Activatable Anti-CTLA4 Antibodies with Protease-Cleavable Masking
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Solution Overview
Problem
The development of anti-CTLA4 antibodies suitable for human use is challenging due to poor translation from animal models to human safety, and there is a need for cross-reactive antibodies that are active in specific contexts, such as the protease-rich tumor microenvironment, to enhance anti-tumor immune responses.
Innovation Solution
Development of cross-reactive antibodies that bind to human CTLA4 with high affinity and are precision/context-dependent, capable of inducing ADCC effects, activating PBMCs, and inhibiting tumor cell growth, while having reduced cytotoxicity and specific binding properties to inhibit CTLA4's interaction with CD80/CD86, using novel masking and cleavable moieties to control activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional anti-CTLA4 antibodies are developed for human use based on animal models, then pre-clinical efficacy is achieved, but translation to human safety is poor
Solution Approach 1:
The patent applies parameter changes by systematically modifying antibody sequences to achieve human-like properties while maintaining cross-reactivity. Specifically, the antibody sequences are engineered to have human IgG constant regions and humanized variable regions, changing the molecular parameters of the antibody to improve human compatibility and safety translation from animal models
Solution Approach 2:
The patent uses chimeric and humanized antibody constructs as intermediaries between animal model antibodies and fully human therapeutic antibodies. These intermediate forms allow testing of cross-reactivity and efficacy in animal models while progressively improving human safety profiles through sequence optimization and humanization
2Productivity
If anti-CTLA4 antibodies are designed to be broadly active, then anti-tumor immune response is enhanced, but cytotoxicity to healthy tissues increases
Solution Approach 1:
The patent employs dynamically controlled antibody activity through protease-cleavable linkers and conditional activation mechanisms. The antibodies are designed to be inactive in circulation but become activated only in the protease-rich tumor microenvironment, allowing dynamic switching between inactive and active states to reduce off-target cytotoxicity while maintaining anti-tumor efficacy
Solution Approach 2:
The patent applies local quality by creating antibodies with spatially differentiated activity - the antibody remains inactive in healthy tissues and only becomes active locally within the tumor microenvironment where specific proteases are present. This localized activation ensures anti-tumor immune response enhancement without systemic cytotoxicity to healthy tissues
3Manufacturing precision
If masking moieties are used to control antibody activity, then specificity is improved, but molecular complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the antibody molecule into distinct functional segments: a masking moiety that blocks activity, a cleavable linker that connects the masking moiety to the antibody, and the antibody itself. This segmentation allows independent optimization of each component and simplifies the control of antibody activity through modular design
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 antibodies effectively bind to human and non-human CTLA4 with high specificity and affinity, induce immune responses, and inhibit tumor growth with reduced cytotoxicity, demonstrating enhanced therapeutic efficacy in cancer treatment.
Implementation Method 1
antibodies that bind to human CTLA4... bind to human, cynomolgus monkey, mouse, rat, and/or dog CTLA4 with a KD of 500 nM or less... block binding of human CTLA4 to human CD80 and/or human CD86
Implementation Method 2
induces ADCC effects (e.g., on Tregs)... binding of the antibody to CTLA4 induces antibody-dependent cell cytotoxicity (ADCC) against a CTLA4-expressing cell
Implementation Method 3
activates human PBMCs (e.g., stimulates secretion of IL-2 and/or IFNγ)... activates human PBMCs (e.g., stimulates secretion of IL-2 and/or IFNγ)
Data Source
AI summary
Provided herein are cross-reactive antibodies (or antigen binding fragments thereof) that bind to human CTLA4, activatable antibodies that bind to human CTLA4, nucleic acid molecules encoding the same, pharmaceutical compositions thereof, and methods of their therapeutic use (e.g., for treatment of cancer).