抗体偶联药物的分子设计与展望OA

Antibody-drug conjugates(ADCs)enable targeted killing of cells by delivering small-molecule toxins to target cells in a site-specific manner via antibodies.Owing to their advantages of high specificity and low systemic toxicity,ADCs have achieved clinical breakthroughs in the treatment of tumors such as breast cancer and gastric cancer.Although their efficacy,safety,and druggability have been significantly improved after four rounds of technology iterations,their complex structure still poses challenges to molecular design and production.Herein,we reviewed the key design aspects of ADCs:In terms of target and antibody selection,ideal targets should possess tissue specificity,stability,and high internalization efficiency.After summarizing common targets for solid tumors and hematological tumors,we discussed the application value and challenges of antibody,bispecific antibodies,and antibody fragments.Regarding small-molecule toxins,we presented the mechanism of action,current application status,and limitations of payloads such as tubulin inhibitors and DNA-damaging agents.In terms of conjugation methods,we outlined the characteristics of non-specific conjugation,site-specific non-selective conjugation,and site-specific selective conjugation.As for linkers,we analyzed the mechanisms,advantages,and disadvantages of cleavable linkers(including chemically unstable and enzyme-responsive types)and non-cleavable linkers.Finally,we provided the outlook for the application of ADCs.Overall,this review provides general references for the research,development,and production of ADCs.