Use of Amivantamab to Treat Colorectal Cancer

Abstract

The present invention relates to a method of treating colorectal cancer (CRC), such as metastatic colorectal cancer (mCRC), in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of an antibody (e.g., a bispecific antibody), where the antibody specifically binds to epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (c-Met).

Description

[Technical field]

[0001] (Reference to electronically submitted sequence listing) The sequence listing of the present application is being submitted electronically through the Patent Center at the U.S. Patent and Trademark Center as an XML format sequence listing with the filename "JBI6688WOPCT1SEQLIST.xml", created on December 2, 2022, and 20 kilobytes (KB) in size. This submitted sequence listing is a part of the present specification and is incorporated herein by reference in its entirety.

[0002] FIELD OF THEINVENTION The present invention relates to a method of treating colorectal cancer (CRC), such as metastatic colorectal cancer (mCRC), in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of an antibody (e.g., a bispecific antibody), where the antibody specifically binds to epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (c-Met). [Background technology]

[0003] Colorectal cancer (CRC) is characterized by the uncontrolled division of abnormal cells in the colon or rectum. CRC is one of the most common malignant neoplasms, ranking second to fourth worldwide in terms of incidence according to location, type, or sex (see Sawicki et al., Cancers (Basel) 13(9):2025 (2021)). CRC is the third leading cause of cancer deaths in the United States (see Biller & Schrag, JAMA 325(7):669-85 (2021)). Among people diagnosed with metastatic colorectal cancer (mCRC), less than 20% of patients survive more than 5 years from diagnosis, with a 5-year survival rate of 14% for metastatic CRC (see supra). Summary of the Invention

[0004] Improved therapeutic agents or combinations of therapeutic agents are needed to develop more effective treatments for colorectal cancer (CRC), including metastatic CRC (mCRC).

[0005] The present disclosure relates generally to methods useful for treating CRC, such as metastatic colorectal cancer (mCRC).

[0006] In one aspect, the disclosure provides a method of treating CRC in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody.

[0007] In some embodiments, the antibody is a bispecific antibody.

[0008] In some embodiments, an antibody (e.g., a bispecific antibody) comprises: a) a first domain that specifically binds to EGFR, comprising the heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively; and b) a second domain that specifically binds to c-Met, comprising the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 amino acid sequences of SEQ ID NOs: 7, 8, 9, 10, 11, and 12, respectively.

[0009] In one embodiment, the first domain comprises a heavy chain variable region (VH) of SEQ ID NO: 13 and a light chain variable region (VL) of SEQ ID NO: 14, and the second domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0010] In certain embodiments, the antibody (e.g., a bispecific antibody) comprises a first heavy chain (HC1) of SEQ ID NO: 17, a first light chain (LC1) of SEQ ID NO: 18, a second heavy chain (HC2) of SEQ ID NO: 19, and a second light chain (LC2) of SEQ ID NO: 20.

[0011] In some embodiments, the antibody (e.g., bispecific antibody) is of the IgG1 isotype. In certain embodiments, the antibody (e.g., bispecific antibody) comprises a biantennary glycan structure with a fucose content of about 1% to about 15%. In certain embodiments, the antibody (e.g., bispecific antibody) is amivantamab.

[0012] In some embodiments, the antibody (e.g., bispecific antibody) is administered at a dose of about 700 mg to about 1400 mg. In certain embodiments, the antibody (e.g., bispecific antibody) is administered once a week or once every two weeks. In certain embodiments, the antibody (e.g., bispecific antibody) is administered once a week for the first four weeks, then once every two weeks. In some embodiments, the antibody (e.g., bispecific antibody) is administered in a 28 day cycle.

[0013] In some embodiments, the antibody (e.g., bispecific antibody) is administered as a monotherapy. In other embodiments, the method further comprises administering one or more chemotherapeutic agents to the subject. In some embodiments, the one or more chemotherapeutic agents include FOLFOX, where FOLFOX includes folinic acid, fluorouracil, and oxaliplatin. In some embodiments, the one or more chemotherapeutic agents include FOLFIRI, where FOLFIRI includes folinic acid, fluorouracil, and irinotecan.

[0014] In some embodiments, the CRC is mCRC. In certain embodiments, the subject has been diagnosed with left-sided mCRC. In other embodiments, the subject has been diagnosed with right-sided mCRC.

[0015] In some embodiments, the subject has not previously received an anti-EGFR therapy. In other embodiments, the subject has previously received an anti-EGFR therapy. In certain embodiments, the subject is relapsed or refractory to treatment with one or more previous anti-cancer therapies. In some embodiments, the subject is treatment naive. In some embodiments, the subject has not previously received oxaliplatin-based chemotherapy in the metastatic setting.

[0016] In some embodiments, the subject is over the age of 18. In some embodiments, the subject is characterized with wild-type KRAS, NRAS, and BRAF.

[0017] In another aspect, the disclosure also provides a method of treating mCRC in a subject, comprising administering to the subject a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-MET antibody comprises a first domain that specifically binds EGFR and a second domain that specifically binds c-MET, wherein the first domain comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, and the second domain comprises HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11, and LCDR3 of SEQ ID NO: 12.

[0018] In another aspect, the disclosure also provides a method of treating mCRC in a subject, comprising administering to the subject a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds EGFR and a second domain that specifically binds c-Met, wherein the first domain comprises a VH of SEQ ID NO: 13 and a VL of SEQ ID NO: 14, and the second domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0019] In another aspect, the disclosure also provides a method of treating mCRC in a subject, comprising administering to the subject a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises an HC1 of SEQ ID NO: 17, an LC1 of SEQ ID NO: 18, an HC2 of SEQ ID NO: 19, and an LC2 of SEQ ID NO: 20.

[0020] In another aspect, the disclosure also provides a method of treating mCRC in a subject, comprising administering to the subject a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody is amivantamab. [Brief description of the drawings]

[0021] [Figure 1] FIG. 1 shows the study design for a Phase 1b / 2 open-label study of amivantamab in patients with advanced or metastatic colorectal cancer. [Diagram 2] FIG. 1 is a schematic showing the structure of amivantamab, an EGFR and cMet bispecific antibody. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] definition All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if fully set forth.

[0023] It should be understood that the terms used herein are used only to describe particular embodiments and are not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0024] Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present invention, exemplary materials and methods are described herein. In describing and claiming the present invention, the following terminology is used.

[0025] When lists are presented, unless otherwise stated, it is to be understood that each individual element of that list and every combination of that list is a separate embodiment. For example, a list of embodiments presented as "A, B, or C" should be interpreted to include the embodiments "A," "B," "C," "A or B," "A or C," "B or C," or "A, B, or C."

[0026] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a cell" includes a combination of two or more cells, and the like.

[0027] The conjunction phrase "and / or" between multiple listed elements is understood to encompass both individual and combined options. For example, when two elements are connected by "and / or," the first option refers to the first element being applicable without the second element. The second option refers to the second element being applicable without the first element. The third option refers to the first and second elements being applicable together. Any one of these options is understood to be within the meaning and thus meets the requirements of the term "and / or" as used herein. The simultaneous applicability of two or more of the options is also understood to be within the meaning and thus meets the requirements of the term "and / or."

[0028] The transitional phrases "comprising," "consisting essentially of," and "consisting of" are intended to connote their generally accepted meanings in patent language, i.e., (i) "comprising" is synonymous with "comprising," "containing," or "characterized by," is inclusive or open-ended, and does not exclude other unrecited elements or method steps; (ii) "consisting of" excludes any element, step, or ingredient not specified in the claim; and (iii) "consisting essentially of" limits the claim to the materials or steps specified and those that do not materially affect the "basic and novel characteristic(s)" of the claimed invention. An embodiment described with the phrase "comprising" (or its synonyms) also provides as an embodiment an embodiment described independently with "consisting of" and "consisting essentially of."

[0029] "About" means within an acceptable range of error for a particular value as determined by one of ordinary skill in the art, which will depend in part on the limitations of the method by which the value is measured or determined, i.e., the measurement system. In the context of a particular assay, result, or embodiment, unless expressly stated otherwise in the Examples or elsewhere herein, "about" means within one standard deviation, or up to 5%, whichever is greater, as per practice in the art.

[0030] The term "antibody" (singular or plural) is intended in a broad sense and includes immunoglobulin molecules including monoclonal antibodies (including murine, human, humanized, and chimeric monoclonal antibodies), full-length antibodies, antigen-binding fragments, multispecific antibodies such as bispecific, trispecific, tetraspecific, etc., dimeric, tetrameric, or multimeric antibodies, single chain antibodies, domain antibodies, and any other modified form of immunoglobulin molecule that contains an antigen-binding site of the required specificity.

[0031] "Specific binding," "specifically binds," or "specific binding" or "binds" refers to an antibody binding to an antigen or an epitope within an antigen with higher affinity than to other antigens. Typically, antibodies bind with an equilibrium dissociation constant (K D ) is the K for binding to non-specific antigens (e.g., BSA, casein) D At least 100 times smaller than about 5 × 10 -8 M or less, for example, about 1×10 -9 M or less, approximately 1×10 -10 M or less, approximately 1×10 -11 M or less, approximately 1×10 -12 K below M D The dissociation constant can be measured using known protocols. However, an antibody that binds to an antigen or an epitope within an antigen may have cross-reactivity to other related antigens, e.g., the same antigen (homolog) from other species, such as humans or monkeys, e.g., Macaca fascicularis (cynomolgus monkey, cyno) or Pan troglodytes (chimp). A monospecific antibody binds to one antigen or one epitope, whereas a bispecific antibody binds to two different antigens or two different epitopes.

[0032] "Complementarity determining region (CDR)" is the region of an antibody that binds to an antigen. CDRs can be defined using various descriptions, such as Kabat (Wu et al. (1970) J Exp Med 132:211-50) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et al. (1987) J Mol Biol 196:901-17), IMGT (Lefranc et al. (2003) Dev Comp Immunol 27:55-77), and AbM (Martin and Thornton (1996) J Bmol Biol 263:800-15). Correspondence between the various descriptions and numbering of the variable regions has been described (see, for example, Lefranc et al. (2003) Dev Comp Immunol 27:55-77; Honegger and Pluckthun, (2001) J Mol Biol 309:657-70; and the International ImMunoGeneTics (IMGT) database; web resource, http: / / www_imgt_org). Available programs such as abYsis by UCL Business PLC can be used to describe the CDRs. As used herein, the terms "CDR", "HCDR1", "HCDR2", "HCDR3", "LCDR1", "LCDR2" and "LCDR3" include CDRs defined by any of the methods of Kabat, Chothia, IMGT or AbM as described above, unless otherwise expressly stated in the specification.

[0033] A "full-length antibody" is composed of two heavy chains (HC) and two light chains (LC), and multimers thereof (e.g., IgM), interconnected by disulfide bonds. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region (consisting of domains CH1, hinge, CH2, and CH3). Each light chain is composed of a light chain variable region (VL) and a light chain constant region (CL). The VH and VL regions are interspersed with framework regions (FR) and may be further subdivided into regions of hypervariability called complementarity determining regions (CDRs). Each VH and VL is composed of three CDR and four FR segments, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0034] "Antigen-binding fragment" refers to a portion of an immunoglobulin molecule that binds to an antigen. The antigen-binding fragment may be a synthetic, enzymatically obtainable, or genetically engineered polypeptide, and includes VH, VL, VH and VL, Fab, F(ab')2, Fd, and Fv fragments, domain antibodies (dAbs) consisting of one VH domain or one VL domain, shark variable IgNAR domain, camelized VH domain, and the minimum recognition unit consisting of amino acid residues reproducing the CDRs of an antibody, such as the FR3-CDR3-FR4 portion, HCDR1, HCDR2, and / or HCDR3, and LCDR1, LCDR2, and / or LCDR3. The VH and VL domains can be linked to each other via synthetic linkers to form various types of single chain antibody designs; when the VH and VL domains are expressed as separate single chain antibody constructs, the VH / VL domains can pair intramolecularly or intermolecularly to form monovalent antigen binding sites, such as single chain Fvs (scFvs) or diabodies, as described, for example, in WO 1998 / 44001, WO 1988 / 01649, WO 1994 / 13804, and WO 1992 / 01047.

[0035] By "monoclonal antibody" is meant an antibody obtained from a substantially homogeneous population of antibody molecules, i.e., individual antibodies that make up the population, that are identical except for possible well-known alterations, such as removal of the C-terminal lysine from the antibody heavy chain, or post-translational modifications such as isomerization or deamidation of amino acids, oxidation of methionine, or deamidation of asparagine or glutamine. A monoclonal antibody typically binds to one antigenic epitope. A bispecific monoclonal antibody binds to two different antigenic epitopes. A monoclonal antibody may have heterogeneous glycosylation within the antibody population. A monoclonal antibody may be monospecific or multispecific, such as bispecific, and may be monovalent, bivalent, or multivalent.

[0036] "Humanized antibody" refers to an antibody in which the antigen binding site is derived from a species other than human and the variable region framework is derived from a human immunoglobulin sequence. Because humanized antibodies may contain mutations intentionally introduced within the framework regions, such frameworks may not be exact copies of expressed human immunoglobulin or germline gene sequences.

[0037] "Human antibody" refers to an antibody having heavy and light chain variable regions in which both the framework and antigen binding sites are derived from sequences of human origin. If the antibody contains a constant region or a portion of a constant region, the constant region also is derived from sequences of human origin. Antibodies in which the antigen binding site is derived from a non-human species are not included in the definition of "human antibody."

[0038] A human antibody comprises a heavy or light chain variable region derived from a sequence of human origin when the variable region of the antibody is obtained from a system using human germline immunoglobulin or rearranged immunoglobulin genes. Non-limiting exemplary systems include human immunoglobulin gene libraries displayed on phage, and transgenic non-human animals carrying human immunoglobulin loci, such as mice or rats. Human antibodies typically contain amino acid differences compared to human germline or rearranged immunoglobulin sequences due to, for example, naturally occurring somatic mutations, deliberate substitutions in frameworks or antigen-binding sites, and substitutions introduced during cloning or VDJ recombination in the non-human animal. Typically, human antibodies are at least 80% identical in amino acid sequence to the amino acid sequences encoded by human germline or rearranged immunoglobulin genes. For example, about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. In some cases, the human antibody may contain consensus framework sequences obtained from human framework sequence analysis (see, e.g., Knappik et al., J Mol Biol 296:57-86 (2000)), or synthetic HCDR3s incorporated into a human immunoglobulin gene library displayed on phage (see, e.g., Shi et al., J Mol Biol 397:385-96 (2010), and WO 2009 / 085462).

[0039] "Bispecific" refers to an antibody that specifically binds to two different antigens or two different epitopes on the same antigen. Bispecific antibodies may have cross-reactivity to other related antigens, e.g., the same antigen (homolog) from other species such as humans or monkeys, e.g., Macaca cynomolgus (cyno) or chimpanzees, or may bind to an epitope that is shared between two or more different antigens.

[0040] A "bispecific anti-EGFR / c-Met antibody" or "bispecific EGFR / c-Met antibody" refers to a bispecific antibody having a first domain that specifically binds EGFR and a second domain that specifically binds c-Met. The domains that specifically bind EGFR and c-Met are typically VH / VL paired, and the bispecific anti-EGFR / c-Met antibody is monovalent with respect to binding to EGFR and c-Met.

[0041] "Isolated" refers to a homogenous population of molecules (e.g., synthetic polynucleotides, polypeptides, vectors, or viruses) that have been substantially separated and / or purified away from other components of the system in which they are produced, such as recombinant cells, as well as proteins that have been subjected to at least one purification or isolation step. "Isolated" refers to molecules that are substantially free of other cellular material and / or chemicals, and includes molecules that have been isolated to greater degrees of purity, e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% purity.

[0042] Immunoglobulins can be assigned to five major classes, IgA, IgD, IgE, IgG, and IgM, depending on the amino acid sequence of the heavy chain constant domain. IgA and IgG are further subdivided into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. The antibody light chain of any vertebrate species can be assigned to one of two clearly distinct types, kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain.

[0043] As used herein, "low fucose" or "low fucose content" refers to an antibody having a fucose content of between about 1% and 15%.

[0044] As used herein, "normal fucose" or "normal fucose content" refers to an antibody having a fucose content of greater than about 50%, usually greater than 80%, or greater than 85%.

[0045] "Recombinant" refers to DNA, antibodies, and other proteins that are prepared, expressed, produced, or isolated by recombinant means when segments from different sources are joined to produce the recombinant DNA, antibody, or protein.

[0046] "Carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the antibody of the present invention is administered. Such vehicles may be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like. For example, 0.4% saline and 0.3% glycine may be used to formulate the bispecific anti-EGFR / c-Met antibody. These solutions are sterile and generally free of particulate matter. They may be sterilized by conventional, well-known sterilization techniques (e.g., filtration). For parenteral administration, the carrier may comprise sterile water, with other excipients added to enhance or preserve solubility. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers with appropriate additives. Suitable vehicles and formulations, including other human proteins, e.g., human serum albumin, are described, for example, in Remington: The Science and Practice of Pharmacy, 21 st Edition, Troy, DB ed., Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing pp 691-1092, see in particular pp. 958-989.

[0047] "Dosage" refers to information regarding the amount of a therapeutic agent or drug taken by a subject and the frequency of times the therapeutic agent is taken by a subject. "Dose" refers to the amount or quantity of a therapeutic agent or drug taken each time.

[0048] "Therapeutically effective amount" refers to an amount effective to obtain the desired therapeutic result at the dosage and duration required. The therapeutically effective amount may vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the therapeutic agent or combination of therapeutic agents to elicit a desired response in the individual. Exemplary indicators of an effective therapeutic agent or combination of therapeutic agents include, for example, improved health of the patient.

[0049] "Co-administration," "administered with," "administered in combination with," "in combination with," and the like are intended to encompass administration of selected therapeutic agents or drugs to a single patient, and include treatment regimens in which the therapeutic agents or drugs are administered by the same or different routes of administration or at the same or different times.

[0050] A "fixed combination" refers to a single pharmaceutical composition which comprises two or more compounds.

[0051] A "non-fixed combination" refers to separate pharmaceutical compositions each containing one or more compounds. One or more compounds or unit dosage forms can be administered as separate entities simultaneously, concurrently, or sequentially without specific intervening time limits, such administration providing effective levels of the two compounds in the subject's body.

[0052] A "PD-(L)1 axis inhibitor" refers to a molecule that inhibits PD-1 downstream signaling. A PD-(L)1 axis inhibitor may be a molecule that binds to PD-1, PD-L1, or PD-L2.

[0053] "Antagonist" or "inhibitor" refers to a molecule that, when bound to a cellular protein, inhibits at least one response or activity induced by the protein's natural ligand. A molecule is an antagonist when at least one response or activity is inhibited by at least about 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% more than the at least one response or activity inhibited in the absence of the antagonist (e.g., a negative control), or when the inhibition is statistically significant compared to inhibition in the absence of the antagonist.

[0054] "Treating," "treating," or "treatment" of a disease or disorder, such as cancer, hereinafter refers to achieving one or more of the following: reducing the severity and / or duration of the disorder, inhibiting the worsening of symptoms characteristic of the disorder being treated, limiting or preventing the recurrence of the disorder in a subject who previously had the disorder, or limiting or preventing the recurrence of symptoms in a subject who was previously symptomatic for the disorder.

[0055] "Prevent", "preventing", "prevention", or "prophylaxis" of a disease or disorder means preventing the disorder from occurring in a subject.

[0056] "Responsive," "responsive," or "likely to respond" refers to any type of improvement or positive response, whether detectable or undetectable, such as a reduction or amelioration of one or more symptoms, a decrease in the extent of the disease, a stabilized (i.e., not worsening) disease state, prevention of the spread of the disease, a delay or slowing of the progression of the disease, a amelioration or palliation of the disease state, and remission (whether partial or total).

[0057] A "subject" includes any human or non-human animal. "Non-human animals" include all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc. The terms "subject" and "patient" are used interchangeably herein.

[0058] "Cancer" refers to an abnormal growth of cells that tend to proliferate uncontrolled and, in some cases, metastasize (spread) to other areas of the patient's body.

[0059] "EGFR or c-Met expressing cancer" refers to a cancer that has detectable expression of EGFR or c-Met, or has mutations or amplifications of EGFR or c-Met. EGFR or c-Met expression, amplification, and mutation status can be detected using known methods such as sequencing, next generation sequencing, fluorescent in situ hybridization, immunohistochemistry, flow cytometry, or Western blotting.

[0060] "Epidermal growth factor receptor" or "EGFR" refers to human EGFR (also known as HER1 or ErbB1 (Ullrich et al., Nature 309:418-425, 1984) having the amino acid sequence set forth in GenBank Accession No. NP_005219), as well as naturally occurring variants thereof.

[0061] As used herein, "hepatocyte growth factor receptor" or "c-Met" refers to human c-Met having the amino acid sequence set forth in GenBank Accession No. NP_001120972 and naturally occurring variants thereof.

[0062] "Newly diagnosed" refers to a subject who has been diagnosed with an EGFR or c-Met expressing cancer but has not yet received treatment for CRC (eg, mCRC).

[0063] "Refractory" refers to a disease that does not respond to treatment. A refractory disease may be resistant to treatment before or at the start of treatment, or a refractory disease may become resistant during treatment.

[0064] "Relapse" refers to the return of a disease or signs and symptoms of a disease after a period of improvement following prior treatment with a therapeutic agent.

[0065] "Diagnosing" or "diagnosis" refers to a method of determining whether a subject is afflicted with a given disease or condition, or may develop a given disease or condition in the future, or is likely to respond to treatment for a previously diagnosed disease or condition, i.e., stratifying a patient population for the likelihood of responding to treatment. Diagnosis is typically made by a physician based on a general guide to the disease being diagnosed, or other criteria that indicate that a subject is likely to respond to a particular treatment.

[0066] A "biological sample" refers to a collection of fluids, cells, or tissues present within a subject, as well as similar fluids, cells, or tissues isolated from a subject. Exemplary samples are biological fluids, such as blood, serum and serous fluid, plasma, lymphatic fluid, urine, saliva, cyst fluid, tears, feces, sputum, mucosal secretions of secretory tissues and organs, vaginal secretions, ascites, fluids of the pleural, pericardial, peritoneal, abdominal cavities, and other body cavities, fluids collected by bronchial lavage, synovial fluid, liquid solutions in contact with a subject or biological source, such as cell and organ culture media, including conditioned media of cells or organs, lavage fluids, and the like, tissue biopsies, tumor tissue biopsies, tumor tissue samples, fine needle aspirations, surgically resected tissues, organ cultures, or cell cultures.

[0067] Methods of the Disclosure In one aspect, the disclosure provides a method of treating CRC in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody.

[0068] Anti-EGFR / c-Met antibody In some embodiments, the anti-EGFR / c-Met antibody is a bispecific antibody. In certain embodiments, the antibody is an isolated antibody. In certain embodiments, the antibody is an isolated bispecific antibody.

[0069] In some embodiments, the antibody (eg, a bispecific antibody) comprises a first domain that specifically binds EGFR and a second domain that specifically binds c-Met.

[0070] EGFR binding arm In some embodiments, the first domain that specifically binds to EGFR is: a) the amino acid sequences of heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 of SEQ ID NOs: 1, 2, and 3, respectively; and / or b) comprising the amino acid sequences of light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 of SEQ ID NOs: 4, 5 and 6, respectively.

[0071] In one embodiment, the first domain that specifically binds to EGFR is: a) the amino acid sequences of HCDR1, HCDR2, and HCDR3 of SEQ ID NOs: 1, 2, and 3, respectively; and b) comprising the amino acid sequences of LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, and 6, respectively.

[0072] HCDR1: TYGMH (SEQ ID NO: 1)

[0073] HCDR2: VIWDDGSYKYYGDSVKG (SEQ ID NO: 2)

[0074] HCDR3: DGITMVRGVMKDYFDY (SEQ ID NO: 3)

[0075] HCDR1: RASQDISSALV (SEQ ID NO: 4)

[0076] HCDR2: DASSLES (SEQ ID NO:5)

[0077] HCDR3: QQFNSYPLT (SEQ ID NO: 6)

[0078] In some embodiments, the first domain comprises a heavy chain variable region (VH) amino acid sequence that is at least 90% identical to SEQ ID NO:13, e.g., about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO:13. In some embodiments, the sequence identity is about 90-99.9%, 90-99.8%, 92-99.8%, 92-99.6%, 94-99.6%, 94-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2%, or 97-99%. In certain embodiments, the first domain comprises a VH of SEQ ID NO:13.

[0079] In one embodiment, the first domain comprises a light chain variable region (VL) amino acid sequence that is at least 90% identical to SEQ ID NO:14, e.g., about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO:14. In some embodiments, the sequence identity is about 90-99.9%, 90-99.8%, 92-99.8%, 92-99.6%, 94-99.6%, 94-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2%, or 97-99%. In certain embodiments, the first domain comprises a VL of SEQ ID NO:14.

[0080] As used herein, the term "identical" or "having sequence identity" refers to the degree to which two amino acid sequences have the same residues at the same positions when the sequences are aligned to achieve the maximum level of identity, expressed as a percentage. For sequence alignment comparison, typically one sequence is designated as a reference sequence against which the test sequence is compared. The sequence identity between the reference sequence and the test sequence is expressed as the percentage of positions over the entire length of the reference sequence where the reference sequence and the test sequence share the same amino acid when the reference sequence and the test sequence are aligned to achieve the maximum level of identity. As an example, two sequences are considered to have 70% sequence identity if the test sequence has the same amino acid residues at 70% of the same positions over the entire length of the reference sequence when aligned to achieve the maximum level of identity.

[0081] In some embodiments the first domain is: a) a VH amino acid sequence that is at least 90% identical to SEQ ID NO: 13; and / or b) a VL amino acid sequence that is at least 90% identical to SEQ ID NO:14.

[0082] In some embodiments the first domain is: a) a VH amino acid sequence that is at least 90% identical to SEQ ID NO: 13; and b) a VL amino acid sequence that is at least 90% identical to SEQ ID NO:14.

[0083] In some embodiments the first domain is: a) the VH of SEQ ID NO: 13; and / or b) comprises a VL of SEQ ID NO: 14.

[0084] In certain embodiments, the first domain comprises: a) VH of SEQ ID NO: 13; and b) comprises a VL of SEQ ID NO: 14.

[0085] VH: QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSS (SEQ ID NO: 13)

[0086] VL: AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIK (SEQ ID NO: 14)

[0087] In some embodiments, the first domain comprises a first heavy chain (HC1) amino acid sequence that is at least 80% identical to SEQ ID NO:17, e.g., about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical. In certain embodiments, the sequence identity is about 80-99.9%, 80-99.8%, 85-99.8%, 85-99.6%, 90-99.6%, 90-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2%, or 97-99%. In certain embodiments, the first domain comprises the HC1 amino acid sequence of SEQ ID NO:17.

[0088] In some embodiments, the first domain comprises a first light chain (LC1) amino acid sequence that is at least 80% identical to SEQ ID NO:18, e.g., about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical. In certain embodiments, the sequence identity is about 80-99.9%, 80-99.8%, 85-99.8%, 85-99.6%, 90-99.6%, 90-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2%, or 97-99%. In certain embodiments, the first domain comprises the LC1 amino acid sequence of SEQ ID NO:18.

[0089] In some embodiments the first domain is: a) an HC1 amino acid sequence that is at least 80% identical to SEQ ID NO: 17; and / or b) an LC1 amino acid sequence that is at least 80% identical to SEQ ID NO:18.

[0090] In some embodiments the first domain is: a) an HC1 amino acid sequence that is at least 80% identical to SEQ ID NO:17; and b) an LC1 amino acid sequence that is at least 80% identical to SEQ ID NO:18.

[0091] In some embodiments the first domain is: a) HC1 of SEQ ID NO: 17; and / or b) Contains LC1 of sequence number 18.

[0092] In some embodiments the first domain is: a) HC1 of SEQ ID NO: 17; and b) Contains LC1 of sequence number 18.

[0093] HC1:QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYF DYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 17)

[0094] LC1: AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 18)

[0095] c-Met binding arm In one embodiment, the second domain that specifically binds c-Met is: a) the amino acid sequences of HCDR1, HCDR2, and HCDR3 of SEQ ID NOs: 7, 8, and 9, respectively; and / or b) comprising the amino acid sequences of LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, and 12, respectively.

[0096] In one embodiment, the second domain that specifically binds c-Met is: a) the amino acid sequences of HCDR1, HCDR2, and HCDR3 of SEQ ID NOs: 7, 8, and 9, respectively; and b) comprising the amino acid sequences of LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, and 12, respectively.

[0097] HCDR1: SYGIS (SEQ ID NO: 7)

[0098] HCDR2: WISAYNGYTNYAQKLQG (SEQ ID NO: 8)

[0099] HCDR3: DLRGTNYFDY (SEQ ID NO: 9)

[0100] HCDR1: RASQGISNWLA (SEQ ID NO: 10)

[0101] HCDR2: AASSLLS (SEQ ID NO: 11)

[0102] HCDR3: QQANSFPIT (SEQ ID NO: 12)

[0103] In some embodiments, the second domain comprises a VH amino acid sequence that is at least 90% identical to SEQ ID NO: 15, e.g., about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO: 15. In some embodiments, the sequence identity is about 90-99.9%, 90-99.8%, 92-99.8%, 92-99.6%, 94-99.6%, 94-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2%, or 97-99%. In a specific embodiment, the second domain comprises a VH of SEQ ID NO:15.

[0104] In certain embodiments, the second domain comprises a VL amino acid sequence that is at least 90% identical to SEQ ID NO: 16, e.g., about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO: 16. In some embodiments, the sequence identity is about 90-99.9%, 90-99.8%, 92-99.8%, 92-99.6%, 94-99.6%, 94-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2%, or 97-99%. In a specific embodiment, the second domain comprises a VL of SEQ ID NO:16.

[0105] In some embodiments, the second domain is: a) a VH amino acid sequence that is at least 90% identical to SEQ ID NO: 15; and / or b) a VL amino acid sequence that is at least 90% identical to SEQ ID NO:16.

[0106] In some embodiments, the second domain is: a) a VH amino acid sequence that is at least 90% identical to SEQ ID NO: 15; and b) a VL amino acid sequence that is at least 90% identical to SEQ ID NO:16.

[0107] In some embodiments, the second domain is: a) the VH of SEQ ID NO: 15; and / or b) comprises a VL of SEQ ID NO: 16.

[0108] In certain embodiments, the second domain comprises: a) VH of SEQ ID NO: 15; and b) comprises a VL of SEQ ID NO: 16.

[0109] VH: QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVSS (SEQ ID NO: 15)

[0110] VL:DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIK (SEQ ID NO: 16)

[0111] In some embodiments, the second domain comprises a second heavy chain (HC2) amino acid sequence that is at least 80% identical to SEQ ID NO:19, e.g., about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO:19. In certain embodiments, the sequence identity is about 80-99.9%, 80-99.8%, 85-99.8%, 85-99.6%, 90-99.6%, 90-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2%, or 97-99%. In certain embodiments, the second domain comprises the HC2 amino acid sequence of SEQ ID NO:19.

[0112] In some embodiments, the second domain comprises a second light chain (LC2) amino acid sequence that is at least 80% identical to SEQ ID NO:20, e.g., about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO:20. In certain embodiments, the sequence identity is about 80-99.9%, 80-99.8%, 85-99.8%, 85-99.6%, 90-99.6%, 90-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2%, or 97-99%. In certain embodiments, the second domain comprises the LC2 amino acid sequence of SEQ ID NO:20.

[0113] In some embodiments, the second domain is: a) an HC2 amino acid sequence that is at least 80% identical to SEQ ID NO:19; and / or b) an LC2 amino acid sequence that is at least 80% identical to SEQ ID NO:20.

[0114] In some embodiments, the second domain is: a) an HC2 amino acid sequence that is at least 80% identical to SEQ ID NO:19; and b) an LC2 amino acid sequence that is at least 80% identical to SEQ ID NO:20.

[0115] In some embodiments, the second domain is: a) HC2 of SEQ ID NO: 19; and / or b) Contains LC2 of sequence number 20.

[0116] In some embodiments, the second domain is: a) HC2 of SEQ ID NO: 19; and b) Contains LC2 of sequence number 20.

[0117] HC2:QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 19)

[0118] LC2: DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 20)

[0119] In some embodiments, an antibody (e.g., a bispecific antibody) comprises: a) a first domain that specifically binds to EGFR, comprising the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively; and / or b) a second domain that specifically binds to c-Met, comprising the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 amino acid sequences of SEQ ID NOs: 7, 8, 9, 10, 11, and 12, respectively.

[0120] In one embodiment, an antibody (e.g., a bispecific antibody) comprises: a) a first domain that specifically binds to EGFR, comprising the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively; and b) a second domain that specifically binds to c-Met, comprising the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 amino acid sequences of SEQ ID NOs: 7, 8, 9, 10, 11, and 12, respectively.

[0121] In some embodiments, an antibody (e.g., a bispecific antibody) comprises: a) a first domain comprising a VH amino acid sequence at least 90% identical to SEQ ID NO: 13; b) a first domain comprising a VL amino acid sequence at least 90% identical to SEQ ID NO: 14; c) a second domain comprising a VH amino acid sequence that is at least 90% identical to SEQ ID NO: 15; and / or d) a second domain comprising a VL amino acid sequence that is at least 90% identical to SEQ ID NO:16.

[0122] In one embodiment, an antibody (e.g., a bispecific antibody) comprises: a) a first domain comprising a VH amino acid sequence at least 90% identical to SEQ ID NO: 13; b) a first domain comprising a VL amino acid sequence at least 90% identical to SEQ ID NO: 14; c) a second domain comprising a VH amino acid sequence that is at least 90% identical to SEQ ID NO: 15; and d) a second domain comprising a VL amino acid sequence that is at least 90% identical to SEQ ID NO:16.

[0123] In some embodiments, an antibody (e.g., a bispecific antibody) comprises: a) a first domain comprising a VH of SEQ ID NO: 13; b) a first domain comprising a VL of SEQ ID NO: 14; c) a second domain comprising a VH of SEQ ID NO: 15; and / or d) a second domain comprising the VL of SEQ ID NO:16.

[0124] In some embodiments, an antibody (e.g., a bispecific antibody) comprises: a) a first domain comprising a VH of SEQ ID NO: 13; b) a first domain comprising a VL of SEQ ID NO: 14; c) a second domain comprising a VH of SEQ ID NO: 15; and d) a second domain comprising the VL of SEQ ID NO:16.

[0125] In one embodiment, an antibody (e.g., a bispecific antibody) comprises: a) an HC1 amino acid sequence that is at least 80% identical to SEQ ID NO:17; b) an LC1 amino acid sequence that is at least 80% identical to SEQ ID NO:18; c) an HC2 amino acid sequence that is at least 80% identical to SEQ ID NO: 19; and / or d) an LC2 amino acid sequence that is at least 80% identical to SEQ ID NO:20.

[0126] In one embodiment, an antibody (e.g., a bispecific antibody) comprises: a) an HC1 amino acid sequence that is at least 80% identical to SEQ ID NO:17; b) an LC1 amino acid sequence that is at least 80% identical to SEQ ID NO:18; c) an HC2 amino acid sequence that is at least 80% identical to SEQ ID NO:19; and d) an LC2 amino acid sequence that is at least 80% identical to SEQ ID NO:20.

[0127] In one embodiment, an antibody (e.g., a bispecific antibody) comprises: a) HC1 of SEQ ID NO: 17; b) LC1 of SEQ ID NO: 18; c) HC2 of SEQ ID NO: 19; and / or d) LC2 of sequence number 20.

[0128] In certain embodiments, an antibody (e.g., a bispecific antibody) comprises: a) HC1 of SEQ ID NO: 17; b) LC1 of SEQ ID NO: 18; c) HC2 of SEQ ID NO: 19; and d) LC2 of sequence number 20.

[0129] In some embodiments, the antibody (e.g., bispecific antibody) is of the IgG isotype. In certain embodiments, the antibody (e.g., bispecific antibody) is of the IgG1 isotype. There is some variation (e.g., known allotypes) within the IgG1 constant domain, for example at positions 214, 356, 358, 422, 431, 435, and / or 436 (residue numbering according to EU numbering) (see, e.g., IMGT Web resources; IMGT Repertoire (IG and TR); Proteins and alleles; allotypes). The bispecific anti-EGFR / c-Met antibody may be of any IgG1 allotype, such as G1m17, G1m3, G1m1, G1m2, G1m27, or G1m28.

[0130] In some embodiments, the antibody is a human antibody.

[0131] In certain embodiments, the antibody is amivantamab. Amivantamab or JNJ-61186372 (JNJ-372) is an IgG1 anti-EGFR / c-Met bispecific antibody described in U.S. Patent No. 9,593,164. The structure of amivantamab is shown in FIG. 2. The present disclosure is based, at least in part, on the discovery that amivantamab is effective in treating CRC, such as mCRC.

[0132] Other anti-EGFR / c-Met antibodies (e.g., bispecific antibodies) can also be used in the methods of the disclosure, for example, by combining publicly available EGFR-binding VH / VL domains and c-Met-binding VH / VL domains.

[0133] In some embodiments, the antibody (eg, a bispecific antibody) comprises a biantennary glycan structure having a fucose content of about 1% to about 15%.

[0134] Antibodies with low fucose content can be produced using various methods that have been reported to successfully express relatively highly defucosylated antibodies with biantennary complex type Fc oligosaccharides, such as: control of the osmolarity of the culture (Konno et al., Cytotechnology 64(:249-65, 2012), application of the variant CHO line Lec13 as a host cell line (Shields et al., J Biol Chem 277:26733-26740, 2002), application of the variant CHO line EB66 as a host cell line (Olivier et al., MAbs;2(4), 2010; Epub ahead of print; PMID:20562582), application of the rat hybridoma cell line YB2 / 0 as a host cell line (Shinkawa et al., J Biol Chem 278:3466-3473, 2003), introduction of small interfering RNA specific for the α1,6-fucosyltransferase (FUT8) gene (Mori et al., Biotechnol Bioeng 88:901-908, 2004), or co-expression of β-1,4-N-acetylglucosaminyltransferase III and Golgi α-mannosidase II or kifunensine, a potent α-mannosidase I inhibitor (Ferrara et al., J Biol Chem 281:5032-5036, 2006; Ferrara et al., Biotechnol Bioeng 93:851-861, 2006; Zhou et al., Biotechnol Bioeng 99:652-65, 2008). In general, reducing the fucose content in the glycans of antibodies enhances antibody-mediated cellular cytotoxicity (ADCC).

[0135] Preparation of anti-EGFR / c-Met antibody The anti-EGFR / c-Met antibodies used in the disclosed methods can be generated using Fab arm exchange (or half molecule exchange) between two monospecific bivalent antibodies, for example, by introducing substitutions in the heavy chain CH3 interface in each half molecule to favor the formation of heterodimers of two antibody half molecules with different specificities, in a cell-free environment in vitro or using co-expression. The Fab arm exchange reaction is the result of a disulfide bond isomerization reaction and dissociation-association of the CH3 domains. The heavy chain disulfide bonds in the hinge region of the parent monospecific antibodies are reduced. The resulting free cysteine ​​of one of the parent monospecific antibodies forms an intra-heavy chain disulfide bond with a cysteine ​​residue of the second parent monospecific antibody molecule, and at the same time, the CH3 domain of the parent antibody is released and reformed by dissociation-association. The CH3 domain of the Fab arm can be engineered to favor heterodimerization over homodimerization. The resulting product is a bispecific antibody with two Fab arms or half molecules that each bind a different epitope, i.e., an epitope in EGFR and an epitope in c-Met. For example, bispecific antibodies of the invention can be generated using the techniques described in WO 2011 / 131746. For IgG1 antibodies, the mutation F405L in one heavy chain and K409R in the other heavy chain can be used. For IgG2 antibodies, wild type IgG2 and IgG2 antibodies with F405L and R409K substitutions may be used. For IgG4 antibodies, wild type IgG4 and IgG4 antibodies with F405L and R409K substitutions may be used. To generate a bispecific antibody, a first monospecific bivalent antibody and a second monospecific bivalent antibody are engineered to have the aforementioned mutations in the Fc region, and the antibodies are incubated together under sufficient reducing conditions to allow the cysteines in the hinge region to undergo disulfide bond isomerization, thereby generating the bispecific antibody by Fab arm exchange. Incubation conditions may optimally be returned to non-reducing conditions.Exemplary reducing agents that may be used are 2-mercaptoethylamine (2-MEA), dithiothreitol (DTT), dithioerythritol (DTE), glutathione, tris(2-carboxyethyl)phosphine (TCEP), L-cysteine, and β-mercaptoethanol. For example, incubation at a temperature of at least 20° C., in the presence of at least 25 mM 2-MEA or in the presence of at least 0.5 mM dithiothreitol, at a pH of 5-8, e.g., pH 7.0 or pH 7.4, for at least 90 minutes may be used.

[0136] Bispecific anti-EGFR / c-Met antibodies for use in the methods of the disclosure can also be generated using designs such as knobs-in-holes (Genentech), CrossMAb (Roche) and electrostatically-matched (Chugai, Amgen, NovoNordisk, Oncomed), LUZ-Y (Genentech), Strand Exchange Engineered Domain body (SEEDbody) (EMD Serono), and Biclonic (Merus).

[0137] In the "knobs-in-holes" approach (see, for example, WO 2006 / 028936), selected amino acids that form the interface of the CH3 domain of human IgG can be mutated at positions that affect CH3 domain interactions to promote heterodimer formation. Amino acids with small side chains (holes) are introduced into the heavy chain of an antibody that specifically binds to a first antigen, and amino acids with large side chains (knobs) are introduced into the heavy chain of an antibody that specifically binds to a second antigen. After co-expression of the two antibodies, heterodimers are formed as a result of the preferential interaction of heavy chains with "holes" and heavy chains with "knobs". Exemplary CH3 substitution pairs that form knobs and holes are T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V (expressed as modification position in the first CH3 domain of the first heavy chain / modification position in the second CH3 domain of the second heavy chain).

[0138] In addition to utilizing the "knobs-in-holes" approach to facilitate Fab arm exchange, CrossMAb technology utilizes CH1 / CL domain swapping in one of the half-arms to ensure correct light chain pairing of the resulting bispecific antibody (see, e.g., U.S. Pat. No. 8,242,247).

[0139] Other crossover techniques may be used to generate full length bispecific antibodies of the invention by swapping variable or constant, or both, domains in one or both arms between the heavy and light chains of the bispecific antibody or within the heavy chain, including, for example, VH-CH1 and VL-CL, VH and VL, CH3 and CL, and CH3 and CH1 as described in WO 2009 / 080254, WO 2009 / 080251, WO 2009 / 018386, and WO 2009 / 080252.

[0140] Other approaches, such as promoting heavy chain heterodimerization using electrostatic interactions by substituting positively charged residues on one CH3 surface and negatively charged residues on the second CH3 surface, may be used as described in U.S. Patent Application Publication No. 2010 / 0015133, U.S. Patent Application Publication No. 2009 / 0182127, U.S. Patent Application Publication No. 2010 / 028637, or U.S. Patent Application Publication No. 2011 / 0123532. In another approach, heterodimerization can be achieved by the following substitutions: L351Y_F405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y ... A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, or T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W (represented as modification position in the first CH3 domain of the first heavy chain / modification position in the second CH3 domain of the second heavy chain).

[0141] SEEDbody technology may be utilized to generate bispecific antibodies of the invention. SEEDbodies have selected IgG residues in their constant domains substituted with IgA residues to promote heterodimerization, as described in US Patent Application Publication No. 20070287170.

[0142] Mutations are typically made at the DNA level, using standard methods, on molecules such as the constant domain of an antibody.

[0143] Administration The anti-EGFR / c-Met antibody (e.g., a bispecific antibody) and / or an additional therapeutic agent (e.g., a chemotherapeutic agent) may be administered in a pharmaceutical composition or compositions. In some embodiments, the pharmaceutical composition further comprises a pharma- ceutical acceptable carrier.

[0144] The mode of administration may be any suitable route of delivery of an antibody (e.g., a bispecific antibody) to a subject in need thereof, for example, parenteral administration, e.g., intradermal, intramuscular, intraperitoneal, intravenous, or subcutaneous, pulmonary, transmucosal (oral, intranasal, intravaginal, rectal), using tablet, capsule, liquid, powder, gel, particle formulations, which may be contained in a syringe, implantable device, osmotic pump, cartridge, micropump; or other means well known in the art and recognized by the skilled artisan. Site-specific administration may be achieved, for example, by intratumoral, intracolonic, intraperitoneal, intragastric, intracavitary, intrapelvic, intraperitoneal, intrarectal, intrathoracic, intravascular, intralesional, rectal, buccal, sublingual, intranasal, or transdermal delivery.

[0145] In some embodiments, a pharmaceutical composition comprising an anti-EGFR / c-Met antibody (e.g., a bispecific antibody) is administered via intravenous infusion. In some embodiments, an additional therapeutic agent (e.g., a chemotherapeutic agent) is administered via intravenous infusion.

[0146] In some embodiments, a pharmaceutical composition comprising an anti-EGFR / c-Met antibody (eg, a bispecific antibody) is administered via subcutaneous injection.

[0147] In some embodiments, the antibody (eg, a bispecific antibody) is administered at a dose of about 140 mg to about 1750 mg, for example, about 700 mg to about 1400 mg, about 700 mg to about 1050 mg, or about 1050 mg to about 1400 mg.

[0148] In some embodiments, the antibody (e.g., bispecific antibody) has a length of about 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660 , 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070, 1080, 1090, 1100, 1110, 1120, 1130, 1140, 1150, 1160 , 1170, 1180, 1190, 1200, 1210, 1220, 1230, 1240, 1250, 1260, 1270, 1280, 1290, 1300, 1310, 1320, 1330, 1340, 1350, 1360, 1370, 1380, 1390, 1400, 1410, 1420, 1430, 1440, 1450, 1460, 1470, 1480, 1490, 1500, 1510, 1520, 1530, 1540, 1550, 1560, 1570, 1580, 1590, 1 and / or 2000 mg.

[0149] In some embodiments, the antibody is administered at a dose of about 700 mg, about 1050 mg, or about 1400 mg. In some embodiments, the antibody is administered at a dose of about 1050 mg. In certain embodiments, the antibody is administered at a dose of about 1400 mg. In certain embodiments, the antibody is administered at a dose of about 700 mg.

[0150] In some embodiments, the antibody is administered at a dose of about 350 mg.

[0151] In some embodiments, the antibody is administered at a dose of about 750 mg.

[0152] In some embodiments, the antibody is administered at a dose of about 800 mg.

[0153] In some embodiments, the antibody is administered at a dose of about 850 mg.

[0154] In some embodiments, the antibody is administered at a dose of about 900 mg.

[0155] In some embodiments, the antibody is administered at a dose of about 950 mg.

[0156] In some embodiments, the antibody is administered at a dose of about 1000 mg.

[0157] In some embodiments, the antibody is administered at a dose of about 1100 mg.

[0158] In some embodiments, the antibody is administered at a dose of about 1150 mg.

[0159] In some embodiments, the antibody is administered at a dose of about 1200 mg.

[0160] In some embodiments, the antibody is administered at a dose of about 1250 mg.

[0161] In some embodiments, the antibody is administered at a dose of about 1300 mg.

[0162] In some embodiments, the antibody is administered at a dose of about 1350 mg.

[0163] In one embodiment, the antibody is administered at a dose of 1050 mg for those weighing less than 80 kg and 1400 mg for those weighing 80 kg or more.

[0164] In a specific embodiment, the antibody is administered at a dose of 700 mg for those weighing less than 80 kg and 1050 mg for those weighing 80 kg or more.

[0165] In some embodiments, the antibody is administered twice weekly.

[0166] In one embodiment, the antibody is administered once a week.

[0167] In some embodiments, the antibody is administered once every two weeks.

[0168] In one embodiment, the antibody is administered once every three weeks.

[0169] In some embodiments, the antibody is administered once every four weeks.

[0170] In certain embodiments, the antibody is administered once a week or once every two weeks. In certain embodiments, the antibody is administered once a week for the first four weeks, then once every two weeks.

[0171] In some embodiments, the antibody is administered in a 28 day cycle.

[0172] In some embodiments, the subject has a body weight (BW) of less than 80 kg and the antibody (e.g., a bispecific antibody such as amivantamab) is administered at a dose of 700 mg once per week for the first 4 weeks, then once every 2 weeks for a 28 day cycle. In other embodiments, the subject has a body weight of less than 80 kg and the antibody (e.g., a bispecific antibody such as amivantamab) is administered at a dose of 1050 mg once per week for the first 4 weeks, then once every 2 weeks for a further 28 day cycle. In some embodiments, the antibody is administered once per week for the first 4 weeks, then on days 1 and 15 (28 day cycle). In other embodiments, the subject is administered amivantamab by intravenous infusion on days 1, 2, 8, and 22 of cycle 1 at a dose of 1050 mg or 700 mg if the subject weighs less than 80 kg, or at a dose of 1400 mg or 1050 mg if the subject weighs 80 kg or more, and is administered amivantamab by intravenous infusion with FOLFOX6 chemotherapy (e.g., mFOLFOX6 SoC chemotherapy agent) on days 1 and 15 of cycle 1 and days 1 and 15 of cycle 2 (each cycle is 28 days). In other embodiments, the subject is administered amivantamab by intravenous infusion with FOLFIRI chemotherapy on days 1, 2, and 8 of cycle 1 and days 1 and 15 of cycle 2.

[0173] In one embodiment, the subject has a body weight (BW) of 80 kg or more and is administered an antibody (e.g., a bispecific antibody such as amivantamab) at a dose of 1050 mg once per week for the first four weeks, then once every two weeks for a 28 day cycle. In another embodiment, the subject has a body weight of 80 kg or more and is administered an antibody (e.g., a bispecific antibody such as amivantamab) at a dose of 1400 mg once per week for the first four weeks, then once every two weeks for a 28 day cycle. In other embodiments, the subject is administered amivantamab by intravenous infusion on days 1, 2, 8, and 22 of cycle 1 at a dose of 1050 mg or 700 mg if the subject weighs less than 80 kg, or at a dose of 1400 mg or 1050 mg if the subject weighs 80 kg or more, and is administered amivantamab by intravenous infusion with FOLFOX6 chemotherapy (e.g., mFOLFOX6 SoC chemotherapy agent) on days 1 and 15 of cycle 1 and days 1 and 15 of cycle 2 (each cycle is 28 days). In other embodiments, the subject is administered amivantamab by intravenous infusion with FOLFIRI chemotherapy on days 1, 2, and 8 of cycle 1 and days 1 and 15 of cycle 2.

[0174] Pharmaceutical compositions containing 1400 mg, 1050 mg, and 700 mg doses of an anti-EGFR / c-Met antibody can be administered in total volumes of approximately 28 mL, 21 mL, and 14 mL, respectively, using a 350 mg / 7 mL (50 mg / mL) solution in a single-dose vial.

[0175] Additional information regarding amivantamab can be found, for example, in the prescribing information of the RYBREVANT® product insert (amivantamab-vmjw) (www.janssenlabels.com / package-insert / product-monograph / prescribing-information / RYBREVANT-pi.pdf), which is incorporated herein by reference.

[0176] Further information regarding the use of amivantamab in patients can be found, for example, in Amivantamab in EGFR Exon 20 Insertion-Mutated Non-Small-Cell Lung Cancer Progressing on Platinum Chemotherapy: Initial Results From the CHRYSALIS Phase I Study. J Clin Oncol. 2021 Oct 20;39(30):3391-3402; Vyse S, Huang PH. Amivantamab for the treatment of EGFR exon 20 insertion mutant non-small cell lung cancer. Expert Rev Anticancer Ther. 2021 Dec 16; and Cho BC et al., MARIPOSA: phase 3 study of first-line amivantamab+lazertinib versus osimertinib in EGFR-mutant non-small cell lung cancer. Future Oncol. 2021 Dec 16, which are incorporated by reference herein.

[0177] In some embodiments, the antibody is administered as a monotherapy.

[0178] Additional Therapeutic Agents In some embodiments, the one or more chemotherapeutic agents include folinic acid (leucovorin, FOL), fluorouracil (5-FU, F), and oxaliplatin (eloxatin, OX). Chemotherapy regimens for colorectal cancer, such as FOLFOX, e.g., FOLFOX6, e.g., mFOLFOX6, are known to those skilled in the art. Further information regarding FOLFOX can be found, for example, in de Gramont et al., J Clin Oncol. 18(16):2938-47(2000), Tournigand et al., J Clin Oncol. 22(2):229-37(2004), Goldberg et al., J Clin Oncol. 22(1):23-30(2004), Tsai et al., Springerplus. 5(1):1318(2016), Neugut et al., Clin Colorectal Cancer 18(2):133-40(2019), and Sobrero et al., Journal of Clinical Oncology 36(15):1478-85(2018), each of which is incorporated herein by reference.

[0179] In some embodiments, the one or more chemotherapeutic agents include folinic acid (leucovorin, FOL), fluorouracil (5-FU, F), and irinotecan (camptosar, IRI). FOLFIRI, a chemotherapy regimen for the treatment of colorectal cancer, is known to those skilled in the art. Further information regarding FOLFIRI can be found, for example, in Touringand et al., J Clin Oncol. 22(2):229-37(2004); Kamnerdsupaphon et al., J Med Assoc Thai. 90(10):2121-7(2007); Kirstein et al., Oncologist 19(11):1156-68(2014); Chen et al., Medicine (Baltimore) 95(46):e5221(2016), each of which is incorporated herein by reference.

[0180] In some embodiments, the method further comprises administering to the subject one or more additional therapeutic agents. Non-limiting examples of the one or more additional therapeutic agents include chimeric antigen receptor (CAR)-expressing T cells (CAR-T cells), CAR-expressing natural killer cells (CAR-NK cells), CAR-expressing macrophages (CAR-M cells), chemotherapeutic agents, immune checkpoint inhibitors, T cell redirectors, radiation therapy, surgery, and standard of care treatments. In some embodiments, the one or more additional therapeutic agents comprise chemotherapy, radiation therapy, surgery, targeted anti-cancer therapy, kinase inhibitors, or any combination thereof.

[0181] In some embodiments, the one or more additional therapeutic agents are one or more anti-cancer therapies, hi some embodiments, the one or more additional therapeutic agents comprise one or more chemotherapeutic agents.

[0182] A non-exhaustive list of chemotherapeutic agents contemplated for use in combination therapy includes anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purintor®), methotrexate (Folex®), mitoxantrone (Novantron®), Milotarg, paclitaxel (Taclitaxel®), and rifampicin (Ricardo®). , phoenix (yttrium-90 / MX-DTPA), pentostatin, porifeprosan 20 with carmustine implant (Gliadel®), dactinomycin (Actinomycin D, Cosmegen), daunorubicin hydrochloride (Cerbizin®), daunorubicin citrate liposomal injection (Daunoxom®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Bepesid, trademark), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), )), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adolcil®, Efudex®), flutamide (Eurexin®), tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea (Hydrea®), idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®),L-asparaginase (ELSPAR®), tamoxifen citrate (Nolvadex®), teniposide (Bumone®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), injectable topotecan hydrochloride (Hycamtin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®).

[0183] Examples of alkylating agents include, but are not limited to, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes, uracil mustard (Aminouracil Mustard®, Chlorethaminacil®, Hemanthamin®, Nordpan®, Uracil Nitrogen Mustard®, Uracillost®, Uracilmostaza®, Uramustin®, Uramustine®), chlormethine (Mustalgen®), cyclophosphamide (Cytoxan®, Neosar®, Clafen®, Endoxan®, Procytox®, Revimmune®), isoflurane (Isofen®), and the like. These include phosphamide (Mitoxantrone®), melphalan (Alkeran®), chlorambucil (Leukeran®), pipobroman (Amedel®, Vercite®), triethylenemelamine (Hemel®, Hexylene®, Hexastat®), desmethyldopan®, desmethyldopan®, triethylenethiophosphoramine, temozolomide (Temodar®), thiotepa (Thioplex®), busulfan (Busilbex®, Myleran®), carmustine (BiCNU®), lomustine (CeeNU®), streptozocin (Zanosar®), and dacarbazine (DTIC-Dome®).Further examples of alkylating agents include, but are not limited to, oxaliplatin (Eloxatin®); melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, Alkeran®); altretamine (hexamethylmelamine (HMM), also known as Hexylen®); carmustine (BiCNU®); bendamustine (Treanda®); busulfan (Busulfex® and Myleran®); carboplatin (Paraplatin®); temozolomide (Temodar® and Temodal®); dactinomycin (Actinomycin-D, also known as Cosmegen®); lomustine (CCNU, also known as CeeNU®); cisplatin (CDDP, also known as Platinol® and Platinol®-AQ); chlorambucil (Leukeran®); cisplatin (CDDP, also known as Platinol® and Platinol®-AQ); chlorambucil (Leukeran®); Clophosphamide (Cytoxan® and Neosar®); Dacarbazine (also known as DTIC, DIC, and imidazole carboxamide, DTIC-DOME®); Altretamine (hexamethylmelamine (HMM), also known as Hexylen®); Ifosfamide (Ifex®); Prednummustine; Procarbazine (Matulane®); Mechlorethamine (nitrogen mustard, mustine, and mechlorethamine hydrochloride, also known as Mustargen®); streptozocin (Zanosar®); thiotepa (thiophosphoamide, TESPA, and TSPA, also known as Thioplex®), cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®, Revimmune®); and bendamustine HCl (Treanda®).

[0184] In some embodiments, the one or more additional therapeutic agents comprise a kinase inhibitor. In some embodiments, the kinase inhibitor comprises an inhibitor of EGFR, an inhibitor of c-Met, an inhibitor of HER2, an inhibitor of HER3, an inhibitor of HER4, an inhibitor of VEGFR, an inhibitor of AXL, or a combination thereof. In certain embodiments, the kinase inhibitor is an inhibitor of EGFR. In certain embodiments, the kinase inhibitor is an inhibitor of c-Met. In some embodiments, the kinase inhibitor is an inhibitor of HER2. In certain embodiments, the kinase inhibitor is an inhibitor of HER3. In certain embodiments, the kinase inhibitor is an inhibitor of HER4. In some embodiments, the kinase inhibitor is an inhibitor of VEGFR. In certain embodiments, the kinase inhibitor is an inhibitor of AXL.

[0185] In some embodiments, the kinase inhibitor comprises erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, cliotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, sunitinib, or combinations thereof. In some embodiments, the kinase inhibitor is erlotinib. In certain embodiments, the kinase inhibitor is gefitinib. In some embodiments, the kinase inhibitor is lapatinib. In some embodiments, the kinase inhibitor is vandetanib. In some embodiments, the kinase inhibitor is afatinib. In some embodiments, the kinase inhibitor is osimertinib. In some embodiments, the kinase inhibitor is lazertinib. In certain embodiments, the kinase inhibitor is poziotinib. In some embodiments, the kinase inhibitor is cliotinib. In certain embodiments, the kinase inhibitor is cabozantinib. In some embodiments, the kinase inhibitor is capmatinib. In some embodiments, the kinase inhibitor is axitinib. In certain embodiments, the kinase inhibitor is lenvatinib. In some embodiments, the kinase inhibitor is nintedanib. In certain embodiments, the kinase inhibitor is regorafenib. In certain embodiments, the kinase inhibitor is pazopanib. In some embodiments, the kinase inhibitor is sorafenib. In certain embodiments, the kinase inhibitor is sunitinib.

[0186] In certain embodiments, the one or more prior anticancer therapies comprise carboplatin, paclitaxel, gemcitabine, cisplatin, vinorelbine, docetaxel, palbociclib, crizotinib, PD-(L)1 axis inhibitors, EGFR inhibitors, c-Met inhibitors, HER2 inhibitors, HER3 inhibitors, HER4 inhibitors, VEGFR inhibitors, AXL inhibitors, erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, cliotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib, or any combination thereof.

[0187] Anti-cancer therapies that may be administered in combination with anti-EGFR / c-Met antibodies (e.g., bispecific antibodies) in the methods of the present disclosure include any one or more of chemotherapeutic agents or other anti-cancer therapeutic agents known to those of skill in the art. Chemotherapeutic agents are chemical compounds useful in the treatment of cancer, including growth inhibitors or other cytotoxic agents, including alkylating agents, antimetabolites, anti-microtubule inhibitors, topoisomerase inhibitors, receptor tyrosine kinase inhibitors, angiogenesis inhibitors, and the like. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembitine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;Antibiotics such as aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin , streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-FU; folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, etc; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; adrenal cortical hormone synthesis inhibitors such as aminoglutethimide, mitotane, trilostane; folic acid supplements (folic acid replenishers, such as folinic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; amsacrine; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin;Podophyllic acid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; schizophyllan; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; members of the taxoid or taxane family, such as paclitaxel (TAXOL®), docetaxel (TAXOTE®), RE (registered trademark) and its analogues; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogues such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitors RFS2000; difluoromethylornithine (DMFO); retinoic acid; esperamicin; capecitabine;Inhibitors of receptor tyrosine kinases and / or inhibitors of angiogenesis, including sorafenib (NEXAVAR®), sunitinib (SUTENT®), pazopanib (VOTRIENT™), toceranib (PALLADIA™), vandetanib (ZACTIMA™), cediranib (RECENTIN®), regorafenib (BAY73-4506), axitinib (AG013736), lestaurtinib (CEP-701), erlotinib (TARCEVA®), gefitinib (IRESSA®), afatinib (BIBW 2992), lapatinib (TYKERB®), neratinib (HKI-272), and the like, as well as pharmaceutical acceptable salts, acids, or derivatives of any of the foregoing. Also included in this definition are anti-hormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens, including tamoxifen, raloxifene, aromatase-inhibiting 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY 117018, onapristone, and toremifene (FARESTON®); and antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as pharma- ceutical acceptable salts, acids, or derivatives of any of the above. Other conventional cytotoxic compounds disclosed in Wiemann et al., 1985, Medical Oncology (Calabresi et al, eds.), Chapter 10, McMillan Publishing, are also applicable to the methods of the present invention.

[0188] In some embodiments, the anti-EGFR / c-Met antibody (e.g., a bispecific antibody) and one or more additional therapeutic agents (e.g., chemotherapeutic agents) are administered simultaneously. In other embodiments, the antibody and one or more additional therapeutic agents are administered separately (e.g., sequentially).

[0189] In the case of combination therapy, one or more anti-cancer agents may be administered using the recommended doses and administration amounts of the anti-cancer agents.

[0190] subject The terms "subject" and "patient" can be used interchangeably herein. A "patient in need thereof" or "subject in need thereof" refers to a mammalian subject, preferably a human, diagnosed with or suspected of having a disease to which a bispecific anti-EGFR, anti-MET antibody is or has been administered in accordance with the methods of the invention. A "patient in need thereof" or "subject in need thereof" includes subjects already having an undesirable physiological change or disease, as well as subjects predisposed to having said physiological change or disease.

[0191] In some embodiments, the subject is 18 years of age or older, e.g., 18-40 years of age or younger, 18-45 years of age or younger, 18-50 years of age or younger, 18-55 years of age or younger, 18-60 years of age or younger, 18-65 years of age or younger, 18-70 years of age or younger, 18-75 years of age or younger, 40-75 years of age or younger, 45-75 years of age or younger, 50-75 years of age or younger, 55-75 years of age or younger, 60-75 years of age or younger, 65-75 years of age or younger, 60-75 years of age or younger, 40 years of age or older, 45 years of age or older, 50 years of age or older, 55 years of age or older, 60 years of age or older, 60 years of age or older, 65 years of age or older, 70 years of age or older, or 75 years of age or older.

[0192] In some embodiments, the subject is a child. In some embodiments, the subject is 18 years of age or younger, e.g., 0-18 years of age, 0-12 years of age, 0-16 years of age, 0-17 years of age, 2-12 years of age, 2-16 years of age, 2-17 years of age, 2-18 years of age, 3-12 years of age, 3-16 years of age, 3-17 years of age, 3-18 years of age, 4-12 years of age, 4-16 years of age, 4-17 years of age, 4-18 years of age, 6-12 years of age, 6-16 years of age, 6-17 years of age, 6-18 years of age, 9-12 years of age, 9-16 years of age, 9-17 years of age, 9-18 years of age, 12-16 years of age, 12-17 years of age, or 12-18 years of age.

[0193] In some embodiments, the subject has been diagnosed with CRC (e.g., mCRC) for at least about 1 month, e.g., at least about 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 18 months, 2 years, 30 months, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years. In certain embodiments, the subject is newly diagnosed with CRC (e.g., mCRC). In some embodiments, the CRC is an adenocarcinoma.

[0194] In certain embodiments, the subject is treatment naive.

[0195] In some embodiments, the subject has previously undergone one or more anti-cancer therapies. In some embodiments, the one or more previous anti-cancer therapies include one or more chemotherapeutic agents, checkpoint inhibitors, targeted anti-cancer therapies, or kinase inhibitors, or any combination thereof. In certain embodiments, the subject is relapsed or resistant to treatment with one or more previous anti-cancer therapies.

[0196] In some embodiments, the subject is resistant or has acquired resistance to an EGFR inhibitor. Exemplary EGFR inhibitors to which cancers may develop resistance include the anti-EGFR antibodies cetuximab (ERBITUX®), panchinumumab (VECTIBIX®), matuzumab, and nimotuzumab; the small molecule EGFR inhibitors erlotinib (TARCEVA®), gefitinib (IRESSA®), EKB-569 (pelitinib, an irreversible EGFR TKI); the pan-ErbB and other receptor tyrosine kinase inhibitors lapatinib (EGFR and HER2 inhibitor), pelitinib (EGFR and HER2 inhibitor), vandetanib (ZD6474, ZACTIMA™, an EGFR, VEGFR2, and RET TKI); PF00299804 (dacomitinib, an irreversible pan-ErbB TKI); CI-1033 (an irreversible pan-erbB TKI); TKI), afatinib (BIBW2992, irreversible pan-ErbB TKI), AV-412 (dual EGFR and ErbB2 inhibitor), EXEL-7647 (EGFR, ErbB2, GEVGR, and EphB4 inhibitor), CO-1686 (irreversible mutant-selective EGFR TKI), AZD9291 (irreversible mutant-selective EGFR TKI), and HKI-272 (neratinib, irreversible EGFR / ErbB2 inhibitor). In some embodiments, the subject is anti-EGFR therapy naive.

[0197] Various qualitative and / or quantitative methods can be used to determine whether a subject is resistant, develops resistance, or is prone to develop resistance to treatment with anticancer therapy. Symptoms that may be associated with resistance to anticancer therapy include a decline or plateau in the patient's health, an increase in tumor size, a halt or slowdown in tumor growth reduction, and / or the spread of cancerous cells from one location to other organs, tissues, or cells in the body. Re-establishment or worsening of various symptoms associated with cancer, such as loss of appetite, cognitive impairment, depression, dyspnea, fatigue, hormone disruption, neutropenia, pain, peripheral neuropathy, and sexual dysfunction, can also be indicators that a subject is developing or is prone to develop resistance to anticancer therapy. Symptoms associated with cancer can vary depending on the type of cancer. For example, symptoms associated with cervical cancer can include abnormal bleeding, abnormal heavy vaginal discharge, pelvic pain not associated with the normal menstrual cycle, bladder pain or pain during urination, and bleeding during regular menstrual periods, sexual intercourse, vaginal douching, or pelvic exam. Symptoms associated with lung cancer can include persistent cough, hemoptysis, shortness of breath, wheezing chest pain, loss of appetite, unintentional weight loss, and fatigue.Symptoms associated with liver cancer can include loss of appetite and weight, abdominal pain, especially in the upper right part of the abdomen, which can extend to the back and shoulders, nausea and vomiting, general weakness and fatigue, liver enlargement, abdominal swelling (ascites), and yellowing of the skin and whites of the eyes (jaundice).Those skilled in the art of oncology can easily identify the symptoms associated with certain types of cancer.

[0198] Exemplary PD-(L)1 axis inhibitors are antibodies that bind to PD-1, such as nivolumab (OPDIVO®), pembrolimab (KEYTRUDA®), sintilimab, cemiplimab (LIBTAYO®), tripolibamab, tislelizumab, spartalizumab, camrelizumab, dostralimab, genolimuzumab, or cetrelimab, or antibodies that bind to PD-L1, e.g., PD-L1 antibodies are embafolimab, atezolizumab (TECENTRIQ®), durvalumab (IMFINZI®), and avelumab (BAVENCIO®).

[0199] Commercially available antibodies can be purchased through an authorized distributor or pharmacy. The amino acid sequence structures of the small molecules can be found in the USAN and / or INN deposits by the companies in the CAS registry.

[0200] In some embodiments, the subject has an EGFR or c-Met expressing cancer.

[0201] Exemplary c-Met activating mutations include point mutations, deletion mutations, insertion mutations, inversions, or gene amplifications that increase at least one biological activity of the c-Met protein, such as increased tyrosine kinase activity, formation of receptor homodimers and heterodimers, and enhanced ligand binding. The mutations can be located in any part of the c-Met gene or in regulatory regions associated with the gene, such as mutations in the kinase domain of c-Met. Exemplary c-Met activating mutations are mutations at residue positions N375, V13, V923, R175, V136, L229, S323, R988, S1058 / T1010, and E168. Methods for detecting EGFR and c-Met mutations or gene amplifications are well known.

[0202] In some embodiments, the subject is characterized with wild-type KRAS, NRAS, and BRAF, hi some embodiments, the subject is characterized with wild-type EGFR.

[0203] diagnosis Certain embodiments of the present disclosure relate to determining the presence of mutations in KRAS, NRAS, BRAF, or EGFR genes. Mutation detection methods are known in the art and include PCR followed by nucleic acid sequencing, FISH, CGH, or next-generation sequencing (NGS). In some embodiments, mutations are detected by DNA sequencing, such as next-generation sequencing (NGS), by using circulating free DNA from tumor tissue samples or plasma.

[0204] In some embodiments, the method further comprises: a) providing a biological sample from a subject; b) determining the presence or absence of a mutation in the KRAS, NRAS, BRAF, or EGFR gene in the sample; and c) administering, or providing for administration, an anti-EGFR / c-Met antibody to a subject determined to have a wild-type KRAS, NRAS, BRAF, or EGFR gene.

[0205] In certain embodiments, the biological sample is a blood sample. In certain embodiments, the biological sample is a tumor tissue biopsy.

[0206] In another aspect, the disclosure also provides a method of treating mCRC in a subject having a wild-type KRAS, NRAS, BRAF, or EGFR gene, comprising administering to the subject a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-MET antibody comprises a first domain that specifically binds EGFR and a second domain that specifically binds c-MET, wherein the first domain comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, and the second domain comprises HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11, and LCDR3 of SEQ ID NO: 12.

[0207] In another aspect, the disclosure also provides a method of treating mCRC in a subject having a wild-type KRAS, NRAS, BRAF, or EGFR gene, comprising administering to the subject a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises a first domain that specifically binds EGFR and a second domain that specifically binds c-Met, wherein the first domain comprises a VH of SEQ ID NO: 13 and a VL of SEQ ID NO: 14, and the second domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0208] In another aspect, the disclosure also provides a method of treating mCRC in a subject having a wild-type KRAS, NRAS, BRAF, or EGFR gene, comprising administering to the subject a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met antibody, wherein the bispecific anti-EGFR / c-Met antibody comprises an HC1 of SEQ ID NO: 17, an LC1 of SEQ ID NO: 18, an HC2 of SEQ ID NO: 19, and an LC2 of SEQ ID NO: 20.

[0209] In another aspect, the disclosure provides a method of treating mCRC in a subject having a wild-type KRAS, NRAS, BRAF, or EGFR gene, comprising administering to the subject a therapeutically effective amount of an isolated bispecific anti-EGFR / c-Met, wherein the bispecific anti-EGFR / c-Met is amivantamab.

[0210] Embodiment 1. A method of treating colorectal cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody. 2. The antibody: a) a first domain that specifically binds to EGFR, comprising the heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively; and and b) a second domain that specifically binds to c-Met comprising the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 amino acid sequences of SEQ ID NOs: 7, 8, 9, 10, 11, and 12, respectively. 3. The method of embodiment 2, wherein the first domain comprises a heavy chain variable region (VH) of SEQ ID NO: 13 and a light chain variable region (VL) of SEQ ID NO: 14, and the second domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16. 4. The method of any one of embodiments 1 to 3, wherein the antibody is of the IgG1 isotype. 5. The method of any one of embodiments 1 to 4, wherein the antibody comprises a first heavy chain (HC1) of SEQ ID NO: 17, a first light chain (LC1) of SEQ ID NO: 18, a second heavy chain (HC2) of SEQ ID NO: 19, and a second light chain (LC2) of SEQ ID NO: 20. 6. The method of any one of embodiments 1 to 5, wherein the antibody is an isolated bispecific antibody. 7. The method of embodiment 6, wherein the bispecific antibody is amivantamab. 8. The method of any one of embodiments 1 to 7, wherein the antibody comprises a biantennary glycan structure having a fucose content of about 1% to about 15%. 9. The method of any one of embodiments 1-8, wherein the antibody is administered at a dose of about 700 mg to about 1400 mg. 10. The method of embodiment 9, wherein the antibody is administered at a dose of about 700 mg, about 1050 mg, or about 1400 mg. 11. The method of embodiment 10, wherein the antibody is administered at a dose of about 1400 mg. 12. The method of embodiment 10, wherein the antibody is administered at a dose of about 1050 mg. 13. The method of embodiment 10, wherein the antibody is administered at a dose of about 700 mg. 14. The method of any one of embodiments 1-13, wherein the antibody is administered once a week or once every two weeks. 15. The method of embodiment 14, wherein the antibody is administered once a week for the first 4 weeks, then once every 2 weeks. 16. The method of any one of embodiments 1-15, wherein the antibody is administered in a 28 day cycle. 17. The method of any one of embodiments 1-16, wherein the antibody is administered as a monotherapy. 18. The method of any one of embodiments 1-16, wherein the method further comprises administering one or more chemotherapeutic agents to the subject. 19. The method of embodiment 18, wherein the one or more chemotherapeutic agents comprises FOLFOX, which comprises folinic acid, fluorouracil, and oxaliplatin. 20. The method of embodiment 18, wherein the one or more chemotherapeutic agents comprises FOLFIRI, which comprises folinic acid, fluorouracil, and irinotecan. 21. The method of any one of embodiments 1-20, wherein the colorectal cancer is metastatic colorectal cancer (mCRC). 22. The method of any one of embodiments 1-21, wherein the subject has been characterized with wild-type KRAS, NRAS, and BRAF. 23. The method of any one of embodiments 1-22, wherein the subject has been diagnosed with left-sided mCRC. 24. The method of any one of embodiments 1-22, wherein the subject has been diagnosed with right-sided mCRC. 25. The method of any one of embodiments 1-24, wherein the subject is anti-EGFR therapy naive. 26. The method of any one of embodiments 1-24, wherein the subject has previously received anti-EGFR therapy. 27. The method of any one of embodiments 1-25, wherein the subject is treatment naive. 28. The method of any one of embodiments 1-26, wherein the subject is relapsed or refractory to treatment with one or more previous anti-cancer therapies. 29. The method of any one of embodiments 1-28, wherein the subject is 18 years of age or older.

[0211] Example 1. Amivantamab in patients with advanced or metastatic colorectal cancer. This is an open-label, multicenter, phase 1b / 2 study of amivantamab as monotherapy and in combination with chemotherapy in patients with metastatic colorectal cancer (mCRC). Part 1 dose confirmation will evaluate safety and confirm the recommended phase 2 dose of amivantamab as monotherapy (RP2D) or the recommended phase 2 combination dose of amivantamab in combination with FOLFOX or FOLFIRI (RP2CD). Part 2 expansion will evaluate the preliminary antitumor activity of amivantamab as monotherapy and in combination with FOLFOX or FOLFIRI in each population. Study details are listed in Table 1 and Figure 1.

[0212] [Table 1-1]

[0213] [Table 1-2]

[0214] [Table 1-3]

[0215] Example 2. Amivantamab monotherapy and amivantamab added to standard of care chemotherapy in participants with advanced or metastatic colorectal cancer. This is an open-label, multicenter, Phase 1b / 2 study of amivantamab as monotherapy and in combination with chemotherapy in patients with metastatic colorectal cancer (mCRC), as described in Table 2.

[0216] [Table 2-1]

[0217] [Table 2-2]

[0218]

Table 2-3

[0219]

Table 2-4

Claims

1. 1. A pharmaceutical composition for use in treating colorectal cancer in a subject in need thereof, the pharmaceutical composition comprising a therapeutically effective amount of an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody.

2. The antibody: a) a first domain that specifically binds to EGFR, comprising the heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively; and b) a second domain that specifically binds c-Met, comprising the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 amino acid sequences of SEQ ID NOs: 7, 8, 9, 10, 11, and 12, respectively; 2. The pharmaceutical composition of claim 1, comprising:

3. 3. The pharmaceutical composition of claim 2, wherein the first domain comprises a heavy chain variable region (VH) of SEQ ID NO: 13 and a light chain variable region (VL) of SEQ ID NO: 14, and the second domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO:

16.

4. The pharmaceutical composition of claim 3 , wherein the antibody is of the IgG1 isotype.

5. 5. The pharmaceutical composition of claim 4, wherein the antibody comprises a first heavy chain (HC1) of SEQ ID NO: 17, a first light chain (LC1) of SEQ ID NO: 18, a second heavy chain (HC2) of SEQ ID NO: 19, and a second light chain (LC2) of SEQ ID NO:

20.

6. The pharmaceutical composition of claim 5 , wherein the antibody is an isolated bispecific antibody.

7. 7. The pharmaceutical composition of claim 6, wherein the bispecific antibody is amivantamab.

8. 8. The pharmaceutical composition of claim 7, wherein the antibody comprises a biantennary glycan structure having a fucose content of about 1% to about 15%.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the antibody is administered at a dose of about 700 mg to about 1400 mg.

10. 10. The pharmaceutical composition of claim 9, wherein the antibody is administered at a dose of about 700 mg, about 1050 mg, or about 1400 mg.

11. 11. The pharmaceutical composition of claim 10, wherein the antibody is administered at a dose of about 1400 mg.

12. 11. The pharmaceutical composition of claim 10, wherein the antibody is administered at a dose of about 1050 mg.

13. 11. The pharmaceutical composition of claim 10, wherein the antibody is administered at a dose of about 700 mg.

14. The pharmaceutical composition according to any one of claims 1 to 8, wherein the antibody is administered once a week or once every two weeks.

15. 15. The pharmaceutical composition of claim 14, wherein the antibody is administered once a week for the first four weeks, then once every two weeks.

16. The pharmaceutical composition according to any one of claims 1 to 8, wherein the antibody is administered in a 28-day cycle.

17. The pharmaceutical composition according to any one of claims 1 to 8, wherein the antibody is administered as a monotherapy.

18. A pharmaceutical composition described in any one of claims 1 to 8, wherein the antibody is administered in combination with one or more chemotherapeutic agents.

19. 20. The pharmaceutical composition of claim 18, wherein the one or more chemotherapeutic agents comprises FOLFOX, wherein the FOLFOX comprises folinic acid, fluorouracil, and oxaliplatin.

20. 19. The pharmaceutical composition of claim 18, wherein the one or more chemotherapeutic agents comprises FOLFIRI, wherein the FOLFIRI comprises folinic acid, fluorouracil, and irinotecan.

21. The pharmaceutical composition according to any one of claims 1 to 8, wherein the colorectal cancer is metastatic colorectal cancer (mCRC).

22. The pharmaceutical composition of any one of claims 1 to 8, wherein the subject has been characterized with wild-type KRAS, NRAS, and BRAF.

23. The pharmaceutical composition of any one of claims 1 to 8, wherein the subject has been diagnosed with left-sided mCRC.

24. The pharmaceutical composition of any one of claims 1 to 8, wherein the subject has been diagnosed with right-sided mCRC.

25. The pharmaceutical composition according to any one of claims 1 to 8, wherein the subject is anti-EGFR therapy naive.

26. The pharmaceutical composition of any one of claims 1 to 8, wherein the subject has previously received anti-EGFR therapy.

27. The pharmaceutical composition of any one of claims 1 to 8, wherein the subject is treatment-naive.

28. The pharmaceutical composition of any one of claims 1 to 8, wherein the subject is relapsed or refractory to treatment with one or more previous anti-cancer therapies.

29. The pharmaceutical composition according to any one of claims 1 to 8, wherein the subject is 18 years of age or older.

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