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CN-122003434-A - High affinity antibodies recognizing the variant MUC5AC antigen core 2O-glycans, compositions containing the same and uses thereof

CN122003434ACN 122003434 ACN122003434 ACN 122003434ACN-122003434-A

Abstract

The present invention relates to novel affinity variants of NEO-102, such as PB223, which bind to core 2O-glycans of MUC5AC antigen (comprising core 2O-glycans), expressed by different cancers, such as lung, ovarian, cervical, gastric, liver, uterine, pancreatic, breast and colon cancers. The invention also relates to the use of such affinity variants of NEO-102, such as PB223, for the treatment and/or detection of cancers expressing such core 2O-glycans, such as lung, ovary, cervix, uterus, stomach, liver, pancreas, breast and colon cancers, wherein such treatment optionally may comprise the use of other agents and/or treatment regimens for the treatment of cancer.

Inventors

  • P. M. Alan
  • K. Y. Texan
  • M. Fantine

Assignees

  • 精密生物制品股份有限公司

Dates

Publication Date
20260508
Application Date
20240919
Priority Date
20230920

Claims (20)

  1. 1. An antibody or antibody fragment that is an affinity variant of NEO-102 (wherein NEO-102 comprises a Variable Light (VL) chain and a Variable (VH) chain polypeptide comprising the amino acid sequences in table 2) that binds to the same MUC5AC variant antigen (comprising core 2O-glycans) bound by NEO-102 and has a KD value that is at least 2-, 3-, or 4-fold lower (at least 2-, 3-, or 4-fold higher increase in affinity binding) than the KD value of NEO-102.
  2. 2. The antibody or antibody fragment of claim 1, comprising a Variable Heavy (VH) region and a Variable Light (VL) region comprising one or more of (I) an (s→e) modification of VH residue 28, (ii) an (n→i) modification at VH (CDR 1) residue 35, (iii) an (g→k) modification at VH (CDR 2) residue 62, (V) an (s→v) modification at VH (CDR 2) residue 58, (vi) an (a→g) modification at VL (CDR 2) position 54, and a Variable Heavy (VH) region comprising an (s→l) modification at VH (CDR 2) residue 61, relative to NEO-102.
  3. 3. The antibody or antibody fragment of claim 2, comprising at least 2,3, 4 or 5 of the modifications.
  4. 4. The antibody or antibody fragment of claim 1, 2 or 3, comprising a Variable Heavy (VH) region and a Variable Light (VL) region comprising all of the following mutations with respect to NEO-102, (I) a (s→e) modification at VH residue 28, (ii) a (n→i) modification at VH (CDR 1) residue 35, and (iii) a (g→k) modification at VH (CDR 2) residue 62.
  5. 5. The antibody or antibody fragment of claim 1, 2 or 3, comprising a Variable Heavy (VH) region and a Variable Light (VL) region comprising all of the following mutations with respect to NEO-102, (I) the (s→e) modification of VH residue 28, (ii) the (n→i) modification at VH (CDR 1) residue 35, (iii) the (g→k) modification at VH (CDR 2) residue 62, (iv) the (s→v) modification at VH (CDR 2) residue 58, and (V) the (a→g) modification at VL (CDR 2) position 54.
  6. 6. The antibody or antibody fragment of claim 1, 2 or 3, comprising a Variable Heavy (VH) region and a Variable Light (VL) region comprising all of the following mutations with respect to NEO-102, (I) the (s→e) modification at VH residue 28, (ii) the (n→i) modification at VH (CDR 1) residue 35, (iii) the (g→k) modification at VH (CDR 2) residue 62, and (s→l) modification at VH (CDR 2) residue 61.
  7. 7. An antibody or antibody fragment comprising the same CDRs as AHF-18095 (NEO-102 m or PB 223) or AHF-18104 or AHF-18100.
  8. 8. The antibody or antibody fragment of any one of the preceding claims, comprising (i) a VH polypeptide having an amino acid sequence that has at least 90% sequence identity to a VH polypeptide of NEO-102, and (ii) a VL polypeptide having an amino acid sequence that has at least 90% sequence identity to a VL polypeptide of NEO-102.
  9. 9. The antibody or antibody fragment of any one of the preceding claims, comprising (i) a VH polypeptide having an amino acid sequence that has at least 95% sequence identity to a VH polypeptide of NEO-102, and (ii) a VL polypeptide having an amino acid sequence that has at least 95% sequence identity to a VL polypeptide of NEO-102.
  10. 10. The antibody or antibody fragment of any one of the preceding claims, comprising (i) a VH polypeptide having an amino acid sequence with at least 98-99% sequence identity (excluding the CDR modifications) to a VH polypeptide of NEO-102, and (ii) a VL polypeptide having an amino acid sequence with at least 98-99% sequence identity to a VL polypeptide of NEO-102.
  11. 11. The antibody or antibody fragment of any one of the preceding claims, comprising (i) a VH polypeptide having an amino acid sequence identical to a VH polypeptide of PB223, and (ii) a VL polypeptide identical to a VL polypeptide of PB 223.
  12. 12. The antibody or antibody fragment of any one of the preceding claims, comprising (i) a VH polypeptide having an amino acid sequence identical to a VH polypeptide of AHF-18104, and (ii) a VL polypeptide identical to a VL polypeptide of AHF-18104.
  13. 13. The antibody or antibody fragment of any one of the preceding claims, comprising (i) a VH polypeptide having an amino acid sequence identical to a VH polypeptide of AHF-18100, and (ii) a VL polypeptide identical to a VL polypeptide of AHF-18100.
  14. 14. The antibody or antibody fragment of any one of the preceding claims, comprising an Fc or constant region, optionally a human Fc or constant region.
  15. 15. The antibody or antibody fragment of any one of the preceding claims, comprising a human IgG1, igG2, igG3 or IgG4 Fc region or constant region, optionally comprising at least one modification that enhances or inhibits at least one antibody effector function.
  16. 16. The antibody or antibody fragment of any one of the preceding claims, which is a Fab or scFv.
  17. 17. The antibody or antibody fragment of any one of the preceding claims, comprising a human IgG1, igG2, igG3 or IgG4 Fc region or constant region comprising at least one modification that enhances or inhibits at least one antibody effector function selected from glycosylation, fcR binding, fcRN binding, phagocytosis, antibody-dependent cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC).
  18. 18. An immunoconjugate, an Antibody Drug Conjugate (ADC) or a Chimeric Antigen Receptor (CAR) comprising the antibody or antibody fragment of any one of the preceding claims.
  19. 19. The antibody or antibody fragment of any one of the preceding claims, or an immunoconjugate, antibody Drug Conjugate (ADC) or Chimeric Antigen Receptor (CAR) comprising the same, expressed in a recombinant host cell, optionally a mammalian cell, a yeast cell, a fungal cell, a plant cell, an insect cell or a bacterial cell.
  20. 20. The antibody or antibody fragment of any one of the preceding claims, or an immunoconjugate, antibody Drug Conjugate (ADC) or Chimeric Antigen Receptor (CAR) comprising the same, expressed in CHO cells, BHK cells, COS cells or Hela cells or HEK cells.

Description

High affinity antibodies recognizing the variant MUC5AC antigen core 2O-glycans, compositions containing the same and uses thereof RELATED APPLICATIONS The present application claims priority from U.S. provisional application No. 63/583,996 filed on month 20 of 2023 and U.S. provisional application No. 63/688,904 filed on month 8 of 2024, the contents of which are hereby incorporated by reference in their entirety. Sequence disclosure The present application includes as part of its disclosure the bioelectronic sequence listing (size: 219,331 bytes; and date of creation: 2024, 9, 18) contained in the file titled 1143282o005213, which is hereby incorporated by reference in its entirety. Sequences that are not allowed to be entered into the st.26 XML file due to sequence length Table A below lists the sequences present in this application, but these sequences are omitted from the XML sequence table due to the sequence length. Technical Field The present application relates generally to novel high affinity monoclonal antibodies that recognize variant forms of MUC5AC (comprising core 2O-glycans) as well as specific glycans specifically expressed by human pancreatic, colorectal and other cancers. The application also relates to their use as cancer diagnostic and therapeutic agents. Exemplary embodiments provide methods for detecting, diagnosing, monitoring and/or treating cancer using innovative novel high affinity monoclonal antibodies. These high affinity monoclonal antibodies can be used as monotherapy or combination therapy, i.e., comprising administration of an antibody as disclosed herein and another anti-cancer agent or cancer treatment regimen, such as another anti-tumor antibody, checkpoint inhibitor fusion protein, chemotherapeutic agent, toxin, checkpoint inhibitor antibody or cytokine, chimeric Antigen Receptor (CAR) -T and CAR-NK. Background Cancer is caused by dysfunction of the cell growth control system. Cells control their growth via a combination of inhibition of proliferation by tumor suppressor genes (e.g., retinoblastoma proteins (pRb), p 53), and activation of proliferation by oncogenes (proto-oncogenes) (e.g., RAS, WNT, MYC, EKR and TRK). Mutations in the oncogene and/or proto-oncogene in cells result in abnormally high proliferation rates of cells (e.g., tumor cells). See Knudson (1971) Proc. Natl. Acad. Sci. USA 68 (4): 820-823. Cells may exhibit early signs of abnormal growth, such as morphological abnormalities or abnormally increased size (hyperplasia). Tumor cells may also proliferate at a rate higher than normal but not fatal, forming a growth called benign tumor (dysplasia). In the later stages of cancer, tumor cells proliferate at abnormally high rates, resulting in uncontrolled growth, threatening the health of the patient, a condition known as malignancy (or carcinoma in situ). Many tumors can "metastasize" or spread to systemic tumors. Metastasis is often a sign of advanced, end-stage cancer. Weinberg (9 th 1996) "How CANCER ARISES" SCIENTIFIC AMERICAN-70. The applicant owned previous applications describe various cancer-related antigens and specific antibodies thereof that can be used to treat cancers, optionally cancers in which these antigens are expressed, e.g., WO/2012/040617, WO/2011/163401, WO/2009/062050, WO/2006/113546, U.S. patent nos. 7,829,678, 7,763,720, and 7,314,622, and U.S. pre-grant publication nos. 2012/0034227, 2011/0165599, 2011/0158902, 2011/0129116, 2011/007661, 2010/0310559, 2009/0162931, and 2008/0227965, each of which is hereby incorporated by reference in its entirety. These antibodies target different cancer specific antigens, including in particular the "NPC-1 antigen" or the "MUC5AC antigen" (comprising core 2O-glycans). MUC5AC is a mucin that contains cysteine regions and contributes to extracellular gel formation and is normally expressed in the stomach and respiratory tract. MUC5AC has become a potentially important biomarker because its overexpression is associated with pancreatic and colon cancers (Byrd JC, Bresalier RS, "Mucins and mucin binding proteins in colorectal cancer", Cancer Metastasis Rev. 2004; 23:77-99). furthermore, in colon and other cancers, MUC5AC exists in the form of aberrant glycosylation (Patel SP, bristol A, saric O, wang XP et al , "Antitumor activity of a novel monoclonal antibody NPC-1, optimized for recognition of tumor antigen MUV5AC variant in preclinical models", Cancer Immunol Immunother 2013, 62:1011-1019). The human Mucin (MUC) family consists of members numbered MUC1 through MUC21, which in turn can be subdivided into secreted and transmembrane forms. Secreted mucins (e.g., MUC2, MUC5AC, MUC5B, and MUC 6) form a physical barrier, act as mucus gels, and provide protection to the airway and inner wall epithelial cells of the gastrointestinal tract and the catheter surfaces of organs such as the liver, breast, pancreas, and kidneys. Transmembrane mucins (e.g., MUC1, MUC4, MUC 13 and MUC 16) have a single transmembr