In previous blog, we introduced AMG 487 as a potent, orally active and selective CXCR3 antagonist, which inhibits the binding of CXCL10 and CXCL11 to CXCR3 with IC₅₀ values of 8.0 and 8.2 nM, respectively.

Today, I’d like to describe the antitumor effect of AMG 487 on metastatic cancer.

Tumor cells aberrantly express chemokines and/or chemokine receptors, and some may promote tumor growth and metastasis. Previous studies have verified that AMG487 blocked in vitro lymphocyte migration mediated by CXCL9, CXCL10, or CXCL11.

Additionally, a study from Tonya C. Walser examined the expression and function of chemokine receptor CXCR3 in a syngeneic murine model of metastatic breast cancer. Subsequently, the authors verified the effect of AMG 487 on lung metastasis in breast cancer animal models. And this anti-metastatic activity was compromised in mice depleted of natural killer cells.

As a result, the CXCR3 antagonist did not affect proliferation of the tumor cells at 24, 48, or 72 hours under normal or serum-free growth conditions. However, AMG487 did, inhibit the migration of 66.1 tumor cells to CXCL9 by ~70%. Furthermore, AMG487-treated mice had developed fewer metastases than vehicle-treated mice (113 versus 171 metastases; P = 0.01). And AMG487 with the concentration of 1 μM developed into fewer lung metastases than control group (40 versus 104 metastases; P < 0.001).

Due to its toxicity to tumor cells, the authors carried out a proliferation assay in immune-competent mice, depleted of NK cells, and mice lacking functional T cells (SCID mice) injected by 66.1 tumor cells to rule out the possibility of the inhibitory of AMG 487 on lung metastases. As a result, groups treated by AMG487 developed fewer lung metastases than control groups (98 versus 190 metastases; P = 0.02). When the host was depleted of NK cells, however, all therapy normally conferred by AMG487 was abolished. These data confirmed AMG 487 as a promising clinical candidate in metastatic cancer treatment.