自 1997 年批准用于治疗淋巴瘤的 CD20 靶向单克隆抗体 (mAb) 利妥昔单抗以来，mAb 疗法已显着改变了癌症治疗。 FDA 批准了 90 多种单克隆抗体用于治疗各种血液癌和实体癌，现代癌症治疗在很大程度上依赖于这些疗法。单克隆抗体作为癌症治疗药物的巨大成功归因于其广泛的适用性、高安全性以及对癌症相关表面抗原的精确靶向。此外，单克隆抗体可以诱导各种抗肿瘤细胞毒性效应机制，包括抗体依赖性细胞毒性（ADCC）、抗体依赖性细胞吞噬作用（ADCP）和补体依赖性细胞毒性（CDC），所有这些都是通过其片段可结晶介导的。 Fc) 域。在过去的几十年里，这些效应机制通过 Fc 域工程得到了显着改善。在这篇综述中，我们将概述通过 mAb 的 Fc 工程增强 Fc 效应器功能的不同方法，特别强调所谓的“HexaBody”技术，该技术旨在增强 mAb 在靶细胞表面的六聚化，从而诱导更大的补体激活、CDC和受体聚集。该综述将总结几种设计用于治疗 B 细胞恶性肿瘤的 HexaBody 的开发、临床前和临床测试，以及 HexaBody 技术在 Fc 介导的效应器功能之外的潜在用途。© 2024 作者。约翰·威利出版的免疫学评论

Since the approval of the CD20-targeting monoclonal antibody (mAb) rituximab for the treatment of lymphoma in 1997, mAb therapy has significantly transformed cancer treatment. With over 90 FDA-approved mAbs for the treatment of various hematological and solid cancers, modern cancer treatment relies heavily on these therapies. The overwhelming success of mAbs as cancer therapeutics is attributed to their broad applicability, high safety profile, and precise targeting of cancer-associated surface antigens. Furthermore, mAbs can induce various anti-tumor cytotoxic effector mechanisms including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC), all of which are mediated via their fragment crystallizable (Fc) domain. Over the past decades, these effector mechanisms have been substantially improved through Fc domain engineering. In this review, we will outline the different approaches to enhance Fc effector functions via Fc engineering of mAbs, with a specific emphasis on the so-called "HexaBody" technology, which is designed to enhance the hexamerization of mAbs on the target cell surface, thereby inducing greater complement activation, CDC, and receptor clustering. The review will summarize the development, preclinical, and clinical testing of several HexaBodies designed for the treatment of B-cell malignancies, as well as the potential use of the HexaBody technology beyond Fc-mediated effector functions.© 2024 The Author(s). Immunological Reviews published by John Wiley & Sons Ltd.