PT  - JOURNAL ARTICLE
AU  - Donglu Zhang
AU  - Shang-Fan Yu
AU  - Yong Ma
AU  - Keyang Xu
AU  - Peter S. Dragovich
AU  - Thomas H. Pillow
AU  - Luna Liu
AU  - Geoffrey Del Rosario
AU  - Jintang He
AU  - Zhonghua Pei
AU  - Jack D. Sadowsky
AU  - Hans K. Erickson
AU  - Cornelis E. C. A. Hop
AU  - S. Cyrus Khojasteh
TI  - Chemical Structure and Concentration of Intratumor Catabolites Determine Efficacy of Antibody Drug Conjugates
AID  - 10.1124/dmd.116.070631
DP  - 2016 Sep 01
TA  - Drug Metabolism and Disposition
PG  - 1517--1523
VI  - 44
IP  - 9
4099  - http://dmd.aspetjournals.org/content/44/9/1517.short
4100  - http://dmd.aspetjournals.org/content/44/9/1517.full
SO  - Drug Metab Dispos2016 Sep 01; 44
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.