Abstract 3916: Relationship of guanylyl cyclase C (GCC) expression and efficacy of TAK-164, a GCC-targeted antibody-drug conjugate in a panel of 68 subcutaneous HuPrime colorectal cancer PDX models
Authors: Koenig Erik M. , Li Cong , Yang Huyuan , Zhu Andy , Shah Pooja , Nishimura Kazuho , Bannerman Bret , zhang Mengkun , Stringer Bradley , Bahamon Brittany , Veiby O. Petter , Abu-Yousif Adnan 
Published: August 2018

Guanylyl cyclase C (GCC) is a cell surface protein expressed in more than 95% of metastatic colorectal cancers and in the majority of gastric and pancreatic cancers, making GCC an attractive antibody-drug conjugate (ADC) target.

TAK-164 is an ADC comprised of a full-length, fully human IgG1 monoclonal antibody (mAb) directed toward the extracellular domain of GCC. The mAb is conjugated using ImmunoGen's peptide-linked indolinobenzodiazepine DNA alkylator DGN549. Previously presented preclinical studies using TAK-164 have demonstrated in vivo efficacy in a select number of GCC-expressing tumor models following a single administration of TAK-164. Here, we describe the selection of an appropriate dose for broad testing in a panel of patient-derived xenograft models of colorectal cancer. The efficacy data generated following a single administration of 15 µg/kg TAK-164 (payload concentration) were compared with molecular features that could aid in understanding drivers of TAK-164 activity, including GCC expression by immunohistochemistry (IHC).

Primary colorectal cancer models were derived from colorectal adenocarcinomas and implanted in immunocompromised mice. Once tumors reached a stratified mean volume of 150-250 mm3, animals were randomized into treatment groups (n = 1/group) and dosing was initiated on Day 0 of the study. There were three tumor groups (Vehicle treated, TAK-164 treated, and naïve), which were used to characterize genomic and molecular features of the model. The planned study endpoint was 60 days or until a humane endpoint was reached.

For all models included in the study, an IHC assay to detect GCC was used to explore the relationship between GCC expression and time to rise (TTR), a preclinical tumor progression measurement. TTR is the Delta duration in days on study for each PDX model (TAK-164 - Vehicle) to reach 1000 mm3 tumor volume. In the present study, a mixed effects Cox regression analysis, using a continuous or binary stratification of GCC IHC expression, resulted in a statistically significant (p&lt;0.05) increase in TTR in TAK-164−treated mice with higher expression levels of GCC.

Ongoing analysis aims to better understand additional molecular drivers of TAK-164 treatment that may be useful for patient enrichment strategies in the clinic. TAK-164 is scheduled to enter phase I evaluation in 2018 in GCC-positive colorectal cancer and other GI malignancies.

Citation Format: Erik M. Koenig, Cong Li, Huyuan Yang, Andy Zhu, Pooja Shah, Kazuho Nishimura, Bret Bannerman, Mengkun zhang, Bradley Stringer, Brittany Bahamon, O. Petter Veiby, Adnan Abu-Yousif. Relationship of guanylyl cyclase C (GCC) expression and efficacy of TAK-164, a GCC-targeted antibody-drug conjugate in a panel of 68 subcutaneous HuPrime colorectal cancer PDX models [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 3916.