On-target restoration of a split T cell-engaging antibody for precision immunotherapy
| العنوان: | On-target restoration of a split T cell-engaging antibody for precision immunotherapy |
|---|---|
| المؤلفون: | 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 |
| المصدر: | Nature Communications, Vol 10, Iss 1, Pp 1-10 (2019) Nature Communications |
| بيانات النشر: | Nature Portfolio, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| اللغة: | English |
| تدمد: | 2041-1723 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b418ff6f6b9473f3d0d0f1d2b09a16ec https://doaj.org/article/2c0baf0c95d243a58f06fcb336d652c2 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b418ff6f6b9473f3d0d0f1d2b09a16ec |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
|---|