Department of Pharmaceutics and Pharmaceutical Chemistry, Center for Controlled Chemical Delivery , University of Utah , Salt Lake City , Utah 84112 , United States.
Department of Biomedical Engineering , University of Utah , Salt Lake City , Utah 84112 , United States.
ACS Nano. 2019 Oct 22;13(10):11422-11432. doi: 10.1021/acsnano.9b04868. Epub 2019 Oct 3.
Monoclonal antibody therapy has offered treatment benefits. Nonetheless, a lack of efficacy still exists, partially because monovalent binding of antibodies to specific receptors fails to translate into an active response. Here, we report a pretargeting-postassembly approach that exploits the selective Watson-Crick base pairing properties of oligonucleotides and multivalently tethers receptor-prebound antibodies to albumin at the cell surface. We demonstrate that this two-step self-assembling strategy allows sequential actions of receptor binding and clustering that broadens and strengthens the functions of antibodies. We show that anti-CD20 obinutuzumab (OBN) modified with one morpholino oligonucleotide (OBN-MORF1) maintains the feature of naked OBN antibody upon CD20 binding, and results in actin redistribution, homotypic adhesion, and lysosome-mediated cell death. Consecutive treatment with albumin grafted with multiple copies of a complementary morpholino oligonucleotide (HSA-(MORF2)) hybridizes with surface-attached OBN-MORF1, manipulates CD20 clustering, and engages additional signals to induce calcium influx and caspase-related apoptosis. With the two types of different mechanisms collaborating in one system, the simple design exerted a notable survival extension of mice bearing disseminated B-cell lymphomas.
单克隆抗体治疗提供了治疗益处。然而，仍然存在疗效不足的情况，部分原因是抗体对特定受体的单价结合不能转化为有效的反应。在这里，我们报告了一种前靶向-后组装方法，该方法利用寡核苷酸的选择性沃森-克里克碱基配对特性，将受体预结合的抗体多价连接到细胞表面的白蛋白上。我们证明，这种两步自组装策略允许受体结合和聚类的顺序作用，从而拓宽和增强了抗体的功能。我们表明，用一个吗啉代寡核苷酸（OBN-MORF1）修饰的抗 CD20 奥滨尤妥珠单抗（OBN）在与 CD20 结合时保持了裸 OBN 抗体的特性，并导致肌动蛋白重排、同型黏附和溶酶体介导的细胞死亡。随后用多个互补的吗啉代寡核苷酸（HSA-（MORF2））接枝的白蛋白处理，与表面附着的 OBN-MORF1 杂交，操纵 CD20 聚类，并引发额外的信号，诱导钙内流和半胱天冬酶相关的细胞凋亡。两种不同机制在一个系统中协同作用，这种简单的设计显著延长了患有弥散性 B 细胞淋巴瘤的小鼠的存活期。
