The Serum Protein Transthyretin As a Platform for Dimerization and Tetramerization of Antibodies and Fab Fragments to Enable Target Clustering

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2020 Jun 11

PMID 32518163

Citations 1

Authors

Kenneth W Walker

Ian N Foltz

Tina Wang

Hossein Salimi-Moosavi

Julie M Bailis

Fei Lee

Phillip An

Stephen Smith

Richele Bruno

Zhulun Wang

Affiliations

Soon will be listed here.

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.

Citing Articles

Evaluation of the Higher Order Structure of Biotherapeutics Embedded in Hydrogels for Bioprinting and Drug Release.

Rizzo D, Cerofolini L, Perez-Rafols A, Giuntini S, Baroni F, Ravera E Anal Chem. 2021; 93(32):11208-11214.

PMID: 34339178 PMC: 8382223. DOI: 10.1021/acs.analchem.1c01850.

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