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Neutralizing gp41 antibodies and their use

A technology of antibodies and monoclonal antibodies, applied in the direction of antibodies, applications, antiviral agents, etc., can solve the problems of cross-reactivity or limited potency of antibody strains, and the inability to provide therapeutic interventions, etc.

Active Publication Date: 2014-10-01
US DEPT OF HEALTH & HUMAN SERVICES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, these antibodies are limited in their strain cross-reactivity or potency and therefore do not provide a viable option for therapeutic intervention

Method used

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  • Neutralizing gp41 antibodies and their use
  • Neutralizing gp41 antibodies and their use
  • Neutralizing gp41 antibodies and their use

Examples

Experimental program
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Embodiment approach

[0409]Several embodiments include methods for producing monoclonal antibodies that specifically bind to a target antigen, wherein the method comprises: (a) isolating a population of memory B cells from a subject that has been exposed to the target antigen, wherein the memory B cells are CD19+IgA-IgD-IgM-B cells; (b) contacting the isolated memory B cell population with an effective amount of IL-21, IL-2 and CD40; (c) from the isolated memory B cell isolating a nucleic acid molecule from a cell population; (d) amplifying nucleic acid encoding a variable heavy chain and a variable light chain from said nucleic acid; (e) expressing a variable heavy chain and a variable light chain from said nucleic acid to obtain from said nucleic acid The variable heavy and variable light chains generate antibody molecules; and (f) selecting monoclonal antibodies that specifically bind to the target antigen.

[0410] Certain embodiments include methods for isolating a repertoire of B cells speci...

Embodiment 1

[0418] Isolation and characterization of broadly neutralizing MPER-specific monoclonal antibodies

[0419] This example illustrates the isolation and characterization of HIV-1 gp41-specific binding antibodies from HIV-1 infected subjects.

[0420] Summary. Characterization of human monoclonal antibodies has provided considerable insight into the mechanisms of broad HIV-1 neutralization. This example describes the isolation of an HIV-1 gp41 membrane proximal outer region (MPER) specific antibody designated 10E8, which neutralized -98% of the virus tested. Analysis of sera from 78 healthy HIV-1 infected donors demonstrated that 27% contained MPER-specific antibodies and 8% contained 10E8-like specificity. In contrast to other neutralizing MPER antibodies, 10E8 does not bind phospholipids, is not autoreactive, and binds to cell surface envelopes. The structure of 10E8 in complex with the intact MPER revealed a susceptibility site comprising a narrow stretch of highly conserved...

Embodiment 2

[0464] neutralization assay

[0465] This example describes the methods used to test the neutralization breadth and potency of the antibodies disclosed herein.

[0466] Neutralization of monoclonal antibodies was measured using a single round of infection of HIV-1 Env-pseudovirus and TZM-bl target cells. HIV-1 Env-pseudoviruses were generated by co-transfecting 293T cells with a pSG3ΔEnv backbone containing a luciferase reporter gene and a second plasmid expressing HIV-1 Env. At 72 hours after transfection, the pseudovirus-containing supernatant was harvested and frozen at -80°C until further use. Anti-gp41 membrane proximal outer region (MPER) specific activity of patient sera and antibodies was measured using HIV-2 / HIV-1 MPER chimeras. Wild-type HIV-27312A was used as a control. The 50% inhibitory concentration (IC50) was calculated as the antibody / inhibitor concentration that caused a 50% reduction in infection. For competition assays, a fixed concentration of peptide w...

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Abstract

Monoclonal neutralizing antibodies are disclosed that specifically bind to the HIV-1 gp41 membrane-proximal external region (MPER). Also disclosed are compositions including the disclosed antibodies that specifically bind gp41, nucleic acids encoding these antibodies, expression vectors including the nucleic acids, and isolated host cells that express the nucleic acids. The antibodies and compositions disclosed herein can be used for detecting the presence of HIV-1 in a biological sample, or detecting an HIV-1 infection or diagnosing AIDS in a subject. In additional, the broad neutralization breadth of the disclosed antibodies makes them ideal for treating a subject with an HIV infection. Thus, disclosed are methods of treating and / or preventing HIV infection.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Application No. 61 / 702,703, filed September 18, 2012, U.S. Provisional Application No. 61 / 698,480, filed September 7, 2012, U.S. Provisional Application No. 61 / 672,708, filed July 17, 2012 and the benefit of U.S. Provisional Application No. 61 / 556,660, filed November 7, 2011. Each of these prior applications is hereby incorporated by reference in its entirety. technical field [0003] The present invention relates to the identification of monoclonal neutralizing antibodies, such as, but not limited to, antibodies that bind to the membrane-proximal region of HIV-1 gp41. Background technique [0004] An effective human immunodeficiency virus type 1 (HIV-1) vaccine may require the induction of neutralizing antibodies (NAbs) that block HIV-1 entry into human cells. To be effective, vaccine-induced antibodies must be active against most circulating strains of HIV-1. Unfortunately,...

Claims

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Application Information

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IPC IPC(8): C07K16/10A61K39/42A61P31/18C12N15/13
CPCG01N33/56972C07K2317/55A61K49/0004C07K2317/34C07K16/1063C07K2317/76A61K45/06C07K2317/56C07K2317/565C07K2317/14G01N2333/161G01N33/56983A61K39/42C07K16/1045C07K16/00A61P31/18A61K2039/505C07K2317/21C07K2317/31C07K2317/567G01N33/56988
Inventor 马克·康纳斯黄竞荷利奥·B·劳布邝达平嘉里·纳贝尔约翰·R·玛斯考拉张宝山里贝卡·S·里迪塞尔伊万琳·格奥尔基耶夫杨永平朱江吉拉德·欧费克
Owner US DEPT OF HEALTH & HUMAN SERVICES
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