The long-term objective of this work is to design bi-functional peptide-drug conjugates that specifically target leukocytes. The peptide sequences are derived from ICAM-1 and bind to LFA-1 on activated leukocytes. The peptide-drug conjugates are internalized where the drug portion of the conjugate is available to elicit its pharmacological action. This technology may be used to treat autoimmune diseases, leukemia, and HIV infection. The proposed research will initially study the utility of methotrexate-ICAM-1 peptide (MTX-peptide) conjugates to suppress T-cell activation. These MTX-peptide conjugates inhibit T-cell activation by a dual function mechanism: (1) they inhibit the cell adhesion signal during T-cell activation, and (2) they target MTX to LFA-1 on T-cells and induce T-cell death by internalizing MTX. Preliminary in vivo and in vitro studies have shown that an MTX-peptide conjugate utilizing a twelve amino acid peptide cyclized by a disulfide bond is internalized, inhibits cell adhesion, causes death of activated T-cells and is useful for inhibiting the progression of rheumatoid arthritis in a mouse model. The SBIR Phase I project is focused on designing small cyclic hexapeptides from the original clBR cyclic peptide with 12 amino acid sequence and a disulfide bond. The cyclic hexapeptide will be formed using the N- to C-terminal cyclization method. This cyclic hexapeptides will be conjugated to MTX and evaluated in in vitro cell culture assays to cause T-cell death. The studies will be used to select an optimal candidate for the in vivo animal studies planned for the Phase II SBIR application. It is envisioned that at the end of Phase II in vivo animal studies sufficient data will be generated to select a peptide-drug conjugate for potential clinical evaluation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
1R43AI052556-01A1
Application #
6739994
Study Section
Special Emphasis Panel (ZRG1-HP (10))
Program Officer
Prograis, Lawrence J
Project Start
2004-09-15
Project End
2005-08-31
Budget Start
2004-09-15
Budget End
2005-08-31
Support Year
1
Fiscal Year
2004
Total Cost
$100,000
Indirect Cost
Name
Admunex Therapeutics, Inc.
Department
Type
DUNS #
City
Lawrence
State
KS
Country
United States
Zip Code
66047