PO.CL05.02 · 临床研究
推进 FCRL5 导向的免疫疗法以改善 B 细胞淋巴瘤的治疗
Advancing FCRL5 directed immunotherapy for improved treatment of B cell lymphoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
尽管 B 细胞淋巴瘤疗法取得了显著进展，包括单克隆抗体、双特异性 T 细胞衔接器（BiTE）以及 CD19/CD20 导向的嵌合抗原受体（CAR）T 细胞疗法，但疾病复发和治疗耐药仍是主要的临床挑战。治疗失败的主要驱动因素是抗原逃逸，其特征为恶性 B 细胞上 CD19 和/或 CD20 的下调或缺失¹，使当前的免疫疗法失效。这些局限凸显了对能够规避抗原丢失的替代靶抗原和下一代免疫治疗策略的迫切需求。Fc 受体样蛋白 5（FcRL5）是一种跨膜免疫球蛋白超家族蛋白，选择性表达于恶性 B 细胞和浆细胞，在正常组织中表达极少²，是一种极具吸引力的肿瘤相关抗原。我们利用源自免疫羊驼文库的基于纳米抗体的单域抗体（VHH），生成并功能表征了 FcRL5 靶向 CAR T 细胞。抗 FcRL5 VHH 被整合到含 4-1BB-CD3ζ 信号结构域的第二代 CAR 构建体中。首先在 Jurkat NFAT-GFP 报告细胞中筛选 CAR 候选物的表面表达、抗原特异性活化和基础强直信号，以鉴定表现最佳者。所选 CAR 构建体在原代人 CD3+ T 细胞中进一步评估，检测其与 FcRL5+ 弥漫性大 B 细胞淋巴瘤（DLBCL）细胞系（Su-DHL-6、Toledo）及 FcRL5- 对照共培养后 FcRL5 依赖的活化、细胞毒性、细胞因子分泌和记忆分化。这些分析证明了对表达 FcRL5 的淋巴瘤细胞具有稳健且选择性的活化、强效的效应功能和强烈的细胞毒性，凸显了其治疗潜力。总之，这些发现确立了基于纳米抗体的 FcRL5 靶向 CAR T 细胞是一种有前景的下一代免疫疗法，能够克服 B 细胞淋巴瘤中的抗原逃逸。无论单独使用还是与 FDA 批准的靶点联合使用，FcRL5 CAR T 细胞在转化为针对复发或难治性疾病患者的首次人体临床试验方面均具有巨大潜力。资助：由 SACF 药物发现研究基金支持。参考文献：1. Spiegel JY 等. Nat Med 2021;27:1419-31. 2. Capone M 等. J Clin Cell Immunol 2016;7:427.
查看英文原文 English abstract
Despite significant advances in B-cell lymphoma therapies including monoclonal antibodies, bispecific T-cell engagers (BiTEs), and CD19/CD20-directed chimeric antigen receptor (CAR) T-cell therapies disease relapse and treatment resistance remain major clinical challenges. The principal driver of therapeutic failure is antigen escape, characterized by the downregulation or loss of CD19 and/or CD20 on malignant B cells 1 , rendering current immunotherapies ineffective. These limitations underscore the urgent need for alternative target antigens and next-generation immunotherapeutic strategies capable of circumventing antigen loss. Fc receptor-like 5 (FcRL5), a transmembrane immunoglobulin superfamily protein selectively expressed on malignant B cells and plasma cells with minimal expression in normal tissues², represents a compelling tumor-associated antigen. We generated and functionally characterized FcRL5-targeted CAR T cells using nanobody-based single-domain antibodies (VHHs) derived from an immunized llama library. Anti-FcRL5 VHHs were incorporated into second-generation CAR constructs incorporating 4-1BB-CD3ζ signaling domains. CAR candidates were first screened in Jurkat NFAT-GFP reporter cells for surface expression, antigen-specific activation, and basal tonic signaling to identify top performers. Selected CAR constructs were further evaluated in primary human CD3+ T cells for FcRL5-dependent activation, cytotoxicity, cytokine secretion, and memory differentiation following co-culture with FcRL5+ diffuse large B-cell lymphoma (DLBCL) cell lines (Su-DHL-6, Toledo) and FcRL5 - controls. These analyses demonstrated robust and selective activation, potent effector function, and strong cytotoxicity against FcRL5-expressing lymphoma cells, highlighting their therapeutic potential. Collectively, these findings establish FcRL5-targeted nanobody-based CAR T cells as a promising next-generation immunotherapy capable of overcoming antigen escape in B-cell lymphomas. Evaluated alone or in combination with FDA-approved targets, FcRL5 CAR T cells hold strong potential for translation into first-in-human clinical trials for patients with relapsed or refractory disease. Funding: Supported by the SACF Drug Discovery Research Fund References: 1.Spiegel JY, et al. Nat Med 2021;27:1419-31.2.Capone M, et al. J Clin Cell Immunol 2016;7:427.
利益披露 Disclosure
C. Tripathi, None..
J. Nguyen, None..
F. Hsu, None..
F. Luh, None..
Y. Yen, None.