BMS-986458 a Potential First-in-Class, Highly Selective, Potent and Well Tolerated BCL6 Ligand Directed Degrader (LDD) Demonstrates Multi-Modal Anti-Tumor Efficacy for the Treatment of B-Cell Non-Hodgkin's Lymphoma

• Published in: Blood 2024-11, Vol.144 (Supplement 1), p.957-957
• Main Authors: Groocock, Lynda, Deb, Gauri, Zhu, Jinyi, Gamez, Jim, Castiglioni, Paola, Sanchez-Castillo, Manuel, Schumacher, Justin, Rondan, Alicia Benitez, Jankeel, Diana, Martinez-Garcia, Karla, Wood, Scott, Christoforou, Andy, Guarinos, Carla, Zhang, Wei, Narla, Rama Krishna, Zapf, Christoph W., Carrancio, Soraya, Pierce, Daniel W., Rolfe, Mark, Bence, Neil, Lopez-Girona, Antonia, Mortensen, Deborah S.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2024-210951

In malignant B-cell diseases, BCL6 is one of several critical mis-regulated oncogenic factors that are commonly over-expressed in high-risk patient segments in need of safe and tolerable alternatives to immuno-chemotherapeutic standard of care regimens. Furthermore, as a lineage defining factor within the immune microenvironment of follicular diseases (e.g. Teff, Tregs, Tfr and Tfh), targeting BCL6 in this cellular compartment provides an additional layer to the direct anti-tumor mechanism and should lead to therapeutic benefit. Herein, we describe the discovery and preclinical characterization of BMS-986458, a highly selective, orally bioavailable CRL4CRBN E3 ubiquitin ligase-dependent BCL6 ligand directed degrader, as a heterobifunctional molecule that simultaneously co-opts cereblon (CRBN) and the BCL6 N-terminal BTB domain to catalyze proximity induced degradation of BCL6. In vitro, BMS-986458 rapidly degrades BCL6 protein to levels that drive broad anti-tumor effects in 80% of BCL6 expressing NHL cell lines and all ex vivo patient derived xenograft (PDX) models evaluated. Extensive transcriptomic analysis shows the anti-tumor effect of BCL6 degradation is achieved through modulation of a regulon associated with cell-cycle checkpoints, anti-proliferative signaling and interferon response pathways. A novel component of the BCL6 regulon is repression of the highly efficacious therapeutic surface target CD20, whose downregulation is associated with relapsed/refractory (R/R) disease. Using BMS-986458, we demonstrate a broad enhancement of CD20 transcription, surface expression and clustering, increasing up to 20-fold within 72 hrs across multiple Diffuse Large B-cell Lymphoma (DLBCL) cell line models. This enhancement results in potent synergism of BMS-986458 with anti-CD20 agents from both cell intrinsic and ADCC-mediated anti-tumor mechanisms. The cell intrinsic anti-tumor impact of BCL6 degradation was confirmed in vivo using human cell line-derived xenograft (CDX) and PDX models of R/R DLBCL. In these studies, once daily oral dosing of BMS-986458, resulted in deep and sustained degradation of BCL6 leading to CDX tumor regression and significant survival benefit of PDX models. Furthermore, BMS-986458 in combination with anti-CD20, resulted in tumor regression and tumor free animals (