PO.CL05.12 · 临床研究
利用 pH 依赖性双特异性 TCE 靶向实体瘤：CT-202 的首次人体开发
Targeting solid tumors with pH-dependent dual-specific TCEs: First-in-human development of CT-202
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：Nectin-4 已成为治疗尿路上皮癌、结直肠癌、肺癌、乳腺癌及其他实体恶性肿瘤的临床验证抗原。然而，Nectin-4 在表皮角质形成细胞中的生理性表达限制了双特异性 T 细胞衔接器（TCE）和嵌合抗原受体 T 细胞（CAR-T）等强效免疫治疗策略的应用，原因在于靶向、脱肿瘤毒性。CT-202 是一种全人源、双重 pH 依赖性的 Nectin-4 x CD3 双特异性 TCE，经工程化设计以在酸性肿瘤微环境（TME）内选择性靶向 Nectin-4 和 CD3，从而拓宽治疗窗口。
方法：对 CT-202 进行了对 Nectin-4 和 CD3 双者 pH 依赖性结合的表征，采用跨越 pH 梯度的体外亲和力实验，模拟生理（pH 7.4）和肿瘤（pH ~6.5）条件。在非人灵长类动物中进行了体内药理学和安全性评估，将 CT-202 与非 pH 依赖性双特异性对照进行比较。采用体外功能实验（包括细胞毒性和细胞因子释放）来确定剂量-反应关系，以指导初始人体给药策略。
结果：CT-202 仅在 TME 特征性的较低 pH 下表现出对 Nectin-4 和 CD3 的高亲和力和特异性；在中性 pH 下，结合显著减弱。这种条件性双重结合对于体外有效的 T 细胞介导的肿瘤靶细胞毒性至关重要。在非人灵长类动物毒理学研究中，与缺乏 pH 调节的传统双特异性抗体相比，CT-202 的最高非严重毒性剂量（HNSTD）改善了 >30 倍，勾勒出更优的安全性特征。对体外效力和体内毒理学数据的综合分析支持了对即将开展的临床研究起始剂量的合理选择。
结论：CT-202 是一种新型的双重 pH 选择性双特异性 TCE，靶向 Nectin-4 x CD3，旨在优化肿瘤选择性并最大限度减少脱肿瘤毒性。临床前数据验证了该模式差异化的药理学和安全性特性，支持其推进至首次人体 1 期试验。该方法凸显了双重 pH 依赖性双特异性抗体作为下一代平台用于 Nectin-4 表达实体瘤选择性免疫治疗的潜力。
查看英文原文 English abstract
Introduction: Nectin-4 has emerged as a clinically validated antigen for the treatment of urothelial, colorectal, lung, breast, and other solid malignancies. However, Nectin-4's physiological expression in epidermal keratinocytes restricts the utility of potent immunotherapeutic strategies such as bispecific T cell engagers (TCEs) and chimeric antigen receptor T cells (CAR-Ts), due to on-target, off-tumor toxicity. CT-202 is a fully humanized, dual pH-dependent Nectin-4 x CD3 bispecific TCE engineered to widen the therapeutic window by selectively targeting Nectin-4 and CD3 within the acidic tumor microenvironment (TME).
Methods: CT-202 was characterized for pH-dependent binding to both Nectin-4 and CD3, employing in vitro affinity assays across pH gradients mimicking physiological (pH 7.4) and tumoral (pH ~6.5) conditions. In vivo pharmacology and safety assessments were performed in non-human primates comparing CT-202 and non-pH-dependent bispecific controls. In vitro functional assays, including cytotoxicity and cytokine release, were used to determine dose-response relationships to inform initial human dosing strategies.
Results: CT-202 demonstrated high affinity and specificity for Nectin-4 and CD3 exclusively at the lower pH characteristic of the TME; at neutral pH, binding was markedly attenuated. This conditional dual engagement was essential for effective T cell-mediated cytotoxicity against tumor targets in vitro . In non-human primate toxicology studies, CT-202 exhibited a >30-fold improvement in the Highest Not Severely Toxic Dosage (HNSTD) relative to traditional bispecifics lacking pH modulation, delineating a superior safety profile. Integrated analysis of in vitro potency and in vivo toxicology data supported a rational selection of starting dose for forthcoming clinical investigation.
Conclusion: CT-202 represents a novel dual pH-selective bispecific TCE targeting Nectin-4 x CD3, designed to optimize tumor selectivity and minimize off-tumor toxicity. Preclinical data validate the differentiated pharmacological and safety attributes of this modality, justifying its advancement to first-in-human Phase 1 trials. This approach highlights the potential of dual pH-dependent bispecific antibodies as a next-generation platform for the selective immunotherapy of Nectin-4-expressing solid tumors.
利益披露 Disclosure
S. Roberts, None..
K. Byrnes-Blake, None..
H. Ansorge, None..
E. Butz, None.
D. Olson,
Bristol Myers Squibb Other, Consultant.
Iovance Biotherapeutics Other, Consultant.
Deciphera Other, Consultant.
Springworks Therapeutics Other, Consultant.
Novartis Other, Consultant.
Astellas Other, Institutional Support.
Immunocore Other, Institutional Support.
Bayer Other, Institutional Support.