Use of bispecific anti-egfr / c-met antibodies for the treatment of solid tumors

Abstract

The present invention relates to methods of treating a cancer that expresses epidermal growth factor receptor (EGFR) or expresses hepatocyte growth factor receptor (c-Met) in a subject in need thereof. These methods comprise administering to the subject a therapy comprising an isolated bispecific anti-EGFR / c-Met antibody, wherein the administration comprises a dose that is administered once per 28-day cycle.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 563,567, filed March 11, 2024, which is incorporated herein by reference in its entirety.

[0003] sequence list

[0004] This application contains a sequence list that has been electronically submitted in XML format, and is incorporated herein by reference in its entirety. The XML copy created on March 10, 2025, is named JBI6892WOPCT1_SL.xml and has a size of 37,799 bytes. Technical Field

[0005] This invention relates to methods for treating subjects with cancers expressing epidermal growth factor receptor (EGFR) or hepatocyte growth factor receptor (c-Met). These methods include administering to the subject a therapy comprising an isolated bispecific anti-EGFR / c-Met antibody, wherein the administration comprises a dose administered once every 28 days. Background Technology

[0006] Amivantamab (a low-fucose, fully IgG1-based bispecific antibody targeting the EGF and cMet receptors) has shown activity against tumors with primary or second-site resistant EGFR mutations, overexpression of wild-type EGFR, and activation of the cMet pathway. By inhibiting EGFR and cMet signaling function, amivantamab disrupts these signaling pathways, thereby preventing tumor growth and progression. Furthermore, the presence of high levels of EGFR and cMet on the surface of tumor cells allows these cells to be targeted and destroyed by immune effector cells via antibody-dependent cytotoxicity (ADCC) and antibody-dependent phagocytosis (ADCP) mechanisms.

[0007] Evantuximab administration can cause frequent infusion-related reactions (IRRs) in a certain proportion of patients (67% of patients, according to Minchom A et al., submitted to the American Society of Clinical Oncology (ASCO) 2023; June 2–6, 2023; Chicago, IL, USA). Signs and symptoms of IRR include, but are not limited to, dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting. Systemic IRR, including severe reactions, is frequently observed when a new protein therapy infusion is introduced, but the mechanisms inducing the response vary.

[0008] There is a need for an improved treatment regimen that is both effective and reduces infusion-related reactions (IRR) in patients treated with EGFR / c-Met bispecific antibodies, such as ervantumab. Summary of the Invention

[0009] This disclosure generally relates to a method of treating a subject in need of cancer expressing epidermal growth factor receptor (EGFR) or hepatocyte growth factor receptor (c-Met), comprising administering to the subject an isolated bispecific anti-EGFR / c-Met antibody comprising a first domain binding to EGFR and a second domain binding to c-Met, wherein the first domain comprises heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, light chain complementarity-determining region 1 (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. 12 of LCDR3, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 3520 mg to approximately 4640 mg.

[0010] In some implementations, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 3520 mg.

[0011] In some implementations, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 4640 mg.

[0012] In some implementations, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 3520 mg for subjects weighing less than 80 kg, and at a dose of approximately 4640 mg for subjects weighing 80 kg or more.

[0013] In some implementations, the bispecific anti-EGFR / c-Met antibody is administered once every 28 days.

[0014] In some implementations, bispecific anti-EGFR / c-Met antibodies are administered subcutaneously.

[0015] In some implementations, the bispecific anti-EGFR / c-Met antibody is co-formulated with hyaluronidase.

[0016] In some implementations, the method also includes an initial cycle (cycle 1) comprising administering the bispecific antibody once a week for four weeks at a dose of approximately 1600 mg if the subject weighs less than 80 kg, or at a dose of approximately 2240 mg if the subject weighs 80 kg or more.

[0017] In some implementations, the first domain binding to EGFR includes the heavy chain variable region (VH) of SEQ ID NO: 13 and the light chain variable region (VL) of SEQ ID NO: 14, and the second domain binding to c-Met includes the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16.

[0018] In some implementations, the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype.

[0019] In some implementations, the bispecific anti-EGFR / c-Met antibody comprises the first heavy chain (HC1) of SEQ ID NO: 17, the first light chain (LC1) of SEQ ID NO: 18, the second heavy chain (HC2) of SEQ ID NO: 19, and the second light chain (LC2) of SEQ ID NO: 20.

[0020] In some implementations, the bispecific anti-EGFR / c-Met antibody has a bibranched glycan structure with a fucose content between about 1% and about 15%.

[0021] In some implementations, the cancer expressing EGFR or c-Met is a solid tumor. In some implementations, the cancer expressing EGFR or c-Met is non-small cell lung cancer (NSCLC).

[0022] On the other hand, this disclosure generally relates to a method of subcutaneously administering an isolated bispecific anti-EGFR / c-Met antibody to a subject with cancer expressing EGFR or c-Met, the antibody comprising a first domain binding EGFR and a second domain binding c-Met, wherein the first domain comprises heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, light chain complementarity-determining region 1 (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, wherein the administration of the bispecific anti-EGFR / c-Met antibody produces approximately 325 µg / mL of Phase 2 C2 antibody. trough Value and / or approximately 286612 µg•h / mL AUC 0-672h value.

[0023] In some implementations, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 3520 mg.

[0024] In some implementations, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 4640 mg.

[0025] In some implementations, the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 3520 mg for subjects weighing less than 80 kg, and at a dose of approximately 4640 mg for subjects weighing 80 kg or more.

[0026] In some implementations, the bispecific anti-EGFR / c-Met antibody is administered once every 28 days.

[0027] In some implementations, bispecific anti-EGFR / c-Met antibodies are administered subcutaneously.

[0028] In some implementations, the bispecific anti-EGFR / c-Met antibody is co-formulated with hyaluronidase.

[0029] In some implementations, the method also includes an initial cycle (cycle 1) comprising administering the bispecific antibody once a week for four weeks at a dose of approximately 1600 mg if the subject weighs less than 80 kg, or at a dose of approximately 2240 mg if the subject weighs 80 kg or more.

[0030] In some implementations, the first domain binding to EGFR includes the heavy chain variable region (VH) of SEQ ID NO: 13 and the light chain variable region (VL) of SEQ ID NO: 14, and the second domain binding to c-Met includes the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16.

[0031] In some implementations, the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype.

[0032] In some implementations, the bispecific anti-EGFR / c-Met antibody comprises the first heavy chain (HC1) of SEQ ID NO: 17, the first light chain (LC1) of SEQ ID NO: 18, the second heavy chain (HC2) of SEQ ID NO: 19, and the second light chain (LC2) of SEQ ID NO: 20.

[0033] In some implementations, the bispecific anti-EGFR / c-Met antibody has a bibranched glycan structure with a fucose content between about 1% and about 15% or less than 20%.

[0034] In some implementations, cancers expressing EGFR or c-Met are solid tumors.

[0035] In some implementations, cancers that express EGFR or c-Met are non-small cell lung cancer (NSCLC).

[0036] In some implementations, infusion-related reactions (IRRs) occurred less frequently in the group of subjects receiving bispecific anti-EGFR / c-Met antibodies every 4 weeks (Q4W) compared to the group receiving bispecific anti-EGFR / c-Met antibodies every 2 weeks (Q2W).

[0037] In some implementations, infusion-related reactions (IRRs) were less severe in the group of subjects receiving bispecific anti-EGFR / c-Met antibodies every 4 weeks (Q4W) compared to the group receiving bispecific anti-EGFR / c-Met antibodies every 2 weeks (Q2W).

[0038] In some implementations, the frequency of infusion-related reactions (IRRs) was lower in the group of subjects who received bispecific anti-EGFR / c-Met antibodies subcutaneously every 4 weeks (Q4W) compared to the group who received intravenous administration of bispecific anti-EGFR / c-Met antibodies every 2 weeks (Q2W).

[0039] In some implementations, infusion-related reactions (IRRs) were less severe in a group of subjects receiving bispecific anti-EGFR / c-Met antibodies subcutaneously every 4 weeks (Q4W) compared to a group receiving intravenous administration of bispecific anti-EGFR / c-Met antibodies every 2 weeks (Q2W). Attached Figure Description

[0040] Figure 1 This study shows the incidence of IRR and IRR-related symptoms in subjects receiving SC Ami Q4W (every 4 weeks) compared to subjects receiving IV Ami Q2W (every 2 weeks). Ami, ervantumab; h, hour; IRR, infusion-related reaction; IV, intravenous; min, minute; SC, subcutaneous. Detailed Implementation

[0041] definition

[0042] All publications cited in this specification, including but not limited to patents and patent applications, are incorporated herein by reference as if they were given in their entirety.

[0043] It should be understood that the terminology used herein is for the purpose of describing particular embodiments only and is 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 pertains.

[0044] While any methods and materials similar to or equivalent to those described herein may be used in the practice of testing the invention, exemplary materials and methods are described herein. The following terminology will be used in describing and claiming the invention.

[0045] When a list is provided, unless otherwise indicated, it should be understood that each individual element in the list and each combination of the list is a separate implementation. For example, a list of implementations presented as “A, B or C” will be understood to include implementations “A”, “B”, “C”, “A or B”, “A or C”, “B or C”, or “A, B or C”.

[0046] As used in this specification and the appended claims, unless otherwise expressly stated, the singular forms “a,” “an,” and “the” include plural references. Thus, for example, a reference to “a cell” includes a combination of two or more cells, and so on.

[0047] The connecting term "and / or" between multiple listed elements is understood to encompass both individual options and combined options. For example, in the case where two elements are connected by "and / or," the first option means applying the first element in the absence of the second element. The second option means applying the second element in the absence of the first element. The third option means applying both the first and second elements together. Any of these options is understood to fall within the meaning and therefore satisfies the requirement of the term "and / or" as used herein. The concurrent applicability of more than one option is also understood to fall within the meaning and therefore satisfies the requirement of the term "and / or".

[0048] The transitional terms “comprising,” “substantially consisting of,” and “consisting of” are intended to imply their accepted meaning in patent terminology; that is, (i) “comprising” is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open at the end, and does not exclude additional, unlisted elements or method steps; (ii) “consisting of” excludes any element, step, or component not specified in the claims; and (iii) “substantially consisting of” limits the scope of the claims to the specified material or step “and material or step that does not substantially affect the essential and novel features of the invention protected by the claims.” Embodiments described with the phrase “comprising” (or its equivalents) are also provided, as are those described independently with “consisting of” and “substantially consisting of”.

[0049] “About” means within the acceptable range of error for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. In the context of a particular measurement, result, or implementation, unless otherwise expressly stated in the implementation or elsewhere in the specification, “about” means within one standard deviation or up to 5% (whichever is greater) in accordance with convention in the art.

[0050] The term "antibody" broadly refers to and includes immunoglobulin molecules, specifically including monoclonal antibodies, including murine monoclonal antibodies, human monoclonal antibodies, humanized monoclonal antibodies and chimeric monoclonal antibodies, full-length antibodies, antigen-binding fragments, multispecific antibodies (such as bispecific antibodies, trispecific antibodies, tetraspecific antibodies, etc.), dimer, tetramer or multimer antibodies, single-chain antibodies, domain antibodies, and any other modified conformation of immunoglobulin molecules containing an antigen-binding site with the desired specificity.

[0051] "Specific binding," "specifically binding," or simply "binding" refers to an antibody binding to an antigen or an epitope within an antigen with a higher affinity than it would to other antigens. Typically, the binding of an antibody to an antigen or an epitope within an antigen occurs at an equilibrium dissociation constant (K). D (Approximately 5 × 10) -8 M or smaller, for example, about 1×10 -9 M or smaller, approximately 1×10 -10 M or smaller, approximately 1×10 -11 M or smaller, or approximately 1×10 -12 M or smaller, usually K D The K-type antibody binds to non-specific antigens (e.g., BSA, casein). D The dissociation constant is low, at most 1 / 100th of the latter. The dissociation constant can be measured using known protocols. However, antibodies binding to an antigen or an epitope within an antigen may exhibit cross-reactivity with other related antigens, for example, cross-reactivity with the same antigen from other species (homologous) (such as humans or monkeys, e.g., cynomolgus macaques or chimpanzees). Monospecific antibodies bind to one antigen or one epitope, while bispecific antibodies bind to two different antigens or two different epitopes.

[0052] The 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). The correspondence between various depictions and variable area numbers is described (see, for example, Lefranc et al., (2003) Dev Comp Immunol 27: 55-77; Honegger and Pluckthun, (2001) J Mol Biol 309:657-70; International ImMunoGeneTics (IMGT) database; Web resource, http: / / www_imgt_org). Available programs (such as abYsis for UCL Business PLC) can be used to depict CDRs. Unless otherwise expressly stated in the specification, as used herein, the terms “CDR,” “HCDR1,” “HCDR2,” “HCDR3,” “LCDR1,” “LCDR2,” and “LCDR3” include CDRs as defined by any of the above methods (Kabat, Chothia, IMGT, or AbM).

[0053] A full-length antibody consists of two heavy chains (HC) and two light chains (LC) linked by disulfide bonds, as well as their polymers (e.g., IgM). Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (composed of domains CH1, hinge, CH2, and CH3). Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL). The VH and VL regions can be further subdivided into hypervariable regions, called complementarity-determining regions (CDRs), interspersed with framework regions (FRs). Each VH and VL consists of three CDRs and four FR segments, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0054] An "antigen-binding fragment" refers to the portion of an immunoglobulin molecule that binds to an antigen. Antigen-binding fragments can be synthetic, enzymatically obtained, or genetically engineered polypeptides, and include VH, VL, VH and VL, Fab, F(ab')2, Fd, and Fv fragments; domain antibodies (dAbs) consisting of a VH domain or a VL domain; shark variable IgNAR domains; humped VH domains; and minimal recognition units consisting of amino acid residues from CDRs of analog antibodies, such as FR3-CDR3-FR4, HCDR1, HCDR2, and / or HCDR3, and LCDR1, LCDR2, and / or LCDR3. The VH and VL domains can be linked together via synthetic linkers to form various types of single-chain antibody designs. Where the VH and VL domains are expressed by separate single-chain antibody constructs, the VH / VL domains can be paired intramolecularly or intermolecularly to form monovalent antigen-binding sites, such as single-chain Fv (scFv) or bivalent antibodies; as described, for example, in International Patent Publications Nos. WO1998 / 44001, WO1988 / 01649, WO1994 / 13804 and WO1992 / 01047.

[0055] "Monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibody molecules, meaning that the individual antibodies comprising that population are identical, except for well-known modifications such as removal of a C-terminal lysine from the antibody heavy chain or post-translational modifications such as amino acid isomerization or deamidation, methionine oxidation, or asparagine or glutamine deamidation. Monoclonal antibodies typically bind to one antigenic epitope. Bispecific monoclonal antibodies bind to two different antigenic epitopes. Monoclonal antibodies can have heterogeneous glycosylation within the antibody population. Monoclonal antibodies can be monospecific or multispecific, such as bispecific, monovalent, divalent, or multivalent.

[0056] "Humanized antibodies" are antibodies whose antigen-binding sites are derived from non-human species and whose variable region framework is derived from human immunoglobulin sequences. Humanized antibodies may contain deliberately introduced mutations in the framework region, such that the framework may not be an exact copy of the expressed human immunoglobulin sequence or germline gene sequence.

[0057] "Human antibody" refers to an antibody containing both heavy chain and light chain variable regions, where the framework and antigen-binding site are derived from human-origin sequences. If the antibody contains a constant region or a portion of a constant region, that constant region is also derived from a human-origin sequence. The definition of "human antibody" does not include antibodies whose antigen-binding sites are derived from non-human species.

[0058] If the variable region of an antibody is obtained using a system that utilizes human germline immunoglobulin or rearranged immunoglobulin genes, the human antibody contains a heavy chain variable region or a light chain variable region derived from a human-origin sequence. Non-limiting example systems include libraries of human immunoglobulin genes displayed on bacteriophages, and transgenic nonhuman animals, such as mice or rats carrying human immunoglobulin gene loci. When compared to human germline immunoglobulin sequences or rearranged immunoglobulin sequences, human antibodies typically contain amino acid differences due to, for example, naturally occurring somatic mutations, deliberate substitutions in the framework or antigen-binding site, and substitutions introduced during cloning or VDJ recombination in nonhuman animals. Typically, human antibodies are at least 80% identical in amino acid sequence to the sequence encoded by human germline or rearranged immunoglobulin genes. For example, approximately 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, human antibodies may contain a common frame sequence derived from human frame sequence analysis (see, for example, Knappik et al., J. Mol. Biol. 296:57-86 (2000)), or be incorporated into a synthetic HCDR3 in a human immunoglobulin gene library displayed on a phage (see, for example, Shi et al., J. Mol. Biol. 397:385-96 (2010) and International Patent Publication WO2009 / 085462).

[0059] "Bispecific" refers to antibodies that specifically bind to two different antigens or two different epitopes within the same antigen. Bispecific antibodies may have cross-reactivity with other related antigens, for example, cross-reactivity with the same antigen from other species (homologous) (such as humans or monkeys, such as cynomolgus macaques (cyno) or chimpanzees), or they may bind to epitopes shared between two or more different antigens.

[0060] "Bispecific anti-EGFR / c-Met antibody" or "bispecific EGFR / c-Met antibody" refers to a bispecific antibody that has a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met. The domains that specifically bind to EGFR and c-Met are usually a VH / VL pair, and the bispecific anti-EGFR / c-Met antibody is monovalent in binding to both EGFR and c-Met.

[0061] "Isolated" refers to a homogeneous group of molecules (such as synthetic polynucleotides, polypeptide carriers, or viruses) that have been substantially isolated and / or purified from other components of the system that produced the molecules (such as recombinant cells), as well as proteins that have undergone at least one purification or isolation step. "Isolated" also refers to molecules that are substantially free of other cellular material and / or chemicals, and encompasses molecules isolated to higher purities (such as 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% purity).

[0062] Immunoglobulins can be classified into five major types based on the amino acid sequence of their heavy chain constant domain: IgA, IgD, IgE, IgG, and IgM. IgA and IgG are further subdivided into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. Based on the amino acid sequence of their constant domain, the antibody light chain of any vertebrate species can be designated as one of two completely different types: κ and λ.

[0063] As used in this application, "low fucose" or "low fucose content" means that the fucose content of the antibody is approximately between 1% and 15% or less than 20%.

[0064] As used in this article, "normal fucose" or "normal fucose content" means that the fucose content of the antibody is approximately higher than 50%, typically higher than 80% or higher than 85%.

[0065] "Recombinant" refers to DNA, antibodies, and other proteins that are prepared, expressed, formed, or isolated through recombination when fragments from different sources are joined to produce recombinant DNA, antibodies, or proteins.

[0066] "Carrier" refers to the diluent, adjuvant, excipient, or medium used with the antibody of this invention for administration. Such media can be liquids, such as water and oils, including petroleum, animal, plant, or synthetic oils, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. For example, 0.4% saline and 0.3% glycine can be used to formulate bispecific anti-EGFR / c-Met antibodies. These solutions are sterile and generally free of particulate matter. They can be sterilized using conventional, known sterilization techniques, such as filtration. For parenteral administration, the carrier may include sterile water, and other excipients may be added to increase solubility or preservative properties. Suspensions or solutions for injection can also be prepared using water-based carriers along with suitable additives. Suitable mediators and formulations that include other human proteins (e.g., human serum albumin) are described, for example, in Remington: The Science and Practice of Pharmacy, 21st edition, edited by Troy, DB, Lipincott Williams and Wilkins, Philadelphia, PA, 2006, Part 5, "Pharmaceutical Manufacturing", pp. 691–1092 (see especially pp. 958–989).

[0067] "Dosing regimen" refers to the amount of therapeutic agent or drug to be taken by the subject and the frequency of taking the therapeutic agent. "Dosage" refers to the amount or dosage of the therapeutic agent or drug to be taken each time.

[0068] "Therapeutic effective dose" refers to the amount that effectively achieves the desired therapeutic outcome at the required dose and time period. Therapeutic effective doses can vary depending on factors such as an individual's disease state, age, sex, and weight, as well as the ability of the therapeutic agent or combination of therapeutic agents to elicit the desired response in the individual. Exemplary indicators of an effective therapeutic agent or combination of therapeutic agents include, for example, improved patient health.

[0069] "Together with", "in combination with", "in combination with", etc., encompass the administration of selected therapeutic agents or drugs to a single patient and are intended to include treatment regimens in which these therapeutic agents or drugs are administered via the same or different routes of administration or at the same or different times.

[0070] "Fixed combination" refers to a single pharmaceutical composition containing two or more compounds.

[0071] "Non-fixed combination" refers to individual pharmaceutical compositions, each comprising one or more compounds. One or more compounds or unit dosage forms may be administered as independent entities simultaneously, in parallel, or sequentially without a specific time interval, wherein such administration provides an effective level of the two compounds in the subject.

[0072] An "antagonist" or "inhibitor" is 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 considered 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 in the absence of an antagonist (e.g., a negative control), or when the inhibition is statistically significant compared to the inhibition in the absence of an antagonist.

[0073] "Treatment" for a disease or condition (such as cancer) means achieving one or more of the following results: reducing the severity and / or shortening the duration of the condition, suppressing the worsening of characteristic symptoms of the treated condition, limiting or preventing the recurrence of the condition in a subject with a history of the condition, or limiting or preventing the recurrence of symptoms in a subject with a history of the condition.

[0074] "Prevention" of disease or symptom means preventing the development of symptoms in the test subjects.

[0075] "Response", "responsiveness" or "probable response" means any type of improvement or positive response, such as relief or improvement of one or more symptoms, reduction of disease severity, stabilization of disease status (i.e., no worsening), prevention of disease spread, delay or slowing of disease progression, improvement or mitigation of disease status, and remission (whether partial or complete), whether detectable or undetectable.

[0076] "Subject" includes any human or non-human animal. "Non-human animal" includes all vertebrates, such as mammals and non-mammals, including non-human primates, sheep, dogs, cats, horses, cattle, chickens, amphibians, reptiles, etc. The terms "subject" and "patient" are used interchangeably in this document.

[0077] "Cancer" refers to the abnormal growth of cells that tend to proliferate uncontrollably and, in some cases, metastasize (spread) to other areas of the patient's body.

[0078] "Cancer expressing EGFR or c-Met" refers to cancer with detectable EGFR or c-Met expression, or with EGFR or c-Met mutations or amplifications. EGFR or c-Met expression, amplification, and mutation status can be detected using known methods such as sequencing, next-generation sequencing, fluorescence in situ hybridization, immunohistochemistry, flow cytometry, or Western blotting.

[0079] "Epidermal growth factor receptor" or "EGFR" refers to human EGFR (also known as HER1 or ErbB1 (Ullrich et al., Nature 309:418-425, 1984)) with the amino acid sequence shown in GenBank accession number NP_005219, as well as its naturally occurring variants.

[0080] As used herein, “hepatocyte growth factor receptor” or “c-Met” or “MET” refers to human c-Met and its natural variants having the amino acid sequence shown in GenBank accession number NP_001120972.

[0081] "Newly diagnosed" refers to a subject who has been diagnosed with cancer (such as a solid tumor) but has not yet received treatment for that cancer.

[0082] "Metastasis" refers to cancer in which cancer cells separate from the original tumor, enter the bloodstream or lymphatic system, and spread to other areas of the body.

[0083] "Refractory" refers to a disease that does not respond to treatment. Refractory diseases may be resistant to treatment before or at the start of treatment, or they may develop resistance during treatment.

[0084] "Relapse" refers to the recurrence of the disease or its signs and symptoms after a period of improvement following previous treatment with therapeutic agents.

[0085] "Diagnosis" refers to the method of determining whether a subject has a given disease or condition, or is likely to 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 based on the likelihood of responding to treatment). Diagnosis is typically made by a physician based on general guidelines for the disease to be diagnosed or other criteria indicating a subject's likely response to a particular treatment.

[0086] "Biological sample" refers to a collection of fluid-like substances, cells, or tissues isolated from a subject, as well as fluids, cells, or tissues present within the subject's body. Exemplary samples are biological fluids, such as blood, serum and serous fluid, plasma, lymph, urine, saliva, cystic fluid, tears, excretions, sputum, mucosal secretions of secretory tissues and organs, vaginal secretions, ascites, pleural fluid, pericardial fluid, peritoneal fluid, peritoneal fluid and other body cavity fluids, fluids collected by bronchoalveolar lavage fluid, synovial fluid, liquid solutions that come into contact with the subject or biological sources (e.g., cell and organ culture media (including cell or organ conditioned media), lavage fluid, etc.), tissue biopsies, tumor tissue biopsies, tumor tissue samples, fine needle aspirates, surgically removed tissue, organ cultures, or cell cultures.

[0087] “C max "" refers to the highest observed serum concentration.

[0088] “C trough "This refers to the serum concentration observed just before the next drug administration."

[0089] AUC (0-t) "" refers to the area under the plasma / serum concentration-time curve from time zero to time t.

[0090] "Hyaluronase" refers to a class of enzymes that degrade hyaluronic acid. Hyaluronase is an endoglucosidase used when subcutaneously administered (e.g., subcutaneous injection, subcutaneous infusion such as subcutaneous perfusion) to increase the dispersion and absorption of other co-administered drugs. Hyaluronases include, but are not limited to, bacterial hyaluronase (EC 4.2.2.1 or EC 4.2.99.1), hyaluronases derived from leeches, other parasites, and crustaceans (EC 3.2.1.36), and mammalian hyaluronase (EC 3.2.1.35). Recombinant human hyaluronase has a molecular weight of approximately 61 kDa. Hyaluronases include non-human hyaluronases, including but not limited to those from mice, dogs, cats, rabbits, birds, cattle, sheep, pigs, horses, fish, sheep, bacteria, and any hyaluronase derived from leeches, other parasites, and crustaceans. Exemplary human hyaluronidases include HYAL1, HYAL2, HYAL3, HYAL4, and PH20. Hyaluronidases also include soluble hyaluronidases, including sheep and bovine PH20, and soluble forms of PH20. Exemplary hyaluronidases include those shown in U.S. Publication No. 2013 / 0302275, which is incorporated herein by reference, including, for example, hyaluronidases shown as SEQ ID NO: 6, 7-31, 69, 70, 71, 72, 856-861, 869-921 from U.S. Publication No. 2013 / 0302275 (which is incorporated herein by reference), their mature forms (lacking a signal sequence), their allelic variants, and their truncated forms exhibiting hyaluronidase activity, including soluble C-terminal truncated variants.

[0091] As used in this article, PH20 refers to a type of hyaluronidase that is present in sperm and has neutral activity.

[0092] Soluble PH20 refers to polypeptides characterized by their solubility under physiological conditions. Generally, soluble PH20 lacks all or part of the glycosylphosphatidyl anchor (GPI) attachment sequence, or cannot otherwise adequately anchor to the cell membrane. For example, soluble PH20 can be a C-terminal truncated variant of PH20 that lacks all or part of the continuous amino acid sequence corresponding to the GPI anchor attachment sequence. Therefore, when expressed from cells, soluble PH20 is secreted into the culture medium.

[0093] Soluble human PH20 (sHuPH20) comprises a human PH20 polypeptide lacking the continuous amino acid sequence from the C-terminus of human PH20, and includes all or part of the GPI anchoring sequence (a C-terminally truncated PH20 polypeptide) such that the polypeptide is soluble under physiological conditions when expressed. For example, a soluble human PH20 polypeptide is a C-terminally truncated polypeptide of human PH20, its precursor form or mature form lacking the signal sequence, or its allele variant, as shown in SEQ ID NO: 36-42 herein, and disclosed as in SEQ ID NO: 6, 7, and 68-72 of U.S. Publication No. 20130302275, which is incorporated herein by reference.

[0094] U.S. Publication No. 2004 / 0268425 (which is incorporated herein by reference) describes members of the family of soluble, neutral active hyaluronidase glycoproteins, particularly human soluble PH-20 hyaluronidase glycoprotein (also known as sHASEGP). U.S. Publication No. 20100143457 (which is incorporated herein by reference) describes shorter active soluble PH20 (i.e., 36-469, -470, 471, and longer forms, i.e., 36-495 to 36-500), the sequences of which are also incorporated herein by reference.

[0095] Hyaluronidase activity refers to the ability of an enzyme to catalyze the cleavage of hyaluronic acid. The United States Pharmacopeia (USP) XXII assay for hyaluronidase indirectly determines hyaluronidase activity by measuring the amount of remaining higher molecular weight hyaluronic acid or hyaluronic acid (HA) substrate after the enzyme has been reacted with HA at 37°C for 30 minutes (USP XXII-NF XVII (1990) 644-645 United States Pharmacopeia Convention, Inc., Rockville, MD). Reference standard solutions can be used in the assay to determine the relative activity (in units) of any hyaluronidase. In vitro assays for determining the activity of hyaluronidases such as PH20, including modified PH20 peptides, are known in the art and are described herein. Exemplary assays include microturbidity assays, which indirectly measure the cleavage of hyaluronic acid by hyaluronidase by detecting the insoluble precipitate formed when uncleaved hyaluronic acid binds to serum albumin. Reference standards can be used, for example, to generate standard curves, thereby determining the activity of the tested hyaluronidase in units.

[0096] Specific activity refers to the number of active units per mg of protein. The number of milligrams of hyaluronidase is defined by the absorption of the solution at 280 nm, assuming a molar extinction coefficient of approximately 1.7, expressed in M⁻¹cm⁻¹.

[0097] Neutral activity refers to the ability of PH20 peptides to enzymatically catalyze the cleavage of hyaluronic acid under neutral pH conditions (such as at or around pH 6.0 to pH 7.8).

[0098] Human recombinant DNA-derived hyaluronidase PH20 (rHuPH20) is a glycosylated single-stranded protein produced by CHO cells containing a DNA plasmid encoding residues 36-482 of SEQ ID NO:36, yielding a heterogeneous mixture of human hyaluronidase (PH20) in soluble form, which begins at residue 36 of SEQ ID NO:36 and terminates at residues 478, 479, 480, 481, and 482, including any one of SEQ ID NO:31, 35, 34, 33, and 32.

[0099] A “variant” is a polypeptide or polynucleotide that differs from a reference polypeptide or reference polynucleotide due to one or more modifications (e.g., substitution, insertion, or deletion).

[0100] The method disclosed herein

[0101] It is well known in the art that drug development is an unpredictable field. This lack of predictability is evidenced by the requirements of health authorities (such as the Food and Drug Administration) to establish safe and effective dosing regimens for each individual drug candidate in clinical trials. In the past decade (2011–2020), only 7.9% of all drug candidates in development received FDA approval from Phase I clinical trials. See Clinical Development Success Rates and Influencing Factors 2011–2020. Success rates are even lower in oncology, resulting in only 5.3% success rate for oncology drug candidates.

[0102] In oncology, even for drugs with established dosages for specific indications, the Food and Drug Administration (FDA) recommends further clinical studies to determine the optimal dosage for new indications; otherwise, patients may be exposed to unreasonable and significant risks, as well as other potential drawbacks. (See, for example, Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases; Draft Guidance for Industry; January 2023).

[0103] Non-small cell lung cancer and other cancers expressing EGFR or c-Met remain an unmet medical need, with significant morbidity and mortality. The inventors have developed a novel dosing regimen for an EGFR-MET bispecific antibody that provides an improved safety profile compared to currently approved regimens while achieving comparable exposure.

[0104] Evantumab is an EGFR-MET bispecific antibody with immune cell-directing activity, approved by the FDA for intravenous (IV) administration. Parenteral administration of EGFR / c-Met bispecific antibodies can cause adverse reactions or adverse events (AEs) in patients or subjects, particularly infusion-related reactions (IRRs). As reported in the US prescribing information for RYBREVANT (amivantamab) (www.janssenlabels.com / package-insert / product-monograph / prescribing-information / RYBREVANT-pi.pdf), in the CHRYSALIS study, 302 patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) received IV anteumab as monotherapy at the recommended Phase 2 dose (RP2D), and IRR was one of the most common adverse reactions, occurring in 66% of cases.

[0105] An adverse reaction or adverse event (AE) is any adverse medical event that occurs in a patient or subject who is receiving or has received an EGFR / c-Met bispecific antibody. In some implementations, an AE is an IRR. In some implementations, an IRR is a mild IRR, manifested as, but not limited to, chills, nausea, dyspnea, flushing, chest discomfort, hypotension, vomiting, tachycardia, fever, or any other symptoms that occur during or after the infusion. In some implementations, an IRR is a systemic IRR that occurs upon the introduction of a novel protein therapy infusion (such as an EGFR / c-Met bispecific antibody), including severe reactions. In some implementations, the EGFR / c-Met bispecific antibody is ervantuzumab. In some implementations, the severity of the IRR is graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. The severity grades range from Grade 1 (mild) to Grade 5 (death). Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Death related to the adverse event. In some implementations, the presence of an IRR in a patient or subject is assessed at any time from day 1 of cycle 1 until 30 days after the end of treatment with the EGFR / c-Met bispecific antibody. In some implementations, the presence of an IRR in a patient or subject is assessed on day 1 of cycle 1 of treatment with the EGFR / c-Met bispecific antibody. In some implementations, the presence of an IRR in a patient or subject is assessed up to 3 months after the start of treatment with the EGFR / c-Met bispecific antibody. In some implementations, the presence of an IRR in a patient or subject is assessed at any time between 1 day and 30 days after the end of treatment with the EGFR / c-Met bispecific antibody. In some implementations, the presence of an IRR in a patient or subject is assessed at any time between 1 day and 5 days after the end of treatment with the EGFR / c-Met bispecific antibody. In some implementations, the presence of an IRR in a patient or subject is assessed at any time between 1 day and 10 days after the end of treatment with the EGFR / c-Met bispecific antibody. In some implementations, the presence of an IRR in a patient or subject is assessed at any time between 1 day and 15 days after the end of treatment with the EGFR / c-Met bispecific antibody. In some implementations, patients or subjects are assessed for IRR at any time between 1 day and 20 days after the end of treatment with the EGFR / c-Met bispecific antibody.

[0106] In one aspect, this disclosure provides a method for treating a subject in need of a cancer (e.g., NSCLC) expressing epidermal growth factor receptor (EGFR) or hepatocyte growth factor receptor (c-Met), the method comprising administering to the subject an isolated bispecific anti-EGFR / c-Met antibody comprising a first domain binding to EGFR and a second domain binding to c-Met.

[0107] Anti-EGFR / c-Met antibody

[0108] In some embodiments, the anti-EGFR / c-Met antibody is a bispecific antibody. In some embodiments, the antibody is a separation antibody. In a specific embodiment, the antibody is a separated bispecific antibody.

[0109] In some implementations, the antibody (e.g., a bispecific antibody) comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met.

[0110] EGFR conjugate arm

[0111] In some implementations, the first domain that specifically binds to EGFR includes:

[0112] a) The amino acid sequences of heavy chain complementarity-determining regions 1 (HCDR1), HCDR2, and HCDR3 of SEQ ID NO: 1, 2, and 3, respectively; and / or

[0113] b) The amino acid sequences of light chain complementarity-determining regions 1 (LCDR1), LCDR2, and LCDR3 of SEQ ID NO:4, 5, and 6, respectively.

[0114] In some implementations, the first domain that specifically binds to EGFR includes:

[0115] a) The amino acid sequences of HCDR1, HCDR2, and HCDR3, respectively, for SEQ ID NO: 1, 2, and 3; and

[0116] b) The amino acid sequences of LCDR1, LCDR2 and LCDR3, respectively, are SEQ ID NO:4, 5 and 6.

[0117] HCDR1:TYGMH (SEQ ID NO:1)

[0118] HCDR2:VIWDDGSYKYYGDSVKG (SEQ ID NO:2)

[0119] HCDR3: DGITMVRGVMKDYFDY (SEQ ID NO:3)

[0120] HCDR1:RASQDISSALV (SEQ ID NO:4)

[0121] HCDR2: DASSLES (SEQ ID NO:5)

[0122] HCDR3: QQFNSYPLT (SEQ ID NO:6)

[0123] In some embodiments, the first domain comprises at least 90% identical to SEQ ID NO:13, for example, 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 heavy chain variable region (VH) amino acid sequence to SEQ ID NO:13. In some embodiments, 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 implementation, the first structural domain includes VH of SEQ ID NO:13.

[0124] In some embodiments, the first domain comprises at least 90% identical to SEQ ID NO:14, for example, 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 the light chain variable region (VL) amino acid sequence of SEQ ID NO:14. In some embodiments, 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 implementation, the first structural domain includes VL of SEQ ID NO:14.

[0125] As used herein, the term "identical" or "having sequence identity" refers, expressed as a percentage, to the extent that two amino acid sequences share the same residues at the same positions when aligned to achieve the maximum level of identity. For sequence alignment and comparison, one sequence is typically designated as the reference sequence, and the test sequence is compared to it. Sequence identity between the reference and test sequences is expressed as the percentage of positions where the reference and test sequences share the same amino acid along the entire length of the reference sequence when aligned to achieve the maximum level of identity. For example, when aligned to achieve the maximum level of identity, the two sequences are considered to have 70% sequence identity if the test sequence shares the same amino acid residues at 70% of the same positions along the entire length of the reference sequence.

[0126] In some implementations, the first domain includes:

[0127] a) A VH amino acid sequence that is at least 90% identical to SEQ ID NO:13; and / or

[0128] b) The VL amino acid sequence is at least 90% identical to that of SEQ ID NO:14.

[0129] In some implementations, the first domain includes:

[0130] a) A VH amino acid sequence that is at least 90% identical to SEQ ID NO:13; and

[0131] b) The VL amino acid sequence is at least 90% identical to that of SEQ ID NO:14.

[0132] In some implementations, the first domain includes:

[0133] a) VH of SEQ ID NO:13; and / or

[0134] b) VL of SEQ ID NO:14.

[0135] In a specific implementation scheme, the first structural domain includes:

[0136] a) VH of SEQ ID NO:13; and

[0137] b) VL of SEQ ID NO:14.

[0138] VH: QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSS (SEQ ID NO: 13)

[0139] VL: AIQLTQSPSSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIK (SEQ ID NO:14)

[0140] In some embodiments, the first domain contains at least 80% of the same first heavy chain (HC1) amino acid sequence as SEQ ID NO:17, for example, 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% of the same first heavy chain (HC1) amino acid sequence as SEQ ID NO:17. In some embodiments, the sequence identity is approximately 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 a specific embodiment, the first domain comprises the HC1 amino acid sequence of SEQ ID NO:17.

[0141] In some embodiments, the first domain contains at least 80% of the same first light chain (LC1) amino acid sequence as SEQ ID NO:18, for example, 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% of the same. In some embodiments, sequence identity is approximately 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 a specific embodiment, the first domain comprises the LC1 amino acid sequence of SEQ ID NO:18.

[0142] In some implementations, the first domain includes:

[0143] a) An HC1 amino acid sequence that is at least 80% identical to SEQ ID NO:17; and / or

[0144] b) An LC1 amino acid sequence that is at least 80% identical to SEQ ID NO:18.

[0145] In some implementations, the first domain includes:

[0146] a) An HC1 amino acid sequence that is at least 80% identical to SEQ ID NO:17; and

[0147] b) An LC1 amino acid sequence that is at least 80% identical to SEQ ID NO:18.

[0148] In some implementations, the first domain includes:

[0149] a) HC1 of SEQ ID NO:17; and / or

[0150] b) LC1 of SEQ ID NO:18.

[0151] In some implementations, the first domain includes:

[0152] a) HC1 of SEQ ID NO:17; and

[0153] b) LC1 of SEQ ID NO:18.

[0154] HC1: QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDY FDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:17)

[0155] LC1: AIQLTQSPSSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:18)

[0156] c-Met (MET) combined arm

[0157] In some implementations, the second domain that specifically binds to c-Met includes:

[0158] a) The amino acid sequences of HCDR1, HCDR2, and HCDR3, respectively, for SEQ ID NO:7, 8, and 9; and / or

[0159] b) The amino acid sequences of LCDR1, LCDR2 and LCDR3 of SEQ ID NO:10, 11 and 12, respectively.

[0160] In some implementations, the second domain that specifically binds to c-Met includes:

[0161] a) The amino acid sequences of HCDR1, HCDR2, and HCDR3, respectively, for SEQ ID NO: 7, 8, and 9; and

[0162] b) The amino acid sequences of LCDR1, LCDR2 and LCDR3 of SEQ ID NO:10, 11 and 12, respectively.

[0163] HCDR1:SYGIS (SEQ ID NO:7)

[0164] HCDR2: WISAYNGYTNYAQKLQG (SEQ ID NO:8)

[0165] HCDR3:DLRGTNYFDY (SEQ ID NO:9)

[0166] HCDR1:RASQGISNWLA (SEQ ID NO:10)

[0167] HCDR2:AASSLLS (SEQ ID NO:11)

[0168] HCDR3: QQANSFPIT (SEQ ID NO:12)

[0169] In some embodiments, the second domain comprises at least 90% identical to SEQ ID NO:15, for example, approximately 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 the VH amino acid sequence of SEQ ID NO:15. In some embodiments, sequence identity is approximately 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 the VH of SEQ ID NO:15.

[0170] In some embodiments, the second domain comprises at least 90% identical to SEQ ID NO:16, for example, approximately 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 the VL amino acid sequence of SEQ ID NO:16. In some embodiments, sequence identity is approximately 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 the VL of SEQ ID NO:16.

[0171] In some implementations, the second domain includes:

[0172] a) A VH amino acid sequence that is at least 90% identical to that in SEQ ID NO:15; and / or

[0173] b) The VL amino acid sequence is at least 90% identical to that of SEQ ID NO:16.

[0174] In some implementations, the second domain includes:

[0175] a) A VH amino acid sequence that is at least 90% identical to SEQ ID NO:15; and

[0176] b) The VL amino acid sequence is at least 90% identical to that of SEQ ID NO:16.

[0177] In some implementations, the second domain includes:

[0178] a) VH of SEQ ID NO:15; and / or

[0179] b) VL of SEQ ID NO:16.

[0180] In a specific implementation plan, the second structural domain includes:

[0181] a) VH of SEQ ID NO:15; and

[0182] b) VL of SEQ ID NO:16.

[0183] VH: QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVSS (SEQ ID NO: 15)

[0184] VL: DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIK (SEQ ID NO:16)

[0185] In some embodiments, the second domain contains at least 80% of the same second heavy chain (HC2) amino acid sequence as SEQ ID NO:19, for example, 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% of the same second heavy chain (HC2) amino acid sequence as SEQ ID NO:19. In some embodiments, the sequence identity is approximately 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 a specific embodiment, the second domain comprises the HC2 amino acid sequence of SEQ ID NO:19.

[0186] In some embodiments, the second domain contains at least 80% of the same second light chain (LC2) amino acid sequence as SEQ ID NO:20, for example, 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% of the same second light chain (LC2) amino acid sequence as SEQ ID NO:20. In some embodiments, the sequence identity is approximately 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 a specific embodiment, the second domain comprises the LC2 amino acid sequence of SEQ ID NO:20.

[0187] In some implementations, the second domain includes:

[0188] a) An HC2 amino acid sequence that is at least 80% identical to SEQ ID NO:19; and / or

[0189] b) An LC2 amino acid sequence that is at least 80% identical to that of SEQ ID NO:20.

[0190] In some implementations, the second domain includes:

[0191] a) An HC2 amino acid sequence that is at least 80% identical to SEQ ID NO:19; and

[0192] b) An LC2 amino acid sequence that is at least 80% identical to that of SEQ ID NO:20.

[0193] In some implementations, the second domain includes:

[0194] a) HC2 of SEQ ID NO:19; and / or

[0195] b)LC2 of SEQ ID NO:20.

[0196] In some implementations, the second domain includes:

[0197] a) HC2 of SEQ ID NO:19; and

[0198] b)LC2 of SEQ ID NO:20.

[0199] HC2: QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:19)

[0200] LC2: DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:20)

[0201] In some implementations, the antibody (e.g., a bispecific antibody) comprises:

[0202] a) Specifically binds to the first domain of EGFR, the first domain comprising the amino acid sequences HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 1, 2, 3, 4, 5, and 6, respectively; and / or

[0203] b) A second domain that specifically binds to c-Met, the second domain comprising the amino acid sequences HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:7, 8, 9, 10, 11, and 12, respectively.

[0204] In some embodiments, the antibody (e.g., a bispecific antibody) comprises:

[0205] a) Specifically binds to the first domain of EGFR, the first domain comprising the amino acid sequences HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 1, 2, 3, 4, 5, and 6, respectively; and

[0206] b) A second domain that specifically binds to c-Met, the second domain comprising the amino acid sequences HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:7, 8, 9, 10, 11, and 12, respectively.

[0207] In some implementations, the antibody (e.g., a bispecific antibody) comprises:

[0208] a) Contains a first domain that is at least 90% identical to the VH amino acid sequence of SEQ ID NO:13;

[0209] b) Contains a first domain that is at least 90% identical to the VL amino acid sequence of SEQ ID NO:14;

[0210] c) A second domain containing at least 90% of the same VH amino acid sequence as SEQ ID NO:15; and / or

[0211] d) Contains a second domain containing at least 90% of the same VL amino acid sequence as SEQ ID NO:16.

[0212] In some embodiments, the antibody (e.g., a bispecific antibody) comprises:

[0213] a) Contains a first domain that is at least 90% identical to the VH amino acid sequence of SEQ ID NO:13;

[0214] b) Contains a first domain that is at least 90% identical to the VL amino acid sequence of SEQ ID NO:14;

[0215] c) A second domain containing at least 90% of the VH amino acid sequence identical to that in SEQ ID NO:15; and

[0216] d) Contains a second domain containing at least 90% of the same VL amino acid sequence as SEQ ID NO:16.

[0217] In some implementations, the antibody (e.g., a bispecific antibody) comprises:

[0218] a) The first structural domain of VH containing SEQ ID NO:13;

[0219] b) The first structural domain of VL containing SEQ ID NO:14;

[0220] c) A second domain of VH containing SEQ ID NO:15; and / or

[0221] d) A second structural domain containing VL of SEQ ID NO:16.

[0222] In some implementations, the antibody (e.g., a bispecific antibody) comprises:

[0223] a) The first structural domain of VH containing SEQ ID NO:13;

[0224] b) The first structural domain of VL containing SEQ ID NO:14;

[0225] c) The second domain of VH containing SEQ ID NO:15; and

[0226] d) A second structural domain containing VL of SEQ ID NO:16.

[0227] In some embodiments, the antibody (e.g., a bispecific antibody) comprises:

[0228] a) An HC1 amino acid sequence that is at least 80% identical to SEQ ID NO:17;

[0229] b) An LC1 amino acid sequence that is at least 80% identical to SEQ ID NO:18;

[0230] c) An HC2 amino acid sequence that is at least 80% identical to SEQ ID NO:19; and / or

[0231] d) The LC2 amino acid sequence is at least 80% identical to that of SEQ ID NO:20.

[0232] In some embodiments, the antibody (e.g., a bispecific antibody) comprises:

[0233] a) An HC1 amino acid sequence that is at least 80% identical to SEQ ID NO:17;

[0234] b) An LC1 amino acid sequence that is at least 80% identical to SEQ ID NO:18;

[0235] c) An HC2 amino acid sequence that is at least 80% identical to SEQ ID NO:19; and

[0236] d) The LC2 amino acid sequence is at least 80% identical to that of SEQ ID NO:20.

[0237] In some embodiments, the antibody (e.g., a bispecific antibody) comprises:

[0238] a) HC1 of SEQ ID NO:17;

[0239] b) LC1 of SEQ ID NO:18;

[0240] c) HC2 of SEQ ID NO:19; and / or

[0241] d)LC2 of SEQ ID NO:20.

[0242] In a specific implementation, the antibody (e.g., a bispecific antibody) comprises:

[0243] a) HC1 of SEQ ID NO:17;

[0244] b) LC1 of SEQ ID NO:18;

[0245] c) HC2 of SEQ ID NO:19; and

[0246] d)LC2 of SEQ ID NO:20.

[0247] In some embodiments, the antibody (e.g., a bispecific antibody) is an IgG isotype. In some embodiments, the antibody (e.g., a bispecific antibody) is an IgG1 isotype. There are variations within the constant domain of IgG1 (e.g., well-known allotypes), such as those at positions 214, 356, 358, 422, 431, 435, and / or 436 (residue numbers according to EU numbers) (see, for example, IMGT Web Resources; IMGT Library (IG and TR); Proteins and Alleles; Allotypes). A bispecific anti-EGFR / c-Met antibody can be any IgG1 allotype, such as G1m17, G1m3, G1m1, G1m2, G1m27, or G1m28.

[0248] In some implementations, the antibody is a human antibody.

[0249] In this specific implementation, the antibody is ervantumab. Evantumab is an IgG1 anti-EGFR / c-Met bispecific antibody described in U.S. Patent No. 9,593,164.

[0250] Other anti-EGFR / c-Met antibodies (e.g., bispecific antibodies) may also be used in the methods disclosed herein, for example, by combining publicly available EGFR-binding VH / VL domains and c-Met-binding VH / VL domains.

[0251] In some embodiments, the antibody (e.g., a bispecific antibody) comprises a bibranched glycan structure with a fucose content between about 1% and about 15% or less than 20%.

[0252] Antibodies with reduced fucose content can be prepared using various methods reported for the successful expression of relatively high defucosylation antibodies with Fc oligosaccharides of the biantennary complex type. These methods include controlling culture osmotic pressure (Konno et al., Cytotechnology 64(:249-65, 2012)), using the variant CHO cell line Lec13 as the host cell line (Shields et al., J Biol Chem 277:26733-26740, 2002), using the variant CHO cell line EB66 as the host cell line (Olivier et al., MAbs; 2(4), 2010; electronic version prior to print; PMID:20562582), and using the rat hybridoma cell line YB2 / 0 as the host cell line (Shinkawa et al., J Biol Chem 278:3466-3473, (2003) Introducing small interfering RNA specifically targeting the α1,6-fucosyltransferase (FUT8) gene (Mori et al., Biotechnol Bioeng 88:901-908, 2004), or co-expressing β-1,4-N-acetylglucosyltransferase III and Golgi α-mannosidase II or potent α-mannosidase I inhibitors chifrine (Ferrara et al., JBiol Chem 281:5032-5036, 2006; Ferrara et al., Biotechnol Bioeng 93:851-861, 2006; Zhou et al., Biotechnol Bioeng 99:652-65, 2008). Generally, reducing the fucose content in the antibody glycan enhances antibody-mediated cytotoxicity (ADCC).

[0253] Generate anti-EGFR / c-Met antibodies

[0254] The anti-EGFR / c-Met antibody used in the methods disclosed herein can be generated, for example, by Fab arm exchange (or half-molecule exchange) between two monospecific bivalent antibodies, in the following manner: substitution is introduced at the heavy chain CH3 junction in each half-molecule to facilitate the formation of heterodimers of two antibody half-molecules with different specificities in an in vitro cell-free environment or using co-expression. The Fab arm exchange reaction is the result of a disulfide bond isomerization reaction and CH3 domain dissociation-association. The heavy chain disulfide bond in the hinge region of the parent monospecific antibody is reduced. The resulting free cysteine ​​of one of the parent monospecific antibodies forms an inter-heavy chain disulfide bond with the cysteine ​​residue of the second parent monospecific antibody molecule, and simultaneously the CH3 domain of the parent antibody is released and reformed through 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, each binding different epitopes (i.e., epitopes on EGFR and c-Met). For example, the bispecific antibody of the present invention can be used as described in International Patent Publication No. WO2011 / 131746. In the case of IgG1 antibody, a mutant F405L in one heavy chain and K409R in the other heavy chain can be used. For IgG2 antibody, wild-type IgG2 and IgG4 antibodies with F405L and R409K substitutions can be used. For IgG4 antibody, wild-type IgG4 and IgG4 antibodies with F405L and R409K substitutions can be used. To generate bispecific antibody, a first monospecific bivalent antibody and a second monospecific bivalent antibody are engineered to have the aforementioned mutation in the Fc region, and then these antibodies are incubated together under reducing conditions sufficient to allow disulfide isomerization of cysteine ​​in the hinge region; thereby generating bispecific antibody through Fab arm exchange. Ideally, the incubation conditions can be restored to non-reducing conditions. Exemplary reducing agents that can 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 for at least 90 minutes at a pH of 5-8, such as pH 7.0 or pH 7.4, in the presence of at least 25 mM 2-MEA or at least 0.5 mM dithiothreitol, at a temperature of at least 20°C.

[0255] The bispecific anti-EGFR / c-Met antibodies used in the methods disclosed herein can also be generated using designs such as those from Genentech, CrossMAbs (Roche), electrostatic matching (Chugai, Amgen, NovoNordisk, Oncomed), LUZ-Y (Genentech), chain exchange engineered domain bodies (SEEDbody) (EMD Serono), and Biclonic (Merus).

[0256] In the "mortar and pestle" strategy (see, for example, International Publication No. WO 2006 / 028936), selected amino acids at the interface forming the CH3 domain in human IgG can be mutated at positions affecting CH3 domain interactions, thereby promoting heterodimer formation. Amino acids with small side chains (mortar) are introduced into the heavy chain of an antibody that specifically binds to the first antigen, and amino acids with large side chains (mortar) are introduced into the heavy chain of an antibody that specifically binds to the second antigen. After co-expression of the two antibodies, heterodimers are formed due to the preferential interaction between the heavy chain with the "mortar" and the heavy chain with the "mortar". The exemplary CH3 substitution pairs forming the pestle and mortar (represented as the modification position in the first CH3 domain of the first heavy chain / the modification position in the second CH3 domain of the second heavy chain) are: T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V.

[0257] In addition to using a "mortar and pestle" strategy to facilitate Fab arm exchange, the CrossMAb technology also utilizes CH1 / CL domain replacement in one half of the arm to ensure that the resulting bispecific antibody is properly paired with light chains (see, for example, U.S. Patent No. 8,242,247).

[0258] Other exchange strategies can be used to generate the full-length bispecific antibody of the present invention as follows: in one or both arms of the bispecific antibody, a variable domain or a constant domain, or both, can be exchanged between or within the heavy chain and the light chain. These exchanges include, for example, VH-CH1 and VL-CL, VH and VL, CH3 and CL, and CH3 and CH1, as described in International Patent Publications Nos. WO2009 / 080254, WO2009 / 080251, WO2009 / 018386, and WO2009 / 080252.

[0259] Other strategies can also be used, such as promoting heavy chain heterodimerization by electrostatic interactions through substitution of positively charged residues on one CH3 surface and substitution of negatively charged residues on a second CH3 surface, as described in U.S. Patent Publication No. US2010 / 0015133, U.S. Patent Publication No. US2009 / 0182127, U.S. Patent Publication No. US2010 / 028637, or U.S. Patent Publication No. US2011 / 0123532. In other strategies, heterodimerization can be promoted by the following substitutions (represented as modified positions in the first CH3 domain of the first heavy chain / modified positions in the second CH3 domain of the second heavy chain): L351Y_F405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y _Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F or T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W, as described in U.S. Patent Publication No. US2012 / 0149876 or U.S. Patent Publication No. US2013 / 0195849.

[0260] SEEDbody technology can be used to generate the bispecific antibodies of the present invention. SEEDbody has selected IgG residues replaced by IgA residues in its constant domain to promote heterodimerization, as described in U.S. Patent No. US20070287170.

[0261] Standard methods are typically used to mutate molecules (such as the constant result domain of antibodies) at the DNA level.

[0262] In some embodiments, the antibody (e.g., a bispecific antibody) comprises a bibranched glycan structure with a fucose content between about 1% and about 15%. In some embodiments, the antibody comprises a bibranched glycan structure with a fucose content of less than about 20%.

[0263] Antibodies with reduced fucose content can be prepared using various methods reported for the successful expression of relatively high defucosylation antibodies with Fc oligosaccharides of the biantennary complex type. These methods include controlling culture osmotic pressure (Konno et al., Cytotechnology 64(:249-65, 2012)), using the variant CHO cell line Lec13 as the host cell line (Shields et al., J Biol Chem 277:26733-26740, 2002), using the variant CHO cell line EB66 as the host cell line (Olivier et al., MAbs; 2(4), 2010; electronic version prior to print; PMID:20562582), and using the rat hybridoma cell line YB2 / 0 as the host cell line (Shinkawa et al., J Biol Chem 278:3466-3473, (2003) Introducing small interfering RNA specifically targeting the α1,6-fucosyltransferase (FUT8) gene (Mori et al., Biotechnol Bioeng 88:901-908, 2004), or co-expressing β-1,4-N-acetylglucosyltransferase III and Golgi α-mannosidase II or potent α-mannosidase I inhibitors chifrine (Ferrara et al., JBiol Chem 281:5032-5036, 2006; Ferrara et al., Biotechnol Bioeng 93:851-861, 2006; Zhou et al., Biotechnol Bioeng 99:652-65, 2008). Generally, reducing the fucose content in the antibody glycan enhances antibody-mediated cytotoxicity (ADCC).

[0264] application

[0265] Anti-EGFR / c-Met antibodies (e.g., bispecific antibodies) and / or adjunctive therapies (e.g., chemotherapy) may be administered in one or more pharmaceutical compositions. In some embodiments, the pharmaceutical composition may also comprise a pharmaceutically acceptable carrier.

[0266] Methods for the subcutaneous formulation and administration of anti-EGFR / c-Met antibodies, such as ervantumab, are described in WO2022224187, which is incorporated herein by reference.

[0267] In some embodiments, a pharmaceutical composition comprising an anti-EGFR / c-Met antibody (e.g., a bispecific antibody) is administered via subcutaneous injection.

[0268] In some embodiments, the antibody (e.g., a bispecific antibody) is administered at a dose of about 140 mg to about 4,640 mg, such as about 1,050 mg to about 1,400 mg, about 1,750 mg to about 2,100 mg, about 1,600 mg to about 2,240 mg, about 3,200 mg to about 4,320 mg, about 1,600 mg to about 4,320 mg, about 3,520 mg to about 4,640 mg, or about 1,600 mg to about 4,640 mg.

[0269] In some embodiments, the antibody (e.g., a bispecific antibody) is administered in doses of approximately the following: 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, and 550 mg. , 560mg, 570mg, 580mg, 590mg, 600mg, 610mg, 620mg, 630mg, 640mg, 650mg, 660mg, 670mg, 680mg, 690mg, 700mg, 710mg, 720mg, 730mg, 740mg, 750mg, 760 mg, 770mg, 780mg, 790mg, 800mg, 810mg, 820mg, 830mg, 840mg, 850mg, 860mg, 870mg, 880mg, 890mg, 900mg, 910mg, 920mg, 930mg, 940mg, 950mg, 960mg, 97 0mg, 980mg, 990mg, 1,000mg, 1,010mg, 1,020mg, 1,030mg, 1,040mg, 1,050mg, 1,060mg, 1,070mg, 1,080mg, 1,090mg, 1,100mg, 1,110mg, 1,120mg, 1,13 0mg, 1,140mg, 1,150mg, 1,160mg, 1,170mg, 1,180mg, 1,190mg, 1,200mg, 1,210mg, 1,220mg, 1,230mg, 1,240mg, 1,250mg, 1,260mg, 1,270mg, 1,280mg, 1 ,290mg, 1,300mg, 1,310mg, 1,320mg, 1,330mg, 1,340mg, 1,350mg, 1,360mg, 1,370mg, 1,380mg, 1,390mg, 1,400mg, 1,410mg, 1,420mg, 1,430mg, 1,440 mg, 1,450mg, 1,460mg, 1,470mg, 1,480mg, 1,490mg, 1,500mg, 1,510mg, 1,520mg, 1,530mg, 1,540mg, 1,550mg, 1,560mg, 1,570mg, 1,580mg, 1,590mg, 1,600 mg, 1,610 mg, 1,620 mg, 1,630 mg, 1,640 mg, 1,650 mg, 1,660 mg, 1,670 mg, 1,680 mg, 1,690 mg, 1,700 mg, 1,710 mg, 1,720 mg, 1,730 mg, 1,740 mg, 1,750 mg, 1,760 mg, 1,770 mg, 1,780 mg, 1,790 mg, 1,800 mg, 1,810 mg, 1,820 mg, 1,830 mg, 1,840 mg, 1,850 mg, 1,860 mg, 1,870 mg, 1,880 mg, 1,890 mg, 1,900 mg, 1,910 mg, 1,920 mg, 1,930 mg, 1,940 mg, 1,950 mg, 1,960 mg, 1,970 mg, 1,980 mg, 1,990 mg, 2,000 mg, 2,010 mg, 2,020 mg, 2,030 mg, 2,040 mg, 2,050 mg, 2,060 mg, 2,070 mg, 2,080 mg, 2,090 mg, 2,100 mg, 2,110 mg, 2,120 mg, 2,130 mg, 2,140 mg, 2,150 mg, 2,200 mg, 2,230 mg, 2,240 mg, 2,250 mg, 2,300 mg, 2,350 mg, 2,400 mg, 2,450 mg, 2,500 mg, 2,550 mg, 2,600 mg, 2,650 mg, 2,700 mg, 2,750 mg, 2,800 mg, 2,850 mg, 2,900 mg, 3,000 mg, 3,100 mg, 3,200 mg, 3,300 mg, 3,350 mg, 3,360 mg, 3,370 mg, 3,400 mg, 3,450 mg, 3,500 mg, 3,510 mg, 3,515 mg, 3,520 mg, 3,525 mg, 3,530 mg, 3,540 mg, 3,550 mg, 3,560 mg, 3,570 mg, 3,580 mg, 3,590 mg, 3,600 mg, 3,650 mg, 3,700 mg, 3,750 mg, 3,800 mg, 3,850 mg, 3,900 mg, 3,950 mg, 4,000 mg, 4,100 mg, 4,200 mg, 4,300 mg, 4,310 mg, 4,320 mg, 4,330 mg, 4,400 mg, 4,500 mg, 4,600 mg, 4,610 mg, 4,620 mg, 4,630 mg, 4,640 mg, 4,650 mg or 4,700 mg.

[0270] In some embodiments, the antibody is administered at doses of about 700 mg, about 1,050 mg, about 1,400 mg, about 1,750 mg, about 2,100 mg, about 1,600 mg, about 2,240 mg, about 2,400 mg, about 3,360 mg, about 3,200 mg, about 4,320 mg, about 3,520 mg, or about 4,640 mg. In some embodiments, the antibody is administered at a dose of about 1,050 mg. In some embodiments, the antibody is administered at a dose of about 1,400 mg. In some embodiments, the antibody is administered at a dose of about 700 mg. In some embodiments, the antibody is administered at a dose of about 1,750 mg. In some embodiments, the antibody is administered at a dose of about 1,600 mg. In some embodiments, the antibody is administered at a dose of about 2,100 mg. In some embodiments, the antibody is administered at a dose of about 2,240 mg. In some embodiments, the antibody is administered at a dose of about 2,400 mg. In some embodiments, the antibody is administered at a dose of about 3,360 mg. In some embodiments, the antibody is administered at a dose of about 3,200 mg. In some embodiments, the antibody is administered at a dose of about 4,320 mg. In some embodiments, the antibody is administered at a dose of about 3,520 mg. In some embodiments, the antibody is administered at a dose of about 4,640 mg.

[0271] In some implementations, the antibody is administered at a dose of approximately 350 mg.

[0272] In some implementations, the antibody is administered at a dose of approximately 750 mg.

[0273] In some implementations, the antibody is administered at a dose of approximately 800 mg.

[0274] In some implementations, the antibody is administered at a dose of approximately 850 mg.

[0275] In some implementations, the antibody is administered at a dose of approximately 900 mg.

[0276] In some implementations, the antibody is administered at a dose of approximately 950 mg.

[0277] In some implementations, the antibody is administered at a dose of approximately 1,000 mg.

[0278] In some implementations, the antibody is administered at a dose of approximately 1,050 mg.

[0279] In some implementations, the antibody is administered at a dose of approximately 1,100 mg.

[0280] In some implementations, the antibody is administered at a dose of approximately 1,150 mg.

[0281] In some implementations, the antibody is administered at a dose of approximately 1,200 mg.

[0282] In some implementations, the antibody is administered at a dose of approximately 1,250 mg.

[0283] In some implementations, the antibody is administered at a dose of approximately 1,300 mg.

[0284] In some implementations, the antibody is administered at a dose of approximately 1,350 mg.

[0285] In some implementations, the antibody is administered at a dose of approximately 1,400 mg.

[0286] In some implementations, the antibody is administered at a dose of approximately 1,600 mg.

[0287] In some implementations, the antibody is administered at a dose of approximately 1,750 mg.

[0288] In some implementations, the antibody is administered at a dose of approximately 2,240 mg.

[0289] In some implementations, the antibody is administered at a dose of approximately 2,100 mg.

[0290] In some implementations, the antibody is administered at a dose of approximately 2,400 mg.

[0291] In some implementations, the antibody is administered at a dose of approximately 3,200 mg.

[0292] In some implementations, the antibody is administered at a dose of approximately 3,520 mg.

[0293] In some implementations, the antibody is administered at a dose of approximately 3,360 mg.

[0294] In some implementations, the antibody is administered at a dose of approximately 4,320 mg.

[0295] In some implementations, the antibody is administered at a dose of approximately 4,640 mg.

[0296] In some embodiments, the antibody is administered at a dose of at least about 3,000 mg, or at least about 3,100 mg, or at least about 3,200 mg, or at least about 3,300 mg, or at least about 3,400 mg, or at least about 3,500 mg. In some embodiments, the antibody is administered at a dose greater than about 3,000 mg, or greater than about 3,100 mg, or greater than about 3,200 mg.

[0297] In some embodiments, the antibody is administered to subjects weighing <80 kg at a dose of at least about 3,000 mg, or at least about 3,100 mg, or at least about 3,200 mg, or at least about 3,300 mg, or at least about 3,400 mg, or at least about 3,500 mg. In some embodiments, the antibody is administered to subjects weighing <80 kg at a dose greater than about 3,000 mg, or greater than about 3,100 mg, or greater than about 3,200 mg.

[0298] In some embodiments, the antibody is administered to subjects weighing ≥80 kg at a dose of at least about 4,000 mg, or at least about 4,100 mg, or at least about 4,200 mg, or at least about 4,300 mg, or at least about 4,400 mg, or at least about 4,500 mg, or at least about 4,600 mg. In some embodiments, the antibody is administered to subjects weighing ≥80 kg at a dose greater than about 4,300 mg, or greater than about 4,400 mg, or greater than about 4,500 mg, or greater than about 4,600 mg.

[0299] In some implementations, the antibody is administered at a dose of 1,600 mg for individuals weighing <80 kg and at a dose of 2,240 mg for individuals weighing ≥80 kg.

[0300] In a specific implementation plan, for individuals weighing <80 kg, the antibody is administered at a dose of 3,200 mg; for individuals weighing ≥80 kg, the antibody is administered at a dose of 4,320 mg.

[0301] In a specific implementation plan, for individuals weighing <80 kg, the antibody is administered at a dose greater than 3,200 mg; for individuals weighing ≥80 kg, the antibody is administered at a dose greater than 4,320 mg.

[0302] In a specific implementation plan, for individuals weighing <80 kg, the antibody is administered at a dose of 3,520 mg; for individuals weighing ≥80 kg, the antibody is administered at a dose of 4,640 mg.

[0303] In some implementations, the antibody is administered twice a week.

[0304] In some implementations, the antibody is administered once a week.

[0305] In some implementations, the antibody is administered every two weeks.

[0306] In some implementations, the antibody is administered once every three weeks.

[0307] In some implementations, the antibody is administered once every four weeks.

[0308] In some implementations, the antibody is administered once a week or once every four weeks. In a specific implementation, the antibody is administered once a week for the first four weeks, and then once every four weeks thereafter.

[0309] In some implementations, the antibody is administered over a 28-day cycle.

[0310] In some embodiments, the subject's body weight (BW) is <80 kg, and the antibody (e.g., a bispecific antibody, such as ervantumab) is administered once weekly at a dose of 1600 mg for the first 4 weeks (days 1, 8, 15, and 22 of cycle 1), and then once every 4 weeks at a dose of 3200 mg starting from cycle 2 (Q4W). In one embodiment, the composition is administered subcutaneously.

[0311] In some embodiments, the subject's body weight (BW) is 80 kg or more, and the antibody (e.g., a bispecific antibody, such as ervantomab) is administered once weekly at a dose of 2240 mg for the first 4 weeks (days 1, 8, 15, and 22 of cycle 1), and then once every 4 weeks at a dose of 4320 mg starting from cycle 2 (Q4W). In one embodiment, the composition is administered subcutaneously.

[0312] In some embodiments, the subject's body weight (BW) is <80 kg, and the antibody (e.g., a bispecific antibody, such as ervantumab) is administered once weekly at a dose of 1600 mg for the first 4 weeks (days 1, 8, 15, and 22 of cycle 1), and then once every 4 weeks at a dose of 3520 mg starting from cycle 2 (Q4W). In one embodiment, the composition is administered subcutaneously.

[0313] In some embodiments, the subject's body weight (BW) is <80 kg, and the antibody (e.g., a bispecific antibody, such as ervantumab) is administered once weekly at a dose of 1600 mg for the first 4 weeks (days 1, 8, 15, and 22 of cycle 1), and then administered once every 4 weeks at a dose of approximately 3,500 mg starting from cycle 2 (Q4W). In one embodiment, the composition is administered subcutaneously.

[0314] In some embodiments, the subject's body weight (BW) is <80 kg, and the antibody (e.g., a bispecific antibody, such as ervantomab) is administered once weekly at a dose of 1600 mg for the first 4 weeks (days 1, 8, 15, and 22 of cycle 1), and then administered once every 4 weeks at a dose greater than 3200 mg starting from cycle 2 (Q4W). In one embodiment, the composition is administered subcutaneously.

[0315] In some embodiments, the subject's body weight (BW) is 80 kg or more, and the antibody (e.g., a bispecific antibody, such as ervantumab) is administered once weekly at a dose of 2240 mg for the first 4 weeks (days 1, 8, 15, and 22 of cycle 1), and then once every 4 weeks at a dose of 4640 mg starting from cycle 2 (Q4W). In one embodiment, the composition is administered subcutaneously.

[0316] In some embodiments, the subject's body weight (BW) is 80 kg or more, and the antibody (e.g., a bispecific antibody, such as ervantumab) is administered once weekly at a dose of 2240 mg for the first 4 weeks (days 1, 8, 15, and 22 of cycle 1), and then once every 4 weeks at a dose of approximately 4600 mg starting from cycle 2 (Q4W). In one embodiment, the composition is administered subcutaneously.

[0317] In some embodiments, the subject's body weight (BW) is 80 kg or more, and the antibody (e.g., a bispecific antibody, such as ervantomab) is administered once weekly at a dose of 2240 mg for the first 4 weeks (days 1, 8, 15, and 22 of cycle 1), and then administered once every 4 weeks at a dose greater than 4,320 mg every 4 weeks starting from cycle 2. In one embodiment, the composition is administered subcutaneously.

[0318] In some embodiments, the subject's body weight (BW) is <80 kg, and the antibody (e.g., a bispecific antibody, such as ervantomab) is administered at a dose of 3520 mg every 4 weeks (Q4W). In one embodiment, the composition is administered subcutaneously.

[0319] In some embodiments, the subject's body weight (BW) is 80 kg or more, and the antibody (e.g., a bispecific antibody, such as ervantomab) is administered at a dose of 4640 mg every 4 weeks (Q4W). In one embodiment, the composition is administered subcutaneously.

[0320] In some implementations, an antibody (e.g., a bispecific antibody) is administered to generate approximately 325 µg / mL of the second cycle C. trough Value or approximately 286612 µg•h / mL AUC 0-672h Value. In some implementations, an antibody (e.g., a bispecific antibody) is administered to produce a second-cycle C value of approximately 300 µg / mL to approximately 350 µg / mL. trough Value. In some implementations, the antibody is administered to produce a second-cycle C value of approximately 310 µg / mL to approximately 340 µg / mL. troughValue. In some implementations, the antibody is administered to produce a second-cycle C value of approximately 320 µg / mL to approximately 330 µg / mL. trough value.

[0321] In some implementations, an antibody (e.g., a bispecific antibody) is administered to produce a second-cycle AUC of approximately 286,000 µg•h / mL to approximately 287,000 µg•h / mL. 0-672h Value. In some implementations, the antibody is administered to produce a second-cycle AUC of approximately 286,100 µg•h / mL to approximately 286,900 µg•h / mL. 0-672h Value. In some implementations, the antibody is administered to produce a second-cycle AUC of approximately 286,200 µg•h / mL to approximately 286,800 µg•h / mL. 0-672h Value. In some implementations, the antibody is administered to produce a second-cycle AUC of approximately 286,300 µg•h / mL to approximately 286,700 µg•h / mL. 0-672h Value. In some implementations, the antibody is administered to produce a second-cycle AUC of approximately 286,400 µg•h / mL to approximately 286,700 µg•h / mL. 0-672h Value. In some implementations, the antibody is administered to produce a second-cycle AUC of approximately 286,500 µg•h / mL to approximately 286,700 µg•h / mL. 0-672h Value. In some implementations, the antibody is administered to produce a second-cycle AUC of approximately 286,550 µg•h / mL to approximately 286,650 µg•h / mL. 0-672h Value. In some implementations, the antibody is administered to produce a second-cycle AUC of approximately 286,600 µg•h / mL to approximately 286,650 µg•h / mL. 0-672h value.

[0322] In some implementations, infusion-related reactions (IRRs) occurred less frequently in the group of subjects receiving bispecific anti-EGFR / c-Met antibodies every 4 weeks (Q4W) compared to the group receiving bispecific anti-EGFR / c-Met antibodies every 2 weeks (Q2W).

[0323] In some implementations, infusion-related reactions (IRRs) were less severe in the group of subjects receiving bispecific anti-EGFR / c-Met antibodies every 4 weeks (Q4W) compared to the group receiving bispecific anti-EGFR / c-Met antibodies every 2 weeks (Q2W).

[0324] In some implementations, the frequency of infusion-related reactions (IRRs) was lower in the group of subjects who received bispecific anti-EGFR / c-Met antibodies subcutaneously every 4 weeks (Q4W) compared to the group who received intravenous administration of bispecific anti-EGFR / c-Met antibodies every 2 weeks (Q2W).

[0325] In some implementations, infusion-related reactions (IRRs) were less severe in a group of subjects receiving bispecific anti-EGFR / c-Met antibodies subcutaneously every 4 weeks (Q4W) compared to a group receiving intravenous administration of bispecific anti-EGFR / c-Met antibodies every 2 weeks (Q2W).

[0326] In some implementations, the cancer is NSCLC, the bispecific anti-EGFR / c-Met antibody is ervantumab, and ervantumab is administered subcutaneously, wherein (i) if the subject's body weight (BW) is <80 kg, ervantumab is administered once weekly at a dose of 1600 mg for the first 4 weeks (days 1, 8, 15, and 22 of cycle 1), and then once every 4 weeks at a dose greater than 3200 mg (Q4W) starting from cycle 2; or (ii) if the subject's body weight (BW) is 80 kg or heavier, ervantumab is administered once weekly at a dose of 2240 mg for the first 4 weeks (days 1, 8, 15, and 22 of cycle 1), and then once every 4 weeks at a dose greater than 4,320 mg (Q4W) starting from cycle 2.

[0327] In some implementations, the cancer is NSCLC, the bispecific anti-EGFR / c-Met antibody is ervantumab, and ervantumab is administered subcutaneously, wherein (i) if the subject's body weight (BW) is <80 kg, ervantumab is administered once weekly at a dose of 1600 mg for the first 4 weeks (days 1, 8, 15, and 22 of cycle 1), and then once every 4 weeks at a dose of approximately 3,500 mg starting from cycle 2 (Q4W); or (ii) if the subject's body weight (BW) is 80 kg or heavier, ervantumab is administered once weekly at a dose of 2240 mg for the first 4 weeks (days 1, 8, 15, and 22 of cycle 1), and then once every 4 weeks at a dose of approximately 4,600 mg starting from cycle 2 (Q4W).

[0328] In some implementations, the cancer is NSCLC, the bispecific anti-EGFR / c-Met antibody is ervantumab, and ervantumab is administered subcutaneously, wherein (i) if the subject's body weight (BW) is <80 kg, ervantumab is administered once weekly at a dose of 1600 mg for the first 4 weeks (days 1, 8, 15, and 22 of cycle 1), and then once every 4 weeks at a dose of approximately 3,520 mg starting from cycle 2 (Q4W); or (ii) if the subject's body weight (BW) is 80 kg or heavier, ervantumab is administered once weekly at a dose of 2240 mg for the first 4 weeks (days 1, 8, 15, and 22 of cycle 1), and then once every 4 weeks at a dose of approximately 4,640 mg starting from cycle 2 (Q4W).

[0329] In some implementations, the subjects are also given one or more anticancer agents.

[0330] In some implementations, the subject is further administered a chemotherapy agent.

[0331] Additional information about erybrivantabine can be found in, for example, rybrivantabine. ® The prescription information for (amivantamab-vmjw) can be found in the product information leaflet (www.janssenlabels.com / package-insert / product-monograph / prescribing-information / RYBREVANT-pi.pdf), which is incorporated herein by reference.

[0332] Additional information regarding the use of amivantamab in patients can be found, for example, in the following literature: Park K. et al., Amivantamab in EGFR Exon 20 Insertion-Mutated Non-Small-Cell Lung Cancer Progressing on Platinum Chemotherapy: Initial Results From the CHRYSALISPhase I Study. J Clin Oncol. 20 Oct 20, 2021; 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. 16 Dec 2021; 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., December 16, 2021; these references are incorporated herein by reference.

[0333] In some implementations, the antibody is administered as a single therapy.

[0334] In some implementations, the method achieves partial or complete remission in subjects as defined by investigator assessment using the Remission Standards for Solid Tumors (RECIST) version 1.1.

[0335] Hyaluronidase

[0336] This composition may contain a certain amount of hyaluronidase, which leads to increased dispersion of the bispecific antibody during subcutaneous administration. The hyaluronidase has no adverse effect on the molecular integrity of the bispecific antibody. Furthermore, the hyaluronidase only alters the delivery of the bispecific antibody into systemic circulation but does not possess any properties that provide or facilitate the therapeutic effect of the bispecific antibody for systemic absorption. The hyaluronidase is not systemically bioavailable and does not adversely affect the molecular integrity of the bispecific antibody under the recommended storage conditions of this composition. Many suitable hyaluronidases are known. Preferred enzymes are human hyaluronidases, such as soluble human PH20 hyaluronidase, preferably a recombinant human hyaluronidase product referred to as rHuPH20. The amino acid sequence of soluble human PH20 hyaluronidase includes soluble human PH20 known as rHuPH20 and available under CAS Registry No. 757971-58-7. Soluble human PH20 hyaluronidase is described in International Publication No. WO2004 / 078140 and U.S. Patent No. 7,767,429, the entire contents of which are incorporated herein by reference. In some embodiments, the soluble hyaluronidase includes those whose sequences are shown in any of SEQ ID NO: 31-35. When expressed in cells, the soluble PH20 hyaluronidase includes a signaling sequence for transport in cells. Thus, in some embodiments, the amino acid sequence of the soluble PH20 hyaluronidase comprises SEQ ID NO: 36. In some embodiments, the amino acid sequence of the soluble PH20 hyaluronidase comprises SEQ ID NO: 32, namely residues 36-482 of wild-type human hyaluronidase. In some embodiments, the amino acid sequence of the soluble PH20 hyaluronidase comprises SEQ ID NO: 33. In some embodiments, the amino acid sequence of the soluble PH20 hyaluronidase comprises SEQ ID NO: 34. In some embodiments, the soluble PH20 hyaluronidase comprises rHuPH20, which contains the amino acid sequence of SEQ ID NO: 35. In some embodiments, the amino acid sequence of the soluble PH20 hyaluronidase comprises SEQ ID NO: 31. In some embodiments, when expressed in cells, the soluble PH20 hyaluronidase comprises a mixture of substances that may contain any of SEQ ID NO: 31, 32, 33, 34, and 35 in varying abundances. The average molecular weight is 61 kDa.

[0337] rHuPH20 refers to a composition typically linked to a native or heterologous signal sequence (residues 1-35 of SEQ ID NO: 36) produced when a nucleic acid encoding residues 36-482 of SEQ ID NO: 36 is expressed in cells such as CHO cells. rHuPH20 is produced by expressing nucleic acid molecules (such as those encoding amino acids 1-482 as shown in SEQ ID NO: 36) in mammalian cells. Post-translational processing removes the 35-amino acid signal sequence. Due to heterogeneity at the C-terminus when produced in culture media, products named rHuPH20 include mixtures of substances that may contain one or more of peptides 36-480, 36-481, and 36-482 of SEQ ID NO: 36 in varying abundances, as well as some shorter peptides. Typically, rHuPH20 is produced in cells that promote proper N-glycosylation to maintain viability (such as CHO cells, e.g., DG44 CHO cells). In some embodiments, the hyaluronidase is soluble human PH20 (rHuPH20) containing the amino acid sequence of SEQ ID NO: 35. In some embodiments, the hyaluronidase is soluble human PH20 (rHuPH20) containing the amino acid sequence of SEQ ID NO: 31. In some embodiments, the hyaluronidase is soluble human PH20 (rHuPH20) containing the amino acid sequence of SEQ ID NO: 32. In some embodiments, the hyaluronidase is soluble human PH20 (rHuPH20) containing the amino acid sequence of SEQ ID NO: 33. In some embodiments, the hyaluronidase is soluble human PH20 (rHuPH20) containing the amino acid sequence of SEQ ID NO: 34.

[0338]

[0339]

[0340]

[0341] Additional treatment agents

[0342] In some embodiments, the subject is also administered one or more anticancer agents. In some embodiments, an anti-EGFR / c-Met antibody (e.g., a bispecific antibody) and one or more additional therapeutic agents (e.g., a chemotherapy agent) are administered during the same treatment cycle according to each of their respective dosing regimens. In some embodiments, the antibody and one or more additional therapeutic agents are administered separately (e.g., sequentially). For combination therapy, one or more anticancer agents may be administered using recommended doses and dosage forms of the anticancer agents.

[0343] In some embodiments, one or more additional therapeutic agents are one or more anticancer therapies. In some embodiments, one or more additional therapeutic agents include one or more chemotherapeutic agents.

[0344] In some implementations, the subject is further administered a tyrosine kinase inhibitor (TKI). In some implementations, the TKI is lazertinib. In some implementations, lazertinib is administered at a dose of 240 mg daily.

[0345] Subjects

[0346] The terms “subject” and “patient” are used interchangeably herein. “Patient in need” or “subject in need” refers to a mammalian subject, preferably a human, who has been diagnosed with or suspected of having a disease and to whom, according to the method of the invention, will be or has already been administered the bispecific anti-EGFR anti-MET antibody. “Patient in need” or “subject in need” includes those subjects who already have undesirable physiological changes or diseases, as well as those subjects who are predisposed to having such changes or diseases.

[0347] In some implementation schemes, the subjects are 18 years of age or older, such as 18 to under 40, 18 to under 45, 18 to under 50, 18 to under 55, 18 to under 60, 18 to under 65, 18 to under 70, 18 to under 75, 40 to under 75, 45 to under 75, 50 to under 75, 55 to under 75, 60 to under 75, 65 to under 75, 60 to under 75, 40 or older, 45 or older, 50 or older, 55 or older, 60 or older, 65 or older, 70 or older, or 75 or older.

[0348] In some implementations, the subjects are children. In some implementations, the subjects are 18 years of age or younger, such as 0-18 years, 0-12 years, 0-16 years, 0-17 years, 2-12 years, 2-16 years, 2-17 years, 2-18 years, 3-12 years, 3-16 years, 3-17 years, 3-18 years, 4-12 years, 4-16 years, 4-17 years, 4-18 years, 6-12 years, 6-16 years, 6-17 years, 6-18 years, 9-12 years, 9-16 years, 9-17 years, 9-18 years, 12-16 years, 12-17 years, or 12-18 years.

[0349] In some implementations, the subject has been diagnosed with cancer for at least approximately 1 month, for example, at least approximately: 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 other implementations, the subject is newly diagnosed with cancer.

[0350] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is advanced cancer. In some embodiments, the cancer is an advanced solid malignant tumor. In some embodiments, the cancer is recurrent and / or metastatic. In some embodiments, the cancer is recurrent. In some embodiments, the cancer is metastatic. In some embodiments, the cancer is unresectable.

[0351] In some implementation schemes, the subjects have been diagnosed with advanced solid malignancies and have received all standard treatment options or are no longer suitable for other standard treatment options.

[0352] In some implementations, the subjects have cancer that expresses EGFR or c-Met.

[0353] In some implementations, the subject has cancer with at least one mutation in EGFR. In some implementations, the at least one mutation in EGFR is exon 19 deletion (Ex19del) or L858R substitution.

[0354] In some implementations, the subjects did not receive any treatment.

[0355] In some implementations, the subject has received one or more prior anticancer therapies. In some implementations, one or more prior anticancer therapies include one or more chemotherapy agents, checkpoint inhibitors, targeted anticancer therapies, or kinase inhibitors, or any combination thereof. In specific implementations, the subject has relapsed or developed resistance to one or more prior anticancer therapies.

[0356] In some implementations, the subject has received prior treatment with platinum-based chemotherapy and a PD-1 / PD-L1 inhibitor. In some implementations, the subject has received prior treatment with platinum-based chemotherapy. In some implementations, the subject has received prior treatment with a PD-1 / PD-L1 inhibitor.

[0357] In some implementations, the subject has not previously received anti-EGFR therapy. In some implementations, the subject has not previously received anti-EGFR antibody therapy. In some implementations, the subject has not previously received anti-EGFR tyrosine kinase inhibitor (TKI) therapy.

[0358] Implementation Plan

[0359] The following provides enumerated embodiments of the invention. These embodiments are merely exemplary and do not limit the scope of this disclosure or the appended claims.

[0360] 1. A method for treating a subject with cancer expressing epidermal growth factor receptor (EGFR) or hepatocyte growth factor receptor (c-Met), the method comprising administering to the subject an isolated bispecific anti-EGFR / c-Met antibody, said antibody comprising a first domain binding to EGFR and a second domain binding to c-Met.

[0361] The first structural domain includes the heavy chain complementarity determination region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity determination region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6.

[0362] Furthermore, the second structural domain includes 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.

[0363] The bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 3520 mg to approximately 4640 mg.

[0364] 2. The method according to embodiment 1, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 3520 mg.

[0365] 3. The method according to embodiment 1, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 4640 mg.

[0366] 4. The method according to embodiment 1, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 3520 mg when the subject weighs less than 80 kg, and at a dose of approximately 4640 mg when the subject weighs 80 kg or more.

[0367] 5. The method according to any one of embodiments 1 to 4, wherein the bispecific anti-EGFR / c-Met antibody is administered once every 28 days.

[0368] 6. The method according to any one of embodiments 1 to 5, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously.

[0369] 7. The method according to any one of embodiments 1 to 6, wherein the bispecific anti-EGFR / c-Met antibody is co-prepared with hyaluronidase.

[0370] 8. The method according to any one of embodiments 1 to 7, wherein the method further comprises an initial cycle (cycle 1), the initial cycle comprising administering the bispecific antibody once weekly for four weeks at a dose of about 1600 mg if the subject weighs less than 80 kg or at a dose of about 2240 mg if the subject weighs 80 kg or more.

[0371] 9. The method according to any one of embodiments 1 to 8, wherein the first domain of EGFR includes the heavy chain variable region (VH) of SEQ ID NO: 13 and the light chain variable region (VL) of SEQ ID NO: 14, and the second domain of c-Met includes the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16.

[0372] 10. The method according to any one of embodiments 1 to 9, wherein the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype.

[0373] 11. The method according to any one of embodiments 1 to 10, wherein the bispecific anti-EGFR / c-Met antibody comprises the first heavy chain (HC1) of SEQ ID NO: 17, the first light chain (LC1) of SEQ ID NO: 18, the second heavy chain (HC2) of SEQ ID NO: 19, and the second light chain (LC2) of SEQ ID NO: 20.

[0374] 12. The method according to any one of embodiments 1 to 11, wherein the bispecific anti-EGFR / c-Met antibody has a bibranched polysaccharide structure with a fucose content between about 1% and about 15% or less than 20%.

[0375] 13. The method according to any one of embodiments 1 to 12, wherein the cancer expressing EGFR or c-Met is a solid tumor.

[0376] 14. A method of subcutaneously administering an isolated bispecific anti-EGFR / c-Met antibody to a subject with cancer expressing EGFR or c-Met, said antibody comprising a first domain binding to EGFR and a second domain binding to c-Met.

[0377] The first structural domain includes the heavy chain complementarity determination region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity determination region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6.

[0378] Furthermore, the second structural domain includes 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.

[0379] The bispecific anti-EGFR / c-Met antibody was administered to generate approximately 325 µg / mL of the second cycle C. trough Value or approximately 286612 µg•h / mL AUC 0-672h value.

[0380] 15. The method according to embodiment 14, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 3520 mg.

[0381] 16. The method according to embodiment 14, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 4640 mg.

[0382] 17. The method according to embodiment 14, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 3520 mg when the subject weighs less than 80 kg, and at a dose of about 4640 mg when the subject weighs 80 kg or more.

[0383] 18. The method according to any one of embodiments 14 to 17, wherein the bispecific anti-EGFR / c-Met antibody is administered once every 28 days.

[0384] 19. The method according to any one of embodiments 14 to 18, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously.

[0385] 20. The method according to any one of embodiments 14 to 19, wherein the bispecific anti-EGFR / c-Met antibody is co-formulated with hyaluronidase.

[0386] 21. The method according to any one of embodiments 14 to 20, wherein the method further comprises an initial cycle (cycle 1), the initial cycle comprising administering the bispecific antibody once weekly for four weeks at a dose of about 1600 mg if the subject weighs less than 80 kg or at a dose of about 2240 mg if the subject weighs 80 kg or more.

[0387] 22. The method according to any one of embodiments 14 to 21, wherein the first domain of EGFR comprises the heavy chain variable region (VH) of SEQ ID NO: 13 and the light chain variable region (VL) of SEQ ID NO: 14, and the second domain of c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16.

[0388] 23. The method according to any one of embodiments 14 to 22, wherein the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype.

[0389] 24. The method according to any one of embodiments 14 to 23, wherein the bispecific anti-EGFR / c-Met antibody comprises the first heavy chain (HC1) of SEQ ID NO: 17, the first light chain (LC1) of SEQ ID NO: 18, the second heavy chain (HC2) of SEQ ID NO: 19, and the second light chain (LC2) of SEQ ID NO: 20.

[0390] 25. The method according to any one of embodiments 14 to 24, wherein the bispecific anti-EGFR / c-Met antibody has a bibranched glycan structure with a fucose content between about 1% and about 15% or less than 20%.

[0391] 26. The method according to any one of embodiments 14 to 25, wherein the cancer expressing EGFR or c-Met is a solid tumor.

[0392] 27. The method according to any one of embodiments 1 to 26, wherein the cancer expressing EGFR or c-Met is non-small cell lung cancer (NSCLC).

[0393] 28. The method according to any one of embodiments 1 to 27, wherein the frequency of infusion-related reactions (IRRs) is lower in the subject population that receives the bispecific anti-EGFR / c-Met antibody every 4 weeks (Q4W) compared to the subject population that receives the bispecific anti-EGFR / c-Met antibody every 2 weeks (Q2W).

[0394] 29. The method according to any one of embodiments 1 to 28, wherein the infusion-related response (IRR) is less severe in the subject population administered the bispecific anti-EGFR / c-Met antibody every 4 weeks (Q4W) compared to the subject population administered the bispecific anti-EGFR / c-Met antibody every 2 weeks (Q2W).

[0395] 30. The method according to any one of embodiments 1 to 27, wherein the frequency of infusion-related reactions (IRRs) is lower in the subject population that receives the bispecific anti-EGFR / c-Met antibody subcutaneously every 4 weeks (Q4W) compared to the subject population that receives the bispecific anti-EGFR / c-Met antibody intravenously every 2 weeks (Q2W).

[0396] 31. The method according to any one of embodiments 1 to 28, wherein the infusion-related response (IRR) is less severe in the subject population that receives the bispecific anti-EGFR / c-Met antibody subcutaneously every 4 weeks (Q4W) compared to the subject population that receives the bispecific anti-EGFR / c-Met antibody intravenously every 2 weeks (Q2W).

[0397] 32. The method according to any one of embodiments 1 to 31, wherein the cancer is NSCLC, the bispecific anti-EGFR / c-Met antibody is ervantumab, and the ervantumab is administered subcutaneously, wherein (i) if the subject's body weight (BW) is <80 kg, the ervantumab is administered once weekly at a dose of 1600 mg for the first 4 weeks (days 1, 8, 15, and 22 of cycle 1), and then administered once every 4 weeks at a dose greater than 3200 mg (Q4W) starting from cycle 2; or (ii) if the subject's body weight (BW) is 80 kg or heavier, the ervantumab is administered once weekly at a dose of 2240 mg for the first 4 weeks (days 1, 8, 15, and 22 of cycle 1), and then administered once every 4 weeks at a dose greater than 4,320 mg (Q4W) starting from cycle 2.

[0398] 33. The method according to any one of embodiments 1 to 31, wherein the cancer is NSCLC, the bispecific anti-EGFR / c-Met antibody is ervantumab, and the ervantumab is administered subcutaneously, wherein (i) if the subject's body weight (BW) is <80 kg, the ervantumab is administered once weekly at a dose of 1600 mg for the first 4 weeks (days 1, 8, 15, and 22 of cycle 1), and then administered once every 4 weeks at a dose of about 3,500 mg starting from cycle 2 (Q4W); or (ii) if the subject's body weight (BW) is 80 kg or heavier, the ervantumab is administered once weekly at a dose of 2240 mg for the first 4 weeks (days 1, 8, 15, and 22 of cycle 1), and then administered once every 4 weeks at a dose of about 4,600 mg starting from cycle 2 (Q4W).

[0399] 34. The method according to any one of embodiments 1 to 31, wherein the cancer is NSCLC, the bispecific anti-EGFR / c-Met antibody is ervantumab, and the ervantumab is administered subcutaneously, wherein (i) if the subject's body weight (BW) is <80 kg, the ervantumab is administered once weekly at a dose of 1600 mg for the first 4 weeks (days 1, 8, 15, and 22 of cycle 1), and then administered once every 4 weeks at a dose of approximately 3,520 mg starting from cycle 2 (Q4W); or (ii) if the subject's body weight (BW) is 80 kg or heavier, the ervantumab is administered once weekly at a dose of 2240 mg for the first 4 weeks (days 1, 8, 15, and 22 of cycle 1), and then administered once every 4 weeks at a dose of approximately 4,640 mg starting from cycle 2 (Q4W).

[0400] 35. The method according to any one of embodiments 1 to 34, wherein the cancer is a cancer expressing EGFR or c-Met, wherein EGFR contains one or more mutations.

[0401] 36. The method according to embodiment 35, wherein the one or more EGFR mutations are deletions (Ex19del) or L858R substitutions in exon 19.

[0402] 37. The method according to any one of embodiments 1 to 36, wherein the subject has not received treatment.

[0403] 38. The method according to any one of embodiments 1 to 36, wherein the subject has received one or more prior anticancer therapies.

[0404] 39. The method according to embodiment 38, wherein the one or more prior anticancer therapies comprise at least one standard of care (SOC).

[0405] 40. The method according to any one of embodiments 1 to 39, wherein the bispecific anti-EGFR / c-Met antibody is administered in combination with hyaluronidase.

[0406] 41. The method according to any one of embodiments 1 to 39, wherein the bispecific anti-EGFR / c-Met antibody is co-prepared with hyaluronidase.

[0407] 42. The method according to embodiment 40 or 41, wherein the hyaluronidase is PH20.

[0408] 43. The method according to any one of embodiments 40 to 42, wherein the PH20 is recombinant human PH20 (rHuPH20).

[0409] 44. The method according to any one of embodiments 40 to 43, wherein the PH20 comprises any one or more of SEQ ID NO:31-42.

[0410] 45. The method according to any one of embodiments 40 to 44, wherein the PH20 comprises any one or more of SEQ ID NO: 31, 35, 34, 33 or 32.

[0411] Example

[0412] Example 1. Subcutaneous administration of ervantumab every 4 weeks (Q4W) in patients with advanced solid malignancies: 1b Phase 1 PALOMA study .

[0413] summary

[0414] background Evantuximab (ami) is an EGFR-MET bispecific antibody with immune cell-directed activity, approved for intravenous (IV) administration. Compared with historical experience (Minchom ASCO 2023), the subcutaneous (SC) formulation of ami using Q2W (1600 mg (2240 ​​mg if ≥80 kg)) and Q3W (2400 mg (3360 mg if ≥80 kg)) regimens significantly reduced the IRR rate (16% for SC compared to 67% for IV) and administration time (≤7 minutes for SC compared to 2 to 4 hours for IV). We sought to identify an ami Q4W SC dose that would improve patient (pt) convenience.

[0415] method The objective of PALOMA (NCT0406381) is to evaluate the feasibility, safety, and pharmacokinetics of ami SC in patients with advanced solid tumors who may benefit from EGFR / MET-guided therapy. ami SC is administered weekly for the first 4 weeks (1600 mg [≥80 kg: 2240 mg]), followed by 3200 mg [≥80 kg: 4320 mg] every 4 weeks. ami SC is administered via manual bolus injection over the abdominal region.

[0416] result Of the 127 patients recruited by PALOMA, 19 (median age: 62 years) received ami SCQ4W. The majority of patients were Asian (68%) and female (53%); 17 (89%) had non-small cell lung cancer, and 2 (11%) had other solid tumors. Four patients (21%) experienced IRR, all of which were grade 1-2. IRR-related symptoms were fever (2 patients), chills, pruritus, urticaria, and myalgia (1 patient each). Rash was the most common AE (79%), primarily grade 1-2, with 2 cases being grade 3. Eight patients (42%) reported ≥ grade 3 AEs, of which 3 (16%) were related to ami SC (2 patients with rash, 1 patient with hypokalemia). Two patients discontinued SC due to AEs, neither of which were unrelated to treatment.

[0417] No antidrug antibodies were detected in 17 patients with immunogenicity data. The Q4W SC dose was tested during cycle 2 of C. trough and AUC 0-672hThe geometric mean values ​​were 325 µg / mL and 286612 µg•h / mL, respectively. Based on these data, SC Q4W RP2D was refined to 3520 mg (≥80 kg: 4640 mg). The simulated geometric mean ratio of Q4W RP2D to the reference IV dose for C trough The value was 1.20 (90% CI, 1.12–1.30), and for AUC 0-662h was 1.31 (90% CI, 1.24-1.39).

[0418] in conclusion Compared to historical ami IV rates, ami SC Q4W had a lower IRR rate and fewer qualitative symptoms. SC Q4W R2PD at 3520 mg (≥80 kg: 4640 mg) achieved exposure comparable to the approved IV dose and was further evaluated in the Phase 2 PALOMA-2 (NCT05498428) study. Monthly SC dosing of ami will improve the patient and provider experience.

[0419] result

[0420] Patient demographic and baseline characteristics are shown in Table 1.

[0421] Table 1. Demographic and Baseline Characteristics

[0422]

[0423] One patient has colorectal cancer, and the other has renal cell carcinoma.

[0424] SC Q4W Pharmacokinetics

[0425] As previously reported, the ervantumab SC Q2W dose is 1600 mg (≥80 kg: 2240 mg) and the SC Q3W dose is 2400 mg (≥80 kg: 3360 mg) (Minchom A et al., submitted to the American Society of Clinical Oncology (ASCO) 2023; June 2-6, 2023; Chicago, IL, USA).

[0426] First, the Q4W dose of ervantumab was evaluated as follows:

[0427] Cycle 1: The first 4 weeks (QW) consist of 1600 mg per week for subjects weighing less than 80 kg [2240 mg per week for subjects weighing 80 kg or more], and

[0428] Cycle 2+: Thereafter Q4W (3200mg if subject weighs less than 80kg [4320mg if subject weighs 80kg or more]); administered manually via abdominal injection.

[0429] However, when compared to these values ​​for the approved Q2W IV dose of 1050 mg (≥80 kg: 1400 mg), this dosing regimen results in a lower C. max Equal or higher C trough Non-inferiority AUC 0-672h .

[0430] Next, if the subject weighs less than 80 kg, the SC Q4W dose is increased to 3520 mg (4640 mg if the subject weighs 80 kg or more) as RP2D to achieve steady-state C at the approved IV Q2W dose. trough The predicted steady-state C of SC Q4W max (not exceeding the approved IV dose of C) max (125% of the original value). Pharmacokinetic parameters for Q4W SC 3520 mg (≥80 kg: 4640 mg) administration compared to Q2W IV administration are shown in Table 2. The administration time for SC ervantumab in Q4W was consistent with that in Q2W and Q3W administration (approximately 7 to 10 minutes), assuming an injection rate of 3 mL / min. No anti-drug antibodies were observed with SC ervantumab.

[0431] Table 2. 3520mg (≥80kg: 4640mg) Q4W SC dose compared to reference 1050mg (≥80kg: 1400mg) Q2W IV dose simulated GMR

[0432]

[0433] Security Overview

[0434] The most common adverse events (AEs) were EGFR and MET-related, primarily grade 1-2. The safety profile of SC ervantumab Q4W was consistent with previous experience with ervantumab monotherapy (Minchom A et al., ASCO 2023). ≥ grade 3 AEs occurred in 9 patients (47%) using SC ervantumab, including 3 reported treatment-related events (2 cases of acneiform dermatitis and 1 case of paronychia). Cumulative grouped rashes of all grades occurred in 15 patients (79%). Rash was defined by the following preferred terms: dermatitis, acneiform dermatitis, erythematous rash, and maculopapular rash. Three patients experienced dose reductions due to treatment-related AEs. Two patients discontinued SC ervantumab due to treatment-independent AEs. A safety profile summary is shown in Table 3.

[0435] Table 3. Security Overview

[0436]

[0437] Incidence of IRR and IRR-related symptoms

[0438] Three patients (16%) experienced infusion-related reactions (IRRs) with SC ervantumab Q4W; all were grade 1-2 and occurred after the first dose. For the three types of IRR, onset occurred at 3 hours, 11 hours, and >24 hours after SC administration. One patient received diphenhydramine and clotrimazole (as IRR treatment) for pruritus. No recurrent IRR was reported with continuous administration. The incidence of IRR and IRR-related symptoms in SC ervantumab Q4W compared to IV ervantumab Q2W is shown in... Figure 1 middle.

[0439] in conclusion

[0440] The SC ervantumab Q4W dose is 3520 mg (≥80 kg: 4640 mg); SC ervantumab Q4W is administered weekly (QW) for the first 4 weeks (1600 mg [≥80 kg: 2240 mg]), and thereafter Q4W; administered manually via abdominal injection. The identified SC ervantumab Q4W dose achieved exposure comparable to the approved IV formulation. The administration time of SC ervantumab Q4W is consistent with the administration time of Q2W and Q3W (approximately 7 to 10 minutes).

[0441] The safety profile of SC ervantumab demonstrated a reduced IRR. The observed IRR rate was 16%. Compared to Q2W IV ervantumab, IRR was less severe and less frequent with Q4W dosing of SC ervantumab.

[0442] Example 2. Subcutaneous (SC) administration of ervantumab every 4 weeks (Q4W) in advanced NSCLC with EGFR mutation (EGFRm). Galazacitinib as first-line treatment: Results from the Phase 2 PALOMA-2 study

[0443] backgroundBased on the MARIPOSA study, intravenous (IV) ervantumab (ami) galazinetinib (laz) was approved for first-line (1L) treatment of EGFRm advanced NSCLC. In MARIPOSA (median follow-up, 22.0 months), ami IV + laz administered every 2 weeks (Q2W) significantly prolonged progression-free survival (PFS) compared to osimertinib (HR, 0.70; P < 0.001). Among all responders, the objective response rate (ORR) was 86% in participants treated with ami IV + laz, as determined by a blinded, independent central review. In cohorts 1 and 6 of the bridging PALOMA-2 study (NCT05498428), 1L amiSC Q2W + laz demonstrated similar response rates to historical ami IV Q2W + laz data in EGFRm NSCLC, with an improved safety profile including a significantly lower administration-related response (ARR). The PALOMA-2 cohort 5 evaluated the efficacy, PK, and safety of 1L amiSC Q4W + laz in EGFRm NSCLC.

[0444] method This study recruited participants with treatment-naïve EGFRm (Ex19del / L858R) advanced NSCLC. ami SC (conformed with hyaluronidase; rHuPH20) was administered via abdominal injection, with a dosing regimen of 1600 mg (2240 ​​mg if ≥80 kg) once weekly for the first 4 weeks, followed by 3520 mg (4640 mg if ≥80 kg) once weekly for 4 weeks thereafter. Laz 240 mg was administered orally daily. Prophylactic anticoagulation was recommended for the first 4 months of treatment. The primary endpoint was the objective response rate (ORR) assessed by the investigator according to RECIST v1.1.

[0445] result As of the data cutoff (October 24, 2024), Cohort 5 was fully enrolled with 77 participants who received ami SC Q4W+ laz (median follow-up, 6.5 months). The median age was 63 years; 68% of participants were female and 62% were Asian. 43% of participants had brain metastases at screening. At the data cutoff, 67 (87%) participants were undergoing study treatment.

[0446] The investigator-provided ORR was 82% (95% CI, 71-90), and the independent central review (ICR) ORR was 87% (95% CI, 77-94). The investigator-provided confirmed ORR was 79% (95% CI, 69-88), and the ICR-provided confirmed ORR was 83% (95% CI, 73-91). The median time to response was 8.1 weeks (range, 7.0-16.5). The median duration of response, PFS, and overall survival were not estimable.

[0447] No new safety signals were observed. Most adverse events (AEs) occurring during treatment were EGFR / MET-related, with paronychia, hypoalbuminemia, and rash being the most common. Nine (12%) participants reported an ARR (grade ≥3:1 [1%]). A total of 67 (87%) participants received any prophylactic anticoagulation. Ten (13%) participants reported venous thromboembolic events (VTE) (no grade ≥3). The bleeding rate for grade ≥3 events was low (1%).

[0448] The interruption rate of ami was 8% due to treatment-related adverse events. The mean (SD) ami concentration on day 1 of cycle 2 was 366 (112) µg / mL (n=56), consistent with historical ami IV and SC Q2W data.

[0449] in conclusion In participants with EGFRm advanced NSCLC, 1L treatment with ami SC Q4W + laz showed similar response rates to historical ami IV Q2W data with lower ARR; the incidence of VTE due to prophylactic anticoagulation was lower. The ami SC Q4W regimen is expected to further improve participant convenience and overall treatment experience.

Claims

1. A method for treating a subject with cancer expressing epidermal growth factor receptor (EGFR) or hepatocyte growth factor receptor (c-Met), the method comprising administering to the subject an isolated bispecific anti-EGFR / c-Met antibody, said antibody comprising a first domain binding to EGFR and a second domain binding to c-Met. The first structural domain includes the heavy chain complementarity determination region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity determination region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO:

6. Furthermore, the second structural domain includes 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. The bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 3520 mg to approximately 4640 mg.

2. The method of claim 1, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 3520 mg.

3. The method of claim 1, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 4640 mg.

4. The method of claim 1, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 3520 mg when the subject weighs less than 80 kg, and at a dose of about 4640 mg when the subject weighs 80 kg or more.

5. The method according to any one of claims 1 to 4, wherein the bispecific anti-EGFR / c-Met antibody is administered once every 28 days.

6. The method according to any one of claims 1 to 5, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously.

7. The method according to any one of claims 1 to 6, wherein the bispecific anti-EGFR / c-Met antibody is co-formulated with hyaluronidase.

8. The method according to any one of claims 1 to 7, wherein the method further comprises an initial cycle (cycle 1), the initial cycle comprising administering the bispecific antibody once weekly for four weeks at a dose of about 1600 mg if the subject weighs less than 80 kg or at a dose of about 2240 mg if the subject weighs 80 kg or more.

9. The method according to any one of claims 1 to 8, wherein the first domain of EGFR comprises the heavy chain variable region (VH) of SEQ ID NO: 13 and the light chain variable region (VL) of SEQ ID NO: 14, and the second domain of c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO:

16.

10. The method according to any one of claims 1 to 9, wherein the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype.

11. The method according to any one of claims 1 to 10, wherein the bispecific anti-EGFR / c-Met antibody comprises the first heavy chain (HC1) of SEQ ID NO: 17, the first light chain (LC1) of SEQ ID NO: 18, the second heavy chain (HC2) of SEQ ID NO: 19, and the second light chain (LC2) of SEQ ID NO:

20.

12. The method according to any one of claims 1 to 11, wherein the bispecific anti-EGFR / c-Met antibody has a bibranched glycan structure with a fucose content between about 1% and about 15% or less than about 20%.

13. The method according to any one of claims 1 to 12, wherein the cancer expressing EGFR or c-Met is a solid tumor.

14. A method of subcutaneously administering an isolated bispecific anti-EGFR / c-Met antibody to a subject with cancer expressing EGFR or c-Met, said antibody comprising a first domain binding to EGFR and a second domain binding to c-Met. The first structural domain includes the heavy chain complementarity determination region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity determination region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO:

6. Furthermore, the second structural domain includes 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. The bispecific anti-EGFR / c-Met antibody was administered to generate approximately 325 µg / mL of the second cycle C. trough Value or approximately 286612 µg•h / mL AUC 0-672h value.

15. The method of claim 14, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 3520 mg.

16. The method of claim 14, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 4640 mg.

17. The method of claim 14, wherein the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 3520 mg when the subject weighs less than 80 kg, and at a dose of about 4640 mg when the subject weighs 80 kg or more.

18. The method according to any one of claims 14 to 17, wherein the bispecific anti-EGFR / c-Met antibody is administered once every 28 days.

19. The method according to any one of claims 14 to 18, wherein the bispecific anti-EGFR / c-Met antibody is administered subcutaneously.

20. The method according to any one of claims 14 to 19, wherein the bispecific anti-EGFR / c-Met antibody is co-formulated with hyaluronidase.

21. The method according to any one of claims 14 to 20, wherein the method further comprises an initial cycle (cycle 1), the initial cycle comprising administering the bispecific antibody once weekly for four weeks at a dose of about 1600 mg if the subject weighs less than 80 kg or at a dose of about 2240 mg if the subject weighs 80 kg or more.

22. The method according to any one of claims 14 to 21, wherein the first domain of EGFR comprises the heavy chain variable region (VH) of SEQ ID NO: 13 and the light chain variable region (VL) of SEQ ID NO: 14, and the second domain of c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO:

16.

23. The method according to any one of claims 14 to 22, wherein the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype.

24. The method according to any one of claims 14 to 23, wherein the bispecific anti-EGFR / c-Met antibody comprises the first heavy chain (HC1) of SEQ ID NO: 17, the first light chain (LC1) of SEQ ID NO: 18, the second heavy chain (HC2) of SEQ ID NO: 19, and the second light chain (LC2) of SEQ ID NO:

20.

25. The method according to any one of claims 14 to 24, wherein the bispecific anti-EGFR / c-Met antibody has a bibranched glycan structure with a fucose content between about 1% and about 15% or less than 20%.

26. The method according to any one of claims 14 to 25, wherein the cancer expressing EGFR or c-Met is a solid tumor.

27. The method according to any one of claims 1 to 26, wherein the cancer expressing EGFR or c-Met is non-small cell lung cancer (NSCLC).

28. The method according to any one of claims 1 to 27, wherein the frequency of infusion-related reactions (IRRs) is lower in the subject population that receives the bispecific anti-EGFR / c-Met antibody every 4 weeks (Q4W) compared to the subject population that receives the bispecific anti-EGFR / c-Met antibody every 2 weeks (Q2W).

29. The method according to any one of claims 1 to 28, wherein the infusion-related response (IRR) is less severe in the subject population administered the bispecific anti-EGFR / c-Met antibody every 4 weeks (Q4W) compared to the subject population administered the bispecific anti-EGFR / c-Met antibody every 2 weeks (Q2W).

30. The method according to any one of claims 1 to 27, wherein the frequency of infusion-related reactions (IRRs) is lower in the subject population that receives the bispecific anti-EGFR / c-Met antibody subcutaneously every 4 weeks (Q4W) compared to the subject population that receives the bispecific anti-EGFR / c-Met antibody intravenously every 2 weeks (Q2W).

31. The method according to any one of claims 1 to 28, wherein the infusion-related response (IRR) is less severe in the subject population receiving the bispecific anti-EGFR / c-Met antibody subcutaneously every 4 weeks (Q4W) compared to the subject population receiving intravenous administration of the bispecific anti-EGFR / c-Met antibody every 2 weeks (Q2W).

32. The method according to any one of claims 1 to 31, wherein the cancer is NSCLC, the bispecific anti-EGFR / c-Met antibody is ervantumab, and the ervantumab is administered subcutaneously, wherein (i) if the subject's body weight (BW) is <80 kg, the ervantumab is administered once weekly at a dose of 1600 mg for the first 4 weeks (days 1, 8, 15, and 22 of cycle 1), and then once every 4 weeks at a dose of about 3,520 mg starting from cycle 2 (Q4W); or (ii) if the subject's body weight (BW) is 80 kg or heavier, the ervantumab is administered once weekly at a dose of 2240 mg for the first 4 weeks (days 1, 8, 15, and 22 of cycle 1), and then once every 4 weeks at a dose of about 4,640 mg starting from cycle 2 (Q4W).

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