delivering the composition of the present disclosure to in vivo T cells of the subject to modify the genome of the T cells and obtain chimeric antigen receptor (CAR) T cells in vivo.

[0016] In one aspect, there is provided a method of treating cancer for a subject in need thereof, the method comprising delivering the composition of the present disclosure to in vivo T cells of the subject to modify the genome of the T cells and obtain chimeric antigen receptor (CAR) T cells in vivo.

[0017] In one aspect, there is provided a method of producing a CAR-T cell, the method comprising internalizing the composition of the present disclosure by binding to the cellular membrane of a T cell, and incubating the T cells to allow the composition to edit the genome of the T cell.

[0018] In one aspect, there is provided a polynucleotide-modifying enzyme comprising: a functional nuclease domain comprising a nuclease catalytic pocket; an antigen binding domain selected from Fab, single-domain antibody (sdAb), V_HH, or camelid antibody domain, in a loop that is positioned on an external surface of the polynucleotide-modifying enzyme, and said antigen binding domain recognizes a target cell receptor of a target cell to allow cell internalization of the polynucleotide-modifying enzyme in said target cell; and a linker of from 0 to 30 amino acids, upstream of the antigen binding domain. In some embodiments, the nanobody is a VHH. The linker sequence is preferably from 16 to 23 amino acids. The nuclease catalytic pocket is preferably a Cas nuclease catalytic pocket, recombinase catalytic pocket or a meganuclease catalytic pocket. The Cas can be a type II Cas such as cas9, a functional analog thereof, a variant thereof or a derivative thereof. In some embodiments, the nuclease catalytic pocket comprises a HNH nuclease domain. In some embodiments, the Cas is a type V Cas such as Cas12, a functional analog thereof, a variant thereof or a derivative thereof. In some embodiments, the Cas is a type VI Cas such as Cas13, a functional analog thereof, a variant thereof or a derivative thereof. In some embodiments, the Cas is a Cas14, a functional analog thereof, a variant thereof or a derivative thereof. In some embodiments, the nuclease catalytic pocket comprises a RuvC nuclease domain. In one aspect, there is provided a vector encoding the polynucleotide modifying enzyme comprising: a 5′ end and a 3′ end of a nuclease enzyme and in between the 5′ end and the 3′ end of the nuclease enzyme: an encoded functional nuclease domain coding the functional nuclease domain; an encoded antigen binding domain coding the antigen binding domain, the antigen binding domain; a linker sequence coding the linker, upstream of a 5′ end of the encoded antigen binding domain, coding the linker sequence.

[0019] Many further features and combinations thereof concerning the present improvements will appear to those skilled in the art following a reading of the instant disclosure.

[0195] As used herein, the term “cell recognition domain” (or “CRD”) refers to a natural or synthetic peptide or nucleic acid domain capable of specific non-covalent association with a cell-surface antigen or receptor.

[0196] As used herein, the term “polynucleotide modifying enzyme” (or “PNME”) refers to a peptide enzyme capable of cleaving the phosphodiester backbone of a nucleic acid (e.g. DNA or RNA) or altering the identity of one or more nitrogenous bases within a nucleic acid.

[0197] As used herein, the term “endosome escape domain” (or “EE domain”) refers to a peptide sequence which, when associated with a molecular cargo, facilitates diffusion of the cargo from the endosomal compartment to the cytosol and/or alters the steady state distribution of the cargo between the endosomal compartment and in favor of the cytosol.

[0198] As used herein, the term “display domain” refers to a peptide sequence capable of specific non-covalent association with a cell-surface antigen or receptor. The display domain is incorporated in the PNME and does not disrupt the activity of the functional nuclease domain. The display domain can have a size and/or be positioned in the sequence of the PNME such that the nuclease catalytic pocket is not disrupted and retains at least 50%, at least 60%, at least 70%, preferably at least 80%, and more preferably at least 90%, of its cleaving activity. For example, the three dimensional conformation of the nuclease catalytic pocket can correspond substantially (e.g. same alpha helix and same beta sheets) to the three dimensional conformation that would be obtained without the insertion of the display domain in the PNME.

[0199] As used herein, the term “hapten” refers to a small molecule, which when combined with a larger carrier such as a protein, is capable of high affinity binding to an antibody or antibody mimetic (“hapten binding domain”). In some embodiments, the molecular weight of the organic compound is less than 500 Daltons. In some embodiments, the affinity (K_D) of the hapten for the hapten binding domain is less than 10⁻⁶ molar. In some embodiments, the affinity (K_D) of the hapten for the peptide or nucleic acid aptamer is less than 10⁻⁷ molar. In some embodiments, the affinity (K_D) of the hapten for the peptide or nucleic acid aptamer is less than 10⁻⁸ molar. In some embodiments, the affinity (K_D) of the hapten for the peptide or nucleic acid aptamer is less than 10⁻⁹ molar. As used herein, the term “linker”, “linker group” or “linker domain” means a group that can link one chemical moiety to another chemical moiety. In some embodiments, a linker is a chemical bond. In some embodiments, the linker is an organic molecule, group, polymer, or chemical moiety. In some embodiments, the linker is a cleavable linker, e.g., the linker comprises a linkage that can be cleaved upon exposure to a cleavage activity such as UV light or a hydrolase, such as a lysosomal protease. In some embodiments, the linker may comprise one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, 20 or more, 25 or more, 30 or more, 40 or more, 50 or more amino acids. In some embodiments, the peptide linker comprises a repeat of a tri-peptide Gly-Gly-Ser, including, for example, sequence (GGS)_n, wherein n is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more repeats. In some embodiments, the linker can comprise at least two polyethyleneglycol (PEG) residues. In some embodiments, a PEG linker comprises three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more PEG residues. In some embodiments, the PNME described herein comprises linkers joining two or more domains described herein, such as any combination of two or more of endosome escape domains, nuclear localization sequences, or PNME domains.

[0200] The term “tracrRNA” or “tracr sequence”, as used herein, refers to a nucleic acid with at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% sequence identity and/or sequence similarity to a wild type exemplary tracrRNA sequence (e.g., a tracrRNA from S. pyogenes, S. aureus, etc). tracrRNA can refer to a nucleic acid with at most about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% sequence identity and/or sequence similarity to a wild type exemplary tracrRNA sequence. tracrRNA may refer to a modified form of a tracrRNA that can comprise a nucleotide change such as a deletion, insertion, or substitution, variant, mutation, or chimera. A tracrRNA may refer to a nucleic acid that can be at least about 60% identical to a wild type exemplary tracrRNA sequence over a stretch of at least 6 contiguous nucleotides. For example, a tracrRNA sequence can be at least about 60% identical, at least about 65% identical, at least about 70% identical, at least about 75% identical, at least about 80% identical, at least about 85% identical, at least about 90% identical, at least about 95% identical, at least about 98% identical, at least about 99% identical, or 100% identical to a wild type exemplary tracrRNA sequence over a stretch of at least 6 contiguous nucleotides.

[0201] As used herein, a “guide nucleic acid” refers to a nucleic acid that can hybridize to another nucleic acid. A guide nucleic acid may preferably be RNA or DNA. The guide nucleic acid may be programmed to bind specifically to a nucleic acid with a particular sequence. The nucleic acid to be targeted, or the target nucleic acid, may comprise nucleotides. The guide nucleic acid may comprise nucleotides. A portion of the target nucleic acid may be complementary to a portion of the guide nucleic acid. The strand of a double-stranded target polynucleotide that is complementary to and hybridizes with the guide nucleic acid may be called the complementary strand. The strand of the double-stranded target polynucleotide that is complementary to the complementary strand, and therefore may not be complementary to the guide nucleic acid may be called a noncomplementary strand. A guide nucleic acid may comprise a polynucleotide chain and can be called a “single guide nucleic acid”. A guide nucleic acid may comprise two polynucleotide chains and may be called a “double guide nucleic acid”. If not otherwise specified, the term “guide nucleic acid” may be inclusive, referring to both single guide nucleic acids and double guide nucleic acids. Guide nucleic acids may comprise a nucleic acid targeting segment (e.g. a crRNA) and a protein binding sequence. Guide nucleic acids may comprise a nucleic acid targeting segment (e.g. a crRNA) a protein binding sequence, and a trans-activating RNA (e.g. a tracrRNA). In some cases, a guide RNA described herein comprises a sequence of n nucleotides counting from a 1^st nucleotide at a 5′ end to an n^th nucleotide at a 3′ end, wherein one or more of the nucleotides at positions 1, 2, n−1 and n are phosphorothioate modified nucleotides. The guide nucleic acid can comprise one or more bridged nucleotides in a seed region of the guide oligonucleotide.

[0202] A guide nucleic acid may comprise a segment that can be referred to as a “nucleic acid-targeting segment”, a “nucleic acid-targeting sequence” or a “seed sequence”. In some embodiments, the sequence is 19-21 nucleotides in length. In some embodiments, the “nucleic acid-targeting segment” or the “nucleic acid-targeting sequence” comprises a crRNA. A nucleic acid-targeting segment may comprise a sub-segment that may be referred to as a “protein binding segment”, a “protein binding sequence” or a “Cas protein binding segment”.

[0203] A “host cell” generally includes an individual cell or cell culture which can be or has been a recipient for the subject vectors into which exogenous nucleic acid has been introduced, such as those described herein. Host cells include progeny of a single host cell. The progeny may not necessarily be completely identical (in morphology or in genomic of total DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation. A host cell includes cells transfected in vivo with a vector of this invention.

[0204] The term a “derivative” when referring to a protein means that the protein was modified with the addition or removal of a sequence while retaining its function. The term a “functional analog” means a different sequence that performs the same function. The term a “variant” thereof means that the protein was mutated while retaining or enhancing its function.

[0205] T cells are immune cells that express a T cell receptor which is encoded by the T cell receptor a constant (TRAC) gene. T cells include CD4 T cells, CD8 T cells and NK cells and each characteristically express CD4, CD8, and CD16-CD56 respectively at their cell surface. Natural Killer (NK) cells and CD8 cytotoxic T cells are two types of immune cells that can kill target cells through similar cytotoxic mechanisms. CD4 and CD8 CAR T cell therapies have been the main focus of research and development as opposed to NK cells because NK cell immunotherapy approaches require an efficient gene transfer method in the primary NK cells that current gene editing methods do not achieve. CD16 and/or CD56 can be used as targets for specific NK cell modification. CD56 and CD16 are key clusters of differentiation for defining natural killer cells within white blood cell populations, as such they can be targeted for example by antibodies as a means to enrich, identify and characterise NK cells. Bispecific targeting can be performed by targeting both CD16 and CD56. Particularly CD56 Bright is the most active NK cell population with regards to anti cancer activity.

[0206] The present disclosure achieves a significant improvement in the efficiency of CAR-T gene editing by providing a protein based interaction to bind the cell membrane of T cells and get the genetic material and PNME internalized. The present disclosure achieves a transduction efficiency of more than 75%, preferably more than 80%, more preferably more than 90%, and even more preferably more than 95%. In contrast, traditional methods have only achieved efficiencies that are in the order of 25-30%. The efficiency that is generally reported in the literature is the efficiency post selection after a step of cell sorting, antibiotic selection, magnetic separation or the like. On the other hand, the present disclosure reports the efficiency directly without any step that artificially inflates the efficiency rate. The efficiency rate is calculated based on the total starting cell population not just the cell population that received the vector.

[0207] The presently improved efficiency means that the CAR-T cells methods described herein can be applied to NK T cells. The advantage of NK cells is that they generally offer an improved safety to the subject receiving same (i.e. a lack or minimal cytokine release syndrome and neurotoxicity), and they offer multiple mechanisms for activating cytotoxicity.

[0208] The present disclosure contemplates all types of CAR T cell receptors. These include multi-targeted CAR configurations such as:

• • [0209] dual CARs that co-express two different CARs in one cell,
  • [0210] tandem CARs containing two different scFvs in a single CAR molecule that can either be stacked in series or as a looped structure.
  • [0211] combinatorial CARs combine two constructs: one bears the CD3z signaling motif and the other bears the costimulatory signaling domain,
  • [0212] synthetic Notch (syn-Notch) receptors induce the transcription of a CAR after antigen recognition of their cognate antigen, and
  • [0213] inhibitory CARs (iCAR) inhibit T cell activation following antigen recognition in normal cells.

[0214] The present disclosure provides a protein complex comprising a polynucleotide-modifying enzyme domain (with a functional nuclease catalytic pocket) and an endosome escape domain, a guide oligonucleotide targeting TRAC and donor DNA. In some cases, the PNME enzymes are programmable nucleases. Such nucleases are preferably engineered to target a specific DNA or RNA sequence for cleavage. The nucleases are for example CRISPR endonucleases such as Cas9, Cas12a (Cpf1), Cas12b, Cas12c, Cas12d, Cas12e, Cas13a, Cas13b, and Cas14. For the purpose of CAR T cell therapy, the CRISPR endonucleases are preferably selected from Cas9, Cas12a (Cpf1), Cas12b, Cas12c, Cas12d, and Cas12e. In some embodiments, CRISPR endonucleases are class II CRISPR endonucleases. In some cases, CRISPR endonucleases are class II, type II, V, or VI endonucleases. In preferred embodiments for the purpose of CAR T cell production, the CRISPR endonuclease is a type II or type V Cas. In some cases, such nucleases comprise at least one nuclease deficient nuclease domain. In some embodiments, the CRIPSR endonuclease is encoded by a sequence having at least at least 75% identity, at least 78% identity, at least 80% identity, at least 81% identity, at least 82% identity, at least 83% identity, at least 84% identity, at least 85% identity, at least 86% identity, at least 87% identity, at least 88% identity, at least 89% identity, at least 90% identity, at least 91% identity, at least 92% identity, at least 93% identity, at least 94% identity, at least 95% identity, at least 96% identity, at least 97% identity, at least 98% identity, at least 99% identity, or 100% identity to any one of SEQ ID NOs: 1, 3, 5, 7, or 9. In some embodiments, the CRIPSR endonuclease has at least 75% identity, at least 78% identity, at least 80% identity, at least 81% identity, at least 82% identity, at least 83% identity, at least 84% identity, at least 85% identity, at least 86% identity, at least 87% identity, at least 88% identity, at least 89% identity, at least 90% identity, at least 91% identity, at least 92% identity, at least 93% identity, at least 94% identity, at least 95% identity, at least 96% identity, at least 97% identity, at least 98% identity, at least 99% identity, or 100% identity to any one of SEQ ID NOs: 2, 4, 6, 8 or 10.

TABLE 1
Exemplary nucleases
SEQ
ID NO:	Protein	Sequence
1	spCas9	ATGGATAAAAAATACAGCATTGGTCTGGACATTGGCACGAATAGCGTTGGTTGGGCA
	(nucleotide	GTGATTACCGATGAATACAAAGTCCCGTCGAAAAAATTCAAAGTGCTGGGTAACACC
	sequence)	GATCGCCATAGCATTAAGAAAAACCTGATCGGTGCGCTGCTGTTTGATTCTGGCGAA
		ACCGCGGAAGCAACGCGTCTGAAACGTACCGCACGTCGCCGTTACACGCGCCGTAAA
		AATCGTATTTGCTATCTGCAGGAAATCTTTAGCAACGAAATGGCGAAAGTCGATGAC
		TCATTTTTCCACCGCCTGGAAGAATCGTTTCTGGTGGAAGAAGATAAAAAACATGAA
		CGTCACCCGATTTTCGGCAATATCGTTGATGAAGTCGCGTACCATGAAAAATATCCG
		ACGATTTACCACCTGCGTAAAAAACTGGTGGATTCTACCGACAAAGCCGATCTGCGC
		CTGATTTATCTGGCACTGGCTCATATGATCAAATTTCGTGGTCACTTCCTGATTGAA
		GGCGACCTGAACCCGGATAATAGTGACGTCGATAAACTGTTTATTCAGCTGGTGCAA
		ACCTATAATCAGCTGTTCGAAGAAAACCCGATCAATGCAAGTGGTGTTGATGCGAAA
		GCCATTCTGTCCGCTCGCCTGAGTAAATCCCGCCGTCTGGAAAACCTGATTGCACAG
		CTGCCGGGTGAAAAGAAAAACGGTCTGTTTGGCAATCTGATCGCTCTGTCACTGGGC
		CTGACGCCGAACTTTAAATCGAATTTCGACCTGGCAGAAGATGCTAAACTGCAGCTG
		AGCAAAGATACCTACGATGACGATCTGGACAACCTGCTGGCGCAAATTGGCGACCAG
		TATGCCGACCTGTTTCTGGCGGCCAAAAATCTGTCAGATGCCATTCTGCTGTCGGAC
		ATCCTGCGCGTGAACACCGAAATCACGAAAGCGCCGCTGTCAGCCTCGATGATTAAA
		CGCTACGATGAACATCACCAGGACCTGACCCTGCTGAAAGCACTGGTTCGTCAGCAA
		CTGCCGGAAAAATACAAAGAAATTTTCTTTGACCAAAGTAAAAATGGTTATGCAGGC
		TACATCGATGGCGGTGCTTCCCAGGAAGAATTCTACAAATTCATCAAACCGATCCTG
		GAAAAAATGGATGGTACGGAAGAACTGCTGGTGAAACTGAATCGTGAAGATCTGCTG
		CGTAAACAACGCACCTTTGACAACGGTAGCATTCCGCATCAGATCCACCTGGGCGAA
		CTGCATGCGATTCTGCGCCGTCAGGAAGATTTTTATCCGTTCCTGAAAGACAACCGT
		GAAAAAATCGAAAAAATCCTGACGTTTCGCATCCCGTATTACGTTGGTCCGCTGGCA
		CGTGGTAATAGCCGCTTCGCATGGATGACCCGCAAATCTGAAGAAACCATTACGCCG
		TGGAACTTTGAAGAAGTGGTTGATAAAGGCGCAAGCGCTCAGTCTTTTATCGAACGT
		ATGACCAATTTCGATAAAAACCTGCCGAATGAAAAAGTGCTGCCGAAACATTCTCTG
		CTGTATGAATACTTTACCGTTTACAACGAACTGACGAAAGTGAAATATGTTACCGAG
		GGTATGCGCAAACCGGCGTTTCTGAGTGGCGAACAGAAAAAAGCCATTGTGGATCTG
		CTGTTCAAAACCAATCGTAAAGTTACGGTCAAACAGCTGAAAGAAGATTACTTCAAG
		AAAATTGAATGTTTCGACAGCGTGGAAATTTCTGGTGTTGAAGATCGTTTCAACGCC
		TCTCTGGGCACCTATCATGACCTGCTGAAAATCATCAAAGACAAAGATTTTCTGGAT
		AACGAAGAAAACGAAGACATTCTGGAAGATATCGTGCTGACCCTGACGCTGTTCGAA
		GATCGTGAAATGATTGAAGAACGCCTGAAAACGTACGCACACCTGTTTGACGATAAA
		GTTATGAAACAGCTGAAACGCCGTCGCTATACCGGTTGGGGCCGTCTGAGCCGCAAA
		CTGATTAATGGTATCCGCGATAAACAATCAGGCAAAACGATTCTGGATTTCCTGAAA
		TCGGACGGCTTTGCCAACCGTAATTTCATGCAGCTGATCCATGACGATTCCCTGACC
		TTTAAAGAAGACATTCAGAAAGCACAAGTGTCAGGTCAAGGCGATTCGCTGCATGAA
		CACATTGCGAACCTGGCCGGTTCACCGGCTATCAAAAAAGGCATCCTGCAGACCGTG
		AAAGTCGTGGATGAACTGGTGAAAGTTATGGGTCGTCACAAACCGGAAAACATTGTT
		ATCGAAATGGCGCGCGAAAATCAGACCACGCAAAAAGGCCAGAAAAACTCGCGTGAA
		CGCATGAAACGCATTGAAGAAGGTATCAAAGAACTGGGCAGCCAGATTCTGAAAGAA
		CATCCGGTCGAAAACACCCAGCTGCAAAATGAAAAACTGTACCTGTATTACCTGCAA
		AATGGTCGTGACATGTATGTGGATCAGGAACTGGACATCAACCGCCTGTCTGACTAT
		GATGTCGACCACATTGTGCCGCAGAGCTTTCTGAAAGACGATTCTATCGATAACAAA
		GTTCTGACCCGTAGTGATAAAAACCGCGGCAAAAGCGACAATGTCCCGTCTGAAGAA
		GTTGTGAAGAAAATGAAAAACTACTGGCGTCAACTGCTGAATGCGAAACTGATTACG
		CAGCGTAAATTCGATAACCTGACCAAAGCGGAACGCGGCGGTCTGTCCGAACTGGAT
		AAAGCCGGTTTTATCAAACGTCAACTGGTTGAAACCCGCCAGATTACGAAACATGTC
		GCCCAGATCCTGGATTCACGCATGAACACGAAATACGACGAAAACGATAAACTGATC
		CGTGAAGTCAAAGTGATCACCCTGAAAAGTAAACTGGTTTCCGATTTCCGTAAAGAC
		TTTCAGTTCTACAAAGTCCGCGAAATTAACAATTACCATCACGCACACGATGCTTAT
		CTGAATGCAGTGGTTGGTACCGCTCTGATCAAAAAATATCCGAAACTGGAAAGCGAA
		TTTGTGTATGGCGATTACAAAGTCTATGACGTGCGCAAAATGATTGCGAAATCCGAA
		CAGGAAATCGGCAAAGCGACCGCCAAATACTTTTTCTATTCAAACATCATGAACTTT
		TTCAAAACCGAAATTACGCTGGCAAATGGTGAAATTCGTAAACGCCCGCTGATCGAA
		ACCAACGGTGAAACGGGCGAAATTGTGTGGGATAAAGGCCGTGACTTCGCGACCGTT
		CGCAAAGTCCTGTCGATGCCGCAAGTGAATATCGTGAAGAAAACCGAAGTGCAGACG
		GGCGGTTTTAGTAAAGAATCCATCCTGCCGAAACGTAACAGCGATAAACTGATTGCG
		CGCAAAAAAGATTGGGACCCGAAAAAATACGGCGGTTTTGATAGTCCGACGGTTGCA
		TATTCCGTCCTGGTCGTGGCTAAAGTCGAAAAAGGTAAAAGTAAAAAACTGAAATCC
		GTGAAAGAACTGCTGGGCATTACCATCATGGAACGTAGCTCTTTTGAGAAAAACCCG
		ATTGACTTCCTGGAAGCCAAAGGTTACAAAGAAGTGAAAAAAGATCTGATCATCAAA
		CTGCCGAAATATAGCCTGTTCGAACTGGAAAACGGCCGTAAACGCATGCTGGCATCT
		GCTGGTGAACTGCAGAAAGGCAATGAACTGGCACTGCCGAGTAAATATGTTAACTTT
		CTGTACCTGGCTAGCCATTATGAAAAACTGAAAGGTTCTCCGGAAGATAACGAACAG
		AAACAACTGTTCGTCGAACAACATAAACACTACCTGGATGAAATCATCGAACAGATC
		TCAGAATTCTCGAAACGCGTGATTCTGGCGGATGCCAATCTGGACAAAGTTCTGAGC
		GCGTATAACAAACATCGTGATAAACCGATTCGCGAACAGGCCGAAAATATTATCCAC
		CTGTTTACCCTGACGAACCTGGGCGCACCGGCAGCTTTTAAATACTTCGATACCACG
		ATCGACCGTAAACGCTATACCTCAACGAAAGAAGTTCTGGATGCTACCCTGATTCAT
		CAATCGATCACCGGTCTGTATGAAACGCGTATTGATCTGAGTCAGCTGGGCGGTGAC
2	spCas9	MDKKYSIGLDIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGE
	(protein	TAEATRLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHE
	sequence)	RHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIE
		GDLNPDNSDVDKLFIQLVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQ
		LPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQ
		YADLFLAAKNLSDAILLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVRQQ
		LPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFIKPILEKMDGTEELLVKLNREDLL
		RKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVGPLA
		RGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMTNFDKNLPNEKVLPKHSL
		LYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQLKEDYFK
		KIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIVLTLTLFE
		DREMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDFLK
		SDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTV
		KVVDELVKVMGRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKE
		HPVENTQLQNEKLYLYYLQNGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDSIDNK
		VLTRSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELD
		KAGFIKRQLVETRQITKHVAQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKD
		FQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFVYGDYKVYDVRKMIAKSE
		QEIGKATAKYFFYSNIMNFFKTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATV
		RKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIARKKDWDPKKYGGFDSPTVA
		YSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLIIK
		LPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASHYEKLKGSPEDNEQ
		KQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAENIIH
		LFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQLGG
3	IbCPF1	ATGTCAAAGCTGGAGAAATTCACCAACTGTTATAGCCTGTCTAAGACCCTGCGCTTC
	(nucleotide	AAGGCAATCCCAGTGGGCAAGACACAAGAGAACATTGACAACAAACGGCTCCTGGTG
	sequence)	GAGGATGAGAAGAGGGCTGAAGATTACAAGGGCGTTAAGAAGCTGCTGGATAGGTAC
		TATCTGTCATTCATCAACGATGTCCTCCACAGTATCAAGCTGAAGAATCTGAACAAT
		TACATTTCTCTGTTCCGGAAGAAGACACGGACCGAGAAGGAGAACAAAGAGCTGGAG
		AATCTGGAGATCAACCTGAGGAAAGAAATAGCTAAGGCTTTCAAAGGGAACGAGGGT
		TACAAGTCCCTGTTCAAGAAAGACATTATCGAGACTATTCTGCCTGAGTTCCTGGAC
		GATAAAGATGAGATCGCCCTCGTCAATTCCTTCAATGGGTTTACCACAGCCTTTACC
		GGCTTCTTCGACAATAGAGAGAATATGTTCTCTGAAGAGGCCAAATCCACTAGCATC
		GCCTTTCGCTGCATAAACGAGAACCTGACTAGGTACATCAGCAATATGGACATCTTT
		GAGAAAGTCGATGCCATATTCGACAAACATGAGGTGCAGGAGATTAAGGAGAAGATC
		CTGAACTCAGATTACGATGTCGAAGATTTCTTCGAGGGAGAGTTCTTCAACTTCGTG
		CTCACACAAGAGGGCATTGATGTGTACAATGCAATCATTGGAGGGTTCGTGACAGAG
		AGTGGCGAGAAGATAAAGGGCCTGAACGAGTATATCAACCTCTACAACCAGAAAACC
		AAGCAGAAACTGCCTAAGTTCAAGCCACTGTACAAACAAGTGCTCTCAGATAGGGAA
		AGCCTGAGCTTCTACGGTGAAGGGTATACATCAGATGAAGAAGTGCTCGAAGTGTTC
		CGCAACACCCTCAATAAGAACAGTGAAATCTTCTCTTCAATCAAGAAGCTGGAGAAA
		CTGTTCAAGAATTTCGATGAGTACTCCTCTGCCGGAATCTTTGTGAAGAATGGCCCT
		GCAATATCCACTATTAGCAAAGACATCTTTGGCGAGTGGAACGTTATCAGGGATAAG
		TGGAATGCCGAGTACGATGATATTCATCTCAAGAAGAAAGCCGTGGTTACAGAGAAA
		TACGAGGATGATAGACGCAAGAGCTTTAAGAAGATTGGTAGCTTCTCTCTCGAACAG
		CTGCAGGAGTACGCCGACGCTGACCTGTCAGTCGTGGAGAAACTCAAGGAGATCATA
		ATCCAGAAGGTGGATGAAATCTACAAAGTGTATGGAAGCTCTGAGAAACTCTTCGAT
		GCAGACTTTGTTCTGGAGAAGAGTCTGAAGAAGAACGACGCAGTGGTTGCTATCATG
		AAGGACCTGCTGGATTCTGTTAAGTCTTTCGAGAATTACATTAAGGCATTCTTTGGT
		GAAGGGAAGGAGACAAATAGGGACGAGAGCTTCTATGGCGACTTTGTTCTGGCCTAC
		GACATCCTCCTCAAGGTTGACCACATCTATGACGCTATACGGAATTACGTTACCCAG
		AAGCCCTATAGCAAAGACAAGTTCAAGCTGTATTTCCAGAATCCACAGTTTATGGGT
		GGGTGGGATAAAGACAAAGAAACAGATTACAGGGCCACTATCCTGCGGTACGGCAGC
		AAATACTATCTGGCTATCATGGATAAGAAGTACGCCAAATGCCTCCAGAAGATCGAC
		AAGGACGACGTGAACGGTAACTACGAGAAGATCAATTACAAGCTCCTGCCAGGACCT
		AACAAGATGCTGCCCAAGGTGTTCTTCTCCAAGAAATGGATGGCCTACTATAACCCA
		AGCGAGGACATTCAGAAGATATACAAGAATGGGACATTCAAGAAGGGCGATATGTTC
		AACCTCAACGACTGCCACAAGCTGATTGATTTCTTCAAGGATAGCATTTCTCGCTAT
		CCCAAGTGGTCTAATGCATACGATTTCAACTTCAGCGAGACTGAGAAGTACAAAGAC
		ATCGCTGGCTTCTACCGGGAGGTGGAAGAGCAAGGCTATAAGGTGTCATTCGAATCC
		GCTTCTAAGAAGGAAGTGGATAAGCTCGTGGAAGAGGGTAAGCTGTACATGTTCCAG
		ATATACAACAAAGACTTCAGCGATAAGAGCCACGGCACTCCAAACCTCCATACTATG
		TATTTCAAGCTGCTGTTTGACGAGAACAACCACGGACAGATTAGGCTGTCAGGAGGC
		GCAGAACTCTTCATGCGCAGAGCTTCACTGAAGAAGGAGGAACTCGTTGTCCACCCA
		GCCAATAGCCCTATAGCCAATAAGAATCCAGACAATCCTAAGAAAACCACTACTCTG
		TCTTACGATGTGTATAAGGATAAGAGATTCTCTGAAGATCAGTACGAACTGCACATA
		CCCATTGCCATTAACAAGTGCCCTAAGAACATCTTCAAGATTAACACAGAGGTTAGA
		GTGCTCCTGAAACACGACGATAACCCTTATGTTATAGGCATTGATCGCGGAGAGAGA
		AACCTGCTGTACATCGTCGTGGTGGACGGCAAAGGCAACATCGTGGAACAGTACAGT
		CTCAATGAAATCATTAACAATTTCAACGGAATCCGCATTAAGACCGACTACCATTCT
		CTCCTCGACAAGAAGGAGAAAGAAAGGTTCGAAGCAAGACAGAATTGGACAAGTATA
		GAGAATATCAAAGAACTGAAGGCTGGGTACATCTCTCAGGTTGTGCACAAGATATGT
		GAGCTGGTGGAGAAGTACGACGCTGTTATCGCCCTCGAGGACCTGAATAGCGGCTTC
		AAGAACTCCAGGGTGAAGGTGGAGAAGCAGGTGTATCAGAAGTTCGAGAAGATGCTG
		ATCGACAAGCTCAACTATATGGTGGACAAGAAATCCAATCCTTGCGCTACTGGTGGA
		GCCCTGAAGGGCTATCAAATCACCAATAAGTTCGAATCTTTCAAGTCTATGAGCACC
		CAGAATGGCTTCATCTTCTACATACCCGCATGGCTGACATCCAAGATTGATCCCTCT
		ACCGGATTTGTTAATCTGCTCAAGACTAAGTACACCTCTATTGCTGACTCAAAGAAG
		TTCATATCATCATTTGACCGCATCATGTACGTGCCAGAAGAGGACCTGTTCGAGTTT
		GCCCTGGATTACAAGAATTTCTCTCGGACTGACGCCGACTACATCAAGAAGTGGAAG
		CTCTACTCTTATGGTAATCGGATTCGCATATTCCGCAATCCCAAGAAGAATAACGTG
		TTCGATTGGGAGGAAGTTTGCCTCACCAGCGCTTACAAGGAGCTGTTCAATAAGTAT
		GGGATTAACTACCAGCAGGGCGACATAAGAGCCCTGCTGTGCGAACAATCTGATAAG
		GCATTCTATTCCTCTTTCATGGCACTGATGTCACTGATGCTGCAAATGCGCAATTCC
		ATCACCGGAAGAACAGACGTGGACTTTCTGATCTCTCCTGTCAAGAACTCAGATGGC
		ATCTTCTACGATTCCCGCAACTATGAAGCACAGGAGAATGCTATCCTGCCTAAGAAT
		GCCGATGCAAATGGAGCCTATAACATCGCCAGAAAGGTCCTCTGGGCCATAGGACAA
		TTCAAGAAAGCTGAAGATGAGAAGCTGGACAAGGTGAAGATCGCCATTTCAAACAAA
		GAGTGGCTCGAATATGCTCAGACCTCAGTGAAGCAT
4	IbCPF1	MSKLEKFTNCYSLSKTLRFKAIPVGKTQENIDNKRLLVEDEKRAEDYKGVKKLLDRY
	(protein	YLSFINDVLHSIKLKNLNNYISLFRKKTRTEKENKELENLEINLRKEIAKAFKGNEG
	sequence)	YKSLFKKDIIETILPEFLDDKDEIALVNSFNGFTTAFTGFFDNRENMFSEEAKSTSI
		AFRCINENLTRYISNMDIFEKVDAIFDKHEVQEIKEKILNSDYDVEDFFEGEFFNFV
		LTQEGIDVYNAIIGGFVTESGEKIKGLNEYINLYNQKTKQKLPKFKPLYKQVLSDRE
		SLSFYGEGYTSDEEVLEVFRNTLNKNSEIFSSIKKLEKLFKNFDEYSSAGIFVKNGP
		AISTISKDIFGEWNVIRDKWNAEYDDIHLKKKAVVTEKYEDDRRKSFKKIGSFSLEQ
		LQEYADADLSVVEKLKEIIIQKVDEIYKVYGSSEKLFDADFVLEKSLKKNDAVVAIM
		KDLLDSVKSFENYIKAFFGEGKETNRDESFYGDFVLAYDILLKVDHIYDAIRNYVTQ
		KPYSKDKFKLYFQNPQFMGGWDKDKETDYRATILRYGSKYYLAIMDKKYAKCLQKID
		KDDVNGNYEKINYKLLPGPNKMLPKVFFSKKWMAYYNPSEDIQKIYKNGTFKKGDMF
		NLNDCHKLIDFFKDSISRYPKWSNAYDENFSETEKYKDIAGFYREVEEQGYKVSFES
		ASKKEVDKLVEEGKLYMFQIYNKDFSDKSHGTPNLHTMYFKLLFDENNHGQIRLSGG
		AELFMRRASLKKEELVVHPANSPIANKNPDNPKKTTTLSYDVYKDKRFSEDQYELHI
		PIAINKCPKNIFKINTEVRVLLKHDDNPYVIGIDRGERNLLYIVVVDGKGNIVEQYS
		LNEIINNFNGIRIKTDYHSLLDKKEKERFEARQNWTSIENIKELKAGYISQVVHKIC
		ELVEKYDAVIALEDLNSGFKNSRVKVEKQVYQKFEKMLIDKLNYMVDKKSNPCATGG
		ALKGYQITNKFESFKSMSTQNGFIFYIPAWLTSKIDPSTGFVNLLKTKYTSIADSKK
		FISSFDRIMYVPEEDLFEFALDYKNFSRTDADYIKKWKLYSYGNRIRIFRNPKKNNV
		FDWEEVCLTSAYKELFNKYGINYQQGDIRALLCEQSDKAFYSSFMALMSLMLQMRNS
		ITGRTDVDFLISPVKNSDGIFYDSRNYEAQENAILPKNADANGAYNIARKVLWAIGQ
		FKKAEDEKLDKVKIAISNKEWLEYAQTSVKH
5	M7	ATGAACAACGGCACAAATAATTTTCAGAACTTCATCGGGATCTCAAGTTTGCAGAAA
	(nucleotide	ACGCTGCGCAATGCTCTGATCCCCACGGAAACCACGCAACAGTTCATCGTCAAGAAC
	sequence)	GGAATAATTAAAGAAGATGAGTTACGTGGCGAGAACCGCCAGATTCTGAAAGATATC
		ATGGATGACTACTACCGCGGATTCATCTCTGAGACTCTGAGTTCTATTGATGACATA
		GATTGGACTAGCCTGTTCGAAAAAATGGAAATTCAGCTGAAAAATGGTGATAATAAA
		GATACCTTAATTAAGGAACAGACAGAGTATCGGAAAGCAATCCATAAAAAATTTGCG
		AACGACGATCGGTTTAAGAACATGTTTAGCGCCAAACTGATTAGTGACATATTACCT
		GAATTTGTCATCCACAACAATAATTATTCGGCATCAGAGAAAGAGGAAAAAACCCAG
		GTGATAAAATTGTTTTCGCGCTTTGCGACTAGCTTTAAAGATTACTTCAAGAACCGT
		GCAAATTGCTTTTCAGCGGACGATATTTCATCAAGCAGCTGCCATCGCATCGTCAAC
		GACAATGCAGAGATATTCTTTTCAAATGCGCTGGTCTACCGCCGGATCGTAAAATCG
		CTGAGCAATGACGATATCAACAAAATTTCGGGCGATATGAAAGATTCATTAAAAGAA
		ATGAGTCTGGAAGAAATATATTCTTACGAGAAGTATGGGGAATTTATTACCCAGGAA
		GGCATTAGCTTCTATAATGATATCTGTGGGAAAGTGAATTCTTTTATGAACCTGTAT
		TGTCAGAAAAATAAAGAAAACAAAAATTTATACAAACTTCAGAAACTTCACAAACAG
		ATTCTATGCATTGCGGACACTAGCTATGAGGTCCCGTATAAATTTGAAAGTGACGAG
		GAAGTGTACCAATCAGTTAACGGCTTCCTTGATAACATTAGCAGCAAACATATAGTC
		GAAAGATTACGCAAAATCGGCGATAACTATAACGGCTACAACCTGGATAAAATTTAT
		ATCGTGTCCAAATTTTACGAGAGCGTTAGCCAAAAAACCTACCGCGACTGGGAAACA
		ATTAATACCGCCCTCGAAATTCATTACAATAATATCTTGCCGGGTAACGGTAAAAGT
		AAAGCCGACAAAGTAAAAAAAGCGGTTAAGAATGATTTACAGAAATCCATCACCGAA
		ATAAATGAACTAGTGTCAAACTATAAGCTGTGCAGTGACGACAACATCAAAGCGGAG
		ACTTATATACATGAGATTAGCCATATCTTGAATAACTTTGAAGCACAGGAATTGAAA
		TACAATCCGGAAATTCACCTAGTTGAATCCGAGCTCAAAGCGAGTGAGCTTAAAAAC
		GTGCTGGACGTGATCATGAATGCGTTTCATTGGTGTTCGGTTTTTATGACTGAGGAA
		CTTGTTGATAAAGACAACAATTTTTATGCGGAACTGGAGGAGATTTACGATGAAATT
		TATCCAGTAATTAGTCTGTACAACCTGGTTCGTAACTACGTTACCCAGAAACCGTAC
		AGCACGAAAAAGATTAAATTGAACTTTGGAATACCGACGTTAGCAGACGGTTGGTCA
		AAGTCCAAAGAGTATTCTAATAACGCTATCATACTGATGCGCGACAATCTGTATTAT
		CTGGGCATCTTTAATGCGAAGAATAAACCGGACAAGAAGATTATCGAGGGTAATACG
		TCAGAAAATAAGGGTGACTACAAAAAGATGATTTATAATTTGCTCCCGGGTCCCAAC
		AAAATGATCCCGAAAGTTTTCTTGAGCAGCAAGACGGGGGTGGAAACGTATAAACCG
		AGCGCCTATATCCTAGAGGGGTATAAACAGAATAAACATATCAAGTCTTCAAAAGAC
		TTTGATATCACTTTCTGTCATGATCTGATCGACTACTTCAAAAACTGTATTGCAATT
		CATCCCGAGTGGAAAAACTTCGGTTTTGATTTTAGCGACACCAGTACTTATGAAGAC
		ATTTCCGGGTTTTATCGTGAGGTAGAGTTACAAGGTTACAAGATTGATTGGACATAC
		ATTAGCGAAAAAGACATTGATCTGCTGCAGGAAAAAGGTCAACTGTATCTGTTCCAG
		ATATATAACAAAGATTTTTCGAAAAAATCAACCGGGAATGACAACCTTCACACCATG
		TACCTGAAAAATCTTTTCTCAGAAGAAAATCTTAAGGATATCGTCCTGAAACTTAAC
		GGCGAAGCGGAAATCTTCTTCAGGAAGAGCAGCATAAAGAACCCAATCATTCATAAA
		AAAGGCTCGATTTTAGTCAACCGTACCTACGAAGCAGAAGAAAAAGACCAGTTTGGC
		AACATTCAAATTGTGCGTAAAAATATTCCGGAAAACATTTATCAGGAGCTGTACAAA
		TACTTCAACGATAAAAGCGACAAAGAGCTGTCTGATGAAGCAGCCAAACTGAAGAAT
		GTAGTGGGACACCACGAGGCAGCGACGAATATAGTCAAGGACTATCGCTACACGTAT
		GATAAATACTTCCTTCATATGCCTATTACGATCAATTTCAAAGCCAATAAAACGGGT
		TTTATTAATGATAGGATCTTACAGTATATCGCTAAAGAAAAAGACTTACATGTGATC
		GGCATTGATCGGGGCGAGCGTAACCTGATCTACGTGTCCGTGATTGATACTTGTGGT
		AATATAGTTGAACAGAAAAGCTTTAACATTGTAAACGGCTACGACTATCAGATAAAA
		CTGAAACAACAGGAGGGCGCTAGACAGATTGCGCGGAAAGAATGGAAAGAAATTGGT
		AAAATTAAAGAGATCAAAGAGGGCTACCTGAGCTTAGTAATCCACGAGATCTCTAAA
		ATGGTAATCAAATACAATGCAATTATAGCGATGGAGGATTTGTCTTATGGTTTTAAA
		AAAGGGCGCTTTAAGGTCGAACGGCAAGTTTACCAGAAATTTGAAACCATGCTCATC
		AATAAACTCAACTATCTGGTATTTAAAGATATTTCGATTACCGAGAATGGCGGTCTC
		CTGAAAGGTTATCAGCTGACATACATTCCTGATAAACTTAAAAACGTGGGTCATCAG
		TGCGGCTGCATTTTTTATGTGCCTGCTGCATACACGAGCAAAATTGATCCGACCACC
		GGCTTTGTGAATATCTTTAAATTTAAAGACCTGACAGTGGACGCAAAACGTGAATTC
		ATTAAAAAATTTGACTCAATTCGTTATGACAGTGAAAAAAATCTGTTCTGCTTTACA
		TTTGACTACAATAACTTTATTACGCAAAACACGGTCATGAGCAAATCATCGTGGAGT
		GTGTATACATACGGCGTGCGCATCAAACGTCGCTTTGTGAACGGCCGCTTCTCAAAC
		GAAAGTGATACCATTGACATAACCAAAGATATGGAGAAAACGTTGGAAATGACGGAC
		ATTAACTGGCGCGATGGCCACGATCTTCGTCAAGACATTATAGATTATGAAATTGTT
		CAGCACATATTCGAAATTTTCCGTTTAACAGTGCAAATGCGTAACTCCTTGTCTGAA
		CTGGAGGACCGTGATTACGATCGTCTCATTTCACCTGTACTGAACGAAAATAACATT
		TTTTATGACAGCGCGAAAGCGGGGGATGCACTTCCTAAGGATGCCGATGCAAATGGT
		GCGTATTGTATTGCATTAAAAGGGTTATATGAAATTAAACAAATTACCGAAAATTGG
		AAAGAAGATGGTAAATTTTCGCGCGATAAACTCAAAATCAGCAATAAAGATTGGTTC
		GACTTTATCCAGAATAAGCGCTATCTCTAA
6	M7 (protein	MNNGTNNFQNFIGISSLQKTLRNALIPTETTQQFIVKNGIIKEDELRGENRQILKDI
	sequence)	MDDYYRGFISETLSSIDDIDWTSLFEKMEIQLKNGDNKDTLIKEQTEYRKAIHKKFA
		NDDRFKNMFSAKLISDILPEFVIHNNNYSASEKEEKTQVIKLFSRFATSFKDYFKNR
		ANCFSADDISSSSCHRIVNDNAEIFFSNALVYRRIVKSLSNDDINKISGDMKDSLKE
		MSLEEIYSYEKYGEFITQEGISFYNDICGKVNSFMNLYCQKNKENKNLYKLQKLHKQ
		ILCIADTSYEVPYKFESDEEVYQSVNGELDNISSKHIVERLRKIGDNYNGYNLDKIY
		IVSKFYESVSQKTYRDWETINTALEIHYNNILPGNGKSKADKVKKAVKNDLQKSITE
		INELVSNYKLCSDDNIKAETYIHEISHILNNFEAQELKYNPEIHLVESELKASELKN
		VLDVIMNAFHWCSVFMTEELVDKDNNFYAELEEIYDEIYPVISLYNLVRNYVTQKPY
		STKKIKLNFGIPTLADGWSKSKEYSNNAIILMRDNLYYLGIFNAKNKPDKKIIEGNT
		SENKGDYKKMIYNLLPGPNKMIPKVFLSSKTGVETYKPSAYILEGYKQNKHIKSSKD
		FDITFCHDLIDYFKNCIAIHPEWKNFGFDFSDTSTYEDISGFYREVELQGYKIDWTY
		ISEKDIDLLQEKGQLYLFQIYNKDFSKKSTGNDNLHTMYLKNLFSEENLKDIVLKLN
		GEAEIFFRKSSIKNPIIHKKGSILVNRTYEAEEKDQFGNIQIVRKNIPENIYQELYK
		YFNDKSDKELSDEAAKLKNVVGHHEAATNIVKDYRYTYDKYFLHMPITINFKANKTG
		FINDRILQYIAKEKDLHVIGIDRGERNLIYVSVIDTCGNIVEQKSFNIVNGYDYQIK
		LKQQEGARQIARKEWKEIGKIKEIKEGYLSLVIHEISKMVIKYNAIIAMEDLSYGFK
		KGRFKVERQVYQKFETMLINKLNYLVFKDISITENGGLLKGYQLTYIPDKLKNVGHQ
		CGCIFYVPAAYTSKIDPTTGFVNIFKFKDLTVDAKREFIKKFDSIRYDSEKNLFCFT
		FDYNNFITQNTVMSKSSWSVYTYGVRIKRRFVNGRFSNESDTIDITKDMEKTLEMTD
		INWRDGHDLRQDIIDYEIVQHIFEIFRLTVQMRNSLSELEDRDYDRLISPVLNENNI
		FYDSAKAGDALPKDADANGAYCIALKGLYEIKQITENWKEDGKFSRDKLKISNKDWF
		DFIQNKRYL
7	saCas9	ATGAAAAGGAACTACATTCTGGGGCTGGACATCGGGATTACAAGCGTGGGGTATGGG
	(nucleotide	ATTATTGACTATGAAACAAGGGACGTGATCGACGCAGGCGTCAGACTGTTCAAGGAG
	sequence)	GCCAACGTGGAAAACAATGAGGGACGGAGAAGCAAGAGGGGAGCCAGGCGCCTGAAA
		CGACGGAGAAGGCACAGAATCCAGAGGGTGAAGAAACTGCTGTTCGATTACAACCTG
		CTGACCGACCATTCTGAGCTGAGTGGAATTAATCCTTATGAAGCCAGGGTGAAAGGC
		CTGAGTCAGAAGCTGTCAGAGGAAGAGTTTTCCGCAGCTCTGCTGCACCTGGCTAAG
		CGCCGAGGAGTGCATAACGTCAATGAGGTGGAAGAGGACACCGGCAACGAGCTGTCT
		ACAAAGGAACAG
		ATCTCACGCAATAGCAAAGCTCTGGAAGAGAAGTATGTCGCAGAGCTACAGCTGGAA
		CGGCTGAAGAAAGATGGCGAGGTGAGAGGGTCAATTAATAGGTTCAAGACAAGCGAC
		TACGTCAAAGAAGCCAAGCAGCTGCTGAAAGTGCAGAAGGCTTACCACCAGCTGGAT
		CAGAGCTTCATCGATACTTATATCGACCTGCTGGAGACTCGGAGAACCTACTATGAG
		GGACCAGGAGAAGGGAGCCCCTTCGGATGGAAAGACATCAAGGAATGGTACGAGATG
		CTGATGGGACATTGCACCTATTTTCCAGAAGAGCTGAGAAGCGTCAAGTACGCTTAT
		AACGCAGATCTGTACAACGCCCTGAATGACCTGAACAACCTGGTCATCACCAGGGAT
		GAAAACGAGAAACTGGAATACTATGAGAAGTTCCAGATCATCGAAAACGTGTTTAAG
		CAGAAGAAAAAGCCTACACTGAAACAGATTGCTAAGGAGATCCTGGTCAACGAAGAG
		GACATCAAGGGCTACCGGGTGACAAGCACTGGAAAACCAGAGTTCACCAATCTGAAA
		GTGTATCACGATATTAAGGACATCACAGCACGGAAAGAAATCATTGAGAACGCCGAA
		CTGCTGGATCAGATTGCTAAGATCCTGACTATCTACCAGAGTTCCGAGGACATCCAG
		GAAGAGCTGACTAACCTGAACAGCGAGCTGACCCAGGAAGAGATCGAACAGATTAGT
		AATCTGAAGGGGTACACCGGAACACACAACCTGTCCCTGAAAGCTATCAATCTGATT
		CTGGATGAGCTGTGGCATACAAACGACAATCAGATTGCAATCTTTAACCGGCTGAAG
		CTGGTACCAAAAAAGGTGGACCTGAGTCAGCAGAAAGAGATCCCAACCACACTGGTG
		GACGATTTCATTCTGTCACCCGTGGTCAAGCGGAGCTTCATCCAGAGCATCAAAGTG
		ATCAACGCCATCATCAAGAAGTACGGCCTGCCCAATGATATCATTATCGAGCTGGCT
		AGGGAGAAGAACAGCAAGGACGCACAGAAGATGATCAATGAGATGCAGAAACGAAAC
		CGGCAGACCAATGAACGCATTGAAGAGATTATCCGAACTACCGGGAAAGAGAACGCA
		AAGTACCTGATTGAAAAAATCAAGCTGCACGATATGCAGGAGGGAAAGTGTCTGTAT
		TCTCTGGAGGCCATCCCCCTGGAGGACCTGCTGAACAATCCATTCAACTACGAGGTC
		GATCATATTATCCCCAGAAGCGTGTCCTTCGACAATTCCTTTAACAACAAGGTGCTG
		GTCAAGCAGGAAGAGAACTCTAAAAAGGGCAATAGGACTCCTTTCCAGTACCTGTCT
		AGTTCAGATTCCAAGATCTCTTACGAAACCTTTAAAAAGCACATTCTGAATCTGGCC
		AAAGGAAAGGGCCGCATCAGCAAGACCAAAAAGGAGTACCTGCTGGAAGAGCGGGAC
		ATCAACAGATTCTCCGTCCAGAAGGATTTTATTAACCGGAATCTGGTGGACACAAGA
		TACGCTACTCGCGGCCTGATGAATCTGCTGCGATCCTATTTCCGGGTGAACAATCTG
		GATGTGAAAGTCAAGTCCATCAACGGCGGGTTCACATCTTTTCTGAGGCGCAAATGG
		AAGTTTAAAAAGGAGCGCAACAAAGGGTACAAGCACCATGCCGAAGATGCTCTGATT
		ATCGCAAATGCCGACTTCATCTTTAAGGAGTGGAAAAAGCTGGACAAAGCCAAGAAA
		GTGATGGAGAACCAGATGTTCGAAGAGAAGCAGGCCGAATCTATGCCCGAAATCGAG
		ACAGAACAGGAGTACAAGGAGATTTTCATCACTCCTCACCAGATCAAGCATATCAAG
		GATTTCAAGGACTACAAGTACTCTCACCGGGTGGATAAAAAGCCCAACAGAGAGCTG
		ATCAATGACACCCTGTATAGTACAAGAAAAGACGATAAGGGGAATACCCTGATTGTG
		AACAATCTGAACGGACTGTACGACAAAGATAATGACAAGCTGAAAAAGCTGATCAAC
		AAAAGTCCCGAGAAGCTGCTGATGTACCACCATGATCCTCAGACATATCAGAAACTG
		AAGCTGATTATGGAGCAGTACGGCGACGAGAAGAACCCACTGTATAAGTACTATGAA
		GAGACTGGGAACTACCTGACCAAGTATAGCAAAAAGGATAATGGCCCCGTGATCAAG
		AAGATCAAGTACTATGGGAACAAGCTGAATGCCCATCTGGACATCACAGACGATTAC
		CCTAACAGTCGCAACAAGGTGGTCAAGCTGTCACTGAAGCCATACAGATTCGATGTC
		TATCTGGACAACGGCGTGTATAAATTTGTGACTGTCAAGAATCTGGATGTCATCAAA
		AAGGAGAACTACTATGAAGTGAATAGCAAGTGCTACGAAGAGGCTAAAAAGCTGAAA
		AAGATTAGCAACCAGGCAGAGTTCATCGCCTCCTTTTACAACAACGACCTGATTAAG
		ATCAATGGCGAACTGTATAGGGTCATCGGGGTGAACAATGATCTGCTGAACCGCATT
		GAAGTGAATATGATTGACATCACTTACCGAGAGTATCTGGAAAACATGAATGATAAG
		CGCCCCCCTCGAATTATCAAAACAATCGCCTCTAAGACTCAGAGTATCAAAAAGTAC
		TCAACCGACATTCTGGGAAACCTGTATGAGGTGAAGAGCAAAAAGCACCCTCAGATT
		ATCAAAAAGGGCTAA
8	(protein	MKRNYILGLDIGITSVGYGIIDYETRDVIDAGVRLFKEANVENNEGRRSKRGARRLK
	sequence)	RRRRHRIQRVKKLLFDYNLLTDHSELSGINPYEARVKGLSQKLSEEEFSAALLHLAK
		RRGVHNVNEVEEDTGNELSTKEQISRNSKALEEKYVAELQLERLKKDGEVRGSINRF
		KTSDYVKEAKQLLKVQKAYHQLDQSFIDTYIDLLETRRTYYEGPGEGSPFGWKDIKE
		WYEMLMGHCTYFPEELRSVKYAYNADLYNALNDLNNLVITRDENEKLEYYEKFQIIE
		NVFKQKKKPTLKQIAKEILVNEEDIKGYRVTSTGKPEFTNLKVYHDIKDITARKEII
		ENAELLDQIAKILTIYQSSEDIQEELTNLNSELTQEEIEQISNLKGYTGTHNLSLKA
		INLILDELWHTNDNQIAIFNRLKLVPKKVDLSQQKEIPTTLVDDFILSPVVKRSFIQ
		SIKVINAIIKKYGLPNDIIIELAREKNSKDAQKMINEMQKRNRQTNERIEEIIRTTG
		KENAKYLIEKIKLHDMQEGKCLYSLEAIPLEDLLNNPFNYEVDHIIPRSVSFDNSEN
		NKVLVKQEENSKKGNRTPFQYLSSSDSKISYETFKKHILNLAKGKGRISKTKKEYLL
		EERDINRFSVQKDFINRNLVDTRYATRGLMNLLRSYFRVNNLDVKVKSINGGFTSFL
		RRKWKFKKERNKGYKHHAEDALIIANADFIFKEWKKLDKAKKVMENQMFEEKQAESM
		PEIETEQEYKEIFITPHQIKHIKDFKDYKYSHRVDKKPNRELINDTLYSTRKDDKGN
		TLIVNNLNGLYDKDNDKLKKLINKSPEKLLMYHHDPQTYQKLKLIMEQYGDEKNPLY
		KYYEETGNYLTKYSKKDNGPVIKKIKYYGNKLNAHLDITDDYPNSRNKVVKLSLKPY
		RFDVYLDNGVYKFVTVKNLDVIKKENYYEVNSKCYEEAKKLKKISNQAEFIASFYNN
		DLIKINGELYRVIGVNNDLLNRIEVNMIDITYREYLENMNDKRPPRIIKTIASKTQS
		IKKYSTDILGNLYEVKSKKHPQIIKKG
9	asCPF1	ATGACCCAGTTCGAGGGGTTTACCAATCTGTATCAAGTGAGCAAGACGCTGCGCTTT
	(nucleotide	GAACTGATCCCACAGGGAAAAACCTTAAAACATATTCAAGAGCAGGGCTTTATCGAA
	sequence)	GAAGATAAGGCCCGTAATGACCATTACAAAGAGTTAAAGCCGATTATTGATCGTATC
		TACAAGACCTATGCGGACCAGTGCTTACAATTGGTACAGCTTGATTGGGAGAACCTC
		TCTGCCGCCATCGATTCCTATCGTAAAGAAAAAACTGAAGAAACGCGCAACGCCCTG
		ATTGAAGAGCAGGCCACCTATCGTAACGCGATTCATGACTATTTTATTGGCCGTACG
		GACAATCTGACGGACGCGATCAACAAGCGCCATGCGGAGATTTACAAAGGACTGTTT
		AAGGCTGAACTGTTCAATGGTAAGGTCCTTAAACAGCTTGGGACCGTCACAACGACG
		GAACATGAAAACGCGTTATTACGTAGCTTCGACAAGTTTACCACGTATTTCTCCGGC
		TTTTACGAAAATCGCAAAAACGTTTTCAGTGCCGAGGATATTTCCACTGCTATCCCT
		CATCGCATTGTGCAAGACAACTTCCCAAAATTCAAAGAAAATTGTCATATCTTCACC
		CGCTTAATCACCGCTGTACCGTCCCTGCGTGAGCATTTCGAAAACGTGAAAAAGGCC
		ATTGGTATCTTCGTGTCTACTTCGATTGAGGAGGTATTTTCCTTTCCATTCTATAAT
		CAGCTGCTGACCCAGACCCAAATTGATCTGTACAACCAGCTGCTTGGCGGTATTTCT
		CGTGAAGCAGGAACCGAAAAAATCAAAGGGTTGAACGAGGTGCTTAATCTGGCAATC
		CAGAAAAATGATGAAACCGCCCACATCATTGCTTCGTTACCTCATCGTTTTATCCCG
		TTGTTCAAGCAAATTTTAAGTGATCGCAATACGCTGTCGTTTATTCTGGAAGAATTC
		AAAAGTGATGAAGAGGTAATTCAGTCGTTTTGCAAATATAAAACCCTGTTACGTAAC
		GAAAATGTCCTGGAAACAGCCGAGGCTTTGTTTAACGAACTGAATAGCATTGACCTG
		ACGCATATCTTTATTAGCCACAAAAAATTAGAGACCATCTCATCAGCTCTGTGCGAT
		CATTGGGATACACTGCGCAATGCGCTGTATGAACGTCGTATTTCGGAATTGACTGGC
		AAAATCACTAAAAGCGCGAAAGAGAAAGTACAGCGCTCGCTTAAACATGAAGATATC
		AACCTGCAGGAGATCATCAGCGCCGCGGGTAAAGAACTGTCGGAGGCATTTAAACAG
		AAGACGAGCGAGATTCTGTCCCACGCACATGCCGCCTTAGACCAGCCGCTCCCGACC
		ACTCTGAAGAAACAGGAAGAGAAAGAAATCCTTAAAAGTCAACTGGACAGTTTACTG
		GGTCTCTATCATCTGCTGGATTGGTTTGCGGTAGACGAAAGCAATGAAGTGGATCCG
		GAGTTTAGTGCCCGTCTGACAGGAATCAAGCTGGAAATGGAGCCTTCGCTTAGCTTC
		TACAACAAAGCCCGCAATTATGCCACGAAAAAACCCTATAGTGTCGAAAAATTTAAA
		CTCAACTTTCAAATGCCGACCCTTGCGTCGGGCTGGGATGTCAACAAAGAAAAAAAC
		AACGGAGCTATTCTGTTCGTTAAAAATGGTCTGTACTACCTGGGCATCATGCCGAAA
		CAGAAAGGTCGCTACAAAGCCCTTTCGTTCGAGCCCACGGAAAAAACAAGCGAAGGC
		TTCGACAAAATGTACTACGATTACTTTCCGGATGCAGCAAAAATGATCCCGAAATGT
		TCCACACAGCTGAAAGCCGTTACAGCACATTTTCAGACGCACACCACCCCCATCTTA
		CTGTCCAACAATTTTATTGAACCGCTGGAGATTACTAAAGAAATTTATGATTTGAAC
		AATCCGGAAAAAGAGCCAAAAAAGTTTCAAACCGCCTACGCTAAAAAAACCGGGGAT
		CAGAAAGGGTACCGCGAAGCGTTGTGCAAGTGGATTGATTTCACCCGCGATTTTCTC
		AGTAAATATACCAAGACTACCTCGATTGACCTGAGCTCACTGCGCCCGAGCTCTCAA
		TATAAGGATTTGGGTGAGTACTATGCTGAATTAAACCCTTTATTGTACCACATTTCT
		TTTCAGCGCATCGCCGAAAAGGAAATTATGGACGCAGTCGAAACCGGGAAACTGTAC
		CTGTTCCAGATCTATAATAAGGACTTCGCCAAAGGACATCATGGCAAACCGAACCTG
		CACACCCTTTACTGGACCGGGCTTTTCTCTCCGGAAAATTTGGCGAAAACCTCGATC
		AAGCTTAACGGTCAAGCTGAGCTGTTTTACCGTCCAAAATCCCGCATGAAGCGCATG
		GCGCATCGTTTAGGTGAAAAAATGCTGAATAAGAAACTGAAAGATCAGAAAACCCCT
		ATCCCGGATACCCTCTACCAGGAACTGTATGATTACGTGAACCATCGTCTCTCGCAT
		GACCTGTCAGACGAAGCGCGTGCGTTACTGCCCAATGTAATCACAAAAGAAGTTTCG
		CATGAAATTATTAAAGATCGTCGTTTTACATCTGATAAATTCTTTTTTCATGTTCCG
		ATCACCCTCAACTATCAGGCCGCAAACAGTCCAAGTAAGTTTAACCAGCGCGTTAAT
		GCTTACCTGAAGGAACATCCGGAGACTCCGATTATTGGAATTGATCGCGGTGAACGT
		AATTTGATCTATATCACTGTGATCGATAGTACCGGTAAGATTCTGGAGCAGCGCAGC
		TTGAACACAATTCAACAGTTTGATTATCAGAAAAAATTAGACAACCGCGAAAAAGAG
		CGCGTGGCTGCCCGTCAGGCGTGGTCTGTTGTCGGTACCATTAAAGATCTGAAGCAG
		GGCTATCTTTCTCAGGTTATTCACGAAATTGTAGATCTGATGATCCATTATCAGGCG
		GTTGTTGTGTTGGAGAATCTCAATTTCGGTTTTAAGAGTAAGCGCACAGGCATCGCT
		GAAAAAGCAGTTTATCAGCAGTTTGAAAAAATGCTGATCGACAAATTGAACTGTTTA
		GTTCTCAAAGATTACCCAGCGGAAAAGGTGGGCGGAGTGCTGAATCCGTACCAATTA
		ACGGATCAATTCACTTCCTTCGCAAAGATGGGTACCCAAAGCGGCTTTCTGTTCTAT
		GTGCCGGCCCCGTATACCTCGAAAATCGATCCACTGACGGGCTTCGTAGATCCGTTC
		GTGTGGAAAACCATTAAAAATCATGAAAGTCGTAAACATTTTCTCGAAGGCTTCGAC
		TTCCTGCACTACGACGTGAAAACTGGCGATTTCATTCTGCATTTTAAAATGAACCGC
		AACCTTTCGTTTCAGCGCGGTCTGCCGGGCTTTATGCCGGCTTGGGACATTGTTTTT
		GAGAAAAATGAAACCCAGTTTGATGCTAAAGGCACTCCTTTCATCGCCGGTAAACGC
		ATCGTACCTGTGATTGAAAACCATCGTTTTACAGGGCGTTACCGTGATTTATACCCG
		GCGAACGAATTGATCGCGCTGCTGGAGGAAAAGGGCATCGTTTTCCGTGACGGCTCC
		AATATTCTGCCGAAATTACTGGAAAACGACGATTCACACGCAATTGATACCATGGTC
		GCACTGATTCGCTCAGTCTTACAGATGCGTAACTCTAATGCAGCCACAGGAGAAGAT
		TATATTAATTCGCCAGTCCGCGATTTGAACGGTGTTTGCTTCGACAGCCGTTTTCAG
		AATCCTGAATGGCCGATGGACGCTGATGCCAACGGAGCTTATCATATCGCCCTGAAA
		GGCCAGCTCCTGCTGAACCACCTGAAGGAAAGCAAAGATCTGAAATTGCAGAACGGC
		ATTAGCAACCAGGACTGGTTAGCATACATCCAGGAACTGCGTAAC
10	asCPF1	MTQFEGFTNLYQVSKTLRFELIPQGKTLKHIQEQGFIEEDKARNDHYKELKPIIDRI
	(protein	YKTYADQCLQLVQLDWENLSAAIDSYRKEKTEETRNALIEEQATYRNAIHDYFIGRT
	sequence)	DNLTDAINKRHAEIYKGLFKAELFNGKVLKQLGTVTTTEHENALLRSFDKFTTYFSG
		FYENRKNVFSAEDISTAIPHRIVQDNFPKFKENCHIFTRLITAVPSLREHFENVKKA
		IGIFVSTSIEEVFSFPFYNQLLTQTQIDLYNQLLGGISREAGTEKIKGLNEVLNLAI
		QKNDETAHIIASLPHRFIPLFKQILSDRNTLSFILEEFKSDEEVIQSFCKYKTLLRN
		ENVLETAEALFNELNSIDLTHIFISHKKLETISSALCDHWDTLRNALYERRISELTG
		KITKSAKEKVQRSLKHEDINLQEIISAAGKELSEAFKQKTSEILSHAHAALDQPLPT
		TLKKQEEKEILKSQLDSLLGLYHLLDWFAVDESNEVDPEFSARLTGIKLEMEPSLSF
		YNKARNYATKKPYSVEKFKLNFQMPTLASGWDVNKEKNNGAILFVKNGLYYLGIMPK
		QKGRYKALSFEPTEKTSEGFDKMYYDYFPDAAKMIPKCSTQLKAVTAHFQTHTTPIL
		LSNNFIEPLEITKEIYDLNNPEKEPKKFQTAYAKKTGDQKGYREALCKWIDFTRDEL
		SKYTKTTSIDLSSLRPSSQYKDLGEYYAELNPLLYHISFQRIAEKEIMDAVETGKLY
		LFQIYNKDFAKGHHGKPNLHTLYWTGLFSPENLAKTSIKLNGQAELFYRPKSRMKRM
		AHRLGEKMLNKKLKDQKTPIPDTLYQELYDYVNHRLSHDLSDEARALLPNVITKEVS
		HEIIKDRRFTSDKFFFHVPITLNYQAANSPSKFNQRVNAYLKEHPETPIIGIDRGER
		NLIYITVIDSTGKILEQRSLNTIQQFDYQKKLDNREKERVAARQAWSVVGTIKDLKQ
		GYLSQVIHEIVDLMIHYQAVVVLENLNFGFKSKRTGIAEKAVYQQFEKMLIDKLNCL
		VLKDYPAEKVGGVLNPYQLTDQFTSFAKMGTQSGFLFYVPAPYTSKIDPLTGFVDPF
		VWKTIKNHESRKHFLEGFDFLHYDVKTGDFILHFKMNRNLSFQRGLPGFMPAWDIVE
		EKNETQFDAKGTPFIAGKRIVPVIENHRFTGRYRDLYPANELIALLEEKGIVERDGS
		NILPKLLENDDSHAIDTMVALIRSVLQMRNSNAATGEDYINSPVRDLNGVCFDSRFQ
		NPEWPMDADANGAYHIALKGQLLLNHLKESKDLKLQNGISNQDWLAYIQELRN

[0215] In some aspects, the PNME of the present disclosure is linked to cationic peptides adapted to bind the negatively charged cell membrane. The cationic peptide confers the protein complex a non covalent positive charge. The physical adsorption of the cationic peptide to the surface of oppositely charged proteins on a cell membrane enables cationic transfection of cell membranes. Accordingly in such aspects, the cell targeting and internalization is not specific to T cells. However, cationic peptides can be used in vitro when the T cells are the cells in culture and there is no specific cell targeting needed. Cationic peptides can have a length of 10 to 20 amino acids, and contain repeating or non-repeating positively charged amino acids such as R and L. In one example, the cationic peptide is SEQ ID NO: 11 which is RRRRRRRLLLLLLLL. On the other hand, in vivo applications of CAR T gene editing generally require the specific targeting of the T cells. Accordingly, in other aspects, the PNME is modified to have a domain that targets and binds T cells or a specific subtype of T cells.

[0216] Accordingly, in some aspects, the present disclosure provides for a PNME that is modified and comprises a cell recognition domain, an endosome escape domain, and a polynucleotide-modifying enzyme domain, with the endosome escape domain being covalently coupled to the cell recognition domain. The cell recognition domain targets a T cell marker such as CD4, CD8, CD16 or CD56.

[0217] The cell recognition domain can be a natural or synthetic peptide or nucleic acid domain capable of specific non-covalent association with a cell-surface antigen or receptor. The cell recognition domain can bind to an epitope of the cell-surface antigen or receptor. In some embodiments, the cell recognition domain is an antibody or antigen-binding fragment thereof, or an antibody mimetic. Antibodies include camelid antibodies. Antigen-binding fragments include Fab fragments, Fab′ fragments, F(ab′)₂ fragments, fragments produced by Fab expression libraries, Fd fragments, Fv fragments, disulfide linked Fv (dsFv) domains, single chain antibody (e.g. scFv) domains, VHH domains, or single domain antibodies. Antibody mimetics are non-antibody derived peptides or nucleic acids that bind with similar affinity to antibodies and include affibodies, affilins, affimers, affitins, alphabodies, anticalins, atrimers, avimers, aptamers, DARPins, fynomers, knottins, Kunitz domain peptides, monobodies, nanoCLAMPs, and linear peptides of 6-20 amino acids. Suitable antibody mimetics can be derived by mammalian cell, bacterial cell, or bacteriophage display by systematic evolution of ligands by exponential enrichment (SELEX™) or DNA encoded library approaches involving e.g. immobilization of a given antigen on a surface followed by binding selection. In some cases, the cell recognition domain is an aptamer oligonucleotide, such as a polyribonucleotide or a polydeoxyribonucleotide; design. Such oligonucleotide aptamers can comprise non-canonical nucleotides, such as 2′-OMe, 2′-F, or 4′-S nucleotides, 2′-FANAs, HNAs, or locked nucleic acid residues. In some embodiments, the cell recognition domain comprises a chemical ligand with a molecular weight of less than about 800 Da. Such ligands include small-molecule ligands of cell-surface small-molecule receptors such as folate (which binds to the folate receptor), piperidine carboxyamides (which bind to FSHR), phenylpyrazole or thienopyrimidine compounds (which bind to LHR), cinacalcet or analogs (which bind to CRF1) or nitro-bezoxadiazole compounds (which bind to EGFR). Such ligands also include protein ligands of cell-surface receptors such as IL2 (which binds to IL2alpha receptor), EGF (which binds to EGFR), or HFG (which binds to HFGR). In some cases, the cell recognition domain does not directly associate with a cell surface antigen but rather is capable of binding a protein ligand that is selective for a cell-surface receptor or carbohydrate. In some cases, the cell recognition domain comprises a protein ligand that is selective for a cell-surface receptor or carbohydrate. In some cases, the protein ligand that is selective for a cell-surface receptor or carbohydrate comprises 5-15 amino acids in length. In some cases, the protein ligand is a peptide growth hormone. In some cases, the protein ligand has a globular or cyclical structure.

[0218] In some aspects, the PNME of the present disclosure has been modified to incorporate a display domain to achieve a display on the exterior surface of the PNME that targets a T cell marker such as CD4, CD8, CD16 or CD56. The PNME can therefore, in such aspects, be considered a single protein delivery platform. In some embodiments, a “single protein” means that an entire sequence of the single protein is contained between the N and C terminus and that no linkage or fusion is performed at the N or C terminus. In some embodiments, the display domains of the present disclosure are positioned at least 25 amino acids after the N terminus or at least 25 amino acids before the C terminus of the polynucleotide-modifying enzyme. In some embodiments, the display domain is positioned at least 30, at least 40, at least 50, at least 75 or at least 100 amino acids after the N terminus, or at least 30, at least 40, at least 50, at least 75 or at least 100 amino acids before the C terminus. Cell penetrating peptides have been used as a platform for the delivery of biomolecules. However, generally, cell penetrating peptides do not have the same specificity and success as delivery platforms that include immunoglobulin approaches. An exemplary immunoglobulin approach can be that the antibody or antibody mimetic is first screened against a defined biological target such as a receptor and then validated with respect to target recognition. CRISPR proteins have been fused with peptides such as RGB, SV40NLS at the C and N terminal of the protein, or associated by charge to CRISPR RNP affecting non-specific entry to cells. It is preferable in order to influence organ tropism or preferential tissue accumulation that receptor specific binding should be a feature of the PNME which thus acts as a cell penetrating peptide. In some embodiments, the cell recognition domain is a peptidic sequence of SEQ ID NO: 12: QQYYSYRT which targets CD4.

[0219] In some aspect, the PNME of the present disclosure was modified to include an antigen binding domain, in a loop that is positioned on an external surface of the PNME. The PNME of this aspect is also a single protein since the antigen binding domain is inserted in an external loop between the N and C terminus of the PNME. It was surprisingly found that large a domain (e.g. more than 20 amino acids, more than 50 amino acids, more than 100 amino acids, from 100 to 200 amino acids or from 136 to 156 amino acids) can be incorporated in a loop of the PNME without disrupting the folding of the catalytic active nuclease pocket of the PNME. Indeed, the antigen binding domain is selected from Fab, single-domain antibody (sdAb), V_HH, or camelid antibody domain, positioned in a loop on an external surface of the polynucleotide-modifying enzyme. A linker domain is preferably included upstream of the antigen binding domain which helps the three dimensional conformation of the PNME to maintain its catalytic activity while providing a specific targeting to a desired cell type. In some embodiments, the linker domain has a size of from 0 to 30, from 8 to 30, from 10 to 30, from 12 to 28, from 16 to 25 or from 18 to 23 amino acids. In some embodiments, the antigen binding domain targets a T cell marker however, the antigen binding domain may target any other cell type or cell receptor. For example, the antigen binding domain can target any of the targets provided in Table 2 relating to cancer or any of the epitopes of Table 3. In one example, the PNME is spCas9 and the linker and antigen binding domains are inserted at ser1154.

[0220] Table 2. List of Cancer-associated Antigens that can be used for specific delivery of nucleases according to some embodiments described herein

TABLE 2
List of Cancer-associated Antigens that can be used for specific delivery
of nucleases according to some embodiments described herein
	Example UniProt Accession ID, Chemical Name,
Target	or Literature Reference
cd44v6	Tremmel et al. Blood 114: 5236-5244(2009)
CAIX (Carbonic Anhydrase 9, CA9)	Q16790 (CAH9_HUMAN)
CEA (CEA Cell Adhesion Molecule 5,	P06731 (CEAM5_HUMAN)
CEACAM5, Carcinoembryonic antigen)
CD133 (Prominin 1, PROM1)	O43490 (PROM1_HUMAN)
cMet hepatocyte growth factor receptor	P08581 (MET_HUMAN)
(MET)
EGFR (Epidermal Growth Factor	P00533 (EGFR_HUMAN)
Receptor, HER1)
EGFR vIII	Koga et al. Neuro Oncol. 2018 Sep; 20(10): 1310-
	1320.
EPCAM (Epithelial Cell Adhesion	P16422 (EPCAM_HUMAN)
Molecule)
EphA2 (EPH Receptor A2)	P29317 (EPHA2_HUMAN)
Fetal acetylcholine receptor	Nayak et al. Proc Natl Acad Sci USA. 2013 Aug. 13;
	110(33): 13654-9.
FRalpha folate receptor (FOLR1)	P15328 (FOLR1_HUMAN)
GD2 (Ganglioside G2)	(2R,4R,5S,6S)-2-[3-[(2S,3S,4R,6S)-6-
	[(2S,3R,4R,5S,6R)-5-[(2S,3R,4R,5R,6R)-3-
	acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-
	yl]oxy-2-[(2R,3S,4R,5R,6R)-4,5-dihydroxy-2-
	(hydroxymethyl)-6-[(E)-3-hydroxy-2-
	(octadecanoylamino)octadec-4-enoxy]oxan-3-
	yl]oxy-3-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3-
	amino-6-carboxy-4-hydroxyoxan-2-yl]-2,3-
	dihydroxypropoxy]-5-amino-4-hydroxy-6-(1,2,3-
	trihydroxypropyl)oxane-2-carboxylic acid
GPC3 (Glypican 3)	P51654 (GPC3_HUMAN)
GUCY2C (Guanylate Cyclase 2C)	P25092 (GUC2C_HUMAN)
HER2 (ERBB2)	P04626 (ERBB2_HUMAN)
ICAM1 (Intercellular Adhesion Molecule	P05362 (ICAM1_HUMAN)
1)
IL13Ralpha2 (IL13RA2)	Q14627 (I13R2_HUMAN)
IL11 receptor alpha (IL11RA)	Q14626 (I11RA_HUMAN)
Kras	P01116 (RASK_HUMAN)
Kras G12D	P01116 (RASK_HUMAN) with G12D substitution
L1cam (L1 Cell Adhesion Molecule)	P32004 (L1CAM_HUMAN)
MAGE (melanoma-associated antigen)	P43360 (MAGA6_HUMAN)
	P43355 (MAGA1_HUMAN)
	Q9Y5V3 (MAGD1_HUMAN)
	P43356 (MAGA2_HUMAN)
	Q9UBF1 (MAGC2_HUMAN)
	P43364 (MAGAB_HUMAN)
	P43365 (MAGAC_HUMAN)
	Q9UNF1 (MAGD2_HUMAN)
	P43357 (MAGA3_HUMAN)
	Q9HCI5 (MAGE1_HUMAN)
	P43358 (MAGA4_HUMAN)
	P43361 (MAGA8_HUMAN)
	Q96JG8 (MAGD4_HUMAN)
	Q9HAY2 (MAGF1_HUMAN)
	O15481 (MAGB4_HUMAN)
	O15479 (MAGB2_HUMAN)
	P43363 (MAGAA_HUMAN)
	Q96M61 (MAGBI_HUMAN)
	P43362 (MAGA9_HUMAN)
	Q8TD91 (MAGC3_HUMAN)
	O60732 (MAGC1_HUMAN)
	Q9H213 (MAGH1_HUMAN)
	P43359 (MAGA5_HUMAN)
Mesothelin (MSLN)	Q13421 (MSLN_HUMAN)
MUC1 (Mucin 1, Cell Surface Associated)	P15941 (MUC1_HUMAN)
MUC16 (Mucin 16, Cell Surface	Q8WX17 (MUC16_HUMAN)
Associated)
NKG2D (Killer Cell Lectin Like Receptor	P26718 (NKG2D_HUMAN)
K1, KLRK1, NK Cell receptor D, CD314)
NY-ESO1 (New York Esophageal	P78358 (CTG1B_HUMAN)
Squamous Cell Carcinoma 1, CTAG1B,
Cancer/Testis Antigen 1B)
PSCA (Prostate Stem Cell Antigen,	O43653 (PSCA_HUMAN)
PRO232)
WT1 (WT1 Transcription Factor, Wilms	P19544 (WT1_HUMAN)
Tumor Protein)
PSMA (prostate-specific membrane	Q04609 (FOLH1_HUMAN)
antigen, Glutamate carboxypeptidase II,
GCPII, N-acetyl-L-aspartyl-L-glutamate
peptidase I, NAALADase I, NAAG
peptidase, FOLH1, folate hydrolase 1)
5t4 or TPBG (Trophoblast Glycoprotein)	Q13641 (TPBG_HUMAN)
Transferrin receptor (TFRC, CD71,	P02786 (TFR1_HUMAN)
GPNMB Breast cancer, melanoma	Q14956 (GPNMB_HUMAN)
(Glycoprotein Nmb)
LeY (Lewis y antigen, Lewis y	N-[(3R,4R,5S,6R)-5-[(2S,3R,4S,5R,6R)-4,5-
Tetrasaccharide)	dihydroxy-6-(hydroxymethyl)-3-[(2R,3R,4S,5R,6R)-
	3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-
	yl]oxy-2-hydroxy-6-(hydroxymethyl)-4-
	[(2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-methyloxan-
	2-yl]oxyoxan-3-yl]acetamide
CA6 (Carbonic anhydrase 6, CA-VI)	P23280 (CAH6_HUMAN)
Av integrin (ITGAV, Integrin Subunit	P06756 (ITAV_HUMAN)
Alpha V)
SLC44A4 (Solute Carrier Family 44	Q53GD3 (CTL4_HUMAN)
Member 4)
Nectin-4 (NECTIN4, NECT4, PVRL4,	Q96NY8 (NECT4_HUMAN)
EDSS1) Solid tumors
AGS-16 (Ectonucleotide	O14638 (ENPP3_HUMAN)
Pyrophosphatase/Phosphodiesterase 3,
ENPP3)
Cripto (CFC1, FRL-1, Cryptic Family 1)	P0CG37 (CFC1_HUMAN)
ALCAM (Activated Leukocyte Cell	Q13740 (CD166_HUMAN)
Adhesion Molecule, CD166, MEMD)
TENB2 (Transmembrane Protein With	Q9UIK5 (TEFF2_HUMAN)
EGF Like And Two Follistatin Like
Domains 2, TMEFF2, Tomoregulin-2,
HPP1, TPEF)
EPCAM (Epithelial Cell Adhesion	P16422 (EPCAM_HUMAN)
Molecule, Tumor-Associated Calcium
Signal Transducer 1, Major
Gastrointestinal Tumor-Associated
Protein GA733-2, Trophoblast Cell
Surface Antigen 1, TACSTD1, EGP314,
CD326)
indicates data missing or illegible when filed

TABLE 3
Examples of receptors with high tissue expression that may be used for tissue specific
delivery according to some embodiments of the current disclosure Gene/Protein
	Example Gene/Protein
	Symbol or Uniprot
Receptor	Accession	Tissue
L-SIGN (CLEC4M, C-Type Lectin	Q9H2X3 (CLC4M_HUMAN)	liver
Domain Family 4 Member M, CD299)
ASGPR (ASGR1, ASGR2,	P07306 (ASGR1_HUMAN)	liver
Asialoglycoprotein receptor 1 or 2)	P07307 (ASGR2_HUMAN)
AT1 (Angiotensin II Receptor Type 1,	P30556 (AGTR1_HUMAN)	kidney
AGTR1)
B2/B1 receptor (Bradykinin Receptor	P46663 (BKRB1_HUMAN)	lung
B1 or B2, BDKRB1, BDKRB2, BKRB1,	P30411 (BKRB2_HUMAN)
BKRB2)
Muscarinic receptors (Muscarinic	CHRM1, CHRM2, CHRM3,	lung/Bladder
acetylcholine receptors, mAChRs)	CHRM4, CHRM5
FGFR4 (Fibroblast Growth Factor	P22455 (FGFR4_HUMAN)	Liver, kidney lung
Receptor 4)		pancreatic cells
FGFR3 (Fibroblast Growth Factor	P22607 (FGFR3_HUMAN)	Brain kidney testes
Receptor 3)
FGFR1 (Fibroblast Growth Factor	P11362 (FGFR1_HUMAN)	Epithelial, endothelial
Receptor 1)		fibroblasts
		mesenchymal,
		cardiomyocytes
Frizzled 4 (Frizzled Class Receptor 4,	Q9ULV1 (FZD4_HUMAN)	Ubiquitous
FZD4)
S1PR1 (Sphingosine-1-Phosphate	P21453 (S1PR1_HUMAN)	Endosomal
Receptor 1)		vascular
		smooth muscle
		fibroblasts
TSHR (Thyroid Stimulating Hormone	P16473 (TSHR_HUMAN)	thyroid
Receptor)
GPR41 (Free Fatty Acid Receptor 3, G	O14843 (FFAR3_HUMAN)	colon
Protein-Coupled Receptor 41, FFAR3)
GPR43 (G Protein-Coupled Receptor	O15552 (FFAR2_HUMAN)	colon
43, FFAR2, Free Fatty Acid Receptor
2)
GPR109A (G Protein-Coupled	Q8TDS4 (HCAR2_HUMAN)	colon
Receptor 109A, Niacin Receptor 1,
NIACR1, Hydroxycarboxylic Acid
Receptor 2, HCAR2)
TFRC (Transferrin Receptor, CD71,	P02786 (TFR1_HUMAN)	Blood brain barrier
TFR1)
Insulin receptor (INSR, CD220)	P06213 (INSR_HUMAN)	Blood brain barrier
Insulin-like growth factor 2 receptor	P11717 (MPRI_HUMAN)	Blood brain barrier
(IGF2R, Cation-independent
mannose-6-prosphate receptor, CI-
MPR, MPRI)
LRP1 (LDL Receptor Related Protein	Q07954 (LRP1_HUMAN)	General cell delivery
1, Apolipoprotein E Receptor, APOER,
CD91)
IGF1R (Insulin Like Growth Factor 1	P08069 (IGF1R_HUMAN)	Prostate
Receptor, CD221)
Prolactin receptor (PRLR)	P16471 (PRLR_HUMAN)	Ovarian normal and
Follicle stimulating hormone receptor	P23945 (FSHR_HUMAN)	Ovarian
(FSHR, FSH receptor, Follitropin
Receptor, LGR1)
indicates data missing or illegible when filed

[0221] In some embodiments, a CRISPR modified nuclease such as C9mAur or M7 ma modified with either peptide for general delivery (cationic and non specific cell entry) or grafted with a CDR peptide sequence in a loop of the 09 modified (C9m) scaffold (delivery via receptor specific binding and receptor mediated endocytosis or C9m is fused with an anti 004 nanobody either chemically or through being part of a single protein expressed in a protein expression system. A generalised transfection option is provided by complexation of any of the CRISPR enzyme derivatives described herein with a cationic peptide. In the formulations, a protein complex is provided by the formation of a complex between the monoavidin:biotin interaction with a biotinylated donor encoding a chimeric antigen receptor (sequence) and a polynucleotide modifying enzyme.

[0222] FIG. 1 shows the homology directed repair (HDR) enhanced formulations and delivery. Generalised delivery is defined herein as being driven by a cationic peptide complexation of the PNME where the nuclease is Cas9, Cas12 or Type II or Type V CRISPR system enzymes capable of producing a double strand break. Delivery will be cationic in nature non-specifically interacting with oppositely charge cell membrane. Receptor mediated delivery requires the PNME to have a domain capable of recognizing a cell receptor or marker such that it can be selectively internalized.

[0223] In some embodiments, the PNME of the present disclosure can be combined with an endosome escape domain to form a fusion polypeptide. The endosome escape domain allows the fusion peptide to exit the endosome and enter the cytoplasm after being endocytosed. The endosome escape domain can be incorporated in the sequence of the PNME or can be linked at the N or C terminus of the PNME. Table 4 details non-limitative examples of endosome escape (EE) domains.

TABLE 4
Examples of Endosome escape sequences
SEQ ID NO:	Peptide Sequence (N- to C-terminus)
	X1X2X3X4X5X6X7X8X9; wherein
	X1 is P or C;
	X2,X3,X4, and X5 are independently
	selected from C, R, or K;
	and
	X6,X7,X8, and X9 are independently
	selected from C, R, K, A,
	or W.
	X1X2X3X4X5X6X7X8X9; wherein
	X1 is P or C;
	X2,X3,X4, and X5 are independently
	selected from C, R, or K;
	and
	X6,X7,X8, and X9 are independently
	selected from C, R, K, A,
	or W., and wherein at least 3 of
	X1-X9 are C and no more
	than 8 of X1-X9 are C.
13	PCRKCACCA
14	PRCCRWCCA
15	PRRCKRCKC
16	CKKCRKCCK
17	CCRCKCWCC
18	CCRKCCCCC
19	PRKCCCCCC
20	HHHHHHHHHH
21	CCCCCC

[0224] Double strand breaks caused by CRISPR can be repaired either by non-homologous end joining (NHEJ) or through homology directed repair (HDR) or single strand annealing. In the case of CRISPR editing NHEJ is preferred as for the majority of the cell cycle it is the predominant method of resolving double strand breaks by the action of Ku70/80, artemis, DNA-Pk and lig4, resulting in small insertion and deletions through can inactivate a gene. Where a donor template is present and cell cycle permits (S1 G2) homologous recombination can guide repair where the donor provides a template for the double strand break to be resolved. Unfortunately HDR with CRISPR is highly inefficient due to many factors, among which is the availability of donor DNA at the point of double strand break formation, and the limited period of the cell cycle when HDR is preferred. To resolve the donor availability, donor DNA can be associated via the biotin interaction to the fusion CRISPR proteins where a nuclease is expressed with a Monoavidin domained attached. This is an advantage over other gene delivery systems such as viral delivery (e.g. AAV) due to packaging volumes constraints. Indeed, CRISPR nucleases and donors have to be delivered separately and the advantage of co-localisation is lost both in time domain and spatial co-localisation. Other iterations of co-localisation have used snap tag, aptamers and nanoparticle systems. The advantages of the present system are the use of a protein with additional endosomal escape function and optional delivery via generalised cationic methods or preferentially receptor mediated delivery.

[0225] In some embodiments, the PNME further comprises a hapten binding domain to link an additional protein or nucleic acid ligand to the PNME. A “hapten binding domain” is a peptide or oligonucleotide domain that binds a hapten. “Hapten” refers to a small molecule, which when combined with a larger carrier such as a protein, is capable of high affinity binding to an antibody or antibody mimetic (“hapten binding domain”). In some embodiments, hapten/hapten binding domain pairs are derived from natural proteins or engineered variants thereof, such as the biotin/avidin pair or amylose/MBP pair. Engineered alternatives for biotin include D-desthiobiotin. Alternatives for avidin include streptavidin, NeutrAvidin, and CaptAvidin. In some embodiments, hapten/hapten binding domain pairs are synthetically engineered pairs such as 3-methylindole/anti-3-methylindole monoclonal antibody (such as 14G8, 3F12, 4A1G, 8F2, or 8H1 monoclonal antibodies), fumonisin B1/anti-fumonisin antibody, 1,2-Naphthoquinone/anti-1,2-Naphthoquinone antibody, 15-Acetyldeoxynivalenol/anti-15-Acetyldeoxynivalenol antibody, (2-(2,4-dichlorophenyl)-3(1H-1,2,4-triazol-1-yl)propanol)/anti-(2-(2,4-dichlorophenyl)-3(1H-1,2,4-triazol-1-yl)propanol) antibody, 22-oxacalcitriol/anti-22-oxacalcitriol antibody, (24,25(OH)2D3)/anti-(24,25(OH)2D3) antibody, 2,4,5-Trichlorophenoxyacetic acid/anti-2,4,5-Trichlorophenoxyacetic acid antibody, 2,4,6-Trichlorophenol/anti-2,4,6-Trichlorophenol antibody, 2,4,6-Trinitrotoluene/anti-2,4,6-Trinitrotoluene antibody, 2,4-Dichlorophenoxyacetic acid/anti-2,4-Dichlorophenoxyacetic acid antibody, 2-hydroxybiphenyl/anti-2-hydroxybiphenyl antibody, 3,5,6-trichloro-2-pyridinol/anti-3,5,6-trichloro-2-pyridinol antibody, 3-Acetyldeoxynivalenol/anti-3-Acetyldeoxynivalenol antibody, 3-phenoxybenzoic acid/anti-3-phenoxybenzoic acid antibody, digoxin/anti-digoxin antibody, fluorescein/anti-fluorescein antibody, or hexahistidine/Ni-NTA. The hapten binding domain can be located N- or C-terminal to the PNME, or both. The hapten binding domain can be separated from another domain described herein by a linker or can be directly fused to the domain sequence without intervening amino acids. In some cases, the hapten binding domain is within a linker domain separating two other domains of the PNME. In some cases, the PNME comprises at least one, at least two, at least 3, at least 4, at least 5, or more hapten binding domains.

[0226] In some embodiments there is provided a composition comprising the PNME and a hapten-binding domain. The composition can further comprise a peptide, protein, oligonucleotide, or polynucleotide linked to the corresponding hapten. The oligonucleotide can comprise a deoxyribonucleotide or a ribonucleotide. The oligonucleotide can comprise a single-stranded or double-stranded oligonucleotide.

[0227] In some embodiments when the PNME comprises a hapten-binding domain and a programmable or site directed nuclease, the PNME further comprises a nucleic acid with homology arms complementary to regions flanking the target site for the programmable or site directed nuclease (e.g. a repair template or donor DNA). By this method, a nuclease can be delivered to the cell in vicinity of the site to be cleaved. In some cases, the repair template or donor DNA is a single- or double-stranded DNA repair template or donor DNA comprising from 5′ to 3′: a first homology arm comprising a sequence of at least about 20 nucleotides 5′ to the target sequence, an insert DNA sequence or region of at least about 10 nucleotides, and a second homology arm comprising a sequence of at least about 20 nucleotides 3′ to the target sequence. In some embodiments, the first or said second homology arms comprise a sequence of at least about 20, 40, 50, 80, 120, 150, 200, 300, 500, or 1000 nucleotides. In some embodiments, the 5′ and 3′ homology regions have different lengths. In some embodiments, the 5′ and 3′ homology regions have the same length. In some embodiments, the repairtemplate or donor DNA is a single stranded polynucleotide and the 5′ homology region comprises 50-100 nucleotides and the 3′ homology region comprises 20-60 nucleotides. In some embodiments, the 3′ end of the 5′ homology region is homologous to a sequence within 5 nucleotides of the double-stranded break. In some embodiments, the 5′ end of the 3′ homology region is homologous to a sequence within 5 nucleotides of the double strand break. The insert region can comprise an exon, an intron, a transgene, a stop codon (e.g. a stop codon in frame with the gene ORF into which it is inserted), a coding sequence of a gene comprising at least one nonsense or missense mutation, or a mutation ablating activity of a PAM site in the vicinity of a sequence targeted by a PNME CRISPR enzyme. Example transgenes include selectable markers such as BlaS, HSV-tk, puromycin N-acetyl-transferase, or Tn5 NEO gene, which can be used to select for cells that have undergone recombination with the donor DNA or repair template. Example transgenes also include detectable labels such as fluorescent enzymes, proteins sequences capable of high-affinity detection with antibodies, epitope tags, or fluorescent proteins.

[0228] In one example, the PNME is built on a C9m scaffold, where a fusion of Cas9 is made with a mono avidin domain, with peptide sequences or an antigen binding domain grafted on to loop domains identified above. The antigen binding domain (e.g. VHH) can be selected as binders targeting specific receptors, for example CD4, CD8, CD16 or CD56. Grafting of the antigen binding domain can be achieved by insertion of the corresponding DNA sequence to an expression vectors encoding the C9m.

[0229] In some embodiments, the PNME can comprise a nuclear localization sequence (NLS). The NLS can be located at the N- or C-terminus of the PNME, or both. The NLS can be separated from the PNME peptide sequence by a linker or can be directly fused to the PNME sequence without intervening amino acids. In embodiments, the PNME comprises at least one, at least two, at least 3, at least 4, at least 5, or more NLSs. In some embodiments, NLSs comprise 7-25 amino acid residues. In some embodiments, NLSs are derived from mammalian nuclear entering proteins such as splicing factors or transcription factors. In some embodiments, an NLS interacts with an importin. In some embodiments, the NLS is a bipartite NLS wherein amino acids within an N-terminal portion of the NLS involved in the recognition of an importin and amino acids within a C-terminal portion of the NLS involved in the recognition of an importin are split by an amino acid sequence not involved in the recognition of an importin. In some embodiments, an NLS comprises at least one sequence depicted in Table 5 below or a combination of sequences from Table 5 (i.e. SEQ ID NOs: 22-37), a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% sequence identity to a sequence described in Table 5, or a sequence identical to any of the sequences in Table 5. When more than one NLS is included in a PNME or PNME composition, the NLSs may comprise the same sequence or comprise different sequences. In some embodiments, two or more NLS sequences are included (e.g. NLS of SV40) and the NLS sequences can be positioned in a linker between the PNME and a mono avidin domain.

TABLE 5
Examples of Nuclear Localization
Sequences (NLSs)
SEQ ID
NO:	Peptide Sequence (N- to C-terminus)
22	KRRRRQERAKEREKRR
23	MRKTKALAPTA
24	KKKRRP
25	KKFK
26	KKKKYN
27	PPAKRERLD
28	RGRGRRRRRRRR
29	PKKNKLKKKS
30	PKKKRKV
31	NYKRPMDGTYGPPAKRHEGE
32	KRSGSKAF
33	PPAKRERLD
34	RKKSGMQIALNDHLKQRR
35	KKAFQNVLRIQCLCRK
36	RRLLCRCGRRLPPEPCAAARPALFPSGVPAARSSP
37	SVLGKRKFA

[0230] In some embodiments, the PNME is bi-specific, that is to say carrying two domains or peptide sequences that can recognise the same or different cell receptors (e.g. T cell receptors). The cell recognition domain, the display domain and/or the antigen binding domain can be combined to form bi or multi specific protein complexes. Accordingly a bispecificity can be produced where the PNME effectively has two receptor binding domains (e.g. a display domain such as a CDR and a cell recognition domain, or a display domain such as a CDR and an antigen binding domain such as an inserted VHH).

[0231] In some embodiments, there is provided a CRISPR system for introduction of a CAR by first formulating a CRISPR protein complex via either of the delivery mechanisms (cationic or receptor mediated) with a sgRNA molecule specific to TRAC. The intention is to introduce a chimeric antigen receptor by forming double strand break in the early exons of the TRAC receptor, removing its native expression and placing the CAR under the control of the endogenous promoter of the TRAC gene. FIG. 2 illustrates the system mechanism of action with respect to receptor mediated delivery of the protein complex targeting CD4 receptor for delivery. The anti CD4 domain binds a cell receptor and get internalized by receptor mediated endocytosis. Then, endosomal escape is affected by the endosome escape domain (e.g. endosomal peptide escape sequences) and a transit to the nucleus is achieved by the NLS. In the nucleus, a homologous recombination is performed with the genomic DNA and repair template homologous sequences (left and right homology arms) flanking CAR insert on donor DNA.

[0232] To achieve co delivery once the protein complex has been formed (e.g. CRISPR nuclease plus guide RNA) the biotin mono avidin relationship is exploited by biotinylating a CAR encoded donor DNA molecule with a 5′ or 3 or internal biotin label. Mixing the CRISPR nuclease in equal molar parts enables binding of the donor to the protein complex. At this point the enhanced HDR CRISPR complex is ready for delivery to cells. If using a CRISPR protein complex without anti CD4 binding domain and a cationic peptide is used this will enable delivery non specifically via the cationic interaction of the peptide with the oppositely charged cell membrane. Where an anti CD4 domain is present, delivery will be achieved to cells by interaction with the CD4 receptor upon a T-cell or T-cell model.

[0233] Compared to virus vectors, the presently described genetic delivery systems have low immunogenicity, increased biosafety, decreased production costs, and a capacity to transduce large gene fragment>100 kb in length, making them an advantageous means for CAR insertion into T cell genomes, including NK cells, with long-lasting expression

[0234] In some embodiments, there is provided a vector comprising a nucleotide sequence encoding a PNME. In some cases, the vector further comprises a hapten-binding domain within the same open reading frame (ORF) as the endosome escape domain, and PNME. A “vector” is a nucleic acid sequence capable of transferring other operably-linked heterologous or recombinant nucleic acid sequences to target cells. In some examples, a vector is a minicircle, plasmid, yeast artificial chromosome (YAC), bacterial artificial chromosome (BAC), cosmid, phagemid, bacteriophage genome, or baculovirus genome. Suitable vectors also include vectors derived from bacteriophages or plant, invertebrate, or animal (including human) viruses such as CELiD vectors, adeno-associated viral vectors (e.g. AAV1, AAV2, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, or pseudotyped combinations thereof such as AAV2/5, AAV2/2, AAV-DJ, or AAV-DJ8), retroviral vectors (e.g. MLV or self-inactivating or SIN versions thereof, or pseudotyped versions thereof), herpesviral (e.g. HSV- or EBV-based), lentiviral vectors (e.g. HIV-, FIV-, or EIAV-based, or pseudotyped versions thereof), adenoviral vectors (e.g. Ad5-based, including replication-deficient, replication-competent, or helper-dependent versions thereof) or baculoviral vectors (which are suitable to transfect insect cells as described herein). In some embodiments, a vector is a replication competent viral-derived vector.

[0235] Accordingly, in some aspects the present disclosure also provides for host cells comprising any of the vectors described herein. In some embodiments, the host cells are animal cells. The term “animal cells” encompasses any animal cell, including but not limiting to, invertebrate, non-mammalian vertebrate (e.g., avian, reptile, and amphibian), and mammalian cells. A number of mammalian cell lines are suitable host cells for recombinant expression of polypeptides of interest. Mammalian host cell lines include, for example, COS, PER.C6, TM4, VERO076, MDCK, BRL-3A, W138, Hep G2, MMT, MRC 5, FS4, CHO, 293T, A431, 3T3, CV-1, C3H10T1/2, Colo205, 293, HeLa, L cells, BHK, HL-60, FRhL-2, U937, HaK, Jurkat cells, Rat2, BaF3, 32D, FDCP-1, PC12, M1x, murine myelomas (e.g., SP2/0 and NSO) and C2C12 cells, as well as transformed primate cell lines, hybridomas, normal diploid cells, and cell strains derived from in vitro culture of primary tissue and primary explants. Any eukaryotic cell that is capable of expressing recombinant and/or transgenic proteins may be used in the disclosed cell culture methods. Numerous cell lines are available from commercial sources such as the American Type Culture Collection (ATCC). The host cells can be CHO cells. In some embodiments, the host cells are bacterial cells suitable for protein expression such as derivatives of E. coli K12 strain. In some embodiments, the host cells comprise plant cells into which genes have been introduced by a vector single-stranded RNA virus tobacco mosaic virus. “Host cells” can be insect cells which are utilized for the production of large quantities of the polypeptides according to the disclosure. In some embodiments, the baculovirus system (which provides all the advantages of higher eukaryotic organisms) is utilized. The host cells for the baculovirus system include, but are not limited to Spodoptera frugiperda ovarian cell lines SF9 and SF21 and the Trichoplusia ni egg-derived cell line High Five.

[0236] In some embodiments, the PNME described herein is delivered to cells (e.g. in vitro or in vivo) via a pharmaceutical composition or dose form of particular design. The pharmaceutical composition may comprise sterile water alongside a pharmaceutically acceptable excipient, and optional electrolytes to ensure the composition is isotonic. Because the PNME and the pharmaceutical composition comprising same as described herein do not require chemical transfection agents to enter cells, in some embodiments, a liquid formulation for delivery does not comprise a polyetherimide (PEI), polyethylene glycol (PEG), polyamidoamine (PAMAM), or sugar (dextran) derivative polymer comprising more than three subunits.

[0237] The CAR-T cells of the present disclosure can be engineered to target diverse antigens, enhance the proliferation and persistence in vivo, increase infiltration into solid tumours, overcome resistant tumour microenvironment, and ultimately achieve an effective anti-tumour response.

[0238] In some embodiments, the T cell target is a CD8 T cell. The cytotoxic CD8 T cells can eliminate tumor cells through recognition of peptide epitopes presented on major histocompatibility complex class I (MHC-I) molecules by the alpha-beta T cell receptor (apTCR). T cells can recognize peptides derived from tumor-associated antigens, cancer-testis antigens, viral antigens (in the case of virally derived tumors), and neoantigens. Neoantigens are peptides derived from mutated “self” proteins that the immune system detects as “nonself.” Many neoantigens are “private” to individual tumors, and immunity to these antigens can be exploited with immunotherapies such as checkpoint blockade or personalized vaccines. Some neoantigens are derived from common or “hotspot” mutations such as those arising in the RAS proteins and p53. The RAS family (H, N, and KRAS) of small GTPases are among the most commonly mutated oncogenes in cancer. Among them, the G12D mutation in KRAS occurs most frequently.

[0239] In some embodiments, a safety check is introduced in the CAR T cells. This can be done by the inclusion of a suicide gene to knock back CAR cells if a cytokine storm situation occurs. This achieved by packaging the gene in place of the GFP on the CAR, and then minimizing donor size in base pairs. In such embodiments, interchangable CAR heads can be obtained by placing a monoavidin domain in place of the scFV, enabling a generic CAR T cell to be created, and easy exchange of targeting. An anti-CD4 targeting DNA complex can carry and introduce a donor DNA, with a standard CAR design but with the scFV exchange for monoavidin (MAV). After generation of the CAR-CD4+ T cells, activation of the cells towards a specific cell marker can be achieved by intravenously injecting a biotinylated scFV, nanobody, circular peptide, or antibody mimetic, which will then bind to the CAR-CD4+ T cell. As long as the biotinylated ligand is in excess and expansion occurs due to the interaction of the MAV:biotinylated ligand with target cell, as expansion occurs the new cells will lack the biotinylated target. These cells become in a situation where the biointylated ligands is in excess and systemically distributed which will immediately associate with ligand and target the appropriate cells. A conceptual advantage of such embodiments is that as selective pressure results in selection of cancer cells lacking the original target receptor (e.g. CD19) a subsequent maintained receptor could be immediately selected. For example, CD19 targeting can be switched to CD22 targeting by intravenuus injection of a CD22 biotinylated VHH, which can switch the targeting without further genetic manipulation.

[0240] An autologous CAR-T cell therapy can comprise several steps. First, T cells are isolated from a patient's or donor's blood. Subsequently, cells are transduced with CAR-encoding genes using the protein complexes described herein. CAR-modified immune cells are expanded until sufficient cell numbers are attained and are adoptively transferred into the patient to fight malignant cells. Prior to infusion of the CAR-modified immune cells, lymphodepletion is performed in most therapeutic settings to allow efficient cell engraftment.

[0241] Conventional treatment of cancer includes radiotherapy, chemotherapy, and surgery. These are associated with poor efficacy and significant side effects. Therefore, novel strategies with higher efficacy and fewer complications, such as CAR-T based immunotherapy, have been developed. Immunotherapy is the modification and enhancement of the host immune system to combat different pathologies, such as cancer. Adoptive cell therapy (ACT) is a type of immunotherapy that includes the application of immune cells to treat cancer of which CAR T cell therapy is an example.

[0242] In some embodiments, the CAR-T cell therapy can be combined with other therapies such as chemotherapy, radiation therapy, and immune checkpoint blockade. The CAR-T cell therapy may allow for a reduce dose of chemotherapy or radiation therapy when used in combination which would reduce the side effects suffered by the patient receiving these traditional treatments.

[0243] The evolution of resistance in cancer populations is a major factor limiting patient remission and curing. One way to mitigate the development of resistance is to make a bi-specific CAR T cell, this way if one receptor is selected against, the other can replace it and be relied on for the target cell binding. The situation where the two receptors of the bi-specific CAR T cell are selected against and the cancer evolves to prevent or their lower expression, has a much lower probability than a single receptor mutational change being selected for in the case of a monospecific CAR T cell. One alternative approach as explained above is the MAV-CAR where, interchangeability is achieved upon a “headless or exchanging platform”, by the addition of a biotinylated receptor binder. Yet another approach to tackle cancer resistance is to evaluate a patient for the change of cancer cell expression (for example by flow cytometry) and then inject the protein complex of the present disclosure with a donor that targets an alternative receptor validated to be expressed upon the cancer cells. This approach could also benefit from the cancer patient being used to pre-select the appropriate binder from a library of VHH, antibodies mimitics or peptides to provide a robust validation prior to treatment of the cellular recognition.

[0244] Examples of diseases that can be treated by the present CAR T cell therapies and some exemplary cell targets for each disease are provided: multiple myeloma (MM) (CD138, CS1), glioblastoma (EGFR, EGFRVIII, CD73, HER2), lymphoma (CD22, CD19, CD4), acute lymphocytic leukemia (ALL) (CD7, CD19, CD5, FLT3), acute myelocytic leukemia (AML) (CD33, CD19, CD4, CD123), chronic lymphocytic leukemia (CLL) (CD19), breast cancer (HER2, EpCAM, TF, EGFR), colorectal cancer (HER2, EpCAM, NKG2D, MUC 1), ovarian cancer (HER2, mesothelin), renal cell carcinoma (RCC) (HER2, EGFR), prostate (PSMA), neuroblastoma (GD2, CD244, CD276), melanoma (GPA7), Ewing sarcoma (GD2), Hepatocellular cancer (HCC) (GPC3), pancreatic cancer (MUC 1), gastric cancer (MUC 1), non-small cell lung cancer (MUC 1), hepatocellular carcinoma (MUC 1), glioma (MUC 1), triple-negative breast cancer (TNBC) (MUC 1), and B cell malignancies (CD19, CD20).

[0245] In some embodiments, allogeneic CAR NK cells are produced using the delivery and genetic editing described herein. Allogeneic CAR NK cells generally have reduced risk for graft versus host disease (GVHD). Moreover, cytokine release syndrome (CRS) and neurotoxicity are less likely to occur in CAR-NK immunotherapy partly due to a different spectrum of the secreted cytokines: activated NK cells usually produce IFN-γ and GM-CSF, whereas CAR-T cells predominantly induce cytokines, such as IL-1a, IL-1Ra, IL-2, IL-2Ra, IL-6, TNF-α, MCP-1, IL-8, IL-10, and IL-15, that are highly associated with CRS and severe neurotoxicity.

[0246] In some embodiments, subsequent genetic modification can be performed after the introduction of the CAR construct by the protein complex of the present disclosure. For example, the genetic ablation of PD1 can improve T cell function and in the case of cancer treatment also improves tumour targeting and treatment efficacy. In embodiments where NK cells are the CAR T cells, B2M can be genetically ablated or other genetic modifications that interfere with the HLA presentation.

[0247] Allograft rejection is mainly driven by CD8 T-cell, CD4 T cells, NK cells and, to a lesser extent, by macrophages. However, in the context of CAR T-cell therapy, the relative contribution of these cell types to allograft rejection may vary depending on their absolute numbers and reconstitution kinetics following preconditioning regimen. In some embodiments, a dual targeting approach and adapter CARs is used in order to avoid therapy resistance caused by antigen loss.

[0248] The following reagents were purchased from Wisent™: Dulbecco's Modified Eagle Medium (DMEM), fetal bovine serum (FBS) premium heat deactivated, Penicillin/streptomycin (Pen/Strep), F12, Luria Bertani (LB), peptone, yeast extract and super broth. The following reagents were purchased by Biobasic: ethanol, isopropanol, phosphate buffer saline (PBS), DNA ladder 1 kb, DNA ladder 100 bp, Protein Ladder 250 kda, 33:1 acrylamide pre mix, N-2-hydroxyethylpiperazine-N-2-ethane sulfonic acid (HEPES), tris(hydroxymethyl)aminomethane (TRIS), glucose, arabinose, NaCl, KCl, HCl, Ammonium Hydroxiude, Calcium chloride, SOC broth, ethylenediaminetetraacetic acid (EDTA), agar, agarose, Tris-acetate-EDTA (TAE) 50× buffer, micropipette tips, serological pipettes (10 ml, 25 ml, 5 ml), 15 ml sterile tubes, 1.5 ml sterile tubes 50 ml sterile tubes, PCR tubes, Culture plates (6 well, 12 well, 24 well, 96 well flat, 96 well round bottom, 10 cm plates), and Plastic Petri Dishes. The following Monarch RNA Cleanup Columns was purchased from BioLabs™ which includes Monarch DNA, RNA, Plasmid prep kits and restriction enzymes, T7 endonuclease I (and buffer NEB 2.0), Protease K, hifi assembly mix, and PCR enzymes. PCR enzymes were obtained from Transgen™ and the primers from Biocorp™. Mutagenesis service were provided by ABM™. Primers and gblocks were obtained from IDT™. Large DNA synthesis was performed with TwistBio™. The following reagents were purchased from Thermofischer™: pierce dye removal columns, 4 ml bacterial culture tubes, PCR enzymes (Direct Phire/Phusion), Various fluorescent dyes (DAPI, NHS fluorescence), Luminoprobe: Cy5.5 NHS ester and TAMRA nhs ester. NiNTA beads and the endotox kit were purchased from Genscript™.

[0249] Donor DNA for the CAR antigen receptor was encoded in the following manner to contain domains required for CAR function:

• • [0250] Left homology arm (LHA): a sequence homologous to the exon1 TRAC loci located around the guide positions that dictate the position of the double strand break,
  • [0251] CD28 signal peptide: translocation to cell membrane,
  • [0252] Three Flag tags: for the identification of CAR construct,
  • [0253] Anti CD19 scFV: for recognition of CD19 upon B cell lymphoma cells,
  • [0254] CD8 hinge region: couples anti CD19 to transmembrane domain and allows transmission of signal through CAR protein construct, presentation of the anti CD19 domain and receptor expression is also influenced by the CD8 hinge region sequence and amino acid length,
  • [0255] CD28 transmembrane domain: allows presentation of receptor in bi-lipid membrane,
  • [0256] Cd3z: intracellular signalling and initiation of T-cell anti-cancer function,
  • [0257] P2A: cleavage domain that removes down stream peptide sequence from rest of CAR construct, releasing in this case a eGFP fluorescent protein tag,
  • [0258] eGFP: green fluorescent protein tag to confirm both in-frame CAR insertion to genome and receptor full length expression, presence of P2A cleavage sequence prevent eGFP being part of the final CAR receptor
  • [0259] Posttranscriptional Regulatory Element (WPRE) sequence to improve RNA stability and protein yield, in frame with GFP, and
  • [0260] Right homology arm (RHA): a sequence homologous to the exon1 TRAC loci located around the guide positions that will dictate the position of double strand break.

[0261] The map of the CAR construct is shown in FIG. 3.

[0262] Bacterial expression vectors using T7 promoters were used to expressed proteins in E. coli. Inserts were synthesized to encode the PNME and complementary sequences. Vectors apply a pB322 origin, repressor of primer (ROP) element for low copy number, kanamycin or amplicillin resistance genes, Lac Repressor for inhibition of transcription until isopropyl β-D-1-thiogalactopyranoside (IPTG) is introduced, T7 promoter and ribosomal binding site, completes the basic architecture of the expression vectors. Vector plus inserts were ordered through commercial suppliers or produced from a library of DNA parts for each component and assembly using either golden gate or Gibson assembly. The base C9m and M7 bacterial expression vectors were synthesized by assembly cloning.

[0263] For grafting inserts of under 15 amino acids or 30 DNA base pairs to vector sequences, site directed mutagenesis services from commercial suppliers were utilised, where the base C9m and M7 nuclease expression vectors were the template vectors and inserts were determined by the desired amino acid sequence required at the insertion site labeled “SP3” as required. The SP3 site is on an external loop of spCas9 and was identified as a suitable location for the insertion of an antigen binding domain. More specifically, the site SP3 is ser1154 which is situated as part of a loop domain that is external and not obscured. The designs decided upon included “Zero”-no linker, “L1”—N terminal linker to improve VHH presentation, and “L2”—alternative linker sequence of 23 amino acids to improve VHH presentation and offer greater flexibility of VHH presentation.

TABLE 6
Primer list
Name	Sequence	SEQ ID NO
C9mRpnew	CGATTTCCCTTTTTCCACCTTAGCAA	38
	CCACTAGGAC
C9mFpnew	CACCGTTACCGTTAGCAGCAAGAAGT	39
	TAAAATCCGTTAAAG
C9m_fwd	AAGAAGTTAAAATCCGTTAAAG	40
C9m_rev	CGATTTCCCTTTTTCCAC	41
minC4n_	AGGTGGAAAAAGGGAAATCGGATCGA	42
fwd	TGGGGATCCCAG
Common	TTAACGGATTTTAACTTCTTGCTGCT	43
C4n_rev	AACGGTAACGGTG
L1 For	GGGAGCGCAGGATCCGCTGCCGGTTCA	44
	GGAGAGTTTGATCGATGGGGATCCCAG
L2 For	AAAGAGTCGGGAAGCGTCTCTTCGGAA	45
	CAGTTAGCGCAGTTCCGCTCACTGGAT
	GATCGATGGGGATCCCAG
L1_c4n2c9m	AGGTGGAAAAAGGGAAATCGGGGAGCG	46
fwd	CAGGATCCGCT
L2_C4n2c9m	AGGTGGAAAAAGGGAAATCGAAAGAG	47
fwd	TCGGGAAGCGTC

[0264] The common C9mAur fragment was amplified using the following primers: C9m_fwd and C9m_rev. The template for amplification was C9mAur vector. The product size was confirmed by gel electrophoresis. The fragment linearized the plasmid and split C9mAur at the location of the loop domain we are going to clone into. A Dpn1 treatment was performed to digest the template plasmid. Dpn1 was first deactivated (PCR cleanup column of fragment and quantification), and the Dpn1 digestion was confirmed by DH5a transformation resulting in zero colonies.

[0265] The C4n1 amplification fragment was performed with the primers minC4n_fwd and commonC4n_rev and the template for the amplification was C4n Vector. The product size was confirmed by gel electrophoresis. A Dpn1 treatment was performed to digest the template plasmid. Dpn1 was first deactivated (PCR cleanup column of fragment and quantification), and the Dpn1 digestion was confirmed by DH5a transformation resulting in zero colonies. The resulting fragment was purified and quantified and was then used for cloning.

[0266] Two linkers (L1 and L2) were added to C4n the “Zero” since it contained zero linkers. The primers L1 For and L2 For from Table 7 were used to add the 5′ linkers to C4n, resulting in L1-C4n and L2-C4n (i.e. the template for amplification was the C4n vector). The amplification employed a common reverse primer common C4n_rev. The amplification created the reverse overhang using the common primer and introduced the linker at the 5′ end of the C4n VHH sequence. A PCR clean up purification of both L1-C4n and L2-C4n was then performed.

TABLE 7
Linkers L1 and L2
Name	Sequence	SEQ ID NO
L1 (DNA)	GGGAGCGCAGGATCCGCTGCCGGTTC	48
	AGGAGAGTTTGATCGATGGGGATCC
L1 (a.a)	GSAGSAAGSGEFDRWGS	49
L2 (DNA)	AAAGAGTCGGGAAGCGTCTCTTCGGA	50
	ACAGTTAGCGCAGTTCCGCTCACTGG
	ATGATCGATGGGGATCC
L2 (a.a.)	KESGSVSSEQLAQFRSLDDRWGS	51

Introduction of Overhangs for Gibson Cloning with C9mAur Fragment

[0267] The fragments with overhang primers were amplified to introduce overhangs to a C9m fragment. The amplification of L1-C4n was performed with the L1_c4n2c9m_fwd forward primer and the amplification of L2-C4n was performed with the L2_C4n2c9m_fwd forward primer. The amplification used the common reverse primer C4n_Comm_rev. The product size was confirmed by gel electrophoresis. A Dpn1 treatment was performed to digest the template plasmid. Dpn1 was first deactivated (PCR cleanup column of fragment and quantification), and the Dpn1 digestion was confirmed by DH5a transformation resulting in zero colonies. The resulting fragment was purified and quantified and was then used for cloning.

[0268] The vectors are synthesized are shown in FIGS. 4-8. More specifically, FIG. 4 shows the map of the vector of M7 Mav anti CD8. FIG. 5 shows the map of the vector of M7-Mav-anti CD4. FIG. 6 shows the map of the vector of C9mAur. FIG. 7 shows the map of the vector of C9mC4. FIG. 8 shows the map of the vector of C9C4 anti CD4n1.

TABLE 8
Vector sequences
Name	Sequence	SEQ ID NO
Basic CAR	AGTTTGCTTTGCTGGGCCTTTTTCCCATGCCTGCCTTTACTCTGCCAGAGTT	52
construct	ATATTGCTGGGGTTTTGAAGAAGATCCTATTAAATAAAAGAATAAGCAGTAT
	TATTAAGTAGCCCTGCATTTCAGGTTTCCTTGAGTGGCAGGCCAGGCCTGGC
	CGTGAACGTTCACTGAAATCATGGCCTCTTGGCCAAGATTGATAGCTTGTGC
	CTGTCCCTGAGTCCCAGTCCATCACGAGCAGCTGGTTTCTAAGATGCTATTT
	CCCGTATAAAGCATGAGACCGTGACTTGCCAGCCCCACAGAGCCCCGCCCTT
	GTCCATCACTGGCATCTGGACTCCAGCCTGGGTTGGGGCAAAGAGGGAAATG
	AGATCATGTCCTAACCCTGATCCTCTTGTCCCACAGATGCTCAGGCTGCTCT
	TGGCTCTCAACTTATTCCCTTCAATTCAAGTAACAGGAGGGTCTTCGGACTA
	CAAGGATCATGACGGAGACTATAAGGATCACGATATTGATTACAAAGATGAC
	GACGACAAAGACATCCAGATGACACAGACTACATCCTCCCTGTCTGCCTCTC
	TGGGAGACAGAGTCACCATCAGTTGCAGGGCAAGTCAGGACATCTCTAAGTA
	TTTGAATTGGTATCAGCAGAAACCAGATGGAACTGTTAAACTCCTGATCTAC
	CATACATCAAGATTACACTCAGGAGTCCCATCAAGGTTCAGTGGCAGTGGGT
	CTGGAACAGATTATTCTCTCACCATTAGCAACCTGGAGCAAGAAGATATTGC
	CACTTACTTTTGCCAACAGGGTAATACGCTTCCGTACACGTTCGGAGGGGGG
	ACTAAGTTGGAAATAACAGGCTCCACCTCTGGATCCGGCAAGCCCGGATCTG
	GCGAGGGATCCACCAAGGGCGAGGTGAAACTGCAGGAGTCAGGACCTGGCCT
	GGTGGCGCCCTCACAGAGCCTGTCCGTCACATGCACTGTCTCAGGGGTCTCA
	TTACCCGACTATGGTGTAAGCTGGATTCGCCAGCCTCCACGAAAGGGTCTGG
	AGTGGCTGGGAGTAATATGGGGTAGTGAAACCACATACTATAATTCAGCTCT
	CAAATCCAGACTGACCATCATCAAGGACAACTCCAAGAGCCAAGTTTTCTTA
	AAAATGAACAGTCTGCAAACTGATGACACAGCCATTTACTACTGTGCCAAAC
	ATTATTACTACGGTGGTAGCTATGCTATGGACTACTGGGGTCAAGGAACCTC
	AGTCACCGTCTCCTCAGCGGCCGCAGGTACCACCACAACGCCCGCTCCTCGG
	CCACCGACGCCAGCGCCAACTATTGCGAGTCAGCCTCTCAGTCTGCGACCTG
	AGGCTTGTCGACCAGCAGCCGGAGGCGCAGTGCACACGAGGGGGCTGGACTT
	CGCCTGTGATAGAAGACCTCCTTCTAAGCCCTTTTGGGTGCTGGTGGTGGTT
	GGTGGAGTCCTGGCTTGCTATAGCTTGCTAGTAACAGTGGCCTTTATTATTT
	TCTGGGTGAGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACAT
	GACTCCCAGGCGGCCCGGACCCACCCGCAAGCATTACCAGCCCTATGCCCCA
	CCACGCGACTTCGCAGCCTATCGCTCCGCTAGCCTGAGAGTGAAGTTCAGCA
	GGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCAGCTCTATAACGA
	GCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGC
	CGGGACCCTGAGATGGGGGGAAAGCCGCAGAGAAGGAAGAACCCTCAGGAAG
	GCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGAT
	TGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAG
	GGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCC
	TGCCCCCTCGCGCTAGCGCCACGAACTTCTCTCTGTTAAAGCAAGCAGGCGA
	CGTGGAAGAAAACCCCGGTCCCGTGAGCAAGGGCGAGGAGCTGTTCACCGGG
	GTGGTGCCCATCCTGGTCGAGCTGGACGGCGACGTAAACGGCCACAAGTTCA
	GCGTGTCCGGCGAGGGCGAGGGCGATGCCACCTACGGCAAGCTGACCCTGAA
	GTTCATCTGCACCACCGGCAAGCTGCCCGTGCCCTGGCCCACCCTCGTGACC
	ACCCTGACCTACGGCGTGCAGTGCTTCAGCCGCTACCCCGACCACATGAAGC
	AGCACGACTTCTTCAAGTCCGCCATGCCCGAAGGCTACGTCCAGGAGCGCAC
	CATCTTCTTCAAGGACGACGGCAACTACAAGACCCGCGCCGAGGTGAAGTTC
	GAGGGCGACACCCTGGTGAACCGCATCGAGCTGAAGGGCATCGACTTCAAGG
	AGGACGGCAACATCCTGGGGCACAAGCTGGAGTACAACTACAACAGCCACAA
	CGTCTATATCATGGCCGACAAGCAGAAGAACGGCATCAAGGTGAACTTCAAG
	ATCCGCCACAACATCGAGGACGGCAGCGTGCAGCTCGCCGACCACTACCAGC
	AGAACACCCCCATCGGCGACGGCCCCGTGCTGCTGCCCGACAACCACTACCT
	GAGCACCCAGTCCGCCCTGAGCAAAGACCCCAACGAGAAGCGCGATCACATG
	GTCCTGCTGGAGTTCGTGACCGCCGCCGGGATCACTCTCGGCATGGACGAGC
	TGTACAAGTAAATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGAC
	TCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAA
	CAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGT
	GCTAGACATGAGGTCTATGGACTTCAAGAGCAACAGTGCTGTGGCCTGGAGC
	AACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAG
	AAGACACCTTCTTCCCCAGCCCAGGTAAGGGCAGCTTTGGTGCCTTCGCAGG
	CTGTTTCCTTGCTTCAGGAATGGCCAGGTTCTGCCCAGAGCTCTGGTCAATG
	ATGTCTAAAACTCCTCTGATTGGTGGTCTCGGCCTTATCCATTGCCA
Anti CD4	CAGGTGCAGCTGCAGGAGTCTGGAGGAGGCTTGGTGCAGCCTGGGGGGTCTC	53
VHH	TGAGACTCTCCTGTGCAGCCTCTGGATTCACATTCAGTAGCTACGACATGAG
	CTGGGTCCGCCAGGCTCCGGGGAAGGGGCTCGAGTGGGTCTCAGGTATGAAT
	AGTGGTGGTGGTAGAACATACTATGAAGACTCCGTGAAGGGCCGATTCACCA
	TCTCCAGGTCCAACGCCAAGAACACGCTGTATCTGCAACTGAACAGCCTGAA
	AACTGACGACACGGCCATGTATTACTGTGTCACATCCGACTTTGCTTACTGG
	GGCCAGGGGACCCAGGTCACCGTCTCCTCATGTTGTTGTTGTTGTTGTTAA
Anti CD8	CAGGTTCAGCTGGAAGAATCTGGTGGTGGTCTGGTTCAGGCGGGTGGTTCTC	54
VHH	TGCGTCTGTCTTGCGCGGCGTCTGGTCGTACCTCTTCTAACACCTTCGTTGG
	TTGGTTCCGTCAGGCGCCGGGTAAAGAACGTGAATTCGTTGCGGCGATCCGT
	CGTTCTGACGACCGTACCTACTACGCGGCGTCTGTTCGTGGTCGTTTCACCA
	TCTCTGGTGACTCTGCGAAAAACGTTGTTGCGCTGCAGATGTCTTCTCTGCG
	TCCGGAAGACACCGCGGTTTACTACTGCGCGGCGACCCGTACCTGGCTGGTT
	ACCGGTCAGTCTGACTACCCGTACTGGGGTCAGGGTACCCAGGTTACCGTTT
	CTTCTTGTTGTTGTTGTTGTTGTTAA
M7-Mav-CD8	TTCTTGAAGACGAAAGGGCCTCGTGATACGCCTATTTTTATAGGTTAATGTC	55
(C8-2) full	ATGATAATAATGGTTTCTTAGACGTCAGGTGGCACTTTTCGGGGAAATGTGC
vector plus	GCGGAACCCCTATTTGTTTATTTTTCTAAATACATTCAAATATGTATCCGCT
insert	CATGAGACAATAACCCTGATAAATGCTTCAATAATATTGAAAAAGGAAGAGT
	ATGAGTATTCAACATTTCCGTGTCGCCCTTATTCCCTTTTTTGCGGCATTTT
	GCCTTCCTGTTTTTGCTCACCCAGAAACGCTGGTGAAAGTAAAAGATGCTGA
	AGATCAGTTGGGTGCACGAGTGGGTTACATCGAACTGGATCTCAACAGCGGT
	AAGATCCTTGAGAGTTTTCGCCCCGAAGAACGTTTTCCAATGATGAGCACTT
	TTAAAGTTCTGCTATGTGGCGCGGTATTATCCCGTGTTGACGCCGGGCAAGA
	GCAACTCGGTCGCCGCATACACTATTCTCAGAATGACTTGGTTGAGTACTCA
	CCAGTCACAGAAAAGCATCTTACGGATGGCATGACAGTAAGAGAATTATGCA
	GTGCTGCCATAACCATGAGTGATAACACTGCGGCCAACTTACTTCTGACAAC
	GATCGGAGGACCGAAGGAGCTAACCGCTTTTTTGCACAACATGGGGGATCAT
	GTAACTCGCCTTGATCGTTGGGAACCGGAGCTGAATGAAGCCATACCAAACG
	ACGAGCGTGACACCACGATGCCTGCAGCAATGGCAACAACGTTGCGCAAACT
	ATTAACTGGCGAACTACTTACTCTAGCTTCCCGGCAACAATTAATAGACTGG
	ATGGAGGCGGATAAAGTTGCAGGACCACTTCTGCGCTCGGCCCTTCCGGCTG
	GCTGGTTTATTGCTGATAAATCTGGAGCCGGTGAGCGTGGGTCTCGCGGTAT
	CATTGCAGCACTGGGGCCAGATGGTAAGCCCTCCCGTATCGTAGTTATCTAC
	ACGACGGGGAGTCAGGCAACTATGGATGAACGAAATAGACAGATCGCTGAGA
	TAGGTGCCTCACTGATTAAGCATTGGTAACTGTCAGACCAAGTTTACTCATA
	TATACTTTAGATTGATTTAAAACTTCATTTTTAATTTAAAAGGATCTAGGTG
	AAGATCCTTTTTGATAATCTCATGACCAAAATCCCTTAACGTGAGTTTTCGT
	TCCACTGAGCGTCAGACCCCGTAGAAAAGATCAAAGGATCTTCTTGAGATCC
	TTTTTTTCTGCGCGTAATCTGCTGCTTGCAAACAAAAAAACCACCGCTACCA
	GCGGTGGTTTGTTTGCCGGATCAAGAGCTACCAACTCTTTTTCCGAAGGTAA
	CTGGCTTCAGCAGAGCGCAGATACCAAATACTGTCCTTCTAGTGTAGCCGTA
	GTTAGGCCACCACTTCAAGAACTCTGTAGCACCGCCTACATACCTCGCTCTG
	CTAATCCTGTTACCAGTGGCTGCTGCCAGTGGCGATAAGTCGTGTCTTACCG
	GGTTGGACTCAAGACGATAGTTACCGGATAAGGCGCAGCGGTCGGGCTGAAC
	GGGGGGTTCGTGCACACAGCCCAGCTTGGAGCGAACGACCTACACCGAACTG
	AGATACCTACAGCGTGAGCTATGAGAAAGCGCCACGCTTCCCGAAGGGAGAA
	AGGCGGACAGGTATCCGGTAAGCGGCAGGGTCGGAACAGGAGAGCGCACGAG
	GGAGCTTCCAGGGGGAAACGCCTGGTATCTTTATAGTCCTGTCGGGTTTCGC
	CACCTCTGACTTGAGCGTCGATTTTTGTGATGCTCGTCAGGGGGGCGGAGCC
	TATGGAAAAACGCCAGCAACGCGGCCTTTTTACGGTTCCTGGCCTTTTGCTG
	GCCTTTTGCTCACATGTTCTTTCCTGCGTTATCCCCTGATTCTGTGGATAAC
	CGTATTACCGCCTTTGAGTGAGCTGATACCGCTCGCCGCAGCCGAACGACCG
	AGCGCAGCGAGTCAGTGAGCGAGGAAGCGGAAGAGCGCCTGATGCGGTATTT
	TCTCCTTACGCATCTGTGCGGTATTTCACACCGCATATATGGTGCACTCTCA
	GTACAATCTGCTCTGATGCCGCATAGTTAAGCCAGTATACACTCCGCTATCG
	CTACGTGACTGGGTCATGGCTGCGCCCCGACACCCGCCAACACCCGCTGACG
	CGCCCTGACGGGCTTGTCTGCTCCCGGCATCCGCTTACAGACAAGCTGTGAC
	CGTCTCCGGGAGCTGCATGTGTCAGAGGTTTTCACCGTCATCACCGAAACGC
	GCGAGGCAGCTGCGGTAAAGCTCATCAGCGTGGTCGTGAAGCGATTCACAGA
	TGTCTGCCTGTTCATCCGCGTCCAGCTCGTTGAGTTTCTCCAGAAGCGTTAA
	TGTCTGGCTTCTGATAAAGCGGGCCATGTTAAGGGCGGTTTTTTCCTGTTTG
	GTCACTGATGCCTCCGTGTAAGGGGGATTTCTGTTCATGGGGGTAATGATAC
	CGATGAAACGAGAGAGGATGCTCACGATACGGGTTACTGATGATGAACATGC
	CCGGTTACTGGAACGTTGTGAGGGTAAACAACTGGCGGTATGGATGCGGCGG
	GACCAGAGAAAAATCACTCAGGGTCAATGCCAGCGCTTCGTTAATACAGATG
	TAGGTGTTCCACAGGGTAGCCAGCAGCATCCTGCGATGCAGATCCGGAACAT
	AATGGTGCAGGGCGCTGACTTCCGCGTTTCCAGACTTTACGAAACACGGAAA
	CCGAAGACCATTCATGTTGTTGCTCAGGTCGCAGACGTTTTGCAGCAGCAGT
	CGCTTCACGTTCGCTCGCGTATCGGTGATTCATTCTGCTAACCAGTAAGGCA
	ACCCCGCCAGCCTAGCCGGGTCCTCAACGACAGGAGCACGATCATGCGCACC
	CGTGGCCAGGACCCAACGCTGCCCGAGATGCGCCGCGTGCGGCTGCTGGAGA
	TGGCGGACGCGATGGATATGTTCTGCCAAGGGTTGGTTTGCGCATTCACAGT
	TCTCCGCAAGAATTGATTGGCTCCAATTCTTGGAGTGGTGAATCCGTTAGCG
	AGGTGCCGCCGGCTTCCATTCAGGTCGAGGTGGCCCGGCTCCATGCACCGCG
	ACGCAACGCGGGGAGGCAGACAAGGTATAGGGCGGCGCCTACAATCCATGCC
	AACCCGTTCCATGTGCTCGCCGAGGCGGCATAAATCGCCGTGACGATCAGCG
	GTCCAGTGATCGAAGTTAGGCTGGTAAGAGCCGCGAGCGATCCTTGAAGCTG
	TCCCTGATGGTCGTCATCTACCTGCCTGGACAGCATGGCCTGCAACGCGGGC
	ATCCCGATGCCGCCGGAAGCGAGAAGAATCATAATGGGGAAGGCCATCCAGC
	CTCGCGTCGCGAACGCCAGCAAGACGTAGCCCAGCGCGTCGGCCGCCATGCC
	GGCGATAATGGCCTGCTTCTCGCCGAAACGTTTGGTGGCGGGACCAGTGACG
	AAGGCTTGAGCGAGGGCGTGCAAGATTCCGAATACCGCAAGCGACAGGCCGA
	TCATCGTCGCGCTCCAGCGAAAGCGGTCCTCGCCGAAAATGACCCAGAGCGC
	TGCCGGCACCTGTCCTACGAGTTGCATGATAAAGAAGACAGTCATAAGTGCG
	GCGACGATAGTCATGCCCCGCGCCCACCGGAAGGAGCTGACTGGGTTGAAGG
	CTCTCAAGGGCATCGGTCGAGATCCCGGTGCCTAATGAGTGAGCTAACTTAC
	ATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGC
	CAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTG
	GGCGCCAGGGTGGTTTTTCTTTTCACCAGTGAGACGGGCAACAGCTGATTGC
	CCTTCACCGCCTGGCCCTGAGAGAGTTGCAGCAAGCGGTCCACGCTGGTTTG
	CCCCAGCAGGCGAAAATCCTGTTTGATGGTGGTTAACGGCGGGATATAACAT
	GAGCTGTCTTCGGTATCGTCGTATCCCACTACCGAGATATCCGCACCAACGC
	GCAGCCCGGACTCGGTAATGGCGCGCATTGCGCCCAGCGCCATCTGATCGTT
	GGCAACCAGCATCGCAGTGGGAACGATGCCCTCATTCAGCATTTGCATGGTT
	TGTTGAAAACCGGACATGGCACTCCAGTCGCCTTCCCGTTCCGCTATCGGCT
	GAATTTGATTGCGAGTGAGATATTTATGCCAGCCAGCCAGACGCAGACGCGC
	CGAGACAGAACTTAATGGGCCCGCTAACAGCGCGATTTGCTGGTGACCCAAT
	GCGACCAGATGCTCCACGCCCAGTCGCGTACCGTCTTCATGGGAGAAAATAA
	TACTGTTGATGGGTGTCTGGTCAGAGACATCAAGAAATAACGCCGGAACATT
	AGTGCAGGCAGCTTCCACAGCAATGGCATCCTGGTCATCCAGCGGATAGTTA
	ATGATCAGCCCACTGACGCGTTGCGCGAGAAGATTGTGCACCGCCGCTTTAC
	AGGCTTCGACGCCGCTTCGTTCTACCATCGACACCACCACGCTGGCACCCAG
	TTGATCGGCGCGAGATTTAATCGCCGCGACAATTTGCGACGGCGCGTGCAGG
	GCCAGACTGGAGGTGGCAACGCCAATCAGCAACGACTGTTTGCCCGCCAGTT
	GTTGTGCCACGCGGTTGGGAATGTAATTCAGCTCCGCCATCGCCGCTTCCAC
	TTTTTCCCGCGTTTTCGCAGAAACGTGGCTGGCCTGGTTCACCACGCGGGAA
	ACGGTCTGATAAGAGACACCGGCATACTCTGCGACATCGTATAACGTTACTG
	GTTTCACATTCACCACCCTGAATTGACTCTCTTCCGGGCGCTATCATGCCAT
	ACCGCGAAAGGTTTTGCGCCATTCGATGGTGTCCGGGATCTCGACGCTCTCC
	CTTATGCGACTCCTGCATTAGGAAGCAGCCCAGTAGTAGGTTGAGGCCGTTG
	AGCACCGCCGCCGCAAGGAATGGTGCATGCAAGGAGATGGCGCCCAACAGTC
	CCCCGGCCACGGGGCCTGCCACCATACCCACGCCGAAACAAGCGCTCATGAG
	CCCGAAGTGGCGAGCCCGATCTTCCCCATCGGTGATGTCGGCGATATAGGCG
	CCAGCAACCGCACCTGTGGCGCCGGTGATGCCGGCCACGATGCGTCCGGCGT
	AGAGGATCGAGATCTCGATCCCGCGAAATTAATACGACTCACTATAGGGGAA
	TTGTGAGCGGATAACAATTCCCTCTAGAAATAATTTTGTTTAACTTTAAGAA
	GGAGATATACCATGCATCATCATCATCATCACAGCAGCGGCAGAGAAAACTT
	GTATTTCCAGGGCATGAACAACGGCACCAACAACTTTCAGAACTTTATTGGC
	ATTAGCAGCCTGCAGAAAACCCTGCGCAACGCGCTGATTCCGACCGAAACCA
	CCCAGCAGTTTATTGTGAAAAACGGCATTATTAAAGAAGATGAACTGCGCGG
	CGAAAACCGCCAGATTCTGAAAGATATTATGGATGATTATTATCGCGGCTTT
	ATTAGCGAAACCCTGAGCAGCATTGATGATATTGATTGGACCAGCCTGTTTG
	AAAAAATGGAAATTCAGCTGAAAAACGGCGATAACAAAGATACCCTGATTAA
	AGAACAGACCGAATATCGCAAAGCGATTCATAAAAAATTTGCGAACGATGAT
	CGCTTTAAAAACATGTTTAGCGCGAAACTGATTAGCGATATTCTGCCGGAAT
	TTGTGATTCATAACAACAACTATAGCGCGAGCGAAAAAGAAGAAAAAACCCA
	GGTGATTAAACTGTTTAGCCGCTTTGCGACCAGCTTTAAAGATTATTTTAAA
	AACCGCGCGAACTGCTTTAGCGCGGATGATATTAGCAGCAGCAGCTGCCATC
	GCATTGTGAACGATAACGCGGAAATTTTTTTTAGCAACGCGCTGGTGTATCG
	CCGCATTGTGAAAAGCCTGAGCAACGATGATATTAACAAAATTAGCGGCGAT
	ATGAAAGATAGCCTGAAAGAAATGAGCCTGGAAGAAATTTATAGCTATGAAA
	AATATGGCGAATTTATTACCCAGGAAGGCATTAGCTTTTATAACGATATTTG
	CGGCAAAGTGAACAGCTTTATGAACCTGTATTGCCAGAAAAACAAAGAAAAC
	AAAAACCTGTATAAACTGCAGAAACTGCATAAACAGATTCTGTGCATTGCGG
	ATACCAGCTATGAAGTGCCGTATAAATTTGAAAGCGATGAAGAAGTGTATCA
	GAGCGTGAACGGCTTTCTGGATAACATTAGCAGCAAACATATTGTGGAACGC
	CTGCGCAAAATTGGCGATAACTATAACGGCTATAACCTGGATAAAATTTATA
	TTGTGAGCAAATTTTATGAAAGCGTGAGCCAGAAAACCTATCGCGATTGGGA
	AACCATTAACACCGCGCTGGAAATTCATTATAACAACATTCTGCCGGGCAAC
	GGCAAAAGCAAAGCGGATAAAGTGAAAAAAGCGGTGAAAAACGATCTGCAGA
	AAAGCATTACCGAAATTAACGAACTGGTGAGCAACTATAAACTGTGCAGCGA
	TGATAACATTAAAGCGGAAACCTATATTCATGAAATTAGCCATATTCTGAAC
	AACTTTGAAGCGCAGGAACTGAAATATAACCCGGAAATTCATCTGGTGGAAA
	GCGAACTGAAAGCGAGCGAACTGAAAAACGTGCTGGATGTGATTATGAACGC
	GTTTCATTGGTGCAGCGTGTTTATGACCGAAGAACTGGTGGATAAAGATAAC
	AACTTTTATGCGGAACTGGAAGAAATTTATGATGAAATTTATCCGGTGATTA
	GCCTGTATAACCTGGTGCGCAACTATGTGACCCAGAAACCGTATAGCACCAA
	AAAAATTAAACTGAACTTTGGCATTCCGACCCTGGCGGATGGCTGGAGCAAA
	AGCAAAGAATATAGCAACAACGCGATTATTCTGATGCGCGATAACCTGTATT
	ATCTGGGCATTTTTAACGCGAAAAACAAACCGGATAAAAAAATTATTGAAGG
	CAACACCAGCGAAAACAAAGGCGATTATAAAAAAATGATTTATAACCTGCTG
	CCGGGCCCGAACAAAATGATTCCGAAAGTGTTTCTGAGCAGCAAAACCGGCG
	TGGAAACCTATAAACCGAGCGCGTATATTCTGGAAGGCTATAAACAGAACAA
	ACATATTAAAAGCAGCAAAGATTTTGATATTACCTTTTGCCATGATCTGATT
	GATTATTTTAAAAACTGCATTGCGATTCATCCGGAATGGAAAAACTTTGGCT
	TTGATTTTAGCGATACCAGCACCTATGAAGATATTAGCGGCTTTTATCGCGA
	AGTGGAACTGCAGGGCTATAAAATTGATTGGACCTATATTAGCGAAAAAGAT
	ATTGATCTGCTGCAGGAAAAAGGCCAGCTGTATCTGTTTCAGATTTATAACA
	AAGATTTTAGCAAAAAAAGCACCGGCAACGATAACCTGCATACCATGTATCT
	GAAAAACCTGTTTAGCGAAGAAAACCTGAAAGATATTGTGCTGAAACTGAAC
	GGCGAAGCGGAAATTTTTTTTCGCAAAAGCAGCATTAAAAACCCGATTATTC
	ATAAAAAAGGCAGCATTCTGGTGAACCGCACCTATGAAGCGGAAGAAAAAGA
	TCAGTTTGGCAACATTCAGATTGTGCGCAAAAACATTCCGGAAAACATTTAT
	CAGGAACTGTATAAATATTTTAACGATAAAAGCGATAAAGAACTGAGCGATG
	AAGCGGCGAAACTGAAAAACGTGGTGGGCCATCATGAAGCGGCGACCAACAT
	TGTGAAAGATTATCGCTATACCTATGATAAATATTTTCTGCATATGCCGATT
	ACCATTAACTTTAAAGCGAACAAAACCGGCTTTATTAACGATCGCATTCTGC
	AGTATATTGCGAAAGAAAAAGATCTGCATGTGATTGGCATTGATCGCGGCGA
	ACGCAACCTGATTTATGTGAGCGTGATTGATACCTGCGGCAACATTGTGGAA
	CAGAAAAGCTTTAACATTGTGAACGGCTATGATTATCAGATTAAACTGAAAC
	AGCAGGAAGGCGCGCGCCAGATTGCGCGCAAAGAATGGAAAGAAATTGGCAA
	AATTAAAGAAATTAAAGAAGGCTATCTGAGCCTGGTGATTCATGAAATTAGC
	AAAATGGTGATTAAATATAACGCGATTATTGCGATGGAAGATCTGAGCTATG
	GCTTTAAAAAAGGCCGCTTTAAAGTGGAACGCCAGGTGTATCAGAAATTTGA
	AACCATGCTGATTAACAAACTGAACTATCTGGTGTTTAAAGATATTAGCATT
	ACCGAAAACGGCGGCCTGCTGAAAGGCTATCAGCTGACCTATATTCCGGATA
	AACTGAAAAACGTGGGCCATCAGTGCGGCTGCATTTTTTATGTGCCGGCGGC
	GTATACCAGCAAAATTGATCCGACCACCGGCTTTGTGAACATTTTTAAATTT
	AAAGATCTGACCGTGGATGCGAAACGCGAATTTATTAAAAAATTTGATAGCA
	TTCGCTATGATAGCGAAAAAAACCTGTTTTGCTTTACCTTTGATTATAACAA
	CTTTATTACCCAGAACACCGTGATGAGCAAAAGCAGCTGGAGCGTGTATACC
	TATGGCGTGCGCATTAAACGCCGCTTTGTGAACGGCCGCTTTAGCAACGAAA
	GCGATACCATTGATATTACCAAAGATATGGAAAAAACCCTGGAAATGACCGA
	TATTAACTGGCGCGATGGCCATGATCTGCGCCAGGATATTATTGATTATGAA
	ATTGTGCAGCATATTTTTGAAATTTTTCGCCTGACCGTGCAGATGCGCAACA
	GCCTGAGCGAACTGGAAGATCGCGATTATGATCGCCTGATTAGCCCGGTGCT
	GAACGAAAACAACATTTTTTATGATAGCGCGAAAGCGGGCGATGCGCTGCCG
	AAAGATGCGGATGCGAACGGCGCGTATTGCATTGCGCTGAAAGGCCTGTATG
	AAATTAAACAGATTACCGAAAACTGGAAAGAAGATGGCAAATTTAGCCGCGA
	TAAACTGAAAATTAGCAACAAAGATTGGTTTGATTTTATTCAGAACAAACGC
	TATCTGGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCG
	GCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCACCAGCCC
	TAAGAAAAAACGAAAAGTTGAGGATCCTAAAAAGAAACGAAAAGTTCATCAT
	CATCATCATCATGAATTTGCGAGCGCGGAAGCGGGCATTACCGGCACCTGGT
	ATAACCAGCATGGCAGCACCTTTACCGTGACCGCGGGCGCGGATGGCAACCT
	GACCGGCCAGTATGAAAACCGCGCGCAGGGCACCGGCTGCCAGAACAGCCCG
	TATACCCTGACCGGCCGCTATAACGGCACCAAACTGGAATGGCGCGTGGAAT
	GGAACAACAGCACCGAAAACTGCCATAGCCGCACCGAATGGCGCGGCCAGTA
	TCAGGGCGGCGCGGAAGCGCGCATTAACACCCAGTGGAACCTGACCTATGAA
	GGCGGCAGCGGCCCGGCGACCGAACAGGGCCAGGATACCTTTACCAAAGTGA
	AACCGAGCGCGGCGAGCGGCAGCGATTATAAAGATGATGATGATAAAAAACG
	CAAAAGAAAATGCCGATATCCTATTGGCATTGACGTCAGGTGGCACTTTTCG
	AGGAGATCATGCACAGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCG
	GCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCAGCCCATG
	GCAGGTTCAGCTGGAAGAATCTGGTGGTGGTCTGGTTCAGGCGGGTGGTTCT
	CTGCGTCTGTCTTGCGCGGCGTCTGGTCGTACCTCTTCTAACACCTTCGTTG
	GTTGGTTCCGTCAGGCGCCGGGTAAAGAACGTGAATTCGTTGCGGCGATCCG
	TCGTTCTGACGACCGTACCTACTACGCGGCGTCTGTTCGTGGTCGTTTCACC
	ATCTCTGGTGACTCTGCGAAAAACGTTGTTGCGCTGCAGATGTCTTCTCTGC
	GTCCGGAAGACACCGCGGTTTACTACTGCGCGGCGACCCGTACCTGGCTGGT
	TACCGGTCAGTCTGACTACCCGTACTGGGGTCAGGGTACCCAGGTTACCGTT
	TCTTCTTGTTGTTGTTGTTGTTGTTAAGCGGCCGCACTCGAGGATCCGGCTG
	CTAACAAAGCCCGAAAGGAAGCTGAGTTGGCTGCTGCCACCGCTGAGCAATA
	ACTAGCATAACCCCTTGGGGCCTCTAAACGGGTCTTGAGGGGTTTTTTGCTG
	AAAGGAGGAACTATATCCGGATATCCCGCAAGAGGCCCGGCAGTACCGGCAT
	AACCAAGCCTATGCCTACAGCATCCAGGGTGACGGTGCCGAGGATGACGATG
	AGCGCATTGTTAGATTTCATACACGGTGCCTGACTGCGTTAGCAATTTAACT
	GTGATAAACTACCGCATTAAAGCTTATCGATGATAAGCTGTCAAACATGAGA
	A
M7 Mav anti	TTCTTGAAGACGAAAGGGCCTCGTGATACGCCTATTTTTATAGGTTAATGTC	56
CD4 (DNA	ATGATAATAATGGTTTCTTAGACGTCAGGTGGCACTTTTCGGGGAAATGTGC
vector +	GCGGAACCCCTATTTGTTTATTTTTCTAAATACATTCAAATATGTATCCGCT
sequence)	CATGAGACAATAACCCTGATAAATGCTTCAATAATATTGAAAAAGGAAGAGT
	ATGAGTATTCAACATTTCCGTGTCGCCCTTATTCCCTTTTTTGCGGCATTTT
	GCCTTCCTGTTTTTGCTCACCCAGAAACGCTGGTGAAAGTAAAAGATGCTGA
	AGATCAGTTGGGTGCACGAGTGGGTTACATCGAACTGGATCTCAACAGCGGT
	AAGATCCTTGAGAGTTTTCGCCCCGAAGAACGTTTTCCAATGATGAGCACTT
	TTAAAGTTCTGCTATGTGGCGCGGTATTATCCCGTGTTGACGCCGGGCAAGA
	GCAACTCGGTCGCCGCATACACTATTCTCAGAATGACTTGGTTGAGTACTCA
	CCAGTCACAGAAAAGCATCTTACGGATGGCATGACAGTAAGAGAATTATGCA
	GTGCTGCCATAACCATGAGTGATAACACTGCGGCCAACTTACTTCTGACAAC
	GATCGGAGGACCGAAGGAGCTAACCGCTTTTTTGCACAACATGGGGGATCAT
	GTAACTCGCCTTGATCGTTGGGAACCGGAGCTGAATGAAGCCATACCAAACG
	ACGAGCGTGACACCACGATGCCTGCAGCAATGGCAACAACGTTGCGCAAACT
	ATTAACTGGCGAACTACTTACTCTAGCTTCCCGGCAACAATTAATAGACTGG
	ATGGAGGCGGATAAAGTTGCAGGACCACTTCTGCGCTCGGCCCTTCCGGCTG
	GCTGGTTTATTGCTGATAAATCTGGAGCCGGTGAGCGTGGGTCTCGCGGTAT
	CATTGCAGCACTGGGGCCAGATGGTAAGCCCTCCCGTATCGTAGTTATCTAC
	ACGACGGGGAGTCAGGCAACTATGGATGAACGAAATAGACAGATCGCTGAGA
	TAGGTGCCTCACTGATTAAGCATTGGTAACTGTCAGACCAAGTTTACTCATA
	TATACTTTAGATTGATTTAAAACTTCATTTTTAATTTAAAAGGATCTAGGTG
	AAGATCCTTTTTGATAATCTCATGACCAAAATCCCTTAACGTGAGTTTTCGT
	TCCACTGAGCGTCAGACCCCGTAGAAAAGATCAAAGGATCTTCTTGAGATCC
	TTTTTTTCTGCGCGTAATCTGCTGCTTGCAAACAAAAAAACCACCGCTACCA
	GCGGTGGTTTGTTTGCCGGATCAAGAGCTACCAACTCTTTTTCCGAAGGTAA
	CTGGCTTCAGCAGAGCGCAGATACCAAATACTGTCCTTCTAGTGTAGCCGTA
	GTTAGGCCACCACTTCAAGAACTCTGTAGCACCGCCTACATACCTCGCTCTG
	CTAATCCTGTTACCAGTGGCTGCTGCCAGTGGCGATAAGTCGTGTCTTACCG
	GGTTGGACTCAAGACGATAGTTACCGGATAAGGCGCAGCGGTCGGGCTGAAC
	GGGGGGTTCGTGCACACAGCCCAGCTTGGAGCGAACGACCTACACCGAACTG
	AGATACCTACAGCGTGAGCTATGAGAAAGCGCCACGCTTCCCGAAGGGAGAA
	AGGCGGACAGGTATCCGGTAAGCGGCAGGGTCGGAACAGGAGAGCGCACGAG
	GGAGCTTCCAGGGGGAAACGCCTGGTATCTTTATAGTCCTGTCGGGTTTCGC
	CACCTCTGACTTGAGCGTCGATTTTTGTGATGCTCGTCAGGGGGGCGGAGCC
	TATGGAAAAACGCCAGCAACGCGGCCTTTTTACGGTTCCTGGCCTTTTGCTG
	GCCTTTTGCTCACATGTTCTTTCCTGCGTTATCCCCTGATTCTGTGGATAAC
	CGTATTACCGCCTTTGAGTGAGCTGATACCGCTCGCCGCAGCCGAACGACCG
	AGCGCAGCGAGTCAGTGAGCGAGGAAGCGGAAGAGCGCCTGATGCGGTATTT
	TCTCCTTACGCATCTGTGCGGTATTTCACACCGCATATATGGTGCACTCTCA
	GTACAATCTGCTCTGATGCCGCATAGTTAAGCCAGTATACACTCCGCTATCG
	CTACGTGACTGGGTCATGGCTGCGCCCCGACACCCGCCAACACCCGCTGACG
	CGCCCTGACGGGCTTGTCTGCTCCCGGCATCCGCTTACAGACAAGCTGTGAC
	CGTCTCCGGGAGCTGCATGTGTCAGAGGTTTTCACCGTCATCACCGAAACGC
	GCGAGGCAGCTGCGGTAAAGCTCATCAGCGTGGTCGTGAAGCGATTCACAGA
	TGTCTGCCTGTTCATCCGCGTCCAGCTCGTTGAGTTTCTCCAGAAGCGTTAA
	TGTCTGGCTTCTGATAAAGCGGGCCATGTTAAGGGCGGTTTTTTCCTGTTTG
	GTCACTGATGCCTCCGTGTAAGGGGGATTTCTGTTCATGGGGGTAATGATAC
	CGATGAAACGAGAGAGGATGCTCACGATACGGGTTACTGATGATGAACATGC
	CCGGTTACTGGAACGTTGTGAGGGTAAACAACTGGCGGTATGGATGCGGCGG
	GACCAGAGAAAAATCACTCAGGGTCAATGCCAGCGCTTCGTTAATACAGATG
	TAGGTGTTCCACAGGGTAGCCAGCAGCATCCTGCGATGCAGATCCGGAACAT
	AATGGTGCAGGGCGCTGACTTCCGCGTTTCCAGACTTTACGAAACACGGAAA
	CCGAAGACCATTCATGTTGTTGCTCAGGTCGCAGACGTTTTGCAGCAGCAGT
	CGCTTCACGTTCGCTCGCGTATCGGTGATTCATTCTGCTAACCAGTAAGGCA
	ACCCCGCCAGCCTAGCCGGGTCCTCAACGACAGGAGCACGATCATGCGCACC
	CGTGGCCAGGACCCAACGCTGCCCGAGATGCGCCGCGTGCGGCTGCTGGAGA
	TGGCGGACGCGATGGATATGTTCTGCCAAGGGTTGGTTTGCGCATTCACAGT
	TCTCCGCAAGAATTGATTGGCTCCAATTCTTGGAGTGGTGAATCCGTTAGCG
	AGGTGCCGCCGGCTTCCATTCAGGTCGAGGTGGCCCGGCTCCATGCACCGCG
	ACGCAACGCGGGGAGGCAGACAAGGTATAGGGCGGCGCCTACAATCCATGCC
	AACCCGTTCCATGTGCTCGCCGAGGCGGCATAAATCGCCGTGACGATCAGCG
	GTCCAGTGATCGAAGTTAGGCTGGTAAGAGCCGCGAGCGATCCTTGAAGCTG
	TCCCTGATGGTCGTCATCTACCTGCCTGGACAGCATGGCCTGCAACGCGGGC
	ATCCCGATGCCGCCGGAAGCGAGAAGAATCATAATGGGGAAGGCCATCCAGC
	CTCGCGTCGCGAACGCCAGCAAGACGTAGCCCAGCGCGTCGGCCGCCATGCC
	GGCGATAATGGCCTGCTTCTCGCCGAAACGTTTGGTGGCGGGACCAGTGACG
	AAGGCTTGAGCGAGGGCGTGCAAGATTCCGAATACCGCAAGCGACAGGCCGA
	TCATCGTCGCGCTCCAGCGAAAGCGGTCCTCGCCGAAAATGACCCAGAGCGC
	TGCCGGCACCTGTCCTACGAGTTGCATGATAAAGAAGACAGTCATAAGTGCG
	GCGACGATAGTCATGCCCCGCGCCCACCGGAAGGAGCTGACTGGGTTGAAGG
	CTCTCAAGGGCATCGGTCGAGATCCCGGTGCCTAATGAGTGAGCTAACTTAC
	ATTAATTGCGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGC
	CAGCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTG
	GGCGCCAGGGTGGTTTTTCTTTTCACCAGTGAGACGGGCAACAGCTGATTGC
	CCTTCACCGCCTGGCCCTGAGAGAGTTGCAGCAAGCGGTCCACGCTGGTTTG
	CCCCAGCAGGCGAAAATCCTGTTTGATGGTGGTTAACGGCGGGATATAACAT
	GAGCTGTCTTCGGTATCGTCGTATCCCACTACCGAGATATCCGCACCAACGC
	GCAGCCCGGACTCGGTAATGGCGCGCATTGCGCCCAGCGCCATCTGATCGTT
	GGCAACCAGCATCGCAGTGGGAACGATGCCCTCATTCAGCATTTGCATGGTT
	TGTTGAAAACCGGACATGGCACTCCAGTCGCCTTCCCGTTCCGCTATCGGCT
	GAATTTGATTGCGAGTGAGATATTTATGCCAGCCAGCCAGACGCAGACGCGC
	CGAGACAGAACTTAATGGGCCCGCTAACAGCGCGATTTGCTGGTGACCCAAT
	GCGACCAGATGCTCCACGCCCAGTCGCGTACCGTCTTCATGGGAGAAAATAA
	TACTGTTGATGGGTGTCTGGTCAGAGACATCAAGAAATAACGCCGGAACATT
	AGTGCAGGCAGCTTCCACAGCAATGGCATCCTGGTCATCCAGCGGATAGTTA
	ATGATCAGCCCACTGACGCGTTGCGCGAGAAGATTGTGCACCGCCGCTTTAC
	AGGCTTCGACGCCGCTTCGTTCTACCATCGACACCACCACGCTGGCACCCAG
	TTGATCGGCGCGAGATTTAATCGCCGCGACAATTTGCGACGGCGCGTGCAGG
	GCCAGACTGGAGGTGGCAACGCCAATCAGCAACGACTGTTTGCCCGCCAGTT
	GTTGTGCCACGCGGTTGGGAATGTAATTCAGCTCCGCCATCGCCGCTTCCAC
	TTTTTCCCGCGTTTTCGCAGAAACGTGGCTGGCCTGGTTCACCACGCGGGAA
	ACGGTCTGATAAGAGACACCGGCATACTCTGCGACATCGTATAACGTTACTG
	GTTTCACATTCACCACCCTGAATTGACTCTCTTCCGGGCGCTATCATGCCAT
	ACCGCGAAAGGTTTTGCGCCATTCGATGGTGTCCGGGATCTCGACGCTCTCC
	CTTATGCGACTCCTGCATTAGGAAGCAGCCCAGTAGTAGGTTGAGGCCGTTG
	AGCACCGCCGCCGCAAGGAATGGTGCATGCAAGGAGATGGCGCCCAACAGTC
	CCCCGGCCACGGGGCCTGCCACCATACCCACGCCGAAACAAGCGCTCATGAG
	CCCGAAGTGGCGAGCCCGATCTTCCCCATCGGTGATGTCGGCGATATAGGCG
	CCAGCAACCGCACCTGTGGCGCCGGTGATGCCGGCCACGATGCGTCCGGCGT
	AGAGGATCGAGATCTCGATCCCGCGAAATTAATACGACTCACTATAGGGGAA
	TTGTGAGCGGATAACAATTCCCTCTAGAAATAATTTTGTTTAACTTTAAGAA
	GGAGATATACCATGCATCATCATCATCATCACAGCAGCGGCAGAGAAAACTT
	GTATTTCCAGGGCATGAACAACGGCACCAACAACTTTCAGAACTTTATTGGC
	ATTAGCAGCCTGCAGAAAACCCTGCGCAACGCGCTGATTCCGACCGAAACCA
	CCCAGCAGTTTATTGTGAAAAACGGCATTATTAAAGAAGATGAACTGCGCGG
	CGAAAACCGCCAGATTCTGAAAGATATTATGGATGATTATTATCGCGGCTTT
	ATTAGCGAAACCCTGAGCAGCATTGATGATATTGATTGGACCAGCCTGTTTG
	AAAAAATGGAAATTCAGCTGAAAAACGGCGATAACAAAGATACCCTGATTAA
	AGAACAGACCGAATATCGCAAAGCGATTCATAAAAAATTTGCGAACGATGAT
	CGCTTTAAAAACATGTTTAGCGCGAAACTGATTAGCGATATTCTGCCGGAAT
	TTGTGATTCATAACAACAACTATAGCGCGAGCGAAAAAGAAGAAAAAACCCA
	GGTGATTAAACTGTTTAGCCGCTTTGCGACCAGCTTTAAAGATTATTTTAAA
	AACCGCGCGAACTGCTTTAGCGCGGATGATATTAGCAGCAGCAGCTGCCATC
	GCATTGTGAACGATAACGCGGAAATTTTTTTTAGCAACGCGCTGGTGTATCG
	CCGCATTGTGAAAAGCCTGAGCAACGATGATATTAACAAAATTAGCGGCGAT
	ATGAAAGATAGCCTGAAAGAAATGAGCCTGGAAGAAATTTATAGCTATGAAA
	AATATGGCGAATTTATTACCCAGGAAGGCATTAGCTTTTATAACGATATTTG
	CGGCAAAGTGAACAGCTTTATGAACCTGTATTGCCAGAAAAACAAAGAAAAC
	AAAAACCTGTATAAACTGCAGAAACTGCATAAACAGATTCTGTGCATTGCGG
	ATACCAGCTATGAAGTGCCGTATAAATTTGAAAGCGATGAAGAAGTGTATCA
	GAGCGTGAACGGCTTTCTGGATAACATTAGCAGCAAACATATTGTGGAACGC
	CTGCGCAAAATTGGCGATAACTATAACGGCTATAACCTGGATAAAATTTATA
	TTGTGAGCAAATTTTATGAAAGCGTGAGCCAGAAAACCTATCGCGATTGGGA
	AACCATTAACACCGCGCTGGAAATTCATTATAACAACATTCTGCCGGGCAAC
	GGCAAAAGCAAAGCGGATAAAGTGAAAAAAGCGGTGAAAAACGATCTGCAGA
	AAAGCATTACCGAAATTAACGAACTGGTGAGCAACTATAAACTGTGCAGCGA
	TGATAACATTAAAGCGGAAACCTATATTCATGAAATTAGCCATATTCTGAAC
	AACTTTGAAGCGCAGGAACTGAAATATAACCCGGAAATTCATCTGGTGGAAA
	GCGAACTGAAAGCGAGCGAACTGAAAAACGTGCTGGATGTGATTATGAACGC
	GTTTCATTGGTGCAGCGTGTTTATGACCGAAGAACTGGTGGATAAAGATAAC
	AACTTTTATGCGGAACTGGAAGAAATTTATGATGAAATTTATCCGGTGATTA
	GCCTGTATAACCTGGTGCGCAACTATGTGACCCAGAAACCGTATAGCACCAA
	AAAAATTAAACTGAACTTTGGCATTCCGACCCTGGCGGATGGCTGGAGCAAA
	AGCAAAGAATATAGCAACAACGCGATTATTCTGATGCGCGATAACCTGTATT
	ATCTGGGCATTTTTAACGCGAAAAACAAACCGGATAAAAAAATTATTGAAGG
	CAACACCAGCGAAAACAAAGGCGATTATAAAAAAATGATTTATAACCTGCTG
	CCGGGCCCGAACAAAATGATTCCGAAAGTGTTTCTGAGCAGCAAAACCGGCG
	TGGAAACCTATAAACCGAGCGCGTATATTCTGGAAGGCTATAAACAGAACAA
	ACATATTAAAAGCAGCAAAGATTTTGATATTACCTTTTGCCATGATCTGATT
	GATTATTTTAAAAACTGCATTGCGATTCATCCGGAATGGAAAAACTTTGGCT
	TTGATTTTAGCGATACCAGCACCTATGAAGATATTAGCGGCTTTTATCGCGA
	AGTGGAACTGCAGGGCTATAAAATTGATTGGACCTATATTAGCGAAAAAGAT
	ATTGATCTGCTGCAGGAAAAAGGCCAGCTGTATCTGTTTCAGATTTATAACA
	AAGATTTTAGCAAAAAAAGCACCGGCAACGATAACCTGCATACCATGTATCT
	GAAAAACCTGTTTAGCGAAGAAAACCTGAAAGATATTGTGCTGAAACTGAAC
	GGCGAAGCGGAAATTTTTTTTCGCAAAAGCAGCATTAAAAACCCGATTATTC
	ATAAAAAAGGCAGCATTCTGGTGAACCGCACCTATGAAGCGGAAGAAAAAGA
	TCAGTTTGGCAACATTCAGATTGTGCGCAAAAACATTCCGGAAAACATTTAT
	CAGGAACTGTATAAATATTTTAACGATAAAAGCGATAAAGAACTGAGCGATG
	AAGCGGCGAAACTGAAAAACGTGGTGGGCCATCATGAAGCGGCGACCAACAT
	TGTGAAAGATTATCGCTATACCTATGATAAATATTTTCTGCATATGCCGATT
	ACCATTAACTTTAAAGCGAACAAAACCGGCTTTATTAACGATCGCATTCTGC
	AGTATATTGCGAAAGAAAAAGATCTGCATGTGATTGGCATTGATCGCGGCGA
	ACGCAACCTGATTTATGTGAGCGTGATTGATACCTGCGGCAACATTGTGGAA
	CAGAAAAGCTTTAACATTGTGAACGGCTATGATTATCAGATTAAACTGAAAC
	AGCAGGAAGGCGCGCGCCAGATTGCGCGCAAAGAATGGAAAGAAATTGGCAA
	AATTAAAGAAATTAAAGAAGGCTATCTGAGCCTGGTGATTCATGAAATTAGC
	AAAATGGTGATTAAATATAACGCGATTATTGCGATGGAAGATCTGAGCTATG
	GCTTTAAAAAAGGCCGCTTTAAAGTGGAACGCCAGGTGTATCAGAAATTTGA
	AACCATGCTGATTAACAAACTGAACTATCTGGTGTTTAAAGATATTAGCATT
	ACCGAAAACGGCGGCCTGCTGAAAGGCTATCAGCTGACCTATATTCCGGATA
	AACTGAAAAACGTGGGCCATCAGTGCGGCTGCATTTTTTATGTGCCGGCGGC
	GTATACCAGCAAAATTGATCCGACCACCGGCTTTGTGAACATTTTTAAATTT
	AAAGATCTGACCGTGGATGCGAAACGCGAATTTATTAAAAAATTTGATAGCA
	TTCGCTATGATAGCGAAAAAAACCTGTTTTGCTTTACCTTTGATTATAACAA
	CTTTATTACCCAGAACACCGTGATGAGCAAAAGCAGCTGGAGCGTGTATACC
	TATGGCGTGCGCATTAAACGCCGCTTTGTGAACGGCCGCTTTAGCAACGAAA
	GCGATACCATTGATATTACCAAAGATATGGAAAAAACCCTGGAAATGACCGA
	TATTAACTGGCGCGATGGCCATGATCTGCGCCAGGATATTATTGATTATGAA
	ATTGTGCAGCATATTTTTGAAATTTTTCGCCTGACCGTGCAGATGCGCAACA
	GCCTGAGCGAACTGGAAGATCGCGATTATGATCGCCTGATTAGCCCGGTGCT
	GAACGAAAACAACATTTTTTATGATAGCGCGAAAGCGGGCGATGCGCTGCCG
	AAAGATGCGGATGCGAACGGCGCGTATTGCATTGCGCTGAAAGGCCTGTATG
	AAATTAAACAGATTACCGAAAACTGGAAAGAAGATGGCAAATTTAGCCGCGA
	TAAACTGAAAATTAGCAACAAAGATTGGTTTGATTTTATTCAGAACAAACGC
	TATCTGGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCG
	GCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCACCAGCCC
	TAAGAAAAAACGAAAAGTTGAGGATCCTAAAAAGAAACGAAAAGTTCATCAT
	CATCATCATCATGAATTTGCGAGCGCGGAAGCGGGCATTACCGGCACCTGGT
	ATAACCAGCATGGCAGCACCTTTACCGTGACCGCGGGCGCGGATGGCAACCT
	GACCGGCCAGTATGAAAACCGCGCGCAGGGCACCGGCTGCCAGAACAGCCCG
	TATACCCTGACCGGCCGCTATAACGGCACCAAACTGGAATGGCGCGTGGAAT
	GGAACAACAGCACCGAAAACTGCCATAGCCGCACCGAATGGCGCGGCCAGTA
	TCAGGGCGGCGCGGAAGCGCGCATTAACACCCAGTGGAACCTGACCTATGAA
	GGCGGCAGCGGCCCGGCGACCGAACAGGGCCAGGATACCTTTACCAAAGTGA
	AACCGAGCGCGGCGAGCGGCAGCGATTATAAAGATGATGATGATAAAAAACG
	CAAAAGAAAATGCCGATATCCTATTGGCATTGACGTCAGGTGGCACTTTTCG
	AGGAGATCATGCACAGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCG
	GCGGCAGCGGCGGCGGCGGCAGCGGCGGCGGCGGCAGCGGCGGCAGCCCATG
	GCAGGTGCAGCTGCAGGAGTCTGGAGGAGGCTTGGTGCAGCCTGGGGGGTCT
	CTGAGACTCTCCTGTGCAGCCTCTGGATTCACATTCAGTAGCTACGACATGA
	GCTGGGTCCGCCAGGCTCCGGGGAAGGGGCTCGAGTGGGTCTCAGGTATGAA
	TAGTGGTGGTGGTAGAACATACTATGAAGACTCCGTGAAGGGCCGATTCACC
	ATCTCCAGGTCCAACGCCAAGAACACGCTGTATCTGCAACTGAACAGCCTGA
	AAACTGACGACACGGCCATGTATTACTGTGTCACATCCGACTTTGCTTACTG
	GGGCCAGGGGACCCAGGTCACCGTCTCCTCATGTTGTTGTTGTTGTTGTTAA
	GCGGCCGCACTCGAGGATCCGGCTGCTAACAAAGCCCGAAAGGAAGCTGAGT
	TGGCTGCTGCCACCGCTGAGCAATAACTAGCATAACCCCTTGGGGCCTCTAA
	ACGGGTCTTGAGGGGTTTTTTGCTGAAAGGAGGAACTATATCCGGATATCCC
	GCAAGAGGCCCGGCAGTACCGGCATAACCAAGCCTATGCCTACAGCATCCAG
	GGTGACGGTGCCGAGGATGACGATGAGCGCATTGTTAGATTTCATACACGGT
	GCCTGACTGCGTTAGCAATTTAACTGTGATAAACTACCGCATTAAAGCTTAT
	CGATGATAAGCTGTCAAACATGAGAA
C9mAur (full	AGCGCCTGATGCGGTATTTTCTCCTTACGCATCTGTGCGGTATTTCACACCG	57
vector	CAATGGTGCACTCTCAGTACAATCTGCTCTGATGCCGCATAGTTAAGCCAGT
sequence)	ATACACTCCGCTATCGCTACGTGACTGGGTCATGGCTGCGCCCCGACACCCG
	CCAACACCCGCTGACGCGCCCTGACGGGCTTGTCTGCTCCCGGCATCCGCTT
	ACAGACAAGCTGTGACCGTCTCCGGGAGCTGCATGTGTCAGAGGTTTTCACC
	GTCATCACCGAAACGCGCGAGGCAGCTGCGGTAAAGCTCATCAGCGTGGTCG
	TGAAGCGATTCACAGATGTCTGCCTGTTCATCCGCGTCCAGCTCGTTGAGTT
	TCTCCAGAAGCGTTAATGTCTGGCTTCTGATAAAGCGGGCCATGTTAAGGGC
	GGTTTTTTCCTGTTTGGTCACTGATGCCTCCGTGTAAGGGGGATTTCTGTTC
	ATGGGGGTAATGATACCGATGAAACGAGAGAGGATGCTCACGATACGGGTTA
	CTGATGATGAACATGCCCGGTTACTGGAACGTTGTGAGGGTAAACAACTGGC
	GGTATGGATGCGGCGGGACCAGAGAAAAATCACTCAGGGTCAATGCCAGCGC
	TTCGTTAATACAGATGTAGGTGTTCCACAGGGTAGCCAGCAGCATCCTGCGA
	TGCAGATCCGGAACATAATGGTGCAGGGCGCTGACTTCCGCGTTTCCAGACT
	TTACGAAACACGGAAACCGAAGACCATTCATGTTGTTGCTCAGGTCGCAGAC
	GTTTTGCAGCAGCAGTCGCTTCACGTTCGCTCGCGTATCGGTGATTCATTCT
	GCTAACCAGTAAGGCAACCCCGCCAGCCTAGCCGGGTCCTCAACGACAGGAG
	CACGATCATGCGCACCCGTGGGGCCGCCATGCCGGCGATAATGGCCTGCTTC
	TCGCCGAAACGTTTGGTGGCGGGACCAGTGACGAAGGCTTGAGCGAGGGCGT
	GCAAGATTCCGAATACCGCAAGCGACAGGCCGATCATCGTCGCGCTCCAGCG
	AAAGCGGTCCTCGCCGAAAATGACCCAGAGCGCTGCCGGCACCTGTCCTACG
	AGTTGCATGATAAAGAAGACAGTCATAAGTGCGGCGACGATAGTCATGCCCC
	GCGCCCACCGGAAGGAGCTGACTGGGTTGAAGGCTCTCAAGGGCATCGGTCG
	AGATCCCGGTGCCTAATGAGTGAGCTAACTTACATTAATTGCGTTGCGCTCA
	CTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCG
	GCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCCAGGGTGGTTTTTC
	TTTTCACCAGTGAGACGGGCAACAGCTGATTGCCCTTCACCGCCTGGCCCTG
	AGAGAGTTGCAGCAAGCGGTCCACGCTGGTTTGCCCCAGCAGGCGAAAATCC
	TGTTTGATGGTGGTTAACGGCGGGATATAACATGAGCTGTCTTCGGTATCGT
	CGTATCCCACTACCGAGATATCCGCACCAACGCGCAGCCCGGACTCGGTAAT
	GGCGCGCATTGCGCCCAGCGCCATCTGATCGTTGGCAACCAGCATCGCAGTG
	GGAACGATGCCCTCATTCAGCATTTGCATGGTTTGTTGAAAACCGGACATGG
	CACTCCAGTCGCCTTCCCGTTCCGCTATCGGCTGAATTTGATTGCGAGTGAG
	ATATTTATGCCAGCCAGCCAGACGCAGACGCGCCGAGACAGAACTTAATGGG
	CCCGCTAACAGCGCGATTTGCTGGTGACCCAATGCGACCAGATGCTCCACGC
	CCAGTCGCGTACCGTCTTCATGGGAGAAAATAATACTGTTGATGGGTGTCTG
	GTCAGAGACATCAAGAAATAACGCCGGAACATTAGTGCAGGCAGCTTCCACA
	GCAATGGCATCCTGGTCATCCAGCGGATAGTTAATGATCAGCCCACTGACGC
	GTTGCGCGAGAAGATTGTGCACCGCCGCTTTACAGGCTTCGACGCCGCTTCG
	TTCTACCATCGACACCACCACGCTGGCACCCAGTTGATCGGCGCGAGATTTA
	ATCGCCGCGACAATTTGCGACGGCGCGTGCAGGGCCAGACTGGAGGTGGCAA
	CGCCAATCAGCAACGACTGTTTGCCCGCCAGTTGTTGTGCCACGCGGTTGGG
	AATGTAATTCAGCTCCGCCATCGCCGCTTCCACTTTTTCCCGCGTTTTCGCA
	GAAACGTGGCTGGCCTGGTTCACCACGCGGGAAACGGTCTGATAAGAGACAC
	CGGCATACTCTGCGACATCGTATAACGTTACTGGTTTCACATTCACCACCCT
	GAATTGACTCTCTTCCGGGCGCTATCATGCCATACCGCGAAAGGTTTTGCGC
	CATTCGATGGTGTCCGGGATCTCGACGCTCTCCCTTATGCGACTCCTGCATT
	AGGAAGCAGCCCAGTAGTAGGTTGAGGCCGTTGAGCACCGCCGCCGCAAGGA
	ATGGTGCATGCAAGGAGATGGCGCCCAACAGTCCCCCGGCCACGGGGCCTGC
	CACCATACCCACGCCGAAACAAGCGCTCATGAGCCCGAAGTGGCGAGCCCGA
	TCTTCCCCATCGGTGATGTCGGCGATATAGGCGCCAGCAACCGCACCTGTGG
	CGCCGGTGATGCCGGCCACGATGCGTCCGGCGTAGAGGATCGAGATCTCGAT
	CCCGCGAAATTAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATT
	CCCCTCTAGAAATAATTTTGTTTAACTTTAAGAAGGAGATATACATATGCAC
	CATCACCATCACCATGGAAAAATCGAAGAAGGTAAACTGGTAATCTGGATTA
	ACGGCGATAAAGGCTATAACGGTCTCGCTGAAGTCGGTAAGAAATTCGAGAA
	AGATACCGGAATTAAAGTCACCGTTGAGCATCCGGATAAACTGGAAGAGAAA
	TTCCCACAGGTTGCGGCAACTGGCGATGGCCCTGACATTATCTTCTGGGCAC
	ACGACCGCTTTGGTGGCTACGCTCAATCTGGCCTGTTGGCTGAAATCACCCC
	GGACAAAGCGTTCCAGGACAAGCTGTATCCGTTTACCTGGGATGCCGTACGT
	TACAACGGCAAGCTGATTGCTTACCCGATCGCTGTTGAAGCGTTATCGCTGA
	TTTATAACAAAGATCTGCTGCCGAACCCGCCAAAAACCTGGGAAGAGATCCC
	GGCGCTGGATAAAGAACTGAAAGCGAAAGGTAAGAGCGCGCTGATGTTCAAC
	CTGCAAGAACCGTACTTCACCTGGCCGCTGATTGCTGCTGACGGGGGTTATG
	CGTTCAAGTATGAAAACGGCAAGTACGACATTAAAGACGTGGGCGTGGATAA
	CGCTGGCGCGAAAGCGGGTCTGACCTTCCTGGTTGACCTGATTAAAAACAAA
	CACATGAATGCAGACACCGATTACTCCATCGCAGAAGCTGCCTTTAATAAAG
	GCGAAACAGCGATGACCATCAACGGCCCGTGGGCATGGTCCAACATCGACAC
	CAGCAAAGTGAATTATGGTGTAACGGTACTGCCGACCTTCAAGGGTCAACCA
	TCCAAACCGTTCGTTGGCGTGCTGAGCGCAGGTATTAACGCCGCCAGTCCGA
	ACAAAGAGCTGGCAAAAGAGTTCCTCGAAAACTATCTGCTGACTGATGAAGG
	TCTGGAAGCGGTTAATAAAGACAAACCGCTGGGTGCCGTAGCGCTGAAGTCT
	TACGAGGAAGAGTTGGCGAAAGATCCACGTATTGCCGCCACTATGGAAAACG
	CCCAGAAAGGTGAAATCATGCCGAACATCCCGCAGATGTCCGCTTTCTGGTA
	TGCCGTGCGTACTGCGGTGATCAACGCCGCCAGCGGTCGTCAGACTGTCGAT
	GAAGCCCTGAAAGACGCGCAGACTAATTCGAGCTCGAACAACAACAACACTA
	GTGAAAACCTGTATTTCCAGGGAGCAGCCTCGATGGATAAGAAATACTCAAT
	AGGCTTAGATATCGGCACAAATAGCGTCGGATGGGCGGTGATCACTGATGAA
	TATAAGGTTCCGTCTAAAAAGTTCAAGGTTCTGGGAAATACAGACCGCCACA
	GTATCAAAAAAAATCTTATAGGGGCTCTTTTATTTGACAGTGGAGAGACAGC
	GGAAGCGACTCGTCTCAAACGGACAGCTCGTAGAAGGTATACACGTCGGAAG
	AATCGTATTTGTTATCTACAGGAGATTTTTTCAAATGAGATGGCGAAAGTAG
	ATGATAGTTTCTTTCATCGACTTGAAGAGTCTTTTTTGGTGGAAGAAGACAA
	GAAGCATGAACGTCATCCTATTTTTGGAAATATAGTAGATGAAGTTGCTTAT
	CATGAGAAATATCCAACTATCTATCATCTGCGAAAAAAATTGGTAGATTCTA
	CTGATAAAGCGGATTTGCGCTTAATCTATTTGGCCTTAGCGCATATGATTAA
	GTTTCGTGGTCATTTTTTGATTGAGGGAGATTTAAATCCTGATAATAGTGAT
	GTGGACAAACTATTTATCCAGTTGGTACAAACCTACAATCAATTATTTGAAG
	AAAACCCTATTAACGCAAGTGGAGTAGATGCTAAAGCGATTCTTTCTGCACG
	ATTGAGTAAATCAAGACGATTAGAAAATCTCATTGCTCAGCTCCCCGGTGAG
	AAGAAAAATGGCTTATTTGGGAATCTCATTGCTTTGTCATTGGGTTTGACCC
	CTAATTTTAAATCAAATTTTGATTTGGCAGAAGATGCTAAATTACAGCTTTC
	AAAAGATACTTACGATGATGATTTAGATAATTTATTGGCGCAAATTGGAGAT
	CAATATGCTGATTTGTTTTTGGCAGCTAAGAATTTATCAGATGCTATTTTAC
	TTTCAGATATCCTAAGAGTAAATACTGAAATAACTAAGGCTCCCCTATCAGC
	TTCAATGATTAAACGCTACGATGAACATCATCAAGACTTGACTCTTTTAAAA
	GCTTTAGTTCGACAACAACTTCCAGAAAAGTATAAAGAAATCTTTTTTGATC
	AATCAAAAAACGGATATGCAGGTTATATTGATGGGGGAGCTAGCCAAGAAGA
	ATTTTATAAATTTATCAAACCAATTTTAGAAAAAATGGATGGTACTGAGGAA
	TTATTGGTGAAACTAAATCGTGAAGATTTGCTGCGCAAGCAACGGACCTTTG
	ACAACGGCTCTATTCCCCATCAAATTCACTTGGGTGAGCTGCATGCTATTTT
	GAGAAGACAAGAAGACTTTTATCCATTTTTAAAAGACAATCGTGAGAAGATT
	GAAAAAATCTTGACTTTTCGAATTCCTTATTATGTTGGTCCATTGGCGCGTG
	GCAATAGTCGTTTTGCATGGATGACTCGGAAGTCTGAAGAAACAATTACCCC
	ATGGAATTTTGAAGAAGTTGTCGATAAAGGTGCTTCAGCTCAATCATTTATT
	GAACGCATGACAAACTTTGATAAAAATCTTCCAAATGAAAAAGTACTACCAA
	AACATAGTTTGCTTTATGAGTATTTTACGGTTTATAACGAATTGACAAAGGT
	CAAATATGTTACTGAAGGAATGCGAAAACCAGCATTTCTTTCAGGTGAACAG
	AAGAAAGCCATTGTTGATTTACTCTTCAAAACAAATCGAAAAGTAACCGTTA
	AGCAATTAAAAGAAGATTATTTCAAAAAAATAGAATGTTTTGATAGTGTTGA
	AATTTCAGGAGTTGAAGATAGATTTAATGCTTCATTAGGTACCTACCATGAT
	TTGCTAAAAATTATTAAAGATAAAGATTTTTTGGATAATGAAGAAAATGAAG
	ATATCTTAGAGGATATTGTTTTAACATTGACCTTATTTGAAGATAGGGAGAT
	GATTGAGGAAAGACTTAAAACATATGCTCACCTCTTTGATGATAAGGTGATG
	AAACAGCTTAAACGTCGCCGTTATACTGGTTGGGGACGTTTGTCTCGAAAAT
	TGATTAATGGTATTAGGGATAAGCAATCTGGCAAAACAATATTAGATTTTTT
	GAAATCAGATGGTTTTGCCAATCGCAATTTTATGCAGCTGATCCATGATGAT
	AGTTTGACATTTAAAGAAGACATTCAAAAAGCACAAGTGTCTGGACAAGGCG
	ATAGTTTACATGAACATATTGCAAATTTAGCTGGTAGCCCTGCTATTAAAAA
	AGGTATTTTACAGACTGTAAAAGTTGTTGATGAATTGGTCAAAGTAATGGGG
	CGGCATAAGCCAGAAAATATCGTTATTGAAATGGCACGTGAAAATCAGACAA
	CTCAAAAGGGCCAGAAAAATTCGCGAGAGCGTATGAAACGAATCGAAGAAGG
	TATCAAAGAATTAGGAAGTCAGATTCTTAAAGAGCATCCTGTTGAAAATACT
	CAATTGCAAAATGAAAAGCTCTATCTCTATTATCTCCAAAATGGAAGAGACA
	TGTATGTGGACCAAGAATTAGATATTAATCGTTTAAGTGATTATGATGTCGA
	TCACATTGTTCCACAAAGTTTCCTTAAAGACGATTCAATAGACAATAAGGTC
	TTAACGCGTTCTGATAAAAATCGTGGTAAATCGGATAACGTTCCAAGTGAAG
	AAGTAGTCAAAAAGATGAAAAACTATTGGAGACAACTTCTAAACGCCAAGTT
	AATCACTCAACGTAAGTTTGATAATTTAACGAAAGCTGAACGTGGAGGTTTG
	AGTGAACTTGATAAAGCTGGTTTTATCAAACGCCAATTGGTTGAAACTCGCC
	AAATCACTAAGCATGTGGCACAAATTTTGGATAGTCGCATGAATACTAAATA
	CGATGAAAATGATAAACTTATTCGAGAGGTTAAAGTGATTACCTTAAAATCT
	AAATTAGTTTCTGACTTCCGAAAAGATTTCCAATTCTATAAAGTACGTGAGA
	TTAACAATTACCATCATGCCCATGATGCGTATCTAAATGCCGTCGTTGGAAC
	TGCTTTGATTAAGAAATATCCAAAACTTGAATCGGAGTTTGTCTATGGTGAT
	TATAAAGTTTATGATGTTCGTAAAATGATTGCTAAGTCTGAGCAAGAAATAG
	GCAAAGCAACCGCAAAATATTTCTTTTACTCTAATATCATGAACTTCTTCAA
	AACAGAAATTACACTTGCAAATGGAGAGATTCGCAAACGCCCTCTAATCGAA
	ACTAATGGGGAAACTGGAGAAATTGTCTGGGATAAAGGGCGAGATTTTGCCA
	CAGTGCGCAAAGTATTGTCCATGCCCCAAGTCAATATTGTCAAGAAAACAGA
	AGTACAGACAGGCGGATTCTCCAAGGAGTCAATTTTACCAAAAAGAAATTCG
	GACAAGCTTATTGCTCGTAAAAAAGACTGGGATCCAAAAAAATATGGTGGTT
	TTGATAGTCCAACGGTAGCTTATTCAGTCCTAGTGGTTGCTAAGGTGGAAAA
	AGGGAAATCGAAGAAGTTAAAATCCGTTAAAGAGTTACTAGGGATCACAATT
	ATGGAAAGAAGTTCCTTTGAAAAAAATCCGATTGACTTTTTAGAAGCTAAAG
	GATATAAGGAAGTTAAAAAAGACTTAATCATTAAACTACCTAAATATAGTCT
	TTTTGAGTTAGAAAACGGTCGTAAACGGATGCTGGCTAGTGCCGGAGAATTA
	CAAAAAGGAAATGAGCTGGCTCTGCCAAGCAAATATGTGAATTTTTTATATT
	TAGCTAGTCATTATGAAAAGTTGAAGGGTAGTCCAGAAGATAACGAACAAAA
	ACAATTGTTTGTGGAGCAGCATAAGCATTATTTAGATGAGATTATTGAGCAA
	ATCAGTGAATTTTCTAAGCGTGTTATTTTAGCAGATGCCAATTTAGATAAAG
	TTCTTAGTGCATATAACAAACATAGAGACAAACCAATACGTGAACAAGCAGA
	AAATATTATTCATTTATTTACGTTGACGAATCTTGGAGCTCCCGCTGCTTTT
	AAATATTTTGATACAACAATTGATCGTAAACGATATACGTCTACAAAAGAAG
	TTTTAGATGCCACTCTTATCCATCAATCCATCACTGGTCTTTATGAAACACG
	CATTGATTTGAGTCAGCTAGGAGGTGACGGGTCACCTAAGAAAAAACGAAAA
	GTTGAGGATCCTAAAAAGAAACGAAAAGTTGATAGCGGTTCAGAGACCCCAG
	GAACTAGCGAGAGCGCTACACCGGAATCGGCGGAAGCGGGTATCACCGGCAC
	GTGGTACAACCAGTCTGGTTCTACCTTCACCGTTACCGCGGGTGCGGACGGT
	AACCTGACCGGTCAGTACGAAAACCGTGCGCAGGGCACTGGTTGCCAGAACT
	CTCCGTACACCCTGACCGGTCGTTACAACGGTACCAAACTGGAATGGCGTGT
	TGAATGGAACAACTCTACCGAAAACTGCCACTCTCGTACCGAATGGCGTGGT
	CAGTACCAGGGTGGTGCGGAAGCGCGTATCAACACCCAGTGGAACCTGACCT
	ACGAAGGTGGTTCTGGTCCGGCGACCGAACAGGGTCAGGACACCTTCACCAA
	AGTTAAACCGTCTGCGGCGTCTTAAGCGGCCGCACTCGAGCACCACCACCAC
	CACCACTGAGATCCGGCTGCTAACAAAGCCCGAAAGGAAGCTGAGTTGGCTG
	CTGCCACCGCTGAGCAATAACTAGCATAACCCCTTGGGGCCTCTAAACGGGT
	CTTGAGGGGTTTTTTGCTGAAAGGAGGAACTATATCCGGATTGGCGAATGGG
	ACGCGCCCTGTAGCGGCGCATTAAGCGCGGCGGGTGTGGTGGTTACGCGCAG
	CGTGACCGCTACACTTGCCAGCGCCCTAGCGCCCGCTCCTTTCGCTTTCTTC
	CCTTCCTTTCTCGCCACGTTCGCCGGCTTTCCCCGTCAAGCTCTAAATCGGG
	GGCTCCCTTTAGGGTTCCGATTTAGTGCTTTACGGCACCTCGACCCCAAAAA
	ACTTGATTAGGGTGATGGTTCACGTAGTGGGCCATCGCCCTGATAGACGGTT
	TTTCGCCCTTTGACGTTGGAGTCCACGTTCTTTAATAGTGGACTCTTGTTCC
	AAACTGGAACAACACTCAACCCTATCTCGGTCTATTCTTTTGATTTATAAGG
	GATTTTGCCGATTTCGGCCTATTGGTTAAAAAATGAGCTGATTTAACAAAAA
	TTTAACGCGAATTTTAACAAAATATTAACGCTTACAATTTAGGTGGCACTTT
	TCGGGGAAATGTGCGCGGAACCCCTATTTGTTTATTTTTCTAAATACATTCA
	AATATGTATCCGCTCATGAATTAATTCTTAGAAAAACTCATCGAGCATCAAA
	TGAAACTGCAATTTATTCATATCAGGATTATCAATACCATATTTTTGAAAAA
	GCCGTTTCTGTAATGAAGGAGAAAACTCACCGAGGCAGTTCCATAGGATGGC
	AAGATCCTGGTATCGGTCTGCGATTCCGACTCGTCCAACATCAATACAACCT
	ATTAATTTCCCCTCGTCAAAAATAAGGTTATCAAGTGAGAAATCACCATGAG
	TGACGACTGAATCCGGTGAGAATGGCAAAAGTTTATGCATTTCTTTCCAGAC
	TTGTTCAACAGGCCAGCCATTACGCTCGTCATCAAAATCACTCGCATCAACC
	AAACCGTTATTCATTCGTGATTGCGCCTGAGCGAGACGAAATACGCGATCGC
	TGTTAAAAGGACAATTACAAACAGGAATCGAATGCAACCGGCGCAGGAACAC
	TGCCAGCGCATCAACAATATTTTCACCTGAATCAGGATATTCTTCTAATACC
	TGGAATGCTGTTTTCCCGGGGATCGCAGTGGTGAGTAACCATGCATCATCAG
	GAGTACGGATAAAATGCTTGATGGTCGGAAGAGGCATAAATTCCGTCAGCCA
	GTTTAGTCTGACCATCTCATCTGTAACATCATTGGCAACGCTACCTTTGCCA
	TGTTTCAGAAACAACTCTGGCGCATCGGGCTTCCCATACAATCGATAGATTG
	TCGCACCTGATTGCCCGACATTATCGCGAGCCCATTTATACCCATATAAATC
	AGCATCCATGTTGGAATTTAATCGCGGCCTAGAGCAAGACGTTTCCCGTTGA
	ATATGGCTCATAACACCCCTTGTATTACTGTTTATGTAAGCAGACAGTTTTA
	TTGTTCATGACCAAAATCCCTTAACGTGAGTTTTCGTTCCACTGAGCGTCAG
	ACCCCGTAGAAAAGATCAAAGGATCTTCTTGAGATCCTTTTTTTCTGCGCGT
	AATCTGCTGCTTGCAAACAAAAAAACCACCGCTACCAGCGGTGGTTTGTTTG
	CCGGATCAAGAGCTACCAACTCTTTTTCCGAAGGTAACTGGCTTCAGCAGAG
	CGCAGATACCAAATACTGTCCTTCTAGTGTAGCCGTAGTTAGGCCACCACTT
	CAAGAACTCTGTAGCACCGCCTACATACCTCGCTCTGCTAATCCTGTTACCA
	GTGGCTGCTGCCAGTGGCGATAAGTCGTGTCTTACCGGGTTGGACTCAAGAC
	GATAGTTACCGGATAAGGCGCAGCGGTCGGGCTGAACGGGGGGTTCGTGCAC
	ACAGCCCAGCTTGGAGCGAACGACCTACACCGAACTGAGATACCTACAGCGT
	GAGCTATGAGAAAGCGCCACGCTTCCCGAAGGGAGAAAGGCGGACAGGTATC
	CGGTAAGCGGCAGGGTCGGAACAGGAGAGCGCACGAGGGAGCTTCCAGGGGG
	AAACGCCTGGTATCTTTATAGTCCTGTCGGGTTTCGCCACCTCTGACTTGAG
	CGTCGATTTTTGTGATGCTCGTCAGGGGGGCGGAGCCTATGGAAAAACGCCA
	GCAACGCGGCCTTTTTACGGTTCCTGGCCTTTTGCTGGCCTTTTGCTCACAT
	GTTCTTTCCTGCGTTATCCCCTGATTCTGTGGATAACCGTATTACCGCCTTT
	GAGTGAGCTGATACCGCTCGCCGCAGCCGAACGACCGAGCGCAGCGAGTCAG
	TGAGCGAGGAAGCGGAAG
C9mC4	AGCGCCTGATGCGGTATTTTCTCCTTACGCATCTGTGCGGTATTTCACACCG	58
	CAATGGTGCACTCTCAGTACAATCTGCTCTGATGCCGCATAGTTAAGCCAGT
	ATACACTCCGCTATCGCTACGTGACTGGGTCATGGCTGCGCCCCGACACCCG
	CCAACACCCGCTGACGCGCCCTGACGGGCTTGTCTGCTCCCGGCATCCGCTT
	ACAGACAAGCTGTGACCGTCTCCGGGAGCTGCATGTGTCAGAGGTTTTCACC
	GTCATCACCGAAACGCGCGAGGCAGCTGCGGTAAAGCTCATCAGCGTGGTCG
	TGAAGCGATTCACAGATGTCTGCCTGTTCATCCGCGTCCAGCTCGTTGAGTT
	TCTCCAGAAGCGTTAATGTCTGGCTTCTGATAAAGCGGGCCATGTTAAGGGC
	GGTTTTTTCCTGTTTGGTCACTGATGCCTCCGTGTAAGGGGGATTTCTGTTC
	ATGGGGGTAATGATACCGATGAAACGAGAGAGGATGCTCACGATACGGGTTA
	CTGATGATGAACATGCCCGGTTACTGGAACGTTGTGAGGGTAAACAACTGGC
	GGTATGGATGCGGCGGGACCAGAGAAAAATCACTCAGGGTCAATGCCAGCGC
	TTCGTTAATACAGATGTAGGTGTTCCACAGGGTAGCCAGCAGCATCCTGCGA
	TGCAGATCCGGAACATAATGGTGCAGGGCGCTGACTTCCGCGTTTCCAGACT
	TTACGAAACACGGAAACCGAAGACCATTCATGTTGTTGCTCAGGTCGCAGAC
	GTTTTGCAGCAGCAGTCGCTTCACGTTCGCTCGCGTATCGGTGATTCATTCT
	GCTAACCAGTAAGGCAACCCCGCCAGCCTAGCCGGGTCCTCAACGACAGGAG
	CACGATCATGCGCACCCGTGGGGCCGCCATGCCGGCGATAATGGCCTGCTTC
	TCGCCGAAACGTTTGGTGGCGGGACCAGTGACGAAGGCTTGAGCGAGGGCGT
	GCAAGATTCCGAATACCGCAAGCGACAGGCCGATCATCGTCGCGCTCCAGCG
	AAAGCGGTCCTCGCCGAAAATGACCCAGAGCGCTGCCGGCACCTGTCCTACG
	AGTTGCATGATAAAGAAGACAGTCATAAGTGCGGCGACGATAGTCATGCCCC
	GCGCCCACCGGAAGGAGCTGACTGGGTTGAAGGCTCTCAAGGGCATCGGTCG
	AGATCCCGGTGCCTAATGAGTGAGCTAACTTACATTAATTGCGTTGCGCTCA
	CTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCG
	GCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCCAGGGTGGTTTTTC
	TTTTCACCAGTGAGACGGGCAACAGCTGATTGCCCTTCACCGCCTGGCCCTG
	AGAGAGTTGCAGCAAGCGGTCCACGCTGGTTTGCCCCAGCAGGCGAAAATCC
	TGTTTGATGGTGGTTAACGGCGGGATATAACATGAGCTGTCTTCGGTATCGT
	CGTATCCCACTACCGAGATATCCGCACCAACGCGCAGCCCGGACTCGGTAAT
	GGCGCGCATTGCGCCCAGCGCCATCTGATCGTTGGCAACCAGCATCGCAGTG
	GGAACGATGCCCTCATTCAGCATTTGCATGGTTTGTTGAAAACCGGACATGG
	CACTCCAGTCGCCTTCCCGTTCCGCTATCGGCTGAATTTGATTGCGAGTGAG
	ATATTTATGCCAGCCAGCCAGACGCAGACGCGCCGAGACAGAACTTAATGGG
	CCCGCTAACAGCGCGATTTGCTGGTGACCCAATGCGACCAGATGCTCCACGC
	CCAGTCGCGTACCGTCTTCATGGGAGAAAATAATACTGTTGATGGGTGTCTG
	GTCAGAGACATCAAGAAATAACGCCGGAACATTAGTGCAGGCAGCTTCCACA
	GCAATGGCATCCTGGTCATCCAGCGGATAGTTAATGATCAGCCCACTGACGC
	GTTGCGCGAGAAGATTGTGCACCGCCGCTTTACAGGCTTCGACGCCGCTTCG
	TTCTACCATCGACACCACCACGCTGGCACCCAGTTGATCGGCGCGAGATTTA
	ATCGCCGCGACAATTTGCGACGGCGCGTGCAGGGCCAGACTGGAGGTGGCAA
	CGCCAATCAGCAACGACTGTTTGCCCGCCAGTTGTTGTGCCACGCGGTTGGG
	AATGTAATTCAGCTCCGCCATCGCCGCTTCCACTTTTTCCCGCGTTTTCGCA
	GAAACGTGGCTGGCCTGGTTCACCACGCGGGAAACGGTCTGATAAGAGACAC
	CGGCATACTCTGCGACATCGTATAACGTTACTGGTTTCACATTCACCACCCT
	GAATTGACTCTCTTCCGGGCGCTATCATGCCATACCGCGAAAGGTTTTGCGC
	CATTCGATGGTGTCCGGGATCTCGACGCTCTCCCTTATGCGACTCCTGCATT
	AGGAAGCAGCCCAGTAGTAGGTTGAGGCCGTTGAGCACCGCCGCCGCAAGGA
	ATGGTGCATGCAAGGAGATGGCGCCCAACAGTCCCCCGGCCACGGGGCCTGC
	CACCATACCCACGCCGAAACAAGCGCTCATGAGCCCGAAGTGGCGAGCCCGA
	TCTTCCCCATCGGTGATGTCGGCGATATAGGCGCCAGCAACCGCACCTGTGG
	CGCCGGTGATGCCGGCCACGATGCGTCCGGCGTAGAGGATCGAGATCTCGAT
	CCCGCGAAATTAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATT
	CCCCTCTAGAAATAATTTTGTTTAACTTTAAGAAGGAGATATACATATGCAC
	CATCACCATCACCATGGAAAAATCGAAGAAGGTAAACTGGTAATCTGGATTA
	ACGGCGATAAAGGCTATAACGGTCTCGCTGAAGTCGGTAAGAAATTCGAGAA
	AGATACCGGAATTAAAGTCACCGTTGAGCATCCGGATAAACTGGAAGAGAAA
	TTCCCACAGGTTGCGGCAACTGGCGATGGCCCTGACATTATCTTCTGGGCAC
	ACGACCGCTTTGGTGGCTACGCTCAATCTGGCCTGTTGGCTGAAATCACCCC
	GGACAAAGCGTTCCAGGACAAGCTGTATCCGTTTACCTGGGATGCCGTACGT
	TACAACGGCAAGCTGATTGCTTACCCGATCGCTGTTGAAGCGTTATCGCTGA
	TTTATAACAAAGATCTGCTGCCGAACCCGCCAAAAACCTGGGAAGAGATCCC
	GGCGCTGGATAAAGAACTGAAAGCGAAAGGTAAGAGCGCGCTGATGTTCAAC
	CTGCAAGAACCGTACTTCACCTGGCCGCTGATTGCTGCTGACGGGGGTTATG
	CGTTCAAGTATGAAAACGGCAAGTACGACATTAAAGACGTGGGCGTGGATAA
	CGCTGGCGCGAAAGCGGGTCTGACCTTCCTGGTTGACCTGATTAAAAACAAA
	CACATGAATGCAGACACCGATTACTCCATCGCAGAAGCTGCCTTTAATAAAG
	GCGAAACAGCGATGACCATCAACGGCCCGTGGGCATGGTCCAACATCGACAC
	CAGCAAAGTGAATTATGGTGTAACGGTACTGCCGACCTTCAAGGGTCAACCA
	TCCAAACCGTTCGTTGGCGTGCTGAGCGCAGGTATTAACGCCGCCAGTCCGA
	ACAAAGAGCTGGCAAAAGAGTTCCTCGAAAACTATCTGCTGACTGATGAAGG
	TCTGGAAGCGGTTAATAAAGACAAACCGCTGGGTGCCGTAGCGCTGAAGTCT
	TACGAGGAAGAGTTGGCGAAAGATCCACGTATTGCCGCCACTATGGAAAACG
	CCCAGAAAGGTGAAATCATGCCGAACATCCCGCAGATGTCCGCTTTCTGGTA
	TGCCGTGCGTACTGCGGTGATCAACGCCGCCAGCGGTCGTCAGACTGTCGAT
	GAAGCCCTGAAAGACGCGCAGACTAATTCGAGCTCGAACAACAACAACACTA
	GTGAAAACCTGTATTTCCAGGGAGCAGCCTCGATGGATAAGAAATACTCAAT
	AGGCTTAGATATCGGCACAAATAGCGTCGGATGGGCGGTGATCACTGATGAA
	TATAAGGTTCCGTCTAAAAAGTTCAAGGTTCTGGGAAATACAGACCGCCACA
	GTATCAAAAAAAATCTTATAGGGGCTCTTTTATTTGACAGTGGAGAGACAGC
	GGAAGCGACTCGTCTCAAACGGACAGCTCGTAGAAGGTATACACGTCGGAAG
	AATCGTATTTGTTATCTACAGGAGATTTTTTCAAATGAGATGGCGAAAGTAG
	ATGATAGTTTCTTTCATCGACTTGAAGAGTCTTTTTTGGTGGAAGAAGACAA
	GAAGCATGAACGTCATCCTATTTTTGGAAATATAGTAGATGAAGTTGCTTAT
	CATGAGAAATATCCAACTATCTATCATCTGCGAAAAAAATTGGTAGATTCTA
	CTGATAAAGCGGATTTGCGCTTAATCTATTTGGCCTTAGCGCATATGATTAA
	GTTTCGTGGTCATTTTTTGATTGAGGGAGATTTAAATCCTGATAATAGTGAT
	GTGGACAAACTATTTATCCAGTTGGTACAAACCTACAATCAATTATTTGAAG
	AAAACCCTATTAACGCAAGTGGAGTAGATGCTAAAGCGATTCTTTCTGCACG
	ATTGAGTAAATCAAGACGATTAGAAAATCTCATTGCTCAGCTCCCCGGTGAG
	AAGAAAAATGGCTTATTTGGGAATCTCATTGCTTTGTCATTGGGTTTGACCC
	CTAATTTTAAATCAAATTTTGATTTGGCAGAAGATGCTAAATTACAGCTTTC
	AAAAGATACTTACGATGATGATTTAGATAATTTATTGGCGCAAATTGGAGAT
	CAATATGCTGATTTGTTTTTGGCAGCTAAGAATTTATCAGATGCTATTTTAC
	TTTCAGATATCCTAAGAGTAAATACTGAAATAACTAAGGCTCCCCTATCAGC
	TTCAATGATTAAACGCTACGATGAACATCATCAAGACTTGACTCTTTTAAAA
	GCTTTAGTTCGACAACAACTTCCAGAAAAGTATAAAGAAATCTTTTTTGATC
	AATCAAAAAACGGATATGCAGGTTATATTGATGGGGGAGCTAGCCAAGAAGA
	ATTTTATAAATTTATCAAACCAATTTTAGAAAAAATGGATGGTACTGAGGAA
	TTATTGGTGAAACTAAATCGTGAAGATTTGCTGCGCAAGCAACGGACCTTTG
	ACAACGGCTCTATTCCCCATCAAATTCACTTGGGTGAGCTGCATGCTATTTT
	GAGAAGACAAGAAGACTTTTATCCATTTTTAAAAGACAATCGTGAGAAGATT
	GAAAAAATCTTGACTTTTCGAATTCCTTATTATGTTGGTCCATTGGCGCGTG
	GCAATAGTCGTTTTGCATGGATGACTCGGAAGTCTGAAGAAACAATTACCCC
	ATGGAATTTTGAAGAAGTTGTCGATAAAGGTGCTTCAGCTCAATCATTTATT
	GAACGCATGACAAACTTTGATAAAAATCTTCCAAATGAAAAAGTACTACCAA
	AACATAGTTTGCTTTATGAGTATTTTACGGTTTATAACGAATTGACAAAGGT
	CAAATATGTTACTGAAGGAATGCGAAAACCAGCATTTCTTTCAGGTGAACAG
	AAGAAAGCCATTGTTGATTTACTCTTCAAAACAAATCGAAAAGTAACCGTTA
	AGCAATTAAAAGAAGATTATTTCAAAAAAATAGAATGTTTTGATAGTGTTGA
	AATTTCAGGAGTTGAAGATAGATTTAATGCTTCATTAGGTACCTACCATGAT
	TTGCTAAAAATTATTAAAGATAAAGATTTTTTGGATAATGAAGAAAATGAAG
	ATATCTTAGAGGATATTGTTTTAACATTGACCTTATTTGAAGATAGGGAGAT
	GATTGAGGAAAGACTTAAAACATATGCTCACCTCTTTGATGATAAGGTGATG
	AAACAGCTTAAACGTCGCCGTTATACTGGTTGGGGACGTTTGTCTCGAAAAT
	TGATTAATGGTATTAGGGATAAGCAATCTGGCAAAACAATATTAGATTTTTT
	GAAATCAGATGGTTTTGCCAATCGCAATTTTATGCAGCTGATCCATGATGAT
	AGTTTGACATTTAAAGAAGACATTCAAAAAGCACAAGTGTCTGGACAAGGCG
	ATAGTTTACATGAACATATTGCAAATTTAGCTGGTAGCCCTGCTATTAAAAA
	AGGTATTTTACAGACTGTAAAAGTTGTTGATGAATTGGTCAAAGTAATGGGG
	CGGCATAAGCCAGAAAATATCGTTATTGAAATGGCACGTGAAAATCAGACAA
	CTCAAAAGGGCCAGAAAAATTCGCGAGAGCGTATGAAACGAATCGAAGAAGG
	TATCAAAGAATTAGGAAGTCAGATTCTTAAAGAGCATCCTGTTGAAAATACT
	CAATTGCAAAATGAAAAGCTCTATCTCTATTATCTCCAAAATGGAAGAGACA
	TGTATGTGGACCAAGAATTAGATATTAATCGTTTAAGTGATTATGATGTCGA
	TCACATTGTTCCACAAAGTTTCCTTAAAGACGATTCAATAGACAATAAGGTC
	TTAACGCGTTCTGATAAAAATCGTGGTAAATCGGATAACGTTCCAAGTGAAG
	AAGTAGTCAAAAAGATGAAAAACTATTGGAGACAACTTCTAAACGCCAAGTT
	AATCACTCAACGTAAGTTTGATAATTTAACGAAAGCTGAACGTGGAGGTTTG
	AGTGAACTTGATAAAGCTGGTTTTATCAAACGCCAATTGGTTGAAACTCGCC
	AAATCACTAAGCATGTGGCACAAATTTTGGATAGTCGCATGAATACTAAATA
	CGATGAAAATGATAAACTTATTCGAGAGGTTAAAGTGATTACCTTAAAATCT
	AAATTAGTTTCTGACTTCCGAAAAGATTTCCAATTCTATAAAGTACGTGAGA
	TTAACAATTACCATCATGCCCATGATGCGTATCTAAATGCCGTCGTTGGAAC
	TGCTTTGATTAAGAAATATCCAAAACTTGAATCGGAGTTTGTCTATGGTGAT
	TATAAAGTTTATGATGTTCGTAAAATGATTGCTAAGTCTGAGCAAGAAATAG
	GCAAAGCAACCGCAAAATATTTCTTTTACTCTAATATCATGAACTTCTTCAA
	AACAGAAATTACACTTGCAAATGGAGAGATTCGCAAACGCCCTCTAATCGAA
	ACTAATGGGGAAACTGGAGAAATTGTCTGGGATAAAGGGCGAGATTTTGCCA
	CAGTGCGCAAAGTATTGTCCATGCCCCAAGTCAATATTGTCAAGAAAACAGA
	AGTACAGACAGGCGGATTCTCCAAGGAGTCAATTTTACCAAAAAGAAATTCG
	GACAAGCTTATTGCTCGTAAAAAAGACTGGGATCCAAAAAAATATGGTGGTT
	TTGATAGTCCAACGGTAGCTTATTCAGTCCTAGTGGTTGCTAAGGTGGAAAA
	AGGGAAATCGCAGCAGTATTATAGCTATCGCACCAAGAAGTTAAAATCCGTT
	AAAGAGTTACTAGGGATCACAATTATGGAAAGAAGTTCCTTTGAAAAAAATC
	CGATTGACTTTTTAGAAGCTAAAGGATATAAGGAAGTTAAAAAAGACTTAAT
	CATTAAACTACCTAAATATAGTCTTTTTGAGTTAGAAAACGGTCGTAAACGG
	ATGCTGGCTAGTGCCGGAGAATTACAAAAAGGAAATGAGCTGGCTCTGCCAA
	GCAAATATGTGAATTTTTTATATTTAGCTAGTCATTATGAAAAGTTGAAGGG
	TAGTCCAGAAGATAACGAACAAAAACAATTGTTTGTGGAGCAGCATAAGCAT
	TATTTAGATGAGATTATTGAGCAAATCAGTGAATTTTCTAAGCGTGTTATTT
	TAGCAGATGCCAATTTAGATAAAGTTCTTAGTGCATATAACAAACATAGAGA
	CAAACCAATACGTGAACAAGCAGAAAATATTATTCATTTATTTACGTTGACG
	AATCTTGGAGCTCCCGCTGCTTTTAAATATTTTGATACAACAATTGATCGTA
	AACGATATACGTCTACAAAAGAAGTTTTAGATGCCACTCTTATCCATCAATC
	CATCACTGGTCTTTATGAAACACGCATTGATTTGAGTCAGCTAGGAGGTGAC
	GGGTCACCTAAGAAAAAACGAAAAGTTGAGGATCCTAAAAAGAAACGAAAAG
	TTGATAGCGGTTCAGAGACCCCAGGAACTAGCGAGAGCGCTACACCGGAATC
	GGCGGAAGCGGGTATCACCGGCACGTGGTACAACCAGTCTGGTTCTACCTTC
	ACCGTTACCGCGGGTGCGGACGGTAACCTGACCGGTCAGTACGAAAACCGTG
	CGCAGGGCACTGGTTGCCAGAACTCTCCGTACACCCTGACCGGTCGTTACAA
	CGGTACCAAACTGGAATGGCGTGTTGAATGGAACAACTCTACCGAAAACTGC
	CACTCTCGTACCGAATGGCGTGGTCAGTACCAGGGTGGTGCGGAAGCGCGTA
	TCAACACCCAGTGGAACCTGACCTACGAAGGTGGTTCTGGTCCGGCGACCGA
	ACAGGGTCAGGACACCTTCACCAAAGTTAAACCGTCTGCGGCGTCTTAAGCG
	GCCGCACTCGAGCACCACCACCACCACCACTGAGATCCGGCTGCTAACAAAG
	CCCGAAAGGAAGCTGAGTTGGCTGCTGCCACCGCTGAGCAATAACTAGCATA
	ACCCCTTGGGGCCTCTAAACGGGTCTTGAGGGGTTTTTTGCTGAAAGGAGGA
	ACTATATCCGGATTGGCGAATGGGACGCGCCCTGTAGCGGCGCATTAAGCGC
	GGCGGGTGTGGTGGTTACGCGCAGCGTGACCGCTACACTTGCCAGCGCCCTA
	GCGCCCGCTCCTTTCGCTTTCTTCCCTTCCTTTCTCGCCACGTTCGCCGGCT
	TTCCCCGTCAAGCTCTAAATCGGGGGCTCCCTTTAGGGTTCCGATTTAGTGC
	TTTACGGCACCTCGACCCCAAAAAACTTGATTAGGGTGATGGTTCACGTAGT
	GGGCCATCGCCCTGATAGACGGTTTTTCGCCCTTTGACGTTGGAGTCCACGT
	TCTTTAATAGTGGACTCTTGTTCCAAACTGGAACAACACTCAACCCTATCTC
	GGTCTATTCTTTTGATTTATAAGGGATTTTGCCGATTTCGGCCTATTGGTTA
	AAAAATGAGCTGATTTAACAAAAATTTAACGCGAATTTTAACAAAATATTAA
	CGCTTACAATTTAGGTGGCACTTTTCGGGGAAATGTGCGCGGAACCCCTATT
	TGTTTATTTTTCTAAATACATTCAAATATGTATCCGCTCATGAATTAATTCT
	TAGAAAAACTCATCGAGCATCAAATGAAACTGCAATTTATTCATATCAGGAT
	TATCAATACCATATTTTTGAAAAAGCCGTTTCTGTAATGAAGGAGAAAACTC
	ACCGAGGCAGTTCCATAGGATGGCAAGATCCTGGTATCGGTCTGCGATTCCG
	ACTCGTCCAACATCAATACAACCTATTAATTTCCCCTCGTCAAAAATAAGGT
	TATCAAGTGAGAAATCACCATGAGTGACGACTGAATCCGGTGAGAATGGCAA
	AAGTTTATGCATTTCTTTCCAGACTTGTTCAACAGGCCAGCCATTACGCTCG
	TCATCAAAATCACTCGCATCAACCAAACCGTTATTCATTCGTGATTGCGCCT
	GAGCGAGACGAAATACGCGATCGCTGTTAAAAGGACAATTACAAACAGGAAT
	CGAATGCAACCGGCGCAGGAACACTGCCAGCGCATCAACAATATTTTCACCT
	GAATCAGGATATTCTTCTAATACCTGGAATGCTGTTTTCCCGGGGATCGCAG
	TGGTGAGTAACCATGCATCATCAGGAGTACGGATAAAATGCTTGATGGTCGG
	AAGAGGCATAAATTCCGTCAGCCAGTTTAGTCTGACCATCTCATCTGTAACA
	TCATTGGCAACGCTACCTTTGCCATGTTTCAGAAACAACTCTGGCGCATCGG
	GCTTCCCATACAATCGATAGATTGTCGCACCTGATTGCCCGACATTATCGCG
	AGCCCATTTATACCCATATAAATCAGCATCCATGTTGGAATTTAATCGCGGC
	CTAGAGCAAGACGTTTCCCGTTGAATATGGCTCATAACACCCCTTGTATTAC
	TGTTTATGTAAGCAGACAGTTTTATTGTTCATGACCAAAATCCCTTAACGTG
	AGTTTTCGTTCCACTGAGCGTCAGACCCCGTAGAAAAGATCAAAGGATCTTC
	TTGAGATCCTTTTTTTCTGCGCGTAATCTGCTGCTTGCAAACAAAAAAACCA
	CCGCTACCAGCGGTGGTTTGTTTGCCGGATCAAGAGCTACCAACTCTTTTTC
	CGAAGGTAACTGGCTTCAGCAGAGCGCAGATACCAAATACTGTCCTTCTAGT
	GTAGCCGTAGTTAGGCCACCACTTCAAGAACTCTGTAGCACCGCCTACATAC
	CTCGCTCTGCTAATCCTGTTACCAGTGGCTGCTGCCAGTGGCGATAAGTCGT
	GTCTTACCGGGTTGGACTCAAGACGATAGTTACCGGATAAGGCGCAGCGGTC
	GGGCTGAACGGGGGGTTCGTGCACACAGCCCAGCTTGGAGCGAACGACCTAC
	ACCGAACTGAGATACCTACAGCGTGAGCTATGAGAAAGCGCCACGCTTCCCG
	AAGGGAGAAAGGCGGACAGGTATCCGGTAAGCGGCAGGGTCGGAACAGGAGA
	GCGCACGAGGGAGCTTCCAGGGGGAAACGCCTGGTATCTTTATAGTCCTGTC
	GGGTTTCGCCACCTCTGACTTGAGCGTCGATTTTTGTGATGCTCGTCAGGGG
	GGCGGAGCCTATGGAAAAACGCCAGCAACGCGGCCTTTTTACGGTTCCTGGC
	CTTTTGCTGGCCTTTTGCTCACATGTTCTTTCCTGCGTTATCCCCTGATTCT
	GTGGATAACCGTATTACCGCCTTTGAGTGAGCTGATACCGCTCGCCGCAGCC
	GAACGACCGAGCGCAGCGAGTCAGTGAGCGAGGAAGCGGAAG
anti CD4	CAGCAGTATTATAGCTATCGCACC	59
CDR (DNA)
anti CD4	QQYYSYRT	60
CDR (a.a.)
C9mC4nab	AGCGCCTGATGCGGTATTTTCTCCTTACGCATCTGTGCGGTATTTCACACCG	61
(full	CAATGGTGCACTCTCAGTACAATCTGCTCTGATGCCGCATAGTTAAGCCAGT
sequence	ATACACTCCGCTATCGCTACGTGACTGGGTCATGGCTGCGCCCCGACACCCG
vector and	CCAACACCCGCTGACGCGCCCTGACGGGCTTGTCTGCTCCCGGCATCCGCTT
insert)	ACAGACAAGCTGTGACCGTCTCCGGGAGCTGCATGTGTCAGAGGTTTTCACC
	GTCATCACCGAAACGCGCGAGGCAGCTGCGGTAAAGCTCATCAGCGTGGTCG
	TGAAGCGATTCACAGATGTCTGCCTGTTCATCCGCGTCCAGCTCGTTGAGTT
	TCTCCAGAAGCGTTAATGTCTGGCTTCTGATAAAGCGGGCCATGTTAAGGGC
	GGTTTTTTCCTGTTTGGTCACTGATGCCTCCGTGTAAGGGGGATTTCTGTTC
	ATGGGGGTAATGATACCGATGAAACGAGAGAGGATGCTCACGATACGGGTTA
	CTGATGATGAACATGCCCGGTTACTGGAACGTTGTGAGGGTAAACAACTGGC
	GGTATGGATGCGGCGGGACCAGAGAAAAATCACTCAGGGTCAATGCCAGCGC
	TTCGTTAATACAGATGTAGGTGTTCCACAGGGTAGCCAGCAGCATCCTGCGA
	TGCAGATCCGGAACATAATGGTGCAGGGCGCTGACTTCCGCGTTTCCAGACT
	TTACGAAACACGGAAACCGAAGACCATTCATGTTGTTGCTCAGGTCGCAGAC
	GTTTTGCAGCAGCAGTCGCTTCACGTTCGCTCGCGTATCGGTGATTCATTCT
	GCTAACCAGTAAGGCAACCCCGCCAGCCTAGCCGGGTCCTCAACGACAGGAG
	CACGATCATGCGCACCCGTGGGGCCGCCATGCCGGCGATAATGGCCTGCTTC
	TCGCCGAAACGTTTGGTGGCGGGACCAGTGACGAAGGCTTGAGCGAGGGCGT
	GCAAGATTCCGAATACCGCAAGCGACAGGCCGATCATCGTCGCGCTCCAGCG
	AAAGCGGTCCTCGCCGAAAATGACCCAGAGCGCTGCCGGCACCTGTCCTACG
	AGTTGCATGATAAAGAAGACAGTCATAAGTGCGGCGACGATAGTCATGCCCC
	GCGCCCACCGGAAGGAGCTGACTGGGTTGAAGGCTCTCAAGGGCATCGGTCG
	AGATCCCGGTGCCTAATGAGTGAGCTAACTTACATTAATTGCGTTGCGCTCA
	CTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCG
	GCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCCAGGGTGGTTTTTC
	TTTTCACCAGTGAGACGGGCAACAGCTGATTGCCCTTCACCGCCTGGCCCTG
	AGAGAGTTGCAGCAAGCGGTCCACGCTGGTTTGCCCCAGCAGGCGAAAATCC
	TGTTTGATGGTGGTTAACGGCGGGATATAACATGAGCTGTCTTCGGTATCGT
	CGTATCCCACTACCGAGATATCCGCACCAACGCGCAGCCCGGACTCGGTAAT
	GGCGCGCATTGCGCCCAGCGCCATCTGATCGTTGGCAACCAGCATCGCAGTG
	GGAACGATGCCCTCATTCAGCATTTGCATGGTTTGTTGAAAACCGGACATGG
	CACTCCAGTCGCCTTCCCGTTCCGCTATCGGCTGAATTTGATTGCGAGTGAG
	ATATTTATGCCAGCCAGCCAGACGCAGACGCGCCGAGACAGAACTTAATGGG
	CCCGCTAACAGCGCGATTTGCTGGTGACCCAATGCGACCAGATGCTCCACGC
	CCAGTCGCGTACCGTCTTCATGGGAGAAAATAATACTGTTGATGGGTGTCTG
	GTCAGAGACATCAAGAAATAACGCCGGAACATTAGTGCAGGCAGCTTCCACA
	GCAATGGCATCCTGGTCATCCAGCGGATAGTTAATGATCAGCCCACTGACGC
	GTTGCGCGAGAAGATTGTGCACCGCCGCTTTACAGGCTTCGACGCCGCTTCG
	TTCTACCATCGACACCACCACGCTGGCACCCAGTTGATCGGCGCGAGATTTA
	ATCGCCGCGACAATTTGCGACGGCGCGTGCAGGGCCAGACTGGAGGTGGCAA
	CGCCAATCAGCAACGACTGTTTGCCCGCCAGTTGTTGTGCCACGCGGTTGGG
	AATGTAATTCAGCTCCGCCATCGCCGCTTCCACTTTTTCCCGCGTTTTCGCA
	GAAACGTGGCTGGCCTGGTTCACCACGCGGGAAACGGTCTGATAAGAGACAC
	CGGCATACTCTGCGACATCGTATAACGTTACTGGTTTCACATTCACCACCCT
	GAATTGACTCTCTTCCGGGCGCTATCATGCCATACCGCGAAAGGTTTTGCGC
	CATTCGATGGTGTCCGGGATCTCGACGCTCTCCCTTATGCGACTCCTGCATT
	AGGAAGCAGCCCAGTAGTAGGTTGAGGCCGTTGAGCACCGCCGCCGCAAGGA
	ATGGTGCATGCAAGGAGATGGCGCCCAACAGTCCCCCGGCCACGGGGCCTGC
	CACCATACCCACGCCGAAACAAGCGCTCATGAGCCCGAAGTGGCGAGCCCGA
	TCTTCCCCATCGGTGATGTCGGCGATATAGGCGCCAGCAACCGCACCTGTGG
	CGCCGGTGATGCCGGCCACGATGCGTCCGGCGTAGAGGATCGAGATCTCGAT
	CCCGCGAAATTAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATT
	CCCCTCTAGAAATAATTTTGTTTAACTTTAAGAAGGAGATATACATATGCAC
	CATCACCATCACCATGGAAAAATCGAAGAAGGTAAACTGGTAATCTGGATTA
	ACGGCGATAAAGGCTATAACGGTCTCGCTGAAGTCGGTAAGAAATTCGAGAA
	AGATACCGGAATTAAAGTCACCGTTGAGCATCCGGATAAACTGGAAGAGAAA
	TTCCCACAGGTTGCGGCAACTGGCGATGGCCCTGACATTATCTTCTGGGCAC
	ACGACCGCTTTGGTGGCTACGCTCAATCTGGCCTGTTGGCTGAAATCACCCC
	GGACAAAGCGTTCCAGGACAAGCTGTATCCGTTTACCTGGGATGCCGTACGT
	TACAACGGCAAGCTGATTGCTTACCCGATCGCTGTTGAAGCGTTATCGCTGA
	TTTATAACAAAGATCTGCTGCCGAACCCGCCAAAAACCTGGGAAGAGATCCC
	GGCGCTGGATAAAGAACTGAAAGCGAAAGGTAAGAGCGCGCTGATGTTCAAC
	CTGCAAGAACCGTACTTCACCTGGCCGCTGATTGCTGCTGACGGGGGTTATG
	CGTTCAAGTATGAAAACGGCAAGTACGACATTAAAGACGTGGGCGTGGATAA
	CGCTGGCGCGAAAGCGGGTCTGACCTTCCTGGTTGACCTGATTAAAAACAAA
	CACATGAATGCAGACACCGATTACTCCATCGCAGAAGCTGCCTTTAATAAAG
	GCGAAACAGCGATGACCATCAACGGCCCGTGGGCATGGTCCAACATCGACAC
	CAGCAAAGTGAATTATGGTGTAACGGTACTGCCGACCTTCAAGGGTCAACCA
	TCCAAACCGTTCGTTGGCGTGCTGAGCGCAGGTATTAACGCCGCCAGTCCGA
	ACAAAGAGCTGGCAAAAGAGTTCCTCGAAAACTATCTGCTGACTGATGAAGG
	TCTGGAAGCGGTTAATAAAGACAAACCGCTGGGTGCCGTAGCGCTGAAGTCT
	TACGAGGAAGAGTTGGCGAAAGATCCACGTATTGCCGCCACTATGGAAAACG
	CCCAGAAAGGTGAAATCATGCCGAACATCCCGCAGATGTCCGCTTTCTGGTA
	TGCCGTGCGTACTGCGGTGATCAACGCCGCCAGCGGTCGTCAGACTGTCGAT
	GAAGCCCTGAAAGACGCGCAGACTAATTCGAGCTCGAACAACAACAACACTA
	GTGAAAACCTGTATTTCCAGGGAGCAGCCTCGATGGATAAGAAATACTCAAT
	AGGCTTAGATATCGGCACAAATAGCGTCGGATGGGCGGTGATCACTGATGAA
	TATAAGGTTCCGTCTAAAAAGTTCAAGGTTCTGGGAAATACAGACCGCCACA
	GTATCAAAAAAAATCTTATAGGGGCTCTTTTATTTGACAGTGGAGAGACAGC
	GGAAGCGACTCGTCTCAAACGGACAGCTCGTAGAAGGTATACACGTCGGAAG
	AATCGTATTTGTTATCTACAGGAGATTTTTTCAAATGAGATGGCGAAAGTAG
	ATGATAGTTTCTTTCATCGACTTGAAGAGTCTTTTTTGGTGGAAGAAGACAA
	GAAGCATGAACGTCATCCTATTTTTGGAAATATAGTAGATGAAGTTGCTTAT
	CATGAGAAATATCCAACTATCTATCATCTGCGAAAAAAATTGGTAGATTCTA
	CTGATAAAGCGGATTTGCGCTTAATCTATTTGGCCTTAGCGCATATGATTAA
	GTTTCGTGGTCATTTTTTGATTGAGGGAGATTTAAATCCTGATAATAGTGAT
	GTGGACAAACTATTTATCCAGTTGGTACAAACCTACAATCAATTATTTGAAG
	AAAACCCTATTAACGCAAGTGGAGTAGATGCTAAAGCGATTCTTTCTGCACG
	ATTGAGTAAATCAAGACGATTAGAAAATCTCATTGCTCAGCTCCCCGGTGAG
	AAGAAAAATGGCTTATTTGGGAATCTCATTGCTTTGTCATTGGGTTTGACCC
	CTAATTTTAAATCAAATTTTGATTTGGCAGAAGATGCTAAATTACAGCTTTC
	AAAAGATACTTACGATGATGATTTAGATAATTTATTGGCGCAAATTGGAGAT
	CAATATGCTGATTTGTTTTTGGCAGCTAAGAATTTATCAGATGCTATTTTAC
	TTTCAGATATCCTAAGAGTAAATACTGAAATAACTAAGGCTCCCCTATCAGC
	TTCAATGATTAAACGCTACGATGAACATCATCAAGACTTGACTCTTTTAAAA
	GCTTTAGTTCGACAACAACTTCCAGAAAAGTATAAAGAAATCTTTTTTGATC
	AATCAAAAAACGGATATGCAGGTTATATTGATGGGGGAGCTAGCCAAGAAGA
	ATTTTATAAATTTATCAAACCAATTTTAGAAAAAATGGATGGTACTGAGGAA
	TTATTGGTGAAACTAAATCGTGAAGATTTGCTGCGCAAGCAACGGACCTTTG
	ACAACGGCTCTATTCCCCATCAAATTCACTTGGGTGAGCTGCATGCTATTTT
	GAGAAGACAAGAAGACTTTTATCCATTTTTAAAAGACAATCGTGAGAAGATT
	GAAAAAATCTTGACTTTTCGAATTCCTTATTATGTTGGTCCATTGGCGCGTG
	GCAATAGTCGTTTTGCATGGATGACTCGGAAGTCTGAAGAAACAATTACCCC
	ATGGAATTTTGAAGAAGTTGTCGATAAAGGTGCTTCAGCTCAATCATTTATT
	GAACGCATGACAAACTTTGATAAAAATCTTCCAAATGAAAAAGTACTACCAA
	AACATAGTTTGCTTTATGAGTATTTTACGGTTTATAACGAATTGACAAAGGT
	CAAATATGTTACTGAAGGAATGCGAAAACCAGCATTTCTTTCAGGTGAACAG
	AAGAAAGCCATTGTTGATTTACTCTTCAAAACAAATCGAAAAGTAACCGTTA
	AGCAATTAAAAGAAGATTATTTCAAAAAAATAGAATGTTTTGATAGTGTTGA
	AATTTCAGGAGTTGAAGATAGATTTAATGCTTCATTAGGTACCTACCATGAT
	TTGCTAAAAATTATTAAAGATAAAGATTTTTTGGATAATGAAGAAAATGAAG
	ATATCTTAGAGGATATTGTTTTAACATTGACCTTATTTGAAGATAGGGAGAT
	GATTGAGGAAAGACTTAAAACATATGCTCACCTCTTTGATGATAAGGTGATG
	AAACAGCTTAAACGTCGCCGTTATACTGGTTGGGGACGTTTGTCTCGAAAAT
	TGATTAATGGTATTAGGGATAAGCAATCTGGCAAAACAATATTAGATTTTTT
	GAAATCAGATGGTTTTGCCAATCGCAATTTTATGCAGCTGATCCATGATGAT
	AGTTTGACATTTAAAGAAGACATTCAAAAAGCACAAGTGTCTGGACAAGGCG
	ATAGTTTACATGAACATATTGCAAATTTAGCTGGTAGCCCTGCTATTAAAAA
	AGGTATTTTACAGACTGTAAAAGTTGTTGATGAATTGGTCAAAGTAATGGGG
	CGGCATAAGCCAGAAAATATCGTTATTGAAATGGCACGTGAAAATCAGACAA
	CTCAAAAGGGCCAGAAAAATTCGCGAGAGCGTATGAAACGAATCGAAGAAGG
	TATCAAAGAATTAGGAAGTCAGATTCTTAAAGAGCATCCTGTTGAAAATACT
	CAATTGCAAAATGAAAAGCTCTATCTCTATTATCTCCAAAATGGAAGAGACA
	TGTATGTGGACCAAGAATTAGATATTAATCGTTTAAGTGATTATGATGTCGA
	TCACATTGTTCCACAAAGTTTCCTTAAAGACGATTCAATAGACAATAAGGTC
	TTAACGCGTTCTGATAAAAATCGTGGTAAATCGGATAACGTTCCAAGTGAAG
	AAGTAGTCAAAAAGATGAAAAACTATTGGAGACAACTTCTAAACGCCAAGTT
	AATCACTCAACGTAAGTTTGATAATTTAACGAAAGCTGAACGTGGAGGTTTG
	AGTGAACTTGATAAAGCTGGTTTTATCAAACGCCAATTGGTTGAAACTCGCC
	AAATCACTAAGCATGTGGCACAAATTTTGGATAGTCGCATGAATACTAAATA
	CGATGAAAATGATAAACTTATTCGAGAGGTTAAAGTGATTACCTTAAAATCT
	AAATTAGTTTCTGACTTCCGAAAAGATTTCCAATTCTATAAAGTACGTGAGA
	TTAACAATTACCATCATGCCCATGATGCGTATCTAAATGCCGTCGTTGGAAC
	TGCTTTGATTAAGAAATATCCAAAACTTGAATCGGAGTTTGTCTATGGTGAT
	TATAAAGTTTATGATGTTCGTAAAATGATTGCTAAGTCTGAGCAAGAAATAG
	GCAAAGCAACCGCAAAATATTTCTTTTACTCTAATATCATGAACTTCTTCAA
	AACAGAAATTACACTTGCAAATGGAGAGATTCGCAAACGCCCTCTAATCGAA
	ACTAATGGGGAAACTGGAGAAATTGTCTGGGATAAAGGGCGAGATTTTGCCA
	CAGTGCGCAAAGTATTGTCCATGCCCCAAGTCAATATTGTCAAGAAAACAGA
	AGTACAGACAGGCGGATTCTCCAAGGAGTCAATTTTACCAAAAAGAAATTCG
	GACAAGCTTATTGCTCGTAAAAAAGACTGGGATCCAAAAAAATATGGTGGTT
	TTGATAGTCCAACGGTAGCTTATTCAGTCCTAGTGGTTGCTAAGGTGGAAAA
	AGGGAAATCGCAGCAGTATTATAGCTATCGCACCAAGAAGTTAAAATCCGTT
	AAAGAGTTACTAGGGATCACAATTATGGAAAGAAGTTCCTTTGAAAAAAATC
	CGATTGACTTTTTAGAAGCTAAAGGATATAAGGAAGTTAAAAAAGACTTAAT
	CATTAAACTACCTAAATATAGTCTTTTTGAGTTAGAAAACGGTCGTAAACGG
	ATGCTGGCTAGTGCCGGAGAATTACAAAAAGGAAATGAGCTGGCTCTGCCAA
	GCAAATATGTGAATTTTTTATATTTAGCTAGTCATTATGAAAAGTTGAAGGG
	TAGTCCAGAAGATAACGAACAAAAACAATTGTTTGTGGAGCAGCATAAGCAT
	TATTTAGATGAGATTATTGAGCAAATCAGTGAATTTTCTAAGCGTGTTATTT
	TAGCAGATGCCAATTTAGATAAAGTTCTTAGTGCATATAACAAACATAGAGA
	CAAACCAATACGTGAACAAGCAGAAAATATTATTCATTTATTTACGTTGACG
	AATCTTGGAGCTCCCGCTGCTTTTAAATATTTTGATACAACAATTGATCGTA
	AACGATATACGTCTACAAAAGAAGTTTTAGATGCCACTCTTATCCATCAATC
	CATCACTGGTCTTTATGAAACACGCATTGATTTGAGTCAGCTAGGAGGTGAC
	GGGTCACCTAAGAAAAAACGAAAAGTTGAGGATCCTAAAAAGAAACGAAAAG
	TTGATAGCGGTTCAGAGACCCCAGGAACTAGCGAGAGCGCTACACCGGAATC
	GGCGGAAGCGGGTATCACCGGCACGTGGTACAACCAGTCTGGTTCTACCTTC
	ACCGTTACCGCGGGTGCGGACGGTAACCTGACCGGTCAGTACGAAAACCGTG
	CGCAGGGCACTGGTTGCCAGAACTCTCCGTACACCCTGACCGGTCGTTACAA
	CGGTACCAAACTGGAATGGCGTGTTGAATGGAACAACTCTACCGAAAACTGC
	CACTCTCGTACCGAATGGCGTGGTCAGTACCAGGGTGGTGCGGAAGCGCGTA
	TCAACACCCAGTGGAACCTGACCTACGAAGGTGGTTCTGGTCCGGCGACCGA
	ACAGGGTCAGGACACCTTCACCAAAGTTAAAGGATCCCAGGTTCAGCTGGTT
	CAGAGCGGTGGTGGTCTGGTTCAGGCAGGCGGTAGCCTGCGTCTGAGCTGTG
	CATTTAGCGGTCGTACCTTTAGCATGTATACCATGGGTTGGTTTCGTCAGGC
	ACCGGGTAAAGAACGTGAATTTGTTGCAGCAAATCGTGGTCGTGGTCTGAGT
	CCGGATATTGCAGATAGCGTTAATGGTCGTTTTACCATTAGCCGTGATAATG
	CCAAAAATACCCTGTACCTGCAGATGGATAGCCTGAAACCGGAAGATACCGC
	AGTGTATTATTGTGCAGCAGCAAGCCGTGAAGATCCGCCTGGTTATTGGGGT
	CAGGGCACCACCGTTACCGTTAGCAGCCCGAAAAAGAAACGTAAAGTGGAAG
	ATCCGAAGAAAAAGCGTAAAGTTGGTGGTGGTGGCAGCCTGCCGGAAACCGG
	TGGTCTGTTTGATATTATCAAGAAAATTGCCGAGAGCTTCCTGGAACATCAT
	CACCATCATCATAAGCTTGATCCGGCTGCTAACAAAGCCCGAAAGGAAGCTG
	AGTTGGCTGCTGCCACCGCTGAGCAATAAGATCCGGCTGCTAACAAAGCCCG
	AAAGGAAGCTGAGTTGGCTGCTGCCACCGCTGAGCAATAACTAGCATAACCC
	CTTGGGGCCTCTAAACGGGTCTTGAGGGGTTTTTTGCTGAAAGGAGGAACTA
	TATCCGGATTGGCGAATGGGACGCGCCCTGTAGCGGCGCATTAAGCGCGGCG
	GGTGTGGTGGTTACGCGCAGCGTGACCGCTACACTTGCCAGCGCCCTAGCGC
	CCGCTCCTTTCGCTTTCTTCCCTTCCTTTCTCGCCACGTTCGCCGGCTTTCC
	CCGTCAAGCTCTAAATCGGGGGCTCCCTTTAGGGTTCCGATTTAGTGCTTTA
	CGGCACCTCGACCCCAAAAAACTTGATTAGGGTGATGGTTCACGTAGTGGGC
	CATCGCCCTGATAGACGGTTTTTCGCCCTTTGACGTTGGAGTCCACGTTCTT
	TAATAGTGGACTCTTGTTCCAAACTGGAACAACACTCAACCCTATCTCGGTC
	TATTCTTTTGATTTATAAGGGATTTTGCCGATTTCGGCCTATTGGTTAAAAA
	ATGAGCTGATTTAACAAAAATTTAACGCGAATTTTAACAAAATATTAACGCT
	TACAATTTAGGTGGCACTTTTCGGGGAAATGTGCGCGGAACCCCTATTTGTT
	TATTTTTCTAAATACATTCAAATATGTATCCGCTCATGAATTAATTCTTAGA
	AAAACTCATCGAGCATCAAATGAAACTGCAATTTATTCATATCAGGATTATC
	AATACCATATTTTTGAAAAAGCCGTTTCTGTAATGAAGGAGAAAACTCACCG
	AGGCAGTTCCATAGGATGGCAAGATCCTGGTATCGGTCTGCGATTCCGACTC
	GTCCAACATCAATACAACCTATTAATTTCCCCTCGTCAAAAATAAGGTTATC
	AAGTGAGAAATCACCATGAGTGACGACTGAATCCGGTGAGAATGGCAAAAGT
	TTATGCATTTCTTTCCAGACTTGTTCAACAGGCCAGCCATTACGCTCGTCAT
	CAAAATCACTCGCATCAACCAAACCGTTATTCATTCGTGATTGCGCCTGAGC
	GAGACGAAATACGCGATCGCTGTTAAAAGGACAATTACAAACAGGAATCGAA
	TGCAACCGGCGCAGGAACACTGCCAGCGCATCAACAATATTTTCACCTGAAT
	CAGGATATTCTTCTAATACCTGGAATGCTGTTTTCCCGGGGATCGCAGTGGT
	GAGTAACCATGCATCATCAGGAGTACGGATAAAATGCTTGATGGTCGGAAGA
	GGCATAAATTCCGTCAGCCAGTTTAGTCTGACCATCTCATCTGTAACATCAT
	TGGCAACGCTACCTTTGCCATGTTTCAGAAACAACTCTGGCGCATCGGGCTT
	CCCATACAATCGATAGATTGTCGCACCTGATTGCCCGACATTATCGCGAGCC
	CATTTATACCCATATAAATCAGCATCCATGTTGGAATTTAATCGCGGCCTAG
	AGCAAGACGTTTCCCGTTGAATATGGCTCATAACACCCCTTGTATTACTGTT
	TATGTAAGCAGACAGTTTTATTGTTCATGACCAAAATCCCTTAACGTGAGTT
	TTCGTTCCACTGAGCGTCAGACCCCGTAGAAAAGATCAAAGGATCTTCTTGA
	GATCCTTTTTTTCTGCGCGTAATCTGCTGCTTGCAAACAAAAAAACCACCGC
	TACCAGCGGTGGTTTGTTTGCCGGATCAAGAGCTACCAACTCTTTTTCCGAA
	GGTAACTGGCTTCAGCAGAGCGCAGATACCAAATACTGTCCTTCTAGTGTAG
	CCGTAGTTAGGCCACCACTTCAAGAACTCTGTAGCACCGCCTACATACCTCG
	CTCTGCTAATCCTGTTACCAGTGGCTGCTGCCAGTGGCGATAAGTCGTGTCT
	TACCGGGTTGGACTCAAGACGATAGTTACCGGATAAGGCGCAGCGGTCGGGC
	TGAACGGGGGGTTCGTGCACACAGCCCAGCTTGGAGCGAACGACCTACACCG
	AACTGAGATACCTACAGCGTGAGCTATGAGAAAGCGCCACGCTTCCCGAAGG
	GAGAAAGGCGGACAGGTATCCGGTAAGCGGCAGGGTCGGAACAGGAGAGCGC
	ACGAGGGAGCTTCCAGGGGGAAACGCCTGGTATCTTTATAGTCCTGTCGGGT
	TTCGCCACCTCTGACTTGAGCGTCGATTTTTGTGATGCTCGTCAGGGGGGCG
	GAGCCTATGGAAAAACGCCAGCAACGCGGCCTTTTTACGGTTCCTGGCCTTT
	TGCTGGCCTTTTGCTCACATGTTCTTTCCTGCGTTATCCCCTGATTCTGTGG
	ATAACCGTATTACCGCCTTTGAGTGAGCTGATACCGCTCGCCGCAGCCGAAC
	GACCGAGCGCAGCGAGTCAGTGAGCGAGGAAGCGGAAG
Anti CD4n1	GGATCCCAGGTTCAGCTGGTTCAGAGCGGTGGTGGTCTGGTTCAGGCAGGCG	62
VHH	GTAGCCTGCGTCTGAGCTGTGCATTTAGCGGTCGTACCTTTAGCATGTATAC
	CATGGGTTGGTTTCGTCAGGCACCGGGTAAAGAACGTGAATTTGTTGCAGCA
	AATCGTGGTCGTGGTCTGAGTCCGGATATTGCAGATAGCGTTAATGGTCGTT
	TTACCATTAGCCGTGATAATGCCAAAAATACCCTGTACCTGCAGATGGATAG
	CCTGAAACCGGAAGATACCGCAGTGTATTATTGTGCAGCAGCAAGCCGTGAA
	GATCCGCCTGGTTATTGGGGTCAGGGCACCACCGTTACCGTTAGCAGCCCGA
	AAAAGAAACGTAAAGTGGAAGATCCGAAGAAAAAGCGTAAAGTTGGTGGTGG
	TGGCAGCCTGCCGGAAACCGGTGGTCTGTTTGATATTATCAAGAAAATTGCC
	GAGAGCTTCCTGGAACATCATCACCATCATCATAAGCTTGATCCGGCTGCTA
	ACAAAGCCCGAAAGGAAGCTGAGTTGGCTGCTGCCACCGCTGAGCAATAA