immunotoxin with greatly reduced immunogenicity by identification and removal of B cell epitopes
Recombinant immunotoxins are hybrid proteins composed of an Fv that binds to a tumor antigen fused to a bacterial or plant toxin. Immunotoxin BL22 targets CD22 positive malignancies and is composed of an anti-CD22 Fv fused to a 38-kDa fragment of Pseudomonas exotoxin A (PE38). BL22 has produced many...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2008-08, Vol.105 (32), p.11311-11316 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Onda, Masanori Beers, Richard Xiang, Laiman Nagata, Satoshi Wang, Qing-cheng Pastan, Ira |
| description | Recombinant immunotoxins are hybrid proteins composed of an Fv that binds to a tumor antigen fused to a bacterial or plant toxin. Immunotoxin BL22 targets CD22 positive malignancies and is composed of an anti-CD22 Fv fused to a 38-kDa fragment of Pseudomonas exotoxin A (PE38). BL22 has produced many complete remissions in drug-resistant Hairy cell leukemia, where many treatment cycles can be given, because neutralizing antibodies do not form. In marked contrast, only minor responses have been observed in trials with immunotoxins targeting solid tumors, because only a single treatment cycle can be given before antibodies develop. To allow more treatment cycles and increase efficacy, we have produced a less immunogenic immunotoxin by identifying and eliminating most of the B cell epitopes on PE38. This was accomplished by mutation of specific large hydrophilic amino acids (Arg, Gln, Glu, Lys) to Ala, Ser, or Gly. The new immunotoxin (HA22-8X) is significantly less immunogenic in three strains of mice, yet retains full cytotoxic and anti-tumor activities. Elimination of B-cell epitopes is a promising approach to the production of less immunogenic proteins for therapeutic purposes. |
| doi_str_mv | 10.1073/pnas.0804851105 |
| format | Article |
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Immunotoxin BL22 targets CD22 positive malignancies and is composed of an anti-CD22 Fv fused to a 38-kDa fragment of Pseudomonas exotoxin A (PE38). BL22 has produced many complete remissions in drug-resistant Hairy cell leukemia, where many treatment cycles can be given, because neutralizing antibodies do not form. In marked contrast, only minor responses have been observed in trials with immunotoxins targeting solid tumors, because only a single treatment cycle can be given before antibodies develop. To allow more treatment cycles and increase efficacy, we have produced a less immunogenic immunotoxin by identifying and eliminating most of the B cell epitopes on PE38. This was accomplished by mutation of specific large hydrophilic amino acids (Arg, Gln, Glu, Lys) to Ala, Ser, or Gly. The new immunotoxin (HA22-8X) is significantly less immunogenic in three strains of mice, yet retains full cytotoxic and anti-tumor activities. Elimination of B-cell epitopes is a promising approach to the production of less immunogenic proteins for therapeutic purposes.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0804851105</identifier><identifier>PMID: 18678888</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>ADP Ribose Transferases - genetics ; ADP Ribose Transferases - immunology ; ADP Ribose Transferases - therapeutic use ; Amino Acid Substitution - immunology ; Amino acids ; Animals ; Antibodies ; Antibodies - genetics ; Antibodies - immunology ; Antibodies - therapeutic use ; Antigens ; B lymphocyte epitopes ; B lymphocytes ; Bacterial Toxins - genetics ; Bacterial Toxins - immunology ; Bacterial Toxins - therapeutic use ; Biological Sciences ; Cells ; Drug resistance ; Drug Resistance, Neoplasm - drug effects ; Drug Resistance, Neoplasm - immunology ; Enterotoxins - genetics ; Enterotoxins - immunology ; Enterotoxins - therapeutic use ; Epitopes ; Epitopes, B-Lymphocyte - genetics ; Epitopes, B-Lymphocyte - immunology ; Exotoxins - genetics ; Exotoxins - immunology ; Exotoxins - therapeutic use ; Humans ; Immune response ; Immunization ; Immunotoxins ; Leukemia, Hairy Cell - drug therapy ; Leukemia, Hairy Cell - immunology ; Mice ; Mice, Inbred BALB C ; Mice, SCID ; Mutation, Missense - immunology ; Proteins ; Pseudomonas ; Pseudomonas aeruginosa Exotoxin A ; Rabbits ; Reactivity ; Recombinant Fusion Proteins - genetics ; Recombinant Fusion Proteins - immunology ; Recombinant Fusion Proteins - therapeutic use ; Tumors ; Virulence Factors - genetics ; Virulence Factors - immunology ; Virulence Factors - therapeutic use</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2008-08, Vol.105 (32), p.11311-11316</ispartof><rights>Copyright 2008 The National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Aug 12, 2008</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c554t-be031ceef6b7c4443198a481b259935b32e6c136cac7d0cd9acfbade4524936c3</citedby><cites>FETCH-LOGICAL-c554t-be031ceef6b7c4443198a481b259935b32e6c136cac7d0cd9acfbade4524936c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/105/32.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/25463335$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/25463335$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18678888$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Onda, Masanori</creatorcontrib><creatorcontrib>Beers, Richard</creatorcontrib><creatorcontrib>Xiang, Laiman</creatorcontrib><creatorcontrib>Nagata, Satoshi</creatorcontrib><creatorcontrib>Wang, Qing-cheng</creatorcontrib><creatorcontrib>Pastan, Ira</creatorcontrib><title>immunotoxin with greatly reduced immunogenicity by identification and removal of B cell epitopes</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Recombinant immunotoxins are hybrid proteins composed of an Fv that binds to a tumor antigen fused to a bacterial or plant toxin. Immunotoxin BL22 targets CD22 positive malignancies and is composed of an anti-CD22 Fv fused to a 38-kDa fragment of Pseudomonas exotoxin A (PE38). BL22 has produced many complete remissions in drug-resistant Hairy cell leukemia, where many treatment cycles can be given, because neutralizing antibodies do not form. In marked contrast, only minor responses have been observed in trials with immunotoxins targeting solid tumors, because only a single treatment cycle can be given before antibodies develop. To allow more treatment cycles and increase efficacy, we have produced a less immunogenic immunotoxin by identifying and eliminating most of the B cell epitopes on PE38. This was accomplished by mutation of specific large hydrophilic amino acids (Arg, Gln, Glu, Lys) to Ala, Ser, or Gly. The new immunotoxin (HA22-8X) is significantly less immunogenic in three strains of mice, yet retains full cytotoxic and anti-tumor activities. Elimination of B-cell epitopes is a promising approach to the production of less immunogenic proteins for therapeutic purposes.</description><subject>ADP Ribose Transferases - genetics</subject><subject>ADP Ribose Transferases - immunology</subject><subject>ADP Ribose Transferases - therapeutic use</subject><subject>Amino Acid Substitution - immunology</subject><subject>Amino acids</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antibodies - genetics</subject><subject>Antibodies - immunology</subject><subject>Antibodies - therapeutic use</subject><subject>Antigens</subject><subject>B lymphocyte epitopes</subject><subject>B lymphocytes</subject><subject>Bacterial Toxins - genetics</subject><subject>Bacterial Toxins - immunology</subject><subject>Bacterial Toxins - therapeutic use</subject><subject>Biological Sciences</subject><subject>Cells</subject><subject>Drug resistance</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Drug Resistance, Neoplasm - immunology</subject><subject>Enterotoxins - genetics</subject><subject>Enterotoxins - immunology</subject><subject>Enterotoxins - therapeutic use</subject><subject>Epitopes</subject><subject>Epitopes, B-Lymphocyte - genetics</subject><subject>Epitopes, B-Lymphocyte - immunology</subject><subject>Exotoxins - genetics</subject><subject>Exotoxins - immunology</subject><subject>Exotoxins - therapeutic use</subject><subject>Humans</subject><subject>Immune response</subject><subject>Immunization</subject><subject>Immunotoxins</subject><subject>Leukemia, Hairy Cell - drug therapy</subject><subject>Leukemia, Hairy Cell - immunology</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, SCID</subject><subject>Mutation, Missense - immunology</subject><subject>Proteins</subject><subject>Pseudomonas</subject><subject>Pseudomonas aeruginosa Exotoxin A</subject><subject>Rabbits</subject><subject>Reactivity</subject><subject>Recombinant Fusion Proteins - genetics</subject><subject>Recombinant Fusion Proteins - immunology</subject><subject>Recombinant Fusion Proteins - therapeutic use</subject><subject>Tumors</subject><subject>Virulence Factors - genetics</subject><subject>Virulence Factors - immunology</subject><subject>Virulence Factors - therapeutic use</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkktv1DAUhS1ERacDa1aA1QUSi7R-Js4GCSqglSqxgK6N4zhTjxI7tZ3S-fc4yqgDbGpZsuT73aNzfA3Aa4zOMKro-ehUPEMCMcExRvwZWGFU46JkNXoOVgiRqhCMsGNwEuMWIVRzgV6AYyzKSuS1Ar_sMEzOJ_9gHfxt0y3cBKNSv4PBtJM2LVyAjXFW27SDzQ7a1rhkO6tVst5B5doMD_5e9dB38DPUpu-hGW3yo4kvwVGn-mhe7c81uPn65efFZXH9_dvVxafrQnPOUtEYRLE2piubSjPGKK6FYgI3hNc15Q0lptSYllrpqkW6rZXuGtUaxgmr8zVdg4-L7jg1g2l1thhUL8dgBxV20isr_604eys3_l4SjktCaBZ4vxcI_m4yMcnBxjmKcsZPURI0v1hNMnj6H7j1U3A5XGYwrbigs9r5AungYwyme3SCkZxHJ-fRycPocsfbvwMc-P2sMgD3wNx5kOOSEokxzXsNPjyByG7q-2QeUmbfLOw2Jh8eYcJZmf3Pft4t9U55qTbBRnnzYw6YfxHhgiD6B_RMwtg</recordid><startdate>20080812</startdate><enddate>20080812</enddate><creator>Onda, Masanori</creator><creator>Beers, Richard</creator><creator>Xiang, Laiman</creator><creator>Nagata, Satoshi</creator><creator>Wang, Qing-cheng</creator><creator>Pastan, Ira</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20080812</creationdate><title>immunotoxin with greatly reduced immunogenicity by identification and removal of B cell epitopes</title><author>Onda, Masanori ; 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Immunotoxin BL22 targets CD22 positive malignancies and is composed of an anti-CD22 Fv fused to a 38-kDa fragment of Pseudomonas exotoxin A (PE38). BL22 has produced many complete remissions in drug-resistant Hairy cell leukemia, where many treatment cycles can be given, because neutralizing antibodies do not form. In marked contrast, only minor responses have been observed in trials with immunotoxins targeting solid tumors, because only a single treatment cycle can be given before antibodies develop. To allow more treatment cycles and increase efficacy, we have produced a less immunogenic immunotoxin by identifying and eliminating most of the B cell epitopes on PE38. This was accomplished by mutation of specific large hydrophilic amino acids (Arg, Gln, Glu, Lys) to Ala, Ser, or Gly. The new immunotoxin (HA22-8X) is significantly less immunogenic in three strains of mice, yet retains full cytotoxic and anti-tumor activities. Elimination of B-cell epitopes is a promising approach to the production of less immunogenic proteins for therapeutic purposes.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>18678888</pmid><doi>10.1073/pnas.0804851105</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | ADP Ribose Transferases - genetics ADP Ribose Transferases - immunology ADP Ribose Transferases - therapeutic use Amino Acid Substitution - immunology Amino acids Animals Antibodies Antibodies - genetics Antibodies - immunology Antibodies - therapeutic use Antigens B lymphocyte epitopes B lymphocytes Bacterial Toxins - genetics Bacterial Toxins - immunology Bacterial Toxins - therapeutic use Biological Sciences Cells Drug resistance Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - immunology Enterotoxins - genetics Enterotoxins - immunology Enterotoxins - therapeutic use Epitopes Epitopes, B-Lymphocyte - genetics Epitopes, B-Lymphocyte - immunology Exotoxins - genetics Exotoxins - immunology Exotoxins - therapeutic use Humans Immune response Immunization Immunotoxins Leukemia, Hairy Cell - drug therapy Leukemia, Hairy Cell - immunology Mice Mice, Inbred BALB C Mice, SCID Mutation, Missense - immunology Proteins Pseudomonas Pseudomonas aeruginosa Exotoxin A Rabbits Reactivity Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - immunology Recombinant Fusion Proteins - therapeutic use Tumors Virulence Factors - genetics Virulence Factors - immunology Virulence Factors - therapeutic use |
| title | immunotoxin with greatly reduced immunogenicity by identification and removal of B cell epitopes |
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