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.
Highlights
Plaque psoriasis is an autoimmune skin condition, affecting approximately 25 million people in North America and Europe[1]
A range of biopharmaceuticals such as monoclonal antibodies or fusion proteins targeting the chemokines implicated in psoriasis pathogenesis have reached the market[6]
An optimal therapeutic agent for psoriasis should be (i) effective in plaque clearing and improving PASI scores (PASI: Psoriasis Area and Severity Index, a diagnostic tool used for the measurement of severity of psoriasis), (ii) preferably administered by the topical route to minimize systemic side-effects and (iii) interact selectively with molecular targets implicated in the deregulated skin immune response
Summary
Plaque psoriasis is an autoimmune skin condition, affecting approximately 25 million people in North America and Europe[1]. Biopharmaceutical therapies are promising because of their selective binding to receptors implicated in the immune response; their invasive parenteral administration and distribution throughout the whole organism may lead to serious side effects such as anaphylaxis[10] or even unpredictable life-threatening “cytokine storms”[11]. They are currently only indicated for severe disease states. The authors suggested that DLX 105 could penetrate into the epidermis via the impaired barrier of the lesion, but could not reach the dermis in sufficient amounts to provoke a clinically meaningful result – leading to the conclusion that: “increasing drug concentration in the dermis by biological, chemical or physical methods and, maybe, the development of a more potent follow-on TNF-α blocker might result in improved clinical efficacy”[12]
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