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Frontiers in Immunology
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Novel bispecific antibodies (bsAbs) enable site-directed complement inhibition by recruiting endogenous regulators. This approach protects cells from complement-mediated damage, offering a targeted therapy for complement-driven diseases.

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Area of Science:

  • Immunology
  • Biotechnology

Background:

  • Complement activation is crucial for immunity but also drives autoimmune diseases and transplant rejection.
  • Current complement inhibitors carry infection risks due to systemic action.
  • Targeted complement inhibition is needed to mitigate pathological effects while preserving immune function.

Purpose of the Study:

  • To develop and assess bispecific antibodies (bsAbs) for site-directed complement inhibition.
  • To investigate the ability of bsAbs to recruit endogenous complement regulators (factor H and C4b-binding protein) to target cells.
  • To evaluate the efficacy of bsAbs in preventing complement-mediated cell lysis.

Main Methods:

  • Designed and analyzed obligate bispecific antibodies (bsAbs) to crosslink target antigens with complement regulators factor H (FH) or C4b-binding protein (C4BP).
  • Assessed bsAbs for their capacity to inhibit complement activation across classical, lectin, and alternative pathways.
  • Tested bsAbs in vitro using antigen-positive liposomes, erythrocytes, and human leukocytes to evaluate protection against complement-mediated lysis.

Main Results:

  • bsAbs successfully recruited endogenous serum FH and C4BP to achieve localized complement inhibition.
  • Inhibition of classical, lectin, and alternative complement pathways was observed.
  • bsAbs effectively protected target cells, including liposomes, erythrocytes, and leukocytes, from complement-mediated lysis.

Conclusions:

  • Bispecific antibodies can achieve localized complement inhibition by recruiting endogenous regulators to cell surfaces.
  • This targeted approach offers a potential therapeutic strategy for complement-mediated diseases.
  • Localized complement inhibition may reduce the risks associated with systemic complement inhibitors.