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Recruitment of properdin by bi-specific nanobodies activates the alternative pathway of complement
- Source :
- Pedersen, D V, Rösner, T, Hansen, A G, Andersen, K R, Thiel, S, Andersen, G R, Valerius, T & Laursen, N S 2020, ' Recruitment of properdin by bi-specific nanobodies activates the alternative pathway of complement ', Molecular Immunology, vol. 124, pp. 200-210 . https://doi.org/10.1016/j.molimm.2020.06.005
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- The complement system represents a powerful part of the innate immune system capable of removing pathogens and damaged host cells. Nevertheless, only a subset of therapeutic antibodies are capable of inducing complement dependent cytotoxicity, which has fuelled the search for new strategies to potentiate complement activation. Properdin (FP) functions as a positive complement regulator by stabilizing the alternative pathway C3 convertase. Here, we explore a novel strategy for direct activation of the alternative pathway of complement using bi-specific single domain antibodies (nanobodies) that recruit endogenous FP to a cell surface. As a proof-of-principle, we generated bi-specific nanobodies with specificity toward FP and the validated cancer antigen epidermal growth factor receptor (EGFR) and tested their ability to activate complement onto cancer cell lines expressing EGFR. Treatment led to recruitment of FP, complement activation and significant deposition of C3 fragments on the cells in a manner sensitive to the geometry of FP recruitment. The bi-specific nanobodies induced complement dependent lysis of baby hamster kidney cells expressing human EGFR but were unable to lyse human tumour cells due to the presence of complement regulators. Our results confirm that FP can function as a surface bound focal point for initiation of complement activation independent of prior C3b deposition. However, recruitment of FP by bi-specific nanobodies appears insufficient for overcoming the inhibitory action of the negative complement regulators overexpressed by many human tumour cell lines. Our data provide general information on the efficacy of properdin as an initiator of complement but suggest that properdin recruitment on its own may have limited utility as a platform for potent complement activation on regulated cell surfaces.
- Subjects :
- 0301 basic medicine
Complement Pathway, Alternative
Immunology
03 medical and health sciences
0302 clinical medicine
Cell Line, Tumor
Cricetinae
Antibodies, Bispecific
Animals
Humans
Complement Activation
Molecular Biology
Innate immune system
Properdin
biology
Chemistry
Single-Domain Antibodies
Complement-dependent cytotoxicity
C3-convertase
Complement system
Complement (complexity)
Cell biology
ErbB Receptors
030104 developmental biology
Alternative complement pathway
biology.protein
Antibody
030215 immunology
Subjects
Details
- ISSN :
- 01615890
- Volume :
- 124
- Database :
- OpenAIRE
- Journal :
- Molecular Immunology
- Accession number :
- edsair.doi.dedup.....16b42e5974830539074fb91ad8ab0e68