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US-20260125489-A1 - ANTI-LEWIS Y ANTIBODY AND PRO-ANTIBODY THEREOF

US20260125489A1US 20260125489 A1US20260125489 A1US 20260125489A1US-20260125489-A1

Abstract

The present disclosure relates to cancer therapies, in particular immunotherapies using antibodies or pro-antibodies to target Lewis Y antigens on tumor cells, thereby eliciting antibody-dependent cellular cytotoxicity (ADCC), complement-mediated cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP).

Inventors

  • Tong-Hsuan Chang
  • Mei-Chun Yang
  • Liahng-Yim Liu
  • Yen-Ying CHEN
  • Chia-Chun Chang
  • Wen-han LEE
  • Yun-Chi Lu
  • Yi-An CHENG

Assignees

  • GLYCONEX INC.

Dates

Publication Date
20260507
Application Date
20251106

Claims (20)

  1. 1 . A pro-antibody, comprising an antigen-binding moiety and a masking moiety, wherein the antigen-binding moiety and the masking moiety are linked via a cleavable linker, comprising a proteinase substrate flanked by a first linkage moiety and a second linkage moiety, and at least one of the first linkage moiety and the second linkage moiety comprises an amino acid sequence of PLAQ (SEQ ID NO: 37); and wherein the antigen-binding moiety comprises a heavy chain variable region (VH) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent identity to SEQ ID NO: 4; and a light chain variable region (VL) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent identity to SEQ ID NO: 11.
  2. 2 . The pro-antibody of claim 1 , wherein at least one of the first linkage moiety and the second linkage moiety comprises an amino acid sequence of Gly-Gly-Ser (GGS).
  3. 3 . The pro-antibody of claim 1 , wherein the first linkage moiety connects the masking moiety to the proteinase substrate, and the second linkage moiety connects the proteinase substrate to the antigen-binding moiety.
  4. 4 . The pro-antibody of claim 1 , wherein the first linkage moiety comprises an amino acid sequence of PLAQG (SEQ ID NO: 38), and the second linkage moiety comprises an amino acid sequence of GGGGS (SEQ ID NO: 39).
  5. 5 . The pro-antibody of claim 4 , wherein the first linkage moiety comprises an amino acid sequence of GGSPLAQG (SEQ ID NO: 40).
  6. 6 . The pro-antibody of claim 1 , wherein the linker is a first linker and the proteinase substrate is a first proteinase substrate, and the pro-antibody further comprises a second linker, and further wherein the first linker connects the masking moiety to a heavy chain of the antigen-binding moiety, and the second linker connects the masking moiety to a light chain of the antigen-binding moiety; and the second linker comprises a second proteinase substrate flanked by a third linkage moiety and a fourth linkage moiety, and at least one of the third linkage moiety and the fourth linkage moiety comprises an amino acid sequence of PLAQ (SEQ ID NO: 37).
  7. 7 . The pro-antibody of claim 6 , wherein the third linkage moiety comprises an amino acid sequence of PLAQG (SEQ ID NO: 38), and the fourth linkage moiety comprises an amino acid sequence of GGGGS (SEQ ID NO: 39).
  8. 8 . The pro-antibody of claim 7 , wherein the third linkage moiety comprises an amino acid sequence of GGSPLAQG (SEQ ID NO: 40).
  9. 9 . The pro-antibody of claim 1 , wherein the masking moiety comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent identity to SEQ ID NO: 27.
  10. 10 . The pro-antibody of claim 9 , wherein at least one of the 4 th , the 8 th , and the 10 th amino acids is replaced with the amino acid other than Serine(S) and Threonine (T).
  11. 11 . The pro-antibody of claim 10 , wherein only one of the 4 th , the 8 th , and the 10 th amino acids is replaced with the amino acid other than Serine(S) and Threonine (T), provided that when the 8 th amino acid of the linker is not Alanine (A), at least one of the 4 th and the 10 th amino acids is replaced with the amino acid other than Serine(S) and Threonine (T).
  12. 12 . The pro-antibody of claim 10 , wherein the 4 th amino acid, the 8 th amino acid, and the 10th amino acid are replaced with Alanine (A).
  13. 13 . The pro-antibody of claim 1 , wherein the 3 rd amino acid of the VH is Glutamine (Q), the 19 th amino acid of the VH is Arginine (R), the 20 th amino acid of the VH is Leucine (L), the 23 rd amino acid of the VH is Alanine (A), the 40 th amino acid of the VH is Alanine (A), the 84 th amino acid of the VH is Asparagine (N), the 85 th amino acid of the VH is Serine(S), the 87 th amino acid of the VH is Arginine (R), the 88 th amino acid of the VH is Alanine (A), and/or the 93 rd amino acid of the VH is Valine (V); and/or wherein the 2 nd amino acid of the VL is Isoleucine (I), the 3 rd amino acid of the VL is Valine (V), the 7 th amino acid of the VL is Threonine (T), the 14 th amino acid of the VL is Threonine (T), the 17 th amino acid of the VL is Glutamine (Q), the 18th amino acid of the VL is Proline (P), the 88 th amino acid of the VL is Valine (V), the 105 th amino acid of the VL is Proline (P), the 109 th amino acid of the VL is Valine (V), and/or the 110 th amino acid of the VL is Aspartic acid (D).
  14. 14 . The pro-antibody of claim 1 , wherein the antigen-binding moiety comprises a heavy chain complementarity determining region 1 (VH CDR1) comprising an amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent identity to SEQ ID NO: 1, a heavy chain complementarity determining region 2 (VH CDR2) comprising an amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent identity to SEQ ID NO: 2, a heavy chain complementarity determining region 3 (VH CDR3) comprising an amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent identity to SEQ ID NO: 3; a light chain complementarity determining region 1 (VL CDR1) comprising an amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent identity to SEQ ID NO: 8, a light chain complementarity determining region 2 (VL CDR2) comprising an amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent identity to SEQ ID NO: 9, and a light chain complementarity determining region 3 (VL CDR3) comprising an amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent identity to SEQ ID NO: 10.
  15. 15 . The pro-antibody of claim 14 , wherein the 4 th amino acid of the VH CDR1 is Isoleucine (I), the 5 th amino acid of the VH CDR2 is Aspartic acid (D), the 12 th amino acid of the VH CDR2 is Glutamine (Q), the 15 th amino acid of the VH CDR2 is Leucine (L), the 4th amino acid of the VH CDR3 is Serine(S), the 5 th amino acid of the VH CDR3 is Glutamic acid (E), the 5 th amino acid of the VL CDR1 is Asparagine (N), and/or the 9th amino acid of the VL CDR1 is Threonine (T).
  16. 16 . The pro-antibody of claim 1 , wherein the antigen-binding moiety has a binding specificity to Lewis Y antigen, and the antigen-binding moiety does not bind Lewis X (LeX), Lewis A (LeA), Lewis B (LeB), or H type 2 antigen.
  17. 17 . An isolated nucleic acid encoding the pro-antibody of claim 1 .
  18. 18 . A recombinant vector, comprising the isolated nucleic acid of claim 17 .
  19. 19 . A host cell, comprising the recombinant vector of claim 18 .
  20. 20 . An isolated antibody or an antigen-binding fragment thereof, comprising: (a) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VH CDR1) comprising an amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent identity to SEQ ID NO: 1, a heavy chain complementarity determining region 2 (VH CDR2) comprising an amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent identity to SEQ ID NO: 2, and a heavy chain complementarity determining region 3 (VH CDR3) comprising an amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent identity to SEQ ID NO: 3; and (b) a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VL CDR1) comprising an amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent identity to SEQ ID NO: 8, a light chain complementarity determining region 2 (VL CDR2) comprising an amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent identity to SEQ ID NO: 9, and a light chain complementarity determining region 3 (VL CDR3) comprising an amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent identity to SEQ ID NO: 10.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims benefit of priority to U.S. Provisional Patent Application No. 63/717,548, filed on Nov. 7, 2024, the contents of which is hereby incorporated by reference in their entirety. REFERENCE TO SEQUENCE LISTING SUBMITTED AS A COMPLIANT XML FILE (.xml) Pursuant to the EFS-Web legal framework and 37 C.F.R. § 1.821(c), a Sequence Listing is submitted herewith as an XML file named “3000179-001001_Sequence_Listing”, created on Nov. 6, 2025, and having a size of 47,755 bytes. The entire contents of the material in the aforementioned file is hereby incorporated by reference in its entirety. BACKGROUND Field The present disclosure is related to cancer therapies, especially immunotherapies using antibodies to target tumor cells, thereby eliciting antibody-dependent cellular cytotoxicity (ADCC), complement-mediated cytotoxicity (CDC), or antibody-dependent cellular phagocytosis (ADCP). Immunotherapies, using monoclonal antibodies (mAbs) for malignancies, infectious diseases, autoimmune diseases, transplant rejection, and chronic inflammatory diseases, have gradually become a mainstream therapeutic option due to their antigen specificity and longer half-life than conventional drugs. The clinical efficacy of monoclonal antibodies (mAbs) with antitumor activity has been demonstrated since the late 1990s (see, e.g., Topalian et al., J. Clin. Oncol. 29 (36): 4828-4836 (2011)), and several blockbuster cancer drugs in clinical uses are mAbs (e.g., rituximab, trastuzumab, and bevacizumab). Antibody-based therapies can specifically target antigen-expressing cells, such as tumor cells, and can affect cytotoxic activity through a number of means, including by eliciting antibody-dependent cellular cytotoxicity (ADCC), complement-mediated cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP). Other approaches involve using antibodies as carrier vehicles to selectively deliver, e.g., cytotoxic or antiproliferative agents to kill target cells and/or to inhibit growth and metastatic spread of such cells. That is to say, antibody-based therapies have become an important tool for treating diseases in various aspects. Glycan antigens, as components of glycoproteins and glycolipids expressed in the cell membrane, are getting increasing attention in cancer research. Lewis antigens are glycosyl antigens believed to mediate adhesion between cancer cells and endothelium via the selectin ligands thereof. It has also been proved that Lewis Y antigen (LewisY or LeY) is overexpressed or misexpressed in a variety of cancers derived from epithelial tissues, including breast, lung, colon, ovarian cancers, etc, making Lewis Y antigen a potential target for antibody-based therapies. BRIEF SUMMARY In one aspect, the present disclosure provides an isolated antibody or an antigen-binding fragment thereof, comprising: (a) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (VH CDR1) comprising an amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent identity to SEQ ID NO: 1, a heavy chain complementarity determining region 2 (VH CDR2) comprising an amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent identity to SEQ ID NO: 2, and a heavy chain complementarity determining region 3 (VH CDR3) comprising an amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent identity to SEQ ID NO: 3; and (b) a light chain variable region (VL) comprising a light chain complementarity determining region 1 (VL CDR1) comprising an amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent identity to SEQ ID NO: 8, a light chain complementarity determining region 2 (VL CDR2) comprising an amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent identity to SEQ ID NO: 9, and a light chain complementarity determining region 3 (VL CDR3) comprising an amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent identity to SEQ ID NO: 10. In one aspect, the present disclosure provides an isolated antibody or an antigen-binding fragment thereof comprising: a heavy chain variable region (VH) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent identity to SEQ ID NO: 4 or SEQ ID NO: 15; a light chain variable region (VL) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% percent identity to SEQ ID NO: 11. In one aspect, the present disclosure provides an isolated nucleic acid encoding the isolated antibody or the antigen-binding fragment thereof of the present disclosure. In one aspect, the present disclosure provides a recombinant vector, comprising a nucleic acid encoding the isolated antibody or the antigen-bind