A nanobody-based complement inhibitor targeting complement component 2 reduces hemolysis in a complement humanized...

Area of Science:

• Immunology
• Complement System Biology

Background:

• The complement system, particularly complement component 2 (C2), is implicated in various complement-mediated diseases.
• Targeting C2 offers a potential therapeutic strategy for these conditions.

Purpose of the Study:

• To develop and characterize a novel anti-C2 nanobody, Nab1B10, for inhibiting complement activation.
• To evaluate the therapeutic efficacy of Nab1B10 and its derivatives in preclinical models.

Main Methods:

• Development of Nab1B10, a nanobody targeting the C2a portion of C2.
• In vitro assays assessing inhibition of classical and lectin complement pathways.
• In vivo studies using a humanized mouse model of autoimmune hemolytic anemia (AIHA).
• Creation and evaluation of multivalent anti-C2 antibodies derived from Nab1B10.

Main Results:

• Nab1B10 potently and selectively inhibits both classical and lectin complement pathways by preventing C3 convertase assembly.
• Nab1B10 demonstrated efficacy in a humanized mouse model of AIHA, abolishing complement-mediated hemolysis in vivo.
• Multivalent antibodies based on Nab1B10 showed superior potency compared to existing anti-C2 monoclonal antibodies in clinical trials.

Conclusions:

• Nab1B10 is a promising therapeutic candidate for complement-mediated diseases driven by the classical and/or lectin pathways.
• Novel C2-neutralizing nanobodies and their multivalent derivatives represent a significant advancement in complement therapeutics.