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BR-112018001931-B1 - Monospecific PD-1 anti-human binding monoclonal antibody, composition, nucleic acid expression vector, and multispecific PD-1 anti-human binding molecule.

BR112018001931B1BR 112018001931 B1BR112018001931 B1BR 112018001931B1BR-112018001931-B1

Abstract

Monospecific monoclonal antihuman PD-1 binding antibody, composition, and multispecific antihuman PD-1 binding molecule. The present invention relates to selected anti-PD-1 antibodies capable of binding to a crab-eating macaque PD-1 and a human PD-1: PD-1 mAb 1, PD-1 mAb 2, PD-1 mAb 3, PD-1 mAb 4, PD-1 mAb 5, PD-1 mAb 6, PD-1 mAb 7, PD-1 mAb 8, PD-1 mAb 9, PD-1 mAb 10, PD-1 mAb 11, PD-1 mAb 12, PD-1 mAb 13, PD-1 mAb 14, or PD-1 mAb 15, and to humanized and chimeric versions of these antibodies. The invention further relates to PD-1 binding molecules comprising PD-1 binding fragments of these anti-PD-1 antibodies, immunoconjugates, and to bispecific molecules, including diabodies, BiTEs, bispecific antibodies, etc., comprising (i) these PD-1 binding fragments, and (ii) a domain capable of binding to an epitope of a molecule involved in the regulation of an immune checkpoint present on the surface of an immune cell. The present invention also relates to methods of using PD-1 binding molecules to stimulate immune responses, as well as methods of detecting PD-1.

Inventors

  • Kalpana Shah
  • DOUGLAS H. SMITH
  • Ross La Motte-Mohs
  • LESLIE S. JOHNSON
  • PAUL A. MOORE
  • Ezio Bonvini
  • Scott Koenig

Assignees

  • MACROGENICS, INC

Dates

Publication Date
20260310
Application Date
20160728
Priority Date
20150730

Claims (20)

  1. 1. ANTI-HUMAN PD-1 MONOSPECIFIC MONOCLONAL ANTIBODY, characterized by comprising a Variable Heavy Chain Domain and a Variable Light Chain Domain, wherein: said Variable Heavy Chain Domain comprises a CDRH1 Domain, a CDRH2 Domain and a CDRH3 Domain, and said Variable Light Chain Domain comprises a CDRL1 Domain, a CDRL2 Domain and a CDRL3 Domain, wherein: (1) the CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain are the mAb 7(1.2) mD-1 Heavy Chain CDRs, and respectively comprise the amino acid sequences: SEQ ID NO:139, SEQ ID NO:140, and SEQ ID NO:141; and (2) the CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain are the Light Chain CDRs of mAb 7(1.2) of hPD-1, and respectively comprise the amino acid sequences: SEQ ID NO:157, SEQ ID NO:145, and SEQ ID NO:146.
  2. 2. ANTIBODY, according to claim 1, characterized in that said antibody is a chimeric antibody or a humanized antibody.
  3. 3. ANTIBODY, according to either of claims 1 or 2, wherein said antibody is characterized by comprising a Variable Heavy Chain Domain having the amino acid sequence of SEQ ID NO:147 or SEQ ID NO:149.
  4. 4. ANTIBODY, according to any one of claims 1 to 3, wherein said antibody is characterized by comprising a Variable Light Chain Domain having the amino acid sequence of SEQ ID NO:153.
  5. 5. ANTIBODY, according to any one of claims 1 to 4, wherein said antibody is characterized by comprising a Variable Heavy Chain Domain comprising the amino acid sequence of SEQ ID NO:147.
  6. 6. ANTIBODY, according to any one of claims 1 to 4, wherein said antibody is characterized by comprising a Variable Heavy Chain Domain having the amino acid sequence of SEQ ID NO:147, and wherein said antibody comprises a Variable Light Chain Domain having the amino acid sequence of SEQ ID NO:153.
  7. 7. ANTIBODY, according to any one of claims 1 to 6, characterized in that said antibody comprises an Fc region.
  8. 8. ANTIBODY, according to claim 7, characterized by said Fc Region being of the IgG1, IgG2, IgG3 or IgG4 isotype.
  9. 9. ANTIBODY, according to claim 8, characterized in that said antibody further comprises a Hinge Domain.
  10. 10. ANTIBODY, according to claim 9, characterized in that said Fc Region and said Hinge Domain are of the IgG4 isotype, and wherein said Hinge Domain comprises a stabilizing mutation.
  11. 11. ANTIBODY, according to any one of claims 7 to 9, characterized in that said antibody comprises SEQ ID NOS: 264 and 265.
  12. 12. ANTIBODY, according to any one of claims 8 to 10, characterized in that said antibody comprises SEQ ID NOS: 264 and 266.
  13. 13. ANTIBODY, according to any one of claims 7 to 10, characterized in that said Fc Region is a variant Fc Region comprising: (a) one or more amino acid modifications that reduce the affinity of the variant Fc Region to an FCYR; and/or (b) one or more amino acid modifications that enhance the serum half-life of the variant Fc Region.
  14. 14. ANTIBODY, according to claim 13, characterized by said modifications that reduce the affinity of the variant Fc Region to an FcyR comprising the replacement of L234A; L235A; or L234A and L235A, wherein said numbering is that of the EU index as in Kabat.
  15. 15. ANTIBODY, according to any one of claims 13 or 14, characterized in that said modifications that improve the serum half-life of the variant Fc Region comprise the substitution of M252Y; M252Y and S254T; M252Y and T256E; M252Y, S254T and T256E; or K288D and H435K, wherein said numbering is that of the EU index as in Kabat.
  16. 16. ANTIBODY, according to any one of claims 1 to 15, characterized in that said antibody is detectably labeled and is used in the detection of PD-1.
  17. 17. COMPOSITION, characterized by comprising the pd-1 binding monoclonal antibody, as defined in any one of claims 1 to 15, and a pharmaceutically acceptable carrier.
  18. 18. ANTIBODY, according to any one of claims 1 to 15, or COMPOSITION, according to claim 17, wherein said antibody or composition is characterized by being used to stimulate a T cell-mediated immune response in an individual who needs it.
  19. 19. ANTIBODY, according to any one of claims 1 to 15, or COMPOSITION, according to claim 17, wherein said antibody or composition is characterized by being used in the treatment of a disease or condition associated with a suppressed immune system.
  20. 20. ANTIBODY, according to claim 19, characterized by the disease or condition being cancer or an infection.

Description

CROSS-REFERENCE TO RELATED ORDERS [0001] This application claims priority to U.S. Patent Applications Serial Nos. 62/198,867 (filed July 30, 2015; pending), 62/239,559 (filed October 9, 2015; pending), 62/255,140 (filed November 13, 2015; pending), and 62/322,974 (filed April 15, 2016; pending), each of which applications is incorporated herein by reference in its entirety. REFERENCE TO THE LISTING OF SEQUENCES [0002] This application includes one or more Sequence Listings pursuant to 37 CFR 1.821 et seq., which are disclosed in machine-readable media (filename: 1301_0122PCT_Sequence_Listing_ST25.txt, created on July 1, 2016, and having a size of 282,789 bytes), this file is incorporated herein by reference in its entirety. FIELD OF THE INVENTION [0003] The present invention relates to PD-1 binding molecules comprising the PD-1 binding domain of selected anti-PD-1 antibodies capable of binding to crab-eating macaque PD-1 and human PD-1: PD-1 mAb 1, PD-1 mAb 2, PD-1 mAb 3, PD-1 mAb 4, PD-1 mAb 5, PD-1 mAb 6, PD-1 mAb 7, PD-1 mAb 8, PD-1 mAb 9, PD-1 mAb 10, PD-1 mAb 11, PD-1 mAb 12, PD-1 mAb 13, PD-1 mAb 14 or PD-1 mAb 15. The invention particularly relates to PD-1 binding molecules that are humanized or chimeric versions of these antibodies, or that comprise PD-1 binding fragments of these anti-PD-1 antibodies (especially immunoconjugates, diabodies, BiTEs, bispecific antibodies, etc.). The invention particularly relates to these PD-1 binding molecules that are additionally capable of binding to an epitope of a molecule involved in the regulation of an immune checkpoint that is present on the surface of an immune cell. The present invention also pertains to methods of utilizing these PD-1 binding molecules to detect PD-1 or stimulate an immune response. The present invention also pertains to combination therapy methods in which a PD-1 binding molecule comprising one or more PD-1 binding domain(s) of these selected anti-PD-1 antibodies is administered in combination with one or more additional molecules that are effective in stimulating an immune response and/or in combination with one or more additional molecules that specifically bind to a cancer antigen. HISTORY OF THE INVENTION Cell-mediated immune responses [0004] The immune system of humans and other mammals is responsible for providing protection against infection and disease. This protection is provided by a humoral immune response and a cell-mediated immune response. The humoral response results in the production of antibodies and other biomolecules that are capable of recognizing and neutralizing foreign targets (antigens). In contrast, the cell-mediated immune response involves the activation of antigen-specific cytotoxic macrophages, Natural Killer (NK) cells, and T-lymphocytes, and the release of various cytokines in response to the recognition of an antigen (Dong, C. et al. (2003) “Immune Regulation by Novel Costimulatory Molecules,” Immunolog. Res. 28(1):39-48). [0005] The ability of T cells to optimally mediate an immune response against an antigen requires two distinct signaling interactions (Viglietta, V. et al. (2007) “Modulating Co-Stimulation,” Neurotherapeutics 4:666675; Korman, A.J. et al. (2007) “Checkpoint Blockade in Cancer Immunotherapy,” Adv. Immunol. 90:297-339). First, the antigen that has been placed on the surface of Antigen-Presenting Cells (APCs) must be presented to an antigen-specific natural CD4+ T cell. This presentation releases a signal via the T Cell Receptor (TCR) that directs the T cell to initiate an immune response that will be specific to the presented antigen. Secondly, a series of co-stimulatory and inhibitory signals, mediated by interactions between the APC and distinct T cell surface molecules, triggers, first, the activation and proliferation of T cells and, ultimately, their inhibition. Thus, the first signal confers specificity to the immune response while the second signal serves to determine the nature, magnitude, and duration of the response. [0006] The immune system is strictly controlled by costimulatory and coinhibitory ligands and receptors. These molecules provide the second signal for T cell activation and provide a balanced network of positive and negative signals to maximize immune responses against infection, while limiting immunity alone (Wang, L. et al. (March 7, 2011) “VISTA, A Novel Mouse Ig Superfamily Ligand That Negatively Regulates T-Cell Responses,” J. Exp. Med. 10.1084/jem.20100619:1-16; Lepenies, B. et al. (2008) “The Role Of Negative Costimulators During Parasitic Infections,” Endocrine, Metabolic & Immune Disorders - Drug Targets 8:279-288). The binding between the B7.1 (CD80) and B7.2 (CD86) ligands of the Antigen-Presenting Cell and the CD28 and CTLA-4 receptors of the CD4+ T lymphocyte is particularly important (Sharpe, A.H. et al. (2002) “The B7-CD28 Superfamily,” Nature Rev. Immunol. 2:116-126; Dong, C. et al. (2003) “Immune Regulation by Novel Costimulatory Molecules,” Immuno