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The renaissance of chemically generated bispecific antibodies

Abstract

Bispecific antibodies (bsAbs) target two different epitopes. These are an up-and-coming class of biologics, with two such therapeutics (emicizumab and blinatumomab) FDA approved and on the market, and many more in clinical trials. While the first reported bsAbs were constructed by chemical methods, this approach has fallen out of favour with the advent of modern genetic engineering techniques and, nowadays, the vast majority of bsAbs are produced by protein engineering. However, in recent years, relying on innovations in the fields of bioconjugation and bioorthogonal click chemistry, new chemical methods have appeared that have the potential to be competitive with protein engineering techniques and, indeed, hold some advantages. These approaches offer modularity, reproducibility and batch-to-batch consistency, as well as the integration of handles, whereby additional cargo molecules can be attached easily, e.g. to generate bispecific antibody–drug conjugates. The linker between the antibodies/antibody fragments can also be easily varied, and new formats (types, defined by structural properties or by construction methodology) can be generated rapidly. These attributes offer the potential to revolutionize the field. Here, we review chemical methods for the generation of bsAbs, showing that the newest examples of these techniques are worthy competitors to the industry-standard expression-based strategies.

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Fig. 1: Examples of the unique mechanisms of action of bsAbs.
Fig. 2: Summary of modern methods for the chemical generation of bsAbs.
Fig. 3: The maleimide stability problem.
Fig. 4: The first published method to chemically create bsAbs.
Fig. 5: Chemical methods for generating bsAbs.
Fig. 6: Combined protein engineering and chemical methods for the generation of bsAbs.
Fig. 7: Reagents used for the generation of homogeneous bispecific protein–protein conjugates via disulfide re-bridging.
Fig. 8: Pyridazinedione-based method for the generation of a dually functionalized bsAb.

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Acknowledgements

P.S. would like to thank the Wellcome Trust for their generous funding.

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P.S. and V.C. co-wrote the Review and co-analysed the literature.

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Correspondence to Vijay Chudasama.

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V.C. is a co-founder and director of the company ThioLogics. P.S. has no competing interests to declare.

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Szijj, P., Chudasama, V. The renaissance of chemically generated bispecific antibodies. Nat Rev Chem 5, 78–92 (2021). https://doi.org/10.1038/s41570-020-00241-6

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