SCR-Ab Constructs for Complement-Mediated Pathogen Lysis
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Solution Overview
Problem
Current treatments for infections and cancer are limited by the intrinsic resistance of pathogens and cancer cells to complement-mediated lysis, due to host-derived proteins and regulators that protect them from complement activation.
Innovation Solution
Development of a short consensus repeat-antibody construct (SCR-Ab) comprising a complement factor H-derived short consensus repeat (fH-derived SCR) and a pathogen- or cancer cell-specific binding molecule, where the fH-derived SCR is capable of binding heparin, to enhance complement activation and lysis of pathogens and cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If host-derived complement regulators (such as factor H) bind to pathogens, then protection against complement-mediated lysis is improved, but resistance to complement activation worsens
Solution Approach 1:
The invention extracts the heparin-binding SCR domains from complement factor H and combines them with pathogen-specific antibodies. This separation allows the regulatory function to be selectively applied only where needed (at the pathogen surface via antibody binding) rather than providing broad protection that would prevent complement activation against all targets.
Solution Approach 2:
The heparin-binding SCR domains act as an intermediary that bridges the antibody and the complement system. By binding to heparan sulfate on the pathogen surface through the SCR domains while being targeted by the antibody, they facilitate controlled complement activation rather than direct antibody-complement interaction, thereby overcoming pathogen resistance mechanisms.
2Reliability
If complement regulators are present on pathogen surface, then protection from complement damage is improved, but complement-mediated lysis efficiency worsens
Solution Approach 1:
The invention applies complement regulation locally only at the pathogen surface through targeted antibody-SCR construct binding, rather than systemically. This localized approach allows complement to be activated efficiently at the infection site while preventing uncontrolled complement activation elsewhere in the body that would cause damage to host tissues.
Solution Approach 2:
The invention changes the parameters of complement regulation by using engineered SCR domains with specific heparin-binding properties rather than native factor H. This modification allows for optimized binding characteristics that enhance complement-mediated lysis efficiency while maintaining protective functions, thereby resolving the contradiction between protection and lysis efficiency.
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 SCR-Ab constructs effectively lyse pathogens and cancer cells by displacing host-derived complement regulators, leading to enhanced complement-mediated lysis and improved treatment outcomes for infections and cancer.
Implementation Method 1
wherein said fH-derived SCR comprises a polypeptide that is capable of binding heparin
Data Source
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AI summary
The present invention relates to a complement activating construct comprising a complement factor H-derived short consensus repeat (fH-derived SCR) and a binding molecule which specifically recognizes a pathogen. More specifically, the fH-derived SCR is selected from the group consisting of SCR7, SCR9, SCR13, SCR18-20 and artificial SCR (aSCR). Furthermore, an in vivo method for screening complement-based approaches for the treatment of the prevention, treatment or amelioration of an infection with a pathogen or a pathological condition associated with an infection with a pathogen is described.