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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/10/17 01:34:37」(JST)

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Natalizumab is a humanized monoclonal antibody against the cell adhesion molecule α4-integrin. Natalizumab is used in the treatment of multiple sclerosis and Crohn's disease. It is co-marketed by Biogen Idec and Élan as Tysabri, and was previously named Antegren. Natalizumab is administered by intravenous infusion every 28 days. The drug is believed to work by reducing the ability of inflammatory immune cells to attach to and pass through the cell layers lining the intestines and blood–brain barrier. Natalizumab has proven effective in treating the symptoms of both diseases, preventing relapse, vision loss, cognitive decline and significantly improving quality of life in people with multiple sclerosis, as well as increasing rates of remission and preventing relapse in Crohn's disease.

Natalizumab was approved in 2004 by the U.S. Food and Drug Administration (FDA). It was subsequently withdrawn from the market by its manufacturer after it was linked with three cases of the rare neurological condition progressive multifocal leukoencephalopathy (PML) when administered in combination with interferon beta-1a, another immunosuppressive drug often used in the treatment of multiple sclerosis. After a review of safety information and no further deaths, the drug was returned to the US market in 2006 under a special prescription program. As of June 2009, ten cases of PML were known. However, twenty-four cases of PML had been reported since its reintroduction by October 2009, showing a sharp rise in the number of fatalities and prompting a review of the chemical for human use by the European Medicines Agency.^[1]^[2]^[3] By January 2010, 31 cases of PML were attributed to natalizumab.^[4] The FDA did not withdraw the drug from the market because its clinical benefits outweigh the risks involved.^[5] In the European Union, it has been approved for human use only for the treatment of multiple sclerosis and only then as a monotherapy because the initial cases of PML, and later the fatalities, were said by the manufacturers to be linked to the use of previous medicines by the patients.

Biogen Idec announced the initiation of the first clinical trial of natalizumab as a potential cancer treatment as of September 5, 2008.^[6]

Indications[edit]

Natalizumab is FDA-approved for the treatment of multiple sclerosis and Crohn's disease and approved for treatment of multiple sclerosis in Europe, but is currently under review by the EMEA.^[7]^[8] Pre-clinical evidence suggests that it could be also used in combination for the treatment of B-cell malignancies where it overcomes the resistance to rituximab .^[9]

Multiple sclerosis[edit]

Further information: Multiple sclerosis and Treatment of multiple sclerosis

Natalizumab was evaluated in two randomized, double-blind, placebo-controlled trials in people with multiple sclerosis. The studies enrolled individuals with MS who experienced at least one clinical relapse during the prior year and had a Kurtzke EDSS score between 0 and 5. In these trials natalizumab was shown to reduce relapses in individuals with MS by 68% vs. placebo, a margin far greater than had been seen for other approved MS therapies.^[10] Natalizumab also slowed the progression of disability in patients with relapsing MS.^[10]^[11] In combination with interferon beta-1a (IB1A), relapsing and disability progression were reduced more than IB1A alone.^[12] Other benefits of natalizumab use by patients with relapsing MS included reduced visual loss,^[13] a significant increase in the proportion of disease-free individuals,^[14] significantly improved assessments of health-related quality of life in relapsing individuals,^[15]^[16] reduced cognitive decline of a portion of individuals with MS,^[17] reduced hospitalizations and steroid use,^[18] and prevention of the formation of new lesions.^[10]^[19] Approximately 6% of individuals receiving natalizumab have been found to develop persistent antibodies to the drug, which reduces its efficacy^[12]^[20]^[21] and produce reactions during the infusion of the drug, as well as hypersensitivity.^[12] Natalizumab is approved in the United States and the European Union. It is indicated as monotherapy (not combined with other drugs) for the treatment of highly active relapsing remitting MS in spite of prior treatments.^[11] Natalizumab offers a limited improvement in efficacy compared to other treatments for MS, but due to the lack of information about long-term use, as well as potentially fatal adverse events, reservations have been expressed over the use of the drug outside of comparative research with existing medications.^[12]

Crohn's disease[edit]

Further information: Crohn's disease

Several randomized controlled trials have demonstrated that natalizumab is effective in increasing rates of remission^[22] and maintaining symptom-free status^[23] in patients with Crohn's disease. Natalizumab may be appropriate in patients who do not respond to medications that block tumor necrosis factor-alpha such as infliximab,^[24] with some evidence to support combination treatment of Crohn's disease with natalizumab and infliximab may be helpful in inducing remission.^[25] Treatment of adolescent patients with natalizumab demonstrates an effectiveness similar to that of adult patients.^[26]

In January 2008, the FDA approved natalizumab for both induction of remission and maintenance of remission for moderate to severe Crohn's disease,^[27] though it has not been approved for this use in the European Union due to concerns over its risk/benefit ratio.^[28]

Adverse effects[edit]

Progressive multifocal leukoencephalopathy, an opportunistic infection caused by the JC virus, and that typically occurs in patients who are immunocompromised, developed in seven patients who received natalizumab;^[29] three cases were noted in clinical trials in 2006^[30] leading to the drug being temporarily pulled from the market; two cases were reported to the FDA in August 2008;^[31] and, two cases were announced in December 2008.^[29] By January 21, 2010 the FDA noted a total of 31 confirmed cases of PML, with the chance of developing the infection increasing as the number of infusions received by a patient increased. Because of this association, the drug label and package insert accompanying the drug will be updated to include this information.^[32] As of May 2011, over 130 cases of PML had been reported in MS patients, all in patients who had taken natalizumab for more than a year.^[33] While none of them had taken the drug in combination with other disease-modifying treatments, previous use of MS treatments increases the risk of PML between 3 and 4-fold.^[33] The estimated prevalence of PML in MS is 1.5 cases per thousand natalizumab users.^[33] Around 20% of MS patients with PML die, while most of the remaining are importantly disabled.^[33]

Postmarketing surveillance in early 2008 revealed that 0.1% of people taking natalizumab experience clinically significant liver injury, leading to the FDA, EMEA and manufacturers recommending that the medication be discontinued in patients with jaundice or other evidence of significant liver damage.^[34]^[35]^[36] This rate is comparable to other immune-suppressing drugs.^[37] Evidence of hepatotoxicity in the form of elevated blood levels of bilirubin and liver enzymes can appear as soon as six days after an initial dose; reactions are unpredictable and may appear even if the patient does not react to previous treatment.^[38] Such signs reoccur upon rechallenge in some patients, indicating that damage is not coincidental.^[38] In the absence of any blockage these liver function tests are predictors of severe liver injury with possible sequelae of liver transplantation or death.^[38]

Common adverse effects include fatigue and allergic reactions with a low risk of anaphylaxis,^[39] headache, nausea, colds and exacerbation of Crohn's disease in a minority of patients with the condition.^[25] Adolescents with Crohn's disease experience headache, fever and exacerbation of Crohn's disease.^[26] Natalizumab is contraindicated for people with known hypersensitivity to the drug or its components and in patients with a history of PML (see interactions).

Natalizumab has also been linked to melanoma, though the association is unclear.^[40] The long-term effects of the drug are unknown^[41] and concern has been expressed over the risks of infection and cancer.^[12]

Mechanism of action[edit]

Structure of a generic antibody

Natalizumab is a humanized monoclonal antibody against alpha-4 (α4) integrin, the first drug developed in the class of selective adhesion molecule inhibitors. α4-integrin is required for white blood cells to move into organs, and natalizumab's mechanism of action is believed to be the prevention of immune cells from crossing blood vessel walls to reach affected organs.^[42]

In multiple sclerosis[edit]

The symptom-causing lesions of MS are believed to be caused when inflammatory cells such as T-lymphocytes pass through the blood–brain barrier through interaction with receptors on the endothelial cells. Natalizumab appears to reduce the transmission of immune cells into the central nervous system by interfering with the α4β1-integrin receptor molecules on the surfaces of cells. The effect appears to occur on endothelial cells expressing the VCAM-1 gene, and in parenchymal cells expressing the osteopontin gene. In animals used to model MS and test therapies, repeated administration of natalizumab reduced migration of leukocytes into the brain's parenchyma, and also reduced lesioning, though it is uncertain if this is clinically significant for humans.^[43]

Individuals with MS dosed with natalizumab demonstrated increased CD34-expressing cells, with research suggesting a peak in expression after 72 hours.^[44]

In Crohn's disease[edit]

The interaction of the α4β7 integrin and the addressin (also known as MADCAM1) endothelial cell receptor is believed to contribute to the chronic bowel inflammation that causes Crohn's disease. Addressin is primarily expressed in the endothelium of venules in the small intestine and are critical in guiding T-lymphocytes to lymphatic tissues in Peyer's patches. In CD patients, sites of active inflammation of the bowel in CD patients have increased expression of addressin, suggesting a connection between the inflammation and the receptor. Natalizumab may block interaction between the α4β7 integrin and addressin at sites of inflammation. Animal models have found higher levels of VCAM-1 expression in mice with irritable bowel syndrome and the VCAM-1 gene may also play a part in CD but its role is not yet clear.^[43]

Interactions[edit]

Natalizumab appears to interact with other immune-modulating drugs to increase the risk of progressive multifocal leukoencephalopathy (PML), an often-fatal opportunistic infection caused by the JC virus. In 2005, two people taking natalizumab in combination with interferon beta-1a developed PML. One died, and the other recovered with disabling sequelae.^[45]^[46] A third fatal case initially attributed to an astrocytoma was reported in a patient being treated for Crohn's disease.^[47] Though the patient was being treated with natalizumab in combination with azathioprine, corticosteroids and infliximab, indications of PML infection appeared only after natalizumab monotherapy was re-introduced.^[47] No deaths have been linked to natalizumab when it was not combined with other immune-modulating drugs^[48] and other rates of opportunistic infections are not increased in patients taking natalizumab^[49] possibly due to the drug’s mechanism of action.^[50] Other than a prior history of PML, there is no known method to identify patients at risk of developing PML.^[51] Natalizumab's label indicates that it is contraindicated for immunosuppressed individuals or those with a history of PML.^[43] Due to the uncertain risk of PML, natalizumab is only available through a restricted distribution program.^[43] As of June 2009, ten cases of PML associated with natalizumab have been reported.^[3] At least one of them had not previously taken any other inmunomodulator therapy.^[52] By January 21, 2010 the United States Food and Drug Administration reported a total of 31 confirmed cases of PML associated with natalizumab.^[4]

Though the small number of cases precludes conclusion on the ability of natalizumab alone to induce PML, its black box warning states that the drug has only been linked to PML when combined with other immune-modulating drugs and natalizumab is contraindicated for use with other immunomodulators.^[43] Corticosteroids may produce immunosuppression, and the Tysabri prescribing information recommends that people taking corticosteroids for the treatment of Crohn's disease have their doses reduced before starting natalizumab treatment.^[43] The risk of developing PML was later estimated to be 1 in 1,000 (0.1%) over 18 months^[20]^[49]^[53] though the longer term risks of PML are unknown.^[20]

Legal status[edit]

Natalizumab was originally approved for treatment of multiple sclerosis in 2004, through the FDA's accelerated Fast Track program, due to the drug's efficacy in one-year clinical trials. In February 2005, four months after its approval, natalizumab was withdrawn voluntarily by the manufacturer after two cases of progressive multifocal leukoencephalopathy. Groups representing individuals with MS lobbied to have the drug returned to the US market^[54] and in June, 2006, after recommendation by an advisory committee and a review of two years of safety and efficacy data, the FDA re-approved natalizumab for patients with all relapsing forms of MS (relapse-remitting, secondary-progressive, and progressive-relapsing) as a first-line or second-line therapy.^[55]^[56] Patients taking natalizumab must enter into a registry for monitoring.^[54] Natalizumab is the only drug after alosetron withdrawn for safety reasons that returned to the US market.

In April, 2006 the Committee for Medicinal Products for Human Use recommended authorizing natalizumab to treat relapsing-remitting MS, and several weeks later the European Medicines Agency approved natalizumab in the European Union for highly-active relapsing remitting MS.^[8]

Health Canada added natalizumab to Schedule F of the Food and Drug Regulations on April 3, 2008 as a prescription drug requiring oversight from a physician.^[57]

References[edit]

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^ "FDA Approves Tysabri to Treat Moderate-to-Severe Crohn's Disease". Food and Drug Administration. 2008-01-14. Retrieved 2008-03-09.
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^ ^a ^b Greene, Robert T. (December 15, 2008). "Biogen, Elan Report Brain Illness in Tysabri Patient". Bloomberg.com. Retrieved December 21, 2008.
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External links[edit]

Tysabri Natalizumab
Elan's Tysabri information center
Biogen's Tysabri information center

UpToDate Contents

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1. 成人における再発寛解型多発性硬化症に対するナタリズマブ natalizumab for relapsing remitting multiple sclerosis in adults
2. 成人におけるクローン病治療のためのナタリズマブ natalizumab for treatment of crohn disease in adults
3. 成人における重症または難治性クローン病の内科的マネージメントの概要 overview of the medical management of severe or refractory crohn disease in adults
4. 進行性多巣性白質脳症：治療および予後 progressive multifocal leukoencephalopathy treatment and prognosis
5. 成人における再発寛解型多発性硬化症の治療 treatment of relapsing remitting multiple sclerosis in adults

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Amezcua L1, Morrow MJ, Jirawuthiworavong GV.
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PURPOSE OF REVIEW: To review important eye movement disorders in multiple sclerosis (MS) and update the ophthalmologist on disease-modifying therapies in MS, from the perspective of expert neurologists.RECENT FINDINGS: A large study confirmed that eye movement abnormalities in MS can be commonly ide
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Journal of neuroimmunology.J Neuroimmunol.2015 Oct 15;287:76-9. doi: 10.1016/j.jneuroim.2015.08.010. Epub 2015 Aug 14.
Natalizumab is a humanized monoclonal antibody against the α4 subunit of VLA-4 integrin that is used to treat conditions such as multiple sclerosis (MS). Although its effects on lymphocytes have been widely described, little is known about its effects on monocytes. Here we described the effects of
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Journal of the neurological sciences.J Neurol Sci.2015 Oct 15;357(1-2):106-8. doi: 10.1016/j.jns.2015.07.007. Epub 2015 Jul 8.
Multiple Sclerosis (MS) is a heterogeneous disorder of the central nervous system (CNS) that begins as an inflammatory autoimmune disorder mediated by auto-reactive lymphocyte followed by microglial activation and chronic degeneration. The etiology of Multiple Sclerosis (MS) is unknown but several d
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多発性硬化症の治療--再発抑制薬の現状と新薬治療の展望 (AYUMI 多発性硬化症と視神経脊髄炎)

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内科 99(2), 354-358, 2007-02
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Related Pictures

★リンクテーブル★

リンク元	「mab」「ナタリズマブ」

「mab」

Natalizumab ^?
Monoclonal antibody
Type	Whole antibody
Source	Humanized (from mouse)
Target	alpha-4 integrin
Clinical data
Trade names	Tysabri
AHFS/Drugs.com	monograph
MedlinePlus	a605006
Licence data	EMA:Link, US FDA:link
Pregnancy cat.	C (AU) C (US)
Legal status	℞ Prescription only
Routes	Intravenous infusion
Pharmacokinetic data
Bioavailability	n/a
Half-life	11 ± 4 days
Identifiers
CAS number	189261-10-7
ATC code	L04AA23
DrugBank	DB00108
UNII	3JB47N2Q2P
ChEMBL	CHEMBL1201607
Chemical data
Formula	?
Mol. mass	149 kDa
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　　[★]

関: モノクローナル抗体

mab

abciximab
adahmumab
adalimumab
afelimomab
alemtuzumab
apolizumab
arcitumomab
basiliximab
bevacizumab
cantuzumab
certolizumab
cetolizumab
cetuximab
clenoliximab
daclizumab
デノスマブ denosumab 抗RANKL抗体
eculizumab
edrecolomab
efalizumab
epratuzumab
galiximab
gemtuzumab
ibritumomab
インフリキシマブ infliximab 抗TNF-α抗体クローン病 Ph⁺ALL
inotuzumab
keliximab
natalizumab
nebacumab
omalilzumab
omalizumab
oregovomab
palivizumab
panitumumab
pertuzumab
pexelizumab
リツキシマブ rituximab：抗CD20抗体：慢性リンパ性白血病、B細胞リンパ腫

「ナタリズマブ」

　　[★]

英: natalizumab
商: タイサブリ

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[2] Hirschler, B; Cowell D (2009-10-29). "EU agency reports 24th case of Tysabri infection". Reuters. Retrieved 2010-08-31.

[June2009-3] Clarke T; Orlofsky S; Von Ahn L (2009-06-29). "Biogen reports 10th case of PML brain infection". Reuters. Retrieved 2010-08-31.

[Medscape-4] Jeffrey, S (2010-02-05). "PML Risk Increases With Repeated Natalizumab Infusions: FDA". Medscape. Retrieved 2010-08-31.

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[7] ttp://www.fiercepharma.com/story/tysabri-safety-falls-under-emea-scrutiny/2009-10-26

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[9] Mraz, M.; Zent, C. S.; Church, A. K.; Jelinek, D. F.; Wu, X.; Pospisilova, S.; Ansell, S. M.; Novak, A. J.; Kay, N. E.; Witzig, T. E.; Nowakowski, G. S. (2011). "Bone marrow stromal cells protect lymphoma B-cells from rituximab-induced apoptosis and targeting integrin α-4-β-1 (VLA-4) with natalizumab can overcome this resistance". British Journal of Haematology 155 (1): 53–64. doi:10.1111/j.1365-2141.2011.08794.x. PMID 21749361. edit

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[pmid18354844-12] "Natalizumab: new drug. Multiple sclerosis: risky market approval". Prescrire Int 17 (93): 7–10. 2008. PMID 18354844.

[13] Balcer LJ, Galetta SL, Calabresi PA, et al. (2007). "Natalizumab reduces visual loss in patients with relapsing multiple sclerosis". Neurology 68 (16): 1299–304. doi:10.1212/01.wnl.0000259521.14704.a8. PMID 17438220.

[Galetta-14] Galetta, S; et al. (2008-04-18). "Natalizumab Increases the Proportion of Patients Free of Clinical or MRI Disease Activity in Relapsing Multiple Sclerosis". unpublished/unpresented conference poster. Retrieved 2008-03-11. ; industry publication - "New TYSABRI Data to Be Presented at the European Committee for Treatment and Research in Multiple Sclerosis". Élan. 2007-10-11. Archived from the original on 2007-10-29. Retrieved 2008-03-09.

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[16] Rudick RA, Miller D, Hass S, et al. (2007). "Health-related quality of life in multiple sclerosis: effects of natalizumab". Ann. Neurol. 62 (4): 335–46. doi:10.1002/ana.21163. PMID 17696126.

[17] "New Data on Natalizumab Demonstrate Significant Improvement in Cognitive Function in Patients With Multiple Sclerosis". Doctor's Guide. 2006-09-28. Retrieved 2008-03-09.

[18] "New Pharmacoeconomic Data On TYSABRI Demonstrate Significant Reduction In Steroid Use And Hospitalizations In Patients With Multiple Sclerosis". webwire. 2006-10-06. Retrieved 2008-03-09.

[19] Miller DH, Soon D, Fernando KT, et al. (2007). "MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS". Neurology 68 (17): 1390–401. doi:10.1212/01.wnl.0000260064.77700.fd. PMID 17452584.

[pmid18360634-20] Hutchinson M (2007). "Natalizumab: A new treatment for relapsing remitting multiple sclerosis". Ther Clin Risk Manag 3 (2): 259–268. doi:10.2147/tcrm.2007.3.2.259. PMC 1936307. PMID 18360634. |accessdate= requires |url= (help)

[21] Calabresi PA, Giovannoni G, Confavreux C, et al. (2007). "The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL". Neurology 69 (14): 1391–403. doi:10.1212/01.wnl.0000277457.17420.b5. PMID 17761550.

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[23] Feagan BG, Sandborn WJ, Hass S, Niecko T, White J (2007). "Health-related quality of life during natalizumab maintenance therapy for Crohn's disease". Am. J. Gastroenterol. 102 (12): 2737–46. doi:10.1111/j.1572-0241.2007.01508.x. PMID 18042106.

[24] Michetti P, Mottet C, Juillerat P, et al. (2007). "Severe and steroid-resistant Crohn's disease". Digestion 76 (2): 99–108. doi:10.1159/000111023. PMID 18239400.

[Sands-25] Sands BE, Kozarek R, Spainhour J, et al. (2007). "Safety and tolerability of concurrent natalizumab treatment for patients with Crohn's disease not in remission while receiving infliximab". Inflamm. Bowel Dis. 13 (1): 2–11. doi:10.1002/ibd.20014. PMID 17206633.

[Hyams-26] Hyams JS, Wilson DC, Thomas A, et al. (2007). "Natalizumab therapy for moderate to severe Crohn disease in adolescents". J. Pediatr. Gastroenterol. Nutr. 44 (2): 185–91. doi:10.1097/01.mpg.0000252191.05170.e7. PMID 17255829.

[27] "FDA Approves Tysabri to Treat Moderate-to-Severe Crohn's Disease". Food and Drug Administration. 2008-01-14. Retrieved 2008-03-09.

[28] "Refusal CHMP assessment report for natalizumab" (PDF). European Medicines Agency. 2007-11-15. Retrieved 2008-04-02. lay-summary PDF (78.5 KB)

[BloombergDec152008-29] Greene, Robert T. (December 15, 2008). "Biogen, Elan Report Brain Illness in Tysabri Patient". Bloomberg.com. Retrieved December 21, 2008.

[pmid15947080-30] Van Assche G, Van Ranst M, Sciot R, et al. (July 2005). "Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease". N. Engl. J. Med. 353 (4): 362–8. doi:10.1056/NEJMoa051586. PMID 15947080.

[FDAAug2008-31] U.S. Food and Drug Administration (August 2008). "Natalizumab Injection for Intraveneous {{sic}} Use (marketed as Tysabri)". Retrieved December 22, 2008. ^{[dead link]}

[32] "FDA Drug Safety Communication: Risk of Progressive Multifocal Leukoencephalopathy (PML) with the use of Tysabri (natalizumab)". FDA. 2010-05-02. Retrieved 2010-08-31.

[.22pmid21777829.22-33] Kappos, L; Bates, D; Edan, G; Eraksoy, M; Garcia-Merino, A; Grigoriadis, N; Hartung, HP; Havrdová, E; Hillert, J; Hohlfeld, R; Kremenchutzky, M; Lyon-Caen, O; Miller, A; Pozzilli, C; Ravnborg, M; Saida, T; Sindic, C; Vass, K; Clifford, DB; Hauser, S; Major, EO; O'Connor, PW; Weiner, HL; Clanet, M; Gold, R; Hirsch, HH; Radü, EW; Sørensen, PS; King, J (2011 Aug). "Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring.". Lancet neurology 10 (8): 745–58. doi:10.1016/S1474-4422(11)70149-1. PMID 21777829.

[FDA_Safety_Alerts_for_Drugs-34] "FDA MedWatch - 2008 Safety Information Alerts". Food and Drug Administration. 2008-02-28. Retrieved 2008-04-05.

[EMEA_press_release-35] "EMEA concludes new advice to doctors and patients for Tysabri (natalizumab) needed" (PDF). European Medicines Agency. 2008-03-20. Retrieved 2008-04-05. ^{[dead link]}

[Q.26A-36] "Questions and answers on Tysabri and liver injury" (PDF). European Medicines Agency. 2008-03-20. Retrieved 2008-04-14. ^{[dead link]}; lay-summary, second summary

[titleMultiple_Sclerosis_-_Natalizumab_.28Tysabri.29_Can_Rarely_Cause_Liver_Problems-37] Kenneth Gross, M.D. (2008-03-03). "Multiple Sclerosis - Natalizumab (Tysabri) Can Rarely Cause Liver Problems". Retrieved 2008-04-05.

[DHP-38] Panzara, M; Francis V (2008-02-01). "Important safety information: Dear Healthcare Practitioner letter" (PDF). Biogen Idec and Élan. Retrieved 2008-04-11. ; lay summary

[pmid17876741-39] Horga A, Horga de la Parte JF (2007). "[Natalizumab in the treatment of multiple sclerosis]". Rev Neurol (in Spanish; Castilian) 45 (5): 293–303. PMID 17876741.

[40] Mullen JT, Vartanian TK, Atkins MB (2008). "Melanoma complicating treatment with natalizumab for multiple sclerosis". N. Engl. J. Med. 358 (6): 647–8. doi:10.1056/NEJMc0706103. PMID 18256405.

[pmid18389881-41] van Bronswijk H, Dubois EA, van Gerven JM, Cohen AF (2008). "[New drugs; natalizumab]". Ned Tijdschr Geneeskd (in Dutch; Flemish) 152 (9): 499–500. PMID 18389881.

[Rice2005-42] Rice GP, Hartung HP, Calabresi PA (2005). "Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale". Neurology 64 (8): 1336–42. doi:10.1212/01.WNL.0000158329.30470.D0. PMID 15851719.

[Tysabri_label-43] ^ ^a ^b ^c ^d ^e ^f "Final TYSABRI PI" (PDF). Retrieved 2008-03-13. ^{[dead link]}

[pmid18235044-44] Zohren F, Toutzaris D, Klarner V, Hartung HP, Kieseier B, Haas R (2008). "The monoclonal anti-VLA4 antibody natalizumab mobilizes CD34+ hematopoietic progenitor cells in humans". Blood 111 (7): 3893–5. doi:10.1182/blood-2007-10-120329. PMID 18235044.

[nejm-pml1-45] Kleinschmidt-DeMasters BK, Tyler KL (2005). "Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis". N. Engl. J. Med. 353 (4): 369–74. doi:10.1056/NEJMoa051782. PMID 15947079.

[nejm-pml2-46] Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D (2005). "Progressive multifocal leukoencephalopathy in a patient treated with natalizumab". N. Engl. J. Med. 353 (4): 375–81. doi:10.1056/NEJMoa051847. PMID 15947078.

[Van_Assche-47] Van Assche G, Van Ranst M, Sciot R, et al. (2005). "Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease". N. Engl. J. Med. 353 (4): 362–8. doi:10.1056/NEJMoa051586. PMID 15947080.

[Yousry-48] Yousry TA, Major EO, Ryschkewitsch C, et al. (2006). "Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy". N. Engl. J. Med. 354 (9): 924–33. doi:10.1056/NEJMoa054693. PMC 1934511. PMID 16510746.

[pmid17136224-49] Berger JR (2006). "Natalizumab". Drugs Today 42 (10): 639–55. doi:10.1358/dot.2006.42.10.1042190. PMID 17136224.

[pmid17521672-50] Ransohoff RM (2007). ""Thinking without thinking" about natalizumab and PML". J. Neurol. Sci. 259 (1–2): 50–2. doi:10.1016/j.jns.2006.04.011. PMID 17521672.

[pmid17122725-51] Aksamit AJ (2006). "Review of progressive multifocal leukoencephalopathy and natalizumab". Neurologist 12 (6): 293–8. doi:10.1097/01.nrl.0000250948.04681.96. PMID 17122725.

[WSJ08-52] Goldstein, Jacob (2008-08-01). "Brain Infections Return for Multiple Sclerosis Drug Tysabri". The Wall Street Journal. Retrieved 2008-08-01.

[pmid17434098-53] Kappos L, Bates D, Hartung HP, et al. (2007). "Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring". Lancet Neurol 6 (5): 431–41. doi:10.1016/S1474-4422(07)70078-9. PMID 17434098.

[NYT-54] Pollack, A (2006-03-09). "F.D.A. Panel Recommends M.S. Drug Despite Lethal Risk". The New York Times. Retrieved 2008-03-13.

[55] "Errata to FDA Background document for the Tysabri (natalizumab) Advisory Committee on July 31, 2007" (PDF). Food and Drug Administration. 2007-07-20. Retrieved 2008-03-09.

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natalizumab