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Antibody moleules to dengue virus and uses thereof

A technology of antibody molecule and dengue virus, which is applied in the field of antibody molecule for dengue virus and its application, can solve the problems of antigenic difference and hindering the effective treatment of serotype

Active Publication Date: 2016-12-07
VISTERRA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Dengue viruses with different serotypes differ by about 25-40% at the amino acid level and have antigenic differences, and this variation will prevent effective treatment against all serotypes

Method used

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  • Antibody moleules to dengue virus and uses thereof
  • Antibody moleules to dengue virus and uses thereof
  • Antibody moleules to dengue virus and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 5

[0251] Example 5 also shows that position 98 in the VH is mutation resistant and that in some embodiments mutations to position 98 enhance binding. Thus, in some embodiments, position 98 has a mutation relative to the antibodies of Table 1.

[0252] In some embodiments, the anti-dengue antibody molecule comprises a heavy chain constant region, a light chain constant region, and the heavy and light chain variable regions of Table 2. In certain embodiments, the anti-dengue antibody molecule comprises a heavy chain constant region, a light chain constant region, and a variable region comprising the CDRs in 1, 2, 3, 4, 5 or 6 of Table 3.

[0253] In some embodiments, the heavy chain variable region is a heavy chain variable region of Table 1, wherein residue 98 in VH can be any amino acid. In certain embodiments, residue 98 may be any uncharged amino acid. In some embodiments, position 98 may be A, V, or S. Example 5 below shows that antibodies with A, V or S at position 98 hav...

Embodiment 1

[0357] Example 1: Structure-Guided Design of Anti-Dengue Antibodies

[0358] Epitope and template identification

[0359] There are multiple neutralizing epitopes within the dengue virus E protein dimer. These epitopes include, for example, regions in EDI, EDII, EDIII, the fusion loop, the EDI / II hinge, and the EDIII "A" beta-strand. EDI and EDII are immunodominant in humans and are able to induce weakly neutralizing but highly cross-reactive antibodies. EDIII is capable of inducing potent neutralizing antibodies. Antibodies against the fusion loop, located in EDII, often show cross-serotype reactivity but not strong neutralizing activity. Antibodies against the EDI / II hinge region can exhibit potent neutralization, but are often serotype-specific due to poor conservation of the epitope region. Antibodies against the EDIII A-chain are generally due in part to the higher accessibility of this region to the antibody, but generally have limited cross-serotype reactivity.

...

Embodiment 2

[0368] Example 2: De126 improves DV-4 neutralization activity

[0369] B11 is an anti-dengue antibody that has a heavy chain deletion at S26 in framework 1 (FR1 ) compared to A11 (4E5A). 4G2 is a control anti-dengue antibody. The neutralizing activity of each antibody against EDIII from the four dengue virus serotypes was tested by the focused reduction neutralization test (FRNT).

[0370] When dengue virus infection host is vero cells (Vero) cells, the focused reduction neutralization assay detects the formed lesions. Briefly, dilutions of antibody were mixed with an equal volume of diluted virus, and the mixture was transferred to Vero cell monolayers, and lesions were detected. Data are presented as relative infectivity. FRNT 50 Represents the antibody concentration required to achieve 50% virus neutralization. A more detailed protocol for the focal reduction neutralization assay can be found in Tharakaraman et al., 2013, Proc Natl Acad Sci US A. 2013; 110(17):E1555-...

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Abstract

Antibody molecules that specifically bind to dengue virus are disclosed. In certain embodiments, the antibody molecule bind to dengue virus serotypes DV-1, DV-2, DV-3, and DV-4. The antibody molecules can be used to treat, prevent, and / or diagnose dengue virus.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Application No. 61 / 938,646, filed 2014, U.S. Provisional Application No. 62 / 017,970, filed June 27, 2014, and U.S. Provisional Application No. 62, filed September 5, 2014 / 046,379 application priority. The disclosure of the prior application is considered part of the disclosure of the present application (and is incorporated herein by reference in its entirety). [0003] sequence listing [0004] This application contains a Sequence Listing, which is filed electronically in ASCII format, and is hereby incorporated by reference in its entirety. The ASCII copy, created on January 7, 2015, is named P2029-7002WO_SL.txt, and has a file size of 75,052 bytes. Background of the invention [0005] Dengue virus is a positive-sense RNA virus belonging to the Flavivirus genus of the family Fkaviviridae. Dengue virus is widely distributed in tropical and subtropical regions of the world an...

Claims

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Application Information

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IPC IPC(8): C07K16/10A61K39/00A61K39/42
CPCC07K2317/33C07K2317/567C07K2317/76C07K2317/92A61K2039/545C07K2317/24C07K2317/94C07K16/1081G01N33/56983G01N2333/185C07K2317/565A61K2039/505A61P31/12Y02A50/30A61K39/42A61K45/06C07K2317/14C07K2317/54C07K2317/55C07K2317/622C07K2317/90
Inventor L·鲁宾逊Z·施莱弗J·麦特G·巴布科克K·维斯瓦纳坦
Owner VISTERRA
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