Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Animal or plant cell
Reexamination Certificate
1997-09-29
2001-03-20
Allen, Marianne P. (Department: 1631)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Animal or plant cell
C514S012200, C514S013800, C514S014800, C514S015800, C514S016700, C514S017400
Reexamination Certificate
active
06203788
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to methods for modulating cadherin-mediated processes, and more particularly to the use of modulating agents comprising a cadherin cell adhesion recognition sequence, or an antibody that specifically recognizes such a sequence, for inhibiting or enhancing functions such as cell adhesion.
BACKGROUND OF THE INVENTION
Multiple sclerosis (MS) is a chronic neurological disease that affects approximately 250,000 individuals in the United States. In a patient afflicted with MS, axons become demyelinated and oligodendrocytes die. Although the clinical course can vary, the most common form is manifested by relapsing neurological deficits, including paralysis, sensory deficits, and visual problems.
In MS and other demyelinating diseases, Schwann cells are generally excluded from areas of demyelination and, following axon damage, regeneration generally fails at Schwann cell-astrocyte boundaries (Carlstedt et al.,
Brain Res. Bulletin
22:93-102, 1989). Inhibition of Schwann cell migration and boundary formation by astrocytes appears to play a significant part in limiting spontaneous repair processes in the damaged central nervous system (CNS).
In theory, Schwann cells from the peripheral nervous system could be used to replace damaged oligodendrocytes in the CNS. However, the efficacy of such treatment has been limited by poor Schwann cell migration and by boundary formation. When Schwann cells are grafted into the adult CNS, they can migrate along blood vessels and meningeal surfaces, but form boundaries where they meet astrocytes. These boundaries can present an obstacle for regenerating axons. Thus, recruitment of regenerating axons into Schwann cell grafts is frequently poor, and axons remaining in the grafts fail to grow back into CNS tissue unless their target neurons are immediately adjacent (Brecknell et al.,
Neurosci.
74:775-784, 1996; Liuzzi and Lasak,
Science
237:642-645, 1987). Transplanted Schwann cells have been found to be capable of remyelinating central axons of normal (Blakemore,
Nature
266:68-69, 1977) or myelin deficient rats (Duncan et al.,
J. Neurocytol
17:351-360, 1988), but in both of these cases the area of remyelination is limited to the region close to the transplantation site.
Other approaches to developing a definitive treatment for MS have also been largely unsuccessful. Corticosteroids and ACTH may hasten recovery from acute exacerbations, but they do not prevent future attacks, the development of additional disabilities or chronic progression of MS. In addition, the substantial side effects of steroid treatments make these drugs undesirable for long-term use. Other toxic compounds, such as azathioprine, a purine antagonist, cyclophosphamide and cyclosporine have also been used to treat symptoms of MS. Like corticosteroids, however, these drugs are beneficial at most for a short term and are highly toxic. More recently, cytokines such as IFN-&ggr; and IFN-&bgr; have been administered in attempts to alleviate the symptoms of MS, but such treatment has led to a clinical exacerbation for some patients. Betaseron has also been employed, but with no effect on the rate of clinical deterioration, and side effects were commonly observed.
Accordingly, there is a need in the art for methods for treating MS that are effective and are not associated with the disadvantages of the present treatments. The present invention fulfills this need and furher provides other related advantages.
SUMMARY OF THE INVENTION
The present invention provides methods for modulating cadherin-mediated cell adhesion. Within one aspect, methods are provided for treating a demyelinating neurological disease, such as multiple sclerosis, in a mammal, comprising administering to a mammal a cell adhesion modulating agent that inhibits cadherin-mediated cell adhesion. The modulating agent may comprise the sequence His-Ala-Val or may comprise an antibody or fragment thereof that specifically binds to a cadherin cell adhesion recognition sequence. A modulating agent may be administered by implantation with Schwann cells or oligodendrocyte progenitor cells and/or may be administered within a pharmaceutical composition.
Within further aspects, the present invention provides methods for reducing unwanted cellular adhesion in a mammal, comprising administering to a mammal a cell adhesion modulating agent that inhibits unwanted cadherin-mediated cell adhesion resulting from surgery, injury, disease or inflammation. The modulating agent may comprise the sequence His-Ala-Val or may comprise an antibody or fragment thereof that specifically binds to a cadherin cell adhesion recognition sequence.
The present invention further provides methods for enhancing the delivery of a drug through the skin of a mammal, comprising contacting epithelial cells of a mammal with a cell adhesion modulating agent that inhibits cadherin-mediated cell adhesion and a drug, wherein the step of contacting is performed under conditions and for a time sufficient to allow passage of said dnug across said epithelial cells. The modulating agent may comprise the sequence His-Ala-Val or may comprise an antibody or fragment thereof that specifically binds to a cadherin cell adhesion recognition sequence.
Within further aspects, methods are provided for enhancing the delivery of a drug to a tumor in a mammal, comprising administering to a mammal a cell adhesion modulating agent that inhibits cadherin-mediated cell adhesion and a drug. The modulating agent may comprise 3-16 amino acid residues including the sequence His-Ala-Val or may comprise an antibody or fragment thereof that specifically binds to a cadherin cell adhesion recognition sequence.
In a related aspect, the present invention provides methods for treating cancer in a mammal, comprising administering to a mammal a cell adhesion modulating agent that inhibits cadherin-mediated cell adhesion and a drug. The modulating agent may comprise 3-16 amino acid residues including the sequence His-Ala-Val or may comprise an antibody or fragment thereof that specifically binds to a cadherin cell adhesion recognition sequence.
Within furter aspects, methods are provided for inhibiting angiogenesis in a mammal, comprising administering to a mammal a cell adhesion modulating agent that inhibits cadherin-mediated cell adhesion. The modulating agent may comprise the sequence His-Ala-Val or may comprise an antibody or fragment thereof that specifically binds to a cadherin cell adhesion recognition sequence.
The present invention further provides methods for enhancing drug delivery to the CNS of a mammal, comprising administering to a mammal a cell adhesion modulating agent that inhibits cadherin-mediated cell adhesion. The modulating agent may comprise 3-16 amino acid residues including the sequence His-Ala-Val or may comprise an antibody or fragment thereof that specifically binds to a cadherin cell adhesion recognition sequence.
Within further aspects, the present invention provides methods for enhancing wound healing in a mammal, comprising contacting a wound in a mammal with a cell adhesion modulating agent that enhances cadherin-mediated cell adhesion. The modulating agent may comprise the sequence His-Ala-Val or may comprise an antibody or fragment thereof that specifically binds to a cadherin cell adhesion recognition sequence.
In a related aspect, methods are provided for enhancing adhesion of foreign tissue implanted within a mammal, comprising contacting a site of implantation of foreign tissue in a mammal with a cell adhesion modulating agent that enhances cadherin-mediated cell adhesion. The modulating agent may comprise the sequence His-Ala-Val or may comprise an antibody or fragment thereof that specifically binds to a cadherin cell adhesion recognition sequence.
Within further aspects, the present invention provides methods for inducing apoptosis in a cadherin-expressing cell, comprising contacting a cadherin-expressing cell with a cell adhesion modulating agent that inhibits cadherin-mediated cell adhesion. The modulat
Blaschuk Orest W.
Gour Barbara J.
Adherex Inc.
Allen Marianne P.
Seed IP Law Group
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