SBIR-STTR Award

This application seeks to develop a long-acting depot formulation for antibodies, using the inverse FlashNanoPrecipitation (iFNP) platform being commercialized by Optimeos Life Sciences. Microparticle depotformulations have been tested for decades to provide sustained release. The therapeutic is traditionallyentrapped in a water-insoluble polymer matrix, with release proceeding as the polymer degrades. The traditionalmicroparticle structure has significant limitations, including low therapeutic content and poor therapeutic stability.Consequently, there are currently no marketed microparticle depots for proteins. By contrast, the microparticlesproduced by Optimeos are formed by aggregating nanoparticles together to produce mechanically strongnanocomposite microparticles. The nanoparticles are produced by iFNP, a scalable and continuous process forencapsulating water-soluble compounds. The nanoparticle structure permits much higher loadings and forms aprotective shell that will limit antibody instability during extended release. The iFNP technology has been extensively studied for peptide delivery, with demonstrated therapeutic weightcontent in the depot up to 10 times higher than currently possible with existing methods, and controlled releaseprofiles ranging from 3 weeks to more than 3 months. The proposed research will extend the iFNP sustainedrelease technology from peptides to proteins. Three Tumor Necrosis Factor alpha (TNFα) antibody formats willbe evaluated to determine the scope of applicability of the technology. These constructs - a VHH single domainnanobody, a Fab fragment, and an IgG antibody - are of increasing complexity. This proposed study will enablethe translation of the iFNP technology to more complex biologics by addressing the key process risks - chemicaland structural instability of the encapsulated antibody during processing and release - through three aims: 1) Aim 1: Identify VHH microparticle formulations, produced using iFNP, with 20-40 wt% functional VHH. 2) Aim 2: Generate sustained release of active VHH over 1 and 3 months from microparticles, with weekly stability assessments indicating released VHH is > 90% native and functional. 3) Aim 3: Apply Aim 1 and Aim 2 findings to the encapsulation of Fab and IgG antibodies, producing sustained release over 1 and 3 months with released antibody > 90% native and functional. The performance of iFNP will be evaluated using VHH antibodies as an initial model because they are rapidlycleared following injection. Formulation design will build on the rules derived for peptide delivery using the iFNPprocess, produced under an STTR grant between Princeton University and Optimeos. Key stabilitymeasurements (ELISA, SEC, mass spectrometry) will be conducted via a collaboration with Integral Molecular.These results will be generalizable to other antibodies, allowing us to expand into the treatment of other diseasesrapidly. Crucially, sustained delivery of proteins other than antibodies could enable vaccine or enzymereplacement applications using the same formulation principles identified by the proposed work.

Public Health Relevance Statement:
This Phase I SBIR pioneers a new approach to injectable therapeutics that aims to reduce injection frequency from daily to quarterly for chronic diseases. The proposed formulation strategy addresses key limitations in current technologies, including inefficient processing and therapeutic instability. Initially using rheumatoid arthritis therapies as model compounds, this work could be used to improve dosing schedules for a range of injectable therapeutics, including vaccines and enzyme replacement therapies.

Project Terms:
Antibodies ; Architecture ; Engineering / Architecture ; Arthritis ; arthritic ; Rheumatoid Arthritis ; Atrophic Arthritis ; rheumatic arthritis ; beta-Galactosidase ; beta-D-Galactosidase ; beta-D-Galactoside galactohydrolase ; lac Z Protein ; β-D-Galactosidase ; β-D-Galactoside galactohydrolase ; β-Galactosidase ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Biological Products ; Biologic Products ; Biological Agent ; biopharmaceutical ; biotherapeutic agent ; Biological Sciences ; Biologic Sciences ; Bioscience ; Life Sciences ; Biophysics ; biophysical foundation ; biophysical principles ; biophysical sciences ; Chronic Disease ; Chronic Illness ; chronic disorder ; Disease ; Disorder ; Emulsions ; Enzyme-Linked Immunosorbent Assay ; ELISA ; Enzymes ; Enzyme Gene ; Exhibits ; Goals ; Grant ; Horseradish Peroxidase ; Immunoglobulin G ; 7S Gamma Globulin ; IgG ; Immunoglobulin Fragments ; Antibody Fragments ; Fab Immunoglobulins ; Antigen Binding Fragment ; Fab Fragments ; Immunoglobulin, F(ab) Fragment ; Methods ; Muramidase ; Lysozyme ; N-Acetylmuramide Glycanhydrolase ; Peptidoglycan N-acetylmuramoylhydrolase ; Office Visits ; physician office visit ; Legal patent ; Patents ; Patients ; Peptides ; Polymers ; Production ; Proteins ; Research ; Risk ; Messenger RNA ; mRNA ; Mass Spectrum Analysis ; Mass Photometry/Spectrum Analysis ; Mass Spectrometry ; Mass Spectroscopy ; Mass Spectrum ; Mass Spectrum Analyses ; Technology ; Testing ; Time ; Translations ; Universities ; Vaccines ; Water ; Hydrogen Oxide ; Weight ; Work ; Beta Carotene ; Betacarotene ; Solatene ; beta,beta-Carotene ; β-Carotene ; Injectable ; Schedule ; Pore Proteins ; improved ; Chronic ; Encapsulated ; Phase ; Biological ; Chemical Structure ; Serum ; Blood Serum ; insight ; Measurement ; Funding ; Collaborations ; Therapeutic ; mechanical ; Mechanics ; Hour ; Frequencies ; Complex ; chemical stability ; experience ; Performance ; success ; bioresorbable polymer ; degradable polymer ; biodegradable polymer ; Protein Replacement Therapy ; enzyme replacement therapy ; Hydrophobicity ; Structure ; expectation ; disorder model ; Disease model ; (TNF)-α ; Cachectin ; Macrophage-Derived TNF ; Monocyte-Derived TNF ; TNF ; TNF A ; TNF Alpha ; TNF-α ; TNFA ; TNFα ; Tumor Necrosis Factor ; Tumor Necrosis Factor-alpha ; TNF gene ; controlled release ; Modeling ; arthritis therapy ; Pharmaceutical Agent ; Pharmaceuticals ; Pharmacological Substance ; Pharmacologic Substance ; small molecule ; Address ; Dose ; liraglutide ; Bolus ; Bolus Infusion ; Data ; in vivo ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Small Business Technology Transfer Research ; STTR ; Monitor ; Molecular ; Process ; Development ; developmental ; nanocomposite ; nano composite ; design ; designing ; novel strategies ; new approaches ; novel approaches ; novel strategy ; nanoparticle ; nano particle ; nano-sized particle ; nanosized particle ; innovation ; innovate ; innovative ; Therapeutic antibodies ; commercialization ; nanobodies ; nanobody ; sdAb ; single domain antibodies ; Formulation ; peptide drug ; therapeutic peptide ; Injections ; lipid nanoparticle ; RNA delivery ;