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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA094966-03
Application #
6724908
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Yovandich, Jason L
Project Start
2002-04-01
Project End
2007-03-31
Budget Start
2004-04-05
Budget End
2005-03-31
Support Year
3
Fiscal Year
2004
Total Cost
$329,656
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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