CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase of PCT Application No. PCT/JP2015/063716, filed May 13, 2015, which claims priority to Japanese Patent Application No. 2014-099707, filed May 13, 2014, each of which is incorporated herein by reference.

REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

The content of the electronically submitted sequence listing (Name: 6663_0006_Sequence_Listing.txt; Size: 74.2 kilobytes; and Date of Creation: Oct. 7, 2018) filed on Oct. 25, 2018 is incorporated herein by reference in its entirety.

TECHNICAL FIELD

The present invention relates to antigen-binding molecules that enable treatment of cancer by damaging cells having an immune response-suppressing function; pharmaceutical compositions for treating various carcinomas comprising the antigen-binding molecule; or methods for treating cancer using the pharmaceutical compositions.

BACKGROUND ART

Antibodies are drawing attention as pharmaceuticals since they are highly stable in plasma and have few side effects. In particular, a number of IgG-type antibody pharmaceuticals are available on the market and many antibody pharmaceuticals are currently being developed (Non-patent Documents 1 and 2).

As cancer therapeutic agents using antibody pharmaceuticals, Rituxan against the CD20 antigen, Cetuximab against the EGFR antigen, Herceptin against the HER2 antigen, and such have been approved so far (Non-patent Document 3). These antibody molecules bind to antigens expressed on cancer cells, and exhibit cytotoxic activity against cancer cells through ADCC and such.

In contrast to such antibody pharmaceuticals that exhibit cytotoxic activities directly against cancer cells, Ipilimumab which is an IgG1-type antibody against CTLA4 was recently confirmed to be effective against metastatic melanoma, and received FDA approval in 2011. In solid cancer microenvironments, effector T cells that recognize tumors are known to be suppressed by various factors in the cancer microenvironment (Non-patent Document 4). Among them, CTLA4 which is an immune checkpoint molecule is known to have the function of suppressing T cell activation, and is strongly expressed in activated effector T cells and regulatory T cells. In cancer microenvironments, tumor-recognizing effector T cells are considered to be suppressed by CTLA4. Ipilimumab is a neutralizing antibody against CTLA4, and it is considered to exhibit antitumor effects by inhibiting the suppression of effector T cell-activation and activating the tumor-recognizing effector T cells (Non-patent Document 5). Similarly, nivolumab which is a neutralizing antibody against the immune checkpoint molecule PD1 has been recently reported to be also highly effective against metastatic melanoma by the activation of tumor-recognizing effector T cells that are suppressed by PD1 (Non-patent Document 6). Furthermore, not only regulatory T cells but also exhausted T cells are known to be present in the cancer microenvironment, and the exhausted T cells are known to not only lack cytotoxic activity (antitumor activity) but also to contribute on immunosuppression in tumors (Non-patent Document 7).

Thus, it was thought that antibody pharmaceuticals against immune checkpoint molecules exert antitumor effects by inhibiting T-cell-suppressing effects of immune checkpoint molecules. However, it has been recently reported that for exhibiting antitumor effects of anti-CTLA4 antibodies such as ipilimumab, not only the neutralizing effects on CTLA4, but the antibody-dependent cytotoxic activity (ADCC activity) against CTLA4-expressing cells is also important (Non-patent Documents 8 and 9). Regulatory T cells and exhausted T cells in the tumor microenvironment are known to strongly express CTLA4, and anti-CTLA4 antibodies having ADCC activity are thought to be able to kill the regulatory T cells and exhausted T cells. In Non-patent Documents 8 and 9, while anti-CTLA4 antibodies having ADCC activity could eliminate regulatory T cells in tumors and exert strong antitumor effects in mice, anti-CTLA4 antibodies whose ADCC activity has been removed by amino acid substitutions could not eliminate regulatory T cells in tumors and could not exert antitumor effects.

Thus, it has been found that ADCC activity plays an important role in antitumor effects of anti-CTLA4 antibodies, and that the killing of regulatory T cells by ADCC activity is an important mechanism of action.

On the other hand, ADCC activity of an antibody is exhibited by binding of its Fc region to an Fcγ receptor. For example, substituting (modifying) amino acids of the Fc region of an IgG1 antibody to increase binding to the Fcγ receptor has been reported to enable enhancement of ADCC activity (Non-Patent Document 10). In fact, an anti-CD19 antibody with enhanced ADCC activity due to modification of the Fc region exerted stronger antitumor effects than natural anti-CD19 antibodies (Non-patent Document 10).

Accordingly, if ADCC activity of anti-CTLA4 antibodies can be enhanced by modifying their Fc-region, the anti-CTLA4 antibodies can eliminate regulatory T cells in tumors more powerfully, and may exhibit stronger antitumor effects.

PRIOR ART DOCUMENTS

Non-Patent Documents

[Non-patent Document 1] Janice M Reichert, Clark J Rosensweig, Laura B Faden & Matthew C Dewitz, Monoclonal antibody successes in the clinic., Nat. Biotechnol. (2005) 23, 1073-1078[Non-patent Document 2] Pavlou A K, Belsey M J., The therapeutic antibodies market to 2008., Eur J Pharm Biopharm. (2005) 59 (3), 389-396[Non-patent Document 3] Monoclonal antibodies: versatile platforms for cancer immunotherapy. Weiner L M, Surana R, Wang S. Nat Rev Immunol. 2010 May; 10(5):317-27.[Non-patent Document 4] Innate and adaptive immune cells in the tumor microenvironment, Thomas F Gajewski, Hans Schreiber & Yang-Xin Fu. Nature Immunology 14, 1014-1022 (2013)[Non-patent Document 5] Anti-cytotoxic T lymphocyte antigen-4 antibodies in melanoma. Tosti G, Cocorocchio E, Pennacchioli E. Clin Cosmet Investig Dermatol. 2013 Oct. 17; 6:245-56[Non-patent Document 6] PD-1 as a potential target in cancer therapy. McDermott D F, Atkins M B. Cancer Med. 2013 October; 2(5):662-73.[Non-patent Document 7] T cell exhaustion. E John Wherry. Nature Immunology, VOLUME 12 NUMBER 6 Jun. 2011:492-499.[Non-patent Document 8] Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. Simpson T R1, Li F, Montalvo-Ortiz W, Sepulveda M A, Bergerhoff K, Arce F, Roddie C, Henry J Y, Yagita H, Wolchok J D, Peggs K S, Ravetch J V, Allison J P, Quezada S A. J Exp Med. 2013 Aug. 26; 210(9): 1695-710.[Non-patent Document 9] Anti-CTLA-4 Antibodies of IgG2a Isotype Enhance Antitumor Activity through Reduction of Intratumoral Regulatory T Cells, Mark J. Selby, John J. Engelhardt, Michael Quigley, Karla A. Henning, Timothy Chen, Mohan Srinivasan, and Alan J. Korman, Cancer Immunol Res; 1(1); 1-11.[Non-patent Document 10] The impact of Fc engineering on an anti-CD19 antibody: increased Fcgamma receptor affinity enhances B-cell clearing in nonhuman primates. Zalevsky J, Leung I W, Karki S, Chu S Y, Zhukovsky E A, Desjarlais J R, Carmichael D F, Lawrence C E. Blood. 2009 Apr. 16; 113(16):3735-43.[Non-patent Document 11] Curiel, T. J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature medicine 10, 942-949, doi:10.1038/nm1093 (2004).[Non-patent Document 12] Sato, E. et al. Intraepithelial CD8+tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proceedings of the National Academy of Sciences of the United States of America 102, 18538-18543, doi:10.1073/pnas.0509182102 (2005).[Non-patent Document 13] Kawaida, H. et al. Distribution of CD4+CD25highregulatory T-cells in tumor-draining lymph nodes in patients with gastric cancer. The Journal of surgical research 124, 151-157, doi:10.1016/j.jss.2004.10.004 (2005).[Non-patent Document 14] Kono, K. et al. CD4+CD25highregulatory T cells increase with tumor stage in patients with gastric and esophageal cancers. Cancer immunology, immunotherapy: CII 55, 1064-1071, doi:10.1007/s00262-005-0092-8 (2006).[Non-patent Document 15] Hiraoka, N., Onozato, K., Kosuge, T. & Hirohashi, S. Prevalence of FOXP3+regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clinical cancer research: an official journal of the American Association for Cancer Research 12, 5423-5434, doi:10.1158/1078-0432.CCR-06-0369 (2006).[Non-patent Document 16] Liotta, F. et al. Frequency of regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes correlates with poor prognosis in renal cell carcinoma. BJU international 107, 1500-1506, doi:10.1111/j.1464-410X.2010.09555.x (2011).[Non-patent Document 17] Kobayashi, N. et al. FOXP3+regulatory T cells affect the development and progression of hepatocarcinogenesis. Clinical cancer research: an official journal of the American Association for Cancer Research 13, 902-911, doi:10.1158/1078-0432.CCR-06-2363 (2007).[Non-patent Document 18] Gobert, M. et al. Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer research 69, 2000-2009, doi:10.1158/0008-5472.CAN-08-2360 (2009).[Non-patent Document 19] Bates, G. J. et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 24, 5373-5380, doi:10.1200/JCO.2006.05.9584 (2006).[Non-patent Document 20] Gerber, A. L. et al. High expression of FOXP3 in primary melanoma is associated with tumour progression. The British journal of dermatology 170, 103-109, doi:10.1111/bjd.12641 (2014).[Non-patent Document 21] Wang, Y. Y., He, X. Y., Cai, Y. Y., Wang, Z. J. & Lu, S. H. The variation of CD4+CD25+regulatory T cells in the periphery blood and tumor microenvironment of non-small cell lung cancer patients and the downregulation effects induced by CpG ODN. Targeted oncology 6, 147-154, doi:10.1007/s11523-011-0182-9 (2011).[Non-patent Document 22] de Vos van Steenwijk, P. J. et al. Tumor-infiltrating CD14-positive myeloid cells and CD8-positive T-cells prolong survival in patients with cervical carcinoma. International journal of cancer. Journal international du cancer 133, 2884-2894, doi:10.1002/ijc.28309 (2013).[Non-patent Document 23] Wainwright, D. A., Dey, M., Chang, A. & Lesniak, M. S. Targeting Tregs in Malignant Brain Cancer: Overcoming IDO. Frontiers in immunology 4, 116, doi:10.3389/fimmu.2013.00116 (2013).[Non-patent Document 24] Yu, P. et al. Simultaneous inhibition of two regulatory T-cell subsets enhanced Interleukin-15 efficacy in a prostate tumor model. Proceedings of the National Academy of Sciences of the United States of America 109, 6187-6192, doi:10.1073/pnas.1203479109 (2012).[Non-patent Document 25] Zheng, J., Liu, P. & Yang, X. YB-1 immunization combined with regulatory T-cell depletion induces specific T-cell responses that protect against neuroblastoma in the early stage. Acta biochimica et biophysica Sinica 44, 1006-1014, doi:10.1093/abbs/gms089 (2012).[Non-patent Document 26] D'Arena, G. et al. Regulatory T-cell number is increased in chronic lymphocytic leukemia patients and correlates with progressive disease. Leukemia research 35, 363-368, doi:10.1016/j.leukres.2010.08.010 (2011).[Non-patent Document 27] French, J. D. et al. Tumor-associated lymphocytes and increased FoxP3+regulatory T cell frequency correlate with more aggressive papillary thyroid cancer. The Journal of clinical endocrinology and metabolism 95, 2325-2333, doi:10.1210/jc.2009-2564 (2010).[Non-patent Document 28] Khan, A. R., Dovedi, S. J., Wilkinson, R. W. & Pritchard, D. I. Tumor infiltrating regulatory T cells: tractable targets for immunotherapy. International reviews of immunology 29, 461-484, doi:10.3109/08830185.2010.508854 (2010).[Non-patent Document 29] Yang, Z. Z., Novak, A. J., Ziesmer, S. C., Witzig, T. E. & Ansell, S. M. Attenuation of CD8+T-cell function by CD4+CD25+regulatory T cells in B-cell non-Hodgkin's lymphoma. Cancer research 66, 10145-10152, doi:10.1158/0008-5472.CAN-06-1822 (2006).[Non-patent Document 30] Yang, Z. Z., Novak, A. J., Stenson, M. J., Witzig, T. E. & Ansell, S. M. Intratumoral CD4+CD25+regulatory T-cell-mediated suppression of infiltrating CD4+T cells in B-cell non-Hodgkin lymphoma. Blood 107, 3639-3646, doi:10.1182/blood-2005-08-3376 (2006).

SUMMARY OF THE INVENTION

Problems to be Solved by the Invention

The present invention was achieved in view of the above circumstances. An objective of the present invention is to provide antigen-binding molecules that exert superior antitumor effects by damaging cells having immune response-suppressing functions, and pharmaceutical compositions comprising the antigen-binding molecule as an active ingredient, or methods for treating cancer using the pharmaceutical compositions.

Means for Solving the Problems

The present inventors discovered that antigen-binding molecules comprising a domain that binds to a molecule expressed on the surface of cells having immune response-suppressing functions and a domain that binds to a T-cell receptor (TCR) complex, damage cells having immune response-suppressing functions and exert more superior antitumor activity than conventional antigen-binding molecules that bind to molecules expressed on the surfaces of regulatory T cells and exhausted T cells and also have ADCC activity. Furthermore, the present inventors discovered pharmaceutical compositions that can treat various carcinomas by having the antigen-binding molecule as an active ingredient.

More specifically, the present invention provides the following:[1] an antigen-binding molecule that inhibits immune response-suppressing activity of a cell having an immune response-suppressing function, comprising:(i) a domain that binds to a molecule expressed on the surface of a cell having an immune response-suppressing function; and(ii) a T cell receptor complex-binding domain;[2] the antigen-binding molecule of [1], wherein the cell having immune response-suppressing function is a regulatory T cell or an exhausted T cell;[3] the antigen-binding molecule of [1], wherein the molecule expressed on the surface of a cell having an immune response-suppressing function is any molecule selected from among CTLA4, PD1, TIM3, LAG3, CD244 (2B4), CD160, GARP, OX40, CD137 (4-1BB), CD25, VISTA, BTLA, TNFR25, CD57, KLRG1, CCR2, CCR5, CCR6, CD39, CD73, CD4, CD18, CD49b, CD1d, CD5, CD21, TIM1, CD19, CD20, CD23, CD24, CD38, CD93, IgM, B220(CD45R), CD317, PD-L1, CD11b, Ly6G, ICAM-1, FAP, PDGFR, Podoplanin, and TIGIT;[4] the antigen-binding molecule of [3], wherein the molecule expressed on the surface of a cell having an immune response-suppressing function is any molecule selected from among CTLA4, TIM3, LAG3, CD137 (4-1BB), CD25, CCR5, CCR6, CD38, TIGIT, and OX40;[5] the antigen-binding molecule of any one of [1] to [4], wherein the T cell receptor complex-binding domain is a T cell receptor-binding domain;[6] the antigen-binding molecule of any one of [1] to [4], wherein the T cell receptor complex-binding domain is a CD3-binding domain;[7] the antigen-binding molecule of any one of [1] to [6], which further comprises an FcRn-binding domain;[8] the antigen-binding molecule of [7], wherein the FcRn-binding domain is an Fc region of an antibody;[9] the antigen-binding molecule of [8], wherein the FcRn-binding domain is an Fc region of an antibody having reduced Fcγ receptor-binding activity;[10] the antigen-binding molecule of any one of [1] to [9], which is a multispecific antibody;[11] a pharmaceutical composition comprising the antigen-binding molecule of any one of [1] to [10] as an active ingredient;[12] a pharmaceutical composition for inhibiting an immune response-suppressing activity, comprising the antigen-binding molecule of any one of [1] to [10] as an active ingredient;[13] the pharmaceutical composition of [12], wherein the inhibition of an immune response-suppressing activity is inhibition caused by a T cell;[14] the pharmaceutical composition of [13], wherein the inhibition caused by a T cell is inhibition resulting from cytotoxic activity of the T cell;[15] the pharmaceutical composition of any one of [12] to [14], wherein the immune response-suppressing activity is an activity by a regulatory T cell or an exhausted T cell;[16] the pharmaceutical composition of any one of [12] to [14], wherein the immune response-suppressing activity is an activity of a cell expressing any molecule selected from among CTLA4, PD1, TIM3, LAG3, CD244 (2B4), CD160, GARP, OX40, CD137 (4-1BB), CD25, VISTA, BTLA, TNFR25, CD57, KLRG1, CCR2, CCR5, CCR6, CD39, CD73, CD4, CD18, CD49b, CD1d, CD5, CD21, TIM1, CD19, CD20, CD23, CD24, CD38, CD93, IgM, B220(CD45R), CD317, PD-L1, CD11b, Ly6G, ICAM-1, FAP, PDGFR, Podoplanin, and TIGIT;[17] the pharmaceutical composition of any one of [11] to [16], which is a therapeutic agent for cancer;[18] the pharmaceutical composition of claim17, which is a therapeutic agent for any cancer selected from among ovarian cancer, gastric cancer, esophageal cancer, pancreatic cancer, renal cell carcinoma, hepatocellular carcinoma, breast cancer, malignant melanoma, non-small-cell lung cancer, cervical cancer, glioblastoma, prostate cancer, neuroblastoma, chronic lymphocytic leukemia, papillary thyroid cancer, colorectal cancer, Hodgkin's lymphoma, and endometriosis;[19] a method for inducing cytotoxicity, suppressing cell proliferation, activating immunity against a cancer cell or a cancer cell-comprising tumor tissue, or treating or preventing cancer, which comprises the step of administering the antigen-binding molecule of any one of [1] to [10] or the pharmaceutical composition of any one of [11] to [18];[20] the antigen-binding molecule of any one of [1] to [10] or the pharmaceutical composition of any one of [11] to [18] for use in inducing cytotoxicity, suppressing cell proliferation, activating immunity against a cancer cell or a cancer cell-comprising tumor tissue, or treating or preventing cancer;[21] use of the antigen-binding molecule of any one of [1] to [10] in the production of the pharmaceutical composition of any one of [11] to [18]; and[22] a method for producing the pharmaceutical composition of any one of [11] to [18], which comprises the step of using the antigen-binding molecule of any one of [1] to [10].

Furthermore, the present invention relates to methods for treating or preventing cancer, or for inhibiting suppression of an immune response, which comprise administering an antigen-binding molecule of the present invention or a pharmaceutical composition of the present invention to patients in need of treatment. The present invention also relates to a kit for use in the methods of the present invention, which comprises an antigen-binding molecule of the present invention. The present invention also relates to the use of an antigen-binding molecule of the present invention in producing a pharmaceutical composition for inhibiting immune response-suppression. Furthermore, the present invention relates to antigen-binding molecules of the present invention or pharmaceutical compositions of the present invention for use in the methods of the present invention.

