Polymyxin B conjugates

Details Polymyxin B conjugates Polymyxin B conjugates

1995-06-07

2003-06-17

Navarro, Mark (Department: 1645)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Enzymatic production of a protein or polypeptide

C514S002600, C530S300000, C530S333000, C530S350000, C530S391700

Reexamination Certificate

active

06579696

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 other animals. In addition, the present invention relates to the molecular compositions consisting of an immunoglobulin-binding epitope linked through a molecular spacer to an antigen-binding epitope. These molecular compositions have utility relating to both the diagnosis and treatment of a variety of diseases including infections and cancers.
BACKGROUND OF THE INVENTION
I. Sepsis
Sepsis is a major cause of morbidity and mortality in humans and other 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. Sepsis has become the leading cause of death in intensive care units among patients with non-traumatic illnesses. [G. W. Machiedo et al., Surg. Gyn. & Obstet. 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, their metabolic end-products or toxins in the blood stream), including bacteremia (i.e., bacteria in the blood), as well as toxemia (ie., toxins in the blood), including endotoxemia (i.e., endotoxin in the blood). The term “bacteremia” includes occult bacteremia observed in young febrile children with no apparent foci of infection. The term “sepsis” also encompasses fungemia (i.e., fungi in the blood), viremia (i.e., viruses or virus particles in the blood), and parasitemia (i.e., helminthic or protozoan parasites in the blood). Thus, septicemia and septic shock (acute circulatory failure resulting from septicemia often associated with multiple organ failure and a high mortality rate) may be caused by a number of organisms.
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 (i.e., septic shock) and oftentimes, death.
There are three major types of sepsis characterized by the type of infecting organism. Gram-negative sepsis is the most common and has a case fatality rate of about 35%. The majority of these infections are caused by
Escherichia coli, Klebsiella pneumoniae
and
Pseudomonas aeruginosa
. Gram-positive pathogens such as the staphylococci and streptococci are the second major cause of sepsis. The third major group includes the fungi, with fungal infections causing a relatively small percentage of sepsis cases, but with a high mortality rate.
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).
A well established mechanism in sepsis is related to the toxic components of gram-negative bacteria. 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 as well studied as gram-negative endotoxin.
Regardless of the etiologic agent, many patients with septicemia or suspected septicemia exhibit a rapid decline over a 24-48 hour period. Thus, rapid methods of diagnosis and treatment delivery are essential for effective patient care. Unfortunately, a confirmed diagnosis as to the type of infection traditionally requires microbiological analysis involving inoculation of blood cultures, incubation for 18-24 hours, plating the causative organism on solid media, another incubation period, and final identification 1-2 days later. 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 (i.e., nosocomial or iatrogenic bacteremia). [D. G. Maki, Am. J. Med. 70:719-732 (1981).] The causes for this are many-fold. First, for many commonly used antibiotics, antibiotic resistance is common among various species of bacteria. This is particularly true of the microbial flora resident in hospitals, where the organisms are under constant selective pressure to develop resistance. Furthermore, in the hospital setting, 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 broad spectra 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 which can cause life-threatening infections of the gastrointestinal (GI) tract such as
Clostridium difficile
. For example, antimicrobial-associated pseudomembranous colitis caused by
C. difficile
is a potentially serious complication associated with administration of certain antimicrobials. Physicians must therefore consider the imp

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