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BR-112018071153-B1 - Human Anti-Vista Antibody, its Use and Pharmaceutical Composition or for Diagnosis

BR112018071153B1BR 112018071153 B1BR112018071153 B1BR 112018071153B1BR-112018071153-B1

Abstract

The invention provides antagonist and agonist antibodies and antibody fragments of human anti-VISTA. These antagonist antibodies and antibody fragments can be used to inhibit or block the suppressive effects of VISTA on T-cell immunity and thereby promote T-cell immunity. These agonist antibodies and antibody fragments can be used to potentiate, enhance, or mimic the suppressive effects of VISTA on T-cell immunity and thereby suppress T-cell immunity. These antagonist antibodies and antibody fragments are especially useful in the treatment of cancer and infectious conditions. These agonist antibodies and antibody fragments are especially useful in the treatment of autoimmunity, allergy, inflammatory conditions, GVHD, sepsis, and transplant recipients. Screening assays for the identification of these agonists are also provided.

Inventors

  • Michael Molloy
  • Jay Rothstein
  • Dov PECHENICK
  • Linda Snyder
  • Gordon Powers

Assignees

  • Janssen Pharmaceuticals, Inc.
  • ImmuNext, Inc

Dates

Publication Date
20260310
Application Date
20170414
Priority Date
20160809

Claims (6)

  1. 1. Isolated antibody, characterized in that it comprises an antigen-binding region that specifically binds to the V domain of the T-cell Activation Suppressor Ig (human VISTA), wherein the antibody agonizes or promotes one or more of the effects of VISTA on T-cell immunity; and wherein said antibody comprises an unmodified human IgG2 Fc region or human IgG2 constant that binds to Fc gamma receptors including human CD32A; and said human IgG2 antibody comprises humanized variable heavy and light polypeptides featuring CDR polypeptides selected from the following: (i) the VH CDRs of SEQ ID NO: 130, 131 and 132 and the VL CDRs of SEQ ID NO: 133, 134 and 135; or (ii) the VH CDRs of SEQ ID NO: 150, 151 and 152 and the VL CDRs of SEQ ID NO: 153, 154 and 155; or(iii) the VH CDRs of SEQ ID NO: 200, 201 and 202 and the VL CDRs of SEQ ID NO: 203, 204 and 205; or(iv) the VH CDRs of SEQ ID NO: 340, 341 and 342 and the VL CDRs of SEQ ID NO: 343, 344 and 345; or (v) the VH CDRs of SEQ ID NO: 370, 371 and 372 and the VL CDRs of SEQ ID NO: 373, 374 and 375; or(vi) the VH CDRs of SEQ ID NO: 380, 381 and 382 and the VL CDRs of SEQ ID NO: 383, 384 and 385; or(vii) the VH CDRs of SEQ ID NO: 400, 401 and 402 and the VL CDRs of SEQ ID NO: 403, 404 and 405; or(viii) the VH CDRs of SEQ ID NO: 470, 471 and 472 and the VL CDRs of SEQ ID NO: 473, 474 and 475; or(ix) the VH CDRs of SEQ ID NO: 500, 501 and 502 and the VL CDRs of SEQ ID NO: 503, 504 and 505; or (x) the VH CDRs of SEQ ID NO: 740, 741 and 742 and the VL CDRs of SEQ ID NO: 743, 744 and 745; or (xi) the VH CDRs of SEQ ID NO: 770, 771 and 772 and the VL CDRs of SEQ ID NO: 773, 774 and 775.
  2. 2. Antibody according to claim 1, characterized in that: (i) it comprises the HV polypeptide of SEQ ID NO: 136 and the VL polypeptide of SEQ ID NO: 138; or (ii) it comprises the HV polypeptide of SEQ ID NO: 156 and the VL polypeptide of SEQ ID NO: 158; or (iii) it comprises the HV polypeptide of SEQ ID NO: 206 and the VL polypeptide of SEQ ID NO: 208; or (iv) it comprises the HV polypeptide of SEQ ID NO: 346 and the VL polypeptide of SEQ ID NO: 348; or (v) it comprises the HV polypeptide of SEQ ID NO: 376 and the VL polypeptide of SEQ ID NO: 378; or(vi) comprises the VH polypeptide of SEQ ID NO: 386 and the VL polypeptide of SEQ ID NO: 388; or(vii) comprises the VH polypeptide of SEQ ID NO: 406 and the VL polypeptide of SEQ ID NO: 408; or(viii) comprises the VH polypeptide of SEQ ID NO: 476 and the VL polypeptide of SEQ ID NO: 478; or(ix) comprises the VH polypeptide of SEQ ID NO: 506 and the VL polypeptide of SEQ ID NO: 508; or(x) comprises the VH polypeptide of SEQ ID NO: 746 and the VL polypeptide of SEQ ID NO: 748; or(xi) comprises the VH polypeptide of SEQ ID NO: 776 and the VL polypeptide of SEQ ID NO: 778.
  3. 3. Pharmaceutical or diagnostic composition, characterized in that it comprises at least one antagonist or agonist antibody, as defined in claim 1 or 2.
  4. 4. Use of at least one agonist antibody, as defined in claim 1 or 2, characterized in that it is for the preparation of a medicament for the treatment of an allergic condition, autoimmune condition, inflammatory condition, GVHD or sepsis, or for treating or preventing inflammatory, autoimmune or allergic side effects associated with transplantation, gene therapy or cancer in a human individual.
  5. 5. Use according to claim 4, characterized in that the medicament further comprises another immunomodulatory antibody or fusion protein selected from immunoinhibitory antibodies or fusion proteins targeting one or more of CTLA4, PD-1, PDL-1, LAG-3, TIM-3, BTLA, B7-H4, B7-H3, VISTA, CD40, CD137, OX40, GITR, CD27, CD28 or ICOS.
  6. 6. Use, according to claim 4 or 5, characterized in that it includes in vitro analysis of the VISTA protein by the individual's cells or in body fluids before, during and/or after treatment, preferably in that it includes in vitro analysis of VISTA levels in hematopoietic cells; more preferably in that it includes in vitro analysis of VISTA levels in selected hematopoietic cells from any one or more of the following cell lines: myeloid and/or lymphocytes, monocytes or neutrophils, T cells, B cells, natural killer (NK) cells or natural killer T (NKT) cells.

Description

RELATED ORDERS [001] This application claims priority for U.S. Provisional Application No. 62/323,193 filed April 15, 2016, 62/343,355 filed May 31, 2016, 62/372,362 filed August 9, 2016, 62/385,627 filed September 9, 2016, 62/425,184 filed November 22, 2016, 62/363,929 filed July 19, 2016, 62/365,085 filed July 21, 2016, 62/385,805 filed September 9, 2016, 62/363,931 filed July 19 of 2016, 62/365.102 deposited on July 21, 2016, 62/385.871 deposited on September 9, 2016, 62/363.917 deposited on July 19, 2016, 62/365.081 deposited on July 21, 2016, 62/385.888 deposited on September 9, 2016, 62/364.073 deposited on July 19, 2016, 62/365.166 deposited on July 21, 2016, 62/385.893 deposited on September 9, 2016, 62/363.925 deposited on July 19, 2016, 62/365.087 filed on July 21, 2016, 62/385.785 filed on September 9, 2016, 62/406.632 filed on October 11, 2016, each and every one of which is incorporated herein by reference. This application refers to PCT Application _______________ filed on April __, 2017 "ANTI-HUMAN VISTA ANTIBODIES AND USE THEREOF" (Legal Registry No. 43260.2214) which is being incorporated by reference and to which priority is also claimed. FIELD [002] The invention relates to the identification of human anti-VISTA antibodies and antibody fragments, that is, VISTA antibodies and antibody fragments (V-region Immunoglobulin-containing Suppressor of T cell Activation ("VISTA"). More specifically, the present application provides novel human VISTA agonists, that is, human anti-VISTA antibodies and antibody fragments that agonize or promote the suppressive effects of human VISTA on immunity, particularly on T cell immunity. Furthermore, the invention relates to the use of such agonists to potentiate or mimic the suppressive effects of VISTA on immunity, such as its suppressive effects on CD4+ or CD8- T cell proliferation or CD4+ or CD8+ cell activation and its suppressive effect on the production of immune cytokines, particularly pro-inflammatory cytokines. The invention also relates to the specific use of these agonist antibodies and antibody fragments as prophylactic or therapeutic agents, especially in the treatment of conditions where the prevention or inhibition of T-cell immunity and the expression of pro-inflammatory cytokines is therapeutically beneficial, such as autoimmunity, inflammation, allergic disorders, sepsis, GVHD, or in relieving the inflammatory side effects of some conditions, such as cancer. [003] The present application also provides novel antagonists, such as human anti-VISTA antibodies and antibody fragments, which antagonize or inhibit the suppressive effects of human VISTA on immunity, particularly the effects of VISTA on T-cell immunity. Furthermore, the invention relates to the use of these novel antagonists to block or inhibit the suppressive effects of VISTA on immunity, that is, its suppressive effects on CD4+ or CD8+ cell proliferation, CD4+ or CD8+ T-cell activation, and immune cytokine production. The invention also relates to the specific use of these antagonist antibodies and antibody fragments as prophylactics or therapeutics, especially in the treatment of conditions where promoting T-cell immunity is therapeutically beneficial, such as in the treatment of cancer and infectious diseases. BACKGROUND [004] Negative checkpoint regulator (NCR) immune pathways have proven to be extraordinary clinical targets in the treatment of immune-related diseases. Blocking two NCRs, CTLA-4 and PD-1, using monoclonal antibodies (mAbs) to potentiate tumor immunity is revolutionizing cancer treatment and has established these pathways as clinically validated targets in human diseases. In addition, soluble versions of NCR ligands that trigger NCR pathways have entered the clinic as immunosuppressive drugs to treat autoimmunity (i.e., AMP-110/B7-H4-Ig for rheumatoid arthritis). [005] VISTA (see Ref 1) is an NCR ligand whose closest phylogenetic relative is PD-L1. VISTA has homology to PD-L1, but shows a unique expression pattern that is restricted to the hematopoietic compartment. Specifically, VISTA is constitutively and highly expressed in CD11balto myeloid cells and expressed at lower levels in CD3+ and CD8+ T cells. Like PD-L1, VISTA is a ligand that profoundly suppresses immunity (Ref 1) and, like PD-L1, VISTA blockade allows the development of therapeutic immunity to cancer in preclinical oncology models (see Ref 2). While VISTA blockade potentiates immunity, especially in CD8+ and CD4+T cell-mediated immunity, treatment with a soluble Ig fusion protein in the extracellular domain of VISTA (VISTA-Ig) suppresses immunity and has been shown to halt progression in multiple murine models of autoimmune disease. [006] Clear scientific evidence has shown that VISTA is a ligand that induces profound T-cell suppression. Several anti-human VISTA antagonist antibodies have been reported by different groups, including Dartmouth College and Jannsen. These antibodies are useful in treati