Effect of neutralizing antibodies on biomarker responses to interferon beta: The INSIGHT study

Interferon beta (IFNbeta) effectively reduces disease activity in patients with multiple sclerosis (MS). Neutralizing antibodies (NAbs) can diminish or abolish the clinical efficacy of IFNbeta therapies. Biomarkers of the IFNbeta response, such as myxovirus resistance protein A (MxA), viperin, and i...

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Veröffentlicht in:Neurology 2009-11, Vol.73 (18), p.1493-1500
Hauptverfasser: PACHNER, Andrew R, WARTH, John D, PACE, Amy, GOELZ, Susan
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creator PACHNER, Andrew R
WARTH, John D
PACE, Amy
GOELZ, Susan
description Interferon beta (IFNbeta) effectively reduces disease activity in patients with multiple sclerosis (MS). Neutralizing antibodies (NAbs) can diminish or abolish the clinical efficacy of IFNbeta therapies. Biomarkers of the IFNbeta response, such as myxovirus resistance protein A (MxA), viperin, and interferon-induced protein with tetratricopeptide repeats 1 (IFIT-1), may be used to measure the in vivo effects of NAbs on IFNbeta bioactivity. In this multicenter, open-label study, antibody status was measured at screening, and then antibody status, levels of MxA, viperin, and IFIT-1 were measured at baseline (< or =8 weeks after screening) and 6 months after baseline in patients with relapsing forms of MS treated with IM IFNbeta-1a, subcutaneous (SC) IFNbeta-1a, or IFNbeta-1b. Treatment with IM IFNbeta-1a was associated with a lower rate of NAb formation among 718 patients screened (p < 0.0001 vs SC IFNbeta-1a 22 microg, 44 microg, and IFNbeta-1b). At baseline, patients who were binding antibody positive (BAb+)/neutralizing antibody positive (NAb+) had lower MxA, viperin, and IFIT-1 response compared with BAb-negative (BAb-)/NAb-negative (NAb-) patients (all p < 0.0001). Analyses stratified by NAb titer level among BAb+/NAb+ patients showed diminished biomarker response in patients with NAb titers from 20 to 99 tenfold reduction units (TRU) and abolished response in patients with NAb titers > or =100 TRU compared with BAb-/NAb- patients. A majority of patients BAb+/NAb+ at screening remained BAb+/NAb+ throughout the study, and biomarker responses remained consistently depressed in these patients at month 6. These data provide evidence that high titers of neutralizing antibodies abolish the in vivo response to interferon beta.
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Neutralizing antibodies (NAbs) can diminish or abolish the clinical efficacy of IFNbeta therapies. Biomarkers of the IFNbeta response, such as myxovirus resistance protein A (MxA), viperin, and interferon-induced protein with tetratricopeptide repeats 1 (IFIT-1), may be used to measure the in vivo effects of NAbs on IFNbeta bioactivity. In this multicenter, open-label study, antibody status was measured at screening, and then antibody status, levels of MxA, viperin, and IFIT-1 were measured at baseline (&lt; or =8 weeks after screening) and 6 months after baseline in patients with relapsing forms of MS treated with IM IFNbeta-1a, subcutaneous (SC) IFNbeta-1a, or IFNbeta-1b. Treatment with IM IFNbeta-1a was associated with a lower rate of NAb formation among 718 patients screened (p &lt; 0.0001 vs SC IFNbeta-1a 22 microg, 44 microg, and IFNbeta-1b). At baseline, patients who were binding antibody positive (BAb+)/neutralizing antibody positive (NAb+) had lower MxA, viperin, and IFIT-1 response compared with BAb-negative (BAb-)/NAb-negative (NAb-) patients (all p &lt; 0.0001). Analyses stratified by NAb titer level among BAb+/NAb+ patients showed diminished biomarker response in patients with NAb titers from 20 to 99 tenfold reduction units (TRU) and abolished response in patients with NAb titers &gt; or =100 TRU compared with BAb-/NAb- patients. A majority of patients BAb+/NAb+ at screening remained BAb+/NAb+ throughout the study, and biomarker responses remained consistently depressed in these patients at month 6. 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Neutralizing antibodies (NAbs) can diminish or abolish the clinical efficacy of IFNbeta therapies. Biomarkers of the IFNbeta response, such as myxovirus resistance protein A (MxA), viperin, and interferon-induced protein with tetratricopeptide repeats 1 (IFIT-1), may be used to measure the in vivo effects of NAbs on IFNbeta bioactivity. In this multicenter, open-label study, antibody status was measured at screening, and then antibody status, levels of MxA, viperin, and IFIT-1 were measured at baseline (&lt; or =8 weeks after screening) and 6 months after baseline in patients with relapsing forms of MS treated with IM IFNbeta-1a, subcutaneous (SC) IFNbeta-1a, or IFNbeta-1b. Treatment with IM IFNbeta-1a was associated with a lower rate of NAb formation among 718 patients screened (p &lt; 0.0001 vs SC IFNbeta-1a 22 microg, 44 microg, and IFNbeta-1b). At baseline, patients who were binding antibody positive (BAb+)/neutralizing antibody positive (NAb+) had lower MxA, viperin, and IFIT-1 response compared with BAb-negative (BAb-)/NAb-negative (NAb-) patients (all p &lt; 0.0001). Analyses stratified by NAb titer level among BAb+/NAb+ patients showed diminished biomarker response in patients with NAb titers from 20 to 99 tenfold reduction units (TRU) and abolished response in patients with NAb titers &gt; or =100 TRU compared with BAb-/NAb- patients. A majority of patients BAb+/NAb+ at screening remained BAb+/NAb+ throughout the study, and biomarker responses remained consistently depressed in these patients at month 6. These data provide evidence that high titers of neutralizing antibodies abolish the in vivo response to interferon beta.</description><subject>Adult</subject><subject>Antibodies - immunology</subject><subject>Biological and medical sciences</subject><subject>Biomarkers - blood</subject><subject>Carrier Proteins - blood</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Female</subject><subject>GTP-Binding Proteins - blood</subject><subject>Humans</subject><subject>Immunologic Factors - therapeutic use</subject><subject>Immunomodulators</subject><subject>Interferon-beta - immunology</subject><subject>Interferon-beta - therapeutic use</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Multiple Sclerosis - blood</subject><subject>Multiple Sclerosis - drug therapy</subject><subject>Multiple Sclerosis - immunology</subject><subject>Myxovirus Resistance Proteins</subject><subject>Neurology</subject><subject>Pharmacology. 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Drug treatments</topic><topic>Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>PACHNER, Andrew R</creatorcontrib><creatorcontrib>WARTH, John D</creatorcontrib><creatorcontrib>PACE, Amy</creatorcontrib><creatorcontrib>GOELZ, Susan</creatorcontrib><creatorcontrib>INSIGHT investigators</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>Neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>PACHNER, Andrew R</au><au>WARTH, John D</au><au>PACE, Amy</au><au>GOELZ, Susan</au><aucorp>INSIGHT investigators</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effect of neutralizing antibodies on biomarker responses to interferon beta: The INSIGHT study</atitle><jtitle>Neurology</jtitle><addtitle>Neurology</addtitle><date>2009-11-03</date><risdate>2009</risdate><volume>73</volume><issue>18</issue><spage>1493</spage><epage>1500</epage><pages>1493-1500</pages><issn>0028-3878</issn><eissn>1526-632X</eissn><coden>NEURAI</coden><abstract>Interferon beta (IFNbeta) effectively reduces disease activity in patients with multiple sclerosis (MS). Neutralizing antibodies (NAbs) can diminish or abolish the clinical efficacy of IFNbeta therapies. Biomarkers of the IFNbeta response, such as myxovirus resistance protein A (MxA), viperin, and interferon-induced protein with tetratricopeptide repeats 1 (IFIT-1), may be used to measure the in vivo effects of NAbs on IFNbeta bioactivity. In this multicenter, open-label study, antibody status was measured at screening, and then antibody status, levels of MxA, viperin, and IFIT-1 were measured at baseline (&lt; or =8 weeks after screening) and 6 months after baseline in patients with relapsing forms of MS treated with IM IFNbeta-1a, subcutaneous (SC) IFNbeta-1a, or IFNbeta-1b. Treatment with IM IFNbeta-1a was associated with a lower rate of NAb formation among 718 patients screened (p &lt; 0.0001 vs SC IFNbeta-1a 22 microg, 44 microg, and IFNbeta-1b). At baseline, patients who were binding antibody positive (BAb+)/neutralizing antibody positive (NAb+) had lower MxA, viperin, and IFIT-1 response compared with BAb-negative (BAb-)/NAb-negative (NAb-) patients (all p &lt; 0.0001). Analyses stratified by NAb titer level among BAb+/NAb+ patients showed diminished biomarker response in patients with NAb titers from 20 to 99 tenfold reduction units (TRU) and abolished response in patients with NAb titers &gt; or =100 TRU compared with BAb-/NAb- patients. A majority of patients BAb+/NAb+ at screening remained BAb+/NAb+ throughout the study, and biomarker responses remained consistently depressed in these patients at month 6. These data provide evidence that high titers of neutralizing antibodies abolish the in vivo response to interferon beta.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott Williams &amp; Wilkins</pub><pmid>19884577</pmid><doi>10.1212/WNL.0b013e3181bf98db</doi><tpages>8</tpages></addata></record>
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subjects Adult
Antibodies - immunology
Biological and medical sciences
Biomarkers - blood
Carrier Proteins - blood
Enzyme-Linked Immunosorbent Assay
Female
GTP-Binding Proteins - blood
Humans
Immunologic Factors - therapeutic use
Immunomodulators
Interferon-beta - immunology
Interferon-beta - therapeutic use
Male
Medical sciences
Middle Aged
Multiple Sclerosis - blood
Multiple Sclerosis - drug therapy
Multiple Sclerosis - immunology
Myxovirus Resistance Proteins
Neurology
Pharmacology. Drug treatments
Proteins - metabolism
title Effect of neutralizing antibodies on biomarker responses to interferon beta: The INSIGHT study
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