GNUV201, a novel human/mouse cross-reactive and low pH-selective anti-PD-1 monoclonal antibody for cancer immunotherapy.

IF 2.9 4区 医学 Q3 IMMUNOLOGY BMC Immunology Pub Date : 2024-05-11 DOI:10.1186/s12865-024-00609-z
Hae-Mi Kim, Kyoung-Jin Kim, Kwanghyun Lee, Myeong Jin Yoon, Jenny Choih, Tae-Joon Hong, Eun Ji Cho, Hak-Jun Jung, Jayoung Kim, Ji Soo Park, Hye Young Na, Yong-Seok Heo, Chae Gyu Park, Heungrok Park, Sungho Han, Donggoo Bae
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引用次数: 0

Abstract

Background: Several PD-1 antibodies approved as anti-cancer therapies work by blocking the interaction of PD-1 with its ligand PD-L1, thus restoring anti-cancer T cell activities. These PD-1 antibodies lack inter-species cross-reactivity, necessitating surrogate antibodies for preclinical studies, which may limit the predictability and translatability of the studies.

Results: To overcome this limitation, we have developed an inter-species cross-reactive PD-1 antibody, GNUV201, by utilizing an enhanced diversity mouse platform (SHINE MOUSE™). GNUV201 equally binds to human PD-1 and mouse PD-1, equally inhibits the binding of human PD-1/PD-L1 and mouse PD-1/PD-L1, and effectively suppresses tumor growth in syngeneic mouse models. The epitope of GNUV201 mapped to the "FG loop" of hPD-1, distinct from those of Keytruda® ("C'D loop") and Opdivo® (N-term). Notably, the structural feature where the protruding epitope loop fits into GNUV201's binding pocket supports the enhanced binding affinity due to slower dissociation (8.7 times slower than Keytruda®). Furthermore, GNUV201 shows a stronger binding affinity at pH 6.0 (5.6 times strong than at pH 7.4), which mimics the hypoxic and acidic tumor microenvironment (TME). This phenomenon is not observed with marketed antibodies (Keytruda®, Opdivo®), implying that GNUV201 achieves more selective binding to and better occupancy on PD-1 in the TME.

Conclusions: In summary, GNUV201 exhibited enhanced affinity for PD-1 with slow dissociation and preferential binding in TME-mimicking low pH. Human/monkey/mouse inter-species cross-reactivity of GNUV201 could enable more predictable and translatable efficacy and toxicity preclinical studies. These results suggest that GNUV201 could be an ideal antibody candidate for anti-cancer drug development.

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用于癌症免疫疗法的新型人/鼠交叉反应和低 pH 选择性抗 PD-1 单克隆抗体 GNUV201。
背景:几种被批准为抗癌疗法的 PD-1 抗体通过阻断 PD-1 与其配体 PD-L1 的相互作用,从而恢复抗癌 T 细胞的活性。这些 PD-1 抗体缺乏种间交叉反应,因此临床前研究必须使用替代抗体,这可能会限制研究的可预测性和可转化性:为了克服这一局限性,我们利用增强多样性小鼠平台(SHINE MOUSE™)开发了一种跨物种交叉反应的 PD-1 抗体 GNUV201。GNUV201 与人 PD-1 和小鼠 PD-1 的结合率相同,同样能抑制人 PD-1/PD-L1 和小鼠 PD-1/PD-L1 的结合,并能有效抑制合成小鼠模型中肿瘤的生长。GNUV201 的表位映射到 hPD-1 的 "FG 环",与 Keytruda® ("C'D 环")和 Opdivo® (N-端)的表位不同。值得注意的是,突出的表位环与 GNUV201 的结合口袋相吻合,这一结构特征支持了因解离速度较慢(比 Keytruda® 慢 8.7 倍)而增强的结合亲和力。此外,GNUV201 在模拟缺氧和酸性肿瘤微环境(TME)的 pH 值为 6.0 时显示出更强的结合亲和力(是 pH 值为 7.4 时的 5.6 倍)。这种现象在市场上销售的抗体(Keytruda®、Opdivo®)中没有观察到,这意味着GNUV201与TME中的PD-1实现了更有选择性的结合和更好的占据:总之,GNUV201 对 PD-1 的亲和力增强,解离速度慢,在模拟低 pH 的 TME 中优先结合。GNUV201 的人/猴/鼠种间交叉反应性可以使临床前研究的疗效和毒性更具可预测性和可转化性。这些结果表明,GNUV201 可能是抗癌药物开发的理想候选抗体。
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来源期刊
BMC Immunology
BMC Immunology 医学-免疫学
CiteScore
5.50
自引率
0.00%
发文量
54
审稿时长
1 months
期刊介绍: BMC Immunology is an open access journal publishing original peer-reviewed research articles in molecular, cellular, tissue-level, organismal, functional, and developmental aspects of the immune system as well as clinical studies and animal models of human diseases.
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