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 superior in vivo efficacy compared to ONO/GS-4059 in combination with rituximab.
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.
a Ono Pharmaceutical Co, Ltd , Osaka , Japan.
Tomoko
T
Yasuhiro
a Ono Pharmaceutical Co, Ltd , Osaka , Japan.
Wako
W
Sawada
b Roche Pharmaceutical Research & Early Development, Roche Innovation Center Zurich , Schlieren , Switzerland.
Christian
C
Klein
a Ono Pharmaceutical Co, Ltd , Osaka , Japan.
Ryohei
R
Kozaki
a Ono Pharmaceutical Co, Ltd , Osaka , Japan.
Shingo
S
Hotta
a Ono Pharmaceutical Co, Ltd , Osaka , Japan.
Toshio
T
Yoshizawa
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D000069283:Rituximab / Q000008:administration & dosage / Q000494:pharmacology; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D061067:Antibodies, Monoclonal, Humanized; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000069283:Rituximab; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; C080813:emt protein-tyrosine kinase; C000608238:tirabrutinib; C543332:obinutuzumab
ABC-DLBCL; Bruton’s tyrosine kinase; obinutuzumab; rituximab