Complement C2 Binding Proteins With pH-Dependent C2 Clearance
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Solution Overview
Problem
Over-activation of the complement system leads to pathology in conditions such as antibody-mediated transplant rejection, fibrosis, and chronic autoimmune diseases, necessitating agents that can inhibit C2 to regulate the classical and lectin complement pathways without affecting the alternative pathway.
Innovation Solution
Development of proteins with antigen binding sites that bind to human complement C2 with higher affinity at neutral pH, allowing internalization and degradation of C2 within endosomes, thereby reducing its circulation and recycling the protein back to the cell surface, thus inhibiting C2 activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If proteins bind to C2 with high affinity at neutral pH to reduce C2 levels in circulation, then C2 inhibition is improved, but the protein may not release C2 for degradation in endosomes
Solution Approach 1:
The antibody is engineered to exhibit pH-dependent binding characteristics, with high affinity for C2 at neutral pH (7.3) in circulation and reduced affinity at acidic pH (6.0) in endosomes. This parameter change enables the antibody to bind C2 effectively in circulation while releasing it for degradation in endosomes, resolving the contradiction between maintaining strong binding for inhibition and enabling release for protein recycling
Solution Approach 2:
The binding affinity of the antibody to C2 is made dynamic rather than static, allowing it to adapt to different pH environments. The antibody dynamically adjusts its binding strength based on the local pH condition, being strong at neutral pH for effective C2 capture and weak at acidic pH for efficient C2 release, thus satisfying both requirements simultaneously
2Quantity of substance
If proteins bind to C2 strongly in circulation to reduce C2 concentration, then C2 level reduction is improved, but protein recycling efficiency may deteriorate
Solution Approach 1:
The pH-dependent binding characteristic serves as a parameter change mechanism that enables the antibody to strongly bind C2 in neutral pH circulation while releasing it in acidic pH endosomes. This ensures effective C2 removal from circulation while allowing the antibody to be recycled through the FcRn pathway, maintaining both C2 level reduction and protein half-life
Solution Approach 2:
The pH-dependent binding mechanism enables the antibody-C2 complex to self-dissociate in the acidic endosomal environment without requiring external intervention. The antibody automatically releases C2 for degradation and prepares for its own recycling via FcRn, making the system self-regulating and efficient
3Reliability
If conventional antibodies are used to bind C2, then C2 binding is achieved, but selective inhibition of classical and lectin pathways without impacting alternative pathway is not achieved
Solution Approach 1:
The antibody is designed to bind to a specific epitope on C2 (residues 266-284 in the first CCP domain) that is critical for the classical and lectin pathways but not involved in alternative pathway activation. This localized binding approach achieves selective inhibition of specific complement pathways while preserving the alternative pathway, resolving the contradiction between effective inhibition and pathway selectivity
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The proteins effectively reduce C2 concentration in circulation and inhibit complement pathways by binding preferentially at neutral pH, facilitating degradation and recycling, providing a therapeutic approach to complement-mediated disorders.
Implementation Method 1
These proteins bind to C2 with a higher affinity at neutral pH (i.e., approximately 7.3) relative to early endosomal pH (i.e., approximately 6.0)
Implementation Method 2
such proteins can bind to C2 at neutral pH, but then have an increased propensity to dissociate from C2 once internalized into the acidic early endosome (approximately pH 6.0)
Implementation Method 3
trafficking of C2 to the lysosome for degradation, and recycling of the protein back to the cell surface via the neonatal Fc receptor (FcRn)
Data Source
AI summary
The present disclosure relates to proteins comprising antigen binding sites that bind to human complement C2 (C2). The present disclosure also relates to methods of inhibiting complement activity in a subject as well as methods of treating or preventing complement-mediated disorders.