Genuv Inc., B1 Shinyoung Building, 14 Gyeonghuigung-gil, Jongno-gu, Seoul, Republic of Korea.
Genuv US Subsidiary, CIC, 1 Broadway, Cambridge, MA, USA.
BMC Immunol. 2024 May 11;25(1):29. doi: 10.1186/s12865-024-00609-z.
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.
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.
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.
几种已被批准用于癌症治疗的 PD-1 抗体通过阻断 PD-1 与其配体 PD-L1 的相互作用来发挥作用，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性，因此需要替代抗体进行临床前研究，这可能会限制研究的可预测性和可转移性。
为了克服这一限制，我们利用增强的多样性小鼠平台（SHINE MOUSE™）开发了一种种间交叉反应性的 PD-1 抗体 GNUV201。GNUV201 与人 PD-1 和小鼠 PD-1 同等结合，同等抑制人 PD-1/PD-L1 和小鼠 PD-1/PD-L1 的结合，并有效抑制同基因小鼠模型中的肿瘤生长。GNUV201 的表位映射到 hPD-1 的“FG 环”，与 Keytruda（“C'D 环”）和 Opdivo（N 端）不同。值得注意的是，突出的表位环适合于 GNUV201 结合口袋的结构特征支持由于较慢的解离而增强的结合亲和力（比 Keytruda 慢 8.7 倍）。此外，GNUV201 在 pH6.0 时显示出更强的结合亲和力（比 pH7.4 时强 5.6 倍），模拟了缺氧和酸性肿瘤微环境（TME）。这种现象在市售抗体（Keytruda、Opdivo）中观察不到，这意味着 GNUV201 在 TME 中对 PD-1 具有更选择性的结合和更好的占有率。
总之，GNUV201 表现出对 PD-1 的增强亲和力，具有缓慢解离和在模拟低 pH 的 TME 中的优先结合。GNUV201 具有人/猴/鼠种间交叉反应性，可实现更可预测和更具转化性的疗效和毒性临床前研究。这些结果表明，GNUV201 可能是抗癌药物开发的理想抗体候选物。
