新型强效CD40激动剂KHK2840增强了抗PD-1抗体和紫杉醇的抗肿瘤疗效。

IF 5.7 2区 医学 Q1 Medicine Cancer Science Pub Date : 2024-10-08 DOI:10.1111/cas.16366
Chiaki Kobayashi, Minami Suzuki-Imaizumi, Yasuko Sakaguchi, Toshihiko Ishii, Maiko Adachi, Ayumi Kaneda, Ritsuko Ebihara, Masato Saito, Takeshi Uemori, Kiyotoshi Mori
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引用次数: 0

摘要

缺乏肿瘤反应性细胞毒性 T 淋巴细胞(CTLs)限制了免疫检查点抑制剂(ICIs)的抗肿瘤疗效。CD40 激动剂有望通过产生对肿瘤有反应的 CTL 来克服这一限制。然而,CD40激动剂抗体的临床疗效并不如非临床研究中那么好。新型人 CD40(hCD40)激动剂 KHK2840 是一种全人源抗 CD40 IgG2 激动剂抗体,经过 Fc 工程设计,可将补体依赖性细胞毒性和抗体依赖性细胞毒性降至最低。与其他 hCD40 激动剂相比,KHK2840 在携带 hCD40 的肿瘤转基因小鼠和人类外周血 B 细胞中表现出最有效的 hCD40 激动信号。此外,KHK2840 还能增强抗程序性细胞死亡 1 抗体和紫杉醇的抗肿瘤疗效。综合免疫分析表明,三联疗法的抗肿瘤免疫反应除涉及肿瘤微环境外,还涉及肿瘤淋巴结。这表明,肿瘤和淋巴结之间协调的抗肿瘤免疫反应可能是三联疗法协同抗肿瘤疗效的基础。最后,一项在金丝猴中进行的毒理学研究表明,KHK2840能激活CD40信号,且毒理学特性可耐受。这些结果表明,KHK2840 是一种新型、强效的 hCD40 激动剂抗体,可用于癌症免疫疗法,有望增强 ICIs 和化疗的抗肿瘤疗效。
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The novel and potent CD40 agonist KHK2840 augments the antitumor efficacy of anti-PD-1 antibody and paclitaxel.

Lack of tumor-reactive cytotoxic T lymphocytes (CTLs) limits the antitumor efficacy of immune checkpoint inhibitors (ICIs). CD40 agonists have been expected to overcome this limitation by generating tumor-reactive CTLs. However, the clinical efficacy of CD40 agonistic antibodies is not as good as in non-clinical studies. The novel human CD40 (hCD40) agonist KHK2840 is a fully human anti-CD40 IgG2 agonistic antibody that is Fc-engineered to minimize complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. Compared to other hCD40 agonists, KHK2840 exhibited the most potent hCD40 agonistic signal in tumor-bearing hCD40 transgenic mice and human peripheral blood B cells. Moreover, KHK2840 enhanced the antitumor efficacy of the antiprogrammed cell death 1 antibody and paclitaxel. Comprehensive immune profiling revealed that the antitumor immune response of the triple combination involved tumor-draining lymph nodes in addition to tumor microenvironments. This suggests that a coordinated antitumor immune response between tumors and lymph nodes may underlie the synergistic antitumor efficacy of the triple combination therapy. Finally, a toxicology study in cynomolgus monkeys demonstrated that KHK2840 activated the CD40 signal with tolerable toxicological properties. These results indicate that KHK2840 is a novel and potent hCD40 agonistic antibody for cancer immunotherapy, which is expected to augment the antitumor efficacy of ICIs and chemotherapy.

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来源期刊
Cancer Science
Cancer Science ONCOLOGY-
CiteScore
9.90
自引率
3.50%
发文量
406
审稿时长
17 weeks
期刊介绍: Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.
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