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

Mol Cancer Ther. 2021 Feb;20(2):367-378. doi: 10.1158/1535-7163.MCT-20-0287. Epub 2020 Dec 9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amanitins / pharmacology
  • Amanitins / therapeutic use*
  • Animals
  • Cell Death / drug effects*
  • Cell Proliferation
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Female
  • Humans
  • Immunoconjugates / pharmacology
  • Immunoconjugates / therapeutic use*
  • Mice
  • Mice, SCID
  • Multiple Myeloma / drug therapy*


  • Amanitins
  • Enzyme Inhibitors
  • Immunoconjugates