Activatable Anti-CTLA4 Antibodies for Tumor-Selective Activation
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Solution Overview
Problem
The development of anti-CTLA4 antibodies suitable for human use is challenging due to poor translation from pre-clinical animal models, and there is a need for antibodies that are cross-reactive among different species and activatable in the protease-rich tumor microenvironment.
Innovation Solution
Development of activatable anti-CTLA4 antibodies with a masking moiety (MM) and cleavable moiety (CM) that inhibit binding to CTLA4 until cleaved, allowing specific targeting in the tumor microenvironment, and can be administered alone or in combination with other therapeutic agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional anti-CTLA4 antibodies are developed for human use, then therapeutic efficacy is improved, but cross-reactivity with animal models deteriorates
Solution Approach 1:
The antibody is divided into functional segments: a species-specific binding region for human CTLA4 and a conserved binding region for animal CTLA4. This segmentation allows the antibody to maintain cross-reactivity with animal models while ensuring human-specific therapeutic efficacy, resolving the contradiction between reliability and adaptability.
Solution Approach 2:
Different regions of the antibody molecule are designed with distinct binding specificities: the first binding region targets human CTLA4 with high affinity for therapeutic efficacy, while the second binding region targets conserved epitopes across species for cross-reactivity. This local differentiation of binding qualities resolves the contradiction between human-specific efficacy and broad cross-reactivity.
2Productivity
If anti-CTLA4 antibodies are made broadly active, then anti-tumor response is improved, but safety and off-target effects deteriorate
Solution Approach 1:
The antibody's binding activity is made dynamic and context-dependent through protease activation mechanisms. The antibody remains inactive in normal tissues but becomes activated in the protease-rich tumor microenvironment, enabling broad anti-tumor response only where needed while minimizing off-target effects in healthy tissues.
Solution Approach 2:
The antibody exhibits different functional qualities in different locations: it maintains low affinity or inactive state in normal tissues but activates high affinity binding in the tumor microenvironment where proteases are present. This spatial differentiation of activity resolves the contradiction between broad anti-tumor response and reduction of off-target effects.
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 activatable anti-CTLA4 antibodies effectively target CTLA4, inducing ADCC and enhancing anti-tumor responses, showing synergistic effects with PD-1 inhibitors and efficacy in various cancers, including resistant or refractory cases.
Implementation Method 1
the CM comprises at least a first cleavage site; wherein: a) the TBM comprises an antibody light chain variable region (VL), and the activatable antibody further comprises a second polypeptide comprising an antibody heavy chain variable region (VH)
Implementation Method 2
The activatable anti-CTLA4 antibodies effectively target CTLA4, inducing ADCC and enhancing anti-tumor responses
Data Source
AI summary
The present application provides compositions and methods for treating cancers using anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibodies, such as activatable anti-CTLA4 antibodies. In some embodiments, combination therapies including an anti-CTLA4 antibody and a PD-1 inhibitor.