Antibody-mediated blockade of gremlin-1 in combination with gemcitabine or MEK inhibition in a genetically engineered mouse model of pancreatic cancer.

Abstract

705 Background: The tumor microenvironment encompasses complex interactions between cancer cells, fibroblasts, and immune cells, including induction of matricellular proteins that can promote tumorigenesis. One such factor is the bone morphogenetic protein (BMP) antagonist gremlin-1, which has been linked to poor prognosis in multiple human cancer types, including pancreatic ductal adenocarcinoma (PDAC), which has a poor 5-year survival and high unmet clinical need. Ginisortamab (a fully human gremlin-1 monoclonal antibody) and its murine analog Ab7326 (mouse immunoglobulin G1) block gremlin-1’s interaction with BMPs 2, 4, & 7, thereby promoting BMP signaling. Methods: We used a genetically engineered mouse model of pancreatic cancer to evaluate the therapeutic effect of antibody-mediated inhibition of gremlin-1 (Ab7326) alone, or in combination with gemcitabine or a MEK 1/2 inhibitor (selumetinib or UCB-554). LSL-Kras G12D/+ ; LSL-Trp53 R172H/+ ; Pdx1-Cre (KPC) mice develop spontaneous tumors that mimic human pancreatic cancer in aggression, metastatic potential, and chemotherapy resistance. Treatment of mice was initiated once the cancer was detected by ultrasound imaging, and tumor growth was measured weekly by high-resolution ultrasound until humane endpoints. The Log-rank Mantel-Cox test was used to compare survival times between treatment groups. Results: Treatment with Ab7326 (30 mg/kg subcutaneous injection [s.c.], twice weekly) or gemcitabine (100 mg/kg intraperitoneal injection, twice weekly) alone had a modest effect on survival in this model; however, mice treated with the combination of the two showed a significant increase in survival (n=6, median 36.5 days [range 20–93], p=0.037) compared with vehicle controls (n=6, median 20 days [range 3–29]). Similarly, treatment with a MEK inhibitor alone had a limited effect on survival, but combination of Ab7326 (30 mg/kg s.c. twice weekly) with either selumetinib (25 mg/kg orally, twice daily), or UCB-554 (10 mg/kg orally, every 2 days), slowed tumor growth and significantly prolonged survival (Ab7326 + selumetinib [n=10]: median 29.5 days [range 12–89], p=0.022; Ab7326 + UCB-554 [n=11]: median 32 days [range 16–61], p=0.003) over vehicle controls (n=10, median 12 days [range 7–56]). Conclusions: Blocking gremlin-1 in combination with gemcitabine or MEK inhibition may have benefit in the treatment of pancreatic cancer. Ginisortamab is now in a Phase 2 clinical trial in patients with PDAC.