AXL-specific antibodies for cancer treatment

Abstract

The present disclosure relates to anti-AXL antibodies, immunoconjugates, and compositions for the treatment of cancers that are resistant, predicted to be resistant, or predicted to become resistant to treatment with programmed cell death-1 / programmed cell death-1 ligand (PD-1 / PD-L1) inhibitors.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to the use of antibodies, immunoconjugates, and compositions comprising such antibodies or immunoconjugates that bind to AXL; in particular, the use of said antibodies and immunoconjugates for the treatment of patients who have failed to respond or have responded poorly to anti-PD-1 / PD-L1 treatment. [Background technology]

[0002] background AXL is a 104–140 kDa transmembrane protein that belongs to the TAM subfamily of mammalian receptor tyrosine kinases (RTKs) and has transforming potential (Paccez et al., 2014). The AXL extracellular domain is composed of a combination of two membrane-distal N-terminal immunoglobulin (Ig)-like domains (Ig1 and Ig2 domains) and two membrane-proximal fibronectin type III (FNIII) repeats (FN1 and FN2 domains) (Paccez et al., 2014). Enhanced or de novo expression of AXL has been reported in various cancers, including gastric, prostate, ovarian, and lung cancers (Paccez et al., 2014).

[0003] AXL can be activated by the binding of its ligand, vitamin K-dependent growth arrest specific factor 6 (Gas6). Binding of Gas6 to AXL leads to AXL dimerization, autophosphorylation and subsequent activation of intracellular signaling pathways, including PI3K / AKT, mitogen-activated protein kinase (MAPK), STAT and NF-κB cascades (Leconet et al., 2013). In cancer cells, AXL expression is associated with tumor cell motility, invasion and migration and is involved in epithelial-mesenchymal transition (EMT) (Linger et al., 2010).

[0004] Inhibition targeting AXL and / or its ligand Gas6 can be effective as an anti-tumor therapy, for example, using small molecules or anti-AXL antibodies (Linger et al., 2010). Anti-AXL antibodies that attenuate the growth of NSCLC and breast cancer xenografts in vivo by downregulating receptor expression, reducing tumor cell proliferation, and inducing apoptosis have been described (Li et al., 2009; Ye et al., 2010 (a); WO 2011 / 159980, Genentech). Various other anti-AXL antibodies have also been reported, including anti-AXL antibodies and ADCs based on pyrrolobenzodiazepine (PBD) dimers (WO 2014 / 174111, Pierre Fabre Medicament and Spirogen Sarl) (Leconet et al., 2013; Iida et al., 2014; WO 2012 / 175691, INSERM; WO 2012 / 175692, INSERM; WO 2013 / 064685, Pierre Fabre Medicaments; WO 2013 / 090776, INSERM; WO 2009 / 063965, Chugai Pharmaceuticals and WO 2010 / 131733).

[0005] Programmed death 1 (PD-1) is a 268 amino acid type I membrane protein. PD-1 is a member of the extended CD28 / CTLA-4 family of T cell regulators, and it has been suggested that PD-1 and its ligands negatively regulate immune responses. PD-L1 is the ligand for PD1; it is highly expressed in several cancers, and the role of PD1 in cancer immune evasion is well established. Recently, several cancer immunotherapy agents have been developed that target PD-1 and / or PDL-1 (Sunshine & Taube, 2015). Although anti-PD1 / PD-L1 therapy is claimed to be one of the most effective anti-cancer immunotherapies available, it has been revealed that as many as 60% of patients receiving such therapy exhibit primary resistance. Furthermore, the development of acquired resistance in melanoma patients with objective responses to anti-PD1 therapy has also been reported (O'Donnell et al., 2016). Little is known regarding the mechanisms responsible for resistance in patients receiving anti-PD1 therapy, and therefore few effective treatment options are available for such patients.

[0006] Thus, there is a need for improved methods of treating cancers that are resistant or predicted to be resistant or become resistant to treatment with PD-1 / PD-L1 inhibitors. Summary of the Invention

[0007] It is an object of the present invention to provide cancer therapy for subjects who are resistant, or who are predicted to become resistant, to treatment via the interaction between the programmed cell death-1 (PD-1) receptor and a PD-1 receptor ligand.

[0008] In a first aspect, the present invention provides an antibody that binds to human AXL or an antibody-drug conjugate (ADC) comprising said antibody for use in treating cancer in a subject, wherein - the cancer is resistant, or is predicted to be resistant or predicted to become resistant to treatment with an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand; - the cancer has failed or is predicted to fail to respond to treatment with an inhibitor of the interaction between the Programmed Cell Death-1 (PD-1) receptor and its ligand; and / or - the subject has relapsed or is predicted to relapse following treatment with an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand.

[0009] In a second aspect, the present invention provides an antibody that binds to human AXL or an antibody-drug conjugate (ADC) comprising an antibody that binds to human AXL for use in the manufacture of a medicament for treating cancer in a subject, wherein - the cancer is resistant, or is predicted to be resistant or predicted to become resistant to treatment with an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand; - the cancer has failed or is predicted to fail to respond to treatment with an inhibitor of the interaction between the Programmed Cell Death-1 (PD-1) receptor and its ligand; and / or - the subject has relapsed or is predicted to relapse following treatment with an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand.

[0010] A third aspect of the invention provides a method of treating cancer in a subject, wherein the cancer is - is resistant or is predicted to be resistant or is predicted to become resistant to treatment with an inhibitor of the interaction between the Programmed Cell Death-1 (PD-1) receptor and its ligand; - has failed or is predicted to fail to respond to treatment with an inhibitor of the interaction between the Programmed Cell Death-1 (PD-1) receptor and its ligand; and / or - has relapsed or is predicted to relapse following treatment with an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand. The method includes administering to the subject a therapeutically effective amount of an antibody that binds to human AXL or an antibody-drug conjugate (ADC) comprising an antibody that binds to human AXL. [The present invention 1001] An antibody that binds to human AXL or an antibody-drug conjugate (ADC) comprising said antibody for use in treating cancer in a subject, wherein - the cancer is resistant, or is predicted to be resistant or to become resistant to treatment with an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand; - the cancer has failed or is predicted to fail to respond to treatment with an inhibitor of the interaction between the Programmed Cell Death-1 (PD-1) receptor and its ligand; and / or - the subject has relapsed or is predicted to relapse following treatment with an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand, The antibody or ADC. [The present invention 1002] The antibody or ADC for use in the present invention 1001, wherein the ligand is programmed cell death-ligand 1 (PD-L1) or programmed cell death-ligand 2 (PD-L2). [The present invention 1003] The antibody or ADC for use in accordance with the present invention 1001 or 1002, wherein the inhibitor is selected from the group consisting of an antibody, such as a monoclonal antibody, that binds to PD-1, an antibody, such as a monoclonal antibody, that binds to PD-L1, and an antibody, such as a monoclonal antibody, that binds to PD-L2. [The present invention 1004] The antibody or ADC for use in the present invention 1001, wherein the cancer is a solid tumor, such as a metastatic solid tumor, such as a metastatic locally advanced tumor. [The present invention 1005] The antibody or ADC for use in accordance with the present invention 1001 or 1002, wherein the cancer is a tumor selected from the group consisting of melanoma, carcinoma, sarcoma (such as undifferentiated pleomorphic sarcoma, liposarcoma, leiomyosarcoma, synovial sarcoma, Ewing's sarcoma, osteosarcoma or chondrosarcoma), adenoma, glioma, blood tumor, and tumor of lymphatic tissue. [The present invention 1006] The antibody or ADC for use in accordance with the present invention 1001 or 1002, wherein the solid tumor is selected from the group consisting of melanoma, carcinoma (such as squamous cell carcinoma of the head and neck (SCCHN)), sarcoma (such as undifferentiated pleomorphic sarcoma, liposarcoma, leiomyosarcoma, synovial sarcoma, Ewing's sarcoma, osteosarcoma or chondrosarcoma), adenoma, and glioma. [The present invention 1007] The antibody or ADC for use in accordance with the present invention 1001 or 1002, wherein the solid tumor is selected from the group consisting of carcinoma, sarcoma (such as undifferentiated pleomorphic sarcoma, liposarcoma, leiomyosarcoma, synovial sarcoma, Ewing's sarcoma, osteosarcoma, gastrointestinal stromal tumor (GIST), rhabdomyosarcoma or chondrosarcoma), adenoma, and glioma. [The present invention 1008] The antibody or ADC for use of the present invention 1001 or 1002, wherein the cancer is selected from the group consisting of endometrial / cervical cancer, lung cancer (such as small cell lung cancer or non-small cell lung cancer), thyroid cancer, colon cancer, kidney cancer, renal cancer, ovarian cancer, breast cancer (such as estrogen receptor alpha negative cancer, estrogen receptor alpha positive cancer or triple negative breast cancer; i.e. breast cancer that tests estrogen receptor negative (ER-), progesterone receptor negative (PR-) and human epidermal growth factor receptor 2 negative (HER2-)), esophageal cancer, skin cancer, melanoma (such as malignant melanoma), pancreatic cancer (such as unresectable advanced or metastatic pancreatic cancer), gastrointestinal stromal tumor (GIST), and hematological cancer (such as leukemia; for example acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia or chronic myeloid leukemia). [The present invention 1009] The antibody or ADC for use in the present invention 1001, wherein the cancer is a metastatic solid tumor other than melanoma. [The present invention 1010] The antibody or ADC for use in any of the preceding inventions, wherein the subject exhibited progressive disease during or after the last pretreatment with an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand. [The present invention 1011] The antibody or ADC for use in any of the preceding inventions, wherein resistance to, failure to respond to, or relapse from treatment with an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand is associated with increased expression of AXL. [The present invention 1012] Inhibitors of the interaction between the programmed cell death-1 (PD-1) receptor and its ligands include Opdivo / nivolumab (Bristol-Myers Squibb), Keytruda / pembrolizumab (Merck & Co), Amp-514 / MEDI0680 (Amplimmune), BGB-A317 (BeiGene), REGN2810 (Regeneron), TSR-042 (Tesaro / AnaptysBio), CBT-501 / genolimzumab (Genor Bio / CBT Pharma), PF-06801591 (Pfizer), JS-001 (Shanghai Junshi Bio), SHR-1210 / INCSHR-1210 (Incyte corp), PDR001 (Novartis), BCD-100 (BioCad), AGEN2034 (AGEN2034), and EGFR-100 (Gene). (Agenus), IBI-308 Innovent Biologics), BI-754091 (Boehringer Ingelheim), or an antibody or ADC for use according to any of the preceding claims. [The present invention 1013] Inhibitors of the interaction between the programmed cell death-1 (PD-1) receptor and its ligands include Tecentriq / RG7446; MPDL-3280A, atezolizumab (Roche), Imfinzi / MEDI-4736 / durvalumab (AstraZeneca), Bavencio / MSB-0010718C / avelumab (Merck Serono / Pfizer), KN-035- (3DMed / Alphamab Co), CX-072 (CytomX), LY-3300054 (Eli Lilly), MSB0011359C * / M-7824 (Merck KGaA), FAZ053 (Novartis), SHR-1316 (Atridia), and CA-170 (Aurigene / Curis), for use in any of the above described embodiments. [The present invention 1014] The antibody or ADC for use according to any of the preceding claims, wherein the antibody or ADC that binds to human AXL is provided to a subject as a monotherapy. [The present invention 1015] The antibody or ADC for use according to any of the preceding claims, wherein the antibody or ADC that binds to human AXL is provided to a subject as part of a combination therapy. [The present invention 1016] An ADC for use in any of the preceding inventions, comprising a therapeutic moiety which is a cytotoxic agent, a chemotherapeutic agent, or a radioisotope, optionally linked to the antibody by a linker. [The present invention 1017] The ADC for use in any of the preceding inventions, wherein the therapeutic moiety is a cytotoxic agent, optionally linked to the antibody by a linker. [The present invention 1018] ADCs for use in the present invention 1017, in which a cytotoxic agent is linked to an antibody that binds human AXL by a cleavable linker such as N-succinimidyl 4-(2-pyridyldithio)-pentanoate (SSP), maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-vc-PAB) or AV-1 K-lock valine-citrulline. [The present invention 1019] An ADC for use in any of the inventions 1017-1018, wherein the cytotoxic agent is linked to an antibody that binds to human AXL by a non-cleavable linker, such as succinimidyl-4(N-maleimidomethyl)cyclohexane-1-carboxylate (MCC) or maleimidocaproyl (MC). [The present invention 1020] The ADC for use in any of the inventions 1017-1019, wherein the cytotoxic agent is selected from the group consisting of DNA targeting agents, e.g., DNA alkylating agents and crosslinking agents, e.g., calicheamicin, duocarmycin, rachelmycin (CC-1065), pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) and indolinobenzodiazepines (IGNs); microtubule targeting agents, e.g., duostatins such as duostatin-3, auristatins such as monomethylauristatin E (MMAE) and monomethylauristatin F (MMAF), dolastatins, maytansine, N(2')-deacetyl-N(2')-(3-mercapto-1-oxopropyl)-maytansine (DM1), and tubulysins; and nucleoside analogs; or analogs, derivatives or prodrugs thereof. [The present invention 1021] (a) the linker is cleavable and the cytotoxic agent has bystander killing capability; (b) the linker is cleavable and the cytotoxic agent does not have bystander killing capability; (c) the linker is non-cleavable and the cytotoxic agent has bystander killing capability; or (d) the linker is non-cleavable and the cytotoxic agent does not have bystander killing capability; An ADC for use in any of claims 1017 to 1020. [The present invention 1022] An ADC for use in any of the inventions 1016 to 1021, wherein the linker is mc-vc-PAB and the cytotoxic agent is MMAE. [The present invention 1023] The ADC for use in any of claims 1016 to 1022, wherein the linker is SSP and the cytotoxic agent is DM1. [The present invention 1024] The ADC for use in any of claims 1017 to 1021, wherein the cytotoxic agent is duostatin-3. [The present invention 1025] An antibody or ADC for use in any of the preceding inventions, wherein the antibody that binds to human AXL does not compete with growth arrest specific 6 (Gas6) for binding to human AXL. [The present invention 1026] The antibody or ADC for use in any of the above described invention, wherein the maximum antibody binding to human AXL in the presence of Gas6 is at least 90%, such as at least 95%, such as at least 97%, such as at least 99%, such as 100% of the binding in the absence of Gas6 as determined by a competition assay, wherein the competition between the binding of the antibody to human AXL and Gas6 is determined in A431 cells pre-incubated with and without Gas6. [The present invention 1027] The antibody that binds to human AXL has a titer of 0.3 × 10 -9 From 63×10 -9 Binding affinities (K D ), optionally wherein the binding affinity is measured using Bio-layer Interferometry using a soluble AXL extracellular domain. [The present invention 1028] The antibody binding to human AXL was 9.7 × 10 -5 From 4.4 × 10 -3 s -1 and optionally wherein the dissociation rate is measured by Bio-layer Interferometry using a soluble recombinant AXL extracellular domain. [The present invention 1029] An antibody or ADC for use according to any of the preceding claims, wherein the amino acid sequence of human AXL is as set forth in SEQ ID NO:130. [The present invention 1030] An antibody or ADC for use in any of the preceding inventions which binds to cynomolgus AXL designated in SEQ ID NO:147. [The present invention 1031] An antibody or ADC for use according to any of the preceding claims, wherein the antibody that binds to human AXL comprises at least one binding region comprising a VH region and a VL region selected from the group consisting of: (a) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 36, 37 and 38, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 39, GAS and 40, respectively; (b) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 46, 47 and 48, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 49, AAS and 50, respectively; (c) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 114, 115 and 116, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 117, 118 and 119, respectively

[0733] ; (d) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 51, 52 and 53, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 55, 56 and 57, respectively; (e) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 51, 52 and 54, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 55, GAS and 56, respectively [154-M103L]; (f) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 57, 58 and 59, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 60, 61 and 62, respectively; (g) A VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 62, 63 and 64 respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 65, GAS and 66 respectively

[0172] ; (h) A VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 67, 68 and 69 respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 70, GAS and 71 respectively

[0181] ; (i) A VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 72, 73 and 75 respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 76, ATS and 77 respectively

[0183] ; (j) A VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 72, 74 and 75 respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 76, ATS and 77 respectively [183-N52Q]; (k) A VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 78, 79 and 80 respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 81, AAS and 82 respectively

[0187] ; (l) A VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 83, 84 and 85 respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 86, GAS and 87 respectively [608-01]; (m) A VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 88, 89 and 90 respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 91, GAS and 92 respectively [610-01]; (n) A VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 93, 94 and 95 respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 96, GAS and 97 respectively

[0613] ; (o) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 98, 99 and 100, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 101, 102 and 103, respectively [613-08]; (p) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 103, 104 and 105, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 106, GAS and 107, respectively [620-06]; (q) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 108, 109 and 110, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 112, AAS and 113, respectively

[0726] ; (r) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 108, 109 and 111, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 112, AAS and 113, respectively [726-M101L]; (s) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 41, 42 and 43, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 44, AAS and 45, respectively; (t) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 93, 94 and 95, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 128, XAS, in which X is D or G, and 129, respectively [613 / 613-08]; (u) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 46, 119 and 120, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 49, AAS and 50, respectively [148 / 140]; (v) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 123, 124 and 125, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 60, GAS and 61, respectively [171 / 172 / 181]; and (w) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 121, 109 and 122, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 112, AAS and 113, respectively [726 / 187]; and (x) a VH region containing the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 93, 126 and 127, respectively, and a VL region containing the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 96, GAS and 97, respectively [613 / 608-01 / 610-01 / 620-06]. [The present invention 1032] An ADC for use according to any of the preceding claims, wherein the antibody that binds to human AXL comprises at least one binding region comprising: (a) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 36, 37 and 38, respectively; and (b) A VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 39, 40 and 41, respectively

[0107] . [The present invention 1033] An ADC for use according to any of the preceding claims, wherein the antibody that binds to human AXL comprises at least one binding region comprising a VH region and a VL region selected from the group consisting of: (a) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 1, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 2; (b) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 5, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 6; (c) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 34, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 35. (d) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 7, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 9; (e) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 10, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 11; (f) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 16, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 18; (g) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 25, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 26

[0613] ; (h) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 31, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 33

[0726] ; (i) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 3, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 4; (j) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 8 and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 9 [154-M103L]; (k) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 12, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 13; (l) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 14, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 15; (m) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 17, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 18 [183-N52Q]; (n) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 19, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 20; (o) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 21 and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 22 [608-01]; (p) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 23 and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 24 [610-01]; (q) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 27 and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 28 [613-08]; (r) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 29, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 30 [620-06]; and (s) a VH region at least 90%, such as at least 95%, such as at least 97%, for example at least 99% identical to SEQ ID No: 32, and a VL region at least 90%, such as at least 95%, for example at least 97%, for example at least 99% identical to SEQ ID No: 33 [726-M101L]. [The present invention 1034] An antibody or ADC for use according to any of the preceding claims, wherein at least one binding region of the antibody comprises a VH region and a VL region selected from the group consisting of: (a) a VH region comprising SEQ ID No: 1 and a VL region comprising SEQ ID No: 2

[0107] ; (b) a VH region comprising SEQ ID No: 5 and a VL region comprising SEQ ID No: 6; (c) a VH region containing SEQ ID No: 34 and a VL region containing SEQ ID No: 35

[0733] (d) a VH region comprising SEQ ID No: 7 and a VL region comprising SEQ ID No: 9

[0154] ; (e) a VH region comprising SEQ ID No: 10 and a VL region comprising SEQ ID No: 11

[0171] ; (f) a VH region comprising SEQ ID No: 16 and a VL region comprising SEQ ID No: 18; (g) a VH region comprising SEQ ID No: 25 and a VL region comprising SEQ ID No: 26

[0613] ; (h) a VH region comprising SEQ ID No: 31 and a VL region comprising SEQ ID No: 33

[0726] ; (i) a VH region comprising SEQ ID No: 3 and a VL region comprising SEQ ID No: 4; (j) a VH region comprising SEQ ID No: 8 and a VL region comprising SEQ ID No: 9[154-M103L]; (k) a VH region comprising SEQ ID No: 12 and a VL region comprising SEQ ID No: 13; (l) a VH region comprising SEQ ID No: 14 and a VL region comprising SEQ ID No: 15

[0181] ; (m) a VH region comprising SEQ ID No: 17 and a VL region comprising SEQ ID No: 18[183-N52Q]; (n) a VH region comprising SEQ ID No: 19 and a VL region comprising SEQ ID No: 20

[0187] ; (o) a VH region comprising SEQ ID No: 21 and a VL region comprising SEQ ID No: 22 [608-01]; (p) a VH region comprising SEQ ID No: 23 and a VL region comprising SEQ ID No: 24 [610-01]; (q) a VH region comprising SEQ ID No: 27 and a VL region comprising SEQ ID No: 28 [613-08]; (r) a VH region comprising SEQ ID No: 29 and a VL region comprising SEQ ID No: 30 [620-06]; and (s) a VH region comprising SEQ ID No: 32 and a VL region comprising SEQ ID No: 33[726-M101L]. [The present invention 1035] An antibody or ADC for use in any of the above described inventions, wherein at least one binding region of an antibody that binds to human AXL comprises a VH region comprising SEQ ID No: 1 and a VL region comprising SEQ ID No: 2

[0107] . [The present invention 1036] An antibody or ADC for use in any of the above-mentioned inventions, wherein the antibody that binds to human AXL comprises a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 36, 37 and 38, respectively, a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 39, GAS and 40, respectively, and at least one binding region comprising

[0107] . [The present invention 1037] An antibody or ADC for use according to any of the preceding claims, wherein the antibody binds to an epitope on AXL, the epitope being recognised by any of the antibodies defined in any of claims 1031 to 1036 of the present invention. [The present invention 1038] An antibody or ADC for use according to any of the preceding inventions, wherein the antibody that binds to human AXL binds to an epitope within the Ig1 or Ig1-like domain of AXL, the epitope comprising or requiring one or more amino acids corresponding to positions L121 to Q129 or T112 to Q124 of human AXL. [The present invention 1039] An antibody or ADC for use in any of the present inventions 1001 to 1037, wherein the antibody that binds to human AXL binds to an epitope within the Ig2 domain or Ig2-like domain of AXL, and the epitope includes or requires an amino acid corresponding to position D170 or D179 in combination with one or more amino acids corresponding to positions T182 to R190 of human AXL. [The present invention 1040] An ADC for use according to any of the present inventions 1001 to 1037, wherein the antibody that binds to human AXL binds to an epitope within the FN1 domain or FN-like domain of human AXL, said epitope comprising or requiring one or more amino acids corresponding to positions Q272 to A287 and G297 to P301 of human AXL. [The present invention 1041] An antibody or ADC for use in any of the present inventions 1001 to 1037, wherein the antibody that binds to human AXL binds to an epitope within the FN2 domain of human AXL, and the epitope includes or requires amino acids corresponding to positions A359, R386 and one or more amino acids corresponding to positions Q436 to K439 of human AXL. [The present invention 1042] The antibody or ADC for use according to any of the preceding claims, wherein the ADC is capable of inducing tumor regression in a SKMel-147 human xenograft mouse model and / or a BLM melanoma xenograft model. [The present invention 1043] The antibody or ADC for use in the present invention 1042, wherein the SKMel-147 human xenograft mouse model and / or the BLM melanoma xenograft model are resistant to anti-PD-1 treatment, such as treatment with an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand. [The present invention 1044] The antibody or ADC for use in the present invention 1042 or 1043, wherein the SKMel-147 human xenograft mouse model is generated as described in Example 5 herein, or essentially as described in Example 5 herein. [The present invention 1045] The antibody or ADC for use in the present invention 1042 or 1043, wherein the BLM melanoma xenograft model is generated as described in Example 6 herein, or essentially as described in Example 6 herein. [The present invention 1046] An antibody or ADC for use according to any of the preceding claims, wherein the antibody that binds to human AXL comprises a heavy chain of an isotype selected from the group consisting of IgG1, IgG2, IgG3 and IgG4. [The present invention 1047] The antibody or ADC for use in the present invention 1046, wherein the isotype of the antibody that binds to human AXL is IgG1, for example human IgG1, optionally allotype IgG1m(f). [The present invention 1048] An antibody or ADC for use in any of the preceding inventions, wherein the antibody that binds to human AXL is a monoclonal antibody or an antigen-binding fragment thereof, such as a full-length monoclonal antibody, such as a full-length monoclonal IgG1,κ antibody. [The present invention 1049] The antibody or ADC for use in any of the preceding inventions, wherein the antibody is a humanized antibody or a human antibody. [The present invention 1050] The antibody or ADC for use according to any of the preceding inventions, wherein the antibody is enapotamab. [The present invention 1051] The antibody or ADC for any of the aforementioned uses of the invention, wherein the ADC is enapotamab vedotin. [The present invention 1052] The antibody or ADC for use in any of the present inventions 1001 to 1043, wherein the antibody that binds to human AXL is an effector function-deficient antibody, a stabilized IgG4 antibody or a monovalent antibody. [The present invention 1053] An antibody or ADC for use in any of the above methods of the present invention, wherein the heavy chain of an antibody that binds to human AXL has been modified such that the entire hinge region is deleted. [The present invention 1054] An antibody or ADC for use in any of the preceding inventions, wherein the sequence of the antibody that binds to human AXL has been modified so that it does not contain any acceptor sites for N-linked glycosylation. [The present invention 1055] The antibody or ADC for use in any of the above methods of the present invention, wherein the antibody that binds to human AXL is a single chain antibody. [The present invention 1056] An antibody or ADC for use according to any of the preceding inventions, wherein the antibody that binds to human AXL is a bispecific antibody comprising a first binding region of any of the antibodies of the present invention and a second binding region that binds to a target or epitope different from the first binding region. [The present invention 1057] An antibody or ADC for use according to the invention 1049, wherein the bispecific antibody binding to human AXL comprises a first and a second heavy chain each comprising at least a hinge region, a CH2 and a CH3 region, wherein in the first heavy chain at least one amino acid at a position corresponding to a position selected from the group consisting of K409, T366, L368, K370, D399, F405 and Y407 in a human IgG1 heavy chain is substituted, and in the second heavy chain at least one amino acid at a position corresponding to a position selected from the group consisting of F405, T366, L368, K370, D399, Y407 and K409 in a human IgG1 heavy chain is substituted, and wherein the substitutions in the first and second heavy chains are not at the same positions. [The present invention 1058] The antibody or ADC for use in any of the preceding inventions, wherein the amino acid at the position corresponding to K409 in a human IgG1 heavy chain is R in the first heavy chain and the amino acid at the position corresponding to F405 in a human IgG1 heavy chain is L in the second heavy chain, or vice versa. [The present invention 1059] The antibody or ADC for any of the above uses of the invention in a formulation, e.g., in a formulation comprising one or more pharma- ceutically acceptable excipients, e.g., in a pharmaceutical formulation. [The present invention 1060] The antibody or ADC for any of the aforementioned uses of the invention, in a lyophilized formulation. [The present invention 1061] The antibody or ADC for use in the present invention 1053 is obtained or can be obtained by lyophilizing an aqueous formulation comprising an antibody or ADC and one or more excipients, wherein the aqueous formulation does not contain any surfactant. [The present invention 1062] an antibody or ADC; a. a buffer providing a pH of about 5 to about 7 in the aqueous formulation; b. at least one filler; and c. at least one non-reducing sugar that forms an amorphous phase with the antibody or ADC in the solid state; The antibody or ADC for use in any of the present inventions 1053 to 1054, wherein a lyophilized formulation is obtained or a lyophilized formulation can be obtained by lyophilizing an aqueous formulation comprising the antibody or ADC. [The present invention 1063] The antibody or ADC for use in any of claims 1054 to 1055, wherein the aqueous formulation does not contain any surfactant. [The present invention 1064] The antibody or ADC for use in any of claims 1054 to 1056, wherein the aqueous formulation comprises a buffer selected from the group consisting of histidine, citrate, 2-(N-morpholino)ethanesulfonic acid (MES), succinate, glycolate, carbonate, and phosphate, or any combination thereof, and wherein the pH of the aqueous formulation is in the range of about 5 to about 7. [The present invention 1065] The antibody or ADC for use in any of claims 1054 to 1057, wherein the aqueous formulation comprises a histidine buffer. [The present invention 1066] The antibody or ADC for use in any of the inventions 1054-1058, wherein the aqueous formulation comprises a buffer at a concentration of about 5 mM to about 100 mM, such as about 10 mM to about 50 mM, for example about 20 mM to about 40 mM, such as about 28 mM to about 32 mM, for example about 30 mM. [The present invention 1067] The antibody or ADC for use according to any of claims 1053 to 1059, wherein the lyophilized formulation comprises a bulking agent selected from mannitol, glycine, and combinations thereof. [The present invention 1068] The antibody or ADC for use in any of claims 1053 to 1060, wherein the lyophilized formulation comprises mannitol. [The present invention 1069] The antibody or ADC for use according to any of claims 1054 to 1061, wherein the aqueous formulation comprises a bulking agent at a concentration of from about 1% (w / v) to about 5% (w / v), such as from about 2% (w / v) to about 4% (w / v), such as from about 2.5% (w / v) to about 3.5% (w / v), such as about 3% (w / v). [The present invention 1070] The antibody or ADC for use according to any of claims 1053 to 1062, wherein the aqueous formulation comprises a bulking agent at a concentration of about 50 mM to about 300 mM, such as about 100 mM to about 225 mM, such as about 150 mM to about 180 mM, for example about 165 mM. [The present invention 1071] The antibody or ADC for use in any of the present inventions 1053 to 1063, wherein any of the lyophilized preparations of the present invention comprises a non-reducing sugar selected from sucrose, trehalose, and a combination thereof. [The present invention 1072] The antibody or ADC for use in any of claims 1053 to 1064, wherein the lyophilized formulation comprises sucrose. [The present invention 1073] The antibody or ADC for use in any of the inventions 1054-1065, wherein the aqueous formulation comprises a non-reducing sugar at a concentration of about 0.5% (w / v) to about 7% (w / v), such as about 0.5% (w / v) to about 4% (w / v), such as about 1% (w / v) to about 3% (w / v) or about 2.5% to about 3.5%, such as about 3% (w / v). [The present invention 1074] The antibody or ADC for use in any of the inventions 1054-1066, wherein the aqueous formulation comprises a non-reducing sugar at a concentration of about 15 mM to about 200 mM, such as about 30 mM to about 150 mM, such as about 80 mM to about 100 mM, such as about 70 to about 90 mM, for example about 84 mM to about 92 mM sucrose, for example about 88 mM sucrose. [The present invention 1075] The antibody or ADC for use in any of the present inventions 1053 to 1067, wherein a lyophilized formulation is obtained or can be obtained by lyophilizing an aqueous formulation in which the antibody or ADC concentration in the aqueous formulation is from about 5 mg / mL to about 30 mg / mL, for example, from about 7 mg / mL to about 20 mg / mL, for example, from about 8 mg / mL to about 15 mg / mL, for example, from about 9 mg / mL to about 11 mg / mL, for example, about 10 mg / mL. [The present invention 1076] The antibody or ADC for use in any of the inventions 1053 to 1068, wherein the lyophilized formulation is obtained or can be obtained by lyophilizing an aqueous formulation having a pH in the range of about 5.5 to 6.5, e.g. about 6. [The present invention 1077] has a pH of about 5 to about 7; and a. about 5 mg / mL to about 30 mg / mL of the antibody or ADC; b. about 10 mM to about 50 mM histidine; c. about 30 mM to about 150 mM sucrose or trehalose; and d. about 150 mM to about 180 mM mannitol or glycine The antibody or ADC for use in any of the present inventions 1053 to 1069, wherein a lyophilized formulation is obtained or a lyophilized formulation can be obtained by lyophilizing an aqueous formulation comprising the antibody or ADC. [The present invention 1078] The aqueous formulation is having a pH within the range of about 5.5 to about 6.5; and a. about 9 mg / mL to about 11 mg / mL of the antibody or ADC, for example about 10 mg / mL of the antibody or ADC; b. about 20 mM to about 40 mM histidine, for example, about 30 mM histidine; c. about 80 mM to about 100 mM sucrose, for example, about 88 mM sucrose; and d. about 150 mM to about 180 mM mannitol, for example about 165 mM mannitol and Does not contain any surfactants An antibody or ADC for use in any of the present inventions 1054 to 1070. [The present invention 1079] The antibody or ADC for use according to any of the inventions 1054 to 1071, wherein the antibody or ADC in the lyophilized formulation is stable for pharmaceutical use at 2 to 8°C, such as at 5°C, for at least 6 months, such as at least 9 months, for example at least 15 months, preferably at least 18 months, or even more preferably at least 24 months, or most preferably at least 36 months. [The present invention 1080] The antibody or ADC for use according to any of the inventions 1054 to 1072 is stable if the lyophilized formulation has less than 10% aggregates, such as less than 5.0% aggregates, such as less than 3.0% aggregates, for example less than 2.0% aggregates when stored at 5° C. for at least 6 months, such as at least 9 months, for example at least 15 months, preferably at least 18 months, or even more preferably at least 24 months, or most preferably at least 36 months. [The present invention 1081] The antibody or ADC for use in the present invention 1073, wherein the stability is determined by size exclusion analysis, cIEF, or both. [The present invention 1082] The antibody or ADC for use according to any of claims 1053 to 1074, wherein the lyophilized formulation contains less than 3.0% water, such as less than 2.0% water, such as less than 1% water, or less than 0.5% water. [The present invention 1083] The antibody or ADC for use in any of claims 1053 to 1075, wherein the lyophilized formulation does not contain any inorganic salts. [The present invention 1084] An antibody or ADC for use according to any of claims 1052 to 1076, wherein a pharmaceutical formulation is obtained or can be obtained by reconstituting a lyophilized formulation as defined in any of claims 1053 to 1075 in a sterile aqueous diluent. [The present invention 1085] The pharmaceutical formulation comprises: has a pH of about 5 to about 7; and In aqueous solution a. about 5 mg / mL to about 30 mg / mL of the antibody or ADC; b. about 10 mM to about 50 mM histidine; c. about 30 mM to about 150 mM sucrose or trehalose; and d. about 50 mM to about 300 mM mannitol or glycine Including, An antibody or ADC for use in any of the present inventions 1052 to 1077. [The present invention 1086] The pharmaceutical formulation comprises: having a pH within the range of about 5.5 to about 6.5; and a. about 9 mg / mL to about 11 mg / mL of the antibody or ADC, for example about 10 mg / mL of the antibody or ADC; b. about 20 mM to about 40 mM histidine, for example, about 30 mM histidine; c. about 80 mM to about 100 mM sucrose, for example, about 88 mM sucrose; and d. about 150 mM to about 180 mM mannitol, for example about 165 mM mannitol Including, The aqueous formulation does not contain any surfactants; An antibody or ADC for use in any of the present inventions 1052 to 1077. [The present invention 1087] The antibody or ADC for any of the foregoing uses of the invention, wherein the antibody or ADC is in an aqueous formulation comprising one or more pharma- ceutically acceptable excipients, and wherein the aqueous formulation does not comprise any surfactant. [The present invention 1088] The antibody or ADC for use in any of the preceding inventions, wherein the antibody or ADC is in an aqueous formulation comprising a buffer and at least one stabilizer, wherein the pH of the aqueous formulation is from about 5 to about 7, and wherein the aqueous formulation does not contain any surfactant. [The present invention 1089] The antibody or ADC for any of the preceding uses of the invention, wherein the antibody or ADC is in an aqueous formulation comprising a buffer selected from the group consisting of histidine, citrate, MES, phosphate, carbonate, succinate, glycolate, or any combination thereof, and wherein the pH of the aqueous formulation is in the range of about 5 to about 7. [The present invention 1090] The antibody or ADC for any of the aforementioned uses of the invention, in an aqueous formulation comprising a histidine buffer. [The present invention 1091] The antibody or ADC for any of the foregoing uses of the invention, in an aqueous formulation comprising a buffer at a concentration of about 10 mM to about 50 mM, such as about 20 mM to about 40 mM, such as about 28 mM to about 34 mM, such as about 29 mM to about 31 mM, for example about 30 mM. [The present invention 1092] The antibody or ADC for any of the preceding uses of the invention, in an aqueous formulation comprising a stabilizer selected from the group consisting of mannitol, sucrose, and trehalose. [The present invention 1093] The antibody or ADC for any of the preceding uses of the invention, in an aqueous formulation which comprises a stabilizer which is mannitol. [The present invention 1094] The antibody or ADC for any of the foregoing uses of the invention, in an aqueous formulation comprising a stabilizer at a concentration of about 20 mM to about 200 mM, such as about 30 mM to about 100 mM, for example about 40 mM to about 80 mM, such as about 50 mM to about 60 mM, for example about 55 mM. [The present invention 1095] The antibody or ADC for any of the aforementioned uses of the invention, in an aqueous formulation comprising a stabilizer selected from sucrose, trehalose, and combinations thereof. [The present invention 1096] The antibody or ADC for any of the aforementioned uses of the invention, in an aqueous formulation that does not contain any one or more of arginine, glycine, glutamic acid, sorbitol, trehalose, sucrose, and sodium chloride. [The present invention 1097] The antibody or ADC for any of the foregoing uses of the invention, in an aqueous formulation having an antibody or ADC concentration of about 5 mg / mL to about 40 mg / mL, such as about 8 mg / mL to about 35 mg / mL, such as about 10 mg / mL to about 30 mg / mL, such as about 15 mg / mL to about 25 mg / mL, for example about 20 mg / mL. [The present invention 1098] The antibody or ADC for any of the foregoing uses of the invention, wherein the antibody or ADC is in an aqueous formulation, wherein the pH of the aqueous formulation is within the range of about 5.5 to 6.5, e.g. about 6. [This invention 1099] the antibody or ADC is in an aqueous formulation; The aqueous formulation comprises: has a pH of about 5 to about 7; and a. about 5 mg / mL to about 40 mg / mL of the antibody or ADC; and b. about 10 mM to about 50 mM histidine; c. about 50 mM to about 300 mM mannitol Including, An antibody or ADC for use according to any of the preceding claims. [The present invention 1100] the antibody or ADC is in an aqueous formulation; The aqueous formulation comprises: having a pH within the range of about 5.5 to about 6.5; and a. about 15 mg / mL to about 25 mg / mL of the antibody or ADC, for example, about 20 mg / mL of the antibody or ADC; b. about 20 mM to about 40 mM histidine, for example, about 30 mM histidine; c. about 50 mM to about 60 mM mannitol, for example about 55 mM mannitol Including, the aqueous formulation does not contain any added surfactants, amino acid excipients, NaCl, or any combination thereof; An antibody or ADC for use according to any of the preceding claims. [The present invention 1101] The antibody or ADC for use according to any of the preceding inventions, in a frozen aqueous formulation obtained or obtainable by freezing an aqueous formulation of any of the definitions XX to XX of the present inventions. [The present invention 1102] In a therapeutically effective amount and frequency, e.g. - in at least one cycle involving administration once every three weeks, such as on day 1 of a 21-day cycle; or - At least one cycle containing 3 consecutive weeks of weekly dosing followed by a 1-week rest period without ADC administration, such that each cycle time, including the rest periods, is 28 days An antibody or ADC for any of the uses of the present invention, administered to a subject. [The present invention 1103] The antibody or ADC for use according to the invention 1095, wherein the dose of the antibody or ADC in a 21 day cycle is between 0.6 mg / kg and 4.0 mg / kg of the subject's body weight, for example between 0.6 mg / kg and 3.2 mg / kg of the subject's body weight, for example about a 0.6 mg / kg dose or about a 0.8 mg / kg dose or about a 1.0 mg / kg dose or about a 1.2 mg / kg dose or about a 1.4 mg / kg dose or about a 1.6 mg / kg dose or about a 1.8 mg / kg dose or about a 2.0 mg / kg dose or about a 2.2 mg / kg dose or about a 2.4 mg / kg dose or about a 2.6 mg / kg dose or about a 2.8 mg / kg dose or about a 3.0 mg / kg dose or about a 3.2 mg / kg dose. [The present invention 1104] The antibody or ADC for use in the present invention 1095, wherein the dose of the antibody or ADC in a 28 day cycle is 0.45 mg / kg to 2.0 mg / kg of the subject's body weight, for example, a 0.45 mg / kg dose or a 0.5 mg / kg dose or a 0.6 mg / kg dose or a 0.7 mg / kg dose or a 0.8 mg / kg dose or a 0.9 mg / kg dose or a 1.0 mg / kg dose or a 1.1 mg / kg dose or a 1.2 mg / kg dose or a 1.3 mg / kg dose or a 1.4 mg / kg dose or a 1.5 mg / kg dose or a 1.6 mg / kg dose or a 1.7 mg / kg dose or a 1.8 mg / kg dose or a 1.9 mg / kg dose or a 2.0 mg / kg dose. [The present invention 1105] The antibody or ADC for use in any of the present inventions 1095 to 1097, wherein the number of 21-day cycles or the number of 28-day cycles is 2 to 48, for example 2 to 36, for example 2 to 24, for example 2 to 15, for example 2 to 12, for example 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, 10 cycles, 11 cycles or 12 cycles. [The present invention 1106] The antibody or ADC for use in any of the inventions 1001-1097, wherein the antibody or ADC is administered for at least four 28 day treatment cycles, where the antibody or ADC in each treatment cycle is administered once weekly for three consecutive weeks at a dose of 0.45 mg / kg body weight, for example a dose of 0.6 mg / kg body weight, 0.8 mg / kg body weight, 1.0 mg / kg body weight, 1.2 mg / kg body weight, 1.4 mg / kg body weight, 1.6 mg / kg body weight, 1.8 mg / kg body weight, or for example a dose of 2.0 mg / kg body weight, followed by a rest week without administration of the antibody or ADC. [The present invention 1107] The conjugate for any of the aforementioned uses of the present invention is administered to a subject at a dose of about 2.0 to about 2.4 mg / kg body weight once every three weeks, or at a weekly dose of about 0.6 to about 1.4 mg / kg body weight for three weeks, optionally followed by one week of no treatment. [The present invention 1108] The conjugate for any of the aforementioned uses of the invention is administered to a subject at a dose of about 2.2 mg / kg body weight once every three weeks, or at a weekly dose of about 1.0 mg / kg body weight for three weeks, optionally followed by one week of no treatment. [The present invention 1109] The conjugate for any of the uses of the present invention, administered to the subject by a weekly dosage of about 0.4 to 1.0 mg / kg body weight. [The present invention 1110] The conjugate for any of the uses of the present invention, administered to the subject by a weekly dosage of about 0.6 to 1.0 mg / kg body weight. [The present invention 1111] The conjugate for any of the uses of the present invention, administered to the subject by a weekly dosage of about 0.4 to 0.8 mg / kg body weight. [The present invention 1112] The conjugate for any of the uses of the present invention, administered to the subject by a weekly dosage of about 0.5 to 0.7 mg / kg body weight. [The present invention 1113] The conjugate for any of the aforementioned uses of the invention, administered to the subject by a weekly dosage of about 0.6 mg / kg body weight. [The present invention 1114] The conjugate for any of the above uses of the present invention, wherein the route of administration is intravenous. [The present invention 1115] A conjugate for use according to any of the preceding inventions, wherein treatment is continued at least until the subject experiences a progression-free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years after administration of the first dose of the conjugate. [The present invention 1116] The conjugate for use in any of the preceding inventions, wherein treatment is continued until disease progression or unacceptable toxicity. [The present invention 1117] 1. An antibody that binds to human AXL or an antibody-drug conjugate (ADC) comprising an antibody that binds to human AXL for use in the manufacture of a medicament for treating cancer in a subject, wherein - the cancer is resistant, or is predicted to be resistant or to become resistant to treatment with an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand; - the cancer has failed or is predicted to fail to respond to treatment with an inhibitor of the interaction between the Programmed Cell Death-1 (PD-1) receptor and its ligand; and / or - the subject has relapsed or is predicted to relapse following treatment with an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand, The antibody or ADC. [The present invention 1118] - the ligand is as defined in claim 1002; - an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand as defined in any of claims 1003, 1012 and 1013; - the cancer is as defined in any one of claims 1004 to 1009 of the present invention; - the subject is as defined in any one of claims 1010-1011; - the antibody or ADC is as defined in any of claims 1014 to 1058 of the present invention; - the formulation is as defined in any of claims 1059 to 1101; and / or - the amount and frequency at which the antibody or ADC is administered to the subject is as defined in any one of claims 1102 to 1116 of the present invention; An antibody or ADC for use in the manufacture of a medicament of the invention 1100. [The present invention 1119] 1. A method of treating cancer in a subject, comprising: - the cancer is resistant, or is predicted to be resistant or to become resistant to treatment with an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand; - the cancer has failed or is predicted to fail to respond to treatment with an inhibitor of the interaction between the Programmed Cell Death-1 (PD-1) receptor and its ligand; and / or - the subject has relapsed or is predicted to relapse following treatment with an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand; The method comprises administering to the subject a therapeutically effective amount of an antibody that binds to human AXL or an antibody-drug conjugate (ADC) comprising an antibody that binds to human AXL. [The present invention 1120] - the ligand is as defined in claim 1002; - an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand as defined in any of claims 1003, 1012 and 1013; - the cancer is as defined in any one of claims 1004 to 1009 of the present invention; - the subject is as defined in any one of claims 1010-1011; - the antibody or ADC is as defined in any of claims 1014 to 1058 of the present invention; - the formulation is as defined in any of claims 1059 to 1101; and / or - the amount and frequency at which the antibody or ADC is administered to the subject is as defined in any one of claims 1102 to 1116 of the present invention; The method of treating cancer of the present invention 1102. [Brief description of the drawings]

[0011] [Figure 1] Antitumor efficacy of IgG1-AXL-107-vcMMAE in the melanoma xenograft model SkMel147 in the presence of tumor-specific human T cells as described in Example 5. Mean tumor size after injection of mice with control or MART-1 T cells in combination with IgG1-b12-vcMMAE (control ADC), IgG1-AXL-107-vcMMAE or IgG1-b12-vcMMAE and anti-PD-1 (pembrolizumab). Error bars indicate standard error of the mean (SEM). [Diagram 2] Kaplan-Meier graph showing survival of mice in various groups (tumor size cutoff >500 mm3) in the SkMel147 model as described in Example 5. [Diagram 3]Tumor sizes in selected mice from melanoma xenograft model SkMel147 sequentially treated with IgG1-AXL-107-vcMMAE as described in Example 5. Tumor sizes in mice initially injected with (A) control T cells and control ADC (n=5), (B) MART-1 T cells and control ADC (n=2), and (C) MART-1 T cells, control ADC and anti-PD-1 (n=2) and then treated with 4 mg / kg IgG1-AXL-107-vcMMAE on the days indicated by the arrows. Tumor sizes per mouse are plotted. [Figure 4] Antitumor efficacy of IgG1-AXL-107-vcMMAE in the melanoma xenograft model BLM in the presence of tumor-specific human T cells as described in Example 6. Mean tumor size after injection of mice with control or MART-1 T cells in combination with IgG1-b12-vcMMAE (control ADC), IgG1-AXL-107-vcMMAE or IgG1-b12-vcMMAE and anti-PD-1 (pembrolizumab). Error bars indicate standard error (SEM). [Diagram 5] Kaplan-Meier graph showing survival of mice in various groups in the BLM model (tumor size cutoff >500 mm3) as described in Example 6. [Figure 6] Phase 2 study design, including dose escalation and expansion. [Figure 7] 1Q3W dosing regimen design: Medication given once every 3 weeks. [Figure 8] 3Q4W dosing regimen design: weekly dosing for 3 weeks followed by 1 week of no treatment. [Figure 9] Lesion snapshot of subject 403. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Detailed Description definition In a first aspect, the present invention provides an antibody that binds to human AXL or an antibody-drug conjugate (ADC) comprising an antibody that binds to human AXL as defined in any aspect or embodiment herein for use in treating cancer in a subject. In particular, the antibody or ADC is for use in treating cancer where previous treatments have been ineffective.

[0013] The term "AXL" or "Axl" as used herein refers to a protein named AXL, also known as UFO or JTK11, an 894 amino acid protein with a molecular weight of 104-140 kDa that is part of the subfamily of mammalian TAM receptor tyrosine kinases (RTKs). The molecular weight is variable due to possible differences in glycosylation of the protein. The AXL protein consists of two extracellular immunoglobulin-like (Ig-like) domains on the N-terminus of the protein, two membrane-proximal extracellular fibronectin type III (FNIII) domains, a transmembrane domain, and an intracellular kinase domain. AXL is activated upon binding of its ligand Gas6 by ligand-independent homophilic interactions between AXL extracellular domains, by autophosphorylation in the presence of reactive oxygen species (Korshunov et al., 2012), or by transactivation through EGFR (Meyer et al., 2013), and is aberrantly expressed in several tumor types. In humans, the AXL protein is encoded by a nucleic acid sequence encoding the amino acid sequence shown in SEQ ID NO:130 (human AXL protein: Swissprot P30530). For the cynomolgus monkey AXL protein, see Genbank accession HB387229.1 (SEQ ID NO:147).

[0014] The term "antibody" as used herein is intended to refer to an immunoglobulin molecule, a fragment of an immunoglobulin molecule, or any derivative thereof, that has the ability to specifically bind to an antigen under typical physiological and / or tumor-specific conditions, with a half-life of a significant period, such as at least about 30 minutes, at least about 45 minutes, at least about 1 hour, at least about 2 hours, at least about 4 hours, at least about 8 hours, at least about 12 hours, about 24 hours or more, about 48 hours or more, about 3, 4, 5, 6, 7 days or more, or any other relevant functionally defined period (a time sufficient to induce, promote, enhance, and / or modulate a physiological response associated with antibody binding to the antigen, and / or a time sufficient for the antibody to be internalized). The binding region (or binding domain, as may be used herein, both have the same meaning) that interacts with the antigen includes the variable regions of both the heavy and light chains of the immunoglobulin molecule. The constant region of antibody (Ab) can mediate the binding of immunoglobulin to host tissues or factors, including various cells of the immune system (such as effector cells) and components of the complement system, such as C1q, the first component in the classical pathway of complement activation.As indicated above, the term antibody used herein includes fragments of antibodies that retain the ability to specifically interact with, e.g., bind to, antigen, unless otherwise stated or clearly denied by the context.It has been shown that the antigen-binding function of antibody can be performed by fragments of full-length antibodies.Examples of binding fragments encompassed within the term "antibody" include: (i) a Fab' or Fab fragment, which is a monovalent fragment consisting of the VL, VH, CL, and CH1 domains, or a monovalent antibody as described in WO 2007 / 059782; (ii) a F(ab')2 fragment, which is a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting essentially of the VH and CH1 domains; (iv) a Fv fragment consisting essentially of the VL and VH domains of a single arm of an antibody; (v) a dAb fragment (Ward et al., 1989), which consists essentially of the VH domain and is also called a domain antibody (Holt et al., 2003); (vi) a camelid or nanobody (Revets et al., 2005), and (vii) an isolated complementarity determining region (CDR). Furthermore, the two domains of the Fv fragment, VL and VH, are encoded by separate genes, but may be connected by a synthetic linker that allows them to be produced using recombinant techniques as a single protein chain in which the VL and VH regions pair to form a monovalent molecule (known as single-chain antibodies or single-chain Fvs (scFvs), see, for example, Bird et al. (1988) and Huston et al. (1988)). Such single-chain antibodies are encompassed within the term antibody unless otherwise stated or clearly indicated by the context. Although such fragments are generally included within the meaning of antibodies, they collectively and each independently are unique features of the present invention and exhibit different biological properties and utilities. These and other useful antibody fragments in the context of the present invention are discussed further herein. The term antibody, unless otherwise specified, should also be understood to include polyclonal antibodies, monoclonal antibodies (mAbs), antibody-like polypeptides, such as chimeric and humanized antibodies, as well as "antibody fragments" or "fragments thereof" (antigen-binding fragments) that retain the ability to specifically bind to an antigen, provided by any known technique, such as enzymatic cleavage, peptide synthesis, and recombinant techniques, and that retain the ability to be conjugated to a toxin.The antibodies generated can possess any isotype.

[0015] The term "inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand" refers broadly to any agent that is an agent capable of inhibiting (e.g., reducing or abolishing) the interaction between the programmed cell death-1 (PD-1) receptor and at least one of its ligands, such as the human programmed cell death-1 (PD-1) receptor. In particular, the term includes such agents that can reduce or abolish any of the responses to activation of the PD-1 receptor, including inhibition of T lymphocyte proliferation, survival and effector functions (cytotoxicity, cytokine release), induction of apoptosis of tumor-specific T cells, promotion of differentiation of CD4+ T cells into Foxp3+ regulatory T cells, and / or resistance of tumor cells to cytotoxic T lymphocyte (CTL) attack.

[0016] The term "inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand" also includes the commonly used term "PD-1 / PD-L1 inhibitor."

[0017] The term "growth arrest specific 6" or "Gas6" as used herein refers to a 721 amino acid protein with a molecular weight of 75-80 kDa that functions as a ligand for the TAM family of receptors, including AXL. Gas6 is composed of an N-terminal region containing multiple gamma-carboxyglutamic acid residues (Gla), which are responsible for specific interactions with negatively charged phospholipid membranes. The Gla domain is not required for binding of Gas6 to AXL, but is required for activation of AXL. Gas6 can also be referred to as a "ligand for AXL."

[0018] As used herein in the context of an antibody and a Gas6 ligand or in the context of two or more antibodies, the terms "compete with" or "cross-compete with" refer to an antibody competing with a ligand or another antibody, respectively, e.g., with a "reference" antibody for binding to an antigen. Example 2 of WO 2016 / 005593 A1 (Genmab) describes an example of a method for testing competition between an anti-AXL antibody and the AXL ligand Gas6. Preferred reference antibodies for cross-competition between two antibodies are those that comprise a binding region comprising the VH and VL regions of an antibody designated herein as 107, 148, 733, 154, 171, 183, 613, 726, 140, 154-M103L, 172, 181, 183-N52Q, 187, 608-01, 610-01, 613-08, 620-06 or 726-M101L, as set forth in Table 2. A particularly preferred reference antibody is the antibody designated 107.

[0019] The term "immunoglobulin" as used herein is intended to refer to a class of structurally related glycoproteins consisting of two pairs of polypeptide chains, one pair of low molecular weight light (L) chains and one pair of heavy (H) chains, all four potentially interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized (see, for example, Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, NY (1989)). Within the structure of an immunoglobulin, two heavy chains are interconnected via disulfide bonds at the so-called "hinge region". Equivalent to a heavy chain, each light chain is typically composed of several regions; a light chain variable region (abbreviated herein as VL region), and a light chain constant region. Furthermore, the VH and VL regions can be further subdivided into regions of hypervariability (or hypervariable regions that may be hypervariable in the sequence and / or shape of structurally defined loops), also referred to as complementarity determining regions (CDRs), interspersed with more conserved regions, referred to as framework regions (FRs). Each VH and VL is typically composed of three CDRs and four FRs, arranged from amino terminus to carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. CDR sequences are defined according to IMGT (see Lefranc et al. (1999) and Brochet et al. (2008)).

[0020] The term "immunoglobulin heavy chain" or "heavy chain of immunoglobulin" as used herein is intended to refer to one of the heavy chains of immunoglobulins. A heavy chain typically consists of a heavy chain variable (abbreviated herein as VH) region and a heavy chain constant region (abbreviated herein as CH) that defines the isotype of an immunoglobulin. A heavy chain constant region typically consists of three domains: CH1, CH2, and CH3.

[0021] The term "immunoglobulin light chain" or "light chain of an immunoglobulin" as used herein is intended to refer to one of the light chains of an immunoglobulin. A light chain typically consists of a light chain variable (abbreviated herein as VL) region and a light chain constant region (abbreviated herein as CL). The light chain constant region typically consists of one domain, CL.

[0022] As used herein, the terms "monoclonal antibody", "monoclonal Ab", "monoclonal antibody composition", "mAb" and the like refer to a preparation of antibody molecules of a single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope. Thus, the term "human monoclonal antibody" refers to an antibody that displays a single binding specificity, with variable and constant regions derived from human germline immunoglobulin sequences. Human monoclonal antibodies can be produced by hybridomas that contain B cells obtained from transgenic or transchromosomal non-human animals, such as transgenic mice with genomes containing human heavy and light chain transgenes, fused to immortalized cells.

[0023] The term "full length antibody" as used herein refers to an antibody (e.g., a parent antibody or a variant antibody) that contains all heavy and light chain constant and variable domains that correspond to those normally found in a wild-type antibody of that isotype.

[0024] As used herein, "isotype" refers to the immunoglobulin class (e.g., IgG1, IgG2, IgG3, IgG4, IgD, IgA, IgE, or IgM) that is encoded by heavy chain constant region genes.

[0025] The term "antigen-binding region" or "binding region" as used herein refers to the region of an antibody capable of binding to an antigen. The antigen may be in solution, attached or bound to a surface, or present, for example, on a cell, bacterium, or virion. The terms "antigen" and "target" may be used interchangeably in the context of the present invention, unless clearly stated otherwise by the context.

[0026] The term "epitope" refers to a protein determinant capable of specific binding to an antibody. Epitopes usually consist of surface groupings of molecules such as amino acids, sugar side chains, or a combination thereof, and usually have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the binding to the former, but not the latter, is lost in the presence of denaturing solvents. Epitopes may include amino acid residues that are directly involved in binding, as well as other amino acid residues that are not directly involved in binding, such as amino acid residues that are effectively blocked or covered by the specific antigen-binding peptide (in other words, the amino acid residues are within the occupied area of ​​the specific antigen-binding peptide).

[0027] As used herein, the term "binding" refers to a binding that is typically greater than about 10, as determined by surface plasmon resonance (SPR) using an antigen as the ligand and a protein as the analyte, for example, on a BIAcore 3000 instrument. -6 M or less, e.g. 10 -7 M or less, e.g., about 10 -8 M or less, e.g., about 10 -9 M or less, about 10 -10 M or less, or about 10 -11 M or lower K DThe binding of an antibody to a predetermined antigen or target with a corresponding binding affinity, which is at least 10-fold lower, e.g., at least 100-fold lower, e.g., at least 1,000-fold lower, e.g., at least 10,000-fold lower, e.g., at least 100,000-fold lower than its affinity for binding to non-specific antigens (e.g., BSA, casein) other than the predetermined antigen or an antigen closely related thereto. K D Binds to the predetermined antigen with a corresponding affinity. A lower amount of affinity depends on the K D of the protein, so when the K D of the protein is very low (i.e., the protein is highly specific), the amount by which the affinity for the antigen is lower than the affinity for non-specific antigens can be at least 10,000-fold. As used herein, the term "K D " (M) refers to the dissociation equilibrium constant of a specific antibody-antigen interaction and is obtained by dividing k d by k a .

[0028] As used herein, the term "k d " (per second -1 ) refers to the dissociation rate constant of a specific antibody-antigen interaction. The said value is also referred to as the k オフ value.

[0029] As used herein, the term "k a " (M -1 × per second -1 ) refers to the association rate constant of a specific antibody-antigen interaction.

[0030] As used herein, the term "K D " (M) refers to the dissociation equilibrium constant of a specific antibody-antigen interaction.

[0031] As used herein, the term "K A " (M -1 ) refers to the association equilibrium constant of a specific antibody-antigen interaction and is obtained by dividing k a by k d .

[0032] The term "internalized" or "internalization" as used herein refers to the biological process in which a molecule, such as AXL-ADC, is enveloped by the cell membrane and drawn into the interior of the cell. It may also be referred to as "endocytosis." Antibody internalization can be assessed, for example, according to the assay described in Example 16 of WO 2016 / 005593 A1.

[0033] As used herein, the term "antibody that binds AXL," "AXL antibody" or "anti-AXL antibody" refers to any antibody that binds to an epitope on the extracellular portion of AXL.

[0034] In the context of the present invention, the term "ADC" refers to an antibody drug conjugate, which in the context of the present invention refers to an anti-AXL antibody coupled to a therapeutic moiety, such as a cytotoxic moiety as described in this application. It can be coupled, for example, to a cysteine ​​using a linker or to another amino acid using other conjugation methods. The moiety can be, for example, a drug or a toxin.

[0035] As used herein, a "therapeutic moiety" refers to a compound that exerts a therapeutic or prophylactic effect when administered to a subject, particularly when delivered as an ADC as described herein. A "cytotoxic" or "cytostatic" moiety is a compound that is detrimental to cells (e.g., kills cells). Some cytotoxic or cytostatic moieties for use in ADCs are hydrophobic, meaning that they have no or only minimal solubility in water, e.g., 1 g / L or less (very soluble), e.g., 0.8 g / L or less, e.g., 0.6 g / L or less, e.g., 0.4 g / L or less, e.g., 0.3 g / L or less, e.g., 0.2 g / L or less, e.g., 0.1 g / L or less (substantially insoluble). Exemplary hydrophobic cytotoxic or cytostatic moieties include, but are not limited to, auristatin and its derivatives, e.g., certain microtubulin inhibitors such as MMAF and MMAE.

[0036] The abbreviation "MMAE" refers to monomethylauristatin E.

[0037] The abbreviation "PAB" refers to self-immolative spacer. TIFF0007681401000001.tif24128

[0038] The abbreviation "MC" refers to the stretcher maleimidocaproyl. TIFF0007681401000002.tif20128

[0039] "Treatment" refers to the administration of an effective amount of a therapeutically active compound described herein to a subject for the purpose of alleviating, ameliorating, inhibiting or eradicating (cure) a symptom or condition in the subject.

[0040] As used herein, the term "subject" refers to a human who is typically administered an antibody that binds AXL or an ADC comprising such an antibody, and a human who may benefit from administration of an antibody that binds AXL or an ADC comprising such an antibody, and includes, for example, a human patient diagnosed with a cancer that may be treated directly or indirectly by killing AXL-expressing cells.

[0041] "Effective amount" or "therapeutically effective amount" refers to an amount effective to achieve a desired therapeutic result at a required dosage for a required period of time. A therapeutically effective amount of AXL-ADC may vary depending on factors such as the individual's medical condition, age, sex, and weight, as well as the ability of the AXL-ADC to elicit a desired response in an individual. A therapeutically effective amount is also an amount in which the toxic or adverse effects of AXL-ADC are outweighed by the therapeutically beneficial effects.

[0042] As used herein, a "resistant" cancer, tumor, etc. refers to a cancer or tumor in a subject where the cancer or tumor is unresponsive to treatment with a therapeutic agent from the start of treatment (referred to herein as "natural resistance"), or where the cancer or tumor initially responds to treatment with a therapeutic agent but becomes unresponsive or hyporesponsive to the therapeutic agent after a period of treatment (referred to herein as "acquired resistance"), resulting in progressive disease. In the case of solid tumors, initial stabilization of disease also constitutes an initial response. Other indicators of resistance include recurrence of cancer despite treatment with a therapeutic agent, increase in tumor burden, newly identified metastases, etc. Whether a tumor or cancer is resistant to a therapeutic agent or has a high tendency to become resistant can be determined by one skilled in the art. For example, the National Comprehensive Cancer Network (NCCN, www.nccn.org) and the European Society for Medical Oncology (ESMO, www.esmo.org / Guidelines) provide guidelines for assessing whether a particular cancer will respond to treatment.

[0043] As used herein, a cancer that is resistant or predicted to become resistant to a therapeutic agent is a cancer that is known to be associated with a high tendency and / or frequency of being resistant or refractory or becoming resistant or refractory to treatment with a therapeutic agent or the class of drugs that the therapeutic agent belongs to.Similarly, a cancer that is predicted to be unable to respond to treatment with a therapeutic agent is a cancer that is known to be associated with a high tendency and / or frequency of being unable to respond to treatment with a therapeutic agent or the class of drugs that the therapeutic agent belongs to.Subjects that are predicted to relapse after treatment with a therapeutic agent are patients with cancer that is known to be associated with a high tendency and / or frequency of relapse after treatment with a therapeutic agent or the class of drugs that the therapeutic agent belongs to.

[0044] The invention also provides, in one embodiment, the use of an antibody comprising a functional variant of the VL region, VH region, or one or more CDRs of an antibody described herein. A functional variant of a VL, VH, or CDR used in the context of an anti-AXL antibody still enables the antibody to retain at least a substantial proportion (at least about 50%, 60%, 70%, 80%, 90%, 95% or more) of the affinity / avidity and / or specificity / selectivity of the parent antibody, and in some cases, such an anti-AXL antibody may be associated with higher affinity, selectivity and / or specificity than the parent antibody.

[0045] Such functional variants typically retain significant sequence identity to the parent antibody. The percent identity between two sequences is a function of the number of identical positions shared by the sequences (i.e., % homology = number of identical positions / total number of positions x 100), taking into account the number of gaps and the length of each gap that need to be introduced for optimal alignment of the two sequences. Comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm, as described in the non-limiting examples below.

[0046] As used herein, the term "isotype" refers to an immunoglobulin class (e.g., IgG1, IgG2, IgG3, IgG4, IgD, IgA, IgE, or IgM, or any allotypes thereof, such as IgG1m(za) and IgG1m(f)) that is encoded by heavy chain constant region genes. Furthermore, each heavy chain isotype can be combined with either a kappa (κ) or lambda (λ) light chain.

[0047] The term "full-length antibody" as used herein refers to an antibody (e.g., parent antibody or variant antibody) that contains all the heavy and light chain constant and variable domains that correspond to those normally found in the wild-type antibody of that isotype. A full-length antibody according to the present invention can be produced by a method that includes (i) cloning the CDR sequence into a suitable vector that contains the complete heavy chain sequence and the complete light chain sequence, and (ii) expressing the complete heavy and light chain sequences in a suitable expression system. It is within the knowledge of a person skilled in the art to produce a full-length antibody when starting from either the CDR sequence or the complete variable region sequence. Thus, a person skilled in the art will know how to generate a full-length antibody according to the present invention.

[0048] The percent identity between two nucleotide sequences can be determined using the GAP program in the GCG software package (available at http: / / www.gcg.com) using a NWSgapdna.CMP matrix and gap weights of 40, 50, 60, 70 or 80, and gap length weights of 1, 2, 3, 4, 5 or 6. The percent identity between two nucleotide or amino acid sequences can also be determined using the algorithm of E. Meyers and W. Miller (Comput. Appl. Biosci 4, 11-17 (1988)) as incorporated into the ALIGN program (version 2.0) using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. Furthermore, the percent identity between two amino acid sequences can be determined using the algorithm of Needleman and Wunsch (J. Mol. Biol. 48, 444-453 (1970)) incorporated into the GAP program of the GCG software package (available at http: / / www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, gap weights of 16, 14, 12, 10, 8, 6 or 4, and gap length weights of 1, 2, 3, 4, 5 or 6.

[0049] The term "amino acid substitution" encompasses substitution with any one of the other 19 naturally occurring amino acids, or with other amino acids, such as non-naturally occurring amino acids. For example, an amino acid can be substituted with another conservative or non-conservative amino acid. Amino acid residues can also be grouped into classes defined by alternative physical and functional properties. Thus, the classes of amino acids can be reflected in one or both of the following lists:

[0050] Conserved classes of amino acid residues: Acidic residues: D and E Basic residues: K, R, and H Hydrophilic uncharged residues: S, T, N, and Q Aliphatic uncharged residues: G, A, V, L, and I Nonpolar uncharged residues: C, M, and P Aromatic residues: F, Y, and W

[0051] Alternative physical and functional classification of amino acid residues: Alcohol group-containing residues: S and T Aliphatic residues: I, L, V and M Cycloalkenyl-related residues: F, H, W and Y Hydrophobic residues: A, C, F, G, H, I, L, M, R, T, V, W and Y Negatively charged residues: D and E Polar residues: C, D, E, H, K, N, Q, R, S and T Positively charged residues: H, K and R Small residues: A, C, D, G, N, P, S, T and V Very small residues: A, G and S Residues involved in turn formation: A, C, D, E, G, H, K, N, Q, R, S, P and T Flexible residues: Q, T, K, S, G, P, D, E and R

[0052] The terms "lyophilized" and "freeze-dried" are used interchangeably herein to refer to a material that is first frozen and then dehydrated by reducing the ambient pressure to sublimate the frozen water in the material.

[0053] The term "buffer" as used herein refers to a pharma- ceutically acceptable buffer. The term "buffer" includes agents that maintain the pH value of a solution, for example, within an acceptable range, including, but not limited to, histidine, citrate, MES, phosphate, TRIS (Tris(hydroxymethyl)aminomethane), carbonate, succinate, glycolate, etc., as described herein. In general, a "buffer" as used herein has a pKa and buffering capacity suitable for a pH range of about 5 to about 7, preferably about 5.5 to 6.5, preferably about 5.8 to 6.2, for example about pH 6 or about pH 6.0.

[0054] The term "bulking agent" includes agents that can provide additional structure to the lyophilized product (e.g., to provide a pharma- ceutically acceptable cake). Commonly used bulking agents include mannitol, glycine, and the like. In addition to providing a pharma- ceutically acceptable cake, bulking agents also typically impart useful properties to the lyophilized composition, such as altering the collapse temperature, providing freeze-thaw protection, further enhancing protein stability over long-term storage, and the like. These agents can also function as tonicity adjusters.

[0055] The term "stabilizer" as used herein includes agents that provide stability to proteins, for example functioning as cryoprotectants during freezing and / or lyoprotectants during the (lyophilization) drying or "dehydration" process. Suitable stabilizers include non-reducing sugars or saccharides and sugar alcohols, such as sucrose, trehalose, mannitol, xylitol, and the like, and amino acids, such as glycine, alanine, and lysine. Stabilizers may also function as bulking agents, tonicity adjusting agents, and / or viscosity enhancing agents.

[0056] As used herein, a "surfactant" is a compound typically used in pharmaceutical formulations to prevent drug adsorption and / or aggregation on surfaces. Additionally, surfactants reduce the surface tension (or interfacial tension) between two liquids or between a liquid and a solid. For example, exemplary surfactants can significantly reduce surface tension when present at very low concentrations (e.g., 5% w / w or less, e.g., 3% w / w or less, e.g., 1% w / w or less). Surfactants are amphiphilic, which means that they are usually composed of both hydrophilic and hydrophobic or lipophilic groups, and thus can form micelles or similar self-assembled structures in aqueous solutions. Known surfactants for pharmaceutical use include glycerol monooleate, benzethonium chloride, docusate sodium, phospholipids, polyethylene alkyl ethers, sodium lauryl sulfate and tricaprylin (anionic surfactants); benzalkonium chloride, cytrimide, cetylpyridinium chloride and phospholipids (cationic surfactants); and alpha tocopherol, glycerol monooleate, myristyl alcohol, phospholipids, poloxamers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbintan fatty acid esters, polyoxyethylene stearate, polyoxyl 15 hydroxystearate, polyoxylglycerides, polysorbates, propylene glycol dilaurate, propylene glycol monolaurate, sorbitan ester sucrose palmitate, sucrose stearate, tricaprylin and TPGS (nonionic and zwitterionic surfactants).

[0057] The "diluent" of interest herein is one that is pharma- ceutically acceptable (safe and non-toxic for administration to humans) and useful for preparing reconstituted formulations. Exemplary diluents are liquid, preferably aqueous, and include sterile water, bacteriostatic water for injection (BWFI), pH buffered solution (e.g., phosphate buffered saline), sterile saline solution, Ringer's solution, or dextrose solution.

[0058] Specific Aspects and Embodiments of the Invention In a first aspect, the present invention provides an antibody that binds to human AXL or an antibody-drug conjugate (ADC) comprising said antibody for use in treating cancer in a subject, wherein - the cancer is resistant or is predicted to be resistant or become resistant to treatment with an inhibitor of the interaction between the Programmed Cell Death-1 (PD-1) receptor and its ligand; - the cancer is unable or is predicted to be unable to respond to treatment with an inhibitor of the interaction between the Programmed Cell Death-1 (PD-1) receptor and its ligand; and / or - the subject has relapsed or is predicted to relapse following treatment with an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand.

[0059] In the context of the present invention, the response to treatment with an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand, as well as whether the cancer is resistant to such treatment or fails to respond to such treatment, and whether the subject relapses after such treatment, can be evaluated by those skilled in the art according to known methods, for example, NCCN or ESMO guidelines. In certain embodiments, the evaluation can be based on the following criteria (RECIST criteria version 1.1):

[0060] (Table 1) Definition of response (RECIST version 1.1) TIFF0007681401000003.tif136158

[0061] The same criteria can be applied when assessing the efficacy of treatment with an antibody or ADC that binds to human AXL according to the present invention.

[0062] The ligand PD-1 may in particular be programmed cell death-ligand 1 (PD-L1) or programmed cell death-ligand 2 (PD-L2).

[0063] The inhibitor may be selected from the group consisting of an antibody, such as a monoclonal antibody, that binds to PD-1, an antibody, such as a monoclonal antibody, that binds to PD-L1, and an antibody, such as a monoclonal antibody, that binds to PD-L2.

[0064] The cancer may be a solid tumor, such as a metastatic solid tumor, such as a metastatic locally advanced tumor.

[0065] The antibody or ADC may be for use in treatment, where the cancer is a tumor selected from the group consisting of melanoma, carcinoma, sarcoma (such as undifferentiated pleomorphic sarcoma, liposarcoma, leiomyosarcoma, synovial sarcoma, Ewing's sarcoma, osteosarcoma or chondrosarcoma), adenoma, glioma, blood tumors, and tumors of lymphatic tissue.

[0066] Further, the antibody or ADC may be for use in treatment, wherein the solid tumor is selected from the group consisting of melanoma, carcinoma (such as squamous cell carcinoma of the head and neck (SCCHN)), sarcoma (such as undifferentiated pleomorphic sarcoma, liposarcoma, leiomyosarcoma, synovial sarcoma, Ewing's sarcoma, osteosarcoma or chondrosarcoma), adenoma, and glioma.

[0067] The solid tumor may in particular be selected from the group consisting of carcinomas, sarcomas (such as undifferentiated pleomorphic sarcoma, liposarcoma, leiomyosarcoma, synovial sarcoma, Ewing's sarcoma, osteosarcoma, gastrointestinal stromal tumor (GIST), rhabdomyosarcoma or chondrosarcoma), adenomas, and gliomas.

[0068] The cancer may be selected from the group consisting of endometrial / cervical cancer, lung cancer (such as small cell lung cancer or non-small cell lung cancer), thyroid cancer, colon cancer, kidney cancer, renal cancer, ovarian cancer, breast cancer (such as estrogen receptor alpha negative cancer, estrogen receptor alpha positive cancer or triple negative breast cancer; i.e. breast cancer that tests estrogen receptor negative (ER-), progesterone receptor negative (PR-) and human epidermal growth factor receptor 2 negative (HER2-)), esophageal cancer, skin cancer, melanoma (such as malignant melanoma), pancreatic cancer (such as unresectable advanced or metastatic pancreatic cancer), gastrointestinal stromal tumor (GIST), and hematological cancer (such as leukemia; e.g. acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia or chronic myeloid leukemia).

[0069] In particular, the cancer may be a metastatic solid tumor other than melanoma.

[0070] The antibody or ADC for use according to the present invention may be for use when the subject shows progressive disease during or after the last pretreatment with an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand. In this case, the skilled artisan may also assess whether the subject shows progressive disease according to known methods; for example, according to the NCCN or ESMO guidelines. The assessment may be based in particular on the RECIST criteria as set forth in Table 1 above.

[0071] The antibodies or ADCs may be used, in particular, to treat subjects in which resistance to, failure to respond to, or relapse from treatment with an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand is associated with increased expression of AXL.

[0072] In the context of the present invention, inhibitors of the interaction between the programmed cell death-1 (PD-1) receptor and its ligands are Opdivo / Nivolumab (Bristol-Myers Squibb), Keytruda / Pembrolizumab (Merck & Co), Amp-514 / MEDI0680 (Amplimmune), BGB-A317 (BeiGene), REGN2810 (Regeneron), TSR-042 (Tesaro / AnaptysBio), CBT-501 / genolimzumab (Genor Bio / CBT Pharma), PF-06801591 (Pfizer), JS-001 (Shanghai Junshi Bio), SHR-1210 / INCSHR-1210 (Incyte corp), PDR001 (Novartis), BCD-100 (BioCad), AGEN2034 (Agenus), IBI-308 Innovent Biologics), and BI-754091 (Boehringer Ingelheim).

[0073] Further, according to the present invention, inhibitors of the interaction between the programmed cell death-1 (PD-1) receptor and its ligands are Tecentriq / RG7446; MPDL-3280A, Atezolizumab (Roche), Imfinzi / MEDI-4736 / Durvalumab (AstraZeneca), Bavencio / MSB-0010718C / Avelumab (Merck Serono / Pfizer), KN-035- (3DMed / Alphamab Co), CX-072 (CytomX), LY-3300054 (Eli Lilly), MSB0011359C * / M-7824 (Merck KGaA), FAZ053 (Novartis), SHR-1316 (Atridia), and CA-170 (Aurigene / Curis).

[0074] An antibody or ADC that binds to human AXL may be provided to a subject as a monotherapy.

[0075] Alternatively, an antibody or ADC that binds to human AXL may be provided to a subject as part of a combination therapy.

[0076] The ADCs used in accordance with the invention may comprise a therapeutic moiety, which is a cytotoxic agent, a chemotherapeutic agent, or a radioisotope, which may be linked to the antibody, optionally by a linker.

[0077] In the ADCs used in accordance with the invention, the therapeutic moiety may be a cytotoxic agent, which may optionally be linked to the ADC by a linker.

[0078] The cytotoxic agent may be linked to the antibody that binds human AXL by a cleavable linker such as N-succinimidyl 4-(2-pyridyldithio)-pentanoate (SSP), maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-vc-PAB) or AV-1 K-lock valine-citrulline.

[0079] In particular, the cytotoxic agent may be linked to the antibody that binds to human AXL by a non-cleavable linker, such as succinimidyl-4(N-maleimidomethyl)cyclohexane-1-carboxylate (MCC) or maleimidocaproyl (MC).

[0080] Preferably, the linker has the formula -MC-vc-PAB-, where a) The MC is: TIFF0007681401000004.tif20128b) vc is the dipeptide valine-citrulline, and c) The PAB is: TIFF0007681401000005.tif18128.

[0081] Cytotoxic agents include DNA targeting agents, such as DNA alkylating agents and crosslinking agents, e.g., calicheamicin, duocarmycin, racheromycin (CC-1065), pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) and indolinobenzodiazepines (IGNs); microtubule targeting agents, such as duostatins, e.g., duostatin-3, auristatins, auristatin peptide analogs, e.g., monomethylauristatin E (MMAE) and monomethylauristatin F (MMAF), dolastatins, maytansine, N(2')-deacetyl-N(2')-(3-mercapto-1-oxopropyl)-maytansine (DM1), and tubulysins, paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, maytansanoids, tubulysins; and nucleoside analogs; or an analogue, derivative or prodrug thereof.

[0082] The cytotoxic agent monomethylauristatin E (MMAE) may be attached to the antibody via a valine-citrulline (VC) linker and a maleimidocaproyl (MC) linker, where the combination of the cytotoxic agent and linker has the chemical structure: TIFF0007681401000006.tif37137 where MAb is an antibody.

[0083] In certain embodiments, the linker is attached to MMAE (vcMMAE), where vcMMAE is: TIFF0007681401000007.tif30157, where p represents a number from 1 to 8, S represents a sulfhydryl residue of an antibody, and Ab represents an antibody or antigen-binding fragment. In particular, p can be 1, 2, 3, 4, 5, 6, 7 or 8. Preferably, p is 4.

[0084] The average value of p in a population of antibody-drug conjugates may in particular be about 1, such as 1; about 2, such as 2; about 3, such as 3; about 4, such as 4; about 5, such as 5; about 6, such as 6; about 7, such as 7 or about 8, such as 8. Preferably, the average value of p in a population of antibody-drug conjugates is about 4, such as 4.

[0085] In particular, the cytotoxic agent may be monomethylauristatin F (MMAF); TIFF0007681401000008.tif22128 Here, the antibody is linked to MMAF at the left nitrogen (N) position of the above chemical structure by a suitable linker.

[0086] In one embodiment, the cytotoxic agent monomethylauristatin F (MMAF) is linked to the antibody via a maleimidocaproyl (mc)-linker, wherein the combination of the cytotoxic agent and linker has the following chemical structure: TIFF0007681401000009.tif30128 where MAb is an antibody.

[0087] In an ADC for use according to the invention, (a) the linker is cleavable and the cytotoxic agent has bystander killing capability; (b) the linker is cleavable and the cytotoxic agent does not have bystander killing capability; (c) the linker is non-cleavable and the cytotoxic agent has bystander killing capability; or (d) the linker is non-cleavable and the cytotoxic agent does not have bystander killing capability; It may be an ADC.

[0088] In the context of the present invention, the term "bystander killing ability" may be used interchangeably with "bystander killing effect", "bystander killing", or "bystander cytotoxicity". This term refers to the effect that a cytotoxic agent conjugated to an antibody by either a cleavable or non-cleavable linker has the ability to diffuse across the cell membrane after release from the antibody, thereby causing the killing of adjacent cells. When a cytotoxic agent is conjugated by a cleavable or non-cleavable linker, it can be either the cytotoxic agent alone or the cytotoxic agent with a portion of the linker that has bystander killing ability. The ability to diffuse across the cell membrane is related to the hydrophobicity of the cytotoxic agent or the combination of the cytotoxic agent and the linker. Such a cytotoxic agent may be advantageously a membrane-permeable toxin, such as MMAE released from the antibody by a protease. In particular, in tumors with heterogeneous target expression and solid tumors where antibody penetration may be limited, a bystander killing effect may be desirable.

[0089] A cytotoxic agent that does not have "bystander killing capability" does not have the ability to diffuse across the cell membrane after release from the antibody. Thus, such a cytotoxic agent or combination of a cytotoxic agent and a linker will not be able to kill adjacent cells upon release from the antibody. Without being bound by theory, such a combination of a cytotoxic agent and either a cleavable or non-cleavable linker is believed to kill only cells that express the target to which the antibody binds.

[0090] Specifically, the linker may be mc-vc-PAB and the cytotoxic agent may be MMAE.

[0091] Alternatively, the linker may be SSP and the cytotoxic agent may be DM1.

[0092] The cytotoxic agent may specifically be duostatin-3.

[0093] With respect to antibodies or ADCs for use as disclosed herein, it is preferred that an antibody that binds to human AXL does not compete with growth arrest specific 6 (Gas6) for binding to human AXL.

[0094] Furthermore, it is preferred that the maximum antibody binding to human AXL in the presence of Gas6 is at least 90%, such as at least 95%, such as at least 97%, such as at least 99%, such as 100% of the binding in the absence of Gas6 as determined by a competition assay, wherein the competition between the binding of the antibody to human AXL and Gas6 is determined in A431 cells pre-incubated with and without Gas6.

[0095] In the antibodies or ADCs for use provided in the present application, the antibody that binds to human AXL is particularly an antibody having a binding affinity of 0.3×10 to human AXL. -9 From 63×10 -9 Binding affinities (K D ), optionally wherein the binding affinity is measured using Bio-layer Interferometry using a soluble AXL extracellular domain.

[0096] The antibody binding to human AXL was 9.7 × 10 -5 From 4.4 × 10 -3 s -1 and optionally wherein the off-rate is measured by Bio-layer Interferometry using a soluble recombinant AXL extracellular domain.

[0097] With respect to the antibodies or ADCs for use provided in the present application, the amino acid sequence of human AXL may be as set forth in SEQ ID NO:130.

[0098] The antibody or ADC for use provided in the application may be an antibody or ADC that binds to cynomolgus AXL designated in SEQ ID NO:147.

[0099] The antibody or ADC for use provided in the present application may be an antibody or ADC in which the antibody that binds to human AXL comprises at least one binding region comprising a VH region and a VL region selected from the group consisting of: (a) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 36, 37 and 38, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 39, GAS and 40, respectively; (b) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 46, 47 and 48, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 49, AAS and 50, respectively; (c) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 114, 115 and 116, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 117, 118 and 119, respectively

[0733] ; (d) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 51, 52 and 53, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 55, 56 and 57, respectively; (e) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 51, 52 and 54, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 55, GAS and 56, respectively [154-M103L]; (f) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 57, 58 and 59, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 60, 61 and 62, respectively; (g) A VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 62, 63, and 64 respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 65, GAS, and 66 respectively

[0172] ; (h) A VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 67, 68, and 69 respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 70, GAS, and 71 respectively

[0181] ; (i) A VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 72, 73, and 75 respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 76, ATS, and 77 respectively

[0183] ; (j) A VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 72, 74, and 75 respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 76, ATS, and 77 respectively [183-N52Q]; (k) A VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 78, 79, and 80 respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 81, AAS, and 82 respectively

[0187] ; (l) A VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 83, 84, and 85 respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 86, GAS, and 87 respectively [608-01]; (m) A VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 88, 89, and 90 respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID No: 91, GAS, and 92 respectively [610-01]; (n) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos. 93, 94 and 95, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos. 96, 97 and 97, respectively

[0613] ; (o) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 98, 99 and 100, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 101, 102 and 103, respectively [613-08]; (p) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 103, 104 and 105, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 106, GAS and 107, respectively [620-06]; (q) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 108, 109 and 110, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 112, AAS and 113, respectively

[0726] ; (r) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 108, 109 and 111, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 112, AAS and 113, respectively [726-M101L]; (s) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 41, 42 and 43, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 44, AAS and 45, respectively; (t) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 93, 94 and 95, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 128, XAS, in which X is D or G, and 129, respectively [613 / 613-08]; (u) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 46, 119 and 120, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 49, AAS and 50, respectively [148 / 140]; (v) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 123, 124 and 125, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 60, GAS and 61, respectively [171 / 172 / 181]; and (w) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 121, 109 and 122, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 112, AAS and 113, respectively [726 / 187]; and (x) a VH region containing the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 93, 126 and 127, respectively, and a VL region containing the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 96, GAS and 97, respectively [613 / 608-01 / 610-01 / 620-06].

[0100] In particular, the antibody or ADC for use provided herein may be an antibody or ADC in which the antibody that binds to human AXL comprises at least one binding region that includes: (a) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 36, 37 and 38, respectively; and (b) A VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 39, 40 and 41, respectively

[0107] .

[0101] Similarly, the antibody or ADC for use provided in the present application may be an antibody or ADC in which the antibody that binds to human AXL comprises at least one binding region comprising a VH region and a VL region selected from the group consisting of: (a) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 1, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 2; (b) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 5, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 6; (c) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 34, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 35. (d) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 7, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 9; (e) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 10, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 11; (f) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 16, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 18; (g) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 25, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 26

[0613] ; (h) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 31, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 33

[0726] ; (i) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 3, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 4; (j) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 8 and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 9 [154-M103L]; (k) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 12, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 13; (l) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 14, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 15; (m) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 17, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 18 [183-N52Q]; (n) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 19, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 20; (o) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 21 and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 22 [608-01]; (p) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 23 and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 24 [610-01]; (q) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 27 and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 28 [613-08]; (r) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 29, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 30 [620-06]; and (s) a VH region at least 90%, such as at least 95%, such as at least 97%, for example at least 99% identical to SEQ ID No: 32, and a VL region at least 90%, such as at least 95%, for example at least 97%, for example at least 99% identical to SEQ ID No: 33 [726-M101L].

[0102] Furthermore, the antibody or ADC for use disclosed in the present application may be an antibody or ADC in which at least one binding region of the antibody comprises a VH region and a VL region selected from the group consisting of: (a) a VH region comprising SEQ ID No: 1 and a VL region comprising SEQ ID No: 2

[0107] ; (b) a VH region comprising SEQ ID No: 5 and a VL region comprising SEQ ID No: 6; (c) a VH region containing SEQ ID No: 34 and a VL region containing SEQ ID No: 35

[0733] (d) a VH region comprising SEQ ID No: 7 and a VL region comprising SEQ ID No: 9

[0154] ; (e) a VH region comprising SEQ ID No: 10 and a VL region comprising SEQ ID No: 11

[0171] ; (f) a VH region comprising SEQ ID No: 16 and a VL region comprising SEQ ID No: 18; (g) a VH region comprising SEQ ID No: 25 and a VL region comprising SEQ ID No: 26

[0613] ; (h) a VH region comprising SEQ ID No: 31 and a VL region comprising SEQ ID No: 33

[0726] ; (i) a VH region comprising SEQ ID No: 3 and a VL region comprising SEQ ID No: 4; (j) a VH region comprising SEQ ID No: 8 and a VL region comprising SEQ ID No: 9[154-M103L]; (k) a VH region comprising SEQ ID No: 12 and a VL region comprising SEQ ID No: 13; (l) a VH region comprising SEQ ID No: 14 and a VL region comprising SEQ ID No: 15

[0181] ; (m) a VH region comprising SEQ ID No: 17 and a VL region comprising SEQ ID No: 18[183-N52Q]; (n) a VH region comprising SEQ ID No: 19 and a VL region comprising SEQ ID No: 20

[0187] ; (o) a VH region comprising SEQ ID No: 21 and a VL region comprising SEQ ID No: 22 [608-01]; (p) a VH region comprising SEQ ID No: 23 and a VL region comprising SEQ ID No: 24 [610-01]; (q) a VH region comprising SEQ ID No: 27 and a VL region comprising SEQ ID No: 28 [613-08]; (r) a VH region comprising SEQ ID No: 29 and a VL region comprising SEQ ID No: 30 [620-06]; and (s) a VH region comprising SEQ ID No: 32 and a VL region comprising SEQ ID No: 33[726-M101L].

[0103] In the antibodies or ADCs for use provided in the present application, at least one binding region of the antibody that binds to human AXL may, in particular, comprise a VH region comprising SEQ ID No: 1 and a VL region comprising SEQ ID No: 2

[0107] .

[0104] In the antibodies or ADCs for use provided in the present application, the antibodies that bind to human AXL may comprise at least one binding region comprising a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 36, 37 and 38, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID Nos: 39, GAS and 40, respectively

[0107] .

[0105] In the antibody or ADC for use provided in the present application, the antibody may bind to an epitope on AXL that is recognized by any of the antibodies defined above, in particular an antibody having a VH region defined above.

[0106] In the antibodies or ADCs for use provided in the present application, the antibody that binds to human AXL may in particular bind to an epitope within the Ig1 or Ig1-like domain of AXL, which epitope includes or requires one or more amino acids corresponding to positions L121 to Q129 or T112 to Q124 of human AXL.

[0107] In the antibodies or ADCs for use provided in the present application, the antibody that binds to human AXL may bind to an epitope within the Ig2 or Ig2-like domain of AXL, which epitope includes or requires an amino acid corresponding to position D170 or a combination of D179 and one or more amino acids corresponding to positions T182 to R190 of human AXL.

[0108] In the antibodies or ADCs for use provided in the application, the antibody may bind to an epitope within the FN1 domain or FN-like domain of human AXL, which epitope includes or requires one or more amino acids corresponding to positions Q272 to A287 and G297 to P301 of human AXL.

[0109] In the antibodies or ADCs for use provided in the application, the antibody that binds to human AXL may bind to an epitope within the FN2 domain of human AXL, which epitope includes or requires one or more amino acids corresponding to positions A359, R386 and positions Q436 to K439 of human AXL.

[0110] With respect to an antibody or ADC for use as provided herein, the ACD may be one that is capable of inducing tumor regression in a SKMel-147 human xenograft mouse model and / or a BLM melanoma xenograft model.

[0111] The SKMel-147 human xenograft mouse model and / or the BLM melanoma xenograft model are preferably resistant to anti-PD-1 treatment, such as treatment with an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand.

[0112] The SKMel-147 human xenograft mouse model can be generated as described in Example 5 herein, or essentially as described in Example 5 herein.

[0113] The BLM melanoma xenograft model can be generated as described in Example 6 herein, or essentially as described in Example 6 herein.

[0114] In the antibodies or ADCs for use provided in the present application, the antibody that binds to human AXL may comprise a heavy chain of an isotype selected from the group consisting of IgG1, IgG2, IgG3 and IgG4.

[0115] In the antibodies or ADCs for use provided in the present application, the isotype of the antibody that binds to human AXL may in particular be IgG1, such as human IgG1, optionally of the allotype IgG1m(f).

[0116] In the antibodies or ADCs for use provided in the present application, the antibody that binds to human AXL can be a monoclonal antibody or an antigen-binding fragment thereof, such as a full-length monoclonal antibody, for example a full-length monoclonal IgG1,κ antibody.

[0117] The antibody is preferably a humanized or human antibody.

[0118] In a currently preferred embodiment, the antibody is enapotamab.

[0119] In an equally preferred embodiment, the ADC is enapotamab vedotin.

[0120] In the antibodies or ADCs for use provided in the present application, the antibody that binds to human AXL may be an effector function-deficient antibody, a stabilized IgG4 antibody or a monovalent antibody.

[0121] In the antibodies or ADCs for use provided in the present application, the heavy chain of the antibody that binds to human AXL may be modified such that the entire hinge region is deleted.

[0122] In the antibodies or ADCs for use provided in the present application, the sequence of the antibody that binds to human AXL may be modified so that it does not contain any acceptor sites for N-linked glycosylation.

[0123] In the antibodies or ADCs for use provided in the present application, the antibody that binds to human AXL may be a single chain antibody.

[0124] In the antibodies or ADCs for use provided in the present application, the antibody that binds to human AXL may be a bispecific antibody comprising a first binding region of an antibody described in any one of the preceding claims and a second binding region that binds to a target or epitope different from the first binding region.

[0125] In the antibodies or ADCs for use provided in the present application, the bispecific antibody that binds to human AXL can comprise a first and a second heavy chain, each comprising at least a hinge region, a CH2 and a CH3 region, wherein in the first heavy chain, at least one amino acid at a position corresponding to a position selected from the group consisting of K409, T366, L368, K370, D399, F405 and Y407 in a human IgG1 heavy chain is substituted, and in the second heavy chain, at least one amino acid at a position corresponding to a position selected from the group consisting of F405, T366, L368, K370, D399, Y407 and K409 in a human IgG1 heavy chain is substituted, and wherein the substitutions in the first and second heavy chains are not at the same positions.

[0126] In the antibodies or ADCs for use provided in the application, the amino acid at the position corresponding to K409 in a human IgG1 heavy chain may be R in the first heavy chain and the amino acid at the position corresponding to F405 in a human IgG1 heavy chain may be L in the second heavy chain, or vice versa.

[0127] The antibody or ADC for the above uses may be in a pharmaceutical formulation, such as a formulation that includes one or more pharma- ceutically acceptable excipients, carriers, stabilizers, fillers, surfactants and / or diluents.

[0128] The antibodies or ADCs for the above uses may particularly be in a lyophilized formulation.

[0129] The lyophilized formulation can be or may be obtained by lyophilizing an aqueous formulation comprising the antibody or ADC and one or more excipients, where the aqueous formulation does not contain any surfactant.

[0130] Lyophilized formulations are particularly useful for the preparation of antibodies or ADCs, as well as a. a buffer providing a pH of about 5 to about 7 in the aqueous formulation; b. at least one filler; and c. at least one non-reducing sugar that forms an amorphous phase with the antibody or ADC in the solid state; It may be obtained or obtainable by lyophilizing an aqueous formulation comprising

[0131] The aqueous formulation may be free of any surfactants.

[0132] The aqueous formulation may comprise a buffer selected from the group consisting of histidine, citrate, 2-(N-morpholino)ethanesulfonic acid (MES), succinate, glycolate, carbonate and phosphate, or any combination thereof, wherein the pH of the aqueous formulation is in the range of about 5 to about 7, e.g., in the range of 5 to 7.

[0133] The aqueous formulation may in particular include a histidine buffer.

[0134] The aqueous formulation may comprise a buffer at a concentration of about 5 mM to about 100 mM, such as a buffer at a concentration of 5 mM to 100 mM, such as a buffer at about 10 mM to about 50 mM, such as a buffer at 10 mM to 50 mM, such as a buffer at about 20 mM to about 40 mM, such as a buffer at 20 mM to 40 mM, such as a buffer at about 28 mM to about 32 mM, such as a buffer at 28 mM to 32 mM, such as a buffer at about 30 mM, such as a buffer at 30 mM.

[0135] The lyophilized formulation may include a bulking agent selected from mannitol, glycine, and combinations thereof.

[0136] The lyophilized formulation may specifically include mannitol.

[0137] The aqueous formulation may comprise the bulking agent in a concentration of about 1% (w / v) to about 5% (w / v), such as 1% (w / v) to 5% (w / v), for example about 2% (w / v) to about 4% (w / v), such as 2% (w / v) to 4% (w / v), for example about 2.5% (w / v) to about 3.5% (w / v), such as 2.5% (w / v) to 3.5% (w / v), for example about 3% (w / v), for example 3% (w / v).

[0138] The aqueous formulation may comprise a bulking agent concentration of about 50 mM to about 300 mM, such as 50 mM to 300 mM, for example about 100 mM to about 225 mM, such as 100 mM to 225 mM, for example about 150 mM to about 180 mM, such as 150 mM to 180 mM, for example about 165 mM, for example 165 mM.

[0139] The lyophilized formulation may include a non-reducing sugar selected from sucrose, trehalose, and combinations thereof.

[0140] The lyophilized formulation may in particular include sucrose.

[0141] The aqueous formulation may contain non-reducing sugars at a concentration of about 0.5% (w / v) to about 7% (w / v), such as 0.5% (w / v) to 7% (w / v), such as about 0.5% (w / v) to about 4% (w / v), such as 0.5% (w / v) to 4% (w / v), such as about 1% (w / v) to about 3% (w / v), such as 1% (w / v) to 3% (w / v), or about 2.5% to about 3.5%, or 2.5% to 3.5%, such as about 3% (w / v), such as 3% (w / v).

[0142] The aqueous formulation may comprise a non-reducing sugar at a concentration of about 15 mM to about 200 mM, such as 15 mM to 200 mM, for example about 30 mM to about 150 mM, such as 30 mM to 150 mM, for example about 80 mM to about 100 mM, such as 80 mM to 100 mM, for example about 70 to about 90 mM, such as 70 to 90 mM, for example about 84 mM to about 92 mM sucrose, for example 84 mM to 92 mM sucrose, for example about 88 mM, for example 88 mM sucrose.

[0143] The lyophilized formulation may be one obtained or obtainable by lyophilizing an aqueous formulation wherein the antibody or ADC concentration in the aqueous formulation is from about 5 mg / mL to about 30 mg / mL, 5 mg / mL to 30 mg / mL, such as from about 7 mg / mL to about 20 mg / mL, for example from 7 mg / mL to 20 mg / mL, such as from about 8 mg / mL to about 15 mg / mL, for example from 8 mg / mL to 15 mg / mL, such as from about 9 mg / mL to about 11 mg / mL, for example from 9 mg / mL to 11 mg / mL, such as about 10 mg / mL, for example 10 mg / mL.

[0144] The lyophilized formulation may be obtained or obtainable by lyophilizing an aqueous formulation having a pH in the range of about 5.5 to 6.5, such as in the range of about 5.5 to 6.5, such as about 6, such as 6.

[0145] The lyophilized formulation is obtained or obtainable by lyophilizing an aqueous formulation having a pH of about 5 to about 7, for example a pH of 5 to 7; and a. about 5 mg / mL to about 30 mg / mL, e.g., 5 mg / mL to 30 mg / mL of an antibody or ADC; b. about 10 mM to about 50 mM histidine, e.g., 10 mM to 50 mM histidine; c. about 30 mM to about 150 mM sucrose or trehalose, e.g., 30 mM to 150 mM sucrose or trehalose; and d. about 150 mM to about 180 mM mannitol or glycine, e.g., 150 mM to 180 mM mannitol or glycine The formulation may include:

[0146] The aqueous formulation has a pH in the range of about 5.5 to about 6.5, for example in the range of 5.5 to 6.5; and a. about 9 mg / mL to about 11 mg / mL of an antibody or ADC, such as about 9 mg / mL to 11 mg / mL of an antibody or ADC, such as about 10 mg / mL of an antibody or ADC, such as a 10 mg / mL antibody or ADC; b. about 20 mM to about 40 mM histidine, e.g., 20 mM to 40 mM histidine, e.g., about 30 mM histidine, e.g., 30 mM histidine; c. about 80 mM to about 100 mM sucrose, e.g., 80 mM to 100 mM sucrose, e.g., about 88 mM sucrose, e.g., 88 mM sucrose; and d. about 150 mM to about 180 mM mannitol, for example 150 mM to 180 mM mannitol, for example about 165 mM mannitol, for example 165 mM mannitol Including, It may be an aqueous formulation that does not contain any surfactants.

[0147] The antibody or ADC in the lyophilized formulation is preferably stable for pharmaceutical use at 2-8°C, e.g. at 5°C, for at least 6 months, such as at least 9 months, for example at least 15 months, preferably at least 18 months, or even more preferably at least 24 months, or most preferably at least 36 months.

[0148] A lyophilized formulation may be considered stable if it has less than 10% aggregates, such as less than 5.0% aggregates, such as less than 3.0% aggregates, such as less than 2.0% aggregates when stored at 5° C. for at least 6 months, such as at least 9 months, such as at least 15 months, preferably at least 18 months, or even more preferably at least 24 months, or most preferably at least 36 months.

[0149] Stability is preferably determined by size exclusion analysis, cIEF, or both.

[0150] Preferably, the lyophilized formulation contains less than 3.0% moisture, such as less than 2.0% moisture, such as less than 1% moisture, or less than 0.5% moisture.

[0151] The lyophilized formulation may be a formulation that does not contain any inorganic salts.

[0152] The pharmaceutical formulation may be obtained or may be obtainable by reconstituting a lyophilized formulation as defined above in a sterile aqueous diluent.

[0153] The pharmaceutical formulation has a pH of about 5 to about 7, for example a pH of about 5 to about 7, and in aqueous solution has: a. about 5 mg / mL to about 30 mg / mL of an antibody or ADC, e.g., 5 mg / mL to 30 mg / mL of an antibody or ADC; b. about 10 mM to about 50 mM histidine, e.g., 10 mM to 50 mM histidine; c. about 30 mM to about 150 mM sucrose or trehalose, e.g., 30 mM to 150 mM sucrose or trehalose; and d. about 50 mM to about 300 mM mannitol or glycine, e.g., 50 mM to 300 mM mannitol or glycine The formulation may include

[0154] The pharmaceutical formulation has a pH in the range of about 5.5 to about 6.5, for example in the range of 5.5 to 6.5; and a. about 9 mg / mL to about 11 mg / mL of an antibody or ADC, such as about 9 mg / mL to 11 mg / mL of an antibody or ADC, such as about 10 mg / mL of an antibody or ADC, such as a 10 mg / mL antibody or ADC; b. about 20 mM to about 40 mM histidine, e.g., 20 mM to 40 mM histidine, e.g., about 30 mM histidine, e.g., 30 mM histidine; c. about 80 mM to about 100 mM sucrose, e.g., 80 mM to 100 mM sucrose, e.g., about 88 mM sucrose, e.g., 88 mM sucrose; and d. about 150 mM to about 180 mM mannitol, for example 150 mM to 180 mM, for example about 165 mM, for example 165 mM mannitol Including, It may be an aqueous formulation that does not contain any surfactants.

[0155] The antibody or ADC for the above uses may be in an aqueous formulation containing one or more pharma- ceutically acceptable excipients, where the aqueous formulation does not contain any surfactants.

[0156] The antibody or ADC for the above uses may be in an aqueous formulation comprising a buffer and at least one stabilizer, wherein the pH of the aqueous formulation is from about 5 to about 7, for example, from 5 to 7, and wherein the aqueous formulation does not contain any surfactant.

[0157] The antibody or ADC for the above uses may be in an aqueous formulation comprising a buffer selected from the group consisting of histidine, citrate, MES, phosphate, carbonate, succinate, glycolate, or any combination thereof, wherein the pH of the aqueous formulation is in the range of about 5 to about 7, for example 5 to 7.

[0158] The antibody or ADC for the above uses may be in an aqueous formulation, particularly one that includes a histidine buffer.

[0159] The antibody or ADC for the above uses may be in an aqueous formulation comprising a buffer at a concentration of about 10 mM to about 50 mM, such as 10 mM to 50 mM, such as a buffer of about 20 mM to about 40 mM, such as a buffer of 20 mM to 40 mM, such as a buffer of about 28 mM to about 34 mM, such as 28 mM to 34 mM, such as a buffer of about 29 mM to about 31 mM, such as 29 mM to 31 mM, such as about 30 mM, such as a buffer of 30 mM.

[0160] The antibody or ADC for the above uses may be in an aqueous formulation comprising a stabilizer selected from the group consisting of mannitol, sucrose and trehalose.

[0161] The antibody or ADC for the above uses may be in an aqueous formulation that includes the stabilizer being mannitol.

[0162] The antibody or ADC for the above uses may be in an aqueous formulation comprising a stabilizer at a concentration of about 20 mM to about 200 mM, such as 20 mM to 200 mM, for example about 30 mM to about 100 mM, such as 30 mM to 100 mM, for example about 40 mM to about 80 mM, such as 40 mM to 80 mM, for example about 50 mM to about 60 mM, such as 50 mM to 60 mM, for example about 55 mM, for example 55 mM.

[0163] The antibody or ADC for the above uses may be in an aqueous formulation comprising a stabilizer selected from sucrose, trehalose, and combinations thereof.

[0164] The antibody or ADC for the above uses may be in an aqueous formulation that does not include one or more of arginine, glycine, glutamic acid, sorbitol, trehalose, sucrose, and sodium chloride.

[0165] The antibody or ADC for the above uses may be in an aqueous formulation having an antibody or ADC concentration of about 5 mg / mL to about 40 mg / mL, such as 5 mg / mL to 40 mg / mL, for example about 8 mg / mL to about 35 mg / mL, such as 8 mg / mL to 35 mg / mL, for example about 10 mg / mL to about 30 mg / mL, such as 10 mg / mL to 30 mg / mL, for example about 15 mg / mL to about 25 mg / mL, such as 15 mg / mL to 25 mg / mL, for example about 20 mg / mL, such as 20 mg / mL.

[0166] The antibodies or ADCs for use provided in the application may be in an aqueous formulation, where the pH of the aqueous formulation is within the range of about 5.5 to 6.5, such as about 5.5 to 6.5, for example about 6, for example 6.

[0167] The antibody or ADC for the above uses may be in an aqueous formulation, the aqueous formulation having a pH of about 5 to about 7, and a. about 5 mg / mL to about 40 mg / mL of an antibody or ADC, for example, 5 mg / mL to 40 mg / mL of an antibody or ADC, and b. about 10 mM to about 50 mM histidine, 10 mM to 50 mM histidine; c. about 50 mM to about 300 mM mannitol, e.g., 50 mM to 300 mM mannitol Includes.

[0168] The antibody or ADC for the uses provided above may be in an aqueous formulation, the aqueous formulation having a pH within the range of about 5.5 to about 6.5, for example within the range of 5.5 to 6.5; a. about 15 mg / mL to about 25 mg / mL of an antibody or ADC, 15 mg / mL to 25 mg / mL of an antibody or ADC, for example, about 20 mg / mL of an antibody or ADC, for example, 20 mg / mL of an antibody or ADC; b. about 20 mM to about 40 mM histidine, 20 mM to 40 mM histidine, for example, about 30 mM histidine; c. about 50 mM to about 60 mM mannitol, 50 mM to 60 mM mannitol, for example about 55 mM, for example 55 mM mannitol and does not contain any added surfactants, amino acid excipients, NaCl, or any combination thereof.

[0169] The antibody or ADC for use provided in the present application may be in a frozen aqueous formulation, which is obtained or may be obtainable by freezing an aqueous formulation as defined herein above.

[0170] The antibody or ADC for the above uses may be administered in a therapeutically effective amount and frequency, e.g. - in at least one cycle involving administration once every three weeks, such as on day 1 of a 21-day cycle; or - At least one cycle containing 3 consecutive weeks of weekly dosing followed by a 1-week rest period without ADC administration, such that each cycle time, including the rest period, is 28 days, such as days 1, 8, and 15 of a 28-day cycle It can be administered to a subject.

[0171] As used herein, the term "resting period" should be understood as a period during which an antibody or ADC is administered at a dose substantially lower than that administered the previous week, or during which no antibody or ADC is administered at all, e.g., no antibody or ADC is administered at all. In a preferred embodiment of any aspect or embodiment herein, an antibody or ADC is not administered during the resting period, in which case the resting period may alternatively be referred to as an "off period". A resting period or off period of one week may also be referred to as a "rest week" or an "off week", respectively.

[0172] As provided for the uses defined herein, the dose of the antibody or ADC in a 21 day cycle is in particular between 0.6 mg / kg and 4.0 mg / kg body weight of the subject, such as between 0.6 mg / kg and 3.2 mg / kg body weight of the subject, such as a dose of about 0.6 mg / kg, such as a dose of 0.6 mg / kg, or a dose of about 0.8 mg / kg, such as a dose of 0.8 mg / kg, or a dose of about 1.0 mg / kg, such as a dose of 1.0 mg / kg, or a dose of about 1.2 mg / kg, such as a dose of 1.2 mg / kg, or a dose of about 1.4 mg / kg, such as a dose of 1.4 mg / kg, or a dose of about 1.6 mg / kg, such as a dose of 1.6 mg / kg, or a dose of about 1.8 mg / kg, such as a dose of 1.8 mg / kg, or a dose of about 2.0 mg / kg, such as a dose of 2.0 mg / kg, or a dose of about 2.2 mg / kg, such as a dose of 2.2 mg / kg. The dose may be about 2.4 mg / kg, for example a 2.4 mg / kg dose, or about 2.6 mg / kg, for example a 2.6 mg / kg dose, or about 2.8 mg / kg, for example a 2.8 mg / kg dose, or about 3.0 mg / kg, for example a 3.0 mg / kg dose, or about 3.2 mg / kg, for example a 3.2 mg / kg dose.

[0173] As provided for use as defined in the present application, the dose of the antibody or ADC in a 28 day cycle may be from 0.45 mg / kg to 2.0 mg / kg body weight of the subject, such as from 0.45 mg / kg to 2.0 mg / kg body weight of the subject, such as a dose of about 0.45 mg / kg, such as a dose of 0.45 mg / kg, or a dose of about 0.5 mg / kg, such as a dose of 0.5 mg / kg, or a dose of about 0.6 mg / kg, such as a dose of 0.6 mg / kg, or a dose of about 0.7 mg / kg, such as a dose of 0.7 mg / kg, or a dose of about 0.8 mg / kg, such as a dose of 0.8 mg / kg, or a dose of about 0.9 mg / kg, such as a dose of 0.9 mg / kg, or a dose of about 1.0 mg / kg, such as a dose of 1.0 mg / kg, or a dose of about 1.1 mg / kg, such as a dose of 1.1 mg / kg, or a dose of about 1.2 mg / kg, such as a dose of 1.2 The dose may be about 1.3 mg / kg, for example a 1.3 mg / kg dose, or about 1.4 mg / kg, for example a 1.4 mg / kg dose, or about 1.5 mg / kg, for example a 1.5 mg / kg dose, or about 1.6 mg / kg, for example a 1.6 mg / kg dose, or about 1.7 mg / kg, for example a 1.7 mg / kg dose, or about 1.8 mg / kg, for example a 1.8 mg / kg dose, or about 1.9 mg / kg, for example a 1.9 mg / kg dose, or about 2.0 mg / kg, for example a 2.0 mg / kg dose.

[0174] With respect to use of an antibody or ADC provided herein, the number of 21 day cycles or the number of 28 day cycles is preferably 2 to 48, such as 2 to 36, for example 2 to 24, for example 2 to 15, for example 2 to 12, such as 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, 10 cycles, 11 cycles or 12 cycles.

[0175] An antibody or ADC for the above uses may be administered for at least four 28 day treatment cycles, wherein the antibody or ADC in each treatment cycle is administered once weekly for three consecutive weeks at a dose of about 0.45 mg / kg body weight, such as a dose of 0.45 mg / kg body weight, about 0.6 mg / kg body weight, about 0.6 mg / kg body weight, about 0.8 mg / kg body weight, such as a dose of 0.8 mg / kg body weight, about 1.0 mg / kg body weight, such as a dose of 1.0 mg / kg body weight, about 1.2 mg / kg body weight, such as a dose of 1.2 mg / kg body weight, about 1.4 mg / kg body weight, such as a dose of 1.4 mg / kg body weight, about 1.6 mg / kg body weight, such as a dose of 1.6 mg / kg body weight, about 1.8 mg / kg body weight, such as a dose of 1.8 mg / kg body weight, or about 2.0 mg / kg body weight, such as a dose of 2.0 mg / kg body weight. The antibody or ADC will be administered at a dose of 100 mg / kg body weight followed by a rest week without administration of the antibody or ADC.

[0176] The conjugate may be administered to a subject at a dose of about 2.0 to about 2.4 mg / kg body weight, e.g., 2.0 to 2.4 mg / kg body weight, once every three weeks, or at a weekly dose of about 0.6 to about 1.4 mg / kg body weight, e.g., 0.6 to 1.4 mg / kg body weight, for three weeks, optionally followed by one week of no treatment.

[0177] The conjugate may be administered to a subject at a dose of about 2.2 mg / kg body weight, e.g., 2.2 mg / kg body weight, once every three weeks, or at about 1.0 mg / kg body weight, e.g., 1.0 mg / kg body weight, administered weekly for three weeks, optionally followed by one week of no treatment.

[0178] The conjugate may be administered to the subject in a weekly dosage of about 0.4 to about 1.0 mg / kg body weight, for example, in a weekly dosage of 0.4 to 1.0 mg / kg body weight.

[0179] The conjugate may be administered to the subject in a weekly dosage of about 0.6 to about 1.0 mg / kg body weight, for example, in a weekly dosage of 0.6 to 1.0 mg / kg body weight.

[0180] The conjugate may be administered to a subject by a weekly dosage of about 0.4 to about 0.8 mg / kg body weight, for example, by a weekly dosage of 0.4 to 0.8 mg / kg body weight.

[0181] The conjugate may be administered to a subject by a weekly dosage of about 0.5 to about 0.7 mg / kg body weight, for example, by a weekly dosage of 0.5 to 0.7 mg / kg body weight.

[0182] The conjugate may be administered to the subject by a weekly dosage of about 0.6 mg / kg body weight, for example by a weekly dosage of 0.6 mg / kg body weight.

[0183] The route of administration may in particular be intravenous.

[0184] The treatment may be continued at least until the subject experiences a progression-free survival of at least about 1 month, such as at least 1 month; at least about 2 months, such as at least 2 months; at least about 3 months, such as at least 3 months; at least about 4 months, such as at least 4 months; at least about 5 months, such as at least 5 months; at least about 6 months, such as at least 6 months; at least about 7 months, such as at least 7 months; at least about 8 months, such as at least 8 months; at least about 9 months, such as at least 9 months; at least about 10 months, such as at least 10 months; at least about 11 months, such as at least 11 months; at least about 12 months, such as at least 12 months; at least about 18 months, such as at least 18 months; at least about 2 years, such as at least 2 years; at least about 3 years, such as at least 3 years; at least about 4 years, such as at least 4 years; or at least about 5 years, such as at least 5 years.

[0185] Treatment may be continued until disease progression or unacceptable toxicity.

[0186] In a second aspect, the invention provides an antibody that binds to human AXL or an antibody-drug conjugate (ADC) comprising an antibody that binds to human AXL for use in the manufacture of a medicament for treating cancer in a subject, wherein - the cancer is resistant to, or predicted to be resistant to, or predicted to become resistant to treatment with an inhibitor of the interaction between programmed cell death-1 (PD-1) receptor and its ligand; - the cancer has been unable to respond, or is predicted to be unable to respond, to treatment with an inhibitor of the interaction between programmed cell death-1 (PD-1) receptor and its ligand; and / or - the subject has relapsed, or is predicted to relapse, after treatment with an inhibitor of the interaction between programmed cell death-1 (PD-1) receptor and its ligand.

[0187] It should be understood that the above disclosure of features relating to the first aspect of the invention also applies to the second aspect of the invention.

[0188] In particular, - the ligand is as defined above; - the inhibitor of the interaction between programmed cell death-1 (PD-1) receptor and its ligand is as defined above; - the cancer is as defined above; - the subject is as defined above; - the antibody or ADC is as defined above; - the formulation is as defined above; and / or - the amount and frequency at which the antibody or ADC is administered to the subject are as defined above An antibody or ADC for use in the manufacture of a medicament.

[0189] A third aspect of the invention provides a method of treating cancer in a subject, wherein the cancer is - is resistant or is predicted to be resistant or is predicted to become resistant to treatment with an inhibitor of the interaction between the Programmed Cell Death-1 (PD-1) receptor and its ligand; - has failed or is predicted to fail to respond to treatment with an inhibitor of the interaction between the Programmed Cell Death-1 (PD-1) receptor and its ligand; and / or - has relapsed or is predicted to relapse following treatment with an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand. The method includes administering to the subject a therapeutically effective amount of an antibody that binds to human AXL or an antibody-drug conjugate (ADC) comprising an antibody that binds to human AXL.

[0190] In particular, the method of treating cancer according to the third aspect of the invention comprises: - the ligand is as defined above; - an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand as defined above; - the cancer is as defined above; - the subject is as defined above; - the antibody or ADC is as defined above; - the formulation is as defined above; and / or - the amount and frequency at which the antibody or ADC is administered to the subject is as defined above This is the method.

[0191] array (Table 2) TIFF0007681401000010.tif235165TIFF0007681401000011.tif235165TIFF0007681401000012.tif234165TIFF000 7681401000013.tif237165TIFF0007681401000014.tif231165TIFF0007681401000015.tif229165TIFF00076814010 00016.tif237165TIFF0007681401000017.tif235165TIFF0007681401000018.tif234165TIFF0007681401000019.t if234165TIFF0007681401000020.tif234165TIFF0007681401000021.tif235165TIFF0007681401000022.tif195165

[0192] This invention is further illustrated by the following examples which should not be construed as further limiting the scope of the disclosure. EXAMPLES

[0193] Example 1 - Axl expression in tumor tissue from patients who were resistant to or who relapsed from PD-1 or PD-L1 targeted therapy immunohistochemistry AXL expression will be assessed in freshly resected paraffin-embedded and formalin-fixed (FFPE) tumor tissues from patients with solid tumors, including esophageal, non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), bladder, prostate, ovarian / fallopian tube, cervical, endometrial, melanoma, colorectal cancer (CRC), pancreatic, renal cell carcinoma (RCC), small cell lung cancer (SCLC), liver, gastrointestinal, breast, glioblastoma, mesothelioma Merkel cell carcinoma, and sarcoma, that were resistant or refractory to, or relapsed from, PD-1 or PD-L1 targeted therapy. Staining is performed manually in Sequenza Slide Racks (Ted Pella Inc., Redding, CA, USA; Cat. No. 36105) or on a Ventana BenchMark Ultra (IHC Autostainer) using anti-human Axl rabbit polyclonal antibody H-124 (Santa Cruz, Dallas, TX, USA).

[0194] Prior to staining, FFPE tissue slides are deparaffinized in 100% xylene (Sigma-Aldrich, Cat. No. 16446; 3 times, 5 min) at room temperature and dehydrated in 96% ethanol (Sigma Aldrich, Cat. No. 32294; 2 times, 5 min). Antigen retrieval is then performed. IHC slides are incubated in citrate buffer (pH 6; DAKO; Cat. No. S2369) for 5 min and then in citrate / phosphate buffer (0.43 M citric acid, 0.35 M NaCl) for 15 min at RT. 2 HPO 4 .2H 2HO; pH 5.8). Slides are incubated in 10% normal human serum in PBS (CLB / Sanquin, Cat. No. K1146) prior to incubation with primary antibodies. Axl expression is determined by incubation with rabbit polyclonal anti-human Axl antibody H-124 in PBS supplemented with 2% normal human serum for 60 min at RT. Slides are washed in PBS supplemented with 0.1% Tween-20 (2 times, 3 min) and binding of rabbit antibody specific for Axl is detected with undiluted Bright Vision poly-HRP anti-rabbit IgG. HRP is visualized with 3-amino-9-ethylcarbazole (AEC) chromophore (red; Sigma, Cat. No. A6926-100TAB); nuclei were counterstained with hematoxylin (DAKO, Cat. No. S3309). Slides are analyzed by a board-certified pathologist who scores the intensity and localization of Axl staining for each sample.

[0195] Example 2 - Antitumor activity of mouse cross-reactive AXL-ADCs in an Axl-expressing syngeneic mouse tumor model Axl antibody YW327.6S2 (Ye et al., 2010 (b)), which cross-reacts with mouse Axl, is conjugated to vcMMAE by previously described methods (WO 2016 / 005593). The in vivo anti-tumor activity of this mouse cross-reactive AXL-ADC is determined in a B16-F10 syngeneic mouse tumor model after pretreatment with PD1 or PD-L1 blocking antibodies. B16-F10 cells (ATCC, Cat. No. CRL-6475) are transfected with full-length mouse Axl, and B16-F10-AXL cells stably expressing Axl are selected and expanded.

[0196] 1 × 10 5 Tumor induction is performed by subcutaneous injection of 100 B16-F10 wild-type or B16-F10-AXL cells. The average tumor size is 100–200 mm. 3Treatment is initiated when tumor growth exceeds 100% and clear tumor growth is observed. Mice are given intraperitoneal injections of 5 mg / kg anti-mouse PD-1 (Bio X Cell, West Lebanon, NH; clone RMP1-14; catalog no. BP0146) or 5 mg / kg anti-mouse PD-L1 (Bio X Cell; clone 10F.9G2; catalog no. BP0101) twice weekly (every 3-4 days) until progression of tumor growth is observed. Mice are then given either a single dose or a total of four doses over two weeks (every 3-4 days) intravenously or intraperitoneally of mouse cross-reactive AXL-ADC (4 and 8 mg / kg), control ADC (IgG1-b12-MMAE, 8 mg / kg) or control antibody (unconjugated IgG1-b12, 8 mg / kg) as indicated. Tumor volumes are determined at least twice weekly. Tumor volumes (mm 3 ) from the caliper (PLEXX) measurement to 0.52 x (length) x (width) 2 Calculate as follows.

[0197] Example 3 - Antibody Production The AXL-specific antibody IgG1-AXL-107 (WO 2016 / 005593) and the isotype control antibody IgG1-b12 (Barbas, CF. J Mol Biol. 1993 Apr 5;230(3):812-23) were expressed as IgG1,κ. Plasmid DNA mixtures encoding the heavy and light chains of the antibodies were transiently transfected into Expi293F cells (Life technologies, USA) using 293fectin (Life technologies) essentially as described by Vink et al. (Vink et al., Methods, 65 (1), 5-10 2014). The antibodies were purified by immobilized protein G chromatography. Protein batches were analyzed by several bioanalytical assays including SDS-PAGE, size exclusion chromatography and measurement of endotoxin levels. Purified antibodies were conjugated with maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl-monomethylauristatin E (vcMMAE), which contains a protease-cleavable valine-citrulline dipeptide as described (Doronina, SO et al. (2003) Nat. Biotechnol. 21, 778-784). The average drug-antibody ratio was 4:1. The anti-PD1 antibody pembrolizumab (KEYTRUDA®, MSD) was obtained commercially from SelleckChem (catalog number: A2005).

[0198] Example 4 - Isolation and generation of human MART-1-specific CD8 T cells MART-1 (1D3) T cell receptor (TCR) retrovirus was produced in a packaging cell line as previously described (Jorritsma et al. (2007) Blood; 110, 3564-3572). Peripheral blood mononuclear cells were isolated from healthy donor buffy coats (Sanquin, Amsterdam, the Netherlands) by density gradient centrifugation using Lymphoprep (Stem Cell Technologies). CD8+ T cells were purified using CD8 Dynabeads (Thermo Fisher Scientific) and 2 × 10 per well. 6 100 T cells were activated for 48 h on non-tissue culture treated 24-well plates pre-coated overnight with αCD3 and αCD28 antibodies (eBioscience, 16-0037-85 and 16-0289-85, respectively). Activated CD8 T cells were collected, mixed with TCR retrovirus (MART-1 T cells) or mock retrovirus (control T cells), and spin-fected at 2000×g for 2 h on RetroNectin-coated (Takara, 25 μg per well) non-tissue culture treated 24-well plates. After 24 hours, T cells were harvested and maintained in RPMI (Gibco) containing 10% human serum (One Lamda), 100 units / mL penicillin, 100 μg / mL streptomycin, 100 units / mL IL-2 (Proleukin, Novartis), 10 ng / mL IL-7 (ImmunoTools) and 10 ng / mL IL-15 (ImmunoTools).

[0199] Example 5 - Antitumor activity of IgG1-AXL-107-vcMMAE in a murine SkMel-147 melanoma xenograft model resistant to anti-PD-1 treatment The antitumor activity of IgG1-AXL-107-vcMMAE (HuMax®-AXL-ADC) versus anti-PD-1 (pembrolizumab) was evaluated in the SkMel-147 human melanoma xenograft model in mice treated with systemic administration of human T cells engineered to express a melanoma-specific T cell receptor (TCR) against MART-1. Prior to inoculation of mice with SkMel-147 cells, the cells were transduced with the antigen (MART-1) and the correct HLA haplotype (HLA-A2) so that MART-1-specific T cells would recognize tumor cells.

[0200] Cell lines and cell culture conditions The melanoma cell line SkMel-147 was cultured under standard conditions in DMEM (Gibco) with fetal bovine serum (Sigma), 100 U / mL penicillin (Gibco), and 0.1 mg / mL streptomycin (Gibco) and was routinely confirmed to be free of mycoplasma by PCR.

[0201] HLA-A2 and MART-1 transduction in SkMel-147 Lentiviral and retroviral constructs were used to introduce MART-126-35 and HLA-A2. Lentiviral constructs were packaged into lentiviruses using two helper plasmids (psPax and MS2G, Addgene) in HEK293T cells. Retroviral constructs were produced in a packaging cell line (fly cells). Viral supernatants were either flash frozen or used immediately for infection. MART-126-35-Katushka and HLA-A2-GFP double positive cells were sorted by flow cytometry and seeded at one cell per well in 96-well plates. Once single cells were expanded, expression of HLA-A2 and MART-Katushka was confirmed by FACS.

[0202] SkMel-147 xenograft model and treatments Male and female 8 - 14 week - old NOD - SCID gamma (NSG) mice (housed in - house at the Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands) were subcutaneously injected with 1×10 6 cells of SkMel - 147 tumor cells into the right flank. Tumors were measured three times a week with calipers, and when the tumors reached 50 mm 3 (9 days later), the animals were randomized across the following treatment groups: 1. Control T cells + control ADC (n = 9) 2. MART - 1 T cells + control ADC (n = 10) 3. Control T cells + IgG1 - AXL - 107 - vcMMAE (n = 10) 4. MART - 1 T cells + IgG1 - AXL - 107 - vcMMAE (n = 10) 5. MART - 1 T cells + control ADC + anti - PD1 (n = 9)

[0203] On day 9, mice were intravenously injected with a single dose (2 mg / kg) of IgG1 - AXL - 107 - vcMMAE or control ADC (IgG1 - b12 - vcMMAE). At the same time, mice were intravenously injected with MART - 1 or control T cells at a dose of 5×10 6 cells / mouse. The total volume injected was diluted to 200 μL per mouse in PBS. To support the T cells, all mice received an intraperitoneal (i.p.) injection of 100,000 IU IL - 2 (Proleukin, Novartis; diluted in 100 μL PBS) for 3 consecutive days.

[0204] One selected group (group 5) received anti - PD1 (pembrolizumab, SelleckChem) at a dose of 5 mg / kg via i.p. injection weekly starting from day 9.

[0205] Tumor volume was blindly measured three times a week by an independent animal technician. Tumor volume was calculated as follows: length (mm)×width (mm) / 2. 1000 mm 3Tumors were harvested at the time point.

[0206] Sequential treatment with SkMel-147 For selected groups (control T cells + control ADC, MART-1 T cells + control ADC, MART+1 T cells + control ADC + anti-PD1), subsets of mice were treated sequentially with IgG1-AXL-107-vcMMAE. Approximately 650 mm 3 Mice were selected for sequential treatment based on similar tumor volumes in the 100-mL mice. IgG1-AXL-107-vcMMAE was injected intravenously weekly at a dose of 4 mg / kg.

[0207] result The antitumor efficacy of IgG1-AXL-107-vcMMAE vs anti-PD1 (pembrolizumab) in the SKMel-147 human xenograft mouse model was evaluated in the context of tumor-specific human T cell responses. Therefore, the human melanoma cell line SkMel-147 expressing AXL was first transduced with both the antigen (MART-1) and the correct HLA haplotype (HLA-A2) for tumor-specific T cells to recognize tumor cells. Mice were then inoculated with these cells, and after the establishment of xenografts, mice were randomized into different treatment groups (see above) and injected with a single dose of ADC and T cells, while one selected group received additional weekly injections of anti-PD-1.

[0208] Mice receiving tumor antigen-specific T cells (MART-1 T cells) in combination with a control ADC showed no differential effect on tumor growth compared to mice receiving control non-specific T cells (control T cells) in combination with a control ADC (Figure 1). Furthermore, no tumor control was observed in mice receiving anti-PD1 treatment in combination with antigen-specific T cells (MART-1 T cells) and a control ADC, indicating that this model is resistant to PD-1 / PDL-1 axis inhibition (Figure 1). In comparison, treatment with IgG1-AXL-107-vcMMAE induced tumor regression after a single dose of 2 mg / kg. This effect was observed in mice receiving control T cells and was further enhanced in the case of MART-1 T cells. IgG1-AXL-107-vcMMAE treatment in the context of MART-1 T cells also extended the lifespan of these mice compared to all other groups, as shown by the survival curves (Figure 2).

[0209] Next, the average tumor size was approximately 650 mm 3 At that time, approximately half of the mice in groups 1 (control T cells + control ADC), 2 (MART-1 T cells + control ADC), and 5 (MART+1 T cells + control ADC + anti-PD1) were sequentially treated with IgG1-AXL-107-vcMMAE at a dose of 4 mg / kg intravenously every week. Whereas tumors that did not receive additional treatment quickly reached maximum tumor volume, IgG1-AXL-107-vcMMAE-treated mice showed robust tumor regression, with tumor volumes reaching 900 mm in 2 weeks. 3 100 mm from front to back 3 (Figure 3).

[0210] This indicates that IgG1-AXL-107-vcMMAE induces antitumor and survival benefits in the SkMel-147 human melanoma model, which is resistant to PD-1 pathway inhibition in the context of tumor-specific T cells. PD-1 blockade in the presence of tumor-specific T cells did not affect tumor growth and survival in this model, whereas IgG1-AXL-107-vcMMAE demonstrated potent antitumor and survival effects in the presence of tumor-specific T cells. These results also indicate that sequential treatment with IgG1-AXL-107-vcMMAE may provide benefit as a single agent in anti-PD-1 resistant tumors in the presence of tumor-specific T cells, indicating that IgG1-AXL-107-vcMMAE may be effective in tumors that have progressed with PD-1 inhibitor treatment.

[0211] Example 6 - Antitumor activity of IgG1-AXL-107-vcMMAE in a BLM melanoma xenograft model resistant to anti-PD-1 treatment The antitumor activity of IgG1-AXL-107-vcMMAE versus anti-PD1 (pembrolizumab) was evaluated in a BLM human melanoma xenograft model in mice treated with systemic administration of human T cells engineered to express a melanoma-specific T cell receptor (TCR) against MART-1. Prior to inoculation of mice with BLM cells, the cells were transduced with the antigen (MART-1) and the correct HLA haplotype (HLA-A2) for MART-1-specific T cells to recognize tumor cells.

[0212] Cell lines and cell culture conditions The melanoma cell line BLM was cultured under standard conditions in DMEM (Gibco) with fetal bovine serum (Sigma), 100 U / mL penicillin (Gibco), and 0.1 mg / mL streptomycin (Gibco) and was routinely confirmed to be free of mycoplasma by PCR.

[0213] HLA-A2 and MART-1 transduction in BLM Lentiviral and retroviral constructs were used to introduce MART-126-35 and HLA-A2. Lentiviral constructs were packaged into lentiviruses using two helper plasmids (psPax and MS2G, Addgene) in HEK293T cells. Retroviral constructs were produced in a packaging cell line (fly cells). Viral supernatants were either flash frozen or used immediately for infection. MART-126-35-Katushka positive cells were sorted by flow cytometry and seeded at one cell per well in 96-well plates. Once single cells were expanded, expression of MART-Katushka and HLA-A2 was confirmed by FACS.

[0214] BLM xenograft model and treatments 1 × 10 cells were injected into the right flank of 8- to 14-week-old male and female NOD-SCID gamma (NSG) mice (housed in-house at the Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands). 6 BLM tumor cells were injected subcutaneously. Tumors were measured three times a week with a caliper and tumors were 100 mm 3 Upon reaching age 65 (7 days), animals were randomized across the following treatment groups: 1. Control T cells + control ADC (n=7) 2. MART-1 T cells + control ADC (n=8) 3. Control T cells + IgG1-AXL-107-vcMMAE (n=8) 4. MART-1 T cells + IgG1-AXL-107-vcMMAE (n=8) 5. MART-1 T cells + control ADC + anti-PD1 (n=10)

[0215] On day 7, mice were intravenously injected with a single dose (4 mg / kg) of IgG1-AXL-107-vcMMAE or control ADC (IgG1-b12-vcMMAE). 6MART-1 or control T cells were injected intravenously at a dose of 10 cells / mouse. The total volume injected was diluted in PBS to 200 μL per mouse. To support the T cells, all mice received intraperitoneal (ip) injections of 100.000 IU IL-2 (Proleukin, Novartis; diluted in 100 μL PBS) for three consecutive days.

[0216] One selected group (Group 5) received anti-PD1 (Pembrolizumab, SelleckChem) at a dose of 5 mg / kg weekly via ip injection from day 7 onwards.

[0217] Tumor volumes were measured three times a week by an independent animal technician in a blinded manner. Tumor volume was calculated as follows: length (mm) x width (mm) / 2. 1000 mm 3 Tumors were harvested at the time point.

[0218] result The antitumor efficacy of IgG1-AXL-107-vcMMAE vs anti-PD1 (pembrolizumab) in the BLM human xenograft mouse model was evaluated in the context of tumor-specific human T cell responses. Therefore, the human melanoma cell line BLM was first transduced with the antigen (MART-1) and the correct HLA haplotype (HLA-A2) for tumor-specific T cells to recognize tumor cells. Mice were then inoculated with these cells, and after the establishment of xenografts, mice were randomized into different treatment groups (see above) and injected with a single dose of ADC and T cells, while one selected group received additional weekly injections of anti-PD-1.

[0219] Mice receiving antigen-specific T cells (MART-1 T cells) in combination with a control ADC showed some tumor growth inhibition compared to mice receiving control non-specific T cells (control T cells) in combination with a control ADC (Figure 4). However, no enhanced tumor growth inhibition was observed in mice receiving anti-PD1 treatment in combination with antigen-specific T cells (MART-1 T cells) and a control ADC, indicating that this model is resistant to PD-1 / PDL-1 axis inhibition (Figure 4). In comparison, treatment with IgG1-AXL-107-vcMMAE induced tumor regression after a single dose of 4 mg / kg. This effect was observed in mice receiving control T cells and was further enhanced in the case of MART-1 T cells. In both cases, treatment with IgG1-AXL-107-vcMMAE resulted in a greater anti-tumor effect compared to tumor-specific T cells alone or in combination with anti-PD1. IgG1-AXL-107-vcMMAE treatment in the context of MART-1 T cells also extended the lifespan of these mice compared to all other groups, as shown by the survival curves (Figure 5).

[0220] These results demonstrate that IgG1-AXL-107-vcMMAE treatment is effective in the BLM human melanoma model, which is resistant to anti-PD1 treatment in the presence of tumor-specific T cells. Although blocking PD-1 in the presence of tumor-specific T cells had no effect on tumor growth and survival, IgG1-AXL-107-vcMMAE conferred strong tumor reduction and survival benefit, consistent with efficacy in tumors resistant to PD-1 / PDL-1 axis blockade.

[0221] Example 7 - A First-in-Human, Open-Label, Dose-Escalation Study with Expansion Cohort to Evaluate the Safety of an Axl-Specific Antibody-Drug Conjugate (HuMax®-AXL-ADC; Enapotamab Vedotin) in Patients with Solid Tumors This was an open-label, multicenter, Phase I / IIa safety study of the HuMax AXL ADC in a mixed population of patients with solid tumors documented to overexpress Axl and receiving systemic tubulin inhibitors as part of standard of care (SoC). The study consisted of two parts: a dose escalation part (first-in-human (FIH) Phase I study) and an expansion part (Phase IIa study).

[0222] The dose escalation part consisted of two alternating arms to identify the optimal dosing regimen: 1Q3W: Administer once every 3 weeks ●3Q4W: Weekly dosing for 3 weeks, followed by a 1-week treatment-free period.

[0223] The purpose of the expansion part of the study was to obtain further data regarding the safety, tolerability, pharmacokinetics (PK) and antitumor activity of selected doses. The overall study design is shown in Figure 6.

[0224] Inclusion Criteria: Before being allowed to participate in the study, participants were required to meet all of the following inclusion criteria: 1. Dose Escalation Part: Patients with recurrent or refractory ovarian, cervical, endometrial, thyroid, non-small cell lung cancer (NSCLC) or melanoma (cutaneous, mucosal, acral or uveal) who have failed available standard therapies or are not candidates for standard therapies and who, in the opinion of the investigator, may benefit from experimental treatment with HuMax-AXL-ADC. 2. Expansion Part: Patients with recurrent or refractory, advanced and / or metastatic cancer who are not candidates for standard therapies and who, in the opinion of the investigator, may benefit from experimental treatment with HuMax-AXL-ADC.

[0225] Patients with solid tumors, such as non-small cell lung cancer (NSCLC) and melanoma (including cutaneous, acral, and mucosal melanoma), were selected for the expansion cohort. Patients were included according to the following criteria: Patients with progressive disease at or after their most recent procedure - Patients whose last treatment prior to enrollment was a PD-1 / PD-L1 inhibitor

[0226] If the following conditions were present in the expansion cohort, approval for enrollment was required from the sponsor's medical director: • There has been no documented progression in measurable disease (i.e., symptomatic progression).

[0227] Patients were required to have measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. One or more lesions in non-irradiated areas measuring 10 mm or more in longest diameter (LD) (or twice the thickness of the section if the section thickness is not 5 mm). Lymph node lesions with a minimum diameter of 15 mm or more in non-irradiated areas. Patients were allowed to enroll if their target lesion was located within a previously irradiated field and met the following criteria: •Target lesions that have not received irradiation within the past 3 months. ● Target lesions are “within the field” and progression is accepted by the sponsor.

[0228] In the dose-escalation portion, only ovarian cancer patients with CA 125 positivity according to the Gynecologic Cancer Intergroup Guideline (Rustin et al., 2004; Rustin et al., 2011), whose samples were collected within 2 weeks prior to the start of treatment and whose values ​​were ≥2x the upper limit of the reference range, were enrolled.

[0229] Patients were not eligible for CA 125 evaluation if they had received mouse antibodies (unless the assay used had been confirmed to be free of human anti-mouse antibodies) or had undergone medical and / or surgical intervention (e.g., paracentesis) involving the peritoneum or pleura within the previous 28 days.

[0230] In the dose escalation portion, all patients were required to provide tumor tissue specimens (formalin-fixed paraffin-embedded (FFPE) blocks / sections) prepared from archived tissue or fresh biopsy specimens taken before cycle 1 on visit 1 (preferably at the stage of disease progression).

[0231] In the expansion part, all patients were required to provide a mandatory fresh biopsy specimen (FFPE tissue block / section) (no aspirates) containing tumor tissue at screening, taken after the most recent treatment failure / discontinuation (unless documented by the investigator as clinically not feasible). Records of shipment of the fresh FFPE biopsy specimen were required to be submitted to the sponsor as part of the eligibility assessment package before the first dose of enapotamab vedotin. Patients who did not meet the criteria for a fresh tumor biopsy specimen were required to receive approval for enrollment from the sponsor's medical director. Additionally, collection of a recent archived tumor tissue specimen taken before the most recent treatment failure / discontinuation (if available) was required. The age limit was 18 years or older. Acceptable renal function was defined as follows: Glomerular filtration rate (GFR) 40 mL / min / 1.73 m 2 The above is calculated using the Modification of Diet in Renal Disease (MDRD) simplified formula. GFR = 186 × (SCr -1.154 )×(age -0.203 ) (If serum creatinine (SCr) is in mg / dL, multiply this by 0.742 for women and 1.212 for African Americans.) Patients not undergoing dialysis Acceptable liver function was defined as follows: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) should be ≤3x the upper limit of normal (ULN), or ≤5x the ULN if liver tumors / metastases are present. ●Bilirubin was kept below 1.5 times the ULN (excluding patients diagnosed with Gilbert syndrome), and direct bilirubin was kept below 2 times the ULN. The definition of acceptable hematological status was as follows: Hemoglobin level is 5.6 mmol / L (approximately 9 g / dL) or higher Absolute neutrophil count (ANC) 1500 / μL (1.5×109 / L) or higher ●Platelet count 100×109 / L or more Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. More than 3 months left to live. Female patients of childbearing potential / male patients of reproductive potential who agree to use sufficient concentrations of enapotamab vedotin during the study and for 6 months after the final dose. Patients who signed the informed consent form (ICF).

[0232] Exclusion criteria Patients who met any of the following criteria were asked not to participate in the study. blood 1. Unstable acute deep vein thrombosis or clinically significant pulmonary embolism ≥4 weeks prior to the first dose of enapotamab vedotin. 2. Patients with a history of thromboembolic events who are not willing to undergo thromboembolic prophylaxis. cardiovascular 3. Clinically significant cardiac disease included: - Unstable angina occurring within 6 months of signing the ICF. Acute myocardial infarction occurring within 6 months of signing the ICF. Known congestive heart failure (New York Heart Association grade III or IV) and / or reduced ejection fraction less than 45% and / or baseline QT interval corrected by Fridericia's formula (QTcF) greater than 480 msec or poorly controlled atrial fibrillation. • Poorly controlled hypertension, manifested as systolic blood pressure ≥160 mmHg and / or diastolic blood pressure ≥100 mmHg despite optimal medical management. immunity 4. Evidence of current or recent (within 1 year) history of a significant autoimmune disease requiring systemic immunosuppressive therapy that indicates a risk of immune-related adverse events. 5. Patients with a history of immune-related adverse events of grade 3 or higher were excluded (adverse events less than grade 3 were required to be discussed with the sponsor). 6. Patients with persistent pneumonitis at screening or a history of non-infectious pneumonitis requiring steroids. Excluded drugs or dosing regimens 7. Patients received supportive therapy with granulocyte colony-stimulating factor (G-CSF) or granulocyte / macrophage colony-stimulating factor 3 weeks prior to the first dose of enapotamab vedotin. 8. Patients with cumulative corticosteroid doses equivalent to >150 mg prednisone (or equivalent dose of corticosteroid) within 2 weeks prior to the first dose of enapotamab vedotin. 9. Patients have a history of grade 3 or higher allergic reactions to monoclonal antibody therapy and have known or suspected allergy or intolerance to any drug administered during the study period. Surgery / Procedure 10. Major surgery performed within 4 weeks prior to enapotamab vedotin administration. Central nervous system 11. History of cerebral arteriovenous malformation, cerebral aneurysm, brain metastasis, or stroke. Transient ischemic attacks occurring more than 6 months prior to screening were permitted. Patients with known or suspected symptoms of central nervous system metastases were required to undergo computed tomography (CT) or magnetic resonance imaging of the brain and / or spinal cord to document baseline pathology. Spinal cord metastases were acceptable, except for patients with known symptomatic spinal cord compression or those who did not have evidence of clinical stability (SD) for ≥28 days without definitive treatment for spinal cord compression. The expansion cohort allowed enrollment of patients with stable brain metastases (asymptomatic for 14 days prior to starting treatment). Symptomatic brain or leptomeningeal metastases that were poorly controlled for at least 2 weeks prior to the first dose of enapotamab vedotin. ["Good control" required prior treatment for central nervous system (CNS) disease (e.g., radiation or chemotherapy). No new or progressive signs or symptoms related to CNS disease were permitted, and patients were required to be taking less than 10 mg of prednisone (or equivalent) per day or to be on no steroids.] Patients with untreated but asymptomatic brain metastases were permitted to enroll if the investigator deemed no treatment necessary for the metastases. Patients with spinal cord compression were permitted to enroll if they had received definitive treatment for their disease and evidence of clinical stability (SD) for at least 28 days. Pretreatment 12. Anticancer drugs (such as small molecules, immunotherapies, chemotherapy drugs, monoclonal antibodies, or any other investigational agent) administered within 5 half-lives prior to the first dose but for up to 4 weeks. Exceptions were accepted for bisphosphonates, denosumab, and gonadotropin-releasing hormone receptor agonists / antagonists, which were allowed to continue during the study. - No chronic toxic effects of previous chemotherapy, such as fatigue, alopecia, or loss of appetite, of grade 2 or less that were not expected to resolve further, precluded participation in the study. 13. History of administration of conjugated or unconjugated auristatin derivatives / vinca-binding site-targeted payloads (history of treatment with vinca alkaloids was acceptable as meeting inclusion criterion #1). 14. Radiation therapy performed within 14 days prior to the first administration of enapotamab vedotin (radiation therapy for palliative purposes was acceptable). Other cancers / metastases 15. Patients with a history or evidence of malignancy other than the diagnoses included in the inclusion criteria, excluding the following: ● Cervical cancer stage 1B or lower. ● Non-invasive basal cell carcinoma or squamous cell carcinoma of the skin. ● Non-invasive superficial bladder cancer. ● Prostate cancer with a current PSA value of less than 0.1 ng / mL. ● Breast cancer diagnosed in patients with BRCA1- or BRCA2-positive ovarian cancer. ● Cancers with a complete response (CR) duration of more than 2 years and a potential for cure. Others 16. Melanoma patients with LDH 3 times or more the ULN. 17. The following ongoing major uncontrolled medical conditions. ● Severe non-healing wounds, skin ulcers (all grades) or fractures. 18. Presence of grade 2 or higher peripheral neuropathy. 19. Clinically significant active viral, bacterial or fungal infections requiring the following treatments. ● Treatment with intravenous antimicrobial agents less than 2 weeks prior to the first dose, or ● Treatment with oral antimicrobial agents less than 1 week prior to the first dose. ● Prophylactic antimicrobial agents administered without clinical symptoms were acceptable (e.g., prophylactic administration of antibiotics before tooth extraction). 20. Patients with evidence of serum positivity for human immunodeficiency virus. 21. Patients with a history / evidence of serum positivity for hepatitis B (excluding vaccination or immunity from resolved natural infection or passive immunity with immunoglobulin therapy). ●Positive antibody test for hepatitis B core antigen (anti-HBc), and ●Negative antibody test for hepatitis B surface antigen (anti-HBs). 22. Patients with obvious serum positivity for hepatitis C (excluding positivity due to immunoglobulin therapy) 23. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the trial or the evaluation of the trial results 24. History of allogeneic organ transplantation (excluding corneal transplantation), autologous / allogeneic bone marrow transplantation or stem cell rescue within 3 months before the first administration of enapotamab vedotin 25. Less than 40 kg in weight 26. Pregnant or lactating women 27. Patients participating in the trial were not permitted to participate in other trials. Special notes regarding NSCLC 28. Pulmonary hemorrhage or hemoptysis exceeding 2.5 ml within 6 weeks (excluding cases where the cause was addressed and resolved medically). 29. History of acute pneumonia.

[0233] Dose escalation and administration method 1Q3W In dose escalation by 1Q3W, HuMax-AXL-ADC was evaluated mainly at 7 doses (0.3, 0.6, 1.0, 1.5, 2.0, 2.4 and 2.8 mg / kg) and 4 optional intermediate doses (1.25, 1.8, 2.2 and 2.6 mg / kg) when administered. Thereafter, if the MTD was not determined up to 2.8 mg / kg, escalation by 0.4 mg / kg and de-escalation by 0.2 mg / kg were tolerated.

[0234] In dose escalation by 1Q3W, HuMax-AXL-ADC was administered once every 3 weeks as shown in Figure 7.

[0235] 3Q4W Dose-limiting toxicity (DLT) was evaluated in eight or more patients, and safety was determined in the 1.5 mg / kg cohort in the 1Q3W group. The predicted AUC at the starting dose in the 3Q4W group was below the predefined limit, so trials in the 3Q4W group were initiated.

[0236] The 3Q4W dose escalation was performed in a standard 3(+3) design evaluating HuMax-AXL-ADC at doses of (0.45), 0.6, 0.8, 1.0, 1.2, and 1.4 mg / kg. Continuation at higher doses was permitted with up to 20% increments, and escalation above 1.4 mg / kg was deemed safe if no significant safety concerns were identified at the 1.4 mg / kg dose. The anticipated starting dose was 0.6 mg / kg (with an additional 0.45 mg / kg allowed), with an additional caveat that the independent Data Monitoring Committee (DMC) recommended administering intermediate doses at any stage during dose escalation.

[0237] 3Q4W dose escalation consisted of weekly dosing for 3 weeks followed by a 1-week treatment-free period as shown in Figure 8. Treatment continued until disease progression or unacceptable toxicity.

[0238] Basis for setting administration frequency In the dose-escalation part, the first dose-escalation group received HuMax-AXL-ADC 1Q3W dosing and the second dose-escalation group received 3Q4W dosing. The dosing frequency was determined based on toxicokinetic and toxicology data obtained from cynomolgus monkeys, suggesting sufficient recovery of neutrophil, platelet, and red blood cell parameters or an acceptable safety profile. No significant accumulation of HuMax-AXL-ADC or MMAE was expected to occur by the next dosing cycle.

[0239] Preparation of therapeutic agents The doses of HuMax-AXL-ADC were prepared using aseptic techniques by the pharmacy at the study site. HuMax-AXL-ADC was provided to the study site / pharmacy in bulk supply cartons. The study drug was labeled in accordance with the study site's standards and regulations.

[0240] The investigational medicinal product (IMP) was provided in a vial containing 40 mg of HuMax-AXL-ADC as a lyophilized powder, which was dissolved in 4 mL of water for injection to give a 10 mg / mL solution.

[0241] After preparation, HuMax-AXL-ADC was diluted with 100 mL of 0.9% sodium chloride in an infusion bag to obtain the dose assigned to that patient.

[0242] HuMax-AXL-ADC (lyophilized vials) were stored in a refrigerator at 2°C to 8°C.

[0243] Administration was required to be completed within 24 hours after preparation of the HuMax-AXL-ADC vial. A 0.2 μm in-line filter was required for administration. The entire amount (100 mL) of the drug in the prepared infusion bag was required to be administered to avoid any residual drug.

[0244] Administration of therapeutic drugs HuMax-AXL-ADC was administered intravenously. The dose for each patient was calculated based on the patient's weight rounded to the nearest kilogram (i.e., dose in mg / kg assigned to the patient multiplied by body weight in kg). Patients with a body mass index (BMI) of 30 kg / m 2 For patients > 30, the investigator was required to use the weight based on the patient's height that corresponds to the maximum BMI of 30. Body mass index (BMI) 30 kg / m 2 The dose above this was calculated using the following formula: Dose (mg) = x(mg / kg) * 30(kg / m 2) * height (m) * height (m) [x indicates the appropriate dose] HuMax-AXL-ADC was administered over 30 minutes and was required to be completed within 4 hours by flushing the infusion line with saline. In the dose-escalation part, there was an interval of at least 2 nights between the first and second patient in each dose cohort to allow for safety concerns with each new dose.

[0245] Treatment duration: Depending on which dose escalation group the patient was enrolled in, HuMax AXL ADC was administered on either a 1Q3W or 3Q4W schedule. Patients were treated with HuMax-AXL-ADC until disease progression or unacceptable toxicity. Patients were followed for 52 weeks after the end of treatment. In the expansion part of the study, patients received HuMax AXL ADC at the maximum tolerated dose (MTD) as determined by the DMC recommended and confirmed by the sponsor's internal safety committee on either a 1Q3W or 3Q4W schedule.

[0246] Evaluation criteria: Primary endpoint ●Dose-limiting toxicity (DLT) ● Adverse Events (AEs): AEs, serious adverse events (SAEs), infusion-related AEs, grade ≥3 AEs and IMP-related AEs during the study.

[0247] Secondary endpoints • Clinical laboratory parameters for safety evaluation (haematological and biochemical tests). PK parameters [clearance, distribution volume and area under the concentration-time curve (AUC 0-Clast and AUC 0-∞ ), highest concentration (C max ), C max Arrival time (T max ), pre-dose values ​​and half-lives of HuMax-AXL-ADC and the free toxin monomethylauristatin E (MMAE)]. -Immunogenicity (anti-drug antibodies) of HuMax-AXL-ADC. Antitumor activity as measured by tumor shrinkage [based on computed tomography (CT) image assessment] and change in CA 125 in patients with ovarian cancer, and change in prostate-specific antigen (PSA) in patients with castration-resistant prostate cancer (CRPC). ●Objective response rate, progression-free survival (PFS), duration of response (DoR) and overall survival (OS). • Axl expression in tumor biopsies.

[0248] Response Responses were assessed using RECIST version 1.1 for patients with solid tumors and RECIST version 1.1 combined with CA 125 as defined by the Gynecological Cancer Intergroup for patients with ovarian cancer ( Rustin et al., 2011 ).

[0249] Table 5. Definition of response (RECIST version 1.1) TIFF0007681401000023.tif156161

[0250] Response evaluation and outcome reporting In the dose-escalation part, response assessments were performed by the investigator and sponsor. In the expansion part, response assessments were performed by the investigator and sponsor as well as a group of external medical experts. Each patient was classified into one of the following categories: 1) CR, 2) PR, 3) SD, 4) PD, or 5) Not assessable.

[0251] Patients in response categories 1 and 2 were considered responders, whereas patients in response categories 4 and 5 were considered treatment failures (disease progression). Patients in response categories 1, 2, and 3 were considered to be included in disease control.

[0252] Individual patient data listings as well as objective response rate, best overall tumour response (assessed primarily based on confirmed but also unconfirmed responses) and a summary of disease control were required.

[0253] Patients with ovarian cancer were required to be evaluated and reported according to RECIST version 1.1 (Eisenhauer et al., 2009), CA 125, and a combination of these two response criteria according to the Gynecological Cancer Intergroup definition (Rustin et al., 2011).

[0254] For patients with prostate cancer, response assessment and reporting was required based on RECIST version 1.1 (Eisenhauer et al., 2009) and PSA in accordance with the Updated Recommendations from the Prostate Cancer Clinical Trials Working Group 3 (Scher et al., 2016).

[0255] Progression-free survival PFS was defined as the number of days from the first visit of cycle 1 to the first PD or death. Deaths were included in the analysis only if they occurred within 30 days of the most recent progression assessment. If no deaths occurred during this time period, PFS at the time of the most recent progression assessment was required to be examined. PFS was assessed for all patients and plotted and summarized using survival analysis. Distribution functions were estimated using the Kaplan-Meier method and the time period was required to be examined according to Table A: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (2007) in Appendix 3 of the FDA Guidance for Industry.

[0256] Duration of response DoR was defined as the number of days from the first documented objective tumor response (CR or PR) to the first confirmed PD or death. DoR was analyzed using the same statistical methods as PFS.

[0257] overall survival Overall survival (OS) was defined as the number of days from the first visit of cycle 1 to death. OS was analyzed using the same statistical methods as PFS and DoR, except that follow-up was not performed in patients who missed a visit or received new anticancer drug treatment.

[0258] Tumor shrinkage Tumor shrinkage (based on CT imaging assessment) was recorded and summarized by source (radiologist, central reading facility).

[0259] result: Dose escalation RESULTS: The phase I study (1Q3W: n=32, 3Q4W: n=15) enrolled 47 patients with NSCLC (n=8), melanoma (n=9), ovarian (n=22), cervical (n=3), and endometrial cancer (n=5). The majority of patients were female (87%), white (94%), and younger than 65 years (66%). The maximum tolerated dose (MTD) was 2.2 mg / kg in the 1Q3W arm and 1.0 mg / kg in the 3Q4W arm. The phase II recommended dose (RP2D) was 2.2 mg / kg for the 1Q3W dosing regimen. The median elimination half-life of enapotamab vedotin ranged from 0.9 to 2.2 days across all doses / dosing regimens. Six DLTs were observed in the 47 enrolled patients (see table). The most common adverse events (any grade occurring in ≥ 40% of patients) were fatigue (64%), nausea (57%), constipation (57%), diarrhea (47%), vomiting (45%), and decreased appetite (43%). Three patients in the 1Q3W arm had partial responses: one with NSCLC (2.2 mg / kg) and two with ovarian cancer (1.5 and 2.4 mg / kg).

[0260] Conclusion: The RP2D for enapotamab vedotin monotherapy in patients with solid tumors with a treatment history was 2.2 mg / kg 1Q3W. Enhanced preliminary antitumor activity was observed with enapotamab vedotin. TIFF0007681401000024.tif59128

[0261] NSCLC patients, example of subjects: Subject 401 This 71-year-old white female patient was enrolled in the GEN1021 trial and signed the informed consent document at a UK medical institution on April 11, 2018.

[0262] The patient was diagnosed with stage IIIA non-small cell lung adenocarcinoma (ALK gene rearrangement negative) on August 5, 2016.

[0263] The cancer treatment history included cisplatin + vinorelbine administration from August to September 2016. Progression was observed during treatment, and the best response was progressive disease (PD). The patient received cisplatin + pemetrexed from October to November 2016. The best response was partial response (PR), but treatment was discontinued due to toxicity. Erlotinib was administered from June to August 2017, and the best response was PD. The last treatment received before GEN1021 trial enrollment was pembrolizumab administration from September 2018 to January 2018, and the best response was stable disease (SD). Treatment with pembrolizumab was discontinued due to disease progression.

[0264] The medical history included childhood polio and subdural hematoma, both of which were confirmed to have disappeared at the time of enrollment. In addition, the patient had peripheral neuropathy, cough, and right cataract, all of which persisted at the time of enrollment. The patient was a non-smoker, and the ECOG at the time of enrollment was 1.

[0265] The first dose of enapotamab vedotin was administered on C1D1 (April 20, 2018).

[0266] Treatment-emergent events included urinary tract infection (G2, "not related"), increased creatine kinase (variable between G1 and G2, "possibly related"), muscle spasm (G1, "possibly related"), worsening cough (G2, "not related"), and increased ALT and AST (both G1, "not related"). None of these events led to a change in study drug administration. Dysphonia and left leg weakness also occurred, both of which were reported as G1 and "possibly related", and study drug administration was discontinued due to these events.

[0267] At screening, two target lesions (TL) were identified in the lung, one in the left lower lobe with a longest diameter of 11 mm and another in the right upper lobe with a longest diameter of 15 mm (sum of diameters at screening: 26 mm).One non-target lesion (NTL) was also identified (location not specified).

[0268] The first post-baseline scan was performed on C2D15 (May 25, 2018). At this time, the diameter of the TL in the left lower lobe was 10 mm, and the TL in the right upper lobe was 12 mm, resulting in a sum of diameters of 22 mm. This corresponds to a 15% reduction in the sum of diameters compared to screening. No new lesions were detected, although NTL was present (SD). The overall response rate was SD according to RECIST version 1.1.

[0269] A second post-baseline scan was performed on C4D15 (July 6, 2018). At this time, the diameter of the TL in the left lower lobe was 8 mm, and the TL in the right upper lobe was 9 mm, resulting in a sum of diameters of 17 mm. Compared to screening, this corresponds to a 34.6% reduction in the sum of diameters. No new lesions were detected, although NTL was present (SD). The overall response rate was PR according to RECIST version 1.1.

[0270] On C6D15 (August 17, 2018), the third post-baseline scan was performed. At this time, the diameter of the TL in the left lower lobe was 5 mm, and the TL in the right upper lobe was 6 mm, resulting in a sum of diameters of 11 mm. Compared to screening, this corresponds to a 57.6% reduction in the sum of diameters. No new lesions were detected, although NTL was present (SD). The overall response rate was PR according to RECIST version 1.1.

[0271] Subject 403 The 63-year-old Caucasian female patient was enrolled in the GEN1021 trial and signed an informed consent form at the UK study site on May 4, 2018.

[0272] The patient was diagnosed with stage IV non-small cell lung adenocarcinoma (EGFR gene mutation and ALK gene rearrangement negative) on January 19, 2017.

[0273] Previous cancer treatments included carboplatin plus pemetrexed administered from February to March 2017, with progression during treatment, with best response being PD. Radiotherapy was administered in April 2017, with best response being PR. The last treatment prior to enrollment in the GEN1021 study was pembrolizumab administered from June to September 2017, with best response being PD.

[0274] Medical history included cervical intraepithelial neoplasia, dizziness, mild headaches, and constipation, all of which were confirmed to have resolved at the time of enrollment.Hypertension, cervical osteoarthritis, gallstones, postural hypotension, fatigue, cough, intermittent left-sided chest pain, anxiety, joint pain, anorexia, and dry skin were noted, and these medical conditions were confirmed to have persisted at the time of enrollment.

[0275] The patient had a history of smoking (47 years) and had quit smoking in January 2017. His ECOG score was 1 at the time of enrollment.

[0276] The first administration of enapotamab vedotin was administered on C1D1 (May 15, 2018).

[0277] Treatment-emergent events included two episodes of nausea (both G1, possibly related), skin and subcutaneous tissue disorders (G1, not related), constipation (G2, possibly related), two episodes of anorexia (G1, first episode not related, second episode possibly related), gastroesophageal reflux (G1, not related), alopecia (G1, possibly related), and AST increased (G1, possibly related). None of these events led to a change in study drug administration.

[0278] At screening, four TLs were identified: a 24 mm mass in the left axillary lymph node, a 15 mm mass in the right lower lobe, a 13 mm mass in the right lower lobe, and a 36 mm mass in the right iliac region. The sum of the sizes at screening was 88 mm. In addition, two NTLs were identified in the right middle lobe and one in the left supraclavicular lymph node.

[0279] The first post-baseline scan was performed on C2D15 (June 19, 2018). At this time, the diameter of the left axillary lymph node mass was 14 mm, the diameter of the right lower lobe lesion was 12 mm, the diameter of the right lower lobe lesion was 9 mm, and the diameter of the right iliac lesion was 36 mm. The sum of the diameters at C2D15 was 71 mm. Compared to screening, this corresponds to a 19.3% reduction in the sum of the diameters. NTL was present (SD), but no new lesions were detected. The overall response rate was SD according to RECIST version 1.1.

[0280] A second post-baseline scan was performed on C4D15 (July 31, 2018). At this time, the diameter of the left axillary lymph node mass was 10 mm, the diameter of the right lower lobe lesion was 9 mm, the diameter of the right lower lobe lesion was 6 mm, and the diameter of the right iliac lesion was 32 mm. The sum of the diameters at C2D15 was 57 mm. Compared to screening, this corresponds to a 35.2% reduction in the sum of the diameters. The presence of one of the two NTLs was confirmed, but the other was absent (SD), and no new lesions were detected. To date, results of the overall response rate assessment have not been reported in the eCRF.

[0281] The third post-baseline scan was performed on C6D15 (September 11, 2018). At this time, the diameter of the left axillary lymph node mass was 10 mm, the diameter of the right lower lobe lesion was 9 mm, the diameter of the right lower lobe lesion was 7 mm, and the diameter of the right iliac lesion was 30 mm. The sum of the diameters at C2D15 was 56 mm. Compared to screening, this corresponds to a 36.4% reduction in the sum of the diameters. To date, the status of the two NTLs has not been reported in the eCRF, and no new lesions have been detected. The overall TL assessment was reported as PR, and the overall NTL status was reported as "not evaluable," but the results of the overall response assessment at this time have not yet been reported.

[0282] Figure 9 shows a snapshot of the lesion.

[0283] Subject 406 The 64-year-old white male patient was enrolled in the GEN1021 trial and signed the informed consent form at the US study site on June 11, 2018.

[0284] The patient was diagnosed with stage IV non-small cell lung adenocarcinoma (EGFR gene mutation and ALK gene rearrangement negative) on December 20, 2016.

[0285] Cancer treatment history included carboplatin + pemetrexed administered from December 2016 to February 2017, with progression during treatment, with best response being PD. Durvalumab + IPH-2201 (anti-NKG2A) administered from March to May 2017, with best response being PD. Docetaxel + ramucirumab administered from May to September 2017, with best response being PD. Gemcitabine administered from October 2017 to January 2018, with best response unknown, and treatment discontinued due to PD. Palliative radiation therapy was administered in March 2018 (treatment efficacy not reported).

[0286] The patient's medical history included hypertension, hyperlipidemia, fatigue, appetite and weight changes, shortness of breath, depression, and back pain. All conditions persisted at the time of enrollment.

[0287] The patient had a history of smoking (32 years) and had quit smoking in January 2004. His ECOG score was 1 at the time of enrollment.

[0288] The first administration of enapotamab vedotin was administered on C1D1 (June 20, 2018).

[0289] Treatment-emergent events included two episodes of back pain (G2 and G3, both unrelated), neutropenia (G3, possibly related), fatigue (G2, not related), hypotension (G3, not related), hyponatremia (G3, not related), pruritus (G1, possibly related), dry skin (G1, possibly related), neuropathy (G1, not related), anorexia (G2, not related), insomnia (G1, not related), and weight loss (G2, possibly related). Back pain in G3 led to dose interruption, but no other events led to dose modifications.

[0290] At screening, two TLs were found in the lungs, one in the right lung measuring 18 mm in diameter and the other in the left lung measuring 14 mm in diameter (sum of the diameters at screening was 32 mm). One NTL was also found, confirming the presence of disease in both lungs.

[0291] The first post-baseline scan was performed on C2D15 (August 8, 2018). At this time, the right lung lesion had a diameter of 8 mm, and the left lung lesion had a diameter of 9 mm. The sum of the diameters at C2D15 was 17 mm. Compared to screening, this corresponds to a 46.8% reduction in the sum of the diameters. No new lesions were detected, although there was still NTL present (SD). The overall response rate was PR according to RECIST version 1.1.

[0292] References TIFF0007681401000025.tif98128TIFF0007681401000026.tif173163

Claims

1. A pharmaceutical comprising an antibody-drug conjugate (ADC) comprising an antibody that binds to human AXL for the treatment of cancer in a subject, wherein - the cancer is resistant, or is predicted to be resistant or to become resistant to treatment with an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand; - the cancer has failed or is predicted to fail to respond to treatment with an inhibitor of the interaction between the Programmed Cell Death-1 (PD-1) receptor and its ligand; and / or - the subject has relapsed or is predicted to relapse following treatment with an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand; the ADC comprises a cytotoxic agent; The antibody comprises at least one binding region comprising a VH region and a VL region selected from the group consisting of: (a) a VH region containing the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 36, SEQ ID No: 37 and SEQ ID No: 38, respectively, and a VL region containing the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 39, GAS and SEQ ID No: 40, respectively [107]; (b) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 93, SEQ ID No: 94 and SEQ ID No: 95, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 96, GAS and SEQ ID No: 97, respectively [613]; (c) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 98, SEQ ID No: 99 and SEQ ID No: 100, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 101, DAS and SEQ ID No: 102, respectively [613-08]; (d) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 83, SEQ ID No: 84 and SEQ ID No: 85, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 86, GAS and SEQ ID No: 87, respectively [608-01]; (e) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 88, SEQ ID No: 89 and SEQ ID No: 90, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 91, GAS and SEQ ID No: 92, respectively [610-01]; and (f) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 103, SEQ ID No: 104 and SEQ ID No: 105, respectively, and a VL region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID No: 106, GAS and SEQ ID No: 107, respectively [620-06]; The medicine.

2. The pharmaceutical of claim 1, wherein the inhibitor is selected from the group consisting of an antibody that binds to PD-1, an antibody that binds to PD-L1, and an antibody that binds to PD-L2.

3. The pharmaceutical described in claim 2, wherein the inhibitor is a monoclonal antibody.

4. the cancer is a tumor selected from the group consisting of melanoma, carcinoma, sarcoma (such as undifferentiated pleomorphic sarcoma, liposarcoma, leiomyosarcoma, synovial sarcoma, Ewing's sarcoma, osteosarcoma or chondrosarcoma), adenoma, glioma, hematological tumors, and tumors of lymphatic tissue; or the cancer is a solid tumor, and the solid tumor is selected from the group consisting of melanoma, carcinoma (such as squamous cell carcinoma of the head and neck (SCCHN)), sarcoma (such as undifferentiated pleomorphic sarcoma, liposarcoma, leiomyosarcoma, synovial sarcoma, Ewing's sarcoma, osteosarcoma or chondrosarcoma), adenoma, and glioma; or the cancer is a solid tumor, and the solid tumor is selected from the group consisting of carcinoma, sarcoma (such as undifferentiated pleomorphic sarcoma, liposarcoma, leiomyosarcoma, synovial sarcoma, Ewing's sarcoma, osteosarcoma, gastrointestinal stromal tumor (GIST), rhabdomyosarcoma, or chondrosarcoma), adenoma, and glioma; The pharmaceutical composition according to any one of claims 1 to 3.

5. The pharmaceutical agent according to any one of claims 1 to 3, wherein the cancer is selected from the group consisting of endometrial / cervical cancer, lung cancer (such as small cell lung cancer or non-small cell lung cancer), thyroid cancer, colon cancer, kidney cancer, renal cancer, ovarian cancer, breast cancer (such as estrogen receptor alpha negative cancer, estrogen receptor alpha positive cancer or triple negative breast cancer; i.e., breast cancer that tests estrogen receptor negative (ER-), progesterone receptor negative (PR-) and human epidermal growth factor receptor 2 negative (HER2-)), esophageal cancer, skin cancer, melanoma (such as malignant melanoma), pancreatic cancer (such as unresectable advanced or metastatic pancreatic cancer), gastrointestinal stromal tumor (GIST), and blood cancer (such as leukemia; for example acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia or chronic myeloid leukemia).

6. The pharmaceutical composition according to any one of claims 1 to 3, wherein the cancer is selected from the group consisting of non-small cell lung cancer, ovarian cancer, melanoma, and malignant melanoma.

7. The pharmaceutical agent of any one of claims 1 to 6, wherein resistance to, failure to respond to, or relapse from treatment with an inhibitor of the interaction between the programmed cell death-1 (PD-1) receptor and its ligand is associated with increased expression of AXL.

8. Inhibitors of the interaction between the programmed cell death-1 (PD-1) receptor and its ligands include Opdivo / nivolumab (Bristol-Myers Squibb), Keytruda / pembrolizumab (Merck & Co), Amp-514 / MEDI0680 (Amplimmune), BGB-A317 (BeiGene), REGN2810 (Regeneron), TSR-042 (Tesaro / AnaptysBio), CBT-501 / genolimzumab (Genor Bio / CBT Pharma), PF-06801591 (Pfizer), JS-001 (Shanghai Junshi Bio), SHR-1210 / INCSHR-1210 (Incyte corp), PDR001 (Novartis), BCD-100 (BioCad), AGEN2034 (AGEN2034), and EGFR-100 (Gene). (Agenus), IBI-308 Innovent Biologics), BI-754091 (Boehringer Ingelheim), or Inhibitors of the interaction between the programmed cell death-1 (PD-1) receptor and its ligands include Tecentriq / RG7446; MPDL-3280A, atezolizumab (Roche), Imfinzi / MEDI-4736 / durvalumab (AstraZeneca), Bavencio / MSB-0010718C / avelumab (Merck Serono / Pfizer), KN-035- (3DMed / Alphamab Co), CX-072 (CytomX), LY-3300054 (Eli Lilly), MSB0011359C ＊ / M-7824 (Merck KGaA), FAZ053 (Novartis), SHR-1316 (Atridia), and CA-170 (Aurigene / Curis); The pharmaceutical composition according to any one of claims 1 to 7.

9. The pharmaceutical agent according to any one of claims 1 to 8, wherein the cytotoxic agent is linked to the antibody by a linker.

10. the cytotoxic agent is linked to the antibody that binds human AXL by a cleavable linker; or The cytotoxic agent is linked to an antibody that binds to human AXL by a non-cleavable linker. The pharmaceutical composition according to claim 9.

11. The pharmaceutical composition of claim 10, wherein the cleavable linker is N-succinimidyl 4-(2-pyridyldithio)-pentanoate (SSP), maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-vc-PAB), or AV-1 K-locked valine-citrulline.

12. The pharmaceutical of claim 10, wherein the non-cleavable linker is succinimidyl-4(N-maleimidomethyl)cyclohexane-1-carboxylate (MCC) or maleimidocaproyl (MC).

13. The pharmaceutical of any one of claims 1 to 12, wherein the cytotoxic agent is selected from the group consisting of DNA targeting agents and microtubule targeting agents.

14. The method of claim 1, wherein the DNA targeting agent is a DNA alkylating or cross-linking agent, and / or the microtubule targeting agent is duostatin, duostatin-3, auristatin, monomethylauristatin E (MMAE), monomethylauristatin F (MMAF), dolastatin, maytansine, N(2')-deacetyl-N(2')-(3-mercapto-1-oxopropyl)-maytansine (DM1), or tubulysin; The pharmaceutical composition according to claim 13.

15. The pharmaceutical composition of claim 14, wherein the DNA alkylating agent or cross-linking agent is a calicheamicin, a duocarmycin, racemicin (CC-1065), a pyrrolo[2,1-c][1,4]benzodiazepine (PBD), or an indolinobenzodiazepine (IGN).

16. The pharmaceutical agent of any one of claims 9 to 11 or 13, wherein the linker is mc-vc-PAB and the cytotoxic agent is MMAE.

17. (a) an antibody that binds to human AXL does not compete with growth arrest specific 6 (Gas6) for binding to human AXL; or (b) the maximum antibody binding to human AXL in the presence of Gas6 is at least 90%, such as at least 95%, such as at least 97%, such as at least 99%, such as 100% of the binding in the absence of Gas6 as determined by a competition assay, wherein the competition between the binding of the antibody to human AXL and the Gas6 is determined in A431 cells pre-incubated with and without Gas6, or (c) The antibody that binds to human AXL has a titer of 0.3 × 10 -9 From 63×10 -9 Binding affinities (K D ), optionally wherein the binding affinity is measured using Bio-layer Interferometry using a soluble AXL extracellular domain; or (d) The antibody binding to human AXL had a titer of 9.7 × 10 -5 From 4.4 × 10 -3 s -1 and optionally wherein the dissociation rate is measured by Bio-layer Interferometry using a soluble recombinant AXL extracellular domain. The pharmaceutical composition according to any one of claims 1 to 16.

18. The medicament according to any one of claims 1 to 17, wherein the antibody that binds to human AXL comprises at least one binding region comprising a VH region and a VL region selected from the group consisting of: (a) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 1, and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 2 [107]; (b) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 25 and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 26 [613]; (c) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 21 and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 22 [608-01]; (d) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 23 and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 24 [610-01]; (e) a VH region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 27 and a VL region at least 90%, such as at least 95%, such as at least 97%, such as at least 99% identical to SEQ ID No: 28 [613-08]; and (f) a VH region at least 90%, such as at least 95%, such as at least 97%, for example at least 99% identical to SEQ ID No: 29, and a VL region at least 90%, such as at least 95%, for example at least 97%, for example at least 99% identical to SEQ ID No: 30 [620-06].

19. (a) the antibody binds to an epitope on AXL, which epitope is recognised by any of the antibodies defined in any one of claims 1 to 18, and / or (b) an antibody that binds to human AXL binds to an epitope within the Ig1 or Ig1-like domain of AXL, the epitope including or requiring one or more amino acids corresponding to positions L121 to Q129 or T112 to Q124 of human AXL; The pharmaceutical composition according to any one of claims 1 to 18.

20. The pharmaceutical according to any one of claims 1 to 19, wherein the antibody that binds to human AXL comprises a heavy chain of an isotype selected from the group consisting of IgG1, human IgG1, allotype IgG1m(f), IgG2, IgG3 and IgG4.

21. The pharmaceutical according to claim 20, wherein the isotype IgG1 is human IgG1 and / or allotype IgG1m(f).

22. The pharmaceutical according to any one of claims 1 to 21, wherein the antibody is a humanized antibody or a human antibody.

23. The pharmaceutical agent of any one of claims 1 to 22, wherein the antibody is enapotamab and the ADC is enapotamab vedotin.

24. The pharmaceutical according to any one of claims 1 to 23, wherein the antibody that binds to human AXL is a bispecific antibody comprising a first binding region of the antibody according to any one of claims 1 to 23 and a second binding region that binds to a target or epitope different from the first binding region.

25. A bispecific antibody that binds to human AXL, comprising first and second heavy chains each comprising at least a hinge region, a CH2 and a CH3 region, wherein in the first heavy chain at least one amino acid substitution is made at a position corresponding to a position selected from the group consisting of K409, T366, L368, K370, D399, F405 and Y407 in a human IgG1 heavy chain, and wherein in the second heavy chain at least one amino acid substitution is made at a position corresponding to a position selected from the group consisting of F405, T366, L368, K370, D399, Y407 and K409 in a human IgG1 heavy chain, and wherein the substitutions in the first and second heavy chains are not at the same position. The pharmaceutical composition according to claim 24.

26. 26. The pharmaceutical of claim 25, wherein the amino acid at the position corresponding to K409 in a human IgG1 heavy chain is R in the first heavy chain and the amino acid at the position corresponding to F405 in a human IgG1 heavy chain is L in the second heavy chain, or vice versa.

27. The pharmaceutical agent of any one of claims 1 to 26, wherein the ADC is in a formulation.

28. 28. The method of claim 27, wherein the formulation comprises one or more pharma- ceutically acceptable excipients.

29. 29. The method of claim 27 or 28, wherein the formulation is a pharmaceutical formulation.

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