Targeting endothelium for gene therapy via receptors up-regulated during angiogenesis and inflammation

Abstract

 Endothelial cells are an attractive target for gene therapy because they are intimately involved in disease processes associated with inflammation and angiogenesis and because endothelial cells are readily accessible to gene therapy vectors via the circulation. Furthermore, specific receptors are up-regulated during angiogenesis or during inflammation. Therefore it should be possible to target the specific populations of endothelial cells involved in each of these disease processes. We have utilized two bispecific antibodies to target entry of an adenovirus vector into endothelial cells expressing a receptor up-regulated during angiogenesis (α_v integrins) and a receptor up-regulated during inflammation (E-selectin). Both bispecific antibodies contain the anti-FLAG M2 mAb, which binds to a FLAG epitope genetically incorporated into the penton base protein of the vector, AdFLAG. The anti-α_v-integrin×anti-FLAG bsAb was able to direct binding and entry of AdFLAG into endothelial cells via α_v integrins. Likewise, the anti-E-selectin×anti-FLAG bsAb was able to direct binding and entry of AdFLAG into tumor-necrosis-factor(TNF)-activated endothelial cells via E-selectin. Endothelial cells not activated with TNF were not efficiently transduced by the AdFLAG/E-selectin bsAb complex. These results demonstrate that bispecific antibodies can be successfully used to target adenovirus to endothelially expressed receptors that are up-regulated during angiogenesis or inflammation.