PO.ET02.12 · 实验与分子治疗
MBS309（一种 PD-1 靶向且 alpha 偏向的 IL-2）的临床前表征，展示出强效抗肿瘤活性和良好的安全性特征
Preclinical characterization of MBS309, a PD-1-targeted and alpha-biased IL-2, demonstrating robust anti-tumor activity and a favorable safety profile
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摘要 Abstract
中文摘要
PD-1/PD-L1 抑制剂的临床影响仍然有限，因为绝大多数癌症患者最终会复发或缺乏持久应答。相反，作为一种开创性免疫治疗细胞因子的 IL-2，其治疗潜力历来因其严重毒性和狭窄的治疗窗而被掩盖。尽管过去开发具有降低 Treg 偏向的更安全 IL-2 变体（非 alpha IL-2）的努力临床成功甚微，但它们推动了一类新型 PD-1/IL-2 双特异性分子的发展。这些药物经过工程改造以实现顺式结合，并将 alpha 偏向的 IL-2 信号特异性递送至肿瘤微环境中 PD-1 高表达和 CD25 高表达的 CD8+ T 细胞。MBS309 经工程改造以增强 IL-2 在对 PD-1/PD-L1 疗法复发或耐药的癌症中的安全性。它由一种 alpha 偏向的 IL-2 变体融合至帕博利珠单抗（Keytruda）C 端构成。该设计保留了 IL-2 与 IL-2Ralpha 的结合，同时显著降低其与 IL-2Rbetagamma 的相互作用。体外研究表明 MBS309 表现出仅限于 PD-1 靶点的活性。作为单药，MBS309 在一系列临床前异种移植模型中引发强效抗肿瘤应答，无论其对 PD-1 抑制的内在敏感性如何。在小鼠中，MBS309 显示出良好的安全性特征，其特点是与临床阶段的基准药物相比半衰期更长且全身毒性显著降低。在 20 mg/kg 剂量下，其毒性更低。药效学研究揭示了这一改善治疗窗的机制基础：MBS309 在正常组织中诱导减弱的 T 细胞激活，同时实现与基准药物相当的强效瘤内 CD8+ T 细胞扩增。MBS309 引人注目的临床前特征，以强效抗肿瘤疗效和良好的安全窗为特点，支持将其作为一种有前景的肿瘤学治疗候选药物进行进一步临床研究。披露：所有作者均为北京天广实生物技术股份有限公司（Beijing Mabworks Biotech Co. Ltd）的员工。
查看英文原文 English abstract
The clinical impact of PD-1/PD-L1 inhibitors remains limited, as the vastmajority of cancer patients ultimately experience relapse or lack a durable response.Conversely, the therapeutic potential of IL-2, a pioneering immunotherapy cytokine,has been historically overshadowed by its severe toxicity and narrow therapeuticwindow. While past efforts to develop safer IL-2 variants with reduced Treg bias(non-alpha IL-2) have seen scant clinical success, they have spurred the development of anew class of PD-1/IL-2 bispecific molecules. These agents are engineered to achievecis-engagement and deliver alpha biased IL-2 signal specifically to PD-1-high andCD25-high CD8+ T cells within the tumor microenvironment.MBS309 was engineered to enhance the safety of IL-2 in cancers relapsed orresistant to PD-1/PD-L1 therapy. It consists of an alpha-biased IL-2 variant fused to theC-terminus of pembrolizumab (Keytruda). This design retains IL-2's binding toIL-2Ralpha while significantly reducing its interaction with IL-2Rbetagamma. In vitro studiesdemonstrated that MBS309 exhibits activity restricted to PD-1 targets. As amonotherapy, MBS309 elicited robust anti-tumor responses across a range ofpreclinical xenograft models, regardless of their intrinsic sensitivity to PD-1 inhibition.In mice, MBS309 showed a favorable safety profile, characterized by a longerhalf-life compared to a clinical-stage benchmark and significantly reduced systemictoxicity. At a dose of 20 mg/kg, it exhibited less toxicity. Pharmacodynamic
investigations revealed the mechanistic basis for this improved therapeutic window:MBS309 induced dampened T cell activation in normal tissues while achieving potentintra-tumoral CD8+ T cell expansion comparable to the benchmark.The compelling preclinical profile of MBS309, characterized by robustanti-tumor efficacy and a favorable safety window, warrants its further clinicalinvestigation as a promising therapeutic candidate for oncology.Disclosures: All the authors are employees from Beijing Mabworks Biotech Co. Ltd
利益披露 Disclosure
J. Li,
Beijing Mabworks Biotech Co. Ltd Employment.
L. Zhang,
Beijing Mabworks Biotech Co. Ltd Employment.
S. Huang,
Beijing Mabworks Biotech Co. Ltd Employment.
S. Qing,
Beijing Mabworks Biotech Co. Ltd Employment.
M. Sun,
Beijing Mabworks Biotech Co. Ltd Employment.
H. Chen,
Beijing Mabworks Biotech Co Ltd Employment.