A conformation-selective monoclonal antibody against a small molecule-stabilised signalling-deficient form of TNF

Daniel J. Lightwood (), Rebecca J. Munro, John Porter, David McMillan, Bruce Carrington, Alison Turner, Anthony Scott-Tucker, Elizabeth S. Hickford, Antje Schmidt, David Fox, Alison Maloney, Tom Ceska, Tim Bourne, James O’Connell and Alastair D. G. Lawson
Additional contact information
Daniel J. Lightwood: UCB Pharma
Rebecca J. Munro: UCB Pharma
John Porter: UCB Pharma
David McMillan: UCB Pharma
Bruce Carrington: UCB Pharma
Alison Turner: UCB Pharma
Anthony Scott-Tucker: UCB Pharma
Elizabeth S. Hickford: UCB Pharma
Antje Schmidt: UCB Pharma
David Fox: UCB Pharma
Alison Maloney: UCB Pharma
Tom Ceska: UCB Pharma
Tim Bourne: UCB Pharma
James O’Connell: UCB Pharma
Alastair D. G. Lawson: UCB Pharma

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: Abstract We have recently described the development of a series of small-molecule inhibitors of human tumour necrosis factor (TNF) that stabilise an open, asymmetric, signalling-deficient form of the soluble TNF trimer. Here, we describe the generation, characterisation, and utility of a monoclonal antibody that selectively binds with high affinity to the asymmetric TNF trimer–small molecule complex. The antibody helps to define the molecular dynamics of the apo TNF trimer, reveals the mode of action and specificity of the small molecule inhibitors, acts as a chaperone in solving the human TNF–TNFR1 complex crystal structure, and facilitates the measurement of small molecule target occupancy in complex biological samples. We believe this work defines a role for monoclonal antibodies as tools to facilitate the discovery and development of small-molecule inhibitors of protein–protein interactions.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20825-6

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DOI: 10.1038/s41467-020-20825-6

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