Humanized M195 monoclonal antibody conjugated to recombinant gelonin: an anti-CD33 immunotoxin with antileukemic activity
The recently characterized immunotoxin HuM195-gelonin consists of a humanized anti-CD33 monoclonal antibody conjugated to the single-chain plant toxin gelonin. Binding of the immunotoxin to hematopoietic cells that express the CD33 differentiation antigen has been demonstrated and results in cytotox...
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| Veröffentlicht in: | Clinical cancer research 1998-08, Vol.4 (8), p.1971-1976 |
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| container_title | Clinical cancer research |
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| creator | PAGLIARO, L. C LIU, B MUNKER, R ANDREEFF, M FREIREICH, E. J SCHEINBERG, D. A ROSENBLUM, M. G |
| description | The recently characterized immunotoxin HuM195-gelonin consists of a humanized anti-CD33 monoclonal antibody conjugated to
the single-chain plant toxin gelonin. Binding of the immunotoxin to hematopoietic cells that express the CD33 differentiation
antigen has been demonstrated and results in cytotoxicity due to ribosomal inactivation by gelonin. Blast cells from most
patients with acute myelogenous leukemia express CD33, whereas normal stem cells necessary for maintenance of hematopoiesis
do not. We asked whether an immunoconjugate using recombinant gelonin rather than plant gelonin is toxic to acute myelogenous
leukemia (AML) cell lines and primary AML blasts obtained from patients and exposed to the immunotoxin in vitro. The CD33pos
cell lines HL60, OCI/AML2, and OCI/ AML5 showed decreased proliferation when exposed to immunotoxin for 24-72 h. The CD33neg
cell line OCI/AML3 was relatively resistant to HuM195, and all cell lines were resistant to equimolar concentrations of unconjugated
antibody and gelonin. Primary blast cultures from seven patients with AML had CD33 detectable on 75.7-99.8% of cells by flow
cytometry, and all showed dose-dependent decreases in clonogenic cell survival during 24-h incubation with the immunotoxin.
Cells selected for low CD33 expression by cell sorting or by prolonged incubation with immunotoxin could reexpress CD33 at
baseline levels and remained sensitive to immunotoxin. We conclude that humanized M195 conjugated to recombinant gelonin has
antileukemic activity and should be considered for clinical testing in Phase I trials. |
| format | Article |
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the single-chain plant toxin gelonin. Binding of the immunotoxin to hematopoietic cells that express the CD33 differentiation
antigen has been demonstrated and results in cytotoxicity due to ribosomal inactivation by gelonin. Blast cells from most
patients with acute myelogenous leukemia express CD33, whereas normal stem cells necessary for maintenance of hematopoiesis
do not. We asked whether an immunoconjugate using recombinant gelonin rather than plant gelonin is toxic to acute myelogenous
leukemia (AML) cell lines and primary AML blasts obtained from patients and exposed to the immunotoxin in vitro. The CD33pos
cell lines HL60, OCI/AML2, and OCI/ AML5 showed decreased proliferation when exposed to immunotoxin for 24-72 h. The CD33neg
cell line OCI/AML3 was relatively resistant to HuM195, and all cell lines were resistant to equimolar concentrations of unconjugated
antibody and gelonin. Primary blast cultures from seven patients with AML had CD33 detectable on 75.7-99.8% of cells by flow
cytometry, and all showed dose-dependent decreases in clonogenic cell survival during 24-h incubation with the immunotoxin.
Cells selected for low CD33 expression by cell sorting or by prolonged incubation with immunotoxin could reexpress CD33 at
baseline levels and remained sensitive to immunotoxin. We conclude that humanized M195 conjugated to recombinant gelonin has
antileukemic activity and should be considered for clinical testing in Phase I trials.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>PMID: 9717827</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Antibodies, Monoclonal - immunology ; Antibodies, Monoclonal - pharmacology ; Antigens, CD - immunology ; Antigens, Differentiation, Myelomonocytic - immunology ; Antineoplastic agents ; Antineoplastic Agents, Phytogenic - pharmacology ; Biological and medical sciences ; Bone Marrow Transplantation ; Cryopreservation ; Humans ; Immunotherapy ; Immunotoxins - pharmacology ; Leukemia, Myeloid, Acute - drug therapy ; Leukemia, Myeloid, Acute - pathology ; Medical sciences ; Pharmacology. Drug treatments ; Plant Proteins - pharmacology ; Recombinant Proteins - pharmacology ; Ribosome Inactivating Proteins, Type 1 ; Sensitivity and Specificity ; Sialic Acid Binding Ig-like Lectin 3 ; Tumor Cells, Cultured</subject><ispartof>Clinical cancer research, 1998-08, Vol.4 (8), p.1971-1976</ispartof><rights>1998 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2365884$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9717827$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>PAGLIARO, L. C</creatorcontrib><creatorcontrib>LIU, B</creatorcontrib><creatorcontrib>MUNKER, R</creatorcontrib><creatorcontrib>ANDREEFF, M</creatorcontrib><creatorcontrib>FREIREICH, E. J</creatorcontrib><creatorcontrib>SCHEINBERG, D. A</creatorcontrib><creatorcontrib>ROSENBLUM, M. G</creatorcontrib><title>Humanized M195 monoclonal antibody conjugated to recombinant gelonin: an anti-CD33 immunotoxin with antileukemic activity</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>The recently characterized immunotoxin HuM195-gelonin consists of a humanized anti-CD33 monoclonal antibody conjugated to
the single-chain plant toxin gelonin. Binding of the immunotoxin to hematopoietic cells that express the CD33 differentiation
antigen has been demonstrated and results in cytotoxicity due to ribosomal inactivation by gelonin. Blast cells from most
patients with acute myelogenous leukemia express CD33, whereas normal stem cells necessary for maintenance of hematopoiesis
do not. We asked whether an immunoconjugate using recombinant gelonin rather than plant gelonin is toxic to acute myelogenous
leukemia (AML) cell lines and primary AML blasts obtained from patients and exposed to the immunotoxin in vitro. The CD33pos
cell lines HL60, OCI/AML2, and OCI/ AML5 showed decreased proliferation when exposed to immunotoxin for 24-72 h. The CD33neg
cell line OCI/AML3 was relatively resistant to HuM195, and all cell lines were resistant to equimolar concentrations of unconjugated
antibody and gelonin. Primary blast cultures from seven patients with AML had CD33 detectable on 75.7-99.8% of cells by flow
cytometry, and all showed dose-dependent decreases in clonogenic cell survival during 24-h incubation with the immunotoxin.
Cells selected for low CD33 expression by cell sorting or by prolonged incubation with immunotoxin could reexpress CD33 at
baseline levels and remained sensitive to immunotoxin. We conclude that humanized M195 conjugated to recombinant gelonin has
antileukemic activity and should be considered for clinical testing in Phase I trials.</description><subject>Antibodies, Monoclonal - immunology</subject><subject>Antibodies, Monoclonal - pharmacology</subject><subject>Antigens, CD - immunology</subject><subject>Antigens, Differentiation, Myelomonocytic - immunology</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents, Phytogenic - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Bone Marrow Transplantation</subject><subject>Cryopreservation</subject><subject>Humans</subject><subject>Immunotherapy</subject><subject>Immunotoxins - pharmacology</subject><subject>Leukemia, Myeloid, Acute - drug therapy</subject><subject>Leukemia, Myeloid, Acute - pathology</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Plant Proteins - pharmacology</subject><subject>Recombinant Proteins - pharmacology</subject><subject>Ribosome Inactivating Proteins, Type 1</subject><subject>Sensitivity and Specificity</subject><subject>Sialic Acid Binding Ig-like Lectin 3</subject><subject>Tumor Cells, Cultured</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo90M9LwzAUwPEiypzTP0HIQfBUSJqkTb3J_DFh4kXPJUmTNbNJRpqq9a83bMPTe_D98A7vJJsjSqscFyU9TTusWA4JLs6zi2HYQogIgmSWzeoKVayo5tm0Gi135le14BXVFFjvvOy94z3gLhrh2wlI77bjhsdkogdBSW-FcSmDjUrUuLtk9zxfPmAMjLWj89H_GAe-Tez2qVfjp7JGAi6j-TJxuszONO8HdXWci-zj6fF9ucrXb88vy_t13hVlFfOaEIgEFLjGWJWYFRS2ircaKyhoSVqtWsiIwJoRTbGghUaUMA1JXXFVUooX2fXh7m4UVrXNLhjLw9QcX5D6zbHzQfJeB-6kGf5ZgUvKGEns9sA6s-m-TVCNTFCFoAbFg-wa0rAGpaP4DxFIdMI</recordid><startdate>19980801</startdate><enddate>19980801</enddate><creator>PAGLIARO, L. C</creator><creator>LIU, B</creator><creator>MUNKER, R</creator><creator>ANDREEFF, M</creator><creator>FREIREICH, E. J</creator><creator>SCHEINBERG, D. A</creator><creator>ROSENBLUM, M. G</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>19980801</creationdate><title>Humanized M195 monoclonal antibody conjugated to recombinant gelonin: an anti-CD33 immunotoxin with antileukemic activity</title><author>PAGLIARO, L. C ; LIU, B ; MUNKER, R ; ANDREEFF, M ; FREIREICH, E. J ; SCHEINBERG, D. A ; ROSENBLUM, M. G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h267t-94401b0b3933e638250deadf3e0b564dfed084b3f84f53b52f1548f0497ae6553</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Antibodies, Monoclonal - immunology</topic><topic>Antibodies, Monoclonal - pharmacology</topic><topic>Antigens, CD - immunology</topic><topic>Antigens, Differentiation, Myelomonocytic - immunology</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents, Phytogenic - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Bone Marrow Transplantation</topic><topic>Cryopreservation</topic><topic>Humans</topic><topic>Immunotherapy</topic><topic>Immunotoxins - pharmacology</topic><topic>Leukemia, Myeloid, Acute - drug therapy</topic><topic>Leukemia, Myeloid, Acute - pathology</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Plant Proteins - pharmacology</topic><topic>Recombinant Proteins - pharmacology</topic><topic>Ribosome Inactivating Proteins, Type 1</topic><topic>Sensitivity and Specificity</topic><topic>Sialic Acid Binding Ig-like Lectin 3</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>PAGLIARO, L. C</creatorcontrib><creatorcontrib>LIU, B</creatorcontrib><creatorcontrib>MUNKER, R</creatorcontrib><creatorcontrib>ANDREEFF, M</creatorcontrib><creatorcontrib>FREIREICH, E. J</creatorcontrib><creatorcontrib>SCHEINBERG, D. A</creatorcontrib><creatorcontrib>ROSENBLUM, M. G</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>PAGLIARO, L. C</au><au>LIU, B</au><au>MUNKER, R</au><au>ANDREEFF, M</au><au>FREIREICH, E. J</au><au>SCHEINBERG, D. A</au><au>ROSENBLUM, M. G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Humanized M195 monoclonal antibody conjugated to recombinant gelonin: an anti-CD33 immunotoxin with antileukemic activity</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>1998-08-01</date><risdate>1998</risdate><volume>4</volume><issue>8</issue><spage>1971</spage><epage>1976</epage><pages>1971-1976</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>The recently characterized immunotoxin HuM195-gelonin consists of a humanized anti-CD33 monoclonal antibody conjugated to
the single-chain plant toxin gelonin. Binding of the immunotoxin to hematopoietic cells that express the CD33 differentiation
antigen has been demonstrated and results in cytotoxicity due to ribosomal inactivation by gelonin. Blast cells from most
patients with acute myelogenous leukemia express CD33, whereas normal stem cells necessary for maintenance of hematopoiesis
do not. We asked whether an immunoconjugate using recombinant gelonin rather than plant gelonin is toxic to acute myelogenous
leukemia (AML) cell lines and primary AML blasts obtained from patients and exposed to the immunotoxin in vitro. The CD33pos
cell lines HL60, OCI/AML2, and OCI/ AML5 showed decreased proliferation when exposed to immunotoxin for 24-72 h. The CD33neg
cell line OCI/AML3 was relatively resistant to HuM195, and all cell lines were resistant to equimolar concentrations of unconjugated
antibody and gelonin. Primary blast cultures from seven patients with AML had CD33 detectable on 75.7-99.8% of cells by flow
cytometry, and all showed dose-dependent decreases in clonogenic cell survival during 24-h incubation with the immunotoxin.
Cells selected for low CD33 expression by cell sorting or by prolonged incubation with immunotoxin could reexpress CD33 at
baseline levels and remained sensitive to immunotoxin. We conclude that humanized M195 conjugated to recombinant gelonin has
antileukemic activity and should be considered for clinical testing in Phase I trials.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>9717827</pmid><tpages>6</tpages></addata></record> |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Antibodies, Monoclonal - immunology Antibodies, Monoclonal - pharmacology Antigens, CD - immunology Antigens, Differentiation, Myelomonocytic - immunology Antineoplastic agents Antineoplastic Agents, Phytogenic - pharmacology Biological and medical sciences Bone Marrow Transplantation Cryopreservation Humans Immunotherapy Immunotoxins - pharmacology Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - pathology Medical sciences Pharmacology. Drug treatments Plant Proteins - pharmacology Recombinant Proteins - pharmacology Ribosome Inactivating Proteins, Type 1 Sensitivity and Specificity Sialic Acid Binding Ig-like Lectin 3 Tumor Cells, Cultured |
| title | Humanized M195 monoclonal antibody conjugated to recombinant gelonin: an anti-CD33 immunotoxin with antileukemic activity |
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