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Journal of Autoimmunity 28 (2007) 62e68
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Review
B cell targeted therapy in autoimmunity
Miri Blank a,b, Yehuda Shoenfeld a,c,d,*
a
The Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel
Department of Human Microbiology, Sackler Faculty of Medicine, Tel-Aviv University, Israel
c
Department of Medicine ‘B’ and The Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, and Sackler Faculty of Medicine,
Tel-Aviv University, Israel
d
Incumbent of the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases, Tel-Aviv University, Israel
b
Abstract
Autoimmunity results from a break in self-tolerance involving humoral and/or cell-mediated immune mechanisms. Part of the pathological
consequence of a failure in central and/or peripheral tolerance, results from survival and activation of self-reactive B cells. Such B cells produce
tissue-damaging pathogenic autoantibodies, and subsequent formation of complement-fixing immune complexes that contribute to tissue
damage.
Current pharmacological strategies for treating autoimmune diseases involve global use of broad-acting immunosuppressants that with long
term use have associated toxicities. The present drive in drug development is towards therapies that target a specific biological pathway or
pathogenic cell population. This review focuses on some of the emerging therapies based on co-stimulation blockers, and compounds which
contribute to a specific B cells depletion, based on studies in animal models and human clinical studies.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Autoimmunity; B cell; Therapy; Autoantibodies
1. Introduction
In recent years, data have emerged suggesting that B lymphocytes play a broader role in immune responses and are not
merely the passive recipients of signals that result in differentiation of antibody-producing plasma cells. Along with their
traditional roles as antigen presenting cells and precursors of
antibody-producing plasma cells, B cells have also been found
to regulate antigen presenting cells (APCs) and T cell functions, produce cytokines, and express receptor/ligand pairs
that previously had been thought to be restricted to other
cell types [1]. Autoimmunity results from a breakdown of
self-tolerance involving humoral and/or cell-mediated immune
mechanisms in. Among of the consequences of failure in
central and/or peripheral tolerance, are survival and activation
* Corresponding author. Department of Medicine B, Sheba Medical Center,
Tel-Hashomer 52621, Israel. Tel.: þ972 3 530 2652; fax: þ972 3 53 528.
E-mail address: [email protected] (Y. Shoenfeld).
0896-8411/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.jaut.2007.02.001
of self-reactive B cells. Such B cells produce pathogenic autoantibodies, which can form complement-fixing immune complexes that contribute to tissue damage.
Several humoral autoimmune diseases, are defined by
excessive activation of both B and T lymphocytes. Activation
of these cells requires in cooperation, antigen engagement
and co-stimulatory signals from interacting lymphocytes [2].
Thus, blockade of co-stimulatory signals offers therapeutic
approach in some autoimmune conditions. Other therapeutic
approaches are based on the fact that signals from the B cell
receptors help determine the B-cell fate, leading to proliferation, differentiation, growth arrest or apoptosis [3e6].
2. Blockade of co-stimulatory signals
Some of the most biologically important signals that B cells
receive from activated cognate T cells are delivered through
membrane-bound tumor necrosis factor (TNF) and TNF receptor families of proteins. Currently, considerable interest is
M. Blank, Y. Shoenfeld / Journal of Autoimmunity 28 (2007) 62e68
focused on the development of modulators of B cell activation
through these surface receptors. Several novel therapeutic
agents that interfere in the co-stimulatory signals were introduced and found to delete autoreactive lymphocytes and block
autoimmune disease progression. These developed co-
63
stimulation blocker include: monoclonal antibodies (mAbs)
directed to the receptor or to the receptor ligand, fusion proteins or DNA vaccination summarized in Table 1.
Lymphocyte activation requires costimulatory signals such
as those provided by the CD28/B7 and CD40/CD40L
Table 1
B cell targeting in autoimmune diseases
Compound
Intervention in
Target molecule
Animal studies
Human studies
References
Co-stimulation blockers
1. CTLA4Ig fusion protein
CD28/B7
1e3. B7
1. NZB NZW F1 mice
Rheumatoid arthritis
phase III
[9e12]
SWR NZB (SNF1) mice,
NZB NZW F1, collageninduced arthritis,
experimental allergic
encephalomyelitis, chronic
graft-vs-host disease,
autoimmune
encephalomyelitis in
monkey
Phase II trials in SLE,
psoriasis and idiopathic
thrombocytopenic purpura
(ITP), Crohn’s disease
[13e26]
2. AdCTLA4Ig gene therapy
3. DNA co-vaccination with
B7-1wa
1. Humanized anti-CD40L mAb
2. MRLlpr/lpr mice
3. Autoimmune diabetes
in NOD mice
CD40/CD40L
2. Anti-CD40 mAb
3. Soluble recombinant CD40L
1. CD40L
2. CD40
3. CD40
4-1BB/4-1BBL
4-1BB
1. MRLlpr, NZB NZW F1
mice
2. baboons (Papio anubis)
Not reported
[27e31]
1. TACI-Fc (sBLySL), AdTACI-Fc
1. BlyS/BR3, TACI
[24,33,42e45]
2. APRIL/BCMA
BLyS/BCMA
3,4. BLyS/BR3
BLyS/TACI
1. NZB NZW F1, MRL
lpr/lpr, B6-lpr/lpr
4. SLE, RA in mice, monkey
4. SLE Phase II
2. BCMA-Fc
1, 2. APRIL,
BLyS
3, 4. BLyS
1. Anti-4-1BB (CD137) mAb
2. Humanized anti-4-1BB mAb
(H4B4)
3. BR3-Fc
4. BLyS
4. LymphoBlast-B (anti-BLyS
mAb)
Specific B cell depletion
Anti-CD20 mAb (Rituximab)
8CD20
CD20
In lymphoma, mice, baboon
Glomerulonephritis,
Goodpasture’s syndrome,
necrotizing vasculitis,
lymphadenitis, periarteritis
nodosa, SLE, RA, TTP,
autoimmune hemolytic
anemias, myasthenia
gravis, Graves’ disease.
Phase III
[47e60]
Anti-CD22
CD22
CD22
Malignancies in mice, baboon
SLE, RA
[60,61]
BCR targeting
1. Anti-idiotype, IVIG
BCR
BCR
1. NZB NZW F1, MRL/lpr
lupus, APS myasthenia gravis,
EAE. Tsk
[62e76]
2. Synthetic peptides
3. Enhancement of inhibitory FcgRIIB
BCR
BCR-FcgIIB
BCR
BCR-FcgIIB
2. Naive mice, APS
3. Lupus-pzone mice
1. SLE, ITP, APS, RA,
dermatopolymyositis,,
multiple sclerosis, fibrosis,
myasthenia gravis,
Guillain-Barre, alopecia,
juvenile diabetes,
psoriasis, cardiomyopathy,
Crohn’s disease,
Graves’ disease,
Sjogren’s syndrome
2. SLE, APS
3. SLE
[78e80]
[81e84]
64
M. Blank, Y. Shoenfeld / Journal of Autoimmunity 28 (2007) 62e68
receptor-ligand pairs [7,8]. B7/CD28 co-stimulatory pathway
is one of the major regulatory pathway for the control of
immune responses. B7-1 and B7-2 are the main ligands for
CD28 (a positive regulator of T cell activity). The cytotoxic
T-lymphocyte antigen-4 (CTLA4)(CD152), expressed on activated T cells, a strong negative regulator of T cell activity, is
an additional ligand for B7. The following compounds were
developed addressing these molecules.
2.1. CTLA4Ig fusion protein
(IDEC-131) was tested also in other autoimmune conditions
such as SLE, idiopathic thrombocytopenic purpura (ITP), in
Crohn’s disease [21]. Phase II clinical studies were conducted
and no further development has been reported.
2.4. Anti-CD40 mAb (5D12)
A chimeric immunoglobulin containing the variable domains of the heavy and light chains of the murine version of
5D12, antagonist of the CD40-CD40L pathway [22]. This
new chimeric mAb was tested successfully in an experimental
autoimmune encephalomyelitis model in cynomolgus monkeys [23].
CTLA4Ig is a soluble molecule composed of the extracellular domain of the CTLA4 (CD152) fused to an immunoglobulin IgGFc domain. It binds B7 ligands on B cells with 20-fold
greater affinity than CD28, thereby blocking the binding of
CD28 to B7-1 (CD80) or B7-2 (CD86) and inhibiting T cell
priming. Long-term administration of CTLA4Ig as a fusion
protein or expressed in adenovirus, to NZB/NZW F1 mice,
prevented the onset of [9,10]. Gene therapy using this approach has also been shown to be beneficial in the MRL lpr/
lpr lupus mice [11]. Clinical studies with CTLA4Ig fusion
protein showed improvement in rheumatoid arthritis activity
when added to methotrexate therapy [12].
Many cell-membrane proteins are subjected to limited
proteolysis (called shedding) that gives rise to soluble forms
consisting of extracellular domain of the protein [24]. Elevated
levels and functional capacity of soluble CD40L was detected
in SLE sera and rheumatoid arthritis (RA) plasma [25,26]. A
recombinant human soluble CD40Ligand was developed for
targeting the CD40L.
2.2. DNA co-vaccination with B7-1wa
2.6. Anti-4-1BB (CD137) mAb
A single substitution in amino acid in B7-1 (B7-1wa), abrogate the binding of B7-1 to CD28 but not to CTLA4.
Thus, B7-1Ig was inhibitory for CTLA-4L [12]. In-vivo,
gene transfer of co-injection of a B7-1wa (membrane-bound
form) plasmid blocked induction of anti-CEA immunity.
DNA covaccination by co-injection of a B7-1wa (membrane-bound form) plasmid into non-obese diabetic (NOD)
mice with autoimmune diabetes abrogated reactivity to insulin
and ameliorated the disease through cDNA encoding selective
CTLA-4L (the B7-1wa) [12].
4-1BB (CD137), a member of the tumor necrosis factor
(TNF) receptor superfamily, is a costimulatory molecule [27]
primarily expressed on activated T cells and natural killer
(NK) cells. Its natural ligand, 4-1BBL (CD137), has been detected on macrophages, dendritic cells and resting B cells. 4-1
BB ligand can costimulate human CD28- T cells, resulting in
cell division, inflammatory cytokine production, increased
perforin levels, enhancement of cytolytic effector function,
as well as the up-regulation of the anti-apoptotic protein
Bcl-X(L) [28]. Promising treatments with anti-4-1BB were
tested in autoimmune animal models (Table 1). Fas deficient
MRL/lpr mice treated with an agonistic anti-4-1BB mAb, specific for costimulatory molecules, blocked lymphadenopathy,
skin lesions, reduced anti-DNA Ab production, attenuated
nephropathy leading to prolonged survival and blocked the
progression of the spontaneously developed autoimmune state
[29]. Anti-4-1BB mAbs treatment reversed acute disease
lupus-prone NZB NZW F1 mice, and extended the mice
lifespan from 10 months to more than 2 years [30]. Furthermore, injection of humanized anti-4-1BB mAbs into nonhuman primates suppressed the development of T-dependent
humoral immunity [31].
2.3. Anti-CD40L mAb
CD40 and its ligand CD40L (CD154) [13]. The interaction
of CD40L on activated T cells with CD40 on B cells induces B
cell proliferation, differentiation, APC activation, cytokine secretion and formation of germinal center and IgG switching
[13]. Studies in murine models using anti-CD40L mAbs as
a costimulatory blockade, showed effective delay in disease
onset in lupus mouse models such as SWR NZB (SNF1),
NZB NZW F1 and MRL lpr/lpr mice [14,15], in collageninduced arthritis [16], experimental allergic encephalomyelitis
(EAE) [17], and chronic graft-vs-host disease [18]. Clinical
studies using humanized anti-CD40L in lupus patients markedly reduced the frequency of IgG anti-DNA antibody-producing B cells, which persisted for several months after cessation
of treatment [19]. Recent data from an open-label study of
a humanized anti-CD40L mAb in the treatment of patients
with active SLE nephritis have shown decreases in serum titer
of anti-dsDNA antibody levels, proteinuria, and SLE Disease
Activity Index (SLEDAI) scores [20]. Anti-CD40L mAb
2.5. Soluble CD40L
2.7. Anti-BLyS mAb
BLyS (B lymphocyte stimulator) is a B cells targeting the
peripheral B cell survival factor that belong to the TNF family,
also known as BAFF (B cell activating factor), or TALL-1
(TNF and apoptosis ligand-related leukocyte-expressed ligand
1) to THANK (TNF homologue that activate apoptosis, NFkB
and Jun NH2-terminal kinase) and ZTNF4, plays a crucial role
M. Blank, Y. Shoenfeld / Journal of Autoimmunity 28 (2007) 62e68
in the regulation of B cell maturation and development
[32,33]. BLyS is synthesized as a type II transmembrane protein that can be cleaved at a specific site in its extracellular
domain to generate a soluble ligand. Soluble form of BLyS
binds specifically to B cells and promote proliferation of B
cells costimulated by Abs to IgM [34]. BLyS also promotes
the survival of both resting and activated B cells possibly by
induction of Bcl-X [35,36]. Elevated levels of BLyS have
been observed in autoimmune models of lupus [37] and in serum of patients with SLE, RA, Sjogren’s syndrome, primary
biliary cirrhosis and autoimmune daibetes [38e41]. The
receptors for BLyS are: two orphan receptors that belong to
the TNF receptor family, transmembrane activator and calcium-modulatingand cyclophilin ligand (CAML) interactor
(TACI) and B cell maturation protein (BCMA) [37]. BCMA
is B cell specific, whereas TACI is expressed on activated T
and B cells, and bind the proliferation-inducing ligand
(APRIL). However, preferred binding was observed with
TACI- BLyS and BCMA-APRIL pairs [32,33]. Considerable
body of evidence implicating BLyS in the induction of B
cell autoimmunity paved the way for developing therapeutic
strategies in several animal models of autoimmune diseases
and proved to be effective [42,43].
LymphoStat-B(tm) is a human monoclonal antibody (scFv),
that specifically recognizes and inhibits the biological activity
of BLyS [44]. LymphoStat-B was developed as a potential
treatment for systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases [45,46]. LymphoStatB inhibits the binding of BLyS to its 3 receptors, TACI,
BCMA and BR3. It significantly reduces the levels of circulating B (CD20) cells in mice and cynomolgus monkeys.
BLyS antagonist TACI-Fc and BR3-Fc (BAFFR-Fc),
BCMA-Fc were generated using a decoy receptor-Fc fusion
protein. TACI-Fc and BR3-Fc were found to delay the onset
of autoimmunity in at least one mouse model of lupus in
NZB W F1 and MRL-lpr/lpr mice [37,43]. BCMA-Fc ameliorated experimental lupus models and experimental autoimmune encephalomyelitis [32,33], Table 1. Treatment of B6-lpr/
lpr mice with adenovirus-encoded soluble TACI, Ad/TACI-Fc,
resulted in elevated serum levels of TACI-Fc protein and inhibition of ongoing autoimmunity [32,33]. Promising results
were obtained in additional autoimmune animal model of collagen II -induced arthritis in DBA/1j mice [45].
3. Selective B cell depletion
3.1. Anti-CD20 mAbs Rituximab
Selective B lymphocyte depletion has been made possible
by the availability of the chimeric anti-CD20 mAb Rituximab
[46e48]. CD20 is a B lymphocyte-restricted antigen that is
expressed on B lymphocyte precursors and mature B lymphocytes. It is lost during differentiation into plasma cells. In autoimmune diseases, Rituximab has been used in many cases as
monotherapy [49e52], or as combined therapy with other
drugs such as cyclophosphamide, corticosteroid, intravenous
65
immunoglobulin (IVIG), plasmapheresis and other immunosuppressive agents [53e59] (Table 1).
3.2. Anti-CD22 mAbs Epratuzumab
CD22 is first expressed in the cytoplasm of pro-B and pre-B
cells, and on the surface of B cells mature to become IgDþ. It
has a role in intercellular interactions, activate B cells and
modulate antigen receptor signaling in vitro [60]. Humanized
anti-CD22 mAbs block CD22 adhesive function, particularly
in diverse autoimmune disease (Table 1) [48,60,61].
4. Specific molecular targeting of B cell antigen
receptor e BCR
Signals generated through the B cell antigen receptor (BCR)
are critical to development and B cell responses to antigen. Defective BCR signaling can result in immunodeficiency as well
as a predisposition to autoimmunity. The BCR is a multiprotein
complex containing an antigen-binding membrane immunoglobulin (Ig) generated via rearrangement and assembly of
heavy and light chains. The generation and maintenance of
self-reactive B cells is regulated by autoantigen signaling
through the BCR complex. Engagement of the BCR initiates
a cascade of signaling events resulting in the induction of cell
proliferation, differentiation, anergy or apoptosis. Autoimmune
state can be modulated through BCR targeting. The classical
molecules controlling the BCR expression are the anti-idiotypic
mAbs leading to specific apoptosis by anti-dsDNA antiidiotypic mAbs [61,62,].
4.1. Intravenous immunoglobulin e IVIG
IVIG is a pooled normal polyspecific IgG obtained from
plasma of several thousand healthy donors increasingly being
used as an immunomodulatory therapy for patients with autoimmune diseases [63e68] (Table 1). Although the precise
mechanism of action of IVIG in autoimmunity is unknown,
one of the dominant hypothesis is that it involves manipulation
of the idiotypic network by neutralization of pathogenic autoantibodies via blocking the idiotypes (e.g. IVIG composed of a cohort of anti-idiotypic Abs characterizing a panel of autoimmune
diseases). This hypothesis is supported by studies in murine
experimental models (Table 1). Administration of IVIG to these
autoimmune mice resulted in abrogation of the clinical manifestations of SLE and prevented fetal loss in APS via immunoregulation of the idiotypic network [69e71].
Recently, we have generated affinity purified lupus specific
enriched fraction of anti-idiotypic polyclonal Abs from IVIG
preparation, using a column constructed from affinity purified
anti-dsDNA from 55 patients with SLE designated superIVIG
(sIVIG). Administrating this sIVIG to lupus mice, NZB NZW F1, resulted in an amelioration of the diverse lupus
manifestations (e.g. decrease in the titers of anti-dsDNA, proteinuria, and glomerulonephritis), 200 times more effective
than IVIG [72]. sIVIG specific to another autoimmune disease,
APS, was recently produced by us by passing IVIG on
66
M. Blank, Y. Shoenfeld / Journal of Autoimmunity 28 (2007) 62e68
a column composed of anti-beta 2-glycoprotein-I (b2GPI) Abs
derived from 15 patients [73]. These results open a new path
for developing IVIG specific to different autoimmune diseases, targeting the BCR.
4.2. BCR specific synthetic peptides
By employing hexapeptide phage display library and antib2GPI mAbs, we were able to identify peptides which are
mimetics of anti-b2GPI target epitopes in APS [78]. These
peptides on a poly-L-Lysine backbone were able to cause
a specific CD19 B cell apoptosis via BCR targeting [75].
LJP 394 also called Abetimus or Riquent, is a synthetic toleragen molecule consisting of four double-stranded oligodeoxyribonucleotides attached to non-immunogenic polyethylene
glycol, a proprietary carrier platform. In patients with highaffinity Abs to its DNA epitope it prolonged the time to renal
flare, decreased the number of renal flares, and required fewer
HDCC treatments compared with placebo [79]. Branched peptides composed of beta-2-glycoprotein-I derived peptides,
were found to be effective in specific B cell depletion also
in antiphospholipid syndrome [77,80].
4.3. Enhancement of inhibitory Fc receptor
(FcgRIIB) expression on B cells
The ability of FcgRIIB to couple the BCR and promote
the B cell to an inhibitory pathway, can potentially determine
the fate of B cells upon IgG immune complex engagement.
Deficiency of RIIB on B cells leads to autoimmune disease
in specific genetic backgrounds [81e84]. Lupus, a multigenic
autoimmune condition in which a breakdown of tolerance results in the development of autoantibodies, leads to a variety
of pathologic outcomes. FcgRIIB regulates a common B cell
checkpoint in genetically diverse lupus-prone mouse strains,
and modest changes in its expression can result in either tolerance or autoimmunity [81e84]. Therefore, increasing
FcgRIIB expression on B cells may be an effective way to
treat humoral mediated autoimmune diseases. Recently, the
group of Ravetch V [82] demonstrated that mice that received FcgRIIB retroviral-transduced bone marrow cells,
exhibite reduced levels of serum antinuclear antibodies
(ANAs), antibodies to DNA, or antibodies to chromatin,
when compared with mice that received autologous bone
marrow transduced with the parent retrovirus. Renal function
in NZM or BXSB mice whose marrow was reconstituted
with marrow that was transduced with the FcgRIIB retroviral
constructs, was comparable to that of wild-type mice, with
the majority showing little to no proteinuria. In contrast,
the majority of control exhibited a marked reduction in their
kidney function associated with severe proteinuria. Histological examination showed that the kidneys of FcgRIIB retroviral-transduced mice resembled those of healthy mice, and
untreated or mock-transduced NZM2410 and BXSB mice
exhibited substantial renal pathology with proliferative
glomerulonephritis, tubulo-interstitial inflammation, and pronounced glomerular sclerosis. Similarly, FcgRIIB retroviral
transduction significantly reduced vasculitis and lung inflammation in NZM 2410 mice as compared with the control
groups [83,84]. This proposed concept of elevation of the
B cell expression of the inhibitory FcgRIIB receptor theoretically can be adapted to other autoimmune conditions with
decreased expression of FcgRIIB.
5. In conclusion
B cell targeting therapy seems a potential specific approach
for various autoimmune conditions apparently associated with
very low side effects.
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