Preclinical evaluation of a diabody-based 177Lu-radioimmunoconjugate for CD22-directed radioimmunotherapy in a non-Hodgkin lymphoma mouse model. Issue 2 (28th October 2016)

• Record Type: Journal Article
• Authors: Weber, Tobias; Bötticher, Benedikt; Arndt, Michaela A.E.; Mier, Walter; Sauter, Max; Exner, Evelyn; Keller, Armin; Krämer, Susanne; Leotta, Karin; Wischnjow, Artjom; Grosse-Hovest, Ludger; Strumberg, Dirk; Jäger, Dirk; Gröne, Hermann-Josef; Haberkorn, Uwe; Brem, Gottfried; Krauss, Jürgen
• Is Part Of: Cancer letters. Volume 381:Issue 2(2016)
• Page Start: 296
• Page End: 304
• Publication Date: 2016-10-28
• Subjects: CD22 -- Diabody -- Lymphoma -- Radioimmunotherapy -- Dual-targeting -- PEGylation; AUC area under the curve -- BLI bioluminescence imaging -- B-NHL B-cell non-Hodgkin lymphoma -- CHX-A″-DTPA N-[(R)-2-amino-3-(p-isothiocyanato-phenyl)propyl]-trans-(S, S)-cyclohexane-1, 2-diamine-N, N, N′, N″, N″-pentaacetic acid -- 64Cu copper-64 -- CYS cystatin C -- Db diabody -- FITC fluorescein isothiocyanate -- HE hematoxylin and eosin -- 124I iodine-124 -- IgG immunoglobulin G -- 111In indium-111 -- ITLC instant thin layer chromatography -- 177Lu lutetium-177 -- mAb monoclonal antibody -- MFImax maximum median fluorescence intensity -- MTD maximum tolerated dose -- NRG mice non-obese diabetic-recombination activating gene-1 (NOD-Rag1null) interleukin (IL)-2 receptor common gamma chain (IL2rγnull) null mice -- PAS periodic acid–Schiff -- PBS phosphate-buffered saline -- PEG polyethylene glycol -- RIC radioimmunoconjugate -- RIT radioimmunotherapy -- SATA N-succinimidyl S-acetylthioacetate -- scFv single-chain variable fragment -- SDS-PAGE sodium dodecyl sulfate polyacrylamide gel electrophoresis -- SEC size exclusion chromatography -- 90Y yttrium-90 -- %IA/g percentage of injected activity per gram tissue; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2016.08.007
• Languages: English
• ISSNs: 0304-3835

Abstract

Highlights: A humanized anti-CD22 diabody was purified from transgenic rabbit milk. The diabody was conjugated to the short-range β-emitter lutetium-177 ( 177 Lu). Size-optimization of the diabody achieved improved pharmacokinetic properties 177 Lu-diabody showed high anti-tumor activity in mice with disseminated lymphoma. The diabody RIC may have potential for the treatment of patients with B-NHL. 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.