The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells
Chang et al. Arthritis Research & Therapy
Betty Y Chang 2
Min Mei Huang 2
Michelle Francesco 2
Jun Chen 2
Jeremy Sokolove 0 1
Padmaja Magadala 2
William H Robinson 0 1
Joseph J Buggy 2
0 VA Palo Alto Health Care System , 3801 Miranda Avenue, Palo Alto, CA, 94304 , USA
1 Stanford University School of Medicine, Division of Immunology and Rheumatology , Stanford, CA. 94305
2 Pharmacyclics, Inc., Research Department , Sunnyvale CA, 94085-4521 , USA
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The Bruton tyrosine kinase inhibitor PCI-32765
ameliorates autoimmune arthritis by inhibition of
multiple effector cells
Chang et al.
Open Access
The Bruton tyrosine kinase inhibitor PCI-32765
ameliorates autoimmune arthritis by inhibition of
multiple effector cells
Introduction: 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.
Methods: 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.
Results: 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,
PCI32765 inhibited BCR-activated primary B cell proliferation (IC50 = 8 nM). Following FcgR stimulation, PCI-32765
inhibited TNFa, IL-1b and IL-6 production in primary monocytes (IC50 = 2.6, 0.5, 3.9 nM, respectively). Following
FcRI stimulation of cultured human mast cells, PCI-32765 inhibited release of histamine, PGD2, TNF-a, IL-8 and
MCP-1.
Conclusions: 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.
Introduction
Rheumatoid arthritis (RA) is a debilitating systemic
disease characterized by circulating autoantibodies, synovial
inflammation, pannus formation, and cartilage and bone
destruction in affected joints. Initiation of the disease
involves the systemic dysregulation of T- and
B-lymphocytes, which leads to a breach of self-tolerance, resulting
in immune responses directed against self-antigens.
* Correspondence:
1Pharmacyclics, Inc., Research Department, Sunnyvale CA, 94085-4521, USA
Full list of author information is available at the end of the article
During the chronic inflammatory phase of the disease,
autoantibodies, and immune complexes (ICs) further
activate sentinel and effector cells such as neutrophils,
monocytes/macrophages, dendritic cells, and mast cells
that infiltrate the synovium and release proinflammatory
cytokines and matrix metalloproteases, leading to
cartilage destruction. Synovial hyperplasia leads to the
formation of a pannus that invades the surrounding
cartilage and bone, and inflammation enhances the
activity of resident osteoclasts leading to bone erosion
[1-3].
Bruton tyrosine kinase (Btk) is a Tec-family kinase
that is specifically required for B cell activation following
engagement of the B cell antigen receptor (BCR) [4]. In
the lymphoid lineage, expression of Btk is restricted to
B cells and is not found in T or natural killer (NK) cells.
Functional null mutations of Btk in humans cause the
inherited disease X-linked agammaglobulinemia (XLA),
characterized by a lack of peripheral B cells and very
low levels of serum immunoglobulin (Ig) (reviewed in
[5,6]). In the mouse, point mutation or deletion of Btk
causes X-linked immunodeficiency (xid), with about
50% fewer conventional B2 B cells, absent B1 B cells,
and reduced serum Ig levels [7,8]. As RA is
characterized by polyclonal B cell activation giving rise to B cell
expansion and the production of autoantibodies, Btk
may be a uniquely attractive target for selective B cell
inhibition in RA.
Btk is also expressed in specific cells of the myeloid
lineage, and evidence suggests that it contributes to
immune-complex mediated activation of the FcgR and
FcR signaling pathways [9-11] in (...truncated)