Abstract 2477: Engineered toxin bodies: A next-generation immunotoxin scaffold with novel immuno-oncology functionality
Authors: Willert Erin K. , Robinson Garrett L. , Rajagopalan Sangeetha , Brieschke Brigitte , Erdman Jennifer , Neill Jane , Flores Rodney , Foree Julia , Null William , Liu Jensing , Higgins Jack P. 
Published: August 2015

The potential of immunotoxins in oncology has been largely limited due to problems with immunogenicity as well as a limited number of appropriate targets. Advances in genetic engineering and molecular biology have been applied to overcome these limitations. Molecular Templates has developed engineered toxin bodies (ETBs), a next-generation recombinant immunotoxin scaffold based on the Shiga-like toxin A subunit specifically directed to cancer cells via antibody fragment binding domains. ETBs have been de-immunogenized through the systematic and comprehensive removal of B- and T-cell epitopes. Data from the repeat administration of ETBs in animal models demonstrates the dramatically reduced immunogenicity of these ETBs and supports the potential for their use in solid tumor settings.

The ETB scaffold was also engineered to force the internalization of receptors that typically do not internalize. This property of forced internalization expands the universe of possible targets; the company's lead compound, MT-3724, is the first immunotoxin to CD20 to enter the clinic and is currently in a phase I study for refractory NHL. MT-3724 rapidly internalizes and potently kills CD20+ lymphoma cells.

Additionally, we have taken advantage of the immunotoxin's localization to the cytosol to engineer in a novel immuno-oncology mechanism of action: MHC class I antigens derived from human cytomegalovirus (HCMV) have been genetically fused to the immunotoxin scaffold in order to mark these cells as targets for cytotoxic T lymphocyte (CTL) mediated cell lysis. We have detected these foreign protein derived antigens displayed on the surface of ETB-intoxicated cancer cells in context with MHC class I molecules. Because antigen presentation does not require de novo protein synthesis, this mechanism of action is complementary to the inactivation of ribosomal function by ETBs. Since a large portion of the populace has a robust population of high-affinity effector T-cells targeting HCMV, the presentation of these antigens on ETB-intoxicated cancer cells may recruit a CTL response to tumor cells that is not dependent on genetically engineering host T-cells or blocking checkpoint inhibitors. The recruitment of a CTL response has the potential to act additively or synergistically to the direct cell kill activity of the ETB and may expand the potential efficacy of these immunotoxins.

Citation Format: Erin K. Willert, Garrett L. Robinson, Sangeetha Rajagopalan, Brigitte Brieschke, Jennifer Erdman, Jane Neill, Rodney Flores, Julia Foree, William Null, Jensing Liu, Jack P. Higgins. Engineered toxin bodies: A next-generation immunotoxin scaffold with novel immuno-oncology functionality. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2477. doi:10.1158/1538-7445.AM2015-2477