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Acta Biochim Biophys
Sin 2008, 40: 636-642
doi:10.1111/j.1745-7270.2008.00443.x
Towards immunotherapeutic drugs and vaccines against multiple
sclerosis
Maria Katsara1,2, John Matsoukas2, George Deraos2, and Vasso Apostolopoulos1*
1 Burnet Institute, Austin Campus, Immunology
and Vaccine Laboratory, Studley Road, Heidelberg, Victoria 3084, Australia
2 Department of Chemistry, Section of Organic
Chemistry, Biochemistry, and Natural Products, University of Patras, Patras
26500, Greece
Received: May 10,
2008
Accepted: May 17,
2008
This work was
supported by grants from the Ministry of Development Secretariat of Research
and Technology of Greece (Grant Aus. 005) and Du Pr? grant from the Multiple
Sclerosis International Federation to MK, and a National Health and Medical
Research Council of Australia R. Douglas Wright Fellowship (223316) to VA
*Corresponding
author: Tel, 613-92870666; Fax, 613-92870600; E-mail, [email protected]
Multiple sclerosis (MS) is an autoimmune,
demyelinating disease of the central nervous system. Numerous treatment options
are available to MS patients; however, these options need to be improved.
Herein, we review the current drugs and therapeutic approaches available to MS
patients, preclinical trial interventions and recent animal model studies for
the potential therapy of MS. Since the current treatment of MS remains elusive
and is limited, animal studies and clinical research offers an optimistic
outlook.
Keywords multiple sclerosis; MS treatment; immunosuppressive drugs;
immunomodulatory drugs; MS clinical trials; peptides; altered peptide ligand
The World Health Organization (WHO) estimates that over 2.5 million
people globally suffer from multiple sclerosis (MS) [1]. With the present
global population growing to an unprecedented height of 6.5 billion in 2005 and
anticipated to reach 7.6 billion by 2020, the prevalence and onset of MS in
children and particularly adults is expected to rise exponentially [2]. It is
estimated that approximately 400,000 people suffer from MS in the US, with
500,000 Europeans and 18,000 Australians also with the disease (http://www.msaustralia.org.au).
T cell recognition of self myelin peptides presented by major
histocompatibility complex (MHC) class II is involved in autoimmune attack in
the human disease multiple sclerosis. MS is a chronic, autoimmune disease of
the central nervous system [3]. T cells, B cells, macrophages and microglia
migrate through the disrupted blood brain barrier which induce inflammation,
demyelination and neurodegeneration [3]. Some of the proteins involved in this
destruction include myelin oligodendrocyte glycoprotein, proteolipid protein
and myelin basic protein (MBP). Depending on the temporal profile and
neurological findings of the patient, there are four distinct subtypes of the
disease characterized by increasing severity: (1) relapsing/remitting MS
(RRMS), (2) secondary progressive MS (SPMS), (3) primary progressive MS (PPMS)
and (4) progressive relapsing MS (PRMS) [4,5]. More than 80% of MS patients are
classified as having RRMS at onset of the disease, and 50% of those will
develop SPMS after 10–15 years of disease progression. Approximately, 15% of MS patients
develop PPMS, and only 5% of these patients will develop (PRMS) [4.5]. The
therapeutic approach to MS has three dimensions: (1) management of acute phase
of the disease, (2) prophylactic treatment, which includes specific and
non-specific immunomodulatory and immunosuppressive agents, and (3) drugs for
the symptoms such as tiredness, spasticity, shakiness of limps and chronic
pain. Although there is no definitive treatment of MS, new clinical and animal
studies give promise and optimism in developing new drugs for MS.
Current Therapies for MSDrugs
Current peptide therapies of MS are relatively immature, with only a
handful of products available on the market which mainly include treatment with
immunomodulatory agents. The interferons available are Schering AGs
Betaferon/Betaseron (IFNb-1b), Biogens Avonex (IFNb-1a), Serono/Pfizers Rebif (IFNb-1a) [2,3],
Tevas Copaxone® (copolymer glatiramer acetate) [6],
Amgen/Seronos (Novantrone®) (mitoxantrone) [7],
azathioprine [8], cyclophosphamide (Endoxan®) and
more recently, the a4-integrin antagonist (Natalizumab®) [7]. These drugs aim to downregulate the autoimmune attack to MS
following the anti-myelin T cell activation.
InterferonsInterferons given by subcutaneous injections reduce the frequency,
severity and duration of exacerbation but their impact on preventing disability
over the long-term is not yet established. Side-effects are also common and
consist of reactions at the injection site, fever, myalgia and flu-like
symptoms. Betaferon® (IFNb-1b), known in the USA as Betaseron®, could be given to people with RRMS who have had two or more
relapses during the last 2 years. It may also be given to people with SPMS with
active disease and is given as a subcutaneous injection, at a dose of 250 mg, every other
day. It is not clear how long patients should be treated with IFNb-1b. Following 2
years of treatment with IFNb-1b, all patients should be assessed by their neurologist and
decisions about longer-term treatment should be made on an individual basis.
The mechanism of action of IFNb-1b is not clear; however, it appears to downregulate the immune
system and reduce relapses (http://www.msactivesource.co.uk). Moreover,
studies have shown that two treatment paradigms have emerged for Betaferon®: (1) initiation of the treatment as early as possible in the course
of the disease and, (2) the use of higher doses with greater frequency to gain
maximum therapeutic effect [9–11]. Rebif® (IFNb-1a) has been approved by the FDA for the
treatment of relapsing states of MS and has been shown to decrease the
frequency of clinical exacerbations and delay the accumulation of physical
disability in patients with MS. The approval of Rebif® was
based on two large multi-center studies evaluating the safety and efficacy of
the drug in patients with RRMS. The first study was a randomized, double-blind,
placebo controlled study of 560 subjects with MS for at least 1 year. Patients
followed therapy with either placebo, or Rebif® (22 mg or 44 mg) administered
three-time/week for 2 years. Treatment was followed for a further 4 years.
Results showed that at both doses of Rebif® given
there were significant reductions in the number of exacerbations in comparison
with placebo (http://www.emea.europa.au). Avonex® (IFNb-1a) is an interferon used to treat patients
with relapsing MS and is used to modify the course of MS. Avonex® is manufactured by isolating IFNb-1a from Chinese hamster
ovary cells. Avonex® is the same as Rebif® but
administered differently. While not a cure, Avonex® has been
shown in clinical trials to reduce the average relapse rate in people with RMMS
[12–15].
A study was done to compare the effects of Rebif® (44 mg) to those of
Avonex® (30 mg) in 677 subjects with RRMS who had not been previously treated
with interferons. Patients received either Rebif® or
Avonex® and underwent repeated clinical and magnetic resonance imaging
(MRI) assessments during the course of treatment. It was noted that during the
first 24 weeks of treatment, 75% of patients receiving Rebif® and 63% of patients receiving Avonex®, did not
experience a relapse, and this was statistically significant.
Antineoplastic drugsMitoxantrone (Novantrone®) is an anthracenedione
antineoplastic agent used in the treatment of certain types of cancer and
leukemia. Due to its immunosuppressive activity, it is commonly used in
patients affected by RRMS, PRMS and SPMS [16]. Novantrone® is a derivative of anthracenedione and was approved by the FDA in
2000, and is not indicated in the treatment of patients with PPMS.
Immunosuppressants other than mitoxantrone, however, have not been shown to
significantly reduce the progression of MS or the frequency of relapses. The
most frequent side-effects are transitory amenorrhoea, nausea and vomiting,
alopecia, urinary tract infections and transitory leucopenia. Moreover, there
is little information on the long term effects of mitoxantrone, especially in
relation to the risk of cardiotoxicity and therapy-related acute leukemias,
which is increasingly reported in published literatures [17]. Mitoxantrone is
moderately effective in reducing the disease progression and the frequency of
relapses in patients affected by RRMS, PRMS and SPMS in the short term
follow-up (2 years). The cyclophosphamide (Endoxan®) is a
chemotherapy drug that works by slowing or stopping cell growth. It also works
by decreasing the immune systems response to various diseases such as MS. It
is believed to be an effective treatment, however it has been reported to be
toxic [18,19]. In addition, cyclophosphamide is administrated in MS patients
with progressive MS after other treatments have failed [18].
Therapeutic monoclonal antibodiesTherapeutic monoclonal antibodiesA recent drug in the market is a humanized monoclonal antibody
against the cellular adhesion molecule a4-integrin
(Natalizumab®) and is used in the treatment of MS and Crohns disease [20].
Natalizumab® was evaluated in two randomized, double-blind, placebo-controlled
trials in patients with MS. In these trials Natalizumab® was
shown to reduce relapses in individuals with MS by 68% in comparison with
placebo, a margin far greater than had been seen for other approved MS
therapies and reduces by 68% the possibility of disability exacerbation [21].
Natalizumab also slowed the progression of disability in patients with
relapsing MS [21,22]. In combination with IFNb, relapsing and disability
progression were reduced more than IFNb alone [23]. Other benefits of Natalizumab® in patients with RRMS is that it increases the quality of life of
patients [24–26], reduces hospitalizations and steroid use, and prevents the
formation of new lesions [24,27–30]. Natalizumab® offers a limited improvement in
efficacy compared with other treatments for MS, but due to the lack of information
about long term use, as well as potential adverse events, there are
reservations over its use outside of comparative research with existing
medications [23]. Thus far the reported benefits from the use of interferons,
copolymer, Natazulimab® and other drugs are restricted
and therefore the need for improved therapeutics are necessary.
Current Therapies for MSPeptide Vaccine
Copaxone® (glatiramer acetate) was originally intended
as a preparation (myelin basic protein mimic) to induce experimental autoimmune
encephalomyelitis (EAE), an animal model for MS. However, it was found to
suppress EAE and it was further developed to use in MS prophylaxis. Among many
selective agents tested for MS, only glatiramer acetate is currently used in
clinical practice. Glatiramer acetate is the acetate salt of randomized mixture
of synthetic oligopeptides such as L-Ala, L-Tyr, L-Lys and L-Glu. Glatiramer
acetate is administrated subcutaneously, which degrades into smaller free amino
acids or peptides, and, thus, probably initiates its major immunological
effects in the periphery. The potential efficiency of glatiramer acetate is
based on immune cells specific for the myelin basic protein (MBP) and possibly
for other myelin components [31,32]. The mechanism of action has been
identified as a competition between the glatiramer acetate and MBP for binding
to MHC molecules [33], T cell receptor binding antagonism [34], activation and
tolerance induction in cells specific for MBP. Glatiramer acetate induces Th2
like regulatory cells that mediate local bystander suppression [35,36]. All
above effects could contribute to the anti-inflammatory effects of glatiramer
acetate [31,37]. Although glatiramer acetate induces an effective, safe
immunomodulation for MS patient and a potential for being neuroprotective, the
partial clinical effect [38] and the need for daily injections remain amongst
the major disadvantages of the treatment.
Current MS Vaccine Clinical Trials
DNA vaccine (BHT-3009)A DNA vaccine (BHT-3009) that encodes a full-length of MBP was
injected in 30 patients with MS [39]. Thirty patients received the vaccine
between 2004 and 2006 and all patients had RMMS or SPMS. A placebo or BHT-3009
injection was administered to the randomly selected patients after 1, 3, 5, and
9 weeks, in doses of 0.5, 1.5 or 3 mg. Some were given 80-mg pills of
atorvastatin calcium. At week 13 those who had been on the placebo received
four BHT-3009 injections. The patients also underwent MRI scans at the
beginning of the week, and then again after 5, 9, 13, 26, 38 and 50 weeks.
BHT-3009 was found to be safe and well tolerated, provided favorable trends on
brain MRI and produced beneficial antigen-specific immune responses [39]. These
included a reduction in the number of cytokine-producing CD4+ T cells. This fall was detected in the cerebrospinal fluid as well
as in the blood of three patients who volunteered after completing the course
of injections. There were no increases in clinical relapses, disability,
drug-associated laboratory abnormalities, adverse events or the number of
lesions on brain MRI with BHT-3009 treatment compared with placebo [39]. A
phase IIb trial with 290 patients is in progress, using BHT-3009.
Mutant peptides as vaccinesThe development of vaccines and immunotherapeutic approaches against
MS is a new and evolving area. One such approach that has been attempted,
involves using mutated peptide analogs of self antigens associated with the
disease. Neurocrine BioSciences Inc. conducted a phase I clinical trial of its
peptide analog, based on modifications of MBP83–99 with D-amino acids at positions 83, 84, 89 and 91 (NBI-5788) [40].
However, these trials and a subsequent phase II trial resulted in adverse
events seen in some patients caused by the cross reaction of the analog to the
native MBP [10]. Th2 responses were induced (IL-5 and IL-13), however, 13 of
142 patients developed immediate-type hypersensitivity, who also generated
anti-NBI-5788 antibodies that cross-reacted with native MBP83–99 peptide [40]. In a 2.0–4.5-year follow-up of these patients it was
demonstrated that IL-5 (Th2) cytokine secretion by T cells persisted [41]. In
another phase II trial, sponsored by the National Institute of Neurological
Disorders and Stroke, a different mutant MBP peptide was used incorporating Ala
D-amino acids for enhanced stability at 83, 84, 89 and 91 (CGP77116) [42]. However, this peptide was poorly tolerated
at the dose tested, and the trial was discontinued. Three patients showed
exacerbations of disease with two being directly linked to CGP77116 injection.
Furthermore, high IFN-g and low IL-4 were generated as well as T cells specific for
CGP77116, which cross-reacted with the native MBP83–99 peptide [43].The problems seen with NBI-5788 and CGP77116
are likely due to inadequate pre-screening of altered peptide ligand (APL)
effects on the many clonotypes that exist in different patients against the
targeted epitope. Thus, although the APL was highly effective at blocking or
switching some clones, it activated others. Thus, further pre-clinical testing
is required and new modified peptides need to be designed to develop a more
effective vaccine for MS that overcomes these problems. T cell receptor (TCR) peptide vaccine A T cell receptor (TCR) peptide vaccine was developed that was based
on the V beta 5.2 sequence which is expressed in MS plaques and on MBP specific
CD4 T cells. This TCR peptide vaccine was injected into progressive MS patients
in a phase I clinical trial [44]. The responding patients showed a reduced
response against MBP and remained clinically stable without side effects during
1 year of therapy, whereas nonresponders had an increased MBP response and
progressed clinically. In vitro, Th2 cells that were generated against
the TCR-peptide inhibited Th1 cells via IL-10 secretion [44]. In another phase
I clinical trial using the TCR V beta 6 CDR2 region, peptide vaccine was
injected in 10 patients with MS [45]. In one arm of the trial, five patients
were injected twice with 100 mg peptide emulsified in incomplete Freunds adjuvant (IFA) and, in
the other arm of the trial, five MS patients were injected with 300 mg peptide in
IFA. Vaccination induced T-cell proliferation and delayed-type hypersensitivity
(DTH) responses in some of the patients. Furthermore, in the cerebrospinal
fluid of patients injected with the higher peptide dose, a slight decrease of
CD4 T cells was observed [45]. In order to compare the immunogenicity of using
TCR peptides from CDR2 versus other regions of the TCR, a clinical trial was
conducted in seven MS patients with overlapping CDR2 (BV5S2) peptides spanning
amino acids 1–94 [46]. Six MS patients generated responses to at least one of
three overlapping or substituted CDR2 peptides consisting of the residues 44–52. One of these
MS patients also responded to a CDR1 peptide. Two MS patients who showed no
response to BV5S2 peptides showed responses to CDR2 peptides from different BV
gene families [46].
More recently, Orchestra Therapeutics, Inc. completed a phase II
study in MS patients of NeuroVax(TM). NeuroVax is a trivalent TCR vaccine
containing CDR2 peptides from BV5S2, BV6S5 and BV13S1 emulsified in IFA. The
vaccine was injected in 23 patients following monthly vaccinations over 1 year.
An increased number of FoxP3 by regulatory T cells (T regs) were generated
which recognized TCR and which secreted high levels of the Th2 cytokine IL-10
[47] (http://www.msrc.co.uk/index.cfm?fuseaction=show&pageid=1313).
This vaccine gives promise for a larger multi-center trial to be conducted.
New and Upcoming MBP83–99/87–99 Peptide Based Vaccines for MS
Bioassay results in the EAE animal models demonstrated that cyclic
analogs have comparable effects with linear peptides. In particular, injection
of Lewis rats with linear agonist guinea pig MBP72–85 peptide (QKSQRSQDENPV) induced EAE; cyclization of MBP72–85 also induced EAE. Alteration of one amino acid at position 81 from
this epitope [i.e. aspartic acid to alanine (QKSQRSQAENPV) resulted to
the APL [Ala81]MBP72–85 that inhibited EAE when
co-injected with the linear or cyclic native peptide] [48–50]. In addition, linear MBP87–99
(VHFFKNIVTPRTP) peptide induced EAE in rats, which was
inhibited by the linear or cyclic APL [Arg91, Ala96]MBP87–99 (VHFFRNIVTARTP).
Furthermore, co-injection of linear guinea pig MBP72–85 native peptide with linear or cyclic APL [Arg91, Ala96]MBP87–99
peptide inhibited EAE in Lewis rats [49,51]. Furthermore, we demonstrated by
rational design and synthesis of peptides based on a combination of
conformational analysis studies and theoretical calculations carried out on the
linear MBP87–99 peptide using 2D NMR spectroscopy, that a head-tail intramolecular
proximity between Val87-Arg97 residues suggesting a
near cyclic conformation for the linear peptide [51]. In particular, NOE
connectivity between distant residues, gVal87-NH Arg97 and eNH Lys91–w/? Arg Arg97 for
linear MBP87–99 suggested a near cyclic conformation, thus, directing to the design
and synthesis of cyclic analogs. The cyclic MBP87–99 peptide, induces EAE in rats, binds to HLA-DR2 and DR4 first to be
reported for cyclic MBP peptide mimics, and, increases CD4 T cell clone
proliferation, like the conformationally related linear MBP87–99 peptide [52]. We furthermore demonstrated that the mutant cyclic
peptides with mutations at positions 91 and 96 suppress CD4 T-cell clone
proliferation in line with their antagonist effects in EAE and scored the best
Th2/Th1 cytokine ratio with MS patients T cells. In addition, the cyclic
analogs were found to be more stable to lysosomal enzymes compared with their
linear counterparts [52].More recently, in our laboratory, we designed and synthesized a
number of novel peptides by mutating principal TCR contact residues based on
MBP83–99 peptide epitope. Immunization of SJL/J mice with MBP83–99 and mutant [A91]MBP83–99, [E91]MBP83–99, [F91]MBP83–99, [Y91]MBP83–99 or [R91, A96]MBP83–99 peptides, induced IFN-g and only [R91, A96]MBP83–99 mutant peptide was able to
induce IL-4 secretion by T cells that were emulsified in complete Freunds
adjuvant (CFA) [53]. T cells against the native MBP83–99 peptide cross-reacted with all peptides except [Y91]MBP83–99 and [R91, A96]MBP83–99. The
double mutant [R91, A96]MBP83–99 was able to antagonize IFN-g production in vitro
by T cells against the native MBP83–99
peptide and antibodies generated to [R91, A96]MBP83–99 did not cross-react with
whole MBP protein [53]. Moreover, all these peptide mutants were conjugated to
reduced mannan [54]. Mannan binds to C-type lectins, such as the mannose
receptor expressed on macrophage dendritic cells (DC). It has been noted that
mannan matures DCs via TLR4 [55]. Mannan stimulates Th1 response (IL-2, IFN-g, IL-12, TNF-a and IgG2a
antibodies) or Th2 responses (not IFN-g or IL-12, but significant amounts of IL-4,
IL-10 and TGF-b and IgG1 antibodies) depending on the mode of conjugation, oxidized
or reduced mannan, respectively [56–65]. We demonstrated that mutated MBP83–99 peptide analogs conjugated to reduced mannan could divert immune
responses from Th1 to Th2 in SJL/J mice producing no IFN-g, and high
levels of IL-4 and IL-10. [Y91]MBP83–99 peptide gave the best cytokine and antibody reactivity profile
being the most promising as a therapeutic peptide against MS [66]. Cyclization of peptide analogs is of great interest, since the
limited stability of linear peptides restricts their potential as therapeutic
agents [67]. Therefore, we synthesized a number of cyclic peptides by mutating
TCR contact sites of the MBP83–99
epitope. A number of cyclic analogs were tested in their ability to antagonize
IFN-g responses and cyclo(83–99)[A91]MBP83–99 mutant peptide was found to be the most efficient
antagonist. We demonstrated that cyclo(83–99)[A91]MBP83–99 peptide emulsified in CFA
enhanced IL-4 and antibody responses in vivo. Moreover, immunization of
mice with cyclo(83–99)[A91]MBP83–99
peptide conjugated to reduced mannan enhanced IL-4 responses compared with
cyclo(83–99)MBP83–99 peptide [68]. Thus,
cyclization of peptides that offer greater stability and enhanced responses are
novel leads for the immunotherapy of MS. Thus, linear and cyclic analogs based
on the MBP83–99 with single or double mutation are
promising new peptide leads for the immunotherapy of MS.
Future Direction
A number of drugs are available to MS patients which prolong disease
progression, however, a cure is yet available. In the last decade, an enormous
amount of research has been undertaken towards the development of a
vaccine/immunotherapeutic drug against MS, and such strategies have entered
into human clinical trials. It is conceived that in the next decade, new
immunotherapeutic approaches will become available which will generate
appropriate responses in patients with MS and treat their disease.
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