CD20-directed antibody-drug conjugates in non-hodgkin lymphoma: translating preclinical promise into clinical reality

Despite the paradigm-shifting success of anti-CD20 monoclonal antibodies like rituximab, limitations such as antigen loss, impaired host immune effector functions, and resistance remain key challenges in non-Hodgkin lymphoma (NHL). Antibody-drug conjugates (ADCs) targeting CD20 represent a promising strategy to overcome these limitations by delivering potent cytotoxic payloads directly to malignant B cells. However, CD20's slow internalization rate poses a unique challenge for conventional ADC design. This review provides a focused analysis of clinical- and preclinical-stage CD20-directed ADCs, examining how innovative design strategies-including cleavable linkers, membrane-permeable payloads (e.g., MMAE), site-specific conjugation, and novel platforms such as extracellular drug conjugates (EDCs) and immune-stimulating antibody conjugates (ISACs)-are being developed to circumvent the internalization barrier. We critically analyze clinical progress (MRG001 and TRS005), preclinical innovations, and future directions for translating the promise of CD20-directed ADCs into clinical reality for patients with NHL.