title: Therapeutic intradermal delivery of tumor necrosis factor-alpha antibodies using tip-loaded dissolvable microneedle arrays.
abstract: Tumor necrosis factor-alpha (TNF-α) specific antibodies (anti-TNF-α Ab) have been shown to be potent TNF inhibitors and effective therapeutics for a range of inflammatory diseases. Typically, these drugs are administered systemically, but systemic dosing sufficient to achieve locally effective concentrations in peripheral tissues has been associated with systemic immunosuppression and related adverse events. Here, we evaluated the use of tip-loaded dissolvable microneedle arrays (MNAs) for localized intradermal delivery of anti-TNF-α Ab. MNAs with obelisk shape microneedles that incorporate the antibody cargo in the needle tips were created from carboxymethylcellulose (CMC) using a micromilling/spin-casting fabrication method. We found that anti-TNF-α Ab integrated into MNAs using this room temperature fabrication process maintained conformationally dependent TNF-α binding activity. Further, these MNAs efficiently delivered anti-TNF-α antibodies to the dermis of human skin with clinically applicable release profiles. To evaluate MNA delivered anti-TNF-α Ab function, we applied anti-TNF-α Ab containing MNAs to established psoriasiform lesions on the skin of mice. MNA anti-TNF-α Ab treatment reduced key biomarkers of psoriasiform inflammation including epidermal thickness and IL-1β expression. Taken together, these results demonstrate efficient and biologically effective MNA delivery of anti-TNF-α Ab to the intradermal microenvironment of the skin in mice and humans, and support the development of MNA mediated antibody delivery for clinical applications.
  
  
  CONCLUSIONS
  Tumor necrosis factor-alpha (TNF-α) specific antibodies (anti-TNF-α Ab) have been shown to be potent TNF inhibitors and effective therapeutics for a range of inflammatory diseases. Typically, these drugs are administered systemically, but systemic dosing sufficient to achieve locally effective concentrations in peripheral tissues has been associated with systemic immunosuppression and related adverse events. Here we demonstrate efficient and biologically effective MNA delivery of anti-TNF-α Ab to the intradermal microenvironment of the skin in mice and humans. These results support the development of MNA mediated antibody delivery of therapeutic antibodies for clinical applications.
authors.affiliation: Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, PA, United States.
authors.forename: Emrullah
authors.initials: E
authors.lastname: Korkmaz
authors.affiliation: Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, United States.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Friedrich
authors.affiliation: Department of Chemistry, Carnegie Mellon University, Pittsburgh, PA, United States.
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Ramadan
authors.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
authors.forename: Geza
authors.initials: G
authors.lastname: Erdos
authors.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
authors.forename: Alicia R
authors.initials: AR
authors.lastname: Mathers
authors.affiliation: Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, PA, United States; Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, United States; Department of Material Science and Engineering, Carnegie Mellon University, Pittsburgh, PA, United States.
authors.forename: O
authors.initials: O
authors.lastname: Burak Ozdoganlar
authors.affiliation: Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, United States; Department of Chemistry, Carnegie Mellon University, Pittsburgh, PA, United States; The McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
authors.forename: Newell R
authors.initials: NR
authors.lastname: Washburn
authors.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States; Clinical and Translational Science Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; The University of Pittsburgh Cancer Institute, Pittsburgh, PA, United States; The McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States. Electronic address: lof2@pitt.edu.
authors.forename: Louis D
authors.initials: LD
authors.lastname: Falo
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007271:Injections, Intradermal / Q000295:instrumentation / Q000379:methods; D053583:Interleukin-1beta / Q000096:biosynthesis; D051379:Mice; D009339:Needles; D011565:Psoriasis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000906:Antibodies; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha
keywords: Dissolvable microneedle arrays; Intradermal delivery; Therapeutic antibody; Tumor necrosis factor-alpha