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
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. 
Published: December 2024

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 (&lt;70%), without body weight loss. In additional studies, we demonstrate using both in vitro T-follicular helper cell (Tfh) differentiation assays and evaluation of immunocompetent mice, that BMS-986458 treatment phenotypically modulates lymph-resident Tfh populations without affecting cellular viability, highlighting the potential functional impact of BCL6 degradation on this pro-tumor immune compartment. Non-clinical safety evaluations show that in addition to the absence of impact on normal bone marrow populations in vitro, BMS-986458 is pharmacodynamically active and well tolerated in vivo following 28-day dog toxicity studies.

In summary, the robust cell intrinsic mechanism of BMS-986458 across BCL6-expressing NHL tumors together with its stimulation of CD20 surface expression and the immunomodulatory impact on Tfh populations, demonstrate that BCL6 degradation using BMS-986458 has the potential to be highly efficacious and represents a novel mechanism of action for NHL therapy. Collectively, this evidence supports its current clinical investigation as an orally dosed single agent or in combination with an anti-CD20 agent (NCT06090539), providing a potential first-in-class chemo-free therapeutic option for B-cell NHL patients.