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AAIC 2023 | Fibrin-targeting immunotherapy in Alzheimer’s Disease

Katerina Akassoglou, PhD, University of California San Francisco, San Francisco, CA, discusses fibrin-targeting immunotherapy. Previous research has identified the blood coagulation factor fibrinogen as a cause of neuroinflammation in neurological disease. This research focused on developing a monoclonal antibody capable of targeting the inflammatory domain of fibrinogen, without interfering with its beneficial coagulation effects. Data from preliminary studies demonstrated that the immunotherapy was able to enter the central nervous system and bind to fibrin, blocking neurodegeneration and inflammatory pathways in Alzheimer’s disease (AD) mouse models. The group are currently moving this through to clinical development. Toxicology tests in two species, including non-human primates, have been completed and the antibody has been humanized for clinical use. Phase I clinical trials started in healthy volunteers in May 2023. This interview took place at the Alzheimer’s Association International Conference® (AAIC) 2023 in Amsterdam, Netherlands.

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Transcript (edited for clarity)

Our findings on the role of blood in the brain and also coupled with data from human research that shows cerebral vascular pathology pathway, independent of amyloid, that might need to be separately targeted to achieve maximum therapeutic benefit, inspired us to be able to develop a first-in-class immunotherapy to neutralize blood toxicity. Of course, the challenge we had to overcome was that fibrin had a very protective function, which is coagulation and hemostasis, but also this detrimental function in inflammation...

Our findings on the role of blood in the brain and also coupled with data from human research that shows cerebral vascular pathology pathway, independent of amyloid, that might need to be separately targeted to achieve maximum therapeutic benefit, inspired us to be able to develop a first-in-class immunotherapy to neutralize blood toxicity. Of course, the challenge we had to overcome was that fibrin had a very protective function, which is coagulation and hemostasis, but also this detrimental function in inflammation. And we needed a pharmacologic tool to be able to separate these two functions of the molecule. So we developed a first-in-class immunotherapy that can selectively recognize only the inflammatory domain of fibrin without adverse effects in hemostasis. And this originally was a mouse monoclonal antibody that had high efficacy in blocking neurodegeneration and also blocking inflammatory pathways in Alzheimer’s disease models, highly linked with inflammation that we observe in also human Alzheimer’s disease patients. And this high efficacy of this antibody in neuroprotection as well as also low adverse effects of interfering with coagulation led to the rationale of moving it forward towards clinical development. The antibody has now been humanized, affinity matured, GMP manufactured. It has completed toxicology in two species, including nonhuman primates, and the Phase I trial in healthy volunteers started in May of this year.

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Disclosures

K.A. is the scientific founder, advisor and shareholder of Therini Bio, Inc. Her interests are managed by Gladstone Institutes according to its conflict of interest policy.