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Compositions and methods for targeting type I interferon producing cells

A cell and compound technology, applied in chemical instruments and methods, drug combinations, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, etc., can solve problems such as being unsuitable for the treatment of chronic autoimmune diseases, etc.

Active Publication Date: 2013-03-27
CSL LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, this class of immunotoxins may not be suitable for the many treatments that may be required to treat chronic autoimmune diseases

Method used

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  • Compositions and methods for targeting type I interferon producing cells
  • Compositions and methods for targeting type I interferon producing cells
  • Compositions and methods for targeting type I interferon producing cells

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0344] IL-3Rα expression

[0345] Use standard techniques to identify PBMC from humans, and isolate various cell lines using antibodies that bind to lineage-specific cell surface markers. Use Quantibrite TM Beads (BD Biosciences) to determine the number of IL-3Rα molecules per cell of each lineage. Such as figure 1 As shown, IL-3Rα is highly expressed on pDC and basophils, while expressed at low levels on other cell lineages tested. This restricted expression pattern makes IL-3Ra a useful target for antibodies designed to selectively eliminate pDC and basophils.

Embodiment 2

[0347] Anti-IL-3Rα mAb depletes human pDC in vitro

[0348] By Ficoll TM Isolation Isolate peripheral blood mononuclear cells (PBMC) from normal donors, and place the PBMC in the absence of antibodies (no antibodies), 10μg / ml anti-ch7G3, or 10μg / ml anti-hz7G3V3 at 37°C. Incubate in RPMI / 10%FCS for different times. In a 96-well U-bottom plate, routinely culture 1x10 in a volume of 200μL 6 Cells. Analysis of the number of plasmacytoid dendritic cells (pDC) and the number of basophils by flow cytometry (Tables 1 and 2, respectively). Identification of human pDC as negative for lineage markers by flow cytometry (CD20 - , CD3 - , CD14 - , CD19 - CD56 - ), HLA-DR positive, CD11c negative and IL-3Rα positive (see the gate control box in the flowchart). Identification of human basophils by flow cytometry as negative for lineage markers (CD20 - , CD3 - , CD14 - , CD19 - CD56 - ), IgE positive and IL-3Rα positive. The modified anti-IL-3Rα antibody (hz7G3V3) contained in the Fc domain c...

Embodiment 3

[0354] In vivo anti-IL-3Rα consumption of pDC and basophils in non-human primates

[0355] Non-GLP cynomolgus monkey non-human primate (NHP) research was conducted in the Australian National Primate Facility in accordance with its standard operating procedures. All operations and modifications were approved by the Institutional Animal Care and Use Committee (Institutional Animal Care and Use Committee). A single dose of neutralizing anti-IL-3Rα antibody (hz7G3V3) was given to young monkeys by intravenous infusion, which has a modification in the Fc domain to enhance the effector function of the antibody. Peripheral blood was collected at different time points and analyzed by flow cytometry for NHP basophils and pDC. NHP basophils were identified as positive for IgE+ / CD123 by flow cytometry. Identification of pDC as negative for lineage markers by flow cytometry (CD20 - , CD3 - , CD14 - , CD19 - , CD56 - ), HLA-DR positive, CD11c negative and IL-3Rα positive.

[0356] At all dose...

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Abstract

The present disclosure provides a method for treating lupus, Sjogren's syndrome or scleroderma, the method comprising administering to the mammal an immunoglobulin which binds an interleukin 3 receptor alpha (IL-3R alpha) chain and which depletes or at least partly eliminates plasmacytoid dendritic cells (p DCs) and basophils to which it binds.

Description

[0001] Referenced related applications [0002] This application requires US Patent Application No. 61 / 374 filed on August 17, 2010, entitled "Compositions and Methods for Targeting type I Interferon-Producing Cells (compositions and methods for targeting type I interferon-producing cells)" , 497, U.S. Patent Application Nos. 61 / 374,489 and 2010 filed on August 17, 2010 entitled "Humanized Anti-Interleukin 3 Receptor Alpha Chain Antibodies" U.S. Patent Application No. 12 / 707,297 filed on February 17, 2005 entitled "Treatment of Chronic Inflammatory Conditions". The entire contents of these applications are incorporated herein by reference. Technical field [0003] The present disclosure relates to the treatment of inflammatory diseases. Background of the invention [0004] The interferon (IFN) family of cytokines includes type I and type II subtypes. Type I subtypes are composed of IFNα, IFNβ, IFNω, IFNκ and IFNτ, and type II is represented by IFNγ. Type I IFN has a variety of i...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61P37/06C07K16/28
CPCA61K39/395C07K16/2866C07K2317/52C07K16/28C07K2317/732C07K2317/41C07K2317/24A61P29/00A61P35/02A61P37/02A61P37/06A61K39/39566A61K2039/505
Inventor 基诺·路易吉·瓦伊洛安德鲁·纳什尤金·马拉斯阔夫斯基尼克·威尔逊萨曼塔·布斯菲尔德
Owner CSL LTD
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