CSO: Dr. Adi Sagiv
Symbol Therapeutics is a drug discovery company developing a novel immunoregulatory therapeutic protein, which is a modified form of the endogenous Semaphorin3A, for the treatment of Systemic Lupus Erythematosus (SLE) and other autoimmune diseases. Our proprietary modified protein is able to activate anti-inflammatory regulatory mechanisms and thereby restore normal immune homeostasis.
Scientific background
Autoimmune diseases are a pathophysiological state wherein immune responses are directed against, and damage, the body’s own tissues. Autoimmunity and immune-mediated inflammation are continuously counterbalanced by the maintenance of efficient self-tolerance, immune regulatory cells and suppressive signals, the failure of which allow the development of autoimmune diseases. Presently, more than 80 autoimmune diseases have been described. They can be systemic, such as Systemic Lupus Erythematosus (SLE), which can affect the skin, joints, kidneys, and CNS, or organ specific, such as Uveitis, which primarily affects the eye. In general, current immune-modulatory drugs used in the treatment of autoimmune diseases are broadly acting, non-disease specific, and consequently associated with severe side effects. Furthermore, it has become clear that most patients are not responding optimally, if at all, to these therapies. Thus, there is a pressing need for development of new drugs.
In the last decade, the involvement of regulatory immune responses in autoimmune diseases has drawn much attention, the normal function of which was proven to maintain immune mediated homeostasis. The early identified immunoregulators include regulatory T cells (Tregs) and inhibitory cytokines. Nevertheless, more recently, other regulatory responses have emerged, such as the involvement of B regulatory cells (Bregs) and the regulatory semaphorins in suppressing autoimmunity.
Semaphorins are a large family of secreted and membrane-bound proteins that were originally identified as guidance cues for developing axons. However, today, its widely established that semaphorins function in many other physiological processes, including regulation of immune responses. Semaphorins that have important roles in immune responses are known as ‘immune semaphorins’. The semaphorins are implicated in most stages of both normal and pathological immune responses and have been revealed to participate in autoimmune pathologies.
Semaphorin3A (Sema3A), a member of the class-3 Semaphorin sub-family, was recognized as one of the most active and potent Semaphorins in the modulation of inflammatory conditions, in all stages of the immune response, including both the early initiation and the late phase of inflammatory processes, therefore receiving special attention. Sema3A was demonstrated to enhance T- and B-cell regulatory properties. Thus, Sema3A has been recently considered as a new paradigm in the pathogenesis of autoimmune diseases, such as SLE. In these diseases, Sema3A was shown to exert an effective immunosuppressive outcome through- restoring the normal function of both T-cell and B-cell autoimmunity.
The inventors of our technology have accumulating data showing the potential role of Sema3A in restoring immune homeostasis in SLE both in-vitro and in-vivo, through the specific binding to a novel receptor, thereby highlighting a novel signaling pathway that may prove beneficial as a drug target. Furthermore, the inventors have generated a potential therapeutic modified form of the Sema3A protein, namely T-sema3A, which is a modified recombinant protein of the wild type Sema3A that is able to bind specifically to the novel receptor (but unable to bind to its known receptor thus far – NRP1), thereby restoring immune tolerance.
Indication
SLE is a multi-system autoimmune disease, which involves the skin, synovia, kidneys, and the brain. Long-lasting organ damage mainly in the kidneys (lupus nephritis) is associated with a high rate of morbidity and mortality. The etiology of SLE is not well understood and is believed to be associated with genetic and epigenetic abnormalities leading to inadequate immune regulation. A key driver is believed to be apoptosis leading to a cascade of pDCs, T cell and B cell activation. This results in production of autoantibodies against nucleic acids and over-production of IFN resulting in further dysregulation of the immune system. There are an estimated of 600,000 SLE patients across the main markets, with 40%-50% having moderate/severe disease. Standard therapy which includes antimalarials, steroidal and non-steroidal anti-inflammatory agents and immunosuppressive drugs, though beneficial and improving survival, is associated with frequent and sometimes severe side effects. Moreover, despite a dramatic improvement in the prognosis for SLE patients, treatment of those with active disease refractory to traditional therapies continues to be a real challenge, as only two drugs were approved for SLE in the last 60 years. Moreover, lack of specific effective drugs is true for other autoimmune diseases. Therefore, there is a need for new and better focused treatment strategies, namely for drugs that target new protein families and novel signaling pathways that are involved in immune regulatory mechanisms that restore immune tolerance and that can serve as a potential therapeutic for SLE and potentially for many other autoimmune diseases. Importantly, while currently, most developments are focused on inhibition of effector signals (e.g., INF, JAK, BAFF), T-sema3A recapitulates the normal endogenous homeostasis and does not aggressively inhibit the immune system. In addition, T-sema3A has the potential to serve as a drug for additional immune mediated diseases such as Uveitis.
Team
Adi Sagiv, PhD, MBA, CSO
Dr. Sagiv holds a PhD from the Weizmann Institute of Science and an MBA from the Hebrew University of Jerusalem. She has vast expertise in studying regulatory mechanisms of immune cells in chronic diseases, in addition to expertise in molecular biology, cell biology, and cell signaling. Dr. Sagiv worked as a pre-clinical project leader and a scientist at CytoD, a drug discovery company for autoimmune diseases, where she was responsible for the development of in vitro and cell-based assays, lead the scientific projects and managed several CROs. In addition, Dr. Sagiv was chosen to participate in the prestigious MERCK Innovation Cup competition due to a novel proposal for drug development in the field of autoimmunity. Lastly, Dr. Sagiv served as Head of US Healthcare Consulting at Signals Analytics LTD where she managed consulting projects in the field of drug development for the Fortune 500 US pharma companies.
Gabe Javitt, PhD, Scientist
Gabe Javitt holds a PhD from the department of Chemical and Structural Biology from the Weizmann Institute of Science in Rehovot. Gabe worked biochemically and structurally on the molecular mechanism of human proteins linked to disease. His main research was on the mucin family of proteins and von Willebrand Factor in the blood where his research provides the first molecular understanding on the polymerization of these protein at the amino-acid residue level. He has extensive experience in molecular biology, biochemistry, advanced microscopy, crystallography, and protein production. He received multiple honors and awards including the Clifford-Felder prize for excellent PhD student, the Professor Shimon Reich Memorial Prize and the National Forum for BioInnovators (“NFBI”) Fellowship sponsored by TEVA.
Adi Kremer, MSc., Scientist
Adi Kremer holds an MSc., graduated Magna Cum Laude, from the Faculty of Medicine at The Hebrew University of Jerusalem. Adi focused her research on the function of TRPM2 calcium channels in neutrophils in cancer and infections. She has extensive experience in immunology as well as in clinical immunological diagnostics, cancer research, and stem cells. In addition, Adi has extensive experience in various in vitro and in vivo mouse models. Adi previously worked in Gamida Cell LTD as a Research Associate where she focused her work on NK cells and cord blood CD34+ cells. Later, she worked at the Bone Marrow Transplantation Department in Hadassah Ein Kerem hospital as a Scientist and Project Manager researching post hematopoietic stem cell transplantation effects in children and adults and immune deficiency in children.
Prof. Elias Toubi, MD, Co-Inventor, and Advisor
Dr. Toubi is a physician specialist in the field of Allergy & Clinical Immunology which served as the director of the division of Allergy & Clinical Immunology at Bnai-Zion Medical Center for 18 years. During this time, Dr. Toubi focused his clinical and research activities on the regulatory mechanisms controlling immune-mediated and autoimmune diseases such as SLE. Specifically, studying the role of T and B regulatory cells and regulatory molecules in autoimmunity. Prof. Toubi co-authored >200 scientific publications in lead journals. During the last decade, together with Prof. Vadasz, they became deeply involved in studying the role of semaphorins, mainly Sema3A in controlling autoimmune diseases. Prof. Toubi co-authored >200 scientific publications in lead journals.
Prof. Zahava Vadasz, MD, PhD, Co-Inventor, and Advisor
Prof. Vadasz is a physician specialist in the field of Allergy & Clinical Immunology and head of laboratory at the Bnai-Zion Medical Center, and a Senior Researcher at the Rappaport Faculty of Medicine, at the Israel Institute of Technology (Technion). In addition, Prof. Vadasz is the head of the Proteomics and Flow Cytometry unit at the Bnai-Zion Medical Center. In addition, Prof. Vadasz holds a PhD from the Israel Institute of Technology (Technion). Throughout the years, Prof. Vadasz focused her clinical and research activities on immune-mediated diseases such as SLE where her main research interests were understanding the regulatory mechanisms of the immune system that control such diseases, especially, the role of T and B regulatory cells and regulatory molecules that control immune-mediated diseases. Prof. Vadasz co-authored >100 scientific publications in lead journals.
Prof. (Emeritus) Gera Neufeld, PhD, Co-Inventor
Prof. Emeritus Gera Neufeld is a member of the cancer research center of the Faculty of Medicine of the Technion, Israel institute of Technology. He obtained his Ph.D. in Biochemistry at the Hebrew University of Jerusalem. He was subsequently a post-doctoral fellow at the University of California at San-Francisco in which he his research was focused primarily on angiogenesis. Following his post-doctorate, he was awarded the Alon fellowship and established his laboratory at the Faculty of Biology of the Technion. Prof. Neufeld was awarded full Technion professorship in 1998. From 2000 to 2002 he served as the dean of the Faculty of Biology of the Technion. In 2003 he was invited to join the cancer center that was established in the Faculty of Medicine. Studies from his laboratory identified the receptors of the Neuropilin family as novel vascular endothelial growth factor receptors. These receptors were already known to function as receptors for class-3 Semaphorins. Subsequent studies from Prof. Neufeld’s laboratory determined that these Semaphorins function as potent angiogenesis and tumor progression inhibitors and have provided important findings that shed a light on their mechanism of action.
Nasren Eiza, PhD, Co-Inventor, and Advisor
Dr. Eiza is a translational immunology researcher, and the lab manager of Prof. Vadasz’s lab at the Faculty of Medicine, Technion and Bnai-Zion Medical Center. Dr. Eiza graduated her MSc., cum-laude, from the Technion under the supervision of Prof. Vadasz and Prof. Toubi. Her research focused on Killing B cells in HCV infection. Following, she completed her PhD, under the supervision of Prof. Vadasz, where she uncovered that the regulatory molecule, Sema3A, binds a novel receptor. She is experienced in cell biology, especially in immune cells, molecular biology, and biochemistry research. In 2022, she received the Outstanding Researcher Award from Bnai-Zion medical center.