Optimised approach to albumin-drug conjugates using monobromomaleimide-C-2 linkers

Conjugation of therapeutics to human serum albumin (HSA) using bromomaleimides represents a promising platform for half-life extension. We show here that the Cys-34 crevice substantially reduces the rate of serum stabilising maleimide hydrolysis in these conjugates, necessitating reagent optimisation. This improved reagent design is applied to the construction of an HSA-paclitaxel conjugate, preventing drug loss during maleimide hydrolysis. Monobromomaleimides with C-2-PEG linkers offer an optimised platform for site-selective albumin conjugation, offering efficient conjugation and accelerated stabilising hydrolysis which prevents loss of drug during construction.