Treatment of Mycobacterial diseases by administration of bacterial/permeability-increasing protein products

Inactive Publication Date: 2005-06-02
XOMA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0016] According to another aspect of the present invention, compositions comprising a BPI protein product are administered to neutralize LAM's physiological effects on a host. For example, methods are provided for neutralizing the effect of low concentrations of LAM capable of stimulating cytokine production in a host. Methods are also provided for neutralizing the inhibitory effect that higher concentrations of Mycobacterial LAM (i.e. 100 μg / ml or more) have upon the interferon-mediated activation of macrophages. Specifically, a BPI protein product may be administered to an immunosuppressed subject failing to respond to microbes or tumor cells due to LAM-induced insensitivity of macrophages to activation by T-cell lymphokines.

Problems solved by technology

As many Mycobacterial strains are drug resistant, serious obstacles exist for control and successful treatment of tuberculosis and other Mycobactenal diseases.
A variety of factors have made treatment of individuals afflicted with Mycobactenal diseases problematic.
Because the principle efferent role of the macrophage in acquired resistance to intracellular pathogens requires activation by T-cell lymphokines, notably gamma-interferon (IFN-γ), macrophages whose activation-response is inhibited are severely compromised in their capacity for both enhanced microbicidal and tumoricidal activities.
However, higher concentrations of LAM (50-100 μg / ml or more) appear to block rather than promote macrophage function.
LPS induces the release of mediators by host inflammatory cells which may ultimately result in irreversible endotoxic shock.
In susceptible bacteria, it is thought that BPI binding disrupts LPS structure, leads to an activation of bacterial enzymes that degrade phospholipids and peptidoglycans, alters the permeability of the cell's outer membrane, and ultimately causes cell death by an as yet unknown mechanism.

Method used

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  • Treatment of Mycobacterial diseases by administration of bacterial/permeability-increasing protein products
  • Treatment of Mycobacterial diseases by administration of bacterial/permeability-increasing protein products

Examples

Experimental program
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example 1

[0041] An enzyme linked immunosorbent assay (ELISA) was conducted to determine binding of a BPI protein product to M. tuberculosis. Specifically, non-viable, desiccated M. tuberculosis H37 RA (Difco, Detroit, Mich.) was suspended in DPBS (25 μg / ml) and used to coat microtiter wells overnight at 37° C. Wells were also coated with either 25 μg / ml Lipid A (E. coli J5 mutant, RIBI, Hamilton, Mont.) or 500 μl DPBS to demonstrate the functionality and specificity of rBPI23. After washing (3× with DPBS+0.05% Tween 20), the plates were blocked for 1 hr. at room temperature with 200 μl / well of DPBS+1% non-fat milk. After washing as above, 50 μl solutions of either various concentrations of rBPI23 (in DPBS containing 0.05% Tween 20) or DPBS (negative control) were added to the wells, which were then incubated for 1 hr. at 37° C. The wells were again washed as above, and the amount of rBPI23 bound to the wells was determined using an anti-rBPI23 mouse monoclonal antibody (designated αBPI MAb-2...

example 2

[0044] In this example, an ELISA Assay is conducted to determine binding of a BPI protein product to the lipoarabinomannan portion of Mycobacteria. The binding activity of BPI protein product (e.g., rBPI23) to LAM is demonstrated as described in the previous example, except LAM purified from a species of Mycobacterium, (e.g., M. tuberculosis or M. leprae) is substituted for the nonviable M. tuberculosis used to coat the ELISA plates in that example. Purified LAM is isolated as described by Hunter et al., J. Biol. Chew., 261: 12345-12351 (1986). Specific binding of biologically active BPI protein product is demonstrated by comparison of the OD 405 readings from the LAM coated wells with positive and negative controls.

example 3

[0045] The following experiment was conducted to determine the effect of a BPI protein product, rBPI23, on Mycobacteria-induced cytokine production in whole human blood. Whole human blood from healthy volunteers was collected into Vacutainer tubes (ACD, Beckton Dickinson, Rutherford, N.J.). Aliquots of blood (225 μl) were mixed with either rBPI23 (10 μg / ml final) or the protein thaumatin (10 μg / ml final in 5 ml) as a negative control. RPMI medium (20 μl) was added to each sample. Varying dilutions (0-8 ng / ml) of either E. coli O113 LPS (Ribi, Hamilton Mich.) or of non-viable, desiccated M. tuberculosis H37 RA (0-100 μg / ml) (Difco, Detroit Mich.) were added to the samples, which were then incubated at 37 C for 6 hours. The reactions were stopped by the addition of 750 μl of RPMI medium, the samples were centrifuged at 500 g for 7 min, and stored at −20° C. until analyzed. The supernatant was assayed for cytokine (TNF) levels based on a standard curve, according to the manufacturers' ...

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Abstract

The present invention relates to methods for treating a subject suffering from infection with Mycobacteria, such as M. leprae or M. tuberculosis comprising administering to the subject a composition comprising a bactericidal / permeability-inducing (BPI) protein product alone or in combination with administration of an anti-Mycobacterial antibiotic.

Description

[0001] This is a continuation-in-part of co-pending U.S. patent application Ser. No. 08 / 031,145, filed Mar. 12, 1993.BACKGROUND OF THE INVENTION [0002] The present invention relates to methods of treating a subject suffering from infection with Mycobacteria by administration of Bactericidal / Permeability-Increasing Protein (BPI) protein products. Mycobacterium is a non-motile, acid-fast, aerobic, genus of bacteria known to cause grave human and animal diseases, such as tuberculosis and leprosy. Infections caused by M. avium are the most common form of disseminated bacterial disease in AIDS patients. Orme, et al., Infect. and Immun., 61 (1): 338-342 (1993). [0003] The administration of conventional antibiotics to treat Mycobacterial infection is known in the art and has achieved varying success depending on the susceptibility of the bacterial strain, the efficacy and toxicity of the antibiotic(s) employed, the duration of treatment, and numerous other factors. Antimicrobials that have...

Claims

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Application Information

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IPC IPC(8): A61K38/17
CPCA61K38/1751Y10S514/924Y10S530/827
Inventor LAMBERT, LEWIS
Owner XOMA CORP
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