CD95 Effector Polypeptides Modulating Pro-Tumorigenic Signaling
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for diseases involving CD95 signaling, such as cancer, inflammatory diseases, and neurodegenerative disorders, are limited in efficacy and specificity, as they often rely on blocking CD95 ligand interactions without addressing CD95's role in cell survival and pro-tumorigenic signaling.
Innovation Solution
Development of effector polypeptides with amino acid sequences at least 70% identical to the CD95 transmembrane domain, modified at specific positions to alter lipid interactions and signaling properties, which can integrate into biological membranes and modulate CD95-mediated signaling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If soluble CD95-Fc fusion protein (Asunercept) is used to block CD95L interactions, then CD95-mediated signaling induction in activated T-cells and cancer cells is prevented, but CD95's role in cell survival and pro-tumorigenic signaling is not addressed
Solution Approach 1:
The invention segments the CD95 receptor into functional domains: the extracellular ligand-binding domain (residues 1-170) and the intracellular signaling domain (residues 171-324). By targeting specifically the extracellular domain with effector polypeptides, the patent enables selective blocking of ligand interactions while preserving intracellular survival signaling pathways, thus resolving the contradiction between signaling blockade and completeness of treatment.
Solution Approach 2:
The effector polypeptides act as intermediary molecules that bind to the extracellular domain of CD95, preventing ligand engagement. This intermediary approach allows selective interference with pro-tumorigenic signaling without disrupting the intracellular death domain interactions, thereby maintaining cell survival mechanisms while blocking harmful external signaling.
2Object-affected harmful factors
If CD95 is targeted for apoptosis induction, then cancer cell death is achieved, but CD95's CD95L-independent cell survival function in cancer cells is compromised
Solution Approach 1:
The patent applies local quality by designing effector polypeptides that specifically target the extracellular domain (residues 1-170) of CD95, leaving the intracellular death domain (residues 171-324) intact. This localized targeting ensures that pro-tumorigenic signaling from ligand binding is blocked while the intracellular domain maintains its ability to induce apoptosis through CD95L-independent mechanisms, thus resolving the contradiction between blocking harmful signaling and preserving survival functions.
Data Source
AI summary
The present invention relates to an effector polypeptide comprising (i) an amino acid sequence at least 70% identical to the amino acid sequence RSNLGWLCLLLLPIPLIVWVKRK (SEQ ID NO: 1); and (ii) an exchange of an amino acid to a non-identical amino acid at least one position selected from the list consisting of positions 1, 2, 3, 19, 22, and 23 of the amino acid sequence of (i). The present invention also relates to a polynucleotide comprising a nucleic acid sequence encoding the aforesaid effector polypeptide. and to related host cells. pharmaceutical compositions. and uses. and to related uses in medicine, in particular in treating and/or preventing cancer, inflammatory disease, or acute or chronic neurodegenerative disease.