Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
1995-06-06
2003-11-11
Kemmerer, Elizabeth C. (Department: 1647)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S133100, C424S141100, C424S130100, C424S158100, C530S387100, C530S387300, C530S387900, C530S388100, C530S388150, C530S389100
Reexamination Certificate
active
06645493
ABSTRACT:
1. INTRODUCTION
The present invention relates to compositions and methods for inhibiting the release and/or biological activity of migration inhibitory factor (MIF). In particular, the invention relates to the uses of such compositions and methods for the treatment of various conditions involving cytokine-mediated toxicity, which include, but are not limited to shock, inflammation, graft versus host disease, and/or autoimmune diseases.
2. BACKGROUND OF THE INVENTION
2.1. Cytokines in Septic Shock
Septic shock is a multifaceted pathological condition characterized most prominently by deleterious hemodynamic changes and coagulopathy leading to multiple organ failure and often to death. The altered physiological mechanisms underlying the septic shock syndrome, and the cellular means by which these changes are induced and controlled, are not yet known in precise detail. In broad outline, however, a consensus view of events culminating in septic shock has emerged over the last several years. In particular, it is now generally accepted that septic shock reflects the individual, combined and concerted effects of a large number of endogenous, host-derived mediator molecules. These mediators are produced in response to initiating stimuli that indicate the host has been invaded, and the class of peptide mediators that were generally first recognized as white blood cell products have come to be known as cytokines. As mediators of toxic effects and pathological alterations in host homeostasis, these endogenous factors represent potentially attractive therapeutic targets, and septic shock remains a potentially lethal cytokine-mediated clinical complication against which there is no generally effective therapeutic approach.
Although traditionally termed “septic” shock, infection by a variety of microorganisms including not only bacteria but also viruses, fungi, and parasites can induce septic shock. In fact, the shock syndrome is more properly associated with the host's response to invasion rather than just infection, as cancer and trauma, for instance, can also serve as initiators. In the case of infection by gram-negative bacteria, one of the best studied examples, it is believed that the appearance of bacterial endotoxins such as lipopolysaccharide (LPS) in the host bloodstream leads to the endogenous production of a variety of host factors that directly and indirectly mediate the toxicity of LPS, which itself is relatively innocuous for most cells. These host-derived mediators include many now well-recognized inflammatory cytokines and classical endocrine hormones in addition to a number of other endogenous factors such as leukotrienes and platelet activating factor. It is generally acknowledged, however, that the full cast of participants and each of their interrelated roles in the host response remains incompletely appreciated.
In general, those mediators that appear earlier in an invaded host are thought to trigger the release of later appearing factors. Also, many endogenous mediators not only exert direct effector functions at their target tissues, but also prime local and remote tissues for subsequent responses to other mediators. This interacting network of host factors has been termed the “cytokine cascade.” This term is meant to indicate the rapid extension and amplification of the host response in such a way that only one or a few initiating stimuli trigger the eventual release and participation of scores of host mediators. Although a number of features of the host response are thought to assist in fighting off invasion, an overly robust or poorly modulated endogenous response can rapidly accelerate to rapidly produce such profound alterations in host homeostasis at the cellular, tissue, and systemic levels that death may ensue within hours.
Among the interacting factors that together comprise the cytokine cascade, the cytokine known as tumor necrosis factor-alpha (TNF&agr;) is the most important identified to date. TNF&agr; is the first cytokine to appear in the circulation after LPS challenge. The hemodynamic and metabolic alterations that result from the experimental administration of TNF&agr; closely resemble those that have been observed in endotoxemia and septic shock. In animal models, TNF&agr; is the only host factor which itself can initiate a lethal syndrome that mimics septic shock in detail. In this respect, TNF&agr; can be considered a sufficient mediator of septic shock. Functionally neutralizing TNF&agr; antagonists such as anti-TNF&agr; antibodies are protective in otherwise lethal bacterial infections, and in this respect TNF&agr; can be considered a necessary mediator of septic shock.
Other cytokines participate in the host response to LPS but appear later in the circulation. However, no other cytokine has been shown to be both necessary and sufficient to mediate septic shock. For example, certain interleukins (IL-1, IL-6 and IL-8) which appear in serum more than 2 hours after LPS challenge, and interferon &ggr; (IFN-&ggr;) which appears after 6 hours, are thought to play a significant role in septic shock, and can be shown to contribute to lethality in certain disease models or under experimental conditions of endotoxemia. Antagonism of the effects of specific interleukins and interferons has been shown to confer a significant protective effect under certain conditions. Nevertheless, none of these other factors can itself induce a full-blown septic shock-like effect in otherwise healthy individuals, and none of these other cytokines appears to play as central and critical role in septic shock as TNF&agr;.
In view of the foregoing, TNF&agr; stands as an ideal target for the treatment of septic shock. Unfortunately, temporal characteristics of the endogenous TNF&agr; response suggest a significant practical limitation for this potential therapy. TNF&agr;, one of the earliest elicited mediators to appear in acute disease, rapidly peaks after bolus endotoxin challenge (30-90 minutes), and diminishes just as promptly. It is presumed that most of the damaging effects of TNF&agr; in septic shock are completed during this early period, hence TNF&agr; antagonists such as anti-TNF&agr; antibodies would ideally be present at this time. Since this therapeutic window is apparently so short and occurs so early, the timely delivery of anti-TNF&agr; based therapeutics may be very difficult to achieve clinically.
Therefore, in order utilize cytokines as targets for the treatment of septic shock and other cytokine-mediated toxic reactions, there exists a desperate need to discover additional targets that are both necessary components of the cytokine cascade and occur at a time during the endogenous response that is accessible for therapeutic antagonism in the course of clinical treatment.
2.2. The Pituitary as a Source of Protective Cytokines
Recent studies suggest that the pituitary gland may produce factors that inhibit endotoxin-induced TNF&agr; and IL-1 production, and thus may serve as a source for potentially protective factors that may be used to treat shock and/or other inflammatory responses. (Suzuki et al., 1986, Am. J. Physiol. 250: E470-E474; Sternberg et al., 1989, Proc. Natl. Acad. Sci. USA 86: 2374-2378; Zuckerman et al., 1989, Eur. J. Immunol. 19: 301-305; Edwards III et al., 1991a, Endocrinol. 128: 989-996; Edwards III et al., 1991b, Proc. Natl. Acad. Sci. USA 88: 2274-2277, Silverstein et al., 1991, J. Exp. Med. 173:357-365). In these studies, hypophysectomized mice (i.e., animals that have had their pituitary glands surgically removed) exhibited a marked increased sensitivity to LPS injection relative to sham-operated control mice. In fact, the LPS LD
100
for control mice was approximately 1-2 logs higher than that determined for the hypophysectomized mice, suggesting that the pituitary gland produces one or more factors that may act to increase the host animal's ability to resist endotoxin challenge. Some of these studies implicate the involvement of ACTH and adrenocorticosteroids (e.g., Edwards III et al., 1991a and 1991b, supra); however, oth
Bernhagen Jurgen
Bucala Richard J.
Calandra Thierry F.
Cerami Anthony
Mitchell Robert A.
Bunner Bridget E.
Kelber Steven B.
Kemmerer Elizabeth C.
Rudnick LLP Piper
The Picower Institute for Medical Research
LandOfFree
Composition containing anti-MIF antibody does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Composition containing anti-MIF antibody, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Composition containing anti-MIF antibody will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3184958