Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues
Patent
1993-03-19
1995-09-19
Lacey, David L.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
530324, 530326, 530351, C07K 700, C07K 1400
Patent
active
054516587
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Gamma interferon is a protein produced by activated helper T cells which manifests antiviral, antiproliferative and immunomodulatory activities. The antiviral and antiproliferative activities of gamma interferon are largely suppressive, while the immunomodulatory activity is primarily expressed through stimulation of a variety of immune functions, although the inhibition of immune function is also known to occur.
Although the mechanism by which gamma interferon exerts its effects on cells is not understood, it is known that it binds to specific cellular receptors [Langer et al, Immunology Today 9:393 (1988)]. Aguet et al. [Cell 55:273 (1988)]have cloned and sequenced a gene for a gamma interferon receptor. The molecular weight of the encoded protein deduced from the sequence is consistent with the molecular weight of a gamma interferon receptor recently isolated from human placenta [Calderon et al., Proc. Natl. Acad. Sci. USA 85:4837 (1988)].
Gamma interferon is believed to be involved in autoimmune disease. Elevated levels of gamma interferon are also believed to stimulate macrophages that erroneously digest myelin in the brain and spinal cord of multiple sclerosis (MS) sufferers.
Because gamma interferon acts at specific cellular receptors and is implicated in autoimmune disease and MS, agents which could inhibit the binding of such interferon to its cellular receptors would be useful therapeutically.
SUMMARY OF THE INVENTION
This invention provides novel polypeptides containing up to 50 amino acid residues and comprising one or more amino acid subsequences selected from the group consisting of the subsequences defined by amino acid residues 15-21 and 132-137 of the sequence defined by SEQ ID NO:1. Preferably the polypeptides contain up to 40, and more preferably up to 35, amino acid residues.
In some polypeptides comprising both of the subsequences, the subsequences are separated by a peptide linker containing from 1 to about 20 amino acid residues. In other polypeptides comprising both subsequences, the subsequences are in two separate polypeptides joined by disulfide bridges.
This invention further provides antibodies against polypeptides containing up to 50, preferably up to 40 and more preferably up to 35, amino acid residues and comprising one or more amino acid subsequences selected from the group consisting of the subsequences defined by amino acid residues 15-21 and 132-137 of the sequence defined by SEQ ID NO:1, which antibodies are characterized by an ability to specifically bind to the polypeptides and to human gamma interferon and to inhibit the binding of such interferon to cellular receptors.
The present invention still further provides anti-idiotypic antibodies against the above-mentioned antibodies. These anti-idiotypic antibodies also inhibit the binding of human gamma interferon to cellular receptors.
All of the antibodies of this invention can be either polyclonal antibodies from an antiserum, or monoclonal antibodies. Binding fragments made from such antibodies and humanized or otherwise engineered antibodies are also a part of this invention.
Also provided are methods for using the foregoing polypeptides and antibodies to inhibit the binding of such interferon to cellular receptors.
One method comprises contacting cells bearing receptors for human gamma interferon with an effective amount of a polypeptide containing up to 50, preferably up to 40 and more preferably up to 35, amino acid residues and comprising one or more amino acid subsequences selected from the group consisting of the subsequences defined by amino acid residues 15-21 and 132-137 of the sequence defined by SEQ ID NO:1.
Another method comprises contacting human gamma interferon with an effective amount of an antibody which specifically binds to human gamma interferon and to a polypeptide containing up to 50, preferably up to 40 and more preferably up to 35, amino acid residues and comprising one or more amino acid subsequences selected from the group consisting of the subsequences defi
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Dulak Norman C.
Gambel Phillip
Lacey David L.
Lunn Paul G.
Nelson James R.
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