Estudo dos determinantes estruturais e termodinâmicos na interação do scFv de Epratuzumab e um receptor de membrana CD22

Abstract

Leukemia, a type of cancer that affects white blood cells in the bone marrow, is one of the deadliest forms of the disease. Acute Lymphoblastic Leukemia (ALL) is the most common type of leukemia in children. Uncontrolled growth of abnormal B lymphocytes describe this disease. CAR-T therapy is a novel treatment approach for ALL-B, utilizing chimeric antigen receptors to recognize and destroy cancer cells. Studies have shown increasing success rates with this therapy, achieving complete remissions in 80% of patients with advanced-stage leukemia or lymphoma. One therapeutic target against ALL-B is the CD22 glycoprotein, a cell surface marker protein for B cells. The hLL2/Epratuzumab antibody is an antibody that binds to the CD22 protein and is utilized in the treatment of non-Hodgkin lymphoma and ALL-B. Molecular dynamics (MD) simulation is a technique used to study molecular interactions at the atomic level. These simulations allow for a better understanding of molecule behavior and can aid in the design of new drugs. In the case of Epratuzumab and CD22, MD simulation can help elucidate how the interactions between these molecules occur and how modifications in CD22's N-glycosylations can affect this interaction. Also, the size and composition of N-glycosylations can significantly alter the affinity of Epratuzumab for CD22. Thus, different structural forms of CD22 (CD22-1g and CD22-6g) were created, encompassing the extracellular D1, D2 and D3 domains, differing in the presence or absence of N-glycosylations in the CD22 structure, for simulation in interaction with the native scFv of Epratuzumab. This study analyzed the interactions between scFv-Epratuzumab and the domains of CD22-6g and CD22-1g through MD simulations. Results revealed that the domains of scFvEpratuzumab and CD22-6g quickly reached equilibrium, while the D1 domain of CD22-1g exhibited larger structural variability before reaching equilibrium. Cluster analysis identified the most representative configurations of the structures. Additionally, glycosylations in the D2 domain of CD22-6g were considered significant for the overall attractiveness between the scFv and CD22. The CDRs CDRH2 and CDRL1 of scFv-Epratuzumab demonstrated a higher affinity for the domains of CD22. The findings contribute to understanding the interactions between scFv-Epratuzumab and CD22-6g/CD22-1g, highlighting the importance of glycosylations and providing new insights for proposing new mutations in this scFv to enhance its affinity with CD22.