Balixafortide is a very potent, well tolerated and highly selective next generation CXCR4 antagonist derived over the past decade through multiple rounds of optimization starting from the natural product polyphemusin. Clinical proof-of-concept was achieved in a Ph 1/2 study in combination with Eribulin in metastatic HER2-neg breast cancer. The anti-cancer effects and pluripotent action of Balixafortide may include sensitization of tumor cells to chemotherapy, suppression of metastatic spread, inhibition of angiogenesis, and activation of the immune system.
Balixafortide was tested in a HTRF-based CXCR4 ligand binding assay, in functional assays (Calcium flux and beta arrestin), and further profiled in a large panel of other receptors including CXCR7. Effects on tumor cell sensitization were followed with an intracellular pERK / pAKT signaling assay. Tumor cell migration was assessed by chemotaxis assays, and inhibition of angiogenesis was determined by HUVEC sprouting. Evidence for immune cell activation came from evaluation of corresponding marker such as interferon gamma. Balixafortide was in detail profiled in an extensive in vitro ADME panel.
Balixafortide binds CXCR4 with high affinity (IC50 < 10nM). It blocks beta arrestin recruitment and Calcium flux with IC50s < 10nM. A high 1000-fold selectivity window was demonstrated in a large panel of receptors including CXCR7. Balixafortide potently inhibits pERK / pAKT signaling in the lymphoma lines Namalwa (IC50 < 200 nM) and Jurkat (IC50 < 400 nM). Balixafortide efficiently blocks SDF-1 dependent chemotaxis of MDA MB 231 breast cancer cells (IC50 < 20 nM), Namalwa and Jurkat cells (IC50 < 10 nM). Receptor occupancy wash-out studies with competitive antibody 12G5 revealed prolonged binding of Balixafortide to CXCR4. In addition, Balixafortide was optimized for favorable mouse and human ADME properties with balanced plasma protein binding, greater plasma and microsomal stability.
Balixafortide is a product of an extensive optimization process which started from polyphemusin and now represents a favorable balance between ADMET properties, potency and tolerability which allows high and frequent dosing of a CXCR4 antagonist in cancer patients.
Has not received any funding.
J. Zimmermann: Employee and shareholder: Polyphor Ltd. T. Remus, G. Lemercier, D. Barker, D. Obrecht, G. Douglas, G. Gambino: Employee: Polyphor Ltd.