L1CAM binding molecules for treating hematological malignancy diseases

Abstract

The present invention relates to an antibody that specifically binds to human L1CAM for use in the treatment or prophylaxis of a human L1CAM-positive hematological malignancy disease in a human subject, and a pharmaceutical composition, kit or kit-of-parts comprising (i) an antibody that specifically binds to human L1CAM and (ii) an active compound selected from a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and an HDAC inhibitor, and related uses and methods.

Description

L1CAM binding molecules for treating hematological malignancy diseasesThe present invention relates to an antibody that specifically binds to human L1 CAM for use in the treatment or prophylaxis of a human L1 CAM-positive hematological malignancy disease in a human subject, and a pharmaceutical composition, kit or kit-of-parts comprising (i) an antibody that specifically binds to human L1 CAM and (ii) an active compound selected from a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and an HDAC inhibitor, and related uses and methods.BackgroundHematological malignancies are commonly divided into leukemias and lymphomas, according to whether they are prevalently located in the blood or the lymph nodes, respectively. Lymphomas originate from cancerous lymphocytes, and comprise a variety of subtypes, which are classically categorized into Non-Hodgkin and Hodgkin Lymphomas. Non-Hodgkin lymphomas account for approximately 90% of all lymphoma cases and can be further divided into B-cell, T-cell, and NK -cell lymphomas. B-cell lymphomas are most common and include diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Burkitt lymphoma (BL) as well as many other subtypes. T-cell lymphomas account for less than 20% of Non-Hodgkin lymphomas, and comprise, among others, anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), and cutaneous T-cell lymphoma (CTCL), with its major subforms Mycosis fungoides (MF) and Sezary syndrome (SS). (Swerdlow SH, Campo E, Harris NL, etal (eds). WHO Classification of Tumors of the Haematopoietic and Lymphoid Tissues. Lyon: International Agency for Research on Cancer; 2017).The choice of treatment depends largely on the type of lymphoma and its grade. Low grade lymphomas often remain indolent for years and may be chosen not to be treated (“watchful waiting”), as in these cases early treatment has not been shown to provide significant benefit compared to regular monitoring without treatment. Once low-grade lymphomas become symptomatic, they can be treated with radiotherapy or chemotherapy and / or the monoclonal antibody Rituximab. The most common treatment for higher grade and aggressive lymphomas is R-CHOP, which consists of a combination of 4 chemotherapy drugs (cyclophosphamide, doxorubicin, vincristine, and prednisone), plus rituximab or obinutuzumab. Recently, also a combination of the antibody drug-conjugate Polatuzumab vedotin with irituximab, cyclophosphamide, doxorubicin and prednisone (Pola-R-CHP) has been introduced as a first line therapy for the Non-Hodkin lymphoma DLBCL.Upon relapse, a common therapy approach is high dose chemotherapy followed by autologous stem cell transplantation. Relapsed and / or refractory B-cell lymphomas can also be successfully treated with CAR T cell therapies directed against CD19, such as axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel. In addition, several other chemotherapeutic agents and targeted agents, including monoclonal antibodies, antibody-drug conjugates, T-cell redirecting bispecific antibodies, kinase inhibitors, and Bcl2-inhibitors have recently been approved for the treatment of advanced disease.While a fraction of patients enters into long term remission after first or subsequent lines of treatment, a large proportion of patients encounters a relapse of the disease. Despite the numerous available treatment options for relapsed and / or refractory disease, progression of the disease can often not be prevented. Additional treatment options addressing novel targets and pathways are therefore still needed to improve the survival and quality of life of patients affected by hematological malignancies. Recently, the transmembrane glycoprotein L1 CAM (L1 cell adhesion molecule) has emerged as a promising new target for the treatment of human cancers. In normal development, L1 CAM is involved in the development of the nervous system, by regulating the outgrowth, fasciculation, and guidance of axons. L1 CAM is overexpressed in many human cancers, where it contributes to disease progression by increasing cancer cell motility, invasion and metastasis. Ovarian cancer, pancreatic cancer, melanoma, and breast cancer are prominent examples of malignancies, where L1 CAM expression has been demonstrated and where anti- L1 CAM antibody-based therapies have shown beneficial effects (EP22196917', Wolterink S, et al., Therapeutic antibodies to human L1CAM: functional characterization and application in a mouse model for ovarian carcinoma. Cancer Res. 2010 Mar 15;70(6):2504-15; Doberstein K, et al., Antibody therapy to human L1 CAM in a transgenic mouse model blocks local tumor growth but induces EMT. Int J Cancer. 2015 Mar 1;136(5):E326-39.). Although L1 CAM expression has been detected on human hematopoietic cells, including B and T cells, and on human hematopoietic tumor cell lines (Ebeling 0, et al. L1 adhesion molecule on human lymphocytes and monocytes: expression and involvement in binding to alpha v beta 3 integrin. Eur J Immunol. 1996 Cct;26(10):2508-16., Pancook JD, etal., Expression and regulation of the neural cell adhesion molecule L1 on human cells of myelomonocytic and lymphoid origin. J Immunol. 1997 May 1;158(9):4413-21), its expression in human hematological malignancies has not been analyzed in detailand no anti-L1 CAM antibody-based therapies directed against hematological malignancies have been proposed or attempted.The present invention demonstrates that L1 CAM is expressed on a variety of human lymphoma cell lines as well as on primary human clinical lymphoma samples and provides evidence that antibody-based therapies directed against L1 CAM can lead to specific killing of lymphoma cells and provide therapeutic benefit in lymphoma disease.Summary of the inventionIn an aspect, an antibody that specifically binds to human L1 CAM is provided for use in the treatment or prophylaxis of a human L1 CAM-positive hematological malignancy disease in a human subject.In one embodiment, the human L1 CAM-positive hematological malignancy disease is a lymphoma.In one embodiment, the human L1 CAM-positive hematological malignancy disease is selected from a T cell lymphoma and a B cell lymphoma.In one embodiment, the human L1 CAM-positive hematological malignancy disease is selected from Mantle cell lymphoma, Sezary Syndrome, Mycosis fungoides, Activated B-cell-diffuse large B cell lymphoma, Germinal center B-cell-diffuse large B cell lymphoma, Follicular lymphoma, Anaplastic large cell lymphoma, Hodgkin lymphoma and Diffuse large B-cell lymphoma.In one embodiment, one or more hematological cells of the subject express human L1 CAM on the cell surface.In one embodiment, the use further comprises:(i) providing a hematological sample of the human subject; and(ii) determining whether one or more hematological cells of the subject express human L1 CAM on the cell surface; wherein the antibody that specifically binds to human L1 CAM is for use in the treatment or prophylaxis of a human L1 CAM-positive hematological malignancy disease in the human subject in case one or more hematological cells of the subject are determined in step (ii) to express human L1 CAM on the cell surface.In one embodiment, the antibody is selected from an antibody comprising an Fc portion and / or an antibody linked to a therapeutically active substance.In one embodiment, the antibody is selected from an internalizing and / or cytotoxic antibody.In one embodiment, the antibody comprises:(a) a heavy chain variable region (VH) comprising a VH CDR1 comprising the amino acid sequence of GYSITSDYTWN (SEQ ID NO: 1 ), a VH CDR2 comprising the amino acid sequence of YISYSGSYSYNPSLKS (SEQ ID NO: 2), and a VH CDR3 comprising the amino acid sequence of SFSYSYGFAY (SEQ ID NO: 3); and(b) a light chain variable region (VL) comprising a VL CDR1 comprising the amino acid sequence of KASQDVSSAVA (SEQ ID NO: 4), a VL CDR2 comprising the amino acid sequence of SASYRYT (SEQ ID NO: 5), and a VL CDR3 comprising the amino acid sequence of QQHYSTPWT (SEQ ID NO: 6).In one embodiment, the antibody comprises:(a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7; and(b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8.In one embodiment, the antibody comprises a heavy chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 9 or 10 and / or a light chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 11 .In one embodiment, the antibody is linked to a therapeutically active substance, wherein the therapeutically active substance is selected from the group consisting of a DNA damaging agent, an anti-apoptotic agent, a mitotic inhibitor, an anti-tumor antibiotic, an immunomodulating agent, a nucleic acid for gene therapy, an anti- angiogenic agent, an anti-metabolite, a boron-containing agent, a chem ©protective agent, a hormone agent, an anti-hormone agent, a corticosteroid, a photoactive therapeutic agent, an oligonucleotide, a radioisotope, a radiosensitizer, a topoisomerase inhibitor, and a tyrosine kinase inhibitor.In one embodiment,(i) the mitotic inhibitor is selected from a maytansinoid and an auristatin, or(ii) the DNA damaging agent is selected from a pyrrolobenzodiazepine (PBD) and a pyridinobenzodiazepine (PDD), or(iii) the therapeutically active substance is selected from monomethyl auristatin E (MMAE), 4-methyl-4-mercapto-1-oxopentyl)-maytansine (DM4), and VA-SG3199 (tesirine), or(iv) the antibody is linked to the therapeutically active substance via a non- cleavable linker, or(v) the antibody is linked to the therapeutically active substance via a cleavable linker.In one embodiment, the therapeutically active substance is selected from monomethyl auristatin E (MMAE), and VA-SG3199 (tesirine).In one embodiment, the human subject is or was treated with a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and / or an HDAC inhibitor.In one aspect, an antibody that specifically binds to human L1 CAM and an active compound selected from a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and an HDAC inhibitor, is provided, for use in a combination therapy in the treatment or prophylaxis of a human L1 CAM-positive hematological tumor disease in a human subject.In one aspect, a pharmaceutical composition, kit or kit-of-parts comprising (i) an antibody that specifically binds to human L1 CAM and (ii) an active compound selected from a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and an HDAC inhibitor, and, optionally, (iii) one or more pharmaceutically acceptable excipients, is provided.In embodiments of any of the aspects herein, (i) the Bcl-2 inhibitor is Obatoclax, or (ii) the tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor is dasatinib, or (iii) the HDAC inhibitor is vorinostat.The present inventionThe present invention is based on the surprising finding that an antibody that specifically binds to human L1 CAM is suitable for the treatment and prophylaxis of human L1 CAM-positive hematological malignancy diseases in a human subject.Among the L1 CAM positive hematological malignancy diseases, a variety of T cell lymphomas and B cell lymphomas were identified. These include Mantle cell lymphoma, Sezary Syndrome, Mycosis fungoides, Activated B-cell-diffuse large B cell lymphoma, Germinal center B-cell-diffuse large B cell lymphoma, Follicular lymphoma, Anaplastic large cell lymphoma, Hodgkin lymphoma and Diffuse large B-cell lymphoma.In particular, it was found that samples of human subjects from a plurality of hematological malignancy diseases exhibit cell surface expression of LCAM. Human subjects suffering from a hematological malignancy disease, which is human L1 CAM-positive, can therefore be treated with the antibody.Moreover, it was surprisingly found that a Bcl-2 inhibitor, Obatoclax, a tyrosine kinase inhibitor of tyrosine kinases BCR / Abl, Src, c-Kit and an ephrin receptors, dasatinib, and an HDAC inhibitor, vorinostat, are suitable for increasing cell surface expression of human L1 CAM on human cells. The compounds are therefore suitable for combination therapy for increasing the effectiveness of an antibody that specifically binds to human L1 CAM and / or responsiveness of a human subject to a treatment with an antibody that specifically binds to human L1 CAM.In an aspect, an antibody that specifically binds to human L1 CAM is provided for use in the treatment or prophylaxis of a human L1 CAM-positive hematological malignancy disease in a human subject.In the present use of one aspect of the invention, an antibody that specifically binds to human L1 CAM is used for therapeutic and / or prophylactic purposes.The term “antibody that specifically binds to human L1 CAM”, as used herein, means any polypeptide which is an antibody as defined herein and is capable of binding to human L1 CAM, wherein the binding specificity is determined by the CDRs of the polypeptide. Such antibody includes an antibody which has structural similarity to a naturally occurring antibody. Hence, “antibody that specifically binds to human L1 CAM” is intended to relate to an immunoglobulin-derived structure with binding to human L1 CAM. The terms “anti-L1 CAM antibody” and “antibody that specifically binds to human L1 CAM” are used interchangeably herein.Anti-L1 CAM antibodies which can be used for the treatment or prophylaxis of a human L1 CAM-positive hematological malignancy disease in a human subject areknown in the art. Suitable prior art anti-L1 CAM antibodies which can be used in the aspects of the present invention include, for example, antibody L1 -OV52.24 or an antibody-binding fragment thereof, or an antibody comprising the set of 6 CDR regions of antibody L1 -OV52.24, or an antibody comprising the VH and the VL region of antibody L1-OV52.24, which are disclosed in WO2016 / 050702, or a humanized version thereof. A further prior art anti-L1 CAM antibody which can be used according to the invention is mAb L1 -9.3 (also called mAb 9.3), disclosed in W02008 / 151819 and the anti-L1 CAM antibodies disclosed in W02020 / 003210 including antibody mAb417 or an antibody-binding fragment thereof, or an antibody comprising the set of 6 CDR regions of antibody mAb417, or an antibody comprising the VH and the VL region of antibody mAb417. Further prior art antibodies specifically binding to L1 CAM are mAb 14.10 Huszar et al. 2006); mab chCE7 (Meli et al., 1999); mAb UJ127.11 (Patel et al., 1991 ); and mAb 5G3 (commercially available, ThermoFisher Scientific, Germany). Further, suitable anti-L1 CAM antibodies for use in the invention include the antibodies exemplified below, in particular antibodies comprising the 6 CDR regions of the antibodies AFF4-WT and AFF4 used in the examples. Such anti-L1 CAM antibody used herein comprises: (a) a heavy chain variable region (VH) comprising a VH CDR1 comprising the amino acid sequence of GYSITSDYTWN (SEQ ID NO: 1 ), a VH CDR2 comprising the amino acid sequence of YISYSGSYSYNPSLKS (SEQ ID NO: 2), and a VH CDR3 comprising the amino acid sequence of SFSYSYGFAY (SEQ ID NO: 3); and (b) a light chain variable region (VL) comprising a VL CDR1 comprising the amino acid sequence of KASQDVSSAVA (SEQ ID NO: 4), a VL CDR2 comprising the amino acid sequence of SASYRYT (SEQ ID NO: 5), and a VL CDR3 comprising the amino acid sequence of QQHYSTPWT (SEQ ID NO: 6).L1 CAM (also called L1 ), is a transmembrane protein; it is a neuronal cell adhesion molecule, member of the L1 protein family, of 200-220 kDa, and involved in axon guidance and cell migration with a strong implication in treatment-resistant cancers. The term “human L1 CAM” according to the present invention is understood as human L1 CAM protein. The human L1 CAM gene sequence has been assigned Gene ID: 3897. The Genbank entry for the isoform 1 precursor of human L1 CAM protein is NP_000416. L1 CAM has also been designated CD171. The term “human L1 CAM” describes any form of protein known to be expressed based on this L1 CAM gene by any cell type of a human being.“Specific binding” is understood that the binding of the binding molecule to L1 CAM is at least 50-fold, preferably at least 100-fold stronger than the binding to a controlprotein such as albumin, as determined e.g. by methods known to the person skilled in the art, such as surface plasmon resonance-based kinetic binding analyses. Alternatively, also methods such as Western Blot analysis, Enzyme-linked Immunosorbent Assay (ELISA) or determining shifts in the fluorescent signal in cytometer-based assays may be used. Such specific binding may be based on any interaction between an antibody and its antigen known to the person skilled in the art, such as non-covalent bonds (e.g. van der Waals contacts, hydrogen-bond formation or hydrophobic interactions).The term “antibody” generally describes any polypeptide having structural similarity to a naturally occurring antibody, such as a protein belonging to the protein family of immunoglobulins. The term “antibody” includes full length antibodies, antigenbinding fragments of antibodies, and molecules comprising antibody VH regions and / or VL regions. Antibodies include monoclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies, including bispecific antibodies, human antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, an antibody light chain monomer, an antibody heavy chain monomer, an antibody light chain dimer, an antibody heavy chain dimer, an antibody light chain-antibody heavy chain pair, intrabodies, heteroconjugate antibodies, single domain antibodies, monovalent antibodies, single chain antibodies or single-chain Fvs (scFv), camelid antibodies, Fab fragments, F(ab’)2 fragments, disulfide-linked Fvs (dsFv), anti-idiotypic (anti-ld) antibodies, and antigen-binding fragments of any of the above. The antibody may be part of fusion proteins or conjugates. For example, an antibody may be comprised in a Chimeric Antigen Receptor (CAR). Antibodies can be of any type (e.g. IgG, IgE, IgM, IgD, IgA or IgY), any isotype (e.g. lgG1 , lgG2, lgG3, lgG-4, lgA1 or lgA2), or any subisotype (e.g., lgG2a or lgG2b) of immunoglobulin molecule. Each heavy and each light chain may have a variable and a constant region or parts thereof. In case the antibody contains a heavy chain constant region or parts thereof, the constant region of a heavy chain may be one of five types of mammalian Ig heavy chains: a, 5, E, y and p. The type of the heavy chain present usually defines the class (isotype) of the antibody: IgA, IgD, IgE, IgG and IgM antibodies, respectively. Similarly, the constant region of a light chain may be one of two types of mammalian Ig light chains: K and A. The variable regions of heavy and light chains are usually made of a unique combination of numerous protein sequences allowing the binding to a particular antigen. The term “antibody” further includes domainscaffolds such as affibodies, anticalins, affilins, atrimers, DARPins, FN3 scaffolds,such as adnectins and centyrins, fynomers, Kunitz domains, pronectins and OBodies.In embodiments, the anti-L1 CAM antibody for use herein may further be selected from monoclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies, including bispecific antibodies, human antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, an antibody light chain monomer, an antibody heavy chain monomer, an antibody light chain dimer, an antibody heavy chain dimer, an antibody light chainantibody heavy chain pair, intrabodies, heteroconjugate antibodies, single domain antibodies, monovalent antibodies, single chain antibodies or single-chain Fvs (scFv), camelid antibodies, affibodies, anticalins, affilins, atrimers, DARPins, FN3 scaffolds, such as adnectins and centyrins, fynomers, Kunitz domains, pronectins and OBodies, Fab fragments, F(ab’)2 fragments, disulfide-linked Fvs (dsFv), anti- idiotypic (anti-ld) antibodies, and antigen-binding fragments of any of the above, and / or wherein the antibody is comprised in a Chimeric Antigen Receptor (CAR).The anti-L1 CAM antibody for use herein may be selected from monoclonal antibodies. Monoclonal antibodies are monospecific antibodies that are identical because they are produced by immune cells that are all clones of a single parent cell, e.g. produced by a single clone of B lymphocytes, or because they have the same amino acid sequence. “Monoclonal antibodies” and the production of monoclonal antibodies belong to the state of the art. In general, monoclonal antibodies can, for example, be prepared in accordance with the known method of Winter & Milstein (Winter, G. and Milstein, C.: Man-made antibodies. Nature, 349: 293-299 (1999)). As an alternative to preparing monoclonal antibody-secreting hybridomas, a monoclonal antibody directed against a polypeptide of interest can be identified and isolated by screening a recombinant combinatorial immunoglobulin library (e.g., an antibody phage display library) with the polypeptide of interest. Kits for generating and screening phage display libraries are commercially available (e.g., the Pharmacia Recombinant Phage Antibody System, Catalog No. 27-9400-01 ; and the Stratagene SurfZAP Phage Display Kit, Catalog No. 240612). Additionally, examples of methods and reagents particularly amenable for use in generating and screening antibody display libraries can be found in, for example, U.S. Patent No. 5,223,409; WO 92 / 18619; WO 91 / 17271 ; WO 92 / 20791 ; WO 92 / 15679; WO 93 / 01288; WO 92 / 01047; WO 92 / 09690; WO 90 / 02809; Fuchs et al. (Targeting recombinant antibodies to the surface of Escherichia coli.Bio / Technology 9:1370-1372 (1991 )); Hay et al. (Bacteriophage cloning and Escherichia coli expression of a human IgM Fab. Hum. Antibod. Hybridomas 3:81 - 85 (1992)); Huse et al.: Generation of a large combinatorial library of the immunoglobulin repertoire in phage lambda. Science 246:1275-1281 (1989); and Griffiths et al.: Human anti-self antibodies with high specificity from phage display libraries. EMBO J. 12:725-734 (1993)).The anti-L1 CAM antibody for use herein may further be selected from synthetic antibodies. The term “synthetic antibody” describes any antibody entirely generated in vitro without any involvement of an animal. Methods for generating synthetic antibodies are well known to the person skilled in the art, such as recombinant protein production. However, while synthetic antibodies are generated in vitro, they may still be produced in vivo, such as in cell lines (such as mammal, insect or bacterial cell lines), in animals or hybridoma cells. Suitable methods are well known to the person skilled in the art.The anti-L1 CAM antibody for use herein may further be selected from recombinantly produced antibodies. The term “recombinantly produced antibodies” comprises any antibody produced in vitro using DNA molecules generated by genetic recombination. Recombinant antibody production may be performed with cell lines (such as mammal, insect or bacterial cell lines), in animals or hybridoma cells. Methods for the recombinant production of antibodies are well known to the person skilled in the art. For example, antibody genes for immune-specific heavy and light antibody chains may be cloned into high-yield expression vectors, which subsequently are introduced into expression hosts (such as bacteria, yeast, insect or mammalian cells) to produce recombinant antibodies. The cells may be cultured in vivo or in vitro and the desired antibody can be isolated.Preferably, the antibodies herein are produced recombinantly in suitable host cells. The DNA encoding the antibody of interest can be placed into expression vectors, which are then transfected into host cells such as E. coli cells, simian COS cells, Chinese hamster ovary (CHO) cells (e.g., CHO cells from the CHO GS System™ (Lonza)), or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of the antibody.The anti-L1 CAM antibody for use herein may further be selected from monovalent antibodies, monospecific antibodies and / or multispecific antibodies, including bispecific antibodies.The valency of an antibody describes the number of antigen-binding sites present per molecule of antibody. The term “monovalent antibodies” therefore describes any antibody having one binding site to an antigen, epitope or cell type or tissue. A bivalent antibody has two binding sites to an antigen, epitope or cell type or tissue. A multivalent antibody has multiple, i.e. two or more, binding sites to an antigen, epitope or cell type or tissue, such as two, three, four or five.The specificity of an antibody in general describes its ability to recognize a single antigen epitope and distinguish it from the rest. The term “monospecific antibody” describes any antibody having specificity to one antigen, epitope, cell type or tissue. For example, monoclonal antibodies are monospecific because they bind with each of their two antigen-binding arms to only one epitope. The term “bispecific antibody”, as used herein, may be understood in the broadest sense describing antibodies interacting with two different epitopes, such as an antibody comprising two functional antigen-binding domains having specificity to two different antigens, or, alternatively, two different epitopes on the same antigen. The bispecific antibody may be derived from two monoclonal antibodies. Optionally, the two different epitopes may be localized on the same antigen, but they may also be localized on two different antigens. Bispecific antibodies may be produced using conventional technologies, specific methods of which include production chemically, or from hybrid hybridomas and other technologies including, but not being limited to, the technologies providing molecules, such as scFv, possessing antigen binding regions of different specificity with a peptide linker, such as a G4S linker, and knobs- into-holes engineering. The term “multispecific”, as used herein, may be understood in the broadest sense describing antibodies interacting with two or more different types of epitopes. Optionally, these epitopes may be localized on the same antigen or on two or more antigens. For example, on a multispecific antibody two or more, or three or more functional antigen-binding domains may be present and may have specificity for two or more, or three or more distinct antigens or distinct epitopes. Therefore, bispecific and multispecific antibodies target two and more antigens or epitopes, respectively.The anti-L1 CAM antibody for use herein may further be a human antibody, a humanized antibody and / or chimeric antibody. A chimeric antibody is an antibody, in which at least one region of an immunoglobulin of one species is fused to another region of an immunoglobulin of another species by genetic engineering in order to reduce the antibody’s immunogenicity. For example murine VL and VH regions maybe fused to the remaining part of a human immunoglobulin. A particular type of chimeric antibodies are humanized antibodies. Humanized antibodies are produced by merging the DNA that encodes the CDRs of a non-human antibody with human antibody-producing DNA. The resulting DNA construct can then be used to express and produce antibodies that are usually not as immunogenic as the non-human parental antibody or as a chimeric antibody, since merely the CDRs are non-human. Further, the antibody may be a human antibody, i.e. the nucleic acid sequence of the antibody is entirely of human origin.The use of a human, humanized or chimeric antibody is preferred for applications in vivo, in particular the human, in particular for the prophylaxis or treatment in vivo.The anti-L1 CAM antibody for use may further be selected from immunoglobulins. The term “immunoglobulin” describes any protein from the class of immunoglobulin that are produced by the immune system to neutralize substances foreign to the body. An immunoglobulin comprises at least one immunoglobulin (Ig) domain.The anti-L1 CAM antibody for use herein may further be selected from tetrameric antibodies comprising two heavy chain and two light chain molecules, from an antibody light chain monomer, an antibody heavy chain monomer, an antibody light chain dimer, an antibody heavy chain dimer and / or an antibody light chain-antibody heavy chain pair.The term “tetrameric antibodies comprising two heavy chain and two light chain molecules” describes any antibody complex comprising two heavy chain and two light chain molecules. These may comprise the complete heavy chain and / or light chain sequences of a full-length antibody or only parts of them. Tetrameric antibodies may especially refer to proteins that comprise two heavy (H) and two light (L) chains inter-connected by disulfide bonds which comprise: (1 ) in terms of the heavy chains, a variable region and a heavy chain constant region which comprises three domains, CH1 , CH2 and CH3; and (2) in terms of the light chains, a light chain variable region and a light chain constant region which comprises one domain, CL. With regard to the term “tetrameric antibody”, any antibody is meant that has a typical overall domain structure of a naturally occurring antibody (i.e. comprising a heavy chain of three or four constant domains and a light chain of one constant domain as well as the respective variable domains). As described above, each domain may comprise further modifications, such as mutations, includingsubstitutions, deletions, and / or insertions, which do not change the overall domain structure. For instance, AFF4 and AFF4-WT are tetrameric antibodies.The term “antibody light chain monomer” describes any antibody comprising a light chain molecule only, but not comprising a heavy chain molecule. Accordingly, the term “antibody heavy chain monomer” describes any antibody comprising one heavy chain molecule only, but not comprising a light chain molecule. Accordingly, the term “antibody light chain dimer” describes a complex of two light chain monomers and the term “antibody heavy chain dimer” describes a complex of two heavy chain monomers. The term “antibody light chain-antibody heavy chain pair” describes any complex comprising a pair of a light chain monomer and a heavy chain monomer.The anti-L1 CAM antibody for use may further be selected from “single domain antibodies”. The term “single domain antibodies” describes an antibody fragment consisting of a single monomeric variable antibody domain, such as the variable domain of the light chain (VL) or the variable domain of the heavy chain (VH).The anti-L1 CAM antibody for use may further be selected from “single chain antibodies”. The term “single chain antibodies” describes an antibody fragment of a single polypeptide chain.The anti-L1 CAM antibody for use may further be selected from intrabodies and / or heteroconjugate antibodies. The term “intrabodies” describes any antibody targeting intracellular proteins within a cell. Methods for transferring an intrabody into the target cell to allow the binding of intracellular target proteins are well known to the person skilled in the art, such as the direct expression of the intrabody by the target cell as applied in gene therapy. “Heteroconjugate antibodies” are complexes of two or more antibodies (e.g. monoclonal antibodies, Fab or scFv) of different specificities that are covalently linked.The anti-L1 CAM antibody for use may further be selected from camelid antibodies, affibodies, anticalins, affilins, atrimers, DARPins, FN3 scaffolds, such as adnectins and centyrins, fynomers, Kunitz domains, pronectins and OBodies, and / or anti- idiotypic (anti-ld) antibodies. The term “camelid antibody” describes any antibody having the structure of an antibody derived from the Camelidae family of mammals (such the llamas, camels, and alpacas), such as an antibody lacking any light chain and consisting of two identical heavy chains. The term “affibodies” describes anyantibody mimetic protein, which is able to bind a large number of antigens with high affinity. For example, affibodies may be based on immunoglobulin binding domains of proteins, such as the Z domain of protein A from Staphylococcus aureus. Further examples are well known to the person skilled in the art. Anticalins, affilins, atrimers, DARPins, FN3 scaffolds, such as adnectins and centyrins, fynomers, Kunitz domains, pronectins and OBodies are further scaffolds which are known in the art and which can be used according to the invention. The scaffolds are for example described in Vazquez-Lombardi R. et al. (Challenges and opportunities for nonantibody scaffold drugs. Drug Discovery Today, 20(10): 1271 -1283 (2015)). The term “anti-idiotypic (anti-ld) antibodies” describes any antibody, which is capable of binding to the idiotype of another antibody.An “antigen-binding fragment” of an antibody is a fragment of an antibody, which preferably exhibits essentially the same function and specificity as the complete antibody of which the fragment is derived from. The antigen-binding fragment is usually understood as polypeptide which comprises at least one antigen-binding fragment of a full-length antibody. In general, antigen binding fragments consist of at least the variable domain of the heavy chain and the variable domain of the light chain, arranged in a manner that both domains together are able to bind to the specific antigen. Limited proteolytic digestion with papain usually cleaves the Ig prototype into three fragments. Two identical amino terminal fragments, each containing one entire L chain and about half an H chain, are the antigen binding fragments (Fab). The third fragment, similar in size but containing the carboxyl terminal half of both heavy chains with their interchain disulfide bond, is the crystallizable fragment (Fc). The Fc contains carbohydrates, complement-binding, and FcR-binding sites. Limited pepsin digestion yields a single F(ab')2 fragment containing both Fab pieces and the hinge region, including the H-H interchain disulfide bond. F(ab')2 is divalent for antigen binding. The disulfide bond of F(ab')2 may be cleaved in order to obtain Fab'. Moreover, the variable regions of the heavy and light chains can be fused together to form a single chain variable fragment (scFv).Variable domains (Fvs) are the smallest fragments with an intact antigen-binding domain consisting of one VL and one VH. Such fragments, with only the binding domains, can be generated by enzymatic approaches or expression of the relevant gene fragments, e.g. in bacterial and eukaryotic cells. Different approaches can be used, e.g. either the Fv fragment alone or Fab-fragments comprising one of the upper arms of the "Y" that includes the Fv plus the first constant domains. Whenonly the variable fragments are used, these are usually stabilized by introducing a polypeptide link between the two chains which results in the production of a single chain Fv (scFv). Alternatively, disulfide-linked Fv (dsFv) fragments may be used. The binding domains of fragments can be combined with any constant domain in order to produce full length antibodies or can be fused with other proteins and polypeptides.A preferred recombinant antibody fragment is the single-chain Fv (scFv) fragment. In general, it has a high affinity for its antigen and can be expressed in a variety of hosts. These and other properties make scFv fragments not only applicable in medicine, but also of potential for biotechnological applications. As detailed above, in the scFv fragment the VH and VL domains are joined with a hydrophilic and flexible peptide linker, which improves expression and folding efficiency. Usually linkers of about 15 amino acids are used, of which the (Gly4Ser)3 linker has been used most frequently. scFv molecules might be easily proteolytically degraded, depending on the linker used. With the development of genetic engineering techniques these limitations could be practically overcome by research focused on improvement of function and stability. An example is the generation of disulfide-stabilized (or disulfide-linked) Fv fragments where the VH-VL dimer is stabilized by an interchain disulfide bond. Cysteines are introduced at the interface between the VL and VH domains, forming a disulfide bridge, which holds the two domains together. scFvs can be complexed into dimers (diabodies), trimers (triabodies) or larger aggregates such as TandAbs and Flexibodies.Antibodies with two binding domains can for example be created either through the binding of two scFv with a simple polypeptide link (scFv)2 or through the dimerization of two monomers (diabodies). The simplest designs are diabodies that have two functional antigen-binding domains.Also, antibody formats comprising four variable domains of heavy chains and four variable domains of light chains have been developed. Examples of these include TandAbs and Flexibodies (Affimed Therapeutics AG, Heidelberg. Germany). Due to its four binding domains the TandAb usually shows better binding properties compared to antibody formats comprising only two binding domains, such as e.g. diabodies. Flexibodies are a combination of scFv with a diabody multimer motif resulting in a multivalent molecule with a high degree of flexibility for joining two molecules which are quite distant from each other on the cell surface.The antibody may further be comprised in a complex with further immunoglobulin molecules or fragments thereof (such as further antibodies) or non-immunoglobulin molecules. For example, the antibody may form a homomultimer with further identical antibodies. Preferably, the antibody is comprised in a Chimeric Antigen Receptor (CAR). The term “CAR” describes any receptor protein, usually on a T cell, which has been specifically designed to allow T cells to target a specific antigen. Methods for preparing CARs are well known to the person skilled in the art.In a preferred embodiment, the anti-L1 CAM antibody for use is selected from monoclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies, including bispecific antibodies, human antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, an antibody light chain monomer, an antibody heavy chain monomer, an antibody light chain dimer, an antibody heavy chain dimer, an antibody light chainantibody heavy chain pair, intrabodies, heteroconjugate antibodies, single domain antibodies, monovalent antibodies, single chain antibodies or single-chain Fvs (scFv), camelid antibodies, affibodies, anticalins, affilins, atrimers, DARPins, FN3 scaffolds, such as adnectins and centyrins, fynomers, Kunitz domains, pronectins and OBodies, Fab fragments, F(ab’)2 fragments, disulfide-linked Fvs (dsFv), anti- idiotypic (anti-ld) antibodies, and antigen-binding fragments of any of the above, and / or wherein the antibody is comprised in a Chimeric Antigen Receptor (CAR).In another further preferred embodiment, the anti-L1 CAM antibody for use is selected from monoclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies, including bispecific antibodies, human antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, an antibody light chain monomer, an antibody heavy chain monomer, an antibody light chain dimer, an antibody heavy chain dimer, an antibody light chain-antibody heavy chain pair, intrabodies, heteroconjugate antibodies, single domain antibodies, monovalent antibodies, single chain antibodies or singlechain Fvs (scFv), camelid antibodies, Fab fragments, F(ab’)2 fragments, disulfide- linked Fvs (dsFv), anti-idiotypic (anti-ld) antibodies, and antigen-binding fragments of any of the above, and / or wherein the antibody is comprised in a Chimeric Antigen Receptor (CAR).Preferably, the antibodies described herein may be IgG antibodies, or an isotype thereof, such as human IgG 1 , human lgG2 or human lgG4.Preferably, the antibody is a humanized monoclonal antibody. Alternatively, the antibody may be a chimeric antibody. Alternatively, the antibody may be a human antibody. For example, an antibody described herein is an IgG 1 or lgG2 antibody.In general, in cases of full-length, intact antibodies, each heavy chain is connected to one of the light chains, whereby the variable regions of a heavy and a light chain combine to form one of the two identical antigen-binding sites and their constant regions combine to form the constant region of the antibody. Further, both constructs of one heavy and one light chain may be connected via the constant regions of their heavy chains, forming a “Y”-shaped molecule, whereby the two arms depict the antigen-binding variable region and the stem depicts the constant region.The anti-L1 CAM antibody for use according to any of the aspects of the invention herein may be an intact antibody, meaning that it usually comprises a heavy chain of three or four constant domains and a light chain of one constant domain as well as the respective variable domains, whereby each domain may comprise further modifications, such as mutations, deletions or insertions, which do not change the overall domain structure.The terms “treatment”, “treat” or “treating” are used interchangeably herein and describe any form of improving the health status of a human or animal body with respect to a disease or a condition. This may comprise a lessening of symptoms, slowing progression, a slight improvement, but also the complete cure of the human or animal body of the disease or condition. The term “prophylactic”, “prophylaxis”, “prophylactically treating”, “prevention” and “preventing” are used interchangeably herein and describe keeping the health status of a human or animal body from suffering from a disease or a condition.In one embodiment, the anti-L1 CAM antibody is for use in the treatment of a human L1 CAM-positive hematological malignancy disease in a human subject. In such embodiment, the human subject is suffering from a L1 CAM-positive hematological malignancy disease. In one embodiment, the human subject is diagnosed to suffer from a human L1 CAM-positive hematological malignancy disease. In one embodiment, the human subject is suspected to suffer from a human L1 CAM- positive hematological malignancy disease. The human subject suspected to sufferor suffering from a human L1 CAM-positive hematological malignancy disease may have one or more symptoms of the hematological malignancy disease.In another embodiment, the anti-L1 CAM antibody is for use in the prophylaxis of a human L1 CAM-positive hematological malignancy disease in a human subject. In such embodiment, the human subject is not suffering from a L1 CAM-positive hematological malignancy disease. In an embodiment, the human subject is diagnosed not to suffer from a L1 CAM-positive hematological malignancy disease. In embodiments, the human subject is at risk of suffering from a hematological malignancy disease or a human L1 CAM-positive hematological malignancy disease.A human subject at risk of suffering from a L1 CAM-positive hematological malignancy disease includes a subject with family history of a hematological malignancy disease and a subject which suffered from a hematological malignancy disease in the past and was successfully treated. Such subjects are at risk of a recurrence or relapse of a L1 CAM-positive hematological malignancy disease.The human subject may be of any age. Preferably, the human subject is a child or an adult, in particular an adult.The anti-L1 CAM antibody is for use in the treatment or prophylaxis of a human L1 CAM-positive hematological malignancy disease in a human subject.The term "malignancy" refers to the presence of cancerous cells that have the ability to spread to other sites in the body, thereby metastasizing, or to invade into tissue locally and destroy tissues. Malignant cells are typically characterized by fast and / or uncontrolled growth.A “malignancy disease” is understood as a disease comprising malignant cells.A “hematological disease” is understood as disease of hematopoietic and / or lymphoid tissues, including a disease affecting the blood, bone marrow, lymph, and / or lymphatic system.A “hematological malignancy disease” is understood as a malignant disease of hematopoietic and / or lymphoid tissues, including a malignant disease affecting the blood, bone marrow, lymph, and / or lymphatic system. The terms “hematologicalmalignancy disease” and “hematological malignancy” are used interchangeably herein.Hematological malignancy diseases, or hematological malignancies, may derive from the myeloid or the lymphoid lineage. Cell types of the myeloid lineage typically comprise granulocytes, erythrocytes, thrombocytes, macrophages and / or mast cells. Cell types of the lymphoid lineage typically comprise B, T, NK and / or plasma cells.For example, a lymphoma, a lymphocytic leukemia, and a myeloma is derived from the lymphoid cell lineage. For example, an acute or chronic myelogenous leukemia, myelodysplastic syndromes and myeloproliferative diseases are derived from the myeloid cell lineage.Methods for diagnosing hematological malignancies are known to a skilled person. For example, the diagnosis may encompass determining a complete blood count and blood film. Typically, malignant cells exhibit typical characteristics in light microscopy. In cases of lymphadenopathy, a biopsy from a lymph node may be taken surgically and analysed for diagnosis. In other cases, a bone marrow biopsy may be obtained for the diagnosis. Biopsy specimens may be examined microscopically to determine and diagnose the hematological malignancy. A number of hematological malignancy diseases can be classified by cytogenetics (AML, CML) or immunophenotyping (lymphoma, myeloma, CLL) of the malignant cells.The hematological malignancy disease treated or prophylactically treated herein is a human L1 CAM-positive hematological malignancy disease.A hematological malignancy disease is understood herein as human L1 CAM- positive hematological malignancy disease in case cell(s) or tissue(s) affected by the hematological malignancy express human L1 CAM protein and / or RNA.For example, in case of a lymphoma in a subject, the lymphoma is a human L1 CAM- positive lymphoma in case lymphoma cells of the subject express human L1 CAM protein and / or human L1 CAM RNA. Typically, the RNA is mRNA.In embodiments, the cell(s) or tissue(s) affected by the hematological malignancy express human L1 CAM RNA.In embodiments, the cell(s) or tissue(s) affected by the hematological malignancy disease express human L1 CAM protein. In embodiments, the cell(s) or tissue(s) affected by the hematological malignancy express of human L1 CAM protein on the cell surface of the cell(s).In this embodiment, the anti-L1 CAM antibody can bind to the malignant cells and thereby exert the desired therapeutic effect.Methods for detecting or determining human L1 CAM protein and / or human L1 CAM RNA in hematological cells, and methods for determining the amount of human L1 CAM protein and / or human L1 CAM RNA in hematological cells, are known in the art and are for example described in the examples.For example, methods for detecting or determining expression of human L1 CAM in hematological cells, and methods for determining the amount of L1 CAM protein expressed by hematological cells, comprise immunohistochemistry (IHC), immune assays, such as ELISA, or flow cytometry methods. For these methods, anti-L 1 CAM antibodies may be used. The anti-L1 CAM antibody may be the same antibody as used for treatment or prophylaxis, or may be a different anti-L1 CAM antibody.Methods for detecting or determining human L1 CAM RNA, in particular mRNA, in hematological cells and methods for determining the amount of L1 CAM RNA, in particular mRNA, expressed by hematological cells are known in the art and include isolating mRNA from the cells, reverse transcription into cDNA, optionally amplifying human L1 CAM cDNA via PCR, and sequencing.It is in general preferred that the amount of L1 CAM protein or L1 CAM RNA in hematological cells is high, as it is expected that a higher amount of human L1 CAM increases the responsiveness of the cells, and therefore, the human subject, to a treatment with an anti-L1 CAM antibody.In an embodiment, the amount of L1 CAM RNA in the cell(s) or tissue(s) affected by the hematological malignancy disease is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or more higher than the amount of L1 CAM RNA in the RAMOS cell line. Preferably the amount of RNA is determined by Real-time PCR using for example QuantiFast® SYBR® Green RT-PCR (Qiagen).In an embodiment, the amount of L1 CAM protein is determined by L1 CAM immunohistochemistry. In particular, one or more of the cell(s) or tissue(s) affected by the hematological malignancy disease may be determined to display an L1 CAM immunohistochemical staining intensity of at least 1 , 2, or 3 on a score from 0 (no staining) to 3 (intense staining) Preferably, the L1 CAM immunohistochemistry method uses the mouse anti- human L1 CAM antibody 14.10 and an anti-mouse secondary antibody conjugated to a horseradish peroxidase-conjugated polymer on an autostainer device.In one embodiment, the human L1 CAM-positive hematological malignancy disease is selected from a T cell lymphoma and a B cell lymphoma.A lymphoma is a blood and lymph tumour that develops from lymphocytes.For example, the lymphoma may be a non-Hodgkin lymphoma, or may be a Hodgkin lymphoma.A T cell lymphoma is a lymphoma that affects T lymphocytes.A B cell lymphoma is a lymphoma that affects B lymphocytes.In one embodiment, the human L1 CAM-positive hematological malignancy disease is selected from Mantle cell lymphoma, Sezary Syndrome, Mycosis fungoides, Activated B-cell-diffuse large B cell lymphoma, Germinal center B-cell-diffuse large B cell lymphoma, Follicular lymphoma, Anaplastic large cell lymphoma, Hodgkin lymphoma and Diffuse large B-cell lymphoma.Mantle Cell lymphoma (MCL) is an aggressive, rare form of non-Hodgkin lymphoma (NHL) that arises from cells originating in the so-called mantle zone. MCL is a B-cell lymphoma.Sezary Syndrome is a type of cutaneous T-cell lymphoma. The affected T cells, known as Sezary's cells or Lutzner cells, have pathological quantities of mucopolysaccharides.Mycosis fungoides, also known as Alibert-Bazin syndrome or granuloma fungoides, is the most common form of cutaneous T-cell lymphoma. It generally affects the skin, but may progress internally over time.Diffuse large B-cell lymphoma (DLBCL) is a B cell lymphoma. It is the most common form of non-Hodgkin lymphoma among adults.Activated B-cell-diffuse large B cell lymphoma is a subset of diffuse large B cell lymphoma (DLBCL). The activated B-cell (ABC) subset of diffuse large B-cell lymphoma (DLBCL) is biologically distinct, characterized by clonic B-cell receptor signaling, and associated with poor outcomes when treated with a standard therapy.Germinal center B-cell-diffuse large B cell lymphoma is a subset of diffuse large B cell lymphoma (DLBCL). Germinal Center B-Cell like (GCB) DLBCLs appear to arise from normal germinal center B cells.Follicular lymphoma (FL) is a B cell lymphoma. FL originates from the uncontrolled division of specific types of B-cells known as centrocytes and centroblasts.Anaplastic large cell lymphoma (ALCL) is a rare form of non-Hodgkin lymphoma in which aberrant T cells proliferate uncontrollably.Hodgkin lymphoma is a type of lymphoma, in which the cancer originates from lymphocytes, where multinucleated Reed-Sternberg cells (RS cells) are present in the patient's lymph nodes.In one embodiment, one or more hematological cells of the subject express human L1 CAM on the cell surface.In an embodiment, the amount of L1 CAM protein is determined by L1 CAM immunohistochemistry. In embodiments, one or more of the cell(s) or tissue(s) affected by the hematological malignancy disease are determined to display an immunohistochemical L1 CAM staining intensity of at least 1 , 2, or 3 on a score from 0 (no staining) to 3 (intense staining). Preferably, the L1 CAM immunohistochemistry method uses the mouse anti-human L1 CAM antibody 14.10 and an anti-mouse secondary antibody conjugated to a horseradish peroxidase-conjugated polymer on an autostainer device..Methods for detecting or determining that one or more hematological cells of the subject express human L1 CAM on the cell surface, and methods for determining the amount of L1 CAM protein expressed on the cell surface of hematological cellsare known in the art and comprise immunohistochemistry (IHC), immune assays, such as ELISA, or flow cytometry methods using anti-L1 CAM antibodies which bind to the extracellular portion of human L1 CAM. The anti-L1 CAM antibody which binds to the extracellular portion of human L1 CAM may be the same antibody as used for treatment or prophylaxis, or may be a different anti-L1 CAM antibody.The extracellular portions of human L1 CAM protein comprise an N-terminal portion encompassing six immunoglobulin domains, which are designated Ig I to Ig VI, followed by five fibronectin type III domains, designated FN III 1 -5.Anti-L1 CAM antibodies binding to the extracellular portion of human L1 CAM, which can be used for the treatment or prophylaxis of a L1 CAM-positive hematological malignancy disease in a human subject are known in the art. Suitable anti-L1 CAM antibodies include antibody L1 -OV52.24 or an antibody-binding fragment thereof, or an antibody comprising the set of 6 CDR regions of antibody L1 -OV52.24, or an antibody comprising the VH and the VL region of antibody L1 -OV52.24, which are disclosed in WO2016 / 050702, or a humanized version thereof. A further prior art anti-L1 CAM antibody which can be used according to the invention is mAb L1 -9.3 (also called mAb 9.3), disclosed in W02008 / 151819 and anti-L1 CAM antibodies disclosed in W02020 / 003210 including antibody mAb417 or an antibody-binding fragment thereof, or an antibody comprising the set of 6 CDR regions of antibody mAb417, or an antibody comprising the VH and the VL region of antibody mAb417. Further prior art antibodies specifically binding to L1 CAM are mAb 14.10 Huszar et al. 2006); mab chCE7 (Meli et al., 1999); mAb UJ127.11 (Patel et al., 1991 ); and mAb 5G3 (commercially available, ThermoFisher Scientific, Germany). Further, suitable anti-L1 CAM antibodies include the antibodies exemplified below, in particular antibodies comprising the 6 CDR regions of the antibodies AFF4-WT and AFF4 used in the examples. Such anti-L1 CAM antibodies used herein comprise: (a) a heavy chain variable region (VH) comprising a VH CDR1 comprising the amino acid sequence of GYSITSDYTWN (SEQ ID NO: 1 ), a VH CDR2 comprising the amino acid sequence of YISYSGSYSYNPSLKS (SEQ ID NO: 2), and a VH CDR3 comprising the amino acid sequence of SFSYSYGFAY (SEQ ID NO: 3); and (b) a light chain variable region (VL) comprising a VL CDR1 comprising the amino acid sequence of KASQDVSSAVA (SEQ ID NO: 4), a VL CDR2 comprising the amino acid sequence of SASYRYT (SEQ ID NO: 5), and a VL CDR3 comprising the amino acid sequence of QQHYSTPWT (SEQ ID NO: 6). In embodiments, the epitope bound by the anti-L1 CAM antibody is within the fibronectin type III domains 1 -5 (FN III 1 -5) of human L1 CAM.In embodiments, the epitope bound by the anti-L1 CAM antibody is within the fibronectin type III domains 1 -3 (FN III 1 -3) of human L1 CAM. A suitable antibody which binds to such epitope is antibody AFF4 or AFF4-WT.In one embodiment, it may be possible to stratify, select and / or identify a human subject in which hematological cell(s) of the subject express human L1 CAM on the cell surface. In case one or more hematological cells of the subject are determined to express human L1 CAM on the cell surface, the human subject may in particular benefit from the treatment or prophylaxis by administering an anti-L1 CAM antibody described herein.Accordingly, in one embodiment, the use further comprises:(i) providing a hematological sample of the human subject; and(ii) determining whether one or more hematological cells of the subject express human L1 CAM on the cell surface; wherein the antibody that specifically binds to human L1 CAM is for use in the treatment or prophylaxis of a human L1 CAM-positive hematological malignancy disease in the human subject in case one or more hematological cells of the subject are determined in step (ii) to express human L1 CAM on the cell surface.For example, in step (i), a suitable sample comprising hematological cells of interest from the human subject may be provided. For example, the sample may be a blood sample or lymphoid sample, such as a lymph node biopsy, or a bone marrow biopsy. Optionally, hematological cells of interest, such as lymphocytes, may be further enriched or purified.In step (ii), it is determined whether one or more hematological cells of the subject express human L1 CAM on the cell surface. Methods for determining that one or more hematological cells of the subject express human L1 CAM on the cell surface are known in the art and comprise immunohistochemistry (IHC), immune assays, such as ELISA, or flow cytometry methods using anti-L1 CAM antibodies which bind to the extracellular portion of human L1 CAM. The anti-L1 CAM antibody which binds to the extracellular portion of human L1 CAM may be the same antibody as used for treatment or prophylaxis, or may be a different anti-L1 CAM antibody.In this embodiment, the antibody that specifically binds to human L1 CAM is for use in the treatment or prophylaxis of a human L1 CAM-positive hematologicalmalignancy disease in the human subject in case one or more hematological cells of the subject are determined in step (ii) to express human L1 CAM on the cell surface.In a preferred embodiment, the antibody that specifically binds to human L1 CAM is for use in the treatment or prophylaxis of a human L1 CAM-positive hematological malignancy disease in the human subject in case one or more hematological cells of the subject are determined by immunohistochemistry in step (ii) to display a L1 CAM immunohistochemical staining intensity of at least 1 , 2, or 3 on a score from 0 (no staining) to 3 (intense staining). Preferably, the L1 CAM immunohistochemistry method uses the mouse anti- human L1 CAM antibody 14.10 and a anti-mouse secondary antibody conjugated to a horseradish peroxidase-conjugated polymer on an autostainer device.In one embodiment of the aspects herein, the human subject is determined to express human L1 CAM on the cell surface.In one embodiment of the aspects herein, the human subject is determined to express an amount of human L1 CAM on the cell surface which results in an L1 CAM immunohistochemical staining intensity of at least 1 , 2, or 3 on a score from 0 (no staining) to 3 (intense staining). Preferably, the L1 CAM immunohistochemistry method uses the mouse anti- human L1 CAM antibody 14.10 and a anti-mouse secondary antibody conjugated to a horseradish peroxidase-conjugated polymer on an autostainer device.In one embodiment, the antibody is selected from an antibody comprising an Fc portion and / or an antibody linked to a therapeutically active substance.In one embodiment, the antibody comprises an Fc portion. In embodiments, the antibody comprises an Fc portion of a human IgG Fc heavy chain constant region.The heavy chain constant region may further be a variant of a wild type human IgG heavy chain constant region, preferably wherein the variant human IgG heavy chain constant region binds to one or more of human Fc gamma receptors. In general Fc receptors are surface proteins of certain cells contributing to the immune system. There are several classes of Fc receptors, which among others may be distinguished by the antibody type they interact with. The term “Fc gamma receptor” therefore describes Fc receptors binding antibodies having an IgG constant region.The class of Fc gamma receptors further comprises several subclasses, such as FcyRI, FcyRIIA, FcyRIIB, FcyRIIIA or FcyRIIIB, which generally differ in their structure and affinity to IgG and the different IgG subclasses. Preferably, the variant human IgG heavy chain constant region of the anti-L1 CAM antibody for use of the invention binds to one or more of human Fc gamma receptors selected from the group consisting of FcyRI, FcyRIIA, FcyRIIIA. Also preferably, the variant human IgG heavy chain constant region binds to one or more of human Fc gamma receptors selected from the group consisting of FcyRI, FcyRIIA, FcyRIIIA with higher affinity than the wild type human IgG heavy chain constant region binds to the human Fc gamma receptors. “Binding with higher affinity” means that the binding of the anti-L1 CAM antibody for use according to the invention to one or more of the human Fc gamma receptors selected from the group consisting of FcyRI, FcyRIIA, FcyRIIIA is at least 2-fold, preferably at least 3-fold stronger than the binding of the wild type human IgG heavy chain constant region to the human Fc gamma receptors, as determined e.g. by methods known to the person skilled in the art, such as Western Blot analysis, ELISA, or surface plasmon resonance.In a yet further preferred embodiment, the heavy chain constant region is a variant of a wild type human IgG heavy chain constant region, preferably wherein the variant human IgG heavy chain constant region binds to one or more of human Fc gamma receptors selected from the group consisting of FcyRI, FcyRIIA, FcyRIIIA with higher affinity than the wild type human IgG heavy chain constant region binds to the human Fc gamma receptors.In one embodiment, the antibody is an antibody linked to a therapeutically active substance. In one embodiment, the antibody comprises an Fc portion and the antibody is linked to a therapeutically active substance.In one embodiment, the antibody is selected from an internalizing and / or cytotoxic antibody.In an embodiment, the cytotoxic antibody may be an anti-L1 CAM antibody linked to a cytotoxic compound, thereby forming an Antibody Drug conjugate (ADC).The term “cytotoxic compound” describes any substance being toxic to cells, e.g. by causing apoptosis or necrosis. Suitable examples of cells are known by the person skilled in the art, such as immune cells. The cytotoxicity of a compound may be measured by common cytotoxicity assays known to the person skilled in the art.Examples of cytotoxic agents include, for example, small molecule toxins or enzymatically active toxins of bacteria (such as Diptheria toxin, Pseudomonas endotoxin and exotoxin, Staphylococcal enterotoxin A), fungi (e.g., a-sarcin, restrictocin), or plants (e.g., abrin, ricin, modeccin, viscumin, pokeweed anti-viral protein, saporin, gelonin, momoridin, trichosanthin, barley toxin, Aleurites fordii proteins, dianthin proteins, Phytolacca mericana proteins (PAPI, PAPII, and PAP- S), Momordica charantia inhibitor, curcin, crotin, saponaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, neomycin, and the tricothecenes), a mitotic inhibitor or a DNA damaging agent.In embodiments, the ADC is an internalizing antibody.An internalizing antibody is internalized by a cell upon binding of the antibody to the cell. Internalization may be determined by methods known in art, such as determining the time course of binding of the antibody on the cell surface, such as by fluorescence microscopy.In another embodiment, the cytotoxic antibody may be an anti-L1 CAM antibody comprising the Fc portion. For example, a wildtype human Fc region may be used or a variant human IgG heavy chain constant region which binds to one or more of human Fc gamma receptors selected from the group consisting of FcyRI, FcyRIIA, FcyRIIIA.In the examples, antibodies designated AFF4-WT and AFF4 were used. In particular, for an antibody conjugated to cytotoxic payloads, thereby providing an ADC, a version of AFF4 was used which contains wild type human lgG1 constant domains. AFF4 is a variant of AFF4-WT which contains the G236A / S239D / A330L / I332E mutations (Ell numbering) in the CH2 domains of the human lgG1 heavy chains. The antibodies designated AFF4-WT and AFF4 contain the identical VH and VL regions and identical sets of 6 CDR regions VH CDR1 consisting of the amino acid sequence of GYSITSDYTWN (SEQ ID NO: 1 ), VH CDR2 consisting of the amino acid sequence of YISYSGSYSYNPSLKS (SEQ ID NO: 2), VH CDR3 consisting of the amino acid sequence of SFSYSYGFAY (SEQ ID NO: 3); VL CDR1 consisting of the amino acid sequence of KASQDVSSAVA (SEQ ID NO: 4), VL CDR2 consisting of the amino acid sequence of SASYRYT (SEQ ID NO: 5), and VL CDR3 consisting of the amino acid sequence of QQHYSTPWT (SEQ ID NO: 6)(Kabat numbering).Table 1. Heavy chain CDR sequences anti-L1 CAM antibodies AFF4 and AFF4- WT11The CDRs in Table 1 are determined according to Kabat.Table 2. Light chain CDR sequences of exemplary anti-L1 CAM antibodies AFF4 and AFF4-WT22The CDRs in Table 2 are determined according to Kabat.In general, each heavy chain variable region and each light chain variable region of an antibody comprises three non-consecutively arranged complementary- determining regions (CDRs).As used herein, the term "CDR" or "complementarity determining region" means the noncontiguous antigen combining sites found within the variable region of both heavy and light chain polypeptides. These particular regions have been described by Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) (

[0012] ) and Kabat et al., Sequences of protein of immunological interest. (1991 ), and by Chothia et al., J. Mol. Biol. 196:901 -917 (1987) and by MacCallum et al., J. Mol. Biol. 262:732-745 (1996) (

[0013] -

[0015] ) where the definitions include overlapping or subsets of amino acid residues when compared against each other. The amino acid residues which encompass the CDRs as defined by each of the above cited references are set forth for comparison.For the antibodies herein, the term "CDR" is a CDR as defined by Kabat, based on sequence comparisons.CDRs usually are numbered CDR1 , CDR2 and CDR3 for the heavy chain variable region and the light chain variable region, respectively. As a result, an arm of an antibody usually has 6 CDRs, which together form an antigen-binding site. In general, CDRs usually each are 1 to 25 amino acids in length, preferably 3 to 20 amino acids in length, such as 3 to 16 amino acids in length. An antibody may comprise one, two or more arms, i.e. one, two or three antigen-binding sites.In one embodiment, the antibody comprises:(a) a heavy chain variable region (VH) comprising a VH CDR1 comprising the amino acid sequence of GYSITSDYTWN (SEQ ID NO: 1 ), a VH CDR2 comprising the amino acid sequence of YISYSGSYSYNPSLKS (SEQ ID NO: 2), and a VH CDR3 comprising the amino acid sequence of SFSYSYGFAY (SEQ ID NO: 3); and(b) a light chain variable region (VL) comprising a VL CDR1 comprising the amino acid sequence of KASQDVSSAVA (SEQ ID NO: 4), a VL CDR2 comprising the amino acid sequence of SASYRYT (SEQ ID NO: 5), and a VL CDR3 comprising the amino acid sequence of QQHYSTPWT (SEQ ID NO: 6).Besides the specific CDRs mentioned above, the heavy and / or light chain variable regions of the anti-L1 CAM antibody for use of the invention may also comprise one or more below-mentioned specific framework regions.The antibody may comprise framework sequences from any species. In embodiments, the antibody comprises human framework sequences or humanized framework sequences. For example, the framework sequences may each be human, wherein optionally non-human positions are present, such as 1 to 10 (including 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 including any sub-range thereof) non-human positions.As used herein the term "framework (FR) amino acid residues" refers to those amino acids in the framework region of an immunoglobulin chain. The term "framework region" or "FR region" as used herein, includes the amino acid residues that are part of the variable region, but are not part of the CDRs (e.g., using the Kabat definition of CDRs). The framework regions usually support the binding of the antibody to an antigen by either supporting the antibody’s structure (and not being in contact with the antigen) or by directly contacting the antigen. The term “antigen” describes any molecule or molecular structure that may be bound by an antibody specific for that antigen.Methods for producing a monoclonal antibody with the CDR sequences as mentioned above are known in the art and include the introduction of the nucleic acid sequences encoding the CDRs into suitable expression vectors encoding the desired framework sequences. The antibodies designated AFF4-WT and AFF4 contain the identical VH region with the amino acid sequence of SEQ ID NO: 7 and the VL region with the amino acid sequence of SEQ ID NO: 8.Table 3. VH and VL sequences of exemplary anti-L1 CAM antibodies AFF4 and AFF4-WT33The CDRs are shown underlined in Table 5. The CDRs in Table 5 are determined according to Kabat.Therefore, in one embodiment, the antibody comprises:(a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7; and(b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8.In the Examples, humanized optimized antibodies were prepared and used. A humanized optimized antibody “AFF4” is provided which is an IgG-type antibody wherein the heavy chain variable region sequence consists of the amino acid sequence of SEQ ID NO: 7 and the light chain variable region sequence consists of the amino acid sequence of SEQ ID NO: 8, linked to a human lgG1 heavy chain constant region with G236A / S239D / A330L / I332E mutations (Ell numbering) in the human lgG1 constant region. The heavy chain of the antibody consists of the amino acid sequence of SEQ ID NO: 9 and the light chain sequence consists of the amino acid sequence of SEQ ID NO: 11 .In the Examples, also the humanized optimized antibody designated “AFF4-WT” was prepared and used. Antibody “AFF4-WT” is an IgG-type antibody wherein the heavy chain variable region sequence consists of the amino acid sequence of SEQ ID NO: 7 and the light chain variable region sequence consists of the amino acid sequence of SEQ ID NO: 8, linked to wildtype human lgG1 constant region. The heavy chain of AFF4-WT consists of the amino acid sequence of SEQ ID NO: 10 and the light chain sequence consists of the amino acid sequence of SEQ ID NO: 11.In one embodiment, the antibody comprises a heavy chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 9 or 10 and / or a light chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 11 .In a yet further preferred embodiment, the antibody comprises a heavy chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 9 or 10 and a light chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 11.In a yet further preferred embodiment, the antibody comprises a heavy chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 9 and / or a light chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 11. In a yet further preferred embodiment, the antibody comprises a heavy chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 9 and a light chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 11 .In a yet further preferred embodiment, the antibody comprises a heavy chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 10 and / or a light chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 11. In a yet further preferred embodiment, the antibody comprises a heavy chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 10 and a light chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 11 .In another further preferred embodiment, the antibody consists of a heavy chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 9 or 10 and / or a light chain sequence comprising or consisting of an amino acidsequence of SEQ ID NO: 11 . In another further preferred embodiment, the antibody consists of a heavy chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 9 or 10 and a light chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 11 .In another further preferred embodiment, the antibody consists of a heavy chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 9 and / or a light chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 11. In another further preferred embodiment, the antibody consists of a heavy chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 9 and a light chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 11 .In another further preferred embodiment, the antibody consists of a heavy chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 10 and / or a light chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 11. In another further preferred embodiment, the antibody consists of a heavy chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 10 and a light chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 11 .Optionally, 1 , 2 or 3 amino acids may be deleted at the C-terminus of a full-length heavy chain. It is known that such deletion(s) do not affect the stability of antibodies. Moreover, it is further possible to use a heavy chain including the C-terminal Lysine of the Fc domain. Depending on the recombinant expression system used, the C- terminal Lysine of the Fc domain may be present or absent.Exemplary combinations of sequences of heavy and light chain regions are given in Table 4 and 5 below.Table 4. Heavy chain (HC) and light chain (LC) sequences of exemplary anti-L1 CAM antibodies AFF4 and AFF4-WT44The CDRs are shown underlined in Table 4. The CDRs in Table 4 are determined according to Kabat. The sequences of FR1 , FR2 and FR3 of the respective variable domain heavy and light chain sequences are shown in italics. Table 5: Sequences of prior art antibody L1 -OV52.24The CDRs in Table 5 are determined according to Kabat.In one embodiment, the antibody is linked to a therapeutically active substance, wherein the therapeutically active substance is selected from the group consisting of a DNA damaging agent, an anti-apoptotic agent, a mitotic inhibitor, an anti-tumor antibiotic, an immunomodulating agent, a nucleic acid for gene therapy, an anti- angiogenic agent, an anti-metabolite, a boron-containing agent, a chem ©protective agent, a hormone agent, an anti-hormone agent, a corticosteroid, a photoactive therapeutic agent, an oligonucleotide, a radioisotope, a radiosensitizer, a topoisomerase inhibitor, and a tyrosine kinase inhibitor.The term “therapeutically active substance” describes any biologically active substance, i.e. a substance causing an effect in a living matter. When used in a pharmaceutical drug, the therapeutically active substance is e.g. responsible for the activity of the medicine. Methods for determining the effect of a substance on living matter are well known to the person skilled in the art. The terms “therapeutically active substance", “therapeutically active substance moiety”, "drug," "agent," and "drug moiety" are used interchangeably herein.The terms "linked" and "conjugated" are also used interchangeably herein and indicate that the antibody and moiety are covalently linked.Herein, an antibody linked to a therapeutically active substance, optionally via a linker, is also referred to as “ADC” or “antibody drug conjugate”.The term “linker” describes any molecule suitable for connecting the antibody herein to the therapeutically active substance via a covalent bond.In an embodiment, the linker provides a stable connection between the antibody of the invention and the therapeutically active substance, when applied to the body and circulating therein and only becomes cleavable within the target cell or when arriving at the target tissue. For example, the linker may be a peptide having a length of 2 to 50 amino acids, such as a dipeptide, or an organic compound, such as succinimidyl 4-(N-maleimidomethyl)cyclohexane-1 -carboxylate (SMCC).A linker may include one conjugating component or may include multiple components.For example, the linker may include a spacer, which is a moiety that extends the drug linkage to avoid, for example, shielding the linker cleavage site or improvingthe solubility of the ADC. Other examples of components of linkers include a stretcher unit and an amino acid unit.Two methods are commonly used for conjugating drugs to antibodies: alkylation of reduced interchain cysteine disulfides through an enzymatically non-cleavable maleimido or simple and cleavable disulfide linker, and acylation of lysines by cleavable linear amino acids.In one aspect, a linker covalently attaches an antibody to a therapeutically active substance. The same applies to a diagnostic compound. An ADC is prepared using a linker having reactive functionality for binding to the antibody and the therapeutically active substance or diagnostic compound. For example, a cysteine thiol, or an amine, e.g., N-terminus or amino acid side chain such as lysine, of the antibody may form a bond with a functional group of the linker.In one embodiment, a linker has a functionality that is capable of reacting with a free cysteine present on an antibody to form a covalent bond. Nonlimiting examples of such reactive functionalities include maleimide, haloacetamides, a-haloacetyl, activated esters such as succinimide esters, 4-nitrophenyl esters, pentafluorophenyl esters, tetrafluorophenyl esters, anhydrides, acid chlorides, sulfonyl chlorides, isocyanates, and isothiocyanates.In some embodiments, a linker has a functionality that is capable of reacting with an electrophilic group present on an antibody. Exemplary such electrophilic groups include, but are not limited to, aldehyde and ketone carbonyl groups. In some embodiments, a heteroatom of the reactive functionality of the linker can react with an electrophilic group on an antibody and form a covalent bond to an antibody unit. Nonlimiting examples of such reactive functionalities include, but are not limited to, hydrazide, oxime, amino, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide.In some embodiments, antibody use herein is linked to at least one therapeutically active substance via a linker, and has the following formula (formula I):Ab-(L-D)n (I) wherein Ab is an antibody described herein for use in an aspect, and (L-D) is a Linker-Drug moiety. The Linker-Drug moiety is made of L- which is a Linker, and -D, which is a therapeutically active substance moiety (or drug moiety) having, for example, cytostatic, cytotoxic, or otherwise therapeutic activity against a target cell, e.g., a cell expressing L1 CAM; and n is an integer from 1 to 20. In some embodiments, n ranges from 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, or is 1.Examples of therapeutically active substances that may be used in ADCs, i.e., therapeutically active substances that may be conjugated to the antibodies of the invention include mitotic inhibitors, antitumor antibiotics, immunomodulating agents, gene therapy vectors, alkylating agents, antiangiogenic agents, antimetabolites, boron-containing agents, chemoprotective agents, hormone agents, glucocorticoids, photoactive therapeutic agents, oligonucleotides, radioactive isotopes, radiosensitizers, topoisomerase inhibitors, tyrosine kinase inhibitors, and combinations thereof.Mitotic InhibitorsIn one embodiment, antibodies may be conjugated to one or more mitotic inhibitor(s) to form an ADC for the treatment of a L1 CAM-positive hematological malignancy. The term "mitotic inhibitor", as used herein, refers to a cytotoxic and / or therapeutic agent that blocks mitosis or cell division, a biological process particularly important to cancer cells. A mitotic inhibitor disrupts microtubules such that cell division is prevented, often by affecting microtubule polymerization (e.g., inhibiting microtubule polymerization) or microtubule depolymerization (e.g., stabilizing the microtubule cytoskeleton against depolymerization). Thus, in one embodiment, an anti-LCAM antibody herein is conjugated to one or more mitotic inhibitor(s) that disrupt(s) microtubule formation by inhibiting tubulin polymerization. In another embodiment, an antibody of the invention is conjugated to one or more mitotic inhibitor(s) that stabilize(s) the microtubule cytoskeleton against depolymerization. Examples of mitotic inhibitors that may be used in the ADCs are provided below. Included in the genus of mitotic inhibitors are auristatins and maytansinoids, which are further described below.DolastatinsThe antibodies may be conjugated to at least one dolastatin to form an ADC. Dolastatins are short peptidic compounds isolated from the Indian Ocean sea hare Dolabella auricularia. Examples of dolastatins include dolastatin 10 and dolastatin 15. Dolastatin 15, a seven-subunit depsipeptide derived from Dolabella auricularia, is a potent antimitotic agent structurally related to the antitubulin agent dolastatin10, a five-subunit peptide obtained from the same organism. Auristatins are synthetic derivatives of dolastatin 10.AuristatinsAntibodies of the invention may be conjugated to at least one auristatin. Auristatins represent a group of dolastatin analogues that have generally been shown to possess anticancer activity by interfering with microtubule dynamics and GTP hydrolysis, thereby inhibiting cellular division. For example, Auristatin E is a synthetic analogue of the marine natural product dolastatin 10, a compound that inhibits tubulin polymerization by binding to the same site on tubulin as the anticancer drug vincristine. Dolastatin 10, auristatin PE, and auristatin E are linear peptides having four amino acids, three of which are unique to the dolastatin class of compounds. Exemplary embodiments of the auristatin subclass of mitotic inhibitors include, but are not limited to, monomethyl auristatin D (MMAD or auristatin D derivative), monomethyl auristatin E (MMAE or auristatin E derivative), monomethyl auristatin F (MMAF or auristatin F derivative), auristatin F phenylenediamine (AFP), auristatin EB (AEB), auristatin EFP (AEFP), and 5- benzoylvaleric acid-AE ester (AEVB).In one embodiment, an antibody is conjugated to at least one MMAE (monomethyl auristatin E). Monomethyl auristatin E (MMAE) inhibits cell division by blocking the polymerization of tubulin. Because of its toxicity, it also cannot be used as a drug itself. In recent cancer therapy developments, it is linked to an antibody that recognizes a specific marker expressed in cancer cells and directs MMAE to the cancer cells. In one embodiment, the linker linking MMAE to an antibody of the invention is stable in extracellular fluid (i.e., the medium or environment that is external to cells), but is cleaved by cathepsin once the ADC has bound to the specific cancer cell antigen and entered the cancer cell, thus releasing the toxic MMAE and activating the potent anti-mitotic mechanism. In one embodiment, the linker linking MMAE to an antibody of the invention is stable in extracellular fluid (i.e., the medium or environment that is external to cells), but is cleaved by glucuronidase once the ADC has bound to the specific cancer cell antigen and entered the cancer cell, thus releasing the toxic MMAE and activating the potent anti-mitotic mechanism.MaytansinoidsThe antibodies of the invention may be conjugated to at least one maytansinoid to form an ADC. Maytansinoids are potent antitumor agents that were originallyisolated from members of the higher plant families Celastraceae, Rhamnaceae, and Euphorbiaceae, as well as some species of mosses. Evidence suggests that maytansinoids inhibit mitosis by inhibiting polymerization of the microtubule protein tubulin, thereby preventing formation of microtubules. Maytansinoids have been shown to inhibit tumor cell growth in vitro using cell culture models, and in vivo using laboratory animal systems. Moreover, the cytotoxicity of maytansinoids is 1 ,000-fold greater than conventional chemotherapeutic agents, such as, for example, methotrexate, daunorubicin, and vincristine. Maytansinoids include for example maytansine, maytansinol, and C-3 esters of maytansinol.Suitable maytansinoids for use in ADCs of the invention can be isolated from natural sources, synthetically produced, or semi-synthetically produced. Moreover, the maytansinoid can be modified in any suitable manner, as long as sufficient cytotoxicity is preserved in the ultimate conjugate molecule. In this regard, maytansinoids lack suitable functional groups to which antibodies can be linked. A linking moiety desirably is utilized to link the maytansinoid to the antibody to form the conjugate.Representative examples of maytansinoids include, but are not limited, to DM1 (N2'~ deacetyl- N2'-(3-mercapto-1 -oxopropyl)-maytansine; also referred to as drug maytansinoid 1 , DM2, DM3 (N2'-deacetyl-N2'-(4-mercapto-1 -oxopentyl)- maytansine), DM4 (4-methyl-4-mercapto-1 -oxopentyl)-maytansine), and maytansinol (a synthetic maytansinoid analog).In one embodiment, an antibody is conjugated to at least one DM1. In one embodiment, an antibody is conjugated to at least one DM2. In one embodiment, an antibody is conjugated to at least one DM3. In one embodiment, an antibody is conjugated to at least one DM4.DNA Damaging AgentsIn one embodiment, an antibody may be conjugated to one or more DNA damaging agents. The term "DNA damaging agent", as used herein, refers to an agent which is capable of damaging DNA and is well known to those of ordinary skill in the art. DNA damaging agents include DNA alkylating agents. DNA damaging agents also include indolino-benzodiazepines (IGNs).In one embodiment, a DNA damaging agent may also include a pyrrolobenzodiazepine (PBD) or pyridinobenzodiazepine (PDD) (Veillard N. et al.:Pyridinobenzodiazepines (PDDs): A new class of sequence-selective DNA monoalkylating ADC payloads with low hydrophobicity. Cancer Res 78 (13_Supplement): 736. (2018); Stefano J.E., et al. : Micro- and Mid-Scale Maleimide-Based Conjugation of Cytotoxic Drugs to Antibody Hinge Region Thiols for Tumor Targeting. In: Ducry L. (eds) Antibody-Drug Conjugates. Methods in Molecular Biology (Methods and Protocols), vol 1045. Humana Press, Totowa, NJ. (2013)).For example, SG3199 or VA-SG3199 (tesirine) may be used. SG3199 is the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload tesirine.In a preferred embodiment, the mitotic inhibitor is selected from a maytansinoid and an auristatin.Auristatin MMAE was successfully used in ADCs of the invention in the Examples.In another preferred embodiment, the DNA damaging agent is selected from a pyrrolobenzodiazepine (PBD) and a pyridinobenzodiazepine (PDD).In the Examples, DNA damaging agent VA-SG3199 (tesirine) was successfully used in an ADC.Suitable linkers include, for example, cleavable and non-cleavable linkers. A linker may be a "cleavable linker", facilitating release of a drug. Nonlimiting exemplary cleavable linkers include acid-labile linkers (e.g., comprising hydrazone), proteasesensitive (e.g., peptidase-sensitive) linkers, glycosylase-sensitive (e.g. glucuronidase-sensitive) linkers, photolabile linkers, or disulfide-containing linkers. A cleavable linker is typically susceptible to cleavage under intracellular conditions. Suitable cleavable linkers include, for example, a peptide linker cleavable by an intracellular protease, such as lysosomal protease or an endosomal protease. In exemplary embodiments, the linker can be a dipeptide linker, such as a valinecitrulline (val-cit or “VC”), a phenylalanine-lysine (phe-lys) or a valine-alanine (val- ala or “VA”) linker.For example, a PEGs-VA linker may be used, e.g. as an ADC conjugate to tesirine.For example, the linker may contain a maleimide group for attachment to the antibody, a PEGs linker, and a cleavable val-ala moiety, bound to the therapeuticallyactive substance. For example, the therapeutically active substance is a pyrrolobenzodiazepine (PBD) such as SG3199, a maytansinoid such as DM4 or an auristatin, such as MMAE.For example, the linker may contain a cleavable betaglucuronide moiety, such as MC-betaglucuronide, bound to the therapeutically active substance. For example, the therapeutically active substance is a PDB such as SG3199, a maytansinoid such as DM4 or an auristatin, such as MMAE.For example, the linker may contain a cleavable val-cit (“VC”) moiety, such as MC- VC-PABC in the examples, bound to the therapeutically active substance. For example, the therapeutically active substance is a PDB such as SG3199, a maytansinoid such as DM4 or an auristatin, such as MMAE.For example, the linker may contain a cleavable val-ala (“VA”) moiety, such as VA- PABC in the examples, bound to the therapeutically active substance. For example, the therapeutically active substance is a PDB such as SG3199, a maytansinoid such as DM4 or an auristatin, such as MMAE.In yet another preferred embodiment, the therapeutically active substance is selected from monomethyl auristatin E (MMAE), 4-methyl-4-mercapto-1 -oxopentyl)- maytansine (DM4), and VA-SG3199 (tesirine).Therefore, in one embodiment,(i) the mitotic inhibitor is selected from a maytansinoid and an auristatin, or(ii) the DNA damaging agent is selected from a pyrrolobenzodiazepine (PBD) and a pyridinobenzodiazepine (PDD), or(iii) the therapeutically active substance is selected from monomethyl auristatin E (MMAE), 4-methyl-4-mercapto-1 -oxopentyl)-maytansine (DM4), and VA- SG3199 (tesirine), or(iv) the antibody is linked to the therapeutically active substance via a non- cleavable linker, or(v) the antibody is linked to the therapeutically active substance via a cleavable linker.For example, ADCs AFF4-WT-VC-MMAE, AFF4-WT-Gluc-MMAE, AFF4-WT-VA- SG3199, and AFF4-WT-sulfo-SPDB-DM4 can be used in one embodiment.VA-SG3199 (MP-PEG8-VA-PABC-SG3199) corresponds to CAS Nr.: 1595275-62- 9. IUPAC: [4-[[(2S)-2-[[(2S)-2-[3-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxopyrrol-1 - yl)propanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]prop anoylamino]-3-methylbutanoyl]amino]propanoyl]amino]phenyl]methyl (6S,6aS)-3- [5-[[(6aS)-2-methoxy-8-methyl-11 -oxo-6a,7-dihydropyrrolo[2, 1 - c][1 ,4]benzodiazepin-3-yl]oxy]pentoxy]-6-hydroxy-2-methoxy-8-methyl-11 -oxo- 6a,7-dihydro-6H-pyrrolo[2, 1 -c][1 ,4]benzodiazepine-5-carboxylate.VC-MMAE (MC-VC-PABC-MMAE), corresponds to CAS Nr. : 646502-53-6. IUPAC: [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrol-1 - yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl N- [(2S)-1 -[[(2S)-1 -[[(3R,4S,5S)-1 -[(2S)-2-[( 1 R,2R)-3-[[(1 S,2R)-1 -hydroxy-1 - phenylpropan-2-yl]amino]-1 -methoxy-2-methyl-3-oxopropyl]pyrrolidin-1 -yl]-3- methoxy-5-methyl-1 -oxoheptan-4-yl]-methylamino]-3-methyl-1 -oxobutan-2- yl]amino]-3-methyl-1 -oxobutan-2-yl]-N-methylcarbamate.Gluc-MMAE (MC-betaglucuronide-MMAE) corresponds to CAS Nr.: 1703778-92-0. IUPAC: (2S,3S,4S,5R,6S)-6-[2-[3-[6-(2,5-dioxopyrrol-1 - yl)hexanoylamino]propanoylamino]-4-[[[(2S)-1 -[[(2S)-1 -[[(3R,4S,5S)-1 -[(2S)-2- [(1 R,2R)-3-[[(1 S,2R)-1 -hydroxy-1 -phenylpropan-2-yl]amino]-1 -methoxy-2-methyl- 3-oxopropyl]pyrrolidin-1 -yl]-3-methoxy-5-methyl-1 -oxoheptan-4-yl]-methylamino]-3- methyl-1 -oxobutan-2-yl]amino]-3-methyl-1 -oxobutan-2-yl]- methylcarbamoyl]oxymethyl]phenoxy]-3, 4, 5-trihydroxyoxane-2 -carboxylic acid.Such antibody drug conjugates were successfully used in the examples.Sulfo-SPDB-DM4 corresponds to CAS Nr. 1626359-59-8; IUPAC: 4-[[5-[[(2S)-1 - [[(1 S,2R,3S,5S,6S, 16E, 18E,20R,21 S)-11 -chloro-21 -hydroxy-12, 20-dimethoxy- 2,5,9, 16-tetramethyl-8,23-dioxo-4,24-dioxa-9, 22- diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26), 16, 18-pentaen-6- yl]oxy]-1 -oxopropan-2-yl]-methylamino]-2-methyl-5-oxopentan-2-yl]disulfanyl]-1 - (2,5-dioxopyrrolidin-1 -yl)oxy-1 -oxobutane-2 -sulfonic acid.It was surprisingly found that (i) Bcl-2 inhibitor Obatoclax, (ii) the tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor dasatinib, and (iii) the HDAC inhibitor vorinostat can increase human L1 CAM cell surface expression. Therefore, treatment of a human subject with Bcl-2 inhibitor Obatoclax, (ii) thetyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor dasatinib, or (iii) the HDAC inhibitor vorinostat can increase the responsiveness of the human subject to treatment with an anti-L1 CAM antibody.An “HDAC inhibitor” or “Histone deacetylase inhibitor” is understood as an agent which is able to inhibit the enzymatic activity of a human histone deacetylaseHuman histone deacetylases are classified into four groups (l-IV):Class I, which includes HDAC1 , -2, -3 and -8;Class HA, which includes HDAC4, -5, -7 and -9; Class IIB -6, and -10;Class III, also known as the sirtuins are related to the Sir2 gene and include SIRT1-7;Class IV, which contains only HDAC11 has features of both Class I and II.An HDAC inhibitor may inhibit one or more human HDAC. For example, the HDAC inhibitor may inhibit one or more of Class I, II and Class IV HDACs.Suitable HDAC inhibitors are known in the art and include hydroxamic acids (or hydroxamates), such as trichostatin A, cyclic tetrapeptides (such as trapoxin B), and depsipeptides, benzamides, electrophilic ketones, and aliphatic acid compounds such as phenylbutyrate and valproic acid, hydroxamic acids vorinostat (SAHA), belinostat (PXD101 ), LAQ824, and panobinostat (LBH589); and the benzamides entinostat (MS-275), tacedinaline (CI994), and mocetinostat (MGCD0103).In a preferred embodiment, the HDAC inhibitor is vorinostat. Vorinostat is also known as Suberoylanilide hydroxamic acid or SAHA. The chemical formula of Vorinostat is shown below:Bcl-2 or “B-cell lymphoma 2” is a protein encoded in humans by the BCL2 gene, and is a member of the Bcl-2 family of regulator proteins that regulate apoptosis.Bcl-2 inhibitors are known in the art and include Obatoclax, Venetoclax and Navitoclax.In a preferred embodiment, the Bcl-2 inhibitor is Obatoclax. For example, the mesylate salt thereof may be used. The IIIPAC name of Obatoclax is 2-(2-((3,5- Dimethyl-1 H-pyrrol-2-yl)methylene)-3-methoxy-2H-pyrrol-5-yl)-1 H-indole. The chemical formula of Obatoclax is shown below:Tyrosine kinase inhibitors of one or more tyrosine kinases selected from BCR / Abl, Src, c-Kit and ephrin receptors are known in the art and include, e.g. dasatinib, imatinib and nilotinib. Dasatinib is a tyrosine kinase inhibitor of the tyrosine kinases BCR / Abl, Src, c-Kit and ephrin receptors, and several other tyrosine kinases. The chemical formula of dasatinib is shown below:In one embodiment, the human subject is or was treated with a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and / or an HDAC inhibitor.In one embodiment, the human subject is treated with a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and / or an HDAC inhibitor. In such embodiment, the treatment with an anti-L1 CAM antibody is in parallel or temporally overlapping with the treatment with a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and / or an HDAC inhibitor.In another embodiment, the treatment with a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and / or an HDAC inhibitor is terminated when the treatment with an anti-L1 CAM antibody is started.In one aspect, an antibody that specifically binds to human L1 CAM and an active compound selected from a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and an HDAC inhibitor, is provided, for use in a combination therapy in the treatment or prophylaxis of a human L1 CAM-positive tumor disease in a human subject.In embodiments, the anti-L1 CAM antibody may be combined with a pharmaceutical composition comprising an active compound selected from a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and an HDAC inhibitor for use in a combination therapy in the treatment or prophylaxis of a human L1 CAM-positive tumor disease in a human subject.The term “tumor disease” describes any disease or condition related to tumors (also called neoplasms), which may be non-malignant (also non-neoplastic), premalignant or malignant.In one aspect, an antibody that specifically binds to human L1 CAM and an active compound selected from a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and an HDAC inhibitor, is provided, for use in a combination therapy in the treatment or prophylaxis of a human L1 CAM-positive hematological tumor disease in a human subject.In an embodiment, the hematological tumor disease is a hematological malignancy disease.In embodiments, the anti-L1 CAM antibody may be combined with a pharmaceutical composition comprising an active compound selected from a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and an HDAC inhibitor for use in a combination therapy in the treatment or prophylaxis of a human L1 CAM-positive hematological malignancy disease in a human subject.The anti-L1 CAM antibody may be administered to the subject simultaneously with a an active compound selected from a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and an HDAC inhibitor, or temporally separated therefrom and / or spatially separate or together, such as a single pharmaceutical composition.In one aspect, a pharmaceutical composition, kit or kit-of-parts comprising (i) an antibody that specifically binds to human L1 CAM and (ii) an active compound selected from a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and an HDAC inhibitor, and, optionally, (iii) one or more pharmaceutically acceptable excipients, is provided.The kit or kit-of-parts may for example comprise a pharmaceutical composition comprising an antibody that specifically binds to human L1 CAM, and a pharmaceutical composition comprising an active compound selected from a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and an HDAC inhibitor.In an embodiment, the kit or kit-of-parts may be provided as a package containing separately packed pharmaceutical compositions comprising an anti-L1 CAM antibody and pharmaceutical compositions comprising the other active agent(s). The pharmaceutical compositions may be provided in containers, vials, syringes, ampules or the like.The anti-L1 CAM antibody and the active compound(s) selected from a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and an HDAC inhibitor as used in the present invention may be independently formulated for the same or different administration routes.For example, it is possible that the anti-L1 CAM antibody is formulated as solution, such as aqueous solution, lyophilizate, suspension or frozen solution, and / or is formulated for systemic, intravenous, subcutaneous or local administration. For example, it is possible that the active compound(s) selected from a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and an HDAC inhibitor are independently formulated therefrom, e.g. as solution, such as aqueous solution, lyophilizate, suspension or frozen solution, pill, dragee or tablet, and / or is formulated for systemic, intravenous, subcutaneous, oral, nasal or local administration and the like.In embodiments of aspects herein, (i) the Bcl-2 inhibitor is Obatoclax, or (ii) the tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor is dasatinib, or (iii) the HDAC inhibitor is vorinostat.In embodiments of aspects herein, the Bcl-2 inhibitor Obatoclax is used.In another aspect, the invention relates to a method of treating or prophylactically treating a human L1 CAM-positive hematological malignancy disease in a human subject, comprising administering to the human subject in need thereof a pharmaceutically effective amount of an anti-L1 CAM antibody.In another aspect, the invention relates to a method of treating or prophylactically treating a human L1 CAM-positive tumor disease in a human subject, comprising administering to the human subject in need thereof a pharmaceutically effective amount of an antibody that specifically binds to human L1 CAM and a pharmaceutically effective amount of an active compound selected from a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and an HDAC inhibitor.In another aspect, the invention relates to a method of treating or prophylactically treating a human L1 CAM-positive hematological tumor disease in a human subject, comprising administering to the human subject in need thereof a pharmaceutically effective amount of an antibody that specifically binds to human L1 CAM and a pharmaceutically effective amount of an active compound selected from a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and an HDAC inhibitor.In another aspect, the invention relates to a method of treating or prophylactically treating a human L1 CAM-positive hematological malignancy disease in a human subject, comprising administering to the human subject in need thereof a pharmaceutically effective amount of an antibody that specifically binds to human L1 CAM and a pharmaceutically effective amount of an active compound selected from a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and an HDAC inhibitor.In another aspect, the invention relates to a method of treating or prophylactically treating a human L1 CAM-positive tumor disease in a human subject, comprising administering to the human subject in need thereof a combination therapy of a pharmaceutically effective amount of an antibody that specifically binds to human L1 CAM and a pharmaceutically effective amount of an active compound selected from a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and an HDAC inhibitor.In another aspect, the invention relates to a method of treating or prophylactically treating a human L1 CAM-positive hematological tumor disease in a human subject, comprising administering to the human subject in need thereof a combination therapy of a pharmaceutically effective amount of an antibody that specifically binds to human L1 CAM and a pharmaceutically effective amount of an active compound selected from a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and an HDAC inhibitor.In another aspect, the invention relates to a method of treating or prophylactically treating a human L1 CAM-positive hematological malignancy disease in a human subject, comprising administering to the human subject in need thereof a combination therapy of a pharmaceutically effective amount of an antibody that specifically binds to human L1 CAM and a pharmaceutically effective amount of an active compound selected from a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and an HDAC inhibitor.In embodiments of the above aspects, the Bcl-2 inhibitor is Obatoclax. In embodiments of the above aspects, the tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor is dasatinib. In embodiments of the above aspects, the HDAC inhibitor is vorinostat.As used herein, the term “pharmaceutically effective amount” in the context of the administration of a therapy to a subject refers to the amount of a therapy that achieves a desired prophylactic or therapeutic effect.A suitable amount and dosage can be determined by persons skilled in the art. For example, an antibody described herein may be administered to a subject (e.g., via intravenous injection) at about 0.001 mg / kg, 0.01 mg / kg 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 6 mg / kg, or about 10 mg / kg.The antibody may be administered once, or may be administered repeatedly, such as 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times. In case the antibody is administered repeatedly, the antibody may be administered for example daily, every 2 days, weekly, biweekly or monthly.For example, a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, or HDAC inhibitor described herein may be administeredto a subject (e.g., via intravenous injection) at about 0.001 mg / kg, 0.01 mg / kg 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 6 mg / kg, or about 10 mg / kg.The Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, or HDAC inhibitor may be administered once, or may be administered repeatedly, such as 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times. In case the active compound is administered repeatedly, the antibody may be administered for example daily, every 2 days, weekly, biweekly or monthly.The anti-L1 CAM antibody may be administered by any route of drug administration known to the person skilled in the art, such as systemic, parenteral, intravenous, intraperitoneal, subcutaneous, oral, local, intranasal or sublingual administration. Suitable dosage regimen are also well known to the person skilled in the art. Preferably, the antibody is administered in a pharmaceutically effective amount, i.e. in a dose or concentration causing a biological response in the body the antibody is administered to.The Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, or HDAC inhibitor may be administered by any route of drug administration known to the person skilled in the art, such as systemic, parenteral, intravenous, intraperitoneal, subcutaneous, oral, local, intranasal or sublingual administration. Suitable dosage regimen are also well known to the person skilled in the art. Preferably, the active compound is administered in a pharmaceutically effective amount, i.e. in a dose or concentration causing a biological response in the body the antibody is administered to.The antibody is in one embodiment in a pharmaceutical composition, comprising an antibody, and optionally one or more pharmaceutically acceptable carriers or excipients.The content of the antibody in the pharmaceutical composition is not limited as far as it is useful for treatment or prevention, but preferably contains 0.0000001 -10% by weight per total composition.The Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, or HDAC inhibitor is in one embodiment in a pharmaceutical composition, comprising the active compound, and optionally one or more pharmaceutically acceptable carriers or excipients.The content of the Bcl-2 inhibitor, the tyrosine kinase inhibitor of BCR / Abl, Src, c- Kit and / or an ephrin receptor, or HDAC inhibitor in the pharmaceutical composition is not limited as far as it is useful for treatment or prevention, but preferably contains 0.0000001 -10% by weight per total composition.The terms “carrier” and “excipient” are used interchangeably and describe any molecule which improves the stability of the formulation or the selectivity, effectiveness and / or safety of administration of an active agent to a human or animal body, such as by continuous or triggered release or by allowing membrane permeation of the active agent.A carrier, or excipient, is further considered as being pharmaceutically acceptable, when it does not have any or not substantially adverse unwanted effects on the human or animal body, e.g. it is considered generally safe, nontoxic and / or does not cause unwanted biological side reactions. Suitable pharmaceutically acceptable carriers are well known to the person skilled in the art. The choice of carrier may depend upon route of administration and concentration of the active agent(s) and the carrier may be in the form of a lyophilised composition or an aqueous solution. Generally, an appropriate amount of a pharmaceutically acceptable salt is used in the carrier to render the composition isotonic. Examples of the carrier include but are not limited to saline, Ringer's solution and dextrose solution. Preferably, acceptable excipients, carriers, or stabilisers are non-toxic at the dosages and concentrations employed, including buffers such as citrate, phosphate, and other organic acids; salt-forming counter-ions, e.g. sodium and potassium; low molecular weight (< 10 amino acid residues) polypeptides; proteins, e.g. serum albumin, or gelatine; hydrophilic polymers, e.g. polyvinylpyrrolidone; amino acids such as histidine, glutamine, lysine, asparagine, arginine, or glycine; carbohydrates including glucose, mannose, or dextrins; monosaccharides; disaccharides; other sugars, e.g. sucrose, mannitol, trehalose or sorbitol; chelating agents, e.g. EDTA; non-ionic surfactants, e.g. Tween, Pluronics or polyethylene glycol; antioxidants including methionine, ascorbic acid and tocopherol; and / or preservatives, e.g. octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, e.g. methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3- pentanol; and m-cresol). Suitable carriers and their formulations are described in greater detail in Remington's Pharmaceutical Sciences, 17th ed., 1985, Mack Publishing Co.In this context, all features described above for (?) any aspect of the invention, where applicable, also apply to the further aspects of the invention, such as the features related to the antibody, antibody conjugates or pharmaceutical compositions comprising such antibody.“About” is understood to mean the indicated value ±10%.In general, the disclosure is not limited to the particular methodology, protocols, and reagents described herein because they may vary. Further, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present disclosure. As used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise. Similarly, the words "comprise", "contain" and "encompass" are to be interpreted inclusively rather than exclusively.Unless defined otherwise, all technical and scientific terms and any acronyms used herein have the same meanings as commonly understood by one of ordinary skill in the art in the field of the disclosure. Although any methods and materials similar or equivalent to those described herein can be used in the practice as presented herein, the specific methods, and materials are described herein.The disclosure is further illustrated by the following figures and examples, although it will be understood that the figures and examples are included merely for purposes of illustration and are not intended to limit the scope of the disclosure unless otherwise specifically indicated.Figure legendFIG. 1 shows the relationship of L1 CAM mRNA and protein expression levels in selected lymphoma cell lines. L1 CAM mRNA expression levels were normalized on GAPDH mRNA expression and represented as Fold Change (FC) compared to the TOLEDO cell line. L1 CAM protein expression was represented as the isotype- subtracted MFI observed in flow cytometry with an L1 CAM-specific phycoerythrin- labeled antibody. Lymphoma subtypes are represented by different symbols as indicated in the figure legend.FIG. 2 shows a skin specimen of a Sezary syndrome patient immunohistochemically stained with an L1 CAM-specific antibody. Membrane staining of lymphoma cells is clearly discernible (indicated by arrows for selected cells).FIG. 3 shows the induction of antibody-dependent cellular cytotoxicity (ADCC) by the anti-L1 CAM antibody AFF4 on a panel of lymphoma cell lines. ADCC activity was measured by an engineered ADCC reporter cell line, in which FcyRllla (V158) stimulation leads to NFAT-mediated expression of firefly luciferase. The indicated lymphoma cell lines were co-incubated for 6h with the ADCC reporter cell line and the indicated concentrations of AFF4 or isotype control antibody, respectively. Luciferase assay substrate was added and luminescence was determined with a plate reader. Isotype-subtracted Luminescence signals from single experiments are shown. / Vo cells: No lymphoma cells, but only ADCC reporter cells have been added.FIG. 4 shows the cytotoxic effects of the anti-L1 CAM ADCs AFF4-WT-VC-MMAE, AFF4-WT-Gluc-MMAE, and AFF4-WT-VA-SG3199 on different lymphoma cell lines. The ADCs were serially diluted in a range between 100 nM and 5 pM and incubated for 6 days with the indicated cell lines. Cell viability was then assessed by the addition of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), and % viability of anti-L1 CAM ADC-treated cells was calculated, using non-treated cells as 100% viability reference values. Shown are individual values and corresponding 4 parameter logistic curves.FIG. 5 shows the anti-tumor effects of two AFF4-WT-drug conjugates in a xenograft model of the human mantle cell lymphoma cell line Z138 in mice. Z138 cells were subcutaneously injected and tumors were grown to an average size of approximately 150 mm3. Mice then received i.v. injections of either AFF4-WT-VC- MMAE (5 mg / kg), AFF4-WT-VA-SG3199 (1 mg / kg), or vehicle as control, and tumor growth was monitored over time.FIG. 6 shows the L1 CAM surface expression levels of the mantle cell lymphoma cell line Z138 after treatment with different anti-lymphoma compounds. Cells were incubated with two different concentrations of the indicated compounds for 6h followed by determination of L1 CAM expression levels by flow cytometry using a fluorescently labeled anti-L1 CAM antibody and respective isotype control antibody. As reference, untreated cells were stained with the same anti-L1 CAM antibody andisotype control antibody. L1 CAM surface expression levels were expressed as the percentage of L1 CAM-specific staining (MFI) as compared to untreated cells.ExamplesEXAMPLE 1Determination of L1CAM expression in lymphoma cell linesThe expression level of L1 CAM was evaluated both on the RNA and on the protein level in a large panel of lymphoma cell lines. Cell lines were cultured according to the conditions recommended by the respective provider. All media were supplemented with fetal bovine serum (10 or 20%, as required) and Penicillin- Streptomycin-Neomycin (~5,000 units penicillin, 5 mg streptomycin and 10 mg neomycin / mL, Sigma Aldrich, US). For the quantification of L1 CAM mRNA, total RNA was first extracted from lymphoma cells with Monarch® Total RNA Miniprep Kit (New England Biolabs Catalog #T2010S), following the manufacturer's instructions. Real-time PCR was then performed with QuantiFast® SYBR® Green RT-PCR (Qiagen, Catalog #204156), using the StepOnePlus™ Real-Time PCR System (Applied Biosystems™) following the manufacturer's instructions. L1 CAM mRNA expression level was normalized on the respective lymphoma cell line specific GAPDH RNA expression and represented as Fold Change (FC) compared to the TOLEDO cell line. The following oligonucleotide primers were used for the amplification of L1 CAM cDNA: 5’-CGACCGATGAAAGATGAGA-3’ (forward); 5’- ACTGAACATCCACGCTGC-3’ (reverse).To determine the surface expression of L1 CAM protein, approximately 1 million lymphoma cells for each condition were collected, centrifuged (1200 rpm, 5 min, room temperature), washed with PBS, and resuspended in PBS + 1 % FBS. Cell number was adjusted to 106 / 100 pL with PBS + 1 % FBS, and a phycoerythrin- conjugated anti-L1 CAM mouse lgG2a antibody (Biolegend, clone L1 -OV198.5, Catalog #371604), or a phycoerythrin-conjugated mouse lgG2a isotype control antibody (Biolegend, clone MOPC-173, Catalog #400214), respectively, was added at a final concentration of 2.5 pg / mL. After an incubation on ice for 20 min, cells were resuspended with 1 mL PBS + 1 % FBS, centrifuged as described above, and supernatant was discarded. Cell pellet was finally resuspended in 100 pL PBS + 1 % FBS and analyzed by flow cytometry on a FACS canto (Becton Dickinson). Propidium Iodide (Sigma Aldrich, Catalog #P4864) staining was used to exclude dead cells. Median fluorescence intensity (MFI) was recorded and L1 CAM specific staining was expressed as the difference between the MFI obtained with the L1 CAM specific antibody and the MFI obtained with the isotype control antibody.Table 1 below shows that most tested lymphoma cell lines displayed low L1 CAM RNA levels and undetectable surface expression of L1 CAM. However, a subgroup of diffuse large B cell lymphoma, mantle cell lymphoma, and Sezary syndrome cell lines, displayed high L1 CAM RNA levels and clearly detectable cell surface L1 CAM specific staining. The highest L1 CAM expression was detected in the Sezary syndrome cell lines HUT78 and H9.Table 1 : L1 CAM expression in lymphoma cell lines1)1)ABC-DLBCL = Activated B-Cell-Diffuse Large B-Cell Lymphoma; ALCL, ALK+ = ALK-positive Anaplastic Large B-Cell Lymphoma; ALCL, ALK- = ALK-negative Anaplastic Large Cell Lymphoma; BCLL = B-Cell Chronic Lymphocytic Leukemia; BL= Burkitt Lymphoma; B-NHL = B-Cell Non-Hodgkin Lymphoma; CLBCL = Cutaneous Large B-Cell Lymphoma; DLBCL = Diffuse Large B-Cell Lymphoma;GCB-DLBCL = Germinal Center B-Cell- Diffuse Large B-Cell Lymphoma; HCL = Hairy Cell Leukemia; MCL = Mantle Cell Lymphoma; NK-ALL / LBL = Natural Killer Cell Lymphoblastic Leukemia / Lymphoma; PCTCL = Primary Cutaneous T-Cell Lymphoma; PMLCL = Primary Mediastinal (Thymic) Large B-Cell Lymphoma; SMZL = Splenic Marginal Zone Lymphoma; SS = Sezary Syndrome; FC = fold changeFigure 1 shows a graphical representation of the relationship between L1 CAM mRNA and protein expression data. Whereas up to a relative RNA expression level of approximately 0.2, no L1 CAM protein is detectable on the surface of lymphoma cell lines, above this RNA level surface L1 CAM becomes clearly detectable and RNA levels correlate with protein levels.EXAMPLE 2Determination of L1CAM expression in clinical specimens from lymphoma patientsL1 CAM expression in clinical lymphoma specimens was determined by immunohistochemistry. Two tissue microarrays of formalin-fixed, paraffin- embedded lymphoma tissue sections (Biomax Catalog #LY1001 d, #LY6161 a) were stained using a kit with an anti-mouse secondary antibody conjugated to a horseradish peroxidase-conjugated polymer (ultraView Universal DAB, Ventana Medical System) and an automatic immunostainer (Ventana Benchmark XT, Roche- Diagnostic). All reagents were dispensed automatically except for the primary anti- L1 CAM antibody that was dispensed manually. Anti-L1 CAM antibody (BioLegend, clone 14.10, Catalog #826701 ) was incubated at room temperature for 20 minutes at a dilution of 1 :100.Table 2 shows the number of cases per lymphoma subtype, in which L1 CAM expression was immunohistochemically detected:Table 2: Immunohistochemical detection of L1 CAM expression in clinical lymphoma specimensPrevalence of L1 CAM expression in mantle cell lymphoma was further investigated in an extended set of clinical specimens. Formalin-fixed, paraffin-embedded tissue sections from 56 mantle cell lymphoma patients were analysed for L1 CAM expression by immunohistochemistry using the same method as described above. Strongly positive L1 CAM staining was detected in 18 / 56 (32%) cases, and weakly positive staining in 16 / 56 (29%) cases, whereas no L1 CAM staining was detected in 22 / 56 (39%) cases.Due to the high L1 CAM expression detected in the two Sezary Syndrome cell lines HUT78 and H9 (Table 1 ), immunohistochemical evaluation of L1 CAM expression was extended to clinical specimens from Mycosis Fungoides patients. Mycosis Fungoides is the most common form of cutaneous T-cell lymphoma and is closely related to Sezary Syndrome. Skin specimens (plaques and tumors) from 11 Mycosis Fungoides patients were subjected to L1 CAM immunohistochemistry using the same method as described above. Strongly positive L1 CAM staining was detected in 6 / 8 (75%) Mycosis fungoides cases, weakly positive L1 CAM staining in 1 / 8 (12.5%) case, and no L1 CAM staining in 1 / 8 (12.5%) case.Figure 2 shows an example of an immunohistochemical staining of a cutaneous form of Sezary syndrome in a patient, demonstrating clear membrane L1 CAM staining on neoplastic cells.EXAMPLE 3Induction of antibody-dependent cellular cytotoxicity (ADCC) by the anti- L1CAM antibody AFF4 on L1CAM-expressing lymphoma cell linesThe expression in a subgroup of lymphoma types indicates that L1 CAM could be a target for antibody-based therapies. It was therefore investigated whether the recently described anti-L1 CAM antibody AFF4 has the ability to induce antibodydependent cellular cytotoxicity on a series of L1 CAM-expressing lymphoma cell lines.Plasmids encoding the heavy and light chain of antibody AFF4 (SEQ ID No: 9 and 11 ) were transiently co-transfected into Chinese Hamster ovary (CHO) K1 cells. Cells were grown in a chemically defined animal-component-free medium and the supernatant containing recombinant AFF4 human lgG1 antibody was harvested by centrifugation and subsequent filtration through a 0.2 pm filter. AFF4 was purified from the supernatant by affinity chromatography using protein A columns (MabSelect SuRe, GE Healthcare) and stored in phosphate-buffered saline (PBS) containing 100 mM arginine.The ability of AFF4 to induce ADCC on L1 CAM expressing lymphoma cells was then evaluated using an ADCC Reporter Bioassay (Promega, Catalog # G7018). In this reporter assay, target cells are incubated with the therapeutic antibody or a nonspecific isotype control antibody and a Jurkat reporter cell line, which has been engineered to stably express FcyRllla (V158) and an NFAT response element driving expression of firefly luciferase. Crosslinking of FcyRllla (V158) mediated by target-bound antibody activates the NFAT response element and leads to the production of luciferase, which converts an assay substrate into a luminescent product, which can be quantified.Lymphoma target cells were cultured as described in example 1 , washed in PBS, and resuspended at a density of 6 x 105 / mL in prewarmed (37°C) ADCC assay buffer (RPMI1640 medium containing 4 % low IgG serum). Twenty-five pL of the cell suspension (15’000 cells) were then dispensed to the wells of a white 96 well assay plate and 25 pL of AFF4 antibody or isotype control antibody solution, respectively, were added. As control, antibodies were dispensed into wells containing only ADCC assay buffer and no target cells. FcyRI I la-expressing Jurkat reporter cells were thawed at 37°C, and 630 pL cells were diluted in 3.6 mL ADCC assay buffer. Twenty-five pL of the diluted cell suspension was then added to the wells already containing the lymphoma target cells (or ADCC assay buffer only) and antibodies. Target to reporter cell ratio was between 1 :3 to 1 :5, depending on the specific lot of reporter cells used in the assay. Final concentrations of AFF4 and isotype control antibody, respectively, in assay samples were 1.0, 0.1 or 0.01 pg / mL. Plates were incubated for 6 hours at 37°C in a humidified CO2 incubator, then removed from the incubator and equilibrated at ambient temperature for 15 min. Seventy-five pL of Bio-Gio™ Luciferase Assay Reagent was then added to each well, and plates were incubated for 10 min at ambient temperature. Luminescence was quantified with a Cytation 3 plate reader (BioTek) and specific ADCC induction was expressed as the % increase in luminescence signal in AFF4 treated wells compared to isotype control antibody treated wells.Figure 3 shows that negligible increase in luminescence was observed when no lymphoma cell lines or when L1 CAM-negative lymphoma cell lines such as HH or SUDHL10 were added. However, a clear increase of luminescence signals was observed when the L1 CAM-positive cell lines HUT78, Z138, RCK8, GRANTA519, TMD8, or REC1 were used. This demonstrates that the anti-L1 CAM antibody AFF4 is able to induce target-specific antibody-dependent cellular cytotoxicity on L1 CAM- expressing lymphoma cells.EXAMPLE 4Cytotoxic effect of anti-L1CAM antibody drug conjugates on L1CAM- expressing lymphoma cell linesThe cytotoxic effects of three anti-L1 CAM antibody drug conjugates were investigated on a series of L1 CAM-positive lymphoma cell lines. HUT78, Z138, RCK8, GRANTA519, TMD8, REC1 , DOHH2, and SUDHL10 lymphoma cells were first seeded in 96-well plates at 10’000 cells / well in 100 pL RPMI I 20% FBS. The anti-L1 CAM ADCs AFF4-WT-VC-MMAE, AFF4-WT-Gluc-MMAE or AFF4-WT-VA- SG3199 (all disclosed in EP22196917.3) were serially diluted in RPMI I 20% FBS and 100 pL / well of each dilution was added to the seeded cells. Final concentrations of antibody-drug conjugates in the assay ranged from 100 nM to 5 pM. Untreated cells were used as control for 100% cell viability. After an incubation of 6 days at 37 °C in a humidified CO2 incubator, cell viability was determined by the addition of 20 pL / well of a 5 mg / mL solution of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) (Abeam). After an additional incubation of 4 h at 37 °C in a humidified CO2 incubator, 50 pL / well of solubilization buffer (10% sodium dodecyl sulfate in 0.01 M HCI) was added. Plates were incubated overnight for full solubilization of the formazan product of MTT, and optical density (OD) at 550 nm was determined with a Cytation 3 imaging device (BioTek). Absorbance values were converted to % viability values, using the wells with non-treated cells as 100% viability reference values. The % viability values obtained at the different anti-L1 CAM drug conjugate concentrations were fitted to 4 parameter logistic curves using GraphPad Prism, and used to calculate the respective IC50 concentrations of the three conjugates.Fig. 4 shows that all three ADCs induced dose-dependent killing of lymphoma cell lines. The respective IC50 values are summarized in Table 3 below. Low cytotoxic activity of all three ADCs was observed on the L1 CAM-negative cell line SUDHL10 and on the L1 CAM-expressing cell line REC1. AFF4-WT-VA-SG3199 induced strong cytotoxic effects on all other tested lymphoma cells lines, with IC50 values at or below 1 nM in all cases. AFF4-WT-Gluc-MMAE displayed weaker cytotoxic activity, but subnanomolar to single digit nM IC50 values were still observed on mosttested cell lines. AFF4-WT-VC-MMAE showed the weakest activity of the three ADCs, with single digit nM IC50 values observed only on the high L1 CAM high expressing cell lines HUT78 and Z138.Table 3: Cytotoxicity of AFF4-WT drug conjugates on different lymphoma cell lines33numbers indicate IC50 values in nM.EXAMPLE 5Inhibition of lymphoma tumor growth in vivo by anti-L1CAM antibody drug conjugatesThe in vivo efficacy of two AFF4-WT drug conjugates was determined in a mouse xenograft model of the human mantle cell lymphoma cell line Z138.Z138 cells (1.5 x 107cells in 100 pL PBS) were subcutaneously injected into the flank of female NOD-Scid (NOD.CB17-Pr c / csc / c / / NCrCrl) mice. Tumors were measured with calipers, and tumor volumes (TV) were calculated using the following formula: TV = (W2x L) / 2 (L=length, W= perpendicular length of tumor, L>W).When tumors had reached an average volume of approximately 150 mm3, mice were randomized into 3 different groups. Two groups (n=9 each) received an i.v. injection of AFF4-WT-VC-MMAE (5 mg / kg) or AFF4-WT-VA-SG3199 (1 mg / kg), respectively, while the third group (n=10) received an i.v. injection of vehicle as control. Tumor volumes were measured every 2-3 days following injection.As shown in Fig. 5, treatment with either of the AFF4-WT drug conjugates induced strong anti-tumor responses. While tumors in untreated mice grew to an average volume of approximately 1700 mm3within 8 days, complete tumor growth arrest was observed during this observation period in mice treated with either AFF4-WT-VC- MMAE or AFF4-WT-VA-SG3199.EXAMPLE 6Regulation of L1CAM expression levels by anti-cancer compounds in Z138 mantle cell lymphoma cellsThe Z138 mantle cell lymphoma cell line was chosen to investigate the effect of 384 anti-cancer compounds on the surface expression level of L1 CAM. To this end a custom library composed of small molecules targeting important pathways in lymphoma (SelleckChem) was used.Z138 cells were seeded at 10’000 cells / well and incubated with 1 pM of the respective compound for 6 hours, followed by analysis of L1 CAM surface expression by flow cytometry as described in Example 1. L1 CAM expression levels were defined as the difference between the mean fluorescence intensity (MFI) obtained with the L1 CAM specific antibody and the MFI obtained with the corresponding isotype control antibody. Relative (%) L1 CAM surface expression of compound-treated cells compared to DMSO-treated cells was expressed as follows:Alterations of less than 50% in L1 CAM expression levels were considered not significant. Table 4 below lists the compounds which led to an at least 50% increase or decrease in L1 CAM expression levels compared to cells treated with DMSO.Table 4: Regulation of L1 CAM cell surface expression levels upon treatment with selected anti-cancer compoundsA limited number of compounds was selected for further validation of their effect on L1 CAM expression levels. Z138 cells were seeded at 10’000 cells / well and incubated for 6h with 0.5 pM, or 1 pM of either Obatoclax, Venetoclax, Vorinostat, Dasatinib, or BAY11 -7082, followed by determination of L1 CAM cell surface expression levels by flow cytometry. Fig. 6 shows that the upregulation of L1 CAM expression by the Bcl-2 / MCL1 family inhibitor Obatoclax, which had been observed in the screening experiment, could be confirmed in the validation experiment. L1 CAM expression levels were increased by 57% and 64% after treatment with 0.5, and 1.0 pM Obatoclax, respectively. As expected from the screening results, also the HDAC inhibitor Vorinostat and the tyrosine kinase inhibitor Dasatinib induced upregulation of L1 CAM expression, albeit to a lesser extent compared to Obatoclax.The downregulation of L1 CAM expression by the NF-KB inhibitor BAY 11 -7082 could also be confirmed in the validation experiment. In addition, also treatment with Venetoclax, a Bcl-2 inhibitor, caused marked downregulation of L1 CAM expression levels.

Claims

Claims1. An antibody that specifically binds to human L1 CAM for use in the treatment or prophylaxis of a human L1 CAM-positive hematological malignancy disease in a human subject.

2. The antibody for use of claim 1 , wherein the human L1 CAM-positive hematological malignancy disease is a lymphoma.

3. The antibody for use of claim 1 or 2, wherein the human L1 CAM-positive hematological malignancy disease is selected from a T cell lymphoma and a B cell lymphoma.

4. The antibody for use of any one of claims 1 to 3, wherein the human L1 CAM- positive hematological malignancy disease is selected from Mantle cell lymphoma, Sezary Syndrome, Mycosis fungoides, Activated B-cell-diffuse large B cell lymphoma, Germinal center B-cell-diffuse large B cell lymphoma, Follicular lymphoma, Anaplastic large cell lymphoma, Hodgkin lymphoma and Diffuse large B-cell lymphoma.

5. The antibody for use of any one of claims 1 to 4, wherein one or more hematological cells of the subject express human L1 CAM on the cell surface.

6. The antibody for use of any one of claims 1 to 5, wherein the use further comprises:(i) providing a hematological sample of the human subject; and(ii) determining whether one or more hematological cells of the subject express human L1 CAM on the cell surface; wherein the antibody that specifically binds to human L1 CAM is for use in the treatment or prophylaxis of a human L1 CAM-positive hematological malignancy disease in the human subject in case one or more hematological cells of the subject are determined in step (ii) to express human L1 CAM on the cell surface.

7. The antibody for use of any one of claims 1 to 6, wherein the antibody is selected from an antibody comprising an Fc portion and / or an antibody linked to a therapeutically active substance.

8. The antibody for use of any one of claims 1 to 7, wherein the antibody is selected from an internalizing and / or cytotoxic antibody.

9. The antibody for use of any one of claims 1 to 8, wherein the antibody comprises:(a) a heavy chain variable region (VH) comprising a VH CDR1 comprising the amino acid sequence of GYSITSDYTWN (SEQ ID NO: 1 ), a VH CDR2 comprising the amino acid sequence of YISYSGSYSYNPSLKS (SEQ ID NO: 2), and a VH CDR3 comprising the amino acid sequence of SFSYSYGFAY (SEQ ID NO: 3); and(b) a light chain variable region (VL) comprising a VL CDR1 comprising the amino acid sequence of KASQDVSSAVA (SEQ ID NO: 4), a VL CDR2 comprising the amino acid sequence of SASYRYT (SEQ ID NO: 5), and a VL CDR3 comprising the amino acid sequence of QQHYSTPWT (SEQ ID NO: 6).

10. The antibody for use of any one of claims 1 -9, wherein the antibody comprises:(a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7; and(b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8.

11. The antibody of any one of claims 1 -10, wherein the antibody comprises a heavy chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 9 or 10 and / or a light chain sequence comprising or consisting of an amino acid sequence of SEQ ID NO: 11 .

12. The antibody for use of any one of claims 1 to 11 , wherein the antibody is linked to a therapeutically active substance, and wherein the therapeutically active substance is selected from the group consisting of a DNA damaging agent, an anti-apoptotic agent, a mitotic inhibitor, an anti-tumor antibiotic, an immunomodulating agent, a nucleic acid for gene therapy, an anti-angiogenic agent, an anti-metabolite, a boron-containing agent, a chemoprotective agent, a hormone agent, an anti-hormone agent, a corticosteroid, a photoactive therapeutic agent, an oligonucleotide, a radioisotope, a radiosensitizer, a topoisomerase inhibitor, and a tyrosine kinase inhibitor.

13. The antibody for use of claim 12, wherein(i) the mitotic inhibitor is selected from a maytansinoid and an auristatin, or(ii) the DNA damaging agent is selected from a pyrrolobenzodiazepine (PBD) and a pyridinobenzodiazepine (PDD), or(iii) the therapeutically active substance is selected from monomethyl auristatin E (MMAE), 4-methyl-4-mercapto-1 -oxopentyl)-maytansine (DM4), and VA-SG3199 (tesirine), or(iv) the antibody is linked to the therapeutically active substance via a non- cleavable linker, or(v) the antibody is linked to the therapeutically active substance via a cleavable linker.

14. The antibody for use of any one of claims 1 -13, wherein the human subject is or was treated with a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and / or an HDAC inhibitor.

15. An antibody that specifically binds to human L1 CAM and an active compound selected from a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c- Kit and / or an ephrin receptor, and an HDAC inhibitor, for use in a combination therapy in the treatment or prophylaxis of a human L1 CAM-positive hematological tumor disease in a human subject.

16. A pharmaceutical composition, kit or kit-of-parts comprising (i) an antibody that specifically binds to human L1 CAM and (ii) an active compound selected from a Bcl-2 inhibitor, a tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor, and an HDAC inhibitor, and, optionally, (iii) one or more pharmaceutically acceptable excipients.

17. The antibody for use of any one of claims 1 to 15 or the pharmaceutical composition, kit or kit-of-parts of claim 16, wherein (i) the Bcl-2 inhibitor is Obatoclax, or (ii) the tyrosine kinase inhibitor of BCR / Abl, Src, c-Kit and / or an ephrin receptor is dasatinib, or (iii) the HDAC inhibitor is vorinostat.