Combinations for the treatment and prevention of cancer

Abstract

This disclosure provides methods for treating or preventing cancer, comprising the administration of antigen-binding molecules that bind to HER3 and taxoids and / or nucleoside analogs. Also provided are methods for treating or preventing cancer, comprising the administration of antigen-binding molecules that bind to HER3 and antigen-binding molecules that bind to EGFR. Furthermore, pharmaceutical compositions and combinations comprising such agents, as well as therapeutic and prophylactic methods using such pharmaceutical compositions / combinations, are also provided.

Description

Technical Field

[0001] This application claims priority from US63 / 459,373 filed on April 14, 2023 and US63 / 459,396 filed on April 14, 2023, the contents and elements of which are hereby incorporated by reference for all purposes.

[0002] This disclosure relates particularly to the medical treatment and prevention of cancer.

Background Art

[0003] Many transmembrane protein kinases are associated with tumorigenesis (Roskoski Jr 2004). Human epidermal growth factor receptor 3 (HER3) has been identified as a major signaling hub in activating major growth factor signaling pathways such as the RAS-ERK and PI3K-Akt pathways by forming heterodimers with either epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2) (Gala and Chandarlapaty, Clinical Cancer Research (2014) 6:1410 - 1416)(Haikala and Janne, Clinical Cancer Research (2021) 27(13):3528 - 3539). Increased HER3 expression is associated with poor prognosis in multiple solid tumors including breast cancer, gastric cancer, head and neck cancer, pancreatic cancer, ovarian cancer, and lung cancer. HER3-mediated signaling has an adverse effect on tumor progression; HER3 upregulation is associated with resistance to anti-HER2 and anti-EGFR therapies, and solid tumors refractory to anti-PD-1 therapy have been shown to have higher HER3 expression compared to responders to anti-PD-1 therapy. HER3 may be involved in acquired resistance to EGFR / HER2 therapy through feedback regulation via Akt signaling. There are two major mechanisms for HER3 activation (Gala and Chandarlapaty, Clinical Cancer Research (2014) 6:1410 - 1416): ligand-dependent activation that depends on NRG1 to stabilize HER3 in a dimerizable state in a low EGFR / HER2 environment, and ligand-independent activation in a high EGFR / HER2 environment where HER3 is already transiently open. Overexpression of HER3 has been observed in multiple tumor types including non-small cell lung cancer (NSCLC) (Janne et al., Cancer Discovery (2022) 12(1):74 - 89).

[0004] HER3-binding antibodies are described, for example, by Zhang et al., Acta Biochimica et Biophysica Sinica (2016) 48(1):39~48. The anti-HER3 antibody LJM-716 binds to epitopes on subdomains II and IV of the HER3 extracellular domain, immobilizing HER3 into an inactive conformation (Garner et al., Cancer Res (2013) 73:6024~6035). MM-121 (also known as cerivanthumb) has been shown to inhibit HER3-mediated signaling by blocking the binding of heregulin (HRG) to HER3 (Schoeberl et al., Sci. Signal. (2009) 2(77):ra31). Patrizumab (also known as U-1287 and AMG-888) also blocks the binding of helegrin to HER3 (see, e.g., Shimizu et al., Cancer Chemother Pharmacol. (2017) 79(3):489-495). RG7116 (also known as rumletuzumab and RO-5479599) recognizes an epitope in subdomain I of the extracellular domain of HER3 (see, e.g., Mirschberger et al., Cancer Research (2013) 73(16) 5183-5194). KTN3379 binds to HER3 through interactions with amino acid residues in subdomain III (corresponding to the following positions in SEQ ID NO: Gly476, Pro477, Arg481, Gly452, Arg475, Ser450, Gly420, Ala451, Gly419, Arg421, Thr394, Leu423, Arg426, Gly427, Lys356, Leu358, Leu358, Lys356, Ala330, Lys329, and Gly337), as well as with Met310, Glu311, and Pro328 in subdomain II (see Lee et al., Proc Natl Acad Sci USA. 2015 Oct 27;112(43):13225).AV-203 (also known as CAN-017) has been shown to block the binding of NRG1 to HER3 and promote the degradation of HER3 (see Meetze et al., Eur J Cancer 2012;48:126). REGN1400 also inhibits ligand binding to HER3 (see Zhang et al., Mol Cancer Ther (2014) 13:1345~1355). RG7597 (durigotuzumab) is a dual-acting Fab (DAF) that can bind to both HER3 and EGFR and binds to subdomain III of HER3 (see Schaefer et al., Cancer Cell (2011) 20(4):472~486). MM-111 and MM-141 are bispecific antibodies that have a HER3-binding arm that inhibits the binding of HRG ligand to HER3 (see McDonagh et al., Mol Cancer Ther (2012) 11:582~593 and Fitzgerald et al., Mol Cancer Ther (2014) 13:410~425).

[0005] Lung cancer is a leading cause of cancer-related mortality worldwide, accounting for nearly one in five cancer-related deaths (Cancer Genome Atlas Research Network 2012). Squamous cell carcinoma of the lung (LUSC) accounts for approximately 30% of all lung cancers (Perez-Moreno et al., Clinical Cancer Research (2012) 18(9):2443~2451). Squamous non-surgical cell carcinoma (NSCLC) develops in epithelial tissue subjected to environmental aggression such as smoking, and patients with NSCLC have a 28% five-year survival rate after diagnosis (Detterbeck and Gibson, Journal of Thoracic Oncology (2008) 3(7):781~792). Metastatic NSCLC reduces the five-year survival rate to just about 9% (American Cancer Society 2023). Because potential biomarkers for the use of approved targeted therapies are rare in this NSCLC subtype, the standard first-line treatment for metastatic LUSCs is immunotherapy combined with or without platinum-based chemotherapy (Yuan et al., Molecules (2021) 26(5):1392). When patients progress after combination therapy, subsequent lines of treatment offer only limited clinical benefit, highlighting a critical area for improvement.

[0006] Early tumorigenesis in squamous cell carcinoma is characterized by amplification of chromosome 3q (Chr3q) and loss of chromosome 3p (Chr3p), which are well-known genetic abnormalities associated with exposure to carcinogens (Rooney et al., Oncologist (2013) 18(6):707~716). Chr3q amplification leads to increased transcriptional activity of numerous genes, including TP63 (which directly promotes the expression of HER3 ligand NRG1), SOX2 (which directly promotes the expression of EGFR ligand), and the PIK3CA gene (which enhances the activation of the PI3K pathway) (Perez-Moreno et al., Clinical Cancer Research (2012) 18(9):2443~2451). On the other hand, loss of Chr3p leads to the deletion of several putative tumor suppressor proteins, including Tumor Suppressor Candidate 2 (TUSC2), which inhibits EGFR (Perez-Moreno et al., Clinical Cancer Research (2012) 18(9):2443~2451). In addition, chromosome 7p (Chr7p), which encodes EGFR, has also been found to be frequently amplified in LUSCs (Couceiro et al., Revista Portuguesa de Pneumologia (2010) 16(3):453~462).

[0007] Supported by significant advances in genomic technology enabling timely patient selection, the successful targeting of driver mutations in cancer has transformed patient outcomes in multiple cancer indications (Martinez-Jimenez et al., Nat Rev Cancer (2020) 20(10):555~572). Neuregrin-1 (NRG1) gene fusions are a relatively recent addition to the advantageous means of potentially acting driver events. These transmembrane chimeric proteins exert oncogenic function via the ErbB receptor family, binding to HER3 and stabilizing the protein in an open conformation, forming heterodimers with EGFR or HER2, resulting in constitutive activation of well-documented standard pathways such as MAPK and PI3K / Akt (Fernandez-Cuesta 2014 et al., Cancer Discov. (2014) 4(4):415~22; Liu et al., Lung Cancer (2021) 158:25~28). Currently, there are no approved treatments for patients with NRG1 fusion cancer. Over the past two years, the US FDA has granted fast-track designation for cerivanthumab (an anti-HER3 IgG2 monoclonal antibody) (OncLive Spotlight, May 26, 2022) and xenoctuzumab (a bispecific antibody that binds to HER2 and HER3) for patients with NRG1 fusion cancer (CancerNetwork Spotlight, January 9, 2021), highlighting a critical unmet clinical need.

[0008] Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer death in developed countries by 2030 (Rahib et al., Cancer Research (2014) 74(11):2913-2921). The prognosis for patients with pancreatic cancer is poor, with a 5-year survival rate of only 11% after initial diagnosis. For patients with metastatic disease, the 5-year survival rate is even worse, at 3% (American Cancer Society 2022).

[0009] The efficacy of a combination chemotherapy approach using gemcitabine and albumin-conjugated paclitaxel (nab-paclitaxel) was established in the Phase III MPACT trial comparing gemcitabine + nab-paclitaxel with gemcitabine monotherapy. Median overall survival improved to 8.7 months compared to 6.6 months with gemcitabine monotherapy, and the overall response rate improved to 23% compared to 7% with gemcitabine monotherapy (Von Hoff et al., N Engl J Med (2013) 369(18):1691~703). A significant need for improved treatment options remains in this patient population.

[0010] Forster et al., Eur J Cancer. (2019) 123:36-47, disclose the treatment of recurrent or metastatic head and neck squamous cell carcinoma (SCCHN) using a combination of the anti-HER3 antibody patritumab and the anti-EGFR antibody cetuximab. Patritumab (also known as U-1287 and AMG-888) has been shown to inhibit HER3-mediated signaling by blocking the binding of heregulin (HRG) to HER3 (see, for example, Shimizu et al., Cancer Chemother Pharmacol. (2017) 79(3):489-495).

[0011] Cleary et al., Investigational New Drugs (2017) 35:68-78, disclose the administration of a combination of the anti-HER3 antibodies cerivanthumab and cetuximab for the treatment of EGFR-dependent cancers. Similar to patritumab, cerivanthumab (also known as MM-121) has been shown to inhibit HER3-mediated signaling by blocking the binding of heregulin (HRG) to HER3 (Schoeberl et al., Sci. Signal. (2009) 2(77):ra31).

[0012] Meulendijks et al., Clin Cancer Res. (2017) 23(18): 5406-5415, disclose the administration of a combination of the anti-HER3 antibodies lumuretuzumab and cetuximab for the treatment of advanced HER3-positive cancer. Only minimal clinical activity was observed. Lumuletuzumab (also known as RG7116 and RO-5479599) recognizes an epitope in subdomain I of the HER3 extracellular domain (see, e.g., Mirschberger et al., Cancer Research (2013) 73(16) 5183-5194).

[0013] Bauman et al., Cancers (Basel) (2022) 14(10):2355, reported the results of a Phase II trial of the anti-HER3 antibody CDX-3379 in combination with cetuximab for the treatment of recurrent / metastatic, HPV-negative, cetuximab-resistant head and neck squamous cell carcinoma (HNSCC). The objective response rate was low. CDX-3379 (also known as KTN3379) binds to HER3 through interactions with amino acid residues in subdomain III (corresponding to the following positions in SEQ ID NO: Gly476, Pro477, Arg481, Gly452, Arg475, Ser450, Gly420, Ala451, Gly419, Arg421, Thr394, Leu423, Arg426, Gly427, Lys356, Leu358, Leu358, Lys356, Ala330, Lys329, and Gly337) as well as with Met310, Glu311, and Pro328 in subdomain II (see Lee et al., Proc Natl Acad Sci USA. 2015 Oct 27;112(43):13225).

[0014] Garner et al., Cancer Res. (2013) 73(19):6024~6035, disclose the treatment of HNSCC using a combination of the anti-HER3 antibody LJM-716 and cetuximab. LJM-716 binds to epitopes on subdomains II and IV of the HER3 extracellular domain, fixing HER3 to an inactive conformation (Garner et al., Cancer Res (2013) 73:6024~6035).

[0015] Papadopoulos et al., Journal of Clinical Oncology (2014) 32(15_suppl):2516~2516, disclose the administration of a combination of the anti-HER3 antibody REGN1400 and cetuximab for the treatment of advanced non-small cell lung cancer (NSCLC), colorectal cancer (CRC), or SCCHN. REGN1400 also inhibits the binding of ligands to HER3 (see Zhang et al., Mol Cancer Ther (2014) 13:1345~1355).

[0016] Kim et al., Annals of Oncology (2020) 31(suppl_4):S599~S628, disclose the treatment of relapsed or metastatic HNSCC using a combination of the anti-HER3 antibody ISU104 and cetuximab. ISU104 (also known as valecetamab) primarily binds to domain III of HER3, weakly interacts with domain I, and exhibits dose-dependent inhibition of HRG binding to HER3 (see Kim et al., Cancer Research (2018) 78(13 Supplement):830~830). [Overview of the project] [Means for solving the problem]

[0017] In a first aspect, the present disclosure provides an antigen-binding molecule for use in a method of treating or preventing cancer, wherein the method comprises the step of administering an antigen-binding molecule that binds to EGFR.

[0018] Furthermore, the present invention provides the use of an antigen-binding molecule that binds to HER3 in the manufacture of a pharmaceutical product for use in a method of treating or preventing cancer, wherein the method comprises the step of administering an antigen-binding molecule that binds to EGFR.

[0019] The present invention also provides a method for treating or preventing cancer, comprising the step of administering a therapeutic or prophylactic effective amount of (i) an antigen-binding molecule that binds to HER3 and (ii) an antigen-binding molecule that binds to EGFR to the target.

[0020] In some embodiments according to various aspects of this disclosure, the method further includes the step of administering a taxoid. Also provided are antigen-binding molecules that bind to HER3 for use in methods of treating or preventing cancer, wherein the method comprises the step of administering a taxoid.

[0021] Also provided is the use of an antigen-binding molecule that binds to HER3 in the manufacture of a pharmaceutical product for use in a method of treating or preventing cancer, wherein the method includes the step of administering a taxoid.

[0022] Also provided are methods for treating or preventing cancer, comprising the step of administering a therapeutic or prophylactic effective amount of (i) an antigen-binding molecule that binds to HER3 and (ii) a taxoid to the target.

[0023] Also provided are antigen-binding molecules that bind to HER3 for use in methods of treating or preventing cancer, wherein the method comprises the step of administering a taxoid and a nucleoside analog.

[0024] Also provided is the use of an antigen-binding molecule that binds to HER3 in the manufacture of a pharmaceutical product for use in a method of treating or preventing cancer, wherein the method comprises the step of administering a taxoid and a nucleoside analog.

[0025] Also provided are methods for treating or preventing cancer, comprising the step of administering a therapeutic or prophylactic effective amount of (i) an antigen-binding molecule that binds to HER3, (ii) a taxoid, and (iii) a nucleoside analog to the target.

[0026] Also provided are antigen-binding molecules that bind to HER3 for use in methods of treating or preventing cancer, wherein the method comprises the step of administering a nucleoside analog.

[0027] Also provided is the use of an antigen-binding molecule that binds to HER3 in the manufacture of a pharmaceutical product for use in a method of treating or preventing cancer, wherein the method comprises the step of administering a nucleoside analog.

[0028] Also provided are methods for treating or preventing cancer, comprising the step of administering a therapeutic or prophylactic effective amount of (i) an antigen-binding molecule that binds to HER3 and (ii) a nucleoside analog to the target.

[0029] Furthermore, a combination of pharmaceuticals is also provided, comprising (i) an antigen-binding molecule that binds to HER3 and (ii) an antigen-binding molecule that binds to EGFR. Furthermore, a combination of pharmaceuticals is also provided, comprising (i) an antigen-binding molecule that binds to HER3, (ii) an antigen-binding molecule that binds to EGFR, and (iii) a taxoid.

[0030] Furthermore, pharmaceutical combinations are also provided that include (i) an antigen-binding molecule that binds to HER3 and (ii) a taxoid. Furthermore, pharmaceutical combinations are also provided that include (i) an antigen-binding molecule that binds to HER3, (ii) a nucleoside analog, and (iii) a taxoid.

[0031] Furthermore, pharmaceutical combinations are also provided that include (i) an antigen-binding molecule that binds to HER3 and (ii) a nucleoside analog. In some embodiments, the pharmaceutical combinations according to this disclosure are provided for use in methods of treating or preventing cancer.

[0032] Furthermore, the use of drug combinations pursuant to this disclosure in the manufacture of pharmaceuticals for treating or preventing cancer is also provided. Also provided are methods for treating or preventing cancer, which include the step of administering a therapeutic or prophylactic effective dose of a combination of pharmaceuticals in accordance with this disclosure.

[0033] In some embodiments according to various aspects of this disclosure, the antigen-binding molecule that binds to HER3 binds to the region of HER3 shown in SEQ ID NO: 77. In some embodiments, the antigen-binding molecule that binds to HER3 is (i) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 40 HC-CDR2 having the amino acid sequence of SEQ ID NO: 43 HC-CDR3 having the amino acid sequence of SEQ ID NO: 48 The heavy chain variable (VH) region incorporating; and (ii) The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 66 LC-CDR2 having the amino acid sequence of SEQ ID NO: 69 LC-CDR3 having the amino acid sequence of SEQ ID NO: 74 Light chain variable (VL) region incorporating Includes.

[0034] In some embodiments, the antigen-binding molecule that binds to HER3 is (i) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 38 HC-CDR2 having the amino acid sequence of SEQ ID NO: 42 HC-CDR3 having the amino acid sequence of SEQ ID NO: 45 The VH region incorporating, and (ii) The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 63 LC-CDR2 having the amino acid sequence of SEQ ID NO: 67 LC-CDR3 having the amino acid sequence of SEQ ID NO: 70 The VL area incorporates Includes.

[0035] In some embodiments, the antigen-binding molecule that binds to HER3 is A VH region containing an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 33, and VL region containing an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 58 Includes.

[0036] In some embodiments, the antigen-binding molecule that binds to HER3 is A polypeptide comprising, or derived from, an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 75, and A polypeptide containing, or derived from, an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 76. Includes.

[0037] In some embodiments according to various aspects of this disclosure, the taxoid is docetaxel or nab-paclitaxel. In some embodiments, the taxoid is docetaxel. In some embodiments according to various aspects of this disclosure, the nucleoside analog is a deoxycytidine nucleoside analog. In some embodiments, the nucleoside analog is gemcitabine or a salt thereof.

[0038] In some embodiments, the antigen-binding molecule that binds to EGFR is (i) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 92 HC-CDR2 having the amino acid sequence of SEQ ID NO: 93 HC-CDR3 having the amino acid sequence of SEQ ID NO: 94 The heavy chain variable (VH) region incorporating; and (ii) The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 96 LC-CDR2 having the amino acid sequence of SEQ ID NO: 97 LC-CDR3 having the amino acid sequence of SEQ ID NO: 98 Light chain variable (VL) region incorporating Includes.

[0039] In some embodiments, the antigen-binding molecule that binds to EGFR is A VH region containing an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 91; and VL region containing an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 95 Includes.

[0040] In some embodiments, the antigen-binding molecule that binds to EGFR is A polypeptide comprising, or derived from, an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 99; and A polypeptide containing, or derived from, an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 100. Includes.

[0041] In some embodiments according to various aspects of this disclosure, cancer is a cancer comprising cells expressing / overexpressing an EGFR family member, or a cancer comprising cells expressing / overexpressing HER3. In some embodiments, cancer is squamous cell carcinoma, lung cancer, non-small cell lung cancer, squamous cell lung cancer, squamous cell non-small cell lung cancer, advanced squamous cell non-small cell lung cancer, metastatic squamous cell non-small cell lung cancer, pancreatic cancer, exocrine cancer, pancreatic ductal adenocarcinoma, advanced pancreatic ductal adenocarcinoma, or metastatic pancreatic ductal adenocarcinoma. In some embodiments, cancer is a cancer comprising cells having mutations resulting in increased expression of ligands for HER3, a cancer comprising cells having an NRG gene fusion, a cancer comprising cells having an NRG1 gene fusion, or a cancer comprising cells having an NRG2 gene fusion. In some embodiments, cancer is CLU-NRG1, CD74-NRG1, DOC4-NRG1, SLC3A2-NRG1, RBPMS-NRG1, WRN-NRG1, SDC4-NRG1, RAB2IL1-NRG1, VAMP2-NRG1, KIF13B-NRG1, THAP7-NRG1, SMAD4-NRG1, MDK-NRG1, TNC-NRG1, DIP2B-NRG1, MRPL13-NRG1, PARP8-NRG1, RO The cells include an NRG gene fusion selected from CK1-NRG1, DPYSL2-NRG1, ATP1B1-NRG1, CDH6-NRG1, APP-NRG1, AKAP13-NRG1, THBS1-NRG1, FOXA1-NRG1, PDE7A-NRG1, RAB3IL1-NRG1, CDK1-NRG1, BMPRIB-NRG1, TNFRSF10B-NRG1, MCPH1-NRG1, and SLC12A2-NRG2.

[0042] In some embodiments, cancer is a cancer comprising cells expressing / overexpressing EGFR family members, a cancer comprising cells expressing / overexpressing HER3, a cancer comprising cells expressing / overexpressing EGFR, a cancer comprising cells expressing / overexpressing HER3 and EGFR, a cancer comprising cells having mutations resulting in increased expression of ligands for HER3, a cancer comprising cells having mutations resulting in increased expression of ligands for EGFR, a cancer comprising cells having an NRG gene fusion, a cancer comprising cells having an NRG1 gene fusion, or a cancer comprising cells having an NRG2 gene fusion, solid tumors, hematological cancers, squamous cell carcinomas, EGFR-amplifying squamous cell carcinomas, breast cancers, breast cancers, invasive breast cancers, ductal carcinomas, metastatic breast cancers, triple-negative breast cancers, HER2-positive breast cancers, gastric cancers, gastric adenocarcinomas, gastrointestinal adenocarcinomas, colorectal cancers, metastatic colorectal cancers, colon cancers, colorectal cancers, colorectal adenocarcinomas, colon adenocarcinomas, head and neck cancers, head and neck squamous cell carcinomas, lung cancers, non-small cell lung cancers, lung Adenocarcinoma, invasive mucinous lung adenocarcinoma, squamous cell lung cancer, squamous cell carcinoma of the lung, squamous non-small cell lung cancer, advanced squamous non-small cell lung cancer, metastatic squamous non-small cell lung cancer, ovarian cancer, serous ovarian adenocarcinoma, serous ovarian cystadenocarcinoma, fallopian tube cancer, kidney cancer, renal cell carcinoma, clear cell carcinoma of the kidney, renal cell adenocarcinoma, papillary renal cell carcinoma, pancreatic cancer, exocrine cancer, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, advanced pancreatic ductal adenocarcinoma, metastatic pancreatic ductal adenocarcinoma, cervical cancer, cervical squamous cell carcinoma, skin cancer, melanoma, oral cancer, oropharyngeal cancer, esophageal cancer, esophageal squamous cell carcinoma The following are selected: skin cancer, esophageal adenocarcinoma, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, uterine cancer, endometrial cancer, endometrial cancer, uterine carcinosarcoma, thyroid cancer, thyroid cancer, thyroid cancer, pheochromocytoma, paraganglioma, bladder cancer, urothelial carcinoma of the bladder, prostate cancer, prostate adenocarcinoma, retinoblastoma, sarcoma, soft tissue sarcoma, peritoneal cancer, thymoma, neuroendocrine tumors, nasopharyngeal neuroendocrine tumors, squamous cell carcinoma of the skin, astrocytoma, low-grade astrocytoma, high-grade astrocytoma, undifferentiated astrocytoma, and glioblastoma multiforme.

[0043] In some embodiments, cancer is selected from cancers comprising cells expressing / overexpressing HER3, cancers comprising cells expressing / overexpressing EGFR, cancers comprising cells expressing / overexpressing HER3 and EGFR, squamous cell carcinoma, EGFR-amplified squamous cell carcinoma, esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, head and neck squamous cell carcinoma, colorectal cancer, metastatic colorectal cancer, colonic adenocarcinoma, pancreatic cancer, exocrine cancer, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, advanced pancreatic ductal adenocarcinoma, metastatic pancreatic ductal adenocarcinoma, lung cancer, squamous cell lung cancer, squamous cell non-small cell lung cancer, advanced squamous cell non-small cell lung cancer, metastatic squamous cell non-small cell lung cancer, and lung squamous cell carcinoma. [Modes for carrying out the invention]

[0044] This disclosure relates to combination therapies for cancer. This disclosure relates to (i) combination therapies for cancer comprising an antigen-binding molecule and a taxoid that binds to HER3; (ii) combination therapies for cancer comprising an antigen-binding molecule and a nucleoside analog that binds to HER3; and (iii) combination therapies for cancer comprising an antigen-binding molecule, a taxoid, and a nucleoside analog that binds to HER3.

[0045] This disclosure also relates to a combination treatment for cancer comprising an antigen-binding molecule that binds to HER3 and an antigen-binding molecule that binds to EGFR. In a preferred embodiment, the antigen-binding molecule that binds to HER3 is 10D1F, and the antigen-binding molecule that binds to EGFR is cetuximab.

[0046] 10D1F binds to a different epitope of HER3 than the epitopes of anti-HER3 antibodies used in combination treatments disclosed in prior art, including anti-HER3 antibodies and cetuximab. More specifically, 10D1F binds to the HER3 dimerization interface, while other anti-HER3 antibodies bind to various sites in the HER3 extracellular domain (e.g., ligand-binding domain, domains II / IV). Because 10D1F inhibits the dimerization of HER3 with its receptor partner and blocks both ligand-dependent and ligand-independent activation of HER3, it results in a more complete shutdown of HER3-mediated signaling.

[0047] In the experimental examples of this application, the inventors demonstrate that the combination of 10D1F and cetuximab yields unexpectedly advantageous properties compared to combination therapies containing anti-HER3 antibodies and cetuximab disclosed in the prior art. Furthermore, the combination of 10D1F and cetuximab yields unexpectedly advantageous effects as an intervention for the treatment / prevention of various different cancers compared to any of the components of combinations used as monotherapies.

[0048] HER3 HER3 (also known as ERBB3, LCCS2, and MDA-BF-1, for example) is a protein identified by UniProt P21860.

[0049] The structure and function of HER3 are described, for example, in Cho and Leahy Science (2002) 297(5585):1330-1333, Singer et al., Journal of Biological Chemistry (2001) 276, 44266-44274, Roskoski et al., Pharmacol. Res. (2014) 79:34-74, Bazley and Gullick Endocrine-Related Cancer (2005) S17-S27, and Mujoo et al., Oncotarget (2014) 5(21):10222-10236, each of which is incorporated herein by reference in its entirety. HER3 is a single-pass transmembrane ErbB receptor tyrosine kinase with an N-terminal extracellular domain (SEQ ID NO: 9) containing two leucine-rich subdomains (domains I and III, shown in SEQ ID NOs. 15 and 17, respectively) and two cysteine-rich subdomains (domains II and IV, shown in SEQ ID NOs. 16 and 18, respectively). Domain II contains a β-hairpin dimerization loop (SEQ ID NO: 19) involved in intermolecular interactions with other HER receptor molecules. The extracellular domain is linked to a cytoplasmic domain (SEQ ID NO: 11) via a transmembrane domain (SEQ ID NO: 10). The cytoplasmic domain contains a proximity-of-membrane segment (SEQ ID NO: 12), a protein kinase domain (SEQ ID NO: 13), and a C-terminal segment (SEQ ID NO: 14).

[0050] In this specification, "HER3" means HER3 derived from any species, and includes isoforms, fragments, variants (including mutants), or homologs of HER3 derived from any species.

[0051] As used herein, a protein “fragment,” “variant,” or “homologous” may optionally be characterized by having at least 60%, preferably 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with respect to the amino acid sequence of a reference protein (e.g., a reference isoform). In some embodiments, a reference protein fragment, variant, isoform, and homologous may be characterized by their ability to perform the function performed by the reference protein.

[0052] A "fragment" generally refers to a portion of a reference protein. A "variant" generally refers to a protein whose amino acid sequence contains one or more amino acid substitutions, insertions, deletions, or other modifications compared to the amino acid sequence of the reference protein, but retains a considerable degree of sequence identity (e.g., at least 60%) to the amino acid sequence of the reference protein. An "isoform" generally refers to a variant of a reference protein expressed by the same species as the reference protein (e.g., human HER3 isoforms 1-5 are all isoforms of each other). A "homologous" generally refers to a variant of a reference protein produced by a different species compared to the species of the reference protein. For example, human HER3 isoform 1 (P21860-1, v1; SEQ ID NO: 1) and rhesus monkey HER3 (UniProt: F7HEH3-1, v2; SEQ ID NO: 20) are homologs of each other. Homologous proteins include orthologues.

[0053] The "fragment" of the reference protein may be of any length (by number of amino acids), but may optionally be at least 20% of the length of the reference protein (i.e., the protein from which the fragment originates), and may have one of the largest lengths of 50%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the length of the reference protein.

[0054] The HER3 fragment may have one minimum length among 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1100, or 1200 amino acids, and one maximum length among 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1100, 1200, or 1300 amino acids.

[0055] In some embodiments, HER3 is HER3 derived from mammals (e.g., HER3 from primates (rhesus monkeys, cynomolgus monkeys, non-human primates, or humans) and / or rodents (e.g., rats or mice)). An isoform, fragment, variant, or homolog of HER3 may be optionally characterized as having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with respect to the amino acid sequence of an immature or mature HER3 isoform derived from a given species, e.g., humans.

[0056] Isoforms, fragments, variants, or homologs may, optionally, be functional isoforms, fragments, variants, or homologs possessing the functional properties / activities of reference HER3 (e.g., human HER3 isoform 1), as determined by analysis using appropriate assays for their functional properties / activity. For example, an isoform, fragment, variant, or homolog of HER3 may associate with one or more of HER2, NRG1 (types I, II, III, IV, V, or VI), or NRG2 (α or β).

[0057] In some embodiments, HER3 contains or consists of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with respect to one of sequence numbers 1 to 8.

[0058] In some embodiments, the HER3 fragment contains or consists of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with respect to one of sequence numbers 9 to 19, for example, one of sequence numbers 9, 16, or 19.

[0059] HER3-mediated signaling involves the heteromultimerization of the receptor (i.e., with other ErBB receptors, e.g., HER2, EGFR) and the resulting autophosphorylation of tyrosine residues in the cytoplasm by the protein kinase domain. HER3 lacks kinase activity and does not form stable homodimers. Therefore, HER3 must be transphosphorylated by binding to a kinase-active heterodimer partner (e.g., EGFR or HER2) to undergo signal transmutation (Berger MB et al., FEBS Lett 2004;569:332~6; Kim HH et al., Biochem J 1998;334:189~95).

[0060] The multimerization (e.g., dimerization) of HER receptor family members is required to activate cell growth signaling pathways, and HER3 can dimerize with other HER family members both ligand-dependently and ligand-independently. The extracellular domain (ECD) of HER3 exists in a reversible equilibrium between a "closed" inactive conformation and an "open" active conformation, exposing the dimerization arms within domain II and enabling dimerization along the dimerization interface of domain II, particularly via the cysteine-rich CR1 region (Carraway, KL et al., Nature, 1997.387(6632):512~6; Riese, DJ et al., Mol Cell Biol, 1995.15(10):5770~6; Harari, D. et al., Oncogene, 1999.18(17):2681~9; Zhang, D. et al., Proc Natl Acad Sci USA, 1997.94(18):9562~7; Meyer et al., Nature, 1995.378(6555):386~90; Jura, N. et al., Proc Natl Acad Sci USA, 2009.106(51):21608~13; Fornaro, L. et al., Nat Rev Gastroenterol Hepatol, 2011.8(7):369~83; Mota et al., Oncotarget (2015) 5:89284~306). HER3 is “activated” when the equilibrium shifts in favor of the open conformation, increasing the likelihood of forming an active heterodimer. Conventional models of activation are ligand-dependent, i.e., when HER3 in the open conformation is stabilized by binding to its ligand, such as neuregulin (NRG), e.g., NRG1 (also known as heregulin, HRG) or NRG2, the equilibrium shifts. In addition, the presence of either dimerizing partner at sufficient concentration shifts the equilibrium in favor of the open conformation because it transiently binds to and stabilizes HER3 in the open conformation.This is known as ligand-independent activation (Jura, N. et al., Proc Natl Acad Sci USA, 2009.106(51):21608~13; Fornaro, L. et al., Nat Rev Gastroenterol Hepatol, 2011.8(7):p.369~83; Mota et al., Oncotarget (2015) 5:89284~306).

[0061] In this specification, “HER3-mediated signaling” refers to signaling mediated by HER3 and / or HER3-containing multimeric ErbB family member receptor complexes. “Signaling” refers to other cellular processes that regulate signal transduction and cellular activity. HER3-mediated signaling may be mediated by HER3 receptor-containing complexes, e.g., heteromultimeric complexes containing HER3 and other HER receptors (e.g., HER2, EGFR). HER3-mediated signaling may be ligand-dependent, for example, triggered by the binding of NRGs (e.g., NRG1, NRG2), or it may be ligand-independent.

[0062] HER3-mediated signaling proceeds within cells via the MAPK / ERK and PI3K / AKT / mTOR pathways, promoting cell survival and proliferation. HER3-mediated signaling is described, for example, in Gala and Chandarlapaty, Clin Cancer Res. (2014) 20(6):1410-1416, Mishra et al., Oncol Rev. (2018) 12(1):355, Baselga et al., Nat Rev Cancer (2009) 9:463-75, Yarden et al., Nat Rev Mol Cell Biol (2001) 2:35052073, Mota et al., Oncotarget (2015) 5:89284-306, and Haikala and Janne, Clin. Cancer Res. (2021) 27:3528-39, all of which are incorporated herein by reference in their entirety.

[0063] Phosphorylated tyrosine residues in the protein kinase domain of the HER3-containing receptor complex recruit the adapter / effector protein GRB2 via interaction with its SH2 domain. Upon ligand stimulation, the activated receptor (EGFR / HER2) undergoes autophosphorylation, providing phosphotyrosine residues for recruiting GRB2. GRB2 binds to the guanine nucleotide exchange factor SOS via its SH3 domain. In the GRB2-SOS complex, activated SOS promotes the removal of GDP from Ras family GTPases such as H-Ras, N-Ras, and K-Ras, and thereby the activation of Ras family GTPases. Activated Ras GTPases then activate RAF kinases such as A-Raf, B-Raf, and C-Raf. RAF kinases then phosphorylate and activate MEK1 and MEK2, which in turn phosphorylate and activate MAPK (also known as ERK). Activated MAPK can directly modulate the activity of transcription factors such as c-Myc. Activated MAPK also upregulates mRNA translation into proteins through phosphorylation of RSK, and consequently phosphorylation and activation of the 40S ribosomal protein S6. Activated MAPK also phosphorylates and activates MNK, which in turn phosphorylates and activates the transcription factor CREB.

[0064] Phosphorylated tyrosine residues in the protein kinase domain of HER3 also recruit the p85 subunit of PI3K via its SH2 domain. The association of p85 triggers allosteric activation of the lipid kinase p100α subunit of PI3K. Activated PI3K leads to the conversion of PIP2 to PIP3, which recruits AKT, which is then phosphorylated and activated by mTORC2 and PDK1. Phosphorylated AKT has many activities, including activating CREB and mTOR. PTEN antagonizes signaling via the PI3K / AKT / mTOR pathway by dephosphorylating PIP3 to PIP2, and PP2A inhibits the PI3K / AKT / mTOR pathway by dephosphorylating AKT.

[0065] Oncogenic Src homologous region 2 protein tyrosine phosphatase 2 (SHP2) promotes tumor progression and functions as a crucial hub connecting multiple oncogenic signaling pathways, including PI3K / AKT and Ras / Raf / MAPK (Dong et al., Front.Cell Dev.Biol., 11 March 2021). GAB2 binds to GRB2 and is phosphorylated at multiple tyrosine residues, making it capable of binding to the SH2 domains of SHP2 and p85 (Adams et al., Mol Cancer Res. 2012 Oct;10(10):1265~70; (Liu et al., Proc. Natl. Acad. Sci. USA (2016) 113, 984~989). The interaction induces conformational changes, reducing autoinhibition of the SHP2 catalytic site (Neel et al., Trends Biochem Sci. 2003 Jun;28(6):284~93) and reducing the inhibition of p85 on the p110 catalytic subunit of PI3K (Cuevas et al., J Biol Chem. 2001 Jul 20;276(29):27455~6). SHP2 directly dephosphorylates RAS (Bunda et al., Nat Commun. 2015 Nov). It has been shown that RAS is activated by inhibiting RASGAP (RAS GTPase activating protein) (Neel et al., Trends Biochem Sci. 2003 Jun;28(6):284~93) and SPRY (Hanafusa et al., J Biol Chem. 2004 May 28;279(22):22992-5). SHP2 overexpression has been shown to enhance tumor invasion by activating the PI3K / AKT axis (Hu et al., Onco Targets Ther. (2017) 10, 3881~3891), while SHP2 knockdown inhibits cell migration, and the tumor-promoting effect of SHP2 is partially related to AKT signaling (Cao et al., Pathol. Res. Pract. (2019) 215:152621).

[0066] STAT3 and STAT5 proteins are transcription factors that enhance the expression of p85α, p110α, and AKT1, thereby increasing signaling via the PI3K / AKT signaling cascade (Radler et al., Mol Cell Endocrinol. 2017 August 15;451:31~39). When activated by JAK2, phosphorylated STAT5 binds to the SH2 domain of the p85α regulatory subunit of PI3K in a PRL signaling-dependent manner, suggesting that STAT5 may also be directly involved in PI3K complex signaling. Another kinase that phosphorylates EGFR is the cytokine-regulated tyrosine kinase Jak2, which therefore enables MAPK activation even by kinase-deficient mutants of EGFR (Mishra et al., Oncol Rev. (2018) 12(1):355, Baselga et al., Nat Rev Cancer (2009) 9:463~75). Population observations in gene models overexpressing or deleting active STAT5 and AKT, or expressing mutant PTEN, support the idea that STAT5 function as a survival factor during normal mammary gland development and as an oncogene during breast cancer development is mediated by the PI3K / AKT pathway (Radler et al., Mol Cell Endocrinol. 2017 August 15;451:31~39).

[0067] EGFR EGFR (also known as ERBB1 or HER1, for example) is a protein identified by UniProt P00533.

[0068] The structure and function of EGFR are described, for example, in Sabbah et al., Curr Top Med Chem. (2020) 20(10):815-834, and Sigismund et al., Mol Oncol. (2018) 12(1):3-20, both of which are incorporated herein by reference in their entirety. EGFR is a single-pass transmembrane ErbB receptor tyrosine kinase having an N-terminal extracellular domain (SEQ ID NO: 88) linked to a cytoplasmic domain (SEQ ID NO: 90) via a transmembrane domain (SEQ ID NO: 89).

[0069] In this specification, "EGFR" means EGFR of any species, and includes isoforms, fragments, variants (including mutants), or homologs of EGFR of any species.

[0070] The EGFR fragment may have the minimum length of one of 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1100, or 1200 amino acids, and may have the maximum length of one of 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1100, or 1200 amino acids.

[0071] In some embodiments, EGFR is mammalian EGFR (e.g., primate (rhesus monkey, cynomolgus monkey, non-human primate, or human) and / or rodent (e.g., rat or mouse) EGFR). An isoform, fragment, variant, or homolog of EGFR may be optionally characterized as having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with respect to the amino acid sequence of an immature or mature EGFR isoform from a given species, e.g., human.

[0072] Isoforms, fragments, variants, or homologs may, optionally, be functional isoforms, fragments, variants, or homologs possessing the functional properties / activities of reference EGFR (e.g., human EGFR isoform 1), as determined by analysis using an appropriate assay for their functional properties / activity. For example, an isoform, fragment, variant, or homolog of EGFR may associate with one or more of HER3, HER2, EGF, TGFα, and amphiregulin.

[0073] In some embodiments, EGFR comprises or consists of amino acid sequences having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with respect to one of sequence numbers 80 to 87.

[0074] In some embodiments, the EGFR fragment comprises or consists of an amino acid sequence having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with respect to one of sequence numbers 88, 89, or 90.

[0075] EGFR-mediated signaling has been described, for example, by Sigismund et al., Mol Oncol. (2018) 12(1):3~20, and by Kovacs et al., Annu Rev Biochem. (2015) 84:739~764, both of which are incorporated herein in their entirety. Canonical EGFR signaling is crucial for various cellular functions, including survival, proliferation, differentiation, and motility. In the absence of a ligand, EGFR exists primarily in an autoinhibited, non-dimerizable state on the cell membrane. Ligand binding induces receptor dimerization and aggregation of the catalytic region, resulting in trans-autophosphorylation of key tyrosine residues in the cytoplasmic domain and triggering an intracellular signaling cascade. Seven known EGFR ligands exist, each eliciting different types and strengths of downstream signaling. EGFR can also heterodimerize with HER2, HER3, and HER4. Signaling from heterodimers is predicted to be more carcinogenic than signaling from EGFR homodimers.

[0076] EGFR activation triggers multiple intracellular signaling pathways, including the Ras / Raf / MAPK pathway, the PI3K / AKT pathway, and the phospholipase C (PLC) / protein kinase C (PKC) signaling cascade.

[0077] antigen binding molecule This disclosure relates to the therapeutic and prophylactic use of antigen-binding molecules that bind to HER3 and antigen-binding molecules that bind to EGFR.

[0078] An "antigen-binding molecule" refers to a molecule that binds to a given target antigen. Antigen-binding molecules include antibodies (i.e., immunoglobulins (Ig)) and their antigen-binding fragments. As used herein, "antibody" includes monoclonal antibodies, polyclonal antibodies, monospecific and polyspecific (e.g., bispecific, trispecific, etc.) antibodies, as well as antigen-binding molecules derived from antibodies such as scFv, scFab, diabody, tribody, scFv-Fc, minibody, and single-domain antibodies (e.g., VhH, etc.). Antigen-binding fragments of antibodies include, for example, Fv, Fab, F(ab')2, and F(ab') fragments. In some embodiments, the antigen-binding molecule may be an antibody or its antigen-binding fragment.

[0079] Antigen-binding molecules according to this disclosure also include antibody-derived molecules, such as molecules containing an antigen-binding region / domain derived from an antibody. Antigen-binding molecules from an antibody may contain or comprise an antigen-binding region / domain of an antibody (e.g., an antigen-binding fragment of an antibody). In some embodiments, the antigen-binding region / domain of an antibody-derived antigen-binding molecule may be or comprise an Fv (e.g., provided as scFv) or Fab region of an antibody, or the entire antibody. For example, antigen-binding molecules according to this disclosure include antibody-drug conjugates (ADCs) containing a (cytotoxic) drug moiety (e.g., as described herein below). Antigen-binding molecules relating to this disclosure also include multispecific antigen-binding molecules such as immune cell engager molecules containing domains for recruiting (effector) immune cells, including BiTE, BiKE, and TriKE (for example, outlined in Goebeler and Bargou, Nat. Rev. Clin. Oncol. (2020) 17:418-434 and Ellerman, Methods (2019) 154:102-117, both of which are incorporated herein by reference in their entirety). Furthermore, antigen-binding molecules relating to this disclosure also include chimeric antigen receptors (CARs), which are recombinant receptors that provide both antigen-binding and T-cell activation functions (the structure, function, and manipulation of CARs are outlined, for example, in Dotti et al., Immunol Rev (2014) 257(1) and Jayaraman et al., EBioMedicine (2020) 58:102931, both of which are incorporated herein by reference in their entirety).

[0080] The antigen-binding molecules of this disclosure comprise one or more portions capable of binding to a target antigen. In some embodiments, the portion capable of binding to a target antigen comprises an antibody heavy chain variable region (VH) and an antibody light chain variable region (VL) capable of specifically binding to the target antigen. In some embodiments, the portion capable of binding to a target antigen comprises or comprises an aptamer capable of binding to the target antigen, such as a nucleic acid aptamer (e.g., outlined in Zhou and Rossi Nat Rev Drug Discov. 2017 16(3):181-202). In some embodiments, the portion capable of binding to a target antigen includes or consists of antigen-binding peptides / polypeptides, such as peptide aptamers, thioredoxins, monobodies, anticharin, Kunitz domains, avimers, knottins, fynomers, atrimers, DARPin, afibodies, nanobodies (i.e., single-domain antibodies (sdAbs)), affilins, armadillo repeat proteins (ArmRPs), OBody, or fibronectin (for example, the whole of which is incorporated herein by reference, outlined in Reverdatto et al., Curr Top Med Chem., 2015;15(12):1082-1101 (see also Boersma et al., J Biol Chem (2011) 286:41273-85 and Emanuel et al., Mabs (20113:38-48))).

[0081] As used herein, “peptide” refers to a chain of two or more amino acid monomers linked by peptide bonds. Peptides typically have a length in the range of about 2 to 50 amino acids. “Polypeptide” is a polymer chain of two or more peptides. Polypeptides typically have a length longer than about 50 amino acids.

[0082] The antigen-binding molecules of this disclosure generally include an antigen-binding domain comprising a VH and VL of an antibody that can specifically bind to a target antigen. In this specification, the antigen-binding domain formed by the VH and VL may also be referred to as the Fv region.

[0083] The antigen-binding molecule may be an antigen-binding polypeptide, an antigen-binding polypeptide complex, or a combination thereof. The antigen-binding molecule may also contain one or more polypeptides that together form an antigen-binding domain. Polypeptides may associate covalently or asynchronously. In some embodiments, polypeptides form part of a larger polypeptide comprising polypeptides (e.g., in the case of scFv containing VH and VL, or in the case of scFab containing VH-CH1 and VL-CL).

[0084] Antigen-binding molecules may refer to non-covalent or covalent complexes of IgG-like antigen-binding molecules containing more than one polypeptide (e.g., two, three, four, six, or eight polypeptides), such as two heavy-chain polypeptides and two light-chain polypeptides.

[0085] The antigen-binding molecules of this disclosure may be designed and prepared using sequences of monoclonal antibodies (mAbs) capable of binding to a given target antigen (e.g., HER3 or EGFR). Antigen-binding regions of antibodies, such as single-chain variable fragments (scFv), Fab, and F(ab')2 fragments, may also be used / provided. The “antigen-binding region” is any fragment of an antibody that binds to a target to which a given antibody is specific.

[0086] Antibodies generally contain six complementarity-determining regions (CDRs): three in the heavy chain variable (VH) region: HC-CDR1, HC-CDR2, and HC-CDR3, and three in the light chain variable (VL) region: LC-CDR1, LC-CDR2, and LC-CDR3. Together, these six CDRs define the antibody paratope, which is the portion of the antibody that binds to the target antigen.

[0087] The VH and VL regions each contain a framework region (FR) on either side of each CDR that provides a scaffold for the CDR. From the N-terminus to the C-terminus, the VH region has the following structure: N-terminus-[HC-FR1]-[HC-CDR1]-[HC-FR2]-[HC-CDR2]-[HC-FR3]-[HC-CDR3]-[HC-FR4]-C-terminus, and the VL region has the following structure: N-terminus-[LC-FR1]-[LC-CDR1]-[LC-FR2]-[LC-CDR2]-[LC-FR3]-[LC-CDR3]-[LC-FR4]-C-terminus.

[0088] There are several different conventions for defining the CDR and FR of antibodies, such as those described by Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991), Chothia et al., J. Mol. Biol. 196:901~917 (1987), and VBASE2 described by Retter et al., Nucl. Acids Res. (2005) 33 (suppl 1):D671~D674. The CDR and FR of the VH and VL regions of the antibody clones described herein are defined according to the international IMGT (ImMunoGeneTics) information system (LeFranc et al., Nucleic Acids Res. (2015) 43 (Database issue): D413-22), using the IMGT V-domain numbering rules described in LeFranc et al., Dev. Comp. Immunol. (2003) 27:55-77. In preferred embodiments, the CDR and FR of the antigen-binding molecules referred to herein are defined according to the IMGT information system.

[0089] The VH and VL regions of the antigen-binding region of an antibody together constitute the Fv region. In some embodiments, the antigen-binding molecule according to this disclosure includes or comprises an Fv region that binds to HER3. In some embodiments, the antigen-binding molecule according to this disclosure includes or comprises an Fv region that binds to EGFR. In some embodiments, the VH and VL regions of Fv are provided as a single polypeptide, i.e., a single-chain Fv (scFv), joined by a linker sequence.

[0090] The VL and light chain constant (CL) regions of the antigen-binding region of an antibody, as well as the VH region and heavy chain constant 1 (CH1) region, together constitute a Fab region. In some embodiments, the antigen-binding molecule includes a Fab region comprising VH, CH1, VL, and CL (e.g., Cκ or Cλ). In some embodiments, the Fab region comprises a polypeptide comprising VH and CH1 (e.g., a VH-CH1 fusion polypeptide), and a polypeptide comprising VL and CL (e.g., a VL-CL fusion polypeptide). In some embodiments, the Fab region comprises a polypeptide comprising VH and CL (e.g., a VH-CL fusion polypeptide), and a polypeptide comprising VL and CH (e.g., a VL-CH1 fusion polypeptide); that is, in some embodiments, the Fab region is a CrossFab region. In some embodiments, the VH, CH1, VL, and CL regions of the Fab or CrossFab are provided as a single polypeptide joined by a linker region, i.e., as a single-chain Fab (scFab) or single-chain CrossFab (scCrossFab).

[0091] In some embodiments, the antigen-binding molecules described herein include or consist of a whole antibody that binds to HER3. In some embodiments, the antigen-binding molecules described herein include or consist of a whole antibody that binds to EGFR. As used herein, “whole antibody” means an antibody having a structure substantially similar to that of an immunoglobulin (Ig). Different types of immunoglobulins and their structures are described, for example, in Schroeder and Cavacini, J Allergy Clin Immunol. (2010) 125(202): S41-S52, which are incorporated herein by reference in their entirety.

[0092] G-type immunoglobulins (i.e., IgG) are glycoproteins of approximately 150 kDa, comprising two heavy chains and two light chains. From the N-terminus to the C-terminus, the heavy chain contains a constant region consisting of VH followed by three constant domains (CH1, CH2, and CH3), and similarly, the light chain contains VL followed by CL. Depending on the heavy chain, immunoglobulins can be classified as IgG (e.g., IgG1, IgG2, IgG3, IgG4), IgA (e.g., IgA1, IgA2), IgD, IgE, or IgM. The light chain may be kappa (κ) or lambda (λ).

[0093] In some embodiments, the antigen-binding molecule includes or consists of IgG (e.g., IgG1, IgG2, IgG3, IgG4), IgA (e.g., IgA1, IgA2), IgD, IgE, or IgM that bind to HER3. In some embodiments, the antigen-binding molecule includes or consists of IgG (e.g., IgG1, IgG2, IgG3, IgG4), IgA (e.g., IgA1, IgA2), IgD, IgE, or IgM that bind to EGFR.

[0094] In some embodiments described herein, one or more amino acids in the amino acid sequences referred herein (e.g., amino acid sequences of antigen-binding molecules, e.g., amino acid sequences of CDR or VH / VL regions) are substituted with other amino acids. Substitutions include substitution of amino acid residues at non-identical “replacement” amino acid residues. The substitute amino acid residues in substitutions according to this disclosure may be naturally occurring amino acid residues (i.e., encoded by the genetic code) selected from alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine ​​(Cys), glutamine (Gln), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (Ile):leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), and valine (Val) that are not identical to the amino acid residues at the relevant positions in the equivalent unsubstituted amino acid sequence. In some embodiments, the substitute amino acid may be an amino acid residue that does not exist naturally, i.e., an amino acid residue other than those listed in the Preamble. Examples of amino acid residues that do not exist in nature include norleucine, ornithine, norvaline, homoserine, aib, and other amino acid residue analogs, such as those described by Ellman et al., Meth. Enzym. 202 (1991) 301-336.

[0095] In some embodiments, the substitution may be biochemically conserved. In some embodiments, if the amino acid to be substituted is provided in one of rows 1-5 of the table below, the substitute amino acid for the substitution is another non-identical amino acid provided in the same row:

[0096] [Table 1] For example, in some embodiments where the substitution is a Met residue, the substitute amino acid may be selected from Ala, Val, Leu, Ile, Trp, Tyr, Phe, and norleucine.

[0097] In some embodiments, the substituted amino acid in a substitution may have the same side-chain polarity as the amino acid residue it replaces. In some embodiments, the substituted amino acid in a substitution may have the same side-chain charge (at pH 7.4) as the amino acid residue it replaces:

[0098] [Table 2] In other words, in some embodiments, nonpolar amino acids are substituted with other, non-identical nonpolar amino acids. In some embodiments, polar amino acids are substituted with other, non-identical polar amino acids. In some embodiments, acidic polar amino acids are substituted with other, non-identical acidic polar amino acids. In some embodiments, basic polar amino acids are substituted with other, non-identical basic polar amino acids. In some embodiments, neutral amino acids are substituted with other, non-identical neutral amino acids. In some embodiments, positive amino acids are substituted with other, non-identical positive amino acids. In some embodiments, negative amino acids are substituted with other, non-identical negative amino acids.

[0099] In some embodiments, the substitution may be functionally conserved. That is, in some embodiments, the substitution may not affect (or substantially affect) one or more functional properties of the antigen-binding molecule containing the substitution (e.g., binding to a target) compared to an equivalent unsubstituted molecule.

[0100] Antigen-binding molecules that bind to HER3 The aspects and embodiments of this disclosure relate to antigen-binding molecules that bind to HER3. In some embodiments, the antigen-binding molecule includes a CDR of the antigen-binding molecule that can bind to HER3. In some embodiments, the antigen-binding molecule includes an FR of the antigen-binding molecule that can bind to HER3. In some embodiments, the antigen-binding molecule includes both a CDR and an FR of the antigen-binding molecule that can bind to HER3. That is, in some embodiments, the antigen-binding molecule includes a VH region and a VL region of the antigen-binding molecule that can bind to HER3.

[0101] In some embodiments, the antigen-binding molecule capable of binding to HER3 according to this disclosure is any embodiment of the antigen-binding molecule described in WO2019 / 185878A1 (which is incorporated herein in its entirety by reference), 10D1F (e.g., described in WO2019 / 185878A1), cerivanthumab (also known as MM-121, e.g., described in Schoeberl et al., Sci.Signal.(2009)2(77):ra31; DrugBank Acc.No.DB11857), ergemtumab (also known as LJM-716, e.g., described in Garner et al., Cancer Res(2013)73:6024~6035; DrugBank Acc.No.DB15430), and patritumab (also known as U-1287 and AMG-888, e.g., Shimizu et al., Cancer Chemother (As described in Pharmacol. (2017) 79(3):489~495; DrugBank Acc. No. DB12090), GSK2849330 (e.g., Clarke et al., Eur J Cancer. (2014) 50:98~9), Lumuletuzumab (also known as RG7116 and RO-5479599, e.g., Mirschberger et al., Cancer Research (2013) 73(16) 5183~5194; DrugBank Acc. No. DB12683), CDX-3379 (also known as KTN3379, e.g., Lee et al., Proc Natl Acad Sci USA. 2015 Oct 27; 112(43):13225), AV-203 (also known as CAN-017, e.g., Meetze et al., Eur J Cancer) (as described in 2012;48:126), valasetamab (also known as ISU104, e.g., Kim et al., Cancer Res (2018) 78 (13 Suppl): Abstract #830), TK-A3, TK-A4 (e.g., Malm et al., MAbs (2016) 8:1195~209), MP-EV20 (e.g., Sala et al., Transl. Oncol.(2013)6:676~84), 1A5-3D4 (e.g., Wang et al., Cancer Lett (2016)380:20~30), 9F7-F11, 16D3-C1 (e.g., Lazrek et al., Neoplasia (2013)15:335~47), NG33, A5, F4 (e.g., Gaborit et al., PNAS USA (2015)112:839~44), huHER3-8 (e.g., Kugel et al., Cancer Res. (2014)74:4122~32), REGN1400 (e.g., Zhang et al., Mol Cancer Ther (2014)13:1345~1355), and xenoctuzumab (also known as MCLA-128, e.g., de Vries Schultink et al., Clin It may be selected from those described in Pharmacokinet. (2020) 59:875-884 (DrugBank Acc. No. DB15559). In some embodiments, the antigen-binding molecule is 10D1F.

[0102] In some embodiments, the antigen-binding molecule binds to the extracellular domain of HER3 (e.g., the domain shown in SEQ ID NO: 9). In some embodiments, the antigen-binding molecule binds to subdomain II of the extracellular domain of HER3 (e.g., the domain shown in SEQ ID NO: 16).

[0103] In some embodiments, the antigen-binding molecule binds to the HER3 region shown in SEQ ID NO: 77. In some embodiments, the antigen-binding molecule contacts one or more amino acid residues in the HER3 region shown in SEQ ID NO: 77. In some embodiments, the antigen-binding molecule binds to the HER3 region shown in SEQ ID NO: 78 and 79. In some embodiments, the antigen-binding molecule contacts one or more amino acid residues in the HER3 region shown in SEQ ID NO: 78 and 79. In some embodiments, the antigen-binding molecule binds to the HER3 region shown in SEQ ID NO: 78. In some embodiments, the antigen-binding molecule contacts one or more amino acid residues in the HER3 region shown in SEQ ID NO: 78. In some embodiments, the antigen-binding molecule binds to the HER3 region shown in SEQ ID NO: 79. In some embodiments, the antigen-binding molecule contacts one or more amino acid residues in the HER3 region shown in SEQ ID NO: 79.

[0104] In some embodiments, the antigen-binding molecule does not bind to the HER3 region corresponding to positions 260-279 of SEQ ID NO: 1. In some embodiments, the antigen-binding molecule does not contact the amino acid residues in the HER3 region corresponding to positions 260-279 of SEQ ID NO: 1.

[0105] The region of the peptide / polypeptide to which the antibody binds can be determined by those skilled in the art using a variety of methods well known in the art, including X-ray cocrystallization of antibody-antigen complexes, peptide scanning, mutagenesis mapping, hydrogen-deuterium exchange analysis by mass spectrometry, phage display, competitive ELISA, and "protection" methods based on proteolysis. Such methods are described, for example, by Gershoni et al., BioDrugs, 2007, 21(3):145-156, which are incorporated herein by reference in their entirety.

[0106] In some embodiments, the antigen-binding molecule can bind to the same region of HER3, or a duplicate region of HER3, to the region of HER3 to which an antibody containing one of the VH and VL sequences from the antibody clones 10D1_c89, 10D1, 10D1_c75, 10D1_c76, 10D1_c77, 10D1_c78v1, 10D1_c78v2, 10D1_11B, 10D1_c85v1, 10D1_c85v2, 10D1_c85o1, 10D1_c85o2, 10D1_c87, 10D1_c90, 10D1_c91, 10D1_c92, and 10D1_c93 described herein is bound. In some embodiments, the antigen-binding molecule can bind to the same region of HER3, or a duplicate region of HER3, to the region of HER3 to which the antibody containing the VH and VL sequences of antibody clone 10D1_c89 is bound.

[0107] In some embodiments, the antigen-binding molecule may contain one of the amino acid sequences of SEQ ID NOs: 1, 3, 4, 6, or 8, or be bound to a polypeptide comprising these sequences. In some embodiments, the antigen-binding molecule may contain the amino acid sequence of SEQ ID NO: 9, or be bound to a polypeptide comprising this sequence. In some embodiments, the antigen-binding molecule may contain the amino acid sequence of SEQ ID NO: 16, or be bound to a polypeptide comprising this sequence. In some embodiments, the antigen-binding molecule may contain the amino acid sequence of SEQ ID NO: 77, or be bound to a peptide / polypeptide comprising this sequence. In some embodiments, the antigen-binding molecule may contain the amino acid sequences of SEQ ID NOs: 78 and 79, or be bound to a peptide / polypeptide comprising these sequences. In some embodiments, the antigen-binding molecule may contain the amino acid sequence of SEQ ID NO: 78, or be bound to a peptide / polypeptide comprising this sequence. In some embodiments, the antigen-binding molecule may contain the amino acid sequence of SEQ ID NO: 79, or be bound to a peptide / polypeptide comprising this sequence.

[0108] In some embodiments, the antigen-binding molecule is unable to bind to the peptide consisting of the amino acid sequence corresponding to positions 260-279 of SEQ ID NO: 1. The ability of an antigen-binding molecule to bind to a given peptide / polypeptide can be analyzed by methods well known to those skilled in the art, including analysis by ELISA, immunoblotting (e.g., Western blotting), immunoprecipitation, surface plasmon resonance (SPR; see, e.g., Hearty et al., Methods Mol Biol (2012) 907:411-442), or biolayer interferometry (see, e.g., Lad et al., (2015) J Biomol Screen 20(4):498-507).

[0109] In embodiments in which an antigen-binding molecule can bind to a peptide / polypeptide containing a reference amino acid sequence, the peptide / polypeptide may contain one or more additional amino acids at one or both ends of the reference amino acid sequence. In some embodiments, the peptide / polypeptide may contain, for example, 1-5, 1-10, 1-20, 1-30, 1-40, 1-50, 5-10, 5-20, 5-30, 5-40, 5-50, 10-20, 10-30, 10-40, 10-50, 20-30, 20-40, or 20-50 additional amino acids at one or both ends of the reference amino acid sequence.

[0110] In some embodiments, the additional amino acids provided at one or both ends of the reference sequence (i.e., the N-terminus and C-terminus) correspond to the terminal positions of the reference sequence in the context of the HER3 amino acid sequence.

[0111] In some embodiments, the antigen-binding molecule can bind to a peptide / polypeptide to which an antibody containing the VH and VL sequences of one of the antibody clones 10D1_c89, 10D1, 10D1_c75, 10D1_c76, 10D1_c77, 10D1_c78v1, 10D1_c78v2, 10D1_11B, 10D1_c85v1, 10D1_c85v2, 10D1_c85o1, 10D1_c85o2, 10D1_c87, 10D1_c90, 10D1_c91, 10D1_c92, and 10D1_c93 described herein is bound. In some embodiments, the antigen-binding molecule can bind to a peptide / polypeptide to which an antibody containing the VH and VL sequences of antibody clone 10D1_c89 is bound.

[0112] In some embodiments, the antigen-binding molecule comprises a CDR of a HER3-binding antibody clone selected from 10D1_c89, 10D1, 10D1_c75, 10D1_c76, 10D1_c77, 10D1_c78v1, 10D1_c78v2, 10D1_11B, 10D1_c85v1, 10D1_c85v2, 10D1_c85o1, 10D1_c85o2, 10D1_c87, 10D1_c90, 10D1_c91, 10D1_c92, and 10D1_c93, or comprises its VH and VL.

[0113] In some embodiments, the antigen-binding molecule is (1) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 40 HC-CDR2 having the amino acid sequence of SEQ ID NO: 43 HC-CDR3 having the amino acid sequence of SEQ ID NO: 48, Alternatively, variants of HC-CDR1, HC-CDR2, or HC-CDR3 in which one or more amino acids are substituted with other amino acids. The VH region incorporating, and The following CDR: LC-CDR1 having the amino acid sequence of SEQ ID NO: 66 LC-CDR2 having the amino acid sequence of SEQ ID NO: 69 LC-CDR3 having the amino acid sequence of SEQ ID NO: 74; Alternatively, variants of LC-CDR1, LC-CDR2, or LC-CDR3 in which one or more amino acids are substituted with other amino acids. The VL area incorporates (2) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 38 HC-CDR2 having the amino acid sequence of SEQ ID NO: 41 HC-CDR3 having the amino acid sequence of SEQ ID NO: 44, Alternatively, variants of HC-CDR1, HC-CDR2, or HC-CDR3 in which one or more amino acids are substituted with other amino acids. The VH region incorporating, and The following CDR: LC-CDR1 having the amino acid sequence of SEQ ID NO: 63 LC-CDR2 having the amino acid sequence of SEQ ID NO: 67 LC-CDR3 having the amino acid sequence of SEQ ID NO: 70; Alternatively, variants of LC-CDR1, LC-CDR2, or LC-CDR3 in which one or more amino acids are substituted with other amino acids. The VL area incorporates (3) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 38 HC-CDR2 having the amino acid sequence of SEQ ID NO: 41 HC-CDR3 having the amino acid sequence of SEQ ID NO: 44, Alternatively, variants of HC-CDR1, HC-CDR2, or HC-CDR3 in which one or more amino acids are substituted with other amino acids. The VH region incorporating, and The following CDR: LC-CDR1 having the amino acid sequence of SEQ ID NO: 64 LC-CDR2 having the amino acid sequence of SEQ ID NO: 67 LC-CDR3 having the amino acid sequence of SEQ ID NO: 70; Alternatively, variants of LC-CDR1, LC-CDR2, or LC-CDR3 in which one or more amino acids are substituted with other amino acids. The VL area incorporates (4) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 38 HC-CDR2 having the amino acid sequence of SEQ ID NO: 41 HC-CDR3 having the amino acid sequence of SEQ ID NO: 44, Alternatively, variants of HC-CDR1, HC-CDR2, or HC-CDR3 in which one or more amino acids are substituted with other amino acids. The VH region incorporating, and The following CDR: LC-CDR1 having the amino acid sequence of SEQ ID NO: 65 LC-CDR2 having the amino acid sequence of SEQ ID NO: 67 LC-CDR3 having the amino acid sequence of SEQ ID NO: 71; Alternatively, variants of LC-CDR1, LC-CDR2, or LC-CDR3 in which one or more amino acids are substituted with other amino acids. The VL area incorporates (5) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 38 HC-CDR2 having the amino acid sequence of SEQ ID NO: 42 HC-CDR3 having the amino acid sequence of SEQ ID NO: 45, Alternatively, variants of HC-CDR1, HC-CDR2, or HC-CDR3 in which one or more amino acids are substituted with other amino acids. The VH region incorporating, and The following CDR: LC-CDR1 having the amino acid sequence of SEQ ID NO: 63 LC-CDR2 having the amino acid sequence of SEQ ID NO: 67 LC-CDR3 having the amino acid sequence of SEQ ID NO: 70; Alternatively, variants of LC-CDR1, LC-CDR2, or LC-CDR3 in which one or more amino acids are substituted with other amino acids. The VL area incorporates (6) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 39 HC-CDR2 having the amino acid sequence of SEQ ID NO: 42 HC-CDR3 having the amino acid sequence of SEQ ID NO: 45, Alternatively, variants of HC-CDR1, HC-CDR2, or HC-CDR3 in which one or more amino acids are substituted with other amino acids. The VH region incorporating, and The following CDR: LC-CDR1 having the amino acid sequence of SEQ ID NO: 63 LC-CDR2 having the amino acid sequence of SEQ ID NO: 67 LC-CDR3 having the amino acid sequence of SEQ ID NO: 70; Alternatively, variants of LC-CDR1, LC-CDR2, or LC-CDR3 in which one or more amino acids are substituted with other amino acids. The VL area incorporates (7) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 38 HC-CDR2 having the amino acid sequence of SEQ ID NO: 42 HC-CDR3 having the amino acid sequence of SEQ ID NO: 44, Alternatively, variants of HC-CDR1, HC-CDR2, or HC-CDR3 in which one or more amino acids are substituted with other amino acids. The VH region incorporating, and The following CDR: LC-CDR1 having the amino acid sequence of SEQ ID NO: 63 LC-CDR2 having the amino acid sequence of SEQ ID NO: 68 LC-CDR3 having the amino acid sequence of SEQ ID NO: 70; Alternatively, variants of LC-CDR1, LC-CDR2, or LC-CDR3 in which one or more amino acids are substituted with other amino acids. The VL area incorporates (8) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 38 HC-CDR2 having the amino acid sequence of SEQ ID NO: 42 HC-CDR3 having the amino acid sequence of SEQ ID NO: 46, Alternatively, variants of HC-CDR1, HC-CDR2, or HC-CDR3 in which one or more amino acids are substituted with other amino acids. The VH region incorporating, and The following CDR: LC-CDR1 having the amino acid sequence of SEQ ID NO: 63 LC-CDR2 having the amino acid sequence of SEQ ID NO: 68 LC-CDR3 having the amino acid sequence of SEQ ID NO: 70; Alternatively, variants of LC-CDR1, LC-CDR2, or LC-CDR3 in which one or more amino acids are substituted with other amino acids. The VL area incorporates (9) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 38 HC-CDR2 having the amino acid sequence of SEQ ID NO: 42 HC-CDR3 having the amino acid sequence of SEQ ID NO: 47, Alternatively, variants of HC-CDR1, HC-CDR2, or HC-CDR3 in which one or more amino acids are substituted with other amino acids. The VH region incorporating, and The following CDR: LC-CDR1 having the amino acid sequence of SEQ ID NO: 63 LC-CDR2 having the amino acid sequence of SEQ ID NO: 68 LC-CDR3 having the amino acid sequence of SEQ ID NO: 70; Alternatively, variants of LC-CDR1, LC-CDR2, or LC-CDR3 in which one or more amino acids are substituted with other amino acids. The VL area incorporates (10) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 38 HC-CDR2 having the amino acid sequence of SEQ ID NO: 42 HC-CDR3 having the amino acid sequence of SEQ ID NO: 45, Alternatively, variants of HC-CDR1, HC-CDR2, or HC-CDR3 in which one or more amino acids are substituted with other amino acids. The VH region incorporating, and The following CDR: LC-CDR1 having the amino acid sequence of SEQ ID NO: 63 LC-CDR2 having the amino acid sequence of SEQ ID NO: 67 LC-CDR3 having the amino acid sequence of SEQ ID NO: 72; Alternatively, variants of LC-CDR1, LC-CDR2, or LC-CDR3 in which one or more amino acids are substituted with other amino acids. The VL area incorporates (11) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 38 HC-CDR2 having the amino acid sequence of SEQ ID NO: 41 HC-CDR3 having the amino acid sequence of SEQ ID NO: 44, Alternatively, variants of HC-CDR1, HC-CDR2, or HC-CDR3 in which one or more amino acids are substituted with other amino acids. The VH region incorporating, and The following CDR: LC-CDR1 having the amino acid sequence of SEQ ID NO: 63 LC-CDR2 having the amino acid sequence of SEQ ID NO: 67 LC-CDR3 having the amino acid sequence of SEQ ID NO: 73; Alternatively, variants of LC-CDR1, LC-CDR2, or LC-CDR3 in which one or more amino acids are substituted with other amino acids. The VL area incorporates Includes.

[0114] In some embodiments, the antigen-binding molecule includes the following: (12) A VH region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 21, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 49, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0115] (13) A VH region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 22, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 50, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0116] (14) A VH region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 23, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 51, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0117] (15) A VH region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 24, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 52, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0118] (16) A VH region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 25, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 53, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0119] (17) A VH region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 26, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 53, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0120] (18) A VH region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 27, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 53, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0121] (19) A VH region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 28, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 54, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0122] (20) A VH region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 29, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 54, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0123] (21) A VH region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 30, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 55, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0124] (22) A VH region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 31, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 56, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0125] (23) A VH region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 32, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 57, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0126] (24) A VH region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 33, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 58, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0127] (25) A VH region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 34, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 59, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0128] (26) A VH region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 35, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 60, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0129] (27) A VH region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 36, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 61, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0130] (28) A VH region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 37, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 62, more preferably one of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0131] In some embodiments, the antigen-binding molecule is (29)(i) One or more (e.g., two) polypeptides comprising or having an amino acid sequence having at least 70%, preferably 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with respect to the amino acid sequence of Sequence ID No. 75; and (ii) One or more (e.g., two) polypeptides comprising an amino acid sequence having at least 70%, preferably 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with respect to the amino acid sequence of SEQ ID NO: 76. It includes or consists of these.

[0132] Antigen-binding molecules that bind to EGFR This disclosure provides an antigen-binding molecule that binds to EGFR. In some embodiments, the antigen-binding molecule includes a CDR of the antigen-binding molecule that can bind to EGFR. In some embodiments, the antigen-binding molecule includes an FR of the antigen-binding molecule that can bind to EGFR. In some embodiments, the antigen-binding molecule includes both a CDR and an FR of the antigen-binding molecule that can bind to EGFR. That is, in some embodiments, the antigen-binding molecule includes a VH region and a VL region of the antigen-binding molecule that can bind to EGFR.

[0133] In some embodiments, the antigen-binding molecule capable of binding to EGFR according to this disclosure is any embodiment of the antigen-binding molecule described in US6,217,866B1 (which is incorporated herein in its entirety by reference), cetuximab (e.g., described in US6,217,866B1 and Wong et al., Clin Ther. (2005) 27(6):684-694; DrugBank Acc. No. DB00002), panitumumab (e.g., described in Foon et al., Int J Radiat Oncol Biol Phys. (2004) 58(3):984-990; DrugBank Acc. No. DB01269), saltumumab (e.g., described in Bastholt et al., Radiother Oncol. (2007) 85(1):24-28; DrugBank Acc. No. DB12202), nesitumumab (e.g., Kuenen et al., Clin Cancer The following drugs may be selected: Res. (2010) 16(6): 1915-1923 (DrugBank Acc. No. DB09559), nimotuzumab (e.g., Ramakrishnan et al., mAbs (2009) 1(1) 41-48 (DrugBank Acc. No. DB06192)), durigotuzumab (e.g., Fayette et al., Front Oncol. (2016) 6:232 (DrugBank Acc. No. DB12142)), and matuzumab (DrugBank Acc. No. DB05101).

[0134] In some embodiments, the antigen-binding molecule is cetuximab. Cetuximab (Erbitux, Eli Lilly and Company / Merck KGaA) is a recombinant chimeric human / mouse IgG1 monoclonal antibody that competitively binds to the epidermal growth factor receptor (EGFR) and competitively inhibits the binding of epidermal growth factor (EGF) (Harding and Burtness, Drugs Today (2005) (Barc) 41(2):107-127). Approved by the FDA in February 2004 under the brand name ERBITUX, cetuximab was the first compound developed as an anti-EGFR antibody for NSCLC. It is administered by intravenous infusion and used as monotherapy or in combination with other chemotherapy regimens, including platinum, radiotherapy, leucovorin, fluorouracil, and irinotecan (United States Food and Drug Administration 2019).

[0135] In some embodiments, the antigen-binding molecule can bind to the same region of EGFR, or to an overlapping region of EGFR, to the region of EGFR to which the antibody containing the VH and VL sequences of cetuximab is bound.

[0136] In some embodiments, the antigen-binding molecule comprises cetuximab CDR or cetuximab VH and VL. In some embodiments, the antigen-binding molecule is (30) CDRs below: HC-CDR1 having the amino acid sequence of SEQ ID NO: 92 HC-CDR2 having the amino acid sequence of SEQ ID NO: 93 HC-CDR3 having the amino acid sequence of SEQ ID NO: 94 The VH region incorporates or variants thereof in which one or more of HC-CDR1, HC-CDR2, or HC-CDR3 have one, two, or three amino acids substituted with other amino acids; and The following CDR: LC-CDR1 having the amino acid sequence of SEQ ID NO: 96 LC-CDR2 having the amino acid sequence of SEQ ID NO: 97 LC-CDR3 having the amino acid sequence of SEQ ID NO: 98 The VL area incorporates Or variants of LC-CDR1, LC-CDR2, or LC-CDR3 in which one or more amino acids are substituted with other amino acids. Includes.

[0137] In some embodiments, the antigen-binding molecule is (31) A VH region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 91, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and VL region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 95, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity. Includes.

[0138] In some embodiments, the antigen-binding molecule is (32)(i) One or more (e.g., two) polypeptides comprising or having an amino acid sequence having at least 70%, preferably 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with respect to the amino acid sequence of Sequence ID No. 99; and (ii) One or more (e.g., two) polypeptides comprising an amino acid sequence having at least 70%, preferably 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with respect to the amino acid sequence of SEQ ID NO: 100. It includes or consists of these.

[0139] Fc area In some embodiments, the antigen-binding molecule of this disclosure includes an Fc region. The Fc region consists of CH2 and CH3 regions derived from one polypeptide, and CH2 and CH3 regions derived from another polypeptide. The CH2 and CH3 regions derived from the two polypeptides together form the Fc region.

[0140] Fc-mediated functions include binding to Fc receptors, antibody-dependent cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), membrane invasion complex (MAC) formation, cell degranulation, cytokine and / or chemokine production, and antigen processing and presentation.

[0141] Taxoid The aspects and embodiments of this disclosure relate to taxoids. As used herein, “taxoid” refers to a taxane-derived diterpenoid. In scientific literature, the term “taxane” is sometimes used interchangeably with “taxoid.” The chemical and functional properties of taxoids are outlined, for example, in Kingston and Newman, Curr Opin Drug Discov Devel. (2007) 10(2):130-144, and in Mosca et al., Drug Resist Updat. (2021) 54:100742, both of which are incorporated herein by reference in their entirety.

[0142] Taxoids are mitotic inhibitors that exert their anticancer effects primarily by disrupting microtubule formation. They stabilize GDP-bound tubulin within microtubules, preventing microtubule depolymerization and thereby inhibiting cell division. Taxoids include docetaxel, paclitaxel, nab-paclitaxel, larotaxel, and cabazitaxel. Paclitaxel, docetaxel, and cabazitaxel are the three main approved taxoids, and they are widely used to treat a variety of solid tumors, including prostate cancer, lung cancer, ovarian cancer, and breast cancer.

[0143] In some embodiments, the taxoid of the Disclosure is selected from docetaxel and nab-paclitaxel. In some embodiments, the taxoid is docetaxel. In some embodiments, the taxoid is nab-paclitaxel.

[0144] Nucleoside analog The aspects and embodiments of this disclosure relate to nucleoside analogs. In particular, this disclosure relates to nucleoside analog inhibitors of DNA replication. These function as antimetabolites and, having a structure sufficiently similar to nucleotides, are incorporated into the elongating DNA strand. However, the incorporation of nucleoside analogs inhibits further synthesis of the DNA strand, ultimately leading to cell death.

[0145] Nucleoside analogs and their use in the treatment of cancer are outlined, for example, in Jordheim et al., Nat. Rev. Drug Discov. (2013) 12:447-464, which is incorporated herein by reference in its entirety. Gemcitabine is used for the treatment of testicular cancer, breast cancer, ovarian cancer, non-small cell lung cancer, pancreatic cancer, biliary tract cancer, and bladder cancer.

[0146] In some embodiments, the nucleoside analog according to this disclosure is a deoxycytidine nucleoside analog. In some embodiments, the nucleoside analog is gemcitabine or a salt thereof (e.g., gemcitabine hydrochloride).

[0147] Pharmaceutical combinations and compositions This disclosure provides combinations or compositions comprising (i) an antigen-binding molecule that binds to HER3 and (ii) a taxoid. It also provides combinations or compositions comprising (i) an antigen-binding molecule that binds to HER3 and (ii) a nucleoside analog. Furthermore, it provides combinations or compositions comprising (i) an antigen-binding molecule that binds to HER3, (ii) a nucleoside analog, and (iii) a taxoid. This disclosure also provides combinations or compositions comprising (i) an antigen-binding molecule that binds to HER3 and (ii) an antigen-binding molecule that binds to EGFR. This disclosure also provides combinations or compositions comprising (i) an antigen-binding molecule that binds to HER3, (ii) an antigen-binding molecule that binds to EGFR, and (iii) a taxoid.

[0148] It will be understood that the antigen-binding molecule that binds to HER3 may be an antigen-binding molecule that binds to HER3 according to any embodiment described herein, and similarly, the antigen-binding molecule that binds to EGFR may be an antigen-binding molecule that binds to EGFR according to any embodiment described herein. In preferred embodiments of the combinations and compositions described in the previous paragraphs, the antigen-binding molecule that binds to HER3 is selected from one of (1) to (29) above, and the antigen-binding molecule that binds to EGFR is selected from one of (30) to (32) above. Similarly, it will be understood that the taxoid may be a taxoid according to any embodiment described herein. In preferred embodiments of the combinations and compositions described in the previous paragraphs, the taxoid is docetaxel or nab-paclitaxel (e.g., docetaxel). Similarly, the nucleoside analog may be a nucleoside analog according to any embodiment described herein. In preferred embodiments of the combinations and compositions described in the previous paragraphs, the nucleoside is a deoxycytidine nucleoside analog, such as gemcitabine or a salt thereof.

[0149] In some embodiments and aspects, a combination is a pharmaceutical combination. As used herein, “pharmaceutical combination” means a product comprising several (typically two or three) different active (i.e., therapeutic / preventive) agents that are intended to be used in combination. The drugs in a pharmaceutical combination may be formulated together or separately, but are typically packaged together and typically packaged with a package insert containing instructions for use of the drugs together.

[0150] In some embodiments, the drugs in a drug combination are contained in a single composition, for example, a pharmaceutical composition containing the drugs. In some embodiments, the drugs in a drug combination are contained in separate compositions. For example, a drug combination containing (i) an antigen-binding molecule that binds to HER3 and (ii) a taxoid may be provided as a pharmaceutical composition containing (i) an antigen-binding molecule that binds to HER3 and (ii) a pharmaceutical composition containing a taxoid. Similarly, a drug combination containing (i) an antigen-binding molecule that binds to HER3 and (ii) an antigen-binding molecule that binds to EGFR may be provided as a pharmaceutical composition containing (i) an antigen-binding molecule that binds to HER3 and (ii) an antigen-binding molecule that binds to EGFR. In another example, a drug combination may be provided as (i) a pharmaceutical composition containing an antigen-binding molecule that binds to HER3, (ii) a pharmaceutical composition containing an antigen-binding molecule that binds to EGFR, and (iii) a chemotherapeutic agent (e.g., docetaxel).

[0151] This disclosure also provides compositions (e.g., pharmaceutical compositions and pharmaceuticals) comprising the agents described herein (i.e., antigen-binding molecules that bind to HER3, antigen-binding molecules that bind to EGFR, taxoids, nucleoside analogs). Such compositions may include formulations suitable for clinical use and related articles.

[0152] In some embodiments, the antigen-binding molecule that binds to HER3 as described herein is provided in a 50 mg / mL solution. In some embodiments, the antigen-binding molecule that binds to HER3 as described herein is formulated in a composition containing 20 mM histidine, 8% (w / v) sucrose, and 0.02% (w / v) polysorbate 80 at pH 5.8.

[0153] In some embodiments, docetaxel is formulated in a composition containing 0.9% (w / v) sodium chloride. In some embodiments, nab-paclitaxel is formulated in a composition containing 0.9% (w / v) sodium chloride.

[0154] In some embodiments, gemcitabine is formulated in a composition containing 0.9% (w / v) sodium chloride. The compositions disclosed herein include one or more pharmaceutically acceptable carriers (e.g., liposomes, micelles, microspheres, nanoparticles), diluents / excipients (e.g., starch, cellulose, cellulose derivatives, polyols, dextrose, maltodextrin, magnesium stearate), adjuvants, fillers, buffers, preservatives (e.g., vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methylparaben, propylparaben), oxidation It may contain inhibitors (e.g., vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium), lubricants (e.g., magnesium stearate, talc, silica, stearic acid, vegetable stearin), binders (e.g., sucrose, lactose, starch, cellulose, gelatin, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), xylitol, sorbitol, mannitol), stabilizers, solubilizers, surfactants (e.g., wetting agents), masking agents, or colorants (e.g., titanium dioxide).

[0155] As used herein, the term “pharmaceutically acceptable” means a compound, component, material, composition, dosage form, etc., suitable for use in contact with the tissue of a subject in question (e.g., a human subject) without excessive toxicity, irritation, allergic reaction, or other problems or complications, within the bounds of sound medical judgment, commensurate with a reasonable benefit / risk ratio. Each carrier, diluent, excipient, adjuvant, filler, buffer, preservative, antioxidant, lubricant, binder, stabilizer, solubilizer, surfactant, masking agent, colorant, flavoring agent, or sweetener of a composition relating to this disclosure must also be “acceptable” in the sense that it is compatible with the other components of the formulation. Suitable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, binders, stabilizers, solubilizers, surfactants, masking agents, colorants, flavoring agents, or sweeteners can be found in standard pharmaceutical texts, such as Remington's "The Science and Practice of Pharmacy" (Ed. A. Adejare), 23rd Edition (2020), Academic Press.

[0156] Pharmaceutical compositions / pharmaceuticals according to this disclosure may be formulated for administration to a subject, for example, through a route of administration appropriate to the properties of the composition / pharmaceutical and the disease / condition being treated / prevented. In some embodiments, pharmaceutical compositions / pharmaceuticals may be formulated for parenteral administration, systemic administration, topical administration, intracavitary administration, intravascular administration, intravenous administration, intra-arterial administration, intramuscular administration, intrathecal administration, intraocular administration, intraconjunctival administration, intratumoral administration, subcutaneous administration, intradermal administration, oral administration, or transdermal administration. In some embodiments, pharmaceutical compositions / pharmaceuticals may be formulated for administration by injection or infusion, or by ingestion.

[0157] Pharmaceuticals and pharmaceutical compositions may be formulated for administration to blood vessels, or to target tissues / organs (e.g., tissues / organs affected by a condition, or affected by a disease / condition; e.g., tissues / organs on which symptoms of a disease / condition appear), or to tumors.

[0158] The pharmaceutical composition / pharmaceutical may contain a drug (i.e., an antigen-binding molecule that binds to HER3, an antigen-binding molecule that binds to EGFR, a taxoid, and / or a nucleoside analog) in a sterile or isotonic medium. The pharmaceutical composition / pharmaceutical may be provided in a fluid, including in gel form. Fluid formulations may be formulated for administration by injection or infusion (e.g., via cannula) into the blood vessels of a human or animal body, or a selected area, or a tumor. The pharmaceutical composition / pharmaceutical may be provided in solid form, for example, in lyophilized form.

[0159] Functional properties The combinations and compositions described herein may be characterized by reference to certain functional properties. In some embodiments, the combinations / compositions described herein may have one or more of the following properties: Increase the death of cells expressing HER3 and / or EGFR; Increase ADCC in cells expressing HER3 and / or EGFR; To inhibit tumor growth and / or reduce tumor size / volume (for example, of cancers described herein, e.g., cancers expressing HER3 and / or EGFR); To extend the survival time of subjects with cancer (for example, cancers described herein, e.g., cancers expressing HER3 and / or EGFR); To inhibit tumor growth and / or reduce tumor size / volume to a greater extent than the inhibition of tumor growth / reduction of tumor size / volume observed when the components of the combination / composition are used individually; To extend the survival of subjects with cancer (e.g., cancers described herein, e.g., cancers expressing HER3 and / or EGFR) to a greater extent than the survival extension observed when the components of the combination / composition are used individually; Compared to the inhibition of tumor growth / reduction of tumor size / volume observed when the components of the combination / composition are used individually, the combination synergistically inhibits tumor growth and / or synergistically reduces tumor size / volume (for example, in cancers described herein, e.g., cancers expressing HER3 and / or EGFR); and / or Compared to the survival extension observed when the components of the combination / composition are used individually, it synergistically extends the survival of subjects with cancer (e.g., cancers described herein, e.g., cancers expressing HER3 and / or EGFR).

[0160] It will be understood that a given combination / composition may exhibit more than one of the properties listed in the previous paragraph. A given combination / composition may be evaluated for the properties listed in the previous paragraph using an appropriate assay. For example, the assay may be, for example, an in vitro assay, optionally, a cell-based assay or a cell-free assay. In some embodiments, the assay may be, for example, an in vivo assay, i.e., performed in a non-human animal. In some embodiments, the assay may be, for example, an ex vivo assay, i.e., performed using cells / tissues / organs obtained from a subject.

[0161] If the assay is a cell-based assay, it may involve treating cells with the combination / composition to determine whether the combination / composition exhibits one or more of the listed properties. The assay may use species labeled with detectable entities to facilitate detection. The assay may involve evaluating the listed properties after treating cells separately with a range of amounts / concentrations (e.g., a dilution series) of the given combination / composition.

[0162] Analysis of the results of such assays may involve determining the concentration at which 50% of the maximum level of the relevant activity is achieved. The concentration of a given drug at which 50% of the maximum level of the relevant activity is achieved may be referred to as the “half-maximal effective concentration” of the drug for the relevant activity, and this is called the “EC 50 It is sometimes also referred to as "[...]. Depending on the characteristics, EC 50 This refers to the "half-maximal inhibitory concentration" or "IC2". 50 This is sometimes referred to as the "maximum inhibition level" of a drug, and it is the concentration at which 50% of the maximum inhibition level of a given characteristic is observed.

[0163] In some embodiments, combinations / compositions according to this disclosure enhance (i.e., upregulate, enhance) cell death of cancer cells (e.g., cancer cells as described herein). In some embodiments, combinations / compositions enhance cell death of cells containing / expressing HER3 and / or EGFR.

[0164] In some embodiments, combinations / compositions according to this disclosure may inhibit the growth of cancers described herein, e.g., cancers containing / expressing HER3 and / or EGFR, or reduce metastasis. In some embodiments, combinations / compositions may enhance (i.e., upregulate and enhance) cell death of cancer cells in cancers described herein, e.g., cancers containing / expressing HER3 and / or EGFR. In some embodiments, combinations / compositions may inhibit the growth of cancer cells described herein, or inhibit the growth of tumors containing cancer cells described herein. In some embodiments, combinations / compositions may inhibit the growth of cancer cells containing / expressing HER3 and / or EGFR, or inhibit tumor growth. In some embodiments, combinations / compositions may inhibit the metastasis of cancers / tumors described herein, e.g., cancers / tumors containing / expressing HER3 and / or EGFR.

[0165] Cell death can be investigated using any of the methods outlined, for example, in Zaritskaya et al., Expert Rev Vaccines (2011), 9(6):601-616, which is incorporated in its entirety herein by reference. Examples of in vitro assays for cytotoxicity / cell death include: 51 Release assays include Cr release assays, lactate dehydrogenase (LDH) release assays, 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) release assays, and calcein-acetoxymethyl (calcein-AM) release assays. These assays measure cell death based on the detection of factors released from lysed cells. Cell death of a given test cell type by a given effector immune cell type can be analyzed, for example, by co-culturing test cells with effector immune cells and measuring the number / percentage of viable / dead (e.g., lysed) test cells after a suitable period. Other suitable assays include the xCELLigence real-time cell lysis in vitro efficacy assay described by Cerignoli et al., PLoS One. (2018) 13(3):e0193498 (which is incorporated herein in its entirety by reference).

[0166] In some embodiments, the combinations / compositions of this disclosure exhibit anticancer activity. In some embodiments, the combinations / compositions increase cancer cell death. In some embodiments, the compositions / combinations cause a reduction in the number of cancer cells in vivo, for example, compared to appropriate control conditions. Cancer may be any of the cancers described herein.

[0167] In some embodiments, combinations / compositions according to this disclosure can reduce the number / percentage of cells expressing HER3 and / or EGFR. In some embodiments, combinations / compositions according to this disclosure can deplete / enhance such cells.

[0168] The antigen-binding molecules of the combinations / compositions according to this disclosure may include one or more moieties to enhance the reduction of the number / percentage of cells expressing HER3 and / or EGFR. For example, the antigen-binding molecule may include, for example, an Fc region and / or a drug moiety.

[0169] The Fc region interacts with Fc receptors and other molecules of the immune system to produce functional effects. Effector functions mediated by IgG Fc are outlined, for example, in Jefferis et al., Immunol Rev 1998 163:59~76 (which is incorporated herein by reference in its entirety), and are mediated through the interaction of the Fc region with Fc receptors expressed by immune cells to mobilize and activate immune cells (e.g., macrophages, dendritic cells, neutrophils, basophils, eosinophils, platelets, mast cells, NK cells, and T cells) via Fc, the mobilization of complement pathway components via the binding of the Fc region to the complement protein C1q, and the resulting activation of the complement cascade. Fc-mediated functions include binding to Fc receptors, antibody-dependent cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), membrane invasion complex (MAC) formation, cell degranulation, cytokine and / or chemokine production, and antigen processing and presentation.

[0170] In some embodiments, the antigen-binding molecules of the combinations / compositions according to this disclosure include an Fc region that can enhance / induce one or more of ADCC, ADCP, and CDC in cells expressing HER3 and / or EGFR (e.g., cells expressing HER3 and / or EGFR on the cell surface) and / or enhance MAC formation or cell degranulation on cells expressing HER3 and / or EGFR (e.g., cells expressing HER3 and / or EGFR on the cell surface).

[0171] In some embodiments, antigen-binding molecules of combinations / compositions according to this disclosure can enhance / induce ADCC in cells expressing HER3 and / or EGFR. The ability of a given antigen-binding molecule to induce ADCC in a given target cell type, and to what extent, is described, for example, in the manner described in Yamashita et al., Scientific Reports (2016) 6:19772 (which is incorporated herein by reference in its entirety) or, for example, in Jedema et al., Blood (2004) 103:2677-82 (which is incorporated herein by reference in its entirety) 51 The ability of a given antigen-binding molecule to induce ADCP, and to what extent, can be analyzed, for example, according to the method described in Kamen et al., J Immunol (2017) 198(1 Supplement) 157.17 (which is incorporated herein by reference in its entirety). The ability of a given antigen-binding molecule to induce CDC, and to what extent, can be analyzed, for example, using a C1q binding assay, as described in Schlothauer et al., Protein Engineering, Design and Selection (2016), 29(10):457-466 (which is incorporated herein by reference in its entirety).

[0172] In some embodiments, the combinations / compositions of this disclosure exhibit anticancer activity. In some embodiments, the combinations / compositions increase cancer cell death. In some embodiments, the combinations / compositions cause a reduction in the number of cancer cells in vivo, for example, compared to appropriate control conditions. The cancer may be one of the cancers described herein, e.g., a cancer expressing / overexpressing HER3 and / or EGFR.

[0173] In some embodiments, the combinations / compositions according to this disclosure reduce / inhibit the growth of cancer and / or cancerous tumors. In some embodiments, the combinations / compositions reduce tissue invasion by cancer cells. In some embodiments, the combinations / compositions reduce cancer metastasis. In some embodiments, the combinations / compositions exhibit anticancer activity. In some embodiments, the combinations / compositions reduce the growth / proliferation of cancer cells. In some embodiments, the combinations / compositions reduce the survival of cancer cells. In some embodiments, the combinations / compositions increase cancer cell death. In some embodiments, the combinations / compositions of this disclosure cause a reduction in the number of cancer cells, for example, in vivo. Cancer may be a cancer described herein, for example, a cancer that expresses / overexpresses HER3 and / or EGFR.

[0174] The combinations / compositions of this disclosure can be analyzed for the properties described in the preceding paragraphs in appropriate assays. Such assays include, for example, in vivo models. Exemplary, Example 3 of this specification describes the evaluation of tumor growth inhibition by a combination of the HER3-binding molecule HMBD-001 IgG1 and the EGFR-binding molecule cetuximab in models derived from human cancer cells of various different cancers.

[0175] In some embodiments, administration of combinations / compositions according to this disclosure may, for example, inhibit the onset / progression of cancer, delay / prevent the onset of cancer, reduce / delay / prevent tumor growth, reduce / delay / prevent tissue invasion, reduce / delay / prevent metastasis, reduce the severity of one or more symptoms of cancer, reduce the number of cancer cells, reduce cancer burden, reduce tumor size / volume, and / or extend the survival of a subject with cancer (e.g., progression-free survival or overall survival), as determined in an appropriate model.

[0176] It will be understood that the properties listed in the previous paragraphs should be evaluated after a sufficient period of time for the effects associated with treatment using the combination / composition to be observed. Tumor growth can be monitored by examining the tumor volume over time, for example, as described in Example 3 of this specification. Tumor growth is monitored by examining the tumor volume over time (e.g., mm 3 It can be evaluated by measuring (units).

[0177] In some embodiments, the combinations / compositions of this disclosure can reduce tumor size / volume (e.g., the average tumor size / volume of a treatment group in an in vivo model, e.g., the cancer described herein) in a given assay to less than 1x of the tumor size / volume observed over the same period (or after treatment with a suitable control composition known not to affect tumor growth) in the absence of treatment with the combination / composition, e.g., ≤0.99x, ≤0.95x, ≤0.9x, ≤0.85x, ≤0.8x, ≤0.75x, ≤0.7x, ≤0.65x, ≤0.6x, ≤0.55x, ≤0.5x, ≤0.45x, ≤0.4x, ≤0.35x, ≤0.3x, ≤0.3x, ≤0.25x, ≤0.2x, ≤0.15x, ≤0.1x, ≤0.05x, or ≤0.01x. In some embodiments, the assessment of tumor size / volume for the purpose of such comparison is performed in the relevant model after more than 5 days following the administration of the initial dose combination / composition, for example, after one of the following: ≥10 days, ≥15 days, ≥20 days, ≥25 days, ≥30 days, ≥35 days, ≥40 days, ≥35 days, ≥50 days, ≥55 days, ≥60 days, ≥65 days, ≥70 days, ≥75 days, ≥80 days, ≥85 days, ≥90 days, ≥95 days, or ≥100 days.

[0178] In some embodiments, the combinations / compositions of the present disclosure achieve, in a given assay, a level of tumor growth inhibition greater than 1x, for example, ≥1.01x, ≥1.02x, ≥1.03x, ≥1.04x, ≥1.05x, ≥1.1x, ≥1.2x, ≥1.3x, ≥1.4x, ≥1.5x, ≥1.6x, ≥1.7x, ≥1.8x, ≥1.9x, ≥2x, ≥3x, ≥4x, ≥5x, ≥6x, ≥7x, ≥8x, ≥9x, or ≥10x (e.g., expressed as tumor growth inhibition %), calculated, for example, against tumor growth observed with treatment with an isotype-matched control antibody. In some embodiments, the evaluation of tumor growth inhibition for such comparative purposes is performed in the relevant model after more than 5 days following the administration of the initial dose combination / composition, for example, ≥10 days, ≥15 days, ≥20 days, ≥25 days, ≥30 days, ≥35 days, ≥40 days, ≥35 days, ≥50 days, ≥55 days, ≥60 days, ≥65 days, ≥70 days, ≥75 days, ≥80 days, ≥85 days, ≥90 days, ≥95 days, or ≥100 days.

[0179] In some embodiments, the combinations / compositions of the present disclosure can increase the median survival of a subject with cancer (e.g., in an in vivo model, e.g., a cancer described herein, e.g., a cancer expressing HER3 and / or EGFR) in a given assay by more than 1 times, e.g., ≥1.01 times, ≥1.02 times, ≥1.03 times, ≥1.04 times, ≥1.05 times, ≥1.1 times, ≥1.2 times, ≥1.3 times, ≥1.4 times, ≥1.5 times, ≥1.6 times, ≥1.7 times, ≥1.8 times, ≥1.9 times, ≥2 times, ≥3 times, ≥4 times, ≥5 times, ≥6 times, ≥7 times, ≥8 times, ≥9 times, or ≥10 times the median survival observed in the absence of treatment with the combination / composition (or after treatment with a suitable control composition known not to affect the survival of a subject with cancer). The median survival time can be expressed as the number of days from the start of the experiment for subjects in the relevant treatment group.

[0180] In some embodiments, the combinations / compositions of this disclosure reduce, delay, prevent tumor growth, reduce the severity of cancer symptoms, reduce the number of cancer cells, reduce the cancer burden, reduce tumor size / volume, and / or extend the survival of subjects with cancer to a greater extent than when the components of the combinations / compositions are used individually. In some embodiments, the combinations / compositions reduce, delay, prevent tumor growth, reduce the severity of one or more cancer symptoms, reduce the number of cancer cells, reduce the cancer burden, reduce tumor size / volume, and / or extend the survival of subjects with cancer to a greater extent than when the components of the combinations / compositions are used as monotherapy.

[0181] In some embodiments, the combinations / compositions of this disclosure inhibit tumor growth and / or reduce tumor size / volume to a greater extent than the tumor growth inhibition / reduction of tumor size / volume observed when the components of the combinations / compositions are used individually. In some embodiments, the combinations / compositions exhibit improved tumor growth inhibition and / or improved tumor size / volume reduction compared to the levels observed when the components of the combinations / compositions are used as monotherapy.

[0182] In some embodiments, the combinations / compositions of this disclosure extend the survival of subjects with cancer to a greater extent than the survival extension observed when the components of the combinations / compositions are used individually. In some embodiments, the components of the combinations / compositions extend the survival of subjects with cancer compared to the survival extension observed when the components of the combinations / compositions are used as monotherapy.

[0183] For the purpose of such comparison, monotherapy preferably uses the same dose of the relevant drug as that used in combination therapy. For example, in the experiment described in Example 3 of this specification, HMBD-001 IgG1 (anti-HER3 antibody) is administered as monotherapy at a dose of 20 mg / kg body weight per dose, and in combination therapy with cetuximab, HMBD-001 IgG1 is similarly administered at a dose of 20 mg / kg body weight per dose. Similarly, cetuximab (anti-EGFR antibody) is administered as monotherapy at a dose of 10 mg / kg body weight per dose, and in combination therapy with HMBD-001 IgG1, cetuximab is similarly administered at a dose of 10 mg / kg body weight per dose.

[0184] In some embodiments, the combinations / compositions of this disclosure can reduce tumor size / volume (e.g., the mean tumor size / volume for a treatment group in an in vivo model of HER3 and / or EGFR-expressing cancer as described herein) to less than 1 times, e.g., ≤0.99, ≤0.95, ≤0.9, ≤0.85, ≤0.8, ≤0.75, ≤0.7, ≤0.65, ≤0.6, ≤0.55, ≤0.5, ≤0.45, ≤0.4, ≤0.35, ≤0.3, ≤0.25, ≤0.2, ≤0.15, ≤0.1, ≤0.05, or ≤0.01 times the size / volume observed at the same time point after treatment with the same amount of one of the components of the combination / composition as monotherapy. In some embodiments, the assessment of tumor size / volume for the purpose of such comparison is performed in the relevant model more than 5 days after administration of the initial dose combination / composition, for example, ≥10 days, ≥15 days, ≥20 days, ≥25 days, ≥30 days, ≥35 days, ≥40 days, ≥35 days, ≥50 days, ≥55 days, ≥60 days, ≥65 days, ≥70 days, ≥75 days, ≥80 days, ≥85 days, ≥90 days, ≥95 days, or ≥100 days.

[0185] In some embodiments, the combinations / compositions of the present disclosure achieve a level of tumor growth inhibition (e.g., expressed as %) greater than 1x the level of tumor growth inhibition observed after treatment of the target with the same amount of one of the components of the combination / composition as monotherapy, for example, ≥1.01x, ≥1.02x, ≥1.03x, ≥1.04x, ≥1.05x, ≥1.1x, ≥1.2x, ≥1.3x, ≥1.4x, ≥1.5x, ≥1.6x, ≥1.7x, ≥1.8x, ≥1.9x, ≥2x, ≥3x, ≥4x, ≥5x, ≥6x, ≥7x, ≥8x, ≥9x, or ≥10x (e.g., expressed as %) tumor growth inhibition, and calculated, for example, against tumor growth observed with treatment with an isotype-matched control antibody. In some embodiments, the evaluation of tumor growth inhibition for the purpose of such comparison is performed in the relevant model more than 5 days after administration of the initial dose combination / composition, for example, ≥10 days, ≥15 days, ≥20 days, ≥25 days, ≥30 days, ≥35 days, ≥40 days, ≥35 days, ≥50 days, ≥55 days, ≥60 days, ≥65 days, ≥70 days, ≥75 days, ≥80 days, ≥85 days, ≥90 days, ≥95 days, or ≥100 days.

[0186] In some embodiments, the combinations / compositions of the Disclosure can extend the survival of a subject with cancer (e.g., the median survival of a subject with cancer, as determined in, for example, an in vivo model of the cancers described herein, e.g., cancers expressing HER3 and / or EGFR) by more than 1x, for example, ≥1.01x, ≥1.02x, ≥1.03x, ≥1.04x, ≥1.05x, ≥1.1x, ≥1.2x, ≥1.3x, ≥1.4x, ≥1.5x, ≥1.6x, ≥1.7x, ≥1.8x, ≥1.9x, ≥2x, ≥3x, ≥4x, ≥5x, ≥6x, ≥7x, ≥8x, ≥9x, or ≥10x compared to the survival observed after treatment of the subject with the same amount of one of the components of the combination / composition as monotherapy.

[0187] In the previous three paragraphs, "the same amount" refers to the amount of the relevant agent used in the combination / composition. By way of example, if a subject is administered a combination according to the present disclosure that includes an antigen-binding molecule that binds to HER3 at 20 mg / kg body weight and an antigen-binding molecule that binds to EGFR at 10 mg / kg body weight, a monotherapy with "the same amount" of the antigen-binding molecule that binds to HER3 is a monotherapy with the antigen-binding molecule that binds to HER3 at 20 mg / kg body weight. Similarly, a monotherapy with "the same amount" of the antigen-binding molecule that binds to EGFR is a monotherapy with the antigen-binding molecule that binds to EGFR at 10 mg / kg body weight.

[0188] In some embodiments, the combinations / compositions of the present disclosure achieve a synergistic therapeutic and / or prophylactic effect. That is, in some embodiments, the combination / composition achieves a treatment effect that is synergistic (i.e., super-additive) compared to what is observed when the components of the combination / composition are used as monotherapies.

[0189] As used herein, a "synergistic" or "super-additive" level of a relevant effect (e.g., tumor growth inhibition, reduction in tumor size / volume, extension of survival time) for a given combination / composition refers to a level of effect that is greater than the sum of the effects observed for the individual components of the combination / composition.

[0190] Quantitative methods for evaluating synergistic effects are described, for example, in Tallarida, Genes Cancer. (2011) 2(11):1003-1008 and Chou, Cancer Res (2010) 70:440-446, both of which are incorporated herein by reference in their entirety. Additive, synergistic, and antagonistic effects can be evaluated in experiments where different dosage ranges of the combination / composition and its individual components are evaluated for the relevant effect. The dose-response curve is plotted and evaluated to determine whether the combination / composition achieves a synergistic level of the relevant effect relative to the individual components of the combination / composition used alone (i.e., as monotherapy). In some embodiments, the synergistic effect can be evaluated using the combination index (CI) value calculated using the Chou-Talalay method described in Chou, Cancer Res (2010) 70:440-446. According to the Chou-Talalay method, for a given combination, CI = 1 indicates an additive effect, CI < 1 indicates a synergistic effect, and CI > 1 indicates an antagonistic effect.

[0191] In some embodiments, the combination / composition of the present disclosure achieves a synergistic (i.e., supra-additive) reduction in tumor growth, a delay in tumor growth, a prevention of tumor growth, a reduction in the severity of one or more symptoms of cancer, a reduction in the number of cancer cells, a reduction in cancer burden, a reduction in tumor size / volume, and / or an extension of the survival period of a subject having cancer, compared to what is observed when the components of the combination / composition are used alone. In some embodiments, the combination / composition achieves a synergistic (i.e., supra-additive) reduction in tumor growth, a delay in tumor growth, a prevention of tumor growth, a reduction in the severity of one or more symptoms of cancer, a reduction in the number of cancer cells, a reduction in cancer burden, a reduction in tumor size / volume, and / or an extension of the survival period of a subject having cancer, compared to what is observed when the components of the combination / composition are used as monotherapy.

[0192] Therapeutic and prophylactic uses This disclosure provides methods and articles (e.g., agents, combinations, and compositions of this disclosure) for the treatment and / or prevention of diseases, such as cancer.

[0193] Accordingly, this disclosure provides an antigen-binding molecule that binds to HER3 for use in a method of treating or preventing cancer (e.g., cancer as described herein), wherein the method further comprises the step of administering the taxoid. Also provided is a taxoid for use in a method of treating or preventing cancer (e.g., cancer as described herein), wherein the method further comprises the step of administering an antigen-binding molecule that binds to HER3. Also provided is a use of an antigen-binding molecule that binds to HER3 in the manufacture of a medicament for use in a method of treating or preventing cancer (e.g., cancer as described herein), wherein the method further comprises the step of administering the taxoid. Also provided is a use of a taxoid in the manufacture of a medicament for use in a method of treating or preventing cancer (e.g., cancer as described herein), wherein the method further comprises the step of administering an antigen-binding molecule that binds to HER3. Furthermore, a method is provided for treating or preventing cancer (e.g., cancer as described herein), comprising the step of administering a therapeutic or prophylactic dose of (i) an antigen-binding molecule that binds to HER3 and (ii) a taxoid to a subject requiring treatment. Also provided is an antigen-binding molecule that binds to HER3 for use in a method for treating or preventing cancer (e.g., cancer as described herein), wherein the method further comprises the step of administering an antigen-binding molecule that binds to EGFR, and optionally the method further comprises the step of administering a taxoid. Also provided is an antigen-binding molecule that binds to EGFR for use in a method for treating or preventing cancer (e.g., cancer as described herein), wherein the method further comprises the step of administering an antigen-binding molecule that binds to HER3, and optionally the method further comprises the step of administering a taxoid.

[0194] Accordingly, this disclosure provides an antigen-binding molecule that binds to HER3 for use in a method for treating or preventing cancer (e.g., cancer as described herein), wherein the method further comprises the step of administering the nucleoside analog. Also provided is a nucleoside analog for use in a method for treating or preventing cancer (e.g., cancer as described herein), wherein the method further comprises the step of administering an antigen-binding molecule that binds to HER3. Also provided is a use of an antigen-binding molecule that binds to HER3 in the manufacture of a medicament for use in a method for treating or preventing cancer (e.g., cancer as described herein), wherein the method further comprises the step of administering the nucleoside analog. Also provided is a use of a nucleoside analog in the manufacture of a medicament for use in a method for treating or preventing cancer (e.g., cancer as described herein), wherein the method further comprises the step of administering an antigen-binding molecule that binds to HER3. Furthermore, there is also a use of an antigen-binding molecule that binds to HER3 in the manufacture of a medicament for use in a method of treating or preventing cancer (e.g., cancer as described herein), wherein the method further comprises the step of administering an antigen-binding molecule that binds to EGFR, and optionally the method further comprises the step of administering a taxoid.

[0195] Furthermore, a method for treating or preventing cancer (e.g., cancer as described herein) is provided, comprising the step of administering a therapeutic or prophylactic dose of an antigen-binding molecule and a nucleoside analog bound to HER3 to a subject requiring treatment. Also provided is a method for treating or preventing cancer (e.g., cancer as described herein) comprising the step of administering a therapeutic or prophylactic dose of (i) an antigen-binding molecule bound to HER3 and (ii) an antigen-binding molecule bound to EGFR to a subject requiring treatment; optionally further comprising the step of administering a taxoid.

[0196] This disclosure also provides an antigen-binding molecule that binds to HER3 for use in a method of treating or preventing cancer (e.g., cancer as described herein), wherein the method further comprises the step of administering a taxoid and a nucleoside analog. Furthermore, a taxoid is provided for use in a method of treating or preventing cancer (e.g., cancer as described herein), wherein the method further comprises the step of administering an antigen-binding molecule that binds to HER3 and a nucleoside analog. Also provided is a nucleoside analog for use in a method of treating or preventing cancer (e.g., cancer as described herein), wherein the method further comprises the step of administering an antigen-binding molecule that binds to HER3 and a taxoid. Finally, a use of the antigen-binding molecule that binds to HER3 in the manufacture of a pharmacopoeia for use in a method of treating or preventing cancer (e.g., cancer as described herein), wherein the method further comprises the step of administering a taxoid and a nucleoside analog. Furthermore, there are also uses of taxoids in the manufacture of pharmaceuticals for use in methods of treating or preventing cancer (e.g., cancers described herein), wherein the method further comprises the step of administering an antigen-binding molecule and a nucleoside analog that bind to HER3. Furthermore, there are also uses of nucleoside analogs in the manufacture of pharmaceuticals for use in methods of treating or preventing cancer (e.g., cancers described herein), wherein the method further comprises the step of administering an antigen-binding molecule and a taxoid that bind to HER3. Furthermore, there are also methods of treating or preventing cancer (e.g., cancers described herein), comprising the step of administering a therapeutic or prophylactic amount of an antigen-binding molecule, a taxoid, and a nucleoside analog that bind to HER3 to a subject requiring treatment.

[0197] This disclosure also provides an antigen-binding molecule that binds to HER3 for use in a method of treating or preventing cancer (e.g., cancer as described herein), wherein the method further comprises the step of administering a taxoid and an antigen-binding molecule that binds to EGFR. Furthermore, a taxoid is provided for use in a method of treating or preventing cancer (e.g., cancer as described herein), wherein the method further comprises the step of administering an antigen-binding molecule that binds to HER3 and an antigen-binding molecule that binds to EGFR. Also provided is an antigen-binding molecule that binds to EGFR for use in a method of treating or preventing cancer (e.g., cancer as described herein), wherein the method further comprises the step of administering an antigen-binding molecule that binds to HER3 and a taxoid. Finally, a use of the HER3-binding antigen-binding molecule in the manufacture of a pharmacopoeia for use in a method of treating or preventing cancer (e.g., cancer as described herein), wherein the method further comprises the step of administering a taxoid and an antigen-binding molecule that binds to EGFR. Furthermore, there are also uses of a taxoid in the manufacture of a medicament for use in a method of treating or preventing cancer (e.g., cancer as described herein), wherein the method further comprises the step of administering an antigen-binding molecule that binds to HER3 and an antigen-binding molecule that binds to EGFR. Furthermore, there are also uses of an antigen-binding molecule that binds to EGFR in the manufacture of a medicament for use in a method of treating or preventing cancer (e.g., cancer as described herein), wherein the method further comprises the step of administering an antigen-binding molecule that binds to HER3 and a taxoid. Furthermore, there are also methods for treating or preventing cancer (e.g., cancer as described herein), comprising the step of administering a therapeutic or prophylactic amount of an antigen-binding molecule that binds to HER3, a taxoid, and an antigen-binding molecule that binds to EGFR to a subject requiring treatment.

[0198] This disclosure also provides (i) an antigen-binding molecule that binds to HER3 and (ii) a taxoid for use in methods of treating or preventing cancer in a subject (e.g., cancer as described herein). Furthermore, the use of (i) an antigen-binding molecule that binds to HER3 and (ii) a taxoid in the manufacture of a pharmaceutical for use in treating or preventing cancer in a subject (e.g., cancer as described herein) is also provided. A method is also provided for treating or preventing cancer in a subject (e.g., cancer as described herein), comprising the step of administering a therapeutic or prophylactic amount of (i) an antigen-binding molecule that binds to HER3 and (ii) a taxoid to a subject. This disclosure also provides (i) an antigen-binding molecule that binds to HER3 and (ii) an antigen-binding molecule that binds to EGFR for use in methods of treating or preventing cancer in a subject (e.g., cancer as described herein). Furthermore, the use of (i) an antigen-binding molecule that binds to HER3 and (ii) an antigen-binding molecule that binds to EGFR in the manufacture of a pharmaceutical for use in treating or preventing cancer in a subject (e.g., cancer as described herein) is also provided. Also provided are methods for treating or preventing cancer in a subject (e.g., cancers described herein), comprising the step of administering to the subject a therapeutic or prophylactic effective amount of (i) an antigen-binding molecule that binds to HER3 and (ii) an antigen-binding molecule that binds to EGFR. In some embodiments, the method further comprises the step of administering a taxoid.

[0199] This disclosure also provides (i) HER3-binding antigen-binding molecules and (ii) nucleoside analogs for use in methods of treating or preventing cancer in a subject (e.g., cancer as described herein). Furthermore, the use of (i) HER3-binding antigen-binding molecules and (ii) nucleoside analogs in the manufacture of pharmaceuticals for use in treating or preventing cancer in a subject (e.g., cancer as described herein) is also provided. Finally, a method is also provided for treating or preventing cancer in a subject (e.g., cancer as described herein), comprising the step of administering a therapeutic or prophylactic effective amount of (i) HER3-binding antigen-binding molecules and (ii) nucleoside analogs to a subject.

[0200] In embodiments according to the embodiments of the previous two paragraphs, the provision of (i) and (ii) may be as a combination therapy. In some embodiments, (i) and (ii) may be provided simultaneously or sequentially.

[0201] The disclosure also provides (i) HER3-binding antigen-binding molecules, (ii) taxoids, and (iii) nucleoside analogs for use in methods of treating or preventing cancer in a subject (e.g., cancer as described herein). The disclosure also provides the use of (i) HER3-binding antigen-binding molecules, (ii) taxoids, and (iii) nucleoside analogs in the manufacture of pharmaceuticals for use in treating or preventing cancer in a subject (e.g., cancer as described herein). The disclosure also provides a method of treating or preventing cancer in a subject (e.g., cancer as described herein), comprising the step of administering a therapeutic or prophylactic effective amount of (i) HER3-binding antigen-binding molecules, (ii) taxoids, and (iii) nucleoside analogs to a subject. The disclosure also provides (i) HER3-binding antigen-binding molecules, (ii) taxoids, and (iii) EGFR-binding antigen-binding molecules for use in methods of treating or preventing cancer in a subject (e.g., cancer as described herein). Also provided is the use of (i) an antigen-binding molecule that binds to HER3, (ii) a taxoid, and (iii) an antigen-binding molecule that binds to EGFR in the manufacture of a pharmaceutical product for use in treating or preventing cancer in a subject (e.g., cancer as described herein). Also provided is a method for treating or preventing cancer in a subject (e.g., cancer as described herein), comprising the step of administering a therapeutic or prophylactic effective amount of (i) an antigen-binding molecule that binds to HER3, (ii) a taxoid, and (iii) an antigen-binding molecule that binds to EGFR to the subject.

[0202] In embodiments according to the aspects of the preceding paragraph, the provision of (i), (ii), and (iii) may be as a combination therapy. In some embodiments, (i), (ii), and (iii) may be provided simultaneously or sequentially.

[0203] This disclosure is directed toward methods and articles for the treatment and / or prevention of cancer (e.g., the agents, combinations, and compositions of this disclosure). As used herein, “cancer” may be or include any unwanted cell proliferation (or any disease that manifests itself as a result of such unwanted cell proliferation), a neoplasm, or a tumor. Cancer may be benign or malignant. Cancer may be primary or secondary (e.g., metastatic). A neoplasm or tumor may be any abnormal growth or proliferation of cells and may be located in any tissue. Cancer can be, for example, cancer of tissues / cells originating from the adrenal gland, adrenal medulla, anus, appendix, bladder, blood, bone, bone marrow, brain, breast, cecum, central nervous system (including or excluding the brain), cerebellum, cervix, colon, duodenum, endometrium, epithelial cells (e.g., renal epithelium), gallbladder, esophagus, glial cells, heart, ileum, jejunum, kidney, lacrimal gland, larynx, liver, lung, lymph, lymph nodes, lymphoblasts, jaw, mediastinum, mesentery, myometrium, nasopharynx, retinoplasm, oral cavity, ovary, pancreas, parotid gland, peripheral nervous system, peritoneum, pleura, prostate, salivary gland, sigmoid colon, skin, small intestine, soft tissue, spleen, stomach, testis, thymus, thyroid, tongue, tonsils, trachea, uterus, vulva, or leukocytes.

[0204] The tumors treated may be neurological tumors or non-neurological tumors. Neurological tumors may originate from either the central or peripheral nervous system and may include, for example, gliomas, medulloblastomas, meningiomas, neurofibromas, ependymomas, Schwann cell tumors, neurofibrosarcomas, astrocytomas, and oligodendrogliomas. Non-neurological cancers / tumors may originate from any other non-neurological tissue; examples include melanoma, mesothelioma, lymphoma, myeloma, leukemia, non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), cutaneous T-cell lymphoma (CTCL), chronic lymphocytic leukemia (CLL), liver cancer, epidermal carcinoma, prostate cancer, breast cancer, lung cancer, colon cancer, ovarian cancer, pancreatic cancer, thymic cancer, NSCLC, hematological cancers, and sarcomas.

[0205] In some embodiments, the cancer to be treated / prevented includes cells expressing EGFR family members (e.g., HER3, EGFR, HER2, or HER4) and / or ligands for EGFR family members. In some embodiments, the cancer to be treated / prevented is a cancer that is positive for EGFR family members. In some embodiments, the cancer includes cells that overexpress EGFR family members and / or ligands for EGFR family members. Overexpression may be determined by detecting expression levels higher than those of equivalent non-cancerous cells / non-tumor tissues.

[0206] Expression can be determined by any appropriate means. Expression may be gene expression or protein expression. Gene expression can be determined, for example, by quantitative real-time PCR (qRT-PCR), for example, by detection of mRNA encoding HER3. Protein expression can be determined, for example, by antibody-based methods, such as Western blotting, immunohistochemistry, immunocytochemistry, flow cytometry, or ELISA.

[0207] In some embodiments, cancer is a cancer in which HER3 and / or EGFR are pathologically involved. That is, in some embodiments, cancer is a cancer caused by or exacerbated by the expression of HER3 and / or EGFR, a cancer in which the expression of HER3 and / or EGFR is a risk factor, and / or a cancer in which the expression of HER3 and / or EGFR is positively associated with the onset, development, progression, severity, or metastasis of the cancer. Cancer may be characterized by the expression of HER3 and / or EGFR; for example, cancer may include cells that express HER3 and / or EGFR (e.g., cells in tumor tissue). Such cancer may be referred to as HER3 and / or EGFR positive. Cancer that is “positive” for HER3 and / or EGFR may include cells that express HER3 and / or EGFR (e.g., on the cell surface). Cancer that is “positive” for HER3 and / or EGFR may overexpress HER3 and / or EGFR.

[0208] In some embodiments, the cancer being treated / prevented includes cells that possess a genetic variant (e.g., a mutation) that causes increased expression and / or activity of HER3 and / or EGFR (gene and / or protein) compared to equivalent cells that possess a reference allele that does not contain the genetic variant (e.g., a non-mutant or “wild-type” allele). The genetic variant may be, or include, an insertion, deletion, substitution, or larger translocation / rearrangement of the nucleotide sequence relative to the reference allele.

[0209] Mutations that "result in" an increase in the expression of HER3 and / or EGFR may be known to, or predicted to, or associated with, cause an increase in the gene / protein expression of HER3 and / or EGFR. Mutations that "result in" an increase in the activity of HER3 and / or EGFR may be known to, or predicted to, or associated with, cause an increase in HER3-mediated signaling and / or EGFR-mediated signaling. Mutations that result in an increase in the expression and / or activity of HER3 and / or EGFR may be referred to as "activating" mutations.

[0210] Mutations that cause an increase in the expression of HER3 and / or EGFR may result in the expression of HER3 and / or EGFR genes or proteins that are not expressed by equivalent cells without the mutation and / or are not encoded by their genomic nucleic acids. That is, HER3 and / or EGFR may be neoantigens resulting from the mutation, and thus the "increase in expression" may be from no expression.

[0211] Mutations that cause an increase in the expression of HER3 and / or EGFR may result in an increase in the expression of HER3 and / or EGFR genes or proteins that are expressed by equivalent cells without the mutation and / or are encoded by their genomic nucleic acids. By way of example, the cell may contain mutations that result in an increase in the transcription level of the nucleic acid encoding HER3 and / or EGFR, as compared to the transcription level of the nucleic acid encoding HER3 and / or EGFR by equivalent cells without the mutation.

[0212] In some embodiments, a mutation that causes increased expression of HER3 and / or EGFR may result in increased gene expression of HER3 and / or EGFR compared to equivalent cells that do not contain the mutation.

[0213] In some embodiments, a mutation that causes increased expression of HER3 and / or EGFR may result in increased levels of HER3 and / or EGFR on the cell surface of the mutated cell compared to equivalent cells that do not contain the mutation.

[0214] Cells exhibiting increased HER3 and / or EGFR expression (e.g., as a result of a mutation) compared to the expression levels of HER3 and / or EGFR in reference cells may be described as having "overexpression" or "upregulated expression" of HER3 and / or EGFR. For example, a cancer containing cells with a mutation that results in increased HER3 and / or EGFR expression compared to equivalent cells lacking the mutation may be described as a cancer containing cells exhibiting overexpression / upregulated expression of HER3 and / or EGFR. In some embodiments, the reference cells lacking the mutation may be non-cancerous cells (e.g., equivalent cell types) or cancerous cells (e.g., equivalent oncological types).

[0215] Mutations that cause increased HER3 and / or EGFR activity may result in increased HER3-mediated and / or EGFR-mediated signaling compared to the levels of HER3-mediated and / or EGFR-mediated signaling in equivalent cells that do not contain the mutation.

[0216] In some embodiments, cancer treated / prevented in accordance with this disclosure may be characterized, for example, by increased expression and / or activity (i.e., gene and / or protein expression) of HER3 and / or EGFR in the diseased organ / tissue / subject compared to a normal organ / tissue / subject (i.e., in the absence of the disease / condition). In some embodiments, cancer cells and / or tumors treated / prevented may be characterized, for example, by increased expression and / or activity of HER3 and / or EGFR compared to the levels of expression and / or activity observed in equivalent non-cancerous cells / non-tumor tissues.

[0217] Cancers that overexpress HER3 may overexpress HER3 as a result of amplification of the HER3 gene. Similarly, cancers that overexpress EGFR may overexpress EGFR as a result of amplification of the EGFR gene.

[0218] In some embodiments, the cancer treated or prevented in accordance with this disclosure is HER3-amplified cancer. In some embodiments, the cancer is EGFR-amplified cancer. In some embodiments, the cancer is a cancer that includes amplification of both HER3 and EGFR. In some embodiments, the cancer treated or prevented in accordance with this disclosure is TP63-amplified cancer.

[0219] HER3, EGFR, and / or TP63 amplification can be identified using techniques well known in the art, such as in situ hybridization. For example, HER3 amplification can be evaluated by fluorescence in situ hybridization, as described, for example, Chung et al., J Gynecol Oncol. (2019) 30(5):e75. HER3-amplified cancers may include two or more ratios of 12q13.2 to the centromere of chromosome 12, as determined by ISH. EGFR amplification can similarly be evaluated by in situ hybridization, as described, for example, French et al., Neuro-Oncology (2019) 21(10):1263~1272. EGFR-amplified cancers may include two or more ratios of 7p11.2-7p12 to the centromere of chromosome 7, as determined by ISH. For example, TP63 amplification can be assessed by fluorescence in situ hybridization, as described, for example, by Massion et al., Cancer Res. (2003) 63(21):7113~21. TP63-amplified cancers may contain two or more ratios of 3q26-3qter to the 3rd chromosome centromere, as determined by ISH.

[0220] EGFR, as well as its association with and role in cancer, are outlined, for example, in Uribe et al., Cancers (Basel) (2021) 13(11):2748, Sigismund et al., Mol Oncol. (2018) 12(1):3-20, and da Silva Santos et al., Int J Pharm. (2021) 592:120082, which are incorporated herein by reference in their entirety. da Silva Santos et al., Int J Pharm. (2021) 592:120082, describes EGFR-targeted interventions for the treatment of cancer, including monoclonal anti-EGFR antibody therapy.

[0221] HER3, as well as its association with and role in cancer, are outlined, for example, in Mishra et al., Oncol Rev. (2018) 12(1):355, Karachaliou et al., BioDrugs. (2017) 31(1):63-73, and Zhang et al., Acta Biochimica et al., Biophysica Sinica (2016) 48(1):39-48, all of which are incorporated herein by reference in their entirety. Mishra et al., Oncol Rev. (2018) 12(1):355 also describes HER3-targeted interventions for the treatment of cancer, including monoclonal anti-HER3 antibody therapy.

[0222] In some embodiments, the cancer to be treated / prevented includes cells expressing ligands for HER3 (e.g., NRG1 and / or NRG2). In some embodiments, the cancer to be treated / prevented includes cells expressing NRG1 and / or NRG2 at levels higher than those of equivalent non-cancerous cells / non-tumor tissues. The cancer may be described as including cells that overexpress NRG1 and / or NRG2.

[0223] The HER3-binding antigen-binding molecules described herein bind to HER3 with extremely high affinity, both when HER3 is bound by an NRG (i.e., when HER3 is provided in an "open" conformation) and when HER3 is not bound by an NRG (i.e., when HER3 is provided in a "closed" conformation). Therefore, they are particularly useful for the treatment / prevention of cancers characterized by the expression / overexpression of HER3 ligands, such as cancers / tumors containing cells that express / overexpress ligands for HER3.

[0224] In some embodiments, the cancer being treated / prevented includes cells that possess a genetic variant (e.g., a mutation) that causes increased expression of ligands (genes and / or proteins) for HER3 compared to equivalent cells that possess a reference allele that does not contain the genetic variant (e.g., an unmutated or “wild-type” allele). The genetic variant may be, or include, an insertion, deletion, substitution, or larger translocation / rearrangement of the nucleotide sequence relative to the reference allele.

[0225] The most common type of nucleotide sequence of a given gene can be called the wild-type allele of the gene. The type of nucleotide sequence of a given gene that includes mutations can be called the mutant allele of the gene. It will be understood that the nucleotide sequence of the mutant allele of a given gene will have a nucleotide sequence that is not identical to that of the wild-type allele.

[0226] Mutations that "result" in increased expression of ligands for HER3 are known, predicted, or may be associated with increased gene / protein expression of ligands for HER3. Mutations that result in increased expression of ligands for HER3 may be referred to as "activating" mutations.

[0227] Mutations that cause increased expression of ligands for HER3 may result in the expression of a ligand for HER3 that is not expressed by equivalent cells that do not harbor the mutation and / or is not encoded by its genomic nucleic acid. That is, the ligand for HER3 may be a novel antigen resulting from the mutation, and therefore the "increased expression" may be from non-expression. For example, cells containing the CD74-NRG1 gene fusion exhibit increased expression of the CD74-NRG1 fusion polypeptide encoded by the gene fusion compared to cells lacking the CD74-NRG1 gene fusion.

[0228] Mutations that result in increased expression of ligands for HER3 may lead to increased gene or protein expression of ligands for HER3, as expressed by and / or encoded by the genomic nucleic acids of equivalent cells that do not contain the mutation. For example, a cell may contain a mutation that results in increased transcription levels of the nucleic acid encoding NRG1 compared to the transcription levels of the nucleic acid encoding NRG1 in equivalent cells that do not contain the mutation.

[0229] In some embodiments, a mutation that causes increased expression of a ligand for HER3 may result in increased gene expression of the ligand for HER3 compared to equivalent cells that do not contain the mutation.

[0230] In some embodiments, a mutation that causes increased expression of a ligand for HER3 may result in increased levels of ligand for HER3 on the cell surface of the mutated cell compared to equivalent cells that do not contain the mutation. In some embodiments, a mutation that causes increased expression of a ligand for HER3 may result in increased secretion levels of ligand for HER3 from the mutated cell compared to equivalent cells that do not contain the mutation.

[0231] Cells exhibiting increased expression of a ligand for HER3 compared to the expression level of a ligand for HER3 in a reference cell (e.g., as a result of a mutation) may be described as having “overexpression” or “upregulated expression” of the ligand for HER3. For example, a cancer containing cells with a mutation that results in increased expression of a ligand for HER3 compared to equivalent cells lacking the mutation may be described as a cancer containing cells exhibiting overexpression / upregulated expression of the ligand for HER3. In some embodiments, the reference cell lacking the mutation may be a non-cancerous cell (e.g., of an equivalent cell type) or a cancerous cell (e.g., of an equivalent cancer type).

[0232] In this specification, “ligand for HER3” is generally intended to refer to a molecule that can bind to HER3 via the ligand-binding region of HER3, which is formed by domains I and III of HER3. In some embodiments, ligands for HER3 bind to HER3 via interaction with domains I and / or III of HER3. Exemplary ligands for HER3 include neuregulins such as NRG1 and NRG2, which bind to HER3 via interaction between their EGF-like domains and the ligand-binding region of HER3.

[0233] HER3 ligands can preferably bind via HER3 receptors and / or HER3-containing receptor complexes to induce signaling. As is evident from this disclosure, HER3-containing receptor complexes may further include HER3 interaction partners described herein, such as HER3, HER2, EGFR, HER4, HGFR, IGF1R, and / or cMet.

[0234] In some embodiments, a ligand for HER3 can bind to a HER3 receptor / receptor complex expressed by cells other than those with increased HER3 ligand expression. For example, in some embodiments, a ligand for HER3 can bind to cancer cells that express HER3.

[0235] In some embodiments, a ligand for HER3 can bind to a HER3 receptor / receptor complex expressed by cells with increased HER3 ligand expression. In some embodiments, the cancer to be treated / prevented includes (i) cells expressing HER3, and (ii) cells expressing ligands for HER3 (for example, cells whose expression of ligands for HER3 is increased as a result of a mutation that leads to increased expression of ligands for HER3).

[0236] In some embodiments, the cancer to be treated / prevented includes cells that (i) express HER3 and (ii) also express a ligand for HER3 (for example, increased expression of a ligand for HER3 as a result of a mutation that leads to increased expression of a ligand for HER3).

[0237] In some embodiments, the ligand for HER3 includes or consists of the amino acid sequence of the HER3-binding region of the ligand for HER3, or an amino acid sequence derived from the HER3-binding region of the ligand for HER3. The amino acid sequence derived from the HER3-binding region of the ligand for HER3 may have at least 60% (e.g., 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) amino acid sequence identity with respect to the amino acid sequence from which it is derived.

[0238] In some embodiments, the ligand for HER3 includes an EGF-like domain or a HER3-binding fragment thereof that can bind to HER3. In some embodiments, the HER3-binding EGF-like domain / fragment is or derived from an EGF family member (e.g., heparin-binding EGF-like growth factor (HB-EGF), transforming growth factor-α (TGF-α), amphiregulin (AR), epiregulin (EPR), epigen, beta-cellulin (BTC), NRG1, NRG2, NRG3, or NRG4).

[0239] Exemplary ligands for HER3 include neuregulin (NRG). Neuregulin includes NRG1 (including its alpha, alpha 2b, and alpha 3 isoforms), NRG2, NRG3, and NRG4. In some embodiments, the NRG is selected from NRG1, NRG2, NRG3, and NRG4. In some embodiments, the NRG is selected from NRG1 and NRG2.

[0240] The EGF-like domain of human NRG1 that binds to HER3 is formed at positions 178-222 of UniProt:Q02297-1. The EGF-like domain of human NRG2 is formed at positions 341-382 of UniProt:O14511-1. The EGF-like domain of human NRG3 is formed at positions 286-329 of UniProt:B9EGV5-1. The EGF-like domain of human NRG4 is formed at positions 5-46 of UniProt:Q8WWG1-1. In some embodiments, the EGF-like domain / fragment contains or consists of an amino acid sequence having at least 60% (e.g., 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) amino acid sequence identity with respect to the EGF-like domain of NRG (NRG1, NRG2, NRG3, or NRG4).

[0241] In some embodiments, the ligand for HER3 is not an EGFR family protein (e.g., HER3, HER2, EGFR, HER4, HGFR, IGF1R, cMet).

[0242] In some embodiments, the mutation resulting in increased expression of a ligand for HER3 is an NRG gene fusion. In some embodiments, the ligand for HER3 is the product of the NRG gene fusion (i.e., the polypeptide encoded thereby). In some embodiments, cancer comprises cells having an NRG gene fusion. As used herein, “NRG gene fusion” means a genetic variant encoding a polypeptide comprising (i) the amino acid sequence of an NRG protein (e.g., NRG1, NRG2, NRG3, or NRG4; e.g., NRG1 or NRG2) and (ii) the amino acid sequence of a protein other than an NRG protein.

[0243] NRG gene fusions can be detected and characterized using appropriate molecular assays well known to those skilled in the art. The NRG gene fusion according to this disclosure preferably encodes a fusion polypeptide comprising an EGF-like domain that is precisely oriented (i.e., having a nucleotide sequence encoding NRG at the 3' end of the transcript) and capable of binding to HER3.

[0244] It will be understood that the NRG gene fusion preferably encodes a HER3 ligand as described herein. In some embodiments, the NRG gene fusion encodes a polypeptide comprising a HER3-binding region of the NRG protein. In some embodiments, the NRG gene fusion encodes a polypeptide comprising an amino acid sequence that can bind to the EGF-like domain of the NRG protein or HER3 and has at least 60% (e.g., 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) amino acid sequence identity with respect to the EGF-like domain of the NRG protein.

[0245] In some embodiments, the NRG gene fusion encodes a fusion polypeptide containing a transmembrane domain. In some embodiments, the NRG gene fusion encodes a fusion polypeptide containing a transmembrane domain of a protein other than the NRG protein.

[0246] In some embodiments, the NRG gene fusion is an NRG1 gene fusion. In some embodiments, the NRG1 gene fusion can bind to the EGF-like domain of NRG1 or HER3 and encodes a polypeptide containing an amino acid sequence having at least 60% (e.g., 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) amino acid sequence identity with respect to the EGF-like domain of NRG1.

[0247] NRG1 gene fusions represent fusions that can act in tissue-agnostic cancers that can be targeted by HER3 inhibition. These are formed by interchromosomal translocations with diverse gene groups, leading to overproduction of NRG1 ligands for HER3 binding and abnormal activation resulting in tumorigenesis. Studies have demonstrated a causal relationship between HER3 pathway activation and NRG1 gene fusions. NRG1 fusions are abundant among subjects with mucinous non-small cell lung cancer and pancreatic ductal adenocarcinoma; 8–32% of subjects with mucinous NSCLC have NRG1 gene fusions, while 10–20% (up to 70% in smaller studies) of subjects with KRAS wild-type PDAC have detectable NRG1 gene fusions. The therapeutic efficacy of monoclonal anti-HER3 antibody therapy targeting NRG1 gene fusions has been demonstrated, for example, in WO2021 / 048274A1.

[0248] NRG1 gene fusions have been described, for example, WO2021 / 048274A1, WO2018 / 182422A1, WO2019 / 051155A1, Dhanasekaran et al., Nat Commun. (2014) 5:5893, Drilon et al., Cancer Discov. (2018) 8(6):686~695, Nagasaka et al., Journal of Thoracic Oncology (2019) 14(8):1354~1359, and Jonna et al., Clin Cancer Res. (2019) 25(16):4966~4972, all of which are incorporated herein by reference in their entirety. The diversity of NRG1 gene fusions may be due to NRG1 located on chromosome 8, which is particularly susceptible to genomic translocation events (Adelaide et al., Genes Chromosomes Cancer. (2003) 37(4):333~45).

[0249] In some embodiments, the NRG1 gene fusions are CLU-NRG1, CD74-NRG1, DOC4-NRG1, SLC3A2-NRG1, RBPMS-NRG1, WRN-NRG1, SDC4-NRG1, RAB2IL1-NRG1, VAMP2-NRG1, KIF13B-NRG1, THAP7-NRG1, SMAD4-NRG1, MDK-NRG1, TNC-NRG1, DIP2B-NRG1, MRPL13 -NRG1 is selected from PARP8-NRG1, ROCK1-NRG1, DPYSL2-NRG1, ATP1B1-NRG1, CDH6-NRG1, APP-NRG1, AKAP13-NRG1, THBS1-NRG1, FOXA1-NRG1, PDE7A-NRG1, RAB3IL1-NRG1, CDK1-NRG1, BMPRIB-NRG1, TNFRSF10B-NRG1, and MCPH1-NRG1. In some embodiments, the NRG1 gene fusion is CLU-NRG1.

[0250] CD74-NRG1 gene fusions are described, for example, by Fernandez-Cuesta et al., Cancer Discov. (2014) 4:415~22, and by Nakaoku et al., Clin Cancer Res (2014) 20:3087~93. DOC4-NRG1 gene fusions are described, for example, by Liu et al., Oncogene. (1999) 18(50):7110~4, and by Wang et al., Oncogene. (1999) 18(41):5718~21. SLC3A2-NRG1 gene fusions are described, for example, by Nakaoku et al., Clin Cancer Res (2014) 20:3087~93, by Shin et al., Oncotarget (2016) 7:69450~65, and by Shin et al., Mol Cancer Ther. (2018) 17(9):2024~2033. The RBPMS-NRG1, WRN-NRG1, RAB2IL1-NRG1, and SDC4-NRG1 gene fusions are described, for example, by Dhanasekaran et al., Nat Commun. (2014) 5:5893. The VAMP2-NRG1 gene fusion is described, for example, by Jung et al., J Thorac Oncol. (2015) 10(7):1107~11, and by Shim et al., J Thorac Oncol. (2015) 10(8):1156~62. The KIF13B-NRG1 gene fusion is described, for example, by Xia et al., Int J Surg Pathol. (2017) 25(3):238~240. The SMAD4-NRG1, AKAP13-NRG1, THBS1-NRG1, FOXA1-NRG1, PDE7A-NRG1, RAB3IL1-NRG1, and THAP7-NRG1 gene fusions are described, for example, by Drilon et al., Cancer Discov. (2018) 8(6):686~695. The MDK-NRG1, TNC-NRG1, DIP2B-NRG1, MRPL13-NRG1, PARP8-NRG1, ROCK1-NRG1, and DPYSL2-NRG1 gene fusions are described, for example, by Jonna et al., Clin Cancer Res. (2019) 25(16):4966~4972.ATP1B1-NRG1 gene fusions are described, for example, by Drilon et al., Cancer Discov. (2018) 8(6):686~695, and by Jones et al., Annals of Oncology (2017) 28:3092~3097. CLU-NRG1 gene fusions are described, for example, by Drilon et al., Cancer Discov. (2018) 8(6):686~695, and by Nagasaka et al., Journal of Thoracic Oncology (2019) 14(8):1354~1359.

[0251] In some embodiments, the NRG gene fusion is an NRG2 gene fusion. In some embodiments, the NRG2 gene fusion can bind to the EGF-like domain of NRG2 or HER3 and encodes a polypeptide containing an amino acid sequence having at least 60% (e.g., 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) amino acid sequence identity with respect to the EGF-like domain of NRG2.

[0252] NRG2 gene fusions include, for example, SLC12A2-NRG2 described in WO2021 / 048274A1 and WO2015 / 093557A1, and ZNF208-NRG2 described by Dupain et al., Mol Ther. (2019) 27(1):200~218.

[0253] Cancers containing cells having mutations that result in increased expression of ligands for HER3 (e.g., cells having NRG gene fusions, e.g., NRG1 gene fusions or NRG2 gene fusions) may be any cancer described herein. In some embodiments, such cancers may be tissue / cell cancers originating from the lung, breast, head, neck, kidney, ovary, pancreas, prostate, uterus, gallbladder, colon, rectum, bladder, soft tissue, or nasopharynx.

[0254] In some embodiments, cancers including cells having mutations that result in increased ligand expression for HER3 (e.g., cells having NRG gene fusions, e.g., NRG1 gene fusions or NRG2 gene fusions) are selected from lung cancer, non-small cell lung cancer, lung adenocarcinoma, invasive mucinous lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, breast cancer, invasive breast cancer, head and neck cancer, head and neck squamous cell carcinoma, kidney cancer, renal clear cell carcinoma, ovarian cancer, serous ovarian cystadenocarcinoma, pancreatic cancer, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, prostate cancer, prostate adenocarcinoma, endometrial cancer, uterine carcinosarcoma, gallbladder cancer, bile duct cancer, colorectal cancer, metastatic colorectal cancer, bladder cancer, urothelial bladder cancer, sarcoma, soft tissue sarcoma, neuroendocrine tumors, and nasopharyngeal neuroendocrine tumors.

[0255] In some embodiments, the cancer to be treated / prevented is lung cancer (e.g., non-small cell lung cancer, lung adenocarcinoma, invasive mucinous lung adenocarcinoma, or lung squamous cell carcinoma) containing cells with NRG1 gene fusions.

[0256] In embodiments of this specification, it will be understood that cancers containing cells having certain characteristics may be or may include tumors containing cells having those characteristics. As is common in the art, cancers / tumors containing cells having certain characteristics may be referred to herein simply as cancers / tumors having those characteristics. For example, cancers / tumors containing cells having an NRG1 gene fusion may be referred to simply as "cancers / tumors containing an NRG1 gene fusion" or "NRG1 gene fusion cancers / tumors."

[0257] In some embodiments, the cancer to be treated / prevented includes a mutation that confers resistance to treatment with a BRAF inhibitor. In some embodiments, the mutation is a mutation in BRAF V600. In some embodiments, the mutation is BRAF V600E or V600K. The cancer may be thyroid cancer or colorectal cancer, for example, RAS wild-type colorectal cancer. In some embodiments, the cancer to be treated / prevented includes a mutation that confers resistance to treatment with a BRAF inhibitor (e.g., a mutation in BRAF V600), and the treatment includes administration of vemurafenib or darafenib.

[0258] In squamous cell carcinoma (SCC), the PI3K / AKT signaling pathway is generally altered by gene amplification and / or mutation. The 3q26 / 28 chromosome region, where PIK3CA is located and which has a high amplification frequency, also contains the cell lineage genes TP63 and SOX2. TP63 is a member of the TP53 gene family and is expressed in the basal compartments of the skin, esophagus, lung airways, and larynx during development and homeostasis. TP63 is used as a diagnostic marker for squamous and adenocarcinoma types of lung and esophageal cancer. Preclinical data suggest that TP63 modulates NRG1 expression in SCC and that the HER3 signaling pathway is active in TP63-amplified squamous cell carcinoma. Furthermore, the association between high NRG1 levels and response rates to anti-HER3 antibodies, and the overexpression of EGFR in a subset of squamous cell carcinoma, support the rationale for combining 10D1F with cetuximab in EGFR-amplified squamous cell carcinoma.

[0259] When cancer is described as having a given mutation state, allele, or genotype, it will be understood that cancer cells have the associated mutation state, allele, or genotype. For example, when cancer is described as containing a given mutation, cancer contains cells containing the mutation. Similarly, when cancer is described as being homozygous for a given allele, cancer contains cells that are homozygous for that allele.

[0260] When cancer is described as having a given mutation state, allele, or genotype, one or more cells of the cancer have the associated mutation state, allele, or genotype. In some embodiments, when cancer is described as having a given mutation state, allele, or genotype, the majority of cancer cells (i.e., more than 50%) have the associated mutation state, allele, or genotype. In some embodiments, one of 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or 100% of the cancer cells have the associated mutation state, allele, or genotype.

[0261] In some embodiments, a cancer containing a given mutation / allele / genotype may be a cancer in which more than 10% of cancer cells (e.g., one of 20% or more, 50% or more, 40% or more, 50% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or 100%) contain the mutation / allele / genotype. In some embodiments, a cancer not containing a given mutation / allele / genotype may be a cancer in which less than 25% of cancer cells (e.g., one of 20% or less, 15% or less, 10% or less, 5% or less, 1% or less, or none) contain the mutation / allele / genotype.

[0262] In this specification, when a cell is described as containing a given mutation, it will be understood that one or both alleles of the relevant gene contain such a mutation (i.e., the cell is heterozygous or homozygous for the mutation / mutant allele). Conversely, when a cell is described as not containing a given mutation, it will be understood that none of the alleles of the relevant gene contain such a mutation (i.e., the cell is neither homozygous nor heterozygous for the mutation / mutant allele).

[0263] Activating mutations according to this disclosure may increase gene transcription; increase the level of RNA encoded by the gene; decrease the degradation of RNA encoded by the gene; increase the level of protein encoded by the gene; increase (or promote) normal splicing of pre-mRNA encoded by the gene; increase the translation of mRNA encoding protein encoded by the gene; increase (or promote) normal post-translational processing of protein encoded by the gene; increase (or promote) normal transport of protein encoded by the gene; decrease the degradation of protein encoded by the gene; increase the level of function of protein encoded by the gene; and / or confer novel properties to protein encoded by the gene. Inactivating mutations pursuant to this disclosure may reduce gene transcription; reduce the level of RNA encoded by the gene; increase the degradation of RNA encoded by the gene; reduce the level of protein encoded by the gene; reduce (disrupt) the normal splicing of pre-mRNA encoded by the gene; reduce the translation of mRNA encoding protein encoded by the gene; reduce (disrupt) the normal post-translational processing of protein encoded by the gene; reduce (disrupt) the normal transport of protein encoded by the gene; increase the degradation of protein encoded by the gene; and / or reduce the level of function of protein encoded by the gene.

[0264] In some embodiments, the treated / prevented cancer is not homozygous for activating mutations to KRAS. In some embodiments, the cancer is not homozygous for activating mutations to PIK3CA. In some embodiments, the cancer is not homozygous for inactivating mutations to PTEN. In some embodiments, the cancer is not homozygous for activating mutations to BRAF. In some embodiments, the cancer is not homozygous for activating mutations to MET. In some embodiments, the treated / prevented cancer is not homozygous for activating mutations to KRAS, not homozygous for activating mutations to PIK3CA, not homozygous for inactivating mutations to PTEN, not homozygous for activating mutations to BRAF, and not homozygous for activating mutations to MET.

[0265] In some embodiments, the cancer does not contain activating mutations to KRAS. In some embodiments, the cancer does not contain activating mutations to PIK3CA. In some embodiments, the cancer does not contain inactivating mutations to PTEN. In some embodiments, the cancer does not contain activating mutations to BRAF. In some embodiments, the cancer does not contain activating mutations to MET. In some embodiments, the cancer does not contain activating mutations to KRAS, does not contain activating mutations to PIK3CA, does not contain inactivating mutations to PTEN, does not contain activating mutations to BRAF, and does not contain activating mutations to MET.

[0266] In some embodiments, the cancer includes a homozygous wild-type genotype for KRAS. In some embodiments, the cancer includes a homozygous wild-type genotype for PIK3CA. In some embodiments, the cancer includes a homozygous wild-type genotype for BRAF. In some embodiments, the cancer includes a homozygous wild-type genotype for PTEN. In some embodiments, the cancer includes a homozygous wild-type genotype for MET. In some embodiments, the cancer includes homozygous wild-type genotypes for KRAS, PIK3CA, BRAF, PTEN, and MET.

[0267] In some embodiments, the cancer being treated / prevented is metastatic cancer. Metastatic cancer is a cancer that is detectable in one or more secondary sites in the body other than the site of origin of the original (primary) cancer from which the metastatic cancer originates.

[0268] In some embodiments, the cancer being treated / prevented is advanced cancer. Advanced cancer is cancer that has spread from the original (primary) site of origin. In some embodiments, the cancer being treated / prevented is locally advanced cancer. Locally advanced cancer is cancer that has spread from the original (primary) site of origin to adjacent tissues or lymph nodes.

[0269] In some embodiments, the cancer being treated / prevented is unresectable cancer. Unresectable cancer is cancer that cannot be completely removed by surgery. This can be due to a variety of reasons, including tumor size, stage, and / or location.

[0270] In some embodiments, the cancer being treated / prevented is locally advanced and unresectable. In some embodiments, the cancer treated / prevented is squamous cell carcinoma, i.e., squamous cell carcinoma. In some embodiments, the cancer is advanced or metastatic squamous cell carcinoma. In some embodiments, the squamous cell carcinoma is selected from EGFR-amplified squamous cell carcinoma, head and neck squamous cell carcinoma (HNSCC), lung squamous cell carcinoma (LUSC), and esophageal squamous cell carcinoma (ESCC), cervical squamous cell carcinoma, cutaneous squamous cell carcinoma (cSCC), thyroid squamous cell carcinoma (SCTC), vaginal squamous cell carcinoma (SCCV), prostate squamous cell carcinoma, and penile squamous cell carcinoma. In some embodiments, the squamous cell carcinoma is selected from EGFR-amplified squamous cell carcinoma, head and neck squamous cell carcinoma (HNSCC), lung squamous cell carcinoma (LUSC), and esophageal squamous cell carcinoma (ESCC).

[0271] In some embodiments, the cancer being treated / prevented is NRG1 and HER3 expressing / overexpressing cancer. In some embodiments, the cancer is NRG1 and HER3 expressing / overexpressing squamous cell carcinoma. In some embodiments, the cancer is NRG1 and HER3 expressing / overexpressing head and neck squamous cell carcinoma. In some embodiments, the cancer is NRG1 and HER3 expressing / overexpressing esophageal squamous cell carcinoma. In some embodiments, the cancer is NRG1 and HER3 expressing / overexpressing hypopharyngeal squamous cell carcinoma.

[0272] In some embodiments, the cancer to be treated / prevented is EGFR-expressing / overexpressing cancer. In some embodiments, the cancer to be treated / prevented is EGFR-expressing / overexpressing squamous cell carcinoma. In some embodiments, the cancer is EGFR-expressing / overexpressing head and neck squamous cell carcinoma. In some embodiments, the cancer is EGFR-expressing / overexpressing esophageal squamous cell carcinoma. In some embodiments, the cancer is EGFR-expressing / overexpressing tongue squamous cell carcinoma.

[0273] In some embodiments, the cancer treated / prevented is EGFR-expressing / overexpressing colorectal cancer. In some embodiments, the cancer treated / prevented is EGFR-expressing / overexpressing colorectal adenocarcinoma.

[0274] In some embodiments, the cancer may be a recurrent cancer. As used herein, “recurrent” cancer refers to cancer that has responded to treatment (e.g., first-line treatment for cancer) but has subsequently reappeared / progressed, for example, after a period of remission. For example, a recurrent cancer may be cancer whose growth / progression was inhibited by treatment (e.g., first-line treatment for cancer) and which has subsequently grown / progressed.

[0275] In some embodiments, the cancer may be a refractory cancer. As used herein, “refractory” cancer refers to cancer that has not responded to treatment (e.g., first-line treatment for cancer). For example, a refractory cancer may be cancer whose growth / progression was not inhibited by treatment (e.g., first-line treatment for cancer). In some embodiments, a refractory cancer may be cancer in which a patient undergoing treatment for cancer did not exhibit a partial or complete response to the treatment.

[0276] In some embodiments, the cancer is recurrent or refractory to platinum-based chemotherapy. Platinum-based chemotherapy includes cisplatin, carboplatin, oxaliplatin, nedaplatin, and lovaplatin.

[0277] In some embodiments, the cancer is advanced squamous cell non-small cell lung cancer. In some embodiments, the cancer is metastatic squamous cell non-small cell lung cancer. In some embodiments, the cancer is locally advanced and unresectable squamous cell non-small cell lung cancer.

[0278] In some embodiments, the cancer is an advanced or metastatic cancer containing an NRG1 gene fusion. In some embodiments, the cancer is an advanced or metastatic pancreatic ductal adenocarcinoma containing an NRG1 gene fusion.

[0279] In some embodiments, the cancer is advanced or metastatic non-small cell lung cancer containing an NRG1 gene fusion. In some embodiments, cancer is a cancer comprising cells expressing / overexpressing an EGFR family member (e.g., HER3, EGFR, HER2, or HER4), a cancer comprising cells expressing / overexpressing HER3, a cancer comprising cells expressing / overexpressing EGFR, a cancer comprising cells expressing / overexpressing HER3 and EGFR, a cancer comprising cells having mutations that result in increased expression of ligands for HER3, a cancer comprising cells having mutations that result in increased expression of ligands for EGFR, Cancers containing cells with NRG gene fusions, cancers containing cells with NRG1 gene fusions, or cancers containing cells with NRG2 gene fusions, solid tumors, hematological cancers, squamous cell carcinoma, EGFR-amplified squamous cell carcinoma, breast cancer, breast cancer, invasive breast cancer, ductal carcinoma, metastatic breast cancer, triple-negative breast cancer, HER2-positive breast cancer, gastric cancer, gastric adenocarcinoma, gastrointestinal adenocarcinoma, colorectal cancer, metastatic colorectal cancer, colon cancer, colorectal cancer, colorectal adenocarcinoma, colon adenocarcinoma, head and neck cancer, head and neck squamous cell carcinoma (HNSCC), lung cancer Hmm, non-small cell lung cancer, lung adenocarcinoma, invasive mucinous lung adenocarcinoma, squamous cell lung cancer, squamous cell carcinoma of the lung (LUSC), squamous non-small cell lung cancer, advanced squamous non-small cell lung cancer, metastatic squamous non-small cell lung cancer, ovarian cancer, ovarian cancer, serous ovarian adenocarcinoma, serous ovarian cystadenocarcinoma, fallopian tube cancer, kidney cancer, renal cell carcinoma, clear cell carcinoma, renal cell adenocarcinoma, papillary renal cell carcinoma, pancreatic cancer, exocrine cancer, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, advanced pancreatic ductal adenocarcinoma, metastatic pancreatic ductal adenocarcinoma, cervical cancer, cervical squamous cell carcinoma, skin cancer, melanoma, oral cancer, oropharyngeal cancer, esophageal cancer The following are selected from esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, uterine cancer, endometrial cancer, endometrial cancer, uterine carcinosarcoma, thyroid cancer, thyroid cancer, thyroid cancer, pheochromocytoma, paraganglioma, bladder cancer, urothelial carcinoma of the bladder, prostate cancer, prostate adenocarcinoma, retinoblastoma, sarcoma, soft tissue sarcoma, peritoneal cancer, thymoma, neuroendocrine tumors, nasopharyngeal neuroendocrine tumors, squamous cell carcinoma of the skin, astrocytoma, low-grade astrocytoma, high-grade astrocytoma, undifferentiated astrocytoma, and glioblastoma multiforme.

[0280] In some embodiments, the cancer is selected from squamous cell carcinoma or squamous cell carcinoma (SCC). SCC may originate from laminar squamous epithelium at any anatomical location. For example, SCC may be non-melanoma skin cancer, head and neck cancer (HNSCC), esophageal cancer (ESCC), or non-small cell lung cancer (sqNSCLC).

[0281] In some embodiments, the cancer is selected from cancers containing cells that express / overexpress HER3, cancers containing cells that express / overexpress EGFR, cancers containing cells that express / overexpress HER3 and EGFR, squamous cell carcinoma, EGFR-amplified squamous cell carcinoma, esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, head and neck squamous cell carcinoma, colorectal cancer, metastatic colorectal cancer, colonic adenocarcinoma, pancreatic cancer, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, lung cancer, and lung squamous cell carcinoma.

[0282] In some embodiments, cancer is a cancer comprising cells expressing / overexpressing EGFR family members, a cancer comprising cells expressing / overexpressing HER3, a cancer comprising cells expressing / overexpressing EGFR, a cancer comprising cells expressing / overexpressing HER3 and EGFR, squamous cell carcinoma, lung cancer, non-small cell lung cancer, squamous cell lung cancer, squamous cell non-small cell lung cancer, advanced squamous cell non-small cell lung cancer, metastatic squamous cell non-small cell lung cancer, pancreatic cancer, exocrine cancer, pancreatic ductal adenocarcinoma, advanced pancreatic ductal adenocarcinoma, metastatic pancreatic ductal adenocarcinoma, a cancer comprising cells having mutations that result in increased expression of ligands for HER3, a cancer comprising cells having mutations that result in increased expression of ligands for EGFR, a cancer comprising cells having an NRG gene fusion, a cancer comprising cells having an NRG1 gene fusion, or a cancer comprising cells having an NRG2 gene fusion.

[0283] Cancer treatments according to the methods of this disclosure achieve one or more of the following treatment effects: reducing the number of cancer cells in a subject; reducing the size of malignant tumors / lesions in a subject; inhibiting (e.g., blocking or delaying) the growth of cancer cells in a subject; inhibiting (e.g., blocking or delaying) the development / progression of cancer (e.g., to late stage or metastasis); reducing the severity of cancer symptoms in a subject; extending the survival of a subject (e.g., progression-free survival or overall survival); reducing the correlation of the number or activity of cancer cells in a subject; and / or reducing the cancer burden in a subject.

[0284] The subjects may be evaluated according to the Response Assessment Criteria (RECIST) for solid tumors, for example, the RECIST 1.1 criteria described in Eisenhauer et al., Eur J Cancer. 2009 Jan;45(2):228-47, which is incorporated herein by reference in its entirety. In some embodiments, the subjects may be evaluated according to the Revised Criteria for Response Assessment: Lugano classification (for example, described in Cheson et al., J Clin Oncol (2014) 32:3059-3068, which is incorporated herein by reference above) to determine the response to treatment.

[0285] In some embodiments, the treatment covered by the method of this disclosure achieves one of the following: overall response, complete response, partial response, or stable disease. Overall response (OR) is either complete response (CR) or partial response (PR).

[0286] Complete response (CR) refers to the complete macroscopic disappearance of all target and / or non-target tumors. CR may include normalization of tumor marker levels. A partial response (PR) refers to a reduction of at least 30% in the total diameter of all target tumors compared to the sum of baseline diameters calculated before treatment.

[0287] A stable disease is defined as a condition where, compared to the tumor burden at the start of treatment, there is neither a partial response nor a progressive disease. Progressive disease (PD) is defined as an increase of at least 20% in the total diameter of target lesions relative to the minimum total value during the study (this minimum value includes the baseline total if the baseline total is the minimum during the study). In addition to a relative increase of 20%, the total must also show an absolute increase of at least 5 mm. Obvious progression of existing non-target lesions or the appearance of one or more new lesions also constitute progressive disease.

[0288] In some embodiments, the treatment covered by the method of this disclosure achieves one of the following (for example, compared to no such treatment or compared to known treatments for the relevant cancer): an extension of overall survival, an extension of progression-free survival, an increase in disease control rates, or an increase in objective response rates.

[0289] Overall survival (OS) refers to the time from randomization to the study arm to death. Progression-free survival (PFS) refers to the time from randomization to the study arm to the first sign of disease progression or death.

[0290] Disease control rate (DCR) refers to the percentage of patients who achieved a complete response, partial response, or stable disease status as a result of treatment intervention. Objective response rate (ORR) refers to the percentage of patients who achieve an overall response.

[0291] Prevention may refer to the prevention of the onset of cancer and / or the progression of cancer, such as to a later stage, or the progression of cancer (e.g., metastasis). In some embodiments, administration of combinations / compositions according to this disclosure may be associated with one or more of the following: inhibition of cancer development / progression, delay / prevention of cancer development, reduction / delay / prevention of tumor growth, reduction / delay / prevention of tissue invasion, reduction / delay / prevention of metastasis, reduction of the severity of one or more symptoms of cancer, reduction of the number of cancer cells, reduction of cancer burden, reduction of tumor size / volume, and / or extension of survival (e.g., progression-free survival or overall survival) of a subject with cancer.

[0292] Depending on various aspects of this disclosure, methods for treating and / or preventing cancer in accordance with this disclosure may include inhibiting tumor growth, reducing tumor size / volume, and / or extending the survival time of a subject having cancer.

[0293] Various aspects of this disclosure provide methods for one or more of the following, or (for example, in the context of cancer, e.g., the treatment / prevention of cancer as described herein) one or more of the following: To kill cells that express HER3 and / or EGFR; To increase ADCC in cells expressing HER3 and / or EGFR; To inhibit tumor growth (for example, of cancers described herein, e.g., cancers expressing HER3 and / or EGFR) and / or reduce tumor size / volume; To extend the survival time of subjects with cancer (for example, cancers described herein, e.g., cancers expressing HER3 and / or EGFR); To inhibit tumor growth (e.g., cancers described herein, e.g., cancers expressing HER3 and / or EGFR) and / or reduce tumor size / volume to a greater extent than the inhibition of tumor growth / reduction of tumor size / volume observed when the drug components of the combination / composition are used individually; To extend the survival time of subjects with cancer (e.g., cancers described herein, e.g., cancers expressing HER3 and / or EGFR) to a greater extent than the survival time extension observed when the drug components of the combination / composition are used individually; Compared to the inhibition of tumor growth / reduction of tumor size / volume observed when the drug components of the combination / composition are used alone, synergistic inhibition of tumor growth and / or synergistic reduction of tumor size / volume (e.g., cancers described herein, e.g., cancers expressing HER3 and / or EGFR); and / or To synergistically extend the survival time of subjects with cancer (e.g., cancers described herein, e.g., cancers expressing HER3 and / or EGFR) compared to the survival time extension observed when the drug components of the combination / composition are used individually.

[0294] Furthermore, the use of agents according to this disclosure in the manufacture of compositions (e.g., pharmaceuticals) for use in such methods is also provided. In some embodiments, it will be understood that the method includes the step of administering an antigen-binding molecule that binds to HER3 and an antigen-binding molecule that binds to EGFR.

[0295] Similarly, one or more of the following may be observed in subjects after a therapeutic or preventive intervention pursuant to this disclosure (e.g., compared to pre-intervention levels / numbers / percentages, etc.): To kill cells that express HER3 and / or EGFR; To increase ADCC in cells expressing HER3 and / or EGFR; To inhibit tumor growth (for example, of cancers described herein, e.g., cancers expressing HER3 and / or EGFR) and / or reduce tumor size / volume; To extend the survival time of subjects with cancer (for example, cancers described herein, e.g., cancers expressing HER3 and / or EGFR); To inhibit tumor growth (e.g., cancers described herein, e.g., cancers expressing HER3 and / or EGFR) and / or reduce tumor size / volume to a greater extent than the inhibition of tumor growth / reduction of tumor size / volume observed when the drug components of the combination / composition are used individually; To extend the survival time of subjects with cancer (e.g., cancers described herein, e.g., cancers expressing HER3 and / or EGFR) to a greater extent than the survival time extension observed when the drug components of the combination / composition are used individually; Compared to the inhibition of tumor growth / reduction of tumor size / volume observed when the drug components of the combination / composition are used alone, synergistic inhibition of tumor growth and / or synergistic reduction of tumor size / volume (e.g., cancers described herein, e.g., cancers expressing HER3 and / or EGFR); and / or To synergistically extend the survival time of subjects with cancer (e.g., cancers described herein, e.g., cancers expressing HER3 and / or EGFR) compared to the survival time extension observed when the drug components of the combination / composition are used individually.

[0296] In some embodiments, a therapeutic / preventive intervention according to this disclosure may be described as “related” to one or more of the effects described in the preceding paragraphs. Those skilled in the art can readily assess such properties using techniques routinely practiced in the art.

[0297] In some embodiments, the therapeutic / preventive interventions according to this disclosure provide improved treatment effects compared to the effects observed when the components of the combination therapy are used as monotherapy. In some embodiments, the therapeutic / preventive interventions provide synergistic (i.e., hyper-enhanced) therapeutic and / or preventive effects compared to the level of associated effects observed when the components of the combination therapy are used individually.

[0298] In some embodiments, therapeutic / preventive interventions with antigen-binding molecules that bind to HER3 and antigen-binding molecules that bind to EGFR according to this disclosure provide improved treatment effects compared to the effects observed when either agent is used as monotherapy. In some embodiments, interventions with antigen-binding molecules that bind to HER3 and antigen-binding molecules that bind to EGFR provide synergistic (i.e., hyper-enhanced) therapeutic and / or preventive effects compared to the level of associated effects observed when either agent is used alone.

[0299] The administration of the agents, drug combinations, and drug compositions of this disclosure is preferably in a “therapeutic effective” or “preventive effective” dose, which is sufficient to demonstrate a therapeutic or preventive benefit to the subject. The actual amount and rate administered, as well as the time course of administration, will depend on the nature and severity of the disease / condition, as well as the specific item being administered. The prescription of the treatment, such as the determination of the dosage, is within the responsibility of the general practitioner and other physicians, typically taking into account the disease / disorder being treated, the condition of the individual subject, the site of delivery, the method of administration, and other factors known to the practitioner. Examples of the techniques and protocols mentioned above can be found in Remington's “The Science and Practice of Pharmacy” (Ed. A. Adejare), 23rd Edition (2020), Academic Press.

[0300] Administration of the articles of this disclosure may be, for example, parenteral, systemic, topical, intracavitary, intravascular, intravenous, intraarterial, intramuscular, intrathecal, intraocular, intraconjunctival, intratumoral, subcutaneous, intradermal, oral, or percutaneous. Administration may also be by injection, infusion, or ingestion.

[0301] In some embodiments and settings, the articles of the Disclosure may be administered to a target tissue / organ affected by a condition (e.g., a tissue / organ affected by a disease / condition) (e.g., a tissue / organ affected by a disease / condition). In some embodiments and settings, the articles of the Disclosure may be administered into the bloodstream by injection or infusion (e.g., via a cannula) (i.e., intravenous / intra-arterial administration), or subcutaneously or orally. In some embodiments and settings, the articles of the Disclosure may be administered to a tumor.

[0302] When two or more drugs (e.g., pharmaceutical compositions according to this disclosure) are administered in combination, the drugs may be administered simultaneously or sequentially. Concurrent administration refers to the combined administration of two or more drugs, for example, administration as a pharmaceutical composition containing both drugs (i.e., as a combination preparation), or administration immediately following each other (e.g., within 1, 4, 6, 8, or 12 hours), via the same route of administration, for example, into the same artery, vein, or other blood vessel.

[0303] Sequential administration refers to the separate administration of one drug followed by another drug after a given time interval. It is not required that the drugs be administered via the same route, although this is the case in some embodiments. The time interval can be any time interval.

[0304] In some embodiments, a therapeutic or prophylactic intervention according to this disclosure includes the steps of (i) administering an antigen-binding molecule that binds to HER3 to a subject having cancer (e.g., cancer as described herein), and (ii) administering an antigen-binding molecule that binds to EGFR to the subject. In some embodiments, (i) and (ii) are performed simultaneously. In some embodiments, (i) and (ii) are performed sequentially (e.g., (i) may be followed by (ii), or (ii) may be followed by (i)).

[0305] Multiple doses of drugs, drug combinations, and drug compositions may be provided. Multiple doses may be separated by predetermined time intervals, which may be selected to be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days, or 1, 2, 3, 4, 5, or 6 months. For illustrative purposes, administration may be given every 7, 14, 21, or 28 days (±3, 2, or 1 day: e.g., 4, 5, 6, 8, 9, or 10 days; 11, 12, 13, 15, 16, or 17 days; 18, 19, 20, 22, 23, or 24 days; or 25, 26, 27, 29, 30, or 31 days). That is, there may be one treatment event every 7 days, every 14 days, every 21 days, or every 28 days. There may be treatment rests between doses / administrations of approximately 7 days (±3, 2, or 1 day), approximately 14 days (±3, 2, or 1 day), approximately 21 days (±3, 2, or 1 day), or approximately 28 days (±3, 2, or 1 day), respectively.

[0306] In some embodiments, a therapeutic or prophylactic intervention according to this disclosure may further include the step of administering another agent for the treatment / prevention of the associated disease / condition. In some embodiments, an antigen-binding molecule that binds to HER3 (e.g., 10D1F) is administered once a week (e.g., every 7 days, ±3, 2, or 1 day). In some embodiments, an antigen-binding molecule that binds to HER3 (e.g., 10D1F) is administered at a dose of 150 to 6000 mg per administration, for example, 600 to 3000 mg per administration, 900 to 3000 mg per administration, 900 to 2400 mg per administration, 1500 to 3000 mg per administration, 1500 to 2400 mg per administration, 1500 to 2100 mg per administration, or one of about 1800 mg per administration. In some embodiments, an antigen-binding molecule that binds to HER3 (e.g., 10D1F) is administered intravenously. In some embodiments, an antigen-binding molecule that binds to HER3 (e.g., 10D1F) is administered substantially as described in Example 2 or Example 4 herein.

[0307] In some embodiments, a taxoid (e.g., docetaxel) is administered every 3 weeks (e.g., every 21 days, ±3, 2, or 1 day). In some embodiments, a taxoid (e.g., docetaxel) is administered at a dose of 10 to 300 mg / m 2 , for example, 20 to 200 mg / m 2 , 25 to 150 mg / m 2 , 30 to 125 mg / m 2 , 50 to 100 mg / m 2 , 60 to 90 mg / m 2 , or one of about 75 mg / m 2 per administration. In some embodiments, a taxoid (e.g., docetaxel) is administered intravenously. In some embodiments, a taxoid (e.g., docetaxel) is administered substantially as described in Example 2 or Example 4 herein.

[0308] In some embodiments, a taxoid (e.g., nab-paclitaxel) is administered on days 1, 8, and 15 (±3, 2, or 1 day) of a 28-day cycle. In some embodiments, a taxoid (e.g., nab-paclitaxel) is administered at a dose of 15 to 420 mg / m 2 , for example, 30 to 300 mg / m2 , 35-210 mg / m² 2 , 40-175 mg / m² 2 70-140 mg / m² 2 , 85-130 mg / m² 2 , or approximately 125 mg / m² 2 It is administered in one of the following doses. In some embodiments, the taxoid (e.g., nab-paclitaxel) is administered intravenously. In some embodiments, the taxoid (e.g., nab-paclitaxel) is administered essentially as described in Example 2 herein.

[0309] In some embodiments, a nucleoside analog (e.g., gemcitabine) is administered on days 1, 8, and 15 (±3, 2, or 1 day), and then every 4 weeks thereafter (e.g., every 28 days, ±3, 2, or 1 day). In some embodiments, the nucleoside analog (e.g., gemcitabine) is administered at a dose of 100-2000 mg / m² per dose. 2 For example, 200-1750 mg / m² per dose. 2 500-1500 mg / m² 2 750-1250 mg / m² 2 900-1100 mg / m² 2 , or approximately 1000 mg / m² 2 It is administered in one of the following doses. In some embodiments, the nucleoside analog (e.g., gemcitabine) is administered intravenously. In some embodiments, the nucleoside analog (e.g., gemcitabine) is administered essentially as described in Example 2 herein.

[0310] In some embodiments, an antigen-binding molecule that binds to EGFR (e.g., cetuximab) is administered once a week (e.g., every 7 days, ±3, 2, or 1 day). In some embodiments, the antigen-binding molecule that binds to EGFR (e.g., cetuximab) is administered at a dose of 50-800 mg / m² per dose. 2 For example, 100-700 mg / m² 2 , 200-600 mg / m² 2 300-500 mg, or approximately 400 mg / m² 2It is administered in one of the following doses. In some embodiments, the antigen-binding molecule that binds to EGFR (e.g., cetuximab) is administered at a dose of 50-500 mg / m² per administration. 2 For example, 75-400 mg / m² 2 , 100-350 mg / m² 2 200-300 mg, or approximately 250 mg / m² 2 It is administered in one of the following doses. In some embodiments, the antigen-binding molecule that binds to EGFR (e.g., cetuximab) is administered intravenously. In some embodiments, the antigen-binding molecule that binds to EGFR (e.g., cetuximab) is administered essentially as described in Example 4 of this specification.

[0311] In embodiments and models of the present disclosure in which docetaxel is administered to a target, the therapeutic / prophylactic intervention may further include the administration of dexamethasone. In some embodiments, 8 mg of dexamethasone is administered orally (i.e., by mouth) twice daily, with or after a meal, on the day before administration of docetaxel, on the day of administration of docetaxel, and on the day after administration of docetaxel.

[0312] In embodiments and models of the present disclosure in which gemcitabine is administered to a subject, the therapeutic / prophylactic intervention may further include the administration of dexamethasone and / or parnosetron. In some embodiments, 8 mg of dexamethasone is administered orally with or after a meal 60 ± 15 minutes prior to the administration of gemcitabine, and 0.25 mg of parnosetron is administered intravenously 30 ± 10 minutes prior to the administration of gemcitabine.

[0313] In embodiments and settings of this disclosure in which nab-paclitaxel is administered to a target, the therapeutic / prophylactic intervention may further include the administration of dexamethasone and / or parnocetron. In some embodiments, 8 mg of dexamethasone is administered orally with or after a meal 60 ± 15 minutes prior to the administration of nab-paclitaxel, and 0.25 mg of parnocetron is administered intravenously 30 ± 10 minutes prior to the administration of nab-paclitaxel.

[0314] In embodiments and models of the present disclosure in which docetaxel is administered to a target, the therapeutic / prophylactic intervention may further include the administration of dexamethasone. In some embodiments, 8 mg of dexamethasone is administered orally (i.e., by mouth) twice daily, with or after a meal, on the day before administration of docetaxel, on the day of administration of docetaxel, and on the day after administration of docetaxel.

[0315] In embodiments and examples of the present disclosure in which cetuximab is administered to a target, the therapeutic / prophylactic intervention may further include the administration of dexamethasone and / or loratadine. In some embodiments, 4 mg of dexamethasone is administered orally with or after a meal, or intravenously, 60 ± 15 minutes prior to the administration of cetuximab, and 10 mg of loratadine is administered orally 60 ± 15 minutes prior to the administration of cetuximab.

[0316] In some embodiments, a therapeutic or prophylactic intervention according to this disclosure may further include the step of administering a chemotherapeutic agent. In some embodiments, a therapeutic or prophylactic intervention according to this disclosure includes the steps of (i) administering an antigen-binding molecule that binds to HER3 to a subject having cancer (e.g., cancer as described herein), (ii) administering an antigen-binding molecule that binds to EGFR to a subject, and (iii) administering a chemotherapeutic agent to a subject. In some embodiments, two or more of (i), (ii), and (iii) are performed simultaneously (e.g., (i), (ii), and (iii) are performed simultaneously, or (i) and (ii) are performed simultaneously, or (iii) is performed sequentially either before or after (i) and (ii)). In some embodiments, at least one of (i), (ii), and (iii) is performed sequentially (e.g., (i), (ii), and (iii) are performed sequentially). For example, (i) may be followed by (ii) followed by (iii); (ii) may be followed by (i) followed by (iii); (iii) may be followed by (i) followed by (ii); or (iii) may be followed by (ii) followed by (i). Preferably, the chemotherapeutic agent is a microtubule targeting agent, such as a taxane. More preferably, the chemotherapeutic agent is a taxane, such as paclitaxel, docetaxel, or cabazitaxel. Most preferably, the chemotherapeutic agent is docetaxel.

[0317] Chemotherapy refers to the treatment of cancer with drugs (chemotherapeutic agents). Chemootherapeutic agents may be chemical entities, such as small molecule drugs, antibiotics, DNA intercalators, protein inhibitors (e.g., kinase inhibitors), or biological agents, such as antibodies, antibody fragments, aptamers, nucleic acids (e.g., DNA, RNA), peptides, polypeptides, or proteins. Chemootherapeutic agents may be formulated as pharmaceutical compositions or pharmaceuticals. A formulation may contain one or more chemotherapeutic agents in combination with one or more pharmaceutically acceptable diluents, excipients, or carriers.

[0318] Chemotherapy agents may be administered via one or more routes of administration, such as parenteral, intravenous injection, oral, subcutaneous, intradermal, intraperitoneal, or intratumor. Chemotherapy may be administered according to a treatment regime. A treatment regime may be a predetermined timetable, plan, scheme, or schedule of chemotherapy administration, which may be created by a physician or healthcare professional and adapted to the patient requiring treatment. A treatment regime may indicate one or more of the following: the type of chemotherapy to be administered to the patient; the dosage of each drug; the interval between administrations; the length of each treatment; and, if any, the number and nature of any treatment holidays. In the case of combination therapy, a single treatment regime may be provided that indicates how each drug is administered.

[0319] The chemotherapy agents include abemaciclib, abiraterone acetate, abitrexate (methotrexate), Abraxane (paclitaxel albumin-stabilized nanoparticle formulation), ABVD, ABVE, ABVE-PC, AC, acalabrutinib, AC-T, Adcetris (brentuximab vedotin), ADE, Ado-trastuzumab emtansine, Adriamycin (doxorubicin hydrochloride), afatinib dimaleate, and Af Nitol (everolimus), Aquinzeo (netupitant and palonosetron hydrochloride), Aldara (imiquimod), Aldesleukin, Alecensa (alecinib), alectinib, alemtuzumab, Alimta (pemetrexed disodium), Alicopa (copanlisib hydrochloride), Alkeran for injection (melphalan hydrochloride), Alkeran tablets (melphalan), Aloxi (palonosetron hydrochloride), Alunbrigg (brigatinib) Ambochlorin (chlorambucil), Ambochlorin (chlorambucil), Amifostin, Aminolevulinic acid, Anastrozole, Aprepitant, Aredia (disodium pamidronate), Arimidex (anastrozole), Aromasin (exemestane), Alanone (nelarabine), Arsenic trioxide, Arzera (ofatumumab), Asparaginase Elwini Acrysanthimy, atezolizumab, Avastin (bevacizumab), avelumab, axicaptagensilolucel, axitinib, azacitidine, Bavencio (avelumab), BEACOPP, Besenam (carmustine), Bereodac (bellinostat), bellinostat, bendamustine hydrochloride, BEP, Besponsa (inotuzumab ozogamicin), bevacizumab, bexarotene, bexal (tositumomab and iodine I 131Tositumomab), bicalutamide, BiCNU (carmustine), bleomycin, blinatumomab, Blincyto (blinatumomab), bortezomib, Bosulif (bosutinib), bosutinib, brentuximab vedotin, brigatinib, BuMel, busulfan, busulfex (busulfan), cabazitaxel, cabometyx (cabozantinib-S-malate), cabozantinib-S-malate, CAF, Calkens (acalabrutinib), Campus (aremtuzumab), Camptosar (irinotecan hydrochloride), capecitabine CAPOX, Carac (fluorouracil - topical), carboplatin, carboplatin-taxol, carfilzomib, carmbris (carmustine), carmustine, carmustine implant, Casodex (bicalutamide), CEM, ceritinib, servidine (daunorubicin hydrochloride), cervarix (recombinant HPV bivalent vaccine), cetuximab, CEV, chlorambucil, chlorambucil-prednisone, CHOP, cisplatin, cladribine, clafen (cyclophosphamide), clofarabine, clofalex (clo) (Farabine), Chloral (clofarabine), CMF, Cobimetinib, Cometric (cabozantinib-S-malate), Copanlisib hydrochloride, COPDAC, COPP, COPP-ABV, Cosmegen (dactinomycin), Cotelic (cobimetinib), Crizotinib, CVP, Cyclophosphamide, Cyfos (ifosfamide), Cyramza (ramucirumab), Cytarabine, Cytarabine liposome, Citosal-U (cytarabine), Cytoxan (cyclophosphamide), Dabrafenib, Dacarbazine, Dacogen (decitabine), Da Cutinomycin, daratumumab, darazalex (daratumumab), dasatinib, daunorubicin hydrochloride, daunorubicin hydrochloride and cytarabine liposomes, decitabine, defibrotide sodium, Defitelio (defibrotide sodium), degarelix, denileukin diffitox, denosumab, DepoCyt (cytarabine liposomes), dexamethasone, dexrazoxane hydrochloride, dinutuximab, docetaxel, doxil (doxorubicin hydrochloride liposomes), doxorubicin hydrochloride, doxorubicin hydrochloride liposomes,Dox-SL (doxorubicin hydrochloride liposome), DTIC-Dome (dacarbazine), durvalumab, Efdex (fluorouracil - topical), Elitec (rasburicase), Elence (epirubicin hydrochloride), elotuzumab, eloxatin (oxaliplatin), eltrombopagolamine, Emend (aprepitant), Empliciti (elotuzumab), enasidenib mesylate, enzalutamide, epirubicin hydrochloride, EPOCH, Erbitux (cetuximab), eribulin mesylate, Erivedge (bismodegib), E Lulotinib hydrochloride, Erwinase (Asparaginase Erwinia chrysanthemum), Etiol (Amifostine), Etopophos (Etoposide phosphate), Etoposide, Etoposide phosphate, Evacet (Doxorubicin hydrochloride liposome), Everolimus, Evista (Raloxifene hydrochloride), Evomela (Melphalan hydrochloride), Exemestane, 5-FU (Fluorouracil injection), 5-FU (Fluorouracil - topical), Fareston (Tremifene), Faridac (Panobinostat), Faslodex (Fulvestrant), FEC, Femara (letrozole), filgrastim, fludarabine phosphate, fludarabine phosphate, fluoroplex (fluorouracil - topical), fluorouracil injection, fluorouracil - topical, flutamide, Forex (methotrexate), Forex PFS (methotrexate), FOLFIRI, FOLFIRI-bevacizumab, FOLFIRI-cetuximab, FOLFIRINOX, FOLFOX, Forotin (pralatrexate), FU-LV, fulvestrant, Gardasil (recombinant HPV tetravalent vaccine), Gar Dasil 9 (recombinant HPV non-valent vaccine), Gazyva (obinutuzumab), gefitinib, gemcitabine hydrochloride, gemcitabine-cisplatin, gemcitabine-oxaliplatin, gemtuzumab ozogamicin, Gemzar (gemcitabine hydrochloride), Giotrif (afatinib dimaleate), Gleevec (imatinib mesylate), Gliadel (carmustine implant), Gliadel wafer (carmustine implant), glucarpidase, goserelin acetate, Halaven (eribulin mesylate), Hemangiol (propranolol hydrochloride),Herceptin (trastuzumab), HPV bivalent vaccine, recombinant, HPV non-valent vaccine, recombinant, HPV tetravalent vaccine, recombinant, Hycamtin (topotecan hydrochloride), Hydrea (hydroxyurea), hydroxyurea, Hyper-CVAD, Ibrance (palbociclib), ibritumomab tiuxetan, ibrutinib, ICE, Iclusig (ponatinib hydrochloride), Idamycin (idarubicin hydrochloride), idarubicin hydrochloride, idelalisib, Idhifa (enasidenib mesylate), If ex (ifosfamide), ifosfamide, ifosfamidedam (ifosfamide), IL-2 (aldesleukin), imatinib mesylate, imbruvica (ibrutinib), imfinzi (durvalumab), imiquimod, imlizic (tarimogenraherparepbec), inlyta (axitinib), inotuzumab ozogamicin, interferon alpha-2b, recombinant, interleukin-2 (aldesleukin), intron A (recombinant interferon alpha-2b), iodine I 131 Tositumomab and tositumomab, ipilimumab, Iressa (gefitinib), irinotecan hydrochloride, irinotecan hydrochloride liposome, Istodax (romidepsin), ixabepyrone, ixazomib citrate, exempra (ixabepyrone), Jakavi (ruxolitinibrate), JEB, Jevtana (cabazitaxel), Kadcyla (Ado-trastuzumab emtansine), keoxifen (raloxifene hydrochloride), kepivans (palifermin), Keytruda (pembrolizumab), Kiscali (ribociclib), Kymriah (tisagenlecleucel), Kyprolis (ca Rufilzomib, lanreotide acetate, lapatinib ditosylate, raltratumob (olaratumab), lenalidomide, lenvatinib mesylate, lenvima (lenvatinib mesylate), letrozole, leucovorin calcium, leukeran (chlorambucil), leuprolide acetate, leustatin (cladribine), levlan (aminolevulinic acid), lymphoridine (chlorambucil), lipodox (doxorubicin hydrochloride liposome), lomustine, lonsurf (trifluridine and tipiracil hydrochloride), leupron (leuprolide acetate), leupron depot (leuprolide acetate),Leupron Depot-Ped (leuprolide acetate), Lynparza (olaparib), Marquivo (vincristine sulfate liposome), Maturan (procarbazine hydrochloride), mechloretamine hydrochloride, megestrol acetate, Mekinist (trametinib), melphalan, melphalan hydrochloride, mercaptopurine, Mesna, Mesnex (mesna), metazolastone (temozolomide), methotrexate, methotrexate LPF (methotrexate), methylnaltrexone bromide, Mexate (methotrexate), Mexate-AQ (methotrexate) Lexart, midostaurin, mitomycin C, mitoxantrone hydrochloride, mitozytrex (mitomycin C), MOPP, mozovir (plelixafor), mustargen (mechloretamine hydrochloride), mutamycin (mitomycin C), mirelan (busulfan), myrosal (azacitidine), mylotarg (gemtuzumab ozogamicin), nanoparticle paclitaxel (paclitaxel albumin-stabilized nanoparticle preparation), navelbine (vinorelbine tartrate), necitumumab, nelarabine, neosal (cyclophosphamide), nerachi Nib maleate, Nerlinx (neratinib maleate), netupitant and palonosetron hydrochloride, Neurasta (pegfilgrastim), Newpogen (filgrastim), Nexavar (sorafenib tosylate), Nilandron (nilutamide), nilotinib, nilutamide, Ninlaro (ixazomib citrate), niraparib tosylate monohydrate, nivolumab, Nolvadex (tamoxifen citrate), N-Plate (romiplostim), obinutuzumab, odomzo (sonidedib), OEPA, ofatumumab, OFF, Ora Parib, olaratumab, omasetaxin mepesuccinate, Oncasper (peguasparagase), ondansetron hydrochloride, Onivid (irinotecan hydrochloride liposome), Ontac (denileukin diffitox), Opdivo (nivolumab), OPPA, osimertinib, oxaliplatin, paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation, PAD, palbociclib, parifermin, palonosetron hydrochloride, palonosetron hydrochloride and netupitant, disodium pamidronate, panitumumab, panobinostat,Paraplatin (carboplatin), Paraplatin (carboplatin), Pazopanib hydrochloride, PCV, PEB, Peguasparagauze, Pegfilgrastim, Peginterferon alpha-2b, PEG-Intron (peginterferon alpha-2b), Pembrolizumab, Pemetrexed disodium, Perjeta (pertuzumab), Pertuzumab, Platinol (cisplatin), Platinol-AQ (cisplatin ), prelixafor, pomalidomide, pomalist (pomalidomide), ponatinib hydrochloride, portraza (necitumumab), pralatrexate, prednisone, procarbazine hydrochloride, proleukin (aldesleukin), prolia (denosumab), promacta (eltrombopagolamine), propranolol hydrochloride, Provenge (ciproisel-T), printol (mercaptopurine), Prixan (mercaptopurine), [No input], Radium-223 dichloride, Raloxifene hydrochloride, Ramucirumab, Rasburicase, R-CHOP, R-CVP, Recombinant human papillomavirus (HPV) bivalent vaccine, Recombinant human papillomavirus (HPV) non-valent vaccine, Recombinant human papillomavirus (HPV) quadrivalent vaccine, Recombinant interferon alpha-2b, Regorafenib, Relistol (methylnaltrexone bromide), R-EPOCH, Revlimid (lenalidomide), Rheumatrex (methotrexate), Ribociclib, R-ICE, Rituxan (rituximab), Ritux Xanhycera (rituximab and human hyaluronidase), rituximab, rituximab and human hyaluronidase, lorapitant hydrochloride, romidepsin, romiplostim, rubidomycin (daunorubicin hydrochloride), rubraca (lucaparibucansylate), lucaparibucansylate, ruxolitinibulinate, ridapt (midostaurine), sclerosol intrapleural aerosol (talc), siltuximab, ciplucel-T, somatuline depot (lanreotide acetate), sonidecib, sorafenib tosylate, sprycel (dasatinib), STANFORD V, Sterile talc powder (talc), Steritalk (talc), Stivarga (regorafenib), sunitinib malate, Sutent (sunitinib malate), Cilatron (pegylated interferon alpha-2b), Silvant (siltuximab), Synribo (omacetaxin mepesuccinate), Tabloid (thioguanine), TAC, Tafinlar (dabrafenib), Tagrisso (osimertinib), talc, tarimodine laherparepbec, tamoxifen citrate, tarabine PFS (cytarabine) Tarceva (erlotinib hydrochloride), Targretin (bexarotene), Tasigna (nilotinib), Taxol (paclitaxel), Taxotere (docetaxel), Tecentriq (atezolizumab), Temodar (temozolomide), temozolomide, temsirolimus, thalidomide, thalomide (thalidomide), thioguanine, thiotepa, tisagenlecroicel, Tolak (fluorouracil - topical), topotecan hydrochloride, toremifene, Tricel (temsirolimus), tositumomab and iodine I131 Tositumomab, Totect (dexrazoxane hydrochloride), TPF, trabectedin, trametinib, trastuzumab, Treanda (bendamustine hydrochloride), trifluridine and tipiracil hydrochloride, Trisenox (arsenic trioxide), Tykerb (lapatinib ditosylate), Unituxin (dinutuximab), uridine triacetate, VAC, barurubicin, Valstar (barurubicin), vandetanib, VAMP, Varubi (lorapitant hydrochloride), Vectibix (panitumumab), VeIP, Vervan (vinblastine Sulfate), Velcade (bortezomib), Versal (vinblastine sulfate), vemurafenib, Benclexta (venetoclax), venetoclax, Verzenio (abemaciclib), Viadur (leuprolide acetate), Vidaza (azacitidine), vinblastine sulfate, Vincasar PFS (vincristine sulfate), vincristine sulfate, vincristine sulfate liposome, vinorelbine tartarate, VIP, bismodegib, Vistagard (uridine triacetate), Boraxazepam ( Voraxaze (glucarpidase), vorinostat, Botrient (pazopanib hydrochloride), Bixeos (daunorubicin hydrochloride and cytarabine liposome), Welcovorin (leucovorin calcium), Xalkori (crizotinib), Xeloda (capecitabine), Xeliri, Xelox, Xgeva (denosumab), Xofigo (radium-223 dichloride), Xtandi (enzalutamide), Yervoy (ipilimumab), Yescarta (axicabutagensilolucel), Yondelis (trabectedin), Zaltrap ( The following can be selected: Ziv-Aflibercept, Zalxio (filgrastim), Zejura (niraparib tosylate monohydrate), Zelboraf (vemurafenib), Zevalin (ibritumomab tiuxetan), Ginecard (dexrazoxane hydrochloride), Ziv-Aflibercept, Zofran (ondansetron hydrochloride), Zoladex (goserelin acetate), zoledronic acid, Zolinza (vorinostat), Zometa (zoledronic acid), Zyderig (idelalisib), Zykadia (ceritinib), and Zytiga (abiraterone acetate).

[0320] Specific intended therapeutic / preventive interventions This disclosure provides a method for treating or prophylactic a cancer comprising cells having an NRG1 gene fusion in a subject, comprising the step of administering an antigen-binding molecule (e.g., 10D1F) and a nucleoside analog (e.g., gemcitabine) that binds to HER3 to the subject. For example, this disclosure provides a method for treating or prophylactic a cancer comprising cells having an NRG1 gene fusion in a subject, comprising the step of administering 10D1F and gemcitabine to the subject. This disclosure also provides the use of the components used in the methods described in the preceding two sentences for use in treating or prophylacticing the relevant cancer, and the use of the components used in the methods described in the preceding two sentences in the manufacture of a medicament for use in treating or prophylacticing the relevant cancer.

[0321] In some embodiments, therapeutic / preventive interventions following the previous paragraph include: Administer 10D1F once a week (for example, at a dose of 1500-2500 mg per dose, e.g., approximately 1800 mg) (e.g., intravenously); and Days 1, 8, and 15, and then every 4 weeks thereafter (for example, 750-1500 mg / m² per dose) 2 For example, approximately 1000 mg / m² 2 Administration of gemcitabine (in a dose of ) (e.g., intravenously).

[0322] This disclosure provides a method for treating or prophylactic a cancer comprising cells having an NRG1 gene fusion in a subject, comprising the step of administering an antigen-binding molecule that binds to HER3 (e.g., 10D1F), a nucleoside analog (e.g., gemcitabine), and a taxoid (e.g., nab-paclitaxel) to the subject. For example, this disclosure provides a method for treating or prophylactic a cancer comprising cells having an NRG1 gene fusion in a subject, comprising the step of administering 10D1F, gemcitabine, and nab-paclitaxel to the subject. This disclosure also provides the use of the components used in the methods described in the preceding two sentences for use in treating or prophylacticing the relevant cancer, and the use of the components used in the methods described in the preceding two sentences in the manufacture of a medicament for use in treating or prophylacticing the relevant cancer.

[0323] In some embodiments, therapeutic / preventive interventions following the previous paragraph are essentially carried out as described in Arm A of Example 2. In some embodiments, therapeutic / preventive interventions following the previous paragraph include: Administer 10D1F once a week (for example, at a dose of 1500-2500 mg per dose, e.g., approximately 1800 mg) (e.g., intravenously); Days 1, 8, and 15, and then every 4 weeks thereafter (for example, 750-1500 mg / m² per dose) 2 For example, approximately 1000 mg / m² 2 Administration of gemcitabine (in a dose of ) (e.g., intravenously); and Days 1, 8, and 15, and then every 4 weeks thereafter (for example, 100-150 mg / m² per dose). 2 For example, approximately 125 mg / m² 2 Administration of nab-paclitaxel (in a dose of ) (e.g., intravenously).

[0324] This disclosure provides a method for treating or preventing cancer involving cells having an NRG1 gene fusion in a subject, comprising the step of administering an antigen-binding molecule (e.g., 10D1F) and a taxoid (e.g., docetaxel) that binds to HER3 to the subject. For example, this disclosure provides a method for treating or preventing cancer involving cells having an NRG1 gene fusion in a subject, comprising the step of administering 10D1F and docetaxel to the subject. This disclosure also provides the components used in the methods described in the preceding two sentences for use in treating or preventing the related cancer, and the use of the components used in the methods described in the preceding two sentences in the manufacture of a medicament for use in treating or preventing the related cancer.

[0325] In some embodiments, therapeutic / preventive interventions following the previous paragraph are essentially carried out as described in Arm B of Example 2. In some embodiments, therapeutic / preventive interventions following the previous paragraph include: Administer 10D1F once a week (for example, at a dose of 1500-2500 mg per dose, e.g., approximately 1800 mg) (e.g., intravenously); and Every 3 weeks (for example, 25-150 mg / m² per dose) 2 For example, approximately 75 mg / m² 2 Administration of docetaxel (in a dose of ) (e.g., intravenously).

[0326] This disclosure provides a method for treating or prophylactically treating pancreatic cancer (e.g., ductal adenocarcinoma containing cells having an NRG1 gene fusion) in a subject, comprising the step of administering an antigen-binding molecule (e.g., 10D1F) and a nucleoside analog (e.g., gemcitabine) that binds to HER3 in a subject. For example, this disclosure provides a method for treating or prophylactically treating pancreatic ductal adenocarcinoma containing cells having an NRG1 gene fusion in a subject, comprising the step of administering 10D1F and gemcitabine in a subject. This disclosure also provides the use of the components used in the methods described in the preceding two sentences for use in treating or prophylactically treating the related cancers, and the use of the components used in the methods described in the preceding two sentences in the manufacture of a medicament for use in treating or prophylactically treating the related cancers.

[0327] In some embodiments, therapeutic / preventive interventions following the previous paragraph include: Administer 10D1F once a week (for example, at a dose of 1500-2500 mg per dose, e.g., approximately 1800 mg) (e.g., intravenously); and Days 1, 8, and 15, and then every 4 weeks thereafter (for example, 750-1500 mg / m² per dose) 2 For example, approximately 1000 mg / m² 2 Administration of gemcitabine (in a dose of ) (e.g., intravenously).

[0328] This disclosure provides a method for treating or prophylactically treating pancreatic cancer (e.g., ductal adenocarcinoma containing NRG1 gene fusion cells) in a subject, comprising the step of administering an antigen-binding molecule (e.g., 10D1F), a nucleoside analog (e.g., gemcitabine), and a taxoid (e.g., nab-paclitaxel) that binds to HER3 in a subject. For example, this disclosure provides a method for treating or prophylactically treating pancreatic ductal adenocarcinoma containing NRG1 gene fusion cells in a subject, comprising the step of administering 10D1F, gemcitabine, and nab-paclitaxel to a subject. This disclosure also provides the use of the components used in the methods described in the preceding two sentences for use in treating or prophylactically treating the related cancers, and the use of the components used in the methods described in the preceding two sentences in the manufacture of a medicament for use in treating or prophylactically treating the related cancers.

[0329] In some embodiments, therapeutic / preventive interventions following the previous paragraph are essentially carried out as described in Arm A of Example 2. In some embodiments, therapeutic / preventive interventions following the previous paragraph include: Administer 10D1F once a week (for example, at a dose of 1500-2500 mg per dose, e.g., approximately 1800 mg) (e.g., intravenously); Days 1, 8, and 15, and then every 4 weeks thereafter (for example, 750-1500 mg / m² per dose) 2 For example, approximately 1000 mg / m² 2 Administration of gemcitabine (in a dose of ) (e.g., intravenously); and Days 1, 8, and 15, and then every 4 weeks thereafter (for example, 100-150 mg / m² per dose). 2 For example, approximately 125 mg / m² 2 Administration of nab-paclitaxel (in a dose of ) (e.g., intravenously).

[0330] This disclosure provides a method for treating or prophylactic squamous cell lung cancer (e.g., squamous cell non-small cell lung cancer containing cells having an NRG1 gene fusion) in a subject, comprising the step of administering an antigen-binding molecule (e.g., 10D1F) and a taxoid (e.g., docetaxel) that binds to HER3 in a subject. For example, this disclosure provides a method for treating or prophylactic squamous cell non-small cell lung cancer containing cells having an NRG1 gene fusion in a subject, comprising the step of administering 10D1F and docetaxel in a subject. This disclosure also provides the components used in the methods described in the preceding two sentences for use in treating or prophylacticizing the related cancers, and the use of the components used in the methods described in the preceding two sentences in the manufacture of a medicament for use in treating or prophylacticizing the related cancers.

[0331] In some embodiments, therapeutic / preventive interventions following the previous paragraph are essentially carried out as described in Arm B of Example 2. In some embodiments, therapeutic / preventive interventions following the previous paragraph include: Administer 10D1F once a week (for example, at a dose of 1500-2500 mg per dose, e.g., approximately 1800 mg) (e.g., intravenously); and Every 3 weeks (for example, 25-150 mg / m² per dose) 2 For example, approximately 75 mg / m² 2 Administration of docetaxel (in a dose of ) (e.g., intravenously).

[0332] This disclosure provides a method for treating or prophylactically treating squamous cell lung cancer in a subject, comprising the step of administering an antigen-binding molecule (e.g., 10D1F) and a taxoid (e.g., docetaxel) that binds to HER3 to the subject. For example, this disclosure provides a method for treating or prophylactically treating squamous cell non-small cell lung cancer, comprising the step of administering 10D1F and docetaxel to a subject. This disclosure also provides the use of the components used in the methods described in the preceding two sentences for use in treating or prophylactically treating the related cancers, and the use of the components used in the methods described in the preceding two sentences in the manufacture of a medicament for use in treating or prophylactically treating the related cancers.

[0333] In some embodiments, therapeutic / preventive interventions following the previous paragraph are essentially carried out as described in Arm A of Example 4. In some embodiments, therapeutic / preventive interventions following the previous paragraph include: Administer 10D1F once a week (for example, at a dose of 1500-2500 mg per dose, e.g., approximately 1800 mg) (e.g., intravenously); and Every 3 weeks (for example, 25-150 mg / m² per dose) 2 For example, approximately 75 mg / m² 2 Administration of docetaxel (in a dose of ) (e.g., intravenously).

[0334] This disclosure provides a method for treating or prophylactically treating squamous cell lung cancer in a subject, comprising the step of administering an antigen-binding molecule that binds to HER3 (e.g., 10D1F), a taxoid (e.g., docetaxel), and an antigen-binding molecule that binds to EGFR (e.g., cetuximab) to the subject. For example, this disclosure provides a method for treating or prophylactically treating squamous cell non-small cell lung cancer, comprising the step of administering 10D1F, docetaxel, and cetuximab to the subject. This disclosure also provides the use of the components used in the methods described in the preceding two sentences for use in treating or prophylactically treating the related cancers, and the use of the components used in the methods described in the preceding two sentences in the manufacture of a medicament for use in treating or prophylactically treating the related cancers.

[0335] In some embodiments, therapeutic / preventive interventions following the previous paragraph are essentially carried out as described in Arm B of Example 4. In some embodiments, therapeutic / preventive interventions following the previous paragraph include: Administer 10D1F once a week (for example, at a dose of 1500-2500 mg per dose, e.g., approximately 1800 mg) (e.g., intravenously); Every 3 weeks (for example, 25-150 mg / m² per dose) 2 For example, approximately 75 mg / m² 2 Administration of docetaxel (in a dose of ) (e.g., intravenously); and For example, 200-600 mg / m² 2 (For example, approximately 400 mg / m²) 2 The initial dose of cetuximab is administered (e.g., intravenously), followed by 125-375 mg / m² per dose thereafter. 2 (For example, approximately 250 mg / m²) 2 ) administered once a week at this dose.

[0336] subject Subjects according to the embodiments described herein may be any animal or human. Subjects may preferably be mammals, more preferably humans. Subjects may be non-human mammals, but more preferably humans. Subjects may be male or female. Subjects may be patients. Subjects may have been diagnosed with a disease or condition requiring treatment (e.g., cancer, e.g., cancer as described herein), may be suspected of having such a disease / condition, or may be at risk of developing such a disease / condition.

[0337] In some embodiments, the subjects treated according to the therapeutic or prophylactic methods of the Disclosure herein are subjects who have cancer, for example, cancer as described herein, or who are at risk of developing it. In embodiments relating to the Disclosure, subjects may be selected for treatment according to the methods based on characterization of certain markers for such disease / condition.

[0338] In some embodiments, subjects may be selected for treatments described herein based on the detection of cancers described herein, such as cancers expressing / overexpressing HER3 and / or EGFR, in a sample obtained from the subject (e.g., a biopsy of a tumor).

[0339] In some embodiments, the subjects treated according to this disclosure have been previously treated with an inhibitor of the PD-L1 / PD-1 signaling axis. In some embodiments, the subjects have been previously treated with an antagonist of PD-L1 / PD-1 mediated signaling. In some embodiments, the subjects have been previously treated with an anti-PD-1 antibody antagonist of PD-L1 / PD-1 mediated signaling. In some embodiments, the subjects have been previously treated with an anti-PD-L1 antibody antagonist of PD-L1 / PD-1 mediated signaling.

[0340] In some embodiments, subjects treated in accordance with this disclosure have not previously received more than two lines of systemic anticancer therapy for a progressive disease. In some embodiments, the subjects have not been previously treated with a HER3 targeting agent. In some embodiments, the subjects treated in accordance with this disclosure have not been previously treated with an anti-HER3 antibody. In some embodiments, the subjects have not been previously treated with HMBD-001 (i.e., 10D1F). In some embodiments, the subjects have not been previously treated with pertuzumab.

[0341] In some embodiments, the subjects treated in accordance with this disclosure have not been previously treated with a tyrosine kinase inhibitor that substantially inhibits HER3 tyrosine kinase activity. In some embodiments, the subjects have not been previously treated with a tyrosine kinase inhibitor. In some embodiments, the subjects have not been previously treated with a pan-HER tyrosine kinase inhibitor.

[0342] In some embodiments, subjects treated according to this disclosure have not been previously treated with agents targeting EGFR activating mutations. In some embodiments, subjects have not been previously treated with agents targeting ALK fusion mutations. In some embodiments, subjects have not been previously treated with agents targeting ROS rearrangement mutations. In some embodiments, subjects have not been previously treated with agents targeting RET fusion mutations or other RET mutations. In some embodiments, subjects have not been previously treated with agents targeting BRAF mutations that confer resistance to treatment with BRAF inhibitors (e.g., V600E or V600K). In some embodiments, subjects have not been previously treated with agents targeting the BRAF mutation V600E. In some embodiments, subjects have not been previously treated with agents targeting MET exon 14 skipping mutations. In some embodiments, subjects have not been previously treated with agents targeting MET exon 14 skipping mutations. In some embodiments, subjects have not been previously treated with agents targeting KRAS activating mutations (e.g., G12A, G12D, G12R, G12C, G12S, or G12V). In some embodiments, subjects have not been previously treated with agents targeting the KRAS mutation G12C.

[0343] In some embodiments, the subject treated in accordance with this disclosure has not undergone prior treatment with a nucleoside analog. In some embodiments, the subject has not undergone prior treatment with gemcitabine or a salt thereof (e.g., gemcitabine hydrochloride).

[0344] In some embodiments, the subjects treated in accordance with this disclosure have not been previously treated with a taxoid. In some embodiments, the subjects have not been previously treated with nab-paclitaxel. In some embodiments, the subjects have not been previously treated with docetaxel.

[0345] In some embodiments, the subjects treated in accordance with this disclosure have a disease measurable according to the RECIST 1.1 criteria described by Eisenhauer et al., Eur J Cancer. 2009 Jan;45(2):228~47.

[0346] In some embodiments, subjects treated in accordance with this disclosure have an Eastern Cooperative Oncology Group (ECOG) performance status ranging from 0 (i.e., fully active and able to continue all pre-disease performance without limitation) to 1 (i.e., physically strenuous activity is limited, but they are able to walk and perform light or sedentary work, e.g., light housework, office work). The ECOG performance status scale is described, for example, Oken et al. Am J Clin Oncol. (1982) 5(6):649-655, which is incorporated herein by reference in its entirety.

[0347] In some embodiments, the subjects addressed in accordance with this disclosure are: (A) (i) Having advanced or metastatic cancer containing an NRG1 gene fusion (e.g., determined by molecular assay, the fusion transcript is precisely oriented and contains an EGF-like domain capable of binding to HER3); (ii) Not having received prior treatment with HMBD-001 (i.e., 10D1F), pertuzumab which is an investigational agent that specifically targets HER3, or a pan-HER tyrosine kinase inhibitor; and / or (iii) Has an ECOG performance status of 0 to 1. (B) (i) Having advanced or metastatic pancreatic ductal adenocarcinoma containing an NRG1 gene fusion (e.g., determined by molecular assay, the fusion transcript is precisely oriented and contains an EGF-like domain capable of binding to HER3); (ii) Not having received prior treatment with HMBD-001 (i.e., 10D1F), pertuzumab, an investigational agent that specifically targets HER3, or a pan-HER tyrosine kinase inhibitor; (iii) Not having received prior treatment with gemcitabine with or without nab-paclitaxel for a progressive disease; (iv) Not having previously received more than two lines of systemic anticancer therapy for an advanced disease; and / or (v) Has an ECOG performance status of 0 to 1. (C) (i) Having advanced or metastatic non-small cell lung cancer containing an NRG1 gene fusion (e.g., determined by molecular assay, the fusion transcript is precisely oriented and contains an EGF-like domain capable of binding to HER3); (ii) Not having received prior treatment with HMBD-001 (i.e., 10D1F), pertuzumab, an investigational agent that specifically targets HER3, or a pan-HER tyrosine kinase inhibitor; (iii) Not having received prior treatment with docetaxel for a progressive disease; (iv) Not having previously received more than two lines of systemic anticancer therapy for an advanced disease; and / or (v) Has an ECOG performance status of 0 to 1.

[0348] In some embodiments, the subject following one of (A) to (C) above is further: (i) The patient has cancer that is resistant or refractory to standard systemic therapy, or there is no standard systemic therapy or a reasonable therapy that, in the physician's judgment, could provide a clinical benefit, or the patient has been shown to be intolerant to such therapy, or the patient has refused such therapy; (ii) Having a disease measurable by RECIST v1.1; (iii) Having sufficient tumor material available for shipment to the central laboratory at the time of registration (i.e., one archived tumor FFPE block or at least 15 consecutive unstained tumor slides), or alternatively, a fresh tumor sample; (iv) Being 18 years of age or older; (v) Having standard contraceptive requirements; (vi) Having adequate baseline organ function demonstrated by the following: Serum creatinine ≤ 2 × institutional ULN Serum albumin ≥ 2.5 g / dl Bilirubin ≤ 2.0 × Facility ULN AST and ALT ≤ 2.5 × institutional ULN. If a subject has liver metastases, registered subjects with hepatitis metastases may have ALT and AST < 5 × institutional ULN; (vii) If the subject is not taking warfarin or other oral anticoagulants, the subject has an international normalized ratio (INR) ≤ 1.5 or prothrombin time (PT) ≤ 1.5 × ULN; and partial thromboplastin time or activated partial thromboplastin time (PTT or aPTT) ≤ 1.5 × ULN.

[0349] (viii) If the patient is taking warfarin, this is a stable dose that results in a stable INR < 3.5. (ix) If the patient is receiving other oral anticoagulant therapy, PT or aPTT is within the intended therapeutic range of the anticoagulant; (x) Appropriate baseline blood function demonstrated by the following: ANC ≥ 1.5 × 10⁹ / L.

[0350] Hemoglobin ≥ 8 g / dL, and no red blood cell (RBC) transfusions in the past 14 days. Platelet count ≥ 100 × 10⁹ / L, and no platelet transfusions in the past 14 days; (xi) Willingness to comply with protocol requirements, including follow-up for survival assessment; (x) No persistent clinically significant toxicity (grade ≥ 2) from previous anticancer therapy (excluding acceptable grade 2 chemotherapy-related neuropathy and alopecia), and no prior toxicity resulting in laboratory abnormalities that have not recovered to grade ≤ 1, unless higher grade abnormalities are acceptable inclusion criteria. If drug therapy is required to treat laboratory abnormalities, the dose and laboratory values ​​should be stable; (xi) If the patient has pancreatic ductal adenocarcinoma, they have not received more than two previous regimens for advanced / metastatic disease, excluding neoadjuvant treatment / adjuvant treatment, unless PDAC has recurred within six months of such treatment; (xii) Not having received prior treatment with chemotherapy, external beam radiation, or other systemic anticancer therapy within 14 days prior to the commencement of treatment in accordance with this disclosure (or 42 days prior to nitrosourea or mitomycin-C); (xiii) Not having received prior cytotoxic chemotherapy, monoclonal antibody therapy, small molecule tyrosine kinase inhibitor therapy, and / or investigational systemic anticancer therapy within 28 days or 5 half-lives (whichever is shorter) prior to the commencement of treatment in accordance with this disclosure; (xiv) Not having received wide-area radiotherapy within 28 days of treatment with HMBD-001 (i.e., 10D1F); excluding palliative treatment for bone metastases or similar narrow-area radiotherapy.

[0351] (xv) No further active malignancies that could interfere with the evaluation of the study endpoint (subjects with the following co-occurring neoplasm diagnoses are excluded: non-melanoma skin cancer, carcinoma in situ (including transitional cell carcinoma, cervical intraepithelial neoplasm, and melanoma in situ), and organ-limited prostate cancer with no evidence of progressive disease); (xvi) No clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association Class 3 or 4 heart failure, uncontrolled angina, a history of myocardial infarction, unstable angina or stroke within 6 months prior to study enrollment, uncontrolled hypertension, or clinically significant arrhythmias that are not controlled by medication); (xvii) Not having uncontrolled clinically significant medical problems such as lung disease (e.g., chronic obstructive pulmonary disease, pulmonary hypertension), or uncontrolled comorbidities including, but not limited to, uncontrolled infections, disseminated intravascular coagulation, or psychotic / social conditions requiring systemic therapy; (xix) Not having known active or suspected brain or leptomeningeal metastases (subjects with stable treated brain metastases are not excluded unless there is evidence of CNS disease progression on imaging at least 4 weeks after radiotherapy or other localized regional resection therapy for CNS); (xx) Within 14 days prior to the commencement of treatment in accordance with this disclosure, the person has not had a condition requiring systemic treatment with any corticosteroid (more than 10 mg of prednisone per day) or other immunosuppressant (inhalation or topical steroids are acceptable if there is no active autoimmune disease); (xxi) Does not have a QTc interval greater than 450ms (male) or 470ms (female); (xxii) Not pregnant or breastfeeding; (xxii) Not positive for human immunodeficiency virus; (xxiv) Not having active or chronic hepatitis B or C; and / or (xxv) The subject does not have a medical condition that would expose them to an unacceptably high risk of toxicity.

[0352] In some embodiments, the subject matter covered by this disclosure conforms to the inclusion and exclusion criteria of Arm A of the Study of Example 2 as specified herein. In some embodiments, the subject matter covered by this disclosure conforms to the inclusion and exclusion criteria of Arm B of the Study of Example 2 as specified herein. In some embodiments, the subject matter covered by this disclosure conforms to the inclusion and exclusion criteria of Arm C of the Study of Example 2 as specified herein.

[0353] In some embodiments, the subjects addressed in accordance with this disclosure are: (D) (i) Having advanced squamous non-small cell lung cancer (e.g., metastatic squamous non-small cell lung cancer or locally advanced and unresectable squamous non-small cell lung cancer); for example, determined by histological or cytological analysis; (ii) Having advanced squamous non-small cell lung cancer including homozygous wild-type genotypes for KRAS, PIK3CA, BRAF, PTEN, and MET; (iii) Having advanced squamous cell non-small cell lung cancer that has relapsed or refractory to platinum-based therapy (e.g., cisplatin, carboplatin, oxaliplatin, nedaplatin, or lovaplatin) for non-small cell lung cancer (i.e., has grown / progressed during treatment); (iv) Previous treatment with an anti-PD-1 or anti-PD-L1 antibody antagonist of PD-L1 / PD-1 mediated signaling: (v) Not having previously received more than two lines of systemic chemotherapy for a progressive disease; (vi) No prior treatment with anti-HER3 antibodies or tyrosine kinase inhibitors that significantly inhibit HER3 tyrosine kinase activity; (vii) Not having received prior treatment with any of the following: drugs targeting EGFR activating mutations, drugs targeting ALK fusion mutations, drugs targeting ROS rearrangement mutations, drugs targeting RET fusion mutations or other RET mutations, drugs targeting BRAF V600E mutations, drugs targeting MET exon 14 skipping mutations, or drugs targeting KRAS G12C mutations; (viii) Having a disease measurable by RECIST v1.1; and / or (ix) Has an ECOG performance status of 0 to 1.

[0354] In some embodiments, the subject following one of the above (D) is further: (i) The patient has cancer that is resistant or refractory to standard systemic therapy, or there is no standard systemic therapy or a reasonable therapy that, in the physician's judgment, could provide a clinical benefit, or the patient has been shown to be intolerant to such therapy, or the patient has refused such therapy; (ii) Having a disease measurable by RECIST v1.1; (iii) Having sufficient tumor material available for shipment to the central laboratory at the time of registration (i.e., one archived tumor FFPE block or at least 15 consecutive unstained tumor slides), or alternatively, a fresh tumor sample; (iv) Being 18 years of age or older; (v) Having standard contraceptive requirements; (vi) Having adequate baseline organ function demonstrated by the following: Serum creatinine ≤ 2 × institutional ULN Serum albumin ≥ 2.5 g / dl Bilirubin ≤ 2.0 × Facility ULN AST and ALT ≤ 2.5 × institutional ULN. If a subject has liver metastases, registered subjects with hepatitis metastases may have ALT and AST < 5 × institutional ULN; (vii) If the subject is not taking warfarin or other oral anticoagulants, the subject has an international normalized ratio (INR) ≤ 1.5 or prothrombin time (PT) ≤ 1.5 × ULN; and partial thromboplastin time or activated partial thromboplastin time (PTT or aPTT) ≤ 1.5 × ULN.

[0355] (viii) If the patient is taking warfarin, this is a stable dose that results in a stable INR < 3.5. (ix) If the patient is receiving other oral anticoagulant therapy, PT or aPTT is within the intended therapeutic range of the anticoagulant; (x) Appropriate baseline blood function demonstrated by the following: ANC ≥ 1.5 × 10⁹ / L.

[0356] Hemoglobin ≥ 8 g / dL, and no red blood cell (RBC) transfusions in the past 14 days. Platelet count ≥ 100 × 10⁹ / L, and no platelet transfusions in the past 14 days; (xi) Willingness to comply with protocol requirements, including follow-up for survival assessment; (x) No persistent clinically significant toxicity (grade ≥ 2) from previous anticancer therapy (excluding acceptable grade 2 chemotherapy-related neuropathy and alopecia), and no prior toxicity resulting in laboratory abnormalities that have not recovered to grade ≤ 1, unless higher grade abnormalities are acceptable inclusion criteria. If drug therapy is required to treat laboratory abnormalities, the dose and laboratory values ​​should be stable; (xi) If the patient has pancreatic ductal adenocarcinoma, they have not received more than two previous regimens for advanced / metastatic disease, excluding neoadjuvant treatment / adjuvant treatment, unless PDAC has recurred within six months of such treatment; (xii) Not having received prior treatment with chemotherapy, external beam radiation, or other systemic anticancer therapy within 14 days prior to the commencement of treatment in accordance with this disclosure (or 42 days prior to nitrosourea or mitomycin-C); (xiii) Not having received prior cytotoxic chemotherapy, monoclonal antibody therapy, small molecule tyrosine kinase inhibitor therapy, and / or investigational systemic anticancer therapy within 28 days or 5 half-lives (whichever is shorter) prior to the commencement of treatment in accordance with this disclosure; (xiv) Not having received wide-area radiotherapy within 28 days of treatment with HMBD-001 (i.e., 10D1F); excluding palliative treatment for bone metastases or similar narrow-area radiotherapy.

[0357] (xv) No further active malignancies that could interfere with the evaluation of the study endpoint (subjects with the following co-occurring neoplasm diagnoses are excluded: non-melanoma skin cancer, carcinoma in situ (including transitional cell carcinoma, cervical intraepithelial neoplasm, and melanoma in situ), and organ-limited prostate cancer with no evidence of progressive disease); (xvi) No clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association Class 3 or 4 heart failure, uncontrolled angina, a history of myocardial infarction, unstable angina or stroke within 6 months prior to study enrollment, uncontrolled hypertension, or clinically significant arrhythmias that are not controlled by medication); (xvii) Not having uncontrolled clinically significant medical problems such as lung disease (e.g., chronic obstructive pulmonary disease, pulmonary hypertension), or uncontrolled comorbidities including, but not limited to, uncontrolled infections, disseminated intravascular coagulation, or psychotic / social conditions requiring systemic therapy; (xix) Not having known active or suspected brain or leptomeningeal metastases (subjects with stable treated brain metastases are not excluded unless there is evidence of CNS disease progression on imaging at least 4 weeks after radiotherapy or other localized regional resection therapy for CNS); (xx) Within 14 days prior to the commencement of treatment in accordance with this disclosure, the person has not had a condition requiring systemic treatment with any corticosteroid (more than 10 mg of prednisone per day) or other immunosuppressant (inhalation or topical steroids are acceptable if there is no active autoimmune disease); (xxi) Does not have a QTc interval greater than 450ms (male) or 470ms (female); (xxii) Not pregnant or breastfeeding; (xxii) Not positive for human immunodeficiency virus; (xxiv) Not having active or chronic hepatitis B or C; and / or (xxv) The subject does not have a medical condition that would expose them to an unacceptably high risk of toxicity.

[0358] In some embodiments, the subject matter covered by this disclosure is subject to the inclusion and exclusion criteria of Arm A of the study in Example 4 herein. In some embodiments, the subject matter covered by this disclosure is subject to the inclusion and exclusion criteria of Arm B of the study in Example 4 herein.

[0359] kit This disclosure also provides component kits. Kits relating to this disclosure may include components for carrying out all or part of the methods described herein.

[0360] The kit may have at least one container containing a predetermined amount of the combination or composition described herein. In some embodiments of this disclosure, a kit of components is provided. In some embodiments, the kit may include an antigen-binding molecule that binds to HER3 as described herein, and a taxoid as described herein. In some embodiments, the kit may include an antigen-binding molecule that binds to HER3 as described herein, and a nucleoside analog as described herein. In some embodiments, the kit may include an antigen-binding molecule that binds to HER3 as described herein, a nucleoside analog as described herein, and a taxoid as described herein. In some embodiments, the kit may include an antigen-binding molecule that binds to HER3 as described herein, and an antigen-binding molecule that binds to EGFR as described herein. In some embodiments, the kit may include an antigen-binding molecule that binds to HER3 as described herein, an antigen-binding molecule that binds to EGFR as described herein, and a taxoid as described herein. Various agents may be provided in predetermined amounts, in separate containers, or in the same container.

[0361] In some embodiments, the kit includes a pharmaceutical combination or pharmaceutical composition in accordance with this disclosure. The kit may be provided with instructions for use for administering to a patient a component of a pharmaceutical combination, a pharmaceutical combination, or a pharmaceutical composition according to this disclosure to treat a specific disease / condition (e.g., a disease / condition described herein, e.g., cancer described herein).

[0362] The kit may further include reagents, buffers, and / or standards required for carrying out the methods according to this disclosure. The kit according to this disclosure may include, for example, instructions for use in the form of a user manual or leaflet. The instructions for use may include protocols for carrying out one or more of the methods described herein.

[0363] Sequence identity As used herein, “sequence identity” means the percentage of nucleotide / amino acid residues in a target sequence that are identical to nucleotide / amino acid residues in a reference sequence after aligning the sequences to achieve the highest possible sequence identity percentage and introducing gaps where necessary. Paired sequence alignments, aimed at determining the sequence identity percentage between two or more amino acid sequences or nucleic acid sequences, can be achieved by various means known to those skilled in the art using commercially available computer software such as ClustalOmega (Soding, J.2005, Bioinformatics 21, 951-960), T-coffee (Notredame et al., 2000, J.Mol.Biol.(2000), 302, 205-217), Kalign (Lassmann and Sonnhammer 2005, BMC Bioinformatics, 6(298)), and MAFFT (Katoh and Standley 2013, Molecular Biology and Evolution, 30(4), 772-780). When using such software, it is preferable to use default parameters, for example, for gap penalties and extension penalties.

[0364] array

[0365] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] Numbered descriptions The following numbered paragraphs (items) describe specific aspects and embodiments of the present invention: 1. An antigen-binding molecule that binds to HER3 for use in a method of treating or preventing cancer, wherein the method comprises the step of administering an antigen-binding molecule that binds to EGFR, and the antigen-binding molecule that binds to HER3 binds to the region of HER3 shown in SEQ ID NO: 77.

[0366] 2. Use of an antigen-binding molecule that binds to HER3 in the manufacture of a medicament for use in a method of treating or preventing cancer, wherein the method comprises the step of administering an antigen-binding molecule that binds to EGFR; the antigen-binding molecule that binds to HER3 binds to the region of HER3 shown in SEQ ID NO: 77.

[0367] 3. A method for treating or preventing cancer, comprising the step of administering a therapeutic or prophylactic effective amount to a target of (i) an antigen-binding molecule that binds to HER3 and (ii) an antigen-binding molecule that binds to EGFR; the method wherein the antigen-binding molecule that binds to HER3 binds to the region of HER3 shown in SEQ ID NO: 77.

[0368] 4. A pharmaceutical combination comprising an antigen-binding molecule that binds to HER3 and an antigen-binding molecule that binds to EGFR, wherein the antigen-binding molecule that binds to HER3 binds to the region of HER3 shown in Sequence ID No. 77.

[0369] 5. The combination of pharmaceuticals described in item 4 for use in methods of treating or preventing cancer. 6. Use of the drug combinations described in item 4 in the manufacture of medicines for treating or preventing cancer.

[0370] 7. A method for treating or preventing cancer, comprising the step of administering a therapeutic or prophylactic effective amount of a combination of pharmaceuticals described in item 4. 8. Antigen-binding molecules that bind to HER3, (i) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 40 HC-CDR2 having the amino acid sequence of SEQ ID NO: 43 HC-CDR3 having the amino acid sequence of SEQ ID NO: 48 The heavy chain variable (VH) region incorporating; and (ii) The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 66 LC-CDR2 having the amino acid sequence of SEQ ID NO: 69 LC-CDR3 having the amino acid sequence of SEQ ID NO: 74 Light chain variable (VL) region incorporating Antigen-binding molecules, uses, or methods for use described in any one of items 1 through 7, including the one described in item 1 through 7.

[0371] 9. Antigen-binding molecules that bind to HER3, (i) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 38 HC-CDR2 having the amino acid sequence of SEQ ID NO: 42 HC-CDR3 having the amino acid sequence of SEQ ID NO: 45 The VH region incorporating; and (ii) The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 63 LC-CDR2 having the amino acid sequence of SEQ ID NO: 67 LC-CDR3 having the amino acid sequence of SEQ ID NO: 70 The VL area incorporates Antigen-binding molecules, uses, or methods for use described in any one of items 1 through 8, including the one described in item 1 through 8.

[0372] 10. Antigen-binding molecules that bind to HER3, A VH region containing an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 33; and VL region containing an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 58 Antigen-binding molecules, uses, or methods for use described in any one of items 1 through 9, including the one described in item 1 through 9.

[0373] 11. Antigen-binding molecules that bind to HER3, A polypeptide comprising, or derived from, an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 75; and A polypeptide containing, or derived from, an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 76. Antigen-binding molecules, uses, or methods for use described in any one of items 1 through 10, including the one described in item 1 through 10.

[0374] 12. Antigen-binding molecules that bind to EGFR, (i) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 92 HC-CDR2 having the amino acid sequence of SEQ ID NO: 93 HC-CDR3 having the amino acid sequence of SEQ ID NO: 94 The heavy chain variable (VH) region incorporating; and (ii) The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 96 LC-CDR2 having the amino acid sequence of SEQ ID NO: 97 LC-CDR3 having the amino acid sequence of SEQ ID NO: 98 Light chain variable (VL) region incorporating Antigen-binding molecules, uses, or methods for use described in any one of items 1 through 11, including the one described in item 1 through 11.

[0375] 13. Antigen-binding molecules that bind to EGFR, A VH region containing an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 91; and VL region containing an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 95 Antigen-binding molecules, uses, or methods for use described in any one of items 1 through 12, including the one described in item 1 through 12.

[0376] 14. Antigen-binding molecules that bind to EGFR, A polypeptide comprising, or derived from, an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 99; and A polypeptide containing, or derived from, an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 100. Antigen-binding molecules, uses, or methods for use described in any one of items 1 through 13, including the one described in item 1 through 13.

[0377] 15. Cancers containing cells expressing / overexpressing EGFR family members, cancers containing cells expressing / overexpressing HER3, cancers containing cells expressing / overexpressing EGFR, cancers containing cells expressing / overexpressing HER3 and EGFR, cancers containing cells with mutations resulting in increased expression of ligands for HER3, cancers containing cells with mutations resulting in increased expression of ligands for EGFR, cancers containing cells with NRG gene fusions, solid tumors, hematological cancers, squamous cell carcinoma, EGFR-amplifying squamous cell carcinoma, breast cancer, breast cancer, invasive breast cancer, ductal carcinoma, metastatic breast cancer, triple-negative breast cancer, HER2-positive breast cancer, gastric cancer, gastric adenocarcinoma, gastrointestinal adenocarcinoma, colorectal cancer, metastatic colorectal cancer, colon cancer, colorectal cancer, colorectal adenocarcinoma, colon adenocarcinoma, head and neck cancer, head and neck squamous cell carcinoma, lung cancer, non-small cell lung cancer, lung adenocarcinoma, invasive mucinous lung adenocarcinoma Lung squamous cell carcinoma, ovarian cancer, serous ovarian adenocarcinoma, serous ovarian cystadenocarcinoma, fallopian tube cancer, kidney cancer, renal cell carcinoma, clear cell carcinoma, renal cell adenocarcinoma, papillary renal cell carcinoma, pancreatic cancer, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, cervical cancer, cervical squamous cell carcinoma, skin cancer, melanoma, oral cancer, oropharyngeal cancer, esophageal cancer, esophageal squamous cell carcinoma, esophageal adenocarcinoma, liver cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, uterine cancer, endometrial cancer, uterine endometrial cancer, uterine carcinosarcoma, thyroid cancer, thyroid cancer Antigen-binding molecules, uses, or methods for use described in any one of items 1 to 14, selected from thyroid cancer, pheochromocytoma, paraganglioma, bladder cancer, urothelial carcinoma of the bladder, prostate cancer, prostate adenocarcinoma, retinoblastoma, sarcoma, soft tissue sarcoma, peritoneal cancer, thymoma, neuroendocrine tumors, neuroendocrine tumors of the nasopharynx, squamous cell carcinoma of the skin, astrocytoma, low-grade astrocytoma, high-grade astrocytoma, undifferentiated astrocytoma, and glioblastoma multiforme.

[0378] 16. Antigen-binding molecules, uses, or methods for use described in any one of items 1 to 15, selected from cancers comprising cells expressing / overexpressing HER3, cancers comprising cells expressing / overexpressing EGFR, cancers comprising cells expressing / overexpressing HER3 and EGFR, squamous cell carcinoma, EGFR-amplified squamous cell carcinoma, esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, head and neck squamous cell carcinoma, colorectal cancer, metastatic colorectal cancer, colonic adenocarcinoma, pancreatic cancer, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, lung cancer, and lung squamous cell carcinoma.

[0379] This disclosure includes combinations of the described embodiments and preferred features, unless such combinations are clearly unacceptable or expressly avoided. The subheadings used in this specification are for structural purposes only and should not be considered as limiting the subject matter described.

[0380] Herein, aspects and embodiments of the present disclosure are illustrated for illustrative purposes with reference to the accompanying drawings. Further aspects and embodiments will be apparent to those skilled in the art. All documents referenced herein are incorporated herein by reference.

[0381] Throughout this Specification, including the subsequent claims, unless the context requires otherwise, the word “comprise,” and variations such as “comprises” and “comprises,” shall be understood to imply the inclusion of a declared integer or step or group of integers or steps, and not the exclusion of any other integer or step or group of integers or steps.

[0382] Note that, unless the context explicitly indicates otherwise, the singular forms “a,” “an,” and “that” used herein and in the accompanying claims refer to multiple subjects. Herein, a range may be expressed as a range from “about” one particular value to and / or “about” another particular value. Where such a range is expressed, another embodiment includes a range from one particular value to and / or other particular values. Similarly, where a value is expressed as an approximation by the use of the antecedent “about,” it will be understood that a particular value forms another embodiment.

[0383] Where a nucleic acid sequence is disclosed or referred to herein, its reverse complement is also expressly assumed. The methods described herein may preferably be carried out in vitro. The term “in vitro” is intended to encompass procedures carried out on cells in a culture, while the term “in vivo” is intended to encompass procedures carried out on / on intact multicellular organisms.

[0384] In this specification, values ​​may be expressed as "approximately" one specific value. Similarly, in this specification, ranges may be expressed as "approximately" from one specific value and / or "approximately" to another specific value. The expression "approximately" with respect to numbers is optional and means, for example, ±10%. For example, a reference to "approximately 10%" should be interpreted as 9% to 11%. In this specification, where "approximately" is used, the value that follows is also specifically intended. For example, a reference to "approximately 10%" also specifically intends 10%.

[0385] Here, embodiments and experiments illustrating the principles of this disclosure are discussed with reference to the accompanying figures. [Brief explanation of the drawing]

[0386] [Figure 1A]These graphs show the effects of treatment with 10D1F (HMBD-001), cetuximab, 10D1F in combination with cetuximab, or vehicle control (PBS) in mice with a KYSE-150 cell-derived mouse model of esophageal squamous cell carcinoma. Figure 1A shows the tumor volume over time for mice in different treatment groups. Figure 1B shows the body weight over time for mice in different treatment groups. [Figure 1B] These graphs show the effects of treatment with 10D1F (HMBD-001), cetuximab, 10D1F in combination with cetuximab, or vehicle control (PBS) in mice with a KYSE-150 cell-derived mouse model of esophageal squamous cell carcinoma. Figure 1A shows the tumor volume over time for mice in different treatment groups. Figure 1B shows the body weight over time for mice in different treatment groups. [Figure 2A] These graphs show the effects of treatment with 10D1F (HMBD-001), cetuximab, 10D1F in combination with cetuximab, or vehicle control (PBS) in mice with an OE21 cell-derived mouse model of esophageal squamous cell carcinoma. Figure 2A shows the tumor volume over time for mice in different treatment groups. Figure 2B shows the body weight over time for mice in different treatment groups. [Figure 2B] These graphs show the effects of treatment with 10D1F (HMBD-001), cetuximab, 10D1F in combination with cetuximab, or vehicle control (PBS) in mice with an OE21 cell-derived mouse model of esophageal squamous cell carcinoma. Figure 2A shows the tumor volume over time for mice in different treatment groups. Figure 2B shows the body weight over time for mice in different treatment groups. [Figure 3A] These graphs show the effects of treatment with 10D1F (HMBD-001), cetuximab, 10D1F in combination with cetuximab, or vehicle control (PBS) in mice with a LIM1215 cell-derived model of colon adenocarcinoma. Figure 3A shows the tumor volume over time for mice in different treatment groups. Figure 3B shows the body weight over time for mice in different treatment groups. [Figure 3B]These graphs show the effects of treatment with 10D1F (HMBD-001), cetuximab, 10D1F in combination with cetuximab, or vehicle control (PBS) in mice with a LIM1215 cell-derived model of colon adenocarcinoma. Figure 3A shows the tumor volume over time for mice in different treatment groups. Figure 3B shows the body weight over time for mice in different treatment groups. [Figure 4A] These graphs show the effects of treatment with 10D1F (HMBD-001), cetuximab, 10D1F in combination with cetuximab, or vehicle control (PBS) in mice with a CAL-27 cell-derived mouse model of squamous cell carcinoma of the tongue. Figure 4A shows the tumor volume over time for mice in different treatment groups. Figure 4B shows the body weight over time for mice in different treatment groups. [Figure 4B] These graphs show the effects of treatment with 10D1F (HMBD-001), cetuximab, 10D1F in combination with cetuximab, or vehicle control (PBS) in mice with a CAL-27 cell-derived mouse model of squamous cell carcinoma of the tongue. Figure 4A shows the tumor volume over time for mice in different treatment groups. Figure 4B shows the body weight over time for mice in different treatment groups. [Figure 5A] These graphs show the effects of treatment with 10D1F (HMBD-001), cetuximab, 10D1F in combination with cetuximab, or vehicle control (PBS) in mice with a FaDu cell-derived mouse model of hypopharyngeal squamous cell carcinoma. Figure 5A shows the tumor volume over time for mice in different treatment groups. Figure 5B shows the body weight over time for mice in different treatment groups. [Figure 5B] These graphs show the effects of treatment with 10D1F (HMBD-001), cetuximab, 10D1F in combination with cetuximab, or vehicle control (PBS) in mice with a FaDu cell-derived mouse model of hypopharyngeal squamous cell carcinoma. Figure 5A shows the tumor volume over time for mice in different treatment groups. Figure 5B shows the body weight over time for mice in different treatment groups. [Figure 6A]These graphs show the effects of treatment with 10D1F (HMBD-001), cetuximab, 10D1F in combination with cetuximab, or vehicle control (PBS) in mice with a BxPC-3 cell-derived mouse model of pancreatic ductal adenocarcinoma. Figure 6A shows the tumor volume over time for mice in different treatment groups. Figure 6B shows the body weight over time for mice in different treatment groups. [Figure 6B] These graphs show the effects of treatment with 10D1F (HMBD-001), cetuximab, 10D1F in combination with cetuximab, or vehicle control (PBS) in mice with a BxPC-3 cell-derived mouse model of pancreatic ductal adenocarcinoma. Figure 6A shows the tumor volume over time for mice in different treatment groups. Figure 6B shows the body weight over time for mice in different treatment groups. [Figure 7A] This graph shows the effects of treatment with 10D1F (HMBD-001), cetuximab, 10D1F in combination with cetuximab, or isotype controls in mice with a human patient-derived mouse model of lung squamous cell carcinoma (CTG-2552). Figure 7A shows the tumor volume over time for mice in different treatment groups. Figure 7B shows the body weight over time for mice in different treatment groups. [Figure 7B] This graph shows the effects of treatment with 10D1F (HMBD-001), cetuximab, 10D1F in combination with cetuximab, or isotype controls in mice with a human patient-derived mouse model of lung squamous cell carcinoma (CTG-2552). Figure 7A shows the tumor volume over time for mice in different treatment groups. Figure 7B shows the body weight over time for mice in different treatment groups. [Figure 8A]This graph shows the effects of treatment in mice with a xenograft (CDX) model derived from a cell line of lung squamous cell carcinoma, using 10D1F (HMBD-001), cetuximab (5 mg / kg and 10 mg / kg), docetaxel, 10D1F combined with cetuximab (5 mg / kg and 10 mg / kg), 10D1F combined with docetaxel, cetuximab (5 mg / kg and 10 mg / kg) combined with docetaxel, cetuximab (5 mg / kg and 10 mg / kg) and docetaxel combined with 10D1F, or a vehicle control (PBS). Figure 8A shows the tumor volume over time for mice in different treatment groups (5 mg / kg cetuximab in the treatment group including cetuximab). Figure 8B shows the tumor volume over time for mice in different treatment groups (10 mg / kg cetuximab in the treatment group including cetuximab). Figure 8C shows the body weight over time for mice in different treatment groups. [Figure 8B] This graph shows the effects of treatment in mice with a xenograft (CDX) model derived from a cell line of lung squamous cell carcinoma, using 10D1F (HMBD-001), cetuximab (5 mg / kg and 10 mg / kg), docetaxel, 10D1F combined with cetuximab (5 mg / kg and 10 mg / kg), 10D1F combined with docetaxel, cetuximab (5 mg / kg and 10 mg / kg) combined with docetaxel, cetuximab (5 mg / kg and 10 mg / kg) and docetaxel combined with 10D1F, or a vehicle control (PBS). Figure 8A shows the tumor volume over time for mice in different treatment groups (5 mg / kg cetuximab in the treatment group including cetuximab). Figure 8B shows the tumor volume over time for mice in different treatment groups (10 mg / kg cetuximab in the treatment group including cetuximab). Figure 8C shows the body weight over time for mice in different treatment groups. [Figure 8C]This graph shows the effects of treatment in mice with a xenograft (CDX) model derived from a cell line of lung squamous cell carcinoma, using 10D1F (HMBD-001), cetuximab (5 mg / kg and 10 mg / kg), docetaxel, 10D1F combined with cetuximab (5 mg / kg and 10 mg / kg), 10D1F combined with docetaxel, cetuximab (5 mg / kg and 10 mg / kg) combined with docetaxel, cetuximab (5 mg / kg and 10 mg / kg) and docetaxel combined with 10D1F, or a vehicle control (PBS). Figure 8A shows the tumor volume over time for mice in different treatment groups (5 mg / kg cetuximab in the treatment group including cetuximab). Figure 8B shows the tumor volume over time for mice in different treatment groups (10 mg / kg cetuximab in the treatment group including cetuximab). Figure 8C shows the body weight over time for mice in different treatment groups. [Examples]

[0387] Example 1 Characterization of 10D1F in WO2019 / 185878A1 and WO2021 / 048274A1 The HER3-binding antibody clone designated 10D1F is described in WO2019 / 185878A1 (which is incorporated in its entirety by reference).

[0388] 10D1F includes a heavy chain variable region shown in Sequence ID No. 36 of WO2019 / 185878A1 (=Sequence ID No. 33 in this disclosure) and a light chain variable region shown in Sequence ID No. 83 of WO2019 / 185878A1 (=Sequence ID No. 58 in this disclosure). 10D1F is also referred to as "10D1_c89" in WO2019 / 185878A1 and may also be referred to as HMBD-001 in this specification.

[0389] Example 2.2 of WO2019 / 185878A1 describes a molecule (molecule

[16] ) comprising the VH and VL regions of 10D1F in the human IgG1 / Vκ format (10D1F hIgG1), formed from Sequence ID No. 206 of WO2019 / 185878A1 (=Sequence ID No. 75 in this disclosure) and Sequence ID No. 207 of WO2019 / 185878A1 (=Sequence ID No. 76 in this disclosure).

[0390] Examples 8.1-8.3 and Figures 42-46 of WO2019 / 185878A1 demonstrate that 10D1F hIgG1 binds to human HER3 with high affinity and specificity (no cross-reactivity with other human EGFR family members), while retaining high affinity binding to cynomolgus monkey, mouse, and rat HER3.

[0391] Example 8.6 and Figures 49A and 49B of WO2019 / 185878A1 demonstrate that 10D1F hIgG1 binds to HER3 in a ligand (NRG)-independent manner and via HER3 epitopes topologically distant from the epitopes to which the anti-HER3 antibodies M-05-74 and M-08-11 are bound. Example 8.10 and Figure 78 of WO2021 / 048274A1 demonstrate that 10D1F hIgG1 binds to human HER3 with sub-picomolecular affinity, in or out of the presence of human NRG1.

[0392] Furthermore, Example 3.5 of WO2021 / 048274A1 also discloses that antibody clone 10D1 and clones derived from 10D1 (including 10D1F) bind to human HER3 in the region corresponding to positions 218-235 of SEQ ID NO: 1 (i.e., SEQ ID NO: 77 in this disclosure), and that two consensus binding site motifs were identified within this region (as shown in SEQ ID NOs: 78 and 79 in this disclosure).

[0393] Examples 4.1 and Figure 65 of WO2019 / 185878A1, and Examples 8.7 and Figure 52, demonstrate that 10D1F hIgG1 is highly effective in inhibiting the interaction between HER3 and HER2, and that this is dose-dependent. Examples 8.7 and Figure 53 of WO2019 / 185878A1 show that 10D1F hIgG1 inhibits the interaction between HER3 and EGFR in a dose-dependent manner.

[0394] Example 8.8 and Figure 54 of WO2019 / 185878A1 demonstrate that 10D1F hIgG1 induces ADCC activity in dose-dependently overexpressing HER3 cells.

[0395] Example 8.9 of WO2019 / 185878A1, as well as Figures 55, 63, and 64, demonstrate that 10D1F hIgG1 inhibits HER3-mediated signaling in cells of HER3-expressing cancer cell lines in vitro.

[0396] Example 11 and Figure 71 of WO2019 / 185878A1 demonstrate that 10D1F hIgG1 also inhibits HER3-mediated signaling in xenograft tumors derived from human cancer cell lines that express HER3 in vivo. Example 14 and Figure 79 of WO2021 / 048274A1 demonstrate that 10D1F is highly effective in inhibiting the growth of xenograft tumors derived from human cancer cell lines that possess an NRG gene fusion.

[0397] Examples 9.3 and 9.4 of WO2019 / 185878A1, as well as Figures 59, 60, 61, 62, 74, and 77, demonstrate that 10D1F potently inhibits the growth of cancer cells in vitro and also potently inhibits the growth of xenograft tumors derived from human cancer cell lines in vivo. Example 10 of WO2019 / 185878 A1, as well as Figures 67 and 68, demonstrate that 10D1F hIgG1 inhibits the in vitro proliferation of thyroid cancer cell lines carrying the V600E BRAF mutation.

[0398] Example 12 of WO2019 / 185878A1 and Figures 72 and 73 demonstrate that 10D1F hIgG1 is not substantially internalized by HER3-expressing cells.

[0399] Example 13 of WO2019 / 185878A1, as well as Figures 75 and 76, demonstrate the usefulness of 10D1F hIgG1 for HER3 detection. Example 8.4 and Figure 47A of WO2019 / 185878A1 demonstrate that 10D1F hIgG1 is heat-resistant and has a melting temperature of 70.0°C, as determined by differential scanning fluorescence quantification.

[0400] Examples 9.1 and 9.2 of WO2019 / 185878A1, as well as Figures 56, 57, 58, and 69, 70, demonstrate that 10D1F hIgG1 has a favorable pharmacological and toxicological profile.

[0401] Example 2 Phase Ib study to evaluate HMBD-001 with or without chemotherapy in patients with advanced solid tumors containing NRG1 gene fusions. We will conduct a Phase 1b study of combination therapy using HMBD-001 (i.e., 10D1F) with chemotherapy in NRG1 gene fusion cancers.

[0402] Targeted therapies against HER2 / HER3 in cancers with NRG1 fusions have shown early signs of clinical efficacy, with a 30% response rate for cerivanthumab (Carrizosa et al., Journal of Clinical Oncology (2022) 40(16_suppl):3006) and 34% for xenoctuzumab (Schram et al., 2022 Journal of Clinical Oncology (2022) 40(16_suppl):105). However, both cerivanthumab and xenoctuzumab primarily inhibit ligand-dependent HER3 activation.

[0403] HMBD-001 (i.e., 10D1F) is the only anti-HER3 mAb in development that blocks both ligand-dependent and ligand-independent HER3 activation and oncogenic signaling by blocking a key epitope located at the interface, independent of upstream processes, when HER3 forms heterodimers with HER2 or EGFR. In preclinical models evaluating 10D1F, superior affinity and tumor control were observed across multiple cancer types, as assessed by direct comparison with other anti-HER3 agents in development. In a Phase 1 study conducted by Cancer Research United Kingdom (CRUK), 10D1F demonstrated promising clinical activity, with 5 out of 17 patients (29.4%) achieving disease stabilization and a median disease control duration of up to 20 weeks.

[0404] In preclinical studies, a potential synergistic effect between PI3K pathway blockade and MAPK pathway blockade was demonstrated in the combination of gemcitabine and nab-paclitaxel chemotherapy, improving survival to 67% in a mouse model (Awasthi et al., Cancer Letters (2019) 459:41;49). Given the preclinical efficacy of 10D1F in blocking the MAPK and PI3K pathways in cancers with NRG1 fusions, this Arm A will investigate the safety, tolerability, and preliminary efficacy indications of the combination of gemcitabine, nab-paclitaxel, and 10D1F in locally advanced, unresectable, or metastatic PDAC.

[0405] NRG1 fusions account for only 1% of all NSCLCs, but have recently been recognized as a distinct group of NSCLCs characterized by little to no programmed cell death ligand-1 (PD-L1) expression, low tumor mutagenesis, and limited response to systemic therapies, including cytotoxic, immunotherapy, and targeted therapy regimens (Drilon et al., J Clin Oncol. (2021) 39(25):2791~2802). There is a critical need to identify effective treatment options for patients with NRG1 fusion NSCLCs. Therefore, Arm B of this study aims to investigate the safety and efficacy of combination therapy with docetaxel and 10D1F in patients with NSCLCs.

[0406] The target is divided into three arms, Arm A, B, and C, and is treated as follows: Arm A: 10D1F 1800 mg administered intravenously, once a week. Gemcitabine is administered intravenously at 1000 mg / m² on days 1, 8, and 15 of each 28-day cycle. 2 Nab-paclitaxel is administered intravenously at 125 mg / m² on days 1, 8, and 15 of each 28-day cycle. 2 Arm B: 10D1F 1800 mg administered intravenously, once a week. Docetaxel administered intravenously at a dose of 75 mg / m². 2 , every 3 weeks Arm C: 10D1F 1800 mg administered intravenously, once a week. In Arms A and B, the treatment period is the initial induction period of up to 6 cycles of chemotherapy in combination with 10D1F, with the option to extend it to 8 cycles per case. Following this induction period, 10D1F monotherapy (i.e., 1800 mg of 10D1F intravenously once weekly) will be administered until the participant discontinues the study treatment at whichever comes first: unacceptable toxicity, confirmed disease progression, withdrawal of consent, loss of follow-up, death, or termination of the study. Reinduction with a combination of chemotherapy and 10D1F may be approved on a case-by-case basis in the event of disease progression during maintenance of 10D1F monotherapy.

[0407] In Arm C, the treatment will continue until the treatment is discontinued at the earliest of the following reasons: unbearable toxicity, confirmed disease progression, withdrawal of consent, loss of follow-up, death, or termination of the study.

[0408] Arm A targets patients with locally advanced, unresectable pancreatic ductal adenocarcinoma or metastatic pancreatic ductal adenocarcinoma having an NRG1 gene fusion with an epidermal growth factor (EGF) signaling domain.

[0409] The subjects in Arm B are patients with non-small cell lung cancer who have an NRG1 gene fusion containing an epidermal growth factor (EGF) signaling domain. Eligible patients in Arm C are those with locally advanced, unresectable solid tumors containing an NRG1 gene fusion with an epidermal growth factor (EGF) signaling domain, or metastatic solid tumors containing an NRG1 gene fusion with an epidermal growth factor (EGF) signaling domain, who are not eligible for Arm A or Arm B.

[0410] The main patient eligibility criteria are as follows: Inclusion Criteria The subjects included in this study must meet all of the following inclusion criteria: 1. Before commencing any research procedure and evaluation, participants must be able to provide and have provided written informed consent, and must be willing to follow all research procedures.

[0411] 2. Adult participants who are 18 years of age or older at the time of informed consent. ECOG performance status from 3.0 to 1. 4. Histological or cytological evidence of advanced malignant solid tumor (any tissue structure) that is resistant / refractory to standard systemic therapy, or there is no reasonable therapy that would provide a clinical benefit in the physician's judgment, or the participant has been demonstrated to be intolerant to such therapy, or the participant has refused such therapy.

[0412] 5. Cancers having an NRG1 gene fusion identified by molecular assay, which is defined as precisely oriented (i.e., having NRG1 encoding mRNA at the 3' end of the transcript) and containing an EGF-like domain capable of binding to HER3.

[0413] Arm A: Locally advanced, unresectable or metastatic pancreatic adenocarcinoma; Participants must not have received prior treatment with gemcitabine or nab-paclitaxel; Participants must not have received more than two lines of prior systemic therapy for a progressive disease. Adjuvant or neoadjuvant therapy within six months from the proposed day 1 of cycle 1 (C1D1) will be counted as one line of treatment.

[0414] Arm B: Locally advanced, unresectable or metastatic non-small cell lung cancer; Participants must not have received prior treatment with docetaxel; Participants must not have received more than two lines of prior systemic therapy for a progressive disease. Adjuvant or neoadjuvant therapy within six months from the proposed day 1 of cycle 1 (C1D1) will be counted as one line of treatment.

[0415] Arm C Participants must not be eligible to participate in either Arm A or Arm B. 6. Participants must have a life expectancy of more than three months, as determined by the principal investigator.

[0416] 7. Participants must have a disease measurable by RECIST V1.1. 8. Participants must have available archive tissue (at least 15 consecutive unstained formalin-fixed paraffin-embedded [FFPE] slides or one FFPE block), or alternatively, a fresh tumor biopsy sample. Participants who do not have archive tissue or a fresh biopsy sample, or who refuse to provide archive tissue, may be approved for enrollment on a case-by-case basis after consultation with the sponsor.

[0417] 9. Women who may become pregnant (WOCBP) must be negative for beta-human chorionic gonadotropin (β-hCG) within 72 hours prior to the first dose of the investigational drug and must not be breastfeeding.

[0418] 10. WOCBP is defined as a woman who is not surgically infertile or postmenopausal. Female participants are considered postmenopausal if they have been amenorrhea for 12 months without other medical causes. Female participants under 50 years of age who meet the criteria for postmenopausal status and have not previously undergone sterilization should be considered for further testing regarding luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels to confirm serological postmenopausal status.

[0419] 11. WOCBP must agree to use highly effective contraception during the study and for 90 days after the last dose of the study procedure. 12. Male participants capable of fathering children must agree to avoid impregnating their partners and to use highly effective contraception during the study and for 90 days after the last dose of the study procedure. All male participants must agree not to provide sperm during the study and for 90 days after the last dose of the study procedure.

[0420] 13. Appropriate baseline organ function demonstrated by the following: • Serum creatinine ≤ 2 × institutional ULN • Serum albumin ≥ 2.5 g / dl.

[0421] Bilirubin ≤ 2.0 × Facility ULN. • AST and ALT ≤ 2.5 × institutional ULN. If a participant has liver metastases, registered participants with hepatitis metastases may have ALT and AST < 5 × institutional ULN.

[0422] 14. If participants are not taking warfarin or other oral anticoagulants: International normalized ratio (INR) ≤ 1.5 or prothrombin time (PT) ≤ 1.5 × ULN; and either partial thromboplastin time or activated partial thromboplastin time (PTT or aPTT) ≤ 1.5 × ULN. Participants taking warfarin must be on a stable dose that results in a stable INR < 3.5. In participants receiving other oral anticoagulant therapy, PT or aPTT must be within the intended therapeutic range of the anticoagulant.

[0423] 15. Appropriate baseline blood function demonstrated by the following: ANC ≥ 1.5 × 10 9 / L. • Hemoglobin ≥ 9 g / dL, and no red blood cell (RBC) transfusions in the past 14 days.

[0424] Platelet count ≥ 100 × 10 9 / L, and no platelet transfusions in the past 14 days; Exclusion criteria Participants who meet any of the following exclusion criteria will be excluded from the study: 1. Prior treatment with an investigational agent specifically targeting HER3, including HMBD-001, pertuzumab, or a pan-HER tyrosine kinase inhibitor.

[0425] 2. Persistent clinically significant toxicity (grade ≥ 2) from previous anticancer therapy. Previous toxicity resulting in abnormal laboratory values ​​must have recovered to grade ≤ 1 unless higher grade abnormalities are acceptable inclusion criteria. If drug therapy is required to treat abnormal laboratory values, the dose and laboratory values ​​should be stable. Participants with residual toxicity of grade 2 or higher that is considered unlikely to expose the participant to high-risk treatment-related toxicity and / or affect the integrity of the study results may be permitted on a case-by-case basis in consultation with the study sponsor (e.g., alopecia, thyroid disorder, or cortisol deficiency during stable hormone replacement therapy).

[0426] 3. Treatment with anticancer therapies, including cytotoxic chemotherapy, monoclonal antibodies, small molecule tyrosine kinase inhibitors, and / or investigational systemic anticancer agents, within 28 days prior to the administration of the study treatment (42 days for previous nitrosourea or mitomycin-C), or within 5 half-lives, whichever is shorter. Participants with advanced prostate cancer receiving luteinizing hormone-releasing hormone (LHRH) agonists should be admitted to the study and continue using these drugs throughout the study treatment.

[0427] 4. Previous radiotherapy or major surgery within four weeks prior to the first dose of the study drug. Local radiotherapy or minor surgery for palliative purposes within four weeks of the first dose of the study drug may be approved on a case-by-case basis in consultation with the study sponsor, provided that it is determined that the participant will not be exposed to high-risk adverse drug effects and / or that the integrity of the study results will not be compromised.

[0428] 5. Participants with brain metastases, unless they meet all of the following criteria: • The patient must be clinically and radiologically stable for at least 28 days prior to the first dose of the study drug (no evidence of progression on imaging; the same imaging method (MRI or computed tomography [CT] scan) must be used for each evaluation); • All neurological symptoms have returned to baseline; Note: Individuals with a history of piatric disease should not participate, even if they are clinically stable.

[0429] 6. Any other known active malignant tumor, excluding treated cervical intraepithelial neoplasms or non-melanoma skin cancer. Participants with a history of a low-probability malignant tumor that has received curative therapy may be approved on a case-by-case basis in consultation with the study sponsor, provided that it is determined that the participant will not be exposed to high-risk adverse drug effects and / or that the integrity of the study results will not be compromised.

[0430] 7. If the participant is enrolled in an arm, a history of uncontrolled allergic reactions to HMBD-001 or any of its excipients, and / or gemcitabine, nab-paclitaxel, or docetaxel, and / or known or anticipated hypersensitivity.

[0431] 8. Participation in any other clinical trial. Left ventricular ejection fraction less than 9.50%. 10. Clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association Class 3 or 4 heart failure, uncontrolled angina, history of myocardial infarction, unstable angina or stroke within 6 months prior to study enrollment, uncontrolled hypertension, or clinically significant arrhythmias that are not controlled by medication).

[0432] 11. Uncontrolled clinically significant medical problems, including but not limited to lung diseases (e.g., chronic obstructive pulmonary disease, pulmonary hypertension), uncontrolled infections requiring systemic therapy, disseminated intravascular coagulation, or psychotic / social conditions that limit compliance with research requirements.

[0433] A QTc interval greater than 12.450ms (male) or greater than 470ms (female). 13. Positive for human immunodeficiency virus. 14. Active or chronic hepatitis B or C.

[0434] 15. Any medical condition that, in the judgment of the principal investigator, exposes the participant to an unacceptably high risk of toxicity. 16. COVID-19 infection within the three months prior to C1D1.

[0435] 17. Receive COVID-19 vaccination within 14 days of C1D1. 18. Any uncontrolled comorbidity or clinically significant uncontrolled condition, including but not limited to active bacterial, fungal, or viral infections requiring systemic therapy.

[0436] In Arms A and B, an initial safety induction strategy will be employed to determine the recommended Phase 2 dose (RP2D) for the combination of HMBD-001 and chemotherapy. The enrollment of the remaining participants will then proceed according to the Simon 2-stage design.

[0437] Safety implementation strategy for arms A and B: 10D1F Dose level (DL) 1 = 1800 mg DL-1 = 1200 mg

[0438] [Table 4]

[0439] [Table 5]

[0440] [Table 6]

[0441] [Table 7]

[0442] [Table 8] Purpose and endpoint

[0443] [Table 9]

[0444] [Table 10]

[0445] [Table 11] result A 59-year-old woman was diagnosed in April 2022 with metastatic pancreatic adenocarcinoma with metastases to the liver and lungs (stage IV). In June 2022, she began first-line systemic therapy with gemcitabine and nab-paclitaxel. The patient remained stable until March 2023, at which point disease progression was detected. At this point, gemcitabine and nab-paclitaxel therapy was discontinued, and second-line systemic therapy with FOLFIRINOX was initiated. The patient remained stable from March to July 2023. In July 2023, FOLFIRINOX therapy was discontinued. Also in July 2023, tumor genome profiling identified an ATP1B1-NRG1 fusion. In September 2023, treatment with HMBD-001 at 1800 mg QW was initiated.

[0446] Target lesion size was analyzed at baseline and after 2.5, 4, and 6 cycles of treatment with HMBD-001. Patients were also characterized after 2, 2.5, 4, and 6 cycles of treatment with HMBD-001 to determine levels of CA19-9 (pancreatic correlation) in the blood. The results are shown below.

[0447] [Table 12] Treatment with HMBD-001 was found to be associated with a significant and sustained reduction in the size of target lesions throughout six treatment cycles. Furthermore, treatment with HMBD-001 was shown to be associated with a dramatic and sustained reduction in blood CA19-9 levels.

[0448] Example 3 Evaluation of the therapeutic effect of combination therapy using 10D1F and cetuximab. The therapeutic effects of a combination of 10D1F hIgG1 (i....

Claims

1. An antigen-binding molecule that binds to HER3 for use in a method of treating or preventing cancer, wherein the method comprises the step of administering an antigen-binding molecule that binds to EGFR.

2. Use of an antigen-binding molecule that binds to HER3 in the manufacture of a pharmaceutical product for use in a method of treating or preventing cancer, wherein the method comprises the step of administering an antigen-binding molecule that binds to EGFR.

3. A method for treating or preventing cancer, comprising the step of administering a therapeutic or prophylactic effective amount to the target of (i) an antigen-binding molecule bound to HER3 and (ii) an antigen-binding molecule bound to EGFR.

4. The method further comprises the step of administering a taxoid, the antigen-binding molecule for use according to claim 1, the use according to claim 2, or the method according to claim 3.

5. An antigen-binding molecule that binds to HER3 for use in a method of treating or preventing cancer, wherein the method comprises the step of administering a taxoid.

6. Use of an antigen-binding molecule that binds to HER3 in the manufacture of a pharmaceutical product for use in a method of treating or preventing cancer, wherein the method comprises the step of administering a taxoid.

7. A method for treating or preventing cancer, comprising the step of administering a therapeutic or prophylactic effective amount of (i) an antigen-binding molecule that binds to HER3 and (ii) a taxoid to the target.

8. An antigen-binding molecule that binds to HER3 for use in methods of treating or preventing cancer, wherein the method comprises the step of administering a taxoid and a nucleoside analog.

9. Use of an antigen-binding molecule that binds to HER3 in the manufacture of a pharmaceutical product for use in a method of treating or preventing cancer, wherein the method comprises the step of administering a taxoid and a nucleoside analog.

10. A method for treating or preventing cancer, comprising the step of administering a therapeutic or prophylactic effective amount of (i) an antigen-binding molecule that binds to HER3, (ii) a taxoid, and (iii) a nucleoside analog to the target.

11. An antigen-binding molecule that binds to HER3 for use in methods of treating or preventing cancer, wherein the method comprises the step of administering a nucleoside analog.

12. Use of an antigen-binding molecule that binds to HER3 in the manufacture of a pharmaceutical product for use in a method of treating or preventing cancer, wherein the method comprises the step of administering a nucleoside analog.

13. A method for treating or preventing cancer, comprising the step of administering a therapeutic or prophylactic effective amount of (i) an antigen-binding molecule bound to HER3 and (ii) a nucleoside analog to the target.

14. A pharmaceutical combination comprising (i) an antigen-binding molecule that binds to HER3 and (ii) an antigen-binding molecule that binds to EGFR.

15. A pharmaceutical combination comprising (i) an antigen-binding molecule that binds to HER3, (ii) an antigen-binding molecule that binds to EGFR, and (iii) a taxoid.

16. A combination of pharmaceuticals comprising (i) an antigen-binding molecule that binds to HER3 and (ii) a taxoid.

17. A pharmaceutical combination comprising (i) an antigen-binding molecule that binds to HER3, (ii) a nucleoside analog, and (iii) a taxoid.

18. A pharmaceutical combination comprising (i) an antigen-binding molecule that binds to HER3 and (ii) a nucleoside analog.

19. A pharmaceutical combination according to any one of claims 14 to 18 for use in a method of treating or preventing cancer.

20. Use of the pharmaceutical combination according to any one of claims 14 to 18 in the manufacture of a pharmaceutical for treating or preventing cancer.

21. A method for treating or preventing cancer, comprising the step of administering a therapeutic or preventive amount of a combination of pharmaceuticals described in any one of claims 14 to 18 to a target.

22. An antigen-binding molecule for use, use, method, pharmaceutical combination, or pharmaceutical combination for use according to any one of claims 1 to 21, wherein the antigen-binding molecule that binds to HER3 binds to the region of HER3 shown in Sequence ID No.

77.

23. Antigen-binding molecules that bind to HER3, (i) The following CD-Rs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 40 HC-CDR2 having the amino acid sequence of SEQ ID NO: 43 HC-CDR3 having the amino acid sequence of SEQ ID NO: 48 The heavy-chain variable (VH) region incorporating the following; and (ii) The following CD-Rs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 66 LC-CDR2 having the amino acid sequence of SEQ ID NO: 69 LC-CDR3 having the amino acid sequence of SEQ ID NO: 74 Light chain variable (VL) region incorporating An antigen-binding molecule for use, use, method, pharmaceutical combination, or pharmaceutical combination for use according to any one of claims 1 to 22, including the antigen-binding molecule for use, use, method, pharmaceutical combination, or pharmaceutical combination for use according to any one of claims 1 to 22.

24. Antigen-binding molecules that bind to HER3, (i) The following CD-Rs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 38 HC-CDR2 having the amino acid sequence of SEQ ID NO: 42 HC-CDR3 having the amino acid sequence of SEQ ID NO: 45 The VH region incorporating the following; and (ii) The following CD-Rs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 63 LC-CDR2 having the amino acid sequence of SEQ ID NO: 67 LC-CDR3 having the amino acid sequence of SEQ ID NO: 70 The VL area that incorporates An antigen-binding molecule for use, use, method, pharmaceutical combination, or pharmaceutical combination for use according to any one of claims 1 to 23, including the antigen-binding molecule for use, use, method, pharmaceutical combination, or pharmaceutical combination for use according to any one of claims 1 to 23.

25. Antigen-binding molecules that bind to HER3, A VH region containing an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 33; and A VL region containing an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:

58. An antigen-binding molecule for use, use, method, pharmaceutical combination, or pharmaceutical combination for use according to any one of claims 1 to 24, including the antigen-binding molecule for use, use, method, pharmaceutical combination, or pharmaceutical combination for use according to any one of claims 1 to 24.

26. Antigen-binding molecules that bind to HER3, Polypeptides comprising, or comprising, an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 75; and A polypeptide containing, or derived from, an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:

76. An antigen-binding molecule for use, use, method, pharmaceutical combination, or pharmaceutical combination for use according to any one of claims 1 to 25, including the antigen-binding molecule for use, use, method, pharmaceutical combination, or pharmaceutical combination for use according to any one of claims 1 to 25.

27. An antigen-binding molecule for use, use, method, pharmaceutical combination, or pharmaceutical combination for use according to any one of claims 1 to 3, 7 to 9, 13, 14, 16, 18, or 19 to 26, wherein the taxoid is docetaxel or nab-paclitaxel.

28. An antigen-binding molecule for use, use, method, pharmaceutical combination, or pharmaceutical combination for use according to any one of claims 4 to 9, 15, 16, or 19 to 27, wherein the nucleoside analog is a deoxycytidine nucleoside analog.

29. An antigen-binding molecule for use, use, method, pharmaceutical combination, or pharmaceutical combination for use according to any one of claims 4 to 9, 15, 16, or 20 to 28, wherein the nucleoside analog is gemcitabine or a salt thereof.

30. Antigen-binding molecules that bind to EGFR, (i) The following CD-Rs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 92 HC-CDR2 having the amino acid sequence of SEQ ID NO: 93 HC-CDR3 having the amino acid sequence of SEQ ID NO: 94 The heavy-chain variable (VH) region incorporating the following; and (ii) The following CD-Rs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 96 LC-CDR2 having the amino acid sequence of SEQ ID NO: 97 LC-CDR3 having the amino acid sequence of SEQ ID NO: 98 Light chain variable (VL) region incorporating An antigen-binding molecule for use, use, method, pharmaceutical combination, or pharmaceutical combination for use according to any one of claims 10 to 14 or 17 to 27, including the antigen-binding molecule for use, use, method, pharmaceutical combination, or pharmaceutical combination for use according to any one of claims 10 to 14 or 17 to 27.

31. Antigen-binding molecules that bind to EGFR, A VH region containing an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 91; and A VL region containing an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:

95. An antigen-binding molecule for use, use, method, pharmaceutical combination, or pharmaceutical combination for use, including, according to any one of claims 10 to 14, 17 to 27, or 30.

32. Antigen-binding molecules that bind to EGFR, A polypeptide comprising or comprising an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 99; and A polypeptide comprising, or derived from, an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:

100. An antigen-binding molecule for use, use, method, pharmaceutical combination, or pharmaceutical combination for use according to any one of claims 10 to 14, 17 to 27, 30 or 31, including the antigen-binding molecule for use, use, method, pharmaceutical combination, or pharmaceutical combination for use.

33. Cancers that include cells expressing / overexpressing EGFR family members, or cancers that include cells expressing / overexpressing HER3, cancers that include cells expressing / overexpressing EGFR, cancers that include cells expressing / overexpressing HER3 and EGFR, cancers that include cells with mutations that result in increased expression of ligands for HER3, cancers that include cells with mutations that result in increased expression of ligands for EGFR, cancers that include cells with NRG gene fusions, and cancers that include cells with NRG1 gene fusions. Cancers containing cells or cells containing NRG2 gene fusions, solid tumors, hematological cancers, squamous cell carcinoma, EGFR-amplified squamous cell carcinoma, breast cancer, breast cancer, invasive breast cancer, ductal carcinoma, metastatic breast cancer, triple-negative breast cancer, HER2-positive breast cancer, gastric cancer, gastric adenocarcinoma, gastrointestinal adenocarcinoma, colorectal cancer, metastatic colorectal cancer, colon cancer, colorectal cancer, colorectal adenocarcinoma, colon adenocarcinoma, head and neck cancer, head and neck squamous cell carcinoma, lung cancer, non-small cell lung cancer, lung adenocarcinoma, invasive mucinous lung adenocarcinoma, squamous cell lung cancer, lung squamous cell carcinoma, squamous non Small cell lung cancer, advanced squamous non-small cell lung cancer, metastatic squamous non-small cell lung cancer, ovarian cancer, serous ovarian adenocarcinoma, serous ovarian cystadenocarcinoma, fallopian tube cancer, kidney cancer, renal cell carcinoma, clear cell carcinoma, renal cell adenocarcinoma, papillary renal cell carcinoma, pancreatic cancer, exocrine cancer, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, advanced pancreatic ductal adenocarcinoma, metastatic pancreatic ductal adenocarcinoma, cervical cancer, cervical squamous cell carcinoma, skin cancer, melanoma, oral cancer, oropharyngeal cancer, esophageal cancer, esophageal squamous cell carcinoma, esophageal adenocarcinoma, liver cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, uterine cancer, endometrial cancer, endometrial cancer, child An antigen-binding molecule for use, use, method, or pharmaceutical combination for use according to any one of claims 1 to 13 or 19 to 32, wherein the antigen-binding molecule for use is a thyroid carcinosarcoma, thyroid cancer, thyroid cancer, thyroid cancer, pheochromocytoma, paraganglioma, bladder cancer, urothelial carcinoma of the bladder, prostate cancer, prostate adenocarcinoma, retinoblastoma, sarcoma, soft tissue sarcoma, peritoneal cancer, thymoma, neuroendocrine tumor, nasopharyngeal neuroendocrine tumor, squamous cell carcinoma of the skin, astrocytoma, low-grade astrocytoma, high-grade astrocytoma, undifferentiated astrocytoma, and glioblastoma multiforme.

34. An antigen-binding molecule for use, use, method, or pharmaceutical combination for use according to any one of claims 1 to 13 or 19 to 33, wherein the cancer is selected from cancers comprising cells expressing / overexpressing HER3, cancers comprising cells expressing / overexpressing EGFR, cancers comprising cells expressing / overexpressing HER3 and EGFR, squamous cell carcinoma, EGFR-amplified squamous cell carcinoma, esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, head and neck squamous cell carcinoma, colorectal cancer, metastatic colorectal cancer, colonic adenocarcinoma, pancreatic cancer, exocrine cancer, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, advanced pancreatic ductal adenocarcinoma, metastatic pancreatic ductal adenocarcinoma, lung cancer, squamous cell lung cancer, squamous cell non-small cell lung cancer, advanced squamous cell non-small cell lung cancer, metastatic squamous cell non-small cell lung cancer, and lung squamous cell carcinoma.

35. An antigen-binding molecule for use, use, method, or pharmaceutical combination for use according to any one of claims 1 to 13 or 19 to 34, wherein the cancer is squamous cell carcinoma, lung cancer, non-small cell lung cancer, squamous cell lung cancer, squamous cell non-small cell lung cancer, advanced squamous cell non-small cell lung cancer, metastatic squamous cell non-small cell lung cancer, pancreatic cancer, exocrine cancer, pancreatic ductal adenocarcinoma, advanced pancreatic ductal adenocarcinoma, or metastatic pancreatic ductal adenocarcinoma.

36. An antigen-binding molecule for use, use, method, or pharmaceutical combination for use according to any one of claims 1 to 13 or 19 to 35, wherein the cancer is a cancer comprising cells having a mutation resulting in increased expression of a ligand for HER3, a cancer comprising cells having an NRG gene fusion, a cancer comprising cells having an NRG1 gene fusion, or a cancer comprising cells having an NRG2 gene fusion.

37. Cancers include CLU-NRG1, CD74-NRG1, DOC4-NRG1, SLC3A2-NRG1, RBPMS-NRG1, WRN-NRG1, SDC4-NRG1, RAB2IL1-NRG1, VAMP2-NRG1, KIF13B-NRG1, THAP7-NRG1, SMAD4-NRG1, MDK-NRG1, TNC-NRG1, DIP2B-NRG1, MRPL13-NRG1, PARP8-NRG1, ROCK1-NRG1, DPYSL2-NRG1, ATP1B1-NRG1, and CDH6 An antigen-binding molecule for use, use, method, or pharmaceutical combination for use according to any one of claims 1 to 13 or 19 to 36, comprising cells containing an NRG gene fusion selected from -NRG1, APP-NRG1, AKAP13-NRG1, THBS1-NRG1, FOXA1-NRG1, PDE7A-NRG1, RAB3IL1-NRG1, CDK1-NRG1, BMPRIB-NRG1, TNFRSF10B-NRG1, MCPH1-NRG1, and SLC12A2-NRG2.

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