Peptide inhibitors of inflammation mediated by selectins

Details Peptide inhibitors of inflammation mediated by selectins Peptide inhibitors of inflammation mediated by selectins

1993-10-12

2003-03-04

Russel, Jeffrey E. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S012200, C514S014800, C514S015800, C514S016700, C514S017400, C530S324000, C530S325000, C530S326000, C530S327000, C530S328000, C530S329000, C530S330000

Reexamination Certificate

active

06528487

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention is generally in the field of methods of the treatment and prevention of inflammatory responses using peptides derived from selectins including GMP-140, ELAM-1, and lymphocyte-homing receptor.
The adherence of platelets and leukocytes to vascular surfaces is a critical component of the inflammatory response, and is part of a complex series of reactions involving the simultaneous and interrelated activation of the complement, coagulation, and immune systems.
The complement proteins collectively play a leading role in the immune system, both in the identification and in the removal of foreign substances and immune complexes, as reviewed by Muller-Eberhard, H. J.,
Ann. Rev. Biochem
. 57:321-347 (1988). Central to the complement system are the C3 and C4 proteins, which when activated covalently attach to nearby targets, marking them for clearance. In order to help control this process, a remarkable family of soluble and membrane-bound regulatory proteins has evolved, each of which interacts with activated C3 and/or C4 derivatives. The coagulation and inflammatory pathways are regulated in a coordinate fashion in response to tissue damage. For example, in addition to becoming adhesive for leukocytes, activated endothelial cells express tissue factor on the cell surface and decrease their surface expression of thrombomodulin, leading to a net facilitation of coagulation reactions on the cell surface. In some cases, a single receptor can be involved in both inflammatory and coagulation processes.
Leukocyte adherence to vascular endothelium is a key initial step in migration of leukocytes to tissues in response to microbial invasion. Although a class of inducible leukocyte receptors, the CD11-CD18 molecules, are thought to have some role in adherence to endothelium, mechanisms of equal or even greater importance for leukocyte adherence appear to be due to inducible changes in the endothelium itself.
Activated platelets have also been shown to interact with both neutrophils and monocytes in vitro. The interaction of platelets with monocytes may be mediated in part by the binding of thrombospondin to platelets and monocytes, although other mechanisms have not been excluded. The mechanisms for the binding of neutrophils to activated platelets are not well understood, except that it is known that divalent cations are required. In response to vascular injury, platelets are known to adhere to subendothelial surfaces, become activated, and support coagulation. Platelets and other cells may also play an important role in the recruitment of leukocytes into the wound in order to contain microbial invasion.
Endothelium exposed to “rapid” activators such as thrombin and histamine becomes adhesive for neutrophils within two to ten minutes, while endothelium exposed to cytokines such as tumor necrosis factor and interleukin-1 becomes adhesive after one to six hours. The rapid endothelial-dependent leukocyte adhesion has been associated with expression of the lipid mediator platelet activating factor (PAF) on the cell surface, and presumably, the appearance of other endothelial surface receptors. The slower cytokine-inducible endothelial adhesion for leukocytes is mediated, at least in part, by an endothelial cell receptor, ELAM-1, that is synthesized by endothelial cells after exposure to cytokines and then transported to the cell surface, where it binds neutrophils. The isolation, characterization and cloning of ELAM-1 is reviewed by Bevilacqua, et al., in
Science
243, 1160-1165 (1989). A peripheral lymph node homing receptor, also called “the murine Mel 14 antigen”, “Leu 8”, the “Leu 8 antigen” and “LAM-1”, is another structure on neutrophils, monocytes, and lymphocytes that binds lymphocytes to high endothelial venules in peripheral lymph nodes. The characterization and cloning of this protein is reviewed by Lasky, et al.,
Cell
56, 1045-1055 (1989) (mouse) and Tedder, et al.,
J. Exp. Med
.170, 123-133 (1989).
GMP-140 (granule membrane protein 140), also known as PADGEM, is a cysteine-rich and heavily glycosylated integral membrane glycoprotein with an apparent molecular weight of 140,000 as assessed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). GMP-140 was first purified from human platelets by McEver and Martin,
J. Biol. Chem
. 259:9799-9804 (1984). The protein is present in alpha granules of resting platelets but is rapidly redistributed to the plasma membrane following platelet activation, as reported by Stenberg, et al., (1985). The presence of GMP-140 in endothelial cells and its biosynthesis by these cells was reported by McEver, et al.,
Blood
70(5) suppl. 1:355a, Abstract No. 1274 (1987). In endothelial ells, GMP-140 is found in storage granules known as the Weibel-Palade bodies. (McEver, et al.
J. Clin. Invest
. 84:92-99 (1989) and Hattori, et al.,
J. Biol. Chem
. 264:7768-7771 (1989)). GMP-140 (called PADGEM) has also been reported to mediate the interaction of activated platelets with neutrophils and monocytes by Larsen, et al., in
Cell
59, 305-312 (October 1989) and Hamburger and McEver,
Blood
75:550-554 (1990).
The cDNA-derived amino acid sequence, reported by Johnston, et al., in
Cell
56, 1033-1044 (Mar. 24 1989), and in U.S. Ser. No. 07/320,408 filed Mar. 8, 1989 now U.S. Pat. No. 8,378,464, indicates that it contains a number of modular domains that are likely to fold independently. Beginning at the N-terminus, these include a “lectin” domain, an “EGF” domain, nine tandem consensus repeats similar to those in complement binding proteins, a transmembrane domain (except in a soluble form that appears to result from differential splicing), and a cytoplasmic tail.
When platelets or endothelial cells are activated by mediators such as thrombin, the membranes of the storage granules fuse with the plasma membrane, the soluble contents of the granules are released to the external environment, and membrane bound GMP-140 is presented within seconds on the cell surface. The rapid redistribution of GMP-140 to the surface of platelets and endothelial cells as a result of activation suggested that this glycoprotein could play an important role at sites of inflammation or vascular disruption.
This important role has been confirmed by the observation that GMP-140 is a receptor for neutrophils (Geng et al.,
Nature
343:757-760 (1990); Hamburger and McEver,
Blood
75:550-554 (1990)), monocytes (Larsen, et al.,
Cell
59:305-312 (1989); Moore, et al.,
J. Cell Biol
. 112:491-499 (1991)), and perhaps a subset of lymphocytes (Moore, et al.,
J. Cell Biol
. 112:491-499 (1991)). Thus, GMP-140 can serve as a receptor for leukocytes following its rapid mobilization to the surfaces of platelets and endothelial cells stimulated with agonists such as thrombin. This role in leukocyte recruitment may be important in hemostatic and inflammatory processes in both physiologic and pathologic states.
Peptides derived from GMP-140 are described in U.S. Ser. No. 07/554,199 entitled “Functionally Active Selectin-Derived Peptides” filed Jul. 17, 1990 by Rodger P. McEver now abandoned, that are useful in diagnostics and in modulating the hemostatic and inflammatory responses in a patient wherein a therapeutically effective amount of a peptide capable of blocking leukocyte recognition of GMP-140 is administered to the patient. U.S. Ser. No. 07/554,199 filed Jul. 17, 1990 now abandoned, also discloses that peptide sequences within the lectin domain of GMP-140, having homology with the lectin domains of other proteins, especially ELAM-1 and the homing receptor, selectively inhibit neutrophil adhesion to purified GMP-140, and can therefore be used in diagnostic assays of patients and diseases characterized by altered binding by these molecules, in screening assays for compounds altering this binding, and in clinical applications to inhibit or modulate interactions of leukocytes with platelets or endothelial cells involving coagulation and/or inflammatory processes.
ELAM-1, the homing receptor, and GMP-140 have been termed “selectins”, b

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