Molecular imaging and biological evaluation of HuMV833 anti-VEGF antibody: implications for trial design of antiangiogenic antibodies.

Abstract

BACKGROUND:

Vascular endothelial growth factor (VEGF) is a potent angiogenic cytokine, and various inhibitory agents, including specific antibodies, have been developed to block VEGF-stimulated angiogenesis. We developed HuMV833, a humanized version of a mouse monoclonal anti-VEGF antibody (MV833) that has antitumor activity against a number of human tumor xenografts, and investigated the distribution and biologic effects of HuMV833 in patients in a phase I trial.

METHODS:

Twenty patients with progressive solid tumors were treated with various doses of HuMV833 (0.3, 1, 3, or 10 mg/kg). Positron emission tomography with (124)I-HuMV833 was used to measure the antibody distribution in and clearance from tissues. Magnetic resonance imaging was used to measure the vascular permeability surface area product with a first-pass pharmacokinetic model (k(fp)) to determine tumor vascular permeability.

RESULTS:

The antibody was generally well tolerated, although the incremental dose, phase I study design, and pharmacodynamic endpoints could not identify the optimum biologically active dose. Antibody distribution and clearance were markedly heterogeneous between and within patients and between and within individual tumors. HuMV833 distribution to normal tissues also varied among patients, but the antibody was cleared from these tissues in a homogeneous fashion. Permeability was strongly heterogeneous between and within patients and between and within individual tumors. All tumors showed a reduction in k(fp) 48 hours after the first treatment (median = 44%; range = 4%-91%).

CONCLUSIONS:

Because of the heterogeneity in tumor biology with respect to antibody uptake and clearance, we suggest that either intrapatient dose escalation approaches or larger, more precisely defined patient cohorts would be preferable to conventional strategies in the design of phase I studies with antiangiogenic compounds like HuMV833.

• Authors: Gordon C Jayson, Jamal Zweit, Alan Jackson, Clive Mulatero, Peter Julyan, Malcolm Ranson, Lynn Broughton, John Wagstaff, Leif Hakannson, Gerard Groenewegen, John Bailey, Nigel Smith, David Hastings, Jeremy Lawrance, Hamied Haroon, Tim Ward, Alan T McGown, Meina Tang, Dan Levitt, Sandrine Marreaud, Frederic F Lehmann, Manfred Herold, Heinz Zwierzina, European Organisation for Research and Treatment of Cancer Biological Therapeutic Development Group
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 94 Issue 19 Pg. 1484-93 (Oct 02 2002) ISSN: 0027-8874 [Print] United States
• PMID: 12359857 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Evaluation Study, Journal Article)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Endothelial Growth Factors
• Iodine Radioisotopes
• Lymphokines
• MV833 monoclonal antibody, human
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors

Topics

• Animals
• Antibodies, Monoclonal (pharmacokinetics, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antibody Formation
• Antineoplastic Agents (pharmacokinetics, therapeutic use)
• Capillary Permeability
• Dose-Response Relationship, Immunologic
• Drug Design
• Drug Evaluation, Preclinical
• Endothelial Growth Factors (immunology, metabolism)
• Humans
• Iodine Radioisotopes
• Lymphokines (immunology, metabolism)
• Macaca fascicularis (immunology)
• Magnetic Resonance Imaging (methods)
• Maximum Tolerated Dose
• Mice
• Mice, Inbred BALB C
• Middle Aged
• Neoplasms (blood supply, diagnostic imaging, immunology, therapy)
• Neovascularization, Pathologic (physiopathology)
• Tissue Distribution
• Tomography, Emission-Computed
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors