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US-20260125450-A1 - NOVEL CTLA4-IG IMMUNOADHESINS

US20260125450A1US 20260125450 A1US20260125450 A1US 20260125450A1US-20260125450-A1

Abstract

The present application relates to CTLA4-Ig immunoadhesins that target CD80 and CD86, and their use, particularly for therapeutic purposes.

Inventors

  • Gregory A. Lazar
  • Matthew J. Bernett

Assignees

  • XENCOR, INC.

Dates

Publication Date
20260507
Application Date
20251029

Claims (8)

  1. 1 . An immunoadhesin comprising a first domain comprising a variant CTLA4 as compared to SEQ ID NO:2 and a second domain comprising an IgG Fc region, wherein said CTLA4 variant comprises an amino acid modification selected from the group consisting of T51N, A29H, M53Y, L61E, and K93Q, wherein said variant provides enhanced binding to B7-1, B7-2, or both B7-1 and B7-2.
  2. 2 . An immunoadhesin according to claim 1 , wherein said variant comprises a combination of substitutions selected from the group consisting of A29H/K93Q, A29H/M53Y, A29H/T51N, T51N/K93Q, T51N/M53Y, A29H/L61E/K93Q, A29H/M53Y/K93Q, A29H/M53Y/L61E, A29H/T51N/L61E, M53Y/L61E/K93Q, T51N/L61E/K93Q, T51N/M53Y/L61E, A29H/M53Y/L61E/K93Q, A29H/T51N/L61E/K93Q, A29H/T51N/M53Y/K93Q, A29H/T51N/M53Y/L61E, T51N/M53Y/L61E/K93Q, and A29H/T51N/M53Y/L61E/K93Q.
  3. 3 . An immunoadhesin according to claim 2 , wherein said variant comprises a combination of substitutions selected from the group consisting of T51N/L61E/K93Q, A29H/T51N/L61E/K93Q, A29H/T51N, T51N/M53Y, and T51N/M53Y/L61E.
  4. 4 . A method of treating a patient with an immune related disorder, wherein said treatment comprises the step of administering to said patient an immunoadhesin comprising an amino acid sequence corresponding to SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, or SEQ ID NO:33.
  5. 5 . A method of treatment according to claim 4 , wherein said immune related disorder is selected from the group consisting of Crohn's disease, systemic lupus erythematosus (SLE), lupus nephritis, psoriatic arthritis, psoriasis, rheumatoid arthritis, ulcerative colitis, and transplant rejection.
  6. 6 . A nucleic acid encoding the immunoadhesin of claim 1 .
  7. 7 . A host cell comprising the nucleic acid of claim 6 .
  8. 8 . A method of making an immunoadhesin comprising culturing the host cell of claim 7 under conditions wherein said immunoadhesin is produced.

Description

This application is a continuation of U.S. application Ser. No. 17/736,917, filed on May 4, 2022, which is a continuation of U.S. application Ser. No. 16/189,917 (now U.S. Pat. No. 11,352,412), filed on Nov. 13, 2018, which is a continuation of U.S. application Ser. No. 15/159,667 (now U.S. Pat. No. 10,155,800), filed on May 19, 2016, which is a divisional of U.S. application Ser. No. 14/142,705 (now U.S. Pat. No. 9,371,397), filed on Dec. 27, 2013, which is a divisional of U.S. application Ser. No. 13/710,305 (now U.S. Pat. No. 8,629,113), filed on Dec. 10, 2012, which is a divisional of U.S. patent application Ser. No. 13/032,491 (now U.S. Pat. No. 8,329,867), filed on Feb. 22, 2011, which claims priority to U.S. Provisional Application No. 61/412,309, filed on Nov. 10, 2010, U.S. Provisional Application No. 61/334,806, filed on May 14, 2010, and U.S. Provisional Application No. 61/306,311, filed on Feb. 19, 2010, the disclosures of each of which are hereby incorporated by reference in their entireties. SEQUENCE LISTING The contents of the electronic sequence listing (121168000409_ZEN-003US8_SL_ST26.xml; Size: 71,778 bytes; and Date of Creation: Nov. 23, 2025) is herein incorporated by reference in its entirety. FIELD OF THE INVENTION The present application relates to CTLA4-Ig immunoadhesins that target CD80 and CD86, and their use, particularly for therapeutic purposes. BACKGROUND OF THE INVENTION T lymphocytes play a central role in the adaptive immune response to antigen. Naive T cells require two signals for their full activation (Bretscher 1999, Proc Natl Acad Sci USA 96:185-90). The first signal is antigen-specific and is provided by interaction of the T-cell receptor (TCR) with MHC/peptide complex on an antigen-presenting cell (APC). The second signal is a costimulatory signal provided by the interactions between receptors on the T cell and their ligands on the APC. Engagement of both TCR/MHC and co-stimulatory interactions leads to T-cell activation via a number of intracellular pathways, including calcium-calcineurin and RAS mitogen-activated protein kinase, and subsequent activation of transcription factors for a number of effector compounds, including cytokines such as IL-2. These events lead to T-cell proliferation, generation of a CD4+ helper T-cell (TH) pool, and expansion of activated CD8+ cytotoxic T cells. Not only is co-stimulation critical for full T-cell activation, its absence during TCR/MHC engagement results in anergy and/or apoptosis. Although multiple positive and negative costimulatory pathways are involved in T-cell regulation, the most critical are between CD28 on T cells and B7-1 (CD80) and B7-2 (CD86) on APCs. CD28 promotes T-cell differentiation into TH1 phenotype cells and enhances antibody production by B cells and activation of T cells. B7-1 and B7-2, expressed on APCs such as dendritic cells (DC) and B cells, have overlapping but distinct functions. B7-2 is constitutively expressed and is rapidly upregulated on APCs coincident with TCR/MHC engagement (signal 1). B7-1 expression is very low on the resting cell, but is typically induced after prolonged T-cell stimulation. These differences suggest that while B7-2 may be important in initialization of T-cell activation, B7-1 may play a greater role in perpetuating the immune response. Subsequent to T-cell activation, a negative regulatory receptor Cytotoxic T-Lymphocyte Antigen 4 (CTLA4 or CTLA-4, also called CD152), is upregulated on T cells (Alegre et al., 2001, Nat Rev Immunol 1:220-8). CTLA4 is structurally homologous to CD28 but binds more tightly to both B7-1 and B7-2 ligands. CLTA4 inhibits the immune response in two principal ways—it competes with CD28 for the B7 ligands and thus blocks costimulation, and it also negatively signals to inhibit T cell activation (Krummel and Allison, 1995, J Exp Med 182:459-465; Walunas et al., 1994, Immunity 1:405-413). Recent work has shown that B7-2 engages CD28 more than CTLA4 at the immune synapse, while B7-1 ligates more CTLA4 than CD28 (Collins et al., 2002, Immunity 17:201-210; Jansson et al., 2005, J Immunol 175:1575-1585). Because of the critical role of the B7 co-stimulatory pathway in promoting and maintaining immune response, therapeutic agents designed to antagonize it are promising for the treatment of autoimmune diseases and disorders. Abatacept (Orencia®), is a CTLA4-Ig immunoadhesin consisting of the extracellular binding domain of CTLA4 linked to the Fc domain of a human IgG. Abatacept was developed to inhibit B7-mediated costimulation (Bluestone et al., 2006, Immunity 24:233-238), and is approved for the treatment of rheumatoid arthritis (RA) and in clinical trials for a number of other autoimmune indications. However, whereas abatacept shows some activity in treating RA, it is not effective for other indications. For example, CTLA4-Ig is far less efficacious in tolerance against transplant rejection (Kirk et al., 1997, Proc Natl Acad Sci USA 94:8789-8794; Leviset