Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1999-12-08
2001-03-20
Minnifield, Nita (Department: 1645)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S005000, C435S007100, C435S007240, C435S007310, C435S007320, C435S024000, C435S034000, C435S962000, C435S968000, C435S975000, C436S513000, C436S534000, C436S536000, C436S539000
Reexamination Certificate
active
06203997
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to methods to quantitate the level of an analyte in a sample of blood. Analytes may include infectious microorganisms, their toxic products, inflammatory mediators, hormones, acute phase proteins, toxins, drugs of abuse, markers of cardiac muscle damage. therapeutic drugs, cytokines, chemokines, and others.
DEFINITIONS
“Analyte” is defined as the specific substance of interest present in a blood sample and being analyzed by the quantitative assay of the present invention. In the case of analytes related to infection and sepsis, these may include microorganisms and their components, including gram positive cell wall constituents and gram negative endotoxin, lipopolysaccharide, lipoteichoic acid, and the inflammatory mediators that appear in circulation as a result of the presence of these components, including tumor necrosis factor (TNF), interleukin-1 (IL-1) and other interleukins and cytokines. Other analytes may include drugs of abuse, hormones, toxins, therapeutic drugs, markers of cardiac muscle damage, etc.
“Sepsis” is defined as a pathological condition of the body resulting from the presence of infectious microorganisms, which clinically manifests as one or more of the following sequelae: pyrexia, hypotension, hypoxemia, tachycardia, hypothermia, neutrophilia, and neutropenia.
“Antigen” as used in the context of the method of the present invention refers specifically to a material used in combination with an antibody to the antigen to maximally stimulate the production of oxidants by white blood cells. This antigen may or may not be the same as the analyte.
“Immunocomplexes” is a synonym for antibody-antigen complexes.
“Opsonized” refers to a particle to which immunoglobulin and complement factors are bound and which results in a more vigorous recognition of the particle by the immune system. For example, the yeast polysaccharide zymosan, or latex particles, may be opsonized by binding of immunoglobulin and complement factors to their surfaces; opsonized zymosan or latex will stimulate increased oxidant production by white cells after they are activated by exposure to immunocomplexes.
“Response” is a measure of the patient's ability to respond to a maximum stimulatory dose of immunocomplex. It is measured by maximally stimulating the patient's white blood cells with immunocomplexes, versus a control stimulation of antigen only, and expressing the result as the light integral difference between the two tests.
BACKGROUND OF THE INVENTION
Rapid quantitation of specific analytes in an individual's blood is critically important for the diagnosis of disease and its severity, often under emergency conditions, in the monitoring of the progression of pathological conditions and following the recovery process brought about by surgical and drug therapies. It is often important to know not only whether a specific analyte is present, but as well its level, in order to determine the present stage of a particular condition or disease in order to prescribe the most effective remedy at that particular stage. In the treatment of many diseases, a particular therapy may be ineffective or toxic if given at the wrong stage of the condition. For example, the levels of specific markers of cardiac muscle damage and the relationship among them may indicate that a patient has had or may be having a heart attack. The level of a therapeutic drug in the circulation may indicate whether the patient is being dosed optimally, and whether presumptive side effects are indeed due to excess levels of the drug. In infection and sepsis, the circulating levels of infectious microorganism toxins and inflammatory mediators produced by the patient's white blood cells may indicate the severity and level or stage of sepsis and help identify the most efficacious course of therapy. Quantitation of analytes under emergency conditions and using this information to prescribe a particular therapy may mean the difference between saving a patient's life and contributing to the patient's death.
For example, in the case of infection, hospital and particularly intensive care unit patients who have acquired nosocomial infections as a result of peri- or post-operative immunosuppression or secondary to other disease processes, such as pancreatitis, hypotensive or hypovolemic shock, physical trauma, burn injury, or organ transplantation, and develop septic shock syndrome have a mortality which has been quoted to range from 30-70% depending upon other co-incident complications. Despite the development of increasingly potent antimicrobial agents, the incidence of nosocomial infections and, in particular, infections leading to sepsis or septicemia is increasing. The difficulty with many of the promising therapeutic agents is that their window of opportunity and indications for use have not been adequately delineated largely due to a lack of appropriate rapid and quantitative diagnostic procedures and partly due to a lack of complete understanding of the pathogenesis of the sepsis syndrome.
As described in co-pending applications Ser. Nos. 08/552,145 and 08/516,204, both incorporated herein by reference, the presence of bacteria, viruses or fungi or their cell wall components including gram-positive peptidoglycans, lipoteichoic and teichoic acids, and gram-negative endotoxin (lipopolysaccharide, LPS) in blood is indicative of an infection. In addition, the immume system's reaction to the presence of these foreign antigens by the production of pro-inflammatory cytokine mediators such as interleukin-1 (IL-1), tumor necrosis factor (TNF) and interleukin-6 (IL-6), is also indicative of an infection. The quantity of these analytes in circulation may be used to indicate the severity and level or stage of sepsis. For instance, at an early stage of Gram-negative sepsis, LPS may be present at a concentration as low as 5 pg/ml of whole blood. At the next stage, sepsis has progressed and a mediator of sepsis, TNF, can be detected and measured using antibody against TNF. At stage 3, TNF may be present in smaller amounts since it is transitory and another transitory mediator. IL-1, may appear. As sepsis progresses further. LPS levels may decrease and TNF be absent, but IL-1 may increase and interleukin-6 (IL-6) may appear. Finally, in a more prolonged case of sepsis, LPS may be present and IL-1 may be at low levels but IL-6 may be at very high levels. Thus, diagnosis of sepsis and identifying its stage in the course the disease are critical for the successful treatment of this serious and potentially lethal consequence of infection. Quantitation of the levels of the sepsis-associated analytes provide information necessary to determine the best course of therapy to treat the acute disease.
Until the recent advent of novel therapeutic strategies, sepsis patients have been managed largely by palliative care and administration of antibiotics. The biotechnology industry has facilitated the large scale production of many new targeted biopharmaceuticals which utilize monoclonal antibodies against such initiators of sepsis as gram-negative endotoxin (Centocor's HA-1A(R) or Xoma's Xomen-E5(R)), tumor necrosis factor (various producers including Hoffman La Roche and Centocor with patents WO 90/06514 and WO 92/16553), interleukins, as well as various soluble receptor antagonists such as IL-1 RA (Synergen) and sCR
1
(soluble complement receptor 1)- a truncated recombinant complement regulatory molecule. The cost of these therapeutic agents is significant, being priced at $3,000.00 to $4,000.00 per dose. Thus providing this therapy indiscriminately to patients would add a considerable burden to the health care system without providing a corresponding benefit to patients. In addition, there is need for means to monitor the efficacy of such novel therapies.
Currently, one of the major problems with many of the therapeutic protocols being tested by the pharmaceutical companies conducting clinical trials in sepsis intervention is their inability to rapidly dete
Romaschin Alexander D.
Walker Paul M.
Baskar Padma
Klauber & Jackson
Minnifield Nita
Sepsis, Inc.
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