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

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.