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标题：Switchable assembly and function of antibody complexes in vivo using a small molecule
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作者：Alexander J. Martinko ; Erin F. Simonds ; Suchitra Prasad 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：9
DOI：10.1073/pnas.2117402119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance Reported here, we describe a molecular protein technology to enable switchable assembly of functional antibody complexes. This approach, which we call ligand-induced transient engagement (LITE), allows for control of an antibody’s intended function in vivo through the dosing of a small-molecule activator. Chemical regulation of antibody therapeutics represents a treatment paradigm to provide physicians with precise control over the therapeutic activity of a biologic drug after it is administered to a patient. Ultimately, this approach may result in a new class of antibody drugs with improved efficacy and safety profiles and the potential to greatly impact the treatment of human disease. 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.
关键词：enantibodieschemical biologybiologicschemically induced dimerization