The human complement receptor type 2 (CR2)/CR1 fusion protein TT32, a novel targeted inhibitor of the classical and alternative pathway C3 convertases, prevents arthritis in active immunization and passive transfer mouse models
| Autor: | Yi Wang, Masha Fridkis-Hareli, Ante S. Lundberg, Nirmal K. Banda, Jeff Hunter, Michael Storek, Fang Sun, Gaurav Mehta, Richard Altman, Eran Or, Suresh Katti, Krista Johnson, Tao Peng, V. Michael Holers |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Recombinant Fusion Proteins Immunology Arthritis chemical and pharmacologic phenomena Complement receptor Article C5-convertase Mice 03 medical and health sciences Complement inhibitor 0302 clinical medicine medicine Animals Humans Molecular Biology Complement C3 Convertase Alternative Pathway Sheep Chemistry Immunization Passive medicine.disease Arthritis Experimental Fusion protein Molecular biology Receptors Complement Complement system 030104 developmental biology Alternative complement pathway iC3b Receptors Complement 3d Rabbits 030215 immunology |
| Zdroj: | Molecular Immunology. 105:150-164 |
| ISSN: | 0161-5890 |
| DOI: | 10.1016/j.molimm.2018.09.013 |
| Popis: | Complement activation in human diseases is characterized by the local covalent deposition of the long-lived C3 fragments iC3b/C3dg/C3d. Previously, TT30, a complement alternative pathway (AP)-selective inhibitor, was designed as a fusion protein linking the first four short consensus repeats (SCRs) of human complement receptor type 2 (CR2) with the first five SCRs of human factor H (fH). TT30 acts by utilizing CR2 SCR1–4 to bind the initially formed iC3b/C3dg/C3d fragments and delivering surface-targeted inhibition of AP C3 and C5 convertases through fH SCR 1-5. In order to combine classical (CP) and lectin (LP) pathway inhibitory abilities employing CR2-mediated targeting, TT32 was developed. TT32 is a CR2-CR1 fusion protein using the first ten SCRs of CR1, chosen because they contain both C3 and C5 convertase inhibitory activity through utilization of decay-acceleration and cofactor activity for both AP and CP. In Wieslab assays, TT32 showed potent inhibition of the CP and AP with IC50 of 11 and 46 nM, respectively. The TT32 inhibitory activity is partially blocked with a molar excess of a competing anti-CR2 mAb, thus demonstrating the importance of the CR2 targeting. TT32 was studied in the type II (CII) collagen-induced arthritis (CIA), an active immunization model, and the CII antibody-induced arthritis (CAIA) passive transfer model. In CIA, injection of 2.0 mg TT32 at day 21 and 28 post disease induction, but not untargeted CR1 alone, resulted in a 51.5% decrease in clinical disease activity (CDA). In CAIA, treatment with TT32 resulted in a 47.4% decrease in CDA. Therefore, a complement inhibitor that targets both the AP and CP/LP C3/C5 convertases was shown to limit complement-mediated tissue damage and inflammation in disease models in which all three complement activation pathways are implicated. |
| Databáze: | OpenAIRE |
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