Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Hormones – e.g. – prolactin – thymosin – growth factors – etc.
Reexamination Certificate
1998-11-12
2001-03-06
Saoud, Christine (Department: 1647)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Hormones, e.g., prolactin, thymosin, growth factors, etc.
C530S402000, C530S412000
Reexamination Certificate
active
06197939
ABSTRACT:
FIELD OF THE INVENTION
This invention relates in general to polypeptides with growth promoting activities. More specifically, the invention concerns: growth factors (herein termed placental-derived prostate factors, or “PDPFs”), having the ability to stimulate the proliferation and growth of prostate cells and other cells; recombinant methods for the production of such growth factors; methods for the use of such growth factors to stimulate cell proliferation, growth and/or survival; diagnostic methods for the detection of such factors in biological samples by the use of PDPF antibodies and labeled nucleic acid probes; and methods for the identification of inhibitors against PDPF that will be potentially useful as anti-cancer agents.
BACKGROUND OF THE INVENTION
It has been estimated that each year, nearly two hundred and fifty thousand men in the United States are diagnosed with prostate cancer and that approximately forty thousand men will die from it; Boring et al., CA Cancer Journal for Clinicians, Volume 44, Number 1, pages 7-26 (1994). Current treatments, which include surgery, radiation and hormone ablation, have some effect on slowing tumor growth but show no significant effect on long term remission or cure; Scher, Current Opinion in Oncology, Volume 3, pages 568-574 (1991). When confined within the organ capsule, prostate carcinoma is relatively easy to treat successfully. However, metastatic disease, which targets to the axial skeleton about eighty percent of the time, is nearly always refractory to treatment; Franks, Journal of Pathology and Bacteriology, Volume 72, pages 603-611 (1956); and Huben et al., CA Cancer Journal for Clinicians., Volume 36, Number 5, pages 274-292 (1986).
The dissemination of prostate carcinoma cells to the bones of the central spine has been ascribed to the presence of paravertebral vessels; Zetter et al., Prostate Cancer and Bone Metastasis, edited by Karr and Yamanaka, Plenum Press, New York (1992), at pages 39-43. However, this direct metastatic route does not explain why the level of tumor cell proliferation in bone is often higher than in the prostate gland itself; Jacobs, Urology, Volume 21, Number 4, pages 337-344 (1983). Additionally, bone metastases are often the first evidence of progression to androgen-independent prostate carcinoma; Logothetis et al., Seminars in Oncology, Volume 21, Number 5, pages 620-629 (1994). The uncoupling of prostate carcinoma cell growth from hormone responsiveness signals the failure or irrelevance of hormone ablation therapy and the increasing ability of prostate carcinoma cells to proliferate in response to paracrine and autocrine peptide growth factors; Thompson, Cancer Cells, Volume 2, Number 11, pages 345-354 (1990); and Scher et al., Seminars in Urology, Volume 10, Number 1, pages 55-64 (1992). Although clinical relevance has not been convincingly established, several growth factors, including bFGF, aFGF, EGF, TGFa, and PDGF, have been isolated from the conditioned media of human prostate carcinoma cells in vitro, and from prostate tissue in vivo.
Bone stromal cells also produce factors that stimulate the proliferation of prostate carcinoma cells; Chackal-Roy et al., Journal of Clinical Investigation, Volume 84, pages 43-50 (1989). The interactions of prostate stromal and epithelial cells with regard to KGF and bFGF have been well established; Chung, Cancer Biology, Volume 4, pages 183-192 (1993). However, the interactions between bone stromal cells and metastatic prostate carcinoma cells has not yet been studied as closely. Conditioned media from bone stromal cells, but not skeletal muscle, keratinocytes or kidney epithelial cells, stimulates the proliferation of prostate carcinoma cells; see Zetter et al. above. Furthermore, bone stromal cell media is not active on kidney carcinoma or melanoma cells, suggesting tissue specific interactions between bone stromal cells and prostate carcinoma cells. This tissue specificity has been confirmed in vivo by co-inoculating stromal cells and LNCaP prostate carcinoma cells, which are normally non-tumorigenic, into nude mice; Gleave et al., Cancer Research, Volume 51, pages 3753-3761 (1991). In these studies, bone or prostate stromal cells supported tumor growth in vivo, whereas lung or kidney stromal cells did not.
One factor, identified in bone stromal cell cultures, that stimulates prostate cell proliferation is transferrin, which is a well-characterized protein involved in the transport of iron across cell membranes; Rossi et al., Proceedings of the National Academy of Science USA, Volume 89, pages 6197-6201 (1992). In addition, published PCT patent application PCT/US95/09261 (WO 96/04379) describes the isolation and expression of DNA encoding a bone and prostate-derived growth factor, termed BPGF-1. The BPGF-1 gene was found to be expressed predominantly in bone, prostate tissue and seminal vesicles, and BPGF-1 polypeptide stimulated the proliferation of prostatic epithelial cells in vitro.
SUMMARY OF THE INVENTION
The present invention provides novel growth factors which stimulate the growth of prostate and other cell types, and which are distinct from BPGF-1. The growth factors of this invention are polypeptides (i.e., proteins) that stimulate the proliferation of several prostate carcinoma cell lines, but not normal prostate epithelial cells. In addition, the growth of other tumor cells derived from placenta, oral epithelium, palate and bone is also stimulated. The growth factors of this invention are herein individually and collectively termed “placenta-derived prostate factor”, or “PDPF”, based on the tissue origin of the CDNA library used to clone the encoding nucleic acid molecules and the fact that these factors have activity against prostate cells. Of two variably spliced forms specifically identified so far, the shorter polypeptide form (termed PDPF-1) appears to be more active in the cell growth assays evaluated.
The present invention also encompasses genes and nucleic acid molecules that encode such polypeptides, as well as recombinant methods for the use of the genes and nucleic acid molecules to produce the polypeptides. Additionally, this invention is directed to the use of the polypeptides to promote the growth of prostate and other cells responsive to the growth promoting effects of the polypeptides, either in vitro or in vivo. The protein growth factors of this invention can also be used in assays and screens for the identification of antagonists, i.e., inhibitors of PDPF cell proliferation stimulating activity, such antagonists being potentially useful as anti-tumor agents for the treatment of responsive tumors. The invention is further concerned with the use of PDPF antibodies and nucleic acid molecules encoding PDPF, or fragments (i.e., segments) thereof, in diagnostic methods for the detection of PDPF in biological samples such as tissue or fluid samples, including their use in diagnostic methods for the detection of tumors.
Especially preferred embodiments of this invention are nucleic acid molecules having the DNA sequences of SEQ ID NOS: 3 or 5, and proteins having the amino acid sequences of SEQ ID NOS: 4 or 6. Also preferred is an alternative nucleic acid sequence to the one of SEQ ID NO: 5, in which the base “C” at position 1260 is changed to “G” (but otherwise encoding the same polypeptide) (SEQ ID NO: 7). In addition to these preferred embodiments, the invention also encompasses fragments (such as truncation analogs or interior segments of the proteins) and other derivative molecules of modified sequence, including substitution, deletion and addition analogs, having the growth promoting activity of the full length sequence of PDPF, as will be more fully described in the following text.
The terms “gene”, “DNA”, and “nucleic acid molecule” used herein with reference to this invention are meant to refer to isolated molecules that are free of total genomic DNA of a particular species, while retaining coding sequences for the described polypeptides.
REFERENCES:
patent: 0 690 127 (1996-01-01), None
patent: WO 96/04379 (1996-
Farrell Catherine L.
Martin Francis H.
Yabkowitz Rachel
Amgen Inc.
Levy Ron K.
Mazza Richard J.
Odre Steven M.
Saoud Christine
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