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Immunotherapy targeting isoDGR-protein damage extends lifespan in a mouse model of protein deamidation

Lookup NU author(s): Professor Raj KalariaORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2023 The Authors. Published under the terms of the CC BY 4.0 license. Aging results from the accumulation of molecular damage that impairs normal biochemical processes. We previously reported that age-linked damage to amino acid sequence NGR (Asn-Gly-Arg) results in “gain-of-function” conformational switching to isoDGR (isoAsp-Gly-Arg). This integrin-binding motif activates leukocytes and promotes chronic inflammation, which are characteristic features of age-linked cardiovascular disorders. We now report that anti-isoDGR immunotherapy mitigates lifespan reduction of Pcmt1−/− mouse. We observed extensive accumulation of isoDGR and inflammatory cytokine expression in multiple tissues from Pcmt1−/− and naturally aged WT animals, which could also be induced via injection of isoDGR-modified plasma proteins or synthetic peptides into young WT animals. However, weekly injection of anti-isoDGR mAb (1 mg/kg) was sufficient to significantly reduce isoDGR-protein levels in body tissues, decreased pro-inflammatory cytokine concentrations in blood plasma, improved cognition/coordination metrics, and extended the average lifespan of Pcmt1−/− mice. Mechanistically, isoDGR-mAb mediated immune clearance of damaged isoDGR-proteins via antibody-dependent cellular phagocytosis (ADCP). These results indicate that immunotherapy targeting age-linked protein damage may represent an effective intervention strategy in a range of human degenerative disorders.


Publication metadata

Author(s): Kalailingam P, Mohd-Kahliab K-H, Ngan SC, Iyappan R, Melekh E, Lu T, Zien GW, Sharma B, Guo T, MacNeil AJ, MacPherson REK, Tsiani EL, O'Leary DD, Lim KL, Su IH, Gao Y-G, Richards AM, Kalaria RN, Chen CP, McCarthy NE, Sze SK

Publication type: Article

Publication status: Published

Journal: EMBO Molecular Medicine

Year: 2023

Volume: 15

Issue: 12

Print publication date: 07/12/2023

Online publication date: 16/11/2023

Acceptance date: 31/10/2023

Date deposited: 04/03/2024

ISSN (print): 1757-4676

ISSN (electronic): 1757-4684

Publisher: John Wiley and Sons Inc.

URL: https://doi.org/10.15252/emmm.202318526

DOI: 10.15252/emmm.202318526

PubMed id: 37971164


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Funding

Funder referenceFunder name
Canada Foundation for Innovation Grant
Canadian Institutes of Health Research Project Grant
CRC-2020-00263
Brock University
Canadian Institutes of Health Research Tier1 Canada Research Chair
e Natural Sciences and Engineering Research Council of Canada Discovery Grant
NMRC/OFIRG/0003/2016
PJT-186091
Ontario Research Fund
RGPIN-2023-04304
Singapore National Medical Research Council

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