HDP101, a Novel B-Cell Maturation Antigen (BCMA)-Targeted Antibody Conjugated to α-Amanitin, Is Active Against Myeloma with Preferential Efficacy Against Pre-Clinical Models of Deletion 17p

Background: Deletion (del) of 17p involving the p53 tumor suppressor (TP53) remains an adverse prognostic factor in multiple myeloma (MM) despite the use of novel agents as well as high-dose chemotherapy with autologous stem cell rescue. Genomic TP53 deletion can cause haploinsufficiency of nearby genes, such as RNA polymerase II subunit A (POLR2A), which ia also located on 17p13.1. We therefore hypothesized that del 17p could reduce POLR2A expression and enhance sensitivity to a-Amanitin, a potent and specific inhibitor of POLR2A and RNA polymerase III. Methods: Pre-clinical studies were performed using HDP101, a monoclonal antibody-drug conjugate (ADC) targeting BCMA linked to a-Amanitin, along with unconjugated BCMA antibody, a-Amanitin, and a non-targeting control ADC in myeloma cell line models. The latter included H929, MM1.S, and MOLP-8 TP53 wild-type (WT) lines and isogenic cells in which TP53 had been knocked out (KO) using CRISPR/Cas9 genome editing techniques. To further model del 17p and POLR2A haploinsufficiency, POLR2A expression was knocked down using shRNAs. Results: Analysis of the Multiple Myeloma Research Foundation CoMMpassSM database revealed that del 17p13 by SeqFISH was associated with a significant reduction in POLR2A expression by RNASeq (26.05431 fragments per kilobase of transcript per million mapped reads (FPKM) with WT vs. 19.2983 FPKM with del 17p13; p Conclusions: Our preliminary data support the possibility that del 17p myeloma may have a therapeutic vulnerability to the POLR2A inhibitor a-Amanitin through loss of TP53, and that this sensitivity is further enhanced by decreased POLR2A expression, which is common among del 17p patients. Moreover, they suggest that HDP101 is a novel potent and specific therapeutic that could show enhanced activity in the clinic especially against high-risk multiple myeloma, where effective therapies are still needed to improve patient outcomes. Disclosures Pahl: Heidelberg Pharma AG: Employment. Orlowski:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Genentech: Consultancy; Poseida: Research Funding; BioTheryX, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium Pharmaceuticals: Consultancy, Research Funding.