Increased plasma vascular endothelial growth factor (VEGF) as a surrogate marker for optimal therapeutic dosing of VEGF receptor-2 monoclonal antibodies

Guido Bocci, Shan Man, Shane K. Green, Giulio Francia, John M L Ebos, Jeanne M. Du Manoir, Adina Weinerman, Urban Emmenegger, Li Ma, Philip Thorpe, Andrew Davidoff, James Huber, Daniel J. Hicklin, Robert S. Kerbel

Research output: Contribution to journalArticle

139 Scopus citations

Abstract

A major obstacle compromising the successful application of many of the new targeted anticancer drugs, including angiogenesis inhibitors, is the empiricism associated with determining an effective biological/therapeutic dose because many of these drugs express optimum therapeutic activity below the maximum tolerated dose, if such a dose can be defined. Hence, surrogate markers are needed to help determine optimal dosing. Here we describe such a molecular marker, increased plasma levels of vascular endothelial growth factor (VEGF), in normal or tumor-bearing mice that received injections of an anti-VEGF receptor (VEGFR)-2 monoclonal antibody, such as DC101. Rapid increases of mouse VEGF (e.g., within 24 hours) up to 1 order of magnitude were observed after single injections of DC101 in non-tumor-bearing severe combined immunodeficient or nude mice; similar increases in human plasma VEGF were detected in human tumor-bearing mice. RAFL-1, another anti-VEGFR-2 antibody, also caused a significant increase in plasma VEGF. In contrast, increases in mouse VEGF levels were not seen when small molecule VEGFR-2 inhibitors were tested in normal mice. Most importantly, the increases in plasma VEGF were induced in a dose-dependent manner, with the maximum values peaking when doses previously determined to be optimally therapeutic were used. Plasma VEGF should be considered as a possible surrogate pharmacodynamic marker for determining the optimal biological dose of antibody drugs that block VEGFR-2 (KDR) activity in a clinical setting.

Original languageEnglish (US)
Pages (from-to)6616-6625
Number of pages10
JournalCancer Research
Volume64
Issue number18
DOIs
Publication statusPublished - Sep 15 2004

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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