The online version of this article (doi:10.1186/ar3400) contains supplementary material, which is available to authorized users.
Dr. Chang, Dr. Huang, Ms. Francesco, Dr. Chen, Ms. Magadala, and Dr. Buggy are employees of Pharmacyclics, and hold stock and/or stock options at Pharmacyclics Inc. Pharmacyclics Inc. owns patents and patent applications covering various aspects of and relating to PCI-32765. Dr. Robinson received research funding from Pharmacyclics for this study. Dr. Sokolove declares no competing interests.
BYC designed, conceived the study, coordinated the project, analyzed the data, performed statistical analysis, and wrote the manuscript. MMH, MF, PM, JC, and JS performed the experiments, analyzed the data, and contributed to the manuscript. JS, and WHR co-designed experiments and contributed to the manuscript. JJB revised the manuscript, managed the project and contributed to the manuscript. All authors read and approved the final manuscript.
The aim was to determine the effect of the Bruton tyrosine kinase (Btk)-selective inhibitor PCI-32765, currently in Phase I/II studies in lymphoma trials, in arthritis and immune-complex (IC) based animal models and describe the underlying cellular mechanisms.
PCI-32765 was administered in a series of murine IC disease models including collagen-induced arthritis (CIA), collagen antibody-induced arthritis (CAIA), reversed passive anaphylactic reaction (RPA), and passive cutaneous anaphylaxis (PCA). Clinical and pathologic features characteristic of each model were examined following treatment. PCI-32765 was then examined in assays using immune cells relevant to the pathogenesis of arthritis, and where Btk is thought to play a functional role. These included proliferation and calcium mobilization in B cells, cytokine and chemokine production in monocytes/macrophages, degranulation of mast cells and its subsequent cytokine/chemokine production.
PCI-32765 dose-dependently and potently reversed arthritic inflammation in a therapeutic CIA model with an ED50 of 2.6 mg/kg/day. PCI-32765 also prevented clinical arthritis in CAIA models. In both models, infiltration of monocytes and macrophages into the synovium was completely inhibited and importantly, the bone and cartilage integrity of the joints were preserved. PCI-32765 reduced inflammation in the Arthus and PCA assays. In vitro, PCI-32765 inhibited BCR-activated primary B cell proliferation (IC50 = 8 nM). Following FcγR stimulation, PCI-32765 inhibited TNFα, IL-1β and IL-6 production in primary monocytes (IC50 = 2.6, 0.5, 3.9 nM, respectively). Following FcεRI stimulation of cultured human mast cells, PCI-32765 inhibited release of histamine, PGD2, TNF-α, IL-8 and MCP-1.
PCI-32765 is efficacious in CIA, and in IC models that do not depend upon autoantibody production from B cells. Thus PCI-32765 targets not only B lymphocytes but also monocytes, macrophages and mast cells, which are important Btk-expressing effector cells in arthritis.
Additional file 1: Table S1. Immunophenotyping of splenocyte subpopulations following 18 days of treatment with PCI-32765. (DOC 40 KB)13075_2011_3163_MOESM1_ESM.DOC
Additional file 2: Figure S1. Serum cytokines/chemokines from collagen-induced arthritis (CIA) mice treated with PCI-32765 at 12.5 mg/kg (n = 12) for 18 days. * P < 0.05 compared with vehicle, analysis of variance. (PDF 131 KB)13075_2011_3163_MOESM2_ESM.PDF
Additional file 3: Supplementary materials and methods. Immunophenotyping of mouse spleens from collagen-induced arthritis (CIA) models. (DOCX 12 KB)13075_2011_3163_MOESM3_ESM.DOCX
Additional file 4: Figure S2. PCI-32765 potentially inhibits multiple pathways in the pathogenesis of rheumatoid arthritis. PCI-32765 inhibits B cell activation, and suppresses cytokine/chemokine production from monocytes, macrophages, and mast cells following immune-complex activation (modified from [ 49]). Art by Jacqueline Schaffer, M.A.M.S., medical illustrator, for Pharmacyclics Inc. (TIFF 8 MB)
Authors’ original file for figure 113075_2011_3163_MOESM5_ESM.pdf
Authors’ original file for figure 213075_2011_3163_MOESM6_ESM.pdf
Authors’ original file for figure 313075_2011_3163_MOESM7_ESM.pdf
Authors’ original file for figure 413075_2011_3163_MOESM8_ESM.pdf
Authors’ original file for figure 513075_2011_3163_MOESM9_ESM.pdf
Authors’ original file for figure 613075_2011_3163_MOESM10_ESM.eps
Hata D, Kawakami Y, Inagaki N, Lantz CS, Kitamura T, Khan WN, Maeda-Yamamoto M, Miura T, Han W, Hartman SE, Yao L, Nagai H, Goldfeld AE, Alt FW, Galli SJ, Witte ON, Kawakami T: Involvement of Bruton's tyrosine kinase in FcepsilonRI-dependent mast cell degranulation and cytokine production. J Exp Med. 1998, 187: 1235-1247. 10.1084/jem.187.8.1235. PubMedCentralCrossRefPubMed
Scribner CL, Hansen CT, Klinman DM, Steinberg AD: The interaction of the xid and me genes. J Immunol. 1987, 138: 3611-3617. PubMed
Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B, Li S, Pan Z, Thamm DH, Miller RA, Buggy JJ: The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci USA. 2010, 107: 13075-13080. 10.1073/pnas.1004594107. PubMedCentralCrossRefPubMed
Fowler N, Sharman JF, Smith SS, Boyd T, Grant B, Kolibaba KS, Furman RR, Buggy J, Loury D, Hamdy A, Advani R: The Btk inhibitor, PCI-32765, induces durable responses with minimal toxicity in patients with relapsed/refractory B-cell malignancies: results from a phase I study. American Society of Hematology Annual Conference: 19 November, 2010. 2010, Orlando, FL. Blood, Abstract 964
Terato K, Hasty KA, Reife RA, Cremer MA, Kang AH, Stuart JM: Induction of arthritis with monoclonal antibodies to collagen. J Immunol. 1992, 148: 2103-2108. PubMed
Munn DH, Cheung NK: Antibody-dependent antitumor cytotoxicity by human monocytes cultured with recombinant macrophage colony-stimulating factor. Induction of efficient antibody-mediated antitumor cytotoxicity not detected by isotope release assays. J Exp Med. 1989, 170: 511-526. 10.1084/jem.170.2.511. CrossRefPubMed
Braselmann S, Taylor V, Zhao H, Wang S, Sylvain C, Baluom M, Qu K, Herlaar E, Lau A, Young C, Wong BR, Lovell S, Sun T, Park G, Argade A, Jurcevic S, Pine P, Singh R, Grossbard EB, Payan DG, Masuda ES: R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther. 2006, 319: 998-1008. 10.1124/jpet.106.109058. CrossRefPubMed
Mankin HJ, Dorfman H, Lippiello L, Zarins A: Biochemical and metabolic abnormalities in articular cartilage from osteo-arthritic human hips. II. Correlation of morphology with biochemical and metabolic data. J Bone Joint Surg Am. 1971, 53: 523-537. PubMed
Pine PR, Chang B, Schoettler N, Banquerigo ML, Wang S, Lau A, Zhao F, Grossbard EB, Payan DG, Brahn E: Inflammation and bone erosion are suppressed in models of rheumatoid arthritis following treatment with a novel Syk inhibitor. Clin Immunol. 2007, 124: 244-257. 10.1016/j.clim.2007.03.543. CrossRefPubMed
Drexler SK, Kong PL, Wales J, Foxwell BM: Cell signalling in macrophages, the principal innate immune effector cells of rheumatoid arthritis. Arthritis Research & Therapy. 2008, 10: 216-10.1186/ar2481. CrossRef
Perezdediego R, Lopezgranados E, Pozo M, Rodriguez C, Sabina P, Ferreira A, Fontan G, Garciarodriguez M, Alemany S: Bruton's tyrosine kinase is not essential for LPS-induced activation of human monocytes. J Allergy Clin Immunol. 2006, 117: 1462-1469. 10.1016/j.jaci.2006.01.037. CrossRef
Takai T: Roles of Fc receptors in autoimmunity. Nat Rev Immunol. 2002, 2: (8):580-592. PubMed
Satterthwaite AB, Willis F, Kanchanastit P, Fruman D, Cantley LC, Helgason CD, Humphries RK, Lowell CA, Simon M, Leitges M, Tarakhovsky A, Tedder TF, Lesche R, Wu H, Witte ON: A sensitized genetic system for the analysis of murine B lymphocyte signal transduction pathways dependent on Bruton's tyrosine kinase. Proc Natl Acad Sci USA. 2000, 97: 6687-6692. 10.1073/pnas.110146697. PubMedCentralCrossRefPubMed
Amoras AL, Kanegane H, Miyawaki T, Vilela MM: Defective Fc-, CR1- and CR3-mediated monocyte phagocytosis and chemotaxis in common variable immunodeficiency and X-linked agammaglobulinemia patients. J Investig Allergol Clin Immunol. 2003, 13: 181-188. PubMed
Ji H, Ohmura K, Mahmood U, Lee DM, Hofhuis FM, Boackle SA, Takahashi K, Holers VM, Walport M, Gerard C, Ezekowitz A, Carroll MC, Brenner M, Weissleder R, Verbeek JS, Duchatelle V, Degott C, Benoist C, Mathis D: Arthritis critically dependent on innate immune system players. Immunity. 2002, 16: 157-168. 10.1016/S1074-7613(02)00275-3. CrossRefPubMed
Firestein GS, Corr M: Common mechanisms in immune-mediated inflammatory disease. J Rheumatol Suppl. 2005, 73: 8-13; discussion 29-30. PubMed
Ravetch JV: Fundamental Immunology. 2003, Paul WE, Lippincott Williams and Wilkins, 690-700. 5
Shinohara M, Koga T, Okamoto K, Sakaguchi S, Arai K, Yasuda H, Takai T, Kodama T, Morio T, Geha RS, Kitamura D, Kurosaki T, Ellmeier W, Takayanagi H: Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals. Cell. 2008, 132: 794-806. 10.1016/j.cell.2007.12.037. CrossRefPubMed
- The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells
Betty Y Chang
Min Mei Huang
William H Robinson
Joseph J Buggy
- BioMed Central
Neu im Fachgebiet Innere Medizin
Meistgelesene Bücher aus der Inneren Medizin
Mail Icon II