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CN-122029196-A - Affinity matured anti-OX 40 antibodies and uses thereof

CN122029196ACN 122029196 ACN122029196 ACN 122029196ACN-122029196-A

Abstract

Provided herein are high affinity antagonistic anti-OX 40 antibodies, methods of making such antibodies, and methods of using such antibodies to treat OX 40-mediated disorders.

Inventors

  • J. Makuaan
  • T. Monet
  • N. Bilis
  • MILNE JAMES CHRISTOPHER
  • C. J. Morabito
  • ZHAO CHUNXIA

Assignees

  • 伊克诺斯科学公司
  • 奥斯提亚治疗股份有限公司

Dates

Publication Date
20260512
Application Date
20241004
Priority Date
20231006

Claims (20)

  1. 1. An antibody or antigen-binding fragment thereof that binds OX40 comprising: a) Three heavy chain Complementarity Determining Regions (CDRs) (CDR-H1, CDR-H2 and CDR-H3) of a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO. 7, and three light chain Complementarity Determining Regions (CDRs) (CDR-L1, CDR-L2 and CDR-L3) of a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO. 8; b) Three heavy chain Complementarity Determining Regions (CDRs) (CDR-H1, CDR-H2 and CDR-H3) comprising the heavy chain variable domain (VH) of the amino acid sequence of SEQ ID NO. 7, and three light chain Complementarity Determining Regions (CDRs) (CDR-L1, CDR-L2 and CDR-L3) comprising the light chain variable domain (VL) of the amino acid sequence of SEQ ID NO. 12; c) Three heavy chain Complementarity Determining Regions (CDRs) (CDR-H1, CDR-H2 and CDR-H3) of a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO. 7, and three light chain Complementarity Determining Regions (CDRs) (CDR-L1, CDR-L2 and CDR-L3) of a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO. 15; d) Heavy chain Complementarity Determining Regions (CDRs) (CDR-H1, CDR-H2 and CDR-H3) of a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO. 7, and three light chain Complementarity Determining Regions (CDRs) (CDR-L1, CDR-L2 and CDR-L3) of a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO. 18; e) Heavy chain Complementarity Determining Regions (CDRs) (CDR-H1, CDR-H2 and CDR-H3) of a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO. 7, and three light chain Complementarity Determining Regions (CDRs) (CDR-L1, CDR-L2 and CDR-L3) of a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO. 21; f) Heavy chain Complementarity Determining Regions (CDRs) (CDR-H1, CDR-H2 and CDR-H3) of a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO. 7, and three light chain Complementarity Determining Regions (CDRs) (CDR-L1, CDR-L2 and CDR-L3) of a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO. 24; g) Heavy chain Complementarity Determining Regions (CDRs) (CDR-H1, CDR-H2 and CDR-H3) of a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO. 7, and three light chain Complementarity Determining Regions (CDRs) (CDR-L1, CDR-L2 and CDR-L3) of a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO. 27; h) Heavy chain Complementarity Determining Regions (CDRs) (CDR-H1, CDR-H2 and CDR-H3) of a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO. 7, and three light chain Complementarity Determining Regions (CDRs) (CDR-L1, CDR-L2 and CDR-L3) of a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO. 30; i) Heavy chain Complementarity Determining Regions (CDRs) (CDR-H1, CDR-H2 and CDR-H3) of a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO. 7, and three light chain Complementarity Determining Regions (CDRs) (CDR-L1, CDR-L2 and CDR-L3) of a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO. 33.
  2. 2. An antibody or antigen-binding fragment thereof that binds to OX40, comprising three heavy chain Complementarity Determining Regions (CDRs) (CDR-H1, CDR-H2, and CDR-H3) comprising the heavy chain variable domain (VH) of the amino acid sequence of SEQ ID No. 7 and three light chain Complementarity Determining Regions (CDRs) (CDR-L1, CDR-L2, and CDR-L3) comprising the light chain variable domain (VL) of the amino acid sequence of SEQ ID No. 8.
  3. 3. The antibody or antigen-binding fragment of any one of claims 1 or 2, wherein: a) The CDR-H1, CDR-H2 and CDR-H3 and the CDR-L1, CDR-L2 and CDR-L3 are defined according to Kabat; b) The CDR-H1, CDR-H2 and CDR-H3 and the CDR-L1, CDR-L2 and CDR-L3 are defined according to Chothia; c) The CDR-H1, CDR-H2 and CDR-H3 and the CDR-L1, CDR-L2 and CDR-L3 are defined according to IMGT; d) The CDR-H1, CDR-H2 and CDR-H3 and the CDR-L1, CDR-L2 and CDR-L3 are defined according to AbM; e) The CDR-H1, CDR-H2 and CDR-H3 and the CDR-L1, CDR-L2 and CDR-L3 are defined according to contacts, or F) The CDR-H1, CDR-H2 and CDR-H3 and the CDR-L1, CDR-L2 and CDR-L3 are defined according to Honneger (AHo).
  4. 4. An antibody or antigen-binding fragment thereof that binds OX40 comprising: a) A heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence shown as SEQ ID NO. 1, a CDR-H2 comprising the amino acid sequence shown as SEQ ID NO. 2, a CDR-H3 comprising the amino acid sequence shown as SEQ ID NO. 3, and B) A light chain variable region comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID No. 4, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID No. 5, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID No. 38 or 71, wherein X 1 is F, T, W or M, wherein X 2 is G, I, V, L or E, wherein X 3 is A, D, E, L, H, T or F, and wherein X 4 is W, P, F, Y or T.
  5. 5. The antibody or antigen-binding fragment thereof of claim 4, wherein the CDR-L3 comprises the amino acid sequence set forth in SEQ ID No. 38.
  6. 6. The antibody or antigen binding fragment thereof of claim 4 or 5, wherein X 1 is F or T, X 2 is L, G or E, X 3 is a, and X 4 is W.
  7. 7. The antibody or antigen-binding fragment thereof of any one of claims 4-6, wherein CDR-L3 comprises the amino acid sequence of SEQ ID No. 6, 11, 14, 17, 20, 23, 26, or 29.
  8. 8. An antibody or antigen-binding fragment thereof that binds OX40 comprising: a) A heavy chain variable region comprising a CDR-H1 comprising the amino acid sequence shown as SEQ ID NO. 1, a CDR-H2 comprising the amino acid sequence shown as SEQ ID NO. 2 and a CDR-H3 comprising the amino acid sequence shown as SEQ ID NO. 3, and B) A light chain variable region comprising CDR-L1 comprising the amino acid sequence set forth in SEQ ID No. 4, CDR-L2 comprising the amino acid sequence set forth in SEQ ID No. 5, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID No. 6, 11, 14, 17, 20, 23, 26, 29 or 32.
  9. 9. An antibody or antigen-binding fragment thereof that binds OX40 comprising: (a) A heavy chain variable region comprising: A heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO. 1, SEQ ID NO. 41, SEQ ID NO. 47, SEQ ID NO. 53, SEQ ID NO. 59 or SEQ ID NO. 65; A heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO.2, SEQ ID NO. 42, SEQ ID NO. 48, SEQ ID NO. 54, SEQ ID NO. 60 or SEQ ID NO. 66, and A heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO.3, SEQ ID NO. 55, SEQ ID NO. 61 or SEQ ID NO. 67, and (B) Comprising a light chain variable region comprising: a light chain CDR1 comprising the amino acid sequence of SEQ ID NO. 4, SEQ ID NO. 56, SEQ ID NO. 62 or SEQ ID NO. 68; A light chain CDR2 comprising the amino acid sequence of SEQ ID NO. 5, SEQ ID NO. 57, amino acid sequence AT or SEQ ID NO. 69, and A light chain CDR3 comprising the amino acid sequence of SEQ ID NO. 6, SEQ ID NO. 58 or SEQ ID NO. 70.
  10. 10. The antibody or antigen-binding fragment thereof of any one of claims 1-9, wherein the heavy chain CDR1 comprises the amino acid sequence of SEQ ID No. 1, the heavy chain CDR2 comprises the amino acid sequence of SEQ ID No. 2, the heavy chain CDR3 comprises the amino acid sequence of SEQ ID No. 3, the light chain CDR1 comprises the amino acid sequence of SEQ ID No. 4, the light chain CDR2 comprises the amino acid sequence of SEQ ID No. 5, and the light chain CDR3 comprises the amino acid sequence of SEQ ID No. 6.
  11. 11. The antibody or antigen-binding fragment thereof of any one of claims 1-9, wherein the heavy chain CDR1 comprises the amino acid sequence of SEQ ID No. 41, the heavy chain CDR2 comprises the amino acid sequence of SEQ ID No. 42, the heavy chain CDR3 comprises the amino acid sequence of SEQ ID No. 3, the light chain CDR1 comprises the amino acid sequence of SEQ ID No. 4, the light chain CDR2 comprises the amino acid sequence of SEQ ID No. 5, and the light chain CDR3 comprises the amino acid sequence of SEQ ID No. 6.
  12. 12. The antibody or antigen-binding fragment thereof of any one of claims 1-9, wherein the heavy chain CDR1 comprises the amino acid sequence of SEQ ID No. 47, the heavy chain CDR2 comprises the amino acid sequence of SEQ ID No. 48, the heavy chain CDR3 comprises the amino acid sequence of SEQ ID No. 3, the light chain CDR1 comprises the amino acid sequence of SEQ ID No. 4, the light chain CDR2 comprises the amino acid sequence of SEQ ID No. 5, and the light chain CDR3 comprises the amino acid sequence of SEQ ID No. 6.
  13. 13. The antibody or antigen-binding fragment thereof of any one of claims 1-9, wherein the heavy chain CDR1 comprises the amino acid sequence of SEQ ID No. 53, the heavy chain CDR2 comprises the amino acid sequence of SEQ ID No. 54, the heavy chain CDR3 comprises the amino acid sequence of SEQ ID No. 55, the light chain CDR1 comprises the amino acid sequence of SEQ ID No. 56, the light chain CDR2 comprises the amino acid sequence of SEQ ID No. 57, and the light chain CDR3 comprises the amino acid sequence of SEQ ID No. 58.
  14. 14. The antibody or antigen-binding fragment thereof of any one of claims 1-9, wherein the heavy chain CDR1 comprises the amino acid sequence of SEQ ID No. 59, the heavy chain CDR2 comprises the amino acid sequence of SEQ ID No. 60, the heavy chain CDR3 comprises the amino acid sequence of SEQ ID No. 61, the light chain CDR1 comprises the amino acid sequence of SEQ ID No. 62, the light chain CDR2 comprises the amino acid sequence AT, and the light chain CDR3 comprises the amino acid sequence of SEQ ID No. 6.
  15. 15. The antibody or antigen-binding fragment thereof of any one of claims 1-9, wherein the heavy chain CDR1 comprises the amino acid sequence of SEQ ID No. 65, the heavy chain CDR2 comprises the amino acid sequence of SEQ ID No. 66, the heavy chain CDR3 comprises the amino acid sequence of SEQ ID No. 67, the light chain CDR1 comprises the amino acid sequence of SEQ ID No. 68, the light chain CDR2 comprises the amino acid sequence of SEQ ID No. 69, and the light chain CDR3 comprises the amino acid sequence of SEQ ID No. 70.
  16. 16. The antibody or antigen-binding fragment thereof of any one of claims 1-15, wherein the OX40 is human OX40.
  17. 17. The antibody or antigen-binding fragment thereof of any one of claims 1-16, wherein the antibody or antigen-binding fragment thereof is an antagonist of OX 40.
  18. 18. The antibody or antigen-binding fragment thereof of any one of claims 1-17, wherein the antibody or antigen-binding fragment thereof is a humanized antibody and/or the CDRs are located between human or humanized framework sequences.
  19. 19. The antibody or antigen-binding fragment thereof of any one of claims 1-18, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID No. 7.
  20. 20. The antibody or antigen-binding fragment thereof of any one of claims 1-19, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising the amino acid sequence of SEQ ID No. 8.

Description

Affinity matured anti-OX 40 antibodies and uses thereof Cross Reference to Related Applications The present application claims priority and benefit from U.S. provisional patent application No. 63/588,662 filed on 6 th 10 th 2023 and U.S. provisional patent application No. 63/645,656 filed on 10 th 5 th 2024, which are incorporated herein by reference in their entireties. Technical Field The present disclosure relates generally to affinity matured anti-OX 40 antibodies and their preparation and use for treating various OX 40-mediated disorders, including inflammatory and autoimmune diseases. Background OX40 (TNFRSF 4, CD 134) is a co-stimulatory receptor member of the NGFR/TNFR superfamily, expressed primarily on activated T lymphocytes including CD4 and CD 8T cells, T helper cells (types 1,2 and 3: th1, th2 and Th 17) and Forkhead box P3 positive (Foxp3+) CD4+ regulatory T cells (Treg). Unlike CD28, which is a classical constitutively expressed T cell co-stimulatory receptor, OX40 is not expressed on naive T lymphocytes. In contrast, OX40 expression was transiently induced on CD4 and CD 8T cells 24 hours to 5 days after initial TCR stimulation (CALDERHEAD et al (1993), J.Immunol.151 (1): 5261-71; gramaglia et al (1998), J.Immunol., 161 (12): 6510-6517; akiba et al (1999), J.Immunol., 162 (12): 7058-7066). Furthermore, OX40 appears to be upregulated on tregs, a population of T cells that is critical for maintaining immune tolerance and fine-tuning T cell activity (Kondelkova et al (2010), ACTA MEDICA, 53 (2): 73-77). Typically, binding of OX40L expressed on Antigen Presenting Cells (APC) to OX40 on T cells promotes effector functions of T cells. OX40 and CD30 are thought to be critical for the later or sustained phase of the T cell response. Binding to OX40 by its ligand OX40L (TNFSF 4-CD 252) results in enhanced T cell survival and proliferation, which can lead to autoimmune diseases. Certain OX40 therapeutic antibodies for autoimmune diseases typically exhibit a certain level of residual agonistic activity that results in T cell activation and proliferation. Thus, despite the advances that have been made in the treatment of OX 40-mediated disorders, there remains a need for additional anti-OX 40 therapeutics. Disclosure of Invention The present disclosure is based in part on the discovery of high affinity, antagonistic anti-OX 40 antibodies, their manufacture, and use in the treatment of OX 40-mediated disorders (including inflammatory and autoimmune disorders). Certain high affinity antibodies disclosed herein do not exhibit detectable agonistic activity (e.g., T cell activation and proliferation), making them particularly useful for treating inflammatory and autoimmune disorders. Certain antibodies disclosed herein (including MAB1 and MAB 10) exhibit increased affinity for OX40 as compared to the parent antibody, terlazomib Li Shan, anti-telazormab, referred to herein as GBR830, also referred to as ISB 830. MAB1 and MAB10 also lack agonistic activity compared to reference antibodies that retain residual agonistic activity, such as nocardine Li Shan antibody (also known as KHK4083 or AMG 451). MAB1 and MAB10 showed a greater potency in inhibiting T cell proliferation than Lazoffiti Li Shan resistance (GBR 830) in vitro. In addition, MAB1 and MAB10 also show reduced ADCC-mediated T cell depletion compared to nocardine Li Shan antibody and the unique potential to limit Treg depletion via ADCC. These and other pharmacological properties support the potential efficacy of MAB1 and MAB10 in the field of OX40 therapy for autoimmune diseases. In one aspect, the disclosure provides an antibody or antigen-binding fragment thereof that binds OX40 (e.g., human OX 40). In one example, an antibody or antigen binding fragment thereof comprises three heavy chain Complementarity Determining Regions (CDRs) (CDR-H1, CDR-H2 and CDR-H3) comprising the heavy chain variable domain (VH) of the amino acid sequence shown in SEQ ID NO. 7 and three light chain CDRs (CDR-L1, CDR-L2 and CDR-L3) of the light chain variable domain (VL) of the amino acid sequence shown in SEQ ID NO. 8. In other examples, the antibody or antigen binding fragment thereof comprises three heavy chain Complementarity Determining Regions (CDRs) (CDR-H1, CDR-H2 and CDR-H3) comprising the heavy chain variable domain (VH) of the amino acid sequence of SEQ ID NO. 7 and three light chain Complementarity Determining Regions (CDRs) (CDR-L1, CDR-L2 and CDR-L3) comprising the light chain variable domain (VL) of the amino acid sequence of SEQ ID NO. 12, SEQ ID NO. 15, SEQ ID NO. 18, SEQ ID NO. 21, SEQ ID NO. 24, SEQ ID NO. 27, SEQ ID NO. 30 or SEQ ID NO. 33. CDR-H1, CDR-H2 and CDR-H3, and CDR-L1, CDR-L2 and CDR-L3 can be defined according to Kabat, chothia, IMGT, abM, contact or Honnecger (AHo) CDR numbering system as discussed herein or other numbering systems known in the art. The antibody or antigen binding fragment thereof may be an isolated antibody or antigen bind