Switchable assembly and function of antibody complexes in vivo using a small molecule
| Autor: | Alexander J. Martinko, Erin F. Simonds, Suchitra Prasad, Alberto Ponce, Colton J. Bracken, Junnian Wei, Yung-Hua Wang, Tiffany-Lynn Chow, Zhong Huang, Michael J. Evans, James A. Wells, Zachary B. Hill |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Proceedings of the National Academy of Sciences. 119 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.2117402119 |
| Popis: | The antigen specificity and long serum half-life of monoclonal antibodies have made them a critical part of modern therapeutics. These properties have been coopted in a number of synthetic formats, such as antibody-drug conjugates, bispecific antibodies, or Fc-fusion proteins to generate novel biologic drug modalities. Historically, these new therapies have been generated by covalently linking multiple molecular moieties through chemical or genetic methods. This irreversible fusion of different components means that the function of the molecule is static, as determined by the structure. Here, we report the development of a technology for switchable assembly of functional antibody complexes using chemically induced dimerization domains. This approach enables control of the antibody's intended function in vivo by modulating the dose of a small molecule. We demonstrate this switchable assembly across three therapeutically relevant functionalities in vivo, including localization of a radionuclide-conjugated antibody to an antigen-positive tumor, extension of a cytokine's half-life, and activation of bispecific, T cell-engaging antibodies. |
| Databáze: | OpenAIRE |
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