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US-12617855-B2 - Anti-PD-L1 antibodies

US12617855B2US 12617855 B2US12617855 B2US 12617855B2US-12617855-B2

Abstract

The invention relates to programmed death-ligand 1 (PD-L1) binding agents, nucleic acids comprising the inventive binding agents, vectors and cells comprising the inventive nucleic acids, and compositions thereof. The invention also relates to methods of producing the inventive binding agents, methods for treating a disease, disorder, or condition in a mammal, and methods for enhancing or reducing or inhibiting an immune response in a mammal.

Inventors

  • Michael N. Alonso
  • David Dornan
  • Karla Henning
  • Justin Kenkel
  • Marcin KOWANETZ
  • Heidi Leblanc
  • William Mallet

Assignees

  • BOLT BIOTHERAPEUTICS, INC.

Dates

Publication Date
20260505
Application Date
20210121

Claims (20)

  1. 1 . A programmed death-ligand 1 (PD-L1) binding agent comprising an immunoglobulin heavy chain variable region polypeptide and an immunoglobulin light chain variable region polypeptide, wherein: (a) the immunoglobulin heavy chain variable region polypeptide comprises a complementarity determining region 1 (HCDR1) comprising SEQ ID NO: 17, a complementarity determining region 2 (HCDR2) comprising SEQ ID NO: 311, and a complementarity determining region 3 (HCDR3) comprising SEQ ID NO: 79, and the immunoglobulin light chain variable region polypeptide comprises a complementarity determining region 1 (LCDR1) comprising SEQ ID NO: 98, a complementarity determining region 2 (LCDR2) comprising SEQ ID NO: 129, and a complementarity determining region 3 (LCDR3) comprising SEQ ID NO: 155, or (b) the immunoglobulin heavy chain variable region polypeptide comprises a HCDR1 comprising SEQ ID NO: 9, a HCDR2 comprising SEQ ID NO: 348, and a HCDR3 comprising SEQ ID NO: 352, and the immunoglobulin light chain variable region polypeptide comprises a LCDR1 comprising SEQ ID NO: 97, a LCDR2 comprising SEQ ID NO: 358, and a LCDR3 comprising SEQ ID NO: 360.
  2. 2 . A programmed death-ligand 1 (PD-L1) binding agent comprising (a) an immunoglobulin heavy chain variable region of SEQ ID NO: 333 or at least the complementarity determining regions (CDRs) thereof; and an immunoglobulin light chain variable region of SEQ ID NO: 281 or at least the CDRs thereof, or (b) an immunoglobulin heavy chain variable region of SEQ ID NO: 363 or at least the CDRs thereof; and an immunoglobulin light chain variable region of SEQ ID NO: 368 or at least the CDRs thereof.
  3. 3 . A programmed death-ligand 1 (PD-L1) binding agent comprising (a) an immunoglobulin heavy chain variable region polypeptide with an amino acid sequence that is at least 90% identical to SEQ ID NO: 333, and an immunoglobulin light chain variable region polypeptide with an amino acid sequence that is at least 90% identical to SEQ ID NO: 281, or (b) an immunoglobulin light chain variable region polypeptide with an amino acid sequence that is at least 90% identical to SEQ ID NO: 363, and an immunoglobulin light chain variable region polypeptide with an amino acid sequence that is at least 90% identical to SEQ ID NO: 368.
  4. 4 . The PD-L1 binding agent of claim 1 , wherein the binding agent is an antibody, an antibody conjugate, or an antigen-binding fragment thereof.
  5. 5 . The PD-L1 binding agent of claim 4 , wherein the binding agent is an antibody fragment selected from F(ab′) 2 , Fab′, Fab, Fv, scFv, dsFv, dAb, and a single chain binding polypeptide.
  6. 6 . The PD-L1 binding agent of claim 4 , wherein the binding agent is an antibody.
  7. 7 . The PD-L1 binding agent of claim 1 , further comprising an immunoglobulin Fc region.
  8. 8 . The PD-L1 binding agent of claim 7 , further comprising a transforming growth factor beta 1 (TGFβ1) receptor, or a fragment thereof that binds TGFβ1, attached to the Fc region.
  9. 9 . The PD-L1 binding agent of claim 6 , wherein the antibody is an IgG, IgM, IgA, IgD or IgE antibody.
  10. 10 . The PD-L1 binding agent of claim 6 , wherein the antibody is an IgG antibody.
  11. 11 . The PD-L1 binding agent of claim 6 , wherein the antibody exhibits antibody dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), or complement dependent cytotoxicity (CDC).
  12. 12 . The PD-L1 binding agent of claim 1 , wherein the binding agent is part of a bispecific antibody, chimeric antigen receptor, chimeric T cell receptor, or bispecific T-cell engager.
  13. 13 . The PD-L1 binding agent of claim 1 , wherein the binding agent is an internalizing binding agent.
  14. 14 . A nucleic acid encoding the heavy chain immunoglobulin polypeptide of the anti-PD-L1 binding agent of claim 1 .
  15. 15 . A nucleic acid encoding the light chain immunoglobulin polypeptide of the anti-PD-L1 binding agent of claim 1 .
  16. 16 . A nucleic acid encoding the heavy chain immunoglobulin polypeptide and the light chain immunoglobulin polypeptide of the PD-L1 binding agent of claim 1 .
  17. 17 . A vector comprising the nucleic acid sequence encoding the heavy and/or light chains of the anti-PD-L1 binding agent of claim 1 .
  18. 18 . An isolated cell comprising the nucleic acid encoding the heavy and/or light chains of the anti-PD-L1 binding agent of claim 1 , optionally in a vector.
  19. 19 . A method of providing a PD-L1 binding agent of claim 1 , the method comprising expressing in a cell in vitro one or more nucleic acids encoding the immunoglobulin heavy and light chain polypeptides thereof.
  20. 20 . A composition comprising the PD-L1 binding agent of claim 1 or a nucleic acid encoding the heavy and/or light chains of same, optionally in a vector, and a pharmaceutically acceptable carrier.

Description

CROSS-REFERENCE TO RELATED APPLICATION This patent application is the U.S. national phase of International Patent Application No. PCT/US2021/014346, filed Jan. 21, 2021, which claims the benefit of U.S. Provisional Patent Application No. 62/963,771, filed Jan. 21, 2020, which is incorporated by reference in its entirety herein. INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ELECTRONICALLY Incorporated by reference in its entirety herein is a computer-readable nucleotide/amino acid sequence listing submitted concurrently herewith and identified as follows: One 187,026 Byte ASCII (Text) file named “763639_ST25.txt” created Jul. 19, 2022. BACKGROUND OF THE INVENTION Programmed Death-Ligand 1 (PD-L1, cluster of differentiation 274, CD274, B7-homolog 1, or B7-H1) belongs to the B7 protein superfamily, and is a ligand of programmed cell death protein 1 (PD-1, PDCD1, cluster of differentiation 279, or CD279). PD-L1 can also interact with B7.1 (CD80) and such interaction is believed to inhibit T cell priming. The PD-L1/PD-1 axis plays a large role in suppressing the adaptive immune response. More specifically, it is believed that engagement of PD-L1 with its receptor, PD-1, delivers a signal that inhibits activation and proliferation of T-cells. Agents that bind to PD-L1 and prevent the ligand from binding to the PD-1 receptor prevent this immunosuppression, and can, therefore, enhance an immune response when desired, such as for the treatment of cancers, or infections. PD-L1/PD-1 pathway also contributes to preventing autoimmunity and therefore agonistic agents against PD-L1 or agents that deliver immune inhibitory payloads may help treatment of autoimmune disorders. Several antibodies targeting PD-L1 have been developed for the treatment of cancer, including atezolizumab (TECENTRIQ™), durvalumab (IMFINZI™), and avelumab (BAVENCIO™). Nevertheless, there continues to be a need for new PD-L1-binding agents, including agents that bind PD-L1 with high affinity and effectively prevent PD-L1/PD-1 signaling and agents that can deliver therapeutic payloads to PD-L1 expressing cells. In addition, there is a need for new PD-L1-binding agents to treat autoimmune disorders and infections. BRIEF SUMMARY OF THE INVENTION Provided herein are PD-L1 binding agents comprising an immunoglobulin heavy chain variable region polypeptide and an immunoglobulin light chain variable region polypeptide. In some embodiments, the PD-L1 binding agents comprise an immunoglobulin heavy chain variable region of any one of SEQ ID NOs: 223-264, 324-334, or 361-365, or at least the CDRs thereof; and an immunoglobulin light chain variable region of any one of SEQ ID NOs: 265-306, 335-344, or 366-370 or at least the CDRs thereof. In other embodiments, the PD-L1 binding agents comprise an immunoglobulin heavy chain variable region polypeptide with an amino acid sequence that is at least 90% identical to any one of SEQ ID NOs: 223-264, 324-334, or 361-365, and an immunoglobulin light chain variable region polypeptide with an amino acid sequence that is at least 90% identical to any one of SEQ ID NOs: 265-306, 335-344, or 366-370. In yet other embodiments, the PD-L1 binding agent, the immunoglobulin heavy chain variable region polypeptide comprises a complementarity determining region 1 (HCDR1) comprising any one of SEQ ID NOs: 1-23, 309, or 345, a complementarity determining region 2 (HCDR2) comprising any one of SEQ ID NOs: 24-57, 310-314, or 346-349, and a complementarity determining region 3 (HCDR3) comprising any one of SEQ ID NOs: 58-95, 315-318, or 350-354; and/or the immunoglobulin light chain variable region polypeptide comprises a complementarity determining region 1 (LCDR1) comprising any one of SEQ ID NOs: 96-128, 319-323, 355, or 356, a complementarity determining region 2 (LCDR2) comprising any one of SEQ ID NOs: 129-151 or 357-359, and a complementarity determining region 3 (LCDR3) comprising any one of SEQ ID NOs: 152-176 or 360. Also provided are nucleic acids encoding the PD-L1 binding agents, or the individual heavy and light chains thereof vectors and cells comprising the nucleic acids; and compositions comprising the binding agents or nucleic acids. Also provided is a method of preparing a binding agent as described herein, which method comprises expressing in a cell one or more nucleic acids encoding the heavy and light chain variable region polypeptides of the binding agent. Further provided is a method of delivering a payload to a cell expressing PD-L1 comprising administering to the cell, or mammal comprising the cell, a PD-L1 binding agent provided herein conjugated to the payload. Also provided is a method for enhancing or reducing or inhibiting an immune response in a mammal, and a method for treating a disease, disorder, or condition in a mammal that is responsive to PD-L1 inhibition, which methods comprise administering a binding agent as described herein, or conjugate thereof, to the mammal. Additional aspects and embodim