Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-03-27
2003-10-28
Allen, Marianne P. (Department: 1631)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C514S013800, C514S014800, C530S324000, C530S328000, C530S387100
Reexamination Certificate
active
06638911
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to methods for modulating desmosomal cadherin-mediated functions, and more particularly to the use of modulating agents derived from desmocollin and desmoglein cell adhesion recognition sequences for inhibiting or enhancing functions mediated by such desmosomal cadherins.
BACKGROUND OF THE INVENTION
Cadherins are a rapidly expanding superfamily of calcium-dependent cell adhesion molecules (CAMs) (for review, see Munro et al., In:
Cell Adhesion and Invasion in Cancer Metastasis,
P. Brodt, ed., pp. 17-34, RG Landes Co., Austin Tex., 1996). All cadherins appear to be membrane glycoproteins that generally promote cell adhesion through homophilic interactions (a cadherin on the surface of one cell binds to an identical cadherin on the surface of another cell), although cadherins also appear to be capable of forming heterotypic complexes with one another under certain circumstances and with lower affinity.
There are many different types of cadherins. The most extensively studied group of cadherins is known as the classical, or type I, cadherins. Classical cadherins have been shown to regulate epithelial, endothelial, neural and cancer cell adhesion, with different cadherins expressed on different cell types. All classical cadherins have a similar structure. As illustrated in
FIG. 1A
, classical cadherins are composed of five extracellular domains (EC1-EC5), a single hydrophobic domain (TM) that transverses the plasma membrane (PM), and two cytoplasmic domains (CP1 and CP2). The calcium binding motifs DXNDN (SEQ ID NO:1), DXD and LDRE (SEQ ID NO:2) are interspersed throughout the extracellular domains, and each 110 amino acid region that contains such motifs is considered a cadherin repeat. The first extracellular domain (EC1) contains the cell adhesion recognition (CAR) sequence, HAV (His-Ala-Val), along with flanking sequences on either side of the CAR sequence that play a role in conferring specificity. Synthetic peptides containing the HAV sequence and antibodies directed against such peptides have been shown to inhibit classical cadherin-dependent processes (Munro et al., supra; Blaschuk et al.,
J. Mol. Biol.
211:679-82, 1990; Blaschuk et al.,
Develop. Biol.
139:227-29, 1990; Alexander et al.,
J. Cell. Physiol
156:610-18, 1993).
Cadherins that contain calcium binding motifs within extracellular domain cadherin repeats, but do not contain an HAV CAR sequence, are considered to be nonclassical cadherins (illustrated in
FIGS. 1B
to
1
AA). To date, nine groups of nonclassical cadherins have been identified (types II-X). These cadherins are also membrane glycoproteins. Type II, or atypical, cadherins include OB-cadherin (cadherin-11; see Getsios et al.,
Developmental Dynamics
211:238-247, 1998; Simonneau et al.,
Cell Adhesion and Communication
3:115-130, 1995; Okazaki et al.,
J. Biological Chemistry
269:12092-12098, 1994), cadherin-5 (VE-cadherin; see Navarro et al.,
J. Cell Biology
140:1475-1484, 1998), cadherin-6 (K-cadherin; see Shimoyama et al.,
Cancer Research
55:2206-2211, 1995; Shimazui et al.,
Cancer Research
56:3234-3237, 1996; Inoue et al.,
Developmental Dynamics
211:338-351, 1998; Getsios et al.,
Developmental Dynamics
211:238-247, 1998), cadherin-7 (see Nakagawa et al.,
Development
121:1321-1332, 1995), cadherin-8 (see Suzuki et al.,
Cell Regulation
2:261-270, 1991), cadherin-12 (Br-cadherin; see Tanihara et al.,
Cell Adhesion and Communication
2:15-26, 1994), cadherin-14 (see Shibata et al.,
J. Biological Chemistry
272:5236-5240, 1997), cadherin-15 (M-cadherin; see Shimoyama et al.,
J. Biological Chemistry
273:10011-10018, 1998), and PB-cadherin (see Sugimoto et al.,
J. Biological Chemistry
271:11548-11556, 1996). For a general review of atypical cadherins, see Redies and Takeichi,
Developmental Biology
180:413-423, 1996 and Suzuki et al.,
Cell Regulation
2:261-270, 1991.
Types III-X include LI-cadherin (type III; see Berndorff et al.,
J. Cell Biology
125:1353-1369, 1994), T-cadherin (type IV; see Ranscht, U.S. Pat. No. 5,585,351; Tkachuk et al.,
FEBS Lett.
421:208-212, 1998; Ranscht et al.,
Neuron
7:391-402, 1991; Sacristan et al.,
J. Neuroscience Research
34:664-680, 1993; Vestal and Ranscht,
J. Cell Biology
119:451-461, 1992; Fredette and Ranscht,
J. Neuroscience
14:7331-7346, 1994; Ranscht and Bronner-Fraser,
Development
111:15-22, 1991), protocadherins (type V; e.g., protocadherins 42, 43 and 68; see Sano et al.,
EMBO J.
12:2249-2256, 1993; GenBank Accession Number AF029343), desmocollins (type VI; e.g., desmocollins 1, 2, 3 and 4; see King et al.,
Genomics
18:185-194, 1993; Parker et al.,
J. Biol Chem.
266:10438-10445, 1991; King et al.,
J. Invest. Dermatol
105:314-321, 1995; Kawamura et al.,
J. Biol Chem.
269:26295-26302, 1994), desmogleins (type VII; e.g., desmogleins 1 and 2; see Wheeler et al.,
Proc. Natl Acad. Sci. USA
88:4796-4800; Koch et al.,
Eur. J. Cell. Biol
55:200-208, 1991), and cadherin-related neuronal receptors (type X; see Kohmura et al.,
Neuron
20:1137-1151, 1998).
Most studies of nonclassical cadherins have focused on atypical or type II cadherins. The structure of such cadherins is similar to that of the type I cadherins, but they do not contain the CAR sequence, HAV (FIG.
1
B). Atypical cadherins appear to mediate a wide variety of functions. Additional variation is seen in the structures of types III-X cadherins. Although less studied, such cadherins also appear to play a role in diverse functions. Desmosomal cadherins, for example, are present within desmosomes, the intercellular junctions that provide adhesion and membrane anchors for the intermediate filament cytoskeleton. These cadherins (e.g., desmogleins and desmocollins) play a role in desmosomal adhesion, which is critically important for normal tissue construction and epidermis structure. Abnormal desmosomes appear in certain types of carcinomas and other skin disorders (see Chidgey,
Histol Histopathol.
12:1159-1168, 1997).
Notwithstanding these recent advances, nonclassical cadherin function remains poorly understood at the biological and molecular levels. Accordingly, there is a need in the art for identifying sequences involved in modulating nonclassical cadherin-dependent functions, such as cell adhesion mediated by desmosomal cadherins, and for the development of methods employing such sequences to inhibit processes such as cell adhesion. The present invention fulfills these needs and further provides other related advantages.
SUMMARY OF THE INVENTION
Briefly stated, this invention provides compositions and methods for modulating desmosomal cadherin-mediated functions, such as cell adhesion. Within certain aspects, modulating agents are provided. Such agents are capable of modulating (i.e., inhibiting or enhancing) one or more functions mediated by the desmosomal cadherins desmoglein (dsg) or desmocollin (dsc). A modulating agent may comprise at least one of: (a) a native dsc or dsg CAR sequence; (b) an analogue of such a CAR sequence that is capable of modulating dsc- or dsg-mediated cell adhesion; (c) a non-peptide peptidomimetic of a dsg or dsg CAR sequence that is capable of modulating dsc- or dsg-mediated cell adhesion; (d) an antibody, or antigen-binding fragment thereof, that specifically binds a dsc or dsg CAR sequence; and/or (e) a polynucleotide encoding a native dsc or dsg CAR sequence or analogue thereof that is capable of modulating dsc- or dsg-mediated cell adhesion. Certain preferred modulating agents comprise a desmoglein-1, desmoglein-2, desmoglein-3, desmocollin-1, desmocoffin-2, desmocollin-3 or desmocollin-4 CAR sequence, or an analogue of any of the foregoing CAR sequences. An analogue is generally a peptide sequence that is at least 50% identical to a dsg or dsc CAR sequence, and (i) detectably inhibits a function that is modulated by the dsg or dsc; or (ii) detectably enhances adhesion of cells that express the dsg or dsc. Modulating agents preferably contain no more than 85, and preferably no more than 50, consecutive amino
Blaschuk Orest W.
Gour Barbara J.
Symonds James Matthew
Adherex Technologies Inc.
Allen Marianne P.
Seed IP Law Group PLLC
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