Protease-Activated T Cell Engager Polypeptides for Safer Targeting
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Solution Overview
Problem
Current T cell engaging bispecific antibodies, such as Blinatumomab, face safety concerns due to neurologic adverse events and systemic side effects, and there is a need for therapeutic compounds that can be conditionally activated at the disease site with minimal off-target activity.
Innovation Solution
A polypeptide comprising a first immunoglobulin single variable domain (ISVD) that binds to human serum albumin and a second ISVD that binds to the T cell receptor, linked by a protease cleavable linker, with a targeting moiety to specifically engage target cells, ensuring activation only when proteases are present at the disease site.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T cell engaging bispecific antibodies are used to activate T cells against cancer cells, then therapeutic efficacy is improved, but safety deteriorates due to neurologic adverse events and systemic side effects
Solution Approach 1:
The patent applies preliminary action by designing a masked T cell engager that is pre-configured with a protease cleavable linker and targeting moiety, but remains inactive until it reaches the disease site. The therapeutic compound is prepared in advance in a masked state, which only becomes active when proteases at the disease site cleave the linker, thereby preventing systemic side effects while maintaining therapeutic efficacy
Solution Approach 2:
The patent implements local quality by enabling the T cell engager to be activated only at the specific location of the disease site through protease cleavage. The masking moiety ensures that the therapeutic compound exhibits different properties in different locations: inactive in circulation and only active at the target site where proteases are present, thus localizing the therapeutic effect and minimizing systemic toxicity
2Power
If T cell engaging formats are used to enhance immune response, then therapeutic potency is improved, but safety profile deteriorates with cytokine release syndrome and infections
Solution Approach 1:
The masked T cell engager is prepared in advance in an inactive state with the protease cleavable linker intact. This preliminary masking prevents the compound from activating T cells systemically, thereby avoiding cytokine release syndrome and infections. Only upon reaching the disease site and being cleaved by proteases does the compound become potent and activate T cells locally
Solution Approach 2:
The protease cleavable linker serves as an intermediary mechanism that mediates between the masked T cell engager and the disease site. This intermediary structure allows the compound to be transported safely through the bloodstream and only becomes active when the intermediary is cleaved by proteases at the target site, thus controlling the activation process and preventing premature therapeutic effects
3Object-affected harmful factors
If conditional activation mechanism is implemented to reduce off-target activity, then safety is improved, but device complexity increases due to protease cleavable linker and masking moiety
Solution Approach 1:
The patent applies merging by combining the T cell engager, protease cleavable linker, and targeting moiety into a single integrated masked polypeptide compound. This unified structure reduces the need for separate components and simplifies the overall system while achieving conditional activation, thereby minimizing off-target activity without excessive complexity
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 polypeptide achieves targeted activation at the disease site with reduced off-target activity and enhanced potency, minimizing systemic side effects and improving safety profiles.
Implementation Method 1
a mechanism called proteolysis. Proteolysis entails the selective cleavage of specific substrates
Data Source
AI summary
The present technology provides polypeptides comprising a first immunoglobulin single variable domain (ISVD) binding to albumin, a second ISVD capable of binding to both the constant domain of a human T cell receptor (TCR) on a T cell and the constant domain of a non-human primate TCR on a T cell, wherein said first and second ISVD are linked by a protease cleavable linker, and a targeting moiety. The present technology further provides nucleic acids encoding said polypeptides as well as vectors, hosts and methods to produce these polypeptides. Moreover, the present technology relates to methods for treatment making use of the polypeptides according to the present technology.