合成免疫招募——一种对抗肿瘤的新方法

作为2018年诺贝尔医学奖的主题，肿瘤免疫疗法已被证明是一种令人兴奋的癌症治疗策略。迄今为止，大多数免疫疗法都集中在T细胞功能上;然而，更多的自然杀伤(NK)细胞疗法正在出现，包括靶向肿瘤抗原的单克隆抗体(mAbs)。单克隆抗体在治疗血液肿瘤和以前难以治疗的实体肿瘤方面都取得了临床成功。单克隆抗体杀死肿瘤细胞的一个基本机制是抗体依赖性细胞毒性(ADCC)。ADCC是指当单克隆抗体通过激活NK细胞引起免疫反应，并由抗体与NK细胞激活受体(CD16α)和靶癌细胞蛋白抗原的双特异性结合触发。这种结合导致细胞毒性分子的释放，导致靶向癌细胞死亡。虽然很有希望，但单克隆抗体具有潜在的免疫原性，可以在体内降解，并且难以运输到实体肿瘤部位。此外，大剂量的单抗需要静脉注射。这增加了生产成本，导致药价上涨，限制了一般患者的可及性。 An approach to utilize tumor immunotherapeutic antibodies directly in vivo using small immune recruiting molecules coined as “covalent immune recruiters” (CIRs) was developed. CIRs selectively link to naturally abundant serum antibodies and redirect them to the sur-face of tumor cells. The resultant display of tumor coated antibodies activates stimulatory receptors on innate immune cells, such as CD16α on NK cells, and triggers an antitumor immune response. The efficacy of these CIRs as modulators of protein proximity can be characterized by the Octet® Bio-Layer Interferometry (BLI) platform. Octet® systems are capable of real-time, high-throughput analysis of small molecule and biomolecule binding kinetics under equilibrium conditions. Due to its flexibility and compatibility for alternative assay format arrangements, it is a powerful tool for characterizing the CIR dependent binding equilibrium (e.g., tumor antigen:CIR:Ab) in addition to its use in determining CIR-antibody covalent recruitment kinetics. The label-free and highly sensitive nature of the Octet® BLI technology also enables analysis under dilute conditions, conserving expensive biologic reagents and attenuating aggregation phenomena intrinsic to isothermal titration calorimetry (ITC) and fluorescence polarization (FP) assays. Octet® systems also present a unique method to simultaneously characterize multiple protein binding and covalent labeling processes and discern reversible binding from a covalent reaction. Octet® system can be employed to efficiently characterize CIR binding affinities against both a prostate tumor antigen and human serum antibodies, as well as measure the selective covalent recruitment of these antibodies to the tumor antigen. These assays can accelerate the advancement of lead compounds to in vivo validation studies, and have additional utility in characterizing emerging classes of covalent inhibitor drugs.