Development of a therapeutic monoclonal antibody against circulating adipocyte fatty acid binding protein to treat ischaemic stroke.

Autor: Liao B; Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.; State Key Laboratory of Pharmacological Biotechnology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China.; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China., Yang S; Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China., Geng L; State Key Laboratory of Pharmacological Biotechnology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China.; Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China., Zong J; Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.; State Key Laboratory of Pharmacological Biotechnology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China., Zhang Z; Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.; State Key Laboratory of Pharmacological Biotechnology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China., Jiang M; Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.; State Key Laboratory of Pharmacological Biotechnology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China., Jiang X; State Key Laboratory of Pharmacological Biotechnology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China.; Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China., Li S; Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China., Xu A; Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.; State Key Laboratory of Pharmacological Biotechnology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China.; Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China., Chang J; Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China., Hoo RLC; Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.; State Key Laboratory of Pharmacological Biotechnology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 Apr; Vol. 181 (8), pp. 1238-1255. Date of Electronic Publication: 2023 Dec 26.
DOI: 10.1111/bph.16282
Abstrakt: Background and Purpose: Adipocyte fatty acid-binding protein (A-FABP) exacerbates cerebral ischaemia injury by disrupting the blood-brain barrier (BBB) through inducing expression of MMP-9. Circulating A-FABP levels positively correlate with infarct size in stroke patients. We hypothesized that targeting circulating A-FABP by a neutralizing antibody would alleviate ischaemic stroke outcome.
Experimental Approach: Monoclonal antibodies (mAbs) against A-FABP were generated using mouse hybridoma techniques. Binding affinities of a generated mAb named 6H2 towards various FABPs were determined using Biacore. Molecular docking studies were performed to characterize the 6H2-A-FABP complex structure and epitope. The therapeutic potential and safety of 6H2 were evaluated in mice with transient middle cerebral artery occlusion (MCAO) and healthy mice, respectively.
Key Results: Replenishment of recombinant A-FABP exaggerated the stroke outcome in A-FABP-deficient mice. 6H2 exhibited nanomolar to picomolar affinities to human and mouse A-FABP, respectively, with minimal cross-reactivities with heart and epidermal FABPs. 6H2 effectively neutralized JNK/c-Jun activation elicited by A-FABP and reduced MMP-9 production in macrophages. Molecular docking suggested that 6H2 interacts with the "lid" of the fatty acid binding pocket of A-FABP, thus likely hindering the binding of its substrates. In mice with transient MCAO, 6H2 significantly attenuated BBB disruption, cerebral oedema, infarction, neurological deficits, and decreased mortality associated with reduced cytokine and MMP-9 production. Chronic 6H2 treatment showed no obvious adverse effects in healthy mice.
Conclusion and Implications: These results establish circulating A-FABP as a viable therapeutic target for ischaemic stroke, and provide a highly promising antibody drug candidate with high affinity and specificity.
(© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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