Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,...
Reexamination Certificate
1999-08-31
2004-02-17
Smith, Lynette R. F. (Department: 1645)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
C424S137100, C424S150100, C424S185100, C530S387100, C530S387500, C530S388200, C530S388400
Reexamination Certificate
active
06692739
ABSTRACT:
BACKGROUND OF THE INVENTION
The staphylococci are Gram-positive spherical cells, usually arranged in grape-like irregular clusters. Some are members of the normal flora of the skin and mucous membranes of humans, others cause suppuration, abscess formation, a variety of pyogenic infections, and even fatal septicemia. Pathogenic staphylococci often hemolyze blood, coagulate plasma, and produce a variety of extracellular enzymes and toxins. The most common type of food poisoning is caused by a heat-stable staphylococci enterotoxin.
The genus Staphylococcus has at least 30 species. Three main species of clinical importance are
Staphylococcus aureus, Staphylococcus epidermidis,
and
Staphylococcus haemolyticus. Staphylococcus aureus
is coagulase-positive, which differentiates it from the other species.
S. aureus
is a major pathogen for humans. Almost every person has some type of
S. aureus
infection during a lifetime, ranging in severity from food poisoning or minor skin infections to severe life-threatening infections. The coagulase-negative staphylococci are normal human flora which sometimes cause infection, often associated with implanted devices, especially in very young, old and immunocompromised patients. Approximately 75% of the infections caused by coagulase-negative staphylococci are due to parasitic
S. epidermidis
. Infections due to
Staphylococcus haemolyticus, Staphylococcus hominis,
and other species are less common.
S. saprophyticus
is a relatively common cause of urinary tract infections in young women.
Staphylococcus bacteria such as
S. aureus
thus cause a spectrum of infections that range from cutaneous lesions such as wound infections, impetigo, and furuncles to life-threatening conditions that include pneumonia, septic arthritis, sepsis, endocarditis, and biomaterial related infections.
S. aureus
colonization of the articular cartilage, of which collagen is a major component, within the joint space appears to be an important factor contributing to the development of septic arthritis. Hematogenously acquired bacterial arthritis remains a serious medical problem. This rapidly progressive and highly destructive joint disease is difficult to eradicate. Typically less than 50% of the infected patients failing to recover without serious joint damage.
S. aureus
is the predominant pathogen isolated from adult patients with hematogenous and secondary osteomyelitis.
In hospitalized patients,
Staphylococcus aureus
is a major cause of infection. Initial localized infections of wounds or indwelling medical devices can lead to more serious invasive infections such as septicemia, osteomyelitis, mastitis and endocarditis. In infections associated with medical devices, plastic and metal surfaces become coated with host plasma and matrix proteins such as fibrinogen and fibronectin shortly after implantation. The ability of Staphylococcus bacteria such as
S. aureus
to adhere to these proteins is essential to the initiation of infection. Vascular grafts, intravenous catheters, artificial heart valves, and cardiac assist devices are thrombogenic and prone to bacterial colonization.
S. aureus
is the most damaging pathogen of such infections, and other Staphylococci bacteria such as
S. epidermidis
are also responsible for a significant amount of dangerous infections, particularly those associated with implanted devices.
There is a strong and rapidly growing need for therapeutics to treat infections from Staphylococcus bacteria such as
S. aureus
and
S. epidermidis
infections which are effective against antibiotic resistant strains of the bacteria. The U.S. National Institutes for Health has recently indicated that this goal is now a national priority.
MSCRAMMs
The successful colonization of the host is a process required for most microorganisms to cause infections in animals and humans. Microbial adhesion is the first crucial step in a series of events that can eventually lead to disease. Pathogenic microorganisms colonize the host by attaching to host tissues or serum conditioned implanted biomaterials, such as catheters, artificial joints, and vascular grafts, through specific adhesins present on the surface of the bacteria. MSCRAMMs (Microbial Surface Components Recognizing Adhesive Matrix Molecules) are a family of cell surface adhesins that recognize and specifically bind to distinct components in the host's extracellular matrix. Once the bacteria have successfully adhered to and colonized host tissues, their physiology is dramatically altered and damaging components such as toxins and proteolytic enzymes are secreted. Moreover, adherent bacteria often produce a biofilm and quickly become more resistant to the killing effect of most antibiotics.
For example,
S. aureus
is known to express a repertoire of different MSCRAMMs that can act individually or in concert to facilitate microbial adhesion to specific host tissue components. MSCRAMMs provide an excellent target for immunological attack by antibodies. The presence of the appropriate anti-MSCRAMM high affinity antibodies has a double-edged attack, first the antibodies prevent microbial adherence and second the increased titers of MSCRAMM antibodies facilitate a rapid clearance of the organism from the body through bacterial lysis, opsonization, phagocytosis and complement activation.
PASSIVE IMMUNIZATION TO BACTERIAL INFECTIONS
Immunoglobulins (A, D, E, G, and M) are used by the body as a primary defense to infections. Complement, available as a precursor protein which is activated by the presence of microorganisms and globulins, also exhibits antibacterial activities. After previous antigenic exposure, the immune system produces a series of globulins which attach to and coat bacteria or neutralize viruses so that they are readily recognized, phagocytized and destroyed by neutrophils and macrophages. Foreign proteins of invading organisms also stimulate a humoral immune response which over a period of time from three to six weeks amplifies the number of cells designed to recognize and destroy specific invaders.
In the last decade, intravenous immunoglobulin (IVIG) therapy has become a major treatment regime for bacterial infections, especially in immunocompromised patients (Siber,
New Eng. J. Med.,
327:269-271, 1992). IVIG therapy has exhibited efficacy against more than thirty-five diseases caused by immunopathologic mechanisms. Passive immunization against infections has been particularly successful with immune globulins specific for tetanus, hepatitis B, rabies, chicken pox and cytomegalovirus. There has been an inconsistent and disappointing response to the use of immunoglobulins to prevent nosocomial infections, likely due to the variety of strains of bacteria found in hospitals and the emergence of new serotypes. Passive immunization requires the presence of high and consistent titers of antibodies to the infecting pathogens.
Supplemental immunoglobulin therapy has been shown to provide some measure of protection against certain encapsulated bacteria such as
Hemophilus influenzae
and
Streptococcus pneumoniae.
Infants who are deficient in antibody are susceptible to infections from these bacteria and bacteremia and sepsis are common. When anti-Streptococcal and anti-Hemophilus antibodies are present, they provide protection by promoting clearance of the respective bacteria from the blood. In the case of antibody to Staphylococcus, the potential use of supplemental immunoglobulin to prevent or treat infection has been much less clear.
Early attempts to treat Staphylococcus infections focused on the potential use of supplemental immunoglobulin to boost peritoneal defenses, such as opsonic activity, in patients receiving continuous ambulatory peritoneal dialysis. Standard intravenous immunoglobulin (IVIG) was shown to have lot to lot variability for opsonic activity to
S. epidermidis
(L. A. Clark and C. S. F. Easmon,
J. Clin. Pathol.
39:856 (1986)). In this study, one third of the IVIG lots tested had poor opsonization with complement, and only two of fourteen were opsonic witho
Foster Timothy J.
Hook Magnus
Patti Joseph M.
Inhibitex, Inc.
Larson & Taylor PLC
Portner Ginny Allen
Smith Lynette R. F.
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