title: Preclinical evaluation of a diabody-based (177)Lu-radioimmunoconjugate for CD22-directed radioimmunotherapy in a non-Hodgkin lymphoma mouse model.
abstract: Radioimmunotherapy is considered as treatment option in recurrent and/or refractory B-cell non-Hodgkin lymphoma (B-NHL). To overcome the dose limiting bone marrow toxicity of IgG-based radioimmunoconjugates (RICs), we modified a humanized diabody with 5-, 10-, or 20-kDa polyethylene glycol (PEG) for CD22-targeted radioimmunotherapy using the low-energy β-emitter lutetium-177 ((177)Lu). A favorable pharmacokinetic profile was observed for the 10-kDa-PEG-diabody in nude mice being xenografted with subcutaneous human Burkitt lymphoma. Even at high doses of 16 MBq this diabody RIC was well tolerated by NOD Rag1(null) IL2rγ(null) (NRG) mice and did not reveal signs of organ long-term toxicity 80 days post injection. Combination therapy of the diabody RIC with unconjugated anti-CD20 Rituximab demonstrated therapeutic efficacy in established disseminated mantle cell lymphoma xenograft models. When compared with the combination of the IgG formatted (177)Lu anti-CD22 antibody and Rituximab, dual targeted therapy with the diabody RIC achieved an improved reduction of disease burden in the first nine days following treatment. The data indicate that the PEGylated anti-CD22 diabody may have potential for extending the repertoire of radiopharmaceuticals for the treatment of patients with B-NHL.
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Weber
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Bötticher
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany; Immunotherapy Program, National Center for Tumor Diseases, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Michaela A E
authors.initials: MA
authors.lastname: Arndt
authors.affiliation: Department of Nuclear Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Mier
authors.affiliation: Department of Nuclear Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany; Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Max
authors.initials: M
authors.lastname: Sauter
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Exner
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Keller
authors.affiliation: Department of Nuclear Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Krämer
authors.affiliation: Department of Nuclear Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Leotta
authors.affiliation: Department of Nuclear Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
authors.forename: Artjom
authors.initials: A
authors.lastname: Wischnjow
authors.affiliation: Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Grosse-Hovest
authors.affiliation: Department of Hematology and Medical Oncology, Marienhospital Herne, University of Bochum, Hölkeskampring 40, 44625 Herne, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Strumberg
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Jäger
authors.affiliation: Division of Cellular and Molecular Pathology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.affiliation: Department of Nuclear Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany; Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Haberkorn
authors.affiliation: Institute of Animal Breeding and Genetics, VUW, Veterinärplatz 1, Wien 1210, Austria.
authors.forename: Gottfried
authors.initials: G
authors.lastname: Brem
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany. Electronic address: juergen.krauss@nct-heidelberg.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Krauss
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D002051:Burkitt Lymphoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D005260:Female; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D016756:Immunoglobulins, Intravenous / Q000494:pharmacology; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D008187:Lutetium / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D020522:Lymphoma, Mantle-Cell / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008819:Mice, Nude; D016499:Radioimmunotherapy / Q000009:adverse effects / Q000379:methods*; D011868:Radioisotopes / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D000069283:Rituximab / Q000494:pharmacology; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000276:immunology* / Q000378:metabolism; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D061067:Antibodies, Monoclonal, Humanized; C497867:CD22 protein, human; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; C507942:Il2rg protein, mouse; D018796:Immunoconjugates; D016756:Immunoglobulins, Intravenous; D053631:Interleukin Receptor Common gamma Subunit; D011868:Radioisotopes; D051918:Sialic Acid Binding Ig-like Lectin 2; C090140:Whn protein; C064658:RAG-1 protein; D000069283:Rituximab; D008187:Lutetium
keywords: CD22; Diabody; Dual-targeting; Lymphoma; PEGylation; Radioimmunotherapy