Modulation of immune cell reactivity with cis-binding Siglec-9 agonists

Primary inflammatory pathologies caused by phagocytes lead to numerous debilitating conditions, ranging from chronic pain to permanent blindness. Siglec-9 is an immunoinhibitory receptor expressed on many types of phagocytes and is a promising target for anti-inflammatory therapeutics. We developed a lipid-tethered glycopolypeptide that spontaneously inserts into cell membranes and specifically binds Siglec-9 in cis on the surface of cells. We demonstrate that when inserted in a cell membrane and cis-binding, but not as a soluble trans-binding agent, this glycopolypeptide and agonizes Siglec-9, inhibiting inflammatory activity in reporter systems, phagocytic cell lines, and primary human macrophages. Thus, membrane-tethered cis-agonists of Siglec-9 are a new modality for therapeutic suppression of immune cell reactivity.