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

Authors

Changrim Lee, Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy , University of Southern California , Los Angeles , California 90089 , United States.
Hao Guo, Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy , University of Southern California , Los Angeles , California 90089 , United States.
Wannita Klinngam, Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy , University of Southern California , Los Angeles , California 90089 , United States.
Srikanth R. Janga, Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine , University of Southern California , Los Angeles , California 90089 , United States.
Frances Yarber, Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine , University of Southern California , Los Angeles , California 90089 , United States.
Santosh Peddi, Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy , University of Southern California , Los Angeles , California 90089 , United States.
Maria C. Edman, Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine , University of Southern California , Los Angeles , California 90089 , United States.
Nishant Tiwari, Department of Pathology, Keck School of Medicine , University of Southern California , Los Angeles , California 90089 , United States.
Siyu Liu, Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy , University of Southern California , Los Angeles , California 90089 , United States.
Stan G. Louie, Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy , University of Southern California , Los Angeles , California 90089 , United States.
Sarah F. Hamm-Alvarez, Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy , University of Southern California , Los Angeles , California 90089 , United States.
J Andrew MacKay, Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy , University of Southern California , Los Angeles , California 90089 , United States.

Document Type

Article

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 elastin-like 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 immunomodulatory effects by significantly suppressing lymphocytic infiltration, gene expression of IFN-γ, MHC II, type I collagen and IL-12a, and cathepsin S (CTSS) activity in LG compared to controls. Serum chemistry and histopathological analyses in major organs revealed no apparent toxicity of FAF-Rapa. Given its improved PK and equipotent therapeutic efficacy compared to free Rapa, FAF-Rapa is of further interest for systemic treatments for autoimmune diseases like SS.

Medical Subject Headings

Animals; Cathepsins (analysis); Disease Models, Animal; Drug Carriers (chemistry, pharmacokinetics); Drug Compounding (methods); Drug Liberation; Drug Stability; Elastin (chemistry); Immunosuppressive Agents (administration & dosage, blood, chemistry, therapeutic use); Injections, Subcutaneous; Male; Mice; Mice, Inbred NOD; Peptides (chemistry); Sirolimus (administration & dosage, blood, chemistry, therapeutic use); Sjogren's Syndrome (blood, drug therapy); Tacrolimus Binding Protein 1A (chemistry)

Publication Date

7-1-2019

Publication Title

Molecular pharmaceutics

E-ISSN

1543-8392

Volume

16

Issue

7

First Page

3024

Last Page

3039

PubMed ID

31095909

Digital Object Identifier (DOI)

10.1021/acs.molpharmaceut.9b00263

Recommended Citation

Lee, Changrim; Guo, Hao; Klinngam, Wannita; Janga, Srikanth R.; Yarber, Frances; Peddi, Santosh; Edman, Maria C.; Tiwari, Nishant; Liu, Siyu; Louie, Stan G.; Hamm-Alvarez, Sarah F.; and MacKay, J Andrew, "Berunda Polypeptides: Biheaded Rapamycin Carriers for Subcutaneous Treatment of Autoimmune Dry Eye Disease" (2019). Neuropathology. 4.
https://scholar.barrowneuro.org/neuropathology/4