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OP0085 Therapeutic Inhibition of Anti-Apoptotic BCL-2 Family Proteins in a Murine Model of Lupus Nephritis
  1. L. C. Wang1,
  2. S. Perper2,
  3. D. Perron3,
  4. E. Tarcsa4,
  5. P. Bardwell5,
  6. N. Mozaffarian6,
  7. A. Souers7,
  8. S. Elmore8,
  9. T. Ghayur5,
  10. L. Olson1
  1. 1Immunology
  2. 2Pharmacology
  3. 3Molecular Cellular Pharmacology
  4. 4Drug Metabolism Pharmacokinetics
  5. 5Biologics, AbbVie Bioresearch Center, Worcester
  6. 6Clinical Development
  7. 7Chemistry
  8. 8Early Discovery, AbbVie Inc., Chicago, United States

Abstract

Background Apoptosis is both a conserved and highly regulated process that is essential for normal development and tissue homeostasis. This process, also known as programmed cell death, is tightly regulated by the BCL-2 family proteins. Dysregulation of these proteins has been linked to survival of autoreactive lymphocytes and to Systemic Lupus Erythematosus (SLE). Inhibition of BCL-2 proteins may therefore ameliorate autoimmunity.

Objectives To determine the effect of inhibition of BCL-2 survival proteins in a murine model of lupus nephritis, as well as the effect on human leukocytes ex vivo.

Methods We have established previously that adenovirus vector-mediated delivery of murine IFN-α in lupus-prone (NZB × NZW)F1 mice induces a rapid and severe disease with many characteristics of SLE, including death due to severe glomerulonephritis. These mice were treated daily with vehicle or 3, 10, 30 mg/kg of navitoclax, a BH3 mimetic that binds with high affinity to BCL-2, BCL-XL, and BCL-W. Mycophenolate (100 mg/kg) was used as a clinical benchmark and positive treatment control. Proteinuria and survival data were presented as Kaplan-Meyer survival curves using Prism. For ex vivo human lymphocyte studies, B and T cells from healthy donors were cultured and treated with navitoclax overnight, prior to flow cytometric analysis. Some cultures were incubated with anti-CD40L/IgM or anti-CD3/CD28 to stimulate B or T cells, respectively. IC50 calculations were performed using Prism software (GraphPad). Results were considered significant at the level of p < 0.05.

Results BCL-2 family inhibition by navitoclax in the IFNa-induced (NZB x NZW) F1 lupus model significantly reduced both the incidence of severe proteinuria (≥ 300mg/dL) and mortality in a dose-dependent fashion as compared to vehicle controls (p < 0.05). In addition, chronic administration of navitoclax at 30 mg/kg demonstrated 95% survival rate and 50% of animals without proteinuria as compared to 80% and 20%, respectively, in mycophenolate-treated animals. Consistent with its mechanism of action, navitoclax caused a dose-dependent reduction in murine lymphocyte counts, which correlated with long-term efficacy. In ex vivo human cell cultures, navitoclax treatment led to a rapid reduction in the numbers of both stimulated and unstimulated human lymphocytes, with B cells showing a higher sensitivity to navitoclax compared to T cells.

Conclusions Treatment of lupus nephritis-prone mice with the BCL-2 family inhibitor navitoclax resulted in significantly higher numbers of animals with preservation of renal function and overall survival. Furthermore, BCL-2 inhibition in ex vivo human lymphocyte cultures led to a rapid and selective reduction of B and T cells via apoptosis. Taken together, these data support a role for BCL-2 inhibition in the treatment of autoimmune diseases such as SLE.

Disclosure of Interest L. C. Wang Shareholder of: AbbVie Bioresearch Center, Employee of: AbbVie Bioresearch Center, S. Perper Shareholder of: AbbVie Bioresearch Center, Employee of: AbbVie Bioresearch Center, D. Perron Shareholder of: AbbVie Bioresearch Center, Employee of: AbbVie Bioresearch Center, E. Tarcsa Shareholder of: AbbVie Bioresearch Center, Employee of: AbbVie Bioresearch Center, P. Bardwell Shareholder of: AbbVie Bioresearch Center, Employee of: AbbVie Bioresearch Center, N. Mozaffarian Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., A. Souers Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., S. Elmore Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., T. Ghayur Shareholder of: AbbVie Bioresearch Center, Employee of: AbbVie Bioresearch Center, L. Olson Shareholder of: AbbVie Bioresearch Center, Employee of: AbbVie Bioresearch Center

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