Bessor Pharma

STEM CELL PLATFORM TECHNOLOGY

STEM CELL/STEM CELL SIGNALING TECHNOLOGY PLATFORM

We are advancing a platform for developing novel therapeutics for tissue repair and inflammatory diseases based on mesenchymal stem cells (MSCs) and MSC signaling molecules. MSCs have been the subject of many scientific papers and clinical trials. We have focused on improving predictability, reproducibility and understanding their mechanisms of action to advance potential innovative therapeutic products. Our technology platform and translational projects are built around work of a pioneer in these fields, Dr. Darwin Prockop and colleagues at the Texas A&M Institute of Regenerative Medicine. Bessor has formed, a highly experienced and integrated project team to translate these discoveries into therapeutics. To date, we have:

  • Identified and selected MSC populations with anti-inflammatory and immune-modulating activity based on expression and secretion of TSG-6, an anti-inflammatory protein effective in a number of models of tissue injury and inflammatory diseases.
  • Demonstrated that TSG-6 administration is effective as a novel anti-inflammatory in multiple preclinical models; and
  • Developed innovative new technologies to fuel product advances, such as production methods for TSG-6.

Our initial projects are focused on TSG-6 and analogs.

TSG-6

Innovations and Potential Advantages
MSC Technologies: MSCs, which consist of diverse populations of cells have been studied extensively in clinical trials for a number of inflammatory disorders and cancer, with mixed results. Prockop and colleagues have demonstrated that the anti-inflammatory/immune-modulating activities of MSCs are largely attributable to expression of TSG-6. MSCs lacking or with minimal TSG-6 do not possess such activities. Our team has shown TSG-6 expression, used as a biomarker, provides a powerful potential tool for producing and selecting MSCs for more successful therapeutic use. We have also developed methods for culturing MSCs to optimize TSG-6 expression and their therapeutic activity.

TSG-6: TSG-6 attacks inflammation through novel mechanisms of action. The protein has been shown to block early mediators of inflammation. If inflammation remains untreated, over-reaction of host defense paradoxically can worsen tissue repair. TSG-6 is expressed in mammalian cells in response to injury and challenge by TNF-α and may therefore represent a natural regulator against undesirable excessive activity of host defense systems. TSG-6 also ”buffers” delayed inflammatory-immune responses by inhibiting excessive neutrophil infiltration to the site of tissue damage and regulates undesired tissue destructive actions of serine metalloproteases.

Production of TSG-6 has been rate limiting to its therapeutic development. Prockop and colleagues have developed a manufacturing process to enable supply for subsequent research and development activities. The intellectual property, process and subsequent know-how, licensed to us, has potential to be optimized for efficient production and clinical use.

Status
Along with Prockop and colleagues, we have developed project plans and demonstrated in vitro as well as in vivo preclinical proof of concept with both MSCs and TSG-6 in a number of preclinical models. Our team has demonstrated potential application of our therapeutic approaches in traumatic brain injury, cardiovascular injury, transplants, periodontal disease, tissue injury following chemotherapy (bleomycin), dry eye and corneal injury. In studies with human MSCs from different donors, TSG-6 expression can be a predictor of efficacy in several sterile inflammation models.

In a mouse model of traumatic brain injury, TSG-6 administration has been shown to decrease lesion size and inhibit pro-inflammatory proteins (first 24 hours), and demonstrate longer term effects (6-10 week) such as improvements in memory, decreases in depressive-like behavior and importantly, increases in the number of newly formed-neurons (stimulates neurogenesis). In a mouse model of bleomycin-induced lung injury, i.v. administration of TSG-6 at the early inflammatory phase ameliorated decreases in oxygen saturation levels and increased survival. Our first in man applications are directed towards ocular inflammation, specifically the treatment of dry eye disease (see A New Therapeutic Approach to Treating Ocular Inflammatory Conditions)

We have formed an LLC, Temple Therapeutics, to focus on and accelerate product development. Several patents have been issued and a broad portfolio of patent applications has been submitted.

Team
We have assembled an experienced world class R&D team who are developing the product candidates, that includes as advisors, Armand Keating, MD, FRCP(C), Princess Margaret Hospital/University of Toronto, a world leader in cell therapy, and Tony Day, PhD, University of Manchester (UK) a leading expert on TSG-6 and cell matrix research.

Know-How and Intellectual Property
Dr Prockop and colleagues are pioneers in these fields and have substantial and unique know how. We have licensed these technologies and assets, made additional inventions and translational progress. The development team we formed has a strong record of productive cooperation and accomplishments. In addition, we are leveraging three issued patents and portfolio of patent applications.

Issued Patents
US Patent: 8,785,395: Adult stem cells/progenitor cells and stem cell proteins for treatment of eye injuries and diseases. Prockop DJ, Oh JY, Roddy GW, Rossa R and Berkowitz, BA

US Patent: 9,062,103: Adult Stem Cells/Progenitor Cells and Stem Cell Proteins for Treatment of Corneal Injuries and Diseases (including dry eye). Prockop DJ, Oh JY, Berkowitz BA, Roddy GW, Rossa, R

U.S. Patent: 7,485,460: Enhanced Growth of Adult Stem Cells with DKK-1. Prockop DJ, Sekiya I, Gregory C, Spees J, Smith J, Pochampally R

Additional patents have been filed, including patents covering the TSG-6 manufacturing process.

Publications
TSG-6 secreted by human umbilical cord-MSCs attenuates severe burn-induced excessive inflammation via inhibiting activations of P38 and JNK signaling. Sci Rep. 2016 Jul 22;6:30121

Mechanisms of mesynchymal/stromal stem cell function. Stem Cell Res Ther. 2016; 7(1): 125

Comparison of Topical Application of TSG-6, Cyclosporine and Prednisolone for Treating Dry Eye. Cornea. 2016 Apr;35(4):536-42.

Mesenchymal stem/stromal cells precondition lung monocytes/macrophages to produce tolerance against allo- and autoimmunity in the eye. Proc Natl Acad Sci U S A 2016 Jan 5; 113(1): 158–163

Topical TSG-6 administration protects the ocular surface in two mouse models of inflammation-related dry eye. Invest Ophthalmol Vis Sci. 2015;56:5175–5181.

MSCs derived from iPSCs with a modified protocol are tumor-tropic but have much less potential to promote tumors than bone marrow MSCs. Proc Natl Acad Sci U S A. 2015 Jan 13;112(2):530-5.

TSG-6 as a biomarker to predict efficacy of human mesenchymal stem/progenitor cells (hMSCs) in modulating sterile inflammation in vivo. Proc Natl Acad Sci U S A. 2014 Nov 25;111(47), 16766-71

Phase-directed therapy: TSG-6 targeted to early inflammation improves bleomycin-injured lungs. Am J Physiol Lung Cell Mol Physiol. 2014 Jan;306(2):L120-3

Anti-Inflammatory Protein TSG-6 Promotes Early Gingival Wound Healing: An In Vivo Study. Periodontol. 2014 Sep 30:1-17

Administration of TSG-6 improves memory after traumatic brain injury in mice. Neurobiol Dis. 2013 Nov;59:86-99.

Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-κB signaling in resident macrophages. Blood. 2011 Jul 14;118(2):330-8.

Intravenous mesenchymal stem cells prevented rejection of allogeneic corneal transplants by aborting the early inflammatory response. Mol Ther. 2012 Nov;20(11):2143-52

Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell. 2009 Jul 2;5(1):54-63

Multipotent human stromal cells improve cardiac function after myocardial infarction in mice without long-term engraftment. Biochem Biophys Res Commun 354: 700–706, 2007

NOVEL THERAPEUTIC FOR OCULAR INFLAMMATORY DISEASES

We are developing a new class of drugs for treating ocular inflammation, initially with topical recombinant TNF-alpha-stimulated gene/protein 6 (TSG-6). The first use in man is planned for dry eye syndrome (DES). Inflammation at the ocular surface plays a key role in the pathogenesis of DES. TSG-6 is an anti-inflammatory protein, which is the key mediator of the tissue repair functions of stem cells, with novel therapeutic mechanisms of action on key disease targets.TSG-6’s potential in ocular inflammation emerged from work with our collaborator, Darwin Prockop, MD/PhD, Director of Texas A&M’s Institute of Regenerative Medicine, and colleagues. It was demonstrated that mesynchymal stem/stromal cells (MSCs) protect the ocular surface in mice, including those with DES, in a novel manner by suppressing inflammation in the lacrimal glands and the ocular surface. The team also showed that TSG-6 primarily accounted for the anti-inflammatory effects in the eye produced by the MSCs and demonstrated therapeutic activity in several disease models, including dry eye and corneal injury. The technology has also been shown to have important potential in the treatment of other ophthalmic conditions, including retinal disorders and uveitis. The intellectual property is exclusively licensed to us, patents have issued, others filed. We believe an IND can be submitted within 18 months.

Target Markets
Moderate to severe DES, our initial focus, affects an estimated nine million people in the US with an additional 20-30 million suffering from milder disease. The current market, $3.4 billion is estimated to reach $4.5 billion by 2020, according to MarketScope. There remains a significant need for an effective therapy in patients suffering from the advanced effects of dry eye syndrome. Cyclosporine, the leading therapy, represents an advance yet is only effective in a minority of patients (as little as 15 percent) and can be poorly tolerated, leading to non-adherence in approximately 20 percent of patients. Steroids, which can be effective, carry serious cataract and glaucoma risks with long term use. There is also an important need for better treatments for the “orphan” population of patients at risk of diminished vision or blindness such as those due to chemical, mechanical or thermal-induced corneal injury. Corneal injury is an additional opportunity. Although corneal injury represents a smaller market, there are no approved drugs for this indication.

Innovations and Potential Advantages
TSG-6 therapy attacks inflammation central to these disorders through novel mechanisms of action. The protein has been shown to block early mediators of inflammation. If untreated this over-reaction of host defense paradoxically can worsen tissue repair. TSG-6 is expressed in mammalian cells in response to injury and challenge by TNF-α and may therefore represent a natural regulator against excess biological activity of host defense systems. TSG-6 also ”buffers” delayed inflammatory-immune responses by inhibiting excessive neutrophil infiltration to the site of tissue damage and inhibits protease action equivalent to dexamethasone without the steroid side effects. TSG-6 is emerging as an innovative and promising regulator of inflammation with new mechanisms and advantaged therapeutic index

Production of TSG-6 has been rate limiting to its therapeutic development. Prockop and colleagues have developed a scalable manufacturing process to enable supply for subsequent research and development. The process and subsequent know-how have potential to be optimized for efficient production and use of clinical material.

Status
In vivo preclinical proof-of-concept has been demonstrated in multiple models of DES. Topical administration is effective and TSG-6 increased tear production, reduced corneal defects, and decreased expression of pro-inflammatory cytokines in the cornea, conjunctiva, and intraorbital gland. In models of chemical and mechanical ocular injury, intraorbital injection of TSG-6 markedly reduced corneal opacity, neovascularization, and neutrophil infiltration and decreased proinflammatory cytokine, chemokine, and matrix metalloproteinase levels. Topical application was also effective. Current studies suggest significant therapeutic index advantages compared with steroids (prednisolone or dexamethasone).

The first in man trials with TSG-6 for dry eye are designed to confirm and extend proof of concept and proof of mechanism, and provide additional support for development of additional ophthalmic and other indications. With experts in corneal injury and treatment, we have designed the clinical trial protocol for this indication, for which we have an issued patent.

We have also identified and are developing novel analogs and complementary technologies therapeutic potential which are included in our granted patents.

Intellectual Property
US Patent: 8,785,395: Adult stem cells/progenitor cells and stem cell proteins for treatment of eye injuries and diseases (including dry eye). Prockop DJ, Oh JY, Roddy GW, Rossa R and Berkowitz, BA

US Patent: 9,062,103: Adult Stem Cells/Progenitor Cells and Stem Cell Proteins for Treatment of Corneal Injuries and Diseases (including dry eye), Prockop DJ, Oh JY, Berkowitz BA, Roddy GW, Rossa, R.

Additional patent applications have been filed, including patents covering the TSG-6 manufacturing process.

Publications
Comparison of the anti-inflammatory effects of induced pluripotent stem cell-derived and bone marrow-derived mesenchymal stromal cells in a murine model of corneal injury. Cytotherapy. 2016 Nov 10.

Comparison of Topical Application of TSG-6, Cyclosporine and Prednisolone for Treating Dry Eye. Cornea. 2016 Apr;35(4):536-42.

Scalable Production of a Multifunctional Protein (TSG-6) That Aggregates with Itself and the CHO Cells That Synthesize It. PLoS One. 2016 Jan 21;11(1):e0147553.

Mesenchymal stem/stromal cells precondition lung monocytes/macrophages to produce tolerance against allo- and autoimmunity in the eye. Oh. Proc Natl Acad Sci U S A. 2016 Jan 5;113(1):158-63

Topical TSG-6 administration protects the ocular surface in two mouse models of inflammation-related dry eye. Invest Ophthalmol Vis Sci. 2015;56:5175–5181.

Mesenchymal stem/stromal cells protect the ocular surface by suppressing inflammation in an experimental dry eye. Mol Ther. 2015 Jan;23(1):139-46.

Intraperitoneal infusion of mesenchymal stem/stromal cells prevents experimental autoimmune uveitis in mice. MK.Mediators Inflamm. 2014;2014:624640.

Anti-inflammatory TSG-6 stabilizes the progression of focal retinal degeneration in a murine model. J Neuroinflammation. 2012 Mar 27;9:59.

Anti-inflammatory protein TSG-6 reduces inflammatory damage to the cornea following chemical and mechanical injury. Proc Natl Acad Sci USA. 2010 Sep 28;107(39):16875-80