Maekawa Naoya, Konnai Satoru, Watari Kei, Takeuchi Hiroto, Nakanishi Takeshi, Tachibana Taro, Hosoya Kenji, Kim Sangho, Kinoshita Ryohei, Owaki Ryo, Yokokawa Madoka, Kagawa Yumiko, Takagi Satoshi, Deguchi Tatsuya, Ohta Hiroshi, Kato Yukinari, Yamamoto Satoshi, Yamamoto Keiichi, Suzuki Yasuhiko, Okagawa Tomohiro, Murata Shiro, Ohashi Kazuhiko
Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Cancer Research Unit, One Health Research Center, Hokkaido University, Sapporo, Japan.
Front Immunol. 2025 May 20;16:1570717. doi: 10.3389/fimmu.2025.1570717. eCollection 2025.
Immune checkpoint inhibitors (ICIs) are widely used for cancer immunotherapy; however, the clinical efficacy of anti-PD-1/PD-L1 monotherapy is generally limited, highlighting the need to develop combination therapies. Dogs develop spontaneous tumors in immunocompetent settings, and anti-PD-1/PD-L1 antibodies exert similar clinical benefits. However, no clinically relevant anti-CTLA-4 antibody has been reported, limiting the value of canine tumors as comparative models for human ICI research. Here, canine CTLA-4 was molecularly characterized, and a caninized anti-CTLA-4 antibody (ca1C5) that blocks CTLA-4/ligand binding was developed. Treatment with ca1C5 increased cytokine production in canine immune cell cultures, and the immunostimulatory effect was enhanced when used in combination with the anti-PD-L1 antibody c4G12. As a proof-of-concept, a veterinary clinical study was conducted to demonstrate the safety and clinical efficacy of anti-CTLA-4 antibody as salvage combination therapy in dogs with advanced tumors refractory to prior c4G12 monotherapy. The combination treatment (c4G12 plus ca1C5) was well-tolerated, and evidence of antitumor activity was observed in one dog with oral malignant melanoma. Further studies are warranted to advance veterinary care for dogs and to better characterize canine ICI models for human onco-immunology research.
免疫检查点抑制剂（ICIs）被广泛用于癌症免疫治疗；然而，抗PD-1/PD-L1单药治疗的临床疗效通常有限，这凸显了开发联合疗法的必要性。犬类在免疫健全的环境中会发生自发性肿瘤，抗PD-1/PD-L1抗体也能产生类似的临床益处。然而，尚未有临床相关的抗CTLA-4抗体的报道，这限制了犬类肿瘤作为人类ICI研究比较模型的价值。在此，对犬类CTLA-4进行了分子特征分析，并开发了一种能阻断CTLA-4/配体结合的犬源化抗CTLA-4抗体（ca1C5）。用ca1C5处理可增加犬类免疫细胞培养物中的细胞因子产生，当与抗PD-L1抗体c4G12联合使用时，免疫刺激作用增强。作为概念验证，开展了一项兽医临床研究，以证明抗CTLA-4抗体作为挽救性联合疗法在先前接受c4G12单药治疗后难治的晚期肿瘤犬中的安全性和临床疗效。联合治疗（c4G12加ca1C5）耐受性良好，在一只患有口腔恶性黑色素瘤的犬中观察到了抗肿瘤活性的证据。有必要进一步开展研究，以推进犬类的兽医护理，并更好地描述用于人类肿瘤免疫学研究的犬类ICI模型。
