Medical Research Institute, College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, P. R. China.
Department of Breast and Thyroid Surgery, Southwest Hospital, Chongqing, 400038, P. R. China.
Adv Sci (Weinh). 2023 Mar;10(9):e2206912. doi: 10.1002/advs.202206912. Epub 2023 Jan 22.
Antibody-based therapies could be led astray when target receptors are expressed on nontarget sites, and the on-target toxicity poses critical challenges to clinical applications. Here, a biomimetic indirect active targeting (INTACT) strategy is proposed based on receptor expression disparities between nontarget sites and the targets. By prebinding the antibodies using cell membrane vesicles with appropriate receptor expressions, the INTACT strategy could filter out the interactions on nontarget sites due to their inferior receptor expression, whereas ensure on-demand release at the targets by competitive binding. The strategy is verified on CD47 antibody, realizing drastic alleviation of its clinically concerned hematotoxicity on a series of animal models including humanized patient-derived xenograft platforms, accompanied by preferable therapeutic effects. Furthermore, the INTACT strategy proves extensive applicability for various systems including antibody, antibody-drug conjugate, and targeted delivery systems, providing a potential platform refining the specificity for frontier antibody-related therapies.
基于抗体的疗法可能会在靶受体表达于非靶部位时误入歧途，而靶毒性对临床应用构成了关键挑战。在此，提出了一种基于非靶部位和靶部位之间受体表达差异的仿生间接主动靶向（INTACT）策略。通过使用具有适当受体表达的细胞膜囊泡预先结合抗体，INTACT 策略可以滤除由于受体表达较低而导致的非靶部位的相互作用，而通过竞争结合确保在靶部位按需释放。该策略在 CD47 抗体上得到了验证，在包括人源化患者来源异种移植平台在内的一系列动物模型中，实现了其临床关注的血液毒性的显著缓解，同时具有更好的治疗效果。此外，INTACT 策略证明了其在各种系统中的广泛适用性，包括抗体、抗体药物偶联物和靶向递药系统，为前沿抗体相关疗法的特异性提供了一个潜在的平台。
