Monoclonal antibody therapy has numerous benefits but can lack efficacy, often because monovalent binding of antibodies to specific receptors fails to translate into an active response. The Kopeček laboratory has built on their track record in polymeric drug delivery to develop a novel approach to therapeutic design, termed “Drug-Free Macromolecular Therapeutics (DFMT)”. DFMT exploits the selective Watson-Crick base-pairing properties of oligonucleotides to tether receptor-prebound antibodies to receptors at the cell surface.
This two-step self-assembly strategy uses both sequential receptor binding and clustering to broaden and strengthen antibody functions, including the anti-CD20 antibody obinutuzumab, which increases apoptotic cell death in cancer cells both in vitro and in vivo. Their second-generation DFMT combines the activation pathways of Type I and Type II antibodies into one system and will be developed into a new class of drug-free macromolecular therapeutics suitable for a broad spectrum of B-cell malignancies, including treatment-resistant tumors.
Sequential combination therapy of ovarian cancer with degradable N-(2-hydroxypropyl)methacrylamide copolymer paclitaxel and gemcitabine conjugates. Zhang R, Yang J, Sima M, Zhou Y, Kopeček J. Proc Natl Acad Sci USA. 2014 Aug;111(33):12181.
Backbone degradable N-(2-Hydroxypropyl)methacrylamide copolymer conjugates with gemcitabine and paclitaxel: impact of molecular weight on activity toward human ovarian carcinoma xenografts. Yang J, Zhang R, Pan H, Li Y, Fang Y, Zhang L, Kopeček J. Mol Pharm. 2017 May;14(5):1384.
Broadening and enhancing functions of antibodies by self-assembling multimerization at cell surface. Li L, Wang J, Li Y, Radford DC, Yang J, Kopeček J ACS Nano. 2019 Oct;13(10):11422.