Monoclonal Antibody TB-403: A First-in-Human, Phase I, Double-Blind, Dose Escalation Study Directed Against Placental Growth Factor in Healthy Male Subjects

• Published in: Clinical therapeutics 2011-09, Vol.33 (9), p.1142-1149
• Main Authors: Martinsson-Niskanen, Titti, PhD, Riisbro, Rikke, MD, PhD, Larsson, Leonard, PhD, Winstedt, Lena, PhD, Stenberg, Yvonne, PhD, Pakola, Steve, MD, Stassen, Jean-Marie, PhD, Glazer, Steven, MD
• Format: Article
• Language: English
• Subjects: Adult; Angiogenesis; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacokinetics; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - immunology; Antineoplastic Agents - pharmacokinetics; anti–placental growth factor; Binding sites; Biological and medical sciences; Blood pressure; Cancer; Committees; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug dosages; Drug therapy; Heart rate; Humans; Infusions, Intravenous; Internal Medicine; Male; Medical Education; Medical sciences; Middle Aged; monoclonal antibody; Pharmacology. Drug treatments; Phase I study; Placenta Growth Factor; Pregnancy Proteins - antagonists & inhibitors; Pregnancy Proteins - blood; Protein Binding; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - blood; Young Adult
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2011.08.007

Abstract Background TB-403 (RO5323441) is a humanized monoclonal antibody directed against placental growth factor (PlGF). Preclinical studies have demonstrated that targeting PlGF can result in significant inhibition of tumor growth and metastasis. Objectives The purpose of this study was to assess the safety profile, tolerability, and pharmacokinetics of TB-403, developed for the treatment of solid tumors. Methods Healthy male subjects were exposed to a single intravenous infusion of TB-403 or placebo. Blood samples for hematology, clinical chemistry, coagulation factors, and urinalysis were collected; vital signs and ECGs were recorded; and serial blood samples were drawn for pharmacokinetic and immunogenicity measurements and circulating levels of pharmacodynamics markers PlGF and (VEGF) vascular endothelial growth factor. Sixteen subjects received either placebo or TB-403 at doses ranging from 0.3 to 5.0 mg/kg. Results Mild (grade 1 or 2) nasopharyngitis, headache, neck pain, and joint pain were the most frequently reported adverse events (AEs). There were no serious AEs in the study, and none of the AEs led to withdrawal. None of the safety laboratory assessments was considered clinically significant, and none was reported as an AE. There were no apparent differences in terms of safety profiles among the 3 dose levels of active treatment compared with placebo. Clearance, volume of distribution, and terminal t½ (mean values) for TB-403 in all 3 cohorts were in the range of 4.2 to 4.9 (mL/d/kg), 56 to 79 (mL/kg), and 8 to 13 (days), respectively. Conclusion The highest dose of TB-403 (5.0 mg/kg) was well tolerated in this study of a single intravenous infusion to healthy males. This result allowed a higher starting dose level in a subsequent Phase I study in cancer patients, the patient population for which this antibody is developed.