A Novel Multimeric CD4 Fusion Protein for Treating HIV Infection
Posted Jun 13 2010 5:00pm
Description of Invention: This invention could potentially provide an alternative to antiretroviral therapy (ART), especially in cases where productively-infected cells persist with ART. This multimeric CD4 fusion protein acts as a decoy to inhibit human immunodeficiency virus (HIV-1) entry into host cells. More specifically, this multimeric CD4 inhibits the interaction between HIV-1 gp120 and CD4 present on the surface of CD4 T-cells, the major HIV-1 target cell. There is strong evidence that binding between gp120, as part of a virion spike, and CD4 on cell surface is the first step for HIV entry into host cells. This multimeric CD4 provides a number of advantages over inhibitory CD4 molecules previously developed. First, this CD4 multimer is capable of binding at least 10 gp120 simultaneously with high avidity. Second, it does not enhance HIV infection at suboptimal concentrations, a phenomenon observed with previously developed recombinant CD4 molecules. Third, it has been demonstrated that this CD4 fusion protein hyper-crosslinks CD16 on natural killer (NK) cells and as a consequence delivers an exceptionally strong signal to NK cells, promoting potent Antibody-Dependent Cellular Cytotoxicity (ADCC) and lysis of HIV-infected cells. The inventors have shown that this recombinant CD4 multimer efficiently neutralizes primary isolates from different HIV subgroups.
The invention comprises an immunoglobulin construct having up to 12 amino terminal domains of CD4 (D1D2), the epitope responsible for HIV-1 gp120 binding activity. It also comprises domains of a human IgG1 heavy chain, as well as the IgA tailpiece that drives its polymerization. The two amino terminal domains of CD4 are fused to the CH2CH3 domains (which bears the FC receptor recognition epitopes) of a human IgG1 heavy chain.
Applications: HIV therapeutics and HIV vaccine development
Advantages: Efficient inhibition of HIV-1 viral entry without enhancement of infection at suboptimal concentrations. Potent activation of Antibody-Dependent Cellular Cytotoxicity (ADCC) and lysis of HIV-infected cells.
Development Status: The anti-HIV activity of this multimeric CD4 protein has been well characterized in vitro.
Inventors: James Arthos (NIAID) Claudia Cicala (NIAID) Anthony S Fauci (NIAID)
J Arthos et al. Biochemical and biological characterization of a dodecameric CD4-Ig fusion protein: implications for therapeutic and vaccine strategies. J Biol Chem. 2002 Mar 29;277(13):11456-11464. [ PubMed abs ]
PD Kwong et al. HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites. Nature. 2002 Dec 12;420(6916):678-682. [ PubMed abs ]
N Gupta et al. Targeted lysis of HIV-infected cells by natural killer cells armed and triggered by a recombinant immunoglobulin fusion protein: implications for immunotherapy. Virology. 2005 Feb 20;332(2):491-497. [ PubMed abs ]
T Zhou et al. Structural definition of a conserved neutralization epitope on HIV-1 gp120. Nature. 2007 Feb 15;445(7129):732-737. [ PubMed abs ]
A Bennett et al. Cryoelectron tomographic analysis of an HIV-neutralizing protein and its complex with native viral gp120. J Biol Chem. 2007 Sep 21;282(38):27754-27759. [ PubMed abs ]
Licensing Status: Available for licensing.
Collaborative Research Opportunity: The National Institute of Allergy and Infectious Diseases, Laboratory of Immunoregulation, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this invention. Please contact William Ronnenberg at 301-451-3522 or email@example.com for more information.
For Additional Information Please Contact: Susan Ano Ph.D. NIH Office of Technology Transfer 6011 Executive Blvd. Suite 325, Rockville, MD 20852 United States Email: firstname.lastname@example.org Phone: 301-435-5515 Fax: 301-402-0220