1. A coiled-coil masking domain for selective activation of therapeutic antibodies.
- Author
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Trang VH, Zhang X, Yumul RC, Zeng W, Stone IJ, Wo SW, Dominguez MM, Cochran JH, Simmons JK, Ryan MC, Lyon RP, Senter PD, and Levengood MR
- Subjects
- Animals, Antibodies, Monoclonal chemistry, Cell Survival, Cytokines metabolism, HEK293 Cells, Humans, Immunoconjugates, Integrins metabolism, Mice, Models, Molecular, Protein Conformation, Protein Domains, Antibodies, Monoclonal therapeutic use, Neoplasms therapy
- Abstract
The use of monoclonal antibodies in cancer therapy is limited by their cross-reactivity to healthy tissue. Tumor targeting has been improved by generating masked antibodies that are selectively activated in the tumor microenvironment, but each such antibody necessitates a custom design. Here, we present a generalizable approach for masking the binding domains of antibodies with a heterodimeric coiled-coil domain that sterically occludes the complementarity-determining regions. On exposure to tumor-associated proteases, such as matrix metalloproteinases 2 and 9, the coiled-coil peptides are cleaved and antigen binding is restored. We test multiple coiled-coil formats and show that the optimized masking domain is broadly applicable to antibodies of interest. Our approach prevents anti-CD3-associated cytokine release in mice and substantially improves circulation half-life by protecting the antibody from an antigen sink. When applied to antibody-drug conjugates, our masked antibodies are preferentially unmasked at the tumor site and have increased anti-tumor efficacy compared with unmasked antibodies in mouse models of cancer.
- Published
- 2019
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