Mantle Cell Lymphoma
Potential Use of Bispecific Antibodies Designed to Target CD20 on B Cells and CD3 on T Cells
T-cell bispecific (TCB) antibodies redirect the activity of CD3+ T cells against malignant CD20+ B cells by binding to both cell types, resulting in the killing of B cells and tumor regression. Our featured expert reviews the potential role of TCB antibodies in the treatment of mantle cell lymphoma (MCL).
Neumann M. and Mildred E. Harris Professor
“The current data on investigational CD20-TCB antibodies are limited, but their activity in patients with aggressive B-NHL subtypes who have failed multiple other therapies is intriguing, and a number of CRs have been observed.”
Sustained durable responses to standard-of-care treatments are elusive in several types of non-Hodgkin lymphoma (NHL), including MCL. TCB antibodies are a new class of disease-targeting agents that has been shown to promote the activation of a patient’s own T cells to attack and kill malignant cells. The current data on investigational CD20-TCB antibodies are limited, but their activity in patients with aggressive B-cell non-Hodgkin lymphoma (B-NHL) subtypes who have failed multiple other therapies is intriguing, and a number of complete responses (CRs) have been observed. CD3 is part of the T-cell receptor complex on the surface of T cells. The binding of a TCB antibody to CD20 on malignant B cells and CD3 on T cells engages T cells and redirects their activity against B cells. CD20-TCB (also known as RO7082859, RG6026) is a novel TCB antibody with immunoglobulin G–like pharmacokinetic properties and a unique “2:1” structure with 2 CD20 binders and 1 CD3 binder. The CD20-binding Fabs were derived from obinutuzumab. In preclinical studies, this unique configuration showed increased tumor antigen avidity, T-cell activation, and tumor cell killing, as compared with several other TCB molecular formats.
A recent multicenter phase 1 trial examined the outcomes of single-agent CD20-TCB in 64 patients: 47 with aggressive relapsed/refractory B-NHL and 17 with indolent relapsed/refractory follicular lymphoma. A single dose of 1000 mg obinutuzumab pretreatment was given 7 days prior to the start of CD20-TCB to debulk peripheral B cells and reduce systemic cytokine release. A total of 55 patients had at least 1 post-baseline response assessment and were eligible for efficacy analysis. At doses of 300 µg or higher (n=29), the overall response rate and CR rate by investigator assessment was 38% and 24%, respectively (follicular lymphoma: 3/5 patients and 2/5 patients, respectively; aggressive B-NHL: 8/24 patients and 5/24 patients, respectively), and all CRs were sustained with a median follow-up of 96 days (range, 26-152). The most commonly reported adverse events among patients in the study were pyrexia, neutropenia, and cytokine release syndrome. The responses were observed across various NHL subtypes and prognostic factors (eg, prior lines of therapy, refractoriness to the most recent line of therapy, tumor burden).
Depending on the production method and structure, TCB antibodies vary in the number of antigen-binding sites, geometry, serum half-lives, and effector functions. The design of future TCB antibodies will likely include the ability to bind 2 or more tumor antigens in combination with the attraction of T cells and assistant cells into the immunological synapse. Of particular importance are the increasing specificity and sensitivity of TCB antibodies, as well as reducing cytotoxicity to nontumor cells.
Bacac M, Umaña P, Herter S, et al. CD20 Tcb (RG6026), a novel “2:1” T cell bispecific antibody for the treatment of B cell malignancies. Blood. 2016;128:1836.
Duell J, Lammers PE, Djuretic I, et al. Bispecific antibodies in the treatment of hematologic malignancies. Clin Pharmacol Ther. 2019 Feb 15. doi: 10.1002/cpt.1396.
Hutchings M, Iacoboni G, Morschhauser F, et al. CD20-Tcb (RG6026), a novel “2:1” format T-cell-engaging bispecific antibody, induces complete remissions in relapsed/refractory B-cell non-Hodgkin’s lymphoma: preliminary results from a phase I first in human trial. Blood. 2018;132:226. doi: https://doi.org/10.1182/blood-2018-99-110207.