Inhibitors of Tumor Progression and Metastasis
Antibody-based compositions and methods for preventing metastasis through polarization of macrophages to a pro-inflammatory state.
C-C motif Chemokine Receptor 2 (CCR2) is a receptor for CCL2, a chemokine that is secreted by cells during inflammatory episodes and which not only serves to mediate monocyte chemotaxis but also contributes to macrophage polarization toward the anti-inflammatory M2 phenotype. Because M2 macrophages effectively promote tumor progression and metastasis, attempts have been made to target the CCL2/CCR2 pathway and influence macrophages toward an M1 antitumor phenotype.
Provided here are antibody-based anticancer agents and methods for inhibiting the growth and metastasis of a tumor. These agents, which bind distinct epitopes of CCR2, have been shown to prevent CCL2 binding and block its signaling pathway. When these agents were deployed against multiple epitopes, cellular migration was reduced by ~75% while an approximately 27-fold increase in the ratio of M1:M2 genes was observed. In vivo, significant reductions in tumor growth were seen, likely due to the resulting alterations in the cellular makeup of the tumor microenvironment. Specifically, the strategy resulted in significant reductions in myeloid-derived-suppressor cells (MDSCs), CD68+ tumor-associated macrophages (TAMs), CD206+ M2-like macrophages and CD4+/Foxp3 T-regulatory cells and an increase in major histocompatibility (MHC) class IIhi M1-like macrophages as well as anti-tumor CD4+ and CD8+ T-cells.
Because CCL2 can bind CCR2 even when the primary epitope is blocked, the multi-epitope blocking afforded by this approach provides superior results when compared to a small molecule inhibitor that binds only one epitope. These agents and this approach offer potential as an adjuvant therapy in solid tumors where immune cells contribute to tumor progression (e.g. triple negative breast cancer).
PCT Patent Application PCT/US20/32683 filed May 13, 2020.
In vivo demonstration.
Available for licensing or collaboration.