RT Journal Article SR Electronic T1 Chemical Structure and Concentration of Intratumor Catabolites Determine Efficacy of Antibody Drug Conjugates JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1517 OP 1523 DO 10.1124/dmd.116.070631 VO 44 IS 9 A1 Donglu Zhang A1 Shang-Fan Yu A1 Yong Ma A1 Keyang Xu A1 Peter S. Dragovich A1 Thomas H. Pillow A1 Luna Liu A1 Geoffrey Del Rosario A1 Jintang He A1 Zhonghua Pei A1 Jack D. Sadowsky A1 Hans K. Erickson A1 Cornelis E. C. A. Hop A1 S. Cyrus Khojasteh YR 2016 UL http://dmd.aspetjournals.org/content/44/9/1517.abstract AB Despite recent technological advances in quantifying antibody drug conjugate (ADC) species, such as total antibody, conjugated antibody, conjugated drug, and payload drug in circulation, the correlation of their exposures with the efficacy of ADC outcomes in vivo remains challenging. Here, the chemical structures and concentrations of intratumor catabolites were investigated to better understand the drivers of ADC in vivo efficacy. Anti-CD22 disulfide-linked pyrrolobenzodiazepine (PBD-dimer) conjugates containing methyl- and cyclobutyl-substituted disulfide linkers exhibited strong efficacy in a WSU-DLCL2 xenograft mouse model, whereas an ADC derived from a cyclopropyl linker was inactive. Total ADC antibody concentrations and drug-to-antibody ratios (DAR) in circulation were similar between the cyclobutyl-containing ADC and the cyclopropyl-containing ADC; however, the former afforded the release of the PBD-dimer payload in the tumor, but the latter only generated a nonimmolating thiol-containing catabolite that did not bind to DNA. These results suggest that intratumor catabolite analysis rather than systemic pharmacokinetic analysis may be used to better explain and predict ADC in vivo efficacy. These are good examples to demonstrate that the chemical nature and concentration of intratumor catabolites depend on the linker type used for drug conjugation, and the potency of the released drug moiety ultimately determines the ADC in vivo efficacy.