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Clin Cancer Res. 2018 May 1. doi: 10.1158/1078-0432.CCR-18-0455. [Epub ahead of print]

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

Author information

1
Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, pRED, Zurich, Switzerland. marina.bacac@roche.com pablo.umana@roche.com.
2
Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, pRED, Zurich, Switzerland.
3
Roche Innovation Center Basel, Roche Pharmaceutical Research and Early Development, pRED, Basel, Switzerland.
4
Roche Innovation Center Munich, Roche Pharmaceutical Research and Early Development, pRED, Munich, Germany.
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Contributed equally

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); 1-13. ©2018 AACR.See related commentary by Prakash and Diefenbach, p. 4355.

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