Vascular Imaging of Solid Tumors in Rats with a Radioactive Arsenic-Labeled Antibody that Binds Exposed Phosphatidylserine

Abstract

Purpose: We recently reported that anionic phospholipids, principally phosphatidylserine, become exposed on the external surface of vascular endothelial cells in tumors, probably in response to oxidative stresses present in the tumor microenvironment. In the present study, we tested the hypothesis that a chimeric monoclonal antibody that binds phosphatidylserine could be labeled with radioactive arsenic isotopes and used for molecular imaging of solid tumors in rats. As (h -,T 1/2 1.6 days) using a novel procedure. The radionuclides of arsenic were selected because their long half-lives are consistent with the long biological half lives of antibodies in vivo and because their chemistry permits stable attachment to antibodies. The radiolabeled antibodies were tested for the ability to image subcutaneous Dunning prostate R3227-AT1tumors in rats. Results: Clear images of the tumors were obtained using planar g-scintigraphy and positron emission tomography. Biodistribution studies confirmed the specific localization of bavituximab to the tumors. The tumor-to-liver ratio 72 h after injection was 22 for bavituximab compared with 1.5 for an isotype-matched control chimeric antibody of irrelevant specificity. Immunohistochemical studies showed that the bavituximab was labeling the tumor vascular endothelium. Conclusions: These results show that radioarsenic-labeled bavituximab has potential as a new tool for imaging the vasculature of solid tumors.

Novel surface targets and serum biomarkers from the ovarian cancer vasculature

“…Important discovery work in the area of tumor vascular targeting has already been done 6,17,18 and selective markers for tumor vasculature have been identified, including the tumor endothelial marker 1 (TEM1) and other TEMs; the extracellular domain B isoform of fibronectin; exposed phosphatidylserine; the prostate specific membrane antigen (PSMA); and integrin αvβ3.…”

“…17,[20][21][22] However, the heterogeneous expression of endothelial markers in tumors and the lack of suitable imaging beacons and effector molecules have delayed harnessing the potential of these targets. Thus, identifying additional markers of tumor vasculature and developing affinity reagents is a high priority.…”

Phase I Safety and Pharmacokinetic Study of Bavituximab, a Chimeric Phosphatidylserine-Targeting Monoclonal Antibody, in Patients with Advanced Solid Tumors

“…Various pathophysiologic processes disrupt this asymmetry, resulting in exposure of PS on the outer membrane leaflet, where it is available for binding by bavituximab (2). PS is exposed on tumor vascular endothelium within solid tumors, where hypoxia and other physiologic stresses induce PS exposure, rendering bavituximab vascular targeting tumor specific (3). In animal models, cytotoxic therapies, including chemotherapy and ionizing radiation, further induce PS exposure, thereby enhancing bavituximab binding (4,5).…”

Antiphosphatidylserine Antibody Combined with Irradiation Damages Tumor Blood Vessels and Induces Tumor Immunity in a Rat Model of Glioblastoma

“…Bavituximab is a chimeric monoclonal antibody that indirectly binds to anionic phospholipids, principally phosphatidylserine (3). Phosphatidylserine is normally tightly segregated to the internal surface of the plasma membrane in most cell types, including the vascular endothelium (4).…”