On-target restoration of a split T cell-engaging antibody for precision immunotherapy

Banaszek, Agnes; Bumm, Thomas G. P.; Nowotny, Boris; Geis, Maria; Jacob, Kim; Woelfl, Matthias; Trebing, Johannes; Kucka, Kirstin; Kouhestani, Dina; Gogishvili, Tea; Krenz, Bastian; Lutz, Justina; Rasche, Leo; Hoenemann, Dirk; Neuweiler, Hannes; Heiby, Julia C.; Bargou, Ralf C.; Wajant, Harald; Einsele, Hermann; Riethmüller, Gert and Stuhler, Gernot (2019): On-target restoration of a split T cell-engaging antibody for precision immunotherapy. In: Nature Communications, Vol. 10, 5387

Abstract

T cell-engaging immunotherapies are changing the landscape of current cancer care. However, suitable target antigens are scarce, restricting these strategies to very few tumor types. Here, we report on a T cell-engaging antibody derivative that comes in two complementary halves and addresses antigen combinations instead of single molecules. Each half, now coined hemibody, contains an antigen-specific single-chain variable fragment (scFv) fused to either the variable light (V-L) or variable heavy (V-H) chain domain of an anti-CD3 antibody. When the two hemibodies simultaneously bind their respective antigens on a single cell, they align and reconstitute the original CD3-binding site to engage T cells. Employing preclinical models for aggressive leukemia and breast cancer, we show that by the combinatorial nature of this approach, T lymphocytes exclusively eliminate dual antigen-positive cells while sparing single positive bystanders. This allows for precision targeting of cancers not amenable to current immunotherapies.

• Item Type: Journal article
• Faculties: Medicine
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 2041-1723
• Language: English