Aiming to precisely target tumors, Banaszek and Bumm et al. designed a tri-specific antibody split into two halves (hemibodies) – one composed of a VH domain of anti-CD3 fused to an scFv targeting one antigen, and the other containing the VL domain of anti-CD3 fused to an scFv targeting a second antigen. The two hemibodies associated and reconstituted the CD3-binding site only upon binding both target antigens on the same cell. Unlike BiTEs, the hemibodies stimulated donor T cells to lyse double-positive, but not single-positive, leukemia and breast cancer cells in vitro and in NSG mice, leading to prolonged survival.
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.
Author Info: (1) University Clinic Wurzburg, Department of Internal Medicine II, Hematology and Oncology, Wurzburg, Germany. (2) University Clinic Wurzburg, Department of Internal Medicine II,
Author Info: (1) University Clinic Wurzburg, Department of Internal Medicine II, Hematology and Oncology, Wurzburg, Germany. (2) University Clinic Wurzburg, Department of Internal Medicine II, Hematology and Oncology, Wurzburg, Germany. (3) University Clinic Wurzburg, Department of Internal Medicine II, Hematology and Oncology, Wurzburg, Germany. (4) University Clinic Wurzburg, Department of Internal Medicine II, Hematology and Oncology, Wurzburg, Germany. (5) University Clinic Wurzburg, Department of Internal Medicine II, Hematology and Oncology, Wurzburg, Germany. (6) University Clinic Wurzburg, Children's Hospital, Pediatric Oncology, Hematology and Stem Cell Transplantation, Wurzburg, Germany. (7) University Clinic Wurzburg, Department of Internal Medicine II, Division of Molecular Internal Medicine, Wurzburg, Germany. (8) University Clinic Wurzburg, Department of Internal Medicine II, Division of Molecular Internal Medicine, Wurzburg, Germany. (9) University Clinic Wurzburg, Department of Internal Medicine II, Hematology and Oncology, Wurzburg, Germany. (10) University Clinic Wurzburg, Department of Internal Medicine II, Hematology and Oncology, Wurzburg, Germany. (11) University Clinic Wurzburg, Department of Internal Medicine II, Hematology and Oncology, Wurzburg, Germany. (12) University Clinic Wurzburg, Department of Internal Medicine II, Hematology and Oncology, Wurzburg, Germany. (13) University Clinic Wurzburg, Department of Internal Medicine II, Hematology and Oncology, Wurzburg, Germany. (14) University Clinic Wurzburg, Department of Internal Medicine II, Hematology and Oncology, Wurzburg, Germany. (15) Department of Biotechnology and Biophysics, University Wurzburg, Wurzburg, Germany. (16) Department of Biotechnology and Biophysics, University Wurzburg, Wurzburg, Germany. (17) University Clinic Wurzburg, Department of Internal Medicine II, Hematology and Oncology, Wurzburg, Germany. Comprehensive Cancer Center Mainfranken, Universitatsklinikum, Wurzburg, Germany. (18) University Clinic Wurzburg, Department of Internal Medicine II, Division of Molecular Internal Medicine, Wurzburg, Germany. (19) University Clinic Wurzburg, Department of Internal Medicine II, Hematology and Oncology, Wurzburg, Germany. (20) Ludwig-Maximilians-University, Institute for Immunology, Munich, Germany. (21) University Clinic Wurzburg, Department of Internal Medicine II, Hematology and Oncology, Wurzburg, Germany. stuhler_g@ukw.de.
