PO.CL05.12 · 临床研究
QLS2313，一种采用双靶向策略开发的 CD79b/CD20 三特异性 T 细胞衔接器，作为治疗 DLBCL 的新型疗法
QLS2313, a CD79b/CD20 tri-specific T cell engager with dual-targeting strategy developed as a new therapeutics for the treatment of DLBCL
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摘要 Abstract
中文摘要
弥漫性大 B 细胞淋巴瘤（DLBCL）是非霍奇金淋巴瘤（NHL）中最常见的亚型，约 40% 的患者在初始治疗应答后发展为难治性疾病或复发。虽然 CD20 靶向 T 细胞衔接器（TCE）已展现出临床疗效并获得 FDA 批准用于 DLBCL，但研究表明，8-64% 的患者在接受 CD20 导向治疗后会发生 CD20 表达丢失。这种丢失常与转化为高级别淋巴瘤和总生存期不良相关。为应对这一挑战，在靶向 CD20 之外双重靶向另一个 DLBCL 表面抗原可能增强治疗效果。CD79b 是一个经充分验证的治疗靶点，在 90% 的 DLBCL 病例中表达，对 DLBCL 细胞的存活至关重要。与 CD20 不同，CD79b 靶向药物较少因抗原丢失而产生耐药，使其成为极具吸引力的 TCE 靶点。因此，与单抗原靶向 TCE 相比，双重靶向 CD79b 和 CD20 的 TCE 可能克服耐药并提高疗效。QLS2313 是一种人 IgG1 三特异性抗体，具有抗 CD3 单链可变片段（scFv）、抗 CD20 Fab、抗 CD79b Fab 和一个效应功能沉默的 Fc 区。在体外，QLS2313 对 DLBCL 细胞系的亲和力高于 JNJ-80948543（一种来自 Janssen 的临床阶段 CD79b/CD20 TCE），同时相比 JNJ-80948543 及 FDA 批准的 CD20/CD3 双特异性抗体（mosunetuzumab 和 glofitamab），对原代人 T 细胞和 Jurkat 细胞的亲和力显著更低。QLS2313 有效清除了双靶点和单靶点表达的细胞，表现出优于 JNJ-80948543 的细胞毒性和低于 glofitamab 的 IL-6 释放。在体内，QLS2313 在三重转基因（人 CD3/CD20/CD79b）小鼠中表现出线性药代动力学，半衰期约为 5 天。它以剂量依赖性方式抑制肿瘤生长，并表现出优于 JNJ-80948543 的抗肿瘤疗效，尤其是在 CD20 低表达模型中。QLS2313 在转基因小鼠（QW×4）GLP 毒性研究中耐受性良好，静脉和皮下给药的最高非严重毒性剂量（HNSTD）均为 30 mg/kg。总之，QLS2313 表现出优越的疗效、良好的药代动力学和安全性特征，支持这一 DLBCL 治疗新型疗法的临床开发。
查看英文原文 English abstract
Diffuse large B-cell lymphoma (DLBCL) is the most prevalent subtype of non-Hodgkin lymphoma (NHL), with approximately 40% of patients developing refractory disease or relapsing after initial therapy response. While CD20-targeted T cell engagers (TCEs) have demonstrated clinical efficacy and gained FDA approval for DLBCL, studies indicate that CD20 expression loss occurs in 8-64% of patients following CD20-directed therapies. This loss is often associated with transformation to high-grade lymphoma and poor overall survival. To address this challenge, Dual targeting another DLBCL surface antigen as well as CD20 may enhance therapeutic effects. CD79b is a well-validated therapeutic target expressed in 90% of DLBCL cases anditis critical for the viability of DLBCL cells. Unlike CD20, CD79b-targeted agents are less prone to resistance caused by antigen loss, making it an attractive TCE target. Therefore, a TCE dual targeting of CD79b and CD20 may overcome resistance and improve efficacy compared to a single-antigen targeting TCE. QLS2313 is a human IgG1 tri-specific antibody featuring an anti-CD3 single-chain variable fragment (scFv), an anti-CD20 Fab, an anti-CD79b Fab, and an effector-silent Fc region. In vitro , QLS2313 exhibited higher affinity for DLBCL cell lines than JNJ-80948543 (a clinical-stage CD79b/CD20 TCE from Janssen) while demonstrating significantly lower affinity for primary human T cells and Jurkat cells compared to JNJ-80948543 and FDA-approved CD20/CD3 bi-specifics (mosunetuzumab and glofitamab). QLS2313 effectively depleted both dual- and single-target-expressing cells, showing superior cytotoxicity to JNJ-80948543 and lower IL-6 release than glofitamab. In vivo , QLS2313 demonstrated linear pharmacokinetics in triple transgenic (human CD3/CD20/CD79b) mice, with a half-life of ~5 days. It inhibited tumor growth in a dose-dependent manner and exhibited greater antitumor efficacy than JNJ-80948543, particularly in CD20-low expression models. QLS2313 was well tolerated in a transgenic mice (QW × 4) GLP toxicity study, with the highest non-severely toxic dose (HNSTD) at 30 mg/kg for both intravenous and subcutaneous administration. In conclusion, QLS2313 show superior efficacy, favorable pharmacokinetics and safety profile, which support the clinical development of this novel therapy for DLBCL treatment.
利益披露 Disclosure
T. Lu, None..
L. Yang, None..
F. Yao, None..
D. Wu, None..
S. Zhao, None..
H. Ying, None..
W. Tao, None.