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CN-118574855-B - Antigen binding molecules that specifically bind PSMA and CD3 and medical uses thereof

CN118574855BCN 118574855 BCN118574855 BCN 118574855BCN-118574855-B

Abstract

Antigen binding molecules that specifically bind PSMA and CD3 and their medical uses are provided. The antigen binding molecules are useful in the treatment of tumor-related diseases.

Inventors

  • YING HUA
  • SHI JINPING
  • YANG HAO
  • ZHANG XIAOMIN
  • JIN XINSHENG
  • TAO WEIKANG

Assignees

  • 江苏恒瑞医药股份有限公司
  • 上海恒瑞医药有限公司

Dates

Publication Date
20260512
Application Date
20230207
Priority Date
20220207

Claims (20)

  1. 1. An antigen binding molecule that specifically binds PSMA and CD3, comprising: one or two antigen binding domains that specifically bind PSMA, and One or two antigen binding domains that specifically bind CD 3; The antigen-binding domain that specifically binds PSMA comprises a heavy chain variable region PSMA-VH and a light chain variable region PSMA-VL, The antigen binding domain that specifically binds CD3 comprises a heavy chain variable region CD3-VH and a light chain variable region CD3-VL, wherein (I) The PSMA-VH has a PSMA-HCDR1 of the amino acid sequence shown in SEQ ID NO. 13, a PSMA-HCDR2 of the amino acid sequence shown in SEQ ID NO. 14 and a PSMA-HCDR3 of the amino acid sequence shown in SEQ ID NO. 15, and The PSMA-VL has a PSMA-LCDR1 with an amino acid sequence shown as SEQ ID NO. 16, a PSMA-LCDR2 with an amino acid sequence shown as SEQ ID NO. 17 and a PSMA-LCDR3 with an amino acid sequence shown as SEQ ID NO. 18.
  2. 2. The antigen binding molecule of claim 1, wherein: (i) The amino acid sequence of the PSMA-VH is shown as SEQ ID NO. 112, and the amino acid sequence of the PSMA-VL is shown as SEQ ID NO. 115, or The amino acid sequence of the PSMA-VH is shown as SEQ ID NO. 110, and the amino acid sequence of the PSMA-VL is shown as SEQ ID NO. 114, or The amino acid sequence of the PSMA-VH is shown as SEQ ID NO. 77, and the amino acid sequence of the PSMA-VL is shown as SEQ ID NO. 78, or The amino acid sequence of the PSMA-VH is shown as SEQ ID NO. 107, and the amino acid sequence of the PSMA-VL is shown as SEQ ID NO. 113, or The amino acid sequence of the PSMA-VH is shown as SEQ ID NO. 108, and the amino acid sequence of the PSMA-VL is shown as SEQ ID NO. 113, or The amino acid sequence of the PSMA-VH is shown as SEQ ID NO. 109, and the amino acid sequence of the PSMA-VL is shown as SEQ ID NO. 113, or The amino acid sequence of the PSMA-VH is shown as SEQ ID NO. 110, and the amino acid sequence of the PSMA-VL is shown as SEQ ID NO. 113, or The amino acid sequence of the PSMA-VH is shown as SEQ ID NO. 111, and the amino acid sequence of the PSMA-VL is shown as SEQ ID NO. 113, or The amino acid sequence of the PSMA-VH is shown as SEQ ID NO. 107, and the amino acid sequence of the PSMA-VL is shown as SEQ ID NO. 114, or The amino acid sequence of the PSMA-VH is shown as SEQ ID NO. 108, and the amino acid sequence of the PSMA-VL is shown as SEQ ID NO. 114, or The amino acid sequence of the PSMA-VH is shown as SEQ ID NO. 109, and the amino acid sequence of the PSMA-VL is shown as SEQ ID NO. 114, or The amino acid sequence of the PSMA-VH is shown as SEQ ID NO. 111, and the amino acid sequence of the PSMA-VL is shown as SEQ ID NO. 114.
  3. 3. The antigen binding molecule of claim 2, wherein: (i) The amino acid sequence of the PSMA-VH is shown as SEQ ID NO. 112, and the amino acid sequence of the PSMA-VL is shown as SEQ ID NO. 115, or The amino acid sequence of the PSMA-VH is shown as SEQ ID NO. 110, and the amino acid sequence of the PSMA-VL is shown as SEQ ID NO. 114.
  4. 4. The antigen binding molecule of claim 1, wherein The CD3-VH has a CD3-HCDR1 of the amino acid sequence shown in SEQ ID NO:160, a CD3-HCDR2 of the amino acid sequence shown in SEQ ID NO:161, and a CD3-HCDR3 of the amino acid sequence shown in SEQ ID NO:162, and the CD3-VL has a CD3-LCDR1 of the amino acid sequence shown in SEQ ID NO:163, a CD3-LCDR2 of the amino acid sequence shown in SEQ ID NO:164, and a CD3-LCDR3 of the amino acid sequence shown in SEQ ID NO: 165.
  5. 5. The antigen binding molecule of claim 4, wherein The amino acid sequence of the CD3-VH is shown as SEQ ID NO. 166, and the amino acid sequence of the CD3-VL is shown as SEQ ID NO. 167.
  6. 6. The antigen binding molecule of any one of claims 1 to 5, wherein the antigen binding molecule comprises an Fc region that is an IgG Fc region.
  7. 7. The antigen binding molecule of claim 6, wherein the Fc region is an IgG 1 Fc region.
  8. 8. The antigen binding molecule of claim 7, wherein the Fc region comprises one or more amino acid substitutions capable of reducing binding of the Fc region to an fcγ receptor.
  9. 9. The antigen binding molecule of claim 8, wherein the Fc region is a human IgG 1 Fc region and the amino acid residues at positions 234 and 235 are a, numbering according to the EU index.
  10. 10. The antigen binding molecule of any one of claims 1 to 5, wherein the antigen binding molecule comprises an Fc region comprising a first subunit Fc1 and a second subunit Fc2 capable of associating with each other, each of the Fc1 and Fc2 independently having one or more amino acid substitutions that reduce homodimerization of the Fc region.
  11. 11. The antigen binding molecule of claim 10, wherein the Fc1 has a raised structure according to the pestle and mortar technique and the Fc2 has a pore structure according to the pestle and mortar technique, or The Fc2 has a convex structure according to a pestle-and-mortar technique, and the Fc1 has a hole structure according to a pestle-and-mortar technique.
  12. 12. The antigen binding molecule of claim 11, 1) The amino acid residue at position 366 of said Fc1 is W, and The amino acid residue at 366 position of Fc2 is S, the amino acid residue at 368 position is A, and the amino acid residue at 407 position is V, the numbering is based on EU index, or 2) The amino acid residue at position 366 of said Fc2 is W, and The amino acid residue at position 366, the amino acid residue at position 368, and the amino acid residue at position 407 of Fc1 are S, A, and V, respectively, with the numbering according to the EU index.
  13. 13. The antigen binding molecule of any one of claims 1 to 5, wherein the antigen binding molecule comprises: An antigen binding domain that specifically binds PSMA, and An antigen binding domain that specifically binds CD 3; the antigen-binding domain that specifically binds PSMA and the antigen-binding domain that specifically binds CD3 are scFv; The antigen binding molecule comprises: A first chain having a structure represented by formula (a), and A second chain having a structure represented by formula (b); Formula (a) [ PSMA-VH ] - [ linker 1] - [ PSMA-VL ] - [ linker 2] - [ CD3-VH ] - [ linker 3] - [ CD3-VL ] - [ linker 4] - [ Fc2], Formula (b) [ Fc1], The structures shown in the formula (a) and the formula (b) are arranged from the N end to the C end, and the linker 1, the linker 2, the linker 3 and the linker 4 are identical or different peptide linkers.
  14. 14. The antigen binding molecule of claim 13, which has a first strand having an amino acid sequence as set forth in SEQ ID NO:192 and a second strand having an amino acid sequence as set forth in SEQ ID NO:169, or The antigen binding molecule has a first chain with an amino acid sequence shown as SEQ ID NO. 191 and a second chain with an amino acid sequence shown as SEQ ID NO. 169.
  15. 15. The antigen binding molecule of any one of claims 1 to 5, wherein the antigen binding domain that specifically binds PSMA or the antigen binding domain that specifically binds CD3 each independently comprises a tin chain and a Obscurin chain; the amino acid sequence of the Titin chain is shown as SEQ ID NO. 226, and the amino acid sequence of the Obscurin chain is shown as SEQ ID NO. 264.
  16. 16. The antigen binding molecule of claim 15, wherein the antigen binding molecule comprises two antigen binding domains that specifically bind PSMA and one antigen binding domain that specifically binds CD3, The antigen binding domain that specifically binds to PSMA is a Fab, the antigen binding domain that specifically binds to CD3 is a substituted Fab comprising a Titin chain and a Obscurin chain; the antigen binding molecule comprises a first chain having a structure represented by formula (c), two second chains having a structure represented by formula (d), a third chain having a structure represented by formula (g), and a fourth chain having a structure represented by formula (h), Formula (c) [ PSMA-VH ] - [ CH1] - [ Fc1], Formula (d) [ PSMA-VL ] - [ CL ], Formula (g) [ PSMA-VH ] - [ CH1] - [ CD3-VH ] - [ linker 7] - [ tin chain ] - [ Fc2], (H) [ CD3-VL ] - [ linker 8] - [ Obscurin strand ], The structures of formulae (C), (d), (g) and (h) are arranged from N-terminal to C-terminal, and the linker 7 and the linker 8 are identical or different peptide linkers.
  17. 17. The antigen binding molecule of claim 16, The antigen binding molecule has a first chain with an amino acid sequence shown as SEQ ID NO. 187, a second chain with two amino acid sequences shown as SEQ ID NO. 188, a third chain with an amino acid sequence shown as SEQ ID NO. 189 and a fourth chain with an amino acid sequence shown as SEQ ID NO. 174.
  18. 18. The antigen binding molecule of any one of claims 1 to 5, wherein the antigen binding molecule comprises two antigen binding domains that specifically bind PSMA, which is a Fab, and two antigen binding domains that specifically bind CD3, which is a scFv; the antigen binding molecule comprises two first chains having a structure represented by formula (k) and two second chains having a structure represented by formula (d), Formula (k) [ PSMA-VH ] - [ CH1] - [ CD3-VH ] - [ linker 10] - [ CD3-VL ] - [ linker 11] - [ subunit of Fc ] - [ linker ] -. Formula (d) [ PSMA-VL ] - [ CL ], The structures of formula (k) and formula (d) are arranged from N-terminus to C-terminus, and the linker 10 and the linker 11 are identical or different peptide linkers.
  19. 19. The antigen binding molecule of claim 18, The antigen binding molecule has two first chains with the amino acid sequence shown as SEQ ID NO. 190 and two second chains with the amino acid sequence shown as SEQ ID NO. 188.
  20. 20. An antibody capable of specifically binding PSMA, said antibody comprising a heavy chain variable region PSMA-VH and a light chain variable region PSMA-VL, wherein (I) The PSMA-VH has a PSMA-HCDR1 with an amino acid sequence shown as SEQ ID NO. 13, a PSMA-HCDR2 with an amino acid sequence shown as SEQ ID NO. 14 and a PSMA-HCDR3 with an amino acid sequence shown as SEQ ID NO. 15, and the PSMA-VL has a PSMA-LCDR1 with an amino acid sequence shown as SEQ ID NO. 16, a PSMA-LCDR2 with an amino acid sequence shown as SEQ ID NO. 17 and a PSMA-LCDR3 with an amino acid sequence shown as SEQ ID NO. 18.

Description

Antigen binding molecules that specifically bind PSMA and CD3 and medical uses thereof The present application claims priority from chinese patent application 202210116684.6 filed on day 2022, month 02 and 07. Technical Field The present disclosure is in the field of biotechnology, more specifically, the disclosure relates to antigen binding molecules and uses thereof. Background The statements herein merely provide background information related to the present disclosure and may not necessarily constitute prior art. PSMA belongs to glutamate carboxypeptidase II (Glutamate carboxypeptidase II, GCPII), consisting of 750 amino acids, 19 intracellular, 24 transmembrane, 707 extracellular. The extracellular portion of PSMA consists of 3 domains, protease-like, therapeutic and C-terminal. Three domains are involved in substrate binding, and protease-like and apical bind directly to the substrate and C-terminal function to dimerize PSMA. The expression level of PSMA in tumor tissue in prostate cancer patients is increased by 100-1000 times compared with normal prostate. PSMA is also expressed on endometrial cancer cell surfaces, gastric (66.4%) and colorectal (84.6%) neovascular, non-small cell lung cancer neovascular and part of tumor cells. Therefore, PSMA can be used as a target for developing prostate cancer, and can be applied to other tumor types. CD3 is an isotype or heterodimeric antigen expressed on T cells. Functional CD3 is formed by the dimeric binding of two of four different chains epsilon, zeta, delta and gamma. CD3 dimer arrangements include y/ε, δ/ε, ζ/ζ. CD3 binds to the T cell receptor complex (TCR) and is required for T cell activation. Thus, anti-CD 3 antibodies that activate T cells have been proposed for therapeutic purposes. However, administration of anti-CD 3 antibodies may trigger T cell activation and associated cytokine release. Excessive cytokine release results in severe Cytokine Release Syndrome (CRS), which is a significant challenge in clinical administration of anti-CD 3 antibodies. Thus, there is an unmet need to provide PSMA/CD3 bispecific antibodies with high activity and low cytokine release. Disclosure of Invention The present disclosure provides an antigen binding molecule that specifically binds PSMA and CD3 and an antibody that specifically binds PSMA. In one aspect, the present disclosure provides an antigen-binding molecule comprising at least one antigen-binding moiety that specifically binds PSMA comprising a heavy chain variable region (PSMA-VH) and a light chain variable region (PSMA-VL), and at least one antigen-binding moiety that specifically binds CD3 comprising a heavy chain variable region (CD 3-VH) and a light chain variable region (CD 3-VL). In some embodiments, an antigen binding molecule as described previously, wherein (I) The PSMA-HCDR1, PSMA-HCDR2 and PSMA-HCDR3 in the PSMA-VH comprise the amino acid sequences of PSMA-HCDR1, PSMA-HCDR2 and PSMA-HCDR3 in SEQ ID NO:77, respectively, and the PSMA-LCDR1, PSMA-LCDR2 and PSMA-LCDR3 in the PSMA-VL comprise the amino acid sequences of PSMA-LCDR1, PSMA-LCDR2 and PSMA-LCDR3 in SEQ ID NO:78, respectively, or (Ii) The PSMA-HCDR1, PSMA-HCDR2 and PSMA-HCDR3 in the PSMA-VH comprise the amino acid sequences of PSMA-HCDR1, PSMA-HCDR2 and PSMA-HCDR3 in SEQ ID NO:73, respectively, and the PSMA-LCDRl, PSMA-LCDR2 and PSMA-LCDR3 in the PSMA-VL comprise the amino acid sequences of PSMA-LCDR1, PSMA-LCDR2 and PSMA-LCDR3 in SEQ ID NO:74, respectively, or (Iii) The PSMA-HCDR1, PSMA-HCDR2 and PSMA-HCDR3 in the PSMA-VH comprise the amino acid sequences of PSMA-HCDR1, PSMA-HCDR2 and PSMA-HCDR3 in SEQ ID NO:75, respectively, and the PSMA-LCDR1, PSMA-LCDR2 and PSMA-LCDR3 in the PSMA-VL comprise the amino acid sequences of PSMA-LCDR1, PSMA-LCDR2 and PSMA-LCDR3 in SEQ ID NO:76, respectively, or (Iv) The PSMA-HCDR1, PSMA-HCDR2 and PSMA-HCDR3 in the PSMA-VH comprise the amino acid sequences of PSMA-HCDR1, PSMA-HCDR2 and PSMA-HCDR3 in SEQ ID NO:79, respectively, and the PSMA-LCDR1, PSMA-LCDR2 and PSMA-LCDR3 in the PSMA-VL comprise the amino acid sequences of PSMA-LCDR1, PSMA-LCDR2 and PSMA-LCDR3 in SEQ ID NO:80, respectively, or (V) The PSMA-HCDR1, PSMA-HCDR2 and PSMA-HCDR3 in the PSMA-VH comprise the amino acid sequences of PSMA-HCDRl, PSMA-HCDR2 and PSMA-HCDR3 in SEQ ID NO:81, and the PSMA-LCDR1, PSMA-LCDR2 and PSMA-LCDR3 in the PSMA-VL comprise the amino acid sequences of PSMA-LCDRl, PSMA-LCDR2 and PSMA-LCDR3 in SEQ ID NO:82, respectively, or (Vi) The PSMA-HCDR1, PSMA-HCDR2 and PSMA-HCDR3 in the PSMA-VH comprise the amino acid sequences of PSMA-HCDR1, PSMA-HCDR2 and PSMA-HCDR3 in SEQ ID NO:83, respectively, and the PSMA-LCDR1, PSMA-LCDR2 and PSMA-LCDR3 in the PSMA-VL comprise the amino acid sequences of PSMA-LCDR1, PSMA-LCDR2 and PSMA-LCDR3 in SEQ ID NO:84, respectively, or (Vii) The PSMA-HCDR1, PSMA-HCDR2 and PSMA-HCDR3 in the PSMA-VH comprise the amino acid sequences of PSMA-HCDR1, PSMA-HCDR2 and PSMA-HCDR3 in SEQ ID NO:85, respectiv