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New class of antibody-drug bio-conjugates

Courtesy of Ella Marushchenko.

A group of researchers led by Gonçalo Bernardes have developed a new site-selective method for the construction of complex protein/antibody conjugates.

The scientists have designed a new class of carbonylacrylic cysteine-selective reagents that may vastly improve the effectiveness of targeted drug delivery while cutting problems of low efficacy and side-toxicity associated with current methods.
The team, located in Cambridge and Portugal, use very small amounts of carbonylacrylic derivatives bearing a drug or fluorophore that react irreversibly with cysteine residues to produce chemically defined protein and antibody conjugates.

Current methods of antibody-drug bioconjugation are based on maleimide chemistry. But the resulting conjugates often undergo thiol-exchange reactions while in circulation, which leads to the premature release of the drug. Gonçalo said: “If this happens, the drug is released prematurely which not only limits the efficacy of the treatment but also leads to side-toxicity”.

Therapeutic protein/antibody-drug conjugates built using carbonylacrylic derivatives that selectively modify cysteine residues are highly stable in plasma. Gonçalo said: “By making antibody-drug conjugates more stable in the circulation we know the drug is only going to be delivered in the site of disease.” The work raises important questions and possibilities regarding the delivery of cytotoxic drugs, particularly during cancer treatments or therapy.


 Stoichiometric and irreversible cysteine-selective protein modification using carbonylacrylic reagents,' Barbara Bernardim et al, Nature Communications, Oct/Nov 2016: 10.1038/ncomms13128