James A. Matriano

Macroflux Microprojection Array Patch Technology: A New and Efficient Approach for Intracutaneous Immunization

AbstractPurpose. We evaluated the Macroflux® microprojection array patch technology as a novel system for intracutaneous delivery of protein antigens. Methods. Macroflux® microprojection array systems (330-μm microprojection length, 190 microprojections/cm2, 1- and 2-cm2 area) were coated with a model protein antigen, ovalbumin (OVA), to produce a dry-film coating. After system application, microprojection penetration depth, OVA delivery, and comparative immune responses were evaluated in a hairless guinea pig model. Results. Macroflux® microprojections penetrated into hairless guinea pig skin at an average depth of 100 μm with no projections deeper than 300 μm. Doses of 1 to 80 μg of OVA were delivered via 1- or 2-cm2 systems by varying the coating solution concentration and wearing time. Delivery rates were as high as 20 μg in 5 s. In a prime and boost dose immune response study, OVA-coated Macroflux® was most comparable to equivalent doses injected intradermally. Higher antibody titers were observed when OVA was administered with the microprojection array or intradermally at low doses (1 and 5 μg). Macroflux® administration at 1- and 5-μg doses gave immune responses up to 50-fold greater than that observed after the same subcutaneous or intramuscular dose. Dry coating an adjuvant, glucosaminyl muramyl dipeptide, with OVA on the Macroflux® resulted in augmented antibody responses. Conclusions. Macroflux® skin patch technology provides rapid and reproducible intracutaneous administration of dry-coated antigen. The depth of skin penetration targets skin immune cells; the quantity of antigen delivered can be controlled by formulation, patch wearing time, and system size. This novel needle-free patch technology may ultimately have broad applications for a wide variety of therapeutic vaccines to improve efficacy and convenience of use.

Effect of Transdermal Teriparatide Administration on Bone Mineral Density in Postmenopausal Women

CONTEXT Treatment of osteoporosis with an anabolic agent, teriparatide [human PTH 1-34 (TPTD)], is effective in reducing incident fractures, but patient resistance to daily sc injections has limited its use. A novel transdermal patch, providing a rapid, pulse delivery of TPTD, may provide a desirable alternative. OBJECTIVE The aim of the study was to determine the safety and efficacy of a novel transdermal TPTD patch compared to placebo patch and sc TPTD 20-microg injection in postmenopausal women with osteoporosis. DESIGN Our study consisted of 6-month, randomized, placebo-controlled, positive control, multidose daily administration. PATIENTS We enrolled 165 postmenopausal women (mean age, 64 yr) with osteoporosis. INTERVENTIONS A TPTD patch with a 20-, 30-, or 40-microg dose or a placebo patch was self-administered daily for 30-min wear time, or 20 microg of TPTD was injected daily. OUTCOMES The primary efficacy measure was mean percentage change in lumbar spine bone mineral density (BMD) from baseline at 6 months. RESULTS TPTD delivered by transdermal patch significantly increased lumbar spine BMD vs. placebo patch in a dose-dependent manner at 6 months (P < 0.001). TPTD 40-microg patch increased total hip BMD compared to both placebo patch and TPTD injection (P < 0.05). Bone turnover markers (procollagen type I N-terminal propeptide and C-terminal cross-linked telopeptide of type I collagen) increased from baseline in a dose-dependent manner in all treatment groups and were all significantly different from placebo patch (P < 0.001). All treatments were well tolerated, and no prolonged hypercalcemia was observed. CONCLUSION Transdermal patch delivery of TPTD in postmenopausal women with osteoporosis for 6 months is safe and effective in increasing lumbar spine and total hip BMD.

B cells engineered to express Fas ligand suppress pre-sensitized antigen-specific T cell responses in vivo.

Inducing apoptosis of activated lymphocytes via Fas ligand (FasL, CD95) may be a useful strategy for the treatment of autoimmune diseases mediated by pathogenic T cells. We propose that B cells may be ideal tools for effective delivery of a FasL‐mediated apoptotic signal to pathogenic T cells for a variety of reasons, including their unique ability to efficiently take up and present antigen to T cells that share the same specificity. Here, we demonstrate that B cell clones engineered to express CD95 can effectively suppress a systemic primed antigen‐specific T cell response in vivo. Intravenous injection of antigen‐pulsed FasL‐expressing B cells eliminated antigen‐specific (TCR transgenic) T cells from the draining lymph nodes within 12–60 h, and suppressed a delayed‐type hypersensitivity response in an antigen‐specific manner. These results indicate that B cells can be engineered to express FasL, and used to impair T cell function in vivo, suggesting that FasL‐expressing B cells may be an effective tool for the treatment of established T cell‐mediated autoimmune and inflammatory diseases.