Exploration and Evaluation of Therapeutic Efficacy of Drug-Free Macromolecular Therapeutics in Collagen-Induced Rheumatoid Arthritis Mouse Model.

Abstract

Monoclonal antibodies (mAbs) against B cell antigens are extensively used in the treatment of rheumatoid arthritis (RA). The B cell depletion therapy prevents RA symptoms and/or alleviates existing inflammation. The previously established two-step drug-free macromolecular therapeutics (DFMT) is applied in the treatment of collagen-induced rheumatoid arthritis in a collagen-induced rheumatoid arthritis mouse model. DFMT is a B cell depletion strategy utilizing Fab' fragment of anti-CD20 mAb for biorecognition and receptor crosslinking to induce B cell apoptosis. DFMT is composed from two nanoconjugates: 1) bispecific engager, Fab'-MORF1 (anti-CD20 Fab' fragment conjugated with morpholino oligonucleotide MORF1), and 2) a crosslinking (effector) component P-(MORF2)X (N-(2-hydroxypropyl)methacrylamide copolymer grafted with multiple copies of complementary morpholino oligonucleotide MORF2). The absence of Fc fragment has the potential to avoid development of resistance and infusion-related reactions. DFMT produces B cell depletion, keeps the RA score low for more than 100 days, and shows minimal cartilage and bone erosion and inflammatory cell infiltration. Further improvements will be explored to optimize DFMT strategy in autoimmune disease treatment.