Oncofetal antigens are structures expressed during specific stages of embryogenesis and fetal development. Their expression declines during oncogenesis and is suppressed in most established adult tissues, with a few exceptions. Some polypeptide oncofetal antigens, such as .alpha.-fetoprotein, are primary gene products highly expressed at specific stages of embryogenesis, and their synthesis is repressed in adult tissue. In such cases, in which the state of de-differentiation is associated with cancer, dormant genomes may become de-repressed, and fetal antigens may reappear as an index of neoplastic transformation (Sulitzeanu, D. (1985) Advances in Cancer Research, Klein G. and Weinhouse S. (ed.) Academic Press. New York. 44, 1-31).
By application of the monoclonal antibody approach, a number of oncodevelopmentally regulated antigens have been identified as carbohydrates, particularly as extended globo-series structures (Hakomori S. and Kannagi R. (1983) J. Natl. Cancer Inst. 71, 231-251 and Kannagi R.. et al. (1983) J. Biol. Chem. 258, 8934-8942). fucosylated, and fucosylated-sialylated lactoseries structures (Hakomori S. and Kannagi R. (1983) J. Natl. Cancer Inst. 71, 231-251, Fukushi Y., Hakomori S., and Shepard T. (1984) J. Exp. Med. 159, 506-520 and Fukushi Y., et al. (1985) Cancer Res., 45, 3711-3717). Since these carbohydrate antigens are secondary gene products and their expression is controlled by concerted action and organization of glycosyltransferases, the genetic basis for their expression remains unknown.
One group of oncodevelopmentally regulated antigens is comprised of fibronectins.
Fibronectins (FNs) are disulfide-linked dimers of 250-kDa subunits, and play an important role in various contact processes, such as cell attachment and spreading, cell migration, embryonic development, wound healing, hemostasis, opsonization, and oncogenic transformation (Yamada, K.M. (1983) Ann. Rev. Biochem. 52, 761-799). Two major isotypes of FN have been known; one (plasma FN) is found in plasma, and the other (cellular FN) is present in the pericellular matrix and is secreted into the culture medium of fibroblasts. The exact sequence and domain structure of both plasma FN and cellular FN have been fully described, and the genetic mechanism yielding such FN isotypes has been investigated (Hynes, R.O. (1985) Annu. Rev. Cell Biol. 1, 69-90). Both FNs are two different products of a single gene (Kornblihtt, A.R., et al. (1983) Proc. Natl. Acad. Sci. USA 80, 2318-3222) and each subunit has three different types of internal repeats (homology types I. II, and III) (Petersen, T.E. et al. (1983) Proc. Natl. Acad. Sci. USA 80, 137-141). The primary structural differences between the subunits are the result of a complex pattern of alternative splicing of the precursor MRNA. To date, three regions, designated as IIICS, EDI, and EDII, of alternative splicing have been identified (Gutman, A. and Kornblihtt, A.R. (1987) Proc. Natl. Acad. Sci. USA 84, 7179-7182). The IIICS (type III connecting segment) region is located between the penultimate and the last type III repeats, i.e., between, the Hep-2 and Fib-2 domain.
Additionally, monoclonal FDC-6 was established, which reacts specifically with cellular FN but not with plasma FN. FNs extracted from normal adult tissues do not react with this antibody. In contrast, FNs isolated from various fetal tissues, amniotic fluid, and placenta as well as from various types of human carcinomas and sarcomas and their cell lines are found to react with FDC-6 (Matsuura, H. and Hakomori, S. (1985) Proc. Natl. Acad. Sci. USA 82 6517-6521). Thus, a new concept developed that FNs are clearly defined with two classes which can be distinguished by monoclonal antibody FDC-6 and which are related in much the same way as .alpha.-fetoprotein (AFP) to albumin and carcinoembryonic antigen (CEA) to nonspecific cross-reacting antigen (NCA): (i) oncofetal FN (onfFN) derived from cancer and fetal cells and tissues, and previously known as cellular FN, and (ii) normal FN (norFN) derived from normal adult tissues and plasma, and previously known as plasma FN (Matsuura, H. and Hakomori, S. (1985) Proc. Natl. Acad. Sci. USA 82 6517-6521).
USPTO Backgrounds
USPTO Backgrounds