WO2020010250A2 - Anti-tcr antibody molecules and uses thereof - Google Patents

Anti-tcr antibody molecules and uses thereof Download PDF

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Publication number
WO2020010250A2
WO2020010250A2 PCT/US2019/040592 US2019040592W WO2020010250A2 WO 2020010250 A2 WO2020010250 A2 WO 2020010250A2 US 2019040592 W US2019040592 W US 2019040592W WO 2020010250 A2 WO2020010250 A2 WO 2020010250A2
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WIPO (PCT)
Prior art keywords
tcrpv
tcrp
antibody molecule
molecule
seq
Prior art date
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PCT/US2019/040592
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English (en)
French (fr)
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WO2020010250A3 (en
Inventor
Seng-Lai TAN
Brian Edward Vash
Jonathan Hsu
Dilini Charmain GUNASEKERA
Sangeetha Sagar PALAKURTHI
Andreas Loew
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Marengo Therapeutics Inc
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Elstar Therapeutics Inc
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Publication date
Application filed by Elstar Therapeutics Inc filed Critical Elstar Therapeutics Inc
Priority to AU2019297451A priority Critical patent/AU2019297451A1/en
Priority to EP19745444.0A priority patent/EP3818083A2/en
Priority to US17/256,917 priority patent/US11845797B2/en
Priority to CN201980057685.4A priority patent/CN112955465A/zh
Priority to CA3105448A priority patent/CA3105448A1/en
Priority to JP2021521940A priority patent/JP7554742B2/ja
Publication of WO2020010250A2 publication Critical patent/WO2020010250A2/en
Publication of WO2020010250A3 publication Critical patent/WO2020010250A3/en
Anticipated expiration legal-status Critical
Priority to US17/529,017 priority patent/US20220064297A1/en
Priority to US17/820,794 priority patent/US11965025B2/en
Priority to US17/820,634 priority patent/US20230025484A1/en
Priority to US17/820,811 priority patent/US20230142522A1/en
Priority to US17/820,800 priority patent/US20230127740A1/en
Priority to US17/820,818 priority patent/US20230031734A1/en
Priority to US17/820,806 priority patent/US20230034161A1/en
Priority to US17/820,805 priority patent/US12286477B2/en
Priority to US18/472,920 priority patent/US12351632B2/en
Priority to US18/431,634 priority patent/US20240301060A1/en
Priority to JP2024154806A priority patent/JP2024170589A/ja
Priority to US19/080,243 priority patent/US20250215085A1/en
Priority to US19/214,564 priority patent/US20250340640A1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/11—T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/42—Cancer antigens
    • A61K40/4202—Receptors, cell surface antigens or cell surface determinants
    • A61K40/421—Immunoglobulin superfamily
    • A61K40/4211—CD19 or B4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/42—Cancer antigens
    • A61K40/4202—Receptors, cell surface antigens or cell surface determinants
    • A61K40/4214—Receptors for cytokines
    • A61K40/4215—Receptors for tumor necrosis factors [TNF], e.g. lymphotoxin receptor [LTR], CD30
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/283—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against Fc-receptors, e.g. CD16, CD32, CD64
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterized by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/55—Fab or Fab'
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • the VH comprises a sequence having a consensus sequence of SEQ ID NO: 231 or 3290.
  • the anti-TCRpV antibody molecule comprises an antigen binding domain comprising a light chain variable region (VL) comprising one, two or all (e.g., three) of a LC CDR1, a LC CDR2 and a LC CDR3 of SEQ ID NO: 2, SEQ ID NO: 10 or SEQ ID NO: 11, or an amino acid sequence listed in Table 1.
  • VL light chain variable region
  • the anti-TCRpV antibody molecule comprises a framework region (FR) having at least 95% identity with all of: a FR1, a FR2, a FR3, and a FR4 of a humanized B- H HC of Table 2.
  • FR framework region
  • TEMRA cells have low or no expression of CCR7, e.g., CCR7- or CCR7 low. In some embodiments, expression of CCR7 on TEMRA cells cannot be detected by a method disclosed herein, e.g., flow cytometry.
  • TEMRA cells express CD95, e.g., CD95+.
  • expression of CD95 on TEMRA cells can be detected by a method disclosed herein, e.g., flow cytometry.
  • the proliferative capability of T cells can be detected by a method disclosed herein, e.g., a method described in Example 4.
  • cytokine expression of T cells can be detected by a method disclosed herein, e.g., a method described in Examples 10 and 21.
  • the expansion is at least about 1.1-10 fold expansion ( e.g ., at least about 1.1, 1.2, 1.3, 1.4, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 fold expansion).
  • the expansion is compared to expansion of a similar population of cells with an antibody that binds to a CD3 molecule, e.g., CD3 epsilon (CD3e) molecule; or a TCR alpha (TCRa) molecule.
  • a CD3 molecule e.g., CD3 epsilon (CD3e) molecule; or a TCR alpha (TCRa) molecule.
  • a delay e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more hours delay, in increased level, e.g., expression level, and/or activity of IL-2;
  • (x) increased level, e.g., expression level, and/or activity of IL-15;
  • CD3 molecule e.g., CD3 epsilon (CD3e) molecule
  • TCRa TCR alpha
  • an anti-TCRpV antibody molecule disclosed herein does not comprise a viral peptide-MHC complex, e.g., as disclosed in Oncoimmunology. 2016; 5(1): el052930, herein incorporated by reference in its entirety.
  • a multispecific antibody molecule disclosed herein does not comprise a viral peptide-MHC complex, e.g., as disclosed in Oncoimmunology. 2016; 5(1): el052930, herein incorporated by reference in its entirety.
  • TCRP V10 subfamily comprising, e.g., one or more of TCRP Vl0-l*0l, TCRP V10- 1*02, TCRp Vl0-3*0l or TCRp Vl0-2*0l;
  • TCRP V19 subfamily comprising e.g., one or more of TCRP VI 9*01, or TCRP Vl9*02;
  • TCRp V10 e.g., one or more of TCRp Vl0-l*0l, TCRp Vl0-l*02, TCRp Vl0-3*0l or TCRp Vl0-2*0l;
  • a multispecific molecule e.g ., a bispecific molecule
  • a first moiety e.g., a first immune cell engager
  • TCRpV T cell receptor beta variable region
  • binding of the first moiety to the TCRpV region results in a cytokine profile, e.g., cytokine secretion profile, that differs from that of a T cell engager that binds to a receptor or molecule other than a TCRpV region (“a non-TCRpV-binding T cell engager”).
  • a cytokine profile e.g., cytokine secretion profile
  • the multispecific molecule further comprises: a tumor-targeting moiety, a cytokine molecule, an immune cell engager, e.g., a second immune cell engager, and/or a stromal modifying moiety.
  • a second moiety comprising one or more of: a tumor-targeting moiety; a second immune cell engager; a cytokine molecule or a stromal modifying moiety.
  • a multispecific molecule comprising an anti-TCRpV antibody molecule for use in the manufacture of a medicament for treating a disease, e.g., cancer, in a subject.
  • a method of treating a disease e.g., cancer, in a subject comprising administering to the subject an effective amount, e.g., a therapeutically effective amount, of an anti-TCRpV antibody molecule or a multispecific molecule comprising an anti- TCRpV antibody molecule disclosed herein, thereby treating the disease.
  • an effective amount e.g., a therapeutically effective amount, of an anti-TCRpV antibody molecule or a multispecific molecule comprising an anti- TCRpV antibody molecule disclosed herein, thereby treating the disease.
  • composition comprising an anti-TCRpV antibody molecule or a multispecific molecule comprising an anti-TCRpV antibody molecule disclosed herein, for use in the treatment of a disease, e.g., cancer, in a subject.
  • a disease e.g., cancer
  • the disease is a cancer, e.g. , a solid tumor or a hematological cancer, or a metastatic lesion.
  • (i) and (ii) are administered simultaneously or concurrently.
  • the disclosure provides, a method of targeting a T cell, e.g., in a subject having a disease, e.g., cancer, with an anti-TCRpV antibody disclosed herein or a multispecific molecule comprising an anti-TCRpV antibody disclosed herein.
  • the disclosure provides a method of treating, e.g., preventing or reducing, cytokine release syndrome (CRS) and/or neurotoxicity (NT) in a subject, e.g., CRS and/or NT associated with a treatment, e.g., a previously administered treatment, comprising administering to the subject an effective amount of an anti-TCRpV antibody disclosed herein or a multispecific molecule comprising an anti-TCRpV antibody disclosed herein, wherein, the subject has a disease, e.g., a cancer, thereby treating, e.g., preventing or reducing, CRS and/or NT in the subject.
  • CRS cytokine release syndrome
  • NT neurotoxicity
  • the biological sample comprising the population of immune effector cells is contacted with an anti- TCRpV antibody molecule that does not bind to the one or more TCRpV molecules (e.g., a different TCRpV molecule) identified as being higher, e.g., increased, in the biological sample.
  • an anti- TCRpV antibody molecule that does not bind to the one or more TCRpV molecules (e.g., a different TCRpV molecule) identified as being higher, e.g., increased, in the biological sample.
  • TCRP V19 subfamily comprising e.g., one or more of TCRP Vl9*0l, or TCRP Vl9*02;
  • the cancer is a solid tumor including but not limited to: melanoma, pancreatic (e.g., pancreatic adenocarcinoma) cancer, breast cancer, colorectal cancer (CRC), lung cancer (e.g., small or non- small cell lung cancer), skin cancer, ovarian cancer, or liver cancer.
  • pancreatic e.g., pancreatic adenocarcinoma
  • breast cancer colorectal cancer (CRC)
  • lung cancer e.g., small or non- small cell lung cancer
  • skin cancer e.g., ovarian cancer, or liver cancer.
  • myelodysplastic syndrome multiple myeloma, and acute lymphocytic leukemia.
  • a higher, e.g., increased, level or activity of one or more TCRpV molecules in a subject, e.g., in a sample from a subject, is indicative of a bias, e.g., a preferential expansion, e.g., clonal expansion, of T cells expressing said one or more TCRpV molecules in the subject.
  • a subject having B-CLL has a higher, e.g., increased, level or activity of a TCRP V3 subfamily comprising TCRP V3-l*0l.
  • the subject is administered an anti-TCRpV molecule (e.g., an agonistic anti- TCRpV molecule as described herein) that binds to one or more members of the TCRP V3 subfamily.
  • administration of the an anti-TCRpV molecule results in expansion of immune cells expressing one or more members of the TCRP V3 subfamily.
  • a subject having B-CLL has a higher, e.g., increased, level or activity of a TCRP V2 subfamily comprising TCRP V2*0l.
  • the subject is administered an anti-TCRpV molecule (e.g., an agonistic anti- TCRpV molecule as described herein) that binds to one or more members of the TCRP V2 subfamily.
  • administration of the an anti-TCRpV molecule results in expansion of immune cells expressing one or more members of the TCRP V2 subfamily.
  • a subject having B-CLL has a higher, e.g., increased, level or activity of a TCRP V19 subfamily comprising TCRP Vl9*0l, or TCRP Vl9*02.
  • the subject is administered an anti-TCRpV molecule (e.g., an agonistic anti- TCRBV molecule as described herein) that binds to one or more members of the TCRP V19 subfamily.
  • administration of the an anti-TCRpV molecule results in expansion of immune cells expressing one or more members of the TCRP V19 subfamily.
  • the subject has DLBCL.
  • a subject having melanoma has a higher, e.g., increased, level or activity of one or more TCRpV molecules, e.g., one or more TCRpV molecules comprising: (i) TCRP V13 subfamily comprising TCRP Vl3*0l; (ii) TCRP V3 subfamily comprising TCRP V3-l*0l; or (iii) TCRP V23 subfamily.
  • a subject having DLBCL has a higher, e.g., increased, level or activity of a TCRP V3 subfamily comprising TCRP V3-l*0l.
  • the subject is administered an anti-TCRpV molecule (e.g., an agonistic anti- TCRpV molecule as described herein) that binds to one or more members of the TCRP V3 subfamily.
  • administration of the an anti-TCRpV molecule results in expansion of immune cells expressing one or more members of the TCRP V3 subfamily.
  • TCRP V16 subfamily comprising TCRP Vl6*0l; or (iv) TCRP V21 subfamily.
  • a subject having CRC has a higher, e.g., increased, level or activity of a TCRP V19 subfamily comprising TCRP Vl9*0l, or TCRP Vl9*02.
  • the subject is administered an anti-TCRpV molecule (e.g., an agonistic anti- TCRpV molecule as described herein) that binds to one or more members of the TCRP V19 subfamily.
  • administration of the an anti-TCRpV molecule results in expansion of immune cells expressing one or more members of the TCRP V19 subfamily.
  • a subject having CRC has a higher, e.g., increased, level or activity of a TCRP V12 subfamily comprising TCRP Vl2-4*0l, TCRP Vl2-3*0l, or TCRP Vl2-5*0l.
  • the subject is administered an anti-TCRpV molecule (e.g., an agonistic anti- TCRpV molecule as described herein) that binds to one or more members of the TCRP V12 subfamily.
  • administration of the an anti-TCRpV molecule results in expansion of immune cells expressing one or more members of the TCRP V12 subfamily.
  • a subject having CRC has a higher, e.g., increased, level or activity of a TCRP V16 subfamily comprising TCRP Vl6*0l.
  • the subject is administered an anti-TCRpV molecule (e.g., an agonistic anti- TCRpV molecule as described herein) that binds to one or more members of the TCRP V16 subfamily.
  • administration of the an anti-TCRpV molecule results in expansion of immune cells expressing one or more members of the TCRP V16 subfamily.
  • an anti-TCRpV antibody molecule which:
  • (i) binds specifically to an epitope on TCRpV, e.g., the same or similar epitope as the epitope recognized by an anti-TCRpV antibody molecule as described herein, e.g., a second anti- TCRpV antibody molecule;
  • (ii) shows the same or similar binding affinity or specificity, or both, as an anti-TCRpV antibody molecule as described herein, e.g., a second anti-TCRpV antibody molecule;
  • the second anti-TCRpV antibody molecule comprises an antigen binding domain chosen from Table 1 or Table 2, or a sequence substantially identical thereto.
  • the second anti-TCRpV antibody molecule comprises an antigen binding domain, comprising:
  • HC CDR1 heavy chain complementarity determining region 1
  • HC CDR2 heavy chain complementarity determining region 2
  • HC CDR3 heavy chain complementarity determining region 3
  • LC CDR3 light chain complementarity determining region 1
  • LC CDR2 light chain complementarity determining region 2
  • LC CDR3 light chain complementarity determining region 3
  • HC CDR1 heavy chain complementarity determining region 1
  • HC CDR2 heavy chain complementarity determining region 2
  • HC CDR3 heavy chain complementarity determining region 3
  • LC CDR1 light chain complementarity determining region 1
  • LC CDR2 light chain complementarity determining region 2
  • LC CDR3 light chain complementarity determining region 3
  • the anti- TCRpV antibody molecule comprises an antigen binding domain comprising a light chain variable region (VL) comprising one, two or all ( e.g ., three) of a LC CDR1, a LC CDR2 and a LC CDR3 of SEQ ID NO: 2, SEQ ID NO: 10 or SEQ ID NO: 11.
  • VL light chain variable region
  • the anti- TCRpV antibody molecule comprises an antigen binding domain comprising a heavy chain variable region (VH) comprising one, two or all (e.g., three) of a HC CDR1, a HC CDR2 and a HC CDR3 of SEQ ID NO: 1 or SEQ ID NO: 9.
  • VH heavy chain variable region
  • the anti- TCRpV antibody molecule comprises an antigen binding domain comprising:
  • a VL comprising: a LC CDR1 amino acid sequence of SEQ ID NO: 6 (or an amino acid sequence with not more than 1, 2, 3 or 4 modifications, e.g., substitutions, additions or deletions thereof), a LC CDR2 amino acid sequence of SEQ ID NO:7 (or an amino acid sequence with not more than 1, 2, 3 or 4 modifications, e.g., substitutions, additions or deletions thereof), and/or a LC CDR3 amino acid sequence of SEQ ID NO:8 (or an amino acid sequence with not more than 1, 2, 3 or 4 modifications, e.g., substitutions, additions or deletions thereof); and/or
  • a VH comprising: a HC CDR1 amino acid sequence of SEQ ID NO: 3 (or an amino acid sequence with not more than 1, 2, 3 or 4 modifications, e.g., substitutions, additions or deletions thereof), a HC CDR2 amino acid sequence of SEQ ID NO:4 (or an amino acid sequence with not more than 1, 2, 3 or 4 modifications, e.g., substitutions, additions or deletions thereof), and/or a HC CDR3 amino acid sequence of SEQ ID NO:5 (or an amino acid sequence with not more than 1, 2, 3 or 4 modifications, e.g., substitutions, additions or deletions thereof).
  • the anti- TCRpV antibody molecule comprises an antigen binding domain comprising:
  • VH variable heavy chain
  • the anti- TCRpV antibody molecule comprises an antigen binding domain comprising the VH amino acid sequence of SEQ ID NO: 9 and the VL amino acid sequence of SEQ ID NO: 10.
  • the anti- TCRpV antibody molecule comprises a light chain comprising a framework region, e.g., framework region 2 (FR2), comprising one or both of: (i) a Histidine at position 36, e.g., a substitution at position 36 according to Kabat numbering, e.g., a Tyrosine to Histidine substitution; or (ii) an Alanine at position 46, e.g., a substitution at position 46 according to Kabat numbering, e.g., a Arginine to Alanine substitution.
  • the substitution is relative to a human germline light chain framework region sequence.
  • the anti- TCRpV antibody molecule binds to TCRp V6, e.g., TCRp V6-4*0l, TCRp V6-4*02, TCRp V6- 9*01, TCRp V6-8*0l, TCRp V6-5*0l, TCRp V6-6*02, TCRp V6-6*0l, TCRp V6-2*0l, TCRp V6-3*0l or TCRP V6-l*0l. In some embodiments the anti-TCRpV antibody molecule binds to TCRp V6-5*0l.
  • TCRp V6 e.g., TCRp V6-4*0l, TCRp V6-4*02, TCRp V6-9*0l, TCRp V6-8*0l, TCRp V6-5*0l, TCRp V6-6*02, TCRp V6-6*0l, TCRp V6-2*0l, TCRp V6- 3*01 or TCRP V6-l*0l, is recognized, e.g., bound, by SEQ ID NO: 1 and/or SEQ ID NO: 2.
  • TCRp V6 e.g., TCRp V6-4*0l, TCRp V6-4*02, TCRp V6-9*0l, TCRp V6-8*0l, TCRp V6-5*0l, TCRp V6-6*02, TCRp V6-6*0l, TCRp V6-2*0l, TCRp V6-3*0l or TCRP V6-l*0l, is recognized, e.g., bound, by SEQ ID NO: 9 and/or SEQ ID NO: 10.
  • the anti- TCRpV antibody molecule comprises an antigen binding domain comprising:
  • HC CDR1 heavy chain complementarity determining region
  • HC CDR2 heavy chain complementarity determining region
  • HC CDR3 of SEQ ID NO: 15, SEQ ID NO: 23, SEQ ID NO: 24 or SEQ IC NO: 25, or a sequence disclosed in Table 2;
  • LC CDR1 light chain complementarity determining region 1
  • LC CDR2 light chain complementarity determining region 1
  • LC CDR3 a light chain complementarity determining region 1 (LC CDR1), a LC CDR2, and/or a LC CDR3 of SEQ ID NO: 16, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29 or SEQ ID NO:30, or a sequence disclosed in Table 2.
  • the anti- TCRpV antibody molecule comprises an antigen binding domain comprising a light chain variable region (VL) comprising one, two or all of a LC CDR1, a LC CDR2 and a LC CDR3 of SEQ ID NO: 16, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29 or SEQ ID NO:30.
  • VL light chain variable region
  • VL variable light chain
  • Asparagine substitution or a Tyrosine to Asparagine substitution; or (iii) a Leucine at position 4, e.g., a substitution at position 4 according to Rabat numbering, e.g., a Methionine to Leucine substitution.
  • the substitution is relative to a human germline light chain framework region sequence.
  • the anti- TCRpV antibody molecule comprises a light chain comprising a framework region, e.g., framework region 3 (FR3), comprising one, two or all (e.g., three) of: (i) a Glycine as position 66, e.g., a substitution at position 66 according to Rabat numbering, e.g., a Lysine to Glycine substitution, or a Serine to Glycine substitution; or (ii) an Asparagine at position 69, e.g., a substitution at position 69 according to Rabat numbering, e.g., a Threonine to Asparagine substitution; or (iii) a Tyrosine at position 71, e.g., a substitution at position 71 according to Rabat numbering, e.g., a Phenylalanine to Tyrosine substitution, or an Alanine to Tyrosine substitution.
  • FR3 framework region 3
  • the anti- TCRpV antibody molecule binds to TCRp V12, e.g., TCRp Vl2-4*0l, TCRp Vl2-3*0l, or TCRP Vl2-5*0l. In some embodiments the anti-TCRpV antibody molecule binds to TCRP V12- 4*01 or TCRp Vl2-3*0l.
  • TCRp V12 e.g., TCRp Vl2-4*0l, TCRp Vl2-3*0l, or TCRp Vl2-5*0l
  • TCRp V12 is recognized, e.g., bound, by any one of SEQ ID NOs 23-25, and/or any one of SEQ ID NO: 26- 30, or an amino acid sequence having at least about 75%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto.
  • TCRP Vl2-4*0l is recognized, e.g., bound, by any one of SEQ ID NOs 23-25, and/or any one of SEQ ID NO: 26-30, or an amino acid sequence having at least about 75%, 80%, 85%, 90%, 95%, or 99% sequence identity thereto.
  • TCRP Vl2-3*0l is recognized, e.g., bound, by any one of SEQ ID NOs 23-25, and/or any one of SEQ ID NO: 26-30, or an amino acid sequence having at least about 75%,
  • the anti- TCRpV antibody molecule comprises the anti-TCRpV antibody molecule comprises an antigen binding domain comprising a single chain Fv (scFv) or a Fab. In some embodiments of any of the compositions or methods disclosed herein, the anti- TCRpV antibody molecule comprises binds to a conformational or a linear epitope on the T cell.
  • the anti- TCRpV antibody molecule is a full antibody (e.g., an antibody that includes at least one, and preferably two, complete heavy chains, and at least one, and preferably two, complete light chains), or an antigen-binding fragment (e.g., a Fab, F(ab')2, Fv, a single chain Fv fragment, a single domain antibody, a diabody (dAb), a bivalent antibody, or bispecific antibody or fragment thereof, a single domain variant thereof, a camelid antibody, or a rat-derived VH.
  • an antigen-binding fragment e.g., a Fab, F(ab')2, Fv, a single chain Fv fragment, a single domain antibody, a diabody (dAb), a bivalent antibody, or bispecific antibody or fragment thereof, a single domain variant thereof, a camelid antibody, or a rat-derived VH.
  • the anti- TCRpV antibody molecule comprises a heavy chain constant region of an IgJ or a fragment thereof, optionally wherein the IgJ heavy chain constant region comprises the sequence of SEQ ID NO: 76 or a sequence with at least 85%, 90%, 95%, or 99% sequence identity thereto.
  • the anti- TCRpV antibody molecule comprises a heavy chain constant region of an IgGA2, or a fragment thereof, optionally wherein the IgGA2 heavy chain constant region comprises a sequence listed in Table 3, e.g., SEQ ID NO: 75, or a sequence with at least 85%, 90%, 95%, or 99% sequence identity thereto.
  • (xii) expansion e.g., at least about 1.1-10 fold expansion (e.g., at least about 1.1, 1.2, 1.3, 1.4, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 fold expansion), of a population of memory T cells, e.g., wherein (ix)-(xii) are relative to the non-TCRpV-binding T cell engager.
  • the anti-TCRbV antibody molecule in a multispecific molecule disclosed herein is a first immune cell engager moiety.
  • the anti-TCRbV antibody molecule does not bind to ⁇ b V12, or binds to TCRb V12 with an affinity and/or binding specificity that is less than (e.g., less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and/or binding specificity of the 16G8 murine antibody or a humanized version thereof as described in US Patent 5,861,155.
  • the anti- TCRpV antibody molecule binds to a TCRpV region other than TCRP V5-5*0l or TCRP V5- 1*01 (e.g., TCRpV region as described herein, e.g., TCRP V6 subfamily (e.g., TCRP V6-5*0l) with an affinity and/or binding specificity that is greater than (e.g., greater than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and/or binding specificity of the TM23 murine antibody or a humanized version thereof as described in US Patent 5,861,155.
  • the anti-TCRpV antibody molecule does not comprise the CDRs of the TM23 murine antibody.
  • the second immune cell engager comprises a T cell engager which binds to CD3, TCRa, TCRy, TCR , ICOS, CD28, CD27, HVEM, LIGHT, CD40, 4-1BB, 0X40, DR3, GITR, CD30, TIM1, SLAM, CD2, or CD226.
  • a multispecific molecule disclosed herein comprises a tumor targeting moiety.
  • the tumor-targeting moiety comprises an antibody molecule (e.g ., Fab or scFv), a receptor molecule (e.g., a receptor, a receptor fragment or functional variant thereof), or a ligand molecule (e.g., a ligand, a ligand fragment or functional variant thereof), or a combination thereof, that binds to a cancer antigen.
  • the tumor-targeting moiety binds to a cancer antigen present on a cancer, e.g., a hematological cancer, a solid tumor, a metastatic cancer, soft tissue tumor, metastatic lesion, or a combination thereof.
  • the tumor-targeting moiety binds to a cancer antigen, e.g.,
  • the tumor-targeting antibody molecule binds to a conformational or a linear epitope on the tumor antigen.
  • the BCMA antigen can be present on a tumor, e.g., a tumor of a class typified by having one or more of: limited tumor perfusion, compressed blood vessels, or fibrotic tumor interstitium.
  • the tumor targeting moiety comprising a BCMA targeting moiety comprises an anti-BCMA antibody or antigen-binding fragment thereof described in US8920776, US9243058, US9340621, US8846042, US7083785, US9545086, US7276241, US9034324, US7799902, US9387237, US8821883, US861745, US20130273055, US20160176973, US20150368351, US20150376287, US20170022284, US20160015749, US20140242077, US20170037128, US20170051068, US20160368988, US20160311915, US20160131654, US20120213768, US20110177093, US20160297885,
  • EP3137500 EP2699259, EP2982694, EP3029068, EP3023437, W02016090327,
  • the FcRH5 antigen can be present on a tumor, e.g., a tumor of a class typified by having one or more of: limited tumor perfusion, compressed blood vessels, or fibrotic tumor interstitium.
  • the tumor targeting moiety comprising a FcRH5 targeting moiety comprises an anti- FcRH5 antibody or antigen-binding fragment thereof described in US Patent 7,999,077 the entire contents of which are incorporated herein by reference.
  • the cancer is a hematological cancer including, but not limited to: a B-cell or T cell malignancy, e.g., Hodgkin’s lymphoma, Non-Hodgkin’s lymphoma (e.g., B cell lymphoma, diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia), acute myeloid leukemia (AML), chronic myeloid leukemia, myelodysplastic syndrome, multiple myeloma, and acute lymphocytic leukemia.
  • the hematological cancer is multiple myeloma.
  • a multispecific molecule disclosed herein further comprises a cytokine molecule, e.g., one or two cytokine molecules.
  • the cytokine molecule is chosen from interleukin-2 (IL-2), interleukin-7 (IL-7), interleukin- 12 (IL-12), interleukin- 15 (IL-15), interleukin- 18 (IL-18), interleukin -21 (IL-21), or interferon gamma, or a fragment, variant or combination thereof.
  • IL-2 interleukin-2
  • IL-7 interleukin-7
  • IL-12 interleukin- 12
  • IL-15 interleukin- 15
  • IL-18 interleukin- 18
  • interleukin -21 interferon gamma
  • the cytokine molecule further comprises a receptor dimerizing domain, e.g., an ILl5Ralpha dimerizing domain.
  • a tumor-targeting antibody molecule e.g., an antibody molecule that binds to a hematological antigen as described herein, e.g., chosen from one or more of BCMA, FcRH5, CD19, CD22, CD33, CD123, FcRH5, CDl79a, or CLEC12.
  • the dimerization of the immunoglobulin chain constant region is enhanced by providing an Fc interface of a first and a second Fc region with one or more of: a paired cavity-protuberance (“knob-in-a hole”), an electrostatic interaction, or a strand- exchange, such that a greater ratio of heteromultimenhomomultimer forms, e.g., relative to a non-engineered interface.
  • Fc region a paired cavity-protuberance
  • electrostatic interaction e.g., electrostatic interaction
  • strand- exchange e.g., strand- exchange
  • a multispecific molecule disclosed herein further comprises a linker, e.g., a linker described herein, optionally wherein the linker is selected from: a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, or a non-helical linker.
  • a linker e.g., a linker described herein, optionally wherein the linker is selected from: a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, or a non-helical linker.
  • the dimerization module comprises an immunoglobulin constant domain, e.g., a heavy chain constant domain (e.g., a homodimeric or heterodimeric heavy chain constant region, e.g., an Fc region), or a constant domain of an immunoglobulin variable region (e.g., a Fab region); and
  • an immunoglobulin constant domain e.g., a heavy chain constant domain (e.g., a homodimeric or heterodimeric heavy chain constant region, e.g., an Fc region), or a constant domain of an immunoglobulin variable region (e.g., a Fab region); and
  • At least one, two, or three of A, B, C, and D comprises an antigen binding domain that preferentially binds to a TCRpV region disclosed herein, and
  • any of the remaining A, B, C, and D is absent or comprises one of a tumor targeting moiety, a second immune cell engager, a cytokine molecule, or a stromal modifying moiety.
  • the dimerization module comprises one or more immunoglobulin chain constant regions (e.g ., Fc regions) comprising one or more of: a paired cavity-protuberance (“knob-in-a hole”), an electrostatic interaction, or a strand-exchange.
  • the one or more immunoglobulin chain constant regions e.g., Fc regions
  • the one or more immunoglobulin chain constant regions comprise an amino acid substitution at a position chosen from one or more of 347, 349, 350, 351, 366, 368, 370, 392,
  • the disease is a cancer chosen from: a hematological cancer, a solid tumor, a metastatic cancer, soft tissue tumor, metastatic lesion, or a combination thereof.
  • FIGs. 1A-1B shows the alignment of the Antibody A source mouse VH and VL framework 1, CDR 1, framework 2, CDR 2, framework 3, CDR3, and framework 4 regions with their respective humanized sequences. Rabat CDRs are shown in bold, Chothia CDRs are shown in italics, and combined CDRs are shown in boxes. The framework positions that were back mutated are double underlined.
  • FIG. 1A shows VH sequences for murine Antibody A (SEQ ID NO: 1) and humanized Antibody A-H (SEQ ID NO: 9).
  • FIG. IB shows VL sequences for murine Antibody A (SEQ ID NO: 2) and humanized Antibody A-H (SEQ ID NO: 10 and SEQ ID NO: 11).
  • FIG. 3 depicts the phylogenetic tree of TCRBV gene family and subfamilies with corresponding antibodies mapped. Subfamily identities are as follows: Subfamily A: TCRP V6; Subfamily B: TCRP V10; Subfamily C: TCRP V12; Subfamily D: TCRP V5; Subfamily E:
  • Subfamily T TCRP V24; Subfamily U: TCRP V20; Subfamily V: TCRP V25; and Subfamily W:TCRP V29 subfamily. Subfamily members are described in detail herein in the Section titled “TCR beta V (TCRpV)”.
  • FIGs. 6A-6B show IFNg production by human PBMCs activated with the indicated antibodies.
  • Human PBMCs were isolated from whole blood from the indicated number of donors, followed by solid-phase (plate-coated) stimulation with the indicated antibodies at lOONm. Supernatant was collected on Days 1, 2, 3, 5, or 6.
  • FIG. 6A is a graph comparing the production of IFNg in human PBMCs activated with the antibodies indicated activated with anti- TCR nb13.1 antibodies (A-H.l or A-H.2) or anti-CD3e antibodies (OKT3 or SP34-2) on Day 1, 2, 3, 5, or 6 post-activation.
  • FIG. 6B shows IFNg production in human PBMCs activated with the antibodies indicated activated with the indicated anti-TCR nb13.1 antibodies or anti-CD3e antibody (OKT3) on Day 1, 2, 3, 5, or 6 post-activation.
  • FIGs. 7A-7B show IL-2 production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described for FIGs 6A-6B was used.
  • FIGs. 8A- 8B show IL-6 production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described for FIGs 6A-6B was used.
  • FIGs. 9A- 9B show TNF-alpha production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described for FIGs 6A-6B was used.
  • FIGs. 10A- 10B show IL-lbeta production by human PBMCs activated with the indicated antibodies. A similar experimental setup as described for FIGs 6A-6B was used.
  • FIG. 12 depicts increased CD8+ TSCM and Temra T cell subsets in human PBMCs activated by anti-TCR nb13.1 antibodies (A-H.l or A-H.2) compared to PBMCs activated by anti-CD3e antibodies (OKT3 or SP34-2).
  • FIG. 13C is a graph showing IFN-g secretion by PBMCs stimulated with an anti-TCRVb antibody, or anti-CD3 antibodies.
  • FIG. 13D shows target cell lysis by T cells stimulated with an anti-TCRVb antibody, or anti-CD3 antibodies. Cells were stimulated for 4 days followed by 2 days incubation with multiple myeloma target cells for assessment of cell killing.
  • FIGS. 15A-15C show secretion of cytokines in PBMCs stimulated with an anti-TCRVb antibody, or anti-CD3 antibodies.
  • FIGs 16A-16B show killing of MM cells by dual targeting BCMA-TCRvb antibody molecules.
  • FIG.16A shows in vitro killing by one of the following dual-targeting antibody molecules: BCMA-TCRVb (Molecule I), BCMA-CD3, or Control-TCRVb; or an isotype control.
  • FIG. 16B shows in vivo killing of MM cells by a dual-targeting BCM-TCRVb antibody (Molecule I).
  • FIGs 18A-18B demonstrate cytokine production from human PBMCs activated by anti- TCR Vp8a antibodies (B-H. l) when compared to those activated by anti-CD3e antibodies (OKT3 or SP34-2).
  • FIG. 18A shows that human PBMCs activated by anti-TCR Vp8a antibodies (B-H. l) produce similar or reduced levels of IFNy.
  • FIGs 19A-19C demonstrate cytokine production from human PBMCs activated by anti- TCR Vp8a antibodies (B-H.l).
  • Human PBMCs activated by anti-TCR Vp8a antibodies (B-H.l) do not significantly produce IL-6 (FIG. 19A), ILlb (FIG. 19B), and less TNFa (FIG. 19C), when compared to PBMCs activated by anti-CD3e antibodies (OKT3 or SP34-2).
  • FIGs. 20A-20E demonstrate cytokine production from human PBMCs activated by anti- TCRpV Antibody D antibody compared to control anti-CD3e antibody (OKT3).
  • FIG. 20A shows that human PBMCs activated by anti-TCRpV Antibody D antibody produce similar or reduced levels of IFNy.
  • FIG. 20B shows human PBMCs activated by anti-TCRpV Antibody D antibody produce higher levels of IL-2 when compared to those activated by anti-CD3e antibodies (OKT3).
  • FIGs. 21A-21B demonstrate cytokine production from human PBMCs activated by anti- TCR nb5 antibody (Antibody E).
  • FIG. 21A shows that human PBMCs activated by anti-TCR nb5 antibody produce similar or reduced levels of IFNy compared to PBMCS activated by anti- CD3e antibodies (OKT3 or SP34-2).
  • FIGs. 23A-23E demonstrate cytokine production from human PBMCs activated by a dual targeting (bispecific molecule) comprising an anti-TCRbV binding moiety and a BCMA binding moiety.
  • FIG. 23A shows that human PBMCs activated by the bispecific molecule produce similar or reduced levels of IFNy as PBMCS activated by anti-CD3e antibodies (OKT3).
  • FIG. 23B shows human PBMCs activated by the bispecific molecule produce higher levels of IL-2 when compared to PBMCs activated by anti-CD3e antibodies (OKT3).
  • FIG. 28 is a graph depicting mean tumor volume in N O D/S C I D/ 1 L- 2 Ry null (NSG) mice engrafted with Raji-luc cells at days 10 to 28.
  • the Star denotes PBMC implantation.
  • Open triangles denote antibody treatment with the indicated antibodies.
  • FIGs. 29A-B depicting Mean tumor burden (Total Flux) in N O D/S C I D/ 1 L- 2 Ry null (NSG) mice engrafted with cancer cells and treated with the indicated antibody.
  • NSG mice were implanted with PBMCs on Day 1 followed by injection with cancer cells on Day 7 (Raji-luc in FIG. 29A; K562-Luc control in FIG. 29B).
  • Antibody treatment with the indicated antibodies began on Day 16.
  • FIG. 29A shows mean tumor burden at days 16 to 37 in NOD/SCID/IL- 2Rynull (NSG) mice engrafted with Raji-luc cells.
  • FIG. 29B shows mean tumor burden (Total Flux) at days 16 to 30 in animals engrafted with K562-luc cells.
  • FIG. 30 is a graph depicting Mean tumor burden (Total Flux) mean tumor volume in NOD/SCID/IL-2Rynull (NSG) mice engrafted with RPMI-8226 cells.
  • the RPMI-8226 cells were engrafted on Day 1.
  • PBMCs were implanted into the mice and antibody treatment began on Day 17.
  • FIG.31A shows data generated using anti-TCR Vpi 3.1/anti-CD19 (Molecule F), anti-CD3/anti-CDl9, and anti-TCR nb13.1 (A-H.l).
  • FIG. 31B shows data generated using anti-TCR Vpl3.l/anti-BCMA (Molecule G), anti-CD3/anti-BCMA, and anti-TCR Vpl3.l (A- H.l).
  • FIGs. 32A-32F are graphs showing cytokine secretion stimulated by anti-TCR nb/anti- BCMA (Molecule H) or anti-CD3 (OKT3) at Days 1, 2, 3, and 5. Cytokines examined include: IFNy, IL-2, IL- I b, IL-6, IL-10, and TNFa (FIGs. 32A-32F, respectively).
  • FIGs. 33A-33F are graphs showing cytokine secretion stimulated by anti-TRBCl (Antibody F) or anti-CD3 (OKT3) at Days 2 and 5. Cytokines examined include: IFNy, IL-2,
  • IL- 1 b IL-6, IL-10, and TNFa (FIGs. 33A-33F, respectively).
  • cytokine release syndrome (CRS) (Shimabukuro-Vomhagen et ah, J Immunother Cancer. 2018 Jun l5;6(l):56, herein incorporated by reference in its entirety).
  • CRS cytokine release syndrome
  • This invention features molecules targeting the TCRpV chain of TCR and methods thereof. Without wishing to be bound by theory, such molecules are capable of binding, activating, and/or expanding only a subset of T cells, avoiding or reducing CRS and/or NT and minimizing potential immunosuppressive effects of anti-CD3 mAbs.
  • TCR is a disulfide-linked membrane- anchored heterodimeric protein normally consisting of the highly variable alpha (a) and beta (b) chains expressed as part of a complex with the invariant CD3 chain molecules.
  • TCR on ab T cells is formed by a heterodimer of one alpha chain and one beta chain.
  • Each alpha or beta chain consists of a constant domain and a highly variable domain classified as the Immunoglobulin superfamily (IgSF) fold.
  • the ⁇ bn chains can be further classified into 30 subfamilies (TRBV1-30). Despite their high structural and functional homology, the amino acid sequence homology in the TRBV genes is very low.
  • TCRs formed between alpha and beta chains of highly diverse sequences show a remarkable structural homology (FIGs. 24A and 24B) and elicit a similar function, e.g., activation of T cells.
  • the anti-TCRpV antibody molecules disclosed herein bind to an outward facing epitope of a TCRpV protein when it is in a complex with a TCRalpha protein, e.g., as denoted by the circled area in FIG. 24A.
  • the anti-TCRpV antibody molecules disclosed herein recognize (e.g., bind to), a domain (e.g., an epitope) on the TCRpV protein that is: (1) structurally conserved among different TCRpV subfamilies; and (2) has minimal sequence identity among the different TCRpV subfamilies.
  • TCRpV proteins from the different TCRBV subfamilies share minimal sequence similarity.
  • FIG. 24A-B TCRpV proteins which have minimal sequence similarity, share a similar 3D
  • the anti-TCRpV antibody molecules disclosed herein do not recognize, e.g., bind to, a constant region of a TCRpV protein. In some embodiments, the anti-TCRpV antibody molecules disclosed herein do not recognize, e.g., bind to, one or more (e.g., all) of a complementarity determining region (e.g., CDR1, CDR2 and/or CDR3) of a TCRpV protein.
  • a complementarity determining region e.g., CDR1, CDR2 and/or CDR3
  • TCRpV beta subunit of TCR
  • the anti- TCRpV antibody molecules disclosed herein result in lesser or no production of cytokines associated with CRS, e.g., IL-6, IL-lbeta, IL-10 and TNF alpha; and enhanced and/or delayed production of IL-2 and IFNg.
  • the anti-TCRpV antibodies disclosed herein have a cytokine profile, e.g., as described herein, which differs from a cytokine profile of a T cell engager that binds to a receptor or molecule other than a TCRpV region (“a non-TCRpV-binding T cell engager”).
  • the anti-TCRpV antibodies disclosed herein result in expansion of TCRpV+ T cells, e.g., a subset of memory effector T cells known as TEMRA.
  • compositions comprising anti-TCRpV antibody molecules of the present disclosure can be used, e.g., to: (1) activate and redirect T cells to promote tumor cell lysis for cancer immunotherapy; and/or (2) expand TCRpV+ T cells.
  • compositions comprising anti-TCRpV antibody molecules as disclosed herein limit the harmful side-effects of CRS and/or NT, e.g., CRS and/or NT associated with anti-CD3e targeting.
  • the anti-TCRpV antibody molecule does not bind to TCRP V12, or binds to TCRP V12 with an affinity and/or binding specificity that is less than (e.g., less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and/or binding specificity of the 16G8 murine antibody or a humanized version thereof as described in US Patent 5,861,155.
  • the anti-TCRpV antibody molecule binds to TCRP V12 with an affinity and/or binding specificity that is greater than (e.g., greater than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and/or binding specificity of the 16G8 murine antibody or a humanized version thereof as described in US Patent 5,861,155.
  • the anti-TCRpV antibody molecule does not bind to TCRP V5- 5*01 or TCRP V5-l*0l, or binds to TCRP V5-5*0l or TCRP V5-l*0l with an affinity and/or binding specificity that is less than (e.g., less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and/or binding specificity of the TM23 murine antibody or a humanized version thereof as described in US Patent 5,861,155.
  • the anti-TCRpV antibody molecule binds to a TCRpV region other than TCRP V5-5*0l or TCRP V5-l*0l (e.g ., TCRpV region as described herein, e.g., TCRP V6 subfamily (e.g., TCRP V6-5*0l) with an affinity and/or binding specificity that is greater than (e.g., greater than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or about 2-, 5-, or 10- fold) the affinity and/or binding specificity of the TM23 murine antibody or a humanized version thereof as described in US Patent 5,861,155.
  • TCRpV region e.g ., TCRpV region as described herein, e.g., TCRP V6 subfamily (e.g., TCRP V6-5*0l) with an affinity and/or binding specificity that is greater than (e.g., greater than about 10%, 20%, 30%, 40%
  • the anti-TCRpV antibody molecule does not comprise the CDRs of the TM23 murine antibody.
  • “a” and“an” refers to one or to more than one (i.e., to at least one) of the grammatical object of the article.
  • “an element” means one element or more than one element.
  • Directly acquiring a physical entity includes performing a process that includes a physical change in a physical substance, e.g., a starting material.
  • Directly acquiring a value includes performing a process that includes a physical change in a sample or another substance, e.g., performing an analytical process which includes a physical change in a substance, e.g., a sample.
  • human-like antibody molecule refers to a humanized antibody molecule, human antibody molecule or an antibody molecule having at least 95% identity with a non-murine germline framework region, e.g., FR1, FR2, FR3 and/or FR4.
  • the human-like antibody molecule comprises a framework region having at least 95% identity to a human germline framework region, e.g., a FR1, FR2, FR3 and/or FR4 of a human germline framework region.
  • the human-like antibody molecule is a recombinant antibody.
  • the human-like antibody molecule is a humanized antibody molecule.
  • cytokine profile refers to the level and/or activity of on one or more cytokines or chemokines, e.g., as described herein.
  • a cytokine profile comprises the level and/or activity of a naturally occurring cytokine, a fragment or a variant thereof.
  • a cytokine profile comprises the level and/or activity of one or more cytokines and/or one or more chemokines (e.g., as described herein).
  • a cytokine profile comprises the level and/or activity of one or more of: IL-2 (e.g., full length, a variant, or a fragment thereof); IL-lbeta (e.g., full length, a variant, or a fragment thereof); IL-6 (e.g., full length, a variant, or a fragment thereof); TNFa (e.g., full length, a variant, or a fragment thereof); IFNg (e.g., full length, a variant, or a fragment thereof) IL-10 (e.g., full length, a variant, or a fragment thereof); IL-4 (e.g., full length, a variant, or a fragment thereof); TNF alpha (e.g., full length, a variant, or a fragment thereof) ;IL-l2p70 (e.g., full length, a variant, or a fragment thereof); IL-13 (e.g., full length, a variant, or a fragment thereof);
  • a cytokine in a cytokine profile can be modulated, e.g., increased or decreased, by an anti-TCRBV antibody molecule described herein.
  • the cytokine profile includes cytokines associated with a cytokine storm or cytokine release syndrome (CRS), e.g., IL-6, IL-lbeta, TNFalpha and IL-10.
  • CRS cytokine storm or cytokine release syndrome
  • variant refers to a polypeptide that has a substantially identical amino acid sequence to the naturally-occurring sequence, or are encoded by a substantially identical nucleotide sequence.
  • the variant is a functional variant.
  • a TCRpV variant can bind to TCRa and form a TCR a:b complex.
  • “functional variant” refers to a polypeptide that has a substantially identical amino acid sequence to the naturally-occurring sequence, or are encoded by a substantially identical nucleotide sequence, and are capable of having one or more activities of the naturally- occurring sequence.
  • a“multifunctional” or a“multispecific” molecule refers to molecule, e.g., a polypeptide, that has two or more functionalities, e.g., two or more binding specificities.
  • the functionalities can include one or more immune cell engagers, one or more tumor binding molecules, one or more cytokine molecules, one or more stromal modifiers, and other moieties described herein.
  • the multispecific molecule is a multispecific antibody molecule, e.g., a bispecific antibody molecule.
  • the multispecific molecule includes an anti-TCRVb antibody molecule as described herein.
  • the multifunctional molecule includes an immune cell engager.
  • An immune cell engager refers to one or more binding specificities that bind and/or activate an immune cell, e.g., a cell involved in an immune response.
  • the immune cell is chosen from a T cell, an NK cell, a B cell, a dendritic cell, and/or the macrophage cell.
  • the immune cell engager when it is an antibody molecule, it binds to an immune cell antigen (e.g., a T cell antigen, an NK cell antigen, a B cell antigen, a dendritic cell antigen, and/or a macrophage cell antigen) with a dissociation constant of less than about 10 nM.
  • an immune cell antigen e.g., a T cell antigen, an NK cell antigen, a B cell antigen, a dendritic cell antigen, and/or a macrophage cell antigen
  • the multifunctional molecule includes a cytokine molecule.
  • a“cytokine molecule” refers to full length, a fragment or a variant of a cytokine; a cytokine further comprising a receptor domain, e.g., a cytokine receptor dimerizing domain; or an agonist of a cytokine receptor, e.g., an antibody molecule (e.g., an agonistic antibody) to a cytokine receptor, that elicits at least one activity of a naturally-occurring cytokine.
  • the cytokine molecule is chosen from interleukin-2 (IL-2), interleukin-7 (IL-7), interleukin- 12 (IL-12), interleukin- 10 (IL-10), interleukin- 15 (IL-15), interleukin- 18 (IL-18), interleukin-21 (IL-21), or interferon gamma, or a fragment or variant thereof, or a combination of any of the aforesaid cytokines.
  • the cytokine molecule can be a monomer or a dimer.
  • the cytokine molecule can further include a cytokine receptor dimerizing domain.
  • the cytokine molecule is an agonist of a cytokine receptor, e.g., an antibody molecule ( e.g ., an agonistic antibody) to a cytokine receptor chosen from an IL-l5Ra or IL-21R.
  • a cytokine receptor e.g., an antibody molecule ( e.g ., an agonistic antibody) to a cytokine receptor chosen from an IL-l5Ra or IL-21R.
  • the multifunctional molecule includes a stromal modifying moiety.
  • A“stromal modifying moiety,” as used herein refers to an agent, e.g., a protein (e.g., an enzyme), that is capable of altering, e.g., degrading a component of, the stroma.
  • a protein e.g., an enzyme
  • the articles“a” and“an” refer to one or more than one, e.g., to at least one, of the grammatical object of the article.
  • the use of the words “a” or “an” when used in conjunction with the term “comprising” herein may mean “one,” but it is also consistent with the meaning of "one or more,” “at least one,” and “one or more than one.”
  • “about” and“approximately” generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given range of values.
  • antibody fragment or“functional fragment” also include isolated fragments consisting of the variable regions, such as the“Fv” fragments consisting of the variable regions of the heavy and light chains or recombinant single chain polypeptide molecules in which light and heavy variable regions are connected by a peptide linker (“scFv proteins”).
  • an antibody fragment does not include portions of antibodies without antigen binding activity, such as Fc fragments or single amino acid residues.
  • Exemplary antibody molecules include full length antibodies and antibody fragments, e.g., dAb (domain antibody), single chain, Fab, Fab’, and F(ab’) 2 fragments, and single chain variable fragments (scFvs).
  • the antibody molecule is an antibody mimetic.
  • an“immunoglobulin variable domain sequence” refers to an amino acid sequence which can form the structure of an immunoglobulin variable domain.
  • the sequence may include all or part of the amino acid sequence of a naturally-occurring variable domain.
  • the sequence may or may not include one, two, or more N- or C-terminal amino acids, or may include other alterations that are compatible with formation of the protein structure.
  • an antibody molecule is monospecific, e.g., it comprises binding specificity for a single epitope.
  • an antibody molecule is multispecific, e.g., it comprises a plurality of immunoglobulin variable domain sequences, where a first immunoglobulin variable domain sequence has binding specificity for a first epitope and a second immunoglobulin variable domain sequence has binding specificity for a second epitope.
  • an antibody molecule is a bispecific antibody molecule.“Bispecific antibody molecule” as used herein refers to an antibody molecule that has specificity for more than one ( e.g ., two, three, four, or more) epitope and/or antigen.
  • an antigen can be synthesized or can be derived from a biological sample, e.g., a tissue sample, a tumor sample, a cell, or a fluid with other biological components.
  • a“tumor antigen” or interchangeably, a“cancer antigen” includes any molecule present on, or associated with, a cancer, e.g., a cancer cell or a tumor microenvironment that can provoke an immune response.
  • an“immune cell antigen” includes any molecule present on, or associated with, an immune cell that can provoke an immune response.
  • the three hypervariable regions of a light chain and the three hypervariable regions of a heavy chain are disposed relative to each other in three dimensional space to form an antigen-binding surface, which is complementary to the three-dimensional surface of a bound antigen.
  • the three hypervariable regions of each of the heavy and light chains are referred to as“complementarity-determining regions,” or“CDRs.”
  • cancer includes relapsed and/or resistant cancer.
  • cancer includes relapsed and/or resistant cancer.
  • the terms“cancer” and“tumor” can be used interchangeably. For example, both terms encompass solid and liquid tumors.
  • the term“cancer” or“tumor” includes premalignant, as well as malignant cancers and tumors.
  • an“immune cell” refers to any of various cells that function in the immune system, e.g., to protect against agents of infection and foreign matter.
  • this term includes leukocytes, e.g., neutrophils, eosinophils, basophils, lymphocytes, and monocytes.
  • leukocytes include phagocytes (e.g., macrophages, neutrophils, and dendritic cells), mast cells, eosinophils, basophils, and natural killer cells.
  • phagocytes e.g., macrophages, neutrophils, and dendritic cells
  • mast cells e.g., eosinophils, basophils, and natural killer cells.
  • Innate leukocytes identify and eliminate pathogens, either by attacking larger pathogens through contact or by engulfing and then killing microorganisms, and are mediators in the activation of an adaptive immune response.
  • lymphocytes The cells of the adaptive immune system are special types of leukocytes, called lymphocytes.
  • B cells and T cells are important types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow. B cells are involved in the humoral immune response, whereas T cells are involved in cell-mediated immune response.
  • the term“immune cell” includes immune effector cells.
  • Immuno effector cell refers to a cell that is involved in an immune response, e.g., in the promotion of an immune effector response.
  • immune effector cells include, but are not limited to, T cells, e.g., alpha/beta T cells and gamma/delta T cells, B cells, natural killer (NK) cells, natural killer T (NK T) cells, and mast cells.
  • effector function or“effector response” refers to a specialized function of a cell. Effector function of a T cell, for example, may be cytolytic activity or helper activity including the secretion of cytokines.
  • nucleotide sequence in the context of nucleotide sequence, the term "substantially identical" is used herein to refer to a first nucleic acid sequence that contains a sufficient or minimum number of nucleotides that are identical to aligned nucleotides in a second nucleic acid sequence such that the first and second nucleotide sequences encode a polypeptide having common functional activity, or encode a common structural polypeptide domain or a common functional polypeptide activity.
  • variant refers to a polypeptide that has a substantially identical amino acid sequence to a reference amino acid sequence, or is encoded by a substantially identical nucleotide sequence. In some embodiments, the variant is a functional variant.
  • the term“functional variant” refers to a polypeptide that has a substantially identical amino acid sequence to a reference amino acid sequence, or is encoded by a substantially identical nucleotide sequence, and is capable of having one or more activities of the reference amino acid sequence.
  • the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes).
  • the length of a reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70%, 80%, 90%, 100% of the length of the reference sequence.
  • the amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared.
  • amino acid or nucleic acid “identity” is equivalent to amino acid or nucleic acid “homology”
  • the comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm.
  • the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J. Mol. Biol. 48:444-453 ) algorithm which has been incorporated into the GAP program in the GCG software package (available at http://www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.
  • the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available at http://www.gcg.com), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6.
  • a particularly preferred set of parameters are a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.
  • the percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4:11-17) 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.
  • nucleic acid and protein sequences described herein can be used as a "query sequence" to perform a search against public databases to, for example, identify other family members or related sequences. Such searches can be performed using the NBLAST and
  • Gapped BLAST can be utilized as described in Altschul et al, (1997) Nucleic Acids Res. 25:3389-3402.
  • NBLAST NBLAST
  • a “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain.
  • Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).
  • polymers of amino acids of any length may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non amino acids.
  • the terms also encompass an amino acid polymer that has been modified; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component.
  • the polypeptide can be isolated from natural sources, can be a produced by recombinant techniques from a eukaryotic or prokaryotic host, or can be a product of synthetic procedures.
  • nucleic acid refers to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof.
  • the polynucleotide may be either single- stranded or double-stranded, and if single-stranded may be the coding strand or non-coding (antisense) strand.
  • a polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs.
  • the sequence of nucleotides may be interrupted by non-nucleotide components.
  • a polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component.
  • the nucleic acid may be a recombinant polynucleotide, or a polynucleotide of genomic, cDNA, semisynthetic, or synthetic origin which either does not occur in nature or is linked to another polynucleotide in a non-natural arrangement.
  • isolated refers to material that is removed from its original or native environment (e.g ., the natural environment if it is naturally occurring).
  • a naturally-occurring polynucleotide or polypeptide present in a living animal is not isolated, but the same polynucleotide or polypeptide, separated by human intervention from some or all of the co-existing materials in the natural system, is isolated.
  • Such polynucleotides could be part of a vector and/or such polynucleotides or polypeptides could be part of a composition, and still be isolated in that such vector or composition is not part of the environment in which it is found in nature.
  • TCR Human T cell receptor
  • TCR alpha chain consists of V, J and C regions.
  • the rearrangement of the T-cell receptor (TCR) through somatic recombination of V (variable), D (diversity), J (joining), and C (constant) regions is a defining event in the development and maturation of a T cell. TCR gene rearrangement takes place in the thymus.
  • TCR beta V TCRflV
  • the TCR V beta repertoire varies between individuals and populations because of, e.g., 7 frequently occurring inactivating polymorphisms in functional gene segments and a large insertion/deletion-related polymorphism encompassing 2 V beta gene segments.
  • a TCRBV gene family comprises one or more subfamilies, e.g., as described herein, e.g., in FIG. 3, Table 8A or Table 8B.
  • the TCRpV gene family comprises: a TCRP V6 subfamily, a TCRP V10 subfamily, a TCRP V12 subfamily, a TCRP V5 subfamily, a TCRP V7 subfamily, a TCRP VI 1 subfamily, a TCRP V14 subfamily, a TCRP V16 subfamily, a TCRp VI 8 subfamily, a TCRp V9 subfamily, a TCRp V13 subfamily, a TCRp V4 subfamily, a TCRP V3 subfamily, a TCRP V2 subfamily, a TCRP V15 subfamily, a TCRP V30 subfamily, a TCRp V19 subfamily, a TCRp V27 subfamily, a TCRp V28 subfamily, a TCR
  • TCRP V6 subfamily is also known as TCRP V13.1.
  • the TCRP V6 subfamily comprises: TCRP V6-4*0l, TCRP V6-4*02, TCRP V6- 9*01, TCRp V6-8*0l, TCRp V6-5*0l, TCRp V6-6*02, TCRp V6-6*0l, TCRp V6-2*0l, TCRp V6-3*0l or TCRP V6-l*0l, or a variant thereof.
  • TCRP V6 comprises TCRP V6-4*0l, or a variant thereof.
  • TCRP V6 comprises TCRP V6- 4*02, or a variant thereof.
  • TCRP V6 comprises TCRP V6-9*0l, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-8*0l, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-5*0l, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-6*02, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-6*0l, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-2*0l, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-3*0l, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6- 1*01, or a variant thereof.
  • TCRP V6 comprises TCRP V6-5*0l, or a variant thereof.
  • TCRP V6, e.g., TCRP V6-5*0l is recognized, e.g., bound, by SEQ ID NO: 1 and/or SEQ ID NO: 2.
  • TCRP V6, e.g., TCRP V6-5*0l is recognized, e.g., bound, by SEQ ID NO: 9 and/or SEQ ID NO: 10.
  • TCRP V6 is recognized, e.g., bound, by SEQ ID NO: 9 and/or SEQ ID NO: 11.
  • TCRP V12 subfamily is also known as TCRP V8.1.
  • the TCRP V12 subfamily comprises: TCRP Vl2-4*0l, TCRP Vl2-3*0l, or TCRP Vl2-5*0l, or a variant thereof.
  • TCRP V12 is recognized, e.g., bound, by SEQ ID NO: 15 and/or SEQ ID NO: 16.
  • TCRP V12 is recognized, e.g., bound, by any one of SEQ ID NOs 23-25, and/or any one of SEQ ID NO: 26-30:
  • the TCRP V5 subfamily is chosen from: TCRP V5-5*0l, TCRP V5-6*0l, TCRp V5-4*0l, TCRp V5-8*0l, TCRp V5-l*0l, or a variant thereof.
  • the TCRP V7 subfamily comprises TCRP V7-7*0l, TCRP V7- 6*01, TCRp V7 -8*02, TCRp V7 -4*01, TCRp V7-2*02, TCRp V7-2*03, TCRp V7-2*0l,
  • the TCRP VI 1 subfamily comprises: TCRP VI 1-1*01, TCRP VI 1-2*01 or TCRP VI 1-3*01, or a variant thereof.
  • the TCRP V14 subfamily comprises TCRP Vl4*0l, or a variant thereof.
  • the TCRP V16 subfamily comprises TCRP Vl6*0l, or a variant thereof.
  • the TCRP V18 subfamily comprises TCRP Vl8*0l, or a variant thereof.
  • the TCRP V9 subfamily comprises TCRP V9*0l or TCRP V9*02, or a variant thereof.
  • the TCRP V13 subfamily comprises TCRP Vl3*0l, or a variant thereof.
  • the TCRP V4 subfamily comprises TCRP V4-2*0l, TCRP V4- 3*01, or TCRP V4-l*0l, or a variant thereof.
  • the TCRP V3 subfamily comprises TCRP V3-l*0l, or a variant thereof.
  • the TCRP V2 subfamily comprises TCRP V2*0l, or a variant thereof.
  • the TCRP V15 subfamily comprises TCRP Vl5*0l, or a variant thereof.
  • the TCRP V30 subfamily comprises TCRP V30*0l, or TCRP V30*02, or a variant thereof.
  • the TCRP V19 subfamily comprises TCRP Vl9*0l, or TCRP VI 9*02, or a variant thereof.
  • the TCRP V27 subfamily comprises TCRP V27*0l, or a variant thereof.
  • the TCR3 V28 subfamily comprises TCR3 V28*0l, or a variant thereof.
  • V20-l*02 or a variant thereof.
  • the TCR3 V25 subfamily comprises TCR3 V25-l*0l, or a variant thereof.
  • the TCR3 V29 subfamily comprises TCR3 V29-l*0l, or a variant thereof.
  • Table 8A List of TCRpV subfamilies and subfamily members
  • TCRBV amino acid sequences in Table 9 underscores the diversity of TCR sequences.
  • TRBV sequences from different subfamilies are considerably different from each other.
  • the anti-TCRpV antibody molecules disclosed herein do not recognize, e.g., bind to, an interface of a TCRpV:TCRalpha complex.
  • the anti-TCRpV antibody molecules disclosed herein do not recognize, e.g., bind to, a constant region of a TCRpV protein.
  • An exemplary antibody that binds to a constant region of a TCRBV region is JOVI.l as described in Viney el al., (Hybridoma.
  • the anti-TCRpV antibody molecules disclosed herein do not recognize, e.g., bind to, one or more (e.g., all) of a complementarity determining region (e.g., CDR1, CDR2 and/or CDR3) of a TCRpV protein. In some embodiments, the anti-TCRpV antibody molecules disclosed herein binds (e.g., specifically binds) to a TCRpV region.
  • a complementarity determining region e.g., CDR1, CDR2 and/or CDR3
  • binding of anti-TCRpV antibody molecules disclosed herein results in a cytokine profile that differs from a cytokine profile of a T cell engager that binds to a receptor or molecule other than a TCRpV region (“a non-TCRpV- binding T cell engager”).
  • the non-TCRpV-binding T cell engager comprises an antibody that binds to a CD3 molecule ( e.g ., CD3 epsilon (CD3e) molecule); or a TCR alpha (TCRa) molecule.
  • the non-TCRpV-binding T cell engager is an OKT3 antibody or an SP34-2 antibody.
  • the disclosure provides an anti-TCRpV antibody molecule that binds to human TCRpV, e.g., a TCRpV gene family, e.g., one or more of a TCRpV subfamily, e.g., as described herein, e.g., in FIG. 3, Table 8A, or Table 8B.
  • a TCRpV gene family e.g., one or more of a TCRpV subfamily, e.g., as described herein, e.g., in FIG. 3, Table 8A, or Table 8B.
  • the anti-TCRpV antibody molecule binds to a TCRP V6 subfamily comprising: TCRp V6-4*0l, TCRp V6-4*02, TCRp V6-9*0l, TCRp V6-8*0l, TCRp V6-5*0l, TCRp V6-6*02, TCRp V6-6*0l, TCRp V6-2*0l, TCRp V6-3*0l or TCRp V6-l*0l, or a variant thereof.
  • the TCRP V6 subfamily comprises TCRP V6-5*0l, or a variant thereof.
  • TCRP V6 comprises TCRP V6-4*0l, or a variant thereof.
  • TCRP V6 comprises TCRP V6-4*02, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-9*0l, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-8*0l, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-5*0l, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-6*02, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-6*0l, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6- 2*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-3*0l, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6- 1*01, or a variant thereof.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule, may include any CDR described herein.
  • substantially identical e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical
  • substantially identical e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical
  • amino acid alteration but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, three, four, five, or six CDRs according to Kabat et al. shown in Table 1.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule, includes at least one, two, three, four, five, or six CDRs according to Chothia et al.
  • a combined CDR as set out in Table 1 is a CDR that comprises a Rabat CDR and a Chothia CDR.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule, molecule includes a combination of CDRs or hypervariable loops identified as combined CDRs in Table 1.
  • the anti- TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule, can contain any combination of CDRs or hypervariable loops according the“combined” CDRs are described in Table 1.
  • LC CDR3 complementarity determining region 3
  • HC CDR3 complementarity determining region 3
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti- TCRp V6-5*0l) antibody molecule comprises a LC CDR1, LC CDR2, and LC CDR3 of SEQ ID NO: 10, and a HC CDR1, HC CDR2, and HC CDR3 of SEQ ID NO: 9.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti- TCRP V6-5*0l) antibody molecule comprises:
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule comprises:
  • VL light chain variable region
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti- TCRP V6-5*0l) antibody molecule comprises:
  • VL light chain variable region
  • VH heavy chain variable region
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti- TCRP V6-5*0l) antibody molecule comprises:
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule comprises:
  • VL light chain variable region
  • the light or the heavy chain variable framework (e.g., the region encompassing at least FR1, FR2, FR3, and optionally FR4) of the anti-TCRpV antibody molecule, e.g., anti-TCRP V6 (e.g ., anti-TCRP V6-5*0l) antibody molecule can be chosen from: (a) a light or heavy chain variable framework including at least 80%, 85%, 87% 90%, 92%, 93%, 95%, 97%, 98%, or 100% of the amino acid residues from a human light or heavy chain variable framework, e.g., a light or heavy chain variable framework residue from a human mature antibody, a human germline sequence, or a human consensus sequence; (b) a light or heavy chain variable framework including from 20% to 80%, 40% to 60%, 60% to 90%, or 70% to 95% of the amino acid residues from a human light or heavy chain variable framework, e.g., a light or heavy chain variable framework residue from a human mature antibody,
  • the light or heavy chain variable framework region (particularly FR1, FR2 and/or FR3) includes a light or heavy chain variable framework sequence at least 70, 75, 80, 85, 87, 88, 90, 92, 94, 95, 96, 97, 98, 99% identical or identical to the frameworks of a VL or VH segment of a human germline gene.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule, comprises the light chain framework region 1 of A-H.l or A-H.2, e.g., as shown in FIG. IB.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule, comprises the light chain framework region 2 of A-H.l or A-H.2, e.g., as shown in FIG. IB.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule, comprises the light chain framework region 3 of A-H.l or A-H.2, e.g., as shown in FIG. IB.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule, comprises the light chain framework region 4 of A-H.l or A-H.2, e.g., as shown in FIG. IB.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule
  • the FR1 comprises a Phenylalanine at position 10, e.g., a Serine to Phenyalanine substitution.
  • the substitution is relative to a human germline light chain framework region sequence.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule
  • FR2 comprises a Histidine at position 36, e.g., a substitution at position 36 according to Rabat numbering, e.g., a Tyrosine to Histidine substitution.
  • FR2 comprises an Alanine at position 46, e.g., a substitution at position 46 according to Rabat numbering, e.g., an Arginine to Alanine substitution.
  • the substitution is relative to a human germline light chain framework region sequence.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule, comprises a light chain variable domain comprising a framework region, e.g., framework region 3 (FR3), comprising a change, e.g., a substitution (e.g., a conservative substitution) at a position disclosed herein according to Rabat numbering.
  • FR3 framework region 3
  • FR3 comprises a Phenyalanine at position 87, e.g., a substitution at position 87 according to Rabat numbering, e.g., a Tyrosine to Phenyalanine substitution.
  • the substitution is relative to a human germline light chain framework region sequence.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule
  • Phenyalanine substitution e.g., as shown in the amino acid sequence of SEQ ID NO: 10.
  • the substitution is relative to a human germline light chain framework region sequence.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule, comprises the heavy chain framework region 1 of A- H.l or A-H.2, e.g., as shown in FIG. 1A.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule, comprises the heavy chain framework region 2 of A- H.l or A-H.2, e.g., as shown in FIG. 1A
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule, comprises the heavy chain framework region 4 of A- H.l or A-H.2, e.g., as shown in FIG. 1A.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule
  • FR3 comprises a Threonine at position 73, e.g., a substitution at position 73 according to Rabat numbering, e.g., a Glutamic Acid to Threonine substitution.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule
  • FR3 framework region 3
  • Threonine at position 73 e.g., a substitution at position 73 according to Kabat numbering, e.g., a Glutamic Acid to Threonine substitution
  • a Glycine at position 94 e.g.,
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule, comprises the heavy chain framework regions 1-4 of A- H.l or A-H.2, e.g., SEQ ID NO: 9, or as shown in FIGs. 1A and IB.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule, comprises the light chain framework regions 1-4 of A- H.l, e.g., SEQ ID NO: 10, or as shown in FIGs. 1A and IB.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule, comprises the light chain framework regions 1-4 of A- H.2, e.g., SEQ ID NO: 11, or as shown in FIGs. 1A and IB.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule
  • the anti-TCRpV antibody molecule comprises the heavy chain framework regions 1-4 of A- H.l, e.g., SEQ ID NO: 9; and the light chain framework regions 1-4 of A-H.l, e.g., SEQ ID NO:
  • FIGs. 1A and IB are numbered 10, or as shown in FIGs. 1A and IB.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule
  • the anti-TCRpV antibody molecule comprises the heavy chain framework regions 1-4 of A- H.2, e.g., SEQ ID NO: 9; and the light chain framework regions 1-4 of A-H.2, e.g., SEQ ID NO:
  • FIGs. 1A and IB are identical to FIGs. 1A and IB.
  • the heavy or light chain variable domain, or both, of the anti- TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule
  • the anti- TCRpV antibody molecule includes an amino acid sequence, which is substantially identical to an amino acid disclosed herein, e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical to a variable region of an antibody described herein, e.g., an antibody chosen from A-H.l or A-H.2, or as described in Table 1, or encoded by the nucleotide sequence in Table 1; or which differs at least 1 or 5 residues, but less than 40, 30, 20, or 10 residues, from a variable region of an antibody described herein.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule includes a VH and/or VL domain encoded by a nucleic acid having a nucleotide sequence as set forth in Table 1, or a sequence substantially identical thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, or which differs by no more than 3, 6, 15, 30, or 45 nucleotides from the sequences shown in Table 1.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule, comprises:
  • VH domain comprising the amino acid sequence of SEQ ID NO: 9, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence of SEQ ID NO: 9, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 9; and/or
  • VL domain comprising the amino acid sequence of SEQ ID NO: 10, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence of SEQ ID NO: 10, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 10.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule, comprises:
  • VL domain comprising the amino acid sequence of SEQ ID NO: 11, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence of SEQ ID NO: 11, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 amino acid residues from the amino acid sequence of SEQ ID NO: 11.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule is a full antibody or fragment thereof (e.g., a Fab,
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule is a monoclonal antibody or an antibody with single specificity.
  • the anti-TCRpV antibody molecule, e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule can also be a humanized, chimeric, camelid, shark, or an in vitro- generated antibody molecule.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6- 5*01) antibody molecule
  • the heavy and light chains of the anti-TCRpV antibody molecule can be full-length (e.g., an antibody can include at least one, and preferably two, complete heavy chains, and at least one, and preferably two, complete light chains) or can include an antigen-binding fragment (e.g., a Fab, F(ab')2, Fv, a single chain Fv fragment, a single domain antibody, a diabody (dAb), a bivalent antibody, or bispecific antibody or fragment thereof, a single domain variant thereof, or a camelid antibody).
  • an antibody can include at least one, and preferably two, complete heavy chains, and at least one, and preferably two, complete light chains
  • an antigen-binding fragment e.g., a Fab, F(ab')2, Fv, a single chain Fv fragment,
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule
  • the Fc region is chosen from the heavy chain constant regions of IgGl, IgG2, IgG3, and IgG4.
  • the Fc region is chosen from the heavy chain constant region of IgGl or IgG2 (e.g., human IgGl, or IgG2).
  • the heavy chain constant region is human IgGl.
  • the constant region is altered, e.g., mutated, to modify the properties of the anti- TCRpV antibody molecule, e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule (e.g., to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function).
  • anti-TCRP V6 e.g., anti-TCRP V6-5*0l
  • Fc receptor binding e.g., anti-TCRP V6-5*0l
  • the constant region is mutated at positions 296 (M to Y), 298 (S to T), 300 (T to E), 477 (H to K) and 478 (N to F) to alter Fc receptor binding (e.g., the mutated positions correspond to positions 132 (M to Y), 134 (S to T), 136 (T to E), 313 (H to K) and 314 (N to F) of SEQ ID NOs: 212 or 214; or positions 135 (M to Y), 137 (S to T), 139 (T to E), 316 (H to K) and 317 (N to F) of SEQ ID NOs: 215, 216, 217 or 218), e.g., relative to human IgGl.
  • the mutated positions correspond to positions 132 (M to Y), 134 (S to T), 136 (T to E), 313 (H to K) and 314 (N to F) of SEQ ID NOs: 212 or 214; or positions 135 (M to
  • Antibody A-H.l comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 3278 and a light chain comprising the amino acid sequence of SEQ ID NO: 72.
  • Antibody A-H.2 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 3278 and a light chain comprising the amino acid sequence of SEQ ID NO: 3279.
  • Table 1 Amino acid and nucleotide sequences for murine, chimeric and humanized antibody molecules.
  • the antibody molecules include murine mAb Antibody A, and humanized mAb Antibody A-H Clones A-H.l and A-H.2.
  • the amino acid the heavy and light chain CDRs, and the amino acid and nucleotide sequences of the heavy and light chain variable regions, and the heavy and light chains are shown.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule comprises a VH and/or a VL of an antibody described in Table 1, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V6 (e.g., anti-TCRP V6-5*0l) antibody molecule comprises a VH and a VL of an antibody described in Table 1, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V12 antibody molecule
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V12 antibody molecule
  • the anti-TCRpV antibody molecule includes a kappa light chain constant region, e.g., a human kappa light chain constant region.
  • the light chain constant region comprises an amino sequence set forth in Table 3, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) thereto.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V12 antibody molecule includes at least one, two, three, four, five, or six CDRs according to Rabat et al. (e.g., at least one, two, three, four, five, or six CDRs according to the Rabat definition as set out in Table 2) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody as described in Table 2, or encoded by the nucleotide sequence in Table 2; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, three, four, five, or six CDRs
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V12 antibody molecule includes at least one, two, or three CDRs according to Chothia et al. (e.g., at least one, two, or three CDRs according to the Chothia definition as set out in Table 2) from a light chain variable region of an antibody described herein, e.g., an antibody as described in Table 2, or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to one, two, or three CDRs according to Chothia et al. shown in Table 2.
  • alterations e.g., substitutions, deletions, or insertions, e
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V12 antibody molecule includes at least one, two, three, four, five, or six CDRs according to Chothia et al.
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V12 antibody molecule includes all six CDRs according to Chothia et al. (e.g., all six CDRs according to the Chothia definition as set out in Table 2) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody as described in Table 2, or encoded by the nucleotide sequence in Table 2; or encoded by the nucleotide sequence in Table 2; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences; or which have at least one amino acid alteration, but not more than two, three or four alterations (e.g., substitutions, deletions, or insertions, e.g., conservative substitutions) relative to all six CDRs according to Chothia et al.
  • alterations e.g., substitutions
  • the anti-TCRpV antibody molecule e.g., anti-TCRP V12 antibody molecule includes at least one, two, three, four, five, or six CDRs according to a combined CDR. (e.g., at least one, two, three, four, five, or six CDRs according to the combined CDR definition as set out in Table 2) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody as described in Table 2, or encoded by the nucleotide sequence in Table 2; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%,

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US17/820,794 US11965025B2 (en) 2018-07-03 2022-08-18 Method of treating solid cancers with bispecific interleukin-anti-TCRß molecules
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