This technology involves an array of applications relating to a key discovery regarding adrenomedullin-binding proteins.

Adrenomedullin (AM) is a ubiquitously-expressed peptide first found in human pheochromocytoma, a cancer of the adrenal medulla.  AM appears to function as a universal autocrine growth factor, driving cell proliferation, as a vasodilator, as a mechanism for protecting cells against oxidative stress in hypoxic injury, and as a dose-dependent inhibitor of insulin secretion.  Accordingly, methods for measuring in vivo levels of AM accurately, and methods for regulating the activity of available AM, may be critically important in diagnosis and treatment of many conditions, such as heart disease, pulmonary disease, liver cirrhosis, cancer, diabetes, sepsis, and inflammation.

The present technology centers on the observation that AM binds to Complement Factor H (CFH) in vivo.  Without a means to determine the amount of AM that is bound to CFH, measurements of AM are inaccurate, and therapies focused on the AM-CFH complex may have advantages compared to therapies focused on AM alone.

The technology includes methods for measuring and utilizing purified AM-binding proteins, or functional portions thereof, to diagnose, treat, and monitor AM-related diseases. A second aspect includes the identification and isolation of the AM-CFH complex.  Antibodies and small-molecule antagonists (which can down-regulate the function of AM, CFH, and the AM-CFH complex) have also been isolated. Collectively, the technology provides methods for diagnosis and treatment of conditions such as cancer, diabetes, or other conditions that are influenced by AM levels.

Applications and Advantages:

• More accurate measurements of serum adrenomedullin than current tests
• Antibodies targeting AM-CFH decrease bioavailable AM, which may be useful in suppressing angiogenesis in cancers
• Antibodies targeting the CFH binding site increase bioavailable AM, which may be useful in therapies involving vasodilation, angiogenesis, and tolerance for hypoxic or ischemic injury during stroke or myocardial infarction

Development Status: 

In vivo and in vitro proof of concept data are available.

Related Publications:

1. AJ Dwivedi et al. Adrenomedullin and adrenomedullin binding protein-1 prevent acute lung injury after gut ischemia-reperfusion. J Am Coll Surg. 2007 Aug;205(2):284-293.  [PubMed abs]
2. D Ajona et al. Down-regulation of human complement factor H sensitizes non-small cell lung cancer cells to complement attack and reduces in vivo tumor growth. J Immunol. 2007 May 1;178(9):5991-5998.  [PubMed abs]
3. A Martínez et al. Mapping of the adrenomedullin-binding domains in human complement factor H. Hypertens Res. 2003 Feb;26 Suppl:S55-59.  [PubMed abs]
4. R Pio et al. Complement factor H is a serum-binding protein for adrenomedullin, and the resulting complex modulates the bioactivities of both partners. J Biol Chem. 2001 Apr 13;276(15):12292-12300.  [PubMed abs]

HHS Reference No. E-256-1999/0 –

• U.S. Patent Application No. 11/530,441 filed 08 Sept 2006, claiming priority to 10 Sept 1999
• Foreign counterparts in Australia, Canada, France, Germany, Great Britain, Italy, Spain, and Portugal

Inventors: 

Frank Cuttitta et al. (NCI)

Licensees Sought: 

Available for exclusive or non-exclusive licensing.

Collaborative Research Opportunity: 

The National Cancer Institute (NCI)/Angiogenesis Core Facility is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize AM-CFH complex involvement with tumor angiogenesis and identifying potential Rxs to disrupt this effect.  Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.