Compounds and methods for modulating OB-cadherin mediated...

Details Compounds and methods for modulating OB-cadherin mediated... Compounds and methods for modulating OB-cadherin mediated...

1998-05-05

2002-10-29

Allen, Marianne P. (Department: 1631)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S011400, C514S012200, C514S016700, C514S017400, C514S018700, C530S317000, C530S324000, C530S326000, C530S327000, C530S328000

Reexamination Certificate

active

06472367

ABSTRACT:

TECHNICAL FIELD
The present invention relates generally to methods for modulating OB-cadherin-mediated processes, and more particularly to the use of modulating agents comprising OB-cadherin cell adhesion recognition sequences, or antibodies that specifically recognize such sequences, for inhibiting or enhancing functions such as cell adhesion, tumor cell invasion and metastasis.
BACKGROUND OF THE INVENTION
Cadherins are a rapidly expanding family 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). There are many different types of cadherins (abbreviated CADs). The most extensively studied group of CADs is known as the classical, or type I, CADs. These CADs are integral membrane glycoproteins that generally promote cell adhesion through homophilic interactions (a CAD on the surface of one cell binds to an identical CAD on the surface of another cell), although CADs also appear to be capable of forming heterotypic complexes with one another under certain circumstances and with lower affinity. Cadherins have been shown to regulate epithelial, endothelial, neural and cancer cell adhesion, with different CADs expressed on different cell types. N (neural)—cadherin is predominantly expressed by neural cells, endothelial cells and a variety of cancer cell types. E (epithelial)—cadherin is predominantly expressed by epithelial cells. Other CADs are P (placental)—cadherin, which is found in human skin and R (retinal)—cadherin. A detailed discussion of the classical cadherins is provided in Munro S B et al.,
In: Cell Adhesion and Invasion in Cancer Metastasis,
P. Brodt, ed., pp. 17-34 (RG Landes Company, Austin, Tex., 1996).
The structures of the CADs are generally similar. As illustrated in
FIG. 1A
, CADs 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. The first extracellular domain (EC1) contains the classical cadherin cell adhesion recognition (CAR) sequence, HAV (His-Ala-Val), along with flanking sequences on either side of the CAR sequence that may play a role in conferring specificity. Synthetic peptides containing the CAR sequence and antibodies directed against the CAR sequence have been shown to inhibit CAD-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).
A second group of CADs is known as the atypical, or type II CADs (Munro et al., supra). Although the structure of these CADs is similar to that of the type I CADs, they do not contain the CAR sequence, HAV (FIG.
1
B). Furthermore, the functions of the type II CADs are poorly understood.
OB-cadherin, which is also known as cadherin-11, is an atypical CAD (Okazaki et al.,
J. Biol. Chem.
269:12092-98, 1994; Suzuki et al.,
Cell Regulation
2:261-70, 1991; Munro et al., supra). This CAD can promote cell adhesion through homophilic interactions. Recent studies have shown that OB-cadherin is not expressed by well-differentiated, poorly invasive cancer cells, whereas it is expressed by invasive cancer cells (Stephen W. Byers, Georgetown University, Washington DC, personal communication; Shimazui et al.,
Cancer Res.
56:3234-37, 1996; Shibata et al.,
Cancer Letters
99:147-53, 1996). OB-cadherin levels are also high in stromal cells and osteoblasts (Shibata et al.,
Cancer Letters
99:147-53, 1996; Simonneau et al.,
Cell Adhes. Commun.
3:115-30, 1995; Matsuyoshi and Imamura,
Biochem. Biophys. Res. Commun.
23:355-58, 1997; Okazaki et al.,
J. Biol. Chem.
269:12092-98, 1994). Collectively, these observations have led to the hypothesis that OB-cadherin may mediate the interaction between malignant tumor cells and other cell types, such as stromal cells and osteoblasts, thus facilitating tumor cell invasion and metastasis.
OB-cadherin is expressed in certain specific cell types. In some invasive cancer cells, OB-cadherin is not only found at sites of cell—cell contact, but it is also found in lamellopodia-like projections which do not interact with other cells (Stephen W. Byers, Georgetown University, Washington DC, personal communication). These observations suggest that OB-cadherin may also play a role in modulating cell-substrate interactions. In adipocytes, OB-cadherin is the only known expressed cadherin. OB-cadherin is therefore likely to mediate adhesion between adipocytes, and it is likely to be an important regulator of adipogenesis. Another cell type that expresses OB-cadherin is the pericyte (also known as the peri-endothelial cell). Pericytes are contractile cells which are similar to smooth muscle cells. They encircle the endothelial cells of blood vessels. Pericytes are involved in maintaining the structural integrity of blood vessels (Hanahan,
Science
277:48-50, 1997; Lindahl et al.,
Science
277:242-245, 1997). Loss of pericytes causes blood vessels to regress.
Notwithstanding these recent advances, OB-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 OB-cadherin-dependent cell adhesion, and for the development of methods employing such sequences to inhibit cancer cell adhesion, invasion and metastasis. 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 OB-cadherin-mediated processes, such as cancer cell adhesion, invasion, and metastasis. Within certain aspects, cell adhesion modulating agents capable of modulating OB-cadherin mediated cell adhesion are provided. Such modulating agents may comprise at least one of: (a) a native OB-cadherin CAR sequence; (b) an analogue of a native OB-cadherin CAR sequence that is capable of modulating OB-cadherin-mediated cell adhesion; (c) a non-peptide peptidomimetic of an OB-cadherin CAR sequence that is capable of modulating OB-cadherin-mediated cell adhesion; (d) an antibody, or antigen-binding fragment thereof, that specifically binds an OB-cadherin CAR sequence; and/or (e) a polynucleotide encoding a native OB-cadherin CAR sequence or analogue thereof that is capable of modulating OB-cadherin-mediated cell adhesion. Certain preferred modulating agents may comprise a peptide that comprises one or more of the following peptide sequences: DDK, IDDK (SEQ ID NO:32), DDKS (SEQ ID NO:33), VIDDK (SEQ ID NO:3), IDDKS (SEQ ID NO:4), VIDDKS (SEQ ID NO:34), DDKSG (SEQ ID NO:35), IDDKSG (SEQ ID NO:24), VIDDKSG (SEQ ID NO:36), FVIDDK (SEQ ID NO:37), FVIDDKS (SEQ ID NO:38), FVIDDKSG (SEQ ID NO:5), IFVIDDK (SEQ ID NO:39), IFVIDDKS (SEQ ID NO:40) or IFVIDDKSG (SEQ ID NO:6), or an analogue or peptidomimetic of any of the foregoing peptide sequences. Within other embodiments, a modulating agent may comprise a cyclic peptide having one of the following sequences:
CDDKC
(SEQ ID NO:7),
CIDDKC
(SEQ ID NO:41),
CDDKSC
(SEQ ID NO:42),
CVIDDKC
(SEQ ID NO:8),
CIDDKSC
(SEQ ID NO:9),
CVIDDKSC
(SEQ ID NO:43),
CDDKSGC
(SEQ ID NO:44),
CIDDKSGC
(SEQ ID NO:45),
CVIDDKSGC
(SEQ ID NO:31),
CFVIDDKC
(SEQ ID NO:46),
CFVIDDKSC
(SEQ ID NO:47),
CFVIDDKSGC
(SEQ ID NO:10),
CIFVIDDKC
(SEQ ID NO:48),
CIFVIDDKSC
(SEQ ID NO:49), or
CIFVIDDKSGC
(SEQ ID NO:11),
DDDK
(SEQ ID NO:50),
DIDDK
(SEQ ID NO:51),
DVIDDK
(SEQ ID NO:52),
DFVIDDK
(SEQ ID NO:53),
DIFVIDDK
(SEQ ID NO:54),
EDDK
(SEQ ID NO:55),
EIDDK
(SEQ ID NO:56),
EVIDDK
(SEQ ID NO:57),
EFVIDDK
(SEQ ID NO:58),
EIFVIDDK
(SEQ ID NO:59),
KDDKD
(SEQ ID NO:14),
KIDDKD
(SEQ ID NO:60),
KDDKSD
(SEQ ID NO:61),
KVIDDKD
(SEQ ID NO:62),
KIDDKSD
(SEQ ID NO:63),
KVIDDKSD
(SEQ ID NO:64),
KDDKSGD
(SEQ ID NO:65),

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