Gene expression data from multiple myeloma cell lines treated with Novel Anti-B-cell Maturation Antigen α-Amanitin Antibody-drug Conjugate, HDP-101.

ABSTRACT: Deletion (Del) of 17p involving the TP53 tumor suppressor remains an adverse prognostic factor in multiple myeloma, and more effective targeted therapies are needed for these patients. Genomic studies revealed that del17p was associated with reduced copy number and mRNA expression of RNA polymerase II subunit alpha (POLR2A), which is located near TP53. We therefore studied HDP-101, an anti-B-cell maturation antigen (BCMA) antibody drug conjugate (ADC) with the POLR2A poison α-amanitin, which showed potent anti-proliferative and pro-apoptotic activity against cell lines and primary samples. POLR2A knockdown (KD) in both TP53 wild-type (WT) and knockout (KO) cells, with the latter being a model of del17p, enhanced sensitivity to HDP-101 compared to POLR2A WT cells. Gene expression profiling and proteomic studies showed evidence for activation of endoplasmic reticulum stress and the unfolded protein response, as well as a reduction of anti-apoptotic proteins such as Myeloid cell leukemia (MCL)-1. Bortezomib enhanced the activity of HDP-101, as did a gamma-secretase inhibitor, and this ADC overcame resistance both due to microenvironmental factors and in acquired drug resistance models. Finally, HDP-101 was well tolerated in vivo, reduced disease burden with single, 2-4 mg/kg doses, and no evidence of relapse was seen out to 100 days, even in xenografts that modeled del17p through dual TP53 KO/POLR2A KD, which grew more aggressively without treatment. Together, the data validate the efficacy of a new BCMA ADC that is ready for clinical translation, and suggest that it could be equipotent, or perhaps even more effective against myeloma with del17p. We used microarray to investigate the global changes caused by HDP-101 across p53 Wt and p53 KO multiple myeloma cell lines

ORGANISM(S): Homo sapiens

PROVIDER: GSE148242 | GEO | 2020/04/08

REPOSITORIES: GEO