Abstract 1296: Safety, tolerability, and pharmacokinetics of the novel αv-integrin antibody DI17E6 in healthy subjects after ascending single intravenous doses
Authors: Zühlsdorf Michael , Kovar Andreas , Uhl Wolfgang , Forssmann Ulf 
Published: June 2012

Abstract
Introduction: Integrins play an important role in cancer. They are highly expressed in angiogenic, proliferating tumor blood vessels and on certain tumor cells. Apart from their classical role in mediating cell attachment and migration, αv-integrins play a direct role in tumor progression, angiogenesis, and metastasis. DI17E6 (EMD 525797) is a deimmunized monoclonal antibody against αv-integrins, with clinical potential in a range of cancers. This study assessed the safety, tolerability, and pharmacokinetics (PK) of single iv doses of DI17E6 in healthy subjects.
Methods: In this first-in-man, single-center, randomized, double-blind, placebo-controlled study, DI17E6 was infused as single doses of 35, 100, 250, 500, 1000, or 1500 mg in 6 consecutive groups. Within each dose-group, 6 subjects were randomized to receive DI17E6 and 3 to receive placebo. Each subject was followed-up for 42 days. Safety, tolerability, and PK were assessed, and plasma parameters and urine biomarkers (including those related to cytokine activation and inflammatory response) were analyzed.
Results: In total, 55 healthy male subjects (age 18-45 years) received infusions of DI17E6 or placebo. Of the 37 subjects receiving any dose of DI17E6, 73% reported at least one adverse event (AE) compared to 77.8% in the placebo group. AEs were mainly general or gastrointestinal disorders and injection site reactions. Most of the AEs were reported to a similar extent for DI17E6 and placebo. No serious AEs occurred and all AEs had resolved at the end of the study. Hematology, biochemistry, markers of coagulation and inflammation, and urinalysis showed no clinically relevant changes over time. No influence of DI17E6 on vital signs, physical and ophthalmologic examination, ECG, and spirometry was observed. The DI17E6 Cmax increased nearly dose-proportionally, whereas the increase in the DI17E6 AUC was more than dose-proportional. The clearance (CL) decreased with increasing doses. This dose dependency was more pronounced in lower dose groups; at doses above 250 mg CL started to level off.
In 18.9% of the subjects who received DI17E6, anti-DI17E6 antibodies were detected. This was not associated with any clinical signs or symptoms and did not influence the PK of DI17E6.
In healthy subjects, DI17E6 did not induce changes in pharmacodynamic parameters (endogenous thrombin potential, D-dimer, platelet activation, CRP, TNFα, IL-8, and CH50) nor in circulating endothelial cells and progenitors.
Conclusion: In this healthy subject study, DI17E6 was safe and well tolerated. There were no clinically relevant dose-related changes in any of the safety parameters assessed. PK of DI17E6 are driven by nonlinear elimination, as already described for other antibodies targeting cell surface antigens.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1296. doi:10.1158/1538-7445.AM2011-1296