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  • The serum protein transthyretin as a platform for dimerization and tetramerization of antibodies and Fab fragments to enable target clustering.

The serum protein transthyretin as a platform for dimerization and tetramerization of antibodies and Fab fragments to enable target clustering.

The Journal of biological chemistry (2020-06-11)
Kenneth W Walker, Ian N Foltz, Tina Wang, Hossein Salimi-Moosavi, Julie M Bailis, Fei Lee, Phillip An, Stephen Smith, Richele Bruno, Zhulun Wang
ABSTRACT

Transthyretin (TTR) is an abundant homotetrameric serum protein and was selected here for engineering higher-valency molecules because of its compact size, simple structure, and natural propensity to tetramerize. To demonstrate this utility, we fused TTR to the C terminus of conatumumab, an antibody that targets tumor necrosis factor-related apoptosis-inducing ligand receptor 2, as heavy chains to form antibody dimers and Fab heavy chains to form Fab tetramers. Moreover, we used constant heavy domain 3 heterodimerization substitutions to create TTR-mediated conatumumab tetramers. The conatumumab-TTR fusions displayed substantially enhanced potency in cell-based assays, as well as in murine tumor xenograft models. We conclude that antibody-TTR fusions may provide a powerful platform for multimerizing antibody and Fab fragments to enhance the capabilities of human therapeutics that benefit from target clustering and higher-order antigen-binding valency.

MATERIALS
Product Number
Brand
Product Description

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