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EP-4739712-A1 - ANTI-ROR1 ANTIBODIES AND USES THEREOF

EP4739712A1EP 4739712 A1EP4739712 A1EP 4739712A1EP-4739712-A1

Abstract

Provided are antibodies or fragments thereof having binding specificity to the human ROR1 protein. In various examples, the antibodies or fragments thereof include a VH and VL CDRs as disclosed herein, or variants thereof. Methods of using the antibodies or fragments thereof for treating cancer are also provided.

Inventors

  • LIU, CHANJUAN
  • Xing, Xiaojun

Assignees

  • TJ Biopharma (Shanghai) Co., Ltd.

Dates

Publication Date
20260513
Application Date
20240704

Claims (20)

  1. An antibody or antigen-binding fragment thereof having specificity to a human Receptor tyrosine kinase-like orphan receptor 1 (ROR1) protein, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and a light chain variable region comprising light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively, comprise the sequences selected from the group consisting of: (a) HCDR1: SYAMS (SEQ ID NO: 1) , or RYAMS (SEQ ID NO: 36) , HCDR2: SISSGGTTYYPDTVKGR (SEQ ID NO: 2) or SISSGGNTYYPDTVKGR (SEQ ID NO: 38) or SISSGGTRYYPDTVKGR (SEQ ID NO: 39) , HCDR3: DSLYYGSSLYYAMDY (SEQ ID NO: 3) , DALYYGGSLYYAMDY (SEQ ID NO: 40) or DALYYGSSLYYAMDY (SEQ ID NO: 85) , LCDR1: RASQDIYSYLS (SEQ ID NO: 4) , LCDR2: RANRLVDG (SEQ ID NO: 5) , RENRLVDA (SEQ ID NO: 41) or RANRLVDA (SEQ ID NO: 86) , and LCDR3: LQYDEFPYT (SEQ ID NO: 6) ; and (b) HCDR1: TYVMH (SEQ ID NO: 7) or NYVMH (SEQ ID NO: 87) , HCDR2: YINPYNGGIRYNEKFKG (SEQ ID NO: 8) , YINPYNGVIRYNEKFKG (SEQ ID NO: 43) or YINPYSGGIRYNEKFKG (SEQ ID NO: 88) , HCDR3: RERGVYYGMDE (SEQ ID NO: 9) , RERGVYYGMSE (SEQ ID NO: 44) , RERGVYYGMDF (SEQ ID NO: 45) or RERGVTAGMDE (SEQ ID NO: 89) , LCDR1: KSSQSLLHSNGKTYLN (SEQ ID NO: 10) , KSSQSLLHSNGKVYLN (SEQ ID NO: 46) or KSSQSLLHSNDKTYLN (SEQ ID NO: 90) , LCDR2: LVSKLESG (SEQ ID NO: 11) or LVSKLSSG (SEQ ID NO: 47) , and LCDR3: LQATYFPYT (SEQ ID NO: 12) or YQATYFPYT (SEQ ID NO: 48) .
  2. The antibody or antigen-binding fragment thereof of claim 1, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively, comprise the sequences of: (a) HCDR1: SYAMS (SEQ ID NO: 1) , HCDR2: SISSGGTTYYPDTVKGR (SEQ ID NO: 2) , HCDR3: DSLYYGSSLYYAMDY (SEQ ID NO: 3) , LCDR1: RASQDIYSYLS (SEQ ID NO: 4) , LCDR2: RANRLVDG (SEQ ID NO: 5) , and LCDR3: LQYDEFPYT (SEQ ID NO: 6) , (b) HCDR1: SYAMS (SEQ ID NO: 1) , HCDR2: SISSGGTTYYPDTVKGR (SEQ ID NO: 2) , HCDR3: DALYYGSSLYYAMDY (SEQ ID NO: 85) , LCDR1: RASQDIYSYLS (SEQ ID NO: 4) , LCDR2: RANRLVDA (SEQ ID NO: 86) , and LCDR3: LQYDEFPYT (SEQ ID NO: 6) , (c) HCDR1: SYAMS (SEQ ID NO: 1) , HCDR2: SISSGGTTYYPDTVKGR (SEQ ID NO: 2) , HCDR3: DALYYGGSLYYAMDY (SEQ ID NO: 40) , LCDR1: RASQDIYSYLS (SEQ ID NO: 4) , LCDR2: RANRLVDA (SEQ ID NO: 86) , and LCDR3: LQYDEFPYT (SEQ ID NO: 6) , (d) HCDR1: RYAMS (SEQ ID NO: 36) , HCDR2: SISSGGNTYYPDTVKGR (SEQ ID NO: 38) , HCDR3: DALYYGSSLYYAMDY (SEQ ID NO: 85) , LCDR1: RASQDIYSYLS (SEQ ID NO: 4) , LCDR2: RENRLVDA (SEQ ID NO: 41) , and LCDR3: LQYDEFPYT (SEQ ID NO: 6) , or (e) HCDR1: SYAMS (SEQ ID NO: 1) , HCDR2: SISSGGTRYYPDTVKGR (SEQ ID NO: 39) , HCDR3: DALYYGSSLYYAMDY (SEQ ID NO: 85) , LCDR1: RASQDIYSYLS (SEQ ID NO: 4) , LCDR2: RENRLVDA (SEQ ID NO: 41) , and LCDR3: LQYDEFPYT (SEQ ID NO: 6) .
  3. The antibody or antigen-binding fragment thereof of claim 2, wherein the heavy chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 49, 61-64, 75-76, and 78, or a peptide having at least 90%sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 49, 61-64, 75-76, and 78.
  4. The antibody or antigen-binding fragment thereof of claim 2 or 3, wherein the light chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 50, 65-68, and 77 or a peptide having at least 90%sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 50, 65-68, and 77.
  5. The antibody or antigen-binding fragment thereof of any one of claims 2-4, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 49, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 50.
  6. The antibody or antigen-binding fragment thereof of any one of claims 2-4, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 64, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 68.
  7. The antibody or antigen-binding fragment thereof of any one of claims 2-4, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 75, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 68.
  8. The antibody or antigen-binding fragment thereof of any one of claims 2-4, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 76, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 77.
  9. The antibody or antigen-binding fragment thereof of any one of claims 2-4, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 78, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 77.
  10. The antibody or antigen-binding fragment thereof of claim 1, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively, comprise the sequences of (a) HCDR1: TYVMH (SEQ ID NO: 7) , HCDR2: YINPYNGGIRYNEKFKG (SEQ ID NO: 8) , HCDR3: RERGVYYGMDE (SEQ ID NO: 9) , LCDR1: KSSQSLLHSNGKTYLN (SEQ ID NO: 10) , LCDR2: LVSKLESG (SEQ ID NO: 11) , and LCDR3: LQATYFPYT (SEQ ID NO: 12) ; (b) HCDR1: TYVMH (SEQ ID NO: 7) , HCDR2: YINPYNGVIRYNEKFKG (SEQ ID NO: 43) , HCDR3: RERGVYYGMDE (SEQ ID NO: 9) , LCDR1: KSSQSLLHSNGKTYLN (SEQ ID NO: 10) , LCDR2: LVSKLSSG (SEQ ID NO: 47) , and LCDR3: LQATYFPYT (SEQ ID NO: 12) ; (c) HCDR1: TYVMH (SEQ ID NO: 7) , HCDR2: YINPYNGGIRYNEKFKG (SEQ ID NO: 8) , HCDR3: RERGVYYGMSE (SEQ ID NO: 44) , LCDR1: KSSQSLLHSNGKTYLN (SEQ ID NO: 10) , LCDR2: LVSKLESG (SEQ ID NO: 11) , and LCDR3: YQATYFPYT (SEQ ID NO: 48) ; (d) HCDR1: TYVMH (SEQ ID NO: 7) , HCDR2: YINPYNGGIRYNEKFKG (SEQ ID NO: 8) , RERGVYYGMDF (SEQ ID NO: 45) , LCDR1: KSSQSLLHSNGKVYLN (SEQ ID NO: 46) , LCDR2: LVSKLESG (SEQ ID NO: 11) , and LCDR3: YQATYFPYT (SEQ ID NO: 48) ; (e) HCDR1: TYVMH (SEQ ID NO: 7) , HCDR2: YINPYSGGIRYNEKFKG (SEQ ID NO: 88) , HCDR3: RERGVTAGMDE (SEQ ID NO: 89) , LCDR1: KSSQSLLHSNGKTYLN (SEQ ID NO: 10) , LCDR2: LVSKLESG (SEQ ID NO: 11) , and LCDR3: LQATYFPYT (SEQ ID NO: 12) ; (f) HCDR1: NYVMH (SEQ ID NO: 87) , HCDR2: YINPYSGGIRYNEKFKG (SEQ ID NO: 88) , HCDR3: RERGVYYGMDE (SEQ ID NO: 9) , LCDR1: KSSQSLLHSNGKTYLN (SEQ ID NO: 10) , LCDR2: LVSKLESG (SEQ ID NO: 11) , and LCDR3: LQATYFPYT (SEQ ID NO: 12) ; or (g) HCDR1: TYVMH (SEQ ID NO: 7) , HCDR2: YINPYSGGIRYNEKFKG (SEQ ID NO: 88) , RERGVYYGMSE (SEQ ID NO: 44) , LCDR1: KSSQSLLHSNDKTYLN (SEQ ID NO: 90) , LCDR2: LVSKLESG (SEQ ID NO: 11) , and LCDR3: YQATYFPYT (SEQ ID NO: 48) .
  11. The antibody or antigen-binding fragment thereof of claim 10, wherein the heavy chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 51, 69-71, 79, 81, 83 and 91-93, or a peptide having at least 90%sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 51, 69-71, 79, 81, 83 and 91-93.
  12. The antibody or antigen-binding fragment thereof of claim 10 or 11, wherein the light chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 52, 72-74, 80, 82, 84 and 94, or a peptide having at least 90%sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 52, 72-74, 80, 82, 84 and 94.
  13. The antibody or antigen-binding fragment thereof of any one of claims 10-12, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 50, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 51.
  14. The antibody or antigen-binding fragment thereof of any one of claims 10-12, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 69, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 72.
  15. The antibody or antigen-binding fragment thereof of any one of claims 10-12, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 79, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 80.
  16. The antibody or antigen-binding fragment thereof of any one of claims 10-12, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 81, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 82.
  17. The antibody or antigen-binding fragment thereof of any one of claims 10-12, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 83, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 84.
  18. The antibody or antigen-binding fragment thereof of any one of claims 10-12, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 91, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 72.
  19. The antibody or antigen-binding fragment thereof of any one of claims 10-12, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 92, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 72.
  20. The antibody or antigen-binding fragment thereof of any one of claims 10-12, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 93, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 94.

Description

ANTI-ROR1 ANTIBODIES AND USES THEREOF CROSS REFERENCE TO RELATED APPLICATIONS This application claims the priority of PCT Application No. PCT/CN2023/105698, filed July 4, 2023, the content of which is hereby incorporated by reference in its entirety. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING The content of the electronic sequence listing (375238. xml; Size: 86, 786 bytes; and Date of Creation: July 4, 2024) is herein incorporated by reference in its entirety. BACKGROUND Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1) is a 106-kDa member of the receptor tyrosine kinase family. Structurally, the extracellular domain of the ROR1 receptor is composed of three distinct domains: a membrane-distal Immunoglobulin-Like Domain; a membrane-proximal Kringle Domain; and an intervening Frizzled Domain. ROR1 is expressed in the process of embryo and fetal development, and controls cell polarity, cell migration and neurite growth, etc. The expression is gradually reduced according to progress of development, and it is hardly expressed in adults, and it is temporarily expressed in the process of development of B cell, and only little expression has been reported in adipocytes. While ROR1 expression is tightly regulated in normal adult tissues, high levels have been noted in both hematological and solid tumors. ROR1 is normally expressed during early development, but becomes activated by tumor specific mechanisms and may contribute to disease progression in the adult. The ligands of ROR1 are believed to be wnt5a and NKX1-2. Wnt5a has been shown to bind to the Frizzled Domain in the extracellular part of ROR1 and, in transfected cells, has been shown to modulate NF-κΒ activation and proliferation of normal and lung tumor cell lines. Binding of NKX1-2 to ROR1 has been shown to play a role in the survival of lung cancer cell lines through both kinase-dependent and kinase-independent mechanisms. ROR1 has been shown to interact with EGFR through the Kringle domain, and this interaction modulates signaling pathways that control apoptosis in lung cancer cell lines. While ROR1 expression does correlate with a worse prognosis in ovarian cancer, no link between ROR1 expression and clinical stage or reduced survival has been shown for lung cancer. Furthermore, although ROR1 siRNA knockdown of lung tumor cell lines leads to reduced  viability in vitro, there is no evidence that targeting of ROR1 on primary lung cancer cells results in increased cell death. The cancer cell-specific expression of ROR1 indicates that ROR1 can be a potential cancer target for antibody therapy. SUMMARY The present disclosure provides antibodies or fragments thereof having binding specificity to the human Receptor tyrosine kinase-like orphan receptor 1 (ROR1) protein. These antibodies and fragments are useful in the treatment of diseases and conditions such as cancers. In one aspect, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and a light chain variable region comprising light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are selected from the group consisting of: (a) HCDR1: SYAMS (SEQ ID NO: 1) , or RYAMS (SEQ ID NO: 36) , HCDR2: SISSGGTTYYPDTVKGR (SEQ ID NO: 2) or SISSGGNTYYPDTVKGR (SEQ ID NO: 38) or SISSGGTRYYPDTVKGR (SEQ ID NO: 39) , HCDR3: DSLYYGSSLYYAMDY (SEQ ID NO: 3) , DALYYGGSLYYAMDY (SEQ ID NO: 40) or DALYYGSSLYYAMDY (SEQ ID NO: 85) , LCDR1: RASQDIYSYLS (SEQ ID NO: 4) , LCDR2: RANRLVDG (SEQ ID NO: 5) , RENRLVDA (SEQ ID NO: 41) or RANRLVDA (SEQ ID NO: 86) , and LCDR3: LQYDEFPYT (SEQ ID NO: 6) ; and (b) HCDR1: TYVMH (SEQ ID NO: 7) or NYVMH (SEQ ID NO: 87) , HCDR2: YINPYNGGIRYNEKFKG (SEQ ID NO: 8) , YINPYNGVIRYNEKFKG (SEQ ID NO: 43) or YINPYSGGIRYNEKFKG (SEQ ID NO: 88) , HCDR3: RERGVYYGMDE (SEQ ID NO: 9) , RERGVYYGMSE (SEQ ID NO: 44) , RERGVYYGMDF (SEQ ID NO: 45) or RERGVTAGMDE (SEQ ID NO: 89) , LCDR1: KSSQSLLHSNGKTYLN (SEQ ID NO: 10) , or KSSQSLLHSNGKVYLN (SEQ ID NO: 46) or KSSQSLLHSNDKTYLN (SEQ ID NO: 90) , LCDR2: LVSKLESG (SEQ ID NO: 11) or LVSKLSSG (SEQ ID NO: 47) , and LCDR3: LQATYFPYT (SEQ ID NO: 12) or YQATYFPYT (SEQ ID NO: 48) . In certain embodiments, the antibody is a chimeric antibody or a humanized antibody. In certain embodiments, the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are (a) HCDR1: SYAMS (SEQ ID NO: 1) , HCDR2: SISSGGTTYYPDTVKGR (SEQ ID NO: 2) , HCDR3: DSLYYGSSLYYAMDY (SEQ ID NO: 3) , LCDR1: RASQDIYSYLS (SEQ ID NO: 4) , LCDR2: RANRLVDG (SEQ ID NO: 5) , and LCDR3: LQYDEFPYT (SEQ ID NO: 6) , (b) HCDR1: SYAMS (SEQ ID NO: 1) , HCDR2: SISSGGTTYYPDTVKGR (SEQ ID NO: 2) , HCDR3: DALYYGSSLYYAMDY (SEQ ID NO: 85) , LCDR1: RASQDIYSYLS (SEQ ID NO: 4) , LCDR2: RANRLVDA (SEQ ID NO: 86) , and LCDR3: LQYDEFPYT (SEQ ID NO: 6) , (c) HCDR1: SYAMS (SEQ ID NO: 1) , HCDR2: SISSGGTTYYPDTVKGR (SEQ ID NO: 2) , HCDR3: DALYYGGSLYYAMDY