A Novel Class of HIV Therapeutics: Monoclonal Antibodies that Neutralize Previously Resistant HIV Primary Isolates

Summary Background: Molecular studies of the genomic organization of HIV-1 show that it encodes a number of genes common to all retroviruses, such as the gag, pol, and env genes. The env gene of HIV-1 produces a cleaved envelope glycoprotein (gp120) that is expressed on the exterior viral envelope surface. The binding and fusion of HIV-1 viruses with cells is mediated by specific interactions between the external subunit of gp120 and the CD4 receptor on the target cell surface. Studies have shown that serum antibodies reacting with HIV-1 gp120 can neutralize viral infection by interfering with the binding of gp120 and CD4. But envelope glycoprotein variation can allow escape of viruses from neutralization by these antibodies because epitopes on gp 120 of these viruses are not accessible. As a consequence, attempts to produce vaccines based on inducing neutralizing antibodies have been difficult.

Invention: A novel class of HIV antibody therapeutics. Three monoclonal antibodies (E.1, E.3, and E.5) directed against previously inaccessible glycans present on the HIV surface glycoprotein gp120/41 that function by sterically hindering fusion of the HIV-1 virus to the body's CD4 cells. Each monoclonal Antibody (E.1, E.3, and E.5) is able to neutralize M-tropic, T-tropic, and dual-tropic HIV-1 primary isolates 60-80 % compared to control, regardless of the preferential coreceptor usage of the isolate

Advantages: E.1, E.3, and E.5 antibodies inhibit isolates of HIV-1 characteristically resistant to HIV-1 antibody-positive sera, regardless of the stains preferred coreceptor usage. The antibodies can be used individually or part of a cocktail. Additionally, HIV is part of Nucleotide sequences from viral genomes of a family of retroviruses called Lentiviruses contain the structural env genes as well as other regulatory sequences. Thus, the antibodies can be used as therapeutics for all classes and families of lentiviruses. The epitopes for E.1, E.3, and E.5 can also used in the construction of conjugate vaccines.

Applications Commercial Applications: The monoclonal antibodies can be used to treat individual's refractory to drug treatment, infected pregnant women prior to delivery to prevent mother to child transmissions, and infants born to HIV-1 infected mothers to neutralize any transmitted virus (via breast milk). The E.5 antibody can be used as a therapeutic agent using drug, toxin, or radionuclide conjugated E.5 to target and kill tumor/cancer cells. The novel epitopes can also be used as part of a vaccine for the prevention HIV infection and subsequent development of AIDS.

Patent Status: Pending

Publications Mello et. al, Inhibition of HIV-1 infection by monoclonal antibodies to carbohydrates of Schistosoma mansoni, Medical Microbiology and Immunology, 194, 61-65, 2005. For Further Information Please Contact the Director of Business Development Vivian Berlin Email: vivian_berlin@harvard.edu Telephone: (617) 495-0474

Inventor(s): Harn, Donald Alfred

Type of Offer: Licensing

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