背景:靶向共刺激受体CD137已显示出有望作为癌症免疫治疗的治疗方法,导致临床试验中证明的抗肿瘤功效。然而,最初的CD137激动性抗体,urelumab和utomilumab,由于肝脏毒性或缺乏疗效,在临床试验中面临挑战,分别。同时,c-MET已被鉴定为在各种实体和软性肿瘤中高表达的肿瘤相关抗原(TAA)。
方法:在本研究中,我们旨在开发一种同时靶向c-MET和CD137的双特异性抗体(BsAb),优化BsAb形式和CD137结合剂,将CD137激动剂有效递送至肿瘤微环境(TME).我们采用单价c-MET基序和三聚体CD137重链可变重链结构域(VHH)进行BsAb设计。
结果:我们的结果表明,c-METxCD137BsAb通过表达c-MET的肿瘤细胞的交联为T细胞提供共刺激。功能性免疫测定证实了c-METxCD137BsAb的功效和效力增强,如CD137信号的激活所示,靶细胞杀伤,和细胞因子在各种肿瘤细胞系中的释放。此外,c-METxCD137BsAb与Pembrolizumab的组合显示靶诱导的T细胞细胞因子释放的剂量依赖性增强.
结论:总体而言,c-METxCD137BsAb通过将脱靶效应降至最低,同时有效递送免疫激动作用,作为肿瘤靶向免疫激动剂,表现出了有希望的可开发性特征.它具有克服对抗PD-(L)1疗法的抗性的潜力。
BACKGROUND: Targeting the costimulatory receptor
CD137 has shown promise as a therapeutic approach for cancer immunotherapy, resulting in anti-tumor efficacy demonstrated in clinical trials. However, the initial
CD137 agonistic antibodies, urelumab and utomilumab, faced challenges in clinical trials due to the liver toxicity or lack of efficacy, respectively. Concurrently, c-MET has been identified as a highly expressed tumor-associated antigen (TAA) in various solid and soft tumors.
METHODS: In this study, we aimed to develop a bispecific antibody (BsAb) that targets both c-MET and CD137, optimizing the BsAb format and
CD137 binder for efficient delivery of the
CD137 agonist to the tumor microenvironment (TME). We employed a monovalent c-MET motif and a trimeric
CD137 Variable Heavy domain of Heavy chain (VHH) for the BsAb design.
RESULTS: Our results demonstrate that the c-MET x
CD137 BsAb provides co-stimulation to T cells through cross-linking by c-MET-expressing tumor cells. Functional immune assays confirmed the enhanced efficacy and potency of the c-MET x CD137 BsAb, as indicated by activation of CD137 signaling, target cell killing, and cytokine release in various tumor cell lines. Furthermore, the combination of c-MET x CD137 BsAb with Pembrolizumab showed a dose-dependent enhancement of target-induced T cell cytokine release.
CONCLUSIONS: Overall, the c-MET x CD137 BsAb exhibits a promising developability profile as a tumor-targeted immune agonist by minimizing off-target effects while effectively delivering immune agonism. It has the potential to overcome resistance to anti-PD-(L)1 therapies.