Evaluation Of Gucy2c-Cd3 Bispecific Targeting Gi Cancers In An Orthotopic Colorectal Tumor Model

GUCY2c is a tumor target expressed in \u003e90% of colorectal cancer (CRC). It is also expressed on the apical side of intestinal epithelial tight junctions, where it regulates intestinal fluidity. PF-07062119, a GUCY2c-CD3 bispecific antibody that recruits T cells to GUCY2c expressing gastrointestinal tumors, has shown anti-tumor efficacy in several subcutaneous colorectal cancer models without any signs of intestinal toxicity. Here we describe the effects of PF-07062119 in an intestinal orthotopic xenograft model, created surgically in NSG mice using LS1034 CRC cells expressing luciferase. To establish this model, LS1034-luc tumor fragments were sutured onto the cecum proximal to the colon. Tumor growth was monitored through detection of luciferin bioluminescence. PF-07062119 was administered at 0.03, 0.1 and 0.3 mg/kg iv weekly, along with an adoptive transfer of 2x106 human T cells the day after bispecific compound dosing. At 0.3 mg/kg dose, the bioluminescence signal was significantly reduced compared with the isotype control group. Necropsies at the end of study revealed complete tumor clearance, or residual calcified or fibrotic tissues, at the tumor implant site in all animals of the 0.3 mg/kg group, compared with tumor presence in 9 of 9 animals and liver metastases in 2 of 9 animals in the isotype control group. The average tumor weight of 0.1 mg/kg dose group decreased relative to the control group, but the difference did not reach statistical significance. The results of histological examination indicate enhanced T cell infiltration in the tumor tissues compared with the normal intestinal tissues in PF-07062119 treated animals. No body weight loss or other clinical signs were observed in all groups. These results demonstrate that PF-07062119 can eliminate LS1034 orthotopic tumors and potential metastasis with no observable toxicities. This supports our hypothesis that apical restriction of GUCY2c expression in normal intestine creates tumor-vs-normal differential for selective targeting of GUCY2c positive tumors, and the GUCY2c-CD3 bispecific antibody redirects T cells to lyse the CRC tumor cells. Citation Format: Johnny Yao, Divya Mathur, Sharon Yang, Roger Conant, Jessica Kearney, Vlad Buklan, Jonathan Golas, Edward Rosfjord. Evaluation of GUCY2c-CD3 bispecific targeting GI cancers in an orthotopic colorectal tumor model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4549.