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Nanoscale spatial dependence of avidity in an IgG1 antibody

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Antibodies are secreted proteins that are crucial to recognition of pathogens by the immune system and are also efficient pharmaceuticals. The affinity and specificity of target recognition can increase remarkably through avidity effects, when the antibody can bind a multivalent antigen through more than one epitope simultaneously. A key goal of antibody engineering is thus to optimize avidity, but little is known about the nanoscale spatial dependence of avidity in antibodies. Here, we develop a set of anti-parallel coiled-coils spanning from 7 to 20 nm and validate their structure using biophysical techniques. We use the coiled-coils to control the spacing between two epitopes, and measure how antigen spacing affects the stability of the bivalent antibody:antigen complex. We find a maximal avidity enhancement at a spacing of 13 nm. In contrast to recent studies, we find the avidity to be relatively insensitive to epitope spacing near the avidity maximum as long as it is within the spatial tolerance of the antibody. We thus only see a ~ twofold variation of avidity in the range from 7 to 20 nm. The coiled-coil systems developed here may prove a useful protein nanocaliper for profiling the spatial tolerance and avidity profile of bispecific antibodies.

TidsskriftScientific Reports
StatusUdgivet - jun. 2021

Bibliografisk note

Funding Information:
Funding was provided by Independent Research Fund Denmark - (DFF-FTP) (Grant No. 7017-00024B) and Villum Fonden (Grant No. 13165).

Funding Information:
We would like to thank Cy M. Jeffries for the assistance in using the Petra III beamline, Nykola Jones for assistance in SR-CD experiments, and Michael Ploug and Gregers R. Andersen for critical comments to the manuscript. This work was funded by a grants from the Villum Young Investigator program, The Independent Research Fund Denmark and the Marie Curie COFUND program. Access to the SR-CD beam line was granted by ISA, Centre for Storage Ring Facilities, Aarhus at Aarhus University.

Publisher Copyright:
© 2021, The Author(s).

Copyright 2021 Elsevier B.V., All rights reserved.

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