AACR 2017 | Poster 3651/24 – Preclinical examination of the effects of a CD20-specific engineered toxin body, MT-3724, in Mantle Cell Lymphoma

At the American Association for Cancer Research (AACR) annual meeting in Washington, DC, USA, on Tuesday 4^th April, a poster session titled “BITES Bispecifics and Checkpoints” took place.

One of the posters on display (3651 / 24) was titled “Preclinical examination of the effects of MT-3724, an engineered toxin body targeting CD20, in mantle cell lymphoma” by Shengjiang Huang from the University of Texas MD Anderson Cancer Center, Houston, TX, and colleagues.

MT-3724 binds CD20 and is take up by the cell where the toxin travels to the cytosol to enzymatically and permanently inactivates ribosomes preventing protein synthesis. MT-3724 may decrease cell proliferation and induce apoptosis in MCL.

The group analyzed 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). Levels of apoptotic cells in ibrutinib-sensitive and -resistant cell lines treated with MT-3724 was measured by Annexin V/ PI staining. In addition, an in vivo efficacy assay of MT-3724 in a MCL PDX model, derived from a patient resistant to a wide-range of drugs including ibrutinib, was conducted.

Key Highlights:

• MT-3724 effectively and efficiently inhibited cell proliferation in a dose-dependent manner in the majority of ibrutinib-sensitive and -resistant cell lines
• IC₅₀ <500ng/ml was considered as sensitive to MT-3724 and IC₅₀ >500ng/ml was determined resistant to MT-3724
• Three ibrutinib-sensitive cell lines (Jeko-1, Mino, and Rec-1) were sensitive to MT-3724: IC₅₀ values = 139.1, 309.3, and 457.7ng/ml, respectively
• Four ibrutinib-resistant cell lines (Maver-1, JVM-13, Jeko-R, and Granta519) were sensitive to MT-3724: IC₅₀ values = 124.6, 155.1, 266.2, and 442.4ng/ml, respectively
• One cell line (Z-138) was resistant to MT-3724 (IC₅₀ = 1231ng/ml)
• No significant differences in IC₅₀ values found between ibrutinib-sensitive and -resistant cell lines (P = 0.36)
• In a time-dependent assay, 300ng/ml MT-3724 decreased cell proliferation in two ibrutinib-sensitive cell lines (Mino and Jeko-1) and two resistant cell lines (Jeko-R and Maver-1)
• MT-3724 induced apoptosis in both sensitive (Jeko-1) and resistant (Jeko-R and Maver-1) lines
• Apoptosis was induced by MT-3724 by increasing expression of cleaved PARP, as well as decreasing expression of BCL-2 and MCL-1
• MT-3724 was administered via intraperitoneal injection for three consecutive weeks in PDX model resistant to a wide-range of targeted agents; MT-3724 greatly reduced tumor burden and increased survival (median of 27 days) of the PDX mice

In conclusion, MT-3724 appears to be a potential therapeutic agent for combating ibrutinib resistance in MCL; combinations with this agent should be investigated to achieve higher efficacy.