Conditional Immunoglobulin Binding Moiety for Tumor-Selective Activation
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Solution Overview
Problem
T cell engagers face limitations in targeting solid tumors due to the scarcity of tumor antigens with sufficient differential expression between tumor and normal tissue, and there is a need to extend the half-life of therapeutic molecules in circulation while improving their ability to reach their target without non-specific binding.
Innovation Solution
A binding moiety comprising a non-CDR loop and a cleavable linker is used to mask the binding of immunoglobulin molecules, which can bind to bulk serum proteins like albumin, and upon cleavage, the target antigen binding domain activates, allowing specific targeting of tumor antigens.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If T cell engagers are used to target solid tumors, then tumor cell targeting is achieved, but the scarcity of differentially expressed tumor antigens limits effective targeting
Solution Approach 1:
The patent introduces a conditional activation mechanism as an intermediary layer between the T cell engager and tumor antigen. The engager is masked with a peptide that prevents binding until proteolytic cleavage occurs in the tumor microenvironment, effectively mediating the interaction and enabling targeting of antigens that would otherwise be unavailable or poorly differentiated.
Solution Approach 2:
The patent changes the activation state parameter of the T cell engager from permanently active to conditionally active. By controlling the binding capability through proteolytic cleavage of a masking peptide, the system can transition between inactive (in circulation) and active (in tumor microenvironment) states, enabling versatile targeting despite limited antigen availability.
2Duration of action of stationary object
If the half-life of therapeutic molecules is extended in circulation, then therapeutic efficacy is improved, but non-specific binding to off-target tissues increases
Solution Approach 1:
The patent applies preliminary masking action to the T cell engager by attaching a peptide that blocks the binding interface before the molecule reaches the tumor microenvironment. This preliminary action prevents non-specific binding during circulation while maintaining the molecule's potential for specific targeting, and the mask is removed only when needed through proteolytic cleavage.
Solution Approach 2:
The masking peptide performs a preliminary anti-action by blocking the binding site of the T cell engager, preventing harmful non-specific interactions with off-target tissues during circulation. This counter-action is maintained until the molecule reaches the tumor microenvironment where proteolytic cleavage removes the mask, allowing specific binding to occur.
3Speed
If T cell engagers are activated in circulation, then immediate tumor targeting is achieved, but systemic toxicity increases due to off-target effects
Solution Approach 1:
The patent extracts the activation function from the T cell engager structure itself and separates it into a conditional event triggered by proteolytic cleavage in the tumor microenvironment. This extraction allows the engager to remain inactive (non-toxic) during circulation and only become active when the masking peptide is removed by tumor-specific proteases, eliminating systemic toxicity while maintaining rapid local activation.
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 solution enables selective targeting of a wider range of tumor antigens and extends the half-life of therapeutic molecules, enhancing their efficacy in the tumor microenvironment.
Implementation Method 1
the moiety is linked to the target antigen binding domain via a cleavable linker... upon cleavage, the target antigen binding domain activates
Data Source
AI summary
Disclosed herein are binding moieties that comprise non-CDR loops for masking the binding of a binding molecule to its target and CDRs for binding bulk serum proteins. Conditionally active target binding proteins that contain the binding moieties are also provided. Pharmaceutical compositions comprising the binding proteins disclosed herein and methods of using such formulations are further provided.