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JP-7855319-B2 - Combination therapy with anti-CD26 antibodies and immune checkpoint inhibitors

JP7855319B2JP 7855319 B2JP7855319 B2JP 7855319B2JP-7855319-B2

Inventors

  • 森本 幾夫
  • 波多野 良
  • 大沼 圭
  • 金子 有太郎

Assignees

  • ワイズ・エー・シー株式会社
  • 学校法人順天堂

Dates

Publication Date
20260508
Application Date
20210531

Claims (6)

  1. A pharmaceutical composition for cancer treatment comprising an immune checkpoint inhibitor and an anti-CD26 antibody or its antigen-binding fragment as active ingredients, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody, or their antigen-binding fragments, the anti-CD26 antibody has an antigen-binding site composed of a heavy chain consisting of the sequence described in SEQ ID NO: 17 and a light chain consisting of the sequence described in SEQ ID NO: 18, and the antigen-binding fragment is selected from Fv, Fab, Fab', or F(ab') 2 .
  2. A pharmaceutical composition for cancer treatment, comprising an anti-CD26 antibody or an antigen-binding fragment thereof as an active ingredient for use in combination with an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody, or an antigen-binding fragment thereof, the anti-CD26 antibody has an antigen-binding site composed of a heavy chain consisting of the sequence described in SEQ ID NO: 17 and a light chain consisting of the sequence described in SEQ ID NO: 18, and the antigen-binding fragment is selected from Fv, Fab, Fab', or F(ab') 2 .
  3. A pharmaceutical composition for cancer treatment containing an immune checkpoint inhibitor as an active ingredient for use in combination with an anti-CD26 antibody or an antigen-binding fragment thereof, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody, or an antigen-binding fragment thereof, the anti-CD26 antibody has an antigen-binding site composed of a heavy chain consisting of the sequence described in SEQ ID NO: 17 and a light chain consisting of the sequence described in SEQ ID NO: 18, and the antigen-binding fragment is selected from Fv, Fab, Fab', or F(ab') 2 .
  4. A pharmaceutical composition according to any one of claims 1 to 3, wherein an immune checkpoint inhibitor and an anti-CD26 antibody or its antigen-binding fragment are administered simultaneously, consecutively, or separately at intervals.
  5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the cancer is a cancer that expresses CD26.
  6. The pharmaceutical composition according to any one of claims 1 to 3, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an antigen-binding fragment thereof.

Description

This invention relates to the field of cancer treatment. Malignant pleural mesothelioma is a refractory malignant tumor originating from the pleural mesothelium, caused by asbestos exposure. The latency period from asbestos exposure to the onset of symptoms is approximately 30 years, and the number of patients is expected to increase significantly in Asia and the Middle East, including Japan, China, and India. The prognosis is extremely poor, and while surgical treatment, chemotherapy, and radiation therapy are employed, none have satisfactory results, highlighting the need for new treatment methods. Furthermore, lung cancer is the most common type of cancer in Japan, with a low five-year survival rate of around 20%. Therefore, the establishment of safe and effective new treatment methods is also crucial for lung cancer. Anti-CD26 antibodies are known to have anticancer effects (Patent Documents 1 and 2). A First-in-Human Phase I clinical trial was conducted in France, focusing on malignant mesothelioma. Aside from an injection reaction, there were no notable side effects, confirming safety. Furthermore, 10 out of 19 patients with anticancer drug-resistant malignant mesothelioma achieved Stable Disease (SD) in the modified RESIST evaluation, with 5 of these maintaining SD for more than 6 months, and the longest being 399 days, suggesting efficacy (Non-Patent Document 1). In Japan, a Phase I/II clinical trial for anticancer drug-resistant malignant mesothelioma was also conducted. Phase I involved 9 patients (3 patients each in 1-3 cohorts), and Phase II involved 31 patients. The final patient in Phase II was administered in 2019. In domestic clinical trials, a high percentage of patients with chemotherapy-resistant malignant mesothelioma achieved partial response (PR) or stable disease (SD), demonstrating an antitumor effect (Non-Patent Literature 2). However, complete response (CR) was not achieved, and some patients progressed from SD to progressive disease (PD) in a relatively short period. Therefore, developing a treatment method using this antibody that exhibits a longer-lasting antitumor effect and provides progression-free survival is a crucial challenge. Previously, attempts have been made to enhance therapeutic effects by combining anti-CD26 antibodies with small molecule compounds (Patent Document 3). Immune checkpoint inhibitors (ICIs) are a general term for drugs that inhibit the binding of inhibitory receptors expressed on immune cells, particularly T cells, to their ligands, thereby inhibiting the transmission of inhibitory signals to immune cells and the subsequent suppression of their function. Representative examples that are already approved include anti-CTLA-4 (cytotoxic T-lymphocyte associated ptothein 4) antibody, anti-PD-1 (programmed cell death 1) antibody, and anti-PD-L1 (programmed cell death-ligand 1) antibody. ICIs (infectious disease inhibitors) are effective against various cancers, including malignant melanoma, non-small cell lung cancer, renal cell carcinoma, rectal cancer, and Hodgkin lymphoma. While there are reports of extended symptom-free periods with monotherapy, achieving complete response (CR) remains difficult, and attempts are being made to enhance their therapeutic effect through combination therapy with other drugs. For example, to improve the therapeutic effect of non-small cell lung cancer, combination therapy with anti-PD-1 antibodies and anti-CTLA-4 antibodies has been attempted. However, reports on additive effects are mixed, with some indicating an additive effect and others not. In all cases, the high incidence of toxicity associated with combination therapy is a problem, and further development of combination therapies is anticipated (Non-Patent Documents 3 and 4). The same applies to mesothelioma, where the results of combination therapy with anti-PD-1 and anti-CTLA-4 antibodies are varied (Non-Patent Document 5). Thus, while various methods of combination therapy with ICIs are being attempted, it is known that even achieving an additive effect is difficult. International Publication No. 2002/14462International Publication No. 2007/114876International Publication No. 2017/043613 Angevin, E. , et al. , Br J Cancer 116, 1126-1134 (2017)Takeda, M. , et al. , Lung Cancer 137, 64-70 (2019)Michael Boyer, et al. , Journal of Clinical Oncology Published online January 29, 2021. DOI: 10.1200/JCO. 20.03579 PMID:33513313.Young Kwang Chae, et al. , Journal for ImmunoTherapy of Cancer 6:39 (2018)Cornedine J. de Gooijer, et al. , Frontiers in Oncology; 10: p. 187 (2020) DOI=10.3389/fonc. 2020.00187 The inventors have previously focused on CD26, a molecule expressed in cancer cells, as a therapeutic target molecule for cancer, and have developed humanized CD26 antibodies. To develop a new combination therapy that exhibits a longer-lasting antitumor effect and provides progression-free survival compared to administration of humanized anti-CD26 antibodies alone, we conduc