PureTech Health Advances New Program Targeting Immunosuppressive Gamma Delta T Cells and Related Mechanisms

On April 11, 2019 PureTech Health plc ("PureTech Health" or the "Company", LSE: PRTC), an advanced, clinical-stage biopharmaceutical company, reported the launch of a new immuno-oncology program developing monoclonal antibodies to target newly discovered immunosuppressive mechanisms in pancreatic cancer and other solid tumors (Press release, PureTech Health, APR 11, 2017, View Source [SID1234533948]).

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The approach is based on the work of Dr. George Miller, Director of S. Arthur Localio Laboratories and Director of the Cancer Immunology Program at NYU School of Medicine. Part of the body of data supporting this approach was published recently in Nature Medicine and builds upon his work previously published in Cell.

"Most solid, malignant tumors establish an immunosuppressive environment to ward off the body’s natural defenses. Dr. Miller’s work in pancreatic ductal carcinoma has revealed that inflammatory processes drive the immunosuppression through certain gamma delta T cells and macrophages," said Dr. Joseph Bolen, Chief Scientific Officer of PureTech Health. "Our novel approach builds on this finding and selectively disrupts the immunosuppression to potentially have a therapeutic effect on cancer."

This technology, exclusively licensed from the NYU School of Medicine, is being developed in a new subsidiary of PureTech Health called Nybo Therapeutics. Nybo builds on PureTech’s strength in immunology and joins PureTech’s advanced pipeline of immunology and T cell biology programs that includes a Phase IIB immunosenescence program, microbiome-based T cell mediated therapies, and CAR-T therapies.

"Pancreatic cancer is the only major cancer with a five-year survival rate in the single digits, and there has been far too little progress towards meaningful treatments," said Dr. Diane Simeone, Director of the Pancreatic Cancer Center at NYU School of Medicine and a member of Nybo’s Scientific Advisory Board. "Novel therapeutic approaches are important to pursue, and I look forward to helping advance this promising technology."

Dr. Miller commented on this announcement, "I am excited to translate our findings into first-in-class therapies for patients who desperately need new treatment options. Our work on immunosuppressive mechanisms in pancreatic cancer has shed light on new therapeutic approaches that form the foundation for Nybo, and we look forward to a great partnership with PureTech Health with whom to advance these findings."

PureTech Health has gathered a group of leading expert collaborators and advisors around this platform, including:

Erin Adams, Ph.D., is the Joseph Regenstein Professor at the Department of Biochemistry and Molecular Biology, and on the Committees of Immunology and Cancer Biology at the University of Chicago. Dr. Adams’ research is focused on understanding how events at the molecular level allow the immune system to differentiate between self and non-self with particular attention given to nonconventional T cell recognition, such as that of gamma delta T cells. The scientific approach she undertakes to tackle these questions spans multiple levels including genetics, protein biochemistry, structure, biophysics, function and cell biology and imaging. Dr. Adams is one of the pioneer researchers discovering how gamma delta T cells recognize antigens and how this recognition process regulates their activity in various tissues in which they reside.

Elizabeth Jaffee, M.D., currently serves as Deputy Director for the Johns Hopkins Kimmel Cancer Center, Associate Director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy; Associate Director for Translational Research, Co-Director of Gastrointestinal cancer and diseases program, and Co-Director of the Skip Viragh Center for Pancreatic Cancer Clinical Research and Patient Care. Dr. Jaffee is chair and member of the National Cancer Advisory Board, and served as co-chair of the NCI Blue Ribbon Panel for the National Moonshot Initiative. Dr. Jaffee is an active member of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), and has just been named President-Elect of AACR (Free AACR Whitepaper) (2017-2018). She will assume the presidency in April, 2018.

Steven Leach, M.D., is the Director of the David M. Rubenstein Center for Pancreatic Cancer Research of Memorial Sloan-Kettering. Prior to this, Dr. Leach served as Professor of Surgery, Oncology and Cell Biology, and the Paul K. Neumann Professor in Pancreatic Cancer at Johns Hopkins Medicine. Dr. Leach received his undergraduate degree from Princeton University, where he currently serves on the Board of Trustees. He then pursued his MD degree at Emory University, followed by postdoctoral training at Yale University and at M.D. Anderson. Dr. Leach is also the current Chair of the Pancreatic Cancer Action Network’s Scientific and Medical Advisory Board.

George Miller, M.D., is the Director of S. Arthur Localio Laboratories, vice chair for research in NYU, Langone’s Department of Surgery and the leader of Perlmutter Cancer Center’s Immunology Program, as well as the director of the only training program in the country in gastrointestinal oncology that is funded by the National Institutes of Health. In addition to his laboratory research, Dr. Miller is a highly experienced pancreatic and hepatobiliary surgeon with an extensive background in the evaluation and treatment of pancreatic tumors, as well as liver, bile duct cancers.

Diane M. Simeone, M.D., is currently the director of the Pancreatic Cancer Center at the NYU School of Medicine and the Associate Director of Translational Research, Perlmutter Cancer Center, NYU Langone Medical Center. She is the chair-elect of the Scientific and Medical Advisory Board of the Pancreatic Cancer Action Network, one of the country’s leading organizations advancing the battle against the disease through research funding, community engagement and government advocacy. She is a member of the Institute of Medicine of the National Academy of Sciences, serves on the National Cancer Institute’s Pancreatic Cancer Task Force, and previously was president of the Society of University Surgeons and the American Pancreatic Association.

"We will be exploring both pancreatic cancer and other solid tumor types such as colorectal cancer. In addition to monotherapy, Dr. Miller’s work suggests that this approach may enhance the effect of checkpoint inhibitors that have historically not worked in pancreatic cancer opening up the possibility of combination therapy," commented Dr. Aleksandra Filipovic, Therapeutic Lead for Oncology at PureTech.

The underlying research described above has been supported by the NYU School of Medicine’s drug discovery accelerator, the Office of Therapeutics Alliances.

About NYU Office of Therapeutics Alliances and Office of Industrial Liaison
The NYU Office of Therapeutics Alliances (OTA) was created in 2013 to accelerate and de-risk drug discovery projects developed at NYU School of Medicine towards partnerships with investors, biopharma, and non-profits. The NYU Office of Industrial Liaison (OIL) promotes the commercial development of NYU discoveries and actively seeks commercial partners for licensing and research collaborations. Over the past ten years NYU has ranked first among all universities in income from technology licensing. For more information, please visit View Source and View Source

Apogenix Announces Initiation of Clinical Development for ABBV-621 to Treat Solid and Hematologic Tumors by Partner AbbVie

On April 11, 2017 Apogenix AG, a biopharmaceutical company developing next-generation immuno-oncology therapeutics, reported that a clinical phase I study with ABBV-621 has been initiated by its partner AbbVie (Press release, Apogenix, APR 11, 2017, View Source [SID1234524574]). In this study, 92 patients suffering from solid tumors, non-Hodgkins’s lymphoma (NHL) or acute myeloid leukemia (AML) will be recruited. The study ("An Open-Label, Phase 1, First-In-Human Study of Safety and Tolerability of TRAIL Receptor Agonist ABBV-621 in Subjects With Previously Treated Solid Tumors and Hematologic Malignancies"; Clinicaltrials.gov ID: NCT03082209) will be recruiting in the US, EU and Japan. The phase I objectives will be to establish the safety and tolerability of ABBV-621, as well as to understand its pharmacokinetic properties.

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ABBV-621 is a novel, second-generation TRAIL-receptor agonist consisting of six receptor binding domains of TRAIL (TRAIL: TNF-related apoptosis inducing ligand), fused to the Fc-domain of a human IgG1 antibody. This novel protein was engineered by Apogenix employing its proprietary HERA technology platform (HERA: hexavalent receptor agonists; Gieffers et al., Mol. Cancer Ther. 2013, 2735-2747). The substance acts as a pure agonist by binding to TRAIL-receptors on tumor cells, thereby inducing their apoptosis (programmed cell death). ABBV-621 is designed to maximize receptor clustering but does not require Fc?-receptor-mediated crosslinking for optimal efficacy. This has been deemed an activity-limiting step for competitor antibodies in the clinic. ABBV-621 induces dose-dependent apoptotic cell death at sub- to single-digit nanomolar potencies across a large panel of human hematologic and solid tumor cell lines in vitro. In tumor xenograft models, ABBV-621 exhibits potent antitumor activity in vivo as a monotherapy and in combination with targeted agents or chemotherapy using xenograft tumors derived from colorectal, lung, leukemia, and lymphoma cell lines. In toxicity studies, ABBV-621 was well tolerated with no adverse drug-related findings.

"We are excited to see our first HERA-ligand enter clinical development. The unique mechanism of action has the potential to induce apoptosis, thereby eliminating cancer cells, and offers a new treatment option in the fight against cancer," Thomas Hoeger, Ph.D., Chief Executive Officer of Apogenix, said. "We are looking forward to see first results of the recently initiated clinical study."

In summer 2014, AbbVie acquired the worldwide rights for all TRAIL-receptor agonists developed by Apogenix. AbbVie is responsible for preclinical and clinical development of these compounds.

About HERA

Apogenix has developed a proprietary technology platform for the construction of novel hexavalent TNF superfamily receptor agonists (HERA). The specific molecular structure of HERA induces a well-defined clustering of functional TNF receptors on the surface of target immune cells. By stimulating different TNF signaling pathways, HERA-ligands can increase the anti-tumor immune response. In contrast to agonistic antibodies, the fusion proteins are pure agonists whose potent signaling capacity is independent of secondary Fc?-receptor mediated crosslinking. In addition, HERA-ligands cause neither antibody dependent cellular cytotoxicity (ADCC) nor complement-dependent cytotoxicity (CDC) and exhibit a shorter half-life than antibodies. It is therefore expected that HERA-ligands will cause less side effects in clinical development. Apogenix is utilizing its HERA technology platform to develop GITR, CD40, CD27, 4-1BB, HVEM, and OX40 receptor agonists for cancer immunotherapy. The TRAIL program was licensed to AbbVie in 2014.

Kyorin acquired licenses from Merck & Co., Inc., Kenilworth, N.J., U.S.A. for Investigational Therapy for Overactive Bladder (Code:KRP-114V) in Asia

On April 11, 2017 Kyorin Holdings reported that its wholly owned subsidiary, KYORIN Pharmaceutical Co., Ltd. ("Kyorin", Head office: Chiyoda-ku, Tokyo, President & CEO: Mitsutomo Miyashita), has entered into a license agreement with Merck & Co., Inc., Kenilworth, N.J., U.S.A. ( "Merck", Head office: Kenilworth, N.J., U.S.A., CEO: Kenneth C. Frazier ) for Merck’s investigational overactive bladder (OAB) therapeutic agent, KRP-114V (INN: Vibegron) in Asia. (Press release, Kyorin, APR 11, 2017, View Source [SID1234519929]) Under the terms of this agreement, Kyorin will expand the license, which the company acquired from Merck for Japan in July 2014, to also cover Asia. Through this agreement, Kyorin acquires th e licenses to develop, manufacture and commercialize KRP-114V in Korea, Taiwan, Hong Kong and ten member states of ASEAN (Association of South East Asian Nations).

KRP-114V is an investigational selective beta 3 adrene rgic receptor agonist discovered by Merck that is being evaluated as a once-daily therapy for OAB. Kyorin entered into a co-development and co-marketing agreement for this agent with Kissei Pharmaceutical Co., Ltd. in March 2016, and both companies are currently conducting a Phase 3 clinical trial in Japan.

Urology is one of Kyorin’s focus areas, and the comp any is developing this agent in Japan toward the expansion of its product lineup as well as the establishment of its presence in that field. By acquiring the license to KRP-114V for Asia in addition to Jap an, Kyorin is committed to further improving the QOL of the Asian patients with OAB symptoms coupled with Uritos already available in Asia through Kyorin’s alliance partners.

This transaction will have no impact on the comp any’s consolidated earnings forecast in FY2016

New mechanistic insights into 4SC-202’s epigenetic mode of action

On 11 April 2017 4SC AG (4SC, FSE Prime Standard: VSC) reported that 4SC’s collaboration partner Prof. Steven A. Johnsen and his team at the Clinic for General, Visceral and Pediatric Surgery in Göttingen, Germany, published results from a preclinical study providing new insights into the epigenetic mode of action of 4SC’s anti-cancer compound 4SC-202 (Press release, 4SC, APR 11, 2017, View Source [SID1234518595]).

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4SC-202 is an orally administered small molecule for the treatment of cancer. As an epigenetic modulator with a unique mechanism of action, 4SC-202 inhibits both the lysine-specific demethylase (LSD1) and class I histone deacetylases (HDAC 1, 2 and 3), which play roles in the regulation of cancer signaling pathways. Through 4SC-202-mediated changes in the methylation or acetylation pattern of histone proteins (packaging proteins, around which the DNA is wrapped), expression of some genes is promoted, whereas expression of others is suppressed. These changes ultimately lead to more differentiation and less proliferation of cancer cells. The tumor ceases to grow and the immune system is then able to detect and destroy it.

4SC-202 affects gene expression via two well-known molecular cancer players

Prof. Johnsen and his team conducted experiments in multiple pancreatic cancer cell lines. "Mechanistically we observed that the effects on the induction of gene expression mediated by 4SC-202 were elicited by the Bromodomain-containing Protein 4 (BRD4) and MYC, both of which are able to interact with the regulatory sequences located close to the target genes following the changes caused by treatment with 4SC-202," stated Prof. Johnsen.

BRD4 is a well-characterized ‘epigenetic reader’ that recognizes and binds to acetylated lysine residues on both histone and non-histone proteins and plays an important role in maintaining cancer-induced transcriptional programs in the malignant cells. MYC on the other hand is one of the most studied human oncogenes and has been frequently associated with tumor growth and progression due to its involvement in a myriad of biological processes including cell growth, proliferation and cell death.

Prof. Johnsen continued: "Based on the data, we believe that 4SC-202-mediated down-regulation of target gene expression is most likely associated with changes in the acetylation patterns in the regulatory regions located farther from the target genes."

Frank Hermann, MD, Chief Development Officer of 4SC, commented, "These data provide valuable new insights into 4SC-202’s molecular mode of action in cancer cells. In addition to these direct effects on cancer cells, we know that 4SC-202 has various biologic effects, especially enhancing the immune response against cancer tissue. Considering these multiple biological effects, we believe that 4SC-202 is a very attractive partner for combination treatment approaches in hematology and oncology with a special focus on immuno-oncology therapies such as checkpoint inhibitors. Therefore, we plan to investigate this very promising combination in cancer patients who are not responding to treatment with checkpoint inhibitors alone. In these patients, the epigenetic effects of 4SC-202 have the potential to modulate the cancer tissue and help to reactivate the immune system to fight the cancer."

– Press release ends –

Original publication

Histone deacetylase class-I inhibition promotes epithelial gene expression in pancreatic cancer cells in a BRD4- and MYC-dependent manner.
Mishra VK, Wegwitz F, Kosinsky RL, Sen M, Baumgartner R, Wulff T, Siveke JT, Schildhaus HU, Najafova Z, Kari V, Kohlhof H, Hessmann E, Johnsen SA.
Nucleic Acids Research, View Source

Related articles

21 March 2017, 4SC-202 – a promising combination partner for cancer treatment
View Source

2 June 2016, 4SC at ASCO (Free ASCO Whitepaper): 4SC 202 and checkpoint inhibitors – strong partners in cancer treatment

21 March 2016, Epigenetic compound 4SC-202 strengthens endogenous immune response to cancer



Further information

About 4SC-202

4SC-202 is an orally administered small molecule for the treatment of cancer. 4SC-202 is an epigenetic modulator with a unique mechanism of action that inhibits both the lysine-specific demethylase (LSD1) protein and class I histone deacetylase proteins (HDAC 1, 2 and 3), which play significant roles in the regulation of signaling pathways in cancer cells.

4SC-202 has been investigated in a Phase I study with 24 intensively pretreated patients with several types of highly advanced hematologic cancers, and has proven to be tolerated. Positive signs of anti-tumor efficacy were observed with one complete remission for 28 months and one partial responder for 8 months.

Data from preclinical investigations showed that 4SC-202 strengthens the anti-tumor immune response. Treatment with 4SC-202 alters the tumor microenvironment and increases infiltration of immune cells into the tumor. Further preclinical investigations showed that the combination of 4SC-202 with checkpoint inhibitors resulted in better anti-tumor activity than treatment with checkpoint inhibitors alone, suggesting a very promising clinical development path for 4SC-202 in both refractory and non-responding patients to treatment with checkpoint inhibitors.

Moleculin Biotech Appoints Theradex Systems as CRO to Manage Phase I/II Annamycin Trial

On April 11, 2017Moleculin Biotech, Inc., (NASDAQ: MBRX) ("Moleculin" or the "Company"), a preclinical pharmaceutical company focused on the development of anti-cancer drug candidates, some of which are based on license agreements with The University of Texas System on behalf of the M.D. Anderson Cancer Center ("MD Anderson"), reported that it has appointed Theradex Systems, Inc. as its contract research organization ("CRO") for its planned Phase I/II clinical trial for Annamycin for the treatment of relapsed or refractory acute myeloid leukemia ("AML") (Press release, Moleculin, APR 11, 2017, View Source [SID1234518526]).

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Walter Klemp, Chairman and CEO of Moleculin stated: "We are pleased to announce this key milestone. We selected Theradex for their extensive US and international expertise with clinical research and development of pharmaceutical compounds in the areas of oncology and life-threatening diseases, including considerable experience with AML. Engaging Theradex is a key step in preparing to initiate our Phase I/II clinical trial for Annamycin and we look forward to moving ahead with them as we continue to work with the FDA on our IND, which must go into effect for clinical trials to begin. We are confident in Theradex’s ability to assist us in executing a high-quality and efficient trial."

About AML
Leukemia is a cancer of the white blood cells and the acute forms of leukemia can manifest quickly and leave patients with limited treatment options. AML is the most common type of acute leukemia in adults. It occurs when a clone of leukemic progenitor white blood cells proliferates in the bone marrow suppressing the production of normal blood cells. In order to qualify for a curative bone marrow transplant, patients must first undergo induction therapy. The current standard of care is the combining of 2 chemotherapeutic drugs, always including an anthracycline intended to induce a CR or complete response, which has not improved since it was first used in the 1970’s. We estimate that it has the same cure rate of about 20% as then. Currently, the only viable long term option for acute leukemia patients is a bone marrow transplant for those 20%, which is successful in a significant number of patients. For more information on AML click: View Source

About Annamycin
Annamycin is an anthracycline intended for the treatment of relapsed or refractory AML. Annamycin is a unique liposome formulated anthracycline (also referred to in literature as "L-Annamycin") that has been designed to produce little to no cardiotoxicity and avoid the multidrug resistance mechanisms that often defeat current anthracyclines. It has been tested in 114 patients in 6 clinical trials, 3 of which focused on leukemia, with little to no cardiotoxicity. The Company is working with the FDA on an investigative new drug application for a Phase I/II trial for second line treatment of relapsed or refractory AML, for which no approved therapy currently exists.