CD20×CD3 Bispecific Antibodies in B-NHL: A Review of Translational Science, Pharmacokinetics, Pharmacodynamics, and Dose Strategy in Clinical Research

Abstract

Despite advancements in treatment for B-cell non-Hodgkin lymphoma (B-NHL) in recent decades, many patients still relapse or are refractory to treatment, which represents a high unmet medical need. Novel CD20 × CD3 T-cell-engaging bispecific antibodies (bsAbs) have created a new paradigm for the treatment of B-NHL. Pivotal studies of four CD20 × CD3 bsAbs, mosunetuzumab, glofitamab, epcoritamab, and odronextamab, as monotherapy, have demonstrated robust responses with generally manageable safety profiles in patients with relapsed or refractory follicular lymphoma and diffuse large B-cell lymphoma after ≥ 2 lines of systemic therapy. These agents have presented unique challenges (e.g., cytokine release syndrome [CRS]), which have required different strategies to overcome. This review provides a comprehensive overview of the clinical development of these four CD20 × CD3 bsAbs that have been investigated for the treatment of B-NHL, with a specific focus on translational assessments to select starting doses in first-in-human studies, management of CRS, application of modeling and simulation approaches to aid dose escalation and optimization/selection, and strategies used in the design of phase I-III clinical trials. By highlighting learnings and experiences from these four bsAbs assessed, which have not been summarized collectively elsewhere, we aim to promote more efficient study design for novel bsAbs in B-NHL in the future.

Keywords: clinical trials; dose; drug development; exposure response; hematology; model‐based drug development; monoclonal antibodies; oncology; pharmacodynamics; pharmacokinetics.

FIGURE 1

Schematic representation of the clinical development pathways for mosunetuzumab, glofitamab, epcoritamab, and odronextamab. Start dates of studies refer to the dates on which the first participant was enrolled (actual date) or was expected to enroll (expected date), as reported on ClinicalTrials.gov (accessed November 20, 2024) and summarized in Table S1. Studies in the ≥ 1 L rows include those whose inclusion criteria allowed patients with a minimum of no prior lines of therapy; those in the ≥ 2 L rows had criteria that allowed patients with a minimum of one prior line of therapy, and those in the ≥ 3 L rows had criteria that allowed patients with a minimum of two prior lines of therapy. Ph III studies represented by a star symbol are those sponsored by the pharmaceutical company responsible for each molecule. 1 L, first‐line; aNHL, aggressive non‐Hodgkin lymphoma; BCL, B‐cell lymphoma; B‐NHL, B‐cell non‐Hodgkin lymphoma; combo, combination therapy; DLBCL, diffuse large B‐cell lymphoma; EU, European Union; Fc, fragment crystallizable; FIH, first‐in‐human; FL, follicular lymphoma; iNHL, indolent non‐Hodgkin lymphoma; IV, intravenous; LBCL, large B‐cell lymphoma; mono, monotherapy; NHL, non‐Hodgkin lymphoma; NS, (route of administration) not specified; Ph, phase; R/R, relapsed/refractory; SC, subcutaneous; t‐iNHL, transformed indolent non‐Hodgkin lymphoma; US, United States; ≥ 1/2/3 L, first‐/second‐/third‐line plus therapy.