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Targeted complement inhibition using bispecific antibodies that bind local antigens and endogenous complement regulators

Wang, Haiyu ; van de Bovenkamp, Fleur S. ; Dijkstra, Douwe J. ; Abendstein, Leoni ; Borggreven, Nicole V. ; Pool, Jos ; Zuijderduijn, Rob ; Gstöttner, Christoph ; Gelderman, Kyra A. and Damelang, Timon , et al. (2024) In Frontiers in Immunology 15.
Abstract

Complement activation protects against infection but also contributes to pathological mechanisms in a range of clinical conditions such as autoimmune diseases and transplant rejection. Complement-inhibitory drugs, either approved or in development, usually act systemically, thereby increasing the risk for infections. We therefore envisioned a novel class of bispecific antibodies (bsAbs) which are capable of site-directed complement inhibition by bringing endogenous complement regulators in the vicinity of defined cell surface antigens. Here, we analyzed a comprehensive set of obligate bsAbs designed to crosslink a specific target with either complement regulator factor H (FH) or C4b-binding protein (C4BP). The bsAbs were assessed for... (More)

Complement activation protects against infection but also contributes to pathological mechanisms in a range of clinical conditions such as autoimmune diseases and transplant rejection. Complement-inhibitory drugs, either approved or in development, usually act systemically, thereby increasing the risk for infections. We therefore envisioned a novel class of bispecific antibodies (bsAbs) which are capable of site-directed complement inhibition by bringing endogenous complement regulators in the vicinity of defined cell surface antigens. Here, we analyzed a comprehensive set of obligate bsAbs designed to crosslink a specific target with either complement regulator factor H (FH) or C4b-binding protein (C4BP). The bsAbs were assessed for their capacity to inhibit complement activation and cell lysis in an antigen-targeted manner. We observed that the bsAbs inhibited classical, lectin, and alternative pathway complement activation in which sufficient endogenous serum FH and C4BP could be recruited to achieve local inhibition. Importantly, the bsAbs effectively protected antigen-positive liposomes, erythrocytes, and human leukocytes from complement-mediated lysis. In conclusion, localized complement inhibition by bsAbs capable of recruiting endogenous human complement regulators (such as FH or C4BP) to cell surfaces potentially provides a novel therapeutic approach for the targeted treatment of complement-mediated diseases.

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type
Contribution to journal
publication status
published
subject
keywords
antibobies, autoimmunity, complement, inhibition, targeted
in
Frontiers in Immunology
volume
15
article number
1288597
publisher
Frontiers Media S. A.
external identifiers
  • pmid:38817607
  • scopus:85194842969
ISSN
1664-3224
DOI
10.3389/fimmu.2024.1288597
language
English
LU publication?
yes
id
95d1e222-bc11-4414-b649-64f9bbbd6b99
date added to LUP
2024-10-14 14:51:59
date last changed
2025-06-24 11:13:25
@article{95d1e222-bc11-4414-b649-64f9bbbd6b99,
  abstract     = {{<p>Complement activation protects against infection but also contributes to pathological mechanisms in a range of clinical conditions such as autoimmune diseases and transplant rejection. Complement-inhibitory drugs, either approved or in development, usually act systemically, thereby increasing the risk for infections. We therefore envisioned a novel class of bispecific antibodies (bsAbs) which are capable of site-directed complement inhibition by bringing endogenous complement regulators in the vicinity of defined cell surface antigens. Here, we analyzed a comprehensive set of obligate bsAbs designed to crosslink a specific target with either complement regulator factor H (FH) or C4b-binding protein (C4BP). The bsAbs were assessed for their capacity to inhibit complement activation and cell lysis in an antigen-targeted manner. We observed that the bsAbs inhibited classical, lectin, and alternative pathway complement activation in which sufficient endogenous serum FH and C4BP could be recruited to achieve local inhibition. Importantly, the bsAbs effectively protected antigen-positive liposomes, erythrocytes, and human leukocytes from complement-mediated lysis. In conclusion, localized complement inhibition by bsAbs capable of recruiting endogenous human complement regulators (such as FH or C4BP) to cell surfaces potentially provides a novel therapeutic approach for the targeted treatment of complement-mediated diseases.</p>}},
  author       = {{Wang, Haiyu and van de Bovenkamp, Fleur S. and Dijkstra, Douwe J. and Abendstein, Leoni and Borggreven, Nicole V. and Pool, Jos and Zuijderduijn, Rob and Gstöttner, Christoph and Gelderman, Kyra A. and Damelang, Timon and Vidarsson, Gestur and Blom, Anna M. and Domínguez-Vega, Elena and Parren, Paul W.H.I. and Sharp, Thomas H. and Trouw, Leendert A.}},
  issn         = {{1664-3224}},
  keywords     = {{antibobies; autoimmunity; complement; inhibition; targeted}},
  language     = {{eng}},
  publisher    = {{Frontiers Media S. A.}},
  series       = {{Frontiers in Immunology}},
  title        = {{Targeted complement inhibition using bispecific antibodies that bind local antigens and endogenous complement regulators}},
  url          = {{http://dx.doi.org/10.3389/fimmu.2024.1288597}},
  doi          = {{10.3389/fimmu.2024.1288597}},
  volume       = {{15}},
  year         = {{2024}},
}