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A Plug-and-Play Approach for the De Novo Generation of Dually Functionalised Bispecifics

preprint
submitted on 02.05.2019 and posted on 03.05.2019 by Antoine Maruani, Peter A. Szijj, Calise Bahou, João C. F. Nogueira, Stephen Caddick, James R. Baker, Vijay Chudasama

Diseases are multifactorial, with redundancies and synergies between various pathways. However, most of the antibody-based therapeutics in clinical trials and on the market interact with only one target thus limiting their efficacy. The targeting of multiple epitopes could improve the therapeutic index of treatment and counteract mechanisms of resistance. To this effect, a new class of therapeutics emerged: bispecific antibodies.

Bispecific formation using chemical methods is rare and low yielding and/or requires a large excess of one of the two proteins to avoid homodimerisation. In order for chemically prepared bispecifics to deliver their full potential, high-yielding, modular and reliable cross-linking technologies are required. Herein, we describe a novel approach not only for the rapid and high-yielding chemical generation of bispecific antibodies from native antibody fragments, but also for the site-specific dual functionalisation of the resulting bioconjugates. Based on orthogonal clickable functional groups, this strategy enables the assembly of functionalised bispecifics with controlled loading in a modular and convergent manner.

Funding

EPSRC EP/M01792X/1

CASE Award with LifeArc, 173621

Marie Skłodowska-Curie grant agreement No. 675007

Wellcome Trust

History

Email Address of Submitting Author

antoine.maruani@ucl.ac.uk

Institution

University College London

Country

United Kingdom

ORCID For Submitting Author

0000-0002-8677-8977

Declaration of Conflict of Interest

There are no immediate conflicts to declare, but we make clear that J.R.B., S.C. and V.C. are Directors of the spin-out ThioLogics.

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