Broadening and Enhancing Functions of Antibody by Self-Assembling Multimerization at Cell Surface

Monoclonal antibody therapy has offered treatment benefits. Nonetheless, lack of efficacy still exists, partially because monovalent binding of antibody to specific receptor fails to translate into 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 cell surface. We demonstrate this two-step self-assembling strategy allows sequential actions of receptor binding and clustering that broadens and strengthens the functions of antibody. 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)x) 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 notable survival extension of mice bearing disseminated B-cell lymphomas.