Activatable Anti-CTLA-4 Antibodies for Tumor-Selective Binding
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Solution Overview
Problem
Current anti-CTLA-4 antibodies, such as ipilimumab, suffer from dose-limiting toxicities like colitis, necessitating the development of modified forms with reduced toxicity but comparable anti-tumor efficacy.
Innovation Solution
Development of activatable anti-CTLA-4 antibodies with a masking moiety and a cleavable moiety that are specifically designed to bind CTLA-4 only in the tumor microenvironment, reducing off-target binding and side effects while maintaining therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If anti-CTLA-4 antibodies (e.g., ipilimumab) are used to treat tumors, then anti-tumor efficacy is improved, but dose-limiting toxicities (e.g., colitis) occur
Solution Approach 1:
The patent applies local quality by creating an activatable antibody that has different binding properties in different locations. The antibody is designed to be activated (remove masking moiety) specifically in the tumor microenvironment through proteolytic cleavage, allowing it to bind CTLA-4 and exert anti-tumor effects only at the tumor site, while remaining inactive in normal tissues to avoid toxicities like colitis.
Solution Approach 2:
The patent implements preliminary action by incorporating a masking moiety that is pre-attached to the antibody's variable region. This masking moiety prevents off-target binding before the antibody reaches the tumor. Upon arrival at the tumor, the masking moiety is cleaved off by tumor-specific proteases, activating the antibody's CTLA-4 binding capability. This preliminary masking ensures safety during circulation and delivery.
2Productivity
If anti-CTLA-4 antibodies bind CTLA-4 systemically, then T cell activation is promoted, but autoimmunity and inflammation increase
Solution Approach 1:
The patent applies dynamics by creating an antibody that transitions from an inactive state (masked) to an active state (unmasked) based on the environmental conditions. The masking moiety is dynamically removed by proteolytic cleavage in the tumor microenvironment, allowing the antibody to activate T cells only where needed. This dynamic activation prevents systemic autoimmunity while maintaining tumor-specific T cell activation.
3Reliability
If anti-CTLA-4 antibodies are administered at high doses to maximize anti-tumor effect, then tumor regression improves, but toxicity increases
Solution Approach 1:
The patent uses a masking moiety as an intermediary element that controls the antibody's activity. The masking moiety acts as a protective layer that prevents the antibody from binding CTLA-4 in normal tissues. Only in the tumor microenvironment, where proteases are present, is the masking moiety removed, allowing the antibody to exert its anti-tumor effects. This intermediary mechanism enables high anti-tumor efficacy without proportional increases in toxicity.
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 antibodies retain anti-tumor activity by selectively binding CTLA-4 in tumors, minimizing side effects and enhancing treatment safety.
Implementation Method 1
a masking moiety (MM)... wherein the MM is selected from the group consisting of YV04, YV23, YV24, and YV39
Implementation Method 2
the masking moiety is removed by proteolytic cleavage of the cleavable moiety by tumor-specific proteases
Implementation Method 3
Such activatable anti-human CTLA-4 antibodies have CTLA-4 binding activity in the tumor microenvironment
Data Source
Figure 1A~1C
Figure 2A~2C
Figure 3A~3E
AI summary
Provided herein are activatable anti-human CTLA-4 antibodies comprising a heavy chain comprising a VH domain and a light chain comprising a masking moiety (MM), a cleavable moiety (CM), and a VL domain. Such activatable anti-human CTLA-4 antibodies have CTLA-4 binding activity in the tumor microenvironment, where the masking moiety is removed by proteolytic cleavage of the cleavable moiety by tumor-specific proteases, but exhibit greatly reduced binding to CTLA-4 outside the tumor. In this way, the activatable anti-human CTLA-4 antibodies of the present invention retain anti-tumor activity while reducing the side effects associated with anti-CTLA-4 activity outside the tumor.