New treatment of non-small cell lung cancer

Abstract

The present invention discloses a method for treating cancerous tumours and / or metastasis with MET mutations and / or amplifications using an anti-MET antibody fragment. The method involves administering the antibody fragment, which features a single antigen- binding arm and a silenced Fc region, in effective doses ranging from 350 mg to 5000 mg. This dosage regimen is intended for the effective treatment of cancer, in particular NSCLC.

Description

[0001] NEW TREATMENT OF NON-SMALL CELL LUNG CANCER

[0002] INTRODUCTION

[0003] The present disclosure relates to the treatment of Non-Small Cell Lung Cancer (NSCLC), comprising administering to a human or animal affected by the cancer a therapeutically effective amount of an anti -MET antibody fragment.

[0004] Mesenchymal-Epithelial Transition (MET) proto-oncogene encodes MET that belongs to a family of Receptor Tyrosine Kinases (RTKs), (along with its ligand Hepatocyte Growth Factor [HGF, also known as scatter factor, SF]), that is involved in transduction pathways and modulates essential cellular processes under normal physiological conditions. The HGF / MET signalling axis is a potent driver of cell proliferation, and evidence has indicated that diverse oncogenic alterations, including MET mutations, or MET amplification, cause dysregulation and lead to a wide range of human cancers.

[0005] It has been established that in patients with NSCLC, 2%-4% of the patients harbour MET exon 14 (METex14) skipping alterations, and 1-5% of the patients have MET amplifications.

[0006] According to National Comprehensive Cancer Network Guidelines, capmatinib, crizotinib, and tepotinib are recommended as first-line therapy or subsequent therapy in patients with NSCLC harbouring METex14 skipping mutation (METex14 mutation) or MET amplification. According to European Society for Medical Oncology (ESMO) 2023, capmatinib and tepotinib are recommended following prior treatment with immunotherapy and / or platinum-based chemotherapy in patients with METex14 mutation.

[0007] Capmatinib and tepotinib have been approved by the European Medicine Agency (EMA) and Food and Drug Administration (FDA) only for patients with METex14 mutation, and to date no drug has been approved for the treatment of patients with NSCLC exhibiting MET amplification.

[0008] Although approved MET Tyrosine Kinase Inhibitors (TKIs) capmatinib and tepotinib are efficacious in NSCLC with METex14 mutation, they have limited efficacy in NSCLC with MET amplification.

[0009] Indeed Capmatinib (Tabrecta®), has been approved by the FDA and recommended by the National Comprehensive Cancer Network Guidelines as first-line therapy or subsequent therapy in patients with NSCLC harboring MET exon 14 (METex14) skipping mutation. Crizotinib, another MET TKI is recommended for use in patients with NSCLC with METex14 skipping mutation. Eventually Tepotinib (Tepmetko® has been approved by the European Medicine Agency (EMA) and FDA only for patients with METex14 mutation and is recommended following prior treatment with immunotherapy and / or platinum-based chemotherapy in patients with METex14 mutation according to the European Society for Medical Oncology (ESMO) 2023.

[0010] While Tepotinib has proven efficacy in NSCLC with METex14 mutation, it has limited efficacy in NSCLC with MET amplification.

[0011] The safety profile of these MET TKIs has limitations that affect treatment tolerance, such as peripheral edema, nausea, vomiting, pneumonitis, and hepatotoxicity.

[0012] There are several agents in clinical development using different mechanisms of action such as antibody-drug conjugates (ADC), bispecifics. Overall, those agents have shown sub-optimal MET inhibition underlining the importance of adequately selecting patients eligible to MET-targeting approaches. Their safety profile has shown limitations due either to the toxicity of the payload or the targeting of Epidermal Growth Factor Receptor (EGFR) (for EGFR-MET bispecifics). In addition, there is growing evidence that patients treated with MET TKI may present with on-target emerging resistance. Finally, the patients developing secondary resistance to non-MET TKI treatment (e.g., post EGFR TKI) have currently no available options, although being reported in about 15-20% of the cases (Remon and al., MET alterations in NSCLC-Current Perspectives and Future Challenges, J. of Thoracic Oncology, 2023).

[0013] Therefore, there is still a high unmet medical need in patients with solid tumours including NSCLC with MET alterations, more specifically those with MET amplification, in the absence of approved or suitable therapies.

[0014] New monovalent agents specific for MET have recently been described (see e.g., W02020 / 074459). In these agents, one arm of the antibody was deleted by molecular engineering, leading to an improved in vivo stability which is attributable to the activity of the Fc domain, which binds the Fc receptor expressed in the organs. One of these monovalent agents, hOA-DN30, is further described in J Exp Clin Cancer Res 2022 41(1):112. hOA-DN30 induces shedding through the cleavage of the extracellular portion of the receptor, followed by the rapid degradation of the MET intracellular kinase domain. As a consequence, MET could be physically removed from the cell surface and the extracellular domain acts as soluble decoy', preventing ligand binding by sequestering HGF. In addition, an Fc-silenced derivative of h0A-DN30 designated VERT-002 shows improved safety whilst maintaining the same high therapeutic efficacy as h0A-DN30 (see PCT Application No. EP2024 / 065156).

[0015] The unique ability of anti-MET antibody fragments such as VERT-002 to simultaneously erase cell surface MET and release the ‘decoy’ receptor extracellular region results in a paramount MET blocking action. It shows remarkable efficacy with promising pharmacological features in a large number of pre-clinical models (EBC-1 and Hs746T cell lines and xenograft mice models), as well as promising PK parameters in non-human primates. These fragments - notably VERT-002 - are therefore strong candidates for a successful clinical application for the therapy of MET-addicted cancers.

[0016] Also VERT-002, with its unique mechanism of action as a one-armed, Fc-silent monoclonal antibody targeting MET, is particularly positioned to address the unmet medical need in patients with solid tumours, including NSCLCwith MET alterations, particularly those with MET amplification. VERT-002 provides a new treatment option for this patient population, potentially overcoming some of the limitations of the available MET TKIs.

[0017] Indeed, the unique mechanism of action of VERT-002 makes it a promising therapeutic candidate for the treatment of MET-altered tumours, including non-small cell lung cancer (NSCLC). More specifically, VERT-002 is a one-armed, Fc-silent monoclonal antibody that binds specifically to the MET receptor at the juxta-membrane extracellular Ig-like Plexins Transcription factors 4 (IPT4) domain.

[0018] Also by the induction of MET ectodomain shedding, VERT-002 triggers the cleavage of the MET extracellular domain (ECD) by cell surface proteases such as ADAM10 and ADAM17. This cleavage of MET receptor by VERT-002 triggering the release of MET ECD is a unique aspect of VERT-002's mode of action.

[0019] Subsequently to the cleavage of the MET receptor or the shedding of the extracellular domain, the truncated MET receptor undergoes intracellular proteolytic cleavage and triggers degradation mediated by y-secretase. Thus, by enhancing MET ECD shedding and subsequent degradation of the MET receptor, VERT-002 effectively downregulates MET signaling pathway, leading to the inhibition of downstream effectors such as ERK and AKT. This results in the inhibition of cancer cell proliferation that is dependent on MET signaling, a condition known as "MET addiction."

[0020] Eventually, the lack of effector functions is also a particularly beneficial effect of VERT-002. Due to its Fc-silencing, VERT-002 does not exert typical antibody effector functions such as Antibody-Dependent Cell-mediated Cytotoxicity (ADCC), Antibody-Dependent Cell-mediated Phagocytosis (ADCP), or Complement-Dependent Cytotoxicity (CDC).

[0021] Of special interest, the compound of the invention shows activity in both liganddependent and independent settings. Indeed, VERT-002's mode of action is designed to abrogate signaling in both ligand-dependent and independent settings, which may occur through activating mutations of the MET gene or through ligand-dependent signaling via Hepatocyte Growth Factor (HGF).

[0022] VERT-002 shows potent anti-proliferative activity against established MET-addicted cell lines and elicited full tumour growth inhibition in human tumour grafted on mice (Patient Derived Xenograft model), particularly in a PDX from a patient resistant to chemotherapy (i.e. capmatinib), when administered at certain doses. Also VERT-002 makes it a promising therapeutic candidate for patient resistant following MET Tyrosine Kinase Inhibitors treatment. This unique mechanism of action, which involves both the shedding of the MET receptor, release of MET ECD and the degradation of the whole MET molecule, distinguishes VERT-002 from other MET-targeting therapies and contributes to its potential as a first-in-class treatment for cancers with MET alterations.

[0023] The problem to be solved by the present disclosure is therefore to provide the administration of a dose of an anti-Met antibody fragment efficient in humans whilst minimising toxicity.

[0024] DESCRIPTION

[0025] Definitions

[0026] The disclosure pertains to antibodies and antibody-based constructs which specifically bind to Met, and the uses of such constructs, in particular therapeutic uses, such as the treatment of tumours and metastasis.

[0027] The terms “Met”, “cMET”, “cMet” and “MET”, refer to a protein also known as Hepatocyte Growth Factor Receptor, HGFR, or c-Met. Human Met has the following amino acid sequence (UniProt P08581):

[0028] MKAPAVLAPGILVLLFTLVQRSNGECKEALAKSEMNVNMKYQLPNFTAETPIQNVILHEH HIFLGATNYIYVLNEEDLQKVAEYKTGPVLEHPDCFPCQDCSSKANLSGGVWKDNINMAL VVDTYYDDQLISCGSVNRGTCQRHVFPHNHTADIQSEVHCIFSPQIEEPSQCPDCWSAL GAKVLSSVKDRFINFFVGNTINSSYFPDHPLHSI SVRRLKETKDGFMFLTDQSYIDVLPE FRDSYPIKYVHAFESNNFIYFLTVQRETLDAQTFHTRIIRFCSINSGLHSYMEMPLECIL TEKRKKRSTKKEVFNILQAAYVSKPGAQLARQIGASLNDDILFGVFAQSKPDSAEPMDRS AMCAFPIKYVNDFFNKIVNKNNVRCLQHFYGPNHEHCFNRTLLRNSSGCEARRDEYRTEF TTALQRVDLFMGQFSEVLLTSI STFIKGDLTIANLGTSEGRFMQVWSRSGPSTPHVNFL LDSHPVSPEVIVEHTLNQNGYTLVITGKKITKIPLNGLGCRHFQSCSQCLSAPPFVQCGW CHDKCVRSEECLSGTWTQQICLPAIYKVFPNSAPLEGGTRLTICGWDFGFRRNNKFDLKK TRVLLGNE SCTLTL SE STMNTLKCTVGPAMNKHFNMS III SNGHGTTQY STF S YVDPVI T SISPKYGPMAGGTLLTLTGNYLNSGNSRHISIGGKTCTLKSVSNSILECYTPAQTISTEF AVKLKIDLANRETSIFSYREDPIVYEIHPTKSFISGGSTITGVGKNLNSVSVPRMVINVH EAGRNFTVACQHRSNSEI ICCTTPSLQQLNLQLPLKTKAFFMLDGILSKYFDLIYVHNPV FKPFEKPVMI SMGNENVLEIKGNDIDPEAVKGEVLKVGNKSCENIHLHSEAVLCTVPNDL LKLNSELNIEWKQAI S STVLGKVI VQPDQNFTGL IAGVVS I STALLLLLGFFLWLKKRKQ IKDLGSELVRYDARVHTPHLDRLVSARSVSPTTEMVSNESVDYRATFPEDQFPNSSQNGS CRQVQYPLTDMSPILTSGDSDISSPLLQNTVHIDLSALNPELVQAVQHVVIGPSSLIVHF NEVIGRGHFGCVYHGTLLDNDGKKIHCAVKSLNRITDIGEVSQFLTEGI IMKDFSHPNVL SLLGICLRSEGSPLVVLPYMKHGDLRNFIRNETHNPTVKDLIGFGLQVAKGMKYLASKKF VHRDLAARNCMLDEKFTVKVADFGLARDMYDKEYYSVHNKTGAKLPVKWMALESLQTQKF TTKSDVWSFGVLLWELMTRGAPPYPDVNTFDITVYLLQGRRLLQPEYCPDPLYEVMLKCW HPKAEMRPSFSELVSRISAIFSTFIGEHYVHVNATYVNVKCVAPYPSLLSSEDNADDEVD TRPASFWETS ( SEQ ID No. 1)

[0029] The term “antibody” as used herein refers to a protein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, which interacts with an antigen. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FR’s arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1 q) of the classical complement system. The term “antibody” includes for example, monoclonal antibodies, human antibodies, humanised antibodies, camelised antibodies and chimeric antibodies. The antibodies can be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., lgG1, lgG2, lgG3, lgG4, lgA1 and lgA2) or subclass. Both the light and heavy chains are divided into regions of structural and functional homology.

[0030] The term “antibody fragment”, as used herein, refers to one or more portions of an antibody that retain the ability to specifically interact with (e.g., by binding, steric hindrance, stabilising spatial distribution) an antigen. Examples of binding fragments include, but are not limited to, a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; a F(ab)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment consisting of the VH and CH1 domains; a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a dAb fragment (Ward et al., (1989) Nature 341:544-546), which consists of a VH domain; and an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al., (1988) Science 242:423-426; and Huston et al., (1988) Proc. Natl. Acad. Sci. 85:5879-5883). Such single chain antibodies are also intended to be encompassed within the term “antibody fragment”. These antibody fragments are obtained using conventional techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies. Antibody fragments can also be incorporated into single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, (2005) Nature Biotechnology 23:1126-1136). Antibody fragments can be grafted into scaffolds based on polypeptides such as Fibronectin type III (Fn3) (see U. S. Pat. No. 6,703,199, which describes fibronectin polypeptide monobodies). Antibody fragments can be incorporated into single chain molecules comprising a pair of tandem Fv segments (VH-CH1 -VH-CH1 ) which, together with complementary light chain polypeptides, form a pair of antigen-binding sites (Zapata etal., (1995) Protein Eng. 8: 1057-1062; and U.S. Pat. No. 5,641,870).

[0031] The structures and locations of immunoglobulin variable domains, e.g., CDRs, may be defined using well known numbering schemes, e.g., the Kabat numbering scheme, the Chothia numbering scheme, or a combination of Kabat and Chothia (see, e.g. Sequences of Proteins of Immunological Interest, U. S. Department of Health and Human Services (1991 ), eds. Kabat et al.; Lazikani et al., (1997) J. Mol. Bio. 273:927-948); Kabat et al., (1991) Sequences of Proteins of Immunological Interest, 5th edit., NIH Publication no. 91-3242 U. S. Department of Health and Human Services; Chothia et al., (1987) J. Mol. Biol. 196:901 -917; Chothia et al., (1989) Nature 342:877-883; and Al-Lazikani et al., (1997) J. Mol. Biol.

[0032] 273:927-948; Annals of the New York Academy of Sciences, 764, 47-49 (1995); Nucleic Acids Research, 25, 206-211 (1997).

[0033] A “human antibody” or “human antibody fragment”, as used herein, is an antibody and antibody fragment having variable regions in which both the framework and CDR regions are from sequences of human origin. Human antibodies can also be isolated from synthetic libraries or from transgenic mice (e.g. Xenomouse, OmniMouse, Harbour Mouse, ATX-Gx Mouse, Trianni Mouse) provided the respective system yield in antibodies having variable regions in which both the framework and CDR regions are derived from sequences of human origin. Furthermore, if the antibody contains a constant region, the constant region also is derived from such sequences. Human origin includes, e.g., human germline sequences, or mutated versions of human germline sequences or antibody containing consensus framework sequences derived from human framework sequences analysis, for example, as described in Knappik et al., (2000) J Mol Biol 296:57-86).

[0034] A “humanised antibody” or “humanised antibody fragment” is defined herein as an antibody molecule, which has constant antibody regions derived from sequences of human origin and the variable antibody regions or parts thereof or only the CDRs are derived from another species. For example, a humanised antibody can be CDR-grafted, wherein the CDRs of the variable domain are from a non-human origin, while one or more frameworks of the variable domain are of human origin and the constant domain (if any) is of human origin.

[0035] The term "antigen binding arm", as used herein, refers to a component part of an antibody fragment of the invention that has an ability to bind specifically a target molecule of interest. The antigen binding arm is a complex of variable domain sequences (VL and VH), including the CDRs and the framework regions of an immunoglobulin light and heavy chain, and constant domain sequences (CL and CH) of an immunoglobulin light and heavy chain.

[0036] The "hinge region ", "hinge sequence", and variations thereof, as used herein, includes the meaning known in the art, which is illustrated in, for example, Janeway et al., Immuno Biology: the immune system in health and disease, (Elsevier Science Ltd., NY) (4th ed., 1999).

[0037] The phrase "truncated hinge region ", as used herein, refers to a polypeptide comprising parts, but not all, of a hinge sequence. The truncated hinge region is capable of linkage to the "first" Fc polypeptide. If the wild type hinge sequence is not present, the remaining sequence in the "second" Fc polypeptide would comprise a component that is capable of linkage to the "first" Fc polypeptide. For example, said component can be a modified residue or an added cysteine residue capable of forming a disulfide linkage.

[0038] A "knob" refers to at least one amino acid side chain which projects from the interface of a first Fc polypeptide and is therefore positionable in a compensatory hole in the adjacent interface (i.e. the interface of a second Fc polypeptide) so as to stabilise the heteromulti mer, and thereby favour heteromulti mer formation over homomulti mer formation, for example. The knob may exist in the original interface or may be introduced synthetically (e.g. by altering nucleic acid encoding the interface). Normally, a nucleic acid encoding the interface of the first polypeptide is altered to encode the knob. To achieve this, the nucleic acid encoding at least one "original" amino acid residue in the interface of the first polypeptide is replaced with nucleic acid encoding at least one "import" amino acid residue which has a larger side chain volume than the original amino acid residue. It will be appreciated that there can be more than one original and corresponding import residue. The upper limit for the number of original residues which are replaced is the total number of residues in the interface of the first polypeptide.

[0039] A "hole" refers to at least one amino acid side chain which is recessed from the interface of a second Fc polypeptide and therefore accommodates a corresponding knob on the adjacent interface of a first Fc polypeptide. The hole may exist in the original interface or may be introduced synthetically (e.g. by altering nucleic acid encoding the interface). Normally, nucleic acid encoding the interface of the second polypeptide is altered to encode the hole. To achieve this, the nucleic acid encoding at least one "original" amino acid residue in the interface of the second polypeptide is replaced with nucleic acid encoding at least one "import" amino acid residue which has a smaller side chain volume than the original amino acid residue. It will be appreciated that there can be more than one original and corresponding import residue. The upper limit for the number of original residues which are replaced is the total number of residues in the interface of the second polypeptide.

[0040] The knob is "positionable'' into the hole which means that the spatial location of the knob and hole on the interface of a first Fc polypeptide and second Fc polypeptide respectively and the sizes of the knob and hole are such that the knob can be located into the hole without significantly perturbing the normal association of the first and second polypeptides at the interface. Since knobs do not typically extend perpendicularly from the axis of the interface and have preferred conformations, the alignment of a knob with a corresponding hole relies on modelling the knob / hole pair based upon a three-dimensional structure such as that obtained by X-ray crystallography or nuclear magnetic resonance (NMR). This can be achieved using widely accepted techniques in the art.

[0041] The term “domain” or “protein domain” refers to a region of a protein’s polypeptide chain that forms a functional unit and / or independently forms a three-dimensional structure.

[0042] “Compositions” or of the present disclosure may be used for therapeutic or prophylactic applications. The present disclosure, therefore, includes a pharmaceutical composition containing an antibody or antibody fragment as disclosed herein and a pharmaceutically acceptable carrier or excipient therefore. In a related aspect, the present disclosure provides a method for treating inflammatory diseases, autoimmune diseases, hematologic malignancies and potentially other diseases. Such method contains the steps of administering to a subject in need thereof an effective amount of the pharmaceutical composition that contains an antibody or antibody fragment as described herein.

[0043] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated. In particular, “pharmaceutically acceptable” as used herein means being approved by a regulatory agency of the Federal or a state government, or listed in the U. S. Pharmacopeia, European Pharmacopeia or other generally recognised Pharmacopeia for use in animals, and more particularly in humans.

[0044] The present disclosure provides therapeutic methods comprising the administration of a therapeutically effective amount of an antibody or antibody fragment as disclosed herein to a subject in need of such treatment. A “therapeutically effective amount” or “effective amount”, as used herein, refers to the amount of an anti-Met antibody necessary to elicit the desired biological response. Accordingly, the therapeutic effective amount is the amount of an anti-MET antibody fragment that is effective to cause a measurable improvement in one or more symptoms of a disease or condition or the progression of such disease or condition. A therapeutically effective dose further refers to that amount of the anti-Met antibody fragment sufficient to result in at least partial amelioration of symptoms, e.g., treatment, healing, prevention or amelioration of the relevant medical condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions. An effective amount of a therapeutic, e.g. the present anti-MET antibody fragment, will result in an improvement of a diagnostic measure or parameter by at least 10%; usually by at least 20%; preferably at least about 30%; more preferably at least 40%, and most preferably by at least 50%. An effective amount can also result in an improvement in a subjective measure in cases where subjective measures are used to assess disease severity.

[0045] “Administered” or “administration” includes but is not limited to delivery of a drug by an injectable form, such as, for example, an intravenous, intramuscular, intradermal or subcutaneous route or mucosal route, for example, as a nasal spray or aerosol for inhalation or as an ingestible solution, capsule or tablet. Preferably, the administration is by an injectable form.

[0046] As used herein, “treatment”, “treat” or “treating” and the like refers to clinical intervention in an attempt to alter the natural course of a disease in the subject being treated and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. In some embodiments, antibodies or antibody fragments according to the preset disclosure are used to delay development of a disease or to slow the progression of a disease.

[0047] As used herein, the term “in combination” in the context of the administration of other therapies refers to the use of more than one therapy. The use of the term “in combination” does not restrict the order or the time in which therapies are administered to a subject (e.g., one therapy before, concurrent with, or after another therapy). A first therapy can be administered before (e.g., 1 minute, 45 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks), concurrently, or after (e.g., 1 minute, 45 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks) the administration of a second therapy to a subject in need thereof. Any additional therapy can be administered in any order or time with the other additional therapies.

[0048] “Preventing” or “prevention” refers to a reduction in risk of acquiring or developing a disease (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset). “Prevention” also refers to methods which aim to prevent the onset of a disease or its symptoms or which delay the onset of a disease or its symptoms. “Subject” or “species” or as used in this context refers to any mammal, including rodents, such as mouse or rat, and primates, such as cynomolgus monkey (Macaca fascicularis), Marmoset monkey (Callithrix jacchus), rhesus monkey (Macaca mulatta) or humans (Homo sapiens). Preferably, the subject is a primate, most preferably a human. A human subject may be a “patient”.

[0049] Throughout this specification, unless the context requires otherwise, the words “comprise”, “have” and “include” and their respective variations such as “comprises”, “comprising”, “has”, “having”, “includes” and “including” will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.

[0050] The term “amino acid mutation” as used herein is meant to encompass amino acid substitutions, deletions, insertions, and modifications. Any combination of substitution, deletion, insertion, and modification can be made as long as the final construct possesses the desired characteristics, e.g., reduced binding to an Fc receptor. Amino acid sequence deletions and insertions include N-and / or C-terminal deletions and insertions of amino acid residues. Particular amino acid mutations are amino acid substitutions. Amino acid substitutions include replacement by non-naturally occurring amino acids or by naturally occurring amino acid derivatives of the twenty standard amino acids. Amino acid mutations can be generated using genetic or chemical methods well known in the art. Genetic methods may include site-directed mutagenesis, PCR, gene synthesis and the like. It is contemplated that methods of altering the side chain group of an amino acid residue by methods other than genetic engineering, such as chemical modification, may also be useful. Various designations may be used herein to indicate the same amino acid mutation. For example, a substitution of glycine at position 237 of the antibody Fc region to alanine can be indicated as 237A, G237A, or Gly237Ala.

[0051] A “wild-type” protein is a version or variant of the protein as it is found in nature. An amino acid sequence of a wildtype protein, e.g., a Fc region of a human IgG1 antibody, is the amino acid sequence of the protein as it occurs in nature. Due to allotypic differences, there can be more than one amino acid sequence for a wildtype protein. For example, there are several allotypes of naturally occurring human IGg1 heavy chain constant regions (see, e.g., Jeffries et al. (2009) mAbs 1 :1).

[0052] The “Fc region” is used to define the C-terminal region of an immunoglobulin heavy chain. The Fc region of an immunoglobulin generally comprises two constant domains, a CH2 domain and a CH3 domain. Although the boundaries of the Fc region of an IgG heavy chain might vary slightly, the human IgG heavy chain Fc region is usually defined to extend from Cys226, or from Pro230, to the C-terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, numbering of amino acid residues in the Fc region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991. Various Fc modifications are commonly used. For a review see for example Antibodies (2020) 9: 64.

[0053] The terms “silent”, “silenced” as used herein in the context of a silenced antibody or an antibody comprising a silencing mutation refers to a mutation in the Fc domain of such antibody which decreases, partially or wholly, binding to one or more cell surface Fcgamma receptors, thereby reducing or dampening, and in some embodiments abrogating substantially completely, one or more Fc-mediated antibody effector functions, such as ADCC, ADCP, and CDC complement response (see, e.g., Kang and Jung, Experimental and Molecular Medicine (2019) 51: 138). Silenced effector functions can be obtained by mutation in the Fc region of the antibody and have been described in the Art (e.g., Strohl, Biotechnology 20: 685-91 for LALA and N297A; Baudino et al., J. Immunol. 181: 6664-69 for D265A).

[0054] Embodiments of the invention

[0055] The present disclosure provides an anti-MET antibody fragment for use in treating a cancerous tumour and / or metastasis, with MET mutations and / or amplifications, in a subject,

[0056] • the anti-Met antibody fragment comprising a single antigen binding arm and a silenced Fc region, wherein the Fc region comprises a complex of a first and a second Fc polypeptide, wherein the antibody fragment comprises:

[0057] (i) a first polypeptide comprising a humanised light chain variable (VL) domain, and one human light chain constant (CL) domain, wherein the humanised VL domain contains three complementary determining regions (CDRs) having amino acid sequences as set forth in SEQ ID No.: 3, 5 and 6;

[0058] (ii) a second polypeptide comprising a humanised heavy chain variable (VH) domain, a human heavy chain constant CH1 domain and the first Fc polypeptide, wherein the first Fc polypeptide comprises a hinge region, a human constant CH2 domain and a human CH3 constant domain, wherein the humanised VH domain contains three complementary determining regions (CDRs) having amino acid sequences as set forth in SEQ ID No.: 8, 10 and 12, and

[0059] (iii) a third polypeptide comprising the second human Fc polypeptide, wherein the second human Fc polypeptide comprises a human hinge region, a human constant CH2 domain and a human CH3 constant domain,

[0060] wherein the Fc region of the first FC polypeptide and the second Fc polypeptide comprise the mutations L234A, L235A and P329A (according to EU index);

[0061] • the use comprising administering an effective amount of the anti-Met antibody fragment to the subject,

[0062] wherein the effective amount is 350 mg, 700 mg, 1200 mg, 1400 mg, 1700 mg, 2100 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 4500 mg or 5000 mg of the anti-Met antibody fragment.

[0063] More specifically, the present invention concerns an anti-MET antibody fragment for use in treating a cancerous tumour and / or metastasis, with MET mutations and / or amplifications, in a subject,

[0064] • the anti-Met antibody fragment comprising a single antigen binding arm and a silenced Fc region, wherein the Fc region comprises a complex of a first and a second Fc polypeptide, wherein the antibody fragment comprises:

[0065] (i) a first polypeptide comprising the amino acid sequence of SEQ ID No. 19; (ii) a second polypeptide comprising the first human Fc polypeptide, wherein the second polypeptide comprises the amino acid sequence of SEQ ID No. 20, and (iii) a third polypeptide comprising the second human Fc polypeptide, wherein the third polypeptide comprises the amino acid sequence of SEQ ID No. 18;

[0066] • the use comprising administering an effective amount of the anti-Met antibody fragment to the subject, wherein the effective amount is 350 mg, 700 mg, 1200 mg, 1400 mg, 1700 mg, 2100 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 4500 mg or 5000 mg of the anti-Met antibody fragment.

[0067] In the following description, numerous specific details are given to provide a thorough understanding of the embodiments. The embodiments can be practiced without one or more of the specific details, or with other methods, components, materials, etc. In other instances, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the embodiments. Dosing regimen

[0068] The present disclosure provides, inter alia, efficacious dosing regimens for the treatment of cancerous tumours and / or metastasis with MET mutations and / or amplifications (‘addicted to MET’), notably a METex14 mutation, a MET kinase domain activating mutation (e.g., H1094L / R / Y, D1228H / N / V, Y1230A / C / D / H), a MET amplification or combination thereof. The dosing regimens provided in the present disclosure are particular useful for treating NSCLC patients.

[0069] The present disclosure thus relates to an anti -MET antibody fragment (such as e.g., VERT-002) for use in treating a cancerous tumour and / or metastasis, preferably NSCLC, addicted to MET, notably a cancerous tumour and / or metastasis, preferably NSCLC, with a METex14 mutation, a MET kinase domain activating mutation (e.g., H1094L / R / Y, D1228H / N / V, Y1230A / C / D / H), a MET amplification or any combination thereof in a subject, the use comprising administering an effective amount of the anti-MET antibody fragment to the subject.

[0070] In another aspect, the present disclosure relates to a method of treatment of a cancerous tumour and / or metastasis, preferably NSCLC, addicted to MET, notably a cancerous tumour and / or metastasis, preferably NSCLC, with a METex14 mutation, a MET kinase domain activating mutation (e.g., H1094L / R / Y, D1228H / N / V, Y1230A / C / D / H), a MET amplification or a combination thereof, the method comprising administering an effective amount of an anti-MET antibody fragment (such as e.g., VERT-002) to the subject in need thereof.

[0071] In yet another aspect, the present disclosure relates to the use of an anti-MET antibody fragment (such as e.g., VERT-002) for making a medicament for the treatment of a cancerous tumour and / or metastasis, preferably NSCLC, addicted to MET, notably a tumour, preferably NSCLC, with a METex14 mutation, a MET kinase domain activating mutation (e.g., H1094L / R / Y, D1228H / N / V, Y1230A / C / D / H), a MET amplification or a combination thereof the treatment comprising administering an effective amount of the anti-MET antibody fragment to a subject in need thereof.

[0072] An effective amount can be administered in one or more administrations, applications or dosages. Such delivery is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the bioavailability of the agent, the route of administration, etc. In some embodiments, effective amount also refers to the amount of an anti-MET antibody fragment provided herein to achieve a specified result (e.g., killing of MET-expressing cancer cells). In some embodiments, this term refers to the amount of a therapy (e.g., an anti-MET antibody fragment provided herein, such as e.g., VERT-002) which is sufficient to reduce and / or ameliorate the severity and / or duration of a given disease, disorder or condition and / or a symptom related thereto. This term also encompasses an amount necessary for the reduction or amelioration of the advancement or progression of a given disease, disorder or condition, reduction or amelioration of the recurrence, development or onset of a given disease, disorder or condition, and / or to improve or enhance the prophylactic or therapeutic effect(s) of another therapy (e.g., a therapy other than said anti-Met antibody fragment). In the context of cancer therapy, a therapeutic benefit means for example any amelioration of cancer, including any one of, or combination of, halting or slowing the progression of cancer (e.g., from one stage of cancer to the next), halting or delaying aggravation or deterioration of the symptoms or signs of cancer, reducing the severity of cancer, inducing remission of cancer, inhibiting tumour cell proliferation, tumour size, or tumour number, or reducing levels of biomarker(s) indicative of the cancer.

[0073] In an embodiment, the effective amount is at least 350 mg, at least 700 mg, at least 1200 mg, at least 1400 mg, at least 1700 mg, at least 2100 mg, at least 2500 mg, at least 3000 mg, at least 3500 mg, at least 4000 mg, at least 4500 mg and up to 5000 mg of the anti-MET antibody fragment disclosed herein, such as e.g., VERT-002. In an embodiment, the effective amount is 350 mg, 700 mg, 1200 mg, 1400 mg, 1700 mg, 2100 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 4500 mg or 5000 mg of the anti -MET antibody fragment disclosed herein, such as e.g., VERT-002.

[0074] According to this embodiment, the present disclosure thus relates to an anti-MET antibody fragment (such as e.g., VERT-002) for use in treating a cancerous tumour and / or metastasis, preferably NSCLC, addicted to MET, notably a cancerous tumour and / or metastasis, preferably NSCLC, with a METex14 mutation, a MET kinase domain activating mutation (e.g., H1094L / R / Y, D1228H / N / V, Y1230A / C / D / H), and / or a MET amplification, in a subject, the use comprising administering an effective amount of the anti-MET antibody fragment to the subject, wherein the effective amount is 350 mg, 700 mg, 1200 mg, 1400 mg, 1700 mg, 2100 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 4500 mg or 5000 mg of the anti-MET antibody fragment.

[0075] In another embodiment, the effective amount is comprised between 350 mg and 5000 mg, between 700 mg and 5000 mg, between 1200 mg and 4500 mg, between 1700 mg and 4000 mg, between 2100 mg and 3500 mg, or between 2500 mg and 3000 mg of the anti -MET antibody fragment disclosed herein, such as e.g., VERT-002. In a particular embodiment, the effective amount is comprised between 1700 mg and 5000 mg, more particularly between 2500 mg and 3000 mg of the anti-MET antibody fragment disclosed herein, such as e.g., VERT-002.

[0076] According to this embodiment, the present disclosure thus relates to an anti-MET antibody fragment (such as e.g., VERT-002) for use in treating a cancerous tumour and / or metastasis, preferably NSCLC, addicted to MET, notably a cancerous tumour and / or metastasis, preferably NSCLC, with a METex14 mutation, a MET kinase domain activating mutation (e.g., H1094L / R / Y, D1228H / N / V, Y1230A / C / D / H), and / or a MET amplification, in a subject, the use comprising administering an effective amount of the anti-MET antibody fragment to the subject, wherein the effective amount is comprised between 350 mg and 5000 mg, between 700 mg and 5000 mg, between 1200 mg and 4500 mg, between 1700 mg and 4000 mg, between 2100 mg and 3500 mg, or between 2500 mg and 3000 mg of the anti-MET antibody fragment. In a particular embodiment, the present disclosure relates to an anti-MET antibody fragment (such as e.g., VERT-002) for use in treating a cancerous tumour and / or metastasis, preferably NSCLC, addicted to MET, notably a cancerous tumour and / or metastasis, preferably NSCLC, with a METex14 mutation, a MET kinase domain activating mutation (e.g., H1094L / R / Y, D1228H / N / V, Y1230A / C / D / H), and / or a MET amplification, in a subject, the use comprising administering an effective amount of the anti-MET antibody fragment to the subject, wherein the effective amount is comprised between 1700 mg and 5000 mg, more particularly between 2500 mg and 3000 mg of the anti-MET antibody fragment.

[0077] In another embodiment, the effective amount is at least 350 mg, at least 400 mg, at least 450 mg, at least 500 mg, at least 550 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, at least 850 mg, at least 900 mg, at least 950 mg, at least 1000 mg, at least 1050 mg, at least 1100 mg, at least 1150 mg, at least 1200 mg, at least 1250 mg, at least 1300 mg, at least 1350 mg, at least 1400 mg, at least 1450 mg, at least 1500 mg, at least 1550 mg, at least 1600 mg, at least 1650 g, at least 1700 mg, at least 1750 mg, at least 1800 mg, at least 1850 mg, at least 1900 mg, at least 1950 mg, at least 2000 mg, at least 2050 mg, at least 2100 mg, at least 2150 mg, at least 2200 mg, at least 2250 mg, at least 2300 mg, at least 2350 mg, at least 2400 mg, at least 2450 mg, at least 2500 mg, at least 2550 mg, at least 2600 mg, at least 2650 mg, at least 2700 mg, at least 2750 mg, at least 2800 mg, at least 2850 mg, at least 2900 mg, at least 2950 mg, at least 3000 mg, at least 3050 mg, at least 3100 mg, at least 3150 mg, at least 3200 mg, at least 3250 mg, at least 3300 mg, at least 3350 mg, at least 3400 mg, at least 3450 mg, at least 3500 mg, at least 3550 mg, at least 3600 mg, at least 3650 mg, at least 3700 mg, at least 3750 mg, at least 3800 mg, at least 3850 mg, at least 3900 mg, at least 3950 mg, at least 4000 mg, at least 4050 mg, at least 4100 mg, at least 4150 mg, at least 4200 mg, at least 4250 mg, at least 4300 mg, at least 4350 mg, at least 4400 mg, at least 4450 mg, at least 4500 mg, at least 4550 mg, at least 4600 mg, at least 4650 mg, at least 4700 mg, at least 4750 mg, at least 4800 mg, at least 4850 mg, at least 4900 mg, at least 4950 mg and up to 5000 mg of the anti-MET antibody fragment disclosed herein, such as e.g., VERT-002.

[0078] In another embodiment, the effective amount is 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, 3050 mg, 3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, 3600 mg, 3650 mg, 3700 mg, 3750 mg, 3800 mg, 3850 mg, 3900 mg, 3950 mg, 4000 mg, 4050 mg, 4100 mg, 4150 mg, 4200 mg, 4250 mg, 4300 mg, 4350 mg, 4400 mg, 4450 mg, 4500 mg, 4550 mg, 4600 mg, 4650 mg, 4700 mg, 4750 mg, 4800 mg, 4850 mg, 4900 mg, 4950 mg or 5000 mg of the anti-MET antibody fragment disclosed herein, such as e.g., VERT-002.

[0079] According to this embodiment, the present disclosure thus relates to an anti-MET antibody fragment (such as e.g., VERT-002) for use in treating a cancerous tumour and / or metastasis, preferably NSCLC, addicted to MET, notably a cancerous tumour and / or metastasis, preferably NSCLC, with a METex14 mutation, a MET kinase domain activating mutation (e.g., H1094L / R / Y, D1228H / N / V, Y1230A / C / D / H), a MET amplification or any combination thereof, in a subject, the use comprising administering an effective amount of the anti-MET antibody fragment to the subject, wherein the effective amount is 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, 3050 mg, 3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, 3600 mg, 3650 mg, 3700 mg, 3750 mg, 3800 mg, 3850 mg, 3900 mg, 3950 mg, 4000 mg, 4050 mg, 4100 mg, 4150 mg, 4200 mg, 4250 mg, 4300 mg, 4350 mg, 4400 mg, 4450 mg, 4500 mg, 4550 mg, 4600 mg, 4650 mg, 4700 mg, 4750 mg, 4800 mg, 4850 mg, 4900 mg, 4950 mg or 5000 mg of the anti -MET antibody fragment disclosed herein, such as e.g., VERT-002.

[0080] Although it can be advantageous in certain specific situations to administer the efficacious amount of the anti -MET antibody fragment only once to the patient, the administration of the effective amount is preferably repeated over time. More preferably, the effective amount of the anti -MET antibody fragment disclosed herein, such as e.g., VERT-002, is administered several times, in a sequential manner. For example, the effective amount may be administered at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, and up to 20 times to the patient.

[0081] In an embodiment, the time interval between two administrations of an effective amount of the anti-MET antibody fragment disclosed herein, such as e.g., VERT-002, is at least 1 week, at least 2 weeks, and up to 3 weeks. According to this specific embodiment, the effective amount of the anti-MET antibody fragment disclosed herein, e.g., VERT-002, is administered several times, in a sequential manner, wherein the administration occurs at least every 1 week, at least every 2 weeks, or up to every 3 weeks. In an embodiment, the time interval between two administrations of an effective amount of the anti-Met antibody fragment disclosed herein, e.g., VERT-002, is 1 week, 2 weeks, or 3 weeks. According to this specific embodiment, the effective amount of the anti-Met antibody fragment disclosed herein, e.g., VERT-002, is administered several times, in a sequential manner, wherein the administration occurs every week, every 2 weeks, or every 3 weeks.

[0082] In an embodiment, the effective amount of the anti-Met antibody fragment disclosed herein, e.g., VERT-002, is first administered at a certain frequency (e.g., every week, every 2 weeks, or every 3 weeks) for a first period of time, and at another frequency for a second period of time.

[0083] Preferably, the effective amount of the anti-MET antibody fragment disclosed herein, e.g., VERT-002, is administered every week for a first period of time. More preferably, the effective amount of the anti-Met antibody fragment disclosed herein, e.g., VERT-002, is administered every 2 weeks or every 3 weeks for a second period of time.

[0084] Preferably, the present disclosure thus relates to an anti -MET antibody fragment (such as e.g., VERT-002) for use in treating a cancerous tumour and / or metastasis, preferably NSCLC, addicted to MET, notably a cancerous tumour and / or metastasis, preferably NSCLC, with a METex14 mutation, a MET kinase domain activating mutation (e.g., H1094L / R / Y, D1228H / N / V, Y1230A / C / D / H), a MET amplification or any combination thereof, in a subject, the use comprising administering an effective amount of the anti-MET antibody fragment to the subject,

[0085] wherein the effective amount is 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, 3050 mg, 3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, 3600 mg, 3650 mg, 3700 mg, 3750 mg, 3800 mg, 3850 mg, 3900 mg, 3950 mg, 4000 mg, 4050 mg, 4100 mg, 4150 mg, 4200 mg, 4250 mg, 4300 mg, 4350 mg, 4400 mg, 4450 mg, 4500 mg, 4550 mg, 4600 mg, 4650 mg, 4700 mg, 4750 mg, 4800 mg, 4850 mg, 4900 mg, 4950 mg or 5000 mg of the said anti-MET antibody fragment, and

[0086] wherein the effective amount of the anti-MET antibody fragment is:

[0087] a) administered to the subject every week for a first period of time and;

[0088] b) administered to the subject every 2 weeks for a second period of time.

[0089] Alternatively, the present disclosure thus relates to an anti-MET antibody fragment (such as e.g., VERT-002) for use in treating a cancerous tumour and / or metastasis, preferably NSCLC, addicted to MET, notably a cancerous tumour and / or metastasis, preferably NSCLC, with a METex14 mutation, a MET kinase domain activating mutation (e.g., H1094L / R / Y, D1228H / N / V, Y1230A / C / D / H), and / or a MET amplification, in a subject, the use comprising administering an effective amount of the said anti-MET antibody fragment to the subject,

[0090] wherein the effective amount is 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, 3050 mg, 3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, 3600 mg, 3650 mg, 3700 mg, 3750 mg, 3800 mg, 3850 mg, 3900 mg, 3950 mg, 4000 mg, 4050 mg, 4100 mg, 4150 mg, 4200 mg, 4250 mg, 4300 mg, 4350 mg, 4400 mg, 4450 mg, 4500 mg, 4550 mg, 4600 mg, 4650 mg, 4700 mg, 4750 mg, 4800 mg, 4850 mg, 4900 mg, 4950 mg or 5000 mg of the anti -MET antibody fragment, and

[0091] wherein the effective amount of the anti-Met antibody fragment is:

[0092] a) administered to the subject every week for a first period of time and;

[0093] b) administered to the subject every 3 weeks for a second period of time.

[0094] In certain embodiments, the first period of time is 28 days. In certain embodiments, the second period of time is 21 days. In certain embodiments, step b) is repeated.

[0095] More preferably, the present disclosure thus relates to an anti -MET antibody fragment (such as e.g., VERT-002) for use in treating a cancerous tumour and / or metastasis, preferably NSCLC, addicted to MET, notably a cancerous tumour and / or metastasis, preferably NSCLC, with a METex14 mutation, a MET kinase domain activating mutation (e.g., H1094L / R / Y, D1228H / N / V, Y1230A / C / D / H), a MET amplification or any combination thereof, in a subject, the use comprising administering an effective amount of the anti-MET antibody fragment to the subject,

[0096] wherein the effective amount is 350 mg, 700 mg, 1200 mg, 1400 mg, 1700 mg, 2100 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 4500 mg or 5000 mg of the anti -MET antibody fragment, and

[0097] wherein the effective amount of the anti-MET antibody fragment is:

[0098] a) administered to the subject every week for a first period of time and;

[0099] b) administered to the subject every 2 weeks for a second period of time.

[0100] Alternatively, the present disclosure thus relates to an anti -MET antibody fragment (such as e.g., VERT-002) for use in treating a cancerous tumour and / or metastasis, preferably NSCLC, addicted to MET, notably a cancerous tumour and / or metastasis, preferably NSCLC, with a METex14 mutation, a MET kinase domain activating mutation (e.g., H1094L / R / Y, D1228H / N / V, Y1230A / C / D / H), and / or a MET amplification, in a subject, the use comprising administering an effective amount of the anti-MET antibody fragment to the subject,

[0101] wherein the effective amount is 350 mg, 700 mg, 1200 mg, 1400 mg, 1700 mg, 2100 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 4500 mg or 5000 mg of the anti -MET antibody fragment, and wherein the effective amount of the anti-MET antibody fragment is:

[0102] a) administered to the subject every week for a first period of time and;

[0103] b) administered to the subject every 3 weeks for a second period of time.

[0104] In certain embodiments, the first period of time is 28 days. In certain embodiments, the second period of time is 21 days. In certain embodiments, step b) is repeated.

[0105] Methods of treatment

[0106] The present anti-MET antibody fragment is particularly useful, when administered to the subject at an efficacious dose, for treating a cancerous tumour and / or metastasis, with MET mutations / amplifications (‘addicted to MET’), notably a METex14 mutation, a MET kinase domain activating mutation (e.g., H1094L / R / Y, D1228H / N / V, Y1230A / C / D / H), and / or a MET amplification.

[0107] In certain embodiments, the cancerous tumour is selected from the group consisting of lymphoma, leukaemia, myeloma, Acute myelogenous leukaemia (AML), T-ALL, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell cancer, melanoma, stomach cancer, brain cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, head and neck cancer, uterine cancer, adenocarcinoma, or adrenal cancer. Preferably, the cancerous tumour is a lung cancer tumour. More preferably, the lung cancer is a non-small cell lung cancer (NSCLC). The NSCLC can be an adenocarcinoma, squamous cell carcinoma, large cell carcinoma, adenosquamous carcinoma or a sarcomatoid carcinoma.

[0108] In an embodiment, the cancerous tumour addicted to MET which can be treated by administration of an effective amount of the anti-MET antibody fragment disclosed herein, such as, e.g., VERT-002, is a relapsed and / or refractory locally advanced or metastatic tumour. Such tumours are usually identified by histological analysis of a biopsy sample of the patient. Preferably, the NSCLC is metastatic Stage IIIB / C or IV.

[0109] In an embodiment, the cancerous tumour addicted to MET which can be treated by administration of an effective amount of the anti-MET antibody fragment disclosed herein, such as, e.g., VERT-002, is a tumour comprising a mutation such as METex14 mutation, a MET kinase domain activating mutation (e.g., H1094L / R / Y, D1228H / N / V, Y1230A / C / D / H), a MET amplification or any combination thereof. In an embodiment, the presence of a mutation such as a METex14 mutation, a MET kinase domain activating mutation (e.g., H1094L / R / Y, D1228H / N / V, Y1230A / C / D / H), and / or a MET amplification in the cancerous tumour / metastasis is assayed before the administration of the anti-Met antibody fragment disclosed herein, such as, e.g., VERT-002, to the patient. For example, a sample (e.g., a tissue sample, a lung cancer biopsy or a liquid biopsy such as a blood sample or plasma sample for detecting tumour derived DNA and / or circulating tumour cells or circulating exosomes) from the patient is tested for the presence of the mutations. Suitable methods for obtaining tissue samples include tissue biopsy, endobronchial biopsy, transbronchial biopsy, brushing cytology, washing cytology, fine needle aspiration cytology, fluid cytology, or bone biopsy. Testing for MET mutations and / or amplification can be done by any suitable analytic technique, including quantitative realtime polymerase chain reaction (PCR), allele-specific PCR, Flow Cytometry In Situ Hybridisation (FISH), or nucleic acid sequencing, notably next-generation sequencing (NGS). If one or more mutations and / or amplifications are detected, the patient is administered a therapeutic amount of the anti-MET antibody fragment disclosed herein, such as, e.g., VERT -002.

[0110] In another aspect, the patient has previously received one chemotherapy regimen. Preferably, the cancer has failed at least one prior chemotherapy regimen. Most preferably, the cancer has failed a maximum of two prior chemotherapy regimens.

[0111] In an embodiment, the prior chemotherapy is a MET TKI. MET TKIs notably comprise type I MET TKI and type II MET TKIs. Type I MET TKIs (e.g., capmatinib, tepotinib, savolitinib, and crizotinib) are ATP -competitive and interact with the MET activation loop to prevent the dysregulation of the MET / HGF pathway. Type II inhibitors (e.g., cabozantinib, merestinib, glesatinib) are also ATP-competitive, but they bind to the ATP adenine binding site. Preferably, the MET-TKI is a type I MET TKI. Still preferably, the MET-TKI is selected in the group consisting of capmatinib, tepotinib, savolitinib, crizotinib, and osimertinib. More preferably, the MET-TKI is capmatinib, tepotinib, crizotinib or osimertinib.

[0112] In an embodiment, the prior chemotherapy comprises a combination of MET TKI and another therapy. For example, the other therapy can be a “parent” TKI targeting an individual oncogene, such as the EGFR, ALK, ROS1, RET, NTRK, BRAF V600E, or HER2 oncogenes, particularly EGFR.

[0113] In some embodiments, the anti-MET antibody fragment disclosed herein (such as e.g., VERT-002) can be administered in combination with one or more anti -cancerous therapies. Non-limiting examples of anti -cancerous therapies that can be administered in combination with the anti-MET antibody fragment include a chemotherapeutic agent, radiation, or immunomodulatory agents.

[0114] Said combination can be administered simultaneously, separately or sequentially.

[0115] “Simultaneous administration” as used herein refers to the administration of the two therapies in a single and identical pharmaceutical form.

[0116] “Separate administration” as used herein refers to the administration, at the same time, of the two therapies in distinct pharmaceutical forms.

[0117] “Sequential administration” as used herein refers to the successive administration of the two therapies, each in a distinct pharmaceutical form.

[0118] In particular embodiments, the anti-MET antibody fragment disclosed herein (such as e.g., VERT-002) can be administered in combination with a cytotoxic agent, in particular with a kinase inhibitor, more particularly a tyrosine kinase inhibitor (TKI).

[0119] As described herein, a “cytotoxic agent” refers to an agent which, when administered to a subject, treats or prevents the development of cell proliferation, preferably the development of cancer in the subject's body, by inhibiting or preventing a cellular function and / or causing cell death. The cytotoxic agent that can be used herein includes any agent, part thereof, or residue having cytotoxic effect or inhibitory effect on cell proliferation. The term is intended to include alkylating agents, anthracyclines, cytoskeletal disruptors (taxanes), epothilones, histone deacetylase Inhibitors (HDAC), inhibitors of Topoisomerase I, Inhibitors of Topoisomerase II, kinase inhibitors, nucleotide analogs, peptide antibiotics, platinum-based agents, retinoids, Vinca alkaloids or derivatives thereof, radioisotopes, tubulin stabilizers, tubulin destabilizers, DNA alkylators, DNA minor groove binders, DNA intercalators, gyrase inhibitors, protein synthesis inhibitors, proteosome inhibitors, and antimetabolites.

[0120] Non-limiting examples of cytotoxic agents include actinomycin, in particular actinomycin D, all-trans retinoic acid, amonafide, auristatin, azacitidine, azathioprine, benzophenone, benzothiazole, bleomycin, bortezomib, calicheamicin, camptothecin, carboplatin, capecitabine, CC-1065 (NSC 298223), cemadotin, cisplatin, chlorambucil, colchicine, combretastatin A4, cyclophosphamide, cytarabine, daunorubicin, docetaxel, dolastatin, doxifluridine, doxorubicin, elinafide, emtansine (DM1), epirubicin, epothilone, etoposide, fluorouracil, gemcitabine, hydroxyurea, idarubicin, imatinib, irinotecan, leinamycin, maytansinoids, mechlorethamine, mercaptopurine, methotrexate, mitoxantrone, nocodazole, oxaliplatin, paclitaxel, pemetrexed, proteosome inhibitor 1 (PSI 1), roridin A, T-2 toxin (trichothecene analog), taxol, teniposide, tioguanine, topotecan, tubulysins, valrubicin, velcade®, vinblastine, vincristine, vindesine, and vinorelbine.

[0121] As described herein, a “tyrosine kinase inhibitor” or “TKI” refers to any of a variety of therapeutic agents or drugs that act as selective or non-selective inhibitors of receptor and / or non-receptor tyrosine kinases.

[0122] Examples of tyrosine kinase inhibitors include, but are not limited to, abivertinib, acalabrutinib, afatinib, alectinib, asciminib, avapritinib, axitinib, bosutinib, brigatinib, brivanib (BMS-540215), brivanib alaninate (BMS-582664), cabozantinib, canertinib (CI-1033), capmatinib, cediranib, ceritinib, crenolanib, crizotinib, dacomitinib, dactolisib (BEZ-235), dasatinib, deucravacitinib, dovitinib, entrectinib, erdafitinib, erlotinib, fedratinib, flumatinib, foretinib, fostamatinib, gefitinib, geldamycin, genistein, gilteritinib, glesatinib, ibrutinib, icotinib, imatinib, infigratinib, lapatinib, Larotrectinib, lavendustin A, lavendustin B, Lenvatinib, lestaurtinib (CEP-701), linifanib (ABT-869), loriatinib, methyl 2,5-dihydroxycinnamate, midostaurin, mirdametinib (PD-0325901), mobocertinib, motesanib (AMG 706), mubritinib (TAK-165), neratinib, nilotinib, nintedanib, orantinib (SU6668), osimertinib, pacritinib, palbociclib (PD-0332991), pazopanib, pexidartinib, piceatannol, pirtobrutinib, ponatinib, quizartinib, radicicol, radotinib, regorafenib, repotrectinib, ruxolitinib, saracatinib (AZD-0530), savolitinib, seliciclib (CYC202), selpercatinib, selumetinib, semaxinib (SU5416), sorafenib, sunitinib, sunvozertinib, taletrectinib, tandutinib (MLN-518), telatinib, tepotinib, tesevatinib, tirbanibulin, tivozanib (AV-951), tucatinib, tyrphostin AG 879, tyrphostin B48, tyrphostin B56, vandetanib, vatalanib (PTK787), vemurafenib, Zanubrutinib, PP2, MK-2206 (8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3(2H)-one), PD173955 (Cas No.: 260415-63-2) BMS-599626 (CAS No. 714971-09-2), KRN-633 (CAS No.: 286370-15-8), CEP-11981 (CAS No.: 856691-93-5), AZM-475271 (CAS No.: 476159-98-5), CP-724714 (CAS No.: 383432-38-0), CP-547632 (CAS No.: 252003-65-9), AEE788 (CAS No.: 497839-62-0), OSI-930 (CAS No.: 728033-96-3), SNS-032 (CAS No.: 345627-80-7), MKC-I, SU-14813 (CAS No.: 627908-92-3), MLN-8054 (CAS No.: 869363-13-3), and AEW-541 (CAS No.: 475489-16-8).

[0123] In a particular embodiment, the disclosure relates to a method for treating non-small cell lung cancer (NSCLC) in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition comprising an anti-MET antibody fragment (such as e.g., VERT-002), wherein the antibody specifically binds to the MET receptor, wherein: a) the antibody is administered at a starting dose of 350 mg, 700 mg, 1200 mg, 1400 mg, 1700 mg, 2100 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 4500 mg or 5000 mg;

[0124] b) the starting dose is administered on Day 1 (D1), Day 8 (D8), and Day 15 (D15) of a first 28-day treatment cycle;

[0125] c) subsequent doses are administered every two weeks on D1 and D15 of each subsequent 28-day treatment cycle;

[0126] d) the patient has been diagnosed with NSCLC harboring a MET exon 14 (METex14) skipping mutation or MET amplification.

[0127] In an alternative embodiment, the disclosure relates to a method for treating non-small cell lung cancer (NSCLC) in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition comprising an anti-MET antibody fragment (such as e.g., VERT-002) wherein the antibody specifically binds to the MET receptor, wherein:

[0128] a) the antibody is administered at a dose of 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, 3050 mg, 3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, 3600 mg, 3650 mg, 3700 mg, 3750 mg, 3800 mg, 3850 mg, 3900 mg, 3950 mg, 4000 mg, 4050 mg, 4100 mg, 4150 mg, 4200 mg, 4250 mg, 4300 mg, 4350 mg, 4400 mg, 4450 mg, 4500 mg, 4550 mg, 4600 mg, 4650 mg, 4700 mg, 4750 mg, 4800 mg, 4850 mg, 4900 mg, 4950 mg or 5000 mg;

[0129] b) the starting dose is administered on Day 1 (D1), Day 8 (D8), and Day 15 (D15) of a first 28-day treatment cycle;

[0130] c) subsequent doses are administered every two weeks on D1 and D15 of each subsequent 28-day treatment cycle;

[0131] d) the patient has been diagnosed with NSCLC harboring a MET exon 14 (METex14) skipping mutation or MET amplification. In a particular embodiment of the method for treating a NSCLC, the administration of the pharmaceutical composition is intravenous, in particular intravenous infusion.

[0132] Anti-MET antibody fragments

[0133] The present disclosure relates to an anti-MET antibody fragment comprising a single antigen binding arm and a silenced Fc region, wherein the Fc region comprises a complex of a first and a second Fc polypeptide, wherein the antibody fragment comprises:

[0134] (i) a first polypeptide comprising the amino acid sequence of SEQ ID No. 19; (ii) a second polypeptide comprising the first human Fc polypeptide, wherein the second polypeptide comprises the amino acid sequence of SEQ ID No. 20, and (iii) a third polypeptide comprising the second human Fc polypeptide, wherein the third polypeptide comprises the amino acid sequence of SEQ ID No. 18.

[0135] More generally, the present disclosure relates to an anti-MET antibody fragment comprising a single antigen binding arm and a silenced Fc region, wherein the Fc region comprises a complex of a first and a second Fc polypeptide, wherein the antibody fragment comprises:

[0136] (i) a first polypeptide comprising a humanised light chain variable (VL) domain, and one human light chain constant (CL) domain, wherein the humanised VL domain contains three complementary determining regions (CDRs) having amino acid sequences as set forth in SEQ ID No.: 3, 5 and 6;

[0137] (ii) a second polypeptide comprising a humanised heavy chain variable (VH) domain, a human heavy chain constant CH1 domain and the first Fc polypeptide, wherein the first Fc polypeptide comprises a hinge region, a human constant CH2 domain and a human CH3 constant domain, wherein the humanised VH domain contains three complementary determining regions (CDRs) having amino acid sequences as set forth in SEQ ID No.: 8, 10 and 12, and

[0138] (iii) a third polypeptide comprising the second human Fc polypeptide, wherein the second human Fc polypeptide comprises a human hinge region, a human constant CH2 domain and a human CH3 constant domain,

[0139] wherein the Fc region of the first FC polypeptide and the second Fc polypeptide comprise the mutations L234A, L235A and P329A (according to EU index).

[0140] In certain embodiments, the humanised VL domain is fused to the human CL domain in the N- to C-terminal direction. In certain embodiments, the humanised VH domain is fused to the human CH1 domain, that is fused to the human hinge region, that is fused to the human CH2 domain, that is fused to the human CH3 domain in the N- to C-terminal direction. In certain embodiments, the human hinge region is fused to the CH2 domain that is fused to the human CH3 domain in the N- to C-terminal direction, wherein the human hinge region is truncated at the N -terminus.

[0141] In certain embodiments, the humanised VL domain is fused to the human CL domain in the N- to C-terminal direction,

[0142] the humanised VH domain is fused to the human CH1 domain, that is fused to the human hinge region, that is fused to the human CH2 domain, that is fused to the human CH3 domain in the N- to C-terminal direction, and

[0143] the human hinge region is fused to the CH2 domain that is fused to the human CH3 domain in the N- to C-terminal direction, wherein the human hinge region is truncated at the N -terminus.

[0144] In certain embodiments, the humanised VL domain has an amino acid sequence as set forth in SEQ ID No.: 13. In certain embodiments, the humanised VH domain has an amino acid sequence as set forth in SEQ ID No.: 14. In certain embodiments, the humanised VL domain has an amino acid sequence as set forth in SEQ ID No.: 13 and the humanised VH domain has an amino acid sequence as set forth in SEQ ID No.: 14.

[0145] In certain embodiments, the human CL domain is a human light kappa type domain. In certain embodiments, the human hinge region and the human constant domains CH1, CH2 and CH3 are from a human IgG 1. In certain embodiments, the human CL domain is a human light kappa type domain, and the human hinge region and the human constant domains CH1, CH2 and CH3 are from a human IgG 1.

[0146] In certain embodiments, the two Fc polypeptides are linked through intermolecular disulfide bonds at the hinge region.

[0147] In certain embodiments, the first Fc polypeptide and the second Fc polypeptide meet at an interface, and one between the first and the second Fc polypeptide comprises a knob at the interface, and the other between the first and the second Fc polypeptide comprises a hole at the interface, wherein the knob is positionable into the hole.

[0148] In certain embodiments, either the first or the second Fc polypeptide comprises a mutated CH3 constant domain, wherein the mutated CH3 constant domain carries an amino acid mutation at position 389, wherein the original amino acid at position 389 has been mutated to import an amino acid having a larger side chain volume than the original amino acid; and wherein the other Fc polypeptide comprises a mutated CH3 constant domain, wherein the mutated CH3 constant domain carries three amino acid mutations at positions 389, 391 and 438, wherein the original amino acids have been mutated to import amino acids having smaller side chains volume than the original amino acids, wherein the amino acid numbering is according to the EU numbering scheme of Kabat.

[0149] In certain embodiments, the original amino acids at positions 389, 391 and 438 are threonine, leucine and tyrosine respectively; and wherein in the first or the second Fc polypeptide the threonine in position 389 has been mutated to tryptophan; and wherein in the other Fc polypeptide the threonine at position 389 has been mutated to serine, the leucine at position 391 has been mutated to alanine and the tyrosine at position 438 has been mutated to valine.

[0150] In certain embodiments, the human CL domain has an amino acid sequence as set forth in SEQ ID No.: 15 and the human CH1 domain has an amino acid sequence as set forth in SEQ ID No.: 16.

[0151] In certain embodiments, the first human Fc polypeptide has an amino acid sequence as set forth in SEQ ID No.: 17, and the second human Fc polypeptide has an amino acid sequence as set forth in SEQ ID No.: 18.

[0152] In certain embodiments, the first polypeptide comprises the amino acid sequence of SEQ ID No. 19, the second polypeptide comprises the amino acid sequence of SEQ ID No. 20, and the third polypeptide comprises the amino acid sequence of SEQ ID No. 18.

[0153] In a preferred embodiment, the anti-MET antibody fragment is VERT-002. VERT-002 is an anti-MET antibody fragment with an Fc effector-independent mode of action, which is described in PCT Application No. EP2024 / 065156. VERT-002 has the following mutations in the CH2 domain: L234A, L235A and P329A.

[0154] The anti-MET antibody fragment, ie VERT-002, herein described differs from known anti-MET antibody fragment in the silenced effective functions of Fc, thanks to three specific and purposive mutations / substitutions (L234A, L235A, and P329A) in the Fc. Known technologies in relation to silencing discloses many combinations of various mutations in order to reduce Fc-induced effector functions. Among many mutations, the “LALAPG” is the most common of Fc designs and includes three point mutations: L234A, L235A, and P329G. The combination of the 3 mutations “LALAPA” as disclosed herein is never suggested by any prior art. Prior art is rich in many examples of therapeutic IgG 1 antibodies which include combinations of mutations in the Fc region for reducing effective functions, however of P329A is never suggested when it is about stacking with L234A / L235A.

[0155] Amino acid sequences of the binders are shown in the following Table.

[0156] Table 1:

[0157]

[0158]

[0159]

[0160]

[0161] Pharmaceutical compositions

[0162] Various delivery systems can be used to administer the anti-MET antibody fragment disclosed herein.

[0163] The present anti-MET antibody fragment may be administered to the subject as part of a pharmaceutical composition. The compositions described herein are useful for treating cancerous tumours and / or metastasis with MET mutations / amplifications addicted to MET. Such pharmaceutical compositions may comprise, in addition to the anti-MET antibody fragment disclosed herein, at least an excipient and / or a pharmaceutical acceptable vehicle.

[0164] The compositions will usually be supplied as part of a sterile, pharmaceutical composition that will normally include a pharmaceutically acceptable carrier and / or excipient. In another aspect, the invention thus provides a pharmaceutical composition comprising the anti-Met antibody fragment disclosed herein, and a pharmaceutical acceptable carrier and / or an excipient. The type of carrier can be selected based upon the intended route of administration. The amount of each carriers used may vary within ranges conventional in the art. As a pharmaceutically acceptable carrier in the composition which is prepared as a liquid solution, physiological saline, sterilised water, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, and a mixture of one or more of them can be used as a sterilised carrier suitable for a living organism. If necessary, common additives like antioxidant, buffer solution, and bacteriostat may be added. Furthermore, by additionally adding a diluent, a dispersant, a surfactant, a binder, or a lubricant, the composition can be prepared as a formulation for injection like aqueous solution, suspension, and emulsion, a pill, a capsule, a granule, or a tablet.

[0165] This composition can be in any suitable form (depending upon the desired method of administering it to a patient). The compositions utilised in the methods described herein can be administered, for example, intravitreally (e.g., by intravitreal injection), by eye drop, intramuscularly, intravenously, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intra tracheally, intra thecally, intranasally, intravaginally, intrarectally, topically, intratumourally, peritoneally, subcutaneously, subconjunctivally, intra vesicularly, mucosally, intrapericardially, intraumbilically, intraocularly, intraorbitally, orally, topically, transdermally, by inhalation, by injection, by implantation, by infusion, by continuous infusion, by localised perfusion bathing target cells directly, by catheter, by lavage, in cremes, or in lipid compositions. The compositions utilised in the methods described herein can also be administered systemically or locally. The method of administration can vary depending on various factors (e.g., the compound or composition being administered and the severity of the condition, disease, or disorder being treated). The most suitable route for administration in any given case will depend on the particular antibody, the subject, and the nature and severity of the disease and the physical condition of the subject. Various delivery systems can thus be used to administer anti-MET antibody fragments. In certain preferred embodiments of the present invention, the present anti-MET antibody fragment is formulated as an aqueous solution and administered by intravenous infusion. In some embodiments, administration is by a one-hour intravenous infusion.

[0166] Pharmaceutical compositions can be conveniently presented in unit dose forms containing a predetermined amount of the anti-MET antibody fragment per dose. Such a unit can contain for example but without limitation 5 mg to 5 g, for example 10 mg to 1 g, or 20 to 50 mg. Preferably, a unit dose contains 350 mg, 700 mg, 1200 mg, 1400 mg, 1700 mg, 2100 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 4500 mg or 5000 mg of the anti-Met antibody fragment disclosed herein. Alternatively, a unit dose contains 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, 3050 mg, 3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, 3600 mg, 3650 mg, 3700 mg, 3750 mg, 3800 mg, 3850 mg, 3900 mg, 3950 mg, 4000 mg, 4050 mg, 4100 mg, 4150 mg, 4200 mg, 4250 mg, 4300 mg, 4350 mg, 4400 mg, 4450 mg, 4500 mg, 4550 mg, 4600 mg, 4650 mg, 4700 mg, 4750 mg, 4800 mg, 4850 mg, 4900 mg, 4950 mg or 5000 mg of the anti -MET antibody fragment disclosed herein. Advantageously, a unit dose will be presented in a form convenient for administration to the patient. For example, a particularly desirable feature for an injectable depot formulation relates to the ease with which it can be administered. Accordingly, a unit dose of 350 mg, 700 mg, 1200 mg, 1400 mg, 1700 mg, 2100 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 4500 mg or 5000 mg of the anti-MET antibody fragment disclosed herein will be presented in a syringe. Alternatively, a unit dose of 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, 3050 mg, 3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, 3600 mg, 3650 mg, 3700 mg, 3750 mg, 3800 mg, 3850 mg, 3900 mg, 3950 mg, 4000 mg, 4050 mg, 4100 mg, 4150 mg, 4200 mg, 4250 mg, 4300 mg, 4350 mg, 4400 mg, 4450 mg, 4500 mg, 4550 mg, 4600 mg, 4650 mg, 4700 mg, 4750 mg, 4800 mg, 4850 mg, 4900 mg, 4950 mg or 5000 mg of the anti-MET antibody fragment disclosed herein will be presented in a syringe.

[0167] Pharmaceutically acceptable carriers for use in the disclosure can take a wide variety of forms depending, e.g., on the condition to be treated or route of administration.

[0168] Pharmaceutical compositions of the disclosure can be prepared for storage as lyophilised formulations or aqueous solutions by mixing the antibody having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilisers typically employed in the art (all of which are referred to herein as “carriers”), i.e., buffering agents, stabilising agents, preservatives, isotonifiers, non-ionic detergents, antioxidants, and other miscellaneous additives. See, Remington’s Pharmaceutical Sciences, 16th edition (Osol, ed.

[0169] 1980). Such additives must be nontoxic to the recipients at the dosages and concentrations employed.

[0170] Buffering agents help to maintain the pH in the range which approximates physiological conditions. They can be present at concentration ranging from about 2 mM to about 50 mM. Suitable buffering agents for use with the present disclosure include both organic and inorganic acids and salts thereof such as citrate buffers (e.g., monosodium citrate-disodium citrate mixture, citric acid-trisodium citrate mixture, citric acid-monosodium citrate mixture, etc.), succinate buffers (e.g., succinic acid-monosodium succinate mixture, succinic acid-sodium hydroxide mixture, succinic acid-disodium succinate mixture, etc.), tartrate buffers (e.g., tartaric acid-sodium tartrate mixture, tartaric acid-potassium tartrate mixture, tartaric acid-sodium hydroxide mixture, etc.), fumarate buffers (e.g., fumaric acid-monosodium fumarate mixture, fumaric acid-disodium fumarate mixture, monosodium fumarate-disodium fumarate mixture, etc.), gluconate buffers (e.g., gluconic acid-sodium gluconate mixture, gluconic acid-sodium hydroxide mixture, gluconic acid-potassium gluconate mixture, etc.), oxalate buffer (e.g., oxalic acid-sodium oxalate mixture, oxalic acid-sodium hydroxide mixture, oxalic acid-potassium oxalate mixture, etc.), lactate buffers (e.g., lactic acid-sodium lactate mixture, lactic acid-sodium hydroxide mixture, lactic acid-potassium lactate mixture, etc.) and acetate buffers (e.g., acetic acid-sodium acetate mixture, acetic acid-sodium hydroxide mixture, etc.). Additionally, phosphate buffers, histidine buffers and trimethylamine salts such as Tris can be used.

[0171] Preservatives can be added to retard microbial growth and can be added in amounts ranging from 0.2%-1% (w / v). Suitable preservatives for use with the present disclosure include phenol, benzyl alcohol, meta-cresol, methyl paraben, propyl paraben, octadecyldimethylbenzyl ammonium chloride, benzalconium halides (e.g., chloride, bromide, and iodide), hexamethonium chloride, and alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, and 3-pentanol. Isotonicifiers sometimes known as “stabilisers” can be added to ensure isotonicity of liquid compositions of the present disclosure and include polyhydric sugar alcohols, for example trihydric or higher sugar alcohols, such as glycerine, erythritol, arabitol, xylitol, sorbitol and mannitol. Stabilisers refer to a broad category of excipients which can range in function from a bulking agent to an additive which solubilises the therapeutic agent (i.e., the anti -Met antibody fragment disclosed herein) or helps to prevent denaturation or adherence to the container wall. Typical stabilisers can be polyhydric sugar alcohols (enumerated above); amino acids such as arginine, lysine, glycine, glutamine, asparagine, histidine, alanine, ornithine, L-leucine, 2-phenylalanine, glutamic acid, threonine, etc., organic sugars or sugar alcohols, such as lactose, trehalose, stachyose, mannitol, sorbitol, xylitol, ribitol, myoinisitol, galactitol, glycerol and the like, including cyclitols such as inositol; polyethylene glycol; amino acid polymers; sulfur containing reducing agents, such as urea, glutathione, thioctic acid, sodium thioglycolate, thioglycerol, o-monothioglycerol and sodium thiosulfate; low molecular weight polypeptides (e.g., peptides of 10 residues or fewer); proteins such as human serum albumin, bovine serum albumin, gelatine or immunoglobulins; hydrophylic polymers, such as polyvinylpyrrolidone monosaccharides, such as xylose, mannose, fructose, glucose; disaccharides such as lactose, maltose, sucrose and trisaccacharides such as raffinose; and polysaccharides such as dextran. Stabilisers can be present in the range from 0.1 to 10,000 weights per part of weight active protein (e.g., the anti-Met antibody fragment disclosed herein).

[0172] Non-ionic surfactants or detergents (also known as “wetting agents”) can be added to help solubilise the anti-Met antibody fragment disclosed herein as well as to protect the therapeutic protein against agitation-induced aggregation, which also permits the formulation to be exposed to shear surface stressed without causing denaturation of the protein. Suitable non-ionic surfactants include polysorbates (20, 80, etc.), polyoxamers (184, 188, etc.), pluronic polyols, polyoxyethylene sorbitan monoethers (TWEEN®-20, TWEEN®-80, etc.). Non-ionic surfactants can be present in a range of about 0.05 mg / ml to about 1.0 mg / ml, for example about 0.07 mg / ml to about 0.2 mg / ml.

[0173] Additional miscellaneous excipients include bulking agents (e.g., starch), chelating agents (e.g., EDTA), antioxidants (e.g., ascorbic acid, methionine, vitamin E), and cosolvents.

[0174] The present disclosure also provides kits for the treatment of a cancerous tumour and / or metastasis with MET mutations / amplifications addicted to MET. The kit can comprise at least a container containing the anti-MET antibody fragment. Preferably, the container contains a therapeutically effective dose of the anti-MET antibody fragment. More preferably, the container contains 350 mg, 700 mg, 1200 mg, 1400 mg, 1700 mg, 2100 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 4500 mg or 5000 mg of anti -MET antibody fragment. Alternatively, the container contains 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, 3050 mg, 3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, 3600 mg, 3650 mg, 3700 mg, 3750 mg, 3800 mg, 3850 mg, 3900 mg, 3950 mg, 4000 mg, 4050 mg, 4100 mg, 4150 mg, 4200 mg, 4250 mg, 4300 mg, 4350 mg, 4400 mg, 4450 mg, 4500 mg, 4550 mg, 4600 mg, 4650 mg, 4700 mg, 4750 mg, 4800 mg, 4850 mg, 4900 mg, 4950 mg or 5000 mg of anti -MET antibody fragment.

[0175] Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Printed instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit.

[0176] The rationale for targeting the specific MET alterations as described herein with VERT-002 is based on the following:

[0177] MET as an oncogenic driver: MET alterations, such as METex14 skipping mutations and MET amplifications, are oncogenic drivers in NSCLC and other cancers. They lead to uncontrolled cell growth and survival, contributing to cancer progression and metastasis.

[0178] Unmet medical need: Patients with NSCLC harbouring these MET alterations have limited treatment options, especially those with MET amplification. There is a need for new therapies that can effectively target these alterations and VERT-002 can address such a need.

[0179] Resistance to current therapies: There is evidence that patients treated with existing MET TKIs may develop resistance, and VERT-002's unique mechanism of action provides an alternative therapeutic option for these patients.

[0180] VERT-002 has potent anti-proliferative activity against ET-addicted cell lines and can induce tumour regression in xenograft models, supporting its potential clinical utility in MET-altered cancers.

[0181] The mechanism of action of VERT-002, which involves MET receptor degradation, offers a therapeutic advantage by improving safety and efficacy over existing MET-targeting therapies. The underlying technical problem addressed by the various embodiments of the present invention in relation with the dose regimen of VERT-002 is the need for an effective and safe treatment for patients with non-small cell lung cancer (NSCLC) harboring specific MET alterations, such as METex14 skipping mutations and / or MET amplification. These MET alterations are associated with oncogenic activity that drives tumour growth and progression, and patients with these alterations have limited treatment options, especially those who have developed resistance to existing therapies or have an inadequate response to them.

[0182] The various embodiments of the present invention solve this problem by providing a method of treatment that includes:

[0183] Specific dosing regimen: The various embodiments define specific dosing regimens that start with a safe dose and allow for dose escalation based on patient tolerability and clinical response. The dosing schedule is designed to maintain effective drug levels over time, with administration every two weeks, providing a balance between efficacy and patient convenience.

[0184] VERT-002 induces MET conformational changes leading to MET-ECD shedding and subsequent degradation of the MET receptor, which may offer advantages over existing MET TKIs, including the potential to overcome off-target resistance mechanisms and on target mutation.

[0185] By addressing these aspects, the proposed claims aim to provide a solution to the technical problem of treating NSCLC patients with MET alterations more effectively and safely, potentially improving clinical outcomes for this patient population.

[0186] The invention is further described in the following examples, which are in not intended to limit the scope of the invention.

[0187] EXAMPLE

[0188] The goal of this FIH Phase l / ll trial is to establish the safety profile, identify the Recommended Phase II Dose (RP2D), explore the Pharmacokinetic (PK) exposures, immunogenicity and Pharmacodynamic (PDs) properties as well as to assess the efficacy of VERT-002 in adult patients with solid tumours including NSCLC harbouring MET alterations, including METex14 mutation and MET amplification.

[0189] OVERALL DESIGN F60089IV101 is an open-label, international, multicentre, FIH Phase l / ll trial designed to evaluate the safety, tolerability, PK, PDs, preliminary antitumour activity and efficacy of VERT-002. This trial includes 3 parts (Part 1: Dose Escalation, Part 2: Dose Range Optimisation, Part 3: Expansion at RP2D).

[0190] Part 1 (Phase la: Dose Escalation): participants with solid tumours (including NSCLC) and harbouring MET alterations (at the exception of MET fusion) will be enrolled in Part 1 of the trial to reach up to 30 evaluable participants. Participants could either have received prior MET-TKI treatment or not (i.e. MET TKI naive). Dose escalation will open with a participant assigned to the VERT-002 starting dose level.

[0191] Subsequent participants will be assigned to higher dose levels (at least 2 dose levels anticipated) per the Bayesian Optimal Interval (BOIN) design recommendation. The BOIN design will guide the dose escalation to determine the MTD (or the MAD if the MTD cannot be reached). The dose escalation will determine a dose range for further optimisation (Part 2) from the lower limit (OBD) and upper limit (MTD or MAD if MTD not reached).

[0192] The two doses for the Dose range optimisation Part will be selected from this interval. The OBD will be declared by the Data Review Committee (DRC) based on the review of all relevant data: safety, tolerability, preliminary PK and preliminary PDs, and preliminary antitumour activity of VERT-002.

[0193] For each new dose level, a safety interval of at least 72 hours (3 calendar days) will be respected between the first and next patient.

[0194] An intra-participant dose escalation could be allowed, if criteria specified in the protocol are MET, with no more than 2 intra-participant dose escalations.

[0195] Part 2 (Preliminary Activity Assessment (Part 2-a) and Dose Range Optimisation (Part 2-b): RP2D selection will open after the completion of Part 1 to estimate the RP2D, and better characterise the safety, anti-tumour activity, and PK of VERT-002. Part 2 will be divided in 2 Parts: Part 2-a Preliminary Activity Assessment in NSCLC with METex14 skipping mutation, and Part 2-b Dose Range Optimisation in NSCLC with METex14 skipping mutation and / or MET de novo amplification.

[0196] Part 2-a: participants with locally advanced or metastatic NSCLC harbouring METex14 mutation will be enrolled and treated at a dose where safety is acceptable, and activity may be expected. The DRC will be consulted for the determination of this dose. The target sample size for this cohort is anticipated to be up to 20 evaluable participants.

[0197] • Part 2-b: participants with locally advanced or metastatic NSCLC harbouring MET alteration (METex14 mutation or MET amplification) will be randomly allocated (1:1 ) to 2 or 3 dose level cohorts of VERT-002. The target sample size for each dose level cohort is anticipated to be approximately 20 evaluable participants, with up to 90 evaluable participants enrolled. A stratification will be performed based on the type of MET alteration, and prior treatment with MET TKI for METex14 mutation.

[0198] Part 3 (Phase II: Expansion at RP2D): Part 3 will open after the completion of Part 2, using a Simon’s 2-stage design to assess the efficacy of VERT-002 administered at RP2D. In all Parts, participants will receive VERT-002 administered as IV infusion for 2 hours (+ / -10 min), primarily Q2W (an alternative Q3W schedule may be explored during the trial if suggested by the data) and will be treated until disease progression, loss of clinical benefit, discontinuation of treatment due to adverse event or for any other reason, withdrawal of informed consent, lost to follow-up, death, whichever occurs first. The Q3W schedule could be tested at the end of the Part 1, and the DRC could be consulted for the decision to implement this Q3W schedule. Only the best schedule chosen based on data, will be moved forward throughout the trial.

[0199] Part 1 (Phase la - Dose Escalation) will test the safety, tolerability, PK, PDs, and preliminary anti-tumour activity of VERT-002 in participants with solid tumours (including NSCLC) and harbouring MET alterations (at the exception of MET fusion). Part 2 (Phase lb -Preliminary Activity Assessment and Dose Range Optimisation) will confirm the safety profile and test the efficacy of VERT-002 in participants with locally advanced or metastatic NSCLC harbouring for Part 2-a METex14 mutation and for Part 2-b MET alteration ( METex14 mutation or MET amplification).

[0200] Part 1: Dose Escalation (Phase la)

[0201] During this part of the trial, successive cohorts of participants will be treated with VERT-002 in order to determine a dose range for further optimisation (Part 2) from the lower limit (OBD) and upper limit (MTD or MAD if MTD is not reached).

[0202] MTD is defined as the VERT-002 dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate of 30%. If there are ties, the higher dose level will be selected when the isotonic estimate is lower than the target toxicity rate; and the lower dose level will be selected when the isotonic estimate is greater than the target toxicity rate.

[0203] OBD is defined as: the VERT-002 dose (i) based on preliminary PK exposures, and preliminary clinical activity data at which effective inhibition of the anticipated molecular target(s) can be achieved, (ii) that is pharmacokinetically distinguishable from the MTD (or MAD) (e.g., does not have any major overlapping PK exposure), and (iii) that leads to a different clinical safety profile without frequent and severe (i.e., CTCAE Grade > 2 [NCI, 2017]) drug-related toxicities that could limit the long-term clinical use of VERT-002 (i.e., that requires treatment interruption, dose reduction, or therapy discontinuation).

[0204] The dose escalation guided by a BOIN design will enrol up to 30 evaluable participants, with 4 dose levels anticipated.

[0205] Provisional dose levels in Part 1: Dose escalation

[0206]

[0207] *Any additional / intermediate dose levels may be tested based upon emerging data if deemed necessary by the Sponsor.

[0208] The starting dose for VERT-002 is 350 mg administered as an IV infusion according to the primarily explored Q2W schedule: on D1, D8, and D15 during cycle 1, and then every 2 weeks (D1 and D15) for the subsequent cycles, one cycle lasting 28 days. An alternative Q3W schedule could be tested based upon data obtained from Part 1, with VERT-002 administered on D1, D8, and D15 during Cycle 1 (this cycle lasting 28 days), and then every 3 weeks for the subsequent cycles (one cycle lasting 21 days). Part 2: Preliminary Activity Assessment and Dose Range Optimization (Phase lb)

[0209] Part 2-a: Preliminary Activity Assessment

[0210] Participants with locally advanced or metastatic NSCLC harbouring METex14 mutation will be enrolled and treated at a dose where safety is acceptable, and activity may be expected. The DRC will be consulted for the determination of this dose.

[0211] When all evaluable participants have had the opportunity to reach a confirmed response (i.e. at least 4 cycles of VERT-002), the DRC will review the safety, tolerability, preliminary PK, preliminary PDs, preliminary efficacy collected for all participants treated in Part 1 and Part 2-a of the trial to recommend the doses to be evaluated in Part 2-b.

[0212] Part 2-b: Dose Range Optimisation

[0213] Part 2-b will assess PK, PDs, efficacy and safety of VERT-002 and identify the RP2D. Participants will be randomly assigned (1:1) to be treated with one of the 2 or 3 doses selected for the Part 2-b (i.e.: 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, 3050 mg, 3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, 3600 mg, 3650 mg, 3700 mg, 3750 mg, 3800 mg, 3850 mg, 3900 mg, 3950 mg, 4000 mg, 4050 mg, 4100 mg, 4150 mg, 4200 mg, 4250 mg, 4300 mg, 4350 mg, 4400 mg, 4450 mg, 4500 mg, 4550 mg, 4600 mg, 4650 mg, 4700 mg, 4750 mg, 4800 mg, 4850 mg, 4900 mg, 4950 mg or 5000 mg). These doses will be either the MTD (or MAD) and the OBD, or 2 or 3 doses within the lower range of the OBD and the upper range of the MTD (determined in Part 1 of the trial). Participants will be stratified by METex14 mutation or MET amplification or, and by previous MET TKI treatment.

[0214] Sample size determination

[0215] The study is expected to enroll up to 140 participants (and 18 additional patients in case of alternative schedule) in total (for Parts 1 and 2). Part 1 (Phase la: Dose Escalation): up to 30 evaluable participants will be enrolled in Part 1 of the study (Q2W schedule). This sample size is adapted with the objective to estimate the OBD and MTD. If applicable, approximately 18 patients may be enrolled to be treated with optional an alternative schedule (Q3W schedule). Part 2 (Phase lb: Preliminary Activity Assessment and Dose Range Optimization): in Part 2-a, at least 20 evaluable participants will be enrolled at a dose where safety is acceptable, and activity may be expected; in Part 2-b, a minimum of 10 and a maximum of 30 evaluable participants will be randomly allocated (1:1) to each cohort, with 2 or 3 cohorts to be treated within the lower range of OBD and upper range of MTD (or MAD). The target sample size for each dose level cohort is anticipated to be approximately 20 evaluable participants.

[0216] ELIGIBILITY CRITERIA

[0217] Inclusion criteria

[0218] Screening (for all parts unless otherwise specified)

[0219] 1. Signed and dated informed consent for participation in the trial obtained according to ICH GCP, and national / local regulations.

[0220] 2. Male or female > 18 years of age at the time of signing informed consent, but at least of legal age in their country.

[0221] 3. Part 1: histological confirmation of relapsed and / or refractory locally advanced or metastatic solid tumour for which no standard of care treatment is available.

[0222] 4. Parts 2: histological confirmation of locally advanced or metastatic NSCLC Stage IIIB / C or IV (AJCC 8th edition) not eligible for curative intent surgery, chemoradiation or radiotherapy.

[0223] 5. Part 1: presence of at least one of the following MET alterations documented locally on archival blood or tissue sample:

[0224] METex14 mutation.

[0225] MET kinase domain activating gene mutations (e.g. H1094L / R / Y, D1228H / N / V, Y1230A / C / D / H).

[0226] MET amplification.

[0227] MET amplification positivity criteria are defined by either method as follows: - GCN > 5 or MET to CEP7 ratio > 2 (FISH)

[0228] - GCN > 5 (NGS)

[0229] 6. Part 2-a: presence of METex14 mutation and for Part 2-b of at least one of the following MET alterations: METex14 mutation, de novo MET amplification, documented locally (archived tissue sample). Confirmation after enrollment in the trial will be performed by central testing from an archival tumour biopsy (either tissue block or at least 15 serial cut unstained slides of 5 µm, at least 20% tumour content). In case no archival biopsy is available for central testing, the patient must be willing to undergo a fresh tumour biopsy and the tumour biopsy should be deemed safe and feasible by the investigator.

[0230] MET amplification positivity criteria are defined by either method as follows:

[0231] - GCN > 5 or MET to CEP7 ratio > 2 (FISH)

[0232] - GCN > 5 (NGS)

[0233] 7. Parts 2: at least one measurable target lesion according to RECIST v1.1.

[0234] 8. Eastern cooperative oncology group (ECOG) performance status 0 or 1.

[0235] 9. Part 1: participants may have received MET TKI as part of previous treatment, regardless of the line of therapy (first or second line) and regardless of the MET TKI being combined or not. Note: crizotinib will be considered as a prior MET TKI.

[0236] 10. Part 2: a maximum of 2 prior lines of systemic therapies (that may or not include prior MET TKI, regardless of the setting (1st or 2nd line) and regardless of the MET TKI (being combined or not) is allowed. Note: crizotinib will be considered as a prior MET TKI.

[0237] 11. Adequate hematologic function prior to the first dose of VERT-002 defined as:

[0238] Absolute Neutrophil Count (ANC) > 1.5 x 109 / L.

[0239] Platelets > 75 x 109 / L.

[0240] Haemoglobin > 90 g / L.

[0241] 12. Adequate hepatic function defined as:

[0242] Serum total bilirubin < 1.5 x Upper Limit of Normal range (ULN) or < 3.0 x ULN for participants with documented Gilbert’s syndrome. Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) < 3.0 x ULN. If the participant has liver metastases, AST and ALT < 5 x ULN.

[0243] Adequate renal function defined as:

[0244] Calculated creatinine clearance > 50 mL / min by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.

[0245] Albumin ≥ 3g / dL.

[0246] Adequate coagulation function within the institutional normal ranges: Activated Partial Thromboplastin Time (aPTT) or Prothrombin (PT).

[0247] Adequate cardiac function defined as:

[0248] Mean QT interval corrected for heart rate according to Fridericia’s formula (QTcF) value ≤ 450 msec in male and ≤ 470 msec in female and no history of long QT syndrome or risk factors for torsade de pointe.

[0249] Systolic blood pressure < 150 mmHg and diastolic blood pressure < 100 mmHg (blood pressure must be stable if the participant is treated with antihypertensive therapy).

[0250] Female participant of childbearing potential must:

[0251] Have a negative highly sensitive serum B-HCG test performed within 7 days prior to first dose of VERT-002 and a negative urine pregnancy test performed at C1D1 prior to the first VERT-002 dose.

[0252] Agree to use one highly effective method of contraception, starting at screening period, throughout the trial and until at least 8 months (i.e. more than 5 estimated VERT-002 half-lives (60 days) plus 6 months (180 days) after the last dose administered of VERT-002. If the highly effective method of contraception is a hormonal contraceptive method, it must be supplemented by one additional effective (barrier) method of contraception.

[0253] Agre to not donate eggs (ova, oocytes) for the purpose of assisted reproduction during the trial and for a period of 8 months after the last dose administration of VERT-002.

[0254] Male participants or partners Male participants / partners with female spouse / partners of childbearing potential must agree to take appropriate precautions to avoid fathering a child, i.e.:

[0255] Consistently use a barrier method [e.g., condom with spermicidal foam / gel / film / cream / suppository], and his female partner, to use a highly effective method of contraception, starting at screening and continuing throughout the trial and until at least 5 months (i.e. more than 5 estimated VERT-002 half-lives (60 days) plus 3 months (90 days)) after the last dose administered of VERT- 002.

[0256] Not donate sperm from Day 1 (first administration of VERT-002) until at least 5 months after the last dose of VERT-002.

[0257] Exclusion criteria

[0258] 1. Parts 2: Documented evidence by local testing of targetable oncogene driver mutations including MET fusion, KRAS, EGFR, ALK, ROS1.

[0259] 2. History of a primary malignancy other than the cancer under trial (as defined for Parts 1 and 2) with the exception of:

[0260] Participants with a previous malignancy who completed their anticancer treatment at least 2 years before signing informed consent and with no evidence of residual disease from the prior malignancy at screening.

[0261] Malignancies with a negligible risk of metastasis or death (i.e. 5-year overall survival rate > 90%) that are adequately treated. Examples include, but are not limited to, completely resected basal cell carcinoma and squamous cell carcinoma of skin, curatively treated in situ skin melanoma, curatively treated prostate cancer, breast cancer and early gastric cancer cured by endoscopic mucosal resection or endoscopic submucosal dissection.

[0262] 3. Uncontrolled Central Nervous System (CNS) metastases or spinal cord compression that are associated with progressive neurological symptoms or require increasing doses of corticosteroids to control the CNS disease. If a participant requires corticosteroids for management of CNS disease, the dose must have been stable for 2 weeks prior to enrolment in the trial.

[0263] 4. History of hypersensitivity to active or inactive ingredients of VERT-002, or drugs with a similar chemical structure or from a similar class. Active, bacterial, fungal, or viral infection, including, but not limited to: HBV, HCV, and known HIV or AIDS-related illness, tuberculosis or an infection requiring systemic treatment within 2 weeks prior to the first dose of VERT-002 (C1D1).

[0264] Positive Severe Acute Respiratory syndrome Coronavirus 2 (SARs-CoV-2) or variants of SARs-CoV2 Reverse Transcription Polymerase Chain Reaction (RT-PCR) test within 2 weeks prior to first dose administration of VERT-002 (C1D1) or with suspected infection with SARs-CoV-2 or variants of SARs-CoV-2 and confirmation pending.

[0265] Impaired cardiovascular function or clinically significant cardiovascular disease (either active or within 6 months prior to signing main informed consent), including any of the following:

[0266] Myocardial infarction, acute coronary syndromes including unstable angina, coronary / peripheral artery bypass graft, coronary angioplasty or stenting, Symptomatic congestive heart failure (New York Heart Association Classification Class > II),

[0267] Cerebrovascular accident or transient ischemic attack,

[0268] Symptomatic bradycardia, requirement for anti-arrhythmic medication, Ongoing cardiac dysrhythmias of National Cancer Institute Common Terminology Criteria For Adverse Events (NCI-CTCAE) Grade > 2.

[0269] Uncontrolled hypertension. Defined as persistent systolic blood pressure > 150 mmHg or diastolic blood pressure > 100 mmHg despite effective antihypertensive therapy.

[0270] Uncontrolled intercurrent illness including, but not limited to psychiatric illness or social situation (including alcoholism) that would limit compliance with trial requirements.

[0271] Past medical history of Interstitial Lung Disease (ILD), drug induced ILD, radiation pneumonitis that requires steroid treatment, or any evidence of clinically active ILD.

[0272] Women who are pregnant or breastfeeding.

[0273] Prior anticancer therapy:

[0274] MET TKI within 7 days prior to the first dose of VERT-002, Any other systemic anticancer therapy within 28 days or 5 half-lives of the anticancer therapy whichever is the shortest, but with a minimum of 14 days interval, prior to the first dose of VERT-002 (C1D1),

[0275] Radiotherapy to a large field or including a vital organ (including whole brain radiotherapy or stereotactic radiosurgery to brain) within 14 days prior to the first dose of VERT-002 (C1D1).

[0276] 12. Live attenuated vaccine within 28 days prior to the first dose of VERT -002 (C1D1).

[0277] 13. Any toxicities from prior therapy with an NCI-CTCAE Grade > 1 at the time of the first dose administration of VERT-002 (C1D1). Exceptions include alopecia (any grade), fatigue with a grade < 2, and peripheral neuropathy with a grade < 2.

[0278] 14. Major surgical procedure within 14 days of the first dose of VERT-002 (C1D1) (procedures such as central venous catheter placement, tumour needle biopsy, and feeding tube placement are not considered major surgical procedures).

[0279] 15. Participation in a clinical trial with administration of an investigational drug within 5 half-lives plus 14 days of the investigational drug, prior to the first dose of VERT-002 (C1D1).

[0280] OBJECTIVES, ENDPOINTS, AND ESTIMANDS IF APPLICABLE

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Claims

1. CLAIMS1. An anti-MET antibody fragment for use in treating a cancerous tumour and / or metastasis, with MET mutations and / or amplifications, in a subject,3.• the anti-Met antibody fragment comprising a single antigen binding arm and a silenced Fc region, wherein the Fc region comprises a complex of a first and a second Fc polypeptide, wherein the antibody fragment comprises:4.(i) a first polypeptide comprising the amino acid sequence of SEQ ID No. 19; (ii) a second polypeptide comprising the first human Fc polypeptide, wherein the second polypeptide comprises the amino acid sequence of SEQ ID No. 20, and (iii) a third polypeptide comprising the second human Fc polypeptide, wherein the third polypeptide comprises the amino acid sequence of SEQ ID No. 18;5.• the use comprising administering an effective amount of the anti-Met antibody fragment to the subject,6.wherein the effective amount is 350 mg, 700 mg, 1200 mg, 1400 mg, 1700 mg, 2100 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 4500 mg or 5000 mg of the anti-Met antibody fragment.

2. The anti-MET antibody fragment for the use of claim 1, wherein the cancerous tumour and / or metastasis, with MET mutations and / or amplifications is Non-Small Cell Lung Cancer (NSCLC).

3. The anti-MET antibody fragment for the use of claim 1 or 2, wherein the NSCLC carries a METex14 mutation; a MET kinase domain activating mutation, notably H1049L / R / Y, D1228H / N / V, or Y1230A / C / D / H; and / or a MET amplification.

4. The anti-Met antibody fragment for the use of any one of claims 1 to 3, the use comprising administering the effective amount of the anti-Met antibody fragment to the subject every week, every two weeks or every three weeks.

5. The anti-MET antibody fragment for the use of claim 4, the use comprising:11.(a) administering the effective amount of the anti-MET antibody fragment to the subject every week for a first period of time; and12.(b) administering the effective amount of the anti-MET antibody fragment to the subject every two weeks or every three weeks for a second period of time.

6. The anti-MET antibody fragment for the use of any one of claims 1 to 5, the use comprising a prior step of assaying the presence of a METex14 mutation; a MET kinasedomain activating mutation, notably H1049L / R / Y, D1228H / N / V, or Y1230A / C / D / H; and / or a MET amplification in the cancerous tumour and / or metastasis,14.wherein the patient is administered a therapeutic amount of the anti-Met antibody fragment if one or more mutations and / or amplifications are detected.

7. The anti-MET antibody fragment for the use of claim 6, wherein the presence of a METex14 mutation; a MET kinase domain activating mutation, and / or amplification is assayed by quantitative real-time polymerase chain reaction (PCR), allele-specific PCR, Flow Cytometry In Situ Hybridisation (FISH), or nucleic acid sequencing, notably next-generation sequencing (NGS).

8. The anti-MET antibody fragment for the use of any one of claims 1 to 7, the use comprising administering the anti-MET antibody fragment to a subject who has previously received one or two chemotherapy regimens.

9. The anti-MET antibody fragment for the use of claim 8, wherein the previous chemotherapy regimens failed.

10. The anti-MET antibody fragment for the use of any one of claims 1 to 9, wherein the previous chemotherapy is a MET Tyrosine Kinase Inhibitor (MET TKI), notably capmatinib, tepotinib, crizotinib, or osimertinib.

11. A syringe comprising a unit dose of 350 mg, 700 mg, 1200 mg, 1400 mg, 1700 mg, 2100 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 4500 mg, or 5000 mg of the anti-MET antibody fragment according to claim 1.

12. A kit for the treatment of a cancerous tumour and / or metastasis with MET mutations and / or amplifications, the kit comprising: (a) a container containing 350 mg, 700 mg, 1200 mg, 1400 mg, 1700 mg, 2100 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 4500 mg, or 5000 mg of the anti-MET antibody fragment according to claim 1, and (b) a pharmaceutically acceptable carrier and / or excipient, and optionally (c) a leaflet.

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