CD3/CD20-Targeted Bispecific Antibody (Adimab)

Non-Hodgkin's Lymphoma (NHL) remains a significant challenge in hematology, with chemotherapy and radiation therapy as conventional treatment options, albeit with limitations such as adverse effects. Immunotherapy, particularly bispecific antibodies (BsAbs) T cell engagers (TCEs), has emerged as a promising approach. Despite their potential, TCEs pose challenges, including adverse events like cytokine release syndrome. Understanding the structural details of TCEs and their interactions with target proteins is crucial for optimizing their therapeutic efficacy and toxicity. In this study, we further developed our protocol MCCS-Docker for protein-protein interactions and applied it to investigate the structural intricacies of CD3 interactions with therapeutic antibodies such as OKT3, UCHT1, Mosunetuzumab, Odronextumab, Glofitamab, and Epcoritamab using computational modeling techniques. Our analysis not only approved the effectiveness of our updated MCCS-Docker protocol but also revealed detailed binding interactions between the BsAbs and CD3, elucidating key residues of Tyrosine and Asparagine in the antibodies involved in the binding interface. Molecular dynamics simulations validated the stability of these interactions over time, confirming the reliability of the binding poses generated from docking studies. Overall, our study offered a novel method to predict critical residues in protein-protein interactions and enhanced the understanding of the structural determinants governing BsAb interactions with target proteins, offering valuable insights for designing and optimizing immunotherapeutic agents for NHL and related hematologic malignancies.

Follicular lymphoma (FL) is the most common subtype of indolent lymphoma. Survival outcomes for FL have improved since the introduction of anti-CD20 monoclonal antibodies, such as rituximab, and median overall survival has reached 15-20 years. However, FL is an incurable disease that subsequently progresses or relapses, and progression-free and overall survival tend to shorten with repeated relapses. For patients with limited-stage disease, radiation therapy is generally the treatment of choice and results in a median survival of approximately nearly 20 years. For advanced-stage patients with low tumor burden, watchful waiting continues to be the appropriate strategy at present. It remains unclear whether rituximab monotherapy might change this watchful waiting approach and result in a benefit from early intervention in patients with low tumor burden. For advanced-stage patients with high tumor burden, chemoimmunotherapy including rituximab or obinutuzumab followed by maintenance therapy is the standard treatment. For relapsed or refractory patients, treatment options such as chemoimmunotherapy, lenalidomide-rituximab, tazemetostat, chimeric antigen receptor T-cell therapies, and CD3/CD20 bispecific antibodies are available or in development. This review presents current standard treatments, recent advances, and future perspectives on the management of FL.