Antibody-drug conjugates:Recent advances in linker chemistry

Antibody-drug conjugates(ADCs)are gradually revolutionizing clinical cancer therapy.The antibody-drug conjugate linker molecule determines both the efficacy and the adverse effects,and so has a major influence on the fate of ADCs.An ideal linker should be stable in the circulatory system and release the cytotoxic payload specifically in the tumor.However,existing linkers often release payloads nonspecifically and inevitably lead to off-target toxicity.This defect is becoming an increasingly important factor that restricts the development of ADCs.The pursuit of ADCs with optimal therapeutic windows has resulted in remarkable progress in the discovery and development of novel linkers.The present review summarizes the advance of the chemical trigger,linker-antibody attachment and linker-payload attachment over the last 5 years,and describes the ADMET properties of ADCs.This work also helps clarify future developmental directions for the linkers.

LDL receptor-related protein 1 (LRP1),a novel target for opening the blood-labyrinth barrier(BLB)

Inner ear disorders are a cluster of diseases that cause hearing loss in more than 1.5 billion people worldwide.However,the presence of the blood-labyrinth barrier(BLB)on the surface of the inner ear capillaries greatly hinders the effectiveness of systemic drugs for prevention and intervention due to the low permeability,which restricts the entry of most drug compounds from the bloodstream into the inner ear tissue.Here,we report the finding of a novel receptor,low-density lipoprotein receptor-related protein 1(LRP1),that is expressed on the BLB,as a potential target for shuttling therapeutics across this barrier.As a proof-ofconcept,we developed an LRP1-binding peptide,IETP2,and covalently conjugated a series of model small-molecule compounds to it,including potential drugs and imaging agents.All compounds were successfully delivered into the inner ear and inner ear lymph,indicating that targeting the receptor LRP1 is a promising strategy to enhance the permeability of the BLB.The discovery of the receptor LRP1 will illuminate developing strategies for crossing the BLB and for improving systemic drug delivery for inner ear disorders.

From prodrug to pro-prodrug:hypoxia-sensitive antibody–drug conjugates

Dear Editor,Antibody‒drug conjugates(ADCs),famous as biological targeting prodrugs,are gradually revolutionizing clinical cancer therapy.However,less than 1%of the dosed ADCs accumulate in the tumors.1 Therefore,the nonspecific release of the highly toxic payload(MMAE et al.,10−12–10−10 M)is a real threat,which could induce severe off-target toxicity.2 This danger necessitates strict requirements for the design of the linker.To date,the mainstream enzyme cleavable linkers,includingβ-glucuronidase cleavable linkers,sulfatase-cleavable linkers,and the most popular cathepsin cleavable linkers(valine-citrulline linker),all face this nonspecific release problem,3 because their cleaving enzymes are widely distributed with no significant difference in their quantities between tumor tissues and normal tissues.