Project Summary: Polyethylene glycol (PEG) is routinely used in protein and nanoparticle therapeutics, with dozens of PEGylated drugs approved to date. Although PEG itself is exceptionally safe, patients can form high titers of anti-PEG antibodies (APA) to some PEGylated drugs. This results not only in loss of efficacy from APA- induced rapid clearance of the drug, but also increases the risks of severe allergic responses, as exemplified by adverse clinical experiences with Krystexxa, Oncaspar and Palynziq that leave tens of thousands of Americans without viable treatments. Furthermore, APA induced by one drug can impact the efficacy and safety of a second PEGylated drug. Given the increasing number of PEGylated drugs on the market (including COVID-19 mRNA vaccines), there is an urgent need for safe and effective interventions that prevent APA induction and PEG-allergy. Mucommune has in-licensed a technology that can safely and effectively overcome the impact of APA on PEGylated medicines, without the need for broad immunosuppression or new polymers to replace PEG. The technology is based on the use of high MW free PEG to competitively saturate circulating APA and B-cell receptors on the surface of APA+ B-cells, thereby limiting the “hapten” effect of PEG-drugs. In published and pilot studies, free PEG markedly suppresses APA-induction against PEG-liposomes and Krystexxa (PEG- uricase) in immunocompetent mice and swine, and effectively restored the prolonged circulation of both in animals with high APA titers. Importantly, repeated injection of free PEG does not simulate further APA induction, unlike PEG-proteins or PEG-liposomes. Perhaps most surprisingly, free PEG completely eliminated hypersensitive reactions to PEG-liposomes in swine (the gold standard model for PEG-induced pseudoallergy). Swine receiving PEG-liposomes alone experienced strong anaphylaxis requiring immediate epinephrine intervention and resuscitation. These findings strongly underscore the promise of using free PEG to overcome allergic response to PEGylated medicines and to restore their efficacious use. Free PEG is inexpensive (pennies per dose), offers outstanding safety, and can be rapidly advanced into late stage clinical studies. Our overarching goal in this Phase 1 SBIR proposal is to establish the foundation to quickly advance this intervention into the clinic. We will file a pre-IND (Type B) application with the FDA to confirm the suitability of our proposed preclinical and clinical pathway, and will develop and qualify key assays for quantifying APA and free PEG necessary to support GLP and future clinical studies. We will then execute a GLP tox study in rats (a common model for PEG-drugs) to support first-in-human studies. Successful completion of these activities will allow us to file IND for MM010, putting us at the doorstep of advancing this intervention into the clinic, potentially providing relief for the tens of thousands of Americans suffering from respons...