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A novel elastin-like polypeptide drug carrier for cyclosporine A improves tear flow in a mouse model of Sjögren's syndrome

Author:
Guo, Hao, Lee, Changrim, Shah, Mihir, Janga, Srikanth R., Edman, Maria C., Klinngam, Wannita, Hamm-Alvarez, Sarah F., MacKay, J. Andrew
Source:
Journal of controlled release 2018 v.292 pp. 183-195
ISSN:
0168-3659
Subject:
adverse effects, animal models, bioavailability, cyclophilins, cyclosporine, drug carriers, drug toxicity, eye diseases, half life, humans, hydrophobicity, inhibitory concentration 50, interleukin-2, intravenous injection, macrolides, males, mice, molecular weight, nephrotoxicity, neurotoxicity, pharmacokinetics, polypeptides, protein synthesis, psoriasis, recombinant proteins, rheumatoid arthritis, signal transduction, solubility, subcutaneous injection, temperature, tropoelastin
Abstract:
As a potent macrolide immunosuppressant, cyclosporine A (CsA) is used to treat multiple autoimmune diseases, including non-autoimmune and autoimmune-mediated dry eye disease, rheumatoid arthritis and psoriasis. Despite its potency, CsA has poor solubility, poor bioavailability, and can cause serious adverse reactions such as nephrotoxicity and neurotoxicity. To overcome these limitations, we invented a new strategy to carry CsA by fusing its cognate human receptor, cyclophilin A (CypA), to a 73 kDa elastin-like polypeptide (ELP) termed A192 using recombinant protein expression. Derived from human tropoelastin, ELPs are characterized by the ability to phase separate above a temperature that is a function of variables including concentration, molecular weight, and hydrophobicity. The resultant fusion protein, termed CA192, which assembles into a dimeric species in solution, effectively binds and solubilizes CsA with a Kd of 189 nM, comparable to that of endogenous CypA with a Kd of 35.5 nM. The release profile of CsA from CA192 follows a one phase decay model with a half-life of 957.3 h without a burst release stage. Moreover, CA192-CsA inhibited IL-2 expression induced in Jurkat cells through the calcineurin-NFAT signaling pathway with an IC50 of 1.2 nM, comparable to that of free CsA with an IC50 of 0.5 nM. The intravenous pharmacokinetics of CA192 followed a two-compartment model with a mean residence time of 7.3 h. Subcutaneous administration revealed a bioavailability of 30% and a mean residence time of 15.9 h. When given subcutaneously for 2 weeks starting at 14 weeks in male non-obese diabetic (NOD) mice, a model of autoimmune dacryoadenitis used to study Sjögren's syndrome (SS), CA192-CsA (2.5 mg/kg, every other day) significantly (p = 0.014) increased tear production relative to CA192 alone. Moreover, CA192 delivery reduced indications of CsA nephrotoxicity relative to free CsA. CA192 represents a viable new approach to deliver this effective but nephrotoxic agent in a modality that preserves therapeutic efficacy but suppresses drug toxicity.
Agid:
6195927