Topical Delivery of Nivolumab, a Therapeutic Antibody, by Fractional Laser and Pneumatic Injection

Abstract

Background and Objectives PD‐L1 is a tumor ligand that binds to the PD‐1 receptor on immune cells, thereby inhibiting the antitumor immune response. The antibody nivolumab is a PD‐1 inhibitor, Food and Drug Administration approved for systemic treatment of several aggressive cancer types. Topically applied nivolumab may hold potential as a future strategy to treat keratinocyte cancer, but its molecular properties preclude unassisted topical uptake. The aim of this study was to investigate uptake and biodistribution of topically delivered nivolumab, assisted by two physical enhancement techniques with different delivery kinetics; ablative fractional laser (AFL) and electronically controlled pneumatic injection (EPI). Study Design/Materials and Methods In vitro porcine skin was exposed to CO2 AFL (20 mJ/mb, 5% density), followed by passive diffusion of nivolumab in a Franz cell (1 mg/ml, 18 hours, n = 6) or treated with EPI (4 bar) for immediate delivery of nivolumab (1 mg/ml, 10 minutes, n = 6). The resulting nivolumab skin concentrations were quantified by enzyme‐linked immunosorbent assay (ELISA) at three skin depths (100, 500, and 1500 µm), comparing the uptake from assisted delivery with intact skin. Biodistribution of nivolumab in the skin for all interventions was visualized by laser ablation‐inductively coupled plasma‐mass spectrometry (LA‐ICP‐MS) and fluorescence microscopy. Results Delivery of nivolumab by AFL‐assisted passive diffusion and immediate EPI both resulted in significantly enhanced uptake of nivolumab in all skin depths compared with intact skin (P < 0.05). With AFL, nivolumab concentrations reached 86.3 µg/cm3 (100 µm), 105.8 µg/cm3 (500 µm), and 19.3 µg/cm3 (1500 µm), corresponding to 2–10% of the applied concentration, with the highest deposition in the mid dermis. Immediate EPI delivered 429.4 µg/cm3 (100 µm), 584.9 µg/cm3 (500 µm), and 295.9 µg/cm3 (1500 µm) into the skin, corresponding to 29–58% of the applied nivolumab concentration. From qualitative visualization of the biodistribution, it appeared that nivolumab distributed in a horizontal and continuous homogenous band in the upper and mid dermis through AFL‐exposed skin, whereas EPI‐delivery showed a deep focal deposition extending into the deep dermis. Conclusions AFL‐assisted passive diffusion and immediate EPI‐assisted delivery show the potential to deliver therapeutic antibodies locally. Future in vivo and pharmacokinetic studies would reveal the full potential for topical antibody delivery by energy‐based devices. Lasers Surg. Med. © 2020 Wiley Periodicals LLC

Topical delivery of PD‐1 inhibitors with laser‐assisted passive diffusion and active intradermal injection: Investigation of cutaneous pharmacokinetics and biodistribution patterns

“…1 Nivolumab and cemiplimab are both human monoclonal immunoglobulin G4 antibodies, where nivolumab is widely studied, including in our previous study. 6 Immunotherapeutic anti-PD-1 antibodies like nivolumab are administered systemically by intravenous infusion, either in flat dosing regimen (240 mg once every 2 weeks [Q2W] or 480 mg Q4W) or by mg/kg body weight dosing (3 mg/kg Q2W), 7 which gives a serum concentration in the range of 50-100 µg/ml. 7,8 Common side effects following the systemic administration of the PD-1 inhibitors are nausea, fatigue or skin-and gastrointestinal-related, 9 while more severe adverse events are, for example, diabetes mellitus type 1, hepatitis, or acute allograft rejection.…”

“…Active intradermal injection could either be needle injection or using an energy-based device. 6 AFL-assisted passive diffusion has provided delivery of several drugs locally into dermal layers. Physiochemical properties of the drugs such as molecular weight, polarity, and Log P are factors that will determine their ability to penetrate the skin.…”

Laser Immunotherapy: A Potential Treatment Modality for Keratinocyte Carcinoma

“…Indeed, strong evidence already supports the use of laser assisted drug delivery for SCC precursors such as actinic keratosis and Bowens disease [ 73 ]. In this paper’s context, it is worth noting that successful in vitro, topical delivery of the PD1 inhibitor nivolumab was recently published [ 74 ], providing further support of the feasibility of topical AFL-based LIT in the treatment of KC.…”

The Influence of Different Anti-PD-1 Monoclonal Antibody Concentrations On T Cell Activation in in - Vitro Culture – A Preliminary Study

“…Despite the higher effectiveness of immunotherapy in lung cancer treatment, several speci c side effects indicate the need for optimizing the drug dose 32 . The failure of dependence in drug-response correlation for nivolumab treatment suggests a necessity to improve the methods of nivolumab use in clinical practice, e.g., in combination with other ICIs 7,25,31,33,34 . Seldom-distributed higher doses of nivolumab might be more convenient for cancer-bearing patients, especially during a pandemic of SARS Covid-19.…”