Session Type: Abstract Submissions (ACR)
PRTX-100 is a highly-purified GMP staphylococcal protein A (SpA) that is currently in Phase I trials in patients with active rheumatoid arthritis (RA). SpA has diverse activities in vitro and in vivo: forming immune complexes with IgG, SpA induces a “suppressor” phenotype in murine and human macrophages; IP or IV administration reduces disease severity in the murine CIA model. SpA can also inhibit activation of human monocyte-derived macrophages by LPS and gamma-IFN. SpA binds to Vh3 B-lymphocytes, and relocates with them to lymphoid tissues. Since anti-cytokine biologic DMARDS, in particular anti-TNF products, have been shown to increase patient susceptibility to pathogens such as listeria, fungi and TB, we compared the effects of SpA treatment to that of etanercept and anti-mouse TNF in murine models of Listeria and Candida infection.
Methods: For Listeria challenges, groups of 15 Balb/C mice were treated ip with either 10 mL/kg of 0.1% BSA, 15 mg/kg of etanercept, 50 or 250 μg/kg of SpA, or 0.2 mL of rabbit anti-mouse TNF antisera. After 4 hours mice were administered 5 x 10^10 CFU of L. monocytogenes orally. Mice were then re-treated with drugs every 48 hours x 2. Weights and mortality were recorded daily. On Days 3, 5, and 8, five mice/group were sacrificed for spleen cultures and CFU counts. For Candida challenges, groups of 15 female CD-1 mice received the same treatments. Four hours after the first treatments they were injected IV with 2 x 10^6 CFU of Candida albicans. Daily weights and mortality were recorded. On days 3, 5, and 8, five mice/group were sacrificed for kidney cultures and CFU counts.
Results: Mean values for weights, bacterial load: Listeria challenge – BSA: 20% mortality.10% weight loss at Day 4 was regained by Day 6. Anti-TNF: 21% weight loss on Day 5, 100% lethality by Day 6. Etanercept: 17% weight loss by Day 5, maintained through to end of study; no mortality. Spleen bacterial counts were higher (p<0.05) than with BSA treatment at Day 5. SpA, 25 or 250 μg/kg; no mortality, weight loss similar to BSA-treated mice. Lower bacterial counts at Day 5 than seen following etanercept or anti-TNF treatment. Candida challenge – BSA: 17% weight loss by Day 5 and 10% mortality by Day 8. Anti-TNF: 23% weight loss on Day 5 with 100% mortality by Day 6. Kidney yeast counts higher (p<0.05) than BSA group on days 3 and 5. Etanercept: 30% weight loss by Day 7 and 60% mortality by Day 8. Mean kidney counts higher (p<0.05) than BSA group at days 3, 5, and 8. SpA groups: weight loss similar to BSA group. Kidney counts not significantly different at days 5 and 8 from BSA group; no mortality by Day 8.
Conclusion: In contrast to etanercept or anti-TNF treatment, repeated injections of SpA at 50 or 250 μg/kg did not affect disease severity or pathogen load in these challenge models with bacterial or fungal intracellular pathogens.
Washington Biotechnology Inc.,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/treatment-with-staphyloccocal-protein-a-which-is-immuno-modulatory-in-the-murine-collagen-arthritis-model-does-not-increase-infection-severity-in-murine-listeria-or-candida-challenge-models-in-contr/