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

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

Molecular cancer therapeutics (2020-12-11)
Vianihuini Figueroa-Vazquez, Jonathan Ko, Christian Breunig, Anja Baumann, Nicola Giesen, Anikó Pálfi, Christoph Müller, Christian Lutz, Torsten Hechler, Michael Kulke, Carsten Müller-Tidow, Alwin Krämer, Hartmut Goldschmidt, Andreas Pahl, Marc S Raab
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Pomalidomide, ≥98% (HPLC)
Sigma-Aldrich
α-Amanitin, from Amanita phalloides, ≥85% (HPLC), powder
Sigma-Aldrich
Human TNFRSF17 ELISA Kit