Subhajit Dasgupta et al., J Immunol Tech Infect Dis 2015, 4:1
http://dx.doi.org/10.4172/2329-9541.1000131
Review Article
Journal of Immunological
Techniques in Infectious
Diseases
A SCITECHNOL JOURNAL
Prospect of CD52 Targeted
Alemtuzumab in Treatment of
CNS Demyelination in Multiple
Sclerosis
Subhajit Dasgupta1* and Mausumi Bandyopadhyay2
1Department
of Microbiology, Immunology and Department of Biochemistry, Saint
James School of Medicine, Albert Lake drive, The Quarter, A-I-2640, P.O Box
318, Anguilla BWI, Anguilla
2Biological Sciences, Trident Technical College, North Charleston, South Carolina
29406, USA
*Correspondence author: Subhajit Dasgupta, Department of Microbiology,
Immunology, Saint James School of Medicine, Albert Lake Drive, The Quarter,
P.O Box 318, A-I-2640, Anguilla BWI, Anguilla; Tel: +1-264-497-5125 E-mail:
[email protected]
Rec date: 19 Nov, 2014 Acc date: 15 Jan, 2015 Pub date: 19 Jan, 2015
Abstract
The choice of humanized monoclonal antibody is a novel
therapeutic approach for autoimmune relapsing remitting
multiple sclerosis (RRMS). In addition to anti-alpha-4 integr in
monoclonal antibody Natalizumab, introduction of CAMPATH-1
(Alemtuzumab) is a fairly new approach in MS research and
clinical trials. The uniqueness of this monoclonal antibodyis
that it depletes CD52 marker expressing circulatory T and B
cells including monocytes and dendritic cells. However, it has
no impact on progenitor cells. Thus, the use of Alemtuzumab
has gained importance in delaying rejection in allograft during
transplantation. Very recently, Alemtuzumab has been
approved for treatment of severe cases of RRMS. While
therapeutic monoclonal antibody to prevent inflammatory
cytokine mode of action is still under investigation in EAE
model, Alemtuzumab, in addition to existing drug Natalizumab,
was found to have importance in the treatment of RRMS. In the
context of clinical findings, we analyze the prospect of
Alemtuzumab in long term therapy of multiple sclerosis.
Keywords: Multiple sclerosis; CD52; Lymphocytes; Monoclonal
antibody; Alemtuzumab
Introduction
Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of
the central nervous system [1-3]. Progression of this disease causes
chronic inflammation and initiates demyelination and axonal
degeneration in white matter. The damage, or death of myelin
synthesizing oligodendrocytes, is known to initiate demyelinating foci
in MS, predominantly in females [4,5]. In order to prevent progression
of disease, the major aims in MS drug discovery are first, to decrease
generation of myelin antigen specific T helper cells and thereby to
induce antigen specific immunosuppression; secondly, to prevent the
entry of these T cells into the central nervous system; and, lastly, to
initiate regeneration of oligodendrocytes, axon, and re-myelination of
white matter in central nervous system.
Recent advancement of MS research suggested several standpoints
to attenuate mode of action of myelin antigen responsive T- bet
positive T cells in experimental autoimmune encephalomyelitis (EAE),
murine model for multiple sclerosis[6-8].Researches in different
laboratories also suggested role of T helper 17 in autoimmune
response of MS and its animal model EAE [9-11]. The outcome of
these findings demonstrated a pivotal role of myelin-antigen
responsive T helper 1, T helper 17 cells causing inflammation and
demyelination during progression of disease. Thus, the strategies for
MS drug discovery are developed to control these myelin antigen
specific circulatory T cells, either attenuating their function or
depleting them from peripheral circulation.
The existing drugs for MS like betaseron (rebif), copaxonewere
successful in clinical trials [12]. The laboratory based experimental
findings on inhibitors of Hydroxymethyl glutaryl CoA reductase
(HMG CoA reductase) [13,14], inhibitors of NF-kappaB activation
[15,16], inhibitors of poly-ADP-ribose-polymerase 2 (PARP) [17,18]
are mostly focused on attenuation of T helper cells in EAE. These
inhibitors are currently awaiting clinical trials.
The successful monoclonal antibody therapy of MS has been
introduced with discovery of Natalizumab, a FDA approved drug for
MS [19,20]. The recent experimental findings in EAE also suggested
efficacy of laboratory raised monoclonal antibody for IL12p40/p40
homodimer in attenuation of clinical symptoms of EAE [21-23]. In
addition, several investigations also indicated evidence of B cell
activation and production of anti-myelin auto antibodies in MS and
EAE [24-26]. Thus, keeping all the information under consideration,
the generation of new monoclonal antibodies and clinical trials are
accountable for MS therapy [27,28].
The existing therapeutic monoclonal antibodies for EAE and
multiple sclerosis (MS)
The existing therapy for MS includes three distinct classes of
medicine: I. Immunomodulators; II. Immunosuppresive medicines III.
Monoclonal antibodies [29,30].The screening of proper
immunomodulators is an important target of MS drug discovery. The
immunosuppressive agents, commonly used corticosteroids, are still in
use for temporary relief from autoimmune inflammatory responses
and allergic manifestations. However, alternatives of these drugs are
necessary to minimize inadvertent side effects. The humanized
monoclonal antibodies are comparatively new generation anti-MS
drugs with certain level of success. The anti-alpha4 integin
monoclonal antibody Natalizumab is approved by Food and Drug
Administration (FDA) to treat MS patients. After that, several other
humanized monoclonal antibodies have been under clinical trials and
received various range of success. The table 1 summarizes different
monoclonal antibodies which are currently under clinical trial and
included in the list of MS therapy (Table 1).
All articles published in Journal of Immunological Techniques in Infectious Diseases are the property of SciTechnol, and
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Citation:
Subhajit D, Mausumi B (2015) Prospect of CD52 Targeted Alemtuzumab in Treatment of CNS Demyelination in Multiple Sclerosis. J Immunol Tech
Infect Dis 4:1.
doi:http://dx.doi.org/10.4172/2329-9541.1000131
Name of therapeutic
monoclonal antibody
Specific Target
Clinical trials / under
investigation
in
laboratory
References
Natalizumab (Tysabri)
α-4 integrin
Clinical trials (FDA
approved for MS drug)
McCormack 2013; Drugs 73 (13), 1463-1481; Clerico et al. 2014; JAMA Neurol. 71 (8),
954-960; Mindur et al. 2014; PLoS One 9 (6 ), e99068 doi: 10.1371/journal. Pone
0099068; Cree 2014; Neurohospitalist 4 (2), 63-65
Rituximab (Zytux)
CD20
Clinical trials
Gasperini et al. 2013; Expert Opin Investig Drugs 22 (10), 1243-1253; Fernandez et al.
2012; Rev Neurol. 54 (12), 734- 749
Daclizumab (Zenapax)
CD25
Clinical trial/
investigation
Ocrelizumab
CD20
Clinical trial
Gasperini et al. 2013; Expert Opin Investig Drugs 22 (10), 1243-1253; Fernandez et al.
2012; Rev Neurol. 54 (12), 734- 749
Ofatumumab (Arzerra)
CD20
Clinical trial
Cross and Naismith 2014; J Intern Med 275 (4), 350-63 doi: 10.1111/joim.12203;
Fernandez et al. 2012; Rev Neurol. 54 (12), 734- 749
Ustekinumab
1275)
IL12/IL23
inhibitor)
(CNTO
(IL-17A
Under
Clinical trial/
investigation
under
Bielekova 2013; Neurotherapeutics 10 (1 ), 55-67; Zhang et al. 2014 Mult Scler. ; 20 (2),
156-164
Benson et al. 2011; Nature Biotechnology 29 615-624 doi: 10.1038/nbt.1903;
www.fda.gov/ohrms/dockets/ac/08/.../2008-4361b1-02-CENTOCOR.
Tabalumab (Ly-2127399)
Bcell activating factor
(BAFF)
Under investigation
Gensicke et al. 2012 CNS Drugs 26 (1 ), 11-37
Secukinumab (AIN 457)
IL-17A inhibitor
Clinical trial/
investigation
under
Rudick et al. 2013; European Committee for treatment and research in multiple sclerosis
(2-5th October, Copenhagen, Denmark
Alemtuzumab
(CAMPATH 1H)
CD52
Clinical trial/
investigation
under
Coles AJ 2013; Neurotherapeutics 10 (1 ), 29-33
Monoclonal antibody
IL12p40/402
homodimer
Under investigation
Dasgupta et al. 2008; Hybridoma 27 (3), 141-151; Mondal S et al. 2009; J Immunol. 182
(8), 5013-5033
Monoclonal antibody for
MHC II
MHCII
Under
(EAE)
Smith et al. 1994; Immunology 83, 1-8
Monoclonal antibody for
CD4
CD4 (T helper cell)
Clinical trial/
investigation
investigation
Under
Van Oosten et al. 1997; Neurology 49 (2), 351-357;
Llewellyn-Smith et al. 1997; Neurology 48 (4), 810-816
Table 1: Therapeutic monoclonal antibodies for multiple sclerosis
The anti-CD20 monoclonal antibody Rituximab and anti-CD52
monoclonal antibody Alemtuzumab have ability to deplete T and B
cells, thus causing attenuation of circulatory pool of reactive
lymphocytes. The European Medicine Agency (EMA) approved
Alemtuzumab as MS drug (trade name Lemtrada).Very recently; the
drug has received approval from Food and Drug Administration
(FDA, USA) for treatment of RRMS.
Alemtuzumab has prospect to treat demyelination in
relapsing-remitting multiple sclerosis (RRMS)
In recent clinical trials, Coles et al. [31-33] and several other
investigators [34-36] demonstrated the prospect of Alemtuzumab in
reducing relapsing remitting multiple sclerosis (RRMS) and
attenuating rate of sustained disability. Jones and Coles [37] described
that the drug showed efficacy to reduce relapse by 70% as compared to
betaseron. Cohen et al. [38] demonstrated the safety profile and
benefit of Alemtuzumab treatment in RRMS while also comparing its
efficacy with interferon beta 1A. The observations in the 2 year ratermarked randomized controlled phase 3 trial among adults (age 18-50
years) without any report of RRMS suggested that, the treatment has
ability to reduce severity of RRMS. Despite this, there are incidences of
herpes virus infection in the patients treated with Alemtuzumab. A
group of patients also reported to develop thrombocytopenia, which
Volume 4 • Issue 1 • 1000131
was not found in interferon beta treated patient group. In addition, a
patient was found to develop thyroid papillary carcinoma after
Alemtuzumab treatment. Thus, the prospect of Alemtuzumab requires
modification of treatment schedule to minimize unwanted microbial
infections during progression of RRMS. In a recent review article,
Cross and Naismith depicted the benefit to risk ratio in MS treatment
strategies which included mechanism of action and safety profiles of
different drugs [39].
Weindl and Kieseier [40] recently highlighted the
immunotherapeutic role of T and B cell depleting monoclonal
antibody Alemtuzumab in RRMS. In a pilot case-control study on
twenty-four patients, McCarthy et al. [41] showed that depletion of
lymphocytes by Alemtuzumab has minimal effect on memory B cells
for production of secondary antibody. Also, efficacy of Alemtuzumab
treatment has no adverse effect on vaccination against microbial
antigens like tetanus, diphtheria, polio, meningococcus C, Tindependent pneumococcal antigen, and common vaccination for
measles as well as mumps. The observations of the pilot study
indicated presence of a quick balance mechanism in
immunocompetent hosts following CD52 marker positive lymphocyte
depletion during Alemtuzumab treatment. The findings lead a new
direction in MS translational research to address the cell signal
• Page 2 of 5 •
Citation:
Subhajit D, Mausumi B (2015) Prospect of CD52 Targeted Alemtuzumab in Treatment of CNS Demyelination in Multiple Sclerosis. J Immunol Tech
Infect Dis 4:1.
doi:http://dx.doi.org/10.4172/2329-9541.1000131
mechanisms which generate a new pool of lymphocytes thus lack of
self – myelin antigen responsiveness.
transplantation is a new direction of future translational study of
autoimmune diseases. In this aspect, the monoclonal antibody
Alemtuzumab gains a prospect in treatment of demyelination in
relapsing remitting multiple sclerosis.
However, many investigators reported side effects in patient’s
during long term Alemtuzumab treatment [42-44]. Recently, Daniels
et al. [45], Tsourdi et al. [46] reported emergence of thyroid disorder
and onset of Graves’ disease after Alemtuzumab treatment. The
reports on adverse effects thus restrict its use in RRMS treatment and
indicate a requirement for a strategic development of new generation
of CD52 monoclonal antibody with minimum side effects.
Conclusion
The depletion of lymphocytes due to Alemtuzumab treatment
causes transient lymphopenia [47,48]. However, generation of
functional B and T cells from lymphoid progenitor cells have an
option to replenish lymphocytes in MS patients. The property of B
cells to present antigen is another important aspect in the context of
Alemtuzumab therapy. Considering the fact that, infiltration of
peripheral immune cells, predominantly T cells and B cells, monocyte/
macrophages, neutrophils, and dendritic cells into CNS through blood
brain barrier initiate CNS inflammation. In subsequent phases,
microglial activation takes place in CNS. There is possibility that B
cells express Major Histocompatibility Complex class II (MHC II) and
act as antigen presenting cells (APC) to present myelin antigens to T
cells within CNS. Thus, repriming of antigen specific T cells inside
CNS generates long lasting and sustained inflammatory responses,
causing demyelination. In support of this hypothesis, a few related
investigations are found demonstrating the abilities of B cells to
function as APC [49,50].
Acknowledgement
The recent evidence of clinical trials, since the discovery of the
humanized monoclonal antibody Alemtuzumab, suggest an
immunotherapeutic prospect of Alemtuzumab in treatment of RRMS
patients within a restricted domain of dose-time in treatment to
minimize the side effects.
Prospect of Alemtuzumab in transplant therapy of MS
The only advantage of using Alemtuzumab is its ability to deplete
lymphocytes and delaya chance of rejection due to Graft versus Host
disease (GVHD) in transplantation. In this aspect, the mode of action
of CD52 monoclonal antibody is different than other existing drugs
for MS. The prospect of Alemtuzumab is reported in treatment of
terminal kidney failure [51-53]. In recent years, bone marrow
transplantation has been found as a new approach for treatment of
autoimmune disease [54,55]. The procedure, though still under
experimental stage, undoubtedly, provides with future promise for
therapy of relapsing remitting multiple sclerosis [55,56]. The recent
developments indicate autologous bone marrow transplantation as
well as umbilical cord-derived mesenchymal stem cells transplantation
as new directions of MS therapy [57-60].
It can be postulated that instead of direct treatment for long period,
autologous or HLA matched heterologous bone marrow
transplantation in presence of low dose of CD52 depleting
Alemtuzumab is a better way to minimize drug-induced side effects.
The in vitro treatment of bone marrow with Alemtuzumab prior to
transplantation will deplete mature CD52 positive lymphocytes,
mostly T helper cells in immuno competent MS patients. At the same
time, presence of Alemtuzumab in circulation will decrease CD52
positive T and B cells in MS patients thereby, reducing the chances of
self myelin antigen primed T cell activation in RRMS.
Consequently, the improvement of treatment strategy from prolong
therapy to immunotherapy in conjunction with bone marrow
Volume 4 • Issue 1 • 1000131
The therapeutic efficacy of Alemtuzumab in relapsing remitting
multiple sclerosis is shown in clinical trials. However, its mode of
action has limitations in long-term treatment. The prospect of
Alemtuzumab has been found in kidney transplantation where the
monoclonal antibody delays graft versus host disease-mediated tissue
rejection. In modern therapy for autoimmune diseases, bone marrow
transplantation is a new approach in medicinal sciences and may be an
indication of a new treatment strategy of MS. Thus, further research
needs to delineate function of CD52 in lymphocytes in context of
Alemtuzumab for treatment of autoimmune MS.
I (SDG) acknowledge Saint James School of Medicine for resources.
I am thankful to Kishmelle Richardson and Karol Brooks for their
contributions. We are thankful to Shaoni Dasgupta for her
involvement in formatting the manuscript.
Conflicts of Interests
We do not have any conflicts of interests
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