A new model for intermediate molecular weight recombinant bispecific and trispecific antibodies by efficient heterodimerization of single chain variable domains through fusion to a Fab-chain

Biomolecular Engineering
R SchoonjansN Mertens

Abstract

Due to their specificity and versatility in use, bispecific antibodies (BsAbs) are promising therapeutic tools in tomorrow's medicine, provided sufficient BsAb can be produced. Expression systems favoring efficient heterodimerization of intermediate-sized bispecific antibodies will significantly improve existing production methods. Recombinant BsAb can be made by fusing single chain variable fragments (scFv) to a heterodimerization domain. We compare the efficiency of the isolated CL and CH1 constant domains with complete Fab chains to drive heterodimerization of BsAbs in mammalian cells. We found that the isolated CL:CH1 domain interaction was inefficient for secretion of heterodimers. However, when the complete Fab chains were used, secretion of a heterodimerized bispecific antibody was successful. Since the Fab chain encodes a binding specificity on its own, bispecific (BsAb) or trispecific (TsAb) antibodies can be made by C-terminal fusion of scFv molecules to the L or Fd Fab chains. This gave rise to disulphide stabilized Fab-scFv BsAb (Bibody)or Fab-(scFv)2 TsAb (Tribody) of intermediate molecular size. Heterodimerization of the L and Fd-containing fusion proteins was very efficient, and up to 90% of all secreted antibody...Continue Reading

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Citations

Dec 1, 2001·Expert Opinion on Biological Therapy·P J Hudson, C Souriau
May 8, 2010·Trends in Biotechnology·Angel M CuestaLuis Alvarez-Vallina
Mar 12, 2015·Drug Discovery Today·Natalia Nuñez-PradoLuis Álvarez-Vallina
Mar 29, 2012·MAbs·Roland E Kontermann
Nov 12, 2014·Proceedings of the National Academy of Sciences of the United States of America·Koen WagnerHergen Spits
Oct 16, 2008·Journal of Immunological Methods·Martin LarsenPeter Kristensen
Jan 11, 2017·MAbs·Ulrich Brinkmann, Roland E Kontermann
May 8, 2008·The Journal of Veterinary Medical Science·Yoshiko TateishiHaruo Matsuda
Nov 18, 2004·Bioconjugate Chemistry·Todd M CorneillieClaude F Meares
Apr 18, 2014·Molecular Pharmaceutics·Haiming LuoWeibo Cai

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