Targeting BCMA with HDP-101: A Promising Antibody-Drug Conjugate for Multiple Myeloma Therapy

A new type of antibody-drug conjugate (ADC) called ATACs, which use amanitin as a toxic payload to bind to eukaryotic RNA pol II and inhibit cellular transcription, has been studied. The research focuses on HDP-101, an ADC targeting BCMA, a protein found on malignant plasma cells in multiple myeloma (MM), making it an ideal target for this therapy. In vitro and in vivo studies were conducted using MM cell lines and an antibody produced by Heidelberg Pharma. HDP-101 was synthesized by conjugating maleimide amanitin compounds to the anti-BCMA antibody. Cytotoxicity was measured using CellTiter Glo 2.0 and WST.1 assays, and animal models included both subcutaneous and metastatic MM xenograft tumors in mice and tolerability studies in mice and nonhuman primates.

HDP-101 demonstrated potent in vitro cytotoxicity against BCMA-positive cell lines at a picomolar level, with no effect on BCMA-negative cells. In mouse models, HDP-101 induced tumor regression and complete remission at specific doses. Safety studies in monkeys showed good tolerability, with minor and temporary increases in liver enzymes and LDH. The ADC had a serum half-life of 7-9 days, and the free toxin was barely detectable.

The study concludes that HDP-101, an anti-BCMA-ATAC, effectively delivers targeted cytotoxic drugs to BCMA-positive MM cells. Amanitin's mode of action resulted in significant anti-tumor effects both in vitro and in vivo, with promising tolerability in nonhuman primates. This approach to treating MM with ADCs is considered promising, especially given the unique action of the cytotoxic agent used. A first-in-human trial is anticipated to commence in 2018.