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Abstract Number: 858

ABT-199, a Potent and Selective BCL-2 Inhibitor, Prevents Lupus Nephritis in the Spontaneous NZB/W F1 Mouse Model By Depleting Selective Lymphocyte Populations While Sparing Platelets

Li Chun Wang1, Stuart Perper1, Annette Schwartz2, Christian Goess3, Liz O'connor4, Dawna Hartman2, Candace Graff2, Andrew Souers5, Joel Leverson5, Steven Elmore5 and Lisa Olson2, 1Immunology, AbbVie Inc, AbbVie Bioresearch Center, Worcester, MA, 2AbbVie Inc, AbbVie Bioresearch Center, Worcester, MA, 3Pharmacology, AbbVie Inc, AbbVie Bioresearch Center, Worcester, MA, 4Toxicology, AbbVie Inc, AbbVie Bioresearch Center, Worcester, MA, 5AbbVie Inc, North Chicago, IL

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: animal models and apoptosis, B cells, Lupus, T cells

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Session Information

Session Title: Systemic Lupus Erythematosus - Animal Models

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/

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