APRIL 2003

Anti-VEGF agent pairs up with PET and MRA

By: James Borwick

CONTEXT: A phase I study conducted by Dr. Gordon Jayson and colleagues sought to evaluate the efficacy of HuMV833, an anti-VEGF (vascular endothelial growth factor) agent, with progressive solid tumors on 20 patients. The study employed both MR angiography and PET to establish the intramural concentration of the antibody and the biologic response. Findings were reported in the Journal of the National Cancer Institute (J Natl Cancer Inst 2002;94[19]:1484-1493).

RESULTS: Dynamic contrast-enhanced MRA was applied to measure vascular permeability, which increases in the presence of VEGF, and which was assumed to decrease if the antibody was active. The results were extremely variable between patients, within patients, and even within individual tumors. Nevertheless, permeability decreased for all tumors 48 hours after initial treatment (median = 44%; range = 4% to 91%).

A PET pharmacokinetic evaluation of the uptake and clearance of HuMV833 (labeled with iodine-124) was performed on tumor and normal tissue. The I-124 PET data showed a more than threefold variability of antibody concentrations in tumors within individual patients and a reduction of drug concentration anywhere from 16% to 75% over a period of 24 hours.

IMAGE: MRA image (A) of an ovarian cancer patient acquired 24 hours after I-124 HuMV833 and unlabeled HuMV833 were administered reveals similar antibody concentrations in the liver, spleen, left kidney, femoral artery, and the pelvic ovarian tumor. Substantial differences in antibody concentrations are observed (B) in the liver and poorly vascularized para-aortic colon carcinoma metastasis of another patient who underwent imaging 24 hours after receiving the agent. The MRA study (C) of a patient with metastatic neuroblastoma reveals different antibody concentrations in a left neck metastasis and anterior mediastinal mass. Additional MRA (D) performed 24 hours later shows that different antibody concentrations were still detected in the two metastases (Images reprinted with permission of Oxford University Press).

IMPLICATIONS: The PET-pharmacokinetic study was the first performed on an antiangiogenic agent, allowing for the calculation of total antibodies in the patients' tumors and organs. The dissimilarity in response seen between tumors (high variability) as opposed to organs and normal tissue (general consistency) demonstrates that different tumors take up and clear HuMV833 in different ways. The combination of the two-superimposing PET on MR data-revealed a close relationship between distribution of the antibody and regional vascular permeability.