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

Abstract

ObjectivesRadioimmunotherapy (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 213Bi, 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 213Bi for α-RIT or 177Lu for β-RIT.MethodsA 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 177Lu-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.Resultsα-RIT performed with 3.7 MBq of 213Bi-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 177Lu-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.ConclusionThis study revealed the advantages of α-RIT in the treatment of MM in a preclinical model where β-RIT shows almost no efficacy.

Bifunctional aryliodonium salts for highly efficient radioiodination and astatination of antibodies

“…24 Conjugation yields were high (75 ± 3% with [ 125 I]SIB and 77 ± 3% with [ 211 At]SAB) with good preservation of immunoreactivity (86 ± 2%).…”

Comparison of Immuno-PET of CD138 and PET imaging with 64CuCl2 and 18F-FDG in a preclinical syngeneic model of multiple myeloma

“…The present work demonstrated the high targeted-tumor uptake of 64 Cu-TE2A-9E7.4 in MM tumor-bearing mice. Based on our experience with the B-B4 mAb [ 24 , 25 ], our group had developed this rat anti-mouse syndecan mAb (9E7.4, IgG2a κ isotype) that specifically recognizes the extracellular domain of mouse syndecan-1 [ 26 ]. This study showed that 64 Cu-TE2A-9E7.4 binds effectively to CD138 tumors and allows MM imaging in a syngeneic mouse model with high contrast.…”

“…The 9E7.4 mAb was produced by immunization of a rat with a 40-amino-acid peptide (GeneCust, Luxembourg) derived from the murine CD138 protein (aa 90–130) (GenBank: CAA80254.1). Its characterization was ensured within the team as previously described [ 26 ]. The isotype of this antibody is IgG2a,κ, and its binding specificity was around 1 × 10 −10 M.…”

Multiple myeloma in the marrow: pathogenesis and treatments

“…178,179 Recent work has shown that coupling this antibody to radioactive isotopes significantly increased survival in animal models of MM. 179 The targeting of antigens and other cell-surface proteins in the treatment of cancers is rapidly expanding through the use of antibodydrug conjugates, which combine the specificity of a monoclonal antibody with a small anticancer drug molecule. Preclinical in vitro and in vivo work with these conjugates has demonstrated promise in the treatment of MM and other hematological cancers.…”