Abstract A3: A first-in-man, phase I, dose escalation study of TB-403, a monoclonal antibody directed against PlGF, in healthy male subjects
Authors: Riisbro Rikke , Larsson Leonard , Winstedt Lena , Niskanen Titti , Pakola Steve , Stassen Jean-Marie , Lassen Ulrik , Glazer Steven 
Published: June 2012

Abstract
Rationale and Objectives: TB-403 is a humanised recombinant immunoglobulin G isotype 1 (IgG1) monoclonal antibody expressed in Chinese hamster ovary (CHO) cells and directed to the receptor-binding site of placental growth factor (PlGF). The antibody is highly specific and does not cross-react with vascular endothelial growth factor (VEGF). Whilst VEGF is involved both in physiological and pathological angiogenesis, the levels of PlGF are low in normal tissues, but up-regulated in several pathological conditions, including several types of cancer. TB-403 has been shown to significantly inhibit tumor growth in xenograft tumor models. In all preclinical studies performed with TB-403 there were no drug-related findings up to and including the maximum feasible doses tested (300 mg/kg/wk IV in the cynomolgus monkey for 13 weeks). This first-in-man (FIM) study was designed to investigate the safety and tolerability of a single dose of TB-403 in healthy male subjects. A secondary objective included the investigation of the single dose pharmacokinetics of TB-403.
Methods: This FIM study was a phase 1, double-blind, randomized, placebo-controlled, single-dose escalation study in healthy male subjects. Sixteen male subjects in 3 dose groups were exposed to a single, intravenous infusion of TB-403 or placebo over 60 minutes at dose levels of 0.3, 1.25 or 5.0 mg/kg with 2+2, 4+2 and 4+2 subjects per group, respectively. The starting dose was selected as 1/10th of the Minimum Anticipated Biological Effect Level (MABEL) determined in a xenograft tumor model. TB-403 was given at escalating doses and safety was closely monitored up to Day 56. Review of adverse events, safety laboratory results, electrocardiogram and vital sign measurements up to and including Day 7 was performed by a Data Monitoring Committee before dose escalation.
Results: All 16 subjects were Caucasians with the age, body weight, and body mass index range of 22–46 years, 63.1–114.5 kg and 20.4–31.4 kg/m2, respectively. The most frequently reported adverse events were nasopharyngitis, headache, neck pain and joint pain with no significant difference in frequency or severity between TB-403 and placebo for these or other reported adverse events. The adverse events were either not related or unlikely related to TB-403 and 16 were mild, 8 moderate and 3 severe in intensity. There were no serious adverse events, and none of the events led to withdrawal. Pharmacokinetic properties of TB-403 were investigated and showed a terminal half-life of TB-403 ranging from 8 to 13 days and a dose-proportional exposure in terms of both Cmax and AUC.
Conclusion: TB-403 was safely administered to healthy males in this study without dose-limiting toxicity after an intravenous infusion in the dose range of 0.3 mg/kg to 5.0 mg/kg. The safe administration of TB-403 to healthy male subjects allowed a higher initial safe start dose level in a subsequent study in cancer patients.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A3.