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Chemokine Receptor Antagonists: ChemoCentryx Is An Aged Red Wine Ripe For Success

Mar. 07, 2018 12:15 PM ETAmgen Inc. (AMGN)AUPH26 Comments


  • Chemokine biology gained scientific prominence in 1996 when it was discovered that chemokine receptors act as co-receptors for the binding and entry of HIV into target cells.
  • 25 years after the initial characterization of chemokine receptors, chemokine receptor antagonists are now used therapeutically to treat HIV/AIDS infection, adult T-cell leukemia/lymphoma and induce hematopoietic stem cells mobilization.
  • Chemokines and their receptors are key regulators of leukocyte trafficking and activation to sites of inflammation/injury where they promote interactions between the innate and adaptive immune systems.
  • The CDC estimates that >30 million adults in the US have chronic kidney diseases (CKDs) costing$100 billion annually.  Their standard steroid therapy has a myriad of side effects.
  • No chemokine receptor antagonist(s) has been approved therapeutically for inflammatory diseases.  I analyze pioneering clinical data in support of chemokine receptor antagonist, CCX140-B, in a new therapeutic approach to rare CKDs.

Background on Chemokines and their Receptors

Chemokines, chemoattractant cytokines, are a family of small (8 to 15-kDa) structurally related proteins that are one of the most important regulators of leukocyte trafficking and activation (Rollins, Blood, 1997; Baggiolini, Nature, 1998). They control cell migration and cell positioning throughout development, homeostasis, and inflammation and also play a key regulatory role in the biology of non-immune cells important for tumor growth and progression (Sokol & Luster, Cold Spring Harb. Perspect. Biol., 2015). Chemokines exhibit a high degree of conservation between mice and humans. At present, the chemokine superfamily consists of approximately 50 endogenous chemokine ligands and their actions are mediated by a family of 7-transmembrane G-protein–coupled receptors, which is made up of 23 members (Bachelerie et. al. Pharmacol. Reviews, 2014). Chemokines and their receptors are structurally subdivided into four subfamilies, XC, C-C, C-X-C, and C-X-X-X-C, based on the position of the first two amino terminal cysteine residues present on the ligand. Thus, CXC chemokine ligands have one amino acid separating first two N-terminal cysteine residues, CC chemokine ligands (CCLs) have two adjoining amino-terminal cysteine residues and CX3CL has three amino acids separating the two initial cysteine residues (Rollins, Blood, 1997). The N-terminal domain in chemokine is important for chemokine receptor recognition since selective deletion or substitution of N-terminal amino acid residues on chemokine produces chemokines with antagonistic effects (Baggiolini & Moser, J. Exp. Med, 1997). The functions of chemokines could be described as being homeostatic or inflammatory (Bachelerie et. al. Pharmacol. Reviews, 2014). Most chemokines are secreted into the extracellular space where they remain soluble or are bound to extracellular matrix components, forming transient or stable concentration gradients, respectively. Chemokines and their gradients are detected by binding to specific chemokine receptors.

Chemokine receptors primarily signal via pertussis toxin-sensitive Gi-type G proteins (Rollins, Blood

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