"The complement system is a potent driver of inflammation in many diseases, including Alzheimer’s where inflammation is a major factor in the pathogenesis. I hope to develop a new approach to Alzheimer's disease therapy; brain penetrant anti-complement drug(s), providing better ways of treating Alzheimer's disease and other dementias." Wioleta Zelek
UK DRI Emerging Leader
Dr Wioleta Zelek is a UK DRI Emerging Leader with a prestigious Race Against Dementia (RAD) Fellowship – sponsored by Group Leader Prof Paul Morgan (UK DRI at Cardiff). Dr Zelek trained in Chemistry and after several years in the Biotech sector, returned to academia and undertook a PhD in Immunology, focused on the complement system. During her PhD, and Fellowships (ISSF Wellcome Trust, Health and Care Research Wales) she developed a toolbox of novel complement inhibitors, including patent protected drug candidates (PCT/EP2020/073430) and other tool reagents enabling the study of complement in animal disease models. Dr Zelek’s main goal over the course of the Fellowship project is to develop brain penetrant anti-complement drug candidates to target neuroinflammation, a critical driver of pathology in Alzheimer's disease.
1. At a glance
Complement is a system of proteins in blood that exists to counter bacterial infections, either by directly killing bacteria or provoking white blood cells to eat them. The direct-killing part of complement is a protein complex called MAC which bursts bacteria and human cells alike by poking holes in their surfaces like a pinprick in a balloon. Leaking cells cause lots of inflammation, which is implicated in many diseases, including Alzheimer’s.
Dr Wioleta Zelek is testing the idea that overactivity in MAC and the inflammation it causes is an important driver of Alzheimer’s disease. Her research involves developing new methods of targeting MAC in ways that will prevent the "hole-punching” activity that is most harmful to our own cells and the most inflammatory, while leaving intact the important roles of complement in killing bacteria. As part of this, Dr Zelek is generating MAC-blocking drugs capable of entering the brain that can stop MAC-driven brain inflammation. Dr Zelek is using test-tube models of the barrier between the blood and brain, to develop these agents and select the best ones to provide proof-of-concept for their use in Alzheimer’s, by testing them in appropriate animal models, and laying the groundwork for future human therapies.
2. Scientific goals
Complement is a central component of innate immunity, a network of plasma proteins interacting to provide defence against infection and efficient removal of dead cells and debris. Because of its complexity and destructive character, complement is tightly regulated by numerous fluid-phase and membrane regulators. Activation of complement initiates formation of enzymes, termed convertases. These include the C5 convertase, which cleaves C5 into C5a and C5b, the latter seeding formation of the lytic membrane attack complex (MAC), the subject of Dr Wioleta Zelek’s research.
Critically, genetic and epidemiological studies, cerebrospinal fluid and plasma biomarker measurements and pathological analysis have all implicated complement as a driver of pathology in Alzheimer’s disease and other dementias. To test this, Dr Zelek will develop efficient, blood-brain barrier-penetrant inhibitors. This research will lay the foundations for developing novel, transformative therapies targeting brain inflammation, providing better ways of treating Alzheimer’s and other dementias with resultant positive impact on human health.
Main objectives and research goals:
1. Making small fragments of MAC-inhibitory antibodies and testing their blood-brain barrier penetrance in vitro.
2. Exploring new ways of delivery of antibodies, antibody fragments and small molecules into the brain.
3. Identifying the MAC binding sites of the antibody fragments to enable the design and screening of small molecule MAC inhibitors.
4. After confirming that the inhibitors can cross in vitro blood-brain barrier models, the best agents will be tested for in vivo blood-brain barrier penetrance and impact on disease in Alzheimer’s disease models.
Within UK DRI:
• Professor Julie Williams, UK DRI at Cardiff
• Professor Paul Morgan, UK DRI at Cardiff
• Professor Bart De Strooper, UK DRI at UCL
Beyond UK DRI:
• Professor John Davis, Alzheimer’s Research UK Oxford Drug Discovery Institute
• Professor John Atack, Medicines Discovery Institute, Cardiff University
• Professor Andrea Brancale, School of Pharmacy and Pharmaceutical Sciences, Cardiff University
complement, therapeutics, neuroinflammation, animal models, biomarkers
Antibodies and antibody fragments generation, bispecific antibodies, in vitro platforms for testing BBB penetrance.
6. Key publications
1. Zelek WM, Morgan BP. Monoclonal Antibodies Capable of Inhibiting Complement Downstream of C5 in Multiple Species. Front Immunol (2021) 10:11:612402.
2. Zelek WM, Menzies GE, Brancale A, Stockinger B, Morgan BP. Characterizing the original anti-C5 function-blocking antibody, BB5.1, for species specificity, mode of action and interactions with C5. Immunology (2020) 161(2):103-13
3. Zelek WM, Fathalla D, Morgan A, Touchard S, Loveless S, Tallantyre E, Robertson NP, Morgan BP. Cerebrospinal fluid complement system biomarkers in demyelinating disease. Mult Scler J (2019) 8:1352458519887905.
4. Zelek WM, Xie L, Morgan BP, Harris CL. Compendium of current complement therapeutics. Mol Immunol (2019) 114:341–352.
5. Zelek WM, Taylor PR, Morgan BP. Development and characterization of novel anti-C5 monoclonal antibodies capable of inhibiting complement in multiple species. Immunology (2019) 157:283–295.
6. Kopczynska M*, Zelek WM*, Touchard S, Gaughran F, Di Forti M, Mondelli V, Murray R, O’Donovan MC, Morgan BP. Complement system biomarkers in first episode psychosis. Schizophr Res (2019) 204:16–22. *co-first authorship.