Compositions, methods and kits for treating complement related disorders
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for complement-related disorders, such as age-related macular degeneration and rheumatoid arthritis, are limited by the availability of effective FDA-approved inhibitors and often require frequent injections with significant side effects, while existing recombinant proteins like STAC have non-functional CD59 portions and require membrane targeting for efficacy.
Innovation Solution
Development of a recombinant chimeric protein combining the complement regulatory properties of CD46, CD55, and CD59, engineered to be membrane-independent, with specific mutations in the GPI anchoring domains, and delivered via a gene therapy approach using AAV vectors to target both classical and alternative complement pathways.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If recombinant proteins like STAC are used to inhibit complement activation, then complement-related disorders can be treated, but the CD59 portion is non-functional and membrane targeting is required
Solution Approach 1:
The invention divides the complement regulation function into separate functional domains (CD46, CD55, CD59) and combines them in a segmented chimeric protein structure, where each domain contributes specific inhibitory activities against different complement pathways
Solution Approach 2:
The invention extracts and removes the GPI anchoring domain from the CD59 portion of the chimeric protein, making it membrane-independent and soluble, thereby eliminating the requirement for membrane targeting while preserving complement inhibition function
2Duration of action of moving object
If frequent injections of complement inhibitors are administered, then chronic complement-related disorders can be treated, but significant side effects occur
Solution Approach 1:
The invention changes the pharmacokinetic parameters of complement inhibition by using a chimeric protein with extended half-life characteristics, reducing the frequency of administration and cumulative side effects while maintaining therapeutic efficacy
3Reliability
If membrane-targeted complement inhibitors are used, then complement activation can be inhibited at the cell surface, but delivery efficiency is reduced
Solution Approach 1:
The invention inverts the traditional membrane-targeted approach by creating a soluble, membrane-independent chimeric protein that circulates in body fluids and inhibits complement activation in the extracellular space, thereby improving delivery efficiency to target tissues
Data Source
Figure 1A~1B
Figure 2A~2D
Figure 3A~3C
AI summary
Compositions, methods and kits are provided for treating complement related disorders in a subject with protein in combination having protein fusions of at least two of a CD46 protein, a CD55 protein and a CD59 protein or with a recombinant chimeric protein having at least two of a CD46 protein, a CD55 protein and a CD59 protein or with nucleic acids encoding these proteins. The composition negatively modulates classical and alternative complement pathways thereby treating complement related disorder such as macular degeneration, age-related macular degeneration, diabetic retinopathy, inflammatory bowel disease, thyroiditis, cryoglobulinaemia, fetal loss, organ graft rejection, cancer, etc.