Alpha-defensins (HNPs) Effectively Inhibit Anthrax-related Toxemia


Medicine : Therapeutics

Ref.-Nr.: 0305-3252-LI

Anthrax is an acute infectious disease caused by the spore-forming bacterium Bacillus anthracis. B.anthracis can cause human disease via the gastrointestinal, cutaneous or inhalational routes. There is still a considerably high rate of mortality from inhalational anthrax of up to 75 percent, even though fluorquinolone class antibiotics (e.g., ciprofloxacin) are being administered as a first-line therapy. This strategy, in addition, is being threatened by the spread of plasmid-mediated resistance to quinolones (1).

The threat of misusing B. anthracis as a biological weapon has led to the assessment of novel pre- and post-infection vaccination strategies. Currently available vaccines provide only weak protection. The US administration once cancelled the most advanced contract for the development of a next-generation vaccine within the BioShield program, obviously due to continuing development difficulties (2). While antibiotics are capable of interfering with the lifecycle of B. anthracis, they cannot directly influence its most dangerous aspect: lethal toxin (LeTx). LeTx is a combination of lethal factor (LF) and protective antigen (PA), plays a central role in anthrax pathogenesis, and is a major cause of mortality from anthrax infection.

Technology

Scientists from the Max Planck Institute for Infection Biology in Berlin revealed that human neutrophil alpha-defensins (HNP-1/-2/-3) are potent inhibitors of LF. They showed that human neutrophil protein HNP-1 protected murine macrophages from B. anthracis-induced cytotoxicity in vitro. Even more encouraging, they also found that in vivo treatment with HNPs protected mice against the fatal consequences of anthrax LeTx (3). Alpha-defensins are natural peptides of human origin. Hence, they have a higher potential to be more useful than any known synthetic anthrax therapeutic.

Development and Commercialization Opportunities

A large scale solid-phase synthesis manufacturing protocol has been described for HNPs (4). Moreover, in December 2006, novel legislation relating to biodefense research and development came into effect in the US. Biotech companies can now receive funds upfront, and reimbursement of costs is no longer dependent on previous licensure of a product by the FDA.
Therefore HNPs provide a perfect opportunity from a scientific and technical as well as from an economic perspective to launch a novel therapeutic, possibly in combination with antibiotics or vaccines to effectively inhibit anthrax-related toxemia.

Patent Information

European priority application filed in July 2004, via PCT extended to EP, US and CA.

Literature

  1. “The worldwide emergence of plasmid-mediated quinolone resistance”, Lancet Infect Dis. 2006 6: 629-40.
  2. Nature 2007, Vol. 445: 12.
  3. “Human alpha-defensins neutralize anthrax lethal toxin and protect against its fatal consequences”, Proc Natl Acad Sci USA 2005 102: 4830-35.
  4. “Large scale synthesis and functional elements for the antimicrobial activity of defensins”, Biochem J 2000 347:633-641.

Figure: MPI for Infection Biology / Volker Brinkmann

Mechanism of action - Taken from nature:

A neutrophile granulocyte phagocytes anthrax bacteria, thereby exposing them to alpha defensins stored in its granuloma that can neutralize B. anthracis's most deadly weapon: lethal toxin.
It seems that in the lung neutrophile granulocytes are present in amounts too low to control B. anthracis infection. However, mice control anthrax infection after administration of alpha-defensins.

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Dr. Dieter Link

Senior Patent- & License Manager

Biologist

Phone: +49 89 / 29 09 19-28
E-Mail:
dieter.link@max-planck-innovation.de

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