生体内における改変型CCL20ロックドダイマーの生物学的安全性評価

Immune dysregulation by aberrant chemokine production underlies many diseases. Targeting chemokine receptors with small molecule inverse agonists, antagonists, or neutralizing antibodies has proven challenging due to non-specific effects and receptor upregulation. Locked dimers of chemokines, generated via cysteine substitutions to produce constitutively homodimeric molecules, offer a promising alternative for receptor-specific inhibition. This study evaluates the in vivo safety and dosing of an engineered CCL20 locked dimer (CCL20LD), which selectively binds CCR6 without inducing chemotaxis. The antagonist-like properties of CCL20LD make it a potential therapeutic for CCL20-CCR6 driven diseases. Daily 14-day subcutaneous administration of CCL20LD at doses previously shown to be therapeutically effective in preclinical models of psoriasis or psoriatic arthritis did not result in weight loss or immune suppression. CCL20LD administration had little to no effects on the complete blood count with differential, comprehensive metabolic panel, urinalysis, organ weights, or bone marrow progenitors. At single cell resolution, doses near 7.5mg/kg/day modestly disrupted T cell dependent B cell activation. While splenomegaly due to extramedullary hematopoiesis was observed at the highest tested dose, serum cytokine levels were largely unchanged. Combined, these findings indicate that selective targeting of CCR6 with an engineered CCL20 dimer is broadly safe in vivo, exhibiting a wide therapeutic window with minimal adverse or immunomodulatory effects.