ANTI DIFFERENTIATION GROUP 137 (CD137) ANTIGENCY BINDING MOLECULE AND ITS USE

Abstract

The present invention relates to anti-CD137 antigen-binding molecules that have an immune cell-activating effect, cytotoxic activity, or antitumor activity, while simultaneously having a reduced effect on non-tumor tissues, such as normal tissues, and producing fewer side effects, and methods for using the same. Anti-CD137 antigen-binding molecules that have an immune cell-activating effect, cytotoxic activity, or antitumor activity, while simultaneously having a reduced effect on non-tumor tissues, such as normal tissues, and producing fewer side effects, are provided by the discovery and production of CD137 antigen-binding molecules whose CD137-binding activity depends on various substances (e.g., small-molecule compounds) in tissues of interest. Methods for using the same, pharmaceutical formulations, and the like are also provided.An antigen-binding molecule is also provided, whose antigen-binding activity varies depending on the small molecule compound, the method of preparation, and its uses.

Description

MOLECULE BINDING THE ΑΝΤΙ GROUP OF DIFFERENTIATION 137 (CD137) ANTIGEN AND ITS USE Field of Invention The present disclosure relates to anti-CD137 antigen binding molecules and methods of using the same. Background of the Invention Cancer is a fatal disease that is difficult to cure completely except for a few cases. The result of treatment with chemotherapeutic agents, which is the most important therapeutic method, is not good. It has been suggested that not only the heterogeneity of the cancer cells themselves but also the tumor microenvironment plays a significant role as a factor that makes cancer treatment difficult (NPL 1). Recently, an unresectable and similar malignant melanoma was found to be potentially curable with an anti-CTLA-4 antibody, which suppresses the immunosuppressive function of CTLA-4 and thereby promotes T-cell activation (NPL 2 ). In 2011, a human anti-CTLA-4 monoclonal antibody (ipilimumab) was approved by the US Food and Drug Administration (EDA) as the first immunoactivating antibody drug worldwide. world. In addition, other PD-1 and PD-L1 inhibitory antibodies have also been described, other Ref. 314534 immunological checkpoint molecules in addition to CTLA4, with therapeutic effects (NPL 3), and which were approved by the PDA. It will be understood that T cells, which play important roles in tumor immunity, are activated by two signals: 1) binding of a T cell receptor (TCR) to an antigenic peptide presented by major histocompatibility complex (MHC) molecules from class I and TCR activation; and 2) binding of a costimulatory molecule present on the surface of T cells to its ligands on antigen-presenting cells and activation of the costimulatory molecule. In addition, activation of costimulatory molecules belonging to the tumor necrosis factor receptor superfamily (TNFRSF), including CD137 (4-1BB), on the T cell surface has been reported to be important for T cell activation. (NLP 4) . TNFRSF includes CD137, CD40, 0X40, RANK, GITR, and the like. It has been reported that CD137 is not only expressed on the surface of T cells but also on the surface of other immune cells such as dendritic cells (DC), B cells, NK cells, macrophages and neutrophils (NPL 5 ). An agonist antibody to CD137 has already been shown to have antitumor effects in a mouse model, and Lnn / Lznz / Ε / ΥΙΛΙ Lnn / Lznz / Ε / ΥΙΛΙ has been shown to be primarily the result of activation of CD8-positive T cells and NK cells in experiments with the mouse model (NPL 6). However, side effects due to non-specific hepatotoxicity of CD137 agonist antibody have become clinical and non-clinical problems, thus preventing the desired advancement of drug development (NPL 7, NPL 8). It is suggested that the side effects are caused primarily by activation of immune cells in non-tumor, non-immunological tissues, such as the liver, which involves binding of the antibody to the Fcy receptor through the constant region of the antibody (NPL 9). On the other hand, it has been reported that for agonist antibodies to members of the TNF receptor superfamily to have agonist activity in vivo, the antibody must cross-link with Fcy receptor-expressing cells (FcyRII-expressing cells) (NPL 10). . That is, the binding of the CD137 agonist antibody to the Fcy receptor is involved in the efficacy of the drug in the antitumor effect of the antibody and in its side effects, such as hepatotoxicity. Therefore, an increase in the binding between the antibody and the Fcy receptor is expected to improve the efficacy of the drug but may also increase the hepatotoxic side effects and the reduction of the binding between the antibody and the Fcy receptor may reduce the effects. secondary Lnn / Lznz / Ε / ΥΙΛΙ but can also reduce the effectiveness of the drug. A CD137 agonist antibody whose drug efficacy and side effects are separated has not been reported so far. Furthermore, the antitumor effect of the CD137 agonist antibody itself is not clinically potent at all, and it is sought to improve the efficacy of the drug while avoiding toxicity. Therefore, it is desired to develop a new drug that can induce antitumor immune responses while reducing such side effects. When a therapeutic antibody is administered to a living organism, it is desirable to express its target antigen specifically only at the site of injury. However, in many cases, the same antigen is also expressed at sites other than the lesion, ie in normal tissues, and this could be the cause of unwanted side effects from a treatment point of view. For example, although antibodies against tumor antigens may have cytotoxic activity for tumor cells by ADCC etc., they could also cause damage to normal cells if the same antigen is expressed on such normal cells. In order to solve the problems mentioned above, attention was focused on the phenomenon whereby certain compounds are abundantly present in target tissues (for example, tumor tissues), and a technology was developed to search for antigen-binding molecules. with variable antigen binding activity depending on the concentration of such compounds (eg PTL 1). Appointment List patent literature PTL 1 - WO2013 / 180200 Non-patent literature NPL 1 - Hanahan, Cell, 2011, 144, 646-74 NPL 2 - Prieto, Clin Cancer Res. 2012, 18, 2039-47 NPL 3 - Hamid, Expert Opinion. Biol. Ther., 2013, 6, 847-61 NPL 4-Summers, Nat Rev Immunol, 2012, 12, 339-51 NPL 5 - Vinay, Cellular & Molecular Immunology, 2011, 8, 281-284 NPL 6 - Hoot, Blood, 2009, 114, 3431-8 NPL 7 - Ascierto, Semin Oncol, 2010, 37, 508-16 NPL 8 - Dubrot, Cancer Immunol Immunother, 2010, 59, 1223-33 NPL 9-Schabowsky, Vaccine, 2009, 28, 512-22 NPL 10-Li, Proc Nati Acad Sci USA. 2013, 110(48), 19501-6 Brief Description of the Invention technical problem The present description is molecules of Lnn / Lznz / Ε / ΥΙΛΙ binding to anti-CD137 antigen and methods of using the same. Solution to the problem In order to provide anti-CD137 antigen binding molecules that have immunocyte activating effect, cytotoxic activity or antitumor activity and at the same time a reduced effect on non-tumor tissues, such as normal tissues, and fewer side effects, and provide For methods of using the same, the present disclosure provides anti-CD137 antigen binding molecules characterized in that their CD137-binding activity varies depending on various compounds (eg, small molecule compounds) in target tissues (eg, tumor tissues) and provides methods of using the same, pharmaceutical formulations and the like. In one embodiment, the anti-CD137 antigen-binding molecules of the present disclosure have few side effects, and therefore the dosage can be increased without concern for side effects and, as a result, may exhibit more effective drug efficacy. strong (cytotoxic activity or antitumor activity). Specifically, the present disclosure provides anti-CD137 antigen binding molecules, methods of using the same, pharmaceutical formulations, and the like, as described below by way of example. Lnn / Lznz / Ε / ΥΙΛΙ [1] An anti-CD137 antigen binding molecule that exhibits small molecule compound-dependent CD137 binding activity. [2] The anti-CD137 antigen binding molecule of [1], wherein the CD137 binding activity in the presence of 10 μΜ, 50 μΜ, 100 μΜ, 150 μΜ, 200 μΜ or 250 μΜ of the molecule compound small is twice as high or more than the CD137 binding activity in the absence of the small molecule compound. [2.1] The anti-CD137 antigen binding molecule of [1] or [2], wherein the binding activity to CD137 in the presence of 10 μΜ or more of the small molecule compound is two times higher or more than CD137 binding activity in the absence of the small molecule compound. [2.2] The anti-CD137 antigen binding molecule of any of [1] to [2.1], wherein the KD value for CD137 in the presence of 10 μΜ or more of the small molecule compound is 5 x 10~ 7M or less. [2.3] The anti-CD137 antigen binding molecule of any of [1] to [2.2], wherein the KD value for CD137 in the absence of the small molecule compound is 1x10 -6M or more. [2.4] The anti-CD137 antigen binding molecule of [1], where the KD value for CD137 in a solution that is prepared such that the concentration of the Lnn / Lznz / Ε / ΥΙΛΙ small molecule compound is 10 μΜ or more is 5 x 10~7M or less, and the KD value for CD137 in a solution to which the small molecule compound is not added is 1 x 10-6M or more. [2.5] The anti-CD137 antigen binding molecule of [1], wherein the KD value for CD137 in a solution that is prepared such that the concentration of the small molecule compound is 10 μΜ or more, and the KD value for CD137 in a solution to which the small molecule compound is not added, are each measured by Biacore assay within 24 hours after contact of CD137 and anti-CD137 antigen binding molecule in the solution. [2.6] The anti-CD137 antigen binding molecule of any of [1] to [2.5], which forms a trimolecular complex with the small molecule compound and CD137. [2.7] The anti-CD137 antigen binding molecule of any of [1] to [2.6], which binds human and monkey-derived CD137. [2.8] The anti-CD137 antigen binding molecule of any of [1] to [2.7], wherein the small molecule compound is an adenosine-containing compound. [2.9] The anti-CD137 antigen binding molecule of any of [1] to [2.8], wherein the small molecule compound is ATP. Lnn / Lznz / Ε / ΥΙΛΙ [3] The anti-CD137 antigen binding molecule of any of [1] to [2.9], comprising any combination of HVR-H1, HVR-H2, and HVR-H3 selected from (a) to (k) as follows: (a) An HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8 and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (b) An HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 9 and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (c) An HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 10 and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) An HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 11 and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (e) An HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8 and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (f) An HVR-H1 comprising the sequence of Lnn / Lznz / Ε / ΥΙΛΙ amino acids of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 12 and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (g) An HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 13 and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (h) An HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 14 and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19; (i) An HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15 and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (j) An HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 16 and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; and (k) An HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 14 and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17. [3.1] The anti-CD137 antigen binding molecule of any of [1] to [ 3 ] , which includes any Lnn / Lznz / Ε / ΥΙΛΙ combination of HVR-L1, HVR-L2 and HVR-L3 which are selected from (a) to (g) as follows: (a) An HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27; (b) An HVR-L1 comprising the amino acid sequence of SEQ ID NO: 22, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27; (c) An HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28; (d) An HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 29; (e) An HVR-L1 comprising the amino acid sequence of SEQ ID NO: 23, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27; (f) An HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26 and an HVR-L3 comprising Lnn / Lznz / Ε / ΥΙΛΙ comprises the amino acid sequence of SEQ ID NO: 27; and (g) An HVR-L1 comprising the amino acid sequence of SEQ ID NO: 25, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27. [4] An anti-CD137 antigen binding molecule comprising any combination of HVR-H1, HVR-H2, HVRH3, HVR-L1, HVR-L2 and HVR-L3 which is selected from (a) to (m) as go on: (a) An HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8, an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17, an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27; (b) An HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 9, an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17, an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 22, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27; Lnn / Lznz / Ε / ΥΙΛΙ (c) An HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 10, an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17, an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 22, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27; (d) An HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 11, an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18, an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27; (e) An HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8, an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18, an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27; (f) An HVR-H1 comprising the sequence of Lnn / Lznz / Ε / ΥΙΛΙ amino acids of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 12, an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18, an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28; (g) An HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 13, an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18, an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 29; (h) An HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 14, an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19, an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 23, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27; (i) An HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the Lnn / Lznz / Ε / ΥΙΛΙ amino acid sequence of SEQ ID NO: 15, an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20, an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27; (j) An HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15, an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20, an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 25, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27; (k) An HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 16, an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20, an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 25, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27; (1) An HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 14, an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19, an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27; and (m) An HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 14, an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17, an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27. [5] An anti-CD137 antigen binding molecule comprising: (a) a VH having at least 95% sequence identity to any of the amino acid sequences of SEQ ID NO: 43 to 53; or (b) a VL that has at least 95% sequence identity to any of the amino acid sequences of SEQ ID NO: 54 to 60. [5.1] An anti-CD137 antigen binding molecule, comprising any combination of VH and VL that is selected Lnn / Lznz / Ε / ΥΙΛΙ Lnn / Lznz / Ε / ΥΙΛΙ between (a) to (m) as follows: (a) a VH that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 43 and a VL that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: :54; (b) a VH that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 44 and a VL that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: :55; (c) a VH that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 45 and a VL that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: :55; (d) a VH that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 46 and a VL that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: :54; (e) a VH that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 47 and a VL that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: :54; (f) a VH that has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 48 and a VL that has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: :56; Lnn / Lznz / Ε / ΥΙΛΙ (g) a VH having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 49 and a VL having at least 95% sequence identity to the sequence of amino acids of SEQ ID NO: 57; (h) a VH that has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 50 and a VL that has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: :58; (i) a VH that has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 51 and a VL that has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: :59; (j) a VH that has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 51 and a VL that has at least 95% sequence identity with the amino acid sequence of SEQ ID NO: :60; (k) a VH that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 52 and a VL that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: :60; (1) a VH that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 50 and a VL that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: :59; and (m) a VH that has at least 95% identity of Lnn / ίΖΠΖ / Β / ΥΙΛΙ sequence with the amino acid sequence of SEQ ID NO: 53 and a VL having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 54. [5.2] An anti-CD137 antigen binding molecule, comprising any combination of VH and VL selected from (a) to (m) as follows: (a) a VH comprising the amino acid sequence of SEQ ID NO: 43 and a VL comprising the amino acid sequence of SEQ ID NO: 54; (b) a VH comprising the amino acid sequence of SEQ ID NO: 44 and a VL comprising the amino acid sequence of SEQ ID NO: 55; (c) a VH comprising the amino acid sequence of SEQ ID NO: 45 and a VL comprising the amino acid sequence of SEQ ID NO: 55; (d) a VH comprising the amino acid sequence of SEQ ID NO: 4-6 and a VL comprising the amino acid sequence of SEQ ID NO: 54; (e) a VH comprising the amino acid sequence of SEQ ID NO: 47 and a VL comprising the amino acid sequence of SEQ ID NO: 54; (f) a VH comprising the amino acid sequence of SEQ ID NO: 4-8 and a VL comprising the amino acid sequence of SEQ ID NO: 56; Lnn / ίΖΠΖ / Β / ΥΙΛΙ (g) a VH comprising the amino acid sequence of SEQ ID NO: 4 9 and a VL comprising the amino acid sequence of SEQ ID NO: 57; (h) a VH comprising the amino acid sequence of SEQ ID NO: 50 and a VL comprising the amino acid sequence of SEQ ID NO: 58; (i) a VH comprising the amino acid sequence of SEQ ID NO: 51 and a VL comprising the amino acid sequence of SEQ ID NO: 59; (j) a VH comprising the amino acid sequence of SEQ ID NO: 51 and a VL comprising the amino acid sequence of SEQ ID NO: 60; (k) a VH comprising the amino acid sequence of SEQ ID NO: 52 and a VL comprising the amino acid sequence of SEQ ID NO: 60; (1) a VH comprising the amino acid sequence of SEQ ID NO: 50 and a VL comprising the amino acid sequence of SEQ ID NO: 59; and (m) a VH comprising the amino acid sequence of SEQ ID NO: 53 and a VL comprising the amino acid sequence of SEQ ID NO: 54. [5.3] An anti-CD137 antigen binding molecule whose value of [binding activity (amount of binding) to CD137 in the presence of 10 μΜ or more of a small molecule compound] / [binding activity (amount of binding) ) to CD137 in Lnn / ίΖΠΖ / Β / ΥΙΛΙ the absence of the small molecule compound] is equal to or greater than the value of a reference antigen binding molecule, wherein the reference antigen binding molecule is an anti antigen binding molecule. -CD137 comprising a combination of an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8, an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17, an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26 and an HVR- L3 comprising the amino acid sequence of SEQ ID NO: 27. [5.4] The anti-CD137 antigen binding molecule of [5.3], wherein the reference antigen binding molecule is an anti-CD137 antigen binding molecule comprising a combination of a VH comprising the amino acid sequence of SEQ ID NO: 43 and a VL comprising the amino acid sequence of SEQ ID NO: 54. [5.5] An anti-CD137 antigen-binding molecule whose value of [binding activity (KD) to CD137 in the presence of 1 μΜ of a small molecule compound] / [binding activity (KD) to CD137 in the presence of of 10 μΜ or more of the small molecule compound is equal to or greater than the value of a reference antigen-binding molecule, Lnn / Lznz / Ε / ΥΙΛΙ wherein the reference antigen binding molecule is an anti-CD137 antigen binding molecule comprising a combination of an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8, an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17, an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27. [5.6] The anti-CD137 antigen binding molecule of [5,5], wherein the reference antigen binding molecule is an anti-CD137 antigen binding molecule comprising a combination of a VH comprising the sequence of amino acids of SEQ ID NO: 43 and a VL comprising the amino acid sequence of SEQ ID NO: 54. [5.7] An anti-CD137 antigen binding molecule exhibiting small molecule compound dependent CD137 binding activity, wherein the anti-CD137 antigen binding molecule competes with the antigen binding molecule of either [ 3] to [5.2] by binding to CD137 in the presence of 10 μΜ or more, 50 μΜ or more, 100 μΜ or more, 150 μΜ or more, 200 μΜ or more or 250 μΜ or more of the small molecule compound. [5.8] An anti-CD137 antigen-binding molecule Lnn / ίΖΠΖ / Β / ΥΙΛΙ exhibiting small molecule compound-dependent CD137-binding activity, wherein the anti-CD137 antigen-binding molecule binds to the same epitope on CD137 that the anti-CD137 antigen-binding molecule binds to of any of [3] to [5.2] in the presence of 10 μΜ or more, 50 μΜ or more, 100 μΜ or more, 150 μΜ or more, 200 μΜ or more, or 2 50 μΜ or more of the small molecule compound. [5.8Ά] The anti-CD137 antigen binding molecule of any of [5.3] to [5.8], wherein the small molecule compound is an adenosine-containing compound. [5.8B] The anti-CD137 antigen binding molecule of any of [5.3] to [5.8A], wherein the small molecule compound is ATP. [5.9] The anti-CD137 antigen-binding molecule of any of [1] to [5.8B], which is a monoclonal antibody or an antigen-binding fragment thereof. [5.10] The anti-CD137 antigen-binding molecule of any of [1] to [5.9], which is a human antibody, a humanized antibody or a chimeric antibody, or an antigen-binding fragment thereof. [5.11] The anti-CD137 antigen binding molecule of any of [1] to [5.10], which is a full length IgGl antibody. [5.12] The anti-CD137 antigen-binding molecule of any of [1] to [5.11], comprising an altered Fe region in which at least one amino acid is altered, wherein the altered Fe region has increased activity of FcyRIIb binding compared to an altered parental Fc region not comprising the amino acid alteration. [5.13] The anti-CD137 antigen binding molecule of [5.12], where the binding activity of the altered Fe region to FcyRIIb is equal to or greater than that of a reference altered Fe region, where the reference Fe is an altered human IgGl Fe region comprising a combination of amino acid substitutions G236N / H268D / A330K according to EU numbering. [5.14] The anti-CD137 antigen binding molecule of [5.12] or [5.13], wherein the reference altered Fe region comprises the amino acid sequence of SEQ ID NO: 153. [5.15] The anti-CD137 antigen binding molecule of [5.12], wherein such at least one amino acid alteration comprises at least one amino acid substitution which is selected from the group consisting of G236N, H268D and A330K according to the EU numbering. [5.16] The anti-CD137 antigen binding molecule of [5.12] or [5.15], wherein such at least one amino acid alteration is a combination of amino acid substitutions G236N / H268D / A330K according to numbering us. Lnn / ίΖΠΖ / Β / ΥΙΛΙ [5.17] The anti-CD137 antigen binding molecule of any of [5.12] to [5.16], wherein the altered parental Fe region is derived from an altered human IgGl Fe region. [5.18] The anti-CD137 antigen binding molecule of any of [1] to [5.17], comprising an altered Fc region in which at least one amino acid is altered, wherein the anti-CD137 antigen binding molecule it has a higher isoelectric point (pl) compared to that of a parent anti-CD137 antigen binding molecule comprising an altered parent Fc region that does not comprise the amino acid alteration. [5.19] The anti-CD137 antigen binding molecule of [5.18], wherein such at least one amino acid alteration is an alteration of an amino acid residue that may be exposed on the surface of the altered parental Fe region. [5.20] The anti-CD137 antigen binding molecule of [5.18] or [5.19], wherein such at least one amino acid alteration is: (i) a substitution of at least one amino acid residue bearing a negative side chain charge in the altered parent Fe region with an amino acid residue not bearing a side chain charge, (ii) substitution of at least one amino acid residue that does not have a side chain charge in the parent Fe region altered by an amino acid residue that has a positive side chain charge and / or (iii) a substitution of at least one amino acid residue that has a side-chain negative charge in the parent Fe region altered by an amino acid residue bearing a side-chain positive charge. [5.21] The anti-CD137 antigen binding molecule of any of [5.18] to [5.20], wherein such at least one amino acid alteration is a combination of amino acid substitutions, and wherein the amino acid substitutions are located at positions that are conformationally close to each other. [5.22] The anti-CD137 antigen binding molecule of any of [5.18] to [5.21], wherein the binding activity of the altered Fc region to an Fcy receptor (FcyR) is not substantially reduced compared to that from the altered parental Fe region. [5.23] The anti-CD137 antigen binding molecule of [5.22], where the Fcy receptor (FcyR) is FcyRIIb. [5.24] The anti-CD137 antigen binding molecule of any of [5.18] to [5.23], wherein such at least one amino acid alteration comprises at least one amino acid substitution which is selected from the group consisting of Q311R, P343R and D413K according to the EU numbering. Lnn / ίΖΠΖ / Β / ΥΙΛΙ Lnn / ίΖΠΖ / Β / ΥΙΛΙ [5.25] The anti-CD137 antigen binding molecule of any of [5.18] to [5.24], wherein such at least one amino acid alteration is (i) a P343R amino acid substitution, (ii) a combination of the substitutions of amino acid substitutions Q311R / P343R or (iii) a combination of amino acid substitutions Q311R / D413K, according to EU numbering. [6] The anti-CD137 antigen binding molecule of any of [1] to [5.25], comprising an altered Fe region, wherein the altered Fe region comprises any combination of amino acid alterations selected from the following: L235W / G236N / H268D / Q295L / K326T / A330K / P343R / D413K; K214R / L235W / G236N / H268D / Q295L / K326T / A330K / P343R / D41 3K; L234Y / P238D / T250V / V264I / T307P / A330K / P343R / D413K; L234Y / P238D / V264I / A330K / P343R / D413K; L234Y / G237D / P238D / T250V / T307P / A330K / P343R / D413K; L234Y / G237D / P238D / A330K / P343R / D413K; L235W / G236N / H268D / Q295L / K326T / A330K / Q311R / P343R; L234Y / P238D / T250V / V264I / T307P / A330K / Q311R / P343R; L234Y / P238D / V264I / A330K / Q311R / P343R; L234Y / G237D / P238D / T250V / T307P / A330K / Q311R / P343R; L234Y / G237D / P238D / A330K / Q311R / P343R; L235W / G236N / H268D / Q295L / K326T / A330K / P343R; Lnn / ίΖΠΖ / Β / ΥΙΛΙ K214R / L235W / G236N / H268D / Q295L / K326T / A330K / P343R; L235W / G236N / H268D / Q295L / K326T / A330K / D413K; Κ214R / G236Ν / Η268D / A330K / P343R; Κ214R / L235W / G236Ν / Η268D / A330Κ / Ρ343R; Κ214R / G236Ν / Η268D / A330K / D413K; K2 1 4R / G23 6Ν / Η2 68D / A33 0Κ / Ρ34 3R / D4 1 3Κ; Κ214R / L235W / G236Ν / Η268D / A330Κ / Ρ343R / D413Κ; Κ214R / G236Ν / Η268D / A330K / Q311R; K214R / L235W / G236N / H268D / A330K / Q311R; K214R / G236N / H268D / A330K / Q311R / P343R; Κ214R / L235W / G236Ν / Η268D / A330K / Q311R / P343R; Κ214R / G236Ν / Η268D / A330K / Q311R / D413Κ; Κ214R / L235W / G236Ν / Η268D / A330K / Q311R / D413Κ; and Κ214R / L235W / G236Ν / Η268D / Q295L / K326Τ / Α330K / Q311R, according to EU numbering. [6.1] The anti-CD137 antigen binding molecule of any of [1] to [6], wherein the altered Fe region is derived from an altered human IgGl Fe region. [6.2] The anti-CD137 antigen binding molecule of any of [1] to [6.1], wherein the altered Fe region further comprises deletions at positions 446 and 447 according to EU numbering. [7] The anti-CD137 antigen binding molecule of any of [1] to [6.2], comprising a heavy chain constant region comprising any of the Lnn / ίΖΠΖ / Β / ΥΙΛΙ amino acid sequences of SEQ ID NO: 64 to 85. [7. 1] An anti-CD137 antigen binding molecule comprising any combination of VH, VL, CH and CL selected from (i) to (xxxviii) described below: (i) a VH comprising the amino acid sequence of SEQ ID NO: 43, a CH comprising the amino acid sequence of SEQ ID NO: 64, a VL comprising the amino acid sequence of SEQ ID NO: 54 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (ii) a VH comprising the amino acid sequence of SEQ ID NO: 43, a CH comprising the amino acid sequence of SEQ ID NO: 66, a VL comprising the amino acid sequence of SEQ ID NO: 54 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (iii) a VH comprising the amino acid sequence of SEQ ID NO: 43, a CH comprising the amino acid sequence of SEQ ID NO: 67, a VL comprising the amino acid sequence of SEQ ID NO: 54 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (iv) a VH comprising the amino acid sequence of SEQ ID NO: 43, a CH comprising the amino acid sequence of SEQ ID NO: 68, a VL comprising the amino acid sequence of SEQ ID NO: 54 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (v) a VH comprising the amino acid sequence of SEQ ID NO: 43, a CH comprising the amino acid sequence of SEQ ID NO: 69, a VL comprising the amino acid sequence of SEQ ID NO: 54 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (vi) a VH comprising the amino acid sequence of SEQ ID NO: 43, a CH comprising the amino acid sequence of SEQ ID NO: 70, a VL comprising the amino acid sequence of SEQ ID NO: 54 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (vii) a VH comprising the amino acid sequence of SEQ ID NO: 43, a CH comprising the amino acid sequence of SEQ ID NO: 71, a VL comprising the amino acid sequence of SEQ ID NO: 54 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (viii) a VH comprising the amino acid sequence of SEQ ID NO: 43, a CH comprising the amino acid sequence of SEQ ID NO: 73, a VL comprising Lnn / ίΖΠΖ / Β / ΥΙΛΙ Lnn / ίΖΠΖ / Β / ΥΙΛΙ comprises the amino acid sequence of SEQ ID NO: 54 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (ix) a VH comprising the amino acid sequence of SEQ ID NO: 43, a CH comprising the amino acid sequence of SEQ ID NO: 75, a VL comprising the amino acid sequence of SEQ ID NO: 54 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (x) a VH comprising the amino acid sequence of SEQ ID NO: 43, a CH comprising the amino acid sequence of SEQ ID NO: 78, a VL comprising the amino acid sequence of SEQ ID NO: 54 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (xi) a VH comprising the amino acid sequence of SEQ ID NO: 43, a CH comprising the amino acid sequence of SEQ ID NO: 80, a VL comprising the amino acid sequence of SEQ ID NO: 54 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (xii) a VH comprising the amino acid sequence of SEQ ID NO: 43, a CH comprising the amino acid sequence of SEQ ID NO: 82, a VL comprising the amino acid sequence of SEQ ID NO: 54 and Lnn / ίΖΠΖ / Β / ΥΙΛΙ a CL comprising the amino acid sequence of SEQ ID NO: 63; (xiii) a VH comprising the amino acid sequence of SEQ ID NO: 43, a CH comprising the amino acid sequence of SEQ ID NO: 84, a VL comprising the amino acid sequence of SEQ ID NO: 54 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (xiv) a VH comprising the amino acid sequence of SEQ ID NO: 43, a CH comprising the amino acid sequence of SEQ ID NO: 85, a VL comprising the amino acid sequence of SEQ ID NO: 54 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (xv) a VH comprising the amino acid sequence of SEQ ID NO: 51, a CH comprising the amino acid sequence of SEQ ID NO: 65, a VL comprising the amino acid sequence of SEQ ID NO: 59 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (xvi) a VH comprising the amino acid sequence of SEQ ID NO: 51, a CH comprising the amino acid sequence of SEQ ID NO: 72, a VL comprising the amino acid sequence of SEQ ID NO: 59 and a CL comprising the amino acid sequence of SEQ ID Lnn / ίΖΠΖ / Β / ΥΙΛ NOT: 63; (xvii) a VH comprising the amino acid sequence of SEQ ID NO: 51, an OH comprising the amino acid sequence of SEQ ID NO: 74, a VL comprising the amino acid sequence of SEQ ID NO: 59 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (xviii) a VH comprising the amino acid sequence of SEQ ID NO: 51, a CH comprising the amino acid sequence of SEQ ID NO: 75, a VL comprising the amino acid sequence of SEQ ID NO: 59 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (xix) a VH comprising the amino acid sequence of SEQ ID NO: 51, a CH comprising the amino acid sequence of SEQ ID NO: 77, a VL comprising the amino acid sequence of SEQ ID NO: 59 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (xx) a VH comprising the amino acid sequence of SEQ ID NO: 51, a CH comprising the amino acid sequence of SEQ ID NO: 78, a VL comprising the amino acid sequence of SEQ ID NO: 59 and a CL comprising the amino acid sequence of SEQ ID NOT: 63; Lnn / ίΖΠΖ / Β / ΥΙΛΙ (xxi) a VH comprising the amino acid sequence of SEQ ID NO: 51, a CH comprising the amino acid sequence of SEQ ID NO: 7 9, a VL comprising the sequence of amino acids of SEQ ID NO: 59 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (xxii) a VH comprising the amino acid sequence of SEQ ID NO: 51, a CH comprising the amino acid sequence of SEQ ID NO: 80, a VL comprising the amino acid sequence of SEQ ID NO: 59 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (xxiii) a VH comprising the amino acid sequence of SEQ ID NO: 51, a CH comprising the amino acid sequence of SEQ ID NO: 81, a VL comprising the amino acid sequence of SEQ ID NO: 59 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (xxiv) a VH comprising the amino acid sequence of SEQ ID NO: 51, a CH comprising the amino acid sequence of SEQ ID NO: 82, a VL comprising the amino acid sequence of SEQ ID NO: 59 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (xxv) a VH comprising the amino acid sequence of SEQ ID NO: 51, a CH comprising the amino acid sequence of SEQ ID NO: 83, a VL comprising the amino acid sequence of SEQ ID NO: 59 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (xxvi) a VH comprising the amino acid sequence of SEQ ID NO: 51, a CH comprising the amino acid sequence of SEQ ID NO: 84, a VL comprising the amino acid sequence of SEQ ID NO: 59 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (xxvii) a VH comprising the amino acid sequence of SEQ ID NO: 51, a CH comprising the amino acid sequence of SEQ ID NO: 72, a VL comprising the amino acid sequence of SEQ ID NO: 60 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (xxviii) a VH comprising the amino acid sequence of SEQ ID NO: 51, a CH comprising the amino acid sequence of SEQ ID NO: 74, a VL comprising the amino acid sequence of SEQ ID NO: 60 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (xxix) a VH comprising the amino acid sequence of SEQ ID NO: 51, a CH comprising the Lnn / ίΖΠΖ / Β / ΥΙΛΙ amino acid sequence of SEQ ID NO: 75, a VL comprising the amino acid sequence of SEQ ID NO: 60 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (xxx) a VH comprising the amino acid sequence of SEQ ID NO: 51, a CH comprising the amino acid sequence of SEQ ID NO: 77, a VL comprising the amino acid sequence of SEQ ID NO: 60 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (xxxi) a VH comprising the amino acid sequence of SEQ ID NO: 51, a CH comprising the amino acid sequence of SEQ ID NO: 78, a VL comprising the amino acid sequence of SEQ ID NO: 60 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (xxxii) a VH comprising the amino acid sequence of SEQ ID NO: 51, a CH comprising the amino acid sequence of SEQ ID NO: 7 9, a VL comprising the amino acid sequence of SEQ ID NO: 60 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (xxxiii) a VH comprising the amino acid sequence of SEQ ID NO: 51, a CH comprising the amino acid sequence of SEQ ID NO: 80, a VL comprising Lnn / ίΖΠΖ / Β / ΥΙΛΙ comprises the amino acid sequence of SEQ ID NO: 60 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (xxxiv) a VH comprising the amino acid sequence of SEQ ID NO: 51, a CH comprising the amino acid sequence of SEQ ID NO: 81, a VL comprising the amino acid sequence of SEQ ID NO: 60 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (xxxv) a VH comprising the amino acid sequence of SEQ ID NO: 51, a CH comprising the amino acid sequence of SEQ ID NO: 82, a VL comprising the amino acid sequence of SEQ ID NO: 60 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (xxxvi) a VH comprising the amino acid sequence of SEQ ID NO: 51, a CH comprising the amino acid sequence of SEQ ID NO: 83, a VL comprising the amino acid sequence of SEQ ID NO: 60 and a CL comprising the amino acid sequence of SEQ ID NO: 63; (xxxvii) a VH comprising the amino acid sequence of SEQ ID NO: 51, a CH comprising the amino acid sequence of SEQ ID NO: 84, a VL comprising the amino acid sequence of SEQ ID NO: 60 and Lnn / Lznz / Ε / ΥΙΛΙ Lnn / ίΖΠΖ / Β / ΥΙΛΙ a CL comprising the amino acid sequence of SEQ ID NO: 63; and (xxxviii) a VH comprising the amino acid sequence of SEQ ID NO: 51, a CH comprising the amino acid sequence of SEQ ID NO: 85, a VL comprising the amino acid sequence of SEQ ID NO: 60 and a CL comprising the amino acid sequence of SEQ ID NO: 63; [8] An isolated nucleic acid encoding the anti-CD137 antigen binding molecule of any of [1] to [7.1]. [9] A vector comprising the nucleic acid of [8].

[10] A host cell comprising the nucleic acid of [8] or the vector of [9].

[11] A method of producing an anti-CD137 antigen binding molecule, which comprises culturing the host cell of

[10] to thereby produce the anti-CD137 antigen binding molecule.

[12] An immunoconjugate comprising the anti-CD137 antigen binding molecule of any of [1] to [7.1] and a cytotoxic agent.

[13] A pharmaceutical formulation comprising the anti-CD137 antigen binding molecule of any of [1] to [7.1] or the immunoconjugate of

[12] ; and a vehicle Lnn / ίΖΠΖ / Β / ΥΙΛΙ pharmaceutically acceptable.

[14] The anti-CD137 antigen binding molecule of any of [1] to [7.1] or the immunoconjugate of

[12] , which is for use as a medicament. [14.1] The anti-CD137 antigen binding molecule of any of [1] to [7.1], the immunoconjugate of

[12] or the pharmaceutical formulation of

[13] , which is for use in the treatment of a tumor. [14.2] The anti-CD137 antigen binding molecule, immunoconjugate, or pharmaceutical formulation of [14.1], wherein the tumor is a solid tumor infiltrated by a B cell, dendritic cell, natural killer cell, macrophage, and / or a CD8-positive T cell. [14.3] The anti-CD137 antigen binding molecule, immunoconjugate, or pharmaceutical formulation of [14.1], wherein the tumor is a solid tumor infiltrated by a regulatory T cell (Treg).

[15] The anti-CD137 antigen binding molecule of any of [1] to [7.1], the immunoconjugate of

[12] or the pharmaceutical formulation of

[13] , which is for use in the activation of an immune cell . [15.1] The anti-CD137 antigen binding molecule, immunoconjugate or pharmaceutical formulation of

[15] , wherein the immune cell is a B cell, a dendritic cell, a natural killer cell, a macrophage and / or a Lnn / ίΖΠΖ / Β / ΥΙΛ T cell. [15.2] The anti-CD137 antigen binding molecule of any of [1] to [7.1], or the pharmaceutical formulation of

[13] , which is for activating an immune cell in a tumor tissue. [15.3] The anti-CD137 antigen binding molecule or the pharmaceutical formulation of [15.2], wherein the immune cell is a B cell, a dendritic cell, a natural killer cell, a macrophage, and / or a T cell. [15.4] The anti-CD137 antigen binding molecule of any of [1] to [7.1], the immunoconjugate of

[12] , or the pharmaceutical formulation of

[13] , which is for damaging a cell.

[16] The anti-CD137 antigen binding molecule of any of [1] to [7.1], the immunoconjugate of

[12] , or the pharmaceutical formulation of

[13] , whose level of activation of immunity in a tissue does not tumor is less than that of an anti-CD137 antigen binding molecule that does not have CD137 binding activity dependent on a small molecule compound. [16.1] The anti-CD137 antigen binding molecule, immunoconjugate or pharmaceutical formulation of

[16] , wherein the non-tumor tissue is from a lymph node, spleen and / or liver. [16.2] The anti-CD137 antigen-binding molecule Lnn / ίΖΠΖ / Β / ΥΙΛΙ of any of [1] to [7.1] or the immunoconjugate of

[12] , which does not substantially bind to CD137 expressed in a non-tumor tissue. [16.3] The anti-CD137 antigen binding molecule of any of [1] to [7.1] or the immunoconjugate of

[12] , which has a longer blood half-life than an anti-CD137 antigen binding molecule. CD137 not exhibiting small molecule compound dependent CD137 binding activity.

[17] The anti-CD137 antigen-binding molecule of any of [1] to [7.1], the immunoconjugate of

[12] , or the pharmaceutical formulation of

[13] , which has a lower level of side effects than a Anti-CD137 antigen binding molecule that does not exhibit CD137 binding activity dependent on a small molecule compound. [17.1] Anti-CD137 antigen binding molecule, immunoconjugate or pharmaceutical formulation of

[17] , where the side effect is increased AST, increased ALT, fever, nausea, acute hepatitis, liver disease, splenomegaly, enteritis , purulent inflammation of the skin, neutrophil reduction, lymphocyte reduction, platelet reduction, transaminase expression and / or hyperbilirubinemia.

[18] An anti-CD137 antigen binding molecule that has CD137 agonist activity dependent on a small molecule compound. [18.1] The anti-CD137 antigen binding molecule of

[18] , wherein the agonist activity for CD137 in the presence of 10 μΜ, 50 μΜ, 100 μΜ, 150 μΜ, 200 μΜ or 250 μΜ of the small molecule compound it is twice as high or more than the agonist activity for CD137 in the absence of the small molecule compound. [18.2] The anti-CD137 antigen-binding molecule of

[18] or [18.1], wherein the agonist activity for CD137 in the presence of 10 μΜ or more of the small molecule compound is twice or more than the agonist activity for CD137 in the absence of the small molecule compound. [18.3] The anti-CD137 antigen-binding molecule of

[18] or [18.1], wherein the agonist activity for CD137 in the presence of 50 μΜ or more of the small molecule compound is twice or more than the agonist activity for CD137 in the absence of the small molecule compound. [18.4] The anti-CD137 antigen-binding molecule of

[18] or [18.1], wherein the agonist activity for CD137 in the presence of 250 μΜ or more of the small molecule compound is twice or more than the agonist activity for CD137 in the absence of the small molecule compound. [18.5] The anti-CD137 antigen binding molecule of any of

[18] to [18.4], wherein the agonist activity for CD137 is assessed by the amount of IL-2 and / or Lnn / ίΖΠΖ / Β / ΥΙΛΙ Lnn / ίΖΠΖ / Β / ΥΙΛΙ IFN-γ produced by a cell expressing CD137. [18.6] The anti-CD137 antigen binding molecule of [18.5], wherein the cell expressing CD137 is an isolated human peripheral blood mononuclear cell (PBMC) or a PBMC-derived human T cell. [18.7] The anti-CD137 antigen binding molecule of any of

[18] to [18.4], wherein agonist activity for CD137 is assessed by a reporter gene assay. [18.8] The anti-CD137 antigen binding molecule of

[18] , which exhibits agonist activity for CD137 in a solution that is prepared such that the final concentration of a small molecule compound is 50 μΜ or more, and which exhibits substantially no agonist activity for CD137 in a solution to which the small molecule compound is not added. [18.9] The anti-CD137 antigen binding molecule of [18.8], wherein the agonist activity for CD137 in a solution that is prepared such that the final concentration of a small molecule compound is 50 μΜ or more, and the agonist activity for CD137 in a solution to which the small molecule compound is not added are each evaluated with the amount of IL-2, IFN-γ, and / or IL-6 measured within 72 hours after contact of a cell expressing CD137 with the anti-CD137 antigen binding molecule in solution. [18.10] The anti-CD137 antigen binding molecule of [18.8], wherein the agonist activity for CD137 in a solution that is prepared such that the final concentration of a small molecule compound is 50 μΜ or more, and agonist activity for CD137 in a solution to which the small molecule compound is not added are each assessed with a luciferase luminescence signal that is measured within 6 hours after contact of a T cell that expresses an NF-kappaB-luciferase reporter construct and CD137 with the anti-CD137 antigen binding molecule. [18.11] The anti-CD137 antigen binding molecule of any of

[18] to [18.10], wherein the small molecule compound is an adenosine-containing compound. [18.12] The anti-CD137 antigen binding molecule of any of

[18] to [18.11], wherein the small molecule compound is ΆΤΡ.

[19] The anti-CD137 antigen binding molecule of any of [1] to [7.1], having CD137 agonist activity dependent on a small molecule compound. [19.1] The anti-CD137 antigen binding molecule of

[19] , wherein the agonist activity for CD137 in the presence of 10 μΜ, 50 μΜ, 100 μΜ, 150 μΜ, 200 μΜ or 250 μΜ of the small molecule compound is twice or higher than the agonist activity for CD137 in the absence of the compound Lnn / ίΖΠΖ / Β / ΥΙΛΙ Lnn / ίΖΠΖ / Β / ΥΙΛΙ small molecule. [19.2] The anti-CD137 antigen-binding molecule of

[19] or [19.1], wherein the agonist activity for CD137 in the presence of 10 μΜ or more of the small molecule compound is twice or more than the agonist activity for CD137 in the absence of the small molecule compound. [19.3] The anti-CD137 antigen-binding molecule of

[19] or [19.1], wherein the agonist activity for CD137 in the presence of 50 μΜ or more of the small molecule compound is twice or more than the agonist activity for CD137 in the absence of the small molecule compound. [19.4] The anti-CD137 antigen-binding molecule of

[19] or [19.1], wherein the agonist activity for CD137 in the presence of 250 μΜ or more of the small molecule compound is twice or more than the agonist activity for CD137 in the absence of the small molecule compound. [19.5] The anti-CD137 antigen binding molecule of any of

[19] to [19.4], wherein the agonist activity for CD137 is assessed by the amount of IL-2 and / or IFN-γ produced by a cell that expresses CD137. [19.6] The anti-CD137 antigen binding molecule of [19.5], wherein the cell expressing CD137 is an isolated human peripheral blood mononuclear cell (PBMC) or a PBMC-derived human T cell. [19.7] The anti-CD137 antigen binding molecule of any of

[19] to [19.4], wherein agonist activity for CD137 is assessed by a reporter gene assay. [19.8] The anti-CD137 antigen binding molecule of

[19] , which exhibits agonist activity for CD137 in a solution that is prepared such that the final concentration of a small molecule compound is 50 μΜ or more, and which exhibits substantially no agonist activity for CD137 in a solution to which the small molecule compound is not added. [19.9] The anti-CD137 antigen binding molecule of [19.8], wherein the agonist activity for CD137 in a solution that is prepared such that the final concentration of a small molecule compound is 50 μΜ or more, and the agonist activity for CD137 in a solution to which the small molecule compound is not added are each evaluated with the amount of IL-2, IFN-γ, and / or IL-6 measured within 72 hours after contact of a cell expressing CD137 with the anti-CD137 antigen binding molecule in solution. [19.10] The anti-CD137 antigen binding molecule of [19.8], wherein the agonist activity for CD137 in a solution that is prepared such that the final concentration of a small molecule compound is 50 μΜ or more, and agonist activity for CD137 in a solution to which the small molecule compound is not added are each assessed with a luciferase luminescence signal that is measured within 6 hours after contact of a T cell that expresses an NF-kappaB-luciferase reporter construct and CD137 with the anti-CD137 antigen binding molecule. [19.11] The anti-CD137 antigen binding molecule of any of

[19] to [19.10], wherein the small molecule compound is an adenosine-containing compound. [19.12] The anti-CD137 antigen binding molecule of any of

[19] to [19.11], wherein the small molecule compound is ATP.

[20] An agonist antigen binding molecule comprising an altered Fe region, wherein the altered Fe region comprises at least one amino acid alteration leading to a higher isoelectric point (pl) compared to that of an agonist antigen binding molecule. parental agonist antigen comprising an altered parental Fe region, and wherein the agonist antigen binding molecule has increased agonist activity compared to that of the parent agonist antigen binding molecule. [20.1] The antigen-binding molecule of

[20] , wherein such at least one amino acid alteration is an alteration of an amino acid residue that may be exposed on the surface of the altered parental Fe region. Lnn / ίΖΠΖ / Β / ΥΙΛΙ [20.2] The antibody binding to the agonist antigen of

[20] or [20.1], wherein such at least one amino acid alteration is: (i) a substitution of at least one amino acid residue bearing a negative side chain charge in the altered parent Fe region with an amino acid residue not bearing a side chain charge, (ii) substitution of at least one amino acid residue that does not have a side chain charge in the parent Fe region altered by an amino acid residue that has a positive side chain charge and / or (iii) a substitution of at least one amino acid residue that has a side-chain negative charge in the parent Fe region altered by an amino acid residue bearing a side-chain positive charge. [20.3] The agonist antigen binding molecule of any of

[20] to [20.2], wherein such at least one amino acid alteration is a combination of amino acid substitutions, and wherein the amino acid substitutions are located at positions that They are conformationally close to each other. [20.4] The agonist antigen binding molecule of any of

[20] to [20.3], wherein the binding activity of the altered Fc region to an Fcy receptor is not substantially reduced compared to that of the Fcy region. Lnn / ίΖΠΖ / Β / ΥΙΛΙ Altered parental faith. [20.5] The agonist antigen binding molecule of [20.4], wherein the Fcy receptor is FcYRIIb. [20.6] The agonist antigen binding molecule of any of

[20] to [20.4], wherein such at least one amino acid alteration comprises at least one amino acid substitution which is selected from the group consisting of Q311R, P343R and D413K according to EU numbering. [20.7] The agonist antigen binding molecule of any of

[20] to [20.6], wherein such at least one amino acid alteration is an amino acid alteration of (i) P343R / D413K, (ii) Q311R / P343R, (iii) P343R, (iv) D413K, (v) Q311R or (vi) Q311R / D413K or a combination thereof, according to EU numbering. [20.8] The agonist antigen binding molecule of any of

[20] to [20.7], which is an anti-CD137 antigen binding molecule. [20.9] The agonist antigen binding molecule of any of

[20] to [20.8], which is an anti-CD137 antibody.

[21] A method of producing an agonist antigen binding molecule comprising an altered Fc region, wherein such method comprises: introducing into a parent Fe at least one amino acid alteration that leads to a higher isoelectric point (pl) compared to that of a molecule of Lnn / ίΖΠΖ / Β / ΥΙΛΙ binding to the parental agonist antigen comprising the altered parental Fe region, wherein the agonist activity of the binding molecule to the agonist antigen comprising the altered Fe region is increased compared to that of the binding molecule to the parental agonist antigen. [21.1] The method of

[21] , wherein the agonist activity of the agonist antigen-binding molecule for the antigen in the presence of 10 μΜ, 50 μΜ, 100 μΜ, 150 μΜ, 200 μΜ or 250 μΜ of a compound The small molecule compound is twice as high or more than the agonist activity for the antigen in the absence of the small molecule compound. [21.2] The method of

[21] or [21.1], wherein the agonist activity of the agonist antigen-binding molecule for the antigen in the presence of 10 μΜ or more of a small molecule compound is twice as high or more than the agonist activity for the antigen in the absence of the small molecule compound. [21.3] The method of

[21] or [21.1], wherein the agonist activity of the agonist antigen-binding molecule for the antigen in the presence of 50 μΜ or more of a small molecule compound is twice as high or more than the agonist activity for the antigen in the absence of the small molecule compound. [21.4] The method of

[21] or [21.1], where the Lnn / ίΖΠΖ / Β / ΥΙΛΙ agonist activity of the antigen-binding molecule agonist for the antigen in the presence of 250 μΜ or more of a small molecule compound is twice as high or more than the agonist activity for the antigen in the absence of the small molecule compound. [21.5] The method of any of

[21] to [21.4], wherein the agonist activity for the antigen is evaluated with the amount of IL-2 and / or ΙΕΝ-γ produced by a cell expressing the antigen. [21.6] The method of [21.5], wherein the antigen-expressing cell is an isolated human peripheral blood mononuclear cell (PBMC) or a human PBMC-derived T cell. [21.7] The method of any of

[21] to [21.4], wherein the agonist activity for the antigen is assessed by a reporter gene assay. [21.8] The method of any of

[21] to [21.7], further comprising: (i) obtaining an expression vector comprising an appropriate promoter operatively linked to a gene encoding the agonist antigen binding molecule produced by the method of any of

[21] to [21.7], (ii) introducing the vector into a host cell and culturing the host cell to produce the agonist antigen binding molecule, and Lnn / ίΖΠΖ / Β / ΥΙΛΙ (iii) harvesting the agonist antigen binding molecule from the host cell culture. [21.9] The method of any of

[21] to [21.8], which is an anti-CD137 antigen binding molecule. [21.10] The method of any of

[21] to [21.9], which is an anti-CD137 antibody. [21.11] The method of any of [21.1] to [21.10], wherein the small molecule compound is an adenosine-containing compound. [21.12] The method of any of [21.1] to [21.11], where the small molecule compound is ATP.

[22] A method of increasing the agonist activity of an agonist antigen binding molecule comprising an altered Fe, wherein such method comprises introducing into the altered Fe at least one amino acid alteration leading to a higher isoelectric point (pl) compared to that of a parental agonist antigen binding molecule comprising an altered parental Fe region. [22.1] The method of

[22] , wherein the agonist activity of the agonist antigen binding molecule for the antigen in the presence of 10 μΜ, 50 μΜ, 100 μΜ, 150 μΜ, 200 μΜ or 250 μΜ of a compound The small molecule compound is twice as high or more than the agonist activity for the antigen in the absence of the small molecule compound. [22.2] The method of

[22] or [22.1], wherein the agonist activity of the agonist antigen-binding molecule for the antigen in the presence of 10 μΜ or more of a small molecule compound is twice as high or more than the agonist activity for the antigen in the absence of the small molecule compound. [22.3] The method of

[22] or [22.1], wherein the agonist activity of the agonist antigen binding molecule for the antigen in the presence of 50 μΜ or more of a small molecule compound is twice as high or more than the agonist activity for the antigen in the absence of the small molecule compound. [22.4] The method of

[22] or [22.1], wherein the agonist activity of the agonist antigen-binding molecule for the antigen in the presence of 250μΜ or more of the small molecule compound is twice as high or more than the agonist activity by the antigen in the absence of the small molecule compound. [22.5] The method of any of

[22] to [22.4], wherein the agonist activity for the antigen is evaluated with the amount of IL-2 and / or IFN-γ produced by a cell expressing the antigen. [22.6] The method of [22.5], wherein the antigen-expressing cell is an isolated human peripheral blood mononuclear cell (PBMC) or a T cell derived from human PBMC. Lnn / ίΖΠΖ / Β / ΥΙΛΙ [22.7] The method of any of

[22] to [22.4], wherein the agonist activity for the antigen is assessed by a reporter gene assay. [22.8] The method of any of

[22] to [22.7], which is an anti-CD137 antigen-binding molecule. [22.9] The method of any of

[22] to [22.8], which is an anti-CD137 antibody. [22.10] The method of any of [22.1] to [22.9], wherein the small molecule compound is an adenosine-containing compound. [21.11] The method of any of [22.1] to [22.10], where the small molecule compound is ATP.

[23] A method of using at least one amino acid alteration to increase the agonist activity of an agonist antigen binding molecule comprising an Fe region, wherein the amino acid alteration leads to a higher isoelectric point (pl) compared to with that of a parent agonist antigen binding molecule comprising a parent Fc region. [23.1] The method of

[23] , wherein the agonist activity of the agonist antigen binding molecule for the antigen in the presence of 10 μΜ, 50 μΜ, 100 μΜ, 150 μΜ, 200 μΜ or 250 μΜ of a compound The small molecule compound is twice as high or more than the agonist activity for the antigen in the absence of the small molecule compound. Lnn / ίΖΠΖ / Β / ΥΙΛΙ [23.2] The method of

[23] or [23.1], wherein the agonist activity of the agonist antigen binding molecule for the antigen in the presence of 10 μΜ or more of a small molecule compound is twice as high or more than the agonist activity for the antigen in the absence of the small molecule compound. [23.3] The method of

[23] or [23.1], wherein the agonist activity of the agonist antigen-binding molecule for the antigen in the presence of 50 μΜ or more of a small molecule compound is twice as high or more than the agonist activity for the antigen in the absence of the small molecule compound. [23.4] The method of

[23] or [23.1], wherein the agonist activity of the agonist antigen binding molecule for the antigen in the presence of 250 μΜ or more of a small molecule compound is twice as high or more than the agonist activity for the antigen in the absence of the small molecule compound. [23.5] The method of any of

[23] to [23.4], wherein the agonist activity for the antigen is assessed with the amount of IL-2 and / or IFN-γ produced by a cell expressing the antigen. [23.6] The method of [23.5], wherein the antigen-expressing cell is an isolated human peripheral blood mononuclear cell (PBMC) or a T cell derived from Lnn / ίΖΠΖ / Β / ΥΙΛΙ human PBMC. [23.7] The method of any of

[23] to [23.4], wherein the agonist activity for the antigen is assessed by a reporter gene assay. [23.8] The method of any of

[23] to [23.7], which is an anti-CD137 antigen binding molecule. [23.9] The method of any of

[23] to [23.8], which is an anti-CD137 antibody. [23.10] The method of any of [23.1] to [23.9], wherein the small molecule compound is an adenosine-containing compound. [23.11] The method of any of [23.1] to [23.10], wherein the small molecule compound is ATP.

[24] A method of selecting an antigen-binding domain or an antigen-binding molecule having antigen-binding activity dependent on a small molecule compound, wherein such method comprises: (a) bringing an antigen binding domain or antigen binding molecule or a library of antigen binding domains or antigen binding molecules into contact with a fusion molecule in the presence of a small molecule compound, in where in the fusion molecule there are two or more units of an antigen fused to one unit of a fusion partner, (b) locating an antigen-binding domain or a Lnn / ίΖΠΖ / Β / ΥΙΛΙ antigen binding molecule bound to the antigen within the fusion molecule from step (a) in the absence or in the presence of a low concentration of the small molecule compound, and (c) isolating a domain antigen-binding molecule or an antigen-binding molecule cleaved in step (b). [24.1] The method of

[24] , where the fusion member molecule is a dimeric Fe region. [24.2] The method of [24.1], wherein the Fe region comprises a first Fe subunit and a second Fe subunit, and wherein one unit of the antigen is fused to each of such first and second Fe subunits. [24.3] The method of [24.1] or [24.2], wherein one unit of the antigen is fused at the N-terminus of each such first and second Fe subunit. [24.4] The method of any of

[24] to [24.3], wherein the library of antigen binding domains or antigen binding molecules is a phage library. [24.5] The method of any of

[24] to [24.4], wherein the phage included in the phage library are phage displaying on their surface two or more antigen-binding domains or antigen-binding molecules. [24.6] The method of any of

[24] to [24.5], wherein the phage included in the phage library are phage having a defect in the helper phage-derived pIII gene.

[25] A method of selecting an antigen-binding domain or an antigen-binding molecule that has dependent antigen-binding activity of two or more different small molecule compounds, wherein such method comprises: (a) bringing an antigen binding domain or antigen binding molecule or a library of antigen binding domains or antigen binding molecules into contact with an antigen in the presence of a first small molecule compound, (b ) locating an antigen-binding domain or an antigen-binding molecule bound to the antigen in step (a) in the absence or presence of a low concentration of the first small molecule compound, (c) isolating an antigen-binding domain antigen or an antigen-binding molecule dissociated in step (b), (d) bringing an antigen-binding domain or an antigen-binding molecule isolated in step (c) into contact with the antigen in the presence of a second small molecule compound, (e) locating an antigen-binding domain or antigen-binding molecule bound to the antigen in step (d) in the absence or presence of a low concentration of the second small molecule compound, and Lnn / ίΖΠΖ / Β / ΥΙΛΙ Lnn / ίΖΠΖ / Β / ΥΙΛΙ (f) isolating an antigen-binding domain or an antigen-binding molecule cleaved in step (e), where the method does not comprise, between steps (c) and (d), amplifying a gene encoding the antigen binding domain or an antigen binding molecule isolated in step (c). [25 .1] The method of

[25] , wherein the library of antigen binding domains or antigen binding molecules comprises a phage library.

[26] A method of selecting an antigen-binding domain or an antigen-binding molecule having antigen-binding activity dependent on a small molecule compound, wherein such method comprises: (a) bringing a previously unused library of antigen-binding domains or antigen-binding molecules into contact with an antigen in the presence of a small molecule compound, (b) locating an antigen-binding domain or molecule binding domain to the antigen bound in step (a) in the absence or presence of a low concentration of the small molecule compound, and (c) isolating an antigen-binding domain or an antigen-binding molecule dissociated on the step (b), where the previously unused library is a Lnn / ίΖΠΖ / Β / ΥΙΛΙ phage library including phage displaying two or more antigen-binding domains or antigen-binding molecules on their surface.

[27] A method of selecting an antigen-binding domain or an antigen-binding molecule having antigen-binding activity dependent on a small molecule compound, wherein such method comprises: (a) bringing a library of antigen-binding domains or antigen-binding molecules into contact with an antigen in the presence of a small molecule compound, (b) locating an antigen-binding domain or antigen-binding molecule antigen bound to the antigen in step (a) in the absence or presence of a low concentration of the small molecule compound, and (c) isolating an antigen-binding domain or antigen-binding molecule cleaved in step (b). ), wherein the library is a library including phage having a defect in the helper phage-derived pIII gene.

[28] A method of selecting an antigen-binding domain or an antigen-binding molecule having antigen-binding activity dependent on a small molecule compound, wherein such method comprises: (a) put a library of binding domains into the Lnn / ίΖΠΖ / Β / ΥΙΛΙ antigen or antigen-binding molecules in contact with an antigen in the presence of a small molecule compound, (b) locate an antigen-binding domain or antigen-binding molecule bound to the antigen in step (a) in the absence or presence of a low concentration of the small molecule compound, and (c) isolating an antigen-binding domain or antigen-binding molecule cleaved in step (b), wherein the library is a library that includes phage prepared by increasing the expression of the antigen-binding domain or an antigen-binding molecule with the addition of a small molecule that increases the level of expression from the promoter that regulates the expression of the antigen-binding domain or of an antigen-binding molecule. [28.1] The selection method of

[28] , wherein the small molecule additive is isopropyl-βthiogalactopyranoside or arabinose. [28.2] The method of any of

[24] to [28.1], wherein the small molecule compound is an adenosine-containing compound. [28.3] The method of any of

[24] to [28.2], where the small molecule compound is ATE.

[29] An antigen-binding molecule that has Lnn / ίΖΠΖ / Β / ΥΙΛΙ concentration-dependent antigen-binding activity of a compound specific to tumor tissue, wherein the antigen-binding activity in the presence of 100 μΜ of the compound is twice or more than the activity antigen binding in the absence of the compound. [29.1] The antigen-binding molecule of

[29] , where the KD value in the presence of 100 μΜ of the compound is 5 x 10 -7M or less. [29.2] The antigen-binding molecule of

[29] or [29.1], where the KD value in the absence of the compound is 1 x 10~6M or more. [29.3] The antigen-binding molecule of any of

[29] to [29.2], which has neutralizing activity against the antigen. [29.4] The antigen-binding molecule of any of

[29] to [29.3], which has cytotoxic activity against a cell expressing the antigen. [29.5] The antigen binding molecule of any of

[29] to [29.4], wherein the antigen is an antigen expressed or secreted by any of a tumor cell, an immune cell, and a stromal cell of a tumor tissue. [29.6] The antigen-binding molecule of any of

[29] to [29.5], wherein the compound is an adenosine-containing compound. Lnn / ίΖΠΖ / Β / ΥΙΛΙ [29.7] The antigen-binding molecule of any of

[29] to [29.6], comprising an Fe region. [29.8] The antigen binding molecule of [29.7], wherein the Fc region is a mutated Fc region comprising an amino acid alteration, wherein the mutated Fc region exhibits enhanced binding activity to at least one Fcy receptor which is selected from the group consisting of FcyRIa, FcyRIIa, FcyRIIb and FcyRIIIa, compared to a wild-type Fc region. [29.9] The antigen binding molecule of any of

[29] to [29.8], wherein the antigen binding molecule is an antibody or an antibody fragment.

[30] A pharmaceutical formulation comprising the antigen binding molecule of any of

[29] to [29.9] and a pharmaceutically acceptable carrier. [30.1] The pharmaceutical formulation of

[30] , which is for use in the treatment of a tumor. [30.2] The pharmaceutical formulation of [30.1], which has lower cytotoxic activity in non-tumor tissue than a pharmaceutical formulation comprising a control antigen binding molecule. [30.3] The pharmaceutical formulation of [30.1] or [30.2], which has a lower level of side effects than a pharmaceutical formulation comprising a control antigen binding molecule. Lnn / ίΖΠΖ / Β / ΥΙΛΙ [30.4] The pharmaceutical formulation of [30.2] or [30.3], wherein the control antigen-binding molecule is an antigen-binding molecule that does not exhibit concentration-dependent antigen-binding activity of a tissue-specific compound tumor.

[31] A method of producing an antigen-binding molecule for use in the treatment of a tumor, wherein such method comprises the step of selecting an antigen-binding molecule whose antigen-binding activity in the presence of 100 μΜ of a tumor tissue-specific compound is twice as high or more than the antigen-binding activity in the absence of the compound.

[32] A method of producing a pharmaceutical formulation for use in the treatment of a tumor, wherein such method comprises the step of mixing the antigen-binding molecule of any of

[29] to [29.9] with a pharmaceutically acceptable carrier.

[33] An antigen-binding molecule that has concentration-dependent antigen-binding activity of a tissue-specific compound of interest, wherein the antigen-binding activity in the presence of 1 μΜ of the compound is two-fold less or more than antigen binding activity in the presence of a sufficient amount of the compound. [33.1] The antigen-binding molecule of

[33] , in Lnn / ίΖΠΖ / Β / ΥΙΛΙ where the value of KD in the presence of 1 μΜ of the compound is 2 x 10~7M or more. [33.2] The antigen-binding molecule of

[33] or [33.1], wherein the KD value in the presence of a sufficient amount of the compound is 1 x 10~7M or less. [33.3] The antigen binding molecule of any of

[33] to [33.2], wherein the compound is a compound specific for tumor tissue. [33.4] The antigen binding molecule of [33.3], wherein the compound is an adenosine-containing compound. [33.5] The antigen binding molecule of any of

[33] to [33.4], which has greater plasma retention and / or has a lower ability to accumulate antigen in plasma than a control antigen binding molecule. [33.6] The antigen-binding molecule of [33.5], wherein the control antigen-binding molecule is an antigen-binding molecule that does not exhibit concentration-dependent antigen-binding activity of a tissue-specific compound of interest. [33.7] The antigen binding molecule of any of

[33] to [33.6], wherein the antigen binding molecule is an antibody or an antibody fragment.

[34] A pharmaceutical formulation comprising the antigen binding molecule of any of

[33] to [33.7] Lnn / ίΖΠΖ / Β / ΥΙΛΙ and a pharmaceutically acceptable vehicle.

[35] A method of producing an antigen-binding molecule that exhibits a higher plasma dwelling property and / or a lower ability to accumulate antigen in plasma than a control antigen-binding molecule, wherein such method comprises the following: steps of (a) producing an antigen-binding molecule whose antigen-binding activity increases as the concentration of a tissue-specific compound of interest increases, and (b) measuring the plasma permanence property and / or ability to accumulating the antigen in plasma from the antigen binding molecule produced in (a). [35 .1] The method of

[35] , comprising the step of selecting an antigen-binding molecule whose antigen-binding activity in the presence of 1 μΜ of a tissue-specific compound of interest is two-fold lower or more than antigen binding activity in the presence of a sufficient amount of the compound. [35.2] The method of

[35] or [35.1], wherein the control antigen-binding molecule is an antigen-binding molecule that does not exhibit concentration-dependent antigen-binding activity of a specific compound of the tissue of interest.

[36] A method of producing a pharmaceutical formulation, comprising the step of mixing the antigen-binding molecule of any of

[33] to [33.7] with a pharmaceutically acceptable carrier.

[37] A method for measuring the concentration of ATP in a solution, comprising the steps of (i) bringing a divided Luc / HEK293 cell expressing P2Y11 into contact with the solution and (ii) measuring the luciferase activity in the cell. [37.1] The method of

[37] , further comprising the step of bringing a solution containing a luciferase substrate into contact with the cell. [37.2] The method of

[37] or [37.1], where the solution is the intercellular fluid present in a tissue in vivo. [37.3] The method of [37.2], wherein the tissue is a tumor tissue. [37.4] The method of [37.2] or [37.3], wherein step (i) comprises the step of transplanting a divided Luc / HEK293 cell expressing P2Y11 into the tissue in vivo. Brief Description of the Figures Figure 1 is a diagram showing the agonist activity of various anti-CD137 antibodies evaluated using Jurkat cells in the presence or absence of ATP. The X-axis shows the antibody concentration (pg / mL) and the Y-axis shows the units of Lnn / ίΖΠΖ / Β / ΥΙΛΙ relative light. Lnn / ίΖΠΖ / Β / ΥΙΛΙ Figure 2 is a diagram showing the agonist activity of various anti-CD137 antibodies assessed using Jurkat cells in the presence or absence of ADP. The X-axis shows the antibody concentration (pg / ml) and the Y-axis shows the relative light units. Figure 3 is a diagram showing the agonist activity of various anti-CD137 antibodies evaluated using human T cells in the presence or absence of ADPbetaS. Figure 4 is a diagram showing the agonist activity of dBBAT119-P253 / dBBAT119L-LamLib (small molecule activable anti-CD137 antibody) or NS1P253 (non-activatable anti-CD137 antibody) assessed using human T cells in the presence or absence. of ADPbetaS. The X axis shows the antibody concentration (pg / ml) and the Y axis shows the amount of IFN-γ produced (ng / ml). Figure 5 is a diagram showing the ATP-dependent antigen binding activity of various anti-CD137 antibodies (activatable anti-CD137 antibody with enhanced binding activity) assessed with a phage ELISA. The Y-axis shows the S / N ratio of absorbance in the presence / absence of ATP, and the X-axis shows the S / N ratio in the presence / absence of antigen. Figure 6 is a diagram showing the binding activity of various variants of the antiCD137 antibody (dBBAT119H-P253 / dBBAT119L-LamLib) to human CD137 in the presence or absence of ATP. The top row shows human CD137 binding activity in the absence of ATP and the bottom row shows human CD137 binding activity in the presence of ATP. Figures 7A and 7B are a diagram showing the agonist activity of dBBAT119H-P253 / dBBAT119LLamLib, dBBATkll9H024-P253 / dBBATkll9L020-LamLib, IC17HdKh!gGl / IC17L-kO (control) or NS1-P253 (non-activable anti-CD137 antibody). ) evaluated using human T cells in the presence or absence of ADPbetaS. Figure 7A shows the results of the study in the absence of ADPbetaS and Figure 7B shows the results of the study in the presence of ADPbetaS. The X axis shows the antibody concentration (pg / ml) and the Y axis shows the amount of IFN-γ produced (ng / ml). Figures 8A and 8B are a diagram showing the agonist activity of various activatable anti-CD137 antibodies assessed using the gene assay. Lnn / ίΖΠΖ / Β / ΥΙΛΙ reporter 4-1BB Jurkat in the presence or absence of ATP. Figure 8A shows the results of the study in the absence of ATP and Figure 8B shows the results of the study in the presence of ATP. Figures 9A and 9B are a diagram showing the enhancement of the agonist activity of several anti-CD137 antibodies activated in the presence of ATP due to the increased activity of binding of constant regions of the heavy chain to Fcy receptors, evaluated using human peripheral blood mononuclear cells. Figure 9A shows agonist activity determined using the amount of IL-2 produced as an index, and Figure 9B shows agonist activity determined using the amount of IFN-γ produced as an index. Figures 10A and 10B are a diagram showing enhancement of the agonist activity of various anti-CD137 antibodies activable in the presence of ATP due to increased activity of binding of constant regions of the heavy chain to Fcy receptors or the increased pI of heavy chain constant regions, assessed using human peripheral blood mononuclear cells. Shown in Figure 10A is agonist activity determined using the amount of IL-2 produced as a Lnn / ίΖΠΖ / Β / ΥΙΛΙ index, and the agonist activity determined using the amount of IFN-γ produced as an index is shown in Figure 10B. Figures 11A and 11B are a diagram showing the enhancement of agonist activity of various anti-CD137 antibodies activable in the presence or absence of ATP due to increased Fcy receptor heavy chain constant region binding activity. , evaluated using human peripheral blood mononuclear cells. Figure 11A shows agonist activity determined using the amount of IL-2 produced as an index, and Figure 11B shows agonist activity determined using the amount of IFN-γ produced as an index. Figures 12A and 12B are a diagram showing the enhancement of agonist activity of various anti-CD137 antibodies activable in the presence or absence of ATP due to increased Fcy receptor heavy chain constant region binding activity. , evaluated using human peripheral blood mononuclear cells. Figure 12A shows agonist activity determined using the amount of IL-2 produced as an index, and Figure 12B shows agonist activity determined using the amount of IFN-γ produced as an index. Lnn / ίΖΠΖ / Β / ΥΙΛΙ Figures 13A and 13B are a diagram showing the enhancement of the agonist activity of various anti-CD137 antibodies that are activated in the presence or absence of ATP due to the increased activity of binding heavy chain constant regions to Fcy receptors. , evaluated using human peripheral blood mononuclear cells. Figure 13A shows agonist activity determined using the amount of IL-2 produced as an index, and Figure 13B shows agonist activity determined using the amount of IFN-γ produced as an index. Figures 14A and 14B are a diagram showing the enhancement of agonist activity of various anti-CD137 antibodies activable in the presence or absence of ATP due to increased Fcy receptor heavy chain constant region binding activity. , evaluated using human peripheral blood mononuclear cells. Figure 14A shows agonist activity determined using the amount of IL-2 produced as an index, and Figure 14B shows agonist activity determined using the amount of IFN-γ produced as an index. Figures 15A and 15B are a diagram showing enhancement of agonist activity of various activatable anti-CD137 antibodies in the presence or absence. ATP Lnn / ίΖΠΖ / Β / ΥΙΛΙ due to increased heavy chain constant region binding activity to Fcy receptors, as assessed using human peripheral blood mononuclear cells. Figure 15A shows agonist activity determined using the amount of IL-2 produced as an index, and Figure 15B shows agonist activity determined using the amount of IFN-γ produced as an index. Figures 16A and 16B are a diagram showing the enhancement of agonist activity of various anti-CD137 antibodies that are activated in the presence or absence of ATP due to increased pI of heavy chain constant regions, as assessed using mononuclear cells. human peripheral blood. Figure 16A shows agonist activity determined using the amount of IL-2 produced as an index, and Figure 16B shows agonist activity determined using the amount of ΙΕΝ-γ produced as an index. Figures 17A and 17B are a diagram showing the enhancement of agonist activity of various anti-CD137 antibodies that are activated in the presence or absence of ATP due to increased pI of heavy chain constant regions, as assessed using mononuclear cells of the heavy chain. human peripheral blood. Lnn / ίΖΠΖ / Β / ΥΙΛΙ Figure 17A shows agonist activity determined using the amount of IL-2 produced as an index, and Figure 17B shows agonist activity determined using the amount of ΙΕΝ-γ produced as an index. Figures 18A and 18B are a diagram showing the enhancement of agonist activity of various anti-CD137 antibodies that are activated in the presence or absence of ATP due to increased pI of heavy chain constant regions, as assessed using mononuclear cells. human peripheral blood. Figure 18A shows agonist activity determined using the amount of IL-2 produced as an index, and Figure 18B shows agonist activity determined using the amount of IFN-γ produced as an index. Figures 19A and 19B are a diagram showing the enhancement of agonist activity of various anti-CD137 antibodies that are activated in the presence or absence of ATP due to increased pI of heavy chain constant regions, as assessed using mononuclear cells. human peripheral blood. Figure 19A shows agonist activity determined using the amount of IL-2 produced as an index, and Figure 19B shows agonist activity determined using the amount of IFN-γ produced as an index. Figures 2 0A and 2 0B are a diagram showing enhancement of agonist activity of various activable anti-CD137 antibodies in the presence or absence of ATP due to increased pI of heavy chain constant regions, assessed using cells. human peripheral blood mononuclear cells. Figure 20A shows agonist activity determined using the amount of IL-2 produced as an index, and Figure 20B shows agonist activity determined using the amount of IFN-γ produced as an index. Figures 21A and 21B are a diagram showing the enhancement of the agonist activity of various anti-CD137 antibodies activable in the presence or absence of ATP due to the increase in pI of heavy chain constant regions, as assessed using mononuclear cells of the heavy chain. human peripheral blood. Figure 21A shows the agonist activity determined using the amount of IL-2 produced as an index, and Figure 21B shows the agonist activity determined using the amount of IFN-γ produced as an index. Lnn / ίΖΠΖ / Β / ΥΙΛΙ Figures 22A and 22B are a diagram where Lnn / ίΖΠΖ / Β / ΥΙΛΙ shows enhancement of agonist activity of various anti-CD137 antibodies activable in the presence or absence of ATP due to increased pI of heavy chain constant regions, assessed using human peripheral blood mononuclear cells . Figure 22A shows agonist activity determined using the amount of IL-2 produced as an index, and Figure 22B shows agonist activity determined using the amount of IFN-γ produced as an index. Figures 23A and 23B are a diagram showing the enhancement of agonist activity of various anti-CD137 antibodies activable in the presence or absence of ATP due to increased Fcy receptor heavy chain constant region binding activity. , evaluated using human peripheral blood mononuclear cells. Figure 23A shows the agonist activity determined using the amount of IL-2 produced as an index, and Figure 23B shows the agonist activity determined using the amount of IFN-γ produced as an index. Figure 24 is a diagram showing the plasma concentration of various activatable and non-activatable anti-CD137 antibodies assessed using human CD137 knockout mice. Lnn / ίΖΠΖ / Β / ΥΙΛΙ The Fe are all from mlgGl. Figure 25 is a diagram showing the plasma concentration of various activatable and non-activatable anti-CD137 antibodies assessed using human CD137 knockout mice. The Fe are all MB110. Figure 26 is a diagram showing the plasma concentration of various activatable and non-activatable anti-CD137 antibodies assessed using human CD137 knockout mice. The Fe are all from MB492. Figure 27 is a diagram showing the antitumor effect of A375-mIgGl / B167-ml0r in a mouse model transplanted with MC38 cells. Each point shows the average value of a group (n = 5) of tumor volumes. Figures 28A and 28B are a diagram showing organ weights in a mouse model transplanted with MC38 cells after administration of the antibodies (NOl-mlgGl or A375-mIgGl / Bl67-mlOr). In Figure 28A the weight of lymph nodes is shown and in Figure 28B the weight of spleens is shown. Figures 29A-29C are a diagram showing the degree of T cell activation in the lymph nodes of a cell-transplanted mouse model. Lnn / ίΖΠΖ / Β / ΥΙΛΙ MC38 after administration of NOl-mlgGl or A375mlgGl / Bl67-miOr. Figure 29A shows the percentage of PD-1 positive T cells in CD8 positive T cells, Figure 29B shows the percentage of ICOS positive T cells in CD8 positive T cells and Figure 29C shows the percentage of CD8 positive T cells. T Granzyme positive in CD8 positive T cells. Figures 30A-30C are a diagram showing the degree of T cell activation in the spleen of a mouse model transplanted with the MC38 cell line after administration of NOl-mlgGl or A375-mIgGl / B167mlOr. Figure 30A shows the percentage of PD-1 positive T cells in CD8 positive T cells, Figure 30B shows the percentage of ICOS positive T cells in CD8 positive T cells and Figure 30C shows the percentage of CD8 positive T cells. T Granzyme positive in CD8 positive T cells. Figures 31A and 31B are a diagram showing the degree of T-cell activation in the liver of a mouse model transplanted with the MC38 cell line after NOl-mlgGl or A375-mIgGl / B167mlOr administration. Figure 31A shows the percentage of Lnn / ίΖΠΖ / Β / ΥΙΛΙ PD-1 positive T cells in CD8 positive T cells, and in Figure 31B the percentage of Granzyme positive T cells in CD8 positive T cells is shown. Figure 32 is a diagram showing the antitumor effect of A356-MB110 / B040-ml0r in a mouse model transplanted with the MC38 cell line. Each point shows the average value of a group (n = 5) of tumor volumes. Figures 33A and 33B are a diagram showing organ weights in a mouse model transplanted with the MC38 cell line after administration of NS2-MB110 or A356-MB110 / B040-ml0r. In Figure 33A the weight of lymph nodes is shown and in Figure 33B the weight of spleens is shown. Figures 34A and 34B are a diagram showing the degree of T cell activation in the liver of a mouse model transplanted with the MC38 cell line after administration of NS2-MB110 or A356-MB110 / B040mlOr. Figure 34A shows the percentage of PD-1 positive T cells in CD8 positive T cells and Figure 34B shows the percentage of ICOS positive T cells in CD8 positive T cells. Figure 35 is a diagram showing the antitumor effect of A372-mIgGl / B040-ml0r in a model of Lnn / ίΖΠΖ / Β / ΥΙΛΙ mouse transplanted with the MC38 cell line. Each point shows the average value of a group (n = 5) of tumor volumes. Figures 36A and 36B show the number of lymph node cells (Figure 36A) and the weight of the spleen (Figure 36B) in a mouse model transplanted with the MC38 cell line after administration of A372migGl / B04 0- mlOr. Figure 37 is a diagram showing the degree of T cell activation in the liver of a mouse model transplanted with the MC38 cell line after administration of A372-mIgGl / B040-ml0r (percentage of Granzyme positive T cells on CD8 positive T cells). Figure 38 is a diagram showing the antitumor effect of A372-MB110 / B040-ml0r in a mouse model transplanted with the MC38 cell line. Each point shows the average value of a group (n = 5) of tumor volumes. Figures 39A and 39B are a diagram showing organ weights in a mouse model transplanted with the MC38 cell line after administration of NS2-MB110 or A372-MB110 / B040-ml0r. In Figure 39A the weight of lymph nodes is shown and in Figure 39B the weight of spleens is shown. Figure 40 is a diagram showing the Lnn / ίΖΠΖ / Β / ΥΙΛΙ degree of T cell activation in the liver of a mouse model transplanted with the MC38 cell line after administration of NS2-MB110 or A372-MB110 / B040-ml0r (percentage of PD T cells -1 positive on CD8 positive T cells). Figure 41 is a diagram showing the antitumor effect of A372-MB492 / B040-ml0r in a mouse model transplanted with the MC38 cell line. Each point shows the average value of a group (n = 5) of tumor volumes. Figures 42A and 42B are a diagram showing lymph node cell number and spleen weight in a mouse model transplanted with the MC38 cell line after administration of NS1-MB492 or A372-MB492 / B040- mlOr . In Figure 42A the number of lymph node cells is shown and in Figure 42B the weight of the spleen is shown. Figure 43 is a diagram showing the degree of T cell activation in the liver of a mouse model transplanted with the MC38 cell line after administration of NS1-MB492 or A372-MB492 / B040-ml0r (percentage of Granzyme-positive T cells to CD8-positive T cells). Figure 44 is a diagram showing the antitumor effect of A486-MB492 / B167-ml0r or A488-MB492 / B226mlOr in a mouse model transplanted with the MC38 cell line. Each point shows the average value of a group (n = 5) of tumor volumes. Figures 45A and 45B are a diagram showing the number of cells per lymph node and the weight of the spleen in a mouse model transplanted with the MC38 cell line after administration of NS1-MB492, A486MB492 / B167-mlOr or A488-MB492 / B226-mlOr. In Figure 45A the number of cells per lymph node is shown and in Figure 45B the weight of the spleen is shown. Figure 46 is a diagram showing the level of effector cell infiltration in the liver of a mouse model transplanted with the MC38 cell line after administration of NS1-MB492, A486-MB492 / B167mlOr or A488-MB492 / B226-ml0r (percentage of CD3-positive and CD8-positive T cells in CD45-positive T cells). Figure 47 is a diagram showing the antitumor effect of A489-MB492 / B223-ml0r in a mouse model transplanted with the MC38 cell line. Each point shows the average value of a group (n = 5) of tumor volumes. Figures 48A and 48B are a diagram where Lnn / ίΖΠΖ / Β / ΥΙΛΙ shows the number of lymph node cells and the number of cells in a lymphocyte fraction of the spleen in a mouse model transplanted with the MC38 cell line after administration of NS1-MB492 or A489- MB492 / B223-ml0r. In Figure 48A the number of cells in the lymph node is shown and in Figure 48B the number of cells in a fraction of spleen lymphocytes is shown. Figure 49 is a diagram showing the degree of T-cell activation in the liver of a mouse model transplanted with the MC38 cell line after administration of NS1-MB492 or A489-MB492 / B223-ml0r (percentage of CD8-positive T cells to CD45-positive T cells). Figures 50A and 50B are a diagram showing the antitumor effect of A548-mIgGl / B256-ml0r and A551m!gGl / B256-ml0r in a mouse model transplanted with the MC38 cell line. In Figure 50A the antitumor effect of A548-mIgGl / B256-ml0r is shown and in Figure 50B the antitumor effect of A551-mIgGl / B256-ml0r is shown. Figures 51A and 51B are a diagram showing organ weights in a mouse model transplanted with the MC38 cell line after administration of NSl-mlgGl, A548-mIgGl / B256-ml0r or A551m!gGl / B256- ml0r. Lnn / ίΖΠΖ / Β / ΥΙΛΙ In Figure 51A the weight of lymph nodes is shown and in Figure 51B the weight of spleens is shown. Figures 52A and 52B are a diagram showing the degree of T cell activation in the liver of a mouse model transplanted with the MC38 cell line after administration of NSl-mlgGl, A548-mIgGl / B256mlOr or A551- mIgGl / B256-ml0r. Figure 52A shows the percentage of PD-1 positive T cells in CD8 positive T cells, and Figure 52B shows the percentage of Granzyme positive T cells in CD8 positive T cells. Figure 53 is a diagram showing the antitumor effect of A551-MB110 / B379-ml0r in a mouse model transplanted with the MC38 cell line. Figures 54A and 54B are a diagram showing organ weights in a mouse model transplanted with the MC38 cell line after administration of NS1-mlgG1 or A551-MB110 / B379-ml0r. In Figure 54A the weight of lymph nodes is shown and in Figure 54B the weight of spleens is shown. Figures 55A-55C are a diagram showing the degree of T cell activation in the spleen of a mouse model transplanted with the MC38 cell line after administration of NS1-mlgG1 or A551-MB110 / B379 mlOr. Lnn / ίΖΠΖ / Β / ΥΙΛΙ Figure 55A shows the percentage of PD-1 positive T cells in CD8 positive T cells, Figure 55B shows the percentage of ICOS positive T cells in CD8 positive T cells and Figure 55C shows the percentage of ICOS positive T cells in CD8 positive T cells. T Granzyme positive in CD8 positive T cells. Figures 56A-56C are a diagram showing the degree of T cell activation in the liver of a mouse model transplanted with the MC38 cell line after administration of NSl-mlgGl or A551-MB110 / B379mlOr. Figure 56A shows the percentage of PD-1 positive T cells in CD8 positive T cells, Figure 56B shows the percentage of ICOS positive T cells in CD8 positive T cells, and Figure 56C shows the percentage of ICOS positive T cells in CD8 positive T cells. T Granzyme positive in CD8 positive T cells. Figure 57 is a diagram showing the agonist activity of various anti-CD137 antibodies assessed using Jurkat cells in the presence or absence of L-kynurenine. The X-axis shows the antibody concentration (pg / ml) and the Y-axis shows the relative light units. Figure 58 is a diagram showing the agonist activity of various anti-CD137 antibodies assessed using 4-1BB Jurkat cells in the presence or absence of the small molecule compound (ATP or ADP). The X-axis shows the antibody concentration (pg / ml) and the Y-axis shows the relative light units. Figure 59 is a diagram showing ATP (ATP concentration-dependent luciferin luminescence) responsiveness of produced Luc / HEK293 P2Y11 split cells to determine extracellular ATP levels. Figure 60 is a diagram showing the in vivo ATP (ATP concentration-dependent luciferin luminescence) responsiveness of split P2Y11 Luc / HEK293 cells when transplanted subcutaneously into mice. Figure 61 is a diagram showing the results of luminescence imaging of mice subcutaneously transplanted with split P2Y11 Luc / HEK293 cells and predetermined ATP concentrations, and of mice bearing FM3A tumors subcutaneously transplanted with split P2Y11 Luc / HEK293 cells. HEK293. Marks on the ventral portion of the mice indicate the detected luminescence. Lnn / ίΖΠΖ / Β / ΥΙΛΙ Figure 62 is a diagram showing the ATP concentration-dependent binding activity (KD value) of the anti-hIL6R antibodies MRAH-G4Tl / MRAL-kO (control antibody) and H0002-G4Tl / L1058-laml, H0041G4Tl. / L1088-laml and H0052-G4Tl / L1083-laml (all are activatable antibodies) against hIL6R. Figure 63 is a diagram showing the ADP concentration-dependent binding activity (KD value) of the anti-hIL6R antibodies MRAH-G4Tl / MRAL-kO (control antibody) and H0002-G4Tl / L1058-laml, H0041G4Tl. / L1088-laml and H0052-G4Tl / L1083-laml (all are activatable antibodies) against hIL6R. Figure 64 is a diagram showing the AMP concentration-dependent binding activity (KD value) of the anti-hIL6R antibodies MRAH-G4Tl / MRAL-kO (control antibody) and H0002-G4Tl / L1058-laml, H0041G4Tl. / L1088-laml and H0052-G4Tl / L1083-laml (all are activatable antibodies) against LIL6R. Figure 65 is a diagram showing the ADCC activity dependent on the ATP concentration of the anti-hIL6R antibodies MRAH-mFa55 / MRAL-mkO (control antibody) and H0002-mFa55 / L1058-ml0, H0041-mFa55 / L1088- ml0 and H0052-mFa55 / L1083-ml0 (all are activatable antibodies). Figure 66 is a diagram showing the in vivo antitumor activity of anti-hIL6R antibodies. MRAH-mFa55 / MRAL-mkO (control antibody), H0002Lnn / ίΖΠΖ / Β / ΥΙΛΙ Lnn / ίΖΠΖ / Β / ΥΙΛΙ mFa55 / L1058-ml0, H0041-mFa55 / L1088-ml0 and H0052-mFa55 / L1083mlO (all are activatable antibodies). IC17Hdk-mFa55 / IC17Lmkl is the negative control antibody. Figure 67 is a diagram showing the comparison of the kinetics in plasma of an anti-hIL6R antibody MRAH-mFa55 / MRAL-mkO (control antibody), in normal mice and in hIL6R transgenic mice. The vertical axis of the graph shows the plasmatic concentration of the antibody. Figure 68 is a diagram showing the comparison of the kinetics in plasma of an anti-hIL6R antibody H0002-mFa55 / L1058-ml0 (activatable antibody), in normal mice and in hIL6R transgenic mice. The vertical axis of the graph shows the plasmatic concentration of the antibody. Figure 69 is a diagram showing the comparison of the kinetics in plasma of an anti-hIL6R antibody H0041-mFa55 / L1088-ml0 (activatable antibody), in normal mice and in hIL6R transgenic mice. The vertical axis of the graph shows the plasmatic concentration of the antibody. Figure 70 is a diagram showing the comparison of the kinetics in plasma of an anti-hIL6R antibody H0052-mFa55 / L1083-ml0 (activatable antibody), in normal mice and in hIL6R transgenic mice. The vertical axis of the graph shows the plasmatic concentration of the antibody. Figure 71 is a diagram showing antigen accumulation in hIL6R transgenic mice after administration of each between a non-activatable anti-hIL6R antibody MRAH-mFa55 / MRAL-mkO (control antibody), and anti-hIL6R antibodies. activatable H0002mFa55 / L1058-ml0, H0041-mFa55 / L1088-ml0 and H0052-mFa55 / L1083mlO (all are activatable antibodies). The vertical axis of the graph shows the plasma concentration of soluble hIL6R. IC17Hdk-mFa55 / IC17L-mkl (indicated as KLHmFa55 in the figure) was used as the negative control antibody. Figure 72 is a diagram showing the in vivo antitumor activity of a non-activatable anti-hIL6R antibody MRAH-mFa55 / MRAL-mkO (control antibody), and the activatable anti-hIL6R antibodies H0002-mFa55 / L1058-ml0 and H0041. -mFa55 / L1088-ml0 (both antibodies activatable). IC17Hdk-mFa55 / IC17L-mkl is the negative control antibody. Figure 73 is a diagram showing the comparison of the kinetics in plasma of a non-activatable anti-hIL6R antibody MRAH-mFa55 / MRAL-mkO (control antibody), and the activatable anti-hIL6R antibodies H0002-mFa55 / L1058-ml0 and H0041. -mFa55 / L1088-ml0 (both are activatable antibodies). The vertical axis of the graph shows the plasmatic concentration of the antibody. Lnn / ίΖΠΖ / Β / ΥΙΛΙ Lnn / ίΖΠΖ / Β / ΥΙΛΙ Figure 74 is a diagram showing the accumulation of antigens after administration of each between a non-activatable anti-hIL6R antibody MRAHmFa55 / MRAL-mkO (control antibody), and the activatable anti-hIL6R antibodies H0002-mFa55 / L1058-ml0. and H0041-mFa55 / L1088mlO (both are activatable antibodies). The vertical axis of the graph shows the plasma concentration of soluble hIL6R. IC17Hdk-mFa55 / IC17L-mkl (indicated as KLHmFa55 in the figure) was used as the negative control antibody. Figure 75 is a diagram showing the in vivo antitumor activity of a non-activatable anti-hIL6R antibody MRAH-mFa55 / MRAL-mkO (control antibody), and the activatable anti-hIL6R antibodies H0041-mFa55 / L1088-ml0 and H0052. -mFa55 / L1083-ml0 (both are activatable antibodies). IC17Hdk-mFa55 / IC17L-mkl is the negative control antibody. Figure 7 6 is a diagram showing the comparison of the kinetics in plasma of a non-activatable anti-hIL6R antibody MRAH-mFa55 / MRAL-mkO (control antibody) and an activatable anti-hIL6R antibody H0052-mFa55 / L1083-ml0 (control antibody). activatable). The vertical axis of the graph shows the plasmatic concentration of the antibody. Figure 77 is a diagram showing the accumulation of antigens after the administration of each one between a non-activatable anti-hIL6R antibody MRAHmFa55 / MRAL-mkO (control antibody) and an anti-Lnn / ίΖΠΖ / Β / ΥΙΛΙ hIL6R antibody H0052. -mFa55 / L1083-ml0 (activatable antibody). The vertical axis of the graph shows the plasma concentration of soluble hIL6R. IC17Hdk-mFa55 / IC17L-mkl (indicated as KLH-mFa55 in the figure) was used as the negative control antibody. Figure 7-8 is a diagram showing the ATP concentration-dependent activity of the anti-PDl antibodies mPDlF2VH-mF18 / mPDlF2VL-mkl (control antibody) and H5029-mFa31 / L3021-ml0 (activatable antibody) to inhibit the PD-1 / PDL-1 binding. Figure 79 is a diagram showing the ATP concentration-dependent activity of the anti-PDl antibodies mPDlF2VH-mF18 / mPDlF2VL-mkl (control antibody) and H5041-mFa31 / L3021-ml0 (activatable antibody) to inhibit binding of PD-1 / PDL-1. Figure 80 is a diagram showing the neutralizing activity dependent on the in vitro AMP concentration of the anti-PDl antibodies mPDlF2VHmF18 / mPDlF2VL-mkl (control antibody), and H5029-mFa31 / L3021mlO and H5041-mFa31 / L3021-ml0 (both are activatable antibodies). Figure 81 is a diagram showing the in vitro ATP concentration-dependent neutralizing activity of the anti-PDl antibodies mPDlF2VHmF18 / mPDlF2VL-mkl (control antibody), and H5029-mFa31 / L3021Lnn / ίΖΠΖ / Β / ΥΙΛΙ mlO and H5041-mFa31 / L3021-ml0 (both are activatable antibodies). Figure 82 is a diagram showing the in vivo antitumor activity of the anti-PD1 antibodies mPD1F2VH-mFa55 / mPD1F2VL-mk1 (control antibody) and H5041mFa55 / L3023-ml0 (activatable antibody). IC17Hdk-mFa55 / IC17Lmkl is the negative control antibody. Figures 83A and 83B are a diagram showing the activity of the anti-PD1 antibodies mPD1F2VHmFa55 / mPD1F2VL-mkl (control antibody) and H5041-mFa55 / L3023mlO (activatable antibody) to kill cells expressing PD-1 (Figure 83A). of the tumor and (Figure 83B) of the spleen. In these figures, the isotype represents the negative control antibody (IC17Hdk-mFa55 / IC17L-mkl). Figure 84 is a diagram showing the mode of binding between ATP and the Fab fragment of the activatable anti-hIL6R antibody H0041L1088. In the figure, ATP is shown with the ball and stick model and the amino acid residues that interact with ATP are shown with the stick model. Broken lines indicate hydrogen bonds between the antibody and ATP. Figure 85 is a diagram showing the amino acid sequence of the hIL6R extracellular domain (shIL6R) mapped to the epitope of the activatable anti-hIL6R antibody H0041L1088. In the figure, the gray shaded amino acid residues (epitope residues) are shIL6R residues that comprise one or more non-hydrogen atoms located at a distance of 4.2 Angstrom or less from ATP or Fab H0041L1088 in a structure. crystalline. Figure 86 is a diagram showing the details of the binding between shIL6R and the ATP bound H0041L1088 Fab fragment. In the figure, the heavy chain of the antibody is shown in black, the light chain is shown in gray and shIL6R is shown in white. In the figure, ATP is shown with the ball pattern, and the shIL6R epitope residue within 4.2 Angstroms from the antibody or ATP and the antibody paratop residue within 4.2 Angstroms from the epitope residue are show with rods model. The broken lines indicate the hydrogen bonds between the antibody and the shIL6R. To clearly show the interaction with ATP, only the shIL6R F298 with the bead pattern is shown. Figure 87 is a diagram showing a structure in which the structure of Figure 86 is rotated 180 degrees (viewed from behind). Figure 88 is a diagram showing the agonist activity of various activatable anti-CD137 antibodies tested using Jurkat 41BB reporter gene assay in the presence of ATP. Lnn / ίΖΠΖ / Β / ΥΙΛΙ Lnn / ίΖΠΖ / Β / ΥΙΛΙ Figure 89 is a diagram showing the comparison in plasma kinetics of each of the activatable anti-CD37 antibodies A375-SCF041aPh / B167-Lamlib and A375-MY201aPh / B167-Lamlib. The vertical axis of the graph shows the plasma concentration of each artibody. Figure 90 is a diagram showing the anti-tumor effect of each of A375 / B167-SCF04laPh and A375 / B167MY201aPh in a mouse model prepared by transplanting the LLC1 / OVA / GPC3 cell line into hCD137KT / mFcYR2bKO / hFcyR2bTg# mice. 90. Each point shows the mean value of a group (n=5) of tumor volumes. Figure 91 is a diagram showing the agonist activity of various anti-CD3 antibodies tested by a reporter gene assay using a T-Cell Activation Bioassay (NFAT) in the presence of ATP. Detailed description of the invention I. Definitions The term binding activity refers to the sum total strength of non-covalent interactions between one or more binding sites on a molecule (eg, an antibody) and its binding member (eg, an antigen). Herein, binding activity is not strictly limited to a 1:1 interaction between members of a binding pair (eg, antibody and antigen). By For example, when the members of a binding pair reflect a monovalent 1:1 interaction, the binding activity is referred to in particular as the intrinsic binding affinity (affinity). When a member of a binding pair can bind monovalently and multivalently, the binding activity is the sum of each binding strength. The binding activity of a molecule X by its member Y can generally be represented by the dissociation constant (KD) or amount of binding of analyte per unit amount of ligand (hereinafter referred to as amount of binding). Those skilled in the art will understand that, in general, a lower value of dissociation constant (KD) means higher binding activity, and a higher value of amount of analyte binding per unit amount of ligand or amount of binding means increased binding activity. Binding activity can be measured by common methods known in the art, including those described herein. Specific exemplary and illustrative modalities for measuring binding activity will be described below. An antigen-binding molecule or antibody matured for binding activity, or an antigen-binding molecule or antibody of increased (enhanced) binding activity refers to an antibody with one or more alterations in one or more hypervariable regions (HVRs). , as compared to a parent antigen binding molecule or a parent antibody that does not comprise these alterations, where such alterations result in an improvement in the binding activity of the antigen binding molecule or the antibody to the antigen. The terms anti-CD137 antigen-binding molecule or anti-CD137 antibody and an antigen-binding molecule that binds to CD137 or an antibody that binds to CD137 refer to an antigen-binding molecule or antibody that can bind to CD137. with sufficient binding activity such that the antibody or antigen binding molecule will be of utility as a diagnostic and / or therapeutic agent in targeting CD137. In certain embodiments, an anti-CD137 antibody binds to an epitope on CD137 that is conserved between CD137 from different species. The term "anti-CD137 antigen binding molecule or anti-CD137 antibody having small molecule compound-dependent CD137 binding activity" refers to an antigen binding molecule or antibody exhibiting increased CD137 binding activity. in the presence of the small molecule compound compared to CD137 binding activity in the absence of the small molecule compound. In one embodiment, the presence of a small molecule compound refers to Lnn / ίΖΠΖ / Β / ΥΙΛΙ Lnn / ίΖΠΖ / Β / ΥΙΛΙ that condition where the small molecule compound is present at a concentration of 10 micromolar or more, 50 micromolar or more, 100 micromolar or more, 150 micromolar or more, 200 micromolar or more, or 250 micromolar or more further. In one embodiment, the extent of binding activity of an anti-CD137 antibody or antigen-binding molecule to an unrelated, non-CD137 protein in the presence of a small molecule compound is less than about 10% binding. of the antigen or antibody binding molecule to CD137 measured, for example, by a radioimmunoassay (RIA) or by surface plasmon resonance (SPR). In certain embodiments, in the presence of a low molecular weight compound, an anti-CD137 antibody or antigen binding molecule has a dissociation constant (KD) of 1 micromolar or less, 100 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 0.01 nM or less, or 0.001 nM or less (for example, 10-6M or less, 10-7M or less, 10-8M or less, 10~9M or less, 10~ 10M or less, for example, between 10~6M and 10~10M, between 10~7M and 10~9M, for example, between 10~7M and 10~8M) . As used herein, the term "antigen-binding molecule" is used in its broadest sense, and refers to a molecule that specifically binds to an antigenic determinant. In one embodiment, the antigen binding molecule is an antibody, an antibody fragment, or an antibody derivative. An agonist antigen binding molecule or agonist antibody, as used herein, is an antibody or antigen binding molecule that significantly induces or potentiates a biological activity of the antigen to which it binds (eg, CD137 and CD3). Therefore, if the antigen is, for example, CD137, such an antigen-binding molecule or antibody having agonist action is called an agonist CD137 antigen-binding molecule or an agonist CD137 antibody, respectively. In the same way, if the antigen is, for example, CD3, such an antigen-binding molecule or antibody having agonist action is called an agonist CD3 antigen-binding molecule or agonist CD3 antibody, respectively. The term antibody is used herein in its broadest sense and encompasses various antibody structures including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecies antibodies (eg, bispecific antibodies), and antibody fragments as long as have the desired antigen binding activity. An antibody fragment refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds to antigen at the Lnn / ίΖΠΖ / Β / ΥΙΛΙ that binds intact antibody. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2,' diabodies; linear antibodies; single chain antibody molecules (eg, scFv); and multispecific antibodies formed from antibody fragments. An antigen-binding molecule that binds to the same epitope or antibody that binds to the same epitope as a reference antigen-binding molecule or reference antibody refers to an antibody or antigen-binding molecule that blocks binding of the same epitope. reference antibody or a reference antigen molecule binds its antigen in a competition assay by 50% or more, and, conversely, the reference antibody blocks the binding of the antibody to its antigen in a competition assay by 50% or more. An example of a proficiency test is provided here. In one embodiment, in the case where the reference antigen-binding molecule or reference antibody exhibits antigen-binding activity in a low-molecular-weight compound-dependent manner, the competitive assay is performed in the presence of the reference antibody. low molecular weight compound. The term "chimeric antibody" refers to an antibody in which a portion of the heavy chain and / or Lnn / ίΖΠΖ / Β / ΥΙΛΙ 100 light is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species. The class of an antibody refers to the type of constant domain or constant region present in its heavy chain. There are five broad classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and some of these can be further divided into subclasses (isotypes), for example, IgG1, IgG2, IgG3, IgG4, IgAl, and IgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. Effector functions refer to those biological activities attributable to the Fe region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: Clq binding and complement dependent cytotoxicity (CDC); Fe receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; decreased expression of cell surface receptors (eg, B cell receptors); and activation of B lymphocytes. Cytotoxicity refers to activity that inhibits or prevents cell function, and / or causes cell death or destruction. The cytotoxicity can be, for example, a cell-mediated cytotoxicity activity Lnn / ίΖΠΖ / Β / ΥΙΛΙ 101 antibody-dependent cytotoxicity (ADCC), a complement-dependent cytotoxicity (CDC) activity, and a T-cell cytotoxicity; and may be cytotoxicity caused by cytotoxic agents (eg, radioisotopes and chemotherapeutic agents) such as immunoconjugates. The term Fe region is used herein to define a C-terminal region of an immunoglobulin heavy chain that contains at least a constant region portion. The term includes native sequences of Fe regions and variant Fe regions. In one embodiment, a human IgG heavy chain Fe region extends from Cys226, or from Pro230, to the carboxy terminus of the heavy chain. However, the C-terminal Lysin (Lys447) or glycine-lysine (residues 446-447) of the Fe region may or may not be present. Unless otherwise specified herein, the numbering of amino acid residues in the Fe region or constant region is according to the EU numbering system, also known as the EU index, which is described in Kabat et al. ., Sequences of Proteins of Immunological Interest, 5th Edition Public Health Service, National Institutes of Health, Bethesda, MD, 1991. The term Fe region variant comprises herein an amino acid sequence that differs from the native sequence of the Fe region by at least one amino acid modification, preferably one or more amino acid substitutions. Lnn / ίΖΠΖ / Β / ΥΙΛΙ 102 amino acids. Preferably, the variant of an Fc region contains at least one amino acid substitution compared to a native sequence of the Fc region or the Fc region of a parent polypeptide, for example between about one and about ten amino acid substitutions, and preferably between about one and about five amino acid substitutions, either in the native sequence of the Fc region or in the Fc region of the parent polypeptide. The Fc region variant presently preferably has at least about 80% homology to a native Fc region sequence and / or to an Fc region of a parent polypeptide, and more preferably at least about 90% homology to the Fc region sequence. same, more preferably at least about 95% homology thereto. Herein, amino acid alterations or substitutions in an Fe region or a constant region may be represented by the combination of the EU numbering system and amino acids. For example, S424N represents a substitution at position 424 in accordance with EU numbering from serine (Ser) to asparagine (Asn). EU424N represents a substitution at position 424 according to EU numbering of an amino acid (of any type) with asparagine (Asn). The term antibody comprising an Fe region Lnn / ίΖΠΖ / Β / ΥΙΛΙ 103 refers herein to an antibody comprising an Fe region. The C-terminal lysine (residue 447 according to the EU numbering system) or a C-terminal glycine-lysine (residues 446-447) of the Fe region it can be removed, for example, during purification of the antibody or by recombinant modification of the nucleic acid encoding the antibody. Thus, a composition comprising an antibody having an F region according to the present disclosure may comprise an antibody with G446-K447, with G446 and without K447, with deletion of all G446-K447, or a mixture of all three. antibody types as described above. The terms full-length antibody, intact antibody, and whole antibody are used interchangeably herein to refer to an antibody that is substantially similar in structure to the structure of a native antibody or that has heavy chains that contain an Fe region or a variant. of a region Fe defined herein. A human antibody is one having an amino acid sequence corresponding to that of an antibody produced by a human or a human cell or one derived from a non-human source using repertoires of human antibodies or other human antibody-encoding sequences. This definition of a human antibody 104 specifically excludes humanized antibodies that comprise non-human antigen-binding residues. A framework or FR refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4. Therefore, the HVR and FR sequences generally appear in the following sequence in the VH (or VL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)FR4 . A human acceptor framework for purposes herein is a framework comprising the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human acceptor framework. human immunoglobulin or a human consensus framework, defined below. A human acceptor framework derived from a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence thereof, or may contain amino acid sequence changes. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the human VL acceptor framework is identical in sequence to the VL framework sequence of a human immunoglobulin or the consensus framework sequence. Lnn / ίΖΠΖ / Β / ΥΙΛΙ 105 human . A human consensus framework is a framework that represents the most common amino acid residues in a selection of VL or VH framework sequences of a human immunoglobulin. In general, the selection of the VL or VH sequences of a human immunoglobulin is from a subset of variable domain sequences. In general, the sequence subset is a subset of Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication, 91-3242, Bethesda MD (1991), Volumes 1-3. In one embodiment, for VL, the subgroup is the kappa I subgroup of Kabat et al., supra. In one embodiment, for OAB, the subgroup is subgroup III of Kabat et al., supra. A humanized antibody refers to a chimeric antibody comprising non-human HVR amino acid residues and human FR amino acid residues. In certain embodiments, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, all or substantially all of the HVRs (eg, CDRs) corresponding to those of a non-human antibody, and all or substantially all the RFs correspond to those of a human antibody. A humanized antibody may optionally comprise at least a portion of an antibody constant region derived from a Lnn / ίΖΠΖ / Β / ΥΙΛΙ 106 HUMAN ANTIBODY. A humanized form of an antibody, eg, a non-human antibody, refers to an antibody that has undergone humanization. The term variable region or variable domain refers to the domain of an antibody heavy or light chain, which is involved in the binding of the antibody to antigen. The heavy chain and light chain variable domains (Vh and Vl, respectively) of a native antibody generally have similar structures, each domain comprising four conserved framework regions (FR) and three hypervariable regions (HVR). (See, for example, Kindt et al. Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91 (2007). A single Vh or Vl domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind to a particular antigen can be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively See, for example, Portolano et al., J. Immunol 150: 880-887 (1993), Clarkson et al., Nature 352: 624-628 (1991). The term hypervariable region or HVR, as used herein, refers to each of the regions of an antibody variable domain that are sequence hypervariable (regions determining regions). Lnn / ίΖΠΖ / Β / ΥΙΛΙ Lnn / ίΖΠΖ / Β / ΥΙΛΙ 107 complementarity or CDR) and / or form structurally defined loops (hypervariable loops) and / or contain residues in contact with antigen (antigen contacts). In general, the antibodies comprise six HVRs: three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). Examples of HVR include herein: (a) hypervariable loops present at amino acid residues 26-32 (Ll), 50-52 (L2), 91-96 (L3), 26-32 (Hl), 53-55 (H2), and 96-101 ( H3) (Chothia and Lesk, J. Mol. Biol. 196: 901-917 (1987)); (b) CDRs present at amino acid residues 24-34 (Ll), 50-56 (L2), 89-97 (L3), 31-35b (Hl), 50-65 (H2) and 95-102 (H3 ) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition Public Health Service, National Institutes of Health, Bethesda, MD (1991)); (c) contacts of antigens present at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (Hl), 47-58 (H2) and 93-101 (H3) (MacCallum et al., J. Mol. Biol. 262: 732-745 (1996)); and (d) combinations of (a), (b) and / or (c), including HVR amino acid residues 46-56 (L2), 47-56 (L2), 48-56 (L2), 49 -56 (L2), 26-35 (Hl), 26-35b (Hl), 49-65 (H2), 93-102 (H3) and 94-102 (H3). Unless otherwise indicated, HVR residues and other variable domain residues (for example, 108 residues FR) are numbered herein according to Kabat et al., supra. Herein, HVR residues or other residues within a variable domain (eg, FR residues) and amino acid alterations or substitutions in such residues may be represented by the combination of the Kabat numbering system and amino acids. For example, N99 represents asparagine (Asn) at position 99 according to Kabat numbering, and N99A represents a substitution at position 99 according to Kabat numbering of asparagine (Asn) with alanine (Ala). An immunoconjugate is an antibody conjugated to one or more heterologous molecules, including, but not limited to, a cytotoxic agent. The term cytotoxic agent, as used herein, refers to a substance that inhibits or prevents a cell function and / or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (eg, 211At,131I,125I,90Y,186Re,188Re,153Sm,212Bi,32P,212Pb and the radioactive isotopes of Lu); chemotherapeutic agents or drugs (eg, methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin, or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof such as Lnn / ίΖΠΖ / Β / ΥΙΛΙ 109 nucleolytic enzymes, antibiotics and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and / or variants thereof, and the various antitumor or anticancer agents described below. An isolated antibody is one that has been separated from a component of its natural environment. In some embodiments, an antibody is purified to a purity greater than 95% or 99% determined, for example, by electrophoresis (for example, SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (for example, HPLC ion exchange or reverse phase). For a review of methods for assessing antibody purity, see, eg, Flatman et al., J. Chromatogr. B 848: 79-87 (2007). An isolated nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in cells that ordinarily contain the nucleic acid molecule, but such nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location. The term "vector" as used herein refers to a nucleic acid molecule capable of propagating Lnn / ίΖΠΖ / Β / ΥΙΛΙ 110 other nucleic acid to which it is attached. The term includes the vector as a self-replicating nucleic acid structure, as well as the vector incorporated into the genome of a host cell into which it was introduced. Certain vectors are capable of directing the expression of the nucleic acids to which they are operatively linked. These types of vectors are referred to herein as expression vectors. A nucleic acid encoding the anti-CD137 antigen binding molecule refers to one or more nucleic acid molecules that encode one or more of the polypeptides constituting the antigen binding molecule. An isolated nucleic acid encoding an anti-CD137 antibody refers to one or more nucleic acid molecules encoding the heavy and light chains (or fragments thereof) of an antibody, including nucleic acid molecules in a single vector or in separate vectors, and like nucleic acid molecules present at one or more locations in a host cell. The terms host cell, host cell line, and host cell culture are used interchangeably and refer to cells into which exogenous nucleic acids have been introduced, including the progeny of such cells. Host cells include transformants and transformed cells, which include Lnn / ίΖΠΖ / Β / ΥΙΛΙ 111 transformed primary cells and the progeny derived therefrom without regard to the number of passages. The progeny may not be completely identical, in terms of nucleic acid content, to a parent cell, but may contain mutations. Included herein are mutant progeny that have the same function or biological activity as that sought or selected for in the originally transformed cell. The term monoclonal antibody, as used herein, refers to an antibody derived from or belonging to a population of substantially homogeneous antibodies, that is, the individual antibodies that make up the population are identical and / or bind to the same epitope, except by possible antibody variants, eg, that contain natural mutations or that arise during the production of a monoclonal antibody preparation, where such variants are generally present in minor amounts. Unlike polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody in a monoclonal antibody preparation is directed against a single determinant on an antigen. Therefore, the monoclonal modifier indicates the character of the antibody as having been obtained from a substantially homogeneous population of antibodies, and not Lnn / ίΖΠΖ / Β / ΥΙΛΙ Lnn / ίΖΠΖ / Β / ΥΙΛΙ 112 implies that no particular method should be used in the production of antibodies. For example, the monoclonal antibodies to be used in accordance with the present disclosure can be obtained by a variety of techniques including, but not limited to, the hybridoma method, recombinant DNA methods, phage display methods, and methods that transgenic animals containing all or part of the human immunoglobulin loci, similar methods, and other exemplary methods are used to make the monoclonal antibodies described herein. A "naked" antibody refers to an antibody that is not conjugated to a heterologous moiety (eg, a cytotoxic moiety) or radiolabel. The naked antibody may be present in a pharmaceutical formulation. Native antibodies refer to natural immunoglobulin molecules with variable structures. For example, native IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 daltons, composed of two identical light chains and two identical heavy chains that are linked by disulfide bonds. Between the N- and C-terminus, each heavy chain has a variable (VH) region, also called the heavy variable domain or the variable domain. 113 heavy chain, followed by three constant domains (CH1, CH2 and CH3). Similarly, between the N- and C-terminal ends, each light chain has a variable region (VL), also called a variable light domain or a light chain variable domain, followed by a constant light (CL) domain. The light chain of an antibody can comprise one of two types, termed kappa (k) and lambda (λ), based on the amino acid sequence of its constant domain. Percent (%) amino acid sequence identity to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to amino acid residues in the reference polypeptide sequence, then to align the sequences and introduce gaps or mismatches, if necessary, to achieve the maximum percentage of sequence identity, and without considering any conservative substitutions as part of the sequence identity. Alignment to determine percent amino acid sequence identity can be performed in a number of ways that are within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN software. o Megalign (DNASTAR) o GENETYX (registered trademark) (Genetyx Lnn / ίΖΠΖ / Β / ΥΙΛΙ 114 Co., Ltd.) . Those skilled in the art can determine the appropriate parameters for aligning sequences, including any algorithms necessary to achieve maximum alignment over the full length of the sequences being compared. The ALIGN-2 sequence comparison computer program was created by Genentech, Inc., and the source code was filed with the user documentation at the U.S. Copyright Office, Washington D.C., 20559, where it is registered under Registry Number of United States Intellectual Property TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, or can be compiled from source code. The ALIGN-2 program must be compiled for use with a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are defined by the ALIGN-2 program and do not vary. In situations where ALIGN-2 is used for amino acid sequence comparisons, the % amino acid sequence identity of an amino acid sequence A to, with, or against a given amino acid sequence B (which, alternatively, can be put as a given amino acid sequence A having or comprising a given % amino acid sequence identity to, with, or against an amino acid sequence Lnn / ίΖΠΖ / Β / ΥΙΛΙ 115 given B) is calculated as follows: 100 times the fraction X / Y where X is the number of amino acid residues scored as identical matches by the ALIGN-2 sequence alignment program in the ALIGN-2 sequence alignment program of A and B, and where Y is the total number of residues of amino acids in B. It will be appreciated that when the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity between A and B will not equal the % sequence identity of amino acids between B and A. Unless specifically defined otherwise, all % amino acid sequence identity values ​​used herein are obtained as described in the preceding paragraph using the ALIGN-2 computer program. The term "pharmaceutical formulation" refers to a preparation that is in a form that will allow the biological activity of an active ingredient contained therein to be effective, and that does not contain additional components that are unacceptably toxic to a subject to whom it is administered. will administer the formulation. A pharmaceutically acceptable carrier refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, that is non-toxic to the subject. A pharmaceutically acceptable vehicle includes, but Lnn / ίΖΠΖ / Β / ΥΙΛΙ 116 in a non-limiting sense, a buffer, an excipient, a stabilizer or a preservative. An effective amount of an agent, eg, a pharmaceutical formulation, refers to an effective amount, at dosages and for periods of time necessary, to obtain the desired therapeutic or prophylactic result. An individual or subject is a mammal. Mammals include, but are not limited to, domesticated animals (for example, cows, sheep, cats, dogs, and horses), primates (for example, humans and non-human primates such as monkeys), rabbits, and rodents (for example, mice and rats). In certain embodiments, the individual or subject is a human being. The term CD137, as used herein, refers to any native CD137 from any vertebrate source, including mammals such as primates (eg, humans) and rodents (eg, mice and rats), unless otherwise indicated. otherwise. The term encompasses a full length unprocessed CD137, as well as any form of CD137 that resulted from processing in the cell. The term also encompasses natural variants of CD137, eg, splice variants or allelic variants. The amino acid sequence of an example of CD137 Lnn / ίΖΠΖ / Β / ΥΙΛΙ Full-length human 117 is shown in SEQ ID NO: 1 (NCBI, Reference Sequence: NP 001552.2) and an amino acid sequence of an example of the extracellular region of human CD137 is shown in SEQ ID NO: 2. amino acid sequence of an example of full-length mouse CD137 is shown in SEQ ID NO: 3 (NCBI, Sequence Reference: NP 035742.1) and an amino acid sequence of an example of the extracellular region of mouse CD137 is shown. in SEQ ID NO: 4. The amino acid sequence of an example of full-length monkey CD137 is shown in SEQ ID NO: 5 (NCBI, Reference Sequence: ABY47575.1) and an amino acid sequence of an example of the extracellular region of monkey CD137 is shown in SEQ ID NO: 6. CD137 is a member of the tumor necrosis factor (TNF) receptor family. Its alternative names are tumor necrosis factor receptor superfamily member 9 (TNFRSF9), 4-1BB, and ILA. In addition to its expression on activated CD4+ and CD8+ T cells, CD137 is expressed on B cells, dendritic cells, natural killer (NK) and N T cells, macrophages, monocytes, neutrophils, CD4+ CD25+ regulatory T cells, and CD4+ CD25+ T cells. of the vascular endothelium. Its expression in cancer cells has also been reported (Labiano, et al., Oncoimmunology, Volume 24: el062967 (2015)). The natural CD137 ligand, CD137L, is presented by antigen-presenting cells. Lnn / ίΖΠΖ / Β / ΥΙΛΙ 118 such as B cells, monocytes / macrophages and dendritic cells (Watts, et al., Annu. Rev. Immunol., Volume 23: pages 23-68 (2005)). This interaction with the ligand allows CD137 to increase TCR-induced T cell proliferation, cytokine production, functional maturation, suppression of apoptosis, and long-term survival of CD8+ T cells (Nam, et al., Curr. Cancer Drug Targets, Volume 5: pages 357-363 (2005; Watts, et al., Annu. Rev. Immunol., Volume 23: pages 23-68 (2005)). The terms carcinoma, cancer, and cancerous refer to or describe the physiological condition in mammals typically characterized by unregulated cell growth / proliferation. The term tumor refers to all growth and proliferation of neoplastic cells, whether malignant or benign, and all precancerous and cancerous cells and tissues. The terms carcinoma, cancer, cancerous, proliferative cell disorder, proliferative disorder, and tumor are not mutually exclusive as used herein. The terms proliferative cell disorder and proliferative disorder refer to disorders that are associated to some degree with abnormal cell proliferation. In one embodiment, the proliferative cell disorder is cancer. Lnn / ίΖΠΖ / Β / ΥΙΛΙ 119 As used herein, a treatment (and grammatical variations thereof, such as treat or treating) refers to a clinical intervention in an attempt to alter the natural course of the individual or cell under treatment, and may be for prophylaxis. or during the course of a clinical pathology. Desirable effects of treatment include, but are not limited to, prevention of disease onset or recurrence, relief of symptoms, reduction of any direct or indirect pathological consequences of the disease, prevention of metastasis, slowing of the rate of progression of the disease, alleviation or palliation of the disease state and remission or improvement of the prognosis. In some embodiments, the antibodies of the present disclosure are used to delay the development of a disease or to slow the progress of a disease. II. Compositions and Methods (Anti-CD137 Agonist Antigen-Binding Molecules) In one aspect, the present disclosure is based, in part, on agonist anti-CD137 antigen binding molecules and their uses. In certain embodiments, antibodies that bind to CD137 are provided. The antibodies of the present description may have an activating action on immune cells, cytotoxicity or antitumor activity and are therefore useful, for example, in Lnn / ίΖΠΖ / Β / ΥΙΛΙ 120 the diagnosis or treatment of cancer. A. Examples of antigen-binding molecules or anti-CD137 antibodies In one aspect, the present disclosure provides isolated antigen binding molecules or antibodies that bind to CD137. In certain embodiments, antigen-binding molecules or anti-CD137 antibodies - have CD137 binding activity dependent on a small molecule compound; - bind to the extracellular region of CD137; they form a ternary complex together with a low molecular weight compound and CD137; - bind to a human-derived CD137 and a monkey-derived CD137; - are agonists of CD137 activity; show CD137 agonist activity in the presence of a low molecular weight compound; - have a low agonist activity with CD137 in the absence of the low molecular weight compound; I - they do not exhibit substantially agonist activity for CD137 in the absence of the low molecular weight compound. Binding activity of antigen-binding molecules or antibodies In certain embodiments, the binding activity of 121 The antigen or antibody binding molecules provided herein comprise, in the presence of a low molecular weight compound, a dissociation constant (KD) of 1 micromolar or less, 100 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 0.01 nM or less, or 0.001 nM or less (for example, 10~6M or less, 10~7M or less, 10~8M or less, 10~9M or less, 10~10M or less, for example between 10~6M and 10_ 10M, between 10-7M and 10-9M, for example between ΙΟ-7M and 10-8M) . In one embodiment, the binding activity of an antibody or antigen binding molecule is measured by a radiolabeled antigen binding assay (RIA) and represented by the KD value. In one embodiment, a RIA is conducted with the Fab version of an antibody of interest and its antigen. For example, the solution binding affinity of Fab for antigen is measured by equilibrating the Fab with a minimal concentration of (125I)-labelled antigen in the presence of a titration series of unlabelled antigen, then capturing the bound antigen with a plate coated with the anti-Fab antibody (see, for example, Chen et al., J. Mol. Blol., 293: 865-881(1999)). To establish assay conditions, MICROTITER (Trade Mark) multiwell plates (Thermo Scientific) are coated overnight with 5 microgram / ml of an anti-Fab capture antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), and then blocked with 2% (w / v) of Lnn / ίΖΠΖ / Β / ΥΙΛΙ Lnn / ίΖΠΖ / Β / ΥΙΛΙ 122 bovine serum albumin in PBS for two to five hours at room temperature (approximately 23 degrees C). On a non-adsorbent plate (Nunc #: 269620), mix 100 pM or 26 pM [ 125 I]-antigen serial dilutions of a Fab of interest (eg, consistent with the evaluation of the anti-VEGF antibody, Fab-12 , in Presta et al., Cancer Res. 57: 45934599 (1997)). The Fab of interest is then incubated overnight; however, incubation may continue for a longer period (eg, about 65 hours) to ensure that equilibration is reached. The mixtures are then transferred to the capture plate for incubation at room temperature (eg, for one hour). The solution is then removed and the plate is washed eight times with 0.1% polysorbate 20 (TWEEN-20 (Trade Mark)) in PBS. When the plates are dry, 150 microliters / well scintillation fluid (MICROSCINT-20™; Packard) is added and the plates are counted in a TOPCOUNT™ gamma counter (Packard) for ten minutes. Concentrations of each Fab giving less than or equal to 20% maximum binding are chosen for use in competitive binding assays. In one embodiment, to measure the binding activity of an antibody, ligand capture methods are employed, for example, using BIACORE (trademark) T200 or BIACORE (trademark) 4000 (GE Healthcare, Uppsala, Sweden), which Lnn / Lznz / Ε / ΥΙΛΙ 123 is based on surface plasmon resonance analysis methods as the measurement principle. The control software of BIACORE (registered trademark) is used for the operation of the devices. In one embodiment, an amine coupling kit (GE Healthcare, Uppsala, Sweden) is used according to the supplier's instructions to attach a ligand-capture molecule, eg, an anti-label antibody, an anti-IgG antibody , protein A, etc. on a sensor chip (GE Healthcare, Uppsala, Sweden) coated with carboxymethyldextran. The ligand capture molecule is diluted with 10 mM sodium acetate solution at an appropriate pH and injected at the appropriate flow rate and for the appropriate injection time. Measurements of binding activity are measured using a buffer containing 0.05% polysorbate 20 (other name: Tween (Trade Mark)-20) as measurement buffer, at a flow rate of 10-30 microliters / minute. and at a measurement temperature of preferably 25 degrees C or 37 degrees C. For measurement performed with an antibody captured by the ligand capture molecule as a ligand, an antibody is injected to allow the capture of an amount of interest of the captured antibody, and then a serial dilution of an antigen and / or an Fe receptor (analyte) that was prepared using the Fe buffer solution is injected. 124 measurement. For measurement performed with an antigen and / or Fe receptor captured by the ligand capture molecule as ligand, an antigen and / or Fe receptor is injected to allow the capture of an amount of interest thereof, and then a serial dilution of an antibody (analyte) that was prepared using the measurement buffer is injected. In one embodiment, the measurement results are analyzed using BIACORE (registered trademark) evaluation software. Kinetics parameter calculation is carried out by fitting association and dissociation sensorograms at the same time using a 1:1 binding model, and the association rate (kasOc or ka), the dissociation rate (kdisoc or kd ) and the equilibrium dissociation constant (KD). In the case of weak binding activity, particularly in cases where dissociation is rapid and kinetic parameters are difficult to calculate, the steady-state model can be used to calculate the equilibrium dissociation constant (KD). . As additional parameters relating to binding activity, the amount of analyte binding per unit amount of ligand can be calculated by dividing the amount of analyte binding (resonance unit: RU) at a specific concentration by an amount of the captured ligand. Lnn / ίΖΠΖ / Β / ΥΙΛΙ Lnn / ίΖΠΖ / Β / ΥΙΛΙ 125 Binding activity dependent on a small molecule compound In one aspect, the anti-CD137 antibody or antigen binding molecule has small molecule compound-dependent CD137 binding activity. In a non-limiting embodiment, the anti-CD137 antibody or antigen binding molecule has increased CD137 binding activity in the presence of a small molecule compound compared to CD137 binding activity in the absence of the small molecule compound. small. In a different embodiment, the anti-CD137 antibody or antigen binding molecule has increased CD137 binding activity in the presence of a high concentration of a small molecule compound compared to CD137 binding activity in the presence of a low concentration of the small molecule compound. In a preferred embodiment, the binding activity of the anti-CD137 antibody or antigen binding molecule to CD137 in the presence of a small molecule compound is 2-fold or more, 3-fold or more, 5-fold or more, 10-fold or more, 15 times or more, 20 times or more, 25 times or more, 30 times or more, 50 times or more, 100 times or more, 200 times or more, 300 times or more, 500 times or more 1 x 103 times or more, 2 x 103 times or more, 3 x 103 times or more, 5 x 103 times or more, 1 x 104 times or more, 2 x 104 times or more, 3 x 104 times or more, 5 x 104 times or more, or 1 x 105 times or more , compared Lnn / ίΖΠΖ / Β / ΥΙΛΙ 126 with the binding activity in the absence of the small molecule compound. In a different preferred embodiment, the binding activity of the anti-CD137 antibody or antigen binding molecule to CD137 in the presence of a small molecule compound is greater than 2-fold, greater than 3-fold, greater than 5-fold greater, more than 10 times greater, more than 15 times greater, more than 20 times greater, more than 25 times greater, more than 30 times greater, more than 50 times greater, more than 100 times greater, more than 200 times, more more than 300 times greater, more than 500 times greater, more than 1 x 103 times, more than 2 x 103 times, more than 3 x 103 times greater, more than 5 x 103 times greater, more than 1 x 104 times greater, more than 2 x 104 times greater , greater than 3 x 104 times greater, greater than 5 x 104 times greater, or greater than 1 x 105 times greater, compared to the binding activity in the absence of the small molecule compound. The concentration of the small molecule compound can comprise any arbitrary concentration as long as a difference in the binding activity of the anti-CD137 antibody or antigen binding molecule can be detected. In one embodiment, the concentration of the small molecule compound in the presence of a small molecule compound and / or in the presence of a high concentration of a small molecule compound comprises, for example, 100 nM or more, 50 0 nM or more, 1 μΜ or more, 3 μΜ or more, 5 μΜ or more, 10 μΜ or more, 50 μΜ or more, 100 μΜ or more, 150 μΜ or more, 200 μΜ or more 127 Lnn / ίΖΠΖ / Β / ΥΙΛΙ more, 250 μΜ or more, 300 μΜ or more, 400 μΜ or more, 500 μΜ or more, or 1 mM or more. Alternatively, the concentration can be defined as the amount that is sufficient for the anti-CD137 antibody or antigen binding molecule to exhibit maximal binding activity. Furthermore, in one embodiment, the concentration of the small molecule compound in the presence of a low concentration of a small molecule compound may comprise, for example, 500 μΜ or less, 250 μΜ or less, 200 μΜ or less, 150 μΜ or less. less, 100 μΜ or less, 50 μΜ or less, 10 μΜ or less, 1 μΜ or less, 50 0 μM or less, 100 nM or less, 50 nM or less, or lOnM or InM or less. The case where the concentration of the small molecule compound is zero, or the substantial concentration is zero, can also be selected as a low concentration mode. Here, the term "substantial concentration is zero" means, for example, a concentration that is so low that it cannot be detected by current technology even though the small molecule compound is present. In one embodiment, the CD137 binding activity in the presence of a small molecule compound at a concentration of 10 μΜ, 50 μΜ, 100 μΜ, 150 μΜ, 200 μΜ or 250 μΜ is 2-fold or more, 5-fold or more, 10 times or more, 15 times or more, 16 times or more, 17 times or more, 18 times or more, 19 times or more, or 20 times or more, compared to the Lnn / ίΖΠΖ / Β / ΥΙΛΙ 128 CD137 binding activity in the absence of the small molecule compound. In one embodiment, the binding activity of the antigen binding molecule or an anti-CD137 antibody against CD137 in the presence of a small molecule compound at 10 μΜ or more is 2-fold or more, 5-fold or more, 10 times or more, 15 times or more, 16 times or more, 17 times or more, 18 times or more, 19 times or more, or 20 times or more, compared to the CD137 binding activity in the absence of the molecule compound small. In one embodiment, the binding activity of the antigen binding molecule or an anti-CD137 antibody against CD137 in the presence of a small molecule compound at 100 μΜ or more is 2-fold or more, 5-fold or more, 10 times or more, 15 times or more, 16 times or more, 17 times or more, 18 times or more, 19 times or more, or 20 times or more, compared to the CD137 binding activity in the absence of the molecule compound small. In one embodiment, the binding activity (KD) of the anti-CD137 antibody or antigen binding molecule to CD137 in the presence of a small molecule compound at 10 mM or greater exhibits a dissociation constant (KD) of 9 x 10~7M or less, 8 x 10~7M or less, 7 x 10~7M or less, 6 x 10~7M or less, 5 x 10~7M or less, or 4 x 10~7M or less, or preferably, a dissociation constant (KD) of 5 x 10~7M or less. In a further embodiment, the binding activity (KD) of the binding molecule to the anti-129 antigen or antibody Lnn / ίΖΠΖ / Β / ΥΙΛΙ CD137 to CD137 in the absence of a small molecule compound is too large to be calculated by Biacore (weak binding activity), or has a dissociation constant (KD) of 1 x ΙΟ-7M or more, 5 x ΙΟ- 7M or more, 7 x 10~7M or more, 8 x 10~7M or more, 9 x 10~7M or more, 1 x ICE6M or more, 2 x 10~6M or more, 3 x 10~6M or more, or 4 x 10~6M or more, or preferably, a dissociation constant (KD) of 1 x ΙΟ-6M or more. In another embodiment, the binding activity (KD) of the antigen binding molecule or an anti-CD137 antibody to CD137 in the presence of a small molecule compound at 100 mM or more comprises 9 x 10 -7M or less, x 10~7M or less, 7 x 10~7M or less, 6 x 10~7M or less, 5 x 10~7M or less, 4 x 10~7M or less, 3 x 10~7M or less, 2 x 10~7 M or less, or 1 x 10~7M or less, or preferably, the dissociation constant (KD) comprises 2 x 10~7M or less. In a further embodiment, the binding activity (KD) of the antigen binding molecule or an anti-CD137 antibody to CD137 in the absence of the small molecule compound is too large to be calculated by Biacore (weak binding activity). , or has a dissociation constant (KD) of 1 x 10~7M or more, 5 x 10~7M or more, 7x 10~7M or more, 8 x ICr7M or more, 9 x 10-7M or more, 1 x 10-6M or more, 2 x 10~6M or more, 3 x 10~6M or more, or 4 x 10~6M or plus, or preferably, a dissociation constant (KD) of 1 x 10~6 M or more. Lnn / ίΖΠΖ / Β / ΥΙΛΙ 130 In one embodiment, the binding activity (KD) of the anti-CD137 antibody or antigen binding molecule to CD137 in the presence of a small molecule compound at 10 μΜ or greater comprises a dissociation constant (KD) of 8 x ΙΟ-8M or less, and the binding activity (KD) to CD137 in the absence of compound is too large to be calculated by Biacore (weak binding activity). In another embodiment, the binding activity (KD) of the anti-CD137 antibody or antigen binding molecule to CD137 in the presence of a small molecule compound at 100 mM comprises a dissociation constant (KD) of 2 x 10~ 8M or less, and the binding activity to CD137 in the absence of the small molecule compound is too great to be calculated by Biacore (weak binding activity). In one aspect, the present disclosure provides an anti-CD137 antibody or antigen binding molecule wherein the value of [binding activity (amount of binding) to CD137 in the presence of a low molecular weight compound at 10 μΜ or more ] / [binding activity (amount of binding) to CD137 in the absence of the small molecule compound) ] is equal to or greater than the value of a reference anti-CD137 antigen binding molecule. In a different aspect, the present disclosure provides an anti-CD137 antibody or antigen binding molecule wherein the value of [binding activity (amount of binding) to CD137 in the Lnn / ίΖΠΖ / Β / ΥΙΛΙ 131 presence of a low molecular weight compound at 100 μΜ or more] / [binding activity (amount of binding) to CD137 in the absence of the small molecule compound)] is equal to or greater than the value of a binding molecule to the reference anti-CD137 antigen. In any of the preceding aspects, the reference anti-CD137 antigen binding molecule can be selected from among anti-CD137 antibodies containing the HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2 and HVR -L3 having the same amino acid sequences as HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2 and HVR-L3 contained in A375 / B167, A372 / B040, A356 / B040, A486 / B167, A487 / B167, A488 / B226, A489 / B223, A548 / B376, A551 / B256, A551 / B379, A555 / B379, A548 / B256 or A549 / B167 described in Table 17. In one embodiment, the reference anti-CD137 antigen binding molecule is an antibody comprising the amino acid sequence of A375 / B167, A372 / B040, A356 / B040, A486 / B167, A487 / B167, A488 / B226, A489 / B223, A548 / B376, A551 / B256, A551 / B379, A555 / B379, A548 / B256 or A549 / B167 described in Table 17 as a heavy chain variable region / light chain variable region combination. In a preferred embodiment, the reference antigen binding molecule is an anti-CD137 antibody comprising HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2 and HVR-L3 that have the same sequences. of amino acids than HVRH, HVR-H2, HVR-H3, HVR-L1, HVR-L2 and HVR-L3 included in Lnn / ίΖΠΖ / Β / ΥΙΛΙ 132 Α375 / Β167. In a further embodiment, the reference anti-CD137 antigen binding molecule is an anti-CD137 antibody comprising A375 / B167 as a heavy chain variable region / light chain variable region combination. In a different preferred embodiment, the reference antigen binding molecule is an anti-CD137 antibody comprising HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2 and HVR-L3 that have the same amino acid sequences than HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2 and HVR-L3 comprised in A551 / B379. In a further embodiment, the reference anti-CD137 antigen binding molecule is an anti-CD137 antibody comprising A551 / B379 as a heavy chain variable region / light chain variable region combination. In a preferred embodiment, the reference antigen binding molecule comprises heavy and light chain constant regions of human origin (eg, G1T3 (SEQ ID NO: 138) as heavy chain constant region, Lamlib human λ chain ( SEQ ID NO: 63) as a constant region of the light chain). In one aspect, the present disclosure provides an anti-CD137 antibody or antigen binding molecule wherein the binding activity (amount of binding) to CD137 in the absence of a small molecule compound is equal to or less than that of a small molecule. of binding to the reference anti-CD137 antigen, and in addition, the binding activity (amount of Lnn / ίΖΠΖ / Β / ΥΙΛΙ 133 binding) to CD137 in the presence of the small molecule compound at 10 μΜ or more is equal to or greater than that of the reference anti-CD137 antigen binding molecule to CD137 under the same conditions. In a different aspect, the present disclosure provides an anti-CD137 antigen binding molecule or antibody wherein the binding activity (amount of binding) to CD137 in the absence of a small molecule compound is equal to or less than that of CD137. a reference anti-CD137 antigen binding molecule, and in addition, the binding activity (amount of binding) to CD137 in the presence of the small molecule compound at 10 μΜ or more is equal to or greater than that of the binding molecule to the anti-CD137 antigen of reference to CD137 under the same conditions. In any of the preceding aspects, the reference anti-CD137 antigen binding molecule can be selected from among anti-CD137 antibodies containing the HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2 and HVR -L3 having the same amino acid sequences as HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2 and HVR-L3 contained in A375 / B167, A372 / B040, A356 / B040, A486 / B167, A487 / B167, A488 / B226, A489 / B223, A548 / B376, A551 / B256, A551 / B379, A555 / B379, A548 / B256 or A549 / B167 described in Table 17. In one embodiment, the reference anti-CD137 antigen binding molecule is an anti-CD137 antibody comprising the amino acid sequence of A375 / B167, 134 Α372 / Β040, Α356 / Β040, Α486 / Β167, Α487 / Β167, Α488 / Β226, Α489 / Β223, Α548 / Β376, Α551 / Β256, Α551 / Β379, Α548 / Β55 or Β25 549 / B167 described in the Table 17 as a heavy chain variable region / light chain variable region combination. In a different preferred embodiment, the reference antigen binding molecule is an anti-CD137 antibody comprising HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2 and HVR-L3 that have the same amino acid sequences than HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2 and HVR-L3 comprised in A375 / B167. In a further embodiment, the reference anti-CD137 antigen binding molecule is an anti-CD137 antibody comprising A375 / B167 as a heavy chain variable region / light chain variable region combination. In a preferred embodiment, the reference antigen binding molecule is an anti-CD137 antibody comprising HVRH1, HVR-H2, HVR-H3, HVR-L1, HVR-L2 and HVR-L3 that have the same amino acid sequences. than HVR-H1, HVR-H2, HVRH3, HVR-L1, HVR-L2 and HVR-L3 included in A551 / B379. In a further embodiment, the reference anti-CD137 antigen binding molecule is an anti-CD137 antibody comprising A551 / B379 as a heavy chain variable region / light chain variable region combination. In a preferred embodiment, the reference antigen binding molecule comprises constant chain regions Lnn / ίΖΠΖ / Β / ΥΙΛΙ 135 heavy and light chain of human origin (eg, G1T3 (SEQ ID NO: 138) as the heavy chain constant region, Lamlib human λ chain (SEQ ID NO: 63) as the light chain constant region). In one aspect, the present disclosure provides an anti-CD137 antibody or antigen binding molecule wherein the value of, [binding activity (KD) to CD137 in the presence of a low molecular weight compound at 1 μΜ] / [ binding activity (KD) to CD137 in the presence of the low molecular weight compound at ΙΟμΜ or more] is equal to or greater than the value of a reference antigen binding molecule. In a different aspect, the present disclosure provides an anti-CD137 antibody or antigen binding molecule wherein the value of, [binding activity (KD) to CD137 in the presence of a low molecular weight compound at 1 μΜ] / [binding activity (KD) to CD137 in the presence of the low molecular weight compound at 100 μΜ or more] is equal to or greater than the value of a reference antigen binding molecule. In any of the preceding aspects, the reference antigen binding molecule can be selected from anti-CD137 antibodies containing the HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2 and HVR-L3 that have the same amino acid sequences as HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2 and HVR-L3 contained in A375 / B167, A372 / B040, A356 / B040, A486 / B167, A487 / B167, A488 / B226, 136 Α489 / Β223, Α548 / Β376, Α551 / Β256, Α551 / Β379, Α555 / Β379, Α548 / Β256 or A549 / B167 described in Table 17. In one embodiment, the reference antigen binding molecule is an antibody comprising the amino acid sequence of A375 / B167, A372 / B040, A356 / B040, A486 / B167, A487 / B167, A488 / B226, A489 / B223, A548 / B376, A551 / B256, A551 / B379, A555 / B379, A548 / B256 or A549 / B167 described in Table 17 as a heavy chain variable region / light chain variable region combination. In a preferred embodiment, the reference antigen binding molecule is an antibody comprising HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 that have the same amino acid sequences as the HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2 and HVR-L3 included in A375 / B167. In a further embodiment, the reference antigen binding molecule is an antibody comprising A375 / B167 as a heavy chain variable region / light chain variable region combination. In a different embodiment, the reference antigen-binding molecule is an antibody comprising HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 that have the same amino acid sequences as the HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2 and HVR-L3 included in A551 / B379. In a further embodiment, the reference antigen binding molecule is an antibody comprising A551 / B379 as a combination of the region 137 heavy chain variable / light chain variable region. In a preferred embodiment, the reference antigen binding molecule comprises heavy and light chain constant regions of human origin (eg, G1T3 (SEQ ID NO: 138) as heavy chain constant region, Lamlib human λ chain ( SEQ ID NO: 63) as a constant region of the light chain). In one embodiment, the binding activity of the anti-CD137 antibody to CD137, in the presence, absence, high concentration, and / or low concentration of a small molecule compound, is measured, for example, by a ligand capture method. using BIACORE (registered trademark) T200 with surface plasmon resonance spectroscopy as measurement principle. Details of an exemplary method for measuring anti-CD137 antibody binding activity to CD137 are described below. In one embodiment, the binding activity of the anti-CD137 antibody to CD137 is assessed by BIACORE (Trade Mark) T200. In a preferred embodiment, this assay uses 20 mM ACES (pH 7.4), 150 mM NaCl, 2 mM MgC12, and 0.05% Tween 20 as running buffer and is performed at 37°C. In one embodiment, this measurement is made after capturing an antibody as a ligand with the ligand capture molecule. Specifically, an adequate amount is caught (for Lnn / ίΖΠΖ / Β / ΥΙΛΙ Lnn / ίΖΠΖ / Β / ΥΙΛΙ 138 example, approximately 100 RU, 200 RU, 300 RU, 400 RU or 500 RU) of the antibody by interaction of an antibody solution prepared using the running buffer with a chip already prepared by immobilization of Protein A Sure (GE Healthcare ) with the S Series CM3 sensor chip (GE Healthcare). In a preferred embodiment, between about 100 and 500 RU, preferably between about 250 and 400 RU of antibody are captured. Next, CD137 binding activity in the presence and absence of a small molecule compound is assessed by interaction of a CD137 solution prepared using a running buffer to which a small molecule compound has been added at a target concentration. (eg, 1 mM, 10 mM, 50 mM, or 100 mM), or a solution of CD137 prepared using a running buffer that does not contain the small molecule compound. Although the concentration of CD137 in the CD137 solution can be appropriately determined, for example, when hCD137HisBAP (see Example 1-1) is used as the antigen, the measurement is carried out using an antigen concentration of 0 nM, 15.625 nM. , 62.5 nM, 250 nM, and 1000 nM, respectively. In one embodiment, the dissociation constant (KD) for the anti-CD137 antibody to human CD137 is calculated using Biacore T200 2.0 evaluation software. Specifically, the Lnn / ίΖΠΖ / Β / ΥΙΛΙ 139 binding rate constant ka (L / mol / s) and dissociation rate constant kd (1 / s) are calculated by a global fit of a sensorogram obtained by measurement using the 1:1 Langmuir binding model . The dissociation constant KD (mol / 1) is calculated from these values. In the following, other examples of assay methods for measuring the binding activity of the anti-CD137 antibody to CD137 will be described in detail. Binding of anti-CD137 antibodies to human CD137 is assessed with Biacore T200. Binding to human CD137 was measured using 20 mM ACES (pH 7.4), 150 mM NaCl, 2 mM MgC12 and 0.05% Tween 20 as running buffer and this was done at 37°C. First, an antibody between approximately 250 and 400 RU is captured by interaction of an antibody solution prepared using the running buffer with a chip already immobilized with Protein A Sure (GE Healthcare) on a Series S CM3 sensor chip. (GE Healthcare). Next, a solution of human CD137 prepared using a running buffer to which ATP has been added at a target concentration (eg, 1 mM, 10 mM, 50 mM, or 100 mM) and a solution of CD137 are interacted. prepared using a running buffer containing no ATP, to assess CD137 binding activity in the presence and Lnn / ίΖΠΖ / Β / ΥΙΛΙ 140 absence of ATP. The hCD137-HisBAP prepared by the method of Example (1-1) is used as human CD137 which is the antigen, and the measurement is carried out at antigen concentrations of 0 nM, 15.625 nM, 62.5 nM, 250 nM and 1000 nM, respectively. The chip is regenerated using 25 mM NaOH and 10 mM glycine-HCl (pH 1.5), and the measurement is performed by repeated capture of the antibodies. The dissociation constant of each antibody to human CD137 is calculated using the Biacore T200 2.0 evaluation software. Specifically, the binding rate constant ka (L / mol / s) and the dissociation rate constant kd (1 / s) are calculated by a global fit of the sensorogram obtained by a measurement using the Langmuir binding model 1 :1. The dissociation constant KD (mol / 1) is calculated from these values. In one embodiment, the binding activity of the anti-CD137 antibody to CD137 (preferably human CD137) can also be expressed as the amount of binding to CD137 per unit amount of antibody. Specifically, using the sensorograms obtained by the above assay method using BIACORE (Trade Mark) T200, the amount of CD137 binding to the antibody (RU) is divided by the amount of antibody captured to calculate the amount of CD137 binding per unit amount. of antibody. In one embodiment, the binding activity of the Anti-CD137 antibody to CD137 (preferably human CD137) can also be measured by the method described in Example 5-3 or 6-2. The terms small molecule and small molecule compound refer to a natural chemical substance other than biopolymers present in the living organism or to an unnatural chemical substance. Preferably, it is, but is not limited to, a compound specific to the tissue of interest or a non-natural compound. In one embodiment, the small molecule compound of the present disclosure is a cancer tissue-specific compound or a cancer tissue-specific metabolite. In the present description, the term a cancer tissue-specific compound (cancer tissue-specific compound) refers to a compound that differentially exists in a tumor tissue, compared to a non-tumor tissue. As used herein, the term cancer is generally used to describe a malignant neoplasm and can be metastatic or non-metastatic. The term metabolism refers to the chemical changes that take place within the tissue of an organism, including assimilation and catabolism. Assimilation refers to the biosynthesis or accumulation of molecules, and catabolism refers to the breakdown of molecules. A metabolite is an intermediate or product resulting from the metabolism of substances. Lnn / ίΖΠΖ / Β / ΥΙΛΙ 142 The term "target tissue or tissue of interest" refers to any tissue of the living organism to which it is intended to deliver the antigen-binding molecule of the present invention. The target tissue may be a histologically distinguishable tissue, such as from various organs, or a pathologically distinguishable tissue, such as normal tissues and diseased tissues. In certain embodiments, the target tissue is a tumor tissue. In contrast, a non-target tissue refers to tissues in the living organism other than the target tissue. The term "tumor tissue" refers to a tissue that comprises at least one tumor cell. In general, a tumor tissue is made up of a population of humoral cells that constitute the main body of the tumor (parenchyma) and the connective tissues and blood vessels that exist between the tumor cells and provide support to the tumor (stroma). In some cases they are clearly distinguishable, but there are cases where they are interspersed. In some cases, there are cells such as immune cells that have infiltrated the tumor tissue. In contrast, a non-tumor tissue refers to a tissue in the living body other than one or more tumor tissues. Healthy non-disease tissues / normal tissues are representative of such non-tumor tissues. Lnn / ίΖΠΖ / Β / ΥΙΛΙ 143 By way of a non-limiting embodiment of a cancer tissue-specific compound, or cancer tissue-specific metabolite, as used herein, at least one compound selected from the compounds listed below are suitable examples. The meaning of at least one compound includes, in addition to the case where the antigen-binding activity by the same antigen-binding domains described below depends on a cancer tissue-specific type of compound or a cancer tissue-specific metabolite, in the case where the binding activity depends on several types of cancer tissue-specific compounds or cancer tissue-specific metabolites. As used herein, the term "target tissue-specific compound" refers to a compound that is differentially present in target tissue compared to non-target tissue. In various embodiments, the target tissue-specific compound may be a compound defined by a qualitative specificity to the target tissue such as presence in the target tissue but not in non-target tissues, or presence in a non-target tissue but not in the target tissue. In a different embodiment, the target tissue-specific compound may be a compound 144 defined by a quantitative target tissue specificity such as the presence in the target tissue at a concentration that is different (eg, a higher concentration or a lower concentration) compared to a non-target tissue. In a specific embodiment, the target tissue-specific compound is present in the target tissue at a concentration that is, for example, 1.05-fold or more, 1.1-fold or more, 1.15-fold or more, 1.2-fold or more, 1.25-fold or more, 1.3 times or more, 1.35 times or more, 1.4 times or more, 1.45 times or more, 1.5 times or more, 1.55 times or more, 1.6 times or more, 1.65 times or more, 1.7 times or more, 1.75 times or more more, 1.8 times or more, 1.85 times or more, 1.9 times or more, 1.95 times or more, 2 times or more, 2.1 times or more, 2.2 times or more, 2.3 times or more, 2.4 times or more, 2.5 times or more, 3 times or more, 5 times or more, 10 times or more, 50 times or more, 100 times or more, 103 times or more, 104 times or more, 105 times or more, 106 times or more, or more compared to tissue non objective. In another embodiment, the target tissue-specific compound is present in the target tissue at a concentration that is, for example, 1.05-fold or more, 1.1-fold or more, 1.15-fold or more, 1.2-fold or more, 1.25-fold or more , 1.3 times or more, 1.35 times or more, 1.4 times or more, 1.45 times or more, 1.5 times or more, 1.55 times or more, 1.6 times or more, 1.65 times or more, 1.7 times or more, 1.75 times or more , 1.8 times or Lnn / ίΖΠΖ / Β / ΥΙΛ 145 more, 1.85 times or more, 1.9 times or more, 1.95 times or more, 2 times or more, 2.1 times or more, 2.2 times or more, 2.3 times or more, 2.4 times or more, 2.5 times or more, 3 times or more, 5 times or more, 10 times or more, 50 times or more, 100 times or more, 103 times or more, 104 times or more, 105 times or more, 106 times or more, or more compared to a non-target tissue. In a specific embodiment, a compound specific to the tissue of interest, as compared to a non-target tissue, is present in a target tissue at a concentration that is statistically significantly higher or lower (i.e., determined using any of the Welch's t-test or Wilcoxon rank-sum test, where the p-value is less than 0.05 and / or the q-value is less than 0.10). In a specific embodiment, the target tissue-specific compound is a tumor tissue-specific compound. In a specific embodiment, a tumor tissue-specific compound is a metabolite produced by the specific metabolism of a tumor cell. The metabolite can be a product generated by metabolism essential for life activities (primary metabolite) or a product generated by metabolism that is not necessarily required for life activities (secondary metabolite). Examples of primary metabolites may include sugars, Lnn / ίΖΠΖ / Β / ΥΙΛΙ 146 proteins, lipids, nucleic acids and the like. Examples of secondary metabolites include antibiotics and dyes. The metabolite can be a biopolymer or a small molecule. In a specific embodiment, the biopolymer is a molecule having a molecular weight of about 5,000 or more, consisting of one or more types of repeating units including, for example, polysaccharides, polypeptides, and polynucleotides. In a specific embodiment, small molecules are molecules having a molecular weight of about 500 or less and are the chemical substances present in the living organism. In a further embodiment, the tumor tissue-specific compound is a small molecule metabolite produced specifically in tumor cells (Eva Gottfried, Katrin Peter and Marina P. Kreutz, in Molecular and Modular Tumor Therapy (2010) 3(2), 111- 132) . In a further embodiment, the tumor tissue-specific compound is a metabolite produced specifically by a cell infiltrating tumor tissue (eg, an immune cell) or a stromal cell (eg, a cancer-associated fibroblast (CAE). ) present in tumor tissue. Examples of immune cells that infiltrate tumor tissue are dendritic cells, suppressor dendritic cells, regulatory T cells, depleted T cells, suppressor cells 147 derived from myeloma (MDSC) and the like. In a further embodiment, a metabolite produced by cells present in tumor tissue (eg, tumor cells, immune cells, a stromal cell, etc.), that is released outside the cell when cells die by apoptosis or necrosis , or the like, may also be included in the tumor tissue-specific compound of the present disclosure. To identify a specific compound from tumor tissue, an analysis at the transcriptome level can be appropriately employed (eg, Dhanasekaran et al., (Nature (2001) 41 2, 822-826), Lapointe et al., (Proc. Nati . Acad. Sel. USA (2004) 101, 811-816), or Perou et al., (Nature (2000) 406, 747-752)), an analysis at the proteome level (for example, Ahram et al., (Mol. Carcinog. (2002) 33, 9-15), and Hood et al., (Mol. Cell. Proteomics (2005) 4, 1741-1753)) and metabolomic analysis focused on the determination of the metabolomic profile (metabolomics ). That is, in order to identify a metabolite in a sample under study, one can conveniently use high pressure liquid chromatography (HPLC), nuclear magnetic resonance (NMR) (Brindle et al., (J. Mol. Recognit. (1997 ) 10, 182-187)), mass spectrometry (GC / MS and LC / MS) (Gates and Sweeley (Clin. Chem. (1978) 24, 16631673)) and metabolic profiling using Lnn / ίΖΠΖ / Β / ΥΙΛΙ Lnn / ίΖΠΖ / Β / ΥΙΛΙ 148 ELISA and the like, either alone and / or in combination. In a specific embodiment, the tumor tissue-specific compound comprises at least one compound that is selected from the group consisting of: nucleosides having a purine ring structure, amino acids and metabolites thereof, lipids and metabolites thereof, metabolites primary carbohydrate metabolism, as well as nicotinamide and its metabolites. In a further embodiment, the tumor tissue-specific compound is at least one compound selected from the following (1) to (6): (1) nucleosides having a purine structure such as adenosine (ADO), adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), and inosine; (2) amino acids such as alanine, glutamic acid, and aspartic acid; (3) metabolites of amino acids such as kynurenine, anthranilic acid, 3-hydroxykynurenine and kynurenic acid; (4) arachidonic acid metabolites such as prostaglandin E2; (5) primary metabolites of the glycolytic pathway or Krebs cycle, such as lactic acid, succinic acid, and citric acid; and, Lnn / ίΖΠΖ / Β / ΥΙΛΙ 149 (6) metabolites of nicotinamide such as 1-methylnicotinamide. (1) Nucleosides having, a purine structure such as adenosine (ADO), adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and inosine; It is known that when immoral cells undergo cell death, a large amount of intracellular ATP is leaked. Therefore, the ATP concentration in tumor tissue is significantly higher than that in normal tissue (PLoS One; (2008) 3, e2599). AMP is metabolized by cell surface enzymes such as extracellular 5'nucleotidase (eco-5'-nucleotidase) (CD73) (Resta and Thompson (Immunol. Rev. (1998) 161, 95-109) and Sadej et al. ., (Melanoma Res., (2006) 16, 21 3-222)). Adenosine is a purine nucleoside that is constitutively present at low concentrations in the extracellular environment, but a marked increase in extracellular adenosine concentration has been reported in hypoxic tissues present in solid tumors (Blay and Hoskin (Cancer Res ., (1997) 57, 260 2-2605) ) . CD73 is expressed on the surface of tumors and immune cells (Kobie et al., (J. Immunol. (2006) 17 7, 6780-6786)) and elevated activity has been observed in breast cancer (Canbolat et al ., (Breast Cancer Res. Treat. (1996) 37, 189-193)), stomach cancer (Durak 150 et al., (Cancer Lett., (1994) 84, 199-202)), pancreatic cancer (Flocke and Mannherz (Biochim. Biophys. Acta (1991) 1076, 273-281)) and glioblastomas (Bardot et al. ., (Br. J. Cancer (1994) 70, 212-218) ). It has been proposed that the accumulation of adenosine in tumor tissue is the result of increased dephosphorylation of AMP by cytoplasmic 5'nucleotidase (Headrick and Willis (Biochem. J. (1989) 261, 541-550)). In addition, regulatory T cells infiltrating tumor tissue also express ATPase and produce adenosine (Proc. Nati. Acad. Sel. USA (2006) 103(35), 13132-13137; Curr. Med. Chem. (2011) 18: 5217-5223). The produced adenosine is believed to maintain tumor tissues in an immunosuppressive environment via adenosine receptors such as the A2A receptor ( Curr. Med. Chem. (2011) 18, 5217-5223 ). Therefore, ATP, ADP, AMP, adenosine and the like, which are considered to accumulate to a high concentration in tumor tissue due to purine nucleotide metabolism, are examples of tumor tissue-specific compounds used in the present disclosure. Additionally, as adenosine is broken down to inosine by adenosine deaminase, inosine accumulates to a high concentration. In a specific embodiment, nucleosides having a purine ring structure include adenosine-containing compounds. In specific modalities, the Lnn / ίΖΠΖ / Β / ΥΙΛΙ 151 adenosine-containing compounds include, for example, adenosine (ADO), adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), cyclic adenosine monophosphate (cAMP), deoxyadenosine (dADO), deoxyadenosine triphosphate (dATP) , deoxyadenosine diphosphate (dADP), deoxyadenosine monophosphate (dAMP), adenosine [gthio]triphosphate (ATPgS) and the like. In another embodiment, nucleosides having a purine ring structure include inosine, which is a metabolite of adenosine. Furthermore, in a specific embodiment, nucleosides having a purine ring structure include commercially available nucleosides having a purine ring structure such as ADPbetaS (Sigma Inc.). (2) Amino acids such as alanine, glutamic acid and aspartic acid The rate of uptake of glutamine, which acts as a nitrogen transporter in the living body, is increased in tumor cells, and glutamine uptake and resulting conversion to glutamic acid and lactic acid (glutamine degradation (glutaminolysis)) is thought to ) are characteristic of tumor cells (Mazurek and Eigenbrodt (Antícancer Res., (2003) 23, 1149-1154, and Mazurek et al., (J. Cell. Physiol. (1999) 181, 136-146). of glutamine in plasma decreases Lnn / ίΖΠΖ / Β / ΥΙΛΙ 152 in cancer patients, while the glutamic acid concentration increases (Droge et al., (Immunobiology (1987) 174, 473-479)), and studies on the metabolism of 13C-labeled glucose in cancer tissue Lung samples showed a correlation between the concentrations of 13C-labeled succinic acid, 13C-labeled alanine, 13C-labeled glutamic acid, and 13C-labeled citrate. For these reasons, alanine, glutamic acid, aspartic acid, and the like, which are believed to accumulate at high concentrations in tumor tissue due to, for example, glutamine degradation, are examples of tumor tissue-specific compounds used in this technique. description. (3) Amino acid metabolites such as kynurenine, anthranilic acid, 3-hydroxykynurenine and kynurenic acid; Indolamine-2,3-dioxygenase (IDO) is a tryptophan-metabolizing enzyme highly expressed in many types of cancer such as melanoma, colon cancer, kidney cancer and the like (Uyttenhove et al., (Nat. Med. (2003) 9, 1269-1274) ). IDO catalyzes the conversion of tryptophan to kynurenine. In gliomas that do not express IDO, tryptophan produces tryptophan 2,3-dioxygenase (TDO) in the liver (Opitz et al., (Nature (2011) 478(7368), 197-203)). IDO is also expressed on dendritic cells that infiltrate tumor tissue, and dendritic cells Lnn / ίΖΠΖ / Β / ΥΙΛΙ 153 also produce kynurenine (J. Immunol. (2008). In addition, IDO is also expressed in myeloma-derived suppressor cells (MDSCs) from tumor tissues, and MDSCs also produce kynurenine (Yu et al., (J. Immunol. (2013) 190, 3783-3797).) Kynurenine is converted to anthranilic acid by kynureninase, and to 3-hydroxykynurenine by kynurenine 3-hydroxylase.Both anthranilic acid and 3-hydroxynurenine are converted to 3-hydroxyanthranilic acid, a precursor of NAD.Kynurenine is converted to kynurenic acid by kynurenic aminotransferase.For these reasons, kynurenine and its metabolite, i.e., anthranilic acid, 3-hydroxykynurenine, kynurenic acid and the like, are examples of tissue-specific compounds tumor that are used in the present description, in particular, the specific metabolites of tumor cells. (4) Arachidonic acid metabolites such as prostaglandin E2 Prostaglandin E2 (PGE2) promotes the growth of colon cancer cells and suppresses their apoptosis (Sheng et al., (Cancer Res., (1998) 58, 362-366)). Among the PGE2 synthetases, it has been found that mainly COX-1 is expressed constitutively in almost all tissues, while COX-2 is induced by certain inflammatory cytokines and oncogenes in tumors (Warner and Mitchell (FASEB J. (2004) Lnn / ίΖΠΖ / Β / ΥΙΛΙ 154 18, 790-804)). COX-2 overexpression has been reported to be associated with poor prognosis in breast cancer (Denkert et al., {Clin. Breast Cancer (2004) 4, 428-433)) and rapid disease progression in the ovarian cancer (Denker et al., (Mod. Pathol. (2006) 19, 1261-1269)). Furthermore, regulatory T cells infiltrating tumor tissue also produce PGE2 (Curr. Med. Chem. (2011) 18, 5217-5223). For these reasons, arachidonic acid metabolites such as PGE2 are examples of tumor tissue-specific compounds, in particular tumor cell-specific metabolites or tumor tissue-infiltrating immune cell-specific metabolites. In addition to PGE2, thromboxane A2 (TXA2) production is increased in tumor tissues such as colon cancer (J. Lab. Clin. Med. (1993) 122, 518-523). (5) Primary metabolites of the glycolytic pathway or Krebs cycle, such as lactic acid, succinic acid, and citric acid The glycolytic phenotype characterized by upregulation of glycolytic enzymes (Embden-Meyerhof pathway) such as pyruvate kinase, hexokinase, and lactate dehydrogenase (LDH) is conventionally known as the Warburg effect, a feature of solid tumors. Lactic acid, which is the end product of glycolysis, as well as succinic acid and citric acid, are known to Lnn / ίΖΠΖ / Β / ΥΙΛΙ 155 produced by the Krebs cycle, accumulate in tumor tissues (Teresa et al., (Mol. Cáncer (2009) 8, 41-59)). Due to these reasons, lactic acid, succinic acid, citric acid and the like, which are primary metabolites produced by glycolysis, are examples of tumor tissue-specific compounds, in particular tumor cell-specific metabolites, which are used in the present disclosure. . Furthermore, it is known that due to cell death, succinate, which is present at a high concentration in cells, leaks out of cells (Nature Immunology, (2008) 9, 1261-1269). This is believed to be the reason for the increased concentration of succinic acid in tumor tissues, where cell death is common. (6) Nicotinamide metabolites such as 1-methylnicotinamide. Nicotinamide N-methyltransferase is known to be highly expressed in a variety of human tumor tissues. It is also known that 1-methyl-nicotinamide, which is a stable metabolite of nicotinamide produced by this enzyme, is secreted out of tumor cells (Yamada et al., (J. Nutr. Sci. Vitaminol. (2010 ) 56, 83-86)). For this reason, 1-methylnicotinamide, and the like, which are believed to accumulate in tumor tissue at a high concentration as a result of nicotinamide metabolism, are examples of the specific compounds of the drug. Lnn / ίΖΠΖ / Β / ΥΙΛΙ 156 tumor tissue that are used in the present description. An antigen binding molecule of the present disclosure comprises an antigen binding domain. As the antigen binding domain, a domain of any structure can be used as long as it binds to the target antigen. In one embodiment, the antigen-binding domains of this disclosure include, for example, variable regions of the heavy chains and / or light chains of antibodies, avimers containing a module (A-domain) of approximately 35 amino acids present in various proteins of the cell membrane in the living organism (International publications WO2004 / 044011 and WO2005 / 040229), adnectins containing the 10Fn3 domain of fibronectin, which is a glycoprotein expressed in the cell membrane (International publication WO2002 / 032925), affibodies using a 58 amino acid IgG-binding domain of protein A as a scaffold (WO WO1995 / 001937), DARPins (designed ankyrin repeat proteins) using an ankyrin repeat (AR) which is a repetitive sequence of 33 amino acids as a base (International publication WO2002 / 020565), anticalins containing a lipocalin such as lipocalin-associated lipocalin neutrophil gelatinase (NGAL) as a base (International publication WO2003 / 029462), variable lymphocyte receptors (VLR) which are proteins that function in immune systems 157 adaptive from jawless vertebrates, such as Lampetra japonica and Eptatretus, and contain a leucine-rich repeat (LRR) module (International publication WO2008 / 016854) and the like. In a specific embodiment, the antigen-binding domain of this disclosure comprises variable regions of the heavy and light chains of an antibody. In a further embodiment, the antigen binding domain of the present disclosure includes, for example, scFv (single chain Fv), single chain antibodies, Fv, scFv2 (single chain Fv2), Fab or F(ab') 2. HVR and Variable Region In one aspect, the present disclosure provides an anti-CD137 antibody or antigen binding molecule comprising at least one, at least two, or all three of the VH HVR sequences selected from: (a) an HVR-H1 comprising the amino acid sequence from SEQ ID NO: 7; (b) an HVR-H2 comprising any of the amino acid sequences selected from SEQ ID NO: 8, 9, 10, 11, 12, 13, 14, 15 and 16; and (c) an HVR-H3 comprising any of the amino acid sequences selected from SEQ ID NO: 17, 18, 19 or 20. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises: (a ) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising any of the sequences of Lnn / ίΖΠΖ / Β / ΥΙΛΙ 158 amino acids selected from SEQ ID NO: 8, 9, 10, 11, 12, 13, 14, 15 and 16; and (c) an HVR-H3 comprising any of the amino acid sequences selected from SEQ ID NO: 17, 18, 19 or 20. In one embodiment, the anti-CD137 antigen binding molecule is an antibody comprising the amino acid sequence of A375 / B167, A372 / B040, A356 / B040, A486 / B167, A487 / B167, A488 / B226, A489 / B223 , A548 / B376, A551 / B256, A551 / B379, A555 / B379, A548 / B256 or A549 / B167 described in Table 17 as a heavy chain variable region / light chain variable region combination. In a preferred embodiment, the antigen binding molecule is an anti-CD137 antibody comprising HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2 and HVR-L3 that have the same amino acid sequences. than HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2 and HVR-L3 included in A375 / B167. In a further embodiment, the anti-CD137 antigen binding molecule is an anti-CD137 antibody comprising A375 / B167 as a heavy chain variable region / light chain variable region combination. In a different preferred embodiment, the antigen-binding molecule is an anti-CD137 antibody comprising HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 that have the same sequences of amino acids than HVRH, HVR-H2, HVR-H3, HVR-L1, HVR-L2 and HVR-L3 comprised in A551 / B379. Lnn / ίΖΠΖ / Β / ΥΙΛΙ 159 Lnn / ίΖΠΖ / Β / ΥΙΛΙ In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; and (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 9; and (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 10; and (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 11; and (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18. In one embodiment, the antigen-binding molecule Lnn / ίΖΠΖ / Β / ΥΙΛΙ 160 or anti-CD137 antibody comprises (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; and (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 12; and (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 13; and (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 14; and (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises (a) an HVR-H1 that Lnn / ίΖΠΖ / Β / ΥΙΛΙ 161 comprises the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15; and (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 16; and (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 14; and (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17. In a different aspect, the present description provides an anti-CD137 antigen or antibody binding molecule comprising at least one, at least two or the three HVR VL sequences selected from: (a) an HVR-L1 comprising any of the following amino acid sequences selected from SEQ ID NO: 21, 22, 23, 24 and 25; (b) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (c) an HVR-L3 comprising any of the amino acid sequences selected from SEQ IDs Lnn / ίΖΠΖ / Β / ΥΙΛΙ 162 NO: 27, 28 and 29. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises (a) an HVR-L1 comprising any of the amino acid sequences selected from SEQ ID NO: 21, 22, 23, 24 and 25; (b) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (c) an HVR-L3 comprising any of the amino acid sequences selected from SEQ ID NO: 27, 28 and 29. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises (a) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21; (b) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (c) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises (a) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 22; (b) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (c) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises (a) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21; (b) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (c) an HVR-L3 comprising the sequence 163 amino acids of SEQ ID NO: 28. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises (a) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21; (b) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (c) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 29. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises (a) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 23; (b) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (c) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises (a) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (b) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (c) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises (a) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 25; (b) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (c) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27. Lnn / ίΖΠΖ / Β / ΥΙΛΙ 164 In another aspect, the anti-CD137 antigen or antibody binding molecule of this disclosure comprises (a) a VH domain comprising at least one, at least two, or the three HVR VH sequences selected from (i) an HVR-H1 that comprises the amino acid sequence of SEQ ID NO: 7; (ii) an HVR-H2 comprising any of the amino acid sequences selected from SEQ ID NO: 8, 9, 10, 11, 12, 13, 14, 15 and 16; and (iii) an HVR-H3 comprising any of the amino acid sequences selected from SEQ ID NO: 17, 18, 19 or 20; and (b) a VL domain comprising at least one, at least two or all three HVR VL sequences selected from (i) an HVR-L1 comprising any of the amino acid sequences selected from SEQ ID NO: 21, 22, 23, 24 and 25; (ii) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (iii) an HVR-L3 comprising any of the amino acid sequences selected from SEQ ID NO: 27, 28 and 29. In another aspect, the present disclosure provides an anti-CD137 antibody or antigen binding molecule comprising (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) an HVR-L1 comprising the sequence 165 amino acids of SEQ ID NO: 21; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27 . In another aspect, the present disclosure provides an anti-CD137 antibody or antigen binding molecule comprising (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 9; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 22; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27. In another aspect, the present disclosure provides an anti-CD137 antibody or antigen binding molecule comprising (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 10; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 22; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (f) an HVR-L3 comprising the sequence of Lnn / ίΖΠΖ / Β / ΥΙΛΙ 166 amino acids of SEQ ID NO: 27. In another aspect, the present disclosure provides an anti-CD137 antibody or antigen binding molecule comprising (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 11; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27. In another aspect, the present disclosure provides an anti-CD137 antibody or antigen binding molecule comprising (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27. In another aspect, the present disclosure provides an antigen or antibody binding molecule. 167 anti-CD137 comprising (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 12; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28. In another aspect, the present disclosure provides an anti-CD137 antibody or antigen binding molecule comprising (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 13; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 29. In another aspect, the present disclosure provides an anti-CD137 antibody or antigen binding molecule comprising (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: Lnn / ίΖΠΖ / Β / ΥΙΛΙ Lnn / ίΖΠΖ / Β / ΥΙΛΙ 168 14; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 23; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27. In another aspect, the present disclosure provides an anti-CD137 antibody or antigen binding molecule comprising (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: fifteen; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27. In another aspect, the present disclosure provides an anti-CD137 antibody or antigen binding molecule comprising (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 15; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 25; (e) an HVR-L2 Lnn / ίΖΠΖ / Β / ΥΙΛΙ 169 comprising the amino acid sequence of SEQ ID NO: 26; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27. In another aspect, the present disclosure provides an anti-CD137 antibody or antigen binding molecule comprising (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 16; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 25; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27. In another aspect, the present disclosure provides an anti-CD137 antibody or antigen binding molecule comprising (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 14; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27. 170 Lnn / ίΖΠΖ / Β / ΥΙΛΙ In another aspect, the present disclosure provides an anti-CD137 antibody or antigen binding molecule comprising (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 14; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 21; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27. In a specific embodiment, any one or more amino acids of the anti-CD137 antibody described above are substituted at the following positions in the HVR: In the HVR-H2 (SEQ ID NO: 30): positions 5, 6, 7, 10, 13, 14 and / or 17 On the HVR-H3 (SEQ ID NO: 31): position 3 and / or 6 In the HVR-L1 (SEQ ID NO: 32): positions 4, 5, 9 and / or 11 In HVR-L3 (SEQ ID NO: 33): positions 6, 7 and / or 8. In a specific embodiment, the substitutions provided by the present disclosure are conservative substitutions. In a specific modality, any one of Lnn / ίΖΠΖ / Β / ΥΙΛΙ 171 One or more of the following substitutions may be made in any combination: In HVR-H2 (SEQ ID NO: 8): K5H or S; S6G; T7S; E10Y; D13E; S14Q; V17G or L In HVR-H3 (SEQ ID NO: 17): A3P, K or I; F6E In HVR-L1 (SEQ ID NO: 21): R4S; Y5T; Y9F; E11N In HVR-L3 (SEQ ID NO: 27): E6P; H7A; Q8I All possible combinations of the aforementioned substitutions are included in the consensus sequences of SEQ ID NO: 30, 31, 32 and 33 for HVR-H2, HVR-H3, HVR-L1 and HVR-L3, respectively. In any of the foregoing embodiments, an anti-CD137 antibody or antigen binding molecule is humanized. In one embodiment, an anti-CD137 antibody or antigen binding molecule comprises the HVRs of any of the preceding embodiments, and further comprises a human acceptor framework, for example a human immunoglobulin framework or a human consensus framework. In another embodiment, an anti-CD137 antibody or antigen binding molecule comprises an HVR of any of the above embodiments, and further comprises a heavy chain variable region (VH) or a light chain variable region (VL) comprising a frame sequence (FR). In one embodiment, in the variable region of the heavy chain FR1 comprises the amino acid sequence of SEQ ID NO: 35, in the region Lnn / ίΖΠΖ / Β / ΥΙΛΙ 172 heavy chain variable FR2 comprises the amino acid sequence of SEQ ID NO: 36, heavy chain variable region FR3 comprises the amino acid sequence of SEQ ID NO: 37 and heavy chain variable region FR4 comprises the amino acid sequence of SEQ ID NO: 38. In one embodiment, in the light chain variable region FR1 comprises the amino acid sequence of SEQ ID NO: 39, in the light chain variable region FR2 comprises the amino acid sequence of SEQ ID NO: 40, in the FR3 light chain variable region comprises the amino acid sequence of SEQ ID NO: 41 and in the FR4 light chain variable region comprises the amino acid sequence of SEQ ID NO: 42. In another aspect, an anti-CD137 antibody or antigen binding molecule comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 or 53 In certain embodiments, a VH sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical contains substitutions (eg, substitutions conservative), insertions or deletions relative to the reference sequence, but an antigen-binding molecule or anti-CD137 antibody comprising such sequence Lnn / ίΖΠΖ / Β / ΥΙΛΙ 173 retains the ability to bind CD137. In certain embodiments, a total of between 1 and 10 amino acids have been substituted, inserted, and / or deleted in SEQ ID NO: 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, or 53. In In certain embodiments, substitutions, insertions, or deletions take place in regions outside of the HVRs (ie, in the FRs). Optionally, the anti-CD137 antibody comprises the VH sequence of SEQ ID NO: 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 or 53, including post-translational modifications of such sequence. In a particular embodiment, the VH comprises one, two or three HVRs selected from: (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising any of the amino acid sequences selected from SEQ ID NO: 8, 9, 10, 11, 12, 13, 14, 15 and 16; and (c) an HVR-H3 comprising any of the amino acid sequences selected from SEQ ID NO: 17, 18, 19, or 20. Post-translational modifications include, but are not limited to, a glutamine or glutamate modification. at the N-terminus of the heavy chain or light chain by pyroglutamic acid via pyroglutamylation. In another aspect, an anti-CD137 antibody or antigen binding molecule is provided, wherein the antibody comprises a light chain (VL) variable domain having at least 90%, 91%, 92%, 93%, 94 %, 95%, 96%, Lnn / Lznz / Ε / ΥΙΛΙ 174 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 54, 55, 56, 57, 58, 59, or 60. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (eg, conservative substitutions), insertions, or deletions relative to the sequence but an anti-CD137 antibody or antigen binding molecule comprising such a sequence retains the ability to bind CD137. In certain embodiments, a has substituted, inserted, and / or deleted a total of between 1 and 10 amino acids in SEQ ID NO: 54, 55, 56, 57, 58, 59, or 60. In certain embodiments, substitutions, insertions, or deletions take place in regions outside of the HVRs (ie, in the FRs). Optionally, the anti-CD137 antibody or antigen binding molecule comprises the VL sequence of SEQ ID NO: 54, 55, 56, 57, 58, 59 or 60, including post-translational modifications of such sequence. In a particular embodiment, the VL comprises one, two or three HVRs selected from (a) an HVR-L1 comprising any amino acid sequence selected from SEQ ID NO: 21, 22, 23, 24 and 25; (b) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 2-6; and (c) an HVR-L3 comprising any amino acid sequence selected from SEQ ID NO: 27, 28 and 29. Post-translational modifications include, Lnn / ίΖΠΖ / Β / ΥΙΛΙ 175 but in a non-limiting sense, a modification of glutamine or glutamate at the N-terminus of the heavy chain or light chain by pyroglutamic acid via pyroglutamylation. In another aspect, an anti-CD137 antibody or antigen binding molecule is provided, wherein the antibody or antigen binding molecule comprises a VH of any of the modalities provided above, and a VL of any of the modalities provided above. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises the VH and VL sequences of SEQ ID NO: 43 and SEQ ID NO: 54, respectively, including post-translational modifications of such sequences. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises the VH and VL sequences of SEQ ID NO: 44 and SEQ ID NO: 55, respectively, including post-translational modifications of such sequences. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises the VH and VL sequences of SEQ ID NO: 45 and SEQ ID NO: 55, respectively, including post-translational modifications of such sequences. In one embodiment, the molecule binding to the 176 anti-CD137 antigen or antibody comprises the VH and VL sequences of SEQ ID NO: 46 and SEQ ID NO: 54, respectively, including post-translational modifications of such sequences. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises the VH and VL sequences of SEQ ID NO: 47 and SEQ ID NO: 54, respectively, including post-translational modifications of such sequences. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises the VH and VL sequences of SEQ ID NO: 48 and SEQ ID NO: 56, respectively, including post-translational modifications of such sequences. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises the VH and VL sequences of SEQ ID NO: 49 and SEQ ID NO: 57, respectively, including post-translational modifications of such sequences. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises the VH and VL sequences of SEQ ID NO: 50 and SEQ ID NO: 58, respectively, including post-translational modifications of such sequences. In one embodiment, the molecule binding to the Lnn / ίΖΠΖ / Β / ΥΙΛΙ 177 anti-CD137 antigen or antibody comprises the VH and VL sequences of SEQ ID NO: 51 and SEQ ID NO: 59, respectively, including post-translational modifications of such sequences. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises the VH and VL sequences of SEQ ID NO: 51 and SEQ ID NO: 60, respectively, including post-translational modifications of such sequences. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises the VH and VL sequences of SEQ ID NO: 52 and SEQ ID NO: 60, respectively, including post-translational modifications of such sequences. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises the VH and VL sequences of SEQ ID NO: 50 and SEQ ID NO: 59, respectively, including post-translational modifications of such sequences. In one embodiment, the anti-CD137 antibody or antigen binding molecule comprises the VH and VL sequences of SEQ ID NO: 53 and SEQ ID NO: 54, respectively, including post-translational modifications of such sequences. Lnn / ίΖΠΖ / Β / ΥΙΛΙ The aforementioned post-translation modifications 178 above include, but are not limited to, a modification of glutamine or glutamate at the N-terminus of the heavy chain or light chain by pyroglutamic acid via pyroglutamylation. The following Table shows the SEQ ID NOs corresponding to the preferred heavy chain variable region and light chain variable region amino acid sequences and their HVR1, 2 and 3 for each antigen binding molecule or anti antibody. -CD137 of the present description. Table 1 Heavy Chain / Light Chain Variable Regions Variable Region SEQ ID NO Hypervariable Region (HVR) SEQ ID NO Heavy Chain Light Chain H1 H2 H3 L1 L2 L3 A375 / B167 43 54 7 8 17 21 26 27 A372 / B040 44 55 7 9 17 22 26 27 A356 / B040 45 55 7 10 17 22 26 27 A486 / B167 46 54 7 11 18 21 26 27 A487 / B167 47 54 7 8 18 21 26 27 A488 / B256 1 8 2 226 1 8 256 26 28 A489 / B223 49 57 7 13 18 21 26 29 A548 / B376 50 58 7 14 19 23 26 27 A551 / B256 51 59 7 15 20 24 26 27 A551 / B379 51 60 7 15 25 25 20 9 52 60 7 16 20 25 26 27 A548 / B256 50 59 7 14 19 24 26 27 A549 / B167 53 54 7 14 17 21 26 27 Lnn / ίΖΠΖ / Β / ΥΙΛΙ 179 When an anti-CD137 antibody or antigen binding molecule provided herein has glutamine as the N-terminal amino acid of the heavy or light chain, such amino acid may be substituted for glutamic acid. When an anti-CD137 antibody provided herein has glutamic acid as the N-terminal amino acid of the heavy or light chain, such amino acid may be substituted for glutamine. In a preferred embodiment, the anti-CD137 antigen-binding molecules or antibodies comprising the above-described HVRs, heavy chain variable regions and / or light chain variable regions all have compound-dependent CD137 binding activities. low molecular weight as described above. constant regions In another aspect, the antigen binding molecules or anti-CD137 antibodies comprise a constant region. The constant region can be a heavy chain constant region (including an Fe region), a light chain constant region, or both. In a further aspect, anti-CD137 antibody or antigen binding molecules comprise an Fc region. In some embodiments, the constant region is that which comprises the native sequence. Examples of heavy chain constant regions derived from native antibodies include, for example, a human IgG1 heavy chain constant region (SEQ ID NO: Lnn / ίΖΠΖ / Β / ΥΙΛΙ 180 61, 62), human IgG2, human IgG3, human IgG4 and the like. Examples of light chain constant regions derived from native antibodies include, for example, the human kappa chain, the human lambda chain (eg, SEQ ID NO: 63), and the like. An altered parental constant region or Fe used herein refers to the constant region or an Fe region prior to introducing one or more amino acid alterations described herein. A parent antigen binding molecule refers to an antigen binding molecule comprising the parent constant region or the parent Fe region. In some embodiments, the parent Fc region is an Fc region having a native sequence (or an Fc region of a native antibody). Antibodies include, for example, IgA (IgAl, IgA2), IgD, IgE, IgG (IgG1, IgG2, IgG3, IgG4), IgM, etc. The antibodies may be derived from humans or monkeys (eg, cynomolgus, rhesus macaque, marmoset, chimpanzee, or baboon). Native antibodies can also include naturally occurring mutations. A plurality of IgG allotype sequences due to genetic polymorphism are described in Sequences of proteins of immunological interest, NIH publication No. 91-3242, and any of them may be used in the present disclosure. In one embodiment, the parent Fe region is an Fe region derived from a constant region Lnn / ίΖΠΖ / Β / ΥΙΛΙ 181 of the human IgG1 heavy chain, shown in SEQ ID NO: 61, 62 or 182. In one aspect, anti-CD137 antigen-binding molecules or antibodies have a higher isoelectric point (pl), compared to anti-CD137 antigen-binding molecules or antibodies comprising a native Fc region sequence or a parental Fe region. In some embodiments, the variant Fe regions include at least one amino acid alteration. In additional embodiments, amino acid alteration leads to elevation of the isoelectric point (pl) of the variant Fe region compared to the original Fe region. Without regard to any particular theory, it is believed that the pH of biological fluids (eg, plasma) is in a neutral pH range. In biological fluids, the net positive charge of an antigen- or antibody-binding molecule is increased due to the larger pl and, as a result, the antigen- or antibody-binding molecule is more strongly attracted by the Coulomb physicochemical interaction to the endothelial cell surface that has a net negative charge compared to an antibody or antigen-binding molecule that does not have an increased pI. In this way, the molecules binding to the agonist antigen (or antibodies), or the binding molecules to the antigen (or antibodies) bound by an agonist are Lnn / ίΖΠΖ / Β / ΥΙΛΙ 182 can be brought closer to the surface of cells expressing the Fc-gamma receptor, resulting in increased binding of antigen-binding molecules or antibodies to cells expressing Fc-gamma. In the case of those antigen-binding molecules or agonist anti-CD137 antibodies that exhibit CD137 agonist activity based on the contribution by Fc-gamma receptor binding activity, the antigen-binding molecules or anti-CD137 antibodies Agonists exhibiting increased binding to cells expressing the Fc-gamma receptor due to amino acid alterations that increase pI may exhibit stronger CD137 agonist activity compared to antigen-binding molecules or anti-CD137 antibodies agonists that do not comprise amino acid alterations that increase pl. In the present description, the pl may be a theoretical pl or an experimentally determined pl. The pl value can be determined, for example, by isoelectric focusing known to those skilled in the art. The value of a theoretical pl can be calculated, for example, using amino acid and gene sequence analysis software (Genetyx, etc.). By performing calculations, the properties of an antibody can be reflected in a calculation formula. For example, (i) in general, the Cys conserved in an antibody forms a disulfide bond and carries no charge Lnn / ίΖΠΖ / Β / ΥΙΛΙ 183 electric in the side chain; therefore, such Cys can be excluded from the calculation and only free Cys that do not form disulfide bonds will be included in the calculation. Alternatively, (ii) the charge state or isoelectric point of antibodies may change due to post-translational modifications; therefore, the calculation formula can be modified as follows, taking into account such post-translational modifications: (a) when the N-terminus of the heavy chain is Q (glutamine), the N-terminal group is excluded from the calculation, assuming that pyroglutamylation occurs, (b) when the C-terminus of the heavy chain is K (Usin), K (only one residue) is excluded from the calculation, assuming truncation occurs; and (c) the side chains of all Cs (cysters) present in generally conserved positions are excluded from the calculation, assuming that all these Cs form disulfide bonds within the molecule. In a preferred embodiment, both (i) and (ii) described above can be reflected in the calculation formula. In one embodiment, the value of pl can be increased, for example, by at least 0.01, 0.03, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5 or more, by at least 0.6, 0.7, 0.8, 0.9 or more, in at least 1.0, 1.1, 1.2, 1.3, 1.4, 1.5 or more or by at least 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 3.0 or more, compared to the previous modification. Lnn / ίΖΠΖ / Β / ΥΙΛΙ 184 In one embodiment, amino acid alterations related to increased pl and methods for increasing the pl of an antibody or antigen-binding molecule are described in detail herein under III. Compositions and methods (agonist antigen-binding molecules comprising a variant of an Fe region with increased isoelectric point (pl)). Those skilled in the art will understand that any amino acid alterations and method of increasing pl described in III. Compositions and methods (agonist antigen-binding molecules comprising a variant of the Fe region with an increased isoelectric point (pl)) can be applied to antigen-binding molecules or anti-CD137 antibodies. In one embodiment, the antigen-binding molecules or anti-CD137 antibodies have an Fc region variant with an increased pI, and the Fc region variant comprises at least one amino acid alteration in at least one position selected from the group that consists of positions 285, 311, 312, 315, 318, 333, 335, 337, 341, 342, 343, 384, 385, 388, 390, 399, 400, 401, 402, 413, 420, 422 and 431, according to EU numbering. In additional embodiments, variant Fe regions with increased pl comprise Arg or Lys at each selected position. In additional embodiments, binding molecules Lnn / ίΖΠΖ / Β / ΥΙΛΙ 185 to the antigen or anti-CD137 antibodies have an Fe region variant with an increased pI, and the Fe region variant comprises at least one amino acid alteration at at least one position selected from the group consisting of positions 311, 343 and 413, according to the EU numbering. In additional embodiments, variants of the Fe regions with increased pI comprise an amino acid alteration at positions 311, 343, or 413 according to EU numbering. In a further embodiment, variant Fe regions with increased pl comprise Arg or Lys at each selected position. In another aspect, the present description provides antigen-binding molecules or anti-CD137 antibodies comprising a variant of the Fe region with an increased pI, comprising amino acid alterations in any of the following options (1) to (3): (1) at positions 311 and 343; (2) at positions 311 and 413; and (3) at positions 343 and 413, according to EU numbering. In additional embodiments, variant Fe regions with increased pl comprise Arg or Lys at each selected position. In one embodiment, the anti-CD137 antibody or antigen binding molecules of the present disclosure comprise a variant of the Fe region comprising one or more of the amino acid alterations identified in the invention. Lnn / ίΖΠΖ / Β / ΥΙΛΙ 186 following Table 2. Amino acid alterations to increase the pl of an Fe region Table 2 Number Amino acid substitutions (EU numbering) 1 P343R / D413K 2 Q311R / P343R 3 P343R 4 D413K 5 Q311R 6 Q311R / D413K In one embodiment, the antigen-binding molecules or anti-CD137 antibodies comprise a variant of the Fc region prepared by amino acid alterations in an Fc region having a native sequence. In one embodiment, variants of the Fe regions have increased binding activity for at least one Fc-gamma receptor selected from the group consisting of Fc-gamma Ría, Fc-gamma Rila, Fc-gamma Rllb, Fc-gamma RlIIa and Fc-gamma RlIIb, compared to an Fc region having a native sequence or a parent Fc region. Preferably, the variant Fc regions have increased binding activity to Fc-gamma Rllb compared to an Fc region having a native sequence or a parent Fc region. It has been reported that an anti-CD137 antibody comprising a variant of the Fe region with increased CD137 binding activity Lnn / ίΖΠΖ / Β / ΥΙΛΙ 187 Fc-gamma Rllb has a higher agonist activity compared to the anti-CD137 antibody comprising an Fc region with a native sequence. In one embodiment, since amino acid alterations can increase Fc-gamma Rllb binding activity, for example, the amino acid alterations described in WO2012 / 115241, WO2014 / 030728, WO2014 / 163101 and / or WO2017 can be used. / 104783. In a preferred embodiment, the alterations to increase Fc-gamma Rllb binding activity are amino acid alterations at at least one position selected from the group consisting of positions 234, 235, 236, 237, 238, 264, 268, 295 , 326 and 330, according to the EU numbering. The Fe gamma receptors (referred to herein as Fe gamma, Fe gamma R, or FcyR receptors) refer to receptors that can bind to the Fe region of IgG1, IgG2, IgG3, and IgG4 monoclonal antibodies, and include virtually any member of the family of proteins encoded by the Fe gamma receptor genes. In humans, this family includes Fe gamma RI (CD64) including the Fe gamma Ría, Fe gamma RIb and Fe gamma Ríe isoforms; Fe gamma RII (CD32) including Fe gamma Rila (including allotypes H131 (H-type) and R131 (R-type)), Fe gamma Rllb (including Fe gamma RIIb-1 and Fe gamma RIIb-2) and Fe gamma RII isoforms ; and Fe gamma RUI (CD16) including Fe gamma RlIIa isoforms (including allotypes V158 and F158), and Fe gamma RlIIb Lnn / ίΖΠΖ / Β / ΥΙΛΙ 188 (including but not limited to the Fe gamma RIIIb-NAl and Fe gamma RlIIbNA2 allotypes), and any human Fe gamma R, isoforms or allotypes of Fe gamma R yet to be discovered. It has been reported that Fe gamma Rllbl and Fe gamma RIIb2 are splice variants of human Fe gamma Rllb. In addition, a splice variant called Fe gamma RIIb3 has been described (J Exp Med, 1989, 170: 1369-1385). In addition to these splice variants, human Fe gamma Rllb includes NCBI registered AAI46679.1 and all NCBI registered splice variants comprising NP_001002273.1, NP_001002274.1, NP_001002275.1, NP_001177757.1 and NP_003992.3. In addition, human Fe gamma Rllb includes all previously reported genetic polymorphisms, as well as Fe gamma Rllb (Arthritis Rheum. 48: 3242-3252 (2003); Kono et al., Hum. Mol. Genet. 14: 2881-2892 (2005); and Kyogoju et al., Arthritls Rheum., 46: 1242-1254 (2002)), and each genetic polymorphism to be described in the future. In Fe gamma Rila there are two allotypes, one where the amino acid at position 131 of Fe gamma Rila is histidine (type H) and the other where the amino acid at position 131 is replaced by arginine (type R) (Warrmerdam, J Exp 172: 19-25 (1990)). The Fe gamma R includes, but is not limited to, the Fe gamma R derived from humans, mice, rats, rabbits, and monkeys, and may be derived from any organism. The Faith Lnn / ίΖΠΖ / Β / ΥΙΛΙ 189 mouse R gamma include Fe gamma RI (CD64), Fe gamma RII (CD32), Fe gamma RUI (CD16), and Fe gamma RIII-2 (CD16-2), and any mouse Fe gamma R or isoforms of these Fe gamma R, but are not limited thereto. In another aspect, the present disclosure provides anti-CD137 antibody or antigen binding molecules comprising a variant of the Fc region having increased Fc-gamma Rllb binding activity, comprising any of the following amino acid alterations (1 ) to (8): (1) at positions 234, 238, 264 and 330; (2) at positions 234, 238 and 330; (3) at positions 234, 237, 238 and 330; (4) at positions 236, 268 and 330; (5) at positions 235, 236, 268, 295, 326, and 330; according to EU numbering. In one embodiment, the antigen-binding molecules or anti-CD137 antibodies of the present disclosure comprise a variant of the Fe region comprising the amino acid alterations identified in Table 3 below. In a further embodiment, the antigen-binding molecules or anti-CD137 antibodies of the present description comprise a variant of the Fe region that also comprises, in addition to one or more of the amino acid alterations described in Table 2 (amino acid alterations that involve an increase in the pl of an Fe region) , any combination of amino acid alterations Lnn / ίΖΠΖ / Β / ΥΙΛΙ 190 identified in the following Table 3. Amino acid alterations to increase the Fc-gamma Rllb binding activity of an Fe region Table 3 Number Amino Acid Substitution (EU Numbering) 1 L234Y / P238D / V264I / A330K 2 L234Y / P238D / A330K 3 L234Y / G237D / P238D / A330K 4 G236N / H268D / A330K 5 L235W / G236N / H268D / K365L In one embodiment, the present disclosure provides Fc region variants, including those Fc region variants that have an alteration of at least one amino acid and have Fcgamma Rllb binding activity equivalent to or greater than that of a reference Fc region. In one embodiment, the reference Fe region is an Fe region comprising any of the combinations of amino acid alterations identified in Table 3 above. In a preferred embodiment, the reference Fe region is a Fe region comprised in a constant region of the heavy chain TT14 (SEQ ID NO: 149), TT16 (SEQ ID NO: 150), MY201 (SEQ ID NO: 153) or MY518 (SEQ ID NO: 154). In a preferred embodiment, the reference Fe region is a Fe region comprised in a constant region of the MY201 (SEQ ID NO: 153) or MY518 (SEQ ID NO: 153) heavy chain. 154) . Lnn / ίΖΠΖ / Β / ΥΙΛΙ 191 In another aspect, the present disclosure provides isolated antigen-binding molecules or agonist antibodies comprising a variant of the Fc region with increased Fc-gamma receptor (preferably, Fc-gamma Rllb) binding activity and increased pI. In a certain embodiment, the Fc region variants described herein comprise at least two amino acid alterations in the parent Fc regions. As described above, an antigen-binding molecule or antibody with an increased pI is more strongly attracted by the Coulomb physicochemical interaction to the endothelial cell surface that has a net negative charge compared to an antigen-binding molecule or antibody that does not have an increased pl. Therefore, in the case of those antigen-binding molecules or agonist antibodies that exhibit agonist activity based on the contribution of binding activity to the Fc-gamma receptor (preferably Fc-gamma Rllb), the agonist activity of the molecules Antigen or antibody binding can be increased by combining one or more amino acid alterations to increase binding to the Fc-gamma receptor (preferably Fc-gamma Rllb) and one or more amino acid alterations to increase pl. In one embodiment, the antigen-binding molecules or anti-CD137 antibodies comprise a variant of Lnn / ίΖΠΖ / Β / ΥΙΛΙ 192 the Fe region comprising both an amino acid alteration to increase Fc-gamma receptor binding activity (eg, Fc-gamma Rllb) and an amino acid alteration to increase the isoelectric point (pl), as described above. As described above, an antigen-binding molecule or antibody with an increased pI is more strongly attracted by the Coulomb physicochemical interaction to the endothelial cell surface that has a net negative charge compared to an antigen-binding molecule or antibody that does not have an increased pl. Therefore, in the case of those antigen-binding molecules or agonist anti-CD137 antibodies that exhibit CD137 agonist activity based on the contribution of binding activity to the Fc-gamma receptor (preferably Fc-gamma Rllb), the Anti-CD137 agonist activity of antigen or antibody binding molecules can be increased by combining one or more amino acid alterations to increase binding to the Fc-gamma receptor (preferably Fc-gamma Rllb) and one or more amino acid alterations to increase binding. pl. In one aspect, the present disclosure provides polypeptides comprising a variant of an Fc region with increased Fc-gamma Rllb binding activity and with increased pI, comprising at least three amino acid alterations including (a) at least one alteration of 193 Lnn / ίΖΠΖ / Β / ΥΙΛΙ amino acid at at least one position selected from the group consisting of positions 234, 235, 236, 237, 238, 264, 268, 295, 326, and 330, according to EU numbering, and (b) at least two amino acid alterations at at least two positions that are selected from the group consisting of positions 311, 343, and 413, according to EU numbering. In another aspect, the present disclosure provides polypeptides comprising a variant of an Fc region with increased Fc-gamma Rllb binding activity and increased pl, comprising any of the following amino acid alterations (1) to (26): (1) positions 235, 236, 268, 295, 326, 330, 343 and 413; (2) positions 214, 235, 236, 268, 295, 326, 330, 343, and 413; (3) positions 234, 238, 250, 264, 307, 330, 343, and 413; (4) positions 234, 238, 264, 330, 343 and 413; (5) positions 234, 237, 238, 250, 307, 330, 343y 413; (6) positions 234, 237, 238, 330, 343 and 413; (7) positions 235, 236, 268, 295, 326, 330, 311y 3; (8) positions 234, 238, 250, 264, 307, 330, 311y 194 3; (9) positions 234, 238, 264, 330, 311 and 343; and 34 3; (10) positions 234, 237, 238, 250, 307, 330, 311 5 (11) positions 234, 237, 238, 330, 311 and 343; (12) positions 235, 236, 268, 295, 326, 330 and 34 3; (13) positions 214, 235, 236, 268, 295, 326, 330 and 34 3; 10 (14) positions 235, 236, 268, 295, 326, 330 and 413; (15) positions 214, 236, 268, 330 and 343; (16) positions 214, 235, 236, 268, 330 and 34 3; (17) positions 214, 236, 268, 330 and 413; 15 (18) positions 214, 236, 268, 330, 343 and 413; (19) positions 214, 235, 236, 268, 330, 343 and 413; (20) positions 214, 236, 268, 330 and 311; (21) positions 214, 235, 236, 268, 330 and 311; 20 (22) positions 214, 236, 268, 330, 311 and 343; (23) positions 214, 235, 236, 268, 330, 311 and 34 3; (24) positions 214, 236, 268, 330, 311 and 413; (25) positions 214, 235, 236, 268, 330, 311 and 25,413; 195 Lnn / ίΖΠΖ / Β / ΥΙΛ (26) positions 214, 235, 236, 268, 295, 326, 330 and 311, according to EU numbering. In one embodiment, the F region variants of the present disclosure comprise any of the combinations of amino acid alterations identified in Table 4 below. Table 4 Number Amino acid substitutions (EU numbering) 1 L235W / G236N / H268D / Q295L / K326T / A330K / P343R / D413K 2 K214R / L235W / G236N / H268D / Q295L / K326T / A330K / P343R / D413K 3 L234 / T253V / T307P / A330K / P343R / D413K 4 L234Y / P238D / V264I / A330K / P343R / D413K 5 L234Y / G237D / P238D / T250V / T307P / A330K / P343R / D413K 6 L234Y / G237D / D / A330R4D4 13K7 L235W / G236N / H268D / Q295L / K326T / A330K / Q311R / P343R 8 L234Y / P238D / T250V / V264I / T307P / A330K / Q311R / P343R 9 L234Y / P238D / V264I / A330K / Q311R / 1G33P7P324 238D / T250V / T307P / A330K / Q311R / P343R 11 L234Y / G237D / P238D / A330K / Q311R / P343R 12 L235W / G236N / H268D / Q295L / K326T / A330K / P343R 13 K214R / L235W / G268D / K235T / K29 / A330K / P343R 14 L235W / G236N / H268D / Q295L / K326T / A330K / D413K 15 K214R / G236N / H268D / A330K / P343R 16 K214R / L235W / G236N / H268D / A330K / P343R 17 K214 / R / H338D4 3K18K214R / G236N / H268D / A330K / P343R / D413K 19 K214R / L235W / G236N / H268D / A330K / P343R / D413K 20 K214R / G236N / H268D / A330K / Q311R 196 Lnn / ίΖΠΖ / Β / ΥΙΛΙ K214R / L235W / G236N / H268D / A330K / Q311R 0K / Q311R / D413K 25 K214R / L235W / G236N / H268D / A330K / Q311R / D413K 26 K214R / L235W / G236N / H268D / Q295L / K326T / A330K / Q311R In one embodiment, variants of the Fc regions comprising any of the combinations of amino acid alterations described above in Table 4 lack the amino acid at position 447 according to EU numbering. In a preferred embodiment, variants of the Fc regions comprising any of the combinations of amino acid alterations described above in Table 4 lack the amino acid positions 446 and 447 according to EU numbering. Those skilled in the art will understand that at least one amino acid alteration may be employed to increase binding activity to Fc-gamma R (including Fcgamma Rllb) compared to the parent Fc region described or suggested, for example, in WO2013 / 047752 , WO2013 / 125667, WO2014 / 030728, WO2014 / 163101 or WO2017104783, and at least one amino acid alteration to increase pI compared to the parent Fe region described or suggested, for example, in WO2017 / 104783, WO2017 / 046994, and any combination of these amino acid alterations, in addition to the alterations 197 provided illustrated above. In addition, amino acid alterations intended for other purposes can be combined into a variant of an Fc region described herein. For example, amino acid substitutions that increase FcRn binding activity can be added (Hinton et al., J. Immunol. 176(1) : 346-356 (2006); Dalí 'Acqua et al., J. Biol. Chem.281(33):23514-23524(2006);Petkova et al., Intl. Immunol.18(12):1759-1769 (2006);Zalevsky et al., Nat. Biotechnol.28(2):157 -159 (2010); WO 2006 / 019447; WO 2006 / 053301; and WO 2009 / 086320), and amino acid substitutions to improve antibody heterogeneity or stability (WO 2009 / 041613). Alternatively, polypeptides with the property of promoting antigen clearance, which are described in WO 2011 / 122011, WO 2012 / 132067, WO 2013 / 046704 or WO 2013 / 180201, polypeptides with the property of specifically binding to an antigen, can be combined. target tissue, which are described in WO 2013 / 180200, polypeptides with the property of repeatedly binding to a plurality of antigen molecules, which are described in WO 2009 / 125825, WO 2012 / 073992 or WO 2013 / 047752, with a variant of an Fe region described herein. Alternatively, in order to confer binding activity to other antigens, the amino acid alterations described in EP1752471 and EP1772465 can be combined in the CH3 of a variant Fe region. Lnn / ίΖΠΖ / Β / ΥΙΛΙ 198 described herein. In one embodiment, the anti-CD137 antibody or antigen binding molecules of the present disclosure comprise a heavy chain constant region comprising any of the amino acid sequences selected from SEQ ID NO: 64-85. Preferably, the anti-CD137 antibody or antigen binding molecules of the present disclosure comprise a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 75 or 82. In a preferred embodiment, anti-CD137 antigen binding molecules or antibodies comprising the Fc region variant described above have a CD137 binding activity described above that is dependent on a small molecule compound. In one embodiment, the anti-CD137 antibody or antigen binding molecules of the present disclosure comprise the following variable region and constant region: a variable region comprising the HVR described above, a heavy chain variable region, and / or a variable region light chain variable; and the one region Fe variant described above. In a preferred embodiment, the anti-CD137 antibody or antigen binding molecules of the present disclosure may comprise any of the anti-CD137 antibodies selected from the antibodies that are Lnn / ίΖΠΖ / Β / ΥΙΛΙ Lnn / ίΖΠΖ / Β / ΥΙΛΙ 199 described in Table 52. In a further aspect, the present disclosure provides antigen binding molecules or antibodies that bind to the same epitope on CD137 as the anti-CD137 antibody or antigen binding molecules provided herein, in the presence of a low weight compound. molecular weight (eg, in the presence of 10 micromolar or more, 50 micromolar or more, 100 micromolar or more, 150 micromolar or more, 200 micromolar or more, or 250 micromolar or more of the low molecular weight compound). For example, in a certain embodiment, antigen binding molecules or antibodies are provided that bind to the same epitope as anti-CD137 antigen binding molecules or antibodies comprising A375 / B167, A372 / B040, A356 / B040, A486 / B167, A487 / B167, A488 / B226, A489 / B223, A548 / B376, A551 / B256, A551 / B379, A555 / B379, A548 / B256 and / or A549 / B167 described in Table 17, as a combination of the heavy chain variable region / light chain variable region. In one embodiment, the antigen-binding molecules or anti-CD137 antibodies of the present disclosure having a binding activity to CD137 that is dependent on the antigen-binding activity dependent on a small molecule compound recognizes an epitope formed by a complex formed with the antigen (eg CD137) and the low molecular weight compound (eg ATP). Lnn / ίΖΠΖ / Β / ΥΙΛΙ 200 In a further aspect, the present disclosure provides antigen-binding molecules or antibodies that compete for binding to CD137 with the anti-CD137 antigen-binding molecules or antibodies provided herein, in the presence of a low molecular weight compound. (eg, in the presence of 10 micromolar or more, 50 micromolar or more, 100 micromolar or more, 150 micromolar or more, 200 micromolar or more, or 250 micromolar or more of the low molecular weight compound). For example, in a certain embodiment, they compete for the CD137 binding site with antigen-binding molecules or anti-CD137 antibodies including A375 / B167, A372 / B040, A356 / B040, A486 / B167, A487 / B167, A488 / B226, A489 / B223, A548 / B376, A551 / B256, A551 / B379, A555 / B379, A548 / B256 and / or A549 / B167 described in Table 17, as a heavy chain variable region combination / variable region of the light chain. In a further aspect of the present disclosure, an anti-CD137 antibody or antigen binding molecule according to any of the foregoing embodiments is a monoclonal antibody, including a chimeric, humanized or human antibody. In one embodiment, an anti-CD137 antibody is an antibody fragment, eg, an Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a Lnn / ίΖΠΖ / Β / ΥΙΛΙ 201 full-length antibody, eg, an intact IgGl antibody or another antibody class or isotype defined herein. In a further aspect, an anti-CD137 antibody or antigen binding molecule according to any of the foregoing embodiments may incorporate any of the features, individually or in combination, as described below in Sections 1-7: 1. Agonist activity of the antigen-binding molecule or anti-CD137 antibody In a specific embodiment, the anti-CD137 antibody or antigen binding molecule herein has CD137 agonist activity. CD137 signaling not only stimulates ΙΕΝ-γ secretion and NK cell proliferation (Buechele et al., 2012; Lin et al., 2008; Melero et al., 1998), but also enhances their survival and DC activation indicated by upregulation of costimulatory molecules and cytokine secretion (Choi et al., 2009; Futagawa et al., 2002; Wilcox et al., 2002). However, CD137 is best characterized as a costimulatory molecule that regulates TCR-induced activation in CD4+ and CD8+ T cell subsets. The combination of TCR activation with agonist anti-CD137 antibodies increases the proliferation of Lnn / ίΖΠΖ / Β / ΥΙΛΙ 202 T cells, stimulates lymphokine secretion and reduces the sensitivity of T lymphocytes to activation-induced cell death (reviewed in Snelet al., 2011). Among those events, the physiological events observed after CD137 signaling on T cells are mediated by signals downstream activated by CD137 signaling, such as TRAF2, TRAF1, in particular NF-kappaB, JNK, Erk, Akt, survivin, Bcl-XL, and / or Bcl-2 (Ward-Kavanagh et al., Immunity, 44:1005 (2016)). In one embodiment, the agonist anti-CD137 antigen binding molecule or agonist anti-CD137 antibody is an antibody or antigen binding molecule that, by binding to CD137, transduces the CD137 signal and significantly induces or enhances IFN secretion. -yamma, proliferation and increased survival of NK cells; DC activation indicated by upregulation of secretion of cytokines and costimulatory molecules; TCR induction; T cell proliferation; and / or secretion of lymphokines. In a different embodiment, the agonist anti-CD137 antigen binding molecule or agonist anti-CD137 antibody is an antibody or antigen binding molecule that transduces the CD137 signal by binding to CD137 on T cells, and significantly induces activation of CD137. NF-kappaB on T cells. In addition, the antigen-binding molecule or an antibody shows agonist activity of Lnn / ίΖΠΖ / Β / ΥΙΛΙ 203 CD137 refers to any of the above-mentioned physiological phenomena being observed when the antigen-binding molecule or antibody binds to CD137. The method for measuring CD137 agonist activity is described in detail below in section C. Assays. In a specific embodiment, the anti-CD137 antibody or antigen binding molecule of the present disclosure has a small molecule compound-dependent CD137 agonist activity. In a non-limiting embodiment, the anti-CD137 antibody or antigen binding molecule of the present disclosure has small molecule compound-dependent CD137 agonist activity. In a different embodiment, the CD137 agonist activity of the anti-CD137 antigen-binding molecule or antibody in the presence of a high concentration of a small molecule compound is greater compared to the CD137 agonist activity in the presence of a low concentration of the small molecule compound. small molecule compound. In a further embodiment, the CD137 agonist activity of the anti-CD137 antibody or antigen binding molecule in the presence of a small molecule compound is 2-fold or more, 3-fold or more, 5-fold or more, 10-fold or more, 20 times or more, 30 times or more, 50 times or more, 100 times or more, 200 times or more, 300 times or more, 500 times or more, 1 x 103 times or more, 2 x 103 times or more, 3 x 103 times or more, 5 x 103 times or more, 1 204 χ 104-fold or more, 2 x 104-fold or more, 3 x 104-fold or more, 5 x 104-fold or more, or 1 χ 105-fold or more, compared to CD137 agonist activity in the absence of the small molecule compound. Any suitable concentration may be selected as the concentration of the small molecule compound as long as a difference in the binding activity of the anti-CD137 antigen or antibody binding molecule is detected. In one embodiment, the anti-CD137 antibody or antigen binding molecule transduces the CD137 signal by binding to CD137 on the cell surface. Therefore, one skilled in the art will understand that anti-CD137 antibody or antigen binding molecule that exhibits a small molecule compound-dependent CD137 binding activity has a small molecule compound-dependent CD137 agonist activity. However, on the other hand, since the methods for measuring binding activity and agonist activity are different, one skilled in the art will understand that the concentration of a small molecule compound for which a difference in binding activity is detected binding may be different from the concentration of the small molecule compound for which a difference in agonist activity is detected (for example, for an anti-CD137 antigen-binding molecule or antibody whose binding activity to CD137 in the presence of a Lnn / ίΖΠΖ / Β / ΥΙΛΙ Lnn / ίΖΠΖ / Β / ΥΙΛΙ 205 small molecule compound at 10 μΜ is 2-fold or more compared to the CD137 binding activity in the absence of the small molecule compound, the agonist activity of CD137 (assay value) in the presence of the small molecule compound at 10 μΜ may be less than 2-fold compared to the CD137 agonist activity (assay value) in the absence of the small molecule compound). Furthermore, it will be understood by those skilled in the art that the determination of agonist activity may vary depending on the CD137 agonist activity assay (see C. Assays). In one embodiment, the anti-CD137 antibody or antigen binding molecule (i) exhibits CD137 agonist activity in the presence of a small molecule compound at 10 μΜ, 5 0 μΜ, 10 0 μΜ, 150 μΜ, 2 0 0 μΜ ο 250 μΜ, and (i i) has substantially no CD137 agonist activity in the absence of the small molecule compound, or has low CD137 agonist activity in the absence of the small molecule compound (as compared to the presence of the small molecule compound). In one embodiment, when the agonist activity of the anti-CD137 antibody or antigen binding molecule is assessed by a) An agonist activity assay (PBMC) which will be explained in detail in C. Assays, the antigen binding molecule or anti-CD137 antibody (i) presents 206 CD137 agonist activity in the presence of a small molecule compound at 250 μΜ, and (ii) has low CD137 agonist activity in the absence of the small molecule compound (compared to the presence of the small molecule compound). In a further embodiment, the anti-CD137 antibody or antigen binding molecule (i) exhibits CD137 agonist activity in the presence of a small molecule compound at 250 µΜ, and (ii) exhibits substantially no CD137 agonist activity in the absence of the CD137 agonist. small molecule compound. In one embodiment, when the agonist activity of the anti-CD137 antibody or antigen binding molecule is assessed by b) An agonist activity assay (reported gene assay) which will be explained in detail in C. Assays, the binding molecule to anti-CD137 antigen or antibody (i) exhibits CD137 agonist activity in the presence of 10 μΜ, 50 μΜ, 100 μΜ, 150 μΜ, 200 μΜ or 250 μΜ of a small molecule compound, and (ii) has substantially no activity CD137 agonist or has less agonist activity in the absence of the small molecule compound (as compared to the presence of the small molecule compound). Antibody concentrations in the reporter gene assay can be selected arbitrarily, for example, the final antibody concentration is 0, 0.001, 0.01, 0.1, 1, or 10 pg / ml. Lnn / ίΖΠΖ / Β / ΥΙΛΙ Lnn / ίΖΠΖ / Β / ΥΙΛΙ 207 In a preferred embodiment, the final concentration of the antibody is 0.1 pg / ml or 1 pg / ml. In one modality, when the final concentration of the antibody is 0.1 pg / ml in b) The agonist activity assay (reporter gene assay) which will be explained in detail in C. Assays, (i) the agonist activity of CD137 (units relative light) of the antigen-binding molecule or anti-CD137 antibody in the presence of 10 μΜ of a small molecule compound is 2-fold or more, 3-fold or more, 5-fold or more, 10-fold or more, 20 times or more, 30 times or more, 50 times or more, 60 times or more, 70 times or more, 80 times or more, or 90 times or more, compared to (ii) CD137 agonist activity (light units relative) in the absence of the small molecule compound. In one modality, when the final concentration of the antibody is 0.1 pg / ml in b) The agonist activity assay (reporter gene assay) which will be explained in detail in C. Assays, (i) the agonist activity of CD137 (units relative light) of the antigen-binding molecule or anti-CD137 antibody in the presence of 10 μΜ of a small molecule compound is 2-fold or more, 3-fold or more, 5-fold or more, 100-fold or more, 20 times or more, 30 times or more, 50 times or more, 60 times or more, 70 times or more, 80 times or more, or 90 times or more, compared to (ii) CD137 agonist activity (light units relative) in Lnn / ίΖΠΖ / Β / ΥΙΛΙ 208 absence of the small molecule compound. In one modality, when the final concentration of the antibody is 0.1 pg / ml in b) The agonist activity assay (reporter gene assay) which will be explained in detail in C. Assays, (i) the agonist activity of CD137 (units relative light) of the antigen-binding molecule or anti-CD137 antibody in the presence of 10 μΜ of a small molecule compound is 2-fold or more, 3-fold or more, 5-fold or more, 250-fold or more, 20 times or more, 30 times or more, 50 times or more, 60 times or more, 70 times or more, 80 times or more, or 90 times or more, compared to (ii) CD137 agonist activity (light units relative) in the absence of the small molecule compound. In any of the foregoing embodiments, a 0.1 pg / ml concentration of an anti-CD137 antibody or antigen binding molecule exhibits substantially no CD137 agonist activity in the absence of the small molecule compound. In one embodiment, when the final concentration of the antibody is 1 pg / ml in b) The agonist activity assay (reporter gene assay) which will be explained in detail in C. Assays, (i) the agonist activity of CD137 (units relative light) of the antigen-binding molecule or anti-CD137 antibody in the presence of 10 μΜ of a small molecule compound is 2-fold or more, 3-fold or more, 5-fold or more, 10-fold or more, 20 times or more, 30 209-fold or more, 50-fold or more, 60-fold or more, 70-fold or more, 80-fold or more, or 90-fold or more, compared to (ii) CD137 agonist activity (relative light units) in the absence of the small molecule compound. In one modality, when the final concentration of the antibody is 0.1 pg / ml in b) The agonist activity assay (reporter gene assay) which will be explained in detail in Assays, (i) the agonist activity of CD137 (light units relative) of the antigen-binding molecule or anti-CD137 antibody in the presence of 100 μΜ of a small molecule compound is 2-fold or more, 3-fold or more, 5-fold or more, 10-fold or more, 20-fold or more, 30-fold or more, 50-fold or more, 60-fold or more, 70-fold or more, 80-fold or more, or 90-fold or more, compared to (ii) CD137 agonist activity (relative light units) in the absence of the small molecule compound. In one modality, when the final concentration of the antibody is 0.1 pg / ml in b) The agonist activity assay (reporter gene assay) which will be explained in detail in C. Assays, (i) the agonist activity of CD137 (units relative light) of the antigen-binding molecule or anti-CD137 antibody in the presence of 250 μΜ of a small molecule compound is 2-fold or more, 3-fold or more, 5-fold or more, 10-fold or more, 20 times or more, 30 times or more, 50 times or more, 60 times or more, 70 times or 210 more, 80-fold or more, or 90-fold or more, compared to (ii) the CD137 agonist activity (relative light units) in the absence of the small molecule compound. In any of the foregoing embodiments, a 1 pg / ml concentration of an anti-CD137 antibody or antigen binding molecule exhibits substantially no CD137 agonist activity in the absence of the small molecule compound. 2. Antibody fragments In certain embodiments, an antibody provided herein is an antibody fragment. Antibody fragments include, but are not limited to, Fab, Fab', Fab'-SH, F(ab')2, Fv and scFv fragments, and other fragments to be described below. For a review of some antibody fragments, see Hudson et al., Nat. Med. 9: 129-134 (2003). For a review of scFv fragments, see, eg, Pluckthun, in The Pharmacology of Monoclonal Antibodies, Volume 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pages 269-315 (1994); see also WO 93 / 16185; and US Patent Nos: 5,571,894 and 5,587,458. For a description of Fab and F(ab')2 fragments comprising rescue receptor-binding epitope residues and having a longer half-life in vivo, see US Patent No: 5,869,046. Lnn / ίΖΠΖ / Β / ΥΙΛΙ Lnn / ίΖΠΖ / Β / ΥΙΛΙ 211 Diabodies or diabodies are antibody fragments with two antigen-binding sites that can be bivalent or bispecific. See, for example, EP 404,097; WO 1993 / 01161; Hudson et al., Nat. Med. 9: 129-134 (2003); and Hollinger et al., Proc. nati. Acad. Sel. USA 90: 6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat. Med. 9: 129-134 (2003). Single domain antibodies are antibody fragments comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain embodiments, a single domain antibody is a human single domain antibody (Domantis, Inc., Waltham, MA; see, for example, US Patent No: 6,248,516 Bl). Antibody fragments can be made by a number of techniques including, but not limited to, proteolytic digestion of an intact antibody as well as production by recombinant host cells (eg, E. coli or phage), as described herein. . 3. Chimeric and humanized antibodies In certain embodiments, an antibody provided herein is a chimeric antibody. Some chimeric antibodies are described, for example, in US Patent No: 4,816,567; and Morrison et al., Proc. nati. 212 Acad. Sci. USA, 81: 6851-6855 (1984)). In one example, a chimeric antibody comprises a non-human variable region (eg, a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant region. In another example, a chimeric antibody is a class-switched antibody in which the class or subclass has changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof. In certain embodiments, a chimeric antibody is a humanized antibody. Typically, a non-human antibody will be humanized to reduce immunogenicity in humans, while preserving the specificity and affinity of the parent non-human antibody. In general, a humanized antibody comprises one or more variable domains in which the HVRs, eg, CDRs (or portions thereof) are derived from a non-human antibody, and the FRs (or portions thereof) are derived from antibody sequences. humans. A humanized antibody will optionally also comprise at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are replaced by corresponding residues in a non-human antibody (eg, the antibody from which the HVR residues are derived), for example, to restore or improve specificity or affinity. of the 213 antibody . Humanized antibodies and methods for making them are reviewed, for example, in Almagro and Fransson, Front. Biosci. 13: 1619-1633 (2008), and are also described, for example, in Riechmann et al., Nature 332: 323-329 (1988); Queen et al., Proc. Nati Acad. Sci. USA 86: 10029-10033 (1989); US Patent Nos: 5,821,337, 7,527,791, 6,982, 321 and 7,087,409; Kashmiri et al., Methods 36: 25-34 (2005) (discussing the grafting of specificity determining regions (SDRs)); Padlan, Mol. Immunol. 28: 489-498 (1991) (describing resurfacing); Dalí' Acqua et al., Methods 36: 43-60 (2005) (discussing FR interleaving); and Osboum et al., Methods 36: 61-68 (2005) and Klimka et al., Br. J. Cancer, 83: 252-260 (2000) (describing the guided selection approach to FR interleaving). Human framework regions that can be used for humanization include, but are not limited to: framework regions selected using the best fit method (see, for example, Sims et al., J. Immunol. 151: 2296 ( 1993)); framework regions derived from the human antibody consensus sequence of a particular subset of heavy or light chain variable regions (see, for example, Carter et al., Proc. Nati. Acad. Sci. USA, 89: 4285 (1992 ), and Presta et al., J. Immunol., 151: Lnn / ίΖΠΖ / Β / ΥΙΛΙ Lnn / ίΖΠΖ / Β / ΥΙΛΙ 214 2623 (1993)); mature (somatically mutated) human framework regions or human germline framework regions (see, eg, Almagro and Fransson, Front. Biosci. 13: 1619-1633 (2008)); and framework regions derived from selection in FR libraries (see, for example, Baca et al., J. Biol. Chem. 2Ί2ι 10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271: 22611-22618 (1996)). 4. Human antibodies In certain embodiments, an antibody provided herein is a human antibody. Human antibodies can be produced using various techniques known in the art. Human antibodies are generally described in van Dijk and van de Winkel, Curr. Opinion. Pharmacol. 5: 368-74 (2001) and Lonberg, Curr. Opinion. Immunol. 20: 450-459 (2008). Human antibodies can be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to an antigenic challenge. Such animals typically contain all or a portion of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, or which are present extrachromosomally or randomly integrated into the animal's chromosomes. In such transgenic mice, the loci of the Lnn / ίΖΠΖ / Β / ΥΙΛΙ 215 Endogenous Immunoglobulins. For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23: 1117-1125 (2005). See, for example, US Patent Nos: 6,075,181 and 6,150,584 which describe the XENOMOUSE™ technology; US Patent No: 5,770,429 describing the HuMab technology (registered trademark); US Patent No: 7,041,870 describing the K-M MICE technology (registered trademark) and US Patent Application Publication No: US 2007 / 0061900 describing the VelociMouse technology (registered trademark)). Human variable regions of intact antibodies generated by such animals can be further modified, for example, by combination with a different human constant region. Human antibodies can also be made by hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines have been described for the production of human monoclonal antibodies. (See, for example, Kozbor J. Immunol., 133: 3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pages 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol., 147: 86 (1991).) Human antibodies generated by human B-cell hybridoma technology are also Lnn / ίΖΠΖ / Β / ΥΙΛΙ 216 describe in Li et al., Proc. nati. Acad. Sci. USA, 103: 3557-3562 (2006). Additional methods include those described, for example, in US Patent No: 7,189,826 (describing the production of human IgM monoclonal antibodies from hybridoma cell lines) and in Ni, Xiandai Mianyixue, 26(4): 265-268 (2006) (describing human-human hybridomas). Human hybridoma technology (Trioma technology) is also described in Vollmers and Brandlein, Histology and Histopathology, 20(3): 927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27 (3): 185-91 (2005). Human antibodies can also be generated by isolating selected Fv clone variable domain sequences from among human-derived phage display libraries. Such variable domain sequences can then be combined with the desired human constant domain. Techniques for selecting human antibodies from antibody libraries are described below. 5. Library-Derived Antibodies The antibodies of the present disclosure can be isolated by screening in combinatorial libraries for antibodies with the desired activities. For example, a variety of methods are known in the art for generating phage display libraries and selecting such Lnn / ίΖΠΖ / Β / ΥΙΛΙ 217 libraries consistent with antibodies exhibiting the desired binding characteristics. Such methods are reviewed, for example, in Hoogenboom et al., in Methods in Molecular Blology 178: 1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001) and are also described, for For example, in McCafferty et al., Nature 348: 552-554; Clackson et al., Nature 352: 624-628 (1991); Marks et al., J. Mol. Biol. 222: 581-597 (1992); Marks and Bradbury, in Methods in Molecular Blology 248: 161-175 (Lo, ed., Human Press, Totowa, NJ, 2003); Sidhu et al., J. Mol. Biol. 338(2): 299-310 (2004); Lee et al., J. Mol. Biol. 340(5): 1073-1093 (2004); Fellouse, Proc. nati. Acad. Sci. USA 101(34): 12467-12472 (2004); and Lee et al., J. Immunol. Methods 284(1-2): 119-132(2004). In certain phage display methods, the VH and VL gene repertoires are cloned separately by polymerase chain reaction (PCR) and randomly recombined into phage libraries, which can then be screened for phage-binding phage. antigen as described in Winter et al., Ann. Rev. Immunol., 12: 433-455 (1994). Phage typically display antibody fragments, either as single chain Fv (scFv) fragments or as Fab fragments. Immunized source libraries provide high affinity antibodies to the immunogen without the need to construct hybridomas. Alternatively, previously unused repertoire can be Lnn / ίΖΠΖ / Β / ΥΙΛΙ 218 cloning (eg, from humans) to provide a single source of antibodies against a wide variety of non-self and also self antigens without any immunization as described in Griffiths et al., EMBO J, 12: 725-734 (1993) . Finally, previously unused libraries can also be made synthetically by cloning unrearranged V gene segments from stem cells, and using PCR primers containing a random sequence to encode the highly variable CDR3 regions and to achieve in vitro rearrangement. , as described by Hoogenboom and Winter, J. Mol. Biol., 227: 381-388 (1992). Patent publications describing human antibody phage libraries include, for example: US Patent Nos: 5,750,373 and US Patent Publication Nos: 2005 / 0079574, 2005 / 0119455, 2005 / 0266000, 2007 / 0117126, 2007 / 0160598, 2007 / 0237764, 2007 / 0292936 and 2009 / 0002360. Antibodies, or antibody fragments, isolated from human antibody libraries are considered herein as human antibodies or human antibody fragments. Antigen-binding molecules or antibodies having an antigen-binding activity dependent on a low molecular weight compound of the present disclosure can be selected by performing a Lnn / ίΖΠΖ / Β / ΥΙΛΙ 219 selection in a library of antigen-binding molecules. The combinatorial libraries described above can be used as such a library. The library of antigen binding molecules can be found with an unbiased repertoire of antigen binding molecules (previously unused library) or it can be found with a biased repertoire of antigen binding molecules. Examples of the latter type of library include a library of antigen-binding molecules that have been conferred in advance with binding activity to a specific compound. In a certain embodiment, a library of antigen-binding molecules is a library of antigen-binding molecules to which an amino acid alteration has been introduced in advance that confers binding activity to a specific compound. Examples of such a type of library include the libraries that are described, for example, in the International publication WO 2015 / 083764. 6. Multispecies antibodies In certain embodiments, an antibody provided herein is a multispecific antibody, eg, a bispecific antibody. Multispecies antibodies are monoclonal antibodies that have binding specificities for at least two different sites. In certain embodiments, one of the binding specificities is for CD137 and the other is 220 for any other antigen. In certain embodiments, bispecific antibodies can bind to two different CD137 epitopes. Bispecific antibodies can also be used to localize cytotoxic agents to cells expressing CD137. Bispecific antibodies can be prepared as full length antibodies or as antibody fragments. In one embodiment, the antigen-binding molecules or anti-CD137 antibodies of the present disclosure are bispecific antibodies, one arm of which has CD137-binding activity dependent on a small molecule compound and the other arm binds a different antigen. from CD137. The non-CD137 antigen is not particularly limited in structure. In other words, the antigen may comprise inorganic or organic substances. Examples of antigens are described in the present Description (eg, IV. Compositions and methods (antigen-binding molecules whose antigen-binding activity changes depending on the concentration of a small molecule compound), B. Antigens). In one embodiment, the antigens are preferably antigens expressed on cancer cells, immune cells, stromal cells, or the like in cancerous tissues or inflammatory tissues. Techniques for making antibodies Lnn / ίΖΠΖ / Β / ΥΙΛΙ 221 Multispecies Lnn / ίΖΠΖ / Β / ΥΙΛΙ include, but are not limited to, recombinant co-expression of two pairs of immunoglobulin heavy chains and light chains having different specificities (see Milstein and Cuello, Nature 305: 537 (1983)), WO 93 / 08829 and Traunecker et al., EMBO J. 10: 3655 (1991)), and buttonhole engineering (see, for example, US Patent No: 5,731,168). Multispecies antibodies can also be made by genetic engineering of electrostatic targeting effects to produce heterochimeric antibody Fe molecules (WO 2009 / 089004A1); cross-linking of two or more antibodies or fragments (see, for example, US Patent No: 4,676,980, and Brennan et al., Science, 229: 81 (1985)); use of leucine locks to produce bispecific antibodies (see, eg, Kostelny et al., J. Immunol., 148(5):1547-1553 (1992)); use of diabody technology to obtain bispecific antibody fragments (see, eg, Hollinger et al., Proc. Nati. Acad. Sci. USA, 90: 6444-6448 (1993)); and the use of single chain Fv (scFv) dimers (see, for example, Gruber et al., J. Immunol., 152: 5368 (1994)); and preparation of trispecific antibodies as described, for example, in Tutt et al., J. Immunol. 147: 60 (1991). Antibodies modified with three or more sites 222 functional antigen-binding antibodies, including Octopus antibodies, are also included herein (see, for example, US 2006 / 0025576A1). The present antibody or fragment also includes a dual acting Fab or DAF comprising an antigen binding site that binds to CD137 as well as a different antigen (see eg US 2008 / 0069820). 7. Antibody variants In certain embodiments, amino acid sequence variants of the antibodies provided herein are contemplated. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibody. Amino acid sequence variants of an antibody can be prepared by introducing appropriate modifications to the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions and / or insertions and / or substitutions of residues in the amino acid sequences of the antibody. Any combination of deletion, insertion, and substitution can be used to obtain the final construct, as long as the final construct possesses the desired characteristics, eg, antigen binding. a) Substitution, insertion and deletion variants In certain embodiments, variants are provided Lnn / ίΖΠΖ / Β / ΥΙΛΙ 223 Lnn / ίΖΠΖ / Β / ΥΙΛΙ of antibodies comprising one or more amino acid substitutions. Sites of interest for substitutional mutagenesis include HVRs and FRs. Conservative substitutions are shown in Table 1, under the heading of preferred substitutions. Further substantive changes are provided in Table 1 under the heading of exemplary substitutions, and are described below with reference to classes of amino acid side chains. Amino acid substitutions can be introduced into an antibody of interest and the products selected for a desired activity, eg, retained / enhanced antigen binding, decreased immunogenicity, or enhanced ADCC or CDC. Table 5 Parent Residue Examples of Substitutions Preferred Substitutions Ala (A) Val; read; Lie Val Arg(R) Lys; glin; Asn Lys Asn (N) Gln; his; Asp, Lys; Arg Gln Asp(D)Glu; Asn Glu Cys (C) Ser; Ala Ser Gln (Q) Asn; Glu Asn Glu (E) Asp; Gln Asp Gly (G) Ala Ala His (H) Asn; glin; Lys; Arg Arg lie (I) Leu; Val; Met Norleucine ; To the; Phe; Leu Leu (L) Norleucine; met; To the; Phe Lie; Val; lie Lys(K)Arg; glin; asn arg 224 Lnn / ίΖΠΖ / Β / ΥΙΛΙ Met(M)Leu; Phe; lie Leu Phe (F) Trp; Tyr Leu; Val; lies; To the; Tyr Pro (P) Ala Ala Ser (S) Thr Thr Thr (T) Val; Ser Ser Trp (W) Tyr; Phe Tyr Tyr (Y) Trp; Phe; Thr; Ser Phe Val(V)lie; read; met; Norleucine Phe; To the; read Amino acids can be grouped according to the common properties of the side chains: (1) hydrophobic: Norleucine, Met, Ala, Val, Leu, lie; (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) acids: Asp, Glu; (4) basic: His, Lys, Arg; 5) residues that affect the orientation of the chain: Gly, Pro; (6) aromatics: Trp, Tyr, Phe. None of the conservative substitutions will involve exchanging a member of one of these classes for another class. One type of substitutional variant comprises substituting one or more hypervariable region residues of a parent antibody (eg, a humanized or human antibody). In general, the resulting variants selected for further study will have Lnn / ίΖΠΖ / Β / ΥΙΛΙ 225 modifications (eg, improvements) in certain biological properties (eg, increased affinity, reduced immunogenicity) relative to the parent antibody and / or will have substantially retained some biological properties of the parent antibody. An example of a substitutional variant is an affinity-matured antibody, which can be conveniently generated, for example, using phage display-based affinity maturation techniques such as those described herein. Briefly, one or more HVR residues are mutated and the antibody variants are displayed on phage and selected for a particular biological activity (eg, binding affinity). Alterations (eg, substitutions) can be made in HVR, for example, to improve the affinity of the antibodies. Such alterations can be made at HVR hot spots, that is, at residues encoded by codons that undergo mutations with high frequency during the process of somatic maturation (see, for example, Chowdhury, Methods Mol. Biol. 207: 17 9196 (2008)), and / or on residues contacting the antigen, and the resulting VH or VL variant is evaluated for binding affinity. Affinity maturation by construction and reselection of secondary libraries has been described, for example, in Hoogenboom et al. Lnn / ίΖΠΖ / Β / ΥΙΛΙ 226 al., in Methods in Molecular Biology 178: 1-37 (O'Brien et al., Ed., Human Press, Totowa, NJ, (2001)). In some embodiments of affinity maturation, diversity is introduced into the variable genes selected for maturation by any of a variety of methods (eg, error-prone PCR, strand interleaving, or oligonucleotide-directed mutagenesis). Then a child library is created. The library is then screened to identify any antibody variants with the desired affinity. Another method of introducing diversity comprises HVR-directed approaches, in which several HVR residues are randomly assigned (eg, 4-6 residues at a time). HVR residues involved in antigen binding can be specifically identified, for example, using mutagenesis or alanine scanning patterning. In particular, CDR-H3 and CDRL3 are often searched for. In certain embodiments, they can produce substitutions, insertions, or deletions within one or more HVRs as long as such alterations do not substantially reduce the ability of the antibody to bind antigen. For example, conservative alterations (eg, the conservative substitutions provided herein) can be made that do not substantially reduce the binding affinity in HVRs. Such alterations can 227 can be found, for example, outside the antigen-contacting residues in HVRs. In certain embodiments of the variant VH and VL sequences provided above, each HVR is either unaltered or contains no more than one, two, or three amino acid substitutions. A useful method for identifying residues or regions of an antibody that can be targeted for mutagenesis is called alanine scanning mutagenesis as described in Cunningham and Wells (1989) Science, 244: 1081-1085. In this method, a target residue or group of residues (for example, charged residues such as arg, asp, his, lys, and glu) is identified and replaced with a negatively charged or neutral amino acid (for example, alanine or polyalanine). ) to determine if the interaction of the antibody with the antigen is affected. Other substitutions can be introduced at amino acid locations that demonstrate functional sensitivity to the initial substitutions. Alternatively, or additionally, the crystal structure of an antigen-antibody complex can be analyzed to identify contact points between the antibody and the antigen. Such contact residues and neighboring residues can be selected or eliminated as candidates for substitution. Variants can be selected to determine if they contain the properties Lnn / ίΖΠΖ / Β / ΥΙΛΙ 228 desired. Amino acid sequence insertions include amino- and / or carboxy-terminal fusions ranging in length from one residue to polypeptides containing one hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include an antibody with an N-terminal methionyl residue. Other insertion variants of the antibody molecule include the fusion of an enzyme (eg, for ADEPT) or polypeptide into the N- or C-terminus of the antibody that increases the plasma half-life of the antibody. b) Glycosylation variants In certain embodiments, an antibody provided herein is altered to increase or decrease the degree to which the antibody is glycosylated. The addition or deletion of glycosylation sites in an antibody can be conveniently effected by altering the amino acid sequence such that one or more glycosylation sites are created or deleted. When the antibody comprises an Fe region, the carbohydrate attached to it can be altered. Native antibodies produced by mammalian cells typically comprise a branched double-stranded oligosaccharide that is generally linked by a bond. Lnn / ίΖΠΖ / Β / ΥΙΛΙ 229 N to Asn297 of the CH2 domain of the Fe region. See, for example, Wright et al., TIBTECH 15: 26-32 (1997). The oligosaccharide can include various carbohydrates, for example, mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as a fucose attached to a GlcNAc in the stem of the double-stranded oligosaccharide structure. In some embodiments, oligosaccharide modifications of an antibody of the present disclosure can be made to create antibody variants with certain improved properties. In one embodiment, variant antibodies are provided that have a carbohydrate structure that lacks a fucose attached (directly or indirectly) to an Fe region. For example, the amount of fucose in such an antibody can comprise between 1% and 80%, between 1% and 65%, between 5% and 65% or between 20% and 40%. The amount of fucose is determined by calculating the average amount of fucose in the sugar chain on Asn297 relative to the sum of all Asn 297-bound glycostructures (e.g., complex, hybrid, and high-mannose structures) according to with a measurement by MALDI-TOF mass spectrometry, as described, for example, in WO 2008 / 077546. Asn297 refers to the asparagine residue located at approximately position 297 of the Fe region (EU numbering of Fe region residues); without Lnn / ίΖΠΖ / Β / ΥΙΛΙ However, Asn297 can also be located approximately + / 3 amino acids 5' or 3' from position 297, ie, between positions 294 and 300, due to minor sequence variations of the antibodies. Such fucosylation variants may have improved ADCC function. See, for example, US Patent Nos: 6773900, 6740506, 6713282, 6635449, 6605449, 6537776, US 2003 / 0157108 (Presta, L.); US 2004 / 0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications relating to defucosylated or fucose-deficient variants of the antibodies include: US 2003 / 0157108; WO 2000 / 61739; WO 2001 / 29246; US 2003 / 0115614; US 2002 / 0164328; US 2004 / 0093621; US 2004 / 0132140; US 2004 / 0110704; US 2004 / 0110282; US 2004 / 0109865; WO 2003 / 085119; WO 2003 / 084570; WO 2005 / 035586; WO 2005 / 035778; WO2005 / 053742; WO2002 / 031140; Okazaki et al., J. Mol. Biol. 336: 1239-1249 (2004); Yamane-Ohnuki et al., Biotech. bloeng. 87:614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Lecl3 CHO cells deficient in protein fucosylation (Ripka et al., Arch. Biochem. Biophys. 249: 533-545 (1986); US Patent Application No: US 2003 / 0157108 Al, Presta, L; and WO 2004 / 056312 Al, Adams et al., especially in Example 11), and knockout cell lines, such as for alpha-1.6fucosyltransferase gene, FUT8, CHO knockout cells (see, for For example, Yamane-Ohnuki et al., Biotech Bloeng 87: 614 Lnn / ίΖΠΖ / Β / ΥΙΛΙ 231 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94 (4): 680688 (2006); and WO2003 / 085107). Additionally provided are variants of antibodies with bisected oligosaccharides, eg, in which GlcNAc cleaves a bisected oligosaccharide attached to the Fe region of the antibody. Such antibody variants may exhibit reduced fucosylation and / or enhanced ADCC function. Examples of such antibody variants are described, for example, in WO 2003 / 011878 (Jean-Mairet et al.); US Patent No: 6,602,684 (Umana et al.); and US 2005 / 0123546 (Umana et al.). Antibody variants with at least one galactose residue in the oligosaccharide attached to the Fe region are also provided. Such antibody variants may exhibit improved CDC function. These antibody variants are described, for example, in WO 1997 / 30087 (Patel et al.); WO 1998 / 58964 (Raju, S.); and WO 1999 / 22764 (Raju, S. ). c) Variants of the Fe region In certain embodiments, one or more amino acid modifications can be introduced into the Fe region of an antibody provided herein, thereby generating a variant Fe region (which may also be called an altered Fe region). The Fc region variant may comprise a human Fc region sequence (eg, a human IgG1, IgG2, IgG3, or IgG4 Fc region) that 232 comprises an amino acid modification (eg, substitution) at one or more amino acid positions. In certain embodiments, the present disclosure contemplates a variant antibody that possesses some, but not all, effector functions, making it a desirable candidate for applications in which antibody half-life in vivo is important even though certain effector functions are not present. (such as complement and ADCC) are unnecessary or harmful. In vitro and / or in vivo cytotoxicity assays can be performed to confirm the reduction / suppression of CDC and / or ADCC activities. For example, Fe receptor (FcR) binding assays can be performed to ensure that the antibody does not bind to the Fe gamma R (hence probably no ADCC activity), but retains FcRn binding activity. The primary cells to mediate ADCC, NK cells, only express Fe gamma RUI, whereas monocytes express Fe gamma RI, Fe gamma RII, and Fe gamma RUI. The expression of FcR on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457492 (1991). Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest are described in US Patent No: 5,500,362 (see, for example, Hellstrom, I. et al., Proc. Nat ' 1 Acad. Sci. USA 83: 7059-7063 (1986)) and Hellstrom, I et al., Proc. Nat Acal. Lnn / ίΖΠΖ / Β / ΥΙΛΙ 233 Sci. USA 82: 1499-1502 (1985); 5,821,337 (see Bruggemann, M. et al., J. Exp. Med. 166: 1351-1361 (1987)). Alternatively, non-radioactive assay methods may be employed (see, for example, the ACT1™ non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, CA; and the CytoTox 96 (registered trademark) non-radioactive cytotoxicity assay). ) (Promega, Madison, WI).Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and natural killer (NK) cells.Alternatively, or in addition, one can assess the ADCC activity of the of interest in vivo, for example, in an animal model, such as that described in Clynes et al., PNAS (USA) 95:652-656 (1998).Binding assays can also be carried out to Clq to confirm that the antibody cannot bind to Clq and therefore lacks CDC activity See, for example, Clq and C3c binding ELISA in WO 2006 / 029879 and WO 2005 / 100402. complement activation, a CDC assay can be performed (see, for example, Gazzano-Santoro et al., J. Immunoi. Methods 202: 163 (1996); Cragg, MS et al., Blood 101: 1045-1052 (2003); and Cragg, M.S. and M.J. Glennie, Blood 103: 2738-2743 (2004)). Determinations of FcRn binding and in vivo clearance / half-life can also be performed using methods known in the art (see, for example, Petkova, SB et al., Int'l. Immunoi. Lnn / ίΖΠΖ / Β / ΥΙΛ 234(12):1759-1769 (2006)). Antibodies with reduced effector function include those comprising a substitution of one or more of residues 238, 265, 269, 270, 297, 327, and 329 of the Fe region (US Patent No: 6,737,056). Such Fe mutants include Fe mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297, and 327, including the so-called Fe DANA mutant with substitution of residues 265 and 297 with alanine (US Patent No. : 7,332,581). Some variants of antibodies with greater or lesser binding to the FcR are described. (See, for example, US Patent No: 6,737,056; WO 2004 / 056312, and Shields et al., J. Biol. Chem. 9(2): 6591-6604 (2001)). In certain embodiments, a variant antibody comprises an Fc region with one or more ADCC-enhancing amino acid substitutions, eg, substitutions at Fc region positions 298, 333, and / or 334 (EU residue numbering). In some embodiments, alterations are made in the Fe region that result in impaired (i.e., increased or decreased) Clq binding and / or complement-dependent cytotoxicity (CDC), for example, as described in US Pat. No: 6,194,551, WO 99 / 51642 and Idusogie et al., J. Immunol. 164: 4178-4184 Lnn / ίΖΠΖ / Β / ΥΙΛ 235 (2000). Antibodies with increased half-lives and increased neonatal Fe receptor (FcRn) binding, which is responsible for the transfer of maternal IgG to the fetus (Guyer et al., J. Immunol. 117: 587 (1976) and Kim et al. , J. Immunol. 24: 249 (1994)), are described in US2005 / 0014934A1 (Hinton et al. ). These antibodies comprise an Fe region with one or more substitutions that increase the binding of the Fe region to FcRn. Such Fe variants include those having substitutions at one or more of the following Fe region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, ​​413, 424 or 434, for example, a substitution of residue 434 of the Fe region (US Patent No: 7,371,826). See also Duncan & Winter, Nature 322: 738-40 (1988); US Patent No: 5,648,260; US Patent No: 5,624,821; and WO 94 / 29351 for other examples of Fe region variants. In one embodiment, the binding activity to each human Fc-gamma receptor (Fc-gamma R) of an antibody Fc region (including a Fc region variant (the same applies hereinafter)) can be measured. by a ligand capture method using, for example, BIACORE (registered trademark) T200, which is based on surface plasmon resonance analysis methods as the principle of 236 measurement. In the following, details of an exemplary method for measuring the binding activity of the Fc region of the antibody to various human Fc-gamma receptors (Fc-gamma R) are described. In one embodiment, the binding activity of an antibody Fc region to the Fc-gamma R is assessed using BIACORE (Trade Mark) T200. In a preferred embodiment, this measurement is carried out at 25 degrees C, using a measurement buffer of 50 mM phosphate, 150 mM NaCl, 0.05% w / v P20, pH 7.4. Specifically, approximately 1000 RU of an antibody comprising a variant of the Fe region is first captured on a sensor chip with the CaptureSelect (trademark) Human Fablambda Kinetícs Biotin Conjugate (ThermoFisher Scientific) immobilized as a ligand capture molecule. Human Fcgamma R's are diluted with measurement buffer to 8 nM for Fc-gamma Ría and 1000 nM for other Fcgamma R's, and allowed to bind to the captured antibody. The binding activity of each antibody to each Fc-gamma R is evaluated by calculating the amount of Fc-gamma R bound per unit amount of antibody (RU) using the Biacore T200 2.0 evaluation software. In one embodiment, the binding activity of an antibody Fc region to various human Fc-gamma receptors (Fc-gamma R) can be measured by the method described in Example 7-4. Lnn / ίΖΠΖ / Β / ΥΙΛΙ Lnn / ίΖΠΖ / Β / ΥΙΛΙ 237 In a preferred embodiment, the Fc-gamma R used in the measurement method described above may comprise an extracellular domain of an Fc-gamma R prepared with the method described below. First, gene synthesis of an extracellular domain of an Fc-gamma R is carried out by a method known to those skilled in the art. For this synthesis, the sequences of each Fc-gamma R are prepared based on the information registered with NCBI. More specifically, the sequence of Fc-gamma RI is prepared based on the sequence of NCBI, accession #: NM_000566.3, the sequence of Fc-gamma Rila is prepared based on the sequence of NCBI, accession #: NM 001136219.1, the Fc-gamma Rllb sequence is prepared based on the NCBI sequence, accession #: NM_004001.3, and the Fc-gamma RlIIa sequence is prepared based on the NCBI sequence, accession #: NM_001127593.1, and a His tag is added to the C-terminus. Polymorphic sites for Fc-gamma Rila are prepared with reference to J. Exp. Med., 1990, 172, 19-25, and polymorphic sites for Fc-gamma RlIIa are prepared with reference to J. Clin. Invest., 1997, 100, 1059-1070. The obtained gene fragments are inserted into an expression vector for animal cells to prepare expression vectors. The prepared expression vectors are transiently introduced into FreeStyle293 cells (Invitrogen) derived from human embryonic kidney cancer cells and Lnn / ίΖΠΖ / Β / ΥΙΛΙ 238 the protein of interest is allowed to express itself. The culture supernatant is collected and filtered through a 0.22 micron filter, and then basically purified through the four steps described below. As a first step, a cation exchange column chromatography (SP Sepharose FF) is carried out; as a second step, an affinity column chromatography with His tags (HisTrap HP); as a third step, a gel filtration column chromatography (Superdex200); and as a fourth step, an aseptic filtration. It should be noted that for the Fcgamma RI, an anion exchange column chromatography is carried out using Q sepharose FF as the first step. The concentration of the purified protein is calculated based on the absorption coefficient, calculated by measuring the absorbance at 280 nm using a spectrophotometer and using PACE or a similar method for the measured values ​​(Protein Science, 1995, 4, 2411-2423). In one embodiment, the binding activity of an antibody Fc region to human FcRn can be measured by a ligand capture method using, for example, BIACORE (Trade Mark) T200, which is based on plasmon resonance analysis methods. of surface as a principle of measurement. Details of an exemplary method for measuring the binding activity of the Fe region of an antibody to the FcRn Lnn / ίΖΠΖ / Β / ΥΙΛΙ 239 human are described later. In one embodiment, the binding activity of an antibody Fc region to human FcRn is assessed using BIACORE (Trade Mark) T200. In a preferred embodiment, this measurement is carried out at 25 degrees C, using a measurement buffer of 50 mM phosphate, 150 mM NaCl, 0.05% w / v P20, pH 6.0. Specifically, about 400 RU of an antibody comprising an Fe region is first captured on a sensor chip, onto which has been immobilized Human Fab-lambda Kinetics Biotin Conjugate (ThermoFisher Scientific) CaptureSelect (Trade Mark) conjugate as the capture molecule. ligand, and then human FcRn diluted using the measurement buffer is allowed to bind to it. The binding activity of each antibody to the FcRn is assessed by calculating the KD(M) using the steady state model with the Biacore T200 2.0 evaluation software. In a preferred embodiment, the human FcRn protein used in this measurement is prepared according to the method described in Reference Example 2 of WO201010711. In one embodiment, the binding activity of an antibody Fc region to various Fc-Rn) receptors can be measured by the method described in Example 7-5. d) Cysteine-modified antibody variants In certain embodiments, it may be desirable to create Lnn / ίΖΠΖ / Β / ΥΙΛΙ 240 cysteine-modified antibodies, eg, thioMAbs, in which one or more of the residues of an antibody are substituted with cysteine ​​residues. In particular embodiments, the substituted residues are found at accessible sites on the antibody. By substituting those residues with cisternae, the reactive thiol groups are then located at accessible sites on the antibody and can be used to conjugate the antibody to other units, such as drug units or linker drug units, to create an immunoconjugate, as will be described. later in the present. In certain embodiments, one or more of the following residues may be substituted for cisternae: V205 (Kabat numbering) of the light chain; A118 (EU numbering) of the heavy chain; and S400 (EU numbering) of the Fe region of the heavy chain. Cystern-modified antibodies can be generated as described, for example, in US Patent No: 7,521,541. e) Derivatives of antibodies In certain embodiments, an antibody provided herein can also be modified to contain additional non-proteinaceous units that are known in the art and readily available. Units suitable for antibody derivatization include, but are not limited to, water-soluble polymers. Non-limiting examples of water soluble polymers include, but are not limited to Lnn / ίΖΠΖ / Β / ΥΙΛΙ 241 in a non-limiting sense, polyethylene glycol (PEG), ethylene glycol / propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly1,3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymers, polyamino acids (either homopolymers or random copolymers) and dextran or poly(vinylpyrrolidone)polyethylene glycol, polypropylene glycol homopolymers, polypropylene oxide / ethylene oxide copolymers, polyoxyethylated polyols (eg, glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may offer advantages in processing due to its stability in water. The polymer can be of any molecular weight and can be branched or unbranched. The number of polymers bound to the antibody can vary, and if more than one polymer is bound, they can be the same or different molecules. In general, the number and / or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular properties or functions of the antibody to be improved, whether the antibody derivative will be used in a therapy under defined conditions, etc. In another embodiment, conjugates of an antibody and a non-protein unit are provided that can be selectively heated by exposure to radiation. In one mode, Lnn / ίΖΠΖ / Β / ΥΙΛΙ 242 the non-protein unit is a carbon nanotube (Kam et al., Proc. Nati. Acad. Sci. USA 102: 11600-11605 (2005)). The radiation can be of any wavelength, including, but not limited to, wavelengths that do not injure ordinary cells, but that heat the non-protein unit to a temperature at which cells proximal to it are destroyed. the non-protein unit of the antibody. B. Recombinant Compositions and Methods Antibodies can be produced using recombinant methods and compositions, for example, as described in US Patent No: 4,816,567. In one embodiment, an isolated nucleic acid is provided that encodes an anti-CD137 antibody or antigen binding molecule described herein. Such nucleic acid may encode an amino acid sequence comprising the Vl and / or an amino acid sequence comprising the Vh of the antibody (eg, the light and / or heavy chains of the antibody). In a further embodiment, one or more vectors (eg, expression vectors) comprising such a nucleic acid are provided. In a further embodiment, a host cell comprising such a nucleic acid is provided. In such an embodiment, a host cell comprises (eg, was transformed therewith): (1) a vector comprising a nucleic acid encoding an amino acid sequence comprising the antibody V1 and a sequence of 243 amino acids comprising the antibody Vh or (2) a first vector comprising a nucleic acid encoding an amino acid sequence comprising the antibody Vl and a second vector comprising a nucleic acid encoding an amino acid sequence comprising the Vh of the antibody. In one embodiment, the host cell is eukaryotic, eg, a Chinese Hamster Ovary (CHO) cell or a lymphoid cell (eg, YO, NSO, Sp2 / 0 cells). In one embodiment, a method of making an anti-CD137 antibody or antigen binding molecule is provided, wherein the method comprises culturing a host cell comprising a nucleic acid encoding the antibody, provided above, under conditions suitable for expression. of the antigen binding molecule or anti-CD137 antibody and optionally recovering the antibody from the host cell (or host cell culture medium). For recombinant production of an anti-CD137 antibody or antigen-binding molecule, nucleic acid encoding an antibody is isolated, for example, as previously described, and inserted into one or more vectors for subsequent cloning and production. / or expression in a host cell. Such nucleic acid can be readily isolated and sequenced using standard procedures (for example, with oligonucleotide probes that bind 244 specifically to the genes encoding the heavy and light chains of the antibody). Host cells suitable for cloning or expression of antibody-encoding vectors include the prokaryotic or eukaryotic cells described herein. For example, antibodies can be produced in bacteria, particularly when Fe glycosylation and effector function is not required. For expression of antibody fragments and polypeptides in bacteria, see, for example, US Patent Nos: 5,648,237, 5,789,199 and 5,840,523. (See also Charlton, Methods in Molecular Blology^ volume 248 (B.K.C. Lo, ed., Humana Press, Totowa, NJ, 2003), pages 245-254, describing the expression of antibody fragments in E. coli). After expression, the antibody can be isolated from the bacterial cell paste in a soluble fraction and further purified. In addition to prokaryotes, suitable cloning or expression hosts for the antibody-encoding vectors are eukaryotic microorganisms, such as filamentous fungi or yeasts, including fungi and yeast strains whose glycosylation pathways have been humanized, resulting in the production of an antibody with a partially or fully human glycosylation pattern. See Gerngross, Nat. Biotech. 22: 1409-1414 (2004), Lnn / ίΖΠΖ / Β / ΥΙΛΙ 245 and Li et al., Nat. Biotech. 24: 210-215 (2006). Host cells suitable for the expression of glycosylated antibodies are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include insect and plant cells. Numerous baculovirus strains have been identified that can be used in conjunction with insect cells, in particular for the transfection of Spodoptera frugiperda cells. Plant cell cultures can also be used as hosts. See, for example, US Patent Nos: 6,773,900, 6,740,506, 6,713,282, 6, 635, 449, 6, 605, 449, 6, 537,776, 5, 959, 177, 6, 040,498, 6,420,7,548, 7,420,7,525, 7, 97, 4, 7, 528 9 (where describes the PLANTIBODIES™ technology for producing antibodies in transgenic plants). Vertebrate cells can also be used as hosts. For example, mammalian cell lines adapted to grow in suspension may be useful. Other examples of useful mammalian host cell lines include the monkey kidney line CV1 transformed with SV40 (COS-7); the human embryonic kidney line (293 or 293 cells as described, for example, in Graham et al., J. Gen Virol. 36: 59 (1977)); newborn hamster kidney (BHK) cells; cells of Lnn / ίΖΠΖ / Β / ΥΙΛΙ 246 Mouse Sertoli (TM4 cells, described, for example, in Mather, Biol. Reprod. 23: 243-251 (1980)); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma (HELA) cells; canine kidney cells (MDCK); buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells, which are described, for example, in Mather et al., Annals N.Y. Acad. Sel. 383: 4468 (1982); MRC 5 cells; and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR-CHO cells (Urlaub et al., Proc. Nati. Acad. Sel. USA 77: 4216 (1980) ). ); and myeloma cell lines such as YO, NSO, and Sp2 / 0. For a review of some mammalian host cell lines suitable for antibody production, see, eg, Yazaki and Wu, Methods in Molecular Biology, Volume 248. (B.K.C. Lo, ed., Humana Press, Totowa, NJ), pages 255-268 (2003). C. Trials The antigen-binding molecules or anti-CD137 antibodies provided herein can be identified, selected or ...

Claims

1. An anti-CD137 antigen-binding molecule, characterized in that it exhibits CD137-binding activity dependent on a small molecule compound.

2. The anti-CD137 antigen-binding molecule according to claim 1, characterized in that the CD137 binding activity in the presence of 10 μM, 50 μM, 100 μM, 150 μM, 200 μM or 250 μM of the small molecule compound is twice as high or more than the CD137 binding activity in the absence of the small molecule compound.

3. The anti-CD137 antigen-binding molecule according to claim 1 or 2, characterized in that it comprises any combination of HVR-H1, HVR-H2, and HVR-H3 selected from (a) to (k) as follows: (a) An HVR-H1 comprising the amino acid sequence of SEC ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEC ID NO: 8, and an HVR-H3 comprising the amino acid sequence of SEC ID NO: 17; (b) An HVR-H1 comprising the amino acid sequence of SEC ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEC ID NO: 9, and an HVR-H3 comprising the amino acid sequence of SEC ID NO: 17; Lnn / ίZΖΠΖ / Β / YΙΛΙ 615 (c) An HVR-H1 comprising the amino acid sequence of SEC ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEC ID NO: 10 and an HVR-H3 comprising the amino acid sequence of SEC ID NO: 17;(d) An HVR-H1 comprising the amino acid sequence of SEC ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEC ID NO: 11, and an HVR-H3 comprising the amino acid sequence of SEC ID NO: 18; (e) An HVR-H1 comprising the amino acid sequence of SEC ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEC ID NO: 8, and an HVR-H3 comprising the amino acid sequence of SEC ID NO: 18; (f) An HVR-H1 comprising the amino acid sequence of SEC ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEC ID NO: 12, and an HVR-H3 comprising the amino acid sequence of SEC ID NO: 18; (g) An HVR-H1 comprising the amino acid sequence of SEC ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEC ID NO: 13 and an HVR-H3 comprising the amino acid sequence of SEC ID NO: 18;(h) An HVR-H1 comprising the amino acid sequence of SEC ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEC ID NO: 14, and an HVR-H3 comprising the amino acid sequence of SEC ID NO: 19; (i) An HVR-H1 comprising the 616 amino acid sequence of SEC ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEC ID NO: 15, and an HVR-H3 comprising the amino acid sequence of SEC ID NO: 20; (j) An HVR-H1 comprising the amino acid sequence of SEC ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEC ID NO: 16, and an HVR-H3 comprising the amino acid sequence of SEC ID NO: 20; and (k) An HVR-H1 comprising the amino acid sequence of SEC ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEC ID NO: 14 and an HVR-H3 comprising the amino acid sequence of SEC ID NO: 17.; 4. An anti-CD137 antigen-binding molecule, characterized in that it comprises any combination of HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 selected from (a) to (m) as follows: (a) An HVR-H1 comprising the amino acid sequence of SEC ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEC ID NO: 8, an HVR-H3 comprising the amino acid sequence of SEC ID NO: 17, an HVR-L1 comprising the amino acid sequence of SEC ID NO: 21, an HVR-L2 comprising the amino acid sequence of SEC ID NO: 26, and an HVR-L3 comprising the amino acid sequence of SEC ID NO: 27;(b) An HVR-H1 comprising the amino acid sequence of SEC ID NO: 7, an HVR-H2 comprising the Lnn / įZРZ� / B / YILI 617 amino acid sequence of SEC ID NO: 9, an HVR-H3 comprising the amino acid sequence of SEC ID NO: 17, an HVR-L1 comprising the amino acid sequence of SEC ID NO: 22, an HVR-L2 comprising the amino acid sequence of SEC ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEC ID NO: 27; (c) An HVR-H1 comprising the amino acid sequence of SEC ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEC ID NO: 10, an HVR-H3 comprising the amino acid sequence of SEC ID NO: 17, an HVR-L1 comprising the amino acid sequence of SEC ID NO: 22, an HVR-L2 comprising the amino acid sequence of SEC ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEC ID NO: 27;(d) An HVR-H1 comprising the amino acid sequence of SEC ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEC ID NO: 11, an HVR-H3 comprising the amino acid sequence of SEC ID NO: 18, an HVR-L1 comprising the amino acid sequence of SEC ID NO: 21, an HVR-L2 comprising the amino acid sequence of SEC ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEC ID NO: 27; (e) An HVR-H1 comprising the amino acid sequence of SEC ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEC ID NO: 8, an HVR-H3 comprising the amino acid sequence of SEC ID NO: 18, an HVR-L1 comprising the amino acid sequence of SEC ID NO: 21, an HVR-L2 comprising the amino acid sequence of SEC ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEC ID NO: 27;(f) An HVR-H1 comprising the amino acid sequence of SEC ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEC ID NO: 12, an HVR-H3 comprising the amino acid sequence of SEC ID NO: 18, an HVR-L1 comprising the amino acid sequence of SEC ID NO: 21, an HVR-L2 comprising the amino acid sequence of SEC ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEC ID NO: 28; (q) An HVR-H1 comprising the amino acid sequence of SEC ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEC ID NO: 13, an HVR-H3 comprising the amino acid sequence of SEC ID NO: 18, an HVR-L1 comprising the amino acid sequence of SEC ID NO: 21, an HVR-L2 comprising the amino acid sequence of SEC ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEC ID NO: 29;(h) An HVR-H1 comprising the amino acid sequence of SEC ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEC ID NO: 14, an HVR-H3 comprising the amino acid sequence of SEC ID NO: 19, an HVR-L1 comprising the amino acid sequence of SEC ID NO: 23, an HVR-L2 comprising the amino acid sequence of SEC ID NO: 26, and an HVR-L3 comprising the amino acid sequence of SEC ID NO: 27; (i) An HVR-H1 comprising the amino acid sequence of SEC ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEC ID NO: 15, an HVR-H3 comprising the amino acid sequence of SEC ID NO: 20, an HVR-L1 comprising the amino acid sequence of SEC ID NO: 24, an HVR-L2 comprising the amino acid sequence of SEC ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEC ID NO: 27;(j) An HVR-H1 comprising the amino acid sequence of SEC ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEC ID NO: 15, an HVR-H3 comprising the amino acid sequence of SEC ID NO: 20, an HVR-L1 comprising the amino acid sequence of SEC ID NO: 25, an HVR-L2 comprising the amino acid sequence of SEC ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEC ID NO: 27; (k) An HVR-H1 comprising the amino acid sequence of SEC ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEC ID NO: 16, an HVR-H3 comprising the amino acid sequence of SEC ID NO: 20, an HVR-L1 comprising the amino acid sequence of Lnn / įZЖРZ� / B / YILI 620 SEC ID NO: 25, an HVR-L2 comprising the amino acid sequence of SEC ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEC ID NO: 27;(1) An HVR-H1 comprising the amino acid sequence of SEC ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEC ID NO: 14, an HVR-H3 comprising the amino acid sequence of SEC ID NO: 19, an HVR-L1 comprising the amino acid sequence of SEC ID NO: 24, an HVR-L2 comprising the amino acid sequence of SEC ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEC ID NO: 27; and (m) An HVR-H1 comprising the amino acid sequence of SEC ID NO: 7, an HVR-H2 comprising the amino acid sequence of SEC ID NO: 14, an HVR-H3 comprising the amino acid sequence of SEC ID NO: 17, an HVR-L1 comprising the amino acid sequence of SEC ID NO: 21, an HVR-L2 comprising the amino acid sequence of SEC ID NO: 26 and an HVR-L3 comprising the amino acid sequence of SEC ID NO: 27.; 5. An anti-CD137 antigen-binding molecule, characterized in that it comprises: (a) a VH having at least 95% sequence identity with any of the amino acid sequences in SEC ID NO: 43 to 53; or (b) a VL having at least 95% sequence identity with any of the amino acid sequences in SEC ID NO: 54 to 60.

6. The anti-CD137 antigen-binding molecule according to any one of claims 1 to 5, characterized in that it comprises an altered Fe region, wherein the altered Fe region comprises any of the following combinations of amino acid alterations selected from: L235W / G236N / H268D / Q295L / K326T / A330K / P343R / D413K; K214R / L235W / G236N / H268D / Q295L / K326T / A330K / P343R / D413K; L234Y / P238D / T250V / V264I / T307P / A330K / P343R / D413K; L234Y / P238D / V264I / A330K / P343R / D413K; L234Y / G237D / P238D / T250V / T307P / A330K / P343R / D413K; L234Y / G237D / P238D / A330K / P343R / D413K; L235W / G236N / H268D / Q295L / K326T / A330K / Q311R / P343R; L234Y / P238D / T250V / V264I / T307P / A330K / Q311R / P343R; L234Y / P238D / V264I / A330K / Q311R / P343R; L234Y / G237D / P238D / T250V / T307P / A330K / Q311R / P343R; L234Y / G237D / P238D / A330K / Q311R / P343R; L235W / G236N / H268D / Q295L / K326T / A330K / P343R; K214R / L235W / G236N / H268D / Q295L / K326T / A330K / P343R; L235W / G236N / H268D / Q295L / K326T / A330K / D413K; K214R / G236N / H268D / A330K / P343R;K214R / L235W / G236N / H268D / A330K / P343R; Lnn / ίΖΠΖ / Β / ΥΙΛΙ Lnn / ίΖΠΖ / Β / ΥΙΛΙ 622 ​​K214R / G236N / H268D / A330K / D413K; K214R / G236N / H268D / A330K / P343R / D413K; Κ214R / L235W / G236Ν / Η268D / A330Κ / Ρ343R / D413Κ; K214R / G236N / H268D / A330K / Q311R; K214R / L235W / G236N / H268D / A330K / Q311R; K214R / G236N / H268D / A330K / Q311R / P343R; Κ214R / L235W / G236Ν / Η268D / A330K / Q311R / P343R; Κ214R / G236Ν / Η268D / A330K / Q311R / D413Κ; Κ214R / L235W / G236Ν / Η268D / A330K / Q311R / D413Κ; and Κ214R / L235W / G236Ν / Η268D / Q295L / K326Τ / Α330K / Q311R.; 7. The anti-CD137 antigen-binding molecule according to any of claims 1 to 6, characterized in that it comprises a heavy chain constant region comprising any of the amino acid sequences of SEC ID NO: 64 to 85.

8. An isolated nucleic acid, characterized in that it encodes the anti-CD137 antigen-binding molecule according to any of claims 1 to 7.

9. A vector, characterized in that the nucleic acid is introduced therein in accordance with claim 8.

10. A host cell, characterized in that it comprises the nucleic acid according to claim 8 or the vector according to claim 9. Lnn / įZРZ� / В / YęЛΙ 623 11. A method for producing an anti-CD137 antigen-binding molecule, characterized in that it comprises culturing the host cell according to claim 10 to produce the anti-CD137 antigen-binding molecule.

12. An immunoconjugate, characterized in that it comprises the anti-CD137 antigen-binding molecule according to any of claims 1 to 7 and a cytotoxic agent.

13. A pharmaceutical formulation, characterized in that it comprises the anti-CD137 antigen-binding molecule according to any of claims 1 to 7 or the immunoconjugate according to claim 12; and a pharmaceutically acceptable vehicle.