PD-1 Targeted Immunotoxin Constructs for Selective Cell Elimination
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Solution Overview
Problem
Current treatments for autoimmune diseases are ineffective and often come with severe side effects, and there is a need for targeted therapies that can selectively eliminate PD-1 positive cells without harming naive cells.
Innovation Solution
Development of polypeptides comprising a truncated diphtheria toxin linked with PD1 targeting moieties, specifically designed to target and kill PD-1 positive cells, utilizing a yeast expression system for production and purification to enhance binding and reduce immunotoxin loss.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional immunosuppressive drugs are used to treat autoimmune diseases, then immune system suppression is achieved, but severe side effects such as infections occur
Solution Approach 1:
The patent segments the immune system targeting approach by creating immunotoxins that specifically target only activated lymphocytes expressing PD-1, rather than suppressing the entire immune system. This is achieved by combining a toxin (diphtheria toxin or exotoxin A) with a PD-1 binding moiety, ensuring the toxic effect is delivered only to PD-1 positive cells while leaving naive cells and other immune cells unaffected.
Solution Approach 2:
The invention applies local quality by making the treatment effect localized to specific cell types (PD-1 positive activated lymphocytes) rather than having a systemic effect on all immune cells. The PD-1 binding moiety ensures that the toxin is only internalized and exerted its cytotoxic effect in cells that express PD-1, creating a locally targeted therapeutic effect.
2Manufacturing precision
If diphtheria toxin is linked with PD1 targeting moiety to create immunotoxin, then cytotoxicity against PD-1 positive cells is enhanced, but immunotoxin loss and reduced stability may occur
Solution Approach 1:
The patent introduces linkers as intermediary components connecting the toxin to the PD-1 binding moiety. These linkers (such as flexible peptide linkers or disulfide bonds) serve as mediators that maintain the structural integrity of the immunotoxin while allowing the binding moiety to effectively engage PD-1. The intermediary linker protects the overall construct stability while enabling the functional components to work together.
Solution Approach 2:
The immunotoxin is constructed as a composite material combining three distinct components: the toxin (diphtheria toxin or exotoxin A), a linker, and the PD-1 binding moiety (single-chain variable fragment or nanobody). This composite structure leverages the strengths of each component - the cytotoxicity of the toxin, the specificity of the binding moiety, and the structural stability provided by the linker - creating a more stable and effective therapeutic agent.
3Reliability
If targeted therapy is developed to selectively eliminate PD-1 positive cells, then autoimmune disease treatment is improved, but device and manufacturing complexity increases
Solution Approach 1:
The patent segments the complex targeting function into separate modular components: the toxin module, the linker module, and the PD-1 binding module. Each module can be independently optimized, characterized, and manufactured. This segmentation allows for systematic development and reduces the overall complexity by breaking down the challenging task of creating a selective immunotoxin into manageable, independent functional units.
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 immunotoxin constructs demonstrate potent cytotoxicity against PD-1 positive cells with safe doses established in animal models, indicating potential for treating autoimmune diseases and other conditions like cancer and Type 1 Diabetes by selectively eliminating pathogenic immune cells.
Implementation Method 1
Programmed Death 1 (PD-1) proteins are inducibly expressed upon activation of lymphocytes
Implementation Method 2
Disclosed are polypeptides comprising a diphtheria toxin and a PD1 targeting moiety
Data Source
AI summary
Disclosed are polypeptides comprising a diphtheria toxin and a PD1 targeting moiety. Disclosed are polypeptides comprising, from N- to C-terminus, a truncated diphtheria toxin, and two anti-PD-1 scFvs. Disclosed are nucleic acid constructs comprising a nucleic acid sequence encoding any one of the disclosed polypeptides. Disclosed are nucleic acid constructs comprising a nucleic acid sequence encoding a diphtheria toxin linked to a nucleic acid sequence encoding a PD1 targeting moiety. Disclosed are methods of treating a subject in need thereof comprising administering to the subject a composition comprising one or more of the disclosed polypeptides, vectors, or pharmaceutical compositions.