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ApoM-Fc Fusion Protein in Complex with S1P for the Treatment of Vascular Diseases
Boston Children's Hospital
Protein
Cardiovascular disease
Pre-Clinical
Unmet Needs
• Endothelial
cell function is critical for normal cardiovascular homeostasis. Endothelial
dysfunction hence leads to the development of cardiovascular diseases such as
hypertension and Ischemia. Recently, endogenous factors - such as plasma
•
Apolipoprotein M-containing high density lipoproteins (ApoM-HDLs) - have
been shown to promote the well-being of the endothelium. Thus, ApoM-based
therapeutics have a great potential in reducing the burden of cardiovascular
disease – the leading cause of death globally.
Technology Description
ApoM-HDL is the physiological
carrier of the bioactive lipid sphingosine-1-phosphate (S1P) and engages S1P receptors
to promote endothelial survival. The Hla lab devised a strategy to develop a
soluble ApoM therapeutic that carries S1P to activate vascular S1P receptors
during pathological conditions.
Technology Proof of Concept
• Fusion of
ApoM with with the constant domain (Fc) of immunoglobulins stabilizes it
• The ApoM-Fc
fusion bound tightly to S1P with an EC50 of ~0.22 µM
• ApoM-Fc-S1P
complex activated S1P receptors in reporter assays
• In vitro:
ApoM-Fc-S1P induces sustained enhancement of endothelial cell barrier function
of endothelial HUVEC cells
• In vivo:
ApoM-Fc bound S1P was stabilized and potently reduced blood pressure in a mouse
model of hypertension
• In vivo:
ApoM-Fc administration attenuated ischemia/reperfusion (MI/R) injury in the brain
and heart in mouse models
Applications
• Treatment of
of hypertension, ischemia of the heart and brain, accelerated atherosclerosis
and peripheral vascular disease
• Reducing the
side effect of Fingolimod (S1P agonist) in patients being treated with it.
Advantages
• ApoM-Fc has
increased in vivo stability with half-life of 93.5 hours
• ApoM-Fc does not activate immune and hematopoietic S1P receptors, hence circulating numbers of lymphocytes, white blood cells, red blood cells and platelets not altered.
Steven L Swendeman, Yuquan Xiong
US 10870689 B2 (2020.12.22)
Patent Family: US, EP, JP, CN, CA
"An engineered S1P chaperone attenuates hypertension and ischemic injury". Swendeman, Steven L, et al., Sci Signal. 2017 Aug 15;10(492):eaal2722.
"Apolipoprotein M:
bridging HDL and endothelial function". Christoffersen, Christina, and Lars Bo Nielsen. Current opinion in lipidology vol.
2013, 24,4: 295-300.
