Abstract 5769: Targeted Engineered Toxin Bodies provide a novel mechanism of action against HER2 positive cancers
Authors: Brieschke Brigitte , Robinson Garrett L. , Rajagopalan Sangeetha , Ramos Hilario J. , Liu Jensing , Higgins Jack P. , Willert Erin K. 
Published: August 2018

Molecular Templates develops highly potent, specific, next-generation immunotoxins that are proprietarily de-immunized to avoid both innate and adaptive immune recognition. These Engineered Toxin Bodies (ETBs) destroy cancer cells by enzymatic destruction of ribosomes, a mechanism of action (MOA) distinct from that of other therapeutics. Molecular Templates' lead compound, MT-3724, has seen clinical activity in heavily pre-treated lymphoma patients, underscoring the potential for this class of agents to work in the refractory/relapsed setting.

Current modalities for the targeted treatment of HER2 positive breast cancer include monoclonal antibodies, antibody-drug conjugates, and tyrosine kinase inhibitors. Although all these modalities have demonstrated clinical benefit, the majority of patients will unfortunately relapse due to a variety of resistance mechanisms. Upon relapse, most of these patients will still express HER2, allowing for the development of new HER2-targeted modalities.

MT-5111, a HER2-targeted ETB with picomolar potency against HER2 expressing cells, was designed to overcome mechanisms of resistance to current HER2 modalities such as: escape from antibody dependent cell-mediated cytotoxicity (ADCC), alterations in signal transduction, epitope masking, and enhanced small molecule efflux. Additionally, MT-5111 was genetically engineered to reduce the anti-drug antibody response and signalling through innate receptors, allowing for repeat dosing.

MT-5111 binds to an epitope on HER2 distinct from trastuzumab and ado-trastuzumab emtansine (T-DM1), and exhibits effective cytotoxicity on both T-DM1 sensitive and T-DM1 resistant HER2 positive cell lines. The targeting of MT-5111 to a distinct epitope allows for activity of the ETB on cell lines where the trastuzumab epitope is masked, and allows for combination with targeted agents trastuzumab or T-DM1 without competition for binding to HER2. Previous reports have shown that resistance to T-DM1 may be due to increased drug efflux; however, the MT-5111 cytotoxic payload is a large molecule not subject to this mechanism of resistance. Additionally, the novel MOA for MT-5111 should allow for cell kill independent of changes to the tumor microenvironment or alterations in HER2-mediated signal transduction.

Pre-clinical data demonstrate the potent activity of MT-5111, including in T-DM1-resistant cell lines, as well as the potential for co-administering MT-5111 and trastuzumab or T-DM1, allowing for concurrent treatment of two HER2-targeted agents with distinct and non-interfering mechanisms of action. In vitro and in vivo data will be presented, highlighting the potential for MT-5111 as a novel agent under development for treatment of breast carcinomas, and other malignancies overexpressing the HER2 receptor. Molecular Templates intends to initiate clinical studies with MT-5111 in 2018.

Citation Format: Brigitte Brieschke, Garrett L. Robinson, Sangeetha Rajagopalan, Hilario J. Ramos, Jensing Liu, Jack P. Higgins, Erin K. Willert. Targeted Engineered Toxin Bodies provide a novel mechanism of action against HER2 positive cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5769.