Glutamic acid-valine-citrulline linkers ensure stability and efficacy of antibody-drug conjugates in mice.

ABSTRACT: Valine-citrulline linkers are commonly used as enzymatically cleavable linkers for antibody-drug conjugates. While stable in human plasma, these linkers are unstable in mouse plasma due to susceptibility to an extracellular carboxylesterase. This instability often triggers premature release of drugs in mouse circulation, presenting a molecular design challenge. Here, we report that an antibody-drug conjugate with glutamic acid-valine-citrulline linkers is responsive to enzymatic drug release but undergoes almost no premature cleavage in mice. We demonstrate that this construct exhibits greater treatment efficacy in mouse tumor models than does a valine-citrulline-based variant. Notably, our antibody-drug conjugate contains long spacers facilitating the protease access to the linker moiety,

SUBMITTER: Anami Y 

PROVIDER: S-EPMC6023893 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature