CD20-TCB with Obinutuzumab Pretreatment as Next-Generation Treatment of Hematologic Malignancies.

Abstract

Purpose: Despite promising clinical activity, T-cell-engaging therapies including T-cell bispecific antibodies (TCB) are associated with severe side effects requiring the use of step-up-dosing (SUD) regimens to mitigate safety. Here, we present a next-generation CD20-targeting TCB (CD20-TCB) with significantly higher potency and a novel approach enabling safer administration of such potent drug.Experimental Design: We developed CD20-TCB based on the 2:1 TCB molecular format and characterized its activity preclinically. We also applied a single administration of obinutuzumab (Gazyva pretreatment, Gpt; Genentech/Roche) prior to the first infusion of CD20-TCB as a way to safely administer such a potent drug.Results: CD20-TCB is associated with a long half-life and high potency enabled by high-avidity bivalent binding to CD20 and head-to-tail orientation of B- and T-cell-binding domains in a 2:1 molecular format. CD20-TCB displays considerably higher potency than other CD20-TCB antibodies in clinical development and is efficacious on tumor cells expressing low levels of CD20. CD20-TCB also displays potent activity in primary tumor samples with low effector:target ratios. In vivo, CD20-TCB regresses established tumors of aggressive lymphoma models. Gpt enables profound B-cell depletion in peripheral blood and secondary lymphoid organs and reduces T-cell activation and cytokine release in the peripheral blood, thus increasing the safety of CD20-TCB administration. Gpt is more efficacious and safer than SUD.Conclusions: CD20-TCB and Gpt represent a potent and safer approach for treatment of lymphoma patients and are currently being evaluated in phase I, multicenter study in patients with relapsed/refractory non-Hodgkin lymphoma (NCT03075696). Clin Cancer Res; 24(19); 4785-97. ©2018 AACR See related commentary by Prakash and Diefenbach, p. 4631.

• Authors: Marina Bacac, Sara Colombetti, Sylvia Herter, Johannes Sam, Mario Perro, Stanford Chen, Roberta Bianchi, Marine Richard, Anne Schoenle, Valeria Nicolini, Sarah Diggelmann, Florian Limani, Ramona Schlenker, Tamara Hüsser, Wolfgang Richter, Katharine Bray-French, Heather Hinton, Anna Maria Giusti, Anne Freimoser-Grundschober, Laurent Lariviere, Christiane Neumann, Christian Klein, Pablo Umaña
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 24 Issue 19 Pg. 4785-4797 (10 01 2018) ISSN: 1557-3265 [Electronic] United States
• PMID: 29716920 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Antibodies, Bispecific
• Antibodies, Monoclonal, Humanized
• Antigens, CD20
• Rituximab
• obinutuzumab

Topics

• Animals
• Antibodies, Bispecific (administration & dosage)
• Antibodies, Monoclonal, Humanized (administration & dosage)
• Antigens, CD20 (genetics)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Cell Line, Tumor
• Disease Models, Animal
• Gene Expression Regulation, Neoplastic (drug effects)
• Hematologic Neoplasms (drug therapy, immunology, pathology)
• Humans
• Macaca fascicularis
• Mice
• Rituximab (administration & dosage)
• T-Lymphocytes (drug effects, immunology)