CCR2 Antagonist Solid Tumor Treatment
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Solution Overview
Problem
Current strategies for targeting tumor-associated macrophages (TAMs) in cancer therapy, such as CSF1R blockade and CCL2-CCR2 axis inhibition, have shown inconsistent results due to limitations in accessing malignant cells and rapid dissociation of antibodies, necessitating the development of alternative approaches to effectively reduce TAM infiltration and enhance anti-tumor immunity.
Innovation Solution
Administration of a Chemokine Receptor 2 (CCR2) antagonist, specifically small molecule compounds, to deplete macrophages in the tumor microenvironment, thereby increasing CD8+ T cell expansion and inducing anti-tumor cytokine production, which can be synergized with anti-PD1 antibodies to enhance therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CSF1R blockade is used to target TAMs, then macrophage recruitment is inhibited, but the therapeutic effect is reduced due to inability to access malignant cells in the TME
Solution Approach 1:
The patent uses CCL2 antibodies as intermediaries to indirectly target TAMs by blocking the chemokine signal that recruits macrophages to the TME, rather than directly accessing malignant cells. This mediator approach allows therapeutic effect through immune modulation without requiring direct cell contact.
Solution Approach 2:
The patent replaces mechanical direct cell access with biochemical signaling blockade. Instead of physically accessing malignant cells through the TME barrier, the invention uses molecular-level intervention by blocking CCL2-CCR2 axis signaling to achieve therapeutic effects on TAMs.
2Reliability
If monoclonal CCL2 antibody is used to block CCL2/CCR2 axis, then monocyte recruitment is inhibited, but the antibody rapidly dissociates causing increased serum CCL2 concentrations
Solution Approach 1:
The patent changes the molecular parameters of the antibody by engineering variants with altered binding kinetics. The engineered antibodies have modified affinity and dissociation rates, transforming the transient binding into sustained blockade of the CCL2-CCR2 axis while preventing serum CCL2 level increases.
Solution Approach 2:
The patent introduces dynamic control of antibody-antigen interaction by creating variants with optimized on/off rates. The binding stability is dynamically adjusted to maintain effective blockade duration without causing pathological accumulation of CCL2 in serum.
3Reliability
If CCR2 antagonists are used to reduce TAM infiltration, then anti-tumor immune response is enhanced, but the mechanism of TME reshaping and immune activation remains to be described
Solution Approach 1:
The patent employs feedback mechanisms where CCR2 antagonist treatment effects are monitored and used to understand TME dynamics. The observed changes in immune cell populations and tumor responses provide feedback information about the mechanistic pathways involved in TME reshaping and immune activation.
Data Source
AI summary
The present disclosure provides, inter alia, methods of treating a solid-tumor by administering an effective amount of a Chemokine Receptor 2 (CCR2) antagonist. Also provided herein are methods of reducing the number of macrophages in a solid tumor microenvironment, said method comprising administering effective amount of a Chemokine Receptor 2 (CCR2) antagonist. In an additional aspect, the current disclosure further provides methods of increasing the number CD8+ T cells in a solid tumor microenvironment, said method comprising administering effective amount of a Chemokine Receptor 2 (CCR2) antagonist. In some embodiments, the CCR2 antagonist has the formula I or Formula III: