A novel strategy to reduce the immunogenicity of biological therapies
Biological therapies, even humanized mAbs, may induce antiglobulin responses that impair efficacy. We tested a novel strategy to induce tolerance to a therapeutic mAb. Twenty patients with relapsing-remitting multiple sclerosis received an initial cycle of alemtuzumab (Campath-1H), up to 120 mg over...
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| Veröffentlicht in: | The Journal of immunology (1950) 2010-07, Vol.185 (1), p.763-768 |
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| container_title | The Journal of immunology (1950) |
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| creator | Somerfield, Jennifer Hill-Cawthorne, Grant A Lin, Andrew Zandi, Michael S McCarthy, Claire Jones, Joanne L Willcox, Michael Shaw, David Thompson, Sara A J Compston, Alastair S Hale, Geoff Waldmann, Herman Coles, Alasdair J |
| description | Biological therapies, even humanized mAbs, may induce antiglobulin responses that impair efficacy. We tested a novel strategy to induce tolerance to a therapeutic mAb. Twenty patients with relapsing-remitting multiple sclerosis received an initial cycle of alemtuzumab (Campath-1H), up to 120 mg over 5 d, preceded by 500 mg SM3. This Ab differs from alemtuzumab by a single point mutation and is designed not to bind to cells. Twelve months later, they received a second cycle of alemtuzumab, up to 72 mg over 3 d. One month after that, 4 of 19 (21%) patients had detectable serum anti-alemtuzumab Abs compared with 145 of 197 (74%) patients who received two cycles of alemtuzumab without SM3 in the phase 2 CAMMS223 trial (p < 0.001). The efficacy and safety profile of alemtuzumab was unaffected by SM3 pretreatment. Long-lasting "high-zone" tolerance to a biological therapy may be induced by pretreatment with a high i.v. dose of a drug variant, altered to reduce target-binding. |
| doi_str_mv | 10.4049/jimmunol.1000422 |
| format | Article |
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We tested a novel strategy to induce tolerance to a therapeutic mAb. Twenty patients with relapsing-remitting multiple sclerosis received an initial cycle of alemtuzumab (Campath-1H), up to 120 mg over 5 d, preceded by 500 mg SM3. This Ab differs from alemtuzumab by a single point mutation and is designed not to bind to cells. Twelve months later, they received a second cycle of alemtuzumab, up to 72 mg over 3 d. One month after that, 4 of 19 (21%) patients had detectable serum anti-alemtuzumab Abs compared with 145 of 197 (74%) patients who received two cycles of alemtuzumab without SM3 in the phase 2 CAMMS223 trial (p < 0.001). The efficacy and safety profile of alemtuzumab was unaffected by SM3 pretreatment. 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We tested a novel strategy to induce tolerance to a therapeutic mAb. Twenty patients with relapsing-remitting multiple sclerosis received an initial cycle of alemtuzumab (Campath-1H), up to 120 mg over 5 d, preceded by 500 mg SM3. This Ab differs from alemtuzumab by a single point mutation and is designed not to bind to cells. Twelve months later, they received a second cycle of alemtuzumab, up to 72 mg over 3 d. One month after that, 4 of 19 (21%) patients had detectable serum anti-alemtuzumab Abs compared with 145 of 197 (74%) patients who received two cycles of alemtuzumab without SM3 in the phase 2 CAMMS223 trial (p < 0.001). The efficacy and safety profile of alemtuzumab was unaffected by SM3 pretreatment. Long-lasting "high-zone" tolerance to a biological therapy may be induced by pretreatment with a high i.v. dose of a drug variant, altered to reduce target-binding.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Alemtuzumab</subject><subject>Amino Acid Substitution - genetics</subject><subject>Amino Acid Substitution - immunology</subject><subject>Antibodies, Anti-Idiotypic - biosynthesis</subject><subject>Antibodies, Anti-Idiotypic - blood</subject><subject>Antibodies, Monoclonal - genetics</subject><subject>Antibodies, Monoclonal - immunology</subject><subject>Antibodies, Monoclonal - therapeutic use</subject><subject>Antibodies, Monoclonal, Humanized</subject><subject>Antibodies, Neoplasm - genetics</subject><subject>Antibodies, Neoplasm - immunology</subject><subject>Antibodies, Neoplasm - therapeutic use</subject><subject>Dose-Response Relationship, Immunologic</subject><subject>Drug Administration Schedule</subject><subject>Female</subject><subject>Humans</subject><subject>Immune Tolerance</subject><subject>Magnetic Resonance Imaging</subject><subject>Male</subject><subject>Multiple Sclerosis, Relapsing-Remitting - diagnosis</subject><subject>Multiple Sclerosis, Relapsing-Remitting - immunology</subject><subject>Multiple Sclerosis, Relapsing-Remitting - therapy</subject><subject>Pilot Projects</subject><subject>Point Mutation - genetics</subject><subject>Point Mutation - immunology</subject><subject>Randomized Controlled Trials as Topic</subject><subject>Treatment Outcome</subject><subject>Young Adult</subject><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kMFOAjEURRujEUT3rkx_YPD1dVqmS0IQTUjc6HrSKW_GkhlK2sGEvxcy4Opu7rk3OYw9C5jmkJvXre-6wy60UwEAOeINGwulINMa9C0bAyBmYqZnI_aQ0vbU0YD5PRshKGG0EmO2nPNd-KWWpz7anpoj7wOPtDk44v0P8eGgoZ13vj_yUPPKhzY03tn2XIh27yk9srvatomeLjlh32_Lr8V7tv5cfSzm68yhKfoMFRamEqpwyhCaHAUoqmQha2lhg7YSMieriITTs5qs1qhlVRAV5BzVRk4YDLsuhpQi1eU--s7GYymgPBspr0bKi5ET8jIg-0PV0eYfuCqQf2KdX1s</recordid><startdate>20100701</startdate><enddate>20100701</enddate><creator>Somerfield, Jennifer</creator><creator>Hill-Cawthorne, Grant A</creator><creator>Lin, Andrew</creator><creator>Zandi, Michael S</creator><creator>McCarthy, Claire</creator><creator>Jones, Joanne L</creator><creator>Willcox, Michael</creator><creator>Shaw, David</creator><creator>Thompson, Sara A J</creator><creator>Compston, Alastair S</creator><creator>Hale, Geoff</creator><creator>Waldmann, Herman</creator><creator>Coles, Alasdair J</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20100701</creationdate><title>A novel strategy to reduce the immunogenicity of biological therapies</title><author>Somerfield, Jennifer ; Hill-Cawthorne, Grant A ; Lin, Andrew ; Zandi, Michael S ; McCarthy, Claire ; Jones, Joanne L ; Willcox, Michael ; Shaw, David ; Thompson, Sara A J ; Compston, Alastair S ; Hale, Geoff ; Waldmann, Herman ; Coles, Alasdair J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c298t-25289b158c59e2942105eb383f3a0d2ab134ea5ee1c67fea66263b8ee8eccef93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Alemtuzumab</topic><topic>Amino Acid Substitution - genetics</topic><topic>Amino Acid Substitution - immunology</topic><topic>Antibodies, Anti-Idiotypic - biosynthesis</topic><topic>Antibodies, Anti-Idiotypic - blood</topic><topic>Antibodies, Monoclonal - genetics</topic><topic>Antibodies, Monoclonal - immunology</topic><topic>Antibodies, Monoclonal - therapeutic use</topic><topic>Antibodies, Monoclonal, Humanized</topic><topic>Antibodies, Neoplasm - genetics</topic><topic>Antibodies, Neoplasm - immunology</topic><topic>Antibodies, Neoplasm - therapeutic use</topic><topic>Dose-Response Relationship, Immunologic</topic><topic>Drug Administration Schedule</topic><topic>Female</topic><topic>Humans</topic><topic>Immune Tolerance</topic><topic>Magnetic Resonance Imaging</topic><topic>Male</topic><topic>Multiple Sclerosis, Relapsing-Remitting - diagnosis</topic><topic>Multiple Sclerosis, Relapsing-Remitting - immunology</topic><topic>Multiple Sclerosis, Relapsing-Remitting - therapy</topic><topic>Pilot Projects</topic><topic>Point Mutation - genetics</topic><topic>Point Mutation - immunology</topic><topic>Randomized Controlled Trials as Topic</topic><topic>Treatment Outcome</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Somerfield, Jennifer</creatorcontrib><creatorcontrib>Hill-Cawthorne, Grant A</creatorcontrib><creatorcontrib>Lin, Andrew</creatorcontrib><creatorcontrib>Zandi, Michael S</creatorcontrib><creatorcontrib>McCarthy, Claire</creatorcontrib><creatorcontrib>Jones, Joanne L</creatorcontrib><creatorcontrib>Willcox, Michael</creatorcontrib><creatorcontrib>Shaw, David</creatorcontrib><creatorcontrib>Thompson, Sara A J</creatorcontrib><creatorcontrib>Compston, Alastair S</creatorcontrib><creatorcontrib>Hale, Geoff</creatorcontrib><creatorcontrib>Waldmann, Herman</creatorcontrib><creatorcontrib>Coles, Alasdair J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>The Journal of immunology (1950)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Somerfield, Jennifer</au><au>Hill-Cawthorne, Grant A</au><au>Lin, Andrew</au><au>Zandi, Michael S</au><au>McCarthy, Claire</au><au>Jones, Joanne L</au><au>Willcox, Michael</au><au>Shaw, David</au><au>Thompson, Sara A J</au><au>Compston, Alastair S</au><au>Hale, Geoff</au><au>Waldmann, Herman</au><au>Coles, Alasdair J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A novel strategy to reduce the immunogenicity of biological therapies</atitle><jtitle>The Journal of immunology (1950)</jtitle><addtitle>J Immunol</addtitle><date>2010-07-01</date><risdate>2010</risdate><volume>185</volume><issue>1</issue><spage>763</spage><epage>768</epage><pages>763-768</pages><issn>0022-1767</issn><eissn>1550-6606</eissn><abstract>Biological therapies, even humanized mAbs, may induce antiglobulin responses that impair efficacy. We tested a novel strategy to induce tolerance to a therapeutic mAb. Twenty patients with relapsing-remitting multiple sclerosis received an initial cycle of alemtuzumab (Campath-1H), up to 120 mg over 5 d, preceded by 500 mg SM3. This Ab differs from alemtuzumab by a single point mutation and is designed not to bind to cells. Twelve months later, they received a second cycle of alemtuzumab, up to 72 mg over 3 d. One month after that, 4 of 19 (21%) patients had detectable serum anti-alemtuzumab Abs compared with 145 of 197 (74%) patients who received two cycles of alemtuzumab without SM3 in the phase 2 CAMMS223 trial (p < 0.001). The efficacy and safety profile of alemtuzumab was unaffected by SM3 pretreatment. 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| ispartof | The Journal of immunology (1950), 2010-07, Vol.185 (1), p.763-768 |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Adolescent Adult Alemtuzumab Amino Acid Substitution - genetics Amino Acid Substitution - immunology Antibodies, Anti-Idiotypic - biosynthesis Antibodies, Anti-Idiotypic - blood Antibodies, Monoclonal - genetics Antibodies, Monoclonal - immunology Antibodies, Monoclonal - therapeutic use Antibodies, Monoclonal, Humanized Antibodies, Neoplasm - genetics Antibodies, Neoplasm - immunology Antibodies, Neoplasm - therapeutic use Dose-Response Relationship, Immunologic Drug Administration Schedule Female Humans Immune Tolerance Magnetic Resonance Imaging Male Multiple Sclerosis, Relapsing-Remitting - diagnosis Multiple Sclerosis, Relapsing-Remitting - immunology Multiple Sclerosis, Relapsing-Remitting - therapy Pilot Projects Point Mutation - genetics Point Mutation - immunology Randomized Controlled Trials as Topic Treatment Outcome Young Adult |
| title | A novel strategy to reduce the immunogenicity of biological therapies |
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