Preclinical discovery and clinical development of glofitamab in relapsed/ refractory large B-cell lymphomas

INTRODUCTION: Relapsed/refractory (R/R) large B-cell lymphoma (LBCL) remains a clinical challenge, particularly for patients with primary refractory or relapsed disease and ineligible for cellular therapies. T-cell engagers in the form of CD20xCD3 bispecific antibodies (BsAb) offer an effective 'off-the-shelf' therapy option that redirects endogenous T cells against malignant B cells. AREAS COVERED: This review summarizes the preclinical and translational development of glofitamab, a full-length 2:1 BsAb, focusing on R/R LBCL. The authors discuss the molecular design rationale, mechanism of action, and preclinical efficacy that enabled clinical translation. They review clinical development milestones across monotherapy and combination regimens in heavily pretreated R/R LBCL, activity after CAR T-cell therapy, and data supporting movement into earlier lines and strategies for older/unfit patients. This article is based on clinical trial reports and major trial registrations in B-cell lymphomas obtained via PubMed and ClinicalTrials.gov, covering literature published up to January 2026. EXPERT OPINION: Glofitamab provides clinically meaningful, time-limited treatment achieving disease control in patients who are ineligible for autologous HCT and/or CAR T-cell therapy and for those relapsing after CAR T-cell therapy. Future research will be needed on biomarker-guided sequencing, optimized toxicity/infection mitigation, and combination strategies that improve durable response rates.