Search

US-20260125480-A1 - Bispecific EGFR/C-Met Antibodies

US20260125480A1US 20260125480 A1US20260125480 A1US 20260125480A1US-20260125480-A1

Abstract

Bispecific EGFR/c-Met antibodies and methods of making and using the molecules.

Inventors

  • Mark Chiu
  • Sheri Moores
  • Joost Neijssen
  • Paul Parren
  • Janine Schuurman

Assignees

  • JANSSEN BIOTECH, INC.

Dates

Publication Date
20260507
Application Date
20251113

Claims (20)

  1. 1 . An isolated bispecific epidermal growth factor receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody, comprising: a) a first heavy chain (HC1) comprising a HC1 constant domain 3 (HC1 CH3) and a HC1 variable region 1 (VH1); b) a first light chain (LC1) comprising a light chain variable region 1 (VL1); c) a second heavy chain (HC2) comprising a HC2 constant domain 3 (HC2 CH3) and a HC2 variable region 2 (VH2); and d) a second light chain (LC2) comprising a light chain variable region 2 (VL2), wherein the VH1 comprises a heavy chain complementarity determining region 1 (HCDR1), a HCDR2 and a HCDR3 amino acid sequences of SEQ ID NOs: 210, 211 and 212, respectively; the VL1 comprises a light chain complementarity determining region 1 (LCDR1), a LCDR2 and a LCDR3 amino acid sequences of SEQ ID NOs: 213, 214 and 215, respectively, the VH2 comprises the HCDR1, the HCDR2 and the HCDR3 amino acid sequences of SEQ ID NOs: 216,217 and 218, respectively; and the VL2 comprises the LCDR1, the LCDR2 and the LCDR3 amino acid sequences of SEQ ID NOs: 219, 220 and 221, respectively.
  2. 2 . The bispecific antibody of claim 1 , wherein the antibody inhibits growth of NCI-H292 or NCI-H1975 cells with an IC 50 value that is at least about 300-fold less, at least about 400-fold less, at least about 500-fold less, at least about 600-fold less, at least about 700-fold less or at least about 800-fold less when compared to the IC 50 value of inhibition of growth of NCI-H292 or NCI-H1975 cells with cetuximab when NCI-H292 or NCI-H1975 cells are grown in low attachment conditions.
  3. 3 . The bispecific antibody of claim 1 , wherein the antibody inhibits growth of HGF-expressing SKMES-1 cell tumor in SCID Beige mice with a percentage (%) T/C value of at least 500-fold less on day 36 when compared to cetuximab, when the bispecific antibody and cetuximab are administered at 20 mg/kg dose.
  4. 4 . The bispecific antibody of claim 1 , wherein the VH1, the VL1, the VH2 and the VL2 comprise the amino acid sequences of SEQ ID NOs: 189, 190, 193 and 194, respectively.
  5. 5 . The bispecific antibody of claim 4 , wherein the HC1 and the HC2 are an IgG1 isotype.
  6. 6 . The bispecific antibody of claim 5 , wherein the HC1 CH3 comprises at least one substitution and the HC2 CH3 comprises at least one substitution at residue positions 405 or 409.
  7. 7 . The bispecific antibody of claim 6 , wherein the HC1 CH3 comprises a K409R or a F405L substitution and the HC2 CH3 comprises a K409R or a F405L substitution.
  8. 8 . The bispecific antibody of claim 7 , wherein a) the HC1 CH3 comprises the F405L substitution and the HC2 CH3 comprises the K409R substitution; or b) the HC1 CH3 comprises the K409R substitution and the HC2 CH3 comprises the F405L substitution.
  9. 9 . The bispecific antibody of claim 1 , wherein the HC1 comprises the amino acid sequence of SEQ ID NO: 204 and the HC2 comprises the amino acid sequence of SEQ ID NO: 203.
  10. 10 . The bispecific antibody of claim 9 , wherein the antibody has a biantennary glycan structure with a fucose content of about between 1% to about 15%.
  11. 11 . A method of treating a subject having cancer, comprising administering a therapeutically effective amount of the bispecific EGFR/c-Met antibody of claim 1 to a patient in need thereof to treat the cancer.
  12. 12 . The method of claim 11 , wherein the cancer is associated with an EGFR activating mutation, an EGFR gene amplification, increased levels of circulating HGF, a c-Met activating mutation, a c-Met gene amplification or a mutant KRAS.
  13. 13 . The method of claim 12 , wherein the EGFR activating mutation is G719A, G719X (X being any amino acid), L861X (X being any amino acid), L858R, E746K, L747S, E749Q, A750P, A755V, V765M, L858P or T790M substitution, deletion of E746-A750, deletion of R748-P753, insertion of Ala (A) between M766 and A767, insertion of Ser, Val and Ala (SVA) between S768 and V769, and insertion of Asn and Ser (NS) between P772 and H773.
  14. 14 . The method of claim 12 , wherein the mutant KRAS has a G12V or G12C substitution.
  15. 15 . The method of claim 11 , wherein the subject is resistant or has acquired resistance to treatment with erlotinib, gefitinib, afatinib, CO-1686, AZD9192 or cetuximab.
  16. 16 . The method of claim 11 , wherein the cancer is an epithelial cell cancer, breast cancer, ovarian cancer, lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, small cell lung cancer, colorectal cancer, anal cancer, prostate cancer, kidney cancer, bladder cancer, head and neck cancer, pharynx cancer, cancer of the nose, pancreatic cancer, skin cancer, oral cancer, cancer of the tongue, esophageal cancer, vaginal cancer, cervical cancer, cancer of the spleen, testicular cancer, gastric cancer, cancer of the thymus, colon cancer, thyroid cancer, liver cancer, hepatocellular carcinoma (HCC) or sporadic or hereditary papillary renal cell carcinoma (PRCC).
  17. 17 . The method of claim 11 , wherein the subject is homozygous for phenylalanine at position 158 of CD16 or heterozygous for valine and phenylalanine at position 158 of CD16.
  18. 18 . The method of claim 11 , comprising administering a second therapeutic agent.
  19. 19 . The method of claim 18 , wherein the second therapeutic agent is a chemotherapeutic agent or a targeted anti-cancer therapy.
  20. 20 . The method of claim 11 , wherein the second therapeutic agent is cisplatin, vinblastine or a tyrosine kinase inhibitor of EGFR, c-Met, HER2, HER3, HER4 or VEGFR.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 19/027,363, filed on 17 Jan. 2025, which is a continuation of U.S. application Ser. No. 17/398,294, filed on 10 Aug. 2021 (now U.S. Pat. No. 12,247,077), which is a continuation of U.S. application Ser. No. 16/697,249, filed on 27 Nov. 2019 (now abandoned), which is a continuation of U.S. application Ser. No. 15/989,532, filed on 25 May 2018 (now abandoned), which is a continuation of U.S. application Ser. No. 15/616,016, filed on 7 Jun. 2017 (now abandoned), which is a continuation-in-part of U.S. application Ser. No. 15/386,195, filed on 21 Dec. 2016 (now U.S. Pat. No. 9,695,242), which is a divisional application of U.S. application Ser. No. 14/283,257, filed on 21 May 2014 (now U.S. Pat. No. 9,580,508), which is a continuation-in-part of U.S. application Ser. No. 14/086,588, filed on 21 Nov. 2013 (now U.S. Pat. No. 9,593,164), which claims the benefit of U.S. Provisional Application No. 61/728,912, filed on 21 Nov. 2012, U.S. Provisional Application No. 61/782,550, filed on 14 Mar. 2013, U.S. Provisional Application No. 61/809,541, filed on 8 Apr. 2013, U.S. Provisional Application No. 61/864,717, filed on 12 Aug. 2013, and U.S. Provisional Application No. 61/892,797, filed on 18 Oct. 2013, the entire contents of which are hereby incorporated by reference in their entireties. SEQUENCE LISTING The contents of the electronic sequence listing (JB15032.xml; Size: 369,845 bytes; and Date of Creation: Apr. 23, 2025) is herein incorporated by reference in its entirety. FIELD OF THE INVENTION The present invention relates to bispecific EGFR/c-Met antibodies and methods of making and using the molecules. BACKGROUND OF THE INVENTION Epidermal growth factor receptor (EGFR, ErbB1 or HER1) is a Type I transmembrane glycoprotein of 170 kDa that is encoded by the c-erbBl proto-oncogene. EGFR is a member of the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases (RTK) which includes HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). EGFR signaling is initiated by ligand binding followed by induction of conformational change, homodimerization or heterodimerization of the receptor with other ErbB family members, and trans-autophosphorylation of the receptor (Ferguson et al., Annu Rev Biophys, 37: 353-73, 2008), which initiates signal transduction cascades that ultimately affect a wide variety of cellular functions, including cell proliferation and survival. Increases in expression or kinase activity of EGFR have been linked with a range of human cancers, making EGFR an attractive target for therapeutic intervention (Mendelsohn et al., Oncogene 19: 6550-6565, 2000; Grünwald et al., J Natl Cancer Inst 95: 851-67, 2003; Mendelsohn et al., Semin Oncol 33: 369-85, 2006). Increases in both the EGFR gene copy number and protein expression have been associated with favorable responses to the EGFR tyrosine kinase inhibitor, IRESSA® (gefitinib), in non-small cell lung cancer (Hirsch et al., Ann Oncol 18:752-60, 2007). EGFR therapies include both small molecules and anti-EGFR antibodies, approved for treatment of colorectal cancer, pancreatic cancer, head and neck cancer, and non-small cell lung cancer (NSCLC) (Baselga and Arteaga, J Clin Oncol 23:2445-2459 (20005; Gill et al., J Biol Chem, 259:7755-7760, 1984; Goldstein et al., Clin Cancer Res, 1:1311-1318; 1995; Prewett et al., Clin Cancer Res, 4:2957-2966, 1998). Efficacy of anti-EGFR therapies may depend on tumor type and EGFR mutation/amplification status in the tumor. Side effects of current therapeutics may include skin toxicity (De Roock et al., Lancet Oncol 11:753-762, 2010; Linardou et al., Nat Rev Clin Oncol, 6: 352-366, 2009; Li and Perez-Soler, Targ Oncol 4: 107-119, 2009). EGFR tyrosine kinase inhibitors (TKI) are commonly used as 2nd line therapies for non-small cell lung cancer (NSCLC), but often stop working within twelve months due to resistance pathways (Riely et al., Clin Cancer Res 12: 839-44, 2006). c-Met encodes a transmembrane tyrosine kinase receptor. It was first identified as a proto-oncogene in 1984 after it was found that treatment with a carcinogen resulted in a constitutively active fusion protein TPR-MET (Cooper et al., Nature 311:29-33, 1984). Activation of c-Met by its ligand hepatocyte growth factor (HGF) stimulates a plethora of cell processes including growth, motility, invasion, metastasis, epithelial-mesenchymal transition, angiogenesis/wound healing, and tissue regeneration (Christensen et al., Cancer Lett 225:1-26, 2005; Peters and Adjei, Nat Rev Clin Oncol 9:314-26, 2012). c-Met is synthesized as a single chain protein that is proteolytically cleaved into a 50 kDa alpha- and 140 kDa beta-subunits that are linked by a disulphide bond (Ma et al., Cancer and Metastasis Reviews, 22: 309-325, 2003). c-Met is structurally similar to other membrane receptors such as RON and Sea. The exact stoichiometry of HGF:c-Met binding