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Anti-CCR5 antibody

A technology of antibodies and antibody fragments, applied in the direction of antibodies, antibody medical components, antiviral agents, etc., can solve problems such as unrelated

Inactive Publication Date: 2011-06-15
赛特戴恩公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

All mAbs inhibited HIV-1 fusion and invasion, but the ability of mAbs to inhibit fusion and invasion was associated with inhibition of gp120 / sCD4 binding to CCR5 + There is no correlation between the ability of cells

Method used

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0183] A. Materials and methods

[0184] 1) Reagent

[0185] MAb 2D7 was purchased from Pharmingen (San Diego, CA), while CC- and CXC-chemokines were obtained from R&D Systems (Minneapolis, MN). CD4-IgG2(1), soluble(s)CD4(2) and recombinant HIV-1 JR-FL gp120 is produced by Progenics Pharmaceuticals (59).

[0186] 2) Isolation and purification of anti-CCR5 mAb

[0187] L1.2-CCR5 + Cells (63) were incubated for 16 hours in the presence of 5 mM sodium butyrate, which activated expression from the cytomegalovirus (CMV) promoter controlling CCR5 expression, resulting in a 10-fold increase in cell surface coreceptor density. Female Balb / c mice were immunized intraperitoneally for 10 7 L1.2-CCR5 + cells at 3-week intervals and 10 days before splenectomy 7 L1.2-CCR5 + Intravenous enhancement of cells. Splenocytes were fused with the Sp2 / 0 cell line. In the initial screening, tests were made from 10 4 Supernatants of hybridoma cultures; 120 of these inhibited the intera...

Embodiment 2

[0228] background:

[0229] The increasing number of multidrug-resistant HIV-1 calls for the search for novel antiretroviral agents. CCR5 is an essential fusion coreceptor for primary HIV-1 isolates and provides a promising target for antiviral therapy. PRO140 is an anti-CCR5 monoclonal antibody that effectively inhibits HIV-1 invasion and replication in vitro at concentrations that do not affect the activity of CCR5 chemokine receptors. In this study, we evaluated the in vivo therapeutic potential of PRO 140 using a therapeutic animal model of HIV-1 infection.

[0230] method:

[0231] CD-17SCID mice were reconstituted with normal human PBMCs and infected with R5 isolate HIV-1JR-CSF. Upon reaching viral steady state, animals were treated intraperitoneally with PRO 140 or a control antibody, and viral load was monitored using the Roche Amplicor assay. A pilot study examined a single 1 mg dose of PRO 140. In the multiple-dose study, PRO 140 was administered every three...

Embodiment 3

[0237] method:

[0238] Using the methods described herein, a humanized CCR5 antibody (huPRO 140) was tested for its ability to block calcium mobilization induced by RANTES in L1.2-CCR5 cells and for its ability to block HIV-1 CASEC 1 / 85 replication in human PBMCs. ability.

[0239] result:

[0240] Figure 19 The results shown in show that the humanized CCR5 antibody efficiently blocks HIV-1 but not RANTES.

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Abstract

The invention relates to an anti-CCR5 antibody and a segment which combines CCR5 on the surface of human cell. The antibody comprises two light chains (1), wherein each light chain comprises expression products of plastid pVK: HuPRO140-VK (ATCC preservation number PTA-4097), and two heavy chains (2), wherein each heavy chain comprises plastid pVg 4: HuPRO140 HG2-VH (ATCC preservation number PTA-4098) or expression products of pVg 4: HuPRO140 (mut B+D+I)-VH (ATCC preservation number PTA-4099).

Description

[0001] This application is a continuation-in-part of and claims priority from US Application Serial No. 10 / 081,128 filed February 22, 2002, the contents of which are hereby incorporated by reference. [0002] Throughout this application, various publications are referred to in Arabic numerals. Full citations to these publications can be found at the end of the specification immediately preceding the claims. The disclosures of these publications are hereby incorporated by reference into this application in order to more fully describe the field to which this invention pertains. Background of the invention [0003] Human immunodeficiency virus type 1 (HIV-1) induces virus-cell membrane fusion, enabling entry into target cells (8, 15, 66). The first high-affinity interaction between the virion and the cell surface is the binding of the viral surface glycoprotein gp120 to the CD4 antigen (13, 30, 41, 42), which in turn induces a conformational change in gp120 that enables it to a...

Claims

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Application Information

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IPC IPC(8): C07K16/28C12N5/07A61K39/395A61P31/18C12P21/08A61K39/44C07K16/08C12N15/13C12N15/63
CPCC07K16/2866A61K2039/505C07K2317/24C07K2317/00A61K39/39541A61P31/00A61P31/18A61K2300/00C07K16/28
Inventor W·C·奥尔森P·J·马东N·楚鲁西塔P·R·欣顿M·瓦斯克斯
Owner 赛特戴恩公司
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