Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 9, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2117402119
Keywords
antibodies; chemical biology; biologics; chemically induced dimerization
Categories
Funding
- National Cancer Institute of the NIH [R43CA240063]
- NIH NCI [CA191018]
- NIH [R35GM122451, GM097316]
- Harry and Dianna Hind Professorship
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Monoclonal antibodies with antigen specificity and long serum half-life are crucial in modern therapeutics. We have developed a technology for switchable assembly of functional antibody complexes using chemically induced dimerization domains, allowing control of the antibody's intended function in vivo by modulating the dose of a small molecule.
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 halflife, and activation of bispecific, T cell-engaging antibodies.
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