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.
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