High treatment efficacy by dual targeting of Burkitt's lymphoma xenografted mice with a (177)Lu-based CD22-specific radioimmunoconjugate and rituximab.
OBJECTIVE
Dual-targeted therapy has been shown to be a promising treatment option in recurrent and/or refractory B-cell non-Hodgkin's lymphoma (B-NHL). We generated radioimmunoconjugates (RICs) comprising either a novel humanized anti-CD22 monoclonal antibody, huRFB4, or rituximab, and the low-energy β-emitter (177)Lu. Both RICs were evaluated as single agents in a human Burkitt's lymphoma xenograft mouse model. To increase the therapeutic efficacy of the anti-CD22 RIC, combination therapy with unlabelled anti-CD20 rituximab was explored.


METHODS
The binding activity of CHX-A″-DTPA-conjugated antibodies to target cells was analysed by flow cytometry. To assess tumour targeting of (177)Lu-labelled antibodies, in vivo biodistribution experiments were performed. For radioimmunotherapy (RIT) studies, non-obese diabetic recombination activating gene-1 (NOD-Rag1 (null) ) interleukin-2 receptor common gamma chain (IL2rγ (null) ) null mice (NRG mice) were xenografted subcutaneously with Raji Burkitt's lymphoma cells. (177)Lu-conjugated antibodies were administered at a single dose of 9.5 MBq per mouse. For dual-targeted therapy, rituximab was injected at weekly intervals (0.5 - 1.0 mg). Tumour accumulation of RICs was monitored by planar scintigraphy.


RESULTS
Conjugation of CHX-A"-DTPA resulted in highly stable RICs with excellent antigen-binding properties. Biodistribution experiments revealed higher tumour uptake of the (177)Lu-labelled anti-CD22 IgG than of (177)Lu-labelled rituximab. Treatment with (177)Lu-conjugated huRFB4 resulted in increased tumour growth inhibition and significantly longer survival than treatment with (177)Lu-conjugated rituximab. The therapeutic efficacy of the anti-CD22 RIC could be markedly enhanced by combination with unlabelled rituximab.


CONCLUSIONS
These findings suggest that dual targeting with (177)Lu-based CD22-specific RIT in combination with rituximab is a promising new treatment option for refractory B-NHL.
Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
Tobias
T
Weber
Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
Benedikt
B
Bötticher
Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany.
Walter
W
Mier
Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany.|Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Max
M
Sauter
Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany.
Susanne
S
Krämer
Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany.
Karin
K
Leotta
Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
Armin
A
Keller
Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
Anne
A
Schlegelmilch
Department of Immunology, University of Tübingen, Tübingen, Germany.
Ludger
L
Grosse-Hovest
Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
Dirk
D
Jäger
Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany.|Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Uwe
U
Haberkorn
Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.|Immunotherapy Program, National Center for Tumor Diseases, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Michaela A E
MA
Arndt
Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany. juergen.krauss@nct-heidelberg.de.
Jürgen
J
Krauss
D000818:Animals; D002051:Burkitt Lymphoma / Q000532:radiotherapy / Q000628:therapy*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000627:therapeutic use; D008187:Lutetium / Q000737:chemistry*; D020714:Maximum Tolerated Dose; D051379:Mice; D016688:Mice, Inbred NOD; D016499:Radioimmunotherapy / Q000379:methods*; D000069283:Rituximab / Q000627:therapeutic use*; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
C497867:CD22 protein, human; D018796:Immunoconjugates; D007074:Immunoglobulin G; D051918:Sialic Acid Binding Ig-like Lectin 2; D000069283:Rituximab; D008187:Lutetium
177Lu; CD22; Lymphoma; Radioimmunotherapy; huRFB4