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1141 DKN-01 demonstrates immune modulatory activity and robust efficacy in colorectal cancer models
  1. Michael Haas1,
  2. Michael Kagey1,
  3. Walter Newman1,
  4. James Rottman2,
  5. Milad Moloudizargari3,
  6. Ajay Goel3,
  7. Cynthia Sirard1 and
  8. Jason Baum1
  1. 1Leap Therapeutics, Cambridge, MA, USA
  2. 2Athenaeum Pathology Consulting, LLC, Sudbury, MA, USA
  3. 3Beckman Research Institute, Duarte, CA, USA


Background Colorectal cancer (CRC) is the third most prevalent cancer and the second leading cause of cancer-related death worldwide. CRC has elevated Wnt signaling activity in which DKK1 plays a regulatory role. DKN-01 is an IgG4 clinical stage antibody that specifically neutralizes DKK1. Fluorouracil (5FU)-based therapies are the standard backbone treatment for CRC and have demonstrated clinical activity in combination with DKN-01 in gastroesophageal adenocarcinoma (GEA). DKK1 expression has been shown to correlate with 5FU resistance in CRC tumors and cell lines. We evaluated the efficacy of DKN-01 alone and in combination with 5FU in parental and 5FU-resistant HCT116 and SW480 xenograft models. Further, given the established role of DKK1 on TME modulation, we also explored treatment with DKN-01 as a monotherapy and in combination with anti-PD-1 in a CT26 syngeneic CRC model.

Methods For the xenograft models, athymic nude mice were inoculated subcutaneously (SC) with either parental or 5FU-resistant colon carcinoma cell lines. Once tumors reached 50mm3, dosing was initiated with either isotype control, DKN-01, 5FU, or the combination. For the CT26 syngeneic model, BALB/c mice were inoculated SC with CT26 mouse colon carcinoma cells. Once tumors reached 50mm3, dosing initiated with either isotype control, a murinized version of DKN-01 (mDKN-01), anti-PD-1, or the combination.

Results In the parental HCT116 model, 30%, 39%, and 55% tumor growth inhibition (TGI) were observed in the DKN-01, 5FU, and combination treatment groups compared to isotype controls. Strikingly, in the HCT116 5FU-resistant model, 5FU had a negligible effect on TGI compared to DKN-01 monotherapy; and combination treatment groups in both 5FU-resistant models experienced 100% tumor regression. In the CT26 syngeneic model, mDKN-01 monotherapy resulted in 71% TGI with 47% of the group experiencing tumor regression at study termination unlike the anti-PD-1 monotherapy which had negligible TGI. The effect of mDKN-01 was further enhanced by the combination resulting in an additional 58% TGI with 73% of the group experiencing tumor regression. Notably, a robust inflammatory infiltrate was observed in the tumors of mDKN-01 monotherapy and combination groups, correlating with the level of necrosis. In addition, a significant increase in PD-L1 staining occurred with mDKN-01 monotherapy.

Conclusions In multiple models of CRC, DKN-01 showed strong anti-tumor effects. This included tumor regression in a 5FU-resistant setting reflective of second line CRC, as well as significant monotherapy efficacy and synergy with anti-PD-1.

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