Abstract C117: Preclinical pharmacokinetics of an antibody-drug conjugate targeting 5T4

• Published in: Molecular cancer therapeutics 2011-11, Vol.10 (11_Supplement), p.C117-C117
• Main Authors: Leal, Mauricio, Wentland, Joann, Clark, Tracey, Zhang, Jenny, Marcek, John, Khandke, Kiran, DiJoseph, John, Lucas, Judy, Groeber, Elizabeth, Han, Xiaognag, Hu, George, Gerber, Hans-Peter, Sapra, Puja
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-11-C117

The pharmacokinetics of a novel antibody (huA1)-drug (auristatin tubulin inhibitor MMAF) conjugate, targeting 5T4-expressing cells, were obtained in female nu/nu mice after a single IV dose of 1, 3 or 10 mg/kg and in male cynomolgus monkeys from a 2-cycle exploratory toxicity study at doses of 1, 3 or 10 mg/kg/cycle. Plasma/serum samples, collected over a 336 hr period after dosing, were analyzed using an ELISA-based method for antibody and conjugate (ADC) as well as for the Auristatin payload using an LC/MS/MS method. A comparison across doses (1 − 10 mg/kg) suggests lower CL values at the higher doses (3 and 10 mg/kg) in mice. Exposure in the mouse at anti-tumor doses was within the exposure observed at nontoxic doses with the monkeys. The huA1 and conjugate toxicokinetic data in monkeys dosed with A1mcMMAF indicates that exposure (AUC) increases with increasing dose although it appears to increase in a greater than proportional manner at the higher doses. In both mice and monkeys, the elimination half-life was longer as the dose increased from 1 to 10 mg/kg (from 4.2 to 8.7 days in monkeys, respectively). Systemic exposure (as assessed by Cmax and AUC) of the released payload increased with increasing dose although exposure was very low and its pharmacokinetics appeared to be formation rate limited. The analytical data from these studies are being used to inform PKPD models, to both quantitatively characterize the system and ultimately provide dose projections for this ADC construct Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C117.