Drug – bio-affecting and body treating compositions – Conjugate or complex of monoclonal or polyclonal antibody,... – Conjugated via claimed linking group – bond – chelating agent,...
Reexamination Certificate
1994-09-12
2003-12-09
Smith, Lynette F. (Department: 1645)
Drug, bio-affecting and body treating compositions
Conjugate or complex of monoclonal or polyclonal antibody,...
Conjugated via claimed linking group, bond, chelating agent,...
C424S179100, C424S180100, C424S184100, C424S282100, C530S319000, C530S320000, C530S390100, C530S391700
Reexamination Certificate
active
06660267
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to therapeutics for the prevention and treatment of blood-borne and toxin mediated diseases, and in particular the prevention and treatment of sepsis in humans as well as animals.
BACKGROUND OF THE INVENTION
I. Sepsis
Sepsis is a major cause of morbidity and mortality in humans and animals. It is estimated that 400,000-500,000 episodes of sepsis resulted in 100,000-175,000 human deaths in the U.S. alone in 1991 and has become the leading cause of death in intensive care units among patients with non-traumatic illnesses [G. W. Machiedo et al., Surg. Gyn. & Ob., 152:757-759 (1981)]. It is also the leading cause of death in young livestock, affecting 7.5-29% of neonatal calves [D. D. Morris et al., Am. J. Vet. Res., 47:2554-2565 (1986)], and is a common medical problem in neonatal foals [A. M. Hoffman et al., J. Vet. Int. Med., 6:89-95 (1992)]. Despite the major advances of the past several decades in the treatment of serious infections, the incidence and mortality due to sepsis continues to rise [S. M. Wolff, New Eng. J. Med., 324:486-488 (1991)].
Sepsis is a systemic reaction characterized by arterial hypotension, metabolic acidosis, decreased systemic vascular resistance, tachypnea and organ dysfunction. Sepsis can result from septicemia (i.e., organisms in the blood stream), including bacteremia (i.e., bacteria in the blood), as well as toxemia (i.e., toxins in the blood), including endotoxemia (i.e., endotoxin in the blood). Thus, the systemic invasion of microorganisms presents two distinct problems. First, the growth of the microorganisms can directly damage tissues, organs, and vascular function. Second, toxic components of the microorganisms can lead to rapid systemic inflammatory responses that can quickly damage vital organs and lead to circulatory collapse (septic shock). Most patients who enter septic shock die.
There are three major types of sepsis characterized by the type infecting organism. Gram-negative sepsis is the most common type of sepsis and the majority of these infections are caused by
Escherichia coli, Klebsiella pneumoniae
and
Pseudomonas aeruginosa,
and have a case fatality rate of about 35%. Gram-positive pathogens such as the Staphylococci and Streptococci are the other major cause of sepsis, with fungal infections causing a relatively small percentage of cases (with a high incidence of mortality, however). Many of these infections are acquired in a hospital setting and can result from certain types of surgery (e.g., abdominal procedures), immune suppression due to cancer or transplantation therapy, immune deficiency diseases, and exposure through intravenous catheters. Sepsis is also commonly caused by trauma, difficult newborn deliveries, and intestinal torsion (especially in dogs and horses).
The toxic components of gram-negative bacteria are the best understood. There is a common cell-wall structure known as lipopolysaccharide (LPS) that is widely shared among gram-negative bacteria. The “endotoxin” produced by gram-negative organisms is comprised of three major structures, a lipoprotein, a lipid (lipid A), thought to be responsible for most of the biological properties of endotoxin, and polysaccharide structures unique to each species and distinct strains of bacteria [D. C. Morrison, Rev. Infect. Dis., 5(Supp 4):S733-S747 (1983)]. Research over the past decade or so has demonstrated that purified endotoxin can elicit all of the features of full-blown gram-negative bacteremia. Furthermore, several of the host responses to endotoxin have been identified. Two key mediators of septic shock are tumor necrosis factor (TNF) and interleukin-1 (IL-1) which are released by macrophages and appear to act synergistically in causing a cascade of physiological changes leading to circulation collapse and organ failure [R. C. Bone, Ann. Intern. Med., 115:457-469 (1991)]. Indeed, large doses of TNF [K. J. Tracey et al., Science 234:470-474 (1986)] and/or IL-1 [A. Tewari et al., Lancet 336:712-714 (1990)] can mimic the symptoms and outcome of sepsis.
It is generally thought that the distinct cell wall substances of gram-positive bacteria and fungi trigger a similar cascade of events, although the structures involved are not generally as well studied as gram-negative endotoxin. Many patients with septicemia or suspected of having septicemia exhibit a rapid decline over a 24-48 hour period. Unfortunately, a confirmed diagnosis as to the type of infection requires that microbiological cultures be made, which usually requires several days for plating, growth, and identification. Therefore, therapy must be initiated without any knowledge of the type and species of the pathogen, and with no means of knowing the extent of the infection.
II. Prevention and Treatment
A. Antibiotics
Antibiotics of enormously varying structure [Bérdy in
Advances in Applied Microbiology,
(D. Perlman, ed.), Academic Press, New York, 18:309-406 (1974)] are widely used to prevent and control infections. Nonetheless, up to one half of the patients in whom bacteremia develops in the hospital die [D. G. Maki, Am. J. Med., 70:719-732 (1981)]. The causes for this are many-fold. First, antibiotic resistance is common among most species of bacteria for many antibiotics. Therefore, while physicians commonly prescribe antibiotics for patients at risk, this only aids the selection for antibiotic-resistant organisms. Furthermore, in a hospital setting, the spread of antibiotic-resistant organisms is facilitated by the high density of potentially infected patients and the extent of staff-to-staff and staff-to-patient contact. Second, those antibiotics that are the most economical, safest, and easiest to administer may not have a broad enough spectrum to suppress certain infections. For example, many antibiotics with broader spectrums are not deliverable orally and physicians are reluctant to place patients on intravenous lines due to the enhanced risk of infection. Third, antibiotics can be toxic to varying degrees including causing allergy, untoward interactions with other drugs and direct damage to major organs (e.g., kidneys, liver). Many potent antibiotics are eliminated from routine use due to the probability of adverse reactions at therapeutic doses. Fourth, many antibiotics alter the normal intestinal flora and frequently cause diarrhea and nutritional malabsorption; some may even unleash opportunistic organisms such as
Clostridium difficile
that can cause life-threatening infections of the gastrointestinal tract. Physicians must therefore consider the impact of prophylactic antibiotic use on the development of resistant organisms, on patient health, and on the economics of health care.
While many infections are controlled by antibiotics, gram-negative bacteremia presents some special challenges. It has been shown that treatment of bacteria with antibiotics actually catalyzes endotoxin release from dying cells as their cell walls disintegrate. In experimental
E. coli
sepsis in rabbits, antibiotics cause a 10 to 2,000 fold increase in endotoxin levels despite decreasing levels of bacteremia [J. L. Shenep and K. A. Morgan, J. Inf. Dis., 150:380-388 (1984)]. Thus, once gram-negative bacteremia is established, there is justifiable concern that antibiotic therapy may augment symptoms while mitigating the infection.
Certain antibiotics are known that neutralize the activity of endotoxin. The polymyxin antibiotics, most notably polymyxin B and polymyxin E (also known as colistin) are cyclic polypeptide compounds produced by certain strains of
Bacillus polymyxa.
These antibiotics bind to the lipid A portion of endotoxin [D. C. Morrison and D. M. Jacobs, Immunochem., 13:813-818 (1976)] and neutralize endotoxin activity as measured by lethality tests in animals [D. Rifkind and J. D. Palmer, J. Bact., 92:815-819 (1966)], activation of serum complement [D. C. Morrison and D. M. Jacobs, Infect. Immun., 13:298-301 (
Medlen & Carroll LLP
Promega Corporation
Smith Lynette F.
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