PRODUCTS UNDER DEVELOPMENT
1.) Epigenetic Agents
2.) OPN Monoclonal Antibodies
3.) COVID-19 Antagonists
PHONE: 706-721-2319

OPN Monocional Antibody

OPN Monocional Antibody

OPN Monocional Antibody

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.
E-mail: Caclark@augusta.edu
Tel; 1-706-721-4055

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.

C. Scientific Data that support OPN as a promising immunotherapeutic agent

C1. Our published data:

  1. Christopher Gromisch, Motaz Qadan, Mariana Albuquerque Machado, Kebin Liu, Yolonda Colson and Mark W. Grinstaff. 2020. Pancreatic Adenocarcinoma: Unconventional Approaches for an Unconventional Disease. Cancer Res. doi: 10.1158/0008-5472.CAN-19-2731. [Epub ahead of print].
  2. John D. Klement, Amy V. Paschall, Priscilla S. Redd, Mohammed L. Ibrahim, Chunwan Lu, Dafeng Yang, Esteban Celis, Scott I. Abrams, Keiko Ozato, and Kebin Liu. 2018. An Osteopontin/CD44 immune checkpoint controls CD8+ T cell activation and tumor immune evasion. J Clin Invest. 128:5549-5560. PMCID: PMC6264631.
  3. Mohammed L. Ibrahim, John D. Klement, Chunwan Lu, Priscilla S. Redd, Wei Xiao, Dafeng Yang, Darren D. Browning, Natasha M. Savage, Phillip J. Buckhaults, Herbert C. Morse III, and Kebin Liu. 2018. Myeloid-Derived Suppressor Cells Produce IL-10 to Elicit DNMT3b-Dependent IRF8 Silencing to Promote Colitis-Associated Colon Tumorigenesis. Cell Rep. 25:3036-3046.
  4. Priscilla S. Redd, Mohammed Ibrahim, Sarah K. Sharman, Amy V. Paschall, Dafeng Yang, and Kebin Liu. 2017. SETD1B activate iNOS expression in myeloid-derived suppressor cells. Cancer Res. 77:2834-2843. PMCID: PMC5495112
  5. Chunwan Lu, Asif Talukder, Natasha Savage, Nagendra Singh and Kebin Liu. 2017. Jak-STAT-mediated chronic inflammation impairs cytotoxic T lymphocyte activation to decrease anti-PD-1 immunotherapy efficacy in pancreatic cancer. OncoImmunology. 6:e1291106. PMCID: PMC5384417
  6. Chunwan Lu, Amy V. Paschall, Huidong Shi, Natasha Savage, Jennifer L. Waller, Maria E. Sabbatini, Nicholas H. Oberlies, Cedric Pearce, Kebin Liu. 2017. The MLL1-H3K4me3 Axis-Mediated Up-Regulation of PD-L1 Contributes to Pancreatic Cancer Immune Evasion. J Natl Cancer Inst. 109:djw283. PMCID: PMC5291187.

C2. Development of the first-in-class OPN monoclonal antibody for human colorectal and pancreatic cancer immunotherapy.

C2.1. PD-L1 expression pattern in human colorectal and pancreatic cancers

We have recently determined that PD-L1 is expressed in human colorectal cancer13. In the literature, it has been reported that PD-L1 expression is sparse in human pancreatic carcinoma tissues18, 19. We made use of a recently developed highly specific and FDA-approved anti-human PD-L1 antibody20 and analyzed human pancreatic carcinoma specimens by IHC. Human tonsil and adrenal tumor tissues were used as

Figure 1. PD-L1 protein levels in human pancreatic carcinomas. A. IHC staining of tumor tissues with anti-PD-L1 antibody. A1: Human tonsil tissues. Yellow arrows indicate PD-L1+ epithelial cells. A2: negative staining without anti-PD-L1 antibody of human tonsil tissue. A3&4: Human adrenal tumor tissues. Yellow arrows indicates PD-L1+ tumor cells and the black arrows point to PD-L1+ monocytes. A5&6: Two human pancreatic adenocarcinoma tissues. Pink arrows indicate PD-L1 protein staining in both cell membrane and cytoplasm. PD-L1-specific staining is indicated by brown color and nuclei were counterstained with hematoxylin in blue. Scale bar=50 mm. B. Nine human pancreatic cancer cell lines were stained with IgG isotype control and PD-L1-specific MAb, respectively, and analyzed by flow cytometry.

positive controls. As expected, epithelial cells surrounding the crypts in the tonsil tissue are PD-L1+ (Fig.1. A1&2). Adrenal tumor tissues exhibit two distinct PD-L1-staining patterns: tumor cells with PD-L1 membrane staining; tumor cells and leukocyte aggregate area with tumor cell membrane staining and monocytes both membrane and cytoplasmic staining (Fig.1. A3&4). PD-L1 protein was detected in approximately 60-90% of tumor cells in all thirteen tumor specimens (Fig.1. A5 & 6). PDL1 protein was detected on the cell membrane and in the cytoplasms of almost all tumor cells. Flow cytometry analysis revealed that 8 of the 9 cell lines express high level of PD-L1 and all tumor cells uniformly express PD-L1 (Fig.1B).

C2.2. PD-L1 is elevated in pancreatic cancer and PD-1 is highly expressed in pancreatic tumor-infiltrating CTLs

The underlying mechanism of human colorectal and pancreatic cancer non-response to ICI immunotherapy is currently unknown. One notion is that human MSS colorectal cancer lacks CTL infiltration. However, our recent studies determined that CTLs equally infiltrate both MSS and MSI human colorectal cancer13. On the other hand, it is believed that pancreatic cancer is a non-immunogenic“cold”cancer21. Human pancreatic carcinoma, except for the MMR-D subtype, exhibits a median mutational load of 4, much lower than more immunogenic cancers, such as melanoma and lung cancer21, 22. It might be expected that a lower mutational load would decrease neoantigen presentation on pancreatic tumors, thereby decreasing tumor-infiltration by CTL, and limiting anti-PD-1 therapy 9, 23, 24. However, several studies show that CTLs do  infiltrate human pancreatic carcinoma25-27 suggesting that CTL tumor-infiltration level is unlikely a major factor that underlies human pancreatic cancer non-response to ICI immunotherapy. Yet, despite the abundant PD-L1 expression in tumor cells and presence of tumor-infiltrating CTLs, human colorectal and pancreatic cancers do not respond to anti-PD-1 immunotherapy. Therefore, it is reasonable to suspected that a PD-L1-independent mechanism may compensate PD-L1 function in colorectal and pancreatic tumors to promote tumor immune evasion and progression.

C2.3. Development of the first-in-class OPN monoclonal antibody for human colorectal and pancreatic cancer immunotherapy.

C2.3a. Identification of OPN as a new immune checkpoint: OPN negatively regulates T cell activation. We have recently discovered, for the first time, that OPN, the physiological ligand for T cell receptors CD44 and other receptors, is highly expressed in myeloid-derived suppressor cells (MDSCs) and tumor cells28. We determined that OPN protein exhibits potent inhibitory activity against mouse and human T cell activation28 (Fig. 2A-C). We further determined that OPN mRNA level is higher in human colorectal carcinoma as compared to normal colon tissues (Fig. 2D), and OPN protein level is significantly elevated in serum of human CRC patients as compared to healthy donors28 (Fig. 2E). Literature has shown that elevated OPN level is significantly correlated with a poor prognosis and tumor progression in CRC patients and other cancer patients29, 30. The next generation genomic data also indicate that increased OPN expression elvel is significantly correlated with decreased survuival time in human CRC patients(Fig. 2F). Our published data and the literature thus determined that OPN is a new immune checkpoint that may compensate PD-L1 functions in human colorectal and pancreatic cancer immune evasion.

Figure 2. OPN promotes human colon cancer immune evasion. A. Human CD3+ T cells (n=5) were labelled with CFSE, and stimulated with anti-CD3/CD28 and OPN at the indicated doses for 3 days. CD8+ T cells were analyzed for CFSE intensity. Shown is representative blot of one of the five donors. B. Quantification of CD8+ T cell division of 5 healthy donors (HD)1-5). C. IFNg level in the culture supernatant. D.    OPN mRNA expression data sets in normal colon and colon carcinoma were extracted from TCGA database and compared as indicated. E. Serum OPN protein level by ELISA. Each dot represents serum OPN protein level from one donor or patient. F. Kaplan-Meier survival analysis of OPN expression level and colorectal cancer patient survival.

C2.3b.  We have developed four first-in-class OPN neutralization monoclonal antibodies. The above findings provide a strong rationale to develop a monoclonal antibody (mAb) to block OPN for cancer immunotherapy. We then used mammarian cell-expressed recombinant OPN protein as antigen to develop OPN neutraliztion mAb as outlined in Fig. 3. We used a two-step functional assays to screen and validate hybridoma clones. The ELISA assay was used to determine the binding affinity of the OPN antibody to recombinant OPN protein. The T cell proliferation rescue assay was used to determine the efficacy of the OPN mAb in blocking recombinant OPN-mediated suppression of CFSE-labelled T cells. We have obtained 4 hybridoma clones with high potentency (Fig. 3).

Figure 3. Summary of the development of OPN neutraliztion monoclonal antibodies.

C2.3c. OPN neutralization mAbs are effective in blocking OPN-mediated inhibition of T cell activation. Preliminary studies indicate that all four OPN mAb clones showed significantly efficacy in blocking recombinant mouse OPN protein-mediated suppression CD8+ T cell activation ex vivo. Ongoing in vivo studies determined that knocking out OPN in mouse tumor cells resulted in significantly decreased tumor growth in immune competent mice, and these neutraliztion mAbs are effective in suppressing tumor growth in immune competent mice. We are currently conducting more in vivo studies to further evaluate the efficacy of these foure mAb clones in cancer immunotherapy for colon and pancreatic cancer, and in the process of humanize the lead clone for human colorectal and pancreatic cancer immunotherapy.

D. Market Need

According to Clarivate Analytics, the global market for ICI cancer immunotherapy in 2022 is projected at about $34.652 billion. It is very clear that the PD-1 and PD-L1 inhibitors are the biggest growth area in colorectal and pancreatic cancer market since there is no ICI immunotherapeutic agents for these two cancers. We estimate the annual value of OPN is in the billions if successfully developed.

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