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

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 and Gernot Stuhler ()
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Agnes Banaszek: Department of Internal Medicine II, Hematology and Oncology
Thomas G. P. Bumm: Department of Internal Medicine II, Hematology and Oncology
Boris Nowotny: Department of Internal Medicine II, Hematology and Oncology
Maria Geis: Department of Internal Medicine II, Hematology and Oncology
Kim Jacob: Department of Internal Medicine II, Hematology and Oncology
Matthias Wölfl: Pediatric Oncology, Hematology and Stem Cell Transplantation
Johannes Trebing: Division of Molecular Internal Medicine
Kirstin Kucka: Division of Molecular Internal Medicine
Dina Kouhestani: Department of Internal Medicine II, Hematology and Oncology
Tea Gogishvili: Department of Internal Medicine II, Hematology and Oncology
Bastian Krenz: Department of Internal Medicine II, Hematology and Oncology
Justina Lutz: Department of Internal Medicine II, Hematology and Oncology
Leo Rasche: Department of Internal Medicine II, Hematology and Oncology
Dirk Hönemann: Department of Internal Medicine II, Hematology and Oncology
Hannes Neuweiler: University Würzburg
Julia C. Heiby: University Würzburg
Ralf C. Bargou: Department of Internal Medicine II, Hematology and Oncology
Harald Wajant: Division of Molecular Internal Medicine
Hermann Einsele: Department of Internal Medicine II, Hematology and Oncology
Gert Riethmüller: Institute for Immunology
Gernot Stuhler: Department of Internal Medicine II, Hematology and Oncology

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: 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 (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.

Date: 2019
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DOI: 10.1038/s41467-019-13196-0

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