A biparatopic agonistic antibody that mimics fibroblast growth factor 21 ligand activity

The Journal of Biological Chemistry
Sally Yu ShiYang Li

Abstract

Bispecific antibodies have become important formats for therapeutic discovery. They allow for potential synergy by simultaneously engaging two separate targets and enable new functions that are not possible to achieve by using a combination of two monospecific antibodies. Antagonistic antibodies dominate drug discovery today, but only a limited number of agonistic antibodies (i.e. those that activate receptor signaling) have been described. For receptors formed by two components, engaging both of these components simultaneously may be required for agonistic signaling. As such, bispecific antibodies may be particularly useful in activating multicomponent receptor complexes. Here, we describe a biparatopic (i.e. targeting two different epitopes on the same target) format that can activate the endocrine fibroblast growth factor (FGF) 21 receptor (FGFR) complex containing β-Klotho and FGFR1c. This format was constructed by grafting two different antigen-specific VH domains onto the VH and VL positions of an IgG, yielding a tetravalent binder with two potential geometries, a close and a distant, between the two paratopes. Our results revealed that the biparatopic molecule provides activities that are not observed with each paratope ...Continue Reading

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Citations

Jan 23, 2019·Frontiers in Immunology·Starlynn C ClarkeShelley Force Aldred
Aug 9, 2020·Nature Reviews. Endocrinology·Leiluo GengAimin Xu
Jun 17, 2020·Computational and Structural Biotechnology Journal·Steffen DickopfUlrich Brinkmann
Jun 17, 2020·Computational and Structural Biotechnology Journal·Guy J GeorgesSabine Imhof-Jung
Nov 12, 2020·Antibodies·Anusuya RamasubramanianPartha S Chowdhury
Feb 17, 2020·Antibody Therapeutics·Siwei NieJijie Gu
May 16, 2021·Protein Engineering, Design & Selection : PEDS·Kasandra Bélanger, Jamshid Tanha

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Methods Mentioned

BETA
transgenic
bio-layer interferometry
biosensor
biosensors
transfection
bio-layer
fluorescence activated cell sorting
PCR
FACS

Software Mentioned

GraphPad Prism
GraphPad
ForteBio Octet Data Analysis

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