Methods of use of the TACI/TACI-L interaction
AssigneeImmunex Corporation
InventorsRaymond G. Goodwin, Wanwan S. Din
Life of this patent
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Abstract
The invention discloses a novel interaction between a TNF receptor (TACI) and its interacting ligand (TACI-L). Also disclosed are methods of screening candidate molecules to determine potential antagonists and agonists of the TACI/TACI-L interaction. The use of the antagonists and agonists as therapeutics to treat autoimmune diseases, inflammation, and to inhibit graft vs. host rejections is further disclosed.
Claims14
A method of screening a candidate molecule to identify its ability to inhibit or prevent the dissociation of a TACI/TACI-L complex, said method comprising the steps of:
- a. forming said TACI/TACI-L complex or a TACI/TACI-L fragment complex in the absence of said candidate molecule;
- b. adding said candidate molecule to a medium containing said TACI/TACI-L complex or said TACI/TACI-L fragment complex;
- c. changing the conditions of said medium so that, but for the presence of said candidate molecule, said TACI or TACI fragments, would be released from the complex;
- d. measuring the concentration of free or bound said TACI, TACI-L or fragments thereof;
- and
- e. determining the dissociation constant of said TACI/TACI-L complex or said TACI/TACI-L fragment complex and comparing said constant to a dissociation constant of a TACI/TACI-L complex or TACI/TACI-L fragment complex measured in a medium not containing the candidate molecule.
A method of screening a candidate molecule to identify its ability to inhibit a TACI/TACI-L complex, said method comprising the steps of:
- a. adding TACI to a medium containing TACI-L and said candidate molecule, wherein one of either said TACI or said TACI-L is labeled and the other is bound;
- b. measuring the level of signal produced;
- and
- c. comparing the level of signal produced in step (b) to the level of signal produced by a TACI/TACI-L complex or TACI/TACI-L fragment complex formed with said labeled TACI or TACI-L in the absence of said candidate molecule;
- wherein diminished levels of signal produced in step (b) indicate that said candidate molecule inhibited said TACI/TACI-L complex.
A method of screening a candidate molecule to identify its ability to mimic the biological activity of the TACI/TACI-L complex, said method comprising the steps of:
- a. determining if said candidate molecule binds to TACI, TACI-L or fragments thereof;
- b. adding said candidate molecule to a biological assay to determine its biological effects;
- and
- c. comparing said biological effects of said candidate molecule with the biological effects of said TACI/TACI-L complex or a TACI/TACI-L fragment complex.
A method of screening a candidate molecule to identify its ability to be useful in the treatment of diseases modulated by the TACI/TACI-L complex, said method comprising the steps of:
- a. forming said TACI/TACI-L complex or a TACI/TACI-L fragment complex in the absence of said candidate molecule;
- b. adding said candidate molecule to a medium containing said TACI/TACI-L complex or said TACI/TACI-L fragment complex;
- c. changing the conditions of said medium so that, but for the presence of said candidate molecule, said TACI or TACI fragments, would be released from said TACI/TACI-L complex or said TACI/TACI-L fragment complex;
- d. measuring the concentration of free or bound said TACI, TACI-L or fragments thereof;
- and
- e. determining the dissociation constant of said TACI/TACI-L complex or said TACI/TACI-L fragment complex and comparing said constant to a dissociation constant of a TACI/TACI-L complex or TACI/TACI-L fragment complex measured in a medium not containing the candidate molecule.
A method of screening a candidate molecule to identify its ability to be useful in the treatment of diseases modulated by the TACI/TACI-L complex, said method comprising the steps of:
- a. adding TACI to a medium containing TACI-L and said candidate molecule, wherein one of either said TACI or said TACI-L is labeled and the other is bound;
- b. measuring the level of signal produced;
- and
- c. comparing the level of signal produced in step (b) to the level of signal produced by a TACI/TACI-L complex or TACI/TACI-L fragment complex formed with said labeled TACI or TACI-L in the absence of said candidate molecule.
A method of screening a candidate molecule to identify its ability to be useful in the treatment of diseases modulated by the TACI/TACI-L complex, said method comprising the steps of:
- a. determining if said candidate molecule binds to TACI or TACI-L;
- b. adding said candidate molecule to a biological assay to determine its biological effects;
- and
- c. comparing the biological effects of said candidate molecule with the biological effects of said TACI/TACI-L complex or a TACI/TACI-L fragment complex.
A method of screening a candidate molecule to identify its ability to inhibit (antagonize) or agonize a TACI/TACI-L complex, said method comprising the steps of:
- (a) adding said candidate molecule to a medium which contains cells expressing TACI and cells expressing TACI-L;
- (b) changing the conditions of said medium so that, but for the presence of said candidate molecule, said TACI/TACI-L complex and/or a TACI/TACI-L fragment complex would be formed;
- (c) determining the level of biological activity of said TACI/TACI-L complex and/or said TACI/TACI-fragment complex formed in said medium;
- and
- (d) comparing the level of biological activity of step (c) with the level of biological activity that occurs in said medium in the absence of said candidate molecule.
A method of modulating an intracellular signaling cascade mediated by the TACI/TACI-L complex in a mammal comprising administering to such a mammal an effective amount of an agonist or an antagonist of the TACI/TACI-L complex.
Dependencies are inferred from the claim text.