Ig-Aim Fusion Proteins for Selective Pathogenic B-Cell Erasure
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Solution Overview
Problem
Current therapeutic approaches for autoimmune diseases and B-cell related disorders target the entire B-cell population non-specifically, leading to the elimination of both pathogenic and non-pathogenic cells, resulting in immune deficiencies and inefficiencies, and there is a need for a method to selectively target and eliminate only pathogenic B cells.
Innovation Solution
Development of fusion proteins or conjugates, named cell surface Ig-Aimed immune memory erasers (Ig-Aim), which replace the receptor-binding domain of diphtheria toxin with surface immunoglobulin (slg) targeting peptides, such as SpA, SpG, or affibodies, to specifically target and eliminate slg+ B cells, including those expressing IgG, IgA, or IgE, without harming non-target B cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional therapies target the entire B-cell population, then pathogenic B cells are eliminated, but non-pathogenic B cells are also destroyed causing immune deficiency
Solution Approach 1:
The invention segments the B-cell population into pathogenic (slg+) and non-pathogenic (slg-) subsets, using surface immunoglobulin expression as the dividing criterion. The fusion protein specifically targets slg+ B cells for elimination while leaving slg- B cells intact, thereby achieving therapeutic efficacy without causing broad immune deficiency.
Solution Approach 2:
The fusion protein exhibits local quality by having different functional properties for different B-cell subsets. It specifically binds to and kills slg+ B cells through the slg-targeting domain, while having no effect on slg- B cells. This localized action allows selective elimination of pathogenic cells without harming healthy B cells.
2Adaptability or versatility
If non-specific B-cell targeting is used, then treatment coverage is comprehensive, but therapeutic precision is low
Solution Approach 1:
The fusion protein uses surface immunoglobulin (slg) as an intermediary marker to identify and target pathogenic B cells. By coupling the slg-targeting domain with the cytotoxic diphtheria toxin A fragment, the invention creates a mediator that specifically delivers the killing effect only to slg+ cells, achieving high therapeutic precision while maintaining comprehensive coverage of pathogenic B-cell disorders.
Solution Approach 2:
The fusion protein exhibits local quality by having different functional properties for different B-cell subsets. It specifically binds to and kills slg+ B cells through the slg-targeting domain, while having no effect on slg- B cells. This localized action allows selective elimination of pathogenic cells without harming healthy B cells.
3Power
If diphtheria toxin is used directly, then cytotoxicity is high, but specificity is low causing off-target effects
Solution Approach 1:
The invention merges two distinct functional domains into a single fusion protein: the slg-targeting domain (such as SpA, SpG, or affibody) that provides specificity for binding to surface immunoglobulin on pathogenic B cells, and the diphtheria toxin A fragment that provides potent cytotoxicity. This combination ensures that the high-power cytotoxic effect is delivered only to slg+ target cells, eliminating off-target effects.
Solution Approach 2:
The fusion protein uses surface immunoglobulin (slg) as an intermediary marker to identify and target pathogenic B cells. By coupling the slg-targeting domain with the cytotoxic diphtheria toxin A fragment, the invention creates a mediator that specifically delivers the killing effect only to slg+ cells, achieving high therapeutic precision while maintaining comprehensive coverage of pathogenic B-cell disorders.
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 fusion proteins effectively kill 90-99% of target B cells while sparing non-pathogenic cells, providing a safe and specific therapeutic option for autoimmune diseases and B-cell disorders.
Implementation Method 1
The A fragment (N-terminal) of diphtheria toxin (DtA) contains a catalytic domain that disrupts protein synthesis in eukaryotic cells resulting in cytotoxicity in susceptible cells
Implementation Method 2
The variable regions of antibodies are generated by V(D)J recombination and further modified by somatic hypermutation, resulting in increased affinity following exposure to antigens
Implementation Method 3
B cells can also employ endocytosis when exposed to an antigen. This can occur when a membrane-bound immunoglobulin on the B cell's surface is exposed to a specific antigen. The antibody-antigen complex is then internalized and degraded.
Data Source
Figure 1A~1C
Figure 1D~1F
Figure 2A~2C
AI summary
The present invention refers to a fusion protein or conjugate comprising or consisting of: a) a Diphtheria toxin deprived of the receptor binding domain or functional fragments or derivatives or a biologically active variant thereof; and b) at least one surface immunoglobulin (slg) B-cell targeting peptide or functional fragments or derivatives or a biologically active variant thereof. Isolated nucleic acids, vectors and pharmaceutical compositions related to said fusion protein, as well as their medical uses, are also objects of the invention.