Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
1995-02-21
2002-09-10
Spector, Lorraine (Department: 1646)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S320100, C435S325000, C435S252300, C435S254100, C435S069700, C530S350000, C530S306000, C530S312000, C530S300000, C536S023100, C536S023400, C536S023500, C536S024330
Reexamination Certificate
active
06448032
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a DNA fragment encoding the human melanocyte stimulating hormone receptor (MSH receptor) or an analogue or subsequence thereof. The DNA fragment contains an open reading frame of 951 bp which codes for a polypeptide of 317 amino acids, said DNA fragment as well as its analogues, subsequences or modifications constitute an important aspect of the invention. The DNA fragment has been expressed in an eukaryotic cell line and the expressed protein has been found to have properties identical to that of a native MSH receptor. The invention also relates to a DNA fragment encoding a subtype of the human MSH receptor (in this application designated MC-2) which contains an open reading frame of 975 bp which codes for a polypeptide of 325 amino acids, said DNA fragment as well as its analogues, subsequences or modifications also constitute an important aspect of the invention. This DNA fragment has also been expressed in a eukaryotic cell line and the expressed protein has been found to have properties similar to that of an MSH receptor subtype.
The invention also relates to a polypeptide encoded by a DNA fragment of the invention and to analogues and subsequences of said polypeptide. Furthermore, the invention relates to the use of the DNA fragments or analogues or subsequences thereof, and to the use of polypeptides of the invention encoded by the DNA fragments of the invention. Especially interesting is the use of the polypeptides of the invention which have MSH receptor activity. The use of the polypeptides of the invention or analogues or subsequences thereof for generation of antibodies constitutes yet another aspect of the invention. Also, the invention relates to diagnostic and therapeutic methods and diagnostic and therapeutic agents for use in the diagnosis and treatment of MSH receptor expressing disease conditions such as vitiligo, melanoma, skin cancer, pyretic conditions, inflammatory conditions and nociceptive conditions, catatonic conditions and impaired memory conditions, and to methods for detecting and quantitating the MSH receptor. In addition, the invention provides methods for testing substances capable of interfering with the activity of the MSH receptor and methods for treatment of MSH receptor expressing disease conditions. The patent application also relates to the use of the MSH receptor coding fragments or the MSH receptor during non-disease conditions for the control or diagnosis and/or determination and/or production control of skin and/or hair and/or fur colour in man and/or animals. Moreover, the patent application relates to the elucidation of the structure of the MSH receptor in three dimensions by the utilization of computer modelling methods and/or by application of structure analysis by crystallo-graphic approaches and/or NMR (Nuclear Magnetic Resonance) and to the use of the knowledge of the receptor structure for the design of drugs with binding affinity for the MSH receptor and/or its subtype (MC-2).
The present invention which comprises a DNA fragment encoding the MSH receptor or analogues thereof and the application of these and in this connection methods for identifying products which pertains to the MSH receptor and/or its biological functions constitutes significant contributions which will become useful for biotechnological, pharmaceutical, medical and veterinary practices. As a background to the uses of a DNA fragment and analogues and subsequences thereof and the application of these, some of the most important facts regarding the MSH receptor and its biological functions in man and animals are summarized below.
GENERAL BACKGROUND
Although information existed regarding the MSH receptor (reviewed below), the structure of the MSH receptor gene as well as the primary amino acid sequence of the MSH receptor has not been known before the priority date of the present patent application. As appears from the following, the MSH receptor is a very important receptor with a number of different functions such as anti-inflammatory and antipyretic function and involved in a number of diseases such as melanoma and skin cancer and moreover, it is having an important role in the control of skin, hair and fur colour in man and animals.
MSH Receptor and Its Biological Functions
The MSH receptor belongs to a large class of receptors showing functional and structural similarities. These receptors mediate their cellular effects via coupling proteins termed guanine nucleotide regulatory proteins (G-proteins), of which several types are known (e.g. G
s
, G
i
, G
k
and others). The MSH receptor is a cell membrane bound protein which serves as a recognition site for &agr;-MSH (melanocyte stimulating hormone). The term MSH relates to several peptides among which &agr;-MSH, &bgr;-MSH and &ggr;-MSH may be mentioned; the &agr;-MSH generally showing the largest activity. These hormones are generally referred to as melanotropic hormones to which also the ACTH (adreno-corticotropic hormone) belongs as well as a number of related peptides, being present in man and animals. In the present patent application, peptides which have binding affinity for MSH receptors will collectively be referred to as MSH peptides or MSH receptor ligands. Upon binding of MSH receptor ligands to the MSH receptor, an activation of the receptor ensues which leads to altered activity of the cell in which the receptor is located. MSH receptors are known to be present in melanocytes which are pigment cells and in humans give the skin a varying amount of dark pigmentation and which have a role in protecting the skin from UV-radiation. In animals, melanocytes also have a role in skin pigmentation. In both animals and man changes in skin colour are at least partly mediated by melanocytes and these changes are also partly regulated by the degree of activation of MSH receptors by the peptide hormones that bind to the MSH receptor (Nordlund 1991; Levine 1991).
MSH receptors may also be localized in cell types other than melanocytes (Tatro 1987) where they may have other types of important physiological roles. &agr;-MSH is known to be produced in certain areas of the brain, such as the hypothalamus, corpus amygdaloideum and cerebral cortex. Moreover, proopiomelanocortin, which is the precursor molecule for &agr;-MSH, is found in lymphocytes of the thymus and spleen, neutrophils, placenta, ovary as well as in the epidermis (Nordlund 1991). There is evidence that by acting on MSH receptors, &agr;-MSH may have roles in (i) mediating neurotransmitter effects in the CNS, (ii) participating in endocrine regulation, (iii) modulating immune-inflammatory responses, besides (iv) regulating the skin pigmentation, as mentioned above (Nordlund 1991, Levine 1991). MSH receptors perform various functions in neurochemical processes, such as the induction of antinociceptive effects, the perturbation of grooming behaviour, the alteration of stretch and yawn reflexes and the potentiation of catatonic states (Hirsh and O'Donohue 1986). Moreover, MSH receptors are implicated to have a function in the enhancement of visual and verbal learning (Veith et al. 1978; Ward et al. 1979, Handelman et al. 1983). The role for MSH receptors in endocrine function is indicated, for example, by observations that &agr;-MSH may affect cortisol secretion from the adrenal gland, and increase plasma levels of growth hormone, luteinizing hormone and follicle-stimulating hormone (Reid et al. 1984).
MSH receptors also seem to be mediating the powerful antipyretic effect caused by &agr;-MSH (Clark et al. 1985) as well as the anti-inflammatory actions induced by &agr;-MSH (Rheins et al. 30 1989). Central MSH receptors are also involved in the mediation of anti-convulsive effects since MSH peptides exert anti-epileptic effects (De Wied 1993). Moreover, MSH receptors seem to mediate the growth factor effect of MSH peptides which mediates accelerated and enhanced nerve generation and muscle reinnervation after peripheral nerve injury (Strand et al. 1993).
MSH Receptors on Melanoma Cells
Melanom
Chhajlani Vijay
Wikberg Jarl
Kaufman Claire M.
Spector Lorraine
Sterne Kessler Goldstein & Fox P.L.L.C.
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