MATERIALS AND METHODS FOR CELL GROWTH
Patent Information
- Authority / Receiving Office
- MX · MX
- Patent Type
- Applications
- Current Assignee / Owner
- JANSSEN BIOTECH INC
- Filing Date
- 2026-01-23
- Publication Date
- 2026-05-04
Abstract
Description
MATERIALS AND METHODS FOR CELL GROWTH CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Ser. No.63 / 515,672, filed on July 26, 2023, the disclosure of which is incorporated by reference herein in its entirety. SEQUENCE LISTING
[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. Said XML copy, created on July 10, 2024, is named JBI6790WOPCT_SL.xml and is 674,000 bytes in size. FIELD OF THE INVENTION
[0003] The disclosure provided herein relates to molecules, such as antibodies and antigen- binding fragments thereof, that specifically bind and are agonistic to a gamma-delta (γδ) T cell receptor (TCR) (TCRγδ), and methods of producing and using same. The disclosure provided herein also relates to methods of expanding a population of effector cells (e.g., γδ T cells obtained from induced pluripotent stems cells (iPSCs) and / or peripheral blood mononuclear cells (PBMCs)) using the described antibodies and antigen-binding fragments. BACKGROUND
[0004] T cell immunotherapy, such as autologous chimeric antigen receptor (CAR) T cells, has been reported to be efficacious therapy for the treatment of some cancers, such as hematologic malignancies; however, applications of cell therapy to treat various cancer types has met numerous and varied challenges (see, e.g., Advances and challenges of CAR T therapy and suitability of animal models (Review), Authors: Xavier E. Ramos-Cardona Weichuan Luo Sulma I. Mohammed; Published online on: July 12, 2022).SUMMARY OF THE INVENTION
[0005] Advances in T cell immunotherapy have been reported, such as in autologous CAR T cell therapy; however, applications of cell therapy to treat various cancer types has unmet challenges and the present invention, against this backdrop, meets various of these challenges which impede access to therapeutic cell products, such as prohibitive, high manufacturing costs, increased complexity, lack of a consistent and scalable manufacturing process, etc. For example, the inventors of the present disclosure use induced pluripotent stem cells (iPSCs), which can undergo inter alia self-renewal, gene editing, multilineage differentiation, etc., to advance off-the-shelf, allogeneic, CAR-engineered T cell therapy platforms with more commercially viable, automated, energy efficient, and resource sparing manufacturing processes. For example, an iPSC-derived cell therapy platform can be based on production of γδ T cells, which possess intrinsic antitumor activity and whose tumor infiltration is associated with favorable outcomes.
[0006] iPSC-derived γδ T cells (e.g., Vγ9Vδ2 T cells) can be used as allogeneic off-the- shelf cell therapy product but need to be grown and expanded to generate sufficient amounts of pure cells required to dose patients. There are no prior reports, in particular, describing expansion of iPSC-derived Vγ9Vδ2 T cells. Generally, peripheral blood mononuclear cell (PBMC)-derived Vγ9Vδ2 T cells are expanded ex vivo following zoledronic acid-induced accumulation of phosphoantigens IPP and DMAPP in monocytes. Binding of these phosphoantigens to the intracellular domain of butyrophilin Subfamily 3 Member A1 (BTN3A1) results in conformational changes of BTN3A1 / 2A1 complex on monocyte surface, leading to subsequent recognition by and expansion of Vγ9Vδ2 T cells. In iPSC- derived systems, monocytes (or other antigen-presenting cells) are not present, and therefore phosphoantigens-based expansion is not feasible. Stimulants, such as antibodies or antigen binding fragment of them, which can mimic TCR-antigen engagement and initiate signal transduction, activation, proliferation and result in expansion of iPSC-derived Vγ9Vδ2 T cells are lacking.
[0007] There is therefore a need in the art for antibody-based cell culture and expansion procedures that yield high expansion and purity of iPSC-derived γδ T cells (e.g., Vγ9Vδ2 T cells). The present application addresses these and other needs.
[0008] In one aspect, provided herein is an isolated antibody, or antigen-binding fragment thereof, comprising:a heavy chain complementarity determining region (CDR) 1 (CDR1), a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 451, 453, 455, 457, 721, 723, 725, 727, 729, 731, or 733 or a sequence having at least about 80% identity thereto; and / or a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 452, 454, 456, 458, 722, 724, 726, 728, 730, 732, or 734, or a sequence having at least about 80% identity thereto.
[0009] In some embodiments, the isolated antibody, or antigen-binding fragment thereof described herein, comprises: a VH comprising an amino acid sequence of SEQ ID NO: 451, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 452, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 453, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 454, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 455, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 456, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 457, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 458, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 721, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 722, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 723, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 724, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 725, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 726, or a sequence having at least about 80% identity thereto;a VH comprising an amino acid sequence of SEQ ID NO: 727, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 728, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 729, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 730, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 731, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 732, or a sequence having at least about 80% identity thereto; or a VH comprising an amino acid sequence of SEQ ID NO: 733, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 734, or a sequence having at least about 80% identity thereto.
[0010] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises: a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 727, 729, 725, 733, 455, 453, 721, 723, 731, or a sequence having at least about 80% identity thereto; and / or a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 728, 730, 726, 734, 456, 454, 722, 724, 732, or a sequence having at least about 80% identity thereto.
[0011] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises: a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 727, 729, 725, 733, or a sequence having at least about 80% identity thereto; and / or a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 728, 730, 726, 734, or a sequence having at least about 80% identity thereto.
[0012] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises: a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 727, or a sequence having at least about 80% identity thereto; and / ora light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 728, or a sequence having at least about 80% identity thereto.
[0013] In one embodiment, the isolated antibody, or antigen-binding fragment thereof, comprises: a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 729, or a sequence having at least about 80% identity thereto; and / or a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 730, or a sequence having at least about 80% identity thereto.
[0014] In one embodiment, the isolated antibody, or antigen-binding fragment thereof, comprises: a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 725, or a sequence having at least about 80% identity thereto; and / or a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 726, or a sequence having at least about 80% identity thereto.
[0015] In one embodiment, the isolated antibody, or antigen-binding fragment thereof, comprises: a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 733, or a sequence having at least about 80% identity thereto; and / or a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 734, or a sequence having at least about 80% identity thereto.
[0016] In one embodiment, the isolated antibody, or antigen-binding fragment thereof, comprises: a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 455, or a sequence having at least about 80% identity thereto; and / ora light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 456, or a sequence having at least about 80% identity thereto.
[0017] In one embodiment, the isolated antibody, or antigen-binding fragment thereof, comprises: a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 453, or a sequence having at least about 80% identity thereto; and / or a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 454, or a sequence having at least about 80% identity thereto.
[0018] In one embodiment, the isolated antibody, or antigen-binding fragment thereof, comprises: a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 721, or a sequence having at least about 80% identity thereto; and / or a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 722, or a sequence having at least about 80% identity thereto.
[0019] In one embodiment, the isolated antibody, or antigen-binding fragment thereof, comprises: a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 723, or a sequence having at least about 80% identity thereto; and / or a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 724, or a sequence having at least about 80% identity thereto.
[0020] In one embodiment, the isolated antibody, or antigen-binding fragment thereof, comprises: a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 731, or a sequence having at least about 80% identity thereto; and / ora light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 732, or a sequence having at least about 80% identity thereto.
[0021] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises: a VH comprising an amino acid sequence of SEQ ID NO: 727, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 728, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 729, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 730, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 725, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 726, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 733, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 734, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 455, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 456, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 453, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 454, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 721, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 722, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 723, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 724, or a sequence having at least about 80% identity thereto; or a VH comprising an amino acid sequence of SEQ ID NO: 731, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 732, or a sequence having at least about 80% identity thereto.
[0022] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises: a VH comprising an amino acid sequence of SEQ ID NO: 727, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 728, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 729, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 730, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 725, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 726, or a sequence having at least about 80% identity thereto; or a VH comprising an amino acid sequence of SEQ ID NO: 733, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 734, or a sequence having at least about 80% identity thereto.
[0023] In some embodiments, the antibody or antigen-binding fragment is recombinant.
[0024] In some embodiments, the antibody or antigen-binding fragment is a human antibody, a monoclonal antibody, a single chain antibody, a Fab, a Fab’, a F(ab’)2, a Fv, a scFv, or a spFv.
[0025] In some embodiments, the antibody or antigen-binding fragment is of IgG1, IgG2, IgG3, or IgG4 isotype.
[0026] In another aspect, provided herein is an isolated polynucleotide encoding an isolated antibody or antigen-binding fragment described herein.
[0027] In another aspect, provided herein is vector comprising a polynucleotide described herein.
[0028] In another aspect, provided herein is a cell expressing an isolated antibody or antigen-binding fragment described herein, comprising a polynucleotide described herein, or comprising a vector described herein.
[0029] In some embodiments, the cell is a hybridoma.
[0030] In some embodiments, the antibody or antigen-binding fragment is recombinantly produced.
[0031] In another aspect, provided herein is a composition comprising (i) the isolated antibody or antigen-binding fragment described herein; (ii) the polynucleotide encoding any of the antibodies or antigen-binding fragments described herein; (iii) the vector comprisingany of the polynucleotides described herein; or (iv) the cell expressing an isolated antibody or antigen-binding fragment described herein, comprising a polynucleotide described herein, or comprising a vector described herein.
[0032] In another aspect, provided herein is a method of expanding a population of effector cells obtained from induced pluripotent stems cells (iPSCs) and / or peripheral blood mononuclear cells (PBMCs), the method comprising: a) coating a tissue culture vessel with an isolated antibody or antigen-binding fragment; and b) expanding the effector cells, wherein the isolated antibody or antigen-binding fragment comprises: (i) a heavy chain complementarity determining region 1 (CDR1), a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 451, 453, 455, 457, 459, 461, 463, 465, 467, 469, 471, 473, 475, 477, 479, 721, 723, 725, 727, 729, 731, or 733, or a sequence having at least about 80% identity thereto; and / or (ii) a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 452, 454, 456, 458, 460, 462, 464, 466, 468, 470, 472, 474, 476, 478, 480, 722, 724, 726, 728, 730, 732, or 734, or a sequence having at least about 80% identity thereto.
[0033] In some embodiments of the above-described method, the isolated antibody or antigen-binding fragment comprises: a VH comprising an amino acid sequence of SEQ ID NO: 451, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 452, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 453, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 454, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 455, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 456, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 457, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 458, or a sequence having at least about 80% identity thereto;a VH comprising an amino acid sequence of SEQ ID NO: 459, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 460, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 461, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 462, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 463, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 464, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 465, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 466, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 467, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 468, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 469, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 470, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 471, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 472, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 473, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 474, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 475, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 476, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 477, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 478, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 479, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 480, or a sequence having at least about 80% identity thereto;a VH comprising an amino acid sequence of SEQ ID NO: 721, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 722, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 723, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 724, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 725, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 726, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 727, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 728, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 729, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 730, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 731, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 732, or a sequence having at least about 80% identity thereto; or a VH comprising an amino acid sequence of SEQ ID NO: 733, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 734, or a sequence having at least about 80% identity thereto.
[0034] In some embodiments of the above-described method, the isolated antibody, or antigen-binding fragment thereof, comprises: a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 727, 729, 725, 733, 455, 453, 721, 723, 731, or a sequence having at least about 80% identity thereto; and / or a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 728, 730, 726, 734, 456, 454, 722, 724, 732, or a sequence having at least about 80% identity thereto.
[0035] In some embodiments of the above-described method, the isolated antibody, or antigen-binding fragment thereof, comprises:a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 727, 729, 725, 733, or a sequence having at least about 80% identity thereto; and / or a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 728, 730, 726, 734, or a sequence having at least about 80% identity thereto.
[0036] In some embodiments of the above-described method, the isolated antibody, or antigen-binding fragment thereof, comprises: a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 727, or a sequence having at least about 80% identity thereto; and / or a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 728, or a sequence having at least about 80% identity thereto.
[0037] In one embodiment of the above-described method, the isolated antibody, or antigen-binding fragment thereof, comprises: a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 729, or a sequence having at least about 80% identity thereto; and / or a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 730, or a sequence having at least about 80% identity thereto.
[0038] In one embodiment of the above-described method, the isolated antibody, or antigen-binding fragment thereof, comprises: a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 725, or a sequence having at least about 80% identity thereto; and / or a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 726, or a sequence having at least about 80% identity thereto.
[0039] In one embodiment of the above-described method, the isolated antibody, or antigen-binding fragment thereof, comprises:a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 733, or a sequence having at least about 80% identity thereto; and / or a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 734, or a sequence having at least about 80% identity thereto.
[0040] In one embodiment of the above-described method, the isolated antibody, or antigen-binding fragment thereof, comprises: a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 455, or a sequence having at least about 80% identity thereto; and / or a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 456, or a sequence having at least about 80% identity thereto.
[0041] In one embodiment of the above-described method, the isolated antibody, or antigen-binding fragment thereof, comprises: a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 453, or a sequence having at least about 80% identity thereto; and / or a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 454, or a sequence having at least about 80% identity thereto.
[0042] In one embodiment of the above-described method, the isolated antibody, or antigen-binding fragment thereof, comprises: a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 721, or a sequence having at least about 80% identity thereto; and / or a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 722, or a sequence having at least about 80% identity thereto.
[0043] In one embodiment of the above-described method, the isolated antibody, or antigen-binding fragment thereof, comprises:a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 723, or a sequence having at least about 80% identity thereto; and / or a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 724, or a sequence having at least about 80% identity thereto.
[0044] In one embodiment of the above-described method, the isolated antibody, or antigen-binding fragment thereof, comprises: a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 731, or a sequence having at least about 80% identity thereto; and / or a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 732, or a sequence having at least about 80% identity thereto.
[0045] In some embodiments of the above-described method, the isolated antibody, or antigen-binding fragment thereof, comprises: a VH comprising an amino acid sequence of SEQ ID NO: 727, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 728, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 729, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 730, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 725, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 726, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 733, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 734, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 455, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 456, or a sequence having at least about 80% identity thereto;a VH comprising an amino acid sequence of SEQ ID NO: 453, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 454, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 721, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 722, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 723, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 724, or a sequence having at least about 80% identity thereto; or a VH comprising an amino acid sequence of SEQ ID NO: 731, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 732, or a sequence having at least about 80% identity thereto.
[0046] In some embodiments of the above-described method, the isolated antibody, or antigen-binding fragment thereof, comprises: a VH comprising an amino acid sequence of SEQ ID NO: 727, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 728, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 729, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 730, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 725, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 726, or a sequence having at least about 80% identity thereto; or a VH comprising an amino acid sequence of SEQ ID NO: 733, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 734, or a sequence having at least about 80% identity thereto.
[0047] In some embodiments, the above-described methods may further comprise: c) cryopreserving the effector cells and / or the expanded effector cells, the cryopreserving step comprising: 1) counting and collecting the effector cells and / or expanded effector cells by centrifugation;2) resuspending the effector cells and / or expanded effector cells in CryoStor® CS10 medium (Biolife Solutions, Bothell USA) at a concentration of 5 x 106cells / mL; 3) aliquoting the effector cells and / or expanded effector cells into cryovials, placing the cryovials in a CoolCell™ FTS30 (Corning, Corning USA) container and storing at -80°C for 24 hours; and 4) storing the cryovials in vapor-phase liquid nitrogen. BRIEF DESCRIPTION OF THE DRAWINGS
[0048] FIG.1 depicts a schematic of peripheral blood mononuclear cell (PBMC)-derived gamma delta (γδ) T cell and induced pluripotent stem cell (iPSC)-derived γδ T cell serum- free, feeder-free (SFFF) expansion. Stim, stimulation.
[0049] FIG.2 illustrates an example of an exemplary flow cytometry gating strategy. Gates were applied on all cells and all beads. From cells, gates were applied on singlets, viable, cluster of differentiation 3 positive (CD3+), and TCR gamma variable 9 region (Vγ9)- positive / TCR delta variable 2 region (Vδ2)-positive (Vγ9+ / Vδ2+). Shown are representative plots for expanded PBMC-derived γδ T cells and expanded iγδ T cells.
[0050] FIGs 3A-3C demonstrate comparable expansion outcomes for iγδ T cells derived from Clone 1 expanded with four γδTCR agonistic mAbs (VG9B1244, VG9B1254, VG9B1348 and VG9B1701) generated either as research-grade (RG) (solid filled bars) or GMP-like grade (pattern filled bars) compositions. The antibodies are titled in the bar graph as 1: VG9B1244, 2: VG9B1254, 3: VG9B1348, 4: VG9B1701, and 5: No mAb (white bars). FIG.3A demonstrates comparable viability observed for iγδ T cells expanded with either research-grade or GMP-like grade γδTCR agonistic mAbs. FIG.3B demonstrates comparable purity observed for iγδ T cells expanded with either research-grade or GMP-like grade γδTCR agonistic mAbs. FIG.3C demonstrates comparable fold expansion per iγδ T cell input observed for iγδ T cells expanded with either research-grade or GMP-like grade γδTCR agonistic mAbs.
[0051] FIGs 4A-4B show comparable γδTCR downregulation (FIG.4A) and cell activation profiles on Day 2 of the expansion process (FIG.4B) for iγδ T cells derived from Clone 1 expanded with four γδTCR agonistic mAbs (VG9B1244, VG9B1254, VG9B1348 and VG9B1701) generated either as research-grade (RG) or GMP-like grade. The antibodies are titled in the table axis as 1: VG9B1244, 2: VG9B1254, 3: VG9B1348, 4: VG9B1701, and5: No mAb. FIG.4A shows MFI of γδTCR expression (via staining with anti-Vδ2 mAb) for each tested mAb normalized to no mAb stimulation condition on Day 2 of expansion process. Comparable γδTCR downregulation values observed for iγδ T cells stimulated with γδTCR agonists generated either as research-grade or GMP-like grade. FIG.4B shows comparable expression of T cell activation and exhaustion markers on iγδ T cells stimulated with γδTCR agonists generated either as research-grade (RG) or GMP-like grade. DETAILED DESCRIPTION
[0052] The present disclosure is directed to materials, methods and expansion procedures for iPSC-derived Vγ9Vδ2 T cells, useful for scaling-up pure iPSC-derived Vγ9Vδ2 T cells (for example, to generate a sufficient number of cells to dose patients). In particular, such expansion procedures comprise anti-TCRγδ molecules (e.g., mAbs) which mimic TCR-antigen engagement and initiate signal transduction, activation, proliferation and result in expansion of iPSC-derived Vγ9Vδ2 T cells, and methods of producing and using same.
[0053] iPSC-derived γδ T cells (e.g., Vγ9Vδ2 T cells) can be used as allogeneic off-the-shelf cell therapy product but will need to be grown and expanded to generate sufficient amounts of pure cells required to dose patients. The present disclosure discusses cell culture and expansion procedures that yield high expansion and purity of iPSC-derived Vγ9Vδ2 T cells. In particular, TCR-agonistic monoclonal antibodies (mAbs) described herein are used to achieve high expansion and purity of the iPSC-derived Vγ9Vδ2 T cells. Expansion is performed in serum- free and feeder-free system to ensure feasibility of expansion procedures for product manufacturing, compliance with regulatory (i.e., FDA) regulations and clinical trials.
[0054] Antibodies that are used to expand iPSC-derived Vγ9Vδ2 T cells described herein can mimic TCR-antigen engagement and initiate signal transduction, activation, proliferation, and result in expansion of iPSC-derived Vγ9Vδ2 T cells. The present disclosure further provides serum-free medium that have resulted in higher (5-fold) increase of expansion compared to conventional RPMI 10% FBS media. Generally, it is challenging to find better alternative to RPMI 10% FBS, however, the present disclosed provides a better option that yields high expansion efficiency. Definitions
[0055] Various terms relating to aspects of the description are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art unlessotherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definitions provided herein.
[0056] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a cell” includes a combination of two or more cells, and the like.
[0057] The term “about” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of up to ±10% from the specified value, as such variations are appropriate to perform the disclosed methods. Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
[0058] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
[0059] “Isolated” means a biological component (such as a nucleic acid, peptide or protein) has been substantially separated, produced apart from, or purified away from other biological components of the organism in which the component naturally occurs, i.e., other chromosomal and extrachromosomal DNA and RNA, and proteins. Nucleic acids, peptides and proteins that have been “isolated” thus include nucleic acids and proteins purified by standard purification methods. “Isolated” nucleic acids, peptides and proteins can be part of a composition and still be isolated if such composition is not part of the native environment of the nucleic acid, peptide, or protein. The term also embraces nucleic acids, peptides and proteins prepared by recombinant expression in a host cell as well as chemically synthesized nucleic acids. An “isolated” antibody or antigen-binding fragment, as used herein, is intendedto refer to an antibody or antigen-binding fragment which is substantially free of other antibodies or antigen-binding fragments having different antigenic specificities.
[0060] “Polynucleotide,” synonymously referred to as “nucleic acid molecule,” “nucleotides” or “nucleic acids,” refers to any polyribonucleotide or polydeoxyribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA. “Polynucleotides” include, without limitation single- and double-stranded DNA, DNA that is a mixture of single- and double-stranded regions, single- and double-stranded RNA, and RNA that is mixture of single- and double-stranded regions, hybrid molecules comprising DNA and RNA that may be single-stranded or, more typically, double-stranded or a mixture of single- and double-stranded regions. In addition, “polynucleotide” refers to triple-stranded regions comprising RNA or DNA or both RNA and DNA. The term polynucleotide also includes DNAs or RNAs containing one or more modified bases and DNAs or RNAs with backbones modified for stability or for other reasons. “Modified” bases include, for example, tritylated bases and unusual bases such as inosine. A variety of modifications may be made to DNA and RNA; thus, “polynucleotide” embraces chemically, enzymatically or metabolically modified forms of polynucleotides as typically found in nature, as well as the chemical forms of DNA and RNA characteristic of viruses and cells. “Polynucleotide” also embraces relatively short nucleic acid chains, often referred to as oligonucleotides.
[0061] The meaning of “substantially the same” can differ depending on the context in which the term is used. Because of the natural sequence variation likely to exist among heavy and light chains and the genes encoding them, one would expect to find some level of variation within the amino acid sequences or the genes encoding the antibodies or antigen- binding fragments described herein, with little or no impact on their unique binding properties (e.g., specificity and affinity). Such an expectation is due in part to the degeneracy of the genetic code, as well as to the evolutionary success of conservative amino acid sequence variations, which do not appreciably alter the nature of the encoded protein. Accordingly, in the context of nucleic acid sequences, “substantially the same” means at least 65% identity between two or more sequences. Preferably, the term refers to at least 70% identity between two or more sequences, more preferably at least 75% identity, more preferably at least 80% identity, more preferably at least 85% identity, more preferably at least 90% identity, more preferably at least 91% identity, more preferably at least 92% identity, more preferably at least 93% identity, more preferably at least 94% identity, morepreferably at least 95% identity, more preferably at least 96% identity, more preferably at least 97% identity, more preferably at least 98% identity, and more preferably at least 99% or greater identity. The percent identity between two sequences is a function of the number of identical positions shared by the sequences (i.e., % homology = # of identical positions / total # of positions x 100), taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The percent identity between two nucleotide or amino acid sequences may e.g. be determined using the algorithm of E. Meyers and W. Miller, Comput. Appl. Biosci 4, 11-17 (1988) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. In addition, the percent identity between two amino acid sequences may be determined using the Needleman and Wunsch, J. Mol. Biol.48, 444-453 (1970) algorithm.
[0062] The degree of variation that may occur within the amino acid sequence of a protein without having a substantial effect on protein function is much lower than that of a nucleic acid sequence, since the same degeneracy principles do not apply to amino acid sequences. Accordingly, in the context of an antibody or antigen-binding fragment, “substantially the same” means antibodies or antigen-binding fragments having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the antibodies or antigen-binding fragments described. Other embodiments include TCRγδ specific antibodies, or antigen- binding fragments, that have framework, scaffold, or other non-binding regions that do not share significant identity with the antibodies and antigen-binding fragments described herein, but do incorporate one or more CDRs or other sequences needed to confer binding that are 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to such sequences described herein.
[0063] A “clone” is a population of cells derived from a single cell or common ancestor by mitosis. A “cell line” is a clone of a primary cell that is capable of stable growth in vitro for many generations. In some examples provided herein, cells are transformed by transfecting the cells with DNA.
[0064] The terms “express” and “produce” (or “expression” and “production”) are used synonymously herein, and refer to the biosynthesis of a gene product. These terms encompass the transcription of a gene into RNA. These terms also encompass translation of RNA into one or more polypeptides, and further encompass all naturally occurring post- transcriptional and post-translational modifications. The expression or production of anantibody or antigen-binding fragment thereof may be within the cytoplasm of the cell, or into the extracellular milieu such as the growth medium of a cell culture.
[0065] The terms “treating” or “treatment” refer to any success or indicia of success in the attenuation or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement, remission, diminishing of symptoms or making the condition more tolerable to the patient, slowing in the rate of degeneration or decline, making the final point of degeneration less debilitating, improving a subject’s physical or mental well-being, or prolonging the length of survival. The treatment may be assessed by objective or subjective parameters; including the results of a physical examination, neurological examination, or psychiatric evaluations.
[0066] An "effective amount" or "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount of an anti-TCRγδ antibody may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody or antibody portion are outweighed by the therapeutically beneficial effects.
[0067] “Antibody” refers to all isotypes of immunoglobulins (IgG, IgA, IgE, IgM, IgD, and IgY) including various monomeric, polymeric and chimeric forms, unless otherwise specified. Specifically encompassed by the term “antibody” are polyclonal antibodies, monoclonal antibodies (mAbs), and antibody-like polypeptides, such as chimeric antibodies and humanized antibodies.
[0068] “Antigen-binding fragments” are any proteinaceous structure that may exhibit binding affinity for a particular antigen. Antigen-binding fragments include those provided by any known technique, such as enzymatic cleavage, peptide synthesis, and recombinant techniques. Some antigen-binding fragments are composed of portions of intact antibodies that retain antigen-binding specificity of the parent antibody molecule. For example, antigen- binding fragments may comprise at least one variable region (either a heavy chain or light chain variable region) or one or more CDRs of an antibody known to bind a particular antigen. Examples of suitable antigen-binding fragments include, without limitation diabodies and single-chain molecules as well as Fab, F(ab’)2, Fc, Fabc, spFv, and Fv molecules, single chain (Sc) antibodies (e.g., scFv), linear antibodies, single domain antibodies such as sdAb (either VL or VH), camelid VHH domains, multi-specific antibodiesformed from antibody fragments, individual antibody light chains, individual antibody heavy chains, chimeric fusions between antibody chains or CDRs and other proteins, protein scaffolds, heavy chain monomers or dimers, light chain monomers or dimers, dimers consisting of one heavy and one light chain, a monovalent fragment consisting of the VL, VH, CL and CH1 domains, or a monovalent antibody as described in WO2007059782, bivalent fragments comprising two Fab fragments linked by a disulfide bridge at the hinge region, a Fd fragment consisting essentially of the VH and CH1 domains; a Fv fragment consisting essentially of the VL and VH domains of a single arm of an antibody, a dAb fragment (Ward et al., Nature 341, 544-546 (1989)), which consists essentially of a VH domain and also called domain antibodies (Holt et al; Trends Biotechnol.2003 Nov.; 21(11):484-90); camelid or nanobodies (Revets et al; Expert Opin Biol Ther.2005 Jan.; 5(1):111-24); an isolated complementarity determining region (CDR), and the like. All antibody isotypes may be used to produce antigen-binding fragments. Additionally, antigen- binding fragments may include non-antibody proteinaceous frameworks that may successfully incorporate polypeptide segments in an orientation that confers affinity for a given antigen of interest, such as protein scaffolds. Antigen-binding fragments may be recombinantly produced or produced by enzymatic or chemical cleavage of intact antibodies. The phrase “an antibody or antigen-binding fragment thereof” may be used to denote that a given antigen-binding fragment incorporates one or more amino acid segments of the antibody referred to in the phrase.
[0069] The terms “CDR”, and its plural “CDRs”, refer to a complementarity determining region (CDR) of which three make up the binding character of a light chain variable region (LCDR1, LCDR2 and LCDR3) and three make up the binding character of a heavy chain variable region (HCDR1, HCDR2 and HCDR3). CDRs contribute to the functional activity of an antibody molecule and are separated by amino acid sequences that comprise scaffolding or framework regions. The exact definitional CDR boundaries and lengths are subject to different classification and numbering systems. CDRs may therefore be referred to by Kabat, Chothia, contact or any other boundary definitions. Despite differing boundaries, each of these systems has some degree of overlap in what constitutes the so called “hypervariable regions” within the variable sequences. CDR definitions according to these systems may therefore differ in length and boundary areas with respect to the adjacent framework region. See for example Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed. NIH Publication No.91-3242 (1991); Chothia et al., “Canonical Structures For the HypervariableRegions of Immunoglobulins,” J. Mol. Biol. 196:901 (1987); and MacCallum et al., “Antibody-Antigen Interactions: Contact Analysis and Binding Site Topography,” J. Mol. Biol. 262:732 (1996)), each of which is hereby incorporated by reference in its entirety.
[0070] Typically, CDRs form a loop structure that can be classified as a canonical structure. The term “canonical structure” refers to the main chain conformation that is adopted by the antigen binding (CDR) loops. From comparative structural studies, it has been found that five of the six antigen binding loops have only a limited repertoire of available conformations. Each canonical structure can be characterized by the torsion angles of the polypeptide backbone. Correspondent loops between antibodies may, therefore, have very similar three dimensional structures, despite high amino acid sequence variability in most parts of the loops (Chothia et al., “Canonical Structures For the Hypervariable Regions of Immunoglobulins,” J. Mol. Biol. 196:901 (1987); Chothia et al., “Conformations of Immunoglobulin Hypervariable Regions,” I 342:877 (1989); Martin and Thornton, “Structural Families in Loops of Homologous Proteins: Automatic Classification, Modelling and Application to Antibodies,” J. Mol. Biol.263:800 (1996), each of which is incorporated by reference in its entirety). Furthermore, there is a relationship between the adopted loop structure and the amino acid sequences surrounding it. The conformation of a particular canonical class is determined by the length of the loop and the amino acid residues residing at key positions within the loop, as well as within the conserved framework (i.e., outside of the loop). Assignment to a particular canonical class can therefore be made based on the presence of these key amino acid residues.
[0071] The term "polypeptide" is used interchangeably with the term "protein" and in its broadest sense refers to a compound of two or more subunit amino acids, amino acid analogs or peptidomimetics. The subunits may be linked by peptide bonds. In another embodiment, the subunit may be linked by other bonds, e.g., ester, ether, etc. As used herein the term "amino acid" refers to either natural and / or unnatural or synthetic amino acids, including glycine and both the D and L optical isomers, amino acid analogs and peptidomimetics. A peptide of three or more amino acids is commonly called an oligopeptide if the peptide chain is short. If the peptide chain is long, the peptide is commonly called a polypeptide or a protein.
[0072] “Specifically bind” or “bind specifically” or derivatives thereof when used in the context of antibodies, or antibody fragments, represents binding via domains encoded by immunoglobulin genes or fragments of immunoglobulin genes to one or more epitopes of aprotein of interest, without preferentially binding other molecules in a sample containing a mixed population of molecules. Typically, an antibody binds to a cognate antigen with a Kd of less than about 1x10-8M, as measured by a surface plasmon resonance assay or a cell- binding assay. Phrases such as “[antigen]-specific” antibody (e.g., TCRγδ-specific antibody) are meant to convey that the recited antibody specifically binds the recited antigen.
[0073] A “vector” is a replicon, such as plasmid, phage, cosmid, or virus in which another nucleic acid segment may be operably inserted so as to bring about the replication or expression of the segment.
[0074] As used herein, the term "host cell" can be any type of cell, e.g., a primary cell, a cell in culture, or a cell from a cell line. In specific embodiments, the term "host cell" refers to a cell transfected with a nucleic acid molecule and the progeny or potential progeny of such a cell. Progeny of such a cell may not be identical to the parent cell transfected with the nucleic acid molecule, e.g., due to mutations or environmental influences that may occur in succeeding generations or integration of the nucleic acid molecule into the host cell genome.
[0075] The term “subject” refers to human and non-human animals, including all vertebrates, e.g., mammals and non-mammals, such as non-human primates, mice, rabbits, sheep, dogs, cats, horses, cows, chickens, amphibians, and reptiles. In many embodiments of the described methods, the subject is a human.
[0076] The term “sample” as used herein refers to any composition or mixture that can contain an analyte of interest. The sample may be a collection of similar fluids, cells, or tissues (e.g., surgically resected tumor tissue, biopsies, including fine needle aspiration), isolated from a subject, as well as fluids, cells, or tissues present within a subject. In some embodiments the sample is a biological fluid. Biological fluids are typically liquids at physiological temperatures and may include naturally occurring fluids present in, withdrawn from, expressed or otherwise extracted from a subject or biological source. Certain biological fluids derive from particular tissues, organs or localized regions and certain other biological fluids may be more globally or systemically situated in a subject or biological source. Examples of biological fluids include blood, serum and serosal fluids, plasma, lymph, urine, saliva, cystic fluid, tear drops, feces, sputum, mucosal secretions of the secretory tissues and organs, vaginal secretions, ascites fluids such as those associated with non-solid tumors, fluids of the pleural, pericardial, peritoneal, abdominal and other body cavities, fluids collected by bronchial lavage and the like. Biological fluids may also include liquid solutions contacted with a subject or biological source, for example, cell and organculture medium including cell or organ conditioned medium, lavage fluids and the like. The term “sample,” as used herein, encompasses materials removed from a subject or materials present in a subject.
[0077] The term “induced pluripotent stem cell” (hereinafter “iPSC”) means a stem cell that is established by introducing reprogramming factors into a somatic cell, has pluripotency permitting differentiation into many cell types present in living organisms, and also has proliferation (i.e., self-renewal) capacity. It encompasses any cell that can be redifferentiated into a hematopoietic stem cell (HSC) to be used in the present invention. The iPSC is preferably derived from a mammal (e.g., mouse, rat, hamster, guinea pig, dog, monkey, orangutan, chimpanzee, human), more preferably human.
[0078] The embodiments described herein are not limited to particular methods, reagents, compounds, compositions, or biological systems, which can, of course, vary. TCRγδ-Specific Antibodies and Antigen-Binding Fragments
[0079] Described herein are isolated antibodies or antigen-binding fragments thereof that specifically bind and are agonistic to a gamma-delta (γδ) T cell receptor (TCR) (TCRγδ).
[0080] The general structure of an antibody molecule comprises an antigen binding domain, which includes heavy and light chains, and the Fc domain, which serves a variety of functions, including complement fixation and binding antibody receptors. In some embodiments, the isolated antibodies or antigen-binding fragments antibody may specifically bind to a fragment or a variant of a TCRγδ.
[0081] The described TCRγδ-specific antibodies or antigen-binding fragments include all isotypes, IgA, IgD, IgE, IgG and IgM, and synthetic multimers of the four-chain immunoglobulin structure. The described antibodies or antigen-binding fragments also include the IgY isotype generally found in hen or turkey serum and hen or turkey egg yolk.
[0082] The TCRγδ-specific antibodies and antigen-binding fragments may be derived from any species by recombinant means. For example, the antibodies or antigen-binding fragments may be mouse, rat, goat, horse, swine, bovine, chicken, rabbit, camelid, donkey, human, or chimeric versions thereof. For use in administration to humans, non-human derived antibodies or antigen-binding fragments may be genetically or structurally altered to be less antigenic upon administration to a human patient.
[0083] In some embodiments, the antibodies or antigen-binding fragments are chimeric. As used herein, the term “chimeric” refers to an antibody, or antigen-binding fragmentthereof, having at least some portion of at least one variable domain derived from the antibody amino acid sequence of a non-human mammal, a rodent, or a reptile, while the remaining portions of the antibody, or antigen-binding fragment thereof, are derived from a human.
[0084] The antibodies may include monoclonal antibodies including murine, human, humanized and chimeric monoclonal antibodies, polyclonal, antigen-binding fragments, bispecific or multispecific antibodies, monomeric, dimeric, tetrameric or multimeric antibodies, single chain antibodies, domain antibodies and any other modified configuration of the immunoglobulin molecule that comprises an antigen binding site of the required specificity. The antibody can be a naturally occurring antibody, e.g., an antibody isolated and / or purified from a mammal, e.g., a murine, primate, mouse, rabbit, goat, horse, chicken, hamster, human, etc. Alternatively, the antibody can be an engineered (e.g., genetically engineered) antibody.
[0085] In some embodiments, the antibodies are humanized antibodies. Humanized antibodies may be chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab’, F(ab’)2, scFv, spFv, or other antigen-binding subsequences of antibodies) that contain minimal sequence derived from non-human immunoglobulin. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a complementary-determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity, and capacity. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are those of a human immunoglobulin sequence. The humanized antibody may include at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
[0086] Humanized antibodies have antigen binding sites derived from non-human species and the variable region frameworks are derived from human immunoglobulin sequences. Human antibodies have heavy and light chain variable regions in which both the framework and the antigen binding site are derived from sequences of human origin.
[0087] The antibodies or antigen-binding fragments described herein can occur in a variety of forms, but will include one or more of the antibody CDRs shown in Tables 1.1-1.5. In some embodiments are provided a TCRγδ-specific antibody, or an antigen-bindingfragment thereof, comprising a heavy chain comprising a CDR1, a CDR2, and a CDR3 of any one of the antibodies described in Tables 1.1-1.5. In some embodiments are provided a TCRγδ-specific antibody, or an antigen-binding fragment thereof, comprising a heavy chain comprising a CDR1, a CDR2, and a CDR3 of any one of the antibodies described in Tables 1.1-1.5 and a light chain comprising a CDR1, a CDR2, and a CDR3 of any one of the antibodies described in Tables 1.1-1.5.
[0088] In some embodiments are provided a TCRγδ-specific antibody, or an antigen- binding fragment thereof, comprising a heavy chain comprising a heavy chain variable domain of any one of the antibodies described in Table 1.6. In some embodiments are provided a TCRγδ-specific antibody, or an antigen-binding fragment thereof, comprising a light chain comprising a light chain variable domain of any one of the antibodies described in Table 1.6. In some embodiments are provided a TCRγδ-specific antibody, or an antigen- binding fragment thereof, comprising a heavy chain comprising a heavy chain variable domain of any one of the antibodies described in Table 1.6 and a light chain comprising a light chain variable domain of any one of the antibodies described in Table 1.6. A person having ordinary skill in the art would appreciate, in view of the teaching in the specification other molecules would be suitable for use with the present invention (see, e.g., PCT Int. Publ. Nos. WO 2020 / 227457 and WO 2021 / 173896, which are hereby incorporated by reference).O Q N ESDI 62181420363243F T T T REISTGSN VST SMbDRG V YY ATD HT TCQ TI QPPFV SNY V SRSN Y V Y V ALMP Q S C T SVSNGSVSSVSSSVSO Q N ESDI 5117132925314) 2P P PMbR R R R R R R R DY SSKSNNASNNSNS(MbsACSLLSTATG A G A ASPVE SK GSPVE SVE SecneOuQNqE 0 6 2 8 4eSDI 4 1 1 2 2 304s R1L L YDNDNDND RSD S QYY CrM Q SN S NS SYLSA YSYSY b DDS T S S TG CSSi DN A AA GVV SLTGSDSTGSSTGSG G VG YSGG V G VeALRLG D R VL TD NTV YQR RTV YGTV Yhtdnia n m a o1L2L3L4L5L6L7LseD V V V V V V Vido ObQN itnESDI 3 95112723393a δγ3S T RVIFSY V E FIV Y D YFSD KIF A A KIA KIRC MD D GFV R G Y M Y GTGFD V GFVAGFT bC GI- A H DTY V D DDTG YGEDSNPVIA GDE IDVIA GVIA Gitn a O Q NyrEaSDI 2 84102622383lpS S Sm2eRSxSSSGIG TSSNG G PNTSSSSEMbD CSSDISSYIY NTYNNIYNYN1A HISYIS I IY R N RTIYIW G RTI IRT.I1elOb QNaTESDI 1 731915213731RGN N NSSNNS STH NS SNS SMbDFMTSFMISWISWFT IYISWISW CTFYTFD G Y G Y Y Y G Y G Y A H G A G Y A Y G Y G G G Y G Y nia m1 2 3 4 5 6 7o H H H H H H H D V V V V V V V yd 978 1 4 2 3 7o9938344935444bitB9B9B9B9B9B9B9nDIG G G G G G G A V V V V V V VOQNESDI844506662787483T RST TST T T S TSTSTSTGTYSIMbD V V V V V YYACY S Y Y Y YQP LSQTL SVSSSVSSSVSSSVSSSVS QPQYPOQNESDI743595561777382P P P P P R R R R R R R LM N N N S TbDS S SNSNS S SACLVE SVE SVE SVE SVE SATA G A VSQOQNESDI642585460767281DNDNDN I RSS YSYSYDSN YDSN Y S Y G SALMbDTGSSTGSSTGSSGSSGSQS SQSCGG VGG VGG VTG VTG V A A A Y AL TV YTV YTV YGTV YGTV Y R VALRRSniamo8 901112 3 4L L L L1L1L1LD V V V V V V V OQNESDI541575369657183 I I I I IT Y VLIR K K K K K VAVAVAVAVAV Y DEDFMbDF F F F FG C G Y M W A A G A G A G G VV VGVA A V G G DDG K D A HIGIGI IVI TY D R OQNESDI440565268647082G G G G S RS S S SG SSSNIMbDS S S S SCYIN TIYIN TIYIN TIYIN TIYINSTSIISYIWL TI H A H R R R R R YLD OQNESDI349455167637971RNSISNS SNS SNS SNS SN T V SISISISISSFNTLGMbD W W W W W C G Y G Y G Y G Y G YTFM DSFV A H G Y G Y G Y G Y G Y G Y GGSGniam8 90111213141o H H H H H H H D V V V V V V Vyd 34054624953 0o4 4 4 4 40474bitB9B9B9B9B9B9B9nDIG G G G G G G A V V V V V V VOQNE 0612 8 4 0 6 2SDI 9 52525354545553SRSV G V PLID YLM Y Y DGTG GEDFMbD YGEY G CSSWDFYDFGPMEPA V D GSY Y GQDY FVSDSIY W A D G Y D G DFH DEK D AL QME P FN R OQNE 951127 3 9 5 1SDI 8 5 525353545552R D S SSSG SN D RMbDNS SSSSYSSSG YTSFIG SFINS SACLN GSSPISFISIITSIYISITS SYSYFIY H R Y Y A GISNISD HKEOQNE4 0 6SDI881525225385345405551NT K RSYSS S N N F A R S NSFNSSSASYSGMbDSSD CGA GKITFMFAIFMSTFMFT MFT MFT MLSMN Y G Y GNFAFAFAF RAL T ID GFG Y G Y G Y G A Mniam51617 8 9 0 1 2oL L1L1L1L2L2L2LD V V V V V V V V OQNE 73191521 7 3 9SDI 8 5 5 5353545453S R DYLR S T R G R R S T NTNTGT GGNTMbD C WARSY YLYFLESSDFHQPSKQ PQ YQPY HL FTLYTL LWQPLQQPSQ P QPA H A YQ S QY OQNESDI628185145205365325485452R G T R L L R ST TR R L NMbDTCFINT S S SRSSSSSATA AT T TSTA H R N G A ASQASQA A A G A G A G A VSQOQNE 51171329 5 1 7SDI 8 5 5 5253545451GS L I I S L S L L I RSNYGVGA YSYVAMbDISWQCS SQS LQS LQS SQSYSQS TQS LD Y ASSH Y A A H G Y R V A RNSA R ASSASSASSA Y R N R V A G V A R V A RSSniam5161718191021222o H H H H H H H H D V V V V V V V Vyd 2o89 1 4 2 5 0 4 5 0 31 12131316171bitB9B9B9B9B9B9B9B9nDIG G 9 G 4 G G G G G A V V V V4V7V8V3V1O Q N E6208 4 0 6SDI 9 101112121t 3F T a REIS GTG T N V T b VSDTD HSTaRYY ACQ TQP FV V N S YRSY V KLMIP QPS CNTSSVSNGSVSSVSO Q N E510703 9 5SDI 9 1 1111121)ta2P R Pb tR R R R RaaR bY SSKSNNN(a DS SAT SNSK CsKLLTG A G A ASPVE SK GSPVE SecnOe QNu0 6 2 8 4qESDI490101111121es Rt 1L DaRSD L S Q Y N Y D NSDSN YLSADSN Y CbDraSYTQSSSSTGSTGSD YSGSCSSDN A AA GVVLG VG YS TG ViKLRLG D R VL TD NGTV YQR RGTV Yehtnida n m a o1L2L3L4L5L6LsD V V V V V VeidO obQN itE 35 1 7 3nSDI 99901111121a δ3S T V FIγtRVIFSY E V Y D YFSD KIF A KIRabD D GFVAR G Y M Y GTGFD VAGFCa C GITY VDTGGEDSNPVADIV ATK H D D D YIGEDIG -itn O aQNy4 0 6rEaSDI2989011112121lpSme t 2S E S a RSSAFGSSA G G NSG P N Y KITYNSQK SSYS PNFG P SSN YSxbDEa CSSDKSSY V Y NLYN KNI TK YN K2K HIS IYVSIS I S I TY D R NSP IRTILSYQ IW G A G RTILS.1eOlb QNa ET1 7309 5 1SDI 9 9 10111211NS StN N a R bMM W WHIW DTD Y Y Y a C Y Y Y YSY Y Y K H A N N G N nia m1 2 3 4 5 6o H H H H H H D V V V V V V yd 9 8 1 4 2o7 939 383449354bitB9B9B9B9B9B9nDIG G G G G G A V V V V V VOQNE238 4 0 6 2 8SDI 1314151516161t 3T T T T T T SaRSbDTSVTS S S SGTVTVT T TYYa KCY Y Y Y V Y V Y V LSSVSSSVSSSVSSSVSSSVSSSVSQPQPSOQNESD1I37133149145151167161P P Pt 2P P P R R R R R R R RabNa DSNSNSNSNSNSSSCV V VATKL E S E S E SVE SVE SVE SG A OQNE0 6 2SDI313148144150166161t 1DSN YDSN YDSN YDSN YDSNDSN S YaRbDSGSSGSSGSSGSSY SSY SQaT SSSGT T T TGTG V G V G V G V G V G V A A KCLGTV YGTV YGTV YGTV YGTV YGTV Y R VALniamo7 8 90 1 2 3L L L1L1L1L1LD V V V V V V V OQNE9 5 1 7 3 9 5SDI21314141515161t 3 I I I I IT VaR K K K K K KIYbD VAFVAFVAFVAFVAFVAFV Y D G M a C G A G A G A G G G Y VV V VA GVA GVA V G DDG K HIGIGIGI I I TY OQNE8I24130 6 2 8 4SD14141515161t 2aR G PbDSG P G P G P G P G P S S N YSSSN YSSSN YSSSN YSSSN YSSSN YSSSA G Y K a CYIN K LYIN K K K K KSL YINL YINYINYINSYIVSK H RTI SRTI SRTI SRTILSRTILSRTILSISY D OQNE72339354157 3SDI 1 1 1 1 15161S S S S S St 1NaR W W W W W W MbD Y Y Y Y Y Y Da C Y Y Y Y Y Y Y K H N N N N N N Nniam7 8 901112131o H H H H H H H D V V V V V V Vyd 743 0 4 2 9 3o4445464445404bitB9B9B9B9B9B9B9nDIG G G G G G G A V V V V V V VOQNE470 8 4 0 6 2SDI 1815565757585t 3YaSSSV G M Y Y VGG RbD YLDTDIL PaQTY SGEY G S WDFYDFGPM Y Y GEA QDFVY S D KCL QYP QM V D GSED G Y D G DFPOQNE37977536965 1SDI 1 1 5 5 57585t 2L R D D S V GSSGGK Aaba DTSNS SS GSKSA Y K Y C ASNSSYV STG RSA YSY K IFIKSY VSIITVSY SSIYIAG SSITS SDSSFIYVSKLVQGP SYSH R D Y Y D A G A GISN D OQNE2787652 8 4 0SDI 1 1 565657585t 1IaR GNbDQ AL SY A N NSA S D MMM M M aSKCLA YSRRSGA TGIKIASDYTYNFA A R KYSYSniam415 6 7 8 9 0oL1L1L1L1L1L2LD V V V V V V V OQNE1777551 7 3 9SDI 1 1 565657575t 3aRLIEDS F DYLR S T R G N RbD WTNTGa C A K WADSY YTLYFLYYTLGFTLK H D RRESSDFHQPSKQ PAQQ PYHQPLQQPSOQNE0767450666278SDI 1 1 5 5 5 575t 2S NSG NSR L L R RaR YbDW ITKLTTY NK SSTSTSRSSSa CLILHSPFI T LSPATASASATATK H D R N G A AQAQG A G A OQNE9 5 3 9 5 1 7SDI61715555657575t 1N L I I L LaR G SbDYGVGAS S V W YQS SQS LHQS LYYQS SQSYSa C G S G Y ASSA A R ASSASSK HTV G R V A RNSR N R V A G V Aniam41516171819102o H H H H H H H D V V V V V V Vyd 0728 9 1 4 2 5 2 0 3 4o4 3 1 1 1 131bitB9B9B9B9B9B9B9nDIG G G G G G G A V V V9V4V4V7V8O OQNQNE8 4 6 2 8 4SDI8595ESDI81919102t 3PIaR GLEDFai 3F EIS T T GTGSbDSIa Y W AhtR o DRQ TYYPAV F VTY V KCLH DEFK DhN R CCLMIPQQPSSCNTSSVSO OQNE7I83 QN 595E5 1 7 3SDSDI81919102)t 2N S G DTSaiai 2P R R R RaRbG Y Ka DS FINSYSNhthtRY SSKSNSKCSLISYVSFID D HKK EL oShohD C(CCSLLSTATG A G A ASPVE SOsOQNecNE682ne QuE4 0 6 2SDI 595q SDI81919102t 1Y GesMai 1L S D L S Y N Y NDSNaR MbD A R RhtRQDaSYTQSSSSTGSSY T GSC Y A N DoChD CSSDN A AA GVVLGG V KLN N MrCLRLG D R VL TD NTV Yniiea1 2htniamo2L2L dmo1L2L3L4LD V V na D V V V V OseOQNidNE581 Q9 oE389 5 1SDI 5 5bit SDI 18191023n R a3S V FItR S GaNTδiFhRVI ST Y E V Y D YFSD KIabD YTLγtD D G GFVAFa CQLW oR Y M Y GTG QPSQQ PRhC GITY VDTGGEDSNPVA K H YCTC H D D D YIG O -iQ tO NE4 0nQN2 8SDI8595a yrESDI8184190102at 2R Llpai 2YSYNIaRbDSSNhtR SSS G G a C ATSTmG A VSeohD CSEC HSSITSSK HQxSSSY Y O3.1OQN3 9 e QNE l E1 7 3 9SDI8585 bD 8 8 9 9aS I 1 1 1 1t 1L ITa1NaR SbDQSYV TQ AiLhtRGFSFSSNISSISASSD a CSA YohCTFYTFG G K H R V A RSSC H G A G Y A Y G Ynianm1i222a1 2 3 4o H H mo H H H H D V V D V V V Vyd5 0y9 8 1 4o6171 d79938344bitB9Bo 9bitB9B9B9B9n G G n G G G G ADIV3V1ADIV V V VOQNE0 6 2 8 4 0 6SDI12122222324242ai 3N V T S T S T S T S T S ThtR D HohD CC RSNTVTVTVTVTSVTV NGY S VSY Y Y Y Y LSVSSSVSSSVSSSVSSSVSSSVSOQNE9051127233935SDI 2 2 2 2 2 242ai 2R P P P P P PhR RtR N R R R Ro N N NhD NS S SNSNSNSCCLK GSPVE SVE SVE SVE SVE SVE SOQNE8 4 0 6SDI02122222238234242ai 1LSADSNDSNDSNDSNDSNDSNhtR Yo SY Y Y Y Y YhD DYSSSSSSSSSSSS TG G VTG G VTG GTGTGTG CLGQGTGTGTVGTG VGTG VGTG V C R R V Y V Y V Y V Y V Y V Yniam50 1oL6L7L8L9L1L1LD V V V V V V V OQNE703 9 5 1 7 3SDI 2121222323242ai 3htR F KIKIKIKIKIKIohD A VAFVAFVAFVAFVAFVAFC D DIG G G G G G V AVAVAVAVA A C HEDIGIGIGIGIGVIG OQNE60218142036 2SDI 2 2 2 2 23242ai 2htRGS I I I I I IoD G G G G G GhCNPSSSSSSSSSSSSC H N Y Y Y Y Y Y Y OQNESD5I01217213229225231242ai 1TNSNSNSNSN NhtRF I I I ISISoDT S S S S SIShC Y Y G G G G G G C H G G G Y G Y G Y G Y G Y G Yniam5 6 7 8 90111o H H H H H H H D V V V V V V Vyd 29357434054 2o3 4 4 4 46444bitB9B9B9B9B9B9B9nDIG G G G G G G A V V V V V V VOQNE2 8 4 0 0 6 2 8SDI5252627206061616ai 3ThtRSSSV G V GTYS SM Y Y DGDTV YY IL TD YLY G YGEDFGPMT PohCYP SLS V Q P Q Y SWDFYESY Y GQDFCS S Q S Q P QM V D GED G Y D G OQNE1 7 3 9SDI52526269295501617616ai 2PShRtR R L R YTo N ShDS STSNSDYSRSG G CCLVE SATA G A VSSSSSS SQN GSPSSSSSSGSOQNE0565268 8 4 0 6SDI 2 2 26295061616ai 1DN INT K ShSStY Go S Q S QL SR R YAY S DSFS SFSFhDTGS S S SG V A YSAKITFFIFTFTFCCLGTA V Y R VALA RRSGTGID G Y G Y GFG Yniam2o131415 6 7 8 9L L L1L1L1L1L1LD V V V V V V V V OQNE945 1 7 7 3 92526265SDI 295060616ai 3T VIStKIYL D YR S T RhR V Y DE FDLG NTGohD VAFG C G Y M W A WASY YTTLYNFLYTLC HVIA V G DDTG K D Y D RRESSDFHQPSKQ PAQ YQPYHQPLOQNE8 4 0 6 6 2 8I42526264SD295060616ai 2HhItRYSD N R L L RohD GSNGCSS S TSSTSTSRSATA A ASA ATC H YSSWLTFGQASQG A OQNESD7I43259255265291507603616ai 1NN TGI I S L G G S LhtRSSohDIS FTL SISQ YSQ VLAQLQ YSC GTFSFVSG D ASS SHSYSA A R ASSC H G Y G Y GSG Y R V A RNSR N R V Aniam2131415161718191o H H H H H H H H D V V V V V V V Vyd 9o53400472489 314 125 120 131bitB9B9B9B9B9B9B9B9nDIG G G G G G G G A V V V V V9V4V4V7O OQNE4 0 6 QN6 2 8SDI263636ESDI728282ai 3G PIhtR A Y GLEDT 3F T EISTGhSI FR GAVoD CC VY W A G DRYYP FV LSD DFPH DEFK D N RMICQ TLMIPQQPSSCNTO OQN3 9 5 QNESDI262636ESDIai 2Y)hT 2tR N DES N D GTRohD CTG N G DS S SLSSSSSFMIM C LA G C Y( I L TsG A OecOQN2nQNE8 4 e 4 0 6SDI262636uqESDI728282eai 1SsSStSN N R1D TSGhRoFSFSL TR N A VLhDTFTFSFMRD G DLCLG S D V D N Y CCLG Y G Y G ArMiICL QD YSQYNSNni ea0 1 2htniodam2L2L2Ln m1a oL2L3LD V V V s D V V V OeQi17 3 dO N oQNESDI262636bitE3SDI79275282nai 3R R a S3D G M ThtR GTδTRRIY Y Y G NohDGFTYT NLγ D G C DTD V D D G YGEDPQLQLWPR G C RSFSRTTY V RSE F IC HQPS QPSQQYCTMIH AVIG A V Y D A YFSDF-i OtQ 0 6 2n O N aQNE 2 2 E2 8 4SDI 6 636yr SDI727282aai 2lp 2Y Y R R R LTRSSSSNhtohDSSSSNmC ATATST eG D GIC H G A G A VS SSSS TQxE4MIC HSI ISI IYI TO.1eOQN9 5 1 QNE 1 2 3 lbaE17773SDI 6 6 6 SDI 2 282aiIT1S L S L1NtShRY YVATRGoFSF ShDQS SQTQL TISC ASS SASS SA Y G D ST TMCFYFD G Y C H G V A R V A RS IH G A G Y A Ynian0iam21222 1 2 3o H H H mo H H H D V V V D V V Vyd4 3 5 6 0 7yd 9 8 1o1 1 1799383bitB9Bo 9B9bitB9B9B9nDG G G nDG G G AIV8V3V1AIV V VOQNE4 0 6 2 8 4 0SDI920303131323333T S N V T S T S T T TTRTD HT TS S SG D V N V VTVT TYRMI L S S SY Y Y Y V Y V CS VNGSVSSVSSSVSSSVSSSVSSSVSOQNESDIT 2RG DSNS S S S SMICLVEK GVEVEVEVEVEOQNE298 4 0 6 2 8SDI 2920313132323T 1R G Y Y Y G Y G Y G Y G Y GG D V V V Y D NSRV V V D N N N N NMICLSSY GLSSSY D GSSY D GSSY D GSSY D GSSY Gniam4 50oL L6L7L8L9L1LD V V V V V V V OQNESD1I972932093053113273233TR G F A D G F A G F F F F A G A G A G VIDIVIV V V VAG D GEDGIGIGIGIGMIC G KIRFG KIG KIG KIG KIG KIH A V A A A A V A A V A A V A A V A A V A OQNE096 2 8 4 0 6SDI 29203031323232TIGSTITITITITITR G G G G G GG DSSNPSSS S S SIHI I T S S S SMCY NYYIYIYIYIYIOQNE9859107031915SDI 2 2 3 3 3 3231TRNSTN N N N NG DI FSYIS S S SS T SISISISISMIC G Y Y Y G Y G Y G Y G Y G Y H G Y G G G Y G Y G Y G Y G Yniam4 5 6 7 8 901o H H H H H H H D V V V V V V Vyd 4o42 3 7 3 0 44935444445464bitB9B9B9B9B9B9B9nDIG G G G G G G A V V V V V V VOQNE6 2 8 4 0 2 8SDI334343536346463T T STYSSSV ED YFTRS SG Y WF SYG DT TYY IL TD DMICY V LSY V SVSSSVSQPQPSQY QYPS GSDQRGEM V AGL RM Y Y A G D OQNE1 7SDI4646T 2T RD RDS S S S S S SGSMICLVEVEA A NS ISSG V GSIYSI IOQNE43046425850 6SDI 3 3 3 3 34646T 1R G Y GSYSYA T R ARG D VGISFSD N V NSIDFMICLSSY D Y V NTFIF SGSSGSQYGQSSY A D G Y G Yniam1o12L13L14L15L16L17L1LD V V V V V V V OQNE339354157 9 5SDI 3 3 3 35336463TF F G M W A R S R G A G A Y A WSYG DVIV GVIG D D G K T Y DDR IRE SDG F YTNTLYMIC G KIG KIRTY V RSSFPH A V A A V A A V Y D ALEDFR A DYLHQPSKQA OQNE238 4 033346SDI 353532TITIYTSD N R G GSN GG DSSSSSSTS SMIC W HYIYISI ILI T TFI TA A H G A OQNE1SDI373333493453573336461NSNSN TGSS HTRSFTLGSSNG DISISVISSIC G Y G YTFSFVMID H G Y G Y G Y GGSD Y G YSQYGQniam11213141516171o H H H H H H H D V V V V V V Vyd 2o49 3 0 29 4 4540474831121bitB9B9B9B9B9B9B9nDG G G G G G G AIV V V V V V9V4OQNDIE4 0 6 2 8 QSDI5666667676ESO6N63T 3P MEQD VDSIY W Atc 3F R Y GF SG DGY D GD FPH DEK DIatREIRYR RFPNRR n DRMICLV K V G D AGT PG A A Y A G ALEDFoQCCLMIPOQN3 9OESDI565566167767QN 6)E5SDI63T 2Y G D EtctRSSNSN Dat c 2R T AG DS GSTnatDYR S GS IGS INSo nIYMICLSI ISITSSIYSIYFIo KC(CCLLLSLOsQNecDIE2SDI58654 0 66667676ne Qu O4qESN63K S S NesT 1RSG DFSTFSTFSN TFS tc 1LG M RaD L t R n DDSYTYMICL FNF FAFATFASF RD C o rCLDN W G G Y G Y G Y G A CLG Dniiea8htniamo19L10L21L22L2L dm n o1LD V V V V V a D V OseOQN1 7 3 9id QNE 556o bitE3SDI 65666667SDI633nTT R R R S at3D RTδcRRIG DNL TG YT GFTG YT NLγatD G DTDICYP L L LWPR nSFMHQQYHQPLQQPSQQPSQQo C RSYCTC H AVIG O -itOQN nQNESDIa yrESD2I632al2SITRptcatRISSYG DS S S SS men DSSMIC A A A ATH A G G G VxEo C V C H WSSD 5 O.Q 1O N9 5 1 e QNESDI465667663676lbE16aSDI 31S S TTTR RSSSSSSYStc 1atRMTG DNIVSID Y C V V nMIGQSQS S Vo C A H Y YQYQYQC H G Nnian8i1910 1 2am2 2 2m1o H H H H H o H D V V V V V D Vyd5 o20 134 135 160 171yd 979bitB9B9B9Bo 9B9biB9n G G G GtDI 4G nDG A V V7V8V3V1AIVDIQESO2N78 4 0 6 2 83738393930404tc 3S TatG T S N V T T T R G HS S Sn D YY AVTDT T To CCLQP FYRQPSSCNTSSVS SN NGY Y Y SSSVSSSVSSSVSOQNE1SDI77373389385391307404tc 2atR G A APEPPEPEPEPRYIRYIR G YRYIRYIRYIR n DoYCILSSM KSM NS IN NNSNSNSCL LALGLVVLKMLVMLVMLVDIQEO0N767288 4 0 6S 3 3 383930404tc 1atR L Y Y Y S Y S R Y S Y N G A S Y Sn D CS VV Y G V G V G Vo LSW GLY G Y YYY Y Y Y S G Y G Y G Y C A A V N W V N W W V N W V N W V N Wniamo2L3L4L5L6L7L8LD V V V V V V V OQNE965718783 9 5SDI 3 3 3 3939304tc 3G M Y T F F F FatR V Y D G G G D N G V A D D G G G V A A An D D o RTYEPIGE IGVIGVIG CTY RSE FFDSDFG K RFG K G K G K C H A V Y D A Y A V A A A A V A A V A A V A OQNE8 4 0 6 2SDI6373838398394304tc 2RSII I YYINTYIN WG YINYINYINatSR RTSRTRTRTn DSSSNIGI I Io C VGIGI GIG MNPNTGIGGIGGIG C H WSSY WTWSSW N Y WSSWSSWSSOQNE763 9 5 1 7 3SDI 3737383939304tc 1WHIW W WatR M D W Y Y Y Y Y n Do C Y Y Y Y Y Y Y Y C HNSNSSNNS SGTNS SNS SNS Sniam2 3 4 5 6 7 8o H H H H H H H D V V V V V V Vyd 89184 2 3 7 3o3 34493544444bitB9B9B9B9B9B9B9nDIG G G G G G G A V V V V V V VDIQEO4 0 6 2 8 4 0SN14242434344454tc 3TatST T T SYSSSV RS S SG Y DT T T TYY ILD no CCY Y Y Y LSSVSSSVSSSVSSSVSQPQPSQYGSQYPSQM OQNE319415421437 3 9SDI 4344444tc 2atR EPEPEPEPG A VQGPnYRYR R R RLR DI IYIYIoYC M NSM NSM NSM NS IYL SS IYL TS ILNSCL LVLVLVLVLALALNDIQEO2 8 4 0 6N1412 8S 42434344444tc 1atR Y S Y S Y S Y S LAn D G V G V G V Y YLY D W o G Y Y G Y Y G Y Y G V G Y YSSW Y Y AKICCLV N W V N W V N W V N W A ARSWGID Yniamo9011 2 3 4 5L L1L1L1L1L1LD V V V V V V V OQNE117132925 1 7SDI 4 4 4 4344444tc 3F F F F G Y M W AatR Gn DVIA G GVIA G A G A V A W GVIGVIG D D G K Y DD R SSDo C G K G K G K G K RTTY RR ERSS FC H A V A A V A A V A A V A A V Y D ALEDFA DYLOQNE0 6 2 8 4 0 6SDI14142424344444tc 2atRYINYTINYINYINSII L TFRSYILHIT n Do CGIRTIRTIRTI SIGSR N C H WS GIGGIGGIG VSALD NGIG S WSSWSSWSSWSSY W WIWTTN OQNE9 5 1SDI041427423439435444tc 1atR W W W W M W D Y Y Y Y D V Y Y YGSG Y no C Y Y Y C HNS SNS SNS SNS SNSNTTV GGSNniam9011121314151o H H H H H H H D V V V V V V Vyd 054 2 9 3 0 2o4644454047483bitB9B9B9B9B9B9B9nDIG G G G G G G A V V V V V V VDIQESO4N80 6 2 8 4 06969607071727tc 3EatR WDFY F Y P M Y GEQDFVSDSIW H A D DSED G Y D DFP EK D n G G D No CCLR AGLR M R Y K A G D V G D AGTR G RFPR R A A A G ALEDFOQNE38985910703 9SDI 6 6 6 7 71717tc 2I I I IatG I I D I RSSDHSRYSSASG SSNSSN H E Dn DSoCVSFIVSSYSIVSYIVSY VSTFIV GFIALNSCLWSSY WSS TWSSY WGSTSWSSY WSSY WSFKDIQEO28884900602 8SN6 6 6 7 71717tc 1atR AMSN A A R n D Y YNFA Y Y A MoC TAR KNSY A Y G CL SMSNSMSSMSSMNSMNSMniam61718191021 2oL L L L L2L2LD V V V V V V V OQNE1SDI87683699695601717717tc 3R SatR T R R R S G N n D YoHLYNLG YLGFG YNLCF YL LWQPSKQ PQQ PHQPLQQPSQQP QPC H A YS QY OQNE0868298940016SDI 6 6 6 6 7 717tc 2A A A A A A TatR Gn A A A GAG A G A V D o CYIY Q Y Q Y Y Y Y QLC HLRILSSLL ILTSLL ILTSLR ILRSLRILSSLRILSSLLNSOQNE97581 7 3 9 5SDI 6 69696070717tc 1AatRLVLALALALALAn DY YLo CSH YYSYNY R YSYYSYTY Y Y C HSWSW N WSSWSSWSSWSSWniam61718191021222o H H H H H H H D V V V V V V Vyd9 o14 2 5 2 0 4 5 0 11 131316171bitB9B9B9B9B9B9B9nDIG 9 G 4 G 4 G G G G A V V V V7V8V3V1DIQESO2N54 6 84545454WSDIK LK QQEPQQQH A LQEYGQQLniYLYL SIYGSaTTFW RWS TINSIWS Tm GDTALT VoL LLSVLdDGN YSeDSYASTSTFY NANTlSGK N DSIADGGLY G NbaLGEir LSVVT SV SGVTGGS LaSFvQRKTQSKIDKSGS LVKV SSD NG KTDS SGTSDPGA V GST SF GS SLniR VQRKaC G GFCSSF TGRGTGFKTRG TCNGR FcTGhSISTILTDQS SIVCNSGtSAhA RPFA PIGIT G VSIVGP YRG FT ISPNTIGFgil E SEIDTYSGdLQRT S SPV PTRV Q G APPGKTY PSRS PS T QRSS G G G ANS TnaVI)PLL MLCL SYS S SPA GGSAFSSTYI SGSVEYHSLQPYILTGYQVSCCV YI S(GYIMSSV SGQALY sPS QVPSLL CP KYAPMCLYni ei Q GPDEQ RYQ PDKYad TKT PY VTLAQPD KAE Tm o ModbitL V VI Q AEL EMSV VQV Y RI AEGP FDA GQPDELA E KAEH ASSGPDEenlaba δirγnia a R m1 2 3 4CoL L L LvnTD V V V Vi-i athnaDIcyyQO1 3 5 7vrESN5a4545454ealhpfomeA RVA W D C T SGTIV SGISsxCELSIY YLASCELRSHGVSQTWTR V AM TWTDecefSLGTFVG SLGIY T V GCTED LIS C T CYG T GLVneo R K )GRAGT QK G RG FRATWL Q L SVSGMTY GSGMuq LLS PD LAKEWS PA GDLK VLKTEDTG VA WITG VesVG (GQV P RSA Y G ERDG QK RVA MEA GS P RS T EA D DS RSdK VALSFS P SRPK V DLY KQKLAFT PPKQKicVLaLWF INDG MVLW ASYRIY N YVLSPATNRP VILSPGIRMYQIN LTG MYIM Y W NVFWDGPNSFSGP SN o GTSSYSG D YQLW YTW YniG YVIG YS TTG NLGGY NmSEASSLSSDSENSYSYTSLSVS EY NKLDSSEYTIA VGF IN6L SG K VSSG DFSN VS QLSSGI SF E QYL NSG S.QT1HeVVF SS L TIVV A RS Q FSK DT QIS TY H YSS QIS SY EGSN W DACVTVEGS SA R V N AVTVQG AIRN KGEVTVQG GIlRbaTnia m1 2 3 4o H H H H D V V V V yd 9 8o71 49938344bitB9B9B9B9nDIG G G G A V V V V0626466684 4 4 464P EQ QLQLQ QLQ QKAL QQQ Q Q LQQA YGSGIYSIYGSIYGSYGTWS TLWS TWLS TW ILS TW VS SVSVLSRITV YAY Y YALSNTNATNATNATY N N N NYSAT LY G Y Y Y GSGGSGGGGR DVTGKLGKLGSKLGSKLLSGSV VDSVDSSGTVSV V V V V VDSGTS SLDSGTLDSGTLGSKQGTS SGT FK S SFS SFS SFCSFG G RT TRKT TRKT TRKTTNG GNG G TNG GNGTIRGF C SGTC SGC SGTC SGR DVPIVSIV GGSFSVGFSIVGFSVGVIGSVGS IVGS FVTQG VTIS HSQPRVTISS PRVTISSQPRVTISSQPRVGPN R GNT QGNTGNTSGNTLGA NSPSSTPSSTPSSTPSSTVN NSVESK DGSYSVEYSVE SVEYSGS SGSYSGSYSV GRSVISACYISCYIS YISPYINSMYVSM VYSMCVYSMCYDVCALQLY YP ALQKPDPKPY ALY ALY DP KPDP KPDTVYTAA QTAAQT AAQT AALPDEALKEKE LKE LKEQAEAG LPDE EGPDEAG DVG DSSG DSQH AYSHSQ P ESQ P EA H A H A5L6L7L8L9LV V V V V95163 5 74 4646464I IK S V V T SGISSGISI SGISC ELVA SSTW DAVTG VTG VTSVGR Q GTDVT CGCTLVSSYSTVCW TGDACTW DA TW D LVSYSCST GCLVYSS CGLVKQFDVLGMYT LG YLGSTL SASGP SLTSLKTV G V VSLKMTVVTSLKMY T VVTSG KMTAA KQQRLG TEAR ASTMTTEG A VATVTEG VATVLTEG VGPRASRS QGSPPQD K AG S P RSDMTSA PRSDMTA SP RSR VNK WTLEYWIKRVI L Q PSPAQTG KE IV RIKLA AGP QT QKKV RI LA AGPT QKQRIKLV HMLW V WI LSPGLSPGV SPA YGSYDFGSNSWW YS A GSNVSWIG WSNVSWLIWGSNG YNS GPVTAPSID DGSY NL F PYTIK AGW Y S Y NSLAPFGW Y S Y NSLAPFGW Y S Y NQ TNILG YTIK A YTIK A YTIVFTSWT ERQQNSG SSSLKEVQNGLSGEQNGLSGEQNGLQY G DACLQISYQGLSQISSSLQKLSQI SSLKLSI SSVGQSMRTTY W M YVGIN QGSRVIGKSGVQG Y VSGIRN G K VVQG YQVQ SGIRN G K VVEG Y GIR5 6 7 8 9H H H H H V V V V V29357 3 03 4444454B9B9B9B9B9G G G G G V V V V V07274764 4 474QQQLQ QLQ QLK EGQGQQQ PYSWSIYSYGSETWSITW ITYLW RVLSVLS SVLSA SIYNATY NATY NALTYTLY N Y N Y NSSTFGGGS LGGS LGGS LADTVKG V VKG V VKVVSGDS SKSGTLDSGTVDSSGTLQSSIESTSFKTSTSFKTSTSFKTAGSV GG RTCNSG G R G G R R G GT NSGT NSGCSSFKTRGSIVGCS VGCS VG LTDQGS F IVGS F IGS FAPIGTISQPRVTISSQPVTIRV SS PV R R V DG FTTYGNPS TGNT QSGNTG APPSSVTEPSSTPSSTPSRSYSVEYSVESY LS SGSYSGSYSGSYS SA GVISSCVISCVISCLTGYAMSMSM YQLYLYLY GIP KY A K Y A K YPSLLQCQ PDPQ PDPQ PDQTRYTLAAETLAAETAAE PY K KLK MSVAS GQ PDEA H AS GQPDEV H AP GQPDEVI QAH A DGP FD0111213L L L1LV V V V96173754 4 474SVGISI S I S I GGISGGISG A W D C TTCWTV DA TCWTV DA TCWTDA SCELRSH YGQT GLVCSYS T GLVCYSST GLVCYSSSLGITV GLSGLKMYSVLS GSM YVLTSGSK M YVRG FRATW VTEGTVT LKTVLKTVTLPVAG VAV G VSA GDEDSAPP RTVTKQ SDTETSA PRTTS DMETSA VAP RTG K S DMTG Q VA M K AP QKAP QKAP R SR G V YV RI LLA GG W ST QKRI LA GK TQRI LA GK DLTQW ASYP S PNVGVLW SGV SGVSPVLWS PVLN Y N Y M Y YSSWIGPN YSSWIGPN YSSWIG G MYIQDG WSY NLAFG W Y NLAFGWQYTIKSY NLAFG D Y YSLYTTVNLSGLASEYTIK L AEYTIK L ASENSSLVSQISSSG V G SLQKNSVLQISSSG SLQKQNSG VLQISSSG SLQK VSF S SG NSVL T SIV KVG Y N G G Y N G YQ FSSDTVEGIRK VVQGIRK VVQG GIRN G K VVEGSA R V N AVT01112131H H H H V V V V462 9 34445404B9B9B9B9G G G G V V V V8708224264 4 7 727P L SSKDEQA Q FSY RSQL VQ Y LSQQPQLQYLVLSVTRS TRSV VVTL W G W N N V N K V W KLW K VYSTIA ILATTWS KIA M A NTN N A NGTQM NALTDLA DG MSGYLYSLYRQDGN DQG YR F RGRTFD V S VTSIRSIW KSISWIEAGTGTIG T SFTWSFTFYSFTFV SLTFY FIFRDFTR DQ GS SNAGSK KR T GDFGG YFG M SSS SGGSK GSK DGK GSGR G A A GKIGVSL VSM VASYC S E GTSFG ACDEACD GAD YT F LF CRFVTRRT SSA WAV YCIDPVLY DLYSESLAGYPYVSPGTV Y RFIR R YIR RYIGR VQV GG LSYACLS TA LSY RDGS SRQSP SGDGRS CGSSVGFMGSY G YCVSQL TR YGPN SS PYSYG SY KSSVPQ SVP SATS PASDV SIA SIAKSIYISLA Y SFIGSN GYS LSTELHTVGS S LYSATSV V VDYEG VDG V ILQS YIQCG W GEDW GEPSLPLLY G EARG EDRG W E AQLQCPTNYQYSE LL SE LL SE LRT KPD V GS LMPN V GSV GSIAYT LA AELQKLQK NLEKV VTGMGMGMIER GAFSQGPDEVE PAQLVE P PAQL SVEAQL41516 7 8L L1L1L1LV V V V V779 1 3 5474272727SFW S DCSGIT R I L F AY TGY TTCEFLK YVTV T W DACVTA RLLTFTLRI LF AC L TT R ILLTTATIA VCLKT T DLVSY V LCSRPDTPS T LIFF CLKDP TKFET GLATMT LYTS GMVG LTART PQGSG V VTASITPT TL PRDT PSV GQ LKTT G VAT QA RGGR GPGSY KSN V KGY RSQ QKPGEARDEH DG GSDGPGT R LDS PSA W G KGSQGPK GSP I SWKI P QKYP QCVK GQCK G WPM KLAS QFYSQ SFVSQ SFVLGSV YNITDFV RILYSP TDVFLSYRD Y AQYQVSY RASY RTPGTM A NSYW V HTLDRGPN W YTL LALTPAILG ALSTFKSSWPYTSVV ALFWPA VGSG DGYNTKS GDI PLEGVSSN VLP LGVE SE Y NLS PSYS SSA REEPVSHSDEKIDSYSKTLTTLWL QWQGISGS QTF S QDSSSELKT TNQL N KL SLPVQRQT NLK DQISTQTN WLVSARG MIGTS QLKT L IGTSV SQ FALSTR SVQDFIV RKSR S I QGSIGQIQASSG QIQA G A GE S E SYTG DSAI PDSA4151617181H H H H H V V V V V0728 9 1 4 2 54 3 1 121B9B9B9B9B9G G G V V V9G V4G V482032347 7 737QLTSQY V VRLSSQRL RIV TRTVSSW VV N V NTVSQW KS SV W K V W N KVTNSKMTNLTA ALTY A M VS GM DGM N DGM NLGTTM DQA RQAQA GYSFIGYSRSG YDRR NKSIGQASWISFTFWTRPSFV WSG NITDFGDFT TFFYFTR DTFWSLLFFFRY SRFAGSK GGSGPGSG KEN KDRAVSGTA K V G A AV FPGSL LADEASASG VSTECAQCDVS CD SITC SWSLY DSL AD SSLY HT YK Y K YR L SNRRFRFID RL TS SACLS IA LY RTLKEG G Y G YCYSDACATDCGGSY GNSG Y N YENSYPQG V ATSSVGPG Y TPYTIATKSIAKSSLKFIVLAGSDEVLSTVL IATVHATGSDESGSDLALDG V A G VAG VEVPWVGPSW R ELG WRG WARGELDEL SSLNEELLSSNEELLSSEA M G V G V G KLK M K K N KNTQLV GE PQL QML LGPHQGPMTGA YSVEALF SVEAQLVPMSQPQTL SV91021 2L L2L2LV V V V729 1 37273737A I L F I I A I L F L FTGRLCLTFTLGLLTFTA L RLLTFTLARYISR LLFTLPDTPLCSRPDARL ATPSCSRPDRL ATPSCT LTFRITKPETWPTAQGSGTG Y AQGSGTF AQGSGYEGY V A R KGS SR GP SHR GPGS QRPGSNG K GESQCG KGESQCG KG QSQD GGPRSLK GQPSQQ FLR YP Q F P QQF CFV S QSY D YS QL YRY D YSL YR SQF CD YAQR YLWTPAIVSWPIVSWPVSYSLG AFKLTA G AFKLTAILG AFKLFWPYVTGPYTDIEGLPYTDIEGPYTDIESPALGSAFKSSAQSREPVTSSSALRQREPVSTA Q REPVSQYSELKTSSSSELKTSSSSELKTQDIETSSLEPVVVISATRSGLVSATRGLVSARGL IN VS QLKTEQSG YITG V GIEQSGSYITG V GIEQSGSYITGQIG DQS TVSSGQ91021222H H H H V V V V 034135 160 171B9B9B9B9G G G G V7V8V3V1DIQE O2 4SN8484WSS V DIIFK VQLECQ EPLKLSAQEY TPA Y N YLδT FA Rγ NDA D V W KA SIR GTDG VV T K HLYTLCTDS-SGR KWiQKESSTFtDSGIEV Y D ADTnLaLSSFV K AVSGRKTAEKSSQyr QaSlSDPG RSPLAGSpR VQYTR G SC GmS SGF FLTCS FReISATINSNSLTD xeA RPfPoEYF LL PSEILSCYC AR I)GLTRQVTEGG DTVSG A D R RCPTYLI(VMSNPSPCKSF SSLLLAYTDSLSAniS QPYIGS QKTLTGaLPSGKLETV P GYPIhc S QV GD QV SSSSLLthQT P E E E LQ RK DT PgilMQ AESPQSGQMSQdCVLV N V LIEY RPFGH I GnT E Pa)CniH(a1 2shCLCni eaiCLdhocbiDIy tnQE O1 3vaSN8484eahfA R YVG TEE G SL S DF V K A W oTeCELSIYLAG GSVcSNPPD V KT P LN GSSGTCELnL FVGSNSSATV PPR YV NSYYFV P GPSSGeR Ku GRAGT QTSGK WSLSKCPPSI RW Y VVKQGPQ LPKTQ S LR KqLS P SYH MN TC E TL L GPesGAKDEW Q VS VT LG NCTLF SN K RVLK WSKSA S A YPD VSVTK NHD VY Y PQCYRNSQGQdGPR VERLF ALPE SCI TK EQ E TK GNKTGP RicKAFSI SPFPFQLKP PEEG KLS ED Y V H K V aVLW G NDIM V Y VYTDKPDER NAV PQTNVLW o GRniY GMTQISSPDAPQ CTSPFHS P LKS QN GLHN G M SLTYSG KFK PLVKTWITKNKS LG D m G S YS L VIK V LTGHL E FD KDQKTSEYAEG YAEASSSD NTS CVSSV V S V AHEIM WLFHSEN7VG.F I1LQT SG K K D AGLG SPKPV NL PEE EFSM VSFelCbHVF SA RSSASG V H V T D A GRV GVSLQTFEGV S N W DACVTAT LVTV A V KL CLTVETLPL SV V V APPAIDDSCSVEGSaTniah1C2CC H H yd 9o78993bitB9B9nDG G AIV V684SPS QPFNH QQQT K T VIFGT LVVQSV YGSSP PSCSVE WSITASS QP L CA AV LA D SYK ASA YLPK R NA D V NAK YT QHSNGWVTV H NLA KR K GGKIW KQEVSVVDKSTTWL VQD Y V NKAEPV DKK ASTGS TG TTAGEKSGFGP LQRPLTTRGSC NYF LSIGFD YGF YT FLTSIVSISSNS TIG VLA SSPNCAYSR VPPNLLS QTGKTLY KSCS LCYCEPSSGTA NESG VTSGG A G AFK N STPY VSDRNSYI SC N AQAQQCA KTSFDSVSAMCLYQK LS VPTYGS QK PYKEYETKVQ PDEETTVVKL TVPSTLAAF EV KESSTPETSA QSS DPVGDELGA GP EH AFGEDQ Q LA H 3 CL584D C T SSF SRNSN P DSHGIYQTSTW LAPV KLTSPDLV K VGISTR V G SS GV PTV VNSY V N G PTWA MTGSSV GKS PR Y R KCSIVV YFPGS CEDIC SNSFRATWSVTYLHPPW YKQGPQ LSTL L SYGQTSW LSGDVSPM D V G NC NFTS CPKTT QL SGMA P STY GKSYS VTLTK N KERVK WS LK VSG VVT LKEML ENHD VY YESPLYRSKTEAR ATWISPV GVA R GPFPFQLCI TKK EQKQCTNQTS PSD DA P SSDLY V Y VYP PEEG GL NK D YP QKAFT L EQASYSDATDKPDER NKS EV H KRI LANPFPF LY N YPKPQ CSP HP LAVQPQTNVLSP TPFV Y VYIM Y G VFT TKF SKWKSN GLHW G N NVSF SPDAPYQD K TLHGLPELFVTKD INKS L PYTSG KFSLTT S CVSV V D AQ TKTSYAEGSW YNLG K VTSY V AGLGSKSPV V NH KEMELTH Y NKDT LCHSSLSGSSASSPKLG V HIPE WE FEQSGLSE SVSIN VV A TLVDC VV AEFSMLSI I SFY AGLGSSSK D A RT TATVGVL T ETLP RSV GVS Q S TY H YSSATT GGSVKTLEVVVLP AID C VGING V ALV N A G VEGSAPDS S QARKE T TA 3CH 1 83B9G V884H A E QPQQFLG LHT ATYGSV KVW I S VP QS T PVS CSYLSASA D Y NATK ASYPRK G NQHWSGGSGA K V DKLS SVV WTT QS G TSLVEPGFT RKTATCNGGP LSSGSLIVYFY TIGGFD S VSISSQSPVLA G RSCA PSNS TS V YSTLKCG VE TNESYSA NTV YIKSPSSCNQA APMLY KVYAQSTQTKPDLPKAETT ELEAEESSTV K SGPDESP ETSV G 4 CL784E G SL S DF K SGISI TLTGK F SIPD V KT P LV G VTGS CHLPELFV TDTTVRNSYYV NPSTCW DACAGVSD KQKESYVI RVFPW Y VQGPG QLSTLGLV SS LGS SV V V AH IGSY ASPKSPV NL PML NFTSKCPEKTTVT QK WLSSLKMY T VVTATTLK G H V A K N K RLYRKTV G AVTD G VV TLPLD VY YEPQCTNSQEG A VARTSM GSGSV V VK L CLT EVVSAK EQK G KTSPPQD ATT NSTE VEG V KP PEKG KLSNED Y KPDE ER KLGS SNPPD VNSP RFHLS PNLAVKQPV H QTLNVILAW SP T QGKSWSLVSSPATV R V KPCR Y YFVKSN G T W DITKTNKSSHLGP SNVSW SP TYLHSIWKCW YSIV G NPPMN TSK YA GY NLAFALP SVCFNV D KQKSE E E SYTIK APE SNTLTKY YEPV A V NHLIM PEG V H V AEW LEFHEFMQNSGLSGFPFQ HD VQK R VSV LQISSSLQK V SPYLCI TVYKKPEPEEGGL CL TVETLPL SPPAIGSD Y V D ATD KD R NLSCSVQGIRN G G KPFQTC PE PV V V A D G K V K VS PH K W 4CH 4 44B9G V094P E T K T KAVVQLS VP QQAPS CSYGASD WTYIA ASRTK P K R ALYS QWHSYSATGLA K V R DVT TWS VQLGSVES KAPDTGS TGP LQ G G CSFGYFSLTIRGFD Y R DSVSI SVPIVLA T G HCV A QSPN YSGLRG LSTKCA NEA N N V N K NTPSK D NSA GRAQVSAYIN QKVLSP TPDVCLYE KETT EQVYS TV T LPDS ETSEASS QAEPPV GGEG DFLA H 5 CL984KTN S SAEK S V E YC ELVA SL S AGSS V V D KD ITKN SAT SPKSPV AQ TSYEMLHSGR GTV AT LVK G V NHLKEMELHEFEWEFM VQDTSV KG QFDG ATD G V H VIPE WFM S VGV VL CTVETAE EFSVRSV GSPPAIDCAS PLA KQRL TGS SVKTNSS T LELPVEVP RSV GSCGVLP AILDSSSFD V K AQGGGPRASRS Q SKWN SLSSPAPTDSAPV DDSSFKL SV KT P LNPVN LGSVKPCR V VNT PDLN GYV YFV GSRT EW STYLHSIY RSYYV GPSQGPPQQLK W SVY EHIMI PV G NPPW Y VVFPYDFALP S CMN TQGPQQLSPEKTVTWLSA YGSAE SVTLT F SKCPKT LSK YN VTPDFPFQNHD K N KEVTWRLKRQ SGGPSV YLCI TVY YRLKRSKP CYQTSQ TNI ID SVYKKPEQ EP CYQGTN KELPDP Q TKTSNED Y VFTSWTRATDEK N Y D G KPQ C KPDE EG GLSNDK V HLAV AVT SKEV H QPQTLNQY G G MRT CKFTSLC TG KPFH RPNLAV P TNKSN G KHLVQSTY H W M Y A G VLSPELF SVKTWKS Q Q LN G KHL5CH 2 93B9G V294494FQ Q LG EQF G EQ LAH QLLAHYGTSKT Q TKTI V SV VQYGSIV SV VWS T P PVLTSAS C WS P PSQCY AS SLD Y VSA AS SD YNATK P ASY R NATK P ASY NQK Y N KRGGWH GQWHGSGVKLASG K GSGSKLA KDSVSGTVVTWV QDSV S GT VLTWQSTSFVE SFVERKTA GPS KA TTRTGPG GP LG GPTT NSGT NSGLCYFSCYFSSIVGLVGLTIGS FD YSVSIISSTIGS FD Y VSISS PVL S PVLSQ RST CAQ RST CAGNANAPSSSV VTGELYSGSSV TLYSSYTKCYEPSVEI SA NYTKCT GESYI SA N TVSSCK N NSPV SCK N NSPM YQASMQAALAPQK VLY AVP Y DQK LSTAPKYQK STTLA KAEEPET KPT EQDLVTAA EPKEL KE ETTVAS GQ PDESST TEG D SST TH APP E S P E E SV GYSH APPV G6C7LCL193494IV T V E F KD INASGISILTW DAAG SCSLGS SV V D AQ TKTSS YEV WTGTS CCGTLVSYSALG YVTATT SLPK V KSPV N VHLKEMELHTCDACAGLD G H V VIPEEWFEFMT GLVSYSSASLKMTV G V V G ATV V GC VETLARVSV SLS GMYVTATEAA G K LTVPSGC LKTVTTM GS SVT LVLP AIG V GSPP RSQDTK AG TNSSNEPEGVSAPDDSSFKTEA VATGQSW L SAPD V V KLTSPDV GSPP RSDMT SKRI LAGKS S S PKP TRY V RNSYLNPSKQKLAG TSV SLWP TGSNV WISPVTYLHCPPSIW Y VV YFV Q GPG PQ LSV RILSPAT QGKSPW YSAV G N MNFTSKQWSV SNSLAF LPESSVCTLCPEKTTWLSGPNSWI PGSY YTIK APFP QNHTK N V K RVLKRKGW Y NSLAFALQGF LCI TDY Y PYS SYQNSGLV SSKSYEQ E QC QTYTIK APP D VYTKKP PETEK N K G D YEQNGLSGFLQIS SLQV G KAGYIN GPQD KDEG KLSNEV HLSI SSLK V SVIK VFT TCSPPH RPNLAV P TNQ SYQVPVQGSRKSTSLCGLKPFL SKTKS Q Q LHLVGIN G G G G H V W N G KQGRK V K6C7CH H357444B9B9G G V V694QQQLF L G E AHGTYSKTWSIV TSPVPVQVLSASSCSYAA K D Y NTY NPA KSRGGQHGSGLW ASVKSVVK DSGTTWQSTSLFVERKTA GPG TCNSGPTGYLFSSIVGF LTIGSD Y V SQP SISR VSSLA NT CG V A PSSSVTLYSGE TKCSYYI SA NES K NTVC PSNSA AMLY AQPQKPY DQKVLSTTLA KAEEPET KTEV A SG D SST TQP EH APP E SV G 8 CL594THGK P F S TITKN SAS I T E VGISTGT LCHGK F S TVL ELFV KDQKTSEYTWASVLPELFV KGSSSV V D AEMLH FCGDCAGLG SSV V D AT SL PK KSPV V NHLIPE WMTLVSYSSASKSV N H V AE EFVSVLG YSV A TPKPV HAVTD G VGV GC VETLPLRSGSSVP AIDCSSLKMTGTVT T LVD G V VAV G ATV GC VEVKNSTLL TV V GVSAPDS FKLKEATTS DV GS P RSDMTGSGSV VKTLL TV V GWSNESLSSP ED V P APPTV VNPSYYLN V GPPSKQATNSRY R VVFP L VIKLGS AT Q SWSNESP ED APV GKS SLS PPTVTYK L HCR PSIW Y TKQGPQCPKTQ SLLSG WS PNVSWISPVTYK L HCR Y PSIWVPG NPMNESF SKEVTK W KPW YS AV G NPMNPSVCFQNTLTN KY YRLEP RC HD VQKQCTYSN KQ GTSY NLAF LPEY QTIK APESSVCNTLFTK GLSGFPFQ C HD VYL I TK ED VYKP PEEG G KLSNED YNV HLSQISSSLQK V YL I TK EVSPD VYKP PK ATD KDERPNLAVQPQTLN Y ATD KDEVPFQTCSPPH K WKSN G KHLVQG GIRN G G K K V K VPFQTCSPPH 8CH 3 44B9G V894QQQLF L G E AHGTYSKTWSIV TS V VQVLP PSASSCSYAA D Y NTK Y NPASRGGQK GSGKLWHASV V K DSVS GTTWSTSLFVQK AEPG RTGPTT NSG GYLCSIV TIG GSF FSLD Y VS SS PIRVLSQSGNPS T CA SSV A VTLYSGESYTK YSA NCETVISK NPSMCNSA ALY AQP KVQKPY DQLSTTPKL A KAEEETESTV V SGQPDE ST TH APP E SV G 9 CL794D ITKN I SASGISGT LCTQGK F S TITKN S KTHESEMEY VLIPE W LH FTMCWT SH VLPELFV KDGDACAGLVLSS YSSAGS SV V D AQKTESY MELK VHLI E WFVE EFSVTLG YT SPKSPV NPH VE EFSTALPLRSV GS SKMP AI C LGTVVTAT LV G AVTD G V ARV GC VETLPL SV AIGVSAPDDSSFTV KLTSPDLV KEA VAN GSPP RTQ SDMATGSGSV VKTNSTLL TV VVSAPPDDSKLNEP EGSD VT PDLVNSYYV GPSKR KLGQ S SSPVNSYYVR VYVFP L VIS ATK WSLKQGPQS PATV R V QS LWPVFPVGSVKPCR Y YKQGPTS CPKT LSNSWKEVTWSGPW YSISP TYLHP SIWTCPKTAV G NPMNSKEVTNYRLKRSKGY NLAF LP SVC LFN RLKYEP CYQSYTIK APE SNT TKY YEP CYQKQ TN KTEGLSGFPFQEC HD VQKQ TNEG G KLSNED YQNV HLSK V YL I TQISSSLQK E EG GLSNVSPD VYKP P EKERPNLAVQPQTLN Y ATD KDER NLAV PKSHLVEGIRN G G KPFQTCSPP PKQ QK W N G K G K V K V H K WSN G 9CH 0 54B9G V002505FQ QF G E QQGQ LLAHLLAYGTSKT Q TKWSIV TS V VYGSV QI S VVLP PSASSC WSS T P PLSASSY A D V Y A DNATK P ASY R NATK P AY N K Y NQKGGQWHGGWGSGLASGSGLAVKKKDSVVVSV VSGTTW DT TS SLFVQESG SSV F VTKAP TKAG RTG TRTGTCNSGPGYLG TNSGPGSIVGF FSL CYSVGFTIGSD YIVS T GS FD VSSQPISR V SLS ICASQPRVISLCGNTV A GNTPSSSVTLYSPSSSV TLGESYTK Y A NCEVEYTAVI SSSK NTPGSYI SK MCNS V SCYQASMNALAPALY AQKPY DQKVLSTP KPY DQLTLAPKQKAEEETETLAAEEES G D STSTV KATAD SSQ P EH APP E SV GS GQP EH APP011C1LCL991405SVGISI GLTCTGK F SITKN SASGISI GCWTATSH VLPELFV T KDTLGDC QKTSEV E YTWTA LVAGSLGSSSV V D AHEIMLH F MCGD VCGSY A K YSSPSPV V NL PEEWEFSVTL L SYS M A TLK H V A VS SGMYLKTVVTVD G VRSG K VTEGTSA VAV G ATV GC VETLPLP AIDCSLT GTVAPP RTQ SDT GSGSV VKTLL TVVSAPDS FKEARTATT NS E VEG V KLTSPDLV GSPPQ SDKK GS SNPDNY NPKKAV RI L QW SAPVSYV GSRLLG W S ATGKS SLS PP S PPTV R Y R VVFPIPQ L V S ATNVSWISPVTYK L HCPSIW Y TKQG CPKTQ STLLSG WS PNVSG W YSV NPMNS EVWPYSSY NLAFALPGQYTIK APF ESSVCNTLFTN K KY YRLK EP RQCSK G W Y NLTY KQTSEYTIKVNGLSGPVFQLCIHTD V EQK N GLD Y VNGLSLSQISSSLQK VSPY D VYTKKP PEEG N KSNEV HLSAV PNQISSSLQVEG Y A D KDERP L Q QTLY GIRN G G K K V KPFQTCSPPKSHLVQGIRN V H K W N G K G K011C1CH H462444B9B9G G V V405ETQQQF G EHLLA GTKHTVYSQW IV TSPVPVQCS SVLASSCYSASDSYRNATK Y P A KSRHY NSGGQWHGSGL SK A VKSV KWQD VGTTWESSLVQPSFKAETT PLG RTG TSLTCNSGPGYLSIVGF FSLYSSTIGSD S Y VISSAS PRVLAAQNST CAYSG PSSSV VTLSTYKNCEGEKCSYSA NENT YIK NTSPV SCSPQASMNQAKVSTALY APP KYQKVTT KT E Q PDLSAPKETVTLKAEEETETSVGPDESTSTV ETSV GPQH APPV G 21CL305TSLCT HGK FAGLPSIELFV TTKN SASGISI TLTGK F KDTSYEV WTGS CHLPELFSS LVSAGS SV V D AQKEMELHTCDACAGLVSK VHLI E WFMT GLVSYSSAGS SV V SSV TPKPV NPH V AE EFSVLG YT SPK KSPTAT LVD G VT RSV GS SLKMTVVTAT LVD GV G ATV GC VE LPLP AIDCS G VAV G ATV GMTGSGSV VK LL TVVAPDS FKTEARTG GVK LLNTVGSKLTSPDV GSPPSDMT S SVTG TSSSNEP ED VNYLNPQKAG TSNSSNEPQW L SPAPTV VSYFV GSKRI LAQW L SPAGKS S SPR Y R VVGPPQ LSVLSP TGKS S SPWISPVTYK L HCPSIW Y TKQCPKTQL G WSNVSWISPVTYK L HCAVFALPG NP S E TWS PYSVPPAPESSVCMNTLFTN K RVLK KRKGW NLA AY YEP CYSQSY T KF LPG N ESSVCTGFPK VFQN LCIHTD VQKQ TN KTEYILAPFP QNHK E EG GL ND YQNSGSG VF LCI TVSPY D VG G K AYTK DP P EKS EV HLKDERPNLAVQPQTNQISSSLKSY VYK YQVPD ATD V K VPFQTCSPPH K WKS LN G KHLVQG GIRN G G K K V K VPFQTCS21CH 9 54B9G V605KSQ QQEP PS PFNHETYLIFGSV W R ALSIVQ ESL CPA YTLA A N Y STA D V SFADV V K VTSTH GRK WKEQSK SG ISE QY V V D A R G CKK A SSF TAEKSLTRG R LDQ P TAPIGY LTRFDGT T FNSY GNSLPAPS RP LLSYCELSSSSS CL A G VTSGRTGYGYQVSD K N SFPIASL QC TDSKQLTRYGS Q TPYETV MSVI QVKLPAFQ VES SSLDGPD DEQG 31CL505SV TD ITKT T N SAEA W D C S NSSN PPD V KLTSPD KV AQK SEYSHEMLHCELRSHGQTSL SATV VNSFSGIY GWS S PPCR Y R Y VYFV NLIPE WMLV H V KTVKSAE EFSV RFRATWS VTYLK HPPSIW YVMN T KC QG KCTVETLPLRSV GSP AIDCL GPSSA GDVPV G NCE DA P SSVTLF STK N KPERVLVVEGVSAPDS FKL S DV K G K GQRVA ML EGPFPFQN LHCI TD VY YK EQ EPQCTPVT PGP SR KP PEK DTV VNSYYLN V GPSK V DLSY Y V Y V SEG GLDYTDK DEKSR Y R VVFPIQ L VW A N YPAPCSW Y TKQGPCPQ S LN Y KS PRPNLAVE KTTLSG MYIM Y GF QTPFHSD K VTKLVKTWKS QNMNSKVWLFK G D YQLT LCHGLPE FKD ITKTN KD VY YRLK QEPKQCTYRSN KQG TSY NSSYTT SV V AGLG SSV V D AQ TKSV NH KEMKPEPEEG GLSNED YEVS SSLSGSASSPKPVLI EHFN VSTLD G V H VP EKDPP ERPNK VLL AVQPQTLNQTFSISSK DVATATAVTVGLCTVETLA PLRSH K WKSN G KHLVEGSR V N AVTG GGSV VKTLEVEV GVSAPP31CH 3 04B9G V637VPPQ E K DS SDE LSSCSQ EQPSPQSGQDYASYELPN RFI G HTK R WWH SI F SV SALTV LS QLECA KY TPA AVTWS FA N QSY SDA D VVETVTV KAPVSGK HGPTLQSR SGKYFSLASI WQKEGEV YD Y R V DSISSCSSFKK TAEALCALR GKSATD GRVPLYSTKCAPILER G GTFYFNTE TLG ATNTAK NP LS APSRP NLSSNAQV LSSS SRL LCSCQKTL SPK LA G YEG VTG TE TYVSEYEIHSD RS TVGTPL QN CA K FS TE SSL T SGQRYDSPPVFGETL PYGSKKQ TLAHTVAV IQL ETVTK VEGAF QVPS61CL537RV A TLP K G V H LIPE FSV A W D C AGVSEAC T TAVTD GC VEV AEE GS A E RYSS LGS SV V GTT RVC C L SASPKYGV VLVLPSD IYV TKYLTGSVKLV GVLP AI SSKSLGTVTAT LVDVST NSS TEPEPDSAPDDFK V G RFRAV G ATVA GT Q SWN A GKSLSSPP TRV V KLTSYVP LNPSL GPGTLTGV RNSY V GKLSA KDEGS SVTDSVTYKCSIW V VYFPPQSGQAGQTSNSSNA WSAYPVLHPPY MTN QGTQLSGPRVSR GWSL SPDVFALPG ESN S VCTLT FTSKK NC PKTKESY PRVK W K K V DLWKS SK FPFQNHD VY Y PLYR VW ASYSPVTYLH NSQT LA Y NLDV G NTLA V YLCI TK EP Q E QCTK Y G MFIMFALP SVKSLSSPD VYKPSSG KAVP TDKPD EEEK G G KLSNED H G P V N G A YQGPE SN YD LFGFPFQF Q CSP H RPNLCILAVQTLH SE T SLLV YFSKQDT LT TKF SK KS QGKLVSFSS S ESPD VYTN WS CH GP LFVTW AGVLS EV D KD IN T N KSAEL SIN W G KAPTSEYQHQTFSK D K VFTKSRESS LAGSSSV KSPV AQV N HKEM WLFMVEGS SA R V N ATSLC THGL61CH 9 11B9G V9837PDKEES SDE LQP S QSGQQ PP NQYLS FHWSTIIFGSV VLTLV SQ EPLACHTFA N A N ITA Y SDD V GG VTV K QSR K H S AGSKIWQKER G D Y CTSIFV V K D T RK AA ST EKVPGR VPRSPD GGGLSF YTFLTVSQTLFN PNLSSATSSASLAL LCSYCESSA N Y V PV TSG R SYIK LQSD CA KN QLTKT SFSMPY YG DTS QKTQIV K K AETV D G VLQVPS71CL737F KVIA L S V K DSADVQ TKN SAED W CSSGSSV D ADQITKNKTSEY HACRSYVATPKSPV NKTPV HHL EMLFELIYTAT LVK G V HHL EMGG VVEVIPETAEWEFMAS VLGTV V G ATD G V VIPER KFRATL GV VL CTVETAELLCTVLEVP RSV GSCLGTGS SVKT L LP RSPEGVLP AI SGPKDEG TNSSE VEV GLPAPDSAPV DDSSFKL S DV K GAQ SG GQVSD GK WNPSLSSPAP VT DSAPV KLPCTV R Y V RNT PSYYLN V GPSPQR V D R LSWSSPVTYLKPHCR V S V I Y RNTSYPPSIW Y VVFPMN T KQGPQQLSEV Y L W Y N V G NPPW Y VVN YDFALP SVCMN T KQCTLF S CTK NPKTKEVTLSGIM YPE SNTLT F S CPK W K GMTQLDFPFQ HD K N KEHTD VY YRLYRSGSRSY V YLCI TVY YRKK EP Q EPQC QTSEY MSD VYKKPEQ EPQDPEK KDE EG GTN K L R SNED Y VS SFSLSSGPIN Y G KAP TDPQC KPD EK EEG GCSP RPNK V HLQIKSEK VFT T SP RPNK PHS LAVQPQTLNFHSTSLCG KFHS LAKPFLVKTWKSN G KHLVEGSA R H V N A A G VLSPELFVKTWKS71CH 4 21B9G V4042747P ESESLP D KDED K QP S QSGQQ EPQ Q PLPFNHQET YLYSI GSW R WSI FQ VSIALTLV SLE APC LTLYTA AYSTRFA NFN D Y IETA VSGG VSDTS TV K K HVSGQRKSSW QSAGSKIRG EQ EGV Y ASGCS LK D RSTF KAC FIT RSTAGEKSSLRD VP QRP TR V GL PYTAIDG FFL R GGS TNT E TQY N SSG A VS L P LPSR ASTSYTL LCSC LSRSL A F A N Y VTEA GLTG SPYILQVS SD RG YISQLLQCATKNPSF S LLT K Y LP GS QSD K T RPQI TYKTKQETALTVLP VAIQD GF QVS EG 819C1LCL931747NSSAEV W DVEYSLGSS S V V D K AD ITKN SAEA WW LHA EFC LRS C SATPK KSPVQNKTSEY HA EEFMSGITYVTAT LVV D G V HHL EMLF CMLVLKF YIV G ATV GC VVIPEEWEF SVLGVSSRGRATT GSGSV VK LL T ETLARVSSR KAIGCLS PGTT NSTE VEVPL SAIGCLSGPDDSSFK GAKDEGS SNPGVSAPPDDSSFGASPDLV N GGQAPPRSAQK WSLSSPAPTD V KL SV K GQDRGSV YKPCR V Y VNT PDLN G PPRYFV GSK V ALWSP T LHPGPSIRSYYFV GS QV PPQ LSVLW YSIVAV G N M W Y VV PPQ LSVLWKTQLNYM DLPESSVCTL NFTSKQG KTQ ST SG MIMPNT CP LSGVW G YQFP QK NE TW G MLKRK GNFSLG VF LCIHTD VYK RVLKRK ACTYSN KQTSSY YSY VYKKPEQYEP CYSQ GSYSLEK YPDP Q TN KTSNED Y VSFSSLSSATDEK I YENGPG KPQ C KPDE EG GLSNDLSFVV HQPQTLNLETH VFYSK Y K VFT T SP RAPNKEV H NLQTG TSLCH G KFHS LAVQPQTL FN G KL EGSV NRA G VLSPELFVKTWKSN G KHLVEGS819C1CH H 5 2 0 131B9B9G G V4V7447EDSESLP D ESESLSPQSGK QEPD SQSGPFNQI HQYEL PPFGS T FNQH V W RGTSIF SVVS QP LEACAILTVQLECALSPAA NYSTFN AA D YSA D YV V VSDTA VTK KVV V KRHSGSTK HKI WE QKEQS RG KWQKEV V Y ASID G GEV Y V DKKTAEACSSFK KTAAGGR KSPLRELTD GR KSAPIGPLGFYTRG YTTFLNLT EGT F FLGTNTP NLSSPALSS RNL SLRL LSGCYC L SSPSL LSCVTE SR L A GCY VEYSGTGTGHVRFQVSRQSDG YI SD AKNPL QNCYT SFSSQ L CATKSFSYGSDQK T RPYGSDQKVETY KAVLVAV KETVFLQ TVPSIE QGAFLQ TVPS02CL347RFYSS K S S LGSSV V D ADQITKN SAEES Y S ASTTPIY ATPK KSPVTV NK SEY HAC LVTVVTAT LVFVVRATAT LVGTV G ATD G V HHL EIMLFG MSKF AV G ATV V GC VVPEEWEFVLRR TL G GSV VKDELTGSGSVK LL T ETLARVSS GLPGDE T SNSTNSS TE VEVPSGCGLP AI SAK AGQTS SVSAGQ SNPPVSAPDDSSFK GQVSR GK WSLSD R GK WSLSSPATD V V KL S DV G G R V DLS SV YALS SSV YKPCR Y VNT PYLNPA W K A N YSP T LY NWP P TVLHPPSIRSW VYFV GSV W Y M DAV GYTMD ASQF LPG ESN M YVS VCTL NFTSKQGPPQ LS LAFIH CFLPPESSKTQLG M YLPPFP QGLGPFPFQNHTD K N KEVTWSA K GNS FG VF LGYGTV YLCI TVY YRLK YRSGYST LSASY D VSLTSPD VYKKPEP Q EPQCTQTSESSNVS PAGSINEQG KAKDP TDK EEK N K G D Y VFSIK D G KPVFK VF QTCS PDEG KLSNEV HL TFSA R KTAS SK NA T LTG KPFH RPNLAV P TNQGSNA TSLCH CS CHLSPELF SKTKS Q Q LH VSVDCA GV V D A G V V W N G KL EA WRYS LG 0 2CH 4 31B9G V8647P K D ES SDE LQEQPQE SSGLPNQYPW RFG HTASIIF SV LTYLVQSLETTPACFN A S A Y SDA D V VTSV V K GSTRK H QSKW KEAGSIE QY R G V C V K D SSFK AA L RT ETDKSAPG I GRPLREGTGFYTFLG P ATLNTS S RNL SLSSSPSLRLC SYCLA G VTETG Y GPYIVSG R SQL QLQ SD AKN FTLR CT S SP FYGSDQKTVAIE QV KEV GAFLQ TVPS12CL547KSKPV A Q TSE A W D C S C H LP LSIV NKMEY VE FV TDTD GV G V HHL ELHAVIPEEWCELRSY AGLSSV V D KQE FMKGI Y SSAGSSKSV AEK LT LCTVEVTLA PR FS VSVSL T LGSR KFRA VTATTL PKPV V NHLID GPV H V ANEPVESPAPGVLP AITDSAPDDCSSFL GPGTV G ATV G KSAT PKDEL GVL CTVE L LV V KLTS DV G GTGS SVKT LV VVAKPCR VNP LNG QRVSAG TNSNEPEGSKHP SIY RSYYVPGS PR VQ SWSSAPD VNNPM W Y VVQ FP LKDSLSGKSLS PP TV VSVCNTLTNFTSKCPGPQE KTT Q SLSVLW Y Y F N I WSSPVTYKC RLHP SIY R V YKCIHTD K N VYK RVY PLK W K G M M YYEYRSG AQLF ALV P G NPS VCM WTCTL NSKYTKKDPEKP QEE QCK GTN KQTG Y DPPE SNT FN YSEN N Y GFPFQ CIHTD KY YEQTCS PDG PE ER G KLSNPNAED V H VS GSLSSIVLKVQK NFN HSPY VYTKPEPEGLK PFHSS ELF SVKLTWK VSQPQTLH LLQTFSID SSK D G KAPD QTCSKEPDERPNLV V D K DITN G K NKSAVEGSA R V N AKTVLFTG KPFH K W 1 2CH 5 61B9G V3847GPFS SDEE LKEDQSGQ P SPNQQ QYL PFHWSI GS TV ASI FQ ELTV LSL CPA N A YSTFA Y SEA D IVV V K VT TK SGH QSR A KW KRQ ERSIEV Y CGSV K D TF K AEA IT R TKSVS G RPRP QLV GYTD GGVSFFLT NTS SQ W NL SALNPL LSSYCYCL ST SVTEFN SPL VS SG V D R SYI QN QL Q ATKSFSTL CLKYGSDQKTQI PAYTK D K AL EQTV VPS22CL747KN SAS E VEK Y T T A T VLT E LPLSAICTSMEYE LHTLCSAIYTTV G V GGLSVVV V APEWFES KTEP EGPDSSFK DSD KS DV G F MRSVTLKLASVGRTMT ST NSNPSTV VLT P LNPGSCTL PN DGQWSLSSA PPCR S Y VNRSY VYV GSVFP Q LP AID PQKVPGKSV YLKPIW YKGP Q SPLDSSTSFTPDV KELSSTHPMN TCQPKTTLSGT RIDWI PV G NC LF SKE VW KYV YLN F V GPPSK WTSMA P SSVT TK N NY N DF L ENHD VY YR LKREP CYSKQTQGPPQPQLSVLMS TK M APFPDFQLCI TK EQKQ TN Y V V KP PEEG GLSND HEKTVTWLSVPGEM DTLR LSY P DA YPTDKCPDEKEV SP RPNLAVQPQTLNRPLKRQCSK G R T YQTSEANSV VEG KF QT FHSWKG W K VTKLVKT SN NKSHLN KGKLNFISN QE D Y KT LCHGLPE FD KD ITKTYAEV HSHSKSVSV V V AQSELHAV LQPQTLNT LSFAK N LSTR AGSS LGS SSPKSPV NHLKEI MFP EWEFMKSN G KHLVQG W DACA V ATLK G V D GVCH VVTAER SV GVS22CH 0 71B9G V1
[0089] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain (HC) comprising an amino acid sequence set forth in Table 1.7, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0090] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain (LC) comprising an amino acid sequence set forth in Table 1.7, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0091] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain (HC) comprising an amino acid sequence set forth in Table 1.7, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; and a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain (LC) comprising an amino acid sequence set forth in Table 1.7, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0092] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain (HC) comprising an amino acid sequence set forth in Table 1.7; and a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain (LC) comprising an amino acid sequence set forth in Table 1.7.
[0093] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain variable region (VH) comprising an amino acid sequence set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0094] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain variable region (VL) comprising an amino acid sequence set forth in Table 1.6, or a sequencehaving at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0095] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain variable region (VH) comprising an amino acid sequence set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; and a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain variable region (VL) comprising an amino acid sequence set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0096] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain variable region (VH) comprising an amino acid sequence set forth in Table 1.6; and a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain variable region (VL) comprising an amino acid sequence set forth in Table 1.6.
[0097] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain CDR1 comprising an amino acid sequence set forth in any of Tables 1.1- 1.5, a heavy chain CDR2 comprising an amino acid sequence set forth in any of Tables 1.1- 1.5, and a heavy chain CDR3 comprising an amino acid sequence of set forth in any of Tables 1.1-1.5.
[0098] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain CDR1 comprising an amino acid sequence set forth in Table 1.1, a heavy chain CDR2 comprising an amino acid sequence set forth in Table 1.1, and a heavy chain CDR3 comprising an amino acid sequence of set forth in Table 1.1; a heavy chain CDR1 comprising an amino acid sequence set forth in Table 1.2, a heavy chain CDR2 comprising an amino acid sequence set forth in Table 1.2, and a heavy chain CDR3 comprising an amino acid sequence of set forth in Table 1.2; a heavy chain CDR1 comprising an amino acid sequence set forth in Table 1.3, a heavy chain CDR2 comprising an amino acid sequence set forth in Table 1.3, and a heavy chain CDR3 comprising an amino acid sequence of set forth in Table 1.3;a heavy chain CDR1 comprising an amino acid sequence set forth in Table 1.4, a heavy chain CDR2 comprising an amino acid sequence set forth in Table 1.4, and a heavy chain CDR3 comprising an amino acid sequence of set forth in Table 1.4; or a heavy chain CDR1 comprising an amino acid sequence set forth in Table 1.5, a heavy chain CDR2 comprising an amino acid sequence set forth in Table 1.5, and a heavy chain CDR3 comprising an amino acid sequence of set forth in Table 1.5.
[0099] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain CDR1 selected from the group consisting of any of the heavy chain CDR1 set forth in Tables 1.1, 1.2, 1.3, 1.4, and 1.5, and variants having conservative modifications thereof.
[0100] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain CDR2 selected from the group consisting of any of the heavy chain CDR2 set forth in Tables 1.1, 1.2, 1.3, 1.4, and 1.5, and variants having conservative modifications thereof.
[0101] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain CDR3 selected from the group consisting of any of the heavy chain CDR3 set for in Tables 1.1, 1.2, 1.3, 1.4, and 1.5, and variants having conservative modifications thereof.
[0102] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a light chain CDR1 comprising an amino acid sequence set forth in any of Tables 1.1- 1.5, a light chain CDR2 comprising an amino acid sequence set forth in any of Tables 1.1-1.5, and a light chain CDR3 comprising an amino acid sequence set forth in any of Tables 1.1-1.5.
[0103] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a light chain CDR1 comprising an amino acid sequence set forth in Table 1.1, a light chain CDR2 comprising an amino acid sequence set forth in Table 1.1, and a light chain CDR3 comprising an amino acid sequence set forth in Table 1.1; a light chain CDR1 comprising an amino acid sequence set forth in Table 1.2, a light chain CDR2 comprising an amino acid sequence set forth in Table 1.2, and a light chain CDR3 comprising an amino acid sequence set forth in Table 1.2;a light chain CDR1 comprising an amino acid sequence set forth in Table 1.3, a light chain CDR2 comprising an amino acid sequence set forth in Table 1.3, and a light chain CDR3 comprising an amino acid sequence set forth in Table 1.3; a light chain CDR1 comprising an amino acid sequence set forth in Table 1.4, a light chain CDR2 comprising an amino acid sequence set forth in Table 1.4, and a light chain CDR3 comprising an amino acid sequence set forth in Table 1.4; or a light chain CDR1 comprising an amino acid sequence set forth in Table 1.5, a light chain CDR2 comprising an amino acid sequence set forth in Table 1.5, and a light chain CDR3 comprising an amino acid sequence set forth in Table 1.5.
[0104] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a light chain CDR1 selected from the group consisting of any of the light chain CDR1 set forth in Tables 1.1, 1.2, 1.3, 1.4, and 1.5, and variants having conservative modifications thereof.
[0105] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a light chain CDR2 selected from the group consisting of any of the of the light chain CDR2 set forth in Tables 1.1, 1.2, 1.3, 1.4, and 1.5, and variants having conservative modifications thereof.
[0106] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a light chain CDR3 selected from the group consisting of any of the light chain CDR3 set forth in Tables 1.1, 1.2, 1.3, 1.4, and 1.5, and variants having conservative modifications thereof.
[0107] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH1 set forth in Table 1.1, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL1 set forth in Table 1.1.
[0108] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH2 set forth in Table 1.1, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL2 set forth in Table 1.1.
[0109] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, andthe heavy chain CDR3 corresponding to VH3 set forth in Table 1.1, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL3 set forth in Table 1.1.
[0110] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH4 set forth in Table 1.1, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL4 set forth in Table 1.1.
[0111] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH5 set forth in Table 1.1, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL5 set forth in Table 1.1.
[0112] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH6 set forth in Table 1.1, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL6 set forth in Table 1.1.
[0113] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH7 set forth in Table 1.1, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL7 set forth in Table 1.1.
[0114] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH8 set forth in Table 1.1, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL8 set forth in Table 1.1.
[0115] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH9 set forth in Table 1.1, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL9 set forth in Table 1.1.
[0116] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH10 set forth in Table 1.1, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL10 set forth in Table 1.1.
[0117] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH11 set forth in Table 1.1, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL11 set forth in Table 1.1.
[0118] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH12 set forth in Table 1.1, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL12 set forth in Table 1.1.
[0119] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH13 set forth in Table 1.1, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL13 set forth in Table 1.1.
[0120] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH14 set forth in Table 1.1, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL14 set forth in Table 1.1.
[0121] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH15 set forth in Table 1.1, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL15 set forth in Table 1.1.
[0122] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH16 set forth in Table 1.1, and the amino acidsequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL16 set forth in Table 1.1.
[0123] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH17 set forth in Table 1.1, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL17 set forth in Table 1.1.
[0124] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH18 set forth in Table 1.1, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL18 set forth in Table 1.1.
[0125] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH19 set forth in Table 1.1, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL19 set forth in Table 1.1.
[0126] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH20 set forth in Table 1.1, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL20 set forth in Table 1.1.
[0127] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH21 set forth in Table 1.1, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL21 set forth in Table 1.1.
[0128] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH22 set forth in Table 1.1, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL22 set forth in Table 1.1.
[0129] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH1 set forth in Table 1.2, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL1 set forth in Table 1.2.
[0130] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH2 set forth in Table 1.2, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL2 set forth in Table 1.2.
[0131] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH3 set forth in Table 1.2, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL3 set forth in Table 1.2.
[0132] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH4 set forth in Table 1.2, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL4 set forth in Table 1.2.
[0133] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH5 set forth in Table 1.2, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL5 set forth in Table 1.2.
[0134] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH6 set forth in Table 1.2, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL6 set forth in Table 1.2.
[0135] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH7 set forth in Table 1.2, and the amino acidsequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL7 set forth in Table 1.2.
[0136] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH8 set forth in Table 1.2, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL8 set forth in Table 1.2.
[0137] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH9 set forth in Table 1.2, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL9 set forth in Table 1.2.
[0138] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH10 set forth in Table 1.2, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL10 set forth in Table 1.2.
[0139] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH11 set forth in Table 1.2, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL11 set forth in Table 1.2.
[0140] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH12 set forth in Table 1.2, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL12 set forth in Table 1.2.
[0141] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH13 set forth in Table 1.2, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL13 set forth in Table 1.2.
[0142] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH14 set forth in Table 1.2, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL14 set forth in Table 1.2.
[0143] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH15 set forth in Table 1.2, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL15 set forth in Table 1.2.
[0144] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH16 set forth in Table 1.2, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL16 set forth in Table 1.2.
[0145] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH17 set forth in Table 1.2, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL17 set forth in Table 1.2.
[0146] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH18 set forth in Table 1.2, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL18 set forth in Table 1.2.
[0147] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH19 set forth in Table 1.2, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL19 set forth in Table 1.2.
[0148] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH20 set forth in Table 1.2, and the amino acidsequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL20 set forth in Table 1.2.
[0149] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH21 set forth in Table 1.2, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL21 set forth in Table 1.2.
[0150] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH22 set forth in Table 1.2, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL22 set forth in Table 1.2.
[0151] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH1 set forth in Table 1.3, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL1 set forth in Table 1.3.
[0152] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH2 set forth in Table 1.3, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL2 set forth in Table 1.3.
[0153] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH3 set forth in Table 1.3, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL3 set forth in Table 1.3.
[0154] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH4 set forth in Table 1.3, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL4 set forth in Table 1.3.
[0155] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH5 set forth in Table 1.3, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL5 set forth in Table 1.3.
[0156] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH6 set forth in Table 1.3, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL6 set forth in Table 1.3.
[0157] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH7 set forth in Table 1.3, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL7 set forth in Table 1.3.
[0158] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH8 set forth in Table 1.3, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL8 set forth in Table 1.3.
[0159] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH9 set forth in Table 1.3, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL9 set forth in Table 1.3.
[0160] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH10 set forth in Table 1.3, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL10 set forth in Table 1.3.
[0161] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH11 set forth in Table 1.3, and the amino acidsequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL11 set forth in Table 1.3.
[0162] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH12 set forth in Table 1.3, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL12 set forth in Table 1.3.
[0163] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH13 set forth in Table 1.3, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL13 set forth in Table 1.3.
[0164] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH14 set forth in Table 1.3, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL14 set forth in Table 1.3.
[0165] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH15 set forth in Table 1.3, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL15 set forth in Table 1.3.
[0166] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH16 set forth in Table 1.3, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL16 set forth in Table 1.3.
[0167] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH17 set forth in Table 1.3, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL17 set forth in Table 1.3.
[0168] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH18 set forth in Table 1.3, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL18 set forth in Table 1.3.
[0169] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH19 set forth in Table 1.3, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL19 set forth in Table 1.3.
[0170] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH20 set forth in Table 1.3, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL20 set forth in Table 1.3.
[0171] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH21 set forth in Table 1.3, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL21 set forth in Table 1.3.
[0172] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH22 set forth in Table 1.3, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL22 set forth in Table 1.3.
[0173] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH1 set forth in Table 1.4, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL1 set forth in Table 1.4.
[0174] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH2 set forth in Table 1.4, and the amino acidsequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL2 set forth in Table 1.4.
[0175] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH3 set forth in Table 1.4, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL3 set forth in Table 1.4.
[0176] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH4 set forth in Table 1.4, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL4 set forth in Table 1.4.
[0177] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH5 set forth in Table 1.4, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL5 set forth in Table 1.4.
[0178] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH6 set forth in Table 1.4, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL6 set forth in Table 1.4.
[0179] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH7 set forth in Table 1.4, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL7 set forth in Table 1.4.
[0180] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH8 set forth in Table 1.4, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL8 set forth in Table 1.4.
[0181] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH9 set forth in Table 1.4, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL9 set forth in Table 1.4.
[0182] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH10 set forth in Table 1.4, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL10 set forth in Table 1.4.
[0183] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH11 set forth in Table 1.4, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL11 set forth in Table 1.4.
[0184] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH12 set forth in Table 1.4, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL12 set forth in Table 1.4.
[0185] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH13 set forth in Table 1.4, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL13 set forth in Table 1.4.
[0186] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH14 set forth in Table 1.4, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL14 set forth in Table 1.4.
[0187] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH15 set forth in Table 1.4, and the amino acidsequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL15 set forth in Table 1.4.
[0188] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH16 set forth in Table 1.4, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL16 set forth in Table 1.4.
[0189] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH17 set forth in Table 1.4, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL17 set forth in Table 1.4.
[0190] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH18 set forth in Table 1.4, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL18 set forth in Table 1.4.
[0191] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH19 set forth in Table 1.4, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL19 set forth in Table 1.4.
[0192] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH20 set forth in Table 1.4, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL20 set forth in Table 1.4.
[0193] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH21 set forth in Table 1.4, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL21 set forth in Table 1.4.
[0194] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH22 set forth in Table 1.4, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL22 set forth in Table 1.4.
[0195] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH1 set forth in Table 1.5, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL1 set forth in Table 1.5.
[0196] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH2 set forth in Table 1.5, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL2 set forth in Table 1.5.
[0197] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH3 set forth in Table 1.5, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL3 set forth in Table 1.5.
[0198] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH4 set forth in Table 1.5, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL4 set forth in Table 1.5.
[0199] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH5 set forth in Table 1.5, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL5 set forth in Table 1.5.
[0200] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH6 set forth in Table 1.5, and the amino acidsequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL6 set forth in Table 1.5.
[0201] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH7 set forth in Table 1.5, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL7 set forth in Table 1.5.
[0202] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH8 set forth in Table 1.5, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL8 set forth in Table 1.5.
[0203] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH9 set forth in Table 1.5, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL9 set forth in Table 1.5.
[0204] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH10 set forth in Table 1.5, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL10 set forth in Table 1.5.
[0205] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH11 set forth in Table 1.5, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL11 set forth in Table 1.5.
[0206] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH12 set forth in Table 1.5, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL12 set forth in Table 1.5.
[0207] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH13 set forth in Table 1.5, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL13 set forth in Table 1.5.
[0208] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH14 set forth in Table 1.5, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL14 set forth in Table 1.5.
[0209] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH15 set forth in Table 1.5, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL15 set forth in Table 1.5.
[0210] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH16 set forth in Table 1.5, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL16 set forth in Table 1.5.
[0211] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH17 set forth in Table 1.5, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL17 set forth in Table 1.5.
[0212] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH18 set forth in Table 1.5, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL18 set forth in Table 1.5.
[0213] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH19 set forth in Table 1.5, and the amino acidsequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL19 set forth in Table 1.5.
[0214] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH20 set forth in Table 1.5, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL20 set forth in Table 1.5.
[0215] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH21 set forth in Table 1.5, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL21 set forth in Table 1.5.
[0216] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the amino acid sequences of the heavy chain CDR1, the heavy chain CDR2, and the heavy chain CDR3 corresponding to VH22 set forth in Table 1.5, and the amino acid sequences of the light chain CDR1, the light chain CDR2 and the light chain CDR3 corresponding to VL22 set forth in Table 1.5.
[0217] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain variable region (VH) comprising an amino acid sequence set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; and / or a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 68, set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0218] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain variable region (VH) comprising an amino acid sequence set forth in Table 1.6; and / or a light chain variable region (VL) comprising an amino acid sequence set forth in Table 1.6.
[0219] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprisesa heavy chain variable region (VH) comprising an amino acid sequence encoded by a nucleotide sequence which can encode any of the VH sequences set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; and / or a light chain variable region (VL) comprising an amino acid sequence encoded by a nucleotide sequence which can encode any of the VL sequences set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0220] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain variable region (VH) comprising an amino acid sequence encoded by a nucleotide sequence which can encode any of the VH sequences set forth in Table 1.6; and / or a light chain variable region (VL) comprising an amino acid sequence encoded by a nucleotide sequence which can encode any of the VL sequences set forth in Table 1.6.
[0221] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain variable region comprising an amino acid sequence corresponding to VH1 set forth in Table 1.6 , or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence corresponding to VL1 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence corresponding to VH2 set forth in Table 1.6 , or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence corresponding to VL2 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence corresponding to VH3 set forth in Table 1.6 , or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence corresponding to VL3 set forth in Table 1.6, or asequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence corresponding to VH4 set forth in Table 1.6 , or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence corresponding to VL4 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence corresponding to VH5 set forth in Table 1.6 , or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence corresponding to VL5 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence corresponding to VH6 set forth in Table 1.6 , or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence corresponding to VL6 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence corresponding to VH7 set forth in Table 1.6 , or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence corresponding to VL7 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence corresponding to VH8 set forth in Table 1.6 , or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence corresponding to VL8 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto;a heavy chain variable region comprising an amino acid sequence corresponding to VH9 set forth in Table 1.6 , or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence corresponding to VL9 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence corresponding to VH10 set forth in Table 1.6 , or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence corresponding to VL10 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence corresponding to VH11 set forth in Table 1.6 , or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence corresponding to VL11 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence corresponding to VH12 set forth in Table 1.6 , or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence corresponding to VL12 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence corresponding to VH13 set forth in Table 1.6 , or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence corresponding to VL13 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence corresponding to VH14 set forth in Table 1.6 , or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variableregion comprising an amino acid sequence corresponding to VL14 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence corresponding to VH15 set forth in Table 1.6 , or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence corresponding to VL15 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence corresponding to VH16 set forth in Table 1.6 , or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence corresponding to VL16 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence corresponding to VH17 set forth in Table 1.6 , or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence corresponding to VL17 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence corresponding to VH18 set forth in Table 1.6 , or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence corresponding to VL18 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence corresponding to VH19 set forth in Table 1.6 , or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence corresponding to VL19 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto;a heavy chain variable region comprising an amino acid sequence corresponding to VH20 set forth in Table 1.6 , or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence corresponding to VL20 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence corresponding to VH21 set forth in Table 1.6 , or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence corresponding to VL21 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; or a heavy chain variable region comprising an amino acid sequence corresponding to VH22 set forth in Table 1.6 , or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence corresponding to VL22 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0222] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain variable region comprising an amino acid sequence corresponding to VH1 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence corresponding to VL1 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence corresponding to VH2 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence corresponding to VL2 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence corresponding to VH3 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence corresponding to VL3 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence corresponding to VH4 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence corresponding to VL4 set forth in Table 1.6;a heavy chain variable region comprising an amino acid sequence corresponding to VH5 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence corresponding to VL5 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence corresponding to VH6 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence corresponding to VL6 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence corresponding to VH7 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence corresponding to VL7 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence corresponding to VH8 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence corresponding to VL8 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence corresponding to VH9 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence corresponding to VL9 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence corresponding to VH10 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence corresponding to VL10 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence corresponding to VH11 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence corresponding to VL11 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence corresponding to VH12 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence corresponding to VL12 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence corresponding to VH13 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence corresponding to VL13 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence corresponding to VH14 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence corresponding to VL14 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence corresponding to VH15 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence corresponding to VL15 set forth in Table 1.6;a heavy chain variable region comprising an amino acid sequence corresponding to VH16 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence corresponding to VL16 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence corresponding to VH17 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence corresponding to VL17 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence corresponding to VH18 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence corresponding to VL18 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence corresponding to VH19 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence corresponding to VL19 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence corresponding to VH20 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence corresponding to VL20 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence corresponding to VH21 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence corresponding to VL21 set forth in Table 1.6; or a heavy chain variable region comprising an amino acid sequence corresponding to VH22 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence corresponding to VL22 set forth in Table 1.6.
[0223] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence corresponding to VH1 set forth in Table 1.6, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence corresponding to VL1 set forth in Table 1.6; a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence corresponding to VH2 set forth in Table 1.6, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence corresponding to VL2 set forth in Table 1.6;a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence corresponding to VH3 set forth in Table 1.6, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence corresponding to VL3 set forth in Table 1.6; a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence corresponding to VH4 set forth in Table 1.6, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence corresponding to VL4 set forth in Table 1.6; a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence corresponding to VH5 set forth in Table 1.6, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence corresponding to VL5 set forth in Table 1.6; a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence corresponding to VH6 set forth in Table 1.6, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence corresponding to VL6 set forth in Table 1.6; a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence corresponding to VH7 set forth in Table 1.6, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence corresponding to VL7 set forth in Table 1.6; a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence corresponding to VH8 set forth in Table 1.6, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence corresponding to VL8 set forth in Table 1.6; a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence corresponding to VH9 set forth in Table 1.6, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chainvariable region comprising an amino acid sequence corresponding to VL9 set forth in Table 1.6; a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence corresponding to VH10 set forth in Table 1.6, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence corresponding to VL10 set forth in Table 1.6; a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence corresponding to VH11 set forth in Table 1.6, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence corresponding to VL11 set forth in Table 1.6; a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence corresponding to VH12 set forth in Table 1.6, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence corresponding to VL12 set forth in Table 1.6; a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence corresponding to VH13 set forth in Table 1.6, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence corresponding to VL13 set forth in Table 1.6; a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence corresponding to VH14 set forth in Table 1.6, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence corresponding to VL14 set forth in Table 1.6; a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence corresponding to VH15 set forth in Table 1.6, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence corresponding to VL15 set forth in Table 1.6;a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence corresponding to VH16 set forth in Table 1.6, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence corresponding to VL16 set forth in Table 1.6; a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence corresponding to VH17 set forth in Table 1.6, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence corresponding to VL17 set forth in Table 1.6; a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence corresponding to VH18 set forth in Table 1.6, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence corresponding to VL18 set forth in Table 1.6; a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence corresponding to VH19 set forth in Table 1.6, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence corresponding to VL19 set forth in Table 1.6; a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence corresponding to VH20 set forth in Table 1.6, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence corresponding to VL20 set forth in Table 1.6; a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence corresponding to VH21 set forth in Table 1.6, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence corresponding to VL21 set forth in Table 1.6; or a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence corresponding to VH22 set forth in Table 1.6, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chainvariable region comprising an amino acid sequence corresponding to VL22 set forth in Table 1.6.
[0224] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a heavy chain variable region corresponding to VH1 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL1 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a heavy chain variable region corresponding to VH2 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL2 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a heavy chain variable region corresponding to VH3 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL3 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a heavy chain variable region corresponding to VH4 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode alight chain variable region corresponding to VL4 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a heavy chain variable region corresponding to VH5 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL5 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a heavy chain variable region corresponding to VH6 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL6 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a heavy chain variable region corresponding to VH7 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL7 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a heavy chain variable region corresponding to VH8 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL8 set forth in Table 1.6, or a sequence havingat least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a heavy chain variable region corresponding to VH9 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL9 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a heavy chain variable region corresponding to VH10 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL10 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a heavy chain variable region corresponding to VH11 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL11 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a heavy chain variable region corresponding to VH12 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL12 set forth in Table 1.6, or a sequencehaving at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a heavy chain variable region corresponding to VH13 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL13 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a heavy chain variable region corresponding to VH14 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL14 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a heavy chain variable region corresponding to VH15 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL15 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a heavy chain variable region corresponding to VH16 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL16 set forth in Table 1.6, or a sequencehaving at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a heavy chain variable region corresponding to VH17 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL17 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a heavy chain variable region corresponding to VH18 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL18 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a heavy chain variable region corresponding to VH19 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL19 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a heavy chain variable region corresponding to VH20 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL20 set forth in Table 1.6, or a sequencehaving at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a heavy chain variable region corresponding to VH21 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL21 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; or a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a heavy chain variable region corresponding to VH22 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL22 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0225] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide which can encode a heavy chain variable region corresponding to VH1 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL1 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide which can encode a heavy chain variable region corresponding to VH2 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL2 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide which can encode a heavy chain variable region corresponding to VH3 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence encoded by anucleotide sequence which can encode a light chain variable region corresponding to VL3 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide which can encode a heavy chain variable region corresponding to VH4 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL4 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide which can encode a heavy chain variable region corresponding to VH5 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL5 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide which can encode a heavy chain variable region corresponding to VH6 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL6 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide which can encode a heavy chain variable region corresponding to VH7 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL7 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide which can encode a heavy chain variable region corresponding to VH8 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL8 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide which can encode a heavy chain variable region corresponding to VH9 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL9 set forth in Table 1.6;a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide which can encode a heavy chain variable region corresponding to VH10 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL10 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide which can encode a heavy chain variable region corresponding to VH11 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL11 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide which can encode a heavy chain variable region corresponding to VH12 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL12 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide which can encode a heavy chain variable region corresponding to VH13 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL13 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide which can encode a heavy chain variable region corresponding to VH14 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL14 set forth in Table 1.6;a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide which can encode a heavy chain variable region corresponding to VH15 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL15 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide which can encode a heavy chain variable region corresponding to VH16 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence encoded bya nucleotide sequence which can encode a light chain variable region corresponding to VL16 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide which can encode a heavy chain variable region corresponding to VH17 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL17 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide which can encode a heavy chain variable region corresponding to VH18 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL18 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide which can encode a heavy chain variable region corresponding to VH19 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL19 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide which can encode a heavy chain variable region corresponding to VH20 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL20 set forth in Table 1.6; a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide which can encode a heavy chain variable region corresponding to VH21 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL21 set forth in Table 1.6; or a heavy chain variable region comprising an amino acid sequence encoded by a nucleotide which can encode a heavy chain variable region corresponding to VH22 set forth in Table 1.6, and a light chain variable region comprising an amino acid sequence encoded by a nucleotide sequence which can encode a light chain variable region corresponding to VL22 set forth in Table 1.6.
[0226] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain (HC) comprising an amino acid sequence of SEQ ID NO: 481, 483, 485, 487, 735, 737, 739, 741, 743, 745, or 747, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0227] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain (LC) comprising an amino acid sequence of SEQ ID NO: 482, 484, 486, 488, 736, 738, 740, 742, 744, 746, or 748, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0228] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain (HC) comprising an amino acid sequence of SEQ ID NO: 741, 743, 739, 747, 485, 483, 735, 737, or 745, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0229] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain (LC) comprising an amino acid sequence of SEQ ID NO: 742, 744, 740, 748, 486, 484, 736, 738, or 746, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0230] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain (HC) comprising an amino acid sequence of SEQ ID NO: 741, 743, 739, or 747, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0231] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain (LC) comprising an amino acid sequence of SEQ ID NO: 742, 744, 740, or 748, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0232] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain (HC) comprising an amino acid sequence of SEQ ID NO: 481, 483, 485, 487, 735, 737,739, 741, 743, 745, or 747, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; and a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain (LC) comprising an amino acid sequence of SEQ ID NO: 482, 484, 486, 488, 736, 738, 740, 742, 744, 746, or 748, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0233] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain (HC) comprising an amino acid sequence of SEQ ID NO: 485, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; and a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain (LC) comprising an amino acid sequence of SEQ ID NO: 486, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0234] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain HC comprising an amino acid sequence of SEQ ID NO: 481, 483, 485, 487, 735, 737, 739, 741, 743, 745, or 747; and a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain (LC) comprising an amino acid sequence of SEQ ID NO: 482, 484, 486, 488, 736, 738, 740, 742, 744, 746, or 748.
[0235] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain HC comprising an amino acid sequence of SEQ ID NO: 741, 743, 739, 747, 485, 483, 735, 737, or 745; and a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain (LC) comprising an amino acid sequence of SEQ ID NO: 742, 744, 740, 748, 486, 484, 736, 738, or 746.
[0236] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain HC comprising an amino acid sequence of SEQ ID NO: 741, 743, 739, or 747; and a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain (LC) comprising an amino acid sequence of SEQ ID NO: 742, 744, 740, or 748.
[0237] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a heavychain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 451, 453, 455, 457, 721, 723, 725, 727, 729, 731, or 733 or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0238] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 727, 729, 725, 733, 455, 453, 721, 723, 731, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0239] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 452, 454, 456, 458, 722, 724, 726, 728, 730, 732, or 734, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0240] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 728, 730, 726, 734, 456, 454, 722, 724, 732, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0241] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 451, 453, 455, 457, 721, 723, 725, 727, 729, 731, or 733, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; and a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 452, 454, 456, 458, 722, 724, 726, 728, 730, 732, or 734, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0242] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 727, 729, 725, 733, 455, 453, 721, 723, 731, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; and a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain variable region (VL)comprising an amino acid sequence of SEQ ID NO: 728, 730, 726, 734, 456, 454, 722, 724, 732, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0243] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 727, 729, 725, or 733, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; and a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 728, 730, 726, or 734, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0244] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 451, 453, 455, 457, 721, 723, 725, 727, 729, 731, or 733; and a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 452, 454, 456, 458, 722, 724, 726, 728, 730, 732, or 734.
[0245] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 727, 729, 725, 733, 455, 453, 721, 723, 731; and a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 728, 730, 726, 734, 456, 454, 722, 724, 732.
[0246] In some embodiments, the isolated antibody, or antigen-binding fragment thereof, comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 727, 729, 725, or 733; and a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 728, 730, 726, or 734.
[0247] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprisesa heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 3; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 7, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 9; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 13, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 19, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 20, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 21; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 511, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 512, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 513; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 517, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 518, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 519; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 523, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 524, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 525; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 529, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 530, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 531; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 535, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 536, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 537; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 541, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 542, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 543; or a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 547, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 548, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 549.
[0248] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 91, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 92, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 93; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 97, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 99; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 103, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 104, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 105; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 109, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 110, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 111; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 553, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 554, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 555; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 559, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 560, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 561; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 565, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 566, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 567; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 571, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 572, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 573; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 577, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 578, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 579; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 583, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 584, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 585; ora heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 589, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 590, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 591.
[0249] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 181, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 182, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 183; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 187, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 188, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 189; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 193, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 194, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 195; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 199, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 200, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 201; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 595, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 596, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 597; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 601, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 602, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 603; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 607, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 608, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 609; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 613, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 614, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 615; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 619, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 620, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 621;a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 625, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 626, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 627; or a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 631, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 632, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 633.
[0250] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 271, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 272, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 273; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 277, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 278, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 279; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 283, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 284, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 285; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 289, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 290, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 291; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 637, a heavy chain CDR2 comprising the amino acid sequence GAS, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 639; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 643, a heavy chain CDR2 comprising the amino acid sequence AAS, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 645; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 649, a heavy chain CDR2 comprising the amino acid sequence AAS, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 651; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 655, a heavy chain CDR2 comprising the amino acid sequence GAS, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 657;a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 661, a heavy chain CDR2 comprising the amino acid sequence GAS, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 663; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 667, a heavy chain CDR2 comprising the amino acid sequence GAS, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 669; or a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 673, a heavy chain CDR2 comprising the amino acid sequence VTS, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 675.
[0251] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 361, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 362, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 363; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 367, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 368, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 369; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 373, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 374, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 375; or a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 379, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 380, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 381; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 679, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 680, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 681; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 685, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 686, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 687; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 691, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 692, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 693;a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 697, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 698, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 699; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 703, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 704, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 705; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 709, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 710, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 711; or a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 715, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 716, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 717.
[0252] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 13, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 15; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 103, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 104, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 105; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 193, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 194, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 195; a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 283, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 284, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 285; or a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 373, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 374, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 375.
[0253] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain CDR1 selected from the group consisting of SEQ ID NOs: 1, 7, 13, 19, 511, 517, 523, 529, 535, 541, 547, 91, 97, 103, 109, 553, 559, 565, 571, 577, 583, 589, 181, 187, 193, 199, 595, 601, 607, 613, 619, 625, 631, 271, 277, 283, 289, 637, 643, 649,655, 661, 667, 673, 361, 367, 373, 379, 679, 685, 691, 697, 703, 709, and 715, and variants having conservative modifications thereof.
[0254] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain CDR2 selected from the group consisting of SEQ ID NOs: 2, 8, 14, 20, 512, 518, 524, 530, 536, 542, 548, 92, 98, 104, 110, 554, 560, 566, 572, 578, 584, 590, 182, 188, 194, 200, 596, 602, 608, 614, 620, 626, 632, 272, 278, 284, 290, the amino acid sequence GAS, the amino acid sequence AAS, the amino acid sequence VTS, SEQ ID NOs: 362, 368, 374, 380, 680, 686, 692, 698, 704, 710, and 716, and variants having conservative modifications thereof.
[0255] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain CDR3 selected from the group consisting of SEQ ID NOs: 3, 9, 15, 21, 513, 519, 525, 531, 537, 543, 549, 93, 99, 105, 111, 555, 561, 567, 573, 579, 585, 591, 183, 189, 195, 201, 597, 603, 609, 615, 621, 627, 633, 273, 279, 285, 291, 639, 645, 651, 657, 663, 669, 675, 363, 369, 375381, 681, 687, 693, 699, 705, 711, and 717, and variants having conservative modifications thereof.
[0256] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 6; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 12; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 16, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 17, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 18; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 22, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 24; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 514, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 515, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 516;a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 520, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 521, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 522; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 526, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 527, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 528; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 532, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 533, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 534; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 538, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 539, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 540; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 544, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 545, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 546; or a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 550, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 551, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 552.
[0257] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 94, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 95, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 96; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 100, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 101, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 102; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 106, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 107, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 108; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 112, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 113, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 114;a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 556, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 557, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 558; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 562, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 563, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 564; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 568, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 569, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 570; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 574, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 575, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 576; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 580, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 581, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 582; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 586, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 587, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 588; or a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 592, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 593, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 594.
[0258] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 184, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 185, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 186; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 190, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 191, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 192; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 196, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 197, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 198;a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 202, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 203, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 204; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 598, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 599, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 600; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 604, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 605, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 606; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 610, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 611, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 612; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 616, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 617, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 618; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 622, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 623, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 624; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 628, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 629, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 630; or a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 634, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 635, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 636.
[0259] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 274, a light chain CDR2 comprising the amino acid sequence TLS, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 276; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 280, a light chain CDR2 comprising the amino acid sequence GAS, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 282;a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 286, a light chain CDR2 comprising the amino acid sequence AGS, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 288; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 292, a light chain CDR2 comprising the amino acid sequence EVS, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 294; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 640, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 641, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 642; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 646, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 647, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 648; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 652, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 653, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 654; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 658, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 659, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 660; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 664, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 665, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 666; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 670, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 671, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 672; or a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 676, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 677, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 678.
[0260] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 364, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 365, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 366;a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 370, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 371, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 372; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 376, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 377, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 378; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 382, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 383, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 384; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 682, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 683, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 684; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 688, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 689, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 690; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 694, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 695, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 696; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 700, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 701, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 702; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 706, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 707, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 708; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 712, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 713, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 714; or a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 718, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 719, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 720.
[0261] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprisesa light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 16, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 17, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 18; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 106, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 107, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 108; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 196, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 197, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 198; a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 286, a light chain CDR2 comprising the amino acid sequence AGS, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 288; or a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 376, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 377, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 378.
[0262] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the heavy chain CDR1, the heavy chain CDR2, the heavy chain CDR3, the light chain CDR1, the light chain CDR2 and the light chain CDR3 comprising the amino acid sequence of a) SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively; b) SEQ ID NOs: 7, 8, 9, 10, 11, and 12, respectively; c) SEQ ID NOs: 13, 14, 15, 16, 17, and 18, respectively; d) SEQ ID NOs: 19, 20, 21, 22, 23, and 24, respectively; e) SEQ ID NOs: 511, 512, 513, 514, 515, and 516, respectively; f) SEQ ID NOs: 517, 518, 519, 520, 521, and 522, respectively; g) SEQ ID NOs: 523, 524, 525, 526, 527, and 528, respectively; h) SEQ ID NOs: 529, 530, 531, 532, 533, and 534, respectively; i) SEQ ID NOs: 535, 536, 537, 538, 539, and 540, respectively; j) SEQ ID NOs: 541, 542, 543, 544, 545, and 546, respectively; or k) SEQ ID NOs: 547, 548, 549, 550, 551, and 552, respectively.
[0263] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the heavy chain CDR1, the heavy chain CDR2, the heavy chain CDR3, the lightchain CDR1, the light chain CDR2 and the light chain CDR3 comprising the amino acid sequence of a) SEQ ID NOs: 91, 92, 93, 94, 95, and 96, respectively; b) SEQ ID NOs: 97, 98, 99, 100, 101, and 102, respectively; c) SEQ ID NOs: 103, 104, 105, 106, 107, and 108, respectively; d) SEQ ID NOs: 109, 110, 111, 112, 113, and 114, respectively; e) SEQ ID NOs: 553, 554, 555, 556, 557, and 558, respectively; f) SEQ ID NOs: 559, 560, 561, 562, 563, and 564, respectively; g) SEQ ID NOs: 565, 566, 567, 568, 569, and 570, respectively; h) SEQ ID NOs: 571, 572, 573, 574, 575, and 576, respectively; i) SEQ ID NOs: 577, 578, 579, 580, 581, and 582, respectively; j) SEQ ID NOs: 583, 584, 585, 586, 587, and 588, respectively; or k) SEQ ID NOs: 589, 590, 591, 592, 593, and 594, respectively.
[0264] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the heavy chain CDR1, the heavy chain CDR2, the heavy chain CDR3, the light chain CDR1, the light chain CDR2 and the light chain CDR3 comprising the amino acid sequence of a) SEQ ID NOs: 181, 182, 183, 184, 185, and 186, respectively; b) SEQ ID NOs: 187, 188, 189, 190, 191, and 192, respectively; c) SEQ ID NOs: 193, 194, 195, 196, 197, and 198, respectively; d) SEQ ID NOs: 199, 200, 201, 202, 203, and 204, respectively; e) SEQ ID NOs: 595, 596, 597, 598, 599, and 600, respectively; f) SEQ ID NOs: 601, 602, 603, 604, 605, and 606, respectively; g) SEQ ID NOs: 607, 608, 609, 610, 611, and 612, respectively; h) SEQ ID NOs: 613, 614, 615, 616, 617, and 618, respectively; i) SEQ ID NOs: 619, 620, 621, 622, 623, and 624, respectively; j) SEQ ID NOs: 625, 626, 627, 628, 629, and 630, respectively; or k) SEQ ID NOs: 631, 632, 633, 634, 635, and 636, respectively.
[0265] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the heavy chain CDR1, the heavy chain CDR2, the heavy chain CDR3, the light chain CDR1, the light chain CDR2 and the light chain CDR3 comprising the amino acid sequence ofa) SEQ ID NOs: 271, 272, 273, 274, the amino acid sequence TLS, and SEQ ID NO: 276, respectively; b) SEQ ID NOs: 277, 278, 279, 280, the amino acid sequence GAS, and SEQ ID NO: 282, respectively; c) SEQ ID NOs: 283, 284, 285, 286, the amino acid sequence AGS, and SEQ ID NO: 288, respectively; d) SEQ ID NOs: 289, 290, 291, 292, the amino acid sequence EVS, and SEQ ID NO: 294, respectively; e) SEQ ID NO: 637, the amino acid sequence GAS, SEQ ID NOs: 639, 640, 641, and 642, respectively; f) SEQ ID NOs: 643, the amino acid sequence AAS, SEQ ID NOs: 645, 646, 647, and 648, respectively; g) SEQ ID NOs: 649, the amino acid sequence AAS, SEQ ID NOs: 651, 652, 653, and 654, respectively; h) SEQ ID NOs: 655, the amino acid sequence GAS, SEQ ID NOs: 657, 658, 659, and 660, respectively; i) SEQ ID NOs: 661, the amino acid sequence GAS, SEQ ID NOs: 663, 664, 665, and 666, respectively; j) SEQ ID NOs: 667, the amino acid sequence GAS, SEQ ID NOs: 669, 670, 671, and 672, respectively; or k) SEQ ID NOs: 673, the amino acid sequence VTS, SEQ ID NOs: 675, 676, 677, and 678, respectively.
[0266] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the heavy chain CDR1, the heavy chain CDR2, the heavy chain CDR3, the light chain CDR1, the light chain CDR2 and the light chain CDR3 comprising the amino acid sequence of a) SEQ ID NOs: 361, 362, 363, 364, 365, and 366, respectively; b) SEQ ID NOs: 367, 368, 369, 370, 371, and 372, respectively; c) SEQ ID NOs: 373, 374, 375, 376, 377, and 378, respectively; d) SEQ ID NOs: 379, 380, 381, 382, 383, and 384, respectively; e) SEQ ID NOs: 679, 680, 681, 682, 683, and 684, respectively; f) SEQ ID NOs: 685, 686, 687, 688, 689, and 690, respectively; g) SEQ ID NOs: 691, 692, 693, 694, 695, and 696, respectively;h) SEQ ID NOs: 697, 698, 699, 700, 701, and 702, respectively; i) SEQ ID NOs: 703, 704, 705, 706, 707, and 708, respectively; j) SEQ ID NOs: 709, 710, 711, 712, 713, and 714, respectively; or k) SEQ ID NOs: 715, 716, 717, 718, 719, and 720, respectively.
[0267] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the heavy chain CDR1, the heavy chain CDR2, the heavy chain CDR3, the light chain CDR1, the light chain CDR2 and the light chain CDR3 comprising the amino acid sequence of SEQ ID NOs: 529, 530, 531, 532, 533, and 534, respectively; SEQ ID NOs: 571, 572, 573, 574, 575, and 576, respectively; SEQ ID NOs: 613, 614, 615, 616, 617, and 618, respectively; SEQ ID NOs: 655, the amino acid sequence GAS, SEQ ID NOs: 657, 658, 659, and 660, respectively; or SEQ ID NOs: 697, 698, 699, 700, 701, and 702, respectively.
[0268] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the heavy chain CDR1, the heavy chain CDR2, the heavy chain CDR3, the light chain CDR1, the light chain CDR2 and the light chain CDR3 comprising the amino acid sequence of SEQ ID NOs: 535, 536, 537, 538, 539, and 540, respectively; SEQ ID NOs: 577, 578, 579, 580, 581, and 582, respectively; SEQ ID NOs: 619, 620, 621, 622, 623, and 624, respectively; SEQ ID NOs: 661, the amino acid sequence GAS, SEQ ID NOs: 663, 664, 665, and 666, respectively; or SEQ ID NOs: 703, 704, 705, 706, 707, and 708, respectively.
[0269] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the heavy chain CDR1, the heavy chain CDR2, the heavy chain CDR3, the light chain CDR1, the light chain CDR2 and the light chain CDR3 comprising the amino acid sequence of SEQ ID NOs: 523, 524, 525, 526, 527, and 528, respectively; SEQ ID NOs: 565, 566, 567, 568, 569, and 570, respectively; SEQ ID NOs: 607, 608, 609, 610, 611, and 612, respectively; SEQ ID NOs: 649, the amino acid sequence AAS, SEQ ID NOs: 651, 652, 653, and 654, respectively; orSEQ ID NOs: 691, 692, 693, 694, 695, and 696, respectively.
[0270] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the heavy chain CDR1, the heavy chain CDR2, the heavy chain CDR3, the light chain CDR1, the light chain CDR2 and the light chain CDR3 comprising the amino acid sequence of SEQ ID NOs: 547, 548, 549, 550, 551, and 552, respectively; SEQ ID NOs: 589, 590, 591, 592, 593, and 594, respectively; SEQ ID NOs: 631, 632, 633, 634, 635, and 636, respectively; SEQ ID NOs: 673, the amino acid sequence VTS, SEQ ID NOs: 675, 676, 677, and 678, respectively; or SEQ ID NOs: 715, 716, 717, 718, 719, and 720, respectively.
[0271] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the heavy chain CDR1, the heavy chain CDR2, the heavy chain CDR3, the light chain CDR1, the light chain CDR2 and the light chain CDR3 comprising the amino acid sequence of SEQ ID NOs: 13, 14, 15, 16, 17, and 18, respectively; SEQ ID NOs: 103, 104, 105, 106, 107, and 108, respectively; SEQ ID NOs: 193, 194, 195, 196, 197, and 198, respectively; SEQ ID NOs: 283, 284, 285, 286, the amino acid sequence AGS, and SEQ ID NO: 288, respectively; or SEQ ID NOs: 373, 374, 375, 376, 377, and 378, respectively.
[0272] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the heavy chain CDR1, the heavy chain CDR2, the heavy chain CDR3, the light chain CDR1, the light chain CDR2 and the light chain CDR3 comprising the amino acid sequence of SEQ ID NOs: 7, 8, 9, 10, 11, and 12, respectively; SEQ ID NOs: 97, 98, 99, 100, 101, and 102, respectively; SEQ ID NOs: 187, 188, 189, 190, 191, and 192, respectively; SEQ ID NOs: 283, 284, 285, 286, the amino acid sequence AGS, and SEQ ID NO: 288, respectively; or SEQ ID Nos: 367, 368, 369, 370, 371, and 372, respectively.
[0273] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the heavy chain CDR1, the heavy chain CDR2, the heavy chain CDR3, the lightchain CDR1, the light chain CDR2 and the light chain CDR3 comprising the amino acid sequence of SEQ ID NOs: 511, 512, 513, 514, 515, and 516, respectively; SEQ ID NOs: 553, 554, 555, 556, 557, and 558, respectively; SEQ ID NOs: 595, 596, 597, 598, 599, and 600, respectively; SEQ ID NOs: 637, the amino acid sequence GAS, SEQ ID NOs: 639, 640, 641, and 642, respectively; or SEQ ID NOs: 679, 680, 681, 682, 683, and 684, respectively.
[0274] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the heavy chain CDR1, the heavy chain CDR2, the heavy chain CDR3, the light chain CDR1, the light chain CDR2 and the light chain CDR3 comprising the amino acid sequence of SEQ ID NOs: 517, 518, 519, 520, 521, and 522, respectively; SEQ ID NOs: 559, 560, 561, 562, 563, and 564, respectively; SEQ ID NOs: 601, 602, 603, 604, 605, and 606, respectively; SEQ ID NOs: 643, the amino acid sequence AAS, SEQ ID NOs: 645, 646, 647, and 648, respectively; or SEQ ID NOs: 685, 686, 687, 688, 689, and 690, respectively.
[0275] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises the heavy chain CDR1, the heavy chain CDR2, the heavy chain CDR3, the light chain CDR1, the light chain CDR2 and the light chain CDR3 comprising the amino acid sequence of SEQ ID NOs: 541, 542, 543, 544, 545, and 546, respectively; SEQ ID NOs: 583, 584, 585, 586, 587, and 588, respectively; SEQ ID NOs: 625, 626, 627, 628, 629, and 630, respectively; SEQ ID NOs: 667, the amino acid sequence GAS, SEQ ID NOs: 669, 670, 671, and 672, respectively; or SEQ ID NOs: 709, 710, 711, 712, 713, and 714, respectively.
[0276] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 451, 453, 455, 457, 721, 723, 725, 727, 729, 731, or 733, or a sequence having at least80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; and / or a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 452, 454, 456, 458, 722, 724, 726, 728, 730, 732, or 734, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0277] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 455, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; and / or a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 456, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0278] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 451, 453, 455, 457, 721, 723, 725, 727, 729, 731, or 733; and / or a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 452, 454, 456, 458, 722, 724, 726, 728, 730, 732, or 734.
[0279] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 455; and / or a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 456.
[0280] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain variable region (VH) comprising an amino acid sequence encoded by a nucleotide which can encode the VH sequence of SEQ ID NO: 451, 453, 455, 457, 721, 723, 725, 727, 729, 731, or 733, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; and / or a light chain variable region (VL) comprising an amino acid sequence encoded by a nucleotide sequence which can encode the VL sequence of SEQ ID NO: 452, 454, 456, 458,722, 724, 726, 728, 730, 732, or 734, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0281] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain variable region (VH) comprising an amino acid sequence encoded by a nucleotide sequence which can encode the VH sequence of SEQ ID NO: 451, 453, 455, or 457, 721, 723, 725, 727, 729, 731, or 733; and / or a light chain variable region (VL) comprising an amino acid sequence encoded by a nucleotide sequence which can encode the VL sequence of SEQ ID NO: 452, 454, 456, 458, 722, 724, 726, 728, 730, 732, or 734.
[0282] In some embodiments, the anti-TCRγδ or antigen-binding fragment comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 451, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 452, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 453, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 454, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 455, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 456, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; or a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 457, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 458, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 721, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%,96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 722, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 723, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 724, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 725, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 726, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 727, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 728, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 729, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 730, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 731, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 732, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; or a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 733, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 734, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0283] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 451, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 452; a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 453, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 454; a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 455, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 456; a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 457, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 458; a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 721, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 722; a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 723, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 724; a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 725, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 726; a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 727, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 728; a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 729, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 730; a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 731, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 732; ora heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 733, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 734.
[0284] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 451, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence of SEQ ID NO: 452; a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 453, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence of SEQ ID NO: 454; a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 455, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence of SEQ ID NO: 456; or a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 457, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence of SEQ ID NO: 458; a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 721, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence of SEQ ID NO: 722; a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 723, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence of SEQ ID NO: 724; a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 725, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence of SEQ ID NO: 726;a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 727, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence of SEQ ID NO: 728; a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 729, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence of SEQ ID NO: 730; a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 731, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence of SEQ ID NO: 732; or a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 of a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 733, and a light chain CDR1, a light chain CDR2 and a light chain CDR3 of a light chain variable region comprising an amino acid sequence of SEQ ID NO: 734.
[0285] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprises a heavy chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VH sequence of SEQ ID NO: 451, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VL sequence of SEQ ID NO: 452, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VH sequence of SEQ ID NO: 453, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VL sequence of SEQ ID NO: 454, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto;a heavy chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VH sequence of SEQ ID NO: 455, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VL sequence of SEQ ID NO: 456, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VH sequence of SEQ ID NO: 457, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VL sequence of SEQ ID NO: 458, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VH sequence of SEQ ID NO: 721, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VL sequence of SEQ ID NO: 722, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VH sequence of SEQ ID NO: 723, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VL sequence of SEQ ID NO: 724, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VH sequence of SEQ ID NO: 725, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VL sequence of SEQ ID NO: 726,or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VH sequence of SEQ ID NO: 727, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VL sequence of SEQ ID NO: 728, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VH sequence of SEQ ID NO: 729, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VL sequence of SEQ ID NO: 730, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a heavy chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VH sequence of SEQ ID NO: 731, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VL sequence of SEQ ID NO: 732, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; or a heavy chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VH sequence of SEQ ID NO: 733, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a light chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VL sequence of SEQ ID NO: 734, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0286] In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment comprisesa heavy chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VH sequence of SEQ ID NO: 451, and a light chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VL sequence of SEQ ID NO: 452; a heavy chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VH sequence of SEQ ID NO: 453, and a light chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VL sequence of SEQ ID NO: 454; a heavy chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VH sequence of SEQ ID NO: 455, and a light chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VL sequence of SEQ ID NO: 456; a heavy chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VH sequence of SEQ ID NO: 457, and a light chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VL sequence of SEQ ID NO: 458; a heavy chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VH sequence of SEQ ID NO: 721, and a light chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VL sequence of SEQ ID NO: 722; a heavy chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VH sequence of SEQ ID NO: 723, and a light chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VL sequence of SEQ ID NO: 724; a heavy chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VH sequence of SEQ ID NO: 725, and a light chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VL sequence of SEQ ID NO: 726; a heavy chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VH sequence of SEQ ID NO: 727, and a light chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VL sequence of SEQ ID NO: 728;a heavy chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VH sequence of SEQ ID NO: 729, and a light chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VL sequence of SEQ ID NO: 730; a heavy chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VH sequence of SEQ ID NO: 731, and a light chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VL sequence of SEQ ID NO: 732; or a heavy chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VH sequence of SEQ ID NO: 733, and a light chain variable region comprising an amino acid sequence encoded by the nucleotide sequence which can encode the VL sequence of SEQ ID NO: 734.
[0287] In various embodiments, the anti-TCRγδ antibody or antigen-binding fragment does not have non-specific binding to Immunoglobulin G (IgG). In some embodiments, the anti-TCRγδ antibody or antigen-binding fragment does not bind to the constant region of Immunoglobulin G (IgG).
[0288] The specific antibodies defined by CDR and / or variable domain sequence discussed in the above paragraphs may include additional modifications.
[0289] The TCRγδ-specific antibodies or antigen-binding fragments described herein include variants having single or multiple amino acid substitutions, deletions, or additions that retain the biological properties (e.g., binding affinity or immune effector activity) of the described TCRγδ-specific antibodies or antigen-binding fragments. In the context of the present disclosure the following notations are, unless otherwise indicated, used to describe a mutation; i) substitution of an amino acid in a given position is written as e.g. S228P which means a substitution of a Serine in position 228 with a Proline; and ii) for specific variants the specific three or one letter codes are used, including the codes Xaa and X to indicate any amino acid residue. Thus, the substitution of Serine for Arginine in position 228 is designated as: S228P, or the substitution of any amino acid residue for Serine in position 228 is designated as S228P. In case of deletion of Serine in position 228 it is indicated by S228*. The skilled person may produce variants having single or multiple amino acid substitutions, deletions, or additions.
[0290] These variants may include: (a) variants in which one or more amino acid residues are substituted with conservative or nonconservative amino acids, (b) variants in which oneor more amino acids are added to or deleted from the polypeptide, (c) variants in which one or more amino acids include a substituent group, and (d) variants in which the polypeptide is fused with another peptide or polypeptide such as a fusion partner, a protein tag or other chemical moiety, that may confer useful properties to the polypeptide, such as, for example, an epitope for an antibody, a polyhistidine sequence, a biotin moiety and the like. Antibodies or antigen-binding fragments described herein may include variants in which amino acid residues from one species are substituted for the corresponding residue in another species, either at the conserved or nonconserved positions. In other embodiments, amino acid residues at nonconserved positions are substituted with conservative or nonconservative residues. The techniques for obtaining these variants, including genetic (deletions, mutations, etc.), chemical, and enzymatic techniques, are known to persons having ordinary skill in the art.
[0291] Amino acid substitutions may be conservative, by which it is meant the substituted amino acid has similar chemical properties to the original amino acid. A skilled person would understand which amino acids share similar chemical properties. For example, the following groups of amino acids share similar chemical properties such as size, charge and polarity: Group 1 - Ala, Ser, Thr, Pro, Gly; Group 2 - Asp, Asn, Glu, Gln; Group 3 - His, Arg, Lys; Group 4 - Met, Leu, Ile, Val, Cys; Group 5 - Phe, Thy, Trp.
[0292] The TCRγδ-specific antibodies or antigen-binding fragments described herein may embody several antibody isotypes, such as IgM, IgD, IgG, IgA and IgE. In some embodiments the antibody isotype is IgG1, IgG2, IgG3, or IgG4 isotype, preferably IgG1 or IgG4 isotype. In some embodiments the antibody isotype is IgA1 or IgA2. Antibody or antigen-binding fragment thereof specificity is largely determined by the amino acid sequence, and arrangement, of the CDRs. Therefore, the CDRs of one isotype may be transferred to another isotype without altering antigen specificity. Alternatively, techniques have been established to cause hybridomas to switch from producing one antibody isotype to another (isotype switching) without altering antigen specificity. Accordingly, such antibody isotypes are within the scope of the described antibodies or antigen-binding fragments.
[0293] The antibody or antigen-binding fragment can have any level of affinity or avidity for a TCRγδ. In some embodiments, the antibody or antigen-binding fragment may bind the TCRγδ with a range of affinities (KD). In various embodiments, the antibody or antigen- binding fragment binds to the TCRγδ with high affinity, for example, with a KD equal to or less than about 10−7M, such as but not limited to, 1-9.9 (or any range or value therein, suchas 1, 2, 3, 4, 5, 6, 7, 8, or 9)×10−8M, 10−9M, 10−10M, 10−11M, 10−12M, 10−13M, 10−14M, 10−15M or any range or value therein, as determined by, e.g., surface plasmon resonance or the Kinexa method, as practiced by those of skill in the art. One example affinity is equal to or less than 1×10−8M. Another example affinity is equal to or less than 1×10−9M.
[0294] Methods of testing antibodies for the ability to bind to the target TCRγδ or any portion thereof are known in the art and include any antibody-antigen binding assay, such as, for example, radioimmunoassay (RIA), Western blot, enzyme-linked immunosorbent assay (ELISA), immunoprecipitation, and competitive inhibition assays.
[0295] Also disclosed are isolated polynucleotides that encode the antibodies or antigen- binding fragments that specifically bind to a TCRγδ. The isolated polynucleotides capable of encoding the heavy chain (HC) sequence, light chain (LC) sequence, heavy chain variable region (VH) sequence, and / or light chain variable region (VL) sequence may be included on the same, or different, vectors to produce antibodies or antigen-binding fragments. Polynucleotide sequences that may encode the HC, LC, VH and / or VL of an anti-TCRγδ antibody described herein, or an antigen-binding fragment thereof, are also within the scope of the present disclosure.
[0296] In some embodiments, an isolated polynucleotide encoding an anti-TCRγδ antibody or antigen-binding fragment comprises a nucleotide sequence which can encode a heavy chain sequence corresponding to HC1-22 set forth in Table 1.7, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; and / or a nucleotide sequence which can encode a light chain sequence corresponding to LC1- 22 set forth in Table 1.7, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0297] In some embodiments, an isolated polynucleotide encoding an anti-TCRγδ antibody or antigen-binding fragment comprises a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH1-22 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; and / or a nucleotide sequence which can encode a light chain variable region sequence corresponding to VL1-22 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0298] In some embodiments, an isolated polynucleotide encoding an anti-TCRγδ antibody or antigen-binding fragment comprises a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH1 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a nucleotide sequence which can encode a light chain variable region corresponding to VL1 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH2 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a nucleotide sequence which can encode a light chain variable region sequence corresponding to VL2 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH3 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a nucleotide sequence which can encode a light chain variable region sequence corresponding to VL3 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH4 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a nucleotide sequence which can encode a light chain variable region sequence corresponding to VL4 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH5 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a nucleotide sequence which can encode a light chain variable region sequence corresponding to VL5 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto;a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH6 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a nucleotide sequence which can encode a light chain variable region sequence corresponding to VL6 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH7 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a nucleotide sequence which can encode a light chain variable region sequence corresponding to VL7 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH8 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a nucleotide sequence which can encode a light chain variable region sequence corresponding to VL8 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH9 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a nucleotide sequence which can encode a light chain variable region sequence corresponding to VL9 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH10 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a nucleotide sequence which can encode a light chain variable region sequence corresponding to VL10 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH11 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and anucleotide sequence which can encode a light chain variable region sequence corresponding to VL11 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH12 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a nucleotide sequence which can encode a light chain variable region sequence corresponding to VL12 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH13 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a nucleotide sequence which can encode a light chain variable region sequence corresponding to VL13 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH14 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a nucleotide sequence which can encode a light chain variable region sequence corresponding to VL14 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH15 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a nucleotide sequence which can encode a light chain variable region sequence corresponding to VL15 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH16 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a nucleotide sequence which can encode a light chain variable region sequence corresponding to VL16 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto;a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH17 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a nucleotide sequence which can encode a light chain variable region sequence corresponding to VL17 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH18 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a nucleotide sequence which can encode a light chain variable region sequence corresponding to VL18 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH19 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a nucleotide sequence which can encode a light chain variable region sequence corresponding to VL19 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH20 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a nucleotide sequence which can encode a light chain variable region sequence corresponding to VL20 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH21 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and a nucleotide sequence which can encode a light chain variable region sequence corresponding to VL21 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; or a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH22 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto, and anucleotide sequence which can encode a light chain variable region sequence corresponding to VL22 set forth in Table 1.6, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.
[0299] In some embodiments, an isolated polynucleotide encoding an anti-TCRγδ antibody or antigen-binding fragment comprises a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH1 set forth in Table 1.6, and a nucleotide sequence of which can encode a light chain variable region sequence corresponding to VL1 set forth in Table 1.6; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH2 set forth in Table 1.6, and a nucleotide sequence of which can encode a light chain variable region sequence corresponding to VL2 set forth in Table 1.6; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH3 set forth in Table 1.6, and a nucleotide sequence of which can encode a light chain variable region sequence corresponding to VL3 set forth in Table 1.6; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH4 set forth in Table 1.6, and a nucleotide sequence of which can encode a light chain variable region sequence corresponding to VL4 set forth in Table 1.6; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH5 set forth in Table 1.6, and a nucleotide sequence of which can encode a light chain variable region sequence corresponding to VL5 set forth in Table 1.6; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH6 set forth in Table 1.6, and a nucleotide sequence of which can encode a light chain variable region sequence corresponding to VL6 set forth in Table 1.6; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH7 set forth in Table 1.6, and a nucleotide sequence of which can encode a light chain variable region sequence corresponding to VL7 set forth in Table 1.6; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH8 set forth in Table 1.6, and a nucleotide sequence of which can encode a light chain variable region sequence corresponding to VL8 set forth in Table 1.6; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH9 set forth in Table 1.6, and a nucleotide sequence of which can encode a light chain variable region sequence corresponding to VL9 set forth in Table 1.6;a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH10 set forth in Table 1.6, and a nucleotide sequence of which can encode a light chain variable region sequence corresponding to VL10 set forth in Table 1.6; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH11 set forth in Table 1.6, and a nucleotide sequence of which can encode a light chain variable region sequence corresponding to VL11 set forth in Table 1.6; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH12 set forth in Table 1.6, and a nucleotide sequence of which can encode a light chain variable region sequence corresponding to VL12 set forth in Table 1.6; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH13 set forth in Table 1.6, and a nucleotide sequence of which can encode a light chain variable region sequence corresponding to VL13 set forth in Table 1.6; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH14 set forth in Table 1.6, and a nucleotide sequence of which can encode a light chain variable region sequence corresponding to VL14 set forth in Table 1.6; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH15 set forth in Table 1.6, and a nucleotide sequence of which can encode a light chain variable region sequence corresponding to VL15 set forth in Table 1.6; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH16 set forth in Table 1.6, and a nucleotide sequence of which can encode a light chain variable region sequence corresponding to VL16 set forth in Table 1.6; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH17 set forth in Table 1.6, and a nucleotide sequence of which can encode a light chain variable region sequence corresponding to VL17 set forth in Table 1.6; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH18 set forth in Table 1.6, and a nucleotide sequence of which can encode a light chain variable region sequence corresponding to VL18 set forth in Table 1.6; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH19 set forth in Table 1.6, and a nucleotide sequence of which can encode a light chain variable region sequence corresponding to VL19 set forth in Table 1.6; a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH20 set forth in Table 1.6, and a nucleotide sequence of which can encode a light chain variable region sequence corresponding to VL20 set forth in Table 1.6;a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH21 set forth in Table 1.6, and a nucleotide sequence of which can encode a light chain variable region sequence corresponding to VL21 set forth in Table 1.6; or a nucleotide sequence which can encode a heavy chain variable region sequence corresponding to VH22 set forth in Table 1.6, and a nucleotide sequence of which can encode a light chain variable region sequence corresponding to VL22 set forth in Table 1.6.
[0300] In some embodiments, an isolated polynucleotide encoding an anti-TCRγδ antibody or antigen-binding fragment comprises a nucleotide sequence which can encode a heavy chain sequence of SEQ ID NO: 481, 483, 485, 487, 735, 737, 739, 741, 743, 745, or 747, or a sequence having at least 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity ...
Claims
WHAT IS CLAIMED IS 1. An isolated antibody, or antigen-binding fragment thereof, comprising: a heavy chain complementarity determining region (CDR) 1 (CDR1), a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 451, 453, 455, 457, 721, 723, 725, 727, 729, 731, or 733 or a sequence having at least about 80% identity thereto; and / or a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 452, 454, 456, 458, 722, 724, 726, 728, 730, 732, or 734, or a sequence having at least about 80% identity thereto.
2. The isolated antibody, or antigen-binding fragment thereof of claim 1, comprising: a VH comprising an amino acid sequence of SEQ ID NO: 451, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 452, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 453, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 454, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 455, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 456, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 457, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 458, or a sequence having at least about 80% identity thereto, a VH comprising an amino acid sequence of SEQ ID NO: 721, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 722, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 723, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 724, or a sequence having at least about 80% identity thereto;a VH comprising an amino acid sequence of SEQ ID NO: 725, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 726, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 727, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 728, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 729, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 730, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 731, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 732, or a sequence having at least about 80% identity thereto; or a VH comprising an amino acid sequence of SEQ ID NO: 733, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 734, or a sequence having at least about 80% identity thereto.
3. The isolated antibody, or antigen-binding fragment thereof of claim 1, comprising: a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 727, 729, 725, 733, 455, 453, 721, 723, 731, or a sequence having at least about 80% identity thereto; and / or a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 728, 730, 726, 734, 456, 454, 722, 724, 732, or a sequence having at least about 80% identity thereto.
4. The isolated antibody, or antigen-binding fragment thereof of claim 3, comprising: a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 727, 729, 725, 733, or a sequence having at least about 80% identity thereto; and / or a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 728, 730, 726, 734, or a sequence having at least about 80% identity thereto.
5. The isolated antibody, or antigen-binding fragment thereof of claim 2, comprising:a VH comprising an amino acid sequence of SEQ ID NO: 727, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 728, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 729, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 730, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 725, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 726, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 733, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 734, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 455, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 456, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 453, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 454, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 721, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 722, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 723, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 724, or a sequence having at least about 80% identity thereto; or a VH comprising an amino acid sequence of SEQ ID NO: 731, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 732, or a sequence having at least about 80% identity thereto.
6. The isolated antibody, or antigen-binding fragment thereof of claim 5, comprising:a VH comprising an amino acid sequence of SEQ ID NO: 727, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 728, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 729, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 730, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 725, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 726, or a sequence having at least about 80% identity thereto; or a VH comprising an amino acid sequence of SEQ ID NO: 733, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 734, or a sequence having at least about 80% identity thereto.
7. The isolated antibody or antigen-binding fragment of either of claims 1-6, wherein the antibody or antigen-binding fragment is recombinant.
8. The isolated antibody or antigen-binding fragment of any one of claims 1-7, wherein the antibody or antigen-binding fragment is a human antibody, a monoclonal antibody, a single chain antibody, a Fab, a Fab’, a F(ab’)2, a Fv, a scFv, or a spFv.
9. The isolated antibody or antigen-binding fragment of any one of claims 1-8, wherein the antibody or antigen-binding fragment is of IgG1, IgG2, IgG3, or IgG4 isotype.
10. An isolated polynucleotide encoding the isolated antibody or antigen-binding fragment of any one of claims 1-9.
11. A vector comprising the polynucleotide of claim 10.
12. A cell expressing the isolated antibody or antigen-binding fragment of any one of claims 1-9, or comprising the polynucleotide of claim 10, or comprising the vector of claim 11.
13. The cell of claim 12, wherein the cell is a hybridoma.
14. The cell of claim 12 or 13, wherein the antibody or antigen-binding fragment is recombinantly produced.
15. A composition comprising (i) the isolated antibody or antigen-binding fragment of any one of claims 1-9; (ii) the polynucleotide of claim 10; (iii) the vector of claim 11; or (iv) the cell of claims 12-14.
16. A method of expanding a population of effector cells obtained from induced pluripotent stems cells (iPSCs) and / or peripheral blood mononuclear cells (PBMCs), the method comprising: a) coating a tissue culture vessel with an isolated antibody or antigen-binding fragment; and b) expanding the effector cells, wherein the isolated antibody or antigen-binding fragment comprises: (i) a heavy chain complementarity determining region 1 (CDR1), a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 451, 453, 455, 457, 459, 461, 463, 465, 467, 469, 471, 473, 475, 477, 479, 721, 723, 725, 727, 729, 731, or 733 or a sequence having at least about 80% identity thereto; and / or (ii) a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 452, 454, 456, 458, 460, 462, 464, 466, 468, 470, 472, 474, 476, 478, 480, 722, 724, 726, 728, 730, 732, or 734, or a sequence having at least about 80% identity thereto.
17. The method of claim 16, wherein the isolated antibody or antigen-binding fragment comprises: a VH comprising an amino acid sequence of SEQ ID NO: 451, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 452, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 453, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 454, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 455, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 456, or a sequence having at least about 80% identity thereto;a VH comprising an amino acid sequence of SEQ ID NO: 457, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 458, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 459, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 460, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 461, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 462, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 463, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 464, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 465, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 466, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 467, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 468, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 469, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 470, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 471, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 472, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 473, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 474, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 475, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 476, or a sequence having at least about 80% identity thereto;a VH comprising an amino acid sequence of SEQ ID NO: 477, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 478, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 479, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 480, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 721, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 722, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 723, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 724, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 725, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 726, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 727, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 728, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 729, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 730, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 731, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 732, or a sequence having at least about 80% identity thereto; or a VH comprising an amino acid sequence of SEQ ID NO: 733, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 734, or a sequence having at least about 80% identity thereto.
18. The method of claim 16, wherein the isolated antibody or antigen-binding fragment comprises:a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 727, 729, 725, 733, 455, 453, 721, 723, 731, or a sequence having at least about 80% identity thereto; and / or a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 728, 730, 726, 734, 456, 454, 722, 724, 732, or a sequence having at least about 80% identity thereto.
19. The method of claim 18, comprising: a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a VH comprising an amino acid sequence of SEQ ID NO: 727, 729, 725, 733, or a sequence having at least about 80% identity thereto; and / or a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising an amino acid sequence of SEQ ID NO: 728, 730, 726, 734, or a sequence having at least about 80% identity thereto.
20. The method of claim 17, comprising: a VH comprising an amino acid sequence of SEQ ID NO: 727, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 728, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 729, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 730, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 725, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 726, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 733, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 734, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 455, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 456, or a sequence having at least about 80% identity thereto;a VH comprising an amino acid sequence of SEQ ID NO: 453, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 454, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 721, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 722, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 723, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 724, or a sequence having at least about 80% identity thereto; or a VH comprising an amino acid sequence of SEQ ID NO: 731, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 732, or a sequence having at least about 80% identity thereto.
21. The isolated antibody, or antigen-binding fragment thereof of claim 20, comprising: a VH comprising an amino acid sequence of SEQ ID NO: 727, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 728, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 729, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 730, or a sequence having at least about 80% identity thereto; a VH comprising an amino acid sequence of SEQ ID NO: 725, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 726, or a sequence having at least about 80% identity thereto; or a VH comprising an amino acid sequence of SEQ ID NO: 733, or a sequence having at least about 80% identity thereto, and a VL comprising an amino acid sequence of SEQ ID NO: 734, or a sequence having at least about 80% identity thereto.
22. The method of any one of claims 16-21, further comprising: c) cryopreserving the effector cells and / or the expanded effector cells, the cryopreserving step comprising: 1) counting and collecting the effector cells and / or expanded effector cells by centrifugation;2) resuspending the effector cells and / or expanded effector cells in CryoStor®CS10 medium at a concentration of 5x106cells / mL; 3) aliquoting the effector cells and / or expanded effector cells into cryovials, placing the cryovials in a CoolCell™ FTS30 container and storing at -80oC for 24 hours; and 4) storing the cryovials in vapor-phase liquid nitrogen.