Masked Anti-CTLA4 Binding Proteins with Tumor-Site Protease Cleavage
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Solution Overview
Problem
Current anti-CTLA4 therapies, such as ipilimumab, cause systemic immune activation leading to severe adverse effects like enterocolitis, dermatitis, and other life-threatening immune-related issues, limiting their efficacy and safety in cancer treatment.
Innovation Solution
Development of activatable masked anti-CTLA4 binding proteins, comprising antibodies or antigen-binding fragments with a masking peptide linked via a cleavable peptide to the antibody chains, which are activated upon protease cleavage at the tumor site, minimizing systemic immune activation and targeting tumors specifically.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If anti-CTLA4 antibodies like ipilimumab are used to block CTLA4 and activate T cells, then tumor immunity is enhanced, but systemic immune activation causes severe adverse effects
Solution Approach 1:
The patent applies local quality by creating a masked antibody where the masking peptide is selectively removed in the tumor microenvironment through protease cleavage. This ensures the anti-CTLA4 activity is activated locally at the tumor site rather than systemically throughout the body, thereby enhancing tumor-specific immunity while avoiding widespread immune activation and its associated adverse effects.
Solution Approach 2:
The masking peptide acts as an intermediary element that temporarily blocks the anti-CTLA4 binding site. This intermediary is designed to be cleaved by proteases present in the tumor microenvironment, releasing the blocked binding site and activating the antibody's therapeutic function only where needed, thus mediating between system administration and localized action.
2Productivity
If anti-CTLA4 antibodies are administered systemically, then therapeutic efficacy is achieved, but immune-related adverse effects increase
Solution Approach 1:
The antibody is administered in a pre-masked state with the binding site blocked by the masking peptide. This preliminary masked state allows safe system circulation without activating immune responses. The activation occurs only after preliminary protease cleavage in the tumor microenvironment, ensuring therapeutic efficacy is achieved only where the tumor resides, thereby minimizing harmful systemic immune effects.
3Object-affected harmful factors
If a masking peptide is added to the anti-CTLA4 antibody, then systemic immune activation is reduced, but the antibody structure becomes more complex
Solution Approach 1:
The antibody molecule is segmented into functional components: the anti-CTLA4 binding protein, the masking peptide, and the cleavable peptide linker. This segmentation allows each component to perform its specific function independently - the binding protein provides therapeutic activity, the masking peptide provides temporary blocking, and the linker provides controlled release. This modular segmentation manages complexity by making each element's role clear and interchangeable.
Solution Approach 2:
The patent utilizes parameter changes in the peptide linker's cleavability to control the transition from masked to active state. By selecting specific cleavable peptide sequences that are sensitive to proteases present in the tumor microenvironment, the system achieves controlled activation without requiring complex regulatory mechanisms. This parameter-based control simplifies the overall system compared to active management approaches.
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 masked anti-CTLA4 proteins reduce systemic immune activation, minimizing adverse effects while maintaining therapeutic efficacy by targeting CTLA4-expressing cells, thereby enhancing tumor-specific immune responses.
Implementation Method 1
a masking peptide comprising an amino acid sequence selected from SEQ ID NOs: 1-46, wherein the masking peptide is linked via a linker comprising a cleavable peptide to an amino-terminus or carboxy-terminus of the first chain or the second chain of the antibody or antigen-binding fragment
Data Source
AI summary
The invention provides activatable masked anti-CTLA4 binding proteins (e.g., antibodies, bispecific antibodies, and chimeric receptors) and their use in treating and preventing cancer, as well as compositions and kits comprising the activatable masked anti-CTLA4 binding proteins.