Related Experiment Video
Updated: Jan 12, 2026
Targeted Antibody Blocking by a Dual-Functional Conjugate of Antigenic Peptide and Fc-III Mimetics DCAF
Published on: September 17, 2019
Long lasting complement neutralisation by RAY121, an engineered anti-C1s antibody with C1q displacement function
Adrian W S Ho1, Taku Fukuzawa2, Hikaru Koga2
1Chugai Pharmabody Research, Singapore, 138623, Singapore.
Insights
RAY121, a novel antibody drug, offers extended complement pathway neutralization via subcutaneous injection, improving patient compliance for autoimmune disorder treatments.
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.
Background:
Antibody drugs blocking the complement classical pathway (CP) often require frequent intravenous administration to overcome the high abundance or rapid turnover of complement proteins. This makes treatment compliance burdensome for patients.
Methods:
Screening was performed to identify anti-C1s antibodies specific for the CUB domain of C1s with CP neutralising function. Antibody engineering was performed on the anti-C1s antibody to prolong its half-life in circulation. The variable region was mutated to confer pH-dependent binding to C1s, and the antibody Fc was modified to lower its isoelectric point and to have enhanced binding to the neonatal Fc receptor.
Findings:
A combination of pH-dependent binding to C1s and optimisation of charge characteristics was required for the final engineered antibody, RAY121, to achieve a long half-life in circulation and long-lasting neutralisation of the CP. In male cynomolgus monkeys, a single subcutaneous injection suppressed CP activity for more than a month. RAY121 neutralises the CP by using a unique mechanism of displacing C1q from the C1 complex and blocking its reassembly. Structure analysis by cryo-electron microscopy revealed that the RAY121 epitope on C1s is distinct from the C1q binding site, and that C1q displacement is mediated by the Fab arm sterically obstructing C1q binding to C1s.
Interpretation:
RAY121 is able to neutralise the CP for an extended duration and is effective at doses that can be administered subcutaneously for convenient treatment. These data present RAY121 as a promising agent for the treatment of CP-driven autoimmune disorders.
Funding:
Chugai Pharmaceutical Co. Ltd.
Related Concept Videos
01:27Complement System
01:26Antibody Actions
Neutralization
Antibodies can bind to pathogens, preventing them from infecting host cells. This process...