Anti-tumor efficacy study of the Bruton’s tyrosine kinase (BTK) inhibitor, ONO/GS-4059, in combination with the glycoengineered type II anti-CD20 monoclonal antibody obinutuzumab (GA101) demonstrates superiorin vivoefficacy compared to ONO/GS-4059 in combination with rituximab

Abstract

The activated B-cell diffuse large B-cell-like lymphoma (ABC-DLBCL) correlates with poor prognosis. The B-cell receptor signaling pathway is known to be dysregulated in NHL/CLL and given BTK is a downstream mediator of BCR signaling, BTK constitutes an interesting and obvious therapeutic target. Given the high potency and selectivity of the BTK inhibitor, ONO/GS-4059, it was hypothesized that, the anti-tumor activity of ONO/GS-4059 could be further enhanced by combining it with the anti-CD20 Abs, rituximab (RTX) or obinutuzumab (GA101). ONO/GS-4059 combined with GA101 or RTX was significantly better than the respective monotherapy with tumor growth inhibition (TGI) of 90% for the GA101 combination and 86% for the RTX combination. In contrast, ibrutinib (PCI-32765) combined with RTX did not result in improved efficacy compared with respective monotherapy. Taken together these data indicate that the combination of ONO/GS-4059 with rituximab and particularly obinutuzumab may be an effective treatment for ABC-DLBCL.

Sensitive Detection of the Natural Killer Cell-Mediated Cytotoxicity of Anti-CD20 Antibodies and Its Impairment by B-Cell Receptor Pathway Inhibitors

“…While the impairment of the ADCC of anti-CD20 mAbs by ibrutinib may be partly due to decreased CD20 expression on the surface of CLL cells [ 23 ], we observed that the enhanced ADCC of Fc- and glycoengineered obinutuzumab was less disturbed by ibrutinib than that of rituximab, similar to ADCC-induced cell lysis as well as NK cell activation and degranulation as surrogate markers in autologous systems [ 24 ]. Also with the second-generation of irreversible BTK inhibitors, the ADCC of obinutuzumab against CLL cells was less impaired than that of rituximab, in agreement with reports about the interference of acalabrutinib or tirabrutinib with the ADCC of anti-CD20 mAbs against Mec1 or SUDHL-4 cells, respectively [ 25 ]. The different capacity of ibrutinib and acalabrutinib for interfering with the ADCC of anti-CD20 mAbs became apparent, at inhibitor concentrations of 1 μ M ( Figure 5(a) ) or 10 μ M [ 26 ] in combinations with rituximab or obinutuzumab, respectively.…”

Obinutuzumab (GA101) vs. rituximab significantly enhances cell death, antibody-dependent cytotoxicity and improves overall survival against CD20+ primary mediastinal B-cell lymphoma (PMBL) in a xenograft NOD-scid IL2Rgnull (NSG) mouse model: a potential targeted agent in the treatment of PMBL

“…Constitutive activation of STAT6 pathway in PMBL has been previously reported by other investigators [27]. Differential regulation of AKT phosphorylation by obinutuzumab has also been reported in a 3D NHL model [28,29]. STAT6, NF-κB and PI3K/AKT pathways were reported to be activated in PMBL [2,23].…”

Bruton's tyrosine kinase (Btk) inhibitor tirabrutinib suppresses osteoclastic bone resorption

“…Tirabrutinib is a covalent type inhibitor with comparable efficacy to ibrutinib in the treatment of B-cell malignancies (Walter et al, 2016) and has greater selectivity for Btk ( in vitro IC 50 , 2 nmol/L) and Tec ( in vitro IC 50 , 5 nmol/L) than other kinases, including Lck, Fyn, Lyn and Itk (KINOMEscan platform: 442 kinases) (Yasuhiro et al, 2017). Tirabrutinib inhibits cell proliferation in some malignant B-cell lines but does not inhibit the activation of T-lymphocytes from human PBMCs (Kozaki et al, 2018).…”