As synthetic protein conjugates grow in therapeutic importance, there is a need to expand current bioconjugation chemistries to allow for greater architectural and synthetic control. Chemistries that allow for site-specific modification and overcome the limitations of conventional ligation techniques, which create stochastic conjugates, will expand the potential of this field. One method to generate site-specific bioconjugates is via incorporation of aldehyde-functionalized biomolecules. Here, we introduce a new aldehyde-specific bioconjugation technique, the Trapped-Knoevenagel Ligation. The reaction proceeds quickly at near neutral pH to yield bioconjugates with high in vitro stability (t1/2~38 days) in human plasma. To demonstrate the utility of this ligation technique, we generated an antibody drug conjugate (ADC) and studied it in vitro and in vivo. When compared to an ADC prepared by conventional lysine conjugation, our ADC demonstrated equal efficacy in vivo with half the drug loading and displayed superior pharmacokinetic properties.

Site-specific antibody-drug conjugates via a trapped-Knoevenagel ligation

248th National Meeting (2014)

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