Long lasting complement neutralisation by RAY121, an engineered anti-C1s antibody with C1q displacement function.

Area of Science:

• Immunology
• Pharmacology
• Biochemistry

Background:

• Antibody drugs targeting the complement classical pathway (CP) often require frequent intravenous infusions.
• High complement protein levels and rapid turnover necessitate burdensome treatment regimens.
• This limits patient compliance and therapeutic efficacy.

Purpose of the Study:

• To identify and engineer an antibody with prolonged CP neutralization.
• To develop a subcutaneously administered antibody for improved patient convenience.
• To investigate the mechanism of action for long-lasting CP inhibition.

Main Methods:

• Screening for anti-C1s antibodies with CP neutralizing function, focusing on the CUB domain.
• Engineering antibodies for pH-dependent C1s binding and enhanced neonatal Fc receptor (FcRn) interaction.
• Utilizing cryo-electron microscopy to elucidate the antibody-antigen interaction and mechanism.

Main Results:

• Engineered antibody RAY121 achieved prolonged circulation half-life and sustained CP neutralization.
• A single subcutaneous injection in cynomolgus monkeys suppressed CP activity for over a month.
• RAY121 displaces C1q from the C1 complex via a unique steric hindrance mechanism.

Conclusions:

• RAY121 demonstrates extended CP neutralization with convenient subcutaneous administration.
• The engineered antibody shows promise for treating complement-driven autoimmune disorders.
• RAY121 offers a potential improvement in treatment compliance and efficacy.