Antibody drug conjugates and therapeutic uses thereof

Abstract

This application relates to, inter alia, anti-cMET antibody drug conjugates ("ADCs") having lower target-specific binding at low versus physiologic pH ("pH-ADCs"), pharmaceutical compositions including the pH-ADCs, methods of making the pH-ADCs, methods of selecting specific patient populations for cancer treatment with an anti-cMET pH-ADC, and methods of using the pH-ADCs to treat cancers, including cMET+ / cMET-expressing or cMET-overexpressing cancers, particularly including cMET+ / cMET-expressing or cMET-overexpressing non-small cell lung cancers ("NSCLCs").

Description

Attorney Docket No. 45395-0071WO1ANTIBODY DRUG CONJUGATES AND THERAPEUTIC USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONSThis application claims priority to U. S. Provisional Application No. 63 / 649,912, filed May 20. 2024, U. S. Provisional Application No. 63 / 690,337, filed September 4, 2024, and U. S. Provisional Application No.63 / 783,902, filed April 4, 2025, the contents of which are incorporated herein by reference in their entireties.SEQUENCE LISTING

[0001] This application contains a Sequence Listing that has been submitted electronically as an XML, file named “cMET_ADC_SL”. The XML file, created on May 20, 2024, is 388.384 bytes in size. Tire material in the XML file is hereby incorporated by reference in its entirety.FIELD

[0002] This application relates to. inter a / 'ia. anti-cMET antibody drug conjugates ("‘ADCs”) having lower target-specific binding at low versus physiologic pH (“pH-dependent ADCs”), pharmaceutical compositions including the ADCs, methods of making the ADCs, methods of selecting specific patient populations for cancer treatment with an anti-cMET ADC, and methods of using the ADCs to treat cancers.SUMMARY

[0003] cMET (cellular mesenchymal-epithelial transition factor) is a receptor tyrosine kinase and proto¬ oncogene whose activity is upregulated across a wide range of cancers. cMET is also expressed in epithelial cells of multiple organs, including the liver, pancreas, prostate, kidney, muscle, and bone marrow, during both embryogenesis and adulthood. cMET regulates many physiological processes including cell proliferation and survival, migration and scattering, organ regeneration, tissue morphogenesis, and tissue remodeling.

[0004] In NSCLC, expression of cMET is upregulated by DNA amplification (2 to 5% of patient tumors) (Dong el al. MET-Targeted Therapies and Clinical Outcomes: A Systematic Literature Review. Molecular Diagnosis & Therapy (2022) 26:203-227), exon 14 skipping mutations (2 to 4%) (Fujino et al. Lung Cancer with MET exon 14 Skipping Mutation: Genetic Feature, Current Treatments, and Future Challenges. Lung Cancer (Auckl). 2021; 12: 35-50), and overexpression (30 to 60%) (Salgia, MET in Lung Cancer: Biomarker Selection Based on Scientific Rationale. Mol Cancer Ther. 2017; 16(4):555-565). cMET is also deregulated in many other cancers including gastric, head and neck, pancreatic, and colon cancer (Sierra 2011; Spigel DR, ei al. Randomized Phase II trial of onartazumab in combination with erlotinib in patients with advanced nonsmall-cell lung cancer. J Clin Oncol. 2013;31(32):41054114; Resnick MB, et al. Epidermal growth factor receptor. cMET, B-catenin, and p53 expression as prognostic indicators in stage II colon cancer: a tissue microarray study. Clin Can Res. 2004;10:3069-3075; Lee HE, el al. MET in gastric carcinomas: comparison between protein express and gene copy number and impact on outcome. Br J Can. 2012; 107(2): 325-333). InAttorney Docket No. 45395-0071WO1NSCLC, cMET upregulation has been studied as a resistance mechanism for several approved EGFR -targeted kinase inhibitors, and this resistance may limit their effectiveness (Fernandes 2021). A non-exhaustive list of FDA-approved EGFR inhibitors include the following: afatimb (GILOTRIF), erlotinib (e.g., TARCEVA), osimertinib (e.g., TAGRISSO). neratmib (e.g.. NERLYNX), cetuximab (e g., ERBITUX), gefitinib (e.g.. TRESSA), pani umumab (e g., VECTIBIX), necituroumab (e.g., PORTRAZZA), vandetanib (e.g., CAPRELSA), mobocertinib (EXKIVITY), lapatinib (e.g., TYKERB), and dacomitinib (e.g., V1ZIMPRO).

[0005] Several antibodies targeting cMET, with various mechanisms of action, have been evaluated in clinical trials but. given limited activity, have failed to obtain FDA approval (Wolf J, et al. Capmatinib in MET Exon 14-Mutated or.'WET- mplified Non- Small-Cell Lung Cancer. New England Journal of Medicine. Massachusetts Medical Society, 2020;383:944-57; Scaglioti G. et al. A Randomized-Controlled Phase 2 Study of the MET Antibody Emibetuzumab in Combination with Erlotinib as First-Line Treatment for EGFR Mutation-Positive NSCLC Patients. Journal of Thoracic Oncology. Elsevier Inc; 2020;15:80-90; Strickler JH, LoRusso P, Salgia R, Kang YK, Yen CJ, Lin CC. et al Phase 1 dose-escalation and -expansion study of telisotuzumab (ABT-700), an Anti-c-met antibody, in patients with advanced solid tumors. Mol Cancer Ther. American Association for Cancer Research Inc.; 2020,19: 1210 -7).

[0006] Recently, novel modalities such as bispecific antibodies and antibody drug conjugates (ADCs) have been generated against cMET Amivantamab, an EGFR x cMET bispecific antibody, was approved in 2021 for patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations (Chon K, et al. FDA Approval Summary: Amivantamab for the Treatment of Patients with Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations. Clinical Cancer Research. AACR; 202.3). Telisotuzumab-vedotin (Teliso-V), an MMAE conjugated ADC, is currently in late-stage development as monotherapy or as combination therapy, and recently received breakthrough designation for patients with locally advanced or metastatic non-squamous NSCLC with EGFR wild type (WT) status and high cMET expression (Coleman N, el al. Antibod -drug conjugates in lung cancer: dawn of a new era? NPJ Precis Oncol. Nature Research; 2023.) Although Teliso-V exhibited activity in cMET high expressing tumors, there remains a much broader population of NSCLC patients whose tumors express intermediate and low levels of expression, for which there are no promising therapies imminent. Accordingly, cMET remains a compelling target for second generation ADCs, of which many are in early clinical development (RC108. TR180L BYON3521, ABBV- 400. AZD9592 and REGN5093-M114).

[0007] And since tumors comprising even relatively low levels of cMET expression have been associated with poor patient outcome, there remains a need for cancer therapeutics that target solid tumors having levels of cMET expression and / or overexpression that are not addressable with current modalities. As used herein, a “cMET-positive” or “cMET-expressing’’ tumor is one that comprises at least some cells that can be detected using an IHC assay and would be assigned an IHC score of at least + 1 And while there is not yet a universally accepted definition for the term "’cMET overexpression”, as used herein, “cMET overexpression” is intended to mean a level of cMET expression in tumor tissue that is significantly higher than the level of cMETAttorney Docket No. 45395-0071WO1expression in non-cancerous tissue comprised of substantially the same type(s) and proportion(s) of cells that gave rise to the tumor tissue. cMET-positivity / expression and cMET overexpression can be measured by a variety of methods known in the art (e.g., IHC scoring of tumor samples, whole body imaging using suitably-labeled target-specific binding agents, etc.) In another embodiment, the anti-cMET ADCs are useful therapeutically for the treatment of cMET -expressing tumors in humans where the cMET is expressed at a level that is beneath the threshold of detection of current IHC assays, but still expressed at a level sufficient to permit the anti-cMET ADCs to exert a significant antitumor effect.[ 00081 We hypothesized that engineering antibodies specifically for ADCs had the potential to augment therapeutic index by increasing tumor delivery' and increasing ADC exposure, to benefit patients whose tumors express lower levels of antigen. Engineering pH-dependent binding in the antibody component of an anti-cMET ADC was posited to permit the release of the ADC from cMET in the acidic endolysosomal environment, enable receptor recycling and boost uptake and efficacy' in cMET+ / cMET-expressing or cMET- overexpressing cancer cells. As disclosed herein, we designed, produced, and demonstrated the superior performance of such pH-engineered anti-cMET antibodies and ADCs made therefrom.)0091 Accordingly, the compositions and therapeutic methods disclosed herein target solid tumors expressing relatively high, moderate, and even low levels of cMET by using anti-cMET antibody drug conjugates (ADCs) that bind better (e.g.. have a higher affinity as indicated by a lower Kd) to cMET at physiologic pH versus acidic pH (“pH-dependent, anti-cMET ADCs” or “pH-ADCs”). Tn some embodiments, the pH-ADCs bind well at physiologic pH and mildly acidic pH (e.g., about pH 6.3), but less well at endolysosomal / lysosomal pH (e.g., about pH 5.3). As a consequence of this pH-dependent, target-specific binding, the disclosed pH-ADCs exhibit superior internalization, and del iver greater amounts of toxic payload to cMET+ZcMET-expressing and cMET-overexpressing tumor cells relative to corresponding non-pH-ADCs. Furthermore, because the pH-ADCs dissociate from cMET in the acidic environment of the endolysosomes and / or lysosomes, cMET is free to be recycled back to the surface of the tumor cell (i.e., rather than being degraded along with a specifically7bound ADC), where it has the opportunity' to engage once more with an extracellular pH-ADC. At the same time, in healthy ceils expressing cMET, the FCRN pathway may pennit the export of the internalized pH-ADC, contributing to a superior safety profile for the disclosed pH-ADCs. Advantageously, internalized anti-cMET pH-ADCs (that dissociate from cMET at lower pH) are exported to a greater extent as compared to their corresponding parent anti-cMET ww-pH-ADCs (that remain bound to cMET at lower pH). Taken together, the disclosed anti-cMET pH-ADCs may be less toxic and more effective (at lower doses and / or reduced dosing frequency) when compared with corresponding anti-cMET non-pH- ADCs.

[0010] Data presented herein demonstrate, for the first time, that pH-ADCs that specifically target cMET exhibit robust anti -tumor activity' against tumors from patients diagnosed with NSCLC. For example, data demonstrating in vivo anti-tumor efficacy of anti-cMET pH-ADCs administered as monotherapy are provided in Examples 4, 5, and 6. Further, an ongoing human clinical trial is expected to confirm the improved safety.Attorney Docket No. 45395-0071WO1efficacy, and PKZPD parameters exhibited by the anti-cMET pH-ADCs in a host of preclinical studies. Early trial findings appear to be consistent with the preclinical safety and PK data disclosed herein.[00111 As disclosed herein, cME’ T- -posit ivity can be defined by a tumor immunohistochemistry (IHC) Id- score of I to 149 and cMET-o verexpression can be defined by a tumor IHC H-score of 150 to 300 when measured by a suitable assay (e.g., as described in Example 11). Briefly, an IHC staining procedure for cMET has been developed using the Ventana cMET CONFIRM (SP44) kit. Tissue samples are fixed (e.g., in formalin), embedded in was, sectioned, stained with the Ventana antibody, and then scored by determining the percentages of target tissue cells staining at various intensity levels of low to high (FIGs 12-15). Additionally, tumor tissues including cMET+ / cMET-expressing cancer cells (i.e., at least some cancer cells having an IHC score of +1 and / or a tumor tissue H-score of 50 to 149) or cMET-overexpressing cancer cells (i.e.. at least some cancer cells having an IHC of +2 / -i-3 and / or a tumor H-score of 150 to 300) may be assigned an IHC score as described in Example 11. As used herein, an H-score between 50 and 149 is equivalent to an IHC score of 1+, an H-score of 150 to 224 is equivalent to an IHC score of 2+, and an H-score of 22.5 to 300 is equivalent to an IHC score of 3+.

[0012] The anti-cMET pH-ADCs may be administered as single therapeutic agents or adj ictively with or to other treatments and / or therapeutics. Indeed, data presented herein demonstrate that xenograft tumors produced from cells from tumors that, had exhibited resistance to other therapies were sensitive to anti-cMET pH-ADCs (see e.g.. Example 5). Furthermore, the anti-cMET pH-ADCs of the present disclosure deliver more toxic payload to tumor cells while impacting healthy cells to a lesser extent relative to corresponding control non-pH ADCs. Accordingly, the anti-cMET pH-ADCs described herein provide significant benefits over cument targeted and non-targeted approaches toward the treatment of cMET+ and / or cMET-overexpressing solid tumors

[0013] Adjunctive therapies and / or therapeutics typically will be used at their regulatory agency-approved dose, route of administration, and frequency of administration, but may be used at lower dosages and / or less frequently. When administered as monotherapy, the anti-cMET pH-ADC will typically- be administered on a schedule that provides therapeutic benefit. It is envisioned that anti-cMET pH-ADCs administered once every three, four, five, six. seven, or eight weeks will provide maximal therapeutic benefit, but more or less frequent administration may also be useful. When administered with other treatment modalities, the anti-cMET pH- ADC may be administered before, after, or simultaneously therewith.

[0014] Administration routes for the anti-cMET pH-ADCs may include, but not be limited to, intravenous infusion and / or injection, subcutaneous injection (e.g., as described in US10,799,597, to Immunomcdics), and / or transdermal or other transcutaneous therapeutic delivery methods. The amount administered will depend upon the route of administration, the dosing schedule, the type of cancer being treated, the stage of the cancer being treated, and other parameters such as the age and weight of the patient, as is well known in the art. Specific exemplary dosing schedules expected to provide therapeutic benefit are provided in the Detailed Description. Generally, an amount of anti-cMET pH-ADC in the range of about 0.005 to about 20 mg / kg whenAttorney Docket No. 45395-0071WO1administered intravenously from about once every two weeks to about once every eight weeks is expected to provide therapeutic benefit. In some embodiments, the amount is about 0.5 to about 15 mg / kg. In some embodiments, dosing every three weeks is sufficient to produce significant treatment benefits. In other embodiments, dosing every' four weeks is sufficient to produce the treatment benefits.

[0015] In an aspect, the disclosure provides a method of treating a cMET+, cMET-overexpressing, and / or A E’T'-amplified solid tumor cancer, comprising administering an effective amount of an anti-cMET antibody drug conjugate (ADC) to a human subject having said cancer, over a sufficient period of time to provide a therapeutic benefit, wherein the antibody or antigen-binding fragment thereof component of the ADC exhibits cMET-specific pH-dependent binding. In one embodiment, the antibody or antigen-binding fragment thereof comprises heavy and light chain CDRs present in the amino acid sequences as set forth in one of the following pairs: SEQ ID NOs: 15 & 16; SEQ ID NOs: 5 & 6; SEQ ID NOs: 7 & 8; SEQ ID NOs: 9 & 10; SEQ ID NOs: 11 & 12; SEQ ID NOs: 13 & 14; SEQ ID NOs: 15 & 16; SEQ ID NOs: 17 & 18: SEQ ID NOs: 19 & 20; SEQ ID NOs: 21 & 22; SEQ ID NOs: 23 & 24; SEQ ID NOs: 25 & 26; SEQ ID NOs: 27 & 28; SEQ ID NOs: 29 & 30; SEQ ID NOs: 31 & 32; and SEQ ID NOs: 33 & 34. In an embodiment, the CDRs are determined using the Rabat or IMGT system.

[0016] in an aspect, the disclosure provides a method of treating a cMET-positive solid tumor cancer having low or intermediate expression of cME'E comprising administering an effective amount of an anti-cMET antibody drug conjugate (ADC) to a human subject previously identified or selected as having said cancer, over a sufficient period of time to provide a therapeutic benefit, wherein the antibody or antigen-binding fragment thereof component of the ADC exhibits cMET-specific pH-dependent binding. In one embodiment, the antibody or antigen-binding fragment thereof compri ses heavy and light chain C DRs present in the ammo acid sequences as set forth in one of the following pairs: SEQ ID NOs: 15 & 16: SEQ ID NOs: 5 & 6; SEQ ID NOs: 7 & 8; SEQ ID NOs: 9 & 10; SEQ ID NOs: 11 & 12; SEQ ID NOs: 13 & 14; SEQ ID NOs: 17 & 18; SEQ ID NOs: 19 & 20; SEQ ID NOs: 21 & 22; SEQ ID NOs: 23 & 24; SEQ ID NOs: 25 & 26; SEQ ID NOs: 27 & 28; SEQ ID NOs: 29 & 30; SEQ ID NOs: 31 & 32; and SEQ ID NOs: 33 & 34 In an embodiment, the CDRs are determined using the Kabat or IMGT system.[0017| In an aspect, the disclosure provides a method of treating a cMET-positive and / or cMET- overexpressrng solid tumor cancer having a cMET immunohistochemistry (IHC) score of 1+. 2+, or 3+. comprising administering an effective amount of an anti-cMET antibody drug conjugate (ADC) to a human subject previously identified or selected as having said cancer, over a sufficient period of time to provide a therapeutic benefit, wherein the antibody or antigen-binding fragment thereof component of the ADC exhibits cMET-specific pH-dependent binding. In one embodiment, the antibody or antigen-binding fragment thereof comprises heavy and light chain CDRs present in the amino acid sequences as set forth in one of the following pairs: SEQ ID NOs: 15 & 16; SEQ ID NOs: 5 & 6; SEQ ID NOs: 7 & 8: SEQ ID NOs: 9 & 10; SEQ ID NOs: 11 & 12; SEQ ID NOs: 13 & 14; SEQ ID NOs: 17 & 18; SEQ ID NOs: 19 & 20: SEQ ID NOs: 21 & 22; SEQ ID NOs: 23 & 24; SEQ ID NOs: 25 & 26; SEQ ID NOs: 27 & 28; SEQ ID NOs: 29 & 30; SEQ ID NOs: 31 &Attorney Docket No. 45395-0071WO132; and SEQ ID NOs: 33 & 34. In an embodiment, the CDRs are determined using the Kabat or IMGT system.

[0018] In an embodiment of the foregoing methods, the cancer is a solid tumor cancer, including a non-small cell lung cancer (“NSCLC*’), including a non-squamous NSCLC. a squamous NSCLC. and a ‘‘not otherwise specified’' (NOS) NSCLC In some embodiment, a biopsy from a tumor of said cancer and / or the entire tumor itself, comprises at least about 1%, 2%, 3%. 4%, 5%, 6%, 7%, 8%, 9%, 10%. 15%, 20%, 25%, 30%. 35%.40%, 45%. 50%. 60%, 70%. 80%, 90%, or 100% of cancer cells having a cMET expression level of at least a 1 +, a 2+. or a 3+, as scored by an applicable and / or regulatory-agency approved immunohistochemistry (IHC) assay. In some embodiments, at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% of the tumor cells have an IHC score of 1+ or 2+. In other embodiments, at least about 1%, 2%, 3%, 4%. 5%, 6%, 7%, 8%. 9%, 10%, 15%, 20%. 25%. 30%.35%. 40%, 45%. 50%,. 60%, 70%, 80%, 90%, or 100% of the tumor cells have an IHC score of 2+. hi still other embodiments, at least about 1%, 2%. 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%. 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%. 70%, 80%, 90%, or 100% of the tumor cells have an IHC score of K

[0019] In some embodiments, the disclosure provides a method of treating a cMET-positive and / or cMET- overexpressing solid tumor cancer having at least about a low or at least about an intermediate expression of cMET, comprising administering an effective amount of an anti -cMET antibody drug conjugate (ADC) to a human subject previously identified or selected as having said cancer, over a sufficient period of time to provide a therapeutic benefit, wherein the antibody or antigen-binding fragment thereof component of the ADC exhibits cMET-specific pH-dependent binding (e.g., superior binding at about pH 7.4 versus about pH 5.4). In some embodiments, the antibody or antigen-binding fragment thereof comprises heavy and light chain CDRs present in the amino acid sequences as set forth in one of the following pairs: SEQ ID NOs: 15 & 16; SEQ ID NOs: 5 & 6: SEQ ID NOs: 7 & 8; SEQ ID NOs: 9 & 10; SEQ ID NOs: II & 12; SEQ ID NOs: 13 & 14; SEQ ID NOs: 17 & 18; SEQ ID NOs: 1 & 20; SEQ ID NOs: 21 & 22; SEQ ID NOs: 23 & 24; SEQ ID NOs: 25 & 26; SEQ ID NOs: 27 & 28; SEQ ID NOs: 29 & 30; SEQ ID NOs: 31 & 32; and SEQ ID NOs: 33 & 34. In an embodiment, the CDRs are determined using the Kabat or IMGT system.

[0020] In some embodiments, the CDRs are as defined by the Kabat system. In other embodiments, the CDRs are as defined by the IMGT system. In still other embodiments, the CDRs are as defined by the Chothia system.

[0021] In some embodiments, the antibody or antigen-binding fragment thereof comprises heavy chain and light chain vanable regions comprising, consisting of, or consisting essentially of the amino acid sequences as set forth in one of the following pairs: SEQ ID NOs: 15 & 16; SEQ ID NOs: 5 & 6; SEQ ID NOs: 7 & 8; SEQ ID NOs: 9 & 10; SEQ ID NOs: 11 & 12; SEQ ID NOs: 13 & 14; SEQ ID NOs: 17 & 18; SEQ ID NOs: 19 & 20; SEQ ID NOs: 21 & 22; SEQ ID NOs: 23 & 24; SEQ ID NOs: 25 & 26; SEQ ID NOs: 27 & 28; SEQ ID NOs: 29 & 30; SEQ ID NOs: 31 & 32; and SEQ ID NOs: 33 & 34. In an embodiment, the CDRs are determined using the Kabat or IMGT system.

[0022] In an aspect, the disclosure provides a method of treating a cMET-positive and / or cMET-Attorney Docket No. 45395-0071WO1overexpressing solid tumor cancer having a cMET immunohistochemistry score of 1+, 2+, or 3+, comprising administering an effective amount of an anti-cMET antibody drug conjugate (ADC) to a human subject previously identified or selected as having said cancer, over a sufficient period of time to provide a therapeutic benefit, wherein the antibody or antigen -binding fragment thereof component of the ADC exhibits c. ME 1 - specific pH-dependent binding, and optionally wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDRs present in the amino acid sequences as set forth in one of the following pairs: SEQ ID NOs: 15 & 16: SEQ ID NOs: 5 & 6: SEQ ID NOs: 7 & 8; SEQ ID NOs: 9 & 10; SEQ ID NOs: 11 & 12; SEQ ID NOs: 13 & 14; SEQ ID NOs: 17 & 18; SEQ ID NOs: 19 & 20; SEQ ID NOs; 21 & 22; SEQ ID NOs: 23 & 24; SEQ ID NOs: 25 & 26; SEQ ID NOs: 27 & 28; SEQ ID NOs: 29 & 30; SEQ ID NOs: 31 & 32; and SEQ ID NOs: 33 & 34. In an embodiment, the CDRs are determined using the Kabat or IMGT system.

[0023] Accordingly, in one aspect, the present disclosure provides pH-ADCs that specifically bind cMET with higher affinity at physiologic pH as compared to acidic pH (‘“anti-cMET pH-ADCs”). In some embodiments, the pH-ADC binds cMET well at physiologic pH and mildly acidic pH, but not well at the acidic pH found in endolysosomes and / or lysosomes. The anti-cMET pH-ADCs comprise cytotoxic and / or cytostatic agents linked by way of linkers to an antigen binding moiety or module that specifically binds cMET. In some embodiments, the antigen binding moiety is an antibody and / or an antigen binding fragment.

[0024] Antibodies and / or binding fragments composing the anti-cMET pH-ADCs generally comprise a heavy chain comprising a heavy chain vanable region (VH) and a light chain comprising a light chain variable region (VL), each VH and VL having three complementarity determining regions (“CDRs”) referred to herein (in amino- to carboxy-terminal order) as VH CDRS (CDRH1, CDRH2, and CDRH3) and VL CDRs (CDRL1, CDRI..2. and CDRL3). The amino acid sequences of exemplary' CDRs, as well as the ammo acid sequence of the VH and VL regions of the heavy and light chains of exemplary anti-cMET pH-antibodies and / or binding fragments that can compose the anti-cMET pH-ADCs are provided herein. Specific embodiments of anti- cMET pH-ADCs include, but are not limited to, an ADC comprising an anti-cMET pH-Ab module comprising one pair of heavy chain and light chain variable sequences having the sequences as set forth in SEQ ID NOs: 15 & 16; SEQ ID NOs: 5 & 6; SEQ ID NOs: 7 & 8; SEQ ID NOs: 9 & 10; SEQ ID NOs: Il & 12; SEQ ID NOs; 13 & 14; SEQ ID NOs: 17 & 18; SEQ ID NOs: 19 & 20; SEQ ID NOs: 21 & 22; SEQ ID NOs: 23 & 24; SEQ ID NOs: 25 & 26: SEQ ID NOs: 27 & 28: SEQ ID NOs: 29 & 30; SEQ ID NOs: 31 & 32; and SEQ ID NOs: 33 &.34. In a particular embodiment, the ADC is MYTX-01 L which is an ADC comprising an Ab module comprising a VH and a VL having the amino acid sequences as set forth in SEQ ID NOs: 15 & 16, respectively, which comprise VH CDRs and VL CDRs having the sequences as set forth in SEQ ID NOs: 236, 237, and 238, and SEQ ID NOs: 239, 240. and 241, respectively.

[0025] In particular embodiments, the anti-cMET pH-antibody module may include CDRs (e.g., as determined by the IMGT', Kabat, and / or Chothia system) and / or variable domains from antibodies exhibiting superior internalization (relative to non-pH-controls), notably including the following: MYT4309 (HC'VD = SEQ ID NO: 242, LCVD - SEQ ID NO: 8); MYT 4310 (HCVD SEQ ID NO: 243, LCVD === SEQ ID NO:Attorney Docket No. 45395-0071WO18): MYT4311 (HCVD = SEQ ID NO: 244, LCVD = SEQ ID NO: 8); MYT4318 (HCVD = SEQ ID NO: 245, LCVD - SEQ ID NO: 8); MYT4319 (HCVD - SEQ ID NO: 229, LCVD - SEQ ID NO: 8); MYT4320 (HCVD = SEQ ID NO: 230, LCVD = SEQ ID NO: 8); MYT4322. HCVD - SEQ ID NO: 246, LCVD = SEQ ID NO: 8): MYT4323 (HCVD = SEQ ID NO: 247, LCVD = SEQ ID NO: 8); MYT4324 (HCVD = SEQ ID NO: 231. LCVD = SEQ ID NO: 8); MYT4325 (HCVD = SEQ ID NO: 9, LCVD = SEQ ID NO: 8); MYT4326 (HCVD - SEQ ID NO: 15, LCVD === SEQ ID NO: 16); MYT4327 (HCVD == SEQ ID NO: 15, LCVD === SEQ ID NO: 248); MY T 4332 (HCVD - SEQ ID NO: 15, LCVD - SEQ ID NO: 249); MYT4334 (HCVD = SEQ ID NO: 15, LCVD = SEQ ID NO: 250); and MYT4336 (HCVD = SEQ ID NO: 15, LCVD = SEQ ID NO: 251), each disclosed in US 20220281984 Al, the content of which is herein incorporated by reference in its entirety.

[0026] In some embodiments, the CDRs are as defined by the Kabat system. In other embodiments, the CDRs are as defined by the IMGT system. In other embodiments, the CDRs are as defined by the Chothia system. In still other embodiments, the CDRs are as defined by another suitable system. Now that the applicant has disclosed the plurality of heavy chain variable domains and light chain variable domains of the high-performing, pH-dependent anti-cMET antibodies, the skilled artisan using routine techniques can extract the sequences of the CDRs—irrespective of the precise system used to define said CDRs—an place them into different antibody contexts, frameworks, and / or formats.

[0027] In other particular embodiments, the anti-cMET pH-antibody module may include CDRs and / or variable domains from antibodies exhibiting superior internalization relative to non-pH-controls, notably' including MYT4849 (SEQ ID NOs: 15 & 16); MYT535I (SEQ ID NOs: 5 & 6); MYT4313 (SEQ ID NOs: 6 &7); MYT4325 (9 & 10); MYT4826 (SEQ ID NOs: 11 & 12), MYT4837 (SEQ ID NOs: 13 & 14); MYT4942 (SEQ ID NOs: 17 & 18): MYT5309 (SEQ ID NOs: 19 & 20); MYT5344 (SEQ ID NOs: 21 & 22); MYT5367 (SEQ ID NOs: 23 & 24); MYT4827 (SEQ ID NOs: 25 & 26): MYT4312 (SEQ ID NOs: 27 & 28); MYT4953 (SEQ ID NOs: 29 & 30); MYT4940 (SEQ ID NOs: 31 & 32); MYT4888 (SEQ ID NOs: 33 & 34). each disclosed in WO 2022 / 169975 (’975 PCT), the complete disclosures of which is incorporated herein.

[0028] In an aspect, the present disclosure provides a method of treating a cMET-positive solid tumor cancer in a population of subjects, wherein treatment results in a decreased incidence of one or more adverse event(s) associated with monomethyl auristatin E (MMAE)-containing antibody drug conjugates as compared to the incidence of the one or more adverse event(s) associated with intravenous administration of two or more doses of about 1.9 mg / kg telisotuzumab vedotin, once every two weeks, over a similar treatment period, wherein the method comprises administering to the subject two or more doses of MYTX-011, wherein the doses of MYTX-011 arc administered to the subject in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W). In some embodiments, the Q3W dosing of an effective amount of MYTX-011 is more effective than Q2W dosing of an effective amount of telisotuzumab vedotin.

[0029] In some embodiments, the decreased incidence is at least a 5% decrease in incidence of the one or more adverse event(s) associated with MMAE-containing antibody drug conjugates In some embodiments, the decreased incidence is at least a 10% decrease in incidence of one or more adverse event(s) associated withAttorney Docket No. 45395-0071WO1MMAE-containing antibody drug conjugates. IN some embodiments, the decreased incidence is at least a 20% decrease in incidence of one or more adverse event(s) associated with MMAE-containing antibody drug conjugates.

[0036] In some embodiments, the one or more adverse event(s) associated with MMAE-containing antibody drug conjugates are selected from the group consisting of: peripheral neuropathy, anemia, thrombocytopenia, neutropenia, hypoalbuminemia, peripheral edema, and AST / ALT elevation.

[0031] In some embodiments, the doses of MYTX-011 are administered to the subject in an amount ranging from about 3.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W). In some embodiments, the doses of MYTX-011 are administered to the subject in an amount ranging from about 4.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

[0032] As used herein, ’'subject’' is intended to encompass “human subject” and “patient”.

[0033] In an aspect, the present disclosure provides a method of treating a cMET-positive solid tumor cancer in a subject, wherein the subject has not responded to 3, 4, 5, or 6 prior lines of treatment, the method comprising administering to the subject two or more doses of MYTX-011, wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).[0034I In some embodiments, the subject lias not responded to 3 prior lines of treatment. In some embodiments, the subject has not responded to 4 prior lines of treatment. In some embodiments, the subject has not responded to 5 prior lines of treatment. In some embodiments, the subject has not responded to 6 prior lines of treatment.[0035 J In some embodiments, the doses of MYTX-011 are administered to the subject in an amount ranging from about 3.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W). In some embodiments, the doses of MYTX-011 are administered to the subject in an amount ranging from about 4.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W). As used herein, “mg / kg” means “mg / kg of body weight” unless otherwise indicated by the context.

[0036] In another aspect, the present disclosure provides a method of treating a cMET-positive solid tumor cancer in a subject, wherein the subject has not responded to prior treatment with a taxane-based therapy, the method comprising administering to the subject two or more doses of MYTX-011, wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

[0037] In some embodiments, the taxane-based therapy is selected from the group of: paclitaxel, docetaxel, and cabazitaxel.

[0038] In some embodiments, the doses of MYTX-011 are administered to the subject in an amount ranging from about 3.0 mg / kg to about 6.0 mg / kg. once every three weeks (Q3W). In some embodiments, the doses of MYTX-011 are administered to the subject in an amount ranging from about 4.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).Attorney Docket No. 45395-0071WO1

[0039] In another aspect, the present disclosure provides a method of treating a cMET-positive solid tumor cancer in a subject, the method comprising: (a) administering to the subject two or more doses of MYTX-011, wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg, once even- three weeks (Q3 W j; and (b) administering one or both of a vasoconstrictor and a corticosteroid to one or both eyes of the subject In some embodiments, the dosing and timing of ad inistration of the vasoconstrictor and / or the corticosteroid is selected to provide efficacy during the period of time when the subject’s plasma concentration of MYTX-011 is at its maximum. In some embodiments, the amount of the vasoconstrictor is effective in reducing or eliminating MMAE-associated ocular toxicity. In some embodiments, the timing and duration of the administration of the vasoconstrictor and / or the corticosteroid is effective in reducing or eliminating MMAE-associated ocular toxicity.

[0040] In some embodiments, step (b) is performed prior to step (a). In some embodiments, step (a) is performed poor to step (b). In some embodiments, steps (a) and (b) are performed at about the same time.

[0041] In some embodiments, step (b) comprises administering a vasoconstrictor to one or both eyes of the subject. In some embodiments, step (b) comprises administering a corticosteroid to one or both eyes of the subject. In some embodiments, step (b) comprises administering a vasoconstrictor and a corticosteroid to one or both eyes of the subject.

[0042] In some embodiments, the doses of MYTX-011 are administered to the subject in an amount ranging from about 3.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W). In some embodiments, the doses of MYTX-011 are administered to the subject in an amount ranging from about 4.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

[0043] In another aspect, the present disclosure provides a method of treating a cMET-positive solid tumor cancer in a subject, the method comprising: administering a first dose of MYTX-011 in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg on day 1; administering a second dose of MYTX-011 in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg on about day 22; and administering a third dose of MYTX- 011 in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg on about day 64,

[0044] In some embodiments, the first, second, and third doses of MYTX-011 are administered to the subject m an amount ranging from about 3.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W). In some embodiments, the first, second, and third doses of MYTX-011 are administered to the subject in an amount ranging from about 4.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

[0045] In some embodiments, the method further comprises: administering a fourth dose of MYTX-011 in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg on about day 85; and administering a fifth dose of MYTX-011 in sin amount ranging from about 2.0 mg / kg to about 6.0 mg / kg on about day 127. In some embodiments, the fourth and fifth doses of MYTX-011 are administered to the subject in an amount ranging from about 3.0 mg / kg to about 6.0 mg / kg. once every three weeks (Q3W). In some embodiments, the fourth and fifth doses of MYTX-011 are administered to the subject in an amount ranging from about 4.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).Attorney Docket No. 45395-0071WO1

[0046] In some embodiments, the cMET-positive solid tumor cancer is a cMET-overexpressing and / or MET- amplified solid tumor cancer. In some embodiments, cMET-positive solid tumor cancer has low or intermediate expression of cMET.

[0047] As of the April 24, 2025, KisMET-01 data cutoff, positive cMET levels (cMET+) are defined as: cMET high (>50% of tumor cells at 3+ staining), cMET intermediate (>25% and <50% of tumor cells at 3+), cMET low (>25% of tumor cells at 2+ and not meeting criteria for high / intermediate); exploratory cMET ultra-low (>25% tumor cells at 1+). Staining may be assessed using the VENTANA® MET (SP44) assay, recently approved by the FDA (the VENTANA® MET (SP44) Assay) or any comparable assay currently known or yet to be developed.

[0048] In some embodiments, the cMET-positive solid tumor cancer has a cMET immunohistochemistry score of 1+, 2+, or 3+. In some embodiments, the cMET-positive solid tumor cancer has an H-score of about 50 to 300. In some embodiments, the H-score is as low as 25.

[0049] In some embodiments, the cMET-positive solid tumor cancer is non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is non-squamous NSCLC, squamous NSCLC, or not otherwise specified NSCLC.

[0050] In some embodiments, a biopsy from a tumor of the cMET-positive solid tumor cancer and / or an entire tumor of the cMET-positive solid tumor cancer, comprises at least about 1 %, 2%, 3%, 4%, 5%. 6%, 7%, 8%, 9%. 10%, 15%. 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% of cancer cells having a cMET expression level of at least a 1+, a 2+, or a 3+, as scored by an applicable and / or regulatory- agency approved immunohistochemistry (IHC) assay. In some embodiments, (a) at least about 1%, 2%, 3%, 4%, 5%. 6%, 7%, 8%, 9%. 10%, 15%, 20%, 25%, 30%, 35%, 40%. 45%. 50%, 60%, 70%, 80%, 90%, or 100% of the cancer cells have an IHC score of 1+ or 2+; (b) at least about 1%. 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%.10%, 15%. 20%, 25%. 30%, 35%. 40%, 45%. 50%, 60%, 70%, 80%, 90%, or 100% of the cancer cells have an IHC score of 2+; (c) at least about 1%. 2%, 3%, 4%. 5%, 6%, 7%. 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% of the cancer cells have an IHC score of 1+; (d) at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, or about 20% of the cancer cells have an IHC score of 1+ and wherein no more than about 1%, 2%, 3%. 4% or 5% of the cancer cells have an IHC score of 2+ or 3+; and / or (e) at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, or about 20% of the cancer cells have an IHC score of 1+ and wherein no more than about 1%, 2%, 3%, 4% or 5% of the cancer cells have an IHC score of 2+ or 3+.

[0051] In some embodiments, (a) no more than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, or about 20% of the cancer cells have an IHC score of 2+ and wherein no more than about 1% of the cancer cells have an IHC score of 3+; (b) no cancer cells have an IHC score of greater than 1 +; or (c) no cancer cells have an IHC score of greater than 2>.

[0052] In some embodiments, the method further comprises a step of determining an H-score for the biopsy or the entire tumor, wherein the H-score is between about 10 and about 300, between about 10 and about 250,Attorney Docket No. 45395-0071WO1between about 20 and about 225, between about 20 and about 200. between about 20 and about 175, or between about 20 and about 150. In some embodiments, the H-score is no more than about 100, about 90, about 80, about 70, or about 50.

[0053] In some embodiments, the biopsy or the entire tumor is homogeneous or heterogeneous for cMET expression and / or MET amplification.

[0054] In some embodiments, at least about 10%, 20%, or 30% of the cancer cells have a first frequently- occurring IHC score selected from one of 0, 1+, 2+, and 3+ and at least about 10%, 20%, or 30% of the cancer cells have a second frequently-occurring IHC score selected from one of 0, 1+, 2+, and 3+, wherein the first and second frequently-occurring IHC scores are different.

[0055] In some embodiments, the first and second frequently-occurring IHC scores are selected from the following pairs of scores: (0, +1), (0, +2), (0, +3), (0, 1, +2), (0,1, +3), and (+2, +3).

[0056] In some embodiments, at least about 10%, 20%, or 30% of the cancer cells have a third frequently-occurring IHC score, wherein the third frequently-occurring IHC score is distinct from the first and second frequently-occurring IHC scores.

[0057] In some embodiments, the cMET-positive solid tumor cancer has developed resistance to targeted therapies against one or more actionable mutation(s) (also interchangeably referred to herein as ‘'actionable genetic alteration” and / or “AGA”) present in one or more gene(s) of the cancer cell(s) of the tumor.

[0058] AGA “Actionable genetic alteration” or “AGA” is understood by the skilled artisan to mean a genetic variant or mutation in a subject’s (including human patient’s) cancer cells that (1) can be reliably detected through genomic profiling methods, (2) has a well-established role in oncogenesis or disease progression, and (3) is clinically actionable such that the alteration can be targeted by an approved therapeutic agent or an investigational agent in clinical trials, resulting in a therapeutic intervention that may provide clinical benefit to the patient.

[0059] Non-limiting examples of AGAs in N on-Small Cell Lung Cancer (NSCLC) include the following:

[0060] I) EGER mutations including, but not solely, Exon 19 deletions; an Exon 21 L858R point mutation, a T790M resistance mutation. Exon 20 insertions, and G719X, S768I, and L861Q mutations. Current tests include: Cobas* EGFR Mutation Test v2 (Roche), Oncomine™ Dx Target Test (Thermo Fisher), FoundationOne® CDx (Foundation Medicine). Guardant360® CDx (Guardant Health), therascreen® EGFR RGQ PCR Kit (QIAGEN), FoundationOne® Liquid CDx (Foundation Medicine);

[0061] 2) ALK gene rearrangements including, but not solely, an EML4-ALK fusion, a KIF5B-ALK fusion, and a TFG-ALK fusion (detected by VENTANA ALK (D5F3) CDx Assay (Roche), Oncomine™ Dx Target Test (Thermo Fisher), FoundationOne® CDx (Foundation Medicine));

[0062] 3) ROS1 gene rearrangements including, but not solely, a CD74-ROSI fusion, an SLC34A2-ROS1 fusion, and an SDC4-ROS1 fusion (detected by Oncomine™ Dx Target Test (Thermo Fisher), FoundationOne® CDx (Foundation Medicine), VENTANA ROSi (SP384) Assay (Roche));

[0063] 4) BRAF mutations including, but not solely, a V600E mutation, and non-V600E mutations (G469A,Attorney Docket No. 45395-0071WO1D594G) (detected by Oncomine™ Dx Target Test (Thermo Fisher), FoundationOne® CDx (Foundation Medicine), FoundationOne® Liquid CDx (Foundation Medicine));[00641 5) MET alterations including, but not solely, MET exon 14 skipping mutations and MET gene amplification (detected by FoundationOne® CDx (Foundation Medicine), Guardant360® CDx (Guardant Health)). And just recently, the Ventana MET (SP44) RxDx Assay (Roche) was approved by the FDA for determining c-MET protein levels in biopsied NSCLC tumor tissue;

[0065] 6) RET gene rearrangements, including, but not solely, a KIF5B-RET fusion, a CCDC6-RET fusion, and an NCOA4-RET fusion (detected by Oncomine™ Dx Target Test (Thermo Fisher), FoundationOne® CDx (Foundation Medicine), Guardant.360® CDx (Guardant Health));

[0066] 7) NTRK gene fusions, including, but not solely, NTRK1 / 2 / 3 fusions (detected by FoundationOne® CDx (Foundation Medicine), VENTANA NTRK (pan-TRK) Assay (Roche));

[0067] 8) HER2 (ERBB2) alterations, including, but not solely, HER2 mutations (e.g., exon 20 insertions) and HER2 amplification (detected by FoundationOne® CDx (Foundation Medicine), Guardant360® CDx (Guardant Health));

[0068] 9) KRAS mutations, including, but not solely, a G 12C mutation, a G12D mutation, a G 12V mutation, and a G13C (QIAGEN therascreen® KRAS RGQ PCR Kit. FoundationOne® CDx (Foundation Medicine). Guardant.360® CDx (Guardant Health));100691 10) NRG1 fusions, including, but not solely, CD74-NRG1 fusion and an SLC3A2-NRG1 fusion (Detected by comprehensive NGS platforms);

[0070] 11) FGFR alterations, including, but not solely, an FGFR1 amplification, FGFR1 / 2 / 3 mutations, and FGFR3 fusions (FoundationOne® CDx (Foundation Medicine));

[0071] 12) PIK3CA mutations, including, but not. solely, an E545 K mutation, an H 1047R mutation (detected by THERASCREEN® PIK3CA RGQ PCR Kit (QIAGEN), FoundationOne® CDx);

[0072] 13) PTEN loss / mutations (detected by comprehensive NGS platforms);

[0073] 14) NRAS mutations (detected by comprehensive NGS platforms);

[0074] 15) AKT1 mutations, including, but not solely, an E 17K mutation (detected by comprehensive NGS platforms);

[0075] 16) DDR2 mutations (detected by comprehensive NGS platforms);

[0076] 17) SMARCA4 / BRG I mutations (detected by comprehensive NGS platforms);[00771 18) High tumor mutational burden (TMB-high) (detected by FoundationOne® CDx (Foundation Medicine), MSK-IMPACT™ (Memorial Sloan Kettering);[00781 19) Microsatellite instability-high (MSI-H) (detected by MSK-IMPACT™ (Memorial Sloan Kettering), FoundationOne® CDx (Foundation Medicine);

[0079] 20) PD-L1 expression (while not a genetic alteration per se, it is often assessed alongside genomic biomarkers) (detected by PD-L1 IHC 22C3 pharmDx (Agilent / Dako), PD-L1 IHC 28-8 pharmDx (Agilent / Dako), VENTANA PD-LI (SP142) Assay (Roche), VENTANA PD-L1 (SP263) Assay (Roche)).Attorney Docket No. 45395-0071WO1

[0080] As used herein, “actionable genetic alteration” or “AGA” may further include emerging biomarkers being evaluated in clinical trials that may become clinically relevant during the term of this patent, as well as combinations of alterations that may predict response or resistance to targeted therapies,

[0081] Recently, the Ventana MET (SP44) RxDx Assay has received approval from the FDA. making it the first companion diagnostic to aid in determining MET (also known as c-Met) protein expression for patients with non-squamous non-small cell lung cancer (May 2025, Roche Diagnostics news release). The news release noted that these patients may now qualify for treatment with the recently approved c-Met-targeted therapy, Emrelis (telisotuzumab vedotin-tllv). This FDA approval was supported by data from the phase 2 LUMINOSITY study, where the test was utilized as an enrollment assay. The clinical trial criteria described MET protein overexpression as when 50% or more tumor cells demonstrate strong (3+) membrane and / or cytoplasmic staining. Results from the LUMINOSITY trial (NCT03539536) showed that of the 84 patients with high c-Met protein expression who received Emrelis achieved an overall response rate of 35%, with a median duration of response of 7.2 months. Peripheral neuropathy, fatigue, decreased appetite and peripheral edema were the most common side effects reported to have occurred in at least 20% of the patients treated. Decreased lymphocytes, increased glucose, increased alanine aminotransferase, increased gamma glutamyl transferase, decreased phosphorus, decreased sodium, decreased hemoglobin and decreased calcium made up the grade 3 (severe) and 4 (life-threatening) laboratory abnormalities which occurred in at least 2% of patients (Abb Vie news release, May 14, 2025).

[0082] In some embodiments, the AGA is present in a gene selected from the group consisting of EGFR, ALK, KRAS, ROS, BRAF, NTRK1 / 2 / 3, MET, RET, ERBB2, and any other gene known to have an actionable mutation associated with the cancer. In some embodiments, the AGA may be selected from (and / or associated with) one or more of the following: EGFR mutations. ALK rearrangements, ROS1 rearrangements. BRAF mutations, MET alterations, MET expression, RET rearrangements, NTRK fusions, HER2 (ERBB2) alterations, KRAS mutations, NRG1 fusions, FGFR alterations, PIK3CA mutations, PTEN loss / mutations, NRAS mutations, AKT1 mutations, DDR2 mutations, SMARCA4 / BRG1 mutations, High TMB, MSI-High.

[0083] In some embodiments, the actionable mutation is selected from one or more of the following: (a) an EGFR gene mutation selected from an exon 20 T790M substitution, an exon 20 C797X substitution, an exon 21 L858R substitution, and an exon 19 deletion, optionally wherein the exon 19 deletion is the E746 _A750 deletion as determined by a regulatory agency approved test: (b) an ALK gene rearrangement; (c) a KRAS gene mutation, optionally wherein the mutation is an exon 2 G12C substitution; (d) a BRAF gene mutation, optionally wherein the mutation is in Exon 15 V600E substitution; (e) a MET gene mutation, optionally wherein the mutation is an ex14 skipping mutation; (f) aROSl gene rearrangement, optionally where the ROS1 gene is fused with a gene or portion of a gene selected from one of the following: CD74, EZR, SDC4, SLC34A2, CCDC6, TFG, SLMAP, MYO5C, FIG, LIMAL, CLTC, GOPC, ZCCHC8, CEP72, MLL3, KDELR2, LRIG3, MSN, MPRIP, WNK1, SLC6A17, TMEM106B, FAM135B, TPM3, and TDP52L (g) a fusion of the NTRK1, 2, or 3 gene; and (h) a RET gene rearrangement, optionally where the rearrangement is a fusion with KIF5BAttorney Docket No. 45395-0071WO1or CCDC6.

[0084] In some embodiments, the cancer has an amplification, mutation, or overexpression of the ERBB2 gene, optionally wherein the ERBB2 gene has insertions in exon 20 and / or nucleotide substitutions encoding amino acid substitutions selected from one or more of the following: L755S. G776C. G660D, R678Q, E693K. and Q709L.

[0085] In some embodiments, the method further comprises administering to the subject an additional anticancer agent according to its regulatory agency-approved dosing regimen. In some embodiments, the additional anticancer agent is an inhibitor and / or targeting agent of EGFR, ALK, KRAS, ROS, BRAF, NTRK1 / 2 / 3, MET, RET. or ERBB2. In some embodiments, the additional anticancer agent is selected from osimertinib, afatinib, axitimb, bosutimb. crizotinib, dasatinib, erlotinib, gefitinib, imatmib, lapatimb. nilotinib. pazopamb. ponatinib, radotimb, regorafemb. sorafenib, sunitinib. toceranib, and vatalamb: and / or wherein the additional anticancer agent is capable of inhibiting EGFR comprising an exon 21 L858R substitution or an exon 19 E746_A750 deletion.[00861 In some embodiments, the ALK inhibitor is selected from alectinib. brigatinib, lorlatinib, ceritinib, and crizotinib, the KRAS inhibitor is selected from sotorasib and adagrasib; the BRAF inhibitor is selected from dabrafmib. vemurafemb, and trametinib: the MET inhibitor is selected from tepotinib, crizotinib, and capmatinib; the ROS 1 inhibitor is selected from entrectinib, crizotinib, ceritinib, and lorlatinib; the NTRK1 / 2 / 3 inhibitor is selected from larotrectinib and entrectinib; the RET inhibitor is selected from selpercatinib, pralsetinib, and cabozantinib; or the ERBB2 targeting agent is selected from trastuzumab-deruxtecan and trastuzumab-emtansine.

[0087] In some embodiments, the additional anticancer agent comprises an inhibitor of PDI, optionally an anti-PD1 antibody, optionally wherein the anti-PD1 antibody is pembrolizumab, nivolumab, or cemiplimab; or an inhibitor of PD-L1, optionally an anti-PD-L1 antibody such as durvalumab, or atezolizumab.

[0088] In some embodiments, the cMET-positive solid tumor cancer is resistant to prior treatment with an anti-cMET antibody, an anti-cMET ADC, a chemotherapy, a small molecule directed against cMET, and / or a radiation therapy.[00891 In some embodiments, the cMET-positive solid tumor cancer is a cMET-overexpressing, MET amplified, and / or MET ex14 skipping mutation non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is wildtype for human EGFR In some embodiments, the NSCLC is mutated for human EGFR In some embodiments, the NSCLC has resisted at least 1, 2, 3, 4, 5, 6, 7, 8, or more prior therapeutic regimen(s).

[0090] In some embodiments, the cMET-positive solid tumor cancer is an FGFR3 amplification or an EML4- ALK fusion NSCLC. In some embodiments, the cMET-positive solid tumor cancer has progressed after prior treatment with a tyrosine kinase inhibitor.

[0091] In some embodiments, the cMET-positive solid tumor cancer comprises one or both of the following: (a) an EGFR mutation substantially similar or identical to the EGFR mutation in the CTG-3414Attorney Docket No. 45395-0071WO1PDX and / or NCI-H1975 CDX model; and / or (b) a KRAS mutation substantially similar or identical to the KRAS mutation in the NCI-H2122 CDX and / or NCI-H1373 CDX model.[00921 In some embodiments, the cMET-positive solid tumor cancer comprises actionable mutation(s) substantially similar or identical to the actionable mutation(s) in one or more of the following: (a) the actionable mutation(s) present in the Hs746T gastric cancer CDX model; (b) the actionable mutations(s) present in the MET TKI sensitive LU-01-1375 NSCLC PDX model; and / or (c) the actionable mutations(s) present in the CTG-2669 NSCLC PDX model.[ 00931 In some embodiments, the cMET-positive solid tumor cancer is characterized as being a MET TKI-sensitive cancer comprising a MET Exon 14 skipping mutation. In some embodiments, the method further comprises administration of a MET TKI. In some embodiments, the MET TKI is capmatinib or tepotinib.

[0094] In some embodiments, the cMET-positive solid tumor cancer is a MET amplified gastric tumor comprising a MET Exon 14 skipping mutation.

[0095] In some embodiments, the cMET-positive solid tumor cancer comprises an actionable mutation substantially similar or identical to the actionable mutations in the LU-01-1476 PDX model.

[0096] In some embodiments, the method further comprises administration of a MET TKI.

[0097] in an aspect, the present disclosure provides a method of treating a cMET-positive solid tumor cancer in a subject, wherein the subject, has not responded to prior treatment with a MEI" tyrosine kinase inhibitor (TKI), tire method comprising administering to the subject two or more doses of MYTX-011, w'herein the doses of MYTX-011 are administered to the subject in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

[0098] In some embodiments, the subject has not responded to 2 prior lines of treatment. In some embodiments, the subject has not responded to 4 prior lines of treatment. In some embodiments, the subject has not responded to 5 prior lines of treatment In some embodiments, the subject has not responded to 6 prior lines of treatment.

[0699] In some embodiments, the MET TKI is capmatinib or tepotinib.

[0100] In some embodiments, the doses of MYTX-011 are administered as a pharmaceutical composition comprising L-histidine, L-histidine HCl monohydrate, D(+)-trehalose dihydrate, and polysorbate 80.

[0101] Alternative versions of each of the foregoing antibodies may include one or more of the following modifications in their respective heavy chain sequences: I) Triple Hinge ('TH”) only (e.g., as present in SEQ ID NO: 35); 2) “TH” + “LS” (e.g., as present in SEQ ID NO: 36); 3) ‘*TH” + “YTE” (e.g., as present in SEQ ID NO: 37); 4) “TH” + “Al 18C” (e.g., as present in SEQ ID NO: 38); 5) “TH” + “LS” + “Al 18C” (e.g. as present in SEQ ID NO: 39); 6) “TH” + “YTE” + “Al 18C” (e.g., as present in SEQ ID NO: 40), each described in the '975 PCT.[0102J As used herein, “Triple Hinge” (alternatively “TH”) refers to the substitution described in Wang J et al (2017) ABBV-399, a c-Met Antibody-Drag Conjugate that Targets Both A / E7'-Amplified and c-Met-Attorney Docket No. 45395-0071WO1Overexpressing Tumors, Irrespective of MET Pathway Dependence, Clin Cancer Res, 23:992-1000. For example, a TH can be added to SEQ ID NO: 155 by making a lysine to cysteine substitution at amino acid position 105 and deleting the threonines at amino acid positions 106 and 108.

[0103] As used herein. ‘YTE” refers to the substitution described in Dali, WF etal., " Increasing the Affinity of a Human IgGl for the Neonatal Fc Receptor: Biological Consequences” Tire Journal of Immunology (2002); 169:5171-5180). For example, a YTE can be added to SEQ ID NO: 155 by making a methionine to tyrosine substitution at ammo acid position 135 (the “Y”), a serine to threonine substitution at amino acid position 137 (the “T”), and a threonine to glutamic acid substitution at amino acid position 139 (the " F )

[0104] As used herein, “LS” refers to the substitution described in Zalevsky J et al., “Enhanced antibody half-life improves in vivo activity.” Nat Biotechnol. (2010) 28:157-9. For example, an LS can be added to SEQ ID NO: 155 by making a methionine to leucine substitution at amino acid position 311 (the “L”) and an asparagine to serine substitution at amino acid position 317 (the “S”).

[0105] As used herein, “Al 18C” refers to the A to C substitution as described in Junutula J. R., et al. Sitespecific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat. Biotechnol.2008;26:925-932.). For example, an “A118C” can be added to SEQ ID NO: 155 by making an A to C substitution at amino acid position 1. And while the varying lengths of the different heavy chain variable domains may alter the precise location of the A to C substitution with respect to the complete heavy chain sequence, the amino acid position with respect to the heavy chain constant domain is 1. This concept is well- exemplified by the multiple sequence alignment of SEQ ID NO: 155 (a heavy chain constant domain with the “A”), SEQ ID NO: 156 (a heavy chain constant domain with a “C”), and SEQ ID NO: 38 (one of the complete heavy chain sequences containing the “A118C” substitution). Accordingly, as used herein, an “A1I8C mutation” or “'A 11 C substitution” means the substitution of C for an A at the amino acid position of a given complete heavy chain sequence that corresponds to position 1 of its included heavy chain constant domain sequence.SEQ 38 QGTTVTVSSCSTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL 165 SEQ 155 - ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL 46 SEQ 156 - CSTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL 46 SEQ 38 TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK 220 SEQ 155 TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK 101 SEQ 156 TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK 101 SEQ 38 SCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV 273SEQ 155 SCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV 156SEQ 156 SCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYISRTPEVTCVVVDVSHEDPEV 154 SEQ 38 KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL 328 SEQ 155 KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL 211Attorney Docket No. 45395-0071WO1SEQ 156 KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL 209 SEQ 38 PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWES 383 SEQ 155 PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWES 266 SEQ 156 PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWES 264 SEQ 38 NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 438 SEQ 155 NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 321 SEQ 156 NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQ 319 SEQ 38 KSLSLSPG 446 SEQ 155 KSLSLSPG 329 SEQ 156 KSLSLSPG 327

[0106] As used herein, “V205C” refers to a V to C substitution in the light chain constant domain as described in Shen et al., Nature Biotechnology Vol 30 No. 2 Feb 2012 (a “V205C” substitution in the light chain constant region of the anti-Her2 mAb trastuzumab). And while the varying lengths of the different light chain variable domains may alter the precise location of the V to C substitution with respect to the complete light chain sequence, the amino acid position with respect to the light chain constant domain is 98 This concept is well- exemplified by the multiple sequence alignment of SEQ ID NO: 157 (LC constant domain with the “V”). SEQ ID NO: 158 (LC constant domain with the “C”), SEQ ID NO: 81 (LC with the '‘V”), SEQ ID NO: 82 (LC with the " C”), SEQ ID NO: 89 (LC with the “V”), and SEQ ID NO: 90 (LC with the “C”):SEQ 157 -SEQ 158 -SEQ 81 DIQMTQSPSSLSASVGDRVTITCSVSSSVSSIL HLHWYQQKPGKAPKLLIYHT 52SEQ 82 DIQMTQSPSSLSASVGDRVTITCSVSSSVSSIL HLHWYQQKPGKAPKLLIYHT 52 SEQ 89 DIVMTQSPDSLAVSLGERATINCKSSESVDSYANSHLHWYQQKPGQPPKLLIYRA 55 SEQ 90 DIVMTQSPDSLAVSLGERATINCKSSESVDSYANSHLHWYQQKPGQPPKLLIYRA 55SEQ 157 - SEQ 158 - SEQ 81 SNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQVYSGYPLTFGGGTKVEI 107 SEQ 82 SNLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQVYSGYPLTFGGGTKVEI 107 SEQ 89 STRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSKEDPLTFGGGTKVEI 110 SEQ 90 STRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSKEDPLTFGGGTKVEI 110SEQ 157 -RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE 54 SEQ 158 -RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE 54 SEQ 81 KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE 162 SEQ 82 KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE 162Attorney Docket No. 45395-0071WO1SEQ 89 KRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE 165 SEQ 90 KRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE 165SEQ 157 SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 107 SEQ 158 SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPCTKSFNRGEC 107 SEQ 81 SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 215 SEQ 82 SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPCTKSFNRGEC 215 SEQ 89 SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 218 SEQ 90 SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPCTKSFNRGEC 218

[0107] Accordingly, as used herein, a “V205C mutation” or “V205C substitution” means the substitution of a C for a V at the amino acid position of a given complete light chain sequence (LC) that corresponds to position 98 of its included light chain constant domain sequence

[0108] In one specific embodiment, the pH-Ab of MYTX-011 is Q397. which comprises a heavy chain as set forth in SEQ ID NO: 75 and a light chain as set forth in SEQ ID NO: 82.

[0109] For therapeutic uses, it may be desirable to utilize anti-cMET pH-ADCs that bind cMET at physiologic pH with an affinity of at least 100 nM. Accordingly, in some embodiments, the anti- cMET pH- ADCs comprise an anti-cMET and / or anti-cMET binding fragment that binds cMET at physiologic pH with an affinity of at least about 100 nM, or even higher, for example, at least about 95 nM, 90 nM, 85 nM, 80 nM, 75 nM, 70 nM, 65 nM, 60 nM, 55 nM, 50 nM, 45 nM, 40 nM, 35 nM, 30 nM, 25 nM, 20 nM, 15 nM, 10 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, or greater. Affinity of anti-cMET pH-antibodies and / or binding fragments can be determined using techniques well known in the art or described herein, such as for example, Bio-Layer Interferometry (BLI) (e.g. Octet Red 96), ELISA, isothermal titration calorimetry (ITC), surface plasmon resonance, flow cytometry, or fluorescent polarization assay. In one embodiment, the anti-cMET pH- antibody or antigen-binding fragment thereof has at least about a 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20- fold, 30-fold, 50-fold, or 100-fold, or greater affinity for cMET at physiologic pH versus pH 5.4. In some embodiments, the anti-cMET pH-antibody also has strong affinity' for cMET at the slightly acidic pH conditions found in the tumor microenvironment (TME).

[0110] The anti-cMET pH-antibody may be. for example, a full-length, a bispecific, a dual variable domain, a multiple chain, or a single chain antibody, or another. Other suitable forms of antibody are disclosed in US 2022 / 0281984, incorporated by reference herein in its entirety

[0111] The antibody may be of, or derived from, any isotype, including, tor example, IgA, IgD, IgE, IgG (e.g., IgGl, IgG2, IgG3 or IgG4), IgM, or IgY. In some embodiments, the anti-cMET pH-antibody is an IgG (e.g., IgGl, IgG2, IgG3 or IgG4), in particular. IgGl. Antibodies may be of human or non-human origin (e.g., simians, equines, camelids, canines, felines, bovines, porcines, rodents, goats, rabbits, or avians). In specific embodiments, anti-cMET pH-ADCs comprise humanized antibodies and / or fully human antibodies, suitableAttorney Docket No. 45395-0071WO1for administration to humans.

[0112] Antigen binding fragments (ABFs) comprising the anti-cMET pH-ADCs may include any fragment of an anti-cMET pH-antibody that retains the ability to specifically bind cMET in a pH-dependent manner. Specific examples of antibody binding fragments that may be included in the anti-cMET pH-ADCs include, but are not limited to, Fab, Fab', F(ab')2, Fv, seFv, scFv-Fc, VHH-scAb, VHH-Fab, Dual scFab, bispecific, multispecific, biparatopic, multiparatopic, and the like.

[0113] In some embodiments, the anti -c MET pH-antibody includes a single polypeptide. In some embodiments, the antigen binding fragment (ABF) is selected from a VH domain, a VHH domain, a VNAR domain, and a scFv. In some embodiments, the antibody is a BiTE, a (scFv)2, a nanobody, a nanobody-HSA, a DART, a TandAb, a scDiabody. a scDiabody-CH3, scFv-CH-CL-scFv, a HSAbody, scDiabody-HSA, or a tandem-scFv.

[0114] In some embodiments, the antibody includes two or more polypeptides In some embodiments, the antibody is selected from the group of an antibody, a VHH-scAb, a VHH-Fab, a Dual scFab, a F(ab’)2, a diabody, a crossMab, a DAF (two-in-one), a DAF (four-in-one), a DutaMab, a DT-IgG, a knobs-in-holes common light chain, a knobs-in-holes assembly, a charge pair, a Fab-arm exchange, a SEEDbody, a LUZ-Y, a Fcab, a κ-body, an orthogonal Fab, a DVD-IgG, IgG(H)-scFv. a scFv-(H)IgG. IgG(L)-scFv, scFv-(L)IgG, IgG(L, H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KJH IgG-scFab, 2scFv-lgG, IgG-2scFv, scFv4-Ig, Zybody, DVI-IgG, Diabody-CH3, a triple body, a miniantibody, a minibody, a TriBi minibody, scFv-CH3 KIH, Fab-scFv, a F(ab’)2-scFv2, a scFv-KIH, a Fab-scFv-Fc, a tetravalent HCAb, a scDiabody-Fc, a Diabody-Fc, a tandem scFv-Fc. a VHH-Fc, a tandem VHH-Fc, a VHH-Fc KIH, a Fab-VHH-Fc, an Intrabody, a dock and lock, an ImmTAC, an IgG-IgG conjugate, a Cov-X-Body, a scFvl-PEG-scFv2, an Adnectin. a DARPin. a fibronectin, a DEP conjugate, and a PROTAB. In some embodiments, the ABPC or ABF includes a proteolysis-targeting antibody (PROTAB) (as described, e g., in Marei et al, “‘Antibody targeting of E3 ubiquitin ligases for receptor degradation. Nature, 6 October 2022). In some embodiments, the PROTAB may tether cell-surface E3 ubiquitin ligases to transmembrane proteins, resulting in target degradation both in vitro and in vivo

[0115] Antibodies and / or ABFs may include modifications that alter the properties of the antibodies and / or ABFs, such as those that increase half-life, increase, or decrease agonistic capacity, and / or increase or decrease ADCC, as is well-known in the art.

[0116] The pH-ADC conjugate may include any cytotoxic and / or cytostatic agents known to inhibit the growth and / or replication of, and / or kill cells. Numerous such cytotoxic and / or cytostatic agents arc known in the art and non-limiting examples include, but are not limited to, apoptosis regulators, cell cycle modulators, protein synthesis inhibitors, kinase inhibitors, DNA cross-linking agents, alkylating agents, intercalating agents, nuclear export inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, mitochondria inhibitors, RNA / DNA antimetabolites and antimitotic agents.

[0117] Antimitotic / antiproliferative agents include, for example, natural products, such as vinca alkaloidsAttorney Docket No. 45395-0071WO1(vincristine, vinblastine) and microtubule disruptors such as taxane (paclitaxel, docetaxel), epothilones, nocodazole, vinblastin, vinorelbine (NAVELBINE®), and epipodophyllotoxins (etoposide, teniposide), allocolchicine; auristatins, such as MMAE (monomethyl auristatin E) and MMAF (niononiethyl auristatin F); halichondrin B; cemadotin; colchicine: any colchicine derivative; dolastatm- 10; dolastatin-15; maytansine: maytansinoids, such as DM1 (N2,-deacet\'l-N2’-(3-mercapto-l-oxopropyl)-maytansine): rhozoxin; paclitaxel or derivative thereof; docetaxel; thiocolchicine; and trityl cysteine.

[0118] Antimetabolites include, for example, purine analogs, folate antagonists (such as pralatrexate, methotrexate), pentostatin, cladribine, fludarabine and related inhibitors.101191 Hormones & hormone analogs (hormonal therapies) include, tor example estrogen, tamoxifen, goserelin, bicalutamide, nilutamide, aromatase inhibitors (e.g., letrozole and anastrozole). anastrozole: exemestane; arzoxifene; bicalutamide; cetrorelix; degarelix; deslorelin; trilostane; dexamethasone: flutamide; raloxifene; fadrozole; toremifene; fulvestrant; letrozole; formestane; glucocorticoids; doxercalciferol; sevelamer carbonate; lasofoxifene; leuprolide acetate; megesterol; mifepristone; nilutamide; tamoxifen citrate; abarelix; prednisone; finasteride; rilostane; buserelin; luteinizing hormone releasing hormone (LHRFI); Histrelin, trilostane or modrastane; fosrelin; and goserelin.

[0120] Apoptosis regulators include, for example, caspase-targeting drags, caspase-regulators, BCL-2 family members, TNF family members, Toll family members, and / or NF-kappa-B proteins.

[0121] Cell cycle modulators include, for example. Paclitaxel; Nab-Pac-Iitaxel; Docetaxel; Vincristine; Vinblastine; ABT-348; AZD-1152; MLN-8054; VX-680; Aurora A-specific kinase inhibitors; Aurora B-specific kinase inhibitors and pan-Aurora kinase inhibitors; AZD-5438; BM1-1040; BMS-032; BMS-387; CVT-2584; flavopyridol; GPC-286199; MCS-5A; PD0332991; PHA-690509; seliciclib (CYC-202, R- roscovitine): ZK-304709; AZD4877, ARRY-520; GSK923295A.

[0122] Protein synthesis inhibitors include, for example. Amikacin: Arbekacin; Bekanamycin; Dibekacin; Dihydrostreptomycin; Streptomycin; Neomycin; Framycetin; Paromomycin; Ribostamycin: Kanamycin; Tobramycin; Spectinomycin; Hygromycin B; Paromomycin; Gentamicin; Netilmicin; Sisomicin; Isepamicin; Verdamicin; Astromicin; Tetracycline; Doxycycline, Chlortetracycline; Clomocy cline, Demeclocycline; Lymecycline; Meclocycline; Metacycline; Minocycline; Oxy tetracycline: Penimepicycline: Rolitetracycline; Tetracycline; Glycylcyclines; Tigecycline; Oxazolidmone: Eperezolid; Linezolid; Posizolid; Radezolid: Ranbezolid; Sutezolid: Tedizolid.

[0123] Kinase inhibitors include, for example, Afatinib (e g., GILOTRIF®); Axitinib; Bosutinib; Cetuximab (e g., ERBITUX®), Panitumumab (e.g., VECTIBIX®), Nccitumumab (e.g., PORTRAZZA®), Vandctanib (e.g., CAPRELSA®), Mobocertmib (EXKIVITY®), Dacomitinib (e.g., VIZIMPRO®); Cnzotmib; Dasatinib; Erlotinib (e.g., TARCEVA*); Fostamatinib; Gefitinib (e.g., IRESSA®); Ibrutimb; Imatimb; Lapatinib (e.g., TYKERB®); Lenvatinib; Mubntinib; Neratimb (e.g.. NERLYNX®); Nilotmib; Osimertmib (e.g., TAGRISSO®), Pazopanib; Pegaptanib; Sorafenib; Sunitinib; SU6656; Vandetanib; Vemurafenib; CEP-701 (lesaurtinib); XL019; INCB018424 (ruxolitinib); ARRY-142886 (selemetinib); ARRY-438162 (binimetinib);Attorney Docket No. 45395-0071WO1PD-325901; PD-98059; AP -23573; CCI-779; everolimus; RAD-001; rapamycin; temsirolimus; ATP- competitive TORC1 / 2 inhibitors including PI-103, PP242, PP30, Torin 1; LY294002; XL-147; CAL-120; ONC-21; AEZS-127, ETP-45658: PX-866; and the bkc[0124 § DN A cross-lmking / damaging agents include, for example, such as actinomycin, amsacrine, busulfan. carbopiatin, chlorambucil, cisplatin, cyclophosphamide (CYTOXAN*"), dactinomycin, daunorubicin, doxorubicin, DEBDOX, epirubicin, iphosphamide, melphalan, merchlorethamine, mitomycin C, mitoxantrone, nitrosourea, procarbazine, taxol, Taxotere, teniposide, etoposide, and triethylenethiophosphoramide.

[0125] DNA-hypomethylating agents, such as guadecitabine (SGI-110), oral decitabine and cedazuridine (ASTX727).

[0126] Alkylating agents include, for example, nitrogen mustards (cyclophosphamide, chlormethine, uramustine, Melphalan, Chlorambucil, Ifosfamide, and Bendamustine), Nitrosoureas (e.g., Carmustine, Lomustine, Streptozocin), and Alkyl sulfonates (e.g., Busulfan). Alkylating-like agents include, for example. Cisplatin, Carbopiatin, Dicycloplatin, Eptaplatin, Lobaplatin, Miriplatin, Nedaplatin, Oxaliplatin, Picoplatin, Satraplatin, and Triplatin tetranitrate.

[0127] intercalating agents include, for example, anthracydines. including doxorubicin, daunorubicin, epirubicin. idarubicin, pirarubicin, aclarubicin, and mitoxantrone.

[0128] Enzymes such as L-asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine (i.e., a cancer or tumor starvation approach). Further example include cnsantaspase (ERWINASE®) and GRASPA^ (ERY-001, ERY-ASP), calaspargase pegol, and pegaspargase.

[0129] Nuclear export inhibitors include, for example, callystatin A; delactonmycin; KPT-185; kazusamycin. A; leptolstatin; leptofuranin A: leptomycin B; ratjadone: and Verdinexor.

[0130] Topoisomerase 1 inhibitors include, for example, camptothecins, including synthetic derivatives thereof, including irinotecan and topotecan, and other analogs (e.g., NSC 100880, NSC 603071, and the like); morpholmisoxorubicin, and SN-38.

[0131] Topoisomerase II inhibitors include, for example, etoposide, doxorubicin, mitoxantrone. teniposide, novobiocin, merbarone, and aclarubicin.

[0132] Mitochondria inhibitors include, for example, pancrati statin; ph enpan tatin; rhodamine- 123: edelfosine; d-alpha-tocopherol succinate; compound 11 p; aspirin; ellipticine; berberine; cerulenin; GX015- 070 (Obatoclax®; IH-Indolc, 2-(2-((3,5-dimcthyl-lFI-pyrrol~2-yl)mcthylcnc)-3-mcthoxy-2H-pyrrol-5-yl)- ); celastrol (tripterine): metformin: Brilliant green: ME-344.

[0133] RNA / DN A antimetabolites include, for example, L-alanosine; 5 -azacytidine; 5-fluorouracil; acivicin; aminopterin derivative: I. -aspartic acid (NSC 132483); aminopterin derivative; antifolate PT523; Baker's soluble antifol (NSC 139105); dichlorallyl lawsone ((2-(3,3-dichloroallyl)-3-hydroxy-l,4-naphthoquinone); brequinar; ftorafiir ((pro-drug; 5-fluoro-l-(tetrahydro-2-furyl)-uracil); 5,6-dihydro-5-azacytidine;Attorney Docket No. 45395-0071WO1methotrexate; methotrexate derivative; PALA ((N-(phosphonoacetyl)-L-aspartate); pyrazofurin; trimetrexate.

[0134] In some embodiments, tire following types of cancer are treated using the indicated combinations of chemotherapeutic agents: breast cancer (cyclophosphamide, methotrexate, 5-fluorouracil, and vinorelbine = “CMF”; or doxorubicin and cyclophosphamide = “AC”). Hodgkin's lymphoma (docetaxel, doxorubicin, and cyclophosphamide = “TAC”; doxorubicin, bleomycin, vinblastine, and dacarbazine = “ABVD”; mustine, vincristine, procarbazine, and prednisolone ~ “MOPP”), non-Hodgkin's lymphoma (cyclophosphamide, doxorubicin, vincristine, and prednisolone - “CHOP” or “R-CVP”), germ cell tumor (bleomycin, etoposide, and cisplatin = “BEP”), stomach cancer (epirubicin, cisplatin, and 5-fluorouracil = “ECF”; or epirubicin, cisplatin, and capecitabine = “ECX”), bladder cancer (methotrexate, vincristine, doxorubicin, and cisplatin = “MVAC”), lung cancer (cyclophosphamide, doxorubicin, vincristine, and vinorelbine:::“CAV”), colorectal cancer (5-fluorouracil, folinic acid, and oxaliplatin = “FOLFOX”), pancreatic cancer (gemcitabine and 5- fluorouracil), and bone cancer (doxorubicin, cisplatin, methotrexate, ifosfamide, and etoposide = “MAP’7”MAPIE”). In a particular embodiment, the cytotoxic and / or cytostatic agent of the anti-cMET pH-ADC is a membrane-permeable antimitotic agent, including, for example, an aunstatin, including, but not limited to, monomethyl auristatin E (“MMAE”).

[0135] Tire linkers linking the cytotoxic and / or cytostatic agents to the anti-cMET portion of the ADC may be short, long, rigid, flexible, hydrophobic, or hydrophilic in character, or may comprise elements having a variety of characteristics, such as elements of rigidity, elements of hydrophilicity, etc. The linker may be chemically' stable in serum and / or the bloodstream, or it may include elements that provide for the release of the cytotoxic and / or cytostatic agents prior to entering cells. In some embodiments, the linkages provide for release of the agents upon internalization of the anti-cMET pH-ADC within the cell. In some particular embodiments, the linkers may be cleaved and / or immolated or otherwise broken down inside cells. A wide variety of useful ADC linkers is known in the art, and any such linkers, as well as others yet to be developed, may be used to link the cytotoxic and / or cytostatic agents to the anti-cMET portion of the pH- ADCs described herein.

[0136] In some embodiments, the anti-cMET pH-ADC is MYTX-011, which is a cMET-targeted val-cit- monomethyl auristatin E (vcMMAE) ADC that was specifically designed to address the shortcomings of existing therapies, including other cMET-targeted ADCs. As described herein. “vcMMAE” is a protease cleavable linker (maleimidocaproyl-valinecitnilline-p-aminobenzyloxycarbonyl (mc-vc-PAB)) attached to the small molecule anti-mitotic agent monomethyl auristatin E (MMAE). In some embodiments, the anti-cMET pI-I-ADCs disclosed herein drive responses for the majority of cMET+ / cMET-cxprcssing and / or cMET- overexpressing NSCLC patients, even those whose tumors express lower levels of cMET than those treatable with current cMET-targeted therapies.

[0137] The anti-cMET pH-ADCs of the present disclosure encompass, for example, any antibody that comprises a light chain comprising the VL-CDRs SVSSSVSSIHLH (SEQ ID NO: 239), HTSNLAS (SEQ ID NO: 240), and QVYSGYPLT (SEQ ID NO: 241); and a heavy chain comprising the VH-CDRsAttorney Docket No. 45395-0071WO1GYTFTDYYMH (SEQ ID NO: 236), RVNPNRRGTTYNQKFEG (SEQ ID NO: 237), and ARANWLDY (SEQ ID NO: 238).[0138| MYTX-011 is an anti-cMET pH-ADC comprising a triple hinge (TH) IgGl format and a vcMMAE linker-toxin, complementarity determining regions (CDRs) comprising the VH CDR 1, 2. and 3 sequences at set forth in SEQ ID NO: 236 (GYTFTDYYMH), SEQ ID NO: 237 (RVNPNRRGTTYNQKFEG), and SEQ ID NO: 238 (ARANWLDY), respectively, and the VL CDR 1. 2, and 3 sequences as set forth in SEQ ID NO: 239 (SVSSSVSSIHLH), SEQ ID NO: 240 (HTSNLAS). and SEQ ID NO: 241 (QVYSGYPLT). respectively, which mediate the pH-dependent binding. MYTX-011 comprises site-specific conjugation of the linker-toxin at an engineered cysteine residue (i.e., a ‘‘V205C substitution”), which results in a drug-to-antibody ratio (DAR) of 2 (Shen el al., Nature Biotechnology Vol 30 No. 2 Feb 2012, and US 20220281984 Al) (FIG. 1A presents a schematic; vcMMAE = mc-vc-PAB-MMAE. CAS No. 646502-53-6). The complete heavy chain variable domain (VH) and light chain variable domain (VL) sequences of the antibody component of MYTX- 011 (i.e., Q397) are as set forth in SEQ ID NO: 1 and SEQ ID NO: 16, respectively, and the entire Q397 heavy chain (HC) and light chain (EC) sequences comprise the amino acid sequences as set forth in SEQ ID NO: 75 and SEQ ID NO: 82, respectively. The entire “Q397noV205C” heavy chain (HC) and light chain (LC) sequences comprise the ammo acid sequences as set forth in SEQ ID NO: 75 and SEQ ID NO: 81, respectively. Preclinical data indicate that MYTX-01 J may be applied to a variety' of cMET-positive / cMET-expressing and / or cMET -overexpressing cancers, including NSCLC. As a non-limiting example attesting to the safety of MYTX-011, two doses administered once every three weeks (Q3W) in cynomolgus monkeys resulted in no MYTX-011 -related cardiovascular, respiratory', or central nervous system effects.[0139 J Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims.BRIEF DESCRIPTION OF THE FIGURES

[0140] Many aspects of the present disclosure can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the present disclosure. Moreover, in the drawings, like reference numerals designate corresponding parts throughout the several views.[01411 FIG, 1A presents a schematic diagram of MYTX-011, including a closeup of the vcMMAE (mc-vc-PAB-MMAE) linker-drug, and FIGs, IB to IE present binding and internalization data for anti-cMET pH-Abs according to this disclosure.

[0142] FIG. IB is a graph showing percent dissociation of pH-dependent anti-cMET mAbs from human cMET at pH 5.4 measured using BLI. Anti-cMET mAbs were immobilized on AHC sensors, associated with recombinant human cMET at pH 7.4, and allowed to dissociate at pH.4. The inverse of the dissociation values was calculated by normalizing maximum response to one across all samples, taking the inverse of this value, and reporting it as a percentage. Greyscale traces represent different anti-cMET m. Ab variantsAttorney Docket No. 45395-0071WO1

[0143] FIG. 1C is a graph showing fold increase in internalization of mAh variants and MYTX-011 mAh (each “pH-Abs”) over non-pH engineered parent inAb in cMET+ Detroit-562 cancer cells.

[0144] FIG. ID is an Octet plot showing pH-dependent binding of MYTX-011 as measured by BLI. MYTX-011 was immobilized on an AHC sensor and tested for binding to human cMET under two conditions: association and dissociation at pH 7.4 (darker grey) or association at pH 7.4 and dissociation at pH 5.4 (light grey).

[0145] FIG. IE is a graph illustrating the internalization of MYTX-011 in NC1-H1975 ceils. MYTX-011 was incubated with pHrodo reagent for 30 rain and the complex added to NCI-H1975 ceils and incubated at 37°C for 24 hours. Fold change was measured by subtracting the IgG control MFI from the MYTX-011 and parent ADC MFI and calculating the ratio of their differences.

[0146] FIG. 2 presents graphs showing the distribution of EBC-1 ceils in Sub-Gl. Gl. S, and G2-M Phases after treatment with MYTX-011. MMAE = Monometbyl auri statin E; RC5-ADC = non-binding control

[0147] FIG. 3 is a graph showing cell proliferation (% viability) of NCI-H441 ceils after treatment with Q397-noV205C. Individual data points represent duplicate wells and bars represent the mean of the two data points. HGF::::positive control, hepatocyte growth factor; RC1 ~ comparative Ab having variable regions matching those of telisotuzumab; RC2 = comparative Ab having variable regions matching those of emibetuzuraab; RC3 = comparative Ab having vanable regions matching the 5D5 anti -human cMET antibody; Q397-noV205C = Q397 with V at position 98 of the polypeptide sequence encoding its light chain constant domain (i.e.. SEQ ID NO: 157); Q397 ~ the anti -cMET IgG antibody component of MYTX-011. Accordingly, the term “noV205C” means that tire antibody has a valine and not a cysteine at amino acid position 98 of its light chain constant domain sequence.

[0148] FIG. 4 presents a graph showing the fold change in phosphorylation of ERK.1 / 2 and Aktl in NCI- H441 cells after treatment with Q397-noV205C.

[0149] FIG. 5A presents representative micrographs showing cMET-specific antibody staining of sections of cMET+ xenograft tumors. Panels A-D: anti-cMET antibody staining (clone SP44) of tumors from H1650, H1975, H1373, and EBC-l xenograft mouse models, respectively. Panels E-H show hematoxylin and eosin (H & E) staining of the same xenograft ti sues.

[0150] FIG. 5B presents additional micrographs. Panels (A-E): SP44 IVD staining of 3 biological replicate tumors from NCT-H1650, NCI-H2I22, NCI-H1373, NCI-H1975, and EBC-1 xenograft mouse models, respectively. Lower panels (F-J) show the representative H & E staining of tumors from NCI-H1650, NCI- I-12122, NCI-H1373, NCI-H1975, and EBC-1 xenograft mouse models, respectively. Scale bar = 50 pm.

[0151] FIGs. 6A-6D present graphs showing tumor volume (TV) in EBC-1 tumor-bearing mice treated with MYTX-011. Panels A & B; Median TV curves for pilot efficacy and dose titration studies, respectively. Panels C & D: TV data corresponding to individual mice

[0152] FIGs. 7 A & 7B present graphs showing survival in EBC 1 tumor-bearing mice treated with MYTX- 011 in the pilot efficacy study (A) and the dose titration study (B).Attorney Docket No. 45395-0071WO1

[0153] FIGs. 8A-8D present graphs showing TV in Hl 975 tumor-bearing mice treated with MYTX-011 Panels A & B: Median tumor growth curves for pilot efficacy and dose titration studies, respectively. C & D: Tumor volume data corresponding to individual mice, n==8 mice per group for all groups except n==:7 for the MYTX-011 4mg / kg group.

[0154] FIGs. 9A & 9B present graphs showing the effect of MYTX-011 on II 1975 mouse survival |0155] FIGs. 10A-10D present graphs showing TV in H1373 treated with MYTX-011.

[0156] FIGs. 11A «& 11B present graphs showing the impact of MYTX-011 on H1373 mouse survival.

[0157] FIG. 12 presents a graph showing median TV (mm?) for the indicated days after administration of test articles (including MYTX-011) to CTG-1353 mice and a representative micrograph showing cMET staining. For each of FIGs. 12-15, the following abbreviations apply: RC5-ADC RC5-ADC-(DAR2); vehicle control == PBS: and TV = tumor volume.

[0158] FIG. 13A presents a graph showing median TV (mm’) for the indicated days after administration of test articles to CTG-3414 mice.

[0159] FIG. 13B presents micrographs showing the levels of cMET overexpression in CTG-3413 tumors. Die middle image is of a tumor tissue section exhibiting both regions of high levels of cMET overexpression and low levels of cMET positivity, and the top and bottom images are magnified views of the left and right rectangular insets, respectively. Images and insets are representative of cMET IHC demonstrating heterogeneous expression of cMET in CTG-3414 PDX. Scale Bar= 50 pm.

[0160] FIG. 14 presents a graph showing median TV (mm’) for the indicated days after administration of test articles to CTG-2669 mice and a micrograph showing cMET staining.

[0161] FIG. 15A presents a graph showing median TV (mm3) for the indicated days after administration of test articles to CTG-2533 mice and a micrograph showing cMET staining

[0162] FIG. 15B presents a graph showing mean TV (mm’) for the indicated days after administration of test articles to CTG-2082, a PDX model negative for cMET expression.

[0163] FIG. 16 presents micrographs of cMET-stained sections from cMET low H2122 tumors.

[0014] FIG. 17 presents a graphical overlay of mean (*SD) total mAh and free MMAE after a single IV dose of MYTX-011 at 2.7 mg / kg to female and males cynomolgus monkeys.

[0165] FIG. 18 presents a graphical overlay of mean MYTX-011, total mAb. and free MMAE multiple IV doses of MYTX-011 at 6, 12, and 18 mg / kg to cynomolgus monkeys.

[0166] FIG. 19 presents graphs showing average MYTX-011 and total mAb exposure after multiple IV doses of MYTX-011 in male and female cynomolgus monkeys (6, 12, and 18 mg / kg).

[0167] FIG. 20 presents graphs showing mean ADC after multiple IV doses of MYTX-011 in male and female cynomolgus monkeys (6, 12. and 18 mg / kg).

[0168] FIG. 21 presents graphs showing tumor volume in NCI-H2122 tumor-bearing mice treated with MYTX-011 and the indicated test articles. A & B: Median tumor growth curves for single-dose and repeat¬ dose efficacy studies, respectively. C& D: Tumor volume data corresponding to individual mice.Attorney Docket No. 45395-0071WO1Abbreviations: RC6-ADC= RC6-ADC-(DAR3.7); RC1-ADC = RC1-ADC-(DAR3. O1); RC5-ADC = RC5-ADC-(DAR1.96), Vehicle control:::PBS. For single-dose efficacy study n:::7 mice / group, for repeat dose efficacy study n::;:8 mice / group.

[0169] FIG. 22 presents graphs showing survival in NCI-H2122 tumor-bearing mice treated with MYTX- 011 Panels A & B: Survival curves for single-dose and repeat dose efficacy studies, respectively.101701 FIG. 23A shows representative images from NC1-H1975 cells treated with for 24 hours with mAbs conjugated with a red pH-sensitive dye. Images are from two independent experiments (N=4 fields of views (FO V) / expe riment).

[0171] FIG. 23B reports the quantification of the images in A (i.e., the time course of mAb uptake by live cell imaging in NCI-H1975 cells). MYTX-011 mAb (filled circles), parental mAb (open triangles), non¬ binding IgG (open squares), and untreated (X).

[0172] FIG. 23C presents representative fluorescence images of NCI-H1975 cells expressing the lysosomal marker LAMP1-RFP treated with AF488-conjugated MYTX-011 or parent mAb Insets show the magnification of the regions where co-localization occurs. These fluorescent images demonstrate the delivery of the mAbs to LAMP1+ organelles (e.g., lysosomes).

[0173] FIG. 23D presents a graph showing the co-localization % of LAMP1-RFP and mAbs-AF488 measured at different time point.

[0014] FIG. 23E presents a graph showing single lysosome intensity of fluorescent-conjugated mAbs (i.e., the image quantitation of LAMP-1 associated mAbs). Statistical comparisons of data were performed using the Kruskal-Wallis test (ns: not significant, *<0.05, **<0.01, ****<0.0001).

[0175] FIG. 24A presents a graph showing the log IC50 values (mg / mL) of MYTX-011, a non-pH-dependent parent ADC (non-pH-ADC control), and a non-binding ADC for 62 different cancer cell lines. Statistical comparisons were performed using one-way ANOVA + Tukey’s post-hoc test. **** < 0 0001

[0176] FIG. 24B presents a graph showing the max killing (%).

[0177] FIG. 24C presents a graph showing a correlation between the in vitro potency of MYTX-011 and both cMET mRNA and protein expression in cancer cell lines (Spearman’s r [IC50 vs Protein]: -0.7; r [IC50 vs RNA]: -0.52).[01781 FIG. 24D presents a waterfall plot representing the relationship between cMET expression and sensitivity to the treatment of the 62 cancer cell lines.

[0179] FIG. 24E presents a dot plot showing the influence of cell-line inherent MMAE sensitivity on ADC cytotoxicity. Data were compared using Kruskal-Wallis test; ns: not significant, ***<0.001.

[0180] FIG. 24F is a plot showing the distribution of 1C50 values of MYTX-011 for the indicated ceil lines.

[0181] FIG.25A presents a graph showing tumor volume in head & neck cancer ceil line Detroit-562 tumor¬ bearing mice treated with MYTX-011 (6 mg / kg body weight; solid squares), non-targeting control ADC (6 mg, 'kg body weight; solid circles), or vehicle control (open circles)

[0182] FIG. 25B presents a graph showing tumor volume in head & neck cancer celi line KYSE-150 tumor-Attorney Docket No. 45395-0071WO1bearing mice treated with MYTX-011 (6 mg / kg body weight; solid squares), non-targeting control ADC (6 mg / kg body weight, solid circles), or vehicle control (open circles).[0183| FIG. 25C presents a graph showing tumor volume in esophageal cancer cell line FaDu tumor-bearing mice treated with MYTX-011 (6 mg / kg body weight: solid squares), non-targeting control ADC (6 mg / kg body weight; solid circles), or vehicle control (open circles).|0184] FIG. 26A presents a graph showing tumor volume in gastric cancer cell line NUGC-4 tumor-bearing mice treated with MYTX-011 (6 mg / kg body weight; solid squares), non-targeting control ADC (6 mg / kg body weight; solid circles), or vehicle control (open circles).[0185 [ FIG. 26B presents a graph showing tumor volume in gastric cancer ceil line SNU-16 tumor-bearing mice treated with MYTX-011 (6 mg / kg body weight; solid squares), non-targeting control ADC (6 mg / kg body weight; solid circles), or vehicle control (open circles).

[0186] FIG. 27 presents an overview of the clinical trial protocol.

[0187] FIG. 28 presents the Part 1 dose escalation schema.

[0188] FIG. 29 presents a graph showing the concentrations of total MYTX-011 and total MYTX-011 mAh.

[0189] FIG. 30 presents a graph showing the concentration of unconjugated MMAE.

[0190] FIG. 31A presents confocal images revealing the distinctive endosomal distributions of pH- engineered anti-cMET antibody MYT6878 compared wdth its non-pH-engineered parent antibody MYT6876.

[0191] FIG. 31B provides a visual framew ork for understanding how the confocal images were evaluated to assign luminal or membrane localization to each tested antibody.

[0192] FIG. 31C provides live cell imaging of Rab5-HaioTag transfected EBC-1 cells confirms that MYTX-011 dissociates from cMET in the acidic lumen of early endosomes (EEs), in contrast to the parent non-pH- engineered antibody

[0193] FIG. 31D is a graph presenting the statistical analysis of the results in in FIG 31C and showing substantially enhanced luminal localization of the pH-engineered MYTX-011 mAb relative to its non¬ engineered parent mAb.

[0194] FIG. 31E FateControl™ engineering allow s MYTX-011 mAb to dissociate from cMET at low pH in comparison to parent mAb as measured by binding on NCI-H1975 cells.

[0195] FIG. 31F is a model for the mechanism of increased uptake of MYTX-011 in cMET+ tumor cells (created using BioRender).

[0196] FIG. 31G Confocal microscopy of NCI-H1 75 cells expressing LAMP1-RFP shows higher lysosomal accumulation of AF-488 labelled MYTX-011 mAb over parent mAb

[0197] FIG. 3111 The fraction of mAbs trafficked to recycling endosomes (REs) was assessed in EBC-1 cells by measuring the colocalization between AF-488-labeled mAbs and the recycling endosome markers Rab4 or Rabi 1. Ns: not significant: **<0.01: ****<0.0001; ND: Binding too low to fit using GraphPad Prism.

[0198] FIG. 32A is a graph showing efficacy of a single dose MYTX-011 in CTG-3414 PDX.

[0199] FIG. 32B is a graph showing efficacy of a single dose MYTX-011 in NCI-H1975 CDX. FIGs. 32AAttorney Docket No. 45395-0071WO1and 32B demonstrate MYTX-011 is active in NSCLC CDX models harboring EGFR mutations

[0200] FIG. 33A is a graph showing the efficacy of repeated dosing of MYTX-011 in the NCI-H2122 CDX mouse model.

[0201] FIG. 33B is a graph showing the efficacy of single dose MYTX-011 in the NCI-H1373 CDX mouse model FIGs. 33 A and 33B demonstrate MYTX-011 is active in NSCLC CDX models harboring KRAS mutations.

[0202] FIG.34A are graphs showing the efficacy and KM survival plot of single dose MYTX-011 in Hs746T gastric cancer CDX either administered alone or in combination with MET TKIs.

[0203] FIG. 34B are graphs showing the efficacy and KM survival plot, of single dose MYTX-011 in MET TKI sensitive LU-01-1375 NSCLC PDX when administered alone or in combination with MET TKIs.

[0204] FIG. 34C are graphs showing the efficacy and KM plot of single dose MYTX-011 in CTG-2669 NSCLC PDX. For each of FIG. 34 A to 34C, MET TKI dosages were determined based on prior available data from literature or contract research organization (CRO) partners. *= P value <0.05; **= P value <0.01; ***= P value <0.001[02051 FIG. 35 are graphs showing the efficacy and KM survival plot of single dose MYTX-011 in LU-01- 1476 PDX either administered alone or in combination with MET TKI. **= P value <0.01; ***= P value <0001

[0206] FIG. 36 is a table summarizing the activity of MYTX-011 across a wide range of human tumor xenografts with various histotypes, mutation profiles and levels of cMET expression.

[0207] FIG. 37 presents an overview of the Kis-MET-01 clinical trial protocol as of the April 24, 202.5, clinical data cutoff.

[0208] FIG. 38 is a table showing the baseline characteristics of patients who received >4.0 mg / kg Q3W.

[0209] FIG. 39 is a graph showing the pharmacokinetics of MYTX-011 at the indicated times post administration of the indicated doses to human subjects

[0210] FIG. 40 is a graph showing the best percentage size change of target lesion(s) from baseline in response-evaluable patients who received 1.0 - 8.3 mg / kg Q3W dose(s) of MYTX-011.

[0211] FIG. 41 is a table showing preliminary anti-tumor activity by cMET, EGFR status, and prior treatment with taxane.

[0212] FIG. 42 is a graph showing best percentage of size change of target lesion(s) from baseline in cMET+ patients who received >4.0 mg / kg Q3W dose(s) of MYTX-011.

[0213] FIG. 43 is a graph showing time on treatment and best response against cMET+ squamous and non- squamous nori-small cell cancer (NSCLC) for patients with dosing from 4.0 - 8.3 mg / kg of MYTX-011.

[0214] FIG. 44 is a table summarizing the safety profile of escalated MYTX-011 dosing (> 4.0 mg / kg).

[0215] Additional advantages of the disclosure will be set. forth m part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the disclosure. The advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointedAttorney Docket No. 45395-0071WO1out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosure, as claimed.DETAILED DESCRIPTION

[0216] Many modifications and other aspects disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific aspects disclosed and that modifications and other aspects are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

[0217] Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim docs not specifically state in the claims or descriptions that the steps arc to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification[0218 All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications arc cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation.

[0219] While aspects of the present disclosure can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only' and one of skill in the art will understand that each aspect of the present disclosure can be described and claimed in any statutory class.

[0220] Priorto describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure.DEFINITIONS

[0221] As used herein, “comprising” is to be interpreted as specifying the presence of the stated features, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by”, “comprising,” “comprises”, “comprised of,” “including,” “includes,” “included.” “involving,” “involves,” “involved.” andAttorney Docket No. 45395-0071WO1“such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms ‘‘consisting essentially of’ and “consisting of.” Similarly, the term “consisting essentially of’ is intended to include examples encompassed by the term “consisting of0222] As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items. Expressions such as “at least one of,” when preceding a list of elements, modify the entire list of elements and do not modify the individual elements of the list.[02231 Reference to “a / an” chemical compound, protein, and antibody each refers to one or more molecules of the chemical compound, protein, and antibody rather than being limited to a single molecule of the chemical compound, protein, and antibody. Furthermore, the one or more molecules may or may not be identical, so long as they fall under the category of the chemical compound, protein, and antibody. Thus, for example, “an” antibody is interpreted to include one or more antibody molecules of the antibody, where the antibody molecules may or may not be identical (e.g., different isotypes and / or different antigen binding sites as may be found in a polyclonal antibody).

[0224] As used herein, the term “antigen-binding protein construct” (“ABPC”) is (i) a single polypeptide that includes at least one ABD or (ii) a complex of two or more polypeptides (e.g., the same or different polypeptides) that together form at least one ABD. Non-limiting examples and aspects of antigen-binding protein constructs are described herein. Addi tional examples and aspects of antigen-binding protein constructs are known in the art.

[0225] A “multi-specific antigen-binding protein construct” is an antigen-binding protein construct that includes two or more different ABDs that collectively specifically bind two or more different epitopes. The two or more different epitopes may be epitopes on the same an tigen or on different antigens. When the differen t epitopes are present on the same antigen, the multi-specific antigen-binding protein construct is called a “multi¬ paratopic antigen-binding protein construct”. In some aspects, the antigen is present on the surface of the cell. In some aspects, a multi-specific antigen-binding protein construct binds two different epitopes (i.e., a “bispecific ABPC”). In some aspects, a multi-specific antigen-binding protein construct binds three different epitopes (i.e., a “trispecific ABPC”).[02261 An “Antigen-Binding Protein” or “ABD” is one or more protein domain(s) (e.g.. formed from ammo acids from a single polypeptide or formed from amino acids from two or more polypeptides (e.g, the same or different polypeptides) that is capable of specifically binding to one or more different antigen(s). In some examples, an ABD can bind to an antigen or epitope with specificity and affinity similar to that of naturally- occurring antibodies. In some embodiments, the ABD can be an antibody or a fragment thereof. In some embodiments, an ABD can include an alternative scaffold. Non-limiting examples of ABDs are described herein Additional examples of ABDs are known tn the art. In some examples, an ABD can bind to a single antigen.0227| The term “antibody” is used herein in its broadest sense and includes certain types of immunoglobulinAttorney Docket No. 45395-0071WO1molecules that include one or more ABDs that specifically bind to an antigen or epitope. An antibody specifically includes, e.g., intact antibodies (e.g., intact immunoglobulins, e.g., human IgG (e.g., IgG 1, IgG2, IgG3, IgG4)), antibody fragments, and multi-specific antibodies. One example of an ABD is an ABD formed by a VH-VL dimer. An antibody also includes a single polypeptide. In some embodiments, the antibody is selected from a VH domain, a VHH domain, a VNAR domain, and a scFv. In some embodiments, the antibody is a BiTe, a (scFv)2, a nanobody, a nanobody-HSA, a DART, a TandAb, a scDiabody, a scDiabody-CH3, scFv-CH-CL-scFv, a HSAbody, scDiabody-HSA, or a tandem-scFv. In some embodiments, the antibody includes two or more polypeptides. In some embodiments, the antibody includes a VHH-scAb, a VHH-Fab, a Dual scFab, a F(ab')2, a diabody, a crossMab, a DAF (two-in-one), a DAF (four-in-one), a DutaMab, a DT- IgG, a knobs-in-holes common light chain, a knobs-in-holes assembly, a charge pair, a Fab-arm exchange, a SEEDbody, a LUZ-Y, a Fcab, a icX-body, an orthogonal Fab, a DVD-IgG. a IgG(H)-scFv, a scFv-(H)IgG, IgG(L)-scFv, scFv-(L)IgG, IgG(L. H)-Fv, IgG(H)-V. V(H)-IgG, IgG(L)-V, V(L)-IgG, KIH IgG-scFab, 2scFv- TgG, IgG-2scFv, scFv4-Ig, Zybody, DVI-IgG, Diabody-CH3, a triple body, a miniantibody, a minibody, a TriBi minibody, scFv-CH3 KIH, Fab-scFv, a F(ab’)2-scFv2, a scFv-KIH, a Fab-scFv-Fc, a tetravalent HCAb, a scDiabody-Fc, a Diabody-Fc, a tandem scFv-Fc, a VHH-Fc, a tandem VHH-Fc, a VHH-Fc KIH, a Fab-VHH-Fc, an Intrabody, a dock and lock, an ImmTAC. an IgG-lgG conjugate, a Cov-X-Body, a scFvl-PEG-scFv2, an Adnectin, a DARPin, a fibronectin, a DEP conjugate, and a PROTAB. Additional examples of an antibody are described herein or known in the art.102281 The phrase '‘endosomal / lysosomal pathway” refers to a network of endosomes (early endosomes, multi-vesicular bodies, late endosomes, and ly sosomes) in tire cytoplasm of a mammalian cell, wherein molecules internalized through cell-mediated internalization processes, e.g.. pinocytosis, micropinocytosis, receptor-mediated endocytosis, and / or phagocytosis, are sorted.

[0229] Once the endosomes in the endosomal / lysosomal pathway are purified or isolated, assays for a target protein (e.g.. an antigen-binding protein construct described herein) can be performed using methods known in the art (ELISA, Western blot, immunofluorescence, and immunoprecipitation followed by an assay for protein concentration), and can be used to determine the concentration or relative level of the target protein in the endosomes. Alternatively, endosomes in the endosomal / lysosomal pathway can be imaged using immunofluorescence microscopy using an detectably-labelled antibody (e.g., a fluorophore-labelled, a dye- labelled, or a GFP-labelled antibody, e g., CellLightTM Early Endosome-GFP) that specifically binds to a characteristic protein present in the endosomes (e.g., EEA1 for early endosomes) and a fluorophore-labelled antibody that specifically binds to the protein of interest (e.g., an antigen-binding protein construct), and the level of lhe target protein in the endosomes can be determined by quantitation of the overlap in the fluorescence emissions of the two different antibodies.

[0230] The phrase “‘endo lysosomal delivery'” refers to rate of accumulation over time or the total accumulation at a specific timepoin t of an an tigen-binding protein construct (e.g., any of the antigen-binding protein constructs described herein) in the endosomal / lysosomal pathway in a mammalian cell (e.g., any of theAttorney Docket No. 45395-0071WO1exemplary target mammalian cells described herein).[0231 [ An exemplary method to calculate the increase in endolysosomal delivery of a pH-engineered ABPC variant as compared to its corresponding starting ABPC from cellular fluorescence data is to measure the ratio of the variant’s mean fluorescence intensity minus the mean fluorescence intensity of a non-binding IgG control, then all divided by the variant’s corresponding starting ABPC’s mean fluorescence intensity minus the mean fluorescence intensity of the IgG control.

[0232] An exemplary assay for measuring endolysosomal delivery of any of the ABPCs described herein include those which involve labeling of an ABPC with a fluorescent dye, followed by incubation of the labeled ABPC with cells and measurement of cellular fluorescence as an indicator of endolysosomal delivery of the ABPC (e.g.. as described generally in Wustoer, Traffic 7(6):699-715, 2006). Alternatively, pH-sensitive dyes which preferentially fluoresce at acidic pH but not neutral pH can be used to label any of the ABPCs described herein, which can then be incubated with cells and the cellular fluorescence measured as an indicator of delivery' of the ABPC into acidic endolysosomal compartments.

[0233] Hie term “population” when used before anoun means two or more of the specific noun. For example, the phrase “a population of cancer cells” means “two or more cancer cells.” Non-limiting examples of cancer ceils are described herein.

[0234] The phrase “cytostatic to a cell” refers to a direct or indirect decrease in the proliferation (cell division) of the cell (e.g., a cancer cell) in vivo or in vitro. When an agent is cytostatic to a cell, the agent can, e.g., directly or indirectly result in cell cycle arrest of the cell (e.g., a cancer cell). In some examples, an agent that is cytostatic to a cell can reduce the number of cells in a population of the cells that are in S phase (as compared to the number of cells in a population of the cells that are in S phase prior to contact with the agent). In some examples, an agent that is cytostatic to a cell can reduce the percentage of the cells in S phase by at least 20%. at least 40%, at least 60%, or at least 80%.

[0235] The phrase “cytotoxic to a cell” refers to the inducement, directly or indirectly, in the death (e.g., necrosis or apoptosis) of the cell (e.g., a mammalian cell, e.g,, a cancer cell).

[0236] “Affinity” refers to the strength of the sum total of non-covalent interactions between an antigen¬ binding site and its binding partner (e.g., an antigen or epitope). Unless indicated otherwise. as used herein, “affinity’’ refers to intrinsic binding affinity, which reflects a 1: 1 interaction between members of an ABD and an antigen or epitope The affinity of a molecule X for its partner Y can be represented by the dissociation equilibrium constant (KD). Affinity' can be measured by' common methods known in the art, including those described herein. Affinity can be determined, for example, using surface plasmon resonance (SPR) technology (e.g., B1ACORE®) or biolayer interferometry (e.g., FORTEBIO®).

[0237] The term “epitope” means a portion of an antigen that is specifically bound by an ABD through a set of physical interactions between: (i) all monomers (e.g, individual amino acid residues, sugar side chains, and post-translationally modified amino acid residues) on the portion of the ABD that specifically binds the antigen and (ii) all monomers (e.g. individual amino acid residues, sugar side chains, post-translationally modifiedAttorney Docket No. 45395-0071WO1amino acid residues) on the portion of the antigen that is specifically bound by the ABD. Epitopes can, e.g., consist of surface-accessible amino acid residues, sugar side chains, phosphorylated amino acid residues, methylated amino acid residues, and / or acetylated amino acid residues and may have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that binding to the former, but not the latter, may be lost in the presence of denaturing solvents. In some embodiments, an epitope is defined by a linear ammo acid sequence of at least about 3 to 6 amino acids, or about 10 to 15 amino acids. In some embodiments, an epitope refers to a portion of a full-length protein or a portion thereof that is defined by a three-dimensional structure (e.g., protein folding). In some embodiments, an epitope is defined by a discontinuous amino acid sequence that is brought together via protein folding. In some embodiments, an epitope is defined by a discontinuous ammo acid sequence that is brought together by quaternary structure (e.g., a cleft formed by the interaction of two different polypeptide chains). The amino acid sequences between the residues that define the epitope may not be critical to three-dimensional structure of the epitope. A conformational epitope may be determined and screened using assay s that compare binding of antigen -binding protein construct to a denatured version of the antigen, such that a linear epitope is generated. An epitope may include amino acid residues that are directly involved m the binding, and other amino acid residues, which are not directly involved in the binding.

[0238] Methods for identifying an epitope to which an ABD specifically' binds are known in the art. e.g, structure-based analysis (e.g. X-ray crystallography, NMR, and / or electron microscopy) (e.g. on the antigen and / or the antigen-ABD complex) and / or mutagenesis-based analysis (e.g. alanine scanning mutagenesis, glycine scanning mutagenesis, and homology scanning mutagenesis) wherein mutants are measured in a binding assay with a binding partner, many' of which are known in the art.

[0239] The term “paratope” means a portion of an ABD that specifically binds to an antigen through a set of physical interactions between: (i) all monomers (e g. individual amino acid residues, sugar side chains, posttranslationally modified amino acid residues) on the portion of the ABD that specifically binds tlie antigen and (ii) all monomers (e.g. individual ammo acid residues, sugar side chains, posttranslationally modified amino acid residues) on the portion of the antigen that is specifically bound by the ABD. Paratopes can, e.g., consist of surface-accessible amino acid residues and may have specific three-dimensional structural characteristics, as well as specific charge characteristics. In some embodiments, a paratope refers to a portion of a full-length ABD or a portion thereofthat is defined by a three-dimensional structure (eg, protein folding). In some embodiments, a paratope is defined by a discontinuous amino acid sequence that is brought together via protein folding. In some embodiments, an epitope is defined by a discontinuous amino acid sequence that is brought together by quaternary structure (e.g.. a cleft formed by the interaction of two different polypeptide chains). The amino acid sequences between the residues that define the paratope may not be critical to three- dimensional structure of the paratope. A paratope may comprise amino acid residues that are directly involved in the binding, and other amino acid residues, which are not directly involved in the binding.102401 Methods for identifying a paratope to which an ABD specifically binds are known in the art, e.g..Attorney Docket No. 45395-0071WO1structure-based analysis (e.g., X-ray crystallography, NMR, and / or electron microscopy) (e.g. on the ABD, and / or the ABD-antigen complex), and / or mutagenesis-based analysis (e.g., alanine scanning mutagenesis, glycine scanning mutagenesis, and homology scanning mutagenesis) wherein mutants are measured in a binding assay with a binding partner, many of which are known in the art.

[0241] The phrase "present on the surface of a mammalian cell” means ( 1 ) an antigen that ph sically attached to or at least partially embedded in the plasma membrane of a mammalian cell (e.g., a transmembrane protein, a peripheral membrane protein, a lipid-anchored protein (e.g., a GPI-anchor), an N-myristoylated protein, or a S-palmitoylated protein) or (2) an antigen that is stably bound to its cognate receptor, where the cognate receptor is physically attached to the plasma membrane of a mammalian cell (e g., a ligand bound to its cognate receptor, where the cognate receptor is physically attached to the plasma membrane). Non-limiting methods lor determining the presence of antigen on the surface of a mammalian cell include fluorescence -activated cell sorting (FACS), immunohistochemistry', cell-fractionation assays and Western blotting.

[0242] The phrase “control ABPC” or “control antigen-binding protein construct’’ means (i) an ABPC that is capable of specifically binding to cMET or an epitope of cMET presented on the surface of a mammalian cell (e.g., a target mammalian cell), where one or both of the following is true: (a) the dissociation rate of the first ABD at a pH of -4.0 to -6.5 is no more than 3-fold faster than the dissociation rate at a pH of -7.0— 8.0; or (b) the dissociation constant (KD) of the first ABD at a pH of -4.0 — 6.5 is no more than 3-fold greater than the KD at a pH of -7.0 — 8.0.

[0243] The term “extracellular space” means the liquid exterior to the plasma membrane of a mammalian cell.

[0244] The term “endolysosomal space” means the fluid encapsulated by the vesicles and organelles that make-up the endosomal / lysosomal pathway in a mammalian cell.

[0245] The phrase “a reduced level” or “a decreased level” can be a reduction or decrease of at least a 1% (e.g., >2%, >4%, >6%, >8%, >10%, >12%, >14%, >16%, >18%, >20%, >22%. >24%, >26%, >30%. >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, >95%, or >99%) reduction as compared to a reference level or value.[0246[ The term “cell killing potency” refers to the ability of an agent to induce, directly or indirectly, the apoptosis and / or necrosis of a mammalian cell, measured as a rate overtime or at a relevant timepoint. Methods for determining the cell killing potency' of a cell are known in the art (e.g, trypan blue staining, microscopy, fluorescence-assisted cell sorting, and assays to detect markers of apoptosis (e.g., Annexin V)). In non-limiting examples, cell killing potency can be measured, e.g., by cell killing at a single concentration of an agent, by the IC50 of the agent, or by the ratio of an agent's dissociation constant KD on mammalian cells divided by its IC50. In some non-limiting examples, the IC50s and / or the KD ratios described herein are compared to those of a control ABPC, and. optionally, demonstrate that the ABPCs described herein have a higher cell killing potency as compared to the control ABPC[0247| The term “toxin liberation” refers to the ability of a mammalian cell (e.g., a non-cancerousAttorney Docket No. 45395-0071WO1mammalian cell or a cancer cell) to internalize (e.g., via pinocytosis and / or receptor-mediated endocytosis) any of the ABPCs described herein (e.g., any of ABPCs or control ABPCs described herein) that are conjugated to a toxin, and subsequently release the toxin conjugated to the ABPC. measured as a rate over time or at a specific timepoint. Toxin liberation can be assessed using a variety of different exemplary assays, e.g., ELISA, immunofluorescence, cell killing assays, cell cycle arrest, assays, DNA damage assays, mass spectrometry, HPLC, and / or an isotope-labeled toxin.

[0248] The phrase “target cell” or “target mammalian cell” or “mammalian target cell” means a mammalian cell that has at least one cMET present on its surface. In some examples, a mammalian target cell can be a cancer cell. In some embodiments of a target mammalian cell can have a total of about the following (each i about 10%); I-10E6, 1-9E6, 1-8E6, 1-7E6, 1-6E6. 1-5E6, 1-4E6, 1-3E6, 1-2E6, I-IE6, 1-800.000, 1-600,000.1-400.000. 1-200,000, 1-100.000. 1-80.000. 1-80,000, 1-75,000, 1-70,000, 1-65,000, 1-60,000. 1-55,000, 1-50.000, 1-45,000, 1-40,000, 1-35,000, 1-30,000, 1-25.000. 1-20,000. 1-15,000, 1-10,000, 1-7,500, 1-5,000, 1-4,000, 1-3,000, 1-2,000, 1-1,000, 1-500. 1-100, 1-50, or 1-10. or any of the ranges of numbers recited in US 2022 / 0281984, which is incorporated by reference herein in its entirety) of the cMET present on the plasma membrane of the target mammalian cell. Current IHC tests have an approximate threshold of detection of between about 1,000 and about 5,000 cMET molecules per cell.

[0249] The phrase “antigen density” means the number of cMET present on the surface of a target mammalian cell or the a verage number of cMET on the surface of a population of particular type of target mammalian cells. It can be measured, e.g., using the Quantibright bead kit or radiolabel {e.g., BD Biosciences PE Phycoerythrin Fluorescence Quantitation Kit, catalog 4340495).[0250J The phrase “amino acid substituted with a histidine” means the substitution of an ammo acid residue that is not histidine in a reference polypeptide sequence with a histidine. Non-limiting methods for substituting an amino acid residue in a reference polypeptide with a histidine are described herein. Additional methods for substituting an amino acid residue in a reference polypeptide with a histidine are known in the art.

[0251] The phrase “amino acid substituted with an alanine” means the substitution of an amino acid residue that is a histidine in a reference polypeptide sequence with an alanine. Non-limiting methods for substituting a histidine in a reference polypeptide with an alanine are described herein. Additional methods for substituting a histidine in a reference polypeptide with an alanine are known in the art.

[0252] As used herein, the terms “treat”, “treatment”, and “treating” refer to the reduction or amelioration of the progression, seventy, and / or duration of a disease or condition resulting from the ad inistration of one or more therapies. Treating may be determined by assessing whether there has been a decrease, alleviation and / or mitigation of one or more symptoms associated with the underlying disorder such that an improvement is observed with the patient, despite that the patient may still be afflicted with the underlying disorder. The term “treating” includes both managing and ameliorating the disease. The terms “manage”, “managing”, and “management” refer to the beneficial effects that a subject derives from a therapy which does not necessarily result m a cure of the disease.Attorney Docket No. 45395-0071WO1

[0253] Treating includes effective cancer treatment with an effective amount of a therapeutic agent (e g., an anti-cMET pH-ADC, e.g., MYTX-011) or combination of therapeutic agents. Treating herein includes, inter alia, adjuvant therapy, neoadjuvant therapy, metastatic cancer therapy, and non-metastatic cancer therapy (e.g., locally advanced cancer therapy). The treatment may be first-line treatment (e.g.. the patient may be naive to prior treatment or may have received prior systemic therapy), or second line, third line, or a later treatment. |0254] The terms ‘‘prevent’; “preventing”, and “prevention” refer to reducing the likelihood of the onset (or recurrence) of a disease, disorder, condition, or associated symptom(s) (e.g.. a cancer).

[0255] As used herein, the term “treatment-related AE” refers to an AE that is judged by an investigator to have occurred as a result of a treatment.[02561 The terms “subject” and “patient” may be used interchangeably. As used herein, in certain embodiments, a subject is a mammal, such as a non-primate (e.g., cow, pig, horse, cat, dog, rat, etc.) or a primate (e g, monkey and human) In specific embodiments, the subject is a human In one embodiment, the subject is a mammal, e.g., a human, diagnosed with a condition or disorder In another embodiment, the subject is a mammal, e.g., a human, at risk of developing a condition or disorder.|0257] “Administer” or “administration” refers to the act of injecting or otherwise physically delivering a substance as it exists outside the body into a patient, such as by mucosal, intradermal, intravenous, intramuscular delivery’, and / or any other method of physical delivery' described herein or known in the art

[0258] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by' one of ordinary' skill in the art to which this invention belongs. Methods and materials arc described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.pH-Antibody Drug Conjugates (pH-ADCs) that Bind to cMET and cMET Overexpressing Cells

[0259] The present disclosure relates to pH-ADCs that bind specifically to human cMET, compositions comprising such pH-ADCs, anti-cMET pFI-antibodics and / or binding fragments (BFs) that can comprise the ADCs, polynucleotides encoding anti-cMET pH-antibodies and / or BFs that comprise such ADCs, host cells and / or expression systems capable of producing the pH-antibodies and / or BFs, methods and compositions useful for making the pH-antibodies. BFs, and pH-ADCs, and a variety of methods of us of such pH-ADCs in the treatment of cancer.

[0260] Data provided herein demonstrate that anti-cMET pH-antibody drug conjugates (“pH-ADCs”) exhibit potent antitumor effects, against cMET i solid tumors, especially those with an IHC-score of 2+ and 3+ when measured by immunohistochemistry with the SP44 antibody. In particular, the disclosed anti -cMET pH-ADCs demonstrated efficacy against tumors characterized by mutations not well -addressed by prior ADCs targetingAttorney Docket No. 45395-0071WO1cMET (see e.g., Example 5). In some embodiments, the anti-cMET pH-ADCs are effective against even 1+ cMET+, including cMET-overexpressing tumors (see e.g.. Example 11). In other embodiments, the anti-cMET pH-ADCs are effective against tumors having heterogeneous levels of cMET overexpression (see e.g., Example 6).

[0261] The term “cMET MYTX-ADC staining procedure” is used throughout to describe the evaluation of tissue / tumor cMET levels, and is described in Example 11. An “H-score”. “IHC score” or other suitable scoring system may be used to express the staining results. In particular embodiments, the CONFIRM™ anti-Total c- MET (SP44) Rabbit Monoclonal Primary Antibody system (Ventana Medical) is used in the practice of this staining procedure. In other embodiments, other approved tests, existing now or later developed, may be used to evaluate the level of cMET expression.

[0262] Utilization of the H-score approach facilitates the determination of cMET-t intensity variation and percent positivity within a given tumor type and across tumor types. It also permits the determination of thresholds for positive staining. And as the skilled person will appreciate, H-scores may be determined manually (e g. by a pathologist), or by software -enabled, automated image processing and analysis. Briefly, multiple sections of tissue (e.g. tumor) are assessed to provide the overall percentage of cells (0-100) in a tumor having staining intensities ranging from 0-3+. It is important to note that some tumors may be homogeneous (e.g. +2 throughout), whereas others may be heterogeneous (e.g. patches of +1 and +3). The staining procedure shows cMET protein expression both in the surface of the cell as well as in the cytoplasm. Fixed fields of —100 cells are visually inspected and a staining score is assigned to each cell in view' of surface staining as follows: 0 - none; 1+ weak; 2~t = moderate; 3+ - strong.[0263 J H-score calculation. H-score = 1 * (% 1+ cells) + 2 * (% 2+ cells) 13 * (% 3+ cells).[0264 § Tumors may also be assigned an IHC score oft), 1 +, 2+, or 3+, which is distinct from H-score values. While the H-score refers to a weighted sum of the staining intensity for all individual cells that were inspected and scored, a tumor IHC score refers to the overall staining of a specific area within a tumor sample. For example, a tumor having an H-Score of 150 could be comprised of pluralities of 1 + and 2+ cells (e.g., 20% 1+ cells and 65% 2+ cells), and given portions of the tumor might have a tumor IHC score of either 1 + or 2+.[02651 As used herein, IHC 0 is assigned in cases where no cell in a fixed field is stained; IHC 1+ where overall staining is low; IHC 2+ where most cells are moderately stained; and IHC 3+ where most cells are strongly stained. In other embodiments. IHC 2+ is assigned if at least 15% of the cells in a fixed field are moderately stained and IHC 3+ is assigned if at least 15% of the cells in a fixed field are strongly stained.

[0266] In another embodiment, “low” tumor cMET expression refers to tumors with cMET expression of 1 + scored by a relevant cMET IHC assay in at least 15%, 25%, 50%, or 75% of tumor cells; “intermediate” tumor cMET overexpression refers to tumors with cMET overexpression of 2+ scored by a relevant cMET IHC assay in at least 15%, 25%, 50%, or 75% of tumor cells; and “high” tumor cMET overexpression refers to tumors with cMET overexpression of 3+ scored by a relevant cMET IHC assay in at least 15%, 25%, 50%, or 75% of tumor cells.Attorney Docket No. 45395-0071WO1

[0267] As used herein, an IHC score of 1+ is equivalent to an H-score between 50 and 149, an IHC score of 2+ is equivalent to an H-score of between 150 and 224, and an IHC score of 3+ is equivalent to an H-score of >225. In another embodiment, an IHC score of 1+ is equivalent to an H-score > about 50 to 149.[0268 J Accordingly, in a first aspect, this disclosure provides ADCs that bind cMET specifically and in a pH-dependent manner (“anti-cMET pH-ADCs”). The anti-cMET pH-ADCs comprise cytotoxic and / or cytostatic agents conjugated by way of linkers to an antigen binding moiety (ABM) that binds cMET specifically, in a pH-dependent manner. In the case of MYTX-0I1, the ABM (Q397) specifically binds the Sema domain of human cMET well at physiologic pH, but substantially less well at acidic pH (e.g. in the lysosomal environment). In other anti-cMET pH-ADCs, the antigen binding moiety may be any other moiety capable of specifically binding cMET at physiologic but not acidic pH. In some embodiments, the ABM is tin antibody or an ABF.

[0269] In a particular embodiment, the cytotoxic and / or cytostatic component of the anti-cMET pH-ADC is a cell-permeating antimitotic agent, such as, for example, an auristatin. Specific examples of cell -permeating auristatins include, but are not limited to, dolastatin-10 and monomethyl auristatin E (“MMAE’’).

[0270] As known by those of skill in the art, antibodies and ABMs consist of modules, for example, VH CDRs. VH domains. VL CDRs and VL domains. Throughout this disclosure, it is intended that each and every particular embodiments) may be combined with each and every other particular embodiments) as though each combination were expressly described one at a time. As a non-limi ting example, each vanant of a “VH CDR1” may be combined with each variant of a corresponding “VH CDR2” or “VH CDR3”, and / or each variant of a “VL CDR1’-may be combined with each variant of a corresponding “VL CDR2” or “VL CDR3 ’, and so on.

[0271] Analogously, the pH-ADCs disclosed herein also consist of modules, for example, antibodies (also shortened to “A"’). linkers (“L”), and cytotoxic and / or cytostatic agents (“D”), from which the disclosed pH- ADCs are built. As with the Ab and ABM modules, all particular embodiments may be combined with each other as though each particular combination were expressly described one at a time.

[0272] Moreover, the pH-ADCs described herein may be provided in the form of salts, for example but not solely, salts that are pharmaceutically acceptable. As is appreciated by the skilled artisan, suitably acidic and / or basic functional groups may be reacted with inorganic bases and / or acids to form an acceptable salt. Alternatively or additionally, inherently’ charged compounds may be reacted with suitable counter ions (e.g. halide) to produce a salt.

[0273] Common acids for forming addition salts include inorganic acids (e.g. HC1, HBr, H2SO4, HI, etc.) and organic acids (e.g. para-toluenesulfonic acid, methanesulfonic acid, oxalic acid, para-bromophenyl¬ sulfonic acid, carbonic acid, citric acid, succinic acid, and the like). Common base addition salts include ammonium and alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and other such bases. pH-Antibodies to cMETAttorney Docket No. 45395-0071WO1

[0274] In particular embodiments, the ABP is an antibody or an ABF. As used herein, the term “anti-cMET pH-antibody” or “anti-cMET pH-Ab” refers to an immunoglobulin molecule that binds specifically to cMET in a pH-dependent manner. The anti-cMET pH-Ab has a relatively high affinity for cMET at physiologic pH, yet a substantially lower affinity for cMET at acidic pH, in particular, pH of about 5.4 or less A pH-dependent antibody particularly well-sui ted to deliver payloads (i.e., a pH-dependent ADC) is one that binds well at both physiologic pH and the slightly acidic pH conditions present in a typical tumor microenvironment (TME), but not well at pH 5.4.102751 As the skilled artisan appreciates, antibodies of a certain format comprise heavy chain variable domain (HCVD) CDRs and light chain variable domain (LCVD) CDRs (also called “hypen-ariable" regions). The less variable portions of the HCVD and LCVD are commonly referred to as the framework (FR). Now that applicant has disclosed CDRs that confer such cMET-specific pH-dependent binding, the skilled artisan will appreciate a variety of reasonable and routine FR variations that can be made whilst holding the CDRs constant.102761 Anti-cMET pH-ADCs comprise pH-antibodies generally comprising a heavy chain (HC) comprising a variable region (VH) having three CDRs (VH CDR1, VH CDR2, and VH CDR3). and a light chain (LC) comprising variable region (VL) having three CDRs (VL CDR1, VL CDR2, and VL CDR3). The ammo acid sequences of particular CDRs, VH and VL regions that may be included in ABPs composing the anti-cMET pH-ADCs are provided herein.

[0277] Anti-cMET pH-ADCs may comprise antibody modules consisting of monoclonal, polyclonal, human-engineered, or naturally-modified antibodies, for example but not solely, humanized, chimeric, primatized, SC, and bispecific antibodies, and the like

[0278] Anti-cMET pH-ADCs may comprise full-length antibodies and cMET-binding ABFs that are capable of specifically binding c ET at physiologic but not acidic pH. In some embodiments, the ABF may be a Fab fragment, an Fv fragment, or an scFv fragment.

[0279] In some embodiments, the anti-cMET pH-ADCs comprise bi specific, multi specific, biparatopic, or multiparatopic an tibodies.102801 In some embodiments, the anti-cMET pH-ADCs comprise denvatized antibodies.[02811 In some embodiments, the antic -cMET pH-antibodies or ABFs have been modified to modify at least one non-variable region-mediated effector function (e.g Fc receptor binding, which can impact phagocytosis, opsonization, and / or ADCC).[0282: In some embodiments, the disclosed anti-cMET pH-antibodies can serve more than one purpose. For example, the pH-antibodies may be used for IHC assays of tumor biopsies obtained from patients to whom the disclosed pl I- ADCs have been (or will be) administered. Hie Ventana SP44 clone, and antibodies having comparable properties may be prepared or acquired and the staining procedure modified such that the IHC method has comparable or better diagnostic power as compared with the Ventana assay. Moreover, anti-cMET antibodies other than SP44 may be used for the IHC assay.Attorney Docket No. 45395-0071WO1

[0283] Examples of anti-cMET pH-anti bodies that can be used for diagnostic, theranostic, therapeutic, and / or other purposes include, but are not limited to, antibodies disclosed m US 2022 / 0281984 and WO 2022 / 169975. The complete disclosures of these applications are incorporated herein by reference, including the ammo acid sequences for the CDRs, HCs (entire and variable regions), and LCs (entire and variable regions).

[0284] In other embodiments, the anti-cMET pH-antibodies are administered for treatment purposes, either as components of ADCs, or before / after / concurrently with tire ADCs.MYTX-011 and Related Antibodies for Treatment Purposes

[0285] The anti-cMET pH-ADC is called “MYTX-011 ”, which is an ADC comprised of the cMET-targeting, pH-antibody Q397 conjugated to the small molecule anti-mitotic agent monomethyl axiristatin E (MMAE) via a valine citrulline linker (“maleimidocaproyl-valmecitrulline-p-ammobenzyloxycarbonyr or “mc-vc-PAB”). MYTX-011 binds specifically to tumor cell-surface cMET (at both physiologic and slightly acidic pH), is internalized, and then rapidly releases cMET at acidic pH (e.g.. the pH conditions typical of lysosomes). The MMAE payload is released after the ADC is internalized, either before, during, or after the ADC dissociates from cMET, resulting in inhibition of microtubule function and disruption of essential processes and cell death. And since MMAE is cell-permeable, the internalized MMAE can then diffuse outside of the cell and into other, “bystander” cells. MYTX-011 is cytotoxic to cancer cells expressing high, moderate (intermediate), and low levels (and potentially “ultra-low” levels) of cMET-expression / cMET-overexpression, and demonstrates antitumor activity- cell derived xenograft (CDX) and patient derived xenograft (PD. X) animal models of cancer. As further disclosed herein, MYTX-011 has demonstrated efficacy in human patients harboring cMET- positive NSCLC tumors across a wide range of cMET expression levels, including cMET-low, cMET-intermediate, and cMET-high.

[0286] As of the April 24, 2025 KisMET-01 data cutoff, positive cMET levels (cMET+j are defined as; cMET high (>50% of tumor cells at 3+ staining), cMET intermediate (>25% and <50% of tumor cells at 3+), cMET low- (>25% of tumor cells at 2+ and not meeting criteria for high / mtermediaie); exploratory cMET ultra¬ low (>25% tumor cells at 1+). Staining was assessed using the VENTANA® MET (SP44) assay, recently approved by the FD A (the VENTAN A® MET (SP44) Assay'). And while not yet part of a cMET-t- clinical trial group, preliminary' clinical results suggest MYTX-011 may be effective against tumors having “ultra-low” cMET expression levels.The Antibody Portion of MYTX-011

[0287] “Q397” is a pH-dependent, humanized anti-cMET antibody, whose general structure was disclosed in WO 2022 / 169975 Al. Prior to this, tire heavy chain variable (VH) and light chain variable (VL) regions of Q397 were disclosed in US 2022 / 0281984 (as SEQ ID NO: 146 and SEQ ID NO: 284 of that application, respectively) The disclosures of the foregoing applications are incorporated by reference herein in their entireties. Specifically, Q397 comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 75 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 82. The amino acidAttorney Docket No. 45395-0071WO1sequences for the heavy and light chain variable regions of Q397 are as set forth in SEQ ID NO: 15 and SEQ ID NO: 16, respectively.[0288| Heavy chain of Q397 (andiiQ397iioV205C’’) with triple hinge (underlined), constant domain (11 ALICrZEl )), and vanable heavy chain region (BOLD) (SEQ ID NO: 75):QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMHWVRQAPGQGLEWMGRVNPNRRGTTYNQKFEGRVTMTTD TS TS TAYMELRSLRSDDTAVYYCARANWLDYWGQGTTVTVSS AS TKGPSVFPLAPSSKS TSGGTAALGCL VKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD CHCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY NS TYRVVS VL TVLHQD WLNGKE YKCKVSNKAL PAPIEKTISKAKGQPREPQVYTL PPSREEMTKNQVSL TCP V KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPG

[0289] Light chain of Q397 with constant domain {ITALICIZED), a Cysteine (C) (underlined) at amino acid position 98 of the constant domain, and variable light chain region (BOLD) (SEQ ID NO: 82):DIQMTQSPSSLSASVGDRVTITCSVSSSVSSIHLHWYQQKPGKAPKLLIYHTSNLASGVPSRFSGSGSGTDFT LTISSLQPEDFATYYCQVYSGYPLTFGGGTKVEIKRTVAAPSV'FZFPPSPEeLKSGTASWCLLWFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPCTKSFNRGEC

[0290] Light chain of “Q397-noV205C” with constant domain ITALICIZED). Valine (V) (underlined) at amino acid position 98 of the constant domain, and vanable light chain region (BOLD) (SEQ ID NO: 81):DIQMTQSPSSLSASVGDRVTITCSVSSSVSSIHLHWYQQKPGKAPKLLIYHTSNLASGVPSRFSGSGSGTDFT LTISSLQPEDFATYYCQVYSGYPLTFGGGTKVEIKFTVAAPSVFTFPPSFF£> LKSGTASWCLLWFYPFFAK VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0291] The anti-cMET pH-ADCs of the present disclosure encompass any antibody that comprises a light chain comprising CDR-L1, CDR-L2 and CDR-L3 contained within the amino acid sequence set forth in SEQ ID NO: 16. Namely, the VL CDR sequences are SVSSSVSSIHLH (CDR-LL SEQ ID NO: 239). HTSNLAS (CDR-L2, SEQ ID NO: 2.40). and QVYSGYPLT (CDR-L3, SEQ ID NO: 2.41); and a heavy chain comprising CDR-Hl, CDR-H2 and CDR-H3 contained within the amino acid sequence set forth in SEQ ID NO: 15. Namely, the VH CDR sequences are GYTFTDYYMH (CDR-Hl, SEQ ID NO: 236), RVNPNRRGTTYNQKFEG (CDR-H2, SEQ ID NO: 237), and ARANWLDY (CDR-H3, SEQ ID NO: 238). (02921 Detecting cMET expression typically involves contacting a biological sample with one or more anti- cMET antibody, and detecting whether the sample is positive for cMET expression, or whether the sample has altered expression as compared to a control sample.Other Exemplary anti-cMET pH-Antibodies|0293] In one embodiment, the anti-cMET antibody comprises the CDRs any one of an anti-cMET pH- ADC comprising one pair of heavy and light chain variable sequences as set forth in SEQ ID NOs: 15 & 16; 5 & 6; 7 & 8; 9 & 10; 11 & 12; 13 & 14; 17 & 18; 19 & 20; 21 & 22; 23 & 24; 2.5 & 2.6; 27 & 28; 29 & 30; 31 & 32;Attorney Docket No. 45395-0071WO1and 33 & 34. In particular embodiments, the anti-cMET pH-antibody may include CDRs and / or variable domains from antibodies exhibiting superior internalization (relative to non-pH-controls), such pH-antibodies notably including: MYT4326 (HCVD = SEQ ID NO: 15, LCVD - SEQ ID NO; 16); MYT4309 (HCVD = SEQ ID NO: 242. LCVD = SEQ ID NO: 8); MYT4310 (HCVD = SEQ ID NO: 243. LCVD = SEQ ID NO: 8); MYT4311 (HCVD = SEQ ID NO: 244, LCVD = SEQ ID NO: 8); MYT4318 (HCVD = SEQ ID NO: 245. LCVD - SEQ ID NO: 8); MYT4319 (HCVD - SEQ ID NO: 229, LCVD = SEQ ID NO: 8): MYT4320 (HCVD - SEQ ID NO: 230, LCVD - SEQ ID NO: 8); MYT4322 (HCVD = SEQ ID NO: 246, LCVD = SEQ ID NO: 8): MYT4323 (HCVD = SEQ ID NO: 247, LCVD = SEQ ID NO: 8); MYT4324 (HCVD = SEQ ID NO: 231, LCVD = SEQ ID NO: 8); MYT4325 (HCVD = SEQ ID NO: 9, LCVD = SEQ ID NO: 8); MYT4327 (HCVD - SEQ ID NO: 15. LCVD = SEQ ID NO: 248); MYT4332 (HCVD - SEQ ID NO: 15, LCVD - SEQ ID NO: 249): MYT4334 (HCVD == SEQ ID NO: 15. LCVD == SEQ ID NO: 250); and MYT4336 (HCVD == SEQ ID NO: 15, LCVD = SEQ ID NO: 251) (each disclosed in US 20220281984 A l). In a specific embodiment, the anti-cMET pH-antibody comprises HC CDRs 1-3 having the sequences as set forth in SEQ ID NOs: 236, 237, and 238. respectively, and the LC CDRs 1-3 having the sequences as set forth in SEQ ID NOs: 239, 240, and 241. respectively.Expression Systems and Methods of Making the Antibodies

[0294] Anti-cMET pH-antibodies can be prepared by recombinant expression, for example, as disclosed in US 20220281984 Al. To express the anti-cMET pH-antibodies, DNAs encoding heavy and light chains are inserted into expression vectors such that the corresponding genes are operatively linked to transcriptional and translational control sequences. As used herein, “operatively linked” means that an gene encoding an antibody is ligated into a vector such that vector control sequences exert their intended transcriptional and translational regulatory functions over the genes. The antibody light and heavy chain genes may be expressed in the same or different expression vectors. In cases where two expression vectors are used, the first vector may encode a heavy chain polypeptide and the second may encode a light chain polypeptide. The two vectors may comprise identical or separate selectable markers Further, recombinant expression vectors carrying the anti-cMET pH- antibody chain gene sequence(s) can also carry regulatory sequences such as those that regulate vector replication in host cells and selectable marker genes. The vcctor(s) may then be transferred into suitable host cells by standard methods (e.g. transient transfections or stable cell generation) to produce the disclosed pH- antibodies.

[0295] Recombinant techniques may also be employed to remove portions of the DNA encoding the heavy and / or light chains that are not required for pH-dependent, cMET-specific binding. Molecules expressed from such truncated cMET-binding molecules are also encompassed by the pH-antibodies of the present disclosure.

[0296] . After an anti-cMET pH-antibody or pH-dependent binding fragment thereof has been produced by recombinant expression, it can be purified by any method known in the art (e.g., chromatography, including ion exchange, affinity, and size exclusion chromatography, and the like), centrifugation, differential solubility.Attorney Docket No. 45395-0071WO1or the like. Once isolated, the anti-cMET pH-antibody or fragment may be further purified.Specific Anti-cMET pH-Antibody Drug Conjugates10297: In specific embodiments, the anti-cMET pH-ADCs are compounds according to structural formula (I): [D-L-XY]n-Ab or salts thereof, where each “D” represents a cytotoxic and / or cytostatic agent (“drug”); each “L” represents a linker; “Ab"' represents a pH-dependent anti-cMET antigen binding moiety; each “XY” represents a linkage formed between a functional group Rxon the linker and a “complementary” functional group R on the antigen binding moiety; and n represents the number of drugs linked to Ab of the ADC. In particular embodiments, n = 2 and the linkers are conjugated to an anti-cMET pH-Ab via cysteine residues.

[0298] In some particular embodiments, each D is the same and / or each I., is the same. Specific embodiments of constituent D and L elements are described in greater detail below.[02991 In some embodiments, at least one polypeptide of any of the antibodies described herein is conjugated to the toxin, the radioisotope, or the drug via a non-cleavable linker. In some embodiments, the conjugated toxin, radioisotope, ordrug is released during lysosomal and / or late endosomal degradation of the antibody

[0300] Non-limiting examples of cleavable linkers include: hydrazone linkers, peptide linkers, disulfide linkers, and thioether linkers. See, e.g., Carter et a!., Cancer J. 14(3): 154-169, 2008; Sanderson el al., Clin. Cancer Res. 11(2 Pt I ): 843-852, 2005; Chari et al., Ace. Chem. Res. 41(1): 98- 107, 2008, Oflazoglu el al., Clin. Cancer Res. 14(19): 6171-6180. 2008; and Lu et al., hit. J. Mol. Sci. 17(4): 561. 2016.

[0301] Non-limiting examples of non-cleavable linkers include: maleimide alkane-linkers and maleimide cyclohexane linker (MMC) (see. e.g., those described in McCombs etal., A APS J. 17(2): 339-351, 2015).

[0302] In some embodiments, any of the antibodies described herein is cytotoxic or cytostatic to the target mammalian cell.

[0303] In some embodiments, the antibodies provided herein can comprise one or more amino acid substitutions to provide a conjugation site (e.g.. conjugated to a drug, a toxin, a radioisotope). In some embodiments, the antibodies provided herein can have one conjugation site. In some embodiments, the antibodies described herein can have two conjugation sites In some embodiments, the antibodies provided herein can have three or more conjugation sites. A non-limiting example of an amino acid substitution to produce a conjugation site (e.g., “a triple hinge” conjugation site) is described in U. S. Patent Application No.2017 / 0348429, which is incorporated herein by reference iu its entirety. For example, a lysine to cysteine substitution at amino acid position 105 and deletion of a threonine at amino acid positions 106 and 108 of SEQ ID NO: 155 or SEQ ID NO: 189 can provide a "triple hinge” conjugation site in any of the antibodies described herein. In some embodiments, an alanine to a cysteine substitution at amino acid position I of SEQ ID NO: 155 or SEQ ID NO: 189 can provide a conjugation site for any of the antibodies described herein. In some embodiments, a valine to cysteine substitution at amino acid position 98 of SEQ ID NO: 157 can provide a conjugation site for any of the antibodies described herein.

[0304] Naturally-occurring cysteine amino acids can also provide a conjugation (e.g,. conjugated to a drug.Attorney Docket No. 45395-0071WO1a toxin, a radioisotope.). In some embodiments, the antibodies provided herein can have a drug, a toxin, or a radioisotope conjugated at one or more (e.g., one, two, three, or four) naturally -occurring conjugation sites. In some embodiments, the cysteine at amino acid position 103 of SEQ ID NO: 155 or 189 is a naturally occurring conjugation site In some embodiments, the cysteine at ammo acid position 109 of SEQ ID NO: 155 or 189 is a naturally occurring conjugation site. In some embodiments, the cysteine at ammo acid position 112 of SEQ ID NO: 155 or SEQ 189 is a naturally-occurring conjugation site. In some embodiments, the cysteine at amino acid position 107 of SEQ ID NO: 157 is a naturally-occurring conjugation site.

[0305] In some embodiments, the antibodies provided herein can have a drug, a toxin, or a radioisotope conjugated at one or more (e.g., two, three, or four) naturally occurring conjugation sites, e.g., the cysteine at amino acid position 103, the cysteine at cysteine at amino acid position 109, and / or the cysteine at amino acid position 112 of SEQ ID NO: 155 or SEQ 189, and / or the cysteine at amino acid position 107 of SEQ ID NO: 157 In some embodiments, the antibodies provided herein can have a drug, a toxin, or a radioisotope conjugated at one or more (e.g., two, three, or four) naturally occurring conjugation sites and one or more (e.g., two, or three) engineered conjugation sites (e.g., engineered by amino acid substitutions, deletions, additions, etc.).

[0306] Conjugation through engineered cysteines is achieved by methods known m the art. Briefly, engineered cysteine-contaimng antibody is prepared for conjugation by treatment with a reducing agent, for example, tris (2-carboxyethyl) phosphine (TCEP), Dithiothreiiol (DTT), or 2-Merca.ptoethanol (BME). In the reduction reaction the reducing reagent with disulfide bonds in the antibody, breaking interchain disulfides arid removing disulfide caps from the engineered cysteines. An optional reoxidation step, achieved by exposure of the solution to air, or an oxidizing agent such as dehydroascorbic acid, allows reformation of the interchain disulfide bonds, leaving the engineered cysteines with a thiolate reactive group. Conjugation with amaleimide functionality on the linker-payload, maleimide-vc-PAB-MMAE, is achieved by reaction with the payload in buffered solution, containing cosolvent such as ethanol, dimethylacetamide (DMA), or dimethyl sulfoxide (DMSO). The crude conjugated antibody solution is purified by size exclusion chromatography, or selective fillration methods, such as tangential flow filtration. In this step, residual unreacted payload, reducing agent and oxidizing agents are removed from the reaction mixture, and the conjugated ADC product may be transferred into a desirable formulation buffer.

[0307] Conjugation through hinge cysteines is achieved by similar methods, using antibodies with, or without, additional engineered cysteine conjugation sites. Briefly, the antibody is prepared for conjugation by treatment with a reducing agent, for example, tris (2-carboxycthyl) phosphine (TCEP) or Dithiothreiiol (DTT). The reducing strength and concentration of the reducing agent are selected such that some or all of the interchain disulfide bonds are reduced leaving free cysteines for conjugation. The solution may be directly conjugated in the presence of excess reducing agent. Conjugation with a roaleimide functionality on the linker¬ payload, maleimide-vc-P B-MMAE, is achieved by reaction with tire payload in buffered solution, containing cosolvent such as ethanol, dimethylacetamide (DMA), or dimethyl sulfoxide (DMSO). Unreacted linker-Attorney Docket No. 45395-0071WO1payload may be rendered non-reactive by addition of a sacrificial tbiolaie molecule such as acetyl-cysteine. Hie crude conjugated antibody solution may be further purified by methods known in the art, including hydrophobic interaction chromatography, ion-exchange chromatography, or mixed-mode chromatography such as ceramic hydroxyapatite chromatography. Isolation of chromatography fractions allows selection of the desired antibody to payload ratio and removal of unreacted antibody, protein aggregates and fragments, and pay! oad -related reaction side products. The purified antibody drug conjugate may be further purified and by size exclusion chromatography, or selective filtration methods, such as tangential flow filtration. In this step the conjugated ADC product may also be transferred into a desirable formulation buffer.

[0308] In some examples, an antibody conjugate can be made composing an antibody linked to monomethyl auristatin E (MMAE) via a valine-citrulline (vc) linker (hereafter, Met-IgG-DC). Conjugation of the antigen¬ binding protein construct with vcMMAE begins with a partial reduction of the Met-lgG followed by reaction with maleimidocaproyl-Val-Cit-PAB-MMAE (vcMMAE). The Met-lgG (10 mg / mL) is partially reduced by addition of TCEP (molar equivalents of TCEP:mAb is 2:1) followed by incubation at 4° C overnight. The reduction reaction is then warmed to 25° C. To conjugate all of the thiols, vcMMAE is added to a final vcMMAE:reduced Cys molar ratio of 1:10. The conjugation reaction is carried out in the presence of 10% v / v of Dimethylacetamide (DMA) and allowed to proceed at 25° C for 60 minutes.

[0309] In some examples, an antibody conjugate (ADC) is made comprising the Met-binding IgG (hereafter, Met-lgG) described herein linked to monomethyl auristatin E (MMAE) via a valine-citrulline (vc) linker (hereafter, Met-IgG-DC). Conjugation of the antigen-binding protein construct with vcMMAE begins with a partial reduction of the Met-lgG followed by reaction with maleimidocaproyl-Val-Cit-PAB-MMAE (vcMMAE). The Met-lgG (10 mg / mL) is reduced by addition of DTT (molar equivalents of DTT:mAb is 100: 1) followed by incubation at 25° C overnight. The reduced Met-lgG (10 mg / mL) is then re-oxidized by exposure to DHAA (molar equivalents of DHAA:mAb is 10: 1) followed by incubation at 25° C for 2 hours. To conjugate all of the thiols, vcMMAE is added to a final vcMMAE:mAb molar ratio of 4: 1. lire conjugation reaction is carried out in 10% v / v DMA and allowed to proceed at 25° C for 3 hours.

[0310] In a particular exemplary embodiment of the anti-cMET pII-ADC, each “D” is the same and is a cell- permeating auristatin (e.g. MMAE); each “L” is the same and is a linker cleavable by an endolysosomal and / or lysosomal enzyme; each “XY” is a linkage formed between a maleimide and a sulfhydryl group; “Ab” is an antibody comprising six CDRs corresponding to the six CDRs of antibody MYTX-01 L or an antibody that competes for binding cMET with such an antibody; and n is 2

[0311] In a. particular exemplary embodiment, the ADC according to formula (I) has the structure of formula (II):Attorney Docket No. 45395-0071WO1

[0312] In one embodiment, the Ab in the compound of formula (II) is Q397.

[0313] In a particular embodiment, the compound of formula (I) has the following structure (III):or a pharmaceutically acceptable salt thereof, wherein n has an average value of 2, or is equal to 2, and the Ab is a full length anti-cMET pH-antibody. In some embodiments, the anti-cMET pH-antibody is Q397.[0314| Unconjugated (free) “MC-Val-Cit-PAB-MMAE’' or “mc-vc-PAB-MMAE"’. or simply " cMMAE” (CAS No 646502-53-6) has the following structure:Cytotoxic and / or Cytostatic Agents

[0315] The cytotoxic and / or cytostatic agents may be any agents known to inhibit the growth and / or replication of and / or kill cells, and in particular cancer and / or tumor cells. Non-limiting examples of classes of such agents include, by way of example and not limitation, radionuclides, alkylating agents, DNA cross-linking agents, DNA intercalating agents (e.g., groove binding agents such as minor groove binders), cell cycle modulators, apoptosis regulators, kinase inhibitors, protein synthesis inhibitors, mitochondria inhibitors.Attorney Docket No. 45395-0071WO1nuclear export inhibitors, topoisomerase I and II inhibitors, RNA / DNA antimetabolites, and antimitotic agents.

[0316] As mentioned, anti-cMET pH-ADCs generally comprise an anti-cMET antigen binding moiety, such as an anti-cMET antibody and / or binding fragment, having one or more cytotoxic and / or cytostatic agents, which may be identical or different, linked thereto by identical or different linker(s). Each antibody may also be conjugated or linked to multiple different cytotoxic or cytostatic agents, each agent having the same or different biological effects.

[0317] In some embodiments, tire antibodies provided herein can be conjugated to a drug (e.g., a chemotherapeutic drug, a small molecule), a toxin, or a radioisotope. Non-limiting examples of drugs, toxins, and radioisotopes (e.g., known to be useful for the treatment of cancer) are known in the art. Particular non¬ limiting examples of drugs / agents are provided below.

[0318] Angiogenesis Inhibitors: ABT-869: AEE-788; axitimb (AG-13736): AZD-2171; CP-547.632: 1M- 862: pegaptamib; sorafenib; BAY43-9006; pazopanib (GW-786034); vatalanib (PTK-787, ZK-222584); sunitinib; SU-l 1248: VEGF trap; vandetanib; ABT-165; ZD-6474; DLI..4 inhibitors.

[0319] Apoptosis Regulators AT-101 ((-)gossypol); G3139 or oblimersen (Bcl-2-targeting antisense oligonucleotide); IPI-194; IP1-565; GX-070 (Obatoclax®); HGS1029; GDC-0145; GDC-0152; LCL-161; LBW-242; venetoclax; TRAIL or death receptor targeting agents (e.g.. DR4 and DR5) such as ETR2-ST01, GDC0145, HGS-1029, LBY-135. PRO- 1762; caspase-targeting drugs, caspase-regulators, BCL-2 family members, TNF family members, Toll family members, and / or NF-kappa-B proteins.

[0320] Antimitotic Agents allocolchicine; auristatins, such as MMAE (monomethyl auristatin E) and MMAF (monomethyl auristatin F); halichondrin B; cemadotin; colchicine; any colchicine derivative; doiastatin-10; dolastatin-15; maytansine; maytansinoids, such as DM1 (N2‘-deacetyl-N2‘-(3-mercapto-l-oxopropyl)-maytansine); rhozoxin; paclitaxel or derivative thereof; docetaxel: thiocolchicine; trityl cysteine; vinblastine sulfate; vincristine sulfate

[0321] Alkylating Agents: asaley; AZQ; BCNU (N, N’-Bis(2-chloroethyl)-N-nitrosourea); busulfan (1,4-butanediol dimethanesulfonate); (carboxyphthalato)platinum; CBDCA; CCNU; CHIP (iproplatin; NSC 256927); chlorambucil; chlorozotocin; cisplatin; clomesone; cyanomorpholinodoxorubicin; cyclodisone; dianhydrogalactitol (5,6-diepoxydulcitol); fluorodopan ((5-[(2-chloroethyl)-(2-fluoroethyl)aminoj-6-metiiyl-uracil); hepsulfam; hycanthone: indoimobenzodiazepme dimer DGN462; melphalan; methyl CCNU ((l-(2- chloroethyl)-3-(trans-4- methy1cyclohexane)-l-nitrosourea); mitomycin C; mitozolamide; nitrogen mustard ((bis(2- chloroethyl) methylamine hydrochloride); PCNU ((l-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-l- nitrosourca)); piperazine alkylator (( 1 -(2-chlorocthyl)-4-(3-chloropropyl)-pipcrazinc dihydrochloridc)); piperazinedione; pipobroman (N, N'-bis(3-bromopropionyl) piperazine); porfiromycin (N-methyhnitomycin C); spirohydantoin mustard; triglycidylisocyanurate; tetraplatin; thio-tepa (N, N', N’’-tri-L2-ethanediylthio phosphoramide): triethylenemelaroine: uracil nitrogen mustard: bi s( 3 -mesyl oxy propylamine hydrochloride.

[0322] Alkylating Antineoplastic Agents: Carboquone; Carmustine; Chlomaphazine; Chlorozotocin; Duocarmycin; Evofosfamide; Fotemustine; Glvrfosfamide; Lomustine; Mannosulfan; Nimustine;Attorney Docket No. 45395-0071WO1Phenanthriplatin; Pipobroman; Ranimustine; Semustine; Streptozotocin; ThioTEPA; Treosulfan; Triaziquone; ssnd Triethylenemelamine.[03231 DNA Alkylating-like Agents’. Cisplatin; Carboplatin: Nedaplatin; Oxaliplatin; Satraplatm; Triplatin tetramtrate; Procarbazine; altretamine; dacarbazme; mitozoloraide; temozolomide

[0324] DNA replication and repair inhibitors'. Altretamine; Bleomycin; Dacarbazine; Dactinomycin; Mitobronitol; Mitomycin; Pingyangmycin; Plicamycin; Procarbazine: Temozolomide; ABT-888 (veliparib); olaparib; KU-59436; AZD-22 1; AG-014699; and B SI-201.

[0325] Cell Cycle Modulators: Paclitaxel; Nab-Paclitaxel; Docetaxel; Vincristine; Vinblastine; ABT-348; AZD-1152; MLN-8054; VX-680; Aurora A-specific kinase inhibitors; Aurora B-specific kinase inhibitors and pan-Aurora kinase inhibitors; AZD-5438; BM1-1040: BMS-032; BMS-387; CVT-2584; flavopyridol; GPC-286199; MCS-5A: PD0332991; PHA-690509; seliciclib (CYC-202. R-roscovitme); ZK-304709; AZD4877, ARR. Y-520; GSK923295.

[0326] Kinase Inhibitors: Afatinib; Axitinib; Bosutinib; Crizotinib; Dasatinib; Erlotinib; Fostamatinib; Gefitinib; Ibrutinib; Iroatinib; Lapatinib; Lenvatinib; Mubritinib; Nilotinib; Pazopanib; Pegaptanib; Sorafenib; Sunitinib; SU6656; Vandetanib; Vemurafenib; CEP-701 (lesaurtinib); XL019; INCB018424 (ruxolitinib); ARRY-142886 (selemetinib); ARRY-43 162 (binimetinib); PD-325901; PD-98059; AP -23573; CCI-779; everolirous; RAD-001; rapamycin; temsirolimus; ATP-competitive TORC1 / 2 inhibitors including PI-103, PP242, PP30, Torin 1; LY294002; XL-147; CAL- 120; ONC-21; AEZS-127; ETP-4565; PX-866; and the like.Proteasome Inhibitors Bortezomib; Carfilzomib; Epoxomicin; and Ixazomib.[0327| Protein Synthesis Inhibitors Amikacin; Arbekacin; Bekanamycin; Dibekacin; Dihydrostreptomycin; Streptomycin; Neomycin; Framycetin; Paromomycin; Ribostamycin; Kanamycin; Tobramycin; Spectinomycin; Hygromycin B; Paromomycin; Gentamicin; Netilmicin; Sisomicin; Isepamicin; Verdamicin; Astromicin; Tetracycline; Doxycycline; Chlortetracycline; Clomocycline; Demeclocycline; Lymecycline; Meclocycline; Metacycline; Minocycline; Oxytetracycline; Penimepicycline; Rolitetracycline; Tetracycline; Glycyl cyclines; Tigecycline; Oxazolidinone; Eperezolid; Linezolid; Posizolid; Radezolid; Ranbezolid; Sutczolid; Tedizolid.

[0328] Peptidyl transferase inhibitors: Azidamfenicol; Chloramphenicol; Thianiphenicol; Florfenicol; Pleuromutilins; Retapamulm; Tiamulin; Valnemulin; Azithromycin; Clarithromycin; Dirithromycin: Erythromycin; Flurithromycin; Josamycm; Midecamycin: Miocamycin; Oleandomycin; Rokitamycin; Roxithromycin; Spiramycin; Troleandomycin; Tylosin; Ketolides; Teiithromycin; Cethromycin; Solithromycin; Clindamycin; Lincomycin; Pirlimycin; Streptogramins; Pristinamycin; Quinupristin / dalfopristin; Virginiamycin.|0329] Histone deacetylase (HDAC) inhibitors: Vormostat; Romidepsin: Chidamide; Panobinostat; Valproic acid; Belmostat; Mocetinostat; Abexmostat; Entinostat; SB939 (praciirostat); Resmmostat; Givinostat;Attorney Docket No. 45395-0071WO1Quisinostat; thioureidobutyronitrile (Kevetrin™); CUDC-10; CHR-2845 (tefinostat); CHR-3996; 4SC-202; CG200745; ACY-1215 (rocilinostat); etc.[0330| Topoisomerase 1 Inhibitors-, camptothecin and an array derivatives and analogs (e.g., NSC 100880, NSC 603071, and the like); morpholmisoxonibicin; SN-38. FDA-Approved ADCs including topoisomerase I inhibitors include: Sacituzumab govitecan (Trodelvy®): Anti-Trop-2 mAb conjugated to SN-38, approved for triple-negative breast cancer and urothelial cancer (Bardia et al., ’‘Sacituzumab Govitecan in Metastatic Triple¬ Negative Breast Cancer,” New England Journal of Medicine, Vol. 384, pp. 1529-1541, 2.021); and Trastuzumab deraxtecan (Enhertu*): Anti-HER2 mAb conjugated to DXd, approved for multiple HER2- expressing cancers (Modi et al., “Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer,’' New England Journal of Medicine, Vol. 382. pp. 610-621, 2020). Late-Stage Clinical ADCs include: Datopotamab deruxtecan: TROP2-targeting ADC with deruxtecan payload in Phase 3 for N SCLC (Spira et al., “Datopotamab Deruxtecan (Dato-DXd) in Advanced NSC1.. C: Updated Results from TROPION- PanTumorOl,” Journal of Clinical Oncology, Vol. 40, p. 9004, 2022); and Patritumab deruxtecan: HER3-targeting ADC with DXd payload in Phase 2 / 3 trials (Janne et al., “Safety and Efficacy of Patritumab Deruxtecan in EGFR-Mutaied NSCLC After EGFR TKI Therapy: Initial Results From HERTHENA- LirngOl.” Journal of Clinical Oncology. Vol. 40, p. 9007. 2022); and Puxitatug samrotecan (AZD8205): B7- H4~t.argeting ADC in Phase 1 / 2 for endometrial and ovarian cancers (Gaillard et al., “Safety and preliminary efficacy of puxitatug samrotecan (AZD8205) in patients with endometrial cancer,” Society of Gynecologic Oncology Annual Meeting, Abstract 933087, 2025).[03311 Topoisomerase II Inihibitors: doxorubicin; amonafide (benzisoquinolinedione); m-AMSA (4'-(9- aciidmylamino)-.3'-met.hoxymethanesulfonanilide); anthrapyrazole derivative ((NSC 355644): etoposide (VP- 16); pyrazoloacridine, 9- methoxy-N, N-dimethyl-5-nitro-. monomethanesulfonate); bisan Irene hydrochloride: daunorubicin; deoxydoxorubicin; mitoxantrone; menogaril; N, N-dibenzyl daunomycin; oxanthrazole; rubidazone; teniposide.

[0332] DNA Intercalating Agents anthramycin; chicamycin A; tomaymycin; DC-81; sibiromycin; pyrrolobenzodiazepine derivative; SGD-1882.[03331 RNA / DNA Antimetabolites-. L-alanosine: 5 -azacytidine, 5 -fluorouracil; acivicin; aminopterin derivative; L-aspartic acid (NSC 132483); aminopterin derivative; antifolate PT523: Baker's soluble antifol (NSC 139105); dichlorallyl lawsone ((2-(3,3-dichloroaliyl)~3-hydroxy-l,4-naphthoquinone); brequinar; ftorafur ((pro-drug; 5-fluoro-l-(tetrahydro-2-furyl)-uracil); 5,6-dihydro-5-azacytidine; methotrexate; methotrexate derivative; PALA ((N-(phosphonoacctyl)-L-aspartatc); pyrazofurin; trimctrcxatc.,0334] DNA Antimetaboliies: 3-HP; 2'-deoxy-5-fluorouridine; 5-HP; a-TGDR (a-T- deoxy-6- thioguanosine); aphidicolin glycinate; ara C (cytosine arabinoside); 5-aza-2'-deoxycytidine; p-TGDR (P-2- deoxy-6-thioguanosine); cyclocytidine; guanazole; hydroxyurea: inosine, glycodi al ehyde; macbecin II; pyrazoloimidazole; thioguanine; thiopurine.

[0335] Mitochondria Inhibitors: pancratistatin; phenpanstatin; rhodamine- 123; edelfosine; d-alpha-Attorney Docket No. 45395-0071WO1tocopherol succinate; compound 11 p; aspirin; ellipticine; berberine; cerulenin; GX015-070 (Obatoclax*; IH-Indole, 2-(2-((3,5-dimethyl-lH-pyrrol-2-yl)methyliene)-3-methoxy-2H-pyrrol-5-yl)- ), celastrol (tripterine); metformin; Brilliant green; ME-344.

[0336] Nuclear Export Inhibitors'. callystatin A; delactonmycin; KPI-185; kazusamycin A; leptolstatin: leptofuranin A; leptomycin B; ratjadone; and Verdinexor.

[0337] Hormonal Therapies', anastrozole; exemestane: arzoxifene; bicalutamide; cetrorelix; degarelix; deslorelin; trilostane; dexamethasone; flutamide; raloxifene; fadrozole; toremifene; fulvestrant; letrozole; formestane; glucocorticoids; doxercalciferol; sevelamer carbonate; lasofoxifene; leuprolide acetate; megesterol; mifepristone; nilutamide; tamoxifen citrate; abarelix; prednisone; finasteride; rilostane; buserelin; luteinizing hormone releasing hormone (LHRH); Histrelin; trilostane or modrastane; fosrelin; goserelin.

[0338] Any of the foregoing agents may be included in the disclosed anti-cMET pH-ADCs.

[0339] In some embodiments, the anti-cMET pH-ADC may include a membrane-permeating cytotoxic and / or cytostatic agent that is cytotoxic and / or cytostatic to both cMET+ tumors and cMET-negative tumor cells. Such pH-ADCs may exhibit a potent and effective "bystander effect’’, whereby cells surrounding cMET+ cells, irrespective of their cMET expression levels, are impacted due to their proximity to the cMET+ cells.

[0340] In a particular embodiment, the agent is a cell-permeable antimitotic agent.

[0341] In another particular embodiment, the agent is a cell-permeable auristatin, such as, for example, MMAE,

[0342] In some embodiments, the linkers linking the agent to the pH-antibody may be cleavable or noncleavable.

[0343] Cleavable linkers may include enzymatically or chemically unstable or degradable linkages, which may be stable in the bloodstream, but become unstable when the ADCs are internalized into cells. Notable cleavable linkers include acid-labile groups that remain intact during systemic circulation in the blood's physiologic pH (about pH 7.3-7.5) and release the agent once the ADC is taken into pH 5.0-6.5 endosomal and pH 4.5-5.0 lysosomal compartments of the cell. Cleavable linkers may also include a disulfide group, such that they are stable at physiologic pH, but then release the agent, upon internalization of the ADC.[03441 Linkers may also include those that are cleavable by specific enzymes and include, for example, regions that are acted upon by enzymes present inside cells. Such linkers are typically more stable in plasma when compared to chemically labile linkers. Release of a drug / payload from an antibody occurs due to specific action of lysosomal proteases, which may be overexpressed in particular tumor cells.

[0345] In particular embodiments, the cleavable element is a dipeptide selected from Val-Cit, Val-Ala, and any other suitable dipeptide.

[0346] Multiple dipeptide-based cleavable linkers have been used to link antibodies to drugs including auristatin / auristatin family members, camptothecin, doxorubicin, mitomycin, and tallysomycin (see, e.g., Dubowchik et al, 1998, J. Org. Chem 67: 1866-1872; Dubowchik et al, 1998, Bioorg. Med. Chem Lett.8(21 ):3341-3346; Walker etal, 2002, Bioorg. Med. Chem. Lett. 12:217-219; Walker et al, 2004, Bioorg. Med.Attorney Docket No. 45395-0071WO1Chem. Let. 14:4323-4327; and Francisco et al, 2003, Blood 102: 1458-1465, Domina et al, 2008, Bioconjugate Chemistry 19: 1960-1963, each of which is incorporated herein by reference in its entirety). Any such dipeptide linkers, or modified versions thereof, may be included in the ADCs described herein. Notable clinically-important examples include, but are not limited to, Brentuximab Vedotin SGN-35 (ADCETRIS™)- Celldex Therapeutics glembatumumab (CDX-011) (anti-NMB, Val-Cit-MMAE), and Cytogen PSMA-ADC (PSMA-ADC-1301) (anti -PS MA, Val-Cit-MMAE), and SGN-75 (anti-CD-70, VC-MMAF).

[0347] Non-cleavable linkers may also be included in tire pH-ADCs disclosed herein. Unlike cleavable linkers, the release of drug / payload from non-cleavable linkers does not depend on differential environmental properties. Instead, payload “release” is proposed to accompany antibody degradation in the lysosomes. As such, inclusion of non-cleavable linkers gives rise to amino acid drug metabolites, which tend to be more hydrophilic and less membrane permeable compared to drugs liberated from cleavable linkers. Accordingly. ADCs including non-cleavable linkers are associated with reduced bystander effects and non-target-specific toxicities relative to ADCs including cleavable linkers. On the other hand, ADCs that include noncleavable linkers tend to be more stable in the bloodstream versus ADCs having cleavable linkers.|0348] Linker-drug modules may be conjugated to antibodies via a variety of attachment groups to generate ADCs. Generally, such groups may be electrophiles, e.g. maleimide groups, activated disulfides, active esters including NHS esters, acid halides, alkyl and benzyl halides such as haloacetamides. and haloformates.

[0349] As regards selecting a linker for a particular ADC, factors to consider include, for example, the site of attachment to the antibody and drug properties, including structural constraints and lipophilicity. For a review, see Nolting, Chapter 5 “Linker Technology in Antibody -Drug Conjugates,” In: Antibody -Drug Conjugates: Methods in Molecular Biology, vol. 1045, pp. 71- 100, Laurent Ducry (Ed.), Springer Science & Business Media, LLC, 2013.

[0350] In specific embodiments, the linker is selected to impact, enhance, and / or augment the cytotoxic bystander effect of the anti-cMET pH-ADCs.Anti-cMET pH-ADC

[0351] As described throughout the specification, MYTX-011 is an ADC comprised of the cMET- targeting antibody Q397 conjugated to the potent cytotoxin MMAE through a vc linker. MYTX-011 is being tested in a Phase I clinical trial (see Example 10) with a DAR of ~2.0.Methods of Producing Anti-cMET pH-Antibody Drug Conjugates

[0352] The pH-ADCs described herein may be produced using well-known synthetic techniques. Generally, pH-ADCs according to formula (1) may be prepared as follows: D-L-Rx+ Ab-Rya (1) [D-L-XY ]n-Ab; where D, L, Ab, XY and n are as defined supra, and Rxand Ryare complementary groups that can form covalent linkages with one another. In particular embodiments, the pH-antibody is engineered to include amino acid residues for conjugation. For example, a C may be included at the amino acid position corresponding to amino acid position 98 of the light chain constant domain sequence set forth in SEQ ID NO: 158. resulting in a DARAttorney Docket No. 45395-0071WO12,0 pH- ADC.Compositions

[0353] The pH-ADCs described herein may be formulated as compositions comprising the pH-ADC plus one or more pharmaceutically acceptable carrier, excipient and / or diluent. The form and precise components of the composition will depend upon the intended uses and route of administration,

[0354] The compositions may be disposed in a sterile vial or a pre-loaded syringe.103551 In some embodiments, the compositions are formulated for different routes of administration (e.g., intravenous, subcutaneous, intramuscular, or intratumoral). In some embodiments, the compositions can include a pharmaceutically acceptable carrier (e.g.. phosphate buffered saline). Single or multiple administrations of any of the compositions described herein can be given to a subject depending on, for example: the dosage and frequency as required and tolerated by the patient. A dosage of the pharmaceutical composition should provide a sufficient quantity of the antibody to effectively treat or ameliorate conditions, diseases, or symptoms.

[0356] Also provided herein are methods of treating a subject having a cancer (e.g., any of the cancers described herein) that include administering a therapeutically effective amount of at least one of any of the compositions or pharmaceutical compositions provided herein.

[0357] Also provided herein are kits that include any of the pH-ADCs described herein, any of the compositions described herein, or any of the pharmaceutical compositions described herein. In some embodiments, the kits can include instructions for performing any of the methods described herein. In some embodiments, the kits can include at least one dose of any of the compositions described herein. In some embodiments, the kits can provide a syringe for administering any of the pharmaceutical compositions described herein,[03581 The compositions may be supplied in bulk form for multiple administrations. Pharmaceutical compositions may take the form of lyophilized formulations or aqueous solutions, comprising selected excipients, including but not limited to buffering agents, preservatives, stabilizing agents, non-ionic detergents, and antioxidants. See, Remington's Pharmaceutical Sciences, 16th edition (Osol, ed. 1980) and Remington: The Science and Practice of Pharmacy, 22ndEdition (Edited by Allen, Loyd V. Jr., 2012).

[0359] Suitable buffering agents include acetate, citrate, fumarate, gluconate, lactate, oxalate, succinate, and tartrate buffers.). Buffering agents may also include, histidine buffers, phosphate buffers, and Tris.

[0360] Preservatives are typically included in amounts from about 0.2%-l% (w / v). Suitable preservatives may- include benzyl alcohol, phenol, meta-cresol, methyl or propyl paraben, octadecyldimethylbenzyl ammonium chloride, benzalconium halides, catechol, hexamethonium chloride, and alkyl parabens, resorcinol, cyclohexanol, and 3-pentanol. Isotonicifiers (“stabilizers”) may- also be added to ensure isotonicity and include sugar alcohols, including arabitol, erythritol, glycerin, mannitol, sorbitol, and xylitol. Stabilizers may include the foregoing isotonicifiers and / or amino acids (e.g. alanine, asparagine, arginine, glycine, glutamine, histidine.Attorney Docket No. 45395-0071WO1lysine, ornithine, L-leucine, glutamic acid, 2 -phenylalanine, threonine), or any other suitable stabilizer,

[0361] Non-ionic surfactants or detergents (or “wetting agents"’) may be added to reduce surface adsorption and to help solubilize the ADC and to protect the ADC against aggregation.

[0362] A particular embodiment of a composition suitable for administration via intravenous infusion comprises 10 mg / mL anti-cMET pH-ADC, 20 mM histidine, pH 5.5. 8.8% (w / v) trehalose dihydrate, 0.02% (w / v) polysorbate 80. Tire composition may be in the form of a lyophilized powder that, upon reconstitution with a suitable amount of sterile water or other acceptable solution for infusion or injection provides the above composition.Methods of Use

[0363] Data provided herein demonstrate that anti-cMET pH-ADCs exert potent antitumor activity against cMET+ / cMET-expressing and cMET-overexpressing tumors in vivo. Accordingly, the pH-ADCs and / or pharmaceutical compositions comprising the pH-ADCs may be used therapeutically to treat cMET+ and / or cMET-overexpressing tumors

[0364] Generally, the methods involve administering a therapeutically effective amount of the pH-ADCs to a patient having a cMET+ or cMET-overexpressing tumor. Any' method known to skilled artisans for assessing cMET receptor protein expression levels in a cell may be used. A particular method for determining cMET expression levels is detailed in Example 15.

[0365] The IHC score (0, 1+, 2+, and 3+) and / or H-scores (0-300) may be assessed by suitable methods known by skilled artisans. In some embodiments, patients having tumors exhibiting any detectable amount of cMET expression are selected for treatment. In one embodiment, patients with H-scores > 100 or 150 and / or IHC scores 1+, 2+ and 3+ are selected for treatment.

[0366] Patients selected for the pH-ADC treatments may have any cMET+ and / or cMET-overexpressing solid tumor (including tumors exhibiting HGF overexpression and / or having abnormal HGF / cMET signaling or expression). More particular examples include: breast cancers; cervical cancers; colorectal cancers; gastric carcinomas; head and neck cancers; lung cancers; pancreatic cancers; ovarian cancers; stomach cancers: kidney cancers; adrenal cancers; gastro / esophageal cancers; gliomas; liver cancers; medulloblastomas; melanomas; myxoid liposarcomas; prostate cancer; salivary gland tumors; sarcomas; parathyroid gland adenocarcinomas; endometrial cancers: epithelioid mesotheliomas; appendix carcinomas; goblet cell carcinomas; anaplastic large cell lymphoma (ALCL); and / or any malignancy including (e.g. relapsed, advanced, and / or refractory subtypes of the recited cancers)

[0367] In one classification system, lung cancer encompasses adenocarcinoma (acinar, micropapillary, mixed, papillary, solid, and lepidic mucinous or nonmucinous), squamous cell carcinoma, large cell carcinoma (e.g., NSCLC (e.g., advanced or non-advanced. LCNEC, LCNEM, NSCLC-not otherwise specified / adenosquamous carcinoma, sarcomatoid carcinoma, adenosquamous carcinoma, and large-cell neuroendocrine carcinoma); and small cell lung cancer or SCLC. In another classification system, lung cancerAttorney Docket No. 45395-0071WO1may be categorized as a preinvasive lesion, a minimally invasive adenocarcinoma, or an invasive adenocarcinoma.

[0368] More typically, lung cancer is categorized as either non-small cell lung cancer (“NSCLC”) or small cell lung cancer (‘‘SCLC”) or. NSCLCs may be subclassified as squamous or non-squamous (nsNSCLC), and an example of a nsNSCLC is adenocarcinoma.

[0369] The cancer may be naive to treatment, or may be relapsed and / or refractory, or a metastasis of a cMET+ or cMET-overexpressing tumor. As disclosed herein (e.g., Examples 5 & 6), cMET+ cancer cells resistant to prior treatments may be sensitive to the anti-cMET pH-ADCs.103701 In one embodiment, the anti-cMET pH-ADCs provide clinical benefit on Objective Response Rate (ORR), Progression-Free Survival (PFS), Duration of Response (DOR), and / or Overall Survival (OS). In some embodiments, the benefit is a Complete Response (CR), a Partial Response (PR), or stable disease (SD) (each benefit as defined by RECIST version 1.1 criteria)

[0371] Methods for assessing therapeutic benefit are detailed in the Examples, and include, for example. (1) the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1; (2) the Eastern Cooperative Oncology Group (ECOG) Performance Status, (3) immune-related response criteria (irRC); (4) disease evaluable by assessment of tumor antigens: (5) Kaplan-Meier estimates for OS and PFS; and / or patient reported outcome scales.

[0372] Important clinical trial endpoints include tumor shrinkage (an OR) and time to disease progression. RECIST criteria are often used in trials where OR is the primary endpoint, and / or when stable disease, tumor progression, or time to progression analy ses are undertaken.

[0373] Secondary outcome measures for determining the therapeutic benefit of the anti-cMET pH-ADCs may include ORR, PFS. DOR. and Depth of Response (DpR).

[0374] The therapeutic benefit of the anti-cMET pH-ADCs may also be determined using any one or combinations of the following tumor antigens and / or biomarkers: 5-HIAA, acid phosphatase, ApoE, ACTA2, ACTH, ADGRE1, EMR1, AIF1, AKR1 Cl, AKR1C2, alkaline phosphatase, alpha-fetoprotein (AFP), CA-125, alpha-HCG, and alpha-TSH. ANGPTL4, ANGPTL4, beta-HCG, BNIP3, C1QA, Cl QB, C-212, CA15-3, CA- 195. CAI 9-9, CA-549, CADM1, calcitonin, catecholamines, cathepsin-D, CCL5, CCL5, CCR5. GDI lb, CD1 1c. CD 16, CD19, CD3. CD3. CD4, CD40, CD45 (PTPRC), CD49D (1TGA4), CD5, CD68, CD7, CD74. CD8. CD80, CD86, CDCP1, CDH1 1, CEA, chromagranin-A, c-Myc, COL6A3, COL7A1, CSF1R, CTGF, CTLA- 4, CTSD, CTSS, CXCL10, CXCL10, CXCL11, DDIT4, EGFR, EGLN, EGLN3, ERA (estrogen receptor assay), ERBB2 (HER2 / ncu), F4 / 80), ferritin, gastrin, GZMB, hCG, HLA-DR, HM0X1, I-IVA, IFI6, IFNG, 1GFBP3, 1L10RA1, IL-6, KISS1R, KRT33A, LDH1-5, LOX, LRRCT5, LUM, L 86, MCPT8. MHC-Class II, MMP10, MMP14, MS4A7, NOG, NSE (neuron specific enolase), pancreatic polypeptide, PD-1. PDGFRA, PDK1, PDL-1, PFKFB3, PGF. PGK.1, PIK3AP1, PIK.3CD. PLAP, PLOD2, PLP, PRA (progesterone receptor A), proinsulin C-peptide, PSA, SCC, SERPINE1, SMA, plasma soluble cMET (sMET) levels, STAT1, STC2, TCF4, TCRa, TCRy5, TDT, TGF, TGFB1, TGFB2, TGFBR1. thyroglobulin, TP A, VEGFA, and / or WNT5 A.Attorney Docket No. 45395-0071WO1Other exemplary markers include FGFR-1, FGFR-2, FGFR-3, FGFR-4, CLDN18.2 (Claudin 18.2), TP53, EPHA1 (Ephrin A2), Integrin avp5, Integrin avp6, Mucin-16 (MUC-16, aka CA-125), MSLN (Mesothelin), TGFBR2, ALK, ROS1, NTRK-1, NTRK-2, NTRK-3, CUL5 (Cullin5). Such antigens and / or biomarkers may be evaluated at the DNA, RNA or protein level using DNA / RNA sequencing, gene microarrays. PCR, flow cytometry or IHC methods known to skilled artisans.

[0375] One particular therapeutic benefit comprises a Complete Response (CR). Another benefit comprises a Partial Response (PR).

[0376] In an aspect, the present disclosure provides a method of treating a cMET-positive solid tumor cancer in a population of subjects, wherein treatment results in a decreased incidence of one or more adverse event(s) associated with monomethyl auristatin E (MMAE)-containing antibody drug conjugates as compared to the incidence of the one or more adverse event(s) associated with intravenous administration of two or more doses of about 1.9 mg / kg telisotuzumab vedotin, once every two weeks, over a similar treatment period, wherein the method comprises administering to the subject two or more doses of MYTX-011, wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

[0377] In some embodiments, the decreased incidence is at least a 5% decrease in incidence of the one or more adverse event(s) associated with MMAE-containing antibody drug conjugates In some embodiments, the decreased incidence is at least a 10% decrease in incidence of one or more adverse event(s) associated with MMAE-containing antibody drug conjugates. In some embodiments, the decreased incidence is at least a 20% decrease in incidence of one or more adverse event(s) associated with MMAE-containing antibody drug conjugates.

[0378] In some embodiments, the one or more adverse event(s) associated with MMAE-containing antibody drug conjugates are selected from the group consisting of: peripheral neuropathy, anemia, thrombocytopenia, neutropenia, hypoalbuminemia, peripheral edema, and AST / ALT elevation.

[0379] In some embodiments, the doses of MYTX-011 are administered to the subject in an amount ranging from about 3.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W). In some embodiments, the doses of MYTX-011 are administered to the subject in an amount ranging from about 4.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

[0380] In an aspect, the present disclosure provides a method of treating a cMET-positive solid tumor cancer in a subject, wherein the subject has not responded to 3, 4, 5, or 6 prior lines of treatment, the method comprising administering to the subject two or more doses of MYTX-011, wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

[0381] In some embodiments, the subject has not responded to 3 prior lines of treatment. In some embodiments, the subject has not responded to 4 prior lines of treatment. In some embodiments, the subject has not responded to 5 prior lines of treatment. In some embodiments, the subject has not responded to 6 priorAttorney Docket No. 45395-0071WO1lines of treatment.

[0382] In some embodiments, the doses of MYTX-011 are administered to the subject in an amount ranging from about 3.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W). In some embodiments, the doses of MYTX-011 are administered to the subject in an amount ranging from about 4.0 mg / kg to about 6.0 mg / kg. once every three weeks (Q3W).

[0383] In another aspect, the present disclosure provides a method of treating a cMET-positive solid tumor cancer in a subject, wherein the subject has not responded to prior treatment with a taxane-based therapy, the method comprising administering to the subject two or more doses of MYTX-011, wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

[0384] In some embodiments, the taxane-based therapy is selected from the group of: paclitaxel, docetaxel, and cabazitaxel.

[0385] In some embodiments, the doses of MYTX-011 are administered to the subject in an amount ranging from about 3.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W). In some embodiments, the doses of MYTX-011 are administered to the subject in an amount ranging from about 4.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

[0386] In another aspect, the present disclosure provides a method of treating a cMET-positive solid tumor cancer in a subject, the method comprising: (a) administering to the subject two or more doses of MYTX-011, wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W); and (b) administering one or both of a vasoconstrictor and a corticosteroid to one or both eyes of the subject,

[0387] In some embodiments, step (b) is performed prior to step (a). In some embodiments, step (a) is performed prior to step (b). In some embodiments, steps (a) and (b) are performed at about the same time.

[0388] In some embodiments, step (b) comprises administering a vasoconstrictor to one or both eyes of tire subject. In some embodiments, step (b) comprises administering a corticosteroid to one or both eyes of the subject. In some embodiments, step (b) comprises administering a vasoconstrictor and a corticosteroid to one or both eyes of the subject.

[0389] In some embodiments, the doses of MYTX-011 are administered to the subject in an amount ranging from about 3.0 mg / kg to about 6.0 mg / kg, once even- three weeks (Q3W). In some embodiments, the doses of MYTX-011 are administered to the subject in an amount ranging from about 4.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

[0390] In another aspect, the present disclosure provides a method of treating a cMET-positive solid tumor cancer in a subject, the method comprising: administering a first dose of MYTX-011 in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg on day 1; administering a second dose of MYTX-011 in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg on about day 22; and administering a third dose of MYTX- 011 m an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg on about day 64.Attorney Docket No. 45395-0071WO1

[0391] In some embodiments, the first second, and third doses of MYTX-011 are administered to the subject m an amount ranging from about 3.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W). In some embodiments, the first, second, and third doses of MYTX-011 are administered to the subject in an amount ranging from about 4.0 mg / kg to about 6.0 mg / kg. once even’ three weeks (Q3W).

[0392] In some embodiments, the method further comprises: administering a fourth dose of MYTX-01 1 in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg on about day 85; and administering a fifth dose of MYTX-011 in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg on about day 127. In some embodiments, the fourth and fifth doses of MYTX-011 are administered to the subject in an amount ranging from about 3.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W). In some embodiments, the fourth and fifth doses of MYTX-011 are administered to the subject in an amount ranging from about 4.0 mg / kg to about 6.0 mg / kg. once every three weeks (Q3W).

[0393] In some embodiments, the cMET-positive solid tumor cancer is a cMET-overexpressing and / or MET-amplified solid tumor cancer. In some embodiments, cMET-positive solid tumor cancer has low or intermediate expression of cMET.

[0394] In some embodiments, the cMET-positive solid tumor cancer has a cMET immunohistochemistry score of 1 ~L 2+. or 3-r. In some embodiments, the cMET-positive solid tumor cancer has an H-score of about 50 to 300.

[0395] In some embodiments, the cMET-positive solid tumor cancer is non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is non-squamous NSCLC, squamous NSCLC, or not otherwise specified NSCLC.

[0396] In some embodiments, a biopsy from a tumor of the cMET-positive solid tumor cancer and / or an entire tumor of the cMET-positive solid tumor cancer, comprises at least about 1%. 2%, 3%.4%. 5%, 6%, 7%.8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% of cancer cells having a cMET expression level of at least a 1+, a 2+, or a 3+, as scored by an applicable and / or regulatory-agency approved immunohistochemistry (IHC) assay In some embodiments, (a) at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% of the cancer cells have an IHC score of 1+ or 2+; (b) at least about 1%, 2%, 3%. 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%. 50%. 60%. 70%. 80%. 90%. or 100% of the cancer cells have an IHC score of 2+; (c) at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%. 45%, 50%, 60%, 70%, 80%, 90%, or 100% of the cancer cells have an IHC score of 1+; (d) at least about. 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, or about 20% of the cancer cells have an IHC score of 1 + and wherein no more than about 1%, 2%, 3%. 4% or 5% of the cancer cells have an IHC score of 2+ or 3+; and / or (e) at least about 1%. 2%, 3%, 4%. 5%, 6%, 7%, 8%, 9%, 10%, 15%, or about 20% of the cancer cells have an IHC score of 1+ and wherein no more than about 1%, 2%. 3%, 4% or 5% of the cancer cells have an IHC score of 2+ or 3+.

[0397] In some embodiments, (a) no more than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%,Attorney Docket No. 45395-0071WO1or about 20% of the cancer cells have an IHC score of 2+ and wherein no more than about 1% of the cancer cells have an IHC score of 3+; (b) no cancer cells have an IHC score of greater than 1+; or (c) no cancer cells have an IHC score of greater than 2+.

[0398] In some embodiments, the method further comprises a step of determining an H-score for the biopsy or the entire tumor, wherein the H-score is between about 10 and about 300, between about 10 and about 250, between about 20 and about 225, between about 20 and about 200, between about 20 and about 175, or between about 20 and about 150 In some embodiments, the H-score is no more than about 100, about 90, about 80, about 70, or about 50.

[0399] In some embodiments, the biopsy or the entire tumor is homogeneous or heterogeneous for cMET expression and / or MET amplification.

[0400] In some embodiments, at least about 10%, 20%, or 30% of the cancer cells have a first frequently-occurring IHC score selected from one of 0, I+, 2+, and 3+ and at least about 10%. 20%, or 30% of the cancer cells have a second frequently-occurring IHC score selected from one of 0, 1+, 2+, and 3+, wherein the first and second frequently-occurring IHC scores are different.

[0401] In some embodiments, the first and second frequently-occurring IHC scores are selected from the following pairs of scores: (0, +1), (0, +2), (0, +3), (+1, +2), (+1, +3), and (+2, +3).

[0402] In some embodiments, at least about 10%, 2.0%, or 30% of the cancer cells have a third frequently- occurring IHC score, wherein the third frequently-occurring IHC score is distinct from the first and second frequently-occurring IHC scores.

[0403] In some embodiments, the cMET-positive solid tumor cancer has developed resistance to targeted therapies against one or more actionable mutation(s) present in one or more gene selected from the group consisting of EGFR, ALK, KRAS, ROS, BRAE, NTRK1 / 2 / 3, MET. RET, ERBB2, and any other gene known to have an actionable mutation associated with the cancer.

[0404] In some embodiments, the actionable mutation is selected from one or more of the following: (a) an EGFR gene mutation selected from an exon 20 T790M substitution, an exon 20 C797X substitution, an exon 21 L858R substitution, and an exon 19 deletion, optionally wherein the exon 19 deletion is the E746_A750 deletion as determined by a regulatory agency approved test, (b) an ALK gene rearrangement; (c) a KRAS gene mutation, optionally wherein the mutation is an exon 2 G12C substitution: (d) a BRAF gene mutation, optionally wherein the mutation is in Exon 15 V600E substitution; (e) a MET gene mutation, optionally wherein the mutation is an ex14 skipping mutation: (f) SLR OS1 gene rearrangement, optionally where the ROS1 gene is fused with a gene or portion of a gene selected from one of the following: CD74, EZR, SDC4, SLC34A2, CCDC6, TFG, SEMAP, MYO5C. FIG, LIMA!, CLTC, GOPC, ZCCHC8, CEP72, MLL3, KDELR2, LRIG3,. MSN, MPRIP. WNKE SLC6AI 7, TMEM106B, FAM135B. TP. M3, and TPM52L (g) a fusion of the NTRK1, 2, or 3 gene; and (h) a RET gene rearrangement, optionally where the rearrangement is a fusion with KIF5B or CCDC6.

[0405] In some embodiments, the cancer has an amplification, mutation, or overexpression of the ERBB2Attorney Docket No. 45395-0071WO1gene, optionally wherein the ERBB2 gene has insertions in exon 20 and / or nucleotide substitutions encoding amino acid substitutions selected from one or more of the following; L755S, G776C, G660D, R678Q, E693K, and Q709L.

[0406] In some embodiments, the method further comprises administering to the subject an additional anticancer agent according to its regulatory agency-approved dosing regimen. In some embodiments, the additional anticancer agent is an inhibitor and / or targeting agent of EGFR, ALK, KRAS, ROS, BRAF, NTRK1 / 2 / 3, MET, RET, or ERBB2. In some embodiments, the additional anticancer agent is selected from osimertinib, afatinib, axitinib, bosutinib, crizotinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, ponatinib, radotinib, regorafenib, sorafenib, sunitinib, toceranib, and vatalanib; and / or wherein the additional anticancer agent is capable of inhibiting EGFR comprising an exon 21 L858R substitution or an exon 19 E746 A750 deletion.

[0407] In some embodiments, the ALK inhibitor is selected from alectinib, brigatinib, lorlatinib, ceritinib, and crizotinib; the KRAS inhibitor is selected from sotorasib and adagrasib; the BRAF inhibitor is selected from dabrafmib. vemurafenib, and trametinib; the MET inhibitor is selected from tepotinib. crizotinib, and capmatinib; the ROS 1 inhibitor is selected from emrectinib, crizotinib, ceritinib, and Iorlatinib; the NTRK 1 / 2 / 3 inhibitor is selected from larotrectinib and entrectinib: the RET inhibitor is selected from selpercatinib, pralsetinib. and cabozantinib; or the ERBB2 targeting agent is selected from trastuzumab-deruxtecan and trastuzumab-emtansine.

[0408] In some embodiments, the additional anticancer agent comprises an inhibitor of PD1, optionally an anti-PDl antibody, optionally wherein the anti-PDl antibody is pembrolizumab, nivolumab, or cemiplimab; or an inhibitor of PD-L1, optionally an anti-PD-Ll antibody such as durvalumab, or atezolizumab.

[0409] In some embodiments, the cMET-positive solid tumor cancer is resistant to prior treatment with an anti-cMET antibody, an anti-cMET ADC, a chemotherapy, a small molecule directed against cMET, and / or a radiation therapy.

[0410] In some embodiments, the cMET-positive solid tumor cancer is a cMET-overexpressing, MET amplified, and / or MET ex 14 skipping mutation non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is wildtype for human EGFR. In some embodiments, the NSCLC is mutated for human EGFR. In some embodiments, the NSCLC has resisted at least 1, 2, 3. 4. 5, 6, 7, 8. or more prior therapeutic regimen(s).

[0411] In some embodiments, the cMET-positive solid tumor cancer is an FGFR3 amplification or an EML4-ALK fusion NSCLC. In some embodiments, the cMET-positive solid tumor cancer has progressed after prior treatment with a tyrosine kinase inhibitor.

[0412] In some embodiments, the cMET-positive solid tumor cancer comprises one or both of the following: (a) an EGFR mutation substantially’ similar or identical to the EGFR mutation in the CTG-3414 PDX and / or NCI-H1975 CDX model, and / or (b) a KRAS mutation substantially similar or identical to the KRAS mutation in the NCI-H2122 CDX and / or NCI-H1373 CDX model.Attorney Docket No. 45395-0071WO1

[0413] In some embodiments, the cMET-positive solid tumor cancer composes actionable mutation(s) substantially similar or identical to the actionable mutation(s) in one or more of the following: (a) the actionable mutation(s) present in the Hs746T gastric cancer CDX model; (b) the actionable mutations(s) present in the MET TKI sensitive LU-01-1375 NSCLC PDX model; and / or (c) the actionable mutations(s) present in the CTG-2669 NSCLC PDX model

[0414] In some embodiments, the cMET-positive solid tumor cancer is characterized as being a MET TKI-sensitive cancer comprising a MET Exon 14 skipping mutation. In some embodiments, the method further comprises administration of a MET TKI. In some embodiments, the MET TKI is capmatinib or tepotinib.

[0415] In some embodiments, the cMET-positive solid tumor cancer is a MET amplified gastric tumor comprising a MET Exon 14 skipping mutation.

[0416] In some embodiments, the cMET-positive solid tumor cancer comprises an actionable mutation substantially similar or identical to the actionable mutations in the LU-01-1476 PDX model.

[0417] In some embodiments, the method further comprises administration of a MET TKI.

[0418] In an aspect, the present disclosure provides a method of treating a cMET-positive solid tumor cancer in a subject, wherein the subject’s tumor had not responded to or has progressed after prior treatment with a MET tyrosine kinase inhibitor (TKI), the method comprising administering to the subject two or more doses of MYTX-011, wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

[0419] In some embodiments, the subject’s tumor has not responded to (or has progressed despite) 2 prior lines of treatment. In some embodiments, the subject’s tumor has not responded to (or has progressed despite) 4 prior lines of treatment. In some embodiments, the subject’s tumor has not responded to (or has progressed despite) 5 prior lines of treatment. In some embodiments, the subject’s tumor has not responded to (or has progressed despite) 6 prior lines of treatment.

[0420] In some embodiments, the MET TKI is capmatinib or tepotinib.

[0421] In some embodiments, the doses of MYTX-011 are administered as a pharmaceutical composition comprising L-histidine, L-histidine HCl monohydrate, D(+)-trehalose dihydrate, and polysorbate 80.

[0422] In some embodiments, the subject’s tumor has not responded to (or has progressed despite) 2. 3, 4, 5, 6, 7, 8, 9, or 10 prior lines of treatment. In some embodiments, one of the prior treatments comprised administration of a non-MET-targeting TKI associated with compensatory upregulation of cMET by the cells of the subject’s tumor (and / or associated metastases as applicable).Tyrosine Kinase Inhibitors in NSCLC Treatment: Focus on MET-Mediated MechanismsEGFR-Targeted TKIs

[0423] I) Gefitinib (Iressa®); Target: EGFR (First-generation, reversible); Resistance in NSCLC: Develops in virtually all patients within 9-14 months (median PFS). MET-Mediated Resistance: Approximately 5-20% of EGFR TKI resistance cases show MET amplification as the primary resistance mechanism. METAttorney Docket No. 45395-0071WO1amplification drives ERBB3 (HE-R3)-dependent activation of PI3K / AKT signaling, bypassing EGFR inhibition (Engelman et al.. Science, Vol. 316, pp. 1039-1043, 2007). Additionally, MET-mediated resistance can occur via MET hyperactivation through HGF upregulation in the tumor microenvironment (Turke et al.. Cancer Cell. Vol. 17, pp. 77-88. 2010).

[0424] 2) Erlotinib (Tarceva®): Target: EGFR (First-generation, reversible); Resistance in NSCLC: Universal development of resistance (median PFS 9-13 months). MET-Mediated Resistance: Similar MET amplification profile to gefitinib (5-20%). In vitro studies confirm that MET-amplified cell lines demonstrate continued P13K / AKT signaling despite EGFR inhibition (Bean et al., PNAS, Vol. 104, pp 20932-20937, 2007). MET overexpression detected in approximately 21% of patients with acquired resistance (Gainor et al., Clinical Cancer Research, Vol. 19, pp. 2240-2247, 2013).

[0425] 3) Afatinib (Gilotrif®); Target: Pan-HER (Second-generation, irreversible - EGFR / HER2 / HER4); Resistance in NSCLC: Common, though slightly delayed compared to first-generation TKIs (median PFS 11 - 14 months). MET-Mediated Resistance: MET amplification observed in 5-8% of afatinib-resistant cases. Some evidence suggests potentially lower incidence compared to first-generation inhibitors due to HER2 / HER4 co-inhibition. but MET remains a significant bypass pathway (Huang et al.. Journal of Clinical Oncology, Vol.36, pp. 1108-1117, 2018).

[0426] 4) Osimertinib (Tagrisso®); Target: EGFR including T790M mutant (Third-generation, irreversible); Resistance in NSCLC: Inevitable despite improved efficacy (median PFS 18-19 months). MET-Mediated Resistance: Higher prevalence of MET amplification (15-30%) compared to first / second-generation EGFR TKIs, representing the most common bypass resistance mechanism to osimertinib (Oxnard et al.. Nature Communications, Vol. 9, pp. 1-8, 2018). Preclinical evidence shows MET pathway activation induces EMT (epithelial-mesenchymal transition) and sternness-related phenotypes in osimertinib-resistant cells (Oztan et al. Clinical Cancer Research, Vol. 27, pp 1789-1803. 2021)

[0427] 5) Lazertinib; Target: EGFR including T790M mutant (Third-generation, irreversible): Resistance in NSCLC: Emerging data show development of resistance similar to osimertinib. MET-Mediated Resistance: Preclinical evidence suggests MET amplification as a major resistance mechanism. In vitro studies demonstrate that combination with savolitinib (MET inhibitor) significantly improves response in MET-amplified models (Cho et al., Journal of Thoracic Oncology, Vol. 15, pp. 1657-1669. 2020).ALK-Targeted TKIs

[0428] 1) Crizotinib (Xalkori®); Target: ALK, ROS1, MET (First-generation, multi-targeted); Resistance in NSCLC: essentially universal within approximately 11 months (median PFS). MET-Mediated Resistance: The field has reported that, despite being a MET inhibitor itself, resistance can develop through MET amplification or MET-independent mechanisms. Inadequate CNS penetration and moderate MET inhibitory potency of crizotinib has been reported to lead to incomplete MET inhibition, particularly in brain metastases (Costa et al. Clinical Cancer Research, Vol. 27, pp. 34-43, 2021).

[0429] 2) Alectinib (Alecensa®); Target: ALK (Second-generation, selective). Resistance in NSCLC:Attorney Docket No. 45395-0071WO1Develops in majority of patients (median PFS 25-34 months). MET-Mediated Resistance: MET pathway activation identified as a bypass mechanism in approximately 8-10% of alectinib-resistant cases. Xenograft models show MET overexpression / amplification drives resistance through downstream MAPK reactivation (Tam et al., Molecular Cancer Therapeutics, Vol. 19, pp. 2277-2289, 202.0).

[0430] 3) Brigatinib (Alunbrig®): Target: ALK, ROS1 (Second-generation); Resistance in NSCLC: Eventually develops despite improved efficacy (median PFS 24-29 months). MET-Mediated Resistance: MET amplification and HGF overexpression documented in clinical specimens, with frequencies of approximately 5-13% in resistance cases. Co-targeting MET was reported to enhance brigatinib activity in resistant models (Recondo et al., Nature Communications, Vol. 11. pp. 1-14, 2020).

[0431] 4) Lorlatinib (Lorbrena®); Target: ALK, ROS1 (Third-generation): Resistance in NSCLC: Develops despite potent activity and CNS penetration. MET-Mediated Resistance: MET amplification identified in approximately 7-10% of resistance cases. Interesting “‘ping-pong” pattern reported where MET-mediated resistance to first / second-generation ALK TKIs may revert to ALK-dependent signaling with lorlatinib, and vice versa (Shaw et al.. Cancer Discovery, Vol. 9, pp. 1736-1751, 2019).MET-Targeted TKIs or other Active Agents

[0432] 1) Tepotinib (Tepmetko®): Target: MET (Selective): Resistance in NSCLC: Emerging data reported to show development of resistance within 8-11 months (median PFS). MET-Mediated Resistance: Secondary MET mutations (D1228 and Y 1230) identified that confer resistance by preventing drug binding. Interestingly, the authors reported that resistance may not be achieved via traditional MET amplification or upregulation, but rather through structural changes to the target itself or activation of parallel signaling pathways (Fujino et al., Nature Medicine, Vol. 25. pp. 615-622, 2019).

[0433] 2) Capmatinib (Tabrecta®): Target: MET (Selective): Resistance in NSCLC: Develops within approximately 9-12 months (median PFS) MET-Mediated Resistance: Secondary MET mutations at D1228 and Y1230 residues are reported to be primary mechanisms. Limited evidence of MET amplification as a resistance mechanism; instead, data reported by Wolf and colleagues suggests a parallel pathway activation (EGFR, HER2, AXL) (Wolf et al., New England Journal of Medicine, Vol. 383, pp. 944-957, 2020).

[0434] 3) Savolitinib; Target: MET (Selective); Resistance in NSCLC: Emerging data suggest development of resistance: ME T-Mediated Resistance: Similar pattern of secondary MET mutations (D1228 and Y1230) as observed with other MET inhibitors. Preclinical evidence suggests potential benefit for alternating MET TKIs with different binding profiles to address specific resistance mutations (Lu et al., Journal of Medicinal Chemistry, Vol. 61, pp. 4290-4302, 2018).

[0435] 4) Amivantamab-vmjw (Rybrevant®); Target; EGFR / MET bispecific antibody (Not a small molecule TKI but relevant to MET targeting); Resistance in NSCLC: Preliminary data suggest eventual development of resistance. MET-Mediated Resistance: Designed specifically to address MET-mediated resistance to EGFR TKIs. Early resistance mechanisms appear to involve parallel pathway activation rather than further MET alterations. According to the publication, the bispecific nature was specifically designed to circumvent MET-Attorney Docket No. 45395-0071WO1mediated resistance to EGFR TKIs (Park et al, Nature Medicine, Vol. 26, pp. 1910-1916, 2020).

[0436] Other TKIs known to induce upregulation of cMET levels in cancer cells are known in the field.

[0437] In an embodiment, treatment with at least one effective dose of MYTX-011 is effective against a NSCLC tumor that has either not responded or has progressed after prior treatment with any one of the preceding TKIs. more particularly, one of the preceding MET-targeting TKIs.Adjunctive Therapies10438] In some embodiments, the anti-cMET pH-ADCs may be used with or adjunctive to other anti-cancer agents and / or treatment regimens. In some embodiments, the anti -c MET and other agent(s) may be co- fonnuiated or separately formulated, and administered via single or different dosing regimens.

[0439] Other agents include, for example, alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, ALK kinase inhibitors (e.g., crizotinib (XALKORI®), ceritinib (ZYKADIA®), and alectinib (ALECENSA®), apoptosis promoters (for example. Bcl-2 family inhibitors), activators of death receptor pathway, Bcr-Abl kinase inhibitors, BiTE antibodies. ADCs, CDK inhibitors, cell cycle inhibitors, Cox-2 inhibitors, DVDs. ErbB2 receptor inhibitors, GF inhibitors, HSP-90 inhibitors, HDAC inhibitors, hormones, immunologicals, inhibitors of inhibitors of apoptosis proteins (IAPs), intercalating antibiotics, kinesin inhibitors, Jak2 inhibitors. mTOR inhibitors, microRNAs, MEK inhibitors, NSAIDs, PARI’ inhibitors, platinum chemotherapeutics, polo-like kinase (Plk) inhibitors. PI3K inhibitors, proteasome inhibitors, purine analogs, pyrimidine analogs. RTK inhibitors, retinoids / deltoids plant alkaloids, siRNAs, topoisomerase inhibitors, ubiquitin ligase inhibitors, and the like, and / or combinations thereof.

[0440] Anti-cMET pH-ADCs may also be used to enhance the efficacy of radiation therapy, e.g., external beam, internal (i.e., brachytherapy) and systemic radiation therapy,

[0441] Anti-cMET pH-ADCs may be administered with or adjunctive to the following: ABRAXANE™ (ABI-007). ABT-100 (tamesyl transferase inhibitor), ADVEXIN®. ALTOCOR® or MEVACOR® (lovastatin). AMPL1GEN®, APTOSYN® (exisulind). AREDIA® (pamidronic acid), arglabin. L- asparaginase, atamestane (1-methyl-3,17-dione-androsta-1,4-diene), AVAGE® (tazarotene), AVE- 8062 (combreastatin derivative) BEC2 (mitumomab), cachectin or cachexin (TNF), canvaxin, CEA VAC® (cancer vaccine), CELEUK®' (celmoleukin), CEPLENE® (histamine dihydrochloride), CERVARIX® (HPV vaccine), CHOP® [C: CYTOXAN® (cyclophosphamide); H: ADRIAMYCIN® (hydroxydoxorubicin); O: Vincristine (ONCOVIN®): P: prednisone], CYPAT™ (cyproterone acetate), combrestatin A4P, DB(389)EGF or TransMID-107R™ (diphtheria toxins), dacarbazine, dactinomycin, 5,6-dimethyixantbenone~4-acetic acid (DMXA ), enihiracil, EVIZON™ (squalamine lactate), DIMERICINE® (T4N5 liposome lotion), discodermolide, DX-8951f (exatecan mesylate), enzastaurm, EPO906 (epithilone B), GARDASIL®, GASTRIMMUNE®, GENASENSE®, GMK (ganglioside conjugate vaccine), GV AX® (prostate cancer vaccine), halofuginone, histrelin, hydroxy carbamide, ibandronic acid. IGN-101, 1L-13-PE38, IL-13-PE38QQR (cintredekin besudotox), IL-13-Attorney Docket No. 45395-0071WO1pseudomonas exotoxin, interferon-a, interferon-y, JUNOVAN™ or MEPACT™ (mifamurtide), lonafamib, 5,10- methylenetetrahydrofolate, miltefosine, NEOVASTAT® (AE-941), NEUTREXIN® (trimetrexate glucuronate), NIPENT® (pentostatin), ONCONASE® (a ribonuclease enzyme). ONCOPHAGE®, ONCOVAX® (IL-2 Vaccine). ORATHECIN™ (rubitecan). OSIDEM®, OVAREX® MAb, paclitaxel. PANDIMEX™, panitumumab, PANVAC®-VF (vaccine), pegaspargase, PEG Interferon A, phenoxodiol, procarbazine, rebimastat, REMOVAB® (catumaxomab), REVLIMID® (lenalidomide), RSR13 (efeproxiral), SOMATULINE® LA (lanreotide), SORIATANE® (acitretin), staurosporine, talabostat (PT100), TARGRETIN® (bexarotene), TAXOPREXIN® (DHA -paclitaxel), TELCYTA® (canfosfamide, TLK286), temilifene, TEMODAR® (temozolomide), tesmilifene, thalidomide, THERATOPE® (STn-KLH), thymitaq, TNFERADE™, TRACLEER® or ZAVESCA® (bosentan), tretinoin (Retin-A), tetrandrine, TRISENOX®. VIRUL1ZEM®, ukram, vitaxm, XCYTRIN® (motexafm gadolinium). XINLAY™ (atrasentan). XYOTAX™ (paclitaxel poliglumex), YONDELIS® (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), ZOMETA® (zolendronic acid), zorubicin, and combinations thereof

[0442] Adjunctive therapies are typically administered according to their FDA label and / or manufacturer’s recommendations, and it is envisioned that the anti-cMET pH-ADCs may produce optimal therapeutic benefit when administered once every two weeks, once every three weeks, or once every four weeks. In some embodiments, more or less frequent administration may also provide benefits.Administration Regimens and Dosages

[0443] The amount of anti-cMET pFI-ADC administered will depend upon multiple factors, including, e g., the particular tumor type and stage, the mode / route and frequency of administration, the nature of the ADC payload, and patient parameters including age, weight, and the like. Skilled artisans will appreciate how to optimize dosages using routine practices. In some embodiments, doses are estimated from in vivo animal models or clinical trials.

[0444] In some embodiments, administration of the anti-cMET pH-ADCs is via a route appropriate for the condition being treated. In some embodiments, tire anti-cMET pH-ADC is administered via a parenteral route (e.g. infusion, intramuscular, subcutaneous, intravenous (IV), intradermal, intrathecal, bolus, intratumoral injection or epidural. In one embodiment, the anti-cMET pH-ADC is provided as a frozen liquid or a lyophilized powder in a vial. Each vial may contain, e.g., 0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, or 100 mg of die anti-cMET pH-ADC. In one embodiment, liquid is brought to a suitable administration volume with sterile water for injection (WFI) to provide a solution containing 10 mg / mL anti-cMET pH-ADC. In some embodiments, infusion is optimally performed once every 14 days, once every 21 days, or once every 28 days. In some optimal embodiments, the infusion is performed once every 21 days.

[0445] In an embodiment, the infusion of the anti-cMET pH-ADC is performed once every 21 days for two cycles followed by a dose break of between 2, 3, and 4 weeks, more particularly, 3 weeks, followed by two additional infusions of the anti-cMET pH-ADC performed once every 21 days after the dose break.Attorney Docket No. 45395-0071WO1

[0446] In one exemplary embodiment, an anti-cMET ADC is administered once every 21 days at about 0.3, 0.6, 0.9, 1.2, 1.5, 1.6, 1.8, 1.9, 2.1, 2.2, 2.4, 2.7, 3.0, 3.3, 3.6, 3.9, 4.2, 4.5, 4.8, 5.0, 5.2, 5.5, 5.8, 6.0, 6.2, 6.5, 6.8, 7.0, 7.2. 7.5, 7.8, 8.0, 8.2, 8.5, 8.8, 9.0, 9.2, 9.5. 9.8, or about 10.0 mg / kg of the subject's body weight. In one embodiment, the administration is at about 1.0 to about 8.0 mg / 'kg, at about 2.0 to about 7.0 mg / kg, at about 3.0 to about 6.0 mg / kg, or is at about 4.0 to about 5.5 mg / kg In a particular embodiment, administration proceeds until disease remission, unacceptable toxicity, or disease progression.

[0447] In one embodiment, the cancer is a cMET+ or cMET-overexpressing NSCLC adenocarcinoma and the anti-cMET ADC is MYTX-011, administered at between about 2,0 and about 10.0 mg / kg or between about 4.0 mg / kg and about 8 mg / kg every 21 days. In other embodiments, the patient has an H-score between 150 to 224 or > 225 and / or a tumor IHC score of 2+ or 3+-. In another embodiment, the cancer is a squamous cell NSCLC carcinoma (scNSCLC), the anti-cMET pH-ADC is MYTX-011 administered at between about 4.0 and 6.0 mg / kg every 21 days, and the patient has an H-score between 100 to 224 or an IHC score of between about 1+ and about 2+. In another embodiment, an anti-cMET pH-ADC is administered once every 28 days.

[0448] In embodiments where additional agents are administered with the anti-cMET pH-ADC, the agent may be selected from cabazitaxel, colcemid, colchicine, cryptophycin, democolcine, docetaxel, nocodazole, paclitaxel, taccalonolide, taxane, and vinblastine.

[0449] In particular embodiments, an anti-cMET pH-ADC is used adjunctive to TARCEVA® (erlotinib) or GILOTRIF® (afatinib) to treat NSCLC. Erlotinib may be administered orally at 150 mg / day, or afatinib may be administered orally at 40 mg / day, each until disease progression or no longer tolerated by the patient. In one embodiment, tire afatinib is administered to patients with tumors having EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. In another embodiment, erlotinib is administered to patients with tumors having EGFR-mutated adenocarcinoma. In a particular embodiment, erlotinib is administered to patients with EGFR wildtype adenocarcinoma tumors

[0450] In another embodiment, an anti-cMET pH-ADC is used adjunctive to TAGRISSO® (osimertinib). The typical adult dose of osimertinib for NSCLC is 80 mg orally once a day. Osimertinib may be used as an adjuvant therapy after tumor resection whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations. Osimertinib may also be used for treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, and for treatment of patients with metastatic EGFR T790M mutation -positive NSCLC, whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy.

[0451] In other embodiments, an anti-cMET pH-ADC is used adjunctive to one of the following agents to treat NSCLC (each pairing represents a specific embodiment): osimertinib (TAGRISSO®); IRESSA® (gefitiiiib); OPDIVO® (nivolumab); OPDIVO® (nivolumab) and YERVOY® (ipilimumab); pembrolizumab (KEYTRUDA®); cisplatin to treat NSCLC; carboplatin; veliparib; veliparib and pemetrexed; cetuximab; ipilimumab (YERVOY®); radiation; AVASTIN® (bevacizumab); gemcitabine (GEMZAR®); afatinib (GILOTRIF®); axitinib (INLYTA®); bosutinib (BOSULIF®); crizotinib (XALKORI®); dasatinib (SPRYCEL®);Attorney Docket No. 45395-0071WO1erlotinib (TARCEVA®); gefitinib (IRESSA®); imatinib (GLEEVEC®); lapatinib (TYVERB®); nilotinib (TASIGNA®); pazopanib (VOTRIENT®); ponatinib (ICLUSIG®); radotinib (SUPECT®); regorafenib (STIVARGA®); sorafenib (NEXAVAR®); sunitinib (SUTENT®); toceranib (PALLADIA®); and vatalamb.

[0452] In yet other embodiments, an anti-cMET pH-ADC is used adjunctive to one of the following agents to treat the indicated cancer (each pairing with each indication represents a specific embodiment): GEMZAR® to treat pancreatic, ovarian, breast, or NSCLC cancer; paclitaxel albumin-stabilized nanoparticle formulation (ABRAXANE®) to treat breast or lung cancer; ABRAXANE® plus GEMZAR® to treat pancreatic cancer; AVASTIN® (bevacizumab) to treat colorectal, lung, or ovarian cancer; or FOLFIRINOX (or FOLFIRI or FOLFOX or irinotecan (optionally ONIVYDE®) or 5-FU or capecitabine) to treat colorectal cancer.

[0453] For each of the foregoing, the anti-cMET pH-ADC may be administered at about 1.0 to about 10.0 mg / kg. about 2.0 to about 9.0 mg / kg. about 3.0 to about 8.0 mg / kg. about 4.0 to about 7.0 mg / kg, about 4.5 to 6.5 mg / kg, about 4.5 to 6.0 mg / kg, or about 5.0 mg / kg of body weight once every 14 or 21 days. The anti-cMET pH-ADC / adjunctive therapy is continued until disease remission, disease progression, or until it is no longer tolerated by the patient

[0454] As will be appreciated by skilled artisans, the various agents described above may be administered at their recommended or customary doses, or the doses may be adjusted to maximize therapeutic benefit and / or to optimize patient response.

[0455] In alternative embodiments, all numbers expressing % purity, quantities of ingredients, and the like, used throughout this disclosure, are modified by the term “about”.Patient Selection

[0456] ADCs described herein may be administered to patients with cMET+ and cMET-overexpressing tumors, including but not solely, any solid tumor. Patients may be selected based upon the level of cMET present in their tumors, as classified by IHC assay (see Example 11). Briefly here. cMET levels are measured using the Ventana cMET (SP44) kit. Tissue samples are stained and then scored by determining the percentages of cells staining at various intensity levels. FIGs. 4A & 4B present representative sections having IHC scores of lx 2+, and 3+

[0457] The anti-cMET pH-ADCs described herein may be used for a variety of purposes, and in one particular embodiment, the pH-ADCs may be used to treat cMET+, cMET-overexpressing, and / or MET-amplified tumors in humans. The pH-ADCs may also be used to treat tumors carrying Exon 14 mutations of the MET gene.

[0458] The anti-cMET pH-ADCs may also be used to treat patients having tumors carrying EGFR Exon 19 deletions and / or EGFR Exon 21 mutations (L858R) (Castaneda-Gonzalez JP et al. Multiple mutations in the EGFR gene in lung cancer: a systematic review. Transl Lung Cancer Res. 2022 Oct; 11( 10):2148-2163, which is herein incorporated by reference in its entirety).

[0459] The anti-cMET pH-ADCs may be used to treat a subject, including a human patient, previouslyAttorney Docket No. 45395-0071WO1identified or selected as having low-expression, intermediate expression, cMET-amplification, cMET exon mutation, or having cMET-positive and EGFR kinase inhibitor resistant cancer. In some embodiments, the method comprises the step of determining that the subject or human subject has low cMET expression, intermediate cMET overexpression, high cMET overexpression. cMET-amplification. a cMET exon mutation, or a cMET-positive and EGFR kinase inhibitor resistant cancer, and selecting the subject or human patient for treatment.

[0460] The anti-cMET pH-ADCs may also be used to treat a subject, including a human patient, wherein the subject or patient has unresectable, metastatic, or advanced solid tumors. In some embodiments, the subject or human patient was previously non-responsive to prior treatment and / or their cancer progressed on the prior treatment. In still other embodiments, the subject or human patient was non-responsive and / or had cancer that progressed upon treatment with an EGFR kinase inhibitor.

[0461] In some embodiments, a human patient (female or male) is selected for treatment with the anti-cMET pH-ADCs of the disclosure because the patient has histologically or cytologically confirmed locally advanced, recurrent, or metastatic NSCLC and has received available standard of care therapy, with any number of prior therapies. The patient also has at least one measurable cancer lesion per RECIST 1.1 and ideally an ECOG performance status of 0 or 1. Acute effects of prior therapy or surgical procedures should be resolved to < Grade 1 or baseline (except alopecia, stable immune related toxicity such as hypothyroidism on hormone replacement, adrenal insufficiency on < 10 mg daily prednisone (or equivalent) or anemia). Tire patient’s cardiac LVEF is > 50% by either echocardiogram or MUGA scan and there is adequate organ function as defined by: a) absolute neutrophil count (ANC) > 1500 cells / mm3(without growth factors within 1 week of first dose); b) Platelet count > 75,000 / mm3(platelet transfusion not allowed within 1 week prior to first dose of study drug administration); c) Hb > 9 g / dL (RBC transfusion not allowed within 1 week prior to first dose); d) International normalized ratio (INR) activated partial thromboplastin time (aPTT) and prothrombin time (PT) < 1.5 X treatment facility's ULN (but patient’s on stable anticoagulant doses may be treated); e) calculated creatinine clearance >30 mL / min as calculated by the Modified Cockcroft-Gault formula; f) Total bilirubin < 1.5 X ULN, < 2.0 X ULN for patients with Gilbert syndrome; g) AST and ALT < 2.5 X ULN for patients without liver metastases; h) alkaline phosphatase < 1.5 X ULN unless clearly attributable to a non-hepatic source; i) serum albumin > 3.0 g / dL j) HbAlC < 7.5%. Diabetic patients should be on a stable dose of antidiabetic medications.

[0462] In some embodiments, patients are selected because they do not have an actionable EGFR mutation, optionally wherein their tumors have other driver mutations. Patients must have progressed on at least 1 line of prior therapy in the locally advanced / metastatic setting (multiple lines of tyrosine kinase inhibitor (TKI ) for the same actionable mutation count as 1 line of therapy). Maintenance therapy is not considered a separate line of therapy. Adjuvant and neoadjuvant therapies count as 1 line of therapy if given within 6 months of treatment with the disclosed pH-ADCs. Patients without any actionable gene alteration must have progressed on (or be considered ineligible for), or be intolerant to, platinum -based chemotherapy and immune checkpointAttorney Docket No. 45395-0071WO1inhibitor (as monotherapy or in combination with chemotherapy).

[0463] Patients with actionable gene alterations (other than EGFR) for which immune checkpoint inhibitor therapy is not SOC (e.g., anaplastic lymphoma kinase [ALK] translocation) must have progressed on (or be considered ineligible for), or be intolerant to. anticancer therapy targeting dri ver gene alterations and platinum¬ based chemotherapy.

[0464] Patients with actionable gene alterations (other than EGFR) for which immune checkpoint inhibitor is SOC must have progressed on (or be considered ineligible for), or be intolerant to, anticancer therapy targeting driver gene alternation and platinum-based chemotherapy, and also progressed on (or be considered ineligible for), or be intolerant to, immune checkpoint inhibitor (as monotherapy or in combination with platinum-based chemotherapy).

[0465] In some embodiments, the selected patients have histologically or cytologically confirmed locally advanced, recurrent (and not a candidate for curative therapy), or metastatic non-squamous NSCLC; and tumor sample with high cMET overexpression by IHC (3+ with tumor cell positivity of >50%) confirmed by central laboratory testing.

[0466] In some embodiments, the selected patients have histologically or cytologically confirmed locally advanced, recurrent (and not a candidate for curative therapy), or metastatic non-squamous NSCLC; and tumor sample with intermediate cMET expression by IHC (3+ with tumor cell positivity of >25% to <50%) confirmed by central laboratory' testing.

[0467] In some embodiments, the selected patients have histologically or cytologically' confirmed locally advanced, recurrent (and not a candidate for curative therapy), or metastatic squamous NSCLC; and tumor sample with cMET overexpression by IHC (2+ with tumor cell positivity of >25%) confirmed by central laboratory testing.

[0468] In some embodiments, the selected patients have histologically or cytologically confirmed locally advanced, recurrent (and not a candidate for curative therapy), or metastatic NSCLC; tumor sample that does not meet cMET IHC entry’ criteria for Cohorts A and B (for subjects with non-squamous NSCLC) and C (for subjects with squamous NSCLC) based on central laboratory testing; known MET amplification or exon 14 skipping mutations, respectively, performed in a CLIA-certified laboratory m the United States (US) or equivalently accredited diagnostic laboratory outside the US; and subjects with MET exon 14 skipping mutations must have received MET TKI therapy, if available and considered SOC

[0469] In some embodiments, the selected patients have histologically or cy tologically confirmed locally advanced, recurrent (and not a candidate for curative therapy), or metastatic NSCLC; evidence of cMET expression by IHC as documented in medical records; evidence of negative cMET expression by IHC would be excluded; and have previously received and had disease progression following either a cMET-targeted ADC or antibody therapy.

[0470] Response to MYTX-011 and other anti-cMET pH-ADCs disclosed herein may correlate with cMET expression at both the genomic and protein level.Attorney Docket No. 45395-0071WO1EMBODIMENTS

[0471] The following listing of exemplary aspects supports and is supported by the disclosure provided herein Each “method of treating” embodiment may be reformulated to produce “use” embodiments. For example, a “method of treating condition Y comprising the step of administering an effective amount of composition X” is intended to include the phrases “use of a composition X for the treatment of condition Y”, “use of a composition X in the manufacture of a medicament for treating condition Y”, and the like.

[0472] Embodiment 1. A method of treating a cMET+, cMET-overexpressing, and / or MET-amplified solid tumor cancer, comprising administering an effective amount of an anti-cMET antibody drug conjugate (ADC) to a human subject having said cancer, over a sufficient period of time to provide a therapeutic benefit, wherein the antibody component of the ADC exhibits cMET-specific pH-dependent binding, and optionally wherein the antibody comprises heavy and light chain CDRs present in the amino acid sequences as set forth in one of the following pairs: SEQ ID NOs: 15 & 16; SEQ ID NOs: 5 & 6; SEQ ID NOs: 7 & 8; SEQ ID NOs: 9 & 10; SEQ ID NOs: 11 & 12; SEQ ID NOs; 13 & 14; SEQ ID NOs: 17 & 18; SEQ ID NOs: 19 & 20; SEQ ID NOs: 21 & 22; SEQ ID NOs: 23 & 24; SEQ ID NOs: 25 & 26, SEQ ID NOs: 27 & 28; SEQ ID NOs: 29 & 30; SEQ ID NOs: 31 & 32; and SEQ ID NOs: 33 & 34; optionally wherein the CDRs are determined using the Rabat or the IMGT system.

[0473] Embodiment 2. A method of treating a cMET-positive or cMET-overexpressing solid tumor cancer having low or intermediate expression of cMET, comprising administering an effective amount of an anti-cMET antibody drug conjugate (ADC) to a human subject previously identified or selected as having said cancer, over a sufficient period of time to provide a therapeutic benefit, wherein the antibody component of the ADC exhibits cMET-specific pH-dependent binding, and optionally wherein the antibody comprises heavy and light chain CDRs present in the ammo acid sequences as set forth in one of the following pairs: SEQ ID NOs: 15 & 16: SEQ ID NOs: 5 & 6; SEQ ID NOs: 7 & 8; SEQ ID NOs: 9 & 10; SEQ ID NOs: 11 & 12; SEQ ID NOs: 13 & 14; SEQ ID NOs: 17 & 18; SEQ ID NOs: 19 & 20; SEQ ID NOs: 21 & 22; SEQ ID NOs: 23 & 24; SEQ ID NOs: 25 & 26; SEQ ID NOs: 27 & 28; SEQ ID NOs: 29 & 30; SEQ ID NOs: 31 & 32; and SEQ ID NOs: 33 & 34; optionally wherein the CDRs are determined using the Kabat or the IMGT system.

[0474] Embodiment 3. A method of treating a cMET-positive or cMET-overexpressing solid tumor cancer having a cMET immunohistochemistry score of 1+, 2+, or 3+, and / or an H-score of at least about 50 to 300, comprising administering an effective amount of an anti-cMET antibody drug conjugate (ADC) to a human subject previously identified or selected as having said cancer, over a sufficient period of time to provide a therapeutic benefit, wherein the antibody component of the ADC exhibits cMET-specific pH-dependent binding, and optionally wherein the antibody comprises heavy and light chain CDRs present in the amino acid sequences as set forth in one of the following pairs: SEQ ID NOs: 15 & 16; SEQ ID NOs: 5 & 6; SEQ ID NOs: 7 & 8; SEQ ID NOs: 9 & 10; SEQ ID NOs: 11 & 12; SEQ ID NOs: 13 & 14; SEQ ID NOs: 17 & 18; SEQ ID NOs: 19 & 20; SEQ ID NOs: 21 & 22, SEQ ID NOs: 23 & 24; SEQ ID NOs: 25 & 26; SEQ ID NOs: 27 & 28;Attorney Docket No. 45395-0071WO1SEQ ID NOs: 29 & 30; SEQ ID NOs: 31 & 32; and SEQ ID NOs: 33 & 34; optionally wherein the CDRs are determined using the Rabat or the IMGT system.;0475 Embodiment 4. The method of any one of embodiments 1-3, wherein the cancer is non-small cell lung cancer (‘'NSCLC”). optionally selected from non-squamous NSCLC. squamous NSCLC, and not otherwise specified NSCLC. Optionally, the heavy chain and the light chain of the antibody component of the ADC comprises the heavy chain CDRs and the light chain CDRs present in SEQ ID NO: 15 and SEQ ID NO: 16, respectively, and / or the heavy chain comprises the sequence set forth in SEQ ID NO: 15 and the light chain comprises the sequence set forth in SEQ ID NO: 16.

[0476] Embodiment 5 The method of any one of embodiments 1-4, wherein a biopsy from a tumor of said cancer and / or the entire tumor itself, comprises at least about 1%, 2%, 3%. 4%, 5%, 6%. 7%, 8%, 9%, 10%.15%. 20%, 25%, 30%. 35%, 40%, 45%. 50%, 60%, 70%, 80%, 90%, or 100% of cancer cells having a cMET expression level of at least a 1+. a 2+, or a 3+. as scored by an applicable and / or regulatory-agency approved immunohistochemistry (IHC) assay.

[0477] Embodiment 6. The method of embodiment 5, wherein at least abou t 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%. 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% of the tumor cells have an IHC score of 1+ or 2+.

[0478] Embodiment 7. The method of embodiment 6, wherein at least about 1%. 2%, 3%, 4%, 5%. 6%, 7%, 8%, 9%. 10%, 15%, 20%, 25%, 30%. 35%, 40%, 45%, 50%,, 60%, 70%, 80%, 90%, or 100% of the tumor cells have an IHC score of 2+.

[0479] Embodiment 8. The method of embodiment 6, wherein at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% of the tumor cells have an IHC score of 1+.

[0480] Embodiment 9 The method of embodiment 5, 6, or 8, wherein at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%. 8%, 9%, 10%, 15%, or about 20% of the tumor cells have an IHC score of 1+ and wherein no more than about 1%, 2%, 3%, 4% or 5% of the tumor cells have an IHC score of 2+ or 3+.

[0481] Embodiment 10. The method of embodiment 9, wherein no more than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, or about 20% of the tumor cells have an IHC score of 2+ and wherein no more than about 1% have an IHC score of 3+.

[0482] Embodiment 11. The method of embodiment 1, wherein no tumor cells have an IHC score of greater than 2+

[0483] Embodiment 12. The method of embodiment 11, wherein no tumors cells have an IHC score of greater than 1+-.

[0484] Embodiment 13. The method of any one of embodiments 1 to 5, further comprising the steps of determining an H-score for the tumor, wherein the H-score is between about 10 and about 250

[0485] Embodiment 14. The method of embodiment 13, wherein the H-score is between about 20 and about 275Attorney Docket No. 45395-0071WO1

[0486] Embodiment 15. The method of embodiment 14, wherein the H-score is between about 20 and about 200.

[0487] Embodiment 16. The method of embodiment 15, wherein the H-score is between about 20 and about 175

[0488] Embodiment 17. The method of embodiment 16, wherein the H-score is between about 20 and about 150.

[0489] Embodiment 18. The method of embodiment 17, wherein the H-score is no more than about 100

[0490] Embodiment 19. The method of embodiment 18, wherein the H-score is no more than about 90,

[0491] Embodiment 20. The method of embodiment 18, wherein the H-score is no more than about 80.

[0492] Embodiment 21. The method of embodiment 18. wherein the H-score is no more than about 70.

[0493] Embodiment 22. The method of embodiment 18, wherein the H-score is no more than about 50.

[0494] Embodiment 23. The method of any one of embodiments 1-22, wherein the tumor is homogeneous for cMET expression and / or MET amplification

[0495] Embodiment 24. The method of any one of embodiments 1-22, wherein the tumor is heterogeneous for cMET expression and / or MET amplification.

[0496] Embodiment 25. The method of embodiment 24. wherein at least about 10%, 20%. or 30% of the tumor cells have a first frequently occurring IHC score selected from one of 0, 1+, 2+, and 3+ and at least about 10%, 20%, or 30% of the tumor cells have a second frequently occurring IHC score selected from one of 0, 1+, 2+, and 3+, wherein the first and second frequently occurring IHC scores are different.

[0497] Embodiment 26. The method of embodiment 25, wherein tire first and second IHC scores are selected from the following pairs of scores: (0, +1), (0, +2), (0. +3), (+1, +2), (+1, +3), and (+2, +3).

[0498] Embodiment 27. The method of embodiment 25 or 26, wherein at least about 10%, 20%, or 30% of the tumor cells have a third frequently occurring IHC score, w'herein the third score is distinct from the first and second frequently occurring IHC scores.

[0499] Embodiment 28. The method of any one of the preceding embodiments, wherein the cancer has developed resistance to targeted therapies against one or more actionable mutation present in one or more gene selected from the group consisting of EGFR, ALK. KRAS. ROS, BRAF, NTRK1 / 2 / 3, MET, RET, ERBB2, and any other gene known to have an actionable mutation associated with the cancer.

[0500] Embodiment 29. The method of embodiment 28, wherein the actionable mutation is selected from one or more of the following: a) an EGFR gene mutation selected from an exon 20 T790M substitution, an exon 20 C797X substitution, an exon 21 L858R substitution, and an exon 19 deletion, optionally wherein the exon 19 deletion is the E746 A750 deletion as determined by a regulatory agency approved test; b) an ALK gene rearrangement; c) a KRAS gene mutation, optionally wherein the mutation is an exon 2 G12C substitution; d) a BRAF gene mutation, optionally wherein the mutation is an Exon 15 V600E substitution; e) a MET gene mutation, optionally wherein the mutation is an ex14 skipping mutation; f) a ROS J gene rearrangement, optionally where tire ROS 1 gene is fused with a gene or portion of a gene selected from one ofAttorney Docket No. 45395-0071WO1the following: CD74, EZR, SDC4, SLC34A2, CCDC6, TFG, SLMAP, MY05C, FIG, LIMA1, CLTC, GOPC, ZCCHC8, CEP72, MLL3, KDELR2, LRIG3, MSN, MPRIP, WNK1, SLC6A17, TMEM106B, FAM135B, TPM3, and TPDS2L1; g) a fusion of the NTRK1, 2, or 3 gene; and h) a RET gene rearrangement, optionally where the rearrangement is a fusion with KIF5B or CCDC6.0501] Embodiment 30. The method of any one of embodiments 1 to 27, wherein the cancer has an amplification, mutation, or overexpression of the ERBB2 gene, optionally wherein the ERBB2 gene has insertions in exon 20 and / or nucleotide substitutions encoding amino acid substitutions selected from one or more of the following: L755S. G776C, G660D, R678Q, E693K, and Q709L.

[0502] Embodiment 31. The method of any one of embodiments 1 to 27, wherein the anti-cMET ADC is administered as a monotherapy or adjunctive to an additional anticancer agent, wherein the additional agent is administered according to its regulatory agency-approved dosing regimen.

[0503] Embodiment 32. The method of embodiment 31, wherein the additional anticancer agent is an inhibitor and / or targeting agent of EGFR, ALK, KRAS, ROS, BRAF, NTRK1 / 2 / 3, MET, RET, or ERBB2.

[0504] Embodiment 33. The method of embodiment 31, wherein the additional anticancer agent is selected from osimertinib (TAGRISSO®), afatinib (GIOTRIF®), axitinib (INLYTA®), bosutinib (BOSULIF®), crizotinib (XALKORI®), dasatinib (SPRYCEL®), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (GLEEVEC®), lapatinib (TYVERB®), nilotinib (TASIGNA®), pazopanib (VOTRIENT®), ponatinib (ICLUSIG®), radotinib (SUPECT®), regorafenib (STIVARGA®), sorafenib (NEXAVAR®), sunitinib (SUTENT®), toceranib (PALLADIA®), and vatalanib.

[0505] Embodiment 34. The method of embodiment 31, w herein the additional anticancer agent is capable of inhibiting EGFR comprising an exon 21 L858R substitution or an exon 19 E746_A750 deletion.

[0506] Embodiment 35 The method of embodiment 32. wherein the ALK inhibitor is selected from alectinib, brigatinib, lorlatinib, ceritinib, and crizotinib; the KRAS inhibitor is selected from sotorasib and adagrasib; the BRAF inhibitor is selected from dabrafenib, vemurafenib, and trametinib; the MET inhibitor is selected from tepotinib, crizotinib, and capmatinib; the ROS1 inhibitor is selected from entrectinib, crizotinib, ceritinib, and lorlatinib; the NTRK1 / 2 / 3 inhibitor is selected from larotrectinib and entrectinib; the RET inhibitor is selected from selpercatinib, pralsetinib, and cabozantinib; the ERBB2 targeting agent is selected from trastuzumab-deruxtecan and trastuzumab-emtansine.

[0507] Embodiment 36. The method of embodiment 32, wherein the additional anticancer agent is an inhibitor of PD1, optionally an anti-PDl antibody, optionally wherein the anti-PDl antibody is pembrolizumab (Kcytruda), nivolumab (Opdivo), or cemiplimab (Libtayo).

[0508] Embodiment 37. Tlie method of embodiment 32, wherein the additional anticancer agent is an inhibitor of PD-L1, optionally an anti-PD-Ll antibody such as durvalumab, or atezolizumab.

[0509] Embodiment 38. The method of any one of the preceding embodiments, wherein the cancer is resistant to prior treatment with an anti-cMET antibody, an anti-cMET ADC, a chemotherapy, a small molecule directed against cMET, and / or a radiation therapy.Attorney Docket No. 45395-0071WO1

[0510] Embodiment 39. The method of any one of the preceding embodiments, wherein the anti-cMET ADC is administered in an amount ranging from about 0.5 mg / kg to about 6.0 mg / kg, about 2.0 mg / kg to about 5.0 mg / kg, or about 4.5 mg / kg once every three weeks (Q3W).[0511 J Embodiment 40. The method of any one of the preceding embodiments, wherein the anti-cMET ADC comprises an anti-cMET antibody linked the drug component of the ADC by way of a linker.

[0512] Embodiment 41. The method of embodiment 40, wherein the anti-cMET antibody is a full-length antibody.

[0513] Embodiment 42. The method of embodiment 40, wherein the anti-cMET antibody binds to cMET in vitro or in vivo with at least a 5-fold. 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 30-fold, 100-fold, 300-fold, or 1000-fold greater affinity at physiologic pH than it does at pH 5.4.

[0514] Embodiment 43. The method of any one of embodiments 40-42, wherein the anti-cMET antibody comprises a VH chain comprising the amino acid sequences as set forth in SEQ ID NO: 236, SEQ ID NO: 237, and SEQ ID NO: 238 and a VL chain comprising the amino acid sequences as set forth in SEQ ID NO: 239, SEQ ID NO: 240, and SEQ ID NO: 241.

[0515] Embodiment 44. The method of any one of embodiments 40-43, wherein the anti-cMET antibody is an IgGl antibody.

[0516] Embodiment 45. The method of embodiment 42, wherein the anti-cMET antibody comprises a VH chain comprising the amino acid sequence of SEQ ID NO: 15 and a VL chain comprising the amino acid sequence of SEQ ID NO: 16.

[0517] Embodiment 46. The method of embodiment 45, wherein tire anti-cMET antibody is an IgGl antibody.

[0518] Embodiment 47. The method of embodiment 43, wherein the anti-cMET antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 75 and a light chain comprising the amino acid sequence of SEQ ID NO: 82.

[0519] Embodiment 48. The method of embodiment 40, wherein the linker is cleavable by a lysosomal enzyme, optionally wherein the enzyme is Cathepsin B.

[0520] Embodiment 49. The method of embodiment 40, wherein the linker comprises a peptide selected from the group consisting of Cit-Cit; Cit-Val; Val-Cit; Cit-Ala; Ala-Cit; Cit-Asn; Asn-Cit; Cit-Ser; Ser-Cit; Cit-Lys; Lys-Cit; Cit-Asp; Asp-Cit; Ala-Ala; Glu-Val; Val-Glu; Ala-Val; and Val-Ala: and salts thereof.

[0521] Embodiment 50. The method of any one of the preceding embodiments, wherein the drug component of the ADC is a microtubule inhibitor, optionally wherein the inhibitor is an auristatin.

[0522] Embodiment 51. The method of embodiment 50, wherein tire microtubule inhibitor is an auristatin.

[0523] Embodiment 52. The method of embodiment 51, wherein the ADC comprises a compound having a structure of formula (I): [D-L-XY]n-Ab or salts thereof, where each “D” represents a cytotoxic and / or cytostatic agent (“drug’’); each “L” represents a linker; “Ab” represents a pH-dependent anti-cMET antigen binding moiety; each “XY” represents a linkage formed between a functional group Rx on the linker and aAttorney Docket No. 45395-0071WO1“complementary” functional group Ry on the antigen binding moiety; and n represents the number of drugs linked to. Ab of the ADC; optionally wherein the compound has the follow ing structure (II):

[0524] Embodiment 53. The method of embodiment 52, wherein the anti-cMET antibody is Q397.

[0525] Embodiment 54. The method of embodiment 53, wherein the compound has the following structure (III):

[0526] or a pharmaceutically acceptable salt thereof, wherein n has an average value of 2, or is equal to 2. and the Ab is a full length anti-cMET pH-antibody.

[0527] Embodiment 55. The method of embodiment 54, wherein the anti-cMET antibody is Q397.

[0528] Embodiment 56. The method of any one of the preceding embodiments, w herein the human subject is a patient diagnosed with cMET-overexpressing, MET amplified and / or MET ex 14 skipping mutation non¬ small ceil lung cancer (“NSCLC”) comprising the step of administering to the patient an effective amount of an anti-cMET antibody drug conjugate (" ADC”) for a period of time sufficient to provide one or more therapeutic benetit(s), wherein the antibody component of the ADC exhibits cMET-specific pH-dependent binding, and optionally wherein the antibody comprises heavy and light chain CDRs present in the ammo acid sequences as set forth in one of the following pairs: SEQ ID NOs: 15 & 16; SEQ ID NOs: 5 & 6; SEQ ID NOs: 7 & 8; SEQ ID NOs: 9 & 10; SEQ ID NOs: 11 & 12; SEQ ID NOs: 13 & 14; SEQ ID NOs: 17 & 18; SEQ ID NOs: 19 & 20. SEQ ID NOs: 21 & 22; SEQ ID NOs: 23 & 24; SEQ ID NOs: 25 & 26; SEQ ID NOs: 27 & 28; SEQ ID NOs: 29 & 30; SEQ ID NOs: 31 & 32; and SEQ ID NOs: 33 & 34.

[0529] Embodiment 57. The method of embodiment 56, wherein the cancer has resisted prior treatment with a microtubule inhibitor.

[0530] Embodiment 58. The method of embodiment 57, wherein the microtubule inhibitor is an auristatm.

[0531] Embodiment 59. The method of embodiment 56, wherein the cancer has resisted prior treatment with an anti-cMET ADC, an anti-cMET antibody, or a small molecule targeting cMET.Attorney Docket No. 45395-0071WO1

[0532] Embodiment 60. The method of any one of embodiments 56-59, wherein the anti-cMET ADC is administered as monotherapy.

[0533] Embodiment 61. The method of any one of embodiments 56-60. wherein the anti-cMET ADC is administered adjunctive to an additional anticancer agent, wherein the additional agent is administered according to its regulatory agency-approved dosing regimen.

[0534] Embodiment 62. The method of any one of the preceding embodiments, wherein the anti-cMET ADC is effective against non-squamous cell and / or squamous cell NSCLC.

[0535] Embodiment 63. The method of embodiment 62, wherein the NSCLC is wildtype for human EGFR.

[0536] Embodiment 64. The method of embodiment 63, wherein the NSCLC is mutated for human EGFR.

[0537] Embodiment 65. The method of embodiment 63 or 64. wherein the NSCLC has resisted at least 1, 2.3, 4, 5, 6, 7. 8, or more prior therapeutic regimen(s).

[0538] Embodiment 66. The method of embodiment 65, wherein the NSCLC has resisted at least 2 regimens.

[0539] Embodiment 67. The method of embodiment 66, wherein the NSCLC has resisted at least 3 regimens,

[0540] Embodiment 68. The method of embodiment 67, wherein the NSCLC has resisted at least 4 regimens.

[0541] Embodiment 69. The method of embodiment 68, wherein the N SCLC has resisted at least 5 regimens.

[0542] Embodiment 70. The method of embodiment 69, wherein the N SCLC has resisted at least 6 regimens.

[0543] Embodiment? 1. The method of embodiment 70, wherein the N SCLC has resisted at least 7 regimens.

[0544] Embodiment 72. A pharmaceutical composition comprising MYTX-011 and a pharmaceutically acceptable carrier.

[0545] Embodiment 73. A method of treating a non-squamous non-small cell lung cancer (“NSCLC”) tumor that expresses c-Met, comprising administering to a human subject having said NSCLC tumor an effective amount of the pharmaceutical composition of embodiment 72, wherein >25% of neoplastic cells from tumor tissue of the c-Met expressing non-squamous NSCLC from the subject have 2-t membrane or membrane + cytoplasmic staining when assessed by c-Met immunohistochemistry (1HC).

[0546] Embodiment 74. Use of the composition of embodiment 72 for treating NSCLC in a human subject.

[0547] Embodiment 75. The method or use of any one of the preceding embodiments, wherein the tumor comprises cells having an FGFR3 amplification, a MET Exon 14 mutation, or an EML4-ALK fusion.

[0548] Embodiment 76. The method or use of embodiment 75. wherein the subject has received at least 2 prior treatment regimens for the NSCLC.

[0549] Embodiment 77. The method or use of embodiment 76, wherein the subject’s tumor is positive for a AffiTExon 14 mutation.

[0550] Embodiment 78. The method or use of embodiment 75, wherein the tumor has progressed after prior treatment with tyrosine kinase inhibitor, optionally osimertinib.

[0551] Embodiment 79, A kit comprising: (i) the pharmaceutical composition of embodiment 72; and (ii) instructions for performing any of the methods of embodiments 1-71, 73, or 75-78.

[0552] Embodiment 80. A pharmaceutical composition comprising a therapeutically effective amount of aAttorney Docket No. 45395-0071WO1pH-dependent. anti-cMET antibody drug conjugate, comprising two (2) heavy chains, each having the sequence set forth in SEQ ID NO: 75 and two (2) light chains, each having the sequence set forth in SEQ ID NO: 82, wherein each light chain constant domain comprises the sequence set forth in SEQ ID NO: 158, wherein each light chain constant domain comprises a linker-drag conjugated thereto at the cysteine (C) located at amino acid position 98 of SEQ ID NO: 158: optionally wherein each linker-drug comprises, consists essentially of, or consists of vcMMAE.

[0553] Embodiment 81. The composition of embodiment 80, which remains effective for treating cancer when frozen and rethawed up to at least 2. times, further comprising L-Histidine; L-Histidine HCl, monohydrate; D (+)-Trehalose dihydrate; and Polysorbate 80.

[0554] Embodiment Al. A method of treating a cMET-positive solid tumor cancer in a population of subjects, wherein treatment results in a decreased incidence of one or more adverse event(s) associated with monomethyl auristatin E (MMAE)-containing antibody drug conjugates as compared to the incidence of the one or more adverse event(s) associated with intravenous administration of two or more doses of an effective amount of a control MMAE-conjugated cMET-targeting ADC, once every two weeks (Q2W), over a similar treatment period, wherein the method comprises administering to the subject two or more doses of MYTX-011. wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg. once every three weeks (Q3W); optionally

[0555] wherein the dose is about 1.9 mg / kg and the control ADC has a DAR of ~3.1 and comprises a heavy chain variable domain sequence of SEQ ID NO: 159 and a light chain variable domain sequence of SEQ ID NO: 160; and / or[0556 J wherein the dose of the control ADC compri ses the same or greater amount of MMAE as compared to the dose of MYTX-011.

[0557] Embodiment A2. The method of embodiment Al, wherein the decreased incidence is at least a 5% decrease in incidence of the one or more adverse event(s) associated with MMAE-containing antibody drug conjugates.

[0558] Embodiment A3. The method of embodiment A 1, wherein the decreased incidence is at least a 10% decrease in incidence of one or more adverse event(s) associated with MMAE-containing antibody drug conjugates.

[0559] Embodiment A4. The method of embodiment 1, wherein the decreased incidence is at least a 20% decrease in incidence of one or more adverse event(s) associated with MMAE-containing antibody drug conjugates.

[0560] Embodiment A5. The method of any one of embodiments A 1 to A4, wherein the one or more adverse event! s) associated with MMAE-containing antibody drug conjugates are selected from the group consisting of: peripheral neuropathy, anemia, thrombocytopenia, neutropenia, hypoalbuminemia, peripheral edema, and AST / ALT elevation

[0561] Embodiment A6. The method of any one of embodiments A1 to A5, wherein the doses of MYTX-011 areAttorney Docket No. 45395-0071WO1administered to the subject in an amount ranging from about 3.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).[05621 Embodiment A7. The method of any one of embodiments Al to A5, wherein the doses of MYTX- 011 are administered to the subject in an amount ranging from about 4.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

[0563] Embodiment A8. A method of treating a cMET-positive solid tumor cancer in a subject, wherein the subject’s cancer has progressed or has not responded to 3, 4, 5. or 6 prior lines of treatment, the method comprising administering to the subject two or more doses of MYTX-011, wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

[0564] Embodiment A9. The method of embodiment A8. wherein the subject’s cancer has progressed or has not responded to 3 prior lines of treatment.

[0565] Embodiment A 10. The method of embodiment A8, wherein tire subject’s cancer has progressed or has not responded to 4 prior lines of treatment.

[0566] Embodiment A11. The method of embodiment A8, wherein the subject’s cancer has progressed or has not responded to 5 prior lines of treatment.

[0567] Embodiment A12. The method of embodiment A8, wherein the subject has not responded to 6 prior lines of treatment.

[0568] Embodiment A13. The method of any one of embodiments A8-A12, wherein the doses of MYTX- 011 are administered to the subject in an amount ranging from about 3.0 mg / kg to about 6.0 mg / kg. once every three weeks (Q3W).

[0569] Embodiment A14. The method of any one of embodiments A8-A12, wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 4.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

[0570] Embodiment A 15. A method of treating a cMET-positive solid tumor cancer in a subject, wherein the subject’s tumor has not responded to or lias progressed after prior treatment with a taxane-based therapy, the method comprising administering to the subject two or more doses of MYTX-011, wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

[0571] Embodiment 16. The method of embodiment A 15, wherein the taxane-based therapy is selected from the group of: paclitaxel, docetaxel, and cabazitaxcl.

[0572] Embodiment A17. The method of embodiment A15 or Al 6, wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 3.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

[0573] Embodiment Al 8. The method of embodiment AI5 or A 16, wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 4.0 mg / kg to about 6.0 mg / kg, once every threeAttorney Docket No. 45395-0071WO1weeks (Q3W)

[0574] Embodiment A19. A method of treating a cMET-positive solid tumor cancer in a subject, the method comprising:

[0575] (a) administering to the subject two or more doses of MYTX-011. wherein the doses of MYTX-01 1 are administered to the subject in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W); and

[0576] (b) administering one or both of a vasoconstrictor and a corticosteroid to one or both eyes of the subject; optionally

[0577] wherein either or both the vasoconstrictor and the corticosteroid are administered around the time of the peak plasma concentration of MYTX-011 to provide the subject with maximum protection against drug-related ocular toxicity.

[0578] Embodiment A2.0. The method of embodiment Al 9, wherein step (b) is performed prior to step (a)

[0579] Embodiment A2.1. The method of embodiment Al 9, wherein step (a) is performed prior to step (b).

[0580] Embodiment A22. Tire method of embodiment A19, wherein steps (a) and (b) are performed at about the same time.

[0581] Embodiment A23. The method of any one of embodiments A19-A22, wherein step (b) comprises administering a vasoconstrictor to one or both eyes of the subject.

[0582] Embodiment A24. The method of any one of embodiments A19-A22, wherein step (b) comprises administering a corticosteroid to one or both eyes of the subject.

[0583] Embodiment A25. The method of any one of embodiments A19-A22, wherein step (b) comprises administering a vasoconstrictor and a corticosteroid to one or both eyes of the subject.

[0584] Embodiment A26. The method of any one of embodiments A19-A25, wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 3.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

[0585] Embodiment A27. The method of any one of embodiments Al 9-A26, wherein the doses of MYTX- 011 are administered to the subject in an amount ranging from about 4.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

[0586] Embodiment A28. A method of treating a cMET-positive solid tumor cancer in a subject, the method comprising:

[0587] administering a first dose of MYTX-011 in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg on day 1;

[0588] administering a second dose of MYTX-011 in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg on about day 22; and

[0589] administering a third dose of MYTX-011 in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg on about day 64.

[0590] Embodiment A29. The method of embodiment A28, wherein the first, second, and third doses ofAttorney Docket No. 45395-0071WO1MYTX-011 are administered to the subject in an amount ranging from about 3.0 mg / kg to about 6.0 mg / kg.

[0591] Embodiment A30. The method of embodiment A29, wherein the first, second, and third doses of MYTX-011 are administered to the subject in an amount ranging from about 4.0 mg / kg to about 6.0 mg / kg.

[0592] Embodiment A31. The method of any one of embodiments A28-A30, wherein the method further comprises:

[0593] administering a fourth dose of MYTX-011 in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg on about day 85; and

[0594] administering a fifth dose of MYTX-011 in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg on about day 127.

[0595] Embodiment A32. The method of embodiment A31, wherein the fourth and fifth doses of MYTX- 011 are administered to the subject in an amount ranging from about 3.0 mg / kg to about 6.0 mg / kg.

[0596] Embodiment A33. The method of embodiment A32, wherein the fourth and fifth doses of MYTX- 011 are administered to the subject in an amount ranging from about 4.0 mg / kg to about 6.0 mg / kg.

[0597] Embodiment A34. The method of any one of embodiments A1-A33, wherein the cMET-positive solid tumor cancer is a cMET-overexpressing and / or MET-amplified solid tumor cancer.

[0598] Embodiment A35. The method of any one of embodiments A1-A33, wherein a biopsy from the cMET-positive solid tumor cancer has an ultra-low. a low or an intermediate level of cMET staining by IHC.

[0599] Embodiment A36. The method of any one of embodiments A1-A33, wherein a biopsy from the cMET-positive solid tumor cancer has an H-score of about 25 to about 300, or about 25 to about 275, or about 25 to about 250, or about 25 to about 225, or about 25 to about 200, or about 25 to about 175, or about 25 to about 150. or about 25 to about 125, or about 25 to about 100, or about 25 to about 75 or about 25 to about 50, or about 25 to about 300, or about 50 to about 275. or about 50 to about 250, or about 50 to about 225, or about 50 to about 200, or about 50 to about 175. or about 50 to about 150. or about 50 to about 125. or about 50 to about 100, or about 50 to about 75.

[0600] Embodiment A37. The method of any one of embodiments 1-A36, wherein the cMET-positive solid tumor cancer is non-small cell lung cancer (“NSCLC").

[0601] Embodiment A38. The method of embodiment A37, wherein the NSCLC is non-squamous NSCLC, squamous NSCLC. or not otherwise specified NSCLC.

[0602] Embodiment A39. The method of any one of embodiments A1, A8, A15, A19, and A28, wherein a biopsy from a tumor of the cMET-positive solid tumor cancer and / or an entire tumor of the cMET-positive solid tumor cancer, comprises at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%. 70%. 80%, 90%, or 100% of cancer cells having a cMET expression level of at least a 1+, a 2+. or a 3+, as scored by an applicable and / or regulatory-agency approved immunohistochemistry (IHC) assay.

[0603] Embodiment A40 The method of embodiment A39, wherein:

[0604] (a) at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,Attorney Docket No. 45395-0071WO145%, 50%, 60%, 70%, 80%, 90%, or 100% of the cancer cells have an IHC score of 1+ or 2+;[06051 (b) at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%. 90%. or 100% of the cancer cells have an IHC score of 2+;

[0606] (c) at least about 1%, 2%, 3%, 4%, 5%, 6%. 7%, 8%, 9%. 10%. 15%. 20%. 25%. 30%. 35%. 40%.45%, 50%, 60%, 70%, 80%, 90%, or 100% of the cancer cells have an IHC score of 1+;

[0607] (d) at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%. 9%, 10%, 15%, or about 20% of the cancer cells have an IHC score of 1+ and wherein no more than about 1%, 2%, 3%, 4% or 5% of the cancer cells have an IHC score of 2+ or 3+; and / or

[0608] (e) at least about 1%, 2%, 3%. 4%, 5%, 6%, 7%, 8%. 9%, 10%, 15%, or about 20% of the cancer cells have an IHC score of 1+ and wherein no more than about 1%, 2%, 3%, 4% or 5% of the cancer cells have an IHC score of 2+ or 3+.

[0609] Embodiment A41. The method of embodiment A40, wherein:

[0610] (a) no more than about 1%, 2%, 3%, 4%, 5%, 6%, 7%. 8%, 9%, 10%, 15%, or about 20% of the cancer cells have an IHC score of 2+ and wherein no more than about 1% of the cancer cells have an IHC score of 3 +;

[0611] (b) no cancer cells have an IHC score of greater than 1+; or

[0612] (c) no cancer cells have an IHC score of greater than 2+.

[0613] Embodiment A42. The method of embodiment A39, further comprising a step of determining an H-score for the biopsy or the entire tumor, wherein the H-score is between about 10 and about 300, between about 10 and about 250, between about 20 and about 225, between about 20 and about 200, between about 20 and about 175. or between about 20 and about 150.

[0614] Embodiment A43. The method of embodiment A39. wherein the H-score is no more than about 100. about 90. about 80. about 70, about 50 or about 25

[0615] Embodiment A44 The method of embodiment A39, wherein the biopsy or the entire tumor is homogeneous or heterogeneous for cMET expression.

[0616] Embodiment A45. The method of embodiment A39, wherein at least about 10%, 20%, or 30% of the cancer cells have a first frequently-occurring IHC score selected from one of 0, 1+, 2+, and 3+ and at least about 10%, 20%, or 30% of the cancer cells have a second frequently-occurring IHC score selected from one of 0, l+, 2+, and 3+. wherein the first and second frequently-occurring IHC scores are different.

[0617] Embodiment A46. The method of embodiment A45, wherein the first and second frequently- occurring IHC scores are selected from the following pairs of scores: (0, +1), (0, +2), (0, +3), (+1, +2), (+1, +3), and (+2, +3).

[0618] Embodiment A47. The method of embodiment A45 or A46, wherein at least about 10%, 20%. or 30% of the cancer cells have a third frequently-occurring IHC score, wherein the third frequently-occurring IHC score is distinct from the first and second frequently-occurring IHC scores.

[0619] Embodiment A48. The method of any one of embodiments A1-A47, wherein the cMET-positive solidAttorney Docket No. 45395-0071WO1tumor cancer has developed resistance to targeted therapies against one or more actionable mutation(s) present in one or more gene selected from the group consisting of EGFR, ALK, KRAS, ROS, BRAF, NTRK1 / 2 / 3, MET, RET, ERBB2, and any other gene known to have an actionable mutation associated with the cancer.

[0620] Embodiment A49. The method of embodiment A48, wherein the actionable mutation is selected from one or more of the following:

[0621] (a) an EGFR gene mutation selected from an exon 20 T790M substitution, an exon 20 C797X substitution, an exon 21 L858R substitution, and an exon 19 deletion, optionally wherein the exon 19 deletion is the E746_A750 deletion as determined by a regulatory agency approved test;

[0622] (b) an ALK gene rearrangement;

[0623] (c) a KRAS gene mutation, optionally wherein the mutation is an exon 2 G12C substitution;

[0624] (d) a BRAF gene mutation, optionally wherein the mutation is in Exon 15 V600E substitution;

[0625] (e) a MET gene mutation, optionally wherein the mutation is an ex14 skipping mutation;

[0626] (f) a ROS1 gene rearrangement, optionally where the ROS I gene is fused with a gene or portion of a gene selected from one of the following: CD74, EZR, SDC4, SLC34A2, CCDC6, TFG, SLMAP, MY05C, FIG. LIMA1, CLTC, GOPC, ZCCHC8. CEP72, MLL3, KDELR2, LRIG3, MSN, MPRIP, WNK1, SLC6A17. TMEM106B, FAM135B, TPM3. and TPDS2L1;

[0627] (g) a fusion of the NTRK 1, 2, or 3 gene; and

[0628] (h) a RET gene rearrangement, optionally where the rearrangement is a fusion with KIF5B or CCDC6.

[0629] Embodiment A50. The method of embodiment A49, wherein the cancer has an amplification, mutation, or overexpression of the ERBB2 gene, optionally wherein the ERBB2 gene has insertions in exon 20 and / or nucleotide substitutions encoding amino acid substitutions selected from one or more of the following: L755S, G776C, G660D, R678Q, E693K, and Q709L.

[0630] Embodiment A51. The method of embodiment A49, wherein the method further comprises administering to the subject an additional anticancer agent according to its regulatory agency-approved dosing regi en.

[0631] Embodiment A52. The method of embodiment A51, wherein the additional anticancer agent is an inhibitor and / or targeting agent of EGFR, ALK, KRAS. ROS. BRAF, NTRK1 / 2 / 3, MET. RET. or ERBB2.

[0632] Embodiment A53. The method of embodiment A5 I. wherein the additional anticancer agent is selected from osimertinib®, afatmib®, axitinib®, bosutinib®, crizotmib®, dasatinib®. erlotinib®, gefitimb®, imatinib®, lapatinib®, nilotinib®, pazopanib®, ponatinib®, radotinib®, rcgorafcnib®, sorafenib®, sunitinib®, toceranib®, and vatalamb; and / or wherein the additional anticancer agent is capable of inhibiting EGFR comprising an exon 21 L858R substitution or an exon 19 E746 A750 deletion.

[0633] Embodiment A54. The method of embodiment A52. wherein the ALK inhibitor is selected from alectinib, brigatinib, lorlatinib, ceritinib, and crizotinib; the KRAS inhibitor is selected from sotorasib and adagrasib; the BRAF inhibitor is selected from dabrafmib. vemurafenib. and trametinib; the MET inhibitor isAttorney Docket No. 45395-0071WO1selected from tepotinib, crizotinib, and capmatinib; the ROS1 inhibitor is selected from entrectinib, crizotinib, ceritinib, and lorlatinib; the NTRK1 / 2 / 3 inhibitor is selected from larotrectinib and entrectinib; the RET inhibitor is selected from selpercatinib, pralsetinib, and cabozantinib; or the ERBB2 targeting agent is selected from trastuzumab-deruxtecan and trastuzumab-emtansine,

[0634] Embodiment A55. The method of embodiment A51, wherein the additional anticancer agent comprises an inhibitor of PD1, optionally an anti-PDl antibody, optionally wherein the anti-PDl antibody is pembrolizumab, nivolumab, or cemiplimab; or an inhibitor of PD-L1, optionally an anti-PD-Ll antibody such as durvalumab, or atezolizumab

[0635] Embodiment A56. The method of any one of embodiments A1-A47, wherein the cMET-positive solid tumor cancer is resistant to and / or otherwise progressed after prior treatment with an anti-cMET antibody, an anti-cMET ADC. a chemotherapy, a small molecule directed against cMET, and / or a radiation therapy.

[0636] Embodiment A57. The method of any7one of embodiments A1-A47, wherein the cMET-positive solid tumor cancer comprises a MET ex!4 skipping imitation.

[0637] Embodiment A58. The method of embodiment A57, wherein the NSCLC is wildtype for human EGFR.

[0638] Embodiment A59. The method of embodiment A58. wherein the NSCLC is mutated for human EGFR.

[0639] Embodiment A60. The method of any one of embodiments A56 to A59, -wherein the NSCLC has resisted at least 1, 2, 3, 4, 5, 6, 7, 8, or more prior therapeutic regimen(s).

[0640] Embodiment A61. The method of any one of embodiments A 1-A47, wherein the cMET-positive solid tumor cancer comprises an FGFR3 amplification or an EML4-ALK fusion.

[0641] Embodiment A62. The method of any one of the preceding embodiments, wherein the cMET-positive solid tumor cancer has progressed after prior treatment with a tyrosine kinase inhibitor.

[0642] Embodiment A63. The method of any one of embodiments A 1-A47. wherein the cMET-positive solid tumor cancer comprises one or both of the following:

[0643] (a) an EGFR mutation substantially similar or identical to the EGFR mutation in the CTG-3414 PDX and / or N CI -H 1975 CDX model: and / or

[0644] (b) a KRAS mutation substantially similar or identical to the KRAS mutation in the C1-H2122 CDX and / or NCI-H 1373 CDX model.

[0645] Embodiment A64. The method of any one of embodiments A1-A47, wherein the cMET-positive solid tumor cancer comprises actionable mutation(s) substantially similar or identical to the actionable mutation(s) in one or more of the following:

[0646] (a) the actionable mutation(s) present in the Hs746T gastric cancer CDX model:

[0647] (b) the actionable mutations(s) present in the MET TKl sensitive LU-01-1375 NSCLC PDX model; and / or[0648 [ (c) the actionable mutations(s) present in the CTG-2669 NSCLC PDX model.Attorney Docket No. 45395-0071WO1

[0649] Embodiment A65. The method of any one of embodiments A 1-A47, wherein the cMET-positive solid tumor cancer is characterized as being a MET TKI-sensitive cancer comprising a MET Exon 14 skipping mutation.

[0650] Embodiment A66. The method of embodiment A65, wherein the method further comprises administration of a MET TKI.

[0651] Embodiment A67. The method of embodiment A66, wherein the MET TKI is capmatinib or tepotinib.

[0652] Embodiment A68. The method of any one of embodiments A 1-A36, wherein the cMET-positive solid tumor cancer is a MET amplified gastric tumor comprising a MET Exon 14 skipping mutation.

[0653] Embodiment A69. The method of any one of embodiments A 1-A36, wherein the cMET-positive solid tumor cancer comprises an actionable mutation substantially similar or identical to the actionable mutations in the LU-01-1476 PDX model.

[0654] Embodiment A70. The method of embodiment A68 or A69. wherein the method further comprises administration of a MET TKI,

[0655] Embodiment A71. A method of treating a cMET-positive solid tumor cancer in a subject, wherein the subject has not responded to prior treatment with a MET tyrosine kinase inhibitor (TKI), the method comprising administering to the subject two or more doses of MYTX-011, wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg, once every’ three weeks (Q3W).[06561 Embodiment A72. The method of embodiment A71, wherein the subject has not responded to 2 prior lines of treatment.

[0657] Embodiment A73. The method of embodiment A72, wherein the subject has not responded to 4 prior lines of treatment.

[0658] Embodiment A74. The method of embodiment A73, wherein the subject has not responded to 5 prior lines of treatment.

[0659] Embodiment A7.5. The method of embodiment A74, wherein the subject has not responded to 6 prior lines of treatment.

[0660] Embodiment A76. Tire method of any one of embodiments A72 to A75, wherein the MET TKI is capmatinib or tepotinib.(0661 ] Embodiment A77. The method of any one of embodiments A I TO A76, wherein the doses of MYTX- 011 are administered as a pharmaceutical composition comprising L-histidine, L-histidine HCl monohydrate, D(+)-trehalose dihydrate, and polysorbate 80.

[0662] From the foregoing, it will be seen that aspects herein are well adapted to attain all the ends and objects hereinabove set forth together with other advantages which are obvious and which are inherent to the structure.

[0663] While specific elements and steps are discussed in connection to one another, it is understood that any element and / or steps provided herein is contemplated as being combinable with any other elements and / orAttorney Docket No. 45395-0071WO1steps regardless of explicit provision of the same while still being within the scope provided herein.

[0664] It will be understood that certain features and subcombinations are of utility and may be employed without reference to other features and subcombinations. This is contemplated by and is within the scope of the claims

[0665] Since many possible aspects may be made without departing from the scope thereof, it is to be understood that all matter herein set forth or shown in the accompanying drawings and detailed description is to be interpreted as illustrative and not in a limiting sense.

[0666] It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

[0667] Now having described the aspects of the present disclosure, in general, the following Examples describe some additional aspects of the present disclosure. While aspects of the present disclosure are described in connection with the following examples and the corresponding text and figures, there is no intent to limit aspects of the present disclosure to this description. On the contrary-, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of the present disclosure.EXAMPLES

[0668] The following examples are put forth so as to provide those of ordinary' skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g, amounts, temperature, etc ), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.

[0669] MYTX-011 is a cMET-targeted val-cit -monomethyl auristatin E (vcMMAE) antibody-drug conjugate (ADC) with a fully humanized IgGl. The drug to antibody ratio (DAR) for MYTX-011 is 2: 1. MYTX-011 binds to cMET with high affinity and specificity and has been engineered to enhance the internalization and delivery of the cytotoxic payload to cancer cells. In the initial clinical trial, single and multiple IV doses of MYTX-011 will be given to late-stage cancer patients. MYTX-011 is being developed for the treatment of cMET+ / cMET-expressing and cMET -overexpressing non-small cell lung cancer (NSCLC). MYTX-011 has been investigated in nonclinical pharmacology, pharmacokinetic, and toxicology studies.

[0670] The nonclinical pharmacology of MYTX-011 was evaluated to determine its binding affinity and pharmacologic effects. MYTX-011 was assessed for species selectivity, as well as binding affinity to cMET using ELISA and BLI assays. The pH-dependent binding and internalization of MYTX-011 was also assessed.Attorney Docket No. 45395-0071WO1Cell cycle arrest and cytotoxic activity of MYTX-011 was assessed in cMET+ tumor cell lines. The potential for the anti-cMET antibody portion of MYTX-011 to enhance cellular proliferation and cell signaling in cMET+ tumor ceil lines was assessed. Fc effector function activities of the anti-cMET antibody portion of MYTX-011 including antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP) were also evaluated. The efficacy of MYTX-011 was assessed in murine xenograft models of non-small cell lung cancer.

[0671] The nonclinical safety profile of MYTX-011 was evaluatedin vivo in cynomolgus monkeys. The monkey was selected as the pharmacologically relevant nonclinical species because of similar cMET protein sequence homology and similar binding affinity of MYTX-011 to monkey cMET, as compared to human cMET. MYTX-011 does not bind to mouse or rat cMET.

[0672] The IV route of exposure was selected for the in vivo monkey studies since it is the intended route of clinical exposure. The once every three-week (Q3W) dosing regimen used in the repeat-dose monkey toxicity studies was selected to align with the clinical dosing regimen.

[0673] The nonclinical PK and TK of MYTX-011 was evaluated in monkeys. Analytical methods wrere developed and validated for the quantitation of intact MYTX-011, total mAb. and MMAE, and for the detection of anti-drug antibodies (ADA) to support TK evaluations. Plasma stability of MYTX-011 was assessed in monkey and human serum.

[0674] MYTX-011 was specifically designed to address the shortcomings of existing therapies, including other anti -cMET. ADCs, by driving responses for the majority of cMET+ZcMET-overexpressing NSCLC patients whose tumors express lower levels of cMET than those treatable with current cMET-targeted therapies. Design of MYTX-011 includes clinically precedented triple hinge (TH) IgGl format and linker / toxin (i.e.. vcMMAE), complementarity determining regions (CDRs) that mediate pH-dependent binding, and site¬ specific conjugation at an engineered cysteine residue (“V205C”, corresponding to a cysteine (C) at position 98 of the light chain constant domain set forth in SEQ ID NO: 157), which results in a drug-to-antibody ratio (DAR) of 2 (Shen et al., Nature Biotechnology Vol 30 No. 2 Feb 2012), MYTX-011 is being developed for the treatment of cMET+, cMET-overexpressing, and MET-amplified cancers, including non-small cell lung cancer (NSCLC).

[0675] MYTX-011 has nanomolar binding affinity for both human and cynomolgus monkey cMET. MYTX- 01 1 did not bind to rat or mouse cMET. MYTX-011 demonstrated pH-dependent binding, showing enhanced dissociation from recombinant human cMET at pH 5.4 as compared to pH 7.4 In addition, MYTX-011 can be effectively internalized into cancer cells expressing cMET, and " Q397-noV205C” (the antibody portion of MYTX-011 except that it lacks the “V205C’ substitution in both of its light chains) had minimal to no ADCC, ADCP or CDC. MYTX-011 also has potent activity in vitro in cMET+ and cMET-overexpressmg human lung cancer cell lines and in vivo in cMET+ and cMET-expressing murine xenograft models of non-small cell lung cancer.

[0676] Two doses of MYTX-011 administered once every' three weeks in cynomolgus monkeys resulted inAttorney Docket No. 45395-0071WO1no MYTX-011 -related cardiovascular, respiratory, or central nervous system effects.Cross Species cMET Protein Sequence Homology

[0677] The predicted human cMET protein sequence was compared to mouse, rat, and cynomolgus monkey sequences. Mouse, rat, and monkey protein sequences were 87.02%, 85.71%, and 98.46% homologous to human cMET. respectively.

[0678] The following Examples, which highlight certain features and properties of exemplary embodiments of anti-cMET ADCs and methods of using these ADCs to treat patients are provided for purposes of illustration, and not limitation.Example 1. Preparation of MYTX-011

[0679] MYTX-011 is an antibody drug conjugate (ADC) that exhibits pH-dcpcndcnt binding comprised of the antibody Q397 conjugated to the cytotoxic microtubule inhibitor monomethylauristatin E (MMAE) via a cleavable valine-citrulline (vc) linker. Q397 is a humanized IgGl monoclonal antibody that specifically binds to cMET in a pH-dependent manner. Q397 is composed of two heavy chains of 442 amino acids (as set forth in SEQ ID NO: 75), disulfide bonded to two Kappa light chains of 215 amino acids (as set forth in SEQ ID NO: 82). with a total molecular weight of 143,988 Da (theoretical mass excluding glycosylation). Engineered cysteines have been introduced to the light chains at position 98 of the constant domain (i.e., the light chain constant domain having the polypeptide sequence of SEQ ID NO: 158), which may be capped by disulfide bond formation with thiol-containmg molecules, such as cysteine or glutathione. In an exemplary MYTX-011 aqueous solution (e.g. 20 mM histidine buffer, 8% (w / v) sucrose, pH 6.0) absorbance at 280 nm yields an extinction coefficient of 1.48 mL / (mg*cm). Non-denaturing size exclusion chromatography demonstrates monomeric purity of intact Q397.

[0680] Q397 for the preclinical studies described below was prepared using techniques essentially as described in WO 2022 / 169975 A1 (to Mythic Therapeutics). Briefly, expression plasmids containing SEQ ID NO: 75 and SEQ ID NO: 82 were transiently transfected into Expi293 cells. After allowing for about four to five days of protein expression, cell culture supernatants were collected, and Q397 was purified using a routine chromatography technique

[0681] Q397 for the clinical studies described herein was prepared substantially as follows. A CHO KI host ceil was thawed and passaged in CD CHO medium for stable transfections. The heavy chain plasmid and the light chain plasmid were added at a ratio of 1:1 and 1:2 to the CHO-K1 host cell line for transfection. After electroporation, cells of each transfection were added to 10 mL pre-wanned CD CHO medium and incubated in spin tubes in a Kuhner shaker (36.5 °C, 75% humidity, 6% CO2, 225 rpm). About 24 hours after transfection, 10 mL of “Selection 1” medium was added to each spin tube. The pools were passaged in “Selection 2” medium every 2-3 days. After cells recovered from selection pressure, both pools were used for cloning.

[0682] Tire major components of the light chain plasmid includes the following genes or regulatory elements in the following order: Regulatory Element (improve target gene expression). HuCMV promoter, light chainAttorney Docket No. 45395-0071WO1coding sequence, TK polyadenylation signal, SV40 early promotor, blasticidin resistance gene (selectable marker), SV40 polyadenylation signal, pUC origin, amp resistance gene. The major components of the heavy¬ chain plasmid includes the following: Regulatory Element, HuCMV promoter, heavy chain coding sequence, EMCV IRES, Zeocin resistance gene, TK polyadenylation signal. pUC origin, amp resistance gene.

[0683] Stable pools were produced and plated into 96-well plates at one cell per well, and the monoclonality was documented by consecutive single ceil imaging of all wells on Day 0. Day 1, and Day 5 after plating. About 50 clones were isolated and screened in fed-batch cultures in spin tubes. A single clone was selected to produce the master cell bank (MCB).

[0684] A single frozen vial of cells is expanded by either shaker culture or cell bags. A larger volume of culture medium is inoculated with the expanded cultures and the cultures expanded further in a bioreactor under standard conditions (e.g. 5% CO2, 36° C. incubator). The cultures are harvested and clarified of cells and debris. The Q397 is purified through a Protein A affinity column, followed by anion exchange chromatography, cation exchange chromatography, viral filtration, ultrafiltration / diafiltration, and final filtration.

[0685] Payload conjugation to Q397. vcMMAE is a linker-payload intermediate used in the manufacture of MYTX-011. ’VcMMAE” is a protease cleavable linker (maleimidocaproyl-valinecitrulline-p- aminobenzyloxy carbonyl, mc-vc-PAB) attached to the small molecule anti-mitotic agent monomethyl auristatin E (MMAE). In the ADC manufacturing process, vcMMAE is covalently linked to Q397 via the cysteine at a position corresponding to amino acid position 98 of its light chain constant domain (SEQ ID NO: 158).

[0686] MYTX-011 of DAR 2.0 was prepared by multi-step process comprising: I) reduction of Q397, 2) a first ultrafiltration / diafiltration (UF / DF), 3) re-oxidation. 4) a second UF / DF, 5) conjugation to vcMMAE, 6) quenching, 7) a third UF / DF, and 8) formulation.

[0687] Briefly, Q397 in Tris-EDTA (about pH 7.6-8.0) is mixed with reduction buffer (50 mM PB buffer, pH 7.8). The reducing agent (RA) is added to yield an RA / Q397 molar ratio of about 130-200 The solution containing reduced Q397 is then subjected to UF / DF membrane (e.g., with a MW cutoff of 30 kD). The product is buffer exchanged into re-oxidation buffer 50 mM PB, 2 mM EDTA, pH 7.2 and filtered through a 0.2 pm filter. The UF / DF 1 pool is then transferred to a reactor for re-oxidation in buffer (50 mM PB, 2 mM EDTA. pH7.2), and (L)-Dehydroascorbic acid (DHAA) solution in DMA is next added to the reactor. Re-oxidation proceeds for several hours. Next, a second UF / DF is performed and product is then buffer exchanged into conjugation buffer (50 mM PB, 2 mM EDTA, pH 7.4) and filtered through a 0.2 pm filter. Tire filtered, re- oxidized Q397 is then conjugated to the linker-payload vcMMAE. VcMMAE powder is weighed, dissolved in DMA, and added into the reactor. The vcMMAE / Q397 molar ratio is about 4.4-4.8 in a final DMA concentration of about 10% (v / v). After several hours, the conjugation reaction is quenched in N-Acetyl-L-cysteine (NAC) dissolved in WFI. Product is filtered again and buffer exchanged into diafiltration buffer and filtered through a 0.2 pm filter.Attorney Docket No. 45395-0071WO1

[0688] The filtered MYTX-011 is then formulated to 10.0 mg / mL MYTX-011, 20 mM histidine buffer, 8.8% (w / v) trehalose, 0.02% (w / v) polysorbate 80, pH 5.5.Example 2. Anti-cMET pH-ADC Binds to Recombinant and Cellular cMET and is Efficiently Internalized by Cells Having Elevated cMET Expression10689! Bio-Layer Interferometry (Bl. I). The binding and binding affinity of MYTX-011 to mouse, rat, cynomolgus monkey, and human cMET was assessed by ELISA or BLI assays. MYTX-011 was captured as ligand onto the surface of an AHC sensor tip through binding to immobilized anti -human Fc-spccific antibodies followed by association with either recombinant human or cynomolgus monkey cMET as analyte in running buffer. Association was measured by an increase in the thickness of the layer on the tip of the AHC sensor in the presence of analyte and dissociation was measured by the loss of thickness in the absence of analyte. Briefly, MYTX-011. in buffer containing 2.7 mM potassium chloride. 4 3 mM disodium phosphate, 1.4 mM monopotassium phosphate, 135 mM sodium chloride, and 0.05% tween-20 (PBST) at pH 7.4, was immobilized onto the surface of an AHC sensor tip followed by a buffer-only step to establish a stable baseline. Association with analyte was achieved in a separate well in lx PBST (pH 7.4) plus 0.1% Bovine Serum Albumin (BSA). The following analyte concentrations and incubations times were tested: Recombinant human cMET at 80. 60, and 20 nM for 120 seconds, or recombinant cynomolgus monkey cMET at 100, 62.5. and 1.2 nM for 60 seconds Following association, sensor tips were moved to wells containing buffer IxPBST pH 7.4 plus 0.1 % BSA only and dissociation was measured for 240 seconds for recombinant human cMET or 180 seconds for recombinant cynomolgus monkey cMET. pH-dependent binding of MYTX-011 to human cMET was assessed using conditions listed above with the following changes; analyte concentration was 50 nM recombinant human cMET; association was performed in IxPBST pH 7.4 for 120 seconds; and the dissociation was performed in either IxPBST pH 7.4 or IxPBST pH 5.4 for 300 seconds.

[0690] As measured by the above BLI assay, binding affinities (KD) of MYTX-011 mAb to recombinant human and cynomolgus monkey cMET were 4.0 nM and 9.44 nM. respectively. In contrast, MYTX-011 mAb did not bind to mouse or rat cMET. Further, MYTX-011 Ab bound to recombinant human and cynomolgus monkey cMET with similar affinity at pH 7.4 and MYTX-011 mAb showed greater dissociation from human cMET at pH 5.4 compared to pH 7.4. The percent dissociation (from human cMET) of multiple pH-dependent anti -cMET mAbs at pH 5.4 was then evaluated (as described above), yielding the dissociation curves presented in FIG. I B. As regards its binding on cMET+ NCI-H1975 cancer ceils, MYTX-011 bound with sub-nanomolar affinity7(IC50= 0.4 nM) at pH 7.4 and binding was maintained at pH 6.4 (IC50 = 0.5 nM) (DNS), which is below estimates of the acidic tumor microenvironment (TME).

[0691] Internalization Assays. Detroit-562 or NCI-H1975 cells were seeded at 5000 cells / well a day prior to treatment. pHrodo reagent (Thermo Fisher Scientific), a secondary anti-huIgG Fab conjugated to a pH- sensitive dye that fluoresces only after internalization, was diluted to 60nM in media. Twenty (20) nM of the hlgGl component of MYTX-011, MYTX-011 mAb, parent and isotype control antibodies or 21 nM of MYTX-Attorney Docket No. 45395-0071WO1011, parent ADC and non-binding ADC were diluted 1: 1 with pHrodo reagent. After incubation for 30 minutes, media was removed from pre-seeded Detroit-562 or NCI-H1975 cells, pHrodo-antibody / ADC complex was added to the plate and incubated at 37°C for 24 hours. Cells were trypsinized using TrypLE (Thermo Fisher Scientific) and washed twice using ice cold FACS buffer pH 7.4. Fluorescence was analyzed using Attune NxT flow cytometer (Thermo Fisher Scientific) and data was analyzed using FlowJo. Fold change was calculated by subtracting median fluorescent intensity (MFI) of the isotype control / non-binding ADC from MFI of MYTX-011 antibody or MYTX-011 and parent antibody or ADC and taking the ratio

[0692] Internalization of MYTX-011 mAb in Detroit-562 cancer cells. The internalization assay was conducted as described above and the results are shown in FIG. 1C. Surprisingly, the enhanced dissociation observed for pH-dependent antibody variants at pH 5.4 (FIG. IB) correlated with an increase in internalization over parent antibody, confirming that greater pH dependence leads to enhanced accumulation of antibody inside cMET positive cancer cells (FIG. 1C).

[0693] Internalization of MYTX-011 in NCI-H1975 cancer cells. The internalization assay was conducted as described above. Briefly, cells were plated a day prior to the experiment date. Test articles were prepared as follows: Human IgGl, MYTX-011, and RC2-ADC-(DAR2) were diluted to 20 nM using cell media. “RC2- ADC-(DAR2)’’ is a comparative ADC comprising a mAb component having variable regions matching those of emibetuzumab and conjugated to vcMMAE via one cysteine on each light chain pHrodo reagent was diluted 3x (60 nM) concentration to that of test articles and were mixed at 1:1 ratio The cells were treated and processed as described above, and as shown in FIG. IE, fluorescently labeled MYTX-011 yielded an impressive 3.9 fold increase in signal in the NCI-H1975 cells relative to non-pH engineered comparator RC2-ADC-(DAR2) (FIG. IE).

[0694] Overall Conclusion. MYTX-011 bound to recombinant human and cynomolgus monkey cMET with similar affinity at pH 7.4, exhibited greater dissociation from human cMET at pH 5.4 compared to pH 7.4, and showed about 3.9x higher internalization relative to non-pH engineered RC2-ADC-(DAR2). This enhanced internalization helps to explain why the anti-cMET, pH-dependent ADC, MYTX-011, delivers superior amounts of toxic payload relative to an appropriate, non-pH-dependent, control anti-cMET ADC. Applicant envisions that any and all such anti-cMET pH-antibodies exhibiting comparable pH-dependent binding characteristics coupled with superior internalization may be particularly useful in the practice of the methods as disclosed herein. In some embodiments, the binding characteristics include greater dissociation from human cMET at about pH 5.4 versus about pH 7.4, and maintenance of good binding (e.g., comparable to binding at pH 7.4) at pH conditions found within a tumor microenvironment (e.g., between about pH 6.4 and about pH 7.4). In some embodiments, the anti-cMET pH-antibody binds to cMET with substantially the same affinity and / or kinetics at pH 6.4 as it does at pH 7.4.

[0695] Non-limiting examples of such anti-cMET ADCs (e.g.. anti-cMET pH-ADCs) include those comprising heavy chain variable and light chain variable sequences as set forth in one of the following pairs of heavy and light chain sequences: SEQ ID NOs: 15 & 16; SEQ ID NOs: 5 & 6; SEQ ID NOs: 7 & 8; SEQAttorney Docket No. 45395-0071WO1ID NOs: 9 & 10; SEQ ID NOs: 11 & 12; SEQ ID NOs: 13 & 14; SEQ ID NOs: 17 & 18; SEQ ID NOs: 19 & 20; SEQ ID NOs: 21 & 22; SEQ ID NOs: 23 & 24, SEQ ID NOs: 25 & 26; SEQ ID NOs: 27 & 28, SEQ ID NOs: 29 & 30; SEQ ID NOs: 31 & 32; and SEQ ID NOs: 33 & 34.

[0696] In some embodiments, the anti-cMET pH-ADC comprises a heavy chain constant (CH1-CH2-CH3) sequence of SEQ ID NO: 155 or SEQ ID NO: 189 comprising one or more of the following: (i) a lysine to cysteine substitution at amino acid position 105 and deletion of a threonine at amino acid positions 106 and 108; (ii) a methionine to tyrosine substitution at amino acid position 135, a serine to threonine substitution at amino acid position 137, and a threonine to glutamic acid substitution at ammo acid position 139; (iii) a methionine to leucine substitution at am o acid position 311 and an asparagine to serine substitution at amino acid position 317; and (iv) an alanine to a cysteine substitution at ammo acid position 1; and / or an LC constant domain sequence of SEQ ID NO: 157 comprising a val to cys substitution at amino acid position 98.Example 3. In vitro Potency of anti-cMET pH-ADC in Tumor Cell Lines

[0697] Cell Cycle Arrest Assay. Briefly, EBC-1 cells were cultured in standard culture media (Eagle’s minimum essential medium + 10% fetal bovine scrum) and conditions recommended by the vendor. Cells were plated at a density of 2 x 104cells per well and incubated at 37°C for 24 hours. Media was removed and test articles (10 nM MYTX-011, MMAE toxin, or a non-binding control ADC) were added to the cells at a final concentration of 10 nM. Plates were incubated for 24 hours at 37°C At the end of the culture period, test articles were removed from the plate. Cells were trypsinized, washed, and fixed in 70% ethanol for 30 minutes. Cells were washed, stained with propidium iodide staining using a cell cycle analysis kit (Abeam), and assessed by flow cytometry.

[0698] An increase in the G2-M fraction was observed in EBC-1 cells 24 hrs after treatment with MYTX-011 and MMAE as compared to untreated cells (FIG. 2). The percentage of untreated cells in G2-M phase was 15.5%. For cells treated with MYTX-011, the percentage of cells in G2-M phase was 64.7%, which was comparable to MMAE treatment (686%) Accordingly, MYTX-011 treatment of cMET+ EBC-1 cells resulted in G2-M phase cell cycle arrest, similar to that of MMAE treatment, and no impact on the cell cycle phase distribution was observed with the non-binding control RC5-ADC-(DAR2).

[0699] Cellular cytotoxicity assay. NCI-H 1975 and NCI-H 1373 cells were cultured in standard culture media (RPMI-1640 + 10% fetal bovine serum) using conditions recommended by the vendor. The following test articles were evaluated in this assay: RC1 = comparative Ab having variable regions matching those of telisotuzumab; RC2 = comparative Ab having variable regions matching those of emibetuzumab; RC3 = comparative Ab having variable regions matching the 5D5 anti-human cMET antibody; and Q397-noV205C (yyy with V at position 98 of its light chain constant domain; Q397:::the anti-cMET IgG antibody component of M YTX-011.

[0700] Cells were plated and incubated overnight at 37°C, The starting concentration of MYTX-011, RC1 ADC-(DAR3.1), RC1-ADC-IDAR2), RC2 ADC-(DAR2), and RC5 ADC-(DAR2) was 100 nM; a 9-point 1:5Attorney Docket No. 45395-0071WO1dilution series was generated. Serially diluted test articles were added to the cells in duplicate the next day. Plates were incubated for 5 days at 37°C with a range of concentrations (0.000256-100 nM) of MYTX-011. At the end of die culture period, viability was assessed using CCK-8. Absorbance was measured using a plate reader MYTX-011 depleted viable NCJ-H1975 and NCI-H1373 cells with a maximum depletion of 90.36% and 65.92%, respectively, relative to the untreated control at 100 nM. MYTX-011 thus demonstrated cytotoxic- activity in cMET+ NCI-H1 75 and NCI-H1373 cells. No cytotoxicity was observed after treatment with the non-binding control, RC5-ADC-(DAR2). MYTX-011 demonstrated cytotoxic activity similar to that of RC1-ADC-(DAR3.1) m NCI-H197.5 and NCI-H 1373 cells.

[0701] MYTX-011 has also demonstrated cytotoxicity against cells from a wide variety of other cancer types, including the following: SNU-5 (amplification), H1993 (amplification), EBC-l (amplification). HS746T (amplification & Exon 14 skipping). MKN45 (amplification). H1975, NUGC-4. PC-9. Calu-6, BxPC-3, KYSE- 410. HCC4006, Detroit 562, Hl 650, H820, 5637, H292. Hl 703, Pane 05.04, SK-MEL-5, CAL-27. FaDu, KYSE-150, H2122, H23, KP4. YCC-2, YCC-10, PANC-1, RT112 / 84, Hl 781, and KYSE-270. See FIGs.24A-24E and the disclosure related thereto.|0702] As cMET agonism can be an oncogenic driver, Q397-noV205C (comprising the sequences set forth in SEQ ID NO: 75 and SEQ ID NO: 81). essentially the mAb component of MYTX-011, was assessed for its potential to enhance cellular proliferation and cell signaling. Q39? itself (i.e, the actual mAb component of MYTX-011) was not used because the C at position 98 of its light chain constant domain (SEQ ID NO: 158) may cause undesirable aggregation. The effects of Q397-noV205C treatment on proliferation of the cMET expressing human lung adenocarcinoma cell fine, NC1-H441, and on cMET receptor signaling in NCI H441 cells using phosphorylated-Aktl (pAktl) and phospho rylated-ERK 1 / 2 (pERKl / 2) as measures of pathway activation were assessed.|0703] Cell Proliferation Assay. Briefly: NCI-H441 cells were cultured in standard culture media (RPMI- 1640 Medium + 10% fetal bovine serum) and conditions recommended by the vendor. NC1-H441 cells were serum starved for approximately 24 hours at 37 °C. Cells were treated with 10 nM test articles, and plates were incubated for 4 days at 37CC. Each sample 'as plated in duplicate technical replicates. At the end of the culture period, proliferation was measured using CellTiter-Glo. Luminescence was measured using a plate reader at 578 nm.107041 Cell Signaling Assay. Briefly: NC1-H441 cells were cultured in standard culture media (RPMI-1640 Medium + 10% fetal bovine serum) using conditions recommended by the vendor. For the cell signaling assay, NCI-H441 cells were seeded in 6-wcll plates at 300,000 cells per well in culture media. Tire next day, the cells were washed with serum-free medium twice and then replenished with 3 mL RPMI + 0.2% fetal bovine serum.

[0705] The following day. cells were treated with 50 ng / mL HGF or 10 pg / mL of test articles and incubated for 30 minutes at 37 °C. Following the 30-minute stimulation, the treatment medium was aspirated, the cells were washed 2 times in an excess volume of ice-cold phosphate buffered saline and collected by cell scraping on ice in 250 pL ice-cold lysis buffer per well and transferred to pre-chilled tubes. Cell lysates were incubatedAttorney Docket No. 45395-0071WO1on ice for 10 minutes with occasional vortexing, and then centrifuged at maximum speed for 5 minutes to clear the lysate. Lysates were frozen at ~20°C until analysis. Lysates were thawed on ice for 1 hour with occasional vortexing, and protein concentrations were measured using the BCA protein assay according to the manufacturer’s instructions. Lysates were diluted in lysis buffer to final concentration 0.5 mg / raL, and 100 pL of each sample was assessed using commercially available ELISA kits to detect total ERK 1 / 2 and Aktl and their phosphorylated forms. ELISAs were performed and analyzed according to the manufacturer’s instructions.

[0706] Results. For FIGs. 3 & 4, abbreviations including RC1, RC2, and RC3 are as defined above, and treatment induced phosphorylation was represented as a ratio of phospho-protem to total protein and normalized to untreated controls (n:::l pooled from 2 technical replicates). HGF:::positive control, hepatocyte growth factor; P-Aktl / Aktl ==:ratio of pAktl to t...

Claims

Attorney Docket No. 45395-0071WO1WHAT IS CLAIMED:

1. A method of treating a cMET-positive solid tumor cancer in a population of subjects, wherein treatment results in a decreased incidence of one or more adverse event(s) associated with monomethyl auristatin E (MMAE) -containing antibody drug conjugates as compared to the incidence of the one or more adverse event(s) associated with intravenous administration of two or more doses of an effective amount of a control MMAE-conjugated cMET-targeting ADC, once every two weeks (Q2W), over a similar treatment period, wherein the method comprises administering to the subject two or more doses of MYTX-011. wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W); optionallywherein the dose is about 1.9 mg / kg and the control ADC has a DAR of ~3.1 and comprises a heavy chain variable domain sequence of SEQ ID NO: 159 and a light chain variable domain sequence of SEQ ID NO: 160; and / orwherein the dose of the control ADC comprises the same or greater amount of MMAE as compared to the dose of MYTX-011.

2. The method of claim 1, wherein the decreased incidence is at least a 5% decrease in incidence of the one or more adverse event(s) associated with MMAE-containing antibody drug conjugates.

3. The method of claim 1, wherein the decreased incidence is at least a 10% decrease in incidence of one or more adverse event(s) associated with MMAE-containing antibody drug conjugates.

4. The method of claim 1, wherein the decreased incidence is at least a 20% decrease in incidence of one or more adverse event(s) associated with MMAE-containing antibody drug conjugates.

5. The method of any one of claims 1-4, wherein the one or more adverse event(s) associated with MMAE-containing antibody drug conjugates are selected from the group consisting of: peripheral neuropathy, anemia, thrombocytopenia, neutropenia, hypoalbuminemia, peripheral edema, and AST / ALT elevation.

6. Tire method of any one of claims 1-5. wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 3.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

7. The method of any one of claims 1-5, wherein the doses of MYTX-011 are administered to tire subject in an amount ranging from about 4.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).Attorney Docket No. 45395-0071WO18. A method of treating a cMET-positive solid tumor cancer in a subject, wherein the subject's cancer has progressed or has not responded to 3. 4, 5, or 6 prior lines of treatment, the method comprising administering to the subject two or more doses of MYTX-011, wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

9. The method of claim 8, wherein the subject’s cancer has progressed or has not responded to 3 prior lines of treatment.

10. The method of claim 8, wherein the subject’s cancer has progressed or has not responded to 4 prior lines of treatment.

11. The method of claim 8, wherein the subject's cancer has progressed or has not responded to 5 prior lines of treatment.

12. The method of claim 8, wherein the subject has not responded to 6 prior lines of treatment.

13. Tire method of any one of claims 8-12, wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 3.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

14. The method of any one of claims 8-12, wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 4.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

15. A method of treating a cMET-positive solid tumor cancer in a subject, wherein the subject’s tumor has not responded to or has progressed after prior treatment with a taxane-based therapy, the method comprising administering to the subject two or more doses of MYTX-011, wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

16. Tire method of claim 15, wherein the taxane-based therapy is selected from the group of: paclitaxel, docetaxel, and cabazitaxel.

17. The method of claim 15 or 16, wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 3.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).Attorney Docket No. 45395-0071WO118. The method of claim 15 or 16, wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 4.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

19. A method of treating a cMET-positive solid tumor cancer in a subject, the method comprising: (a) administering to the subject two or more doses of MYTX-011, wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W); and(b) administering one or both of a vasoconstrictor and a corticosteroid to one or both eyes of the subject; optionallywherein either or both the vasoconstrictor and the corticosteroid are administered around the time of the peak plasma concentration of MYTX-011 to provide the subject with maximum protection against drug-related ocular toxicity.

20. The method of claim 19, w herein step (b) is performed prior to step (a).

21. The method of claim 19, wherein step (a) is performed prior to step (b).

22. The method of claim 19, wherein steps (a) and (b) are performed at about the same time.

23. The method of any one of claims 19-22, wherein step (b) comprises administering a vasoconstrictor to one or both eyes of the subject.

24. The method of any one of claims 19-22, wherein step (b) comprises administering a corticosteroid to one or both eyes of the subject.

25. The method of any one of claims 19-22, wherein step (b) comprises administering a vasoconstrictor and a corticosteroid to one or both eyes of the subject.

26. The method of any one of claims 19-25, wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 3.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

27. The method of any one of claims 19-26, wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 4.0 mg / kg to about 6.0 mg / kg, once every three weeks (Q3W).

28. A method of treating a cMET-positive solid tumor cancer in a subject, tire method comprising:Attorney Docket No. 45395-0071WO1administering a first dose of MYTX-011 in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg on day 1;administering a second dose of MYTX-011 in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg on about day 22; andadministering a third dose of MYTX-011 in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg on about day 64.

29. Tire method of claim 28, wherein the first, second, and third doses of MYTX-011 are administered to the subject in an amount ranging from about 3.0 mg / kg to about 6.0 mg / kg.

30. The method of claim 29, wherein the first, second, and third doses of MYTX-011 are administered to the subject in an amount ranging from about 4.0 mg / kg to about 6.0 mg / kg.

31. The method of any one of claims 28-30, wherein tire method further comprises: administering a fourth dose of MYTX-011 in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg on about day 85; andadministering a fifth dose of MYTX-011 in an amount ranging from about 2.0 mg / kg to about 6.0 mg / kg on about day 127.

32. The method of claim 31, wherein the fourth and fifth doses of MYTX-011 are administered to the subject in an amount ranging from about 3.0 mg / kg to about 6.0 mg / kg.

33. The method of claim 32, wherein the fourth and fifth doses of MYTX-011 are administered to the subject in an amount ranging from about 4.0 mg / kg to about 6.0 mg / kg.

34. The method of any one of claims 1-33, wherein the cMET-positive solid tumor cancer is a cMET-o verexpressing and / or MET-amplified solid tumor cancer.

35. The method of any one of claims 1-33, wherein a biopsy from the cMET-positive solid tumor cancer has an ultra-low, a low or an intermediate level of cMET staining by IHC.

36. The method of any one of claims 1-33, wherein a biopsy from the cMET-positive solid tumor cancer has an H-score of about 25 to about 300, or about 25 to about 275, or about 25 to about 250, or about 25 to about 225, or about 25 to about 200, or about 25 to about 175, or about 25 to about 150, or about 25 to about 125, or about 25 to about 100, or about 25 to about 75 or about 25 to about 50, or about 25 to about 300, or about 50 to about 275, or about 50 to about 250, or about 50 to about 225, or about 50 to about 200,Attorney Docket No. 45395-0071WO1or about 50 to about 175, or about 50 to about 150, or about 50 to about 125, or about 50 to about 100, or about 50 to about 75.

37. The method of any one of claims 1-36, wherein the cMET-positive solid tumor cancer is nonsmall cell lung cancer (“NSCLC”).

38. The method of claim 37, wherein the NSCLC is non-squamous NSCLC, squamous NSCLC, or not otherwise specified NSCLC.

39. The method of any one of claims 1, 8. 15, 19, and 28, wherein a biopsy from a tumor of the cMET-positive solid tumor cancer and / or an entire tumor of the cMET-positive solid tumor cancer, comprises at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% of cancer cells having a cMET expression level of at least a 1+, a 2+, or a 3+, as scored by an applicable and / or regulatory-agency approved immunohistochemistry (IHC) assay.

40. The method of claim 39, wherein:(a) at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%.45%, 50%, 60%, 70%, 80%, 90%, or 100% of the cancer cells have an IHC score of 1+ or 2+;(b) at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%. 90%. or 100% of the cancer cells have an IHC score of 2+:(c) at least about 1%, 2%. 3%. 4%, 5%. 6%. 7%, 8%, 9%. 10%. 15%. 20%. 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% of the cancer cells have an IHC score of 1+;(d) at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, or about 20% of the cancer cells have an IHC score of 1+ and wherein no more than about 1%, 2%, 3%, 4% or 5% of the cancer cells have an IHC score of 2+ or 3+; and / or(e) at least about 1%, 2%, 3%, 4%, 5%, 6%. 7%, 8%, 9%. 10%, 15%, or about 20% of the cancer cells have an IHC score of 1+ and wherein no more than about 1%, 2%. 3%, 4% or 5% of the cancer cells have an IHC score of 2+ or 3+.

41. Tire method of claim 40, wherein:(a) no more than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%. 10%, 15%, or about 20% of the cancer cells have an IHC score of 2+ and wherein no more than about 1% of the cancer cells have an IHC score of 3+;(b) no cancer cells have an IHC score of greater than 1+; or(c) no cancer cells have an IHC score of greater than 2+.Attorney Docket No. 45395-0071WO142. The method of claim 39, further comprising a step of determining an H-score for the biopsy or the entire tumor, wherein the H-score is between about 10 and about 300, between about 10 and about 250, between about 20 and about 225, between about 20 and about 200, between about 20 and about 175, or between about 20 and about 150.

43. The method of claim 39, wherein the H-score is no more than about 100, about 90, about 80, about 70, about 50 or about 25.

44. The method of claim 39, wherein the biopsy or the entire tumor is homogeneous or heterogeneous for cMET expression.

45. Tire method of claim 39, wherein at least about 10%, 20%, or 30% of the cancer cells have a first frequently-occurring IHC score selected from one of 0, 1+, 2+, and 3+ and at least about 10%, 20%, or 30% of the cancer cells have a second frequently-occurring IHC score selected from one of 0, 1+, 2+, and 3+, wherein the first and second frequently-occurring IHC scores are different.

46. The method of claim 45, wherein the first and second frequently-occurring IHC scores are selected from the following pairs of scores: (0, +1), (0, +2), (0, +3), (+1, +2), (+1, +3), and (+2, +3).

47. The method of claim 45 or 46. wherein at least about 10%, 20%, or 30% of the cancer cells have a third frequently-occurring IHC score, wherein the third frequently-occurring IHC score is distinct from the first and second frequently-occurring IHC scores.

48. Tire method of any one of claims 1-47, wherein the cMET-positive solid tumor cancer has developed resistance to targeted therapies against one or more actionable mutation(s) present in one or more gene selected from tire group consisting of EGFR. ALK, KRAS, ROS, BRAF, NTRK1 / 2 / 3, MET, RET, ERBB2, and any other gene known to have an actionable mutation associated with the cancer.

49. The method of claim 48, wherein the actionable mutation is selected from one or more of the following:(a) an EGFR gene mutation selected from an exon 20 T790M substitution, an exon 20 C797X substitution, an exon 21 L858R substitution, and an exon 19 deletion, optionally wherein the exon 19 deletion is the E746 A750 deletion as determined by a regulatory agency approved test;(b) an ALK gene rearrangement;(c) a KRAS gene mutation, optionally wherein the mutation is an exon 2 G12C substitution;Attorney Docket No. 45395-0071WO1(d) a BRAF gene mutation, optionally wherein the mutation is in Exon 15 V600E substitution; (e) aMET gene mutation, optionally wherein the mutation is an exl4 skipping mutation;(f) aROSl gene rearrangement, optionally where the ROS1 gene is fused with a gene or portion of a gene selected from one of the following: ('1)74. EZR. Sl)('4. SLC34A2, CCDC6, TFG, SLMAP, MY05C, FIG, LIMA1, CLTC, GOPC, ZCCHC8, CEP72, MLL3, KDELR2, TRIG 3. MSN, MPR1P, WNK1, SLC6A17, TMEM106B, FAM135B, TPM3, and TDP52LF,(g) a fusion of the NTRK1, 2, or 3 gene; and(h) a RET gene rearrangement, optionally where the rearrangement is a fusion with KIF5B or CCDC6.

50. The method of claim 49, wherein the cancer has an amplification, mutation, or overexpression of the ERBB2 gene, optionally wherein the ERBB2 gene has insertions in exon 20 and / or nucleotide substitutions encoding amino acid substitutions selected from one or more of the following: L755S, G776C, G660D, R678Q, E693K, and Q709L.

51. The method of claim 49, wherein the method further comprises administering to the subject an additional anticancer agent according to its regulatory agency-approved dosing regimen.

52. Tire method of claim 51, wherein the additional anticancer agent is an inhibitor and / or targeting agent of EGFR, ALK, KRAS, ROS, BRAF, NTRK1 / 2 / 3, MET, RET, or ERBB2.

53. The method of claim 51, wherein the additional anti cancer agent is selected from osimertinib®, afatinib®, axitinib®, bosutinib®, crizotinib®, dasatinib®, erlotinib®, gefitinib®, imatinib®, lapatinib®, nilotinib®, pazopanib®, ponatinib®, radotinib®, regorafenib®, sorafenib®, sunitinib®, toceranib®, and vatalanib; and / or wherein the additional anticancer agent is capable of inhibiting EGFR comprising an exon 21 L858R substitution or an exon 19 E746 A750 deletion.

54. The method of claim 52, wherein the ALK inhibitor is selected from alectinib, brigatinib, lorlatinib, ceritinib, and crizotinib; the KRAS inhibitor is selected from sotorasib and adagrasib; the BRAF inhibitor is selected from dabrafmib, vemurafenib, and trametinib; the MET inhibitor is selected from tcpotinib, crizotinib, and capmatinib; the ROS1 inhibitor is selected from cntrcctinib, crizotinib, ceritinib, and lorlatinib; the NTRK1 / 2 / 3 inhibitor is selected from larotrectinib and entrectinib; the RET inhibitor is selected from selpercatinib, pralsetinib, and cabozantinib; or the ERBB2 targeting agent is selected from trastuzumab-deruxtecan and trastuzumab-emtansine.Attorney Docket No. 45395-0071WO155. The method of claim 51, wherein the additional anticancer agent comprises an inhibitor of PD1, optionally an anti-PD 1 antibody, optionally wherein the anti-PD 1 antibody is pembrolizumab. nivolumab. or cemiplimab; or an inhibitor of PD-L1, optionally an anti-PD-Ll antibody such as durvalumab, or atezolizumab.

56. The method of any one of claims 1-47, wherein the cMET-positive solid tumor cancer is resistant to and / or otherwise progressed after prior treatment with an anti-cMET antibody, an anti-cMET ADC, a chemotherapy, a small molecule directed against cMET. and / or a radiation therapy.

57. The method of any one of claims 1-47, wherein the cMET-positive solid tumor cancer comprises а. MET ex 14 skipping mutation.

58. Tire method of claim 57, wherein the NSCLC is wildtype for human EGFR.

59. The method of claim 58, wherein the NSCLC is mutated for human EGFR.

60. The method of any one of claims 56 to 59, wherein the NSCLC has resisted at least 1, 2, 3, 4, 5, б, 7, 8, or more prior therapeutic regimen(s).

61. The method of any one of claims 1-47, wherein the cMET-positive solid tumor cancer comprises an FGFR3 amplification or an EML4-ALK fusion.

62. The method of any one of the preceding claims, wherein the cMET-positive solid tumor cancer has progressed after prior treatment with a tyrosine kinase inhibitor.

63. The method of any one of claims 1-47, wherein the cMET-positive solid tumor cancer comprises one or both of the following:(a) an EGFR mutation substantially similar or identical to the EGFR mutation in the CTG-3414 PDX and / or NCI-H1975 CDX model; and / or(b) a KRAS mutation substantially similar or identical to the KRAS mutation in tire NCI-H2122 CDX and / or NCI-H1373 CDX model.

64. The method of any one of claims 1-47, wherein the cMET-positive solid tumor cancer comprises actionable mutation(s) substantially similar or identical to the actionable mutation(s) in one or more of the following:(a) the actionable mutation(s) present in the Hs746T gastric cancer CDX model;Attorney Docket No. 45395-0071WO1(b) the actionable mutations(s) present in the MET TKI sensitive LU-01-1375 NSCLC PDX model; and / or(c) the actionable mutations(s) present in the CTG-2669 NSCLC PDX model.

65. The method of any one of claims 1-47, wherein the cMET-positive solid tumor cancer is characterized as being a MET TKI-sensitive cancer comprising a MET Exon 14 skipping mutation.

66. Tire method of claim 65, wherein the method further comprises administration of a MET TKI.

67. The method of claim 66, wherein the MET TKI is capmatinib or tepotinib.

68. The method of any one of claims 1-36, wherein the cMET-positive solid tumor cancer is a MET amplified gastric tumor comprising a MET Exon 14 skipping mutation.

69. The method of any one of claims 1-36, wherein the cMET-positive solid tumor cancer comprises an actionable mutation substantially similar or identical to the actionable mutations in the LU-01-1476 PDX model.

70. Tire method of claim 68 or 69, wherein the method further comprises administration of a MET TKI71. A method of treating a cMET-positive solid tumor cancer in a subject, wherein the subject has not responded to prior treatment with a MET tyrosine kinase inhibitor (TKI), the method comprising administering to the subject two or more doses of MYTX-011, wherein the doses of MYTX-011 are administered to the subject in an amount ranging from about 2.0 mg / kg to about 6.0 rng / kg, once every three weeks (Q3W).

72. The method of claim 71, wherein the subject has not responded to 2 prior lines of treatment.

73. The method of claim 72, wherein the subject has not responded to 4 prior lines of treatment.

74. The method of claim 73, wherein the subject has not responded to 5 prior lines of treatment.

75. The method of claim 74, wherein the subject has not responded to 6 prior lines of treatment.

76. The method of any one of claims 72 to 75, wherein the MET TKI is capmatinib or tepotinib.Attorney Docket No. 45395-0071WO177. The method of any one of claims 1-76, wherein the doses of MYTX-011 are administered as a pharmacal composition comprising L-histidine. L-histidine HCl monohydrate. D(+)-trehalose dihydrate, and polysorbate 80.

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