PO.IM01.09 · 免疫学
QL535:一种新型CD2共刺激的PSMA靶向T细胞衔接器,在PDX模型中具有剂量反应性疗效,并在NHP中呈现良好的GLP毒理学特征
QL535: A novel CD2-costimulating PSMA-targeted T-cell engager with dose-responsive efficacy in PDX models and a favorable GLP toxicology profile in NHP
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
前列腺癌仍是癌症死亡的主要原因之一,凸显了对更好的靶向免疫疗法的需求。前列腺特异性膜抗原在恶性前列腺组织中高表达,该结论已在77例患者中经免疫组织化学证实。早期的T细胞衔接器在实体瘤中活性有限,促使人们设计纳入共刺激的方案。对14例转移性去势抵抗性前列腺癌患者的2,170个肿瘤浸润淋巴细胞进行单细胞RNA测序显示,CD2的表达比CD28更广泛且更高,尤其是在CD8阳性T细胞中,支持将CD2作为一个可及的共刺激轴。QL535是一种三特异性PSMA × CD3 × CD2 T细胞衔接器,经工程改造以提供优化的CD3活化和CD2介导的共刺激。在体外,QL535相较于CD2缺失的对照增强了PSMA依赖的细胞毒性,并在效力上与基于CD28的三特异性抗体相当,同时降低了IL-6、TNFα、IFN-γ和IL-8的分泌。使用患者外周血单个核细胞进行的重复刺激实验表明,相较于基于CD28的三特异性抗体和临床基准类似物,其保留了溶细胞活性并减少了耗竭。在体内,QL535在前列腺癌患者来源异种移植模型中产生了明确的剂量反应性肿瘤消退。良好实验室规范(GLP)毒理学研究显示出良好的耐受性。1至10 mg/kg的静脉给药导致剂量依赖性暴露。首次给药后细胞因子短暂升高,伴随单核细胞和淋巴细胞可逆性下降以及中性粒细胞和C反应蛋白的短暂升高。循环T细胞在24小时时下降,并在第7天恢复至基线。QL535在非人灵长类动物中总体耐受性良好,药效学变化与T细胞衔接器活性一致。这些发现表明,QL535能够提供强效的PSMA靶向细胞毒性,在诱导耗竭的条件下维持功能,在患者来源异种移植模型中驱动剂量反应性抗肿瘤活性,并展现出良好的安全性和药理学特征,支持其推进至PSMA阳性前列腺癌的临床评估。
查看英文原文 English abstract
Prostate cancer remains a major cause of cancer mortality, highlighting the need for better targeted immunotherapies. Prostate-specific membrane antigen is highly expressed in malignant prostate tissue, confirmed by immunohistochemistry in 77 patients. Earlier T-cell engagers show limited activity in solid tumors, prompting designs incorporating co-stimulation. Single-cell RNA sequencing of 2,170 tumor-infiltrating lymphocytes from 14 metastatic castration-resistant prostate cancer patients showed broader and higher CD2 expression than CD28, especially in CD8-positive T cells, supporting CD2 as an accessible co-stimulatory axis.QL535 is a trispecific PSMA × CD3 × CD2 T-cell engager engineered to provide optimized CD3 activation and CD2-mediated co-stimulation. In vitro, QL535 enhanced PSMA-dependent cytotoxicity compared to CD2-deficient controls and matched the potency of CD28-based trispecifics while reducing secretion of IL-6, TNFalpha, IFN-gamma, and IL-8. Repeated-stimulation assays using patient peripheral blood mononuclear cells demonstrated preserved cytolytic activity and reduced exhaustion relative to CD28-based trispecifics and clinical benchmark analog. In vivo, QL535 produced clear dose-responsive tumor regression in prostate cancer patient-derived xenograft models. Good Laboratory Practice toxicology studies demonstrated favorable tolerability. Intravenous dosing from 1 to 10 mg/kg resulted in dose-dependent exposure. Cytokines increased transiently after the first dose, accompanied by reversible decreases in monocytes and lymphocytes and transient elevations in neutrophils and C-reactive protein. Circulating T cells declined at 24 hours and returned to baseline by Day 7. QL535 was overall well tolerated in non-human primates, with pharmacodynamic changes consistent with T-cell engager activity. These findings demonstrate that QL535 delivers potent PSMA-targeted cytotoxicity, sustains function under exhaustion-inducing conditions, drives dose-responsive antitumor activity in patient-derived xenograft models, and exhibits a favorable safety and pharmacology profile, supporting advancement toward clinical evaluation in PSMA-positive prostate cancer.
利益披露 Disclosure
X. Liu, None.