Antibodies and their use

Abstract

The present invention relates to an antibody or its antigen-binding fragment that specifically binds to signaling lymphocyte-activating molecule family member 6 (SLAMF6), wherein the antibody or its antigen-binding fragment can induce immune-mediated killing of tumor cells. The agent may be useful in the treatment and / or diagnosis of cancer.

Description

[Technical Field]

[0001] The present invention relates to an antibody or its antigen-binding fragment that specifically binds to signaling lymphocyte-activating molecule family member 6 (SLAMF6), and that the antibody or its antigen-binding fragment can induce immune-mediated killing of tumor cells. The agent may be useful in the treatment and / or diagnosis of myeloid malignancies and / or neoplasms, such as acute myeloid leukemia (AML). [Background technology]

[0002] Acute myeloid leukemia (AML) is a disease induced and maintained by leukemia stem cells that produce a large number of blast cells that disrupt the normal function of the blood system. Current chemotherapy-based treatment regimens are effective in eliminating blast cells but not in eliminating leukemia stem cells, which usually survive treatment and induce treatment-resistant relapses. This treatment also carries serious side effects that can be life-threatening. As a result, AML has a very poor prognosis, with a 5-year survival rate of less than 30%, making it one of the most deadly forms of cancer (Dohner et al, 2022). Therefore, there is a strong need to develop more effective therapies with fewer side effects.

[0003] The past decade has seen the emergence of immunomodulatory therapies that have revolutionized the treatment of melanoma, as well as many other solid tumors such as lung and urinary tract cancers (Robert, 2020). AML also exhibits multiple characteristics of immune evasion, including tumor-mediated dysregulation of both NK cells and multiple T cell compartments. First-generation checkpoint inhibitors against PD-1, PD-L1, CTLA-4, and CD47 have shown only mild effects, suggesting that additional mechanisms may exist that need to be modulated for successful immunotherapy in AML (Stahl & Goldberg, 2019).

[0004] To identify novel therapeutic targets on AML stem cells, we previously performed surface marker screening on cells derived from patients with the TP53 mutation, the most unfavorable AML subtype. Using a series of PE-conjugated antibody arrays against human cell surface markers (Legend Screen, BioLegend), we were able to determine the expression of 362 such proteins in candidate leukemia stem cells and corresponding primordial cells (CD34+CD38-) derived from normal bone marrow.

[0005] Using this approach, we previously discovered that the cell surface marker SLAMF6 is abnormally expressed in primitive AML cells. SLAMF6 is normally expressed only in lymphocytes such as B cells, T cells, and NK cells (Yigit et al, Clin Immunol, 2018), and has never been detected on human stem cells or myeloid progenitor cells, nor has it been shown to be abnormally expressed in any cancer type. Next, we performed a comprehensive characterization of SLAMF6 expression by FACS in a larger cohort of 42 AML cases and demonstrated that SLAMF6 is expressed in the majority of cases, and that this expression is not limited to the TP53 mutation subgroup but includes patients with all major genetic abnormalities.

[0006] SLAMF6 was recently identified as a novel immune checkpoint that modulates T cell activation and depletion (Hajaj et al, eLife, 2020). It has recently been shown that targeting SLAMF6 on depleted T cells can reactivate them and thus induce the killing of leukemia cells (Yigit et al., 2019, Cancer Immunology Research). Furthermore, SLAMF6 has been shown to mediate NK cell activity (Wu et al., 2016, Nature Immunology).

[0007] We previously demonstrated that CRISPR-mediated knockout of SLAMF6 in AML cells leads to increased activation of interacting T cells and subsequent killing of AML cells (WO2021 / 111005).

[0008] The inventors hypothesized that by modulating the SLAMF6-SLAMF6 interaction using therapeutic antibodies, it would be possible to induce a remarkable antitumor response similar to that of PD-1 / PD-L1 inhibitors, which have revolutionized the treatment of multiple cancer types.

[0009] To enable the induction of this effect using therapeutic agents, the inventors have developed several SLAMF6-specific antibodies using phage display technology and mouse immunization, as disclosed herein. In in vitro co-culture systems, the inventors identified several candidate antibodies that exhibit remarkable effects on the activation of immune cells (e.g., T cells) and the killing of tumor cells. The inventors have also shown for the first time that various cell lines and tissue sections derived from solid tumors express SLAMF6, demonstrating that the antibodies disclosed herein are also useful in the treatment of such solid tumors. [Overview of the Initiative]

[0010] A first aspect of the present invention provides an antibody or an antigen-binding fragment thereof that specifically binds to signaling lymphocyte-activating molecule family member 6 (SLAMF6), and that the antibody or antigen-binding fragment thereof can induce immune-mediated killing of tumor cells.

[0011] "Immune-mediated killing of tumor cells" includes any mechanism by which an antibody or antigen-binding fragment can activate the immune system and / or kill tumor cells. In some embodiments, this includes the activation of immune cells expressing SLAMF6 (e.g., T cells, B cells, and / or NK cells). For example, this may be mediated by interfering with SLAMF6-SLAMF6 interactions between immune cells or between immune cells and tumor cells, resulting in the activation or killing of immune cells. This also includes direct killing of SLAMF6-expressing tumor cells, for example, by antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and complement system activation.

[0012] The inventors hereby demonstrate that SLAMF6 is expressed on both immune cells and cancer cells. Therefore, the antibodies disclosed herein can target SLAMF6-SLAMF6 interactions between cancer cells and immune cells, and between immune cells themselves. Furthermore, we have shown for the first time that SLAMF6 is expressed on the surface of solid tumor cells (and non-solid tumor cells), which means that the antibodies described herein can act on such solid tumor cells both by immune cell-mediated killing of cancer cells and by direct killing via antibody binding to cancer cells (e.g., via ADCC).

[0013] Compared to conventional SLAMF6 antibodies, the advantage of the antibodies described herein lies in their ability to induce immune-mediated killing of tumor cells through various mechanisms (both immune cell-mediated mechanisms (e.g., T cell activation and cell killing) and direct antibody-mediated mechanisms). This means that the antibodies disclosed herein have greater anti-cancer therapeutic potential in terms of both the types of cancer that can be targeted and the level of efficacy achieved. In some embodiments, the antibodies disclosed herein have superior therapeutic efficacy (e.g., a higher degree of tumor cell killing) compared to previously disclosed SLAMF6 therapeutic antibodies.

[0014] The terms "Signaling Lymphocyte Activation Molecule Family Member 6" and "SLAMF6" shall include any SLAMF6 protein. Specifically, this includes, for example, the human SLAMF6 protein described in UniProtKB / Swiss-Prot accession number Q96DU3. SLAMF6 is also known in the scientific literature as the activated NK receptor, NK-TB antigen, NTB-A, KALI, natural killer cell antigen, T cell antigen, and B cell antigen, NTBA receptor, CD352 antigen, SF2000, CD352, KALIb, Ly108, and NTBA. SLAMF6 is typically expressed on the surface of NK cells, T cells, B cells, and eosinophils.

[0015] The sequence of human SLAMF6 is as follows: MLWLFQSLLFVFCFGPGNVVSQSSLTPLMVNGILGESVTLPLEFPAGEKVNFITWLFNETSLAFIVPHETKSPEIHVTNPKQGKRLNFTQSYSLQLSNLKMEDTGSYRAQISTKTSAKLSSYTLRILRQLRNIQVTNHSQLFQNMTCELHLTCSVEDADDNVSFRWEALGNTLSSQPNLTVSWDPRISSEQDYTCIAENAVSNLSFSVSAQKLCEDVKIQYTDTKMILFMVSGICIVFGFIILLLLVLRKRRDSLSLSTQRTQGPAESARNLEYVSVSPTNNTVYASVTHSNRETEIWTPRENDTITIYSTINHSKESKPTFSRATALDNVV(Sequence ID 105)

[0016] In some preferred embodiments, the antibody or its antigen-binding fragment specifically binds to human SLAMF6.

[0017] "Specifically binding" means that the antibody or antigen-binding fragment binds to SLAMF6 more strongly than other proteins and more strongly than other non-SLAMF6-specific antibodies.

[0018] In some embodiments, an antibody or its antigen-binding fragment can activate immune cells. In some embodiments, an antibody or its antigen-binding fragment can activate immune cells by binding to them. In some embodiments, an antibody or antigen-binding fragment can bind to SLAMF6 on the surface of an immune cell and activate that immune cell. This can be achieved by directly binding to SLAMF6 on the surface of the immune cell and preventing its interaction with SLAMF6 on the surface of another immune cell and / or tumor cell. In some other embodiments, an antibody or antigen-binding fragment can bind to SLAMF6 on the surface of a tumor cell and activate the immune cell by preventing its interaction with SLAMF6 on the surface of that tumor cell.

[0019] In some embodiments, an antibody or its antigen-binding fragment can activate a T cell. In some embodiments, an antibody or its antigen-binding fragment can activate a T cell by binding to it. In some embodiments, an antibody or antigen-binding fragment can bind to SLAMF6 on the surface of a T cell and activate the T cell. This can be achieved by directly binding to SLAMF6 on the surface of the T cell and preventing its interaction with SLAMF6 on the surface of another immune cell and / or tumor cell. In some other embodiments, an antibody or antigen-binding fragment can bind to SLAMF6 on the surface of a tumor cell and activate the T cell by preventing its interaction with SLAMF6 on the surface of the tumor cell.

[0020] In some embodiments, the antibody or its antigen-binding fragment can activate B cells. In some embodiments, the antibody or its antigen-binding fragment can bind to and activate B cells. In some embodiments, the antibody or antigen-binding fragment can bind to SLAMF6 on the surface of B cells and activate the B cells. This can be achieved by directly binding to SLAMF6 on the surface of B cells and preventing its interaction with SLAMF6 on the surface of other immune cells and / or tumor cells. In some other embodiments, the antibody or antigen-binding fragment can bind to SLAMF6 on the surface of tumor cells and activate B cells by preventing their interaction with SLAMF6 on the surface of the tumor cells.

[0021] In some embodiments, the antibody or its antigen-binding fragment can activate NK cells. In some embodiments, the antibody or its antigen-binding fragment can bind to and activate NK cells. In some embodiments, the antibody or antigen-binding fragment can bind to SLAMF6 on the surface of NK cells and activate the NK cells. This can be achieved by directly binding to SLAMF6 on the surface of NK cells and preventing its interaction with SLAMF6 on the surface of other immune cells and / or tumor cells. In some other embodiments, the antibody or antigen-binding fragment can bind to SLAMF6 on the surface of tumor cells and activate NK cells by preventing their interaction with SLAMF6 on the surface of the tumor cells.

[0022] "Can activate T cells / B cells / NK cells" shall include that the number, activity, and / or killing of T cells / B cells / NK cells can be enhanced as compared to the state without the presence of the antibody or its antigen-binding fragment, or the state with the presence of a control (i.e., an antibody or antigen-binding fragment that does not specifically bind to SLAMF6). In some embodiments, the antibody or its antigen-binding fragment activates T cells / B cells / NK cells.

[0023] For example, an antibody or an antigen-binding fragment thereof can activate T cells by preventing T cell inhibition, i.e., by preventing the initiation of the inhibitory T cell pathway. In some other embodiments, the antibody or an antigen-binding fragment thereof can activate T cells by actively activating the T cells, i.e., by initiating the activated T cell pathway. In some other embodiments, the antibody or antigen-binding fragment can activate T cells by inhibiting or reversing T cell exhaustion.

[0024] "Enhancing the number and / or activity of T cells" can include increasing the number of T cells present and / or increasing the activity of the T cells present, as compared to a control. In some embodiments, the control is when no antibody is present or when an antibody that does not specifically bind to SLAMF6 is present (e.g., an isotype control). In some embodiments, "the number of T cells present" shall mean the number of activated T cells present.

[0025] An increase in the activity of the T cells present can include an increase in the cytotoxic activity of the T cells and / or an increase in the ability of the T cells to activate other effector cells (e.g., by activating an increased number of cytotoxic T cells, B cells, NK cells, and / or macrophages). In some embodiments, an increase in the cytotoxic activity of the T cells includes an increase in the expression of IFN-γ, TNF-α, granzyme B, and / or IL-2.

[0026] "Enhancing the number and / or activity of B cells" can include increasing the number of B cells present and / or increasing the activity of the B cells present, as compared to a control. In some embodiments, the control is when no antibody is present or when an antibody that does not specifically bind to SLAMF6 is present (e.g., an isotype control). In some embodiments, "the number of B cells present" shall mean the number of activated B cells present.

[0027] An increase in the activity of existing B cells may include an increase in the ability of those B cells to produce antibodies specific to tumor cell antigens, thereby increasing the B cells' ability to mediate direct tumor cell killing.

[0028] "Enhancing the number and / or activity of NK cells" may include increasing the number of NK cells present and / or increasing the activity of NK cells present compared to a control. In some embodiments, the control is the absence of an antibody or the presence of an antibody that does not specifically bind to SLAMF6 (e.g., an isotype control). In some embodiments, "number of NK cells present" means the number of activated NK cells present.

[0029] An increase in the activity of existing NK cells may include an increase in the ability of those NK cells to produce effector molecules, thereby increasing their ability to mediate direct tumor cell killing. In some embodiments, the effector molecules include cytokines and chemokines (e.g., IFN-γ, TNF-α, GM-CSF, IL-10, IL-5, IL-13, MIP-1α, MIP-1β, IL-8, and RANTES). The increased production of these cytokines and chemokines contributes to an inflammatory microenvironment, which in turn contributes to immune-mediated tumor cell killing.

[0030] In some embodiments, the number of T cells / B cells / NK cells present may increase by approximately 50% compared to the control. For example, the number of T cells / B cells / NK cells present may increase by approximately 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5%. In some embodiments, the number of T cells present may increase by approximately 50-60%, 40-50%, 30-40%, 20-30%, 10-20%, or 1-10%. In some embodiments, “number of T cells present” means the number of activated T cells present.

[0031] In some embodiments, the number of T cells / B cells / NK cells present may increase by approximately 100% compared to the control. For example, the number of T cells / B cells / NK cells present may increase by approximately 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, or 55%. In some embodiments, the number of T cells / B cells / NK cells present may increase by approximately 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%. In some other embodiments, the number of T cells / B cells / NK cells present may increase by more than 100% compared to the control, for example, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200%.

[0032] In some embodiments, an antibody or its antigen-binding fragment can increase the number or percentage of T cells that are CD25+ and / or CD69+ compared to a control (e.g., no antibody or isotype control).

[0033] In some embodiments, the percentage of T cells that are CD25+ and / or CD69+ increases by about 5% compared to the control. In some embodiments, the percentage of T cells that are CD25+ and / or CD69+ increases by about 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% compared to the control. In some preferred embodiments, the percentage of T cells that are CD25+ and / or CD69+ increases by about 3% compared to the control.

[0034] "T cells" include both helper T cells and cytotoxic T cells, i.e., both CD4+ and CD8+ T cells. In some preferred embodiments, the T cells are CD4+ T cells. In other embodiments, the T cells are CD8+ T cells.

[0035] In some embodiments, the antibody or its antigen-binding fragment induces increased T cell-mediated cell killing. In some embodiments, this is demonstrated when compared to the absence of the antibody or antigen-binding fragment or to the presence of a control (i.e., an antibody or antigen-binding fragment that does not specifically bind to SLAMF6).

[0036] "Increased T cell-mediated cell killing" means that an antibody or its antigen-binding fragment induces cell death via a T cell-mediated mechanism, and that this increases compared to the absence of the antibody or antigen-binding fragment, or to the presence of a control (i.e., an antibody or antigen-binding fragment that does not specifically bind to SLAMF6).

[0037] For example, antibodies or their antigen-binding fragments may recruit T cells to target cells (e.g., pathological stem cells and / or progenitor cells), activate T cells, or induce T cell-mediated apoptosis in target cells via mechanisms known in the art (e.g., release of cytolytic granules, release of cytokines that recruit other effector cells). Alternatively, or in addition, antibodies or their antigen-binding fragments may prevent SLAMF6-mediated responses that otherwise prevent T cell function and / or activation, for example, by masking or blocking the interaction between SLAMF6-expressing cells and T cells. Similarly, SLAMF6 conjugates may recruit, activate, or otherwise stimulate immune cells such as NK cells for increased cytotoxicity.

[0038] In some embodiments, antibodies or their antigen-binding fragments can directly bind to and kill tumor cells.

[0039] In some embodiments, when the antibodies disclosed herein bind to tumor cells expressing SLAMF6, the following occurs: a) Antibody-dependent cellular cytotoxicity (ADCC), b) Antibody-dependent cell phagocytosis (ADCP), and / or c) Complement-dependent cell injury (CDC) It can induce this.

[0040] ADCC refers to the binding of an antibody to target tumor cells expressing SLAMF6, inducing apoptosis of SLAMF6-expressing tumor cells via recognition by immune cells (e.g., NK cells, macrophages, neutrophils, and eosinophils). ADCP refers to the binding of an antibody to target tumor cells expressing SLAMF6, inducing phagocytosis of SLAMF6-expressing tumor cells via recognition by macrophages or monocytes. CDC refers to the binding of an antibody to target cells expressing SLAMF6, inducing a complement cascade via recognition by C1q, which leads to the formation of membrane invasion complexes and the lysis of SLAMF6-expressing tumor cells.

[0041] Therefore, it is shown herein that the antibodies of the present invention can modulate the immune system in several different ways, both by activating immune effector cells and by enhancing the direct killing of tumor cells through the mechanisms described above.

[0042] "Biological activity of SLAMF6" includes any interactions or signaling events involving SLAMF6 on pathological stem cells and / or progenitor cells, as well as more mature neoplastic cells (i.e., tumor cells).

[0043] Such inhibition of the biological activity of SLAMF6 by the antibody or antigen-binding fragment of the present invention may be whole or partial. For example, the agent may inhibit the biological activity of SLAMF6 by at least 10%, preferably at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, most preferably 100%, compared to the biological activity of SLAMF6 in pathological stem cells and / or progenitor cells not exposed to the agent. In a preferred embodiment, the agent may inhibit the biological activity of SLAMF6 by 50% or more compared to the biological activity of SLAMF6 in pathological stem cells and / or progenitor cells not exposed to the agent. The biological activity of SLAMF6 that is inhibited may be, for example, its autoligand activity (SLAMF6 interacting with other SLAMF6) and / or downstream signaling. Examples of downstream signaling include, but are not limited to, the recruitment and / or phosphorylation of mediators such as SAP, Fyn, EAT-2, and SHP-1.2 (as outlined in Yigit et al., 2018, Clinical Immunology). The biological activity of inhibited SLAMF6 may also be due to the expression of specific genes(s).

[0044] SLAMF6 is an autoligand and therefore binds to other SLAMF6 molecules that may be expressed on other immune cells such as NK cells, T cells, and B cells, or other target cells (e.g., cancer cells / tumor cells).

[0045] Therefore, in some embodiments, the antibody or antigen-binding fragment blocks the autoligand interaction of SLAMF6 on different cells or on the same cell.

[0046] By blocking the interaction between SLAMF6 expressed on immune cells and target (e.g., tumor) cells, activation of those immune cells can be achieved. In some preferred embodiments, this activation may be due to the absence of SLAMF6-SLAMF6 interaction, which prevents the initiation of the inhibitory T cell pathway, thereby leading to increased T cell activation. In some other embodiments, T cell activation may be due to the absence of SLAMF6-SLAMF6 interaction that initiates the activating T cell pathway, thereby leading to increased T cell activation. Similar mechanisms also apply to the activation of other types of immune cells.

[0047] In some other embodiments, immune cell activation can be mediated by preventing SLAMF6-SLAMF6 interactions between different immune cells (e.g., T cells, B cells, and / or NK cells) or between SLAMF6 molecules on the same cell.

[0048] For example, with respect to T cells, the antibody or its antigen-binding fragment preferably binds to SLAMF6 expressed on the surface of T cells, thereby activating the T cells.

[0049] In some other embodiments, the antibody or its antigen-binding fragment activates T cells by binding to SLAMF6 on the surface of immune cells other than T cells. For example, the antibody or its antigen-binding fragment may bind to SLAMF6 expressed on the surface of NK cells or B cells.

[0050] In some other embodiments, the antibody or its antigen-binding fragment may bind to SLAMF6 on the surface of tumor cells.

[0051] "Tumor cells" means any type of cancer cell or cancer-associated cell, whether associated with a solid tumor or a liquid tumor (i.e., a blood-derived cancer).

[0052] In some embodiments, tumor cells originate from solid tumors. A “solid tumor” is defined as any abnormal mass of tissue that is primarily non-liquid. There are many types of solid tumors, including, but are not limited to, sarcomas, lymphomas, blastomas, melanomas, carcinomas, lung cancers, pancreatic cancers, breast cancers, gastrointestinal cancers, head and neck cancers, brain cancers, liver cancers, ovarian cancers, prostate cancers, and cervical cancers.

[0053] In some preferred embodiments, the solid tumor is selected from the group consisting of intestinal cancer, colorectal cancer, esophageal cancer, gastric cancer, biliary tract cancer, kidney cancer, lung cancer, ovarian cancer, fallopian tube cancer, pancreatic cancer, or soft tissue cancer (e.g., sarcoma).

[0054] In some preferred embodiments, the solid tumor is colorectal cancer. In some preferred embodiments, the solid tumor is pancreatic cancer.

[0055] In some other embodiments, tumor cells originate from liquid tumors. "Liquid tumor" means cancer of the blood or another bodily fluid. Examples of liquid tumors include leukemia and leukemia-like diseases. In some embodiments, tumor cells originate from myeloid malignancies and / or neoplasms, or lymphoid malignancies and / or neoplasms.

[0056] In some embodiments, the lymphoid malignancy and / or neoplasm is myeloma (also known as multiple myeloma and plasmacytic myeloma) or lymphoma.

[0057] "Myeloid malignancies and / or neoplasms" means any clonal disorder of hematopoietic stem cells or hematopoietic progenitor cells as defined by the WHO classification of hematopoietic and lymphoid tumors (myeloid neoplasms and histiocytic / dendritic neoplasms) (Hematopoietic malignancies (The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic / Dendritic Neoplasms. Leukemia. 2022 Jul;36(7):1703-1719). Specifically, this includes bone marrow cancers and blood cancers (such as leukemia (e.g., acute myeloid leukemia (AML))), as well as leukemia-like disorders (myeloproliferative disorders (MPD) (also called myeloproliferative neoplasms (MPN)), myelodysplastic syndromes and / or myelodysplastic neoplasms (MDS), myelodysplastic neoplasms / myeloproliferative neoplasms (MDS / MPN)), and mastocytosis.

[0058] More specifically, the myeloid malignancies and / or neoplasms may be selected from myelodysplastic syndromes and / or myelodysplastic neoplasms (MDS), myeloproliferative neoplasms (MPNs), mastocytosis, and myelodysplastic neoplasms / myeloproliferative neoplasms (MDS / MPNs). In one particularly preferred embodiment, the myeloid malignancies and / or neoplasms are acute myeloid leukemia (AML).

[0059] In some embodiments, acute myeloid leukemia (AML) may also be called acute myeloid leukemia.

[0060] In further embodiments, cells associated with myeloid malignancies and / or neoplasms may be (i) pathological stem cells, and / or (ii) progenitor cells, and / or (iii) hematopoietic cells associated with myeloid malignancies and / or neoplasms.

[0061] Preferably, the cells are pathological stem cells and / or progenitor cells and / or hematopoietic cells associated with AML, and may be selected from leukemia stem cells (LSCs) and / or blast cells and / or hematopoietic cells derived from said LSCs or blast cells, or normal non-malignant cells (e.g., monocytes or T cells) derived from the innate or adaptive immune system.

[0062] "Pathological stem cells" in relation to myeloid malignancies and / or neoplasms include stem cells involved in the development of myeloid malignancies and / or neoplasms in an individual, i.e., malignant stem cells and / or tumor stem cells. In particular, pathological stem cells may be leukemia stem cells (e.g., acute myeloid leukemia (AML) cells). Such stem cells can be distinguished from normal hematopoietic stem cells (HSCs) by their expression of the cell surface protein C3AR (see examples below).

[0063] "Progenitor cells" associated with myeloid malignancies and / or neoplasms include cells derived from pathogenic stem cells involved in the development of myeloid malignancies and / or neoplasms in an individual. In particular, progenitor cells may be leukemia progenitor cells. Such progenitor cells can be distinguished from normal hematopoietic progenitor cells by their higher expression of the cell surface protein C3AR.

[0064] "Normal non-malignant hematopoietic cells derived from the innate and adaptive immune systems" includes myeloid progenitor cells and lymphoid progenitor cells, mature lymphoid cells (NK cells, T cells and B cells), and mature myeloid cells (dendritic cells, erythrocytes, macrophages / monocytes, megakaryocytes and granulocytes).

[0065] Those skilled in the art will be aware of methods for determining whether an antibody or antigen-binding fragment has activated T cells or a population of T cells. For example, in vitro, this may include a T cell activity assay. A T cell activity assay may include one or more of the following: assessment of proliferation, measurement of upregulation of activation markers, e.g., IL2RA and / or CD25 and / or CD69, and measurement of production of effector cytokines, e.g., INF-γ and / or TNF-α. T cell activation can also be determined in vivo, for example, by measuring the percentage of activated T cells (e.g., those with a CD25+CD69+ marker profile) from subjects treated with the antibodies or antigen-binding fragments described herein, compared to a control antibody. T cell activation can also be observed indirectly, for example, by measuring the amount of cells targeted by activated T cells (e.g., including measuring the number of AML cells compared to a control in an AML model). In some other embodiments, T cell activation can be determined by observing the size and / or granularity of T cells.

[0066] The structure of SLAMF6 consists of an amino-terminal IgV domain, a proximal IgC2 domain, a transmembrane domain, and an intracellular signaling domain.

[0067] In some embodiments, the antibody or its antigen-binding fragment specifically binds to the IgV domain of SLAMF6. In some embodiments, the antibody or antigen-binding fragment does not specifically bind to the IgC2 domain of SLAMF6. In some embodiments, the antibody or its antigen-binding fragment specifically binds to the IgV domain of SLAMF6, exhibiting T-cell-mediated killing of cancer cells.

[0068] In some embodiments, the antibody or its antigen-binding fragment specifically binds to an epitope of SLAMF6 comprising the following sequence SVTLPLEFPAGEKVNF (SEQ ID NO: 102).

[0069] In some embodiments, the antibody or its antigen-binding fragment specifically binds to the SLAMF6 epitope comprising the following sequence AFIVPHETKSPEIHVTNPKQGKRLNFTQS (SEQ ID NO: 103).

[0070] In some embodiments, the antibody or its antigen-binding fragment specifically binds to an epitope of SLAMF6 comprising the following sequence KMEDTGSYRAQISTKTSAKLSSYT (SEQ ID NO: 104).

[0071] Those skilled in the art will be aware of methods for producing antibodies against these epitopes, for example, by hybridoma production.

[0072] LB-031 In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region comprising one or more of the CDRs of SEQ ID NO: 1.

[0073] In some embodiments, the antibody or its antigen-binding fragment is the following CDR, where CDR is defined by Chothia: a) SEQ ID NO: 11, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with SEQ ID NO: 14, or at least 70%, 80%, or 90% sequence identity, and / or c) Amino acid sequences having at least 60% sequence identity with SEQ ID NO: 17, or at least 70%, 80%, or 90% sequence identity. It includes a heavy chain variable region containing the CDR.

[0074] In some embodiments, the antibody or its antigen-binding fragment is defined by Kabat as follows: a) an amino acid sequence having at least 60% sequence identity with sequence number 12, or, for example, at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with SEQ ID NO: 15, or at least 70%, 80%, or 90% sequence identity, and / or c) A heavy chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 18, for example, at least 70%, 80%, or 90% sequence identity.

[0075] In some embodiments, the antibody or its antigen-binding fragment is defined by the following CDR, i.e., a) Amino acid sequences having at least 60% sequence identity with SEQ ID NO: 13, or at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with SEQ ID NO: 16, or at least 70%, 80%, or 90% sequence identity, and / or c) A heavy chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 19, or at least 70%, 80%, or 90% sequence identity.

[0076] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region comprising the CDRs of SEQ ID NOs. 11, 14, and 17.

[0077] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region containing the CDRs of SEQ ID NOs. 12, 15, and 18.

[0078] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region containing the CDRs of SEQ ID NOs. 13, 16, and 19.

[0079] In some embodiments, the antibody or its antigen-binding fragment is • CDR-H1 with sequence number 11, 12, or 13, • CDR-H2 of sequence number 14, 15, or 16, and • CDR-H3 with sequence numbers 17, 18, or 19 It includes a heavy chain variable region containing the CDR.

[0080] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region having the amino acid sequence of SEQ ID NO: 1, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity.

[0081] In some embodiments, the antibody or its antigen-binding fragment includes a light chain variable region comprising one or more of the CDRs of SEQ ID NO: 2.

[0082] In some embodiments, the antibody or its antigen-binding fragment is determined by Chothia, and the following CDRs are used, i.e., a) an amino acid sequence having at least 60% sequence identity with sequence number 20, or at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with SEQ ID NO: 23, or at least 70%, 80%, or 90% sequence identity, and / or c) A light chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 26, for example, at least 70%, 80%, or 90% sequence identity.

[0083] In some embodiments, the antibody or its antigen-binding fragment is determined by Kabat, i.e., the following CDRs: a) SEQ ID NO: 21, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with SEQ ID NO: 24, or at least 70%, 80%, or 90% sequence identity, and / or c) A light chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 27, or at least 70%, 80%, or 90% sequence identity therewith.

[0084] In some embodiments, the antibody or its antigen-binding fragment is determined by the IMGT, and the following CDRs are used: a) SEQ ID NO: 22, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with SEQ ID NO: 25, or at least 70%, 80%, or 90% sequence identity, and / or c) A light chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 28, or at least 70%, 80%, or 90% sequence identity.

[0085] In some embodiments, the antibody or its antigen-binding fragment includes a light chain variable region containing the CDRs of SEQ ID NOs. 20, 23, and 26.

[0086] In some embodiments, the antibody or its antigen-binding fragment includes a light chain variable region containing the CDRs of SEQ ID NOs. 21, 24, and 27.

[0087] In some embodiments, the antibody or its antigen-binding fragment includes a light chain variable region containing the CDRs of SEQ ID NOs. 22, 25, and 28.

[0088] In some embodiments, the antibody or its antigen-binding fragment is • CDR-L1 with sequence numbers 20, 21, or 22, • CDR-L2 of sequence numbers 23, 24, or 25, and • CDR-L3 with sequence numbers 26, 27, or 28 It includes a light chain variable region containing the CDR.

[0089] In some embodiments, the antibody or antigen-binding fragment described in any of the prior claims includes a light chain variable region having the amino acid sequence of SEQ ID NO: 2, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity.

[0090] In some embodiments, the antibody or its antigen-binding fragment comprises six CDRs of amino acid sequences having at least 60% sequence identity, e.g., at least 70%, 80%, or 90% sequence identity, with SEQ ID NOs: 11, 14, 17, 20, 23, and 26.

[0091] In some embodiments, the antibody or its antigen-binding fragment comprises six CDRs of amino acid sequences having at least 60% sequence identity, e.g., at least 70%, 80%, or 90% sequence identity, with SEQ ID NOs: 12, 15, 18, 21, 24, and 27.

[0092] In some embodiments, the antibody or its antigen-binding fragment comprises six CDRs of amino acid sequences having at least 60% sequence identity, e.g., at least 70%, 80%, or 90% sequence identity, with SEQ ID NOs. 13, 16, 19, 22, 25, and 28, or therewith.

[0093] In some embodiments, the antibody or its antigen-binding fragment is • CDR-H1 with sequence number 11, 12, or 13, • CDR-H2 with sequence numbers 14, 15, or 16, • CDR-H3 with sequence numbers 17, 18, or 19, • CDR-L1 with sequence numbers 20, 21, or 22, • CDR-L2 of sequence numbers 23, 24, or 25, and • CDR-L3 with sequence numbers 26, 27, or 28 It includes a light chain variable region containing the CDR.

[0094] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region having the amino acid sequence of SEQ ID NO: 1, and a light chain variable region having the amino acid sequence of SEQ ID NO: 2, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity.

[0095] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region having the amino acid sequence of SEQ ID NO: 1 and a light chain variable region having the amino acid sequence of SEQ ID NO: 2.

[0096] In some preferred embodiments, the antibody or its antigen-binding fragment is LB-031 as described herein.

[0097] LB-032 In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region comprising one or more of the CDRs of SEQ ID NO: 3.

[0098] In some embodiments, the antibody or its antigen-binding fragment is the following CDR, where CDR is defined by Chothia: a) SEQ ID NO: 29, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with SEQ ID NO: 32, or at least 70%, 80%, or 90% sequence identity, and / or c) A heavy chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 35, for example, at least 70%, 80%, or 90% sequence identity.

[0099] In some embodiments, the antibody or its antigen-binding fragment is defined by Kabat as follows: a) an amino acid sequence having at least 60% sequence identity with sequence number 30, or at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with SEQ ID NO: 33, or at least 70%, 80%, or 90% sequence identity, and / or c) A heavy chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 36, for example, at least 70%, 80%, or 90% sequence identity.

[0100] In some embodiments, the antibody or its antigen-binding fragment is defined by the following CDR, i.e., a) SEQ ID NO: 31, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with SEQ ID NO: 34, or at least 70%, 80%, or 90% sequence identity, and / or c) A heavy chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 37, or at least 70%, 80%, or 90% sequence identity therewith.

[0101] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region containing the CDRs of SEQ ID NOs. 29, 32, and 35.

[0102] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region containing the CDRs of SEQ ID NOs. 30, 33, and 36.

[0103] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region containing the CDRs of SEQ ID NOs. 31, 34, and 37.

[0104] In some embodiments, the antibody or its antigen-binding fragment is • CDR-H1 with sequence numbers 29, 30, or 31, · CDR-H2 of sequence number 32, 33, or 34, and • CDR-H3 with sequence numbers 35, 36, or 37 It includes a heavy chain variable region containing the CDR.

[0105] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region having the amino acid sequence of SEQ ID NO: 3, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity.

[0106] In some embodiments, the antibody or its antigen-binding fragment includes a light chain variable region comprising one or more of the CDRs of SEQ ID NO: 4.

[0107] In some embodiments, the antibody or its antigen-binding fragment is determined by Chothia, and the following CDRs are used, i.e., a) SEQ ID NO: 38, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with SEQ ID NO: 41, or at least 70%, 80%, or 90% sequence identity, and / or c) A light chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 44, or at least 70%, 80%, or 90% sequence identity.

[0108] In some embodiments, the antibody or its antigen-binding fragment is determined by Kabat, i.e., the following CDRs: a) Amino acid sequences having at least 60% sequence identity with SEQ ID NO: 39, or at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with SEQ ID NO: 42, or at least 70%, 80%, or 90% sequence identity, and / or c) A light chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 45, or at least 70%, 80%, or 90% sequence identity.

[0109] In some embodiments, the antibody or its antigen-binding fragment is determined by the IMGT, and the following CDRs are used: a) an amino acid sequence having at least 60% sequence identity with sequence number 40, or at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with SEQ ID NO: 43, or at least 70%, 80%, or 90% sequence identity, and / or c) A light chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 46, for example, at least 70%, 80%, or 90% sequence identity.

[0110] In some embodiments, the antibody or its antigen-binding fragment includes a light chain variable region containing the CDRs of SEQ ID NOs. 38, 41, and 44.

[0111] In some embodiments, the antibody or its antigen-binding fragment includes a light chain variable region containing the CDRs of SEQ ID NOs. 39, 42, and 45.

[0112] In some embodiments, the antibody or its antigen-binding fragment includes a light chain variable region containing the CDRs of SEQ ID NOs. 40, 43, and 46.

[0113] In some embodiments, the antibody or its antigen-binding fragment is • CDR-L1 with sequence number 38, 39, or 40, · CDR-L2 of sequence number 41, 42, or 43, and • CDR-L3 with sequence numbers 44, 45, or 46 It includes a light chain variable region containing the CDR.

[0114] In some embodiments, the antibody or antigen-binding fragment described in any of the prior claims includes a light chain variable region having the amino acid sequence of SEQ ID NO: 4, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity.

[0115] In some embodiments, the antibody or its antigen-binding fragment comprises six CDRs of amino acid sequences having at least 60% sequence identity, e.g., at least 70%, 80%, or 90%, with SEQ ID NOs: 29, 32, 35, 38, 41, and 44, or with at least 60% sequence identity, e.g., at least 70%, 80%, or 90%.

[0116] In some embodiments, the antibody or its antigen-binding fragment comprises six CDRs of amino acid sequences having at least 60% sequence identity, e.g., at least 70%, 80%, or 90% sequence identity, with SEQ ID NOs: 30, 33, 36, 39, 42, and 45.

[0117] In some embodiments, the antibody or its antigen-binding fragment comprises six CDRs of amino acid sequences having at least 60% sequence identity, e.g., at least 70%, 80%, or 90% sequence identity, with SEQ ID NOs: 31, 34, 37, 40, 43, and 46.

[0118] In some embodiments, the antibody or its antigen-binding fragment is • CDR-H1 with sequence numbers 29, 30, or 31, • CDR-H2 with sequence numbers 32, 33, or 34, • CDR-H3 with sequence numbers 35, 36, or 37, • CDR-L1 with sequence number 38, 39, or 40, · CDR-L2 of sequence number 41, 42, or 43, and • CDR-L3 with sequence numbers 44, 45, or 46 It includes a light chain variable region containing the CDR.

[0119] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region having the amino acid sequence of SEQ ID NO: 3, and a light chain variable region having the amino acid sequence of SEQ ID NO: 4, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity.

[0120] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region having the amino acid sequence of SEQ ID NO: 3 and a light chain variable region having the amino acid sequence of SEQ ID NO: 4.

[0121] LB-302 In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region comprising one or more of the CDRs of SEQ ID NO: 5.

[0122] In some embodiments, the antibody or its antigen-binding fragment is the following CDR, where CDR is defined by Chothia: a) SEQ ID NO: 47, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity, and / or b) an amino acid sequence having at least 60% sequence identity with sequence number 50, or at least 70%, 80%, or 90% sequence identity, and / or c) A heavy chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 53, for example, at least 70%, 80%, or 90% sequence identity.

[0123] In some embodiments, the antibody or its antigen-binding fragment is defined by Kabat as follows: a) SEQ ID NO: 48, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with SEQ ID NO: 51, or at least 70%, 80%, or 90% sequence identity, and / or c) A heavy chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 54, or at least 70%, 80%, or 90% sequence identity.

[0124] In some embodiments, the antibody or its antigen-binding fragment is defined by the following CDR, i.e., a) SEQ ID NO: 49, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with SEQ ID NO: 52, or at least 70%, 80%, or 90% sequence identity, and / or c) A heavy chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 55, for example, at least 70%, 80%, or 90% sequence identity.

[0125] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region containing the CDRs of SEQ ID NOs. 47, 50, and 53.

[0126] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region containing the CDRs of SEQ ID NOs. 48, 51, and 54.

[0127] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region containing the CDRs of SEQ ID NOs. 49, 52, and 55.

[0128] In some embodiments, the antibody or its antigen-binding fragment is • CDR-H1 with sequence numbers 47, 48, or 49, • CDR-H2 of sequence number 50, 51, or 52, and • CDR-H3 with sequence numbers 53, 54, or 55 It includes a heavy chain variable region containing the CDR.

[0129] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region having the amino acid sequence of SEQ ID NO: 5, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity.

[0130] In some embodiments, the antibody or its antigen-binding fragment includes a light chain variable region comprising one or more of the CDRs of SEQ ID NO: 6.

[0131] In some embodiments, the antibody or its antigen-binding fragment is determined by Chothia, and the following CDRs are used, i.e., a) an amino acid sequence having at least 60% sequence identity with sequence number 56, or, for example, at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with SEQ ID NO: 59, or at least 70%, 80%, or 90% sequence identity, and / or c) A light chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 62, or at least 70%, 80%, or 90% sequence identity.

[0132] In some embodiments, the antibody or its antigen-binding fragment is determined by Kabat, i.e., the following CDRs: a) SEQ ID NO: 57, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity, and / or b) an amino acid sequence having at least 60% sequence identity with sequence number 60, or at least 70%, 80%, or 90% sequence identity, and / or c) A light chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 63, for example, at least 70%, 80%, or 90% sequence identity.

[0133] In some embodiments, the antibody or its antigen-binding fragment is determined by the IMGT, and the following CDRs are used: a) an amino acid sequence having at least 60% sequence identity with sequence number 58, or at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with SEQ ID NO: 61, or at least 70%, 80%, or 90% sequence identity, and / or c) A light chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 64, or at least 70%, 80%, or 90% sequence identity.

[0134] In some embodiments, the antibody or its antigen-binding fragment includes a light chain variable region containing the CDRs of SEQ ID NOs. 56, 59, and 62.

[0135] In some embodiments, the antibody or its antigen-binding fragment includes a light chain variable region containing the CDRs of SEQ ID NOs. 57, 60, and 63.

[0136] In some embodiments, the antibody or its antigen-binding fragment includes a light chain variable region containing the CDRs of SEQ ID NOs. 58, 61, and 64.

[0137] In some embodiments, the antibody or its antigen-binding fragment is • CDR-L1 with sequence numbers 56, 57, or 58, • CDR-L2 of sequence numbers 59, 60, or 61, and • CDR-L3 with sequence numbers 62, 63, or 64 It includes a light chain variable region containing the CDR.

[0138] In some embodiments, the antibody or antigen-binding fragment described in any of the prior claims includes a light chain variable region having the amino acid sequence of SEQ ID NO: 6, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity.

[0139] In some embodiments, the antibody or its antigen-binding fragment comprises six CDRs of amino acid sequences having at least 60% sequence identity, e.g., at least 70%, 80%, or 90% sequence identity, with SEQ ID NOs. 47, 50, 53, 56, 59, and 62, or therewith.

[0140] In some embodiments, the antibody or its antigen-binding fragment comprises six CDRs of amino acid sequences having at least 60% sequence identity, e.g., at least 70%, 80%, or 90%, with SEQ ID NOs: 48, 51, 54, 57, 60, and 63, or with at least 60% sequence identity, e.g., at least 70%, 80%, or 90%.

[0141] In some embodiments, the antibody or its antigen-binding fragment comprises six CDRs of amino acid sequences having at least 60% sequence identity, e.g., at least 70%, 80%, or 90%, with SEQ ID NOs: 49, 52, 55, 58, 61, and 64, or with at least 60% sequence identity, e.g., at least 70%, 80%, or 90%.

[0142] In some embodiments, the antibody or its antigen-binding fragment is • CDR-H1 with sequence numbers 47, 48, or 49, • CDR-H2 with sequence numbers 50, 51, or 52, • CDR-H3 with sequence numbers 53, 54, or 55, • CDR-L1 with sequence numbers 56, 57, or 58, • CDR-L2 of sequence numbers 59, 60, or 61, and • CDR-L3 with sequence numbers 62, 63, or 64 It includes a light chain variable region containing the CDR.

[0143] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region having the amino acid sequence of SEQ ID NO: 5, and a light chain variable region having the amino acid sequence of SEQ ID NO: 6, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity.

[0144] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region having the amino acid sequence of SEQ ID NO: 5 and a light chain variable region having the amino acid sequence of SEQ ID NO: 6.

[0145] LB-116 In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region comprising one or more of the CDRs of SEQ ID NO: 7.

[0146] In some embodiments, the antibody or its antigen-binding fragment is the following CDR, where CDR is defined by Chothia: a) Amino acid sequences having at least 60% sequence identity with sequence number 65, or at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with SEQ ID NO: 68, or at least 70%, 80%, or 90% sequence identity, and / or c) A heavy chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 71, or at least 70%, 80%, or 90% sequence identity.

[0147] In some embodiments, the antibody or its antigen-binding fragment is defined by Kabat as follows: a) SEQ ID NO: 66, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with sequence number 69, or, for example, at least 70%, 80%, or 90% sequence identity, and / or c) A heavy chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 72, or at least 70%, 80%, or 90% sequence identity.

[0148] In some embodiments, the antibody or its antigen-binding fragment is defined by the following CDR, i.e., a) Amino acid sequences having at least 60% sequence identity with sequence number 67, or at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with SEQ ID NO: 70, or at least 70%, 80%, or 90% sequence identity, and / or c) A heavy chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 73, for example, at least 70%, 80%, or 90% sequence identity.

[0149] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region containing the CDRs of SEQ ID NOs. 65, 68, and 71.

[0150] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region containing the CDRs of SEQ ID NOs. 66, 69, and 72.

[0151] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region containing the CDRs of SEQ ID NOs. 67, 70, and 73.

[0152] In some embodiments, the antibody or its antigen-binding fragment is • CDR-H1 with sequence numbers 65, 66, or 67, • CDR-H2 with sequence numbers 68, 69, or 70, and • CDR-H3 with sequence numbers 71, 72, or 73 It includes a heavy chain variable region containing the CDR.

[0153] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity.

[0154] In some embodiments, the antibody or its antigen-binding fragment includes a light chain variable region comprising one or more of the CDRs of SEQ ID NO: 8.

[0155] In some embodiments, the antibody or its antigen-binding fragment is determined by Chothia, and the following CDRs are used, i.e., a) SEQ ID NO: 74, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with sequence number 77, or, for example, at least 70%, 80%, or 90% sequence identity, and / or c) A light chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 80, or at least 70%, 80%, or 90% sequence identity.

[0156] In some embodiments, the antibody or its antigen-binding fragment is determined by Kabat, i.e., the following CDRs: a) an amino acid sequence having at least 60% sequence identity with sequence number 75, or, for example, at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with sequence number 78, or, for example, at least 70%, 80%, or 90% sequence identity, and / or c) A light chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 81, or at least 70%, 80%, or 90% sequence identity.

[0157] In some embodiments, the antibody or its antigen-binding fragment is determined by the IMGT, and the following CDRs are used: a) an amino acid sequence having at least 60% sequence identity with sequence number 76, or, for example, at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with sequence number 78, or, for example, at least 70%, 80%, or 90% sequence identity, and / or c) A light chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 82, or at least 70%, 80%, or 90% sequence identity.

[0158] In some embodiments, the antibody or its antigen-binding fragment includes a light chain variable region containing the CDRs of SEQ ID NOs. 74, 77, and 80.

[0159] In some embodiments, the antibody or its antigen-binding fragment includes a light chain variable region containing the CDRs of SEQ ID NOs. 75, 78, and 81.

[0160] In some embodiments, the antibody or its antigen-binding fragment includes a light chain variable region containing the CDRs of SEQ ID NOs. 76, 78, and 82.

[0161] In some embodiments, the antibody or its antigen-binding fragment is • CDR-L1 with sequence numbers 74, 75, or 76, • CDR-L2 of sequence numbers 77, 78, or 79, and • CDR-L3 with sequence numbers 80, 81, or 82 It includes a light chain variable region containing the CDR.

[0162] In some embodiments, the antibody or antigen-binding fragment described in any of the prior claims includes a light chain variable region having the amino acid sequence of SEQ ID NO: 8, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity.

[0163] In some embodiments, the antibody or its antigen-binding fragment comprises six CDRs of amino acid sequences having at least 60% sequence identity with SEQ ID NOs. 65, 68, 71, 74, 77, and 80, or at least 70%, 80%, or 90% sequence identity.

[0164] In some embodiments, the antibody or its antigen-binding fragment comprises six CDRs of amino acid sequences having at least 60% sequence identity, e.g., at least 70%, 80%, or 90% sequence identity, with SEQ ID NOs. 66, 69, 72, 75, 78, and 81.

[0165] In some embodiments, the antibody or its antigen-binding fragment comprises six CDRs of amino acid sequences having at least 60% sequence identity with SEQ ID NOs. 67, 70, 73, 76, 79, and 82, or at least 70%, 80%, or 90% sequence identity with them.

[0166] In some embodiments, the antibody or its antigen-binding fragment is • CDR-H1 with sequence numbers 65, 66, or 67, • CDR-H2 with sequence numbers 68, 69, or 70, • CDR-H3 with sequence numbers 71, 72, or 73, • CDR-L1 with sequence numbers 74, 75, or 76, • CDR-L2 of sequence numbers 77, 78, or 79, and • CDR-L3 with sequence numbers 80, 81, or 82 It includes a light chain variable region containing the CDR.

[0167] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7, and a light chain variable region having the amino acid sequence of SEQ ID NO: 8, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity.

[0168] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region having the amino acid sequence of SEQ ID NO: 8.

[0169] In some preferred embodiments, the antibody or its antigen-binding fragment is LB-116 as described herein.

[0170] LB-20H10 In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region comprising one or more of the CDRs of SEQ ID NO: 9.

[0171] In some embodiments, the antibody or its antigen-binding fragment is the following CDR, where CDR is defined by Chothia: a) an amino acid sequence having at least 60% sequence identity with sequence number 83, or at least 70%, 80%, or 90% sequence identity, and / or b) an amino acid sequence having at least 60% sequence identity with sequence number 86, or at least 70%, 80%, or 90% sequence identity, and / or c) A heavy chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 89, for example, at least 70%, 80%, or 90% sequence identity.

[0172] In some embodiments, the antibody or its antigen-binding fragment is defined by Kabat as follows: a) an amino acid sequence having at least 60% sequence identity with sequence number 84, or, for example, at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with SEQ ID NO: 87, or at least 70%, 80%, or 90% sequence identity, and / or c) A heavy chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 90, or at least 70%, 80%, or 90% sequence identity therewith.

[0173] In some embodiments, the antibody or its antigen-binding fragment is defined by the following CDR, i.e., a) an amino acid sequence having at least 60% sequence identity with sequence number 85, or, for example, at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with sequence number 88, or, for example, at least 70%, 80%, or 90% sequence identity, and / or c) A heavy chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 91, or at least 70%, 80%, or 90% sequence identity.

[0174] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region containing the CDRs of SEQ ID NOs. 83, 86, and 89.

[0175] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region containing the CDRs of SEQ ID NOs. 84, 87, and 90.

[0176] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region containing the CDRs of SEQ ID NOs. 85, 88, and 91.

[0177] In some embodiments, the antibody or its antigen-binding fragment is • CDR-H1 with sequence numbers 83, 84, or 85, • CDR-H2 of sequence numbers 86, 87, or 88, and • CDR-H3 with sequence numbers 89, 90, or 91 It includes a heavy chain variable region containing the CDR.

[0178] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region having the amino acid sequence of SEQ ID NO: 9, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity.

[0179] In some embodiments, the antibody or its antigen-binding fragment includes a light chain variable region comprising one or more of the CDRs of SEQ ID NO: 10.

[0180] In some embodiments, the antibody or its antigen-binding fragment is determined by Chothia, and the following CDRs are used, i.e., a) an amino acid sequence having at least 60% sequence identity with sequence number 92, or, for example, at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with sequence number 95, or at least 70%, 80%, or 90% sequence identity, and / or c) A light chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 98, for example, at least 70%, 80%, or 90% sequence identity.

[0181] In some embodiments, the antibody or its antigen-binding fragment is determined by Kabat, i.e., the following CDRs: a) an amino acid sequence having at least 60% sequence identity with sequence number 93, or, for example, at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with sequence number 96, or, for example, at least 70%, 80%, or 90% sequence identity, and / or c) A light chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 99, or at least 70%, 80%, or 90% sequence identity.

[0182] In some embodiments, the antibody or its antigen-binding fragment is determined by the IMGT, and the following CDRs are used: a) an amino acid sequence having at least 60% sequence identity with sequence number 94, or, for example, at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with sequence number 97, or at least 70%, 80%, or 90% sequence identity, and / or c) A light chain variable region comprising a CDR of an amino acid sequence having at least 60% sequence identity with SEQ ID NO: 100, or at least 70%, 80%, or 90% sequence identity.

[0183] In some embodiments, the antibody or its antigen-binding fragment includes a light chain variable region containing the CDRs of SEQ ID NOs. 92, 95, and 98.

[0184] In some embodiments, the antibody or its antigen-binding fragment includes a light chain variable region containing the CDRs of SEQ ID NOs. 93, 96, and 99.

[0185] In some embodiments, the antibody or its antigen-binding fragment includes a light chain variable region containing the CDRs of SEQ ID NOs. 94, 97, and 100.

[0186] In some embodiments, the antibody or its antigen-binding fragment is • CDR-L1 with sequence numbers 92, 93, or 94 • CDR-L2 of sequence number 95, 96, or 97, and • CDR-L3 with sequence numbers 98, 99, or 100 Includes a light chain variable region containing CDR.

[0187] In some embodiments, the antibody or antigen-binding fragment described in any of the prior claims includes a light chain variable region having the amino acid sequence of SEQ ID NO: 10, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity.

[0188] In some embodiments, the antibody or its antigen-binding fragment comprises six CDRs of amino acid sequences having at least 60% sequence identity, e.g., at least 70%, 80%, or 90% sequence identity, with SEQ ID NOs. 83, 86, 89, 92, 95, and 98.

[0189] In some embodiments, the antibody or its antigen-binding fragment comprises six CDRs of amino acid sequences having at least 60% sequence identity with SEQ ID NOs. 84, 87, 90, 93, 96, and 99, or at least 70%, 80%, or 90% sequence identity.

[0190] In some embodiments, the antibody or its antigen-binding fragment comprises six CDRs of amino acid sequences having at least 60% sequence identity, e.g., at least 70%, 80%, or 90%, with SEQ ID NOs: 85, 88, 91, 94, 97, and 100, or with them.

[0191] In some embodiments, the antibody or its antigen-binding fragment is • CDR-H1 with sequence numbers 83, 84, or 85, • CDR-H2 with sequence numbers 86, 87, or 88, • CDR-H3 with sequence numbers 89, 90, or 91, • CDR-L1 with sequence numbers 92, 93, or 94 • CDR-L2 of sequence number 95, 96, or 97, and • CDR-L3 with sequence numbers 98, 99, or 100 It includes a light chain variable region containing the CDR.

[0192] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region having the amino acid sequence of SEQ ID NO: 9, and a light chain variable region having the amino acid sequence of SEQ ID NO: 10, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity.

[0193] In some embodiments, the antibody or its antigen-binding fragment includes a heavy chain variable region having the amino acid sequence of SEQ ID NO: 9 and a light chain variable region having the amino acid sequence of SEQ ID NO: 10.

[0194] "Antibody" includes substantially intact antibody molecules, as well as chimeric antibodies, humanized antibodies, human antibodies (in which at least one amino acid is mutated compared to naturally occurring human antibodies), single-chain antibodies, antibody heavy chains, antibody light chains, homodimers and heterodimers of antibody heavy chains and / or light chains, and their antigen-binding fragments and derivatives.

[0195] A typical immunoglobulin molecule comprises four polypeptide chains (two heavy (H) chains and two light (L) chains interconnected by disulfide bonds), as well as their polymers (e.g., IgM). Each heavy chain contains a heavy chain variable region (hereinafter abbreviated as HCVR or VH) and a heavy chain constant region. The heavy chain constant region contains three domains (CH1, CH2, and CH3). Each light chain contains a light chain variable region (hereinafter abbreviated as LCVR or VL) and a light chain constant region. The light chain constant region contains one domain (CL1). The VH and VL regions can be further subdivided into a hypervariable region called the complementarity-determining region (CDR) and a more conserved intervening region called the framework region (FR). Each VH and VL consists of three CDRs and four FRs arranged from the amino terminus to the carboxyl terminus in the order FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0196] Methods and techniques for identifying CDRs within variable region amino acid sequences are well known in the art and can be used to identify CDRs within specific antibodies or fragment amino acid sequences disclosed herein. Exemplary rules that can be used to identify CDR boundaries include, for example, the Kabat definition, the Chothia definition, and the IMGT definition. See, for example, Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Md. (1991); Chothia C, Lesk a M., "Canonical structures for the hypervariable regions of immunoglobulins," J Mol Biol. (1987) 196:901-17; Al-Lazikani et al., J. Mol. Biol. 273:927-948 (1997); and Martin et al., Proc. Natl. Acad. Sci. USA 86:9268-9272 (1989). Public databases for identifying CDR sequences within antibodies are also available to those skilled in the art.

[0197] A CDR sequence can be defined using one of the IMGT, Chothia, and Kabat numbering schemes, or a combination of these numbering schemes. In one embodiment, the CDR is defined using the IMGT numbering system. In one embodiment, the CDR is defined using the Kabat numbering system. In one embodiment, the CDR is defined using the Chothia numbering system.

[0198] "Antigen-binding fragment" refers to a functional fragment of an antibody that can bind to SLAMF6.

[0199] Preferably, the antigen-binding fragment is selected from the group consisting of Fv fragments (e.g., single-chain Fv(scFv), as well as disulfide-linked Fv and di-scFv), Fab-like fragments (e.g., Fab fragment, Fab-SH, Fab' fragment, and F(ab)2 fragment), single variable domains (e.g., VH and VL domains), and domain antibodies (sdAb, including single-format and dual-format [i.e., dAb-linker-dAb]).

[0200] In some embodiments, the antigen-binding fragment is selected from scFv, Fv, Fab, F(ab')2, Fab-SH, dsFv, VH, VL, sdAb, di-scFvs, and Fcabs.

[0201] The advantages of using antibody fragments instead of whole antibodies are numerous. The smaller size of the fragments can result in improved pharmacological properties, such as better penetration into solid tissues. Furthermore, antigen-binding fragments such as Fab, Fv, ScFv, and dAb antibody fragments can be expressed in E. coli and secreted from there, thus enabling the production of large quantities of these fragments.

[0202] Those skilled in the art will understand that, as discussed herein, the antibodies and antigen-binding fragments of the present invention may alternatively include variants of the sequences defined above. The antibodies and their antigen-binding fragments may have at least 60% sequence identity with any of the sequences disclosed herein. For example, they may have at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity.

[0203] Alternatively, an antibody and its antigen-binding fragment may be a variant of a specific sequence disclosed herein, the variant containing a mutation at one or more positions relative to the parent sequence. “Mutation” includes insertions, deletions, and substitutions. Thus, a variant may be a substitutional variant, a deletional variant, or an additional variant. In preferred embodiments, a variant polypeptide may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, up to 10, up to 20, up to 30, up to 40, up to 50, up to 75 or more amino acid mutations. Mutations may be either conserved or non-conservative. For example, a conserved substitution refers to the substitution of an amino acid within the same general class (e.g., an acidic amino acid, a basic amino acid, a nonpolar amino acid, a polar amino acid, or an aromatic amino acid) with another amino acid within the same class. Therefore, the meanings of conserved and non-conservative amino acid substitutions are well known in the art.

[0204] "Deletion" mutants may include the deletion of individual amino acids, a small group of amino acids, e.g., two, three, four, or five amino acids, or a larger amino acid region, e.g., a specific amino acid domain or other characteristic. "Substitution" mutants preferably involve conservative amino acid substitutions, replacing one or more amino acids with an equal number of amino acids. For example, an amino acid may be substituted with an alternative amino acid having similar properties, e.g., another basic amino acid, another acidic amino acid, another neutral amino acid, another charged amino acid, another hydrophilic amino acid, another hydrophobic amino acid, another polar amino acid, another aromatic amino acid, or another aliphatic amino acid. Some properties of the 20 major amino acids available for selecting a suitable substituent are as follows: [Table 1]

[0205] In this specification, amino acids may be referred to by their full name, a three-letter code, or a one-letter code.

[0206] Preferred "mutants" include those in which the amino acids appearing in the sequence are structural analogs of naturally occurring amino acids. The amino acids used in the sequence may also be derivatized or modified, for example, labeled, provided that the antibody function is not significantly adversely affected.

[0207] The above derivatives and variants can be prepared during antibody synthesis or by modification after production, or, if the antibody is recombinant, by site-directed mutagenesis, random mutagenesis, or known techniques of enzymatic cleavage and / or ligation of nucleic acids.

[0208] Suitable variants may be at least 70%, preferably at least 80% or 90%, and more preferably at least 95%, 97%, or 99% homologous to the sequences disclosed herein.

[0209] Preferably, the variant has an amino acid sequence having more than 60%, or more than 70%, for example 75%, or 80%, preferably more than 85%, for example 90%, or more than 95%, with respect to the sequence shown in the sequence disclosed herein (e.g., the VH or VL region sequence, or the CDR sequence therein). This level of amino acid identity may be found over the entire length of the sequence of the relevant sequence number, or over a portion of the sequence, such as over 20, 30, 50, 75, 100, 150, 200, or more amino acids, depending on the size of the full-length polypeptide.

[0210] For example, the variants of the above CDR sequence may contain one, two, three, four, five, six, seven, eight or more amino acid mutations (such as amino acid deletions, substitutions, and / or insertions) compared to the reference sequence.

[0211] The percentage sequence identity between two polypeptides can be determined using a suitable computer program, such as the GAP program from the Genetic Computing Group at the University of Wisconsin, and it will be understood that the percentage identity is calculated in relation to polypeptides whose sequences are optimally aligned. Methods for determining sequence identity are known to those skilled in the art.

[0212] Alternatively, alignment may be performed using the Clustal W program (as described in Thompson et al., 1994, Nuc. Acid Res. 22:4673-4680, which is incorporated herein by reference).

[0213] The parameters used may be as follows: High-speed pairwise alignment parameters: K-tuple (word) size = 1, window size = 5, gap penalty = 3, number of top diagonals = 5. Scoring method: x percent. Multiple alignment parameters: Gap open penalty = 10, Gap extension penalty = 0.05. Scoring matrix: BLOSUM.

[0214] Alternatively, the BESTFIT program can be used to determine local sequence alignment.

[0215] Furthermore, the scope of the present invention also includes modified versions of antibodies and their antigen-binding fragments, for example, those modified by covalent bonding of polyethylene glycol or other suitable polymers (see below).

[0216] Methods for generating antibodies and antibody fragments are well known in the art. For example, antibodies can be generated by one of several methods, including inducing in vivo production of antibody molecules, screening immunoglobulin libraries (Orlandi et al, 1989. Proc. Natl. Acad. Sci. USA 86:3833-3837, Winter et al., 1991, Nature 349:293-299), or generating monoclonal antibody molecules using cell lines in culture. These include, but are not limited to, hybridoma techniques, human B-cell hybridoma techniques, and Epstein-Barr virus (EBV) hybridoma techniques (Kohler et al., 1975. Nature 256:4950497; Kozbor et al., 1985. J. Immunol. Methods 81:31-42; Cote et al., 1983. Proc. Natl. Acad. Sci. USA 80:2026-2030; Cole et al., 1984. Mol. Cell. Biol. 62:109-120).

[0217] Suitable monoclonal antibodies against selected antigens can be prepared by known techniques, such as those disclosed in "Monoclonal Antibodies: A Manual of Techniques," H. Zola (CRC Press, 1988) and "Monoclonal Hybridoma Antibodies: Techniques and Applications," J.G. Hurrell (CRC Press, 1982).

[0218] Similarly, antibody fragments can be obtained using methods well known in the art (see, for example, Harlow & Lane, 1988, "Antibodies: A Laboratory Manual," Cold Spring Harbor Laboratory, New York). For example, antibody fragments according to the present invention can be prepared by proteolytic hydrolysis of the antibody, or by expressing the DNA encoding the fragment in Escherichia coli or mammalian cells (e.g., Chinese hamster ovary cell culture or other protein expression system). Alternatively, antibody fragments can be obtained by pepsin or papain digestion of the whole antibody by conventional methods.

[0219] Those skilled in the art will understand that, for human therapy or diagnosis, human antibodies or humanized antibodies are preferably used. The humanized form of a non-human (e.g., mouse) antibody is preferably a genetically engineered chimeric antibody or antibody fragment having a minimal portion derived from the non-human antibody. Humanized antibodies include antibodies in which the complementary determinant region of a human antibody (recipient antibody) is replaced by residues derived from the complementary determinant region of a non-human species (donor antibody), such as mouse, rat, or rabbit, having the desired function. In some cases, the Fv framework residues of the human antibody are replaced by corresponding non-human residues. Humanized antibodies may also contain residues not found in the recipient antibody or in the transferred complementary determinant region or framework sequence. Generally, humanized antibodies contain substantially all of at least one, and typically two, variable domains, with all or substantially all of the complementary determinant region corresponding to that of the non-human antibody, and all or substantially all of the framework region corresponding to that of the relevant human consensus sequence. Humanized antibodies also, optimally, include at least a portion of the antibody constant region, such as the Fc region, typically derived from a human antibody (see, e.g., Jones et al., 1986, Nature 321:522-525; Riechmann et al., 1988, Nature 332:323-329; Presta, 1992, Curr. Op. Struct. Biol. 2:593-596).

[0220] Methods for humanizing non-human antibodies are well known in the art. Generally, humanized antibodies have one or more amino acid residues introduced into them from a non-human source. These non-human amino acid residues are often called translocated residues and are usually obtained from translocated variable domains. Humanization can be carried out as described by essentially substituting the human complementarity-determining region with the corresponding rodent complementarity-determining region (see, e.g., Jones et al., 1986, Nature 321:522-525; Reichmann et al., 1988, Nature 332:323-327; Verhoeyen et al., 1988, Science 239:1534-1536l, US4,816,567). Thus, such humanized antibodies are chimeric antibodies in which substantially fewer than the intact human variable domain are replaced by corresponding sequences from a non-human species. In practice, humanized antibodies can typically be human antibodies in which several complementarity-determining region residues, and possibly several framework residues, are replaced by residues from similar sites in rodent antibodies.

[0221] Human antibodies can also be identified using a variety of techniques known in the art, including phage display libraries (see, for example, Hoogenboom & Winter, 1991, J.Mol.Biol.227:381; Marks et al., 1991, J.Mol.Biol.222:581; Cole et al., 1985, In:Monoclonal antibodies and Cancer Therapy, Alan R. Liss, pp.77; and Boerner et al., 1991, J.Immunol.147:86-95).

[0222] Once suitable antibodies are obtained, they can be tested for activity, for example, by ELISA.

[0223] In some embodiments, the antigen-binding fragments discussed herein are selected from scFv, Fv, Fab, F(ab')2, Fab-SH, dsFv, sdAb, di-scFvs, and Fcabs.

[0224] In some embodiments, the antibody or antigen-binding fragment described in any of the prior claims includes a heavy chain constant region or a portion thereof.

[0225] In some embodiments, the heavy chain constant region is an immunoglobulin subtype selected from the group consisting of IgG1, IgG2, IgG3, and IgG4.

[0226] In some embodiments, the heavy chain constant region includes an LALA mutation (e.g., Leu234Ala / Leu235Ala in IgG1) that reduces or eliminates binding to a particular Fcγ receptor. In some other embodiments, the heavy chain constant region is modified to have a low level of fucosylation.

[0227] In some embodiments, the antibody or antigen-binding fragment described in any of the prior claims includes a light chain constant region or a portion thereof.

[0228] In some embodiments, the light chain constant region is a kappa light chain or a lambda light chain.

[0229] In some preferred embodiments, the antibody is a whole antibody. "Whole antibody" means an antibody that includes the variable and constant regions of the heavy and light chains.

[0230] In some embodiments, the antibody or its antigen-binding fragment can induce tumor-specific immunity. This can be tested in vitro in a T cell activation assay, for example, by measuring the production of IL-2 and IFNγ. Activation of effector T cells would mean that a tumor-specific T cell response can be achieved in vivo. Furthermore, an antitumor response in an in vivo model such as a mouse model would suggest that a successful immune response against the tumor has been achieved.

[0231] The antibodies and antigen-binding fragments of the present invention may further comprise moieties for increasing the in vivo half-life of the agent, such as, but not limited to, polyethylene glycol (PEG), human serum albumin, glycosylation groups, fatty acids, and dextran. Such additional moieties can be conjugated or otherwise combined with the binding moiety using methods well known in the art.

[0232] Similarly, it will be understood that the antibodies and antigen-binding fragments of the present invention may further comprise a cytotoxic moiety. "Cytotoxic" shall typically mean an agent that is toxic to cells by killing the cells. This toxicity can lead to cell death by necrosis or apoptosis.

[0233] In some other embodiments, the antibody and its antigen-binding fragment may further comprise a cell growth inhibitory moiety. "Cell growth inhibitory" shall mean an agent that inhibits or arrests the growth and / or proliferation of cells.

[0234] In some embodiments, the cytotoxic moiety or cell growth inhibitory moiety can comprise or consist of a radioisotope or a drug molecule.

[0235] A second aspect of the present invention relates to an isolated nucleic acid molecule encoding an antibody or its antigen-binding fragment as disclosed herein, or its constituent polypeptide chains.

[0236] Accordingly, the present invention relates to polynucleotides encoding all or part of the antibody or antigen-binding fragments of the present invention. The terms “nucleic acid molecule” and “polynucleotide” are used interchangeably herein and refer to nucleotides or analogues thereof in polymeric form of any length, whether deoxyribonucleotides or ribonucleotides. Non-limiting examples of polynucleotides include genes, gene fragments, messenger RNA (mRNA), cDNA, recombinant polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. The polynucleotides of the present invention may be provided in isolated or substantially isolated forms. Substantially isolated means that the polypeptide may be substantially isolated, but not completely isolated, from any surrounding medium. Polynucleotides may be mixed with a carrier or diluent that does not interfere with their intended use and may still be considered substantially isolated.

[0237] The nucleic acid sequence that "codes" the selected polypeptide is a nucleic acid molecule that, when controlled by an appropriate regulatory sequence, is transcribed in vivo into a polypeptide (in the case of DNA) and translated (in the case of mRNA). The boundaries of the coding sequence are determined by a start codon at the 5' (amino) terminus and a translation stop codon at the 3' (carboxy) terminus. For the purposes of the present invention, such nucleic acid sequences may include, but are not limited to, viral cDNA, prokaryotic or eukaryotic mRNA, genomic sequences derived from viral or prokaryotic DNA or RNA, and even synthetic DNA sequences. The transcription termination sequence may be located at 3' of the coding sequence.

[0238] Alternatively, a suitable polynucleotide sequence may be a variant of a specific polynucleotide sequence, the variant containing one or more mutations at nucleotide positions relative to the parent (unmutated) sequence. For example, the variant may be a substitution variant, a deletion variant, or an addition variant. The variant polynucleotide may contain 1, 2, 3, 4, 5, up to 10, up to 20, up to 30, up to 40, up to 50, up to 75, or more amino acid substitutions, insertions, and / or deletions.

[0239] A suitable variant may be at least 70% homologous to the polynucleotide, preferably at least 80 or 90%, and more preferably at least 95%, 97%, or 99% homologous. Preferably, homology and identity at these levels exist with respect to at least the coding region of the polynucleotide. Methods for measuring homology are well known in the art, and in this context, it will be understood by those skilled in the art that homology is calculated based on nucleic acid identity. Such homology may exist over regions of at least 15, preferably at least 30, for example, at least 40, 60, 100, 200 or more consecutive nucleotides. Such homology may exist over the entire length of the unmodified polynucleotide sequence.

[0240] Methods for measuring polynucleotide homology or identity are well known in the art. For example, the UWGCG package provides the BESTFIT program, which can be used to calculate homology (for example, used in its default settings) (Devereux et al, 1984, Nucleic Acids Research 12:387-395 (its disclosure is incorporated herein by reference)).

[0241] The PILEUP and BLAST algorithms can also be used to calculate homology or to align sequences (typically with their default settings), as described, for example, in Altschul, 1993, J Mol Evol 36:290-300 and Altschul et al, 1990, J Mol Biol 215:403-10 (their disclosure is incorporated herein by reference).

[0242] Software for performing BLAST analysis is publicly available through the National Centre for Biotechnology Information. This algorithm involves identifying high-scoring sequence pairs (HSPs) by first identifying short words of length W within the query sequence, where these short words, when aligned with words of the same length in the database sequence, match or satisfy a certain positive threshold score T. T is referred to as the neighbor word score threshold (Altschul et al., previously cited). These initial neighbor word hits serve as seeds to initiate a search for HSPs containing them. This word hit is extended in both directions along each sequence as long as it can increase the cumulative alignment score. Extension of word hits in each direction stops when the cumulative alignment score becomes zero or less due to the accumulation of one or more negative scoring residue alignments, or when it reaches the end of either sequence. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLAST program uses, by default, a word length (W) of 11, a BLOSUM62 scoring matrix (see Henikoff & Henikoff, 1992, Proc. Natl. Acad. Sci. USA 89:10915-10919 (its disclosure is incorporated herein by reference)), alignment (B) of 50, expected value (E) of 10, M=5, N=4, and comparison of both strands.

[0243] The BLAST algorithm performs a statistical analysis of the similarity between two sequences, see, for example, Karlin & Altschul, 1993, Proc. Natl. Acad. Sci. USA 90:5873-5787 (its disclosure is incorporated herein by reference). One measure of similarity provided by the BLAST algorithm is the minimum sum probability (P(N)), which provides an indicator of the probability that a match between two nucleotide or amino acid sequences occurs by chance. For example, if the minimum sum probability in the comparison between a first sequence and a second sequence is less than about 1, preferably less than about 0.1, more preferably less than about 0.01, and most preferably less than about 0.001, then the sequences are considered similar to each other.

[0244] Homogenies may differ from the sequence within the associated polynucleotide by only 3, 5, 10, 15, 20 or fewer mutations (each of which may be a substitution, deletion, or insertion). These mutations can be measured across at least 30, e.g., at least 40, 60, or 100 or more consecutive nucleotide regions of the homologue.

[0245] In one embodiment, the mutant sequence may differ from the specific sequence given in the sequence listing due to the redundancy of the gene code. The DNA code has four primary nucleic acid residues (A, T, C, and G) which are used to "spell" three-letter codons that represent the amino acids of the proteins encoded by the genes of an organism. The linear sequence of codons along the DNA molecule is translated into a linear sequence of amino acids in the protein(s) encoded by those genes. This code is highly degenerate and has 61 codons that code for 20 native amino acids and 3 codons that represent a "stop" signal. Thus, most amino acids are coded by one or more codons, and in fact, some are coded by four or more different codons. Therefore, the mutant polynucleotides of the present invention may code for the same polypeptide sequence as another polynucleotide of the present invention, but may have different nucleic acid sequences because they use different codons to code for the same amino acids.

[0246] Therefore, the polypeptide of the present invention may be produced from or delivered in the form of a polynucleotide that can encode and express it.

[0247] The polynucleotide of the present invention is Green & Sambrook (2012, Molecular Cloning - a laboratory manual, 4 th It can be synthesized according to methods well known in the art, as described by example in the edition; Cold Spring Harbor Press (whose disclosure is incorporated herein by reference)).

[0248] The nucleic acid molecules of the present invention may be provided in the form of an expression cassette comprising a control sequence operably linked to an insert sequence, thereby enabling the expression of the polypeptide of the present invention in vivo. These expression cassettes are then typically provided within a vector (e.g., a plasmid or recombinant viral vector). Such expression cassettes may be administered directly to a host subject. Alternatively, a vector containing the polynucleotide of the present invention may be administered to a host subject. Preferably, the polynucleotide is prepared and / or administered using a gene vector. A suitable vector may be any vector capable of carrying a sufficient amount of genetic information and enabling the expression of the polypeptide of the present invention.

[0249] Accordingly, a third aspect of the present invention relates to a vector comprising a nucleic acid molecule as disclosed herein. In some embodiments, the vector is an expression vector.

[0250] Therefore, the present invention includes an expression vector containing such a polynucleotide sequence. Such expression vectors are routinely constructed in the field of molecular biology and include, for example, plasmid DNA and appropriate initiators, promoters, enhancers, and other elements such as polyadenylation signals that may be necessary and are arranged in the correct orientation to enable the expression of the peptides of the present invention. Other suitable vectors will be apparent to those skilled in the art.

[0251] A fourth aspect of the present invention relates to a host cell containing a nucleic acid molecule or vector as disclosed herein. In some embodiments, the host cell is a bacterial cell, a mammalian cell, or a human cell.

[0252] Such cells include transient or preferably stable higher eukaryotic cell lines (such as mammalian or insect cells), lower eukaryotic cells (such as yeast), or prokaryotic cells (such as bacterial cells). Specific examples of cells that can be modified by the insertion of a vector or expression cassette encoding the polypeptide of the present invention include mammalian HEK293T, CHO, HeLa, NS0, and COS cells. Preferably, the cell line selected is not only stable but also enables the mature glycosylation and cell surface expression of the polypeptide.

[0253] Such cell lines of the present invention can be cultured using conventional methods to produce the polypeptides of the present invention or can be used therapeutically or prophylactically to deliver the antibodies of the present invention to a subject. Alternatively, the polynucleotides, expression cassettes, or vectors of the present invention can be administered ex vivo to cells derived from a subject, and then the cells can be returned to the subject's body.

[0254] A fifth aspect of the present invention relates to a pharmaceutical composition comprising an effective amount of an antibody or an antigen-binding fragment thereof as disclosed herein and a pharmaceutically acceptable buffer, diluent, carrier, or excipient. In some embodiments, the pharmaceutical composition is adapted for parenteral delivery or intravenous delivery.

[0255] Further compounds containing chelating agents such as EDTA, citrate, EGTA, or glutathione may also be included in the composition.

[0256] Pharmaceutical compositions can be prepared by methods known in the art, which are sufficiently stable and suitable for administration to humans and animals. For example, pharmaceutical compositions can be freeze-dried, for example, by freeze-drying, spray-drying, spray-cooling, or by using particle formation from supercritical particle formation.

[0257] "Pharmacologically acceptable" means a non-toxic substance that does not impair the efficacy of the SLAMF6 binding activity of the drug of the present invention. Such pharmaceutically acceptable buffers, carriers, or excipients are well known in the art (see Remington's Pharmaceutical Sciences, 18th edition, AR Gennaro, Ed., Mack Publishing Company (1990), and Handbook of Pharmaceutical Excipients, 3rd edition, A. Kibbe, Ed., Pharmaceutical Press (2000) (their disclosures are incorporated by reference)).

[0258] The term "buffer" is intended to mean an aqueous solution containing an acid-base mixture for the purpose of stabilizing the pH. Examples of buffers include Trizma, Bicine, Tricin, MOPS, MOPSO, MOBS, Tris, Hepes, HEPBS, MES, Phosphate, Carbonate, Acetate, Citrate, Glycolate, Lactate, Borate, ACES, ADA, Tartrate, AMP, AMPD, AMPSO, BES, CABS, Cacodylate, CHES, DIPSO, EPPS, Ethanolamine, Glycine, HEPPSO, Imidazole, Imidazoleacetic acid, PIPES, SSC, SSPE, POPSO, TAPS, TABS, TAPSO, and TES.

[0259] The term “diluent” is intended to mean an aqueous or non-aqueous solution used for diluting a drug in a pharmaceutical preparation. Diluents may be one or more of the following: physiological saline, water, polyethylene glycol, propylene glycol, ethanol, or oil (such as safflower oil, corn oil, peanut oil, cottonseed oil, or sesame oil).

[0260] The term "adjuvant" is intended to mean any compound added to a formulation to enhance the biological effect of the drug of the present invention. Adjuvants may be, for example, one or more zinc salts, copper salts, or silver salts having different anions, such as fluorides, chlorides, bromides, iodides, thiocyanates, sulfites, hydroxides, phosphates, carbonates, lactates, glycolates, citrates, borates, tartrates, and acetates with different acyl compositions. Adjuvants may also be cationic polymers such as cationic cellulose ethers, cationic cellulose esters, deacetylated hyaluronic acid, chitosan, and cationic dendrimers, cationic synthetic polymers such as poly(vinylimidazole), and cationic polypeptides such as polyhistidine, polylysine, polyarginine, and peptides containing these amino acids.

[0261] Excipients may be one or more of carbohydrates, polymers, lipids, and minerals. Examples of carbohydrates include lactose, glucose, sucrose, mannitol, and cyclodextrin, which are added to compositions, for example, to promote freeze-drying. Examples of polymers include starch, cellulose ethers, cellulose carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, ethyl hydroxyethylcellulose, alginates, carrageenan, hyaluronic acid, and their derivatives, polyacrylic acid, polysulfonates, polyethylene glycol / polyethylene oxide, polyethylene oxide / polypropylene oxide copolymers, polyvinyl alcohol / polyvinyl acetate with different degrees of hydrolysis, and polyvinylpyrrolidone (all with different molecular weights), which are added to compositions, for example, for viscosity control, to achieve bioadhesion, or to protect lipids from chemical and proteolytic degradation. Examples of lipids include fatty acids, phospholipids, monoglycerides, diglycerides, and triglycerides, ceramides, sphingolipids and glycolipids (all with different acyl chain lengths and saturation levels), egg lecithin, soy lecithin, hydrogenated egg, and soy lecithin, which are added to compositions for similar reasons as polymers. Examples of minerals include talc, magnesium oxide, zinc oxide, and titanium dioxide, which are added to compositions to obtain benefits such as reduced liquid accumulation or favorable pigment properties.

[0262] The agents of the present invention can be formulated into any type of pharmaceutical composition known in the art to be suitable for their delivery.

[0263] In one embodiment, the pharmaceutical composition of the present invention may be in the form of liposomes, in which the drug is combined with an amphiphilic drug, such as a lipid, which exists in aggregate form as a micelle, an insoluble monolayer, or a liquid crystal, in addition to other pharmaceutically acceptable carriers. Suitable lipids for liposomal formulations include, but are not limited to, monoglycerides, diglycerides, sulfatides, lysolecithins, phospholipids, saponins, and bile acids. Suitable lipids also include the above lipids modified with poly(ethylene glycol) at the polar head group to extend blood flow circulation time. Preparation of such liposomal formulations can be found, for example, in US4,235,871, the disclosure of which is incorporated herein by reference.

[0264] The pharmaceutical compositions of the present invention may also be in the form of biodegradable microspheres. Aliphatic polyesters such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), copolymers of PLA and PGA (PLGA), or poly(caprolactone) (PCL), as well as polyanhydrides, are widely used as biodegradable polymers in the production of microspheres. Preparations of such microspheres can be found in US5,851,451 and EP0213303, whose disclosures are incorporated herein by reference.

[0265] In further embodiments, the pharmaceutical compositions of the present invention are provided in the form of polymer gels used to thicken solutions containing pharmaceuticals, including polymers such as starch, cellulose ether, cellulose carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, ethyl hydroxyethylcellulose, alginates, carrageenan, hyaluronic acid, and their derivatives, polyacrylic acid, polyvinylimidazole, polysulfonates, polyethylene glycol / polyethylene oxide, polyethylene oxide / polypropylene oxide copolymers, polyvinyl alcohol / polyvinyl acetate of different degrees of hydrolysis, and polyvinylpyrrolidone. The polymers may also include gelatin or collagen.

[0266] Alternatively, the drug may be simply dissolved in saline solution, water, polyethylene glycol, propylene glycol, ethanol, or oil (such as safflower oil, corn oil, peanut oil, cottonseed oil, or sesame oil), tragacanth gum, and / or various buffers.

[0267] It will be understood that the pharmaceutical composition of the present invention may contain ions and a specified pH to enhance the action of the activator. In addition, the composition may be subjected to conventional pharmaceutical operations such as sterilization and / or may contain conventional adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, and fillers.

[0268] The pharmaceutical compositions according to the present invention may be administered via any preferred route known to those skilled in the art. Possible routes of administration include parenteral (intravenous, subcutaneous, and intramuscular), topical, ocular, nasal, pulmonary, buccal, oral, parenteral, vaginal, and rectal. Administration via implants is also possible.

[0269] In a preferred embodiment, the pharmaceutical composition is administered parenterally, for example, intravenously, intrarebroventricularly, intraarticularly, intraarterially, intraperitoneally, subarachnoidally, intraventricularly, intrathoracically, intracranially, intramuscularly, or subcutaneously, or they may be administered by infusion techniques. They are conveniently used in the form of a sterile aqueous solution that may contain other substances, such as salts or glucose sufficient to make the solution isotonic with blood. The aqueous solution should be buffered as needed (preferably to pH 3-9). Preparation of a suitable parenteral formulation under sterile conditions is readily achieved by standard pharmaceutical techniques well known to those skilled in the art.

[0270] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostatic agents, and solutes that make the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners. Formulations may be presented in single-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a freeze-dried state requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Immediate injection solutions and suspensions may be prepared from the aforementioned types of sterile powders, granules, and tablets.

[0271] Therefore, the pharmaceutical compositions of the present invention are particularly suitable for parenteral administration, such as intravenous administration. In some preferred embodiments, the pharmaceutical compositions of the present invention are administered intravenously.

[0272] Alternatively, the pharmaceutical composition may be administered intranasally or by inhalation (in the form of an aerosol spray presented from a pressurized container, pump, spray, or nebulizer, using a suitable propellant such as a hydrofluoroalkane (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1,1,1,2-tetrafluoroethane (HFA134A3) or 1,1,1,2,3,3,3-heptafluoropropane (HFA227EA3)), carbon dioxide, or other suitable gas). The unit of volume may be determined by providing a valve for delivering the measured amount. Pressurized containers, pumps, sprays, or nebulizers may contain a solution or suspension of the active polypeptide, for example, using a mixture of ethanol and a propellant as a solvent, and may further contain a lubricant, for example, sorbitan trioleate. Capsules and cartridges (for example, made from gelatin) for use in inhalers or insufflers may be formulated to contain a powder mixture of the compound of the present invention and a suitable powder base such as lactose or starch.

[0273] The pharmaceutical composition will be administered to the patient in a pharmaceutically effective dose. As used herein, “therapeutic effective dose,” “effective dose,” or “therapeutably effective” refers to the amount that provides a therapeutic effect for a given disease condition and administration regimen. This is a predetermined amount of the active substance calculated to produce the desired therapeutic effect in relation to the necessary additives and diluents, i.e., carriers or administration vehicles. Furthermore, it is intended to mean an amount sufficient to mitigate, and most preferably prevent, clinically significant deficits in the host’s activity, function, and response. Alternatively, a therapeutic effective dose is sufficient to cause a clinically significant improvement in the disease condition in the host. As will be understood by those skilled in the art, the amount of compound may vary depending on its specific activity. A suitable dose may contain a predetermined amount of the active composition calculated to produce the desired therapeutic effect in relation to the necessary diluents. In the methods for preparing and using the compositions of the present invention, a therapeutic effective dose of the active ingredient is provided. The therapeutic effective dose can be determined by a normally skilled medical or veterinary professional based on patient characteristics such as age, weight, sex, disease condition, complications, and other diseases, as is well known in the art. The pharmacokinetically effective dose can be administered both as a single dose in the form of individual dose units or several smaller dose units, and as multiple doses of subdivided doses at specific intervals. Alternatively, this dose may be provided as a continuous infusion over a long period.

[0274] The compositions of the present invention can be formulated at various concentrations depending on the efficacy / toxicity of the compounds used. Those skilled in the art will recognize suitable techniques for determining the formulation and dosage actually used in patient administration.

[0275] Those skilled in the art will understand that the pharmaceutical compositions of the present invention may be administered alone or in combination with other therapeutic agents used to treat cancer, such as chemotherapeutic agents. In particular, the therapeutic agent(s) may be one known to be effective for the intended indication.

[0276] A sixth aspect of the present invention relates to a kit comprising an antibody or an antigen-binding fragment thereof disclosed herein, or a pharmaceutical composition as defined herein. In some embodiments, the kit includes instructions for use.

[0277] A seventh aspect of the present invention relates to an antibody or its antigen-binding fragment for medical use, as disclosed herein.

[0278] An eighth aspect of the present invention relates to an antibody or antigen-binding fragment as disclosed herein, which is intended for use in the treatment of cancer in an individual.

[0279] In some embodiments, the present invention provides a method for treating cancer in a subject, the method comprising administering a therapeutically effective amount of an antibody or antigen-binding fragment, as disclosed herein, or a pharmaceutical composition as defined herein.

[0280] In some embodiments, cancer is a solid tumor. In some embodiments, the solid tumor is selected from sarcoma, lymphoma, blastoma, melanoma, carcinoma, lung cancer, pancreatic cancer, breast cancer, gastrointestinal cancer, head and neck cancer, brain cancer, liver cancer, ovarian cancer, prostate cancer, and cervical cancer.

[0281] In some other embodiments, the cancer is a liquid tumor, such as leukemia. In some embodiments, the myeloid malignancy / neoplasm is selected from myelodysplastic syndrome and / or myelodysplastic neoplasm (MDS), myeloproliferative neoplasm (MPN), mastocytosis, and myelodysplastic neoplasm / myeloproliferative neoplasm, and optionally, the myeloid malignancy and / or neoplasm is acute myeloid leukemia (AML). In some preferred embodiments, the myeloid malignancy / neoplasm is AML.

[0282] In some embodiments, the present invention provides a method for treating myeloid malignancies and / or neoplasms in a subject, the method comprising administering a therapeutically effective amount of an antibody or antigen-binding fragment disclosed herein, or a pharmaceutical composition as defined herein.

[0283] Accordingly, in some embodiments, the present invention provides methods for the treatment of cancer. “Treatment” shall include both therapeutic and prophylactic treatment of a patient. The term “prophylactic” is used to encompass the use of the polypeptides or formulations described herein that either prevent or reduce the likelihood of myeloid malignancies and / or neoplasms in a patient or subject. It shall also include treatment of a patient to reduce the likelihood of recurrence.

[0284] A ninth aspect of the present invention relates to the use of antibodies or antigen-binding fragments thereof, as disclosed herein, in the preparation of pharmaceuticals for inducing cell death and / or inhibiting the growth and / or proliferation of tumor cells. In some embodiments, this is achieved by the activation of T cells. In some embodiments, the tumor cells express SLAMF6.

[0285] A tenth aspect of the present invention relates to the use of an antibody or its antigen-binding fragment, as disclosed herein, in the preparation of a diagnostic agent for detecting tumor-related cells, wherein the cells express SLAMF6.

[0286] An eleventh aspect of the present invention relates to the use of an antibody or antigen-binding fragment thereof, as disclosed herein, for detecting tumor-related cells, wherein the cells express SLAMF6.

[0287] In some embodiments, the detection of tumor-related cells in an individual is used to diagnose the myeloid malignancy and / or neoplasm in that individual.

[0288] In some embodiments, the invention also provides an in vitro method for diagnosing or prognosticating cancer in a subject using an antibody or antigen-binding fragment as defined herein, or a pharmaceutical composition as defined herein.

[0289] In one embodiment, the method is for determining whether an individual has or is at risk of developing a myeloid malignancy and / or neoplasm, and the method comprises: (a) providing a bone marrow or peripheral blood sample of hematopoietic cells from an individual to be tested; (b) isolating a subpopulation of CD34 + cells and CD38 - cells; (c) determining whether the stem cells contained within the CD34 + cells and CD38 - cells express SLAMF6, a cell surface marker; Stem cells characterized by the cell surface marker profile CD34 + , CD38 - , and SLAMF6 + indicate that the individual has or is developing a myeloid malignancy and / or neoplasm.

[0290] In some other embodiments, the method is for determining whether an individual has or is at risk of developing a solid tumor, and the method comprises: (a) providing a tissue sample of cells from an individual to be tested; (b) determining whether the cells express SLAMF6, a cell surface marker; Cells that are SLAMF6 + indicate that the individual has or is developing a solid tumor and / or a solid tumor that expresses SLAMF6. In some embodiments, the method is immunohistochemical staining.

[0291] In some embodiments, the method also includes a step of quantifying the levels of immune cells (such as B cells, T cells, and / or NK cells), preferably such immune cells expressing SLAMF6.

[0292] The provision of a sample should not necessarily be interpreted as involving surgical steps. The sample may, for example, be a pre-isolated and stored frozen sample.

[0293] A twelfth aspect of the present invention relates to a method for inducing cell death in an individual and / or inhibiting the growth and / or proliferation of tumor cells in order to treat or prevent cancer, comprising the step of administering to the individual an effective amount of an antibody or its antigen-binding fragment, or a pharmaceutical composition as disclosed herein. In some embodiments, the tumor cells express SLAMF6.

[0294] A thirteenth aspect of the present invention relates to a method for detecting tumor-related cells, comprising the step of administering an effective amount of an antibody or antigen-binding fragment as defined herein, or a pharmaceutical composition as defined herein, to an individual, wherein the cells express SLAMF6.

[0295] In some embodiments, the tumor is cancer. In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is a liquid tumor. In some embodiments, the solid tumor is selected from sarcoma, lymphoma, blastoma, melanoma, carcinoma, lung cancer, pancreatic cancer, breast cancer, gastrointestinal cancer, head and neck cancer, brain cancer, liver cancer, ovarian cancer, prostate cancer, and cervical cancer.

[0296] In some preferred embodiments, the solid tumor is selected from the group consisting of intestinal cancer, colorectal cancer, esophageal cancer, gastric cancer, biliary tract cancer, kidney cancer, lung cancer, ovarian cancer, fallopian tube cancer, pancreatic cancer, or soft tissue cancer (e.g., sarcoma).

[0297] In some preferred embodiments, the solid tumor is colorectal cancer. In some preferred embodiments, the solid tumor is pancreatic cancer.

[0298] In some embodiments, the liquid tumor is a myeloid malignancy / neoplasm. In some embodiments, the myeloid malignancy / neoplasm is selected from myelodysplastic syndrome and / or myelodysplastic neoplasm (MDS), myeloproliferative neoplasm (MPN), mastocytosis, and myelodysplastic neoplasm / myeloproliferative neoplasm, and optionally, the myeloid malignancy and / or neoplasm is acute myeloid leukemia (AML). In some preferred embodiments, the myeloid malignancy / neoplasm is AML.

[0299] In some embodiments, the tumor is a preneoplastic condition such as clonal hematopoiesis (CHIP) of indeterminate potential significance or clonal cytopenia of undetermined significance (CCUS).

[0300] In some embodiments, the method or use further includes treating an individual for cancer by administering or performing a treatment for the cancer.

[0301] "Cancer treatment" includes any approved treatment. Treatment may include, but is not limited to, surgery, chemotherapy, radiation therapy, immunotherapy, CAR-T therapy, and bone marrow transplantation.

[0302] Herein, with reference to the following drawings and examples, preferred non-limiting embodiments that embody a particular aspect of the present invention will be described. [Brief explanation of the drawing]

[0303] [Figure 1] This graph shows the binding of the generated SLAMF6 antibody to SLAMF6-positive wild-type KG-1 cells (black) compared to an isotype-matched control antibody (gray). The X-axis represents binding strength, and the Y-axis represents normalized counts. [Figure 2] This graph shows the binding of the generated SLAMF6 antibody to SLAMF6-positive wild-type KG-1 cells (black) and corresponding SLAMF6 knockout cells (gray). The X-axis represents binding strength, and the Y-axis represents normalized counts. [Figure 3] The image shows the induction of T cell-mediated killing (top) and T cell activation (bottom) by SLAMF6 antibodies LB-116 (A) and LB-031 (B) at specified doses (black), compared to an isotype-matched control antibody (gray). T cell activation is measured as the percentage of cells positive for CD25 surface expression. [Figure 4] This image shows the induction of T-cell-mediated killing of AML cells in vivo after treatment with LB-116(A) and LB-031(B). The left image shows AML engraftment in the bone marrow. The center image shows AML engraftment in the spleen. The right image shows spleen weight. Engraftment is determined as the percentage of the total cell population composed of human AML cells in each tissue. [Figure 5] This study describes the induction of T cell-mediated killing by different 1 ug / ml SLAMF6 antibodies compared to isotype-matched control antibodies. It is a representative experiment from three experiments using different T cell donors. [Figure 6] This study describes the induction of T cell-mediated killing by SLAMF6 produced at specified concentrations, compared to isotype-matched control antibodies and SLAMF6 antibody 20F3 from Seagen Inc. Each study presents one representative experiment out of three experiments using T cells from different healthy donors. [Figure 7A] This shows the binding epitopes in SLAMF6 determined by HDX-MS for a SLAMF6 antibody (Seagen 20F3) that does not induce T cell activation. A shaded HDX-MS heatmap showing the level of protection at each position at specified time points is shown along with the binding epitopes (black) in the 3D structure of SLAMF6 (gray). [Figure 7B] This shows the binding epitopes in SLAMF6 determined by HDX-MS for the SLAMF6 antibody (LB-031) that induces T cell activation. The shaded HDX-MS heatmap, showing the level of protection at each position at specified time points, is displayed along with the binding epitopes (black) in the three-dimensional structure of SLAMF6 (gray). [Figure 7C]This shows the binding epitopes in SLAMF6 determined by HDX-MS for the SLAMF6 antibody (LB-116) that induces T cell activation. The shaded HDX-MS heatmap, showing the level of protection at each position at specified time points, is displayed along with the binding epitopes (black) in the three-dimensional structure of SLAMF6 (gray). [Figure 7D] This is the binding epitope on SLAMF6 determined by HDX-MS for the SLAMF6 antibody (LB-20H10) that induces T cell activation. The shaded HDX-MS heatmap, showing the level of protection at each position at specified time points, is displayed along with the binding epitope (black) in the 3D structure of SLAMF6 (gray). [Figure 8] This shows the gene expression of SLAMF6 in all cell lines in the 22Q4 dataset from the Cancer Cell Line Encyclopedia (classified by cell lineage). [Figure 9A] This shows the expression of SLAMF6 protein on the surface of the colorectal cancer cell line C-99 (black) compared to an isotype-matched control antibody (gray). [Figure 9B] This shows the expression of the SLAMF6 protein on the surface of the colorectal cancer cell line DLD-1 (black) compared to an isotype-matched control antibody (gray). [Figure 9C] This shows the expression of the SLAMF6 protein on the surface of the colorectal cancer cell line HCC-56 (black) compared to an isotype-matched control antibody (gray). [Figure 9D] This shows the expression of the SLAMF6 protein on the surface of the colorectal cancer cell line LS-513 (black) compared to an isotype-matched control antibody (gray). [Figure 10] This image shows the protein expression of SLAMF6 on tumor cells in a primary sample of colorectal cancer. The arrows indicate regions where SLAMF6 protein expression is prominent. [Figure 11] This shows the protein expression of SLAMF6 on the surface of pancreatic cancer cell line MAPAC-HS-77 (black) compared to isotype-matched control antibody (gray). [Figure 12]This image shows the protein expression of SLAMF6 on tumor cells in a primary sample of pancreatic cancer. The arrows indicate regions where SLAMF6 protein expression is prominent. [Examples]

[0304] Example 1 - The antibody shows specific binding to SLAMF6. method SLAMF6 antibodies were generated by mouse immunization using the SLAMF6 extracellular domain (Innovagen AB, Lund, Sweden) (GenScript Biotech Corporation, Piscataway, New Jersey, USA) or by phage display scFv library screening using biotinylated SLAMF6 (Acro Biosystems #NTA-H82E6, Innovagen AB, Lund, Sweden) (SciLifeLab DDD Platform, Solna, Sweden). SLAMF6 knockout cells were generated using the Alt-R CRISPR-Cas9 system (Integrated DNA Technologies, Coralville, Iowa, USA), and Cas9 protein, fluorescent dye-conjugated tracrRNA, and SLAMF6-specific crRNA were electroporated into SLAMF6-positive human AML cell line KG-1 (DSMZ, Braunschweig, Germany). Subsequently, fluorescence-activated cell sorting and proliferation of SLAMF6 knockout cells were performed. SLAMF6 knockout was validated by flow cytometry (BioLegend, San Diego, California, USA, #317208).

[0305] Antibody binding to SLAMF6 was determined by incubating SLAMF6 wild-type and knockout cells with 10 ug / ml of primary antibody, followed by incubation with a secondary anti-human antibody (Invitrogen, Waltham, Massachusetts, USA, #H10120) or anti-mouse antibody (BD Biosciences, Franklin Lakes, New Jersey, USA, #550874), and analysis by flow cytometry (BD LSR Fortessa II). KD values ​​were determined by SPR using a Sierra SPR-16 biosensor (Bruker, Billerica, Massachusetts, USA).

[0306] result Figure 1 shows that antibodies LB-031, LB-032, LB-116, LB-302, and LB-20H10 bind to SLAMF6 on the surface of cancer cells.

[0307] Figure 2 shows that the binding of antibodies LB-031, LB-032, LB-116, LB-302, and LB-20H10 is specific to SLAMF6, because the binding is removed by knockout of SLAMF6 by CRISPR-Cas9.

[0308] Table 2 below shows the KD values ​​determined for the antibodies. [Table 2]

[0309] conclusion Antibodies LB-031, LB-032, LB-116, LB-302, and LB-20H10 specifically bind to the human SLAMF6 protein.

[0310] Example 2 SLAMF6 antibodies induce T cell activation and AML cell killing. method In vitro procedure AML cell line HNT-34 was co-cultured with primary T cells isolated from peripheral blood of a healthy donor (Miltenyi Biotec, Bergisch-Gladbach, Germany, #130-050-101) and either LB-031 or an isotype-matched control antibody (LALA mutant hIgG1). After 72 hours, T cell activation and killing were analyzed by flow cytometry. T cell activation was determined by the surface expression of CD25 (BioLegend #344816, BioLegend #302606), and T cell killing was determined by the number of surviving AML cells using CountBright absolute count beads (Invitrogen #C36950, BioLegend #303416).

[0311] In vivo treatment Animal experiments were conducted using the NOD.Cg-PrkdcscidIl2rgtm1Wjl / SzJ-SGM3(NSG-S) mouse strain, a substrain of NSG mice that overexpresses hGM-CSF, hIL-3, and hSCF (Jackson Laboratory, Bar Harbor, Maine, USA). Mice were irradiated with a near-lethal dose (200 cGy) and 5 × 10⁶ of cells were administered. 6 1 x 10¹ HNT-34 cells were transplanted into the tail vein by injection. At 21 and 28 days later, mice were given 1 x 10¹⁶ HNT-34 cells derived from a healthy donor, isolated by Lymphoprep isolation (Axis-Shield, Dundee, UK). 6Peripheral blood mononuclear cells were transplanted. Antibody treatment was administered intraperitoneally at a dose of 2.0 mg per kg of body weight 1 hour and 72 hours after each PBMC transplant. Fourteen days after treatment, the mice were sacrificed, and isolated bone marrow and splenocytes were stained with 7-AAD (BD Biosciences) and a panel of antibodies: CD3-PE / Cy7 (Biolegend #344816), CD33-BV421 (Biolegend #303416), CD34-AF488 (Biolegend #343518), CD45-APC (BD Biosciences #555485), and SLAMF6-PE (Biolegend #317208). Leukemia engraftment was determined by flow cytometry, and hCD45 was detected in viable cells within each compartment. + CD3 - CD33 + CD34 + SLAMF6 + It was defined as a percentage of cells.

[0312] result Figure 3 shows that LB-116 antibody (Figure 3A) and LB-031 antibody (Figure 3B) induce T cell activation and T cell-mediated killing of cancer cells in vitro.

[0313] Figure 4 shows that LB-116 antibody (Figure 4A) and LB-031 antibody (Figure 4B) induce T cell activation and T cell-mediated killing of cancer cells in vivo.

[0314] conclusion LB-031 and LB-116 antibodies induce T cell activation and T cell-mediated killing of cancer cells both in vitro and in vivo.

[0315] Example 3 - Induction of T cell killing is limited to a subset of SLAMF6 antibodies with specific binding properties. method All generated antibodies whose specific binding to SLAMF6 was verified were tested for induction of T cell-mediated killing at 1 ug / ml in three independent experiments using different T cell donors, as described in Example 2 above. Subsequently, antibodies with a strong effect on T cell killing were tested at multiple concentrations and compared with the previously developed SLAMF6 antibody 20F3 from Seagen (Seagen Inc., Bothell, Washington, USA, WO2017 / 004330).

[0316] I C 50 Values ​​were determined based on three independent experiments using different T cell donors (Prism 9.5.1, GraphPad Software, San Diego, California, USA). Epitope mapping was performed by hydrogen / deuterium exchange mass spectrometry (HDX-MS) using automated sample preparation on a LEAP H / DX PAL® platform (Trajan, Ringwood, Australia) interfaced to an LC-MS system featuring an Ultimate 3000 micro-LC coupled to an Orbitrap Q Exactive Plus MS (ThermoFisher, Waltham, Massachusetts, USA). PEAKS Studio X Bioinformatics Solutions Inc. (BSI, Waterloo, Canada) was used for peptide identification after pepsin digestion of non-deuterated samples. Using peptides identified by PEAKS, with a peptide score of logP > 25, and unmodified, a peptide list was generated including peptide sequence, charge state, and retention time, used for HDX data analysis and visualization with HDExaminer version 3.1.1 (Sierra Analytics Inc., Modest, USA). The observed epitopes were mapped onto the AlphaFold model AF-Q96DU3-F1 (DeepMind, London, UK).

[0317] result Figure 5 shows that only a subset of the generated SLAMF6 antibodies (LB-20H10, LB-116, LB-031, LB-302, and LB-032) induced T cell-mediated killing compared to the control antibody. Surprisingly, T cell-mediated killing was induced only against this subset of the generated anti-SLAMF6 antibodies.

[0318] Figure 6 shows that the generated SLAMF6 antibodies LB-031, LB-032, LB-116, LB-302, and LB-20H10 induce T cell-mediated killing, but the Seagen SLAMF6 antibody 20F3 does not.

[0319] Table 3 shows the ICs for LB-031, LB-032, LB-116, LB-302, and LB-20H10. 50 Show the value. [Table 3]

[0320] Figure 7 and Table 4 show that the tested SLAMF6 antibodies that induce T cell killing (LB-031, LB-116, and LB-20H10) bind to the IgV domain of SLAMF6, while the Seagen SLAMF6 antibody (20F3), which does not induce T cell-mediated killing, binds to the IgC2 domain of SLAMF6. [Table 4]

[0321] conclusion Antibodies that bind to the IgV domain of the SLAMF6 protein induce T cell-mediated killing of cancer cells, while antibodies that bind to the IgC2 domain do not. The generated antibodies LB-031, LB-032, LB-116, LB-302, and LB-20H10 induce T cell-mediated killing, while the existing SLAMF6 antibody 20F3 from Seagen does not.

[0322] Therefore, antibodies LB-031, LB-032, LB-116, LB-302, and LB-20H10 are superior to 20F3 antibodies because they induce T-cell-mediated killing of cancer cells, meaning they have superior therapeutic effects.

[0323] Example 4 - SLAMF6 is abnormally expressed in solid tumors derived from multiple tissues. method SLAMF6 gene expression was analyzed across all cell lines in the publicly available 22Q4 dataset from the Cancer Cell Line Encyclopedia (https: / / depmap.org, downloaded February 28, 2023).

[0324] result Figure 8 shows that SLAMF6 is abnormally expressed in cancer cell lines derived from solid tumors of multiple tissues.

[0325] conclusion SLAMF6 is abnormally expressed in solid tumors of multiple tissue origins and therefore represents a potential target for antibody therapy in patients with solid tumors.

[0326] Example 5 - SLAMF6 is abnormally expressed in colorectal cancer. method SLAMF6 surface protein expression on colorectal cancer cells was detected by flow cytometry (BioLegend #317208) in cell lines C-99 (Merck, Darmstadt, Germany), DLD-1 (ATCC, Manassas, Virginia, USA), HCC-56 (provided by Professor Walter Bodmer's laboratory), and LS-513 (ATCC), which were positive for SLAMF6 gene expression in the 22Q4 dataset. SLAMF6 protein expression on primary colorectal cancer samples was detected by immunohistochemical staining (LSBio, Seattle, Washington, USA, #LS-B15877-50).

[0327] result Figure 9 shows that the SLAMF6 protein is expressed on the surface of colorectal cancer cell lines.

[0328] Figure 10 shows that the SLAMF6 protein is expressed in tumor cells in primary material derived from colorectal cancer cases.

[0329] conclusion The SLAMF6 protein is abnormally expressed on the surface of colorectal cancer cells and therefore represents a potential target for antibody therapy in colorectal cancer patients.

[0330] Example 6 - SLAMF6 is abnormally expressed in pancreatic cancer. method The expression of SLAMF6 surface protein on colorectal cancer cells was detected by flow cytometry (BioLegend #317208) in MAPAC-HS-77 (DSMZ) cell lines that were positive for SLAMF6 gene expression in the 22Q4 dataset. The expression of SLAMF6 protein on primary pancreatic cancer samples was detected by immunohistochemical staining (LSBio #LS-B15877-50).

[0331] result Figure 11 shows that the SLAMF6 protein is expressed on the surface of pancreatic cancer cell lines.

[0332] Figure 12 shows that the SLAMF6 protein is expressed in tumor cells in primary material derived from pancreatic cancer cases.

[0333] conclusion The SLAMF6 protein is abnormally expressed on the surface of pancreatic cancer cells and therefore represents a potential target for antibody therapy in patients with pancreatic cancer. [Table 5-1] [Table 5-2] [Table 5-3] Table 5-4 Table 5-5

Claims

1. An antibody or its antigen-binding fragment that specifically binds to signaling lymphocyte-activating molecule family member 6 (SLAMF6), wherein the antibody or its antigen-binding fragment can induce immune cell-mediated killing of tumor cells.

2. The antibody or antigen-binding fragment according to claim 1, wherein the antibody or antigen-binding fragment can bind to and activate immune cells, optionally the immune cells being T cells, B cells, and / or NK cells, optionally the immune cells being T cells, and activating the T cells enhances T cell-mediated killing.

3. The antibody or antigen-binding fragment according to any of the prior claims, wherein the antibody or antigen-binding fragment can directly bind to tumor cells and mediate direct tumor cell killing.

4. An antibody or antigen-binding fragment according to any of the prior claims, comprising a heavy chain variable region including one or more CDRs of SEQ ID NOs: 7, 1, 3, 5, or 9.

5. The following CD-Rs, CDs, a) an amino acid sequence having at least 60% sequence identity with sequence numbers 65, 66, or 67, or, for example, at least 70%, 80%, or 90% sequence identity, and / or b) an amino acid sequence having at least 60% sequence identity with sequence number 68, 69, or 70, or, for example, at least 70%, 80%, or 90% sequence identity, and / or c) Amino acid sequences having at least 60% sequence identity with sequence numbers 71, 72, or 73, or, for example, at least 70%, 80%, or 90% sequence identity, d) Amino acid sequences having at least 60% sequence identity with sequence numbers 11, 12, or 13, or, for example, at least 70%, 80%, or 90% sequence identity, and / or e) an amino acid sequence having at least 60% sequence identity with sequence number 14, 15, or 16, or, for example, at least 70%, 80%, or 90% sequence identity, and / or f) An amino acid sequence having at least 60% sequence identity with sequence numbers 17, 18, or 19, or, for example, at least 70%, 80%, or 90% sequence identity, or g) an amino acid sequence having at least 60% sequence identity with sequence numbers 29, 30, or 31, or, for example, at least 70%, 80%, or 90% sequence identity, and / or h) Amino acid sequences having at least 60% sequence identity with sequence numbers 32, 33, or 34, or, for example, at least 70%, 80%, or 90% sequence identity, and / or i) an amino acid sequence having at least 60% sequence identity with sequence numbers 35, 36, or 37, or, for example, at least 70%, 80%, or 90% sequence identity, j) Amino acid sequences having at least 60% sequence identity with sequence numbers 47, 48, or 49, or, for example, at least 70%, 80%, or 90% sequence identity, and / or k) an amino acid sequence having at least 60% sequence identity with sequence numbers 50, 51, or 52, or, for example, at least 70%, 80%, or 90% sequence identity, and / or l) An amino acid sequence having at least 60% sequence identity with sequence numbers 53, 54, or 55, or, for example, at least 70%, 80%, or 90% sequence identity, or m) Amino acid sequences having at least 60% sequence identity with sequence numbers 83, 84, or 85, or, for example, at least 70%, 80%, or 90% sequence identity, and / or n) Amino acid sequences having at least 60% sequence identity with sequence numbers 86, 87, or 88, or, for example, at least 70%, 80%, or 90% sequence identity, and / or o) Amino acid sequences having at least 60% sequence identity with sequence numbers 89, 90, or 91, for example, at least 70%, 80%, or 90% sequence identity. An antibody or antigen-binding fragment according to any of the prior claims, comprising a heavy chain variable region including a heavy chain variable region.

6. The following sequence numbers, i.e., a) Sequence IDs 65, 68, and 71, b) Sequence IDs 66, 69, and 72, c) Sequence IDs 67, 70, and 73, d) Sequence IDs 11, 14, and 17, e) Sequence IDs 12, 15, and 18, f) Sequence IDs 13, 16, and 19, g) Sequence IDs 29, 32, and 35, h) Sequence IDs 30, 33, and 36, i) Sequence IDs 31, 34, and 37, j) Sequence IDs 47, 50, and 53, k) Sequence IDs 48, 51, and 54, l) Sequence IDs 49, 52, and 55, m) Sequence IDs 83, 86, and 89, n) Sequence IDs 84, 87, and 90, or o) Sequence IDs 85, 88, and 91 An antibody or antigen-binding fragment according to any of the prior claims, comprising a heavy chain variable region including a CDR.

7. An antibody or antigen-binding fragment according to any of the prior claims, comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7, 1, 3, 5, or 9, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity thereto.

8. An antibody or antigen-binding fragment according to any of the prior claims, comprising a light chain variable region including one or more CDRs of SEQ ID NOs: 8, 2, 4, 6, or 10.

9. The following CD-Rs, CDs, a) an amino acid sequence having at least 60% sequence identity with sequence numbers 74, 75, or 76, or, for example, at least 70%, 80%, or 90% sequence identity, and / or b) Amino acid sequences having at least 60% sequence identity with sequence numbers 77, 78, or 79, or, for example, at least 70%, 80%, or 90% sequence identity, and / or c) An amino acid sequence having at least 60% sequence identity with sequence numbers 80, 81, or 82, or, for example, at least 70%, 80%, or 90% sequence identity, or d) Amino acid sequences having at least 60% sequence identity with sequence numbers 20, 21, or 22, or, for example, at least 70%, 80%, or 90% sequence identity, and / or e) an amino acid sequence having at least 60% sequence identity with sequence numbers 23, 24, or 25, or, for example, at least 70%, 80%, or 90% sequence identity, and / or f) An amino acid sequence having at least 60% sequence identity with sequence numbers 26, 27, or 28, or, for example, at least 70%, 80%, or 90% sequence identity, or g) an amino acid sequence having at least 60% sequence identity with sequence number 38, 39, or 40, or, for example, at least 70%, 80%, or 90% sequence identity, and / or h) Amino acid sequences having at least 60% sequence identity with sequence numbers 41, 42, or 43, or, for example, at least 70%, 80%, or 90% sequence identity, and / or i) an amino acid sequence having at least 60% sequence identity with sequence numbers 44, 45, or 46, or, for example, at least 70%, 80%, or 90% sequence identity, j) Amino acid sequences having at least 60% sequence identity with sequence numbers 56, 57, or 58, or, for example, at least 70%, 80%, or 90% sequence identity, and / or k) Amino acid sequences having at least 60% sequence identity with sequence numbers 59, 60, or 61, or, for example, at least 70%, 80%, or 90% sequence identity, and / or l) An amino acid sequence having at least 60% sequence identity with sequence numbers 62, 63, or 64, or, for example, at least 70%, 80%, or 90% sequence identity, or m) Amino acid sequences having at least 60% sequence identity with sequence numbers 92, 93, or 94, or, for example, at least 70%, 80%, or 90% sequence identity, and / or n) Amino acid sequences having at least 60% sequence identity with sequence numbers 95, 96, or 97, or, for example, at least 70%, 80%, or 90% sequence identity, and / or o) Amino acid sequences having sequence numbers 98, 99, or 100, or at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity. An antibody or antigen-binding fragment according to any of the prior claims, comprising a light chain variable region including the above.

10. The following sequence numbers, i.e., a) Sequence IDs 74, 77, and 80, b) Sequence IDs 75, 78, and 81, c) Sequence IDs 76, 79, and 82, d) Sequence IDs 20, 23, and 26, e) Sequence IDs 21, 24, and 27, f) Sequence IDs 22, 25, and 28, g) Sequence IDs 38, 41, and 44, h) Sequence IDs 39, 42, and 45, i) Sequence IDs 40, 43, and 46, j) Sequence IDs 56, 59, and 62, k) Sequence IDs 57, 60, and 63, l) Sequence IDs 58, 61, and 64, m) Sequence IDs 92, 95, and 98, n) Sequence IDs 93, 96, and 99, or o) Sequence IDs 94, 97, and 100 An antibody or antigen-binding fragment according to any of the prior claims, comprising a light chain variable region including a CDR.

11. An antibody or antigen-binding fragment according to any of the prior claims, comprising a light chain variable region having the amino acid sequence of SEQ ID NO: 8, 2, 4, 6, or 10, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity thereto.

12. The following CD-Rs, CDs, a) SEQ ID NOs. 65, 68, 71, 74, 77, and 80, or SEQ ID NOs. 66, 69, 72, 75, 78, and 81, or SEQ ID NOs. 67, 70, 73, 76, 79, and 82, or an amino acid sequence having at least 60% sequence identity with them, for example, at least 70%, 80%, or 90% sequence identity, or b) Amino acid sequences having at least 60% sequence identity with sequence numbers 11, 14, 17, 20, 23, and 26, or sequence numbers 12, 15, 18, 21, 24, and 27, or sequence numbers 13, 16, 19, 22, 25, and 28, for example, at least 70%, 80%, or 90% sequence identity. c) Amino acid sequences having at least 60% sequence identity with sequence numbers 29, 32, 35, 38, 41, and 44, or sequence numbers 30, 33, 36, 39, 42, and 45, or sequence numbers 31, 34, 37, 40, 43, and 46, for example, at least 70%, 80%, or 90% sequence identity. d) Amino acid sequences having at least 60% sequence identity with sequence numbers 47, 50, 53, 56, 59, and 62, or sequence numbers 48, 51, 54, 57, 60, and 63, or sequence numbers 49, 52, 55, 58, 61, and 64, for example, at least 70%, 80%, or 90% sequence identity. e) Amino acid sequences having at least 60% sequence identity with sequence numbers 83, 86, 89, 92, 95, and 98, or sequence numbers 84, 87, 90, 93, 96, and 99, or sequence numbers 85, 88, 91, 94, 97, and 100, or at least 60% sequence identity with them, for example, at least 70%, 80%, or 90% sequence identity. An antibody or antigen-binding fragment thereof as described in any of the prior claims.

13. a) A heavy chain variable region having the amino acid sequence of SEQ ID NO: 7, and a light chain variable region having the amino acid sequence of SEQ ID NO: 8, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity, or b) A heavy chain variable region having the amino acid sequence of SEQ ID NO: 1, and a light chain variable region having the amino acid sequence of SEQ ID NO: 2, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity. c) A heavy chain variable region having the amino acid sequence of SEQ ID NO: 3, and a light chain variable region having the amino acid sequence of SEQ ID NO: 4, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity. d) A heavy chain variable region having the amino acid sequence of SEQ ID NO: 5, and a light chain variable region having the amino acid sequence of SEQ ID NO: 6, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity. e) A heavy chain variable region having the amino acid sequence of SEQ ID NO: 9, and a light chain variable region having the amino acid sequence of SEQ ID NO: 10, or an amino acid sequence having at least 60% sequence identity thereto, for example, at least 70%, 80%, or 90% sequence identity. An antibody or antigen-binding fragment thereof as described in any of the prior claims.

14. The antigen-binding fragment is selected from scFv, Fv, Fab, F(ab')2, Fab-SH, dsFv, sdAb, di-scFvs, and Fcabs, and is an antibody or antigen-binding fragment according to any of the prior claims.

15. An antibody or antigen-binding fragment thereof according to any of the prior claims, comprising a heavy chain constant region or a portion thereof.

16. The antibody or antigen-binding fragment according to any of the prior claims, wherein the heavy chain constant region is an immunoglobulin subtype selected from the group consisting of IgG1, IgG2, IgG3, and IgG4.

17. An antibody or antigen-binding fragment thereof according to any of the prior claims, comprising a light chain constant region or a portion thereof.

18. The antibody or antigen-binding fragment according to claim 17, wherein the constant light chain region is a kappa light chain or a lambda light chain.

19. An antibody or antigen-binding fragment according to any of the prior claims, further comprising a portion for increasing the in vivo half-life of the drug or a cytotoxic portion.

20. The antibody or antigen-binding fragment thereof can induce tumor-specific immunity, as described in any of the prior claims.

21. An isolated nucleic acid molecule encoding an antibody or an antigen-binding fragment thereof, or a constituent polypeptide chain thereof, as described in any one of the prior claims.

22. A vector comprising the nucleic acid molecule described in claim 21, wherein the vector is optionally an expression vector.

23. A host cell comprising the nucleic acid molecule described in claim 21 or the vector described in claim 22, wherein the host cell is optionally a bacterial cell, a mammalian cell, or a human cell.

24. A pharmaceutical composition comprising an effective amount of an antibody or an antigen-binding fragment thereof as defined in any one of the prior claims, and a pharmaceutically acceptable buffer, diluent, carrier, or excipient, which is optionally adapted for parenteral or intravenous delivery.

25. A kit comprising an antibody or antigen-binding fragment thereof as described in any one of the prior claims, or a pharmaceutical composition as defined in claim 24.

26. An antibody or antigen-binding fragment thereof, as described in any of the prior claims, for use in medicine.

27. The antibody or antigen-binding fragment according to claim 26, wherein the antibody or antigen-binding fragment is for use in the treatment of cancer in an individual.

28. The antibody or antigen-binding fragment for use according to claim 27, wherein the cancer is a solid tumor, and optionally, the solid tumor is selected from sarcoma, lymphoma, blastoma, melanoma, carcinoma, lung cancer, pancreatic cancer, breast cancer, gastrointestinal cancer, head and neck cancer, brain cancer, liver cancer, ovarian cancer, prostate cancer, and cervical cancer.

29. The cancer is a myeloid malignant tumor and / or neoplasm, or a lymphoid malignant tumor and / or neoplasm, which is optionally selected from myelodysplastic syndrome and / or myelodysplastic neoplasm (MDS), myeloproliferative neoplasm (MPN), mastocytosis, myelodysplastic neoplasm / myeloproliferative neoplasm, myeloma, and lymphoma, and optionally, the myeloid malignant tumor and / or neoplasm is acute myeloid leukemia (AML), an antibody or antigen-binding fragment for use according to claim 27.

30. (a) In the preparation of pharmaceuticals for inducing cell death and / or inhibiting the growth and / or proliferation of tumor cells, (b) In the preparation of diagnostic agents for detecting tumor-related cells expressing SLAMF6, (c) For detecting tumor-related cells expressing SLAMF6, Use of an antibody or an antigen-binding fragment thereof as defined in any one of claims 1 to 20.

31. A method for inducing cell death and / or inhibiting the growth and / or proliferation of tumor-related cells in order to treat or prevent a tumor in an individual, comprising the step of administering to the individual an effective amount of an agent as defined in any one of claims 1 to 20, or a pharmaceutical composition as defined in claim 24.

32. A method for detecting tumor-related cells in an individual, comprising the step of administering to the individual an effective amount of a drug as defined in any one of claims 1 to 20, or a pharmaceutical composition as defined in claim 24, wherein the cells express SLAMF6.

33. Use or method according to claim 30, or according to claims 31 to 32, wherein the tumor is cancerous, and optionally, the tumor is a solid tumor or a liquid tumor.

34. Use according to claim 33, wherein the solid tumor is selected from sarcoma, lymphoma, blastoma, melanoma, carcinoma, lung cancer, pancreatic cancer, breast cancer, gastrointestinal cancer, colorectal cancer, head and neck cancer, brain cancer, liver cancer, ovarian cancer, prostate cancer, and cervical cancer, or the liquid tumor is a myeloid malignant neoplasm or lymphoid malignant neoplasm, optionally selected from myelodysplastic syndrome and / or myelodysplastic neoplasm (MDS), myeloproliferative neoplasm (MPN), mastocytosis, and myelodysplastic neoplasm / myeloproliferative neoplasm, myeloma, and lymphoma, optionally, the myeloid malignant neoplasm and / or neoplasm is acute myeloid leukemia (AML).

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