Authors: Agnes Banaszek, Thomas G. P. Bumm, Boris Nowotny, Maria Geis, Kim Jacob, Matthias Wölfl, Johannes Trebing, Kirstin Kucka, Dina Kouhestani, Tea Gogishvili, Bastian Krenz, Justina Lutz, Leo Rasche, Dirk Hönemann, Hannes Neuweiler, Julia C. Heiby, Ralf C. Bargou, Harald Wajant, Hermann Einsele, Gert Riethmüller, Gernot Stuhler
Published: 2019-11-26
DOI: 10.1038/s41467-019-13196-0
Source: Full article
AbstractT 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 (VL) or variable heavy (VH) 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.