CN-121971601-A - Anti-CD 137 antigen binding molecules for cancer treatment

CN121971601ACN 121971601 ACN121971601 ACN 121971601ACN-121971601-A

Abstract

The present disclosure aims to provide anticancer agents having an immune cell activating effect, a cytotoxic activity or an antitumor activity, but having a low effect on non-tumor tissues such as normal tissues and few side effects, combination therapies using these anticancer agents and other anticancer agents, and pharmaceutical combinations for these combination therapies. An anticancer agent which is expected to be applied to various types of cancers, has an immune cell activating effect, a cytotoxic activity or an antitumor activity, and has a low effect on non-tumor tissues such as normal tissues and less side effects, by using the anti-CD 137 antigen binding molecule of the present disclosure whose binding activity to CD137 varies depending on various substances (e.g., low molecular weight compounds) in target tissues as an active ingredient, is provided. Combination therapies using these anticancer agents and other anticancer agents, as well as pharmaceutical compositions for use in these combination therapies, are also provided.

Inventors

SAKURAI MIKA
Narita narika
TANIGUCHI KENJI
MIKAMI HIROSHI
HORIKAWA SAYURI
UCHIKAWA RYO
Ono natsuo
KODA TAKASHI

Assignees

中外制药株式会社

Dates

Publication Date: 20260505
Application Date: 20210210
Priority Date: 20200212

Claims (5)

1. A pharmaceutical composition for treating cancer comprising a combination of an anti-CD 137 antigen binding molecule and at least one other anti-cancer agent, wherein the anti-CD 137 antigen binding molecule comprises any combination of HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 selected from (a) to (m) below: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 7, HVR-H2 comprising the amino acid sequence of SEQ ID NO. 8, HVR-H3 comprising the amino acid sequence of SEQ ID NO. 17, HVR-L1 comprising the amino acid sequence of SEQ ID NO. 21, HVR-L2 comprising the amino acid sequence of SEQ ID NO. 26, and HVR-L3 comprising the amino acid sequence of SEQ ID NO. 27; (b) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 7, HVR-H2 comprising the amino acid sequence of SEQ ID NO. 9, HVR-H3 comprising the amino acid sequence of SEQ ID NO. 17, HVR-L1 comprising the amino acid sequence of SEQ ID NO. 22, HVR-L2 comprising the amino acid sequence of SEQ ID NO. 26, and HVR-L3 comprising the amino acid sequence of SEQ ID NO. 27; (c) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 7, HVR-H2 comprising the amino acid sequence of SEQ ID NO. 10, HVR-H3 comprising the amino acid sequence of SEQ ID NO. 17, HVR-L1 comprising the amino acid sequence of SEQ ID NO. 22, HVR-L2 comprising the amino acid sequence of SEQ ID NO. 26, and HVR-L3 comprising the amino acid sequence of SEQ ID NO. 27; (d) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 7, HVR-H2 comprising the amino acid sequence of SEQ ID NO. 11, HVR-H3 comprising the amino acid sequence of SEQ ID NO. 18, HVR-L1 comprising the amino acid sequence of SEQ ID NO. 21, HVR-L2 comprising the amino acid sequence of SEQ ID NO. 26, and HVR-L3 comprising the amino acid sequence of SEQ ID NO. 27; (e) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 7, HVR-H2 comprising the amino acid sequence of SEQ ID NO. 8, HVR-H3 comprising the amino acid sequence of SEQ ID NO. 18, HVR-L1 comprising the amino acid sequence of SEQ ID NO. 21, HVR-L2 comprising the amino acid sequence of SEQ ID NO. 26, and HVR-L3 comprising the amino acid sequence of SEQ ID NO. 27; (f) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 7, HVR-H2 comprising the amino acid sequence of SEQ ID NO. 12, HVR-H3 comprising the amino acid sequence of SEQ ID NO. 18, HVR-L1 comprising the amino acid sequence of SEQ ID NO. 21, HVR-L2 comprising the amino acid sequence of SEQ ID NO. 26, and HVR-L3 comprising the amino acid sequence of SEQ ID NO. 28; (g) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 7, HVR-H2 comprising the amino acid sequence of SEQ ID NO. 13, HVR-H3 comprising the amino acid sequence of SEQ ID NO. 18, HVR-L1 comprising the amino acid sequence of SEQ ID NO. 21, HVR-L2 comprising the amino acid sequence of SEQ ID NO. 26, and HVR-L3 comprising the amino acid sequence of SEQ ID NO. 29; (h) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 7, HVR-H2 comprising the amino acid sequence of SEQ ID NO. 14, HVR-H3 comprising the amino acid sequence of SEQ ID NO. 19, HVR-L1 comprising the amino acid sequence of SEQ ID NO. 23, HVR-L2 comprising the amino acid sequence of SEQ ID NO. 26, and HVR-L3 comprising the amino acid sequence of SEQ ID NO. 27; (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 7, HVR-H2 comprising the amino acid sequence of SEQ ID NO. 15, HVR-H3 comprising the amino acid sequence of SEQ ID NO. 20, HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24, HVR-L2 comprising the amino acid sequence of SEQ ID NO. 26, and HVR-L3 comprising the amino acid sequence of SEQ ID NO. 27; (j) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 7, HVR-H2 comprising the amino acid sequence of SEQ ID NO. 15, HVR-H3 comprising the amino acid sequence of SEQ ID NO. 20, HVR-L1 comprising the amino acid sequence of SEQ ID NO. 25, HVR-L2 comprising the amino acid sequence of SEQ ID NO. 26, and HVR-L3 comprising the amino acid sequence of SEQ ID NO. 27; (k) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 7, HVR-H2 comprising the amino acid sequence of SEQ ID NO. 16, HVR-H3 comprising the amino acid sequence of SEQ ID NO. 20, HVR-L1 comprising the amino acid sequence of SEQ ID NO. 25, HVR-L2 comprising the amino acid sequence of SEQ ID NO. 26, and HVR-L3 comprising the amino acid sequence of SEQ ID NO. 27; (l) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 7, HVR-H2 comprising the amino acid sequence of SEQ ID NO. 14, HVR-H3 comprising the amino acid sequence of SEQ ID NO. 19, HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24, HVR-L2 comprising the amino acid sequence of SEQ ID NO. 26, and HVR-L3 comprising the amino acid sequence of SEQ ID NO. 27, and (M) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 7, HVR-H2 comprising the amino acid sequence of SEQ ID NO. 14, HVR-H3 comprising the amino acid sequence of SEQ ID NO. 17, HVR-L1 comprising the amino acid sequence of SEQ ID NO. 21, HVR-L2 comprising the amino acid sequence of SEQ ID NO. 26, and HVR-L3 comprising the amino acid sequence of SEQ ID NO. 27.
2. A pharmaceutical composition for treating cancer comprising a combination of an anti-CD 137 antigen-binding molecule and at least one other anti-cancer agent, wherein the anti-CD 137 antigen-binding molecule comprises any combination of VH and VL selected from the group consisting of (a) to (m) below: (a) VH comprising the amino acid sequence of SEQ ID NO. 43, and VL comprising the amino acid sequence of SEQ ID NO. 54; (b) VH comprising the amino acid sequence of SEQ ID NO. 44, and VL comprising the amino acid sequence of SEQ ID NO. 55; (c) VH comprising the amino acid sequence of SEQ ID NO. 45, and VL comprising the amino acid sequence of SEQ ID NO. 55; (d) VH comprising the amino acid sequence of SEQ ID NO. 46, and VL comprising the amino acid sequence of SEQ ID NO. 54; (e) VH comprising the amino acid sequence of SEQ ID NO. 47, and VL comprising the amino acid sequence of SEQ ID NO. 54; (f) VH comprising the amino acid sequence of SEQ ID NO. 48, and VL comprising the amino acid sequence of SEQ ID NO. 56; (g) VH comprising the amino acid sequence of SEQ ID NO. 49, and VL comprising the amino acid sequence of SEQ ID NO. 57; (h) VH comprising the amino acid sequence of SEQ ID NO. 50, and VL comprising the amino acid sequence of SEQ ID NO. 58; (i) VH comprising the amino acid sequence of SEQ ID NO. 51, and VL comprising the amino acid sequence of SEQ ID NO. 59; (j) VH comprising the amino acid sequence of SEQ ID NO. 51, and VL comprising the amino acid sequence of SEQ ID NO. 60; (k) VH comprising the amino acid sequence of SEQ ID NO. 52, and VL comprising the amino acid sequence of SEQ ID NO. 60; (l) VH comprising the amino acid sequence of SEQ ID NO. 50, and 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.
3. The pharmaceutical composition of claim 1 or 2, wherein the anti-CD 137 antigen-binding molecule is a human, humanized or chimeric antibody, or an antigen-binding fragment of any of them.
4. The pharmaceutical composition of claim 1 or 2, wherein the anti-CD 137 antigen binding molecule comprises an altered Fc region, and the altered Fc region comprises any combination of amino acid alterations according to EU numbering selected from the group consisting of: 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; K214R/G236N/H268D/A330K/D413K; K214R/G236N/H268D/A330K/P343R/D413K; K214R/L235W/G236N/H268D/A330K/P343R/D413K; K214R/G236N/H268D/A330K/Q311R; K214R/L235W/G236N/H268D/A330K/Q311R; K214R/G236N/H268D/A330K/Q311R/P343R; K214R/L235W/G236N/H268D/A330K/Q311R/P343R; K214R/G236N/H268D/A330K/Q311R/D413K; K214R/L235W/G236N/H268D/A330K/Q311R/D413K, and K214R/L235W/G236N/H268D/Q295L/K326T/A330K/Q311R。
5. A pharmaceutical composition for treating cancer comprising a combination of an anti-CD 137 antigen binding molecule and at least one other anti-cancer agent, wherein the anti-CD 137 antigen binding molecule comprises any combination of VH, VL, CH, and CL selected from the following (i) to (xxxviii): (i) VH comprising the amino acid sequence of SEQ ID NO. 43, CH comprising the amino acid sequence of SEQ ID NO. 64, VL comprising the amino acid sequence of SEQ ID NO. 54, and CL comprising the amino acid sequence of SEQ ID NO. 63; (ii) VH comprising the amino acid sequence of SEQ ID NO. 43, CH comprising the amino acid sequence of SEQ ID NO. 66, VL comprising the amino acid sequence of SEQ ID NO. 54, and CL comprising the amino acid sequence of SEQ ID NO. 63; (iii) VH comprising the amino acid sequence of SEQ ID NO. 43, CH comprising the amino acid sequence of SEQ ID NO. 67, VL comprising the amino acid sequence of SEQ ID NO. 54, and CL comprising the amino acid sequence of SEQ ID NO. 63; (iv) VH comprising the amino acid sequence of SEQ ID NO. 43, CH comprising the amino acid sequence of SEQ ID NO. 68, VL comprising the amino acid sequence of SEQ ID NO. 54, and CL comprising the amino acid sequence of SEQ ID NO. 63; (v) VH comprising the amino acid sequence of SEQ ID NO. 43, CH comprising the amino acid sequence of SEQ ID NO. 69, VL comprising the amino acid sequence of SEQ ID NO. 54, and CL comprising the amino acid sequence of SEQ ID NO. 63; (vi) VH comprising the amino acid sequence of SEQ ID NO. 43, CH comprising the amino acid sequence of SEQ ID NO. 70, VL comprising the amino acid sequence of SEQ ID NO. 54, and CL comprising the amino acid sequence of SEQ ID NO. 63; (vii) VH comprising the amino acid sequence of SEQ ID NO. 43, CH comprising the amino acid sequence of SEQ ID NO. 71, VL comprising the amino acid sequence of SEQ ID NO. 54, and CL comprising the amino acid sequence of SEQ ID NO. 63; (viii) VH comprising the amino acid sequence of SEQ ID NO. 43, CH comprising the amino acid sequence of SEQ ID NO. 73, VL comprising the amino acid sequence of SEQ ID NO. 54, and CL comprising the amino acid sequence of SEQ ID NO. 63; (ix) VH comprising the amino acid sequence of SEQ ID NO. 43, CH comprising the amino acid sequence of SEQ ID NO. 75, VL comprising the amino acid sequence of SEQ ID NO. 54, and CL comprising the amino acid sequence of SEQ ID NO. 63; (x) VH comprising the amino acid sequence of SEQ ID NO. 43, CH comprising the amino acid sequence of SEQ ID NO. 78, VL comprising the amino acid sequence of SEQ ID NO. 54, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xi) VH comprising the amino acid sequence of SEQ ID NO. 43, CH comprising the amino acid sequence of SEQ ID NO. 80, VL comprising the amino acid sequence of SEQ ID NO. 54, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xii) VH comprising the amino acid sequence of SEQ ID NO. 43, CH comprising the amino acid sequence of SEQ ID NO. 82, VL comprising the amino acid sequence of SEQ ID NO. 54, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xiii) VH comprising the amino acid sequence of SEQ ID NO. 43, CH comprising the amino acid sequence of SEQ ID NO. 84, VL comprising the amino acid sequence of SEQ ID NO. 54, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xiv) VH comprising the amino acid sequence of SEQ ID NO. 43, CH comprising the amino acid sequence of SEQ ID NO. 85, VL comprising the amino acid sequence of SEQ ID NO. 54, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xv) VH comprising the amino acid sequence of SEQ ID NO. 51, CH comprising the amino acid sequence of SEQ ID NO. 65, VL comprising the amino acid sequence of SEQ ID NO. 59, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xvi) VH comprising the amino acid sequence of SEQ ID NO. 51, CH comprising the amino acid sequence of SEQ ID NO. 72, VL comprising the amino acid sequence of SEQ ID NO. 59, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xvii) VH comprising the amino acid sequence of SEQ ID NO. 51, CH comprising the amino acid sequence of SEQ ID NO. 74, VL comprising the amino acid sequence of SEQ ID NO. 59, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xviii) VH comprising the amino acid sequence of SEQ ID NO. 51, CH comprising the amino acid sequence of SEQ ID NO. 75, VL comprising the amino acid sequence of SEQ ID NO. 59, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xix) VH comprising the amino acid sequence of SEQ ID NO. 51, CH comprising the amino acid sequence of SEQ ID NO. 77, VL comprising the amino acid sequence of SEQ ID NO. 59, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xx) VH comprising the amino acid sequence of SEQ ID NO. 51, CH comprising the amino acid sequence of SEQ ID NO. 78, VL comprising the amino acid sequence of SEQ ID NO. 59, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xxi) VH comprising the amino acid sequence of SEQ ID NO. 51, CH comprising the amino acid sequence of SEQ ID NO. 79, VL comprising the amino acid sequence of SEQ ID NO. 59, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xxii) VH comprising the amino acid sequence of SEQ ID NO. 51, CH comprising the amino acid sequence of SEQ ID NO. 80, VL comprising the amino acid sequence of SEQ ID NO. 59, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xxiii) VH comprising the amino acid sequence of SEQ ID NO. 51, CH comprising the amino acid sequence of SEQ ID NO. 81, VL comprising the amino acid sequence of SEQ ID NO. 59, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xxiv) VH comprising the amino acid sequence of SEQ ID NO. 51, CH comprising the amino acid sequence of SEQ ID NO. 82, VL comprising the amino acid sequence of SEQ ID NO. 59, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xxv) VH comprising the amino acid sequence of SEQ ID NO. 51, CH comprising the amino acid sequence of SEQ ID NO. 83, VL comprising the amino acid sequence of SEQ ID NO. 59, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xxvi) VH comprising the amino acid sequence of SEQ ID NO. 51, CH comprising the amino acid sequence of SEQ ID NO. 84, VL comprising the amino acid sequence of SEQ ID NO. 59, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xxvii) VH comprising the amino acid sequence of SEQ ID NO. 51, CH comprising the amino acid sequence of SEQ ID NO. 72, VL comprising the amino acid sequence of SEQ ID NO. 60, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xxviii) VH comprising the amino acid sequence of SEQ ID NO. 51, CH comprising the amino acid sequence of SEQ ID NO. 74, VL comprising the amino acid sequence of SEQ ID NO. 60, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xxix) VH comprising the amino acid sequence of SEQ ID NO. 51, CH comprising the amino acid sequence of SEQ ID NO. 75, VL comprising the amino acid sequence of SEQ ID NO. 60, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xxx) VH comprising the amino acid sequence of SEQ ID NO. 51, CH comprising the amino acid sequence of SEQ ID NO. 77, VL comprising the amino acid sequence of SEQ ID NO. 60, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xxxi) VH comprising the amino acid sequence of SEQ ID NO. 51, CH comprising the amino acid sequence of SEQ ID NO. 78, VL comprising the amino acid sequence of SEQ ID NO. 60, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xxxii) VH comprising the amino acid sequence of SEQ ID NO. 51, CH comprising the amino acid sequence of SEQ ID NO. 79, VL comprising the amino acid sequence of SEQ ID NO. 60, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xxxiii) VH comprising the amino acid sequence of SEQ ID NO. 51, CH comprising the amino acid sequence of SEQ ID NO. 80, VL comprising the amino acid sequence of SEQ ID NO. 60, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xxxiv) VH comprising the amino acid sequence of SEQ ID NO. 51, CH comprising the amino acid sequence of SEQ ID NO. 81, VL comprising the amino acid sequence of SEQ ID NO. 60, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xxxv) VH comprising the amino acid sequence of SEQ ID NO. 51, CH comprising the amino acid sequence of SEQ ID NO. 82, VL comprising the amino acid sequence of SEQ ID NO. 60, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xxxvi) VH comprising the amino acid sequence of SEQ ID NO. 51, CH comprising the amino acid sequence of SEQ ID NO. 83, VL comprising the amino acid sequence of SEQ ID NO. 60, and CL comprising the amino acid sequence of SEQ ID NO. 63; (xxxvii) VH comprising the amino acid sequence of SEQ ID NO. 51, CH comprising the amino acid sequence of SEQ ID NO. 84, VL comprising the amino acid sequence of SEQ ID NO. 60, and CL comprising the amino acid sequence of SEQ ID NO. 63, and (Xxxviii) VH comprising the amino acid sequence of SEQ ID NO. 51, CH comprising the amino acid sequence of SEQ ID NO. 85, VL comprising the amino acid sequence of SEQ ID NO. 60, and CL comprising the amino acid sequence of SEQ ID NO. 63.

Description

Anti-CD 137 antigen binding molecules for cancer treatment The present application is a divisional application of International application No. PCT/JP2021/004871, international application No. 2021, month 2, 10, china application No. 202180024000.3, patent application entitled "anti-CD 137 antigen binding molecule for cancer treatment". Technical Field The present disclosure relates to anticancer agents comprising an anti-CD 137 antigen binding molecule, and methods of treatment using such agents in combination with another anticancer agent. Background Cancer is a fatal disease that is difficult to cure completely, except in some cases. The therapeutic results of chemotherapeutic agents as the primary treatment are not very good. It has been proposed that not only heterogeneity of cancer cells themselves plays an important role, but also tumor microenvironment plays an important role as a factor that makes cancer treatment difficult (non-patent document 1). Recently, it has been shown that unresectable malignant melanoma and the like may be cured with an anti-CTLA-4 antibody that inhibits the immunosuppressive function of CTLA-4, thereby promoting activation of T cells (non-patent document 2). In 2011, anti-human CTLA-4 monoclonal antibody (ipilimumab) was approved by the united states Food and Drug Administration (FDA) as the first immune activating antibody drug worldwide. Furthermore, inhibitory antibodies against PD-1 and PD-L1 (other immune checkpoint molecules than CTLA-4) are reported to have therapeutic effects (non-patent document 3), and have been approved by the FDA. It will be appreciated that T cells, which play an important role in tumor immunity, are activated by two signals, 1) the binding of T Cell Receptors (TCR) to antigen peptides presented by Major Histocompatibility Complex (MHC) class I molecules, and the activation of TCR, 2) the binding of costimulatory molecules on the surface of T cells to their ligands on antigen presenting cells, and the activation of the costimulatory molecules. In addition, activation of co-stimulatory molecules belonging to the Tumor Necrosis Factor Receptor Superfamily (TNFRSF) including CD137 (4-1 BB) on the surface of T cells has been described as important for T cell activation (non-patent document 4). The tumor necrosis factor receptor superfamily includes CD137, CD40, OX40, RANK, GITR, and the like. CD137 is reported to be expressed not only on the surface of T cells but also on the surface of other immune cells such as Dendritic Cells (DCs), B cells, NK cells, macrophages and neutrophils (NPL 5). CD137 agonist antibodies have been shown to show anti-tumor effects in a mouse model, and this is mainly caused by the activation of CD8 positive T cells and NK cells in mouse model experiments (NPL 6). However, side effects due to nonspecific hepatotoxicity of CD137 agonist antibodies have become clinical and non-clinical problems, impeding the expected progress of drug development (non-patent document 7, non-patent document 8). It is suggested that side effects are mainly caused by activation of immune cells in non-tumor, non-immune tissues (e.g., liver), which involves binding of antibodies to fcγ receptors through antibody constant regions (non-patent document 9). On the other hand, it has been reported that in order for an agonistic anti-TNF receptor superfamily member antibody to exhibit agonistic activity in vivo, it is necessary to crosslink the antibody with cells expressing fcγrii (cells expressing fcγrii) (non-patent document 10). That is, the binding of CD137 agonist antibodies to fcγ receptor is involved in both the efficacy of the anti-tumor effect of the antibody and its side effects such as hepatotoxicity. Thus, increasing the binding between an antibody and an fcγ receptor is expected to enhance the efficacy, but may also increase hepatotoxic side effects, while decreasing the binding between an antibody and an fcγ receptor may decrease side effects but also decrease efficacy. To date, there has been no report of separate efficacy and side effects of CD137 agonist antibodies. Moreover, the anti-tumor effect of CD137 agonist antibodies themselves is not clinically effective, and further improvement of the efficacy is desired to avoid toxicity. Accordingly, it is desirable to develop a new drug capable of inducing an anti-tumor immune response while reducing those side effects. When a therapeutic antibody is administered to a living body, its target antigen is expected to be specifically expressed only at a lesion site. In many cases, however, the same antigen is also expressed in non-diseased regions, i.e., normal tissues, which may be responsible for the occurrence of undesirable side effects from a therapeutic standpoint. For example, although antibodies against tumor antigens can exhibit cytotoxic activity to tumor cells by ADCC or the like, they may also damage normal cells if the same antigen is expressed in normal cells. In order to solve