Non-blocking CCR8 Binders for Selective Treg Depletion
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Solution Overview
Problem
Current cancer therapies targeting CCR8 often have systemic side effects due to their blocking nature, which can lead to autoimmunity and are not effective in specifically depleting tumour-infiltrating regulatory T-cells without affecting peripheral Tregs.
Innovation Solution
Development of non-blocking CCR8 binders with cytotoxic activity that specifically deplete tumour-infiltrating regulatory T-cells by binding to the N-terminal extracellular region of CCR8, using single-domain antibodies with specific CDR sequences and framework regions, and optionally combining with checkpoint inhibitors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If blocking CCR8 binders are used to deplete tumour-infiltrating Tregs, then anti-tumour immunity is enhanced, but systemic side effects and autoimmunity occur
Solution Approach 1:
The patent applies local quality by designing non-blocking CCR8 binders that selectively deplete Tregs only in the tumour microenvironment where CCL1 is overexpressed, rather than systemically blocking CCR8 signaling. The binders exploit the local overexpression of CCL1 in tumours to achieve selective Treg depletion through ADCC, preserving peripheral Treg function and avoiding systemic autoimmunity while maintaining anti-tumour immunity enhancement.
Solution Approach 2:
The patent inverts the conventional blocking mechanism by using non-blocking CCR8 binders that do not prevent CCL1 from binding to CCR8. Instead of blocking the ligand-receptor interaction, these binders bind to CCR8 and recruit immune effector cells via ADCC to deplete Tregs in situ, reversing the traditional approach from signal blockade to targeted cell elimination.
2Reliability
If systemic removal of Treg cells is performed to enhance anti-tumour immunity, then tumour immunity is improved, but autoimmunity is triggered
Solution Approach 1:
The invention implements local quality by creating a spatially selective therapeutic effect confined to the tumour microenvironment. The non-blocking CCR8 binders exploit the local overexpression of CCL1 in tumours to selectively deplete Tregs at the tumour site through ADCC, while leaving peripheral Treg populations intact. This localized action enhances anti-tumour immunity without triggering systemic autoimmunity that would result from widespread Treg depletion.
3Reliability
If blocking antibodies are used to inhibit Treg migration into tumours, then tumour immunity is enhanced, but peripheral Treg function is affected
Solution Approach 1:
The patent applies local quality by designing a therapeutic mechanism that acts selectively in the tumour microenvironment rather than systemically. The non-blocking CCR8 binders exploit the local overexpression of CCL1 in tumours to recruit immune effector cells and deplete Tregs in situ, preserving peripheral Treg function and CCR8-mediated immune surveillance in healthy tissues while enhancing tumour immunity locally.
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 non-blocking CCR8 binders effectively deplete tumour-infiltrating regulatory T-cells while preserving peripheral Tregs, reducing systemic side effects and enhancing anti-tumour immunity, and can be used in combination with checkpoint inhibitors for improved therapeutic outcomes.
Implementation Method 1
WO2018/181425 suggests that, in mice, a neutralizing anti-CCR8 mAb is able to deplete Treg cells in tumour tissues by antibody-dependent cell-mediated cytotoxicity (ADCC)
Data Source
AI summary
The present invention relates to human CCR8 (hCCR8) binders, wherein the hCCR8 binder is a non-blocking binder of hCCR8. Such binders are particularly useful for the depletion of intra-tumoural regulatory T-cells and immunotherapy in general tumour