PMID- 38260385 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240202 DP - 2024 Jan 11 TI - Novel Anti-B-cell Maturation Antigen Alpha-Amanitin Antibody-drug Conjugate HDP-101 Shows Superior Activity to Belantamab Mafodotin and Enhanced Efficacy in Deletion 17p Myeloma Models. LID - rs.3.rs-3843028 [pii] LID - 10.21203/rs.3.rs-3843028/v1 [doi] AB - B-cell maturation antigen (BCMA) plays a pathobiologic role in myeloma and is a validated target with five BCMA-specific therapeutics having been approved for relapsed/refractory disease. However, these drugs are not curative, and responses are inferior in patients with molecularly-defined high-risk disease, including those with deletion 17p (del17p) involving the tumor suppressor TP53, supporting the need for further drug development. Del17p has been associated with reduced copy number and gene expression of RNA polymerase II subunit alpha (POLR2A) in other tumor types. We therefore studied the possibility that HDP-101, an anti-BCMA antibody drug conjugate (ADC) with the POLR2A poison alpha-amanitin could be an attractive agent in myeloma, especially with del17p. HDP-101 reduced viability in myeloma cell lines representing different molecular disease subtypes, and overcame adhesion-mediated and both conventional and novel drug resistance. After confirming that del17p is associated with reduced POLR2A levels in publicly available myeloma patient databases, we engineered TP53 wild-type cells with a TP53 knockout (KO), POLR2A knockdown (KD), or both, the latter to mimic del17p. HDP-101 showed potent anti-myeloma activity against all tested cell lines, and exerted enhanced efficacy against POLR2A KD and dual TP53 KO/POLR2A KD cells. Mechanistic studies showed HDP-101 up-regulated the unfolded protein response, activated apoptosis, and induced immunogenic cell death. Notably, HDP-101 impacted CD138-positive but not-negative primary cells, showed potent efficacy against aldehyde dehydrogenase-positive clonogenic cells, and eradicated myeloma in an in vivo cell line-derived xenograft (CDX). Interestingly, in the CDX model, prior treatment with HDP-101 precluded subsequent engraftment on tumor cell line rechallenge in a manner that appeared to be dependent in part on natural killer cells and macrophages. Finally, HDP-101 was superior to the BCMA-targeted ADC belantamab mafodotin against cell lines and primary myeloma cells in vitro, and in an in vivo CDX. Together, the data support the rationale for translation of HDP-101 to the clinic, where it is now undergoing Phase I trials, and suggest that it could emerge as a more potent ADC for myeloma with especially interesting activity against the high-risk del17p myeloma subtype. FAU - Singh, Ram Kumar AU - Singh RK AD - The University of Texas MD Anderson Cancer Center. FAU - Jones, Richard J AU - Jones RJ AD - The University of Texas MD Anderson Cancer Center. FAU - Shirazi, Fazal AU - Shirazi F AD - The University of Texas MD Anderson Cancer Center. FAU - Qin, Li AU - Qin L AD - The University of Texas MD Anderson Cancer Center. FAU - Zou, Jianxuan AU - Zou J AD - The University of Texas MD Anderson Cancer Center. FAU - Hong, Samuel AU - Hong S AD - The University of Texas MD Anderson Cancer Center. FAU - Wang, Hua AU - Wang H AD - The University of Texas MD Anderson Cancer Center. FAU - Lee, Hans C AU - Lee HC AD - The University of Texas MD Anderson Cancer Center. FAU - Patel, Krina K AU - Patel KK AD - The University of Texas MD Anderson Cancer Center. FAU - Wan, Jie AU - Wan J AD - The University of Texas MD Anderson Cancer Center. FAU - Choudhary, Rajan Kumar AU - Choudhary RK AD - The University of Texas MD Anderson Cancer Center. FAU - Kuiatse, Isere AU - Kuiatse I AD - The University of Texas MD Anderson Cancer Center. FAU - Pahl, Andreas AU - Pahl A AD - Heidelberg Pharma AG. FAU - Orlowski, Robert Z AU - Orlowski RZ AD - The University of Texas MD Anderson Cancer Center. LA - eng GR - P30 CA016672/CA/NCI NIH HHS/United States GR - R01 CA266612/CA/NCI NIH HHS/United States PT - Preprint DEP - 20240111 PL - United States TA - Res Sq JT - Research square JID - 101768035 PMC - PMC10802748 OTO - NOTNLM OT - Deletion 17p OT - HDP-101 OT - p53 OT - proteasome capacity OT - proteasome inhibitor sensitivity COIS- Disclosure of Conflicts of Interest H.C.L. has provided consultancy services to Amgen, Inc., Celgene, a wholly owned subsidiary of Bristol-Myers Squibb, GlaxoSmithKline, Janssen Pharmaceutical, Sanofi-Aventis, and Takeda Pharmaceutical, and has received research funding from Amgen, Inc., Celgene, a wholly owned subsidiary of Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Janssen Pharmaceutical, and Takeda Pharmaceuticals. K.K.P. declares research support from Celgene, a wholly owned subsidiary of Bristol-Myers Squibb. A.P. is an employee of Heidelberg Pharma AG, which is developing HDP-101. R.Z.O. declares research funding from Heidelberg Pharma AG related to this work, and unrelated funding from Asylia Therapeutics and BioTheryX. Also, R.Z.O. has served on advisory boards for Amgen, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Sanofi-Aventis, Servier, and Takeda Pharmaceuticals North America, Inc., and is a Founder of Asylia Therapeutics, Inc., with an equity interest. The remaining authors have no conflicts of interest to declare. EDAT- 2024/01/23 12:44 MHDA- 2024/01/23 12:45 PMCR- 2024/01/22 CRDT- 2024/01/23 10:36 PHST- 2024/01/23 12:44 [pubmed] PHST- 2024/01/23 12:45 [medline] PHST- 2024/01/23 10:36 [entrez] PHST- 2024/01/22 00:00 [pmc-release] AID - rs.3.rs-3843028 [pii] AID - 10.21203/rs.3.rs-3843028/v1 [doi] PST - epublish SO - Res Sq [Preprint]. 2024 Jan 11:rs.3.rs-3843028. doi: 10.21203/rs.3.rs-3843028/v1.