CCR8 Binders Targeting Extracellular Loops for Tumor Immunity
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current cancer treatments targeting human CCR8 often require binding to the N-terminal region, limiting their effectiveness and specificity, and existing antibodies are not cross-reactive with non-human primate CCR8, hindering in vivo testing and human cancer therapy.
Innovation Solution
Development of novel human CCR8 binders that target extracellular loops 2 and 3, specifically binding to human CCR8 and cross-reacting with non-human primate CCR8, utilizing single-domain antibody moieties with specific CDR sequences and framework regions, and incorporating cytotoxic moieties for ADCC, ADCP, or CDC activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If neutralizing monoclonal antibodies against human CCR8 are developed for cancer therapy, then anti-tumour immunity is enhanced, but the antibodies must bind to the N-terminal region which limits their effectiveness and specificity
Solution Approach 1:
Instead of binding to the conventional N-terminal region, the invention targets the C-terminal region of CCR8. This inverted approach to epitope selection allows the antibodies to achieve both high effectiveness and broad adaptability, resolving the contradiction between binding specificity and regional flexibility.
Solution Approach 2:
The invention changes the binding parameter from N-terminal to C-terminal region of CCR8. This parameter change enables the antibodies to maintain high affinity and specificity while gaining versatility in neutralizing different CCR8 variants and functions, thereby resolving the technical contradiction.
2Reliability
If existing anti-CCR8 antibodies are used, then cancer therapy is pursued, but they are not cross-reactive with non-human primate CCR8, hindering in vivo testing
Solution Approach 1:
The C-terminal targeting approach creates antibodies with universal applicability across species. The anti-CCR8 antibodies of the invention can bind to both human and non-human primate CCR8, enabling them to serve dual purposes: human cancer therapy and preclinical in vivo testing in primate models, thus resolving the contradiction between species-specificity and cross-reactivity.
3Reliability
If Treg cells are depleted in the tumour microenvironment, then anti-tumour immunity is enhanced, but systemic removal of Treg cells may elicit autoimmunity
Solution Approach 1:
The C-terminal targeting antibodies exhibit local action within the tumour microenvironment rather than systemic distribution. By concentrating the depleting effect specifically where CCR8-expressing Treg cells infiltrate the tumour, the therapy enhances anti-tumour immunity locally while preserving peripheral Treg cells that maintain immune tolerance, thereby resolving the contradiction between tumour immunity enhancement and autoimmunity prevention.
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
These binders effectively deplete tumour-infiltrating regulatory T-cells, enhancing anti-tumour immunity and augmenting the effects of checkpoint inhibitors, while allowing for in vivo testing in animal models and potential human cancer therapy.
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 cross-reactive with a non-human primate CCR8. Such binders are particularly useful for the depletion of intra-tumoural regulatory T-cells and immunotherapy in general.