Stoyle, C. L., Stephens, P. E., Humphreys, D. P., Heywood, S., Cain, K. and Bulleid, N. J. (2017) IgG light chain-independent secretion of heavy chain dimers: consequence for therapeutic antibody production and design. Biochemical Journal, 474(18), pp. 3179-3188. (doi: 10.1042/BCJ20170342) (PMID:28784690) (PMCID:PMC5590090)
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Abstract
Rodent monoclonal antibodies with specificity towards important biological targets are developed for therapeutic use by a process of humanisation. This process involves the creation of molecules, which retain the specificity of the rodent antibody but contain predominantly human coding sequence. Here we show that some humanised heavy chains can fold, form dimers and be secreted even in the absence of light chain. Quality control of recombinant antibody assembly in vivo is thought to rely upon folding of the heavy chain CH1 domain. This domain acts as a switch for secretion, only folding upon interaction with the light chain CL domain. We show that the secreted heavy-chain dimers contain folded CH1 domains and contribute to the heterogeneity of antibody species secreted during the expression of therapeutic antibodies. This subversion of the normal quality control process is dependent upon the heavy chain variable domain, is prevalent with engineered antibodies and can occur when only the Fab fragments are expressed. This discovery will impact on the efficient production of both humanised antibodies as well as the design of novel antibody formats.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Bulleid, Professor Neil and Stoyle, Dr Chloe |
Authors: | Stoyle, C. L., Stephens, P. E., Humphreys, D. P., Heywood, S., Cain, K., and Bulleid, N. J. |
College/School: | College of Medical Veterinary and Life Sciences > School of Molecular Biosciences |
Journal Name: | Biochemical Journal |
Publisher: | Portland Press |
ISSN: | 0264-6021 |
ISSN (Online): | 1470-8728 |
Published Online: | 07 August 2017 |
Copyright Holders: | Copyright © 2017 The Authors |
First Published: | First published in Biochemical Journal 474(18):3179-3188 |
Publisher Policy: | Reproduced under a Creative Commons License |
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