Development of MM010, a PEG-specific intervention that blocks allergic response and restores effective repeat dosing of peg-asparaginase in patients with acute lymphoblastic leukemia

Project Summary Acute lymphoblastic leukemia (ALL) accounts for ~80% of all pediatric leukemia and ~20% of all adult leukemia. Since lymphocytes cannot synthesize their own asparagine, the frontline therapy for ALL includes PEG-asparaginase (PEG-ASNase; Oncaspar® and PEG), and sustained suppression of asparagine in the circulation is critical for achieving long-term remission. Unfortunately, up to half of the treated patients develop anti-PEG antibodies (APA) that specifically bind the polyethylene glycol (PEG) polymer on PEG- ASNase. The resulting immune complexes are quickly eliminated from the circulation leading to loss of efficacy, and also directly results in high rates of hypersensitivity reactions, including anaphylaxis. Currently, these immune responses force PEG-allergic patients to switch to non-PEGylated versions of ASNase that require dosing every 2 days (in contrast to every 2-3 weeks for ASNase), substantial rates of allergic reaction (since the underlying ASNase is also immunogenic), and overall nearly 100% increase in medical care costs. To overcome APA-related challenges, Mucommune has been advancing MM010, an adjunctive therapy consisting of high-molecular-weight free PEG that targets APA specifically. MM010 takes advantage of the fact that PEG alone is largely immunogenic and unable to efficiently crosslink B cell receptors on APA+ B cells, in contrast to large PEGylated proteins or PEG-coated drug carriers that potently induce APA. Free PEG can saturate and competitively inhibit pre-existing APA from binding PEGylated drugs, thereby restoring prolonged circulation. In animal models ranging from rodents to pigs, MM010 has reliably suppressed APA induction, restore drug circulation, and eliminate severe allergic reactions, making it a promising solution to enhance the safety and efficacy of PEG-ASNase. Building off these promising findings, we are seeking to extend the use of MM010 to improve the clinical management of ALL. Specifically, we will investigate whether MM010 can effectively block APA induction and restore prolonged circulation (pharmacokinetics) and suppress asparagine levels (pharmacodynamics) for PEG-ASNase in rodents repeatedly infused with Oncaspar (Aim 1A), as well as prevent Oncaspar-induced anaphylaxis in the highly sensitive swine model (Aim 1B). We will in parallel file a pre-IND package with the FDA to gain regulatory clarity on the clinical development pathway (Aim 2A), and initiate stability studies of vialed, clinical grade MM-010 (Aim 2B). Successful completion of this project will provide the foundation for rapidly advancing MM010 as an adjuvant to improve the efficacy and safety of PEG- ASNase based treatment for all ALL patients.