T Cell Costimulus-Independent and Very Efficacious Inhibition of Tumor Growth in Mice Bearing Subcutaneous or Leukemic Human B Cell Lymphoma Xenografts by a CD19-/CD3- Bispecific Single-Chain Antibody Construct
We have recently demonstrated that a recombinant single-chain bispecific Ab construct, bscCD19xCD3, in vitro induces rapid B lymphoma-directed cytotoxicity at picomolar concentrations with unstimulated peripheral T cells. In this study, we show that treatment of nonobese diabetic SCID mice with subm...
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creator | Dreier, Torsten Baeuerle, Patrick A Fichtner, Iduna Grun, Michael Schlereth, Bernd Lorenczewski, Grit Kufer, Peter Lutterbuse, Ralf Riethmuller, Gert Gjorstrup, Per Bargou, Ralf C |
description | We have recently demonstrated that a recombinant single-chain bispecific Ab construct, bscCD19xCD3, in vitro induces rapid B lymphoma-directed cytotoxicity at picomolar concentrations with unstimulated peripheral T cells. In this study, we show that treatment of nonobese diabetic SCID mice with submicrogram doses of bscCD19xCD3 could prevent growth of s.c. human B lymphoma xenografts and essentially cured animals when given at an early tumor stage. The effect was dose dependent, dependent on E:T ratio and the time between tumor inoculation and administration of bscCD19xCD3. No therapeutic effect was seen in the presence of human lymphocytes alone, a vehicle control, or with a bispecific single-chain construct of identical T cell-binding activity but different target specificity. In a leukemic nonobese diabetic SCID mouse model, treatment with bscCD19xCD3 prolonged survival of mice in a dose-dependent fashion. The human lymphocytes used as effector cells in both animal models did not express detectable T cell activation markers at the time of coinoculation with tumor cells. The bispecific Ab therefore showed an in vivo activity comparable to that observed in cell culture with respect to high potency and T cell costimulus independence. These properties make bscCD19xCD3 superior to previously investigated CD19 bispecific Ab-based therapies. |
doi_str_mv | 10.4049/jimmunol.170.8.4397 |
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In this study, we show that treatment of nonobese diabetic SCID mice with submicrogram doses of bscCD19xCD3 could prevent growth of s.c. human B lymphoma xenografts and essentially cured animals when given at an early tumor stage. The effect was dose dependent, dependent on E:T ratio and the time between tumor inoculation and administration of bscCD19xCD3. No therapeutic effect was seen in the presence of human lymphocytes alone, a vehicle control, or with a bispecific single-chain construct of identical T cell-binding activity but different target specificity. In a leukemic nonobese diabetic SCID mouse model, treatment with bscCD19xCD3 prolonged survival of mice in a dose-dependent fashion. The human lymphocytes used as effector cells in both animal models did not express detectable T cell activation markers at the time of coinoculation with tumor cells. The bispecific Ab therefore showed an in vivo activity comparable to that observed in cell culture with respect to high potency and T cell costimulus independence. These properties make bscCD19xCD3 superior to previously investigated CD19 bispecific Ab-based therapies.</description><identifier>ISSN: 0022-1767</identifier><identifier>EISSN: 1550-6606</identifier><identifier>DOI: 10.4049/jimmunol.170.8.4397</identifier><identifier>PMID: 12682277</identifier><language>eng</language><publisher>United States: Am Assoc Immnol</publisher><subject>Animals ; Antibodies, Bispecific - genetics ; Antibodies, Bispecific - pharmacology ; Antigens, CD19 - immunology ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - pharmacology ; CD3 Complex - immunology ; Cells, Cultured ; Graft Survival - genetics ; Graft Survival - immunology ; Growth Inhibitors - chemical synthesis ; Growth Inhibitors - pharmacology ; Humans ; Injections, Intravenous ; Injections, Subcutaneous ; Leukemia, B-Cell - genetics ; Leukemia, B-Cell - immunology ; Leukemia, B-Cell - pathology ; Leukemia, B-Cell - prevention & control ; Lymphocyte Activation - genetics ; Lymphoma, B-Cell - genetics ; Lymphoma, B-Cell - immunology ; Lymphoma, B-Cell - pathology ; Lymphoma, B-Cell - prevention & control ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Neoplasm Transplantation ; Skin Neoplasms - genetics ; Skin Neoplasms - immunology ; Skin Neoplasms - pathology ; Skin Neoplasms - prevention & control ; T-Lymphocyte Subsets - immunology ; Time Factors ; Transplantation, Heterologous - methods ; Tumor Cells, Cultured</subject><ispartof>The Journal of immunology (1950), 2003-04, Vol.170 (8), p.4397-4402</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c409t-a2357f8b53bf32338c3ef5357fbc7d183314c286a2a6eaaf9ca025121fb735083</citedby><cites>FETCH-LOGICAL-c409t-a2357f8b53bf32338c3ef5357fbc7d183314c286a2a6eaaf9ca025121fb735083</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12682277$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dreier, Torsten</creatorcontrib><creatorcontrib>Baeuerle, Patrick A</creatorcontrib><creatorcontrib>Fichtner, Iduna</creatorcontrib><creatorcontrib>Grun, Michael</creatorcontrib><creatorcontrib>Schlereth, Bernd</creatorcontrib><creatorcontrib>Lorenczewski, Grit</creatorcontrib><creatorcontrib>Kufer, Peter</creatorcontrib><creatorcontrib>Lutterbuse, Ralf</creatorcontrib><creatorcontrib>Riethmuller, Gert</creatorcontrib><creatorcontrib>Gjorstrup, Per</creatorcontrib><creatorcontrib>Bargou, Ralf C</creatorcontrib><title>T Cell Costimulus-Independent and Very Efficacious Inhibition of Tumor Growth in Mice Bearing Subcutaneous or Leukemic Human B Cell Lymphoma Xenografts by a CD19-/CD3- Bispecific Single-Chain Antibody Construct</title><title>The Journal of immunology (1950)</title><addtitle>J Immunol</addtitle><description>We have recently demonstrated that a recombinant single-chain bispecific Ab construct, bscCD19xCD3, in vitro induces rapid B lymphoma-directed cytotoxicity at picomolar concentrations with unstimulated peripheral T cells. In this study, we show that treatment of nonobese diabetic SCID mice with submicrogram doses of bscCD19xCD3 could prevent growth of s.c. human B lymphoma xenografts and essentially cured animals when given at an early tumor stage. The effect was dose dependent, dependent on E:T ratio and the time between tumor inoculation and administration of bscCD19xCD3. No therapeutic effect was seen in the presence of human lymphocytes alone, a vehicle control, or with a bispecific single-chain construct of identical T cell-binding activity but different target specificity. In a leukemic nonobese diabetic SCID mouse model, treatment with bscCD19xCD3 prolonged survival of mice in a dose-dependent fashion. The human lymphocytes used as effector cells in both animal models did not express detectable T cell activation markers at the time of coinoculation with tumor cells. The bispecific Ab therefore showed an in vivo activity comparable to that observed in cell culture with respect to high potency and T cell costimulus independence. These properties make bscCD19xCD3 superior to previously investigated CD19 bispecific Ab-based therapies.</description><subject>Animals</subject><subject>Antibodies, Bispecific - genetics</subject><subject>Antibodies, Bispecific - pharmacology</subject><subject>Antigens, CD19 - immunology</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>CD3 Complex - immunology</subject><subject>Cells, Cultured</subject><subject>Graft Survival - genetics</subject><subject>Graft Survival - immunology</subject><subject>Growth Inhibitors - chemical synthesis</subject><subject>Growth Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Injections, Intravenous</subject><subject>Injections, Subcutaneous</subject><subject>Leukemia, B-Cell - genetics</subject><subject>Leukemia, B-Cell - immunology</subject><subject>Leukemia, B-Cell - pathology</subject><subject>Leukemia, B-Cell - prevention & control</subject><subject>Lymphocyte Activation - genetics</subject><subject>Lymphoma, B-Cell - genetics</subject><subject>Lymphoma, B-Cell - immunology</subject><subject>Lymphoma, B-Cell - pathology</subject><subject>Lymphoma, B-Cell - prevention & control</subject><subject>Mice</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>Neoplasm Transplantation</subject><subject>Skin Neoplasms - genetics</subject><subject>Skin Neoplasms - immunology</subject><subject>Skin Neoplasms - pathology</subject><subject>Skin Neoplasms - prevention & control</subject><subject>T-Lymphocyte Subsets - immunology</subject><subject>Time Factors</subject><subject>Transplantation, Heterologous - methods</subject><subject>Tumor Cells, Cultured</subject><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1uEzEUhUcIREPhCZCQV7Ca1D8z48mymZY2UhCLBsTO8jh2xmVsp_5RNK_JE9VRUsGOzbV09Z1zfXSK4iOC8wpWi6tHbUyybpwjCuftvCIL-qqYobqGZdPA5nUxgxDjEtGGXhTvQniEEDYQV2-LC4SbFmNKZ8WfDejkOILOhahNGlMoV3Yr9zIPGwG3W_BT-gncKqUFF9qlAFZ20L2O2lngFNgk4zy48-4QB6At-KaFBEvJvbY78JB6kSK38qjL2Fqm39JoAe6T4RYsT8fXk9kPznDwS1q381zFAPoJcNDdoEV51d2QEix12Euh8y_AQ3YeZdkNPJ-7tlH3bjvlBDZEn0R8X7xRfAzyw_m9LH58vd109-X6-92qu16XooKLWHJMaqravia9IpiQVhCp6uOuF3SLWkJQJXDbcMwbyblaCA5xjTBSPSU1bMll8fnku_fuKckQmdFB5DynuIwSRDGC1X9B1FKMG3R0JCdQeBeCl4rtvTbcTwxBduycvXTOcuesZcfOs-rT2T71Rm7_as4lZ-DLCRj0bjhoL1kwfBwzjtjhcPjH6hlV5Lmg</recordid><startdate>20030415</startdate><enddate>20030415</enddate><creator>Dreier, Torsten</creator><creator>Baeuerle, Patrick A</creator><creator>Fichtner, Iduna</creator><creator>Grun, Michael</creator><creator>Schlereth, Bernd</creator><creator>Lorenczewski, Grit</creator><creator>Kufer, Peter</creator><creator>Lutterbuse, Ralf</creator><creator>Riethmuller, Gert</creator><creator>Gjorstrup, Per</creator><creator>Bargou, Ralf C</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>7T5</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20030415</creationdate><title>T Cell Costimulus-Independent and Very Efficacious Inhibition of Tumor Growth in Mice Bearing Subcutaneous or Leukemic Human B Cell Lymphoma Xenografts by a CD19-/CD3- Bispecific Single-Chain Antibody Construct</title><author>Dreier, Torsten ; Baeuerle, Patrick A ; Fichtner, Iduna ; Grun, Michael ; Schlereth, Bernd ; Lorenczewski, Grit ; Kufer, Peter ; Lutterbuse, Ralf ; Riethmuller, Gert ; Gjorstrup, Per ; Bargou, Ralf C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c409t-a2357f8b53bf32338c3ef5357fbc7d183314c286a2a6eaaf9ca025121fb735083</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Animals</topic><topic>Antibodies, Bispecific - genetics</topic><topic>Antibodies, Bispecific - pharmacology</topic><topic>Antigens, CD19 - immunology</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>CD3 Complex - immunology</topic><topic>Cells, Cultured</topic><topic>Graft Survival - genetics</topic><topic>Graft Survival - immunology</topic><topic>Growth Inhibitors - chemical synthesis</topic><topic>Growth Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Injections, Intravenous</topic><topic>Injections, Subcutaneous</topic><topic>Leukemia, B-Cell - genetics</topic><topic>Leukemia, B-Cell - immunology</topic><topic>Leukemia, B-Cell - pathology</topic><topic>Leukemia, B-Cell - prevention & control</topic><topic>Lymphocyte Activation - genetics</topic><topic>Lymphoma, B-Cell - genetics</topic><topic>Lymphoma, B-Cell - immunology</topic><topic>Lymphoma, B-Cell - pathology</topic><topic>Lymphoma, B-Cell - prevention & control</topic><topic>Mice</topic><topic>Mice, Inbred NOD</topic><topic>Mice, SCID</topic><topic>Neoplasm Transplantation</topic><topic>Skin Neoplasms - genetics</topic><topic>Skin Neoplasms - immunology</topic><topic>Skin Neoplasms - pathology</topic><topic>Skin Neoplasms - prevention & control</topic><topic>T-Lymphocyte Subsets - immunology</topic><topic>Time Factors</topic><topic>Transplantation, Heterologous - methods</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dreier, Torsten</creatorcontrib><creatorcontrib>Baeuerle, Patrick A</creatorcontrib><creatorcontrib>Fichtner, Iduna</creatorcontrib><creatorcontrib>Grun, Michael</creatorcontrib><creatorcontrib>Schlereth, Bernd</creatorcontrib><creatorcontrib>Lorenczewski, Grit</creatorcontrib><creatorcontrib>Kufer, Peter</creatorcontrib><creatorcontrib>Lutterbuse, Ralf</creatorcontrib><creatorcontrib>Riethmuller, Gert</creatorcontrib><creatorcontrib>Gjorstrup, Per</creatorcontrib><creatorcontrib>Bargou, Ralf C</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research 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>Dreier, Torsten</au><au>Baeuerle, Patrick A</au><au>Fichtner, Iduna</au><au>Grun, Michael</au><au>Schlereth, Bernd</au><au>Lorenczewski, Grit</au><au>Kufer, Peter</au><au>Lutterbuse, Ralf</au><au>Riethmuller, Gert</au><au>Gjorstrup, Per</au><au>Bargou, Ralf C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>T Cell Costimulus-Independent and Very Efficacious Inhibition of Tumor Growth in Mice Bearing Subcutaneous or Leukemic Human B Cell Lymphoma Xenografts by a CD19-/CD3- Bispecific Single-Chain Antibody Construct</atitle><jtitle>The Journal of immunology (1950)</jtitle><addtitle>J Immunol</addtitle><date>2003-04-15</date><risdate>2003</risdate><volume>170</volume><issue>8</issue><spage>4397</spage><epage>4402</epage><pages>4397-4402</pages><issn>0022-1767</issn><eissn>1550-6606</eissn><abstract>We have recently demonstrated that a recombinant single-chain bispecific Ab construct, bscCD19xCD3, in vitro induces rapid B lymphoma-directed cytotoxicity at picomolar concentrations with unstimulated peripheral T cells. In this study, we show that treatment of nonobese diabetic SCID mice with submicrogram doses of bscCD19xCD3 could prevent growth of s.c. human B lymphoma xenografts and essentially cured animals when given at an early tumor stage. The effect was dose dependent, dependent on E:T ratio and the time between tumor inoculation and administration of bscCD19xCD3. No therapeutic effect was seen in the presence of human lymphocytes alone, a vehicle control, or with a bispecific single-chain construct of identical T cell-binding activity but different target specificity. In a leukemic nonobese diabetic SCID mouse model, treatment with bscCD19xCD3 prolonged survival of mice in a dose-dependent fashion. The human lymphocytes used as effector cells in both animal models did not express detectable T cell activation markers at the time of coinoculation with tumor cells. The bispecific Ab therefore showed an in vivo activity comparable to that observed in cell culture with respect to high potency and T cell costimulus independence. These properties make bscCD19xCD3 superior to previously investigated CD19 bispecific Ab-based therapies.</abstract><cop>United States</cop><pub>Am Assoc Immnol</pub><pmid>12682277</pmid><doi>10.4049/jimmunol.170.8.4397</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Antibodies, Bispecific - genetics Antibodies, Bispecific - pharmacology Antigens, CD19 - immunology Antineoplastic Agents - chemical synthesis Antineoplastic Agents - pharmacology CD3 Complex - immunology Cells, Cultured Graft Survival - genetics Graft Survival - immunology Growth Inhibitors - chemical synthesis Growth Inhibitors - pharmacology Humans Injections, Intravenous Injections, Subcutaneous Leukemia, B-Cell - genetics Leukemia, B-Cell - immunology Leukemia, B-Cell - pathology Leukemia, B-Cell - prevention & control Lymphocyte Activation - genetics Lymphoma, B-Cell - genetics Lymphoma, B-Cell - immunology Lymphoma, B-Cell - pathology Lymphoma, B-Cell - prevention & control Mice Mice, Inbred NOD Mice, SCID Neoplasm Transplantation Skin Neoplasms - genetics Skin Neoplasms - immunology Skin Neoplasms - pathology Skin Neoplasms - prevention & control T-Lymphocyte Subsets - immunology Time Factors Transplantation, Heterologous - methods Tumor Cells, Cultured |
title | T Cell Costimulus-Independent and Very Efficacious Inhibition of Tumor Growth in Mice Bearing Subcutaneous or Leukemic Human B Cell Lymphoma Xenografts by a CD19-/CD3- Bispecific Single-Chain Antibody Construct |
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