Anti-Tumour Efficacy Study Of The Bruton’s Tyrosine Kinase (Btk) Inhibitor, ONO-4059, In Combination With The Glycoengineered Type II Anti-CD20 Monoclonal Antibody, Obinutuzumab (GA101) Demonstrates Superior In Vivo Efficacy Compared To ONO-4059 In Combination With Rituximab
Authors: Yoshizawa Toshio , Yasuhiro Tomoko , Birkett Joseph TP , Klein Christian , Kawabata Kazuhito 
Published: October 2019

Abstract

Purpose
The activated B-cell-like (ABC) sub-type of diffuse large B-cell lymphoma (DLBCL) correlates with poor prognosis. There is still a high medical need for new therapies, preferably chemo-sparing, to help treat patients with ABC-DLBCL and CLL as well as other B-cell malignancies. The B-cell receptor signaling pathway is known to be dysregulated in NHL/CLL and given Btk is a downstream mediator of BCR signalling, Btk constitutes an interesting and obvious therapeutic target. Given the high potency and selectivity of the novel Btk inhibitor ONO-4059, it was hypothesized that, the anti-tumour activity of ONO-4059 could be further enhanced by combining it with the anti-CD20 Abs, Obinutuzumab (GA101) or Rituximab (RTX), as a novel therapeutic strategy.

Methods
TMD-8 tumour cells, a human ABC-DLBCL cell line, were implanted sub-cutaneously into female SCID mice. Randomization of mice occurred when mean tumour volume was 400-450 mm3. ONO-4059 was administered orally at a dose of 10 mg/kg bid, and GA101 or RTX were administered intravenously both at a sub-optimal dose of 3 mg/kg once weekly. Tumour volumes were measured twice a week after initiation of treatment, and tumour volumes were determined using the formula volume (= width2 x length)/2. Animals were euthanized when the tumours reached a maximum volume of 3,000 mm3.

Results
Treatment with ONO-4059 combined with either GA101 or RTX resulted in a significant inhibition of tumour growth in the TMD-8 xenograft model. GA101 monotherapy showed superior anti-tumour activity compared with RTX monotherapy in terms of tumor growth inhibition (TGI 78% vs 54% at day 21). ONO-4059 combined with GA101 or RTX at sub-optimal doses was significantly better than the respective Abs or ONO-4059 given as monotherapy with TGI of 90% for the GA101 combination and 86% for the rituximab combination. ONO-4059 as single agent mediated a TGI of 63%. In addition combination treatment with GA101 resulted in tumour remission in 3/10 animals, whereas combination treatment with rituximab resulted in tumor remission in only1/10 animals. GA101 monotherapy resulted in 1/10 tumor-free animals, whereas no tumor free animals were observed in the rituximab and ONO-4059 monotherapy groups.

Conclusion
Recent studies indicate that targeting Btk is effective in the treatment of B-cell malignancies. Our results demonstrate that treatment with ONO-4059 in combination with GA101 or rituximab results in a combined effect in vivo and is superior to the respective monotherapies. Furthermore, ONO-4059 in combination with the novel glycoengineered Type II CD20 antibody GA101 is more effective than the combination of ONO-4059 with rituximab in this DLBCL xenograft model. When interpreting these data it should be noted that both, obinutuzumab and rituximab were dosed at sub-optimal doses as they can induce tumor remission when dosed at 10 mg/kg. Taken together these data indicate that the combination of ONO-4059 with rituximab, and particularily obinutuzumab may be an effective treatment for ABC-DLBCL.

Disclosures:
Yoshizawa: Ono Pharmaceutical CO., Ltd: Employment. Yasuhiro:Ono Pharmaceutical Co., Ltd.: Employment. Birkett:Ono Pharma UK: Employment. Klein:Roche Glycart AG: Employment. Kawabata:Ono Pharmaceutical Co., Ltd.: Employment.