Methods of treating chronic inflammatory diseases using a gm-csf antagonist

一种GM-CSF、慢性炎症的技术，应用在使用GM－CSF拮抗剂治疗慢性炎症疾病领域，能够解决TNF抑制剂治疗益处消失、TNF抑制剂不能达到足够的反应等问题

Inactive Publication Date: 2009-12-16
HUMANIGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are still some problems with these treatments
Some patients do not achieve an adequate response to TNF inhibitors
Also, in some patients, the therapeutic benefit of TNF inhibitors fades over time

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0145] The humanized antibody (humaneered antibodies) of embodiment 1 exemplary GM-CSF

[0146] A panel of humanized Fab' molecules with c19 / 2 specificity was prepared from an epitope-focused human V-segment library as described in US Patent Application 20060134098.

[0147] Fab' fragments were expressed from E. coli cells grown in 2xYT medium to an OD600 of 0.6. Expression was induced using IPTG for 3 hours at 33°C. Assembled Fab' was obtained from the periplasmic fraction and purified by affinity chromatography using streptococcal protein G (HiTrap protein G HP column; GE Healthcare) according to standard methods. Fab' were eluted in pH 2.0 buffer, then adjusted to pH 7.0 and dialyzed against PBS pH 7.4.

[0148] Binding kinetics were analyzed by Biacore 3000 surface plasmon resonance (SPR). Recombinant human GM-CSF antigen was biotinylated and immobilized on a streptavidin CM5 sensor chip. Fab samples were diluted to a starting concentration of 3 nM and serial 3-fold di...

Embodiment 2

[0152] EXAMPLE 2 EXEMPLARY CLINICAL PROTOCOL FOR DELIVERY OF ANTI-GM-CSF ANTIBODIES

[0153] Anti-GM-CSF antibody was stored at 10 mg / ml in sterile isotonic saline solution for injection at 4°C and diluted in 100 ml or 200 ml of 0.9% sodium chloride for injection before administration to patients. Antibodies are administered to RA patients at doses of 0.2 to 10 mg / kg by one hour intravenous infusion.

[0154] Patients included in this treatment regimen were selected based on the following criteria: patients exhibited signs of active RA; patients were receiving methotrexate, where patients had received stable doses of DMARDs for at least 6 weeks. In addition, patients included in this study exhibited the following symptoms: a swollen joint count of at least 6 (using a 66-joint count) and a tender joint count of at least 6 (using a 68-joint count). At least two of the following criteria were also included in the inclusion criteria: ESR ≥ 20 mm / hr, CRP ≥ 15 mg / l, morning stiffne...

Embodiment 3

[0158] Example 3 Treatment of Patients with Methotrexate and Anti-GM-CSF Antibodies

[0159] Patients with active RA were treated with methotrexate and anti-GM-CSF antibodies following the clinical protocol described in Example 2. Patients received 0.2 mg / kg of anti-GM-CSF antibody. The patient also received 25mg / week methotrexate treatment.

[0160] Blood counts, measured by standard methods, also include hemoglobin (HGB), total white blood cell count (WBCC), platelets (PLT), neutrophils (Neut; also called absolute neutrophil count ANC), lymphocytes (LYMPH ), monocytes (MONO), eosinophils (EOSIN), basophils (BASO), hematocrit (HCT) values. In addition, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were also measured. Blood counts, ESR and CRP before treatment, during treatment and up to 2 weeks after treatment are shown in Table 2. As can be seen, after 2 weeks, the ESR dropped from an abnormal value of 40 to 18, which is within the normal range for an...

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PUM

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Abstract

The invention is based on the discovery that GM-CSF antagonists can be used for the treatment of chronic inflammatory disease, such as rheumatoid arthirtis. Accordingly, the invention provides methods of administering a GM-CSF antagonist, e.g., a GM-CSF antibody, and an anti-folate compounds, e.g., methotrexate, to a patient that has RA and pharmaceutical compositions comprising such antagonists.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application No. 60 / 860,780, filed November 21, 2006, and U.S. Provisional Application No. 60 / 902,742, filed February 21, 2007, each of which is incorporated by reference This article. Background of the invention [0003] Rheumatoid arthritis (RA) is a chronic and typically progressive inflammatory disease affecting up to 1% of the total adult population worldwide (Gabriel, Rheum Dis CHn North Am27:269-81, 2001). Current recommendations for the treatment of RA include early treatment with disease modifying anti-rheumatic drugs (DMARDs) after diagnosis. While awaiting a confirmed diagnosis or later in the disease course, nonsteroidal anti-inflammatory drugs (NSAIDs) and, until recently, COX-2 inhibitors in combination with DMARDs have been widely used. Methotrexate is the most widely used DMARD, but other agents including hydroxychloroquine, sulfasalazine, gold, min...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/519A61K39/00A61K31/505A61K45/06A61P29/00
CPCA61K31/505A61K45/06A61K2039/505C07K16/243C07K2317/24C07K2317/55C07K2317/92C07K2317/34C07K2317/73A61K31/519A61K39/3955A61P1/04A61P1/16A61P11/00A61P11/02A61P11/06A61P13/12A61P17/00A61P17/04A61P17/06A61P19/02A61P19/06A61P21/00A61P25/00A61P25/02A61P25/28A61P27/02A61P27/16A61P29/00A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00A61P5/14A61P9/00A61P9/10A61K2300/00A61K39/395
Inventor 克里斯托弗·R·贝炳东杰弗里·T·亚兰东
Owner HUMANIGEN INC
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