BCMA-Directed Low Dose Alpha-Emitter Therapy Eliminates Minimal Residual Disease in a Multiple Myeloma Mouse Xenograft Model

• Published in: Blood 2023-11, Vol.142 (Supplement 1), p.53-53
• Main Authors: Comstock, Melissa L, O'Steen, Shyril, Lin, Yukang, Hamlin, Donald, Wilbur, D Scott, Orozco, Johnnie J., Storb, Rainer F., Walter, Roland B., Ataca Atilla, Pinar, Till, Brian G, Hill, Geoffrey R, Sandmaier, Brenda M., Green, Damian J
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2023-188055

BACKGROUND: Unprecedented reductions in multiple myeloma (MM) tumor burden after treatment with B cell maturation antigen (BCMA) directed bispecific T-cell engagers, or chimeric antigen receptor modified T-cells, have translated into improved progression free and overall survival; however, virtually all patients are predicted to ultimately relapse. The mechanisms of resistance to BCMA targeting agents are currently being explored, but presumably reflect persistence of MM cell subpopulations that either lack target antigen or otherwise evade immune-mediated tumor cell killing. Antigen targeted delivery of radiation to tumor cells leverages a unique effector mechanism that capitalizes on the exquisite sensitivity of malignant plasma cells to radiation. The α-emitter astatine-211 ( 211At) has particular promise as it deposits a very large amount of energy (~100 keV/μm) within a few cell diameters (50-90 μm) resulting in irreparable double-stranded DNA breaks. The high energy cell killing mediated by 211At is agnostic to MM cell heterogeneity, facilitates bystander delivery of radiation to target antigen negative clones, and limits radiation exposure to normal cells. We hypothesized that 211At targeting BCMA may be uniquely suited to eliminate residual MM cells. METHODS: We conjugated a human IgG1 anti-BCMA mAb and an isotype matched nonbinding control mAb (ofatumumab), with the amine-reactive labeling agent B10-NCS to enable 211At radiolabeling. In biodistribution studies of 211At-BCMA-B10 and 211At-ofatumumab-B10 using NOD.Cg-Rag1 tm1MomIl2rg tm1Wjl/SzJ (NRG) mice bearing flank MM tumor cell xenografts (MM1R or NCI-H929; n=5 mice/group), we demonstrated tumor-specific uptake of BCMA-B10 relative to control mAb and identified the optimal dose of 211At-mAb-B10 (210μg) for assessing therapeutic efficacy. In subsequent therapy studies, NRG mice (n=7-10/group) received 0.3-0.4e6 NCI-H929 luc tumor cells by tail vein injection 6-7 days prior to administration of 210 µg of 211At-BCMA-B10 or 211At-ofatumumab-B10 or no therapy (non-treatment control). Animal body weight was monitored serially, and disease was tracked using in vivo bioluminescence imaging (IVIS Spectrum) performed at 8 or more timepoints over 150 days. RESULTS: Disease elimination was defined as survival with no measurable disease by IVIS at 150 days following treatment. All mice receiving 6 or 8 µCi of 211At-BCMA-B10 (n=36) were cured (100%) after a single infusion of 211At-BCMA-B10. Mice in the untr