CLL-1 x CD38

The checkpoint inhibitor CD96 was shown conclusively to be an inhibitory receptor on human NK cells in the presence of multiple myeloma (MM) cells expressing CD155 CD96 knock out (KO) using CRISPR/Cas9 gene editing enhanced both NK cell cytotoxicity and cytokine release Efficient engineering of NK cells to genetically eliminate inhibitory receptor expression has the potential to overcome exhaustion and immune evasion in the tumor microenvironment Galway, Ireland and San Diego, USA, 11 June 2021 - ONK Therapeutics Ltd, an innovative natural killer (NK) cell therapy company, welcomes new data presented by John Daly from the academic lab of CSO, Prof. Michael O’Dwyer at the European Hematology Association (EHA) 2021 Virtual Congress illustrating the merit of knocking out the checkpoint inhibitory receptor for CD96 on NK cells in the context of MM. The data is based on research studies carried out at the National University of Ireland, Galway (NUI Galway), College of Medicine, Nursing and Health Sciences, by Prof. O’Dwyer’s academic research group. Contradictory data had previously shown that CD96 could be both an activating and an inhibitory receptor on human NK cells, depending on the tumor type being examined. The data presented during the poster presentation demonstrate conclusively that in the case of MM cells expressing CD155, CD96 is a human NK cell inhibitory receptor, regulating both cytotoxicity and cytokine release. Experiments using CRISPR/Cas9-mediated KO of CD96 in primary NK cells resulted in enhanced cytotoxicity and cytokine release compared to controls. Furthermore, NK cells obtained from MM patient bone marrow had particularly high levels of CD96 expression, suggesting NK cells in the bone marrow of MM patients are more likely to be susceptible to CD155 mediated immune-evasion. Studies carried out in parallel also demonstrated a similar beneficial effect of CRISPR/Cas9-mediated KO of TIGIT in primary NK cells. These new insights support knocking out inhibitory checkpoint receptors, including CD96 KO and TIGIT KO as a promising approach to improving the functionality of off-the-shelf engineered NK cell therapies for the treatment of cancer. E-poster presentation title: Knockout of CD96 or TIGIT using CRISPR/Cas9 enhances NK induced cytotoxicity and cytokine production in the presence of CD155 expressing myeloma cells. Author(s)/Presenters: John Daly, Mark Gurney, Michael O'Dwyer. Session title: Myeloma and other monoclonal gammopathies - Biology & Translational Research. Abstract number: EP941 Date and Time: Available on the virtual platform as an e-poster Friday, June 11 at 9:00 CEST. Download a copy HERE. Chris Nowers, ONK Therapeutics’ CEO said, “The studies carried out by Prof. O’Dwyer’s academic research group are expanding our deep understanding of NK cell biology and are helping to confirm certain gene constructs and edits that will enhance NK cell cytotoxicity, cytokine production and persistence in the tumor microenvironment. Gene edited NK cells lacking CD96 and/or TIGIT could therefore be beneficial for treating CD155 expressing malignancies, such as Multiple Myeloma.” ONK Therapeutics was formed based on technology and intellectual property developed at NUI Galway by Prof. O’Dwyer. The Company is developing off-the-shelf, optimized NK cell therapies for cancer that utilize dual-targeting of the death receptor pathway in addition to incorporating a CAR, along with further strategies that utilize novel gene editing approaches to enhance persistence, metabolic profile, and cytotoxic potential. ONK has exclusive licenses to a broad intellectual property (IP) against a wide range of NK cell checkpoints, including CD96 and TIGIT. -Ends- ONK Therapeutics – ONK Therapeutics Ltd is an innovative cell therapy company dedicated to developing the next generation of ‘off-the-shelf’, dual-targeted NK cell therapies targeting solid and hematological cancers. The company was founded in 2015, by Prof. O’Dwyer MD, of NUI Galway, an expert in translational multiple myeloma research, the tumor microenvironment, and exploitation of NK cells as cellular immunotherapy. Its core proprietary off-the-shelf cell therapy platform is based on a dual-targeted NK cell expressing both a chimeric antigen receptor (CAR) targeting a known tumor antigen and a TNF-related apoptosis-inducing ligand variant (TRAILv) targeting the death receptor pathway (i.e. DR4 or DR5). This unique approach has the potential to enhance efficacy by addressing both intrinsic (e.g. CAR engagement of a tumor-specific antigen) and extrinsic (e.g. signaling through the death receptor pathway) apoptotic pathways and to reduce the susceptibility to possible target antigen escape through the engagement of tumor antigen-independent TRAILv. Its pre-clinical pipeline comprises four programs: The lead program, ONKT101, is a dual-targeted NK cell therapy incorporating a CD19 CAR and TRAILv targeting DR5, intended for the treatment of relapsed/refractory B cell malignancies. This program is partnered with Avectas, with the company having responsibility for development to Phase 1 ONKT102 combines an optimized affinity CD38 CAR and a TRAILv targeting DR5, intended for the treatment of patients with relapsed/refractory multiple myeloma ONKT103 combines a TA-MUC1 CAR with a TRAILv targeting DR5, for the treatment of solid tumors ONKT104 combines a CLL-1 CAR with a TRAILv targeting DR4, for the treatment of AML In addition to the unique off-the-shelf, dual-targeted NK cell therapy platform, the company has a strong focus on engineering strategies to enhance tumor homing and persistence in-vivo, and overcome exhaustion in the tumor microenvironment, including the exploration of proprietary gene edits, such as the deletion of checkpoint inhibitory receptors in NK cells. ONK Therapeutics is headquartered in the med-tech hub of Galway, Ireland, with a wholly-owned US subsidiary, ONK Therapeutics, Inc. based at JLabs @ San Diego. Shareholders include Acorn Bioventures, ALSHC (principally Seamus Mulligan), and Enterprise Ireland Follow us on Twitter and LinkedIn.

Agreement with the National University of Ireland, Galway (NUI Galway), supervised by leading expert in the cellular environment in Acute Myeloid Leukaemia (AML), Dr. Eva Szegezdi Funded by ONK Therapeutics, the research will support engineering and optimization of its dual-targeted NK cell therapy candidate for AML (ONKT104) Aims to explore the potential added benefit of certain gene edits to enhance NK cell cytotoxicity, cytokine production and persistence in the cancer microenvironment in the context of AML Galway, Ireland and San Diego, USA, 17 May 2021 – ONK Therapeutics Ltd, an innovative natural killer (NK) cell therapy company, today announced that it has entered into a research collaboration with the National University of Ireland, Galway (NUI Galway) which provides access to unique expertise in evaluating the cancer cell microenvironment in Acute Myeloid Leukaemia (AML) and targeting of AML stem cells in models mimicking the bone marrow microenvironment. The research will support the optimization of ONK Therapeutics’ dual-targeted NK cell therapy program, ONKT104, being developed for the treatment of AML. ONK Therapeutics will fund a year-long research program in the laboratory of Dr. Eva Szegezdi, lecturer in Biochemistry, NUI Galway, Head of the Blood Cancer Network Ireland. She has particular expertise in the AML microenvironment as well as cell death pathways, especially those initiated by ‘so-called’ death ligands (e.g. TRAIL) used by effector immune cells. AML is the most common form of acute leukemia in adults. It is estimated that some 21,000 patients in the US and 18,000 in Europe are diagnosed with AML each year. It has a high unmet medical need having the lowest survival rate of all types of leukemia. ONKT104 is a dual-targeted NK cell engineered to express a humanized scFv targeting the leukemic stem cell antigen CLL-1 (also known as CLEC12A) obtained through an option license agreement from Cellerant Therapeutics, together with ONK Therapeutics’ proprietary high-affinity TRAIL variant, targeting death receptor 4 (DR4). CLL-1 is selectively expressed on leukemic stem cells with no expression on normal hematopoietic stem cells, which ensures safer targeting and a lower risk of prolonged toxicity to normal bone marrow cells. In pre-clinical research studies, a monoclonal antibody therapy targeting CLL-1 has revealed potential efficacy against AML cells and shown to be effective in reducing AML burden in a xenograft model. In addition, a CLL-1 CAR-T cell model has shown promising pre-clinical activity and has recently entered the clinic. ONK Therapeutics believes its dual-targeted NK cell therapy approach may have several advantages over a CAR-T approach including shorter persistence of NK cells, reducing the risk of sustained neutropenia; proven inherent anti-AML activity of NK cells; the reduced likelihood of toxicity due to cytokine release syndrome or neurotoxicity; and the logistically simpler allogeneic, off-the-shelf nature of NK cells, reducing time to treatment once suitable patients are identified. AML is a very challenging disease in which to achieve sustained, long term disease control due to the high plasticity and adaptability of AML stem cells, and the tendency for resistant cells to emerge and grow. In addition to targeting CLL-1, this project will evaluate multi-targeted approaches by combined targeting of other leukemia stem cell antigens. ONK Therapeutics’ founder and CSO Prof Michael O’Dwyer said, “Alongside our in-house research, the project team at NUI Galway will explore construct design, as well as the potential added benefit of certain gene edits to enhance NK cell cytotoxicity, cytokine production and persistence in the context of AML strengthening our ONKT104 program. The aim is to select an optimized candidate to take forward into clinical development as a treatment for patients with relapsed/refractory AML.” Dr. Eva Szegezdi said, “The project will evaluate different constructs that may be able to achieve synergistic killing of cancer cells and reduce the emergence of disease resistance. These include the co-expression of CARs targeting other AML antigens, in addition to CLL-1, such as CD96, TIM3, and CD38 alongside the TRAIL variant.” ONK Therapeutics was formed based on technology and intellectual property developed at NUI Galway by Prof. Michael O’Dwyer, who retains his academic position as Professor of Haematology, Consultant Haematologist and HRB Clinician Scientist, alongside his role at the company. Over the past 12 months, ONK Therapeutics has expanded its team and operations at its headquarters and R&D facility in Ireland’s med-tech hub in Galway, where it now has 16 employees, with an additional 5 employees based in its US subsidiary in San Diego. -Ends- ONK Therapeutics – ONK Therapeutics Ltd is an innovative cell therapy company dedicated to developing the next generation of ‘off-the-shelf’, dual-targeted NK cell therapies targeting solid and hematological cancers. The company was founded in 2015, by Prof. O’Dwyer MD, of NUI Galway, an expert in translational multiple myeloma research, the tumor microenvironment, and exploitation of NK cells as cellular immunotherapy. Its core proprietary off-the-shelf cell therapy platform is based on a dual-targeted NK cell expressing both a chimeric antigen receptor (CAR) targeting a known tumor antigen and a TNF-related apoptosis-inducing ligand variant (TRAILv) targeting the death receptor pathway (i.e. DR4 or DR5). This unique approach has the potential to enhance efficacy by addressing both intrinsic (e.g. CAR engagement of a tumor-specific antigen) and extrinsic (e.g. signaling through the death receptor pathway) apoptotic pathways and to reduce the susceptibility to possible target antigen escape through the engagement of tumor antigen-independent TRAILv. Its pre-clinical pipeline comprises four programs: The lead program, ONKT101, is a dual-targeted NK cell therapy incorporating a CD19 CAR and TRAILv targeting DR5, intended for the treatment of relapsed/refractory B cell malignancies. This program is partnered with Avectas, with the company having responsibility for development to Phase 1 ONKT102 combines an optimized affinity CD38 CAR and a TRAILv targeting DR5, intended for the treatment of patients with relapsed/refractory multiple myeloma ONKT103 combines a TA-MUC1 CAR with a TRAILv targeting DR5, for the treatment of solid tumors ONKT104 combines a CLL-1 CAR with a TRAILv targeting DR4, for the treatment of AML In addition to the unique off-the-shelf, dual-targeted NK cell therapy platform, the company has a strong focus on engineering strategies to enhance tumor homing and persistence in-vivo, and overcome exhaustion in the tumor microenvironment, including the exploration of proprietary gene edits, such as the deletion of checkpoint inhibitory receptors in NK cells. ONK Therapeutics is headquartered in the med-tech hub of Galway, Ireland, with a wholly-owned US subsidiary, ONK Therapeutics, Inc. based at JLabs @ San Diego. Shareholders include Acorn Bioventures, ALSHC (principally Seamus Mulligan), and Enterprise Ireland. Follow us on Twitter and LinkedIn. Media enquiries (for ONK Therapeutics) International Sue Charles, Charles Consultants – +44 7968 726585 sue.charles59@outlook.com Ireland Ray Gordon, Gordon MRM – +353 87 2417373 ray@gordonmrm.ie

Professor Philippe Moreau brings 20 years of experience in clinical hematology Translational research head at University Hospital of Nantes, France World-renowned expert in multiple myeloma, leading clinical trials Joins US-based SAB members, Prof Malcolm Brenner MD, Ph.D. and Prof Jeffrey Miller MD Galway, Ireland, and San Diego, USA, 8 April 2021 - ONK Therapeutics Ltd, an innovative natural killer (NK) cell therapy company, today announced that Philippe Moreau MD, Professor of Clinical Hematology and Head of the Translational Research Program in Hematology and Oncology, at the University Hospital of Nantes, France, has been appointed to its Scientific Advisory Board (SAB). Professor Moreau has over 20 years’ experience in clinical hematology and has led many pivotal clinical studies. His interests are focused on multiple myeloma (MM) and its treatment with high-dose therapy and novel agents. He has served as the Principal Investigator for many international randomized phase 3 clinical trials evaluating proteasome inhibitors, Immunomodulatory drugs (IMiDs), or CD38 antibodies. He participated in the study of Idecabtagene Vicleucel (Abecma) (1), that received FDA approval last month as the first genetically modified autologous chimeric antigen receptor (CAR) T-cell therapy for the treatment of relapsed and refractory MM. Welcoming Professor Moreau to the SAB, ONK Therapeutics’ founder, CSO, and SAB Chair Professor Michael O’Dwyer MD said, “Philippe adds significant clinical and drug development experience to our SAB and we look forward to his insights guiding the clinical development pathway for our ONKT102 program, which combines an optimized affinity CD38 CAR and a TRAILv targeting DR5, intended for the treatment of patients with relapsed/refractory multiple myeloma.” Currently Chairman of the Intergroupe Francophone du Myélome (IFM) since 2020 and Vice-President of the International Myeloma Society (IMS) since 2019, Professor Moreau has been a member of the steering committee of the International Myeloma Working Group since 2013. A world-recognized expert in his field, Professor Moreau has authored or coauthored more than 400 peer-reviewed publications. In 2018 he received the Robert A. Kyle lifetime achievement award. ONK Therapeutics established its SAB in 2020, as it evolved into a more mature NK cell therapy company, with four pre-clinical programs. Other members of the SAB are Professor Malcolm Brenner MD, Ph.D. from Baylor College of Medicine, and Professor Jeffrey Miller MD from the University of Minnesota. Professor Brenner is a physician-scientist with expertise in the therapeutic use of T cell immunologic approaches and genetic engineering strategies, particularly in the treatment of cancer, whilst Professor Miller’s research is focused on the biology of NK cells and other immune effector cells and their use in clinical immunotherapy. Full profiles of ONK Therapeutics’ scientific advisors are available HERE. -Ends- ONK Therapeutics – ONK Therapeutics Ltd is an innovative cell therapy company dedicated to developing the next generation of ‘off-the-shelf’, dual-targeted NK cell therapies targeting solid and hematological cancers. The company was founded in 2015, by Prof. O’Dwyer MD, of NUI Galway, an expert in translational multiple myeloma research, the tumor microenvironment, and exploitation of NK cells as cellular immunotherapy. Its core proprietary off-the-shelf cell therapy platform is based on a dual-targeted NK cell expressing both a chimeric antigen receptor (CAR) targeting a known tumor antigen and a TNF-related apoptosis-inducing ligand variant (TRAILv) targeting the death receptor pathway (i.e. DR4 or DR5). This unique approach has the potential to enhance efficacy by addressing both intrinsic (e.g. CAR engagement of a tumor-specific antigen) and extrinsic (e.g. signaling through the death receptor pathway) apoptotic pathways and to reduce the susceptibility to possible target antigen escape through the engagement of tumor antigen-independent TRAILv. Its pre-clinical pipeline comprises four programs: The lead program, ONKT101, is a dual-targeted NK cell therapy incorporating a CD19 CAR and TRAILv targeting DR5, intended for the treatment of relapsed/refractory B cell malignancies. This program is partnered with Avectas, with the company having responsibility for development to Phase 1 ONKT102 combines an optimized affinity CD38 CAR and a TRAILv targeting DR5, intended for the treatment of patients with relapsed/refractory multiple myeloma ONKT103 combines a TA-MUC1 CAR with a TRAILv targeting DR5, for the treatment of solid tumors ONKT104 combines a CLL-1 CAR with a TRAILv targeting DR4, for the treatment of AML In addition to the unique off-the-shelf, dual-targeted NK cell therapy platform, the company has a strong focus on engineering strategies to enhance tumor homing and persistence in-vivo, and overcome exhaustion in the tumor microenvironment, including the exploration of proprietary gene edits, such as the deletion of checkpoint inhibitory receptors in NK cells. ONK Therapeutics is headquartered in the med-tech hub of Galway, Ireland, with a wholly-owned US subsidiary, ONK Therapeutics, Inc. based at JLabs @ San Diego. Shareholders include Acorn Bioventures, ALSHC (principally Seamus Mulligan), and Enterprise Ireland. Follow us on Twitter and LinkedIn. Media enquiries (for ONK Therapeutics) International Sue Charles, Charles Consultants - +44 7968 726585 sue.charles59@outlook.com Ireland Ray Gordon, Gordon MRM - +353 87 2417373 ray@gordonmrm.ie