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

Autor:	Lightwood DJ; UCB Pharma, 208 Bath Road, Slough, SL1 3WE, UK. Daniel.Lightwood@ucb.com., Munro RJ; UCB Pharma, 208 Bath Road, Slough, SL1 3WE, UK., Porter J; UCB Pharma, 208 Bath Road, Slough, SL1 3WE, UK., McMillan D; UCB Pharma, 208 Bath Road, Slough, SL1 3WE, UK., Carrington B; UCB Pharma, 208 Bath Road, Slough, SL1 3WE, UK., Turner A; UCB Pharma, 208 Bath Road, Slough, SL1 3WE, UK., Scott-Tucker A; UCB Pharma, 208 Bath Road, Slough, SL1 3WE, UK., Hickford ES; UCB Pharma, 208 Bath Road, Slough, SL1 3WE, UK., Schmidt A; UCB Pharma, 208 Bath Road, Slough, SL1 3WE, UK., Fox D 3rd; UCB Pharma, 7869 NE Day Road W, Bainbridge Island, WA, 98110, USA., Maloney A; UCB Pharma, 208 Bath Road, Slough, SL1 3WE, UK., Ceska T; UCB Pharma, 208 Bath Road, Slough, SL1 3WE, UK., Bourne T; UCB Pharma, 208 Bath Road, Slough, SL1 3WE, UK., O'Connell J; UCB Pharma, 208 Bath Road, Slough, SL1 3WE, UK., Lawson ADG; UCB Pharma, 208 Bath Road, Slough, SL1 3WE, UK.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2021 Jan 25; Vol. 12 (1), pp. 583. Date of Electronic Publication: 2021 Jan 25.
DOI:	10.1038/s41467-020-20825-6
Abstrakt:	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.
Databáze:	MEDLINE
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