Fmoc-Val-Cit-PAB-PNP

Fmoc-Val-Cit-PAB-PNP is a cleavable ADC linker used in the synthesis of antibody-drug conjugates (ADCs). Fmoc-Val-Cit-PAB-PNP has superior plasma stability comparable to that of non-cleavable linkers^[1][2][3]. In Vitro:Fmoc-Val-Cit-PAB-PNP contains peptide sequence degradable by a lysosome enzyme^[1].
Cathepsin B in the lysosome cleaves the peptide bond between Cit-PAB of dipeptide linkers containing Valine (Val)-citrulline (Cit) and p-aminobenzylalcohol (PAB). When PAB and a drug are binded covalently with carbamate bonds, the drug can be released by hydrolysis after cleavage of the peptide bond between Cit-PAB. Antibody-drug conjugates (ADCs) has been developed using this mechanism^[2].
In Vivo:Fmoc-Val-Cit-PAB-PNP linker stabilization in the mouse is an essential prerequisite for designing successful efficacy and safety studies in rodents during preclinical stages of ADC programs^[3].
Conjugation site plays an important role in determining VC-PABC linker stability in mouse plasma, and that the stability of the linker positively correlates with ADC cytotoxic potency both in vitro and in vivo^[3].