Rationally Engineered Therapeutic Proteins with Reduced Immunogenicity
Chronic administration of protein therapeutics may elicit unacceptable immune responses to the specific protein. Our hypothesis is that the immunogenicity of protein drugs can be ascribed to a few immunodominant helper T lymphocyte (HTL) epitopes, and that reducing the MHC binding affinity of these...
Gespeichert in:
| Veröffentlicht in: | The Journal of immunology (1950) 2005-03, Vol.174 (6), p.3187-3196 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 3196 |
|---|---|
| container_issue | 6 |
| container_start_page | 3187 |
| container_title | The Journal of immunology (1950) |
| container_volume | 174 |
| creator | Tangri, Shabnam Mothe, Bianca R Eisenbraun, Julie Sidney, John Southwood, Scott Briggs, Kristen Zinckgraf, John Bilsel, Pamuk Newman, Mark Chesnut, Robert LiCalsi, Cynthia Sette, Alessandro |
| description | Chronic administration of protein therapeutics may elicit unacceptable immune responses to the specific protein. Our hypothesis is that the immunogenicity of protein drugs can be ascribed to a few immunodominant helper T lymphocyte (HTL) epitopes, and that reducing the MHC binding affinity of these HTL epitopes contained within these proteins can generate drugs with lower immunogenicity. To test this hypothesis, we studied the protein therapeutic erythropoietin (Epo). Two regions within Epo, designated Epo 91-120 and Epo 126-155, contained HTL epitopes that were recognized by individuals with numerous HLA-DR types, a property common to immunodominant HTL epitopes. We then engineered analog epitopes with reduced HLA binding affinity. These analog epitopes were associated with reduced in vitro immunogenicity. Two modified forms of Epo containing these substitutions were shown to be bioactive and nonimmunogenic in vitro. These findings support our hypothesis and demonstrate that immunogenicity of protein drugs can be reduced in a systematic and predictable manner. |
| doi_str_mv | 10.4049/jimmunol.174.6.3187 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_67486813</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>17817128</sourcerecordid><originalsourceid>FETCH-LOGICAL-c366t-4565c44745a5016b4c9a22e119d382194b81e0ddec7e37419f423dd535e6d0183</originalsourceid><addsrcrecordid>eNqFkEtLw0AURgdRtD5-gSBZ6Sp1buaZpUh9gKCUuh7Smdt2JI86kxD6701tRXeu7uZ858Ih5BLomFOe3374qurqphyD4mM5ZqDVARmBEDSVkspDMqI0y1JQUp2Q0xg_KKWSZvyYnIBQPNdcj8jDtGh9UxdluUkm9dLXiAFdMlthKNbYtd4mb6Fp0dcx6X27SqboOjsQz9_Pl1h769vNOTlaFGXEi_09I-8Pk9n9U_ry-vh8f_eSWiZlm3IhheVccVEICnLObV5kGQLkjukMcj7XgNQ5tAqZ4pAveMacE0ygdBQ0OyPXO-86NJ8dxtZUPlosy6LGpotGKq6lBvYvCEqDgmxrZDvQhibGgAuzDr4qwsYANdvO5qfzsOFGmm3nYXW113fzCt3vZh92AG52wMovV70PaGI1RB5wMH3f_1F9AbtZiK0</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>17817128</pqid></control><display><type>article</type><title>Rationally Engineered Therapeutic Proteins with Reduced Immunogenicity</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><creator>Tangri, Shabnam ; Mothe, Bianca R ; Eisenbraun, Julie ; Sidney, John ; Southwood, Scott ; Briggs, Kristen ; Zinckgraf, John ; Bilsel, Pamuk ; Newman, Mark ; Chesnut, Robert ; LiCalsi, Cynthia ; Sette, Alessandro</creator><creatorcontrib>Tangri, Shabnam ; Mothe, Bianca R ; Eisenbraun, Julie ; Sidney, John ; Southwood, Scott ; Briggs, Kristen ; Zinckgraf, John ; Bilsel, Pamuk ; Newman, Mark ; Chesnut, Robert ; LiCalsi, Cynthia ; Sette, Alessandro</creatorcontrib><description>Chronic administration of protein therapeutics may elicit unacceptable immune responses to the specific protein. Our hypothesis is that the immunogenicity of protein drugs can be ascribed to a few immunodominant helper T lymphocyte (HTL) epitopes, and that reducing the MHC binding affinity of these HTL epitopes contained within these proteins can generate drugs with lower immunogenicity. To test this hypothesis, we studied the protein therapeutic erythropoietin (Epo). Two regions within Epo, designated Epo 91-120 and Epo 126-155, contained HTL epitopes that were recognized by individuals with numerous HLA-DR types, a property common to immunodominant HTL epitopes. We then engineered analog epitopes with reduced HLA binding affinity. These analog epitopes were associated with reduced in vitro immunogenicity. Two modified forms of Epo containing these substitutions were shown to be bioactive and nonimmunogenic in vitro. These findings support our hypothesis and demonstrate that immunogenicity of protein drugs can be reduced in a systematic and predictable manner.</description><identifier>ISSN: 0022-1767</identifier><identifier>EISSN: 1550-6606</identifier><identifier>DOI: 10.4049/jimmunol.174.6.3187</identifier><identifier>PMID: 15749848</identifier><language>eng</language><publisher>United States: Am Assoc Immnol</publisher><subject>Amino Acid Sequence ; Erythropoietin - chemistry ; Erythropoietin - genetics ; Erythropoietin - immunology ; Erythropoietin - metabolism ; HLA-DR Antigens - metabolism ; Humans ; Immunodominant Epitopes - chemistry ; Immunodominant Epitopes - genetics ; In Vitro Techniques ; Models, Molecular ; Molecular Sequence Data ; Protein Binding ; Protein Engineering - methods ; Recombinant Proteins - chemistry ; Recombinant Proteins - genetics ; Recombinant Proteins - immunology ; Recombinant Proteins - metabolism ; T-Lymphocytes, Helper-Inducer - immunology</subject><ispartof>The Journal of immunology (1950), 2005-03, Vol.174 (6), p.3187-3196</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c366t-4565c44745a5016b4c9a22e119d382194b81e0ddec7e37419f423dd535e6d0183</citedby><cites>FETCH-LOGICAL-c366t-4565c44745a5016b4c9a22e119d382194b81e0ddec7e37419f423dd535e6d0183</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15749848$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tangri, Shabnam</creatorcontrib><creatorcontrib>Mothe, Bianca R</creatorcontrib><creatorcontrib>Eisenbraun, Julie</creatorcontrib><creatorcontrib>Sidney, John</creatorcontrib><creatorcontrib>Southwood, Scott</creatorcontrib><creatorcontrib>Briggs, Kristen</creatorcontrib><creatorcontrib>Zinckgraf, John</creatorcontrib><creatorcontrib>Bilsel, Pamuk</creatorcontrib><creatorcontrib>Newman, Mark</creatorcontrib><creatorcontrib>Chesnut, Robert</creatorcontrib><creatorcontrib>LiCalsi, Cynthia</creatorcontrib><creatorcontrib>Sette, Alessandro</creatorcontrib><title>Rationally Engineered Therapeutic Proteins with Reduced Immunogenicity</title><title>The Journal of immunology (1950)</title><addtitle>J Immunol</addtitle><description>Chronic administration of protein therapeutics may elicit unacceptable immune responses to the specific protein. Our hypothesis is that the immunogenicity of protein drugs can be ascribed to a few immunodominant helper T lymphocyte (HTL) epitopes, and that reducing the MHC binding affinity of these HTL epitopes contained within these proteins can generate drugs with lower immunogenicity. To test this hypothesis, we studied the protein therapeutic erythropoietin (Epo). Two regions within Epo, designated Epo 91-120 and Epo 126-155, contained HTL epitopes that were recognized by individuals with numerous HLA-DR types, a property common to immunodominant HTL epitopes. We then engineered analog epitopes with reduced HLA binding affinity. These analog epitopes were associated with reduced in vitro immunogenicity. Two modified forms of Epo containing these substitutions were shown to be bioactive and nonimmunogenic in vitro. These findings support our hypothesis and demonstrate that immunogenicity of protein drugs can be reduced in a systematic and predictable manner.</description><subject>Amino Acid Sequence</subject><subject>Erythropoietin - chemistry</subject><subject>Erythropoietin - genetics</subject><subject>Erythropoietin - immunology</subject><subject>Erythropoietin - metabolism</subject><subject>HLA-DR Antigens - metabolism</subject><subject>Humans</subject><subject>Immunodominant Epitopes - chemistry</subject><subject>Immunodominant Epitopes - genetics</subject><subject>In Vitro Techniques</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>Protein Binding</subject><subject>Protein Engineering - methods</subject><subject>Recombinant Proteins - chemistry</subject><subject>Recombinant Proteins - genetics</subject><subject>Recombinant Proteins - immunology</subject><subject>Recombinant Proteins - metabolism</subject><subject>T-Lymphocytes, Helper-Inducer - immunology</subject><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkEtLw0AURgdRtD5-gSBZ6Sp1buaZpUh9gKCUuh7Smdt2JI86kxD6701tRXeu7uZ858Ih5BLomFOe3374qurqphyD4mM5ZqDVARmBEDSVkspDMqI0y1JQUp2Q0xg_KKWSZvyYnIBQPNdcj8jDtGh9UxdluUkm9dLXiAFdMlthKNbYtd4mb6Fp0dcx6X27SqboOjsQz9_Pl1h769vNOTlaFGXEi_09I-8Pk9n9U_ry-vh8f_eSWiZlm3IhheVccVEICnLObV5kGQLkjukMcj7XgNQ5tAqZ4pAveMacE0ygdBQ0OyPXO-86NJ8dxtZUPlosy6LGpotGKq6lBvYvCEqDgmxrZDvQhibGgAuzDr4qwsYANdvO5qfzsOFGmm3nYXW113fzCt3vZh92AG52wMovV70PaGI1RB5wMH3f_1F9AbtZiK0</recordid><startdate>20050315</startdate><enddate>20050315</enddate><creator>Tangri, Shabnam</creator><creator>Mothe, Bianca R</creator><creator>Eisenbraun, Julie</creator><creator>Sidney, John</creator><creator>Southwood, Scott</creator><creator>Briggs, Kristen</creator><creator>Zinckgraf, John</creator><creator>Bilsel, Pamuk</creator><creator>Newman, Mark</creator><creator>Chesnut, Robert</creator><creator>LiCalsi, Cynthia</creator><creator>Sette, Alessandro</creator><general>Am Assoc Immnol</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7T5</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20050315</creationdate><title>Rationally Engineered Therapeutic Proteins with Reduced Immunogenicity</title><author>Tangri, Shabnam ; Mothe, Bianca R ; Eisenbraun, Julie ; Sidney, John ; Southwood, Scott ; Briggs, Kristen ; Zinckgraf, John ; Bilsel, Pamuk ; Newman, Mark ; Chesnut, Robert ; LiCalsi, Cynthia ; Sette, Alessandro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c366t-4565c44745a5016b4c9a22e119d382194b81e0ddec7e37419f423dd535e6d0183</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Amino Acid Sequence</topic><topic>Erythropoietin - chemistry</topic><topic>Erythropoietin - genetics</topic><topic>Erythropoietin - immunology</topic><topic>Erythropoietin - metabolism</topic><topic>HLA-DR Antigens - metabolism</topic><topic>Humans</topic><topic>Immunodominant Epitopes - chemistry</topic><topic>Immunodominant Epitopes - genetics</topic><topic>In Vitro Techniques</topic><topic>Models, Molecular</topic><topic>Molecular Sequence Data</topic><topic>Protein Binding</topic><topic>Protein Engineering - methods</topic><topic>Recombinant Proteins - chemistry</topic><topic>Recombinant Proteins - genetics</topic><topic>Recombinant Proteins - immunology</topic><topic>Recombinant Proteins - metabolism</topic><topic>T-Lymphocytes, Helper-Inducer - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tangri, Shabnam</creatorcontrib><creatorcontrib>Mothe, Bianca R</creatorcontrib><creatorcontrib>Eisenbraun, Julie</creatorcontrib><creatorcontrib>Sidney, John</creatorcontrib><creatorcontrib>Southwood, Scott</creatorcontrib><creatorcontrib>Briggs, Kristen</creatorcontrib><creatorcontrib>Zinckgraf, John</creatorcontrib><creatorcontrib>Bilsel, Pamuk</creatorcontrib><creatorcontrib>Newman, Mark</creatorcontrib><creatorcontrib>Chesnut, Robert</creatorcontrib><creatorcontrib>LiCalsi, Cynthia</creatorcontrib><creatorcontrib>Sette, Alessandro</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of immunology (1950)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tangri, Shabnam</au><au>Mothe, Bianca R</au><au>Eisenbraun, Julie</au><au>Sidney, John</au><au>Southwood, Scott</au><au>Briggs, Kristen</au><au>Zinckgraf, John</au><au>Bilsel, Pamuk</au><au>Newman, Mark</au><au>Chesnut, Robert</au><au>LiCalsi, Cynthia</au><au>Sette, Alessandro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rationally Engineered Therapeutic Proteins with Reduced Immunogenicity</atitle><jtitle>The Journal of immunology (1950)</jtitle><addtitle>J Immunol</addtitle><date>2005-03-15</date><risdate>2005</risdate><volume>174</volume><issue>6</issue><spage>3187</spage><epage>3196</epage><pages>3187-3196</pages><issn>0022-1767</issn><eissn>1550-6606</eissn><abstract>Chronic administration of protein therapeutics may elicit unacceptable immune responses to the specific protein. Our hypothesis is that the immunogenicity of protein drugs can be ascribed to a few immunodominant helper T lymphocyte (HTL) epitopes, and that reducing the MHC binding affinity of these HTL epitopes contained within these proteins can generate drugs with lower immunogenicity. To test this hypothesis, we studied the protein therapeutic erythropoietin (Epo). Two regions within Epo, designated Epo 91-120 and Epo 126-155, contained HTL epitopes that were recognized by individuals with numerous HLA-DR types, a property common to immunodominant HTL epitopes. We then engineered analog epitopes with reduced HLA binding affinity. These analog epitopes were associated with reduced in vitro immunogenicity. Two modified forms of Epo containing these substitutions were shown to be bioactive and nonimmunogenic in vitro. These findings support our hypothesis and demonstrate that immunogenicity of protein drugs can be reduced in a systematic and predictable manner.</abstract><cop>United States</cop><pub>Am Assoc Immnol</pub><pmid>15749848</pmid><doi>10.4049/jimmunol.174.6.3187</doi><tpages>10</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-1767 |
| ispartof | The Journal of immunology (1950), 2005-03, Vol.174 (6), p.3187-3196 |
| issn | 0022-1767 1550-6606 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_67486813 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Amino Acid Sequence Erythropoietin - chemistry Erythropoietin - genetics Erythropoietin - immunology Erythropoietin - metabolism HLA-DR Antigens - metabolism Humans Immunodominant Epitopes - chemistry Immunodominant Epitopes - genetics In Vitro Techniques Models, Molecular Molecular Sequence Data Protein Binding Protein Engineering - methods Recombinant Proteins - chemistry Recombinant Proteins - genetics Recombinant Proteins - immunology Recombinant Proteins - metabolism T-Lymphocytes, Helper-Inducer - immunology |
| title | Rationally Engineered Therapeutic Proteins with Reduced Immunogenicity |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-02T16%3A34%3A10IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Rationally%20Engineered%20Therapeutic%20Proteins%20with%20Reduced%20Immunogenicity&rft.jtitle=The%20Journal%20of%20immunology%20(1950)&rft.au=Tangri,%20Shabnam&rft.date=2005-03-15&rft.volume=174&rft.issue=6&rft.spage=3187&rft.epage=3196&rft.pages=3187-3196&rft.issn=0022-1767&rft.eissn=1550-6606&rft_id=info:doi/10.4049/jimmunol.174.6.3187&rft_dat=%3Cproquest_cross%3E17817128%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=17817128&rft_id=info:pmid/15749848&rfr_iscdi=true |