定向补体激活作为her2乳腺癌的一种新的免疫治疗方法。

IF 4.4 Q1 IMMUNOLOGY
ImmunoTargets and Therapy Pub Date : 2025-09-05 eCollection Date: 2025-01-01 DOI:10.2147/ITT.S517584
Carole Seguin-Devaux, Bianca Brandus, Jean-Marc Plesseria, Gilles Iserentant, Jean-Yves Servais, Aubin Pitiot, Georgia Kanli, Iris Behrmann, Rafaëla Schober, Jacques Zimmer, Jacques H M Cohen, Xavier Dervillez
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引用次数: 0

摘要

目的:引导选择性补体激活肿瘤细胞是促进其消除的一种有吸引力的策略。我们已经生成了补体激活多聚体免疫治疗复合物(CoMiX),刺激表达her2的肿瘤细胞的替代途径(通过因子H相关蛋白4 (FHR4))或经典途径(通过三Fc二聚体)。方法:我们利用C4结合蛋白(C4bp)的c端α-链多聚支架生成CoMiX-FHR4和CoMiX-Fc,分别识别曲妥珠单抗或帕妥珠单抗竞争表位,具有2种不同的抗her2 VHH, VHH(T)和VHH(P)。在体外比较不同CoMiX的C3b和C5b9沉积,补体依赖性细胞毒性(CDC),以及它们激活NK细胞和巨噬细胞吞噬的能力。我们进一步探讨了它们对裸鼠移植的人BT474肿瘤的治疗效果。结果:CoMiX-FHR4/VHH(T)和-FHR4/VHH(P)导致BT474肿瘤细胞上最高的C3b和C5b9沉积和CDC (pHH(P)/Fc)导致肿瘤体积减少类似于帕妥珠单抗。两种CoMiX-FHR4或两种CoMiX-Fc联合使用更有效,与曲妥珠单抗和帕妥珠单抗联合使用类似,导致异种移植物中NK细胞浸润增加。重要的是,CoMiX-FHR4对曲妥珠单抗耐药的异种移植物仍有活性,延缓肿瘤生长并诱导大量NK细胞浸润。结论:我们在这里表明,针对肿瘤细胞的定向补体激活是治疗性抗体的替代方案,可用于未来的联合治疗,以应对标准治疗的耐药。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Directed-Complement Activation as a Novel Immunotherapeutic Approach for HER2-Breast Cancer.

Purpose: Directing selective complement activation towards tumor cells is an attractive strategy to promote their elimination. We have generated complement-activating multimeric immunotherapeutic complexes (CoMiX), stimulating either the alternative pathway (via Factor H Related protein 4 (FHR4)) or the classical pathway (via triple Fc dimers) on HER2-expressing tumor cells.

Methods: We used the C-terminal α-chain multimerizing scaffold of the C4 binding protein (C4bp) to generate CoMiX-FHR4 as well as CoMiX-Fc with 2 different anti-HER2 VHH, VHH(T) and VHH(P), recognizing trastuzumab- or pertuzumab-competing epitopes, respectively. The different CoMiX were compared in vitro for C3b and C5b9 depositions, complement-dependent cytotoxicity (CDC), and their ability to activate NK cells and phagocytosis by macrophages. We further explored their therapeutic efficacy on human BT474 tumor xenografts established in nude mice.

Results: CoMiX-FHR4/VHH(T) and -FHR4/VHH(P) lead to the highest C3b and C5b9 depositions and CDC on BT474 tumor cells (p<0.0001), both individually and in combinations with their CoMiX-Fc counterparts, surpassing the low complement activating capacity of trastuzumab and pertuzumab. All CoMiX induced BT474 cell death and phagocytosis of tumor cells by macrophages while CoMiX-Fc also stimulated NK cell activation. In human BT474 xenografts sensitive to trastuzumab, CoMiX induced a massive C3b deposition 6 hours after injection. CoMiX-FHR4 reduced the tumor volume compared to controls (p< 0.05) but to a lesser extent than trastuzumab (p< 0.001) while CoMiX-VHH(P)/Fc led to a tumor volume reduction similar to pertuzumab. Combinations of two CoMiX-FHR4 or two CoMiX-Fc were more potent, similarly to the combination of trastuzumab and pertuzumab, leading to increased NK cell infiltration in xenografts. Importantly, CoMiX-FHR4 was still active against trastuzumab-resistant xenografts, delaying tumor growth and inducing a large NK cell infiltration.

Conclusion: We showed here that directed complement activation on tumor cells is an alternative to therapeutic antibodies for future combination therapies upon resistance to standard-of-care treatment.

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来源期刊
CiteScore
16.50
自引率
0.00%
发文量
7
审稿时长
16 weeks
期刊介绍: Immuno Targets and Therapy is an international, peer-reviewed open access journal focusing on the immunological basis of diseases, potential targets for immune based therapy and treatment protocols employed to improve patient management. Basic immunology and physiology of the immune system in health, and disease will be also covered.In addition, the journal will focus on the impact of management programs and new therapeutic agents and protocols on patient perspectives such as quality of life, adherence and satisfaction.
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