Linker Polypeptides with Protease-Cleavable Sequences
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current protein therapeutics and polypeptides face challenges such as systemic toxicity, short serum half-life, and inseparable activities due to fixed immunoglobulin antigen-binding domains, leading to severe toxicities and limited therapeutic efficacy, especially when targeting cancer cells.
Innovation Solution
Development of linker polypeptides with protease-cleavable sequences that allow for targeted activation in tumor microenvironments, decoupling different functions and enhancing immune cell recruitment and activity, while minimizing systemic exposure.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If systemic administration of immunoglobulin antigen-binding domains is used to target diseased cells, then immune cell response is sustained, but systemic toxicity occurs due to activation of immune cells throughout the body
Solution Approach 1:
The patent divides the therapeutic function into separate modular domains: an immunoglobulin antigen-binding domain for target recognition, a cytokine domain for immune activation, and a pharmacokinetic modulator domain for half-life extension. These domains are connected by protease-cleavable linkers that allow controlled separation, enabling the immunoglobulin domain to target tumors while the cytokine domain activates immune cells locally, thereby sustaining immune response while reducing systemic toxicity
Solution Approach 2:
The patent introduces protease-cleavable linkers as intermediary elements between functional domains. These linkers are designed to be cleaved by tumor-associated proteases, serving as a mediator that controls the activation and separation of functional domains. The linkers enable the immunoglobulin domain to bind tumor antigens while preventing premature activation of the cytokine domain, thus reducing systemic toxicity while maintaining reliable immune cell response at the tumor site
2Reliability
If high doses of peptide, immunoglobulin, or cytokine therapies are administered to achieve optimal effect, then therapeutic efficacy is improved, but severe toxicities occur due to short serum half-life requiring high doses
Solution Approach 1:
The patent merges three critical therapeutic functions into a single polypeptide construct: the immunoglobulin antigen-binding domain for target specificity, the cytokine domain for immune activation, and the pharmacokinetic modulator domain (such as Fc region) for extended serum half-life. This combination allows the therapy to achieve optimal efficacy at lower doses by maintaining sustained drug levels in circulation, thereby reducing the need for high dosing and associated severe toxicities
Solution Approach 2:
The patent creates a multi-functional polypeptide that simultaneously provides target recognition (immunoglobulin domain), immune stimulation (cytokine domain), and extended circulation half-life (pharmacokinetic modulator domain). This universal design allows a single agent to perform multiple therapeutic functions, achieving optimal efficacy without requiring high doses of separate therapies, thus reducing severe toxicities while maintaining reliable therapeutic effect
3Stability of the object's composition
If traditional antibody structure with fixed immunoglobulin antigen-binding domains to Fc region is used, then structural stability is maintained, but activities cannot operate independently at different locations and times
Solution Approach 1:
The patent introduces dynamic elements into the antibody structure by incorporating protease-cleavable linkers between functional domains. These linkers allow the polypeptide to transition from a stable, integrated structure to separated functional domains in response to tumor-associated proteases. This dynamic design enables the immunoglobulin domain to bind tumor antigens while the cytokine domain remains inactive until cleavage occurs, allowing independent activity at different locations and times while maintaining structural stability during circulation
4Reliability
If protease-cleavable linkers are used to enable selective activation in tumors, then immune cell infiltration is increased, but additional structural complexity is introduced
Solution Approach 1:
The patent segments the polypeptide into distinct functional domains connected by standardized protease-cleavable linkers. This segmentation allows each domain to perform its specific function independently while the modular linker design provides a systematic approach to connecting them. The cleavable linkers are strategically placed to enable controlled separation, increasing immune cell infiltration through localized cytokine activation while managing structural complexity through modular, repeatable connection elements
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 linker polypeptides achieve selective activation in tumors, increasing immune cell infiltration and immune response against cancer cells, reducing systemic toxicity and improving therapeutic outcomes.
Implementation Method 1
a first linker between the first targeting sequence and the second targeting sequence, the linker comprising a protease-cleavable polypeptide sequence
Data Source
AI summary
This disclosure relates to linker polypeptides. In some embodiments, the linker polypeptide comprises a first targeting sequence; a second targeting sequence; and a first linker between the first targeting sequence and the second targeting sequence, the linker comprising a protease-cleavable polypeptide sequence. In some embodiments, the linker polypeptide comprises a first active domain; a second active domain; a pharmacokinetic modulator; and a first linker between the pharmacokinetic modulator and the first active domain, the first linker comprising a protease-cleavable polypeptide sequence. In some embodiments, the linker polypeptide comprises a first active domain; an inhibitory polypeptide sequence capable of blocking an activity of the first active domain; a first linker between the first active domain and the inhibitory polypeptide sequence, the linker comprising a protease-cleavable polypeptide sequence; and a first targeting sequence.