Development of a Bruton's Tyrosine Kinase (Btk) Inhibitor, ONO-WG-307: Efficacy in ABC-DLBCL Xenograft Model – Potential Treatment for B-Cell Malignancies,

Abstract

3731 Purpose: ONO-WG-307 is a small molecule inhibitor that covalently binds to Btk. Signals from B cell receptors (BCR) play a central role in signal transduction pathways regulating survival, activation, proliferation, and differentiation of B-lineage lymphoid cells. BCR signaling is implicated in the survival of malignant B cells and recent studies indicate that targeting Btk, an essential component of the BCR pathway, may be effective in the treatment of B-cell lymphoma. The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) correlates with poor prognosis and new therapies, preferably chemo-sparing therapies, or as add-on to existing treatment regimens are required to help treat patients with ABC-DLBCL. Therefore, Btk constitutes an interesting therapeutic target, thus the activity of ONO-WG-307 was evaluated in an ABC-DLBCL xenograft model. Methods: Tumor cells (TMD-8) were implanted subcutaneously into female SCID mice. Tumors were allowed to grow to a volume of 100–200 mm3 before the mice were randomized into groups based on tumor size. ONO-WG-307 was administered orally at doses up to 10 mg/kg bid. Tumors were measured two or three times weekly after initiation of treatment, and tumor volumes were determined using the formula volume (=width2xlength)/2. Animals were euthanized when the tumors reached a maximum volume of 2,000 mm3 or after a maximum period of 2 months. In parallel, an exploratory pharmacodynamic marker of Btk inhibition (Phosphorylated-Btk [P-Btk]) was also investigated in vivo. Results: Treatment with ONO-WG-307 resulted in a dose-dependent inhibition of tumor growth in a TMD-8 xenograft model. Furthermore, parallel analysis of a pharmacodynamic marker, P-Btk, supported that Btk was inhibited and the level of P-Btk inhibition was correlated with the decreased tumor volumes observed in the TMD-8 model. Conclusion: ONO-WG-307 is a highly potent and selective oral Btk inhibitor with evidence of efficacy in the ABC-DLBCL xenograft model, with Btk inhibition further supported using a PD marker. Given the need to treat and overcome disease resistance especially in ABC-DLBCL, the use of a Btk inhibitor is a novel, mechanistic approach to treating B cell malignancies. Additional work is underway, combining ONO-WG-307 with chemotherapy and other targeted agents. Disclosures: No relevant conflicts of interest to declare.

Homogeneous BTK Occupancy Assay for Pharmacodynamic Assessment of Tirabrutinib (GS-4059/ONO-4059) Target Engagement

“… 20 It shows in vitro antiproliferative activity on follicular lymphoma, MCL, and CLL cell lines and on ABC-DLBCL in TMD8 mouse xenograft models. 32 , 33 Tirabrutinib is currently in clinical development for CLL, MCL, and DLBCL and has shown promising clinical activity in patients with B-cell malignancies. 23 Correlation of tirabrutinib target engagement at the molecular level with pharmacological and phenotypic disease observations is crucial for establishing the appropriate clinical dose.…”

Targeting Bruton's tyrosine kinase for the treatment of B cell associated malignancies and autoimmune diseases: Preclinical and clinical developments of small molecule inhibitors

“…In a TMD‐8 xenograft model of ABC‐DLBCL, treatment with ONO‐4059 resulted in a dose‐dependent inhibition of tumor growth. Despite the acrylyl group of ONO‐4059 which is a feature structure of covalently binding ligands, data indicated that ONO‐4059 may adopt a reversible binding mechanism …”

Bruton’s tyrosine kinase inhibitors and their clinical potential in the treatment of B-cell malignancies: focus on ibrutinib

“…2012]. In vitro , ONO-4059 diminishes proliferation or FL, MCL, and CLL cell lines and shows therapeutic promise in combination with rituximab [Kozaki et al . 2011, 2012].…”

“…2011, 2012]. In vivo studies in mouse xenograft models indicate activity against the ABC subtype of DLBCL [Kozaki et al . 2011].…”