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Inhibition of factor B, the alternative complement pathway and methods related thereto

A technology of factor B and antibody, applied in the field of new anti-factor B antibody, can solve the problems of improving susceptibility, limitation of clinical use of lung diseases related to airway hyperresponsiveness, etc.

Inactive Publication Date: 2014-12-10
科罗拉多大学评议会 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these agents can have serious side effects including, but not limited to, increased susceptibility to infection, liver toxicity, drug-induced lung disease, and bone marrow suppression
Therefore, the clinical use of these agents in the treatment of pulmonary diseases associated with airway hyperresponsiveness is limited

Method used

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  • Inhibition of factor B, the alternative complement pathway and methods related thereto
  • Inhibition of factor B, the alternative complement pathway and methods related thereto
  • Inhibition of factor B, the alternative complement pathway and methods related thereto

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0146] The following examples describe the production of novel inhibitors of the complement pathway.

[0147] The present inventors have generated several hybridoma cells that produce mouse monoclonal antibodies that bind mouse factor B. In the present study, the inventors set out to identify the ability of one of these antibodies to inhibit the complement pathway. The inventors also tested this antibody in an antiphospholipid-mediated fetal loss model. As previously described (Girardi), factor B deficient mice are protected from fetal loss in this model, and the inventors hypothesized that exogenous inhibitors of the alternative pathway would be effective therapeutic agents in this disease model.

[0148] method

[0149] Construction of factor B-Ig fusion protein and purification of mouse factor B. A plasmid encoding two short homologous repeats (SCRs) of the Factor B gene linking the hinge, CH2, and CH3 regions of the mouse IgG1 isotype was constructed ( figure 1 ). The...

Embodiment 2

[0185] The following examples demonstrate that complement activation via the alternative pathway is critical in the development of airway hyperresponsiveness and inflammation, and further demonstrate that inhibition of alternative pathway complement activation suppresses airway hyperresponsiveness.

[0186] Given the effectiveness of inhibiting complement activation prior to allergen exposure, the inventors also examined complement activation pathways. In the present study the inventors report that activation of the complement cascade via the alternative pathway is critical in the development of airway hyperresponsiveness and airway inflammation.

[0187] method

[0188] animal

[0189] Eight to 12 week old female C57BL / 6 mice were obtained from Jackson Laboratories (Bar Harbor, ME). As previously described, mice heterozygous deletion of factor B (fB+ / -) were first crossed with the C57BL / 6 strain, then recrossed at the F1 generation, and then recrossed to form the fB- / - st...

Embodiment 3

[0282] The following examples describe additional binding data for a series of anti-Factor B antibodies produced by the inventors. Assays were used to examine binding and / or inhibition of mouse Factor B and human Factor B by various antibodies. As seen, mAB 1379 binds and inhibits mouse and human factor B. In contrast, a mAb called 624 was able to bind mouse and human factor B, but failed to inhibit the human alternative pathway. A competition ELISA was used to further evaluate the antibodies. As seen, antibodies 624, 691 and 1231 did not block 1379 binding. These antibodies must therefore bind the protein at a different site, which explains why they bind factor B in vitro without inhibiting its function. However, antibodies 395, 1322 and 1060 are competitive inhibitors of 1379.

[0283] Table 4

[0284]

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Abstract

Disclosed are novel inhibitors of the alternative complement pathway and particularly, novel anti-factor B antibodies. Also disclosed is the use of such inhibitors to reduce or prevent airway hyperresponsiveness and / or airway inflammation by selectively inhibiting the alternative complement pathway, thereby treating diseases in which such conditions play a role. Also disclosed is the use of such inhibitors to reduce or prevent other diseases and conditions, including ischemia-reperfusion injury, by inhibition of the alternative complement pathway.

Description

technical field [0001] The present invention relates generally to novel inhibitors of the alternative complement pathway, and in particular to novel anti-Factor B antibodies. The invention also generally relates to the use of such inhibitors to reduce or prevent airway hyperresponsiveness and airway inflammation, thereby treating diseases in which this condition plays a role. Background technique [0002] Complement is activated mainly through three pathways: the so-called classical pathway, the lectin pathway and the alternative pathway. The key proteins involved in the activation of the alternative pathway are factor B (fB) and factor D (fD). These proteins work together to initiate and / or amplify the activation of C3, which then leads to the initiation of a number of inflammatory events. A third protein, properdin, stabilizes the complex of C3 and factor B, but is not required for the alternative pathway to function. Factor B also helps solubilize immune complexes and ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K39/395C12P21/08
Inventor V·M·霍勒斯J·M·瑟曼C·陶布E·W·格尔范德G·S·吉尔克森
Owner 科罗拉多大学评议会
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