Development of antigen‐specific blocking monobodies against the β2‐glycoprotein I receptor for the inhibition of systemic lupus erythematosus

Abstract

Autoimmune diseases occur when the body's immune system attacks healthy tissues and organs through the use of antibodies. Current treatments suppress the patient's entire immune system through immunosuppressive drug therapies. These drugs decrease the body's effective immune response to genuine pathogens, increasing the patient's susceptibility to having major complications from basic infections. Therefore, treatments that can eliminate disease progression, as well as preserve the healthy function of the patient's immune system, should be considered. Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder affecting a predicted five million individuals worldwide. One autoantigen targeted in SLE is the β2‐glycoprotein I receptor (β2GPI). The work here focuses on the development of protein monobodies capable of inhibiting interactions between the autoantibody and autoantigen that elicit the immune response. Binding between the monobody and autoantigen may prevent antibody binding, decrease autoimmune complexes, and ultimately halt disease progression. Using in silico programs Phyre2 and Chimera, mutations to the monobody templates 3K2M, 3T04, and 5A43 were introduced to improve binding between the monobody and proposed antibody‐binding β2GPI domains 1, 2, and 5. In silico program ROSIE was used to predict protein‐protein binding scores between the monobody candidates and proposed β2GPI domains. Initial binding scores (in Rosetta Energy Units, or REU) between monobody templates 3K2M, 3T04, and 5A43 with β2GPI domain 5 were −3.105 REU, −2.795 REU, and −3.038 REU, respectively. A double mutation to 5A43 (V46R‐E48H) improved 5A43's binding score with β2GPI domain 5 to −4.122 REU. A slight improvement to binding was made to 3K2M with a single mutation (N47H), with a score of −3.446 REU to β2GPI domain 5. More mutations to each monobody template are being evaluated. Enzyme‐linked immunosorbent assays (ELISAs) will be conducted to evaluate antibody inhibition by monobody candidates in vitro. The goal of the research presented here is to develop safer and effective treatments of autoimmune disease.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.