Binding agents, their uses and pharmaceutical composition.

Abstract

The present invention relates, in certain embodiments, to compositions comprising monoclonal binding agents that bind, in a specific manner, to the extracellular domain of CMET and uses thereof.

Description

1 / 94 Binding agents, their uses and pharmaceutical composition. Technical Field

[001] The embodiments of the present invention relate to compositions comprising binding agents that bind, in a specific manner, to cMET and uses thereof. Antecedent Technique

[002] The cMET protein, sometimes called hepatocyte growth factor receptor (MET) or hepatocyte growth factor receptor (HGFR), is a protein that in humans is encoded by the MET gene (MET proto-oncogene, tyrosine kinase receptor). cMET is a single-pass cell surface receptor that possesses tyrosine kinase activity. The precursor protein of the single main chain of the MET translation product is cleaved post-translationally to produce an alpha and a beta subunit, which are disulfide-linked to form a mature cell surface cMET receptor. cMET is expressed in cells of epithelial origin, as well as in stem cells, progenitor cells, and other cell types. Hepatocyte growth factor / dispersal factor (HGF / SF) and its slicing isoforms (NK1, NK2) have been identified as ligands for cMET.

[003] cMET is considered essential for normal embryonic development, organogenesis, and wound healing. Abnormal expression and / or activity of cMET is associated with certain neoplastic disorders and cancers (e.g., kidney, liver, stomach, breast, and brain cancers) in which cMET is implicated in tumor growth, angiogenesis, and metastasis. Overexpression of cMET, as well as its autocrine activation through co-expression of its ligand, is also implicated in oncogenesis. [Summary of the invention]

[004] The present invention presents new agents for Petition 870260080059, dated 10 / 08 / 2026, page 6 / 234 2 / 94 binding, monoclonal antibodies and their binding portions, which bind, in a specific manner, to cMET, their pharmaceutical compositions and their methods of use.

[005] In some aspects, the present invention provides a binding agent that specifically binds to cMET, an extracellular domain of cMET, or a portion thereof. In some embodiments, a binding agent described in the present invention binds specifically to a protein or polypeptide comprising cMET, an extracellular domain of cMET, or a portion thereof. In certain embodiments, a binding agent binds specifically to one or more mammalian cMETs selected from a human cMET, a non-human primate cMET (e.g., a monkey cMET), a rat cMET, and a mouse cMET. In certain embodiments, a binding agent binds specifically to a variant of human cMET and / or to an extracellular domain of a human cMET comprising one or more naturally occurring variants.In certain embodiments, a binding agent binds, in a specific manner, to a human cMET variant comprising an E168D and / or N375S variant.

[006] In some respects, a cMET-specific binding agent comprises a CDR-L1, a CDR-L2, and / or a CDR-L3, which are three polypeptide sequences from a complementarity-determining region of the light chain (CDR-L), where CDR-L1 is selected from Table 1, CDR-L2 is selected from Table 2, and CDR-L3 is selected from Table 3. In some respects, a cMET-specific binding agent comprises a CDR-H1, a CDR-H2, and / or a CDR-H3, which are three polypeptide sequences from a complementarity-determining region of the heavy chain (CDR-H), Petition 870260080059, dated 10 / 08 / 2026, p. 7 / 234 3 / 94 where CDR-H1 is selected from Table 6, CDR-H2 is selected from Table 7, and CDR-H3 is selected from Table 8. In some aspects, a binding agent that specifically binds to cMET comprises a CDR-L1 selected from Table 1, a CDR-L2 selected from Table 2, a CDR-L3 selected from Table 3, a CDR-H1 selected from Table 6, a CDR-H2 selected from Table 7, and a CDR-H3 selected from Table 8. In some embodiments, a CDR-L1 is selected from SEQ ID NOs: 2, 4, 6, 8, 10, 12, and 14. In some embodiments, a CDR-L2 is selected from SEQ ID NOs: 17, 19, 21, 23, and 25. In some embodiments, a CDRL3 is selected from SEQ ID NOs: 27, 29, 31, 33 and 35. In some modes, a CDR-H1 is selected from the SEQ ID NOs: 51, 53, 55, 57 and 59. In some modes, a CDR-H2 is selected from the SEQ ID NOs: 63, 65, 67, 69, 73 and 75.In some embodiments, a CDR-H3 is selected from Table 8 chosen from SEQ ID NOs: 80, 82, 84, 86, 88, 91, and 93. In some embodiments, the binding agent is an antibody or a cMET-binding fragment thereof.

[007] In certain embodiments, a linking agent comprises a variable light chain region having an amino acid sequence selected from Table 4 or 5 and / or a variable heavy chain region having an amino acid sequence selected from Table 9 or 10. A variable light chain from Table 4 or 5, or a variable heavy chain from Table 9 or 10, may comprise one to twenty, or in some embodiments, one to ten amino acid modifications selected from an amino acid addition, an amino acid deletion, and an amino acid substitution, the linking agent retaining specific binding to cMET.

[008] In certain modalities, a liaison agent is a Petition 870260080059, dated 10 / 08 / 2026, p. 8 / 234 4 / 94 monoclonal antibody or a cMET-binding fragment thereof. In some embodiments, the binding agent comprises a constant region of an IgG1, IgG2, IgG3, or IgG4. In some embodiments, the binding agent comprises a constant region of an IgD, IgE, IgA, or IgM. In certain embodiments, a binding agent is humanized and / or comprises at least one to four humanized or human-structured regions. In certain embodiments, a binding agent comprises at least one to four mouse-structured regions. In some embodiments, a binding agent is a Fab, Fab', F(ab')2, Fv, or scFV fragment of an antibody.

[009] In some aspects, a binding agent described in the present invention has one or more functional properties. In certain embodiments, a binding agent induces or promotes cMET internalization into a human cancer cell.In some embodiments, a binding agent induces or promotes cMET degradation in a human cancer cell. In some embodiments, a binding agent does not possess detectable cMET agonist activity. In some embodiments, a binding agent induces or promotes the death of a cell to which it binds. In certain embodiments, a binding agent is conjugated with an antineoplastic agent.

[0010] In some respects, a binding agent described in the present invention binds, in a specific manner, to cMET, or a portion thereof. In some respects, a binding agent described in the present invention binds, in a specific manner, to cMET, or a portion thereof with a KD of 10 nM or less, or 1 nM or less. In some respects, an affinity of a binding agent for cMET, or a portion thereof, comprises a KD of 10 nM or less, or 1 nM or less.

[0011] In some forms, a linking agent that connects, Petition 870260080059, dated 10 / 08 / 2026, page 9 / 234 5 / 94 Specifically, cMET further comprises a second antigen-binding portion that specifically binds to another antigen (e.g., a non-cMET antigen, or a portion thereof). For example, in some embodiments, a binding agent comprises a first antigen-binding domain that specifically binds to cMET and a second antigen-binding domain that specifically binds to another polypeptide.

[0012] In certain aspects, the present invention presents methods for treating an individual with or suspected of having a neoplastic disorder or cancer. In one embodiment, a method includes administering a therapeutically effective amount of a binding agent described in the present invention to an individual. In some embodiments, a method comprises contacting a cell of the individual (e.g., a neoplastic or cancerous cell) with the binding agent. In certain embodiments, the binding agent is configured to bind, in a specific manner, to the extracellular domain of cMET expressed in one or more cells of the individual. In certain embodiments, the binding agent decreases, inhibits, or reduces mitosis, and / or promotes or induces the death of one or more cells expressing cMET.In certain modalities, the neoplastic disorder or cancer comprises lung carcinoma, breast carcinoma, ovarian carcinoma, kidney carcinoma, colorectal carcinoma, gastric carcinoma, thyroid carcinoma, pancreatic carcinoma, neuroblastoma or squamous cell carcinoma of the head and neck, cervical cancer, hepatocellular carcinoma, sarcomas, mesothelioma, glioblastoma, multiple myeloma, melanoma, and esophageal and prostate carcinoma.

[0013] In some embodiments, a pharmaceutical composition comprising the binding agent is provided. In some embodiments, a pharmaceutical composition comprises, in addition to Petition 870260080059, dated 10 / 08 / 2026, page 10 / 234 6 / 94 binding agent, an excipient, diluent, additive and / or pharmaceutically acceptable vehicle. In some embodiments, a pharmaceutical composition is formulated as a sterile lyophilized powder which, after reconstitution, is suitable for intravenous administration to a mammal.

[0014] Certain aspects of the technology are described further in the description, examples, claims and drawings that follow.

[0015] The drawings illustrate modalities of the technology and are not limiting. For clarity and ease of illustration, the drawings are not made to scale and, in some cases, various aspects may be shown exaggerated or enlarged to facilitate an understanding of particular modalities. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 shows a summary of the workflow used for generating monoclonal antibodies (exemplary binding agents) that bind, in a specific manner, to cMET. The lead monoclonal antibody P3D12 was generated from a mouse immunized with recombinant intact extracellular domain of cMET fused with human Fc.

[0017] Figure 2 shows an immunization scheme used to generate monoclonal antibodies (exemplary binding agents) that bind specifically to cMET. Mice were initially immunized by intraperitoneal (ip) injection with 100 pg of a human cMET-Fc fusion protein (cMETFc), or 50 to 100 pg of a cMET peptide conjugated with KLH in Complete Freund's Adjuvant (CFA) as indicated. cMET-Fc comprises the extracellular domain of human cMET fused to an Fc portion of an antibody. The cMET peptides were strategically selected from a portion of the extracellular domain of cMET. Immunized mice received either Petition 870260080059, dated 10 / 08 / 2026, page 11 / 234 7 / 94 plus booster immunizations comprising 25 or 50 pg of cMET-Fc or peptide in Freund's Incomplete Adjuvant (IFA) as indicated. Some mice received repeat multi-site immunizations (RIMMS). Immunizations included Met-Fc fusions, peptides, traditional, and RIMMS. Spleens from immunized mice were obtained and fused to a suitable fusion partner. Over 20,000 hybridoma clones were obtained and tracked.

[0018] Figure 3 shows a 3D structure of the MET SEMA domain bound to a Fab of a Met-mAb agonist antibody (Fab 5D5) and HGF beta subunit (HGFb). The bottom arrow indicates the position of a cMET portion used to design peptide 3.

[0019] Figure 4 shows the characterization results of an exemplary fusion (FUSION 6B1, plate 3). Anti-cMet hybridomas were selected, in part, for the presence of specific cMet binding as assayed by ELISA (see column named MET binding ELISA OD450nm) and for the ability to induce cMet internalization in human cancer cell lines as measured by flow cytometry (see column named FACS Geometric Mean). A FACS Geo mean value lower than a negative control indicates cMet internalization. The arrow indicates a leader hybridoma F6B1P3D12.

[0020] Figure 5 shows the results of a MET degradation assay. Anti-cMet antibodies isolated from the indicated wells (x-axis) were tested and selected for their ability to induce cMET degradation in human cancer cell lines, as measured by mesoscale (MSD) quantification of cMet protein. Relative Met degradation values ​​are indicated on the y-axis as % control (percent control). Values ​​less than 100% control (negative control level) indicate both internalization and degradation of cMet. Degradation indicates not only internalization but also lysosomal trafficking, a property Petition 870260080059, dated 10 / 08 / 2026, page 12 / 234 8 / 94 important for an antibody-drug conjugate. The arrow indicates the results of a leader hybridoma F6B1P3D12.

[0021] Figure 6 shows the results of a phospho-ERK assay (P-ERK assay) that measures the agonist activity of anti-cMET antibodies by indirectly measuring ERK phosphorylation induced by binding an anti-cMET antibody to cMET on a cell surface. The amount of phosphorylated ERK (shown as the % control, y-axis) detected in cell lysates after treatment of viable cells with an anti-cMET antibody is shown. Anti-cMet antibodies produced from various anti-cMET hybridomas (x-axis) were tested at 6 pg / mL or 30 pg / mL (as indicated on the x-axis) and selected based on their inability to induce significant ERK phosphorylation (i.e., their ability to not induce proliferation, i.e., absence of agonist activity). A leading monoclonal antibody (mAb) P3D12 is indicated by the arrow.

[0022] Figure 7 shows the results of certain cMet mAbs that were assayed by ELISA for binding to human, macaque (Cynomolgus macaque, Cyno), canine, rat, and mouse cMet. All monoclonal antibodies bind human and macaque cMet. P3D12 demonstrated significant cross-reactivity with rat cMet. Various concentrations of each antibody are indicated on the x-axis. The relative amounts bound are indicated on the y-axis (OD450nm).

[0023] Figure 8A shows an alignment of the amino acid sequences of the variable regions of the light chain of nine mouse monoclonal anti-cMET antibodies, whose names are indicated to the left of each sequence. The SEQ ID NOs are indicated to the right of each sequence. The amino acid sequences of the variable regions of the light chain of LC F6B1P1E2 and F6BP3E2 are 100% identical. In addition, the amino acid sequences of the variable regions of the light chain of LC F6B1P3D12 and F6B1P3E9 are 100% Petition 870260080059, dated 10 / 08 / 2026, p. 13 / 234 9 / 94 identical.

[0024] Figure 8B shows an alignment of the amino acid sequences of the variable regions of the heavy chain of nine mouse monoclonal anti-cMET antibodies, whose names are indicated to the left of each sequence. The SEQ ID NOs are indicated to the right of each sequence. The amino acid sequences of the variable regions of the heavy chain of F6B1P3D12H7913 and F6B1P3E9 are 100% identical. In addition, the amino acid sequences of the variable regions of the heavy chain of F6B1P1E2H7819 and F6BP3E2 are 100% identical.

[0025] Figures 9A and 9B show the results of an in vivo mouse xenograft model evaluating the efficacy of targeted anti-cMET antibody drug conjugates (ADCs) using the MKN45 tumor model (a gastric cMet+ cancer model) in nude mice. Animals were treated once with ADCs at 2.5 mg / kg (9A) or 5.0 mg / kg (9B). The efficacy of each drug-conjugated anti-cMET binding agent is compared with PBS or an unrelated non-targeted monoclonal antibody (IgG-ADC). Tumor volume (yy-axis) was measured at various time points after inoculation (yy-axis, days (post-inoculation)). Inhibition of tumor growth indicates positive efficacy. The anti-cMET binding agents and the non-targeted monoclonal antibody (IgG) were conjugated to monomethyl auristatin F (MMAF).

[0026] Figure 10 shows the results of a phospho-ERK assay (P-ERK assay) that measures the agonist activity of anti-cMET antibodies by indirectly measuring ERK phosphorylation induced by binding an anti-cMET antibody to cMET on a cell surface. The amount of phosphorylated ERK (shown as the % control, y-axis) detected in cell lysates after treatment of viable cells with an anti-cMET antibody is shown. The constant regions of Petition 870260080059, dated 10 / 08 / 2026, page 14 / 234 10 / 94 heavy and light chains of a mouse monoclonal antibody isolated as P3D12 were replaced via antibody constant regions of a human IgG1 (P3D12 (hIgG1)), or a human IgG2 (P3D12 (hIgG2)) as indicated on the x-axis. Each antibody was tested at 0.00064 / mL, 0.0032 / mL, 0.016 / mL, 0.08 / mL, 0.4 / mL, 2 / mL, 10 / mL, and 50 / mL, as indicated on the x-axis. Control indicates an untreated negative control. HGF (EC90) is a positive control and indicates cells treated with Hepatocyte Growth Factor (HGF), the natural ligand of the cMet receptor. These data indicate that the human IgG2 isotype does not exhibit detectable agonist activity.

[0027] Figure 11 shows the results of a MET degradation assay. Degradation is a measure of cMET receptor internalization upon antibody binding. Chimeric anti-cMet antibodies were tested for their ability to induce cMET degradation in human cancer cell lines, as measured by mesoscale (MSD) cMet protein quantification. Relative Met degradation values ​​are indicated on the y-axis as % control (percent control). Values ​​less than 100% control indicate cMet internalization and degradation. The chimeric antibodies were generated by replacing the constant regions of the heavy and light chains of an isolated mouse monoclonal antibody designated as P3D12 (P3D12 (mouse)) with antibody constant regions from a human IgG1 (P3D12 (hIgG1)), or a human IgG2 (P3D12 (hIgG2)) as indicated on the x-axis.Each antibody was tested at 0.00064 / mL, 0.0032 / mL, 0.016 / mL, 0.08 / mL, 0.4 / mL, 2 / mL, 10 / mL, and 50 / mL, as indicated on the x-axis. Chimeric cMet antibodies of P3D12 showed internalization / degradation activity similar to that of the parental mouse P3D12 antibody.

[0028] Figure 12 shows a process development flowchart for testing and selecting anti-Petition monoclonal binding agents, dated 10 / 08 / 2026, page 15 / 234 11 / 94 cMET leader.

[0029] Figure 13 shows an alignment of five variable humanized light chain regions from humanized versions of the murine anti-cMET clone P3D12, whose names and SEQ ID NOs are indicated to the left of each sequence. Five independent methods were used to humanize the murine anti-cMET mAbs. Two of the methods gave the same result, therefore there are 4 different light chains shown.

[0030] Figure 14 shows an alignment of five humanized variable heavy chain regions from humanized versions of the murine clone P3D12, whose names and SEQ ID NOs are indicated to the left of each sequence. Five independent methods were used to humanize the murine anti-cMET mAb. Two of the methods gave the same result, therefore there are 4 different light chains (see Figure 13) and 4 different heavy chains that can make a combination of 16 different binding agents.

[0031] Figure 15 shows the results of an in vivo xenograft mouse model testing the efficacy of humanized anti-cMET antibody conjugates (ADCs) indicated at 2.5 mg / kg (2.5 mpk) or 5 mg / kg (5 mpk) demonstrated using an MKN45 tumor model (a gastric cMet+ cancer model). Animals were treated once with the indicated ADCs at 2.5 or 5.0 mg / kg. The efficacy of each anti-cMET binding agent was compared with PBS or the non-target monoclonal antibody Rituximab (Retux), which is an anti-cancer monoclonal antibody that targets CD20, which is primarily found on the surface of B cells of the immune system. Tumor volume (y-axis) was measured at various time points (y-axis) after inoculation. Inhibition of tumor growth indicates positive efficacy. The anti-cMET binding agents were conjugated to monomethyl auristatin F (MMAF). Petition 870260080059, dated 10 / 08 / 2026, page 16 / 234 12 / 94

[0032] Figure 16 shows the binding of monoclonal anti-cMET hD12 and IgG2 MET binding agents to cMET-Fc and recombinant cMET (E168D) Fc mutant fusion proteins. The E168D mutation is a somatic mutation found in small cell lung cancer (SCLC). The mutation is located in the Sema domain and leads to constitutive activation of the cMet receptor. The abundance of somatic cMet mutations is very low. E168D occurs in 0.8% to 3% of SCLC patients. A binding ELISA was performed with human cMET extracellular domains or E168D cMET fused with human IgG1 Fc. cMET proteins were coated in a plate overnight and samples were titrated and detected with a goat anti-human IgG (H+L)-HRP. EC50s were determined using sigmoidal dose-response adjustment. [Description of the modalities]

[0033] Presented in the present invention, in some embodiments, are monoclonal binding agents that bind to cMET, or a portion thereof, as well as the compositions and uses thereof. The MET translation product of the proto-oncogene comprises mesenchymal epithelial transition factor (MET). MET is used synonymously with the term cMET. cMET is also known as hepatocyte growth factor receptor (HGFR). Human cMET (e.g., SEQ ID NO: 109) comprises an immature polypeptide sequence of 1390 amino acids and includes a unique N-terminal sequence of amino acids 1-24, an extracellular human cMET domain from about amino acid 24-932, a transmembrane domain from about amino acid 933 to 955, and a cytoplasmic domain from about amino acid 956 to 1390, numbered from N-terminal to C-terminal.Methods for identifying leader sequences, extracellular domains, transmembrane domains, and cytoplasmic domains of a cMET receptor are known. Petition 870260080059, dated 10 / 08 / 2026, page 17 / 234 13 / 94 Any suitable method may be used to identify such domains or regions in a cMET polypeptide sequence derived from a suitable mammalian species. A human cMET polypeptide may comprise known variant pathways (e.g., see URL: http: / / www.uniprot.org / uniprot / P08581, accessed May 5, 2016, the cMET variants and alternative sequences described in the present invention being incorporated into the present invention by reference). Non-limiting examples of naturally occurring variants of a human cMET include amino acid substitutions at 143, 150, 156, 168, 238, 316, 320, 375, 385, 773, 970, 991 and / or 992 of human cMET (SEQ ID NO: 109). In some embodiments, the cMET or an extracellular cMET domain comprises an E to D substitution at position 168 of human cMET, referred to in the present invention as E168D.In some embodiments, the cMET or an extracellular cMET domain comprises an N to S substitution at the 375 position of human cMET, referred to in the present invention as N375S.

[0034] In some modalities, cMET is a mammalian cMET. In some embodiments, cMET is a primate cMET. In some embodiments, cMET is a human cMET. In some embodiments, cMET is a monkey cMET. In some embodiments, cMET is a rodent cMET (e.g., rat and / or mouse). In some embodiments, cMET is a canine cMET (e.g., dog cMET). Non-limiting examples of a mammalian cMET are provided in Example 5 and / or in a sequence listing of this application. In certain embodiments, an extracellular cMET domain comprises an N-terminal portion of a cMET polypeptide that is typically expressed on the cell surface of an intact mammalian cell. An extracellular cMET domain may comprise two or more polypeptide chains derived from a MET translation product. In certain Petition 870260080059, dated 10 / 08 / 2026, page 18 / 234 In certain embodiments, an extracellular cMET domain can be expressed in a soluble and / or non-membrane-bound form that lacks a cytoplasmic and / or transmembrane domain. In certain embodiments, an extracellular cMET domain is expressed, isolated, and / or purified as a fusion protein. For example, the extracellular domain of a mammalian cMET can be manipulated and expressed as a fusion protein comprising an Fc portion of an immunoglobulin (e.g., cMET-Fc). In certain embodiments, cMET and / or the extracellular cMET domain comprises one or more amino acid additions, deletions, or substitutions. A cMET polypeptide can be at least 80%, at least 85%, at least 90%, or at least 95% of a cMET polypeptide described in the present invention. In certain embodiments, a cMET polypeptide comprises a portion of (e.g., a subsequence of) a cMET protein.In some embodiments, a portion of a cMET comprises an extracellular cMET domain, or a portion thereof.

[0035] Presented in the present invention, in some embodiments, are compositions (e.g., pharmaceutical compositions) comprising one or more binding agents that bind, in a specific manner, to cMET or a portion thereof. In some embodiments, a binding agent presented in the present invention is used for the treatment, prevention and / or diagnosis of a neoplastic disorder and / or cancer in an individual.

[0036] The term individual refers to a mammal. Any suitable mammal can be treated by means of a method or composition described in the present invention. Non-limiting examples of mammals include humans, non-human primates (e.g., monkeys, chimpanzees, orangutans and the like), domestic animals (e.g., dogs and cats), farm animals (e.g., horses, cows, goats, sheep, pigs) and animals Petition 870260080059, dated 10 / 08 / 2026, page 19 / 234 15 / 94 experimental (e.g., mouse, rat, rabbit, guinea pig). In some embodiments, a mammal is a human being. A mammal can be of any age or at any stage of development (e.g., an adult, adolescent, child, infant, or mammal in utero). A mammal can be male or female. A mammal can be a pregnant female.

[0037] In some embodiments, an individual requires a treatment or composition described in the present invention. In certain embodiments, an individual has or is suspected of having a neoplastic disorder or cancer. In some embodiments, an individual in need of a treatment or composition described in the present invention has or is suspected of having a neoplastic disorder or cancer. In certain embodiments, a binding agent or composition described in the present invention is used to treat an individual with, or suspected of having, a neoplastic disorder or cancer.

[0038] In certain embodiments, a binding agent comprises or consists of one or more polypeptides or one or more proteins that bind in a specific manner to at least one antigen (e.g., cMET or a portion thereof). A binding agent often comprises at least one antigen-binding portion (i.e., a binding portion). An antigen-binding portion of a binding agent is that portion that binds specifically to an antigen. In certain embodiments, a binding portion of a binding agent comprises or consists of a single polypeptide (e.g., single-chain antibody). In some embodiments, a binding portion of a binding agent comprises or consists of two polypeptides. In some embodiments, a binding portion of a binding agent comprises or consists of 2, 3, 4 or more polypeptides. In some embodiments, a binding agent comprises one or more portions Petition 870260080059, dated 10 / 08 / 2026, page 20 / 234 16 / 94 structural (e.g., supports, structural polypeptides, constant regions and / or structural regions). In some embodiments, a linking agent, or a portion thereof, is attached to a substrate (e.g., a polymer, a non-organic material, silicone, a bead, and the like).

[0039] A binding agent may comprise one antigen-binding moiety or multiple antigen-binding moieties. For example, a binding agent comprising one binding moiety is sometimes referred to as monovalent. A binding agent comprising two binding moieties is sometimes referred to as divalent. In some embodiments, a binding agent comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more binding moieties. In certain embodiments, all binding moieties of a multivalent binding agent bind to the same antigen. In certain embodiments, all binding moieties of a multivalent binding agent comprise one or more polypeptide sequences that are at least 90%, at least 95%, at least 99%, or 100% identical.

[0040] In certain embodiments, two or more binding moieties of a binding agent bind to different antigens. Such binding agents are sometimes referred to as bispecific or multispecific binding agents (e.g., antibodies). Thus, in certain embodiments, a binding agent comprises a first antigen-binding moiety that specifically binds to cMET, or a portion thereof, and a second antigen-binding moiety that specifically binds to another antigen (e.g., a polypeptide that is not cMET or a portion thereof). A binding agent that specifically binds to cMET is, in some embodiments, covalently or non-covalently linked to another binding agent that does not specifically bind to cMET, or a portion thereof. In certain Petition 870260080059, dated 10 / 08 / 2026, p. 21 / 234 17 / 94 modalities, a binding agent that binds specifically to cMET comprises a second binding agent that binds specifically to another antigen.

[0041] In some embodiments, a binding agent comprises an antibody, or a portion thereof (e.g., a binding portion thereof). In certain embodiments, a binding agent comprises or consists of a suitable antibody, an antibody fragment, and / or an antigen-binding portion of an antibody (e.g., a binding fragment, i.e., a binding portion). In some embodiments, a binding agent is an antibody (e.g., a monoclonal antibody and / or a recombinant antibody). A binding agent or antibody may be generated, manufactured, or produced by a suitable method. In some embodiments, a binding agent is monoclonal. In some embodiments, a binding agent is a monoclonal antibody derived from a suitable species.Certain non-limiting examples of a binding agent include monoclonal antibodies, chimeric antibodies, antibody-binding fragments (e.g., an antigen-binding portion of an antibody), a CDR-grafted antibody, a humanized antibody, a human antibody, or portions thereof. Human antibodies can be obtained by any suitable method. For example, human antibodies can be obtained from transchromosomal animals manipulated to produce fully human antibodies. In certain embodiments, a binding agent is not polyclonal, is not a polyclonal antibody, and the term binding agent does not refer to polyclonal antibodies.

[0042] In some embodiments, a binding agent is derived, produced, obtained, isolated and / or purified from a suitable species. In some embodiments, a binding agent is derived, Petition 870260080059, dated 10 / 08 / 2026, p. 22 / 234 18 / 94 produced, obtained, isolated and / or purified from a rabbit, goat, horse, cow, rat, mouse, fish, bird or llama, for example. In some embodiments, a linking agent is derived, produced, obtained, isolated and / or purified from a bird (e.g., a chicken or a bird egg). In some embodiments, a linking agent is derived, produced, obtained, isolated and / or purified from a plant (e.g., a recombinant linking agent produced by a genetically modified plant). In some embodiments, a linking agent is derived, produced, obtained, isolated and / or purified from a suitable mammal. In certain embodiments, a suitable mammal is a genetically altered mammal (e.g., a transchromosomal or transgenic mammal) manipulated to produce antibodies comprising human heavy chains and / or human light chains or portions thereof.In some embodiments, a linking agent is produced, obtained, isolated, or purified from a prokaryotic or eukaryotic cell (e.g., a recombinant linking agent produced by a genetically engineered cell). In some embodiments, a linking agent is produced, obtained, isolated, or purified from a virus (e.g., a recombinant linking agent produced by a genetically engineered virus). A linking agent may be expressed, isolated from, and / or purified from a suitable expression system, non-limiting examples of which include a suitable expression system for bacteria, phages, insects, viruses, plants, or mammals. For example, a nucleic acid encoding a linking agent may be introduced into a suitable mammalian cell line that expresses and secretes the linking agent into the cell culture medium.

[0043] In certain forms, a binding agent is not found in nature and does not occur naturally. For example, in Petition 870260080059, dated 10 / 08 / 2026, p. 23 / 234 19 / 94 In certain embodiments, a binding agent is artificially generated in an animal by administering an emulsified cocktail that includes a foreign recombinant antigen, a powerful adjuvant, and often a mineral oil and / or a detergent, thereby inducing an artificial immune response to the foreign recombinant antigen (e.g., cMET, cMET-Fc).

[0044] In certain embodiments, a monoclonal antibody or monoclonal binding agent is a substantially homogeneous population of binding agents, or binding fragments thereof, wherein each individual binding agent in the population is substantially identical to and / or binds to the same epitope, with the exception of possible variants that may arise during the production of a monoclonal binding agent. In some embodiments, these variants are generally absent or may be present in minor quantities. In contrast to polyclonal antibody preparations that typically include a population of different antibodies directed against different determinants (epitopes), each binding agent in a population of monoclonal binding agents often binds to a single determinant of an antigen. Monoclonal binding agents are generally not contaminated by other immunoglobulins.One or more different monoclonal binding agents may be purposefully added to a composition to form a mixture.

[0045] The monoclonal modifier should not be interpreted as requiring the production of a binding agent by any particular method. A monoclonal binding agent can be produced by any suitable method. For example, in certain embodiments, a monoclonal antibody is produced by the hybridoma method (e.g., as described by Kohler et al., Nature, 256: 495 (1975)), or a variation thereof. In some embodiments, a Petition 870260080059, dated 10 / 08 / 2026, p. 24 / 234 20 / 94 Monoclonal ligation agent is produced by means of a recombinant DNA method. For example, a monoclonal ligation agent can be produced by screening a recombinant library using a suitable expression system (e.g., a phage expression system). In some embodiments, a monoclonal ligation agent is isolated from a phage library of ligation agents, for example, using a technique described in Clackson et al, Nature, 352: 624 to 628 (1991) and / or Marks et al, J. Mol Biol. 222: 581 to 597 (1991), or a variation thereof.

[0046] In certain embodiments, a linking agent comprises one or more structural portions or parts of the main structure, sometimes referred to as support structures. A linking agent may comprise a support, examples of which are not limiting, including an antibody-derived support, a Protein A Z domain, gamma-B crystallin, ubiquitin, cystatin, Sac7d, a triple helix, a lipocalin, an ankyrin repeat motif, a Fyn SH3 domain, a Kunitz domain of a suitable protease inhibitor, a fibronectin domain, a nucleic acid polymer, and the like, portions or combinations thereof. In some embodiments, a linking agent does not comprise a support. In certain embodiments, a linking agent comprises one or more structural portions of a mammalian antibody.

[0047] In certain embodiments, a linking agent comprises one or more constant regions (e.g., constant regions derived from an antibody, e.g., a mammalian antibody). In certain embodiments, a linking agent comprises a constant region of an antibody light chain and / or a constant region of an antibody heavy chain. In a mammalian antibody there are at least two types of immunoglobulin light chains which are referred to as lambda (γ) and kappa (κ). A linking agent may Petition 870260080059, dated 10 / 08 / 2026, p. 25 / 234 21 / 94 comprise any suitable constant region of an antibody, or one or more portions thereof. In some embodiments, a linking agent comprises a constant region of the lambda light chain or a portion thereof. In some embodiments, a linking agent comprises a constant region of the kappa light chain or a portion thereof. In some embodiments, a linking agent comprises a polypeptide that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to a polypeptide sequence of a constant region, or a portion thereof, of a light chain of a mammalian antibody. In some embodiments, a linking agent comprises a polypeptide that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to a polypeptide sequence of a constant region of a light chain of a human antibody.In some embodiments, a linking agent does not include a constant region of the light chain.

[0048] In certain embodiments, a binding agent comprises a constant region of an antibody heavy chain. In mammals, an antibody may have at least five types / classes of Ig heavy chains indicated as IgA, IgD, IgE, IgG, and IgM, which are determined by the presence of distinct heavy chain constant regions, or portions thereof (e.g., CH1, CL, CH2, CH3 domains). A binding agent may include any suitable heavy chain constant region, or a portion thereof. In some embodiments, a binding agent comprises a heavy chain constant region of an IgG1, IgG2, IgG3, or IgG4, or one or more portions thereof. In some embodiments, a binding agent comprises one or more heavy chain constant regions of an IgM, IgD, IgA, or IgE isotype, or a portion thereof. In Petition 870260080059, dated 10 / 08 / 2026, p. 26 / 234 22 / 94 In some embodiments, a linking agent comprises a polypeptide that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical or 100% identical to a polypeptide sequence of a constant region, or a portion thereof, of a mammalian antibody heavy chain. In some embodiments, a linking agent comprises a polypeptide that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% identical or 100% identical to a polypeptide sequence of a constant region of a human antibody heavy chain. In some embodiments, a linking agent comprises one or more additions, deletions and / or modifications to a constant region. A linking agent is sometimes modified to alter the antibody class, or isotype of a linking agent.In some embodiments, a linking agent comprises one or more additions, deletions, and / or modifications (one or more amino acid substitutions, deletions, or additions) to modify one or more functions of a linking agent, for example, to abolish, increase, or decrease the serum half-life, Fc receptor binding, complement binding (e.g., C1q binding), glycosylation, sialylation, cellular toxicity, antibody-dependent cell-mediated phagocytosis (ADCP), antibody-dependent cell cytotoxicity (ADCC), and the like. In some embodiments, a linking agent does not include one or more portions of a constant region of the heavy chain or the constant region of the light chain. In some embodiments, a linking agent does not include a constant region of the heavy chain.

[0049] In some embodiments, a binding agent comprises or consists of one or more variable regions of an antibody, or a portion thereof. In some embodiments, a Petition 870260080059, dated 10 / 08 / 2026, p. 27 / 234 23 / 94 A binding agent comprises one or more variable light chain regions or a portion thereof. In some embodiments, a binding agent comprises one or more variable heavy chain regions, or a portion thereof. In certain embodiments, a binding agent comprises at least one variable light chain region and at least one variable heavy chain region. A variable light chain region and a variable heavy chain region may be in the same or different polypeptides. In certain embodiments, an antigen-binding portion of a binding agent consists of one or more variable heavy chain regions. In certain embodiments, an antigen-binding portion of a binding agent consists of one or more variable light chain regions. In certain embodiments, an antigen-binding portion of a binding agent consists of one or more variable light chain regions and one or more variable heavy chain regions.

[0050] In some embodiments, a linking agent comprises or consists of a single-chain Fab, Fab', F(ab')2, Fv, Fv fragment (scFv), diabody (Dab), synthetic body, the like, and / or a combination or portion thereof. In some embodiments, a linking agent is a single-chain Fab, Fab', F(ab')2, Fv, Fv fragment (scFv), diabody (Dab), synthetic body, the like, and / or a combination, or a portion thereof (see, for example, U.S. Patents Nos. 6,099,842 and 5,990,296). In some embodiments, a linking agent comprises a single-chain polypeptide comprising one or more antigen-binding moieties. For example, a single-chain binding agent can be constructed by joining a variable heavy chain region, or an antigen-binding portion thereof, with a variable light chain region, or an antigen-binding portion thereof, with a ligand (e.g., an amino acid, a polypeptide ligand) using biological processes. Petition 870260080059, dated 10 / 08 / 2026, p. 28 / 234 24 / 94 recombinant molecular. Such single-chain binding agents frequently exhibit specificities and affinities for an antigen similar to a parental double-chain monoclonal binding agent. The binding agents often comprise modified regions such as CDR-grafted or humanized portions. In certain embodiments, a binding agent is an intact double-chain immunoglobulin, and in other embodiments, a binding agent is a Fab monomer or a Fab dimer.

[0051] Nucleic acids, or portions thereof, that encode a polypeptide of a linking agent may be cloned, subcloned, rearranged, or modified for recombinant expression through a suitable cloning procedure and subsequently expressed using a suitable expression system through a method known to those skilled in the art. (For example, see Maniatis et al., Molecular Cloning: A Manual de Laboratio, Cold Spring Harbor Laboratory, 1982; Antibody: Methods and Protocols, Vol. 248 of Methods in Molecular Biology, edited by Benny K.C. Lo and Springer Science & Business Media, 2004; Antibody Engineering, Vol. 1, Roland E. Kontermann, Stefan Duebel, Edition 2, Springer Science & Business Media, 2010; Antibody Phage Display: Methods and Protocols, Biomed Protocols, Vol. 178 of Methods in Molecular Biology, Editors Philippa M. O'Brien, Robert Aitken, Springer Science & Business Media, 2004).

[0052] In mammals, the variable heavy chain region and the variable light chain region of an antibody each contribute three CDRs (complementarity-determining regions) commonly referred to as CDR1, CDR2, and CDR3, which are separated and / or flanked by structural regions (e.g., FR1, FR2, FR3, and FR4). The term CDR, as used in the present invention, refers to an amino acid sequence of a polypeptide identified as a Petition 870260080059, dated 10 / 08 / 2026, page 29 / 234 25 / 94 complementarity-determining region. In certain embodiments, the definitive delineation of a CDR polypeptide sequence and identification of residues comprising the binding site of a binding agent is achieved by solving the structure of a binding agent and / or solving the structure of a binding agent-antigen complex. In certain embodiments, this can be achieved by any suitable method, such as X-ray crystallography and / or computational modeling. In certain embodiments, several analytical methods can be employed to identify or approximate CDR sequences of a binding agent or antibody.For example, the amino acid sequence and / or the location of CDRs in a polypeptide sequence of a binding agent, an antibody, a binding portion thereof, or a variable region thereof, can be identified using a suitable method, non-limiting examples of which include the Kabat System (e.g., see Kabat, EA, et al., 1991; Sequences of Proteins of Immunological Interest). Fifth Edition, NIH Publication No. 91-3242, as well as Johnson, G. and Wu, TT 2000, Nucleic Acids Research) and / or the Chothia Numbering Scheme (e.g., Chothia and Lesk, (1987) J. Mol. Biol, 196: 90-1917; Chothia et al., Nature, (1989) 342: 878-883; and Al-Lazikani et al. (1997) JMB 273, 927-948). In some embodiments, the amino sequence and / or the location of CDRs of an antibody can be identified using the AbM mode and / or the contact method. The AbM definition uses an integrated set of computer programs produced by the Oxford Molecular Group that model antibody structure (see, for example, Martin et al., Proc. Natl. Acad. Sci. USA, 86: 9268-9272 (1989); AbMTM, a computer program for modeling antibody variable regions, Oxford, UK; Oxford Molecular, Ltd.). The AbM definition models the tertiary structure of an antibody from the primary sequence using a combination of Petition 870260080059, dated 10 / 08 / 2026, page 30 / 234 26 / 94 knowledge databases and ab initio methods, such as those described by Samudrala et al., Ab Initio Protein Structure Prediction Using a Hierarchical Approach, in PROTEINS, Structure, Function and Genetics Suppl, 3: 194-198 (1999). In certain embodiments, a contact definition is based on an analysis of the available complex crystal structures (see, for example, MacCallum et al., J. Mol. Biol. 5: 732-45 (1996)).

[0053] In some embodiments, a binding agent and / or an antigen-binding portion of a binding agent comprises at least 2, at least 3, at least 4, at least 5, or at least 6 CDRs. In some embodiments, a binding agent comprises from 3 to 60 CDRs (e.g., for binding agents that have multiple antigen-binding portions). In some embodiments, a binding agent comprises from 3 to 12 CDRs. In some embodiments, an antigen-binding portion of a binding agent comprises from 1 to 6 CDR polypeptide sequences.

[0054] In certain embodiments, a binding agent and / or an antigen-binding portion of a binding agent comprises one, two, or three CDRs of a variable light chain region. In some embodiments, a variable light chain region of a binding agent comprises one or more CDRs (e.g., one, two, three, or more CDRs). The amino acid sequences representing a CDR in a variable light chain region of an antibody or binding agent are referred to as CDR-L1, CDR-L2, and CDR-L3, which are numbered sequentially (i.e., L1, L2, and L3) in the direction from the amino (N-terminal) to the carboxyl (C-terminal) terminal of a variable light chain region. For example, in a polypeptide representing a variable light chain region of a binding agent, CDR-L1, when present, is the CDR of the N-terminal light chain; CDR-L3, when present, is the CDR of the light chain Petition 870260080059, dated 10 / 08 / 2026, p. 31 / 234 27 / 94 of the C-terminal; and CDR-L2, when present, is located (i) between CDR-L1 and CDR-L3, (ii) on the N-terminal side of CDR-L3, or (iii) on the C-terminal side of CDR-L1, of a variable light chain region or the binding portion of a linking agent. The terms CDR-L1, CDRL2, and CDR-L3 refer, in part, to an amino acid sequence of a polypeptide identified as, or described in the present invention as, a complementarity-determining region of a linking agent (e.g., a CDR of a variable light chain region). Non-limiting examples of amino acid sequences of a CDRL1, CDR-L2, and CDR-L3 are provided in Tables 1-3, respectively. A variable light chain region or antigen-binding portion of a binding agent described in the present invention may comprise any combination of a CDR-L1, a CDR-L2, and a CDR-L3 described in the present invention, wherein the binding agent retains specific binding to cMET or a portion thereof.In certain embodiments, a variable light chain region or antigen-binding portion of a binding agent described in the present invention comprises a single light chain CDR comprising an amino acid sequence at least 70% identical to a CDR-L3 selected from Table 3. In certain embodiments, a variable light chain region or antigen-binding portion of a binding agent described in the present invention comprises an amino acid sequence at least 70% identical to a CDR-L3 selected from Table 3, and any other suitable polypeptide sequence of CDR-L2 and / or CDR-L1, wherein the binding agent retains a specific cMET binding or a portion thereof. In certain embodiments, the light chain CDRs of a variable light chain region or antigen-binding portion of a binding agent consist of a CDR-L3 and a CDR-L2, wherein the CDR-L3 comprises an amino acid sequence at least 70% identical to a CDR-L3 selected from Table 3. Petition 870260080059, dated 10 / 08 / 2026, p. 32 / 234 28 / 94 identical to a CDR-L3 selected from Table 3 and CDR-L2 comprises an amino acid sequence at least 70% identical to a CDR-L2 selected from Table 2. In certain embodiments, a variable light chain region or antigen-binding portion of a binding agent described in the present invention comprises an amino acid sequence at least 70% identical to a CDR-L3 selected from Table 3 and an amino acid sequence at least 70% identical to a CDR-L2 selected from Table 2, and any other suitable CDR-L1 polypeptide sequence, wherein the binding agent retains specific binding to cMET, or a portion thereof.In certain embodiments, a variable region of the light chain or an antigen-binding portion of a binding agent described in the present invention comprises three light chain CDRs consisting of an amino acid sequence at least 70% identical to a CDR-L3 selected from Table 3, an amino acid sequence at least 70% identical to a CDRL2 selected from Table 2, and an amino acid sequence selected at least 70% identical to a CDR-L1 from Table 1.In certain embodiments, a variable light chain region or antigen-binding portion of a binding agent described in the present invention comprises an amino acid sequence at least 70% identical to a CDR-L3 selected from Table 3, an amino acid sequence at least 70% identical to a CDR-L2 selected from Table 2, and an amino acid sequence at least 70% identical to a CDR-L1 selected from Table 1, wherein the binding agent retains the specific cMET binding, or a portion thereof.

[0055] In some embodiments, a linking agent comprises one or more light chain CDRs that are at least 70%, 75%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, Petition 870260080059, dated 10 / 08 / 2026, p. 33 / 234 29 / 94 95%, 96%, 97%, 98%, or at least 99% identical to any of the CDR sequences listed in Tables 1, 2, or 3. In some embodiments, a binding agent or the antigen-binding portion of a binding agent comprises a CDR-L1 that is at least 70%, 75%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% identical to any of the sequences shown in Table 1. In some embodiments, a binding agent or the antigen-binding portion of a binding agent comprises a CDR-L1 of any of the sequences shown in Table 1. CDR-L1 sequences [TABLE 1] ID Clone Sequência de Aminoácidos SEQ ID NO:1 F5_P5_B9_L RSSQTIVHGTGNTYL E SEQ ID NO:2 F5_P5_B9_L QTIVHGTGNTY SEQ ID NO:3 F6A_P8_E2_L KASENVGTYVS SEQ ID NO:4 F6A_P8_E2_L ENVGTY SEQ ID NO:5 F6AP12F12_L RSSQSLLYSINQKNYL A SEQ ID NO:6 F6AP12F12_L QSLLYSINQKNY SEQ ID NO:7 F6B_P1_H5_L RASENIYNTLA SEQ ID NO:8 F6B_P1_H5_L ENIYNT SEQ ID NO:9 F6B1_P3_D12_L / F6B1 P3 E9 L SASSSVTSNYLY SEQ ID NO:10 F6B1_P3_D12_L / F6B1 P3 E9 L SSVTSNY SEQ ID NO:11 F6B_P2_D4_L / F6B1_P1_E2_L / F6B P3 E2 L SASSSVSSNYLY SEQ ID NO:12 F6B_P2_D4_L / F6B1_P1_E2_L / F6B P3 E2 L SSVSSNY SEQ ID NO:13 Consenso SASSSV(S / T)SNYLY SEQ ID NO:14 P3D12 VL-abb / sdr QSVTSNY SEQ ID NO:15 P3D12 VL-abb / sdr RASQSVTSNYLY 0056] The names of the clones refer to our Tabelas 1-10 indicam or a number of fusão (F), or a number of placa (P) or a number of the cavedade Petition: 870260080059, on 10 / 08 / 2026, page. 34 / 234 30 / 94 (A1 to H12) of a 96-cavity plate from which the clone was derived. Therefore, clone F6AP12F12 was derived from Fusion 6A, Plate 12, Cavity F12, for example. The fusion numbers of each clone correspond to the Fusions indicated in Figure 2.

[0057] In some embodiments, a linking agent or the antigen-binding portion of a linking agent comprises a CDRL2 that is at least 70%, 75%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% identical to any of the sequences shown in Table 2. In some embodiments, a linking agent or the antigen-binding portion of a linking agent comprises a CDR-L2 of any of the sequences shown in Table 2. CDR-L2 sequences Table 2 ID Clone Amino Acid Sequence SEQ ID NO:16 F5_P5_B9_L KVSNRFS F5_P5_B9_L KVS SEQ ID NO:17 F6A_P8_E2_L GASNRYT F6A_P8_E2_L GAS SEQ ID NO:18 F6AP12F12_L WASTRES F6AP12F12_L WAS SEQ ID NO:19 F6B_P1_H5_L AATNLAD F6B_P1_H5_L AAT SEQ ID NO:20 F6B1_P3_D12_L / F6B1_P3_E9_L / F6B_P2_D4_L / F6B1_P1_E2_L / F6B P3 E2 L STSNLAS F6B1_P3_D12_L / F6B1_P3_E9_L / F6B_P2_D4_L / F6B1_P1_E2_L / F6B_P3_E2_L STS

[0058] In some embodiments, a binding agent or the antigen-binding portion of a binding agent comprises a CDRL3 that is at least 70%, 75%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% identical to Petition 870260080059, dated 10 / 08 / 2026, p. 35 / 234 31 / 94 any of the sequences shown in Table 3. In some embodiments, a binding agent or the antigen-binding portion of a binding agent comprises a CDR-L3 of any of the sequences shown in Table 3. CDR-L3 sequences Tabela 3 Clone Sequence of Aminoácidos SEQ ID NO:21 F5_P5_B9_L FQGSHVPYTFGGGTKLEIKR SEQ ID NO:22 F5_P5_B9_L FQGSHVPYT SEQ ID NO:23 F6A_P8_E2_L GQSYSYPLTFGAGTKLELKR SEQ ID NO:24 F6A_P8_E2_L GQSYSYPLT SEQ ID NO:25 F6AP12F12_L QQYYTYPLTFGAGTKLELK SEQ ID NO:26 F6AP12F12_L QQYYTYPLT SEQ ID NO:27 QHFWGTPYTFGGGTKLEIK SEQ ID NO:28 QHFWGTPYT SEQ ID NO:29 F6B_P1_H5_L / F6B1_P3_D12_L / F6B1_P3_E9_L / F6B_P2_D4_L / F6B1_P1_E2_L / F6B P3 E2 L HQWSSYPPTFGSGTKLEIK SEQ ID NO:30 F6B_P1_H5_L / F6B1_P3_D12_L / F6B1_P3_E9_L / F6B_P2_D4_L / F6B1_P1_E2_L / F6B P3 E2 L HQWSSYPPT SEQ ID NO:31 Consensus (Xi)Q(X2)(X3)(X4)YP(X5)T onde Xi é H, Q, or G; X2 é W, S or Y; X3 is S or Y; X4 is S or T; e X5 é P ou L.

[0059] In some embodiments, a binding agent or the antigen-binding portion of a binding agent comprises a variable light chain region with at least 70%, 75%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% identical to an amino acid sequence from Table 4. In some embodiments, a binding agent or the antigen-binding portion of a binding agent comprises a sequence of the variable light chain region from Table 4. VARIABLE LIGHT CHAIN ​​SEQUENCES Petition 870260080059, dated 10 / 08 / 2026, page 36 / 234 32 / 94 [TABLE 4] Clone ID Amino Acid Sequence SEQ ID NO:32 F5_P5_B9_L DVLMTQTPLSLPVSLGDQASISCRSSQT IVHGTGNTYLEWYLQKPGQSPKLLIYKV SNRFSGVPDRFSGSGSGTDFTLKISRVE AEDLGVYYCFQGSHGT RGVPQGGGQ ID NO: F6A_P8_E2_L DIVMTQSPKSMSMSVGERVTLSCKASE NVGTYVSWYQQKPDQSPKLLIYGASNR YTGVPDRFTGSATDFTLTISSVQAED LADYHCGQSYSYPLTFGAGTKLELKR SEQ ID NO:34 F6AP12F12F12LSVMSQLVMSQSQVMSSCV SLLYSINQKNYLAWYQQIPGQSPKLLIY WASTRESGVPDRFTGSGTDFTLTIS RVKAEDLALYCQQYTYPLTFGAGTKL ELKR SEQ ID NO:35 F6B_P1_H5_L RCDIQMTQSPASLSSVGETVTITCRAS ADGVPSRFSGSGSGTQYSLKINSLQSE DFGSYYCQHFWGTPYTFGGGTKLEIKR SEQ ID NO:36 F6B1_P3_D12_ L & F6B1_P3_E9_L QIVLTQSPAIMSASPGEKVTLTCSASSSS VTSNYLYWYQQLWKSSLPKLPKYST ASGVPARFSGSGSGTSYSLTISSMEAE DAASYFCHQWSSYPPTFGSGTKLEIKR SEQ ID NO:37 F6B_P2_D4_L QIVLTQSPAIMSASPGEKVTLTCSASSSS VSSNYLYWYQQKPGSSPKLWIYSTSNL ASGVPVRFSGGMSGGASSGESSL DAASYFCHQWSSYPPTFGSGTKLEI KR SEQ ID NO:38 F6B1_P1_E2_L & F6B_P3_E2_L QIVLTQSPAIMSASPGEKVTLTCASSS VSSNYLYWYHQKPGSSPKLWIYSTSNLASGVPVRFSGSGSGTSYSLTISSMEAE DAASYFCHQWSSYPPTFGSGTKLEI KR SEQ ID NO:39 Consensus QIVLTQSPAIMSASPGEKVTLTCSASSS VSSNYLYWY(H / Q)QKPGSSPKLWIYSTS NLASGVP(A / R)FSGSGSGTSYSLTISSM EAEDAASYFCHQWSSYPPTFGSGTKLE IKR

[0060] In some embodiments, a binding agent or the antigen-binding portion of a binding agent comprises a humanized light chain variable region having at least 70%, 75%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% identity with a sequence from Table 5. In some embodiments, a binding agent or the antigen-binding portion of a binding agent comprises a sequence of the humanized light chain variable region from Table 5. Humanized light chains P3D12 Petition 870260080059, dated 10 / 08 / 2026, page 37 / 234 33 / 94 [TABLE 5] ID Clone Sequência de Aminoácidos SEQ ID NO:40 P3D12 VL QIVLTQSPAIMSASPGEKVTLTCSAS SSVTSNYLYWYQQKPGSSPKLWIYS TSNLASGVPARFSGSGSGTSYSLTIS SMEAEDAASYFCHQWSSYPPTFGS GTKLEIKR SEQ ID NO:41 P3D12 VL-ven QIVLTQSPATMSASPGERVTLSCSAS SSVTSNYLYWYQQKPGSSPRLWIYS TSNLASGVPARFSGSGSGTSYTLTIS RMEPEDAASYFCHQWSSYPPTFGS GTKLEIKR SEQ ID NO:42 P3D12 VL-fra QIVLTQSPAILSLSPGERATLSCSASS SVTSNYLYWYQQKPGSSPKLLIYSTS NLASGVPARFSGSGSGTSYTLTISSL EAEDAASYFCHQWSSYPPTFGSGT KLEIKR SEQ ID NO:43 P3D12 VL-abb / sdr QIVLTQSPATLSLSPGERATLSCRAS QSVTSNYLYWYQQKPGSSPRLLIYS TSNLASGVPARFSGSGSGTDYTLTIS RLEPEDFASYFCHQWSSYPPTFGSG TKLEIKR SEQ ID NO:44 P3D12 VL-cdr QIVLTQSPATLSLSPGERATLSCSAS SSVTSNYLYWYQQKPGSSPRLLIYS TSNLASGVPARFSGSGSGTSYTLTIS RLEPEDFASYFCHQWSSYPPTFGSG TKLEIKR

[0061] In certain embodiments, a binding agent and / or an antigen-binding portion of a binding agent comprises one, two, or three CDRs of a variable region of the heavy chain. In some embodiments, a variable region of the heavy chain comprises one or more CDRs (e.g., one, two, three, or more CDRs). The amino acid sequences representing a CDR in a variable region of the heavy chain of an antibody or binding agent are referred to as CDR-H1, CDR-H2, and CDR-H3, which are numbered sequentially (i.e., H1, H2, and H3) in a direction from the amino-terminal (N-terminal) to the carboxyl-terminal (C-terminal) of a variable region of the heavy chain. For example, in a polypeptide representing a variable region of the heavy chain of a binding agent, CDR-H1, when present, is the larger N-terminal CDR; CDR-H3, when present, is the larger C-terminal CDR; Petition 870260080059, dated 10 / 08 / 2026, p. 38 / 234 34 / 94 and CDR-H2, when present, is located (i) between CDR-H1 and CDR-H3, (ii) on the N-terminal side of CDR-H3 or (iii) on the C-terminal side of CDR-H, of a variable heavy chain region. The terms CDRH1, CDR-H2 and CDR-H3 refer, in part, to an amino acid sequence of a polypeptide identified as, or described in the present invention as, a complementarity-determining region of a linking agent (e.g., a CDR of a variable heavy chain region of a linking agent). Non-limiting examples of amino acid sequences of a CDRH1, CDR-H2 and CDR-H3 are provided in Tables 6 to 8, respectively. A variable region of the heavy chain or antigen-binding portion of a binding agent described in the present invention may comprise any combination of a CDR-H1, a CDR-H2, and a CDR-H3 described in the present invention wherein the binding agent retains specific binding to cMET, or a portion thereof.In certain embodiments, a variable region of the heavy chain or antigen-binding portion of a binding agent described in the present invention comprises a single heavy chain CDR consisting of an amino acid sequence at least 70% identical to a CDR-H3 selected from Table 8. In certain embodiments, a variable region of the heavy chain or antigen-binding portion of a binding agent described in the present invention comprises an amino acid sequence at least 70% identical to a CDR-H3 selected from Table 8 and any other suitable CDR-H2 and / or CDR-H1 polypeptide sequence in which the binding agent retains specific binding to cMET, or a portion thereof. In certain embodiments, the heavy chain CDRs of a variable region of the heavy chain or antigen-binding portion of a binding agent consist of a CDR-H3 and a CDR-H2, wherein the CDR-H3 comprises a sequence of... Petition 870260080059, dated 10 / 08 / 2026, p. 39 / 234 35 / 94 amino acids at least 70% identical to a CDR-H3 selected from Table 8 and CDR-H2 comprises an amino acid sequence at least 70% identical to a CDR-H2 selected from Table 7. In certain embodiments, a variable heavy chain region or antigen-binding portion of a binding agent described in the present invention comprises an amino acid sequence at least 70% identical to a CDR-H3 selected from Table 8 and an amino acid sequence at least 70% identical to a CDR-H2 selected from Table 7 and any other suitable CDR-H1 polypeptide sequence, wherein the binding agent retains specific binding to cMET or a portion thereof.In certain embodiments, a variable heavy chain region or antigen-binding portion of a binding agent described in the present invention comprises three heavy chain CDRs consisting of a sequence at least 70% identical to a CDR-H2 selected from Table 7 and an amino acid sequence selected at least 70% identical to a CDR-H1 from Table 6. In certain embodiments, a variable heavy chain region or antigen-binding portion of a binding agent described in the present invention comprises an amino acid sequence at least 70% identical to a CDR-H3 selected from Table 8, an amino acid sequence at least 70% identical to a CDR-H2 selected from Table 7, and an amino acid sequence at least 70% identical to a CDR-H1 selected from Table 6, wherein the binding agent retains the specific cMET binding, or a portion thereof.

[0062] In some embodiments, a linking agent comprises one or more heavy-chain CDRs with at least 70%, 75%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% identity with any Petition 870260080059, dated 10 / 08 / 2026, p. 40 / 234 36 / 94 one of the CDRs in Tables 6, 7, or 8. In some embodiments, a binding agent or the antigen-binding portion of a binding agent comprises a CDR-H1 that is at least 70%, 75%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% identical to any of the sequences shown in Table 6. In some embodiments, a binding agent or the antigen-binding portion of a binding agent comprises a CDR-H1 of any of the sequences shown in Table 6. CDR-H1 sequences [TABLE 6] ID Clone Amino Acid Sequence SEQ ID NO:45 F5_P5_B9_H GFSLTNYGVN SEQ ID NO:46 F5_P5_B9_H GFSLTNYG SEQ ID NO:47 F6A P8 E2 H GFNINDYFMH SEQ ID NO:48 F6A P8 E2 H FNINDYF SEQ ID NO:49 F6A P12 F12 H GFTFTDYYMS SEQ ID NO:50 F6A P12 F12 H GFTFTDYY SEQ ID NO:51 F6B P1 H5 H GYTFTDYNMD SEQ ID NO:52 F6B P1 H5 H YTFTDYN SEQ ID NO:53 F6B1_P3_D12_H / F6B1P3E9_H / F6_B1_P1_E2_H / F6B_P3_E2_H / F6B P2 D4 H GYTFTSYWMH SEQ ID NO:54 F6B1_P3_D12_H / F6B1P3E9_H / F6_B1_P1_E2_H / F6B_P3_E2_H / F6B P2 D4 H YTFTSYW SEQ ID NO:55 Consensus GYTFT(D / S)Y(N / W) SEQ ID NO:56 Consensus G(Y / F)TFT(D / S)Y(N / W / Y)M(H / S)

[0063] In some embodiments, a binding agent or the antigen-binding portion of a binding agent comprises a CDRH2 that is at least 70%, 75%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% identical to any of the sequences shown in Table 7. In some embodiments, a binding agent or the antigen-binding portion Petition 870260080059, dated 10 / 08 / 2026, page 41 / 234 37 / 94 of a binding agent comprises a CDR-H2 of any of the sequences shown in Table 7. CDR-H2 sequences [TABLE 7] ID Clone Aminoacid Sequence SEQ ID NO:57 F5_P5_B9_H LIWGGGDTDYNSALKS SEQ ID NO:58 F5_P5_B9_H IWGGGDT SEQ ID NO:59 F6A_P8_E2_H WIDPENGNTIYDPKFQG SEQ ID NO:60 F6A_P8_E2_H IDPENGNT SEQ ID NO:61 F6A_P12_F12_H FIRNKANGYTTKYSASVKG SEQ ID NO:62 F6A_P12_F12_H IRNKANGYTT SEQ ID NO:63 F6B_P1_H5_H DINPNNGGTIYNQKFKG SEQ ID NO:64 F6B_P1_H5_H INPNNGGT SEQ ID NO:65 F6B1_P3_D12_H / F6B1P3E9_H YIKPSTDNTEYNQKFKD SEQ ID NO:66 F6B1_P3_D12_H / F6B1P3E9_H IKPSTDNT SEQ ID NO:67 F6_B1_P1_E2_H / F6B_P3_E2_H YINPSTDYTEYNQKFKD SEQ ID NO:68 F6_B1_P1_E2_H / F6B P3 E2 H INPSTDYT SEQ ID NO:69 F6B P2 D4 H YINPSTDYIEYNQKFKD SEQ ID NO:70 F6B P2 D4 H INPSTDYI SEQ ID NO:71 Consenso INPSTDY(I / T) SEQ ID NO:72 Consenso (Y / D)I(K / N)PSTD(N / Y)(T / I)EY( A / N)QKF(Q / K)(G / D) SEQ ID NO:73 P3D12 VH-abb / sdr YI KPSTDNTEYAQKFQG

[0064] In some embodiments, a binding agent or the antigen-binding portion of a binding agent comprises a CDR-H3 that is at least 70%, 75%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% identical to any of the sequences shown in Table 8. In some embodiments, a binding agent or the antigen-binding portion of a binding agent comprises a CDR-H3 of any of the sequences shown in Table 8. CDR-H3 sequences Petition 870260080059, dated 10 / 08 / 2026, p. 42 / 234 38 / 94 [TABLE 8] ID Clone Sequência de Aminoácidos SEQ ID NO:74 F5_P5_B9_H CARDYYGFDY SEQ ID NO:75 F5_P5_B9_H DYYGFDY SEQ ID NO:76 F6A_P8_E2_H CARGGNYLRESYYYAMDY SEQ ID NO:77 F6A_P8_E2_H RGGNYLRESYYYAMDY SEQ ID NO:78 F6A_P12_F12_H CSKDRGYFDY SEQ ID NO:79 F6A_P12_F12_H DRGYFDY SEQ ID NO:80 F6B_P1_H5_H RARGDYYGSSRYYYAMDY SEQ ID NO:81 F6B_P1_H5_H RGDYYGSSRYYYAMDY SEQ ID NO:82 F6B1_P3_D12_H / F6B1P3E9_H CARSYGNYPLMDY SEQ ID NO:83 F6B1_P3_D12_H / F6B1P3E9_H & F6_B1_P1_E2_H / F6B_P3_E2_H SYGNYPLMDY SEQ ID NO:84 F6_B1_P1_E2_H / F6B_P3_E2_H CVRSYGNYPLMDY SEQ ID NO:85 F6B_P2_D4_H CARSYGNFPLMDY SEQ ID NO:86 F6B_P2_D4_H RSYGNFPLMDY SEQ ID NO:87 Consenso C(A / V)RSYGN(F / Y)PLMDY SEQ ID NO:88 Consenso RSYGN(F / Y)PLMDY

[0065] In some embodiments, a binding agent or the antigen-binding portion of a binding agent comprises a variable heavy chain region having at least 70%, 75%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% identity with a sequence from Table 9. In some embodiments, a binding agent or the antigen-binding portion of a binding agent comprises a sequence of the variable heavy chain region from Table 9. VARIABLE HEAVY CHAIN ​​SEQUENCES [TABLE 9] ID Clone Amino Acid Sequence SEQ ID NO:89 F5_P5_B9_H QVQLKESGPGLVAPSQSLSITCTVSG FSLTNYGVNWVRQPPGKGLEWLGLI WGGGDTDYNSALKSRLSISKDNSKS QVFLKMETNSLQTDDTARYYCARDY YGFDYWGQGTTLTVSS SEQ ID NO:90 F6A_P12_F12_ H EVKLVESGGGLVQPGGSLRLSCATS GFTFTDYYMSWVRQPPGKALEWLG FIRNKANGYTTKYSASVKGRFTISRD NSQSILYLQMNTLRAEDSATYYCSKD RGYFDYWGQGTTLTVSS Petition 870260080059, dated 10 / 08 / 2026, page 43 / 234 39 / 94 ID Clone Amino Acid Sequence SEQ ID NO:91 F6A_P8E2_H VNSEVQLQQSGAELVRPGALVKLSC KASGFNINDYFMHWVKRPEQGLE WIGWIDPENGNTIYDPKFQGKASITA DTSSSNTAYLQLSSLTSEDTAVYCRESS GGWGYGGYGSVYMDSVKLSC SEQ ID NO:92 F6B_P1_H5_H VLSEVLLQQSGPELVKPGASVKIPCK ASGYTFTDYNMDWVKQSHGKSLEWI GDINPNNGGTIYNQKFKGKATLTVDK SSSTAYMELRSLTSEDTAVYRARG DYYGSRYYYAM DYGSSRYYAM SEQSVGGT SEQUG IDW: NO: F6B1_P3_D12_ H QVQLQQSGAELAKPGASVCVKMSCRA SGYTFTSYWMHWVKRPGQGLDWI GYIKPSTDNTEYNQKFKDKATLTADK SSSTAYMQLSSLTSEDSAVYYCARS YGNYPLM DYWGQGSSVSSQ SEQ1694 IDHB NO: IDH QVQLQQSGAELAKPGASVKMSCRA SGYTFTSYWMHWVKQRPGQGLDWI GYI KPSTDNTEYNQKFKDKATLTADK SSSTAYMQLSSLTSEDSAVYYCARS YGNYPLM DYWGQGTSVTVSS SEQ ID NO:95 F6B1_HP1_HP1_E QVQLQQSGAELAKPGASVKMSCKA SGYTFTSYWMHWVKQRPGQGLEWI GYINPSTDYTEYNQKFKDKATLTADK SSTTAYMQLSSLTSEDSAVYCVRS YGNYPLM DYWGQGTSVTVSS SEQ ID NO:96 F6B_HP3_E2_E2 QVQLQQSGAELAKPGASVKMSCKA SGYTFTSYWMHWVKQRPGQGLEWI GYINPSTDYTEYNQKFKDKATLTADK SSTTAYMQLSSLTSEDSAVYCVRS YGNYPLM DYWGQGTSVTVSS SEQ ID NO:97 F6B_HP2_HP2_D4QVQLQQSGAELAKPGASVKMSCKA SGYTFTSYWMHWVKQRPGQGLEWI GYINPSTDYIEYNQKFKDKATLTAGK SSSTAYMQLSSLTSEDSAVYYCARS YGNFPLM DYWGQGTSVTVSS SEQ ID NO:98 Consensus QVQLQQSGAELAKPGASVKMSC(K / R)ASGYTFTSYWMHWVKQRPGQGL(E / D)WIGYI(K / N)PSTD(Y / N)(T / I)EYNQ KFKDKATLTADKSS(S / T)TAYMQLSS LTSEDSAVYYC(A / V)RSYGN(Y / F)PL MDYWGQGTSVTVSS

[0066] In some embodiments, a binding agent or the antigen-binding portion of a binding agent comprises a humanized heavy chain variable region having at least 70%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% identity with a sequence from Table 10. In some embodiments, an agent Petition 870260080059, dated 10 / 08 / 2026, p. 44 / 234 The 40 / 94 binding site, or the antigen-binding portion of a binding agent, comprises a sequence of the humanized heavy chain variable region of Table 10. Humanized Heavy Prisons P3D12 [TABLE 10] ID Clone Amino Acid Sequence SEQ ID NO:99 P3D12 VH QVQLQQSGAELAKPGASVKMSC RASGYTFTSYWMHWVKQRPGQ GLDWIGY IKPSTDNTEYNQKFKD KATLTADKSSSTAYMQLSSLTSED SAVYYCARSMDSSVYGWYGGWGGSVKMSC ID NO:100 P3D12 VH-fra QVQLQQSGAEVKKPGASVKVSC KASGYTFTSYWMHWVKRPGQG LDWIGY IKPSTDNTEYNQKFKDR VTLTADKSTSTAYMQLSNLISEDT AVYYCARSYGNYPLMDYWGTV1201 SEQ ID3DSV: NO: VH-ven QVQLVQSGAEVAKPGASVKMSC KASGYTFTSYWMHWVKQAPGQG LDWIGYIKPSTDNTEYNQKFKDKA TLTADKSTSTAYMQLSSLRSEDTA VYYCARSYGNYPLMDYWGQGTT VTVSS SEQ ID NO:102 P3D-abb / s VHD1 QVQLVQSGAEVKKPGASVKVSCK ASGYTFTSYWMHWVKQAPGQGL DWMGYIKPSTDNTEYAQKFQGRV TLTADKSTSTAYMELSSLRSEDTA VYYCARSYGNYPLMDYWGQGTT VTVSS SEQ ID NO:103 P3D12 VH-r QVQLVQSGAEVKKPGAGVKVSCK ASGYTFTSYWMHWVKQAPGQGL DWIGYIKPSTDNTEYNQKFKDKAT LTADKSTSTAYMELSSLRSEDTAV YYCARSYGNYPLMDYWGQGTTV TVSS

[0067] In some embodiments, a binding agent, or an antigen-binding portion of a binding agent, comprises a CDR-L3 which comprises an amino acid sequence of at least 70%, at least 75%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least Petition 870260080059, dated 10 / 08 / 2026, page 45 / 234 41 / 94 98%, at least 99%, or 100% identical to any of the amino acid sequences of SEQ ID NOs: 26 to 36 (for example, a CDR-L3 sequence selected from Table 3) and a CDRH3 which comprises an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to any of the amino acid sequences SEQ ID NOs: 79 to 93 (for example, a CDR-H3 sequence selected from Table 8). In some embodiments, a binding agent, or an antigen-binding portion of a binding agent, comprises a CDR-L3 which comprises an amino acid sequence that is at least 70%, at least 90%, at least 95%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 34 or 35, and a CDR-H3 which comprises an amino acid sequence that is at least 70%, at least 90%, at least 95%, at least 98%, less than 99% or 100% identical to the amino acid sequence of SEQ ID NO: 87, 88, 92 or 93.

[0068] In some embodiments, a binding agent, or an antigen-binding portion of a binding agent, comprises a CDR-L3 comprising an amino acid sequence that is at least 70%, at least 90%, or 100% identical to any of the amino acid sequences SEQ ID NOs: 26 to 36 (for example, a CDR-L3 sequence selected from Table 3), a CDR-L2 comprising an amino acid sequence that is at least 70%, at least 90%, or 100% identical to any of the amino acid sequences SEQ ID NOs: 16 to 25 (for example, a CDR-L2 sequence selected from Table 2), a CDR-H3 ...). Petition 870260080059, dated 10 / 08 / 2026, p. 46 / 234 42 / 94 less 90%, or 100% identical to any of the amino acid sequences of SEQ ID NOs: 79 to 93 (for example, a CDR-H3 sequence selected from Table 8) and a CDR-H2 which comprises an amino acid sequence at least 70%, at least 90%, or 100% identical to any of the amino acid sequences of SEQ ID NOs: 62 to 78 (for example, a CDR-H2 sequence selected from Table 7).In some embodiments, a binding agent, or an antigen-binding portion of a binding agent, comprises a CDR-L3 comprising an amino acid sequence at least 70%, at least 90%, or 100% identical to the amino acid sequence of SEQ ID NO: 34 or 35, a CDRL2 comprising an amino acid sequence at least 70%, at least 90%, or 100% identical to the amino acid sequence of SEQ ID NO: 24 or 25, a CDR-H3 comprising an amino acid sequence at least 70%, at least 90%, or 100% identical to the amino acid sequence of SEQ ID NO: 87, 88, 92, or 93, and a CDRH2 comprising an amino acid sequence at least 70%, at least 90%, or 100% identical to the amino acid sequence of SEQ ID NO: 70, 71, or 78.

[0069] In some embodiments, a binding agent, or an antigen-binding portion of a binding agent, comprises a CDR-L3 comprising an amino acid sequence that is at least 70%, at least 90%, or 100% identical to any of the amino acid sequences SEQ ID NOs: 26 to 36 (for example, a CDR-L3 sequence selected from Table 3), a CDR-L2 comprising an amino acid sequence that is at least 70%, at least 90%, or 100% identical to any of the amino acid sequences SEQ ID NOs: 16 to 25 (for example, a CDR-L2 sequence selected from Table 2), a CDR-L1 ...). Petition 870260080059, dated 10 / 08 / 2026, p. 47 / 234 43 / 94 minus 90%, or 100% identical to any of the amino acid sequences. Amino acid sequences of SEQ ID NOs: 1 to 15 (e.g., a CDR-L1 sequence selected from Table 1), a CDR-H3 comprising an amino acid sequence that is at least 70%, at least 90%, or 100% identical to any of the amino acid sequences of SEQ ID NOs: 79 to 93 (e.g., a CDR-H3 sequence selected from Table 8), a CDRH2 comprising an amino acid sequence that is at least 70%, at least 90%, or 100% identical to any of the amino acid sequences of SEQ ID NOs: 62 to 78 (e.g., a CDR-H2 sequence selected from Table 7), and a CDRH1 comprising an amino acid sequence that is at least 70%, at least 90%, or 100% identical to any of the amino acid sequences of SEQ ID NOs: 50 to 61 (e.g., a (sequence CDR-H1 selected from Table 6).In some embodiments, a binding agent, or an antigen-binding portion of a binding agent, comprises a CDR-L3 comprising an amino acid sequence at least 70%, at least 90%, or 100% identical to the amino acid sequence of SEQ ID NOs: 34 or 35; a CDR-L2 comprising an amino acid sequence at least 70%, at least 90%, or 100% identical to the amino acid sequence of SEQ ID NO: 24 or 25; a CDR-L1 comprising an amino acid sequence at least 70%, at least 90%, or 100% identical to the amino acid sequence of SEQ ID NO: 9, 10, or 15; a CDR-H3 comprising an amino acid sequence at least 70%, at least 90%, or 100% identical to the amino acid sequence of SEQ ID NO: 87 or 88; a CDR-H2 comprising a sequence of amino acids at least 70%, at least 90%, or 100% identical to the amino acid sequence of SEQ ID NO: 70, 71, or 78, and a CDR-H1 which comprises an amino acid sequence of at least 70%, at least 90%, or 100% identical to that of SEQ ID NO: 70, 71, or 78, and a CDR-H1 which comprises an amino acid sequence of at least 70%. Petition 870260080059, dated 10 / 08 / 2026, p. 48 / 234 44 / 94 minus 70%, at least 90%, or 100% identical to the amino acid sequence of SEQ ID NO: 58 or 59.

[0070] In some embodiments, a binding agent, or an antigen-binding portion of a binding agent, comprises a variable heavy chain region comprising an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any of the amino acid sequences of SEQ ID NOs: 94 to 108 (e.g., a variable heavy chain region selected from Tables 9 and 10) and a variable light chain region comprising an amino acid sequence that is at least 70%, at least 75%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%,at least 99% or 100% identical to any of the amino acid sequences of SEQ ID NOs: 37 to 49 (for example, a variable light chain region selected from Tables 4 and 5). In some embodiments, a binding agent, or an antigen-binding portion of a binding agent, comprises a variable heavy chain region comprising an amino acid sequence at least 90% identical to any of the amino acid sequences of SEQ ID NOs (a variable heavy chain region selected from Table 10) and a variable light chain region comprising an amino acid sequence at least 90% identical to any of the amino acid sequences of SEQ ID NOs: 45 to 49 (for example, a light chain sequence region selected from Table 5). Petition 870260080059, dated 10 / 08 / 2026, p. 49 / 234 45 / 94

[0071] The abbreviations abb, sdr, fra, ven and cdr as used in the present invention are explained below. The abbreviation cdr or CDR refers to a Complementarity Determinant Region. The abbreviation abb refers to abbreviated CDR according to Padlan et al. (1995) Identification of specificity-determining residues in FASEB antibodies J 9: 133-139. In some embodiments, the abbreviated CDRs are defined as residues 27D-34, 50-55 and 89-96 in the light chain and 31-35B, 50-58 and 95-101 in the heavy chain, which are grafted onto a suitable human core structure. The critical structure residues are generally preserved. The abbreviation sdr refers to specificity-determining residues according to Padlan et al. (1995) which are residues that are thought to be involved in antigen binding.The abbreviation fra refers to the Frankenstein approach based on the suggestion of Wu and Kabat (1992) Possible use of amino acid sequences from the structure-like region between human and mouse immunoglobulins for humanization of mouse antibodies Mol Immunol 29: 1141-1146. The abbreviation ven refers to Veneering according to Padlan (1991), A possible procedure to reduce the immunogenicity of antibody variable domains while preserving their ligand-binding properties Mol Immunol 28: 489-498.

[0072] The term identical percent or percentage of identity refers to the sequence identity between two amino acid sequences. Identity can be determined by comparing a position in each sequence that can be aligned for comparison purposes. When an equivalent position in the compared sequences is occupied by the same amino acid, then the molecules are identical at that position. When the equivalent site is occupied by the same or a similar amino acid residue (e.g., similar in stereochemical and / or electronic nature), Petition 870260080059, dated 10 / 08 / 2026, page 50 / 234 46 / 94 then the molecules can be referred to as homologous (similar) at that position. The expression as a percentage of homology, similarity, or identity refers to a function of the number of identical or similar amino acids at shared positions across the compared sequences. Several alignment algorithms and / or programs can be used, including FASTA, BLAST, or ENTREZ. FASTA and BLAST are available as part of the GCG (University of Wisconsin, Madison, Wis.) sequence analysis package and can be used with, for example, default settings. ENTREZ is available through the National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland.In one embodiment, the percentage of identity of two sequences can be determined by the GCG program with an opening weight of 1, for example, each amino acid interval is weighted as if it were a single amino acid or nucleotide mismatch between the two sequences.

[0073] Other techniques for alignment are described in Methods in Enzymology, vol. 266: Methods for Macromolecular Sequence Analysis (1996), ed. Doolittle, Academic Press, Inc., a division of Harcourt Brace & Co., San Diego, California, USA. In some embodiments, an alignment program that allows gaps in the sequence is used to align the sequences. SmithWaterman is one type of algorithm that allows gaps in sequence alignments. See Meth. Mol. Biol. 70: 173-187 (1997). Additionally, the GAP program using the Needleman and Wunsch alignment method can be used to align the sequences. Petition 870260080059, dated 10 / 08 / 2026, page 51 / 234 47 / 94 An alternative search strategy uses the MPSRCH software, which runs on a MASPAR computer. MPSRCH uses a Smith-Waterman algorithm to score sequences on a massively parallel computer. This approach improves the ability to identify distant matches and is especially tolerant of small gaps and errors in the nucleotide sequence. Nucleic acid-encoded amino acid sequences can be used to search protein and DNA databases.

[0074] In some embodiments, a binding agent or antigen-binding portion of a binding agent comprises one or more CDRs selected from a variable region of the light chain of Tables 4 and 5. In some embodiments, a binding agent or antigen-binding portion of a binding agent comprises one or more CDRs selected from a variable region of the heavy chain of Tables 9 and 10. In some embodiments, a binding agent or antigen-binding portion of a binding agent comprises one or more CDRs selected from a variable region of the light chain of Tables 4 and 5 and one or more CDRs selected from a variable region of the heavy chain of Tables 9 and 10.In certain embodiments, a binding agent, or antigen-binding portion of a binding agent, comprises a CDR-L1, a CDR-L2, and a CDR-L3, each selected from any of the variable regions of the light chain in Tables 4 and 5, and a CDR-H1, a CDR-H2, and a CDR-H3, each selected from any of the variable regions of the heavy chain in Tables 9 and 10. An amino acid sequence of a CDR (e.g., a CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3) can be identified within a variable region of the heavy chain or light chain described in the present invention by means of any suitable method described in the present invention or. Petition 870260080059, dated 10 / 08 / 2026, p. 52 / 234 48 / 94 known through those versed in the art.

[0075] In some embodiments, a linking agent comprises one or more suitable sequences selected from Tables 1-10, wherein the selected polypeptide sequence comprises 0 to 5, 1 to 5, 0 to 10, 1 to 10, 0 to 15 or 1 to 15 amino acid modifications where an amino acid modification may be an addition of amino acids, an elimination of amino acids and / or a substitution of amino acids. In some embodiments, a linking agent described in this invention comprises one or more amino acid analogs, non-native amino acids or amino acid derivatives.

[0076] In certain embodiments, a binding agent or antigen-binding portion of a binding agent comprises one or more structure regions (FRs). Structure regions are frequently located between CDRs and / or flank CDR sequences of a variable heavy or light chain region of an antibody or binding agent. In mammals, a variable heavy chain region frequently comprises four structural regions and a variable light chain region frequently comprises four structural regions. Any suitable method may be used to identify one or more structural regions in an antibody, in a variable region of an antibody, or in a binding agent. A binding agent may comprise synthetic or naturally occurring structural regions that are unmodified or modified (e.g., optimized) as discussed below.

[0077] In some embodiments, a binding agent or antigen-binding portion thereof is chimeric, grafted, and / or humanized. Chimeric, grafted, and / or humanized binding agents often comprise constant regions and / or modified or substituted structural regions, while still maintaining the Petition 870260080059, dated 10 / 08 / 2026, p. 53 / 234 49 / 94 specificity of binding to cMET, or a portion thereof. In some embodiments, a binding agent, or a portion thereof binding to the antigen, comprises constant regions, structural regions or portions thereof, derived from a human antibody. In some embodiments, a binding agent, or a portion thereof binding to the antigen, comprises wholly synthetic portions, one or more amino acids, or amino acid sequences that are not found in native antibody molecules.

[0078] Naturally occurring structural regions, or portions thereof, may be obtained from any suitable species. In certain embodiments, the complementarity-determining regions (CDRs) of the variable regions of the light and heavy chains of a binding agent, or a portion thereof binding to the antigen, are grafted onto structural regions of the same or another species. For example, one or more structural regions of a binding agent may be derived from a rodent species (e.g., a rat or mouse) or from a primate species (e.g., a human).

[0079] In certain embodiments, the CDRs of the variable light and / or heavy chain regions of a binding agent, or a binding portion thereof to the antigen, can be grafted onto consensus regions of human structure. To create the consensus regions of human structure, in certain embodiments, the structural regions of several amino acid sequences of the human heavy chain or light chain can be aligned to identify a consensus sequence. In certain embodiments, the structural regions of the heavy chain or light chain of an antibody or binding agent are replaced by one or more structural regions, or portions thereof, of a different variable heavy chain or light chain region. In some embodiments, a binding agent, or a Petition 870260080059, dated 10 / 08 / 2026, page 54 / 234 50 / 94 portion thereof binding to the antigen, comprises one or more human structural regions. In certain embodiments, a binding agent, or a portion thereof binding to the antigen, comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 human structural regions. In some embodiments, a binding agent, or a portion thereof binding to the antigen, comprises one or more mouse structural regions. In certain embodiments, a binding agent, or a portion thereof binding to the antigen, comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mouse structural regions. In certain embodiments, a binding agent, or a portion thereof binding to the antigen, comprises one or more human structural regions and one or more mouse structural regions.

[0080] Methods for generating chimeric, humanized and / or optimized antibodies or binding agents are known, for example, by modifying, replacing or suppressing structural regions, or portions thereof. Non-limiting examples of CDR grafting are described, for example, in US Patents Nos. 6,180,370, 6,054,297, 5,693,762, 5,859,205, 5,693,761, 5,565,332, 5,585,089 and 5,530,110, and in Jones et al, Nature, 321: 522-525 (1986); Verhoeyen et al, Science, 239: 1534-1536 (1988) and Winter, FEBS Letts., 430: 92-94 (1998). Additional non-limiting examples of generating chimeric, grafted and / or humanized binding agents include US Patent No. 5,530,101; US ​​Patent No. 5,707,622; US Patent No. 5,994,524; US Patent No. 6,245,894; Queen et al., (1988) PNAS 86: 10029-10033; Riechmann et al., Nature (1988) 332: 323-327; Antibody Engineering: Methods and Protocols, vol. 248 of Methods in Molecular Biology, edited by Benny KC Lo, Springer Science & Business Media, (2004); and Antibody Engineering, vol. 1, Roland E. Kontermann, Stefan Duebel, Edition 2, Springer Science & Business Media. Petition 870260080059, dated 10 / 08 / 2026, page 55 / 234 51 / 94 Business Media, (2010). In some embodiments, a binding agent can be humanized by exchanging one or more structural regions, or portions thereof (e.g., one or more amino acids), with one or more structural regions, or portions thereof, of a human antibody. In certain embodiments, an antibody or binding agent can be humanized or grafted by transferring one or more CDRs (e.g., 1, 2, 3, 4, 5, or all 6 CDRs) from a donor binding agent (e.g., a mouse monoclonal antibody) to an acceptor binding agent (e.g., a human antibody) while retaining the binding specificity of the donor binding agent. In certain embodiments, the process of preparing a chimeric, grafted, or humanized binding agent comprises performing one or more amino acid substitutions, additions, or deletions in a constant region or structural region of a binding agent.In certain embodiments, techniques such as remodeling, hyperchimerization, or coating can be used to produce humanized binding agents (e.g., see Vaswami et al., Annals of Allergy, Asthma, & Immunol. 81: 105 (1998); Roguska et al., Prot. Engin., 9: 895-904 (1996) and US Patent No. 6,072,035). In some respects, a binding agent is modified by a method discussed above, or by another suitable method, to reduce immunogenicity (e.g., see Gilliland et al., J. Immunol., 62 (6): 3663-71 (1999)).

[0081] In certain embodiments, an amino acid sequence of a binding agent is modified to optimize binding affinity for a target (e.g., cMET), species cross-reactivity, solubility, and / or function (e.g., agonist activity, or lack thereof). In some embodiments, a specific combination of CDRs described in this invention can be optimized for cMET binding. Petition 870260080059, dated 10 / 08 / 2026, p. 56 / 234 52 / 94 and / or to optimize a function or characteristic of a linking agent described in the present invention. For example, a characterized light chain variable region described in the present invention (e.g., a light chain variable region of SEQ ID NO: 48) can be co-expressed, using a suitable expression system, with a library of heavy chain variable regions comprising a CDR-H1 and CDR-H2 of a characterized heavy chain variable region (e.g., a heavy chain variable region of SEQ ID NO: 107), wherein CDR-H3 is replaced by means of a library of CDR-H3 sequences, which may include one or more CDR-H3 Regions from Table 8, for example. The resulting light chain / heavy chain linking agents can be screened for cMET binding and / or for a specific function. The optimized linking agents can be identified and the amino acid sequence of CDR-H3 can be identified by means of a suitable method.The screening method described above can be used to identify agents comprising specific combinations of CDRs, or specific optimized CDR sequences (e.g., CDR sequences comprising amino acid substitutions, additions, or deletions) that provide a binding agent with improved binding specificity, binding affinity, and / or function. These methods for screening and optimizing binding agents are well-known (e.g., see Portolano et al., (1993) Journal of Immunology 150: 880-887; and Clarkson et al., (1991) Nature 352: 624-628). Such references teach methods for producing antibodies that bind to a specific antigen using known variable light chains, known variable heavy chains, or a portion thereof (e.g., CDRs thereof) by screening a library of complementarity variable regions.

[0082] In certain embodiments, a linking agent is modified Petition 870260080059, dated 10 / 08 / 2026, p. 57 / 234 53 / 94 to eliminate or add glycosylation sites to optimize the affinity and / or function of a linking agent (e.g., see Co et al., Mol. Immunol., 30: 1361-1367 (1993)). In some embodiments, the number and / or type of glycosylation sites on a linking agent is modified or altered. An N-linked glycosylation site is often characterized by the sequence Asn-X-Ser or Asn-X-Thr, where the amino acid residue designated as X can be any amino acid residue except proline. Substitution of amino acid residues to create this sequence provides a new potential site for the addition of an N-linked carbohydrate chain. Alternatively, substitutions that eliminate this sequence will remove an existing N-linked carbohydrate chain.Also provided in certain embodiments is a rearrangement of the N-linked carbohydrate chains, in which one or more N-linked glycosylation sites (typically those that occur naturally) are eliminated and one or more N-linked sites are created. In some embodiments, a linking agent is modified by deletion of one or more cysteine ​​residues or substitution of one or more cysteine ​​residues with another amino acid (e.g., serine) compared to an unmodified linking agent. In certain embodiments, cysteine ​​variants may be useful for optimizing expression, secretion, and / or solubility.

[0083] In certain embodiments, a binding agent is modified to include certain designed or intended amino acid additions, substitutions, or deletions, for example, to reduce the susceptibility of a binding agent to proteolysis, reduce the susceptibility of a binding agent to oxidation, increase the serum half-life, and / or impart or modify other physicochemical, pharmacokinetic, or functional properties of a binding agent.

[0084] In some embodiments, a binding agent binds, in a specific manner, to a mammalian cMET, or portion of Petition 870260080059, dated 10 / 08 / 2026, p. 58 / 234 54 / 94 same. In some embodiments, a linking agent binds in a specific manner to an extracellular domain or extracellular regions of a mammalian cMET, or a portion thereof. In certain aspects, a linking agent binds in a specific manner to a wild-type cMET produced by means of an unaltered (non-genetically modified) mammalian cell found in nature. In certain aspects, a linking agent binds in a specific manner to a naturally occurring cMET variant. In certain aspects, a linking agent binds in a specific manner to a cMET comprising one or more amino acid substitutions, additions, or deletions. In certain embodiments, a linking agent binds in a specific manner to a cMET produced and / or expressed on the surface of a cell from a human, non-human primate, dog, cat, or rodent (e.g., a rat or mouse).In certain embodiments, a linking agent binds in a specific manner to one or more cMET polypeptides, or a portion thereof, having an amino acid sequence of any of the following SEQ IDs: 109 to 113. In certain embodiments, a linking agent binds in a specific manner to a human cMET. In certain embodiments, a linking agent binds in a specific manner to an extracellular domain of a human cMET. In certain embodiments, a linking agent binds in a specific manner to a human cMET and / or its extracellular domain, wherein the human cMET comprises an E168 to D168 substitution (i.e., an E168D variant of cMET). In certain embodiments, a linking agent binds in a specific manner to a human cMET and / or its extracellular domain, wherein the human cMET comprises an N375 to S375 substitution (i.e., an N375S variant of human cMET).

[0085] The term “Se liga, de uma maneira específica” refers to a Petition 870260080059, dated 10 / 08 / 2026, p. 59 / 234 55 / 94 binding agent that binds to a target peptide preferentially binding to other molecules or other peptides as determined, for example, as determined by means of a suitable in vitro assay (e.g., an ELISA, immunoblotting, flow cytometry, and the like). A specific binding interaction discriminates from non-specific binding interactions by about 2 times or more, usually about 10 times or more, and sometimes about 100 times or more, 1000 times or more, 10,000 times or more, 100,000 times or more, or 1,000,000 times or more.

[0086] In some embodiments, a binding agent that specifically binds to cMET, or a portion thereof, is a binding agent that binds to cMET, or a portion thereof (e.g., an extracellular domain of cMET), with a binding affinity constant (KD) equal to or less than 100 nM, equal to or less than 50 nM, equal to or less than 25 nM, equal to or less than 10 nM, equal to or less than 5 nM, equal to or less than 1 nM, equal to or less than 900 pM, equal to or less than 800 pM, equal to or less than 750 pM, equal to or less than 700 pM, equal to or less than 600 pM, equal to or less than 500 pM, equal to or less than 400 pM, equal to or less than 300 pM, equal to or less than 200 pM or equal to or less than 100 pM.In some embodiments, a binding agent that specifically binds to cMET, or a portion thereof, is a binding agent that binds to human cMET, or a portion thereof (e.g., an extracellular domain of human cMET), with a binding affinity constant (KD) of or less than 100 nM, equal to or less than 50 nM, equal to or less than 25 nM, equal to or less than 10 nM, equal to or less than 5 nM, equal to or less than 1 nM, equal to or less than 900 pM, equal to or less than 800 pM, equal to or less than 750 pM, equal to or less than 700 pM, equal to or less than 600 pM, equal to or less than 500 pM. Petition 870260080059, dated 10 / 08 / 2026, p. 60 / 234 56 / 94 equal to or less than 400 pM, equal to or less than 300 pM, equal to or less than 200 pM, or equal to or less than 100 pM. In some embodiments, a binding agent that binds specifically to cMET, or a portion thereof, is a binding agent that binds specifically to cMET, or a portion thereof, derived from a non-human species (e.g., a non-human primate or rodent), for example, a rat or mouse), with a binding affinity constant (KD) equal to or less than 100 nM, equal to or less than 50 nM, equal to or less than 25 nM, equal to or less than 10 nM, equal to or less than 5 nM, equal to or less than 1 nM, equal to or less than 900 pM, equal to or less than 800 pM, equal to or less than 750 pM, equal to or less than 700 pM, equal to or less than less than 600 pM, equal to or less than 500 pM, equal to or less than 400 pM, equal to or less than 300 pM, equal to or less than 200 pM, or equal to or less than 100 pM.In certain embodiments, a binding agent described in the present invention binds in a specific manner to human cMET, or a portion thereof, and binds in a specific manner to cMET, or a portion thereof, derived from a non-human primate. In certain embodiments, a binding agent described in the present invention binds in a specific manner to human cMET, or a portion thereof, and binds in a specific manner to cMET, or a portion thereof, derived from a rodent (e.g., a mouse or rat). In certain embodiments, a binding agent (i) binds in a specific manner to a human cMET, or portion thereof (e.g., an extracellular domain of human cMET) with a KD of 10 nM or less, or 1 nM or less, and (ii) binds in a specific manner to a mouse or rat cMET, or portion thereof (e.g., an extracellular domain of rat or rat cMET) with a KD of 100 nM or less. Petition 870260080059, dated 10 / 08 / 2026, p. 61 / 234 57 / 94 that, 90 nM or less than, 80 nM or less than, 70 nM or less than, 60 nM or less than, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less or 10 nM or less.

[0087] In some embodiments, a linking agent comprises a marker. As used in the present invention, the terms marker or labeled refer to the incorporation of a detectable marker, for example, by incorporation of a labeled amino acid or linking to a polypeptide of biotin moieties that can be detected by labeled avidin (e.g., streptavidin containing a fluorescent marker or enzymatic activity that can be detected by optical or colorimetric methods). In certain embodiments, a marker or label may be linked to a linking agent for the purpose of generating a therapeutic or diagnostic agent. A linking agent may be covalently or non-covalently linked to any suitable marker or label. Various methods of labeling polypeptides and glycoproteins are known to those skilled in the art and can be used.Non-limiting examples of polypeptide markers include, but are not limited to, the following: radioisotopes or radionuclides (e.g., 3H, 14C, 15N, 35S, 90Y, 99Tc, 125I, 131I), fluorescent markers, enzymatic markers (e.g., horseradish peroxidase, β-galactosidase, luciferase, alkaline phosphatase), chemiluminescent markers, a metallic label, a chromophore, an electrochemiluminescent label, a phosphorescent marker, a suppressor (e.g., a fluorophore suppressor), a fluorescence resonance energy transfer (FRET) pair (e.g., donor and acceptor), a dye, an enzymatic substrate, a small molecule, a mass marker, quantum dots, nanoparticles, biotinyl groups, predetermined polypeptide epitopes recognized by a secondary reporter (e.g., Petition 870260080059, dated 10 / 08 / 2026, page 62 / 234 58 / 94 example, leucine zipper pair sequences, secondary antibody binding sites, metal-binding domains, epitope tags), similar or combinations thereof.

[0088] In some embodiments, a linking agent comprises a suitable carrier. A linking agent may be covalently or non-covalently linked to a suitable carrier. Non-limiting examples of a carrier include agents or molecules that alter or prolong the in vivo half-life of a linking agent, polyethylene glycol, glycogen (e.g., by glycosylation of a linking agent), a dextran, a carrier described in U.S. Patent No. 6,660,843, the like, or combinations thereof.

[0089] In some embodiments, a linking agent comprises a suitable therapeutic agent. A linking agent may be covalently or non-covalently linked to any suitable therapeutic agent. Non-limiting examples of a therapeutic agent include a medication, toxin, radioisotope, ligand, receptor, cytokine, antibody, antineoplastic agent, inhibitor (e.g., a receptor antagonist, an enzyme inhibitor), a cytokine, or an agent described in U.S. Patent No. 6,660,843, which is incorporated into the present invention by reference, similars, or combinations thereof.Non-limiting examples of antineoplastic agents include an auristatin (e.g., monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF) and the like), a dolastatin, a maytansine, a tubulisin, an irinotecan or a derivative or metabolite thereof (e.g., SN38), a calicheamicin, a pyrrolobenzodiazepine (PBD), a duocarmycin, a doxorubicin, a Pseudomonas exotoxin A (e.g., PE38), derivatives thereof, similar agents or combinations thereof. Consequently, in certain embodiments, a binding agent described in this invention comprises an agent. Petition 870260080059, dated 10 / 08 / 2026, p. 63 / 234 59 / 94 antineoplastic.

[0090] In some embodiments, a marker, therapeutic agent, or vehicle is linked to a linking agent through the use of a suitable linker. Non-limiting examples of a suitable linker include silanes, thiols, phosphoric acid, polyethylene glycol (PEG), amino acids and peptides, polymers thereof, derivatives thereof, similar substances, and combinations thereof. The methods of linking two or more molecules using a linker are for those skilled in the art and are sometimes referred to as crosslinking.

[0091] In some embodiments, a marker, therapeutic agent, vehicle, or ligand is linked to a suitable thiol group of a linking agent (e.g., a thiol group of a cysteine ​​residue). Any suitable amino acid residue of a constant region or structural region of a linking agent may be substituted by means of an amino acid residue containing a thiol group (e.g., a cysteine) for the purpose of linking a marker, therapeutic agent, vehicle, or ligand. Non-limiting examples of amino acids that may be substituted with a thiol-containing amino acid residue include A118, S119, S239, V282, T289, N361, and V422 of an IgG2, S115, S252, V289, T306, and N384 of an IgG1, or a corresponding position in an IgG1, IgG2, IgG3, or IgG4.Other non-limiting examples of linking a marker, therapeutic agent, vehicle and / or ligand to a linking agent include the reaction of an amine with an N-hydroxysuccinimide (NHS) ester, an imidoester, a pentafluorophenyl ester (PFP), a hydroxymethylphosphine, an oxirane or any other carbonyl compound; reacting a carboxyl with a carbodiimide; a sulfhydryl reacting with a maleimide, a haloacetyl, a pyridyl disulfide and / or a vinyl sulfone; reacting an aldehyde with a hydrazine; reacting any non-selective group with diazirine and / or aryl azide; reacting a hydroxyl with an isocyanate; making a hydroxylamine react with a... Petition 870260080059, dated 10 / 08 / 2026, p. 64 / 234 60 / 94 carbonyl compound; similar compounds and combinations thereof.

[0092] In certain embodiments, a binding agent comprises one or more functional features. Consequently, a binding agent can be described structurally and functionally (e.g., by what it does or what it is capable of doing). The binding agents described in the present invention can bind, in a specific manner, to an extracellular portion of cMET, for example, an extracellular portion of cMET present on the surface of a cell. In some embodiments, a cell is a human cancer cell or a human neoplastic cell expressing cMET. In certain embodiments, after binding to cMET on the surface of a cell, certain binding agents described in the present invention induce the internalization of cMET. In some embodiments, a binding agent binds, in a specific manner, to cMET, or a portion thereof, and induces the degradation of cMET in a cell (e.g., in a cancer cell).The internalization and / or degradation of cell surface-bound receptors induced by the binding of a ligand or binding agent is a known biological process. The ability of a binding agent to induce the internalization and / or degradation of cMET is readily observed, without undue experimentation, by the use of a suitable experimental assay. Consequently, in some embodiments, a binding agent binds, in a specific manner, to cMET, or a portion thereof, on a cell surface and induces the internalization and / or degradation of cMET.

[0093] In some embodiments, a binding agent binds in a specific manner to cMET, or a portion thereof, and induces or promotes signaling (e.g., tyrosine kinase activity). In certain embodiments, a binding agent binds in a specific manner to cMET on a cell surface and does not induce or promote Petition 870260080059, dated 10 / 08 / 2026, p. 65 / 234 61 / 94 detectably signals (e.g., tyrosine kinase activity). Consequently, in certain embodiments, an anti-cMET binding agent described in the present invention does not possess detectable cMET agonist activity. In certain embodiments, an anti-cMET binding agent does not have agonist activity for cMET binding to a cell surface and / or fails to induce or promote detectable tyrosine kinase activity through cMET binding on a cell surface. In some embodiments, an anti-cMET binding agent is a cMET antagonist. In certain embodiments, an anti-cMET binding agent decreases, inhibits, reduces, blocks, or prevents signaling through a cMET receptor and / or decreases, inhibits, reduces, blocks, or prevents a cMET receptor from inducing or promoting detectable tyrosine kinase activity.In some embodiments, an anti-cMET binding agent described in the present invention decreases, inhibits, reduces, prevents, or blocks the binding of cMET to its native cognate ligand (e.g., Hepatocyte Growth Factor or an isoform thereof).

[0094] In certain embodiments, contact of an individual's cell with a binding agent described in the present invention induces or promotes cell death. In certain embodiments, contact of an individual's cell with a binding agent described in the present invention induces or promotes cell death by means of apoptosis or necrosis of a cell expressing cMET. In certain embodiments, contact of an individual's cell with a binding agent described in the present invention induces or promotes cell death by a process of ADCC, ADCP, or complement-dependent cellular cytotoxicity (CDCC).

[0095] In certain embodiments, contact of an individual's cell with a binding agent described in the present invention diminishes, inhibits, or reduces cell mitosis. In certain embodiments, the Petition 870260080059, dated 10 / 08 / 2026, page 66 / 234 62 / 94 Contact of an individual's cell with a binding agent described in the present invention decreases, inhibits, or reduces cell metastasis.

[0096] In some embodiments, the present invention provides a composition or pharmaceutical composition comprising one or more binding agents that bind, in a specific manner, to cMET, or to a portion thereof (for example, an extracellular domain of cMET or a portion thereof).

[0097] A pharmaceutical composition may be formulated for a suitable route of administration. In some embodiments, a pharmaceutical composition is formulated for subcutaneous (sc), intradermal, intramuscular, intraperitoneal and / or intravenous (iv) administration. In certain embodiments, a pharmaceutical composition may contain formulation materials to modify, maintain or preserve, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, dissolution or release rate, adsorption or penetration of the composition.In certain embodiments, suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine, or lysine); antimicrobials; antioxidants (such as ascorbic acid, sodium sulfite, or sodium hydrogen sulfite); buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates (e.g., phosphate-buffered saline) or suitable organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediaminetetraic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin, or hydroxypropyl beta-cyclodextrin); proteins (such as serum albumin, gelatin, or immunoglobulins); coloring, flavoring, and diluent agents; emulsifying agents; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; salt-forming counterions. Petition 870260080059, dated 10 / 08 / 2026, page 67 / 234 63 / 94 (such as sodium); solvents (such as glycerin, propylene glycol or polyethylene glycol); diluents; excipients and / or pharmaceutical adjuvants (Remington's Pharmaceutical Sciences, 18th Ed., AR Gennaro, ed., Mack Publishing Company (1995)).

[0098] In certain embodiments, a pharmaceutical composition comprises a suitable excipient, examples of which, but not limited to, include anti-adherents (e.g., magnesium stearate), a binder, fillers, monosaccharides, disaccharides, other carbohydrates (e.g., glucose, mannose, or dextrins), sugar alcohols (e.g., mannitol or sorbitol), coatings (e.g., cellulose, hydroxypropylmethylcellulose (HPMC), microcrystalline cellulose, synthetic polymers, shellac, gelatin, corn zein protein, enterics, or other polysaccharides), starch (e.g., potato, corn, or wheat starch), silica, colors, disintegrants, flavorings, lubricants, preservatives, sorbents, sweeteners, carriers, suspending agents, surfactants, and / or humectants (such as polyuronic acid, PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate 80, triton, tromethamine, lecithin, cholesterol, tyloxapal),Stability-enhancing agents (such as sucrose or sorbitol) and tonicity-enhancing agents (such as alkali metal halides, sodium or potassium chloride, mannitol, sorbitol), and / or any excipient described in Remington's Pharmaceutical Sciences, 18th Ed., A.R. Gennaro, ed., Mack Publishing Company (1995). The term binder, as used in the present invention, refers to a compound or ingredient that helps to hold a pharmaceutical mixture together. Binders suitable for making pharmaceutical formulations and frequently used in the preparation of pharmaceutical tablets, capsules, and granules are known to those skilled in the art. For clarification, the term binding agent, as used in the present invention, does not refer to a, Petition 870260080059, dated 10 / 08 / 2026, page 68 / 234 64 / 94 binder that is used in certain pharmaceutical formulations. Although a pharmaceutical composition, in certain embodiments, may comprise a binding agent that binds, in a specific manner, to cMET as well as to a binder.

[0099] In some embodiments, a pharmaceutical composition comprises a suitable pharmaceutically acceptable additive and / or carrier. Non-limiting examples of suitable additives include a suitable pH adjuster, a soothing agent, a buffer, a sulfur-containing reducing agent, an antioxidant, and the like. Non-limiting examples of a sulfur-containing reducing agent include those having a sulfhydryl group such as N-acetylcysteine, N-acetylhomocysteine, thioctic acid, thiodiglycol, thioethanolamine, thioglycerol, thiosorbitol, thioglycolic acid and a salt thereof, sodium thiosulfate, glutathione, and a C1-C7 thioalkane acid.Non-limiting examples of antioxidants include erythorbic acid, dibutylhydroxytoluene, butylated hydroxyanisole, alpha-tocopherol, tocopherol acetate, L-ascorbic acid and its salt, L-ascorbyl palmitate, L-ascorbyl stearate, sodium bisulfite, sodium sulfite, triamyl gallate and propyl gallate, as well as chelating agents such as disodium ethylenediaminetetraacetate (EDTA), sodium pyrophosphate and sodium metaphosphate. In addition, diluents, additives and excipients may comprise other commonly used ingredients, for example, inorganic salts such as sodium chloride, potassium chloride, calcium chloride, sodium phosphate, potassium phosphate and sodium bicarbonate, as well as organic salts such as sodium citrate, potassium citrate and sodium acetate.

[00100] The pharmaceutical compositions used in the present invention can be stable for an extended period of time, for example, on the order of months or years. In some embodiments, a pharmaceutical composition comprising one or more suitable preservatives. Non-limiting examples of preservatives include chloride Petition 870260080059, dated 10 / 08 / 2026, page 69 / 234 65 / 94 of benzalkonium, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, hydrogen peroxide, similar substances and / or combinations thereof. A preservative may comprise a quaternary ammonium compound, such as benzalkonium chloride, benzoxonium chloride, benzethonium chloride, cetrimide, sepazonium chloride, cetylpyridinium chloride or domiphene bromide (BRADOSOL (R)). A preservative may comprise an alkylmercury salt of thiosalicylic acid, such as thimerosal, phenylmercuric nitrate, phenylmercuric acetate or phenylmercuric borate. A preservative may comprise a paraben, such as methylparaben or propylparaben. A preservative may comprise an alcohol, such as chlorobutanol, benzyl alcohol or phenyl ethyl alcohol. A preservative may comprise a biguanide derivative, such as chlorhexidine or polyhexamethylene biguanide.A preservative may comprise sodium perborate, imidazolidinyl urea and / or sorbic acid. A preservative may comprise stabilized oxychloro complexes, such as those known and commercially available under the trade name PURITE®. A preservative may comprise polyglycol-polyamine condensation resins, such as those known and commercially available under the trade name POLYQUART® from Henkel KGaA. A preservative may comprise stabilized hydrogen peroxide. A preservative may be benzalkonium chloride. In some embodiments, a pharmaceutical composition is preservative-free.

[00101] In some embodiments, a composition, pharmaceutical composition or binding agent is substantially free of blood, or a blood product contaminant (e.g., blood cells, platelets, polypeptides, minerals, blood-derived compounds or chemicals and the like). In some embodiments, a composition, pharmaceutical composition or binding agent Petition 870260080059, dated 10 / 08 / 2026, page 70 / 234 66 / 94 serum-free or substantially serum-free binding (e.g., serum proteins, serum lipids, serum carbohydrates, serum antigens, and the like). In some embodiments, a composition, pharmaceutical composition, or binding agent is substantially free of a pathogenic agent (e.g., a virus, parasite, or bacterium). In some embodiments, a composition, pharmaceutical composition, or binding agent is substantially free of endotoxin. In some embodiments, a composition, pharmaceutical composition, or binding agent is sterile. In certain embodiments, a composition or pharmaceutical composition comprises a binding agent that binds specifically to an extracellular cMET domain and a diluent (e.g., phosphate-buffered saline solution).In certain embodiments, a composition or pharmaceutical composition comprises a binding agent that binds specifically to an extracellular domain of cMET and an excipient (e.g., dehydrated sodium citrate, or polyoxyethylene sorbitan-20 monooleate (polysorbate 80)).

[00102] The pharmaceutical compositions described in the present invention can be configured for administration to an individual in any form and / or quantity suitable according to the therapy in which they are employed. For example, a pharmaceutical composition configured for parenteral administration (e.g., by injection or infusion) may take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle and may contain formulation agents, excipients, additives, and / or diluents such as aqueous or non-aqueous solvents, co-solvents, suspension solutions, preservatives, stabilizing agents, and / or dispersing agents. In some embodiments, a pharmaceutical composition suitable for parenteral administration may contain one or more excipients. In some embodiments, a pharmaceutical composition is lyophilized for Petition 870260080059, dated 10 / 08 / 2026, page 71 / 234 67 / 94 a dry powder form. In some embodiments, a pharmaceutical composition is lyophilized to a dry powder form, which is suitable for reconstitution with a suitable pharmaceutical solvent (e.g., water, saline solution, an isotonic buffer solution (e.g., PBS) and the like). In certain embodiments, the reconstituted forms of a lyophilized pharmaceutical composition are suitable for parenteral administration (e.g., intravenous administration) to a mammal.

[00103] In some embodiments, the pharmaceutical compositions described in the present invention may be configured for topical administration and may include one or more binding and / or lubricating agents, polymeric glycols, gelatins, cocoa butter, or other suitable waxes or fats. In some embodiments, a pharmaceutical composition described in the present invention is incorporated into a topical formulation containing a topical vehicle that is generally suitable for topical drug administration and comprising any suitable material known to those skilled in the art. In certain embodiments, a topical formulation of a pharmaceutical composition is formulated for administration of a binding agent from a topical patch.

[00104] In certain embodiments, an optimal pharmaceutical composition will be determined by a person skilled in the art, depending, for example, on the intended route of administration, delivery format and desired dosage (see, for example, Remington's Pharmaceutical Sciences, supra). In certain embodiments, such compositions may influence the physical state, stability, in vivo release rate and in vivo clearance rate of the antibodies of the present invention.

[00105] In some embodiments, a composition, pharmaceutical composition or binding agent described in the present invention is Petition 870260080059, dated 10 / 08 / 2026, page 72 / 234 68 / 94 used to treat an individual with or suspected of having a neoplastic disorder or cancer. In certain embodiments, a binding agent or pharmaceutical composition described in the present invention is used in the treatment of a neoplastic disorder or cancer in an individual, wherein the binding agent binds specifically to an extracellular domain of human cMET. Some embodiments presented in the present invention are a method for treating an individual with or suspected of having a neoplastic disorder or cancer. In certain embodiments, a method for treating an individual with or suspected of having a neoplastic disorder or cancer comprises administering a therapeutically effective amount of a composition, pharmaceutical composition, or binding agent described in the present invention to the individual.In certain embodiments, a treatment method comprises contacting a cell (e.g., one or more cells) of an individual with a therapeutically effective amount of a composition, pharmaceutical composition, or binding agent described in the present invention. In certain embodiments, a treatment method comprises contacting a cell (e.g., one or more cells) of an individual with a therapeutically effective amount of a binding agent that binds specifically to an extracellular portion of human cMET or a variant thereof. An individual's cell is often a cell expressing an extracellular portion of cMET. An individual's cell may be found within an individual (e.g., in vivo) or outside the individual (e.g., in vitro or ex vivo).

[00106] A composition, pharmaceutical composition or binding agent described in the present invention can be used to treat a suitable neoplastic disorder or cancer involving a cell type that expresses cMET. Non-limiting examples of a neoplastic disorder or cancer that can be treated by a method include Petition 870260080059, dated 10 / 08 / 2026, page 73 / 234 69 / 94 lung carcinoma, breast carcinoma, ovarian carcinoma, renal carcinoma, colorectal carcinoma, gastric carcinoma, thyroid carcinoma, pancreatic carcinoma, neuroblastoma or squamous cell carcinoma of the head and neck, cervical cancer, hepatocellular carcinoma, sarcomas, mesothelioma, glioblastoma, multiple myeloma, melanoma, esophageal and prostate carcinoma. In certain embodiments, a neoplastic cell of a neoplastic or cancer order can be rapidly tested for cMET expression using a suitable anti-cMET binding agent, or a novel binding agent described in the present invention using a suitable method (e.g., whole-cell ELISA, FACs, any suitable immunoassay and the like).

[00107] Any suitable method of administering a composition, pharmaceutical composition, or binding agent to an individual may be used. The exact formulation and route of administration for a composition for use according to the methods of the present invention described in the present invention may be chosen by the individual physician in view of the patient's condition. See, for example, Fingl et al. 1975, in The Pharmacological Basis of Therapeutics, chap. 1, p. 1; which is incorporated into the present invention by reference in its entirety. Any suitable route of administration may be used for administering a pharmaceutical composition or binding agent described in the present invention.Non-limiting examples of routes of administration include topical or local (e.g., transdermally or cutaneously, for example, on the skin or epidermis), in or within the eye, intranasally, transmucosally, in the ear, inside the ear (e.g., behind the eardrum)), enteral (e.g., administered via the gastrointestinal tract), for example, orally (e.g., tablet, capsule, granule, liquid, emulsification, lozenge or...). Petition 870260080059, dated 10 / 08 / 2026, page 74 / 234 70 / 94 combination thereof), sublingual, by gastric feeding tube, and similar), by parenteral administration (e.g., parenterally, for example, intravenous, intra-arterial, intramuscular, intraperitoneal, intradermal, subcutaneous, intracavitary, intracranial, intra-articular, into a joint space, intracavitary (into the heart), intracavernous injection, intralesional (into a skin lesion), intraosseous infusion (into the bone marrow), intrathecal (into the spinal canal), intrauterine infusion, intravaginal, intravesical, intravitreal, similar or combinations thereof.

[00108] In some embodiments, a composition is provided in the present invention to an individual. A composition that is provided to an individual is sometimes provided to an individual for self-administration or for administration to an individual by another (e.g., a non-medical professional). For example, a composition described in the present invention may be provided as a written instruction by a physician authorizing a patient to receive a composition or treatment described in the present invention (e.g., a prescription). In another example, a composition may be provided to an individual where the individual self-administers a composition orally, intravenously, or via an inhaler, for example.

[00109] Alternatively, the compositions for use according to the methods of the present invention can be administered locally, rather than systemically, for example, by direct application to the skin, mucous membrane or region of interest for treatment, including the use of a depot or sustained-release formulation.

[00110] In some embodiments, a pharmaceutical composition comprising a binding agent may be administered alone (e.g., as a single active ingredient (AI) or, by Petition 870260080059, dated 10 / 08 / 2026, page 75 / 234 71 / 94 example, as a single active pharmaceutical ingredient (API). In other embodiments, a pharmaceutical composition comprising a binding agent may be administered in combination with one or more additional AIs / APIs, for example, as two separate compositions or as a single composition in which one or more additional AIs / APIs are mixed or formulated together with the binding agent in a pharmaceutical composition.

[00111] A pharmaceutical composition may be manufactured by any suitable method, including, for example, by conventional processes of mixing, dissolving, granulation, coating, levigation, emulsification, encapsulation, trapping or compression.

[00112] In some embodiments, a pharmaceutical composition comprising a binding agent is administered at an appropriate frequency or interval, as needed, to achieve an effective therapeutic outcome. An effective therapeutic outcome may be determined by monitoring the number, viability, growth, mitosis, or metastasis of neoplastic or cancerous cells in an individual affected by a neoplastic disorder or cancer. Consequently, in certain embodiments, a decrease in the number, viability, growth, mitosis, or metastasis of neoplastic or cancerous cells in an individual is considered an effective therapeutic outcome.In some embodiments, a pharmaceutical composition comprising a binding agent may be administered hourly, once daily, twice daily, three times daily, four times daily, five times daily and / or at regular intervals, daily, on alternate days, three times weekly, weekly, every two weeks, once monthly and / or simply at a frequency or interval as needed or recommended by a medical professional. Petition 870260080059, dated 10 / 08 / 2026, p. 76 / 234 72 / 94

[00113] In some embodiments, an amount of a binding agent in a composition is an amount necessary to obtain an effective therapeutic result. In certain embodiments, the amount of a binding agent in a composition (e.g., a pharmaceutical composition) is an amount sufficient to prevent, treat, reduce the severity, delay the onset, and / or alleviate a symptom of a neoplastic disorder or cancer, as contemplated in the present invention.

[00114] A therapeutically effective amount means an amount sufficient to obtain an effective therapeutic result and / or an amount sufficient to prevent, treat, reduce the severity, delay the onset and / or alleviate a symptom of a neoplastic disorder or cancer. In certain embodiments, a therapeutically effective amount means an amount sufficient to terminate the growth of, and / or delay the growth of, a neoplasm or cancer. In certain embodiments, a therapeutically effective amount means an amount sufficient to inhibit the replication and / or induce the death of one or more neoplastic cells. Determining a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed description provided in the present invention.

[00115] In some embodiments, the amount of a binding agent in a composition is an amount that is at least a therapeutically effective amount and a sufficiently low amount to minimize unwanted adverse reactions. The exact amount of a binding agent or combinations of active agents required will vary from individual to individual, depending on an individual's age, weight and general condition, the severity of the condition being treated, and the particular combination of drugs administered. Therefore, it is not always possible to specify an amount. Petition 870260080059, dated 10 / 08 / 2026, page 77 / 234 73 / 94 therapeutically effective exact amount to treat a neoplastic disorder in a diverse group of individuals. As is well known, the specific dosage for a given patient under specific conditions and for a specific disease will routinely vary, but the determination of the optimum amount in each case can be readily accomplished by means of simple routine procedures. In this way, a therapeutically effective amount of a binding agent used to treat a neoplastic disorder can be determined by a person skilled in the art using routine experimentation.

[00116] In certain embodiments, an amount of a binding agent in a composition is administered to an appropriate therapeutically effective amount or dose (e.g., to an appropriate volume and concentration, which sometimes depend, in part, on a particular route of administration).In certain embodiments, a binding agent (e.g., a binding agent in a composition) may be administered at a dose of approximately 0.01 mg / kg (e.g., per kg of an individual's body weight) to 500 mg / kg, 0.1 mg / kg to 500 mg / kg, 0.1 mg / kg to 400 mg / kg, 0.1 mg / kg to 300 mg / kg, 0.1 mg / kg to 200 mg / kg, 0.1 mg / kg to 150 mg / kg, 0.1 mg / kg to 100 mg / kg, 0.1 mg / kg to 75 mg / kg, 0.1 mg / kg to 50 mg / kg, 0.1 mg / kg to 25 mg / kg, 0.1 mg / kg to 10 mg / kg, 0.1 mg / kg to 5 mg / kg, or 0.1 mg / kg to 1 mg / kg. In some aspects, the amount of a binding agent may be approximately 10 mg / kg, 9 mg / kg, 8 mg / kg, 7 mg / kg, 6 mg / kg, 5 mg / kg, 4 mg / kg, 3 mg / kg, 2 mg / kg, 1 mg / kg, 0.9 mg / kg, 0.8 mg / kg, 0.7 mg / kg, 0.6 mg / kg, 0.5 mg / kg, 0.4 mg / kg, 0.3 mg / kg, 0.2 mg / kg, or 0.1 mg / kg. In some embodiments, a therapeutically effective amount of a binding agent is between approximately 0.1 mg / kg and 500 mg / kg, or between approximately 1 mg / kg and approximately 300 mg / kg.The appropriate volumes for intravenous administration are well known.

[00117] In some forms, a linking agent is used. Petition 870260080059, dated 10 / 08 / 2026, page 78 / 234 74 / 94 to detect cMET, in vitro or in vivo. In some embodiments, a binding agent is used to detect cMET on a cell surface and / or to determine the presence or absence of a neoplastic cell (e.g., a malignant cell) in which the cell expresses cMET. In some embodiments, a binding agent is used to determine whether an individual has a neoplastic disorder or cancer. In some embodiments, a cMET detection method comprises determining the presence or absence of cMET in a cell in a sample (e.g., a sample obtained directly or indirectly from an individual).

[00118] Any suitable method may be used to detect and / or quantify the presence, absence and / or quantity of a binding agent, in a specific manner, bound to cMET, or a portion thereof; non-limiting examples of such methods may be found in Immunology, Werner Luttmann; Academic Press, 2006 and / or Medical Detection and Quantification of Antibodies to Biopharmaceuticals: Practical and Applied Considerations, Michael G. Tovey; John Wiley & Sons, July 12, 2011.Additional, but not limiting, examples of methods that can be used to detect and / or quantify the presence, absence, and / or quantity of a binding agent, in a specific manner, bound to cMET, or a part thereof, include the use of a competitive immunoassay, a non-competitive immunoassay, western blots, a radioimmunoassay, an ELISA (enzyme-linked immunosorbent assay), a competitive or sandwich ELISA assay, a sandwich immunoassay, an immunoprecipitation assay, an immunoradiometric assay, a fluorescent immunoassay, a protein A immunoassay, a precipitin reaction, a precipitation gel diffusion reaction, an immunodiffusion assay, an agglutination assay, a complement fixation assay, an immunohistochemical assay, a Western blot assay, and an assay. Petition 870260080059, dated 10 / 08 / 2026, p. 79 / 234 75 / 94 immunohistological assay, an immunocytochemical assay, a dot blot assay, a fluorescence polarization assay, a scintillation proximity assay, a time-resolved homogeneous fluorescence assay, an IAsys analysis, a BIAcore analysis, or similar assays, or a combination thereof.

[00119] A pharmaceutical composition comprising an amount or dose of a binding agent may, if desired, be supplied in a kit, package, or dispensing device, which may contain one or more doses of a binding agent. The packaging may, for example, comprise foil or plastic, such as bubble wrap. The package or dispensing device may be accompanied by instructions for administration. The package or dispenser may also be accompanied by a notification associated with the container on a form prescribed by a government agency that regulates the manufacture, use, or sale of pharmaceutical products, a notice reflecting the agency's approval of the drug form for human or veterinary administration. Such a notice may, for example, be the U.S. Food and Drug Administration-approved labeling for controlled substances, or the approved product insert.

[00120] In some embodiments, a kit or package comprises a quantity of a binding agent sufficient to treat a patient for 1 day to 1 year, 1 day to 180 days, 1 day to 120 days, 1 day to 90 days, 1 day to 60 days, 1 day to 30 days, or any day or number of days between 1 to 4 hours, 1 to 12 hours, or 1 to 24 hours.

[00121] A kit may optionally include a product label or packaging inserts, including a description of the components or instructions for in vitro, in vivo, or ex vivo use of the components. Exemplary instructions include instructions for a diagnostic method, treatment protocol, or therapeutic regimen. In certain Petition 870260080059, dated 10 / 08 / 2026, p. 80 / 234 76 / 94 embodiments, a kit comprises packaging material, which refers to a physical structure containing the kit components. The packaging material may keep the components sterile and may be made of material commonly used for such purposes (e.g., paper, corrugated fiber, glass, plastic, foil, ampoules, vials, tubes, etc.). Product labels or inserts include printed material, e.g., paper or cardboard, either separate from or affixed to a component, a kit, or packaging material (e.g., a box), or attached to an ampoule, tube, or vial containing a kit component. Labels or inserts may additionally include a computer-readable medium, such as an optical disc like a CD-ROM or DVD-ROM / RAM, DVD, MP3, magnetic tape, or an electrical storage medium such as RAM and ROM or hybrids thereof such as magnetic / optical storage media, FLASH media, or memory cards.Product labels or inserts may include identifying information for one or more components, dosage amounts, clinical pharmacology of the active ingredient(s), including mechanism of action, pharmacokinetics (PK), and pharmacodynamics (PD). Product labels or inserts may include information identifying the manufacturer, batch numbers, manufacturer location, date, information about an indicated condition, disorder, disease, or symptom for which a component of the kit may be used. Product labels or inserts may include instructions for the clinician or an individual to use one or more components of the kit in a method, treatment protocol, or therapeutic regimen. Instructions may include dosage amounts, frequency or duration, and instructions for practicing any of the methods, treatment protocols, or therapeutic regimens set forth in the present invention.The invention kits may therefore additionally include labels or instructions for practicing any of the methods and uses of the invention described in. Petition 870260080059, dated 10 / 08 / 2026, p. 81 / 234 77 / 94 present invention. Product labels or inserts may include information on possible adverse side effects and / or warnings.

[00122] In certain embodiments, a kit comprises one or more controls with a known quantity of cMET. In some embodiments, a kit comprises cells expressing cMET. The cells in the kit may be maintained under suitable storage conditions until the cells are ready for use.

[00123] In some embodiments, a kit is a diagnostic kit comprising a binding agent. A binding agent comprised in a diagnostic kit may take any suitable form. In some embodiments, a diagnostic comprises a binding agent and a detectable marker.In certain embodiments, for example, a diagnostic kit comprises or consists of an adhesion test, including reagents necessary to perform the method of the invention and to produce, for example, a colorimetric result that can be compared with a color chart or standard curve. A diagnostic kit may also comprise components necessary to detect a binding agent that binds specifically to cMET, for example, a secondary antibody. [Example 1] Antibody Generation

[00124] To induce an antibody response against cMET, mice were immunized with cMET-Fc or cMET peptide as described in Figures 1 and 2. In some embodiments, the peptide derived from strategic regions was selected for immunization. Figure 3 illustrates an example of a structural loop in MET that inspired the design of peptide 3. Spleens from immunized mice were obtained and splenocytes were fused to a suitable fusion partner to produce hybridomas using a standard protocol. Hybridoma clones were isolated and the hybridoma medium was tested. Petition 870260080059, dated 10 / 08 / 2026, page 82 / 234 78 / 94 regarding MET binding and / or the ability to induce cMET internalization in human cancer cell lines, as measured by flow cytometry (Figure 4). Antibodies selected from hybridoma were selected based on their ability to induce MET degradation (Figure 5) or inability to induce ERK phosphorylation (Figure 6).

[00125] Additional tests were performed to select ideal candidates for anti-cMET antibodies. For example, anti-cMET antibodies were tested for species cross-reactivity by determining an antibody's ability to bind to human cMET, monkey cMET (e.g., Macaca fascicularis, i.e., Cynomolgus macaque), rat cMET, and mouse cMET as measured by ELISA (Figures 7 and Table 1). In vivo half-life and other pharmacokinetic characteristics were also evaluated (data not shown). Potency and specificity of antibody-drug conjugates (ADCs) were also determined in cell lines expressing high, medium, and negative cMETs using anti-cMET antibodies that were conjugated with MMAF (Figures 9 and 15, Tables 11 and 12). The ADCs were tested for in vivo efficacy using an MKN45 xenograft model. Petition 870260080059, dated 10 / 08 / 2026, page 83 / 234 79 / 94 [TABLE 11] In vitro score Antibody Mean cytotoxicity EC50, SNU16 cells pM binding (medium Met) Mean cytotoxicity EC50, SNU6 cells pM binding (high Met) Met binding KD (pM) SPR with hMet-Fc Met degradation (pM) MSD ERK phospho assay Cell proliferation (agonist) NHP cross-reactivity Rat Mouse 5D5 800 Yes / very strong Yes No No ABF46 450 67 700 10,000 NO Yes No No 1 F6B1P3D12 25 60 750 140 NO Yes Yes No 2 F6BP2D4 60 33 480 3,000 NO Yes No No 2 F6B1P1E2 70 55 890 1,920 Very low Yes Low No 3 F6AP12F12 180 97 110 450 NO Not tested Not tested Not tested 3 F5P5B9 20 3 80 255 Very low Yes No No 3 F6AP8E2 351 102 160 7,000 Very low at high concentrations Yes No No 3 F6BP1H5 / H6 80 63 340 3,000 Maybe at high concentrations Yes No No SPR = Plasma Surface Resonance MSD = Meso-Scale Discovery Platform NHP = non-human primate (i.e., Cynologous Monkey) 5D5 = positive agonist control ABF46 = MET ADC, positive control Petition 870260080059, dated 10 / 08 / 2026, page 84 / 234 80 / 94 [Example 2] Summary of Characteristics of Selected Humanized Monoclonal Ligands

[00126] Humanized and isotype-linked monoclonal binding agents comprising the heavy chain CDRs and light chain CDRs of the mouse monoclonal antibody P3D12 were generated. Sixteen different heavy chain (HC) and light chain (LC) combinations were tested for solubility in PBS, binding to human cMET, binding to mouse cMET, binding affinity to human and mouse cMET as determined by plasma surface resonance (SPR), presence of agonist activity, and cMET degradation reported as per Meso Scale Discovery Platform (MSD). The results are summarized in Table 12 below. Petition 870260080059, dated 10 / 08 / 2026, page 85 / 234 81 / 94 [Table 12] Score HC IC Clone Solubility in ΡΒΞ ELISA Hmet vs parental ELISA Hmet vs parental vc-MMAF ADC IC5O, pM, SNU-16 (n=l) SPR kD, nM, hMET-Fc SPRkDnM, rMET-Fc pERK (MET-Fc MET agonist) l^a parental? (MSD) VH-dbb / sdr VL-abb / sdr G2aka 0.9 1.1 352 0-9 26 Negative yes VL-fra G2akf 1.0 0.5 368 0.6 23 Negative yes VL-ven G2akv Insoluble 1.6 13 Negative yes VL-cdr G2ak. 1.3 0.7 382 0.7 38 Negative sim VH-fra VL-abb / sdr G2fka 1.8 3.8 Negative sim 3 VL-fra G2fkf 1.7 1.4 266 0.4 30 Negative sim VL-ven G2fkv Inso lútive 1 7 Negative sim. VL-cdr G2fkc 1.7 2.3 Negative sim VH-ven VL-abb / sdr G2vka 0.9 2.7 Negative sim 2 VL-fra G2vkf 1.1 1.0 380 0.3 8 Negative sim VL-ven G2vkv Insoluble 1 6 Negative sim. VL-cdr G2vkc 1.1 1.9 Negative sim 4 VH-cdr VL-abb / sdr G2cka 1.3 2.7 238 0.4 29 Negative sim 1 VL-fra G2ckf 0.7 0.9 302 0.3m 7 Negative sim VL-level G2ck 1.1 1.0 Negative yes VL-cdr G2ckc 1.0 2.0 169 0.9 31 Negative yes chimeric P3D12 249 0.7 30 PBD12de csmundo 42 0.9 16. Petition 870260080059, dated 10 / 08 / 2026, page 86 / 234 82 / 94 [Example 3]

[00127] A human individual presents with multiple metastatic carcinomas of 2 cm or larger, located in the liver and lung. A biopsy is performed to determine if the carcinoma cells express cMET on their cell surface. The presence of cMET cell surface expression is confirmed from the biopsy results.

[00128] The human subject is administered a binding agent that specifically binds to the extracellular domain of human cMET. The binding agent optionally comprises constant kappa and heavy chain regions of human IgG1, the variable light chain region of SEQ ID NO: 41, and the variable heavy chain regions of SEQ ID NO: 98. The binding agent can be administered at a dose of 30 mg / kg intravenously in a volume of 300 ml over a 2-hour period, once daily for six weeks. The presence, size, and viability of the tumor are determined by follow-up biopsy and ultrasound. The subject is determined to be in remission after six weeks of treatment. [Example 4]

[00129] A human individual presents with multiple metastatic carcinomas of 2 cm or larger, located in the liver and lung. A biopsy is performed to determine if the carcinoma cells express cMET on their cell surface. The presence of cMET cell surface expression is confirmed from the biopsy results.

[00130] The human individual is administered a binding agent that binds specifically to the extracellular domain of human cMET. The binding agent optionally comprises constant regions of the human kappa heavy chain and IgG2a, the variable region. Petition 870260080059, dated 10 / 08 / 2026, page 87 / 234 The binding agent is composed of the 83 / 94 humanized light chain of SEQ ID NO: 48 and the variable region of the humanized heavy chain of SEQ ID NO: 107. The binding agent is optionally conjugated to MMAF. The binding agent is administered at a dose of 1 mg / kg intravenously in a volume of 300 ml over a 2-hour period, once daily for six weeks. The presence, size, and viability of the tumor are determined by follow-up biopsy and ultrasound. The individual is considered to be in remission after six weeks of treatment. [Example 5] cMET sequences SEQ ID NO: 104 (cMET Humano - UniProtKB - P08581 (MET_HUMAN)) *Residues E168 and N375 are in bold and underlined. MKAPAVLAPGILVLLFTLVQRSNGECKEALAKSEMNVNMKYQLPNFT AETPIQNVILHEHHIFLGATNYIYVLNEEDLQKVAEYKTGPVLEHPDCF PCQDCSSKANLSGGVWKDNINMALVVDTYYDDQLISCGSVNRGTCQ RHVFPHNHTADIQSEVHCIFSPQIEEPSQCPDCVVSALGAKVLSSVKD RFINFFVGNTINSSYFPDHPLHSISVRRLKETKDGFMFLTDQSYIDVLP EFRDSYPIKYVHAFESNNFIYFLTVQRETLDAQTFHTRIIRFCSINSGLH SYMEMPLECILTEKRKKRSTKKEVFNILQAAYVSKPGAQLARQIGASL NDDILFGVFAQSKPDSAEPMDRSAMCAFPIKYVNDFFNKIVNKNNVR CLQHFYGPNHEHCFNRTLLRNSSGCEARRDEYRTEFTTALQRVDLF MGQFSEVLLTSISTFIKGDLTIANLGTSEGRFMQVVVSRSGPSTPHVN FLLDSHPVSPEVIVEHTLNQNGYTLVITGKKITKIPLNGLGCRHFQSCS QCLSAPPFVQCGWCHDKCVRSEECLSGTWTQQICLPAIYKVFPNSA PLEGGTRLTICGWDFGFRRNNKFDLKKTRVLLGNESCTLTLSESTMN TLKCTVGPAMNKHFNMSIIISNGHGTTQYSTFSYVDPVITSISPKYGPM AGGTLLTLTGNYLNSGNSRHISIGGKTCTLKSVSNSILECYTPAQTIST EFAVKLKIDLANRETSIFSYREDPIVYEIHPTKSFISGGSTITGVGKNLN SVSVPRMVINVHEAGRNFTVACQHRSNSEIICCTTPSLQQLNLQLPLK TKAFFMLDGILSKYFDLIYVHNPVFKPFEKPVMISMGNENVLEIKGNDI Petição 870260080059, de 10 / 08 / 2026, pág. 88 / 234 84 / 94 DPEAVKGEVLKVGNKSCENIHLHSEAVLCTVPNDLLKLNSELNIEWK QAISSTVLGKVIVQPDQNFTGLIAGVVSISTALLLLLGFFLWLKKRKQIK DLGSELVRYDARVHTPHLDRLVSARSVSPTTEMVSNESVDYRATFPE DQFPNSSQNGSCRQVQYPLTDMSPILTSGDSDISSPLLQNTVHIDLSA LNPELVQAVQHVVIGPSSLIVHFNEVIGRGHFGCVYHGTLLDNDGKKI HCAVKSLNRITDIGEVSQFLTEGIIMKDFSHPNVLSLLGICLRSEGSPL VVLPYMKHGDLRNFIRNETHNPTVKDLIGFGLQVAKGMKYLASKKFV HRDLAARNCMLDEKFTVKVADFGLARDMYDKEYYSVHNKTGAKLPV KWMALESLQTQKFTTKSDVWSFGVLLWELMTRGAPPYPDVNTFDIT VYLLQGRRLLQPEYCPDPLYEVMLKCWHPKAEMRPSFSELVSRISAI FSTFIGEHYVHVNATYVNVKCVAPYPSLLSSEDNADDEVDTRPASFW ETS SEQ ID NO: 105 (cMET de rato UniProtKB - P97523 (MET_RAT)) MKAPTALAPGILLLLLTLAQRSHGECKEALVKSEMNVNMKYQLPNFT AETPIHNVVLPGHHIYLGATNYIYVLNDKDLQKVSEFKTGPVVEHPDC FPCQDCSSKANVSGGVWKDNVNMALLVDTYYDDQLISCGSVNRGT CQRHVLPPDNAADIQSEVHCMFSPLAEEESGQCPDCVVSALGAKVL LSEKDRFINFFVGNTINSSYPPDYSLHSISVRRLKETQDGFKFLTDQS YIDVLPEFRDSYPIKYYIHAFESNHFIYFLTVQKETLDAQTFHTRIIRFCSV DSGLHSYMEMPLECILTEKRRKRSTREEVFNILQAAYVSKPGANLAK QIGASPYDDILYGVFAQSKPDSAEPMNRSAVCAFPIKYVNDFNKIV KNNVRCLQHFYGPNHEHCFNRTLLRNSSGCEVRSDEYRTEFTTALQ RVDLFMGRLNHVLLTSISTFIKGDLTIANLGTSEGRFMQVVLSRTAHFT PHVNFLLDSYPVSPEVIVEHPSNQNGYTLVVTGKKITKIPLNGLGCGH FQSCSQCLSPPYFIQCGWCHNRCVHSNECPSGTWTQEICLPAVYKV FPTSAPLEGGTMLTICGWDFGFKKNNKFDLRKTKVLLGNESCTLTLS ESTTNTLKCTVGPAMSEHFNVSVIVSNSRETTQYSAFSYVDPVITSIS PRYGPHAGGTLLTLTGKYLNSGNSRHISIGGKTCTLKSVSDSILECYT PGHTVSAEFPVKLKIDLADRVTSSFSYREDPVVSEIHPTKSFISGGSTI Petition 870260080059, de 10 / 08 / 2026, pág. 89 / 234 85 / 94 TGIGKNLNSVSTPKLVIEVHDVGVNYTVACQHRSSSEIICCTTPSLRQL DLQLPLKTKAFFLLDGILSKHFDLTYVHDPMFKPFEKPVMISMGNENV VEIKGDDIDPEAVKGEVLKVGNKSCENLHWHSEALLCTVPSDLLKLN GGELNIEWKQAVSSTVLGKVIVQPDQNFAGLIIGAVSISVVVLLVSGLF LWLRKRKHKDLGSELVRYDARVHTPHLDRLVSARSVSPTTEMVSNE SVDYRATFPEDQFPNSQNGACRQVQYLLTDLSPILTSGDSDISSPLL QNTVHIDLSALNPELVQAVPHVVIGPSSLIVHFNEVIGRGHFGCVYHG TLLDSDGKKIHCAVKSLNRITDIEEVSQFLTEGIIMKDFSHPNVLSLLGI CLRSEGSPLVVLPYMKHGDLRNFIRNETHNPTVKDLIGFGLQVAKGM KYLVSKKFVHRDLAARNCMLDEKFTVKVADFGLARDMYDKEYYSVH NKTGAKLPVKWMALESLQTQKFTTKSDVWSFGVLLWELMTRGAPPY PDVNTFDITIYLLQGRRLLQPEYCPDALYEVMLKCWHPKAEMRPSVS ELVSRISSIFSTFIGEHYVHVNATYVNVKCVAPYPSLLPSQDNIDGEANT SEQ ID NO: 106 (cMET de Camundongo - UniProtKB - P16056 (MET_MOUSE)) MKAPTVLAPGILVLLLSLVQRSHGECKEALVKSEMNVNMKYQLPNFT AETPIQNVVLHGHHIYLGATNYIYVLNDKDLQKVSEFKTGPVLEHPDC LPCRDCSSKANSSGGVWKDNINMALLVDTYYDDQLISCGSVNRGTC QRHVLPPDNSADIQSEVHCMFSPEEESGQCPDCVVSALGAKVLLSE KDRFINFFVGNTINSSYPPGYSLHSISVRRLKETQDGFKFLTDQSYIDV LPEFLDSYPIKYIHAFESNHFIYFLTVQKETLDAQTFHTRIIRFCSVDSG LHSYMEMPLECILTEKRRKRSTREEVFNILQAAYVSKPGANLAKQIGA SPSDDILFGVFAQSKPDSAEPVNRSAVCAFPIKYVNDFFNKIVNKNNV RCLQHFYGPNHEHCFNRTLLRNSSGCEARSDEYRTEFTTALQRVDL FMGRLNQVLLTSISTFIKGDLTIANLGTSEGRFMQVVLSRTAHLTPHV NFLLDSHPVSPEVIVEHPSNQNGYTLVVTGKKITKIPLNGLGCGHFQS CSQCLSAPYFIQCGWCHNQCVRFDECPSGTWTQEICLPAVYKVFPT SAPLEGGTVLTICGWDFGFRKNNKFDLRKTKVLLGNESCTLTLSESTT NTLKCTVGPAMSEHFNVSVIISNSRETTQYSAFSYVDPVITSISPRYGP Petição 870260080059, de 10 / 08 / 2026, pág. 90 / 234 86 / 94 QAGGTLLTLTGKYLNSGNSRHISIGGKTCTLKSVSDSILECYTPAQTT SDEFPVKLKIDLANRETSSFSYREDPVVYEIHPTKSFISGGSTITGIGT LNSVSLPKLVIDVHEVGVNYTVACQHRSNSEIICCTTPSLKQLGLQLPL KTKAFFLLDGILSKHFDLTYVHNPVFEPFEKPVMISMGNENVVEIKGN NIDPEAVKGEVLKVGNQSCESLHWHSGAVLCTVPSDLLKLNSELNIE WKQAVSSTVLGKVIVQPDQNFAGLIIGAVSISVVLLLSGLFLWMRKR KHKDLGSELVRYDARVHTPHLDRLVSARSVSPTTEMVSNESVDYRA TFPEDQFPNSSQNGACRQVQYPLTDLSPILTSGDSDISSPLLQNTVHI DLSALNPELVQAVQHVVIGPSSLIVHFNEVIGRGHFGCVYHGTLLDND GKKIHCAVKSLNRITDIEEVSQFLTEGIIMKDFSHPNVLSLLGICLRSEG SPLVVLPYMKHGDLRNFIRNETHNPTVKDLIGFGLQVAKGMKYLASK KFVHRDLAARNCMLDEKFTVKVADFGLARDMYDKEYYSVHNKTGAK LPVKWMALESLQTQKFTTKSDVWSFGVLLWELMTRGAPPYPDVNTF DITIYLLQGRRLLQPEYCPDALYEVMLKCWHPKAEMRPSFSELVSRIS SIFSTFIGEHYVHVNATYVNVKVAPYPSLLPSQDNIDGEGNT SEQ ID NO: 107 (dog cMET) MKAPAVLAPGILVLLFTLVQKSYGECKEALVKSEMNVNMKYQLPNFT AETPIQNVVLHKHHIYLGAVNYIYVLNDKDLQKVAEYKTGPVLEHPDC SPCQDCSHKANLSGGVWEDNINMALLVDTYYDDQLISCGSVHRGTC QRHILPPSNIADIQSEVHCMYSSQADEEPSQCPDCVVSALGTKVLISE KDRFINFFVGNTINSSDHPDHSLHSISVRRLKETQDGFKFLTDQSYIDV LPEFRDSYPIKYVHAFESNHFIYFLTVQRETLDAQTFHTRIIRFCSVDS GLHSYMEMPLECILTEKRRKRSTREEVFNILQAAYVSKPGAHLAKQIG ANLNDDILYGVFAQSKPDSAEPMNRSAVCAFPIKYVNEFFNKIVNKNN VRCLQHFYGPNHEHCFNRTLLRNSSGCEARNDEYRTEFTTALQRVD LFMGQFNQVLLTSISTFIKGDLTIANLGTSEGRFMQVVVSRSGLSTPH VNFRLDSHPVSPEAIVEHPLNQNGYTLVVTGKKITRIPLNGLGCEHFQ SCSQCLSAPPFVQCGWCHDRCVHLEECPTGAWTQEVCLPAIYEVFP TSAPLEGGTVLTVCGWDFGFRRNNKFDLKKTKVFLGNESCTLTLSES Petição 870260080059, de 10 / 08 / 2026, pág. 91 / 234 87 / 94 TTNMLKCTVGPAVNEHFNISIIISNGRGTAQYSTFSYVDPIITSISPSYG PKNGGTLLTLTGKYLNSGNSRHISMGGKTCTLKSVSDSILECYTPAQA TATEFPIKLKIDLANREMNSFSYQEDPIVYAIHPTKSFISGGSTITAVGK NLNSVSVLRMVIDVHETRRNFTVACQHRSNSEIICCTTPSLQQLNLQL PLKTKAFFMLDGIHSKYFDLIYVHNPVFKPFEKPVMISIGNENVLEIKG NDIDPEAVKGEVLKVGNKSCETIYSDSKAVLCKVPNDLLKLNNELNIE WKQAVSSTVLGKVIVQPDQNFTGLIAGVISISTIVLLLLGLFLWLKRKK QIKDLGSELVRYDARVHTPHLDRLVSARSVSPTTEMVSNESVDYRAT FPEDQFPNSSQNGSCRQVQYPLTDLSPMLTSGDSDISSPLLQNTVHI DLSALNPELVQAVQHVVIGPSSLIVHFNEVIGRGHFGCVYHGTLLDND DKKIHCAVKSLNRITDIGEVSQFLTEGIIMKDFSHPNVLSLLGICLRSEG SPLVVLPYMKHGDLRNFIRNETHNPTVKDLIGFGLQVAKGMKYLASK KFVHRDLAARNCMLDEKFTVKVADFGLARDMYDKEYYSVHNKTGAK LPVKWMALESLQTQKFTTKSDVWSFGVLLWELMTRGAPPYPDVNTF DITVYLLQGRRLLQPEYCPDPLYEVMLKCWHPRAELRPSFSELVSRIS AIFSTFIGEHYVHVNATYVNVKCVAPYPSLLSSQDNIDGEGDT SEQ ID NO: 108 (Macaca mulatta, Rhesus cMET - Sequência de Referência NCBI: NP_001162100.1) MKAPAVLVPGILVLLFTLVQRSNGECKEALAKSEMNVNMKYQLPNFT AETAIQNVILHEHHIFLGATNYIYVLNEEDLQKVAEYKTGPVLEHPDCF PCQDCSSKANLSGGVWKDNINMALVVDTYYDDQLISCGSVNRGTCQ RHVFPHNHTADIQSEVHCIFSPQIEEPNQCPDCVVSALGAKVLSSVKD RFINFFVGNTINSSYFPHHPLHSISVRRLKETKDGFMFLTDQSYIDVLP EFRDSYPIKYIHAFESNNFIYFLTVQRETLNAQTFHTRIIRFCSLNSGLH SYMEMPLECILTEKRKKRSTKKEVFNILQAAYVSKPGAQLARQIGASL NDDILFGVFAQSKPDSAEPMDRSAMCAFPIKYVNDFFNKIVNKNNVR CLQHFYGPNHEHCFNRTLLRNSGCEARRDEYRAEFTTALQRVDLF MGQFSEVLLTSISTFVKGDLTIANLGTSEGRFMQVVVSRSGPSTPHV NFLLDSHPVSPEVIVEHPLNQNGYTLVVTGKKITKIPLNGLGCRHFQS Petition 870260080059, dated 10 / 08 / 2026, page 92 / 234 88 / 94 CSQCLSAPPFVQCGWCHDKCVRSEECPSGTWTQQICLPAIYKVFPT SAPLEGGTRLTICGWDFGFRRNNKFDLKKTRVLLGNESCTLTLSEST MNTLKCTVGPAMNKHFNMSIIISNGHGTTQYSTFSYVDPIITSISPKYG PMAGGTLLTLTGNYLNSGNSRHISIGGKTCTLKSVSNSILECYTPAQTI STEFAVKLKIDLANRETSIFSYREDPIVYEIHPTKSFISGGSTITGVGKN LHSVSVPRMVINVHEAGRNFTVACQHRSNSEIICCTTPSLQQLNLQLP LKTKAFFMLDGILSKYFDLIYVHNPVFKPFEKPVMISMGNENVLEIKGN DIDPEAVKGEVLKVGNKSCENIHLHSEAVLCTVPNDLLKLNSELNIEW KQAISSTVLGKVIVQPDQNFTGLIAGVVSISIALLLLLGLFLWLKKRKQI KDLGSELVRYDARVHTPHLDRLVSARSVSPTTEMVSNESVDYRATFP EDQFPNSSQNGSCRQVQYPLTDMSPILTSGDSDISSPLLQNTVHIDLS ALNPELVQAVQHVVIGPSSLIVHFNEVIGRGHFGCVYHGTLLDNDGKK IHCAVKSLNRITDIGEVSQFLTEGIIMKDFSHPNVLSLLGICLRSEGSPL VVLPYMKHGDLRNFIRNETHNPTVKDLIGFGLQVAKGMKYLASKKFV HRDLAARNCMLDEKFTVKVADFGLARDMYDKEYYSVHNKTGAKLPV KWMALESLQTQKFTTKSDVWSFGVLLWELMTRGAPPYPDVNTFDIT VYLLQGRRLLQPEYCPDPLYEVMLKCWHPKAEMRPSFSELVSRISAI FSTFIGEHYVHVNATYVNVKCVAPYPSLLSSEDNADDEVDT [Exemplo 6] Modalidades

[00131] A1. A linking agent that specifically binds to cMET, or a portion thereof, wherein the linking agent comprises a CDR-L1, a CDR-L2 and a CDR-L3, each independently selected from a variable domain of the light chain selected from Table 4 or Table 5.

[00132] A2. A linking agent that specifically binds to cMET, or a portion thereof, wherein the linking agent comprises a CDR-H1, CDR-H2 and a CDR-H3, each independently selected from a variable domain of the heavy chain selected from Table 9 or Table 10. Petition 870260080059, dated 10 / 08 / 2026, page 93 / 234 89 / 94

[00133] A3. A linking agent that specifically binds to cMET, or a portion thereof, wherein the linking agent comprises (i) a CDR-L1, CDR-L2 and a CDR-L3, each independently selected from a variable light chain domain selected from Table 4 or Table 5 and (ii) a CDR-H1, CDR-H2 and a CDR-H3, each independently selected from a variable heavy chain domain selected from Table 9 or Table 10.

[00134] A4. Linking agent that links specifically to CMET, or a portion thereof, wherein the linking agent comprises three CDRs of a variable light chain domain selected from the CDRs in Tables 1, 2 and 3, and three CDRs of a variable heavy chain domain selected from the CDRs in Tables 4, 5 and 6.

[00135] A5. A binding agent that binds specifically to CMET, or a portion thereof, wherein the binding agent comprises a CDR-L1 selected from Table 1, a CDRL2 selected from Table 2, a CDR-L3 selected from Table 3, a CDR-H1 selected from Table 4, a CDRH2 selected from Table 5 and a CDR-H3 selected from Table 6.

[00136] A6. A binding agent that binds specifically to CMET, or a portion thereof, wherein the binding agent comprises a CDR-L1 that is at least 80% identical to a CDR selected from Table 1, a CDR-L2 that is at least 80% identical to a CDR selected from Table 2, a CDR-L3 that is at least 80% identical to a CDR selected from Table 3, a CDR-H1 that is at least 80% identical to a CDR selected from Table 4, a CDR-H2 that is at least 80% identical to a CDR selected from Table 5, and a CDR-H3 that is at least Petition 870260080059, dated 10 / 08 / 2026, p. 94 / 234 90 / 94 minus 80% identical to a CDR selected from Table 6.

[00137] A7. The linking agent of any of the modes A1 to A6, where the binding agent is a recombinant monoclonal antibody.

[00138] A8. A pharmaceutical composition comprising: a binding agent of any of the embodiments A1 to A7; and a pharmaceutically acceptable excipient, diluent, additive or vehicle.

[00139] A9. The pharmaceutical composition of embodiment A8, in which the binding agent comprises a constant region of an IgG1, IgG2, IgG3 or IgG4.

[00140] A10. The pharmaceutical composition of embodiment A8 or A9, in which the binding agent comprises a constant region of an IgD, IgE, IgA or IgM.

[00141] A11. The pharmaceutical composition of any of the A8 to A10 modalities, in which the binding agent is humanized.

[00142] B1. A recombinant monoclonal antibody comprising: a CDR-L1 that is at least 80% identical to a CDR selected from Table 1, a CDR-L2 that is at least 80% identical to a CDR selected from Table 2, a CDR-L3 that is at least 80% identical to a CDR selected from Table 3, a CDR-H1 that is at least 80% identical to a CDR selected from Table 4, a CDR-H2 that is at least 80% identical to a CDR selected from Table 5, and a CDR-H3 that is at least 80% identical to a CDR selected from Table 6, wherein the antibody binds specifically to an extracellular domain of human cMET.

[00143] B2. The antibody of type B1, in which the antibody Petition 870260080059, dated 10 / 08 / 2026, p. 95 / 234 91 / 94 humanized, chimerical, or grafted CDR.

[00144] C1. Antibody-binding agent, pharmaceutical composition or antibody of any of the embodiments A1 to A11, B1 and B2, for use in the treatment of a neoplastic disorder or cancer in an individual.

[00145] The entirety of each patent, patent application, publication, or any other reference or document cited herein is incorporated by reference. In case of conflict, the descriptive report, including definitions, shall prevail.

[00146] The citation of any patent, patent application, publication or any other document is not an admission that any of the foregoing is relevant prior art, nor does it constitute any admission as to the content or date of such publications or documents.

[00147] Unless defined otherwise, all technical and scientific terms used in the present invention have the same meaning as that normally understood by a person skilled in the art to which this invention pertains. Although methods and materials similar or equivalent to those described in the present invention may be used in the practice or testing of the present invention, suitable methods and materials are described in the present invention.

[00148] All the features described in the present invention can be combined in any combination. Each feature described in the descriptive report can be replaced by an alternative feature that serves the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the described features (e.g., antibodies) are an example of a kind of equivalent or similar features.

[00149] As used in the present invention, all values Petition 870260080059, dated 10 / 08 / 2026, page 96 / 234 92 / 94 numeric values ​​or numeric ranges include whole numbers within such ranges and fractions of the values ​​or the whole numbers within ranges, unless expressly stated otherwise. Furthermore, when a listing of values ​​is described here (for example, approximately 50%, 60%, 70%, 80%, 85% or 86%), the listing includes all its intermediate and fractional values ​​(for example, 54%, 85.4%). Thus, to illustrate, reference to 80% or more identity includes 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, etc., as well as 81.1%, 81.2%, 81.3%, 81.4%, 81.5%, etc., 82.1%, 82.2%, 82.3%, 82.4%, 82.5%, etc., and so on.

[00150] Reference to an integer that is greater than or less than any number greater than or less than the reference number, respectively. Thus, for example, a reference to less than 100 includes 99, 98, 97, etc. down to the number one (1); and less than 10 includes 9, 8, 7, etc. down to the number one (1).

[00151] As used in the present invention, all numerical values ​​or intervals include fractions of the values ​​and whole numbers within such intervals and fractions of the whole numbers within such intervals, unless the context clearly indicates otherwise. So, to illustrate, reference to a numerical interval, such as 1-10, includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, as well as 1.1, 1.2, 1.3, 1.4, 1.5, etc., and so forth. The reference to a range from 1 to 50 therefore includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc., up to and including 50, as well as 1.1, 1.2, 1.3, 1.4, 1.5, etc., 2.1, 2.2, 2.3, 2.4, 2.5, etc., and so on.

[00152] A reference to a series of intervals includes intervals that combine the limit values ​​of different intervals within the series. Thus, to illustrate a reference to a series of intervals, for example, from 1 to 10, 10 to 20, 20 to 30, 30 to 40, 40 to 50, 50 to 60, 60 to 75, Petition 870260080059, dated 10 / 08 / 2026, p. 97 / 234 93 / 94 to 100, 100 to 150, 150 to 200, 200 to 250, 250 to 300, 300 to 400, 400 to 500, 500 to 750, 750 to 1,000, 1,000 to 1,500, 1,500 to 2,000, 2,000 to 2,500, 2,500 to 3,000, 3,000 to 3,500, 3,500 to 4,000, 4,000 to 4,500, 4,500 to 5,000, 5,500 to 6,000, 6,000 to 7,000, 7,000 to 8,000, or 8,000 to 9,000, includes intervals of 10 to 50, 50 to 100, 100 to 1,000, 1,000 to 3,000, 2,000 to 4,000, etc.

[00153] Modifications may be made to the foregoing without departing from the basic aspects of the technology. Although the technology has been described in substantial detail with reference to one or more specific embodiments, those skilled in the art will recognize that changes may be made to the embodiments specifically described in this application, but such modifications and improvements are within the scope and spirit of the technology.

[00154] The present invention is generally described herein using affirmative language to describe the numerous embodiments and aspects. The present invention also specifically includes embodiments in which the particular subject matter is excluded, wholly or partially, such as substances or materials, method steps and conditions, protocols or procedures. For example, in certain embodiments or aspects of the present invention, materials and / or method steps are excluded. In this way, even though the present invention is not generally expressed herein in terms of what the present invention does not include, aspects that are not expressly excluded from the invention are nevertheless described herein.

[00155] The technology illustratively described in the present invention can be adequately practiced in the absence of any element(s) not specifically described in the present invention. Thus, for example, in each case, any of the terms comprising, consisting essentially of and Petition 870260080059, dated 10 / 08 / 2026, page 98 / 234 94 / 94 consistent in can be replaced by either of the other two terms. The terms and expressions employed are used as descriptive terms and not limiting terms, and the use of such terms and expressions does not exclude any equivalents of the features shown and described or their segments, and various modifications are possible within the scope of the claimed technology. The term "a" or "an" may refer to one or more elements that it modifies (e.g., a reagent may mean one or more reagents), unless it is contextually clear one or more of the elements is described. The term "about" as used in the present invention refers to a value within 10% of the underlying parameter (i.e., plus or minus 10%), and the use of the term "about" at the beginning of a chain of values ​​modifies each of the values ​​(i.e., about 1, 2, and 3 refers to about 1, about 2, and about 3).For example, a weight of about 100 grams may include weights between 90 grams and 110 grams. The term substantially as used in the present invention refers to a value modifier meaning at least 95%, at least 96%, at least 97%, at least 98% or at least 99% and may include 100%. For example, a composition that is substantially free of X may include less than 5%, less than 4%, less than 3%, less than 2% or less than 1% of X and / or X may be absent or undetectable in the composition.

[00156] In this way, it should be understood that, although the present technology has been specifically described by means of representative embodiments and optional features, modifications and variations of the concepts described in the present invention may be used by those skilled in the art, and such modifications and variations are considered within the scope of this technology. Petition 870260080059, dated 10 / 08 / 2026, page 99 / 234

Claims

1 / 3 CLAIMS 1. A binding agent, characterized in that it comprises a combination of a light chain and a heavy chain selected from the group consisting of: a light chain comprising SEQ ID NO: 42 and a heavy chain comprising SEQ ID NO: 103; a light chain comprising SEQ ID NO: 42 and a heavy chain comprising SEQ ID NO: 101; a light chain comprising SEQ ID NO: 42 and a heavy chain comprising SEQ ID NO: 100; and a light chain comprising SEQ ID NO: 43 and a heavy chain comprising SEQ ID NO: 103; wherein the binding agent is an antibody or an antigen-binding fragment thereof.

2. Linking agent, according to claim 1, characterized in that the light chain comprises SEQ ID NO: 42 and the heavy chain comprises SEQ ID NO:

103.

3. Linking agent, according to claim 1, characterized in that the light chain comprises SEQ ID NO: 42 and the heavy chain comprises SEQ ID NO:

101.

4. Linking agent, according to claim 1, characterized in that the light chain comprises SEQ ID NO: 42 and the heavy chain comprises SEQ ID NO:

100.

5. Linking agent, according to claim 1, characterized in that the light chain comprises SEQ ID NO: 43 and the heavy chain comprises SEQ ID NO:

103.

6. A binding agent, according to any one of claims 1 to 5, characterized in that the binding agent is an antibody.

7. Binding agent, according to any one of claims 1 to 6, characterized in that the binding agent Petition 870260080059, dated 10 / 08 / 2026, page 100 / 234 2 / 3 induces the internalization of cMET in a human cancer cell.

8. A binding agent, according to any one of claims 1 to 7, characterized in that the binding agent induces cMET degradation in a human cancer cell.

9. A linking agent, according to any one of claims 1 to 8, characterized in that the linking agent is conjugated to an antineoplastic agent.

10. Pharmaceutical composition, characterized in that it comprises the binding agent, as defined in any one of claims 1 to 9, and a pharmaceutically acceptable excipient, diluent, additive or vehicle.

11. A binding agent according to any one of claims 1 to 9, characterized in that it is for use in a method of treating an individual with a neoplastic disease or cancer involving a type of cell that expresses cMET.

12. A binding agent according to claim 11, characterized in that the binding agent binds specifically to the extracellular domain of cMET expressed in one or more cells of the individual, and / or in that the binding agent inhibits mitosis and / or induces the death of one or more cells expressing cMET.

13. A binding agent according to claim 11 or 12, characterized in that the neoplastic disorder or cancer comprises lung carcinoma, breast carcinoma, ovarian carcinoma, kidney carcinoma, colorectal carcinoma, gastric carcinoma, thyroid carcinoma, pancreatic carcinoma, neuroblastoma or squamous cell carcinoma of the head and neck, cervical cancer, hepatocellular carcinoma, sarcomas, mesothelioma, glioblastoma, multiple myeloma, melanoma, esophageal carcinoma and prostate cancer.

14. Use of a binding agent as defined in any of claims 1 to 9, characterized in that it is for the preparation of a medicament to treat an individual having a neoplastic disorder or cancer involving a type of cell that expresses cMET.

15. Use according to claim 14, characterized in that the binding agent binds specifically to the extracellular domain of cMET expressed in one or more cells of the individual, and / or in that the binding agent inhibits mitosis and / or induces the death of one or more cells expressing cMET.

16. Use, according to claim 14 or 15, characterized in that the neoplastic disorder or cancer comprises lung carcinoma, breast carcinoma, ovarian carcinoma, kidney carcinoma, colorectal carcinoma, gastric carcinoma, thyroid carcinoma, pancreatic carcinoma, neuroblastoma or squamous cell carcinoma of the head and neck, cervical cancer, hepatocellular carcinoma, sarcomas, mesothelioma, glioblastoma, multiple myeloma, melanoma, esophageal carcinoma and prostate carcinoma. Petition 870260080059, dated 10 / 08 / 2026, pp. 102 / 234

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