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`Increased MRI activity and immune
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`activation in two multiple sclerosis
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`patients treated with the monoclonal
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`B.W. van Oosten, MD; F. Barkhof, MD; L. Truyen, MD; J.B. Boringa, MD; F.W. Bertelsmann, MD;
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`B.M.E. von Blomberg, PhD; J .N. Woody, PhD; H.-P. Hartung, MD; and CH. Polman, MD
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`Article abstract—There is evidence that treatment with an antibody to tumor necrosis factor alpha (TNF alpha)
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`improves an animal model of multiple sclerosis (MS) and is beneficial in two systemic inflammatory diseases in humans,
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`but there are no reports about anti-TNF treatment of MS. Therefore, we treated two rapidly progressive MS patients with
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`intravenous infusions of a humanized mouse monoclonal anti-TNF antibody (cA2) in an open-label phase I safety trial and
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`monitored their clinical status, gadolinium-enhanced brain magnetic resonance imaging (MRI), and peripheral blood and
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`cerebrospinal fluid (CSF) immunologic status.
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`We did not notice any clinically significant neurologic changes in either patient. The number of gadolinium-enhancing
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`lesions increased transiently after each treatment in both patients. CSF leukocyte counts and IgG index increased after
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`The transient increase in the number of gadolinium-enhancing lesions that followed each infusion of cA2 together with
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`the increase in cells and immunoglobulin in the CSF of each patient suggest that the treatment caused immune activation
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`and an increase in disease activity. These results suggest that further use of cA2 in MS is not warranted and that
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`studies of other agents that antagonize TNF alpha should be carried out with frequent monitoring of gadolinium-enhanced
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`MRIs.
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`NEUROLOGY 1996;47:1531—1534
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`Although the etiology of multiple sclerosis (MS) is
`ine,11 anti-TNF antibodiesflz"14 or rolipram,15 EAE
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`does not develop or is less severe than in controls.
`not clear, there is evidence for an important role of
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`In other human immune-mediated diseases where
`immunologic mechanisms in the pathogenesis of this
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`high levels of TNF alpha can be found in affected
`disease. Mononuclear cells from the peripheral circu-
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`organs, such as Crohn’s disease (CD) and rheuma-
`lation of MS patients, when examined in a whole-
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`toid arthritis (RA), intravenous treatment with the
`blood mitogen stimulation assay, show an increased
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`humanized monoclonal anti-TNF antibody cA2 re-
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`sulted in significant improvement lasting for 2 to 4
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`feron (IFN) gamma preceding clinical exacerbations.l
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`months after a single infusion, without causing se-
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`In MS patients with active disease, peripheral blood
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`vere adverse events.1“'19
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`mononuclear cells express higher levels of TNF al-
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`In our opinion the results of treatment of EAE
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`pha and TNF beta mRNA compared to those with
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`with anti-TNF antibodies and of treatment of CD
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`stable disease and to normal controlsfiv3 Along with
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`and RA with cA2 justified an open-label phase I
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`other cytokines and adhesion molecules, TNF alpha
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`safety trial of intravenous monoclonal anti-TNF an-
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`and TNF beta are present in MS plaques“,5 There is
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`tibodies (cA2) in two patients who were suffering
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`evidence, derived from in vitro studies, that TNF
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`from an aggressive form of MS that had not re-
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`alpha is able to damage oligodendrocytesfi'7
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`sponded to standard treatment with intravenous
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`In animals suffering from experimental allergic
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`methylprednisolone.
`encephalomyelitis (EAE), the animal model of MS,
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`the symptoms can be aggravated by injection of TNF
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`alpha.8 In animals treated with drugs that are
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`known to inhibit the production or effects of TNF
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`alpha, such as pentoxifylline,9-10 phosphatidylser-
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`Methods. Patients. In patient A, a 26-year-old woman,
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`we diagnosed MS after several episodes of fatigue and
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`sensory disturbances in both legs. Magnetic resonance im-
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`aging (MRI) revealed multiple cerebral white matter le-
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`From the Departments of Neurology (Drs. van Oosten, Truyen, Boringa, Bertelsmann, and Polman), Diagnostic Radiology (Dr. Barkhof), and Pathology (Dr.
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`von Blomberg), Free University Hospital, Amsterdam, The Netherlands; Centocor Inc. (Dr. Woody), Malvern, PA; and the Department of Neurology (Dr.
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`Hartung), Julius-Maximilians-University, Wiirzburg, Germany.
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`Received February 23, 1996. Accepted in final form May 7, 1996.
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`Address correspondence and reprint requests to Dr. C.H. Polman, Professor of Neurology, Free University Hospital, PO. Box 7057, 1007 MB Amsterdam,
`The Netherlands.
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`Page 1 of 4
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`Biogen Exhibit 21 18
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`Mylan V. BiogenCopyright © 1996 by the American Academy of Neurology 1531
`IPR 2018-01403
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`Page 1 of 4
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`Biogen Exhibit 2118
`Mylan v. Biogen
`IPR 2018-01403
`
`

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`sions, and examination of the cerebrospinal fluid (CSF)
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`revealed an IgG index of 1.68 (normal: <0.60). In the 4
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`years following diagnosis we treated a number of relapses
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`which remitted without significant residual disability,
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`with short courses of corticosteroids. Three months after
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`giving birth to a healthy son, patient A experienced an
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`episode of sensory and motor disturbances in the left arm
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`and leg, followed by an acute left-sided optic neuritis and
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`gait instability. Intravenous methylprednisolone (500 mg
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`per day for 5 days) at best resulted in a temporary stabili-
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`zation, but after some weeks she further deteriorated.
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`Gadolinium-enhanced MRI performed 3 weeks after intra-
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`venous steroids revealed many enhancing lesions. In the
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`next few months there was a gradual development of
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`brainstem signs, which resulted in significant disability.
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`Because of this devastating disease course, with an in-
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`crease in the Expanded Disability Status Scale (EDSS)2o
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`from 2.0 to 5.5 in 6 months, the possibility of cA2 treat-
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`ment was discussed with the patient and her partner, and
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`informed consent was obtained.
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`Patient B was a woman aged 25 years when we diag-
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`nosed MS after several episodes of gait disturbance, dysar-
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`thria, and disturbances of eye movements. MRI revealed
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`several cerebral white matter lesions. At CSF examination
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`the IgG index was 0.87 (normal: <0.60). In the next 5
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`years the disease followed a relapsing-remitting course.
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`Relapses were treated with short courses of intravenous
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`corticosteroids. However, after these 5 years the disease
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`started to follow a relapsing progressive course. Over 2
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`years patient B developed ataxia and sensory and pyrami-
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`dal disturbances of the legs, leading to a change of the
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`EDSS from 3.0 to 6.0, despite several courses of intrave-
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`nous corticosteroids. In the next year the progression ac-
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`celerated: her mobility was impaired by a progressive
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`paraparesis and ataxia, and she started to suffer from
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`dysarthria and dysphagia, resulting in an EDSS of 8.0.
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`Because of this aggressive disease course, which did not
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`react to standard corticosteroid treatment, the possibility
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`of cA2 treatment was discussed with the patient and her
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`partner, and informed consent was obtained.
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`Treatment with cA2 and safety procedures. The cA2
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`antibody was supplied by Centocor, Inc. (Malvem, PA) as a
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`sterile, vialed product. Each vial contained 20 ml of a solu-
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`tion of 10.0 mg/ml cA2 in 0.15 M sodium chloride, 0.01 M
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`sodium phosphate, 0.01% polysorbate 80, pH 7.2. This
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`murine-human chimeric monoclonal anti-TNF antibody
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`was constructed by joining the antigen-binding variable
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`regions of a murine monoclonal IgG antibody (A2), which
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`is secreted by the murine hybridoma cell line 0134A and
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`binds with high affinity to natural and recombinant hu-
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`man TNF alpha, to the constant regions of a human IgG1
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`kappa immunoglobulin. This was done in order to lessen a
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`potential human anti-mouse response. Also, the chimeric
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`antibody might be expected to have better effector function
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`and a longer serum half-life.
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`Both patients received two infusions of 10 mg/kg cA2
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`with an interval of 2 weeks. Neither patient had been
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`treated with any corticosteroids within 3 months preceding
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`the cA2 infusions. Before administration, the appropriate
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`amount of cA2 was diluted to 300 ml in sterile saline.
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`During intravenous infusion over 2 hours, this solution
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`was filtered through an 0.2 ul in-line filter (Pall Set Saver,
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`Pall Biomedical Inc., Fajardo, PR, USA). This treatment
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`1532 NEURagG‘Z 4of14ecember 1996
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`regimen was the same as that used in the studies that
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`demonstrated the efficacy of cA2 in the treatment of CD
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`and RA.‘“9
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`Serum levels of the administered cA2 were measured
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`regularly on both treatment days and at least until 2 days
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`after cA2 infusions. In both patients, CSF levels of cA2
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`were measured on each occasion that lumbar puncture was
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`Blood pressure, temperature, respiratory rate, and
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`heart rate were constantly monitored during and for at
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`least 2 hours after both infusions. Before the second infu-
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`sion, an intravenous test dose of 0.1 mg of cA2 was given
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`over 5 minutes, after which the patients were observed for
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`15 minutes for signs of a hypersensitivity reaction. In the
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`absence of any hypersensitivity reaction the full dose was
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`Standard hematologic and biochemical blood tests were
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`performed during and after the infusions (up to 6 months
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`after the second infusion).
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`Measures of efficacy. One day before each infusion, T2-
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`and gadolinium-enhanced Tl-weighted MRI was performed
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`using a standardized protocol.21 The same MRI protocol
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`was repeated 1 day and also 1 week after each infusion.
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`After the second infusion, additional MRI investigations
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`according to the same protocol were performed after 2 and
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`after 7 weeks. All scans were evaluated by an experienced
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`investigator (F.B.), who was blinded for the relation of
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`each scan to the time of the infusions.
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`As a clinical measure of efficacy, Kurtzke’s EDSS was
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`documented on the days that MRI examinations were per-
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`In both patients we obtained CSF by lumbar puncture
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`and assessed cell counts, IgG index, and oligoclonal bands
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`the day before and 24 hours after the first infusion; in
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`patient B these figures were also obtained the day before
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`and 48 hours after the second infusion.
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`To assess possible changes in CSF and serum levels of
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`TNF alpha, intercellular adhesion molecule (ICAM)-1,
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`ICAM-3, vascular cell adhesion molecule (VCAM)-1,
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`L-selectin, and TNF receptor (60 kD), we employed a bat-
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`tery of ELISAs, as described previously.22 We measured
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`the production of TNF alpha, IFN gamma and interleukin
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`(IL)-6 by stimulated peripheral white blood cells before
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`and for several weeks after the two infusions, using meth—
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`ods described elsewhere.”
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`Results.
`cA2 levels and safety. Peak levels of cA2 of
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`approximately 500 pug/ml were reached shortly after infu-
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`sion, followed by a decline to levels around 200 ug/ml after
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`72 hours. However, we did not detect cA2 in the CSF of
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`either patient. The assay used is able to detect levels of
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`cA2 exceeding 64 ng/ml.
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`The infusion of the cA2 antibodies was tolerated well.
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`Patient A’s blood pressure dropped temporarily from
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`127/68 to 95/51 mm Hg during the first infusion, and from
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`110/59 to 94/62 mm Hg during the second infusion, with-
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`out clinical signs of vasovagal collapse or anaphylactic re-
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`actions. We did not see any clinically evident adverse event
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`in patient B. Standard hematologic and biochemical as-
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`sessments remained normal in both patients.
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`Measures of efficacy. The number of gadolinium-
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`enhancing lesions on Tl-weighted scans increased in both
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`patients after the first infusion. With longer follow-up both
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`Page 2 of 4
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`

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`alpha antibody cA2 yielded encouraging results.
`However, treatment of MS with TNF alpha antibod-
`ies has not been reported before. Here we describe
`the results of a phase I open-label study of treatment
`of two MS patients with cA2.
`Unexpectedly, we saw a rise in the number of
`gadolinium-enhancing lesions compared to baseline
`after each infusion in both patients, which was most
`obvious after the first infusion. We would have pre-
`ferred to compare these MRI data with a series of
`monthly pretreatment scans (e.g., 6 or 12 months),
`because this would have allowed a statistical inter-
`
`pretation of our results.”1 However, since this was an
`open-label phase I study in patients who were dete-
`riorating rapidly, this was not a realistic option in
`our view.
`
`We also saw a rise in the IgG index and in the
`number of CSF lymphocytes after each infusion of
`cA2 (see the table), reinforcing the MRI findings and
`suggesting that intravenous administration of cA2
`triggers an intrathecal immune activation in MS pa-
`tients.
`The occurrence of VCAM-1 in the CSF after the
`cA2 infusions is consistent with an intrathecal im-
`
`mune activation as suggested by MRI and other CSF
`data. The lower levels of ICAM-1 and VCAM-l, and
`the decrease in TNF alpha production by stimulated
`white blood cells, seem to suggest that the observed
`immune activation was limited to the intrathecal
`
`compartment. However, little is known about the
`day-to-day variability of these measurements in MS
`patients, which makes it hard to judge their signifi-
`cance.
`
`Taking into account the MRI and CSF (IgG index
`and lymphocyte counts) results, this study provides
`evidence that intravenous treatment of MS patients
`with the anti-TNF antibody cA2 may lead to intra-
`thecal
`immune activation and may therefore be
`harmful for MS patients. One has to bear in mind
`that, because of the small number of patients treated
`and the fact that each patient received only two infu-
`sions, this evidence is only preliminary.
`One possible explanation for these unexpected re-
`sults is that cA2 may not be able to cross the blood—
`brain barrier and therefore does not reach the MS
`
`plaques, since we did not detect the antibody in the
`CSF after treatment. However, one could argue that
`a defective blood-brain barrier, as shown by gado-
`linium enhancement on MRI, would allow passage of
`antibodies into MS lesions, and that absence of cA2
`from the CSF is no proof of its absence from MS
`lesions. A second possible explanation is that TNF
`alpha is not of the same importance for the patho-
`genesis of MS as it appears to be for CD and RA.
`However, neither possibility explains the impression
`that there was an intrathecal immune activation.
`
`Given the limited and preliminary nature of the data
`available, an explanation of this phenomenon can
`only be speculative and premature. Other studies are
`required to confirm our observations and to provide a
`stronger basis for their explanation. For the time
`December 1998 NEUROLOGY 47 1688
`
`o
`
`paiiontA
`
`I
`
`patientB
`
`A cA2Inius|on
`
`so
`
`40
`
`/
`
`.
`
`so
`
`10
`
`0
`
`2
`.9
`
`a2S
`
`O 5 Ea
`
`C
`
`3
`3'0fl
`3 20
`
`-5o 5101520253035404550
`
`days
`
`Figure. Number ofgadolinium-enhancing lesions in pa-
`tients A and B.
`
`patients returned to their (high) pretreatment levels of
`activity (figure).
`On the EDSS patient A improved from 5.5 to 5.0 after
`the first infusion and was stable afterwards; patient B
`improved from 8.0 to 7.5 after the first infusion but re-
`turned to 8.0 after 6 weeks.
`
`Both lymphocyte counts and IgG index were higher
`post-treatment compared to the patients' already abnor-
`mal pretreatment values (table).
`In both patients we did not find any TNF alpha,
`lCAM-l, or L-selectin in the CSF (detection limits of the
`assays were 40 pg/ml, 30 ng/ml, and 80 ng/ml, respective-
`ly), whereas we found VCAM-l levels of 100 ng/ml in pa-
`tient A only after the first infusion and in patient B only
`afier the second infusion. There were no striking changes
`in serum levels of adhesion molecules, but there was a
`trend toward lower serum levels of the soluble form of the
`
`adhesion molecules VCAM-l and ICAM-1 in both patients
`(data not shown). The production of TNF alpha by stimu—
`lated peripheral white blood cells was reduced after treat-
`ment, but there was no effect on production of IFN gamma
`and IL»6 (data not shown).
`
`Discussion. Recent evidence suggests that TNF
`alpha is of major importance in the pathogenesis of
`several autoimmune disorders, such as RA, CD, and
`MS. Treatment of CD"‘-17 and RAW-19 with the TNF
`
`
`Table IgG index and CSF lymphocytes per 3 pl
`
`Patient A
`
`Patient B
`
`Day
`
`IgG index
`
`Lymphocytes
`
`lgG index
`
`Lymphocytes
`
`3.38
`
`5.97
`
`- 1
`
`0
`
`13
`
`14
`
`109
`
`149
`
`2.18
`
`2.65
`
`2.23
`
`Infusion l
`
`Infusion 2
`
`63
`
`85
`
`52
`
`
`
` 2.8816 60
`
`
`
`Page 3 of 4
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`

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`13.
`
`14.
`
`
`
`
`
`15.
`
`
`
`16.
`
`
`
`17.
`
`
`
`18.
`
`
`
`19.
`
`
`
`20.
`
`
`
`21.
`
`22.
`
`23.
`
`24.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Selmaj K, Raine CS, Cross AH. Anti-tumor necrosis factor
`
`
`
`
`
`
`therapy abrogates autoimmune demyelination. Ann Neurol
`
`1991;30:694—700.
`
`
`
`
`
`
`
`
`
`
`
`Baker D, Butler D, Scallon BJ, et a1. Control of established
`
`
`
`
`
`
`
`experimental allergic encephalomyelitis by inhibition of tumor
`
`
`
`
`
`
`
`
`
`necrosis factor (TNF) activity within the central nervous sys—
`
`
`
`
`
`
`
`tem using monoclonal antibodies and TNF receptor-
`
`
`
`
`
`
`immunoglobulin fusion proteins. Eur J Immunol 1994;24:
`
`2040—2048.
`
`
`
`
`
`
`
`
`
`Genain CP, Roberts T, Davis RL, et a1. Prevention of autoim-
`
`
`
`
`
`
`
`mune demyelination in non-human primates by a CAMP-
`
`
`
`
`
`
`
`specific phosphodiesterase inhibitor. Proc Natl Acad Sci USA
`
`1995;92:3601—3605.
`
`
`
`
`
`
`
`
`
`Derkx B, Taminiau J, Radema S, et a1. Tumor-necrosis—factor
`
`
`
`
`
`
`
`antibody treatment in Crohn’s disease. Lancet 1994;342:173—
`
`174.
`
`
`
`
`
`
`
`
`
`
`Van Dullemen HM, Van Deventer SJH, Hommes DW, et al.
`
`
`
`
`
`
`
`
`
`Treatment of Crohn’s disease with anti tumor necrosis factor
`
`
`
`
`
`
`chimeric monoclonal antibody (cA2). Gastroenterology 1995;
`
`109:129—135.
`
`
`
`
`
`
`
`
`
`Elliott MJ, Maini RN, Feldmann M, et a1. Randomised double-
`
`
`
`
`
`
`
`blind comparison of chimeric monoclonal antibody to tumor
`
`
`
`
`
`
`
`
`necrosis factor alpha (cA2) versus placebo in rheumatoid ar-
`
`
`
`thritis. Lancet 1994;344:1105-1110.
`
`
`
`
`
`
`
`
`
`
`Elliott MJ, Maini RN, Feldmann M, et a1. Repeated therapy
`
`
`
`
`
`
`
`
`
`with monoclonal antibody to tumor necrosis factor alpha (cA2)
`
`
`
`
`
`
`
`in patients with rheumatoid arthritis. Lancet 1994;344:1125~
`
`1127.
`
`
`
`
`
`
`
`
`Kurtzke JF. Rating neurologic impairment in multiple sclero-
`
`
`
`
`
`
`
`
`sis: an expanded disability status scale (EDSS). Neurology
`
`
`
`1983;33:1444—1452.
`
`
`
`
`
`
`
`
`
`Barkhof F, Scheltens P, Frequin STFM, et a1. Relapsing-
`
`
`
`
`
`
`
`remitting multiple sclerosis: sequential enhanced MR imaging
`
`
`
`
`
`
`
`
`
`vs. clinical findings in determining disease activity. AJR 1992;
`
`19:1041—1047.
`
`
`
`
`
`
`
`
`Hartung HP, Reiners K, Archelos JJ, et a1. Circulating adhe-
`
`
`
`
`
`
`
`
`sion molecules and tumor necrosis factor receptor in multiple
`
`
`
`
`
`
`sclerosis: correlation with magnetic resonance imaging. Ann
`
`
`Neurol 1995;38:186—193.
`
`
`
`
`
`
`
`
`
`
`
`
`van Oosten BW, Rep MHG, van Lier RAW, et al. A pilot study
`
`
`
`
`
`
`investigating the efl‘ects of orally administered pentoxifylline
`
`
`
`
`
`
`
`
`on selected immune variables in patients with multiple sclero-
`
`
`
`sis. J Neuroimmunol 1996;66:49—55.
`
`
`
`
`
`
`
`
`
`
`
`Stone LA, Frank JA, Albert PS, et al. The effect of
`
`
`
`
`
`
`interferon-B on blood-brain barrier disruptions demonstrated
`
`
`
`
`
`
`
`by contrast enhanced magnetic resonance imaging in
`
`
`
`
`
`relapsing-remitting multiple sclerosis. Ann Neurol 1995;37:
`
`611—619.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`being it seems wise to take measures that enable
`
`
`
`
`
`
`
`
`prompt recognition of signs of immune activation in
`
`
`
`
`
`
`
`MS patients who are treated with (experimental)
`
`
`
`
`
`
`
`
`TNF alpha antagonists, preferably by making use of
`
`
`
`frequent MRI monitoring.
`
`References
`
`
`
`
`
`
`
`
`
`
`
`
`1.
`Beck J, Rondot P, Catinot L, et a1. Increased production of
`
`
`
`
`
`
`
`
`interferon gamma and tumor necrosis factor precedes clinical
`
`
`
`
`
`
`
`
`manifestation in multiple sclerosis: do cytokines trigger ofi'
`
`
`
`
`
`exacerbations? Acta Neurol Scand 1988;78:318—323.
`
`
`
`
`
`
`
`
`
`
`
`. Rieckmann P, Albrecht M, Kitze B, et a1. Cytokine mRNA
`
`
`
`
`
`
`
`
`
`levels in mononuclear blood cells from patients with multiple
`
`
`
`sclerosis. Neurology 1994;44:1523—1526.
`
`
`
`
`
`
`
`
`
`
`. Rieckmann P, Albrecht M, Kitze B, et a1. Tumor necrosis
`
`
`
`
`
`
`factor-alpha messenger RNA expression in patients with
`
`
`
`
`
`
`relapsing-remitting multiple sclerosis is associated with dis-
`
`
`
`
`
`ease activity. Ann Neurol 1995;37:82—88.
`
`
`
`
`
`
`
`
`
`. Cannella B, Raine CS. The adhesion molecule and cytokine
`
`
`
`
`
`
`
`profile of multiple sclerosis lesions. Ann Neurol 1995;37:424—
`
`435.
`
`
`
`
`
`
`
`
`
`
`
`. Selmaj K, Raine CS, Cannella B, Brosnan CF. Identification of
`
`
`
`
`
`
`
`
`lymphotoxin and tumor necrosis factor in multiple sclerosis
`
`
`
`
`lesions. J Clin Invest 1991;87:949—954.
`
`
`
`
`
`
`
`
`
`
`Robbins DS, Shirazi Y, Drysdale BE, et a1. Production of cyto-
`
`
`
`
`
`
`toxic factor for oligodendrocytes by stimulated astrocytes.
`
`
`
`J Immunol 1987;139:2593—2600.
`
`
`
`
`
`
`
`
`
`. Selmaj K, Raine CS. Tumor necrosis factor mediates myelin
`
`
`
`
`
`
`
`and oligodendrocyte damage in vitro. Ann Neurol 1988;23:
`
`339—346.
`
`
`
`
`
`
`
`
`
`. Kuroda Y, Shimamoto Y. Human tumor necrosis factor-alpha
`
`
`
`
`
`
`augments experimental allergic encephalomyelitis in rats.
`
`
`
`J Neuroimmunol 1991;34:159—164.
`
`
`
`
`
`
`
`
`
`Nataf S, Louboutin JP, Chabannes D, et a1. Pentoxifylline
`
`
`
`
`
`
`inhibits experimental allergic encephalomyelitis. Acta Neurol
`
`
`Scand 1993;88:97-99.
`
`
`
`
`
`
`
`
`Rott 0, Cash E, Fleischer B. Phosphodiesterase inhibitor pen-
`
`
`
`
`
`
`
`
`
`
`toxifylline, a selective inhibitor of T helper 1— but not type
`
`
`
`
`
`
`2-associated lymphokine production, prevents induction of ex-
`
`
`
`
`
`
`
`perimental allergic encephalomyelitis in Lewis rats. Eur J Im-
`
`
`munol 1993;213:1745—1751.
`
`
`
`
`
`
`
`
`
`Monastra G, Cross AH, Bruni A, Raine CS. Phosphatidylser—
`
`
`
`
`
`
`
`
`
`ine, a putative inhibitor of tumor necrosis factor, prevents
`
`
`
`
`
`autoimmune demyelination. Neurology 1994;43:153—163.
`
`
`
`
`
`
`
`
`
`
`
`Ruddle NH, Bergman CM, McGrath KM, et al. An antibody to
`
`
`
`
`
`
`
`
`lymphotoxin and tumor necrosis factor prevents transfer of
`
`
`
`
`
`experimental allergic encephalomyelitis. J Exp Med 1990;172:
`
`1193—1200.
`
`
`
`
`
`10.
`
`
`
`ll.
`
`12.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`1534 NEIRBgiBG‘r (Ff 4ecember 1996
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`Page 4 of 4
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