Insights into the molecular basis of a bispecific antibody's target selectivity

MAbs
Yariv MazorWilliam Dall'Acqua

Abstract

Bispecific antibodies constitute a valuable class of therapeutics owing to their ability to bind 2 distinct targets. Dual targeting is thought to enhance biological efficacy, limit escape mechanisms, and increase target selectivity via a strong avidity effect mediated by concurrent binding to both antigens on the surface of the same cell. However, factors that regulate the extent of target selectivity are not well understood. We show that dual targeting alone is not sufficient to promote efficient target selectivity, and report the substantial roles played by the affinity of the individual arms, overall avidity and valence. More particularly, various monovalent bispecific IgGs composed of an anti-CD70 moiety paired with variants of the anti-CD4 mAb ibalizumab were tested for preferential binding and selective depletion of CD4(+)/CD70(+) T cells over cells expressing only one of the target antigens that resulted from antibody dependent cell-mediated cytotoxicity. Variants exhibiting reduced CD4 affinity showed a greater degree of target selectivity, while the overall efficacy of the bispecific molecule was not affected.

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Citations

Jan 11, 2017·MAbs·Ulrich Brinkmann, Roland E Kontermann
Dec 2, 2017·Nature Reviews. Drug Discovery·Paul J Carter, Greg A Lazar
Sep 24, 2019·Antibodies·Anja SchradeUlrich Brinkmann
Apr 16, 2020·Current Protocols in Immunology·Ling HuangGundo Diedrich
May 3, 2018·Protein Engineering, Design & Selection : PEDS·Xiufeng WuStephen J Demarest
Sep 30, 2020·Journal of Cancer Research and Clinical Oncology·Shuyu HuangAndrea van Elsas
Oct 20, 2018·Science Translational Medicine·Dionysos SlagaTeemu T Junttila
Apr 30, 2021·Frontiers in Immunology·Panagiotis F ChristopoulosEirik Sundlisæter
Dec 8, 2017·ACS Applied Materials & Interfaces·Fang PanJian Ren Lu
Dec 7, 2018·Journal of the American Chemical Society·Clifford M CsizmarCarston R Wagner
Feb 1, 2017·New Biotechnology·Simon KrahStefan Becker
Dec 8, 2021·Frontiers of Medicine·Hongyun ZhaoRui-Hua Xu

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Methods Mentioned

BETA
flow-cytometry
size exclusion chromatography
PCR
transfection
biosensors
flow cytometry
FACS
Assay

Software Mentioned

QuickCal
Octet384
Octet
BioAnalyzer
MACSQuant VYB
[UNK]
FlowJo
Tree Star

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