On-target restoration of a split T cell-engaging antibody for precision immunotherapy
| Autor: | Ralf C. Bargou, Gert Riethmüller, Kim Jacob, Matthias Wölfl, Thomas Bumm, Gernot Stuhler, Hermann Einsele, Maria Geis, Dina Kouhestani, Julia C. Heiby, Leo Rasche, Johannes Trebing, Tea Gogishvili, Boris Nowotny, Justina Lutz, Harald Wajant, Dirk Hönemann, Bastian Krenz, Hannes Neuweiler, Kirstin Kucka, Agnes Banaszek |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
CD3 Complex medicine.medical_treatment T-Lymphocytes Cell General Physics and Astronomy Lymphocyte Activation 0302 clinical medicine Antineoplastic Agents Immunological Mice Inbred NOD Precision Medicine lcsh:Science Mice Inbred BALB C Multidisciplinary biology Recombinant Proteins Leukemia medicine.anatomical_structure 030220 oncology & carcinogenesis Tumour immunology Female Immunotherapy Antibody Biotechnology T cell Science Breast Neoplasms General Biochemistry Genetics and Molecular Biology Article Antibodies 03 medical and health sciences Antigen Cell Line Tumor HLA-A2 Antigen medicine Animals Humans Binding Sites Cancer General Chemistry Bystander Effect Single-Domain Antibodies medicine.disease Xenograft Model Antitumor Assays 030104 developmental biology Cell culture biology.protein Cancer research lcsh:Q |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-10 (2019) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. The restriction of appropriate tumour-specific antigens is a current limitation for T cell-engaging immunotherapy. Here, the authors have designed a new system constituted by two halve antibodies, which engage T cells once binding to two different antigens, to specifically eliminate double positive cells in preclinical leukemia and breast cancer mouse models. |
| Databáze: | OpenAIRE |
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