Berunda Polypeptides: Biheaded Rapamycin Carriers for Subcutaneous Treatment of Autoimmune Dry Eye Disease

Abstract

The USFDA-approved immunosuppressive drug rapamycin (Rapa), despite its potency, is limited by poor bioavailability and a narrow therapeutic index. In this study, we sought to improve bioavailability of Rapa with subcutaneous (SC) administration and to test its therapeutic feasibility and practicality in a murine model of Sjögren's syndrome (SS), a systemic autoimmune disease with no approved therapies. To improve its therapeutic index, we formulated Rapa with a carrier termed FAF, a fusion of the human cytosolic FK506-binding protein 12 (FKBP12) and an elastinlike polypeptide (ELP). The resulting 97 kDa FAF (i) has minimal burst release, (ii) is "humanized", (iii) is biodegradable, (iv) solubilizes two Rapa per FAF, and (v) avoids organic solvents or amphiphilic carriers. Demonstrating high stability, FAF remained soluble and monodisperse with a hydrodynamic radius of 8 nm at physiological temperature. A complete pharmacokinetic (PK) analysis of FAF revealed that the bioavailability of SC FAF was 60%, with significantly higher blood concentration during the elimination phase compared to IV FAF. The plasma concentration of Rapa delivered by FAF was 8-fold higher with a significantly increased plasma-to-whole blood ratio relative to free Rapa, 24 h after injection. To evaluate therapeutic effects, FAF-Rapa was administered SC every other day for 2 weeks to male non-obese diabetic (NOD) mice, which develop an SS-like autoimmune-mediated lacrimal gland (LG) inflammation and other characteristic features of SS. Both FAF-Rapa and free Rapa exhibited *

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“…Therefore, the one-compartmental model was used to fit the plasma concentration–time curve. This model assumes that the whole body acts like a single uniform compartment, the drug is distributed instantaneously throughout the entire body, and drug elimination occurs immediately after the intravenous bolus injection. , …”

“…This model assumes that the whole body acts like a single uniform compartment, the drug is distributed instantaneously throughout the entire body, and drug elimination occurs immediately after the intravenous bolus injection. 53,54 Pharmacokinetic parameters are shown in Table 2. The distribution volume of control and Akt-in NPs was almost the same as the blood volume of a mouse.…”

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“…We envisage that new formulations of rapamycin will improve its efficacy for the treatment of DED. Lee et al proposed humanized bi-headed polypeptides for the subcutaneous delivery of rapamycin [ 65 ]. They applied this delivery system in the NOD mouse model of autoimmune dacryoadenitis, obtaining a beneficial reduction in lymphocytic infiltration in the lacrimal gland and levels of some pro-inflammatory cytokines in this tissue with no systemic toxicity.…”