Complement Therapeutic Target-C1 Complex

With excellent knowledge and expertise in complement therapeutics, Creative Biolabs is dedicated to offering a full range of biotherapeutics development services. Based on our well-established antibody engineering platform, protease inhibitor platform, and drug discovery platform, we are fully equipped to reach out our hands to our clients who are doing or may have the desire to work on complement systems for drug discovery and validation.

To date, there primarily exist three pathways in the complement system, which are classical pathway, lectin pathway, and alternative pathway. As the first component in the classical pathway of the complement system, C1 is found to be a calcium-dependent complex with a molecular weight around 800kDa. This complex consists of three modules:

A canonical model entails the tetrameric complex C1s-C1r-C1r-C1s with its serine protease domain tightly packed together in the center. C1q acts as the first subcomponent of the C1 complex and several of its functions have been elucidated including antibody-dependent function and immune-independent function. C1r is an enzyme that cleaves C1s to form the active form of C1s.

Fig. 1 Structure of C1 complex. (Arlaud et al.,2002)

Fig. 1 Structure of C1 complex.¹

C1 Complex Related Disease

Example 1: C1r and SLE

Demirkaya E recently announced their findings on C1r and its related disease systemic lupus erythematosus (SLE) which is a type of autoimmune disease. In the report, Demirkaya’s team identified a novel, homozygous, loss-of-function mutation (p.Pro445Leufs*11) in the C1r gene. The sequencing result confirmed that 4 patients with SLE in their family have the mutagenesis in the C1r gene. Moreover, their complement levels were very low in the sera with truncated C1r proteins.

Example 2: C1q and SLE

For patients with hereditary C1q deficiency, C1q level is very low and is closely associated with the reduced level of other components in the classical pathway. There exists another cause for the reduced levels of C1q in SLE patients, anti-C1q autoantibody. These antibodies bind to a neoepitope in the collagenous region of C1q which is only exposed when C1q is not part of the C1 complex. The presence of the anti-C1q autoantibody is accompanied with intense activation of the classical pathway but with low levels of downstream components. Several studies have confirmed the bond between C1q and its autoantibody.

Creative Biolabs offers a great number of complement therapeutics services based on the C1 complex for several related diseases, include:

With professional knowledge and rich research experiences in drug discovery and complement therapeutic field, Creative Biolabs' outstanding research groups are confident in providing high-quality biotherapeutics development services based on the complement C1 complex of the complement system. We offer turn-key or ala carte services customized to our client’s needs. If you are interested in our platform or you are calling for our services, please contact us.

Reference
1. Arlaud, Gérard J., et al. "Structural biology of the C1 complex of complement unveils the mechanisms of its activation and proteolytic activity." Molecular immunology 39.7-8 (2002): 383-394.

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Questions & Answer

A: Therapeutic strategies targeting the C1 complex include the development of monoclonal antibodies that block C1q binding or inhibit the activity of C1r and C1s proteases. Small molecules and biologics are also being explored to modulate the C1 complex's function and downstream complement activation.

A: Developing C1 complex-targeted therapies requires addressing challenges such as achieving specificity for pathological complement activation while preserving necessary immune functions, ensuring the safety of long-term modulation, and establishing optimal dosing regimens. Additionally, understanding potential off-target effects and predicting patient responses are crucial aspects of successful therapeutic development.

A: Advances in biotechnology, such as gene editing techniques like CRISPR-Cas9, are being investigated for their potential to modify complement-related genes, including those encoding components of the C1 complex. These technologies hold promise for precise modulation of complement activity and could open up new avenues for therapeutic intervention.

For Research Use Only.