Protease-activatable t cell bispecific antibodies
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Solution Overview
Problem
Existing bispecific molecules for T cell activation face challenges in targeting tumor cells without activating normal cells, leading to on-target/off-tumor toxicity, and require improvements in efficacy, toxicity, and producibility.
Innovation Solution
Development of protease-activatable T cell activating bispecific molecules with a masking moiety that conceals antigen binding until reaching the tumor microenvironment, using a peptide linker with a protease recognition sequence to activate only at the site of action.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If bisspecific molecules are used to activate T cells against tumor cells, then tumor cell targeting is improved, but on-target/off-tumor toxicity increases
Solution Approach 1:
The bispecific molecule is designed in a masked or inactive form during circulation, with the masking moiety preventing premature activation. The activation function is performed only after the molecule reaches the tumor microenvironment through proteolytic cleavage of the linker, ensuring T cell activation occurs only at the intended target site and not in normal tissues.
Solution Approach 2:
The molecule exhibits different functional states in different locations: inactive/masked in circulation (safe profile), and active/activated at the tumor site (efficacious). The protease recognition sequence ensures activation occurs locally where the protease is present, creating spatially differentiated functionality.
2Productivity
If bispecific molecules are designed for high T cell activation efficacy, then tumor cell lysis is improved, but toxicity to normal cells increases
Solution Approach 1:
The T cell activation function is prepared in advance but held in check by the masking moiety. Only after reaching the tumor microenvironment does the proteolytic cleavage release the activation function, ensuring high efficacy is achieved only when and where needed, avoiding premature or off-target activation that would cause toxicity.
Solution Approach 2:
The masking moiety acts as an intermediary that temporarily blocks the T cell activation function. It allows the molecule to circulate safely without activating normal T cells, then releases the function at the tumor site where proteolytic cleavage occurs, mediating between safety during circulation and efficacy at the target site.
3Object-affected harmful factors
If a masking moiety is added to reduce toxicity, then safety profile is improved, but device complexity increases
Solution Approach 1:
The bisspecific molecule is segmented into functional modules: the bispecific antibody portion for target binding, the protease recognition sequence for location-specific activation, and the masking moiety for safety. This modular segmentation allows each component to perform its specific function while maintaining overall manageability of the complex structure.
Solution Approach 2:
The molecule's functional parameters change based on environmental conditions: in circulation, the masking moiety prevents activation (safe state); in the tumor microenvironment, proteolytic cleavage changes the structural parameter by removing the mask, enabling activation (efficacious state). This parameter change allows one structure to provide multiple functional states.
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
Enhances safety by reducing toxicity and ensuring efficient activation at the tumor site, while maintaining low activity elsewhere, thus improving therapeutic efficacy.
Implementation Method 1
the masking moiety is capable of binding to the idiotype of the first or the second antigen binding moiety thereby reversibly concealing the first or the second antigen binding moiety
Implementation Method 2
the peptide linker comprises the protease recognition sequence XQARK (SEQ ID NO: 39) wherein X is histidine (H) or proline (P)
Data Source
AI summary
The present invention generally relates to improved protease-activatable antigen-binding molecules that comprise an anti-idiotype-binding moiety which reversibly masks a CD3 antigen binding moiety of the molecule. In addition, the present invention relates to polynucleotides encoding such protease-activatable T cell binding molecules, and vectors and host cells comprising such polynucleotides. The invention further relates to methods for producing the protease-activatable T cell binding molecules of the invention, and to methods of using the same, e.g., in the treatment of disease.