WO2025109119A1

WO2025109119A1 - Methods of treatment with multispecific antigen-binding proteins in combination with s1p receptor modulators

Info

Publication number: WO2025109119A1
Application number: PCT/EP2024/083193
Authority: WO
Inventors: Simone DERTSCHNIG
Original assignee: Priothera SAS
Current assignee: Priothera SAS
Priority date: 2023-11-22
Filing date: 2024-11-21
Publication date: 2025-05-30
Anticipated expiration: 2026-05-22

Abstract

The present invention relates to a multispecific antigen-binding protein composition for use in treating a hematological malignancy in a subject in need thereof, wherein said multispecific antigen-binding protein comprises at least : a first binding domain capable of binding to a cell surface protein of a tumor cell; and, a second binding domain capable of binding to a cell surface protein of an immune cell; and wherein a therapeutically effective amount of said multispecific antigen-binding protein composition is administered in combination with a therapeutically effective amount of an S1P receptor modulator.

Description

METHODS OF TREATMENT WITH MULTISPECIFIC ANTIGEN-BINDING PROTEINS IN COMBINATION WITH S1P RECEPTOR MODULATORS TECHNICAL FIELD The present invention relates to the field of immunotherapy and particularly multispecific antigen-binding proteins and their use in combination therapy with a S1P receptor modulator for the treatment of cancer, e.g., hematological malignancies, in a subject in need thereof. BACKGROUND Many patients with hematological malignancies are incurable with standard therapy. In addition, traditional treatment options often have serious side effects. Attempts have been made with cancer immunotherapies; however, several obstacles render this a very difficult goal to achieve clinical effectiveness. Although hundreds of so-called tumor antigens have been identified, these are generally derived from self and thus are poorly immunogenic. The presence of naturally occurring tumor-reactive T cells has been thoroughly documented in the peripheral blood, and within the tumors, of cancer patients. However, although T cells recognize neoplastic cells, their presence is often insufficient to mediate clinical tumor regressions. Tumors employ a myriad of mechanisms to neutralize or evade immune attack, particularly T cell-mediated responses. These mechanisms include downregulation of MHC molecule expression, or disruption of the antigen processing and presentation machineries, among others. A bispecific antibody can recognize two different targets at the same time and is able to activate regulatory mechanisms of more cells, which may have great potential in the treatment of tumors and other diseases. Bispecific T cell engager antibody is a typical bispecific antibody (see for example Tian et al, J Hematol Oncol 2021, 14:75). It may form an immune synapse by simultaneously binding a T cell surface antigen (such as CD3) and a tumor cell surface antigen (such as CD19) to form an immune synapse. The distance between the tumor cells and T cells may be shortened by the bispecific antibody, followed by direct activation and proliferation of T cells, and activated T cells directly kill tumor cells and/or release cytotoxins to kill tumor cells. Hence, activation process of T cell by bispecific antibody does not involve presentation of tumor antigens to T cells to generate specific T lymphocyte clones. Therefore, the process is not restricted by MHC and is highly applicable in clinical use. Thus, bispecific immunotherapies have the potential to improve both clinical efficacy and safety and can be seen as the next generation of immunotherapies. Interest in bispecific antibodies has therefore grown considerably in recent years, and now numerous bispecific immunotherapies are in clinical or preclinical development. The majority of these constructs are T-cell redirecting compounds typically targeting CD3 and tumor-associated antigens (Brinkmann U and Kontermann RE., MAbs 2017; 9:182–212), with the idea that the compound will bind and activate T cells via CD3, and redirect these T cells to the tumor area via the tumor antigen binding property. However, further improvements are needed either to improve efficacy of such bispecifc immunotherapies and/or to reasonably control activation of T cells and/or release of cytokines in order to improve safety (for example, to avoid the cytokine release syndrome (CRS) (Kauer J, Hörner S et al. Tocilizumab, but not dexamethasone, prevents CRS without affecting antitumor activity of bispecific antibodies. J Immunother Cancer. 2020 May;8(1):e000621). This cytokine release syndrome (CRS) pathology is characterized by high systemic cytokine levels. Activated immune cells will migrate to peripheral sites causing a systemic inflammatory response in tissue, i.e. in vivo T cell expansion (Lee et al. Blood 2014124(2):188-195). There is thus an ongoing need for improved strategies for treating hematological malignancies, in particular, new compositions and methods for improving immunotherapies are highly desirable. SUMMARY The invention described here meets this need. In particular, without being bound by any theory, it is believed that the synergistic therapeutic effect of the combination therapy is provided by preventing immune cells, preferably T cells, to which multispecific antigen-binding proteins are bound, from leaving lymphoid tissues, and consequently, concentrating activated immune cells where we want them to act so, resulting in improved anti-tumor efficacy and/or prevention of the relapse of hematological malignancies patients. The disclosure includes methods of treating a hematological malignancy in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a multispecific antigen-binding protein in combination with a therapeutically effective amount of an S1P receptor modulator, wherein said multispecific antigen-binding protein comprises at least: a first binding domain capable of binding to a cell surface protein of a tumor cell; and, a second binding domain capable of binding to a cell surface protein of an immune cell; and wherein a therapeutically effective amount of said multispecific antigen-binding protein is administered in combination with a therapeutically effective amount of an S1P receptor modulator. The disclosure relates to a multispecific antigen-binding protein for use in treating a hematological malignancy in a subject in need thereof, wherein said multispecific protein comprises at least : a first binding domain capable of binding to a cell surface protein of a tumor cell; and, a second binding domain capable of binding to a cell surface protein of an immune cell; and wherein a therapeutically effective amount of said multispecific antigen-binding protein is administered in combination with a therapeutically effective amount of an S1P receptor modulator. The disclosure also relates to the use of a multispecific antigen-binding protein for the manufacture of a medicament for treating a hematological malignancy in a subject in need thereof, wherein said multispecific antigen-binding protein comprises at least : a first binding domain capable of binding to a cell surface protein of a tumor cell; and, a second binding domain capable of binding to a cell surface protein of an immune cell; and wherein a therapeutically effective amount of said multispecific antigen-binding protein is administered in combination with a therapeutically effective amount of an S1P receptor modulator. The disclosure also relates to the use of a multispecific antigen-binding protein in the preparation of a pharmaceutical composition for treating a hematological malignancy in a subject in need thereof, wherein said multispecific antigen-binding protein comprises at least : a first binding domain capable of binding to a cell surface protein of a tumor cell; and, a second binding domain capable of binding to a cell surface protein of an immune cell; and wherein a therapeutically effective amount of said multispecific antigen-binding protein is administered in combination with a therapeutically effective amount of an S1P receptor modulator. DETAILED DESCRIPTION General Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. The term “about” has herein the meaning that the following value may vary for ± 20%, preferably ± 10%, more preferably ± 5%, even more preferably ± 2%, even more preferably ± 1%. As used herein, the term “protein” refers to any organic compound made of amino acids arranged in one or more linear chains (also referred as “polypeptide chains”) and folded into a globular form. The amino acids in such polypeptide chain are joined together by the peptide bonds between the carboxyl and amino groups of adjacent amino acid residues. The term “protein” further includes, without limitation, peptides, single chain polypeptide or any complex proteins consisting primarily of two or more chains of amino acids. It further includes, without limitation, glycoproteins or other known post-translational modifications. It further includes known natural or artificial chemical modifications of natural proteins, such as without limitation, glycoengineering, pegylation, hesylation and the like, incorporation of non-natural amino acids, amino acid modification for chemical conjugation or any other molecule, etc. As used herein, the term "amino acid" refers to either natural and/or unnatural or synthetic amino acids, including both D or L optical isomers, and amino acid analogs and peptidomimetics. The terms "polypeptide," "peptide" and "protein" expressly include glycoproteins, as well as non-glycoproteins. In specific embodiments, the term “polypeptide” and “protein” refers to any polypeptide or protein that can be encoded by a gene and translated using cell expression system and DNA recombinant means, such as mammalian host cell expression system. It is to be noted that, cell free expression systems may also be used to produce certain multispecific antigen-binding protein as herein disclosed. Typically, methods of cell-free expression of proteins or antibodies are already described (see Stech et al., Sci Rep.2017;7(1):12030.). The term "recombinant protein", as used herein, includes proteins that are prepared, expressed, created or isolated by recombinant means, such as (a) antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom (described further below), (b) fusion proteins isolated from a host cell transformed to express the corresponding protein, e.g., from a transfectoma, etc... The term “antigen binding protein”, "antibody", "immunoglobulin" and the like, have the same meaning and are used interchangeably herein. Antigen binding protein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that immunospecifically binds to an antigen. The term “antigen binding protein” typically includes substantially intact antibody molecules, as well as chimeric antibodies, humanized antibodies, isolated human antibodies, single chain antibodies, bispecific antibodies, antibody heavy chains, antibody light chains, homodimers and heterodimers of antibody heavy and/or light chains. In natural antibodies of rodents and primates, two heavy chains are linked to each other by disulfide bonds, and each heavy chain is linked to a light chain by a disulfide bond. There are two types of light chains, lambda (1) and kappa (k). There are five main heavy chain classes (or isotypes) which determine the functional activity of an antibody molecule: IgM, IgD, IgG, IgA and IgE. Each chain contains distinct sequence domains. IgGs are the most abundant antibodies in the blood and are currently used as backbone for antibody therapeutics. An IgG antibody consists of heavy and light domains that connect to form chains. Light chains consist of two light domains, a variable domain (VL) and a constant domain (CL). Heavy chains consist of four heavy domains, a variable domain (VH) and three constant domains (CH1, CH2 and CH3, collectively referred to as CH). A light and heavy chain together form a pair, and two heavy-light chain pairs form an antibody. The region where the two pairs connect is called the hinge region. Endogenous IgGs have small variations in their hinge regions, resulting in IgG subtypes. The Fab fragment contains the variable fragments that form the binding sites. The Fv fragment is the N-terminal part of the Fab fragment of an immunoglobulin and consists of the variable portions of one light chain and one heavy chain. An antibody can be also divided into functional parts. The variable regions of both light (VL) and heavy (VH) chains determine binding recognition and specificity to the antigen. The constant region domains of the light (CL) and heavy (CH) chains confer important biological properties such as antibody chain association, secretion, trans-placental mobility, complement binding, and binding to Fc receptors (FcR). The Fc region, or antibody’s tail is composed of two identical protein fragments, derived from the second and third constant domains of the antibody's two heavy chains. The Fc region, connected to the Fab region, mediates the effector functions that lead to immune-mediated target-cell killing (Scott, Wolchok, & Old, 2012). The Fc region can also be recognized by a receptor called the neonatal receptor, which is involved in regulating the IgG serum levels and actively prolongs the biological half-life (Roopenian & Akilesh, 2007). This process is called neonatal recycling. The specificity of the antibody resides in the structural complementarity between the antibody combining site and the antigenic determinant. Antibody combining sites are made up of residues that are primarily from the hypervariable or complementarity determining regions (CDRs). Occasionally, residues from non-hypervariable or framework regions (FR) can participate to the antibody binding site or influence the overall domain structure and hence the combining site. Complementarity Determining Regions or CDRs refer to amino acid sequences, which together define the binding affinity and specificity of the natural Fv region of a native immunoglobulin binding site. The light and heavy chains of an immunoglobulin each have three CDRs, designated L-CDR1, L-CDR2, L- CDR3 and H-CDR1, H-CDR2, H-CDR3, respectively. An antigen-binding site, therefore, typically includes six CDRs, comprising the CDRs set from each of a heavy and a light chain V region. Framework Regions (FRs) refer to amino acid sequences interposed between CDRs. Accordingly, the variable regions of the light and heavy chains typically comprise 4 framework regions and 3 CDRs of the following sequence: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. The residues in antibody variable domains are conventionally numbered according to a system devised by Kabat et al. This system is set forth in Kabat et al., 1987, in Sequences of Proteins of Immunological Interest, US Department of Health and Human Services, NIH, USA (hereafter “Kabat et al.”). This numbering system is used in the present specification. The Kabat residue designations do not always correspond directly with the linear numbering of the amino acid residues in SEQ ID sequences. The actual linear amino acid sequence may contain fewer or additional amino acids than in the strict Kabat numbering corresponding to a shortening of, or insertion into, a structural component, whether framework or complementarity determining region (CDR), of the basic variable domain structure. The correct Kabat numbering of residues may be determined for a given antibody by alignment of residues of homology in the sequence of the antibody with a “standard” Kabat numbered sequence. The CDRs of the heavy chain variable domain are located at residues 31-35 (H-CDR1), residues 50-65 (H-CDR2) and residues 95-102 (H-CDR3) according to the Kabat numbering system. The CDRs of the light chain variable domain are located at residues 24-34 (L-CDR1), residues 50-56 (L-CDR2) and residues 89-97 (L-CDR3) according to the Kabat numbering system. As used herein, an antigen-binding protein which “specifically binds to” a particular target refers to an antigen-binding protein that binds to said target (e.g. cell surface protein or tumor antigen) with a K_D of about 10^-7 M or less, such as about 10^-8 M or less, such as about 10^-9 M or less, about 10^-10 M or less, or about 10^-11 M or even less as determined by for instance by surface plasmon resonance (SPR) technology, typically using a soluble form of the antigen as the ligand and the antigen-binding protein as the analyte. The term "multispecific antigen-binding protein" as used herein means that the antigen-binding protein is capable of specifically binding to at least two target entities. Typically, a multispecific antigen-binding protein may be bispecific, trispecific or of higher order of specificities. Using multispecific antigen-binding proteins, such as bispecific antibodies, enables novel and unique mechanisms of actions, such as specific targeting of T cells to the tumor cells or pathogens, and engagement of immune cells to tumor cells (Chames & Baty, 2009; Fan, Wang, Hao, & Li, 2015). The multispecific antigen binding proteins for use as disclosed herein comprise at least a first binding domain capable of binding to a cell surface protein of a tumor cell; and, a second binding domain capable of binding to a cell surface protein of an immune cell. Binding of these multispecific molecules to their specific targets can be confirmed by, for example, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (REA), FACS analysis, bioassay (e.g., growth inhibition and apoptosis), or Western Blot assay. Each of these assays generally detects the presence of protein-antibody complexes of particular interest by employing a labelled reagent (e.g., an antibody) specific for the complex of interest. Antibodies (i.e., monoclonal antibodies (mAb)) and antigen-binding fragments thereof, which can be employed in the multispecific antigen-binding protein as disclosed herein are typically from murine, human, chimeric and humanized monoclonal antibodies. The term “antigen” or “Ag” refers to a molecule that provokes an immune response. This immune response may involve either antibody production, or the activation of specific immunologically-competent cells, or both. The skilled artisan will understand that any macromolecule, including virtually all proteins or peptides, can serve as an antigen. As used herein, a “modulator” is a compound which, when administered to a subject, provides the desired interaction with the target receptor, either by way of the compound acting directly on the receptor itself, or by way of a metabolite of the compound acting on the receptor. Upon administration to a subject, the S1P receptor modulator, preferably mocravimod (also referred as KRP203), interacts with the S1P receptor by downmodulating the receptor resulting in disrupted signal transduction. As used herein, “S1P agonist” refers to a compound which initiates a physiological response when combined with the S1P receptor. Preferably the physiological response initiated is an induced internalization of the S1P receptor. The kinetics of agonist-induced internalization from cell membranes, and the recycling of the S1P receptors to the cell membrane after said compound shedding depends on the compound. Such S1P receptor agonists may also be referred as functional antagonists. The persistence of the internalization conditions the agonist's "functional antagonism" properties. The term “pharmaceutically acceptable salts thereof” includes both acid and base addition salts. Non-limiting examples of pharmaceutically acceptable acid addition salts include chlorides, hydrochlorides, bromides, sulfates, nitrates, phosphates, sulfonates, methane sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, and ascorbates. Non-limiting examples of pharmaceutically acceptable base addition salts include sodium, potassium, lithium, ammonium (substituted and unsubstituted), calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Pharmaceutically acceptable salts may, for example, be obtained using standard procedures well known in the field of pharmaceuticals. For mocravimod, pharmaceutically acceptable salts would typically be acid-addition salts, since mocravimod is itself a base. Preferably, the pharmaceutically acceptable salts thereof is hydrochloride salt. The term “phosphate derivatives thereof” includes phosphate esters such as of formula IIa or IIb. The terms “patient”, “subject”, “individual”, and the like, are used interchangeably herein, and refer to a mammal, preferably a human. In some embodiments, the patient, subject or individual in need of treatment includes those who already have the disease, condition, or disorder, for example, hematological malignancies. As used herein, unless specified otherwise, the term "treating" or "treatment", denotes reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or reversing, alleviating, inhibiting the progress of, or preventing one or more symptoms of the disorder or condition to which such term applies. The term « Cytokine release syndrome » (CRS) refers to a significant complication associated with immunotherapies, which is an acute inflammatory process marked by a spectrum of clinical symptoms and substantial but transient elevations of serum cytokines. The term “severe CRS” in contrast to the term “non severe CRS” refers to grade 3 or 4 CRS. Severe Grade 3 CRS is referring to hospitalization required for management of symptoms related to organ dysfunction, including grade 4 LFTs or grade 3 creatinine related to CRS and not attributable to any other conditions; this; includes hypotension treated with intravenous fluids (defined as multiple fluid boluses for blood pressure support) or low-dose vasopressors, coagulopathy requiring fresh frozen plasma or cryoprecipitate or fibrinogen concentrate, and hypoxia requiring supplemental oxygen (nasal cannula oxygen, high-flow oxygen, CPAP, or BiPAP). Severe Grade 4 CRS covers life-threatening complications such as hypotension requiring high-dose vasopressors, hypoxia requiring mechanical ventilation. As used herein, the term “relapse” or “relapsed” has its ordinary meaning in the art, and refer to the return of the hematological malignancy or the signs and symptoms of hematological malignancy after a period of complete remission (e.g, initial complete remission) due to treatment. As used herein, the term “remission” has its ordinary meaning in the art, and refer to a decrease in or disappearance of signs and symptoms of cancer. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission (CR), all signs and symptoms of cancer have disappeared, although cancer still may be in the body. Multispecific antigen-binding proteins The multispecific antigen-binding protein for use in the combination therapy as disclosed herein, is a protein comprising at least: a first binding domain capable of binding to a cell surface protein of a tumor cell; and, a second binding domain capable of binding to a cell surface protein of an immune cell. In preferred embodiments, said first and second binding domains are antigen-binding fragments of antibodies. As used herein, the term "antigen-binding fragment of an antibody” (or simply "antibody fragment"), refers to full length or one or more fragments of an antibody that retain the ability to specifically bind to an antigen. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed within the term "antigen-binding fragment" of an antibody include - a Fab fragment, i.e. a monovalent fragment consisting of the VL, VH, CL and CH1 domains; - a F(ab)2 fragment, i.e. a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; - a Fd fragment consisting of the VH and CH1 domains; - a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; - a dAb fragment (Ward et al., 1989 Nature 341:544-546), which consists of a VH domain, or any fusion proteins comprising such antigen-binding fragments. Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single chain protein in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al., 1988 Science 242:423-426; and Huston et al., 1988 Proc. Natl. Acad. Sci.85:5879-5883). Such single chain antibodies are also intended to be encompassed within the term "antigen-binding fragment" of an antibody. These antibody fragments are obtained using conventional techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies. The term “antigen-binding fragment” (of an antibody) as used herein also include single domain antibodies such as VHH or nanobodies™. The term "single-domain antibody" (sdAb) or nanobody® (tradename of Ablynx) has its general meaning in the art and refers to an antibody fragment with a molecular weight of only 12-15 kDa consisting of the single heavy chain variable domain of antibodies of the type that can be found in Camelid mammals and which are naturally devoid of light chains. Thus, in some embodiments, such single-domain antibodies can be VHHs (variable heavy homodimers). For a general description of these (single) domain antibodies, reference is also made to the prior art cited above, as well as to EP 0 368 684, Ward et al. (Nature 1989 Oct 12; 341 (6242): 544-6), Holt et al, Trends Biotechnol, 2003, 21(1 l):484-490; and WO 06/030220, WO 06/003388. The amino acid sequence and structure of a single-domain antibody can be considered to be comprised of four framework regions or "FRs" which are referred to in the art and herein as "Framework region 1" or "FR1"; as "Framework region 2" or "FR2"; as "Framework region 3 " or "FR3"; and as "Framework region 4" or "FR4" respectively; which framework regions are interrupted by three complementary determining regions or "CDRs", which are referred to in the art as "Complementary Determining Region 1" or "CDR1"; as "Complementarity Determining Region 2" or "CDR2" and as "Complementarity Determining Region 3" or "CDR3", respectively. Accordingly, the single-domain antibody can also be defined as an amino acid sequence with the general structure: FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4 in which FR1 to FR4 refer to framework regions 1 to 4 respectively, and in which CDR1 to CDR3 refer to the complementarity determining regions 1 to 3. In specific embodiments of the present disclosure the multispecific antigen-binding protein (e.g bispecific or trispecific antibody) comprises a first and second binding domains selected from a Fab, a single domain antibody, or a scFv, or, combinations thereof. In specific embodiments, the multispecific antigen-binding protein for use according to the present disclosure comprises a first and second binding domain which are covalently linked either directly or indirectly via linker. A particularly exemplary linker for covalently linking at least the first and second binding domain of the multispecific antigen-binding protein is the (Gly₄Ser)_n linker wherein, n is an integer from 1 to 5. Other examples include the following amino acid sequences: GGG, DGGGGS, TGEKP, EGKSSGSGSESKVD, KESGSVSSEQLAFRSLD, GGRRGGGS, LRQRDGERP, LRQKDGGGSERP, and GSTSGSGKPGSGEGSTKG. Alternative linkers can be rationally designed using a computer program capable of modeling the 3D structure of proteins and peptides or by phage display methods. For example, in a particular embodiment, the multispecific antigen-binding protein is a bispecific antigen-binding protein which comprises two single chain antibodies which are covalently linked by a linker. Such bispecific antigen-binding protein with a first binding domain and second binding domain as described herein are also known as Bispecific T-cell Engager molecule (BiTE) are disclosed in the art for example in Suurs et al 2019 (Pharmacology and Therapeutics 201: 103-119) or Duell et al 2019 (Clinical Pharmacology and Therapeutics, Vol 106 Number 4, 781-791). In a more specific embodiment, said BiTE include one binding specificity to CD3 and the other binding specificity to BCMA. In another specific embodiment, the multispecific antigen-binding protein is a trispecific antigen-binding protein which comprises a Fab wherein each heavy and light chain fragment of the Fab are fused to single chain antibodies (scFv) via their constant CH1 and CL region respectively. Alternative formats of bispecific antigen-binding proteins for use as disclosed herein are described by Brinkmann and Kontermann in Mabs 2017, Vol 9 No, 2, 182-212. Other examples of multispecific antigen-binding protein are the trispecific antigen-binding proteins as disclosed in WO2019/166650 (CDR-Life AG) which contents is enclosed herein in its entirey. The First Binding Domain To Cell Surface Proteins of Tumor Cells The multispecific antigen-binding protein for use in the combination therapy as disclosed herein should comprise a first binding domain capable of binding to a cell surface protein of a tumor cell. In specific embodiments, the multispecific antigen binding protein is capable of inhibiting the activity of the cell surface protein. In other specific embodiments, the multispecific antigen binding protein serves as a means of recruiting an immune cell specifically to the tumor cell. Examples of cell surface proteins on tumor cells that may be targeted include, but are not limited to, CD19, CD123, CD20, CD22, CD25, CD30, CD33, CD38, LeY, ROR1, CLL-1, BCMA, CD16, CLEC12A, GPRC5D, FcRH5, PSMA, FAP, HER2 and combinations thereof, preferably BCMA. As used herein, the term “CD19” refers to the Cluster of Differentiation 19 protein, which is an antigenic determinant expressed in all B lineage cells and detectable on leukemia precursor cells. The human and murine amino acid and nucleic acid sequences can be found in a public database, such as GenBank, UniProt and Swiss-Prot. For example, the amino acid sequence of human CD19 can be found as UniProt/Swiss-Prot Accession No. P15391 and the nucleotide sequence encoding of the human CD19 can be found at Accession No. NM_00l 178098. As used herein, “CD19” includes proteins comprising mutations, e.g., point mutations, fragments, insertions, deletions and splice variants of full length wild-type CD19. CD19 is expressed on most B lineage cancers, including, e.g., acute lymphoblastic leukemia, chronic lymphocyte leukemia and non-Hodgkin lymphoma. Other diseases associated with expression of CD19 are but not limited to hematological cancers, e.g leukemia, lymphoma, diffuse Large B-Cell Lymphoma (DLBCL), chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia ALL, Hodgkin lymphoma, non-Hodgkin lymphoma, Mantle cell lymphoma (MCL), primary mediastinal large B-cell lymphoma (PMBCL) or multiple myeloma, preferably ALL, DLBCL, PMBCL and MCL, more preferably DLBLC. It is also an early marker of B cell progenitors. See, e.g., Nicholson et al. Mol. Immun.34 (16-17): 1157-1165 (1997). In a specific embodiment, the first binding domain is capable of binding to an antigen within the extracellular domain of the CD 19 protein. As used herein, the term “BCMA” refers to the B-cell maturation antigen, which is a protein that in human is encoded by TNFRSF17 gene. The protein sequence of human BCMA can be found as accession number Q02223 according to UniProtKB/Swiss-Prot reference. In certain embodiments, the first binding domain affinity (K_D) is between 1 nM to about 100 nM, as measured for example by surface plasmon reasonance (SPR) technique (analysed on a BIAcore instrument) (Liljeblad et al, Glyco J 17, 323-329 (2000)). BCMA antigen binding domain sequences are disclosed for example in WO2016094304 and WO2010104949 as an example of binding domains capable of binding a cell surface protein on a tumor cell. CD33 antigen binding domain sequences are disclosed for example in WO2017055318 and WO201907413, as an example of binding domains capable of binding a cell surface protein on a tumor cell. CD30 antigen binding domain sequences are disclosed for example in WO2006125668, as an example of binding domains capable of binding a cell surface protein on a tumor cell. CD123 antigen binding domain sequences are disclosed for example in WO2016116626, as an example of binding domains capable of binding a cell surface protein on a tumor cell. CLEC12A antigen binding domain sequences are disclosed for example in US9,914,777, as an example of binding domains capable of binding a cell surface protein on a tumor cell. CD20 antigen binding domain sequences are disclosed for example in US20140088295 and US2015016661, as an example of binding domains capable of binding a cell surface protein on a tumor cell. Any of the antigen-binding domain sequences may be used in either Fab, scFv or sdAb format as part for example of a bispecific antigen binding protein. The Second Binding Domain To Cell Surface Proteins Of Immune Cells The multispecific antigen-binding protein for use in the combination therapy as disclosed herein should further comprise a second binding domain capable of binding to a cell surface protein of an immune cell. The second binding domain of the multispecific antigen binding proteins are capable of recruiting immune cells specifically to the target tumor cells to be eliminated. Examples of immune cells that may be recruited include, but are not limited to, T cells, B cells, natural killer (NK) cells, and natural killer T (NKT) cells. The term « T cells » (or « T-cells » or “immune T-cells”) refers to a type of lymphocyte that matures in the thymus. T cells play an important role in cell-mediated immunity and are distinguished from other lymphocytes, such as B cells, by the presence of a T-cell receptor on the cell surface. “T cell” includes all types of immune cells expressing CD3 including T-helper cells (CD4+ cells), cytotoxic T-cells (CD8+ cells), natural killer T-cells, T-regulatory cells (Treg) and gamma-delta T cells. As used herein the term “B cells” or “B lymphocyte” or any term commonly used in the field refers to a type of lymphocyte that matures in the bone marrow to develop into a lymphocyte that functions in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules that are membrane bound and do not secrete these antibodies. B cells, unlike the other two classes of lymphocytes, T cells and natural killer cells, express B cell receptors (BCRs) on their cell membrane. BCRs allow the B cell to bind to an antigen, against which it will initiate an antibody response. Naïve or memory B cell are activated by an antigen, depending on the antigen with the help or without the help of T cells, proliferate and differentiate into an antibody-secreting effector cell, known as a plasma blast or plasma cell. Additionally, B cells present antigens, are thus called professional antigen-presenting cells (APCs) and secrete cytokines, thereby modulate immune responses. They have been uncovered as active participants in tumor-draining lymph nodes, tumor-associated tertiary lymphoid structures and tumor micro-environment to prompt anti-tumor response, although specific subsets are polarized with pro-tumoral effects. Their prevailing natures convey several advantages, making B cells attractive as a therapeutic cellular platform such as antigen- specific activation, in vivo persistence, memory pool formation and the potential to secrete proteins in large quantities. As used herein, the term “NK cell” also known as natural killer cell, refers to a type of lymphocyte that originates in the bone marrow and plays a critical role in the innate immune system. NK cells provide rapid immune responses against viral-infected cells, tumor cells or other stressed cells, even in the absence of antibodies and major histocompatibility complex on the cell surfaces. Examples of surface proteins that may be used to recruit immune cells includes, but are limited to, CD3, TCR^, TCR^, CD16, NKG2D, CD89, CD64, CD32a, and CD47, and combinations thereof, preferably CD3. In preferred embodiments, the second binding domain is used to recruit T cells. A preferred T cell recruiting antigen is CD3. Hence, in a specific embodiment, the second binding domain is capable of binding to an antigen within the extracellular domain of the CD3 protein. In a more preferred embodiment, the second binding domain is an antigen-binding fragment of an antibody that binds specifically to CD3. As used herein, “CD3” refers to the protein complex and T cell co-receptor that is involved in activating both the cytotoxic T cell (CD8+ naive T cells) and T helper cells (CD4+ naive T cells). It is composed of four distinct chains. In mammals, the complex contains a CD3γ chain, a CD3δ chain, and two CD3ε chains. These chains associate with the T-cell receptor (TCR) and the CD3-zeta (ζ-chain) to generate an activation signal in T lymphocytes. The TCR, CD3- zeta, and the other CD3 molecules together constitute the TCR complex. Exemplary CD3 antigen binding domains are recited in WO2016086196 and WO2017201493, incorporated herein by reference. Preferred multispecific antigen-binding proteins for use as disclosed herein Any appropriate format may be used for the multispecific antigen-binding proteins for use as disclosed herein. In certain embodiments, said multispecific antigen-binding protein is a BiTE (Bispecific T-cell Engager) format, essentially consisting of two scFvs joined together by a linker. In certain embodiments, said BiTE targets CD3 and BCMA. In other embodiments, said BiTE targets CD33 and CD3. Examples of such BiTEs including without limitation, blinatumomab or AMG420 (BCMA + CD3 BiTE, Amgen), or AMG330 (CD33 + CD3 BiTE, Amgen). In certain embodiments, said multispecific antigen-binding protein is a DART (dual affinity retargeting) format, essentially consisting of a criss-cross format (heavy chain of one arm joined to light chain of second arm). In certain embodiments, said DART targets CD123 and CD3. In certain embodiments, said DART targets CD19 and CD3. Examples of such DARTs include without limitation, MGD006 (Macrogenics/Servier), and MDG011 (Macrogenics/ Johnson&Johnson). In certain embodiments, said multispecific antigen-binding protein is a TandAb (tandem diabody) format. In certain sub-embodiments, said TandAb targets CD19 and CD3. In other sub-embodiments, said TandAb targets CD30 and CD16. In other embodiments, said TandAb targets CD33 and CD3. Examples of such TandAbs include without limitation AFM11 (Affimed), AFM13 (Affimed) and MAV564 (Amphivena Therapeutics). In certain embodiments, said multispecific antigen-binding protein is a full-length IgG with one arm (VH/VL) binding to the first binding domain and the other arm (VH/VL) binding to the second binding domain (bispecific mAb). In certain embodiments, said bispecific mAb targets CD20 and CD3. In certain embodiments, said bispecific mAb targets CD123 and CD3. In certain embodiments, said bispecific mAb targets BCMA and CD3. Examples of such format are catumaxomab (Triomab), and PF 06863135 (Pfizer), JNJ-64007957 (Janssen, Genmab), JNJ63709178 (Janssen, Genmab) and RG7828 (Genentech). In certain embodiments, said multispecific antigen-binding protein is a bispecific killer cell engager, having the same format as BiTEs, but targeting CD16 on NK cells. Other embodiments include TriKEs, incorporating IL15 sandwiched into the design to drive NK expansion in vivo (see for example 1633 BiKE, and 161533 TriKE). In a more preferred embodiment, said multispecific antigen-binding protein is Bispecific T-cell Engager, comprising one single chain antibody specifically binding to CD3 and one single chain antibody specifically binding to BCMA. In more specific embodiment of such preferred BiTE embodiment, the affinity of the monovalent antibody arm targeting CD3 is designed to be low (in the nM range), whereas the affinity of the antibody targeting the tumor antigen is typically higher and varies depending on the tumor target. Pharmaceutical composition comprising the multispecific antigen-binding protein The multispecific antigen-binding protein for use in the combination therapy as disclosed herein defined can be formulated individually with pharmaceutically acceptable carriers, e.g., pharmaceutical compositions. As used herein, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant or excipient and includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. The composition may further comprise one or more of the following compounds in addition to the active compound (i.e., the multispecific antigen-binding protein). Sterile phosphate-buffered saline is one example of a pharmaceutically acceptable carrier. Other suitable carriers are well-known to those in the art. (Remington and Gennaro, 1995) Formulations may further include one or more excipients, preservatives, solubilizers, buffering agents, albumin to prevent protein loss on vial surfaces, etc. The form of the pharmaceutical compositions, the route of administration, the dosage and the regimen naturally depend upon the condition to be treated, the severity of the illness, the age, weight, and sex of the patient, etc. The pharmaceutical compositions comprising the multispecific antigen-binding protein can be formulated for a topical, oral, parenteral, intranasal, intravenous, intramuscular, subcutaneous, or intraocular administration and the like. Preferably, the pharmaceutical compositions comprising the multispecific antigen-binding protein contain vehicles, which are pharmaceutically acceptable for a formulation capable of being injected. These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions. S1P receptor modulators for use in the combination therapy of the disclosure The combination therapy of the disclosure comprises administering a therapeutically efficient amount of a S1P receptor modulator in a subject in need thereof. S1P receptors are divided into five subtype related G-coupled protein receptors (i.e., S1P1, S1P2, S1P3, S1P4 and S1P5), which are expressed in a wide variety of tissues and exhibit different cell specificity. In certain embodiments, a modulator of the S1P receptor for use according to the present methods of the disclosure is a compound which modulates one or more of the five S1P receptor types 1 to 5 (S1PR1-5) by activating or internalizing or inhibiting the receptor for signal transduction. Such compounds are also referred to herein as “S1P agonists” and “S1P inhibitor” respectively. In specific embodiments, said S1P receptor modulator for use in the treatment methods of the present disclosure is selected among KRP203 (mocravimod), FTY720 (fingolimod, Gilenya™), BAF312 (siponimod, Mayzent®), ozanimod (Zeposia®), ponesimod, etrasimod, AKP-11, cenerimod, amiselimod, CBP-307, OPL-307, OPL-002, BMS-986166, SCD-044, BOS-173717, CP-1050. Preferably, said S1P receptor modulator for use in the treatment methods of the present disclosure is selected among KRP203 (mocravimod), FTY720 (fingolimod), and Mayzent® (siponimod), most preferably mocravimod. In an embodiment, said S1P receptor modulator for use in the treatment methods of the present disclosure is a S1P agonist. Examples of such S1P agonist is KRP203 (mocravimod), a S1PR₁ selective agonist, or FTY720 (fingolimod), a multi-S1PR agonist of S1PR₁,_3-5 or siponimod, a S1PR₃ agonist, or any of their pharmaceutically acceptable salts or phosphate derivatives thereof. Preferably, in certain embodiments, said S1P agonist is selected among those S1P agonists selectively activating S1PR₁. In a preferred embodiment, the S1P receptor modulator for use according to the present disclosure is the compound of formula (I):

Wherein R₂ is H, halogen, trihalomethyl, C_1-4alkoxy, C_1-7alkyl, phenethyl or benzyloxy; R₃ is H, halogen, CF₃, OH, C_1-7alkyl, C_1-4alkoxy, benzyloxy, phenyl or C_1-4alkoxymethyl; each of R₄ and R₅, independently is H or a residue of formula (a)

wherein each of R₈ and R₉, independently, is H or C_1-4alkyl optionally substituted by halogen; and n is an integer from 1 to 4; and R₆ is hydrogen, halogen, C_1-7alkyl, C_1-4alkoxy or trifluoromethyl. In specific embodiments, said compoud of formula (I) is an S1P agonist, preferably an S1PR₁ selective agonist. Typically, in preferred embodiments, R₃ is chlorine. More preferably, R₂ is H, R₃ is chlorine and R₆ is hydrogen. For example, R₂ is H, R₃ is chlorine, R₆ is hydrogen, and each of R₃ and R₅, independently is H. In a more preferred embodiment, the S1P receptor modulator for use according to the present disclosure, preferably an S1P agonist, preferably S1PR₁ selective agonist, is 2-amino-2- [4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl-propane-1,3-diol, of formula (II) (also referred as mocravimod or KRP203):

or pharmaceutically acceptable salts thereof. Other S1P receptor modulator for use according to the present disclosure, preferably S1PR₁ selective agonist, includes the phosphate derivatives of the following formulae:

Said compounds and their synthesis methods are also disclosed in WO03/029205, WO2004/074297, WO2006/009092, WO2006/041019 and WO2014128611A1 (which disclosures are incorporated herein by reference). Mocravimod, or a pharmaceutically acceptable salt thereof, or a phosphate derivative thereof, is particularly preferred. Indeed, comparing pharmacodynamic effects of different S1P modulators, such as mocravimod, FTY720 and BAF312 established in healthy volunteers reveals differences in efficacy of lymphocyte sequestration. A measurable parameter that determines maintenance of the mode of action, i.e., sequestering of lymphocytes in secondary lymphoid organs and bone marrow, is reduction of peripheral lymphocyte counts. Recovery of absolute lymphocyte counts to 80% of normal counts after a single 1 mg dose of FTY720, multiple dose applications of BAF312 for 28 days, or a single 3 mg dose of KRP203 was reached after 8, 7 and more than 10 days, respectively. Thus, the lymphocyte recovery time for KRP203 is significantly longer than for BAF312 and FTY720. Pharmaceutical composition comprising the S1P receptor modulator The present disclosure also relates to a pharmaceutical composition of said S1P receptor modulator, preferably mocravimod or a pharmaceutically acceptable salt thereof, or a phosphate derivative thereof, as described above, in particular for their use in the treatment methods as disclosed. In an embodiment, the pharmaceutical composition of the present disclosure comprises the S1P receptor modulator, preferably mocravimod or a pharmaceutically acceptable salt thereof, or a phosphate derivative thereof, and one or more pharmaceutically acceptable excipients. Any suitable excipients known to those of ordinary skill in the art for use in pharmaceutical compositions may be employed in the compositions described herein. The term "excipient", as used herein, refers to a non-active substance that is added alongside the drug substance, and is part of the formulation mixture. Pharmaceutically acceptable excipient are for example fillers, solvents, diluents, carriers, auxiliaries, distributing and sensing agents, delivery agents, such as preserving agents, disintegrants, moisteners, emulsifiers, suspending agents, thickeners, sweeteners, flavoring agents, aromatizing agents, antibacterial agents, fungicides, lubricants, and prolonged delivery controllers, antioxidants, glidants. The choice and suitable proportions of them are depended on the nature and way of administration and dosage. The pharmaceutical composition may be administered in any manner appropriate to the disease or disorder to be treated as determined by persons of ordinary skill in the medical arts. An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as discussed herein, including the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose (or effective dose) and treatment regimen provides the pharmaceutical composition in an amount sufficient to provide a therapeutic effect, for example, an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity or other benefit as described in detail herein. The pharmaceutical compositions described herein may be administered to a subject in need thereof by any of several routes that can effectively deliver an effective amount of the compound. The pharmaceutical composition may be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically, bucally, or as an oral or nasal spray. In a preferred embodiment, the pharmaceutical composition is suitable to be administered orally. In another embodiment, the pharmaceutical composition may be a solid dosage form suitable for oral administration. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In a preferred embodiment, the pharmaceutical composition is a capsule or a tablet. The capsule may be a soft or hard gelatin capsule, preferably a hard gelatin capsule. For example, the capsule is HGC Crushed or HPMC capsules Crushed. In an embodiment, the release of the capsule or tablet content may be immediate or modified such as delayed, targeted or extended. In a preferred embodiment the solid dosage form is an immediate release dosage form. In an embodiment, the pharmaceutical composition comprises the S1P receptor modulator, preferably mocravimod, and one or more pharmaceutically acceptable excipients, and particularly, at least one filler and mixtures thereof, a disintegrant, a lubricant and, a glidant. Examples of fillers include mannitol, microcrystalline cellulose, lactose monohydrate, anhydrous lactose, corn starch, xylitol, sorbitol, sucrose, dicalcium phosphate, maltodextrin, and gelatin. In a preferred embodiment, the pharmaceutical composition comprising the S1P receptor modulator, preferably mocravimod, comprises a mixture of mannitol and microcrystalline cellulose as fillers. Examples of disintegrants include the modified starch such as sodium starch glycolate, sodium carboxymethyl starch, and pre-gelatinized starch, crosslinked polymers, such as crosslinked polyvinylpyrrolidone (crospovidone) or crosslinked sodium carboxymethyl cellulose (croscarmellose sodium), and calcium silicate. In a preferred embodiment, the pharmaceutical composition comprising the S1P receptor modulator, preferably mocravimod, comprises sodium starch glycolate as disintegrant. Examples of lubricants include magnesium stearate, hydrogenated castor oil, glyceryl behenate, calcium stearate, zinc stearate, mineral oil, silicone fluid, sodium lauryl sulfate, L- leucine, and sodium stearyl fumarate. In a preferred embodiment, the pharmaceutical composition comprising the S1P receptor modulator, preferably mocravimod, comprises magnesium stearate as lubricant. Examples of glidants include colloidal silicon dioxide, starch, magnesium stearate and talc. In a preferred embodiment, the pharmaceutical composition comprising the S1P receptor modulator, preferably mocravimod, comprises colloidal silicon dioxide as lubricant. In a more preferred embodiment, the pharmaceutical composition of the S1P receptor modulator, comprises at least one filler selected from mannitol, microcrystalline cellulose and mixtures thereof, sodium starch glycolate as disintegrant, magnesium stearate as lubricant and, colloidal silicon dioxide as glidant. Any suitable excipients known to those of ordinary skill in the art in pharmaceutical compositions may be further employed in the compositions described herein. In an embodiment the dosage strength of the S1P receptor modulator, preferably the hydrochloride salt of formula (I) or the phosphate derivatives of formula IIa or IIb, in the solid dosage form is between 0.05 mg to 15 mg/unit, preferably between 0.1mg to 10mg/unit, for example about 0.1mg/unit, or about 0.4mg/unit, or about 1 mg/unit, or about 10 mg/unit, more preferably about 1 mg/unit. More specifically, the pharmaceutical composition for use of the present disclosure, in particular those comprising mocravimod or a pharmaceutically acceptable salt thereof, or a phosphate derivative thereof, at 1mg/unit, further comprises the following ingredients: - mannitol, preferably at a content from 48 to 88 mg/unit, more preferably from 58 to 78mg/unit, even more preferably at a content about 68 mg/unit; - microcrystalline cellulose, preferably at a content from 5 to 45 mg/unit, more preferably from 15 to 35 mg/unit, even more preferably at a content about 25 mg/unit; - sodium starch glycolate, preferably at a content from 1 to 8 mg/unit, more preferably from 2 to 6 mg/unit, even more preferably at a content about 4 mg/unit; - magnesium stearate, preferably at a content from 0.025 to 4 mg/unit, more preferably from 0.5 to 2 mg/unit, even more preferably at a content about 1 mg/unit; and - colloidal silicon dioxide, preferably at a content from 0.125 to 2 mg/unit, more preferably from 0.25 to 1 mg/unit, even more preferably at a content about 0.5 mg/unit. Combination therapy of the disclosure The present disclosure relates to a combination therapy with a S1P receptor modulator as described herein, and a multispecific antigen-binding protein as described herein, in methods for treating a hematological malignancy in a subject in need thereof, and more particularly in the population of patients and disease indications as defined above. More specifically, the present disclosure relates to a method for treating a hematological malignancy in a subject in need thereof, said method comprising administering a therapeutically efficient amount of a S1P receptor modulator as described herein, in combination, simultaneously, separately or sequentially, with a therapeutically efficient amount of a multispecific antigen-binding protein as described herein. As used herein, the term “in combination” or “combination therapy” means that two (or more) different treatments are delivered to the subject during the course of the subject's affliction with the disorder, e.g., the two or more treatments are delivered after the subject has been diagnosed with the disorder and before the disorder has been cured or eliminated or treatment has ceased for other reasons. In some embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous” or “concurrent delivery”. In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In some embodiments of either case, the treatment is more effective because of combined administration. For example, the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment. In some embodiments, delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive. The delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered. In preferred embodiment, the first agent of the combination therapy, typically a multispecific antigen-binding protein as disclosed herein is administered at the same time or separately within time intervals, with the second agent of the combination therapy, e.g. a S1PR modulator such as mocravimod, in the same subject in need thereof, where these time intervals allow that the combined partners show a cooperative or synergistic effect for treating a disorder, e.g. cancer and more specifically hematological malignancies. It is not intended to imply that the therapeutic agents must be administered at the same time and/or formulated for delivery together although these methods of delivery are within the scope described herein. The S1PR modulator, e.g. mocravimod, as herein disclosed, can be administered concurrently with or prior to, or subsequent to one or more other additional therapies or therapeutic agents comprising such multispecific antigen-binding protein. The terms are also meant to encompass treatment regimens in which the agents are not necessarily administered by the same route of administration. As used herein the term synergy or synergistic effect when used in connection with a description of the efficacy of a combination of agents, means any measured effect of the combination which is greater than the effect predicted from a sum of the effects of the individual agents (i.e., greater than an additive effect). In some embodiments, the rate of tumor growth or tumor size (e.g., the rate of change of the size (e.g., volume, mass of the tumor) is used to determine whether a combination of drugs is synergistic (e.g., the combination of drugs is synergistic when the rate of tumor growth is slower than would be expected if the combination of drugs produced an additive effect). In some embodiments, median overall survival time (e.g. of <12months) is used to determine whether a combination of drugs is synergistic (e.g., a combination of drugs is synergistic when the median overall survival time of a subject or population of subjects is longer than would be expected if the combination of drugs produced an additive effect). In some embodiments, complete remission (CR) and complete remission with incomplete count recovery (CRi) rates is used to determine whether a combination of drugs is synergistic (as compared the monotherapy). In some embodiments, prevention of relapse is used to determine whether a combination of drugs is synergistic. The term “anti-tumor effect” as used herein, refers to a biological effect which can be manifested by a decrease in tumor volume, a decrease in the number of tumor cells, a decrease in the number of metastases, an increase in life expectancy, or amelioration of various physiological symptoms associated with the cancerous condition. The term “effective amount” or “therapeutically effective amount” refers to the amount of a composition that will elicit a biological or medical response of a cell, tissue, system, or subject that is being sought by the researcher, veterinarian, medical doctor or other clinician. For example, the composition comprises an effective amount of multispecific antigen-binding protein, and/or mocravimod, that when administered to a subject, either as a single dose or as part of a series of doses, is effective to produce at least one therapeutic effect, e.g. sufficient to prevent development of, or alleviate to some extent, one or more of the signs or symptoms of the disorder or disease (e.g., hematological cancer) being treated. Effective amounts vary, as recognized by those skilled in the art, depending on, for example, route of administration, excipient usage, and co-usage with other active agents. In the case of treating a particular disease or condition, the desired therapeutic effect is inhibiting the progression of the disease. This may involve only slowing the progression of the disease temporarily, although more preferably, it involves halting the progression of the disease permanently. This can be monitored by routine methods or can be monitored according to diagnostic methods discussed herein. The desired response to treatment of the disease or condition also can be delaying the onset or even preventing the onset of the disease or condition. The precise amount of the multispecific antigen-binding protein to be administered can be determined by a physician with consideration of individual differences in age, weight, tumor size, extent of infection or metastasis, and condition of the patient (subject). In other embodiments, when referring to S1P receptor modulator, an effective amount of S1P receptor modulator (such as mocravimod) may refer to produce a synergistic therapeutic response when administered in combination with an effective amount of multispecific antigen- binding protein in a subject in need thereof. The combination therapies and related methods of treatment disclosed herein are suitable for patients having a hematological malignancy. Hematological malignancies are the types of cancer such as leukemia, lymphoma and malignant lymphoproliferative conditions that affect blood, bone marrow and the lymphatic system. In one embodiment, the hematologic malignancy is leukemia. Leukemia can be classified as acute leukemia and chronic leukemia. Acute leukemia can be further classified as acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Chronic leukemia includes chronic myeloid leukemia (CML) and chronic lymphoblastic leukemia (CLL). Other related conditions include myelodysplastic syndromes (MDS, formerly known as “preleukemia”) which are a diverse collection of hematological conditions united by ineffective production (or dysplasia) of myeloid blood cells and risk of transformation to AML. In other embodiment, the hematologic malignancy is lymphoma. Lymphoma is a group of blood cell tumors that develop from lymphocytes. Exemplary lymphomas include non-Hodgkin lymphoma and Hodgkin lymphoma. Non-Hodgkin lymphoma (NHL) is a group of cancers of lymphocytes, formed from either B or T cells. NHLs occur at any age and are often characterized by lymph nodes that are larger than normal, weight loss, and fever. Different types of NHLs are categorized as aggressive (fast-growing) and indolent (slow-growing) types. B-cell non-Hodgkin lymphomas include Burkitt lymphoma, chronic lymphoblastic leukemia/small lymphoclastic lymphoma (CLL/SLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and mantle cell lymphoma. Examples of T- cell non-Hodgkin lymphomas include mycosis fungoides, anaplastic large cell lymphoma, and precursor T-lymphoblastic lymphoma. Lymphomas that occur after bone marrow or stem cell transplantation are typically B-cell non-Hodgkin lymphomas. See, e.g., Maloney. NEJM. 366.21(2012):2008-16. Diffuse large B-cell lymphoma (DLBCL) is a form of NHL that develops from B cells. In some embodiment the hematological malignancy is selected from the group consisting of leukemia, lymphoma, diffuse Large B-Cell Lymphoma (DLBCL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphoblastic leukemia (CLL), acute lymphoblastic leukemia (ALL), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), Mantle cell lymphoma (MCL), primary mediastinal large B-cell lymphoma (PMBCL) or multiple myeloma. In a preferred embodiment, in particular when the first binding domain is BCMA, the hematological malignancy is multiple myeloma. In specific embodiments, said subject is a subject eligible for a multispecific antigen-binding protein therapy for treating a hematological disorder. Typically, the subject has been, is being, or will be administered an antigen-binding protein, e.g., an antigen-binding protein described herein. In embodiments, the subject has been, is being, or will be administered a bispecific T cell engager (BiTE), such as Blinatumomab. In specific embodiments, said subject is at risk of developing cytokine release syndrome (CRS), after immunotherapy, e.g. bispecific or trispecific therapy. In specific embodiments, said subject has CRS or is diagnosed with CRS, after immunotherapy, e.g. bispecific or trispecific therapy. Selecting a dosage regimen for a combination therapy of the disclosure depends on several factors, including the serum or tissue turnover rate of the entity, the level of symptoms, the immunogenicity of the entity, and the accessibility of the target cells, tissue or organ in the individual being treated. Preferably, a dosage regimen maximizes the amount of each therapeutic agent delivered to the patient consistent with an acceptable level of side effects. Accordingly, the dose amount and dosing frequency of each biotherapeutic and chemotherapeutic agent in the combination depends in part on the particular therapeutic agent, the severity of the cancer being treated, and patient characteristics. In specific embodiments, the amount of S1P receptor modulator, e.g. mocravimod, can be administered per day at a fixed amount. Preferably said fixed daily dosage is 0,05 mg to 40 mg per day, preferably 0,1 mg to 35 mg, more preferably 0,5 mg to 30 mg, even more preferably 1 mg to 15 mg per day, even more preferably 1,5 mg to 7mg, even more preferably 2 mg to 5 mg, even more preferably about 3 mg per day or about 1 mg per day. For example, the S1P receptor modulator can be mocravimod and said mocravimod may be administered at a daily dose of about 1 mg per day. Alternatively, mocravimod may be administered at a dose of about 3mg per day, preferably as three solid dosage forms of about 1mg or as one solid dosage form of about 3mg. Alternatively, mocravimod may be administered at a dose of about 2mg per day, preferably as two solid dosage forms of about 1mg or as one solid dosage form of about 2mg. In some embodiment, said S1P receptor modulator is daily administered for at least 1, 2, or 3 months, or more, preferably from a starting day between 1 – 20 days prior said composition comprising antigen-binding protein, more preferably 11 days before antigen-binding protein administration. In specific embodiments, a therapeutically effective amount of the multispecific antigen-binding protein, e.g. when BCMA is selected as the first binding domain, is an amount sufficient for activating an amount of T cells sufficient to enhance anti-tumor activity against the tumor cells, for example malignant B cells. In specific embodiments, the amount of the multispecific antigen-binding protein, e.g. when BCMA is selected as the first binding domain, as administered intravenously, can be selected at a dose comprised between 20 µg and 1000 mg, notably between 1 mg and 200 mg or more. In specific embodiments, suitable dose for intravenous administration of multispecific antigen- binding protein, such as blinatumomab, can be a continuous intravenous infusion of between 5 and 30 ^g / day for 1 to 5 cycles of 28 days, for example according to the recommended dosage for blinatumomab as monotherapy. In a preferred embodiments of the method of the present disclosure, said S1P receptor modulator is administered in an amount sufficient for preventing immune cells from leaving the lymphoid tissues. Indeed, preventing immune cells from leaving the lymphoid tissues means improving proximity of immune cells and tumor cells. S1P receptor modulator and multispecific antibodies synergistically locate immune cells and tumor cells together. This increased proximity will activate the local immune cells, enhancing killing mechanism of actions, generally shown by increase of markers such as CD69, GrB and PD1. This translates into increased killing of tumor cells, such as malignant B cells, resulting in improved anti-tumor efficacy and/or prevention of the relapse of hematological malignancies patients. In another embodiment, said S1P receptor modulator is administered in an amount sufficient for reducing the risk of cytokine release syndrome (CRS), in particular in a subject receiving a multispecific antigen-binding protein e.g. bispecific or trispecific antibody. Indeed, reducing the risk of cytokine release syndrome, allows to improve patient’s response to said antigen-binding protein treatment. CRS being a result of administered said multispecific antigen-binding protein i.e. for immunotherapy, especially bispecific or trispecific antibody, becoming extensively activated resulting in the release of massive amounts of cytokines such as IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-10 and IL-17A, preventing the release of cytokines, would help preventing CRS, and thus improving patient’s response to said multispecific antigen-binding protein treatment. In consequence, the treatment of hematological malignancies, especially multiple myeloma, in subjects in need thereof will be improved. In an embodiment, said S1P receptor modulator is administered in an amount sufficient for reducing the risk of cytokine release syndrome, in particular systemic cytokine release syndrome, in a subject receiving a multispecific antigen-binding protein, preferably bispecific antibody or trispecific antibody. Hence the present disclosure also relates to S1P receptor modulator for use in preventing or reducing the risk of cytokine release syndrome (CRS), in particular systemic cytokine release syndrome, in a subject receiving a multispecific antigen-binding protein in need thereof, typically undergoing a multispecific antigen-binding protein therapy as disclosed above. Specific Embodiments The present disclosure is provided in various aspects as outlined in the following embodiments: A multispecific antigen-binding protein for use in treating a hematological malignancy in a subject in need thereof, wherein said multispecific antigen-binding protein comprises at least : a first binding domain capable of binding to a cell surface protein of a tumor cell; and, a second binding domain capable of binding to a cell surface protein of an immune cell; and wherein a therapeutically effective amount of said multispecific antigen-binding protein composition is administered in combination with a therapeutically effective amount of an S1P receptor modulator. The multispecific antigen-binding protein for use according to embodiment 1, wherein the cell surface protein of the tumor cell is selected from the group consisting of CD19, CD123, CD20, CD22, CD25, CD30, CD33, CD38, LeY, ROR1, CLL-1, BCMA, CD16, CLEC12A, GPRC5D, FcRH5, PSMA, FAP, HER2, and combinations thereof, preferably BCMA. The multispecific antigen-binding protein for use according to embodiment 1 or 2, wherein the second binding domain binds to a cell surface protein of an immune cell selected from the group consisting of CD3, TCR^, TCR^, CD16, NKG2D, CD89, CD64, and CD32a CD47, and combinations thereof, preferably CD3. The multispecific antigen-binding protein for use according to embodiments 1-3, wherein said S1P receptor modulator is selected among mocravimod, siponimod, fingolimod, ozanimod, ponesimod, etrasimod, AKP-11, cenerimod, amiselimod, CBP-307, OPL-307, OPL-002, BMS-986166, SCD-044, BOS-173717, CP-1050, preferably mocravimod. The multispecific antigen-binding protein for use according to embodiment 4, wherein said S1P receptor modulator is a S1P receptor agonist. The multispecific antigen-binding protein for use according to embodiment 4 or 5, wherein the S1P receptor agonist is of the following formula (I) or (II) or (IIa) or (IIb):

wherein each of R₈ and R₉, independently, is H or C_1-4alkyl optionally substituted by halogen; and n is an integer from 1 to 4; and R₆ is hydrogen, halogen, C_1-7alkyl, C_1-4alkoxy or trifluoromethyl, Or,

or pharmaceutically acceptable salts thereof Or,

. 7. The multispecific antigen-binding protein for use according to anyone of embodiments 1- 6, wherein the S1P receptor agonist is mocravimod, or a pharmaceutically acceptable salt thereof or a phosphate derivative thereof. 8. The multispecific antigen-binding protein for use according to any one of embodiments 1- 7, wherein said hematological malignancy is leukemia and/or lymphoma. 9. The multispecific antigen-binding protein for use according to any one of embodiments 1- 8, wherein said hematological malignancy is selected from the group consisting of diffuse Large B-Cell Lymphoma (DLBCL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphoblastic leukemia (CLL), acute lymphoblastic leukemia (ALL), Hodgkin lymphoma, non-Hodgkin lymphoma, Mantle cell lymphoma (MCL), primary mediastinal large B-cell lymphoma (PMBCL) or multiple myeloma, preferably multiple myeloma. 10. The multispecific antigen-binding protein for use according to any one of embodiments 1- 9, wherein an efficient amount of a multispecific antigen-binding protein targeting BCMA and CD3 is administered to said subject. 11. The multispecific antigen-binding protein for use according to any one of embodiments 1- 10, wherein said S1P receptor modulator is administered per day at a dosage of between 0,05 mg to 40 mg, preferably 0,1 mg to 35 mg, more preferably 0,5 mg to 30 mg, even more preferably 1 mg to 15 mg, even more preferably 1,5 mg to 7mg, even more preferably 2 mg to 5 mg, even more preferably about 3 mg or about 1 mg. 12. The multispecific antigen-binding protein for use according to any one of embodiments 1- 11, wherein said S1P receptor modulator is daily administered for at least 1, 2, or 3 months, or more, preferably from a starting day between 1 – 20 days prior administering said composition comprising a multispecific antigen-binding protein, more preferably 11 days before antigen-binding protein administration. 13. The multispecific antigen-binding protein for use according to any one of embodiments 1- 12, wherein said S1P receptor modulator is administered in an amount sufficient for preventing immune cells bound to said antigen-binding protein from leaving the lymphoid tissues and/or improving the proximity of the tumor cell and the immune cell. 14. A method of treating a hematological malignancy in a subject in need thereof, comprising administering a therapeutically effective amount of a multispecific antigen-binding protein, in combination with a therapeutically effective amount of a S1P receptor modulator, wherein said antigen-binding protein comprises at least : a first binding domain capable of binding to a cell surface protein of a tumor cell; and, a second binding domain capable of binding to a cell surface protein of an immune cell. 15. The method of embodiment 14, wherein the cell surface protein of the tumor cell is selected from the group consisting of CD19, CD123, CD20, CD22, CD25, CD30, CD33, CD38, LeY, ROR1, CLL-1, BCMA, CD16, CLEC12A, GPRC5D, FcRH5, PSMA, FAP, HER2, and combinations thereof, preferably BCMA. 16. The method of embodiment 14 or 15, wherein the second binding domain binds a cell surface protein of an immune cell selected from the group consisting of CD3, TCR^, TCR^, CD16, NKG2D, CD89, CD64, and CD32a, CD47, and combinations thereof, preferably CD3. 17. The method of any one of embodiments 14-16, comprising: 1) administering a therapeutically efficient amount of said multispecific antigen-binding protein to said recipient subject, and 2) administering, for example before or after step 1), to the recipient subject an effective amount of a S1P receptor modulator, preferably mocravimod of formula II or a pharmaceutically acceptable salt thereof or a phosphate derivative thereof such as formula IIa or IIb, for example before step 1). 18. The method of embodiment 17, wherein the multispecific antigen-binding protein composition is administered at a dosage of between 1 and 200 mg, or more. 19. The method of anyone of embodiments 14-18, wherein said S1P receptor modulator is selected among mocravimod, siponimod, fingolimod, ozanimod, ponesimod, etrasimod, AKP-11, cenerimod, amiselimod, CBP-307, OPL-307, OPL-002, BMS-986166, SCD-044, BOS-173717, CP-1050, preferably mocravimod. 20. The method of embodiment 19, wherein said S1P receptor modulator is a S1P receptor agonist. 21. The method of embodiment 20, wherein the S1P receptor agonist is of the following formula (I) or (II) or (IIa) or (IIb) :

wherein R2 is H, halogen, trihalomethyl, C1-4alkoxy, C1-7alkyl, phenethyl or benzyloxy; R3 is H, halogen, CF3, OH, C1-7alkyl, C1-4alkoxy, benzyloxy, phenyl or C1- 4alkoxymethyl; each of R4 and R5, independently is H or a residue of formula (a)

or pharmaceutically acceptable salts thereof,

o_{r, .} 22. The method of anyone of embodiments 14-21, wherein the S1P receptor modulator is mocravimod, or a pharmaceutically acceptable salt thereof or a phosphate derivative thereof. 23. The method of anyone of embodiments 14-22, wherein said S1P receptor modulator is administered per day at a dosage of between 0,05 mg to 40 mg, preferably 0,1 mg to 35 mg, more preferably 0,5 mg to 30 mg, even more preferably 1 mg to 15 mg, even more preferably 1,5 mg to 7mg, even more preferably 2 mg to 5 mg, even more preferably about 3 mg or about 1 mg. 24. The method of anyone of embodiments 14-23, wherein said S1P receptor modulator is mocravimod or a pharmaceutically acceptable salt thereof or a phosphate derivative thereof, and said mocravimod is formulated as a solid dosage form, said solid dosage form comprising: - 1 mg/unit of mocravimod or a pharmaceutically acceptable salt thereof or a phosphate derivative thereof, - mannitol, preferably at a content from 48 to 88 mg/unit, more preferably from 58 to 78mg/unit, even more preferably at a content about 68 mg/unit; - microcrystalline cellulose, preferably at a content from 5 to 45 mg/unit, more preferably from 15 to 35 mg/unit, even more preferably at a content about 25 mg/unit; - sodium starch glycolate, preferably at a content from 1 to 8 mg/unit, more preferably from 2 to 6 mg/unit, even more preferably at a content about 4 mg/unit; - magnesium stearate, preferably at a content from 0.025 to 4 mg/unit, more preferably from 0.5 to 2 mg/unit, even more preferably at a content about 1 mg/unit; and - colloidal silicon dioxide, preferably at a content from 0.125 to 2 mg/unit, more preferably from 0.25 to 1 mg/unit, even more preferably at a content about 0.5 mg/unit. 25. The method of anyone of embodiments 14-24, wherein said S1P receptor modulator is daily administered for at least 1, 2, 3 months, or more, preferably from a starting day between 1 – 20 days prior administering said multispecific antigen-binding protein, more preferably 11 days before multispecific antigen-binding protein administration. 26. The method of anyone of embodiments 14-25, wherein said hematological malignancy is leukemia and/or lymphoma. 27. The method of anyone of embodiments 14-26, wherein said hematological malignancy is selected from the group consisting of diffuse Large B-Cell Lymphoma (DLBCL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphoblastic leukemia (CLL), acute lymphoblastic leukemia (ALL), Hodgkin lymphoma, non-Hodgkin lymphoma, Mantle cell lymphoma (MCL), primary mediastinal large B-cell lymphoma (PMBCL) or multiple myeloma, preferably multiple myeloma. 28. The method of anyone of embodiments 14-27, wherein said S1P receptor modulator is administered in an amount sufficient for preventing immune cells bound to said multispecific antigen-binding protein from leaving the lymphoid organs and/or increasing the efficacy of said antigen-binding protein. 29. A method of preventing cytokine release syndrome, and/or increasing the anti-tumor efficacy of an immune cell, e.g. a T cell, in a subject in need thereof, comprising administering an effective amount of a S1P receptor modulator (e.g., mocravimod), in combination with the multispecific antigen-binding protein, to the subject, thereby preventing CRS and/or increasing the anti-tumor efficacy the immune cell, e.g. a T cell. 30. Use of an multispecific antigen-binding protein composition for the manufacture of a medicament for treating hematological malignancies in a subject in need thereof, wherein said multispecific antigen-binding protein comprises at least : a first binding domain capable of binding to a cell surface protein of a tumor cell; and, a second binding domain capable of binding to a cell surface protein of an immune cell; and wherein a therapeutically effective amount of said multispecific antigen-binding protein composition is administered in combination with a therapeutically effective amount of an S1P receptor modulator. 31. The use according to embodiment 30, wherein the cell surface protein of the tumor cell is selected from the group consisting of CD19, CD123, CD20, CD22, CD25, CD30, CD33, CD38, LeY, ROR1, CLL-1, BCMA, CD16, CLEC12A, GPRC5D, FcRH5, PSMA, FAP, HER2, and combinations thereof, preferably BCMA. 32. The use according to embodiment 30 or 31, wherein the second binding domain binds a cell surface protein of an immune cell selected from the group consisting of CD3, TCR^, TCR^, CD16, NKG2D, CD89, CD64, and CD32a, CD47, and combinations thereof, preferably CD3. 33. The use according to embodiments 30-32, wherein said S1P receptor modulator is selected among mocravimod, siponimod, fingolimod, ozanimod, ponesimod, etrasimod, AKP-11, cenerimod, amiselimod, CBP-307, OPL-307, OPL-002, BMS-986166, SCD-044, BOS-173717, CP-1050, preferably mocravimod. The use according to embodiment 33, wherein said S1P receptor modulator is a S1P receptor agonist. The use according to embodiment 33 or 34, wherein the S1P receptor agonist is of the following formula (I) or (II) or (IIa) or (IIb):

wherein each of R₈ and R₉, independently, is H or C_1-4alkyl optionally substituted by halogen; and n is an integer from 1 to 4; and R₆ is hydrogen, halogen, C_1-7alkyl, C_1-4alkoxy or trifluoromethyl, Or, or pharmaceutically acceptable salts thereof Or,

. 36. The use according to anyone of embodiments 30-35, wherein the S1P receptor agonist is mocravimod, or a pharmaceutically acceptable salt thereof or a phosphate derivative thereof. 37. The use according to any one of Embodiments 30-36, wherein said hematological malignancy is leukemia and/or lymphoma. 38. The use according to any one of Embodiments 30-37, wherein said hematological malignancy is selected from the group consisting of diffuse Large B-Cell Lymphoma (DLBCL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphoblastic leukemia (CLL), acute lymphoblastic leukemia (ALL), Hodgkin lymphoma, non-Hodgkin lymphoma, Mantle cell lymphoma (MCL), primary mediastinal large B-cell lymphoma (PMBCL) or multiple myeloma, preferably multiple myeloma. 39. The use according to any one of embodiments 30-38, wherein an efficient amount of an multispecific antigen-binding protein, preferably targeting CD3 and BCMA, are administered at a dosage of between 1 and 200 mg, or more. 40. The use according to any one of embodiments 30-39, wherein said S1P receptor modulator is administered per day at a dosage of between 0,05 mg to 40 mg, preferably 0,1 mg to 35 mg, more preferably 0,5 mg to 30 mg, even more preferably 1 mg to 15 mg, even more preferably 1,5 mg to 7mg, even more preferably 2 mg to 5 mg, even more preferably about 3 mg or about 1 mg. 41. The use according to any one of embodiments 30-40, wherein said S1P receptor modulator is daily administered for at least 1, 2, or 3 months, or more, preferably from a starting day between 1 – 20 days prior administering said multispecific antigen-binding protein, more preferably 11 days before antigen-binding protein administration. 42. The use according to any one of embodiments 30-41, wherein said S1P receptor modulator is administered in an amount sufficient for preventing immune cells bound to said antigen- binding protein from leaving the lymphoid tissues and/or increasing the efficacy of said antigen-binding protein. 43. Use of a S1P receptor modulator for the manufacture of a medicament for preventing cytokine release syndrome (CRS), with an antigen-binding protein, in a subject in need thereof, comprising administering a S1P receptor modulator (e.g. mocravimod) or a pharmaceutically acceptable salt thereof or a phosphate derivative thereof, in combination with the multispecific antigen-binding protein, to the subject, thereby preventing CRS in the subject. EXAMPLE Measuring improved anti-tumour efficacy of a bi-specific antibody in combination with mocravimod To show an improved anti-tumour efficacy of the BCMAxCD3 bi-specific antibody when administered in combination with mocravimod, humanised B-hCD3EDG mice (C57BL/6- Cd3e^tm1(CD3E)Cd3d^tm1(CD3D)Cd3g^tm(CD3G)/Bcgen) engrafted with two different BCMA-humanised murine multiple myeloma cell lines (MM5080 and MM8273) will be used. Anti-tumour efficacy and T cell phenotyping will be determined in four therapy cohorts: 1) mocravimod daily (3mg/kg i.p.) (monotherapy mocravimod), 2) BCMAxCD3 bi-specific antibody (monotherapy bi-specific antibody), 3) mocravimod (daily; 3mg/kg i.p.) + BCMAxCD3 bi-specific antibody (combination therapy mocravimod and bispecific antibody) and 4) vehicle control. Therapies will be initiated 7-10 days after injection of multiple myeloma cells. Mocravimod treatment will be initiated one day prior to antibody administration. Responses will be determined in OS Kaplan-Meier curves according to log-rank test. A fraction of mice from each cohort will be sacrificed at e.g. day 10 post treatment and tumour and T cells will be characterised by flow cytometry. The remaining mice will be characterised at time of death, or sacrificed at day 75 in case of prolonged tumour control.

Claims

CLAIMS 1. A multispecific antigen-binding protein for use in treating a hematological malignancy in a subject in need thereof, wherein said multispecific antigen-binding protein comprises at least : a first binding domain capable of binding to a cell surface protein of a tumor cell; and, a second binding domain capable of binding to a cell surface protein of an immune cell; and wherein a therapeutically effective amount of said multispecific antigen-binding protein is administered in combination with a therapeutically effective amount of an S1P receptor modulator. 2. The multispecific antigen-binding protein for use according to claim 1, wherein the cell surface protein of the tumor cell is selected from the group consisting of CD19, CD123, CD20, CD22, CD25, CD30, CD33, CD38, LeY, ROR1, CLL-1, BCMA, CD16, CLEC12A, GPRC5D, FcRH5, PSMA, FAP, HER2, and combinations thereof, preferably BCMA. 3. The multispecific antigen-binding protein for use according to claim 1 or 2, wherein the second binding domain binds a cell surface protein of an immune cell selected from the group consisting of CD3, TCR^, TCRP, CD16, NKG2D, CD89, CD64, and CD32a, CD47, and combinations thereof, preferably CD3. 4. The multispecific antigen-binding protein for use according to claims 1-3, wherein said S1P receptor modulator is selected among mocravimod, siponimod, fingolimod, ozanimod, ponesimod, etrasimod, AKP-11, cenerimod, amiselimod, CBP-307, OPL-307, OPL-002, BMS-986166, SCD-044, BOS-173717, CP-1050, preferably mocravimod. 5. The multispecific antigen-binding protein for use according to claim 4, wherein said S1P receptor modulator is a S1P receptor agonist. 6. The multispecific antigen-binding protein for use according to claim 4 or 5, wherein the S1P receptor agonist is of the following formula (I) or (II) or (IIa) or (IIb): wherein R₂ is H, halogen, trihalomethyl, C_1-4alkoxy, C_1-7alkyl, phenethyl or benzyloxy; R₃ is H, halogen, CF₃, OH, C_1-7alkyl, C_1-4alkoxy, benzyloxy, phenyl or C_1-4alkoxymethyl; each of R₄ and R₅, independently is H or a residue of formula (a)

or pharmaceutically acceptable salts thereof Or,

. 7. The multispecific antigen-binding protein for use according to any one of claims 1-6, wherein the S1P receptor agonist is mocravimod, or a pharmaceutically acceptable salt thereof or a phosphate derivative thereof. 8. The multispecific antigen-binding protein composition for use according to any one of claims 1-7, wherein said hematological malignancy is leukemia and/or lymphoma. 9. The multispecific antigen-binding protein composition for use according to any one of claims 1-8, wherein said hematological malignancy is selected from the group consisting of diffuse Large B-Cell Lymphoma (DLBCL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphoblastic leukemia (CLL), acute lymphoblastic leukemia (ALL), Hodgkin lymphoma, non-Hodgkin lymphoma, Mantle cell lymphoma (MCL), primary mediastinal large B-cell lymphoma (PMBCL) or multiple myeloma, preferably multiple myeloma. 10. The multispecific antigen-binding protein for use according to any one of claims 1-9, wherein said multispecific antigen-binding protein binds specifically to CD3 and BCMA, preferably is a Bispecific T-cell Engager that binds specifically to CD3 and BCMA. 11. The multispecific antigen-binding protein for use according to any one of claims 1-10, wherein said S1P receptor modulator is administered per day at a dosage of between 0.05 mg to 40 mg, preferably 0.1 mg to 35 mg, more preferably 0.5 mg to 30 mg, even more preferably 1 mg to 15 mg, even more preferably 1mg to 7mg, even more preferably 1 mg to 5 mg, even more preferably about 1 mg or about 3 mg. 12. The multispecific antigen-binding protein for use according to any one of claims 1-11, wherein said S1P receptor modulator is daily administered for at least 1, 2, or 3 months, or more, preferably from a starting day between 1 – 20 days prior to administering said multispecific antigen-binding protein, more preferably 11 days before said multispecific antigen-binding protein administration. 13. The multispecific antigen-binding protein for use according to any one of claims 1-12, wherein said S1P receptor modulator is administered in an amount sufficient for preventing immune cells bound to said antigen-binding protein from leaving the lymphoid tissues and/or increasing the anti-tumor efficacy of the immune cells, preferably T cells. 14. The multispecific antigen-binding protein for use according to any one of claims 1-13, wherein said S1P receptor modulator is administered in an amount sufficient for reducing the risk of cytokine release syndrome, in particular systemic cytokine release syndrome, in a subject receiving an antigen-binding protein composition. 15. A S1P receptor modulator for use in preventing cytokine release syndrome (CRS) with a multispecific antigen-binding protein in a subject in need thereof, comprising administering a S1P receptor modulator (e.g. mocravimod) or a pharmaceutically acceptable salt thereof or a phosphate derivative thereof, in combination with the multispecific antigen-binding protein, to the subject, thereby preventing CRS in the subject.