Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 15 to 23 amino acid residues in defined sequence
Reexamination Certificate
1998-12-16
2001-08-07
Eyler, Yvonne (Department: 1646)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
15 to 23 amino acid residues in defined sequence
C536S055200, C514S014800
Reexamination Certificate
active
06271344
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel enhanced affinity hyaluronan binding peptides, to methods for modulating cell locomotion and for modulating physiological and pathological conditions involving cell locomotion utilizing the peptides of the invention and to pharmaceutical compositions containing the peptides.
BACKGROUND OF THE INVENTION
Hyaluronic acid or hyaluronan (HA) is a large negatively charged glucosaminoglycan consisting of repeating disaccharides of N-acetylglucosamine and -glucuronic acid. This polymer is ubiquitous in the extracellular matrix and is the major component of skin, cartilage and brain tissue. In addition to its known macrostructural functions, it also performs physicochemical functions, for example, by acting as a lubricant in the synovial fluid in joints.
Synthesis of HA has been associated with the morphogenesis of many tissues, with wound repair, tumour invasion and cellular immune function (Toole, B. P.,
Connect. Tissue Res
. 10: 93-100, 1982; Pauli, B. V. et al., Cancer Met. Rev. 2: 129-152, 1983; Toole, B. P. et al.,
Ciba Found. Symp
. 143: 150-169, 1989; Turley, E. A.,
Cancer Met. Rev
. 3: 325-339, 1984; Iozzo, R. V.,
Lab. Invest
. 53: 373-396, 1985; Weigel, P. H. et al., J. Theol. Biol. 119: 219-234, 1986; Weigel, P. H. et al.,
Ciba Found. Symp
. 143 248-264, 1989; Boudreax, N. et al.,
Dev. Biol
. 143: 235-247, 1991; Turley, E. A.,
Cancer Met. Rev
. 11: 21-30, 1992). The underlying mechanism of action at the cellular level is believed to involve the ability of HA to elicit receptor-mediated alterations of cell motility. High affinity HA receptors have been identified and characterized on a variety of cell types and these are namely the receptor for hyaluronan mediated mobility (or RHAMM) (Turley, E. A. et al.,
J. Cell. Biol
. 112: 1041-1047, 1991; Hardwick, C. et al.,
J. Cell. Biol
. 117: 1343-1350, 1992; Yang, B. et al., J.
Biol. Chem
. 268: 8617-8623, 1993), intercellular adhesion molecule-1 (or ICAM-1) (McCourt, P. A. G. et al.,
J. Biol. Chem
. 269: 30081-30084, 1994) and CD44 (Underhill, C. B. et al.,
J. Biol. Chem
. 262: 13142-13146, 1987; Stamenkovic, I. et al.,
Cell
56: 1057-1062, 1989; Aruffo, A. et al.,
Cell
61: 1303-1313, 1990; Lesley, J. et al.,
Exp. Cell Res
. 187: 224-233, 1990; Miyake, K. et al.,
J. Exp. Med
. 172: 69-76, 1990). Both RHAMM and CD44 have been shown to be associated with cell locomotion, cell proliferation and differentiation. Other HA-binding proteins in the extracellular milieu have also been identified and they are namely link protein, aggrecan, versican, GHAP, collagen type VI and TSG-6.
In tissue trauma, an acute, transient increase in production of HA is observed which is accompanied by an increase in expression of HA receptors such as the receptor for hyaluronan mediated mobility (RHAMM) and CD44. The in vivo physiological implications of these molecular events has not been fully elucidated although an increased production of HA and its accumulation has been shown to regulate locomotion of fibroblasts, inflammatory cells and epidermal cells depending upon the concentration of HA used. Further, HA affects collagen fibril formation and white blood cell phagocytic function, peroxide generation and cytokine expression. Prior research studies have demonstrated that high concentrations of HA act as a RHAMM antagonist to injured tissues including skin burns, ulcers, ruptured tympanic membranes and abraded cornea by reducing tissue fibrosis (Goz, K. L. and Benfield, P.,
Drugs
47: 536, 1994; King, S. R. et al.,
Surgery
109: 76, 1991; Riquelme-Saquier, J. L.,
Dev. Ophthamol
. 22: 50, 1991; Chung, J. H. et al.,
Exp. Eye Res
. 48: 569, 1989; Hellstrom, S. and Laurent, C.,
Acta Otolaryngol
. 442 (Suppl.): 54, 1987; Retanda, G. G.,
Ital. Dermatol. Venereol
. 120: 71-75, 1985; Abatangelo, G. et al.,
J. Surg. Res
. 35: 410, 1983). Fibrosis of adult tissues after trauma is a serious clinical problem that can result in pathologies including malfunction of tissues due to keloids, hypertrophic scars, anatomonic strictures, intra-abdominal adhesions, cirrhosis of the liver, neurological deficits following spinal cord injury, valvular heart diseases, burn-injured joints as well as failure of anastomosis and adhesions following surgery (Bleacher, J. C. et al.,
Dermatologic Clinics
11: 677-683, 1993; Clark, R. A. et al.,
Am. J. Med. Sci
. 306: 42-48, 1993; Hebda, P. A. et al.,
Dermatologic Clinics
11: 685-696, 1993; Adzick, N. S. and Longaker, M. T.,
Ann. Surg
. 215: 3-7, 1992; Folkman, J.,
Ann. Surg
. 215: 1-2, 1992).
Antagonism of RHAMM by antibodies and peptides has also been demonstrated to inhibit HA-promoted cell locomotion (International application PCT/CA93/00158 published as WO 93/21312). For instance, HA-promoted fibroblast locomotion was inhibited by application of a polyclonal or monoclonal antibody against the HA-receptor complex (HARC).
Tumorigenesis is commonly manifested by an uncontrolled proliferation of cells, and the metastatic spread of tumour tissue is associated with the ability of these cells to locomote and invade. Oncogenes and tumour suppressor genes are important factors in the control of tumour cell growth, but extracellular matrix (ECM) molecules such as HA and their receptors also play significant roles. HA and RHAMM have been shown to regulate cell proliferation and differentiation and are implicated in cell transformation and tumour metastasis.
The transforming oncogene H-ras promotes cell locomotion by enhancing the formation and release of autocrine motility factors, growth factors and extracellular matrix (ECM) molecules such as HA (Toole, B. P.,
Curr. Opin. Cell Biol
. 2: 839-844, 1990; Stoker, M. et al.,
Biochim. Biophys. Acta
1072: 81-102, 1991; Hardingham, T. E. and Fosang, A. J.,
FASEB J
. 6: 861-870, 1992; Laurent, T. C. and Fraser, J. R. E.,
FASEB J
. 6: 2397-2404, 1992; Pilarski, L. M. et al.,
Leuk, Lymp
. 14: 363-374, 1994). Enhancement of ras-transformed cell locomotion by HA has been found to depend on the presence of a HA-receptor complex termed HARC occurring at the cell surface or released as soluble proteins (Hall, C. L. et al.,
Cell
82: 1-20, 1995; Hall, C. L. and Turley, E. A.,
J. Neuro
-
Oncol
. 26: 221-229, 1995; Turley, E. A. et al.,
Blood
81: 446-453, 1993; Turley, E. A. et al.,
Exp. Cell Res
. 207: 277-282, 1993; Turley, E. A.,
Cancer Metast. Rev
. 11: 21-30, 1992; Turley, E. A. et al.,
J. Cell Biol
. 112: 1041-1047, 1991). Turley et al. (
Exp. Cell Res
. 207: 277-282, 1993) reported that such HA-promoted cell locomotion was inhibited by monoclonal antibodies specific to RHAMM thereby implicating RHAMM as the major HA-binding component of HARC in tumorigenesis and metastasis.
Under normal physiological conditions, RHAMM is not detectable on B-lymphocytes found in the blood, spleen or lymph node. Among B-cell malignancies, RHAMM is overexpressed on most terminally differentiated B-cells from multiple myeloma bone marrows, certain non-Hodgkin's lymphomas, and splenic hairy leukemic cells (Turley, E. A. et al.,
Blood
81: 446-453, 1993; Masellis-Smith, A. et al.,
Blood
87: 1891-1899, 1996). RHAMM is also overexpressed in breast carcinoma cells (Turley, E. A. et al.,
Exp. Cell Res
. 207: 277-282, 1993; Hall, C. L. & Turley, E. A.,
J. Neuro
-
oncol
. 26: 221-229, 1995), and in combination with an increased level of HA, are responsible for their enhanced motility and metastasis. Administration of RHAMM-transfected cells into animals results in spontaneous metastasis and formation of lung tumour colonies.
RHAMM was one of the first HA receptors to be isolated and characterized at the biochemical and molecular levels. It is an N-linked glycoprotein that binds HA with high affinity (Kd: 1 nM) and specificity. Several isoforms of RHAMM with different subcellular distribution have been identified. Isoforms found intracellularly and on the plasma membrane are designated iRHAMM and pRHAMM, respectively, and the secreted isoform is designated sRHAMM. The molecular structure of the various RHAMM isoforms ma
Andres Janet L.
Bereskin & Parr
Cangene Corporation
Eyler Yvonne
Gravelle Micheline
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