CD4-Nanoparticle Conjugates for the Treatment of HIV/AIDS

Background:
The Laboratory of Cell Biology of the National Cancer Institute is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize polyvalent antiviral dendritic conjugates for the treatment of HIV.

Human immunodeficiency virus type 1 (HIV-1) infection of target cells is initiated by binding of the viral envelope glycoprotein gp120 to the cell surface receptor CD4. D1D2-IgP is a dodecameric CD4-immunoglobulin fusion protein with sub-nanomolar HIV neutralizing potency against patient isolates, capable of viral rupture. However, due to its high molecular weight and polydispersity, this fusion protein cannot be used as an HIV drug.

Technology:
This technology describes the structure-based design and synthesis of monodisperse, homogeneous, CD4-nanoparticle conjugates that mimic the D1D2-IgP fusion protein. These conjugates comprise a soluble, two-domain human CD4 covalently linked to a flexible dendrimer-PEG scaffold. The construct is designed to mimic the structure of D1D2-IgP, and, at 173 kDa, is similar in size to successful antibody therapeutics currently on the market.

Because it retains the key elements of potency and the polyvalent human CD4 moieties of D1D2-IgP, this conjugate is expected to afford the same antiviral properties in a monodisperse, homogeneous, and low-molecular-weight species.

Further R&D Needed:

• Commercial optimization of existing strategies for expressing and purifying a protein-engineered CD4 mutant, and of protein-nanoparticle conjugate assembly reaction
• Infectivity neutralization assays against a wide range of clinical isolate HIV strains
• Pharmacologic characterization, e.g., in vivo half-life
• Testing of pre- and/or post-exposure prophylaxis (person-to-person and mother-to-child)
• Testing as a topical microbicide

R&D Status: Discovery. Proof-of-concept underway.

IP Status: U.S. Provisional Application No. 60/932,464 filed 31 May 2007

Value Proposition--Solution:
A CD4 therapy that overcomes previous failures by addressing conformational masking:

• Mimics the most powerful HIV-neutralizing protein
• Effective against all CD4-dependent strains
• Monodisperse, homogeneous

Contact Information:
John D. Hewes, Ph.D., NCI Technology Transfer Center
Phone: 301-435-3121
E-mail: Hewesj@mail.nih.gov

Reference:  #619 KH

Posted 02/09/2008