Combination therapy of a PARP inhibitor and a multifunctional molecule binding to tcr

Abstract

Provided herein are methods of treating conditions or diseases in a subject using a combination of a PARP inhibitor and a molecule comprising an antigen binding domain that binds to a T cell receptor beta variable region (TCRβV) and a molecule that activates a co-stimulatory receptor or a molecule that inhibits a co-inhibitory receptor. Kits for use in practicing the methods are also provided.

Description

WSGR Docket No. 53676-773.601COMBINATION THERAPY OF A PARP INHIBITOR AND A MULTIFUNCTIONAL MOLECULE BINDING TO TCRCROSS REFERENCE

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 724,491, filed November 25, 2024, the content of which is incorporated by reference herein in its entirety.BACKGROUND

[0002] Monotherapies using current cancer therapeutics (e.g., a multifunctional molecule binding to TCR or a PARP inhibitor) have limited therapeutic effects. Therefore, there is a need for improved therapy such as combination therapy to enhance the therapeutic effects of existing anti -cancer therapies.SUMMARY

[0003] Disclosed herein, in some embodiments, is a method of treating a disease or a condition in a subject in need thereof comprising: administering a therapeutically effective amount of a first agent comprising (i) a first domain that binds to a TCR [3 variable (TCRpV) region and (ii) a molecule that activates a co-stimulatory receptor or a molecule that inhibits a co-inhibitory receptor; and administering a therapeutically effective amount of a second agent comprising a Poly-ADP ribose polymerase (PARP) inhibitor. In some embodiments, the administration of the first agent improves therapeutic efficacy of the second agent to the subject. In some embodiments, the administration of the first agent and the second agent promotes an enhanced anti-tumor immune response in the subject.

[0004] Disclosed herein, in some embodiments, is a combination therapy for treating a disease or a condition in a subject in need thereof, comprising: a first agent comprising (i) a first domain that binds to a TCR P variable (TCRpV) region and (ii) a molecule that activates a co-stimulatory receptor or a molecule that inhibits a co-inhibitory receptor; and a second agent comprising a Poly-ADP ribose polymerase (PARP) inhibitor.

[0005] Also disclosed herein, in some embodiments, is a composition for treating a disease or condition in a subject in need thereof comprising: a first agent comprising (i) a first domain that binds to a TCR P variable (TCRpV) region and (ii) a molecule that activates a co-stimulatory receptor or a molecule that inhibits a co-inhibitory receptor; and a second agent comprising a Poly-ADP ribose polymerase (PARP) inhibitor.

[0006] Also disclosed herein, in some embodiments, is a kit for treating a disease or condition in a subject in need thereof comprising: a first agent comprising (i) a first domain that binds to a TCR P variable (TCRpV) region and (ii) a molecule that activates a co-stimulatory receptor or a molecule that inhibits a co-inhibitory receptor; and a second agent comprising a Poly-ADP ribose polymerase (PARP) inhibitor.

[0007] Also disclosed herein, in some embodiment, is a method of treating a disease or a condition in a subject in need thereof comprising administering a therapeutically effective amount of a first agent to the subject, wherein the first agent comprises (i) a first domain that binds to a TCR P variable (TCRpV) region and (ii) a molecule that binds and / or activates a co-stimulatory receptor or a molecule that bindsWSGR Docket No. 53676-773.601 and / or inhibits a co-inhibitory receptor; wherein the subject was previously administered a second agent, wherein the second agent comprises a Poly-ADP ribose polymerase (PARP) inhibitor.

[0008] Also disclosed herein, in some embodiment, is a method of treating a disease or a condition in a subject in need thereof comprising administering a therapeutically effective amount of a second agent to the subject, wherein the second agent comprises a Poly-ADP ribose polymerase (PARP) inhibitor; wherein the subject was previously administered a first agent, wherein the first agent comprises (i) a first domain that binds to a TCR [3 variable (TCRJ3V) region and (ii) a molecule that binds and / or activates a co-stimulatory receptor or a molecule that binds and / or inhibits a co-inhibitory receptor.

[0009] In some embodiment, the multifunctional molecule comprises a molecule that activates a costimulatory receptor or a molecule that inhibits a co-inhibitory receptor. In some embodiment, the molecule that activates a co-stimulatory receptor is a molecule that binds the co-stimulatory receptor. In some embodiment, the molecule that activates a co-stimulatory receptor is a molecule that activates a co- stimulatory receptor of a T cell. In some embodiment, the molecule that activates a co-stimulatory receptor comprises a ligand of the co-stimulatory receptor. In some embodiment, the molecule that activates a co-stimulatory receptor comprises an extracellular domain of a receptor that binds and / or activates the co-stimulatory receptor. In some embodiment, the molecule that activates a co-stimulatory receptor comprises a cytokine, a functional fragment thereof or a functional variant thereof. In some embodiment, the molecule that activates a co-stimulatory receptor comprises a molecule that binds and / or activates CD28, CD40L (CD154), CD27, 0X40 (CD134), 4-1BB (CD137), GITR (CD357), HVEM (CD270), Galnectin 9, TIM1, LFA1, CD226, CD30 or CD2. In some embodiment, the molecule that activates a co-stimulatory receptor comprises an extracellular domain of a receptor selected from the group consisting of B7-1 (CD80), B7-2 (CD86), CD40, ICOSL, CD70, CD27L, OX40L, 4-1BBL, GITRL, LIGHT (CD258), TIM3, TIM4, ICAM1, CD48, CD56, CD155, CD112, CD30L or LFA3. In some embodiment, the first agent comprises a molecule that inhibits a co-inhibitory receptor. In some embodiment, the molecule that inhibits a co-inhibitory receptor is a molecule that binds the co-inhibitory receptor. In some embodiment, the molecule that inhibits a co-inhibitory receptor is a molecule that inhibits a co-inhibitory receptor of a T cell. In some embodiment, the molecule that inhibits a co- inhibitory receptor is a molecule that inhibits ICOS, CTLA4, PD1, BTLA (CD272), or CD160.

[0010] In some embodiments, administering the first agent and the second agent induces an improved therapeutic effect in the subject, relative to a subject administered the second agent without the first agent. In some embodiments, administering the first agent and the second agent induces more activated and / or expanded T cells in a tumor in the subject, relative to a tumor in a subject administered the second agent without the first agent. In some embodiments, administering the first agent and the second agent induces less exhausted T cells in a tumor in the subject, relative to a tumor in a subject administered the second agent without the first agent. In some embodiments, administering the first agent and the second agent induces a higher anti -tumor efficacy level in the subject, relative to a subject administered the second agent without the first agent. In some embodiments, administering the first agent and the second agent induces a higher number of T cells that are cytotoxic against tumor cells or cancer cells in theWSGR Docket No. 53676-773.601 subject, relative to a subject administered the second agent without the first agent. In some embodiments, administering the first agent and the second agent induces a higher level of cytotoxicity against tumor cells or cancer cells in the subject, relative to a subject administered the second agent without the first agent. In some embodiments, administering the first agent and the second agent expands or activates a higher number of T cells that are cytotoxic against tumor cells or cancer cells in the subject, relative to a subject administered the second agent without the first agent. In some embodiments, administering the first agent and the second agent induces a higher level of cytotoxic activity against tumor cells or cancer cells in the subject, relative to a subject administered the second agent without the first agent. In some embodiments, the subject exhibits an improved therapeutic effect after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent. In some embodiments, the subject produces a higher number of activated and / or expanded T cells after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent. In some embodiments, the subject has less exhausted T cells after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent. In some embodiments, the subject exhibits a higher level of anti -tumor efficacy after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent. In some embodiments, the subject produces a higher number of T cells that are more cytotoxic against tumor cells or cancer cells after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent. In some embodiments, the subject produces a higher number of NK cells that are more cytotoxic against tumor cells or cancer cells after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent. In some embodiments, the subject exhibits a higher level of cytotoxic activity against tumor cells or cancer cells after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent.

[0011] In some embodiments, the T cells are TCR[3V+. In some embodiments, the T cells are CD4+, CD8+, IFNg+, Granzyme B+, PD1+, TNF+, or any combination thereof. In some embodiment, the CD8+ T cells are characterized by stem cell-like characteristics. In some embodiment, the CD8+ T cells are Tpex cells.

[0012] In some embodiment, the subject has decreased level of immunosuppressive cells after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent. In some embodiment, the immunosuppressive cells are M2 macrophages, monocyte- myeloid-derived suppressor cells (M-MDSC), regulatory T cells (Tregs), or any combination thereof.

[0013] In some embodiments, the subject has tumors that are more immune infiltrated after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent. In some embodiments, the tumors are more immune infiltrated with CD4+ T cells, CD8+ T cells, or both. In some embodiment, the CD4+ T cells or the CD8+ T cells are TCR[3V+. In some embodiment, the TCRJ3V is TCRJ3V6 or TCRpVIO. In some embodiments, the subject has tumors that are less infiltrated with Treg cells after administration of the first agent and the second agent, relative to aWSGR Docket No. 53676-773.601 subject not administered the first agent or the second agent. In some embodiments, the Treg cells are CD4+ and FoxP3+. in some embodiment, the subject has elevated levels of TRAIL-R2 expression after administration of the first agent and the second agent, relative to a subject not administered the second agent.

[0014] In some embodiments, the first agent is administered to the subject prior to, concurrently, or after administration of the second agent to the subject.

[0015] In some embodiments, the first agent and the second agent are concomitantly administered to the subject. In some embodiments, the first agent and the second agent are not concomitantly administered to the subject. In some embodiments, the administration of the second agent to the subject is conducted before the administration of the first agent to the subject. In some embodiments, the administration of the first agent to the subject is conducted before the administration of the second agent to the subject.

[0016] In some embodiments, the first agent is administered to the subject at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at least 1, 2, 3, 4, 5, 6, or 7 days, at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years after the subject has been treated with a dose of the second agent.

[0017] In some embodiments, the first agent is administered to the subject at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at least 1, 2, 3, 4, 5, 6, or 7 days, at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years after the subject has been treated with a first dose of the second agent.

[0018] In some embodiments, the first agent is administered to the subject at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at least 1, 2, 3, 4, 5, 6, or 7 days, at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years after the subject has been treated with a last dose of the second agent.

[0019] In some embodiments, the first agent is administered to the subject at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at most 1, 2, 3, 4, 5, 6, or 7 days, at most 1, 2, 3, or 4 weeks, at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at most 1, 2, or 3 years after being treated with the second agent.

[0020] In some embodiments, the first agent is administered to the subject at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at most 1, 2, 3, 4, 5, 6, or 7 days, at most 1, 2, 3, or 4 weeks, at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at most 1, 2, or 3 years after being treated with a dose of the second agent.

[0021] In some embodiments, the first agent is administered to the subject at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at most 1, 2, 3, 4, 5, 6, or 7 days, at most 1, 2, 3, or 4 weeks, at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at most 1, 2, or 3 years after being treated with a first dose of the second agent.

[0022] In some embodiments, the method comprises administering the first agent to the subject at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at most 1, 2, 3, 4, 5, 6, or 7 days, at most 1, 2, 3, or 4 weeks, at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at most 1, 2, or 3 years after being treated with a last dose of the second agent.WSGR Docket No. 53676-773.601

[0023] In some embodiments, the first agent is administered to the subject from 1 hour to 24 hours after being treated with a dose of the second agent.

[0024] In some embodiments, the first agent is administered to the subject from 1 day to 7 days after being treated with a dose of the second agent.

[0025] In some embodiments, the first agent is administered to the subject from 1 week to 4 weeks after being treated with a dose of the second agent.

[0026] In some embodiments, the first agent is administered to the subject from 1 month to 12 months after being treated with a dose of the second agent.

[0027] In some embodiments, the first agent is administered to the subject from 1 year to 3 years after being treated with a dose of the second agent.

[0028] In some embodiments, the first agent is administered to the subject from 1 hour to 24 hours after being treated with a first dose of the second agent.

[0029] In some embodiments, the first agent to the subject from 1 day to 7 days after being treated with a first dose of the second agent.

[0030] In some embodiments, the first agent is administered to the subject from 1 week to 4 weeks after being treated with a first dose of the second agent.

[0031] In some embodiments, the first agent is administered to the subject from 1 month to 12 months after being treated with a first dose of the second agent.

[0032] In some embodiments, the first agent is administered to the subject from 1 year to 3 years after being treated with a first dose of the second agent.

[0033] In some embodiments, the first agent is administered to the subject from 1 hour to 24 hours after being treated with a last dose of the second agent.

[0034] In some embodiments, the first agent is administered to the subject from 1 week to 4 weeks after being treated with a last dose of the second agent.

[0035] In some embodiments, the first agent is administered to the subject from 1 month to 12 months after being treated with a last dose of the second agent.

[0036] In some embodiments, the first agent is administered to the subject from 1 year to 3 years after being treated with a last dose of the second agent.

[0037] In some embodiments, the first agent is administered to the subject on the same day the subject had been previously treated with the second agent.

[0038] In some embodiments, the method is repeated twice or more.

[0039] In some embodiments, the administration of the first agent comprises one or more doses. In some embodiments, the administration of the first agent comprises two or more doses. In some embodiments, the administration of the first agent comprises one dose per week. In some embodiments, the administration of the first agent comprises two or more doses per week. In some embodiments, the first agent is administered to the subject once every two weeks. In some embodiments, the first agent is administered to the subject once every three weeks.WSGR Docket No. 53676-773.601

[0040] In some embodiments, the first agent is administered to the subject once every week for at least 1,2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years. In some embodiments, the administration of the first agent comprises two or more doses per week for at least 1, 2,3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years. In some embodiments, the first agent is administered to the subject once every two weeks for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years. In some embodiments, the first agent is administered to the subject once every three weeks for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years.

[0041] In some embodiments, the administration of the second agent comprises one or more doses. In some embodiments, the administration of the second agent comprises two or more doses. In some embodiments, the administration of the second agent comprises one dose per week. In some embodiments, the administration of the second agent comprises two or more doses per week. In some embodiments, the second agent is administered to the subject once every two weeks. In some embodiments, the second agent is administered to the subject once every three weeks.

[0042] In some embodiments, the second agent is administered to the subject once every week for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years. In some embodiments, the administration of the second agent comprises two or more doses per week for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years. In some embodiments, the second agent is administered to the subject once every two weeks for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years. In some embodiments, the second agent is administered to the subject once every three weeks for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years. In some embodiments, the first agent is administered to the subject at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at least 1, 2, 3, 4, 5, 6, or 7 days, at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years prior to administering the second agent to the subject. In some embodiments, the first agent is administered to the subject at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at most 1, 2, 3, 4, 5, 6, or 7 days, at most 1, 2, 3, or 4 weeks, at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at most 1, 2, or 3 years prior to administering the second agent to the subject.

[0043] In some embodiments, the first agent is administered to the subject from 1 hour to 24 hours prior to administering the second agent to the subject. In some embodiments, the first agent is administered to the subject from 1 day to 7 days prior to administering the second agent to the subject. In some embodiments, the first agent is administered to the subject from 1 week to 4 weeks prior to administering the second agent to the subject. In some embodiments, the first agent is administered to the subject from 1 month to 12 months prior to administering the second agent to the subject. In some embodiments, the first agent is administered to the subject from 1 year to 3 years prior to administering the second agent to the subject. In some embodiments, the administration of the first agent comprises two or more doses, and each dose comprises a same amount of the first agent. In some embodiments, the administration of the first agent comprises two or more doses, and each dose comprises different amounts of the first agent. InWSGR Docket No. 53676-773.601 some embodiments, the administration of the second agent comprises two or more doses, and each dose comprises a same amount of the second agent. In some embodiments, the administration of the second agent comprises two or more doses, and each dose comprises different amounts of the second agent.

[0044] In some embodiments, the first agent is administered to the subject at a dose of from about 0.001 mg / kg to about 20 mg / kg. In some embodiments, the second agent is administered to the subject at a dose of from about 0.001 mg / kg to about 20 mg / kg.

[0045] In some embodiments, the method comprises administering the first agent and the second agent to the subject simultaneously or on the same day. In some embodiments, the second agent is administered to the subject once or twice a day and one or more doses of the first agent is administered to the subject from 1 day to 7 days after being treated with a dose of the first agent. In some embodiments, the first agent is administered at an interval of every 2, every 3, every 4, every 5, every 6, or every 7 days. In some embodiments, the disease or condition in the subject is treated to a higher extent relative to a corresponding method in which the first agent is administered and the second agent is not administered.

[0046] In some embodiments, the method is more effective to treat the disease or condition in the subject relative to a method in which the first agent is administered to the subject but not the second agent. In some embodiments, the method is more effective to treat the disease or condition in the subject relative to a method in which the second agent is administered to the subject but not the first agent.

[0047] In some embodiments, the TCRJ3V region is a human TCRJ3V region. In some embodiments, the first domain binds to one or more of a TCRJ3V subfamily selected from the group consisting of TCRP V 1 subfamily, TCRP V2 subfamily, TCRP V3 subfamily, TCRP V4 subfamily, TCRP V5 subfamily, TCRP V6 subfamily, TCRP V7 subfamily, TCRP V8 subfamily, TCRP V9 subfamily, TCRP V10 subfamily, TCR VI 1 subfamily, TCR V12 subfamily, TCR V13 subfamily, TCR V14 subfamily, TCR V15 subfamily, TCR VI 6 subfamily, TCR V17 subfamily, TCR VI 8 subfamily, TCR VI 9, TCR V20 subfamily, TCRP V21 subfamily, TCRP V22 subfamily TCRP V23 subfamily, TCRP V24 subfamily, TCR V25 subfamily, TCR V26 subfamily, TCR V27 subfamily, TCR V28 subfamily, TCR V29 subfamily, and TCRP V30 subfamily.

[0048] In some embodiments, the first domain binds to one or more of a TCRJ3V subfamily selected from the group consisting of:(i) TCR[3 VI subfamily comprising TCRP VI *01;(ii) TCRP V2 subfamily comprising one or more selected from TCRP V2*01, TCRP V2*02, and TCRP V2*03;(iii) TCRP V3 subfamily comprising one or more selected from TCRP V3-l*01 and TCRP V3-l*02;(iv) TCRP V4 subfamily comprising one or more selected from TCRP V4-l*01, TCRP V4-l*02, TCRP V4-2*01, TCRP V4-2*02, TCRP V4-3*01, TCRP V4-3*02, TCRP V4-3*03, and TCRP V4-3*04;(v) TCRP V5 subfamily comprising one or more selected from TCRP V5-l*01, TCRP V5-l*02, TCRP V5-3*01, TCRP V5-3*02, TCRP V5-4*01, TCRP V5-4*02, TCRP V5-4*03, TCRP V5-4*04, TCRP V5- 5*01, TCRP V5-5*02, TCRP V5-5*03, TCRP V5-6*01, TCRP V5-7*01, TCRP V5-8*01, and TCRP V5- 8*02;WSGR Docket No. 53676-773.601(vi) TCRP V6 subfamily comprising one or more selected from TCRP V6-l*01, TCRP V6-2*01, TCRP V6-3*01, TCRP V6-4*01, TCRP V6-4*02, TCRP V6-5*01, TCRP V6-6*01, TCRP V6-6*02, TCRP V6- 6*03, TCRP V6-6*04, TCRP V6-6*05, TCRP V6-7*01, TCRP V6-8*01, and TCRP V6-9*01;(vii) TCRP V7 subfamily comprising one or more selected from TCRP V7-l*01, TCRP V7-2*01, TCRP V7-2*02, TCRP V7-2*03, TCRP V7-2*04, TCRP V7-3*01, TCRP V7-3*02, TCRP V7-3*03, TCRP V7- 3*04, TCRP V7-3*05, TCRP V7-4*01, TCRP V7-4*02, TCRP V7-6*01, TCRP V7-6*02, TCRP V7- 7*01, TCRP V7-7*02, TCRP V7-8*01, TCRP V7-8*02, TCRP V7-8*03, TCRP V7-9*01, TCRP V7- 9*02, TCRP V7-9*03, TCRP V7-9*04, TCRP V7-9*05, TCRP V7-9*06, and TCRP V7-9*07.(viii) TCRP V8 subfamily comprising one or more selected from TCRP V8-l*01, TCRP V8-l*02, TCRP V8-2*01, and TCRP V8-2*02;(ix) TCRP V9 subfamily comprising one or more selected from TCRP V9-l*01, TCRP V9-l*02, and TCRP V9- 1*03;(x) TCRP V10 subfamily comprising one or more selected from TCRP VI 0-1 *01, TCRP VI 0-1 *02, TCRP V10-l*03, TCRP V10-2*01, TCRP V10-2*02, TCRP V10-3*01, TCRP V10-3*02, TCRP V10- 3*03, and TCRP V10-3*04;(xi) TCRP Vl l subfamily comprising TCRP Vll-l*01, TCRP VI 1-2*01, TCRP VI 1-2*02, TCRP Vll- 2*03, TCRP VI 1-3*01, TCRP VI 1-3*02, TCRP VI 1-3*03, and TCRP VI 1-3*04;(xii) TCRP V12 subfamily comprising one or more selected from TCRP V12-3*01, TCRP V12-4*01, TCRP V12-4*02, and TCRP V12-5*01;(xiii) TCRP V13 subfamily comprising one or more selected from TCRP V13*01 and TCRP V13*02;(xiv) TCRP V14 subfamily comprising one or more comprising from TCRP V14*01 and TCRP V14*02;(xv) TCRP V15 subfamily comprising one or more selected from TCRP V15*01, TCRP V15*02, and TCRP V15*03;(xvi) TCRP V16 subfamily comprising one or more selected from TCRP V16*01, TCRP VI 6* 02, and TCRP VI 6* 03;(xvii) TCRP V17 subfamily comprising TCRP VI 7*01;(xviii) TCRP VI 8 subfamily comprising TCRP VI 8*01;(xix) TCRP V19 subfamily comprising one or more selected from TCRP V19*01, TCRP VI 9* 02, and TCRP VI 9* 03;(xx) TCRP V20 subfamily comprising one or more selected from TCRP V20-l*01, TCRP V20-l*02, TCRP V20-l*03, TCRP V20-l*04, TCRP V20-l*05, TCRP V20-l*06, and TCRP V20-l*07;(xxi) TCRP V21 subfamily comprising one or more selected from TCRP V21-l*01 and TCRP V21- 1*02;(xxii) TCRP V22 subfamily comprising TCRP V22-l*01;(xxiii) TCRP V23 subfamily comprising TCRP V23-l*01;(xxiv) TCRP V24 subfamily comprising TCRP V24-l*01;(xxv) TCRP V25 subfamily comprising TCRP V25-l*01;(xxvi) TCRP V26 subfamily comprising TCRP V26-l*01;WSGR Docket No. 53676-773.601(xxvii) TCRP V27 subfamily comprising TCR[3 V27*01;(xxviii) TCRP V28 subfamily comprising TCRP V28*01;(xxix) TCRP V29 subfamily comprising one or more selected from TCRP V29-l*01, TCRP V29-l*02, and TCRP V29- 1*03; and(xxx) TCRP V30 subfamily comprising one or more selected from TCRP V30*01, TCRP V30*02, TCRP V30*03, TCRP V30*04, and TCRP V30*05.

[0049] In some embodiments, the first domain is a full antibody, an antigen binding domain thereof, or a functional fragment or variant thereof, a bivalent antibody, a bispecific antibody, or a biparatopic antibody that binds to a TCRpV region. In some embodiments, the full antibody, an antigen binding domain thereof, or a functional fragment or variant thereof is a Fab, a Fab', a F(ab’)2, a F(ab)2, a variable fragment (Fv), a single domain antibody, a diabody, a nanobody, a camelid single domain antibody, a VHH or a single chain variable fragment (scFv).

[0050] In some embodiments, the first agent comprises one or more heavy chain constant regions selected from the group consisting of IgGl heavy chain constant region or fragment thereof, IgG2 heavy chain constant region or fragment thereof, IgG3 heavy chain constant region or fragment thereof, IgGAl heavy chain constant region or fragment thereof, IgGA2 heavy chain constant region or fragment thereof, IgG4 heavy chain constant region or fragment thereof, IgJ heavy chain constant region or fragment thereof, IgM heavy chain constant region or fragment thereof, IgD heavy chain constant region or fragment thereof, and IgE heavy chain constant region or fragment thereof. In some embodiments, the first agent comprises a kappa light chain constant region or fragment thereof, a lambda light chain constant region or fragment thereof, or a combination thereof.

[0051] In some embodiments, the first agent is a multifunctional molecule. In some embodiments, the first agent comprises at least two non-contiguous polypeptide chains; wherein a first polypeptide chain of the at least two non-contiguous polypeptide chains comprises a first Fc region, and a second polypeptide chain of the at least two non-contiguous polypeptide chains comprises a second Fc region. In some embodiments, the first Fc region and the second Fc region comprise an Fc interface with a knob-in-a hole. In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises an Asn297Ala mutation, a Leu234Ala / Leu235Ala mutation, or a combination thereof. In some embodiments, the first agent is a multispecific molecule that further comprises one or more of a tumortargeting moiety, a stromal modifying moiety, or an immune cell engager.

[0052] In some embodiments, the first agent comprises a dimerization module, comprising a first immunoglobulin chain constant region and a second immunoglobulin chain constant region. In some embodiments, the first immunoglobulin chain constant region comprises the first fragment crystallizable region (Fc region) and the second first immunoglobulin chain constant region comprises the second fragment crystallizable region (Fc region). In some embodiments, dimerization of the first Fc region and the second Fc region is enhanced by providing an Fc interface of the first Fc region and the second Fc region with one or more of a paired cavity-protuberance, an electrostatic interaction, or a strand-WSGR Docket No. 53676-773.601 exchange, such that a greater ratio of heteromultimer to homomultimer forms relative to a nonengineered interface.

[0053] In some embodiments, the immune cell engager is selected from the group consisting of a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, a macrophage cell engager, and any combination thereof. In some embodiments, the cytokine molecule is selected from the group consisting of interleukin-2 (IL-2) or functional variant thereof, interleukin-7 (IL-7) or functional variant thereof, interleukin- 12 (IL- 12) or functional variant thereof, interleukin- 15 (IL- 15) or functional variant thereof, interleukin- 18 (IL- 18) or functional variant thereof, interleukin-21 (IL-21) or functional variant thereof, interferon gamma or functional variant thereof, and any combination thereof. In some embodiments, the cytokine molecule comprises interleukin-2 (IL-2) or functional variant thereof. In some embodiments, the interleukin-2 (IL-2) or functional variant thereof comprises the sequence of SEQ ID NO: 2270 or SEQ ID NO: 2191.

[0054] In some embodiments, the composition is pharmaceutical composition. In some embodiments, the composition or kit further comprises a pharmaceutically acceptable carrier, diluent, or excipient.

[0055] Also disclosed herein, in some embodiments, is a kit comprising the composition or the kit disclosed herein, and instructions for administering the first agent and the second agent to a human subject in need thereof to treat a disease or condition in the human subject.

[0056] In some embodiments, the first agent comprises a multispecific molecule comprising a first polypeptide, a second polypeptide, and a third polypeptide; wherein the first polypeptide, the second polypeptide and the third polypeptide are non-contiguous, wherein: (i) the first polypeptide comprises a first portion of a dimerization module linked to a first portion of the TCR[3V6-binding moiety comprising a VH of the TCR[3V6-binding moiety; (ii) the second polypeptide comprises a second portion of the dimerization module, wherein the IL-2 or functional fragment or functional variant thereof is covalently linked to the second polypeptide; and (iii) the third polypeptide comprises a second portion of the TCR[3V6-binding moiety comprising a VL of the TCR[3V6-binding moiety. In some embodiments, the first polypeptide comprises a sequence with at least 80% sequence identity to SEQ ID NO: 3517 or 3348, , the second polypeptide comprises a sequence with at least 80% sequence identity to any one of SEQ ID NOs: 3521, 3350, and 3340, and the third polypeptide comprises a sequence with at least 80% sequence identity to SEQ ID NO: 3518 or SEQ ID NO: 3349.

[0057] In some embodiments, the first agent comprises a multispecific molecule comprising a first polypeptide and a second polypeptide; wherein the first polypeptide and the second polypeptide are noncontiguous, wherein the TCR[3V6-binding moiety comprises a heavy chain variable domain (VH) and a light chain variable domain (VL), or a single domain antibody, wherein (i) the first polypeptide comprises a first portion of a dimerization module linked to the TCR[3V6-binding moiety; and (ii) the second polypeptide comprises a second portion of the dimerization module, wherein the IL-2 or functional fragment or functional variant thereof is covalently linked to the second polypeptide. In some embodiments, the first polypeptide comprises a sequence with at least 80% sequence identity to any one of SEQ ID NOs: 80, 83, 86, 89, 92, 95, 98, 101, 104, 110, 113, 116, 119, 122, 125, 128, 131, 134, 137,WSGR Docket No. 53676-773.601140, 143, 146, 149, 153, 156, 159, 162, 165, 168, 171, 174, 177, 180, 183, 186, 189, 192, 195, 198, 201, 204, 206, 208, 210, 214, 216, 218, 220, 222, 224, 1309, 1326-1337, , and the second polypeptide comprises a sequence with at least 80% sequence identity to any one of SEQ ID NOs: 3521, 3350, and 3340.

[0058] In some embodiments, the first agent comprising (i) a first domain that binds to TCR P V6 (TCRJ3V-6) subfamily or TCR P V10 (TCRpV-10) subfamily and (ii) an IL-2 cytokine molecule or a functional variant thereof.

[0059] In some embodiments, the condition or disease is associated with PARP activation. In some embodiments, the condition or disease is reperfusion injury, inflammation, cardiovascular diseases, neurodegenerative diseases, aging, or cancer. In some embodiments, the condition or disease is cancer. In some embodiments, the cancer is a solid tumor, a hematological cancer, a metastatic cancer, a soft tissue tumor, or a combination thereof. T In some embodiments, the cancer is the solid tumor. In some embodiments, the solid tumor is selected from the group consisting of colorectal cancer, gastric cancer, lung cancer, small cell lung cancer, bladder cancer, breast cancer, ovarian cancer, fallopian tube cancer, cervical cancer, peritoneal cancer, prostate cancer, castration-resistant prostate cancer, bile duct cancer, stomach / gastro-esophageal junction cancer, urothelial cancer, pancreatic cancer, peripheral nerve sheath cancer, uterine / endometrial cancer, melanoma, and a combination thereof. In some embodiments, the cancer is a metastatic castration-resistant prostate cancer. In some embodiment, the subject has been previously treated with androgen deprivation therapy. In some embodiment, the subject is non-responsive to androgen deprivation therapy. In some embodiments, the cancer comprises a BRCA1 and / or BRCA2 mutation. In some embodiments, the cancer is Triple Negative Breast Cancer (TNBC). In some embodiments, the cancer is the hematological cancer, and wherein the hematological cancer is selected from the group consisting of Hodgkin’s lymphoma, Non-Hodgkin’s lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia, myelodysplastic syndrome, multiple myeloma, T-cell lymphoma, acute lymphocytic leukemia, and a combination thereof. In some embodiments, the Non-Hodgkin’s lymphoma is selected from the group consisting of B cell lymphoma, diffuse large B cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia (B-CLL), mantle cell lymphoma, marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, and a combination thereof. In some embodiments, the T-cell lymphoma is peripheral T-cell lymphoma. In some embodiments, the cancer is characterized by a cancer antigen present on the cancer.

[0060] In some embodiment, the subject has metastatic castration-resistant prostate cancer. In some embodiment, the subject has been previously treated with androgen deprivation therapy. In some embodiment, the subject is non-responsive to androgen depravation therapy.

[0061] In some embodiments, the cancer antigen is a tumor antigen, a stromal antigen, or a hematological antigen. In some embodiments, the cancer antigen is selected from the group consisting of BCMA, CD19, CD20, CD22, LcRH5, PDL1, CD47, ganglioside 2 (GD2), prostate stem cell antigen (PSCA), prostate specific membrane antigen (PMSA), prostate-specific antigen (PSA), carcinoembryonic antigen (CEA), Ron Kinase, c-Met, Immature laminin receptor, TAG-72, BING-4, Calcium-activated chlorideWSGR Docket No. 53676-773.601 channel 2, Cyclin-Bl, 9D7, Ep-CAM, EphA3, Her2 / neu, Telomerase, SAP-1, Survivin, NY-ESO- 1 / LAGE-l, PRAME, SSX-2, Melan-A / MART-1, Gpl00 / pmell7, Tyrosinase, MC1R, (3-catenin, BRCA1 / 2, CDK4, CML66, Fibronectin, p53, Ras, TGF-B receptor, AFP, ETA, MAGE, CA-125, BAGE, GAGE, CDC27, a actinin-4, TRPl / gp75, TRP2, gangliosides, WT1, Epi-dermal growth factor receptor (EGFR), MART-2, MUC1, MUC2, MUM1, MUM2, MUM3, MSLN, NA88-1, NPM, 0A1, OGT, RCC, RU11, RU12, SAGE, TRG, TSTA, Folate receptor alpha, LI -CAM, CAIX, gpA33, GD3, GM2, VEGFR, Integrins, Carbohydrates, IGF1R, TRAILR1, TRAILR2, RANKL, FAP, TGF-beta, hyaluronic acid, collagen, tenascin C, and tenascin W.

[0062] In some embodiments, the PARP inhibitor is a small molecule; a saccharine; an oligosaccharide; a polysaccharide; a peptide; a protein; a peptide analog; a lipid; an antibody; an antibody or antigenbinding fragment thereof; a nucleic acid; a nucleic acid analog; or any combination thereof. In some embodiments, the PARP inhibitor is a small molecule. In some embodiments, the PARP inhibitor is selected from the group consisting of ABT-767, AZD 2461, BGB-290, BGP 15, CEP 8983, CEP 9722, DR 2313, E7016, E7449, fluzoparib (SHR 3162), IMP 4297, INO1001, JPI 289, JPI 547, monoclonal antibody B3-LysPE40 conjugate, MP 124, niraparib (ZEJULA) (MK-4827), NU 1025, NU 1064, NU 1076, NU1085, olaparib (AZD2281), ONO2231, PD 128763, R 503, R554, rucaparib (RUBRACA) (AG-014699, PF-01367338), SBP 101, SC 101914, Simmiparib, talazoparib (BMN-673), veliparib (ABT-888), WW 46, 2-(4-(Trifluoromethyl)phenyl)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-ol, 4- Iodo-3 -nitrobenzamide (Iniparib), 3 -aminobenzamide, and salts or derivatives thereof. In some embodiments, the PARP inhibitor is selected from the group consisting of niraparib, olaparib, rucaparib, talazoparib, and veliparib. In some embodiments, the PARP inhibitor is niraparib or olaparib.BRIEF DESCRIPTION OF THE DRAWINGS

[0063] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0064] FIGS. 1-25 depict exemplary embodiments of multifunctional molecules as described herein.

[0065] FIGS. 1, 2, and 3 depict exemplary embodiments of multifunctional molecules containing multiple, e.g., two, molecules of a cytokine molecule linked to one or more antibody molecule that binds to a T cell receptor beta variable region (TCRpV) (“anti-TCRpV antibody molecule”). FIG.l shows a first cytokine molecule linked to C-terminus of a light chain of a first antibody molecule and a second cytokine molecule linked to C-terminus of a light chain of a second antibody molecule. FIG.2 shows a first cytokine molecule linked to N-terminus of a heavy chain of a first antibody molecule and a second cytokine molecule linked to N-terminus of a heavy chain of a second antibody molecule. FIG. 3 shows a first cytokine molecule linked to N-terminus of a light chain of a first antibody molecule and a second cytokine molecule linked to N-terminus of a light chain of a second antibody molecule.

[0066] FIGS. 4, 5, and 6 depict exemplary embodiments of multifunctional molecules containing a single molecule of a cytokine molecule linked to an anti-TCRpV antibody molecule. FIG. 4 shows theWSGR Docket No. 53676-773.601 cytokine molecule linked to C-terminus of the antibody molecule light chain. FIG. 5 shows the cytokine molecule linked to N-terminus of the antibody molecule heavy chain. FIG. 6 shows the cytokine molecule linked to N-terminus of the antibody molecule light chain.

[0067] FIGS. 7, 8, 9, and 10 depict exemplary embodiments of multifunctional molecules containing a cytokine molecule linked to a first dimerization module, wherein the multifunctional molecule contains one or more anti-TCRpV antibody molecule. FIG. 7 shows the cytokine molecule linked to N-terminus of the dimerization module. FIG. 8 shows the cytokine molecule linked to C-terminus of the dimerization module. FIG. 9 shows the cytokine molecule linked to C-terminus of the dimerization module. FIG. 10 shows a first cytokine molecule linked to C-terminus of a first dimerization module and a second cytokine molecule linked to C-terminus of a second dimerization module.

[0068] FIGS. 11, 12, and 13 depict exemplary embodiments of multifunctional molecules containing an exemplary dimerization module, e.g., an Fc region comprising aN297A mutation, and multiple, e.g., two, molecules of a cytokine molecule linked to an anti-TCRpV antibody molecule. FIG.ll shows a first cytokine molecule linked to C-terminus of a light chain of a first antibody molecule and a second cytokine molecule linked to C-terminus of a light chain of a second antibody molecule. FIG.12 shows a first cytokine molecule linked to N-terminus of a heavy chain of a first antibody molecule and a second cytokine molecule linked to N-terminus of a heavy chain of a second antibody molecule. FIG. 13 shows a first cytokine molecule linked to N-terminus of a light chain of a first antibody molecule and a second cytokine molecule linked to N-terminus of a light chain of a second antibody molecule.

[0069] FIGS. 14, 15, and 16 depict exemplary embodiments of multifunctional molecules containing an exemplary dimerization module, e.g., an Fc region comprising aN297A mutation (Knob-in-hole), and a single molecule of a cytokine molecule linked to an anti-TCRpV antibody molecule. FIG. 14 shows the cytokine molecule linked to C-terminus of the antibody molecule light chain. FIG. 15 shows the cytokine molecule linked to N-terminus of the antibody molecule heavy chain. FIG. 16 shows the cytokine molecule linked to N-terminus of the antibody molecule light chain.

[0070] FIGS. 17, 18, 19, and 20 depict exemplary embodiments of multifunctional molecules containing an exemplary dimerization module, e.g., an Fc region comprising aN297A mutation (Knob-in-hole), and a cytokine molecule linked to the exemplary dimerization module. FIG. 17 shows the cytokine molecule linked to N-terminus of the dimerization module. FIG. 18 shows the cytokine molecule linked to C- terminus of the dimerization module. FIG. 19 shows the cytokine molecule linked to C-terminus of the dimerization module. FIG. 20 shows a first cytokine molecule linked to C-terminus of a first dimerization module and a second cytokine molecule linked to C-terminus of a second dimerization module.

[0071] FIG. 21 shows an exemplary embodiment of multifunctional molecules comprising a TCRJ3V- binding moiety and a cytokine molecule (“cytokine”) as described herein.

[0072] FIGS. 22, 23, 24, and 25 show exemplary embodiments of multifunctional molecules comprising a first TCR[3V-binding moiety, a second TCRpV-binding moiety, and two cytokine molecules as described herein. FIG. 22 shows a first cytokine molecule linked to C-terminus of a light chain of a firstWSGR Docket No. 53676-773.601 antibody molecule and a second cytokine molecule linked to C-terminus of a light chain of a second antibody molecule. FIG.23 shows a first cytokine molecule linked to N-terminus of a heavy chain of a first antibody molecule and a second cytokine molecule linked to N-terminus of a heavy chain of a second antibody molecule. FIG. 24 shows a first cytokine molecule linked to C-terminus of a first dimerization module and a second cytokine molecule linked to C-terminus of a second dimerization module. FIG. 25 shows a first cytokine molecule linked to C-terminus of a light chain of a first antibody molecule and a second cytokine molecule linked to C-terminus of a light chain of a second antibody molecule.

[0073] In some embodiments, the cytokine molecule comprises IL-2 or a functional fragment or variant thereof, IL2-C125A or a functional fragment or variant thereof, IL- 15 or a functional fragment or variant thereof, IL-7 or a functional fragment or variant thereof, IL- 12 or a functional fragment or variant thereof, or IL-21 or a functional fragment or variant thereof. In some embodiments, the cytokine molecule further comprises a cytokine receptor or a functional fragment or variant thereof. In some embodiments, the cytokine molecule comprises IL- 15 or a functional fragment or variant thereof. In some embodiments, the cytokine molecule further comprises an IL15Ralpha dimerizing domain. In some embodiments, the cytokine molecule further comprises an IL15Ralpha dimerizing domain linked the IL- 15 or a functional fragment or variant thereof. In some embodiments, the cytokine molecule further comprises an IL15Ralpha dimerizing domain covalently linked the IL- 15 or a functional fragment or variant thereof. In some embodiments, the cytokine molecule comprises IL- 15 linked to an IL-15Ra. In some embodiments, the cytokine molecule further comprises an IL15Ralpha dimerizing domain non- covalently linked the IL- 15 or a functional fragment or variant thereof. In some embodiments, the IL15Ralpha dimerizing domain comprises an IL- 15 receptor alpha sushi domain or a functional fragment or variant thereof. In some embodiments, the IL- 15 or a functional fragment or variant thereof is covalently linked to the IL15Ralpha dimerizing domain via a linker. In some embodiments, the cytokine molecule comprises IL-15 linked to an IL-15Ra sushi domain. In some embodiments, the cytokine molecule comprises a cytokine dimer. In some embodiments, the cytokine molecule comprises an IL-12 beta subunit linked to an IL- 12 alpha subunit.

[0074] FIGS. 26A and 26B 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. Kabat 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. 26A shows VH sequences for murine Antibody A (SEQ ID NO: 1) and humanized Antibody A-H (SEQ ID NO: 9). FIG. 26B shows VL sequences for murine Antibody A (SEQ ID NO: 2) and humanized Anti-body A-H (SEQ ID NO: 10 and SEQ ID NO: 11).

[0075] FIG. 27 shows an exemplary dosing schedule of the combination therapy of present technology.

[0076] FIG. 28 shows tumor volume of EMT6 triple -negative breast cancer (TNBC) over time in Balb / C mice treated with control, mBKM0186, niraparib, or the combination.WSGR Docket No. 53676-773.601

[0077] FIG. 29A shows tumor volume of EMT6 triple -negative breast cancer (TNBC) overtime in Balb / C mice treated with control. FIG. 29B shows tumor volume of EMT6 triple-negative breast cancer (TNBC) over time in Balb / C mice treated with mBKMO 186. FIG. 29C shows tumor volume of EMT6 triple -negative breast cancer (TNBC) overtime in Balb / C mice treated with niraparib. FIG. 29D shows tumor volume of EMT6 triple-negative breast cancer (TNBC) over time in Balb / C mice treated with the combination of mBKMO 186 and niraparib.

[0078] FIG. 30A shows Schedule A of TrampC2 tumor model. The first dose of mBKMO 186 (Img / kg / i.p / QlW (once a week)) was administered concurrently with first dose of Olaparib (50mg / kg q.d. (once a day), i.p.). FIG. 30B shows Schedule B of TrampC2 tumor model. The first dose of mBKM0186 (Img / kg / i.p / QlW (once a week)) was administered 5 days after the first dose of Olaparib (50mg / kg q.d., i.p.).

[0079] FIGs. 31A-B show the TrampC2 tumor volume from mice in the vehicle group, the Olaparib monotherapy group, the mBKMO 186 monotherapy group, and the combination therapy group on Schedule A. FIG. 31A is a combined graph of tumor volumes from mice in the vehicle group, the Olaparib monotherapy group, the mBKMO 186 monotherapy group, and the combination therapy group on Schedule A. FIG. 31B shows individual graph of tumor volumes from mice in the vehicle group, the Olaparib monotherapy group, the mBKMO 186 monotherapy group, and the combination therapy group on Schedule A.

[0080] FIGs. 32A-B show the TrampC2 tumor volume from mice in the vehicle group, the Olaparib monotherapy group, the mBKMO 186 monotherapy group, and the combination therapy group on Schedule B. FIG. 32A is a combined graph of tumor volumes from mice in the vehicle group, the Olaparib monotherapy group, the mBKMO 186 monotherapy group, and the combination therapy group on Schedule B. FIG. 32B shows individual graph of tumor volumes from mice in the vehicle group, the Olaparib monotherapy group, the mBKMO 186 monotherapy group, and the combination therapy group on Schedule B.

[0081] FIGs. 33A-B show the survival curve (FIG. 33A) and body weight (FIG. 33B) of mice in the vehicle group, the Olaparib monotherapy group, the mBKMO 186 monotherapy group, and the combination therapy group on Schedule B.

[0082] FIG. 34A shows the number of CD4+ T cells, CD8+ T cells, CD4+ mVpi3+ T cells, and CD8+ mVpi3+ T cells in peripheral blood of mice in the vehicle group, the Olaparib monotherapy group, the mBKMO 186 monotherapy group, and the combination therapy group on Schedule B. FIG. 34B shows the number of CD4+ mVbl3+ Ki67+ cells in peripheral blood of mice in the vehicle group, the Olaparib monotherapy group, the mBKMO 186 monotherapy group, and the combination therapy group on Schedule B.

[0083] FIGs. 35A-B show the number of CD4+ T cells, CD8+ T cells, CD4+ mVpi3+ cells, and CD8+ mVpi3+ T cells in tumors (FIG. 35A) and spleen (FIG. 35B) from mice in the vehicle group, the Olaparib monotherapy group, the mBKMO 186 monotherapy group, and the combination therapy group on Schedule B.WSGR Docket No. 53676-773.601

[0084] FIG. 36A shows the number of Treg cells, CD8+ T cells to Treg cells ratio, and CD8+VP13+ T cells to Treg cells ratio in tumors from mice in the vehicle group, the Olaparib monotherapy group, the mBKM0186 monotherapy group, and the combination therapy group on Schedule B. FIG. 36B shows the percentage of Treg cells in CD4+ FoxP3+ cells population in spleen of mice in the vehicle group, the Olaparib monotherapy group, the mBKM0186 monotherapy group, and the combination therapy group on Schedule B.

[0085] FIG. 37 shows the number of CD8+ IFNy+ T cells, CD8+ GranzymeB+ T cells, CD4+ PD1+ T cells, and CD8+ PD1+ T cells in tumors from mice in the vehicle group, the olaparib monotherapy group, the mBKM0186 monotherapy group, and the combination therapy group on Schedule B.

[0086] FIGs. 38 shows quantification of CD4+ T cells and CD8+ T cells in tumors from mice in the vehicle group, olaparib monotherapy group, the mBKM0186 monotherapy group, and the combination therapy group on Schedule B.

[0087] FIGs. 39 shows quantification of CD4+ Foxp3+ Treg cells in tumors from mice in the olaparib monotherapy group, the mBKM0186 monotherapy group, and the combination therapy group on Schedule B.

[0088] FIG. 40 shows pl5E, Twist, Ptgfr, SPAS-1 WT, and SPAS-1 Mut antigen-specific IFN-y producing CD8+ T cells from mice in the vehicle group, olaparib monotherapy group, the mBKM0186 monotherapy group, and the combination therapy group on Schedule B.

[0089] FIG. 41 shows SPAS-1 WT and SPAS-1 Mut antigen-specific TNF-producing CD8+ T cells from mice in the vehicle group, olaparib monotherapy group, the mBKM0186 monotherapy group, and the combination therapy group on Schedule B.

[0090] FIG. 42 shows schedule of depletion antibody and olaparib and mBKM0186 combination therapy administration.

[0091] FIGs. 43A-B show tumor volume of mice receiving the combination therapy after CD4+ T cells, CD8+ T cells, NK cells, mVpi3.1T cells, or CD4+ CD8+ NK cells depletion. FIG. 43A is a combined graph of tumor volumes from mice receiving the combination therapy after CD4+ T cells, CD8+ T cells, NK cells, mVbl3.1T cells, or CD4+ CD8+ NK cells depletion receiving the combination therapy after CD4+ T cells, CD8+ T cells, NK cells, mVbl3. IT cells, or CD4+ CD8+ NK cells depletion. FIG. 43B shows individual graph of tumor volumes from mice receiving the combination therapy after CD4+ T cells, CD8+ T cells, NK cells, mVbl3.1T cells, or CD4+ CD8+ NK cells depletion.

[0092] FIG. 44A shows tumor volume of mice receiving the combination therapy after IFN-y depletion. FIG. 44B shows the level of IFN-y in mice in the vehicle group, olaparib monotherapy group, the mBKM0186 monotherapy group, and the combination therapy group on Schedule B after IFN-y depletion.

[0093] FIGs. 45A-B show RM-1 tumor volume from mice in the vehicle group, olaparib monotherapy group, the mBKM0186 monotherapy group, and the combination therapy group. FIG. 45A is a combined graph of RM-1 tumor volumes from mice in the vehicle group, olaparib monotherapy group, the mBKM0186 monotherapy group, and the combination therapy group. FIG. 45B shows individual graphsWSGR Docket No. 53676-773.601 of RM-1 tumor volumes from mice in the vehicle group, olaparib monotherapy group, the mBKM0186 monotherapy group, and the combination therapy group.

[0094] FIGs. 46A-F show upregulation of TRAIL-R2 on TRAMP-C2 cells. FIG. 46A shows flow cytometry plots of phenotypic changes on TRAIL-R2 expression after in vitro incubation of TRAMP-C2 cells (2.0 x 106) with olaparib (20 .M) (right) and untreated cells (left) for 72 hours. FIG. 46B shows violin plots of percentage of lysed (B) TRAMP-C2. FIG. 46C shows tumor growth curves of TRAMP - C2 tumor-bearing mice treated with vehicle, olaparib, mBKM0186, and combination therapy with olaparib and mBKM0186. FIG. 46D shows flow cytometry plot of TRAIL-R2 staining for TRAMP-C2 (right), TRAIL-R2 knockout (KO) TRAMP-C2 (left), and TRAMP-C2 unstained cells (middle). FIG. 46E-F show in vitro cytotoxicity assays (FIG. 46E) and tumor growth curves (FIG. 46F) using TRAIL- R2 KO TRAMP-C2 cells.

[0095] FIGs. 47A-C show TRAIL-R2 expression in ovarian or prostate cancer tissues. FIG. 47A shows TRAIL-R2 expression in health prostate tissue (Genotype-Tissue Expression (GTEx) dataset) versus prostate carcinomas (The Cancer Genome Atlas Program (TCGA) dataset) (FIG. 47A) and healthy ovarian tissue (GTEx dataset) versus ovarian carcinoma (TCGA dataset) (FIG. 47B). FIG. 47C shows %TRAIL-R2 expression in percutaneous biopsies of ovarian tumor tissue from three patients before and after Olaparib on day 15 of cycle one.INCORPORATION BY REFERENCE

[0096] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.DETAILED DESCRIPTIONDEFINITION

[0097] Certain specific details of this description are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the present disclosure may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments.

[0098] Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed disclosure.

[0099] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. 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.”WSGR Docket No. 53676-773.601

[0100] It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0101] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below.

[0102] The term “about” when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or in some instances ±10%, or in some instances ±5%, or in some instances ±1%, or in some instances ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods. As used herein, “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.

[0103] The term “acquire” or “acquiring” as the terms are used herein, refer to obtaining possession of a physical entity (e.g. , a sample, a polypeptide, a nucleic acid, or a sequence), or a value, e.g. , a numerical value, by “directly acquiring” or “indirectly acquiring” the physical entity or value. “Directly acquiring” means performing a process (e.g., performing a synthetic or analytical method) to obtain the physical entity or value. “Indirectly acquiring” refers to receiving the physical entity or value from another party or source (e.g., a third party laboratory that directly acquired the physical entity or value). 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.

[0104] “Antibody molecule” as used herein refers to a protein, e.g., an immunoglobulin chain or fragment thereof, comprising at least one immunoglobulin variable domain structure and / or sequence. An antibody molecule encompasses antibodies (e.g., full-length antibodies) and antibody fragments. In some embodiments, an antibody molecule comprises an antigen binding or functional fragment of a full length antibody, or a full length immunoglobulin chain. For example, a full-length antibody is an immunoglobulin (Ig) molecule (e.g., an IgG antibody) that is naturally occurring or formed by normal immunoglobulin gene fragment recombinatorial processes). In embodiments, an antibody molecule refers to an immunologically active, antigen-binding portion of an immunoglobulin molecule, such as an antibody fragment. An antibody fragment, e.g., functional fragment, is a portion of an antibody, e.g., Fab, Fab', F(ab')2, F(ab)2, variable fragment (Fv), domain antibody (dAb), or single chain variable fragment (scFv). A functional antibody fragment binds to the same antigen as that recognized by the intact (e.g., full-length) antibody. The terms “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”). In some embodiments, anWSGR Docket No. 53676-773.601 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). In some embodiments, the antibody molecule is an antibody mimetic. In some embodiments, the antibody molecule is, or comprises, an antibody-like framework or scaffold, such as, fibronectins, ankyrin repeats (e.g., designed ankyrin repeat proteins (DARPins)), avimers, affibody affinity ligands, anticalins, or affilin molecules.

[0105] The term “human-like antibody molecule” as used herein refers to a humanized antibody molecule, human antibody molecule or an antibody molecule having at least 95% sequence identity with a non-murine germline framework region, e.g., FR1, FR2, FR3 and / or FR4. In some embodiments, the human-like antibody molecule comprises a framework region having at least 95% sequence identity to a human germline framework region, e.g., a FR1, FR2, FR3 and / or FR4 of a human germline framework region. In some embodiments, the human-like antibody molecule is a recombinant antibody. In some embodiments, the human-like antibody molecule is a humanized antibody molecule. In some embodiments, the human-like antibody molecule is human antibody molecule. In some embodiments, the human-like antibody molecule is a phage display or a yeast display antibody molecule. In some embodiments, the human-like antibody molecule is a chimeric antibody molecule. In some embodiments, the human-like antibody molecule is a CDR grafted antibody molecule.

[0106] As used herein, an “immunoglobulin variable domain sequence” refers to an amino acid sequence which can form the structure of an immunoglobulin variable domain. For example, the sequence may include all or part of the amino acid sequence of a naturally-occurring variable domain. For example, 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.

[0107] In embodiments, an antibody molecule is monospecific, e.g., it comprises binding specificity for a single epitope. In some embodiments, 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. In some embodiments, 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.

[0108] “Antigen” (Ag) as used herein refers to a molecule that can provoke an immune response, e.g., involving activation of certain immune cells and / or antibody generation. Any macromolecule, including almost all proteins or peptides, can be an antigen. Antigens can also be derived from genomic recombinant or DNA. For example, any DNA comprising a nucleotide sequence or a partial nucleotide sequence that encodes a protein capable of eliciting an immune response encodes an “antigen.” In embodiments, an antigen does not need to be encoded solely by a full length nucleotide sequence of a gene, nor does an antigen need to be encoded by a gene at all. In embodiments, an antigen can be synthesized or can be derived from a biological sample, e.g. , a tissue sample, a tumor sample, a cell, or aWSGR Docket No. 53676-773.601 fluid with other biological components. As used, herein 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. As used, herein an “immune cell antigen” includes any molecule present on, or associated with, an immune cell that can provoke an immune response.

[0109] The “antigen-binding site,” or “binding portion” of an antibody molecule refers to the part of an antibody molecule, e.g., an immunoglobulin (Ig) molecule, that participates in antigen binding. In embodiments, the antigen binding site is formed by amino acid residues of the variable (V) regions of the heavy (H) and light (L) chains. Three highly divergent stretches within the variable regions of the heavy and light chains, referred to as hypervariable regions, are disposed between more conserved flanking stretches called “framework regions,” (FRs). FRs are amino acid sequences that are naturally found between, and adjacent to, hypervariable regions in immunoglobulins. In embodiments, in an antibody molecule, 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.” The framework region and CDRs have been defined and described, e.g., in Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242, and Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917. Each variable chain (e.g., variable heavy chain and variable light chain) is typically made up of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the amino acid order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0110] As used herein, 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. In embodiments, this term includes leukocytes, e.g., neutrophils, eosinophils, basophils, lymphocytes, and monocytes. Innate leukocytes include phagocytes (e.g., macrophages, neutrophils, and dendritic cells), mast cells, 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. 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.

[0111] ‘ ‘Immune effector cell,” as that term is used herein, refers to a cell that is involved in an immune response, e.g., in the promotion of an immune effector response. Examples of 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.WSGR Docket No. 53676-773.601

[0112] The term “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.

[0113] The terms “polypeptide”, “peptide” and “protein” (if single chain) are used interchangeably herein to refer to polymers of amino acids of any length. The polymer 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.

[0114] The terms “nucleic acid,” “nucleic acid sequence,” “nucleotide sequence,” or “polynucleotide sequence,” and “polynucleotide” are used interchangeably. They refer 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 noncoding (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.

[0115] The term “isolated,” as used herein, refers to material that is removed from its original or native environment (e.g., the natural environment if it is naturally occurring). For example, 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. An isolated polynucleotide (ribonucleic acid (RNA), deoxyribonucleic acid (DNA)), or polypeptide is free of the genes / nucleic acids or sequence s / amino acids that flank it in its naturally-occurring state.

[0116] The compositions and methods of the present invention encompass polypeptides and nucleic acids having the sequences specified, or sequences substantially identical or similar thereto, e.g., sequences at least 80%, 85%, 90%, 95% identical or higher to the sequence specified. In the context of an amino acid sequence, the term “substantially identical” is used herein to refer to a first amino acid that contains a sufficient or minimum number of amino acid residues that are i) identical to, or ii) conservative substitutions of aligned amino acid residues in a second amino acid sequence such that the first and second amino acid sequences can have a common structural domain and / or common functional activity. For example, amino acid sequences that contain a common structural domain having at least about 80%, 85%, 90%. 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% 99%, 99.5%, 99.9%, or 100% sequence identityWSGR Docket No. 53676-773.601 to a reference sequence, e.g, a sequence provided herein. 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. For example, nucleotide sequences having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% 99%, 99.5%, 99.9%, or 100% sequence identity to a reference sequence, e.g., a sequence provided herein.

[0117] The term “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. In some embodiments, a TCRJ3V variant can bind to TCRa and form a TCR a: [3 complex.

[0118] 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.

[0119] The term “functional fragment” refers to a polypeptide that has a partial amino acid sequence of a reference amino acid sequence, and is capable of having one or more activities of the reference amino acid sequence. In some embodiments, the functional fragment comprises at least about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% 99%, 99.5%, or 99.9% amino acid sequence of a reference amino acid sequence. In some embodiments, the functional fragment comprises an amino acid sequence that has at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 amino acid deletion from the reference amino acid sequence.In some embodiments, the functional fragment comprises an amino acid sequence that has at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130,140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 350, 400, 450, or500 amino acids of the reference amino acid sequence.

[0120] Calculations of homology or sequence identity between sequences (the terms are used interchangeably herein) are performed as follows. To determine the percent identity of two amino acid sequences, or of two nucleic acid sequences, 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). In a preferred embodiment, 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. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position inWSGR Docket No. 53676-773.601 the second sequence, then the molecules are identical at that position (as used herein amino acid or nucleic acid “identity” is equivalent to amino acid or nucleic acid “homology”).

[0121] The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In a preferred embodiment, 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. In yet another preferred embodiment, 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 (and the one that should be used unless otherwise specified) 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.

[0122] 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. The 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 XBLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. BLAST nucleotide searches can be performed with the NBLAST program, score = 100, wordlength = 12 to obtain nucleotide sequences homologous to a nucleic acid molecule of the invention. BLAST protein searches can be performed with the XBLAST program, score = 50, wordlength = 3 to obtain amino acid sequences homologous to protein molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res. 25:3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used.

[0123] It is understood that the molecules of the present invention may have additional conservative or non-essential amino acid substitutions, which do not have a substantial effect on their functions.

[0124] The term “amino acid” is intended to embrace all molecules, whether natural or synthetic, which include both an amino functionality and an acid functionality and capable of being included in a polymer of naturally-occurring amino acids. Exemplary amino acids include naturally-occurring amino acids; analogs, derivatives and congeners thereof; amino acid analogs having variant side chains; and all stereoisomers of any of any of the foregoing. As used herein the term “amino acid” includes both the D- or L- optical isomers and peptidomimetics.WSGR Docket No. 53676-773.601

[0125] 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).

[0126] As used herein, the term “molecule” as used in, e.g., antibody molecule, cytokine molecule, receptor molecule, includes full-length, naturally-occurring molecules, as well as variants, e.g., functional variants (e.g., truncations, fragments, mutated (e.g., substantially similar sequences) or derivatized form thereof), so long as at least one function and / or activity of the unmodified (e.g., naturally-occurring) molecule remains.

[0127] As used herein, the term “mutation” refers to an alteration in the nucleotide sequence of the genome of an organism, virus, or extrachromosomal DNA. In some embodiments, the mutation may be a large-scale mutation, such as amplifications (or gene duplications) or repetitions of a chromosomal segment, deletions of large chromosomal regions, chromosomal rearrangements (e.g., chromosomal translocations, chromosomal inversions, non-homologous chromosomal crossover, and interstitial deletions), and loss of heterozygosity. In some embodiments, the mutation may be a small-scale mutation, such as insertions, deletions, and substitution mutations. As used herein, the term “substitution mutation” refers to the transition that exchange a single nucleotide for another.

[0128] ‘ ‘Interleukin-2” also known as IL2, IL-2, IL 2, TCGF, lymphokine, and interleukin 2, as referred to herein, includes any of the recombinant or naturally-occurring forms of IL-2 or variants or homologs thereof that have or maintain IL-2 activity (e.g., at least 40% 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity). In some aspects, the variants or homologs have at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g., a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring IL-2. In some embodiments, IL-2 is substantially identical to the protein identified by the UniProt reference number P60568 or a variant or homolog having substantial identity thereto.

[0129] In some embodiments, the terms TCRvB, TCRBV, TCRJ3V, and TCRVJ3 are interchangeably used.

[0130] In some embodiments, the terms antibody-drug conjugate, antibody drug conjugate, and ADC are interchangeably used.WSGR Docket No. 53676-773.601Anti-TCRpV antibodiesHuman T cell receptor (TCR) complex

[0131] TCR is a disulfide-linked membrane -anchored heterodimeric protein normally consisting of the highly variable alpha (a) and beta (P) chains expressed as part of a complex with the invariant CD3 chain molecules. TCR on a 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 TCRpV 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. Only 4 amino acids out of approximately 95 are identical while 10 additional amino acids are conserved among all subfamilies. Nevertheless, TCRs formed between alpha and beta chains of highly diverse sequences show a remarkable structural homology and elicit a similar function, e.g., activation of T cells.

[0132] T cell receptors (TCR) can be found on the surface of T cells. TCRs recognize antigens, e.g., peptides, presented on, e.g., bound to, major histocompatibility complex (MHC) molecules on the surface of cells, e.g, antigen-presenting cells. TCRs are heterodimeric molecules and can comprise an alpha chain, a beta chain, a gamma chain or a delta chain. TCRs comprising an alpha chain and a beta chain are also referred to as TCRap. The TCR beta chain consists of the following regions (also known as segments): variable (V), diversity (D), joining (J) and constant (C) (see Mayer G. and Nyland J. (2010) Chapter 10: Major Histocompatibility Complex and T-cell Receptors-Role in Immune Responses. In: Microbiology and Immunology on-line, University of South Carolina School of Medicine). The 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.

[0133] TCRs can comprise a receptor complex, known as the TCR complex, which comprises a TCR heterodimer comprising of an alpha chain and a beta chain, and dimeric signaling molecules, e.g., CD3 co-receptors, e.g., CD3o / s. and / or CD3y / a.

[0134] As used herein, the term “T cell receptor beta variable chain” or “TCRpV,” refers to an extracellular region of the T cell receptor beta chain which comprises the antigen recognition domain of the T cell receptor. The term TCRJ3V includes isoforms, mammalian, e.g., human TCRJ3V, species homologs of human and analogs comprising at least one common epitope with TCRJ3V. Human TCRJ3V comprises a gene family comprising subfamilies including, but not limited to: 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 V18 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 TCRP V24 subfamily, a TCRP V20 subfamily, TCRP V25 subfamily, a TCRP V29 subfamily, a TCRP VI subfamily, a TCRP V17 subfamily, a TCRP V21 subfamily, a TCRP V23 subfamily, or a TCRP V26 subfamily, as well as family members of said subfamilies, and variantsWSGR Docket No. 53676-773.601 thereof (e.g., a structural or functional variant thereof). In some embodiments, the TCRP V6 subfamily comprises: TCRp V6-4*01, TCRp V6-4*02, TCRp V6-9*01, TCRp V6-8*01, TCRp V6-5*01, TCRp V6-6*02, TCRP V6-6*01, TCRp V6-2*01, TCRp V6-3*01 or TCRp V6-l*01. In some embodiments, TCRpV comprises TCRP V6-5*01, or a variant thereof, e.g., a variant having 85%, 90%, 95%, 99% or more identity the naturally-occurring sequence. TCRP V6-5*01 is also known as TRBV65; TCRBV6S5; TCRBV13S1, or TCRp V13.1. The amino acid sequence of TCRp V6-5*01, e.g., human TCRp V6-5*01, is known in that art, e.g., as provided by IMGT ID L36092. In some embodiments, TCRP V6-5*01 is encoded by the nucleic acid sequence of SEQ ID NO: 43, or a sequence having 85%, 90%, 95%, 99% or more identity thereof. In some embodiments, TCRP V6-5*01 comprises the amino acid sequence of SEQ ID NO: 44, or a sequence having 85%, 90%, 95%, 99% or more identity thereof.

[0135] SEQ ID NO: 43ATGAGCATCGGCCTCCTGTGCTGTGCAGCCTTGTCTCTCCTGTGGGCAGGTCCAGTGAATGC TGGTGTCACTCAGACCCCAAAATTCCAGGTCCTGAAGACAGGACAGAGCATGACACTGCAG TGTGCCCAGGATATGAACCATGAATACATGTCCTGGTATCGACAAGACCCAGGCATGGGGC TGAGGCTGATTCATTACTCAGTTGGTGCTGGTATCACTGACCAAGGAGAAGTCCCCAATGGC TACAATGTCTCCAGATCAACCACAGAGGATTTCCCGCTCAGGCTGCTGTCGGCTGCTCCCTC CCAGACATCTGTGTACTTCTGTGCCAGCAGTTACTC

[0136] SEQ ID NO: 44MSIGLLCCAALSLLWAGPVNAGVTQTPKFQVLKTGQSMTLQCAQDMNHEYMSWYRQDPGMG LRLIHY-SVGAGITDQGEVPNGYNVSRSTTEDFPLRLLSAAPSQTSVYFCASSYTCR beta V (TCR / 3V)

[0137] Diversity in the immune system enables protection against a huge array of pathogens. Since the germline genome is limited in size, diversity is achieved not only by the process of V(D)J recombination but also by junctional (junctions between V-D and D-J segments) deletion of nucleotides and addition of pseudo-random, non-templated nucleotides. The TCR beta gene undergoes gene arrangement to generate diversity.

[0138] 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.

[0139] Provided herein are, inter alia, antibody molecules and fragments thereof, that bind, e.g., specifically bind, to a human TCR beta V chain (TCRpV), e.g. , a TCRpV gene family (also referred to as a group), e.g., a TCRpV subfamily (also referred to as a subgroup), e.g., as described herein. TCR beta V families and subfamilies are known in the art, e.g., as described in Yassai et al., (2009) Immunogenetics 61(7)pp:493-502; Wei S. and Concannon P. (1994) Human Immunology 41(3) pp: 201-206. The antibodies described herein can be recombinant antibodies, e.g., recombinant non-murine antibodies, e.g., recombinant human or humanized antibodies.WSGR Docket No. 53676-773.601

[0140] The terms TCRBV, TCRVB, TRBV, TCRJ3V, TCRV or TR V are used interchangeably herein and refer to a TCR beta V chain, e.g., as described herein.

[0141] In some embodiments, provided herein is an anti-TCRpV antibody molecule that binds to human TCR V, e.g., a TCRJ3V family, e.g., gene family or a variant thereof. In some embodiments a TCRBV gene family comprises one or more subfamilies, e.g., as described herein Table 8A or Table 8B. In some embodiments, 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 TCRP V24 subfamily, a TCRP V20 subfamily, TCRP V25 subfamily, a TCRP V29 subfamily, a TCRP VI subfamily, a TCRP V17 subfamily, a TCRP V21 subfamily, a TCRP V23 subfamily, or a TCRP V26 subfamily.

[0142] In some embodiments, TCRP V6 subfamily is also known as TCRP VI 3.1. In some embodiments, the TCRP V6 subfamily comprises: TCRP V6-4*01, TCRP V6-4*02, TCRP V6-9*01, TCRP V6-8*01, TCRP V6-5*01, TCRP V6-6*02, TCRP V6-6*01, TCRP V6-2*01, TCRP V6-3*01 or TCRP V6-l*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-4*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-4*02, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-9*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-8*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-5*01, 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*01, 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*01, or a variant thereof. In some embodiments, TCRP V6 comprises TCRP V6-l*01, or a variant thereof.

[0143] In some embodiments, TCRP V6 comprises TCRP V6-5*01, or a variant thereof. In some embodiments, TCRP V6, e.g., TCRP V6-5*01, is recognized, e.g., bound, by SEQ ID NO: 1 and / or SEQ ID NO: 2. In some embodiments, TCRP V6, e.g., TCRP V6-5*01, is recognized, e.g., bound, by SEQ ID NO: 9 and / or SEQ ID NO: 10. In some embodiments, TCRP V6 is recognized, e.g., bound, by SEQ ID NO: 9 and / or SEQ ID NO: 11.

[0144] In some embodiments, TCRP V10 subfamily is also known as TCRP V12. In some embodiments, the TCRP V10 subfamily comprises: TCRP V10-l*01, TCRP VI 0-1 *02, TCRP V10-3*01 or TCRP V 10-2*01 , or a variant thereof.

[0145] In some embodiments, TCRP V12 subfamily is also known as TCRP V8.1. In some embodiments, the TCRP V12 subfamily comprises: TCRP V12-4*01, TCRP V12-3*01, or TCRP V12-5*01, or a variant thereof. In some embodiments, TCRP V12 is recognized, e.g., bound, by SEQ ID NO: 15 and / or SEQ ID NO: 16. In some embodiments, 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:WSGR Docket No. 53676-773.601

[0146] In some embodiments, the TCRp V5 subfamily is chosen from: TCRp V5-5*01, TCRp V5-6*01, TCRP V5-4*01, TCRP V5-8*01, TCRp V5-l*01, or a variant thereof

[0147] In some embodiments, the TCRP V7 subfamily comprises TCRP V7-7*0I, TCRP V7-6*0I, TCRP V7 -8*02, TCRP V7 -4*01, TCRp V7-2*02, TCRp V7-2*03, TCRp V7-2*01, TCRp V7-3*01, TCRP V7-9*03, or TCRP V7-9*01, or a variant thereof.

[0148] In some embodiments, 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. In some embodiments, the TCRP V14 subfamily comprises TCRP VI4*01, or a variant thereof. In some embodiments, the TCRP V16 subfamily comprises TCRP V16*01, or a variant thereof. In some embodiments, the TCRP V18 subfamily comprises TCRP V18*01, or a variant thereof. In some embodiments, the TCRP V9 subfamily comprises TCRP V9*01 or TCRP V9*02, or a variant thereof. In some embodiments, the TCRP V13 subfamily comprises TCRP V13*0I, or a variant thereof. In some embodiments, the TCRP V4 subfamily comprises TCRP V4-2*0I, TCRP V4-3*0I, or TCRp V4-I*0I, or a variant thereof. In some embodiments, the TCRp V3 subfamily comprises TCRP V3-I*0I, or a variant thereof. In some embodiments, the TCRP V2 subfamily comprises TCRP V2*0I, or a variant thereof. In some embodiments, the TCRP V15 subfamily comprises TCRP V15*0I, or a variant thereof. In some embodiments, the TCRP V30 subfamily comprises TCRP V30*0I, or TCRP V30*02, or a variant thereof. In some embodiments, the TCRP V19 subfamily comprises TCRp V19*0I, or TCRp VI 9* 02, or a variant thereof. In some embodiments, the TCRp V27 subfamily comprises TCRP V27*01, or a variant thereof. In some embodiments, the TCRP V28 subfamily comprises TCRP V28*01, or a variant thereof. In some embodiments, the TCRP V24 subfamily comprises TCRP V24-l*01, or a variant thereof. In some embodiments, the TCRP V20 subfamily comprises TCRP V20-l*01, or TCRP V20-l*02, or a variant thereof. In some embodiments, the TCRP V25 subfamily comprises TCRP V25-I*0I, or a variant thereof. In some embodiments, the TCRP V29 subfamily comprises TCRP V29-I*0I, or a variant thereof.

[0149] Exemplary amino acid sequences for TCRpV subfamily members can be found on the ImMunoGeneTics Information System website: http: / / www.imgt.org / , or in a similar resource.Anti-TCRfiV antibodies

[0150] Current bispecific constructs designed to redirect T cells to promote tumor cell lysis for cancer immunotherapy typically utilize antibody fragments (Fab, scFv, VH, single domain antibody, etc.) that are derived from monoclonal antibodies (mAb) directed against the CD3e subunit of the T cell receptor (TCR). However, there are limitations to this approach which may prevent the full realization of the therapeutic potential for such bispecific constructs. Previous studies have shown that even low “activating” doses of anti-CD3e mAb can cause long-term T cell dysfunction and exert immunosuppressive effects. In addition, anti-CD3e mAbs have been associated with side effects that result from massive T cell activation. The large number of activated T cells secrete substantial amounts of cytokines, the most important of which is Interferon gamma (IFNy). This excess amount of IFNy in turn activates macrophages which then overproduce proinflammatory cytokines such as IL-lbeta, IL-6,WSGR Docket No. 53676-773.601IL- 10 and TNF-alpha, causing a “cytokine storm” known as the cytokine release syndrome (CRS) (Shimabukuro-Vomhagen et al., J Immunother Cancer. 2018 Jun 15 ;6( 1): 56, herein incorporated by reference in its entirety). Thus, the need exists for developing antibodies that are capable of binding and activating only a subset of effector T cells, e.g., to re-duce the CRS and / or neurotoxicity (NT).

[0151] Described herein are molecules targeting the TCRJ3V 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.

[0152] Described herein is a class of antibodies, i.e., anti-TCRpV antibody molecules as described herein, which despite having low sequence similarity (e.g., low sequence identity among the different antibody molecules that recognize different TCRJ3V subfamilies), recognize a structurally conserved, yet sequence-wise variable, region, e.g., domain, on the TCRJ3V protein and have a similar function (e.g., activation of T cells and a similar cytokine profile as described herein). Thus, the anti-TCRpV antibody molecules as described herein share a structure-function relationship.

[0153] Without wishing to be bound by theory, in some embodiments, the anti-TCRpV antibody molecules as described herein bind to an outward facing epitope of a TCRJ3V protein when it is in a complex with a TCRalpha protein. In some embodiments, the anti-TCRpV antibody molecules as described herein recognize (e.g., bind to), a domain (e.g., an epitope) on the TCRJ3V protein that is: (1) structurally conserved among different TCRJ3V subfamilies; and (2) has minimal sequence identity among the different TCRJ3V subfamilies. TCRJ3V proteins from the different TCRBV subfamilies share minimal sequence similarity. However, TCRJ3V proteins which have minimal sequence similarity, share a similar 3D conformation and structure.

[0154] The alignment of TCRBV amino acid sequences underscores the diversity of TCR sequences. In particular, the TRBV sequences from different subfamilies are considerably different from each other.

[0155] In some embodiments, the anti-TCRpV antibody molecules as described herein do not recognize, e.g., bind to, an interface of a TCRJ3V: TCRalpha complex. In some embodiments, the anti-TCRpV antibody molecules as described herein do not recognize, e.g., bind to, a constant region of a TCRJ3V protein. An exemplary antibody that binds to a constant region of a TCRBV region is JOVI. 1 as described in Viney et al., (Hybridoma. 1992 Dec;l l(6):701-13). In some embodiments, the anti-TCRpV antibody molecules as described 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 TCRJ3V protein.

[0156] Provided herein are, inter alia, antibody molecules directed to the variable chain of the beta subunit of TCR (TCRJ3V) which bind and, e.g., activate a subset of T cells. The anti-TCRpV antibody molecules as described 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 IFNy. In some embodiments, the anti-TCRpV antibodies as described herein have a cytokine profde, e.g., as described herein, which differs from a cytokine profde of a T cell engager that binds to a receptor or molecule other than a TCRJ3V region (“a non-TCRpV-binding T cell engager”). In some embodiments, the non-TCRpV-WSGR Docket No. 53676-773.601 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. In some embodiments, the non-TCRpV-binding T cell engager is an 0KT3 antibody or an SP34-2 antibody.

[0157] In some embodiments, the anti-TCRpV antibodies as described herein result in expansion of TCRPV+ T cells, e.g., a subset of memory effector T cells known as TEMRA. Without wishing to be bound by theory, it is believed that in some embodiments, TEMRA cells can promote tumor cell lysis but not CRS. Accordingly, provided herein are methods of making said anti-TCRpV antibody molecules and uses thereof. Also described herein are multispecific molecules, e.g., bispecific molecules comprising said anti-TCRpV antibody molecules. In some embodiments, 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 immuno-therapy; and / or (2) expand TCRPV+ T cells. In some embodiments, compositions comprising anti-TCRpV antibody molecules as described herein limit the harmful side-effects of CRS and / or NT, e.g., CRS and / or NT associated with anti-CD3e targeting.

[0158] In some embodiments, the anti-TCRpV antibody molecule binds to one or more of TRBV2, TRBV3-1, TRBV4-1, TRBV4-2, TRBV4-3, TRBV5-1, TRBV5-4, TRBV5-5, TRBV5-6, TRBV5-8, TRBV6-1, TRBV6-2, TRBV6-3, TRBV6-4, TRBV6-5, TRBV6-6, TRBV6-8, TRBV6-9, TRBV7-2, TRBV7-3, TRBV7-4, TRBV7-6, TRBV7-7, TRBV7-8, TRBV7-9, TRBV9, TRBV10-1, TRBV10-2, TRBV10-3, TRBV11-1, TRBV11-2, TRBV11-3, TRBV12-3, TRBV12-4, TRBV12-5, TRBV13, TRBV14, TRBV15, TRBV16, TRBV18, TRBV19, TRBV20-1, TRBV24-1, TRBV25-1, TRBV27, TRBV28, TRBV29-1 and TRBV30. In some embodiments, the anti-TCRpV antibody molecule binds to one or more of TRBV6-1, TRBV6-2, TRBV6-3, TRBV6-4, TRBV6-5, TRBV6-6, TRBV6-8 and TRBV6-9. In some embodiments, the anti-TCRpV antibody molecule is an anti-TRBV2, anti-TRBV3-l, anti-TRBV4-l, anti-TRBV4-2, anti-TRBV4-3, anti-TRBV5-l, anti-TRBV5-4, anti-TRBV5-5, anti- TRBV5-6, anti-TRBV5-8, anti-TRBV6-l, anti-TRBV6-2, anti-TRBV6-3, anti-TRBV6-4, anti-TRBV6-5, anti-TRBV6-6, anti-TRBV6-8, anti-TRBV6-9, anti-TRBV7-2, anti-TRBV7-3, anti-TRBV7-4, anti- TRBV7-6, anti-TRBV7-7, anti-TRBV7-8, anti-TRBV7-9, anti-TRBV9, anti-TRBVl 0-1, anti-TRBVlO- 2, anti-TRBVl 0-3, anti-TRBVl 1-1, anti-TRBVl 1-2, anti-TRBVl 1-3, anti-TRBV12-3, anti-TRBV12-4, anti-TRBV12-5, anti-TRBV13, anti-TRBV14, anti-TRBV15, anti-TRBV16, anti-TRBV18, anti- TRBV19, anti-TRBV20-l, anti-TRBV24-l, anti-TRBV25-l, anti-TRBV27, anti-TRBV28, anti- TRBV29-1, or anti-TRBV30. Exemplary anti-TCRpV antibody molecules and the corresponding TCRpV subfamilies recognized by said anti-TCRpV antibody molecules are disclosed in Table 10A.

[0159] In some embodiments, the anti-TCRpV antibody molecule binds specifically to TRBV2, TRBV3- 1, TRBV4-1, TRBV4-2, TRBV4-3, TRBV5-1, TRBV5-4, TRBV5-5, TRBV5-6, TRBV5-8, TRBV6-1, TRBV6-2, TRBV6-3, TRBV6-4, TRBV6-5, TRBV6-6, TRBV6-8, TRBV6-9, TRBV7-2, TRBV7-3, TRBV7-4, TRBV7-6, TRBV7-7, TRBV7-8, TRBV7-9, TRBV9, TRBV10-1, TRBV10-2, TRBV10-3, TRBV11-1, TRBV11-2, TRBV11-3, TRBV12-3, TRBV12-4, TRBV12-5, TRBV13, TRBV14, TRBV15, TRBV16, TRBV18, TRBV19, TRBV20-1, TRBV24-1, TRBV25-1, TRBV27, TRBV28, TRBV29-1 or TRBV30. In some embodiments, the anti-TCRpV antibody molecule binds specifically to TRBV6-1. InWSGR Docket No. 53676-773.601 some embodiments, the anti-TCRpV antibody molecule binds specifically to TRBV6-2. In some embodiments, the anti-TCRpV antibody molecule binds specifically to TRBV6-3. In some embodiments, the anti-TCRpV antibody molecule binds specifically to TRBV6-4. In some embodiments, the anti- TCRpV antibody molecule binds specifically to TRBV6-5. In some embodiments, the anti-TCRpV antibody molecule binds specifically to TRBV6-6. In some embodiments, the anti-TCRpV antibody molecule binds specifically to TRBV6-8. In some embodiments, the anti-TCRpV antibody molecule binds specifically to TRBV6-9.

[0160] In some embodiments, 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 de-scribed in US Patent 5,861,155.

[0161] In some embodiments, 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.

[0162] In some embodiments, the anti-TCRpV antibody molecule binds to a TCRpV region other than TCRp V12 (e.g., TCRpV region as described herein, e.g., TCRp V6 subfamily (e.g., TCRp V6-5*01) 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 de-scribed in US Patent 5,861,155.

[0163] In some embodiments, the anti-TCRpV antibody molecule does not comprise the CDRs of the Antibody B murine antibody.

[0164] In some embodiments, the anti-TCRpV antibody molecule does not bind to TCRp V5-5*01 or TCRP V5-I*0I, or binds to TCRP V5-5*01 or TCRP V5-I*0I 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.

[0165] In some embodiments, the anti-TCRpV antibody molecule binds to TCRP V5-5*01 or TCRP V5- l*01with 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 de-scribed in US Patent 5,861,155.

[0166] In some embodiments, the anti-TCRpV antibody molecule binds to a TCRpV region other than TCRp V5-5*01 or TCRp V5-I*0I (e.g., TCRpV region as described herein, e.g., TCRp V6 subfamily (e.g., TCRP V6-5*01) 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.WSGR Docket No. 53676-773.601

[0167] In some embodiments, the anti-TCRpV antibody molecule does not comprise the CDRs of the TM23 murine antibody.

[0168] In some embodiments, 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*01) 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, a human germline sequence, or a human consensus sequence; (c) a non-human framework (e.g. , a rodent framework); or (d) a non-human framework that has been modified, e.g. , to remove antigenic or cytotoxic determinants, e.g., deimmunized, or partially humanized. In some embodiments, 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.

[0169] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises a heavy chain variable domain having at least one, two, three, four, five, six, seven, ten, fifteen, twenty or more changes, e.g., amino acid substitutions or deletions, from an amino acid sequence of any one of A-H.l to A-H.85, e.g., A-H.l, A-H.2 or A-H.68, e.g., the amino acid sequence of the FR region in the entire variable region, e.g., in SEQ ID NO: 9.

[0170] Alternatively, or in combination with the heavy chain substitutions described herein, the anti- TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises a light chain variable domain having at least one, two, three, four, five, six, seven, ten, fifteen, twenty or more amino acid changes, e.g., amino acid substitutions or deletions, from an amino acid sequence of any one of A-H.l to A-H.85, e.g., A-H. l, A-H.2 or A-H.68, e.g., the amino acid sequence of the FR region in the entire variable region, e.g., SEQ ID NO: 10 or SEQ ID NO: 11.

[0171] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, includes one, two, three, or four heavy chain framework regions or a sequence substantially identical thereto.

[0172] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, includes one, two, three, or four light chain framework regions or a sequence substantially identical thereto.

[0173] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the light chain framework region 1 of A-H. 1 or A-H.2.

[0174] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the light chain framework region 2 of A-H. 1 or A-H.2.WSGR Docket No. 53676-773.601

[0175] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g, anti-TCR[3 V6-5*01) antibody molecule, comprises the light chain framework region 3 of A-H.1 or A-H.2.

[0176] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g., anti-TCR[3 V6-5*01) antibody molecule, comprises the light chain framework region 4 of A-H.1 or A-H.2.

[0177] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g., anti-TCR[3 V6-5*01) antibody molecule, comprises a light chain variable domain comprising a framework region, e.g., framework region 1 (FR1), comprising a change, e.g., a substitution (e.g., a conservative substitution) at position 10 according to Kabat numbering. In some embodiments, the FR1 comprises a Phenylalanine at position 10, e.g., a Serine to Phenylalanine substitution. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0178] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g., anti-TCR[3 V6-5*01) antibody molecule, comprises a light chain variable domain comprising a framework region, e.g., framework region 2 (FR2), comprising a change, e.g., a substitution (e.g., a conservative substitution) at a position as described herein according to Kabat numbering. In some embodiments, FR2 comprises a Histidine at position 36, e.g., a substitution at position 36 according to Kabat numbering, e.g., a Tyrosine to Histidine substitution. In some embodiments, FR2 comprises an Alanine at position 46, e.g., a substitution at position 46 according to Kabat numbering, e.g., an Arginine to Alanine substitution. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0179] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g, anti-TCR[3 V6-5*01) 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 as described herein according to Kabat numbering. In some embodiments, FR3 comprises a Phenylalanine at position 87, e.g., a substitution at position 87 according to Kabat numbering, e.g., a Tyrosine to Phenylalanine substitution. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0180] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g, anti-TCR[3 V6-5*01) antibody molecule, comprises a light chain variable domain comprising: (a) a framework region 1 (FR1) comprising a Phenylalanine at position 10, e.g., a substitution at position 10 according to Kabat numbering, e.g., a Serine to Phenylalanine substitution; (b) a framework region 2 (FR2) comprising a Histidine at position 36, e.g., a substitution at position 36 according to Kabat numbering, e.g., a Tyrosine to Histidine substitution, and a Alanine at position 46, e.g., a substitution at position 46 according to Kabat numbering, e.g., a Arginine to Alanine substitution; and (c) a framework region 3 (FR3) comprising a Phenylalanine at position 87, e.g., a substitution at position 87 according to Kabat numbering, e.g., a Tyrosine to Phenylalanine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 10. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.WSGR Docket No. 53676-773.601

[0181] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g, anti-TCR[3 V6-5*01) antibody molecule, comprises a light chain variable domain comprising: (a) a framework region 2 (FR2) comprising a Histidine at position 36, e.g., a substitution at position 36 according to Kabat numbering, e.g., a Tyrosine to Histidine substitution, and a Alanine at position 46, e.g., a substitution at position 46 according to Kabat numbering, e.g., a Arginine to Alanine substitution; and (b) a framework region 3 (FR3) comprising a Phenylalanine at position 87, e.g., a substitution at position 87 according to Kabat numbering, e.g., a Tyrosine to Phenylalanine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 11. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0182] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g., anti-TCR[3 V6-5*01) antibody molecule, comprises a light chain variable domain comprising: (a) a framework region 1 (FR1) comprising a change, e.g., a substitution (e.g., a conservative substitution) at one or more (e.g., all) positions as described herein according to Kabat numbering, ; (b) a framework region 2 (FR2) comprising a change, e.g., a substitution (e.g., a conservative substitution) at one or more (e.g., all) position as described herein according to Kabat numbering and (c) a framework region 3 (FR3) comprising a change, e.g., a substitution (e.g., a conservative substitution) at one or more (e.g., all) position as described herein according to Kabat numbering. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0183] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g., anti-TCR[3 V6-5*01) antibody molecule, comprises the heavy chain framework region 1 of A-H.l or A-H.2. In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g., anti-TCR[3 V6-5*01) antibody molecule, comprises the heavy chain framework region 2 of A-H.l or A-H.2. In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g., anti-TCR[3 V6-5*01) antibody molecule, comprises the heavy chain framework region 3 of A-H.l or A-H.2. In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g., anti-TCR[3 V6-5*01) antibody molecule, comprises the heavy chain framework region 4 of A-H.l or A-H.2.

[0184] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g., anti-TCR[3 V6-5*01) antibody molecule, comprises a heavy 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 as described herein according to Kabat numbering. In some embodiments, FR3 comprises a Threonine at position 73, e.g., a substitution at position 73 according to Kabat numbering, e.g., a Glutamic Acid to Threonine substitution. In some embodiments, FR3 comprises a Glycine at position 94, e.g., a substitution at position 94 according to Kabat numbering, e.g., an Arginine to Glycine substitution. In some embodiments, the substitution is relative to a human germline heavy chain framework region sequence.

[0185] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g., anti-TCR[3 V6-5*01) antibody molecule, comprises a heavy chain variable domain comprising a framework region 3 (FR3) comprising a Threonine at position 73, e.g., a substitution at position 73 according to KabatWSGR Docket No. 53676-773.601 numbering, e.g., a Glutamic Acid to Threonine substitution, and a Glycine at position 94, e.g., a substitution at position 94 according to Kabat numbering, e.g., a Arginine to Glycine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 10.

[0186] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the heavy chain framework regions 1-4 of A-H. 1 or A-H.2, e.g., SEQ ID NO: 9. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the light chain framework regions 1-4 of A-H.l, e.g., SEQ ID NO: 10. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises the light chain framework regions 1-4 of A-H.2, e.g., SEQ ID NO: 11. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) 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: 10. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) 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: 11.

[0187] In some embodiments, 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*01) antibody molecule, includes an amino acid sequence, which is substantially identical to an amino acid as described 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 any one of A-H. 1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, 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.

[0188] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises at least one, two, three, or four antigen-binding regions, e.g., variable regions, having an amino acid 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 1, 2, 5, 10, or 15 amino acid residues from the sequences shown in Table 1. In another embodiment, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) 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.

[0189] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises: a 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 a VL domain comprising the amino acid sequence of SEQ ID NO: 10, an amino acid sequence at least about 85%, 90%, 95%, 99% orWSGR Docket No. 53676-773.601 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.

[0190] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g, anti-TCRp V6-5*01) antibody molecule, comprises: a 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 a 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.

[0191] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule is a full antibody or fragment thereof (e.g., a Fab, F(ab')2, Fv, single domain antibody, or a single chain Fv fragment (scFv)). In embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule is a monoclonal antibody or an antibody with single specificity. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti- TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, can also be a humanized, chimeric, camelid, shark, or an in vv / ro-gcncratcd antibody molecule. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, is a humanized antibody molecule. The heavy and light chains of the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) 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).

[0192] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, is in the form of a multispecific molecule, e.g., a bispecific molecule, e.g., as described herein.

[0193] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, has a heavy chain constant region (Fc) chosen from, e.g., the heavy chain constant regions of IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgD, and IgE. In some embodiments, the Fc region is chosen from the heavy chain constant regions of IgGl, IgG2, IgG3, and IgG4. In some embodiments, the Fc region is chosen from the heavy chain constant region of IgGl or IgG2 (e.g., human IgGl, or IgG2). In some embodiments, the heavy chain constant region is human IgGl. In some embodiments, the Fc region comprises a Fc region variant, e.g., as described herein.

[0194] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, has a light chain constant region chosen from, e.g., the light chain constant regions of kappa or lambda, preferably kappa (e.g., human kappa). In some embodiments, the constant region is altered, e.g., mutated, to modify the properties of the anti-TCRpV antibody molecule, e.g., anti-WSGR Docket No. 53676-773.601TCRp V6 (e.g., anti-TCRp V6-5*01) 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). For example, 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.

[0195] 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. Antibody A-H.68 comprises the amino acid sequence of SEQ ID NO: 1337, or a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100% sequence identity thereto. Antibody A-H.69 comprises the amino acid sequence of SEQ ID NO: 1500, or a sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100% sequence identity thereto.

[0196] Additional exemplary humanized anti-TCRB V6 antibodies are provided in Table 1. In some embodiments, the anti-TCRp V6 is antibody A, e.g., humanized antibody A (antibody A-H), as provided in Table 1. In some embodiments, the anti-TCRpV antibody comprises one or more (e.g., all three) of a LC CDR1, LC CDR2, and LC CDR3 provided in Table 1; and / or one or more (e.g., all three) of a HC CDR1, HC CDR2, and HC CDR3 provided in Table 1, or a sequence with at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100% sequence identity thereto. In some embodiments, antibody A comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 1, or a sequence with at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or 100% sequence identity thereto.

[0197] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises a VH of A-H.l, A-H.2, A-H.3, A-H.4, A-H.5, A-H.6, A-H.7, A- H.8, A-H.9, A-H. 10, A-H. 11, A-H.12, A-H. 13, A-H.14, A-H.15, A-H. 16, A-H. 17, A-H.18, A-H. 19, A- H.20, A-H.21, A-H.22, A-H.23, A-H.24, A-H.25, A-H.26, A-H.27, A-H.28, A-H.29, A-H.30, A-H.31, A- H.32, A-H.33, A-H.34, A-H.35, A-H.36, A-H.37, A-H.38, A-H.39, A-H.40, A-H. l, A-H.42, A-H.43, A- H.44, A-H.45, A-H.46, A-H.47, A-H.48, A-H.49, A-H.50, A-H.51, A-H.52, A-H.53, A-H.54, A-H.55, A- H.56, A-H.57, A-H.58, A-H.59, A-H.60, A-H.61, A-H.62, A-H.63, A-H.64, A-H.65, A-H.66, A-H.67, A- H.68, A-H.69, A-H.70, A-H.71, A-H.72, A-H.73, A-H.74, A-H.75, A-H.76, A-H.77, A-H.78, A-H.79, A- H.80, A-H.81, A-H.82, A-H.83, A-H.84, or A-H.85, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0198] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCR[3 V6 (e.g., anti-TCRp V6-5*01) antibody molecule comprises a VL of A-H.l, A-H.2, A-H.3, A-H.4, A-H.5, A-H.6, A-H.7, A- H.8, A-H.9, A-H. 10, A-H. 11, A-H.12, A-H. 13, A-H.14, A-H.15, A-H. 16, A-H. 17, A-H.18, A-H. 19, A- H.20, A-H.21, A-H.22, A-H.23, A-H.24, A-H.25, A-H.26, A-H.27, A-H.28, A-H.29, A-H.30, A-H.31, A-WSGR Docket No. 53676-773.601H.32, A-H.33, A-H.34, A-H.35, A-H.36, A-H.37, A-H.38, A-H.39, A-H.40, A-H.l, A-H.42, A-H.43, A-H.44, A-H.45, A-H.46, A-H.47, A-H.48, A-H.49, A-H.50, A-H.51, A-H.52, A-H.53, A-H.54, A-H.55, A-H.56, A-H.57, A-H.58, A-H.59, A-H.60, A-H.61, A-H.62, A-H.63, A-H.64, A-H.65, A-H.66, A-H.67, A-H.68, A-H.69, A-H.70, A-H.71, A-H.72, A-H.73, A-H.74, A-H.75, A-H.76, A-H.77, A-H.78, A-H.79, A-H.80, A-H.81, A-H.82, A-H.83, A-H.84, or A-H.85, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0199] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g, anti-TCR[3 V6-5*01) antibody molecule comprises a VH of A-H.l, A-H.2, A-H.3, A-H.4, A-H.5, A-H.6, A-H.7, A- H.8, A-H.9, A-H.10, A-H.l l, A-H.12, A-H.13, A-H.14, A-H.15, A-H.16, A-H.17, A-H.18, A-H.19, A- H.20, A-H.21, A-H.22, A-H.23, A-H.24, A-H.25, A-H.26, A-H.27, A-H.28, A-H.29, A-H.30, A-H.31, A-H.32, A-H.33, A-H.34, A-H.35, A-H.36, A-H.37, A-H.38, A-H.39, A-H.40, A-H.l, A-H.42, A-H.43, A-H.44, A-H.45, A-H.46, A-H.47, A-H.48, A-H.49, A-H.50, A-H.51, A-H.52, A-H.53, A-H.54, A-H.55, A-H.56, A-H.57, A-H.58, A-H.59, A-H.60, A-H.61, A-H.62, A-H.63, A-H.64, A-H.65, A-H.66, A-H.67, A-H.68, A-H.69, A-H.70, A-H.71, A-H.72, A-H.73, A-H.74, A-H.75, A-H.76, A-H.77, A-H.78, A-H.79, A-H.80, A-H.81, A-H.82, A-H.83, A-H.84, or A-H.85, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto; and a VL of A-H.l, A-H.2, A-H.3, A-H.4, A-H.5, A-H.6, A-H.7, A-H.8, A-H.9, A-H.10, A-H.l l, A-H.12, A-H.13, A-H.14, A-H.15, A-H.16, A-H.17, A-H.18, A- H.19, A-H.20, A-H.21, A-H.22, A-H.23, A-H.24, A-H.25, A-H.26, A-H.27, A-H.28, A-H.29, A-H.30, A-H.31, A-H.32, A-H.33, A-H.34, A-H.35, A-H.36, A-H.37, A-H.38, A-H.39, A-H.40, A-H.l, A-H.42, A-H.43, A-H.44, A-H.45, A-H.46, A-H.47, A-H.48, A-H.49, A-H.50, A-H.51, A-H.52, A-H.53, A-H.54, A-H.55, A-H.56, A-H.57, A-H.58, A-H.59, A-H.60, A-H.61, A-H.62, A-H.63, A-H.64, A-H.65, A-H.66, A-H.67, A-H.68, A-H.69, A-H.70, A-H.71, A-H.72, A-H.73, A-H.74, A-H.75, A-H.76, A-H.77, A-H.78, A-H.79, A-H.80, A-H.81, A-H.82, A-H.83, A-H.84, or A-H.85, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0200] Exemplary anti-TCR[3V antibody molecules and the corresponding TCRJ3V subfamilies recognized by said anti-TCR[3V antibody molecules are disclosed in Table 10A.

[0201] The various TCRJ3V subfamilies and / or subfamily members can be expressed at different levels in individuals, e.g., healthy individuals, as disclosed in Kitaura K. et al (2016), BMC Immunology vol 17: 38, the entire contents of which are hereby incorporated by reference. For example, TCR[3 V6-5 is represented in approximately 3-6% healthy donors.

[0202] The representation of various TCRBV subfamilies and / or subfamily members can also be different in cancer cells. For example, TCRJ3V is present in about 3-6% of tumor infiltrating T cells irrespective of tumor type (see Li B. et al., Nature Genetics, 2016, vol:48(7):725-32 the entire contents of which are hereby incorporated by references). Li et al., also disclose that TCR[3 V6-5 is present at a high frequency in tumor cells.WSGR Docket No. 53676-773.601Anti-TCR / 3 V6 antibodies

[0203] In one aspect, provided herein is an anti-TCRpV antibody molecule that binds to human TCRp V6, e.g., a TCRp V6 subfamily comprising: TCRp V6-4*01, TCRp V6-4*02, TCRp V6-9*01, TCRp V6-8*01, TCRp V6-5*01, TCRp V6-6*02, TCRp V6-6*01, TCRp V6-2*01, TCRp V6-3*01 or TCRp V6-l*01. In some embodiments the TCRP V6 subfamily comprises TCRP V6-5*01 or a variant thereof. In some embodiments, TCRp V6 comprises TCRp V6-4*01, or a variant thereof. In some embodiments, TCRp V6 comprises TCRp V6-4*02, or a variant thereof. In some embodiments, TCRp V6 comprises TCRp V6-9*01, or a variant thereof. In some embodiments, TCRp V6 comprises TCRp V6-8*01, or a variant thereof. In some embodiments, TCRp V6 comprises TCRp V6-5*01, 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*01, 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*01, or a variant thereof. In some embodiments, TCRp V6 comprises TCRp V6-l*01, or a variant thereof.

[0204] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, is a non-murine antibody molecule, e.g., a human or humanized antibody molecule. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti- TCRp V6-5*01) antibody molecule is a human antibody molecule. In some embodiments, the anti- TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule is a humanized antibody molecule.

[0205] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, is isolated or recombinant.

[0206] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises at least one antigen-binding region, e.g., a variable region or an antigen-binding fragment thereof, from an antibody described herein, e.g., an antibody chosen from any one of A-H.l to A-H.85, e.g., A-H.l, A-H.2 or A-H.68, or an antibody described in Table 1, or encoded by a nucleotide sequence in Table 1, 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.

[0207] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises at least one, two, three or four variable regions from an antibody described herein, e.g., an antibody chosen from any one of A-H.l to A-H.85, e.g., A-H.l, A-H.2 or A- H.68, or an antibody described in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23, 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.

[0208] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, comprises at least one or two heavy chain variable regions from an antibody described herein, e.g., an antibody chosen from any one of A-H.l to A-H.85, e.g., A-H.l, A-H.2 or A-H.68, or an antibody molecule described in Table 1, Table 16, or Table 23, or encoded by aWSGR Docket No. 53676-773.601 nucleotide sequence in Table 1, Table 16, or Table 23, 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.

[0209] In some embodiments, the anti-TCR[3V antibody molecule comprises a heavy chain variable region (VH) having a consensus sequence of SEQ ID NO: 231 or 3290.

[0210] SEQ ID NO: 231 - Consensus VHQVQLVQSGAEVKKPGSSVKVSCKASGH / T / G / YD / T / SFH / R / D / K / TL / D / K / T / NW / F / T / I / Y / GYIHWV RQAPGQGLEWMGR / WV / I / FF / S / YA / PGSGN / ST / V / Y / IK / RYNEKFKGRVTITADTSTSTAYMELSS LRSEDTAVYYCAG / VSY / IYSY / AD / GVLDYWGQGTTVTVSS

[0211] SEQ ID NO: 3290 - Consensus VHQVQLVQSGAEVKKPGSSVKVSCKASGXiX2FX3X4X5YIHWVRQAPGQGLEWMGX6X7X8X9GSGX 10X11X12YNEKFKGRVTITADTSTSTAYMELSSLRSEDTAVYYCAX13SX14YSX15X16VLDYWGQGT TVTVSS, where-in: XI is H or T or G or Y; X2 is D or T or S; X3 is H or R or D or K or T; X4 is L or D or K or T or N; X5 is W or F or T or I or Y or G; X6 is R or W; X7 is V or I or F; X8 is F or S or Y; X9 is A or P; X10 is N or S; XI 1 is T or V or Y or I; X12 is K or R; X13 is G or V; X14 is Y or I; X15 is Y or A; and X16 is D or G.

[0212] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g., anti-TCR[3 V6-5*01) antibody molecule, comprises at least one or two light chain variable regions from an antibody described herein, e.g., an antibody chosen from any one of A-H.l to A-H.85, e.g., A-H.l, A-H.2 or A- H.68, or an antibody described in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23, 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.

[0213] In some embodiments, the anti-TCR[3V antibody molecule comprises a light chain variable region (VL) having a consensus sequence of SEQ ID NO: 230 or 3289.

[0214] SEQ ID NO: 230 - Consensus VLDIQMTQSPSFLSASVGDRVTITCKASQNVG / E / A / DN / DR / KVAWY / HQQKPGKAPKALIYSSSHRY K / SGVPSRFSGSGSGTEFTLTISSLQPEDFATYFCQQFKSYPLTFGQGTKLEIK

[0215] SEQ ID NO: 3289 - Consensus VL DIQMTQSPSFLSASVGDRVTITCKASQNVX1X2X3VAWX4QQKPGKAPKALIYSSSHRYX5GVPSRF SGSGSGTEFTLTISSLQPEDFATYFCQQFKSYPLTFGQGTKLEIK, wherein XI is G, E, A or D; X2 is N or D; X3 is R or K; X4 is Y or H; and X5 is K or S

[0216] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g., anti-TCR[3 V6-5*01) antibody molecule, comprises a heavy chain constant region for an IgG4, e.g., a human IgG4. In still another embodiment, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g., anti-TCR[3 V6-5*01) antibody molecule includes a heavy chain constant region for an IgGl, e.g., a human IgGl. In some embodiments, the heavy 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.WSGR Docket No. 53676-773.601

[0217] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g, anti-TCR[3 V6-5*01) antibody molecule, includes a kappa light chain constant region, e.g., a human kappa light chain constant region. In some embodiments, 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.

[0218] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g., anti-TCR[3 V6-5*01) antibody molecule, includes at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region (VH) of an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H. 1, A-H.2 or A-H.68, or an antibody described in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23, 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.

[0219] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g., anti-TCR[3 V6-5*01) antibody molecule, includes at least one, two, or three CDRs (or collectively all of the CDRs) from a heavy chain variable region comprising an amino acid sequence shown in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence shown in Table 1, Table 16, or Table 23. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence shown in Table 1, Table 16, or Table 23.

[0220] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g., anti-TCR[3 V6-5*01) antibody molecule, includes at least one, two, or three complementarity determining regions (CDRs) from a light chain variable region of an antibody described herein, e.g., an antibody chosen from any one of A-H.l to A-H.85, e.g., A-H.l, A-H.2 or A-H.68, or an antibody described in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23, 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.

[0221] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g., anti-TCR[3 V6-5*01) antibody molecule, includes at least one, two, or three CDRs (or collectively all of the CDRs) from a light chain variable region comprising an amino acid sequence shown in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence shown in Table 1, Table 16, or Table 23. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence shown in Table 1, Table 16, or Table 23.

[0222] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g., anti-TCR[3 V6-5*01) antibody molecule, includes at least one, two, three, four, five or six CDRs (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown inWSGR Docket No. 53676-773.601Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence shown in Table 1, Table 16, or Table 23. In some embodiments, one or more of the CDRs (or collectively all of the CD Rs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence shown in Table 1, Table 16, or Table 23.

[0223] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, molecule includes all six CDRs from an antibody described herein, e.g., an antibody chosen from any one of A-H.1 to A-H.85, e.g., A-H. 1, A-H.2 or A-H.68, or an antibody described in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23, or closely related CDRs, e.g., CDRs which are identical 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). In some embodiments, the anti-TCRpV antibody molecule, e.g., anti- TCR[3 V6 (e.g., anti-TCRp V6-5*01) antibody molecule, may include any CDR described herein.

[0224] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule includes at least one, two, or three CDRs according to Kabat et al. (e.g., at least one, two, or three CDRs according to the Kabat definition as set out in Table 1, Table 16, or Table 23) from a heavy chain variable region of an antibody described herein, e.g., an antibody chosen from any one of A-H.l to A-H.85, e.g., A-H.l, A-H.2 or A-H.68, or an antibody described in Table 1, Table 16, or Table 23, 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 Kabat et al. shown in Table 1, Table 16, or Table 23.

[0225] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule includes at least one, two, or three CDRs according to Kabat et al. (e.g., at least one, two, or three CDRs according to the Kabat definition as set out in Table 1, Table 16, or Table 23) from a light chain variable region of an antibody described herein, e.g., an antibody chosen from any one of A-H.l to A-H.85, e.g., A-H. l, A-H.2 or A-H.68, or an antibody described in Table 1, Table 16, or Table 23, 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 Kabat et al. shown in Table 1, Table 16, or Table 23.

[0226] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, includes at least one, two, three, four, five, or six CDRs according to Kabat et al. (e.g., at least one, two, three, four, five, or six CDRs according to the Kabat definition as set out in Table 1, Table 16, or Table 23) from the heavy and light chain variable regions of an antibody described herein, e.g. , an antibody chosen from any one of A-H. 1 to A-H.85, e.g., A-H.1, A-H.2 or A-H.68, or anWSGR Docket No. 53676-773.601 antibody described in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23; 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 according to Kabat et al. shown in Table 1, Table 16, or Table 23.

[0227] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g, anti-TCRp V6-5*01) antibody molecule, includes all six CDRs according to Kabat et al. (e.g., all six CDRs according to the Kabat definition as set out in Table 1, Table 16, or Table 23) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody chosen from any one of A-H.l to A-H.85, e.g., A-H.l, A-H.2 or A-H.68, or an antibody described in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23; 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 Kabat et al. shown in Table 1, Table 16, or Table 23. In some embodiments, the anti- TCRJ3V antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, may include any CDR described herein.

[0228] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, includes at least one, two, or three hypervariable loops that have the same canonical structures as the corresponding hypervariable loop of an antibody described herein, e.g., an antibody chosen from chosen from any one of A-H.l to A-H.85, e.g., A-H.l, A-H.2 or A-H.68, e.g., the same canonical structures as at least loop 1 and / or loop 2 of the heavy and / or light chain variable domains of an antibody described herein. See, e.g., Chothia et al., (1992) J. Mol. Biol. 227:799-817; Tomlinson et al., (1992) J. Mol. Biol. 227:776-798 for descriptions of hypervariable loop canonical structures. These structures can be determined by inspection of the tables described in these references.

[0229] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) 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 1, Table 16, or Table 23) from a heavy chain variable region of an antibody described herein, e.g., an antibody chosen from any one of A-H.l to A-H.85, e.g., A-H.l, A-H.2 or A-H.68, or as described in Table 1, Table 16, or Table 23, 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 1, Table 16, or Table 23.

[0230] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule includes at least one, two, or three CDRs according to Chothia et al. (e.g., atWSGR Docket No. 53676-773.601 least one, two, or three CDRs according to the Chothia definition as set out in Table 1, Table 16, or Table 23) from a light chain variable region of an antibody described herein, e.g., an antibody chosen from any one of A-H.l to A-H.85, e.g., A-H. 1, A-H.2 or A-H.68, or an antibody described in Table 1, Table 16, or Table 23, 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 1, Table 16, or Table 23.

[0231] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, includes at least one, two, three, four, five, or six CDRs according to Chothia et al. (e.g., at least one, two, three, four, five, or six CDRs according to the Chothia definition as set out in Table 1, Table 16, or Table 23) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody chosen from any one of A-H.l to A-H.85, e.g., A-H.l, A-H.2 or A- H.68, or an antibody described in Table 1, Table 16, or Table 23, or encoded by the nucleotide sequence in Table 1, Table 16, or Table 23; 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 according to Chothia et al. shown in Table 1, Table 16, or Table 23.

[0232] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) 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 1, Table 16, or Table 23) from the heavy and light chain variable regions of an antibody described herein, e.g., an antibody chosen from any one of A-H.l to A-H.85, e.g., A-H.l, A-H.2 or A-H.68, or an antibody described in Table 1, Table 16, or Table 23, or encoded by a nucleotide sequence in Table 1, Table 16, or Table 23; 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. shown in Table 1, Table 16, or Table 23. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, may include any CDR described herein.

[0233] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, molecule includes a combination of CDRs or hypervariable loops defined according to Kabat et al., Chothia et al., or as described in Table 1, Table 16, or Table 23.

[0234] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6-5*01) antibody molecule, can contain any combination of CDRs or hypervariable loops according to the Kabat and Chothia definitions.WSGR Docket No. 53676-773.601

[0235] In some embodiments, a combined CDR as set out in Table 1, Table 16, or Table 23 is a CDRthat comprises a Kabat CDR and a Chothia CDR.

[0236] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g, anti-TCR[3 V6-5*01) antibody molecule, molecule includes a combination of CDRs or hypervariable loops identified as combined CDRs in Table 1, Table 16, or Table 23. In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g., anti-TCR[3 V6-5*01) antibody molecule, can contain any combination of CDRs or hypervariable loops according the “combined” CDRs are described in Table 1, Table 16, or Table 23.

[0237] In some embodiments, e.g., an embodiment comprising a variable region, a CDR (e.g., a combined CDR, Chothia CDR or Kabat CDR), or other sequence referred to herein, e.g., in Table 1, Table 16, or Table 23, the antibody molecule is a monospecific antibody molecule, a bispecific antibody molecule, a bivalent antibody molecule, a biparatopic antibody molecule, or an antibody molecule that comprises an antigen binding fragment of an antibody, e.g., a half antibody or antigen binding fragment of a half antibody. In certain embodiments the antibody molecule comprises a multispecific molecule, e.g., a bispecific molecule, e.g., as described herein.

[0238] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g., anti-TCR[3 V6-5*01) antibody molecule comprises a VH and / or a VL of an antibody described in Table 1, Table 16, or Table 23, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0239] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V6 (e.g., anti-TCR[3 V6-5*01) antibody molecule comprises a VH and a VL of an antibody described in Table 1, Table 16, or Table 23, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0240] In some embodiments, an anti-TCRVb antibody as described herein has an antigen binding domain having a VL having a consensus sequence of SEQ ID NO: 230, wherein position 30 is G, E, A or D; position 31 is N or D; position 32 is R or K; position 36 is Y or H; and / or position 56 is K or S.

[0241] In some embodiments, an anti-TCRVb antibody as described herein has an antigen binding domain having a VH having a consensus sequence of SEQ ID NO: 231, wherein: position 27 is H or T or G or Y; position 28 is D or T or S; position 30 is H or R or D or K or T; position 31 is L or D or K or T or N; position 32 is W or F or T or I or Y or G; position 49 is R or W; position 50 is V or I or F; position 51 is F or S or Y; position 52 is A or P; position 56 is N or S; position 57 is T or V or Y or I; position 58 is K or R; position 97 is G or V; position 99 is Y or I; position 102 is Y or A; and / or position 103 is D or G.Anti-TCRfi V5 antibodies

[0242] In one aspect, provided herein is an anti-TCR[3V antibody molecule that binds to human TCR[3 V5. In some embodiments, the TCR[3 V5 subfamily comprises TCR[3 V5-5*0I, TCR[3 V5-6*0I, TCR[3 V5 -4* 01 , TCR V5 -8 * 01 , TCR V5 - 1 * 01 , or a variant thereof.WSGR Docket No. 53676-773.601

[0243] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCRp V5 (e.g., anti-TCRp V5-l*01) antibody molecule, is a non-murine antibody molecule, e.g., a human or humanized antibody molecule. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V5 (e.g., anti- TCRp V-l*0I) antibody molecule is a human antibody molecule. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V5 (e.g., anti-TCRp V5-I*0I) antibody molecule is a humanized antibody molecule.

[0244] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V5 (e.g., anti-TCRp V5-l*01) antibody molecule, is isolated or recombinant.

[0245] Exemplary anti-TCRp V5 antibodies are provided in Table 10B. In some embodiments, the anti- TCRp V5 is an antibody C, e.g., humanized antibody C (antibody C-H), as provided in Table 10B. In some embodiments, the anti-TCRpV antibody comprises one or more (e.g., all three) of a LC CDR1, LC CDR2, and LC CDR3 provided in Table 10B; and / or one or more (e.g., all three) of a HC CDR1, HC CDR2, and HC CDR3 provided in Table 10B, or a sequence with at least 95% sequence identity thereto. In some embodiments, antibody C comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 10B, or a sequence with at least 95% sequence identity thereto.

[0246] Exemplary anti-TCRp V5 antibodies are provided in Table 10C. In some embodiments, the anti- TCRp V5 is antibody N, as provided in Table 10C. In some embodiments, the anti-TCRpV antibody comprises one or more (e.g., all three) of a LC CDR1, LC CDR2, and LC CDR3 provided in Table 10C; and / or one or more (e.g., all three) of a HC CDR1, HC CDR2, and HC CDR3 provided in Table 10C, or a sequence with at least 95% sequence identity thereto. In some embodiments, antibody comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 10C, or a sequence with at least 95% sequence identity thereto.

[0247] Exemplary anti-TCRp V5 antibodies are provided in Table 11. In some embodiments, the anti- TCRP V5 is antibody E, e.g., humanized antibody E (antibody E-H), as provided in Table 11. In some embodiments, the anti-TCRpV antibody comprises one or more (e.g., all three) of a LC CDR1, LC CDR2, and LC CDR3 provided in Table 11; and / or one or more (e.g., all three) of a HC CDR1, HC CDR2, and HC CDR3 provided in Table 11, or a sequence with at least 95% sequence identity thereto. In some embodiments, antibody E comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 11, or a sequence with at least 95% sequence identity thereto.

[0248] In some embodiments, antibody E comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 3284 and / or a light chain comprising the amino acid sequence of SEQ ID NO: 3285, or a sequence with at least 95% sequence identity thereto.

[0249] In some embodiments, the anti-TCRp V5 antibody molecule comprises a VH and / or a VL of an antibody described in Table 10B, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0250] In some embodiments, the anti-TCRp V5 antibody molecule comprises a VH and a VL of an antibody described in Table 10B, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.WSGR Docket No. 53676-773.601

[0251] In some embodiments, the anti-TCRp V5 antibody molecule comprises a VH and / or a VL of an antibody described in Table 10C, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0252] In some embodiments, the anti-TCRp V5 antibody molecule comprises a VH and a VL of an antibody described in Table 10C, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0253] In some embodiments, the anti-TCRp V5 antibody molecule comprises a VH and / or a VL of an antibody described in Table 11, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0254] In some embodiments, the anti-TCRp V5 antibody molecule comprises a VH and a VL of an antibody described in Table 11, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.Anti-TCR / 3 VI 2 antibodies

[0255] In one aspect, provided herein is an anti-TCRpV antibody molecule that binds to human TCRp V12, e.g., a TCRp V12 subfamily comprising: TCRp V12-4*0I, TCRp V12-3*01 or TCRp V12-5*0I. In some embodiments the TCRp V12 subfamily comprises TCRp V12-4*0I. In some embodiments the TCRp V12 subfamily comprises TCRp V12-3*0I.

[0256] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule, is a non-murine antibody molecule, e.g., a human or humanized antibody molecule. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule is a human antibody molecule. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule is a humanized antibody molecule.

[0257] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule, is isolated or recombinant.

[0258] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule, comprises at least one antigen-binding region, e.g., a variable region or an antigen-binding fragment thereof, from an antibody described herein, e.g., an antibody described in Table 2, or encoded by a 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.

[0259] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule, comprises at least one, two, three or four variable regions from an antibody described herein, e.g., an antibody as described in Table 2, or encoded by a 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.

[0260] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule, comprises at least one or two heavy chain variable regions from an antibody described herein, e.g., an antibody as described in Table 2, or encoded by a nucleotide sequence in Table 2, or a sequenceWSGR Docket No. 53676-773.601 substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0261] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule, comprises at least one or two light chain variable regions from an antibody described herein, e.g., an antibody as described in Table 2, or encoded by a 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.

[0262] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule, comprises a heavy chain constant region for an IgG4, e.g., a human IgG4. In still another embodiment, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule, includes a heavy chain constant region for an IgGl, e.g., a human IgGl. In some embodiments, the heavy 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.

[0263] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule, includes a kappa light chain constant region, e.g., a human kappa light chain constant region. In some embodiments, 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.

[0264] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule, includes at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region 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.

[0265] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule, includes at least one, two, or three CDRs (or collectively all of the CDRs) from a heavy chain variable region comprising an amino acid sequence shown in Table 2, or encoded by a nucleotide sequence shown in Table 2. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 2, or encoded by a nucleotide sequence shown in Table 2.

[0266] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule, includes at least one, two, or three complementarity determining regions (CDRs) from a light chain variable region 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.

[0267] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule, includes at least one, two, or three CDRs (or collectively all of the CDRs) from a light chain variable region comprising an amino acid sequence shown in Table 2, or encoded by a nucleotideWSGR Docket No. 53676-773.601 sequence shown in Table 2. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 2, or encoded by a nucleotide sequence shown in Table 2.

[0268] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule, includes at least one, two, three, four, five or six CDRs (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 2, or encoded by a nucleotide sequence shown in Table 2. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 2, or encoded by a nucleotide sequence shown in Table 2.

[0269] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule, molecule includes all six CDRs from an antibody described herein, e.g., an antibody as described in Table 2, or encoded by the nucleotide sequence in Table 2, or closely related CDRs, e.g., CDRs which are identical 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). In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule, may include any CDR described herein.

[0270] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule includes at least one, two, or three CDRs according to Kabat et al. (e.g., at least one, two, or three CDRs according to the Kabat definition as set out in Table 2) from a heavy chain variable region of an antibody described herein, e.g., an antibody chosen 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 Kabat et al. shown in Table 2.

[0271] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule includes at least one, two, or three CDRs according to Kabat et al. (e.g., at least one, two, or three CDRs according to the Kabat 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 Kabat et al. shown in Table 2.

[0272] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule includes at least one, two, three, four, five, or six CDRs according to Kabat et al. (e.g., at least one, two, three, four, five, or six CDRs according to the Kabat 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 inWSGR Docket No. 53676-773.601Table 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 according to Kabat et al. shown in Table 2.

[0273] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule includes all six CDRs according to Kabat et al. (e.g., all six CDRs according to the Kabat 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 Kabat et al. shown in Table 2. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti- TCRp V12 antibody molecule may include any CDR described herein.

[0274] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule includes at least one, two, or three hypervariable loops that have the same canonical structures as the corresponding hypervariable loop of an antibody described herein, e.g., an antibody described in Table 2, e.g., the same canonical structures as at least loop 1 and / or loop 2 of the heavy and / or light chain variable domains of an antibody described herein. See, e.g., Chothia et al., (1992) J. Mol. Biol. 227:799- 817; Tomlinson et al., (1992) J. Mol. Biol. 227:776-798 for descriptions of hypervariable loop canonical structures. These structures can be determined by inspection of the tables described in these references.

[0275] In some embodiments, 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 heavy chain variable region of an antibody described herein, e.g., an antibody chosen 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.

[0276] In some embodiments, 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.WSGR Docket No. 53676-773.601

[0277] In some embodiments, 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. (e.g., at least one, two, three, four, five, or 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 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 according to Chothia et al. shown in Table 2.

[0278] In some embodiments, 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. shown in Table 2. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti- TCRp V12 antibody molecule may include any CDR described herein.

[0279] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule includes at least one, two, or three CDRs according to a combined CDR (e.g., at least one, two, or three CDRs according to the combined CDR definition as set out in Table 2) from a heavy chain variable region of an antibody described herein, e.g., an antibody chosen 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 combined CDR shown in Table 2.

[0280] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule includes at least one, two, or three CDRs according to a combined CDR (e.g., at least one, two, or three CDRs according to the combined CDR 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 a combined CDR shown in Table 2.

[0281] In some embodiments, 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 inWSGR Docket No. 53676-773.601Table 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 according to a combined CDR shown in Table 2.

[0282] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule includes all six CDRs according to a combined CDR (e.g., all 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 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 a combined CDR shown in Table 2. In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule may include any CDR described herein.

[0283] In some embodiments, a combined CDR as set out in Table l is a CDR that comprises a Kabat CDR and a Chothia CDR.

[0284] In some embodiments, the anti-TCR[3V antibody molecule, e e.g., anti-TCR[3 V12 antibody molecule, molecule includes a combination of CDRs or hypervariable loops identified as combined CDRs in Table 1. In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule, can contain any combination of CDRs or hypervariable loops according the “combined” CDRs are described in Table 1.

[0285] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule includes a combination of CDRs or hypervariable loops defined according to the Kabat et al. and Chothia et al., or as described in Table 1.

[0286] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule can contain any combination of CDRs or hypervariable loops according to the Kabat and Chothia definitions.

[0287] In some embodiments, e.g., an embodiment comprising a variable region, a CDR (e.g., a combined CDR, Chothia CDR or Kabat CDR), or other sequence referred to herein, e.g., in Table 2, the antibody molecule is a monospecific antibody molecule, a bispecific antibody molecule, a bivalent antibody molecule, a biparatopic antibody molecule, or an antibody molecule that comprises an antigen binding fragment of an antibody, e.g., a half antibody or antigen binding fragment of a half antibody. In certain embodiments the antibody molecule comprises a multispecific molecule, e.g., a bispecific molecule, e.g., as described herein.

[0288] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule includes: (i) one, two or all of a light chain complementarity determining region 1 (LC CDR1),WSGR Docket No. 53676-773.601 a light chain complementarity determining region 2 (LC CDR2), and a light chain complementarity determining region 3 (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, and / or (ii) one, two or all of a heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and a heavy chain complementarity determining region 3 (HC CDR3) of SEQ ID NO: 15, SEQ ID NO: 23, SEQ ID NO: 24 or SEQ ID NO: 25.

[0289] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule comprises: (i) a LC CDR1 amino acid sequence of SEQ ID NO: 20, a LC CDR2 amino acid sequence of SEQ ID NO: 21, or a LC CDR3 amino acid sequence of SEQ ID NO: 22; and / or (ii) a HC CDR1 amino acid sequence of SEQ ID NO: 17, a HC CDR2 amino acid sequence of SEQ ID NO: 18, or a HC CDR3 amino acid sequence of SEQ ID NO: 19.

[0290] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule comprises: (i) a light chain variable region (VL) comprising a LC CDR1 amino acid sequence of SEQ ID NO: 20, a LC CDR2 amino acid sequence of SEQ ID NO: 21, and a LC CDR3 amino acid sequence of SEQ ID NO: 2; and / or (ii) a heavy chain variable region (VH) comprising a HC CDR1 amino acid sequence of SEQ ID NO: 17, a HC CDR2 amino acid sequence of SEQ ID NO: 18, and a HC CDR3 amino acid sequence of SEQ ID NO: 19.

[0291] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule comprises: (i) a LC CDR1 amino acid sequence of SEQ ID NO: 63, a LC CDR2 amino acid sequence of SEQ ID NO: 64, or a LC CDR3 amino acid sequence of SEQ ID NO: 65; and / or (ii) a HC CDR1 amino acid sequence of SEQ ID NO: 57, a HC CDR2 amino acid sequence of SEQ ID NO: 58, or a HC CDR3 amino acid sequence of SEQ ID NO: 59.

[0292] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule comprises: (i) a light chain variable region (VL) comprising a LC CDR1 amino acid sequence of SEQ ID NO: 63, a LC CDR2 amino acid sequence of SEQ ID NO: 64, or a LC CDR3 amino acid sequence of SEQ ID NO: 65; and / or (ii) a heavy chain variable region (VH) comprising a HC CDR1 amino acid sequence of SEQ ID NO: 57, a HC CDR2 amino acid sequence of SEQ ID NO: 58, or a HC CDR3 amino acid sequence of SEQ ID NO: 59.

[0293] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule comprises: (i) a LC CDR1 amino acid sequence of SEQ ID NO: 66, a LC CDR2 amino acid sequence of SEQ ID NO: 67, or a LC CDR3 amino acid sequence of SEQ ID NO: 68; and / or (ii) a HC CDR1 amino acid sequence of SEQ ID NO: 60, a HC CDR2 amino acid sequence of SEQ ID NO: 61, or a HC CDR3 amino acid sequence of SEQ ID NO: 62.

[0294] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule comprises: (i) a light chain variable region (VL) comprising a LC CDR1 amino acid sequence of SEQ ID NO: 63, a LC CDR2 amino acid sequence of SEQ ID NO: 64, or a LC CDR3 amino acid sequence of SEQ ID NO: 65; and / or (ii) a heavy chain variable region (VH) comprising a HC CDR1WSGR Docket No. 53676-773.601 amino acid sequence of SEQ ID NO: 57, a HC CDR2 amino acid sequence of SEQ ID NO: 58, or a HC CDR3 amino acid sequence of SEQ ID NO: 59.

[0295] In some embodiments, 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 V12 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, a human germline sequence, or a human consensus sequence; (c) a non-human framework (e.g., a rodent framework); or (d) a non-human framework that has been modified, e.g., to remove antigenic or cytotoxic determinants, e.g., deimmunized, or partially humanized. In some embodiments, 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.

[0296] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule, comprises a heavy chain variable domain having at least one, two, three, four, five, six, seven, ten, fifteen, twenty or more changes, e.g., amino acid substitutions or deletions, from an amino acid sequence described in Table 2. e.g., the amino acid sequence of the FR region in the entire variable region, e.g., SEQ ID NOs: 23-25.

[0297] Alternatively, or in combination with the heavy chain substitutions described herein the anti- TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises a light chain variable domain having at least one, two, three, four, five, six, seven, ten, fifteen, twenty or more amino acid changes, e.g., amino acid substitutions or deletions, from an amino acid sequence of an antibody described herein e.g., the amino acid sequence of the FR region in the entire variable region, e.g., SEQ ID NOs: 26-30.

[0298] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule includes one, two, three, or four heavy chain framework regions a sequence substantially identical thereto.

[0299] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule includes one, two, three, or four light chain framework regions or a sequence substantially identical thereto. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises the light chain framework region 1. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises the light chain framework region 2. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody moleculeWSGR Docket No. 53676-773.601 comprises the light chain framework region 3. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises the light chain framework region 4.

[0300] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises a light chain comprising a framework region, e.g., framework region 1 (FR1), comprising a change, e.g., a substitution (e.g., a conservative substitution) at one or more, e.g., all, position as described herein according to Kabat numbering. In some embodiments, FR1 comprises an Aspartic Acid at position 1, e.g., a substitution at position 1 according to Kabat numbering, e.g., an Alanine to Aspartic Acid substitution. In some embodiments, FR1 comprises an Asparagine at position 2, e.g., a substitution at position 2 according to Kabat numbering, e.g., an Isoleucine to Asparagine substitution, Serine to Asparagine substitution or Tyrosine to Asparagine substitution. In some embodiments, FR1 comprises a Leucine at position 4, e.g., a substitution at position 4 according to Kabat numbering, e.g., a Methionine to Leucine substitution.

[0301] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises a light chain comprising a framework region, e.g., framework region 1 (FR1), comprising a substitution at position 1 according to Kabat numbering, e.g., an Alanine to Aspartic Acid substitution, a substitution at position 2 according to Kabat numbering, e.g., an Isoleucine to Asparagine substitution, Serine to Asparagine substitution or Tyrosine to Asparagine substitution, and a substitution at position 4 according to Kabat numbering, e.g., a Methionine to Leucine substitution. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises a light chain comprising a framework region, e.g., framework region 1 (FR1), comprising a substitution at position 1 according to Kabat numbering, e.g., an Alanine to Aspartic Acid substitution, and a substitution at position 2 according to Kabat numbering, e.g., an Isoleucine to Asparagine substitution, Serine to Asparagine substitution or Tyrosine to Asparagine substitution. In some embodiments, the anti- TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises a light chain comprising a framework region, e.g., framework region 1 (FR1), comprising a substitution at position 1 according to Kabat numbering, e.g., an Alanine to Aspartic Acid substitution, and a substitution at position 4 according to Kabat numbering, e.g., a Methionine to Leucine substitution. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises a light chain comprising a framework region, e.g., framework region 1 (FR1), comprising a substitution at position 2 according to Kabat numbering, e.g., an Isoleucine to Asparagine substitution, Serine to Asparagine substitution or Tyrosine to Asparagine substitution, and a substitution at position 4 according to Kabat numbering, e.g., a Methionine to Leucine substitution. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0302] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises a light chain comprising a framework region, e.g., framework region 3 (FR3), comprising a change, e.g., a substitution (e.g., a conservative substitution) at one or more, e.g., all, position as described herein according to Kabat numbering. In some embodiments, FR3 comprises a Glycine at position 66, e.g., a substitution at position 66 according to Kabat numbering, e.g., a Lysine toWSGR Docket No. 53676-773.601Glycine substitution, or a Serine to Glycine substitution. In some embodiments, FR3 comprises an Asparagine at position 69, e.g., a substitution at position 69 according to Kabat numbering, e.g., a Tyrosine to Asparagine substitution. In some embodiments, FR3 comprises a Tyrosine at position 71, e.g., a substitution at position 71 according to Kabat numbering, e.g., a Phenylalanine to Tyrosine substitution, or an Alanine to Tyrosine substitution.

[0303] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises a light chain comprising a framework region, e.g., framework region 3 (FR3), comprising a substitution at position 66 according to Kabat numbering, e.g., a Lysine to Glycine substitution, or a Serine to Glycine substitution, and a substitution at position 69 according to Kabat numbering, e.g., a Tyrosine to Asparagine substitution.. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises a light chain comprising a framework region, e.g., framework region 3 (FR3), comprising a substitution at position 66 according to Kabat numbering, e.g., Lysine to Glycine substitution, or a Serine to Glycine substitution, and a substitution at position 71 according to Kabat numbering, e.g., a Phenylalanine to Tyrosine substitution, or an Alanine to Tyrosine substitution. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises a light chain comprising a framework region, e.g., framework region 3 (FR3), comprising a substitution at position 69 according to Kabat numbering, e.g., a Tyrosine to Asparagine substitution and a substitution at position 71 according to Kabat numbering, e.g., a Phenylalanine to Tyrosine substitution, or an Alanine to Tyrosine substitution. In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises a light chain comprising a framework region, e.g., framework region 3 (FR3), comprising a substitution at position 66 according to Kabat numbering, e.g., a Lysine to Glycine substitution, or a Serine to Glycine substitution, a substitution at position 69 according to Kabat numbering, e.g., a Tyrosine to Asparagine substitution and a substitution at position 71 according to Kabat numbering, e.g., a Phenylalanine to Tyrosine substitution, or an Alanine to Tyrosine substitution. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0304] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises a light chain comprising: a framework region 1 (FR1) comprising a substitution at position 2 according to Kabat numbering, e.g., a Isoleucine to Asparagine substitution; and a framework region 3 (FR3), comprising a substitution at position 69 according to Kabat numbering, e.g., a Threonine to Asparagine substitution and a substitution at position 71 according to Kabat numbering, e.g., a Phenylalanine to Tyrosine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 26. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0305] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises a light chain comprising: (a) a framework region 1 (FR1) comprising a substitution at position 1 according to Kabat numbering, e.g., a Alanine to Aspartic Acid substitution, and a substitution at position 2 according to Kabat numbering, e.g., a Isoleucine to Asparagine substitution; andWSGR Docket No. 53676-773.601(b) a framework region 3 (FR3), comprising a substitution at position 69 according to Kabat numbering, e.g., a Threonine to Asparagine substitution and a substitution at position 71 according to Kabat numbering, e.g., a Phenylalanine to Tyrosine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 27 In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0306] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule comprises a light chain comprising: (a) a framework region 1 (FR1) comprising a substitution at position 2 according to Kabat numbering, e.g., a Serine to Asparagine substitution; and a substitution at position 4 according to Kabat numbering, e.g., a Methionine to Leucine substitution; and (b) a framework region 3 (FR3), comprising a substitution at position 69 according to Kabat numbering, e.g., a Threonine to Asparagine substitution and a substitution at position 71 according to Kabat numbering, e.g., a Phenylalanine to Tyrosine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 28 In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0307] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule comprises a light chain comprising: (a) a framework region 1 (FR1) comprising a substitution at position 2 according to Kabat numbering, e.g., a Serine to Asparagine substitution; and (b) a framework region 3 (FR3) comprising a substitution at position 66 according to Kabat numbering, e.g., a Lysine to Glycine substitution; a substitution at position 69 according to Kabat numbering, e.g., a Threonine to Asparagine substitution; and a substitution at position 71 according to Kabat numbering, e.g., a Alanine to Tyrosine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 29. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0308] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule comprises a light chain comprising: (a) a framework region 1 (FR1) comprising a substitution at position 2 according to Kabat numbering, e.g., a Tyrosine to Asparagine substitution; and (b) a framework region 3 (FR3) comprising a substitution at position 66 according to Kabat numbering, e.g., a Serine to Glycine substitution; a substitution at position 69 according to Kabat numbering, e.g., a Threonine to Asparagine substitution; and a substitution at position 71 according to Kabat numbering, e.g., a Alanine to Tyrosine substitution, e.g., as shown in the amino acid sequence of SEQ ID NO: 29. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0309] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule comprises a light chain variable domain comprising: (a) a framework region 1 (FR1) comprising a change, e.g., a substitution (e.g., a conservative substitution) at one or more (e.g., all) positions as described herein according to Kabat numbering, and (b) a framework region 3 (FR3) comprising a change, e.g., a substitution (e.g., a conservative substitution) at one or more (e.g., all)WSGR Docket No. 53676-773.601 position as described herein according to Kabat numbering. In some embodiments, the substitution is relative to a human germline light chain framework region sequence.

[0310] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises the heavy chain framework region 1. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises the heavy chain framework region 2. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises the heavy chain framework region 3. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises the heavy chain framework region 4. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises the heavy chain framework regions 1-4, e.g., SEQ ID NOS: 20-23. In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises the light chain framework regions 1-4, e.g., SEQ ID NOs: 26-30.

[0311] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises the heavy chain framework regions 1-4, e.g., SEQ ID NOs: 23-25; and the light chain framework regions 1-4, e.g., SEQ ID NOs: 26-30.

[0312] In some embodiments, the heavy or light chain variable domain, or both, of, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule includes an amino acid sequence, which is substantially identical to an amino acid as described 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 as described in Table 2, or encoded by the nucleotide sequence in Table 2; 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.

[0313] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises at least one, two, three, or four antigen-binding regions, e.g., variable regions, having an amino acid sequence as set forth in Table 2, 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 1, 2, 5, 10, or 15 amino acid residues from the sequences shown in Table 2. In another embodiment,, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule includes a VH and / or VL domain encoded by a nucleic acid having a nucleotide sequence as set forth in Table 2, 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 2.

[0314] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises: a VH domain comprising an amino acid sequence chosen from the amino acid sequence of SEQ ID NO: 23, SEQ ID NO:24 or SEQ ID NO:25, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 23, SEQ ID NO:24 or SEQ ID NO:25, 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: 23, SEQ ID NO:24 or SEQ ID NO:25; and / or a VL domain comprising an amino acid sequence chosen from the amino acid sequence of SEQ ID NO:WSGR Docket No. 53676-773.60126, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29 or SEQ ID NO: 30, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence of SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29 or SEQ ID NO: 30, 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: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29 or SEQ ID NO: 30. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 23, 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: 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 26, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 26, 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: 26.

[0315] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 23, 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: 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 27, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 27, 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: 27.

[0316] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 23, 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: 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 28, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 28, 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: 28.

[0317] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 23, 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: 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 29, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 29, 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: 29.WSGR Docket No. 53676-773.601

[0318] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 23, 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: 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 30, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 30, 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: 30.

[0319] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 24 or 25, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 24 or 25, 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: 24 or 25; and a VL domain comprising the amino acid sequence of SEQ ID NO: 26, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 26, 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: 26.

[0320] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 24 or 25, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 24 or 25, 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: 24 or 25; and a VL domain comprising the amino acid sequence of SEQ ID NO: 27, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 27, 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: 27.

[0321] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 24 or 25, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 24 or 25, 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: 24 or 25; and a VL domain comprising the amino acid sequence of SEQ ID NO: 28, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 28, 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: 28.

[0322] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 24 or 25, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 24 or 25, 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: 24 or 25; and a VL domain comprising the amino acid sequence of SEQ ID NO: 29, an amino acid sequence at least about 85%, 90%, 95%, 99% orWSGR Docket No. 53676-773.601 more identical to the amino acid sequence SEQ ID NO: 29, 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: 29.

[0323] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 24 or 25, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 24 or 25, 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: 24 or 25; and a VL domain comprising the amino acid sequence of SEQ ID NO: 30, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 30, 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: 30.

[0324] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 25 or 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 25 or 23, 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: 25 or 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 26, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 26, 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: 26.

[0325] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 25 or 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 25 or 23, 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: 25 or 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 27, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 27, 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: 27.

[0326] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 25 or 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 25 or 23, 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: 25 or 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 28, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 28, 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: 28.

[0327] In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCR[3 V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 25 or 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 25 or 23, or an amino acid sequence which differs by no more than 1, 2, 5, 10, or 15 aminoWSGR Docket No. 53676-773.601 acid residues from the amino acid sequence of SEQ ID NO: 25 or 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 29, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 29, 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: 29.

[0328] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 25 or 23, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 25 or 23, 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: 25 or 23; and a VL domain comprising the amino acid sequence of SEQ ID NO: 30, an amino acid sequence at least about 85%, 90%, 95%, 99% or more identical to the amino acid sequence SEQ ID NO: 30, 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: 30.

[0329] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule is a full antibody or fragment thereof (e.g., a Fab, F(ab')2, Fv, or a single chain Fv fragment (scFv)). In embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V6 (e.g., anti-TCRp V6- 5*01) antibody molecule is a monoclonal antibody or an antibody with single specificity. In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule, can also be a humanized, chimeric, camelid, shark, or an in vitro-generated antibody molecule. In some embodiments, the anti-TCR[3V antibody molecule, e.g., anti-TCRp V12 antibody molecule is a humanized antibody molecule. The heavy and light chains of the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 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).

[0330] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule is in the form of a multispecific molecule, e.g., a bispecific molecule, e.g., as described herein.

[0331] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule has a heavy chain constant region (Fc) chosen from, e.g., the heavy chain constant regions of IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgD, and IgE. In some embodiments, the Fc region is chosen from the heavy chain constant regions of IgGl, IgG2, IgG3, and IgG4. In some embodiments, the Fc region is chosen from the heavy chain constant region of IgGl or IgG2 (e.g., human IgGl, or IgG2). In some embodiments, the heavy chain constant region is human IgGl.

[0332] In some embodiments, the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule has a light chain constant region chosen from, e.g., the light chain constant regions of kappa or lambda, preferably kappa (e.g., human kappa). In some embodiments, the constant region is altered, e.g., mutated, to modify the properties of the anti-TCRpV antibody molecule, e.g., anti-TCRp V12 antibody molecule (e.g., to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, theWSGR Docket No. 53676-773.601 number of cysteine residues, effector cell function, or complement function). For example, 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).

[0333] Antibody B-H.l comprises a first chain comprising the amino acid sequence of SEQ ID NO: 3280 and a second chain comprising the amino acid sequence of SEQ ID NO: 3281.

[0334] Additional exemplary anti-TCRp V12 antibodies are provided in Table 2. In some embodiments, the anti-TCRp V12 is antibody B, e.g., humanized antibody B (antibody B-H), as provided in Table 2. In some embodiments, the anti-TCRpV antibody comprises one or more (e.g., all three) of a LC CDR1, LC CDR2, and LC CDR3 provided in Table 2; and / or one or more (e.g., all three) of a HC CDR1, HC CDR2, and HC CDR3 provided in Table 2, or a sequence with at least 95% sequence identity thereto. In some embodiments, antibody B comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 2, or a sequence with at least 95% sequence identity thereto.

[0335] In some embodiments, the anti-TCRVB 12 antibody molecule (e.g., anti-TCRVB 12-3 or anti- TCRVB 12-4 antibody molecule) comprises a VH ofB-H. lA, B-H. IB, B-H.1C, B-H. ID, B-H. IE, B- H.1F, B-H.1G, B-H. 1H, B-H.l, B-H.2, B-H.3, B-H.4, B-H.5, or B-H.6, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0336] In some embodiments, the anti-TCRVB 12 antibody molecule (e.g., anti-TCRVB 12-3 or anti- TCRVB 12-4 antibody molecule) comprises a VL of B-H.1A, B-H.1B, B-H.1C, B-H.1D, B-H.1E, B- H.1F, B-H.1G, B-H. 1H, B-H.l, B-H.2, B-H.3, B-H.4, B-H.5, or B-H.6, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0337] In some embodiments, the anti-TCRVB 12 antibody molecule (e.g., anti-TCRVB 12-3 or anti- TCRVB 12-4 antibody molecule) comprises a VH ofB-H. lA, B-H. IB, B-H.1C, B-H. ID, B-H. IE, B- H.1F, B-H.1G, B-H. 1H, B-H.l, B-H.2, B-H.3, B-H.4, B-H.5, or B-H.6, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto; and a VL of B-H.1A, B-H.1B, B-H.1C, B-H. ID, B-H. IE, B-H. IF, B-H.1G, B-H.1H, B-H.l, B-H.2, B-H.3, B-H.4, B-H.5, or B-H.6, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.Anti-TCRp VI 0 antibodies

[0338] In one aspect, provided herein is an anti-TCRpV antibody molecule that binds to a human TCRp V10 subfamily member. In some embodiments, TCRP V10 subfamily is also known as TCRP VI 2. In some embodiments, the TCRp V10 subfamily comprises: TCRp V10-I*0I, TCRp V10-I*02, TCRp V 10-3 * 01 or TCRP V 10-2*01 , or a variant thereof.

[0339] Exemplary anti-TCRp V10 antibodies are provided in Table 12. In some embodiments, the anti- TCRP V10 is antibody D, e.g., humanized antibody D (antibody D-H), as provided in Table 12. In some embodiments, antibody D comprises one or more (e.g., three) light chain CDRs and / or one or more (e.g., three) heavy chain CDRs provided in Table 12, or a sequence with at least 95% sequence identity thereto.WSGR Docket No. 53676-773.601In some embodiments, antibody D comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 12, or a sequence with at least 95% sequence identity thereto.

[0340] In some embodiments, the anti-TCRp V10 antibody molecule comprises a VH and / or a VL of an antibody described in Table 12, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0341] In some embodiments, the anti-TCRp V10 antibody molecule comprises a VH and a VL of an antibody described in Table 12, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.Anti-TCRp VI 9 antibodies

[0342] In one aspect, provided herein is an anti-TCRpV antibody molecule that binds to a human TCRp V19 subfamily member. In some embodiments, the TCRP V19 subfamily comprises: TCRP V19-l*01, TCRp VI 9- 1*02, or TCRp VI 9- 1*03, or a variant thereof.

[0343] Exemplary anti-TCRp V19 antibodies are provided in Table 18. In some embodiments, the anti- TCRp V19 is antibody Q, as provided in Table 18. In some embodiments, antibody Q comprises one or more (e.g., three) light chain CDRs and / or one or more (e.g., three) heavy chain CDRs provided in Table 18, or a sequence with at least 95% sequence identity thereto. In some embodiments, antibody Q comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 18, or a sequence with at least 95% sequence identity thereto.

[0344] In some embodiments, the anti-TCRp V19 antibody molecule comprises a VH and / or a VL of an antibody described in Table 18, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0345] In some embodiments, the anti-TCRp V19 antibody molecule comprises a VH and a VL of an antibody described in Table 18, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.Anti-TCR / 3 V20 antibodies

[0346] In one aspect, provided herein is an anti-TCRpV antibody molecule that binds to a human TCRp V20 subfamily member. In some embodiments, the TCRP V20 subfamily comprises: TCRP V20-l*01, TCRP V20-l*02, TCRP V20-l*03, TCRp V20-l*04, TCRp V20-l*05, TCRp V20-l*06, or TCRp V20- 1*07, or a variant thereof.

[0347] Exemplary anti-TCRp V20 antibodies are provided in Table 15. In some embodiments, the anti- TCRP V20 is antibody L, as provided in Table 15. In some embodiments, antibody L comprises one or more (e.g., three) light chain CDRs and / or one or more (e.g., three) heavy chain CDRs provided in Table 15, or a sequence with at least 95% sequence identity thereto. In some embodiments, antibody L comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 15, or a sequence with at least 95% sequence identity thereto.

[0348] In some embodiments, the anti-TCRp V20 is antibody M, as provided in Table 15. In some embodiments, antibody M comprises one or more (e.g., three) light chain CDRs and / or one or more (e.g.,WSGR Docket No. 53676-773.601 three) heavy chain CDRs provided in Table 15, or a sequence with at least 95% sequence identity thereto. In some embodiments, antibody M comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 15, or a sequence with at least 95% sequence identity thereto.

[0349] In some embodiments, the anti-TCRp V20 antibody molecule comprises a VH and / or a VL of an antibody described in Table 15, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0350] In some embodiments, the anti-TCRp V20 antibody molecule comprises a VH and a VL of an antibody described in Table 15, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.Anti-TCRp V28 antibodies

[0351] In one aspect, provided herein is an anti-TCRpV antibody molecule that binds to a human TCRp V28 subfamily member. In some embodiments, the TCRP V28 subfamily comprises: TCRP V28-l*01, or a variant thereof.

[0352] Exemplary anti-TCRp V28 antibodies are provided in Table 17. In some embodiments, the anti- TCR[3 V28 is antibody P, as provided in Table 17. In some embodiments, antibody P comprises one or more (e.g., three) light chain CDRs and / or one or more (e.g., three) heavy chain CDRs provided in Table 17, or a sequence with at least 95% sequence identity thereto. In some embodiments, antibody P comprises a variable heavy chain (VH) and / or a variable light chain (VL) provided in Table 17, or a sequence with at least 95% sequence identity thereto.

[0353] In some embodiments, the anti-TCRp V28 antibody molecule comprises a VH and / or a VL of an antibody described in Table 17, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.

[0354] In some embodiments, the anti-TCRp V28 antibody molecule comprises a VH and a VL of an antibody described in Table 17, or a sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity thereto.Anti-TCRp VI 5 antibodies

[0355] In one aspect, provided herein is an anti-TCRpV antibody molecule that binds to a human TCRp V15 subfamily member. In some embodiments, the TCRP V15 subfamily comprises: TCRP V15*01, TCRP V15*02, or TCRP V15*03, or a variant thereof.Anti-TCRp V7 antibodies

[0356] In one aspect, provided herein is an anti-TCRpV antibody molecule that binds to a human TCRp V7 subfamily member. In some embodiments, the TCRP V7 subfamily comprises: TCRP V7-l*01, TCRP V7-2*01, TCRP V7-2*02, TCRp V2-l*03, TCRp V7-2*04, TCRp V7-3*01, TCRp V7-3*02, TCRP V7-3*03, TCRP V7-3*04, TCRp V7-3*05, TCRp V7-4*01, TCRp V7-4*02, TCRp V7-5*01, TCRP V7-5*02, TCRP V7-6*01, TCRp V7-6*02, TCRp V7-7*01, TCRp V7-7*02, TCRp V7-8*01, TCRP V7-8*02, TCRP V7-8*03, TCRp V7-9*01, TCRp V7-9*02, TCRp V7-9*03, TCRp V7-9*04, TCRP V7-9*05, TCRP V7-9*06, or TCRp V7-9*07, or a variant thereof.WSGR Docket No. 53676-773.601Antibody-like Frameworks or Scaffolds

[0357] A wide variety of antibody / immunoglobulin frameworks or scaffolds can be employed in the anti-TCRvb antibody molecules as described herein or multifunctional formats thereof so long as the resulting polypeptide includes at least one binding region which specifically binds to the target antigen, e.g., a TCRvb, a tumor antigen, among others. Such frameworks or scaffolds include the 5 main idiotypes of human immunoglobulins, or fragments thereof, and include immunoglobulins of other animal species, preferably having humanized aspects. Novel frameworks, scaffolds and fragments continue to be discovered and developed by those skilled in the art.

[0358] In some embodiments, the anti-TCRvb antibody molecules as described herein or multifunctional formats thereof include non-immunoglobulin based antibodies using non- immunoglobulin scaffolds onto which CDRs can be grafted. Any non-immunoglobulin frameworks and scaffolds may be employed, as long as they comprise a binding region specific for the target antigen (e.g., TCRvb or a tumor antigen). Exemplary non-immunoglobulin frameworks or scaffolds include, but are not limited to, fibronectin (Compound Therapeutics, Inc., Waltham, MA), ankyrin (Molecular Partners AG, Zurich, Switzerland), domain antibodies (Domantis, Ltd., Cambridge, MA, and Ablynx nv, Zwijnaarde, Belgium), lipocalin (Pieris Proteolab AG, Freising, Germany), small modular immuno-pharmaceuticals (Trubion Pharmaceuticals Inc., Seattle, WA), maxybodies (Avidia, Inc., Mountain View, CA), Protein A (Affibody AG, Sweden), and affilin (gamma-crystallin or ubiquitin) (Scil Proteins GmbH, Halle, Germany).

[0359] Fibronectin scaffolds are typically based on fibronectin type III domain (e.g., the tenth module of the fibronectin type III (10 Fn3 domain)). The fibronectin type III domain has 7 or 8 beta strands which are distributed between two beta sheets, which themselves pack against each other to form the core of the protein, and further containing loops (analogous to CDRs) which connect the beta strands to each other and are solvent exposed. There are at least three such loops at each edge of the beta sheet sandwich, where the edge is the boundary of the protein perpendicular to the direction of the beta strands (see US 6,818,418). Because of this structure, the non-immunoglobulin antibody mimics antigen binding properties that are similar in nature and affinity to those of antibodies. These scaffolds can be used in a loop randomization and shuffling strategy in vitro that is similar to the process of affinity maturation of antibodies in vivo. These fibronectin-based molecules can be used as scaffolds where the loop regions of the molecule can be replaced with CDRs of the invention using standard cloning techniques.

[0360] The ankyrin technology is based on using proteins with ankyrin derived repeat modules as scaffolds for bearing variable regions which can be used for binding to different targets. The ankyrin repeat module typically is a about 33 amino acid polypeptide consisting of two anti -parallel a-helices and a P-tum. Binding of the variable regions can be optimized by using ribosome display.

[0361] Avimers are used by nature for protein-protein interactions and in human over 250 proteins are structurally based on A-domains. Avimers consist of a number of different “A-domain” monomers (2-10) linked via amino acid linkers. Avimers can be created that can bind to the target antigen using theWSGR Docket No. 53676-773.601 methodology described in, for example, U.S. Patent Application Publication Nos. 20040175756; 20050053973; 20050048512; and 20060008844.

[0362] Affibody affinity ligands are small, simple proteins composed of a three-helix bundle based on the scaffold of one of the IgG-binding domains of Protein A. Protein A is a surface protein from the bacterium Staphylococcus aureus. This scaffold domain consists of 58 amino acids, 13 of which are randomized to generate affibody libraries with a large number of ligand variants (See e.g., US 5,831,012). Affibody molecules mimic antibodies, they have a molecular weight of 6 kDa, compared to the molecular weight of antibodies, which is 150 kDa. In spite of its small size, the binding site of affibody molecules is similar to that of an antibody.

[0363] Anticalins are known commercially, e.g., Pieris ProteoUab AG. They are derived from lipocalins, a widespread group of small and robust proteins that are usually involved in the physiological transport or storage of chemically sensitive or insoluble compounds. Several natural lipocalins occur in human tissues or body liquids. The protein architecture is reminiscent of immunoglobulins, with hypervariable loops on top of a rigid framework. However, in contrast with antibodies or their recombinant fragments, lipocalins are composed of a single polypeptide chain with 160 to 180 amino acid residues, being just marginally bigger than a single immunoglobulin domain. The set of four loops, which makes up the binding pocket, shows pronounced structural plasticity and tolerates a variety of side chains. The binding site can thus be reshaped in a proprietary process in order to recognize prescribed target molecules of different shape with high affinity and specificity. One protein of lipocalin family, the bilin-binding protein (BBP) of Pieris Brassicae has been used to develop anticalins by mutagenizing the set of four loops. One example of a patent application describing anticalins is in PCT Publication No. WO 199916873.

[0364] Affilin molecules are small non-immunoglobulin proteins which are designed for specific affinities towards proteins and small molecules. New affilin molecules can be very quickly selected from two libraries, each of which is based on a different human derived scaffold protein. Affilin molecules do not show any structural homology to immunoglobulin proteins. Currently, two affilin scaffolds are employed, one of which is gamma crystalline, a human structural eye lens protein and the other is “ubiquitin” superfamily proteins. Both human scaffolds are very small, show high temperature stability and are almost resistant to pH changes and denaturing agents. This high stability is mainly due to the expanded beta sheet structure of the proteins. Examples of gamma crystalline derived proteins are described in W0200104144 and examples of “ubiquitin-like” proteins are described in W02004106368.

[0365] Protein epitope mimetics (PEM) are medium-sized, cyclic, peptide-like molecules (MW l-2kDa) mimicking beta-hairpin secondary structures of proteins, the major secondary structure involved in protein-protein interactions.

[0366] Domain antibodies (dAbs) can be used in the anti-TCRvb antibody molecules as described herein or multifunctional formats thereof are small functional binding fragments of antibodies, corresponding to the variable regions of either the heavy or light chains of antibodies. Domain antibodies are well expressed in bacterial, yeast, and mammalian cell systems. Further details of domain antibodies andWSGR Docket No. 53676-773.601 methods of production thereof are known in the art (see, for example, U.S. Pat. Nos. 6,291,158; 6,582,915; 6,593,081; 6,172,197; 6,696,245; European Patents 0368684 & 0616640; WO05 / 035572, W004 / 101790, W004 / 081026, W004 / 058821, W004 / 003019 and W003 / 002609. Nanobodies are derived from the heavy chains of an antibody.

[0367] A nanobody typically comprises a single variable domain and two constant domains (CH2 and CH3) and retains antigen-binding capacity of the original antibody. Nanobodies can be prepared by methods known in the art (See e.g., U.S. Pat. No. 6,765,087, U.S. Pat. No. 6,838,254, WO 06 / 079372). Unibodies consist of one light chain and one heavy chain of an IgG4 antibody. Unibodies may be made by the removal of the hinge region of IgG4 antibodies. Further details of unibodies and methods of preparing them may be found in W02007 / 059782.Anti-TCRVP antibody effector function and Fc variants

[0368] In some embodiments, an anti-TCRVP antibody as described herein comprises an Fc region, e.g., as described herein. In some embodiments, the Fc region is a wildtype Fc region, e.g., a wildtype human Fc region. In some embodiments, the Fc region comprises a variant, e.g., an Fc region comprising an addition, substitution, or deletion of at least one amino acid residue in the Fc region which results in, e.g., reduced or ablated affinity for at least one Fc receptor.

[0369] The Fc region of an antibody interacts with a number of receptors or ligands including Fc Receptors (e.g., FcyRI, FcyRIIA, FcyRIIIA), the complement protein Clq, and other molecules such as proteins A and G. These interactions are essential for a variety of effector functions and downstream signaling events including: antibody dependent cell-mediated cytotoxicity (ADCC), Antibody-dependent cellular phagocytosis (ADCP) and complement dependent cytotoxicity (CDC).

[0370] In some embodiments, an anti-TCRVP antibody comprising a variant Fc region has reduced, e.g., ablated, affinity for an Fc receptor, e.g., an Fc receptor described herein. In some embodiments, the reduced affinity is compared to an otherwise similar antibody with a wildtype Fc region.

[0371] In some embodiments, an anti-TCRVP antibody comprising a variant Fc region has one or more of the following properties: (1) reduced effector function (e.g., reduced ADCC, ADCP and / or CDC); (2) reduced binding to one or more Fc receptors; and / or (3) reduced binding to Clq complement. In some embodiments, the reduction in any one, or all of properties (l)-(3) is compared to an otherwise similar antibody with a wildtype Fc region.

[0372] In some embodiments, an anti-TCRVP antibody comprising a variant Fc region has reduced affinity to a human Fc receptor, e.g., FcyR I, FcyR II and / or FcyR III. In some embodiments, the anti- TCRVP antibody comprising a variant Fc region comprises a human IgGl region or a human IgG4 region.

[0373] In some embodiments, an anti-TCRVP antibody comprising a variant Fc region activates and / or expands T cells, e.g., as described herein. In some embodiments, an anti-TCRVP antibody comprising a variant Fc region has a cytokine profile described herein, e.g., a cytokine profile that differs from a cytokine profile of a T cell engager that binds to a receptor or molecule other than a TCRJ3V region (“aWSGR Docket No. 53676-773.601 non-TCRpV-binding T cell engager”). In some embodiments, 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.

[0374] Exemplary Fc region variants are provided in Table 14 and also disclosed in Saunders O, (2019) Frontiers in Immunology; vol 10, article 1296, the entire contents of which is hereby incorporated by reference.

[0375] In some embodiments, an anti-TCRVP antibody as described herein comprises any one or all, or any combination of Fc region variants disclosed in Table 14.

[0376] In some embodiments, an anti-TCRVP antibody as described herein comprises any one or all, or any combination of Fc region variants, e.g., mutations, disclosed in Table 14. In some embodiments, an anti-TCRVP antibody as described herein comprise an Asn297Ala (N297A) mutation. In some embodiments, an anti-TCRVP antibody as described herein comprise a Leu234Ala / Leu235Ala (LALA) mutation.Multifunctional Molecules

[0377] As used herein, 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. In some embodiments, 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. In some embodiments, the multispecific molecule is a multispecific antibody molecule, e.g., a bispecific antibody molecule. In some embodiments, the multispecific molecule includes an anti- TCRVb antibody molecule as described herein.

[0378] Described herein, in certain embodiments, is a multifunctional polypeptide molecule comprising a first polypeptide, a second polypeptide, a third polypeptide, a fourth polypeptide, and at least one cytokine polypeptide or a functional fragment or a functional variant thereof, wherein the first polypeptide, the second polypeptide, the third polypeptide, and the fourth polypeptide are noncontiguous, wherein: (i) the first polypeptide comprising a first portion of a first T cell receptor variable beta (TCR[3V)-binding moiety and a first dimerization module linked to the first portion of the first TCRpV-binding moiety; (ii) the second polypeptide comprising a second portion of the first TCRJ3V- binding moiety; (iii) the third polypeptide comprising a first portion of a second TCRpV-binding moiety and a second dimerization module linked to the first portion of the second TCRpV-binding moiety; and (iv) the fourth polypeptide comprising a second portion of the second TCRpV-binding moiety; and wherein the at least one cytokine polypeptide or a functional fragment or a functional variant thereof is covalently linked to the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or a combination thereof.

[0379] Described herein, in certain embodiments, is a multifunctional polypeptide molecule comprising a first polypeptide, a second polypeptide, a third polypeptide, and at least one cytokine polypeptide or a functional fragment or a functional variant thereof, wherein the first polypeptide, the second polypeptide,WSGR Docket No. 53676-773.601 and the third polypeptide are non-contiguous, wherein: (i) the first polypeptide comprising a first portion of a first TCRpV-binding moiety and a first dimerization module linked to the first portion of the first TCRpV-binding moiety; (ii) the second polypeptide comprising a second portion of the first TCRJ3V- binding moiety; and (iii) the third polypeptide comprising a second dimerization module; and wherein the at least one cytokine polypeptide or a functional fragment or a functional variant thereof is covalently linked to the first polypeptide, the second polypeptide, the third polypeptide, or a combination thereof.

[0380] Described herein, in certain embodiments, is a multifunctional polypeptide molecule comprising a first polypeptide, a second polypeptide, a third polypeptide, and at least one cytokine polypeptide or a functional fragment or a functional variant thereof, wherein the first polypeptide, the second polypeptide, and the third polypeptide are non-contiguous, wherein: (i) the first polypeptide comprising a first portion of a first TCR[3V-binding moiety and a first dimerization module linked to the first portion of the first TCRpV-binding moiety; (ii) the second polypeptide comprising a second portion of the first TCRJ3V- binding moiety; and (iii) the third polypeptide comprising a second dimerization module; wherein the at least one cytokine polypeptide or a functional fragment or a functional variant thereof is covalently linked to the first polypeptide, the second polypeptide, the third polypeptide, or a combination thereof; and wherein the multifunctional polypeptide molecule does not comprise an additional TCRpV-binding moiety except the first TCR[3V-binding moiety.

[0381] In some embodiments, the first portion of the first TCRpV-binding moiety comprises a first heavy chain variable domain (VH) and a first heavy chain constant domain 1 (CHI) linked to the first VH. In some embodiments, the first CHI is linked to the C-terminus of the first VH. In some embodiments, the second portion of the first TCRpV-binding moiety comprises a first light chain variable domain (VL) and a first light chain constant domain (CL) linked to the first VL. In some embodiments, first CL is linked to the C-terminus of the first VL. In some embodiments, wherein the first dimerization module is linked to the first portion of the first TCRpV-binding moiety. In some embodiments, the first dimerization module is linked to the C-terminus of the first portion of the first TCRpV-binding moiety. In some embodiments, wherein the first portion of the second TCRpV-binding moiety comprises a second VH and a second CHI linked to the second VH. In some embodiments, the second CHI is linked to the C-terminus of the second VH. In some embodiments, the second portion of the second TCRpV-binding moiety comprises a second VL and a second CL linked to the second VL. In some embodiments, the second CL is linked to the C-terminus of the second VL. In some embodiments, the second dimerization module is linked to the first portion of the second TCRpV-binding moiety. In some embodiments, the second dimerization module is linked to the C-terminus of the first portion of the second TCRpV-binding moiety.

[0382] In some embodiments, (a) the N-terminus of the first polypeptide is linked to a first cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to a second cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (b) the N-terminus of the second polypeptide is linked to a third cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to a fourth cytokine polypeptide or a functional fragment or a functionalWSGR Docket No. 53676-773.601 variant thereof; or a combination thereof; (c) the N-terminus of the third polypeptide is linked to a fifth cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the third polypeptide is linked to a sixth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (d) the N-terminus of the fourth polypeptide is linked to a seventh cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the fourth polypeptide is linked to an eighth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; or (e) a combination thereof.

[0383] In some embodiments, (a-1) the N-terminus of the first polypeptide is linked to the first cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to the second cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (a-2) the N-terminus of the second polypeptide is linked to the third cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to the fourth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (b-1) the N-terminus of the first polypeptide is linked to the first cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to the second cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (b-2) the N-terminus of the third polypeptide is linked to the fifth cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the third polypeptide is linked to the sixth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (c-1) the N-terminus of the first polypeptide is linked to the first cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to the second cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (c-2) the N-terminus of the fourth polypeptide is linked to the seventh cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the fourth polypeptide is linked to the eighth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (d-1) the N-terminus of the second polypeptide is linked to the third cytokine polypeptide or a functional fragment or a functional variant thereof; the C- terminus of the second polypeptide is linked to the fourth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (d-2) the N-terminus of the third polypeptide is linked to the fifth cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the third polypeptide is linked to the sixth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (e-1) the N-terminus of the second polypeptide is linked to the third cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to the fourth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (e-2) the N-terminus of the fourth polypeptide is linked to the seventh cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the fourth polypeptide is linked to the eighth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; or (f-1) theWSGR Docket No. 53676-773.601N-terminus of the third polypeptide is linked to the fifth cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the third polypeptide is linked to the sixth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (f-2) the N-terminus of the fourth polypeptide is linked to the seventh cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the fourth polypeptide is linked to the eighth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof.

[0384] In some embodiments, (a-1) the N-terminus of the first polypeptide is linked to the first cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to the second cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (a-2) the N-terminus of the second polypeptide is linked to the third cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to the fourth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (a-3) the N-terminus of the third polypeptide is linked to the fifth cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the third polypeptide is linked to the sixth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (b-1) the N-terminus of the first polypeptide is linked to the first cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to the second cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (b-2) the N-terminus of the second polypeptide is linked to the third cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to the fourth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (b-3) the N-terminus of the fourth polypeptide is linked to the seventh cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the fourth polypeptide is linked to the eighth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; or (c-1) the N-terminus of the second polypeptide is linked to the third cytokine polypeptide or a functional fragment or a functional variant thereof; the C- terminus of the second polypeptide is linked to the fourth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (c-2) the N-terminus of the third polypeptide is linked to the fifth cytokine polypeptide or a functional fragment or a functional variant thereof; the C- terminus of the third polypeptide is linked to the sixth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (c-3) the N-terminus of the fourth polypeptide is linked to the seventh cytokine polypeptide or a functional fragment or a functional variant thereof; the C- terminus of the fourth polypeptide is linked to the eighth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof.

[0385] In some embodiments, (1) the N-terminus of the first polypeptide is linked to the first cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to the second cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (2) the N-terminus of the second polypeptide is linked to the thirdWSGR Docket No. 53676-773.601 cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to the fourth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (3) the N-terminus of the third polypeptide is linked to the fifth cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the third polypeptide is linked to the sixth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (4) the N-terminus of the fourth polypeptide is linked to the seventh cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the fourth polypeptide is linked to the eighth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof.

[0386] In some embodiments, the first cytokine polypeptide, the second cytokine polypeptide, or a combination thereof is within a single contiguous polypeptide chain of the first polypeptide, the third cytokine polypeptide, the fourth cytokine polypeptide, or a combination thereof is within a single contiguous polypeptide chain of the second polypeptide, the fifth cytokine polypeptide, the sixth cytokine polypeptide, or a combination thereof is within a single contiguous polypeptide chain of the third polypeptide, the seventh cytokine polypeptide, the eighth cytokine polypeptide, or a combination thereof is within a single contiguous polypeptide chain of the fourth polypeptide, or a combination thereof.

[0387] In some embodiments, (a) the N-terminus of the first polypeptide is linked to a first cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to a second cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (b) the N-terminus of the second polypeptide is linked to a third cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to a fourth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (c) the N-terminus of the third polypeptide is linked to a fifth cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the third polypeptide is linked to a sixth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; or (d) a combination thereof.

[0388] In some embodiments, (a-1) the N-terminus of the first polypeptide is linked to the first cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to the second cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (a-2) the N-terminus of the second polypeptide is linked to the third cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to the fourth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (b-1) the N-terminus of the first polypeptide is linked to the first cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to the second cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (b-2) the N-terminus of the third polypeptide is linked to the fifth cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the third polypeptide is linked to the sixth cytokine polypeptide or a functional fragment or a functionalWSGR Docket No. 53676-773.601 variant thereof; or a combination thereof; or (c-1) the N-terminus of the second polypeptide is linked to the third cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to the fourth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (c-2) the N-terminus of the third polypeptide is linked to the fifth cytokine polypeptide or a functional fragment or a functional variant thereof; the C- terminus of the third polypeptide is linked to the sixth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof.

[0389] In some embodiments, (1) the N-terminus of the first polypeptide is linked to the first cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to the second cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (2) the N-terminus of the second polypeptide is linked to the third cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to the fourth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; and (3) the N-terminus of the third polypeptide is linked to the fifth cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the third polypeptide is linked to the sixth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof.

[0390] In some embodiments, the first cytokine polypeptide, the second cytokine polypeptide, or a combination thereof is within a single contiguous polypeptide chain of the first polypeptide, the third cytokine polypeptide, the fourth cytokine polypeptide, or a combination thereof is within a single contiguous polypeptide chain of the second polypeptide, the fifth cytokine polypeptide, the sixth cytokine polypeptide, or a combination thereof is within a single contiguous polypeptide chain of the third polypeptide, or a combination thereof.

[0391] In some embodiments, the multifunctional polypeptide molecule as described herein further comprises a linker between the first portion of the first TCR[3V-binding moiety and the first dimerization module, a linker between the first portion of the second TCRpV-binding moiety and the second dimerization module, a linker between the first VH and the first CHI, a linker between the first VL and the first CL, a linker between the second VH and the second CHI, a linker between the second VL and the second CL, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the first polypeptide, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the second polypeptide, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the third polypeptide, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the fourth polypeptide, or a combination thereof.

[0392] In some embodiments, the multifunctional polypeptide molecule as described herein further comprises comprising a linker between the first portion of the first TCR[3V-binding moiety and the first dimerization module, a linker between the first VH and the first CHI, a linker between the first VL and the first CL, a linker between the at least one cytokine polypeptide or a functional fragment or aWSGR Docket No. 53676-773.601 functional variant thereof and the first polypeptide, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the second polypeptide, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the third polypeptide, or a combination thereof. In some embodiments, linker is selected from the group consisting of a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, and a non-helical linker. In some embodiments, the linker is the peptide linker and wherein the linker is a GS linker. In some embodiments, the linker is the peptide linker and wherein the linker comprises the sequence of SEQ ID NO: 3308 or SEQ ID NO: 3643.

[0393] Described herein, in certain embodiments, is a multifunctional polypeptide molecule comprising a first polypeptide, a second polypeptide, a third polypeptide, a fourth polypeptide, a first cytokine polypeptide or a functional fragment or a functional variant thereof, and a second cytokine polypeptide or a functional fragment or a functional variant thereof, wherein the first polypeptide, the second polypeptide, the third polypeptide, and the fourth polypeptide are non-contiguous, wherein: (i) the first polypeptide comprising a first portion of a first TCR[3V-binding moiety and a first dimerization module linked to the first portion of the first TCRpV-binding moiety; (ii) the second polypeptide comprising a second portion of the first TCRpV-binding moiety; (iii) the third polypeptide comprising a first portion of a second TCRpV-binding moiety and a second dimerization module linked to the first portion of the second TCRpV-binding moiety; and (iv) the fourth polypeptide comprising a second portion of the second TCRpV-binding moiety; and wherein the first cytokine polypeptide or a functional fragment or a functional variant thereof is covalently linked to the C-terminus of the second polypeptide, and the second cytokine polypeptide or a functional fragment or a functional variant thereof is covalently linked to the C-terminus of the fourth polypeptide.

[0394] Described herein, in certain embodiments, is a multifunctional polypeptide molecule comprising a first polypeptide, a second polypeptide, a third polypeptide, a fourth polypeptide, a cytokine polypeptide or a functional fragment or a functional variant thereof, wherein the first polypeptide, the second polypeptide, the third polypeptide, and the fourth polypeptide are non-contiguous, wherein: (i) the first polypeptide comprising a first portion of a first TCR[3V-binding moiety and a first dimerization module linked to the first portion of the first TCRpV-binding moiety; (ii) the second polypeptide comprising a second portion of the first TCRpV-binding moiety; (iii) the third polypeptide comprising a first portion of a second TCRpV-binding moiety and a second dimerization module linked to the first portion of the second TCRpV-binding moiety; and (iv) the fourth polypeptide comprising a second portion of the second TCRpV-binding moiety; and wherein the cytokine polypeptide or a functional fragment or a functional variant thereof is covalently linked to the C-terminus of the second polypeptide or the C- terminus of the fourth polypeptide.

[0395] Described herein, in certain embodiments, is a multifunctional polypeptide molecule comprising a first polypeptide, a second polypeptide, a third polypeptide, a fourth polypeptide, a cytokine polypeptide or a functional fragment or a functional variant thereof, wherein the first polypeptide, the second polypeptide, the third polypeptide, and the fourth polypeptide are non-contiguous, wherein: (i) the firstWSGR Docket No. 53676-773.601 polypeptide comprising a first portion of a first TCRpV-binding moiety and a first dimerization module linked to the first portion of the first TCRpV-binding moiety; (ii) the second polypeptide comprising a second portion of the first TCRpV-binding moiety; (iii) the third polypeptide comprising a first portion of a second TCRpV-binding moiety and a second dimerization module linked to the first portion of the second TCRpV-binding moiety; and (iv) the fourth polypeptide comprising a second portion of the second TCRpV-binding moiety; and wherein the cytokine polypeptide or a functional fragment or a functional variant thereof is covalently linked to the C-terminus of the first polypeptide or the C-terminus of the third polypeptide.

[0396] Described herein, in certain embodiments, is a multifunctional polypeptide molecule comprising a first polypeptide, a second polypeptide, a third polypeptide, and a cytokine polypeptide or a functional fragment or a functional variant thereof, wherein the first polypeptide, the second polypeptide, and the third polypeptide are non-contiguous, wherein: (i) the first polypeptide comprising a first portion of a first TCR[3V-binding moiety and a first dimerization module linked to the first portion of the first TCRpV-binding moiety; (ii) the second polypeptide comprising a second portion of the first TCRpV- binding moiety; and (iii) the third polypeptide comprising a second dimerization module; wherein the at least one cytokine polypeptide or a functional fragment or a functional variant thereof is covalently linked to the N terminus of the third polypeptide; and wherein the multifunctional polypeptide molecule does not comprise an additional TCRpV-binding moiety except the first TCRpV-binding moiety.

[0397] In some embodiments, the first portion of the first TCRpV-binding moiety comprises a first VH and a first CHI linked to the first VH. In some embodiments, the first CHI is linked to the C-terminus of the first VH.

[0398] In some embodiments, the second portion of the first TCRpV-binding moiety comprises a first VL and a first CL linked to the first VL. In some embodiments, first CL is linked to the C-terminus of the first VL.

[0399] In some embodiments, the first dimerization module is linked to the first portion of the first TCRpV-binding moiety. In some embodiments, the first dimerization module is linked to the C-terminus of the first portion of the first TCRpV-binding moiety. In some embodiments, the first portion of the second TCRpV-binding moiety comprises a second VH and a second CHI linked to the second VH. In some embodiments, the second CHI is linked to the C-terminus of the second VH. In some embodiments, the second portion of the second TCRpV-binding moiety comprises a second VL and a second CL linked to the second VL. In some embodiments, the second CL is linked to the C-terminus of the second VL. In some embodiments, the second dimerization module is linked to the first portion of the second TCRpV-binding moiety. In some embodiments, the second dimerization module is linked to the C-terminus of the first portion of the second TCRpV-binding moiety.

[0400] In some embodiments, the multifunctional polypeptide molecule as described herein further comprises a linker between the first portion of the first TCRpV-binding moiety and the first dimerization module, a linker between the first portion of the second TCRpV-binding moiety and the second dimerization module, a linker between the first VH and the first CHI, a linker between the first VL andWSGR Docket No. 53676-773.601 the first CL, a linker between the second VH and the second CHI, a linker between the second VL and the second CL, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the first polypeptide, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the second polypeptide, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the third polypeptide, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the fourth polypeptide, or a combination thereof. In some embodiments, the multifunctional polypeptide molecule as described herein further comprises a linker between the first portion of the first TCRpV-binding moiety and the first dimerization module, a linker between the first VH and the first CHI, a linker between the first VL and the first CL, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the third polypeptide, or a combination thereof. In some embodiments, linker is selected from the group consisting of a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, and a nonhelical linker. In some embodiments, the linker is the peptide linker and wherein the linker is a GS linker. In some embodiments, the linker is the peptide linker and wherein the linker comprises the sequence of SEQ ID NO: 3308 or SEQ ID NO: 3643.

[0401] In some embodiments, the first TCRpV-binding moiety, the second TCRpV-binding moiety, or a combination thereof comprises any one selected from the group consisting of a Fab, F(ab')2, Fv, a single chain Fv (scFv), a single domain antibody, a diabody (dAb), a camelid antibody and a combination thereof. In some embodiments, the first TCRpV-binding moiety, the second TCRpV-binding moiety, or a combination thereof comprises a scFv or a Fab.

[0402] In some embodiments, the multifunctional polypeptide molecule does not comprise an additional antigen-binding moiety except the TCRpV-binding moiety. In some embodiments, the multifunctional polypeptide molecule further comprise an additional antigen-binding moiety that is not the TCRpV- binding moiety.

[0403] Described herein, in certain embodiments, is a multifunctional polypeptide molecule comprising a first polypeptide, a second polypeptide, and at least one cytokine polypeptide or a functional fragment or a functional variant thereof, wherein the first polypeptide and the second polypeptide are non-contiguous, wherein: (i) the first polypeptide comprising a first TCRpV-binding moiety and a first dimerization module linked to the C-terminus of the first TCRpV-binding moiety, wherein the first TCRpV-binding moiety comprises a first VL and a first VH; and (ii) the second polypeptide comprising a second TCRpV- binding moiety and a second dimerization module linked to the C-terminus of the second TCRpV- binding moiety; wherein the at least one cytokine polypeptide or a functional fragment or a functional variant thereof is covalently linked to the first polypeptide, the second polypeptide, or a combination thereof; wherein the first TCRpV-binding moiety, the second TCRpV-binding moiety, or a combination thereof comprises a scFv; and wherein the multifunctional polypeptide molecule does not comprise an additional antigen-binding moiety except the first TCRpV-binding moiety and the second TCRpV- binding moiety.WSGR Docket No. 53676-773.601

[0404] Described herein, in certain embodiments, is a multifunctional polypeptide molecule comprising a first polypeptide, a second polypeptide, and at least one cytokine polypeptide or a functional fragment or a functional variant thereof, wherein the first polypeptide and the second polypeptide are non-contiguous, wherein: (i) the first polypeptide comprising a first TCR[3V-binding moiety and a first dimerization module linked to the C-terminus of the first TCRpV-binding moiety, wherein the first TCRpV-binding moiety comprises a first VL and a first VH; and (ii) the second polypeptide comprising a second dimerization module; wherein the at least one cytokine polypeptide or a functional fragment or a functional variant thereof is covalently linked to the first polypeptide, the second polypeptide, or a combination thereof; wherein the first TCRpV-binding moiety comprises a scFv; wherein the multifunctional polypeptide molecule does not comprise an additional antigen-binding moiety except the first TCRpV-binding moiety; and wherein the multifunctional polypeptide molecule does not comprise an additional TCRpV-binding moiety except the first TCRpV-binding moiety.

[0405] In some embodiments, (a) the N-terminus of the first polypeptide is linked to a first cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the first polypeptide is linked to a second cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; (b) the N-terminus of the second polypeptide is linked to a third cytokine polypeptide or a functional fragment or a functional variant thereof; the C-terminus of the second polypeptide is linked to a fourth cytokine polypeptide or a functional fragment or a functional variant thereof; or a combination thereof; or (e) a combination thereof.

[0406] In some embodiments, the first cytokine polypeptide, the second cytokine polypeptide, or a combination thereof is within a single contiguous polypeptide chain of the first polypeptide, the third cytokine polypeptide, the fourth cytokine polypeptide, or a combination thereof is within a single contiguous polypeptide chain of the second polypeptide, or a combination thereof.

[0407] In some embodiments, the multifunctional polypeptide molecule as described herein further comprises a linker between the first TCR[3V-binding moiety and the first dimerization module, a linker between the second TCRpV-binding moiety and the second dimerization module, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the first polypeptide, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the second polypeptide, or a combination thereof.

[0408] In some embodiments, the multifunctional polypeptide molecule as described herein further comprises a linker between the first TCRpV-binding moiety and the first dimerization module, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the first polypeptide, a linker between the at least one cytokine polypeptide or a functional fragment or a functional variant thereof and the second polypeptide, or a combination thereof. In some embodiments, the linker is selected from the group consisting of a cleavable linker, a non-cleavable linker, a peptide linker, a flexible linker, a rigid linker, a helical linker, and a non-helical linker. In some embodiments, the linker is the peptide linker and wherein the linker is a GS linker. In some embodiments, the linker is the peptide linker and wherein the linker comprises the sequence of SEQ ID NO: 3308 or SEQ ID NO: 3643.WSGR Docket No. 53676-773.601

[0409] In some embodiments, the multifunctional polypeptide molecule comprises at least two of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises at least three of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises at least four of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises at least five of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises at least six of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises at least seven of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises at least eight of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises two of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises three of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises four of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises five of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises six of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises seven of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises eight of the cytokine polypeptide. In some embodiments, the multifunctional polypeptide molecule comprises two of the cytokine polypeptide, each of which is linked to the first polypeptide and the second polypeptide; the first polypeptide and the third polypeptide;, the first polypeptide and the fourth polypeptide; the second and the third polypeptide; the second polypeptide and the fourth polypeptide; or the third polypeptide and the fourth polypeptide, respectively. In some embodiments, the multifunctional polypeptide molecule comprises three of the cytokine polypeptide, each of which is linked to the first polypeptide, the second polypeptide, and the third polypeptide; the first polypeptide, the second polypeptide, and the fourth polypeptide; the first polypeptide, the third polypeptide, and the fourth polypeptide; or the second polypeptide, the third polypeptide, and the fourth polypeptide, respectively. In some embodiments, the multifunctional polypeptide molecule comprises four of the cytokine polypeptide, each of which is linked to the first polypeptide, the second polypeptide, the third polypeptide, and the fourth polypeptide, respectively. In some embodiments, the cytokine polypeptide is not linked to the polypeptides that comprise the first TCR[3V-binding moiety.

[0410] In some embodiments, , the at least one cytokine polypeptide is selected from the group consisting of interleukin-2 (IL-2) or a fragment or a functional fragment or a functional variant thereof, interleukin-7 (IL-7) or a fragment or a functional fragment or a functional variant thereof, interleukin- 12 (IL-12) or a fragment or a functional fragment or a functional variant thereof, interleukin- 15 (IL-15) or a fragment or a functional fragment or a functional variant thereof, interleukin- 18 (IL- 18) or a fragment or a functional fragment or a functional variant thereof, interleukin-21 (IL-21) or a fragment or a functional fragment or a functional variant thereof, or interferon gamma or a fragment or a functional fragment or a functional variant thereof, or a combination thereof.WSGR Docket No. 53676-773.601

[0411] In some embodiments, the at least one cytokine polypeptide comprises interieukin-2 (IL-2) or a fragment thereof. In some embodiments, the at least one cytokine polypeptide is interleukin-2 (IL-2) or a fragment thereof. In some embodiments, the at least one cytokine polypeptide comprises a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the sequence of SEQ ID NO: 2191. In some embodiments, the at least one cytokine polypeptide comprises the sequence of SEQ ID NO: 2191. In some embodiments, the sequence of the at least one cytokine polypeptide is a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the sequence of SEQ ID NO: 2191. In some embodiments, the sequence of the at least one cytokine polypeptide is the sequence of SEQ ID NO: 2191.

[0412] In some embodiments, the variant of the at least one cytokine polypeptide comprises an IL-2 variant comprising a mutation. In some embodiments, the mutation comprises an insertion mutation, a deletion mutation, or a substitution mutation. In some embodiments, the mutation comprises the substitution mutation. In some embodiments, the variant comprises an IL-2 variant comprising C125A mutation. In some embodiments, the variant of the at least one cytokine polypeptide is an IL-2 variant comprising a mutation. In some embodiments, the mutation is an insertion mutation, a deletion mutation, or a substitution mutation. In some embodiments, the mutation is the substitution mutation. In some embodiments, the variant is an IL-2 variant comprising C125A mutation. In some embodiments, the variant comprises a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the sequence of SEQ ID NO: 2270. In some embodiments, the variant comprises the sequence of SEQ ID NO: 2270. In some embodiments, the sequence of the variant is a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the sequence of SEQ ID NO: 2270. In some embodiments, the sequence of the variant is the sequence of SEQ ID NO: 2270.

[0413] In some embodiments, the first dimerization module comprises a first immunoglobulin constant regions (Fc regions) and the second dimerization module comprises a second Fc region. In some embodiments, the first dimerization module is a first immunoglobulin constant regions (Fc regions) and the second dimerization module is a second Fc region.

[0414] In some embodiments, the first Fc region, the second Fc region, or a combination thereof is selected from an IgGl Fc region or a fragment thereof, an IgG2 Fc region or a fragment thereof, an IgG3 Fc region or a fragment thereof, an IgGAl Fc region or a fragment thereof, an IgGA2 Fc region or a fragment thereof, an IgG4 Fc region or a fragment thereof, an IgJ Fc region or a fragment thereof, an IgM Fc region or a fragment thereof, an IgD Fc region or a fragment thereof, and an IgE Fc region or a fragment thereof.

[0415] In some embodiments, the first Fc region, the second Fc region, or a combination thereof is selected from a human IgGl Fc region or a fragment thereof, a human IgG2 Fc region or a fragment thereof, and a human IgG4 Fc region or a fragment thereof.

[0416] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises an Fc interface with one or more of: a paired cavity-protuberance, an electrostatic interaction,WSGR Docket No. 53676-773.601 or a strand-exchange, wherein the dimerization of the first Fc region and the second Fc region is enhanced as indicated by a greater ratio of heteromultimer: homomultimer forms relative to a dimerization of Fc regions with a non-engineered interface. In some embodiments, the dimerization of the first Fc region and the second Fc region is enhanced at least by 1.1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 1.6 fold, 1.7 fold, 1.8 fold, 1.9 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 25 fold, 30 fold, 35 fold, 40 fold, 45 fold, 50 fold, 55 fold, 60 fold, 65 fold, 70 fold, 75 fold, 80 fold, 85 fold, 90 fold, 95 fold, 100 fold, 150 fold, 200 fold, 250 fold, 300 fold, 250 fold, 400 fold, 450 fold, 500 fold, 550 fold, 600 fold, 650 fold, 700 fold, 750 fold, 800 fold, 850 fold, 900 fold, 950 fold, 1000 fold, 2000 fold, 3000 fold, 4000 fold, 5000 fold, 6000 fold, 7000 fold, 8000 fold, 9000 fold, or 10000 fold relative to a dimerization of Fc regions with a non-engineered interface. In some embodiments, the dimerization of the first Fc region and the second Fc region is enhanced at most by 1.1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 1.6 fold, 1.7 fold, 1.8 fold, 1.9 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 25 fold, 30 fold, 35 fold, 40 fold, 45 fold, 50 fold, 55 fold, 60 fold, 65 fold, 70 fold, 75 fold, 80 fold, 85 fold, 90 fold, 95 fold, 100 fold, 150 fold, 200 fold, 250 fold, 300 fold, 250 fold, 400 fold, 450 fold, 500 fold, 550 fold, 600 fold, 650 fold, 700 fold, 750 fold, 800 fold, 850 fold, 900 fold, 950 fold, 1000 fold, 2000 fold, 3000 fold, 4000 fold, 5000 fold, 6000 fold, 7000 fold, 8000 fold, 9000 fold, or 10000 fold relative to a dimerization of Fc regions with a nonengineered interface. In some embodiments, the dimerization of the first Fc region and the second Fc region is enhanced by 1.1 fold, 1.2 fold, 1.3 fold, 1.4 fold, 1.5 fold, 1.6 fold, 1.7 fold, 1.8 fold, 1.9 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 25 fold, 30 fold, 35 fold, 40 fold, 45 fold, 50 fold, 55 fold, 60 fold, 65 fold, 70 fold, 75 fold, 80 fold, 85 fold, 90 fold, 95 fold, 100 fold, 150 fold, 200 fold, 250 fold, 300 fold, 250 fold, 400 fold, 450 fold, 500 fold, 550 fold, 600 fold, 650 fold, 700 fold, 750 fold, 800 fold, 850 fold, 900 fold, 950 fold, 1000 fold, 2000 fold, 3000 fold, 4000 fold, 5000 fold, 6000 fold, 7000 fold, 8000 fold, 9000 fold, or 10000 fold relative to a dimerization of Fc regions with a non-engineered interface.

[0417] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises an amino acid substitution listed in Table 14.

[0418] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises an Asn297Ala (N297A) mutation or a Leu234Ala / Leu235Ala (LALA) mutation.

[0419] In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the sequence of SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 3645, SEQ ID NO: 3646, SEQ ID NO: 3647, SEQ ID NO:3648, SEQ ID NO: 3452, or SEQ ID NO: 3649. In some embodiments, the first Fc region, the second Fc region, or a combination thereof comprises the sequence of SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 3645, SEQ ID NO: 3646, SEQ ID NO: 3647, SEQ ID NO:3648, SEQ ID NO: 3452, or SEQ ID NO: 3649.

[0420] In some embodiments, the sequence of the first Fc region, the second Fc region, or a combination thereof is a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequenceWSGR Docket No. 53676-773.601 identity to the sequence of SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 3645, SEQ ID NO: 3646, SEQ ID NO: 3647, SEQ ID NO:3648, SEQ ID NO: 3452, or SEQ ID NO: 3649. In some embodiments, the sequence of the first Fc region, the second Fc region, or a combination thereof is the sequence of SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 3645, SEQ ID NO: 3646, SEQ ID NO: 3647, SEQ ID NO:3648, SEQ ID NO: 3452, or SEQ ID NO: 3649.

[0421] In some embodiments, the first TCRpV-binding moiety, the second TCRpV-binding moiety, or a combination thereof binds to one or more of a TCRpV subfamily selected from the group consisting of: (i) TCRP V2 subfamily comprising TCRP V2*0I; (ii) TCRP V3 subfamily comprising TCRP V3-I*0I; (iii) TCRP V4 subfamily comprising one or more selected from TCRP V4-1, TCRP V4-2, and TCRP V4- 3; (iv) TCRP V5 subfamily comprising one or more selected from TCRP V5-6*0I, TCRP V5-4*0I, TCRP V5-I*0I, and TCRP V5-8*0I; (v) the TCRP V6 subfamily comprising one or more selected from TCRP V6-4*0I, TCRP V6-4*02, TCRP V6-9*0I, TCRP V6-8*0I, TCRP V6-5*0I, TCRP V6-6*02, TCRP V6-6*0I, TCRP V6-2*0I, TCRP V6-3*0I, and TCRP V6-I*0I; (vi) TCRP V9 subfamily; (vii) TCRP V10 subfamily comprising one or more selected from TCRP V10-I*0I, TCRP VI 0-1 *02, TCRP VI 0-3 *01, and TCRP V10-2*0I; (viii) TCRP VI 1 subfamily comprising TCRP VI 1-2; (ix) TCRP V12 subfamily comprising one or more selected from TCRP V12-4*01, TCRP V12-3*01, and TCRP V12- 5*01; (x) TCRP V13 subfamily comprising TCRP V13*01; (xi) TCRP V16 subfamily comprising TCRP V16*01; (xii) TCRP V19 subfamily comprising one or more selected from TCRP VI 9* 01 and TCRP VI 9* 02; (xiii) TCRP V21 subfamily, (xiv) TCRP V23 subfamily, (xv) TCRP V27 subfamily; and (xvi) TCRP V28 subfamily.

[0422] In some embodiments, the first TCRpV-binding moiety and the second TCRpV-binding moiety are same. In some embodiments, the first TCRpV-binding moiety and the second TCRpV-binding moiety are different.

[0423] In some embodiments, the first TCRpV-binding moiety and the second TCRpV-binding moiety binds: (i) one or more of a TCRP V6 subfamily member and one or more of a TCRP V10 subfamily member, respectively; (ii) one or more of a TCRP V6 subfamily member and one or more of a TCRP V5 subfamily member, respectively; (iii) one or more of a TCRP V6 subfamily member and one or more of a TCRP V12 subfamily member, respectively; (iv) one or more of a TCRP V10 subfamily member and one or more of a TCRP V5 subfamily member, respectively; (v) one or more of a TCRP V10 subfamily member and one or more of a TCRP V12 subfamily member, respectively; or (vi) one or more of a TCRP V5 subfamily member and one or more of a TCRP V12 subfamily member, respectively.

[0424] In some embodiments, the first TCRpV-binding moiety, the second TCRpV-binding moiety, or a combination thereof comprises: (i) a HC CDR1, a HC CDR2 and a HC CDR3 of an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to any one of the CDR1, CDR2, and CDR3 sequences listed in Table 1; (ii) a LC CDR1, a LC CDR2, and a LC CDR3 of an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to any one of the CDR1, CDR2, and CDR3 the sequences listed in Table 1; or (iii) a combination thereof. In some embodiments, the first TCRpV-binding moiety, the second TCRpV-WSGR Docket No. 53676-773.601 binding moiety, or a combination thereof comprises: (i) a HC CDR1, a HC CDR2 and a HC CDR3 having any one of the CDR1, CDR2, and CDR3 sequences listed in Table 1; (ii) a LC CDR1, a LC CDR2, and a LC CDR3 having any one of the CDR1, CDR2, and CDR3 the sequences listed in Table 1; or (iii) a combination thereof.

[0425] In some embodiments, the first TCRpV-binding moiety, the second TCRpV-binding moiety, or a combination thereof comprises: (i) a HC CDR1, a HC CDR2 and a HC CDR3 of an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to any one of the CDR1, CDR2, and CDR3 sequences listed in Table 1, respectively; (ii) a LC CDR1, a LC CDR2, and a LC CDR3 of an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to any one of the CDR1, CDR2, and CDR3 the sequences listed in Table 1, respectively; or (iii) a combination thereof. In some embodiments, the first TCRpV-binding moiety, the second TCRpV-binding moiety, or a combination thereof comprises: (i) a HC CDR1, a HC CDR2 and a HC CDR3 having any one of the CDR1, CDR2, and CDR3 sequences listed in Table 1, respectively; (ii) a LC CDR1, a LC CDR2, and a LC CDR3 having any one of the CDR1, CDR2, and CDR3 the sequences listed in Table 1, respectively; or (iii) a combination thereof.

[0426] In some embodiments, the first TCRpV-binding moiety, the second TCRpV-binding moiety, or a combination thereof comprises: (i) a VH comprising a framework region (FR) comprising a framework 1 (FR1), a framework region 2 (FR2), a framework region 3 (FR3), and a framework region 4 (FR4) that have at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity with anon- murine germline FR1, a non-murine germline FR2, a non-murine germline FR3, and a non-murine germline FR4; (ii) a VL comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 that have at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity with a non-murine germline FR1, a non-murine germline FR2, a non-murine germline FR3, and a non-murine germline FR4; or (iii) a combination thereof. In some embodiments, the first TCRpV-binding moiety, the second TCRpV- binding moiety, or a combination thereof comprises: (i) a VH comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 having the sequences of a non-murine germline FR1, a non-murine germline FR2, a non-murine germline FR3, and a non-murine germline FR4; (ii) a VL comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 having the sequences of a non-murine germline FR1, a non-murine germline FR2, a non-murine germline FR3, and a non-murine germline FR4; or (iii) a combination thereof.

[0427] In some embodiments, the first TCRpV-binding moiety, the second TCRpV-binding moiety, or a combination thereof comprises: (i) a VH comprising a FR1, a FR2, a FR3, and a FR4 that have at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity with a non-murine germline FR1, a non-murine germline FR2, a non-murine germline FR3, and a non-murine germline FR4, respectively; (ii) a VL comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 that have at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity with a non-murine germline FR1, a non-murine germline FR2, a non-murine germline FR3, and a non-murine germline FR4, respectively; or (iii) a combination thereof. In some embodiments, the first TCRpV-binding moiety, theWSGR Docket No. 53676-773.601 second TCRpV-binding moiety, or a combination thereof comprises: (i) a VH comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 having the sequences of a non-murine germline FR1, a nonmurine germline FR2, a non-murine germline FR3, and a non-murine germline FR4, respectively; (ii) a VL comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 having the sequences of a non-murine germline FR1, a non-murine germline FR2, a non-murine germline FR3, and a non-murine germline FR4, respectively; or (iii) a combination thereof.

[0428] In some embodiments, the VH comprises the FR3 comprising (i) a Threonine at position 73 according to Kabat numbering; (ii) a Glycine a position 94 according to Kabat numbering; or (iii) a combination thereof. In some embodiments, the VL comprises the FR1 comprising a Phenylalanine at position 10 according to Kabat numbering. In some embodiments, the VL comprises the FR2 comprising (i) a Histidine at position 36 according to Kabat numbering; (ii) an Alanine at position 46 according to Kabat numbering; or (iii) a combination thereof. In some embodiments, the VL comprises the FR3 comprising a Phenylalanine at position 87 according to Kabat numbering.

[0429] In some embodiments, the first TCRpV-binding moiety, the second TCRpV-binding moiety, or a combination thereof comprises: (i) a HC CDR1, a HC CDR2 and a HC CDR3 of an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to any one of the CDR1, CDR2, and CDR3 sequences listed in Table 2; (ii) a LC CDR1, a LC CDR2, and a LC CDR3 of an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to any one of the CDR1, CDR2, and CDR3 sequences listed in Table 2; or (iii) a combination thereof. In some embodiments, the first TCRpV-binding moiety, the second TCRpV- binding moiety, or a combination thereof comprises: (i) a HC CDR1, a HC CDR2 and a HC CDR3 having any one of the CDR1, CDR2, and CDR3 sequences listed in Table 2; (ii) a LC CDR1, a LC CDR2, and a LC CDR3 having any one of the CDR1, CDR2, and CDR3 sequences listed in Table 2; or (iii) a combination thereof.

[0430] In some embodiments, the first TCRpV-binding moiety, the second TCRpV-binding moiety, or a combination thereof comprises: (i) a HC CDR1, a HC CDR2 and a HC CDR3 of an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to any one of the CDR1, CDR2, and CDR3 sequences listed in Table 2, respectively; (ii) a LC CDR1, a LC CDR2, and a LC CDR3 of an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to any one of the CDR1, CDR2, and CDR3 sequences listed in Table 2, respectively; or (iii) a combination thereof. In some embodiments, the first TCRpV-binding moiety, the second TCRpV-binding moiety, or a combination thereof comprises: (i) a HC CDR1, a HC CDR2 and a HC CDR3 having any one of the CDR1, CDR2, and CDR3 sequences listed in Table 2, respectively; (ii) a LC CDR1, a LC CDR2, and a LC CDR3 having any one of the CDR1, CDR2, and CDR3 sequences listed in Table 2, respectively; or (iii) a combination thereof.

[0431] In some embodiments, the first TCRpV-binding moiety, the second TCRpV-binding moiety, or a combination thereof comprises: (i) a VH comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 that have at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity with aWSGR Docket No. 53676-773.601FR1, a FR2, a FR3, and a FR4 of a humanized B-H LC of Table 2; (ii) a VL comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 that have at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity with a FR1, a FR2, a FR3, and a FR4 of a humanized B-H LC of Table 2; or (iii) a combination thereof. In some embodiments, the first TCRpV-binding moiety, the second TCRJ3V- binding moiety, or a combination thereof comprises: (i) a VH comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 that have the sequence of a FR1, a FR2, a FR3, and a FR4 of a humanized B-H LC of Table 2; (ii) a VL comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 that have the sequence of a FR1, a FR2, a FR3, and a FR4 of a humanized B-H LC of Table 2; or (iii) a combination thereof.

[0432] In some embodiments, the first TCRpV-binding moiety, the second TCRpV-binding moiety, or a combination thereof comprises: (i) a VH comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 that have at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity with a FR1, a FR2, a FR3, and a FR4 of a humanized B-H LC of Table 2, respectively; (ii) a VL comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 that have at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity with a FR1, a FR2, a FR3, and a FR4 of a humanized B-H LC of Table 2, respectively; or (iii) a combination thereof. In some embodiments, the first TCRpV-binding moiety, the second TCRpV-binding moiety, or a combination thereof comprises: (i) a VH comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 that have the sequence of a FR1, a FR2, a FR3, and a FR4 of a humanized B-H LC of Table 2, respectively; (ii) a VL comprising a FR comprising a FR1, a FR2, a FR3, and a FR4 that have the sequence of a FR1, a FR2, a FR3, and a FR4 of a humanized B-H LC of Table 2, respectively; or (iii) a combination thereof.

[0433] In some embodiments, the first TCRpV-binding moiety, the second TCRpV-binding moiety, or a combination thereof comprises: (i) a VH comprising a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the VH sequence of a humanized Antibody B-H listed in Table 2; (ii) a VL comprising a sequence having at least at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the VL sequence of a humanized Antibody B-H listed in Table 2; or (iii) a combination thereof. In some embodiments, the first TCRpV-binding moiety, the second TCRpV-binding moiety, or a combination thereof comprises: (i) a VH comprising the VH sequence of a humanized Antibody B-H listed in Table 2; (ii) a VL comprising the VL sequence of a humanized Antibody B-H listed in Table 2; or (iii) a combination thereof. In some embodiments, the first TCRpV-binding moiety, the second TCRpV-binding moiety, or a combination thereof comprises: (i) the VH of a humanized Antibody B-H listed in Table 2; (ii) the VL sequence of a humanized Antibody B-H listed in Table 2; or (iii) a combination thereof.

[0434] In some embodiments, the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or a combination thereof comprises a heavy chain constant region having a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to any one of the sequences listed in Table 3 or a combination thereof. In some embodiments, the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or a combination thereof comprises a heavy chain constant region having any one of the sequences listed in Table 3 or a combination thereof.WSGR Docket No. 53676-773.601In some embodiments, the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or a combination thereof comprises a heavy chain constant region of which sequence is a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to any one of the sequences listed in Table 3 or a combination thereof. In some embodiments, the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or a combination thereof comprises a heavy chain constant region having any one of the heavy chain constant region sequences listed in Table 3 or a combination thereof. In some embodiments, the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or a combination thereof comprises a heavy chain constant region of an IgM or a fragment thereof. In some embodiments, the heavy chain constant region of the IgM comprises a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the sequence of SEQ ID NO: 73. In some embodiments, the heavy chain constant region of the IgM comprises the sequence of SEQ ID NO: 73. In some embodiments, the sequence of the heavy chain constant region of the IgM is the sequence of SEQ ID NO: 73.

[0435] In some embodiments, the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or a combination thereof comprises a heavy chain constant region of an IgJ or a fragment thereof. In some embodiments, the heavy chain constant region of the IgJ comprises a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the sequence of SEQ ID NO: 76. In some embodiments, the heavy chain constant region of the IgJ comprises the sequence of SEQ ID NO: 76. In some embodiments, the sequence of the heavy chain constant region of the IgJ is the sequence of SEQ ID NO: 76.

[0436] In some embodiments, the first polypeptide, the second polypeptide, the third polypeptide, the fourth polypeptide, or a combination thereof comprises a heavy chain constant region of an IgGAl or a fragment thereof. In some embodiments, the heavy chain constant region of the IgGAl comprises a sequence having at least 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 100% sequence identity to the sequence of SEQ ID NO: 74. In some embodiments, the heavy chain constant region of the IgGAl comprises the sequence of SEQ ID NO: 74. In some embodiments, the sequence of the heavy chain constant region...

Claims

WSGR Docket No. 53676-773.601CLAIMSWHAT IS CLAIMED IS:

1. A method of treating a disease or a condition in a subject in need thereof comprising:(a) administering a therapeutically effective amount of a first agent comprising (i) a first domain that binds to a TCR P variable (TCR V) region and (ii) a molecule that activates a costimulatory receptor or a molecule that inhibits a co-inhibitory receptor; and(b) administering a therapeutically effective amount of a second agent comprising a Poly-ADP ribose polymerase (PARP) inhibitor.

2. The method of claim 1, wherein the administration of the first agent improves therapeutic efficacy of the second agent to the subject.

3. The method of claim 1 or 2, wherein the administration of the first agent and the second agent promotes an enhanced anti-tumor immune response in the subject.

4. A method of treating a disease or a condition in a subject in need thereof comprising administering a therapeutically effective amount of a first agent to the subject, wherein the first agent comprises (i) a first domain that binds to a TCR variable (TCRpV) region and (ii) a molecule that binds and / or activates a co-stimulatory receptor or a molecule that binds and / or inhibits a co-inhibitory receptor; wherein the subject was previously administered a second agent, wherein the second agent comprises a Poly-ADP ribose polymerase (PARP) inhibitor.

5. A method of treating a disease or a condition in a subject in need thereof comprising administering a therapeutically effective amount of a second agent to the subject, wherein the second agent comprises a Poly-ADP ribose polymerase (PARP) inhibitor; wherein the subject was previously administered a first agent, wherein the first agent comprises (i) a first domain that binds to a TCR P variable (TCRpV) region and (ii) a molecule that binds and / or activates a co-stimulatory receptor or a molecule that binds and / or inhibits a co-inhibitory receptor.

6. A combination therapy for treating a disease or a condition in a subject in need thereof, comprising:(a) a first agent comprising (i) a first domain that binds to a TCR P variable (TCRpV) region and(ii) a molecule that activates a co-stimulatory receptor or a molecule that inhibits a co-inhibitory receptor; and(b) a second agent comprising a Poly-ADP ribose polymerase (PARP) inhibitor.

7. A composition for treating a disease or condition in a subject in need thereof comprising:(a) a first agent comprising (i) a first domain that binds to a TCR P variable (TCRpV) region and(ii) a molecule that activates a co-stimulatory receptor or a molecule that inhibits a co-inhibitory receptor; and(b) a second agent comprising a Poly-ADP ribose polymerase (PARP) inhibitor.

8. A kit for treating a disease or condition in a subject in need thereof comprising:(a) a first agent comprising (i) a first domain that binds to a TCR P variable (TCRpV) region and(ii) a molecule that activates a co-stimulatory receptor or a molecule that inhibits a co-inhibitory receptor; andWSGR Docket No. 53676-773.601(b) a second agent comprising a Poly-ADP ribose polymerase (PARP) inhibitor.

9. The method, the combination therapy, the composition, or the kit of any one of claims 1-8, wherein the first agent comprises a molecule that activates a co-stimulatory receptor.

10. The method, the combination therapy, the composition, or the kit of any one of claims 1-9, wherein the molecule that activates a co-stimulatory receptor is a molecule that binds the co-stimulatory receptor.

11. The method of any one of claims 1-10, wherein the molecule that activates a co-stimulatory receptor is a molecule that activates a co-stimulatory receptor of a T cell.

12. The method, the combination therapy, the composition, or the kit of any one of claims 1-11, wherein the molecule that activates a co-stimulatory receptor comprises a ligand of the co-stimulatory receptor.

13. The method, the combination therapy, the composition, or the kit of any one of claims 1-12, wherein the molecule that activates a co-stimulatory receptor comprises an extracellular domain of a receptor that binds and / or activates the co-stimulatory receptor.

14. The method, the combination therapy, the composition, or the kit of any one of claims 1-13, wherein the molecule that activates a co-stimulatory receptor comprises a cytokine, a functional fragment thereof or a functional variant thereof.

15. The method, the combination therapy, the composition, or the kit of any one of claims 1-14, wherein the molecule that activates a co-stimulatory receptor comprises a molecule that binds and / or activates CD28, CD40L (CD154), CD27, 0X40 (CD134), 4-1BB (CD137), GITR (CD357), HVEM (CD270), Galnectin 9, TIM1, LFA1, CD226, CD30 or CD2.

16. The method, the combination therapy, the composition, or the kit of any one of claims 1-15, wherein the molecule that activates a co-stimulatory receptor comprises an extracellular domain of a receptor selected from the group consisting of B7-1 (CD80), B7-2 (CD86), CD40, ICOSL, CD70, CD27L, OX40L, 4-1BBL, GITRL, LIGHT (CD258), TIM3, TIM4, ICAM1, CD48, CD56, CD155, CD112, CD30L or LFA317. The method, the combination therapy, the composition, or the kit of any one of claims 1-8, wherein the first agent comprises a molecule that inhibits a co-inhibitory receptor.

18. The method, the combination therapy, the composition, or the kit of any one of claims 1-8, wherein the molecule that inhibits a co-inhibitory receptor is a molecule that binds the co-inhibitory receptor.

19. The method, the combination therapy, the composition, or the kit of any one of claims 1-8 and 18, wherein the molecule that inhibits a co-inhibitory receptor is a molecule that inhibits a co-inhibitory receptor of a T cell.

20. The method, the combination therapy, the composition, or the kit of any one of claims 1-8, 18, and 19, wherein the molecule that inhibits a co-inhibitory receptor is a molecule that inhibits ICOS, CTLA4, PD1, BTLA (CD272), or CD 160.WSGR Docket No. 53676-773.60121. The method, the combination therapy, the composition, or the kit of any one of claims 1-20, wherein administering the first agent and the second agent induces an improved therapeutic effect in the subject, relative to a subject administered the second agent without the first agent.

22. The method, the combination therapy, the composition, or the kit of any one of claims 1-21, wherein administering the first agent and the second agent induces more activated and / or expanded T cells in a tumor in the subject, relative to a tumor in a subject administered the second agent without the first agent.

23. The method, the combination therapy, the composition, or the kit of any one of claims 1-22, wherein administering the first agent and the second agent induces less exhausted T cells in a tumor in the subject, relative to a tumor in a subject administered the second agent without the first agent.

24. The method, the combination therapy, the composition, or the kit of any one of claims 1-23, wherein administering the first agent and the second agent induces a higher anti-tumor efficacy level in the subject, relative to a subject administered the second agent without the first agent.

25. The method, the combination therapy, the composition, or the kit of any one of claims 1-24, wherein administering the first agent and the second agent induces a higher number of T cells that are cytotoxic against tumor cells or cancer cells in the subject, relative to a subject administered the second agent without the first agent.

26. The method, the combination therapy, the composition, or the kit of any one of claims 1-25, wherein administering the first agent and the second agent induces a higher level of cytotoxicity against tumor cells or cancer cells in the subject, relative to a subject administered the second agent without the first agent.

27. The method, the combination therapy, the composition, or the kit of any one of claims 1-26, wherein administering the first agent and the second agent expands or activates a higher number of T cells that are cytotoxic against tumor cells or cancer cells in the subject, relative to a subject administered the second agent without the first agent.

28. The method, the combination therapy, the composition, or the kit of any one of claims 1-27, wherein administering the first agent and the second agent induces a higher level of cytotoxic activity against tumor cells or cancer cells in the subject, relative to a subject administered the second agent without the first agent.

29. The method, the combination therapy, the composition, or the kit of any one of claims 1-28, wherein the subject exhibits an improved therapeutic effect after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent.

30. The method, the combination therapy, the composition, or the kit of any one of claims 1-29, wherein the subject produces a higher number of activated and / or expanded T cells after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent.WSGR Docket No. 53676-773.60131. The method, the combination therapy, the composition, or the kit of any one of claims 1-30, wherein the subject has less exhausted T cells after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent.

32. The method, the combination therapy, the composition, or the kit of any one of claims 1-31, wherein the subject exhibits a higher level of anti -tumor efficacy after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent.

33. The method, the combination therapy, the composition, or the kit of any one of claims 1-32, wherein the subject produces a higher number of T cells that are more cytotoxic against tumor cells or cancer cells after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent.

34. The method, the combination therapy, the composition, or the kit of any one of claims 1-33, wherein the subject produces a higher number of NK cells that are more cytotoxic against tumor cells or cancer cells after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent.

35. The method, the combination therapy, the composition, or the kit of claim 33 or 34, wherein T cells or the NK cells are in the periphery of the subject.

36. The method, the combination therapy, the composition, or the kit of claim 33 or 34, wherein T cells or the NK cells are in the tumor microenvironment of the subject.

37. The method, the combination therapy, the composition, or the kit of any one of claims 1-36, wherein the subject exhibits a higher level of cytotoxic activity against tumor cells or cancer cells after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent.

38. The method, the combination therapy, the composition, or the kit of claims 22, 23, 25, 27, 30, 31, 33, or 34, wherein the T cells are TCRPV+.

39. The method, the combination therapy, the composition, or the kit of claims 22, 23, 25, 27, 30, 31, 33, 34, or 38, wherein the T cells are CD4+, CD8+, IFNg+, Granzyme B+, PD1+, TNF+, or any combination thereof.

40. The method, the combination therapy, the composition, or the kit of claim 39, wherein the CD8+ T cells are characterized by stem cell -like characteristics.

41. The method, the combination therapy, the composition, or the kit of claim 40, wherein the CD8+ T cells are Tpex cells.

42. The method, the combination therapy, the composition, or the kit of any one of claims 1-41, wherein the subject has decreased level of immunosuppressive cells after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent.

43. The method, the combination therapy, the composition, or the kit of claim 42, wherein the immunosuppressive cells are M2 macrophages, monocyte-myeloid-derived suppressor cells (M- MDSC), regulatory T cells (Tregs), or any combination thereof.WSGR Docket No. 53676-773.60144. The method, the combination therapy, the composition, or the kit of any one of claims 1-43, wherein the subject has tumors that are more immune infiltrated after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent.

45. The method, the combination therapy, the composition, or the kit of claim 44, wherein the tumors are more immune infiltrated with CD4+ T cells, CD8+ T cells, or both.

46. The method, the combination therapy, the composition, or the kit of claim 45, wherein the CD4+ T cells or the CD8+ T cells are TCRPV+.

47. The method, the combination therapy, the composition, or the kit of claim 46, wherein the TCRpV is TCRPV6 or TCRpVIO.

48. The method, the combination therapy, the composition, or the kit of any one of claims 1-47, wherein the subject has tumors that are less infiltrated with Treg cells after administration of the first agent and the second agent, relative to a subject not administered the first agent or the second agent.

49. The method, the combination therapy, the composition, or the kit of claim 48, wherein the Treg cells are CD4+ and FoxP3+.

50. The method, the combination therapy, the composition, or the kit of any one of claims 1-49, wherein the subject has elevated levels of TRAIL-R2 expression after administration of the first agent and the second agent, relative to a subject not administered the second agent.

51. The method, the combination therapy, the composition, or the kit of any one of claims 1-50, wherein the first agent is administered to the subject prior to, concurrently, or after administration of the second agent to the subject.

52. The method, the combination therapy, the composition, or the kit of any one of claims 1-51, wherein the first agent and the second agent are concomitantly administered to the subject.

53. The method, the combination therapy, the composition, or the kit of any one of claims 1-51, wherein the first agent and the second agent are not concomitantly administered to the subject.

54. The method, the combination therapy, the composition, or the kit of any one of claims 1-51, wherein the administration of the second agent to the subject is conducted before the administration of the first agent to the subject.

55. The method, the combination therapy, the composition, or the kit of any one of claims 1-51, wherein the administration of the first agent to the subject is conducted before the administration of the second agent to the subject.

56. The method, the combination therapy, the composition, or the kit of any one of claims 1-51, wherein the first agent is administered to the subject at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at least 1, 2, 3, 4, 5, 6, or 7 days, at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years after the subject has been treated with a dose of the second agent.

57. The method, the combination therapy, the composition, or the kit of any one of claims 1-51, wherein the first agent is administered to the subject at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at least 1, 2, 3, 4, 5, 6, or 7 days, at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12WSGR Docket No. 53676-773.601 months, or at least 1, 2, or 3 years after the subject has been treated with a first dose of the second agent.

58. The method, the combination therapy, the composition, or the kit of any one of claims 1-51, wherein the first agent is administered to the subject at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at least 1, 2, 3, 4, 5, 6, or 7 days, at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years after the subject has been treated with a last dose of the second agent.

59. The method, the combination therapy, the composition, or the kit of any one of claims 1-51, wherein the first agent is administered to the subject at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at most 1, 2, 3, 4, 5, 6, or 7 days, at most 1, 2, 3, or 4 weeks, at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at most 1, 2, or 3 years after being treated with the second agent.

60. The method, the combination therapy, the composition, or the kit of any one of claims 1-51, wherein the first agent is administered to the subject at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at most 1, 2, 3, 4, 5, 6, or 7 days, at most 1, 2, 3, or 4 weeks, at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at most 1, 2, or 3 years after being treated with a dose of the second agent.

61. The method, the combination therapy, the composition, or the kit of any one of claims 1-51, wherein the first agent is administered to the subject at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at most 1, 2, 3, 4, 5, 6, or 7 days, at most 1, 2, 3, or 4 weeks, at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at most 1, 2, or 3 years after being treated with a first dose of the second agent.

62. The method, the combination therapy, the composition, or the kit of any one of claims 1-51, wherein the method comprises administering the first agent to the subject at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, or 24 hours, at most 1, 2, 3, 4, 5, 6, or 7 days, at most 1, 2, 3, or 4 weeks, at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at most 1, 2, or 3 years after being treated with a last dose of the second agent.

63. The method, the combination therapy, the composition, or the kit of any one of claims 1-62, wherein the first agent is administered to the subject from 1 hour to 24 hours after being treated with a dose of the second agent.

64. The method, the combination therapy, the composition, or the kit of any one of claims 1-62, wherein the first agent is administered to the subject from 1 day to 7 days after being treated with a dose of the second agent.

65. The method, the combination therapy, the composition, or the kit of any one of claims 1-62, wherein the first agent is administered to the subject from 1 week to 4 weeks after being treated with a dose of the second agent.

66. The method, the combination therapy, the composition, or the kit of any one of claims 1-62, wherein the first agent is administered to the subject from 1 month to 12 months after being treated with a dose of the second agent.WSGR Docket No. 53676-773.60167. The method, the combination therapy, the composition, or the kit of any one of claims 1-62, wherein the first agent is administered to the subject from 1 year to 3 years after being treated with a dose of the second agent.

68. The method, the combination therapy, the composition, or the kit of any one of claims 1-62, wherein the first agent is administered to the subject from 1 hour to 24 hours after being treated with a first dose of the second agent.

69. The method, the combination therapy, the composition, or the kit of any one of claims 1-62, wherein the first agent to the subject from 1 day to 7 days after being treated with a first dose of the second agent.

70. The method, the combination therapy, the composition, or the kit of any one of claims 1-62, wherein the first agent is administered to the subject from 1 week to 4 weeks after being treated with a first dose of the second agent.

71. The method, the combination therapy, the composition, or the kit of any one of claims 1-62, wherein the first agent is administered to the subject from 1 month to 12 months after being treated with a first dose of the second agent.

72. The method, the combination therapy, the composition, or the kit of any one of claims 1-62, wherein the first agent is administered to the subject from 1 year to 3 years after being treated with a first dose of the second agent.

73. The method, the combination therapy, the composition, or the kit of any one of claims 1-62, wherein the first agent is administered to the subject from 1 hour to 24 hours after being treated with a last dose of the second agent.

74. The method, the combination therapy, the composition, or the kit of any one of claims 1-62, wherein the first agent is administered to the subject from 1 week to 4 weeks after being treated with a last dose of the second agent.

75. The method, the combination therapy, the composition, or the kit of any one of claims 1-62, wherein the first agent is administered to the subject from 1 month to 12 months after being treated with a last dose of the second agent.

76. The method, the combination therapy, the composition, or the kit of any one of claims 1-62, wherein the first agent is administered to the subject from 1 year to 3 years after being treated with a last dose of the second agent.

77. The method, the combination therapy, the composition, or the kit of any one of claims 1-62, wherein the first agent is administered to the subject on the same day the subject had been previously treated with the second agent.

78. The method of any one of claims 1-3 and 9-77, wherein the method is repeated twice or more.

79. The method, the combination therapy, the composition, or the kit of any one of claims 1-78, wherein the administration of the first agent comprises one or more doses.

80. The method, the combination therapy, the composition, or the kit of any one of claims 1-79, wherein the administration of the first agent comprises two or more doses.WSGR Docket No. 53676-773.60181. The method, the combination therapy, the composition, or the kit of any one of claims 1-80, wherein the administration of the first agent comprises one dose per week.

82. The method, the combination therapy, the composition, or the kit of any one of claims 1-80, wherein the administration of the first agent comprises two or more doses per week.

83. The method, the combination therapy, the composition, or the kit of any one of claims 1-80, wherein the first agent is administered to the subject once every two weeks.

84. The method, the combination therapy, the composition, or the kit of any one of claims 1-80, wherein the first agent is administered to the subject once every three weeks.

85. The method, the combination therapy, the composition, or the kit of any one of claims 1-80, wherein the first agent is administered to the subject once every week for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years.

86. The method, the combination therapy, the composition, or the kit of any one of claims 1-80, wherein the administration of the first agent comprises two or more doses per week for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years.

87. The method, the combination therapy, the composition, or the kit of any one of claims 1-80, wherein the first agent is administered to the subject once every two weeks for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years.

88. The method, the combination therapy, the composition, or the kit of any one of claims 1-80, wherein the first agent is administered to the subject once every three weeks for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years.

89. The method, the combination therapy, the composition, or the kit of any one of claims 1-88, wherein the administration of the second agent comprises one or more doses.

90. The method, the combination therapy, the composition, or the kit of any one of claims 1-89, wherein the administration of the second agent comprises two or more doses.

91. The method, the combination therapy, the composition, or the kit of any one of claims 1-90, wherein the administration of the second agent comprises one dose per week.

92. The method, the combination therapy, the composition, or the kit of any one of claims 1-90, wherein the administration of the second agent comprises two or more doses per week.

93. The method, the combination therapy, the composition, or the kit of any one of claims 1-90, wherein the second agent is administered to the subject once every two weeks.

94. The method, the combination therapy, the composition, or the kit of any one of claims 1-90, wherein the second agent is administered to the subject once every three weeks.

95. The method, the combination therapy, the composition, or the kit of any one of claims 1-90, wherein the second agent is administered to the subject once every week for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years.

96. The method, the combination therapy, the composition, or the kit of any one of claims 1-90, wherein the administration of the second agent comprises two or more doses per week for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years.WSGR Docket No. 53676-773.60197. The method, the combination therapy, the composition, or the kit of any one of claims 1-90, wherein the second agent is administered to the subject once every two weeks for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years.

98. The method, the combination therapy, the composition, or the kit of any one of claims 1-90, wherein the second agent is administered to the subject once every three weeks for at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years.

99. The method, the combination therapy, the composition, or the kit of any one of claims 1-98, wherein the first agent is administered to the subject at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at least 1, 2, 3, 4, 5, 6, or 7 days, at least 1, 2, 3, or 4 weeks, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at least 1, 2, or 3 years prior to administering the second agent to the subject.

100. The method, the combination therapy, the composition, or the kit of any one of claims 1-99, wherein the first agent is administered to the subject at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 hours, at most 1, 2, 3, 4, 5, 6, or 7 days, at most 1, 2, 3, or 4 weeks, at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months, or at most 1, 2, or 3 years prior to administering the second agent to the subject.

101. The method, the combination therapy, the composition, or the kit of any one of claims 1-100, wherein the first agent is administered to the subject from 1 hour to 24 hours prior to administering the second agent to the subject.

102. The method, the combination therapy, the composition, or the kit of any one of claims 1-100, wherein the first agent is administered to the subject from 1 day to 7 days prior to administering the second agent to the subject.

103. The method, the combination therapy, the composition, or the kit of any one of claims 1-100, wherein the first agent is administered to the subject from 1 week to 4 weeks prior to administering the second agent to the subject.

104. The method, the combination therapy, the composition, or the kit of any one of claims 1-100, wherein the first agent is administered to the subject from 1 month to 12 months prior to administering the second agent to the subject.

105. The method, the combination therapy, the composition, or the kit of any one of claims 1-100, wherein the first agent is administered to the subject from 1 year to 3 years prior to administering the second agent to the subject.

106. The method, the combination therapy, the composition, or the kit of any one of claims 1-105, wherein the administration of the first agent comprises two or more doses, and each dose comprises a same amount of the first agent.

107. The method, the combination therapy, the composition, or the kit of any one of claims 1-105, wherein the administration of the first agent comprises two or more doses, and each dose comprises different amounts of the first agent.

108. The method, the combination therapy, the composition, or the kit of any one of claims 1-107, wherein the administration of the second agent comprises two or more doses, and each dose comprises a same amount of the second agent.WSGR Docket No. 53676-773.601109. The method, the combination therapy, the composition, or the kit of any one of claims 1-107, wherein the administration of the second agent comprises two or more doses, and each dose comprises different amounts of the second agent.

110. The method, the combination therapy, the composition, or the kit of any one of claims 1-109, wherein the first agent is administered to the subject at a dose of from about 0.001 mg / kg to about 20 mg / kg.

111. The method, the combination therapy, the composition, or the kit of any one of claims 1-110, wherein the second agent is administered to the subject at a dose of from about 0.001 mg / kg to about 20 mg / kg.

112. The method, the combination therapy, the composition, or the kit of any one of claims 1-111, wherein the method comprises administering the first agent and the second agent to the subject simultaneously or on the same day.

113. The method, the combination therapy, the composition, or the kit of any one of claims 1-111, wherein the second agent is administered to the subject once or twice a day and one or more doses of the first agent is administered to the subject from 1 day to 7 days after being treated with a dose of the first agent.

114. The method, the combination therapy, the composition, or the kit of claim 105, wherein the first agent is administered at an interval of every 2, every 3, every 4, every 5, every 6, or every 7 days.

115. The method, the combination therapy, the composition, or the kit of any one of claims 1-112, wherein the disease or condition in the subject is treated to a higher extent relative to a corresponding method in which the first agent is administered and the second agent is not administered.

116. The method, the combination therapy, the composition, or the kit of any one of claims 1-113, wherein the method is more effective to treat the disease or condition in the subject relative to a method in which the first agent is administered to the subject but not the second agent.

117. The method, the combination therapy, the composition, or the kit of any one of claims 1-116, wherein the method is more effective to treat the disease or condition in the subject relative to a method in which the second agent is administered to the subject but not the first agent.

118. The method, the combination therapy, the composition, or the kit of any one of claims 1-117, wherein the TCRpV region is a human TCRpV region.

119. The method, the combination therapy, the composition, or the kit of claim 118, wherein the first domain binds to one or more of a TCRpV subfamily selected from the group consisting of TCRP VI subfamily, TCRP V2 subfamily, TCRP V3 subfamily, TCRP V4 subfamily, TCRP V5 subfamily, TCRP V6 subfamily, TCRP V7 subfamily, TCRP V8 subfamily, TCRP V9 subfamily, TCRP V10 subfamily, TCRP VI 1 subfamily, TCRP V12 subfamily, TCRP V13 subfamily, TCRP V14 subfamily, TCRP V15 subfamily, TCRP V16 subfamily, TCRP V17 subfamily, TCRP VI 8 subfamily, TCRPVI 9, TCRP V20 subfamily, TCRP V21 subfamily, TCRP V22 subfamily TCRP V23 subfamily, TCRP V24 subfamily, TCRP V25 subfamily, TCRP V26 subfamily, TCRP V27 subfamily, TCRP V28 subfamily, TCRP V29 subfamily, and TCRP V30 subfamily.WSGR Docket No. 53676-773.601120. The method, the combination therapy, the composition, or the kit of claim 119, wherein the first domain binds to one or more of a TCRpV subfamily selected from the group consisting of:(i) TCRP VI subfamily comprising TCRP VI *01;(ii) TCRP V2 subfamily comprising one or more selected from TCRP V2*01, TCRP V2*02, and TCRP V2* 03;(iii) TCRP V3 subfamily comprising one or more selected from TCRP V3-l*01 and TCRP V3- 1*02;(iv) TCRP V4 subfamily comprising one or more selected from TCRP V4-l*01, TCRP V4- 1*02, TCRP V4-2*01, TCRP V4-2*02, TCRP V4-3*01, TCRP V4-3*02, TCRP V4-3*03, and TCRP V4-3*04;(v) TCRP V5 subfamily comprising one or more selected from TCRP V5-l*01, TCRP V5-l*02, TCRP V5-3*01, TCRP V5-3*02, TCRP V5-4*01, TCRP V5-4*02, TCRP V5-4*03, TCRP V5- 4*04, TCRP V5-5*01, TCRP V5-5*02, TCRP V5-5*03, TCRP V5-6*01, TCRP V5-7*01, TCRP V5-8*01, and TCRP V5-8*02;(vi) TCRP V6 subfamily comprising one or more selected from TCRP V6-l*01, TCRP V6- 2*01, TCRP V6-3*01, TCRP V6-4*01, TCRP V6-4*02, TCRP V6-5*01, TCRP V6-6*01, TCRP V6-6*02, TCRP V6-6*03, TCRP V6-6*04, TCRP V6-6*05, TCRP V6-7*01, TCRP V6-8*01, and TCRP V6-9*O1;(vii) TCRP V7 subfamily comprising one or more selected from TCRP V7-l*01, TCRP V7- 2*01, TCRP V7-2*02, TCRP V7-2*03, TCRP V7-2*04, TCRP V7-3*01, TCRP V7-3*02, TCRP V7-3*03, TCRP V7-3*04, TCRP V7-3*05, TCRP V7-4*01, TCRP V7-4*02, TCRP V7-6*01, TCRP V7-6*02, TCRP V7-7*01, TCRP V7-7*02, TCRP V7-8*01, TCRP V7-8*02, TCRP V7- 8*03, TCRP V7-9*01, TCRP V7-9*02, TCRP V7-9*03, TCRP V7-9*04, TCRP V7-9*05, TCRP V7-9*06, and TCRP V7-9*07.(viii) TCRP V8 subfamily comprising one or more selected from TCRP V8-l*01, TCRP V8- 1*02, TCRP V8-2*01, and TCRP V8-2*02;(ix) TCRP V9 subfamily comprising one or more selected from TCRP V9-l*01, TCRP V9- 1*02, and TCRP V9- 1*03;(x) TCRP V10 subfamily comprising one or more selected from TCRP V10-l*01, TCRP V10- 1*02, TCRP V10-l*03, TCRP V10-2*01, TCRP V10-2*02, TCRP V10-3*01, TCRP V10-3*02, TCRP V10-3*03, and TCRP V10-3*04;(xi) TCRP Vll subfamily comprising TCRP Vll-l*01, TCRP Vll-2*01, TCRP Vll-2*02, TCRP Vll-2*03, TCRP Vll-3*01, TCRP Vll-3*02, TCRP Vll-3*03, and TCRP Vll-3*04;(xii) TCRP V12 subfamily comprising one or more selected from TCRP V12-3*01, TCRP V12- 4*01, TCRP V12-4*02, and TCRP V12-5*01;(xiii) TCRP V13 subfamily comprising one or more selected from TCRP V13*01 and TCRP V13*02;WSGR Docket No. 53676-773.601(xiv) TCRP V14 subfamily comprising one or more comprising from TCRP V14*01 and TCRP V14*02;(xv) TCRP VI 5 subfamily comprising one or more selected from TCRP V15*01, TCRP V15*02, and TCRP V15*03;(xvi) TCRP V16 subfamily comprising one or more selected from TCRP V16*01, TCRP V16*02, and TCRP V16*03;(xvii) TCRP V17 subfamily comprising TCRP V17*01;(xviii) TCRP VI 8 subfamily comprising TCRP V 18*01;(xix) TCRP V19 subfamily comprising one or more selected from TCRP V19*01, TCRP V19*02, and TCRP V19*03;(xx) TCRP V20 subfamily comprising one or more selected from TCRP V20-l*01, TCRP V20- 1*02, TCRP V20-l*03, TCRP V20-l*04, TCRP V20-l*05, TCRP V20-l*06, and TCRP V20- 1*07;(xxi) TCRP V21 subfamily comprising one or more selected from TCRP V21-l*01 and TCRP V21-l*02;(xxii) TCRP V22 subfamily comprising TCRP V22-l*01;(xxiii) TCRP V23 subfamily comprising TCRP V23-l*01;(xxiv) TCRP V24 subfamily comprising TCRP V24-l*01;(xxv) TCRP V25 subfamily comprising TCRP V25-l*01;(xxvi) TCRP V26 subfamily comprising TCRP V26-l*01;(xxvii) TCRP V27 subfamily comprising TCRP V27*01;(xxviii) TCRP V28 subfamily comprising TCRP V28*01;(xxix) TCRP V29 subfamily comprising one or more selected from TCRP V29-l*01, TCRP V29-l*02, and TCRP V29-l*03; and(xxx) TCRP V30 subfamily comprising one or more selected from TCRP V30*01, TCRP V30*02, TCRP V30*03, TCRP V30*04, and TCRP V30*05.

121. The method, the combination therapy, the composition, or the kit of any one of claims 118-120, wherein the first domain is a full antibody, an antigen binding domain thereof, or a functional fragment or variant thereof, a bivalent antibody, a bispecific antibody, or a biparatopic antibody that binds to a TCRpV region.

122. The method or combination therapy of claim 121, wherein the full antibody, an antigen binding domain thereof, or a functional fragment or variant thereof is a Fab', a F(ab’)2, a F(ab)2, a variable fragment (Fv), a single domain antibody, a diabody, a nanobody, a camelid single domain antibody, or a VHH .

123. The method or combination therapy of claim 121, wherein the full antibody, an antigen binding domain thereof, or a functional fragment or variant thereof is a Fab.

124. The method or combination therapy of claim 121, wherein the full antibody, an antigen binding domain thereof, or a functional fragment or variant thereof is a single chain variable fragment (scFv).WSGR Docket No. 53676-773.601125. The method, the combination therapy, the composition, or the kit of any one of claims 1-124, wherein the first agent comprises one or more heavy chain constant regions selected from the group consisting of IgGl heavy chain constant region or fragment thereof, IgG2 heavy chain constant region or fragment thereof, IgG3 heavy chain constant region or fragment thereof, IgGAl heavy chain constant region or fragment thereof, IgGA2 heavy chain constant region or fragment thereof, IgG4 heavy chain constant region or fragment thereof, IgJ heavy chain constant region or fragment thereof, IgM heavy chain constant region or fragment thereof, IgD heavy chain constant region or fragment thereof, and IgE heavy chain constant region or fragment thereof.

126. The method, the combination therapy, the composition, or the kit of any one of claims 1-125, wherein the first agent comprises a kappa light chain constant region or fragment thereof, a lambda light chain constant region or fragment thereof, or a combination thereof.

127. The method, the combination therapy, the composition, or the kit of any one of claims 1-126, wherein the first agent is a multifunctional molecule.

128. The method, the combination therapy, the composition, or the kit of any one of claims 1-127, wherein the first agent comprises at least two non-contiguous polypeptide chains; wherein a first polypeptide chain of the at least two non-contiguous polypeptide chains comprises a first Fc region, and a second polypeptide chain of the at least two non-contiguous polypeptide chains comprises a second Fc region.

129. The method, the combination therapy, the composition, or the kit of claim 128, wherein the first Fc region and the second Fc region comprise an Fc interface with a knob-in-a hole.

130. The method, the combination therapy, the composition, or the kit of claim 128 or 129, wherein the first Fc region, the second Fc region, or a combination thereof comprises an Asn297Ala mutation, a Leu234Ala / Leu235Ala mutation, or a combination thereof.

131. The method, the combination therapy, the composition, or the kit of any one of claims 1-130, wherein the first agent is a multispecific molecule that further comprises one or more of a tumortargeting moiety, a stromal modifying moiety, or an immune cell engager.

132. The method, the combination therapy, the composition, or the kit of any one of claims 1-131, wherein the first agent comprises a dimerization module, comprising a first immunoglobulin chain constant region and a second immunoglobulin chain constant region.

133. The method, the combination therapy, the composition, or the kit of claim 132, wherein the first immunoglobulin chain constant region comprises the first fragment crystallizable region (Fc region) and the second first immunoglobulin chain constant region comprises the second fragment crystallizable region (Fc region).

134. The method, the combination therapy, the composition, or the kit of claim 133, wherein dimerization of the first Fc region and the second Fc region is enhanced by providing an Fc interface of the first Fc region and the second Fc region with one or more of a paired cavity-protuberance, an electrostatic interaction, or a strand-exchange, such that a greater ratio of heteromultimer to homomultimer forms relative to a non-engineered interface.WSGR Docket No. 53676-773.601135. The method, the combination therapy, the composition, or the kit of any one of claims 131-134, wherein the immune cell engager is selected from the group consisting of a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, a macrophage cell engager, and any combination thereof.

136. The method, the combination therapy, the composition, or the kit of any one of claims 1-135, wherein the cytokine molecule comprises interleukin-7 (IL-7) or functional variant thereof.

137. The method, the combination therapy, the composition, or the kit of any one of claims 1-135, wherein the cytokine molecule comprises interleukin- 15 (IL- 15) or functional variant thereof.

138. The method, the combination therapy, the composition, or the kit of any one of claims 1-135, wherein the cytokine molecule comprises interleukin-21 (IL-21) or functional variant thereof.

139. The method, the combination therapy, the composition, or the kit of any one of claims 1-135, wherein the cytokine molecule comprises interleukin- 18 (IL- 18) or functional variant thereof.

140. The method, the combination therapy, the composition, or the kit of any one of claims 131-139, wherein the cytokine molecule comprises interleukin-2 (IL-2) or functional variant thereof.

141. The method, the combination therapy, the composition, or the kit of claim 140, wherein the interleukin-2 (IL-2) or functional variant thereof comprises the sequence of SEQ ID NO: 2270 or SEQ ID NO: 2191.

142. The composition of any one of claims 7 and 9-141, wherein the composition is pharmaceutical composition.

143. The composition or the kit of any one of claims 7-141, wherein the composition or kit further comprises a pharmaceutically acceptable carrier, diluent, or excipient.

144. A kit comprising the composition of any one of claims 7 and 9-143 or the kit of any one of claims 8-141 and 143, and instructions for administering the first agent and the second agent to a human subject in need thereof to treat a disease or condition in the human subject.

145. The method, the combination therapy, the composition, or the kit of any one of claims 1-144, wherein the first agent comprises a multispecific molecule comprising a first polypeptide, a second polypeptide, and a third polypeptide; wherein the first polypeptide, the second polypeptide and the third polypeptide are non-contiguous, wherein:(i) the first polypeptide comprises a first portion of a dimerization module linked to a first portion of the TCRpV6-binding moiety comprising a VH of the TCRpV6-binding moiety;(ii) the second polypeptide comprises a second portion of the dimerization module, wherein the IL-2 or functional fragment or functional variant thereof is covalently linked to the second polypeptide; and(iii) the third polypeptide comprises a second portion of the TCRpV6-binding moiety comprising a VL of the TCRpV6-binding moiety.

146. The method, the combination therapy, the composition, or the kit of claim 145, wherein the first polypeptide comprises a sequence with at least 80% sequence identity to SEQ ID NO: 3517 or 3348, , the second polypeptide comprises a sequence with at least 80% sequence identity to any oneWSGR Docket No. 53676-773.601 of SEQ ID NOs: 3521, 3350, and 3340, and the third polypeptide comprises a sequence with at least 80% sequence identity to SEQ ID NO: 3518 or SEQ ID NO: 3349.

147. The method, the combination therapy, the composition, or the kit of any one of claims 1-144, wherein the first agent comprises a multispecific molecule comprising a first polypeptide and a second polypeptide; wherein the first polypeptide and the second polypeptide are non-contiguous, wherein the TCRpV6-binding moiety comprises a heavy chain variable domain (VH) and a light chain variable domain (VL), or a single domain antibody, wherein(i) the first polypeptide comprises a first portion of a dimerization module linked to the TCRpV6-binding moiety; and(ii) the second polypeptide comprises a second portion of the dimerization module, wherein the IL-2 or functional fragment or functional variant thereof is covalently linked to the second polypeptide.

148. The composition, kit, method, or combination therapy of claim 147, wherein the first polypeptide comprises a sequence with at least 80% sequence identity to any one of SEQ ID NOs: 80, 83, 86, 89, 92, 95, 98, 101, 104, 110, 113, 116, 119, 122, 125, 128, 131, 134, 137, 140, 143, 146, 149, 153, 156, 159, 162, 165, 168, 171, 174, 177, 180, 183, 186, 189, 192, 195, 198, 201, 204, 206, 208, 210, 214, 216, 218, 220, 222, 224, 1309, 1326-1337, , and the second polypeptide comprises a sequence with at least 80% sequence identity to any one of SEQ ID NOs: 3521, 3350, and 3340.

149. The method, the combination therapy, the composition, or the kit of any one of claims 1-148, wherein the first agent comprising (i) a first domain that binds to TCR P V6 (TCRpV-6) subfamily or TCR P V10 (TCRpV-10) subfamily and (ii) an IL-2 cytokine molecule or a functional variant thereof.

150. The method, the combination therapy, the composition, or the kit of any one of claims 1-149, wherein the condition or disease is associated with PARP activation.

151. The method, the combination therapy, the composition, or the kit of any one of claims 1-150, wherein the condition or disease is reperfusion injury, inflammation, cardiovascular diseases, neurodegenerative diseases, aging, or cancer.

152. The method, the combination therapy, the composition, or the kit of any one of claims 1-151, wherein the condition or disease is cancer.

153. The method, the combination therapy, the composition, or the kit of claim 152, wherein the cancer is a solid tumor, a hematological cancer, a metastatic cancer, a soft tissue tumor, or a combination thereof.

154. The method, the combination therapy, the composition, or the kit of any one of claims 151-153, wherein the cancer is the solid tumor.

155. The method, the combination therapy, the composition, or the kit of claim 154, wherein the solid tumor is selected from the group consisting of colorectal cancer, gastric cancer, lung cancer, small cell lung cancer, bladder cancer, breast cancer, ovarian cancer, fallopian tube cancer, cervical cancer, peritoneal cancer, prostate cancer, castration-resistant prostate cancer, bile duct cancer,WSGR Docket No. 53676-773.601 stomach / gastro-esophageal junction cancer, urothelial cancer, pancreatic cancer, peripheral nerve sheath cancer, uterine / endometrial cancer, melanoma, and a combination thereof.

156. The method the combination therapy, the composition, or the kit of any one of claims 151-155, wherein the cancer is a metastatic castration-resistant prostate cancer.

157. The method, the combination therapy, the composition, or the kit of claim 142, wherein the subject has been previously treated with androgen deprivation therapy.

158. The method, the combination therapy, the composition, or the kit of claim 143, wherein the subject is non-responsive to androgen deprivation therapy.

159. The method, the combination therapy, the composition, or the kit of any one of claims 151-156, wherein the cancer comprises a BRCA1 and / or BRCA2 mutation.

160. The method, the combination therapy, the composition, or the kit of any one of claims 151-159, wherein the cancer is Triple Negative Breast Cancer (TNBC).

161. The method, the combination therapy, the composition, or the kit of any one of claims 151-153, wherein the cancer is the hematological cancer, and wherein the hematological cancer is selected from the group consisting of Hodgkin’s lymphoma, Non-Hodgkin’s lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia, myelodysplastic syndrome, multiple myeloma, T-cell lymphoma, acute lymphocytic leukemia, and a combination thereof.

162. The method, the combination therapy, the composition, or the kit of claim 161, wherein the NonHodgkin’s lymphoma is selected from the group consisting of B cell lymphoma, diffuse large B cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia (B-CLL), mantle cell lymphoma, marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, and a combination thereof.

163. The method, the combination therapy, the composition, or the kit of claim 162, wherein the T-cell lymphoma is peripheral T-cell lymphoma.

164. The method, the combination therapy, the composition, or the kit of any one of claims 151-163, wherein the cancer is characterized by a cancer antigen present on the cancer.

165. The method, the combination therapy, the composition, or the kit of claim 164, wherein the cancer antigen is a tumor antigen, a stromal antigen, or a hematological antigen.

166. The method, the combination therapy, the composition, or the kit of claim 164 or 165, wherein the cancer antigen is selected from the group consisting of BCMA, CD 19, CD20, CD22, FcRH5, PDL1, CD47, ganglioside 2 (GD2), prostate stem cell antigen (PSCA), prostate specific membrane antigen (PMSA), prostate-specific antigen (PSA), carcinoembryonic antigen (CEA), Ron Kinase, c- Met, Immature laminin receptor, TAG-72, BING-4, Calcium-activated chloride channel 2, Cyclin- Bl, 9D7, Ep-CAM, EphA3, Telomerase, SAP-1, Survivin, NY-ESO-l / LAGE-1, PRAME, SSX-2, Melan-A / MART-1, Gpl00 / pmell7, Tyrosinase, MC1R, (3-catenin, BRCA1 / 2, CDK4, CML66, Fibronectin, p53, Ras, TGF-B receptor, AFP, ETA, MAGE, CA-125, BAGE, GAGE, CDC27, a actinin-4, TRPl / gp75, TRP2, gangliosides, WT1, Epi-dermal growth factor receptor (EGFR), MART-2, MUC1, MUC2, MUM1, MUM2, MUM3, MSLN, NA88-1, NPM, OA1, OGT, RCC,WSGR Docket No. 53676-773.601RU11, RU12, SAGE, TRG, TSTA, Folate receptor alpha, LI -CAM, CAIX, gpA33, GD3, GM2, VEGFR, Integrins, Carbohydrates, IGF1R, TRAILR1, TRAILR2, RANKL, FAP, TGF-beta, hyaluronic acid, collagen, tenascin C, and tenascin W.

167. The method, the combination therapy, the composition, or the kit of claim 164 or 165, wherein the cancer antigen comprises Her2 / neu.

168. The method, the combination therapy, the composition, or the kit of any one of claims 1-167, wherein PARP inhibitor is a small molecule; a saccharine; an oligosaccharide; a polysaccharide; a peptide; a protein; a peptide analog; a lipid; an antibody; an antibody or antigen-binding fragment thereof; a nucleic acid; a nucleic acid analog; or any combination thereof.

169. The method, the combination therapy, the composition, or the kit of any one of claims 1-168, wherein the PARP inhibitor is a small molecule.

170. The method, the combination therapy, the composition, or the kit of any one of claims 1-169, wherein the PARP inhibitor is selected from the group consisting of ABT-767, AZD 2461, BGB-290, BGP 15, CEP 8983, CEP 9722, DR 2313, E7016, E7449, fluzoparib (SHR 3162), IMP 4297, INO1001, JP1 289, JPI 547, monoclonal antibody B3-LysPE40 conjugate, MP 124, niraparib (ZEJULA) (MK-4827), NU 1025, NU 1064, NU 1076, NU1085, olaparib (AZD2281), ONO2231, PD 128763, R 503, R554, rucaparib (RUBRACA) (AG-014699. PF-01367338). SBP 101. SC 101914, Simmiparib, talazoparib (BMN-673), veliparib (ABT-888), WW 46, 2-(4- (Trifluoromethyl)phenyl)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-ol, 4-lodo-3 -nitrobenzamide (Iniparib), -aminobenzamide, and salts or derivatives thereof.

171. The method, the combination therapy, the composition, or the kit of any one of claims 1-170, wherein the PARP inhibitor is selected from the group consisting of niraparib, olaparib, rucaparib, talazoparib, and veliparib.

172. The method, the combination therapy, the composition, or the kit of any one of claims 1-171, wherein the PARP inhibitor is niraparib or olaparib.

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