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Principal Investigator: Keiichiro Kushiro
Organization: MUCOMMUNE, LLC
Fiscal Year: 2024
Award: $291,458
Funding agency: National Institute of Allergy and Infectious Diseases
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 responses to PEG-drugs that limit their use of essential treatments.
Terms: <Acceleration><Adrenaline><Allergic Reaction><Allergy><American><Anaphylactic Reaction><Anaphylactic Shock><Anaphylaxis><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antibody Response><Antibody titer measurement><Assay><B blood cells><B cell><B cell receptor><B cells><B-Cell Antigen Receptor><B-Cells><B-Lymphocytes><B-cell><Binding><Bioassay><Biological><Biological Assay><Blood Plasma><Buffers><COVID-19><CV-19><Case Study><Circulation><Clinic><Clinical><Clinical Paths><Clinical Pathways><Clinical Research><Clinical Study><Clinical Trials><Common Rat Strains><Coronavirus Infectious Disease 2019><Data><Development><Dose><Drug Kinetics><Drugs><ELISA><Early-Stage Clinical Trials><Emergencies><Emergency Situation><Ensure><Enzyme-Linked Immunosorbent Assay><Epinephrine><Evaluation><Family suidae><Feedback><Formulation><Foundations><Future><Goals><Government><HPLC><Haptens><High Performance Liquid Chromatography><High Pressure Liquid Chromatography><High Speed Liquid Chromatography><Human><Hypersensitivity><Immunochemical Immunologic><Immunocompetent><Immunologic><Immunological><Immunologically><Immunologics><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Individual><Infusion><Infusion procedures><Injections><Intervention><Intervention Strategies><Licensing><Lipids><Liposomal><Liposomes><Macrogols><Marketing><Measures><Mediating><Medication><Medicine><Methods><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Murine><Mus><NOAEL><No-Observed-Adverse-Effect Level><Oncaspar><Outcome><PEG-Asparaginase><PEGLA><Pathway interactions><Patients><Pegaspargase><Persons><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacokinetics><Pharmacologic Substance><Pharmacological Substance><Phase><Phase 1 Clinical Trials><Phase I Clinical Trials><Pigs><Pilot Projects><Plasma><Plasma Serum><Polyethylene Glycols><Polyethylene Oxide><Polyethyleneoxide><Polymers><Polyoxyethylenes><Production><Proteins><Publishing><Qualifying><RNA vaccine><RNA-based vaccine><Rat><Rats Mammals><Rattus><Reaction><Recovery><Reporting><Research><Research Design><Research Specimen><Resuscitation><Reticuloendothelial System, Serum, Plasma><Risk><Runaway><SBIR><Safety><Sampling><Small Business Innovation Research><Small Business Innovation Research Grant><Specimen><Sprague-Dawley Rats><Standard Model><Study Type><Suidae><Surface><Swine><Technology><Therapeutic Epinephrine><Time><Toxic effect><Toxicities><Toxicokinetics><Toxicology><Urine><Work><allergen response><allergic response><allergy response><antibody titering><assay development><biologic><case report><clinical development><clinical lot><clinical translation><clinically translatable><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><cost><cost effective><design><designing><developmental><drug clearance><drug lot production><drug/agent><effective intervention><enzyme linked immunoassay><experience><first in man><first-in-human><immune competent><immune suppression><immune suppressive activity><immune suppressive function><immunosuppressive activity><immunosuppressive function><immunosuppressive response><infusions><interventional strategy><lot production><mRNA vaccine><mRNA-based vaccine><model of animal><nano medicinal><nano medicine><nanomedicinal><nanomedicine><nanoparticle therapy><pathway><pharmaceutical><phase I protocol><pig model><piglet model><pilot study><polymer><polymeric><porcine><porcine model><pre-clinical><preclinical><prevent><preventing><response><risk mitigation><study design><suid><swine model><therapeutic nanoparticles>