Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1998-09-08
2004-05-11
Nolan, Patrick J. (Department: 1644)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007210, C436S065000, C436S814000
Reexamination Certificate
active
06733979
ABSTRACT:
BACKGROUND OF THE INVENTION
Over the past decade, investigators have come to recognize the importance of the extracellular matrix (ECM) in directing the growth, differentiation and function of the overlying epithelium. Getzenberg et al., “The Tissue Matrix: Cell Dynamics and Hormone Action”,
Endocrine Rev
., 11:399-417 (1990). The interaction between cell and extracellular matrix (or substratum) is mediated by several classes of cell adhesion molecules, one of the most important being the integrins. Albelda et al., “Integrins and Other Cell Adhesion Molecules”,
FESEB J
., 4:2868-2880 (1990). Buck et al., “Integrin, a Transmembrane Glycoprotein Complex Mediating Cell-Substratum Adhesion”,
J. Cell Sci. Suppl
., 8:231-250 (1987). This diverse family of glycoprotein receptors is expressed on the cell membrane as heterodimeric &agr; and &bgr; subunits and is involved in both cell-cell and cell-substratum adhesion. Specific recognition and binding of extracellular matrix (ECM) components such as fibronectin (FN), laminin (LM) and collagen (Col) transmit information to the cytoskeletal structure, an interaction which may have major roles in promoting hormone responsiveness and genomic activation. Burridge et al., “Focal Adhesions: Transmembrane Junctions Between the Extracellular Matrix and the Cytoskeleton”,
Ann. Rev. Cell. Biol
. 4: 487-525 (1988) and Getzenberg et al. supra.
Although extensive information exists about specific integrin proteins, for example, Hemler, M. E. “VLA Proteins in the Integrin Family: Structures, Functions and Their Role on Leukocytes”,
Annu. Rev. Immunol
: 365-400 (1990), little is known concerning the distribution of these receptors in the female reproductive tract. In the uterus, the endometrium, composed of glandular epithelium and associated mesenchyme (stroma), maintains complex temporal and spatial functions in response to the cyclic hormonal milieu. The search for morphological or biochemical markers for uterine receptivity has been unsuccessful to date as reported by Rogers and Murphy, “Uterine Receptivity for Implantation: Human Studies”, in
Blastocyst Implantation
, Yoshinaga, K. ed., Serono Symposia, pp. 231-238 (1989). Once such markers are identified, their role in endometrial phenomena including embryo implantation, fertility, contraception and endometrial maturation and receptivity can likely also be identified. Thus, as some integrins appear to meet the criteria for markers of receptivity there is a great need for methods of detecting integrin cell adhesion molecules in endometrium.
SUMMARY OF THE INVENTION
The present invention is directed to methods of detecting receptivity of endometrium to embryo implantation by detecting the &bgr;
3
subunit of the &agr;
v
/&bgr;
3
integrin in endometrium with a monoclonal antibody.
Methods of diagnosing fertility and methods of monitoring endometrial maturation in a mammal are also provided by monitoring the appearance of the &bgr;
3
subunit of integrin in endometrium from a plurality of stages of the endometrial cycle. This is preferably done with a monoclonal antibody.
The present invention also provides methods of detecting the optimal window of embryo implantation in the endometrium by detecting the &bgr;
3
subunit of integrin in an endometrial sample, preferably with a monoclonal antibody.
Further aspects of the invention include methods of preventing embryo implantation by contacting the &bgr;
3
subunit of integrin in the endometrium with neutralizing Fab antibody fragments to &bgr;
3
. Methods of in vitro fertilization are also embodiments of the invention. These comprise detecting the &bgr;
3
subunit of integrin in an endometrial sample, fertilizing an egg in vitro, and introducing the zygote into the uterus having endometrial tissue expressing the &bgr;
3
subunit.
Contraceptive and diagnostic kits are also contemplated hereby.
These and other aspects of the invention will become more apparent from the following detailed description when taken in conjunction with the following figures.
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Fazleabas, et al., “Distribution of integrins and the extracellular matrix proteins in the baboon endometrium during the menstrual cycle and early pregnancy”,Bio of Reprod.56:348-356 (1997).
Fedele et al., “Structural and ultrastructural defects in preovulatory endometrium of normo-ovulating infertile women with minimal or mild endometriosis”,Fertil. Steril.53:989 (1990).
Getzenberg et al., “The tissue matrix: cell dynamics and hormone action endocrine”, Rev. 11:399-417 (1990).
Hahn et al., “Experimental evidence for failure to implant as a mechanism of infertility associated with endometriosis”,Am. J. Obstet. Gynecol.155:1109 (1986).
Harlow and Lane, “Storing and purifying antibodies”,Antibodies A Laboratory ManualCold Spring Harbor Laboratory, 287 (1988).
Hasson, “Incidence of endometriosis in diagnostic laparaoscopy”,J. Reprod. Med.16:135 (1976).
Hemler, M.E. “VLA proteins in the integrin family: structures, functions and their role on Leukocytes”,Annu. Rev. Immunol.8:365-400 (1990).
Hertig, A.T. et al. E.C. “A description of 34 human OVA within the first 17 days of development”,Am. J. Anat.98: 435-493 (1956).
Hornstein et al., “Menstrual cyclicity of CA-125 in patients with endometriosis”,Fertil. Steril.58:279 (1992).
Ilesanmi, et al., “Immunohistochemical markers of uterine receptivity in the human endometrium”,Micro Res and Tech25: 208-222 (1993).
Kao
Heller Ehrman White & McAuliffe LLP
Nolan Patrick J.
Seidman Stephanie L.
The Trustees of the University of Pennsylvania
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