Fractional laser ablation for the targeted cutaneous delivery of an anti-CD29 monoclonal antibody – OS2966

Abstract

Monoclonal antibodies targeting cytokines are administered parenterally for the systemic treatment of severe psoriasis. However, systemic exposure to the biologic increases the risk of side-effects including immunosuppression, whereas only a small fraction of the active molecules actually reaches the target organ, the skin. This preclinical study examines the feasibility of delivering a humanized anti-CD29 monoclonal antibody (OS2966) topically to skin using minimally-invasive fractional laser ablation. This approach would enable the targeted use of a biologic for the treatment of recalcitrant psoriatic plaques in patients with less widespread disease while minimizing the risk of systemic exposure. First, the effect of a wide range of laser poration conditions on skin permeation and deposition of OS2966 was tested in vitro to determine optimal microporation parameters. Subsequently, confocal laser scanning microscopy was employed to visualize the distribution of fluorescently-labelled OS2966 in skin. The results demonstrated that delivery of OS2966 into and across skin was feasible. Above fluences of 35.1 J/cm2, skin deposition and permeation were statistically superior to passive delivery reaching values up to 3.7 ± 1.2 µg/cm2 at the most aggressive condition. Selective targeting of the skin was also possible since ≥70% of the OS2966 was delivered locally to the skin. Although nanogramme quantities were able to permeate across skin, these amounts were orders of magnitude lower than levels seen following subcutaneous or intravenous injection and would result in minimal systemic exposure in vivo. The diffusion of fluorescently-labelled OS2966 into the skin surrounding the pores was clearly higher than in intact skin and demonstrated the feasibility of delivering the antibody at least as deep as the dermo-epithelial junction, a critical border region where inflammatory cells cross to promote disease progression. These preliminary results confirm that fractional laser ablation can be used for the cutaneous delivery of OS2966 and now preclinical/clinical studies are required to demonstrate therapeutic efficacy.

Laser facilitates week-long sustained transdermal drug delivery at high doses

“…Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to quantify AZT levels as in our previous report [28]. In brief, patch extracts, skin surface washes, and AZT standards (5,20,50,100,200, 400 ng/ml) were mixed with 100 ng/ml AZTinternal standard (AZT-IS, 3'-azido-3'-deoxythymidine, MG103, Moravek Biochemicals, Brea, CA). A small amount of blood (~25 µl) was collected before delivery and at different times after delivery to measure serum AZT levels.…”

“…B. Powder SRB-coated reservoir patches were topically applied onto AFL-treated skin or intact skin of BALB/c mice followed by patch removal 3 days later. A small amount of blood was collected at different time points (3,6,9,12,16,20,26,32,36,42,48, 54, 60 and 72 hours) to quantify serum SRB levels. C. Lateral back skin of BALB/c mice was exposed to AFL (2.5 mJ/5%) followed by topical application of powder SRB-coated reservoir patches.…”

“…Patches were removed 6 days later. A small amount of blood (~25 µl) was collected before delivery and 1, 3,6,12,16,20,26,32,40,44,48,54,60,72,96,120, and 144 hours after delivery to measure serum AZT levels. B. BALB/c mice were subjected to AFL-assisted powder AZT delivery as in A. Patches were removed 7 days later.…”

“…AFL was also found to significantly enhance transdermal uptake of porphyrin precursors (methyl 5-aminolevulinate and 5'-aminolevulinic acid) and increase deep penetration of chemotherapy drugs (5-fluorouracil and cisplatin) in pig skin [16][17][18][19]. AFL was also utilized to enhance transdermal delivery of monoclonal antibodies, nanoparticles and microparticles [20][21][22]. Even living human cells could be efficiently delivered into AFL-treated epidermal and dermal tissues [23].…”

Stem Cells as a Target for the Delivery of Active Molecules to Skin by Topical Administration

“…The methods of active improvement of skin penetration, on the other hand, mainly involve the following mechanisms: abrasion of the stratum corneum [50][51][52][53], electroporation to generate transient aqueous pores in the lipid bilayers of the stratum corneum [54], ultrasound waves to interrupt lipid packaging in the stratum corneum [55,56] and the use of microneedle arrays to bypass the stratum corneum [54]. Here following a brief discussion of the enhancement methods that most involve skin stem cells as the final target for skin penetration.…”