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

Jayson, GC; Zweit, J; Jackson, A; Mulatero, C; Julyan, P; Ranson, M; Broughton, L; Wagstaff, J; Hakannson, L; Groenewegen, G; Bailey, J; Smith, N; Hastings, D; Lawrance, J; Haroon, H; Ward, TH; McGown, AT; Tang, M; Levitt, D; Marreaud, S; Lehmann, FF; Herold, M; Zwierzina, H

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 124I-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 (kfp) 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 kfp 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.

• Journal Article Type: Article
• Publication Date: Oct 2, 2002
• Deposit Date: Aug 8, 2007
• Journal: Journal of the National Cancer Institute
• Print ISSN: 14602105
• Peer Reviewed: Peer Reviewed
• Volume: 94
• Issue: 19
• Pages: 1484-1493
• DOI: https://doi.org/10.1093/jnci/94.19.1484
• Publisher URL: http://dx.doi.org/10.1093/jnci/94.19.1484