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Abstract

Grant Number:	1R43GM069113-01
PI Name:	HOUSTON, L L.
PI Email:	lhouston@arizeke.com
PI Title:	MANAGING DIRECTOR
Project Title:	Novel Aerosol Delivery System for Proteins

Abstract: DESCRIPTION (provided by applicant): Because proteins and large macromolecular drugs do not normally cross epithelial barriers (i.e., intestine and lung), they are parenterally administered to patients. Injection is invasive and not well-accepted by patients or the medical community. Delivery of macromolecules, particularly of proteins, by a noninvasive method, such as through the pulmonary system, will have many benefits. Our method using aerosol delivery can be applied to nearly any protein and can serve billion dollar markets. Large molecules cannot pass the epithelial cell barriers that line pulmonary, nasal, and intestinal surfaces and protect against passage of unwanted and toxic materials into tissues and blood. Large molecules, however, can move from the tissues into the lumen of these organs. This is achieved by polymeric immunoglobulin receptor (plgR), which can specifically move immunoglobulins (like 350,000 MW dimeric IgA and 900,000 MW IgM) from the blood stream across the epithelial cell (transcytosis) and into the lumen (the apical side of the epithelial layer) of the lung. This process of receptor-mediated transcytosis is capable of transporting large amounts (grams per day) of IgA in an adult human in order to fight harmful agents in the airways and intestines. Although plgR facilitated transport naturally occurs from the basolateral surface (blood side) of the epithelial cells to the apical surface (lumen side), Arizeke has discovered and demonstrated in animals that the transcytosis route could be used in reverse to transport the drugs from the apical surface to the basolateral surface (i.e., from the lumen of the lung to the bloodstream). plgR (i) efficiently transports IgA at a rapid rate, (ii) can naturally transport molecules that are very large (up to at least 900,000 MW) with transport efficiency essentially independent of molecular weight, and (iii) is abundantly distributed throughout the respiratory tract. Single chain Fv that binds to plgR is transported across the epithelial cell layer and released at the basolateral (tissue or blood) surface. By genetically conjugating erythropoietin to the sFv, efficient and specific transport of the chimeric protein can be achieved when it is delivered to the pulmonary system as an aerosol. Using this noninvasive route of administration, invasive routes (parenteral) administration can be eliminated.

Thesaurus Terms:
aerosol, antibody receptor, chimeric protein, drug delivery system, erythropoietin, protein transport, technology /technique development, transcytosis
biological model, biophysics, blood cell count, chemical synthesis, gene expression, injection /infusion, macromolecule, respiratory system, subcutaneous drug administration
SDS polyacrylamide gel electrophoresis, immunoprecipitation, laboratory mouse, laboratory rat, mass spectrometry, molecular cloning

Institution:	ARIZEKE PHARMACEUTICALS, INC.
	6828 NANCY RIDGE DR, STE 400
	SAN DIEGO, CA 92121
Fiscal Year:	2003
Department:
Project Start:	01-SEP-2003
Project End:	29-FEB-2004
ICD:	NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
IRG:	ZRG1

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