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957 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

Program: Oral and Poster Abstracts
Type: Oral
Session: 605. Molecular Pharmacology and Drug Resistance: Lymphoid Neoplasms: Novel Therapeutic Approaches in Lymphoma
Hematology Disease Topics & Pathways:
Research, Fundamental Science
Monday, December 9, 2024: 5:00 PM

Lynda Groocock1*, Gauri Deb1*, Jinyi Zhu1*, Jim Gamez1*, Paola Castiglioni1*, Manuel Sanchez-Castillo2*, Justin Schumacher3*, Alicia Benitez Rondan2*, Diana Jankeel1*, Karla Martinez-Garcia1*, Scott Wood1*, Andy Christoforou1*, Carla Guarinos2*, Wei Zhang1*, Rama Krishna Narla1*, Christoph W. Zapf1*, Soraya Carrancio, PhD1*, Daniel W. Pierce4*, Mark Rolfe1, Neil Bence1*, Antonia Lopez-Girona1* and Deborah S. Mortensen1*

1Research and Development, Bristol Myers Squibb, San Diego, CA
2Center for Innovation and Translational Research Europe (CITRE), Bristol Myers Squibb, Seville, Spain
3Research and Development, Bristol Myers Squibb, New Brunswick, NJ
4Research and Development, Bristol Myers Squibb, Brisbane, CA

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 (<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.

Disclosures: Groocock: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Deb: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Zhu: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Gamez: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Castiglioni: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Sanchez-Castillo: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Schumacher: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Rondan: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Jankeel: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Martinez-Garcia: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Wood: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Christoforou: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Guarinos: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Zhang: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Narla: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Zapf: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Carrancio: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Pierce: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Rolfe: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Bence: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Lopez-Girona: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Mortensen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

*signifies non-member of ASH