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

• Main Authors: Kalailingam, Pazhanichamy, Mohd-Kahliab, Khalilatul-Hanisah, Ngan, SoFong Cam, Iyappan, Ranjith, Melekh, Evelin, Lu, Tian, Zien, Gan Wei, Sharma, Bhargy, Guo, Tiannan, MacNeil, Adam J., MacPherson, Rebecca Ek, Tsiani, Evangelia Litsa, O'Leary, Deborah D., Lim, Kah-Leong, Su, I Hsin, Gao, Yong-Gui, Richards, A. Mark, Kalaria, Raj N., Chen, Christopher P., McCarthy, Neil E., Sze, Siu Kwan
• Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
• Format: Article
• Language: English
• Published: 2024
• Subjects: Medicine, Health and Life Sciences; Immunotherapy; Inflammation
• Online Access: https://hdl.handle.net/10356/173773
• Institution: Nanyang Technological University

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.