Uveitis is a group of diseases characterized by sight-threatening intraocular inflammation and responsible forroughly 5-10% of blindness cases worldwide. Uveitis flare-ups can be caused by either an active infection or, inin the case of non-infectious uveitis (NIU), a dysregulated immune response including altered cytokineexpression and processing. Thus, there is an urgent and unmet need for more effective treatments. Thestandard first line therapies for chronic NIU are corticosteroids delivered either topically, systemically, or locallythrough intravitreal injections or implants. However, long-term use of these treatments is associated withserious side effects. Alternative anti-inflammatory therapeutics are often used to minimize these side-effectsand inhibition of the pro-inflammatory cytokine, TNFα has become a key approach. Systemic delivery of TNFαinhibitors is effective but costly and carries a risk of side-effects from long-term use. Valitor, Inc. is developingprotein-polymer therapeutics to overcome the vision-threatening effects of chronic ocular inflammation withsubstantially fewer systemic side effects by enabling intravitreal delivery of a biologic anti-TNFα therapy. Wehave conjugated single-domain anti-TNFα antibodies (VHH) to linear chains of the natural biopolymerhyaluronic acid to generate multivalent anti-TNFα conjugates (Anti-TNFα MVP) that are substantially largerthan any other drugs currently delivered by intravitreal injection. In our previous studies, we verified that thelarge sizes of our MVPs are sufficient to substantially reduce their clearance rate out of the vitreous, therebyproviding a sustained treatment effect to inhibit intraocular TNFα. Thus, our strategy for sustained anti-TNFαtherapy has the potential to improve the long-term efficacy, safety, and cost efficacy of anti-TNFα treatment.The overall objective of this Phase I SBIR project is to verify that our Anti-TNFα MVPs exhibit a rapid onsetand durable anti-inflammatory treatment for chronic non-infections uveitis. In Specific Aim #1, we will evaluatethe ability of an Anti-TNFα MVP to generate a rapid anti-inflammatory response compared to that of acorticosteroid. In Specific Aim #2, we will verify the anti-inflammatory durability of our Anti-TNFα MVP to that ofa clinically available TNFα inhibitor. The results of this project will be used to continue the development of ourAnti-TNFα MVP drug product and contribute to a productive pre-IND meeting to confirm the additional testingthat required for our IND submission.
Public Health Relevance Statement: Relevance
Uveitis is a group of sight-threatening intraocular inflammation diseases that is responsible for roughly 5-10%
of blindness cases worldwide. Treatment of chronic uveitis typically requires long-term steroid administration,
which is associated with significant adverse effects. Valitor, Inc. is developing an improved biotechnology
product that will enable the use of anti-TNFα biologics as a steroid-sparing treatment strategy to improve the
long-term efficacy outcomes and reduce the overall adverse event rate.
Project Terms: Adverse effects ; D2E7 antibody ; adalimumab ; Inflammatory Response ; Molecular Interaction ; Binding ; Dose ; Affinity ; Data ; Preclinical Models ; Pre-Clinical Model ; Systemic Therapy ; SYS-TX ; Antiinflammatory Effect ; anti-inflammatory effect ; Flare ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Characteristics ; Therapeutic Effect ; Development ; developmental ; intravitreal injection ; Output ; cost ; pharmacokinetic model ; design ; designing ; uveoretinitis ; Affective ; treatment effect ; Implant ; treatment strategy ; effective therapy ; effective treatment ; clinical risk ; Formulation ; side effect ; off-label use ; off-label application ; off-label prescribing ; efficacy outcomes ; Autoimmune ; nerve damage ; Adrenal Cortex Hormones ; Corticoids ; Corticosteroids ; Affect ; Aftercare ; After Care ; After-Treatment ; post treatment ; Anti-Inflammatory Agents ; Anti-Inflammatories ; Anti-inflammatory ; Antiinflammatories ; Antiinflammatory Agents ; antiinflammatory ; Antibodies ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Biological Response Modifier Therapy ; Biologic Therapy ; Biological Therapy ; biological therapeutic ; biological treatment ; biotherapeutics ; biotherapy ; Biopolymers ; Biotechnology ; Biotech ; Cells ; Cell Body ; Dexamethasone ; Disease ; Disorder ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Endotoxins ; Exhibits ; Eye ; Eyeball ; Eye diseases ; eye disorder ; ophthalmopathy ; Hyaluronic Acid ; Infection ; Inflammation ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Long-Term Effects ; Longterm Effects ; Metabolic Clearance Rate ; clearance rate ; Molecular Weight ; Optic Nerve ; Cranial Nerve II ; Second Cranial Nerve ; Optics ; optical ; Legal patent ; Patents ; Patients ; Polymers ; Privatization ; Proteins ; Oryctolagus cuniculus ; Domestic Rabbit ; Rabbits ; Rabbits Mammals ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Retina ; Risk ; Safety ; Vertebral column ; Spinal Column ; Spine ; backbone ; Steroids ; Steroid Compound ; Technology ; Testing ; Time ; Tissues ; Body Tissues ; Uveitis ; Vision ; Sight ; visual function ; cytokine ; Measures ; tumor necrosis factor-alpha inhibitor ; TNF-alpha inhibitor ; TNF-α inhibitor ; TNFα inhibitor ; Experimental Models ; Apoptosis ; Apoptosis Pathway ; Programmed Cell Death ; base ; macromolecule ; improved ; Acute ; Chronic ; Clinical ; Phase ; Biological ; residence ; residential building ; residential site ; Immunological response ; host response ; immune system response ; immunoresponse ; Immune response ; Therapeutic ; Inflammatory ; scaffolding ; scaffold ; Frequencies ; Immunes ; Immune ; Event ; Treatment Period ; treatment days ; treatment duration ; vision loss ; visual loss ; Blindness ; meetings ; American ; Performance ; Histopathology ; novel ; (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 ; Modeling ; Adverse Experience ; Adverse event ;
