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The Alpha Emitter Astatine-211 Targeted to CD38 can Eradicate Multiple Myeloma in a Disseminated Disease Model

Shyril O'Steen, Melissa L. Comstock, Johnnie J. Orozco, Donald K. Hamlin, D. Scott Scott Wilbur, Jon C. Jones, Aimee Kenoyer, Margaret E. Nartea, Yukang Lin, Brian W. Miller, Theodore A. Gooley, Sherilyn A Tuazon, Brian G. Till, Ajay K. Gopal, Brenda M. Sandmaier, Oliver W. Press and Damian J. Green

Key Points

  • Astatine-211 targeted to CD38 eliminates MM cell clones in murine models of low burden disease.

  • Astatine-211 deposits ≥500 times more energy than beta emitters and provides a mechanism of uniform cell kill unique among MM therapeutics.

Abstract

Minimal residual disease (MRD) has become an increasingly prevalent and important entity in multiple myeloma (MM). Despite deepening responses to frontline therapy, roughly 75% of MM patients never become MRD negative to {less than or equal to}10-5, concerning because MRD negative status predicts significantly longer survival. MM is highly heterogeneous, and MRD persistence may reflect survival of isolated single cells and small clusters of treatment-resistant sub-clones. Virtually all MM clones are exquisitely sensitive to radiation, and the α-emitter astatine‑211 (211At) deposits prodigious energy within three cell diameters, ideal for eliminating MRD if effectively targeted. CD38 is a proven MM target, and we conjugated 211At to an anti-CD38 monoclonal antibody to create an 211At‑CD38 therapy. When examined in a bulky xenograft model of MM, single-dose 211At‑CD38 at 15-45 µCi at least doubled median survival of mice relative to untreated controls (p <0.003), but no mice achieved complete remission and all died within 75 days. In contrast, in a disseminated disease model designed to reflect low burden MRD, three studies demonstrated that single-dose 211At-CD38 at 24-45 µCi produced sustained remission and long-term survival (>150 days) for 50-80% of mice, where all untreated mice died in 20-55 days (p <0.0001). Treatment toxicities were transient and minimal. These data suggest that 211At-CD38 offers the potential to eliminate residual MM cell clones in low disease burden settings, including MRD. We are optimistic that, in a planned clinical trial, addition of 211At-CD38 to an autologous stem-cell transplant (ASCT) conditioning regimen may improve ASCT outcomes for MM patients.

  • Submitted April 22, 2019.
  • Revision received August 8, 2019.
  • Accepted July 31, 2019.