EJM

BSO-Radiosensitized Human Cancer Cell Lines to ¹⁷⁷Lu-DOTATATE

Peptide receptor radionuclide therapy with ¹⁷⁷Lu-DOTATATE is an efficient treatment for patients suffering from metastasized neuroendocrine tumors. Lu-177 induces oxidative stress, eventually leading to tumor cell death. Inhibition of the antioxidant defence mechanisms, using buthionine sulfoximine (BSO), represents an attractive strategy to increase ¹⁷⁷Lu-DOTATATE efficacy. In cells and an animal model, the combination of ¹⁷⁷Lu-DOTATATE and BSO was more effective than ¹⁷⁷Lu-DOTATATE alone. In addition, it did not result in additional toxicity. Targeting the antioxidant defence system opens new safe treatment combination opportunities with ¹⁷⁷Lu-DOTATATE.

Fig. 1. Effect of BSO and its combination with ¹⁷⁷Lu-DOTATATE on the survival of melanoma (HBL and MM162), multiple myeloma (COLO-677 and EJM) and GEP (MIA-PACA-2 and HT-29) cell lines (Delbart, Wendy, et al. 2023).

Ad35K++ and CD59 Inhibitor (rILYD4) Additively Enhance CDC by Daratumumab and Isatuximab in MM Cells

Remarkable progress has been made in the treatment of Multiple myeloma (MM) with anti-CD38 monoclonal antibodies such as daratumumab and isatuximab, which can kill MM cells by inducing complement-dependent cytotoxicity (CDC). We showed that the CDC efficacy of daratumumab and isatuximab is limited by membrane complement inhibitors, including CD46 and CD59, which are upregulated in MM cells. We recently developed a small recombinant protein, Ad35K++, which is capable of transiently removing CD46 from the cell surface. We also produced a peptide inhibitor of CD59 (rILYd4). In this study, we tested Ad35K++ and rILYd4 in combination with daratumumab and isatuximab in MM cells as well as in cells from two other B-cell malignancies. We showed that Ad35K++ and rILYd4 increased CDC triggered by daratumumab and isatuximab. The combination of both inhibitors had an additive effect in vitro in primary MM cells as well as in vivo in a mouse xenograft model of MM.

Fig. 2. The combination of Ad35K++ and rIYd4 additively enhanced the CDC effect of daratumumab and isatuximab. MOLP8 (a), SU-DHL-8 (b), EJM (c) and MM.1?R (d) (Wang, Hongjie, et al. 2024).