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Biodefence Program introduction
Several important bacteria, including staphylococcus
(Staph) and streptococcus (Strep), produce toxins (superantigens)
that can produce debilitating symptoms or death and are currently recognized
as potential
bioterrorism agents. These bacterial superantigens are among the
most lethal toxins known to man. Literally nanogram amounts, or small numbers
of the
organisms that produce them, trigger an excessive cellular immune
response that can lead to lethal toxic shock within 24 hours of ingestion
or aerosol
spray of these toxins. Successful introduction of these agents
into the drinking water supply, aerosol or food would be devastating, incapacitating
large numbers of the population both military and civilian. The
toxins (superantigens)
produced by these bacteria non-specifically activate the immune
system. Aberrant activation leads to overproduction of cytokines (factors
that effect
other cells and are synthesized by immune cells) resulting in shock,
multiple organ failure and death. Notably, weaponized forms of Staph and
Strep are
generally expected to be more easily produced in an aerosolized
form than, for instance, anthrax and could lead to a devastating response
if dispersed
in an appropriate fashion.
Callisto’s superantigen technology has considerable potential for
the development of defensive agents to treat “superantigen” mediated
diseases and was recently awarded a $1.1 million U.S. Army research
grant.
Callisto’s approach is to develop peptides and humanized
antibodies as agents against weaponized bacterial toxins to protect
the military and civilians. Callisto has developed peptides and
antibodies that nullify the actions of superantigen toxins – Zabriskie
et al., Infection and Immunity 69: 875-884, 2001. These include
12-mer peptides that are homologous to a highly conserved segment
of the superantigen toxin. Callisto’s lead peptide, 6343,
has been shown to be protective against a wide range of
superantigen
toxins produced by Streptococci and Staphylococci in animal
models of toxic shock syndrome and sepsis. The development
of ligand-specific
peptides represents a pathway of streamlined rational drug
development and production, since commercial quantities of
specifically designed
peptides can be produced through established contract GMP facilities.
In an important breakthrough, Callisto has recently discovered
and patented D- and L-trimer peptides with comparable activity
to 6343 and demonstrated their efficacy in in vitro studies.
This is a highly significant development as the synthesis,
cost of goods and difficulty of developing a tripeptide would
be
considerably less than those for the 6343 12-mer peptide.
Callisto’s
second drug candidate to protect against a Strep/Staph-based
bioweapon is a neutralizing
antibody. Using a synthetic peptide whose sequence is highly
homologous to a highly conserved region contained in toxins of Gram-positive bacteria, Callisto has developed a proprietary
antibody (Anti Toxic Shock or ATS antibody) that recognizes
the different toxins
and neutralizes their biological effect. This antibody has also
been shown to protect animals from shock. Callisto is developing
several forms of this
antibody to be evaluated for their ability to block the effect
of bacterial toxins and prevent or mitigate the signs and
symptoms
of toxic shock.
A major advantage of Callisto’s superantigen
technology is that these peptide/antibody agents cross-react
against virtually all known strains
of Staph and Strep and would be expected to work against any future
variant strains, either man-made or naturally occurring.
In an important validation
of this concept, peptide 6343 has been shown to act against 3 newly
characterized streptococcal pyrogenic exotoxins, SPEG, SPEH
and SPEZ.
In a separate series of experiments, Callisto has
also been exploring the superantigen technology as a potential
treatment for systemic inflammatory response syndrome (SIRS) (Sepsis), an often-fatal condition.
Most cases of SIRS are due to infection caused by either Gram-negative or
Gram-positive
bacteria. There are an estimated 400,000-500,000 cases of SIRS
annually
in the U.S. As with toxic shock, SIRS involves the over activation
of the immune system beginning with cytokine synthesis and release.
In SIRS due
to infectious disease, however, excess cytokine synthesis is
triggered by components of the cell wall of Gram-positive bacteria or the
outer membrane
of Gram-negative bacteria. Callisto’s ATS antibody has been shown
in animal models of SIRS to block cytokine release triggered by
both cell wall and outer membrane components, and may therefore be effective
in SIRS
cases caused by either Gram-positive or Gram-negative bacterial
infections. In addition, since SIRS caused by Gram-negative bacteria is
often complicated
and aggravated by low-grade infection with Gram-positive bacteria,
the use of ATS antibody or the 6343 peptide is expected to be beneficial.
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