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Tuning the Hydrolytic Stability of Next Generation Maleimide Cross-Linkers Enables Access to Albumin-Antibody Fragment Conjugates and tri-scFvs

Forte, N; Livanos, M; Miranda, E; Morais, M; Yang, X; Rajkumar, VS; Chester, KA; ... Baker, JR; + view all (2018) Tuning the Hydrolytic Stability of Next Generation Maleimide Cross-Linkers Enables Access to Albumin-Antibody Fragment Conjugates and tri-scFvs. Bioconjugate Chemistry , 29 (2) pp. 486-492. 10.1021/acs.bioconjchem.7b00795. Green open access

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Abstract

We describe investigations to expand the scope of next generation maleimide cross-linkers for the construction of homogeneous protein–protein conjugates. Diiodomaleimides are shown to offer the ideal properties of rapid bioconjugation with reduced hydrolysis, allowing the cross-linking of even sterically hindered systems. The optimized linkers are exploited to link human serum albumin to antibody fragments (Fab or scFv) as a prospective half-life extension platform, with retention of antigen binding and robust serum stability. Finally, a triprotein conjugate is formed, by linking scFv antibody fragments targeting carcinoembryonic antigen. This tri-scFv is shown to infer a combination of greater antigen avidity and increased in vivo half-life, representing a promising platform for antibody therapeutic development.

Type: Article
Title: Tuning the Hydrolytic Stability of Next Generation Maleimide Cross-Linkers Enables Access to Albumin-Antibody Fragment Conjugates and tri-scFvs
Open access status: An open access version is available from UCL Discovery
DOI: 10.1021/acs.bioconjchem.7b00795
Publisher version: http://dx.doi.org/10.1021/acs.bioconjchem.7b00795
Language: English
Additional information: ACS AuthorChoice - This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Keywords: Science & Technology, Life Sciences & Biomedicine, Physical Sciences, Biochemical Research Methods, Biochemistry & Molecular Biology, Chemistry, Multidisciplinary, Chemistry, Organic, Chemistry, UNNATURAL AMINO-ACIDS, HALF-LIFE EXTENSION, BISPECIFIC ANTIBODIES, DRUG CONJUGATE, FUSION PROTEINS, CANCER-THERAPY, THERAPEUTICS, PLATFORM, CYSTEINE, POTENT
URI: http://discovery.ucl.ac.uk/id/eprint/10048306
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