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.
David E Gerber  1 ,  Guiyang Hao  2 ,  Linda Watkins  3 ,  Jason H Stafford  4 ,  Jon Anderson  2 ,  Blair Holbein  5 ,  Orhan K Öz  2 ,  Dana Mathews  2 ,  Philip E Thorpe  6 ,  Gedaa Hassan  2 ,  Amit Kumar  2 ,  Rolf A Brekken  7 ,  Xiankai Sun  8
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
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.
Products