Combination therapy for cancer treatment and prevention

Abstract

The present disclosure provides methods for treating or preventing cancer comprising administering antigen binding molecules and taxane and / or nucleoside analogs that bind HER3. Also provided are methods for treating or preventing cancer comprising administering an antigen-binding molecule that binds HER3 and an antigen-binding molecule that binds EGFR. Also provided are pharmaceutical compositions and pharmaceutical combinations comprising such medicaments, as well as therapeutic and prophylactic methods of using the pharmaceutical compositions / pharmaceutical combinations.

Description

[0001] This application claims priority to US 63 / 459,373, filed April 14, 2023 and US 63 / 459,396, filed April 14, 2023, the contents and elements of which are incorporated herein by reference for all purposes. Technical Field

[0002] This invention relates to medicine and prevention, particularly the treatment and prevention of cancer. Technical Background

[0003] Many transmembrane protein kinases are involved in tumorigenesis (Roskoski Jr 2004). Human epidermal growth factor receptor 3 (HER3), by forming a heterodimer with epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2), has been identified as a key signaling hub for activating key growth factor signaling pathways (e.g., RAS-ERK and PI3K-Akt pathways) (Gala and Chandarlapaty, Clinical Cancer Research (2014) 6:1410-1416) (Haikala and Clinical Cancer Research (2021) 27(13):3528-3539. Elevated HER3 expression is associated with poor prognosis in various 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 that are 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 of Akt signaling. There are two key mechanisms for HER3 activation (Gala and Chandarlapaty, Clinical Cancer Research (2014) 6:1410-1416): ligand-dependent activation in a low EGFR / HER2 environment, stabilizing HER3 in a dimerization-ready state; and ligand-independent activation in a high EGFR / HER2 environment, where HER3 is transiently activated. HER3 overexpression has been observed in various tumor types, including non-small cell lung cancer (NSCLC). et al., Cancer Discovery (2022) 12(1):74-89).

[0004] For example, Zhang et al. described HER3-binding antibodies in the Chinese Journal of Biochemistry and Biophysics (2016) 48(1):39-48. The anti-HER3 antibody LJM-716 binds to epitopes of subdomains II and IV of the extracellular domain of HER3, locking HER3 in an inactive conformation (Garner et al., Cancer Res (2013) 73:6024–6035). MM-121 (also known as seribantumab) has been shown to inhibit HER3-mediated signaling by blocking the binding of HER3 to thymosin (HRG) (Schoeberl et al., Sci. Signal. (2009) 2(77):ra31). Patritumab (also known as U-1287 and AMG-888) also blocks the binding of hyalin to HER3 (see, for example, Shimizu et al., Cancer Chemother Pharmacol. (2017) 79(3):489–495). RG7116 (also known as lumretuzumab and RO-5479599) recognizes an epitope of subdomain I of the extracellular domain of HER3 (see, for example, Mirschberger et al., Cancer Research (2013) 73(16) 5183–5194). KTN3379 binds to HER3 by interacting with amino acid residues in subdomain III (corresponding to the following positions in SEQ ID NO:1: Gly476, Pro477, Arg481, Gly452, Arg475, Ser450, Gly420, Ala451, Gly419, Arg421, Thr394, Leu423, Arg426, Gly427, Lys356, Leu358, Leu358, Lys356, Ala330, Lys329, and Gly337) and Met310, Glu311, and Pro328 in subdomain II (see Lee et al., Proc Natl Acad Sci US A. 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 the binding of the ligand to HER3 (see Zhang et al., Mol Cancer Ther (2014) 13:1345–1355).RG7597 (duligotuzumab) is a dual-action Fab (DAF) that binds to both HER3 and EGFR, specifically binding to subdomain III of HER3 (see Schaefer et al., Cancer Cell (2011) 20(4):472-486). MM-111 and MM-141 are bispecific antibodies with a HER3-binding arm that inhibit the binding of HRG ligands to HER3 (see McDonald 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 deaths worldwide, accounting for nearly one-fifth of all 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 NSCLC originates from epithelial tissue and is influenced by environmental factors such as smoking. The 5-year survival rate for NSCLC patients after diagnosis is 28% (Detterbeck and Gibson, Journal of Thoracic Oncology (2008) 3(7):781-792). The 5-year survival rate for metastatic NSCLC is only 9% (American Cancer Society 2023). The standard first-line treatment for metastatic LUSC is immunotherapy with or without platinum-based chemotherapy, as actionable biomarkers for approved targeted therapies are rare in this NSCLC subtype (Yuan et al., Molecular (2021) 26(5):1392). Once a patient progresses after combination therapy, subsequent treatment options offer only limited clinical benefit, indicating a significant need.

[0006] Early carcinogenesis features of squamous cell carcinoma include chromosome 3q (Chr3q) amplification and chromosome 3p (Chr3p) deletion, which are well-known genetic aberrations associated with carcinogen exposure (Rooney et al., Oncologist (2013) 18(6):707-716). Chr3q amplification leads to increased transcriptional activity in many genes, including TP63 (directly promoting the expression of HER3 ligand NRG1), SOX2 (directly promoting the expression of EGFR ligand), and the PIK3CA gene (enhancing the activation of the PI3K pathway) (Perez-Moreno et al., Clinical Cancer Research (2012) 18(9):2443-2451). On the other hand, Chr3p deletion leads to the loss of several putative tumor suppressor proteins, including TUSC2, a tumor suppressor candidate protein that 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 LUSC (Couceiro et al., Portuguese Journal of Pneumonia (2010) 16(3):453-462).

[0007] Precise targeting of cancer-driving mutations, coupled with significant advances in genomics technology enabling timely patient screening, has altered patient outcomes across various cancer indications (Martinez-Jimenez et al., Nat Rev Cancer (2020) 20(10):555-572). Neuroregulatory protein-1 (NRG1) gene fusions are a relatively new category of potentially actionable driving events. These transmembrane chimeric proteins exert their oncogenic function through the ErbB receptor family, binding to HER3 and stabilizing the protein in an open conformation, thereby forming heterodimers with EGFR or HER2, leading to constitutive activation of known classical pathways such as MAPK and PI3K / Akt (Fernandez-Cuesta et al., Cancer Discovery (2014) 4(4):415-22; Liu et al., Lung Cancer (2021) 158:25-28). Currently, there are no approved treatments for NRG1 fusion-positive cancer patients. In the past two years, the U.S. FDA has granted Fast Track designation to serbantumab (an anti-HER3 IgG2 monoclonal antibody) (OncLive Spotlight, May 26, 2022) and zenocutuzumab (a bispecific antibody that binds to HER2 and HER3) for cancer patients with NRG1 fusions (CancerNetwork Spotlight, January 9, 2021), highlighting significant unmet clinical needs.

[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 pancreatic cancer patients is poor, with only 11% surviving to 5 years after initial diagnosis. For patients with metastatic disease, the 5-year survival rate is even lower, at only 3% (American Cancer Society, 2022).

[0009] In the phase III MPACT trial, the efficacy of combination chemotherapy with gemcitabine and nab-paclitaxel was confirmed by comparing gemcitabine alone with gemcitabine alone. This combination improved median overall survival to 8.7 months, compared to 6.6 months with gemcitabine alone, and the overall response rate was 23%, compared to 7% with gemcitabine alone (Von Hoff et al., N Engl J Med (2013) 369(18):1691-703). Further treatment options are needed for this patient population.

[0010] Forster et al., in the European Journal of Cancer (2019) 123:36-47, published a study on the combination therapy of the anti-HER3 antibody patritumab and the anti-EGFR antibody cetuximab for the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Patritumab (also known as U-1287 and AMG-888) has been shown to inhibit HER3-mediated signaling by blocking the binding of modulatory protein (HRG) to HER3 (see, for example, Shimizu et al., Cancer Chemotherapy and Pharmacology (2017) 79(3):489–495).

[0011] Cleary et al., New Drug Research (2017) 35:68-78, disclosed a dosing regimen for the combination therapy of the anti-HER3 antibody seribantumab and cetuximab for EGFR-dependent cancers. Similar to paretuximab, seribantumab (also known as MM-121) has been shown to inhibit HER3-mediated signaling by blocking the binding of hRG to HER3 (Schoeberl et al., Sci. Signal. (2009) 2(77):ra31). Meulendijks et al., Clinical Cancer Research (2017) 23(18):5406-5415, disclosed a dosing regimen for the combination therapy of the anti-HER3 antibody lumretuzumab and cetuximab for advanced HER3-positive cancers. Only mild clinical activity was observed. Lumretuzumab (also known as RG7116 and RO-5479599) recognizes epitopes of subdomain I of the HER3 extracellular domain (see, for example, Mirschberger et al., Cancer Research (2013) 73(16) 5183-5194).

[0012] Bauman et al., Cancer (Basel) (2022) 14(10):2355 reported the results of a phase II trial of 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 moderate. CDX-3379 (also known as KTN3379) binds to HER3 by interacting with amino acid residues in subdomain III (corresponding to the following positions in SEQ ID NO:1: 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 Met310, Glu311, and Pro328 in subdomain II (see Lee et al., NSF 2015 Oct 27; 112(43):13225).

[0013] Garner et al., Cancer Research (2013) 73(19):6024–6035 disclosed the anti-HER3 antibody LJM-716 in combination with cetuximab for the treatment of HNSCC. LJM-716 binds to epitopes of subdomains II and IV of the extracellular domain of HER3, locking HER3 in an inactive conformation (Garner et al., Cancer Research (2013) 73:6024–6035).

[0014] Papadopoulos et al., Journal of Clinical Oncology (2014) 32(15_suppl):2516-2516, disclosed a method of administration of the anti-HER3 antibody REGN1400 in combination with cetuximab for the treatment of advanced non-small cell lung cancer (NSCLC), colorectal cancer (CRC), or SCCHN. REGN1400 also inhibits the binding of the ligand to HER3 (see Zhang et al., Mol Cancer Ther (2014) 13:1345–1355).

[0015] Kim et al., Annals of Oncology (2020) 31(suppl_4):S599-S628, disclosed the use of the anti-HER3 antibody ISU104 in combination with cetuximab for the treatment of relapsed or metastatic HNSCC. ISU104 (also known as barecetamab) primarily binds to domain III of HER3, interacts weakly with domain I, and exhibits dose-dependent inhibition of HRG binding to HER3 (see Kim et al., Cancer Research (2018) 78(13Supplement):830-830).

[0016] summary

[0017] In a first aspect, this disclosure provides an antigen-binding molecule that binds to HER3 for the treatment or prevention of cancer, wherein the method comprises administering an antigen-binding molecule that binds to EGFR.

[0018] The use of antigen-binding molecules that bind to HER3 in the preparation of medicaments for methods of treating or preventing cancer is also provided, wherein the methods include administering antigen-binding molecules that bind to EGFR.

[0019] A method for treating or preventing cancer is also provided, comprising administering to a subject therapeutic or preventative amounts of (i) antigen-binding molecules that bind to HER3 and (ii) antigen-binding molecules that bind to EGFR.

[0020] In some embodiments according to various aspects of this disclosure, the method further includes the application of taxane.

[0021] An antigen-binding molecule that binds to HER3 is also provided for the treatment or prevention of cancer, wherein the method includes the administration of taxane.

[0022] The use of antigen-binding molecules that bind to HER3 in the preparation of medicaments for methods of treating or preventing cancer is also provided, wherein said methods include the administration of taxanes.

[0023] A method for treating or preventing cancer is also provided, comprising administering to a subject a therapeutic or preventative amount of (i) an antigen-binding molecule that binds to HER3 and (ii) taxane.

[0024] An antigen-binding molecule that binds to HER3 is also provided for the treatment or prevention of cancer, wherein the method comprises the administration of taxane and nucleoside analogues.

[0025] It also provides the use of antigen-binding molecules that bind to HER3 in the preparation of medicaments for methods of treating or preventing cancer, wherein said methods include the administration of taxanes and nucleoside analogs.

[0026] A method for treating or preventing cancer is also provided, comprising administering to a subject a therapeutic or preventative amount of (i) an antigen-binding molecule that binds to HER3, (ii) taxane, and (iii) a nucleoside analogue.

[0027] An antigen-binding molecule that binds to HER3 is also provided for the treatment or prevention of cancer, wherein the method includes the administration of a nucleoside analogue.

[0028] It also provides the use of antigen-binding molecules that bind to HER3 in the preparation of medicaments for methods of treating or preventing cancer, wherein said methods include the administration of nucleoside analogs.

[0029] A method for treating or preventing cancer is also provided, comprising administering to a subject a therapeutic or preventative amount of (i) an antigen-binding molecule that binds to HER3 and (ii) a nucleoside analogue.

[0030] A drug combination is also provided, comprising (i) an antigen-binding molecule that binds to HER3 and (ii) an antigen-binding molecule that binds to EGFR.

[0031] A drug combination is also provided, comprising (i) an antigen-binding molecule that binds to HER3, (ii) an antigen-binding molecule that binds to EGFR, and (iii) taxane.

[0032] A drug combination is also provided, comprising (i) an antigen-binding molecule that binds to HER3 and (ii) taxane.

[0033] A drug combination is also provided, comprising (i) an antigen-binding molecule that binds to HER3, (ii) a nucleoside analogue and (iii) taxane.

[0034] A drug combination is also provided, comprising (i) an antigen-binding molecule that binds to HER3 and (ii) a nucleoside analog.

[0035] In some implementations, methods are provided for using drug combinations according to this disclosure to treat or prevent cancer.

[0036] The use of the pharmaceutical combination according to this disclosure in the preparation of a medicament for treating or preventing cancer is also provided.

[0037] A method for treating or preventing cancer is also provided, comprising administering to a subject a therapeutically or preventively effective amount of a combination of drugs according to the present disclosure. In some embodiments according to various aspects of the present disclosure, an antigen-binding molecule that binds to HER3 binds to the HER3 region shown in SEQ ID NO:77. In some embodiments, the antigen-binding molecule that binds to HER3 includes:

[0038] (i) Heavy chain variable (VH) regions containing the following CDRs:

[0039] HC-CDR1 with the amino acid sequence of SEQ ID NO:40

[0040] HC-CDR2 with the amino acid sequence SEQ ID NO:43

[0041] HC-CDR3 having the amino acid sequence of SEQ ID NO:48; and

[0042] (ii) Light chain variable (VL) regions containing the following CDRs:

[0043] LC-CDR1 with the amino acid sequence SEQ ID NO:66

[0044] LC-CDR2 with the amino acid sequence SEQ ID NO:69

[0045] LC-CDR3 having the amino acid sequence of SEQ ID NO:74.

[0046] In some implementations, the antigen-binding molecules that bind to HER3 include:

[0047] (i) VH region containing the following CDRs:

[0048] HC-CDR1 with the amino acid sequence of SEQ ID NO:38

[0049] HC-CDR2 with the amino acid sequence SEQ ID NO:42

[0050] HC-CDR3 having the amino acid sequence of SEQ ID NO:45; and

[0051] (ii) VL regions containing the following CDRs:

[0052] LC-CDR1 with the amino acid sequence of SEQ ID NO:63

[0053] LC-CDR2 with the amino acid sequence SEQ ID NO:67

[0054] LC-CDR3 having the amino acid sequence of SEQ ID NO:70.

[0055] In some implementations, the antigen-binding molecules that bind to HER3 include:

[0056] The VH region comprises an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:33; and

[0057] The VL region contains an amino acid sequence that has at least 70% sequence identity with the amino acid sequence of SEQ ID NO:58.

[0058] In some implementations, the antigen-binding molecules that bind to HER3 include:

[0059] Containing or consisting of a polypeptide having at least 70% sequence identity with an amino acid sequence having the same amino acid sequence as SEQ ID NO:75; and

[0060] A polypeptide comprising or consisting of an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:76.

[0061] In some embodiments according to various aspects of this disclosure, the taxane-like substance is docetaxel or albumin-bound paclitaxel. In some embodiments, paclitaxel is docetaxel.

[0062] 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.

[0063] In some implementations, the antigen-binding molecules that bind to EGFR include:

[0064] (i) Heavy chain variable (VH) regions containing the following CDRs:

[0065] HC-CDR1 with the amino acid sequence SEQ ID NO:92

[0066] HC-CDR2 with the amino acid sequence SEQ ID NO:93

[0067] HC-CDR3 having the amino acid sequence of SEQ ID NO:94; and

[0068] (ii) Light chain variable (VL) regions containing the following CDRs:

[0069] LC-CDR1 with the amino acid sequence of SEQ ID NO:96

[0070] LC-CDR2 with the amino acid sequence SEQ ID NO:97

[0071] LC-CDR3 having the amino acid sequence of SEQ ID NO:98.

[0072] In some implementations, the antigen-binding molecules that bind to EGFR include:

[0073] The VH region comprises an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:91; and

[0074] The VL region contains an amino acid sequence that has at least 70% sequence identity with the amino acid sequence of SEQ ID NO:95.

[0075] In some implementations, the antigen-binding molecules that bind to EGFR include:

[0076] A polypeptide comprising or consisting of an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:99; and

[0077] A polypeptide comprising or consisting of an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:100. In some embodiments according to various aspects of this disclosure, the cancer is: a cancer comprising cells expressing / overexpressing EGFR family members, or a cancer comprising cells expressing / overexpressing HER3. In some embodiments, the cancer is: squamous cell carcinoma, lung cancer, non-small cell lung cancer, squamous cell lung cancer, squamous non-small cell lung cancer, advanced squamous non-small cell lung cancer, metastatic squamous non-small cell lung cancer, pancreatic cancer, exocrine carcinoma, pancreatic ductal adenocarcinoma, advanced pancreatic ductal adenocarcinoma, metastatic pancreatic ductal adenocarcinoma. In some embodiments, the cancer is: a cancer comprising cells with mutations leading to increased HER3 ligand expression, a cancer comprising cells with NRG gene fusions, a cancer comprising cells with NRG1 gene fusions, or a cancer comprising cells with NRG2 gene fusions. In some embodiments, the cells of the cancer comprise NRG gene fusions selected from the group consisting of: CLU-NRG1, CD74-NRG1, DOC4-NRG1, SLC3A2-NRG1, RBPMS-NRG1, WRN-NRG1, SDC4-NRG1, RAB2IL1-NRG1, VAMP2-NRG1, KIF13B-NRG1, THAP7-N RG1, SMAD4-NRG1, MDK-NRG1, TNC-NRG1, DIP2B-NRG1, MRPL13-NRG1, 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, MCPH1-NRG1, and SLC12A2-NRG2.

[0078] In some embodiments, the cancer is selected from: 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 both HER3 and EGFR, cancers containing cells with mutations leading to increased HER3 ligand expression, cancers containing cells with mutations leading to increased EGFR ligand expression, cancers containing cells with NRG gene fusions, and cancers containing cells with NRG1 gene fusions. Cancers of cells, or cancers containing cells with NRG2 gene fusion, solid tumors, hematologic malignancies, squamous cell carcinoma, EGFR-amplified squamous cell carcinoma, breast cancer, breast adenoma, invasive breast cancer, ductal carcinoma, metastatic breast cancer, triple-negative breast cancer, HER2-positive breast cancer, gastric cancer, gastric tumor, 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 lung adenocarcinoma, squamous cell carcinoma. 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, ovarian tumor, ovarian serous adenocarcinoma, ovarian serous cystadenocarcinoma, fallopian tube cancer, kidney cancer, renal cell carcinoma, clear cell renal carcinoma, renal cell adenocarcinoma, papillary cell renal carcinoma, pancreatic cancer, exocrine carcinoma, pancreatic adenocarcinoma, pancreatic duct adenocarcinoma, advanced pancreatic duct adenocarcinoma, metastatic pancreatic duct adenocarcinoma, cervical cancer, cervical squamous cell carcinoma, skin cancer, melanoma, oral cancer, oropharyngeal cancer, esophageal cancer, esophageal squamous cell carcinoma, esophageal gland Cancer, liver cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, uterine cancer, endometrial cancer, uterine sarcoma, thyroid cancer, thyroid adenoma, pheochromocytoma, paraganglioma, bladder cancer, bladder urothelial carcinoma, 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, anaplastic astrocytoma, and glioblastoma multiforme.

[0079] In some embodiments, the cancer is selected from: cancers containing cells expressing / overexpressing HER3, cancers containing cells expressing / overexpressing EGFR, cancers containing cells expressing / overexpressing both 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 pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, advanced pancreatic ductal adenocarcinoma, metastatic pancreatic ductal adenocarcinoma, lung cancer, squamous cell lung cancer, squamous non-small cell lung cancer, advanced squamous non-small cell lung cancer, metastatic squamous non-small cell lung cancer, and lung squamous cell carcinoma.

[0080] describe

[0081] This disclosure relates to combined treatments for cancer.

[0082] This disclosure relates to: (i) combination therapies for cancer, including antigen-binding molecules that bind to HER3 and taxane-like substances; (ii) combination therapies for cancer, including antigen-binding molecules that bind to HER3 and nucleoside analogs; and (iii) combination therapies for cancer, including antigen-binding molecules that bind to HER3, taxane-like substances, and nucleoside analogs.

[0083] This disclosure also relates to combination therapies for cancer, including antigen-binding molecules that bind to HER3 and antigen-binding molecules that bind 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.

[0084] 10D1F binds to an epitope of HER3 that differs from the epitope of anti-HER3 antibodies used in prior art combination therapies involving anti-HER3 antibodies and cetuximab. More specifically, 10D1F binds to the dimerization interface of HER3, while other anti-HER3 antibodies bind to various sites within the extracellular domains of HER3 (e.g., ligand-binding domains, domains II / IV). Because 10D1F inhibits the dimerization of HER3 with its receptor chaperone and blocks both ligand-dependent and ligand-independent activation of HER3, it can more completely shut down HER3-mediated signaling.

[0085] In the experimental embodiments of this application, the inventors demonstrated that the combination of 10D1F and cetuximab exhibits unexpected and superior properties compared to prior art combination therapies comprising anti-HER3 antibodies and cetuximab. The combination of 10D1F and cetuximab as an intervention also demonstrates unexpected beneficial effects in the treatment / prevention of various cancers compared to either component of the combination used as a monotherapy.

[0086] HER3

[0087] HER3 (also known as, for example, ERBB3, LCCS2, MDA-BF-1) is a protein identified as UniProt P21860.

[0088] The structure and function of HER3 have been described in, for example, in *Cho and Leahy, Science (2002) 297(5585):1330-1333*, *Singer et al., Journal of Biochemistry (2001) 276, 44266-44274*, *Roskoski et al., Pharmacol. Res. (2014) 79:34–74*, *Bazley and Gullick, Endocrine-Related Cancers (2005) S17-S27*, and *Mujoo et al., Tumor Targets (2014) 5(21):10222-10236*, all of which are incorporated herein by reference. HER3 is a single-channel transmembrane ErbB receptor tyrosine kinase with an N-terminal extracellular region (SEQ ID NO:9) comprising two leucine-rich subdomains (domains I and III, as shown in SEQ ID NO:15 and 17, respectively) and two cysteine-rich subdomains (domains II and IV, as shown in SEQ ID NO:16 and 18, respectively). Domain II includes a β-hairpin dimer loop (SEQ ID NO:19) and participates in intermolecular interactions with other HER receptor molecules. The extracellular region is connected to the cytoplasmic region (SEQ ID NO:11) via a transmembrane region (SEQ ID NO:10). The cytoplasmic region comprises a juxtamembrane segment (SEQ ID NO:12), a protein kinase domain (SEQ ID NO:13), and a C-terminal segment (SEQ ID NO:14).

[0089] In this specification, "HER3" means HER3 from any species and includes HER3 isotypes, fragments, variants (including mutants) or homologs from any species.

[0090] As used herein, a protein “fragment,” “variant,” or “homologous” may optionally be characterized as 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 a reference protein (e.g., a reference isoform). In some embodiments, fragments, variants, isoforms, and homologs of a reference protein may be characterized as having the ability to perform the functions performed by the reference protein.

[0091] A “fragment” typically refers to a small portion of a reference protein. A “variant” typically refers to a protein having one or more amino acid substitutions, insertions, deletions, or other modifications relative to the amino acid sequence of the reference protein, but maintaining a comparable degree of sequence identity (e.g., at least 60%) with the amino acid sequence of the reference protein. An “isotype” typically refers to a variant of a reference protein expressed by a species of the same species as the reference protein (e.g., human HER3 isotypes 1 through 5 are isotypes of each other). A “homologous” typically refers to a variant of a reference protein produced by a species of a different species than the reference protein. For example, human HER3 isotype 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 compounds include orthologous compounds.

[0092] The “fragment” of the reference protein can be of any length (in terms of amino acid count), optionally at least 20% of the length of the reference protein (i.e., the protein from which the fragment is derived), and can have a maximum length of any one of 50%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the length of the reference protein.

[0093] The minimum length of the HER3 fragment can be 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 the maximum length can be one of 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1100, 1200, or 1300 amino acids.

[0094] In some embodiments, HER3 is HER3 derived from mammals (e.g., primates (rhesus monkeys, cynomolgus monkeys, non-human primates, or humans) and / or rodents (e.g., rats or mice)). Isotypes, fragments, variants, or homologs of HER3 may optionally be characterized as having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with an immature or mature HER3 isotype from a given species (e.g., humans).

[0095] Isotypes, fragments, variants, or homologs can be optional functional isotypes, fragments, variants, or homologs, for example, having the functional properties / activities of a reference HER3 (e.g., human HER3 isotype 1), determined by appropriate analysis of the functional properties / activities. For example, isotypes, fragments, variants, or homologs of HER3 may be associated with one or more of HER2, NRG1 (types I, II, III, IV, V, or VI), or NRG2 (α or β).

[0096] In some embodiments, HER3 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% sequence identity with any one of SEQ ID NO:1 to 8.

[0097] In some embodiments, the HER3 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% sequence identity with any one of SEQ ID NO: 9 to 19 (e.g., one of 9, 16, or 19).

[0098] Signal transduction via HER3 involves receptor heterodimerization (i.e., with other ErBB receptors, such as HER2 and EGFR) and subsequent autophosphorylation by the protein kinase domain of tyrosine residues in the cytoplasm. HER3 lacks kinase activity and cannot form stable homodimers. Therefore, HER3 must be transphosphorylated by binding to a kinase-active heterodimer chaperone (such as EGFR or HER2) to transduce signal (Berger MB et al., FEBS Lett 2004; 569:332-6; KimHH et al., Biochem J 1998; 334:189-95).

[0099] Polymerization (e.g., dimerization) of HER receptor family members is essential for the activation of cell growth signaling pathways. HER3 can dimerize with other HER family members in both ligand-dependent and ligand-independent ways. The HER3 extracellular domain (ECD) exists in a reversible equilibrium between a “closed” inactive conformation and an “open” active conformation, in which dimerizing arms within domain II are exposed to allow dimerization along the domain II dimerization interface, particularly through the cysteine-rich CR1 region (Carraway, KL, et al., Nature 1997.387(6632):512-6; Riese, DJ, et al., Molecular Cell Biology 1995.15(10):5770-6; Harari, D., et al., Oncogenes 1999.18). (17):2681-9》;《Zhang, D., et al., National Association for the Advancement of Science 1997.94(18):9562-7》;《Meyer et al., Nature 1995.378(6555):386-90》;《Jura, N., et al., National Association for the Advancement of Science 2009.106(51):21608-13》;《Fornaro, L., et al., Gastroenterology & Hepatology 2011.8(7):369-83》;《Mota et al., Tumor Targets (2015)5:89284–306》). When the equilibrium shifts towards the open conformation, HER3 is "activated", thereby increasing the likelihood of forming an active heterodimer. Traditional activation models are ligand-dependent, meaning that the equilibrium shifts when the open conformation of HER3 is stabilized by binding its ligands, such as neural regulatory proteins (NRGs), like NRG1 (also known as heregulin, HRG) or NRG2. Furthermore, the presence of any dimerizing chaperones in sufficient concentrations will shift the equilibrium toward the open conformation as they bind to HER3 and transiently stabilize it in the open conformation. This is known as ligand-independent activation (Jura, N., et al., National Association for the Advancement of Science, 2009, 106(51):21608-13; Fornaro, L., et al., Gastroenterology & Hepatology, 2011, 8(7):p.369-83; Mota, et al., Targets of Tumors, (2015) 5:89284–306).

[0100] In this article, "HER3-mediated signaling" refers to signaling mediated by HER3 and / or HER3-containing polymeric ErbB family member receptor complexes. "Signaling" refers to signal transduction and other cellular processes that control cellular activity. HER3-mediated signaling may be mediated by complexes containing HER3 receptors, such as heteromeric complexes composed of HER3 and other HER receptors (e.g., HER2, EGFR). HER3-mediated signaling may be ligand-dependent, such as triggered by NRG binding (e.g., NRG1, NRG2), or ligand-independent.

[0101] HER3-mediated signaling occurs intracellularly via the MAPK / ERK and PI3K / AKT / mTOR pathways to promote cell survival and proliferation. HER3-mediated signaling has been studied in numerous publications, including Gala and Chandarlapaty, Clinical Cancer Research, (2014) 20(6):1410–1416; Mishra et al., Oncol Rev. (2018) 12(1):355; Baselga et al., Nature Reviews Cancer, (2009) 9:463–75; Yarden et al., Cell Biology, (2001) 2:3505-2073; Mota et al., Tumor Targets, (2015) 5:89284–306; and Haikala and The above is described in Clinical Cancer Research, (2021) 27:3528-39, and all of the above is incorporated herein by reference.

[0102] Phosphorylated tyrosine residues in the protein kinase domain of the HER3 receptor complex recruit the adaptor / effect protein GRB2 through interaction with its SH2 domain. Upon ligand stimulation, the activated receptor (EGFR / HER2) undergoes autophosphorylation, providing phosphorylated tyrosine residues for GRB2 recruitment. GRB2 binds to the guanine nucleotide exchange factor SOS via its SH3 domain. Activated SOS in the GRB2-SOS complex promotes the dissociation of GDP from Ras family GTPases (such as H-Ras, N-Ras, and K-Ras), thereby activating them. Activated Ras GTPases sequentially activate RAF kinases, such as A-Raf, B-Raf, and C-Raf. RAF kinases sequentially phosphorylate and activate MEK1 and MEK2, then phosphorylate and activate MAKP (also known as ERK). Activated MAKP can directly regulate the activity of transcription factors such as c-Myc. Activated MAPK also upregulates mRNA-to-protein translation via RSK phosphorylation and subsequent 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.

[0103] Phosphorylated tyrosine residues in the HER3 protein kinase domain also recruit the p85 subunit of PI3K via its SH2 domain. This p85 association induces allosteric activation of the p100α subunit of the PI3K lipid kinase. Activated PI3K leads to the conversion of PIP2 to PIP3, which recruits AKT, which is phosphorylated and activated by mTORC2 and PDK1. Phosphorylated AKT exhibits a variety of activities, including activation of CREB and mTOR. PTEN antagonizes the PI3K / AKT / mTOR pathway signaling by dephosphorylating PIP3 to PIP2, and PP2A inhibits the PI3K / AKT / mTOR pathway by dephosphorylating AKT.

[0104] Oncogenic Src homology region 2 protein tyrosine phosphatase 2 (SHP2) promotes tumor progression and serves as a hub connecting multiple oncogenic signaling pathways, such as PI3K / AKT and Ras / Raf / MAPK (Dong et al., Cell Development Biology, March 11, 2021). GAB2 binds to GRB2 and phosphorylates multiple tyrosine residues, enabling it to bind to the SH2 domain 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). Interactions induce conformational changes that alleviate the self-inhibition of the SHP2 catalytic site (Neel et al., Trends Biochem Sci. 2003 Jun; 28(6):284-93) and alleviate 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 has been shown to activate RAS by directly dephosphorylating RAS (Bunda et al., Nature Communications 2015 Nov 30; 6:8859), inhibiting RASGAP (RAS GTPase activator 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). STAT3 and STAT5 are transcription factors that enhance the expression of p85α, p110α, and AKT1, thereby enhancing signal transduction through the PI3K / AKT signaling cascade (Radler et al., Mol Cell Endocrinol. 2017 August 15; 451: 31–39). Upon activation by JAK2, phosphorylated STAT5 binds to the SH2 domain of the p85α regulatory subunit of PI3K in a PRL-dependent manner, suggesting that STAT5 may also be directly involved in the signal transduction of the PI3K complex.Another phosphorylated EGFR kinase is the cytokine-regulated tyrosine kinase Jak2, thus even EGFR kinase-deficient mutants can activate MAPK (Mishra et al., Oncol Rev. (2018) 12(1):355; Baselga et al., Nat Rev Cancer (2009) 9:463–75). Collective observations in genetic models with overexpression or lack of activated STAT5 and AKT, or expression of mutant PTEN, support the view that STAT5 functions as a survival factor during normal breast development and as an oncogene in breast cancer development mediated by the PI3K / AKT pathway (Radler et al., Mol Cell Endocrinol. 2017 Aug 15; 451:31–39).

[0105] EGFR

[0106] EGFR (also known as ERBB1, HER1, etc.) is a protein identified as UniProt P00533.

[0107] 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*, all of which are incorporated herein by reference. EGFR is a single-channel transmembrane ErbB receptor tyrosine kinase with an N-terminal extracellular domain (SEQ ID NO: 88) that is linked to a cytoplasmic domain (SEQ ID NO: 90) via a transmembrane domain (SEQ ID NO: 89).

[0108] In this specification, “EGFR” means EGFR from any species and includes EGFR isotypes, fragments, variants (including mutants) or homologs from any species.

[0109] The minimum length of an EGFR fragment can be 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 the maximum length can be 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.

[0110] In some embodiments, the EGFR is an EGFR derived from mammals (e.g., primates (rhesus monkeys, cynomolgus monkeys, non-human primates, or humans) and / or rodents (e.g., rats or mice)). Isotypes, fragments, variants, or homologs of EGFR may optionally be characterized as having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with an immature or mature EGFR isotype from a given species (e.g., humans).

[0111] Isotypes, fragments, variants, or homologs can be optional functional isotypes, fragments, variants, or homologs, for example, possessing the functional properties / activities of a reference EGFR (e.g., human EGFR isotype 1), determined through appropriate analysis of the functional properties / activities. For example, an EGFR isotype, fragment, variant, or homolog may be associated with one or more of HER3, HER2, EGF, TGFα, and dual-regulated proteins.

[0112] In some embodiments, EGFR 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% sequence identity with any one of SEQ ID NO: 80 to 87.

[0113] 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% sequence identity with any one of SEQ ID NO: 88, 89, or 90.

[0114] EGFR-mediated signaling has been described in, for example, in *Sigismund et al., Mol Oncol. (2018) 12(1):3-20* and *Kovacs et al., Annu Rev Biochem. (2015) 84:739-764*, all of which are incorporated herein by reference. Classical EGFR signaling is essential for a variety of cellular functions, including survival, proliferation, differentiation, and motility. In the absence of ligands, EGFR is primarily located in the plasma membrane, in a state of self-inhibition and insufficient dimerization. Ligand binding induces receptor dimerization and aggregation of the catalytic domain, leading to trans-autophosphorylation of key tyrosine residues in the cytoplasmic domain, triggering an intracellular signaling cascade. Seven EGFR ligands are known, each inducing a variety of downstream signals with varying types and intensities. EGFR can also heterodimerize with HER2, HER3, and HER4. Signals from heterodimers are predicted to be more carcinogenic than those from EGFR homodimers.

[0115] 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.

[0116] antigen-binding molecules

[0117] This invention relates to the therapeutic and preventive uses of antigen-binding molecules that bind to HER3 and antigen-binding molecules that bind to EGFR.

[0118] An "antigen-binding molecule" is a molecule that binds to a given target antigen. Antigen-binding molecules include antibodies (i.e., immunoglobulins) and their antigen-binding fragments. As used herein, "antibody" includes monoclonal antibodies, polyclonal antibodies, monospecific and multispecific (e.g., bispecific, trispecific, etc.) antibodies, and antibody-derived antigen-binding molecules such as scFv, scFab, biantibodies, triantibodies, scFv-Fc, microantibodies, and single-domain antibodies (e.g., VhH, etc.). Antigen-binding fragments of antibodies include fragments such as Fv, Fab, F(ab')2, and F(ab'). In some embodiments, the antigen-binding molecule may be an antibody or its antigen-binding fragment.

[0119] The antigen-binding molecules according to this disclosure also include antibody-derived molecules, such as molecules comprising an antigen-binding region / domain derived from an antibody. Antibody-derived antigen-binding molecules may include an antigen-binding region / domain comprising or consisting of an antigen-binding region of an antibody (e.g., an antigen-binding fragment of an antibody). In some embodiments, the antigen-binding region / domain of the antibody-derived antigen-binding molecule may be or comprise an Fv (e.g., provided as an scFv) or Fab region of an antibody, or a whole antibody. For example, antigen-binding molecules according to this disclosure include antibody-drug conjugates (ADCs) containing a (cytotoxic) pharmaceutical moiety (e.g., as described below). The antigen-binding molecules according to this disclosure also include multispecific antigen-binding molecules, such as immune cell conjugating molecules containing a domain for recruiting (effective) immune cells (e.g., described in Goebeler and Bargou, Nat. Rev. Clin. Oncol. (2020) 17:418–434 and Ellerman, Methods (2019) 154:102–117, all contents of which are incorporated herein by reference), including BiTEs, BiKEs, and TriKEs. The antigen-binding molecules according to this disclosure also include chimeric antigen receptors (CARs), which are recombinant receptors that provide antigen binding and T cell activation functions (the structure, function, and engineering of CARs are reviewed, for example, in Dotti et al., Immunol Rev (2014) 257(1) and Jayaraman et al., EBioMedicine (2020) 58:102931, all contents of which are incorporated herein by reference).

[0120] The antigen-binding molecules disclosed herein include one or more portions capable of binding to a target antigen. In some embodiments, the portion capable of binding to the target antigen includes an antibody heavy chain variable region (VH) and an antibody light chain variable region (VL) of an antibody capable of specifically binding to the target antigen. In some embodiments, the portion capable of binding to the target antigen includes or consists of an aptamer capable of binding to the target antigen, such as a nucleic acid aptamer (see, for example, Zhou and Rossi, Nat Rev DrugDiscov. 2017 16(3):181-202). In some implementations, the portion capable of binding to the target antigen includes or consists of antigen-binding peptides / peptides, such as peptide aptamers, thioredoxins, monomers, antipeptides, Kunitz domains, avimers, knottins, fynomers, atrimers, DARPins, affinity molecules, nanobodies (i.e., single-domain antibodies (sdAbs)), attachment proteins, armadillo repeat proteins (ArmRPs), OBodys, or fibronectins, see, for example, Reverdatto et al., Curr TopMed Chem. 2015; 15(12):1082–1101, all of which are incorporated herein by reference (see also, for example, Boersma et al., J Biol Chem (2011) 286:41273-85 and Emanuel et al., Mabs (2011) 3:38-48).

[0121] As used herein, a "peptide" is a chain of two or more amino acid monomers linked by peptide bonds. Peptides typically have a length of about 2 to 50 amino acids. A "polypeptide" is a polymer chain composed of two or more peptides. Polypeptides typically have a length of more than about 50 amino acids.

[0122] The antigen-binding molecules disclosed herein typically include an antigen-binding domain comprising VH and VL of an antibody capable of specifically binding to a target antigen. The antigen-binding domain formed by VH and VL may also be referred to herein as the Fv region.

[0123] An antigen-binding molecule may be or may contain an antigen-binding polypeptide or an antigen-binding polypeptide complex. An antigen-binding molecule may contain more than one polypeptide that together form an antigen-binding domain. The polypeptides may be covalently or non-covalently bound. In some embodiments, the polypeptide constitutes a portion of a larger polypeptide containing the polypeptide (e.g., VH and VL contained in scFv, or VH-CH1 and VL-CL contained in scFab).

[0124] An antigen-binding molecule can refer to a non-covalent or covalent complex of more than one polypeptide (e.g., 2, 3, 4, 6, or 8 polypeptides), such as an IgG-like antigen-binding molecule comprising two heavy chain polypeptides and two light chain polypeptides.

[0125] The antigen-binding molecules disclosed herein can be designed and prepared using monoclonal antibody (mAb) sequences capable of binding to a given target antigen (e.g., HER3 or EGFR). The antigen-binding region of the antibody can also be provided using / provided single-chain variable fragments (scFv), Fab, and F(ab')2 fragments. An "antigen-binding region" is any fragment of the antibody that binds specifically to a given antibody target.

[0126] Antibodies typically consist of six complementarity-determining regions (CDRs): three located in the heavy chain variable region (VH): HC-CDR1, HC-CDR2, and HC-CDR3, and three located in the light chain variable region (VL): LC-CDR1, LC-CDR2, and LC-CDR3. These six CDRs collectively define the antibody's complementary sites, which are the regions where the antibody binds to the target antigen.

[0127] The VH and VL regions comprise the frame regions (FRs) on both sides of the CDR, providing support for the CDR. From the N end to the C end, the VH region contains the following structure: N end - [HC-FR1] - [HC-CDR1] - [HC-FR2] - [HC-CDR2] - [HC-FR3] - [HC-CDR3] - [HC-FR4] - C end; and the VL region contains the following structure: N end - [LC-FR1] - [LC-CDR1] - [LC-FR2] - [LC-CDR2] - [LC-FR3] - [LC-CDR3] - [LC-FR4] - C end.

[0128] There are several different conventions for defining antibody CDR and FR, such as those described in Kabat et al., Sequences of Immune-Related Proteins, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991), Chothia et al., J. Mol. Biol. 196:901-917 (1987), and VBASE2, as described in 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., NucleicAcids Res. (2015) 43 (Database issue): D413-22), using the IMGT V-DOMAIN numbering rules as described in Lefranc et al., Dev. Comp. Immunol. (2003) 27: 55-77. In a preferred embodiment, the CDR and FR of the antigen-binding molecule mentioned herein are defined according to the IMGT information system.

[0129] The VH and VL regions of the antibody-antigen binding region together constitute the Fv region. In some embodiments, the antigen-binding molecule according to this disclosure includes or consists of an Fv region that binds to HER3. In some embodiments, the antigen-binding molecule according to this disclosure includes or consists of an Fv region that binds to EGFR. In some embodiments, the VH and VL regions of the Fv are a single polypeptide linked by a linker sequence, i.e., a single-chain Fv (scFv).

[0130] The VL region of the antibody-antigen binding region, together with the light chain constant (CL) region, VH region, and heavy chain constant 1 (CH1) region, constitutes the 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 includes 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 includes 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 single polypeptides linked by linker regions, i.e., a single-chain Fab (scFab) or a single-chain CrossFab (scCrossFab).

[0131] In some embodiments, the antigen-binding molecules described herein comprise or consist of whole antibodies that bind to HER3. In some embodiments, the antigen-binding molecules described herein comprise or consist of whole antibodies that bind 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, Clinical Immunology of Allergy (2010) 125(202):S41-S52, all of which are incorporated herein by reference.

[0132] Immunoglobulins G (IgG) are glycoproteins of approximately 150 kDa, consisting of two heavy chains and two light chains. From the N to the C-terminus, the heavy chain contains a VH domain and a heavy chain constant region containing three constant domains (CH1, CH2, and CH3). Similarly, the light chain contains a VL domain and a CL domain. 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).

[0133] In some embodiments, the antigen-binding molecule comprises 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 comprises or consists of IgG (e.g., IgG1, IgG2, IgG3, IgG4), IgA (e.g., IgA1, IgA2), IgD, IgE, or IgM that bind to EGFR.

[0134] In some embodiments described herein, one or more amino acids of the amino acid sequence mentioned herein (e.g., the amino acid sequence of an antigen-binding molecule, such as the amino acid sequence of the CDR or VH / VL region) are substituted by another amino acid. Substitution includes replacing an amino acid residue with a different “alternative” amino acid residue. The alternative amino acid residue used for substitution according to this disclosure may be a naturally occurring amino acid residue (i.e., encoded by the genetic code) that is different from the amino acid residue at the relevant position in an equivalent, unsubstituted amino acid sequence, selected from: alanine (Ala), arginine (Arg), aspartic acid (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). In some implementations, the substitute amino acid can be a non-naturally occurring amino acid residue, i.e., an amino acid residue different from the amino acid residues described above. Examples of non-naturally occurring amino acid residues include norleucine, ornithine, valine, homoserine, aib, and other amino acid residue analogs, such as those described in Ellman et al., Meth. Enzym. 202 (1991) 301-336.

[0135] In some embodiments, the substitution can be biochemically conserved. In some embodiments, the amino acid to be substituted is one of the amino acids in rows 1 to 5 of the table below, and the substituted amino acid is another non-identical amino acid in the same row:

[0136]

[0137] For example, in some embodiments where the Met residue is replaced, the alternative amino acid may be selected from Ala, Val, Leu, Ile, Trp, Tyr, Phe, and norleucine.

[0138] In some embodiments, the substituted amino acid in the substitution may have the same side chain polarity as the amino acid residue it replaces. In some embodiments, the substituted amino acid in the substitution may have the same side chain charge (at pH 7.4) as the amino acid residue it replaces.

[0139]

[0140] Specifically, in some embodiments, a nonpolar amino acid is replaced by another different nonpolar amino acid. In some embodiments, a polar amino acid is replaced by another different polar amino acid. In some embodiments, an acidic polar amino acid is replaced by another different acidic polar amino acid. In some embodiments, a basic polar amino acid is replaced by another different basic polar amino acid. In some embodiments, a neutral amino acid is replaced by another different neutral amino acid. In some embodiments, a positively charged amino acid is replaced by another different positively charged amino acid. In some embodiments, a negatively charged amino acid is replaced by another different negatively charged amino acid.

[0141] In some embodiments, the substitution may be functionally conserved. That is, in some embodiments, the substitution does not affect (or does not substantially affect) one or more functional properties (e.g., target binding) of the antigen-binding molecule containing the substitution compared to an equivalent unsubstituted molecule.

[0142] Antigen-binding molecules that bind to HER3 Aspects and embodiments of this disclosure relate to antigen-binding molecules that bind to HER3.

[0143] In some embodiments, the antigen-binding molecule includes a CDR of the antigen-binding molecule capable of binding to HER3. In some embodiments, the antigen-binding molecule includes a FR of the antigen-binding molecule capable of binding to HER3. In some embodiments, the antigen-binding molecule includes both a CDR and a FR of the antigen-binding molecule capable of binding to HER3. That is, in some embodiments, the antigen-binding molecule includes a VH region and a VL region of the antigen-binding molecule capable of binding to HER3.

[0144] In some embodiments, the antigen-binding molecules capable of binding to HER3 according to the present invention are selected from: any embodiment of the antigen-binding molecules described in WO2019 / 185878 A1 (all contents of which are incorporated herein by reference), 10D1F (e.g., described in WO 2019 / 185878 A1), seribantumab (also known as MM-121, e.g., described in Schoeberl et al., Sci. Signal. (2009) 2(77): ra31; DrugBank Acc. No. DB11857), elgemtumab (also known as LJM-716, e.g., described in Garner et al., Cancer Res (2013) 73: 6024–6035; DrugBank The following are described in Acc. No. DB15430: patritumab (also known as U-1287 and AMG-888, e.g., in Shimizu et al., Cancer Chemotherapy and Pharmacology (2017) 79(3):489–495; DrugBank Acc. No. DB12090), GSK2849330 (e.g., in Clarke et al., Eur J Cancer. (2014) 50:98–9), lumretuzumab (also known as RG7116 and RO-5479599, e.g., in Mirschberger et al., Cancer Research (2013) 73(16) 5183-5194; DrugBank Acc. No. DB12683), CDX-3379 (also known as KTN3379, e.g., in Lee et al., Proc Natl Acad Sci US A. 2015) (as described in Oct 27; 112(43):13225), AV-203 (also known as CAN-017, e.g., described in Meetze et al., Eur J Cancer 2012; 48:126), barrecetamab (also known as ISU104, e.g., described in Kim et al., Cancer Res (2018) 78(13Suppl): Abstract #830), TK-A3, TK-A4 (e.g., described in Malm et al., MAbs (2016) 8:1195-209), MP-EV20 (e.g., described in Sala et al., Transl. Oncol.(2013)6:676-84), 1A5-3D4 (e.g., described in Wang et al., Cancer Lett (2016)380:20-30), 9F7-F11, 16D3-C1 (e.g., described in Lazrek et al., Neopalasia (2013)15:335–47), NG33, A5, F4 (e.g., described in Gaborit et al., PNAS USA (2015)112:839-44), huHER3-8 (e.g., described in Kugel et al., Cancer Res. (2014)74:4122-32), REGN1400 (e.g., described in Zhang et al., Mol Cancer). (As described in Ther (2014) 13:1345–1355), and zenocutuzumab (also known as MCLA-128, e.g., as described in de Vries Schultink et al., ClinPharmacokinet. (2020) 59:875–884; DrugBank Acc. No. DB15559). In some embodiments, the antigen-binding molecule is 10D1F.

[0145] In some embodiments, the antigen-binding molecule binds to the extracellular region of HER3 (e.g., the region shown in SEQ ID NO:9). In some embodiments, the antigen-binding molecule binds to subdomain II of the extracellular region of HER3 (e.g., the region shown in SEQ ID NO:16).

[0146] 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 regions 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. 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.

[0147] In some embodiments, the antigen-binding molecule does not bind to the region corresponding to positions 260-279 of SEQ ID NO:1 of HER3. In some embodiments, the antigen-binding molecule does not contact the amino acid residues in the HER3 region corresponding to positions 260 to 279 of SEQ ID NO:1.

[0148] The antibody-bound peptide / peptide region can be determined by those skilled in the art using a variety of methods known in the art, including X-ray cocrystallization analysis of antibody-antigen complexes, peptide scanning, mutagenic localization, hydrogen-deuterium exchange analysis by mass spectrometry, phage display, competitive ELISA, and protein hydrolysis-based “protective” methods. These methods are described, for example, in Gershoni et al., BioDrugs, 2007, 21(3):145-156, all of which are incorporated herein by reference.

[0149] In some embodiments, the antigen-binding molecule is capable of binding the same region or overlapping region of HER3 to the HER3 region bound by the antibody, said antibody comprising the VH and VL sequences selected from one of the following group of antibody clones described herein: 10D1_c89, 10D1, 10D1_c75, 10D1_c76, 10D1_c77, 10D1_c78v1, 10D1_c78v2, 10D1_11B, 10D1_c85v1, 10D1_c85v2, 10D1_c85o2, 10D1_c87, 10D1_c90, 10D1_c91, 10D1_c92, and 10D1_c93. In some embodiments, the antigen-binding molecule is capable of binding the same region or overlapping region of HER3 to the HER3 region bound by an antibody containing the VH and VL sequences of antibody clone 10D1_c89.

[0150] In some embodiments, the antigen-binding molecule is capable of binding to a polypeptide comprising or consisting of an amino acid sequence of one of SEQ ID NO: 1, 3, 4, 6, or 8. In some embodiments, the antigen-binding molecule is capable of binding to a polypeptide comprising or consisting of an amino acid sequence of SEQ ID NO: 9. In some embodiments, the antigen-binding molecule is capable of binding to a polypeptide comprising or consisting of an amino acid sequence of SEQ ID NO: 16. In some embodiments, the antigen-binding molecule is capable of binding to a peptide / polypeptide comprising or consisting of an amino acid sequence of SEQ ID NO: 77. In some embodiments, the antigen-binding molecule is capable of binding to a peptide / polypeptide comprising or consisting of an amino acid sequence of SEQ ID NO: 78 and 79. In some embodiments, the antigen-binding molecule is capable of binding to a peptide / polypeptide comprising or consisting of an amino acid sequence of SEQ ID NO: 78. In some embodiments, the antigen-binding molecule is capable of binding to a peptide / polypeptide comprising or consisting of an amino acid sequence of SEQ ID NO: 79.

[0151] In some implementations, the antigen-binding molecule cannot bind to the peptide consisting of the amino acid sequence corresponding to positions 260 to 279 of SEQ ID NO: 1.

[0152] The ability of an antigen-binding molecule to bind to a given peptide / peptide can be analyzed using methods known to those skilled in the art, including ELISA, immunoblotting (e.g., Western blotting), immunoprecipitation, surface plasmon resonance analysis (SPR; see, for example, Hearty et al., Methods Mol Biol (2012) 907:411-442) or biolayer interference (see, for example, Lad et al., (2015) J Biomol Screen 20(4):498-507).

[0153] In embodiments where the antigen-binding molecule can bind to a peptide / polypeptide comprising a reference amino acid sequence, the peptide / polypeptide may include one or more additional amino acids at one or both ends of the reference amino acid sequence. In some embodiments, the peptide / polypeptide includes, 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, 10-40, 10-50, 20-30, 20-40, or 20-50 additional amino acids located at one or both ends of the reference amino acid sequence.

[0154] In some embodiments, the additional amino acids provided at one or both ends (i.e., the N-terminus and C-terminus) of the reference sequence correspond to positions at the ends of the reference sequence in the context of the HER3 amino acid sequence.

[0155] In some embodiments, the antigen-binding molecule is capable of binding to a peptide / polypeptide bound by an antibody comprising the VH and VL sequences selected from one of the following group of antibody clones: 10D1_c89, 10D1, 10D1_c75, 10D1_c76, 10D1_c77, 10D1_c78v1, 10D1_c78v2, 10D1_11B, 10D1_c85v1, 10D1_c85v2, 10D1_c85o2, 10D1_c87, 10D1_c90, 10D1_c91, 10D1_c92, and 10D1_c93. In some embodiments, the antigen-binding molecule is capable of binding to a peptide / polypeptide bound by an antibody comprising the VH and VL sequences of antibody clone 10D1_c89.

[0156] In some embodiments, the antigen-binding molecule includes a CDR of a HER3-binding antibody clone, or VH and VL, said 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.

[0157] In some implementations, the antigen-binding molecule includes:

[0158] (1) VH region containing the following CDRs:

[0159] HC-CDR1 with the amino acid sequence SEQ ID NO:40

[0160] HC-CDR2 with the amino acid sequence SEQ ID NO:43

[0161] HC-CDR3, having the amino acid sequence SEQ ID NO:48,

[0162] Or its variants, wherein one, two, or three of one or more of HC-CDR1, HC-CDR2, or HC-CDR3 are substituted by another amino acid; and

[0163] VL region containing the following CDRs:

[0164] LC-CDR1 with the amino acid sequence SEQ ID NO:66

[0165] LC-CDR2 with the amino acid sequence SEQ ID NO:69

[0166] LC-CDR3, having the amino acid sequence SEQ ID NO:74,

[0167] Or its variants, wherein one or two or three of one or more of LC-CDR1, LC-CDR2 or LC-CDR3 are replaced by another amino acid.

[0168] (2) VH region containing the following CDRs:

[0169] HC-CDR1 with the amino acid sequence SEQ ID NO:38

[0170] HC-CDR2 with the amino acid sequence SEQ ID NO:41

[0171] HC-CDR3, having the amino acid sequence SEQ ID NO:44,

[0172] Or its variants, wherein one, two, or three of one or more of HC-CDR1, HC-CDR2, or HC-CDR3 are substituted by another amino acid; and

[0173] VL region containing the following CDRs:

[0174] LC-CDR1 with the amino acid sequence SEQ ID NO:63

[0175] LC-CDR2 with the amino acid sequence SEQ ID NO:67

[0176] LC-CDR3, having the amino acid sequence SEQ ID NO:70,

[0177] Or its variants, wherein one or two or three of one or more of LC-CDR1, LC-CDR2 or LC-CDR3 are replaced by another amino acid.

[0178] (3) VH region containing the following CDRs:

[0179] HC-CDR1 with the amino acid sequence SEQ ID NO:38

[0180] HC-CDR2 with the amino acid sequence SEQ ID NO:41

[0181] HC-CDR3, having the amino acid sequence SEQ ID NO:44,

[0182] Or its variants, wherein one, two, or three of one or more of HC-CDR1, HC-CDR2, or HC-CDR3 are substituted by another amino acid; and

[0183] VL region containing the following CDRs:

[0184] LC-CDR1 with the amino acid sequence SEQ ID NO:64

[0185] LC-CDR2 with the amino acid sequence SEQ ID NO:67

[0186] LC-CDR3, having the amino acid sequence SEQ ID NO:70,

[0187] Or its variants, wherein one or two or three of one or more of LC-CDR1, LC-CDR2 or LC-CDR3 are replaced by another amino acid.

[0188] (4) VH region containing the following CDRs:

[0189] HC-CDR1 with the amino acid sequence SEQ ID NO:38

[0190] HC-CDR2 with the amino acid sequence SEQ ID NO:41

[0191] HC-CDR3, having the amino acid sequence SEQ ID NO:44,

[0192] Or its variants, wherein one, two, or three of one or more of HC-CDR1, HC-CDR2, or HC-CDR3 are substituted by another amino acid; and

[0193] VL region containing the following CDRs:

[0194] LC-CDR1 with the amino acid sequence SEQ ID NO:65

[0195] LC-CDR2 with the amino acid sequence SEQ ID NO:67

[0196] LC-CDR3, having the amino acid sequence SEQ ID NO:71,

[0197] Or its variants, wherein one or two or three of one or more of LC-CDR1, LC-CDR2 or LC-CDR3 are replaced by another amino acid.

[0198] (5) VH region containing the following CDRs:

[0199] HC-CDR1 with the amino acid sequence SEQ ID NO:38

[0200] HC-CDR2 with the amino acid sequence SEQ ID NO:42

[0201] HC-CDR3, having the amino acid sequence SEQ ID NO:45,

[0202] Or its variants, wherein one, two, or three of one or more of HC-CDR1, HC-CDR2, or HC-CDR3 are substituted by another amino acid; and

[0203] VL region containing the following CDRs:

[0204] LC-CDR1 with the amino acid sequence SEQ ID NO:63

[0205] LC-CDR2 with the amino acid sequence SEQ ID NO:67

[0206] LC-CDR3, having the amino acid sequence SEQ ID NO:70,

[0207] Or its variants, wherein one or two or three of one or more of LC-CDR1, LC-CDR2 or LC-CDR3 are replaced by another amino acid.

[0208] (6) VH region containing the following CDRs:

[0209] HC-CDR1 with the amino acid sequence SEQ ID NO:39

[0210] HC-CDR2 with the amino acid sequence SEQ ID NO:42

[0211] HC-CDR3, having the amino acid sequence SEQ ID NO:45,

[0212] Or its variants, wherein one, two, or three of one or more of HC-CDR1, HC-CDR2, or HC-CDR3 are substituted by another amino acid; and

[0213] VL region containing the following CDRs:

[0214] LC-CDR1 with the amino acid sequence SEQ ID NO:63

[0215] LC-CDR2 with the amino acid sequence SEQ ID NO:67

[0216] LC-CDR3, having the amino acid sequence SEQ ID NO:70,

[0217] Or its variants, wherein one or two or three of one or more of LC-CDR1, LC-CDR2 or LC-CDR3 are replaced by another amino acid.

[0218] (7) VH region containing the following CDRs:

[0219] HC-CDR1 with the amino acid sequence SEQ ID NO:38

[0220] HC-CDR2 with the amino acid sequence SEQ ID NO:42

[0221] HC-CDR3, having the amino acid sequence SEQ ID NO:44,

[0222] Or its variants, wherein one, two, or three of one or more of HC-CDR1, HC-CDR2, or HC-CDR3 are substituted by another amino acid; and

[0223] VL region containing the following CDRs:

[0224] LC-CDR1 with the amino acid sequence SEQ ID NO:63

[0225] LC-CDR2 with the amino acid sequence SEQ ID NO:68

[0226] LC-CDR3, having the amino acid sequence SEQ ID NO:70,

[0227] Or its variants, wherein one or two or three of one or more of LC-CDR1, LC-CDR2 or LC-CDR3 are replaced by another amino acid.

[0228] (8) VH region containing the following CDRs:

[0229] HC-CDR1 with the amino acid sequence SEQ ID NO:38

[0230] HC-CDR2 with the amino acid sequence SEQ ID NO:42

[0231] HC-CDR3, having the amino acid sequence SEQ ID NO:46,

[0232] Or its variants, wherein one, two, or three of one or more of HC-CDR1, HC-CDR2, or HC-CDR3 are substituted by another amino acid; and

[0233] VL region containing the following CDRs:

[0234] LC-CDR1 with the amino acid sequence SEQ ID NO:63

[0235] LC-CDR2 with the amino acid sequence SEQ ID NO:68

[0236] LC-CDR3, having the amino acid sequence SEQ ID NO:70,

[0237] Or its variants, wherein one or two or three of one or more of LC-CDR1, LC-CDR2 or LC-CDR3 are replaced by another amino acid.

[0238] (9) VH region containing the following CDRs:

[0239] HC-CDR1 with the amino acid sequence SEQ ID NO:38

[0240] HC-CDR2 with the amino acid sequence SEQ ID NO:42

[0241] HC-CDR3, having the amino acid sequence SEQ ID NO:47,

[0242] Or its variants, wherein one, two, or three of one or more of HC-CDR1, HC-CDR2, or HC-CDR3 are substituted by another amino acid; and

[0243] VL region containing the following CDRs:

[0244] LC-CDR1 with the amino acid sequence SEQ ID NO:63

[0245] LC-CDR2 with the amino acid sequence SEQ ID NO:68

[0246] LC-CDR3, having the amino acid sequence SEQ ID NO:70,

[0247] Or its variants, wherein one or two or three of one or more of LC-CDR1, LC-CDR2 or LC-CDR3 are replaced by another amino acid.

[0248] (10) VH region containing the following CDRs:

[0249] HC-CDR1 with the amino acid sequence SEQ ID NO:38

[0250] HC-CDR2 with the amino acid sequence SEQ ID NO:42

[0251] HC-CDR3, having the amino acid sequence SEQ ID NO:45,

[0252] Or its variants, wherein one, two, or three of one or more of HC-CDR1, HC-CDR2, or HC-CDR3 are substituted by another amino acid; and

[0253] VL region containing the following CDRs:

[0254] LC-CDR1 with the amino acid sequence SEQ ID NO:63

[0255] LC-CDR2 with the amino acid sequence SEQ ID NO:67

[0256] LC-CDR3, having the amino acid sequence SEQ ID NO:72,

[0257] Or its variants, wherein one or two or three of one or more of LC-CDR1, LC-CDR2 or LC-CDR3 are replaced by another amino acid.

[0258] (11) VH region containing the following CDRs:

[0259] HC-CDR1 with the amino acid sequence SEQ ID NO:38

[0260] HC-CDR2 with the amino acid sequence SEQ ID NO:41

[0261] HC-CDR3, having the amino acid sequence SEQ ID NO:44,

[0262] Or its variants, wherein one, two, or three of one or more of HC-CDR1, HC-CDR2, or HC-CDR3 are substituted by another amino acid; and

[0263] VL region containing the following CDRs:

[0264] LC-CDR1 with the amino acid sequence SEQ ID NO:63

[0265] LC-CDR2 with the amino acid sequence SEQ ID NO:67

[0266] LC-CDR3, having the amino acid sequence SEQ ID NO:73,

[0267] Or its variants, wherein one or two or three of one or more of LC-CDR1, LC-CDR2 or LC-CDR3 are replaced by another amino acid.

[0268] In some implementations, the antigen-binding molecule includes:

[0269] (12) The VH region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:21, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and the VL region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:49, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0270] (13) The VH region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:22, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and the VL region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:50, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0271] (14) The VH region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:23, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and the VL region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:51, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0272] (15) The VH region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:24, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and the VL region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:52, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0273] (16) The VH region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:25, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and the VL region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:53, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0274] (17) The VH region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:26, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and the VL region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:53, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0275] (18) The VH region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:27, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and the VL region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:53, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0276] (19) The VH region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:28, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and the VL region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:54, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0277] (20) The VH region comprises an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:29, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and the VL region comprises an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:54, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0278] (21) The VH region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:30, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and the VL region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:55, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0279] (22) The VH region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:31, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and the VL region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:56, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0280] (23) The VH region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:32, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and the VL region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:57, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0281] (24) The VH region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:33, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and the VL region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:58, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0282] (25) The VH region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:34, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and the VL region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:59, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0283] (26) The VH region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:35, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and the VL region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:60, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0284] (27) The VH region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:36, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and the VL region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:61, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0285] (28) The VH region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:37, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and the VL region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:62, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0286] In some implementations, the antigen-binding molecule includes or consists of the following:

[0287] (29)(i) One or more (e.g., two) polypeptides comprising or consisting of an amino acid sequence having sequence identity with at least 70%, preferably 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the amino acid sequence of SEQ ID NO:75; and

[0288] (ii) One or more (e.g., two) polypeptides comprising or consisting of an amino acid sequence having at least 70%, preferably 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of SEQ ID NO:76.

[0289] Antigen-binding molecules that bind to EGFR

[0290] This invention provides an antigen-binding molecule that binds to EGFR.

[0291] In some embodiments, the antigen-binding molecule includes a CDR of the antigen-binding molecule capable of binding to EGFR. In some embodiments, the antigen-binding molecule includes a FR of the antigen-binding molecule capable of binding to EGFR. In some embodiments, the antigen-binding molecule includes both a CDR and a FR of the antigen-binding molecule capable of binding to EGFR. That is, in some embodiments, the antigen-binding molecule includes a VH region and a VL region of the antigen-binding molecule capable of binding to EGFR.

[0292] In some embodiments, the antigen-binding molecules capable of binding to EGFR according to this disclosure are selected from: any embodiment of the antigen-binding molecules described in US 6,217,866B1 (all contents of which are incorporated herein by reference), cetuximab (e.g., as described in US 6,217,866B1 and Wong et al., Clin Ther. (2005) 27(6):684-694; DrugBank Acc.No.DB00002), panitumumab (e.g., as described in Foon et al., Int J RadiatOncol Biol Phys. (2004) 58(3):984-990; DrugBank Acc.No.DB01269), and zalutumumab (e.g., as described in Bastholt et al., Radiother Oncol. (2007) 85(1):24-28; DrugBank Acc.No.DB01269). The following are described in Acc.No.DB12202: necitumumab (e.g., described in Kuenen et al., Clinical Cancer Research (2010) 16(6):1915-1923; DrugBank Acc.No.DB09559), nimotuzumab (e.g., described in Ramakrishnan et al., mAbs (2009) 1(1):41-48; DrugBank Acc.No.DB06192), duligotuzumab (e.g., described in Fayette et al., Front Oncol. (2016) 6:232; DrugBank Acc.No.DB12142), and matuzumab (DrugBank Acc.No.DB05101).

[0293] In some implementations, the antigen-binding molecule is cetuximab. Cetuximab (Erbitux, EliLilly, 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). Cetuximab, approved by the FDA in February 2004 under the brand name ERBITUX, was one of the first compounds developed for the treatment of NSCLC as an anti-EGFR antibody. It is administered intravenously as a monotherapy or in combination with other chemotherapy regimens, including platinum-based formulations, radiotherapy, leucovorin, fluorouracil, and irinotecan (FDA 2019).

[0294] In some implementations, the antigen-binding molecule is able to bind the same region or overlapping region of EGFR to the EGFR region bound by an antibody containing the VH and VL sequences of cetuximab.

[0295] In some implementations, the antigen-binding molecules include the CDR of cetuximab, or the VH and VL of cetuximab.

[0296] In some implementations, the antigen-binding molecule includes:

[0297] (30) VH region containing the following CDRs:

[0298] HC-CDR1 with the amino acid sequence SEQ ID NO:92

[0299] HC-CDR2 with the amino acid sequence SEQ ID NO:93

[0300] HC-CDR3, having the amino acid sequence SEQ ID NO:94,

[0301] Or its variants, wherein one, two, or three of one or more of HC-CDR1, HC-CDR2, or HC-CDR3 are substituted by another amino acid; and

[0302] VL region containing the following CDRs:

[0303] LC-CDR1 with the amino acid sequence SEQ ID NO:96

[0304] LC-CDR2 with the amino acid sequence SEQ ID NO:97

[0305] LC-CDR3, having the amino acid sequence SEQ ID NO:98,

[0306] Or its variants, wherein one or two or three of one or more of LC-CDR1, LC-CDR2 or LC-CDR3 are replaced by another amino acid.

[0307] In some implementations, the antigen-binding molecule includes:

[0308] (31) The VH region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:91, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and the VL region includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:95, more preferably an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0309] In some implementations, the antigen-binding molecule includes or consists of the following:

[0310] (32)(i) One or more (e.g., two) polypeptides comprising or consisting of an amino acid sequence having sequence identity with at least 70%, preferably 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the amino acid sequence of SEQ ID NO: 99; and

[0311] (ii) One or more (e.g., two) polypeptides comprising or consisting of an amino acid sequence having at least 70%, preferably 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with the amino acid sequence of SEQ ID NO:100.

[0312] Fc area

[0313] In some embodiments, the antigen-binding molecule of this disclosure includes an Fc region.

[0314] The Fc region consists of the CH2 and CH3 regions from one polypeptide and the CH2 and CH3 regions from another polypeptide. The CH2 and CH3 regions of the two polypeptides together constitute the Fc region.

[0315] Fc-mediated functions include Fc receptor binding, antibody-dependent cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), formation of the membrane attack complex (MAC), cell degranulation, production of cytokines and / or chemokines, and antigen processing and presentation.

[0316] Taxanes

[0317] The aspects and embodiments disclosed herein relate to taxane-like substances.

[0318] As used herein, “taxane-like” refers to taxane-derived diterpenes. In scientific literature, the terms “taxane” and “taxane-like” are sometimes used interchangeably. For chemical and functional properties of taxane-like substances, see, for example, Kingston and Newman, CurrOpin Drug Discov Devel. (2007) 10(2):130-144 and Mosca et al., Drug Resist Updat. (2021) 54:100742, the entire contents of which are incorporated herein by reference.

[0319] Taxanes are mitotic inhibitors that exert their anticancer effects primarily by disrupting microtubule formation. They stabilize tubulin bound to GDP in microtubules, preventing microtubule depolymerization and thus inhibiting cell division. Taxanes include docetaxel, paclitaxel, albumin-bound paclitaxel, larotaxel, and cabazitaxel. Paclitaxel, docetaxel, and cabazitaxel are the three main approved paclitaxel-like drugs, widely used to treat a variety of solid tumors, including prostate cancer, lung cancer, ovarian cancer, and breast cancer.

[0320] In some embodiments, the taxanes disclosed herein are selected from docetaxel and albumin-bound paclitaxel. In some embodiments, the taxane is docetaxel. In some embodiments, the taxane is albumin-bound paclitaxel.

[0321] nucleoside analogues

[0322] Several aspects and embodiments of this disclosure relate to nucleoside analogs. In particular, this disclosure relates to nucleoside analog inhibitors of DNA replication. These act as antimetabolites and have a structure sufficiently similar to nucleotides to be integrated into elongated DNA chains. However, the incorporation of nucleoside analogs prevents further DNA chain synthesis and ultimately leads to cell death.

[0323] For information on nucleoside analogues and their use in cancer treatment, see, for example, Jordheim et al., Nat. Rev. Drug Discov. (2013) 12:447-464, all of which are incorporated herein by reference. Gemcitabine is used to treat testicular cancer, breast cancer, ovarian cancer, non-small cell lung cancer, pancreatic cancer, biliary tract cancer, and bladder cancer.

[0324] In some embodiments, the nucleoside analog according to the invention is a deoxycytidine nucleoside analog. In some embodiments, the nucleoside analog is gemcitabine or a salt thereof (e.g., gemcitabine hydrochloride).

[0325] Drug combinations and compositions

[0326] This disclosure provides combinations or compositions comprising (i) an antigen-binding molecule that binds to HER3 and (ii) a taxane class. 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 taxane class. This disclosure further provides a combination or composition comprising (i) an antigen-binding molecule that binds to HER3 and (ii) an antigen-binding molecule that binds to EGFR. This disclosure also provides a combination or composition comprising (i) an antigen-binding molecule that binds to HER3, (ii) an antigen-binding molecule that binds to EGFR, and (iii) a taxane class.

[0327] It should be understood that the antigen-binding molecule binding to HER3 can be any antigen-binding molecule binding to HER3 according to any embodiment described herein, and similarly, the antigen-binding molecule binding to EGFR can be any antigen-binding molecule binding to EGFR according to any embodiment described herein. In preferred embodiments of the combinations and compositions described above, the antigen-binding molecule binding to HER3 is selected from one of (1) to (29) above, and the antigen-binding molecule binding to EGFR is selected from one of (30) to (32) above. It should also be understood that the taxane-like molecule can be any taxane-like molecule according to any embodiment described herein. In preferred embodiments of the combinations and compositions described above, the taxane-like molecule is docetaxel or albumin-bound paclitaxel (e.g., docetaxel). Similarly, the nucleoside analog can be any nucleoside analog according to any embodiment described herein. In preferred embodiments of the combinations and compositions described above, the nucleoside is a deoxycytidine nucleoside analog, such as gemcitabine or a salt thereof.

[0328] In some aspects and implementations, the combination is a pharmaceutical combination. As used herein, a "pharmaceutical combination" refers to a product containing multiple (usually two or three) different active (i.e., therapeutic / preventive) agents intended for combined use. The agents in a pharmaceutical combination may be formulated together or separately, but are typically packaged together, usually with an instruction leaflet containing instructions for use of the agents in the combination.

[0329] In some embodiments, the pharmaceutical agents of the drug combination are included in a single composition, such as a pharmaceutical composition comprising said pharmaceutical agent. In some embodiments, the pharmaceutical agents of the drug combination are included in separate compositions. For example, a drug combination comprising (i) an antigen-binding molecule that binds to HER3 and (ii) a taxane-like substance can be provided as (i) a pharmaceutical composition comprising an antigen-binding molecule that binds to HER3 and (ii) a pharmaceutical composition comprising a taxane-like substance. Similarly, a drug combination comprising (i) an antigen-binding molecule that binds to HER3 and (ii) an antigen-binding molecule that binds to EGFR can be provided as (i) a pharmaceutical composition comprising an antigen-binding molecule that binds to HER3 and (ii) a pharmaceutical composition comprising an antigen-binding molecule that binds to EGFR. In another embodiment, the drug combination can be provided as (i) a pharmaceutical composition comprising an antigen-binding molecule that binds to HER3, (ii) a pharmaceutical composition comprising an antigen-binding molecule that binds to EGFR, and (iii) a chemotherapy drug (e.g., docetaxel).

[0330] This disclosure also provides compositions (e.g., pharmaceutical compositions and pharmaceuticals) comprising the pharmaceutical agents described herein (i.e., antigen-binding molecules that bind to HER3, antigen-binding molecules that bind to EGFR, taxane-like substances, nucleoside analogs). These compositions may include related articles in formulations suitable for clinical use.

[0331] In some embodiments, the HER3-binding antigen-binding molecule described herein is provided in a 50 mg / mL solution. In some embodiments, the HER3-binding antigen-binding molecule described herein is formulated in a composition comprising 20 mM histidine, 8% (w / v) sucrose, and 0.02% (w / v) polysorbate 80 (pH 5.8).

[0332] In some embodiments, docetaxel is formulated as a composition containing 0.9% (w / v) sodium chloride.

[0333] In some embodiments, albumin is combined with paclitaxel to form a composition containing 0.9% (w / v) sodium chloride.

[0334] In some embodiments, gemcitabine is formulated as a composition containing 0.9% (w / v) sodium chloride.

[0335] The compositions disclosed herein may include one or more pharmaceutically acceptable carriers (e.g., liposomes, micelles, microspheres, nanoparticles), diluents / excipients (e.g., starch, cellulose, cellulose derivatives, polyols, glucose, 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), antioxidants (e.g., vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium), lubricants (e.g., magnesium stearate, talc, silica, stearic acid, vegetal 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).

[0336] As used herein, the term "pharmaceutically acceptable" means a compound, ingredient, material, composition, dosage form, etc., suitable for contact with the tissues of the subject under discussion (e.g., human subject) to a reasonable degree of medical judgment, without excessive toxicity, irritation, allergic reactions, or other problems or complications, and proportionate to 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 in the compositions according to this disclosure must also be "acceptable" in the sense of compatibility 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, for example, Remington's "Pharmaceutical Science and Practice" (Ed. A. Adejare), 23rd edition (2020), Academic Press.

[0337] The pharmaceutical compositions / medications according to this disclosure can be formulated for administration, for example, via a route of administration suitable to the properties of the composition / medication and the disease / condition to be treated / prevented. In some embodiments, the pharmaceutical compositions / medications can be formulated for parenteral, systemic, local, intracavitary, intravascular, intravenous, intra-arterial, intramuscular, intrathecal, intraocular, intraconjunctival, intratumoral, subcutaneous, intradermal, oral, or transdermal administration. In some embodiments, the pharmaceutical compositions / medications can be formulated for administration by injection or infusion, or by ingestion.

[0338] Drugs and drug compositions can be formulated for application to blood vessels, or to target tissues / organs (e.g., tissues / organs affected by the disease / symptom; for example, tissues / organs exhibiting symptoms of the disease / symptom) or tumors.

[0339] The pharmaceutical composition / drug may comprise an agent (i.e., an antigen-binding molecule that binds to HER3, an antigen-binding molecule that binds to EGFR, a taxane-like substance, and / or a nucleoside analog) in a sterile or isotonic medium. The pharmaceutical composition / drug may be provided in liquid form, including gel form. Liquid formulations may be formulated for administration by injection or infusion (e.g., via cannula) to a blood vessel, or to a selected area of ​​the human or animal body, or to a tumor. The pharmaceutical composition / drug may be provided in solid form, such as lyophilized form.

[0340] Features

[0341] The combinations and compositions described herein can be characterized by reference to specific functional properties. In some embodiments, the combinations / compositions described herein may have one or more of the following properties:

[0342] Increased killing effect on cells expressing HER3 and / or EGFR;

[0343] Increase ADCC in cells expressing HER3 and / or EGFR;

[0344] Inhibit tumor growth and / or reduce tumor size / volume (e.g., cancers described herein, such as cancers expressing HER3 and / or EGFR);

[0345] Increase survival in subjects with cancer (such as the cancers described in this article, such as cancers expressing HER3 and / or EGFR);

[0346] Inhibits tumor growth and / or reduces tumor size / volume (e.g., cancers described herein, such as cancers expressing HER3 and / or EGFR) to a greater extent than the tumor growth inhibition / tumor size / volume reduction observed when the components of the combination / composition are used alone;

[0347] Increased survival in subjects with cancer (such as the cancers described herein, such as cancers expressing HER3 and / or EGFR) to a greater extent than the survival increase observed when the components of the combination / composition were used alone;

[0348] Compared to tumor growth inhibition / tumor size / volume reduction observed when the components of the combination / composition are used alone, there is synergistic inhibition of tumor growth and / or synergistic reduction of tumor size / volume (e.g., the cancers described herein, such as cancers expressing HER3 and / or EGFR); and / or

[0349] Compared with the survival increase observed when the composition / component of the composition is used alone, there is a synergistic increase in survival in subjects with cancer (e.g., cancers described herein, such as cancers expressing HER3 and / or egfr).

[0350] It should be understood that a given combination / composition may exhibit more than one of the properties described in the foregoing paragraph. The properties described in the foregoing paragraph can be evaluated using suitable assay methods. For example, the assay may be, for instance, an in vitro assay, optionally a cell-based assay, or a cell-free assay. In some embodiments, the assay may be, for instance, an in vivo assay, i.e., performed in a non-human animal. In some embodiments, the assay may be, for instance, an ex vivo assay, i.e., performed using cells / tissues / organs obtained from a subject.

[0351] When the assay is cell-based, it may include treating cells with a combination / composition to determine whether the combination / composition exhibits one or more of the stated properties. The assay may employ species labeled with detectable entities for easy detection. The assay may include evaluating the stated properties after treating cells individually with a given amount / concentration of the combination / composition (e.g., a dilution series).

[0352] Analysis of such assay results may include determining the concentration at which 50% of the maximum relevant activity level is achieved. A given formulation concentration at which 50% of the maximum relevant activity level is achieved may be referred to as the "half-maximum effective concentration" (EC50) of the formulation relative to the relevant activity, or "EC50". 50 Depending on their nature, EC 50 It can also be referred to as "half-maximum inhibition concentration" or "IC50". 50This refers to the formulation concentration at which the maximum inhibitory level for a given property is observed to reach 50%. In some embodiments, the combination / composition of this disclosure enhances (i.e., upregulates, strengthens) the cytotoxicity of cancer cells (e.g., the cancer cells described herein). In some embodiments, the combination / composition enhances the cytotoxicity of cells containing / expressing HER3 and / or EGFR. In some embodiments, the combination / composition according to this disclosure can inhibit the growth of the cancer described herein or reduce metastasis, for example, cancers comprising cells containing / expressing HER3 and / or EGFR. In some embodiments, the combination / composition can enhance (i.e., upregulate, strengthen) the cytotoxicity of the cancer cells described herein, for example, cancers comprising cells containing / expressing HER3 and / or EGFR. In some embodiments, the combination / composition can inhibit the growth of the cancer cells described herein, or can inhibit the growth of tumors containing the cancer cells described herein. In some embodiments, the combination / composition can inhibit the growth of cancer cells, or can inhibit the growth of tumors containing cells containing / expressing HER3 and / or EGFR. In some embodiments, the combination / composition can inhibit the metastasis of the cancer / tumor described herein, for example, cancer / tumors containing cells containing / expressing HER3 and / or EGFR.

[0353] For example, any of the methods described by Zaritskaya et al., Expert Rev Vaccines (2011), 9(6):601-616, all of which are incorporated herein by reference. Examples of in vitro cytotoxicity / cell killing assays include release assays, such as... 51 Cr release assay, lactate dehydrogenase (LDH) release assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) release assay, and calcein-acetoxymethyl (calcein-AM) release assay. These assays measure cell killing based on the detection of factors released from lysed cells. The killing effect of a specific effector immune cell type on a specific test cell type can be analyzed, for example, by co-culturing test cells with effector immune cells and measuring the number / proportion of surviving / dead (e.g., lysed) test cells after an appropriate time. Other suitable assays include the xCELLigence real-time cell lysis in vitro titer assay described in Cerignoli et al., PLoS One. (2018) 13(3):e0193498 (all contents are incorporated herein by reference).

[0354] In some embodiments, the combinations / compositions of the present invention exhibit anticancer activity. In some embodiments, the combinations / compositions increase the killing of cancer cells. In some embodiments, the combinations / compositions result in a reduction in the number of cancer cells in vivo, for example, compared to suitable control conditions. The cancer may be the cancer described herein.

[0355] In some embodiments, the combinations / compositions according to the present invention are capable of reducing the number / proportion of cells expressing HER3 and / or EGFR. In some embodiments, the combinations / compositions according to this disclosure are capable of consuming / enhancing the consumption of such cells.

[0356] The antigen-binding molecule composition of the combination / composition according to this disclosure may include one or more portions for enhancing the reduction of the number / proportion of cells expressing HER3 and / or EGFR. For example, the antigen-binding molecule may include, for instance, an Fc region and / or a pharmaceutical portion.

[0357] The Fc region can interact with Fc receptors and other immune system molecules to produce functional effects. For example, see Jefferis et al., *Immunological Reviews*, 1998, 163: 59-76 (all of which are incorporated herein by reference). These effector functions are generated through Fc-mediated recruitment and activation of immune cells (e.g., macrophages, dendritic cells, neutrophils, basophils, eosinophils, platelets, mast cells, NK cells, and T cells). This is achieved through the interaction between the Fc region and Fc receptors expressed by immune cells, and through the binding of the Fc region to complement protein C1q, which recruits components of the complement pathway, thereby activating the complement cascade. Fc-mediated functions include Fc receptor binding, antibody-dependent cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), formation of the membrane attack complex (MAC), cell degranulation, production of cytokines and / or chemokines, and antigen processing and presentation.

[0358] In some embodiments, the antigen-binding molecule of the combination / composition according to the present disclosure includes an Fc region capable of enhancing / directing one or more of ADCC, ADCP, CDC to antagonize and / or enhance MAC formation or cell degranulation on cells expressing HER3 and / or EGFR (e.g., cells expressing HER3 and / or EGFR on their cell surface).

[0359] In some embodiments, the antigen-binding molecules of the combination / composition according to this disclosure are capable of enhancing / directing ADCC against cells expressing HER3 and / or EGFR.

[0360] The ability and extent to which a given antigen-binding molecule can induce ADCC in a given target cell type can be analyzed by, for example, the methods described in Yamashita et al., *Scientific Reports* (2016) 6:19772 (all contents of which are incorporated herein by reference), or by, for example, the methods described in Jedema et al., *Blood* (2004) 103:2677–82. 51 Cr release assays were performed (all contents of which are incorporated herein by reference). The ability and extent to which a given antigen-binding molecule can induce ADCP can be analyzed by, for example, the method described by Kamen et al., J Immunol (2017) 198(1 Supplement) 157.17 (all contents of which are incorporated herein by reference). The ability and extent to which a given antigen-binding molecule can induce CDC can be analyzed by C1q binding assays, for example, the method described by Schlothauer et al., Protein Engineering, Design & Selection (2016), 29(10):457–466 (all contents of which are incorporated herein by reference).

[0361] In some embodiments, the combinations / compositions of the present invention exhibit anticancer activity. In some embodiments, the combinations / compositions increase the killing of cancer cells. In some embodiments, the combinations / compositions result in a reduction in the number of cancer cells in vivo, for example, compared to suitable control conditions. The cancer can be the cancer described herein, such as cancers that express / overexpress HER3 and / or EGFR.

[0362] In some embodiments, the combination / composition according to the invention reduces / inhibits the growth of cancer and / or cancerous tumors. In some embodiments, the combination / composition reduces tissue invasion by cancer cells. In some embodiments, the combination / composition reduces cancer metastasis. In some embodiments, the combination / composition exhibits anticancer activity. In some embodiments, the combination / composition reduces the growth / proliferation of cancer cells. In some embodiments, the combination / composition reduces cancer cell survival. In some embodiments, the combination / composition increases the killing effect on cancer cells. In some embodiments, the combination / combination of this disclosure can result in a reduction in the number of cancer cells in vivo, such as cancers expressing / overexpressing HER3 and / or EGFR.

[0363] The combinations / compositions disclosed herein can be analyzed in appropriate assays, including in vivo models. For example, Example 3 of this document describes the evaluation of tumor growth inhibition by the HER3-binding molecule HMBD-001IgG1 and the EGFR-binding molecule cetuximab in human cancer cell-derived models of various cancers.

[0364] In some embodiments, application of the combination / composition described in this disclosure may result in one or more of the following effects: inhibiting cancer development / progression, delaying / preventing cancer occurrence, reducing / delaying / preventing tumor growth, reducing / delaying / preventing tissue invasion, reducing / delaying / preventing metastasis, alleviating the severity of cancer symptoms, reducing the number of cancer cells, reducing cancer burden, reducing tumor size / volume, and / or improving the survival rate of patients with cancer (e.g., progression-free survival or overall survival), such as results determined in appropriate models.

[0365] It should be understood that the properties described above are evaluated after a sufficient period of time to observe the effects associated with treatment using the combination / composition. Tumor growth can be monitored by studying changes in tumor volume over time, for example as described in Example 3 of this document. Tumor growth can be measured by measuring tumor volume (e.g., mm). 3 It is evaluated based on how it changes over time.

[0366] In some embodiments, in a given assay, the combination / composition of this disclosure is capable of reducing tumor size / volume (e.g., the mean tumor size / volume in the treatment group in an in vivo model of cancer as described herein) to less than 1 times the tumor size / volume observed at the same time point without combination / composition treatment (or subsequently treated with an appropriate control composition known not to affect tumor growth), such as ≤0.99 times, ≤0.95 times, ≤0.9 times, ≤0.85 times, ≤0.8 times, ≤0.75 times, ≤0.7 times, ≤0.65 times, ≤0.6 times, ≤0.55 times, ≤0.5 times, ≤0.45 times, ≤0.4 times, ≤0.35 times, ≤0.3 times, ≤0.25 times, ≤0.2 times, ≤0.15 times, ≤0.1 times, ≤0.05 times, or ≤0.01 times. In some implementations, in the relevant models, the assessment of tumor size / volume for this comparative purpose is performed more than 5 days after the administration of the first dose of the combination / composition, for example, one of ≥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.

[0367] In some embodiments, in a given assay, the combination / composition of this disclosure achieves a certain level of tumor growth inhibition (e.g., expressed as a percentage of tumor growth inhibition, calculated relative to tumor growth observed when treated with an isotype-matched control antibody), which is higher than 1 times the level of tumor growth inhibition observed at the same time point when not treated with the combination / composition (or subsequently treated with an appropriate control formulation known not to affect tumor growth), for example, ≥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. In some implementations, in the relevant models, the tumor growth inhibition assessment for this comparative purpose is performed more than 5 days after administration of the first dose of the combination / composition, for example, one of ≥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.

[0368] In some embodiments, in a given assay, the combination / composition of this disclosure is capable of increasing the median survival of subjects with cancer (e.g., in an in vivo model, such as the cancer described herein, e.g., cancer expressing HER3 and / or EGFR) to more than 1 times the median survival observed at the same time point without combination / composition treatment (or subsequently treated with an appropriate control composition known not to affect cancer patient survival), for example, ≥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, ≥10 times. For subjects in the relevant treatment group, median survival can be expressed as the number of days after the start of the experiment.

[0369] In some embodiments, the combination / composition of this disclosure reduces tumor growth, slows tumor growth, prevents tumor growth, reduces the severity of cancer symptoms, reduces the number of cancer cells, alleviates cancer burden, reduces tumor size / volume, and / or increases the survival of subjects with cancer to a greater extent than when any component of the combination / composition is used alone. In some embodiments, the combination / composition reduces tumor growth, slows tumor growth, prevents tumor growth, reduces the severity of one or more symptoms of cancer, reduces the number of cancer cells, alleviates cancer burden, reduces tumor size / volume, and / or increases the survival of subjects with cancer to a greater extent than when any component of the combination / composition is used as a monotherapy.

[0370] In some embodiments, the combination / composition of this disclosure inhibits tumor growth and / or reduces tumor size / volume to a greater extent than the degree of tumor growth inhibition / tumor size / volume reduction observed when the components of the combination / composition are used alone. In some embodiments, the combination / composition exhibits superior tumor growth inhibition and / or more effective tumor size / volume reduction compared to levels observed when the components of the combination / composition are used as a monotherapy.

[0371] In some embodiments, the combination / composition of this disclosure increases the survival of cancer subjects to a greater extent than the increase in survival observed when a component of the combination / composition is used alone. In some embodiments, the composition / composition increases the survival of cancer subjects compared to the increase in survival observed when a component of the combination / composition is used as a monotherapy.

[0372] For this comparative purpose, monotherapy preferably uses the same dose of the relevant drug as used in combination therapy. For example, in the experiment described in Example 3 of this document, HMBD-001IgG1 (anti-HER3 antibody) was administered as monotherapy at a dose of 20 mg / kg body weight, and in combination therapy with cetuximab, HMBD-001IgG1 was also administered at a dose of 20 mg / kg body weight. Similarly, cetuximab (anti-EGFR antibody) was administered as monotherapy at a dose of 10 mg / kg body weight, and in combination therapy with HMBD-001IgG1.

[0373] In some embodiments, the combinations / compositions of this disclosure are capable of reducing tumor size / volume (e.g., the mean tumor size / volume in the treatment group in an in vivo model (as described herein) of cancers expressing HER3 and / or EGFR) to less than 1-fold, for example ≤0.99-fold, ≤0.95-fold, ≤0.9-fold, ≤0.85-fold, ≤0.8-fold, ≤0.75-fold, ≤0.7-fold, ≤0.65-fold, ≤0.6-fold, ≤0.55-fold, ≤0.5-fold, ≤0.45-fold, ≤0.4-fold, ≤0.35-fold, ≤0.3-fold, ≤0.25-fold, ≤0.2-fold, ≤0.15-fold, ≤0.1-fold, ≤0.05-fold, or ≤0.01-fold, relative to the tumor size / volume observed at the same time point after treating a subject with one component of the combination / composition alone. In some implementations, in the relevant models, the assessment of tumor size / volume for this comparative purpose is performed more than 5 days after the administration of the first dose of the combination / composition, for example, ≥10 days, ≥15 days, ≥20 days, ≥25 days, ≥30 days, ≥35 days, ≥40 days, ≥45 days, ≥50 days, ≥55 days, ≥60 days, ≥65 days, ≥70 days, ≥75 days, ≥80 days, ≥85 days, ≥90 days, ≥95 days, or ≥100 days.

[0374] In some embodiments, the combination / composition of this disclosure can achieve a certain level of tumor growth inhibition (e.g., expressed as a percentage of tumor growth inhibition, calculated relative to tumor growth observed when treated with an isotype-matched control antibody), with an inhibition level greater than 1-fold, for example, ≥1.01-fold, ≥1.02-fold, ≥1.03-fold, ≥1.04-fold, ≥1.05-fold, ≥1.1-fold, ≥1.2-fold, ≥1.3-fold, ≥1.4-fold, ≥1.5-fold, ≥1.6-fold, ≥1.7-fold, ≥1.8-fold, ≥1.9-fold, ≥2-fold, ≥3-fold, ≥4-fold, ≥5-fold, ≥6-fold, ≥7-fold, ≥8-fold, ≥9-fold, or ≥10-fold, exceeding the level of tumor growth inhibition observed when treated with a single component of the combination / composition at the same dose. In some implementations, in the relevant models, the evaluation of tumor growth inhibition for this comparative purpose is performed more than 5 days after the administration of the first dose of the 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.

[0375] In some embodiments, the combinations / compositions of this disclosure are capable of increasing the survival of subjects with cancer (e.g., the median survival of subjects with such cancer, as determined in in vivo models, such as the cancers described herein, such as cancers expressing HER3 and / or EGFR) by more than 1 times the survival observed when treated with monotherapy of any component of the combination / composition, for example, ≥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.

[0376] In the preceding three paragraphs, "same dose" refers to the mass of the relevant pharmaceutical agent used in the combination / composition. For example, if a subject is administered a composition of this disclosure, which includes 20 mg / kg body weight of a HER3-binding antigen-binding molecule and 10 mg / kg body weight of an EGFR-binding antigen-binding molecule, then using the "same dose" of the HER3-binding antigen-binding molecule alone means using the HER3-binding antigen-binding molecule alone at a dose of 20 mg / kg body weight. Similarly, using the "same dose" of the EGFR-binding antigen-binding molecule alone means using the EGFR-binding antigen-binding molecule alone at a dose of 10 mg / kg body weight.

[0377] In some embodiments, the combinations / compositions of this disclosure achieve synergistic therapeutic and / or preventative effects. That is, in some embodiments, the combinations / compositions achieve synergistic (i.e., additive) therapeutic effects relative to the effects observed when the components of the combinations / compositions are used as a monotherapy.

[0378] As used herein, the “synergistic” or “hyperadditivity” level of a given combination / composition’s relevant effect (e.g., tumor growth inhibition, tumor size / volume reduction, increased survival) refers to the effect level that is greater than the sum of the effects observed in the individual components of the combination / composition.

[0379] Quantitative methods for assessing synergistic effects are described, for example, in Tallarida, Genes and Cancer (2011) 2(11):1003–1008 and Chou, Cancer Research (2010) 70:440–446, all of which are incorporated herein by reference. Additive, synergistic, and antagonistic effects can be evaluated experimentally, assessing the relevant effects of a series of different doses of the combination / combination and its individual components. Dose-response curves can be plotted and evaluated to determine whether the combination / combination achieves a synergistic level of relevant effect relative to the individual components of the combination / combination used alone (i.e., as a monotherapy). In some embodiments, synergistic effects can be assessed using the combination index (CI) value calculated using the Chou-Talalay method described in Chou, Cancer Research (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.

[0380] In some embodiments, the combinations / compositions of this disclosure achieve synergistic (i.e., additive) reduction of tumor growth, delay of tumor growth, prevention of tumor growth, reduction of the severity of one or more symptoms of cancer, reduction of cancer cell number, reduction of cancer burden, reduction of tumor size / volume, and / or increase of survival in subjects with cancer, relative to results observed when a component of the combination / composition is used alone.

[0381] Treatment and preventive applications

[0382] This disclosure provides methods and articles (e.g., reagents, combinations, and compositions of this disclosure) for treating and / or preventing diseases (e.g., cancer). Therefore, this disclosure provides an antigen-binding molecule that binds to HER3 for treating or preventing cancer (e.g., the cancer described herein), wherein the method further comprises administering a taxane-like substance. Taxane-like substances are also provided for methods of treating or preventing cancer (e.g., the cancer described herein), wherein the method further comprises administering an antigen-binding molecule that binds to HER3. Use of an antigen-binding molecule that binds to HER3 in the preparation of a medicament for treating or preventing cancer (e.g., the cancer described herein) is also provided, wherein the method further comprises administering a taxane-like substance. Use of a taxane-like substance in the preparation of a medicament for treating or preventing cancer (e.g., the cancer described herein) is also provided, wherein the method further comprises administering an antigen-binding molecule that binds to HER3. A method for treating or preventing cancer (e.g., the cancer described herein) is further provided, comprising administering to a subject requiring treatment the following components having therapeutic or preventive effects: (i) an antigen-binding molecule that binds to HER3, and (ii) a taxane-like substance. A HER3-binding antigen-binding molecule is also provided for a method of treating or preventing cancer (such as the cancer described herein), wherein the method further comprises administering an EGFR-binding antigen-binding molecule, optionally, the method further comprises administering a taxane-like substance. An EGFR-binding antigen-binding molecule is also provided for a method of treating or preventing cancer (such as the cancer described herein), wherein the method further comprises administering a HER3-binding antigen-binding molecule, optionally, wherein the method further comprises administering a taxane-like substance.

[0383] Therefore, this disclosure provides an antigen-binding molecule that binds to HER3 for the treatment or prevention of cancer (e.g., the cancer described herein), wherein the method further comprises administering a nucleoside analog. Nucleoside analogs for the treatment or prevention of cancer (e.g., the cancer described herein) are also provided, wherein the method further comprises administering an antigen-binding molecule that binds to HER3. Use of an antigen-binding molecule that binds to HER3 in the preparation of a medicament for the treatment or prevention of cancer (e.g., the cancer described herein) is also provided, wherein the method further comprises administering a nucleoside analog. Use of a nucleoside analog in the preparation of a medicament for the treatment or prevention of cancer (e.g., the cancer described herein) is also provided, wherein the method further comprises administering an antigen-binding molecule that binds to HER3. Use of an antigen-binding molecule that binds to HER3 in the preparation of a medicament for the treatment or prevention of cancer (e.g., the cancer described herein) is also provided, wherein the method further comprises administering an antigen-binding molecule that binds to EGFR, optionally, wherein the method further comprises administering a taxane-like substance. Also provided is the use of an antigen-binding molecule that binds to EGFR in the preparation of a medicament for treating or preventing cancer (such as the cancer described herein), wherein the method further comprises administering an antigen-binding molecule that binds to HER3, optionally wherein the method further comprises administering a taxane-like substance.

[0384] Further, a method for treating or preventing cancer (such as the cancer described herein) is provided, the method comprising administering a therapeutically or preventively effective amount of a HER3-binding antigen-binding molecule and a nucleoside analog to a subject requiring treatment. A method for treating or preventing cancer (such as the cancer described herein) is also provided, the method comprising administering a therapeutically or preventively effective amount (i) of a HER3-binding antigen-binding molecule and (ii) of an EGFR-binding antigen-binding molecule to a subject requiring treatment; optionally, said method further comprises administering a taxane-like substance.

[0385] This disclosure also provides an antigen-binding molecule that binds to HER3, a method for treating or preventing cancer (such as the cancer described herein), wherein the method further comprises administering a taxane-like substance and a nucleoside analog. Taxane-like substances are also provided for methods of treating or preventing cancer (such as the cancer described herein), wherein the method further comprises administering an antigen-binding molecule that binds to HER3 and a nucleoside analog. Nucleoside analogs are also provided for methods of treating or preventing cancer (such as the cancer described herein), wherein the method further comprises administering an antigen-binding molecule that binds to HER3 and a taxane-like substance. Use of an antigen-binding molecule that binds to HER3 in the preparation of a medicament for treating or preventing cancer (such as the cancer described herein) is also provided, wherein the method further comprises administering a taxane-like substance and a nucleoside analog. Use of a taxane-like substance in the preparation of a medicament for treating or preventing cancer (such as the cancer described herein) is also provided, wherein the method further comprises administering an antigen-binding molecule that binds to HER3 and a nucleoside analog. Also provided is the use of nucleoside analogs in the preparation of a medicament for treating or preventing cancer (such as the cancer described herein), wherein the method further comprises administering an antigen-binding molecule that binds to HER3 and a taxane-like substance. Further provided is a method for treating or preventing cancer (such as the cancer described herein), comprising administering a therapeutically or preventively effective amount of the antigen-binding molecule that binds to HER3, a taxane-like substance, and a nucleoside analog to a subject in need of treatment.

[0386] This disclosure also provides an antigen-binding molecule that binds to HER3 for the treatment or prevention of cancer (such as the cancer described herein), wherein the method further comprises administering a taxane-like molecule and an EGFR-binding antigen-binding molecule. A taxane-like molecule is also provided for the treatment or prevention of cancer (such as the cancer described herein), wherein the method further comprises administering an EGFR-binding antigen-binding molecule and an EGFR-binding antigen-binding molecule. An EGFR-binding antigen-binding molecule is also provided for the treatment or prevention of cancer (such as the cancer described herein), wherein the method further comprises administering an EGFR-binding antigen-binding molecule and a taxane-like molecule. The use of an EGFR-binding antigen-binding molecule in the preparation of a medicament for the treatment or prevention of cancer (such as the cancer described herein) is also provided, wherein the method further comprises administering a taxane-like molecule and an EGFR-binding antigen-binding molecule. The use of a taxane-like molecule in the preparation of a medicament for the treatment or prevention of cancer (such as the cancer described herein) is also provided, wherein the method further comprises administering an EGFR-binding antigen-binding molecule and an EGFR-binding antigen-binding molecule. Also provided is the use of an EGFR-binding antigen-binding molecule in the preparation of a medicament for a method of treating or preventing cancer (such as the cancer described herein), wherein the method further comprises administering an EGFR-binding antigen-binding molecule and a taxane-like substance. Further provided is a method of treating or preventing cancer (such as the cancer described herein), comprising administering a therapeutically or preventively effective amount of the EGFR-binding antigen-binding molecule, a taxane-like substance, and an EGFR-binding antigen-binding molecule to a subject in need of treatment.

[0387] This disclosure also provides (i) an antigen-binding molecule that binds to HER3 and (ii) a taxane-like substance for treating or preventing cancer (e.g., the cancer described herein) in a subject. Use of (i) the antigen-binding molecule that binds to HER3 and (ii) the taxane-like substance in the preparation of a medicament for treating or preventing cancer (e.g., the cancer described herein) in a subject is also provided. A method for treating or preventing cancer (e.g., the cancer described herein) in a subject is also provided, comprising administering to a subject a therapeutically or preventively effective amount of (i) the antigen-binding molecule that binds to HER3 and (ii) the taxane-like substance. This disclosure also provides (i) an antigen-binding molecule that binds to HER3 and (ii) an antigen-binding molecule that binds to EGFR for treating or preventing cancer (e.g., the cancer described herein) in a subject. Use of (i) the antigen-binding molecule that binds to HER3 and (ii) the antigen-binding molecule that binds to EGFR in the preparation of a medicament for treating or preventing cancer (e.g., the cancer described herein) in a subject is also provided. A method for treating or preventing cancer (such as the cancer described herein) in a subject is also provided, comprising administering to the subject a therapeutically or preventively 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 includes administration of a taxane-like substance.

[0388] This disclosure also provides methods for using (i) HER3-binding antigen-binding molecules and (ii) nucleoside analogs to treat or prevent cancer (e.g., the cancer described herein) in a subject. Use of (i) HER3-binding antigen-binding molecules and (ii) nucleoside analogs in the preparation of a medicament for treating or preventing cancer (e.g., the cancer described herein) in a subject is also provided. Methods for treating or preventing cancer (e.g., the cancer described herein) in a subject are also provided, comprising administering to the subject a therapeutically or preventively effective amount of (i) HER3-binding antigen-binding molecules and (ii) nucleoside analogs.

[0389] According to the implementation schemes described in the first two paragraphs, (i) and (ii) can be used as a combined treatment. In some implementation schemes, (i) and (ii) can be provided simultaneously or sequentially.

[0390] This disclosure also provides (i) an antigen-binding molecule that binds to HER3, (ii) taxanes, and (iii) nucleoside analogs for treating or preventing cancer (e.g., the cancer described herein) in a subject. Use of (i) the antigen-binding molecule that binds to HER3, (ii) taxanes, and (iii) nucleoside analogs in the preparation of a medicament for treating or preventing cancer (e.g., the cancer described herein) in a subject is also provided. Methods for treating or preventing cancer (e.g., the cancer described herein) in a subject are also provided, comprising administering to a subject a therapeutically or preventively effective amount of (i) the antigen-binding molecule that binds to HER3, (ii) taxanes, and (iii) nucleoside analogs. This disclosure also provides (i) an antigen-binding molecule that binds to HER3, (ii) taxanes, and (iii) an antigen-binding molecule that binds to EGFR for treating or preventing cancer (e.g., the cancer described herein) in a subject. Also provided is the use of (i) antigen-binding molecules that bind to HER3, (ii) taxanes, and (iii) antigen-binding molecules that bind to EGFR in the preparation of medicaments for treating or preventing cancer (e.g., the cancer described herein) in a subject. A method of treating or preventing cancer (e.g., the cancer described herein) in a subject is also provided, comprising administering to the subject a therapeutically or preventively effective amount of (i) the antigen-binding molecule that binds to HER3, (ii) the taxane, and (iii) the antigen-binding molecule that binds to EGFR.

[0391] According to the implementation plans outlined in the preceding sections, (i), (ii), and (iii) can be used as a combination therapy. In some implementation plans, (i), (ii), and (iii) can be provided simultaneously or sequentially.

[0392] This disclosure relates to methods and articles for treating and / or preventing cancer (e.g., reagents, combinations, and compositions of this disclosure).

[0393] As used in this article, “cancer” can be or includes any abnormal cell proliferation (or any disease that manifests as abnormal cell proliferation), a tumor, or a neoplasm. Cancer can be benign or malignant. Cancer can be primary or secondary (metastatic). A tumor can be an abnormal growth or proliferation of cells and can be located in any tissue. Cancerous tissue / cells may originate from the adrenal glands, adrenal medulla, anus, appendix, bladder, blood, bones, bone marrow, brain, breast, cecum, central nervous system (including or excluding the brain), cerebellum, cervix, colon, duodenum, endometrium, epithelial cells (such as renal epithelial cells), gallbladder, esophagus, glial cells, heart, ileum, jejunum, kidneys, lacrimal glands, larynx, liver, lungs, lymph nodes, lymphoblasts, maxilla, mediastinum, mesentery, muscle layer, nasopharynx, omentum, oral cavity, ovary, pancreas, parotid gland, peripheral nervous system, peritoneum, pleura, prostate, salivary glands, sigmoid colon, skin, small intestine, soft tissue, spleen, stomach, testes, thymus, thyroid gland, tongue, tonsils, trachea, uterus, vulva, and leukocytes.

[0394] The tumor to be treated may be a nervous system tumor or a non-nervous system tumor. Nervous system tumors can originate from the central or peripheral nervous system, such as gliomas, medulloblastomas, meningiomas, neurofibromas, ependymomas, schwannomas, neurofibrosarcomas, astrocytomas, and oligodendrogliomas. Non-nervous system cancers / tumors can originate from any other non-nervous tissue; examples include melanoma, mesothelioma, lymphoma, myeloma, leukemia, non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), cutaneous T-cell lymphoma (CTCL), chronic lymphocytic leukemia (CLL), liver cancer, epidermoid carcinoma, prostate cancer, breast cancer, lung cancer, colon cancer, ovarian cancer, pancreatic cancer, thymic carcinoma, NSCLC, hematologic malignancies, and sarcomas.

[0395] In some embodiments, the cancer to be treated / prevented comprises cells expressing EGFR family members (e.g., HER3, EGFR, HER2, or HER4) and / or cells expressing EGFR family member ligands. In some embodiments, the cancer to be treated / prevented is EGFR family member-positive cancer. In some embodiments, the cancer comprises cells overexpressing EGFR family members and / or EGFR family member ligands. Overexpression can be determined by detecting expression levels greater than those in equivalent non-cancerous / non-tumor tissue.

[0396] Expression can be determined by any suitable method. Expression may be gene expression or protein expression. Gene expression can be determined by detecting the mRNA encoding HER3, for example, by quantitative real-time PCR (qRT-PCR). Protein expression can be determined by antibody-based methods, such as western blot, immunohistochemistry, immunocytochemistry, flow cytometry, or ELISA.

[0397] In some implementations, the cancer is a HER3 and / or EGFR-related pathology. That is, in some implementations, the cancer is caused or aggravated by the expression of HER3 and / or EGFR, HER3 and / or EGFR expression is a risk factor for cancer, and / or HER3 and / or EGFR expression is positively correlated with the onset, development, progression, severity, or metastasis of cancer. Cancer may be characterized by the expression of HER3 and / or EGFR; for example, cancer may include cells expressing HER3 and / or EGFR (e.g., tumor tissue cells). This type of cancer may be referred to as HER3 and / or EGFR positive. HER3 and / or EGFR “positive” cancer may be cancer composed of cells expressing HER3 and / or EGFR (e.g., on the cell surface). HER3 and / or EGFR “positive” cancer may overexpress HER3 and / or EGFR. In some implementations, the cancer to be treated / prevented comprises cells carrying genetic variations (e.g., mutations) that result in increased expression and / or activity of HER3 and / or EGFR (genes and / or proteins), relative to comparable cells carrying a reference allele that does not contain the genetic variation (e.g., a non-mutated or "wild-type" allele). The genetic variation can be or includes insertions, deletions, substitutions, or larger-scale translocations / rearrangements of nucleotide sequences relative to the reference allele.

[0398] Mutations leading to increased HER3 and / or EGFR expression are known or predicted to result in increased expression of HER3 and / or EGFR genes / proteins, or may be associated with them. Mutations leading to increased HER3 and / or EGFR activity are known or predicted to result in increased HER3-mediated signaling and / or EGFR-mediated signaling, or may be associated with them. Mutations leading to increased HER3 and / or EGFR expression and / or activity can be termed "activating" mutations.

[0399] Mutations that lead to increased HER3 and / or EGFR expression may result in the expression of genes or proteins associated with HER3 and / or EGFR that cannot be expressed by equivalent cells without the mutation and / or cannot be encoded by their genomic nucleic acids. In other words, HER3 and / or EGFR may be neoantigens resulting from mutations, so "increased expression" may originate from a lack of expression.

[0400] Mutations that lead to increased HER3 and / or EGFR expression may result in increased expression of the genes or proteins encoding HER3 and / or EGFR, which are expressed by equivalent cells that do not contain the mutation and / or are encoded by their genomic nucleic acids. For example, a cell may contain a mutation that results in an increased level of transcription of nucleic acids encoding HER3 and / or EGFR relative to the level of transcription of nucleic acids encoding HER3 and / or EGFR in equivalent cells that do not contain the mutation.

[0401] In some embodiments, mutations that lead to increased HER3 and / or EGFR expression can result in increased HER3 and / or EGFR gene expression relative to equivalent cells that do not contain the mutation. In some embodiments, mutations that lead to increased HER3 and / or EGFR expression can result in increased HER3 and / or EGFR protein expression relative to equivalent cells that do not contain the mutation.

[0402] In some implementations, mutations that lead to increased HER3 and / or EGFR expression can result in increased levels of HER3 and / or EGFR on or in the cell surface of cells containing the mutation, relative to equivalent cells that do not contain the mutation.

[0403] Cells with elevated HER3 and / or EGFR expression levels relative to reference cells (e.g., due to mutations) can be described as having HER3 and / or EGFR “overexpression” or “upregulated” expression. For example, a cancer containing cells carrying mutations that lead to increased HER3 and / or EGFR expression might be described as a cancer containing cells with overexpression / upregulated HER3 and / or EGFR expression, compared to equivalent cells lacking the mutation. In some embodiments, the reference cell lacking the mutation can be a non-cancerous cell (e.g., having an equivalent cell type) or a cancerous cell (e.g., having an equivalent cancer type).

[0404] Mutations that lead to increased HER3 and / or EGFR activity may result in increased levels of HER3-mediated and / or EGFR-mediated signaling relative to equivalent cells without the mutation.

[0405] In some embodiments, the cancer to be treated / prevented according to this disclosure may exhibit increased expression and / or activity of HER3 and / or EGFR (i.e., gene and / or protein expression) in organs / tissues / subjects affected by the disease / condition, for example, compared to normal organs / tissues / subjects (i.e., in the absence of disease / condition). In some embodiments, the cells and / or tumors of the cancer to be treated / prevented may exhibit increased expression and / or activity of HER3 and / or EGFR, for example, compared to expression and / or activity levels observed in equivalent non-cancer / non-tumor tissues.

[0406] Cancers that overexpress HER3 may be due to HER3 gene amplification, resulting in HER3 overexpression. Similarly, cancers that overexpress EGFR may be due to EGFR gene amplification, resulting in EGFR overexpression.

[0407] In some embodiments, the cancer to be treated / prevented according to this disclosure is HER3-amplified cancer. In some embodiments, the cancer is EGFR-amplified cancer. In some embodiments, the cancer is cancer containing both HER3 and EGFR amplification. In some embodiments, the cancer to be treated / prevented according to this disclosure is TP63-amplified cancer.

[0408] 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 assessed by fluorescence in situ hybridization, as described in Chung et al., *J Gynecol Oncol.* (2019) 30(5):e75. Cancers with HER3 amplification may include those with a ≥2 ratio of 12q13.2 to the centromere of chromosome 12 as determined by ISH. EGFR amplification can also be assessed by in situ hybridization, as described in French et al., *Neuro-Oncology* (2019) 21(10):1263–1272. Cancers with EGFR amplification may include those with a ≥2 ratio 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 in Masson et al., *Cancer Res.* (2003) 63(21):7113-21. Cancers with TP63 amplification may include those with a ratio of ≥2 centromeres on chromosome 3, as determined by ISH, between 3q26-3qter and chromosome 3.

[0409] For information on EGFR and its relationship and role in cancer, see, for example, 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, all of which are incorporated herein by reference. da Silva Santos et al., *Int J Pharm.* (2021) 592:120082, describes interventions targeting EGFR in cancer treatment, including monoclonal anti-EGFR antibody therapy.

[0410] For information on HER3 and its relationship and role in cancer, see, for example, 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 Biophysica Sinica* (2016) 48(1):39–48. All contents of these publications are incorporated herein by reference. Mishra et al., *Oncol Rev.* (2018) 12(1):355, also describe interventions targeting HER3 in cancer treatment, including monoclonal anti-HER3 antibody therapy.

[0411] In some embodiments, the cancer to be treated / prevented comprises cells expressing HER3 ligands (e.g., NRG1 and / or NRG2). In some embodiments, the cancer to be treated / prevented comprises cells expressing NRG1 and / or NRG2 at levels greater than the equivalent expression levels in non-cancerous / non-tumor tissue. Such cancer can be described as being composed of cells overexpressing NRG1 and / or NRG2.

[0412] The HER3-binding antigen-binding molecules described in this article exhibit extremely high affinity for HER3, both when HER3 binds to NRG (i.e., HER3 is offered in an "open" conformation) and when HER3 does not bind to NRG (i.e., HER3 is offered in a "closed" conformation). Therefore, they are particularly useful for the treatment / prevention of cancers characterized by HER3 ligand expression / overexpression, such as cancers / tumors comprising cells that express / overexpress HER3 ligands.

[0413] In some implementations, the cancer to be treated / prevented comprises cells carrying a genetic variant (e.g., a mutation) that results in increased expression of the HER3 ligand (gene and / or protein), relative to comparable cells carrying a reference allele that does not contain that genetic variant (e.g., a non-mutated or "wild-type" allele). The genetic variant can be or includes insertions, deletions, substitutions, or larger-scale translocations / rearrangements of nucleotide sequences relative to the reference allele.

[0414] The most common version of the nucleotide sequence of a given gene can be called the wild-type allele of that gene. A version of the nucleotide sequence of a given gene containing a mutation can be called the mutant allele of that gene. It should be understood that the nucleotide sequence of the mutant allele of a given gene has a nucleotide sequence that is different from that of the wild-type allele.

[0415] Mutations that lead to increased HER3 ligand expression may be known or predicted to cause, or may be associated with, increased expression of the HER3 ligand gene / protein. Mutations that lead to increased HER3 ligand expression can be called “activating” mutations.

[0416] Mutations leading to increased HER3 ligand expression may result in the expression of the HER3 ligand gene or protein, which cannot be expressed by equivalent cells without the mutation and / or cannot be encoded by their genomic nucleic acids. In other words, the HER3 ligand may be a neoantigen resulting from the mutation, so "increased expression" may originate from a lack of expression. For example, cells containing the CD74-NRG1 gene fusion show increased expression of the CD74-NRG1 fusion peptide encoded by the gene fusion compared to cells lacking the CD74-NRG1 gene fusion.

[0417] Mutations that lead to increased HER3 ligand expression may result in increased expression of the gene or protein encoding the HER3 ligand, which is expressed by equivalent cells that do not contain the mutation and / or by their genomic nucleic acid expression. For example, a cell may contain a mutation that leads to an increased transcriptional level of the nucleic acid encoding NRG1, relative to the transcriptional level of the nucleic acid encoding NRG1 in equivalent cells that do not contain the mutation.

[0418] In some embodiments, mutations that increase HER3 ligand expression can lead to increased gene expression of the HER3 ligand relative to equivalent cells without the mutation. In some embodiments, mutations that increase HER3 ligand expression can lead to increased protein expression of the HER3 ligand relative to equivalent cells without the mutation.

[0419] In some embodiments, a mutation leading to increased HER3 ligand expression can result in increased levels of HER3 ligand on or within the cell surface of cells containing the mutation, relative to equivalent cells not containing the mutation. In some embodiments, a mutation leading to increased HER3 ligand expression can result in increased levels of HER3 ligand secreted from cells containing the mutation, relative to equivalent cells not containing the mutation. Cells with increased HER3 ligand expression relative to reference cells (e.g., due to the mutation) can be described as having “overexpression” or “upregulated expression” of HER3 ligand. For example, a cancer containing cells carrying a mutation leading to increased HER3 ligand expression can be described as a cancer containing cells exhibiting HER3 ligand overexpression / upregulated expression, relative to equivalent cells lacking the mutation. In some embodiments, the reference cell lacking the mutation can be a non-cancerous cell (e.g., having an equivalent cell type) or a cancerous cell (e.g., having an equivalent cancer type).

[0420] In this article, "HER3 ligand" generally refers to a molecule capable of binding to HER3 through a HER3 ligand-binding region formed by HER3 domains I and III. In some embodiments, HER3 ligands bind to HER3 through interactions with HER3 domains I and / or III. Typical HER3 ligands include neuroregulatory proteins such as NRG1 and NRG2, which bind to HER3 through interactions between their EGF-like domains and the HER3 ligand-binding region.

[0421] The HER3 ligand is preferably capable of binding to and triggering signal transduction via the HER3 receptor and / or a receptor complex containing HER3. As described in this disclosure, the receptor complex containing HER3 may further contain the HER3 interacting partners described herein, such as HER3, HER2, EGFR, HER4, HGFR, IGF1R, and / or cMet.

[0422] In some embodiments, HER3 ligands are capable of binding to HER3 receptor / receptor complexes expressed by cells with increased expression of non-HER3 ligands. For example, in some embodiments, HER3 ligands are capable of binding to cancer cells expressing HER3.

[0423] In some implementations, HER3 ligands are able to bind to HER3 receptor / receptor complexes expressed in cells with increased HER3 ligand expression.

[0424] In some implementations, the cancer to be treated / prevented includes (i) cells expressing HER3 and (ii) cells expressing HER3 ligands (e.g., cells with increased expression of HER3 ligands, for example, due to mutations that lead to increased expression of HER3 ligands).

[0425] In some implementations, the cancer to be treated / prevented includes cells that: (i) express HER3; and (ii) simultaneously express a HER3 ligand (e.g., have increased HER3 ligand expression, for example, due to mutations that lead to increased HER3 ligand expression).

[0426] In some embodiments, the HER3 ligand comprises or consists of an amino acid sequence from the HER3-binding region of the HER3 ligand, or consists of an amino acid sequence derived from the HER3-binding region of the HER3 ligand. The amino acid sequence derived from the HER3-binding region of the HER3 ligand 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 the amino acid sequence from which it is derived.

[0427] In some embodiments, the HER3 ligand includes an EGF-like domain capable of binding to HER3 or its HER3-binding fragment. In some embodiments, the HER3-binding EGF-like domain / fragment is or is derived from a member of the EGF family (e.g., heparin-binding EGF-like growth factor (HB-EGF), transforming growth factor-α (TGF-α), amphiregulin (AR), epiregulin (EPR), epigen, betacellulin (BTC), NRG1, NRG2, NRG3, or NRG4).

[0428] Typical ligands for HER3 include neuroregulatory proteins (NRGs). Neuroregulatory proteins include NRG1 (including its alpha, alpha2b, and alpha3 or their isoforms), NRG2, NRG3, and NRG4. In some embodiments, NRGs are selected from NRG1, NRG2, NRG3, and NRG4. In some embodiments, NRGs are selected from NRG1 and NRG2.

[0429] The EGF-like domain of human NRG1, through which it can bind to HER3, consists of bits 178 to 222 of UniProt:Q02297-1. The EGF-like domain of human NRG2 consists of bits 341 to 382 of UniProt:O14511-1. The EGF-like domain of human NRG3 consists of bits 286 to 329 of UniProt:B9EGV5-1. The EGF-like domain of human NRG4 consists of bits 5 to 46 of UniProt:Q8WWG1-1. In some embodiments, the EGF-like domain / fragment includes 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 the EGF-like domain of the NRG (NRG1, NRG2, NRG3, or NRG4).

[0430] In some implementations, the ligand for HER3 is not an EGFR family protein (e.g., HER3, HER2, EGFR, HER4, HGFR, IGF1R, cMet).

[0431] In some embodiments, the mutation leading to increased HER3 ligand expression is an NRG gene fusion. In some embodiments, the HER3 ligand is the product of an NRG gene fusion (i.e., a polypeptide encoded by an NRG gene fusion). In some embodiments, the cancer comprises cells with NRG gene fusions. As used herein, “NRG gene fusion” refers to a genetic variation 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.

[0432] Appropriate molecular tests familiar to those skilled in the art can be used to detect and characterize NRG gene fusions.

[0433] The NRG gene fusion disclosed herein is preferably correctly oriented (i.e. has a nucleotide sequence encoding NRG at the 3' end of the transcript) and encodes a fusion polypeptide containing an EGF-like domain capable of binding to HER3.

[0434] It should be understood that the NRG gene fusion preferably encodes the HER3 ligand described herein. In some embodiments, the NRG gene fusion encodes a polypeptide comprising the HER3-binding region of the NRG protein. In some embodiments, the NRG gene fusion encodes a polypeptide comprising the EGF-like domain of the NRG protein, or an amino acid sequence capable of binding to HER3 and 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 the EGF-like domain of the NRG protein.

[0435] In some embodiments, the NRG gene fusion encodes a fusion polypeptide comprising a transmembrane domain. In some embodiments, the NRG gene fusion encodes a fusion polypeptide comprising a transmembrane domain of a protein other than the NRG protein.

[0436] In some embodiments, the NRG gene fusion is an NRG1 gene fusion. In some embodiments, the NRG1 gene fusion encodes a polypeptide containing the EGF-like domain of NRG1, or an amino acid sequence capable of binding to HER3 and 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 the EGF-like domain of NRG1.

[0437] NRG1 gene fusions are operable fusions in tissue-unknown cancers that can be targeted by HER3 inhibition. They form through interchromosomal translocations with a range of different genes, leading to an overproduction of NRG1 ligands to bind to HER3 and triggering aberrant activation, thereby contributing to tumorigenesis. Studies have shown a causal link between HER3 pathway activation and NRG1 gene fusions. NRG1 fusions are enriched in patients with mucinous non-small cell lung cancer and pancreatic ductal adenocarcinoma; 8–32% of mucinous non-NSCLC patients have NRG1 gene fusions, while 10–20% (up to 70% in small studies) of KRAS wild-type PDAC patients have detectable NRG1 gene fusions. Therapeutic efficacy of monoclonal anti-HER3 antibody therapy targeting NRG1 gene fusions has been demonstrated, for example, as described in WO 2021 / 048274 A1.

[0438] NRG1 gene fusions have been described in publications such as WO 2021 / 048274 A1, WO 2018 / 182422 A1, WO 2019 / 051155A1, Dhanasekaran et al., *Nature Communications* (2014) 5:5893, Drilon et al., *Cancer Discovery* (2018) 8(6):686-695, Nagasaka et al., *Journal of Thoracic Oncology* (2019) 14(8):1354-1359, and Jonna et al., *Clinical Cancer Research* (2019) 25(16):4966-4972, all of which are incorporated herein by reference. The diversity of NRG1 gene fusions may be due to NRG1's location on chromosome 8, which is particularly susceptible to genomic translocation events. et al., *Gene Chromosomal Cancer* (2003) 37(4):333-45. In some implementations, the NRG1 gene fusion is selected from 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, MRP... L13-NRG1, 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 implementations, the NRG1 gene fusion is CLU-NRG1.

[0439] CD74-NRG1 gene fusions have been described, for example, in Fernandez-Cuesta et al., Cancer Discovery (2014) 4:415–22 and Nakaoku et al., Clinical Cancer Research (2014) 20:3087–93. DOC4-NRG1 gene fusions have been described, for example, in Liu et al., Oncogene (1999) 18(50):7110–4 and Wang et al., Oncogene (1999) 18(41):5718–21. SLC3A2-NRG1 gene fusions have been described, for example, in Nakaoku et al., Clinical Cancer Research (2014) 20:3087–93, Shin et al., Oncotarget (2016) 7:69450–65 and Shin et al., Mol Cancer Ther. (2018) 17(9):2024–2033. RBPMS-NRG1, WRN-NRG1, RAB2IL1-NRG1, and SDC4-NRG1 gene fusions have been described, for example, by Dhanasekaran et al., *Nature Communications* (2014) 5:5893. VAMP2-NRG1 gene fusions have been 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. KIF13B-NRG1 gene fusions have been described, for example, by Xia et al., *Int JSurg Pathol.* (2017) 25(3):238-240. Gene fusions of SMAD4-NRG1, AKAP13-NRG1, THBS1-NRG1, FOXA1-NRG1, PDE7A-NRG1, RAB3IL1-NRG1, and THAP7-NRG1 are described, for example, by Drilon et al. in Cancer Discovery (2018) 8(6):686-695. Gene fusions of MDK-NRG1, TNC-NRG1, DIP2B-NRG1, MRPL13-NRG1, PARP8-NRG1, ROCK1-NRG1, and DPYSL2-NRG1 are described, for example, by Jonna et al. in Clinical Cancer Research (2019) 25(16):4966-4972. The ATP1B1-NRG1 gene fusion has been described, for example, in Drilon et al., Cancer Discovery (2018) 8(6):686-695 and Jones et al., Annals of Oncology (2017) 28:3092–3097.CLU-NRG1 gene fusions have been described, for example, by Drilon et al., Cancer Discovery (2018) 8(6):686-695 and by Nagasaka et al., Journal of Thoracic Oncology (2019) 14(8):1354-1359.

[0440] In some implementation schemes, the NRG gene fusion is an NRG2 gene fusion. In some embodiments, the NRG2 gene fusion encodes a polypeptide containing an EGF-like domain of NRG2, or containing an amino acid sequence capable of binding to HER3 and 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 the EGF-like domain of NRG2.

[0441] NRG2 gene fusions, including SLC12A2-NRG2, have been described in, for example, WO 2021 / 048274 A1 and WO 2015 / 093557A1, and ZNF208-NRG2 has been described in Dupain et al., Mol Ther. (2019) 27(1):200-218.

[0442] Cancers containing cells with mutations that lead to increased HER3 ligand expression (e.g., cells containing NRG gene fusions, such as NRG1 or NRG2 fusions) can be any cancer described herein. In some embodiments, such cancer may originate from tissues / cells of the lung, breast, head, neck, kidney, ovary, pancreas, prostate, uterus, gallbladder, colon, rectum, bladder, soft tissue, or nasopharynx.

[0443] In some implementations, cancers comprising cells with mutations leading to increased HER3 ligand expression (e.g., cells comprising NRG gene fusions, such as NRG1 gene fusion or NRG2 gene fusion) are selected from: lung cancer, non-small cell lung cancer, lung adenocarcinoma, invasive mucinous lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, breast adenocarcinoma, invasive breast adenocarcinoma, head and neck cancer, head and neck squamous cell carcinoma, renal cancer, clear cell renal cancer, ovarian cancer, ovarian serous cystadenocarcinoma, pancreatic cancer, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, prostate cancer, prostate adenocarcinoma, endometrial cancer, uterine sarcomatoid carcinoma, 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.

[0444] In some implementations, the cancer to be treated / prevented is lung cancer (e.g., non-small cell lung cancer, lung adenocarcinoma, invasive lung mucinous adenocarcinoma, or lung squamous cell carcinoma) containing cells with NRG1 gene fusion.

[0445] It should be understood that, in the embodiments described herein, a cancer containing cells with specified characteristics may be or may contain a tumor containing cells with those characteristics.

[0446] As is common in the art, cancers / tumors containing cells with specific characteristics may simply be referred to herein as cancers / tumors with those characteristics. For example, cancers / tumors containing cells with NRG1 gene fusions may simply be referred to as "cancers / tumors containing NRG1 gene fusions" or "NRG1 gene fusion cancers / tumors".

[0447] In some embodiments, the cancer to be treated / prevented contains a mutation that confers resistance to BRAF inhibitor treatment. In some embodiments, this mutation is a BRAF V600 mutation. In some embodiments, this mutation is BRAF V600E or V600K. The cancer can be thyroid cancer or colon cancer, such as RAS wild-type colorectal cancer. In some embodiments, the cancer to be treated / prevented contains a mutation that confers resistance to BRAF inhibitor treatment (e.g., a BRAF V600 mutation), and the treatment includes administration of vemurafenib or darafenib.

[0448] In squamous cell carcinoma (SCC), the PI3K / AKT signaling pathway is frequently altered through gene amplification and / or mutation. The frequently amplified 3q26 / 28 chromosomal region contains PIK3CA, as well as TP63 and SOX2 cell lineage genes. TP63, a member of the TP53 gene family, is expressed in the basal layer during development and homeostasis in the skin, esophagus, lung airways, and larynx. TP63 has been used as a diagnostic marker to differentiate squamous cell carcinoma from adenocarcinoma in lung and esophageal cancers. Preclinical data suggest that TP63 regulates NRG1 expression in SCC, indicating 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, along with EGFR overexpression in some squamous cell carcinomas, supports the rationale for combining 10D1F with cetuximab in EGFR-amplified squamous cell carcinoma.

[0449] When describing a cancer as having a specific mutational state, allele, or genotype, it should be understood that the cancer cells have the relevant mutational state, allele, or genotype. For example, when describing a cancer as containing a specific mutation, the cancer contains cells with that mutation. Similarly, when describing a cancer as homozygous for a specific allele, the cancer contains cells homozygous for that allele.

[0450] When describing a cancer as having a specific mutational state, allele, or genotype, one or more cells of that cancer possess the relevant mutational state, allele, or genotype. In some embodiments, when describing a cancer as having a specific mutational state, allele, or genotype, a majority (i.e., >50%) of the cells of that cancer possess the relevant mutational state, allele, or genotype. In some embodiments, ≥60%, ≥65%, ≥70%, ≥75%, ≥80%, ≥85%, ≥90%, ≥95%, or 100% of the cells in the cancer possess the relevant mutational state, allele, or genotype.

[0451] In some embodiments, cancer containing a specific mutation / allele / genotype may refer to cancer in which >10% (e.g., ≥20%, ≥50%, ≥40%, ≥50%, ≥60%, ≥65%, ≥70%, ≥75%, ≥80%, ≥85%, ≥90%, ≥95%, or 100%) of the cells contain that mutation / allele / genotype. In some embodiments, cancer not containing a specific mutation / allele / genotype may refer to cancer in which <25% (e.g., ≤20%, ≤15%, ≤10%, ≤5%, ≤1%, or none) of the cells contain that mutation / allele / genotype.

[0452] Here, when describing a cell as containing a specific mutation, it should be understood that one or both alleles of the relevant gene contain that mutation (i.e., the cell is heterozygous or homozygous for that mutation / mutant allele). Conversely, when describing a cell as not containing a specific mutation, it should be understood that none of the alleles of the relevant gene contain that mutation (i.e., the cell is neither homozygous nor heterozygous for that mutation / mutant allele).

[0453] According to this disclosure, activating mutations can: increase gene transcription; increase the level of gene-encoded RNA; decrease gene-encoded RNA degradation; increase gene-encoded protein levels; increase (promote) normal splicing of gene-encoded pre-mRNA; increase the translation of gene-encoded protein mRNA; increase (promote) normal post-translational processing of gene-encoded protein; increase (promote) normal transport of gene-encoded protein; decrease gene-encoded protein degradation; increase the functional level of gene-encoded protein; and / or confer new properties on gene-encoded protein. According to this disclosure, inactivating mutations can: decrease gene transcription; decrease the level of gene-encoded RNA; increase gene-encoded RNA degradation; decrease the level of gene-encoded protein; decrease (disrupt) normal splicing of gene-encoded pre-mRNA; decrease the translation of gene-encoded protein mRNA; decrease (disrupt) normal post-translational processing of gene-encoded protein; decrease (disrupt) normal transport of gene-encoded protein; increase gene-encoded protein degradation; and / or decrease the functional level of gene-encoded protein.

[0454] In some implementations, the cancer to be treated / prevented is not homozygous for an activating mutation of KRAS. In some implementations, the cancer is not homozygous for an activating mutation of PIK3CA. In some implementations, the cancer is not homozygous for an inactivating mutation of PTEN. In some implementations, the cancer is not homozygous for an activating mutation of BRAF. In some implementations, the cancer is not homozygous for an activating mutation of MET. In some implementations, the cancer to be treated / prevented is not homozygous for activating mutations of KRAS, not homozygous for activating mutations of PIK3CA, not homozygous for inactivating mutations of PTEN, not homozygous for activating mutations of BRAF, and not homozygous for activating mutations of MET.

[0455] In some embodiments, the cancer does not include activating mutations in KRAS. In some embodiments, the cancer does not include activating mutations in PIK3CA. In some embodiments, the cancer does not include inactivating mutations in PTEN. In some embodiments, the cancer does not include activating mutations in BRAF. In some embodiments, the cancer does not include activating mutations in MET. In some embodiments, the cancer does not include activating mutations in KRAS, PIK3CA, PTEN, BRAF, or MET.

[0456] In some embodiments, the cancer includes a homozygous wild-type genotype of KRAS. In some embodiments, the cancer includes a homozygous wild-type genotype of PIK3CA. In some embodiments, the cancer includes a homozygous wild-type genotype of BRAF. In some embodiments, the cancer includes a homozygous wild-type genotype of PTEN. In some embodiments, the cancer includes a homozygous wild-type genotype of MET. In some embodiments, the cancer includes homozygous wild-type genotypes of KRAS, PIK3CA, BRAF, PTEN, and MET.

[0457] In some implementation schemes, the cancer to be treated / prevented is metastatic cancer. Metastatic cancer is cancer that can be detected in secondary sites in the body outside of one or more sites of origin of the primary cancer; metastatic cancer is cancer that has evolved from the primary cancer.

[0458] In some implementations, the cancer to be treated / prevented is advanced cancer. Advanced cancer refers to cancer that has spread from the site of origin of the primary (original) cancer. In some implementations, the cancer to be treated / prevented is locally advanced cancer. Locally advanced cancer refers to cancer that has spread from the site of origin of the primary (original) cancer to nearby tissues or lymph nodes.

[0459] In some implementations, the cancer to be treated / prevented is an unresectable cancer. Unresectable cancer refers to cancer that cannot be completely removed surgically. This can be due to a variety of reasons, including tumor size, stage, and / or location.

[0460] In some implementations, the cancer to be treated / prevented is locally advanced and unresectable cancer.

[0461] In some embodiments, the cancer to be 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), esophageal squamous cell carcinoma (ESCC), cervical squamous cell carcinoma, skin squamous cell carcinoma (cSCC), squamous cell thyroid 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).

[0462] In some embodiments, the cancer to be treated / prevented is a cancer that expresses / overexpresses NRG1 and HER3. In some embodiments, the cancer is squamous cell carcinoma that expresses / overexpresses NRG1 and HER3. In some embodiments, the cancer is head and neck squamous cell carcinoma that expresses / overexpresses NRG1 and HER3. In some embodiments, the cancer is esophageal squamous cell carcinoma that expresses / overexpresses NRG1 and HER3. In some embodiments, the cancer is hypopharyngeal squamous cell carcinoma that expresses / overexpresses NRG1 and HER3.

[0463] In some embodiments, the cancer to be treated / prevented is a cancer that expresses or overexpresses EGFR. In some embodiments, the cancer to be treated / prevented is squamous cell carcinoma that expresses or overexpresses EGFR. In some embodiments, the cancer is head and neck squamous cell carcinoma that expresses or overexpresses EGFR. In some embodiments, the cancer is esophageal squamous cell carcinoma that expresses or overexpresses EGFR. In some embodiments, the cancer is tongue squamous cell carcinoma that expresses or overexpresses EGFR.

[0464] In some implementations, the cancer to be treated / prevented is colorectal cancer that expresses / overexpresses EGFR. In other implementations, the cancer to be treated / prevented is colonic adenocarcinoma that expresses / overexpresses EGFR.

[0465] In some implementations, the cancer may be recurrent. As used herein, “recurrent” cancer refers to cancer that responds to treatment (e.g., first-line treatment for cancer) but subsequently reappears / progresses, for example, after a period of remission. For instance, recurrent cancer may be cancer whose growth / progress was suppressed by treatment (e.g., first-line treatment for cancer) but subsequently grew / progressed again.

[0466] In some implementations, the cancer may be a refractory cancer. As used herein, "refractory" cancer refers to cancer that does not respond to a certain treatment (e.g., first-line treatment for cancer). For example, refractory cancer may refer to cancer whose growth / progression is not inhibited by treatment (e.g., first-line treatment for cancer). In some implementations, refractory cancer may refer to cancer in which a subject receiving cancer treatment does not show a partial or complete response to treatment.

[0467] In some implementations, the cancer is relapsed or refractory to platinum-based chemotherapy. Platinum-based chemotherapy includes cisplatin, carboplatin, oxaliplatin, nindapplatin, and lobaplatin.

[0468] In some embodiments, the cancer is advanced squamous non-small cell lung cancer. In some embodiments, the cancer is metastatic squamous non-small cell lung cancer. In some embodiments, the cancer is locally advanced and unresectable squamous non-small cell lung cancer.

[0469] In some implementations, the cancer is an advanced or metastatic cancer involving NRG1 gene fusion.

[0470] In some implementations, the cancer is advanced or metastatic pancreatic ductal adenocarcinoma containing an NRG1 gene fusion.

[0471] In some implementations, the cancer is advanced or metastatic non-small cell lung cancer containing an NRG1 gene fusion.

[0472] In some embodiments, the cancer is selected from: cancers including cells expressing / overexpressing EGFR family members (e.g., HER3, EGFR, HER2, or HER4), cancers including cells expressing / overexpressing HER3, cancers including cells expressing / overexpressing EGFR, cancers including cells simultaneously expressing / overexpressing HER3 and EGFR, cancers including cells with mutant cells leading to increased HER3 ligand expression, cancers including cells with mutant cells leading to increased EGFR ligand expression, cancers including cells with NRG gene fusion, and cancers including cells with... Cancers containing NRG1 gene fusion cells, or including cancers containing NRG2 gene fusion cells, solid tumors, hematologic malignancies, squamous cell carcinoma, EGFR-amplified squamous cell carcinoma, breast cancer, breast cancer tumors, invasive breast cancer, ductal carcinoma, metastatic breast cancer, triple-negative breast cancer, HER2-positive breast cancer, gastric cancer, gastric tumors, gastric adenocarcinoma, gastrointestinal adenocarcinoma, colorectal cancer, metastatic colorectal cancer, colon cancer, colorectal tumors, colorectal adenocarcinoma, colon adenocarcinoma, head and neck cancer, head and neck squamous cell carcinoma (HNSCC), lung cancer, non-small cell lung cancer, lung adenocarcinoma, invasive cancer Mucinous lung adenocarcinoma, squamous cell lung cancer, lung squamous cell carcinoma (LUSC), squamous non-small cell lung cancer, advanced squamous non-small cell lung cancer, metastatic squamous non-small cell lung cancer, ovarian cancer, ovarian tumor, ovarian serous adenocarcinoma, ovarian serous cystadenocarcinoma, fallopian tube cancer, renal cell carcinoma, renal cell carcinoma, clear cell renal carcinoma, renal cell adenocarcinoma, papillary renal cell carcinoma, pancreatic cancer, exocrine carcinoma, pancreatic adenocarcinoma, pancreatic duct adenocarcinoma, advanced pancreatic duct adenocarcinoma, metastatic pancreatic duct adenocarcinoma, cervical cancer, cervical squamous cell carcinoma, skin cancer, melanoma, oral cancer, pharyngeal cancer, esophageal cancer, esophageal squamous cell carcinoma (E SCC), esophageal adenocarcinoma, liver cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, uterine cancer, endometrial cancer, uterine sarcoma, thyroid cancer, thyroid adenoma, pheochromocytoma, paraganglioma, bladder cancer, transitional cell 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, anaplastic astrocytoma, and glioblastoma multiforme.

[0473] In some implementations, the cancer is selected from squamous cell carcinoma or tumor (SCC). SCC can originate from stratified 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).

[0474] In some embodiments, the cancer is selected from: cancers containing cells expressing / overexpressing HER3, cancers containing cells expressing / overexpressing EGFR, cancers containing cells expressing / overexpressing both 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.

[0475] In some implementations, cancer is: cancer containing cells expressing / overexpressing EGFR family members, cancer containing cells expressing / overexpressing HER3, cancer containing cells expressing / overexpressing EGFR, cancer containing cells expressing / overexpressing both HER3 and EGFR, cancer containing cells expressing / overexpressing both HER3 and EGFR, squamous cell carcinoma, lung cancer, non-small cell lung cancer, squamous cell lung cancer, squamous non-small cell lung cancer, advanced squamous non-small cell lung cancer, metastatic squamous non-small cell lung cancer, pancreatic cancer, exocrine carcinoma, pancreatic ductal adenocarcinoma, advanced pancreatic ductal adenocarcinoma, metastatic pancreatic ductal adenocarcinoma, cancer containing cells with mutations leading to increased HER3 ligand expression, cancer containing cells with mutations leading to increased EGFR ligand expression, cancer containing cells with NRG gene fusions, cancer containing cells with NRG1 gene fusions, or cancer containing cells with NRG2 gene fusions.

[0476] Cancer treatment according to the methods of this disclosure can achieve one or more of the following therapeutic effects: reducing the number of cancer cells in a subject, shrinking the size of cancerous tumors / lesions in a subject, inhibiting (e.g., preventing or slowing) the growth of cancer cells in a subject, inhibiting (e.g., preventing or slowing) the growth of cancerous tumors / lesions in a subject, inhibiting (e.g., preventing or slowing) the development / progression of cancer (e.g., to an advanced stage or metastasis), alleviating cancer symptoms in a subject, prolonging the subject's survival (e.g., progression-free survival or overall survival), reducing indicators related to the number or activity of cancer cells in a subject, and / or reducing the subject's cancer burden.

[0477] Subjects may be evaluated according to the Response Evaluation Criteria for Solid Tumors (RECIST) criteria, such as RECIST 1.1 criteria, as described by Eisenhauer et al., *Eur J Cancer.* 2009 Jan; 45(2):228-47, the entire contents of which are incorporated herein by reference. In some implementation schemes, subjects may be evaluated according to the Revision Response Evaluation Criteria: Lugano Classification (as described by Cheson et al., *J Clin Oncol* (2014) 32:3059-3068, which are incorporated herein by reference) to determine their response to treatment.

[0478] In some implementations, treating subjects according to the methods of this disclosure can achieve one of the following objectives: overall response, complete response, partial response, or disease stabilization.

[0479] Overall response (OR) refers to either a complete response (CR) or a partial response (PR).

[0480] Complete response (CR) refers to the complete macroscopic disappearance of all target tumors and / or non-target tumors. CR may be accompanied by the normalization of tumor marker levels.

[0481] Partial remission (PR) is defined as a reduction of at least 30% in the total diameter of all target tumors compared to the total diameter calculated before treatment.

[0482] Disease stability means that there is neither partial remission nor disease progression compared to the tumor burden at the start of treatment.

[0483] Progressive disease (PD) is defined as an increase of at least 20% in the total diameter of target lesions compared to the minimum (lowest point) during treatment (including the baseline total if it is the minimum in the study). In addition to a relative increase of 20%, the total must also show an absolute increase of at least 5 mm. Clear progression of existing non-target lesions or the appearance of one or more new lesions also constitutes progressive disease.

[0484] In some implementations, treating subjects according to the methods of this disclosure can achieve one of the following (e.g., compared to not receiving such treatment, or compared to known relevant cancer treatments): prolonged overall survival, prolonged progression-free survival, improved disease control rate, or improved objective response rate.

[0485] Overall survival (OS) refers to the time from when a subject is randomly assigned to the study group until death.

[0486] Progression-free survival (PFS) refers to the time from when a subject is randomized to the study group until the first evidence of disease progression or death. Disease control rate (DCR) refers to the proportion of patients who achieve complete remission, partial remission, or stable disease through treatment intervention.

[0487] The objective response rate (ORR) refers to the proportion of patients who respond to the overall disease.

[0488] Prevention may refer to preventing cancer from occurring and / or preventing cancer from worsening, such as preventing cancer from progressing to an advanced stage (e.g., metastasis).

[0489] In some embodiments, administration of the combination / composition according to this disclosure may be associated with one or more of the following: inhibiting cancer development / progression, delaying / preventing cancer occurrence, reducing / delaying / preventing tumor growth, reducing / delaying / preventing tissue invasion, reducing / delaying / preventing metastasis, reducing the severity of one or more cancer symptoms, reducing the number of cancer cells, reducing cancer burden, reducing tumor size / volume, and / or increasing the survival of subjects with cancer (e.g., progression-free survival or overall survival).

[0490] According to various aspects of this disclosure, the methods for treating and / or preventing cancer described in this disclosure may include inhibiting tumor growth, reducing tumor size / volume, and / or increasing the survival rate of subjects suffering from the cancer.

[0491] According to various aspects of this disclosure, methods for or incorporating (e.g., in the context of treating / preventing cancer, such as the cancer described herein) one or more of the following are provided:

[0492] Kills cells expressing HER3 and / or EGFR;

[0493] Increase ADCC in cells expressing HER3 and / or EGFR;

[0494] Inhibit tumor growth and / or reduce tumor size / volume (e.g., cancers described herein, such as cancers expressing HER3 and / or EGFR);

[0495] Increase survival rates in subjects with cancer (such as the cancers described in this article, such as cancers expressing HER3 and / or EGFR);

[0496] Inhibits tumor growth and / or reduces tumor size / volume (e.g., cancers described herein, such as cancers expressing HER3 and / or EGFR) to a greater extent than the tumor growth inhibition or tumor size / volume reduction observed when the components in the combination / composition are used alone.

[0497] It improves the survival rate of subjects with cancer (such as the cancers described herein, such as cancers expressing HER3 and / or EGFR) to a greater extent than the survival increase observed when the components of the combination / composition are used alone;

[0498] The combination / composition synergistically inhibits tumor growth and / or synergistically reduces tumor size / volume (e.g., the cancers described herein, such as cancers expressing HER3 and / or EGFR) compared to tumor growth inhibition / tumor size / volume observed when the components of the combination / composition are used alone; and / or synergistically increases the survival rate of subjects with cancer (e.g., the cancers described herein, such as cancers expressing HER3 and / or EGFR) compared to the survival increase observed when the components of the combination / composition are used alone.

[0499] According to this disclosure, reagents for such methods are also provided, as well as the use of the reagents according to this disclosure in the preparation of compositions (e.g., pharmaceuticals) for such methods. It should be understood that in some embodiments, the method includes administering to a subject an antigen-binding molecule that binds to HER3 and an antigen-binding molecule that binds to EGFR.

[0500] Similarly, following a therapeutic or preventative intervention according to this disclosure (e.g., compared to the level / number / proportion before the intervention), one or more of the following may be observed in the subjects:

[0501] Kills cells expressing HER3 and / or EGFR;

[0502] Increase ADCC in cells expressing HER3 and / or EGFR;

[0503] Inhibit tumor growth and / or reduce tumor size / volume (e.g., cancers described herein, such as cancers expressing HER3 and / or EGFR);

[0504] Increase the survival rate of subjects with cancer (e.g., the cancers described in this article, such as cancers expressing HER3 and / or EGFR);

[0505] Inhibits tumor growth and / or reduces tumor size / volume (e.g., cancers described herein, such as cancers expressing HER3 and / or EGFR) to a greater extent than the tumor growth inhibition or tumor size / volume reduction observed when the components in the combination / composition are used alone.

[0506] It improves the survival rate of subjects with cancer (such as the cancers described herein, such as cancers expressing HER3 and / or EGFR) to a greater extent than the survival increase observed when the components of the combination / composition are used alone;

[0507] Compared to tumor growth inhibition / tumor size / volume observed when the components of the combination / composition are used alone, there is synergistic inhibition of tumor growth and / or synergistic reduction in tumor size / volume (e.g., cancers described herein, such as cancers expressing HER3 and / or EGFR); and / or

[0508] The combination / composition showed a synergistic increase in survival in subjects with cancer (e.g., the cancers described herein, such as cancers expressing HER3 and / or EGFR) compared to the increased survival observed when the components of the combination / composition were used alone.

[0509] In some implementations, the therapeutic / preventive interventions according to this disclosure may be described as being "related" to one or more of the effects described above. Those skilled in the art can readily assess these characteristics using techniques conventionally practiced in the art.

[0510] In some embodiments, the treatment / preventive intervention according to this disclosure provides improved therapeutic efficacy compared to the efficacy of using a component of the combination therapy as monotherapy. In some embodiments, the treatment / preventive intervention provides synergistic (i.e., super-additive) therapeutic and / or preventive effects compared to the level of effect observed when a component of the combination therapy is used alone.

[0511] In some embodiments, according to this disclosure, therapeutic / prophylactic interventions using both HER3-binding antigen-binding molecules and EGFR-binding antigen-binding molecules are more effective than those observed when either agent is used as monotherapy. In some embodiments, interventions using both HER3-binding antigen-binding molecules and EGFR-binding antigen-binding molecules provide synergistic (i.e., additive) therapeutic and / or prophylactic effects compared to those observed when either agent is used alone.

[0512] The reagents, drug combinations, and pharmaceutical compositions disclosed herein are preferably administered in amounts that are "therapeuticly effective" or "preventively effective," sufficient to demonstrate a therapeutic or preventative benefit to the subject. The actual dosage, rate of administration, and duration of administration will depend on the nature and severity of the disease / symptom and the specific item being administered. Prescribing treatment, such as determining the dosage, is the responsibility of general practitioners and other physicians, typically taking into account the disease / disorder to be treated, the individual subject's condition, the site of delivery, the method of administration, and other factors known to the practitioner. Examples of the aforementioned techniques and protocols can be found in (Remington, *The Science and Practice of Pharmacy* (edited by A. Adejare), 23rd edition (2020), Academic Press).

[0513] The articles disclosed herein can be administered, for example, parenteral, systemic, local, intracavitary, intravascular, intravenous, intra-arterial, intramuscular, intrathecal, intraocular, intraconjunctival, intratumoral, subcutaneous, intradermal, oral, or transdermal. Administration can be by injection, infusion, or ingestion.

[0514] In some aspects and embodiments, the articles of this disclosure can be applied to a target tissue / organ (e.g., a tissue / organ affected by a disease / symptom), i.e., a tissue / organ affected by the disease / symptom (e.g., a tissue / organ exhibiting symptoms of the disease / symptom). In some aspects and embodiments, the articles of this disclosure can be administered into the bloodstream by injection or infusion (e.g., via a cannula) (i.e., intravenous / arterial administration), or by subcutaneous injection or oral administration. In some aspects and embodiments, the articles of this disclosure can be applied to tumors.

[0515] When two or more drugs (e.g., drug combinations according to this disclosure) are administered in combination, these drugs may be administered simultaneously or sequentially.

[0516] Simultaneous administration refers to the administration of two or more drugs together, such as as a pharmaceutical composition containing two drugs (i.e., as a combination formulation), or as an immediate (e.g., within 1, 4, 6, 8, or 12 hours) administration of one drug, and optionally via the same route of administration, such as by application to the same artery, vein, or other blood vessel.

[0517] Continuous dosing refers to administering one drug first, followed by another drug administered alone after a specified time interval. It is not required that the drugs be administered via the same route, although this is true in some implementations. The time interval can be any interval.

[0518] In some embodiments, the therapeutic or preventative intervention according to this disclosure includes: (i) administering an antigen-binding molecule that binds to HER3 to a subject with cancer (e.g., the cancer 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 performed after (ii), or (ii) may be performed after (i)).

[0519] Multiple doses of the drug, drug combination, and drug composition may be provided. Multiple doses may be separated by predetermined time intervals, which may be selected from 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 one of 1, 2, 3, 4, 5, or 6 months. For example, the dose may be administered every 7, 14, 21, or 28 days (plus or minus 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). In other words, a treatment event can be performed every 7 days, every 14 days, every 21 days, or every 28 days. Treatment intervals of approximately 7 days (plus or minus 3, 2, or 1 day), approximately 14 days (plus or minus 3, 2, or 1 day), approximately 21 days (plus or minus 3, 2, or 1 day), or approximately 28 days (plus or minus 3, 2, or 1 day) can exist between doses / administrations.

[0520] In some implementations, the therapeutic or preventive intervention according to this disclosure may further include the administration of another formulation for the treatment / prevention of the associated disease / condition.

[0521] In some embodiments, the HER3-binding antigen-binding molecule (e.g., 10D1F) is administered once weekly (e.g., once every 7 days, with a possible fluctuation of 3 days, 2 days, or 1 day). In some embodiments, the dose of the HER3-binding antigen-binding molecule (e.g., 10D1F) is 150-6000 mg per administration, for example, 600-3000 mg, 900-3000 mg, 900-2400 mg, 1500-3000 mg, 1500-2400 mg, 1500-2100 mg, or about 1800 mg per administration. In some embodiments, the HER3-binding antigen-binding molecule (e.g., 10D1F) is administered intravenously. In some embodiments, the administration method of the HER3-binding antigen-binding molecule (e.g., 10D1F) is substantially as described in Embodiment 2 or Embodiment 4 of the present invention.

[0522] In some implementations, taxane-like drugs (e.g., docetaxel) are administered once every three weeks (e.g., once every 21 days, with adjustments of 3, 2, or 1 day). In some implementations, the dosage of taxane-like drugs (e.g., docetaxel) is 10-300 mg / m² per dose. 2 For example, each dose is 20-200 mg / m². 2 25-150mg / m 2 30-125mg / m 2 50-100mg / m2 60-90mg / m 2 or approximately 75 mg / m 2 One of them. In some embodiments, taxanes (e.g., docetaxel) are administered via intravenous injection. In some embodiments, the administration method of taxanes (e.g., docetaxel) is substantially as described in Examples 2 or 4 herein.

[0523] In some embodiments, taxane-like drugs (e.g., albumin-bound paclitaxel) are administered on days 1, 8, and 15 of a 28-day cycle (with the possibility of adding, subtracting, or adding 3, 2, or 1 day). In some embodiments, the dose of taxane-like drugs (e.g., albumin-bound paclitaxel) is 15-420 mg / m² per administration. 2 For example, each dose is 30-300 mg / m². 2 35-210mg / m 2 40-175mg / m 2 70-140mg / m 2 85-130mg / m 2 Or 125mg / m 2 One of them. In some embodiments, taxanes (e.g., albumin-bound paclitaxel) are administered via intravenous injection. In some embodiments, the administration method of taxanes (e.g., albumin-bound paclitaxel) is substantially as described in Example 2 herein.

[0524] In some embodiments, the nucleoside analogue (e.g., gemcitabine) is administered on days 1, 8, and 15 (with or without 3, 2, or 1 day), followed by administration every four weeks (e.g., every 28 days, with or without 3, 2, or 1 day). In some embodiments, the dose of the nucleoside analogue (e.g., gemcitabine) is 100-2000 mg / m² per administration. 2 For example, each dose is 200-1750 mg / m². 2 500-1500mg / m 2 750-1250mg / m 2 900-1100mg / m 2 Or approximately 1000 mg / m 2 One of them. In some embodiments, the nucleoside analog (e.g., gemcitabine) is administered by intravenous injection. In some embodiments, the administration of the nucleoside analog (e.g., gemcitabine) is substantially as described in Example 2 herein.

[0525] In some implementations, the EGFR-binding antigen-binding molecule (e.g., cetuximab) is administered once weekly (e.g., every 7 days, with adjustments for 3 days, 2 days, or 1 day). In some implementations, the dose of the EGFR-binding antigen-binding molecule (e.g., cetuximab) is 50-800 mg / m² per administration.2 For example, each dose is 100-700 mg / m². 2 200-600mg / m 2 300-500mg, or approximately 400mg / m² 2 One of them. In some embodiments, the dose of an EGFR-binding antigen-binding molecule (e.g., cetuximab) administered is 50-500 mg / m² per dose. 2 For example, 75-400mg / m 2 100-350mg / m 2 200-300mg, or approximately 250mg / m² 2 One of them. In some embodiments, the EGFR-binding antigen-binding molecule (e.g., cetuximab) is administered via intravenous injection. In some embodiments, the administration method of the EGFR-binding antigen-binding molecule (e.g., cetuximab) is substantially as described in Example 4 herein.

[0526] In accordance with various aspects and embodiments of this disclosure, when docetaxel is administered to a subject, the therapeutic / preventive intervention may also include administration of dexamethasone. In some embodiments, 8 mg of dexamethasone is administered twice daily via PO (per os: oral), either with or after a meal, the day before docetaxel administration, the day of docetaxel administration, and the day after docetaxel administration.

[0527] According to various aspects and embodiments of this disclosure, gemcitabine is administered to the subject, and therapeutic / prophylactic interventions may further include administration of dexamethasone and / or palnosetron. In some embodiments, 8 mg of dexamethasone is administered 60 min ± 15 min before gemcitabine administration with or after a meal via oral bolus, and 0.25 mg of palnosetron is administered intravenously 30 min ± 10 min before gemcitabine administration.

[0528] According to various aspects and embodiments of this disclosure, in the case of administration of albumin-bound paclitaxel to a subject, the treatment / preventive intervention may also include administration of dexamethasone and / or palonosetron. In some embodiments, 8 mg of dexamethasone is administered orally with a meal or meal 60 min ± 15 min before administration of albumin-bound paclitaxel, and 0.25 mg of palonosetron is administered intravenously 30 min ± 10 min before administration of albumin-bound paclitaxel.

[0529] When administering docetaxel to a subject according to various aspects and embodiments of this disclosure, the therapeutic / preventive intervention may also include administration of dexamethasone. In some embodiments, 8 mg of dexamethasone is administered twice daily via PO (i.e., per os: oral), either with or after a meal, the day before, on, and the day after docetaxel administration.

[0530] In various aspects and embodiments of this disclosure, administration of cetuximab to a subject may also include administration of dexamethasone and / or loratadine. In some embodiments, 4 mg of dexamethasone may be administered orally with or after a meal, or intravenously approximately 60 min ± 15 min before cetuximab administration; 10 mg of loratadine may be administered orally 60 min ± 15 min before cetuximab administration.

[0531] In some implementation schemes, the therapeutic or preventive intervention according to this disclosure may further include the administration of chemotherapy drugs. In some embodiments, the therapeutic or preventive intervention according to this disclosure includes: (i) administering a HER3-binding antigen-binding molecule to a subject with cancer (e.g., the cancer described herein), (ii) administering an EGFR-binding antigen-binding molecule to the subject, and (iii) administering chemotherapy drugs to the subject. In some embodiments, two or more of (i), (ii), and (iii) may be performed simultaneously (e.g., (i), (ii), and (iii) may be performed simultaneously, or (i) and (ii) may be performed simultaneously, while (iii) may be performed sequentially, either before or after (i) and (ii). In some embodiments, at least one of (i), (ii), and (iii) may be performed sequentially (e.g., (i), (ii), and (iii) may be performed sequentially). For example, (i) can be followed by (ii), and (ii) can be followed by (iii); (ii) can be followed by (i), and (i) can be followed by (iii); (iii) can be followed by (i), and (i) can be followed by (ii); or (iii) can be followed by (ii), and (ii) can be followed by (i). Preferably, the chemotherapy drug is a microtubule-targeting drug, such as taxane. More preferably, the chemotherapy drug is taxane, such as paclitaxel, docetaxel, or cabazitaxel. Most preferably, the chemotherapy drug is docetaxel.

[0532] Chemotherapy refers to the treatment of cancer using drugs (chemotherapeutic agents). Chemotherapeutic agents can be chemical entities, such as small molecule drugs, antibiotics, DNA intercalators, protein inhibitors (such as kinase inhibitors), or biological agents, such as antibodies, antibody fragments, aptamers, nucleic acids (such as DNA, RNA), peptides, polypeptides, or proteins. Chemotherapeutic agents can be formulated into pharmaceutical preparations or drugs. These preparations may contain one or more chemotherapeutic agents, as well as one or more pharmaceutically acceptable diluents, excipients, or carriers.

[0533] Chemotherapy agents can be administered via one or more routes of administration, such as parenteral, intravenous, oral, subcutaneous, intradermal, intraperitoneal, or intratumoral.

[0534] Chemotherapy can be administered according to a treatment regimen. A treatment regimen may be a pre-determined chemotherapy management schedule, plan, protocol, or schedule, developed by a physician or medical practitioner and tailored to the patient as needed. A treatment regimen may specify one or more of the following: the type of chemotherapy administered to the patient; the dosage of each drug; the time interval between administrations; the duration of each treatment; the number and nature of any treatment intervals (if any); etc. For combination therapy, a single treatment regimen may be provided, specifying how each drug is administered.

[0535] Chemotherapy drugs available include: abemaxib, abiraterone acetate, methotrexate, afliberceptin (albumin-bound paclitaxel nanoparticle formulation), ABVD, ABVE, ABVE-PC, AC, acarubrutinib, AC-T, adecimetidine (brentuximab), ADE, and trastuzumab-emergentinib. Emtansine, Doxorubicin (doxorubicin hydrochloride), Dafatinib maleate, Everolimus (Afinitor), Netupitant and Palonosetron hydrochloride, Adarax (imimiquimod), Aldestin, Alexina (alectinib), Aletumab, Arecitra (pemetrexed disodium), Alicopa (copanlistatin hydrochloride), Alklan for injection (melphalan hydrochloride), Alklan tablets (melphalan), Aloxic (palonosetron hydrochloride), Alenbrem (brigatinib), Chloramine Acetaminophen (chloroambucil), cloambucil, amifostine, δ-aminolevulinic acid, anastrozole, aprepitant, arimidex (pamidronate disodium), exemestane, nirapana, arsenic trioxide, azela (ofumumab), elveniazolinone aspartate, atezolizumab, bevacizumab (avastin), averumab, axicabtagene cell therapy Ciloleucel, axitinib, azacitidine, avelumab (Bavencio), BEACOPP regimen, besimu (camustine), belinostat, belinositol, bendamustine hydrochloride, BEP regimen, besponza (Ozogamicin), bevacizumab, bexarotine, Bexxar (tocetuzumab and iodine I131 tocetuzumab), bicalutamide, BiCNU (camustine), bleomycin, brinetutumab, Blincyto (brinetutumab), bortezomib, bosulif (bosutinib), brentuximab Dotinib, Brigatinib, BuMel, Busulfen, Busulfex, Cabazitaxel, Cabometyx (Cabozantinib S-malate), Cabozantinib S-malate, CAF, Calquence (Acalabutinib), Camppath (Alemmab), Camptosar (Hydrochlorothiazide Irinotecan), Capecitabine, CAPOX, Carac (Fluorouracil - Topical), Carboplatin-TAXOL, Carfilzomib, Carmubris (Carmustine), Carmustine, Carmustine Implantation, Casodex (Bicalutamide), CEMCeritinib, Cervarix (daunorubicin hydrochloride), Cervarix (recombinant bivalent HPV vaccine), Cetuximab, CEV, Cloambucil, Cloambucil-Prednisone, CHOP, Cisplatin, Clodapoxetine, Clafen (cyclophosphamide), Clofarapoxetine, Clolar (clofarapoxetine), CMF, Cobitinib, Cometriq (cabozotinib S-tartrate), Coparibixib hydrochloride, COPDAC, COPP, COPP-ABV, Cosmegen (dacrotimocin), Cotellic (cobitinib), Crizotinib, CVP, Cyclophosphamide, Cyfos (ifosfamide) Cyramza (ramucirumab), cytarabine, liposomal cytarabine, Cytosar-U (cytarabine), Cytoxan (cyclophosphamide), dabrafenib, dacarbazine, decitabine, dacrotinoxine, dalatumab, dazolid (dalatumab), dasatinib, daunorubicin hydrochloride, daunorubicin hydrochloride and cytarabine liposomes, decitabine, sodium decellulose, defiterio (sodium decellulose), degalelix, denolimus, denosumab, DepoCyt (cytarabine liposomes), dexamethasone, dirazodone hydrochloride, denutramab, docetaxel, doxorubicin liposomes (Doxil), doxorubicin hydrochloride, dox- SL (doxorubicin hydrochloride liposome), DTIC-Dome (dacarbazine), duvalumab, Efudex (fluorouracil - topical), Elitek (recombinant uricase), Ellence (epirarubicin hydrochloride), Elotuzumab, Eloxatin (oxaliplatin), octreotide tartrate, Emend (aprepitant), Empliciti (elotuzumab), enroximatem methanesulfonate, enzalutamide, epirubicin hydrochloride, EPOCH regimen, Erbitux (cetuximab), eribulin mesylate, Erivedge (vemodiger), erlotinib hydrochloride, Erwinaze (Staphylococcus aureus aspartate) Ethylosin, Etopophos, Etoposide, Etoposide, Evacet (rituximab liposome), Everolimus, Raloxifene Hydrochloride, Evoramyl (melphalan Hydrochloride), Exemestane, 5-FU (Fluorouracil Injection), 5-FU (Fluorouracil - Topical), Toremifene, Panobista, Fulvestrant, FEC regimen, Feloli (Letrozole), Filgrastim, Fludarabine (Fluorouracil Phosphate), Fludarabine Phosphate, Flubele (Fluorouracil - Topical), Fluorouracil Injection, Fluorouracil - Topical, Flutamide, Foles (Methotrexate)Folex PFS (Methotrexate), FOLFIRI, FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, Folotyn (Praclostrobin), FU-LV, Fulvestrant (Flavestrant), Gardasil (Recombinant Quadrivalent HPV Vaccine), Gardasil 9 (recombinant HPV 9-valent vaccine), Gazyva (Orbituzumab), Gefitinib, Gemcitabine Hydrochloride, Gemcitabine-Cisplatin, Gemcitabine-Oxaliplatin, Gautozumab / Ozozocin, Gemzar (Gemcitabine Hydrochloride), Gilotrif (Afatinib Maleate), Gleevec (Imatinib Mesylate), Gliadel (Carmustine Implant), Gliadel Tablets (Carmustine Implant), Glucosyl Peptidase, Goserelin Acetate, Halaven (Eribulin Hydrochloride), Hemangeol (Propranolol Hydrochloride), Herceptin (Trastuzumab), HPV Bivalent Vaccine (Recombinant), HPV 9-valent Vaccine (Recombinant), HPV Quadrivalent Vaccine (Recombinant), Hycamtin (Topotecan Hydrochloride), Hydrea (Hydrea), Hydroxyurea, Hyper-CVAD, Ibrance (Pabocenib), Ibritumomab Tiuxetan, Ibrutinib, ICE, Iclusig (ponatinib hydrochloride), Idamycin (idarubicin hydrochloride), Idelalisib, Idhifa (enaxitinib mesylate), Ifex (ifosphosphatamide), Ifosfamidum (ifosphosphatamide), IL-2 (altroximab), metinib (imatinib mesylate), Ibrutinib (Imbruvica), Duvalimumab (Imfinzi), Imaquinone, Talimogen (Imlygic), Axitinib (Inlyta), Inotuzumab Ozogamicin (Inotuzumab), α-2b interferon recombinant, Interleukin-2 (altroximab), Intron A (recombinant α-2b interferon), iodine-131 tocilizumab and tocilizumab, ipilimumab, gefitinib (Iressa), irinotecan hydrochloride, irinotecan liposomes, romidepsin (Istodax), ixabepilone, ixazomib citrate, Ixempra, ruxotinib phosphate (Jakafi), JEB, cabazitaxel (Jevtana), adoro-trastuzumab-metansine (Kadcyla), raloxifene (Keoxifene), palimide (Kepivance), pembrolizumab (Keytruda)Kisqali (liboximab), Kymriah (Tisagenlecleucel, a genetically engineered T-cell therapy drug), Kyprolis (carfilzomib), lenurotinib acetate, lapatinib dimethylsulfonate, Lartruvo (olalatumab), lenalidomide, lenvatinib mesylate, Lenvima (lenvatinib mesylate), letrozole, calcium folic acid, Leukeran (clombucil), leuprolide acetate, Leustatin (clodarabine), Levulan (aminolevulinic acid), Linfolizin (clombucil), LipoDox (doxorubicin hydrochloride liposome), lomustine, Lonsurf (trifluorouridine and tebiclil hydrochloride), Lupron (leuprolide acetate), Lupron Depot (leuprolide acetate), Lupron Depot-Ped (Leuprorelin Acetate), Lynparza (Olaparib), Marqibo (Vincristine Sulfate Liposome), Maturaranin (Procarbazine Hydrochloride), Michloramine Hydrochloride, Mechodone Acetate, Mekinist (Trametinib), Mefran Hydrochloride, Mercaptopurine, Mesna, Mesnex (Mesna), Methozosone (Temozolomide), Methotrexate LPF (Methotrexate), Methylnaloxone Bromide, Methatid (Methotrexate) Methotrexate, Methatine-AQ, Midostiline, Mitomycin C, Daunoromycin Hydrochloride, Mitozytrex, MOPP, Mozobil, Mustargen, Mutamycin C, Myleran, Mylosar, Gelatinumab, Ozogamycin, Paclitaxel Nanoparticles (Formulations), navitabine (vinorelbine tartrate), nesetumab, nerabine, niosaccharide (cyclophosphamide), neratinib maleate, nerlinx (neratinib maleate), netupitan and palonosetron hydrochloride, nilatana (polyethylene glycol phenostilbene), nipotan (phenostilbene), nidavan (sorafenib tosylate), nilandrol (nilutamide), nilotinib, nilutamide, niralo (esazomib citrate), niraparib tosylate monohydrate, nivolumab, novolactam, etc. Vade (tamoxifen citrate), Nplate (romistastatin), obbitutuzumab, odorimonazole (sonide gibberel), OEPA, oflamumab, OFF, olaparib, olaparib, omaxitine methyl ester, Oncaspar (polyasparagine aspartate), ondansetron hydrochloride, Onivyde (irinotecan hydrochloride liposome), Ontak (bitercesimosumab), Opdivo (nivolumab), OPPA, osimertinib, oxaliplatin, paclitaxelPaclitaxel albumin-stabilized nanoparticle formulations, PAD, pembrolizumab, palifermin, palonosetron hydrochloride, palonosetron hydrochloride and netupine, disodium pamidronate, panitumumab, panobinostat, paraplatin, paraplatin, pazopanib hydrochloride, PCV, PEB, peggaszase, peffiglastine, interferon alpha-2b, PEG-Intron, pembrolizumab, pemetrexed disodium, perjeta, trastuzumab, platinum preparations (cisplatin), Platinol-AQ, prasalidomide, pomalyst, pomalyst, ponatinib hydrochloride, Portrazza, prasalidomide, prednisone, purcarbazine hydrochloride, Proleukin. (September), Prolia (denomab), Promacta (olatipag), Propranolol hydrochloride, Provenge (ciprolumab), Purinethol (mercaptopurine), Purixan (mercaptopurine), [No entry], Radium-223 dichloride, Raloxifene hydrochloride, Ramomab, Lasikecase, R-CHOP regimen, R-CVP regimen, Recombinant human papillomavirus (HPV) bivalent vaccine, Recombinant human papillomavirus (HPV) nine-valent vaccine, Recombinant human papillomavirus (HPV) quadrivalent vaccine, Recombinant interferon alpha-2b, Regorafenib, Relistor (bromomethylnaltrexone), R-EPOCH regimen, Revlimid (lenalidomide), Rheumatrex (methotrexate), Ribociclib, R-ICE regimen, Rituxan (rituximab), Rituxan Hycela (rituximab and human hyaluronidase), rituximab, rituximab and human hyaluronidase, rorapitan hydrochloride, romidixin, romistachytin, erythromycin (daunorubicin hydrochloride), Rubraca (rucaparib tartrate), rucaparib tartrate, loxotinib phosphate, Rydapt (midosstatin), intrapleural sclerotherapy aerosol (talc), cetuximab, Sipuleucel-T, Somatuline Depot (lanreotide acetate), soledagricans, sorafenib tosylate, Sprycel (dasatinib), STANFORD V. Sterile talc, Steritalc, Stivarga (regorafenib), Sunitinib maleate, Sutent (sunitinib maleate), Sylatron (pegylated interferon alpha-2b), Sylvant (cetuximab), Synribo (omaxetine mestron hydrochloride), Tabloid (thiopurine), TAC, Tafinlar (dabrafenib), Tagrisso (osimertinib), talc.Talimogene Laherparepvec, Tamoxifen Citrate, Tarabine PFS (Cytarabine), Tarceva (Erlotinib Hydrochloride), Targretin (Bexarotin), Tasigna (Nilotinib), Taxol (Paclitaxel), Taxotere (Docetaxel), Tecentriq (Atezolizumab), Temodar (Temozolomide), Temozolomide, Temozolomide, Texirolimus, Thalidomide, Thalomid (Thalidomide), Thiopurine, Thiocyclophosphamide, Tisagenlecleucel, Tolak (Fluorouracil - Topical), Topotecan Hydrochloride, Toremifene, Torisel (Texirolimus), Tositumomab and Iodine-131 Tositumomab, Totect (Dizalone Hydrochloride), TPF, Trabectedin, Trametinib, Trastuzumab, Treanda ( Bendamustine hydrochloride), Trifluridine and Tiperacil chloride, Trisenox (arsenic trioxide), Tykerb (lapatinib dihydrochloride), Unituxin (denomab), uridine triacetate, VAC, Valenbucin, Valstar, Vandetinib, VAMP, Varubi (rorapitan hydrochloride), Vectibix (panitumumab), VeIP, Velban (vincrine sulfate), Velcade (bortezomib), Velsar (vincrine sulfate), Vemurafenib, Venclexta (Venetoclax), Venetoclax, Verzenio (Abemaciclib), Viadur (Leuprolide) Acetate (leuprorelin acetate), Vidaza (Azacitidine), Vincristine sulfate, Vincasar PFS (vincristine sulfate), Vincristine sulfate, Vincristine sulfate liposomes, Vinorelbine tartrate, VIP, Vismodegib, Visogard (uridine triacetate), Voraxaze (glutaminase), Vorinosta, Votrient (Pazopanib Hydrochloride), Vyxeos (Daunorubicin Hydrochloride and Cytarabine Liposomes), Wellcovorin (calcium lactate), Xalkori (Crizotinib), Xeloda (Capecitabine), XELIRIXELOX, Xgeva (Denosumab), Xofigo (Radium-223 chloride), Xtandi (Enzalutamide), Yervoy (Ipilimumab), Yescarta (Abciximab-modified cells), Yondelis (Trabesimilar), Zaltrap (Aflibercept), Zarxio (Figrex), Zejula (Nirapaliptosu hydrochloride monohydrate), Zelboraf (Vemurafenib), Zevalin (Ibrutinumab / Tescital), Zinecard (Deserafenone hydrochloride), Ziv-Aflibercept, Zofran (Ondansetron hydrochloride), Zoladex (Goserelin acetate), Zoledronic acid, Zolinza (Vorinostat), Zometa (Zoledronate), Zydelig (Idralisinib), Zykadia (Ceritinib), and Zytiga (Abiraterone acetate).

[0536] Specific therapeutic / preventive interventions

[0537] This disclosure provides a method for treating or preventing cancer in a subject containing NRG1 gene fusion cells, the method comprising administering to the subject an antigen-binding molecule capable of binding HER3 (e.g., 10D1F) and a nucleoside analog (e.g., gemcitabine). For example, this disclosure provides a method for treating or preventing cancer in a subject containing NRG1 gene fusion cells, the method comprising administering to the subject 10D1F and gemcitabine. This disclosure also provides a compositional agent for treating or preventing the relevant cancer used in the methods described in the preceding two sentences, and the use of the compositional agent used in the methods described in the preceding two sentences in the preparation of a medicament for treating or preventing the relevant cancer.

[0538] In some implementation schemes, the therapeutic / preventive interventions specified above include:

[0539] Administer 10D1F (e.g., intravenous injection) once weekly (e.g., a dose of 1500-2500 mg, such as approximately 1800 mg per dose); and

[0540] Gemcitabine was administered on days 1, 8, and 15 (e.g., intravenous injection), followed by administration every four weeks (e.g., at a dose of 750-1500 mg / m²). 2 For example, each dose is approximately 1000 mg / m². 2 ).

[0541] This disclosure provides a method for treating or preventing cancer containing NRG1 gene fusion cells in a subject, comprising administering to the subject an antigen-binding molecule that binds to HER3 (e.g., 10D1F), a nucleoside analog (e.g., gemcitabine), and a taxane-like substance (e.g., albumin-bound paclitaxel). For example, this disclosure provides a method for treating or preventing cancer containing NRG1 gene fusion cells in a subject, comprising administering to the subject 10D1F, gemcitabine, and albumin-bound paclitaxel. This disclosure also provides a compositional agent used in the methods described in the foregoing two sentences for treating or preventing the relevant cancer, and the use of the compositional agent used in the methods described in the foregoing two sentences in the preparation of a medicament for treating or preventing the relevant cancer.

[0542] In some embodiments, the treatment / preventive interventions performed according to the preceding paragraph are essentially carried out as described in Group A of Example 2. In some embodiments, the treatment / preventive interventions performed according to the preceding paragraph include:

[0543] Administer 10D1F (e.g., intravenous injection) once a week (e.g., a dose of 1500-2500 mg, approximately 1800 mg per dose);

[0544] Gemcitabine was administered on days 1, 8, and 15 (e.g., intravenous injection), followed by administration every four weeks (e.g., at a dose of 750-1500 mg / m²). 2 Each dose is approximately 1000 mg / m². 2 );

[0545] Administer albumin-bound paclitaxel (e.g., intravenous injection) on days 1, 8, and 15, then every four weeks (e.g., at a dose of 100-150 mg / m²). 2 Each dose is approximately 125 mg / m². 2 ).

[0546] This disclosure provides a method for treating or preventing cancer in a subject containing NRG1 gene fusion cells, the method comprising administering to the subject an antigen-binding molecule that binds to HER3 (e.g., 10D1F) and a taxane-like substance (e.g., docetaxel). For example, this disclosure provides a method for treating or preventing cancer in a subject containing NRG1 gene fusion cells, the method comprising administering to the subject 10D1F and docetaxel. This disclosure also provides a compositional agent for treating or preventing the relevant cancer used in the methods described in the preceding two sentences, and the use of the compositional agent used in the methods described in the preceding two sentences in the preparation of a medicament for treating or preventing the relevant cancer.

[0547] In some implementations, the therapeutic / preventive intervention described in the preceding paragraph is performed substantially as described in Group B of Example 2. In some implementations, the therapeutic / preventive intervention described in the preceding paragraph includes:

[0548] Administer 10D1F (e.g., intravenous injection) once weekly (e.g., a dose of 1500-2500 mg, such as approximately 1800 mg per dose); and

[0549] Administer docetaxel (e.g., intravenous injection) every three weeks (e.g., at a dose of 25-150 mg / m²). 2 For example, each dose is approximately 75 mg / m². 2 ).

[0550] This disclosure provides a method for treating or preventing pancreatic cancer (e.g., pancreatic ductal adenocarcinoma containing NRG1 gene fusion cells) in a subject, the method comprising administering to the subject an antigen-binding molecule (e.g., 10D1F) that binds to HER3 and a nucleoside analog (e.g., gemcitabine). For example, this disclosure provides a method for treating or preventing pancreatic ductal adenocarcinoma containing NRG1 gene fusion cells in a subject, the method comprising administering to the subject 10D1F and gemcitabine. This disclosure also provides a compositional agent for treating or preventing the relevant cancer used in the methods described in the preceding two sentences, and the use of the compositional agent used in the methods described in the preceding two sentences in the preparation of a medicament for treating or preventing the relevant cancer.

[0551] In some implementation schemes, the therapeutic / preventive interventions described above include:

[0552] Administer 10D1F (e.g., intravenous injection) once weekly (e.g., a dose of 1500-2500 mg, such as approximately 1800 mg per dose); and

[0553] Gemcitabine was administered on days 1, 8, and 15 (e.g., intravenous injection), followed by administration every four weeks (e.g., at a dose of 750-1500 mg / m²). 2 For example, each dose is approximately 1000 mg / m². 2 ).

[0554] This disclosure provides a method for treating or preventing pancreatic cancer in a subject, including pancreatic ductal adenocarcinoma with NRG1 gene fusion cells (e.g., pancreatic ductal adenocarcinoma with NRG1 gene fusion cells), comprising administering to the subject an antigen-binding molecule that binds to HER3 (e.g., 10D1F), a nucleoside analog (e.g., gemcitabine), and a taxane-like substance (e.g., albumin-bound paclitaxel). For example, this disclosure provides a method for treating or preventing pancreatic ductal adenocarcinoma cells with NRG1 gene fusion in a subject, comprising administering to the subject 10D1F, gemcitabine, and albumin-bound paclitaxel. This disclosure also provides formulations for treating or preventing the relevant cancer used in the methods described in the preceding two sentences, and the use of the formulations used in the methods described in the preceding two sentences in the preparation of medicaments for treating or preventing the relevant cancer.

[0555] In some embodiments, the therapeutic / preventive interventions performed according to the preceding paragraph are essentially carried out according to Group A of Example 2. In some embodiments, the therapeutic / preventive interventions performed according to the preceding paragraph include:

[0556] Administer 10D1F (e.g., intravenous injection) once a week (e.g., a dose of 1500-2500 mg, such as approximately 1800 mg per dose);

[0557] Gemcitabine was administered on days 1, 8, and 15 (e.g., intravenous injection), followed by administration every four weeks (e.g., at a dose of 750-1500 mg / m²). 2 For example, each dose is approximately 1000 mg / m². 2 );and

[0558] Administer albumin-bound paclitaxel (e.g., intravenous injection) on days 1, 8, and 15, then every four weeks (e.g., at a dose of 100-150 mg / m²). 2 For example, each dose is approximately 125 mg / m². 2 ).

[0559] This disclosure provides a method for treating or preventing squamous cell lung cancer (e.g., squamous non-small cell lung cancer with NRG1 gene fusion cells) in a subject, the method comprising administering to the subject an antigen-binding molecule (e.g., 10D1F) that binds to HER3 and a taxane-like substance (e.g., docetaxel). For example, this disclosure provides a method for treating or preventing squamous non-small cell lung cancer with NRG1 gene fusion cells in a subject, the method comprising administering to the subject 10D1F and docetaxel. This disclosure also provides a compositional agent for treating or preventing the relevant cancer used in the methods described in the preceding two sentences, and the use of the compositional agent used in the methods described in the preceding two sentences in the preparation of a medicament for treating or preventing the relevant cancer.

[0560] In some implementations, the therapeutic / preventive intervention described in the preceding paragraph is performed substantially as described in Group B of Example 2. In some implementations, the therapeutic / preventive intervention described in the preceding paragraph includes:

[0561] Administer 10D1F (e.g., intravenous injection) once weekly (e.g., a dose of 1500-2500 mg, such as approximately 1800 mg per dose); and

[0562] Administer docetaxel (e.g., intravenous injection) every three weeks (e.g., at a dose of 25-150 mg / m²). 2 For example, each dose is approximately 75 mg / m². 2 ).

[0563] This disclosure provides a method for treating or preventing squamous cell lung cancer in a subject, comprising administering to the subject an antigen-binding molecule (e.g., 10D1F) that binds to HER3 and a taxane-like substance (e.g., docetaxel). For example, this disclosure provides a method for treating or preventing squamous non-small cell lung cancer, comprising administering 10D1F and docetaxel to a subject. This disclosure also provides a compositional agent for treating or preventing the relevant cancer used in the methods described in the preceding two sentences, and the use of the compositional agent used in the methods described in the preceding two sentences in the preparation of a medicament for treating or preventing the relevant cancer.

[0564] In some embodiments, the therapeutic / preventive intervention described above is performed substantially as described in Group A of Example 4. In some embodiments, the therapeutic / preventive intervention described above includes:

[0565] Administer 10D1F (e.g., intravenous injection) once weekly (e.g., a dose of 1500-2500 mg, such as approximately 1800 mg per dose); and

[0566] Administer docetaxel (e.g., intravenous injection) every three weeks (e.g., at a dose of 25-150 mg / m²). 2 For example, each dose is approximately 75 mg / m². 2 ).

[0567] This disclosure provides a method for treating or preventing squamous cell lung cancer in a subject, comprising administering to the subject an antigen-binding molecule that binds to HER3 (e.g., 10D1F), a taxane-like substance (e.g., docetaxel), and an antigen-binding molecule that binds to EGFR (e.g., cetuximab). For example, this disclosure provides a method for treating or preventing squamous non-small cell lung cancer, comprising administering to a subject 10D1F, docetaxel, and cetuximab. This disclosure also provides formulations for treating or preventing the relevant cancers used in the methods described in the preceding two sentences, and the use of the formulations used in the methods described in the preceding two sentences in the preparation of a medicament for treating or preventing the relevant cancers.

[0568] In some embodiments, the therapeutic / preventive intervention described in the preceding paragraph is performed substantially as described in Group B of Example 4. In some embodiments, the therapeutic / preventive intervention described in the preceding paragraph includes:

[0569] Administer 10D1F (e.g., intravenous injection) once a week (e.g., a dose of 1500-2500 mg, approximately 1800 mg each time);

[0570] Administer docetaxel (e.g., intravenous injection) every three weeks (e.g., at a dose of 25-150 mg / m²). 2 Approximately 75mg / m² per dose 2 );and

[0571] Administer cetuximab (e.g., intravenous injection), for example, an initial dose of 200-600 mg / m². 2 (e.g., approximately 400 mg / m²) 2 The subsequent weekly dosing dose was 125-37.5 mg / m². 2 (approximately 250mg / m² each time) 2 ).

[0572] Subjects

[0573] Subjects may be any animal or human, as described herein. Subjects are preferably 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, such as the cancer described herein), may be suspected of having such a disease / condition, or may be at risk of developing / contracting such a disease / condition.

[0574] In some embodiments, the subjects treated according to the therapeutic or preventative methods of this disclosure are subjects who have or are at risk of developing cancer, such as the cancer described herein. In various embodiments of this disclosure, subjects may be selected for treatment based on methods characterizing specific biomarkers of such disease / condition.

[0575] In some implementations, subjects may be selected for the treatment described herein based on the detection of the cancer, for example, cancer expressing / overexpressing HER3 and / or EGFR, in samples obtained from the subject (e.g., tumor biopsy).

[0576] In some embodiments, according to this disclosure, the subject to be treated has previously received treatment with a PD-L1 / PD-1 signaling axis inhibitor. In some embodiments, the subject has previously received treatment with a PD-L1 / PD-1 mediated signaling antagonist. In some embodiments, the subject has previously received treatment with an anti-PD-1 antibody antagonist that mediates PD-L1 / PD-1 signaling. In some embodiments, the subject has previously received treatment with an anti-PD-L1 antibody antagonist that mediates PD-L1 / PD-1 signaling.

[0577] In some implementations, subjects treated according to this disclosure have not previously received more than two lines of systemic anticancer therapy for advanced disease.

[0578] In some embodiments, the subject has not previously received prior treatment with a HER3-targeted drug. In some embodiments, the subject treated according to this disclosure has not previously received prior treatment with an anti-HER3 antibody. In some embodiments, the subject has not previously received prior treatment with HMBD-001 (i.e., 10D1F). In some embodiments, the subject has not previously received prior treatment with pertuzumab.

[0579] In some embodiments, the subject being treated according to this disclosure has not previously received prior treatment with a tyrosine kinase inhibitor that substantially inhibits HER3 tyrosine kinase activity. In some embodiments, the subject has not previously received prior treatment with a tyrosine kinase inhibitor. In some embodiments, the subject has not previously received prior treatment with a pan-HER tyrosine kinase inhibitor.

[0580] In some embodiments, the subject treated according to the present disclosure has not previously received prior treatment with a drug targeting EGFR activating mutations. In some embodiments, the subject has not previously received prior treatment with a drug targeting ALK fusion mutations. In some embodiments, the subject has not previously received prior treatment with a drug targeting ROS rearrangement mutations. In some embodiments, the subject has not previously received prior treatment with a drug targeting RET fusion mutations or other RET mutations. In some embodiments, the subject has not previously received prior treatment with a drug targeting BRAF mutations that confer resistance to BRAF inhibitors (e.g., V600E or V600K). In some embodiments, the subject has not previously received prior treatment with a drug targeting the BRAF mutation V600E. In some embodiments, the subject has not previously received prior treatment with a drug targeting MET exon 14 skipping mutations. In some embodiments, the subject has not previously received prior treatment with a drug targeting MET exon 14 skipping mutations. In some implementations, the subject has not received prior treatment with a drug targeting a KRAS activating mutation (e.g., G12A, G12D, G12R, G12C, G12S, or G12V). In some implementations, the subject has not received prior treatment with a drug targeting the KRAS mutation G12C.

[0581] In some embodiments, the subject to be treated according to this disclosure has not previously received treatment with a nucleoside analogue. In some embodiments, the subject has not previously received treatment with gemcitabine or a salt thereof (e.g., gemcitabine hydrochloride).

[0582] In some embodiments, the subjects treated according to this disclosure have not previously received treatment with taxanes. In some embodiments, the subjects have not previously received treatment with albumin-bound paclitaxel. In some embodiments, the subjects have not previously received docetaxel.

[0583] In some embodiments, subjects treated according to this disclosure have a disease measurable according to RECIST 1.1 criteria, as described by Eisenhauer et al., Eur J Cancer. 2009 Jan;45(2):228-47.

[0584] In some implementations, subjects to be treated according to this disclosure are characterized by an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (i.e., fully active and able to perform all pre-disease activities without restriction) to 1 (i.e., limited in physically demanding activities but able to walk and perform light or sedentary work, such as light housework or office work). The ECOG performance status scale is described in Oken et al., Am J Clin Oncol. (1982) 5(6):649-655, the entire contents of which are incorporated herein by reference.

[0585] In some implementations, according to this disclosure, the subject to be treated:

[0586] (A)

[0587] (i) Having advanced or metastatic cancer containing an NRG1 gene fusion (e.g., determined by molecular testing, and the fusion transcript is correctly oriented and contains an EGF-like domain that can bind to HER3);

[0588] (ii) Has not received prior treatment with HMBD-001 (i.e., 10D1F), pertuzumab, an investigational drug specifically targeting HER3, or a pan-HER tyrosine kinase inhibitor; and / or

[0589] (iii) Having an ECOG fitness level of 0-1.

[0590] (B)

[0591] (i) Having advanced or metastatic pancreatic ductal adenocarcinoma containing an NRG1 gene fusion (e.g., determined by molecular testing, and the fusion transcript is correctly oriented and contains an EGF-like domain that can bind HER3).

[0592] (ii) Has not received prior treatment with HMBD-001 (i.e. 10D1F), pertuzumab, investigational drugs that specifically target HER3, or pan-HER tyrosine kinase inhibitors;

[0593] (iii) No prior treatment with gemcitabine (whether or not in combination with albumin-bound paclitaxel) for advanced disease;

[0594] (iv) The patient has received no more than two prior lines of systemic anticancer therapy for advanced disease; and / or

[0595] (v) ECOG fitness level is 0-1.

[0596] (C)

[0597] (i) Having advanced or metastatic non-small cell lung cancer containing an NRG1 gene fusion (e.g., determined by molecular testing, and the fusion transcript is correctly oriented and contains an EGF-like domain that can bind to HER3);

[0598] (ii) Has not received prior treatment with HMBD-001 (i.e. 10D1F), pertuzumab, investigational drugs that specifically target HER3, or pan-HER tyrosine kinase inhibitors;

[0599] (iii) Has not received prior treatment with docetaxel for advanced disease;

[0600] (iv) The patient has received no more than two prior lines of systemic anticancer therapy for advanced disease; and / or

[0601] (v) ECOG fitness level is 0-1.

[0602] In some implementations, the subject, based on one of (A) to (C) above, further:

[0603] (i) Having cancer that is resistant or refractory to standard systemic therapy, or in the physician’s opinion there is no standard systemic therapy or reasonable treatment that would provide clinical benefit, or the patient has shown intolerance to the treatment, or the patient has refused the treatment.

[0604] (ii) Having a RECIST v1.1 measurable disease;

[0605] (iii) Sufficient tumor material (i.e., one archived FFPE tumor slide or at least 15 consecutive unstained tumor slides) can be transported to the central laboratory upon enrollment in OR, or fresh tumor samples can be provided;

[0606] (iv) Age ≥ 18 years;

[0607] (v) There are standard contraceptive requirements;

[0608] (vi) Has sufficient basic organ functions, as shown below:

[0609] Serum creatinine ≤ 2 times the upper limit of institutional normal (ULN)

[0610] Serum albumin ≥2.5g / dl

[0611] Bilirubin ≤ 2.0 times the upper limit of institutional normal (ULN)

[0612] AST and ALT ≤ 2.5 times the upper limit of institutional normal (ULN). If the subject has liver metastases, ALT and AST < 5 times the upper limit of institutional normal (ULN) may be allowed.

[0613] (vii) For participants not taking warfarin or other oral anticoagulants, the international normalized ratio (INR) ≤ 1.5, or the prothrombin time (PT) ≤ 1.5 times the upper limit (ULN); and the partial prothrombin kinase time or activated partial prothrombin kinase time (PTT or aPTT) ≤ 1.5 times the ULN;

[0614] (viii) If the subject is taking warfarin at a stable dose and resulting in a stable international normalized ratio (INR) of less than 3.5;

[0615] (ix) If the subject is receiving other oral anticoagulant therapy, PT or aPTT is within the expected therapeutic range of the anticoagulant;

[0616] (x) Has adequate baseline hematological function, as shown below:

[0617] Absolute neutrophil count (ANC) ≥ 1.5 x 10^9 / L.

[0618] Hemoglobin ≥8g / dL and no red blood cell (RBC) transfusion in the past 14 days.

[0619] Platelet count ≥100x10^9 / L, and no platelet transfusion in the past 14 days;

[0620] (xi) Willing to comply with the program requirements, including follow-up survival assessment;

[0621] (x) No persistent, clinically significant toxicity (≥ Grade 2) during prior anticancer treatment (Grade 2 chemotherapy-related neuropathy and alopecia are permissible), nor any prior toxicity leading to laboratory abnormalities that have not recovered to ≤ Grade 1, unless inclusion criteria allow for a higher grade abnormality. If pharmacological treatment is required to manage laboratory abnormalities, the dosage and laboratory values ​​should remain stable;

[0622] (xi) Subjects are individuals with pancreatic ductal adenocarcinoma who have not previously received more than two regimens for advanced / metastatic disease, excluding neoadjuvant therapy / adjuvants, unless PDAC recurs within 6 months of such treatment;

[0623] (xii) According to this disclosure, the patient has not received chemotherapy, external beam radiation therapy or other prior systemic anticancer treatments within 14 days prior to the start of treatment (42 days if nitrosourea or mitomycin-C was previously used);

[0624] (xiii) In accordance with this disclosure, the patient has not received prior treatment with cytotoxic chemotherapy, monoclonal antibody therapy, small molecule tyrosine kinase inhibitor therapy and / or investigational systemic anticancer drugs within 28 days or 5 half-lives (whichever is shorter) prior to the start of treatment;

[0625] (xiv) No wide-area radiation therapy was received within 28 days prior to HMBD-001 (i.e., 10D1F); excluding palliative radiation therapy for bone metastases or similar local radiotherapy.

[0626] (xv) No other active malignant tumors that could interfere with the assessment of study endpoints (subjects with the following accompanying tumor diagnoses are not excluded: non-melanoma skin cancer, carcinoma in situ (including transitional cell carcinoma, cervical intraepithelial neoplasia and melanoma in situ), organ-limited prostate cancer without evidence of progressive disease);

[0627] (xvi) No clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association grade 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).

[0628] (xvii) No out-of-control, clinically significant medical problems, such as lung diseases (e.g., chronic obstructive pulmonary disease, pulmonary hypertension), or out-of-control complications, including but not limited to out-of-control infections requiring systemic treatment, disseminated intravascular coagulation, or mental illness / social conditions.

[0629] (xix) No known active or suspected brain or meningeal metastases (not excluded for subjects with treated and stable brain metastases, provided that imaging has not shown CNS disease progression at least 4 weeks after receiving radiotherapy or other local ablation therapy targeting the CNS).

[0630] (xx) According to this disclosure, there is no medical condition requiring systemic treatment within 14 days prior to the start of treatment, including glucocorticoids (>10 mg daily prednisone equivalent) or other immunosuppressive drugs (inhaled or topical steroids are permitted in the absence of active autoimmune disease);

[0631] (xxi) The QTc interval is no more than 450ms (male) or 470ms (female);

[0632] (xxii) Not pregnant and not breastfeeding;

[0633] (xxiii) Human immunodeficiency virus (HIV) status is negative;

[0634] (xxiv) Inactive or chronic hepatitis B or C; and / or

[0635] (xxv) No medical conditions were placed on subjects at an unacceptably high risk of toxicity.

[0636] In some embodiments, subjects according to this disclosure meet the inclusion and exclusion criteria for group A in the study of Example 2 herein. In some embodiments, subjects according to this disclosure meet the inclusion and exclusion criteria for group B in the study of Example 2 herein. In some embodiments, subjects according to this disclosure meet the inclusion and exclusion criteria for group C in the study of Example 2 herein.

[0637] In some implementations, according to this disclosure, the subject to be treated:

[0638] (D)

[0639] (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;

[0640] (ii) Patients with advanced squamous non-small cell lung cancer whose KRAS, PIK3CA, BRAF, PTEN and MET genotypes are all homozygous wild-type;

[0641] (iii) Having squamous non-small cell lung cancer and experiencing relapse or refractory disease after platinum-based (such as cisplatin, carboplatin, oxaliplatin, nedaplatin or lobaplatin) treatment for non-small cell lung cancer (i.e. the disease has grown or progressed during treatment);

[0642] (iv) Those who have previously received anti-PD-1 or anti-PD-L1 antibody therapy to block PD-L1 / PD-1 mediated signal transduction;

[0643] (v) Has received no more than two prior lines of systemic anticancer therapy for advanced disease;

[0644] (vi) Has not received prior treatment with anti-HER3 antibodies or prior treatment with tyrosine kinase inhibitors that significantly inhibit HER3 tyrosine kinase activity;

[0645] (vii) Have not received the following treatments: 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.

[0646] (viii) Has RECIST v1.1 to measure disease; and / or

[0647] (ix)ECOG fitness level is 0-1.

[0648] In some implementation schemes, the subject, according to one of the above (D), further:

[0649] (i) Having cancer that is resistant or refractory to standard systemic therapy, or in the physician’s opinion there is no standard systemic therapy or reasonable treatment that would provide clinical benefit, or the patient has shown intolerance to the treatment, or the patient has refused the treatment.

[0650] (ii) Having a RECIST v1.1 measurable disease;

[0651] (iii) Sufficient tumor material (i.e., one archived FFPE tumor slide or at least 15 consecutive unstained tumor slides) can be transported to the central laboratory upon enrollment in OR, or fresh tumor samples can be provided;

[0652] (iv) Age ≥ 18 years;

[0653] (v) There are standard contraceptive requirements;

[0654] (vi) Has sufficient basic organ functions, as shown below:

[0655] Serum creatinine ≤ 2 times the upper limit of institutional normal (ULN)

[0656] Serum albumin ≥2.5g / dl

[0657] Bilirubin ≤ 2.0 times the upper limit of institutional normal (ULN)

[0658] AST and ALT ≤ 2.5 times the upper limit of the normal range (ULN) of the mechanism.

[0659] If a subject has liver metastases, ALT and AST values ​​less than 5 times the upper limit of institutional normal (ULN) may be permitted.

[0660] (vii) For participants not taking warfarin or other oral anticoagulants, the international normalized ratio (INR) ≤ 1.5, or the prothrombin time (PT) ≤ 1.5 times the upper limit (ULN); and the partial prothrombin kinase time or activated partial prothrombin kinase time (PTT or aPTT) ≤ 1.5 times the ULN;

[0661] (viii) If the subject is taking warfarin at a stable dose and resulting in a stable international normalized ratio (INR) of less than 3.5;

[0662] (ix) If the subject is receiving other oral anticoagulant therapy, PT or aPTT is within the expected therapeutic range of the anticoagulant;

[0663] (x) Has adequate baseline hematological function, as shown below:

[0664] Absolute neutrophil count (ANC) ≥ 1.5 x 10^9 / L.

[0665] Hemoglobin ≥8g / dL and no red blood cell (RBC) transfusion in the past 14 days.

[0666] Platelet count ≥100x10^9 / L, and no platelet transfusion in the past 14 days;

[0667] (xi) Willing to comply with the program requirements, including follow-up survival assessment;

[0668] (x) No persistent, clinically significant toxicity (≥ Grade 2) during prior anticancer treatment (Grade 2 chemotherapy-related neuropathy and alopecia are permissible), nor any prior toxicity leading to laboratory abnormalities that have not recovered to ≤ Grade 1, unless inclusion criteria allow for a higher grade abnormality. If pharmacological treatment is required to manage laboratory abnormalities, the dosage and laboratory values ​​should remain stable;

[0669] (xi) Subjects are individuals with pancreatic ductal adenocarcinoma who have not previously received more than two regimens for advanced / metastatic disease, excluding neoadjuvant therapy / adjuvants, unless PDAC recurs within 6 months of such treatment;

[0670] (xii) According to this disclosure, the patient has not received chemotherapy, external beam radiation therapy or other prior systemic anticancer treatments within 14 days prior to the start of treatment (42 days if nitrosourea or mitomycin-C was previously used);

[0671] (xiii) In accordance with this disclosure, the patient has not received prior treatment with cytotoxic chemotherapy, monoclonal antibody therapy, small molecule tyrosine kinase inhibitor therapy and / or investigational systemic anticancer drugs within 28 days or 5 half-lives (whichever is shorter) prior to the start of treatment;

[0672] (xiv) No wide-area radiation therapy was received within 28 days prior to HMBD-001 (i.e., 10D1F); excluding palliative radiation therapy for bone metastases or similar local radiotherapy.

[0673] (xv) No other active malignant tumors that could interfere with the assessment of study endpoints (subjects with the following accompanying tumor diagnoses are not excluded: non-melanoma skin cancer, carcinoma in situ (including transitional cell carcinoma, cervical intraepithelial neoplasia and melanoma in situ), organ-limited prostate cancer without evidence of progressive disease);

[0674] (xvi) No clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association grade 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).

[0675] (xvii) No out-of-control, clinically significant medical problems, such as lung diseases (e.g., chronic obstructive pulmonary disease, pulmonary hypertension), or out-of-control complications, including but not limited to out-of-control infections requiring systemic treatment, disseminated intravascular coagulation, or mental illness / social conditions.

[0676] (xix) No known active or suspected brain or meningeal metastases (not excluded for subjects with treated and stable brain metastases, provided that imaging has not shown CNS disease progression at least 4 weeks after receiving radiotherapy or other local ablation therapy targeting the CNS).

[0677] (xx) According to this disclosure, there is no medical condition requiring systemic treatment within 14 days prior to the start of treatment, including glucocorticoids (>10 mg daily prednisone equivalent) or other immunosuppressive drugs (inhaled or topical steroids are permitted in the absence of active autoimmune disease);

[0678] (xxi) The QTc interval is no more than 450ms (male) or 470ms (female);

[0679] (xxii) Not pregnant and not breastfeeding;

[0680] (xxiii) Human immunodeficiency virus (HIV) status is negative;

[0681] (xxiv) Inactive or chronic hepatitis B or C; and / or

[0682] (xxv) No medical conditions were placed on subjects at an unacceptably high risk of toxicity.

[0683] In some embodiments, the subjects described in this disclosure meet the inclusion and exclusion criteria for study group A in Example 4 of this specification. In some embodiments, the subjects described in this disclosure meet the inclusion and exclusion criteria for study group B in Example 4 of this specification.

[0684] Reagent test kit

[0685] This disclosure also provides kits for the various components. Kits according to this disclosure may include, in whole or in part, the components for performing the methods described herein.

[0686] The kit may have at least one container containing a predetermined quantity of the combination or composition described herein.

[0687] In some aspects of this disclosure, a kit is provided for each component. In some embodiments, the kit may include an antigen-binding molecule that binds to HER3 as described herein, and a taxane-like substance 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 taxane-like substance 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 taxane-like substance as described herein. The various reagents may be provided in predetermined quantities and may be contained in separate containers or in the same container.

[0688] In some embodiments, the kit includes a combination of pharmaceuticals or a pharmaceutical composition according to this disclosure.

[0689] The kit may provide a component of a pharmaceutical combination according to the present disclosure, a pharmaceutical combination according to the present disclosure, or a pharmaceutical composition according to the present disclosure, as well as instructions for administering the drug to a patient to treat a specific disease / condition (e.g., a disease / condition described in this specification, such as cancer described in this specification).

[0690] The kit may also include reagents, buffers, and / or standards required to perform the methods described herein. Kits according to this disclosure may include instructions for use, such as in the form of a user manual or booklet. The user manual may include operating procedures for performing one or more of the methods described herein.

[0691] Sequence identity

[0692] As used herein, "sequence identity" refers to the percentage of nucleotide / amino acid residues in the target sequence that are identical to those in the reference sequence, after alignment of the target sequence with a reference sequence to achieve maximum sequence identity (introducing spacer sequences where necessary). To determine the percentage of sequence similarity between two or more amino acid or nucleic acid sequences, pairwise and multiple sequence alignments can be performed using various methods well known to those skilled in the art, such as publicly available computer software like ClustalOmega. J. 2005, Bioinformatics 21, 951-960), T-coffee (Notredame et al., 2000, Journal of Molecular Biology (2000) 302, 205-217), Kalign (Lassmann and Sonnhammer 2005, BMC Bioinformatics, 6 (298)) and MAFFT (Katoh and Standley, 2013, Molecular Biology & Evolution, 30 (4) 772–780). When using such software, it is best to use the default parameters, such as the space penalty and the expansion penalty.

[0693] sequence

[0694]

[0695]

[0696]

[0697]

[0698]

[0699]

[0700]

[0701]

[0702]

[0703]

[0704]

[0705]

[0706]

[0707] Numbering Explanation

[0708] The following numbered paragraphs describe specific aspects and embodiments of the invention:

[0709] 1. An antigen-binding molecule that binds to HER3 for the treatment or prevention of cancer, wherein the method comprises administering an antigen-binding molecule that binds to EGFR, and wherein the antigen-binding molecule that binds to HER3 binds to the HER3 region shown in SEQ ID NO:77.

[0710] 2. Use of an antigen-binding molecule that binds to HER3 in the preparation of a medicament for a method of treating or preventing cancer, wherein the method comprises administering an antigen-binding molecule that binds to EGFR, and wherein the antigen-binding molecule that binds to HER3 binds to the HER3 region shown in SEQ ID NO:77.

[0711] 3. A method of treating or preventing cancer, comprising administering to a subject a therapeutically or preventively effective amount of (i) an antigen-binding molecule that binds to HER3 and (ii) an antigen-binding molecule that binds to EGFR; wherein the antigen-binding molecule that binds to HER3 binds to the HER3 region shown in SEQ ID NO:77.

[0712] 4. A drug 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 HER3 region shown in SEQ ID NO:77.

[0713] 5. Methods for treating or preventing cancer based on the drug combination described in paragraph 4.

[0714] 6. To prepare a medicine for treating or preventing cancer, based on the use of the drug combination described in paragraph 4.

[0715] 7. A method of treating or preventing cancer, comprising administering to a subject a therapeutically or preventively effective amount of the combination of drugs described in paragraph 4.

[0716] 8. The antigen-binding molecule, use, or method according to any one of paragraphs 1 to 7, wherein the antigen-binding molecule binding to HER3 comprises:

[0717] (i) Heavy chain variable (VH) regions containing the following CDRs:

[0718] HC-CDR1 with the amino acid sequence SEQ ID NO:40

[0719] HC-CDR2 with the amino acid sequence SEQ ID NO:43

[0720] HC-CDR3 having the amino acid sequence SEQ ID NO:48; and

[0721] (ii) Light chain variable (VL) regions containing the following CDRs:

[0722] LC-CDR1 with the amino acid sequence SEQ ID NO:66

[0723] LC-CDR2 with the amino acid sequence SEQ ID NO:69

[0724] LC-CDR3 having the amino acid sequence SEQ ID NO:74.

[0725] 9. The antigen-binding molecule, use, or method according to any one of paragraphs 1 to 8, wherein the antigen-binding molecule binding to HER3 comprises:

[0726] (i) VH region containing the following CDRs:

[0727] HC-CDR1 with the amino acid sequence SEQ ID NO:38

[0728] HC-CDR2 with the amino acid sequence SEQ ID NO:42

[0729] HC-CDR3 having the amino acid sequence SEQ ID NO:45; and

[0730] (ii) VL regions containing the following CDRs:

[0731] LC-CDR1 with the amino acid sequence SEQ ID NO:63

[0732] LC-CDR2 with the amino acid sequence SEQ ID NO:67

[0733] LC-CDR3 having the amino acid sequence SEQ ID NO:70.

[0734] 10. The antigen-binding molecule, use, or method according to any one of paragraphs 1 to 9, wherein the antigen-binding molecule binding to HER3 comprises:

[0735] A VH region containing an amino acid sequence that shares at least 70% sequence identity with the amino acid sequence of SEQ ID NO:33; and

[0736] A VL region containing an amino acid sequence that has at least 70% sequence identity with the amino acid sequence of SEQ ID NO:58.

[0737] 11. The antigen-binding molecule, use, or method according to any one of paragraphs 1 to 10, wherein the antigen-binding molecule binding to HER3 comprises:

[0738] A polypeptide comprising or consisting of: an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:75; and

[0739] A polypeptide comprising or consisting of an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:76.

[0740] 12. The antigen-binding molecule, use, or method according to any one of paragraphs 1 to 11, wherein the antigen-binding molecule binding to EGFR comprises:

[0741] (i) Heavy chain variable (VH) regions containing the following CDRs:

[0742] HC-CDR1 with the amino acid sequence SEQ ID NO:92

[0743] HC-CDR2 with the amino acid sequence SEQ ID NO:93

[0744] HC-CDR3 having the amino acid sequence SEQ ID NO:94; and

[0745] (ii) Light chain variable (VL) regions containing the following CDRs:

[0746] LC-CDR1 with the amino acid sequence SEQ ID NO:96

[0747] LC-CDR2 with the amino acid sequence SEQ ID NO:97

[0748] LC-CDR3 having the amino acid sequence SEQ ID NO:98.

[0749] 13. The antigen-binding molecule, use, or method according to any one of paragraphs 1 to 12, wherein the antigen-binding molecule binding to EGFR comprises:

[0750] A VH region containing an amino acid sequence that shares at least 70% sequence identity with the amino acid sequence of SEQ ID NO:91; and

[0751] A VL region containing an amino acid sequence that has at least 70% sequence identity with the amino acid sequence of SEQ ID NO:95.

[0752] 14. The antigen-binding molecule, use, or method according to any one of paragraphs 1 to 13, wherein the antigen-binding molecule binding to EGFR comprises:

[0753] A polypeptide comprising or consisting of: an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:99; and

[0754] A polypeptide comprising or consisting of an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:100.

[0755] 15. The antigen-binding molecule, use, or method according to any one of paragraphs 1 to 14, wherein the cancer is selected from: cancer containing cells expressing / overexpressing EGFR family members, cancer containing cells expressing / overexpressing HER3, cancer containing cells expressing / overexpressing EGFR, cancer containing cells expressing / overexpressing both HER3 and EGFR, cancer containing cells with increased HER3 ligand expression due to mutation, cancer containing cells with increased EGFR ligand expression due to mutation, cancer containing cells with NRG gene fusion, solid tumors, hematologic malignancies, squamous cell carcinoma, squamous cell carcinoma with epidermal growth factor receptor (EGFR) amplification, breast cancer, breast adenoma, invasive breast cancer, ductal carcinoma, metastatic breast cancer, triple-negative breast cancer, HER2-positive breast cancer, gastric cancer, gastric tumor, 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. Cancer, non-small cell lung cancer, lung adenocarcinoma, invasive mucinous lung adenocarcinoma, lung squamous cell carcinoma, ovarian cancer, ovarian tumor, ovarian serous adenocarcinoma, ovarian serous cystadenocarcinoma, fallopian tube cancer, kidney cancer, renal cell carcinoma, clear cell renal carcinoma, renal cell adenocarcinoma, papillary renal carcinoma, pancreatic cancer, pancreatic adenocarcinoma, pancreatic duct 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 sarcoma, thyroid cancer, thyroid tumor, pheochromocytoma, paraganglioma, bladder cancer, bladder urothelial carcinoma, 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.

[0756] 16. The antigen-binding molecule, use, or method according to any of paragraphs 1 to 15, wherein the cancer is selected from: a cancer comprising cells expressing / overexpressing HER3, a cancer comprising cells expressing / overexpressing EGFR, a cancer comprising cells expressing / overexpressing both 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.

[0757] ***

[0758] This disclosure includes combinations of the described aspects and preferred features, unless such combinations are expressly not permitted or expressly avoided.

[0759] The chapter titles used in this document are for organizational purposes only and should not be construed as limiting the topics described.

[0760] Various aspects and embodiments of this disclosure will be illustrated by way of example and in conjunction with the accompanying drawings. Further aspects and embodiments will be apparent to those skilled in the art. All references herein are incorporated by way of citation.

[0761] In this specification, the following claims are included. Unless the context otherwise requires, the word “comprising” and its variations such as “including” and “including” should be understood to include one or more integers or steps or groups of steps, but not to exclude any other integers or steps or groups of steps.

[0762] It is important to note that, when used in the specification and appended claims, the singular forms of “a,” “an,” and “the” include the plural meaning unless the context clearly indicates otherwise. A range in this document may be expressed as from “about” one specific value to “about” another specific value. When such a range is expressed, another embodiment includes the range from that specific value to another specific value. Similarly, when a numerical value is used to indicate an approximation using the preposition “about,” it should be understood that the specific value constitutes another embodiment.

[0763] Where the nucleic acid sequence is disclosed or mentioned in this article, its reverse complementary sequence is also explicitly considered.

[0764] The methods described herein can preferably be performed in vitro. The term "in vitro" is intended to include procedures performed with cultured cells, while the term "in vivo" is intended to include procedures performed with whole multicellular organisms.

[0765] In this text, numerical values ​​can be expressed as "about" a specific value. Similarly, ranges can be expressed as ranging from "about" a specific value to "about" another specific value. The word "about" in relation to numerical values ​​is optional, for example, indicating + / - 10%. For instance, mentioning "about 10%" should be understood as 9% to 11%. When "about" is used in this text, the preceding numerical value is also specifically considered. For example, mentioning "about 10%" also specifically considers 10%. Brief description of the attached diagram

[0767] The implementation schemes and experiments used to illustrate the principles of this disclosure will now be discussed with reference to the accompanying drawings.

[0768] Figures 1A and 1B: These graphs show the effects of treatment with 10D1F (HMBD-001), cetuximab, 10D1F combined with cetuximab, or vector control (PBS) on mice with a KYSE-150 cell-derived mouse model of esophageal squamous cell carcinoma. Figure 1A shows the changes in tumor volume over time in mice of different treatment groups. Figure 1B The changes in body weight of mice in different treatment groups over time are shown.

[0769] Figure 2A and 2B The chart shows the effects of treatment with 10D1F (HMBD-001), cetuximab, 10D1F combined with cetuximab, or vector control (PBS) on mice carrying an OE21 cell-derived mouse esophageal squamous cell carcinoma model. Figure 2A The changes in tumor volume over time were shown in mice from different treatment groups. Figure 2B The changes in body weight of mice in different treatment groups over time are shown.

[0770] Figure 3A and 3B The chart shows the effects of treatment with 10D1F (HMBD-001), cetuximab, 10D1F combined with cetuximab, or vector control (PBS) on mice carrying a mouse model of LIM1215 cell-derived conjunctivitis. Figure 3A The changes in tumor volume over time were shown in mice from different treatment groups. Figure 3B The changes in body weight of mice in different treatment groups over time are shown.

[0771] Figure 4A and 4B The chart shows the effects of treatment with 10D1F (HMBD-001), cetuximab, 10D1F combined with cetuximab, or vector control (PBS) on mice carrying a CAL-27 cell-derived squamous cell carcinoma model of the tongue. Figure 4A The changes in tumor volume over time were shown in mice from different treatment groups. Figure 4B The changes in body weight of mice in different treatment groups over time are shown.

[0772] Figure 5A and 5B The chart shows the effects of treatment with 10D1F (HMBD-001), cetuximab, 10D1F combined with cetuximab, or vector control (PBS) on a mouse model of subpharyngeal squamous cell carcinoma carrying FaDu cells. Figure 5A This shows the changes in tumor volume in mice over time in different treatment groups. Figure 5B The changes in body weight of mice in different treatment groups over time are shown.

[0773] Figure 6A and 6B The chart shows the effects of treatment with 10D1F (HMBD-001), cetuximab, 10D1F combined with cetuximab, or control (PBS) on mice carrying a mouse model of pancreatic ductal adenocarcinoma derived from BxPC-3 cells. Figure 6AThe changes in tumor volume over time were shown in mice from different treatment groups. Figure 6B The changes in body weight of mice in different treatment groups over time are shown.

[0774] Figure 7A and 7B The chart shows the effects of 10D1F (HMBD-001), cetuximab, 10D1F combined with cetuximab, or allotype control on mice carrying the human mouse lung squamous cell carcinoma model (CTG-2552). Figure 7A The changes in tumor volume over time were shown in mice from different treatment groups. Figure 7B The changes in body weight of mice in different treatment groups over time are shown.

[0775] Figure 8A and 8B The chart shows the effects of treatment with 10D1F (HMBD-001), cetuximab (5 mg / kg and 10 mg / kg), docetaxel, 10D1F in combination with cetuximab (5 mg / kg and 10 mg / kg), 10D1F in combination with docetaxel, cetuximab (5 mg / kg and 10 mg / kg) in combination with docetaxel, 10D1F in combination with cetuximab (5 mg / kg and 10 mg / kg) and docetaxel, or vector control (PBS) on mice carrying a lung squamous cell carcinoma xenograft (CDX) model. Figure 8A The changes in tumor volume over time were shown in mice in different treatment groups (including the cetuximab treatment group, which received 5 mg / kg cetuximab). Figure 8B The changes in tumor volume over time were shown in mice in different treatment groups (including the treatment group treated with cetuximab at 10 mg / kg). Figure 8C The changes in body weight of mice in different treatment groups over time are shown. Example

[0776] Example 1: Features of 10D1F in WO 2019 / 185878 A1 and WO 2021 / 048274 A1

[0777] The HER3-binding antibody clone named 10D1F is described in WO 2019 / 185878 A1 (in which the full text is incorporated herein by reference).

[0778] 10D1F includes the heavy chain variable region shown in SEQ ID NO:36 (=SEQ ID NO:33 of this disclosure) of WO 2019 / 185878 A1, and the light chain variable region shown in SEQ ID NO:83 (=SEQ ID NO:58 of this disclosure) of WO 2019 / 185878 A1. 10D1F is also referred to as “10D1_c89” in WO 2019 / 185878 A1, and is sometimes referred to as HMBD-001 herein.

[0779] Example 2.2 of WO 2019 / 185878 A1 describes a molecule (molecule

[16] ) containing 10D1F VH and VL regions in the form of human IgG1 / Vκ (10D1F hIgG1) and consisting of SEQ ID NO:206 of WO 2019 / 185878 A1 (=SEQ ID NO:75 of this disclosure) and SEQ ID NO:207 of WO 2019 / 185878 A1 (=SEQ ID NO:76 of this disclosure).

[0780] Examples 8.1 to 8.3 and Figures 42 to 46 of WO 2019 / 185878 A1 show that 10D1F hIgG1 can bind to human HER3 with high affinity and specificity (without cross-reactivity to other EGFR family members), while maintaining high affinity binding to HER3 in cynomolgus monkeys, mice and rats.

[0781] Example 8.6 and Figures 49A and 49B of WO 2019 / 185878 A1 show that 10D1F hIgG1 binds to HER3 in a ligand-independent (NRG) manner and binds to the epitopes of anti-HER3 antibodies M-05-74 and M-08-11 via a topologically distant epitope of HER3. Example 8.10 and Figure 78 of WO 2021 / 048274 A1 show that 10D1F hIgG1 binds to human HER3 with subpicomolar affinity in the presence or absence of human NRG1.

[0782] WO 2021 / 048274 A1 also discloses in Example 3.5 that the binding position of antibody clone 10D1 and its derived clones (including 10D1F) to human HER3 corresponds to positions 218 to 235 of SEQ ID NO:1 (i.e. SEQ ID NO:77 of this disclosure), and two common binding site motifs are identified in this region (as shown in SEQ ID NOs:78 and 79 of this disclosure).

[0783] Examples 4.1 and Figure 65 of WO 2019 / 185878 A1, and Examples 8.7 and Figure 52, show that 10D1FhIgG1 is highly potent in inhibiting the interaction between HER3 and HER2, and works in a dose-dependent manner. Example 8.7 of WO 2019 / 185878 A1 and Figure 53 show that 10D1FhIgG1 inhibits the interaction between HER3 and EGFR in a dose-dependent manner.

[0784] Example 8.8 and Figure 54 of WO 2019 / 185878 A1 show that 10D1F hIgG1 can produce dose-dependent ADCC activity in cells overexpressing HER3.

[0785] Example 8.9 of WO 2019 / 185878 A1 and Figures 55, 63 and 64 show that 10D1F hIgG1 inhibits HER3-mediated signaling in HER3-expressing cancer cell lines in vitro.

[0786] Example 11 and Figure 71 of WO 2019 / 185878 A1 show that 10D1F hIgG1 can also inhibit HER3-mediated signaling in xenograft tumors derived from human cancer cell lines expressing HER3 in vivo. Example 14 and Figure 79 of WO 2021 / 048274 A1 show that 10D1F has extremely high efficacy in inhibiting the growth of xenograft tumors derived from human cancer cell lines carrying NRG gene fusions.

[0787] Examples 9.3 and 9.4 of WO 2019 / 185878 A1 and Figures 59, 60, 61, 62, 74, and 77 show that 10D1F effectively inhibits the growth of cancer cells in vitro and also strongly inhibits the growth of xenograft tumors derived from human cancer cell lines in vivo. Example 10 of WO 2019 / 185878 A1 and Figures 67 and 68 show that 10D1F hIgG1 can inhibit the in vitro proliferation of thyroid cancer cell lines carrying the V600EBRAF mutation.

[0788] Example 12 of WO 2019 / 185878 A1 and Figures 72 and 73 show that 10D1F hIgG1 was not significantly internalized by cells expressing HER3.

[0789] Example 13 and Figures 75 and 76 of WO 2019 / 185878 A1 demonstrate the practicality of using 10D1F hIgG1 to detect HER3.

[0790] Example 8.4 and Figure 47A of WO 2019 / 185878 A1 show that 10D1F hIgG1 is thermally stable with a melting point of 70.0 °C, as determined by differential scanning fluorometry.

[0791] Examples 9.1 and 9.2 of WO 2019 / 185878 A1 and Figures 56, 57, 58 and 69, 70 show that 10D1F hIgG1 has good pharmacological and toxicological properties.

[0792] Example 2: A phase 1b study evaluating HMBD-001 monotherapy or in combination with chemotherapy in patients with NRG1 gene fusions at an advanced stage of cancer. Efficacy in patients with stage I solid tumors

[0793] A phase 1b study is underway to evaluate the efficacy of HMBD-001 (i.e., 10D1F) in combination with chemotherapy for NRG1 gene fusion cancers. HER2 / HER3 targeted therapies for cancers with NRG1 fusions have shown early clinical efficacy, with seritubantumab showing a response rate of 30% (Carrizosa et al., *Journal of Clinical Oncology* (2022) 40(16_suppl):3006) and zenocutuzumab showing a response rate of 34% (Schram et al., *Journal of Clinical Oncology* (2022) 40(16_suppl):105). However, both seritubantumab and zenocutuzumab largely inhibit ligand-dependent HER3 activation.

[0794] HMBD-001 (i.e., 10D1F) is currently the only anti-HER3 monoclonal antibody under development that can block ligand-dependent and ligand-independent HER3 activation and oncogenic signaling. It achieves this by blocking key epitopes in the formation of heterodimers between HER3 and HER2 or EGFR, independent of upstream processes. Preclinical evaluations of 10D1F in head-to-head trials have shown significant advantages in affinity and tumor control across multiple cancer types compared to other anti-HER3 drugs in development. In a phase 1 study conducted by Cancer Research UK (CRUK), 10D1F demonstrated good clinical activity, achieving disease stabilization in 5 out of 17 patients (29.4%), with a median duration of disease control of up to 20 weeks.

[0795] Preclinical studies have shown that PI3K and MAPK pathway blockade combined with gemcitabine and albumin-bound paclitaxel chemotherapy has a potential synergistic effect, improving survival by 67% in mouse models (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, Group A studies explored the safety, tolerability, and preliminary efficacy of the combination of gemcitabine, albumin-bound paclitaxel, and 10D1F for the treatment of locally advanced and unresectable or metastatic PDAC. NRG1 fusions account for only 1% of all NSCLC, but they have recently been considered a unique class of NSCLC characterized by zero or low expression of programmed death-ligand-1 (PD-L1), low tumor mutational burden, and limited response to systemic therapies, including cytotoxic drugs, immunotherapy, and targeted therapy (Drilon et al., *J Clin Oncol* (2021) 39(25):2791-2802). There is an urgent need to find effective treatment options for patients with NRG1 fusion-type NSCLC. Therefore, Group B of this study aimed to explore the safety and efficacy of combination therapy with docetaxel and 10D1F in NSCLC patients.

[0796] The subjects were divided into three groups, A, B, and C, and the treatment was as follows:

[0797] Group A:

[0798] 10D1F 1800mg intravenous infusion once a week

[0799] Gemcitabine 1000 mg / m² intravenously on days 1, 8, and 15 of a 28-day cycle. 2

[0800] Albumin-bound paclitaxel 125 mg / m² intravenously on days 1, 8, and 15 of every 28-day cycle. 2

[0801] Group B:

[0802] 10D1F: 1800 mg docetaxel intravenously once weekly; 75 mg / m² intravenously once every three weeks. 2

[0803] Group C:

[0804] 10D1F 1800mg intravenous infusion once a week

[0805] For groups A and B, the treatment period is the initial induction phase, which can consist of up to 6 cycles of combined chemotherapy and 10D1F treatment, and may be extended to 8 cycles depending on the specific circumstances. After the induction phase, 10D1F monotherapy (i.e., weekly intravenous infusion of 1800 mg of 10D1F) will continue until the participant stops treatment due to intolerable toxicity, confirmed disease progression, withdrawal of informed consent, loss to follow-up, death, or study termination, whichever occurs first. During 10D1F monotherapy maintenance therapy, if disease progression occurs, combination chemotherapy and 10D1F re-induction therapy may be approved depending on the specific circumstances.

[0806] For Group C, treatment will continue until the subject stops treatment due to intolerable toxicity, confirmed disease progression, withdrawal of informed consent, loss to follow-up, death, or termination of the study, whichever occurs first.

[0807] Group A subjects had locally advanced, unresectable pancreatic ductal adenocarcinoma with NRG1 gene fusion carrying the epidermal growth factor (EGF) signaling domain, or metastatic pancreatic ductal adenocarcinoma with NRG1 gene fusion carrying the epidermal growth factor (EGF) signaling domain.

[0808] Group B subjects had non-small cell lung cancer and carried the NRG1 gene fusion with the epidermal growth factor (EGF) signaling domain.

[0809] Group C subjects had locally advanced, unresectable solid tumors with NRG1 gene fusion carrying the epidermal growth factor (EGF) signaling domain, or metastatic solid tumors with NRG1 gene fusion carrying the epidermal growth factor (EGF) signaling domain, and did not meet the inclusion criteria of Group A or Group B.

[0810] The main patient eligibility criteria are as follows.

[0811] Inclusion criteria

[0812] Participants in the study must meet all of the following inclusion criteria:

[0813] 1. Before any research procedure and evaluation begins, you must be willing, able, and have provided written informed consent, and be willing to comply with all research procedures.

[0814] 2. Adult participants must be ≥18 years old when giving informed consent.

[0815] 3. ECOG physical fitness status 0-1.

[0816] 4. Histological or cytological evidence shows that the advanced malignant solid tumor (any tissue type) is resistant to / unresponsive to standard systemic therapy, or that, in the physician's opinion, there is no standard systemic therapy or reasonable treatment that would provide clinical benefit, or that the participant has been shown to be unable to tolerate such treatment, or that the participant refuses such treatment.

[0817] 5. Cancer carries NRG1 gene fusion identified by molecular testing. Fusion transcripts are defined as those that are correctly oriented (i.e., the NRG1-encoded mRNA is located at the 3' end of the transcript) and contain an EGF-like domain that can bind to HER3.

[0818] ·Group A:

[0819] o Locally advanced unresectable or metastatic pancreatic adenocarcinoma;

[0820] Participants must not have previously received gemcitabine or albumin-bound paclitaxel treatment;

[0821] Participants must not have previously received more than two lines of systemic therapy for advanced disease. Adjuvant or neoadjuvant therapy received within the six months prior to Day 1 of the proposed Cycle 1 (C1D1) will be counted as one treatment line.

[0822] Group B:

[0823] o Locally advanced unresectable or metastatic non-small cell lung cancer;

[0824] Participants must not have previously received docetaxel treatment;

[0825] Participants must not have previously received more than two lines of systemic therapy for advanced disease. Adjuvant or neoadjuvant therapy received within the six months prior to Day 1 of the proposed Cycle 1 (C1D1) will be counted as one treatment line.

[0826] Group C:

[0827] Participants are not eligible to participate in Group A or Group B.

[0828] 6. Researchers believe that participants' life expectancy must be more than 3 months.

[0829] 7. Participants must have a measurable disease that meets RECIST V1.1 criteria.

[0830] 8. Participants must provide available archival tissue (at least 15 consecutive, unstained, formalin-fixed, paraffin-embedded [FFPE] sections or 1 FFPE tissue block) OR, alternatively, a fresh tumor biopsy sample. Participants without any archival tissue or a fresh biopsy sample, or who refuse to provide archival tissue, may be approved for enrollment on a case-by-case basis after discussion with the sponsor.

[0831] 9. Women of childbearing potential (WOCBP) must undergo a β-human chorionic gonadotropin (β-hCG) test within 72 hours before their first dose of the study drug and have a negative result, and must not be breastfeeding.

[0832] 10. WOCBP is defined as women who have not undergone surgical sterilization or are not menopausal. Female participants who have not menstruated for 12 consecutive months without other medical reasons will be considered menopausal women. Female participants under 50 years of age who meet the menopausal criteria but have not undergone surgical sterilization should be considered for further testing of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels to confirm serological menopausal status.

[0833] 11. WOCBPs must agree to use an effective method of contraception during the study period and for 90 days after the last use of the study drug.

[0834] 12. Fertility-providing male participants must agree to abstain from impregnation by their partners during the study period and for 90 days after the last study medication, and to use highly effective contraception. All male participants must agree not to donate sperm during the study period and for 90 days after the last study medication.

[0835] 13. Possessing adequate baseline organ function, as shown below:

[0836] • Serum creatinine ≤ 2 times the upper limit of institutional normal (ULN)

[0837] Serum albumin ≥2.5g / dl

[0838] • Bilirubin ≤ 2.0 times the upper limit of institutional normal (ULN)

[0839] • AST and ALT ≤ 2.5 times the institutional upper limit of normal (ULN). If the subject has liver metastases, ALT and AST < 5 times the institutional upper limit of normal (ULN) may be acceptable.

[0840] 14. For participants not taking warfarin or other oral anticoagulants, the international normalized ratio (INR) ≤ 1.5, or the prothrombin time (PT) ≤ 1.5 times the upper limit of the ULN; and the partial prothrombin kinase time or activated partial prothrombin kinase time (PTT or aPTT) ≤ 1.5 times the ULN.

[0841] 15. Possesses adequate baseline hematological function, as shown below:

[0842] • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9 / L.

[0843] • Hemoglobin ≥ 8 g / dL and no red blood cell (RBC) transfusion in the past 14 days.

[0844] • Platelet count ≥100x10^9 / L, and no platelet transfusion in the past 14 days.

[0845] Exclusion criteria

[0846] Subjects who meet any of the following exclusion criteria are excluded from the study:

[0847] 1. Previously received HMBD-001, pertuzumab, or experimental drugs specifically targeting HER3, including pan-HER tyrosine kinase inhibitors.

[0848] 2. Persistent clinically significant toxicity (≥ Grade 2) due to prior anticancer therapy. Previous toxicities that caused laboratory abnormalities should be restored to ≤ Grade 1, unless inclusion criteria allow for a higher grade abnormality. If pharmacological treatment is required to manage the laboratory abnormality, the dosage and laboratory values ​​should remain stable. For residual toxicities exceeding Grade 2, but for those considered unlikely to increase the participant's risk of treatment-related toxicities and / or affect the integrity of study results, inclusion may be considered at the discretion of the study sponsor after discussion (e.g., alopecia, thyroid disease, or insufficient cortisol under stable hormone replacement therapy).

[0849] 3. Participants must have received anticancer treatment, including cytotoxic chemotherapy, monoclonal antibodies, small molecule tyrosine kinase inhibitors, and / or experimental systemic anticancer drugs, within 28 days or 5 half-lives (42 days for those previously using nitroureides or mitomycin C) prior to the start of study treatment, whichever is shorter. Participants with advanced prostate cancer receiving luteinizing hormone-releasing hormone (LHRH) agonists are eligible for enrollment and should continue using these drugs during the study treatment period.

[0850] 4. Received radiation therapy or major surgery within 4 weeks prior to the first dose of the investigational drug. Local palliative radiation therapy or minor surgery performed within 4 weeks prior to the first dose of the investigational drug may be approved on a case-by-case basis after discussion with the study funder, provided that it is determined not to increase the participant's risk of adverse drug reactions and / or affect the integrity of the study results.

[0851] 5. Brain transfer participants, unless they meet all of the following criteria:

[0852] • Maintain clinical and imaging stability (no progression shown on imaging; the same imaging method (MRI or CT scan) must be used for each evaluation) for at least 28 days prior to the first use of the investigational drug.

[0853] Neurological symptoms returned to baseline;

[0854] • Note: Subjects with a history of leptomeningeal disease should not participate, even if they are clinically stable.

[0855] 6. Any other known active malignancy, excluding treated cervical intraepithelial neoplasia or non-melanoma skin cancer. For participants with a history of malignancy at low risk of recurrence and who have received radical treatment, approval may be granted on a case-by-case basis after discussion with the study sponsor, provided it is confirmed that this will not increase the participant's risk of adverse drug reactions and / or interfere with the integrity of the study results.

[0856] 7. A history of uncontrolled allergic reactions to HMBD-001 or any of its excipients, and / or gemcitabine, albumin-bound paclitaxel or docetaxel, if relevant to participant enrollment.

[0857] 8. Participate in any other research-based trials.

[0858] 9. Left ventricular ejection fraction <50%.

[0859] 10. Clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association grade 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).

[0860] 11. Uncontrollable clinically significant medical problems, such as lung disease (e.g., chronic obstructive pulmonary disease, pulmonary hypertension), or uncontrollable concurrent illnesses, including but not limited to infections requiring systemic treatment, disseminated intravascular coagulation, or mental illnesses / social conditions that may limit compliance with study requirements.

[0861] 12. QTc interval > 450ms (male) or > 470ms (female).

[0862] 13. The human immunodeficiency virus test was positive.

[0863] 14. Active or chronic hepatitis B or C.

[0864] 15. Any health condition that researchers believe would place participants at an unacceptably high risk of toxicity.

[0865] 16. C1D1 infection with COVID-19 within the past 3 months.

[0866] 17. Receive the COVID-19 vaccine within 14 days after C1D1.

[0867] 18. Any uncontrollable comorbidity or clinically significant uncontrollable condition, including but not limited to active bacterial, fungal, or viral infections requiring systemic treatment.

[0868] For groups A and B, an initial safety induction strategy will be used to determine the recommended phase 2 dose (RP2D) of HMBD-001 in combination with chemotherapy. Subsequently, enrollment of the remaining participants will be conducted according to the Simon phase 2 design.

[0869] Safe import strategies for Group A and Group B

[0870] 10D1F

[0871] Dose level (DL) 1 = 1800 mg

[0872] DL-1 = 1200mg

[0873] Group A Safe Import

[0874]

[0875]

[0876] Group A Unsafe Import

[0877]

[0878] Group B Safe Import

[0879]

[0880]

[0881] Group B Unsafe Import

[0882]

[0883] Group C

[0884]

[0885] Goals and End Points

[0886] Group A

[0887]

[0888]

[0889] Group B

[0890]

[0891]

[0892] Group C

[0893]

[0894]

[0895] result

[0896] A 59-year-old female patient was diagnosed with metastatic pancreatic adenocarcinoma with liver and lung metastases (stage IV) in April 2022. She began first-line systemic therapy in June 2022 using gemcitabine in combination with albumin-bound paclitaxel. Her condition remained stable until March 2023, at which point disease progression was identified. At this time, the gemcitabine and albumin-bound paclitaxel therapy was discontinued, and second-line systemic therapy with FOLFIRINOX was initiated. The patient's condition remained stable from March to July 2023. FOLFIRINOX treatment was discontinued in July 2023. Also in July 2023, tumor genomic analysis revealed an ATP1B1-NRG1 fusion. In September 2023, she began treatment with 1800 mg HMBD-001 once weekly (QW).

[0897] The size of the target lesion was analyzed at baseline and after 2.5, 4, and 6 cycles of HMBD-001 treatment. Patients were also evaluated after 2, 2.5, 4, and 6 cycles of HMBD-001 treatment to determine the level of CA19-9 (a pancreatic-associated marker) in the blood. The results are shown below.

[0898]

[0899] *The patient was experiencing hyperthyroidism, therefore, for safety reasons, a CT scan was performed at the end of the second treatment cycle, and no comparison was made. The study found that HMBD-001 treatment was associated with a significant reduction in target lesion size, an effect that persisted over six treatment cycles. Furthermore, HMBD-001 treatment also showed a significant and durable reduction in blood CA19-9 levels.

[0900] Example 3: Efficacy evaluation of combination therapy with 10D1F and cetuximab

[0901] The therapeutic effects of 10D1F hIgG1 (i.e., an antibody formed from a peptide containing SEQ ID NO:75 and a peptide containing SEQ ID NO:76) combined with cetuximab (i.e., an antibody formed from a peptide containing SEQ ID NO:99 and a peptide containing SEQ ID NO:100) on a variety of different cancers in vivo, in human cells and / or in patient-derived xenograft models were investigated.

[0902] Mice approximately 6–8 weeks old were housed under specific pathogen-free (SPF) conditions and handled according to the Institutional Animal Care and Use Committee (IACUC) guidelines. Tumors were established using human cancer cells mixed with an equal volume of Matrigel (Corning, USA) and injected subcutaneously into the right or left abdomen of the mice as instructed. Tumors were developed when they reached approximately 100–300 mm in size. 3 Treatment began at that time.

[0903] ESCC CDX(1):

[0904] Model: Human esophageal squamous cell carcinoma cell line-derived model

[0905] Cell line: KYSE-150 (CVCL_1348). KYSE-150 cells showed high expression of NRG1 and HER3 (Meetze et al., Clinical Cancer Research (2015) 21(5):1106-1114).

[0906] Model construction: NOD / SCID mice were injected with 1×10⁻⁶ on the right side. 7 Each cell.

[0907] Treatment group:

[0908] Control group (phosphate-buffered saline; intraperitoneal injection, weekly; n=10).

[0909] HMBD-001 (20 mg / kg body weight, intraperitoneal injection, weekly; n = 10).

[0910] Cetuximab (10 mg / kg body weight, intraperitoneal injection, weekly; n=10).

[0911] HMBD-001 + Cetuximab (intraperitoneal injection of 20 mg / kg body weight of HMBD-001 + 10 mg / kg body weight of cetuximab, weekly; n = 10).

[0912] ESCC CDX(2):

[0913] Model: Human esophageal squamous cell carcinoma cell line-derived model

[0914] Cell line: OE21 (CVCL_2661). OE21 cells highly express EGFR dimer (Fichter et al., Int J Cancer (2014) 135(7):1517-1530).

[0915] Model construction: NOD / SCID mice were injected with 1×10⁻⁶ on the right side. 6 Each cell.

[0916] Treatment group:

[0917] Control group (phosphate-buffered saline; intraperitoneal injection, twice a week; n=10).

[0918] HMBD-001 (20 mg / kg body weight, intraperitoneal injection, twice a week; n = 10).

[0919] Cetuximab (10 mg / kg body weight, intraperitoneal injection, twice a week; n=10).

[0920] HMBD-001 + Cetuximab (20 mg / kg body weight HMBD-001 + 10 mg / kg body weight cetuximab, administered intraperitoneally twice a week; n = 10).

[0921] CRC CDX:

[0922] Model: Human colon cancer cell line-derived model

[0923] Cell line: LIM1215 (CVCL_2574). LIM1215 cells express normal levels of EGFR but are sensitive to cetuximab (Misale et al., Nature, (2012) 486(7404):532-536).

[0924] Model construction: Inject 2×10⁻⁶ cells into the right side of a nude mouse. 6 Each cell.

[0925] Treatment group:

[0926] Control group (phosphate-buffered saline; intraperitoneal injection, twice a week; n=10).

[0927] HMBD-001 (20 mg / kg body weight, intraperitoneal injection, twice a week; n = 11).

[0928] Cetuximab (10 mg / kg body weight, intraperitoneal injection, twice a week; n=12).

[0929] HMBD-001 + Cetuximab (20 mg / kg body weight HMBD-001 + 10 mg / kg body weight cetuximab, administered intraperitoneally twice a week; n = 12).

[0930] HNSCC CDX(1):

[0931] Model: Human tongue squamous cell carcinoma cell line-derived model

[0932] Cell line: CAL-27 (CVCL_1107). CAL-27 cells overexpress EGFR (Licitra et al., Annals of Oncology (2011) 22(8):1886-1893).

[0933] Model construction: NOD SCIDγ (NSG) mice were injected with 5 × 10⁻⁶ ppm on the right side. 6 Each cell.

[0934] Treatment group:

[0935] Control group (phosphate-buffered saline; intraperitoneal injection, twice a week; n=8).

[0936] HMBD-001 (20 mg / kg body weight, intraperitoneal injection, twice a week; n = 8).

[0937] Cetuximab (10 mg / kg body weight, intraperitoneal injection, twice a week; n=8).

[0938] HMBD-001 + Cetuximab (20 mg / kg body weight HMBD-001 + 10 mg / kg body weight cetuximab, administered intraperitoneally twice a week; n = 8).

[0939] HNSCC CDX(2):

[0940] Model: Human hypopharyngeal squamous cell carcinoma cell line-derived model

[0941] Cell line: FaDu (CVCL_1218). FaDu cells showed high expression of EGFR and NRG1 (Xiao et al., MolCancer Ther (2016) 15(4):689-701).

[0942] Model construction: 1×10⁻⁶ NCr was injected into the right side of nude mice. 6 Each cell.

[0943] Treatment group:

[0944] Control group (phosphate-buffered saline; intraperitoneal ...

Claims

1. An antigen-binding molecule that binds to HER3, used for the treatment or prevention of cancer, wherein the method comprises administering an antigen-binding molecule that binds to EGFR.

2. Use of an antigen-binding molecule that binds to HER3 in the preparation of a medicament for treating or preventing cancer, wherein the method comprises administering an antigen-binding molecule that binds to EGFR.

3. A method of treating or preventing cancer, comprising administering to a subject a therapeutically or preventively effective amount of (i) an antigen-binding molecule that binds to HER3 and (ii) an antigen-binding molecule that binds to EGFR.

4. The antigen-binding molecule according to claim 1, the use according to claim 2, or the method according to claim 3, wherein the method further comprises administering a taxane-like substance.

5. An antigen-binding molecule that binds to HER3, and a method of using it to treat or prevent cancer, wherein the method comprises administering a taxane-like substance.

6. Use of an antigen-binding molecule that binds to HER3 in the preparation of a medicament for treating or preventing cancer, wherein the method includes the administration of a taxane-like substance.

7. A method of treating or preventing cancer, comprising administering to a subject a therapeutically or preventively effective amount of (i) an antigen-binding molecule that binds to HER3 and (ii) a taxane.

8. An antigen-binding molecule that binds to HER3, used in a method of treating or preventing cancer, wherein the method comprises administering a taxane-like substance and a nucleoside analogue.

9. Use of an antigen-binding molecule that binds to HER3 in the preparation of a medicament for treating or preventing cancer, wherein the method comprises administering a taxane-like substance and a nucleoside analog.

10. A method of treating or preventing cancer, comprising administering to a subject a therapeutically or preventively effective amount of (i) an antigen-binding molecule that binds to HER3, (ii) a taxane, and (iii) a nucleoside analogue.

11. An antigen-binding molecule that binds to HER3, used for the treatment or prevention of cancer, wherein the method comprises administering a nucleoside analogue.

12. Use of an antigen-binding molecule that binds to HER3 in the preparation of a medicament for treating or preventing cancer, wherein the method includes the administration of a nucleoside analog.

13. A method of treating or preventing cancer, comprising administering to a subject a therapeutically or preventively effective amount of (i) an antigen-binding molecule that binds to HER3 and (ii) a nucleoside analogue.

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

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

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

17. A drug combination comprising (i) an antigen-binding molecule that binds to HER3, (ii) a nucleoside analogue and (iii) a taxane.

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

19. The pharmaceutical combination according to any one of claims 14 to 18, a method for treating or preventing cancer.

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

21. A method of treating or preventing cancer, comprising administering to a subject a therapeutically or preventively effective amount of a combination of drugs according to any one of claims 14 to 18.

22. The antigen-binding molecule, the use, the method, the pharmaceutical combination, or the pharmaceutical regimen according to any one of claims 1 to 21, wherein the antigen-binding molecule binding to HER3 binds to the HER3 region shown in SEQ ID NO:

77.

23. The antigen-binding molecule, the use, the method, the pharmaceutical combination, or the pharmaceutical regimen according to any one of claims 1 to 22, wherein the antigen-binding molecule binding to HER3 comprises: (i) Heavy chain variable (VH) regions containing the following CDRs: HC-CDR1 with the amino acid sequence of SEQ ID NO:40 HC-CDR2 with the amino acid sequence SEQ ID NO:43 HC-CDR3 having the amino acid sequence of SEQ ID NO:48; and (ii) Light chain variable (VL) regions containing the following CDRs: LC-CDR1 with the amino acid sequence SEQ ID NO:66 LC-CDR2 with the amino acid sequence SEQ ID NO:69 LC-CDR3 having the amino acid sequence of SEQ ID NO:

74.

24. The antigen-binding molecule, the use, the method, the pharmaceutical combination, or the pharmaceutical regimen according to any one of claims 1 to 23, wherein the antigen-binding molecule binding to HER3 comprises: (i) VH region containing the following CDRs: HC-CDR1 with the amino acid sequence of SEQ ID NO:38 HC-CDR2 with the amino acid sequence SEQ ID NO:42 HC-CDR3 having the amino acid sequence of SEQ ID NO:45; and (ii) VL regions containing the following CDRs: LC-CDR1 with the amino acid sequence of SEQ ID NO:63 LC-CDR2 with the amino acid sequence SEQ ID NO:67 LC-CDR3 having the amino acid sequence of SEQ ID NO:

70.

25. The antigen-binding molecule, the use, the method, the pharmaceutical combination, or the pharmaceutical regimen according to any one of claims 1 to 24, wherein the antigen-binding molecule binding to HER3 comprises: The VH region contains an amino acid sequence that has at least 70% sequence identity with the amino acid sequence of SEQ ID NO:33; and The VL region contains an amino acid sequence that has at least 70% sequence identity with the amino acid sequence of SEQ ID NO:

58.

26. The antigen-binding molecule, the use, the method, the pharmaceutical combination, or the pharmaceutical regimen according to any one of claims 1 to 25, wherein the antigen-binding molecule binding to HER3 comprises: A polypeptide comprising or consisting of an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:75; and A polypeptide comprising or consisting of an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:

76.

27. The antigen-binding molecule, the use, the method, the pharmaceutical combination, or the combination of pharmaceuticals according to any one of claims 1 to 3, 7 to 9, 13, 14, 16, 18, or 19 to 26, wherein the taxane-like substance is docetaxel or albumin-bound paclitaxel.

28. The antigen-binding molecule, the use, the method, the pharmaceutical combination, or the combination of pharmaceuticals 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. The antigen-binding molecule, the use, the method, the pharmaceutical combination, or the combination of pharmaceuticals 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. The antigen-binding molecule, the use, the method, the pharmaceutical combination, or the combination of pharmaceuticals according to any one of claims 10 to 14, or 17 to 27, wherein, Antigen-binding molecules that bind to EGFR include: (i) Heavy chain variable (VH) regions containing the following CDRs: HC-CDR1 with the amino acid sequence SEQ ID NO:92 HC-CDR2 with the amino acid sequence SEQ ID NO:93 HC-CDR3 having the amino acid sequence of SEQ ID NO:94; and (ii) Light chain variable (VL) regions containing the following CDRs: LC-CDR1 with the amino acid sequence of SEQ ID NO:96 LC-CDR2 with the amino acid sequence SEQ ID NO:97 LC-CDR3 having the amino acid sequence of SEQ ID NO:

98.

31. The antigen-binding molecule, the use, the method, the pharmaceutical combination, or the combination of pharmaceuticals according to any one of claims 10 to 14, 17 to 27, or 30, wherein, Antigen-binding molecules that bind to EGFR include: The VH region comprises an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:91; and The VL region contains an amino acid sequence that has at least 70% sequence identity with the amino acid sequence of SEQ ID NO:

95.

32. The antigen-binding molecule, the use, the method, the pharmaceutical combination, or the combination of pharmaceuticals according to any one of claims 10 to 14, 17 to 27, 30, or 31, wherein, Antigen-binding molecules that bind to EGFR include: A polypeptide comprising or consisting of 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 consisting of an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:

100.

33. The antigen-binding molecule, use, method, or pharmaceutical combination according to any one of claims 1 to 13 or 19 to 32, wherein the cancer is: a cancer comprising cells expressing / overexpressing EGFR family members, or a cancer comprising cells expressing / overexpressing HER3, a cancer comprising cells expressing / overexpressing EGFR, a cancer comprising cells expressing / overexpressing both HER3 and EGFR, a cancer comprising cells having mutations leading to increased HER3 ligand expression, a cancer comprising cells having mutations leading to increased EGFR ligand expression, or a cancer comprising cells having N... Cancers containing cells with RG gene fusion, cancers containing cells with NRG1 gene fusion, or cancers containing cells with NRG2 gene fusion, solid tumors, hematologic malignancies, squamous cell carcinoma, EGFR-amplified squamous cell carcinoma, breast cancer, invasive breast cancer, ductal carcinoma, metastatic breast cancer, triple-negative breast cancer, HER2-positive breast cancer, gastric cancer, gastric tumor, gastric adenocarcinoma, gastrointestinal adenocarcinoma, colorectal cancer, metastatic colorectal cancer, colon cancer, colorectal tumor, colorectal adenocarcinoma, colon adenocarcinoma, head and neck cancer, head and neck squamous cell carcinoma, lung cancer, non-small cell lung cancer. Cancer, Lung adenocarcinoma, Invasive pulmonary mucinous 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, Ovarian tumor, Ovarian serous adenocarcinoma, Ovarian serous cystadenocarcinoma, Fallopian tube cancer, Kidney cancer, Renal cell carcinoma, Clear cell renal carcinoma, Renal cell adenocarcinoma, Papillary cell renal carcinoma, Pancreatic cancer, Exocrine carcinoma, Pancreatic adenocarcinoma, Pancreatic duct adenocarcinoma, Advanced pancreatic duct adenocarcinoma, Metastatic pancreatic duct adenocarcinoma, Cervical cancer, Cervical squamous cell carcinoma, Skin cancer, Melanoma, Oral cancer, Oropharyngeal cancer, Esophageal cancer, Tubular squamous cell carcinoma, esophageal adenocarcinoma, liver cancer, hepatocellular carcinoma, bile duct carcinoma, gallbladder cancer, uterine cancer, endometrial cancer, uterine sarcoma, thyroid cancer, thyroid adenoma, pheochromocytoma, paraganglioma, bladder cancer, bladder urothelial carcinoma, prostate cancer, prostate adenocarcinoma, retinoblastoma, sarcoma, soft tissue sarcoma, peritoneal cancer, thymoma, neuroendocrine tumor, nasopharyngeal neuroendocrine tumor, cutaneous squamous cell carcinoma, astrocytoma, low-grade astrocytoma, high-grade astrocytoma, anaplastic astrocytoma, and glioblastoma multiforme.

34. The antigen-binding molecule, use, method, or combination of drugs according to any one of claims 1 to 13 or 19 to 33, wherein the cancer is selected from: cancers including cells expressing / overexpressing HER3, cancers including cells expressing / overexpressing EGFR, cancers including cells expressing / overexpressing both 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 carcinoma, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, advanced pancreatic ductal adenocarcinoma, metastatic pancreatic ductal adenocarcinoma, lung cancer, squamous cell lung cancer, squamous non-small cell lung cancer, advanced squamous non-small cell lung cancer, metastatic squamous non-small cell lung cancer, and lung squamous cell carcinoma.

35. The antigen-binding molecule, use, method, or pharmaceutical combination 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 non-small cell lung cancer, advanced squamous non-small cell lung cancer, metastatic squamous non-small cell lung cancer, pancreatic cancer, exocrine carcinoma, pancreatic ductal adenocarcinoma, advanced pancreatic ductal adenocarcinoma, metastatic pancreatic ductal adenocarcinoma.

36. The antigen-binding molecule, use, method, or combination of drugs according to any one of claims 1 to 13 or 19 to 35, wherein the cancer is: a cancer comprising cells with mutations that lead to increased expression of the HER3 ligand, a cancer comprising cells with NRG gene fusions, a cancer comprising cells with NRG1 gene fusions, or a cancer comprising cells with NRG2 gene fusions.

37. The antigen-binding molecule, use, method, or pharmaceutical combination according to any one of claims 1 to 13 or 19 to 36, wherein, The cancer cells contain NRG gene fusions selected from the group consisting of: 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-N RG1, PARP8-NRG1, ROCK1-NRG1, DPYSL2-NRG1, ATP1B1-NRG1, CDH6-NRG1, APP-NRG1, AKAP13-NRG1, THBS1-NRG1, FO XA1-NRG1, PDE7A-NRG1, RAB3IL1-NRG1, CDK1-NRG1, BMPRIB-NRG1, TNFRSF10B-NRG1, MCPH1-NRG1, and SLC12A2-NRG2.

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