Single-Dose Anti-CD138 Radioimmunotherapy: Bismuth-213 is More Efficient than Lutetium-177 for Treatment of Multiple Myeloma in a Preclinical Model.

Nolwenn Fichou,Michel Chérel,Ludovic Ferrer,Joëlle Gaschet,Alain Faivre-Chauvet,Frank Bruchertseifer,Sébastien Gouard,Catherine Maurel,François Davodeau,Jacques Barbet,Alfred Morgenstern,Edith Bigot-Corbel

doi:10.3389/fmed.2015.00076

Abstract

Radioimmunotherapy (RIT) has emerged as a potential treatment option for multiple myeloma (MM). In humans, a dosimetry study recently showed the relevance of RIT using an antibody targeting the CD138 antigen. The therapeutic efficacy of RIT using an anti-CD138 antibody coupled to (213)Bi, an α-emitter, was also demonstrated in a preclinical MM model. Since then, RIT with β-emitters has shown efficacy in treating hematologic cancer. In this paper, we investigate the therapeutic efficacy of RIT in the 5T33 murine MM model using a new anti-CD138 monoclonal antibody labeled either with (213)Bi for α-RIT or (177)Lu for β-RIT. A new monoclonal anti-CD138 antibody, 9E7.4, was generated by immunizing a rat with a murine CD138-derived peptide. Antibody specificity was validated by flow cytometry, biodistribution, and α-RIT studies. Then, a β-RIT dose-escalation assay with the (177)Lu-radiolabeled 9E7.4 mAb was performed in KalwRij C57/BL6 mice 10 days after i.v. engraftment with 5T33 MM cells. Animal survival and toxicological parameters were assessed to define the optimal activity. α-RIT performed with 3.7 MBq of (213)Bi-labeled 9E7.4 anti-CD138 mAb increased median survival to 80 days compared to 37 days for the untreated control and effected cure in 45% of animals. β-RIT performed with 18.5 MBq of (177)Lu-labeled 9E7.4 mAb was well tolerated and significantly increased mouse survival (54 vs. 37 days in the control group); however, no mice were cured with this treatment. This study revealed the advantages of α-RIT in the treatment of MM in a preclinical model where β-RIT shows almost no efficacy.

Highlights

Multiple myeloma (MM) represents 1% of all cases of cancer and 10% of hematological malignancies [1]
We investigate the therapeutic efficacy of RIT in the 5T33 murine MM model using a new anti-CD138 monoclonal antibody labeled either with 213Bi for α-RIT or 177Lu for β-RIT
The two anti-CD138 mAbs could bind to CD138-expressing MM cell lines 5T33 and SP2/o, whereas no binding to the negative control cell line was observed in either case

Summary

Introduction

Multiple myeloma (MM) represents 1% of all cases of cancer and 10% of hematological malignancies [1]. Common features of MM include organ damage due to plasma cell proliferation – known as CRAB (hypercalcemia, renal failure, anemia, and bone diseases) – at least one focal lesion, and a ratio of involved:uninvolved circulating light chain higher than 100 [2, 3]. Depending on the patient’s age, standard clinical care comprises high-dose therapy, which may be combined with autologous stem cell transplantation [4]. New drugs such as bortezomib and lenalidomide, and new indications, such as for thalidomide, have significantly improved the overall survival rate for patients, MM remains an incurable disease. Treatments must be constantly improved and new drugs or new strategies continuously assessed

Objectives

Methods

Results

Conclusion