Cancer treatment and prevention using HER3 antigen-binding molecules

Abstract

This disclosure provides the use of an antigen-binding molecule that binds to HER3 for the treatment or prevention of HER3-related cancers that do not contain genetic diversity resulting in increased expression of MET or increased activity of its gene product.

Description

Technical Field

[0001] This application claims priority to U.S. Patent Application No. 63 / 457,514, filed Apr. 6, 2023, the content and elements of which are incorporated herein by reference for all purposes.

[0002] This disclosure relates to the fields of molecular biology, more specifically, antibody technology, and methods of medical treatment and prevention.

Background Art

[0003] A significant number of transmembrane protein kinases are associated with carcinogenesis (Roskoski Jr 2004). Human epidermal growth factor receptor 3 (HER3) has been identified as a major signaling hub that activates major growth factor signaling pathways, such as the MAPK / ERK pathway and the PI3K / AKT / mTOR pathway, through the formation of heterodimers with either epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2) (Gala and Chandarlapaty, Clinical Cancer Research (2014) 6:1410-1416) (Haikala and Janne, Clinical Cancer Research (2021) 27(13):3528-3539). HER3 activation has emerged as an important mechanism with respect to both tumor progression and acquired resistance to standard therapies in multiple indications. Current HER3 targeting approaches have not shown the expected clinical effects. Suboptimal inhibition of HER3-mediated signaling is one possible explanation.

[0004] WO / 2023 / 017151 discloses the treatment and prevention of cancer characterized by the presence or absence of mutations in genes encoding factors involved in HER3-mediated signaling.

Summary of the Invention

Means for Solving the Problems

[0005] In a first aspect, the disclosure provides an antigen-binding molecule that binds to HER3 for use in methods of treating or preventing HER3-related cancers that do not contain genetic variation resulting in increased expression of MET or increased activity of its gene product.

[0006] This disclosure further provides the use of an antigen-binding molecule that binds to HER3 in the manufacture of a pharmaceutical product for use in the treatment or prevention of HER3-related cancers that do not contain genetic diversity resulting in increased expression of MET or increased activity of its gene product.

[0007] The disclosure further provides a method for treating or prophylactically treating HER3-related cancers that do not exhibit genetic diversity resulting in increased expression of MET or increased activity of its gene product, the method comprising the step of administering a therapeutically effective or prophylactically effective amount of an antigen-binding molecule that binds to HER3 to the target.

[0008] In some embodiments according to various aspects of this disclosure, HER3-related cancers are characterized by (i) not having genetic diversity resulting in increased expression of KRAS or increased activity of its gene product, or (ii) not having genetic diversity resulting in increased expression of PIK3CA or increased activity of its gene product (e.g., not having activating mutations to PIK3CA), or (iii) not having genetic diversity resulting in increased expression of BRAF or increased activity of its gene product, or (iv) not having genetic diversity resulting in decreased expression of PTEN or decreased activity of its gene product.

[0009] In some embodiments, HER3-related cancers do not include genetic diversity that results in (i) increased expression of KRAS or increased activity of its gene product, (ii) increased expression of PIK3CA or increased activity of its gene product (e.g., not including activating mutations to PIK3CA), (iii) increased expression of BRAF or increased activity of its gene product, or (iv) decreased expression of PTEN or decreased activity of its gene product.

[0010] In some embodiments, HER3-related cancers do not include (i) MET amplification, (ii) activating mutations to KRAS, (iii) activating mutations to PIK3CA, (iv) activating mutations to BRAF, or (iv) PTEN deletion.

[0011] In some embodiments, HER3-related cancers are characterized by (i) lack of MET amplification, (ii) being homozygous for the wild-type allele of KRAS, (iii) being homozygous for the wild-type allele of PIK3CA, (iv) being homozygous for the wild-type allele of BRAF, and (iv) being homozygous for the wild-type allele of PTEN.

[0012] In some embodiments, HER3-related cancers include amplification of one or more genes located on chromosome 3 q. In some embodiments, HER3-related cancers include amplification of one or more genes located within chromosome 3 q26-q28. In some embodiments, HER3-related cancers include amplification of one or more genes selected from TP63, SOX2, and PIK3CA.

[0013] In some embodiments, HER3-related cancers include amplification of one or more genes located on chromosome 7p. In some embodiments, HER3-related cancers include amplification of one or more genes located within chromosome 7p11. In some embodiments, HER3-related cancers include amplification of EGFR.

[0014] In some embodiments, HER3-related cancers include deletions of one or more genes located on chromosome 3 p. In some embodiments, HER3-related cancers include deletions of one or more genes located on chromosome 3 p21. In some embodiments, HER3-related cancers include deletions of TUSC2.

[0015] In some embodiments, HER3-related cancers include genetic diversity that results in increased expression of ligands for HER3. In some embodiments, HER3-related cancers include NRG gene fusion, NRG1 gene fusion, or NRG2 gene fusion.

[0016] In some embodiments, HER3-related cancers include CLU-NRG1, CD74-NRG1, DOC4-NRG1, SLC3A2-NRG1, RBPMS-NRG1, WRN-NRG1, SDC4-NRG1, RAB2IL1-NRG1, VAMP2-NRG1, KIF13B-NRG1, THAP7-NRG1, SMAD4-NRG1, MDK-NRG1, TNC-NRG1, DIP2B-NRG1, MRPL13-NRG1, PARP8- This includes NRG gene fusions selected from 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.

[0017] This disclosure further provides an antigen-binding molecule that binds to HER3 for use in a method for treating or prophylacticizing HER3-related cancers involving amplification of one or more genes located on chromosome 3q. This disclosure further provides the use of an antigen-binding molecule that binds to HER3 for use in the manufacture of a pharmaceutical for treating or prophylacticizing HER3-related cancers involving amplification of one or more genes located on chromosome 3q. This disclosure further provides a method for treating or prophylacticizing HER3-related cancers involving amplification of one or more genes located on chromosome 3q, comprising the step of administering a therapeutically effective or prophylactically effective amount of an antigen-binding molecule that binds to HER3 to the target. In some embodiments, the one or more genes located on chromosome 3q are located within chromosome 3q26-q28. In some embodiments, one or more genes are selected from TP63, SOX2, and PIK3CA.

[0018] This disclosure further provides an antigen-binding molecule that binds to HER3 for use in methods of treating or prophylacticizing HER3-related cancers involving amplification of one or more genes located on chromosome 7p. This disclosure further provides the use of an antigen-binding molecule that binds to HER3 for use in the manufacture of a pharmaceutical for treating or prophylacticizing HER3-related cancers involving amplification of one or more genes located on chromosome 7p. This disclosure further provides a method of treating or prophylacticizing HER3-related cancers involving amplification of one or more genes located on chromosome 7p, comprising the step of administering a therapeutically effective or prophylactically effective amount of an antigen-binding molecule that binds to HER3 to the subject. In some embodiments, the one or more genes located on chromosome 7p are located within chromosome 7p11. In some embodiments, the gene is EGFR.

[0019] This disclosure further provides an antigen-binding molecule that binds to HER3 for use in methods for treating or prophylacticizing HER3-related cancers involving deletions of one or more genes located on chromosome 3p. This disclosure further provides the use of an antigen-binding molecule that binds to HER3 for use in the manufacture of a pharmaceutical for treating or prophylacticizing HER3-related cancers involving deletions of one or more genes located on chromosome 3p. This disclosure further provides a method for treating or prophylacticizing HER3-related cancers involving deletions of one or more genes located on chromosome 3p, comprising the step of administering a therapeutically effective or prophylactically effective amount of an antigen-binding molecule that binds to HER3 to the subject. In some embodiments, the one or more genes located on chromosome 3p are located within chromosome 3p21. In some embodiments, the gene is TUSC2.

[0020] In some embodiments according to various aspects of this disclosure, HER3-related cancers include amplification of one or more genes selected from TP63, SOX2, and PIK3CA.

[0021] In some embodiments, HER3-related cancers include amplification of TP63, amplification of SOX2, and amplification of PIK3CA. This disclosure further provides an antigen-binding molecule that binds to HER3 for use in methods for treating or preventing HER3-related cancers, including genetic diversity resulting in increased expression of MET or increased activity of its gene product, wherein the method further comprises the step of administering a HER3-mediated signaling antagonist.

[0022] The disclosure further provides the use of an antigen-binding molecule that binds to HER3 for use in the manufacture of a pharmaceutical for use in the treatment or prevention of HER3-related cancers, including genetic diversity resulting in increased expression of MET or increased activity of its gene product, wherein the method further comprises the step of administering a HER3-mediated signaling antagonist.

[0023] The present disclosure further provides a method for treating or preventing HER3-related cancer in a subject comprising a genetic diversity that results in increased expression of MET or increased activity of its gene product, the method comprising administering to the subject a therapeutically effective amount or a prophylactically effective amount of an antigen-binding molecule that binds to HER3, and further comprising administering an antagonist of HER3-mediated signaling.

[0024] According to various aspects of the present disclosure, HER3-related cancer comprises (i) a genetic diversity that results in increased expression of KRAS or increased activity of its gene product, or (ii) a genetic diversity that results in increased expression of PIK3CA or increased activity of its gene product, or (iii) a genetic diversity that results in increased expression of BRAF or increased activity of its gene product, or (iv) a genetic diversity that results in decreased expression of PTEN or decreased activity of its gene product.

[0025] In some embodiments, HER3-related cancer comprises (i) a genetic diversity that results in increased expression of KRAS or increased activity of its gene product, (ii) a genetic diversity that results in increased expression of PIK3CA or increased activity of its gene product, (iii) a genetic diversity that results in increased expression of BRAF or increased activity of its gene product, and (iv) a genetic diversity that results in decreased expression of PTEN or decreased activity of its gene product.

[0026] The present disclosure further provides a method of selecting a subject for treatment with an antigen-binding molecule that binds to HER3, comprising: (a) analyzing the cancer of the subject to determine whether the cancer comprises a genetic diversity that results in increased expression of MET or increased activity of its gene product; (b) selecting the subject for treatment with an antigen-binding molecule that binds to HER3 if the cancer of the subject is determined in step (a) not to comprise such genetic diversity. Provide a method including

[0027] In some embodiments, the method (a) (i) Analyzing the cancer of the subject to determine whether the cancer includes genetic diversity that results in increased expression of KRAS or increased activity of its gene product, or (ii) Analyzing the cancer of the subject to determine whether the cancer includes an activating mutation in PIK3CA, or (iii) Analyzing the cancer of the subject to determine whether the cancer includes genetic diversity that results in increased expression of BRAF or increased activity of its gene product, or (iv) Analyzing the cancer of the subject to determine whether the cancer includes genetic diversity that results in decreased expression of PTEN or decreased activity of its gene product, and (b) Selecting the subject for treatment with an antigen-binding molecule that binds to HER3 if the cancer of the subject is determined in step (a) not to include such genetic diversity / mutation including

[0028] In some embodiments, the method (a) (i) Analyzing the cancer of the subject to determine whether the cancer includes genetic diversity that results in increased expression of KRAS or increased activity of its gene product, and (ii) Analyzing the cancer of the subject to determine whether the cancer includes an activating mutation in PIK3CA, and (iii) Analyzing the cancer of the subject to determine whether the cancer includes genetic diversity that results in increased expression of BRAF or increased activity of its gene product, and (iv) Analyzing the cancer of the subject to determine whether the cancer includes genetic diversity that results in decreased expression of PTEN or decreased activity of its gene product, as well as (b) A step of selecting a target for treatment with an antigen-binding molecule that binds to HER3, if it is determined in step (a) that the target cancer does not contain such genetic diversity / mutation. Includes.

[0029] In some embodiments, this method (c) A step in which an antigen-binding molecule that binds to HER3 is administered to the subject selected for treatment in step (b). It also includes.

[0030] The disclosure further provides a method for selecting a target for treatment with (i) an antagonist of HER3-mediated signaling, and (ii) an antigen-binding molecule that binds to HER3, (a) A step of analyzing the target cancer to determine whether the cancer contains genetic diversity that leads to increased expression of MET or increased activity of its gene product, and (b) If the target cancer is determined in step (a) to contain such genetic diversity, the step of selecting the target for treatment with (i) HER3-mediated signaling antagonists and (ii) antigen-binding molecules that bind to HER3. This provides a method that includes [something].

[0031] In some embodiments, this method (a) (i) A step of analyzing the target cancer to determine whether the cancer contains genetic diversity that leads to increased KRAS expression or increased activity of its gene product, or (ii) A step of analyzing the target cancer to determine whether the cancer contains an activating mutation to PIK3CA, (iii) A step of analyzing the target cancer to determine whether the cancer contains genetic diversity that leads to increased expression of BRAF or increased activity of its gene product, (iv) A step of analyzing the target cancer to determine whether the cancer contains genetic diversity that results in decreased expression of PTEN or decreased activity of its gene product, and (b) If the target cancer is determined in step (a) to contain such genetic diversity / mutation, the step of selecting the target for treatment with (i) HER3-mediated signaling antagonists and (ii) antigen-binding molecules that bind to HER3. Includes.

[0032] In some embodiments, this method (a) (i) a step of analyzing the target cancer to determine whether the cancer contains genetic diversity that leads to increased KRAS expression or increased activity of its gene product, and (ii) A step of analyzing the target cancer to determine whether the cancer contains an activating mutation to PIK3CA, and (iii) The step of analyzing the target cancer to determine whether the cancer contains genetic diversity that leads to increased expression of BRAF or increased activity of its gene product, and (iv) A step of analyzing the target cancer to determine whether the cancer contains genetic diversity that results in decreased expression of PTEN or decreased activity of its gene product, and (b) If the target cancer is determined in step (a) to contain such genetic diversity / mutation, the step of selecting the target for treatment with (i) HER3-mediated signaling antagonists and (ii) antigen-binding molecules that bind to HER3. Includes.

[0033] In some embodiments, this method (c) A step of administering (i) a HER3-mediated signaling antagonist and (ii) an antigen-binding molecule that binds to HER3 to the subject selected for treatment in step (b). It also includes.

[0034] In some embodiments according to various aspects of this disclosure, HER3-related cancers are selected from solid tumors, breast cancer, ductal carcinoma, gastric cancer, gastric adenocarcinoma, colorectal cancer, colorectal adenocarcinoma, head and neck cancer, squamous cell carcinoma of the head and neck, lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, kidney cancer, renal cell carcinoma, renal clear cell carcinoma, renal cell adenocarcinoma, papillary renal cell carcinoma, pancreatic cancer, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, cervical cancer, cervical squamous cell carcinoma, skin cancer, melanoma, esophageal cancer, esophageal adenocarcinoma, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, uterine cancer, endometrial cancer, thyroid cancer, thyroid cancer, pheochromocytoma, paraganglioma, bladder cancer, urothelial carcinoma of the bladder, prostate cancer, prostate adenocarcinoma, sarcoma, and thymoma.

[0035] In some embodiments, the antigen-binding molecule that binds to HER3 is selected from 10D1F, cerivanthumab, elgemtumab, patritumab, GSK2849330, lumuretuzumab, CDX-3379, AV-203, valecetamab, TK-A3, TK-A4, MP-EV20, 1A5-3D4, 9F7-F11, 16D3-C1, NG33, A5, F4, huHER3-8, REGN1400, and xenoctuzumab.

[0036] In some embodiments, the antigen-binding molecule that binds to HER3 is (i) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 40 HC-CDR2 having the amino acid sequence of SEQ ID NO: 43 HC-CDR3 having the amino acid sequence of SEQ ID NO: 48 A heavy chain variable (VH) region incorporating, and (ii) The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 66 LC-CDR2 having the amino acid sequence of SEQ ID NO: 69 LC-CDR3 having the amino acid sequence of SEQ ID NO: 74 Light chain variable (VL) region incorporating Includes.

[0037] In some embodiments, the antigen-binding molecule that binds to HER3 is (i) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 38 HC-CDR2 having the amino acid sequence of SEQ ID NO: 42 HC-CDR3 having the amino acid sequence of SEQ ID NO: 45 The VH region that incorporates, and (ii) The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 63 LC-CDR2 having the amino acid sequence of SEQ ID NO: 67 LC-CDR3 having the amino acid sequence of SEQ ID NO: 70 VL area to incorporate Includes.

[0038] In some embodiments, the antigen-binding molecule A VH region containing an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 33, and VL region containing an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 58 Includes.

[0039] In some embodiments, the antigen-binding molecule 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. Includes.

[0040] In some embodiments, according to various different aspects of this disclosure, a method for treating or preventing HER3-related cancer further includes the step of administering an EGFR antagonist.

[0041] In some embodiments, the EGFR antagonist is an antigen-binding molecule that binds to EGFR. In some embodiments, the antigen-binding molecule that binds to EGFR is (i) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 78 HC-CDR2 having the amino acid sequence of SEQ ID NO: 79 HC-CDR3 having the amino acid sequence of SEQ ID NO: 80 The VH region that incorporates, and (ii) The following CDRs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 82 LC-CDR2 having the amino acid sequence of SEQ ID NO: 83 LC-CDR3 having the amino acid sequence of SEQ ID NO: 84 VL area to incorporate Includes.

[0042] In some embodiments, the antigen-binding molecule that binds to EGFR is A VH region containing an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 77, and VL region containing an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 81 Includes.

[0043] In some embodiments, the antigen-binding molecule that binds to EGFR is 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: 85, 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: 86. Includes. explanation This disclosure is based in part on the inventors' determination that cancers containing genetic diversity resulting in elevated MET expression (particularly MET amplification) are less likely to respond well to anti-HER3 antibody therapy. Cancers lacking such genetic diversity have been identified as responsive to treatment with anti-HER3 antibodies. The inventors have found that further determination of MET amplification status, in addition to the assessment of PTEN, KRAS, PIK3CA, and BRAF mutation status as described in International Publication No. 2023 / 017151, provides a prediction of a more highly sensitive positive response to treatment with anti-HER3 antibody therapy (see Example 4).

[0044] This disclosure is further based on the inventors' determination that cancers containing genetic diversity resulting from increased expression of genes located within chromosome 3 q26–q28 (in particular, amplification of such genes) are likely to respond well to anti-HER3 antibody therapy. Cancers containing such genetic diversity have been identified as responsive to treatment with anti-HER3 antibodies.

[0045] This disclosure is further based on the inventors' determination that cancers containing genetic diversity resulting from increased expression of genes located within chromosome 3 q26–q28 (in particular, amplification of such genes) are likely to respond well to anti-HER3 antibody therapy. Cancers containing such genetic diversity have been identified as responsive to treatment with anti-HER3 antibodies. HER3 and HER3-mediated signaling HER3 (also known as ERBB3, LCCS2, and MDA-BF-1, for example) is a protein identified by UniProtP21860.

[0046] The structure and function of HER3 are described, for example, in Cho and Leahy Science (2002) 297(5585):1330-1333, Singer et al., Journal of Biological Chemistry (2001) 276, 44266-44274, Roskoski et al., Pharmacol.Res. (2014) 79:34-74, Bazley and Gullick Endocrine-Related Cancer (2005) S17-S27, and Mujoo et al., Oncotarget (2014) 5(21):10222-10236, the entirety of each of these is incorporated herein by reference. HER3 is a single-pass transmembrane ErbB receptor tyrosine kinase with an N-terminal extracellular domain (SEQ ID NO: 9) containing two leucine-rich subdomains (domains I and III, shown in SEQ ID NOs. 15 and 17, respectively) and two cysteine-rich subdomains (domains II and IV, shown in SEQ ID NOs. 16 and 18, respectively). Domain II contains a β-hairpin dimerization loop (SEQ ID NO: 19) involved in intermolecular interactions with other HER receptor molecules. The extracellular domain is linked to a cytoplasmic domain (SEQ ID NO: 11) via a transmembrane domain (SEQ ID NO: 10). The cytoplasmic domain contains a near-membrane segment (SEQ ID NO: 12), a protein kinase domain (SEQ ID NO: 13), and a C-terminal segment (SEQ ID NO: 14).

[0047] In this specification, "HER3" refers to HER3 from any species and includes HER3 isoforms, fragments, variants (including mutants), or homologs from any species.

[0048] As used herein, a protein “fragment,” “variant,” or “homolog” may be characterized by having at least 60%, preferably 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% single amino acid sequence identity with respect to the amino acid sequence of a reference protein (e.g., a reference isoform). In some embodiments, a reference protein fragment, variant, isoform, and homolog may be characterized by the ability to perform the function performed by the reference protein.

[0049] A "fragment" generally refers to a portion of a reference protein. A "variant" generally refers to a protein that has an amino acid sequence that contains one or more amino acid substitutions, insertions, deletions, or other modifications compared to the amino acid sequence of the reference protein, but retains a considerable degree of sequence identity (e.g., at least 60%) to the amino acid sequence of the reference protein. An "isoform" generally refers to a variant of a reference protein that is expressed by the same species as the reference protein (e.g., human HER3 isoforms 1-5 are all isoforms of each other). A "homolog" generally refers to a variant of a reference protein that is produced by a different species than the reference protein. For example, human HER3 isoform 1 (P21860-1, v1; SEQ ID NO: 1) and rhesus monkey HER3 (UniProt: F7HEH3-1, v2; SEQ ID NO: 20) are homologs of each other. Homologs include orthologues.

[0050] A "fragment" of a reference protein can be of any length (depending on the number of amino acids), but may in some cases be at least 20% of the length of the reference protein (i.e., the protein from which the fragment originates) and may have one maximum length of 50%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the length of the reference protein.

[0051] A HER3 fragment may have one minimum length 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 one maximum length 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.

[0052] In some embodiments, HER3 is HER3 from mammals (e.g., primates (rhesus macaques, crab-eating macaques, non-human primates, or humans) and / or rodents (e.g., rats or mice) HER3). Isoforms, fragments, variants, or homologs of HER3 may be characterized by having at least 70%, preferably 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of a single amino acid sequence identity with respect to the amino acid sequence of an immature or mature HER3 isoform from a given species, e.g., humans.

[0053] Isoforms, fragments, variants, or homologs may, depending on the circumstances, be functional isoforms, fragments, variants, or homologs that possess the functional properties / activities of, for example, reference HER3 (e.g., human HER3 isoform 1), as determined by analysis in appropriate assays for functional properties / activity. For example, an isoform, fragment, variant, or homolog of HER3 may show association with one or more of HER2, NRG1 (types I, II, III, IV, V, or VI), or NRG2 (α or β).

[0054] 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% amino acid sequence identity with respect to one of sequence numbers 1 to 8.

[0055] 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% amino acid sequence identity with one of sequence numbers 9 to 19, for example, 9, 16, or 19.

[0056] HER3-mediated signaling involves receptor heteromultimerization (i.e., with other ErBB receptors, e.g., HER2, EGFR) and, consequently, autophosphorylation of tyrosine residues in the cytoplasm by the protein kinase domain. HER3 lacks kinase activity and does not form stable homodimers. Therefore, for signal transduction to occur, HER3 must be transphosphated by binding to a kinase-active heterodimer partner (e.g., EGFR or HER2) (Berger MB et al., FEBS Lett 2004;569:332~6; Kim HH et al., Biochem J 1998;334:189~95).

[0057] The multimerization (e.g., dimerization) of HER receptor family members is required for the activation of cell growth signaling pathways, and 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 structure and an "open" active structure. In the "open" active structure, the dimerization arms within domain II are exposed, enabling dimerization along the domain II dimerization interface, particularly via the cysteine-rich CR1 region. (Carraway, KL et al., Nature, 1997.387(6632):512~6; Riese, DJ et al., Mol Cell Biol, 1995.15(10):5770~6; Harari, D. et al., Oncogene, 1999.18(17):2681~9; Zhang, D. et al., Proc Natl Acad Sci USA, 1997.94(18):9562~7; Meyer et al., Nature, 1995.378(6555):386~90; Jura, N. et al., Proc Natl Acad Sci USA, 2009.106(51):21608~13; Fornaro, L et al., Nat Rev Gastroenterol Hepatol, 2011.8(7):369~83; Mota et al., Oncotarget (2015) 5:89284~306). HER3 is "activated" when the equilibrium shifts in favor of the open structure, increasing the likelihood of forming an active heterodimer. Conventional models of activation are ligand-dependent, meaning that when HER3 in the open structure is stabilized by the binding of its ligand, such as neuregulin (NRG), for example, NRG1 (also known as heregulin, HRG) or NRG2, the equilibrium shifts. Furthermore, since either dimerizing partner binds to HER3 and transiently stabilizes it in the open structure, the presence of either dimerizing partner at a sufficient concentration shifts the equilibrium in favor of the open structure.This is known as ligand-independent activation (Jura, N. et al., Proc Natl Acad Sci USA, 2009.106(51):21608~13; Fornaro, L. et al., Nat Rev Gastroenterol Hepatol, 2011.8(7):pp. 369~83; Mota et al., Oncotarget (2015) 5:89284~306).

[0058] In this specification, “HER3-mediated signaling” refers to signaling mediated by HER3 and / or HER3-containing multimeric ErBB family member receptor complexes. “Signaling” refers to signaling and other cellular processes that govern cellular activity. HER3-mediated signaling may be mediated by HER3 receptor-containing complexes, e.g., heteromultimeric complexes containing HER3 and other HER receptors (e.g., HER2, EGFR). HER3-mediated signaling may be ligand-dependent, e.g., triggered by NRG (e.g., NRG1, NRG2) binding, or ligand-independent.

[0059] HER3-mediated signaling proceeds intracellularly via the MAPK / ERK and PI3K / AKT / mTOR pathways, promoting cell survival and proliferation. HER3-mediated signaling is described, for example, in Gala and Chandarlapaty, Clin Cancer Res. (2014) 20(6):1410-1416, Mishra et al., Oncol Rev. (2018) 12(1):355, Baselga et al., Nat Rev Cancer (2009) 9:463-75, Yarden et al., Nat Rev Mol Cell Biol (2001) 2:35052073, Mota et al., Oncotarget (2015) 5:89284-306, and Haikala and Janne, Clin. Cancer Res. (2021) 27:3528-39, all of which are incorporated herein by reference.

[0060] Phosphorylated tyrosine residues in the protein kinase domain of the HER3-containing receptor complex recruit the adapter / effector protein GRB2 via interaction with its SH2 domain. Upon ligand stimulation, the activated receptor (EGFR / HER2) autophosphorylates, providing phosphotyrosine residues for recruiting GRB2. GRB2 binds to the guanine nucleotide exchange factor SOS via its SH3 domain. Activated SOS in the GRB2-SOS complex promotes the removal of GDP from Ras family GTPases, e.g., H-Ras, N-Ras, and K-Ras, and their activation. Activated RasGTPases then activate RAF kinases, e.g., A-Raf, B-Raf, and C-Raf. RAF kinases then phosphorylate and activate MEK1 and MEK2, which in turn phosphorylate and activate MAPK (also known as ERK). Activated MAPK can directly regulate the activity of transcription factors, such as c-Myc. Activated MAPK further upregulates translation from mRNA to protein through phosphorylation of RSK, and consequently, phosphorylation and activation of the 40S ribosomal protein S6. Activated MAPK further phosphorylates and activates MNK, which in turn phosphorylates and activates the transcription factor CREB.

[0061] Phosphorylated tyrosine residues in the protein kinase domain of HER3 further recruit the p85 subunit of PI3K via its SH2 domain. The association of p85 triggers allosteric activation of the lipid kinase p100α subunit of PI3K. Activated PI3K causes conversion from PIP2 to PIP3, which recruits AKT, which is then phosphorylated and activated by mTORC2 and PDK1. Phosphorylated AKT has a number of activities, including activation of CREB and mTOR. PTEN antagonizes signaling via the PI3K / AKT / mTOR pathway by dephosphorylating PIP3 to PIP2, and PP2A inhibits the PI3K / AKT / mTOR pathway by dephosphorylating AKT.

[0062] The oncogenic Src homology region 2 protein tyrosine phosphatase 2 (SHP2) promotes tumor progression and functions as a central hub linking multiple oncogenic signaling pathways, such as PI3K / Akt and Ras / Raf / MAPK (Dong et al., Front.Cell Dev.Biol., March 11, 2021). GAB2 binds to GRB2, is phosphorylated at multiple tyrosine residues, and can bind to the SH2 domain of SHP2 and p85 (Adams et al., Mol Cancer Res. October 2012;10(10):1265~70; Liu et al., Proc.Natl.Acad.Sci.USA(2016)113, 984~989). These interactions induce conformational changes, mitigating autoinhibition of the SHP2 catalytic site (Neel et al., Trends Biochem Sci. June 2003; 28(6):284~93) and mitigating p85 inhibition on the p110 catalytic subunit of PI3K (Cuevas et al., J Biol Chem. July 20, 2001; 276(29):27455~6). SHP2 has been shown to activate RAS through direct dephosphorylation of RAS (Bunda et al., Nat Commun. November 30, 2015; 6():8859), inhibition of RASGAP (RAS GTPase activating protein) (Neel et al., Trends Biochem Sci. June 2003; 28(6):284~93), and inhibition of SPRY (Hanafusa et al., J Biol Chem. May 28, 2004; 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).

[0063] STAT3 and STAT5 proteins are transcription factors that enhance signaling via the PI3K / AKT signaling cascade by increasing the expression of p85α, p110α, and AKT1 (Radler et al., Mol Cell Endocrinol. 2017 Aug. 15;451:31~39). HER3-mediated activation of STAT3 leads to upregulation of SOX2 expression and promotes survival. In response to activation by JAK2, phosphorylated STAT5 binds to the SH2 domain of the p85α regulatory subunit of PI3K in a PRL signaling-dependent manner, suggesting that STAT5 may also be directly involved in the signaling of the PI3K complex. Another kinase that phosphorylates EGFR is the cytokine-regulating tyrosine kinase Jak2, and therefore MAPK activation is possible even in kinase-deficient mutants of EGFR (Mishra et al., Oncol Rev. (2018) 12(1):355, Baselga et al., Nat Rev Cancer (2009) 9:463~75). Collective observations in genetic models overexpressing or lacking active STAT5 and AKT, or expressing mutant PTEN, support the view that the function of STAT5 as a survival factor during normal mammary development and as an oncogene during mammary carcinogenesis is mediated by the PI3K / AKT pathway (Radler et al., Mol Cell Endocrinol. 2017 Aug. 15;451:31~39).

[0064] The proto-oncogene MET has been shown to phosphorylate and activate HER3. See Frazier et al., Oncogene(2019)38(11):1936-1950. Increased MET expression has been shown to upregulate HER3 phosphorylation. HER3 preferentially interacts with MET during its maturation along its secretory pathway, leading to the accumulation of phosphorylated HER3 in the Golgi apparatus.

[0065] The PI3K / AKT signaling pathway is commonly altered by gene amplification and / or mutation in certain cancers. The frequently amplified chromosomal region 3q26–3q28 contains PIK3CA, as well as the cell lineage genes TP63 and SOX2. TP63 is a member of the TP53 gene family and is expressed in the basal compartments of the skin, esophagus, lung airways, and larynx during development and homeostasis. TP63 is used as a diagnostic marker for adenocarcinoma versus squamous cell carcinoma in lung and esophageal cancers. Preclinical data suggest that in SCC, TP63 modulates NRG1 expression (see, e.g., Hedge et al., eLife. (2019) 8:e46551) and that the HER3 signaling pathway is active in TP63-amplified squamous cell carcinoma. Genetic diversity, alleles, and genotypes Aspects and embodiments of this disclosure relate to therapeutic and prophylactic interventions for the treatment / prevention of cancer characterized by the absence or presence of specific genetic diversity in genes encoding factors involved in HER3-mediated signaling.

[0066] In particular, this disclosure relates to cancers characterized by the absence or presence of genetic diversity resulting in increased / decreased gene and / or protein expression of genes encoding factors involved in HER3-mediated signaling, or increased / decreased activity of gene products of genes encoding factors involved in HER3-mediated signaling.

[0067] The genetic diversity intended in accordance with this disclosure includes mutations, gene amplification, and gene deletions. As used herein, “mutation” refers to a difference from a reference nucleotide sequence, for example, the most common nucleotide sequence of a given gene (which may be called the “wild-type” nucleotide sequence). In some embodiments, a mutation may be one or more of the following from the reference sequence (e.g., the wild-type sequence): nucleotide polymorphisms (e.g., single nucleotide polymorphisms (SNPs) or polynucleotide polymorphisms (MNPs)), insertions, deletions, frameshift mutations, missense mutations, or translocations.

[0068] Nucleotide polymorphisms (NNPs) may involve substitutions of bases in a reference sequence with other non-identical bases (e.g., SNPs), or substitutions of two or more bases in a reference sequence with non-identical bases (e.g., MNPs). Insertions refer to the introduction of one or more nucleotides into the nucleotide sequence of a reference sequence. Deletions refer to the removal / excision of one or more nucleotides from the nucleotide sequence of a reference sequence. Frameshift mutations refer to insertion or deletion mutations that alter the reading frame of translation from RNA encoded by the mutant nucleotide sequence. Such frameshift mutations may involve insertions / deletions of several nucleotides that are not divisible by three. Missense mutations refer to substitutions (or insertions or deletions) that do not alter the amino acid sequence of the peptide / polypeptide translated from RNA encoded by the mutant nucleotide sequence. Such mutations may result in (a) replacement of one or more nucleotides with non-identical nucleotides, provided that the codon containing the unsubstituted nucleotide and the codon containing the substituted nucleotide both encode the same amino acid (as a result of genetic code degeneracy). Other such missense mutations can occur in non-protein coding regions of nucleotide sequences, such as introns. Translocation refers to a large-scale substitution of a nucleotide, or a sequence of nucleotides, within a reference sequence by a non-identical nucleotide / sequence of nucleotides. Translocation occurs, for example, as a result of recombination between nucleotide sequences donated on different chromosomes.

[0069] As used herein, “activating mutation” refers to a mutation that is known or predicted to result in an increased level of expression of the relevant gene (or protein), and / or a mutation that is known or predicted to result in an increased activity of the product of that gene. An activating mutation may result in, in cells containing one or more alleles of the gene containing the activating mutation, the following: increased transcription of the gene; increased levels of the RNA encoded by the gene; decreased degradation of the RNA encoded by the gene; increased levels of the gene product; increased levels of the peptide / polypeptide encoded by the gene; increased levels of normal splicing of the premRNA encoded by the gene; increased translation of the mRNA encoding the peptide / polypeptide encoded by the gene; increased levels of normal post-translational processing of the peptide / polypeptide encoded by the gene; increased levels of normal transport of the peptide / polypeptide encoded by the gene; decreased degradation of the peptide / polypeptide encoded by the gene; increased levels of one or more functional properties presented by the gene product; increased levels of one or more functional properties presented by the peptide / polypeptide encoded by the gene; novel functional properties presented by the gene product; and / or one or more novel functional properties presented by the peptide / polypeptide encoded by the gene. In some embodiments, the activating mutation according to this disclosure is not an amplification of the relevant gene and does not include amplification.

[0070] Conversely, an "inactivating mutation" refers to a mutation that results in a decrease in the level of expression of a given gene, and / or a decrease in the activity of the product of that gene. In cells containing one or more alleles of a gene containing the inactivating mutation, an inactivating mutation may result in: decreased transcription of the gene; decreased levels of RNA encoded by the gene; increased degradation of RNA encoded by the gene; decreased levels of the product of the gene; decreased levels of peptides / polypeptides encoded by the gene; decreased levels of normal splicing of premRNA encoded by the gene; decreased translation of mRNA encoding the peptides / polypeptides encoded by the gene; decreased levels of normal post-translational processing of the peptides / polypeptides encoded by the gene; decreased levels of normal transport of the peptides / polypeptides encoded by the gene; increased degradation of the peptides / polypeptides encoded by the gene; decreased levels of one or more functional properties presented by the product of the gene; and / or decreased levels of one or more functional properties presented by the peptides / polypeptides encoded by the gene. In some embodiments, the inactivating mutations according to this disclosure are not deletions of the relevant gene and do not include deletions of the gene.

[0071] As used herein, “amplification” refers to an increase in the copy number of a given gene or fragment. Therefore, “amplification” of a given reference gene refers to providing one or more additional copies of the given gene or fragment to the copy number of the gene / fragment present in a healthy (e.g., non-cancerous) diploid cell. Thus, a cell containing amplification of a given reference gene contains one or more additional copies of the given gene or fragment to the copy number of the gene / fragment present in a healthy (e.g., non-cancerous) diploid cell. In some embodiments, a cell containing amplification of a given reference gene / fragment contains three or more copies of the related gene / fragment. In some embodiments, a cell contains one of three, four, five, six, seven, eight, nine, or ten or more copies of the related gene / fragment.

[0072] The amplifications described herein include the term "gain," which may be used in the art to describe a relatively small increase in the copy number of a given gene or fragment (e.g., an increase to three or four copies of the relevant gene / fragment).

[0073] As used herein, “gene deletion” refers to a reduction in the copy number of a given gene or fragment. Therefore, “deletion” of a given reference gene refers to a reduction in the copy number of the given gene or fragment compared to the copy number of the gene / fragment present in a healthy (e.g., non-cancerous) diploid cell. Thus, a cell containing a deletion of a given reference gene has a reduction in the copy number of the given gene or fragment compared to the copy number of the gene / fragment present in a healthy (e.g., non-cancerous) diploid cell. In some embodiments, a cell containing a deletion of a given reference gene / fragment contains fewer than two copies of the associated gene / fragment. In some embodiments, a cell contains zero or one copy of the associated gene / fragment.

[0074] The gene deletions described herein include "shallow" and "deep" deletions. A shallow deletion can be a heterozygous deletion, i.e., one copy of the gene / fragment is deleted. A deep deletion can be a homozygous deletion, i.e., both copies of the gene / fragment are deleted.

[0075] A gene fragment relating to this disclosure may include a sequence of nucleotides of the reference gene that constitutes at least 2% of the complete nucleotide sequence of the reference gene, for example, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, or at least 50%.

[0076] Gene amplification and deletion can be evaluated using copy number analysis algorithms, such as Genomic Identification of Significant Targets in Cancer (GISTIC) 2.0, as described, for example, by Mermel et al., Genome Biology, 12:R41.

[0077] The genetic diversity described herein may result in an increase or decrease in the expression of a given gene. "Expression" may refer to gene expression and / or protein expression. Gene expression may be assessed using techniques that provide detection and / or quantification of RNA transcribed from the relevant gene and / or RNA encoding the gene product encoded by the relevant gene. Such techniques include, for example, quantitative real-time PCR (qRT-PCR). Protein expression may be assessed using techniques that provide detection and / or quantification of peptides / polypeptides encoded by the relevant gene. Such techniques include, for example, antibody-based methods such as Western blotting, immunohistochemistry, immunocytochemistry, and flow cytometry.

[0078] The protein expression of a given gene can also be understood as the expression of the related protein encoded by that gene. For example, "MET protein expression" can be called "c-Met expression."

[0079] The genetic diversity provided in this disclosure may result in increased or decreased activity of the gene product of a given gene. As used herein, “gene product” refers to a molecule produced by gene expression from a given gene. A gene product may be RNA encoded by a gene, e.g., RNA transcribed from a gene, or RNA produced by post-transcriptional processing of RNA transcribed from a gene. A gene product may be a peptide / polypeptide encoded by a gene, e.g., a peptide / polypeptide translated from RNA transcribed from a gene (e.g., after post-transcriptional processing), or a peptide / polypeptide produced by post-translational processing of a protein translated from RNA transcribed from a gene. In some embodiments, the gene product is a peptide / polypeptide encoded by a gene.

[0080] The activity of a gene product (e.g., a peptide / polypeptide encoded by the gene) can be any of the functional properties that the gene product presents. In some embodiments, the activity of a gene product is the functional property presented by the gene product encoded by the wild-type allele of the relevant gene. For example, the activity of the MET gene product can be the functional property presented by c-Met, such as tyrosine kinase activity.

[0081] It may be known or predictable that genetic diversity resulting in increased expression of a given gene (gene and / or protein) may result in, in cells containing such genetic diversity, one or more of the following: an increase in the copy number of the gene (e.g., to three or more copies); increased transcription of the gene; increased levels of RNA encoded by the gene; decreased degradation of RNA encoded by the gene; increased levels of the gene product; increased levels of peptides / polypeptides encoded by the gene; increased levels of normal splicing of premRNA encoded by the gene; increased translation of mRNA encoding peptides / polypeptides encoded by the gene; increased levels of normal post-translational processing of peptides / polypeptides encoded by the gene; increased levels of normal transport of peptides / polypeptides; and / or decreased degradation of peptides / polypeptides encoded by the gene. It may be known or predictable that genetic diversity resulting in increased activity of a given gene product may result in, in cells containing such genetic diversity, an increase in the level of one or more functional properties presented by the gene product; an increase in the level of one or more functional properties presented by the gene-encoded peptide / polypeptide; a novel functional property presented by the gene product; and / or one or more novel functional properties presented by the gene-encoded peptide / polypeptide.

[0082] It may be known or predictable that a genetic diversity resulting in reduced expression of a given gene (gene and / or protein) may result in, in cells containing such genetic diversity, one or more of the following: reduced copy number of the gene (e.g., to fewer than two copies); reduced transcription of the gene; reduced levels of RNA encoded by the gene; increased degradation of RNA encoded by the gene; reduced levels of the gene product; reduced levels of peptides / polypeptides encoded by the gene; reduced levels of normal splicing of premRNA encoded by the gene; reduced translation of mRNA encoding peptides / polypeptides encoded by the gene; reduced levels of normal post-translational processing of peptides / polypeptides encoded by the gene; reduced levels of normal transport of peptides / polypeptides; and / or increased degradation of peptides / polypeptides encoded by the gene. It may be known or predictable that genetic diversity resulting in reduced activity of a given gene product may, in cells containing such genetic diversity, result in: a reduction in the level of one or more functional properties presented by the gene product; and / or a reduction in the level of one or more functional properties presented by the peptide / polypeptide encoded by the gene.

[0083] The most common version of the nucleotide sequence of a given gene can be called the wild-type allele of that gene. Versions of the nucleotide sequence of a given gene that include genetic diversity can be called "variant" or "mutant" alleles of that gene. The nucleotide sequences of variant / mutant alleles of a given gene are understood to have nucleotide sequences that are non-identical to the nucleotide sequence of the wild-type allele.

[0084] In this specification, cancers containing cells having specified features may be simply referred to as cancers having those features. In embodiments of this specification, cancers containing cells having specified features are understood to be one or more tumors containing cells having those features. That is, when cancer is described as having a given genetic diversity, mutation state, allele, or genotype, the cells of that cancer are understood to have the relevant genetic diversity, mutation state, allele, or genotype.

[0085] As an example, if cancer is described as containing a given mutation, then the cancer contains cells containing that mutation. Similarly, if cancer is described as homozygous with respect to a given genetic diversity / allele, then the cancer contains cells that are homozygous with respect to that genetic diversity / allele. Similarly, if cancer is described as heterozygous with respect to a given genetic diversity / allele, then the cancer contains cells that are heterozygous with respect to that genetic diversity / allele.

[0086] When a cancer is described as having a given genetic diversity, mutation status, alleles, or genotype, one or more cells of that cancer have the relevant genetic diversity, mutation status, alleles, or genotype. In some embodiments, when a cancer is described as having a given genetic diversity, mutation status, alleles, or genotype, the majority (i.e., >50%) of the cells of that cancer have the relevant genetic diversity, mutation status, alleles, or genotype. In some embodiments, one of ≥60%, ≥65%, ≥70%, ≥75%, ≥80%, ≥85%, ≥90%, ≥95%, or 100% of the cells of the cancer have the relevant genetic diversity, mutation status, alleles, or genotype. In some embodiments, a cancer containing a given genetic diversity / variation / allelic / genotype may be such that >10% of its cancer cells (e.g., one of ≥20%, ≥50%, ≥40%, ≥50%, ≥60%, ≥65%, ≥70%, ≥75%, ≥80%, ≥85%, ≥90%, ≥95%, or 100%) contain that genetic diversity / variation / allelic / genotype.

[0087] In some embodiments, a cancer that does not contain (i.e., lacks) a given genetic diversity / variation / allelic / genotype may be a cancer in which <25% (e.g., one of ≤20%, ≤15%, ≤10%, ≤5%, ≤1%, or 0%) of the cancer cells contain that genetic diversity / variation / allelic / genotype.

[0088] In this specification, when a cell is described as containing a given genetic diversity / variation, it is understood that one or more alleles of the relevant gene contain such genetic diversity / variation. In some embodiments, a cell containing a given genetic diversity / variation may be heterozygous with respect to the allele containing that genetic diversity / variation. In some embodiments, a cell containing a given genetic diversity / variation may be homozygous with respect to the allele containing that genetic diversity / variation.

[0089] When a cell is described as not containing a given genetic diversity / variation, it is understood that none of the alleles of the related gene contain such genetic diversity / variation (i.e., the cell is neither homozygous nor heterozygous with respect to the variant / mutant allele).

[0090] The aspects and embodiments described herein relate to genetic diversity that results in increased expression of MET or increased activity of its gene product. Genetic diversity known or predicted to increase MET / c-Met expression and / or activity is described, for example, in Tovar and Graveel (2017) 5(10):205, which is incorporated herein by reference in its entirety.

[0091] In some embodiments, activating mutations to MET are genetic variations that result in increased expression of MET or increased activity of its gene product. Activating mutations to MET include mutations in E34 (e.g., E34K), H150 (e.g., H150Y), E168 (e.g., E168D), L269 (e.g., L269V), L299 (e.g., L299F), S323 (e.g., S323G), M362 (e.g., M362T), N375 (e.g., N375S), and C358 (e.g., C358Y). R970 (e.g., R970C), R988 (e.g., R988C), P1009 (e.g., P1009S), T1010 (e.g., T1010I), S1058 (e.g., S1058P), exon 14 skipping mutation, A1108 (e.g., A1108S), V1110 (e.g., V1110I), H1112 (e.g., H1112R, H1112 L, H1112I), H1124 (e.g., H1124D), G1137 (e.g., G1137V), M1149 (e.g., M1149T), T1191 (e.g., T1191I), V1206 (e.g., V1206L), L1213 (e.g., L1213V), D1228 (e.g., D1228V), Y1230 (e.g., Y1230C, Y1230H, This includes Y1230D), Y1235 (e.g., Y1235D), V1238 (e.g., V1238I), D1246 (e.g., D1246N), Y1248 (e.g., Y1248C, Y1248D, Y1248H), K1262 (e.g., K1262R), M1268 (e.g., M1268T, M1268I), and V1312 (e.g., V1312I).

[0092] Therefore, in some embodiments, the activating mutations to MET are mutations to: E34 (e.g., E34K), H150 (e.g., H150Y), E168 (e.g., E168D), L269 (e.g., L269V), L299 (e.g., L299F), S323 (e.g., S323G), M362 (e.g., M362T), N375 (e.g., N375S), C35 8 (e.g., C358Y), R970 (e.g., R970C), R988 (e.g., R988C), P1009 (e.g., P1009S), T1010 (e.g., T1010I), S1058 (e.g., S1058P), exon 14 skipping mutation, A1108 (e.g., A1108S), V1110 (e.g., V1110I), H1112 (e.g., H1112R) , H1112L, H1112I), H1124 (e.g., H1124D), G1137 (e.g., G1137V), M1149 (e.g., M1149T), T1191 (e.g., T1191I), V1206 (e.g., V1206L), L1213 (e.g., L1213V), D1228 (e.g., D1228V), Y1230 (e.g., Y1230C, Y1230H, Select from Y1230D), Y1235 (e.g., Y1235D), V1238 (e.g., V1238I), D1246 (e.g., D1246N), Y1248 (e.g., Y1248C, Y1248D, Y1248H), K1262 (e.g., K1262R), M1268 (e.g., M1268T, M1268I), or V1312 (e.g., V1312I).

[0093] In some embodiments, the genetic diversity resulting in increased expression of MET or increased activity of its gene product is or includes amplification of MET. MET amplification can be identified using techniques well known in the art, such as in situ hybridization. For example, MET amplification can be evaluated by fluorescence in situ hybridization, as described, e.g., Awad et al., J. Clin. Oncol. (2016) 34(7):721-730 or Yeung et al., J Thorac Oncol (2015) 10:1292-300. MET amplification can also be evaluated using next-generation sequencing techniques, as described, e.g., Schubart et al., Cancers (Basel). (2021) 13(19):5023.

[0094] In some embodiments, cells containing MET amplification contain one MET with >2, e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more copies, or a fragment of one MET with >2, e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more copies. MET amplification can result from gene multiplication or polysomaticism. In some embodiments, MET-amplified cancers may include a MET to chromosome 7 ratio ≥1 (e.g., determined by ISH), e.g., ≥1.5, ≥2, ≥2.5. In some embodiments, MET-amplified cancers may include a MET to centromere 7 (CEN7) ratio ≥1 (e.g., determined by ISH), e.g., ≥1.5, ≥2, ≥2.5. In some embodiments, cells of MET-amplified cancers may include MET gene copy number (GCN) >2, ≥3, ≥4, ≥5, ≥6, ≥7, ≥8, ≥9, or ≥10 (e.g., determined by NGS).

[0095] In some embodiments, the genetic diversity resulting in increased MET expression or increased activity of its gene product is not a mutation of MET, or does not include such a mutation. In some embodiments, the genetic diversity resulting in increased MET expression or increased activity of its gene product is a genetic diversity other than a mutation of MET (for example, including, as described herein, an amplification of MET).

[0096] The aspects and embodiments described herein relate to genetic diversity that results in increased KRAS expression or increased activity of its gene product. Genetic diversity known or predicted to increase KRAS / K-Ras expression and / or activity is described, for example, in Hobbs and Der, Cancer Discov. (2019) 9(6):696-698, which is incorporated herein by reference in its entirety. Activating mutations to KRAS include mutations to G12 (e.g., G12A, G12D, G12R, G12C, G12S, and G12V), mutations to G13 (e.g., G13D, G13C), mutations to Q61 (e.g., Q61H, Q61L, Q61K, Q61R), mutations to A146 (e.g., A146T, A146V), and mutations to K117 (e.g., K117N). In some embodiments, the activating mutation to KRAS according to this disclosure is G12C.

[0097] In some embodiments, the genetic diversity resulting in increased KRAS expression or increased activity of its gene product is or includes KRAS amplification. KRAS amplification can be identified using techniques well known in the art, such as in situ hybridization and NGS. For example, KRAS amplification can be evaluated by fluorescence in situ hybridization, as described, for example, by Valtorta et al., Int J Cancer. (2013) 133(5):1259~65.

[0098] In some embodiments, cells containing KRAS amplification contain one KRAS with >2, e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more copies, or a fragment of one KRAS with >2, e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more copies. KRAS amplification can result from gene duplication or polysomaticism. In some embodiments, KRAS-amplified cancers may include a KRAS-to-chromosome 12 ratio ≥1 (e.g., determined by ISH), e.g., ≥1.5, ≥2, ≥2.5. In some embodiments, KRAS-amplified cancers may include a KRAS-to-centromere 12 (CEN12) ratio ≥1 (e.g., determined by ISH), e.g., ≥1.5, ≥2, ≥2.5. In some embodiments, cells of KRAS-amplified cancer may include KRAS gene copy number (GCN) > 2, ≥ 3, ≥ 4, ≥ 5, ≥ 6, ≥ 7, ≥ 8, ≥ 9, or ≥ 10 (determined, for example, by NGS).

[0099] In some embodiments, the genetic diversity resulting in increased KRAS expression or increased activity of its gene product is not KRAS amplification or does not include KRAS amplification. In some embodiments, the genetic diversity resulting in increased KRAS expression or increased activity of its gene product is a genetic diversity other than KRAS amplification (for example, including, as described herein, an activating mutation to KRAS).

[0100] The aspects and embodiments described herein relate to genetic diversity that results in increased expression of PIK3CA or increased activity of its gene product. Genetic diversity known or predicted to increase PIK3CA / PI3K expression and / or activity is described, for example, Ligresti et al., Cell Cycle. (2009) 8(9):1352-1358, which is incorporated herein in its entirety by reference. Activating mutations to PIK3CA include mutations to H1047 (e.g., H1047R, H1047L), E542 (e.g., E542K, E542Q), E545 (e.g., E545K), P449 (e.g., P449T), and Q546 (e.g., Q546R). In some embodiments, the activating mutation to PIK3CA according to this disclosure is Q546R or P449T.

[0101] In some embodiments, the genetic diversity resulting from increased expression of PIK3CA or increased activity of its gene product is or includes amplification of PIK3CA. PIK3CA amplification can be identified using techniques well known in the art, such as in situ hybridization and NGS. For example, PIK3CA amplification can be evaluated by fluorescence in situ hybridization, as described, for example, by Holst et al., Clin Cancer Res. (2019) 25(1):334-345.

[0102] In some embodiments, cells containing PIK3CA amplification contain one PIK3CA with >2, e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more copies, or a fragment of one PIK3CA with >2, e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more copies. PIK3CA amplification can result from gene duplication or polysomaticism. In some embodiments, PIK3CA-amplified cancers may include a PIK3CA to chromosome 3 ratio ≥1 (e.g., determined by ISH), e.g., ≥1.5, ≥2, ≥2.5. In some embodiments, PIK3CA-amplified cancers may include a PIK3CA to chromosome 3 (CEN3) ratio ≥1 (e.g., determined by ISH), e.g., ≥1.5, ≥2, ≥2.5. In some embodiments, PIK3CA-amplified cancer cells may include PIK3CA gene copy number (GCN) > 2, ≥ 3, ≥ 4, ≥ 5, ≥ 6, ≥ 7, ≥ 8, ≥ 9, or ≥ 10 (determined, e.g., by NGS).

[0103] In some embodiments, the genetic diversity resulting in increased expression of PIK3CA or increased activity of its gene product is not amplification of PIK3CA and does not include any such amplification. In some embodiments, the genetic diversity resulting in increased expression of PIK3CA or increased activity of its gene product is a genetic diversity other than amplification of PIK3CA (for example, including, as described herein, an activating mutation to PIK3CA).

[0104] The aspects and embodiments described herein relate to genetic diversity that results in increased expression of BRAF or increased activity of its gene product. Genetic diversity known or predicted to increase BRAF / B-Raf expression and / or activity is described in its entirety by reference in Van Cutsem et al., Journal of Clinical Immunology (2011) 29(15):2011-2019. Activating mutations to BRAF include mutations to V600 (e.g., V600E or V600K), mutations to T119 (e.g., T119S), and mutations to L597 (e.g., L597R). In some embodiments, the activating mutation according to this disclosure is V600E, V600K, T119S, or L597R.

[0105] In some embodiments, the genetic diversity resulting in increased BRAF expression or increased activity of its gene product is or includes BRAF amplification. BRAF amplification can be identified using techniques well known in the art, such as in situ hybridization and NGS. For example, BRAF amplification can be evaluated by fluorescence in situ hybridization, as described, for example, by Corcoran et al., Sci Signal. (2010) 3(149):ra84.

[0106] In some embodiments, cells containing BRAF amplification contain one BRAF with >2, e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more copies, or a fragment of one BRAF with >2, e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more copies. BRAF amplification can result from gene duplication or polysomaticism. In some embodiments, BRAF-amplified cancers may contain a BRAF-to-chromosome 7 ratio ≥1 (e.g., determined by ISH), e.g., ≥1.5, ≥2, ≥2.5. In some embodiments, BRAF-amplified cancers may contain a BRAF-to-centromere 7 (CEN7) ratio ≥1 (e.g., determined by ISH), e.g., ≥1.5, ≥2, ≥2.5. In some embodiments, cells of BRAF-amplified cancers may contain BRAF gene copy number (GCN) >2, ≥3, ≥4, ≥5, ≥6, ≥7, ≥8, ≥9, or ≥10 (e.g., determined by NGS).

[0107] In some embodiments, the genetic diversity resulting in increased BRAF expression or increased activity of its gene product is not BRAF amplification or does not include BRAF amplification. In some embodiments, the genetic diversity resulting in increased BRAF expression or increased activity of its gene product is a genetic diversity other than BRAF amplification (for example, including, as described herein, an activating mutation to BRAF).

[0108] The aspects and embodiments described herein relate to genetic diversity that results in reduced expression of PTEN or reduced activity of its gene product. Genetic diversity known or predicted to reduce PTEN / PTEN expression and / or activity is described, for example, in its entirety by reference to Chang et al., Biomolecules. (2019) 9(11):713. Inactivating mutations to PTEN include mutations to R130, R173, R233, K267, and N323.

[0109] In some embodiments, the genetic diversity resulting from reduced PTEN expression or reduced activity of its gene product is or includes a PTEN deletion. PTEN deletions can be identified using techniques well known in the art, such as in situ hybridization and NGS. For example, PTEN deletions can be evaluated by fluorescence in situ hybridization, as described, for example, by Wang et al., Neoplasia. (2018) 20(6):574-593.

[0110] In some embodiments, cells containing a PTEN deletion may contain one PTEN gene with a copy number <2, e.g., 1 or 0 copies. In some embodiments, cancers containing a PTEN deletion may contain a PTEN to chromosome 17 ratio ≤1 (e.g., determined by ISH). In some embodiments, cancers containing a PTEN deletion may contain a PTEN to centromere 17 (CEN17) ratio ≤1 (e.g., determined by ISH). In some embodiments, cells of cancers containing a PTEN deletion may contain a PTEN gene copy number (GCN) <2, e.g., ≤1.5, ≤1, or ≤0.5 (e.g., determined by NGS).

[0111] In some embodiments, the genetic diversity resulting in reduced PTEN expression or reduced activity of its gene product is not a mutation in PTEN, or does not include such a mutation. In some embodiments, the genetic diversity resulting in reduced PTEN expression or reduced activity of its gene product is a genetic diversity other than a mutation in PTEN (for example, including, as described herein, a deletion of PTEN).

[0112] The aspects and embodiments described herein relate to genetic diversity that results in increased expression of EGFR or increased activity of its gene product. Genetic diversity known or predicted to increase EGFR / EGFR expression and / or activity is described, for example, in Gazdar, Oncogene. (2009) 28(Suppl 1):S24~S31, which is incorporated herein in its entirety by reference. EGFR-activating mutations include mutations to L858 (e.g., L858R), G719 (e.g., G719S, G719A, or G719C), T790 (e.g., T790M), V765 (e.g., V765A), T783 (e.g., T783A), and deletion mutations in exon 19 (e.g., deletions including L747~E749).

[0113] In some embodiments, the genetic diversity resulting in increased EGFR expression or increased activity of its gene product is or includes EGFR amplification. EGFR amplification can be identified using techniques well known in the art, such as in situ hybridization and NGS. For example, EGFR amplification can be evaluated by fluorescence in situ hybridization, as described, for example, by French et al., Neuro-Oncology (2019) 21(10):1263~1272.

[0114] In some embodiments, cells containing EGFR amplification contain one EGFR of >2, e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more copies, or a fragment of one EGFR of >2, e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more copies. EGFR amplification can result from gene duplication or polysomaticism. In some embodiments, EGFR-amplified cancers may include an EGFR-to-chromosome 7 ratio ≥1 (e.g., determined by ISH), e.g., ≥1.5, ≥2, ≥2.5. In some embodiments, EGFR-amplified cancers may include an EGFR-to-centromere 7 (CEN7) ratio ≥1 (e.g., determined by ISH), e.g., ≥1.5, ≥2, ≥2.5. In some embodiments, EGFR-amplified cancer cells may include EGFR gene copy number (GCN) > 2, ≥ 3, ≥ 4, ≥ 5, ≥ 6, ≥ 7, ≥ 8, ≥ 9, or ≥ 10 (determined, e.g., by NGS).

[0115] The aspects and embodiments described herein relate to genetic diversity that results in increased expression of TP63 or increased activity of its gene product. In some embodiments, the genetic diversity resulting in increased expression of TP63 or increased activity of its gene product is or includes amplification of TP63. TP63 amplification can be identified using techniques well known in the art, such as in situ hybridization and NGS. For example, TP63 amplification can be evaluated by fluorescence in situ hybridization, as described, for example, by Massion et al., Cancer Res. (2003) 63(21):7113~21.

[0116] In some embodiments, cells containing TP63 amplification contain one TP63 of >2, e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more copies, or a fragment of one TP63 of >2, e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more copies. TP63 amplification can result from gene duplication or polysomaticism. In some embodiments, TP63-amplified cancers may include a TP63 to chromosome 3 ratio ≥1 (e.g., determined by ISH), e.g., ≥1.5, ≥2, ≥2.5. In some embodiments, TP63-amplified cancers may include a TP63 to centromere 3 (CEN3) ratio ≥1 (e.g., determined by ISH), e.g., ≥1.5, ≥2, ≥2.5. In some embodiments, TP63-amplified cancer cells may include TP63 gene copy number (GCN) > 2, ≥ 3, ≥ 4, ≥ 5, ≥ 6, ≥ 7, ≥ 8, ≥ 9, or ≥ 10 (determined, e.g., by NGS).

[0117] The aspects and embodiments described herein relate to genetic diversity that results in increased expression of SOX2 or increased activity of its gene product. In some embodiments, the genetic diversity resulting from increased expression of SOX2 or increased activity of its gene product is or includes SOX2 amplification. SOX2 amplification can be identified using techniques well known in the art, such as in situ hybridization and NGS. For example, SOX2 amplification can be evaluated by fluorescence in situ hybridization, as described, for example, by Wilbertz et al., Modern Pathology (2011) 24:944-953.

[0118] In some embodiments, cells containing SOX2 amplification contain one SOX2 of >2, e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more copies, or a fragment of one SOX2 of >2, e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more copies. SOX2 amplification can result from gene duplication or polysomaticism. In some embodiments, SOX2-amplified cancers may include a SOX2 to chromosome 3 ratio ≥1 (e.g., determined by ISH), e.g., ≥1.5, ≥2, ≥2.5. In some embodiments, SOX2-amplified cancers may include a SOX2 to centromere 3 (CEN3) ratio ≥1 (e.g., determined by ISH), e.g., ≥1.5, ≥2, ≥2.5. In some embodiments, cells of SOX2-amplified cancer may include SOX2 gene copy number (GCN) > 2, ≥ 3, ≥ 4, ≥ 5, ≥ 6, ≥ 7, ≥ 8, ≥ 9, or ≥ 10 (determined, e.g., by NGS).

[0119] The aspects and embodiments of this disclosure relate to genetic diversity resulting in increased expression of one or more genes located on chromosome 3q, or increased activity of their gene products. In some embodiments, the genetic diversity resulting in increased expression of one or more genes located on chromosome 3q, or increased activity of their gene products, is or includes amplification of the relevant genes. Amplification of one or more genes located on chromosome 3q can be identified using techniques well known in the art, such as in situ hybridization and NGS.

[0120] In some embodiments, cells containing amplification of one or more genes located on chromosome 3q may include one related gene with >2, e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more copies, or a fragment of one related gene with >2, e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more copies. Amplification of one or more genes located on chromosome 3q may result from gene duplication or polysomaticism. In some embodiments, cancers containing amplification of one or more genes located on chromosome 3q may include a related gene to chromosome 3 ratio ≥1 (e.g., determined by ISH), e.g., ≥1.5, ≥2, ≥2.5. In some embodiments, cancers containing amplification of one or more genes located on chromosome 3q may include a related gene to centromere 3 (CEN3) ratio ≥1 (e.g., determined by ISH), e.g., ≥1.5, ≥2, ≥2.5. In some embodiments, cancer cells containing amplification of one or more genes located on chromosome 3 q may have a gene copy number (GCN) of the relevant gene that is >2, ≥3, ≥4, ≥5, ≥6, ≥7, ≥8, ≥9, or ≥10 (determined, for example, by NGS).

[0121] The aspects and embodiments of this disclosure relate to genetic diversity resulting in increased expression of one or more genes located within 3q26–3q28 (e.g., within 3q26, 3q27, or 3q28) or increased activity of their gene products. In some embodiments, the genetic diversity resulting in increased expression of one or more genes located within 3q26–3q28 (e.g., within 3q26, 3q27, or 3q28) or increased activity of their gene products is or includes amplification of the relevant genes. Amplification of one or more genes located within 3q26–3q28 (e.g., within 3q26, 3q27, or 3q28) can be identified using techniques well known in the art, such as in situ hybridization and NGS.

[0122] In some embodiments, cells containing amplification of one or more genes located within 3q26–3q28 (e.g., within 3q26, 3q27, or 3q28) may include one related gene with >2, e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more copies, or a fragment of one related gene with >2, e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more copies. Amplification of one or more genes located within 3q26–3q28 (e.g., within 3q26, 3q27, or 3q28) may result from gene duplication or polysomaticism. In some embodiments, cancers containing amplification of one or more genes located within 3q26–3q28 (e.g., within 3q26, 3q27, or 3q28) may include a related gene to chromosome 3 ratio ≥1 (e.g., determined by ISH), e.g., ≥1.5, ≥2, ≥2.5. In some embodiments, cancers containing amplification of one or more genes located within 3q26–3q28 may include a ratio of related gene to the third centromere (CEN3) ≥ 1 (determined, e.g., by ISH), e.g., ≥ 1.5, ≥ 2, ≥ 2.5. In some embodiments, cancer cells containing amplification of one or more genes located within 3q26–3q28 (e.g., within 3q26, 3q27, or 3q28) may include a gene copy number (GCN) of the related gene > 2, ≥ 3, ≥ 4, ≥ 5, ≥ 6, ≥ 7, ≥ 8, ≥ 9, or ≥ 10 (determined, e.g., by NGS).

[0123] The genes located within 3q26-3q28 include TP63, PIK3CA, and SOX2. The genes located within 3q28 include PIK3CA (3q26.32) and SOX2 (3q26.33). The genes located within 3q28 include TP63.

[0124] The aspects and embodiments described herein relate to genetic diversity resulting in amplification of chromosome 3q. Amplification of chromosome 3q can occur as a result of polysomaticism. The genes located on chromosome 3q are ADIPOQ, AMOTL2, ARHGAP31, TIMMDC1, C3orf70, CAMPD1, CCDC80, CD200R1, CHST13, CLDND1, CPN2, CPOX, DPPA2, DTX3L, DZIP3, EAF2, EFCC1, ETM1, ETV5, FAM3D, FAM43A, FAM162A, FBXO40, FILIP1L, GYG1, HACD2, HGD, IFT122, KIAA1257, LINC01279, LNCR5, and LML. This includes N, LRRC15, LSG1, MB21D2, MCCC1, MORC1, MYLK, NEPRO, NFKBIZ, OTOL1, PARP14, PCCB, PDCD10, PIK3CA, PISRT1, PROSER1, RAB7, RASA2, RETNLB, RHO, RIOX2, SELT, SENP7, SERP1, SOX2, SOX2OT, SPG14, SRPRB, TEX55, TMEM44, TM4SF1, TMPRSS7, TP63, TRAT1, USH3A, ZBED2, and ZNF9. In some embodiments, one or more genes located on chromosome 3q are selected from TP63, PIK3CA, and SOX2.

[0125] The aspects and embodiments of this disclosure relate to genetic diversity resulting in amplification of 3q26. The aspects and embodiments of this disclosure relate to genetic diversity resulting in amplification of 3q27. The aspects and embodiments of this disclosure relate to genetic diversity resulting in amplification of 3q28. The aspects and embodiments of this disclosure relate to genetic diversity resulting in amplification of 3q26-3q28. Such amplification may occur as a result of polysomaticism.

[0126] The aspects and embodiments of this disclosure relate to genetic diversity resulting in increased expression of one or more genes located on chromosome 7p, or increased activity of their gene products. In some embodiments, the genetic diversity resulting in increased expression of one or more genes located on chromosome 7p, or increased activity of their gene products, is or includes amplification of the relevant genes. Amplification of one or more genes located on chromosome 7p can be identified using techniques well known in the art, such as in situ hybridization and NGS.

[0127] In some embodiments, cells containing amplification of one or more genes located on chromosome 7p may contain one related gene with >2, e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more copies, or a fragment of one related gene with >2, e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more copies. Amplification of one or more genes located on chromosome 7p may result from gene duplication or polysomaticism. In some embodiments, cancers containing amplification of one or more genes located on chromosome 7p may include a ratio of related gene to chromosome 7 ≥ 1 (e.g., determined by ISH), e.g., ≥ 1.5, ≥ 2, ≥ 2.5. In some embodiments, cancers containing amplification of one or more genes located on chromosome 7p may include a ratio of related gene to centromere 7 (CEN7) ≥ 1 (e.g., determined by ISH), e.g., ≥ 1.5, ≥ 2, ≥ 2.5. In some embodiments, cancer cells containing amplification of one or more genes located on chromosome 7p may have a gene copy number (GCN) of the relevant gene that is >2, ≥3, ≥4, ≥5, ≥6, ≥7, ≥8, ≥9, or ≥10 (determined, for example, by NGS).

[0128] The aspects and embodiments of this disclosure relate to genetic diversity resulting in increased expression of one or more genes located within 7p11, or increased activity of their gene products. In some embodiments, the genetic diversity resulting in increased expression of one or more genes located within 7p11, or increased activity of their gene products, is or includes amplification of the relevant genes. Amplification of one or more genes located within 7p11 can be identified using techniques well known in the art, such as in situ hybridization and NGS.

[0129] In some embodiments, cells containing amplification of one or more genes located within 7p11 may contain one related gene with >2, e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more copies, or a fragment of one related gene with >2, e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more copies. Amplification of one or more genes located within 7p11 may result from gene duplication or polysomaticism. In some embodiments, cancers containing amplification of one or more genes located within 7p11 may include a related gene to chromosome 3 ratio ≥1 (e.g., determined by ISH), e.g., ≥1.5, ≥2, ≥2.5. In some embodiments, cancers containing amplification of one or more genes located within 7p11 may include a related gene to centromere 7 (CEN7) ratio ≥1 (e.g., determined by ISH), e.g., ≥1.5, ≥2, ≥2.5. In some embodiments, cancer cells containing amplification of one or more genes located within 7p11 may include a gene copy number (GCN) of the relevant gene that is >2, ≥3, ≥4, ≥5, ≥6, ≥7, ≥8, ≥9, or ≥10 (determined, for example, by NGS).

[0130] The genes located within 7p11 include EGFR (7p11.2). The aspects and embodiments of this disclosure relate to genetic diversity resulting in amplification of chromosome 7p. The aspects and embodiments of this disclosure relate to genetic diversity resulting in amplification of 7p11. Such amplification may result from polysomatic properties.

[0131] The aspects and embodiments of this disclosure relate to genetic diversity resulting in reduced expression of one or more genes located on chromosome 3p, or reduced activity of their gene products. In some embodiments, the genetic diversity resulting in reduced expression of one or more genes located on chromosome 3p, or reduced activity of their gene products, includes or includes loss or deletion of the relevant genes. Loss or deletion of one or more genes located on chromosome 3p can be identified using art-known techniques, such as in situ hybridization and NGS.

[0132] In some embodiments, cells containing a deletion of one or more genes located on chromosome 3p may contain one related gene with <2 copies, e.g., 1 or 0 copies, or a fragment of one related gene with <2 copies, e.g., 1 or 0 copies. In some embodiments, cancer containing a deletion of one or more genes located on chromosome 3p may contain a related gene to chromosome 3 ratio ≤1 (e.g., determined by ISH). In some embodiments, cancer containing a deletion of one or more genes located on chromosome 3p may contain a related gene to centromere 3 (CEN3) ratio ≤1 (e.g., determined by ISH). In some embodiments, cells of cancer containing a deletion of one or more genes located on chromosome 3p may contain gene copy numbers (GCNs) of related genes that are <2, e.g., ≤1.5, ≤1, or ≤0.5 (e.g., determined by NGS).

[0133] The aspects and embodiments of this disclosure relate to genetic diversity resulting in reduced expression of one or more genes located within 3p21 (e.g., within 3p21.3) or reduced activity of their gene products. In some embodiments, the genetic diversity resulting in reduced expression of one or more genes located within 3p21 (e.g., within 3p21.3) or reduced activity of their gene products is or includes deletions of the relevant genes. Deletions of one or more genes located within 3p21 (e.g., within 3p21.3) can be identified using techniques well known in the art, such as in situ hybridization and NGS.

[0134] In some embodiments, cells containing deletions of one or more genes located within 3p21 (e.g., within 3p21.3) may contain one related gene with <2 copies, e.g., 1 or 0 copies, or a fragment of one related gene with <2 copies, e.g., 1 or 0 copies. In some embodiments, cancer containing deletions of one or more genes located within 3p21 (e.g., within 3p21.3) may contain a ratio of related gene to chromosome 3 ≤ 1 (e.g., determined by ISH). In some embodiments, cancer containing deletions of one or more genes located within 3p21 may contain a ratio of related gene to centromere 3 (CEN3) ≤ 1 (e.g., determined by ISH). In some embodiments, cancer cells containing deletions of one or more genes located within 3p21 (e.g., within 3p21.3) may contain gene copy numbers (GCNs) of related genes that are <2, e.g., ≤ 1.5, ≤ 1, or ≤ 0.5 (e.g., determined by NGS).

[0135] Genes located within 3p21 (for example, within 3p21.3) include TUSC2. The aspects and embodiments of this disclosure relate to genetic diversity resulting in deletion of chromosome 3p. The aspects and embodiments of this disclosure relate to genetic diversity resulting in deletion of 3p21.

[0136] This disclosure is intended to describe the genetic diversity in genes encoding factors related to HER3-mediated signaling. The aspects and embodiments of this disclosure are intended to result in genetic diversity that leads to increased expression of positive regulators of HER3-mediated signaling or increased activity of their gene products. The aspects and embodiments of this disclosure are intended to result in genetic diversity that leads to increased expression of positive regulators of signaling via the MAPK / ERK pathway or increased activity of their gene products. The aspects and embodiments of this disclosure are intended to result in genetic diversity that leads to increased expression of positive regulators of signaling via the PI3K / AKT / mTOR pathway or increased activity of their gene products.

[0137] The aspects and embodiments of this disclosure are intended to result in genetic diversity that leads to reduced expression of negative regulators of HER3-mediated signaling or reduced activity of their gene products. The aspects and embodiments of this disclosure are intended to result in genetic diversity that leads to reduced expression of negative regulators of signaling via the MAPK / ERK pathway or reduced activity of their gene products. The aspects and embodiments of this disclosure are intended to result in genetic diversity that leads to reduced expression of negative regulators of signaling via the PI3K / AKT / mTOR pathway or reduced activity of their gene products.

[0138] HER3-mediated signaling can be analyzed using assays relating to HER3-mediated signaling, such as cell proliferation, and / or phosphorylation of one or more signaling molecules in the PI3K / AKT / mTOR and / or MAPK / ERK signaling pathways. For example, the level of PI3K / AKT / mTOR and / or MAPK / ERK signaling can be analyzed by detecting and quantifying the level of phosphorylation of one or more components of the PI3K / AKT / mTOR and / or MAPK / ERK pathways. Such analyses can be performed in vitro in cell-based assays of HER3-mediated signaling, as described, for example, in Example 8.9, 4.3 of International Publication No. 2019 / 185878.

[0139] As used herein, a “positive regulator” of signaling via a given pathway (e.g., a positive regulator of HER3-mediated signaling, a positive regulator of signaling via the MAPK / ERK pathway, or a positive regulator of signaling via the PI3K / AKT / mTOR pathway) refers to a factor whose expression / activity contributes positively overall to (i.e., enhances or increases) signaling via the relevant pathway. Increased levels of expression and / or activity of a positive regulator may result in increased levels of signaling via the relevant pathway (determined, for example, by analysis of such signaling correlation phenomena). Decreased levels of expression and / or activity of a positive regulator may result in decreased levels of signaling via the relevant pathway.

[0140] A "negative regulator" of signaling via a given pathway (e.g., a positive regulator of HER3-mediated signaling, a positive regulator of signaling via the MAPK / ERK pathway, or a positive regulator of signaling via the PI3K / AKT / mTOR pathway) refers to a factor whose expression / activity negatively contributes to (i.e., inhibits or antagonizes) signaling via the relevant pathway overall. Increased levels of expression and / or activity of a negative regulator can lead to decreased levels of signaling via the relevant pathway (determined, for example, by analysis of correlational phenomena of such signaling). Decreased levels of expression and / or activity of a negative regulator can lead to increased levels of signaling via the relevant pathway.

[0141] In some embodiments, the gene encoding a positive regulator of HER3-mediated signaling may be selected from KRAS, PIK3CA, PIK3CB, PIK3CD, ERBB3, ERBB2, ERBB4, EGFR, IGF1R, NRG1, NRG2, EGF, IRS2, GRB2, GAB2, PTPN11, SHP2, SOS1, HRAS, NRAS, RAF1, MAP2K1, MAP2K2, MAPK1, MYC, RPS6KA1, RPS6, MKNK1, CREB1, MTOR, PDK1, AKT1, AKT2, AKT3, JAK2, STAT3, STAT5, BRAF, and MET. In some embodiments, the gene encoding a positive regulator of HER3-mediated signaling may be selected from KRAS, PIK3CA, PIK3CB, BRAF, and MET. In some embodiments, the gene encoding a positive regulator of HER3-mediated signaling is KRAS. In some embodiments, the gene encoding a positive regulator of HER3-mediated signaling is PIK3CA. In some embodiments, the gene encoding a positive regulator of HER3-mediated signaling is PIK3CB. In some embodiments, the gene encoding a positive regulator of HER3-mediated signaling is BRAF. In some embodiments, the gene encoding a positive regulator of HER3-mediated signaling is MET.

[0142] In some embodiments, genes encoding positive regulators of HER3-mediated signaling may be selected from PIK3CB, PIK3CD, ERBB3, ERBB2, ERBB4, EGFR, IGF1R, NRG1, NRG2, EGF, IRS2, GRB2, GAB2, PTPN11, SHP2, SOS1, HRAS, NRAS, RAF1, MAP2K1, MAP2K2, MAPK1, MYC, RPS6KA1, RPS6, MKNK1, CREB1, MTOR, PDK1, AKT1, AKT2, AKT3, JAK2, STAT3, and STAT5.

[0143] In some embodiments, the gene encoding a positive regulator of signaling via the MAPK / ERK pathway may be selected from ERBB3, ERBB2, ERBB4, EGFR, IGF1R, NRG1, NRG2, EGF, IRS2, GAB2, GRB2, PTPN11, SHP2, SOS1, HRAS, KRAS, NRAS, RAF1, MAP2K1, MAP2K2, MAPK1, MYC, RPS6KA1, RPS6, MKNK1, CREB1, and BRAF. In some embodiments, the gene encoding a positive regulator of signaling via the MAPK / ERK pathway is KRAS. In some embodiments, the gene encoding a positive regulator of signaling via the MAPK / ERK pathway is BRAF.

[0144] In some embodiments, genes encoding positive regulators of signaling via the MAPK / ERK pathway may be selected from ERBB3, ERBB2, ERBB4, EGFR, IGF1R, NRG1, NRG2, EGF, IRS2, GAB2, GRB2, PTPN11, SHP2, SOS1, HRAS, KRAS, NRAS, RAF1, MAP2K1, MAP2K2, MAPK1, MYC, RPS6KA1, RPS6, MKNK1, and CREB1.

[0145] In some embodiments, the gene encoding a positive regulator of signaling via the PI3K / AKT / mTOR pathway may be selected from ERBB3, ERBB2, ERBB4, EGFR, IGF1R, NRG1, NRG2, EGF, IRS2, GAB2, SHP2, CREB1, PIK3CA, PIK3CB, PIK3CD, MTOR, PDK1, AKT1, AKT2, AKT3, JAK2, STAT3, and STAT5. In some embodiments, the gene encoding a positive regulator of signaling via the PI3K / AKT / mTOR pathway is PIK3CA. In some embodiments, the gene encoding a positive regulator of signaling via the PI3K / AKT / mTOR pathway is PIK3CB.

[0146] In some embodiments, genes encoding positive regulators of signaling via the PI3K / AKT / mTOR pathway may be selected from ERBB3, ERBB2, ERBB4, EGFR, IGF1R, NRG1, NRG2, EGF, IRS2, GAB2, SHP2, CREB1, PIK3CB, PIK3CD, MTOR, PDK1, AKT1, AKT2, AKT3, JAK2, STAT3, and STAT5.

[0147] In some embodiments, the gene encoding a negative regulator of HER3-mediated signaling may be selected from PTEN, PPP2CA, PIK3R1, PIK3R2, NF1, BAD, and PHLPP1. In some embodiments, the gene encoding a negative regulator of signaling via the PI3K / AKT / mTOR pathway may be selected from PTEN, PPP2CA, PIK3R1, PIK3R2, BAD, and PHLPP1. In some embodiments, the gene encoding a negative regulator of signaling via the MAPK / ERK pathway may be NF1. In some embodiments, the gene encoding a negative regulator of HER3-mediated signaling is PTEN. In some embodiments, the gene encoding a negative regulator of signaling via the PI3K / AKT / mTOR pathway is PTEN.

[0148] In some embodiments, genes encoding negative regulators of HER3-mediated signaling may be selected from PPP2CA, PIK3R1, PIK3R2, NF1, BAD, and PHLPP1. In some embodiments, genes encoding negative regulators of signaling via the PI3K / AKT / mTOR pathway may be selected from PPP2CA, PIK3R1, PIK3R2, BAD, and PHLPP1.

[0149] In some embodiments, the cancer to be treated / prevented includes cells expressing ligands for HER3 (e.g., NRG1 and / or NRG2). In some embodiments, the cancer to be treated / prevented includes cells expressing NRG1 and / or NRG2 at levels higher than those expressed by equivalent non-cancerous cells / non-tumor tissues. The cancer may be described as including cells that overexpress NRG1 and / or NRG2.

[0150] The HER3-binding antigen-binding molecules described herein bind to HER3 with very high affinity, whether the NRG is bound to HER3 (i.e., HER3 is provided in an "open" structure) or not (i.e., HER3 is provided in a "closed" structure). Therefore, they are particularly useful for the treatment / prevention of cancers characterized by HER3 ligand expression / overexpression, such as cancers / tumors containing cells that express / overexpress ligands for HER3.

[0151] The aspects and embodiments described herein are intended to result in genetic diversity (e.g., mutation or gene amplification) that leads to increased expression of ligands (genes and / or proteins) for HER3.

[0152] Genetic diversity that causes increased expression of ligands for HER3 can result in the gene or protein expression of ligands for HER3 that are not expressed in equivalent cells lacking that genetic diversity, and / or are not encoded by their genomic nucleic acids. In other words, since ligands for HER3 can be nascent antigens resulting from genetic diversity, “increased expression” can be from non-expression. As an example, cells containing the CD74-NRG1 gene fusion show increased expression of the CD74-NRG1 fusion polypeptide encoded by that gene fusion compared to cells lacking the CD74-NRG1 gene fusion.

[0153] Genetic diversity that causes increased expression of ligands for HER3 may result in increased gene or protein expression of ligands for HER3 expressed by equivalent cells that do not contain that genetic diversity, and / or encoded by their genomic nucleic acids. For example, a cell may contain genetic diversity that results in increased transcription levels of the nucleic acid encoding NRG1 compared to equivalent cells that do not contain that genetic diversity.

[0154] In some embodiments, genetic diversity that causes increased expression of ligands for HER3 can lead to increased gene expression of ligands for HER3 compared to equivalent cells that lack that genetic diversity.

[0155] In some embodiments, genetic diversity that causes increased expression of ligands for HER3 may result in increased levels of ligands for HER3 on or at the cell surface of cells containing that genetic diversity compared to equivalent cells that do not contain that genetic diversity. In some embodiments, genetic diversity that causes increased expression of ligands for HER3 may result in increased levels of ligand secretion for HER3 from cells containing that genetic diversity compared to equivalent cells that do not contain that genetic diversity.

[0156] Cells in which the expression of a ligand for HER3 is elevated (e.g., as a result of mutation) compared to the level of ligand expression in reference cells may be described as “overexpressing” the ligand for HER3 or having “upregulated expression” of the ligand for HER3. For example, a cancer containing cells that have the genetic diversity resulting in elevated expression of the ligand for HER3 compared to equivalent cells lacking that genetic diversity may be described as a cancer containing cells that exhibit overexpression / upregulated expression of the ligand for HER3. In some embodiments, the reference cells lacking genetic diversity may be non-cancerous cells (e.g., equivalent cell types) or cancerous cells (e.g., equivalent cancer types).

[0157] In this specification, “ligand for HER3” is generally intended to refer to a molecule that can bind to HER3 via the ligand-binding region of HER3, which is formed by domains I and III of HER3. In some embodiments, ligands for HER3 bind to HER3 via interaction with domains I and / or III of HER3. Exemplary ligands for HER3 include neuregulins, e.g., NRG1 and NRG2, which bind to HER3 via interaction between their EGF-like domains and the ligand-binding region of HER3.

[0158] HER3 ligands can preferably bind to HER3 receptors and / or receptor complexes containing HER3 to induce signaling through them. As is evident from this disclosure, receptor complexes containing HER3 may further include HER3 interaction partners described herein, such as HER3, HER2, EGFR, HER4, HGFR, IGF1R, and / or cMet.

[0159] In some embodiments, a ligand for HER3 can bind to a HER3 receptor / receptor complex expressed by cells other than those expressing elevated HER3 ligands. For example, in some embodiments, a ligand for HER3 can bind to HER3-expressing cancer cells.

[0160] In some embodiments, a ligand for HER3 can bind to a HER3 receptor / receptor complex expressed in cells with elevated HER3 ligand expression. In some embodiments, the cancer to be treated / prevented includes (i) cells expressing HER3, and (ii) cells expressing ligands for HER3 (e.g., cells with elevated ligand expression for HER3 as a result of genetic diversity that leads to elevated ligand expression for HER3).

[0161] In some embodiments, the cancer to be treated / prevented includes cells that (i) express HER3 and (ii) further express ligands for HER3 (e.g., elevated expression of ligands for HER3 as a result of genetic diversity that leads to elevated expression of ligands for HER3).

[0162] In some embodiments, the ligand for HER3 comprises or consists of the amino acid sequence of the HER3 binding region of the ligand for HER3, or an amino acid sequence derived from the HER3 binding region of the ligand for HER3. The amino acid sequence derived from the HER3 binding region of the ligand for HER3 may have at least 60% (e.g., 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) amino acid sequence identity with respect to the source amino acid sequence.

[0163] In some embodiments, the ligand for HER3 includes an EGF-like domain or a HER3-binding fragment thereof that can bind to HER3. In some embodiments, the HER3-binding EGF-like domain / fragment is or derived from an EGF family member (e.g., heparin-binding EGF-like growth factor (HB-EGF), transforming growth factor-α (TGF-α), amphiregulin (AR), epiregulin (EPR), epigen, beta-cerulin (BTC), NRG1, NRG2, NRG3, or NRG4).

[0164] Exemplary ligands for HER3 include neuregulin (NRG). Neuregulin includes NRG1 (including its alpha, alpha 2b, and alpha 3 isoforms), NRG2, NRG3, and NRG4. In some embodiments, NRG is selected from NRG1, NRG2, NRG3, and NRG4. In some embodiments, NRG is selected from NRG1 and NRG2.

[0165] The EGF-like domain of human NRG1, which binds to HER3 via this, is formed at positions 178-222 of UniProt:Q02297-1. The EGF-like domain of human NRG2 is formed at positions 341-382 of UniProt:O14511-1. The EGF-like domain of human NRG3 is formed at positions 286-329 of UniProt:B9EGV5-1. The EGF-like domain of human NRG4 is formed at positions 5-46 of UniProt:Q8WWG1-1. In some embodiments, the EGF-like domain / fragment comprises or consists of an amino acid sequence having at least 60% (e.g., 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) amino acid sequence identity with respect to the EGF-like domain of NRG (NRG1, NRG2, NRG3, or NRG4).

[0166] In some embodiments, the ligand for HER3 is not an EGFR family protein (e.g., HER3, HER2, EGFR, HER4, HGFR, IGF1R, cMet).

[0167] In some embodiments, the genetic diversity resulting in increased expression of a ligand for HER3 is the NRG gene fusion. In some embodiments, the ligand for HER3 is the product of the NRG gene fusion (i.e., the polypeptide encoded by the NRG gene fusion). In some embodiments, the cancer comprises cells having an NRG gene fusion. As used herein, “NRG gene fusion” refers to a genetic variant encoding a polypeptide comprising (i) the amino acid sequence of an NRG protein (e.g., NRG1, NRG2, NRG3, or NRG4; e.g., NRG1 or NRG2) and (ii) the amino acid sequence of a protein other than an NRG protein.

[0168] NRG gene fusions can be detected and characterized using appropriate molecular assays well known to those skilled in the art. The NRG gene fusions described herein preferably encode a fusion polypeptide that is correctly oriented (i.e., the nucleotide sequence encoding NRG is located at the 3' end of the transcript) and contains an EGF-like domain capable of binding to HER3.

[0169] The NRG gene fusion is preferably understood to encode a HER3 ligand as 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 that can bind to HER3 and has at least 60% (e.g., 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) amino acid sequence identity to the EGF-like domain of the NRG protein.

[0170] In some embodiments, the NRG gene fusion encodes a fusion polypeptide containing a transmembrane domain. In some embodiments, the NRG gene fusion encodes a fusion polypeptide containing a transmembrane domain of a protein other than the NRG protein.

[0171] In some embodiments, the NRG gene fusion is an NRG1 gene fusion. In some embodiments, the NRG1 gene fusion encodes an amino acid sequence that can bind to a polypeptide containing the EGF-like domain of NRG1 or to HER3, and has at least 60% (e.g., 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) amino acid sequence identity with respect to the EGF-like domain of NRG1.

[0172] NRG1 gene fusions are actionable fusions in tissue-agnostic cancers that can be targeted via HER3 inhibition. These fusions are formed by interchromosomal translocations of diverse gene sets, leading to overproduction of NRG1 ligands for HER3 binding, and abnormal activation results in tumorigenesis. Studies have demonstrated a causal relationship between HER3 pathway activation and NRG1 gene fusions. NRG1 fusions are enriched among subjects with mucinous non-small cell lung cancer and pancreatic ductal adenocarcinoma, with 8–32% of subjects with mucinous NSCLC having NRG1 gene fusions, while 10–20% (up to 70% in smaller studies) of subjects with KRAS wild-type PDAC have detectable NRG1 gene fusions. The therapeutic utility of monoclonal anti-HER3 antibody therapy targeting NRG1 gene fusions is demonstrated, for example, in International Publication No. 2021 / 048274.

[0173] NRG1 gene fusions are described, for example, in International Publication No. 2021 / 048274, International Publication No. 2018 / 182422, International Publication No. 2019 / 051155, Dhanasekaran et al., Nat Commun. (2014) 5:5893, Drilon et al., Cancer Discov. (2018) 8(6):686~695, Nagasaka et al., Journal of Thoracic Oncology (2019) 14(8):1354~1359, and Jonna et al., Clin Cancer Res. (2019) 25(16):4966~4972, all of which are incorporated herein by reference. The diversity of NRG1 gene fusions may arise from NRG1 located on chromosome 8, which is particularly sensitive to genomic translocation events (Adelaide et al., Genes Chromosomes Cancer. (2003) 37(4):333~45).

[0174] In some embodiments, the NRG1 gene fusion is CLU-NRG1, CD74-NRG1, DOC4-NRG1, SLC3A2-NRG1, RBPMS-NRG1, WRN-NRG1, SDC4-NRG1, RAB2IL1-NRG1, VAMP2-NRG1, KIF13B-NRG1, THAP7-NRG1, SMAD4-NRG1, MDK-NRG1, TNC-NRG1, DIP2B-NRG1, MRPL13 -NRG1 is selected from PARP8-NRG1, ROCK1-NRG1, DPYSL2-NRG1, ATP1B1-NRG1, CDH6-NRG1, APP-NRG1, AKAP13-NRG1, THBS1-NRG1, FOXA1-NRG1, PDE7A-NRG1, RAB3IL1-NRG1, CDK1-NRG1, BMPRIB-NRG1, TNFRSF10B-NRG1, and MCPH1-NRG1. In some embodiments, the NRG1 gene fusion is CLU-NRG1.

[0175] CD74-NRG1 gene fusions are described, for example, by Fernandez-Cuesta et al., Cancer Discov. (2014) 4:415~22, and by Nakaoku et al., Clin Cancer Res (2014) 20:3087~93. DOC4-NRG1 gene fusions are described, for example, by Liu et al., Oncogene. (1999) 18(50):7110~4, and by Wang et al., Oncogene. (1999) 18(41):5718~21. SLC3A2-NRG1 gene fusions are described, for example, by Nakaoku et al., Clin Cancer Res (2014) 20:3087~93, by Shin et al., Oncotarget (2016) 7:69450~65, and by Shin et al., Mol Cancer Ther. (2018) 17(9):2024~2033. Gene fusions of RBPMS-NRG1, WRN-NRG1, RAB2IL1-NRG1, and SDC4-NRG1 are described, for example, by Dhanasekaran et al., Nat Commun. (2014) 5:5893. Gene fusions of VAMP2-NRG1 are 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. Gene fusions of KIF13B-NRG1 are described, for example, by Xia et al., Int J Surg 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., Cancer Discov. (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., Clin Cancer Res. (2019) 25(16):4966~4972.ATP1B1-NRG1 gene fusions are described, for example, by Drilon et al., Cancer Discov. (2018) 8(6):686~695, and by Jones et al., Annals of Oncology (2017) 28:3092~3097. CLU-NRG1 gene fusions are described, for example, by Drilon et al., Cancer Discov. (2018) 8(6):686~695, and by Nagasaka et al., Journal of Thoracic Oncology (2019) 14(8):1354~1359.

[0176] In some embodiments, the NRG gene fusion is an NRG2 gene fusion. In some embodiments, the NRG2 gene fusion encodes an amino acid sequence that can bind to a polypeptide containing the EGF-like domain of NRG2 or to HER3, and has at least 60% (e.g., 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) amino acid sequence identity with respect to the EGF-like domain of NRG2.

[0177] NRG2 gene fusions include, for example, SLC12A2-NRG2 described in International Publication No. 2021 / 048274 and International Publication No. 2015 / 093557, and ZNF208-NRG2 described in Dupain et al., Mol Ther. (2019) 27(1):200~218. cancer This disclosure relates to the treatment and prevention of cancer.

[0178] Cancer as described in this disclosure may be any unwanted cell proliferation (or any disease that manifests itself through unwanted cell proliferation), a neoplasm, or a tumor. Cancer may be benign or malignant. Cancer may be primary or secondary (e.g., metastatic). A neoplasm or tumor may be any abnormal growth or proliferation of cells and may be located in (and / or originate from) any organ / tissue.

[0179] Cancer may be, for example, of cells originating from the adrenal gland, adrenal medulla, anus, appendix, bladder, blood, bone, bone marrow, brain, breast, cecum, central nervous system (with or without brain), cerebellum, cervix, colon, duodenum, endometrium, epithelial cells (e.g., renal epithelium), gallbladder, esophagus, glial cells, heart, ileum, jejunum, kidney, lacrimal gland, larynx, liver, lung, lymph, lymph nodes, lymphoblasts, maxilla, mediastinum, mesentery, myometrium, nasopharynx, reticulum, oral cavity, ovary, pancreas, parotid gland, peripheral nervous system, peritoneum, pleura, prostate, salivary gland, sigmoid colon, skin, small intestine, soft tissue, spleen, stomach, testes, thymus, thyroid gland, tongue, tonsils, trachea, uterus, vulva, and / or leukocytes.

[0180] Cancer may be or may include one or more tumors. Cancer may be a glioma, medulloblastoma, meningioma, neurofibroma, ependymoma, schwannoma, neurofibrosarcoma, astrocytoma and oligodendroglioma, melanoma, mesothelioma, myeloma, lymphoma, non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, cutaneous T-cell lymphoma (CTCL), leukemia, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), hepatoma, epidermal carcinoma, prostate cancer, breast cancer, lung cancer, NSCLC, colon cancer, ovarian cancer, pancreatic cancer, thymic cancer, hematological cancer, or sarcoma.

[0181] In some embodiments, the cancers according to the present disclosure are selected from solid tumors, breast cancer, ductal carcinoma, gastric cancer, gastric adenocarcinoma, colorectal cancer, colorectal adenocarcinoma, head and neck cancer, squamous cell carcinoma of the head and neck (SCCHN), lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, kidney cancer, renal cell carcinoma, renal clear cell carcinoma, renal cell adenocarcinoma, papillary renal cell carcinoma, pancreatic cancer, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, cervical cancer, cervical squamous cell carcinoma, skin cancer, melanoma, esophageal cancer, esophageal adenocarcinoma, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, uterine cancer, endometrial cancer, thyroid cancer, thyroid cancer, pheochromocytoma, paraganglioma, bladder cancer, urothelial carcinoma of the bladder, prostate cancer, prostate adenocarcinoma, sarcoma, and thymoma.

[0182] In some embodiments, the cancer is a cancer comprising cells expressing / overexpressing an EGFR family member (e.g., HER3, EGFR, HER2, or HER4), a cancer comprising cells expressing / overexpressing HER3, a cancer comprising cells expressing / overexpressing EGFR, a cancer comprising cells expressing / overexpressing HER3 and EGFR, a cancer comprising cells having mutations that result in increased expression of a ligand for HER3, or a cancer comprising cells having mutations that result in increased expression of a ligand for EGFR. Cancers containing cells with NRG gene fusion, cancers containing cells with NRG1 gene fusion, or cancers containing cells with NRG2 gene fusion, solid tumors, hematological cancers, squamous cell carcinoma, EGFR-amplifying squamous cell carcinoma, breast cancer, invasive breast cancer, ductal carcinoma, metastatic breast cancer, triple-negative breast cancer, HER2-positive breast cancer, gastric cancer, gastric adenocarcinoma, gastrointestinal adenocarcinoma, colorectal cancer, metastatic colorectal cancer, colon cancer, colorectal cancer, colorectal adenocarcinoma, colon adenocarcinoma, head and neck cancer, head and neck squamous cell carcinoma, lung cancer, non-minor Cellular lung cancer, lung adenocarcinoma, invasive mucinous lung adenocarcinoma, lung squamous cell carcinoma, lung squamous cell carcinoma, squamous non-small cell lung cancer, advanced squamous non-small cell lung cancer, metastatic squamous non-small cell lung cancer, ovarian cancer, ovarian serous adenocarcinoma, ovarian serous cystadenocarcinoma, fallopian tube cancer, kidney cancer, renal cell carcinoma, clear cell carcinoma, renal cell adenocarcinoma, papillary renal cell carcinoma, pancreatic cancer, exocrine cancer, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, advanced pancreatic ductal adenocarcinoma, metastatic pancreatic ductal adenocarcinoma, cervical cancer, cervical squamous cell carcinoma, skin cancer, melanoma, oral cancer, oropharyngeal cancer, esophageal cancer, esophageal squamous cell carcinoma The following are selected: cutaneous carcinoma (ESCC), esophageal adenocarcinoma, liver cancer, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, uterine cancer, endometrial cancer, endometrial carcinoma of the uterine body, uterine carcinosarcoma, thyroid cancer, thyroid cancer, thyroid cancer, pheochromocytoma, paraganglioma, bladder cancer, urothelial carcinoma of the bladder, prostate cancer, prostate adenocarcinoma, retinoblastoma, sarcoma, soft tissue sarcoma, peritoneal cancer, thymoma, neuroendocrine tumors, nasopharyngeal neuroendocrine tumors, squamous cell carcinoma of the skin, astrocytoma, low-grade astrocytoma, high-grade astrocytoma, anaplastic astrocytoma, and glioblastoma multiforme.

[0183] In some embodiments, the cancer to be treated / prevented includes cells expressing EGFR family members (e.g., HER3, EGFR, HER2, or HER4) and / or ligands for EGFR family members. In some embodiments, the cancer to be treated / prevented is a cancer that is positive for EGFR family members. In some embodiments, the cancer includes cells that overexpress EGFR family members and / or ligands for EGFR family members. Overexpression can be determined by detecting expression levels higher than those of equivalent non-cancerous cells / non-tumor tissues.

[0184] Expression can be determined by any appropriate means. Expression may be gene expression or protein expression. Gene expression can be determined, for example, by detecting mRNA encoding HER3, for example by quantitative real-time PCR (qRT-PCR). Protein expression can be determined, for example, by antibody-based methods, for example by Western blotting, immunohistochemistry, immunocytochemistry, flow cytometry, or ELISA.

[0185] In some embodiments, cancer is cancer in which HER3 is pathologically involved. That is, in some embodiments, cancer is cancer caused or aggravated by HER3 expression, cancer in which HER3 expression is a risk factor, and / or cancer in which HER3 expression is positively associated with the onset, development, progression, severity, or metastasis of the cancer. Cancer may be characterized by HER3 expression; for example, cancer may include cells that express HER3 (e.g., cells in tumor tissue). Such cancer may be considered HER3-positive. Cancer that is "HER3-positive" may include cells that express HER3 (e.g., on the cell surface). Cancer that is "HER3-positive" may overexpress HER3.

[0186] In some embodiments, the cancer to be treated / prevented includes cells containing genetic diversity (e.g., mutations) that causes increased expression and / or activity of HER3 (gene and / or protein) compared to equivalent cells containing a reference allele that does not contain genetic diversity (e.g., a non-mutant or "wild-type" allele).

[0187] In some embodiments, a mutation that causes increased HER3 expression may result in elevated levels of HER3 on or near the cell surface of cells containing the mutation compared to equivalent cells that do not contain the mutation.

[0188] Cells whose HER3 expression is elevated (e.g., as a result of a mutation) compared to the level of HER3 expression in reference cells may be described as having “overexpression” of HER3 or “upregulated expression” of HER3. For example, a cancer containing cells that have a mutation resulting in elevated HER3 expression compared to equivalent cells lacking that mutation may be described as a cancer containing cells that exhibit HER3 overexpression / upregulated expression. In some embodiments, the reference cells lacking the mutation may be non-cancerous cells (e.g., equivalent cell types) or cancerous cells (e.g., equivalent cancer types).

[0189] In some embodiments, cancer to be treated / prevented in accordance with this disclosure may be characterized by elevated HER3 expression and / or activity (i.e., gene and / or protein expression) in the affected organ / tissue / subject compared to, for example, a normal organ / tissue / subject (i.e., in the absence of the disease / condition). In some embodiments, cancer cells and / or tumors to be treated / prevented may be characterized by elevated HER3 expression and / or activity compared to, for example, the levels of expression and / or activity observed in equivalent non-cancerous cells / non-tumor tissues.

[0190] HER3-overexpressing cancers can overexpress HER3 as a result of amplification of the HER3 gene. In some embodiments, the cancer to be treated / prevented according to this disclosure is a HER3-amplified cancer.

[0191] HER3 amplification can be identified using techniques well known in the field, such as in situ hybridization. For example, HER3 amplification can be evaluated by fluorescence in situ hybridization, as described, for example, by Chung et al., J Gynecol Oncol. (2019) 30(5):e75.

[0192] In some embodiments, cells containing HER3 amplification contain one HER3 of >2, e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more copies, or a fragment of one HER3 of >2, e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more copies. HER3 amplification can result from gene duplication or polysomaticism. In some embodiments, HER3-amplified cancers may include a HER3 to chromosome 12 ratio ≥1 (e.g., determined by ISH), e.g., ≥1.5, ≥2, ≥2.5. In some embodiments, HER3-amplified cancers may include a HER3 to centromere 12 (CEN12) ratio ≥1 (e.g., determined by ISH), e.g., ≥1.5, ≥2, ≥2.5. In some embodiments, HER3-amplified cancer cells may include HER3 gene copy number (GCN) > 2, ≥ 3, ≥ 4, ≥ 5, ≥ 6, ≥ 7, ≥ 8, ≥ 9, or ≥ 10 (determined, for example, by NGS).

[0193] HER3, and its association with and role in cancer, are outlined, for example, in Mishra et al., Oncol Rev. (2018) 12(1):355, Karachaliou et al., BioDrugs. (2017) 31(1):63-73, and Zhang et al., Acta Biochimica et Biophysica Sinica (2016) 48(1):39-48, all of which are incorporated herein by reference. Mishra et al., Oncol Rev. (2018) 12(1):355 further describes HER3-targeted interventions for the treatment of cancer, including monoclonal anti-HER3 antibody therapy.

[0194] In some aspects and embodiments of this disclosure, the cancers described herein are not identical to the cancers described in International Publication No. 2023 / 017151. That is, in some embodiments, the cancers described herein are not the cancers described in International Publication No. 2023 / 017151. In some aspects and embodiments, the cancers described herein include one or more features that distinguish them from the cancers described in International Publication No. 2023 / 017151.

[0195] As an example, in some embodiments, the cancers according to the Disclosure (e.g., cancers suitable for therapeutic / preventive interventions using antigen-binding molecules that bind to HER3) do not include genetic diversity resulting in increased expression of MET or increased activity of its gene product (e.g., no MET amplification). As a further example, in some embodiments, the cancers according to the Disclosure (e.g., cancers suitable for therapeutic / preventive interventions using antigen-binding molecules that bind to HER3) include genetic diversity resulting in increased expression of one or more genes located within chromosome 3 q26-q28 or increased activity of their gene product (e.g., one or more genes selected from TP63, SOX2, and PIK3CA; e.g., including amplification of one or more TP63, SOX2, and PIK3CA). In some embodiments, the cancer according to this disclosure (e.g., a cancer suitable for therapeutic / preventive intervention using an antigen-binding molecule that binds to HER3) is a cancer that includes genetic diversity resulting in increased expression of one or more genes located within chromosome 7p, or increased activity of their gene products (e.g., one or more genes located within chromosome 7p11; e.g., EGFR; e.g., amplification of EGFR). In some embodiments, the cancer according to this disclosure (e.g., a cancer suitable for therapeutic / preventive intervention using an antigen-binding molecule that binds to HER3) is a cancer that includes genetic diversity resulting in decreased expression of one or more genes located within chromosome 3p, or decreased activity of their gene products (e.g., one or more genes located within chromosome 3p21; e.g., TUSC2; e.g., deletion of TUSC2).

[0196] Conversely, in some embodiments, the cancers according to the Disclosure (e.g., cancers suitable for therapeutic / preventive interventions using an antigen-binding molecule that binds to HER3 in combination with an antagonist of HER3-mediated signaling) include genetic diversity resulting in increased expression of MET or increased activity of its gene product (e.g., including MET amplification). Further illustrating, in some embodiments, the cancers according to the Disclosure (e.g., cancers suitable for therapeutic / preventive interventions using an antigen-binding molecule that binds to HER3 in combination with an antagonist of HER3-mediated signaling) do not include genetic diversity resulting in increased expression of one or more genes located within chromosome 3 q26-q28 or increased activity of their gene product (e.g., one or more genes selected from TP63, SOX2, and PIK3CA; e.g., not including amplification of one or more of TP63, SOX2, and PIK3CA). In some embodiments, cancers according to the disclosure (e.g., cancers suitable for therapeutic / preventive interventions using an antigen-binding molecule that binds to HER3 in combination with an antagonist of HER3-mediated signaling) do not contain genetic diversity resulting in increased expression of one or more genes located on chromosome 7p or increased activity of their gene products (e.g., one or more genes located on chromosome 7p11; e.g., EGFR; e.g., not including amplification of EGFR). In some embodiments, cancers according to the disclosure (e.g., cancers suitable for therapeutic / preventive interventions using an antigen-binding molecule that binds to HER3 in combination with an antagonist of HER3-mediated signaling) do not contain genetic diversity resulting in decreased expression of one or more genes located on chromosome 3p or decreased activity of their gene products (e.g., one or more genes located on chromosome 3p21; e.g., TUSC2; e.g., not including deletion of TUSC2). Cancer characterized by the absence of genetic diversity that leads to increased HER3-mediated signaling. Aspects and embodiments of this disclosure relate to cancers lacking genetic diversity resulting in elevated HER3-mediated signaling. Such cancers may be considered sensitive / highly susceptible / lowly resistant (and therefore likely to respond well) to therapeutic / prophylactic interventions using antigen-binding molecules that bind to HER3 (e.g., as monotherapy). The cancers described in this section may be further characterized by the preceding section titled “Cancer.”

[0197] In the embodiments and aspects of this disclosure, the cancer to be treated / prevented with an antigen-binding molecule that binds to HER3 is characterized by one or more of the following features: (1a)(i) Not homozygous for activating mutations to MET (e.g., activating mutations to MET as described herein). (1a)(ii) Not heterozygous for activating mutations to MET (e.g., activating mutations to MET as described herein). (1a)(iii) Not including amplification of MET (e.g., amplification of MET as described herein). (1a)(iv)Does not contain genetic diversity that results in increased expression of MET or increased activity of its gene product. (2a)(i) Not homozygous for activating mutations to KRAS (e.g., activating mutations to KRAS as described herein). (2a)(ii) Not heterozygous for activating mutations to KRAS (e.g., activating mutations to KRAS as described herein). (2a)(iii) Not including amplification of KRAS (e.g., amplification of KRAS as described herein). (2a)(iv) Does not contain genetic diversity that results in increased KRAS expression or increased activity of its gene product. (3a)(i) Not homozygous for activating mutations to PIK3CA (e.g., activating mutations to PIK3CA as described herein). (3a)(ii) Not heterozygous for an activating mutation to PIK3CA (e.g., an activating mutation to PIK3CA as described herein). (3a)(iii) Amplification of PIK3CA (e.g., amplification of PIK3CA as described herein). (3a)(iv) Does not contain genetic diversity that results in increased expression of PIK3CA or increased activity of its gene product. (4a)(i) Not homozygous for activating mutations to BRAF (e.g., activating mutations to BRAF as described herein). (4a)(ii) Not heterozygous for activating mutations to BRAF (e.g., activating mutations to BRAF as described herein). (4a)(iii) Not including amplification of BRAF (e.g., amplification of BRAF as described herein). (4a)(iv) Does not contain genetic diversity that results in increased expression of BRAF or increased activity of its gene product. (5a)(i) Does not contain genetic diversity that results in reduced expression of PTEN or reduced activity of its gene product. (5a)(ii) Not homozygous for inactivating mutations to PTEN (e.g., inactivating mutations to PTEN as described herein). (5a)(iii) Not heterozygous for inactivating mutations to PTEN (e.g., inactivating mutations to PTEN as described herein). (5a)(iv) Does not contain PTEN deletions (e.g., PTEN deletions as described herein). (6a)(i)Includes genetic diversity that results in increased expression of TP63 or increased activity of its gene product. (6a)(ii) Amplification of TP63 (e.g., amplification of TP63 as described herein). (7a)(i)Includes genetic diversity that results in increased expression of PIK3CA or increased activity of its gene product. (7a)(ii) Amplification of PIK3CA (e.g., amplification of PIK3CA as described herein). (8a)(i)Includes genetic diversity that results in increased expression of SOX2 or increased activity of its gene product. (8a)(ii) Amplification of SOX2 (e.g., amplification of SOX2 as described herein). (9a)(i)Includes genetic diversity that results in increased expression of ligands for HER3 (e.g., those described herein). (9a)(ii) comprising NRG gene fusion (for example, NRG gene fusion as described herein). (9a)(iii) comprising an NRG1 gene fusion (for example, an NRG1 gene fusion as described herein). (10a)(i)Includes genetic diversity that results in increased EGFR expression or increased activity of its gene product. (10a)(ii) Amplification of EGFR (e.g., EGFR amplification as described herein). (11a)(i) Does not contain genetic diversity that results in reduced expression of TUSC2 or reduced activity of its gene product. (11a)(ii) Not including any deletion of TUSC2 (e.g., the deletion of TUSC2 as described herein).

[0198] In some embodiments, cancers to be treated / prevented using antigen-binding molecules that bind to HER3 are combinations of the following features (see previous paragraph): (1a), (2a); (1a), (3a); (1a), (4a); (1a), (5a); (1a), (6a); (1a), (7a); (1a), (8a); (1a), (9a); (1a), (10a); (1a), (11a); (1a), (2a), (3a); (1a), (2a), (4a); (1a), (2a), (5a); (1a), (2a), (6a); (1a), (2a), (7a); (1 a), (2a), (8a); (1a), (2a), (9a); (1a), (2a), (10a); (1a), (2a), (11a);( 1a), (3a), (4a);(1a), (3a), (5a);(1a), (3a), (6a);(1a), (3a), (7a);(1 a), (3a), (8a); (1a), (3a), (9a); (1a), (3a), (10a); (1a), (3a), (11a);( 1a), (4a), (5a); (1a), (4a), (6a); (1a), (4a), (7a); (1a), (4a), (8a); (1a ), (4a), (9a); (1a), (4a), (10a); (1a), (4a), (11a); (1a), (5a), (6a); (1 a), (5a), (7a); (1a), (5a), (8a); (1a), (5a), (9a); (1a), (5a), (10a); (1 a), (5a), (11a); (1a), (6a), (7a); (1a), (6a), (8a); (1a), (6a), (9a); (1 a), (6a), (10a); (1a), (6a), (11a); (1a), (7a), (8a); (1a), (7a), (9a); (1 a), (7a), (10a); (1a), (7a), (11a); (1a), (8a), (9a); (1a), (8a), (10a); (1a), (8a), (11a); (1a), (9a), (10a); (1a), (9a), (11a); (1a), (10a), (11 a);(1a),(2a),(3a),(4a);(1a),(2a),(3a),(5a);(1a),(2a),(3a),(6a );(1a), (2a), (3a), (7a);(1a), (2a), (3a), (8a);(1a), (2a), (3a), (9a);(1a)、(2a)、(3a)、(10a);(1a)、(2a)、(3a)、(11a);(1a)、(2a)、(4a)、(5a);(1a)、(2a)、(4a)、(6a);(1a)、(2a)、(4a)、(7a);(1a)、(2a)、(4a)、(8a); (1a)、(2a)、(4a)、(9a);(1a)、(2a)、(4a)、(10a);(1a)、(2a)、(4a)、(11a);(1a)、(2a)、(5a)、(6a);(1a)、(2a)、(5a)、(7a);(1a)、(2a)、(5a)、(8a);( (1a)、(2a)、(5a)、(9a);(1a)、(2a)、(5a)、(10a);(1a)、(2a)、(5a)、(11a);(1a)、(2a)、(6a)、(7a);(1a)、(2a)、(6a)、(8a);(1a)、(2a)、(6a)、(9a);(1 a)、(2a)、(6a)、(10a);(1a)、(2a)、(6a)、(11a);(1a)、(2a)、(7a)、(8a);(1a)、(2a)、(7a)、(9a);(1a)、(2a)、(7a)、(10a);(1a)、(2a)、(7a)、(11a);( (1a)、(2a)、(8a)、(9a);(1a)、(2a)、(8a)、(10a);(1a)、(2a)、(8a)、(11a);(1a)、(2a)、(9a)、(10a);(1a)、(2a)、(9a)、(11a);(1a)、(2a)、(10a)、(11 a);(1a)、(3a)、(4a)、(5a);(1a)、(3a)、(4a)、(6a);(1a)、(3a)、(4a)、(7a);(1a)、(3a)、(4a)、(8a);(1a)、(3a)、(4a)、(9a);(1a)、(3a)、(4a)、(10a) ;(1a)、(3a)、(4a)、(11a);(1a)、(3a)、(5a)、(6a);(1a)、(3a)、(5a)、(7a);(1a)、(3a)、(5a)、(8a);(1a)、(3a)、(5a)、(9a);(1a)、(3a)、(5a)、(10a); (1a)、(3a)、(5a)、(11a);(1a)、(3a)、(6a)、(7a);(1a)、(3a)、(6a)、(8a);(1a)、(3a)、(6a)、(9a);(1a)、(3a)、(6a)、(10a);(1a)、(3a)、(6a)、(11a);(1a)、(3a)、(7a)、(8a);(1a)、(3a)、(7a)、(9a);(1a)、(3a)、(7a)、(10a);(1a)、(3a)、(7a)、(11a);(1a)、(3a)、(8a)、(9a);(1a)、(3a)、(8a)、(10a); (1a)、(3a)、(8a)、(11a);(1a)、(3a)、(9a)、(10a);(1a)、(3a)、(9a)、(11a);(1a)、(3a)、(10a)、(11a);(1a)、(4a)、(5a)、(6a);(1a)、(4a)、(5a)、(7a) ;(1a)、(4a)、(5a)、(8a);(1a)、(4a)、(5a)、(9a);(1a)、(4a)、(5a)、(10a); (1a)、(4a)、(5a)、(11a);(1a)、(4a)、(6a)、(7a);(1a)、(4a)、(6a)、(8a);( 1a)、(4a)、(6a)、(9a);(1a)、(4a)、(6a)、(10a);(1a)、(4a)、(6a)、(11a);( 1a)、(4a)、(7a)、(8a);(1a)、(4a)、(7a)、(9a);(1a)、(4a)、(7a)、(10a);(1 a)、(4a)、(7a)、(11a);(1a)、(4a)、(8a)、(9a);(1a)、(4a)、(8a)、(10a);( 1a)、(4a)、(8a)、(11a);(1a)、(4a)、(9a)、(10a);(1a)、(4a)、(9a)、(11a); (1a)、(4a)、(10a)、(11a);(1a)、(5a)、(6a)、(7a);(1a)、(5a)、(6a)、(8a);(1a)、(5a)、(6a)、(9a);(1a)、(5a)、(6a)、(10a);(1a)、(5a)、(6a)、(11a); (1a), (5a), (7a), (8a); (1a), (5a), (7a), (9a); (1a), (5a), (7a), (10a); (1a), (5a), (7a), (11a); (1a), (5a), (8a), (9a); (1a), (5a), (8a), (10a); (1a)、(5a)、(8a)、(11a);(1a)、(5a)、(9a)、(10a);(1a)、(5a)、(9a)、(11a);(1a)、(5a)、(10a)、(11a);(1a)、(6a)、(7a)、(8a);(1a)、(6a)、(7a)、(9a);(1a)、(6a)、(7a)、(10a);(1a)、(6a)、(7a)、(11a);(1a)、(6a)、(8a)、(9a) ;(1a)、(6a)、(8a)、(10a);(1a)、(6a)、(8a)、(11a);(1a)、(6a)、(9a)、(10a) (1a)、(6a)、(9a)、(11a);(1a)、(6a)、(10a)、(11a);(1a)、(7a)、(8a)、(9a);(1a)、(7a)、(8a)、(10a);(1a)、(7a)、(8a)、(11a);(1a)、(7a)、(9a)、(1 (0a);(1a)、(7a)、(9a)、(11a);(1a)、(7a)、(10a)、(11a);(1a)、(8a)、(9a)、(10a);(1a)、(8a)、(9a)、(11a);(1a)、(8a)、(10a)、(11a);(1a)、(9a)、(1 (0a)、(11a);(1a)、(2a)、(3a)、(4a)、(5a);(1a)、(2a)、(3a)、(4a)、(6a);(1a)、(2a)、(3a)、(4a)、(7a);(1a)、(2a)、(3a)、(4a)、(8a);(1a)、(2a)、(3a) (4a) (9a); (1a) (2a) (3a) (4a) (10a); (1a) (2a) (3a) (4a) (11a); (1a) (2a) (3a) (5a) (6a); (1a) (2a) (3a) (5a) (7a); (1a) (2a) (3a)、(5a)、(8a);(1a)、(2a)、(3a)、(5a)、(9a);(1a)、(2a)、(3a)、(5a)、(10a);(1a)、(2a)、(3a)、(5a)、(11a);(1a)、(2a)、(3a)、(6a)、(7a);(1a)、(2 a)、(3a)、(6a)、(8a);(1a)、(2a)、(3a)、(6a)、(9a);(1a)、(2a)、(3a)、(6a)、(10a);(1a)、(2a)、(3a)、(6a)、(11a);(1a)、(2a)、(3a)、(7a)、(8a);(1a) (2a), (3a), (7a), (9a); (1a), (2a), (3a), (7a), (10a); (1a), (2a), (3a), (7a), (11a); (1a), (2a), (3a), (8a), (9a); (1a), (2a), (3a), (8a), (10a);(1a)、(2a)、(3a)、(8a)、(11a);(1a)、(2a)、(3a)、(9a)、(10a);(1a)、(2a)、(3a)、(9a)、(11a);(1a)、(2a)、(3a)、(10a)、(11a);(1a)、(2a)、(4a)、(5a)、 (6a);(1a)、(2a)、(4a)、(5a)、(7a);(1a)、(2a)、(4a)、(5a)、(8a);(1a)、(2a)、(4a)、(5a)、(9a);(1a)、(2a)、(4a)、(5a)、(10a);(1a)、(2a)、(4a)、(5a) 、(11a);(1a)、(2a)、(4a)、(6a)、(7a);(1a)、(2a)、(4a)、(6a)、(8a);(1a)、 (2a)、(4a)、(6a)、(9a);(1a)、(2a)、(4a)、(6a)、(10a);(1a)、(2a)、(4a)、(6 a)、(11a);(1a)、(2a)、(4a)、(7a)、(8a);(1a)、(2a)、(4a)、(7a)、(9a);(1a)、(2a)、(4a)、(7a)、(10a);(1a)、(2a)、(4a)、(7a)、(11a);(1a)、(2a)、(4a) (8a) (9a); (1a) (2a) (4a) (8a) (10a); (1a) (2a) (4a) (8a) (11a); (1a) (2a) (4a) (9a) (10a); (1a) (2a) (4a) (9a) (11a); (1a) (2a) (4a) (9a) (11a) (1a) (2a) (4a)、(10a)、(11a);(1a)、(2a)、(5a)、(6a)、(7a);(1a)、(2a)、(5a)、(6a)、(8a);(1a)、(2a)、(5a)、(6a)、(9a);(1a)、(2a)、(5a)、(6a)、(10a);(1a)、(2 a)、(5a)、(6a)、(11a);(1a)、(2a)、(5a)、(7a)、(8a);(1a)、(2a)、(5a)、(7a)、(9a);(1a)、(2a)、(5a)、(7a)、(10a);(1a)、(2a)、(5a)、(7a)、(11a);(1a) (2a), (5a), (8a), (9a); (1a), (2a), (5a), (8a), (10a); (1a), (2a), (5a), (8a), (11a); (1a), (2a), (5a), (9a), (10a); (1a), (2a), (5a), (9a), (11a);(1a), (2a), (5a), (10a), (11a); (1a), (2a), (6a), (7a), (8a); (1a), (2a), (6a), (7a), (9a); (1a), (2a), (6a), (7a), (10a); (1a), (2a), (6a), (7a), (11a); (1a), (2a), (6a), (8a), (9a); (1a), (2a), (6a), (8a), (10a; (1a), (2a), (6a), (8a), (11a); (1a), (2a), (6a), (9a), (10a); (1a), (2a), (6a), (9a), (11a); (1a), (2a), (6a), (10a), (11a); (1a), (2a), (7a) (8a)、(9a);(1a)、(2a)、(7a)、(8a)、(10a);(1a)、(2a)、(7a)、(8a)、(11a);(1a)、(2a)、(7a)、(9a)、(10a);(1a)、(2a)、(7a)、(9a)、(11a);(1a)、(2a) (7a), (10a), (11a); (1a), (2a), (8a), (9a), (10a); (1a), (2a), (8a), (9a), (11a); (1a), (2a), (8a), (10a), (11a); (1a), (2a), (9a), (10a), (11a (1a), (3a), (4a), (5a), (6a); (1a), (3a), (4a), (5a), (7a); (1a), (3a), (4a), (5a), (8a); (1a), (3a), (4a), (5a), (9a); (1a), (3a), (4a), (5a) 10a);(1a)、(3a)、(4a)、(5a)、(11a);(1a)、(3a)、(4a)、(6a)、(7a);(1a)、 (3a)、(4a)、(6a)、(8a);(1a)、(3a)、(4a)、(6a)、(9a);(1a)、(3a)、(4a)、( 6a)、(10a);(1a)、(3a)、(4a)、(6a)、(11a);(1a)、(3a)、(4a)、(7a)、(8a); (1a)、(3a)、(4a)、(7a)、(9a);(1a)、(3a)、(4a)、(7a)、(10a);(1a)、(3a)、( 4a)、(7a)、(11a);(1a)、(3a)、(4a)、(8a)、(9a);(1a)、(3a)、(4a)、(8a)、( 10a);(1a)、(3a)、(4a)、(8a)、(11a);(1a)、(3a)、(4a)、(9a)、(10a);(1a)、 (3a)、(4a)、(9a)、(11a);(1a)、(3a)、(4a)、(10a)、(11a);(1a)、(3a)、(5a)、(6a)、(7a);(1a)、(3a)、(5a)、(6a)、(8a);(1a)、(3a)、(5a)、(6a)、(9a);(1a)、(3a)、(5a)、(6a)、(10a);(1a)、(3a)、(5a)、(6a)、(11a);(1a)、(3a)、(5a)、(7a)、(8a);(1a)、(3a)、(5a)、(7a)、(9a);(1a)、(3a)、(5a)、(7a)、 (10a);(1a)、(3a)、(5a)、(7a)、(11a);(1a)、(3a)、(5a)、(8a)、(9a);(1a)、(3a)、(5a)、(8a)、(10a);(1a)、(3a)、(5a)、(8a)、(11a);(1a)、(3a)、(5a) (9a) (10a); (1a) (3a) (5a) (9a) (11a); (1a) (3a) (5a) (10a) (11a); (1a) (3a) (6a) (7a) (8a); (1a) (3a) (6a) (7a) (9a); (1a) (3a) (6a), (7a), (10a); (1a), (3a), (6a), (7a), (11a); (1a), (3a), (6a), (8a), (9a); (1a), (3a), (6a), (8a), (10a); (1a), (3a), (6a), (8a), (11a); (1 a)、(3a)、(6a)、(9a)、(10a);(1a)、(3a)、(6a)、(9a)、(11a);(1a)、(3a)、(6a)、(10a)、(11a);(1a)、(3a)、(7a)、(8a)、(9a);(1a)、(3a)、(7a)、(8a)、 (10a);(1a)、(3a)、(7a)、(8a)、(11a);(1a)、(3a)、(7a)、(9a)、(10a);(1a)、(3a)、(7a)、(9a)、(11a);(1a)、(3a)、(7a)、(10a)、(11a);(1a)、(3a)、(8 a)、(9a)、(10a);(1a)、(3a)、(8a)、(9a)、(11a);(1a)、(3a)、(8a)、(10a)、(11a);(1a)、(3a)、(9a)、(10a)、(11a);(1a)、(4a)、(5a)、(6a)、(7a);(1a) 、(4a)、(5a)、(6a)、(8a);(1a)、(4a)、(5a)、(6a)、(9a);(1a)、(4a)、(5a)、 (6a)、(10a);(1a)、(4a)、(5a)、(6a)、(11a);(1a)、(4a)、(5a)、(7a)、(8a);(1a)、(4a)、(5a)、(7a)、(9a);(1a)、(4a)、(5a)、(7a)、(10a);(1a)、(4a)、(5a)、(7a)、(11a);(1a)、(4a)、(5a)、(8a)、(9a);(1a)、(4a)、(5a)、(8a)、( 10a);(1a)、(4a)、(5a)、(8a)、(11a);(1a)、(4a)、(5a)、(9a)、(10a);(1a) 、(4a)、(5a)、(9a)、(11a);(1a)、(4a)、(5a)、(10a)、(11a);(1a)、(4a)、(6a )、(7a)、(8a);(1a)、(4a)、(6a)、(7a)、(9a);(1a)、(4a)、(6a)、(7a)、(10a) );(1a)、(4a)、(6a)、(7a)、(11a);(1a)、(4a)、(6a)、(8a)、(9a);(1a)、(4a) 、(6a)、(8a)、(10a);(1a)、(4a)、(6a)、(8a)、(11a);(1a)、(4a)、(6a)、(9a) )、(10a);(1a)、(4a)、(6a)、(9a)、(11a);(1a)、(4a)、(6a)、(10a)、(11a);( 1a)、(4a)、(7a)、(8a)、(9a);(1a)、(4a)、(7a)、(8a)、(10a);(1a)、(4a)、( 7a)、(8a)、(11a);(1a)、(4a)、(7a)、(9a)、(10a);(1a)、(4a)、(7a)、(9a)、( 11a);(1a)、(4a)、(7a)、(10a)、(11a);(1a)、(4a)、(8a)、(9a)、(10a);(1a (1a)、(4a)、(8a)、(10a)、(11a);(1a)、(4a)、(9) a)、(10a)、(11a);(1a)、(5a)、(6a)、(7a)、(8a);(1a)、(5a)、(6a)、(7a)、(9a);(1a)、(5a)、(6a)、(7a)、(10a);(1a)、(5a)、(6a)、(7a)、(11a);(1a)、( (5a)、(6a)、(8a)、(9a);(1a)、(5a)、(6a)、(8a)、(10a);(1a)、(5a)、(6a)、(8a)、(11a);(1a)、(5a)、(6a)、(9a)、(10a);(1a)、(5a)、(6a)、(9a)、(11a);(1a)、(5a)、(6a)、(10a)、(11a);(1a)、(5a)、(7a)、(8a)、(9a);(1a)、(5a)、(7a)、(8a)、(10a);(1a)、(5a)、(7a)、(8a)、(11a);(1a)、(5a)、(7a)、(9a) (10a); (1a), (5a), (7a), (9a), (11a); (1a), (5a), (7a), (10a), (11a); (1a), (5a), (8a), (9a), (10a); (1a), (5a), (8a), (9a), (11a); (1a), (5a), (9a), (11a) (8a)、(10a)、(11a);(1a)、(5a)、(9a)、(10a)、(11a);(1a)、(6a)、(7a)、(8a)、(9a);(1a)、(6a)、(7a)、(8a)、(10a);(1a)、(6a)、(7a)、(8a)、(11a);(1a (6a), (7a), (9a), (10a); (1a), (6a), (7a), (9a), (11a); (1a), (6a), (7a), (10a), (11a); (1a), (6a), (8a), (9a), (10a); (1a), (6a), (8a), (9a), (1) (1a);(1a)、(6a)、(8a)、(10a)、(11a);(1a)、(6a)、(9a)、(10a)、(11a);(1a)、(7a)、(8a)、(9a)、(10a);(1a)、(7a)、(8a)、(9a)、(11a);(1a)、(7a)、(8a (10a) (11a); (1a) (7a) (9a) (10a) (11a); (1a) (8a) (9a) (10a) (11a); (1a) (2a) (3a) (4a) (5a) (6a); (1a) (2a) (3a) (4a) (5a) ( (7a); (1a), (2a), (3a), (4a), (5a), (8a); (1a), (2a), (3a), (4a), (5a), (9a); (1a), (2a), (3a), (4a), (5a), (10a); (1a), (2a), (3a), (4a), (5a), (11 a);(1a)、(2a)、(3a)、(4a)、(6a)、(7a);(1a)、(2a)、(3a)、(4a)、(6a)、(8a);(1a)、(2a)、(3a)、(4a)、(6a)、(9a);(1a)、(2a)、(3a)、(4a)、(6a)、(10a);(1a)、(2a)、(3a)、(4a)、(6a)、(11a);(1a)、(2a)、(3a)、(4a)、(7a)、(8a);(1a)、(2a)、(3a)、(4a)、(7a)、(9a);(1a)、(2a)、(3a)、(4a)、(7a)、(10a); (1a)、(2a)、(3a)、(4a)、(7a)、(11a);(1a)、(2a)、(3a)、(4a)、(8a)、(9a);(1a)、(2a)、(3a)、(4a)、(8a)、(10a);(1a)、(2a)、(3a)、(4a)、(8a)、(11a); (1a)、(2a)、(3a)、(4a)、(9a)、(10a);(1a)、(2a)、(3a)、(4a)、(9a)、(11a);(1a)、(2a)、(3a)、(4a)、(10a)、(11a);(1a)、(2a)、(3a)、(5a)、(6a)、(7a) ;(1a)、(2a)、(3a)、(5a)、(6a)、(8a);(1a)、(2a)、(3a)、(5a)、(6a)、(9a);(1a)、(2a)、(3a)、(5a)、(6a)、(10a);(1a)、(2a)、(3a)、(5a)、(6a)、(11a); (1a)、(2a)、(3a)、(5a)、(7a)、(8a);(1a)、(2a)、(3a)、(5a)、(7a)、(9a);(1a)、(2a)、(3a)、(5a)、(7a)、(10a);(1a)、(2a)、(3a)、(5a)、(7a)、(11a); (1a)、(2a)、(3a)、(5a)、(8a)、(9a);(1a)、(2a)、(3a)、(5a)、(8a)、(10a);(1a)、(2a)、(3a)、(5a)、(8a)、(11a);(1a)、(2a)、(3a)、(5a)、(9a)、(10a); (1a)、(2a)、(3a)、(5a)、(9a)、(11a);(1a)、(2a)、(3a)、(5a)、(10a)、(11a);(1a)、(2a)、(3a)、(6a)、(7a)、(8a);(1a)、(2a)、(3a)、(6a)、(7a)、(9a); (1a)、(2a)、(3a)、(6a)、(7a)、(10a);(1a)、(2a)、(3a)、(6a)、(7a)、(11a);(1a)、(2a)、(3a)、(6a)、(8a)、(9a);(1a)、(2a)、(3a)、(6a)、(8a)、(10a);(1a)、(2a)、(3a)、(6a)、(8a)、(11a);(1a)、(2a)、(3a)、(6a)、(9a)、(10a);(1a)、(2a)、(3a)、(6a)、(9a)、(11a);(1a)、(2a)、 (3a)、(6a)、(10a)、(11a);(1a)、(2a)、(3a)、(7a)、(8a)、(9a);(1a)、(2a)、(3a)、(7a)、(8a)、(10a);(1a)、(2a)、(3a)、(7a); (8a) (11a); (1a) (2a) (3a) (7a) (9a) (10a); (1a) (2a) (3a) (7a) (9a) (11a); (1a) (2a) (3a) (7a) (10a) (11a); (1a) (2a) (3a) (7a) (10a) (11a) (1a) (2a) (3a) (8a) (9a) (10a); (1a) (2a) (3a) (8a) (9a) (11a); (1a) (2a) (3a) (8a) (10a) (11a); (1a) (2a) (3a) (9a) (10a) (11a); (1a) (2a) (4a) (5a (6a) (7a); (1a) (2a) (4a) (5a) (6a) (8a); (1a) (2a) (4a) (5a) (6a) (9a); (1a) (2a) (4a) (5a) (6a) (10a); (1a) (2a) (4a) (5a) (6a) (10a) a)、(11a);(1a)、(2a)、(4a)、(5a)、(7a)、(8a);(1a)、(2a)、(4a)、(5a)、(7a)、(9a);(1a)、(2a)、(4a)、(5a)、(7a)、(10a);(1a)、(2a)、(4a)、(5a)、(7a)、 (11a);(1a)、(2a)、(4a)、(5a)、(8a)、(9a);(1a)、(2a)、(4a)、(5a)、(8a)、(10a);(1a)、(2a)、(4a)、(5a)、(8a)、(11a);(1a)、(2a)、(4a)、(5a)、(9a)、(1 (1a), (2a), (4a), (5a), (9a), (11a); (1a), (2a), (4a), (5a), (10a), (11a); (1a), (2a), (4a), (6a), (7a), (8a); (1a), (2a), (4a), (6a), (7a), (9a) (1a) (2a) (4a) (6a) (7a) (10a) (1a) (2a) (4a) (6a) (7a) (11a) (1a) (2a) (4a) (6a) (8a) (9a) (1a) (2a) (4a) (6a) (8a) (10a) (1a)、(2a)、(4a)、(6a)、(8a)、(11a);(1a)、(2a)、(4a)、(6a)、(9a)、(10a); (1a)、(2a)、(4a)、(6a)、(9a)、(11a);(1a)、(2a)、(4a)、(6a)、(10a)、(11a);(1a)、(2a)、(4a)、(7a)、(8a)、(9a);(1a)、(2a)、(4a)、(7a)、(8a)、(10a);(1a)、(2a)、(4a)、(7a)、(8a)、(11a);(1a)、(2a)、(4a)、(7a)、(9a)、(10a);( (1a)、(2a)、(4a)、(7a)、(9a)、(11a);(1a)、(2a)、(4a)、(7a)、(10a)、(11a);(1a)、(2a)、(4a)、(8a)、(9a)、(10a);(1a)、(2a)、(4a)、(8a)、(9a)、(11a); (1a)、(2a)、(4a)、(8a)、(10a)、(11a);(1a)、(2a)、(4a)、(9a)、(10a)、(11a);(1a)、(2a)、(5a)、(6a)、(7a)、(8a);(1a)、(2a)、(5a)、(6a)、(7a)、(9a); (1a)、(2a)、(5a)、(6a)、(7a)、(10a);(1a)、(2a)、(5a)、(6a)、(7a)、(11a);(1a)、(2a)、(5a)、(6a)、(8a)、(9a);(1a)、(2a)、(5a)、(6a)、(8a)、(10a);( (1a)、(2a)、(5a)、(6a)、(8a)、(11a);(1a)、(2a)、(5a)、(6a)、(9a)、(10a);(1a)、(2a)、(5a)、(6a)、(9a)、(11a);(1a)、(2a)、(5a)、(6a)、(10a)、(11a); (1a)、(2a)、(5a)、(7a)、(8a)、(9a);(1a)、(2a)、(5a)、(7a)、(8a)、(10a);(1a)、(2a)、(5a)、(7a)、(8a)、(11a);(1a)、(2a)、(5a)、(7a)、(9a)、(10a);( (1a)、(2a)、(5a)、(7a)、(9a)、(11a);(1a)、(2a)、(5a)、(7a)、(10a)、(11a);(1a)、(2a)、(5a)、(8a)、(9a)、(10a);(1a)、(2a)、(5a)、(8a)、(9a)、(11a); (1a)、(2a)、(5a)、(8a)、(10a)、(11a);(1a)、(2a)、(5a)、(9a)、(10a)、(11a);(1a)、(2a)、(6a)、(7a)、(8a)、(9a);(1a)、(2a)、(6a)、(7a)、(8a)、(10a);(1a)、(2a)、(6a)、(7a)、(8a)、(11a);(1a)、(2a)、(6a)、(7a)、(9a)、(10a);(1a)、(2a)、(6a)、(7a)、(9a)、(11a);(1a)、(2a)、(6a)、(7a)、(10a)、(11a (1a), (2a), (6a), (8a), (9a), (10a); (1a), (2a), (6a), (8a), (9a), (11a); (1a), (2a), (6a), (8a), (10a), (11a); (1a), (2a), (6a), (9a), (10a), (1) (1a);(1a)、(2a)、(7a)、(8a)、(9a)、(10a);(1a)、(2a)、(7a)、(8a)、(9a)、(11a);(1a)、(2a)、(7a)、(8a)、(10a)、(11a);(1a)、(2a)、(7a)、(9a)、(10a)、 (11a);(1a),(2a),(8a),(9a),(10a),(11a);(1a),(3a),(4a),(5a),(6a),(7a);(1a),(3a),(4a),(5a),(6a),(8a);(1a),(3a),(4a),(5a),(6a),( (9a);(1a)、(3a)、(4a)、(5a)、(6a)、(10a);(1a)、(3a)、(4a)、(5a)、(6a)、(11a);(1a)、(3a)、(4a)、(5a)、(7a)、(8a);(1a)、(3a)、(4a)、(5a)、(7a)、(9a (1a) (3a) (4a) (5a) (7a) (10a) (1a) (3a) (4a) (5a) (7a) (11a) (1a) (3a) (4a) (5a) (8a) (9a) (1a) (3a) (4a) (5a) (8a) (10a) ;(1a)、(3a)、(4a)、(5a)、(8a)、(11a);(1a)、(3a)、(4a)、(5a)、(9a)、(10a);(1a)、(3a)、(4a)、(5a)、(9a)、(11a);(1a)、(3a)、(4a)、(5a)、(10a)、(11a (1a) (3a) (4a) (6a) (7a) (8a) (1a) (3a) (4a) (6a) (7a) (9a) (1a) (3a) (4a) (6a) (7a) (10a) (1a) (3a) (4a) (6a) (7a) (11a)(1a)、(3a)、(4a)、(6a)、(8a)、(9a);(1a)、(3a)、(4a)、(6a)、(8a)、(10a);( 1a)、(3a)、(4a)、(6a)、(8a)、(11a);(1a)、(3a)、(4a)、(6a)、(9a)、(10a);( 1a)、(3a)、(4a)、(6a)、(9a)、(11a);(1a)、(3a)、(4a)、(6a)、(10a)、(11a); (1a)、(3a)、(4a)、(7a)、(8a)、(9a);(1a)、(3a)、(4a)、(7a)、(8a)、(10a);( (1a)、(3a)、(4a)、(7a)、(8a)、(11a);(1a)、(3a)、(4a)、(7a)、(9a)、(10a);(1a)、(3a)、(4a)、(7a)、(9a)、(11a);(1a)、(3a)、(4a)、(7a)、(10a)、(11a); (1a)、(3a)、(4a)、(8a)、(9a)、(10a);(1a)、(3a)、(4a)、(8a)、(9a)、(11a); (1a)、(3a)、(4a)、(8a)、(10a)、(11a);(1a)、(3a)、(4a)、(9a)、(10a)、(11a) (1a) (3a) (5a) (6a) (7a) (8a) (1a) (3a) (5a) (6a) (7a) (9a) (1a) (3a) (5a) (6a) (7a) (10a) (1a) (3a) (5a) (6a) (7a) (11a) (1a)、(3a)、(5a)、(6a)、(8a)、(9a);(1a)、(3a)、(5a)、(6a)、(8a)、(10a);(1a)、(3a)、(5a)、(6a)、(8a)、(11a);(1a)、(3a)、(5a)、(6a)、(9a)、(10a);( (1a)、(3a)、(5a)、(6a)、(9a)、(11a);(1a)、(3a)、(5a)、(6a)、(10a)、(11a);(1a)、(3a)、(5a)、(7a)、(8a)、(9a);(1a)、(3a)、(5a)、(7a)、(8a)、(10a);( (1a)、(3a)、(5a)、(7a)、(8a)、(11a);(1a)、(3a)、(5a)、(7a)、(9a)、(10a);(1a)、(3a)、(5a)、(7a)、(9a)、(11a);(1a)、(3a)、(5a)、(7a)、(10a)、(11a);(1a)、(3a)、(5a)、(8a)、(9a)、(10a);(1a)、(3a)、(5a)、(8a)、(9a)、(11a);(1a)、(3a)、(5a)、(8a)、(10a)、(11a);(1a)、(3a)、(5a)、(9a)、(10a)、(11a (1a) (3a) (6a) (7a) (8a) (9a) (1a) (3a) (6a) (7a) (8a) (10a) (1a) (3a) (6a) (7a) (8a) (11a) (1a) (3a) (6a) (7a) (9a) (10a) (1a)、(3a)、(6a)、(7a)、(9a)、(11a);(1a)、(3a)、(6a)、(7a)、(10a)、(11a);(1a)、(3a)、(6a)、(8a)、(9a)、(10a);(1a)、(3a)、(6a)、(8a)、(9a)、(11a) ;(1a)、(3a)、(6a)、(8a)、(10a)、(11a);(1a)、(3a)、(6a)、(9a)、(10a)、(11a);(1a)、(3a)、(7a)、(8a)、(9a)、(10a);(1a)、(3a)、(7a)、(8a)、(9a)、(11a (1a) (3a) (7a) (8a) (10a) (11a) (1a) (3a) (7a) (9a) (10a) (11a) (1a) (3a) (8a) (9a) (10a) (11a) (1a) (4a) (5a) (6a) (7a) ( (8a);(1a)、(4a)、(5a)、(6a)、(7a)、(9a);(1a)、(4a)、(5a)、(6a)、(7a)、(10a);(1a)、(4a)、(5a)、(6a)、(7a)、(11a);(1a)、(4a)、(5a)、(6a)、(8a)、(9a) ;(1a)、(4a)、(5a)、(6a)、(8a)、(10a);(1a)、(4a)、(5a)、(6a)、(8a)、(11a) ;(1a)、(4a)、(5a)、(6a)、(9a)、(10a);(1a)、(4a)、(5a)、(6a)、(9a)、(11a) ;(1a)、(4a)、(5a)、(6a)、(10a)、(11a);(1a)、(4a)、(5a)、(7a)、(8a)、(9a);(1a)、(4a)、(5a)、(7a)、(8a)、(10a);(1a)、(4a)、(5a)、(7a)、(8a)、(11a);(1a)、(4a)、(5a)、(7a)、(9a)、(10a);(1a)、(4a)、(5a)、(7a)、(9a)、(11a);(1a)、(4a)、(5a)、(7a)、(10a)、(11a);(1a)、(4a)、(5a)、(8a)、(9a)、(10a);(1a)、(4a)、(5a)、(8a)、(9a); (11a); (1a), (4a), (5a), (8a), (10a), (11a); (1a), (4a), (5a), (9a), (10a), (11a); (1a), (4a), (6a), (7a), (8a), (9a); (1a), (4a), (6a), (7a), ( 8a)、(10a);(1a)、(4a)、(6a)、(7a)、(8a)、(11a);(1a)、(4a)、(6a)、(7a)、 (9a)、(10a);(1a)、(4a)、(6a)、(7a)、(9a)、(11a);(1a)、(4a)、(6a)、(7a) 、(10a)、(11a);(1a)、(4a)、(6a)、(8a)、(9a)、(10a);(1a)、(4a)、(6a)、(8 a)、(9a)、(11a);(1a)、(4a)、(6a)、(8a)、(10a)、(11a);(1a)、(4a)、(6a)、 (9a)、(10a)、(11a);(1a)、(4a)、(7a)、(8a)、(9a)、(10a);(1a)、(4a)、(7a) )、(8a)、(9a)、(11a);(1a)、(4a)、(7a)、(8a)、(10a)、(11a);(1a)、(4a)、(7 a)、(9a)、(10a)、(11a);(1a)、(4a)、(8a)、(9a)、(10a)、(11a);(1a)、(5a)、(6a)、(7a)、(8a)、(9a);(1a)、(5a)、(6a)、(7a)、(8a)、(10a);(1a)、(5a) (6a), (7a), (8a), (11a); (1a), (5a), (6a), (7a), (9a), (10a); (1a), (5a), (6a), (7a), (9a), (11a); (1a), (5a), (6a), (7a), (10a), (11a); (1a), (5a), (5a), (6a), (7a), (10a), (11a); (1a), (5 a)、(6a)、(8a)、(9a)、(10a);(1a)、(5a)、(6a)、(8a)、(9a)、(11a);(1a)、(5a)、(6a)、(8a)、(10a)、(11a);(1a)、(5a)、(6a)、(9a)、(10a)、(11a);(1a (5a), (7a), (8a), (9a), (10a); (1a), (5a), (7a), (8a), (9a), (11a); (1a), (5a), (7a), (8a), (10a), (11a); (1a), (5a), (7a), (9a), (10a), (11a);(1a)、(5a)、(8a)、(9a)、(10a)、(11a);(1a)、(6a)、(7a)、(8a)、(9a)、(10a);(1a)、(6a)、(7a)、(8a)、(9a)、(11a);(1a)、(6a)、(7a)、(8a)、(10a)、( (11a);(1a)、(6a)、(7a)、(9a)、(10a)、(11a);(1a)、(6a)、(8a)、(9a)、(10a)、(11a);(1a)、(7a)、(8a)、(9a)、(10a)、(11a);(1a)、(2a)、(3a)、(4a)、 (5a)、(6a)、(7a);(1a)、(2a)、(3a)、(4a)、(5a)、(6a)、(8a);(1a)、(2a)、(3a)、(4a)、(5a)、(6a)、(9a);(1a)、(2a)、(3a)、(4a)、(5a)、(6a)、(10a); (1a), (2a), (3a), (4a), (5a), (6a), (11a); (1a), (2a), (3a), (4a), (5a), (7a), (8a); (1a), (2a), (3a), (4a), (5a), (7a), (9a); (1a), (2a), (3a), (4a), (5a), (7a), (9a) (4a), (5a), (7a), (10a); (1a), (2a), (3a), (4a), (5a), (7a), (11a); (1a), (2a), (3a), (4a), (5a), (8a), (9a); (1a), (2a), (3a), (4a), (5a), (8a) (10a);(1a)、(2a)、(3a)、(4a)、(5a)、(8a)、(11a);(1a)、(2a)、(3a)、(4a)、(5a)、(9a)、(10a);(1a)、(2a)、(3a)、(4a)、(5a)、(9a)、(11a);(1a)、(2 a)、(3a)、(4a)、(5a)、(10a)、(11a);(1a)、(2a)、(3a)、(4a)、(6a)、(7a)、(8a);(1a)、(2a)、(3a)、(4a)、(6a)、(7a)、(9a);(1a)、(2a)、(3a)、(4a)、( (6a)、(7a)、(10a);(1a)、(2a)、(3a)、(4a)、(6a)、(7a)、(11a);(1a)、(2a)、(3a)、(4a)、(6a)、(8a)、(9a);(1a)、(2a)、(3a)、(4a)、(6a)、(8a)、(10a);(1a)、(2a)、(3a)、(4a)、(6a)、(8a)、(11a);(1a)、(2a)、(3a)、(4a)、(6a)、(9a)、(10a);(1a)、(2a)、(3a)、(4a)、(6a)、(9a)、(11a);(1a)、(2a)、(3a (4a), (6a), (10a), (11a); (1a), (2a), (3a), (4a), (7a), (8a), (9a); (1a), (2a), (3a), (4a), (7a), (8a), (10a); (1a), (2a), (3a), (4a), (7a), (8a) a)、(11a);(1a)、(2a)、(3a)、(4a)、(7a)、(9a)、(10a);(1a)、(2a)、(3a)、(4a)、(7a)、(9a)、(11a);(1a)、(2a)、(3a)、(4a)、(7a)、(10a)、(11a);(1a (2a), (3a), (4a), (8a), (9a), (10a); (1a), (2a), (3a), (4a), (8a), (9a), (11a); (1a), (2a), (3a), (4a), (8a), (10a), (11a); (1a), (2a), (3a) (4a), (9a), (10a), (11a); (1a), (2a), (3a), (5a), (6a), (7a), (8a); (1a), (2a), (3a), (5a), (6a), (7a), (9a); (1a), (2a), (3a), (5a), (6a), (7a) (10a);(1a)、(2a)、(3a)、(5a)、(6a)、(7a)、(11a);(1a)、(2a)、(3a)、(5a)、(6a)、(8a)、(9a);(1a)、(2a)、(3a)、(5a)、(6a)、(8a)、(10a);(1a)、(2a) (3a), (5a), (6a), (8a), (11a); (1a), (2a), (3a), (5a), (6a), (9a), (10a); (1a), (2a), (3a), (5a), (6a), (9a), (11a); (1a), (2a), (3a), (5a), (6a), (9a), (11a) a)、(10a)、(11a);(1a)、(2a)、(3a)、(5a)、(7a)、(8a)、(9a);(1a)、(2a)、(3a)、(5a)、(7a)、(8a)、(10a);(1a)、(2a)、(3a)、(5a)、(7a)、(8a)、(11a);(1a)、(2a)、(3a)、(5a)、(7a)、(9a)、(10a);(1a)、(2a)、(3a)、(5a)、(7a)、(9a)、(11a);(1a)、(2a)、(3a)、(5a)、(7a)、(10a)、(11a);(1a)、(2a)、(3a (5a), (8a), (9a), (10a); (1a), (2a), (3a), (5a), (8a), (9a), (11a); (1a), (2a), (3a), (5a), (8a), (10a), (11a); (1a), (2a), (3a), (5a), (8a), (10a), (11a); (1a), (2a), (3a), (5a), (9a) (10a)、(11a);(1a)、(2a)、(3a)、(6a)、(7a)、(8a)、(9a);(1a)、(2a)、(3a)、(6a)、(7a)、(8a)、(10a);(1a)、(2a)、(3a)、(6a)、(7a)、(8a)、(11a);(1a) (2a), (3a), (6a), (7a), (9a), (10a); (1a), (2a), (3a), (6a), (7a), (9a), (11a); (1a), (2a), (3a), (6a), (7a), (10a), (11a); (1a), (2a), (3a), (6a) a)、(8a)、(9a)、(10a);(1a)、(2a)、(3a)、(6a)、(8a)、(9a)、(11a);(1a)、(2a)、(3a)、(6a)、(8a)、(10a)、(11a);(1a)、(2a)、(3a)、(6a)、(9a)、(10a) (11a); (1a), (2a), (3a), (7a), (8a), (9a), (10a); (1a), (2a), (3a), (7a), (8a), (9a), (11a); (1a), (2a), (3a), (7a), (8a), (10a), (11a); (1a) (2a)、(3a)、(7a)、(9a)、(10a)、(11a);(1a)、(2a)、(3a)、(8a)、(9a)、(10a)、(11a);(1a)、(2a)、(4a)、(5a)、(6a)、(7a)、(8a);(1a)、(2a)、(4a)、(5a) (6a), (7a), (9a); (1a), (2a), (4a), (5a), (6a), (7a), (10a); (1a), (2a), (4a), (5a), (6a), (7a), (11a); (1a), (2a), (4a), (5a), (6a), (8a), (9a);(1a)、(2a)、(4a)、(5a)、(6a)、(8a)、(10a);(1a)、(2a)、(4a)、(5a)、(6a)、 (8a)、(11a);(1a)、(2a)、(4a)、(5a)、(6a)、(9a)、(10a);(1a)、(2a)、(4a) (5a), (6a), (9a), (11a); (1a), (2a), (4a), (5a), (6a), (10a), (11a); (1a), (2a), (4a), (5a), (7a), (8a), (9a); (1a), (2a), (4a), (5a), (7a), (8a) (10a); (1a), (2a), (4a), (5a), (7a), (8a), (11a); (1a), (2a), (4a), (5a), (7a), (9a), (10a); (1a), (2a), (4a), (5a), (7a), (9a), (11a); (1a) (2a)、(4a)、(5a)、(7a)、(10a)、(11a);(1a)、(2a)、(4a)、(5a)、(8a)、(9a)、(10a);(1a)、(2a)、(4a)、(5a)、(8a)、(9a)、(11a);(1a)、(2a)、(4a)、(5a) (8a), (10a), (11a); (1a), (2a), (4a), (5a), (9a), (10a), (11a); (1a), (2a), (4a), (6a), (7a), (8a), (9a); (1a), (2a), (4a), (6a), (7a), (8a), (1 (1a), (2a), (4a), (6a), (7a), (8a), (11a); (1a), (2a), (4a), (6a), (7a), (9a), (10a); (1a), (2a), (4a), (6a), (7a), (9a), (11a); (1a), (2a) (4a)、(6a)、(7a)、(10a)、(11a);(1a)、(2a)、(4a)、(6a)、(8a)、(9a)、(10a) );(1a)、(2a)、(4a)、(6a)、(8a)、(9a)、(11a);(1a)、(2a)、(4a)、(6a)、(8a) (10a) (11a); (1a) (2a) (4a) (6a) (9a) (10a) (11a); (1a) (2a) (4a) (7a) (8a) (9a) (10a); (1a) (2a) (4a) (7a) (8a) (9a) (10a); (1a) (2a) (4a) (7a) (8a) (9a) (11a);(1a)、(2a)、(4a)、(7a)、(8a)、(10a)、(11a);(1a)、(2a)、(4a)、(7a)、(9a)、(10a)、(11a);(1a)、(2a)、(4a)、(8a)、(9a)、(10a)、(11a);(1a)、(2a)、(5 a)、(6a)、(7a)、(8a)、(9a);(1a)、(2a)、(5a)、(6a)、(7a)、(8a)、(10a);(1a)、(2a)、(5a)、(6a)、(7a)、(8a)、(11a);(1a)、(2a)、(5a)、(6a)、(7a)、(9a; (10a); (1a), (2a), (5a), (6a), (7a), (9a), (11a); (1a), (2a), (5a), (6a), (7a), (10a), (11a); (1a), (2a), (5a), (6a), (8a), (9a), (10a); (1a) (2a), (5a), (6a), (8a), (9a), (11a); (1a), (2a), (5a), (6a), (8a), (10a), (11a); (1a), (2a), (5a), (6a), (9a), (10a), (11a); (1a), (2a), (5a), (7a) (8a)、(9a)、(10a);(1a)、(2a)、(5a)、(7a)、(8a)、(9a)、(11a);(1a)、(2a)、(5a)、(7a)、(8a)、(10a)、(11a);(1a)、(2a)、(5a)、(7a)、(9a)、(10a)、(11 a);(1a)、(2a)、(5a)、(8a)、(9a)、(10a)、(11a);(1a)、(2a)、(6a)、(7a)、(8a)、(9a)、(10a);(1a)、(2a)、(6a)、(7a)、(8a)、(9a)、(11a);(1a)、(2a)、(6 a)、(7a)、(8a)、(10a)、(11a);(1a)、(2a)、(6a)、(7a)、(9a)、(10a)、(11a);(1a)、(2a)、(6a)、(8a)、(9a)、(10a)、(11a);(1a)、(2a)、(7a)、(8a)、(9a) (10a) (11a); (1a) (3a) (4a) (5a) (6a) (7a) (8a); (1a) (3a) (4a) (5a) (6a) (7a) (9a); (1a) (3a) (4a) (5a) (6a) (7a) (10a); (1a) (3a)、(4a)、(5a)、(6a)、(7a)、(11a);(1a)、(3a)、(4a)、(5a)、(6a)、(8a)、(9a);(1a)、(3a)、(4a)、(5a)、(6a)、(8a)、(10a);(1a)、(3a)、(4a)、(5a)、( (6a)、(8a)、(11a);(1a)、(3a)、(4a)、(5a)、(6a)、(9a)、(10a);(1a)、(3a)、(4a)、(5a)、(6a)、(9a)、(11a);(1a)、(3a)、(4a)、(5a)、(6a)、(10a)、(11a);(1a)、(3a)、(4a)、(5a)、(7a)、(8a)、(9a);(1a)、(3a)、(4a)、(5a)、(7a)、(8a)、(10a);(1a)、(3a)、(4a)、(5a)、(7a)、(8a)、(11a);(1a)、(3a)、(4a)、 (5a)、(7a)、(9a)、(10a);(1a)、(3a)、(4a)、(5a)、(7a)、(9a)、(11a);(1a)、(3a)、(4a)、(5a)、(7a)、(10a)、(11a);(1a)、(3a)、(4a)、(5a)、(8a)、(9a (10a); (1a) (3a) (4a) (5a) (8a) (9a) (11a) (1a) (3a) (4a) (5a) (8a) (10a) (11a) (1a) (3a) (4a) (5a) (8a) (10a) (11a) (1a) (3a) (4a) (5a) (9a) (10a) (11a) (1a) 、(3a)、(4a)、(6a)、(7a)、(8a)、(9a);(1a)、(3a)、(4a)、(6a)、(7a)、(8a)、 (10a);(1a)、(3a)、(4a)、(6a)、(7a)、(8a)、(11a);(1a)、(3a)、(4a)、(6a)、 (7a)、(9a)、(10a);(1a)、(3a)、(4a)、(6a)、(7a)、(9a)、(11a);(1a)、(3a)、(4a)、(6a)、(7a)、(10a)、(11a);(1a)、(3a)、(4a)、(6a)、(8a)、(9a)、(10 a);(1a)、(3a)、(4a)、(6a)、(8a)、(9a)、(11a);(1a)、(3a)、(4a)、(6a)、(8 a)、(10a)、(11a);(1a)、(3a)、(4a)、(6a)、(9a)、(10a)、(11a);(1a)、(3a) (4a), (7a), (8a), (9a), (10a); (1a), (3a), (4a), (7a), (8a), (9a), (11a); (1a), (3a), (4a), (7a), (8a), (10a), (11a); (1a), (3a), (4a), (7a), (8a), (10a), (11a) a)、(10a)、(11a);(1a)、(3a)、(4a)、(8a)、(9a)、(10a)、(11a);(1a)、(3a)、(5a)、(6a)、(7a)、(8a)、(9a);(1a)、(3a)、(5a)、(6a)、(7a)、(8a)、(10a);(1a)、(3a)、(5a)、(6a)、(7a)、(8a)、(11a);(1a)、(3a)、(5a)、(6a)、(7a)、(9a)、(10a);(1a)、(3a)、(5a)、(6a)、(7a)、(9a)、(11a);(1a)、(3a)、(5a) (6a), (7a), (10a), (11a); (1a), (3a), (5a), (6a), (8a), (9a), (10a); (1a), (3a), (5a), (6a), (8a), (9a), (11a); (1a), (3a), (5a), (6a), (8a), (10a) a)、(11a);(1a)、(3a)、(5a)、(6a)、(9a)、(10a)、(11a);(1a)、(3a)、(5a)、(7a)、(8a)、(9a)、(10a);(1a)、(3a)、(5a)、(7a)、(8a)、(9a)、(11a);(1a)、 (3a)、(5a)、(7a)、(8a)、(10a)、(11a);(1a)、(3a)、(5a)、(7a)、(9a)、(10a)、(11a);(1a)、(3a)、(5a)、(8a)、(9a)、(10a)、(11a);(1a)、(3a)、(6a)、(7 a)、(8a)、(9a)、(10a);(1a)、(3a)、(6a)、(7a)、(8a)、(9a)、(11a);(1a)、(3a)、(6a)、(7a)、(8a)、(10a)、(11a);(1a)、(3a)、(6a)、(7a)、(9a)、(10a) (11a); (1a), (3a), (6a), (8a), (9a), (10a), (11a); (1a), (3a), (7a), (8a), (9a), (10a), (11a); (1a), (4a), (5a), (6a), (7a), (8a), (9a); (1a), (4 a) (5a) (6a) (7a) (8a) (10a) (1a) (4a) (5a) (6a) (7a) (8a) (11a) (1a) (4a) (5a) (6a) (7a) (9a) (10a) (1a) (4a) (5a) (6a) (7a) (9a) (10a) (1a) (4a) (5a) (6a) (7a) a)、(9a)、(11a);(1a)、(4a)、(5a)、(6a)、(7a)、(10a)、(11a);(1a)、(4a)、(5a)、(6a)、(8a)、(9a)、(10a);(1a)、(4a)、(5a)、(6a)、(8a)、(9a)、(11a);(1a)、(4a)、(5a)、(6a)、(8a)、(10a)、(11a);(1a)、(4a)、(5a)、(6a)、(9a) 、(10a)、(11a);(1a)、(4a)、(5a)、(7a)、(8a)、(9a)、(10a);(1a)、(4a)、(5 a)、(7a)、(8a)、(9a)、(11a);(1a)、(4a)、(5a)、(7a)、(8a)、(10a)、(11a);(1a)、(4a)、(5a)、(7a)、(9a)、(10a)、(11a);(1a)、(4a)、(5a)、(8a)、(9a) 、(10a)、(11a);(1a)、(4a)、(6a)、(7a)、(8a)、(9a)、(10a);(1a)、(4a)、(6 a)、(7a)、(8a)、(9a)、(11a);(1a)、(4a)、(6a)、(7a)、(8a)、(10a)、(11a); (1a), (4a), (6a), (7a), (9a), (10a), (11a); (1a), (4a), (6a), (8a), (9a), (10a), (11a); (1a), (4a), (7a), (8a), (9a), (10a), (11a); (1a), (5a) (6a)、(7a)、(8a)、(9a)、(10a);(1a)、(5a)、(6a)、(7a)、(8a)、(9a)、(11a);(1a)、(5a)、(6a)、(7a)、(8a)、(10a)、(11a);(1a)、(5a)、(6a)、(7a)、(9a) (10a) (11a); (1a) (5a) (6a) (8a) (9a) (10a) (11a); (1a) (5a) (7a) (8a) (9a) (10a) (11a); (1a) (6a) (7a) (8a) (9a) (10a) (11a) (1a) (2a) (3a) (4a) (5a) (6a) (7a) (8a) (1a) (2a) (3a) (4a) (5a) (6a) (7a) (9a) (1a) (2a) (3a) (4a) (5a) (6a) (7a) (10a) ;(1a)、(2a)、(3a)、(4a)、(5a)、(6a)、(7a)、(11a);(1a)、(2a)、(3a)、(4a)、(5a)、(6a)、(8a)、(9a);(1a)、(2a)、(3a)、(4a)、(5a)、(6a)、(8a)、(10a);(1a)、(2a)、(3a)、(4a)、(5a)、(6a)、(8a)、(11a);(1a)、(2a)、(3a)、(4a)、(5a)、(6a)、(9a)、(10a);(1a)、(2a)、(3a)、(4a)、(5a)、(6a)、(9a)、(11a); (1a)、(2a)、(3a)、(4a)、(5a)、(6a)、(10a)、(11a);(1a)、(2a)、(3a)、(4a)、(5a)、(7a)、(8a)、(9a);(1a)、(2a)、(3a)、(4a)、(5a)、(7a)、(8a)、(10a);( (1a)、(2a)、(3a)、(4a)、(5a)、(7a)、(8a)、(11a);(1a)、(2a)、(3a)、(4a)、(5a)、(7a)、(9a)、(10a);(1a)、(2a)、(3a)、(4a)、(5a)、(7a)、(9a)、(11a);( (1a)、(2a)、(3a)、(4a)、(5a)、(7a)、(10a)、(11a);(1a)、(2a)、(3a)、(4a)、(5a)、(8a)、(9a)、(10a);(1a)、(2a)、(3a)、(4a)、(5a)、(8a)、(9a)、(11a);( (1a)、(2a)、(3a)、(4a)、(5a)、(8a)、(10a)、(11a);(1a)、(2a)、(3a)、(4a)、(5a)、(9a)、(10a)、(11a);(1a)、(2a)、(3a)、(4a)、(6a)、(7a)、(8a)、(9a); (1a)、(2a)、(3a)、(4a)、(6a)、(7a)、(8a)、(10a);(1a)、(2a)、(3a)、(4a)、(6a)、(7a)、(8a)、(11a);(1a)、(2a)、(3a)、(4a)、(6a)、(7a)、(9a)、(10a);( (1a)、(2a)、(3a)、(4a)、(6a)、(7a)、(9a)、(11a);(1a)、(2a)、(3a)、(4a)、(6a)、(7a)、(10a)、(11a);(1a)、(2a)、(3a)、(4a)、(6a)、(8a)、(9a)、(10a);( (1a)、(2a)、(3a)、(4a)、(6a)、(8a)、(9a)、(11a);(1a)、(2a)、(3a)、(4a)、(6a)、(8a)、(10a)、(11a);(1a)、(2a)、(3a)、(4a)、(6a)、(9a)、(10a)、(11a);(1a)、(2a)、(3a)、(4a)、(7a)、(8a)、(9a)、(10a);(1a)、(2a)、(3a)、(4a)、(7a)、(8a)、(9a)、(11a);(1a)、(2a)、(3a)、(4a)、(7 a)、(8a)、(10a)、(11a);(1a)、(2a)、(3a)、(4a)、(7a)、(9a)、(10a)、(11a);(1a)、(2a)、(3a)、(4a)、(8a)、(9a)、(10a)、(11a); ;(1a)、(2a)、(3a)、(5a)、(6a)、(7a)、(8a)、(9a);(1a)、(2a)、(3a)、(5a)、(6a)、(7a)、(8a)、(10a);(1a)、(2a)、(3a)、(5a)、(6a)、(7a)、(8a)、(11a);( (1a)、(2a)、(3a)、(5a)、(6a)、(7a)、(9a)、(10a);(1a)、(2a)、(3a)、(5a)、(6a)、(7a)、(9a)、(11a);(1a)、(2a)、(3a)、(5a)、(6a)、(7a)、(10a)、(11a);( (1a)、(2a)、(3a)、(5a)、(6a)、(8a)、(9a)、(10a);(1a)、(2a)、(3a)、(5a)、(6a)、(8a)、(9a)、(11a);(1a)、(2a)、(3a)、(5a)、(6a)、(8a)、(10a)、(11a);( (1a)、(2a)、(3a)、(5a)、(6a)、(9a)、(10a)、(11a);(1a)、(2a)、(3a)、(5a)、(7a)、(8a)、(9a)、(10a);(1a)、(2a)、(3a)、(5a)、(7a)、(8a)、(9a)、(11a);( (1a)、(2a)、(3a)、(5a)、(7a)、(8a)、(10a)、(11a);(1a)、(2a)、(3a)、(5a)、(7a)、(9a)、(10a)、(11a);(1a)、(2a)、(3a)、(5a)、(8a)、(9a)、(10a)、(11a) ;(1a)、(2a)、(3a)、(6a)、(7a)、(8a)、(9a)、(10a);(1a)、(2a)、(3a)、(6a)、(7a)、(8a)、(9a)、(11a);(1a)、(2a)、(3a)、(6a)、(7a)、(8a)、(10a)、(11a) ;(1a)、(2a)、(3a)、(6a)、(7a)、(9a)、(10a)、(11a);(1a)、(2a)、(3a)、(6a)、(8a)、(9a)、(10a)、(11a);(1a)、(2a)、(3a)、(7a)、(8a)、(9a)、(10a)、(11 a);(1a)、(2a)、(4a)、(5a)、(6a)、(7a)、(8a)、(9a);(1a)、(2a)、(4a)、(5a)、(6a)、(7a)、(8a)、(10a);(1a)、(2a)、(4a)、(5a)、(6a)、(7a)、(8a)、(11a);(1a)、(2a)、(4a)、(5a)、(6a)、(7a)、(9a)、(10a);(1a)、(2a)、(4a)、(5a)、(6a)、(7a)、(9a)、(11a);(1a)、(2a)、(4a)、(5a)、(6a)、(7a)、(10a)、(11a); (1a)、(2a)、(4a)、(5a)、(6a)、(8a)、(9a)、(10a);(1a)、(2a)、(4a)、(5a)、(6a)、(8a)、(9a)、(11a);(1a)、(2a)、(4a)、(5a)、(6a)、(8a)、(10a)、(11a);( (1a)、(2a)、(4a)、(5a)、(6a)、(9a)、(10a)、(11a);(1a)、(2a)、(4a)、(5a)、(7a)、(8a)、(9a)、(10a);(1a)、(2a)、(4a)、(5a)、(7a)、(8a)、(9a)、(11a);(1 a)、(2a)、(4a)、(5a)、(7a)、(8a)、(10a)、(11a);(1a)、(2a)、(4a)、(5a)、(7a)、(9a)、(10a)、(11a);(1a)、(2a)、(4a)、(5a)、(8a)、(9a)、(10a)、(11a);( (1a)、(2a)、(4a)、(6a)、(7a)、(8a)、(9a)、(10a);(1a)、(2a)、(4a)、(6a)、(7a)、(8a)、(9a)、(11a);(1a)、(2a)、(4a)、(6a)、(7a)、(8a)、(10a)、(11a);( (1a)、(2a)、(4a)、(6a)、(7a)、(9a)、(10a)、(11a);(1a)、(2a)、(4a)、(6a)、(8a)、(9a)、(10a)、(11a);(1a)、(2a)、(4a)、(7a)、(8a)、(9a)、(10a)、(11a); (1a)、(2a)、(5a)、(6a)、(7a)、(8a)、(9a)、(10a);(1a)、(2a)、(5a)、(6a)、(7a)、(8a)、(9a)、(11a);(1a)、(2a)、(5a)、(6a)、(7a)、(8a)、(10a)、(11a);( (1a)、(2a)、(5a)、(6a)、(7a)、(9a)、(10a)、(11a);(1a)、(2a)、(5a)、(6a)、(8a)、(9a)、(10a)、(11a);(1a)、(2a)、(5a)、(7a)、(8a)、(9a)、(10a)、(11a);(1a)、(2a)、(6a)、(7a)、(8a)、(9a)、(10a)、(11a);(1a)、(3a)、(4a)、(5a)、(6a)、(7a)、(8a)、(9a);(1a)、(3a)、(4a)、(5a)、(6a)、(7a)、(8a)、(10a);( (1a)、(3a)、(4a)、(5a)、(6a)、(7a)、(8a)、(11a);(1a)、(3a)、(4a)、(5a)、(6a)、(7a)、(9a)、(10a);(1a)、(3a)、(4a)、(5a)、(6a)、(7a)、(9a)、(11a);(1 a)、(3a)、(4a)、(5a)、(6a)、(7a)、(10a)、(11a);(1a)、(3a)、(4a)、(5a)、(6a)、(8a)、(9a)、(10a);(1a)、(3a)、(4a)、(5a)、(6a)、(8a)、(9a)、(11a);(1 a)、(3a)、(4a)、(5a)、(6a)、(8a)、(10a)、(11a);(1a)、(3a)、(4a)、(5a)、(6a)、(9a)、(10a)、(11a);(1a)、(3a)、(4a)、(5a)、(7a)、(8a)、(9a)、(10a);(1 a)、(3a)、(4a)、(5a)、(7a)、(8a)、(9a)、(11a);(1a)、(3a)、(4a)、(5a)、(7a)、(8a)、(10a)、(11a);(1a)、(3a)、(4a)、(5a)、(7a)、(9a)、(10a)、(11a);( (1a), (3a), (4a), (5a), (8a), (9a), (10a), (11a); (1a), (3a), (4a), (6a), (7a), (8a), (9a), (10a); (1a), (3a), (4a), (6a), (7a), (8a), (9a), (11a); ( 1a)、(3a)、(4a)、(6a)、(7a)、(8a)、(10a)、(11a);(1a)、(3a)、(4a)、(6a)、( 7a)、(9a)、(10a)、(11a);(1a)、(3a)、(4a)、(6a)、(8a)、(9a)、(10a)、(11a) ;(1a)、(3a)、(4a)、(7a)、(8a)、(9a)、(10a)、(11a);(1a)、(3a)、(5a)、(6a)、(7a)、(8a)、(9a)、(10a);(1a)、(3a)、(5a)、(6a)、(7a)、(8a)、(9a)、(11a);(1a)、(3a)、(5a)、(6a)、(7a)、(8a)、(10a)、(11a);(1a)、(3a)、(5a)、(6a)、(7a)、(9a)、(10a)、(11a);(1a)、(3a)、(5a)、(6a)、(8a)、(9a)、(10a) (11a); (1a), (3a), (5a), (7a), (8a), (9a), (10a), (11a); (1a), (3a), (6a), (7a), (8a), (9a), (10a), (11a); (1a), (4a), (5a), (6a), (7a), (8a) (9a) (10a); (1a) (4a) (5a) (6a) (7a) (8a) (9a) (11a); (1a) (4a) (5a) (6a) (7a) (8a) (10a) (11a); (1a) (4a) (5a) (6a) (7a) (8a) (10a) (11a) (9a)、(10a)、(11a);(1a)、(4a)、(5a)、(6a)、(8a)、(9a)、(10a)、(11a);(1a)、(4a)、(5a)、(7a)、(8a)、(9a)、(10a)、(11a);(1a)、(4a)、(6a)、(7a) (8a), (9a), (10a), (11a); (1a), (5a), (6a), (7a), (8a), (9a), (10a), (11a); (1a), (2a), (3a), (4a), (5a), (6a), (7a), (8a), (9a); (1a), (2a) (3a)、(4a)、(5a)、(6a)、(7a)、(8a)、(10a);(1a)、(2a)、(3a)、(4a)、(5a)、(6a)、(7a)、(8a)、(11a);(1a)、(2a)、(3a)、(4a)、(5a)、(6a)、(7a)、(9a (10a); (1a), (2a), (3a), (4a), (5a), (6a), (7a), (9a), (11a); (1a), (2a), (3a), (4a), (5a), (6a), (7a), (10a), (11a); (1a), (2a), (3a), (4a) (5a), (6a), (8a), (9a), (10a); (1a), (2a), (3a), (4a), (5a), (6a), (8a), (9a), (11a); (1a), (2a), (3a), (4a), (5a), (6a), (8a), (10a), (11a);(1a)、(2a)、(3a)、(4a)、(5a)、(6a)、(9a)、(10a)、(11a);(1a)、(2a)、(3a)、(4a)、(5a)、(7a)、(8a)、(9a)、(10a);(1a)、(2a)、(3a)、(4a)、(5a)、(7a) (8a), (9a), (11a); (1a), (2a), (3a), (4a), (5a), (7a), (8a), (10a), (11a); (1a), (2a), (3a), (4a), (5a), (7a), (9a), (10a), (11a); (1a), (2a) (3a), (4a), (5a), (8a), (9a), (10a), (11a); (1a), (2a), (3a), (4a), (6a), (7a), (8a), (9a), (10a); (1a), (2a), (3a), (4a), (6a), (7a), (8a), (9a) (11a);(1a)、(2a)、(3a)、(4a)、(6a)、(7a)、(8a)、(10a)、(11a);(1a)、(2a)、(3a)、(4a)、(6a)、(7a)、(9a)、(10a)、(11a);(1a)、(2a)、(3a)、(4a)、(6a (8a), (9a), (10a), (11a); (1a), (2a), (3a), (4a), (7a), (8a), (9a), (10a), (11a); (1a), (2a), (3a), (5a), (6a), (7a), (8a), (9a), (10a); (1a) (2a)、(3a)、(5a)、(6a)、(7a)、(8a)、(9a)、(11a);(1a)、(2a)、(3a)、(5a)、(6a)、(7a)、(8a)、(10a)、(11a);(1a)、(2a)、(3a)、(5a)、(6a)、(7a)、(9a)、 (10a)、(11a);(1a)、(2a)、(3a)、(5a)、(6a)、(8a)、(9a)、(10a)、(11a);(1a)、(2a)、(3a)、(5a)、(7a)、(8a)、(9a)、(10a)、(11a);(1a)、(2a)、(3a)、( (6a)、(7a)、(8a)、(9a)、(10a)、(11a);(1a)、(2a)、(4a)、(5a)、(6a)、(7a)、(8a)、(9a)、(10a);(1a)、(2a)、(4a)、(5a)、(6a)、(7a)、(8a)、(9a)、(11a);(1a)、(2a)、(4a)、(5a)、(6a)、(7a)、(8a)、(10a)、(11a);(1a)、(2a)、(4a)、(5a)、(6a)、(7a)、(9a)、(10a)、(11a);(1a)、 (2a)、(4a)、(5a)、(6a)、(8a)、(9a)、(10a)、(11a);(1a)、(2a)、(4a)、(5a)、(7a)、(8a)、(9a)、(10a)、(11a);(1a)、(2a)、; (4a), (6a), (7a), (8a), (9a), (10a), (11a); (1a), (2a), (5a), (6a), (7a), (8a), (9a), (10a), (11a); (1a), (3a), (4a), (5a), (6a), (7a), (8a), (9 a)、(10a);(1a)、(3a)、(4a)、(5a)、(6a)、(7a)、(8a)、(9a)、(11a);(1a)、(3a)、(4a)、(5a)、(6a)、(7a)、(8a)、(10a)、(11a);(1a)、(3a)、(4a)、(5a) (6a) (7a) (9a) (10a) (11a) (1a) (3a) (4a) (5a) (6a) (8a) (9a) (10a) (11a) (1a) (3a) (4a) (5a) (7a) (8a) (9a) (10a) (11a) ;(1a)、(3a)、(4a)、(6a)、(7a)、(8a)、(9a)、(10a)、(11a);(1a)、(3a)、(5a)、(6a)、(7a)、(8a)、(9a)、(10a)、(11a);(1a)、(4a)、(5a)、(6a)、(7a)、(8 a)、(9a)、(10a)、(11a);(1a)、(2a)、(3a)、(4a)、(5a)、(6a)、(7a)、(8a)、(9a)、(10a);(1a)、(2a)、(3a)、(4a)、(5a)、(6a)、(7a)、(8a)、(9a)、(11a) ;(1a)、(2a)、(3a)、(4a)、(5a)、(6a)、(7a)、(8a)、(10a)、(11a);(1a)、(2a)、(3a)、(4a)、(5a)、(6a)、(7a)、(9a)、(10a)、(11a);(1a)、(2a)、(3a)、(4 a)、(5a)、(6a)、(8a)、(9a)、(10a)、(11a);(1a)、(2a)、(3a)、(4a)、(5a)、(7a)、(8a)、(9a)、(10a)、(11a);(1a)、(2a)、(3a)、(4a)、(6a)、(7a)、(8a) (9a), (10a), (11a); (1a), (2a), (3a), (5a), (6a), (7a), (8a), (9a), (10a), (11a); (1a), (2a), (4a), (5a), (6a), (7a), (8a), (9a), (10a), (11a);Characterized by one of (1a), (3a), (4a), (5a), (6a), (7a), (8a), (9a), (10a), (11a); (1a), (2a), (3a), (4a), (5a), (6a), (7a), (8a), (9a), (10a), (11a).

[0199] In the combinations in the preceding paragraph, "(1a)" is independently selected from (1a)(i), (1a)(ii), (1a)(iii), and (1a)(iv); "(2a)" is independently selected from (2a)(i), (2a)(ii), (2a)(iii), and (2a)(iv); "(3a)" is independently selected from (3a)(i), (3a)(ii), (3a)(iii), and (3a)(iv); "(4a)" is independently selected from (4a)(i), (4a)(ii), (4a)(iii), and (4a)(i v) is selected; (5a) is independently selected from (5a)(i), (5a)(ii), (5a)(iii), and (5a)(iv); (6a) is independently selected from (6a)(i) and (6a)(ii); (7a) is independently selected from (7a)(i) and (7a)(ii); (8a) is independently selected from (8a)(i) and (8a)(ii); (9a) is independently selected from (9a)(i), (9a)(ii), and (9a)(iii).

[0200] All possible combinations of such features, as described above, are explicitly intended. Simply as an example, cancers containing the combination of features "(1a), (2a)" are specifically (1a)(i) and (2a)(i); (1a)(i) and (2a)(ii); (1a)(i) and (2a)(iii); (1a)(i) and (2a)(iv); (1a)(ii) and (2a)(i); (1a)(ii) and (2a)(ii); (1a)(ii) and (2a)(iii); (1a This refers to cancers including (ii) and (2a)(iv); (1a)(iii) and (2a)(i); (1a)(iii) and (2a)(ii); (1a)(iii) and (2a)(iii); (1a)(iii) and (2a)(iv); (1a)(iv) and (2a)(ii); (1a)(iv) and (2a)(iii); and (1a)(iv) and (2a)(iv).

[0201] In embodiments in which the cancer is characterized by (7a)(i) or (7a)(ii), the cancer may not be characterized by (3a)(iii) or (3a)(iv). Conversely, in embodiments in which the cancer is characterized by (3a)(iii) or (3a)(iv), the cancer may not be characterized by (7a)(i) or (7a)(ii). However, in some embodiments in which the cancer is characterized by (3a)(i) or (3a)(ii), the cancer may further be characterized by (7a)(i) or (7a)(ii).

[0202] In aspects and embodiments of this disclosure, the cancer to be treated / prevented with an antigen-binding molecule that binds to HER3 is not homozygous for activating mutations in genes encoding positive regulators of HER3-mediated signaling, selected from PIK3CB, PIK3CD, ERBB3, ERBB2, ERBB4, EGFR, IGF1R, NRG1, NRG2, EGF, IRS2, GRB2, GAB2, PTPN11, SHP2, SOS1, HRAS, NRAS, RAF1, MAP2K1, MAP2K2, MAPK1, MYC, RPS6KA1, RPS6, MKNK1, CREB1, MTOR, PDK1, AKT1, AKT2, AKT3, JAK2, STAT3, and STAT5. In some embodiments, the cancer is not heterozygous for activating mutations in genes encoding positive regulators of HER3-mediated signaling, selected from PIK3CB, PIK3CD, ERBB3, ERBB2, ERBB4, EGFR, IGF1R, NRG1, NRG2, EGF, IRS2, GRB2, GAB2, PTPN11, SHP2, SOS1, HRAS, NRAS, RAF1, MAP2K1, MAP2K2, MAPK1, MYC, RPS6KA1, RPS6, MKNK1, CREB1, MTOR, PDK1, AKT1, AKT2, AKT3, JAK2, STAT3, and STAT5. In some embodiments, the cancer does not contain genetic diversity that results in increased expression of genes encoding positive regulators of HER3-mediated signaling, or increased activity of their gene products, selected from PIK3CB, PIK3CD, ERBB3, ERBB2, ERBB4, EGFR, IGF1R, NRG1, NRG2, EGF, IRS2, GRB2, GAB2, PTPN11, SHP2, SOS1, HRAS, NRAS, RAF1, MAP2K1, MAP2K2, MAPK1, MYC, RPS6KA1, RPS6, MKNK1, CREB1, MTOR, PDK1, AKT1, AKT2, AKT3, JAK2, STAT3, and STAT5.

[0203] In this specification, a reference to “one gene” is understood to mean “at least one gene” and to include “one or more genes.” Thus, “one gene” selected from a given list may be one gene from that list, or one of two, three, four, five, six, seven, nine, ten or more genes from the list, or all of them (depending on the number of genes enumerated in that list).

[0204] In aspects and embodiments of this disclosure, the cancer to be treated / prevented with an antigen-binding molecule that binds to HER3 is not homozygous for activating mutations in genes encoding positive regulators of signaling via the MAPK / ERK pathway, selected from ERBB3, ERBB2, ERBB4, EGFR, IGF1R, NRG1, NRG2, EGF, IRS2, GAB2, GRB2, PTPN11, SHP2, SOS1, HRAS, KRAS, NRAS, RAF1, MAP2K1, MAP2K2, MAPK1, MYC, RPS6KA1, RPS6, MKNK1, and CREB1. In some embodiments, the cancer is not heterozygous for activating mutations in genes encoding positive regulators of signaling via the MAPK / ERK pathway, selected from ERBB3, ERBB2, ERBB4, EGFR, IGF1R, NRG1, NRG2, EGF, IRS2, GAB2, GRB2, PTPN11, SHP2, SOS1, HRAS, KRAS, NRAS, RAF1, MAP2K1, MAP2K2, MAPK1, MYC, RPS6KA1, RPS6, MKNK1, and CREB1. In some embodiments, the cancer does not exhibit genetic diversity that results in increased expression of genes encoding positive regulators of signaling via the MAPK / ERK pathway, or increased activity of their gene products, selected from ERBB3, ERBB2, ERBB4, EGFR, IGF1R, NRG1, NRG2, EGF, IRS2, GAB2, GRB2, PTPN11, SHP2, SOS1, HRAS, KRAS, NRAS, RAF1, MAP2K1, MAP2K2, MAPK1, MYC, RPS6KA1, RPS6, MKNK1, and CREB1.

[0205] In aspects and embodiments of this disclosure, the cancer to be treated / prevented with an antigen-binding molecule that binds to HER3 is not homozygous for activating mutations in genes encoding positive regulators of signaling via the PI3K / AKT / mTOR pathway, selected from ERBB3, ERBB2, ERBB4, EGFR, IGF1R, NRG1, NRG2, EGF, IRS2, GAB2, SHP2, CREB1, PIK3CB, PIK3CD, MTOR, PDK1, AKT1, AKT2, AKT3, JAK2, STAT3, and STAT5. In some embodiments, the cancer is not heterozygous for activating mutations in genes encoding positive regulators of signaling via the PI3K / AKT / mTOR pathway, selected from ERBB3, ERBB2, ERBB4, EGFR, IGF1R, NRG1, NRG2, EGF, IRS2, GAB2, SHP2, CREB1, PIK3CB, PIK3CD, MTOR, PDK1, AKT1, AKT2, AKT3, JAK2, STAT3, and STAT5. In some embodiments, the cancer does not exhibit genetic diversity that results in increased expression of genes encoding positive regulators of signaling via the PI3K / AKT / mTOR pathway, or increased activity of their gene products, selected from ERBB3, ERBB2, ERBB4, EGFR, IGF1R, NRG1, NRG2, EGF, IRS2, GAB2, SHP2, CREB1, PIK3CB, PIK3CD, MTOR, PDK1, AKT1, AKT2, AKT3, JAK2, STAT3, and STAT5.

[0206] In aspects and embodiments of this disclosure, the cancer to be treated / prevented with an antigen-binding molecule that binds to HER3 is not homozygous for inactivating mutations in genes encoding negative regulators of HER3-mediated signaling, selected from PPP2CA, PIK3R1, PIK3R2, NF1, BAD, and PHLPP1. In some embodiments, the cancer is not heterozygous for inactivating mutations in genes encoding negative regulators of HER3-mediated signaling, selected from PPP2CA, PIK3R1, PIK3R2, NF1, BAD, and PHLPP1. In some embodiments, the cancer does not contain genetic diversity that results in reduced expression of genes encoding negative regulators of HER3-mediated signaling, selected from PPP2CA, PIK3R1, PIK3R2, NF1, BAD, and PHLPP1, or reduced activity of their gene products.

[0207] In the embodiments and aspects of this disclosure, the cancer to be treated / prevented with an antigen-binding molecule that binds to HER3 is not homozygous for inactivating mutations to NF1. In some embodiments, the cancer is not heterozygous for inactivating mutations to NF1. In some embodiments, the cancer does not contain genetic diversity that results in reduced expression of NF1 or reduced activity of its gene product.

[0208] In aspects and embodiments of this disclosure, the cancer to be treated / prevented with an antigen-binding molecule that binds to HER3 is not homozygous for inactivating mutations in a gene encoding a negative regulator of signaling via the PI3K / AKT / mTOR pathway, selected from PPP2CA, PIK3R1, PIK3R2, BAD, and PHLPP1. In some embodiments, the cancer is not heterozygous for inactivating mutations in a gene encoding a negative regulator of signaling via the PI3K / AKT / mTOR pathway, selected from PPP2CA, PIK3R1, PIK3R2, BAD, and PHLPP1. In some embodiments, the cancer does not contain genetic diversity that results in reduced expression of a gene encoding a negative regulator of signaling via the PI3K / AKT / mTOR pathway, selected from PPP2CA, PIK3R1, PIK3R2, BAD, and PHLPP1, or reduced activity of its gene product.

[0209] In aspects and embodiments of this disclosure, the cancer to be treated / prevented with an antigen-binding molecule that binds to HER3 does not include genetic diversity that results in (i) increased expression of MET or increased activity of its gene product, and (ii) increased expression of KRAS or increased activity of its gene product. In some embodiments, the cancer does not include (i) amplification of MET, and (ii) activating mutations to KRAS.

[0210] In aspects and embodiments of this disclosure, the cancer to be treated / prevented with an antigen-binding molecule that binds to HER3 does not include genetic diversity that results in (i) increased expression of MET or increased activity of its gene product, and (ii) increased expression of PIK3CA or increased activity of its gene product. In some embodiments, the cancer does not include (i) amplification of MET, and (ii) activating mutations to PIK3CA.

[0211] In aspects and embodiments of this disclosure, the cancer to be treated / prevented with an antigen-binding molecule that binds to HER3 does not include genetic diversity that results in (i) increased expression of MET or increased activity of its gene product, and (ii) increased expression of BRAF or increased activity of its gene product. In some embodiments, the cancer does not include (i) amplification of MET, and (ii) activating mutations to BRAF.

[0212] In aspects and embodiments of this disclosure, the cancer to be treated / prevented with an antigen-binding molecule that binds to HER3 does not include genetic diversity that results in (i) increased expression of MET or increased activity of its gene product, and (ii) decreased expression of PTEN or decreased activity of its gene product. In some embodiments, the cancer does not include (i) amplification of MET, and (ii) inactivating mutations to PTEN.

[0213] In the embodiments of this disclosure, the cancer to be treated / prevented with an antigen-binding molecule that binds to HER3 is free from genetic diversity that (i) results in increased expression of MET or increased activity of its gene product, (ii) results in increased expression of KRAS or increased activity of its gene product, and (iii) results in increased expression of PIK3CA or increased activity of its gene product. In some embodiments, the cancer is free from (i) amplification of MET, (ii) activating mutations to KRAS, and (iii) activating mutations to PIK3CA.

[0214] In the embodiments and aspects of this disclosure, the cancer to be treated / prevented with an antigen-binding molecule that binds to HER3 is free from genetic diversity that (i) results in increased expression of MET or increased activity of its gene product, (ii) results in increased expression of KRAS or increased activity of its gene product, and (iii) results in increased expression of BRAF or increased activity of its gene product. In some embodiments, the cancer is free from (i) amplification of MET, (ii) activating mutations to KRAS, and (iii) activating mutations to BRAF.

[0215] In the embodiments and aspects of this disclosure, the cancer to be treated / prevented with an antigen-binding molecule that binds to HER3 does not include genetic diversity that results in (i) increased expression of MET or increased activity of its gene product, (ii) increased expression of KRAS or increased activity of its gene product, or (iii) decreased expression of PTEN or decreased activity of its gene product. In some embodiments, the cancer does not include (i) amplification of MET, (ii) activating mutations to KRAS, or (iii) inactivating mutations to PTEN.

[0216] In aspects and embodiments of this disclosure, the cancer to be treated / prevented with an antigen-binding molecule that binds to HER3 does not include genetic diversity that results in (i) increased expression of MET or increased activity of its gene product, (ii) increased expression of PIK3CA or increased activity of its gene product, or (iii) increased expression of BRAF or increased activity of its gene product. In some embodiments, the cancer does not include (i) amplification of MET, (ii) activating mutations to PIK3CA, or (iii) activating mutations to BRAF.

[0217] In aspects and embodiments of this disclosure, the cancer to be treated / prevented with an antigen-binding molecule that binds to HER3 does not include genetic diversity that results in (i) increased expression of MET or increased activity of its gene product, (ii) increased expression of PIK3CA or increased activity of its gene product, or (iii) decreased expression of PTEN or decreased activity of its gene product. In some embodiments, the cancer does not include (i) amplification of MET, (ii) activating mutations to PIK3CA, or (iii) inactivating mutations to PTEN.

[0218] In aspects and embodiments of this disclosure, the cancer to be treated / prevented with an antigen-binding molecule that binds to HER3 does not include genetic diversity that results in (i) increased expression of MET or increased activity of its gene product, (ii) increased expression of BRAF or increased activity of its gene product, or (iii) decreased expression of PTEN or decreased activity of its gene product. In some embodiments, the cancer does not include (i) amplification of MET, (ii) activating mutations to BRAF, or (iii) inactivating mutations to PTEN.

[0219] In aspects and embodiments of this disclosure, the cancer to be treated / prevented with an antigen-binding molecule that binds to HER3 is free from genetic diversity that (i) results in increased expression of MET or increased activity of its gene product, (ii) results in increased expression of KRAS or increased activity of its gene product, (iii) results in increased expression of PIK3CA or increased activity of its gene product, and (iv) results in increased expression of BRAF or increased activity of its gene product. In some embodiments, the cancer is free from (i) amplification of MET, (ii) activating mutations to KRAS, (iii) activating mutations to PIK3CA, and (iv) activating mutations to BRAF.

[0220] In the embodiments of this disclosure, the cancer to be treated / prevented with an antigen-binding molecule that binds to HER3 is free from genetic diversity that (i) results in increased expression of MET or increased activity of its gene product, (ii) results in increased expression of KRAS or increased activity of its gene product, (iii) results in increased expression of PIK3CA or increased activity of its gene product, and (iv) results in decreased expression of PTEN or decreased activity of its gene product. In some embodiments, the cancer is free from (i) amplification of MET, (ii) activating mutations to KRAS, (iii) activating mutations to PIK3CA, and (iv) inactivating mutations to PTEN.

[0221] In the embodiments and aspects of this disclosure, the cancer to be treated / prevented with an antigen-binding molecule that binds to HER3 is free from genetic diversity that (i) results in increased expression of MET or increased activity of its gene product, (ii) results in increased expression of KRAS or increased activity of its gene product, (iii) results in increased expression of BRAF or increased activity of its gene product, and (iv) results in decreased expression of PTEN or decreased activity of its gene product. In some embodiments, the cancer is free from (i) amplification of MET, (ii) activating mutations to KRAS, (iii) activating mutations to BRAF, and (iv) inactivating mutations to PTEN.

[0222] In aspects and embodiments of this disclosure, cancers to be treated / prevented with HER3-binding antigen-binding molecules are free from: (i) genetic diversity resulting in increased expression of MET or increased activity of its gene product; (ii) genetic diversity resulting in increased expression of PIK3CA or increased activity of its gene product; (iii) genetic diversity resulting in increased expression of BRAF or increased activity of its gene product; and (iv) genetic diversity resulting in decreased expression of PTEN or decreased activity of its gene product. In some embodiments, the cancer is free from: (i) amplification of MET; (ii) activating mutations to PIK3CA; (iii) activating mutations to BRAF; and (iv) inactivating mutations to PTEN.

[0223] In the embodiments and aspects of this disclosure, the cancer to be treated / prevented with an antigen-binding molecule that binds to HER3 is free from genetic diversity that (i) results in increased expression of MET or increased activity of its gene product, (ii) results in increased expression of KRAS or increased activity of its gene product, (iii) results in increased expression of PIK3CA or increased activity of its gene product, (iv) results in increased expression of BRAF or increased activity of its gene product, and (v) results in decreased expression of PTEN or decreased activity of its gene product. In some embodiments, the cancer is free from genetic diversity that (i) results in amplification of MET, (ii) results in activating mutations to KRAS, (iii) results in activating mutations to PIK3CA, (iv) results in activating mutations to BRAF, and (v) results in inactivating mutations to PTEN.

[0224] In the embodiments and aspects of this disclosure, the cancer to be treated / prevented with an antigen-binding molecule that binds to HER3 is (i) free from MET amplification, (ii) free from activating mutations to KRAS, (iii) free from activating mutations to PIK3CA, (iv) free from activating mutations to BRAF, and (v) free from PTEN deletion. Cancer characterized by the presence of genetic diversity that leads to increased HER3-mediated signaling. Aspects and embodiments of this disclosure relate to cancers involving genetic diversity resulting in elevated HER3-mediated signaling. Such cancers may be considered less sensitive / less susceptible / more resistant (and therefore less likely to respond well) to therapeutic / prophylactic interventions using HER3-binding antigen-binding molecules as monotherapy. Administration of HER3-mediated signaling antagonists may be effective in making cancers more sensitive / receptive (and therefore more likely to respond well) to therapeutic / prophylactic interventions using HER3-binding antigen-binding molecules. The cancers described in this section may be further characterized by the preceding section titled “Cancer”.

[0225] In the embodiments and aspects of this disclosure, the cancer to be treated / prevented with an antigen-binding molecule that binds to HER3 in combination with a HER3-mediated signaling antagonist is characterized by one or more of the following features: (1b)(i) Homozygous for activating mutations to MET (e.g., activating mutations to MET as described herein). (1b)(ii)Heterozygous for activating mutations to MET (e.g., activating mutations to MET as described herein). (1b)(iii) Amplification of MET (e.g., amplification of MET as described herein). (1b)(iv)Includes genetic diversity that results in increased expression of MET or increased activity of its gene product. (2b)(i) Homozygous for activating mutations to KRAS (e.g., activating mutations to KRAS as described herein). (2b)(ii) Heterozygous for activating mutations to KRAS (e.g., activating mutations to KRAS as described herein). (2b)(iii) Amplification of KRAS (e.g., amplification of KRAS as described herein). (2b)(iv)Includes genetic diversity that results in increased KRAS expression or increased activity of its gene product. (3b)(i) Homozygous for activating mutations to PIK3CA (e.g., activating mutations to PIK3CA as described herein). (3b)(ii)Heterozygous for activating mutations to PIK3CA (e.g., activating mutations to PIK3CA as described herein). (3b)(iii) Amplification of PIK3CA (e.g., amplification of PIK3CA as described herein). (3b)(iv)Includes genetic diversity that results in increased expression of PIK3CA or increased activity of its gene product. (4b)(i) Homozygous for activating mutations to BRAF (e.g., activating mutations to BRAF as described herein). (4b)(ii)Heterozygous for activating mutations to BRAF (e.g., activating mutations to BRAF as described herein). (4b)(iii) Amplification of BRAF (e.g., amplification of BRAF as described herein). (4b)(iv)Includes genetic diversity that results in increased expression of BRAF or increased activity of its gene product. (5b)(i)Includes genetic diversity that results in reduced expression of PTEN or reduced activity of its gene product. (5b)(ii) Homozygous for inactivating mutations to PTEN (e.g., inactivating mutations to PTEN as described herein). (5b)(iii)Heterozygous with respect to inactivating mutations to PTEN (e.g., inactivating mutations to PTEN as described herein). (5b)(iv) Including the deletion of PTEN (for example, the deletion of PTEN as described herein). (6b)(i)Includes genetic diversity that results in increased expression of TP63 or increased activity of its gene product. (6b)(ii) Amplification of TP63 (e.g., amplification of TP63 as described herein). (7b)(i)Includes genetic diversity that results in increased expression of SOX2 or increased activity of its gene product. (7b)(ii) Amplification of SOX2 (for example, amplification of SOX2 as described herein). (8b)(i) comprising genetic diversity resulting in increased expression of ligands for HER3 (e.g., those described herein). (8b)(ii) comprising an NRG gene fusion (for example, an NRG gene fusion as described herein). (8b)(iii) comprising an NRG1 gene fusion (for example, an NRG1 gene fusion as described herein). (9b)(i)Includes genetic diversity that results in increased EGFR expression or increased activity of its gene product. (9b)(ii) Amplification of EGFR (e.g., EGFR amplification as described herein). (10b)(i) Does not contain genetic diversity that results in reduced expression of TUSC2 or reduced activity of its gene product. (10b)(ii) Not including any deletion of TUSC2 (e.g., the deletion of TUSC2 as described herein).

[0226] In some embodiments, cancers to be treated / prevented using an antigen-binding molecule that binds to HER3 in combination with an antagonist of HER3-mediated signaling are characterized by the following combinations (see previous paragraph): (1b), (2b); (1b), (3b); (1b), (4b); (1b), (5b); (1b), (6b); (1b), (7b); (1b), (8b); (1b), (9b); (1b), (10b); (1b), (2b), (3b); (1b), (2b), (4b); (1b), (2b), (5b); (1b), (2b), (6b); (1b) ,(2b),(7b);(1b),(2b),(8b);(1b),(2b),(9b);(1b),(2b),(10b);(1b), (3b), (4b); (1b), (3b), (5b); (1b), (3b), (6b); (1b), (3b), (7b); (1b), (3 b), (8b); (1b), (3b), (9b); (1b), (3b), (10b); (1b), (4b), (5b); (1b), (4b ), (6b); (1b), (4b), (7b); (1b), (4b), (8b); (1b), (4b), (9b); (1b), (4b), ( 10b);(1b),(5b),(6b);(1b),(5b),(7b);(1b),(5b),(8b);(1b),(5b),(9 b);(1b),(5b),(10b);(1b),(6b),(7b);(1b),(6b),(8b);(1b),(6b),(9b );(1b), (6b), (10b);(1b), (7b), (8b);(1b), (7b), (9b);(1b), (7b), (10b );(1b), (8b), (9b);(1b), (8b), (10b);(1b), (9b), (10b);(1b), (2b), (3b ), (4b); (1b), (2b), (3b), (5b); (1b), (2b), (3b), (6b); (1b), (2b), (3b), (7b);(1b),(2b),(3b),(8b);(1b),(2b),(3b),(9b);(1b),(2b),(3b),(1 0b);(1b), (2b), (4b), (5b);(1b), (2b), (4b), (6b);(1b), (2b), (4b), (7b );(1b), (2b), (4b), (8b);(1b), (2b), (4b), (9b);(1b), (2b), (4b), (10b);(1b)、(2b)、(5b)、(6b);(1b)、(2b)、(5b)、(7b);(1b)、(2b)、(5b)、(8b);(1 b)、(2b)、(5b)、(9b);(1b)、(2b)、(5b)、(10b);(1b)、(2b)、(6b)、(7b);(1b )、(2b)、(6b)、(8b);(1b)、(2b)、(6b)、(9b);(1b)、(2b)、(6b)、(10b);(1b) 、(2b)、(7b)、(8b);(1b)、(2b)、(7b)、(9b);(1b)、(2b)、(7b)、(10b);(1b)、 (2b)、(8b)、(9b);(1b)、(2b)、(8b)、(10b);(1b)、(2b)、(9b)、(10b);(1b)、(3b)、(4b)、(5b);(1b)、(3b)、(4b)、(6b);(1b)、(3b)、(4b)、(7b);(1b)、(3b)、(4b)、(8b);(1b)、(3b)、(4b)、(9b);(1b)、(3b)、(4b)、(10b);(1b)、(3b)、(5b)、(6b);(1b)、(3b)、(5b)、(7b);(1b)、(3b)、(5b)、(8b);(1b)、(3b)、( 5b)、(9b);(1b)、(3b)、(5b)、(10b);(1b)、(3b)、(6b)、(7b);(1b)、(3b)、(6b)、(8b);(1b)、(3b)、(6b)、(9b);(1b)、(3b)、(6b)、(10b);(1b)、(3b)、(7b)、(8b);(1b)、(3b)、(7b)、(9b);(1b)、(3b)、(7b)、(10b);(1b)、(3b)、(8b)、(9b);(1b)、(3b)、(8b)、(10b);(1b)、(3b)、(9b)、(10b);(1b)、(3b)、(9b)、(4b)、(5b) ,(6b);(1b)、(4b)、(5b)、(7b);(1b)、(4b)、(5b)、(8b);(1b)、(4b)、(5b)、(9b);(1b)、(4b)、(5b)、(10b);(1b)、(4b)、(6b)、(7b);(1b)、(4b)、(6b)、(8b);(1b)、(4b)、(6b)、(9b);(1b)、(4b)、(6b)、(10b);(1b)、(4b)、(7b)、(8b);(1b)、(4b)、(7b)、(9b);(1b)、(4b)、(7b)、(10b);(1b)、(4b)、(8b)、(9b);(1b)、(4b)、(8b)、(10b);(1b)、(4b)、(9b)、(10b);(1b)、(5b)、(6b)、(7b);(1b)、(5b)、(6b)、(8b);(1b)、(5b)、(6b)、(9b);(1b)、(5b)、(6b)、(10b);(1b)、(5b)、(7b)、(8b);(1b)、(5b)、(7b)、(9b);(1b)、(5b)、(7b)、(10b);(1b)、(5b)、(8b)、(9b);(1b)、(5b)、(8b)、(10b);(1b)、(5b)、(9b)、(10b) ;(1b)、(6b)、(7b)、(8b);(1b)、(6b)、(7b)、(9b);(1b)、(6b)、(7b)、(10b);(1b)、(6b)、(8b)、(9b);(1b)、(6b)、(8b)、(10b);(1b)、(6b)、(9b)、(10b);(1b)、(7b)、(8b)、(9b);(1b)、(7b)、(8b)、(10b);(1b)、(7b)、(9b)、(10b);(1b)、(8b)、(9b)、(10b);(1b)、(2b)、(3b)、(4b)、(5b);(1b)、(2b)、(3b)、(5b);(1b)、(2b)、(3b) ,(4b)、(6b);(1b)、(2b)、(3b)、(4b)、(7b);(1b)、(2b)、(3b)、(4b)、(8b);(1b)、(2b)、(3b)、(4b)、(9b);(1b)、(2b)、(3b)、(4b)、(10b);(1b)、(2b)、(3b)、(5b)、(6b);(1b)、(2b)、(3b)、(5b)、(7b);(1b)、(2b)、(3b)、(5b)、(8b);(1b)、(2b)、(3b)、(5b)、(9b);(1b)、(2b)、(3b)、(5b)、(10b);(1b)、(2b )、(3b)、(6b)、(7b);(1b)、(2b)、(3b)、(6b)、(8b);(1b)、(2b)、(3b)、(6b) 、(9b);(1b)、(2b)、(3b)、(6b)、(10b);(1b)、(2b)、(3b)、(7b)、(8b);(1b)、 (2b)、(3b)、(7b)、(9b);(1b)、(2b)、(3b)、(7b)、(10b);(1b)、(2b)、(3b)、 (8b)、(9b);(1b)、(2b)、(3b)、(8b)、(10b);(1b)、(2b)、(3b)、(9b)、(10b);(1b)、(2b)、(4b)、(5b)、(6b);(1b)、(2b)、(4b)、(5b)、(7b);(1b)、(2b)、( 4b)、(5b)、(8b);(1b)、(2b)、(4b)、(5b)、(9b);(1b)、(2b)、(4b)、(5b)、(10 b);(1b)、(2b)、(4b)、(6b)、(7b);(1b)、(2b)、(4b)、(6b)、(8b);(1b)、(2b) 、(4b)、(6b)、(9b);(1b)、(2b)、(4b)、(6b)、(10b);(1b)、(2b)、(4b)、(7b)、 (8b);(1b)、(2b)、(4b)、(7b)、(9b);(1b)、(2b)、(4b)、(7b)、(10b);(1b)、( 2b)、(4b)、(8b)、(9b);(1b)、(2b)、(4b)、(8b)、(10b);(1b)、(2b)、(4b)、(9 b)、(10b);(1b)、(2b)、(5b)、(6b)、(7b);(1b)、(2b)、(5b)、(6b)、(8b);(1b )、(2b)、(5b)、(6b)、(9b);(1b)、(2b)、(5b)、(6b)、(10b);(1b)、(2b)、(5b) 、(7b)、(8b);(1b)、(2b)、(5b)、(7b)、(9b);(1b)、(2b)、(5b)、(7b)、(10b) ;(1b)、(2b)、(5b)、(8b)、(9b);(1b)、(2b)、(5b)、(8b)、(10b);(1b)、(2b)、 (5b)、(9b)、(10b);(1b)、(2b)、(6b)、(7b)、(8b);(1b)、(2b)、(6b)、(7b)、( 9b);(1b)、(2b)、(6b)、(7b)、(10b);(1b)、(2b)、(6b)、(8b)、(9b);(1b)、(2 b)、(6b)、(8b)、(10b);(1b)、(2b)、(6b)、(9b)、(10b);(1b)、(2b)、(7b)、(8b)、(9b);(1b)、(2b)、(7b)、(8b)、(10b);(1b)、(2b)、(7b)、(9b)、(10b);(1b)、(2b)、(7b)、(9b)、(10b);(1b)、(2b)、(8b)、(9b)、(10b);(1b)、(3b)、(4b)、(5b)、(6b);(1b)、(3b)、(4b)、(5b)、(7b);(1b)、(3b)、(4b)、(5b)、(8b);(1b)、(3b)、(4b)、(5b)、(9b);(1b)、(3b)、(4b)、(5b)、(10b);(1b)、(3b)、(4b)、(6b)、(7b);(1b)、(3b)、(4b)、(6b)、(8b);(1b)、(3b)、(4b)、(6b)、(9b);(1b)、(3b)、(4b)、(6b)、(10b);(1b)、(3b)、(4b)、(7b)、(8b);(1b)、(3b)、(4b)、(7b)、(9b);(1b)、(3b)、(4b)、(7b)、(10b);(1b)、(3b)、(4b)、(8b)、(9b);(1b)、(3b)、(4b)、(8b)、(9b);(1b)、(3b)、(4b)、(8b)、 (10b);(1b)、(3b)、(4b)、(9b)、(10b);(1b)、(3b)、(5b)、(6b)、(7b);(1b)、(3b)、(5b)、(6b)、(8b);(1b)、(3b)、(5b)、(6b)、(9b);(1b)、(3b)、(5b)、(6b)、(10b);(1b)、(3b)、(5b)、(7b)、(8b);(1b)、(3b)、(5b)、(7b)、(9b);(1b)、(3b)、(5b)、(7b)、(10b);(1b)、(3b)、(5b)、(8b)、(9b);(1b)、(3b)、(5b) ,(8b)、(10b);(1b)、(3b)、(5b)、(9b)、(10b);(1b)、(3b)、(6b)、(7b)、(8b);(1b)、(3b)、(6b)、(7b)、(9b);(1b)、(3b)、(6b)、(7b)、(10b);(1b)、(3b)、(6b)、(8b)、(9b);(1b)、(3b)、(6b)、(8b)、(10b);(1b)、(3b)、(6b)、(9b)、(10b);(1b)、(3b)、(7b)、(8b)、(9b);(1b)、(3b)、(7b)、(8b)、(10b);(1b)、( 3b), (7b), (9b), (10b);(1b), (3b), (8b), (9b), (10b);(1b), (4b), (5b), (6b), (7b);(1b), (4b), (5b), (6b), (8b);(1b), (4b), (5b), (6b), (9b);(1b), (4b), (5b), (6b), (10b);(1b), (4b), (5b), (7b), (8b);(1b), (4b), (5b), (7b), (9b);(1b), (4b), (5b), (7b), (9b);(1b), (4b), (5b), (7b), (10b);(1b), (4b), (5b), (8b), (9b);(1b)、(4b)、(5b)、(8b)、(10b);(1b)、(4b)、(5b)、(9b)、(10b);(1b)、(4b)、(6b)、(7b)、(8b);(1b)、(4b)、(6b)、(7b)、(9b);(1b)、(4b)、(6b)、(7b)、(10b);(1b)、(4b)、(6b)、(8b)、(9b);(1b)、(4b)、(6b)、(9b);(1b)、(4b)、(6b); ,(8b)、(10b);(1b)、(4b)、(6b)、(9b)、(10b);(1b)、(4b)、(7b)、(8b)、(9b);(1b)、(4b)、(7b)、(8b)、(10b);(1b)、(4b)、(7b)、(9b)、(10b);(1b)、(4b)、(7b)、(9b)、(10b);(1b)、(4b)、(8b)、(9b)、(10b);(1b)、(5b)、(6b)、(7b)、(8b)、(9b);(1b)、(5b)、(6b)、(7b)、(9b);(1b)、(5b)、(6b)、(7b)、(10b);(1b)、(5b)、(6b)、(8b)、(9b);(1b )、(5b)、(6b)、(8b)、(10b);(1b)、(5b)、(6b)、(9b)、(10b);(1b)、(5b)、(7 b)、(8b)、(9b);(1b)、(5b)、(7b)、(8b)、(10b);(1b)、(5b)、(7b)、(9b)、(1 0b);(1b)、(5b)、(8b)、(9b)、(10b);(1b)、(6b)、(7b)、(8b)、(9b);(1b)、( 6b)、(7b)、(8b)、(10b);(1b)、(6b)、(7b)、(9b)、(10b);(1b)、(6b)、(8b)、( 9b)、(10b);(1b)、(7b)、(8b)、(9b)、(10b);(1b)、(2b)、(3b)、(4b)、(5b)、(6b);(1b)、(2b)、(3b)、(4b)、(5b)、(7b);(1b)、(2b)、(3b)、(4b)、(5b)、(8b);(1b)、(2b)、(3b)、(4b)、(5b)、(9b);(1b)、(2b)、(3b)、(4b)、(5b)、(10b);(1b)、(2b)、(3b)、(4b)、(6b)、(7b);(1b)、(2b)、(3b)、(4b)、(6b)、(8b );(1b)、(2b)、(3b)、(4b)、(6b)、(9b);(1b)、(2b)、(3b)、(4b)、(6b)、(10b);(1b)、(2b)、(3b)、(4b)、(7b)、(8b);(1b)、(2b)、(3b)、(4b)、(7b)、(9b);(1b)、(2b)、(3b)、(4b)、(7b)、(10b);(1b)、(2b)、(3b)、(4b)、(8b)、(9b);(1b)、(2b)、(3b)、(4b)、(8b)、(10b);(1b)、(2b)、(3b)、(4b)、(9b)、(10b);(1b)、(2b)、(3b)、(4b)、(9b)、(10b);(1b)、(2b)、(3b)、(5b)、(6b)、(7b);(1b)、(2b)、(3b)、(5b)、(6b)、(8b);(1b)、(2b)、(3b)、(5b)、(6b)、(9b);(1b)、(2b)、(3b)、(5b)、(6b)、(10b);(1b)、(2b)、(3b)、(5b)、(7b)、(8b)、(9b);( 1b),(2b),(3b),(5b),(8b),(10b);(1b),(2b),(3b),(5b),(9b),(10b);(1b),(2b),(3b),(6b),(7b),(8b);(1b),(2b),(3b),(6b),(7b),(9b);(1b),(2b),(3b),(6b),(7b),(9b);(1b),(2b),(3b),(6b),(7b),(10b);(1b),(2b),(3b),(6b),(8b),(9b);(1b),(2b),(3b),(6b),(8b),(10b);(1b),(2b),(3b),(6b),(9b),(10b); (1b)、(2b)、(3b)、(7b)、(8b)、(9b);(1b)、(2b)、(3b)、(7b)、(8b)、(10b);(1b)、(2b)、(3b)、(7b)、(9b)、(10b);(1b)、(2b)、(3b)、(8b)、(9b)、(10b);(1b)、(2b)、(4b)、(5b)、(6b)、(7b);(1b)、(2b)、(4b)、(5b)、(6b)、(8b);(1b)、(2b)、(4b)、(5b)、(6b)、(9b);(1b)、(2b)、(4b)、(5b)、(6b)、(10b) ;(1b)、(2b)、(4b)、(5b)、(7b)、(8b);(1b)、(2b)、(4b)、(5b)、(7b)、(9b);(1b)、(2b)、(4b)、(5b)、(7b)、(10b);(1b)、(2b)、(4b)、(5b)、(8b)、(9b);(1b)、(2b)、(4b)、(5b)、(8b)、(10b);(1b)、(2b)、(4b)、(5b)、(9b)、(10b);(1b)、(2b)、(4b)、(6b)、(7b)、(8b));(1b)、(2b)、(4b)、(6b)、(7b)、(9b);(1b)、(2b)、(4b)、(6b)、(7b)、(10b);(1b)、(2b)、(4b)、(6b)、(8b)、(9b);(1b)、(2b)、(4b)、(6b)、(8b)、(10b);(1b)、(2b)、(4b)、(6b)、(9b)、(10b);(1b)、(2b)、(4b)、(7b)、(8b)、(9b)、(10b);(1b)、(2b)、(4b)、(7b)、(8b)、(10b);(1b)、(2b)、(4b)、(7b)、(9b)、(10b );(1b)、(2b)、(5b)、(6b)、(7b)、(8b);(1b)、(2b)、(5b)、(6b)、(7b)、(9b) ;(1b)、(2b)、(5b)、(6b)、(7b)、(10b);(1b)、(2b)、(5b)、(6b)、(8b)、(9b) ;(1b)、(2b)、(5b)、(6b)、(8b)、(10b);(1b)、(2b)、(5b)、(6b)、(9b)、(10b );(1b)、(2b)、(5b)、(7b)、(8b)、(9b);(1b)、(2b)、(5b)、(7b)、(8b)、(10b) ;(1b)、(2b)、(5b)、(7b)、(9b)、(10b);(1b)、(2b)、(5b)、(8b)、(9b)、(10b);(1b)、(2b)、(6b)、(7b)、(8b)、(9b);(1b)、(2b)、(6b)、(7b)、(8b)、(10b);(1b)、(2b)、(6b)、(7b)、(9b)、(10b);(1b)、(2b)、(6b)、(8b)、(9b)、(10b);(1b)、(2b)、(6b)、(8b)、(9b)、(10b);(1b)、(2b)、(7b)、(8b)、(9b)、(10b);(1b)、(3b)、(4b)、(5b)、(6b)、(7b) );(1b)、(3b)、(4b)、(5b)、(6b)、(8b);(1b)、(3b)、(4b)、(5b)、(6b)、(9b);(1b)、(3b)、(4b)、(5b)、(6b)、(10b);(1b)、(3b)、(4b)、(5b)、(7b)、(8b);(1b)、(3b)、(4b)、(5b)、(7b)、(9b);(1b)、(3b)、(4b)、(5b)、(7b)、(10b);(1b)、(3b)、(4b)、(5b)、(8b)、(9b);(1b)、(3b)、(4b)、(5b)、(8b)、(10b);(1b)、(3b)、(4b)、(5b)、(9b)、(10b);(1b)、(3b)、(4b)、(6b)、(7b)、(8b);(1b)、(3b)、(4b)、(6b)、(7b)、(9b);(1b)、(3b)、(4b)、(6b)、(7b)、(10b);(1b)、(3b)、(4b)、(6b)、(8b)、(9b);( 1b)、(3b)、(4b)、(7b)、(8b)、(10b);(1b)、(3b)、(4b)、(7b)、(9b)、(10b);(1b)、(3b)、(4b)、(8b)、(9b)、(10b);(1b)、(3b)、(5b)、(6b)、(7b)、(8b)、(10b);( 1b), (3b), (5b), (6b), (9b), (10b);(1b), (3b), (5b), (7b), (8b), (9b);(1b), (3b), (5b), (7b), (8b), (10b);(1b), (3b), (5b), (7b), (9b), (10b);(1b), (3b), (5b), (7b), (9b), (10b);(1b), (3b), (6b), (7b), (8b), (9b), (10b);(1b), (3b), (6b), (7b), (8b), (9b), (10b); (1b)、(3b)、(6b)、(8b)、(9b)、(10b);(1b)、(3b)、(7b)、(8b)、(9b)、(10b);(1b)、(4b)、(5b)、(6b)、(7b)、(8b);(1b)、(4b)、(5b)、(6b)、(7b)、(9b);(1b)、(4b)、(5b)、(6b)、(7b)、(10b);(1b)、(4b)、(5b)、(6b)、(8b)、(9b)、(10b);(1b)、(4b)、(5b)、(6b)、(8b)、(10b);(1b)、(4b)、(5b)、(6b)、(9b)、(10b);(1b)、(4b)、(5b)、(7b)、(8b)、(9b);(1b)、(4b)、(5b)、(7b)、(8b)、(10b);(1b)、(4b)、(5b)、(7b)、(9b)、(10b);(1b)、(4b)、(5b)、(8b)、(9b)、(10b);(1b)、(4b)、(6b)、(7b)、(8b)、(9b)、(10b);(1 b)、(4b)、(7b)、(8b)、(9b)、(10b);(1b)、(5b)、(6b)、(7b)、(8b)、(9b);(1b)、(5b)、(6b)、(7b)、(8b)、(10b);(1b)、(5b)、(6b)、(7b)、(9b)、(10b);(1b)、(5b)、(6b)、(8b)、(9b)、(10b);(1b)、(5b)、(7b)、(8b)、(9b)、(10b);(1b)、(6b)、(7b)、(8b)、(9b)、(10b);(1b)、(2b)、(3b)、(4b)、(5b)、(6b)、(7b) ;(1b)、(2b)、(3b)、(4b)、(5b)、(6b)、(8b);(1b)、(2b)、(3b)、(4b)、(5b)、(6b)、(9b);(1b)、(2b)、(3b)、(4b)、(5b)、(6b)、(10b);(1b)、(2b)、(3b)、(4b)、(5b)、(7b)、(8b);(1b)、(2b)、(3b)、(4b)、(5b)、(7b)、(9b);(1b)、(2b)、(3b)、(4b)、(5b)、(7b)、(10b);(1b)、(2b)、(3b)、(4b)、(5b)、(8b)、(9b); (1b)、(2b)、(3b)、(4b)、(5b)、(8b)、(10b);(1b)、(2b)、(3b)、(4b)、(5b)、(9b)、(10b);(1b)、(2b)、(3b)、(4b)、(6b)、(7b)、(8b);(1b)、(2b)、(3b)、(4b)、(6b)、(7b)、(9b);(1b)、(2b)、(3b)、(4b)、(6b)、(7b)、(10b);(1b)、(2b)、(3b)、(4b)、(6b)、(8b)、(9b);(1b)、(2b)、(3b)、(4b)、(6b)、(8b)、(10b);(1b)、(2b)、(3b)、(4b)、(6b)、(9b)、(10b);(1b)、(2b)、(3b)、(4b)、(7b)、(8b)、(9b);(1b)、(2b)、(3b)、(4b)、(7b)、(8b)、(10b);(1b)、(2b)、(3b)、(4b)、(7b)、(9b)、(10b);(1b)、(2b)、(3b)、(4b)、(8b)、(9b)、(10b);(1b)、(2b)、(3b)、(5b)、(6b)、(7b)、(8b); (1b)、(2b)、(3b)、(5b)、(6b)、(7b)、(9b);(1b)、(2b)、(3b)、(5b)、(6b)、(7b)、(10b);(1b)、(2b)、(3b)、(5b)、(6b)、(8b)、(9b);(1b)、(2b)、(3b)、(5b)、(6b)、(8b)、(10b);(1b)、(2b)、(3b)、(5b)、(6b)、(9b)、(10b);(1b)、(2b)、(3b)、(5b)、(7b)、(8b)、(9b);(1b)、(2b)、(3b)、(5b)、(7b)、(8b)、(10b); (1b)、(2b)、(3b)、(5b)、(7b)、(9b)、(10b);(1b)、(2b)、(3b)、(5b)、(8b)、(9b)、(10b);(1b)、(2b)、(3b)、(6b)、(7b)、(8b)、(9b)、(10b);(1b)、(2b)、(3b)、(6b)、(7b)、(8b)、(10b);(1b)、(2b)、(3b)、(6b)、(7b)、(9b)、(10b);(1b)、(2b)、(3b)、(6b)、(8b)、(9b)、(10b) ;(1b)、(2b)、(4b)、(5b)、(6b)、(7b)、(8b);(1b)、(2b)、(4b)、(5b)、(6b)、(7b)、(9b);(1b)、(2b)、(4b)、(5b)、(6b)、(7b)、(10b);(1b)、(2b)、(4b)、(5b)、(6b)、(8b)、(9b);( 1b), (2b), (4b), (5b), (7b), (8b), (10b);(1b), (2b), (4b), (5b), (7b), (9b), (10b);(1b), (2b), (4b), (5b), (8b), (9b), (10b);(1b), (2b), (4b), (6b), (7b), (8b), (9b);(1b), (2b), (4b), (6b), (7b), (8b), (10b);(1b), (2b), (4b), (6b), (7b), (8b), (10b);(1b), (2b), (4b), (6b), (7b), (9b), (10b);(1b), (2b), (4b), (6b), (7b), (9b), (10b);(1b)、(2b)、(4b)、(7b)、(8b)、(9b)、(10b);(1b)、(2b)、(5b)、(6b)、(7b)、(8b)、(9b);(1b)、(2b)、(5b)、(6b)、(7b)、(8b)、(10b);(1b)、(2b)、(5b)、(6b)、(7b)、(9b)、(10b);(1b)、(2b)、(5b)、(6b)、(8b)、(9b)、(10b);(1b)、(2b)、(5b)、(7b)、(8b)、(9b)、(10b) ;(1b)、(3b)、(4b)、(5b)、(6b)、(7b)、(8b);(1b)、(3b)、(4b)、(5b)、(6b)、(7b)、(9b);(1b)、(3b)、(4b)、(5b)、(6b)、(7b)、(10b);(1b)、(3b)、(4b)、(5b)、(6b)、(8b)、(9b);( 1b), (3b), (4b), (5b), (7b), (8b), (10b);(1b), (3b), (4b), (5b), (7b), (9b), (10b);(1b), (3b), (4b), (5b), (8b), (9b), (10b);(1b), (3b), (4b), (6b), (7b), (8b), (9b);(1b), (3b), (4b), (6b), (7b), (8b), (10b);(1b), (3b), (4b), (6b), (7b), (8b), (10b);(1b), (3b), (4b), (6b), (7b), (9b), (10b);(1b), (3b), (4b), (6b), (7b), (9b), (10b); (1b)、(3b)、(4b)、(7b)、(8b)、(9b)、(10b);(1b)、(3b)、(5b)、(6b)、(7b)、(8b)、(9b);(1b)、(3b)、(5b)、(6b)、(7b)、(8b)、(10b);(1b)、(3b)、(5b)、(6b)、(7b)、(9b)、(10b);(1b)、(3b)、(5b)、(6b)、(8b)、(9b)、(10b);(1b)、(3b)、(5b)、(7b)、(8b)、(9b)、(10b);(1b)、(4b)、(5b)、(6b)、(7b)、(8b)、(9b);(1b)、(4b)、(5b)、(6b)、(7b)、(8b)、(10b);(1b)、(4b)、(5b)、(6b)、(7b)、(9b)、(10b);(1b)、(4b)、(5b)、(6b)、(8b)、(9b)、(10b);(1b)、(4b)、(5b)、(7b)、(8b)、(9b)、(10b);(1b)、(4b)、(6b)、(7b)、(8b)、(9b)、(10b);(1b)、(5b)、(6b)、(7b)、(8b)、(9b)、(10b) (10b);(1b),(2b),(3b),(4b),(5b),(6b),(7b),(8b);(1b),(2b),(3b),(4b),(5b),(6b),(7b),(9b);(1b),(2b),(3b),(4b),(5b),(6b),(7b),(10b);(1b),(2b),(3b),(4b),(5b),(6b),(8b),(9b);(1b),(2b),(3b),(4b),(5b),(6b),(8b),(10b);(1b),(2b),(3b),(4b),(5b),(6b),(9b),(10 b);(1b)、(2b)、(3b)、(4b)、(5b)、(7b)、(8b)、(9b);(1b)、(2b)、(3b)、(4b)、(5b)、(7b)、(8b)、(10b);(1b)、(2b)、(3b)、(4b)、(5b)、(7b)、(9b)、(10b);(1b)、(2b)、(3b)、(4b)、(5b)、(8b)、(9b)、(10b);(1b)、(2b)、(3b)、(4b)、(6b)、(7b)、(8b)、(9b);(1b)、(2b)、(3b)、(4b)、(6b)、(7b)、(8b)、(10b) ;(1b)、(2b)、(3b)、(4b)、(6b)、(7b)、(9b)、(10b);(1b)、(2b)、(3b)、(4b)、(6b)、(8b)、(9b)、(10b);(1b)、(2b)、(3b)、(4b)、(7b)、(8b)、(9b)、(10b);(1b)、(2b)、(3b)、(5b)、(6b)、(7b)、(8b)、(9b)、(10b);(1b)、(2b)、(3b)、(5b)、(6b)、(7b)、(8b)、(10b);(1b)、(2b)、(3b)、(5b)、(6b)、(7b)、(9b)、(10b);(1b)、(2b)、(3b)、(5b)、(6b)、(8b)、(9b)、(10b);(1b)、(2b)、(3b)、(5b)、(7b)、(8b)、(9b)、(10b);(1b)、(2b)、(3b)、(6b)、(7b)、(8b)、(9b)、(10b);(1b)、(2b)、(4b)、(5b)、(6b)、(7b)、(8b)、(9b)、(10b);(1b)、(2b)、(4b)、(5b)、(6b)、(7b)、(8b)、(10b);(1b)、(2b)、(4b)、(5b)、(6b)、(7b)、(9b)、(1 0b);(1b)、(2b)、(4b)、(5b)、(6b)、(8b)、(9b)、(10b);(1b)、(2b)、(4b)、(5b)、(7b)、(8b)、(9b)、(10b);(1b)、(2b)、(4b)、(6b)、(7b)、(8b)、(9b)、(10b);(1b)、(2b)、(5b)、(6b)、(7b)、(8b)、(9b)、(10b);(1b)、(3b)、(4b)、(5b)、(6b)、(7b)、(8b)、(9b)、(1b)、(3b)、(4b)、(5b)、(6b)、(7b)、(8b)、(9b);8b) )、(10b);(1b)、(3b)、(4b)、(5b)、(6b)、(7b)、(9b)、(10b);(1b)、(3b)、(4b)、(5b)、(6b)、(8b)、(9b)、(10b);(1b)、(3b)、(4b)、(5b)、(7b)、(8b)、(9b)、(10b);(1b)、(3b)、(4b)、(6b)、(7b)、(8b)、(9b)、(10b);(1b)、(3b)、(5b)、(6b)、(7b)、(8b)、(9b)、(10b);(1b)、(4b)、(5b)、(6b)、(7b)、(8b)、(9b)、(10b);(1b)、(4b)、(5b)、(6b)、(7b)、(8b)、(9b)、(10b) )、(9b)、(10b);(1b)、(2b)、(3b)、(4b)、(5b)、(6b)、(7b)、(8b)、(9b);(1b)、(2b)、(3b)、(4b)、(5b)、(6b)、(7b)、(8b)、(10b);(1b)、(2b)、(3b)、(4b)、(5b)、(6b)、(7b)、(9b)、(10b);(1b)、(2b)、(3b)、(4b)、(5b)、(6b)、(8b)、(9b)、(10b);(1b)、(2b)、(3b)、(4b)、(5b)、(7b)、(8b)、(9b)、(10b);(1b), (2b), (3b), (4b), (6b), (7b), (8b), (9b), (10b); (1b), (2b), (3b), (5b), (6b), (7b), (8b), (9b), (10b); (1b), (2b), (4b), (5b), (6b), (7b), (8b), (9b), (10b); (1b), (3b), (4b), (5b), (6b), (7b), (8b), (9b), (10b) ; characterized by one of (1b), (2b), (3b), (4b), (5b), (6b), (7b), (8b), (9b), (10b). ;

[0227] In the combinations in the previous paragraph, "(1b)" is independently selected from (1b)(i), (1b)(ii), (1b)(iii), and (1b)(iv); "(2b)" is independently selected from (2b)(i), (2b)(ii), (2b)(iii), and (2b)(iv); "(3b)" is independently selected from (3b)(i), (3b)(ii), (3b)(iii), and (3b)(iv); "(4b)" is independently selected from (4b)(i), (4 b)(ii), (4b)(iii), and (4b)(iv) are selected; "(5b)" is independently selected from (5b)(i), (5b)(ii), (5b)(iii), and (5b)(iv) above; "(6b)" is independently selected from (6b)(i) and (6b)(ii) above; "(7b)" is independently selected from (7b)(i) and (7b)(ii) above; and "(8b)" is independently selected from (8b)(i) and (8a)(ii) above.

[0228] All possible combinations of such features, as described above, are explicitly intended. Simply as an example, cancers containing the combination of features "(1b), (2b)" are specifically: (1b)(i) and (2b)(i); (1b)(i) and (2b)(ii); (1b)(i) and (2b)(iii); (1b)(i) and (2b)(iv); (1b)(ii) and (2b)(i); (1b)(ii) and (2b)(ii); (1b)(ii) and (2b)(iii); (1b This refers to cancers including (ii) and (2b)(iv); (1b)(iii) and (2b)(i); (1b)(iii) and (2b)(ii); (1b)(iii) and (2b)(iii); (1b)(iii) and (2b)(iv); (1b)(iv) and (2b)(ii); (1b)(iv) and (2b)(iii); and (1b)(iv) and (2b)(iv).

[0229] In the embodiments and aspects of this disclosure, cancers to be treated / prevented with an antigen-binding molecule that binds to HER3 in combination with an antagonist of HER3-mediated signaling are homozygous for activating mutations in genes encoding positive regulators of HER3-mediated signaling, selected from PIK3CB, PIK3CD, ERBB3, ERBB2, ERBB4, EGFR, IGF1R, NRG1, NRG2, EGF, IRS2, GRB2, GAB2, PTPN11, SHP2, SOS1, HRAS, NRAS, RAF1, MAP2K1, MAP2K2, MAPK1, MYC, RPS6KA1, RPS6, MKNK1, CREB1, MTOR, PDK1, AKT1, AKT2, AKT3, JAK2, STAT3, and STAT5. In some embodiments, the cancer is heterozygous with respect to activating mutations in genes encoding positive regulators of HER3-mediated signaling, selected from PIK3CB, PIK3CD, ERBB3, ERBB2, ERBB4, EGFR, IGF1R, NRG1, NRG2, EGF, IRS2, GRB2, GAB2, PTPN11, SHP2, SOS1, HRAS, NRAS, RAF1, MAP2K1, MAP2K2, MAPK1, MYC, RPS6KA1, RPS6, MKNK1, CREB1, MTOR, PDK1, AKT1, AKT2, AKT3, JAK2, STAT3, and STAT5. In some embodiments, the cancer includes genetic diversity resulting from increased expression of genes encoding positive regulators of HER3-mediated signaling, or increased activity of their gene products, selected from PIK3CB, PIK3CD, ERBB3, ERBB2, ERBB4, EGFR, IGF1R, NRG1, NRG2, EGF, IRS2, GRB2, GAB2, PTPN11, SHP2, SOS1, HRAS, NRAS, RAF1, MAP2K1, MAP2K2, MAPK1, MYC, RPS6KA1, RPS6, MKNK1, CREB1, MTOR, PDK1, AKT1, AKT2, AKT3, JAK2, STAT3, and STAT5.

[0230] In aspects and embodiments of this disclosure, cancers to be treated / prevented with an antigen-binding molecule that binds to HER3 in combination with an antagonist of HER3-mediated signaling are homozygous for activating mutations in genes encoding positive regulators of signaling via the MAPK / ERK pathway, selected from ERBB3, ERBB2, ERBB4, EGFR, IGF1R, NRG1, NRG2, EGF, IRS2, GAB2, GRB2, PTPN11, SHP2, SOS1, HRAS, KRAS, NRAS, RAF1, MAP2K1, MAP2K2, MAPK1, MYC, RPS6KA1, RPS6, MKNK1, and CREB1. In some embodiments, the cancer is heterozygous with respect to activating mutations in genes encoding positive regulators of signaling via the MAPK / ERK pathway, selected from ERBB3, ERBB2, ERBB4, EGFR, IGF1R, NRG1, NRG2, EGF, IRS2, GAB2, GRB2, PTPN11, SHP2, SOS1, HRAS, KRAS, NRAS, RAF1, MAP2K1, MAP2K2, MAPK1, MYC, RPS6KA1, RPS6, MKNK1, and CREB1. In some embodiments, the cancer includes genetic diversity resulting from increased expression of genes encoding positive regulators of signaling via the MAPK / ERK pathway, or increased activity of their gene products, selected from ERBB3, ERBB2, ERBB4, EGFR, IGF1R, NRG1, NRG2, EGF, IRS2, GAB2, GRB2, PTPN11, SHP2, SOS1, HRAS, KRAS, NRAS, RAF1, MAP2K1, MAP2K2, MAPK1, MYC, RPS6KA1, RPS6, MKNK1, and CREB1.

[0231] In aspects and embodiments of this disclosure, cancers to be treated / prevented with an antigen-binding molecule that binds to HER3 in combination with an antagonist of HER3-mediated signaling are homozygous for activating mutations in genes encoding positive regulators of signaling via the PI3K / AKT / mTOR pathway, selected from ERBB3, ERBB2, ERBB4, EGFR, IGF1R, NRG1, NRG2, EGF, IRS2, GAB2, SHP2, CREB1, PIK3CB, PIK3CD, MTOR, PDK1, AKT1, AKT2, AKT3, JAK2, STAT3, and STAT5. In some embodiments, the cancer is heterozygous with respect to activating mutations in genes encoding positive regulators of signaling via the PI3K / AKT / mTOR pathway, selected from ERBB3, ERBB2, ERBB4, EGFR, IGF1R, NRG1, NRG2, EGF, IRS2, GAB2, SHP2, CREB1, PIK3CB, PIK3CD, MTOR, PDK1, AKT1, AKT2, AKT3, JAK2, STAT3, and STAT5. In some embodiments, the cancer includes genetic diversity resulting from increased expression of genes encoding positive regulators of signaling via the PI3K / AKT / mTOR pathway, or increased activity of their gene products, selected from ERBB3, ERBB2, ERBB4, EGFR, IGF1R, NRG1, NRG2, EGF, IRS2, GAB2, SHP2, CREB1, PIK3CB, PIK3CD, MTOR, PDK1, AKT1, AKT2, AKT3, JAK2, STAT3, and STAT5.

[0232] In aspects and embodiments of this disclosure, the cancer to be treated / prevented with an antigen-binding molecule that binds to HER3 in combination with an antagonist of HER3-mediated signaling is homozygous for inactivating mutations in a gene encoding a negative regulator of HER3-mediated signaling, selected from PPP2CA, PIK3R1, PIK3R2, NF1, BAD, and PHLPP1. In some embodiments, the cancer is heterozygous for inactivating mutations in a gene encoding a negative regulator of HER3-mediated signaling, selected from PPP2CA, PIK3R1, PIK3R2, NF1, BAD, and PHLPP1. In some embodiments, the cancer includes genetic diversity resulting in reduced expression of a gene encoding a negative regulator of HER3-mediated signaling, selected from PPP2CA, PIK3R1, PIK3R2, NF1, BAD, and PHLPP1, or reduced activity of its gene product.

[0233] In the embodiments and aspects of this disclosure, the cancer to be treated / prevented with an antigen-binding molecule that binds to HER3 in combination with a HER3-mediated signaling antagonist is homozygous for an inactivating mutation to NF1. In some embodiments, the cancer is heterozygous for an inactivating mutation to NF1. In some embodiments, the cancer includes genetic diversity that results in reduced expression of NF1 or reduced activity of its gene product.

[0234] In aspects and embodiments according to the present disclosure, the cancer to be treated / prevented by using an antigen-binding molecule that binds to HER3 in combination with an antagonist of HER3-mediated signal transduction is homozygous with respect to an inactivating mutation in a gene encoding a negative regulator of signal transduction via the PI3K / AKT / mTOR pathway, which is selected from PPP2CA, PIK3R1, PIK3R2, BAD, and PHLPP1. In some embodiments, the cancer is heterozygous with respect to an inactivating mutation in a gene encoding a negative regulator of signal transduction via the PI3K / AKT / mTOR pathway, which is selected from PPP2CA, PIK3R1, PIK3R2, BAD, and PHLPP1. In some embodiments, the cancer comprises genetic diversity that results in a decrease in the expression of a gene encoding a negative regulator of signal transduction via the PI3K / AKT / mTOR pathway, which is selected from PPP2CA, PIK3R1, PIK3R2, BAD, and PHLPP1, or a decrease in the activity of the gene product.

[0235] In aspects and embodiments according to the present disclosure, the cancer to be treated / prevented by using an antigen-binding molecule that binds to HER3 in combination with an antagonist of HER3-mediated signal transduction comprises (i) genetic diversity that results in an increase in the expression of MET or an increase in the activity of the gene product, and (ii) genetic diversity that results in an increase in the expression of KRAS or an increase in the activity of the gene product. In some embodiments, the cancer comprises (i) amplification of MET and (ii) an activating mutation in KRAS.

[0236] In aspects and embodiments according to the present disclosure, the cancer to be treated / prevented by using an antigen-binding molecule that binds to HER3 in combination with an antagonist of HER3-mediated signal transduction comprises (i) genetic diversity that results in an increase in the expression of MET or an increase in the activity of the gene product, and (ii) genetic diversity that results in an increase in the expression of PIK3CA or an increase in the activity of the gene product. In some embodiments, the cancer comprises (i) amplification of MET and (ii) an activating mutation in PIK3CA.

[0237] In aspects and embodiments according to the present disclosure, the cancer to be treated / prevented by using an antigen-binding molecule that binds to HER3 in combination with an antagonist of HER3-mediated signaling includes (i) genetic diversity that results in increased expression of MET or increased activity of its gene product, and (ii) genetic diversity that results in increased expression of BRAF or increased activity of its gene product. In some embodiments, the cancer includes (i) MET amplification and (ii) activating mutations in BRAF.

[0238] In aspects and embodiments according to the present disclosure, the cancer to be treated / prevented by using an antigen-binding molecule that binds to HER3 in combination with an antagonist of HER3-mediated signaling includes (i) genetic diversity that results in increased expression of MET or increased activity of its gene product, and (ii) genetic diversity that results in decreased expression of PTEN or decreased activity of its gene product. In some embodiments, the cancer includes (i) MET amplification and (ii) inactivating mutations in PTEN.

[0239] In aspects and embodiments according to the present disclosure, the cancer to be treated / prevented by using an antigen-binding molecule that binds to HER3 in combination with an antagonist of HER3-mediated signaling includes (i) genetic diversity that results in increased expression of MET or increased activity of its gene product, (ii) genetic diversity that results in increased expression of KRAS or increased activity of its gene product, and (iii) genetic diversity that results in increased expression of PIK3CA or increased activity of its gene product. In some embodiments, the cancer includes (i) MET amplification, (ii) activating mutations in KRAS, and (iii) activating mutations in PIK3CA.

[0240] In aspects and embodiments of the present disclosure, cancers to be treated / prevented with an antigen-binding molecule that binds to HER3 in combination with an antagonist of HER3-mediated signaling include: (i) genetic diversity resulting in increased expression of MET or increased activity of its gene product; (ii) genetic diversity resulting in increased expression of KRAS or increased activity of its gene product; and (iii) genetic diversity resulting in increased expression of BRAF or increased activity of its gene product. In some embodiments, the cancer includes: (i) amplification of MET; (ii) activating mutations to KRAS; and (iii) activating mutations to BRAF.

[0241] In aspects and embodiments of the present disclosure, cancers to be treated / prevented with an antigen-binding molecule that binds to HER3 in combination with an antagonist of HER3-mediated signaling include: (i) genetic diversity resulting in increased expression of MET or increased activity of its gene product; (ii) genetic diversity resulting in increased expression of KRAS or increased activity of its gene product; and (iii) genetic diversity resulting in decreased expression of PTEN or decreased activity of its gene product. In some embodiments, the cancer includes (i) amplification of MET, (ii) activating mutations to KRAS, and (iii) inactivating mutations to PTEN.

[0242] In aspects and embodiments of the present disclosure, cancers to be treated / prevented with an antigen-binding molecule that binds to HER3 in combination with an antagonist of HER3-mediated signaling include: (i) genetic diversity resulting in increased expression of MET or increased activity of its gene product; (ii) genetic diversity resulting in increased expression of PIK3CA or increased activity of its gene product; and (iii) genetic diversity resulting in increased expression of BRAF or increased activity of its gene product. In some embodiments, the cancer includes: (i) amplification of MET; (ii) activating mutations to PIK3CA; and (iii) activating mutations to BRAF.

[0243] In aspects and embodiments of the present disclosure, cancers to be treated / prevented with an antigen-binding molecule that binds to HER3 in combination with an antagonist of HER3-mediated signaling include: (i) genetic diversity resulting in increased expression of MET or increased activity of its gene product; (ii) genetic diversity resulting in increased expression of PIK3CA or increased activity of its gene product; and (iii) genetic diversity resulting in decreased expression of PTEN or decreased activity of its gene product. In some embodiments, the cancer includes (i) amplification of MET, (ii) activating mutations to PIK3CA, and (iii) inactivating mutations to PTEN.

[0244] In aspects and embodiments of the present disclosure, cancers to be treated / prevented with an antigen-binding molecule that binds to HER3 in combination with an antagonist of HER3-mediated signaling include: (i) genetic diversity resulting in increased expression of MET or increased activity of its gene product; (ii) genetic diversity resulting in increased expression of BRAF or increased activity of its gene product; and (iii) genetic diversity resulting in decreased expression of PTEN or decreased activity of its gene product. In some embodiments, the cancer includes (i) amplification of MET, (ii) activating mutations to BRAF, and (iii) inactivating mutations to PTEN.

[0245] In aspects and embodiments of the present disclosure, cancers to be treated / prevented with an antigen-binding molecule that binds to HER3 in combination with an antagonist of HER3-mediated signaling include: (i) genetic diversity resulting in increased expression of MET or increased activity of its gene product; (ii) genetic diversity resulting in increased expression of KRAS or increased activity of its gene product; (iii) genetic diversity resulting in increased expression of PIK3CA or increased activity of its gene product; and (iv) genetic diversity resulting in increased expression of BRAF or increased activity of its gene product. In some embodiments, the cancer includes: (i) amplification of MET; (ii) activating mutations to KRAS; (iii) activating mutations to PIK3CA; and (iv) activating mutations to BRAF.

[0246] In aspects and embodiments of the present disclosure, cancers to be treated / prevented with an antigen-binding molecule that binds to HER3 in combination with an antagonist of HER3-mediated signaling include: (i) genetic diversity resulting in increased expression of MET or increased activity of its gene product; (ii) genetic diversity resulting in increased expression of KRAS or increased activity of its gene product; (iii) genetic diversity resulting in increased expression of PIK3CA or increased activity of its gene product; and (iv) genetic diversity resulting in decreased expression of PTEN or decreased activity of its gene product. In some embodiments, the cancer includes: (i) amplification of MET; (ii) activating mutations to KRAS; (iii) activating mutations to PIK3CA; and (iv) inactivating mutations to PTEN.

[0247] In aspects and embodiments of the present disclosure, cancers to be treated / prevented with an antigen-binding molecule that binds to HER3 in combination with an antagonist of HER3-mediated signaling include: (i) genetic diversity resulting in increased expression of MET or increased activity of its gene product; (ii) genetic diversity resulting in increased expression of KRAS or increased activity of its gene product; (iii) genetic diversity resulting in increased expression of BRAF or increased activity of its gene product; and (iv) genetic diversity resulting in decreased expression of PTEN or decreased activity of its gene product. In some embodiments, the cancer includes: (i) amplification of MET; (ii) activating mutations to KRAS; (iii) activating mutations to BRAF; and (iv) inactivating mutations to PTEN.

[0248] In aspects and embodiments of the present disclosure, cancers to be treated / prevented with an antigen-binding molecule that binds to HER3 in combination with an antagonist of HER3-mediated signaling include: (i) genetic diversity resulting in increased expression of MET or increased activity of its gene product; (ii) genetic diversity resulting in increased expression of PIK3CA or increased activity of its gene product; (iii) genetic diversity resulting in increased expression of BRAF or increased activity of its gene product; and (iv) genetic diversity resulting in decreased expression of PTEN or decreased activity of its gene product. In some embodiments, the cancer includes: (i) amplification of MET; (ii) activating mutations to PIK3CA; (iii) activating mutations to BRAF; and (iv) inactivating mutations to PTEN.

[0249] In aspects and embodiments of the present disclosure, cancers to be treated / prevented with an antigen-binding molecule that binds to HER3 in combination with an antagonist of HER3-mediated signaling include: (i) genetic diversity resulting in increased expression of MET or increased activity of its gene product; (ii) genetic diversity resulting in increased expression of KRAS or increased activity of its gene product; (iii) genetic diversity resulting in increased expression of PIK3CA or increased activity of its gene product; (iv) genetic diversity resulting in increased expression of BRAF or increased activity of its gene product; and (v) genetic diversity resulting in decreased expression of PTEN or decreased activity of its gene product. In some embodiments, the cancer includes: (i) amplification of MET; (ii) activating mutations to KRAS; (iii) activating mutations to PIK3CA; (iv) activating mutations to BRAF; and (v) inactivating mutations to PTEN. Cancer characterized by the presence of genetic diversity that leads to increased expression of the gene on chromosome 3q, or increased activity of its gene product. The aspects and embodiments of this disclosure relate to cancers involving genetic diversity resulting from increased expression of a gene located on chromosome 3q, or increased activity of its gene product. The cancers described in this section may be further characterized by the preceding section titled “cancer.”

[0250] Early-stage squamous cell carcinogenesis is characterized by amplification of chromosome 3q (Chr3q), a well-known genetic abnormality associated with exposure to carcinogens (Rooney et al., Oncologist (2013) 18(6):707~716). Chr3q amplification leads to increased transcriptional activity of several oncogenes, including TP63 (which directly promotes the expression of HER3 ligand NRG1), SOX2 (which directly promotes the expression of EGFR ligand), and PIK3CA (which enhances the activation of the PI3K pathway) (Perez-Moreno et al., Clinical Cancer Research (2012) 18(9):2443~2451).

[0251] In the aspects and embodiments of this disclosure, the cancer to be treated / prevented in accordance with this disclosure is characterized by one or more of the following features: (6a)(i)Includes genetic diversity that results in increased expression of TP63 or increased activity of its gene product. (6a)(ii) Amplification of TP63 (e.g., amplification of TP63 as described herein). (7a)(i)Includes genetic diversity that results in increased expression of PIK3CA or increased activity of its gene product. (7a)(ii) Amplification of PIK3CA (e.g., amplification of PIK3CA as described herein). (8a)(i)Includes genetic diversity that results in increased expression of SOX2 or increased activity of its gene product. (8a)(ii) Amplification of SOX2 (e.g., amplification of SOX2 as described herein).

[0252] In some embodiments, the cancer to be treated / prevented in accordance with this disclosure is characterized by one of the following combinations of features (see previous paragraph): (6a); (7a); (8a); (6a), (7a); (6a), (8a); (7a), (8a); (6a), (7a), (8a).

[0253] In the combinations described in the preceding paragraph, "(6a)" is independently selected from (6a)(i) and (6a)(ii) above; "(7a)" is independently selected from (7a)(i) and (7a)(ii) above; and "(8a)" is independently selected from (8a)(i) and (8a)(ii) above.

[0254] All possible combinations of such features, as described above, are explicitly intended. For illustrative purposes only, cancers containing the combination of features "(6a), (7a)" are specifically intended to include cancers containing (6a)(i) and (7a)(i); (6a)(i) and (7a)(ii); (6a)(ii) and (7a)(i); and cancers containing (6a)(ii) and (7a)(ii).

[0255] In aspects and embodiments according to the present disclosure, the cancer to be treated / prevented according to the present disclosure includes amplification of chromosome 3q. In aspects and embodiments according to the present disclosure, the cancer to be treated / prevented according to the present disclosure includes genetic diversity that results in increased expression of genes selected from ADIPOQ, AMOTL2, ARHGAP31, TIMMDC1, C3orf70, CAMPD1, CCDC80, CD200R1, CHST13, CLDND1, CPN2, CPOX, DPPA2, DTX3L, DZIP3, EAF2, EFCC1, ETM1, ETV5, FAM3D, FAM43A, FAM162A, FBXO40, FILIP1L, GYG1, HACD2, HGD, IFT122, KIAA1257, LINC01279, LNCR5, LMLN, LRRC15, LSG1, MB21D2, MCCC1, MORC1, MYLK, NEPRO, NFKBIZ, OTOL1, PARP14, PCCB, PDCD10, PIK3CA, PISRT1, PROSER1, RAB7, RASA2, RETNLB, RHO, RIOX2, SELT, SENP7, SERP1, SOX2, SOX2OT, SPG14, SRPRB, TEX55, TMEM44, TM4SF1, TMPRSS7, TP63, TRAT1, USH3A, ZBED2, and ZNF9, or increased activity of the gene products thereof. In some embodiments, the cancer includes genetic diversity that results in increased expression of genes selected from TP63, PIK3CA, and SOX2, or increased activity of the gene products thereof.

[0256] In the aspects and embodiments of this disclosure, the cancers to be treated / prevented in accordance with this disclosure are ADIPOQ, AMOTL2, ARHGAP31, TIMMDC1, C3orf70, CAMPD1, CCDC80, CD200R1, CHST13, CLDND1, CPN2, CPOX, DPPA2, DTX3L, DZIP3, EAF2, EFCC1, ETM1, ETV5, FAM3D, FAM43A, FAM162A, FBXO40, FILIP1L, GYG1, HACD2, HGD, IFT122, KIAA1257, LINC01279, and LNCR5. This includes amplification of genes selected from LMLN, LRRC15, LSG1, MB21D2, MCCC1, MORC1, MYLK, NEPRO, NFKBIZ, OTOL1, PARP14, PCCB, PDCD10, PIK3CA, PISRT1, PROSER1, RAB7, RASA2, RETNLB, RHO, RIOX2, SELT, SENP7, SERP1, SOX2, SOX2OT, SPG14, SRPRB, TEX55, TMEM44, TM4SF1, TMPRSS7, TP63, TRAT1, USH3A, ZBED2, and ZNF9. In some embodiments, the cancer includes amplification of genes selected from TP63, PIK3CA, and SOX2.

[0257] In aspects and embodiments of this disclosure, the cancer to be treated / prevented in accordance with this disclosure includes genetic diversity resulting in increased expression of TP63 or increased activity of its gene product. In some embodiments, the cancer includes amplification of TP63.

[0258] In aspects and embodiments of this disclosure, the cancer to be treated / prevented in accordance with this disclosure includes genetic diversity resulting in increased expression of PIK3CA or increased activity of its gene product. In some embodiments, the cancer includes amplification of PIK3CA.

[0259] In aspects and embodiments of this disclosure, the cancer to be treated / prevented in accordance with this disclosure includes genetic diversity resulting in increased expression of SOX2 or increased activity of its gene product. In some embodiments, the cancer includes amplification of SOX2.

[0260] In aspects and embodiments of the present disclosure, the cancer to be treated / prevented in accordance with the present disclosure includes genetic diversity resulting in (i) increased expression of TP63 or increased activity of its gene product, and (ii) increased expression of PIK3CA or increased activity of its gene product. In some embodiments, the cancer includes (i) amplification of TP63 and (ii) amplification of PIK3CA.

[0261] In aspects and embodiments of this disclosure, the cancer to be treated / prevented in accordance with this disclosure includes genetic diversity resulting in (i) increased expression of TP63 or increased activity of its gene product, and (ii) increased expression of SOX2 or increased activity of its gene product. In some embodiments, the cancer includes (i) amplification of TP63 and (ii) amplification of SOX2.

[0262] In aspects and embodiments of the present disclosure, the cancer to be treated / prevented in accordance with the present disclosure includes genetic diversity resulting in (i) increased expression of PIK3CA or increased activity of its gene product, and (ii) increased expression of SOX2 or increased activity of its gene product. In some embodiments, the cancer includes (i) amplification of PIK3CA and (ii) amplification of SOX2.

[0263] In aspects and embodiments of the present disclosure, the cancer to be treated / prevented in accordance with the present disclosure includes: (i) genetic diversity resulting in increased expression of TP63 or increased activity of its gene product; (ii) genetic diversity resulting in increased expression of PIK3CA or increased activity of its gene product; and (iii) genetic diversity resulting in increased expression of SOX2 or increased activity of its gene product. In some embodiments, the cancer includes: (i) amplification of TP63; (ii) amplification of PIK3CA; and (iii) amplification of SOX2. Cancer characterized by the presence of genetic diversity resulting in increased expression of the gene on chromosome 7p, or increased activity of its gene product. Aspects and embodiments of this disclosure relate to cancers involving genetic diversity resulting from increased expression of a gene located on chromosome 7p, or increased activity of its gene product. The cancers described in this section may be further characterized by the preceding section titled “cancer.”

[0264] Chromosome 7p (Chr7p), which encodes EGFR, has been found to be frequently amplified in LUSCs (Couceiro et al., Revista Portuguesa de Pneumologia (2010) 16(3):453~462).

[0265] In the aspects and embodiments of this disclosure, the cancer to be treated / prevented in accordance with this disclosure is characterized by one or more of the following features: (10a)(i)Includes genetic diversity that results in increased EGFR expression or increased activity of its gene product. (10a)(ii) Amplification of EGFR (e.g., EGFR amplification as described herein).

[0266] In aspects and embodiments of this disclosure, the cancer to be treated / prevented in accordance with this disclosure includes amplification of chromosome 7p. In aspects and embodiments of this disclosure, the cancer to be treated / prevented in accordance with this disclosure includes genetic diversity resulting in increased EGFR expression or increased activity of its gene product. In aspects and embodiments of this disclosure, the cancer to be treated / prevented in accordance with this disclosure includes EGFR amplification. Cancer characterized by the presence of genetic diversity that results in decreased expression of the gene on chromosome 3p or decreased activity of its gene product. Aspects and embodiments of this disclosure relate to cancers involving genetic diversity resulting in reduced expression of a gene located on chromosome 3p, or reduced activity of its gene product. The cancers described in this section may be further characterized by the preceding section titled “cancer.”

[0267] Early-stage squamous cell carcinoma is characterized by a deletion of chromosome 3p (Chr3p), a well-known genetic abnormality associated with exposure to carcinogens (Rooney et al., Oncologist (2013) 18(6):707-716). Chr3p deficiency results in the deletion of several putative tumor suppressor proteins, including tumor suppressive candidate 2 (TUSC2), which inhibits EGFR (Perez-Moreno et al., Clinical Cancer Research (2012) 18(9):2443-2451). TUSC2 has been found to be deleted in approximately 12-17% of squamous cell carcinoma patients (TCGA). Furthermore, studies have shown that TUSC2 can negatively regulate EGFR signaling (Dai et al., PLoS One (2015) 10(6):e0123967; Cao et al., Sci Rep. (2016) 6:35741).

[0268] In the aspects and embodiments of this disclosure, the cancer to be treated / prevented in accordance with this disclosure is characterized by one or more of the following features: (11a)(i) Does not contain genetic diversity that results in reduced expression of TUSC2 or reduced activity of its gene product. (11a)(ii) Not including any deletion of TUSC2 (e.g., the deletion of TUSC2 as described herein).

[0269] In aspects and embodiments of this disclosure, the cancer to be treated / prevented in accordance with this disclosure includes a deletion of chromosome 3p. In aspects and embodiments of this disclosure, cancers to be treated / prevented in accordance with this disclosure include genetic diversity resulting in reduced expression of TUSC2 or reduced activity of its gene product. In aspects and embodiments of this disclosure, cancers to be treated / prevented in accordance with this disclosure include deletion of TUSC2. antigen binding molecule This disclosure relates to the therapeutic and prophylactic use of antigen-binding molecules that bind to HER3.

[0270] An "antigen-binding molecule" refers to a molecule that binds to a given target antigen. Antigen-binding molecules include antibodies (i.e., immunoglobulins (Ig)) and their antigen-binding fragments. As used herein, "antibodies" include monoclonal antibodies, polyclonal antibodies, monospecific and multispecific (e.g., bispecific, trispecific, etc.) antibodies, and antibody-derived antigen-binding molecules, such as scFv, scFab, diabodies, triabodies, scFv-Fc, minibodies, and single-domain antibodies (e.g., VhH, etc.). Antigen-binding fragments of antibodies include, for example, Fv, Fab, F(ab')2, and F(ab') fragments. In some embodiments, the antigen-binding molecule may be an antibody or its antigen-binding fragment.

[0271] The antigen-binding molecules according to this disclosure further include antibody-derived molecules, for example, molecules containing an antigen-binding region / domain derived from an antibody. The antibody-derived antigen-binding molecule may include an antigen-binding region / domain containing 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 include an Fv (e.g., prepared as scFv), or a Fab region of an antibody, or the whole antibody. For example, the antigen-binding molecule according to this disclosure includes an antibody-drug conjugate (ADC) containing a (cytotoxic) drug portion (e.g., as described below). The antigen-binding molecules of this disclosure further include multispecific antigen-binding molecules, such as immune cell engager molecules containing a domain for recruiting (effector) immune cells (e.g., Goebeler and Bargou, Nat. Rev. Clin. Oncol. (2020) 17:418-434, and Ellerman, Methods (2019) 154:102-117, both of which are incorporated herein by reference in their entirety), BiTE, BiKE, and TriKE. The antigen-binding molecules of this disclosure further include chimeric antigen receptors (CARs), which are recombinant receptors that provide both antigen-binding and T-cell activation functions (CAR structures, functions, and engineering are outlined, for example, Dotti et al., Immunol Rev (2014) 257(1), and Jayaraman et al., EBioMedicine (2020) 58:102931, both of which are incorporated herein by reference in their entirety).

[0272] The antigen-binding molecules of this disclosure include a portion capable of binding to a target antigen. In some embodiments, the portion capable of binding to a target antigen includes an antibody heavy chain variable region (VH) and an antibody light chain variable region (VL) that can specifically bind to the target antigen. In some embodiments, the portion capable of binding to a target antigen includes or consists of an aptamer capable of binding to the target antigen, such as a nucleic acid aptamer (for example, as outlined in Zhou and Rossi Nat Rev Drug Discov. 2017 16(3):181-202). In some embodiments, the portion capable of binding to a target antigen comprises or consists of antigen-binding peptides / polypeptides, such as peptide aptamers, thioredoxin, monobodies, antikalin, Knitz domains, avimers, Nottin, finomers, atrimers, DARPin, afibodies, nanobodies (i.e., single-domain antibodies (sdAbs)), affilins, armadillo repeat proteins (ArmRPs), OBody, or fibronectin, for example, the entirety of which is incorporated herein by reference in Reverdatto et al., Curr Top Med Chem. 2015;15(12):1082~1101 (see also, e.g., Boersma et al., J Biol Chem (2011) 286:41273~85, and Emanuel et al., Mabs (2011) 3:38~48).

[0273] As used herein, "peptide" refers to a chain of two or more amino acid monomers linked by peptide bonds. Peptides typically have a length ranging from about 2 to 50 amino acids. A "polypeptide" is a polymer chain of two or more peptides. Polypeptides typically have a length of more than about 50 amino acids.

[0274] The antigen-binding molecules of this disclosure generally include an antigen-binding domain comprising a VH and VL of an antibody that can specifically bind to a target antigen. The antigen-binding domain formed by the VH and VL may also be referred to herein as the Fv region.

[0275] The antigen-binding molecule may be or may comprise an antigen-binding polypeptide or an antigen-binding polypeptide complex. The antigen-binding molecule may comprise two or more polypeptides that together form an antigen-binding domain. These polypeptides may associate covalently or non-covalently. In some embodiments, these polypeptides form part of a larger polypeptide containing them (e.g., in the case of scFv containing VH and VL, or in the case of scFab containing VH-CH1 and VL-CL).

[0276] An antigen-binding molecule may refer to a non-covalent or covalent complex of two or more polypeptides (e.g., two, three, four, six, or eight polypeptides), such as an IgG-like antigen-binding molecule containing two heavy-chain polypeptides and two light-chain polypeptides.

[0277] The antigen-binding molecules of this disclosure may be designed and prepared using sequences of monoclonal antibodies (mAbs) capable of binding to HER3. Antigen-binding regions of antibodies, such as single-strand variable fragments (scFv), Fab, and F(ab')2 fragments, may also be used / prepared. An "antigen-binding region" is any fragment of a given antibody that binds to a target to which the antibody is specific.

[0278] Antibodies typically contain six complementarity-determining regions (CDRs): three in the heavy chain variable (VH) region, i.e., HC-CDR1, HC-CDR2, and HC-CDR3, and three in the light chain variable (VL) region, i.e., LC-CDR1, LC-CDR2, and LC-CDR3. The six CDRs work together to define the antibody paratope, which is the part of the antibody that binds to the target antigen.

[0279] The VH and VL regions each contain a framework region (FR) on both sides of each CDR that provides a scaffold for the CDR. From the N-terminus to the C-terminus, the VH region has the following structure: N-terminus-[HC-FR1]-[HC-CDR1]-[HC-FR2]-[HC-CDR2]-[HC-FR3]-[HC-CDR3]-[HC-FR4]-C-terminus, and the VL region has the following structure: N-terminus-[LC-FR1]-[LC-CDR1]-[LC-FR2]-[LC-CDR2]-[LC-FR3]-[LC-CDR3]-[LC-FR4]-C-terminus.

[0280] There are several different conventions for defining the CDR and FR of antibodies, such as those described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991), Chothia et al., J.Mol.Biol.196:901~917 (1987), and VBASE2 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 by the International IMGT (ImMunoGeneTics) Information System (LeFranc et al., Nucleic Acids Res. (2015) 43 (Database issue): D413~22), which uses the IMGT V-DOMAIN numbering rules described by Lefranc et al., Dev. Comp. Immunol. (2003) 27: 55~77. In preferred embodiments, the CDR and FR of the antigen-binding molecules referred to herein are defined by the IMGT Information System.

[0281] The VH and VL regions of the antigen-binding domain of an antibody combine to form 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 VH and VL regions of Fv are provided as a single polypeptide, i.e., a single-stranded Fv (scFv), linked by a linker sequence.

[0282] The VL and light chain constant (CL) regions, as well as the VH region and heavy chain constant 1 (CH1) region of the antigen-binding region of an antibody, together constitute 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 comprises a polypeptide comprising VH and CH1 (e.g., a VH-CH1 fusion polypeptide) and a polypeptide comprising VL and CL (e.g., a VL-CL fusion polypeptide). In some embodiments, the Fab region comprises a polypeptide comprising VH and CL (e.g., a VH-CL fusion polypeptide) and a polypeptide comprising VL and CH (e.g., a VL-CH1 fusion polypeptide). In other words, in some embodiments, the Fab region is a CrossFab region. In some embodiments, the VH, CH1, VL, and CL regions of the Fab or CrossFab are provided as a single polypeptide, i.e., a single-stranded Fab (scFab) or single-stranded CrossFab (ScCrossFab), linked by a linker region.

[0283] In some embodiments, the antigen-binding molecules described herein include or consist of a whole antibody that binds to HER3. As used herein, “whole antibody” refers to an antibody having a structure substantially similar to that of an immunoglobulin (Ig). Different types of immunoglobulins and their structures are described, for example, in Schroeder and Cavacini J Allergy Clin Immunol. (2010) 125(202): S41-S52, which are incorporated herein by reference in their entirety.

[0284] G-type immunoglobulins (i.e., IgG) are glycoproteins of approximately 150 kDa, containing two heavy chains and two light chains. From the N-terminus to the C-terminus, the heavy chains contain a constant region with VH followed by three constant domains (CH1, CH2, and CH3), and similarly, the light chains contain VL followed by CL. Depending on the heavy chains, immunoglobulins can be classified as IgG (e.g., IgG1, IgG2, IgG3, IgG4), IgA (e.g., IgA1, IgA2), IgD, IgE, or IgM. The light chains can be kappa (κ) or lambda (λ).

[0285] 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.

[0286] In some embodiments, the antigen-binding molecule includes a CDR of the antigen-binding molecule that can bind to HER3. In some embodiments, the antigen-binding molecule includes an FR of the antigen-binding molecule that can bind to HER3. In some embodiments, the antigen-binding molecule includes both a CDR and an FR of the antigen-binding molecule that can bind to HER3. In other words, in some embodiments, the antigen-binding molecule includes a VH region and a VL region of the antigen-binding molecule that can bind to HER3.

[0287] In some embodiments, the antigen-binding molecule capable of binding to HER3 according to this disclosure is any embodiment relating to the antigen-binding molecule described in International Publication No. 2019185878 (which is incorporated herein in its entirety by reference), 10D1F (for example, described in International Publication No. 2019185878), cerivanthumab (also known as MM-121, for example, described in Schoeberl et al., Sci.Signal. (2009) 2(77):ra31), ergemtumab (also known as LJM-716, described in Garner et al., Cancer Res (2013) 73:6024~6035), and patritumab (also known as U-1287 and AMG-888, for example, Shimizu et al., Cancer Chemother (as described in Pharmacol. (2017) 79(3):489~495), GSK2849330 (e.g., Clarke et al., Eur J Cancer. (2014) 50:98~9), lumuretuzumab (also known as RG7116 and RO-5479599, e.g., Mirschberger et al., Cancer Research (2013) 73(16) 5183~5194), CDX-3379 (also known as KTN3379, e.g., Lee et al., Proc Natl Acad Sci US A. October 27, 2015; 112(43):13225), AV-203 (also known as CAN-017, e.g., Meetze et al., Eur J Cancer) (described in 2012;48:126), valecetamab (also known as ISU104, e.g., Kim et al., Cancer Res (2018) 78(13 Suppl):Abstract#830), TK-A3, TK-A4 (e.g., Malm et al., MAbs (2016) 8:1195~209), MP-EV20 (e.g., Sala et al., Transl. Oncol.(As described in 2013)6:676~84), 1A5-3D4 (e.g., Wang et al., Cancer Lett (2016) 380:20~30), 9F7-F11, 16D3-C1 (e.g., Lazrek et al., Neoplasia (2013) 15:335~47), NG33, A5, F4 (e.g., Gaborit et al., PNAS USA (2015) 112:839~44), huHER3-8 (e.g., Kugel et al., Cancer Res. (2014) 74:4122~32), REGN1400 (e.g., Zhang et al., Mol Cancer Ther (2014) 13:1345~1355), as well as xenoctuzumab (also known as MCLA-128, e.g., de Vries It can be selected from those described by Schultink et al., Clin Pharmacokinet. (2020) 59:875-884.

[0288] In some embodiments, the antigen-binding molecule is selected from 10D1F and ceribanthumab. In some embodiments, the antigen-binding molecule is 10D1F. In some embodiments, the antigen-binding molecule comprises a CDR or VH and VL of a HER3-binding antibody clone selected from 10D1_c89, 10D1, 10D1_c75, 10D1_c76, 10D1_c77, 10D1_c78v1, 10D1_c78v2, 10D1_11B, 10D1_c85v1, 10D1_c85v2, 10D1_c85o1, 10D1_c85o2, 10D1_c87, 10D1_c90, 10D1_c91, 10D1_c92, and 10D1_c93.

[0289] In some embodiments, the antigen-binding molecule (1) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 40 HC-CDR2 having the amino acid sequence of SEQ ID NO: 43 HC-CDR3 having the amino acid sequence of SEQ ID NO: 48, Alternatively, a VH region incorporating variants of HC-CDR1, HC-CDR2, or HC-CDR3, in which one or more amino acids are substituted with other amino acids, and The following CDR: LC-CDR1 having the amino acid sequence of SEQ ID NO: 66 LC-CDR2 having the amino acid sequence of SEQ ID NO: 69 LC-CDR3 having the amino acid sequence of SEQ ID NO: 74, Alternatively, a VL region incorporating a variant of LC-CDR1, LC-CDR2, or LC-CDR3, in which one or more amino acids are substituted with other amino acids; (2) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 38 HC-CDR2 having the amino acid sequence of SEQ ID NO: 41 HC-CDR3 having the amino acid sequence of SEQ ID NO: 44, Alternatively, a VH region incorporating variants of HC-CDR1, HC-CDR2, or HC-CDR3, in which one or more amino acids are substituted with other amino acids, and The following CDR: LC-CDR1 having the amino acid sequence of SEQ ID NO: 63 LC-CDR2 having the amino acid sequence of SEQ ID NO: 67 LC-CDR3 having the amino acid sequence of SEQ ID NO: 70, Alternatively, a VL region incorporating a variant of LC-CDR1, LC-CDR2, or LC-CDR3, in which one or more amino acids are substituted with other amino acids; (3) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 38 HC-CDR2 having the amino acid sequence of SEQ ID NO: 41 HC-CDR3 having the amino acid sequence of SEQ ID NO: 44, Alternatively, a VH region incorporating variants of HC-CDR1, HC-CDR2, or HC-CDR3, in which one or more amino acids are substituted with other amino acids, and The following CDR: LC-CDR1 having the amino acid sequence of SEQ ID NO: 64 LC-CDR2 having the amino acid sequence of SEQ ID NO: 67 LC-CDR3 having the amino acid sequence of SEQ ID NO: 70, Alternatively, a VL region incorporating a variant of LC-CDR1, LC-CDR2, or LC-CDR3, in which one or more amino acids are substituted with other amino acids; (4) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 38 HC-CDR2 having the amino acid sequence of SEQ ID NO: 41 HC-CDR3 having the amino acid sequence of SEQ ID NO: 44, Alternatively, a VH region incorporating variants of HC-CDR1, HC-CDR2, or HC-CDR3, in which one or more amino acids are substituted with other amino acids, and The following CDR: LC-CDR1 having the amino acid sequence of SEQ ID NO: 65 LC-CDR2 having the amino acid sequence of SEQ ID NO: 67 LC-CDR3 having the amino acid sequence of SEQ ID NO: 71, Alternatively, a VL region incorporating a variant of LC-CDR1, LC-CDR2, or LC-CDR3, in which one or more amino acids are substituted with other amino acids; (5) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 38 HC-CDR2 having the amino acid sequence of SEQ ID NO: 42 HC-CDR3 having the amino acid sequence of SEQ ID NO: 45, Alternatively, a VH region incorporating variants of HC-CDR1, HC-CDR2, or HC-CDR3, in which one or more amino acids are substituted with other amino acids, and The following CDR: LC-CDR1 having the amino acid sequence of SEQ ID NO: 63 LC-CDR2 having the amino acid sequence of SEQ ID NO: 67 LC-CDR3 having the amino acid sequence of SEQ ID NO: 70, Alternatively, a VL region incorporating a variant of LC-CDR1, LC-CDR2, or LC-CDR3, in which one or more amino acids are substituted with other amino acids; (6) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 39 HC-CDR2 having the amino acid sequence of SEQ ID NO: 42 HC-CDR3 having the amino acid sequence of SEQ ID NO: 45, Alternatively, a VH region incorporating variants of HC-CDR1, HC-CDR2, or HC-CDR3, in which one or more amino acids are substituted with other amino acids, and The following CDR: LC-CDR1 having the amino acid sequence of SEQ ID NO: 63 LC-CDR2 having the amino acid sequence of SEQ ID NO: 67 LC-CDR3 having the amino acid sequence of SEQ ID NO: 70, Alternatively, a VL region incorporating a variant of LC-CDR1, LC-CDR2, or LC-CDR3, in which one or more amino acids are substituted with other amino acids; (7) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 38 HC-CDR2 having the amino acid sequence of SEQ ID NO: 42 HC-CDR3 having the amino acid sequence of SEQ ID NO: 44, Alternatively, a VH region incorporating variants of HC-CDR1, HC-CDR2, or HC-CDR3, in which one or more amino acids are substituted with other amino acids, and The following CDR: LC-CDR1 having the amino acid sequence of SEQ ID NO: 63 LC-CDR2 having the amino acid sequence of SEQ ID NO: 68 LC-CDR3 having the amino acid sequence of SEQ ID NO: 70, Alternatively, a VL region incorporating a variant of LC-CDR1, LC-CDR2, or LC-CDR3, in which one or more amino acids are substituted with other amino acids; (8) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 38 HC-CDR2 having the amino acid sequence of SEQ ID NO: 42 HC-CDR3 having the amino acid sequence of SEQ ID NO: 46, Alternatively, a VH region incorporating variants of HC-CDR1, HC-CDR2, or HC-CDR3, in which one or more amino acids are substituted with other amino acids, and The following CDR: LC-CDR1 having the amino acid sequence of SEQ ID NO: 63 LC-CDR2 having the amino acid sequence of SEQ ID NO: 68 LC-CDR3 having the amino acid sequence of SEQ ID NO: 70, Alternatively, a VL region incorporating a variant of LC-CDR1, LC-CDR2, or LC-CDR3, in which one or more amino acids are substituted with other amino acids; (9) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 38 HC-CDR2 having the amino acid sequence of SEQ ID NO: 42 HC-CDR3 having the amino acid sequence of SEQ ID NO: 47, Alternatively, a VH region incorporating variants of HC-CDR1, HC-CDR2, or HC-CDR3, in which one or more amino acids are substituted with other amino acids, and The following CDR: LC-CDR1 having the amino acid sequence of SEQ ID NO: 63 LC-CDR2 having the amino acid sequence of SEQ ID NO: 68 LC-CDR3 having the amino acid sequence of SEQ ID NO: 70, Alternatively, a VL region incorporating a variant of LC-CDR1, LC-CDR2, or LC-CDR3, in which one or more amino acids are substituted with other amino acids; (10) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 38 HC-CDR2 having the amino acid sequence of SEQ ID NO: 42 HC-CDR3 having the amino acid sequence of SEQ ID NO: 45, Alternatively, a VH region incorporating variants of HC-CDR1, HC-CDR2, or HC-CDR3, in which one or more amino acids are substituted with other amino acids, and The following CDR: LC-CDR1 having the amino acid sequence of SEQ ID NO: 63 LC-CDR2 having the amino acid sequence of SEQ ID NO: 67 LC-CDR3 having the amino acid sequence of SEQ ID NO: 72, Alternatively, a VL region incorporating a variant of LC-CDR1, LC-CDR2, or LC-CDR3, in which one or more amino acids are substituted with other amino acids; (11) The following CDRs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 38 HC-CDR2 having the amino acid sequence of SEQ ID NO: 41 HC-CDR3 having the amino acid sequence of SEQ ID NO: 44, Alternatively, a VH region incorporating variants of HC-CDR1, HC-CDR2, or HC-CDR3, in which one or more amino acids are substituted with other amino acids, and The following CDR: LC-CDR1 having the amino acid sequence of SEQ ID NO: 63 LC-CDR2 having the amino acid sequence of SEQ ID NO: 67 LC-CDR3 having the amino acid sequence of SEQ ID NO: 73, Alternatively, a VL region incorporating a variant of LC-CDR1, LC-CDR2, or LC-CDR3, in which one or more amino acids are substituted with other amino acids; Includes.

[0290] In some embodiments, the antigen-binding molecule (12) A VH region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 21, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 49, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; (13) A VH region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 22, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 50, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; (14) A VH region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 23, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 51, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; (15) A VH region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 23, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 52, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; (16) A VH region containing an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 23, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region containing an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 53, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; (17) A VH region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 26, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 53, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; (18) A VH region containing an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 27, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region containing an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 53, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; (19) A VH region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 28, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 54, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; (20) A VH region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 29, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 54, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; (21) A VH region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 30, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 54, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; (22) A VH region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 31, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 54, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; (23) A VH region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 32, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 57, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; (24) A VH region containing an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 33, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region containing an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 58, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; (25) A VH region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 34, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 59, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; (26) A VH region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 35, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 60, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; (27) A VH region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 22, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 61, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; (28) A VH region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 32, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; and a VL region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 62, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; Includes.

[0291] In some embodiments described herein, one or more amino acids in the amino acid sequences referred herein (e.g., amino acid sequences of antigen-binding molecules, e.g., amino acid sequences of CDR or VH / VL regions) are substituted with other amino acids. Substitutions include substitution of amino acid residues by non-identical "alternative" amino acid residues. The substitute amino acid residues for substitutions according to this disclosure may be native amino acid residues (i.e., those encoded by the genetic code) that are non-identical to amino acid residues at relevant positions in equivalent unsubstituted amino acid sequences, selected from alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine ​​(Cys), glutamine (Gln), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), and valine (Val). In some embodiments, the substitute amino acid may be a non-native amino acid residue, i.e., an amino acid residue other than those listed in the Preamble. Examples of non-natural amino acid residues include norleucine, ornithine, norvaline, homoserine, aib, and other amino acid residue analogs, such as those described by Ellman et al., Meth. Enzym. 202 (1991) 301-336.

[0292] In some embodiments, the substitution may be biochemically conserved. In some embodiments, the amino acid to be substituted is provided in one of rows 1-5 of the table below, and the substitute amino acid for the substitution is another non-identical amino acid provided in the same row.

[0293] [Table 1] For example, in some embodiments, the substitution is for a Met residue, and the substitute amino acid may be selected from Ala, Val, Leu, Ile, Trp, Tyr, Phe, and norleucine.

[0294] In some embodiments, the substitute amino acid in a substitution may have the same side-chain polarity as the amino acid residue it substitutes for. In some embodiments, the substitute amino acid in a substitution may have the same side-chain charge (at pH 7.4) as the amino acid residue it substitutes for.

[0295] [Table 2] In other words, in some embodiments, nonpolar amino acids are substituted with other non-identical nonpolar amino acids. In some embodiments, polar amino acids are substituted with other non-identical polar amino acids. In some embodiments, acidic polar amino acids are substituted with other non-identical acidic polar amino acids. In some embodiments, basic polar amino acids are substituted with other non-identical basic polar amino acids. In some embodiments, neutral amino acids are substituted with other non-identical neutral amino acids. In some embodiments, positively charged amino acids are substituted with other non-identical positively charged amino acids. In some embodiments, negatively charged amino acids are substituted with other non-identical negatively charged amino acids.

[0296] In some embodiments, the substitution may be functionally conserved. That is, in some embodiments, the substitution may not affect (or may 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.

[0297] The VH and VL regions of the antigen-binding domain of an antibody combine to form 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 VH and VL regions of Fv are provided as a single polypeptide, i.e., a single-stranded Fv (scFv), linked by a linker region.

[0298] In some embodiments, the antigen-binding molecule of the Disclosure comprises one or more regions of an immunoglobulin heavy chain constant sequence. In some embodiments, the immunoglobulin heavy chain constant sequence is or is derived from an IgG (e.g., IgG1, IgG2, IgG3, IgG4), IgA (e.g., IgA1, IgA2), IgD, IgE, or IgM heavy chain constant sequences.

[0299] The VL and light chain constant (CL) regions, as well as the VH region and heavy chain constant 1 (CH1) region of the antigen-binding domain of the antibody, together constitute the Fab region. In some embodiments, the antigen-binding molecule of this disclosure includes or consists of a Fab region that binds to HER3.

[0300] In some embodiments, the antigen-binding molecules described herein include or consist of a whole antibody that binds to HER3. As used herein, “whole antibody” refers to an antibody having a structure substantially similar to that of an immunoglobulin (Ig). Different types of immunoglobulins and their structures are described, for example, in Schroeder and Cavacini J Allergy Clin Immunol. (2010) 125(202): S41-S52, which are incorporated herein by reference in their entirety.

[0301] G-type immunoglobulins (i.e., IgG) are glycoproteins of approximately 150 kDa, containing two heavy chains and two light chains. From the N-terminus to the C-terminus, the heavy chains contain a constant region with VH followed by three constant domains (CH1, CH2, and CH3), and similarly, the light chains contain VL followed by CL. Depending on the heavy chains, immunoglobulins can be classified as IgG (e.g., IgG1, IgG2, IgG3, IgG4), IgA (e.g., IgA1, IgA2), IgD, IgE, or IgM. The light chains can be kappa (κ) or lambda (λ).

[0302] 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.

[0303] In some embodiments, the antigen-binding molecule (i) 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% amino acid sequence identity with respect to the amino acid sequence of SEQ ID NO: 75, and (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% amino acid sequence identity with respect to the amino acid sequence of SEQ ID NO: 76. It includes or consists of.

[0304] The antigen-binding molecules described herein may be provided in the form of compositions comprising such antigen-binding molecules. The antigen-binding molecules may be formulated as pharmaceutical compositions or pharmaceuticals for clinical use and may comprise pharmaceutically acceptable carriers, diluents, excipients, or adjuvants. The compositions may be formulated for local, parenteral, systemic, intracavitary, intravenous, intra-arterial, intramuscular, subarachnoid, intraocular, intraconjunctival, intratumoral, subcutaneous, intradermal, subarachnoid, oral, or transdermal administration routes, which may comprise injection or infusion.

[0305] A suitable formulation may contain antigen-binding molecules in a sterile or isotonic medium. Pharmaceuticals and pharmaceutical compositions may be formulated in fluids, including gels and foams. Fluid formulations may be formulated for administration by injection or infusion (e.g., via cannula) into blood, tumors, or selected areas of the human or animal body. In some embodiments, compositions may be formulated for injection or infusion, for example, into blood vessels or tumors. HER3-mediated signaling antagonist The aspects and embodiments of this disclosure relate to (i) HER3-mediated signaling antagonists and (ii) antigen-binding molecules that bind to HER3 for therapeutic / preventive interventions.

[0306] While the HER3-binding antigen-binding molecules of this disclosure may act as antagonists of HER3-mediated signaling, it is understood that, according to the aspects and embodiments of this disclosure relating to combination therapy, the combination components (i) and (ii) are preferably non-identical (i.e., they are different drugs).

[0307] Treatment with HER3-mediated signaling antagonists as described herein is intended in particular in connection with therapeutic / preventive interventions for the treatment / prevention of cancers as described in the section entitled “Cancers characterized by the presence of genetic diversity resulting in elevated HER3-mediated signaling.” In such embodiments, treatment with HER3-mediated signaling antagonists may be effective in restoring the level of signaling to the level observed in the absence of mutation (i.e., the level of signaling by equivalent cells containing only wild-type alleles).

[0308] In this manner, treatment with a HER3-mediated signaling antagonist may be useful for acclimatizing the target to treatment with the HER3-binding antigen-binding molecules described herein. That is, administration of a HER3-mediated signaling antagonist is preferably effective in making the cancer sensitive to treatment with the HER3-binding antigen-binding molecule (i.e., making the cancer susceptible) so that treatment with the HER3-binding antigen-binding molecule is more effective than in the absence of treatment with the HER3-mediated signaling antagonist.

[0309] It is understood that the specific HER3-mediated signaling antagonists to be used in the combination therapies described herein may be selected according to the mutational state / genotype of the cancer to be treated. For example, if the cancer contains an activating mutation to KRAS, the antagonist may be an antagonist of signaling via the MAPK / ERK pathway. Similarly, if the cancer contains an activating mutation to PIK3CA or an inactivating mutation to PTEN, the antagonist may be an antagonist of signaling via the PI3K / AKT / mTOR pathway.

[0310] In some embodiments, the HER3-mediated signaling antagonist according to this disclosure is a pan-ErbB inhibitor (e.g., sapitinib or Sym013). In some embodiments, the HER3-mediated signaling antagonist is an EGFR-mediated signaling inhibitor (e.g., cetuximab, panitumumab, gefitinib, erlotinib, lapatinib, afatinib, brigatinib, icotinib, osimertinib, zaltumumab, vandetanib, nesitumumab, nimotuzumab, dacomitinib, durigotuzumab, or matuzumab). In some embodiments, the antagonist of HER3-mediated signaling is an inhibitor of HER2-mediated signaling (e.g., trastuzumab, pertuzumab, lapatinib, neratinib, afatinib, dacomitinib, MM-111, xenoctuzumab, MCLA-128, or margetuximab). In some embodiments, the antagonist of HER3-mediated signaling is an inhibitor of HER3-mediated signaling (e.g., cerivantumab, lumuretuzumab, elgemzumab, KTN3379, AV-203, GSK2849330, REGN1400, MP-RM-1, EV20, pertuzumab, duligotuzumab, MM-111, xenoctuzumab, istilazumab, MCLA-128, patrizumab, EZN-3920, RB200, U3-1402, TX2-121-2, EZN-3920, and miR-205). In some embodiments, the antagonist of HER3-mediated signaling is an inhibitor of HER4-mediated signaling (e.g., lapatinib, ibrutinib, afatinib, dacomitinib, or neratinib).

[0311] In some embodiments, HER3-mediated signaling antagonists inhibit downstream effectors of HER3 signaling. Downstream effectors of HER3 signaling include, for example, PI3K, AKT, K-Ras, B-Raf, MEK / ERK, and mTOR. In some embodiments, HER3-mediated signaling antagonists are inhibitors of the MAPK / ERK pathway. In some embodiments, HER3-mediated signaling antagonists are inhibitors of the PI3K / ATK / mTOR pathway.

[0312] In some embodiments, the HER3-mediated signaling antagonist is a PI3K inhibitor (e.g., pictilisib, buparlisib, dactrisib, SAR245409, AZD8186, idelalisib, copanlisib, or duvelisib). In some embodiments, the HER3-mediated signaling antagonist is an AKT inhibitor (e.g., MK-2206, AZD5363, GSK690693, GSK2110183, ipatasertib, VQD-002, perifosin, or miltefosin). In some embodiments, the HER3-mediated signaling antagonist is a KRAS inhibitor (e.g., sotrasib (also known as AMG510), ARS-1620, adagrasib (also known as MRTX849), LY3499446, ARS-3248 / JNJ-74699157, BI2852, or RRSP chimeric toxin). In some embodiments, the HER3-mediated signaling antagonist is a BRAF inhibitor (e.g., vemurafenib, dabrafenib, SB590885, XL281, RAF265, encorafenib, berbarafenib, PLX8394, LY3009120, LXH254, GDC-0879, PLX-4720, sorafenib, or LGX818). In some embodiments, the HER3-mediated signaling antagonist is a MEK / ERK inhibitor (e.g., trametinib, cobimetinib, binimetinib, selumetinib, pimacertib, PD-325901, CI-1040, PD035901, or TAK-733). In some embodiments, the HER3-mediated signaling antagonist is an mTOR inhibitor (e.g., rapamycin, deforolimus, temsirolimus, everolimus, ridafololimus, or sapanicertib). Therapeutic and preventive interventions The aspects and embodiments of this disclosure relate to therapeutic and prophylactic interventions for the treatment and prevention of cancer as described herein.

[0313] This disclosure provides HER3-binding antigen-binding molecules for use in methods of treating or preventing cancer as described herein. Also provided are the use of HER3-binding antigen-binding molecules in the manufacture of pharmaceuticals for use in treating or preventing cancer as described herein. Furthermore, methods of treating or preventing cancer as described herein are also provided, comprising the step of administering a therapeutically effective or prophylactically effective amount of the HER3-binding antigen-binding molecule to the subject.

[0314] This disclosure provides an antigen-binding molecule that binds to HER3 for use in a method for treating or preventing cancer as described herein, wherein the method further comprises the step of administering a HER3-mediated signaling antagonist. Also provided is a HER3-mediated signaling antagonist for use in a method for treating or preventing cancer as described herein, wherein the method further comprises the step of administering a HER3-binding antigen-binding molecule. Also provided is a use of a HER3-binding antigen-binding molecule in the manufacture of a medicament for use in a method for treating or preventing cancer as described herein, wherein the method further comprises the step of administering a HER3-mediated signaling antagonist. Also provided is a use of a HER3-mediated signaling antagonist in the manufacture of a medicament for use in a method for treating or preventing cancer as described herein, wherein the method further comprises the step of administering a HER3-binding antigen-binding molecule. A method for treating or preventing cancer as described herein is further provided, comprising the step of administering a therapeutically effective or prophylactically effective amount of (i) an antigen-binding molecule that binds to HER3, and (ii) an antagonist of HER3-mediated signaling, to a subject requiring treatment.

[0315] This disclosure further provides HER3-binding antigen-binding molecules and HER3-mediated signaling antagonists (in the form of a pharmaceutical combination or pharmaceutical composition, e.g., comprising an antigen-binding molecule that binds to HER3 and a HER3-mediated signaling antagonist) for use in methods of treating or preventing cancer as described herein. Also provided are the use of HER3-binding antigen-binding molecules and HER3-mediated signaling antagonists (in the form of a pharmaceutical combination or pharmaceutical composition, e.g., comprising an antigen-binding molecule that binds to HER3 and a HER3-mediated signaling antagonist) in the manufacture of pharmaceuticals for use in methods of treating or preventing cancer as described herein. A method for treating or preventing cancer as described herein is further provided, comprising the step of administering a therapeutically effective or prophylactic amount of an antigen-binding molecule that binds to HER3 (for example, in the form of a pharmaceutical combination or pharmaceutical composition comprising an antigen-binding molecule that binds to HER3 and an antagonist of HER3-mediated signaling) to a subject requiring treatment.

[0316] In some embodiments and designs, an antigen-binding molecule that binds to HER3 and an antagonist of HER3-mediated signaling may be provided as a combination therapy. In some embodiments, the antigen-binding molecule that binds to HER3 and the antagonist of HER3-mediated signaling may be administered simultaneously or sequentially.

[0317] Concurrent administration refers to the combined administration of two or more drugs, for example, as a pharmaceutical composition containing both drugs (i.e., as a combined preparation), or sequentially (e.g., within 1, 4, 6, 8, or 12 hours), and optionally via the same route of administration, for example, to the same artery, vein, or other blood vessel.

[0318] Sequential administration refers to the separate administration of one drug followed by the administration of the other drug after a given time interval. The drugs do not need to be administered via the same route, although this is the case in some embodiments. The time interval can be any of the following.

[0319] In some embodiments, the therapeutic or prophylactic intervention according to this disclosure includes the steps of (i) administering a HER3-mediated signaling antagonist (e.g., a HER3-mediated signaling antagonist as described herein) to a subject having cancer (e.g., a cancer characterized by the presence of genetic diversity resulting in increased HER3-mediated signaling as described herein), and (ii) administering an antigen-binding molecule that binds to HER3 (e.g., a HER3-binding antigen-binding molecule as described herein) to the subject. In some embodiments, (i) and (ii) are performed simultaneously. In some embodiments, (i) and (ii) are performed sequentially (e.g., (i) may be followed by (ii), or (ii) may be followed by (i)).

[0320] Therapeutic or prophylactic interventions relating to this disclosure may be effective in reducing the onset or progression of cancer, alleviating one or more symptoms of cancer, or reducing cancer pathology. Interventions may be effective in halting cancer progression, for example, in halting cancer worsening or slowing its rate of development. In some embodiments, interventions may result in improvement of cancer, for example, a reduction in cancer symptoms, or a reduction in several other correlational phenomena related to cancer severity / activity. In some embodiments, the methods may prevent the development of cancer to later stages (e.g., more severe stages or metastasis).

[0321] In some embodiments, therapeutic or prophylactic interventions may aim to delay / prevent the onset / progression of cancer symptoms, reduce the severity of cancer symptoms, reduce the survival / growth / invasion / metastasis of cancer cells, reduce the number of cancer cells, and / or extend the subject's survival time.

[0322] In some embodiments, therapeutic or prophylactic interventions according to this disclosure may be associated with inhibiting the development / progression of cancer, delaying / preventing the onset of cancer, reducing / delaying / preventing tumor growth, reducing / delaying / preventing tissue invasion, reducing / delaying / preventing metastasis, reducing the severity of one or more symptoms of cancer, reducing the number of cancer cells, reducing cancer burden, reducing tumor size / volume, and / or extending the survival of a person with cancer (e.g., progression-free survival or overall survival).

[0323] The administration of the drugs, pharmaceutical combinations, and pharmaceutical compositions of this disclosure is preferably a “therapeutically effective” or “preventively effective” dose sufficient to demonstrate a therapeutic or preventive benefit to the subject. Actual doses, rates of administration, and time courses depend on the nature and severity of the disease / condition, as well as the specific administration. Prescribing treatment, e.g., determining dosage, is the responsibility of the general practitioner and other physicians, typically taking into account the disease / disorder to be treated, the condition of the individual subject, the site of delivery, the method of administration, and other factors known to the practitioner. Examples of the aforementioned techniques and protocols can be found in Remington's “The Science and Practice of Pharmacy” (edited by A. Adejare), 23rd edition (2020), Academic Press.

[0324] Administration of the articles of this disclosure may be, for example, parenteral, systemic, topical, intracavitary, intravascular, intravenous, intraarterial, intramuscular, subarachnoid, intraocular, intraconjunctival, intratumoral, subcutaneous, intradermal, oral, or transdermal. Administration may be by injection, infusion, or ingestion.

[0325] In some embodiments and aspects, the articles of the Disclosure may be administered to a target tissue / organ affected by a condition (e.g., a tissue / organ affected by a disease / condition) (e.g., a tissue / organ on which symptoms of the disease / condition appear). In some embodiments and aspects, the articles of the Disclosure may be administered into the bloodstream by injection or infusion (e.g., via a cannula) (i.e., intravenous / intra-arterial administration), or subcutaneously or orally. In some embodiments and aspects, the articles of the Disclosure may be administered to a tumor.

[0326] Multiple doses of drugs, pharmaceutical combinations, and pharmaceutical compositions may be provided. These multiple doses may be separated by predetermined time intervals and may be selected to be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days, or 1, 2, 3, 4, 5, or 6 months. For example, doses may be administered once 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, there may be one treatment event every 7 days, every 14 days, every 21 days, or every 28 days. Between doses / administrations, there may be treatment breaks 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), respectively.

[0327] In some embodiments, the intervention includes additional therapeutic or prophylactic interventions, for example, for the treatment / prevention of cancer. In some embodiments, the therapeutic or prophylactic intervention is selected from chemotherapy, immunotherapy, radiotherapy, surgical procedures, vaccination, and / or hormone therapy. In some embodiments, the therapeutic or prophylactic intervention includes leukocyte apheresis. In some embodiments, the therapeutic or prophylactic intervention includes stem cell transplantation. Therapeutic / preventive interventions utilizing EGFR antagonists The therapeutic / preventive interventions and embodiments described herein utilize EGFR antagonists.

[0328] This disclosure provides an antigen-binding molecule that binds to HER3 for use in a method of treating or preventing cancer as described herein, wherein the method further comprises the step of administering an EGFR antagonist. Also provided is an EGFR antagonist for use in a method of treating or preventing cancer as described herein, wherein the method further comprises the step of administering an antigen-binding molecule that binds to HER3.

[0329] Also provided is the use of an antigen-binding molecule that binds to HER3 in the manufacture of a medicament for use in a method of treating or preventing cancer as described herein, wherein the method further comprises the step of administering an EGFR antagonist.

[0330] A method for treating or preventing cancer as described herein is further provided, comprising the step of administering a therapeutically effective or prophylactically effective amount of (i) an antigen-binding molecule that binds to HER3, and (ii) an EGFR antagonist, to a subject requiring treatment.

[0331] This disclosure further provides (i) an antigen-binding molecule that binds to HER3, and (ii) an EGFR antagonist, for use in methods of treating or preventing cancer as described herein. Also provided are the use of (i) an antigen-binding molecule that binds to HER3, and (ii) an EGFR antagonist, in the manufacture of a pharmacopoeia for use in treating or preventing cancer as described herein. Also provided are methods of treating or preventing cancer as described herein, comprising the step of administering to the subject a therapeutically effective or prophylactically effective amount of (i) an antigen-binding molecule that binds to HER3, and (ii) an EGFR antagonist.

[0332] In embodiments according to the aspects of the preceding paragraph, the supply of (i) and (ii) may be as a combination therapy. In some embodiments, (i) and (ii) may be given simultaneously or sequentially.

[0333] In some embodiments, an EGFR antagonist is an inhibitor of one or more functions / activities of EGFR, or an inhibitor of EGFR expression (i.e., gene and / or protein expression). EGFR antagonists include inhibitors of EGFR-mediated signaling.

[0334] In some embodiments, an EGFR antagonist binds to EGFR. An EGFR-binding antagonist of EGFR can inhibit one or more functions of EGFR. Examples of EGFR-binding antagonists include EGFR-binding antibodies, as well as their antigen-binding fragments and derivatives, EGFR-binding peptides / polypeptides, EGFR-binding nucleic acid aptamers, and EGFR-binding small molecule inhibitors.

[0335] In some embodiments, EGFR antagonists are agents that inhibit EGFR expression. Such EGFR antagonists include small molecule inhibitors of EGFR expression and nucleic acids (e.g., antisense oligonucleotides) that can block or reduce EGFR expression.

[0336] In some embodiments, the EGFR antagonist according to this disclosure is an EGFR small molecule inhibitor. In some embodiments, the EGFR antagonist is a pan-ErbB inhibitor (e.g., sapitinib or Sym013). In some embodiments, the EGFR antagonist is selected from gefitinib, erlotinib, lapatinib, afatinib, brigatinib, icotinib, osimertinib, vandetanib, and dacomitinib.

[0337] In some embodiments, the EGFR antagonist is an antigen-binding molecule that binds to EGFR, such as an EGFR-binding antibody, or an antigen-binding fragment or derivative thereof. In some embodiments, the EGFR antagonist is selected from cetuximab, panitumumab, zaltumumab, durigotuzumab, and matuzumab.

[0338] In some embodiments, the antigen-binding molecule that binds to EGFR includes a CDR of the antigen-binding molecule that can bind to EGFR. In some embodiments, the antigen-binding molecule includes an FR of the antigen-binding molecule that can bind to EGFR. In some embodiments, the antigen-binding molecule includes both a CDR and an FR of the antigen-binding molecule that can bind to EGFR. In other words, in some embodiments, the antigen-binding molecule includes a VH region and a VL region of the antigen-binding molecule that can bind to EGFR.

[0339] In some embodiments, the antigen-binding molecules capable of binding to EGFR as described herein are any embodiment relating to the antigen-binding molecules described in U.S. Patent No. 6,217,866 (which is incorporated herein by reference in its entirety), cetuximab (e.g., U.S. Patent No. 6,217,866, and Wong et al., Clin Ther. (2005) 27(6):684-694; DrugBank registration number DB00002), panitumumab (e.g., Foon et al., Int J Radiat Oncol Biol Phys. (2004) 58(3):984-990; DrugBank registration number DB01269), saltumumab (e.g., Bastholt et al., Radiother Oncol. (2007) 85(1):24-28; DrugBank registration number DB12202), nesitumumab (e.g., Kuenen et al., Clin Cancer The antigen-binding molecule may be selected from Res. (2010) 16(6): 1915-1923 (DrugBank registration number DB09559), nimotuzumab (e.g., Ramakrishnan et al., mAbs (2009) 1(1): 41-48 (DrugBank registration number DB06192)), durigotuzumab (e.g., Fayette et al., Front Oncol. (2016) 6: 232 (DrugBank registration number DB12142)), and matuzumab (DrugBank registration number DB05101). In some embodiments, the antigen-binding molecule is cetuximab.

[0340] In some embodiments, an antigen-binding molecule can bind to the same EGFR region as the antibody containing the VH and VL sequences of cetuximab, or to an overlapping region thereof.

[0341] In some embodiments, the antigen-binding molecule comprises cetuximab CDR or cetuximab VH and VL. In some embodiments, the antigen-binding molecule that binds to EGFR is The following CDR: HC-CDR1 having the amino acid sequence of SEQ ID NO: 78 HC-CDR2 having the amino acid sequence of SEQ ID NO: 79 HC-CDR3 having the amino acid sequence of SEQ ID NO: 80, Alternatively, a VH region incorporating variants of HC-CDR1, HC-CDR2, or HC-CDR3, in which one or more amino acids are substituted with other amino acids, and The following CDR: LC-CDR1 having the amino acid sequence of SEQ ID NO: 82 LC-CDR2 having the amino acid sequence of SEQ ID NO: 83 LC-CDR3 having the amino acid sequence of SEQ ID NO: 84, Alternatively, a VL region incorporating a variant of LC-CDR1, LC-CDR2, or LC-CDR3 in which one or more amino acids are substituted with other amino acids. Includes.

[0342] In some embodiments, the antigen-binding molecule that binds to EGFR is A VH region comprising an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 77, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, and A VL region containing an amino acid sequence having at least 70% sequence identity with respect to the amino acid sequence of SEQ ID NO: 81, more preferably at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity. Includes.

[0343] In some embodiments, the antigen-binding molecule that binds to EGFR is (i) 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% amino acid sequence identity with respect to the amino acid sequence of SEQ ID NO: 85, and (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% amino acid sequence identity with respect to the amino acid sequence of SEQ ID NO: 86. It includes or consists of.

[0344] In some embodiments, the antigen-binding molecule that binds to EGFR is cetuximab. Diagnostic methods, prognosis prediction methods, and patient selection. This disclosure further provides diagnostic methods, prognostic methods, and predictive methods related to cancer as described herein.

[0345] These methods may be performed in vitro on samples obtained from subjects, or following processing of samples obtained from subjects. Since the presence of a subject is not required for the in vitro method to be performed once the sample has been collected, the methods may not be practiced on human or animal bodies. However, in some embodiments, the methods may be performed in vivo.

[0346] The sample may be taken from any tissue or body fluid. The sample may include or be derived from a certain amount of blood; a certain amount of serum, which may include the fluid portion of the blood obtained after removal of fibrin clots and blood cells derived from the blood of the subject; a tissue sample or biopsy; pleural fluid; cerebrospinal fluid (CSF); or cells isolated from the subject. In some embodiments, the sample may be obtained from or derived from tissue affected by the disease / condition (e.g., tissue in which symptoms of the disease appear, or tissue involved in the development of the disease / condition). In some embodiments, the sample may be obtained from or derived from cancer, tumors, or their cells.

[0347] This method may be used for the purpose of diagnosing cancer (e.g., cancers described herein). This method may be used for the purpose of predicting / foreseeing a likely response in a subject to a therapeutic / preventive intervention described herein. This method may be useful for predicting a likely response to a given therapeutic / preventive intervention, for example, in terms of efficacy, and therefore may be useful in supporting clinical judgment. This method may be used for the purpose of identifying / selecting subjects suitable for a therapeutic / preventive intervention described herein.

[0348] In some aspects and embodiments, the method includes the step of analyzing the cancer in question to determine whether the cancer is a cancer as described herein, for example, a cancer according to the embodiments described in the section titled "Cancer characterized by the absence of genetic diversity resulting in increased HER3-mediated signaling," or a cancer according to the embodiments described in the section titled "Cancer characterized by the presence of genetic diversity resulting in increased HER3-mediated signaling," or a cancer according to the embodiments described in the section titled "Cancer characterized by the presence of genetic diversity resulting in increased expression of a gene on chromosome 3 q or increased activity of its gene product," or a cancer according to the embodiments described in the section titled "Cancer characterized by the presence of genetic diversity resulting in increased expression of a gene on chromosome 7 p or increased activity of its gene product," or a cancer according to the embodiments described in the section titled "Cancer characterized by the presence of genetic diversity resulting in decreased expression of a gene on chromosome 3 p or decreased activity of its gene product."

[0349] In some embodiments, the method includes the step of evaluating the cancer to determine whether the cancer contains the genetic diversity described herein. In some embodiments, the method includes the step of evaluating the cancer to determine whether the cancer contains cells containing the genetic diversity described herein.

[0350] Aspects and embodiments of this disclosure further include the step of selecting subjects suitable for therapeutic or preventive interventions in accordance with this disclosure. Following such analysis, subjects having cancer identified as one of the cancers described herein (for example, cancers characterized by the absence of genetic diversity resulting in increased HER3-mediated signaling, or cancers characterized by the presence of genetic diversity resulting in increased expression of a gene on chromosome 3 q or increased activity of its gene product, or cancers characterized by the presence of genetic diversity resulting in increased expression of a gene on chromosome 7 p or increased activity of its gene product, or cancers characterized by the presence of genetic diversity resulting in decreased expression of a gene on chromosome 3 p or decreased activity of its gene product) may be selected for therapeutic / preventive interventions using HER3-binding antigen-binding molecules as described herein.

[0351] Following such analysis, subjects having a cancer identified as one of the cancers described herein (for example, a cancer according to the embodiments described in the section titled “Cancers characterized by the presence of genetic diversity resulting in elevated HER3-mediated signaling”) may be selected for (i) HER3-mediated signaling antagonists as disclosed herein, and (ii) HER3-binding antigen-binding molecules as disclosed herein.

[0352] In some embodiments, the subject is selected / not selected for therapeutic / preventive intervention according to this disclosure based on the results of an analysis of the subject cancer to determine whether the subject cancer is one of the cancers described herein, for example, a cancer according to an embodiment described in the section titled "Cancer characterized by the absence of genetic diversity resulting in increased HER3-mediated signaling," or a cancer according to an embodiment described in the section titled "Cancer characterized by the presence of genetic diversity resulting in increased expression of a gene on chromosome 3 q or increased activity of its gene product," or a cancer according to an embodiment described in the section titled "Cancer characterized by the presence of genetic diversity resulting in increased expression of a gene on chromosome 7 p or increased activity of its gene product," or a cancer according to an embodiment described in the section titled "Cancer characterized by the presence of genetic diversity resulting in decreased expression of a gene on chromosome 3 p or decreased activity of its gene product."

[0353] In some aspects and embodiments, this method (a) A step of analyzing the cancer in order to determine whether the cancer in question is a cancer according to the embodiment described in the section titled “Cancer characterized by the absence of genetic diversity resulting in increased HER3-mediated signaling,” or a cancer according to the embodiment described in the section titled “Cancer characterized by the presence of genetic diversity resulting in increased expression of the gene on chromosome 3 q or increased activity of its gene product,” or a cancer according to the embodiment described in the section titled “Cancer characterized by the presence of genetic diversity resulting in increased expression of the gene on chromosome 7 p or increased activity of its gene product,” or a cancer according to the embodiment described in the section titled “Cancer characterized by the presence of genetic diversity resulting in decreased expression of the gene on chromosome 3 p or decreased activity of its gene product,” and (b) If the cancer in question is determined in step (a) to be a cancer according to the embodiment described in the section titled “Cancer characterized by the absence of genetic diversity resulting in increased HER3-mediated signaling,” or a cancer according to the embodiment described in the section titled “Cancer characterized by the presence of genetic diversity resulting in increased expression of the gene on chromosome 3 q or increased activity of its gene product,” or a cancer according to the embodiment described in the section titled “Cancer characterized by the presence of genetic diversity resulting in increased expression of the gene on chromosome 7 p or increased activity of its gene product,” or a cancer according to the embodiment described in the section titled “Cancer characterized by the presence of genetic diversity resulting in decreased expression of the gene on chromosome 3 p or decreased activity of its gene product,” the step of selecting a subject for treatment with an antigen-binding molecule that binds to HER3 according to the Disclosure Includes.

[0354] In some embodiments, this method (c) A step of administering an antigen-binding molecule that binds to HER3 according to the present disclosure to a subject selected for treatment in step (b). It also includes.

[0355] In some aspects and embodiments, this method (a) a step of analyzing the cancer in question to determine whether the cancer is a cancer according to the embodiments described in the section titled “Cancer characterized by the presence of genetic diversity resulting in elevated HER3-mediated signaling”; and (b) If it is determined in step (a) that the target cancer includes or is a cancer according to the embodiments described in the section titled “Cancers characterized by the presence of genetic diversity resulting in increased HER3-mediated signaling,” then the step of selecting the target for treatment with (i) a HER3-mediated signaling antagonist according to the Disclosure, and (ii) an antigen-binding molecule that binds to HER3 according to the Disclosure. Includes.

[0356] In some embodiments, this method (c) A step of administering (i) a HER3-mediated signaling antagonist according to the present disclosure, and (ii) an antigen-binding molecule that binds to HER3 according to the present disclosure, to a subject selected for treatment in step (b). It also includes.

[0357] In some aspects and embodiments, this method (a) a step of analyzing the cancer in question to determine whether the cancer is a cancer according to the embodiments described in the section titled “Cancer characterized by the presence of genetic diversity resulting in elevated HER3-mediated signaling”; and (b) If the cancer of interest is determined in step (a) to include or be a cancer according to the embodiments described in the section titled “Cancers characterized by the presence of genetic diversity resulting in increased HER3-mediated signaling,” then the step of selecting the subject for treatment with (i) a HER3-mediated signaling antagonist according to the Disclosure, and (ii) an antigen-binding molecule that binds to HER3 according to the Disclosure; (c) the step of administering a HER3-mediated signaling antagonist according to the present disclosure to a subject selected for treatment in step (b); and (d) A step of administering an antigen-binding molecule that binds to HER3 according to the present disclosure to a subject selected for treatment in step (b). Includes.

[0358] Steps (c) and (d) in the preceding paragraph are understood to be performed simultaneously or sequentially. In accordance with the various embodiments described above, in some embodiments, the method is (c) A step of administering an EGFR antagonist according to the present disclosure to a subject selected for treatment in step (b). It also includes.

[0359] The analysis of cancer may include the step of analyzing the nucleotide sequences of genes / genetic regions described herein (for example, in nucleic acid-containing samples obtained from the cancer) to determine whether the cancer contains the genetic diversity described herein. The analysis may be on cancer cells. The analysis may be on cancer / nucleic acid...

Claims

1. An antigen-binding molecule that binds to HER3, for use in methods of treating or preventing HER3-related cancers that do not involve genetic diversity resulting from increased MET expression or increased activity of its gene product.

2. The use of an antigen-binding molecule that binds to HER3 in the manufacture of a pharmaceutical product for use in the treatment or prevention of HER3-related cancers that does not contain genetic diversity resulting in increased expression of MET or increased activity of its gene product.

3. A method for treating or preventing HER3-related cancers that do not exhibit genetic diversity resulting from increased expression of MET or increased activity of its gene product, comprising the step of administering a therapeutically effective or prophylactically effective amount of an antigen-binding molecule that binds to HER3 to the subject.

4. An antigen-binding molecule for use according to claim 1, the use according to claim 2, or the method according to claim 3, wherein the HER3-related cancer does not contain genetic diversity that results in (i) increased expression of KRAS or increased activity of its gene product, or (ii) increased expression of PIK3CA or increased activity of its gene product, or (iii) increased expression of BRAF or increased activity of its gene product, or (iv) decreased expression of PTEN or decreased activity of its gene product.

5. An antigen-binding molecule for use according to claim 1 or 4, the use according to claim 2 or 4, or the method according to claim 3 or 4, wherein the HER3-related cancer does not include genetic diversity that results in (i) increased expression of KRAS or increased activity of its gene product, (ii) increased expression of PIK3CA or increased activity of its gene product, (iii) increased expression of BRAF or increased activity of its gene product, or (iv) decreased expression of PTEN or decreased activity of its gene product.

6. An antigen-binding molecule for use according to any one of claims 1, 4, or 5, wherein the HER3-related cancer does not include (i) amplification of MET, (ii) an activating mutation to KRAS, (iii) an activating mutation to PIK3CA, (iv) an activating mutation to BRAF, or (iv) a deletion of PTEN; the use according to any one of claims 2, 4, or 5; or the method according to any one of claims 3 to 5.

7. The antigen-binding molecule for use according to any one of claims 1 or 4 to 6, wherein the HER3-related cancer comprises amplification of one or more genes located on chromosome 3 q, optionally the one or more genes located on chromosome 3 q are located within chromosome 3 q26 to q28, and optionally the one or more genes are selected from TP63, SOX2, and PIK3CA, the use according to any one of claims 2 or 4 to 6, or the method according to any one of claims 3 to 6.

8. The antigen-binding molecule for use according to claim 1 or any one of claims 4 to 7, wherein the HER3-related cancer comprises amplification of one or more genes located on chromosome 7 p, optionally the one or more genes located in chromosome 7 p11, and optionally the gene is EGFR, the use according to claim 2 or any one of claims 4 to 7, or the method according to any one of claims 3 to 7.

9. The antigen-binding molecule for use according to any one of claims 1 or 4 to 7, wherein the HER3-associated cancer comprises a deletion of one or more genes located on chromosome 3 p, optionally the one or more genes located in chromosome 3 p21, and optionally the gene is TUSC2, the use according to any one of claims 2 or 4 to 7, or the method according to any one of claims 3 to 7.

10. The antigen-binding molecule for use according to any one of claims 1 or 4 to 9, wherein the HER3-related cancer includes genetic diversity resulting in increased expression of ligands for HER3, the use according to any one of claims 2 or 4 to 9, or the method according to any one of claims 3 to 9.

11. The antigen-binding molecule for use according to any one of claims 1 or 4 to 10, wherein the HER3-related cancer comprises an NRG gene fusion, an NRG1 gene fusion, or an NRG2 gene fusion, the use according to any one of claims 2 or 4 to 10, or the method according to any one of claims 3 to 10.

12. The aforementioned HER3-related cancers include CLU-NRG1, CD74-NRG1, DOC4-NRG1, SLC3A2-NRG1, RBPMS-NRG1, WRN-NRG1, SDC4-NRG1, RAB2IL1-NRG1, VAMP2-NRG1, KIF13B-NRG1, THAP7-NRG1, SMAD4-NRG1, MDK-NRG1, TNC-NRG1, DIP2B-NRG1, MRPL13-NRG1, PARP8-NRG1, ROCK1-NRG1, DPYSL2-NRG1, ATP1B1-NRG1, CDH6-NRG1, An antigen-binding molecule for use according to any one of claims 1 or 4 to 11, comprising an NRG gene fusion selected from APP-NRG1, AKAP13-NRG1, THBS1-NRG1, FOXA1-NRG1, PDE7A-NRG1, RAB3IL1-NRG1, CDK1-NRG1, BMPRIB-NRG1, TNFRSF10B-NRG1, MCPH1-NRG1, and SLC12A2-NRG2; a use according to any one of claims 2 or 4 to 11; or the method according to any one of claims 3 to 11.

13. An antigen-binding molecule that binds to HER3 for use in methods for treating or preventing HER3-related cancers, wherein the HER3-related cancer comprises amplification of one or more genes located on chromosome 3 q, optionally the one or more genes located on chromosome 3 q are located within chromosome 3 q26-q28, and optionally the one or more genes are selected from TP63, SOX2, and PIK3CA.

14. Use of an antigen-binding molecule that binds to HER3 in the manufacture of a pharmaceutical product for use in the treatment or prevention of HER3-related cancer, wherein the HER3-related cancer comprises amplification of one or more genes located on chromosome 3 q, optionally the one or more genes located on chromosome 3 q are located within chromosome 3 q26-q28, and optionally the one or more genes are selected from TP63, SOX2, and PIK3CA.

15. A method for treating or preventing HER3-related cancer in a subject, the method comprising the step of administering a therapeutically effective or prophylactically effective amount of an antigen-binding molecule that binds to HER3 to the subject, wherein the HER3-related cancer comprises amplification of one or more genes located on chromosome 3 q, optionally the one or more genes located on chromosome 3 q are located within chromosome 3 q26 to q28, and optionally the one or more genes are selected from TP63, SOX2, and PIK3CA.

16. The HER3-related cancer comprises amplification of TP63, amplification of SOX2, and amplification of PIK3CA, an antigen-binding molecule for use according to claim 13 or 16, the use according to claim 14 or 16, or the method according to claim 15 or 16.

17. An antigen-binding molecule that binds to HER3, for use in methods for treating or preventing HER3-related cancers, wherein the HER3-related cancer comprises amplification of one or more genes located on chromosome 7 p, optionally the one or more genes located on chromosome 7 p11, and optionally the gene is an EGFR.

18. Use of an antigen-binding molecule that binds to HER3 in the manufacture of a pharmaceutical product for use in the treatment or prevention of HER3-related cancer, wherein the HER3-related cancer comprises amplification of one or more genes located on chromosome 7 p, optionally the one or more genes located within chromosome 7 p11, and optionally the gene is EGFR.

19. A method for treating or preventing HER3-related cancer in a subject, the method comprising the step of administering a therapeutically effective or prophylactically effective amount of an antigen-binding molecule that binds to HER3 to the subject, wherein the HER3-related cancer comprises amplification of one or more genes located on chromosome 7 p, optionally the one or more genes located in chromosome 7 p11, and optionally the genes are EGFRs.

20. An antigen-binding molecule that binds to HER3, for use in methods for treating or preventing HER3-related cancers, wherein the HER3-related cancer comprises a deletion of one or more genes located on chromosome 3 p, optionally the one or more genes located on chromosome 3 p21, and optionally the gene is TUSC2.

21. Use of an antigen-binding molecule that binds to HER3 in the manufacture of a pharmaceutical product for use in the treatment or prevention of HER3-related cancer, wherein the HER3-related cancer comprises a deletion of one or more genes located on chromosome 3 p, optionally the one or more genes located on chromosome 3 p21, and optionally the gene is TUSC2.

22. A method for treating or preventing HER3-related cancer in a subject, the method comprising the step of administering a therapeutically effective or prophylactically effective amount of an antigen-binding molecule that binds to HER3 in the subject, wherein the HER3-related cancer comprises a deletion of one or more genes located on chromosome 3 p, optionally the one or more genes located in chromosome 3 p21, and optionally the gene is TUSC2.

23. An antigen-binding molecule that binds to HER3, for use in methods for treating or preventing HER3-related cancers, including those involving genetic diversity resulting in increased expression of MET or increased activity of its gene product, wherein the method further comprises the step of administering a HER3-mediated signaling antagonist.

24. Use of an antigen-binding molecule that binds to HER3 for use in the manufacture of a pharmacopoeia for use in the treatment or prevention of a subject, the method further comprising the step of administering a HER3-mediated signaling antagonist of a HER3-related cancer, which includes genetic diversity resulting in increased expression of MET or increased activity of its gene product.

25. A method for treating or preventing HER3-related cancers, comprising the steps of administering a therapeutically effective or prophylactically effective amount of an antigen-binding molecule that binds to HER3 to the subject, and further comprising the step of administering a HER3-mediated signaling antagonist.

26. The antigen-binding molecule for use according to claim 23, the use according to claim 24, or the method according to claim 25, wherein the HER3-related cancer includes genetic diversity that results in (i) increased expression of KRAS or increased activity of its gene product, or (ii) increased expression of PIK3CA or increased activity of its gene product, or (iii) increased expression of BRAF or increased activity of its gene product, or (iv) decreased expression of PTEN or decreased activity of its gene product.

27. The antigen-binding molecule for use according to claim 23 or claim 26, the use according to claim 24 or claim 26, or the method according to claim 25 or claim 26, wherein the HER3-related cancer comprises (i) genetic diversity resulting in increased expression of KRAS or increased activity of its gene product; (ii) genetic diversity resulting in increased expression of PIK3CA or increased activity of its gene product; (iii) genetic diversity resulting in increased expression of BRAF or increased activity of its gene product; and (iv) genetic diversity resulting in decreased expression of PTEN or decreased activity of its gene product.

28. A method for selecting a target for treatment with an antigen-binding molecule that binds to HER3, (a) A step of analyzing the target cancer to determine whether the cancer contains genetic diversity that results in increased expression of MET or increased activity of its gene product, and (b) If it is determined in step (a) that the target cancer does not contain such genetic diversity, the step of selecting a target for treatment with an antigen-binding molecule that binds to HER3. A method that includes this.

29. (a) (i) A step of analyzing the target cancer to determine whether the cancer contains genetic diversity that leads to increased expression of KRAS or increased activity of its gene product, or (ii) A step of analyzing the target cancer to determine whether the cancer contains an activating mutation to PIK3CA, or (iii) A step of analyzing the target cancer to determine whether the cancer contains genetic diversity that leads to increased expression of BRAF or increased activity of its gene product, or (iv) A step of analyzing the target cancer to determine whether the cancer contains genetic diversity that results in decreased expression of PTEN or decreased activity of its gene product, and (b) If it is determined in step (a) that the target cancer does not contain such genetic diversity / mutation, the step of selecting a target for treatment with an antigen-binding molecule that binds to HER3. The method according to claim 28, including the method described in claim 28.

30. (a) (i) a step of analyzing the target cancer to determine whether the cancer contains genetic diversity that leads to increased expression of KRAS or increased activity of its gene product, and (ii) A step of analyzing the target cancer to determine whether the cancer contains an activating mutation to PIK3CA, and (iii) A step of analyzing the target cancer to determine whether the cancer contains genetic diversity that leads to increased expression of BRAF or increased activity of its gene product, and (iv) A step of analyzing the target cancer to determine whether the cancer contains genetic diversity that results in decreased expression of PTEN or decreased activity of its gene product, and (b) If it is determined in step (a) that the target cancer does not contain such genetic diversity / mutation, the step of selecting a target for treatment with an antigen-binding molecule that binds to HER3. The method according to claim 28 or claim 29, including the method according to claim 29.

31. (c) A step in which an antigen-binding molecule that binds to HER3 is administered to the subject selected for treatment in step (b). The method according to any one of claims 28 to 30, further comprising:

32. (i) an antagonist of HER3-mediated signaling, and (ii) a method for selecting a target for treatment with an antigen-binding molecule that binds to HER3, (a) A step of analyzing the target cancer to determine whether the cancer contains genetic diversity that results in increased expression of MET or increased activity of its gene product, and (b) If the target cancer is determined in step (a) to contain such genetic diversity, the step of selecting the target for treatment with (i) an antagonist of HER3-mediated signaling and (ii) an antigen-binding molecule that binds to HER3. A method that includes this.

33. (a) (i) A step of analyzing the target cancer to determine whether the cancer contains genetic diversity that leads to increased expression of KRAS or increased activity of its gene product, or (ii) A step of analyzing the target cancer to determine whether the cancer contains an activating mutation to PIK3CA, or (iii) A step of analyzing the target cancer to determine whether the cancer contains genetic diversity that leads to increased expression of BRAF or increased activity of its gene product, or (iv) A step of analyzing the target cancer to determine whether the cancer contains genetic diversity that results in decreased expression of PTEN or decreased activity of its gene product, and (b) If the target cancer is determined in step (a) to contain such genetic diversity / mutation, the step of selecting the target for treatment with (i) a HER3-mediated signaling antagonist and (ii) an antigen-binding molecule that binds to HER3. The method according to claim 32, including the method described in claim 32.

34. (a) (i) a step of analyzing the target cancer to determine whether the cancer contains genetic diversity that leads to increased expression of KRAS or increased activity of its gene product, and (ii) A step of analyzing the target cancer to determine whether the cancer contains an activating mutation to PIK3CA, and (iii) A step of analyzing the target cancer to determine whether the cancer contains genetic diversity that leads to increased expression of BRAF or increased activity of its gene product, and (iv) A step of analyzing the target cancer to determine whether the cancer contains genetic diversity that results in decreased expression of PTEN or decreased activity of its gene product, and (b) If the target cancer is determined in step (a) to contain such genetic diversity / mutation, the step of selecting the target for treatment with (i) a HER3-mediated signaling antagonist and (ii) an antigen-binding molecule that binds to HER3. The method according to claim 32 or claim 33, including the method according to claim 33.

35. (c) A step of administering (i) a HER3-mediated signaling antagonist and (ii) an antigen-binding molecule that binds to HER3 to the subject selected for treatment in step (b). The method according to any one of claims 32 to 34, further comprising:

36. The aforementioned HER3-related cancers include solid tumors, breast cancer, ductal carcinoma, gastric cancer, gastric adenocarcinoma, colorectal cancer, colorectal cancer, colorectal adenocarcinoma, head and neck cancer, squamous cell carcinoma of the head and neck, lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, kidney cancer, renal cell carcinoma, clear cell carcinoma of the kidney, renal cell adenocarcinoma, papillary renal cell carcinoma, pancreatic cancer, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, cervical cancer, cervical squamous cell carcinoma, skin cancer, melanoma, esophageal cancer, esophageal adenocarcinoma, liver cancer, hepatocellular carcinoma, bile duct cancer, uterine cancer, endometrial cancer. An antigen-binding molecule for use according to any one of claims 1, 4 to 13, 16, 17, 20, 23, 26 or 27, selected from thyroid cancer, thyroid cancer, pheochromocytoma, paraganglioma, bladder cancer, urothelial carcinoma of the bladder, prostate cancer, prostate adenocarcinoma, sarcoma, and thymoma; a use according to any one of claims 2, 4 to 12, 14, 16, 18, 21, 24, 26 or 27; or the method according to any one of claims 3 to 12, 15, 19, 22, 25 or 28 to 35.

37. The antigen-binding molecules that bind to HER3 include 10D1F, cerivanthumab, elgemtumab, patritumab, GSK2849330, lumuletuzumab, CDX-3379, AV-203, valecetamab, TK-A3, TK-A4, MP-EV20, 1A5-3D4, 9F7-F11, 16D3-C1, NG33, A5, F4, huHER3-8, REGN1400, and An antigen-binding molecule selected from xenoctuzumab for use according to any one of claims 1, 4 to 13, 16, 17, 20, 23, 26, 27, or 36; a use according to any one of claims 2, 4 to 12, 14, 16, 18, 21, 24, 26, 27, or 36; or the method according to any one of claims 3 to 12, 15, 19, or 22 to 36.

38. The antigen-binding molecule that binds to HER3, (i) The following CD-Rs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 40 HC-CDR2 having the amino acid sequence of SEQ ID NO: 43 HC-CDR3 having the amino acid sequence of SEQ ID NO: 48 A heavy chain variable (VH) region incorporating, and (ii) The following CD-Rs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 66 LC-CDR2 having the amino acid sequence of SEQ ID NO: 69 LC-CDR3 having the amino acid sequence of SEQ ID NO: 74 Light chain variable (VL) region incorporating An antigen-binding molecule for use according to any one of claims 1, 4 to 13, 16, 17, 20, 23, 26, 27, 36 or 37, including the use according to any one of claims 2, 4 to 12, 14, 16, 18, 21, 24, 26, 27, 36 or 37, or the method according to any one of claims 3 to 12, 15, 19 or 22 to 37.

39. The antigen-binding molecule that binds to HER3, (i) The following CD-Rs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 38 HC-CDR2 having the amino acid sequence of SEQ ID NO: 42 HC-CDR3 having the amino acid sequence of SEQ ID NO: 45 The VH region that incorporates, and (ii) The following CD-Rs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 63 LC-CDR2 having the amino acid sequence of SEQ ID NO: 67 LC-CDR3 having the amino acid sequence of SEQ ID NO: 70 VL area to incorporate An antigen-binding molecule for use according to any one of claims 1, 4 to 13, 16, 17, 20, 23, 26, 27 or 36 to 38, including the use according to any one of claims 2, 4 to 12, 14, 16, 18, 21, 24, 26, 27 or 36 to 38, or the method according to any one of claims 3 to 12, 15, 19 or 22 to 38.

40. The antigen-binding molecule that binds to HER3, A VH region containing an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 33, and A VL region containing an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:

58. An antigen-binding molecule for use according to any one of claims 1, 4 to 13, 16, 17, 20, 23, 26, 27 or 36 to 39, including the use according to any one of claims 2, 4 to 12, 14, 16, 18, 21, 24, 26, 27 or 36 to 39, or the method according to any one of claims 3 to 12, 15, 19 or 22 to 39.

41. The antigen-binding molecule that binds to HER3, 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. An antigen-binding molecule for use according to any one of claims 1, 4 to 13, 16, 17, 20, 23, 26, 27 or 36 to 40, including the use according to any one of claims 2, 4 to 12, 14, 16, 18, 21, 24, 26, 27 or 36 to 40, or the method according to any one of claims 3 to 12, 15, 19 or 22 to 40.

42. An antigen-binding molecule for use according to any one of claims 1, 4 to 13, 16, 17, 20, 23, 26, 27 or 36 to 41, wherein the method for treating or preventing the HER3-related cancer further comprises the step of administering an EGFR antagonist to the subject; the use according to any one of claims 2, 4 to 12, 14, 16, 18, 21, 24, 26, 27 or 36 to 41; or the method according to any one of claims 3 to 12, 15, 19 or 22 to 41.

43. The antigen-binding molecule for use according to claim 42, the use according to claim 42, or the method according to claim 42, wherein the antagonist of EGFR is an antigen-binding molecule that binds to EGFR.

44. The antigen-binding molecule that binds to EGFR, (i) The following CD-Rs: HC-CDR1 having the amino acid sequence of SEQ ID NO: 78 HC-CDR2 having the amino acid sequence of SEQ ID NO: 79 HC-CDR3 having the amino acid sequence of SEQ ID NO: 80 The VH region that incorporates, and (ii) The following CD-Rs: LC-CDR1 having the amino acid sequence of SEQ ID NO: 82 LC-CDR2 having the amino acid sequence of SEQ ID NO: 83 LC-CDR3 having the amino acid sequence of SEQ ID NO: 84 VL area to incorporate An antigen-binding molecule for use according to claim 43, the use according to claim 43, or the method according to claim 43.

45. The antigen-binding molecule that binds to EGFR, A VH region containing an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: 77, and A VL region containing an amino acid sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:

81. An antigen-binding molecule for use according to claim 43 or claim 44, the use according to claim 43 or claim 44, or the method according to claim 43 or claim 44.

46. The antigen-binding molecule that binds to EGFR, 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: 85, 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:

86. An antigen-binding molecule for use according to any one of claims 43 to 45, the use according to any one of claims 43 to 45, or the method according to any one of claims 43 to 45.

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