An IgG‐based bispecific antibody for improved dual targeting in PSMA‐positive cancer

EMBO Molecular Medicine

Jonas S Heitmann¹  Stefanie Müller¹  Ilona Hagelstein¹  Melanie Märklin¹  Helmut R Salih¹  Lars Zender²  Christian laFougère²  Bence Sipos²  Bernd Pichler²  Andreas Maurer³  Carsten Calaminus³  Timo Manz⁴  Martin Pflügler⁴  Hans‐Georg Rammensee⁴  Latifa Zekri⁴  Joseph Kauer⁴  Fabian Vogt⁴  Lukas Osburg⁴  Gundram Jung⁴  Sebastian Hörner⁴  Arnulf Stenzl⁵  Tilmann Todenhöfer⁵  Marc A Schneider⁶ 

[1] Clinical Collaboration Unit Translational Immunology German Cancer Consortium (DKTK) Department of Internal Medicine University Hospital Tuebingen Tuebingen Germany;DFG Cluster of Excellence 2180 “Image‐guided and Functional Instructed Tumor Therapy” (IFIT) Eberhard Karls University Tuebingen Tuebingen Germany;Department for Preclinical Imaging and Radiopharmacy Werner Siemens Imaging Center Eberhard Karls University Tuebingen Tuebingen Germany;Department of Immunology Institute for Cell Biology Eberhard Karls University TuebingenGerman Cancer Consortium (DKTK)Partner Site Tuebingen Tuebingen Germany;Department of Urology University Hospital Tuebingen Tuebingen Germany;Translational Research Unit Thorax Clinic at University Hospital Heidelberg Translational Lung Research Center (TLRC) HeidelbergMember of the German Center for Lung Research (DZL) Heidelberg Germany;

关键词: bispecific antibody;    immunotherapy;    lung cancer;    prostate cancer;    PSMA;   

DOI  :  10.15252/emmm.201911902

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown