Molecular imaging and biological evaluation of HuMV833 anti-VEGF antibody: implications for trial design of antiangiogenic antibodies.
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.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000917:Antibody Formation; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002199:Capillary Permeability; D004306:Dose-Response Relationship, Immunologic; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D016228:Endothelial Growth Factors / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007457:Iodine Radioisotopes; D008222:Lymphokines / Q000276:immunology* / Q000378:metabolism; D008252:Macaca fascicularis / Q000276:immunology; D008279:Magnetic Resonance Imaging / Q000379:methods*; D020714:Maximum Tolerated Dose; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009369:Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging* / Q000276:immunology / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D007457:Iodine Radioisotopes; D008222:Lymphokines; C466953:MV833 monoclonal antibody, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors