THERAPY REVIEW
`
`Biodrugs 2002; 16 (3): 183-200
`1173-8804/02/0003-0183/$25.00/0
`
`© Adis International Limited. All rights reserved.
`
`Therapeutic Approaches in Multiple Sclerosis
`Lessons from Failed and Interrupted Treatment Trials
`Heinz Wiendl1 and Reinhard Hohlfeld2,3
`1 Department of Neurology, School of Medicine, University of Tuebingen, Tuebingen, Germany
`2 Institute for Clinical Neuroimmunology, Klinikum Grosshadern, Munich, Germany
`3 Department of Neuroimmunology, Max-Planck-Institute for Neurobiology, Martinsried, Germany
`
`Contents
` . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
`Abstract
`1.
`Immunopathology of Multiple Sclerosis and Therapeutic Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
`2. Modification of the Cytokine Pattern . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
`2.1 Tumour Necrosis Factor-α Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
`2.1.1 Infliximab (CA2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
`2.1.2 Lenercept
` . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
`2.1.3 Commentary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
`2.2 Transforming Growth Factor-β2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190
`2.3 Interleukin-10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190
`2.4 Interleukin-4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
`2.5 Commentary on Cytokine Modulators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
`3. Various Immunosuppressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
`3.1 Roquinimex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
`3.2 Sulfasalazine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
`3.3 Gusperimus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
`3.4 Cladribine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
`4. Aspects of Remyelination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
`4.1 Intravenous Immunoglobulins (IVIg) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
`4.1.1 IVIg in Optic Neuritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
`4.1.2 IVIg in Permanent Neurological Deficits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
`4.1.3 Commentary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
`5. Antigen-Derived Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
`5.1 Oral Tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
`5.1.1 Oral Myelin (AI-100) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
`5.2 Altered Peptide Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
`5.2.1 Tiplimotide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
`5.3 Commentary on Antigen-Derived Therapies
` . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
`6. Targeting Leucocyte Differentiation Molecules with Monoclonal Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
`6.1 Anti-CD3 (Muromonab-CD3) and Anti-CD4 (Priliximab) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
`Inactivation of Circulating T Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
`7.1 Extracorporeal Photopheresis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
`8. Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
`
`7.
`
`Abstract
`
`The therapy for multiple sclerosis (MS) has changed dramatically over the past decade. Recent im-
`munobiological findings and current pathophysiological concepts together with advances in biotechnology,
`improvements in clinical trial design and development of magnetic resonance imaging have led to a variety of
`evaluable therapeutic approaches in MS. However, in contrast to the successfully introduced and established
`immunomodulatory therapies (e.g. interferon-β and glatiramer acetate), there have been a remarkable number
`of therapeutic failures as well. Despite convincing immunological concepts, impressive data from animal models
`and promising results from phase I/II studies, the drugs and strategies investigated showed no benefit or even
`turned out to have unexpectedly severe adverse effects.
`Although to date there is no uniformly accepted model for MS, there is agreement on the significance of
`
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`IPR 2018-01403
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`184
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`Wiendl & Hohlfeld
`
`inflammatory events mediated by autoreactive T cells in the CNS. These can be modified therapeutically at the
`individual steps of a hypothetical pathogenetic cascade. Crucial corners like: (i) the prevalence and peripheral
`activation of CNS-autoreactive T cells in the periphery; (ii) adhesion and penetration of T cells into the CNS;
`(iii) local activation and proliferation and; (iv) de- and remyelination processes can be targeted through their
`putative mediators. Like a ‘specificity pyramid’, therapeutic approaches therefore cover from general immuno-
`suppression up to specific targeting of T-cell receptor peptide major histocompatibility (MHC) complex.
`We discuss in detail clinical MS trials that failed or were discontinued for other reasons. These trials include
`cytokine modulators [tumour necrosis factor (TNF)-α antagonists, interleukin-10, interleukin-4, transforming
`growth factor-β2], immunosuppressive agents (roquinimex, gusperimus, sulfasalazine, cladribine), inducers of
`remyelination [intravenous immunoglobulins (IVIg)], antigen-derived therapies [oral tolerance, altered peptide
`ligands (APL), MHC-Peptide blockade], T cell and T-cell receptor directed therapies (T cell vaccination, T-cell
`receptor peptide vaccination), monoclonal antibodies against leucocyte differentiation molecules (anti-CD3,
`anti-CD4), and inactivation of circulating T cells (extracorporeal photopheresis).
`The main conclusions that can be drawn from these ‘negative’ experiences are as follows. Theoretically
`promising agents may paradoxically increase disease activity (lenercept, infliximab), be associated with unfore-
`seen adverse effects (e.g. roquinimex) or short-term favourable trends may reverse with prolonged follow-up
`(e.g. sulfasalzine). One should not be too enthusiastic about successful trials in animal models (TNFα blockers;
`oral tolerance; remyelinating effect of IVIg) nor be irritated by non-scientific media hype (deoxyspergualine;
`bone marrow transplantation). More selectivity can imply less efficacy (APL, superselective interventions like
`T-cell receptor vaccination) and antigen-related therapies can stimulate rather than inhibit encephalitogenic
`cells. Failed strategies are of high importance for a critical revision of assumed immunopathological mecha-
`nisms, their neuroimaging correlates, and for future trial design. Since failed trials add to our growing under-
`standing of multiple sclerosis, ‘misses’ are nearly as important to the scientific process as the ‘hits’.
`
`in MS clinical trial methodology, which is largely based on ad-
`vances in nuclear MRI techniques as a ‘surrogate marker’ in the
`assessment of potential therapeutic drug effects.[5,6] However,
`despite rational therapeutic concepts, convincing preliminary an-
`imal experiments or positive experiences with other autoimmune
`diseases, some initial studies showed no proof of efficacy or
`failed because of unforeseen adverse effects (table II). Whereas
`the positive trials usually make it into prestigious journals, many
`negative trials are published merely as abstracts or not at all.[1]
`This is unfortunate, because there is a lot to learn from a negative
`result, and critical reflection is highly important for under-
`standing human MS immunopathogenesis and appropriate trial
`
`300
`
`250
`
`200
`
`150
`
`100
`
`50
`
`Number of publications
`
`0
`1965
`
`1970
`
`1975 1980
`
`1985 1990
`Year
`
`1995 2000
`
`Fig. 1. Number of yearly publications on multiple sclerosis therapy (data from
`Medline) [reproduced from Hohlfeld et al.,[1] with permission from copyright hold-
`ers, John Wiley & Sons, Inc.].
`
`1. Immunopathology of Multiple Sclerosis and
`Therapeutic Approaches
`
`Multiple sclerosis (MS) therapy has changed dramatically
`over the past decade. Based on the growing immunopathogenetic
`understanding of MS and with the assistance of modern biotech-
`nology, a growing arsenal of potential therapeutic drugs has been
`developed. Several agents have been approved and are now being
`widely used, and a whole battery of new immunomodulatory
`treatments is currently under development. The methodology of
`MS trials has evolved in parallel with the therapeutic agents,
`utilising magnetic resonance imaging (MRI) techniques to great
`advantage. The sense of excitement in the field of MS therapeu-
`tics is reflected by the soaring number of publications (figure 1).
`Although to date there is no uniformly accepted model for
`MS, there is agreement on the significance of inflammatory
`events mediated by autoreactive T cells in the CNS.[2] These can
`be modified therapeutically at the individual steps of a hypothet-
`ical pathogenetic cascade (figure 2). Crucial steps such as the
`prevalence and peripheral activation of CNS-autoreactive T cells
`in the periphery, adhesion and penetration of T cells into the CNS,
`local activation and proliferation, and de- and remyelination pro-
`cesses can be targeted through their putative mediators (table I).
`Like a ‘specificity pyramid’, therapeutic approaches therefore
`cover the field from general immunosuppression to specific tar-
`geting of T-cell receptor peptide major histocompatibility com-
`plex (MHC).[3,4] In addition, significant progress has been made
`
`© Adis International Limited. All rights reserved.
`
`Biodrugs 2002; 16 (3)
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`185
`Therapeutic Approaches in Multiple Sclerosis
`
`
`
`Myelln sheath
`
` : } Myelln antigens
`
`—> Cell mlgratlon
`
`—> Soluble mediators, cytokhes.
`chemoklnes a pretenses
`
`Fig. 2. Cnicial steps in miltiple sclerosis pathogenesis. Pre-exist'ng autoreac'tive T cells are activabd outside the CNS. The activated T cells traverse the blood-brain
`barrier and are locdly re-activated when they recognise ’their‘ antigen on the surface at local antigen-presenting cells. The activated T cells secrete cytokines that
`stimulate microgia eels and astrocytes. recruit additional inflammatory cells, and induce antibody production by plasma cells. Antinyelin antbodies and activated
`macrophages/microglia cells are thought to cooperate in dernyelination. Dilterent steps at the putative immunopathological cascade and ditterent mediators can be
`targeted therapeutically (see table II) [reproduced from Hatfield,“ with permission from copyright holders. Oxford University Press]. MHC = rmior histocornpatibility
`corrpIex; TCR = T-cell receptor.
`
`design. In this review we discuss the immunobiological back-
`ground, the experimental basis and the clinical studies of some
`agents and therapeutic strategies in MS treatment which were not
`effective or led to early trial termination for other reasons.
`
`2. Modification ot the Cytoklne Pattern
`
`2.1 Tumour Necrosis Factor—a Antagonists
`
`Tumour necrosis factor (TNF)-0t, initially characterised for
`its tumoricidal activity, plays an important role in acute and
`
`chronic inflammation (reviewed by Aggarwal and Nataljan,[3°]
`Beutlerp”). TNFa, mainly produced by T cells and macro-
`phages, activates the vascular endothelium and increases penne-
`ability. Together with interferon (IFN)-'y, TNFa stimulates the
`production of nitric oxide (NO) and reactive oxygen derivates,
`the release of interleukin (IL)-1 and many other cytokines, as well
`
`OAdshtemotlondLhitedAl
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`htS reserved
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`as all metabolites of arachidonic acid. TNFa is one of at least ten
`
`(known) members of a ligand family that activates a correspond-
`
`ing family of structurally related receptorslm The receptors trig-
`ger signals for cell proliferation and apoptosis which play an
`important role in development as well as in the induction of an
`
`immune response.
`There are two types of TNF receptors: TNFRI-p55 and
`
`TNFRII—p75. They are found either in a transmembrane or in a
`secreted form, consisting of two subunits, which are stimulated
`
`not only by TNFa but also by lymphotoxin-a. Most known bio-
`
`logical effects are mediated by the TNFRI-p55 subunit, which
`
`binds ligands with a higher affinity than TNFRII-p75. It is im-
`
`portant to mention that the receptors are able to mediate different
`
`signalling pathways, which partly explains the pleiotropism and
`
`the dependence of TNF effects on the cellular context.
`Numerous investigations have identified TNFa as an essen-
`
`tial pathogenetic factor in different models of experimental aller-
`
`Blodrugszmz-Ioo)
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`

`

`186
`
`Wiendl & Hohlfeld
`
`Table I. Examples of recent multiples sclerosis (MS) trials that did not show a convincing clinical benefit (adapted from Hohlfeld and Wiendl,[1] with permission
`from copyright holders, John Wiley & Sons, Inc.)
`
`Agent
`
`Mechanism of action
`
`MS type (no. of patients)
`[trial duration]
`
`References Outcome/MRI Clinical
`effect
`
`Problems
`
`Sulfasalazine
`
`Gusperimus
`
`Immunosuppressants
`Roquinimex
`Synthetic immunomodulator:
`inhibition of IFNγ and TNFα
`Anti-inflammatory and
`immunomodulatory properties
`Interaction with intracellular
`heat-shock protein (hsp 70) and
`activation of NF-κB
`Adenosindeaminase-resistant
`purine nucleoside: induction of
`long-lasting lymphopenia
`
`Cladribine
`
`Cytokine modulators
`Lenercept
`Soluble TNF-receptor p55:
`inhibition of TNFα-functions
`
`Infliximab
`
`TGFβ2
`
`IL-10
`
`IL-4 (BAY
`36-1677)
`
`TNFα neutralising antibody;
`human/murine chimeric IgG1:
`inhibition of TNFα-functions
`Immune suppression, pleiotropic
`growth factor
`Recombinant cytokine: inhibition
`of macrophage APC-function,
`up-regulation of Th2-cells
`Recombinant cytokine: mutein
`with 2 AA exchanges and
`selectivity for T, B cells and
`monocytes, up-regulation of
`Th2-cells
`
`Inducers of remyelination
`Diverse immunomodulatory
`IVIg
`(Gamimune® bN)
`effects; in addition, promotion of
`remyelination in animal model
`
`RR, SP (715)
`[terminated early]
`PP, RR, SP (199) [36mo] 9
`
`7,8
`
`RR, SP (236) [12mo]
`
`10,11
`
`Positive
`
`Positive
`
`Cardiopulmonary toxicity
`
`No sustained
`effect
`No effect
`
`No sustained
`effect
`No effect
`
`Initially positive effect,
`absence of long-term benefit
`Overall effects unconvincing
`
`PP, SP (159) [12mo]
`
`12-14
`
`Positivea
`
`No effect
`
`RR (168) [11mo]
`
`SP (2) [2mo]
`
`SP (11) [6mo]
`
`15
`
`16
`
`17
`
`No effect
`
`Worsening
`
`Worsening
`
`No effect on
`EDSS
`
`No effect
`
`No effect
`
`RR, SP [terminated]
`
`Unpublished
`
`Discrepancy between MRI
`and clinical effect; probably
`no effect on tissue injury
`
`Paradoxical effect of TNFα;
`discrepancy between MRI
`and clinical effects
`Paradoxical effect of TNFα
`
`Bioavailability in the CNS?;
`nephrotoxicity
`Insufficient efficacy; possible
`induction of exacerbations
`
`[terminated]
`
`Unpublished
`
`Insufficient efficacy
`
`SDON (55) [12mo]
`
`18
`
`Not done
`
`No overall
`effect
`
`Remyelination potential may
`depend on disease activity,
`timepoint, dose and duration
`of treatment
`
`Antigen-derived therapies
`AI-100
`Oral bovine MBP; induction of
`systemic tolerance via stimulation
`of antigen-specific regulatory
`(Th2-, Th3-) cells
`
`RR, SP (TND) (67) [6mo] 19
`RR (10) [6wk]
`20
`
`No effectc
`Not done
`
`No effect
`No effect
`
`RR (30) [12mo]
`RR (515) [24mo]
`
`21
`22,23
`
`Not done
`Not
`documented
`
`Possible
`No effect
`
`Tiplimotide
`
`Altered peptide ligand; peptide
`analogue of human MBP 83-99
`
`RR (8) [terminated,
`maximum 9mo]
`
`24
`
`Worsening
`
`Worsening
`
`AG284
`(DR2:MBP84-102)
`
`Soluble HLA-DR2 with a single
`noncovalently bound MBP peptide
`
`RR (142) [terminated,
`4mo planned]
`SP (33) [3mo]
`
`25
`
`26
`
`Positived
`
`No effect
`
`No effect
`
`No effect
`
`Interindividual differences in
`target epitopes (e.g. ‘epitope
`spreading’)?; unexpected
`effects on different T cell
`populations; allergic reactions
`
`© Adis International Limited. All rights reserved.
`
`Biodrugs 2002; 16 (3)
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`

`Therapeutic Approaches in Multiple Sclerosis
`
`187
`
`Table I. Contd
`
`Agent
`
`Mechanism of action
`
`TCR-directed therapies
`T cell vaccination Attenuated autologous
`MBP-reactive T cell clones,
`induction of anticlonotypic T cell
`responses
`
`MS type (no. of patients)
`[trial duration]
`
`References Outcome/MRI Clinical
`effect
`
`Problems
`
`RR (8) [22-38mo]
`
`27
`
`Mixede
`
`Mixede
`
`TCR peptide
`vaccination
`
`TCR Vß5.2 (residues 38-58),
`induction of anti-TCR-regulatory
`effects
`
`PP, SP (23, all
`HLA-DRB1*1501
`positive) [12mo]
`
`28
`
`Not done
`
`No effect
`
`Small number of patients;
`complexity and diversity of
`human autoimmune T cells;
`role of MBP in MS
`pathogenesis?
`Small number of patients;
`marginal effect on disease
`progression; heterogeneity
`and individuality of
`TCR-repertoire and
`antigen-specificity
`
`T cell inactivation
`Extracorporeal
`Direct or indirect induction of
`photopheresis
`apoptosis on circulating T cells
`
`SP (16) [18mo]
`
`29
`
`No effect
`
`No effect
`
`Quantities of peripheral
`CNS-antigen reactive T cells
`in chronic MS? Relevance of
`CNS-specific milieu for
`perpetuation of immune
`response in chronic MS
`a Favourable effect on presence, number and volume of gadolinium-enhanced T1 brain lesions and T2-lesion load,[12] no effect on the T1(hypointense)-lesion volume,[13] or on
`whole brain volume changes in patients with progressive MS.[14]
`b Use of tradenames is for product identification only and does not imply endorsement
`c Only a small number of patients (5 of each group) underwent MRI.
`d Secondary analysis of patients completing the study and receiving the lowest dose (5mg).
`e Beneficial effects on MRI and/or clinical course in 5 patients, worsening of lesions and/or relapses in 3 patients.
`AA = amino acid; APC = antigen-presenting cell; EDSS = Expanded Disability Scale; IFN = Interferon; IgG = immunoglobulin G; IL = interleukin; IVIg =
`intravenous immunoglobulin; MBP = myelin basic protein; MRI = magnetic resonance imaging; NF = nuclear factor; PP = primary progressive MS; RR =
`relapsing-remitting MS; SDON = stable demyelinating optic neuritis; SP = secondary chronic progressive MS; TCR = T-cell receptor; TGF = transforming
`growth factor; Th = T helper cell; TND = targeted neurological deficit; TNF = tumour necrosis factor.
`
`gic encephalomyelitis (EAE) and MS. It has been detected in
`inflammatory CNS lesions; in active lesions it is involved in
`pathological tissue damage (inflammation as well as demyelin-
`ation).[33,34] In vitro TNFα is cytotoxic for oligodendrocytes. The
`elimination of TNF-producing macrophages, as well as an-
`tagonisation with TNF antibodies, administration of various ther-
`apeutic drugs affecting TNFα production (e.g. thalidomide, pen-
`toxifylline, rolipram), or doses of soluble TNF receptor
`(lenercept), clearly showed a positive effect on pathogenesis and
`demyelination in various animal models.[35,36]
`A series of studies in MS patients showed a correlation of
`TNF levels in blood, serum or cerebrospinal fluid (CSF) with the
`clinical course or disease activity.[37-43]
`
`2.1.1 Infliximab (CA2)
`In an open phase I study, two patients with a severe second-
`ary chronic progressive form of MS (SPMS) were treated with a
`monoclonal antibody against TNFα (infliximab).[16] Inflamma-
`
`tory activity as measured by MRI, CSF lymphocytic pleocytosis
`and IgG index was clearly increased after receiving the infusions.
`After 2 to 3 weeks, values dropped back to their initial level; the
`Expanded Disability Status Scale (EDSS) was not altered.
`
`2.1.2 Lenercept
`In a phase II study [168 patients with mainly relapsing-re-
`mitting MS (RRMS)], the effect of the soluble TNF-receptor im-
`munoglobulin fusion protein lenercept on the development of
`new lesions in MRI was examined.[15] In this four-armed study,
`patients received 10, 50 or 100mg of the drug or placebo every 4
`weeks (up to 12 months). Baseline MRI was taken as a reference
`and followed up every 4 weeks (up to week 24 of the study).
`MRI showed no significant difference between lenercept and
`placebo (primary endpoint: cumulative number of new active le-
`sions). However, the number of clinical exacerbations was sig-
`nificantly higher in the lenercept group (annual relapse rate was
`0.98 with placebo vs 1.64 with lenercept 50mg; p = 0.007). In the
`
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`
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`188
`
`Wiendl & Hohlfeld
`
`Table II. Immunotherapeutic strategies based on putative immunepathological mechanisms in multiple sclerosis (see also figure 2)
`
`Process in immunopathological cascade
`
`Key mediators
`
`Therapeutic approaches
`
`Pre-existing autoreactive T cells
`Nonselective activation of T cells
`
`T cells
`
`Selective activation of myelin-reactive T cells
`
`Molecular mimicry?
`Superantigens?
`Other factors?
`
`Adhesion and penetration of T cells into the CNS
`Adherence and diapedesis
`Selectins (L-, E-, P-)
`Integrins (VLA-4, VLA-5, VLA-6, LFA-1, MAC-1,
`CR4)
`Ig superfamily (ICAM-1, ICAM-2, ICAM-3, VCAM,
`LFA-2, LFA-3)
`MMPs
`Cytokines
`
`Blood-brain barrier disruption
`
`Cellular CNS invasion
`
`Cell recruitment in the CNS
`
`? Infection (viral, bacterial)
`? Reactive metabolites
`
`MMPs
`TIMPs
`Integrins (VLA-4, VLA-5, VLA-6, LFA-1, MAC-1,
`CR4)
`Chemokines
`
`Local activation and proliferation of immune cells in the CNS
`APC-T cell interaction
`
`interaction of the trimolecular complex
`
`MHC class II
`TCR
`
` activation of ‘second signals’
`
`Costimulatory molecules (B7-1, B7-2,
`CD40-CD40-L, CTLA-4, other CD-molecules)
`
`Cytokine network
`
`Th1-predominance, Th1/Th2-dysbalance
`
`Soluble toxic mediators
`
`TNFα, IFNγ, lymphotoxin
`
`Cell-mediated damage
`
`MMPs/proteases
`CD4+, CD8+ T cells, macrophages, microglia
`
`Humorally mediated damage
`
`B cells
`
`Antibodies
`
`Complement system
`
`Bone marrow transplantation, extracorporeal
`photopheresis
`T cell vaccination
`T-cell receptor (TCR) peptide vaccination
`Antigen-derived therapies
`
`Selectin inhibitors, antiselectin MAbs
`Integrin/ligand inhibitors, anti-integrin MAbs
`
`Antiadhesion molecule MAbs
`
`MMP inhibitors, anti-MMP MAbs
`Cytokine modulators (anticytokine drugs,
`anticytokine MAbs, cytokines)
`Antiviral/antimicrobial therapies
`Free radical scavengers, nitric oxide synthase
`inhibitors
`MMP inhibitors, anti-MMP MAbs
`TIMP promoters
`Integrin/ligand inhibitors, anti-integrin MAbs
`
`Chemokine inhibitors, antichemokine MAbs,
`Cytokine modulators (anticytokine drugs,
`anticytokine MAbs, cytokines)
`
`MHC peptide vaccine, anti-MHC MAbs
`TCR peptide vaccination, TCR MAbs, T cell
`vaccination, antigen-derived therapies (e.g. altered
`peptide ligands)
`Anti-B7 MAbs CD40/CD40-L interaction, CTLA-4-Ig
`fusion protein, anti-T cell MAbs (e.g. CD2), T cell
`vaccines
`Anti-Th1 cytokines, Th1 cytokine inhibitors, Th2
`cytokines (IL-4, IL-10, TGFβ), Th2 cytokine
`promoters (e.g. glatiramer acetate), shift Th1 to Th2
`(e.g. glatiramer acetate, drugs, manipulation of
`costimulation, etc.)
`Cytokine modulators (anticytokine drugs,
`anticytokine-MAbs, cytokines)
`MMP inhibitors, anti-MMP MAbs, TIMP promoters
`Immunosuppression, cell-specific MAbs, autologous
`stem cell transplantation
`Immunosuppression, cell-specific MAbs, autologous
`stem cell transplantation
`Anti-autoantibody MAbs, intravenous
`immunoglobulins (IVIg), plasmapheresis
`Complement inhibitors, MAC (C5b-C9 membrane
`attack complex inhibitors), CD59, CD46, DAF
`
`© Adis International Limited. All rights reserved.
`
`Biodrugs 2002; 16 (3)
`
`Page 6 of 18
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`Therapeutic Approaches in Multiple Sclerosis
`
`189
`
`Table II. Contd
`
`Process in immunopathological cascade
`Other damage mechanisms
`
`Key mediators
`Glutamate
`Reactive oxygen species
`Reactive nitrogen species
`Apoptosis
`Viral infection
`Microbial infection
`
`Therapeutic approaches
`AMPA/kainate inhibitors
`Free radical scavengers
`Nitric oxide synthase inhibitors
`Fas/Fas-L and other receptor modulations
`Antiviral therapies
`Antibiotics
`
`Demyelination and remyelination
`
`Survival and maturation of oligodendrocyte
`precursors
`Availability of oligodendrocyte precursors
`
`BDNF, GDNF, CNTF, IGF-1, leukaemia inhibitory
`factor, neurotrophin-3, PDGF
`Stem cell transplantation, precursor cell
`implantation, immortalised cell transplantation,
`Schwann cell transplantation, xenotransplantation
`AMPA = alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate; APC = antigen-presenting cell; BDNF = brain-derived neurotrophic factor; CD = cluster
`of differentiation; CNTF = ciliary neurotrophic factor; CR = complement receptor; CTLA = cytotoxic T lymphocyte-associated molecule; DAF =
`decay-accelerating factor; GDNF = glial cell-derived growth factor; ICAM = intercellular adhesion molecule; IFNγ = interferon-γ; Ig = immunoglobulin; IGF
`= insulin-like growth factor; IL = interleukin; LFA = lymphocyte function-associated antigen; MAb = monoclonal antibody; MAC = membrane attack complex;
`MHC = major histocompatibility complex; MMP = matrix metalloproteinase; PDGF = platelet-derived growth factor; TGF = transforming growth factor; Th
`= T helper cell; TIMP = tissue inhibitor of MMP; TNFα = tumour necrosis factor-α; VCAM = vascular cell adhesion molecule; VLA = very late antigen.
`
`group receiving lenercept, exacerbations occurred earlier (p =
`0.006), duration of relapses was longer, time until appearance of
`clinical exacerbations was shortened and neurological deficits
`appeared to be more serious (not significant; EDSS not altered).
`Adverse events such as headaches, nausea, abdominal pain or hot
`flushes occurred more frequently with lenercept. Antibodies
`against lenercept were generated in 88 to 100% of the patients,
`which did not interfere with neutralisation of TNF but accelerated
`elimination of the drug. A first evaluation after all patients were
`treated for 24 weeks led to early termination of the study.
`
`2.1.3 Commentary
`Blockage of TNFα, a putative ‘key cytokine’ in MS, failed
`in two trials. In contrast, anti-TNF strategies showed impressive
`beneficial effects in other T cell-mediated autoimmune diseases,
`particularly rheumatoid arthritis.[44-48] The unexpected and sur-
`prising negative results for infliximab and lenercept require care-
`ful analysis, particularly as they question present concepts of MS
`pathogenesis. The discrepancy between clinical exacerbations
`and MRI findings in the lenercept study is remarkable. Whereas
`the increase in clinical exacerbation rate was overt, MRI findings
`showed only a trend towards increased activity during therapy.
`Detection of new active lesions in MRI is assumed to be a highly
`sensitive indicator for disease activity (approximately ten new
`lesions correspond to about one clinical exacerbation). MRI as-
`sessment as a primary endpoint in MS studies therefore can help
`
`in rapidly gaining information but using lower patient numbers.[5]
`However, an exact correlation of ‘positive’ MRI findings with
`clinical parameters is not guaranteed. In the lenercept study the
`number of new lesions did not differ significantly from the lesion
`number in the placebo group. It is not clear whether MRI as the
`primary endpoint parameter for the efficacy assessment was
`wrong, or whether ‘technical reasons’ in the study protocol could
`account for the difference. The MRI scans were taken before each
`intravenous infusion; in other words, 4 weeks after the last infu-
`sion. In contrast, in the infliximab study, where the increased
`MRI activity appeared, examinations were conducted shortly af-
`ter the infusions of the antibodies. After 2 to 3 weeks, MRI ac-
`tivity dropped back to its initial level. Obviously lenercept pro-
`moted the formation of clinically relevant lesions without
`detectable correlates in MRI.
`In almost all patients antibodies against the TNF receptor
`construct lenercept were generated. Although they did not inhibit
`binding to TNF, they accelerated elimination and thereby may
`have shortened the duration of the drug effect. Anti-TNF antibod-
`ies that bind TNF may, per se, act as a ‘TNF sink’, which may
`then release TNF later and induce exacerbation of disease.
`Lenercept itself also possesses the Fc portion of IgG immuno-
`globulins. The Ig backbone may increase the longevity of the
`antibody in the circulation and increase Fc binding events. It is
`likely that Fc fragments stimulated the formation of immune
`complexes as well as the activation of Fc receptors on lympho-
`
`© Adis International Limited. All rights reserved.
`
`Biodrugs 2002; 16 (3)
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`Page 7 of 18
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`190
`
`Wiendl & Hohlfeld
`
`cytes. This effect could potentially be a trigger for inflammatory
`events. However, the use of Fab fragments or the extracellular
`portions of receptors linked by a polyglycine/serine linker may
`confer a short half-life and reduce peripheral adverse effects.
`Studies determining the efficacy of a therapeutic agent often
`study its effect prior to the onset of disease. Very few EAE animal
`studies target therapy after the onset or following the acute phase
`of disease during remission. In the case of TNF, a study deliver-
`ing a dimeric TNF receptor to mice with EAE demonstrated that
`the anti-TNF treatment was more efficacious when delivered
`prior to onset rather than during remission, although therapy at
`both timepoints could significantly inhibit disease sever-
`ity.[49]Although mechanisms for this were not demonstrated, it
`was suggested that the secondary relapse phase may be less de-
`pendent on TNF than the initial priming event. This is also sug-
`gested by TNF gene-deleted mice, in which the onset of disease
`was delayed compared with that in wild-type mice, but EAE de-
`veloped in the absence