A novel BCMA PBD-ADC with ATM/ATR/WEE1 inhibitors or bortezomib induce synergistic lethality in multiple myeloma

Leukemia. 2020 Aug;34(8):2150-2162. doi: 10.1038/s41375-020-0745-9. Epub 2020 Feb 14.


To target mechanisms critical for multiple myeloma (MM) plasma cell adaptations to genomic instabilities and further sustain MM cell killing, we here specifically trigger DNA damage response (DDR) in MM cells by a novel BCMA antibody-drug conjugate (ADC) delivering the DNA cross-linking PBD dimer tesirine, MEDI2228. MEDI2228, more effectively than its anti-tubulin MMAF-ADC homolog, induces cytotoxicity against MM cells regardless of drug resistance, BCMA levels, p53 status, and the protection conferred by bone marrow stromal cells and IL-6. Distinctly, prior to apoptosis, MEDI2228 activates DDRs in MM cells via phosphorylation of ATM/ATR kinases, CHK1/2, CDK1/2, and H2AX, associated with expression of DDR-related genes. Significantly, MEDI2228 synergizes with DDR inhibitors (DDRi s) targeting ATM/ATR/WEE1 checkpoints to induce MM cell lethality. Moreover, suboptimal doses of MEDI2228 and bortezomib (btz) synergistically trigger apoptosis of even drug-resistant MM cells partly via modulation of RAD51 and accumulation of impaired DNA. Such combination further induces superior in vivo efficacy than monotherapy via increased nuclear γH2AX-expressing foci, irreversible DNA damages, and tumor cell death, leading to significantly prolonged host survival. These results indicate leveraging MEDI2228 with DDRi s or btz as novel combination strategies, further supporting ongoing clinical development of MEDI2228 in patients with relapsed and refractory MM.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors*
  • B-Cell Maturation Antigen / immunology*
  • Benzodiazepines / administration & dosage
  • Bortezomib / therapeutic use*
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Line, Tumor
  • DNA Damage
  • Drug Synergism
  • Humans
  • Immunoconjugates / therapeutic use*
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / genetics
  • Multiple Myeloma / pathology
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Pyrroles / administration & dosage


  • B-Cell Maturation Antigen
  • Cell Cycle Proteins
  • Immunoconjugates
  • Pyrroles
  • pyrrolo(2,1-c)(1,4)benzodiazepine
  • Benzodiazepines
  • Bortezomib
  • Protein-Tyrosine Kinases
  • WEE1 protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins