Adjunct antibody administration with standard treatment reduces relapse rates in a murine tuberculosis model of necrotic granulomas

Abstract

Matrix metalloproteinase (MMP)-9 is a zinc-dependent protease associated with early immune responses to Mycobacterium tuberculosis infection, macrophage recruitment and granuloma formation. We evaluated whether adjunctive inhibition of MMP-9 could improve the response to standard TB treatment in a mouse model that develops necrotic lesions. Six weeks after an aerosol infection with M. tuberculosis, C3HeB/FeJ mice received standard TB treatment (12 weeks) comprising rifampin, isoniazid and pyrazinamide alone or in combination with either anti-MMP-9 antibody, etanercept (positive control) or isotype antibody (negative control) for 6 weeks. Anti-MMP-9 and the isotype control had comparable high serum exposures and expected terminal half-life. The relapse rate in mice receiving standard TB treatment was 46.6%. Compared to the standard TB treatment, relapse rates in animals that received adjunctive treatments with anti-MMP-9 antibody or etanercept were significantly decreased to 25.9% (P = 0.006) and 29.8% (P = 0.019) respectively, but were not different from the arm that received the isotype control antibody (25.9%). Immunostaining demonstrated localization of MMP-9 primarily in macrophages in both murine and human lung tissues infected with M. tuberculosis, suggesting the importance of MMP-9 in TB pathogenesis. These data suggest that the relapse rates in M. tuberculosis-infected mice may be non-specifically improved by administration of antibodies in conjunction with standard TB treatments. Future studies are needed to evaluate the mechanism(s) leading to improved outcomes with adjunctive antibody treatments.

<p>Profiling the mRNA and miRNA in Peripheral Blood Mononuclear Cells in Subjects with Active Tuberculosis</p>

“… 23 , 24 Various MMP inhibitors have been used to study the immunomodulatory role of MMPs in Mtb infection and showed promising effect. 25 , 26 For example, Xu et al reported that inhibition of matrix metalloproteinase (MMP) enhances the in vivo potency of isoniazid and rifampicin. 27 In summary, our results revealed a series of processes and pathways related to Mtb infection, which provide a new basis for further explore the pathogenesis of ATB.…”

Matrix Metalloproteinases in Pulmonary and Central Nervous System Tuberculosis—A Review

“…Conversely, the cipemastat-treated group had a trend toward worse cavitary disease. Ordonez et al used cipemastat monotherapy in the C3HeB/FeJ mouse model that develops cavitary lesions after aerosol infection with Mtb [117]. Similar to rabbits, cipemastat-treated mice had worse cavitation and more disease severity compared to controls.…”

“…Marimastat also reduced vascular leakage surrounding TB granulomas and increased the concentration of isoniazid in Mtb -infected lungs compared to controls. Similarly, targeting MMP-9 with a specific antibody in addition to anti-TB therapy (rifampin, pyrazinamide, and isoniazid) reduced pulmonary bacterial burden and significantly lowered relapse rates in a cavitary mouse model of pTB [117]. Therefore, MMP inhibition in conjunction with antibiotic therapy may be beneficial, whilst MMP inhibition monotherapy seems to be harmful, further demonstrating the complexity of events in vivo and the importance of performing translational preclinical studies that most closely reflect the intended therapeutic use in patients.…”

Treatment-shortening effect of a novel regimen combining high-dose rifapentine and clofazimine in pathologically distinct mouse models of tuberculosis

“…In this model, mice can develop necrotic caseous lung lesions with a significant extracellular bacterial population and even lung cavities (7, 22–24, 31–35). The standard TB treatment regimen performs similarly in this model as in the BALB/c model (9, 22, 36–38), thus allowing for the specific evaluation of clofazimine and rifapentine activity in this disease setting.…”