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Human immunodeficiency virus neutralizing antibodies adn methods of use thereof

An antibody and virus technology, which is used in the preparation and application of broad-spectrum neutralizing antibodies

Active Publication Date: 2014-05-14
THE ROCKEFELLER UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This high frequency of mutations is a potential obstacle for antibody cloning, as the mutated sequence may no longer be complementary to the primers used for cloning

Method used

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  • Human immunodeficiency virus neutralizing antibodies adn methods of use thereof
  • Human immunodeficiency virus neutralizing antibodies adn methods of use thereof
  • Human immunodeficiency virus neutralizing antibodies adn methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0161] Materials, Methods and Instruments

[0162] sample. Human samples were collected from all participating institutions after signing informed consent according to protocols evaluated by the Institutional Review Board (IRB). Patient 1 was selected from a cohort of long-term non-progressors at the Aaron Diamod Aids Research Center in New York. Patients 3 and 8 were selected from an elite group of controllers at the Ragon Institute in Boston. Patients 1, 3 and 8 were selected based on their broad-spectrum neutralizing serum activity against a standard set of HIV isolates. Patient 12 was selected from the Protocol G Cohort of the International Aids Vaccine Initiative based on broad-spectrum serum neutralizing activity.

[0163]Staining, single cell sorting and antibody cloning. Staining and single cell sorting of 2CC nuclear and gp140-specific Ig+ memory B cells were performed (J.F. Scheid et al., Nature 458, 636 (Apr2, 2009)). Briefly, CD19+ B cells were enriched from p...

Embodiment 2

[0179] Isolate HIV Antibody

[0180] To determine whether HIV antibody cloning is restricted by somatic mutation, a series of new primers were designed to remove this potential problem (Table 1). The new primer set was tested by sorting B cells bound to the HIV-gp120 nucleoprotein (2CC nucleus) lacking the V1-3 loop and containing a pair of stabilizing disulfide bonds. In contrast to the re-surfaced bait used to clone VRCOl, the 2CC nuclear bait also allowed capture of antibodies against the CD4-induced co-receptor binding site (CD4i).

[0181] In comparison, the new primer set increased the recovery of the IgH chain when compared to the original primer set (Fig. 4(a)). Antibodies obtained with the new primer set had more mutations (average 35.6 vs 19.8p=<0.0001 and a maximum of 85 vs 50 for IgH) and contained clones not found with the original primer set (Fig. 4(a)) . To determine whether the new primers could rescue VRCOl-like antibodies from cells that had been sorted wi...

Embodiment 3

[0184] Binding specificity of HIV antibodies

[0185] The antibody clones captured by the 2CC nuclear bait varied widely in size, ranging from 2-76 different members (Table 3). To determine whether antibodies captured by the 2CC core could bind to the HIV spike, an ELISA was performed with YU2gp120 on representative members of each expanded clone. All tested antibodies bound to gp120 (Table 3).

[0186] Sites of antibody binding on the HIV spike were mapped using muteins that interfere with CD4bs (gp120(D368R)) or CD4-induced co-receptor binding sites (CD4i, gp120(I420R)). As reported by X. Wu et al., Science 329, 856 (13 August 2010), since VRC01 is sensitive to the D368R mutation, it is listed as a CD4bs antibody, but due to its proximity to the CD4i site, it also shows some sensitivity to the I420R mutation sensitive. NIH45-46, antibodies 3BNC60, 8ANC131 and 12A12, belonging to VRC01 variants, had ELISA profiles similar to VRC01 (these clone members were selected based o...

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Abstract

The invention provides broadly neutralizing antibodies directed to epitopes of Human Immunodeficiency Virus, or HIV. The invention further provides compositions containing HIV antibodies used for prophylaxis, and methods for diagnosis and treatment of HIV infection.

Description

[0001] Cross References to Related Applications [0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 61 / 486,960, filed May 17, 2011. The disclosure of this provisional application is incorporated herein in its entirety. [0003] Statement of Federally Funded Research [0004] Research leading to the present invention was supported in part by National Institutes of Health Grant No. P01AI08677-01. Accordingly, the US Government has certain rights in this invention. technical field [0005] The present invention relates to antibodies directed against epitopes of the human immunodeficiency virus ("HIV"). The invention also relates to the preparation and application of broad-spectrum neutralizing antibody against gp120 envelope protein of HIV for preventing and treating HIV infection. Background technique [0006] HIV causes acquired immunodeficiency syndrome ("AIDS"). Immune responses to HIV infection in long-term non-progres...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/08A61K39/21
CPCC07K16/1063A61K2039/505C07K2317/76C07K2317/92C07K2317/24C07K2317/21C07K2317/34C07K2317/565C07K2317/55C07K2317/10C07K2317/56A61P31/12A61P31/18A61P43/00C07K16/1045G01N33/56983A61K39/395
Inventor 约翰内斯·谢德米歇尔·努森兹韦格帕梅拉·J·比约克曼罗恩·迪斯金
Owner THE ROCKEFELLER UNIV
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