complement C5

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Ligands
complement C5 (Human)

GtoPdb Ligand ID: 8712

Compound class: Endogenous peptide in human, mouse or rat

Comment: This is the full length, pre-pro-protein structure as represented in NCBI Reference Sequence: NP_001726. This peptide is cleaved into the complement C5 beta chain, complement C5 alpha chain and C5a anaphylatoxin (see the UniProt entry for the human protein P01031).

C5 inhibition is a clinically validated mechanism that is utilised for the control and suppression of complement-induced hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH). Eculizumab is a clinically approved anti-C5 monoclonal antibody for PNH. Investigational Phase 1/2 anti-C5 monoclonal RG6101 (SKY59 [4]; IMGT 783) was granted FDA orphan drug designation in September 2017 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). Ra Pharmaceuticals is developing a C5 binding synthetic 15-amino-acid macrocyclic peptide (designated research code RA101495; Phase 2) for PNH and other complement-mediated illnesses. RA101495 was granted FDA orphan drug designation for PNH in July 2017. RA101495 binds to a site on C5 distinct from the eculizumab binding site, with the aim of overcoming eculizumab resistance, such as that observed in patients with the Arg885His C5 variant [6] (note that RA101495 is also effective against this variant [4]). It is also designed for subcutaneous self-administration, which would be more convenient for patients, who must be given eculizumab by i.v. infusion by a healthcare professional.

SARS-CoV-2 and COVID-19: Clinically approved and investigation candidates that target C5 are being evaluated in a number of clinical trials to determine their potential to combat complement-mediated inflammatory tissue damage in the organs of pateints with severe COVID-19.

Species: Human

References
1. Beecher G, Putko BN, Wagner AN, Siddiqi ZA. (2019) Therapies Directed Against B-Cells and Downstream Effectors in Generalized Autoimmune Myasthenia Gravis: Current Status. Drugs, 79 (4): 353-364. [PMID:30762205]
2. Diefenbach-Streiber B, Eberth A, Guild BC, Kim Y-I, Roguska M, Splawski I. (2012) Compositions and methods for antibodies targeting complement protein C5. Patent number: US8241628 B2. Assignee: Novartis Ag.. Priority date: 05/07/2008. Publication date: 14/07/2012.
3. Evans MJ, Matis L, Mueller EE, Nye SH, Rollins S, Rother RP, Springhorn JP, Squinto SP, Thomas TC, Wang Y et al.. (1995) Methods and compositions for the treatment of glomerulonephritis and other inflammatory diseases. Patent number: WO1995029697A1. Assignee: Alexion Pharma Inc.. Priority date: 02/05/1994. Publication date: 09/11/1995.
4. Fukuzawa T, Sampei Z, Haraya K, Ruike Y, Shida-Kawazoe M, Shimizu Y, Gan SW, Irie M, Tsuboi Y, Tai H et al.. (2017) Long lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases. Sci Rep, 7 (1): 1080. [PMID:28439081]
5. Latuszek A, Liu Y, Olsen O, Foster R, Cao M, Lovric I, Yuan M, Liu N, Chen H, Zhang Q et al.. (2020) Inhibition of complement pathway activation with Pozelimab, a fully human antibody to complement component C5. PLoS One, 15 (5): e0231892. [PMID:32384086]
6. Nishimura J, Yamamoto M, Hayashi S, Ohyashiki K, Ando K, Brodsky AL, Noji H, Kitamura K, Eto T, Takahashi T et al.. (2014) Genetic variants in C5 and poor response to eculizumab. N Engl J Med, 370 (7): 632-9. [PMID:24521109]
7. Sampei Z, Haraya K, Tachibana T, Fukuzawa T, Shida-Kawazoe M, Gan SW, Shimizu Y, Ruike Y, Feng S, Kuramochi T et al.. (2018) Antibody engineering to generate SKY59, a long-acting anti-C5 recycling antibody. PLoS One, 13 (12): e0209509. [PMID:30592762]
8. Sheridan D, Yu ZX, Zhang Y, Patel R, Sun F, Lasaro MA, Bouchard K, Andrien B, Marozsan A, Wang Y et al.. (2018) Design and preclinical characterization of ALXN1210: A novel anti-C5 antibody with extended duration of action. PLoS ONE, 13 (4): e0195909. [PMID:29649283]

References

1. Beecher G, Putko BN, Wagner AN, Siddiqi ZA. (2019)
Therapies Directed Against B-Cells and Downstream Effectors in Generalized Autoimmune Myasthenia Gravis: Current Status.
Drugs, 79 (4): 353-364. [PMID:30762205]

2. Diefenbach-Streiber B, Eberth A, Guild BC, Kim Y-I, Roguska M, Splawski I. (2012)
Compositions and methods for antibodies targeting complement protein C5.
Patent number: US8241628 B2. Assignee: Novartis Ag.. Priority date: 05/07/2008. Publication date: 14/07/2012.

3. Evans MJ, Matis L, Mueller EE, Nye SH, Rollins S, Rother RP, Springhorn JP, Squinto SP, Thomas TC, Wang Y et al.. (1995)
Methods and compositions for the treatment of glomerulonephritis and other inflammatory diseases.
Patent number: WO1995029697A1. Assignee: Alexion Pharma Inc.. Priority date: 02/05/1994. Publication date: 09/11/1995.

4. Fukuzawa T, Sampei Z, Haraya K, Ruike Y, Shida-Kawazoe M, Shimizu Y, Gan SW, Irie M, Tsuboi Y, Tai H et al.. (2017)
Long lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases.
Sci Rep, 7 (1): 1080. [PMID:28439081]

5. Latuszek A, Liu Y, Olsen O, Foster R, Cao M, Lovric I, Yuan M, Liu N, Chen H, Zhang Q et al.. (2020)
Inhibition of complement pathway activation with Pozelimab, a fully human antibody to complement component C5.
PLoS One, 15 (5): e0231892. [PMID:32384086]

6. Nishimura J, Yamamoto M, Hayashi S, Ohyashiki K, Ando K, Brodsky AL, Noji H, Kitamura K, Eto T, Takahashi T et al.. (2014)
Genetic variants in C5 and poor response to eculizumab.
N Engl J Med, 370 (7): 632-9. [PMID:24521109]

7. Sampei Z, Haraya K, Tachibana T, Fukuzawa T, Shida-Kawazoe M, Gan SW, Shimizu Y, Ruike Y, Feng S, Kuramochi T et al.. (2018)
Antibody engineering to generate SKY59, a long-acting anti-C5 recycling antibody.
PLoS One, 13 (12): e0209509. [PMID:30592762]

8. Sheridan D, Yu ZX, Zhang Y, Patel R, Sun F, Lasaro MA, Bouchard K, Andrien B, Marozsan A, Wang Y et al.. (2018)
Design and preclinical characterization of ALXN1210: A novel anti-C5 antibody with extended duration of action.
PLoS ONE, 13 (4): e0195909. [PMID:29649283]