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Methods and compositions for targeting agents into and across the blood-barrier and other endothelial cell microvascular barriers

  • US 8,026,209 B2
  • Filed: 02/10/2004
  • Issued: 09/27/2011
  • Est. Priority Date: 02/10/2003
  • Status: Expired due to Fees
First Claim
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1. A method of delivering a therapeutic agent into and across an endothelial cell (EC) of a microvascular blood-central nervous system (CNS) barrier in a Diphtheria toxin (DT) sensitive subject in need thereof, comprising:

  • (a) administering to the subject a moiety that increases binding of DT to DT receptors (DTR) selected from the group consisting of heparin, heparan sulfate, a heparan sulfate proteoglycan, a matrix metalloproteinase inhibitor, BB-94 (batimastat), an inhibitor of ADAM12 or ADAM10, or a MAP/ERK kinase inhibitor;



    followed by(b) administering to said subject a therapeutic agent with a pharmaceutically acceptable carrier, which therapeutic agent or carrier is conjugated to a DTR-binding targeting molecule which is selected from the group consisting of(i) a non-toxic portion of DT polypeptide chain;

    (ii) all or a portion of DT B chain; and

    (iii) all or a portion of a non-toxic DT mutant CRM197, 

    to constitute a conjugate that specifically binds to the DTR on target tissue cells, such that an effective barrier-entering, barrier-crossing amount of said therapeutic agent enters and crosses the EC microvascular barrier.

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