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Article

Novel Selection Approaches to Identify Antibodies Targeting Neoepitopes on the C5b6 Intermediate Complex to Inhibit Membrane Attack Complex Formation

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Biopharm Discovery, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK
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Screening, Profiling and Mechanistic Biology, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK
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Immunology Research Unit, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK
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Clinical Pharmacology & Experimental Medicine, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK
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Systems Modelling and Translational Biology, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK
*
Author to whom correspondence should be addressed.
These two authors contributed equally.
Current affiliations: AstraZeneca PLC 1 Francis Crick Avenue Cambridge Biomedical Campus, Cambridge CB2 0AA, UK.
§
Current affiliations: Translation and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE1 7RU, UK.
Current affiliations: Gyroscope Therapeutics, Stevenage Bio-Science Catalyst, Gunnels Wood Rd., Stevenage SG1 2FX, UK.
Academic Editor: Philippe Billiald
Received: 20 July 2021 / Revised: 18 August 2021 / Accepted: 25 September 2021 / Published: 12 October 2021
The terminal pathway of complement is implicated in the pathology of multiple diseases and its inhibition is, therefore, an attractive therapeutic proposition. The practicalities of inhibiting this pathway, however, are challenging, as highlighted by the very few molecules in the clinic. The proteins are highly abundant, and assembly is mediated by high-affinity protein–protein interactions. One strategy is to target neoepitopes that are present transiently and only exist on active or intermediate complexes but not on the abundant native proteins. Here, we describe an antibody discovery campaign that generated neoepitope-specific mAbs against the C5b6 complex, a stable intermediate complex in terminal complement complex assembly. We used a highly diverse yeast-based antibody library of fully human IgGs to screen against soluble C5b6 antigen and successfully identified C5b6 neoepitope-specific antibodies. These antibodies were diverse, showed good binding to C5b6, and inhibited membrane attack complex (MAC) formation in a solution-based assay. However, when tested in a more physiologically relevant membrane-based assay these antibodies failed to inhibit MAC formation. Our data highlight the feasibility of identifying neoepitope binding mAbs, but also the technical challenges associated with the identification of functionally relevant, neoepitope-specific inhibitors of the terminal pathway. View Full-Text
Keywords: therapeutic antibody; complement; antibody discovery; neoepitope; terminal pathway therapeutic antibody; complement; antibody discovery; neoepitope; terminal pathway
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MDPI and ACS Style

Stach, L.; Dinley, E.K.H.; Tournier, N.; Bingham, R.P.; Gormley, D.A.; Bramhall, J.L.; Taylor, A.; Clarkson, J.E.; Welbeck, K.A.; Harris, C.L.; Feeney, M.; Hughes, J.P.; Sepp, A.; Batuwangala, T.D.; Kitchen, S.J.; Nichols, E.-M. Novel Selection Approaches to Identify Antibodies Targeting Neoepitopes on the C5b6 Intermediate Complex to Inhibit Membrane Attack Complex Formation. Antibodies 2021, 10, 39. https://0-doi-org.brum.beds.ac.uk/10.3390/antib10040039

AMA Style

Stach L, Dinley EKH, Tournier N, Bingham RP, Gormley DA, Bramhall JL, Taylor A, Clarkson JE, Welbeck KA, Harris CL, Feeney M, Hughes JP, Sepp A, Batuwangala TD, Kitchen SJ, Nichols E-M. Novel Selection Approaches to Identify Antibodies Targeting Neoepitopes on the C5b6 Intermediate Complex to Inhibit Membrane Attack Complex Formation. Antibodies. 2021; 10(4):39. https://0-doi-org.brum.beds.ac.uk/10.3390/antib10040039

Chicago/Turabian Style

Stach, Lasse, Emily K.H. Dinley, Nadia Tournier, Ryan P. Bingham, Darren A. Gormley, Jo L. Bramhall, Adam Taylor, Jane E. Clarkson, Katherine A. Welbeck, Claire L. Harris, Maria Feeney, Jane P. Hughes, Armin Sepp, Thil D. Batuwangala, Semra J. Kitchen, and Eva-Maria Nichols. 2021. "Novel Selection Approaches to Identify Antibodies Targeting Neoepitopes on the C5b6 Intermediate Complex to Inhibit Membrane Attack Complex Formation" Antibodies 10, no. 4: 39. https://0-doi-org.brum.beds.ac.uk/10.3390/antib10040039

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