It is estimated that there were approximately 2.9 million cases of hospital-acquired infections in the US in 2005.  1.2 million of those were due to Gram-positive organisms, such as staphylococcus.  That number is expected to increase to 1.9 million by 2010.  Over the same time period infections resistant to multiple anti-bacterials are expected to almost double from over 600,000 to close to 1.2 million. The rise of resistant bacteria has made infectious disease the only field of medicine that is becoming less effective at treating patients.

 

Unfortunately, the late-stage development pipeline for new anti-bacterials has run somewhat dry, especially when considered in the context of the ongoing need for new and novel agents.  Because of the above there is virtually an unlimited need for new and better drugs with which to treat these infections. Products such as the monoclonal antibody under development at Alopexx present a real opportunity.

Methicillin-resistant S. Aureus (MRSA)

Staphylococcus aureus (S. aureus) is arguably one of the most important causes of life-threatening infections in the developed world.  The majority of hospital acquired S. aureas infections are now resistant to most antibiotics and are known as Methicillin-resistant S. aureas (MRSA). The incidence of MRSA infections has dramatically increased in the last decade, occurring in both community-acquired and hospital-acquired cases. It has become the most common pathogen causing HAIs in hospitals. In the decade of the 1990s the number of MRSA HAIs tripled despite current infection control recommendations. It is estimated that annual cost of MRSA infections to US hospitals is between $3.2 billion and $4.2 billion.

It is generally accepted that the incidence of MRSA is rapidly increasing and is grossly under-estimated.   Reliance on discharge data is known to be inaccurate as many diagnoses are not reported or occur following discharge from the hospital.  One recent study found that as many as 20% of the 4.4 million patients admitted to US Intensive Care Units become infected or colonized with MRSA. That same study noted that as many as 30% of those patients develop a second MRSA infections following discharge.

Current therapy of MRSA often relies on the use of the antibiotic vancomycin.  However, since the late 1990’s there has been an increasing incidence of S. aureus that are resistant to this antibiotic as well. MRSA is not quite yet, but certainly on its way to becoming a “superbug” - one that is resistant to antibiotics.  

The Alopexx Solution - Fully Human mab F598

A compelling alternative to antibiotics is the administration of pre-formed antibodies that can be given to individuals that develop or are at a significant risk of developing an infection.  The major advantage this affords is that it provides "instant" immunity at the time the antibodies are given. It can be given to individuals who go from low to high risk situation quickly (burns, trauma, non-elective surgery, etc.) and potentially can be delivered to specific sites (eye, lungs, wounds, blood, etc.). As it remains active in the blood stream for 14-21 days one or two administrations would provide a sufficient duration of protection in most instances.  Finally, if properly targeted, an antibody, unlike antibiotics, will not lead to the development of resistance.

The most promising antibody, developed by Dr. Gerald Pier at Harvard’s Brigham and Women’s Hospital, is a fully human monoclonal antibody, F598.  Of all the anti-staphylococcal monoclonal antibodies in development only F598 possesses all the key characteristics necessary for effective targeting and killing of the bacteria.  It is an intact fully human monoclonal antibody, directed against a clinically relevant target and capable of inducing killing by the patient’s white blood cells – a critical process known as “opsonophagocytosis”. 

F598 antibody binds to a conserved surface polysaccharide known as poly-N-acetyl glucosamine (PNAG).  This polysaccharide has been found to be a critical factor in the virulence and immune response to staphylococcal infections. S. aureus strains that cannot produce PNAG have a significantly reduced ability to cause infections.  The association of the target of the antibody with the bacteria’s virulence is an important component of therapeutic potential mAb F598. Bacteria cannot simply avoid this immune therapy by mutating to not produce the target antigen.  Such a mutation would severely cripple the bacterium’s ability to cause infection.