Proteinläkemedelsdesign-gruppen
Greta Hultqvist, Principal Investigator of ProDDe
I am the PI of the Protein drug design group and I am very excited about all the projects we are running, which are described below. In the research group we have competencies stretching from advanced biochemistry, cell studies, microscopy techniques, In vivo work, protein expression and purification. We have a large capacity to express a wide range of proteins and antibodies transiently in mammalian cells. We also have an in vitro BBB assay. Contact me here if you to get in touch!
Our projects
BBB-transporters
The selectively permeable blood-brain-barrier (BBB) is one of the hurdles that large molecular drugs such as protein-based drugs need to overcome to efficiently reach targets in the brain.
Much of today’s research on BBB focuses on the transferrin receptor, to hijack the transferrin transcytosis to improve uptake of biologics in the brain. Since the transferrin seems to be different in humans compared to mice and is also present on blood cells, there is a need for finding other ways over the BBB. In one of our research projects, we are working on finding alternative receptors on the brain endothelium that allow transport and suitable binders for these receptors. The ideal receptor would be highly similar in both mouse and human and thus allow for designing a binder that can be used both in pre-clinical and clinical studies.
Click here to reach Jamie, Andrés, Inga or Greta.
Alzheimer’s & Parkinson's disease - novel treatment and diagnostic strategies
Multivalent antibodies
Amyloid-b (Ab) immunotherapy is a promising therapeutic strategy in the fight against Alzheimer’s disease. Despite the number of monoclonal antibodies entering clinical trials, most of them have been discontinued due to lack of efficacy or adverse side-effects. One further reason for the ineffectiveness of the antibodies is that they target the wrong species of Ab. The soluble intermediate species of Ab (oligomers and protofibrils) are believed to be the toxic species in Alzheimer’s disease.
In this project, we are designing and recombinantly producing multivalent antibodies that have very strong and selective binding to oligomers and protofibrils. Using different biochemical/biophysical methods, we are characterizing their binding properties to different species of Ab. In addition, we are using transgenic mouse models of Alzheimer’s disease, to test the effectiveness of the generated proteins as diagnostic/therapeutic tools.
Click here to reach Inga, Nicole or Greta.
Degradation of amyloid beta projects
Aggregation of the amyloid-beta (Ab) peptide is one of the main neuropathological events in Alzheimer’s disease. Enhancing the degradation of Ab prior to aggregate formation or stabilizing the monomers is a potential therapeutic intervention in Alzheimer’s disease. The overall aim of these studies are to develop protein-based therapies to decrease the concentration of Ab in the brain by enhancing the activity and/or expression levels of the major Ab degrading enzymes or by adding factors that stabilize the monomers. Using transgenic mouse models of Alzheimer’s disease, the pharmacokinetic properties and the therapeutic potentials of the generated fusion proteins are evaluated.
Click here to reach Nicole or Greta.
Parkinson’s disease - novel treatment and diagnostic strategies
In Parkinson´s disease – a disease as of yet without a cure – aggregation of α-synuclein (α‑syn) is an accelerator of pathogenesis. Oligomers of α-syn are believed to be toxic for neurons and blocking the uptake of aggregated α-syn in neurons can be a way of preventing pathogenesis. In one of our projects, we aim to develop a protein-based drug that can bind and sponge up oligomeric α-syn in the intercellular space, which prevents the spread of aggregation, thereby decreasing neuron degeneration.
Furthermore, we are generating high affinity binders using antibody derivates against α‑syn to improve the recognition of early stages of α‑syn aggregates.
Click here to reach Inga or Greta.
In vivo experiments
Many of our novel protein designs are evaluated in-vivo in transgenic mice. The proteins are labeled with radioactive substances, and then injected intravenously via the tail vein. With help of a gamma counter, we can assess the biodistribution of our proteins, their half-life in blood, study therapeutic effects and much more. Click here to reach Nicole or Greta.
Intracellular transporters
For some targets, it might not be enough to transport the protein drug over the BBB. Uptake into specific cell types might be needed to reach their target as shown in the case of the Parkinson’s disease, where the pathological aggregation of the protein alpha-synuclein takes place particularly within the dopaminergic neurons of the brain.
We are working on developing cell specific protein shuttle domains that enable biologics to be transported through the neuronal cell membrane by receptor mediated transcytosis to reach their targets within the affected neurons.
Click here to reach Inga or Greta.
In vitro blood brain barrier
Identifying and deciphering the receptor mediated endocytosis/transcytosis pathways (RMT) of the BBB is crucial if one would like to develop new BBB transporters through intelligent design. To enable the study of these pathways and to help us screen drug candidates for transport across the BBB, we are working on developing a murine and human based in vitromodel of the BBB that can be used for studies into macromolecular trafficking and signaling, as well as providing an invaluable pre-in vivo screening tool for BBB permeability of drug candidates. In addition, the in vitro model will aid in the reduction of current in vivo protocols, ultimately reducing the use of animal experiments to study drug candidate efficacy. The development of a robust and reproducible in vitro model of the BBB opens up the possibility to spearhead pre-clinical studies into the development of improved therapeutic delivery ap proaches in patients with neurological pathologies.
Click here to reach Jamie, Ana or Greta.
Protein expression and -purification optimization
In addition to the more therapeutical projects above, which all involve the use of recombinant proteins, we also study how to improve transient or semistable expression in mammalian cells. We aim to standardise the expression of proteins in mammalian cells through testing and validating methodological variables such as growth conditions, cell types, transfection reagents, DNA preparation and vector types.
Click here to reach Andrés, Ana or Greta.
Epilepsy/Neuroinflammation
Neuroinflammation is strongly associated with a growing number of diseases like Alzheimer’s disease, multiple sclerosis, chronic pain and now also with epilepsy. In epilepsy, the inflammation seems to be part of both the epileptogenesis as well as in seizure initiation. Around 30% of people with epilepsy do not respond to any of the current therapies, emphasizing an urgent need for the development of new drugs that hinder epileptogenesis or other causative factors. In this project, our purpose is to develop, re-design and test biological drugs targeting inflammation, which can pass the BBB by using a BBB transporter. Our overall aim is to inhibit neuroinflammatory cytokines, providing a cure to drug resistant TLE.
Click here to reach Canan or Greta.
Bladder cancer and urothelial transporter
It is not only the brain that is protected by barriers, the bladder is also protected by the highly impermeable urothelium. We have found a receptor that is highly expressed in the urothelium. The expression of this receptor is also high on immune cells like B cells, T cells and dendritic cells. Importantly, the receptor has an elevated expression level on several cancer cell types, when compared to normal, healthy cells. In this project, we are recombinantly producing bispecific antibodies with the aim of enabling locally administered therapeutic proteins to pass through the urothelium, improving the efficacy/safety profile of immunomodulatory protein-based drugs.
Click here to reach Greta.