Tumor-specific targeting by Bavituximab, a phosphatidylserine-targeting monoclonal antibody with vascular targeting and immune modulating properties, in lung cancer xenografts

David E Gerber; Guiyang Hao; Linda Watkins; Jason H Stafford; Jon Anderson; Blair Holbein; Orhan K Öz; Dana Mathews; Philip E Thorpe; Gedaa Hassan; Amit Kumar; Rolf A Brekken; Xiankai Sun

Tumor-specific targeting by Bavituximab, a phosphatidylserine-targeting monoclonal antibody with vascular targeting and immune modulating properties, in lung cancer xenografts

Am J Nucl Med Mol Imaging. 2015 Oct 12;5(5):493-503. eCollection 2015.

Authors

Affiliations

¹ Division of Hematology-Oncology, University of Texas Southwestern Medical Center Dallas, Texas 75390-8852, USA ; Department of Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center Dallas, Texas 75390-8852, USA.
² Department of Radiology, University of Texas Southwestern Medical Center Dallas, Texas 75390-8852, USA.
³ Department of Pharmacology, University of Texas Southwestern Medical Center Dallas, Texas 75390-8852, USA.
⁴ Department of Pharmacology, University of Texas Southwestern Medical Center Dallas, Texas 75390-8852, USA ; Current Address: Stanford University Medical Center USA.
⁵ Department of Clinical Sciences, University of Texas Southwestern Medical Center Dallas, Texas 75390-8852, USA.
⁶ Department of Pharmacology, University of Texas Southwestern Medical Center Dallas, Texas 75390-8852, USA ; Department of Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center Dallas, Texas 75390-8852, USA.
⁷ Department of Surgery, University of Texas Southwestern Medical Center Dallas, Texas 75390-8852, USA ; Department of Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center Dallas, Texas 75390-8852, USA.
⁸ Department of Radiology, University of Texas Southwestern Medical Center Dallas, Texas 75390-8852, USA ; Department of Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center Dallas, Texas 75390-8852, USA.

PMID: 26550540
PMCID: PMC4620176

Abstract

Bavituximab is a chimeric monoclonal antibody with immune modulating and tumor-associated vascular disrupting properties demonstrated in models of non-small cell lung cancer (NSCLC). The molecular target of Bavituximab, phosphatidylserine (PS), is exposed on the outer leaflet of the membrane bi-layer of malignant vascular endothelial cells and tumor cells to a greater extent than on normal tissues. We evaluated the tumor-targeting properties of Bavituximab for imaging of NSCLC xenografts when radiolabeled with (111)In through conjugation with a bifunctional chelating agent, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). In vitro binding of (111)In-DOTA-Bavituximab to PS was determined by enzyme-linked immunosorbent assay (ELISA). Biodistribution of (111)In-DOTA-Bavituximab was conducted in normal rats, which provided data for dosimetry calculation. Single-photon emission computed tomography/computed tomography (SPECT/CT) imaging was performed in athymic nude rats bearing A549 NSCLC xenografts. At the molar conjugation ratio of 0.54 DOTA per Bavituximab, the PS binding affinity of (111)In-DOTA-Bavituximab was comparable to that of unmodified Bavituximab. Based on the quantitative SPECT/CT imaging data analysis, (111)In-DOTA-Bavituximab demonstrated tumor-specific uptake as measured by the tumor-tomuscle ratio, which peaked at 5.2 at 72 hr post-injection. In contrast, the control antibody only presented a contrast of 1.2 at the same time point.These findings may underlie the diagnostic efficacy and relative low rates of systemic vascular and immune-related toxicities of this immunoconjugate. Future applications of (111)In-DOTA-bavituximab may include prediction of efficacy, indication of tumor immunologic status, or characterization of radiographic findings.

Keywords: 111In; Bavituximab; immunotherapy; lung cancer; phosphatidylserine; vascular targeting.

Grants and funding

S10 RR029674/RR/NCRR NIH HHS/United States