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Method of Inducing Neutralizing Antibodies to Human Immunodeficiency Virus

a technology of immunodeficiency virus and neutralizing antibody, which is applied in the field of inducing neutralizing antibodies to human immunodeficiency virus, can solve the problems of easy escape of antibodies that cannot control hiv-1

Inactive Publication Date: 2010-02-04
DUKE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about a way to make antibodies that can neutralize HIV. The invention uses special proteins that show the virus's vulnerable parts in their natural environment. The invention also includes methods for using these proteins to break the body's tolerance to the virus. The technical effect of this invention is to provide a better way to make antibodies that can help fight HIV.

Problems solved by technology

However, these antibodies do not control HIV-1 and are easily escaped (Burton et al, Nature Immun.

Method used

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  • Method of Inducing Neutralizing Antibodies to Human Immunodeficiency Virus
  • Method of Inducing Neutralizing Antibodies to Human Immunodeficiency Virus
  • Method of Inducing Neutralizing Antibodies to Human Immunodeficiency Virus

Examples

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example 1

[0045]Design of an HIV-1 immunogen that can induce broadly reactive neutralizing antibodies is a major goal of HIV-1 vaccine development. While rare human mabs exist that broadly neutralize HIV-1, HIV-1 envelope immunogens do not induce these antibody specificities. In this study, it was demonstrated that the two most broadly reactive HIV-1 envelope gp41 human mabs, 2F5 and 4E10, are polyspecific, autoantibodies reactive with cardiolipin. Thus, current HIV-1 vaccines may not induce antibodies against membrane proximal gp41 epitopes because of gp41 membrane proximal epitopes mimicry of autoantigens.

Experimental Details

[0046]Monoclonal Antibodies. Mabs 2F5, 2G12, and 4E10 were produced as described (Steigler et al, AID Res. Human Retroviruses 17:1757 (2001), Purtscher et al, AIDS 10:587 (1996), Trkola et al, J. Virol. 70:1100 (1996)). IgG1b12 (Burton et al, Science 266:1024-1027 (1994)) was the generous gift of Dennis Burton, Scripps Institute, La Jolla, Calif. Mab 447-52D (Zolla-Pazn...

example 2

[0053]The ability of autoantigens of the invention to induce the production of neutralizing antibodies was studied using, as autoantigen, cardiolipin (lamellar and hexagonal phases), 1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-L-serine] (POPS) (lamellar and hexagonal phases), 1-palmitoyl-2-oleoyl-phosphatidylethanolamine (POPE) (lamellar phase) and dioleoyl phosphatidylethanolamine (DOPE) (hexagonal phase). Guinea pigs (4 per group) were immunized with phospholipid (cardiolipin lamellar phase, cardiolipin hexagonal phase, POPS lamellar phase, POPS hexagonal phase, POPE lamellar phase or DOPE hexagonal phase) in 10 μg of oCpGs, four times, with each immunization being two weeks apart. Following the four phospholipid immunizations, a final immunization was made IP with 10 μg of oCpGs with 100 μg of group M consensus Env, CON-S gp140CFI oligomer (that is, the CFI form of the protein shown in FIG. 4A).

[0054]Neutralization assays were performed using an Env pseudotype neutralization assay...

example 3

Immunogen Design

[0063]Peptide sequences that include the nominal epitopes of mAbs 2F5 and 4E10, respectively, linked to a hydrophobic linker (GTH1) were synthesized and embedded into synthetic liposomes (FIG. 6). The first generation of immunogens was designed with the 2F5 and 4E10 epitope sequences at the distal end of the lipid bilayer (FIG. 6A). These constructs provided unconstrained access of mAbs to their respective epitopes. The second generation constructs have been designed to mimic the native orientation of the MPER region with the 2F5 and 4E10 mAb epitope sequences linked proximal to the hydrophobic linker (FIGS. 6A, 6B).

[0064]The composition of the synthetic liposomes comprised the following phospholipids, POPC (1-Palmitoyl-2-Oleoyl-sn-Glycero-3-Phosphocholine), POPE (1-Palmitoyl-2-Oleoyl-sn-Glycero-3-Phosphoethanolamine), DMPA (1,2-Dimyristoyl-sn-Glycero-3-Phosphate), and Cholesterol dissolved in chloroform (purchased from Avanti Polar Lipids (Alabaster, Ala.)).

[0065]Sy...

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Abstract

The present invention relates, in general, to human immunodeficiency virus (HIV), and, in particular, to a method of inducing neutralizing antibodies to HIV and to compounds and compositions suitable for use in such a method.

Description

[0001]This application claims priority from U.S. Prov. Appln. No. 60 / 670,243, filed Apr. 12, 2005, U.S. Prov. Appln. No. 60 / 675,091, filed Apr. 27, 2005, U.S. Prov. Appln. No. 60 / 697,997, filed Jul. 12, 2005, and U.S. Prov. Appln. No. 60 / 757,478, filed Jan. 10, 2006, the entire contents of which are incorporated herein by reference.TECHNICAL FIELD[0002]The present invention relates, in general, to human immunodeficiency virus (HIV), and, in particular, to a method of inducing neutralizing antibodies to HIV and to compounds and compositions suitable for use in such a method.BACKGROUND[0003]The first antibodies that are made in acute HIV-1 infection are against the CD4 binding site (Moore et al, J. Virol. 68(8) 5142 (1994)), the CCR5 co-receptor binding site (Choe et al, Cell 114(2):161-170 (2003)), and the V3 loop (Moore et al, J. Acquir. Immun. Def. Syn. 7(4):332 (1994)). However, these antibodies do not control HIV-1 and are easily escaped (Burton et al, Nature Immun. 5:233-236 (20...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/127A61K39/00A61P31/18C12P21/00
CPCA61K39/0005A61K39/12A61K2039/55561A61K2039/6018C07K16/1063C07K16/18C12N2740/16134C12N2740/16011C12N2740/16111A61K39/21A61K39/385A61K2039/55555A61K2039/55566C07K2316/96C07K2317/76A61P31/18A61P37/04Y02A50/30C12N7/00A61K9/127A61K2039/55505A61K2039/57C07K14/005C07K2319/00C12N2740/16122
Inventor HAYNES, BARTON F.ALAM, S. MUNIRLIAO, HUA-XIN
Owner DUKE UNIV
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