(175aq) Immunoengineered Therapeutic Platform for Selective Immune Cell Activation

Cytokines are a class of soluble proteins produced by immune cells that orchestrate essential physiological processes, in particular those relevant to the regulation of immunity and inflammation. Cytokine treatment has proven beneficial in the treatment of cancers, autoimmune disorders, and in regenerative medicine applications, with some cytokine treatments already clinically approved. However, high toxicity, short serum half-life, and lack of specificity limit the current clinical potential of cytokine treatments. Recent work has shown that complexing cytokines with anti-cytokine antibodies can increase the efficacy and reduce toxicity of the cytokine by both extending its in vivo half-life and selectively targeting its functions toward particular immune cell subsets. Although this approach is promising, clinical translation of these complexes is complicated by the need for optimization of dosing ratios and by the instability of the complex, as dissociation will lead to toxicity and rapid clearance of the free cytokine. To overcome these challenges, single-chain cytokine/antibody fusion proteins have been developed to improve the stability and efficacy of cytokine/antibody complexes. Here, we have leveraged insights from structural biology to engineer a single-chain fusion protein that tethers a human cytokine to an anti-cytokine antibody for selective expansion of specific immune cell subsets. We have also combined this technology with recent breakthroughs in the design of biodegradable T cell-activating nanoparticles known as artificial antigen presenting cells (aAPCs). Our innovative, off-the-shelf immunotherapeutic presents a versatile platform for selective immune activation, which can be used for a wide range of medical applications.