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Methods of treating cancer using IL-21 and monoclonal antibody therapy

An IL-21, monoclonal antibody technology, applied in the direction of antibody medical components, chemical instruments and methods, antibodies, etc., can solve the problem of not being able to stimulate human immune effector cells, human anti-mouse, etc.

Inactive Publication Date: 2011-09-21
ZYMOGENETICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The development of monoclonal antibody (MAb) therapy has evolved from mouse hybridoma technology (Kohler et al. Nature 256 : 495-497, 1975) developed due to its inability to stimulate the activity of human immune effector cells and produce human anti-mouse antibodies (HAMA; Khazaeli et al., J. Immunother. 15 : 42-52, 1994), so this monoclonal antibody has limited therapeutic efficacy

Method used

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  • Methods of treating cancer using IL-21 and monoclonal antibody therapy
  • Methods of treating cancer using IL-21 and monoclonal antibody therapy
  • Methods of treating cancer using IL-21 and monoclonal antibody therapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0103] IL-21 enhances antibody-dependent NK cell activity

[0104] a.

[0105] Peripheral blood was obtained, and mononuclear cells (MNC's) were prepared by ficoll centrifugation. Using StemSep TM Human NK Cell Stem CellTechnologies (Vancouver, British Columbia) human NK cell negative enrichment kit, natural killer (NK) cells were purified from MNC populations by negative enrichment. Briefly, MNCs were labeled with lineage-specific antibodies (excluding NK lineages), which were in turn magnetically labeled. The labeled MNCs are then passed through a magnetic column, where labeled cells are retained, while unlabeled NK cells flow through the column.

[0106] at 5x10 5 Density of cells / mL NK cells were plated in αMEM / 10% autologous serum / 50 μM β-mercaptoethanol and 0, 1, 10 or 100 ng / mL hIL-21 (A794F) or 10 ng / mL IL-12 (positive control) All events were performed in the presence or absence of Fc stimulation for 3 days. NKs were incubated on the surface to provide Fc sti...

Embodiment 2

[0117] IL-21 Up-regulates the Expression of Granzyme B in Human NK Cells

[0118] Human NK cells were isolated from Ficoll-Paque purified monocytes by negative selection using a Magnetic Bead Isolation Kit (Miltenyi Biotech, CA). Purified NK cells were then cultured in culture medium alone or in the presence of 20 ng / mL human IL-21. Cells are harvested, washed, and stained with surface markers. After surface marker staining, cells were washed and then treated with Cytofix / Cytoperm TM Cells were permeabilized with buffer (BD Biosciences, San Jose, CA) for 20 minutes. Cells were then stained with APC-labeled anti-human granzyme B antibody or an isotype control antibody (Caltag, Burlingame, CA) in Perm / Wash buffer. Wash the cells, then in the FACSCalibur TM Read on flow cytometer. Use Cellquest TM Software (BD Biosciences) was used to analyze the data.

[0119] figure 1 showed that incubation of human NKs in the presence of IL-21 resulted in a dramatic increase in the ...

Embodiment 3

[0121] IL-21 + rituximab increased the expression of mice injected with HS Sultan lymphoma cells survival rate

[0122] A study was performed to assess whether tumor growth was delayed in CB-17 SCID mice injected with HS-Sultan cells, treated with rituximab, mouse IL-21 (mIL-21 ) or the combination of mIL-21 and rituximab treated mice. The study was designed to characterize the survival of HS-Sultan-loaded mice in each treatment group.

[0123] The protocol described and those known in the art (see, Cattan et al. Leuk Res. 18(7) : 513-522, 1994; Ozaki et al., Blood 90 (8) : 3179-86, 1997) similarly. CD17-SCID mice were administered 20 μg of rituximab (dosed every 4 days for a total of 5 injections), 100 μg of mIL-21 (dosed for 5 days) or rituximab by intraperitoneal route injection Combination of anti and mIL-21 (5 doses per treatment).

[0124] Mice were monitored for moribund or non-viable conditions such as paralysis or rapid weight loss. Body weights were co...

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Abstract

Methods for treating cancer by co-administering a therapeutic monoclonal antibody with IL-21 are described. Exemplary monoclonal antibodies that can be used are rituximab, trastuzumab and anti-CTLA-4 antibodies. The enhanced antitumor of the combination therapy is particularly useful for patient populations that are recalcitrant to monoclonal therapy, relapse after treatment with monoclonal antibodies or where the enhanced IL-21 antitumor effect reduces toxicities associated with treatment using the monoclonal antibodies.

Description

[0001] This application is a divisional application of an invention patent application with an application date of May 20, 2005, an application number of 200580021262.5, and an invention title of "Method for Treating Cancer Using IL-21 and Monoclonal Antibody Therapy". Background of the invention [0002] Cytokines typically stimulate the proliferation or differentiation of cells of the hematopoietic lineage, or participate in the body's immune and inflammatory response mechanisms. Interleukins are a family of cytokines that mediate immune responses. At the heart of the immune response are T cells, which produce many cytokines and influence adaptive immunity to antigens. Cytokines produced by T cells have been classified as TH1 and TH2 (Kelso, A. Immun. Cell Biol. 76 : 300-317, 1998). Type 1 cytokines include IL-2, IFN-γ, LT-α, which are involved in inflammatory responses, viral immunity, intracellular parasite immunity, and allograft rejection. Type 2 cytokines include IL...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61P35/00A61K38/20C07K16/28C07K16/32
CPCA61K39/395A61K39/39558C07K16/2818A61K38/20C07K16/2896C07K16/32C07K2317/732A61P35/00A61P37/04A61P43/00A61K2300/00A61K38/16
Inventor W·R·金德斯沃格尔S·D·胡格赫斯R·D·豪雷C·H·克雷格D·C·弗斯特R·A·约翰逊M·D·黑佩尔P·V·斯瓦库玛
Owner ZYMOGENETICS INC
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