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

A monoclonal antibody, IL-21 technology, applied in the direction of antibodies, anti-tumor drugs, pharmaceutical formulations, etc., can solve the problem of not being able to stimulate human immune effector cells, human anti-mouse, etc.

Inactive Publication Date: 2007-12-05
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

[0100] IL-21 enhances antibody-dependent NK cell activity

[0101] a.

[0102] 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.

[0103] Take 5×10 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 s...

Embodiment 2

[0114] IL-21 Up-regulates the Expression of Granzyme B in Human NK Cells

[0115]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.

[0116] Figure 1 shows that incubation of human NK in the presence of IL-21 resulted in a dramatic increase in the expre...

Embodiment 3

[0118] IL-21 + rituximab increased the expression of mice injected with HS Sultan lymphoma cells survival rate

[0119] 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 mice treated with a combination of mIL-21 and rituximab. The study was designed to characterize the survival of HS-Sultan-loaded mice in each treatment group.

[0120] 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).

[0121] Mice were monitored for moribund or non-viable conditions such as paralysis or rapid weight loss. Body weights were...

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Abstract

A method of treating cancer by co-administering a therapeutic monoclonal antibody and IL-21 is described. Exemplary monoclonal antibodies that may be used are rituximab, trastuzumab, and anti-CTLA-4 antibodies. For patient populations resistant to monoclonal antibody therapy, relapsed after treatment with monoclonal antibodies, or in which enhanced IL-21 antitumor effects reduce toxicity associated with therapy with monoclonal antibodies, the The enhanced antitumor properties of the combination therapy described above are particularly useful.

Description

Background of the invention [0001] 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 into 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-4, IL-5, IL-6, IL-10, and IL-13, which are involved in humoral responses, helminth immunity, and allergic responses. Cytokines shared between type 1 and type 2 include IL-3, GM-CSF and TNF-α. Some evidence suggests that type 1 and type 2 productive T cell populations...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61P35/00A61K38/20
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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