C1q Peptides Redirect Autoantibodies to Mitigate Lupus Pathology
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Solution Overview
Problem
Current therapies for autoimmune conditions like systemic lupus erythematosus (SLE) are inadequate in addressing the activation of autoreactive B cells and the resulting autoantibodies, particularly those targeting nuclear antigens, which contribute to renal involvement and inflammation.
Innovation Solution
Development of isolated peptides and fusion proteins comprising specific amino acid sequences, such as EAX1X2X3 and X4WX5YX6, that mimic or inhibit the binding of autoantibodies to C1q and dsDNA, thereby reducing autoantibody levels and modulating immune responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies are used for autoimmune conditions, then treatment is provided, but they are inadequate in addressing activation of autoreactive B cells and resulting autoantibodies
Solution Approach 1:
The patent uses C1q peptides as intermediary molecules that bind to autoantibodies, preventing them from binding to self-antigens. The C1q peptide acts as a mediator between the autoantibody and the immune system, redirecting the autoantibody's binding specificity away from self-tissues toward the C1q peptide itself, thereby reducing autoimmune pathology while maintaining the autoantibody's structural integrity
Solution Approach 2:
The invention creates simplified peptide copies of the C1q collagen-like domain that replicate the key binding function of the full C1q protein. These peptide copies (e.g., EADSV, EAGRP sequences) mimic the C1q structure sufficient to bind autoantibodies and activate protective immune responses without the complexity of the full 460 kDa C1q protein
2Reliability
If C1q is used to clear immune complexes and apoptotic cells, then immune tolerance is maintained, but C1q deficiency leads to enhanced IFNα production and lupus development
Solution Approach 1:
The patent extracts the critical functional domain from the full C1q protein - specifically the collagen-like N-terminal domain containing the EADSV or EAGRP sequences. This extracted peptide fragment retains the ability to bind autoantibodies and modulate immune responses without requiring the complete C1q structure, providing a targeted therapeutic intervention
Solution Approach 2:
The invention changes the molecular size and complexity parameter from the full 460 kDa C1q protein to small peptides of 5-20 amino acids. This parameter change maintains the essential binding function while improving pharmacokinetic properties, reducing immunogenicity, and enabling better tissue penetration and clearance
3Object-affected harmful factors
If autoantibodies bind to nuclear antigens and C1q, then immune complexes form causing renal involvement, but blocking this binding can reduce inflammation and renal pathology
Solution Approach 1:
The patent converts the harmful autoantibody-self antigen interaction into a beneficial autoantibody-C1q peptide interaction. By providing C1q peptides as therapeutic agents, the autoantibodies are redirected to bind harmless C1q peptides instead of self-tissues, effectively converting the pathogenic mechanism into a protective one where the autoantibodies are sequestered in a non-damaging complex
Data Source
AI summary
Isolated C1q peptides, fusion proteins and compositions comprising such and fusion proteins comprising are provided. Isolated fusion proteins comprising X4WX5YX6 as defined herein and compositions comprising such are also provided. Methods of treating autoimmune disorders are provided.