Effects of anti-VEGF on pharmacokinetics, biodistribution, and tumor penetration of trastuzumab in a preclinical breast cancer model.
Both human epidermal growth factor receptor 2 (HER-2/neu) and VEGF overexpression correlate with aggressive phenotypes and decreased survival among breast cancer patients. Concordantly, the combination of trastuzumab (anti-HER2) with bevacizumab (anti-VEGF) has shown promising results in preclinical xenograft studies and in clinical trials. However, despite the known antiangiogenic mechanism of anti-VEGF antibodies, relatively little is known about their effects on the pharmacokinetics and tissue distribution of other antibodies. This study aimed to measure the disposition properties, with a particular emphasis on tumor uptake, of trastuzumab in the presence or absence of anti-VEGF. Radiolabeled trastuzumab was administered alone or in combination with an anti-VEGF antibody to mice bearing HER2-expressing KPL-4 breast cancer xenografts. Biodistribution, autoradiography, and single-photon emission computed tomography-X-ray computed tomography imaging all showed that anti-VEGF administration reduced accumulation of trastuzumab in tumors despite comparable blood exposures and similar distributions in most other tissues. A similar trend was also observed for an isotype-matched IgG with no affinity for HER2, showing reduced vascular permeability to macromolecules. Reduced tumor blood flow (P < 0.05) was observed following anti-VEGF treatment, with no significant differences in the other physiologic parameters measured despite immunohistochemical evidence of reduced vascular density. In conclusion, anti-VEGF preadministration decreased tumor uptake of trastuzumab, and this phenomenon was mechanistically attributed to reduced vascular permeability and blood perfusion. These findings may ultimately help inform dosing strategies to achieve improved clinical outcomes.
Genentech Research and Early Development, South San Francisco, California, USA.
Cinthia V
CV
Pastuskovas
Eduardo E
EE
Mundo
Simon P
SP
Williams
Tapan K
TK
Nayak
Jason
J
Ho
Sheila
S
Ulufatu
Suzanna
S
Clark
Sarajane
S
Ross
Eric
E
Cheng
Kathryn
K
Parsons-Reponte
Gary
G
Cain
Marjie
M
Van Hoy
Nicholas
N
Majidy
Sheila
S
Bheddah
Josefa
J
dela Cruz Chuh
Katherine R
KR
Kozak
Nicholas
N
Lewin-Koh
Peter
P
Nauka
Daniela
D
Bumbaca
Mark
M
Sliwkowski
Jay
J
Tibbitts
Frank-Peter
FP
Theil
Paul J
PJ
Fielder
Leslie A
LA
Khawli
C Andrew
CA
Boswell
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry / Q000493:pharmacokinetics*; D000915:Antibody Affinity / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007205:Indium Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D007457:Iodine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D051379:Mice; D008819:Mice, Nude; D064847:Multimodal Imaging; D049268:Positron-Emission Tomography; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed; D000068878:Trastuzumab; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D042461:Vascular Endothelial Growth Factor A