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

2.50
Hdl Handle:
http://hdl.handle.net/10541/81265
Title:
Molecular imaging and biological evaluation of HuMV833 anti-VEGF antibody: implications for trial design of antiangiogenic antibodies.
Authors:
Jayson, Gordon C ( 0000-0002-8515-8944 ) ; Zweit, Jamal; Jackson, Alan; Mulatero, Clive; Julyan, Peter J; Ranson, Malcolm R; Broughton, Lynn; Wagstaff, John; Hakannson, L; Groenewegen, Gerard; Bailey, John; Smith, Nigel K; Hastings, David L; Lawrance, Jeremy A L; Haroon, Hamied; Ward, Timothy H; McGown, Alan T; Tang, Meina; Levitt, Dan; Marreaud, Sandrine; Lehmann, Frederic F; Herold, Manfred; Zwierzina, Heinz
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.
Affiliation:
Cancer Research UK Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, UK. Gordon.Jayson@christie-tr.nwest.nhs.uk
Citation:
Molecular imaging and biological evaluation of HuMV833 anti-VEGF antibody: implications for trial design of antiangiogenic antibodies. 2002, 94 (19):1484-93 J. Natl. Cancer Inst.
Journal:
Journal of the National Cancer Institute
Issue Date:
2-Oct-2002
URI:
http://hdl.handle.net/10541/81265
PubMed ID:
12359857
Type:
Article
Language:
en
ISSN:
0027-8874
Appears in Collections:
All Christie Publications ; All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorJayson, Gordon C-
dc.contributor.authorZweit, Jamal-
dc.contributor.authorJackson, Alan-
dc.contributor.authorMulatero, Clive-
dc.contributor.authorJulyan, Peter J-
dc.contributor.authorRanson, Malcolm R-
dc.contributor.authorBroughton, Lynn-
dc.contributor.authorWagstaff, John-
dc.contributor.authorHakannson, L-
dc.contributor.authorGroenewegen, Gerard-
dc.contributor.authorBailey, John-
dc.contributor.authorSmith, Nigel K-
dc.contributor.authorHastings, David L-
dc.contributor.authorLawrance, Jeremy A L-
dc.contributor.authorHaroon, Hamied-
dc.contributor.authorWard, Timothy H-
dc.contributor.authorMcGown, Alan T-
dc.contributor.authorTang, Meina-
dc.contributor.authorLevitt, Dan-
dc.contributor.authorMarreaud, Sandrine-
dc.contributor.authorLehmann, Frederic F-
dc.contributor.authorHerold, Manfred-
dc.contributor.authorZwierzina, Heinz-
dc.date.accessioned2009-09-16T11:33:10Z-
dc.date.available2009-09-16T11:33:10Z-
dc.date.issued2002-10-02-
dc.identifier.citationMolecular imaging and biological evaluation of HuMV833 anti-VEGF antibody: implications for trial design of antiangiogenic antibodies. 2002, 94 (19):1484-93 J. Natl. Cancer Inst.en
dc.identifier.issn0027-8874-
dc.identifier.pmid12359857-
dc.identifier.urihttp://hdl.handle.net/10541/81265-
dc.description.abstractBACKGROUND: 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.en
dc.language.isoenen
dc.subjectCanceren
dc.subject.meshAnimals-
dc.subject.meshAntibodies, Monoclonal-
dc.subject.meshAntibody Formation-
dc.subject.meshAntineoplastic Agents-
dc.subject.meshCapillary Permeability-
dc.subject.meshDose-Response Relationship, Immunologic-
dc.subject.meshDrug Design-
dc.subject.meshDrug Evaluation, Preclinical-
dc.subject.meshEndothelial Growth Factors-
dc.subject.meshHumans-
dc.subject.meshIodine Radioisotopes-
dc.subject.meshLymphokines-
dc.subject.meshMacaca fascicularis-
dc.subject.meshMagnetic Resonance Imaging-
dc.subject.meshMaximum Tolerated Dose-
dc.subject.meshMice-
dc.subject.meshMice, Inbred BALB C-
dc.subject.meshMiddle Aged-
dc.subject.meshNeoplasms-
dc.subject.meshNeovascularization, Pathologic-
dc.subject.meshTissue Distribution-
dc.subject.meshTomography, Emission-Computed-
dc.subject.meshVascular Endothelial Growth Factor A-
dc.subject.meshVascular Endothelial Growth Factors-
dc.titleMolecular imaging and biological evaluation of HuMV833 anti-VEGF antibody: implications for trial design of antiangiogenic antibodies.en
dc.typeArticleen
dc.contributor.departmentCancer Research UK Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, UK. Gordon.Jayson@christie-tr.nwest.nhs.uken
dc.identifier.journalJournal of the National Cancer Instituteen

Related articles on PubMed

All Items in Christie are protected by copyright, with all rights reserved, unless otherwise indicated.