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Treatment and prophylaxis with 4-1BB-binding agents

An agonist and B cell technology, applied in gene therapy, anti-inflammatory agents, drug combinations, etc., can solve the problems of long-term treatment and inability to clear autoreactive lymphocytes

Pending Publication Date: 2005-10-26
MAYO FOUND FOR MEDICAL EDUCATION & RES +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Drawbacks of these therapies include the need for long-term treatment and their inability to clear autoreactive lymphocytes and reverse disease progression

Method used

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  • Treatment and prophylaxis with 4-1BB-binding agents
  • Treatment and prophylaxis with 4-1BB-binding agents
  • Treatment and prophylaxis with 4-1BB-binding agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] Example 1: Materials and methods

[0082] mouse

[0083] B6.MRL-Tnfrsf6 lpr , (B6 / lpr), MRL / MpJ-Tnfrsf6 lpr (MRL / lpr), and MRL.129P2(B6)-Tnfsf6 tmlqsa (Fas - / - ) mice were purchased from The Jackson Laboratory (Bar Harbor, Maine). C57BL / 6 wild-type (B6 / wt) mice were purchased from the National Cancer Institute (Frederick, MD).

[0084] In vitro antibody treatment

[0085] An agonistic monoclonal antibody (mAb), 2A, against 4-1BB was generated as previously described (Wilcox et al., supra). Rat IgG was purchased from Sigma Chemical Company (St. Louis, MO) and served as a control antibody. Starting at 2-3 months of age, each mouse was injected weekly intraperitoneally (i.p.) with 200 μg / mouse 2A or rat IgG for three weeks.

[0086] Flow Cytometry Analysis

[0087] The following antibodies were purchased from BD-PharMingen (San Diego, CA): Cy-Chrome TM Labeled CD4 (H129.19), R-phycoerythrin (R-PE)-conjugated anti-mouse CD8a (53-6.7), R-PE-conjugated anti-mouse Th...

Embodiment 2

[0105] Example 2: Treatment of B6 / lpr mice with agonistic anti-4-1BB mAb (2A) preferentially activates CD8 + T cells, but reduced DNTC and B cell populations

[0106] B6 / lpr mice are naturally deficient in Fas and develop a lymphoproliferative disorder characterized by accumulation of autoreactive lymphocytes shortly after birth. To investigate the role of 4-1BB signaling in the activation of autoreactive lymphocytes, two- or three-month-old B6 / lpr and B6 / wt mice were treated with agonistic anti-4-1BB mAb (2A) or control rat IgG . Mice were treated at weekly intervals for three weeks, and splenocytes were analyzed by flow cytometry at various time points. Three weeks after the start of treatment, CD8 in spleens of 2A-treated mice compared with control mice + The percentage of T cells increased about 3-4 fold, while CD4 + The percentage of T cells remained unchanged ( Figure 1a on the left). In addition, in 2A-treated mice, CD4 + The number of T cells decreased, while CD...

Embodiment 3

[0108] Example 3: Administration of 2A greatly ameliorated lymphadenopathy in MRL / lpr mice

[0109] Compared to B6 / lpr mice, MRL / lpr mice typically exhibit more severe lymphoproliferative disease at a younger age and truly exhibit lupus-like features. 9-10 week old MRL / lpr mice generally have a significant number of abnormal DNTC and display higher levels of autoantibody IgG anti-DNA in serum. To test whether 2A has a potential therapeutic effect in the treatment of autoimmune diseases, 9-10 week old MRL / lpr mice were treated for three weeks with a weekly dose of 200 μg 2A or control rat IgG. All control mice exhibited progressive severe lymphadenopathy, whereas only two of 10 mice in the 2A-treated group developed 1-2 small palpable lymph nodes (LN) at 5 months of age ( Figure 2a ). In addition, at 4 months of age, 2A-treated mice had considerably smaller spleens and peripheral lymph nodes compared to control mice ( Figure 2b ). In the spleen and peripheral lymph nodes ...

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Abstract

Material and method for using 4-1BB agonizes to treat or prevent autoimmune disorders, lymphoproliferative diseases, and allergies are provided.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application Serial No. 60 / 395,896, filed July 15,2002. technical field [0003] The present invention relates to materials and methods for treating and / or preventing autoimmune diseases, allergies and lymphoproliferative diseases, more specifically, relates to the use of 4-1BB agonists to treat and / or prevent autoimmune diseases, allergies and Lymphoproliferative Disease Materials and Methods. Background of the invention [0004] Elimination of autoreactive lymphocytes in peripheral lymphoid tissues by apoptosis is an important mechanism for maintaining immune tolerance. This was demonstrated in MRL / lpr mice, which carry a lymphoproliferative (lpr) mutation of the Fas receptor gene on an autoimmune-prone background. These mice spontaneously developed lymphoproliferative disease and lupus-like autoimmune disease due to lack of functional Fas / Fas ligand interaction. M...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61K31/7088A61K38/21A61K39/00A61K39/02A61K39/36A61K39/395A61K48/00A61P1/00A61P1/04A61P1/16A61P3/10A61P5/14A61P7/06A61P9/04A61P15/00A61P17/00A61P21/00A61P21/04A61P27/02A61P29/00A61P37/06A61P37/08A61P43/00C07K16/28
CPCA61K39/39541C07K2316/95A61K2039/505C07K16/2878C07K2319/30A61P1/00A61P1/04A61P1/16A61P3/10A61P5/14A61P7/06A61P9/04A61P15/00A61P17/00A61P21/00A61P21/04A61P27/02A61P29/00A61P37/06A61P37/08A61P43/00C07K2317/73A61K2300/00
Inventor 陈烈平付阳新
Owner MAYO FOUND FOR MEDICAL EDUCATION & RES
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