Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose
Proteins in the BCL-2 family are key regulators of apoptosis, or programmed cell death. Navitoclax, a selective inhibitor of both BCL-2 and BCL-X(L) demonstrated efficacy in the IFN-α induced lupus model in NZB/W F1 mice suggesting that dysregulation of this pathway is operative in lupus disease. However, thrombocytopenia caused by BCL-X(L) inhibition limits the chronic use of this therapeutic agent. We have conducted studies to evaluate a highly potent and orally available BCL-2-selective inhibitor, ABT-199, for efficacy and mechanism of action in the spontaneous NZB/W F1 mouse model.
Methods
26 week old NZB/W F1 mice were treated daily for 24 weeks with vehicle or ABT-199. Proteinuria and survival data are presented as Kaplan-Meyer survival curves. Changes in lymphocytes and platelets in peripheral blood were assessed by Celldyn 3700 blood analyzer. Renal pathology was evaluated by a board certified pathologist. IgG deposition and changes in leukocyte subsets in the kidney were evaluated by immunohistochemistry. Circulating anti-dsDNA antibody levels were determined using a semi-quantitative ELISA assay. In a separate study NZB/W F1 mice were treated daily with vehicle or ABT-199 at 30mg/kg for 16 weeks, leukocyte subsets in spleen, kidney and bone marrow were analyzed by flow cytometry.
Results
ABT-199 treatment dose-dependently reduced the incidence of severe proteinuria compared to vehicle control and conferred 100% survival at the higher doses in the spontaneous NZB/W F1 lupus model. Treatment with ABT-199 also resulted in attenuated glomerulonephritis, tubular dilatation and IgG deposition in the kidney. ABT-199 treatment resulted in reductions in numbers of B220+, CD3+, F4/80+ and CD138+ cells in the kidneys compared with vehicle-treated mice. Consistent with its BCL-2 selectivity profile, ABT-199 mediated efficacy in NZB/WF1 mice correlated with a dose‑dependent reduction of lymphocytes in peripheral blood (45% reduction for ABT-199 11mg/kg vs. vehicle; 70% reduction for ABT-199 100 mg/kg vs. vehicle) with no effect on platelet numbers. ABT-199 also demonstrated a significant reduction in the numbers of splenic T cells (CD4+, CD8+), B cells (transitional 2, germinal center, and mature). Interestingly, other B cell subsets (transitional 1, marginal zone, and B1) were largely unaltered. ABT-199 did not impair early B cell development or the number of CD138+ long-lived plasma cells in the bone marrow. These data were consistent with the unaltered anti-dsDNA titers in these animals.
Conclusion
Treatment of spontaneous lupus in NZB/W F1 mice with the BCL-2 selective inhibitor ABT-199 resulted in preservation of renal function and complete protection against severe proteinuria and mortality. ABT-199 treatment resulted in lymphopenia and a reduction of cell infiltration into the kidney while sparing circulating platelets. Splenic marginal zone B cells, the first line of defense against blood-borne pathogens, were resistant to ABT-199. Taken together, these data underscore the essential role of BCL-2 in the pathogenesis of lupus and support a role for BCL-2 selective inhibition in the treatment of autoimmunity.
Disclosure:
L. C. Wang,
AbbVie Inc.,
3;
S. Perper,
AbbVie Inc.,
3;
A. Schwartz,
AbbVie Inc.,
3;
C. Goess,
AbbVie Inc. ,
3;
L. O’connor,
AbbVie Inc.,
3;
D. Hartman,
AbbVie Inc. ,
3;
C. Graff,
AbbVie Inc.,
3;
A. Souers,
AbbVie Inc.,
3;
J. Leverson,
AbbVie Inc,
3;
S. Elmore,
AbbVie Inc.,
3;
L. Olson,
AbbVie Inc.,
3.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/abt-199-a-potent-and-selective-bcl-2-inhibitor-prevents-lupus-nephritis-in-the-spontaneous-nzbw-f1-mouse-model-by-depleting-selective-lymphocyte-populations-while-sparing-platelets/