The emerging molecular picture of tumor angiogenesis has inspired new strategies for cancer therapy, which are currently in various stages of preclinical and clinical development. Among these are monoclonal antibodies that target individual molecular components involved in the pathologic process. In the proposed project, we hypothesize that a more specific strategy would result from targeting two rather than one molecular component. In particular, we are testing the hypothesis that selective neutralization of VEGF at the site of tumor angiogenesis is superior to unselective neutralization. For this, we will develop bifunctional antibody constructs that combine a VEGF neutralization activity with a targeting device and compare them to the corresponding monofunctional antibody constructs. Our antibody constructs are designed to facilitate (i) selective VEGF neutralization through Tie-2 or Tie-2/ang-2 complex targeting, (ii) systemic delivery by gene transfer using recombinant adenoviruses, and (iii) preclinical evaluation in syngeneic mouse tumor models. Compared to existing monoclonal antibodies that target tumor angiogenesis, we anticipate our antibody constructs to be superior in terms of efficacy. In addition, they are designed to facilitate a faster transition from preclinical to clinical development based on (i) cross-reactivity with human and mouse antigen and (ii) established antibody humanization strategies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Yovandich, Jason L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
Popkov, Mikhail; Jendreyko, Nina; Gonzalez-Sapienza, Gualberto et al. (2004) Human/mouse cross-reactive anti-VEGF receptor 2 recombinant antibodies selected from an immune b9 allotype rabbit antibody library. J Immunol Methods 288:149-64
Popkov, Mikhail; Rader, Christoph; Barbas 3rd, Carlos F (2004) Isolation of human prostate cancer cell reactive antibodies using phage display technology. J Immunol Methods 291:137-51
Rader, Christoph; Turner, James M; Heine, Andreas et al. (2003) A humanized aldolase antibody for selective chemotherapy and adaptor immunotherapy. J Mol Biol 332:889-99
Popkov, Mikhail; Mage, Rose G; Alexander, Cornelius B et al. (2003) Rabbit immune repertoires as sources for therapeutic monoclonal antibodies: the impact of kappa allotype-correlated variation in cysteine content on antibody libraries selected by phage display. J Mol Biol 325:325-35
Jendreyko, Nina; Popkov, Mikhail; Beerli, Roger R et al. (2003) Intradiabodies, bispecific, tetravalent antibodies for the simultaneous functional knockout of two cell surface receptors. J Biol Chem 278:47812-9