PET diagnostics and immunotherapy with bispecific antibodies

Members of the group

Stina Syvänen, PhD, Associate Professor
Dag Sehlin, PhD, Associate Professor
Sahar Roshanbin, PhD
Wojciech Piotr Michno, PhD
Sara Lopes van den Broek, PhD
Ximena Aguilar, PhD, research engineer
Tobias Gustavsson, PhD
Mengfei Xiong, PhD
Lara Garcia Varela, PhD
Gillian Bonvicini, PhD
Amelia Dahlén, PhD student
Elin Wik, PhD student

Novel diagnostics and immunotherapy for neurodegenerative diseases

In Alzheimer’s disease, the amyloid-β (Aβ) protein aggregates to form insoluble deposits – senile plaques – in the brain. However, recent findings indicate that a pre-stage of plaques, soluble Aβ protofibrils, cause the neurodegeneration that eventually lead to dementia. In Parkinson’s disease, a similar process leads to the formation of Lewy bodies, consisting of the protein α-synuclein. Soluble, aggregated forms of Aβ and α-synuclein are therefore important targets for both diagnosis and treatment of these neurodegenerative diseases.

Positron emission tomography (PET) is a medical imaging technique that can be used for diagnosing Alzheimer’s disease without any biological sampling (i.e. blood or CSF). Today, a number of PET radioligands can be used to visualize the amount and location of senile plaques in the brain of Alzheimer’s disease patients. This method can clearly distinguish a patient with Aβ pathology from a healthy person. However, there is a pronounced ceiling effect of the PET signal, i.e. the signal does not increase with disease progression during the clinical stages of the Alzheimer’s disease. It is therefore difficult to measure disease stage or effects of therapeutic interventions, which hampers the development of new drugs for Alzheimer’s disease.

Our research is mainly based on antibodies, which bind specifically to different forms of Aβ or α-synuclein. The antibodies are modified to bind also the transferrin receptor (TfR), which is normally involved in iron transport into the brain. The interaction with TfR works like a molecular Trojan horse, which transports the antibody into the brain, where it can bind to its target. Antibody modifications are partly done in collaboration with Greta Hultqvist’s research group.

Schematic image of TfR-mediated transcytosis. The bispecific antibody binds to TfR for active transport across the blood-brain barrier into the brain, where it binds its target molecule, the Aβ protofibril.

Based on these bispecific antibodies, we develop a new type of PET radioligands with the aim to enable dynamic monitoring of disease progression and effect of Alzheimer’s disease therapies, e.g. in clinical trials. Our main focus is to visualize soluble aggregates if Aβ and inflammatory markers, but we also use traditional PET ligands to study e.g. neuroreceptors, that may have an altered expression or function in Alzheimer’s disease. We also develop antibody ligands to α-synuclein for diagnosis of Parkinson’s disease.

PET study with modified, radiolabeled antibody, visualizing the progression of Aβ pathology with age in Alzheimer transgenic mice.

In parallel with the development of new PET radioligands we study immunotherapy against neurodegenerative diseases. We have previously generated the antibody mAb158, which binds selectively to Aβ protofibrils. A modified variant of mAb158, with increased brain uptake, is currently evaluated for therapeutic efficacy and its therapeutic mechanisms of action are studied.

Selected publications

Xiong M, Roshanbin S, Rokka J, Schlein E, Ingelsson M, Sehlin D, Eriksson J, Syvänen S (2021). In vivo imaging of synaptic density with [¹¹C]UCB-J PET in two mouse models of neurodegenerative disease. Neuroimage. 239: 118302.

Meier SR, Sehlin D, Roshanbin S, Lim Falk V, Saito T, Saido TC, Neumann U, Rokka J, Eriksson J, Syvanen S (2021). ¹¹C-PIB and ¹²⁴I-antibody PET provide differing estimates of brain amyloid-beta after therapeutic intervention. J Nucl Med.

Faresjö R, Bonvicini G, Fang XT, Aguilar X, Sehlin D, Syvänen S (2021). Brain pharmacokinetics of two BBB penetrating bispecific antibodies of different size. Fluids Barriers CNS. 18: 26.

Gustavsson T, Syvänen S, O'Callaghan P, Sehlin D (2020). SPECT imaging of distribution and retention of a brain-penetrating bispecific amyloid-β antibody in a mouse model of Alzheimer's disease. Transl Neurodegener. 9: 37.

Sehlin D, Stocki P, Gustavsson T, Hultqvist G, Walsh FS, Rutkowski JL, Syvänen S (2020). Brain delivery of biologics using a cross-species reactive transferrin receptor 1 VNAR shuttle. FASEB J. 34: 13272-13283.

Sehlin D, Syvänen S; MINC faculty (2019). Engineered antibodies: new possibilities for brain PET? Eur J Nucl Med Mol Imaging. 46: 2848-2858.

Syvanen S, Hultqvist G, Gustavsson T, Gumucio A, Laudon H, Soderberg L, Ingelsson M, Lannfelt L and Sehlin D (2018). Efficient clearance of Abeta protofibrils in AbetaPP-transgenic mice treated with a brain-penetrating bifunctional antibody. Alzheimers Res Ther. 10: 49.

Hultqvist G, Syvanen S, Fang XT, Lannfelt L and Sehlin D (2017). Bivalent Brain Shuttle Increases Antibody Uptake by Monovalent Binding to the Transferrin Receptor. Theranostics. 7: 308-318.

Sehlin D, Fang XT, Cato L, Antoni G, Lannfelt L and Syvanen S (2016). Antibody-based PET imaging of amyloid beta in mouse models of Alzheimer's disease. Nat Commun. 7: 10759.