Gamain Benoît, Brousse Carine, Rainey Nathan E, Diallo Béré K, Paquereau Clara-Eva, Desrames Alexandra, Ceputyte Jolita, Semblat Jean-Philippe, Bertrand Olivier, Gangnard Stéphane, Teillaud Jean-Luc, Chêne Arnaud
Université de Paris, Biologie Intégrée du Globule Rouge, UMR_S1134, INSERM, F-75015 Paris, France.
Laboratory "Immune Microenvironment and Immunotherapy", INSERM U.1135, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Faculté de Médecine, Sorbonne Université, 91 boulevard de l'Hôpital, 75013 Paris, France.
Sci Adv. 2022 Feb 11;8(6):eabl4363. doi: 10.1126/sciadv.abl4363.
Industrial production of therapeutic monoclonal antibodies is mostly performed in eukaryotic-based systems, allowing posttranslational modifications mandatory for their functional activity. The resulting elevated product cost limits therapy access to some patients. To address this limitation, we conceptualized a novel immunotherapeutic approach to redirect a preexisting polyclonal antibody response against Epstein-Barr virus (EBV) toward defined target cells. We engineered and expressed in bacteria bimodular fusion proteins (BMFPs) comprising an Fc-deficient binding moiety targeting an antigen expressed at the surface of a target cell, fused to the EBV-P18 antigen, which recruits circulating endogenous anti-P18 IgG in EBV individuals. Opsonization of BMFP-coated targets efficiently triggered antibody-mediated clearing effector mechanisms. When assessed in a P18-primed mouse tumor model, therapy performed with an anti-huCD20 BMFP significantly led to increased survival and total cancer remission in some animals. These results indicate that BMFPs could represent potent and useful therapeutic molecules to treat a number of diseases.
治疗性单克隆抗体的工业生产大多在基于真核生物的系统中进行，这能实现对其功能活性至关重要的翻译后修饰。然而，由此导致的产品成本升高限制了一些患者获得治疗的机会。为解决这一限制，我们构思了一种新型免疫治疗方法，将针对爱泼斯坦 - 巴尔病毒（EBV）的预先存在的多克隆抗体反应重定向至特定靶细胞。我们在细菌中设计并表达了双模块融合蛋白（BMFPs），其包含一个靶向靶细胞表面表达抗原的Fc缺陷结合部分，与EBV - P18抗原融合，该抗原可招募EBV个体中循环的内源性抗P18 IgG。BMFP包被靶标的调理作用有效触发了抗体介导的清除效应机制。在P18预致敏的小鼠肿瘤模型中评估时，用抗人CD20 BMFP进行的治疗显著提高了部分动物的生存率并实现了完全癌症缓解。这些结果表明，BMFPs可能是治疗多种疾病的有效且有用的治疗分子。
