Abstract 2793: Preclinical pharmacokinetics in cynomolgus monkeys and first in human dose prediction of DB-1303, a HER2-targeting antibody-drug conjugate

Abstract

Abstract Background: DB-1303 is a novel antibody-drug conjugate comprised of trastuzumab biosimilar, enzymatically cleavable peptide-linker, and a proprietary topoisomerase I inhibitor P1003. It is designed to have high plasma stability, low free payload in circulation and wide therapeutic index. Herein, the preclinical pharmacokinetics (PK) characteristics of DB-1303 in cynomolgus monkeys is reported, and human PK exposure in a first in human study was predicted using population PK model with allometric scaling. Material and Methods: The PK parameters of DB-1303 were obtained from single PK and repeated TK studies in female and male cynomolgus monkeys. Concentrations of DB-1303 ADC, total antibody and released payload P1003 were measured using ELISA or LC-MS/MS. In a PK study, single dose of DB-1303 at 1, 3 and 10 mg/kg were determined in cynomolgus monkeys via IV infusion. In TK studies, cynomolgus monkeys were intravenously administered with DB-1303 at 50, 80 mg/kg once every 3 weeks for 2 repeated doses, or 10, 40, 80 mg/kg once every 3 weeks (Q3W) for 3 repeated doses followed by a 4-week recovery. A population PK model was developed based on the collective PK/TK data in monkeys. Results: The non-compartment analysis PK parameters of three analytes (DB-1303 ADC, total antibody and released payload P1003) are summarized following single and multiple doses of DB-1303 in cynomolgus monkeys. To predict the human PK for DB-1303, a target mediated drug disposition (TMDD) model was constructed, incorporating binding to serum HER2 and subsequent elimination of the complex into a standard 2-compartmental PK model. The 2-compartment linear parameters were scaled from cynomolgus monkey population PK parameters using allometric scaling exponents of 1 for volumes and 1 for clearance. The binding of DB-1303 to HER2 was incorporated into the model and assumed to be the same for HER2 ECD and transmembrane domain. The PK profiles for DB-1303 in human at the proposed doses in the first in human study are predicted. The safety margins from the monkey HNSTD for each proposed human dose are calculated. Conclusions: DB-1303 exhibited favorable PK characteristics of DB-1303 in cynomolgus monkeys, and is predicted to have large safety margins at the selected doses in the first in human study. At the time of presentation, the first-in-human phase 1/2 study in patients with advanced solid tumors is in progress (NCT05150691). Citation Format: Rong Shi, Shengchao Lin, Yu Zhang, Bing Li, Haiqing Hua, Yang Qiu. Preclinical pharmacokinetics in cynomolgus monkeys and first in human dose prediction of DB-1303, a HER2-targeting antibody-drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2793.