HDP-101, an Anti-BCMA Antibody–Drug Conjugate, Safely Delivers Amanitin to Induce Cell Death in Proliferating and Resting Multiple Myeloma Cells

Abstract

Despite major treatment advances in recent years, patients with multiple myeloma inevitably relapse. The RNA polymerase II complex has been identified as a promising therapeutic target in both proliferating and dormant cancer cells. Alpha-amanitin, a toxin so far without clinical application due to high liver toxicity, specifically inhibits this complex. Here, we describe the development of HDP-101, an anti–B-cell maturation antigen (BCMA) antibody conjugated with an amanitin derivative. HDP-101 displayed high efficacy against both proliferating and resting myeloma cells in vitro, sparing BCMA-negative cells. In subcutaneous and disseminated murine xenograft models, HDP-101 induced tumor regression at low doses, including durable complete remissions after a single intravenous dose. In cynomolgus monkeys, HDP-101 was well tolerated with a promising therapeutic index. In conclusion, HDP-101 safely and selectively delivers amanitin to myeloma cells and provides a novel therapeutic approach to overcome drug resistance in this disease.

Genetic Abnormalities in Multiple Myeloma: Prognostic and Therapeutic Implications

“…This gene encodes an RNA polymerase II enzyme, which can be inhibited by amanitins [156,157]. This drug, conjugated with a targeted antibody against BCMA, has been tested in MM cell lines and mouse models with promising results [158]. Furthermore, the decrease of polymerase activity can be compensated by the overexpression of RBX1.…”

Toxic Effects of Amanitins: Repurposing Toxicities toward New Therapeutics

“…Moreover, HDP-101 (an anti-B-cell maturation antigen (BCMA) antibody conjugated with an amanitin derivative) displayed high efficacy against both proliferating and resting myeloma cells in vitro, sparing BCMA-negative cells. These findings might provide a novel therapeutic approach to overcome drug resistance in this disease [56]. Recently, Gallo et al (2021) showed that α-amanitin-based small-molecule drug conjugates grafted onto an immunoglobulin Fc domain increased the pharmacokinetic properties and therapeutic efficacy over the small-molecule drug conjugates in a prostate cancer xenograft mouse model [57].…”

Impact of Endocytosis Mechanisms for the Receptors Targeted by the Currently Approved Antibody-Drug Conjugates (ADCs)—A Necessity for Future ADC Research and Development

“…Soluble BCMA has been shown to interfere with anti-BCMA therapies by reducing the levels of active drug that reach multiple myeloma cells [ 155 ]. However, the H929 cell line, which expressed the highest relative amounts of cell surface and soluble BCMA, displayed the highest sensitivity to an investigational ADC [ 158 ]. This indicates that BCMA cell surface levels might have a greater impact on efficacy than the soluble BCMA concentration.…”

“…However, the level of expression in normal B cells and multiple myeloma cells was not reported until recently. Utilizing a novel anti-BCMA ADC (HDP-101), Figueroa et al determined that the level of antibody-bound molecules against BCMA per cell ranged from 1171–8987 in the multiple myeloma cell lines H929, INA-6, U266, MM.1S-Luc, RPMI-8226, MM.1S, LP-1, OPM-2, SKMM.1, and L363 [ 158 ]. Importantly, this finding was in agreement with the number of bound antibodies per cell (1170–8987) measured in bone marrow plasma cells from patients with newly diagnosed or relapsed multiple myeloma.…”