Protease-Activatable T Cell Bispecific Molecules
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current bispecific molecules used in cancer therapy often activate T cells non-specifically, leading to toxicity in both target and non-target cells, as they do not require proximity to the target cell for activation, which can result in damage to healthy tissues.
Innovation Solution
Development of protease-activatable T cell activating bispecific molecules with a masking moiety that conceals the CD3-binding site until proximity to a target cell is achieved, utilizing a protease-cleavable linker and anti-idiotypic scFv to mask the antigen-binding moieties, ensuring activation only in the presence of the target cell.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If bispecific molecules are used to activate T cells against target cells, then immune response against tumor is improved, but toxicity to healthy tissues occurs due to non-specific activation
Solution Approach 1:
The patent applies preliminary action by pre-masked the CD3-binding site with an anti-idiotypic antibody before administration. The bispecific molecule is designed with the CD3-binding site already concealed, and activation only occurs when the molecule reaches the target tissue and is cleaved by proteases. This preliminary masking prevents premature or non-specific T cell activation in healthy tissues, thereby reducing toxicity while maintaining the ability to activate T cells against tumor cells.
2Productivity
If CD3-binding site is exposed to activate T cells, then T cell activation efficiency is improved, but non-specific binding to healthy cells increases
Solution Approach 1:
The patent uses an anti-idiotypic antibody as an intermediary to mask the CD3-binding site. This masking moiety acts as a temporary barrier that prevents direct interaction between the CD3-binding site and CD3 molecules on T cells. The masking is reversible through protease cleavage, which occurs specifically in the target tissue environment. This intermediary approach allows the molecule to circulate safely without activating T cells non-specifically, while still enabling efficient T cell activation when and where needed.
3Reliability
If masking moiety is added to conceal CD3-binding site, then specificity of activation is improved, but molecular complexity increases
Solution Approach 1:
The patent merges multiple functional elements into a single integrated bispecific molecule structure. The CD3-specific binding moiety, target cell antigen-binding moiety, and anti-idiotypic masking moiety are all incorporated into one molecular construct. This merging approach allows the molecule to perform multiple functions (targeting, masking, and activation) simultaneously, reducing the need for separate components and simplifying the overall therapeutic approach while maintaining high selectivity.
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
This approach selectively activates T cells only when in close proximity to target cells, reducing toxicity to healthy tissues by maintaining the CD3-binding site in a masked state until the protease is activated by the target cell, thereby enhancing the specificity and efficacy of cancer therapy.
Implementation Method 1
a protease-cleavable linker, wherein the masking moiety is capable of specific binding to the idiotype of the first or the second antigen binding moiety thereby reversibly concealing the first or second antigen binding moiety
Data Source
Figure 1A
Figure 1B
Figure 1C
AI summary
The present invention generally relates to novel protease-activatable T cell activating bispecific molecules and idiotype-specific polypeptides acting as masking moieties. The present invention also relates to polynucleotides encoding such protease-activatable T cell activating bispecific molecules and idiotype-specific polypeptides, and vectors and host cells comprising such polynucleotides. The invention further relates to methods for producing the protease-activatable T cell activating bispecific molecules and idiotype-specific polypeptides of the invention, and to methods of using these protease-activatable T cell activating bispecific molecules and idiotype-specific polypeptides in the treatment of disease.