Abstract 2384: TAK-169, an exceptionally potent CD38 targeted engineered toxin body, as a novel direct cell kill approach for the treatment of multiple myeloma
Authors: Willert Erin K. , Robinson Garrett L. , Higgins Jack P. , Liu Jensing , Lee Janice , Syed Sakeena , Zhang Yuhong , Tavares Dan , Lublinsky Anya , Chattopadhyay Nibedita , Wang Haiqing , Packer Laura , Shi Pu , Harbison Carole , Patel Sanjay , Newcomb John 
Published: August 2019

Abstract
Advances in the treatment of multiple myeloma have been driven by the development of new modalities, including proteasome inhibitors, immunomodulatory agents and monoclonal antibodies. TAK-169 is an engineered toxin body (ETB) comprising a proprietarily engineered, deimmunized form of the ribosome inactivating Shiga-like toxin A-subunit (SLTA) genetically fused to an antibody fragment that specifically targets the CD38 cell surface receptor. Although CD38 is a poorly internalizing receptor, TAK-169 is able to efficiently internalize and directly kill CD38-expressing cells through the enzymatic and irreversible inhibition of protein synthesis. This novel mechanism of action may be relevant in patients who have progressed after or are unlikely to respond to CD38-targeted antibody therapy. A library of unique CD38-targeting antibodies fused to deimmunized SLTA was screened in a variety of efficacy and safety models to identify TAK-169. TAK-169 demonstrated potent cytotoxicity across a range of myeloma cell lines with a range of CD38 expression in vitro as well as in patient-derived samples including with previous exposure to daratumumab. TAK-169 retains activity in whole blood and PBMCs, indicating that the presence of red blood cells is not restrictive to cytotoxicity. Furthermore, TAK-169 retains activity in the presence of excess approved, CD38 targeted therapeutic daratumumab. TAK-169 is efficacious in several myeloma xenograft models, both subcutaneous and disseminated. Complete regressions were observed using both a once-weekly and bi-weekly schedule. In addition, a syngeneic model cell line expressing human CD38 was shown to be responsive to TAK-169 treatment in an immunocompetent mouse model, suggesting the possibility of immune mediated cell death induced by TAK-169. Tolerability studies in non-human primates demonstrate that repeat administration is tolerated at doses expected to be efficacious. Takeda Pharmaceuticals and Molecular Templates jointly discovered TAK-169 and are co-developing the molecule for the treatment of multiple myeloma. TAK-169 is expected to enter clinical studies in 2019.
Citation Format: Erin K. Willert, Garrett L. Robinson, Jack P. Higgins, Jensing Liu, Janice Lee, Sakeena Syed, Yuhong Zhang, Dan Tavares, Anya Lublinsky, Nibedita Chattopadhyay, Haiqing Wang, Laura Packer, Pu Shi, Carole Harbison, Sanjay Patel, John Newcomb. TAK-169, an exceptionally potent CD38 targeted engineered toxin body, as a novel direct cell kill approach for the treatment of multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2384.