With regard to real estate, it is said, location is everything. Location may prove to be almost as important with respect to the delivery and application of novel, especially macromolecular, therapeutic agents. Specifically targeted delivery should enhance efficacy while at the same time reducing toxicity.
In this issue of Blood, Murciano and colleagues (page 3977) report the delivery and localization of immunoconjugates of tissue plasminogen activator (tPA) to the pulmonary vasculature. Although the concept of immunotargeting therapeutic agents is not new, several aspects of the strategy employed by Murciano et al are noteworthy. Intercellular adhesion molecule-1 (ICAM-1) appears to be an especially good target. It is constitutively expressed on the vascular endothelium at a high level that is unaltered by inflammatory cytokines. Furthermore, anti-ICAM conjugates greater than 1 μm in diameter are not readily internalized but remain exposed on the endothelial surface for some time. Such conjugates are thus well positioned to function as molecular therapeutic bioreactors working at the blood–vessel wall interface. As a proof of concept, Murciano et al describe the efficacious lysis of pulmonary fibrin microemboli using an anti-ICAM/tPA conjugate.
While the results of the work described by Murciano et al are exciting in their own right, the work also offers a glimpse of the future promise of endothelial-targeted therapeutics. Given the large surface area of the (pulmonary) endothelium, enzyme bioreactors positioned at the endothelial surface may represent an exciting new approach to the removal or inactivation of noxious metabolites or toxins. By exploiting more specific vascular addressins as immunotargets, selected vascular beds may be targeted. Perhaps by targeting tumor vasculature with an enzyme to facilitate the conversion of a prodrug to an active antitumor agent, or conversely targeting the pulmonary or hepatic vascular spaces with an enzyme to inactivate chemotherapeutic agents, tumors may be exposed to higher and more effective doses of chemotherapeutic agents while minimizing systemic toxicity. Although the work described by Murciano et al is still in an early stage and there is much work to be done, the future is exciting; the promise is great.
