212Pb α-Radioimmunotherapy Targeting CD38 in Multiple Myeloma: A Preclinical Study.

Multiple myeloma (MM) is a plasma cell cancer and represents the second most frequent hematologic malignancy. Despite new treatments and protocols, including high-dose chemotherapy associated with autologous stem cell transplantation, the prognosis of MM patients is still poor. α-radioimmunotherapy (α-RIT) represents an attractive treatment strategy because of the high-linear-energy transfer and short pathlength of α-radiation in tissues, resulting in high tumor cell killing and low toxicity to surrounding tissues. In this study, we investigated the potential of α-RIT with 212Pb-daratumumab (anti-hCD38), in both in vitro and in vivo models, as well as an antimouse CD38 antibody using in vivo models. Methods: Inhibition of cell proliferation after incubation of the RPMI8226 cell line with an increasing activity (0.185-3.7 kBq/mL) of 212Pb-isotypic control or 212Pb-daratumumab was evaluated. Biodistribution was performed in vivo by SPECT/CT imaging and after death. Dose-range-finding and acute toxicity studies were conducted. Because daratumumab does not bind the murine CD38, biodistribution and dose-range finding were also determined using an antimurine CD38 antibody. To evaluate the in vivo efficacy of 212Pb-daratumumab, mice were engrafted subcutaneously with 5 × 106 RPMI8226 cells. Mice were treated 13 d after engraftment with an intravenous injection of 212Pb-daratumumab or control solution. Therapeutic efficacy was monitored by tumor volume measurements and overall survival. Results: Significant inhibition of proliferation of the human myeloma RPMI8226 cell line was observed after 3 d of incubation with 212Pb-daratumumab, compared with 212Pb-isotypic control or cold antibodies. Biodistribution studies showed a specific tumoral accumulation of daratumumab. No toxicity was observed with 212Pb-daratumumab up to 370 kBq because of lack of cross-reactivity. Nevertheless, acute toxicity experiments with 212Pb-anti-mCD38 established a toxic activity of 277.5 kBq. To remain within realistically safe treatment activities for efficacy studies, mice were treated with 185 kBq or 277.5 kBq of 212Pb-daratumumab. Marked tumor growth inhibition compared with controls was observed, with a median survival of 55 d for 277.5 kBq of 212Pb-daratumumab instead of 11 d for phosphate-buffered saline. Conclusion: These results showed 212Pb-daratumumab to have efficacy in xenografted mice, with significant tumor regression and increased survival. This study highlights the potency of α-RIT in MM treatment.

Effects of small-fiber neuropathy induced by resiniferatoxin on skin healing and axonal regrowth after burn.

BACKGROUND: Damage to the peripheral nervous system influences wound healing and, after a deep burn, imperfect cutaneous nerve regeneration occurs. A third-degree burn model was developed in rats combined with the use of resiniferatoxin (RTX), known to promote sensory neuropathy. METHODS: Rats were injected intraperitoneally either with RTX or vehicle. A mechanical sensory assay and the hot plate thermal sensory test were performed. The structural integrity of the sciatic nerve was assessed using transmission electron microcopy. After RTX injection, third-degree thermal burns were performed. Wound closure was monitored and samples were collected for histological analysis, immunohistochemistry and immunoblotting for neuronal markers. RESULTS: RTX promoted both mechanical and thermal hypoalgesia. This transient RTX-mediated sensory deficit occurred without damaging the integrity of nerve fibers and induced a significant depletion of neuropeptides in both neuronal bodies and intraepidermal nerve fibers. Although wound closure rates were similar in both groups, the kinetic of granulation tissue remodeling was delayed in the RTX group compared with control group. A significant reduction of the peripherin expression in the RTX group was observed indicating impaired axonal regrowth of small fibers within the wound. CONCLUSION: Our study confirms the important roles of innervation during skin healing and the defect of nerve regeneration after burn.