Alpha radioimmunotherapy of B-lineage non-Hodgkin’s lymphoma using 213Bi-labeled anti-CD19- and anti-CD20-CHX-A"-DTPA conjugates


Steffen Heeger1, Gerhard Moldenhauer1, Gerlinde Egerer2, Horst Wesch3, Simona Martin4, Tuomo Nikula4, Christos Apostolidis4, Martin W. Brechbiel5, Anthony D. Ho2, and Rainer Haas6. (1) Department of Molecular Immunology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany, (2) Oncology and Haematology, University Hospital Heidelberg, 69115 Heidelberg, Germany, (3) Department of Radiology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany, (4) Nuclear Chemistry, European Commission, Joint Research Centre, Institute for Transuranium Elements, PO Box 2340, Karlsruhe, 76125, Germany, (5) NCI, NIH, Building 10, Room B3B69, 10 Center Drive, Bethesda, MD 20892-1002, (6) Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Moorenstr. 5, Duesseldorf, 40225, Germany
The therapeutic potential of high LET alpha-emitting 213Bi coupled to various antibody constructs was investigated for the use in B-lineage lymphoma. In preclinical experiments the strong cytotoxic potency of 213Bi-labeled anti-CD19 and anti-CD20 antibodies including recombinant constructs (diabodies, tetrabodies) for targeting lymphoma cells was demonstrated. Additionally, antibody conjugates showed favorable in vivo stability and biodistribution behavior. After 6 hours 55-70 % of the injected activity was still detectable in blood circulation and 32-45 % after 24 hours, respectively. Beside the induced myelosuppression, no other toxic side effects occurred. We are currently conducting a phase I dose escalation trial to determine safety and feasibility as well as pharmacology and dosimetry. So far, nine patients received activities of the 213Bi-CHX-A"-anti-CD20 radioconjugate ranging from 385 up to 1640 MBq. Acute toxic side effects were not observed except two cases of mild leukopenia (grade 1 CTC). Two patients responded to alpha-radioimmunotherapy. Our data indicate that 213Bi-labelled antibody conjugates represent promising tools for an improved therapy of refractory B-cell malignancies.