Preclinical Examination Of The Effects Of Mt-3724, An Engineered Toxin Body Targeting Cd20, In Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) accounts for 6-8% of all non-Hodgkin lymphoma cases and is a therapeutic challenge. MCL is characterized by the expression of different B-cell markers such as CD-19, CD-20 and BSAP/PAX5, and CD-20 is strongly expressed and can be used as a potential target. MT-3724 was developed by Molecular Templates and is an engineered toxin body (ETB) targeting CD-20. MT-3724 binds CD-20 and forces its own internalization into the target cell where it subsequently self-routes to the cytosol to enzymatically and permanently inhibit protein synthesis via ribosome inactivation. By selectively and specifically targeting CD20-positive cells, MT-3724 may decrease cell proliferation and induce apoptosis in MCL. We tested the effects of MT-3724 by in vitro cell proliferation in 3 ibrutinib-sensitive cell lines and 5 ibrutinib-resistant cell lines (4 primary resistant and 1 acquired resistant). We also measured the levels of apoptotic cells in both ibrutinib-sensitive and -resistant cell lines treated with MT-3724 by Annexin V/ PI staining. Lastly, we conducted an in vivo efficacy assay of MT-3724 in a MCL PDX model resistant to a wide-range of drugs, including ibrutinib. MT-3724 inhibited cell proliferation effectively and efficiently in most ibrutinib-sensitive and ibrutinib-resistant cell lines in a dose-dependent manner. IC 50 50 u003e 500 ng/ml was considered resistant to MT-3724. Regarding the ibrutinib-sensitive cell lines, the 3 cell lines (Jeko-1, Mino and Rec-1) were sensitive to MT-3724 with IC 50 values of 139.1, 309.3 and 457.7 ng/ml, respectively. Regarding the ibrutinib-resistant cell lines, 4 cell lines (Maver-1, JVM-13, Jeko-R and Granta519) were sensitive to MT-3724 with IC 50 values of 124.6, 155.1, 266.2 and 442.4 ng/ml, respectively, and 1 cell line (Z-138) was resistant to MT-3724 (IC 50 = 1231 ng/ml). However, no significant differences in IC 50 values were found between ibrutinib-sensitive and -resistant cell lines (p = 0.36). In a time-dependent assay, 300 ng/ml MT-3724 also reduced cell proliferation in 2 ibrutinib-sensitive cell lines (Mino and Jeko-1) and 2 ibrutinib-resistant cell lines (Jeko-R and Maver-1) over time. Furthermore, MT-3724 also induced cell apoptosis in both ibrutinib-sensitive (Jeko-1) and -resistant (Jeko-R and Maver-1) cell lines. Lastly, MT-3724 was administered intraperitoneally for three consecutive weeks in a PDX model resistant to a wide-range of targeted agents. Interestingly, MT-3724 dramatically reduced tumor burden and increased survival (median of 27 days) of the PDX mice. MT-3724 is the first toxin engineered body targeting CD-20 used in MCL, which may be a potential therapeutic candidate for MCL, especially for drug-resistant cases. Citation Format: Shengjian Huang, Taylor Bell, Yang Liu, Hui Guo, Carrie Li, Makhdum Ahmed, Laura Lam, Hui Zhang, Zhihong Chen, Michael L. Wang, Leo Zhang, Krystle Nomie. Preclinical examination of the effects of MT-3724, an engineered toxin body targeting CD20, in mantle cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3651. doi:10.1158/1538-7445.AM2017-3651