Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-05-23
2003-06-24
Russel, Jeffrey E. (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S014800
Reexamination Certificate
active
06583110
ABSTRACT:
BACKGROUND OF THE INVENTION
Septic shock (also known as sepsis) causes more than 150,000 deaths annually in the United States. Sepsis is defined as a clinical disorder whose symptoms may include well defined abnormalities in body temperature, heart rate, breathing rate, white blood cell count, hypotension, organ perfusion abnormalities, and multiple organ dysfunction. There are several causes of sepsis including bacterial (either gram negative or gram positive), fungal and viral infections, as well as non-infective stimuli such as multiple trauma, severe burns, organ transplantation and pancreatitis.
Septic patients usually die as a result of poor tissue perfusion and injury followed by multiple organ failure. It is well recognized that many of the responses that occur during septic shock are initiated by bacterial endotoxin, a glycolipid antigen present on the surface of gram negative bacteria. This endotoxin (also referred to herein as lipopolysacchride or LPS) is released upon the death or multiplication of the bacteria and is known to activate monocytes/macrophages or endothelial cells causing them to produce various mediatior molecules such as toxic oxygen radicals, hydrogen peroxide, tumor neurosis factor-alpha (TNF&agr;), and interleukin (IL-1, IL-6, and IL-8). These cellular and humoral inflammatory mediators evoke septic shock with symptoms ranging from chills and fever to circulatory failure, multiorgan failure, and death.
The impact of sepsis is particularly devastating to patients with compromised cardiac and hepatic function and to immunocompromised patients. Patients at high risk are elderly, chemotherapy patients and those requiring surgery or invasive instrumentation. The current therapy of antibiotics and hemodynamic support has not proven to be successful. An improved method for treating or preventing septic shock would be of great value.
The major LPS receptor for monocytes/macrophages is the glycosylphosphatidylinositol (GPI) anchored glycoprotein CD14. It is the interaction of LPS with the LPS receptor CD14 that initiates the cascade of signaling events that cause cytokine gene transcription. The precise mechanism through which LPS interacts with CD14 is unknown. Much of the controversy regarding the role of CD14 in LPS-induced signal transduction and cytokine production stems from the fact that CD14 is attached to the cell membrane by a glycosylphosphatidylinositol (GPI)-anchor and contains neither transmembrane nor cytoplasmic amino acid sequences. As such, CD14 cannot interact with signal transduction molecules in the same way as transmembrane receptors. Recently, it has been demonstrated that GPI-anchored proteins expressed on many cell types can physically interact with lipid-linked signal transduction molecules, but the functional consequences of these interactions remain unresolved (Stefanova et al.,
Science
, 254: 1016-1018, 1991; Shenoy-Scaria et al.,
Mol Cell Biol
., 13: 6385-6392, 1993; Solomon et al.,
Proc. Nat. Acad. Sci
., 93: 6053-6058, 1996).
Although the precise mechanism through which LPS binding to CD14 leads to cell activation is not known, it has been demonstrated that this interaction is enhanced by the serum factor LPS-binding protein (LBP) (Shumann et al.,
Science
, 249: 1429-1432, 1990; Hailman et al.,
J. Exp. Med
., 179: 269-277, 1994). The interaction of LPS/LBP with CD14 causes the exchange of LPS with lipids in target membranes (Wurfel et al.,
J. Exp. Med
., 181: 1743-1754, 1997; Yu et al.,
J. Clin. Med
., 99: 315-324, 1997; Wurfel et al.,
J. Immunol
., 158: 3925-3934, 1997). It has been suggested that this lipid transfer is responsible for LPS-induced signal transduction. The rate of the exchange reaction depends on the lipid composition of the target membranes, which has led to speculation that CD14 functions only to direct LPS insertion into particular membrane domains (Hailman et al.,
J. Exp. Med
., 179: 269-277, 1994; Wurfel et al.,
J. Immunol
., 158: 3925-3934, 1997). While the mechanism that leads to LPS-induced signal transduction has not been demonstrated, it is known that monocyte activation by LPS leads to the phosphorylation of p38 mitogen activated protein kinase (MAPK), and production of inflammatory cytokines (i.e., TNF-&agr;, IL-6) (Sweet, M. J. and Hume D. A.,
J. Leuk. Biol
., 60: 8-26, 1996).
SUMMARY OF THE INVENTION
The present invention is based, at least in part, on the discovery that CD14 on monocytes/macrophages physically interacts with heterotrimeric G proteins and, in particular, that such G proteins specifically regulate LPS-induced mitogen activated protein (MAP) kinase activation and cytokine production in human monocytes/macrophages. This invention is further based on the discovery that agents which bind G proteins, such as G protein binding peptides, inhibit G protein signal transduction to thereby treat or prevent septic shock in vivo.
Accordingly, this invention provides compositions and methods for treating or preventing septic shock in a subject at risk of developing septic shock The method comprises administering an effective amount of an agent which binds G protein such that septic shock is treated or prevented in the subject. The agents which bind G protein are useful for both prophylactic and/or therapeutic treatments of septic shock.
The invention also pertains to compositions for treating or preventing septic shock in a subject which include an effective amount of an agent which binds G protein and, optionally, an antibiotic. The composition can further include a pharmaceutically acceptable carrier.
The present invention also provides methods for using agents which bind G proteins in combination with other agents and/or treatment regimens (e.g., antibiotics, intravenous fluids, cardiovascular and respiratory support) to prophylactically and/or therapeutically treat a subject for septic shock. Other aspects of the invention include packaged agents which bind G proteins and instructions for using such agents for treatment of septic shock.
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Finberg Robert W.
Kurt-Jones Evelyn A.
Solomon Keith R.
Lahive & Cockfield LLP
Mandragouras Esq. Amy E.
Russel Jeffrey E.
Smith, Esq. DeAnn F.
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