Dr. Daniela Novick, Weizmann Institute of Science, Department of Molecular Genetics, Rehovot, Israel
Dr. Daniela Novick has been chosen to receive the 2023 ICIS Honorary Lifetime Membership Award in recognition of her ground-breaking discoveries in cytokine biology which have impacted the field significantly, as well as her contributions to clinical medicine. She is a treasured member to the ICIS, a woman scientist in a field which was mostly dominated by men, who has contributed so much to basic science and to translational medicine, ultimately playing a pivotal role in the development of four drugs, two of which she discovered and three are blockbusters.
She will accept her award at Cytokines 2023 on Sunday evening, October 15th at the Divani Caravel Hotel in Athens, Greece.
For more information about Dr. Daniela Novick, please click here.
The International Cytokine & Interferon Society recognized Daniela’s exceptional work by awarding her the 2005 Milstein Award for Excellence in Cytokine & Interferon Research.
Dr. Novick was born in Poland in 1948, a daughter to two Auschwitz survivors. In 1957 her family immigrated to Israel. She received her Ph.D. in 1979 from The Weizmann Institute of Science, Rehovot, Israel and is since at the Weizmann in the Molecular Genetics Department.
In the early 80’s when it was challenging and pioneering, together with Prof. Michel Revel and Prof. Menachem Rubinstein, Daniela generated a panel of monoclonal antibodies to various cytokines. Her antibody to interferon-beta (IFN-b) accelerated the characterization of this interferon and submission of its file to the FDA. Thus, Daniela had a major role in the development of IFN-b into the blockbuster drug Rebif for the treatment of multiple sclerosis. Daniela was also instrumental in the generation of the first monoclonal antibodies to TNF. These antibodies were translated to Remicade and Humira for the treatment for inflammatory bowel disease.
Daniela’s ground-breaking discoveries in cytokine biology impacted the field significantly and contributed in an outstanding manner to clinical medicine. Her unique approach that combines a highly specific and efficient isolation method, ligand affinity chromatography, and a very rich protein source, 1000-fold concentrated human urine, yielded novel proteins that specifically bind to a given ligand. Thus, she isolated not only soluble receptors but also unpredicted binding proteins that are not receptors. Drug companies recognized the therapeutic potential of this naturally occurring proteins.
In 1989, using her approach, Dr. Novick isolated the p50 and the novel p75 TNF soluble receptors, homologs of their corresponding extracellular cell surface receptors. She showed a 20,000-fold purification in one step, a high yield and over 80% recovery of bioactivity. Based on the amino acid sequence of these soluble receptors, their cell surface counterparts were easily cloned. Moreover, it was the p75 soluble receptor that proved beneficial in patients with rheumatoid arthritis and became the biological drug Enbrel. Patients with psoriatic arthritis, juvenile idiopathic arthritis and ankylosing spondylitis benefit too from this drug.
Adding to this list two soluble receptors, IL-6 receptor and IFNg receptor, isolated from normal human urine too, Daniela coined the notion that soluble cytokine receptors are normal constituents of body fluids and introduced this topic to her laboratory headed by Prof. Menachem Rubinstein.
In 1994 she discovered the Interferon alpha-beta receptor, a milestone in cytokine biology. It ended a 30-year search for the ligand-binding chain of the cell-surface type I interferon receptor. Daniela also contributed to the understanding of mechanism of action of Type I interferon. She had elegantly showed the stepwise ligand induced formation of the trimeric complex of the Type I IFN receptor chains and was the first to demonstrate the physical interaction of the ligand binding receptor with the transcription factor JAK1. Using her neutralizing monoclonal antibodies raised against this receptor, she reported that the JAK-STAT pathway does not fully explain the biological activities of Type I IFN.
In 1997, in a collaboration with Prof. Charles Dinarello, and in a search for the IL-18 receptor, Dr. Novick found a family of binding proteins that bind the same ligand as the cell surface receptor but are encoded by a separate gene. Once again, using ligand affinity chromatography with an immobilized recombinant IL-18, and human urine as the source of proteins, Daniela isolated the IL-18 Binding Protein (IL-18BP). She showed that IL-18BP has an exceptionally high affinity to IL-18 and, as such, serves as the natural defense against high levels of IL-18. In collaboration with clinicians all over the world she established the levels of this cytokine and its binding protein in health and disease. High levels of IL-18 are found in a fatal inherited IL-18BP deficiency in human fulminant viral hepatitis A, in children born with mutations in the NLRC4 inflammasome or a mutation in XIAP/BIRC4. These mutations lead to an over production of IL-18 resulting in organ damage due to Macrophage Activation Syndrome (MAS) (also termed hemophagocytic lympho- histiocytosis). Recombinant IL-18BP was translated to a drug and named Tadekinig alfa. Tadekinig alfa is now in a phase III clinical trial in children born with those mutations. Lives of these children had been saved by continuous compassionate treatment with Tadekinig alfa, for 7 years now. A successful phase II clinical study in the autoimmune Still’s disease is completed. Tadekinig alfa has also been submitted to the FDA for use in severe MAS and is considered in the treatment of the cytokine storm in patients undergoing CAR T therapy and in severe cases of COVID 19.
Employing her approach, Daniela identified several soluble receptors and binding proteins, not only those specific for the cytokines TNF, IL-6, IFNs, IL-18 and IL-32, but also to other molecules such as LDL and heparanase. The soluble LDL receptor, present in urine, has an unanticipated antiviral activity and its cell surface counterpart, present in all types of cells, is the entry receptor of VSV. These findings explain the pantropism of this virus used successfully in gene therapy. Daniela showed that resistin, an adipogen in mice and a pro-inflammatory cytokine in humans, is a heparanase binding protein and that the enzyme proteinase 3 (PR3) is an IL-32 binding protein. PR3 is the auto-antigen in autoimmune blood vessel disease named Wegener’s disease. Blood levels of IL-32 were reported to be upregulated in these patients.
Concentrated human urine provided a goldmine of naturally occurring proteins. Daniela’s approach yielded both expected and unexpected proteins. The most prominent are the two receptors for TNF, the Type I and Type II interferon receptors (IFNa/bR, IFNgR) and the unique IL-18 Binding Protein. In addition, she isolated a soluble LDL receptor, IL-32 binding protein (proteinase 3) and heparanase binding protein (Resistin). Daniela is the champion of the concept that soluble receptors and binding proteins are normal constituents of body fluids. Being antagonists, agonists or carrier proteins, they have and immunoregulatory roles, and any imbalance with the corresponding ligand/cytokine results in a pathological situation. In this context, Daniela introduced the calculation of a free cytokine concentration that most likely dictates pathology. Each of the proteins that Daniela isolated opened fascinating avenues of basic research, and together with her collaborators enabled studies in health and disease. Drug companies recognized the therapeutic potential of these soluble receptors and binding proteins and translated some into drugs. IFN-b (Rebif) proved beneficial in multiple sclerosis and Enbrel is a blockbuster in the treatment of rheumatoid arthritis. Tadekinig alfa, the recombinant IL-18BP, is in a phase III clinical study for the treatment of inflammatory and autoimmune diseases and is in compassionate use.