A. Intellectual Property
US provisional patent application No. 62/944,777: Osteopontin Monoclonal Antibodies for Cancer and Osteoporosis Immunotherapy, was file on December 12, 2019
Licensing Contact: Mr. Carl Clark, Director Innovation Commercialization, Augusta University, 1120 15th Street, Augusta. GA 30912. USA.
B. Colorectal and Pancreatic Cancer Immunotherapy Background and Market Value
B1. A significant challenge in human colorectal cancer therapy: Human colorectal cancer does not respond to immune checkpoint inhibitor immunotherapy.
Immunotherapy is an emerging field that represents a paradigm shift in human cancer treatment. Immune checkpoint inhibitor (ICI) monoclonal antibodies that target cytotoxic T lymphocyte-associated protein 4 (CTLA-4) or programmed death ligand 1 (PD-L1)/programmed death 1 (PD-1) have generated durable efficacy in many types of human cancers. Compelling data from human colorectal cancer (CRC) patients and mouse tumor models demonstrated that colorectal cancer is a highly immunogenic tumor type1-8. It is therefore unexpected that CRC, except for the small subset of microsatellite instable CRC (MSI, ~4% of total CRC cases)9, 10, does not respond to ICI immunotherapy11. Our published studies determined that PD-L1 is highly expressed in human colon carcinoma cells12 and CTL infiltrates are present in both MSS and MSI human colon carcinoma13. Our published studies thus indicate that CTL functional deficiency, not CTL infiltration level, is likely one of the underlying mechanisms of MSS CRC non-response to anti-PD-1 immunotherapy. It is therefore likely that other immune checkpoint(s) may compensate PD-L1 function in suppression of tumor-infiltrating CTLs in human CRC, resulting in non-response of human CRC to anti-PD-1 immunotherapy. We have recently determined that OPN as such another immune checkpoint in human colorectal cancer.
B2. Human pancreatic cancer also does not respond to ICI immunotherapy.
According to the American Cancer Society, the 5-year survival rate for human pancreatic cancer patients is 6%, and the median survival time for patients with locally advanced pancreatic cancer that accounts for over 80% of all pancreatic cancer cases is 6-10 months14. Gemcitabine is the standard therapy for human pancreatic cancer, but Gemcitabine increased a medium suivival time of only 5 weeks. Pancreatic cancer is thus essentially a death sentence for patients with this disease as there are few treatment options.
Three clinical trials for anti-PD-1/PD-L1 immunotherapy in pancreatic have been published. The first was a phase I trial evaluating the anti-PD-L1 antibody MS-936559 in several cancer types. While objective responses were achieved in melanoma, non-small cell lung cancer, renal-cell cancer, and ovarian cancer, no response was observed in the 14 pancreatic cancer patients11. Similarly disappointing results were seen in a phase IIA trial with anti-PD-L1 antibody Durvalumab; no objective response was seen in 60 pancreatic cancer patients15. However, a robust 62% objective response rate to pembrolizumab was observed in pancreatic cancer patients with mismatch repair deficient (MMR-D) (n=8)10. Therefore, limited efficacy of anti-PD-1 therapy is confounded by the low prevalence of MMR-D tumors in pancreatic cancer patients, only 0.8%16. Similar short-comings were seen in response to anti-CTLA-4 mAb immunotherapy. In a phase II trial, no response to Ipilimumab was observed in the 27 subjects, with delayed regression seen in only one patient17. Similarly, no objective response was achieved in a phase IIA trial with 60 pancreatic cancer patients17. Combinational immunotherapy of anti-PD-L1 and anti-CTLA-4 mAbs has shown increased efficacy, albeit at a low rate with an objective response rate of 3.1%17. Human pancreatic cancer therefore essentially does not respond to current ICI immunotherapy. As discussed above, our experimental data support the notion that OPN is another immune checkpoint that compensates PD-L1 function to confer pancreatic cancer non-response to ICI/anti-PD-1 immunotherapy.
There are currently no effective immunotherapy for human colorectal and pancreatic cancers. There is therefore a large market for immunoptherapeutic agnets for treating colorectal and pancreatic cancer patients. OPN monoclonal antibody represents a first-in-class promissing immunotherapeutic agent for human clolorectal and pancreatic cancers.