Chemical Structure and Concentration of Intratumor Catabolites Determine Efficacy of Antibody Drug Conjugates

• DOI: 10.1124/dmd.116.070631
• Publication Date: 2016-07-15T01:53:54Z
• Authors: Donglu Zhang; Shang-Fan Yu; Yong Ma; Keyang Xu; Peter S Dragovich; Thomas H Pillow; Luna Liu; Geoffrey Del Rosario; Jintang He; Zhonghua Pei; Jack D Sadowsky; Hans K Erickson; Cornelis E. C. A Hop; S. Cyrus Khojasteh
• Keywords: Conjugate; Antibody-drug conjugate; Linker; Moiety

Despite recent technological advances in quantifying antibody drug conjugate (ADC) species, such as total antibody, conjugated drug, and payload circulation, the correlation of their exposures with efficacy ADC outcomes vivo remains challenging. Here, chemical structures concentrations intratumor catabolites were investigated to better understand drivers efficacy. Anti-CD22 disulfide-linked pyrrolobenzodiazepine (PBD-dimer) conjugates containing methyl- cyclobutyl-substituted disulfide linkers exhibited strong a WSU-DLCL2 xenograft mouse model, whereas an derived from cyclopropyl linker was inactive. Total drug-to-antibody ratios (DAR) circulation similar between cyclobutyl-containing cyclopropyl-containing ADC; however, former afforded release PBD-dimer tumor, but latter only generated nonimmolating thiol-containing catabolite that did not bind DNA. These results suggest analysis rather than systemic pharmacokinetic may be used explain predict are good examples demonstrate nature concentration depend on type for conjugation, potency released moiety ultimately determines