Department of Medicine, McMaster Immunology Research Center, Center for Discovery in Cancer Research, Hamilton, Ontario L8S 4K1, Canada.
Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario L8S 4L8, Canada.
ACS Chem Biol. 2022 May 20;17(5):1269-1281. doi: 10.1021/acschembio.2c00233. Epub 2022 May 6.
Covalent antibody recruiting molecules (cARMs) constitute a proximity-inducing chemical strategy to modulate the recognition and elimination of cancer cells by the immune system. Recognition is achieved through synthetic bifunctional molecules that use covalency to stably bridge endogenous hapten-specific antibodies like anti-dinitrophenyl (anti-DNP), with tumor antigens on cancer cell surfaces. To recruit these antibodies, cARMs are equipped with the native hapten-binding molecule. The majority of cancer-killing immune machinery, however, recognizes epitopes on protein ligands and not small molecule haptens (e.g., Fc receptors, pathogen-specific antibodies). To access this broader class of immune machinery for recruitment, we developed a covalent immune proximity-inducing strategy. This strategy uses derived from the native protein ligand. These bifunctional peptides are engineered to contain both a tumor-targeting molecule and a sulfonyl (VI) fluoride exchange (SuFEx) electrophile. As a proof of concept, we synthesized bifunctional electrophilic peptides derived from glycoprotein D (gD) on herpes simplex virus (HSV), to recruit gD-specific serum anti-HSV antibodies to cancer cells expressing the prostate-specific membrane antigen (PSMA). We demonstrate that serum anti-HSV antibodies can be selectively and targeted by these electrophilic peptides and that the reaction rate can be uniquely enhanced by tuning SuFEx chemistry . In cellular assays, electrophilic peptides demonstrated enhanced anti-tumor immunotherapeutic efficacy compared to analogous peptides lacking electrophilic functionality. This enhanced efficacy was especially prominent in the context of (a) natural anti-HSV antibodies isolated from human serum and (b) harder to treat tumor cells associated with lower PSMA expression levels. Overall, we demonstrate a new covalent peptide-based approach to immune proximity induction and reveal the potential utility of anti-viral antibodies in synthetic tumor immunotherapy.
共价抗体募集分子（cARMs）构成了一种诱导邻近的化学策略，用于调节免疫系统对癌细胞的识别和消除。识别是通过使用共价键将内源性半抗原特异性抗体（如抗二硝基苯（anti-DNP））与癌细胞表面的肿瘤抗原稳定桥接的合成双功能分子来实现的。为了募集这些抗体，cARMs 配备了天然半抗原结合分子。然而，大多数杀伤癌细胞的免疫机制识别蛋白配体上的表位，而不是小分子半抗原（例如，Fc 受体、病原体特异性抗体）。为了利用更广泛的免疫机制进行招募，我们开发了一种共价免疫邻近诱导策略。该策略使用衍生自天然蛋白配体的小分子半抗原。这些双功能肽被设计成包含肿瘤靶向分子和磺酰（VI）氟化物交换（SuFEx）亲电体。作为概念验证，我们合成了源自单纯疱疹病毒（HSV）糖蛋白 D（gD）的双功能亲电子肽，以募集 gD 特异性血清抗 HSV 抗体到表达前列腺特异性膜抗原（PSMA）的癌细胞上。我们证明，血清抗 HSV 抗体可以被这些亲电子肽选择性和靶向，并且可以通过调谐 SuFEx 化学来独特地增强反应速率。在细胞测定中，与缺乏亲电子功能的类似肽相比，亲电子肽显示出增强的抗肿瘤免疫治疗功效。这种增强的功效在以下情况下尤为明显：（a）从人血清中分离的天然抗 HSV 抗体，（b）与较低 PSMA 表达水平相关的更难治疗的肿瘤细胞。总体而言，我们展示了一种新的基于共价肽的免疫邻近诱导方法，并揭示了抗病毒抗体在合成肿瘤免疫治疗中的潜在应用。
