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Principal Investigator: Chester Edward Markwalter
Organization: OPTIMEOS LIFE SCIENCES, INC.
Fiscal Year: 2021
Award: $255,351
Funding agency: National Institute of General Medical Sciences
This application seeks to develop a long-acting depot formulation for antibodies, using the inverse Flash
NanoPrecipitation (iFNP) platform being commercialized by Optimeos Life Sciences. Microparticle depot
formulations have been tested for decades to provide sustained release. The therapeutic is traditionally
entrapped in a water-insoluble polymer matrix, with release proceeding as the polymer degrades. The traditional
microparticle 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 microparticles
produced by Optimeos are formed by aggregating nanoparticles together to produce mechanically strong
nanocomposite microparticles. The nanoparticles are produced by iFNP, a scalable and continuous process for
encapsulating water-soluble compounds. The nanoparticle structure permits much higher loadings and forms a
protective shell that will limit antibody instability during extended release.
The iFNP technology has been extensively studied for peptide delivery, with demonstrated therapeutic weight
content in the depot up to 10 times higher than currently possible with existing methods, and controlled release
profiles ranging from 3 weeks to more than 3 months. The proposed research will extend the iFNP sustained
release technology from peptides to proteins. Three Tumor Necrosis Factor alpha (TNFα) antibody formats will
be evaluated to determine the scope of applicability of the technology. These constructs – a VHH single domain
nanobody, a Fab fragment, and an IgG antibody – are of increasing complexity. This proposed study will enable
the translation of the iFNP technology to more complex biologics by addressing the key process risks – chemical
and 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 rapidly
cleared following injection. Formulation design will build on the rules derived for peptide delivery using the iFNP
process, produced under an STTR grant between Princeton University and Optimeos. Key stability
measurements (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 diseases
rapidly. Crucially, sustained delivery of proteins other than antibodies could enable vaccine or enzyme
replacement applications using the same formulation principles identified by the proposed work.
Terms: <(TNF)-α><7S Gamma Globulin><Address><Antibodies><Antibody Fragments><Antigen Binding Fragment><Architecture><Arthritis><Assay><Atrophic Arthritis><Beta Carotene><Betacarotene><Bioassay><Biologic Assays><Biologic Products><Biologic Sciences><Biological><Biological Agent><Biological Assay><Biological Products><Biological Sciences><Biophysics><Bioscience><Blood Serum><Bolus><Bolus Infusion><Cachectin><Chemical Structure><Chronic><Chronic Disease><Chronic Illness><Collaborations><Complex><Data><Development><Disease><Disease model><Disorder><Dose><ELISA><Emulsions><Encapsulated><Engineering / Architecture><Enzyme Gene><Enzyme-Linked Immunosorbent Assay><Enzymes><Exhibits><Fab Fragments><Fab Immunoglobulins><Formulation><Frequencies><Funding><Goals><Grant><Horseradish Peroxidase><Hour><Hydrogen Oxide><Hydrophobicity><IgG><Immunoglobulin Fragments><Immunoglobulin G><Immunoglobulin, F(ab) Fragment><Injectable><Injections><Legal patent><Life Sciences><Lysozyme><Macrophage-Derived TNF><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measurement><Mechanics><Messenger RNA><Methods><Modeling><Molecular><Monitor><Monocyte-Derived TNF><Muramidase><N-Acetylmuramide Glycanhydrolase><Office Visits><Patents><Patients><Peptides><Peptidoglycan N-acetylmuramoylhydrolase><Performance><Pharmaceutical Agent><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Phase><Polymers><Pore Proteins><Process><Production><Protein Replacement Therapy><Proteins><RNA delivery><Research><Rheumatoid Arthritis><Risk><SBIR><STTR><Schedule><Serum><Small Business Innovation Research><Small Business Innovation Research Grant><Small Business Technology Transfer Research><Solatene><Structure><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Technology><Testing><Therapeutic><Therapeutic antibodies><Time><Translations><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Universities><Vaccines><Water><Weight><Work><arthritic><arthritis therapy><beta,beta-Carotene><beta-D-Galactosidase><beta-D-Galactoside galactohydrolase><beta-Galactosidase><biodegradable polymer><biopharmaceutical><biophysical foundation><biophysical principles><biophysical sciences><bioresorbable polymer><biotherapeutic agent><chemical stability><chronic disorder><commercialization><controlled release><degradable polymer><design><designing><developmental><disorder model><enzyme replacement therapy><expectation><experience><improved><in vivo><innovate><innovation><innovative><insight><lac Z Protein><lipid nanoparticle><liraglutide><mRNA><mechanical><nano composite><nano particle><nano-sized particle><nanobodies><nanobody><nanocomposite><nanoparticle><nanosized particle><new approaches><novel approaches><novel strategies><novel strategy><peptide drug><physician office visit><rheumatic arthritis><sdAb><single domain antibodies><small molecule><success><therapeutic peptide><β-Carotene><β-D-Galactosidase><β-D-Galactoside galactohydrolase><β-Galactosidase>