RT Journal Article
SR Electronic
T1 <strong>Pharmacokinetics and Catabolism of [<sup>3</sup>H]TAK-164, a G</strong><strong>uanylyl Cyclase C Targeted Antibody-Drug Conjugate</strong>
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP DMD-AR-2020-000194
DO 10.1124/dmd.120.000194
A1 Jayaprakasam Bolleddula
A1 Abhi Shah
A1 Mohammad Shadid
A1 Afrand Kamali
A1 Michael D. Smith
A1 Swapan K. Chowdhury
YR 2020
UL http://dmd.aspetjournals.org/content/early/2020/08/25/dmd.120.000194.abstract
AB TAK-164 is an antibody-drug conjugate (ADC) comprising human anti-guanylyl cyclase C (GCC) monoclonal antibody conjugated to indolinobenzodiazepine DNA alkylator IGN-P1 through a cleavable alanine-alanine (Ala-Ala) dipeptide linker. TAK-164 is currently being evaluated for the treatment of gastrointestinal (GI) cancers expressing guanylyl cyclase C (GCC). The catabolism of TAK-164 was studied using [3H]-labeled ADC using GCC expressing HEK-293 (GCC-HEK-293) cells, rat tristosomes, cathepsin B, and tumor bearing mice. Time and target dependent uptake of [3H]TAK-164 was observed in GCC-HEK-293 cells with approximately 12% of radioactivity associated with DNA after 24 hours of incubation. Rat liver tritosomes and cathepsin B yielded IGN-P1 aniline, sulfonated IGN-P1 (s-IGN-P1) aniline and a lysine conjugate of IGN-P1 (IGN-P1-Lys) aniline as catabolites. In tumor bearing mice [3H]TAK-164 exhibited terminal half-life (t1/2) approximately 41 and 51 hours in plasma and blood, respectively with low plasma clearance (0.75 mL/hr/kg). The extractable radioactivity in plasma and tumor samples revealed the presence of s-IGN-P1 aniline and IGN-P1 aniline as payload related components. The use of a radiolabeled payload in the ADC in tumor uptake investigations provided direct and quantitative evidence for tumor uptake, DNA-binding and proof of mechanism of action of the payload. Significance Statement Since payload related species are potent cytotoxins, a thorough characterization of released products of ADCs, metabolites and their drug interaction potential are necessary prior to clinical investigations. This study characterized in vitro and in vivo DNA binding mechanism and released products of TAK-164. The methodologies described here will be highly useful for characterization of payload-related products of ADCs in general.