148 : Modulation of cytokine activity through advanced polymer conjugation

Abstract

Cytokines have proven to be effective therapies in multiple indications including those in oncology, inflammation, and immunology. Modification of cytokines for therapeutic use by covalent attachment of a polymer such as polyethylene glycol (PEG) has been used to reduce the renal clearance rate and therefore extend exposure. The next generation of polymer conjugation technology enables more complex and profound modification of cytokine activity. With a deeper understanding of the effect polymer size and architecture have on biodistribution, coupled to the development of polymer-protein linkers with differing site-selectivity and variable release rates, the therapeutic potential of cytokines can be significantly enhanced through polymer conjugation. The engineered cytokine NKTR-214 is a multi-PEGylated form of IL-2 with greatly improved efficacy in pre-clinical tumor models relative to IL-2. The polymer conjugation strategy was designed to improve efficacy and safety by optimizing localization to the tumor, by enhancing the PK profile through reduced Cmax and increased exposure, and by altering the receptor binding profile to enhance tumor killing, without any changes to the amino-acid sequence. We present in vitro and in vivo data demonstrating the achievement of these objectives, and discuss how this approach may be generalized to enhance other cytokine-based therapies.