PO.ET05.01 · 实验与分子治疗
临床前研究揭示蛋白酶介导的载荷释放及免疫肿瘤学/免疫调节效应促成HLX43的抗肿瘤活性
Preclinical studies reveal that protease-mediated payload release and immuno-oncology/immunomodulatory effects contribute to the antitumor activity of HLX43
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
HLX43是一种为癌症治疗设计的创新型PD-L1靶向抗体-药物偶联物（ADC）。它由工程化的抗PD-L1人源化IgG1抗体HLX20组成，通过蛋白酶可切割的三肽连接子偶联至一种强效的喜树碱衍生拓扑异构酶I抑制剂（C24），药物抗体比（DAR）为8。先前报道的临床前研究已证明，HLX43保留了亲本HLX20抗体的结合亲和力和内化动力学，并表现出良好的稳定性和强效的抗肿瘤活性。
HLX43的作用机制（MoA）是多方面的，将免疫检查点阻断与载荷诱导的细胞毒性相整合。此处报道的临床前研究表明，作为一种抗PD-L1药物，HLX43有效阻断PD-1/PD-L1相互作用并重新激活T细胞活性，这在混合淋巴细胞反应试验中IL-2和IFNγ分泌增加得到证实。HLX43的直接细胞毒性源于对DNA修复的抑制和细胞凋亡的诱导，如切割的PARP和增加的γH2AX所证实。此外，HLX43诱导以细胞表面钙网蛋白增加为标志的免疫原性细胞死亡（ICD），从而促成其免疫调节效应。同时，蛋白酶介导的对肿瘤微环境（TME）内连接子的切割——通过基质金属蛋白酶（MMP）和半胱氨酸蛋白酶等酶——使载荷释放得以独立于PD-L1结合而进行。细胞外释放的载荷通过扩散到邻近组织并杀伤相邻的PD-L1阴性癌细胞而发挥旁观者效应，这一特性是HLX43在PD-L1表达异质的患者来源异种移植（PDX）模型中稳健疗效的基础。除直接细胞毒性外，HLX43还重塑TME，体内研究显示细胞毒性CD8+T细胞浸润增加，调节性T细胞（Treg）减少。这些CD8+T细胞表现出增强的效应功能，包括IFNγ和颗粒酶B表达升高。
总之，HLX43的趋同机制——结合免疫检查点抑制、靶向细胞毒性和TME调节——支持其作为单药疗法以及与其他免疫肿瘤学药物联合使用的潜力，使HLX43成为跨多种肿瘤类型的有前景的治疗候选药物。
查看英文原文 English abstract
HLX43 is an innovative PD-L1-targeted antibody-drug conjugate (ADC) designed for cancer treatment. It consists of HLX20, an engineered anti-PD-L1 humanized IgG1 antibody, conjugated via a protease-cleavable tripeptide linker to a potent camptothecin-derived topoisomerase I inhibitor (C24) at a drug-to-antibody ratio (DAR) of 8. Previously reported preclinical studies have demonstrated that HLX43 retains the binding affinity and internalization kinetics of the parental HLX20 antibody and exhibits favorable stability and potent antitumor activity.
The mechanism of action (MoA) of HLX43 is multifaceted, integrating immune checkpoint blockade with payload-induced cytotoxicity. The preclinical studies reported here show that, as an anti-PD-L1 agent, HLX43 effectively blocks PD-1/PD-L1 interaction and reactivates T-cell activity, evidenced by increased IL-2 and IFNgamma secretion in mixed lymphocyte reaction assays. The direct cytotoxicity of HLX43 arises from inhibition of DNA repairing and induction of cell apoptosis as evidenced by cleaved PARP and increased gammaH2AX. In addition, HLX43 induces immunogenic cell death (ICD) marked by increased cell-surface calreticulin, contributing to its immunomodulatory effects. In parallel, protease-mediated cleavage of the linker within the tumor microenvironment (TME)-by enzymes such as matrix metalloproteinases (MMPs) and cysteine proteases-enables payload release independent of the PD-L1 binding. The extracellularly released payload exerts a bystander effect by diffusing into neighbor tissues and killing adjacent PD-L1-negative cancer cells, a feature that underlies HLX43's robust efficacy in patient-derived xenograft (PDX) models with heterogeneous PD-L1 expression. Beyond direct cytotoxicity, HLX43 also remodels the TME, with in vivo studies showing increased infiltration of cytotoxic CD8 + T cells and reduced regulatory T cells (Tregs). These CD8 + T cells display enhanced effector function, including elevated IFNgamma and Granzyme B expression.
In summary, HLX43's convergent mechanisms-combining immune checkpoint inhibition, targeted cytotoxicity, and TME modulation-support its potential as both a monotherapy and in combination with other immuno-oncology agents, positioning HLX43 as a promising therapeutic candidate across diverse tumor types
利益披露 Disclosure
L. Feng, None.
J. Yuan,
Shanghai Hengrui Medical Co., Ltd. Employment.
W. Yang, None..
C. Jia, None..
G. Song, None..
Q. Wang, None..
J. Zhu, None.