An IgG‐based bispecific antibody for improved dual targeting in PSMA‐positive cancer
Abstract The prostate‐specific membrane antigen (PSMA) has been demonstrated in numerous studies to be expressed specifically on prostate carcinoma cells and on the neovasculature of several other cancer entities. However, the simultaneous expression of PSMA on both, tumor cells as well as tumor ves...
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| Format: | Article |
| Language: | English |
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Springer Nature
2020-12-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201911902 |
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| author | Latifa Zekri Fabian Vogt Lukas Osburg Stefanie Müller Joseph Kauer Timo Manz Martin Pflügler Andreas Maurer Jonas S Heitmann Ilona Hagelstein Melanie Märklin Sebastian Hörner Tilmann Todenhöfer Carsten Calaminus Arnulf Stenzl Bernd Pichler Christian la Fougère Marc A Schneider Hans‐Georg Rammensee Lars Zender Bence Sipos Helmut R Salih Gundram Jung |
| author_facet | Latifa Zekri Fabian Vogt Lukas Osburg Stefanie Müller Joseph Kauer Timo Manz Martin Pflügler Andreas Maurer Jonas S Heitmann Ilona Hagelstein Melanie Märklin Sebastian Hörner Tilmann Todenhöfer Carsten Calaminus Arnulf Stenzl Bernd Pichler Christian la Fougère Marc A Schneider Hans‐Georg Rammensee Lars Zender Bence Sipos Helmut R Salih Gundram Jung |
| author_sort | Latifa Zekri |
| collection | DOAJ |
| description | Abstract The prostate‐specific membrane antigen (PSMA) has been demonstrated in numerous studies to be expressed specifically on prostate carcinoma cells and on the neovasculature of several other cancer entities. However, the simultaneous expression of PSMA on both, tumor cells as well as tumor vessels remains unclear, even if such “dual” expression would constitute an important asset to facilitate sufficient influx of effector cells to a given tumor site. We report here on the generation of a PSMA antibody, termed 10B3, which exerts superior dual reactivity on sections of prostate carcinoma and squamous cell carcinoma of the lung. 10B3 was used for the construction of T‐cell recruiting bispecific PSMAxCD3 antibodies in Fab‐ and IgG‐based formats, designated Fabsc and IgGsc, respectively. In vitro, both molecules exhibited comparable activity. In contrast, only the larger IgGsc molecule induced complete and durable elimination of established tumors in humanized mice due to favorable pharmacokinetic properties. Upon treatment of three patients with metastasized prostate carcinoma with the IgGsc reagent, marked activation of T cells and rapid reduction of elevated PSA levels were observed. |
| format | Article |
| id | doaj-art-c7fa60882d054b8bb603dab8b98336df |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2020-12-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-c7fa60882d054b8bb603dab8b98336df2025-08-20T03:05:53ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-12-0113211510.15252/emmm.201911902An IgG‐based bispecific antibody for improved dual targeting in PSMA‐positive cancerLatifa Zekri0Fabian Vogt1Lukas Osburg2Stefanie Müller3Joseph Kauer4Timo Manz5Martin Pflügler6Andreas Maurer7Jonas S Heitmann8Ilona Hagelstein9Melanie Märklin10Sebastian Hörner11Tilmann Todenhöfer12Carsten Calaminus13Arnulf Stenzl14Bernd Pichler15Christian la Fougère16Marc A Schneider17Hans‐Georg Rammensee18Lars Zender19Bence Sipos20Helmut R Salih21Gundram Jung22Department of Immunology, Institute for Cell Biology, Eberhard Karls University Tuebingen, German Cancer Consortium (DKTK), Partner Site TuebingenDepartment of Immunology, Institute for Cell Biology, Eberhard Karls University Tuebingen, German Cancer Consortium (DKTK), Partner Site TuebingenDepartment of Immunology, Institute for Cell Biology, Eberhard Karls University Tuebingen, German Cancer Consortium (DKTK), Partner Site TuebingenClinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital TuebingenDepartment of Immunology, Institute for Cell Biology, Eberhard Karls University Tuebingen, German Cancer Consortium (DKTK), Partner Site TuebingenDepartment of Immunology, Institute for Cell Biology, Eberhard Karls University Tuebingen, German Cancer Consortium (DKTK), Partner Site TuebingenDepartment of Immunology, Institute for Cell Biology, Eberhard Karls University Tuebingen, German Cancer Consortium (DKTK), Partner Site TuebingenDepartment for Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University TuebingenClinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital TuebingenClinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital TuebingenClinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital TuebingenDepartment of Immunology, Institute for Cell Biology, Eberhard Karls University Tuebingen, German Cancer Consortium (DKTK), Partner Site TuebingenDepartment of Urology, University Hospital TuebingenDepartment for Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University TuebingenDepartment of Urology, University Hospital TuebingenDFG Cluster of Excellence 2180 “Image‐guided and Functional Instructed Tumor Therapy” (IFIT), Eberhard Karls University TuebingenDFG Cluster of Excellence 2180 “Image‐guided and Functional Instructed Tumor Therapy” (IFIT), Eberhard Karls University TuebingenTranslational Research Unit, Thorax Clinic at University Hospital Heidelberg, Translational Lung Research Center (TLRC) Heidelberg, Member of the German Center for Lung Research (DZL)Department of Immunology, Institute for Cell Biology, Eberhard Karls University Tuebingen, German Cancer Consortium (DKTK), Partner Site TuebingenDFG Cluster of Excellence 2180 “Image‐guided and Functional Instructed Tumor Therapy” (IFIT), Eberhard Karls University TuebingenDFG Cluster of Excellence 2180 “Image‐guided and Functional Instructed Tumor Therapy” (IFIT), Eberhard Karls University TuebingenClinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital TuebingenDepartment of Immunology, Institute for Cell Biology, Eberhard Karls University Tuebingen, German Cancer Consortium (DKTK), Partner Site TuebingenAbstract The prostate‐specific membrane antigen (PSMA) has been demonstrated in numerous studies to be expressed specifically on prostate carcinoma cells and on the neovasculature of several other cancer entities. However, the simultaneous expression of PSMA on both, tumor cells as well as tumor vessels remains unclear, even if such “dual” expression would constitute an important asset to facilitate sufficient influx of effector cells to a given tumor site. We report here on the generation of a PSMA antibody, termed 10B3, which exerts superior dual reactivity on sections of prostate carcinoma and squamous cell carcinoma of the lung. 10B3 was used for the construction of T‐cell recruiting bispecific PSMAxCD3 antibodies in Fab‐ and IgG‐based formats, designated Fabsc and IgGsc, respectively. In vitro, both molecules exhibited comparable activity. In contrast, only the larger IgGsc molecule induced complete and durable elimination of established tumors in humanized mice due to favorable pharmacokinetic properties. Upon treatment of three patients with metastasized prostate carcinoma with the IgGsc reagent, marked activation of T cells and rapid reduction of elevated PSA levels were observed.https://doi.org/10.15252/emmm.201911902bispecific antibodyimmunotherapylung cancerprostate cancerPSMA |
| spellingShingle | Latifa Zekri Fabian Vogt Lukas Osburg Stefanie Müller Joseph Kauer Timo Manz Martin Pflügler Andreas Maurer Jonas S Heitmann Ilona Hagelstein Melanie Märklin Sebastian Hörner Tilmann Todenhöfer Carsten Calaminus Arnulf Stenzl Bernd Pichler Christian la Fougère Marc A Schneider Hans‐Georg Rammensee Lars Zender Bence Sipos Helmut R Salih Gundram Jung An IgG‐based bispecific antibody for improved dual targeting in PSMA‐positive cancer EMBO Molecular Medicine bispecific antibody immunotherapy lung cancer prostate cancer PSMA |
| title | An IgG‐based bispecific antibody for improved dual targeting in PSMA‐positive cancer |
| title_full | An IgG‐based bispecific antibody for improved dual targeting in PSMA‐positive cancer |
| title_fullStr | An IgG‐based bispecific antibody for improved dual targeting in PSMA‐positive cancer |
| title_full_unstemmed | An IgG‐based bispecific antibody for improved dual targeting in PSMA‐positive cancer |
| title_short | An IgG‐based bispecific antibody for improved dual targeting in PSMA‐positive cancer |
| title_sort | igg based bispecific antibody for improved dual targeting in psma positive cancer |
| topic | bispecific antibody immunotherapy lung cancer prostate cancer PSMA |
| url | https://doi.org/10.15252/emmm.201911902 |
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