Tak-164, A Gcc-Targeted Antibody-Drug Conjugate (Adc) For The Treatment Of Colorectal Cancers And Other Gi Malignancies

TAK-164 is an antibody-drug conjugate comprising a full-length, fully human IgG1 monoclonal antibody (mAb) directed towards the extracellular domain of guanylyl cyclase C (GCC). The mAb is conjugated using the peptide-linked indolino-benzodiazepine DNA alkylator DGN549 (also known as IGN-P1). TAK-164 demonstrates efficient binding to antigen-expressing cells in vitro, and GCC-dependent uptake that results in cytotoxicity. Following a single administration of TAK-164 in female SCID mice bearing GCC-positive xenografts, the pharmacokinetics of the conjugated antibody component of TAK-164 displayed low plasma clearance. Exposure to the ADC resulted in a dose- and time-dependent increase in DNA damage as measured by the pharmacodynamic marker pH2A.X in GCC-positive tumor-bearing xenografts. To further these observations, antitumor activity of TAK-164 was evaluated in multiple GCC-positive patient-derived xenografts. In these studies, a single intravenous administration of TAK-164 resulted in durable antitumor activity. Furthermore, the use of preclinical imaging demonstrated that TAK-164 preferentially accumulates in GCC-positive tumors, and that treatment response can be monitored using FDG-PET. These promising preclinical data warrant advancement of this ADC to clinical evaluation. Citation Format: Adnan O. Abu-Yousif, Bret M. Bannerman, Donna Cvet, Melissa Gallery, Michelle L. Ganno, Michael D. Smith, Katharine C. Lai, Thomas A. Keating, Jayaprakasam Bolleddula, Bradley Stringer, Mark G. Qian, Afrand Kamali, Kurt Eng, Secil Koseoglu, Cindy Q. Xia, O. Petter Veiby. TAK-164, a GCC-targeted antibody-drug conjugate (ADC) for the treatment of colorectal cancers and other GI malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B120.