Active C1s-Selective Antibodies for Lower-Dose Complement Inhibition
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Solution Overview
Problem
Current treatments for complement classical pathway-mediated diseases, such as hemolysis and transplant rejection, are limited by the lack of specificity and high dosing requirements of existing C1s inhibitors like sutimlimab, which are not specific to the active form of C1s and require high doses.
Innovation Solution
Development of antibodies or antigen-binding fragments that selectively target the active form of C1s (C1s) with low binding to its inactive zymogen (proC1s), thereby inhibiting the classical complement pathway and providing therapeutic options for disorders like hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia, Myastenia Gravis, Glomerulopaties, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, or transplant rejection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If sutimlimab is used to inhibit C1s, then the classical complement pathway is inhibited, but the treatment requires very high doses due to lack of specificity for active C1s
Solution Approach 1:
The antibody is designed to bind specifically to the active form of C1s (not proC1s) through engineered complementarity determining regions (CDRs), creating a localized specific binding property that distinguishes active from inactive forms. This specificity allows the antibody to target only the therapeutically relevant form, reducing the dose required compared to non-specific inhibitors like sutimlimab.
2Reliability
If non-specific C1s inhibitors are used, then complement pathway inhibition is achieved, but specificity for active C1s is lost
Solution Approach 1:
The antibody incorporates specifically engineered CDR sequences (HCDR1: SEQ ID NO: 9, HCDR2: SEQ ID NO: 10, HCDR3: SEQ ID NO: 11; LCDR1: SEQ ID NO: 12, LCDR2: SEQ ID NO: 13, LCDR3: SEQ ID NO: 14) that create a binding interface with high specificity for the active C1s conformation, enabling discrimination between active and inactive forms through localized structural properties.
Solution Approach 2:
The antibody's binding characteristics are optimized by modifying the CDR regions to achieve high affinity (KD ≤ 10^-7 M) and high specificity for active C1s. This parameter optimization ensures the antibody binds preferentially to the active form over proC1s, achieving both effective inhibition and molecular-level specificity.
Data Source
AI summary
Embodiments that are provided for herein relate to antibodies and compositions that bind to C1s. Also provided are methods of producing the antibodies of the present disclosure, as well as uses of the provided antibodies and compositions for the treatment of C1s mediated diseases and disorders.