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AssigneesThe Board of Trustees of the Leland Stanford Junior University, President and Fellows of Harvard College
InventorsGerald R. Crabtree, Stuart L. Schreiber, David M. Spencer, Thomas J. Wandless, Peter Belshaw, Steffan Ho
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Methods and compositions are provided for modified cells, where a chimeric protein consisting of a ligand binding domain fused to an action domain is employed which initiates a signal which activates a biological process: transcription of at least one gene, usually a second construct introduced into the host cells; exocytosis; or an extracellular process. The second construct optimally present provides for a promoter which responds to a transcriptional activation action domain to provide for transcription, when an appropriate ligand binds to the ligand binding domain. Exemplary of the system is the use of an FKBP/CD3.zeta. or transcription factor fusion protein, using dimeric FK506 or FK520 as the ligand and a promoter responsive to NF-AT or other transcription factor requiring two molecules for transcriptional activation.
A compound comprising two or more multimerized ligands each independently selected from the group consisting of FK506, FK520 and cyclosporin, or macrocyclic derivatives thereof.
A compound comprising two or more multimerized ligands each independently selected from the group consisting of FK506, FK520, and macrocyclic derivatives thereof, which compound cross-links two or more FKBP proteins.
A compound comprising two or more multimerized ligands independently selected from cyclosporin A or macrocyclic derivatives thereof, which compound cross-links two or more cyclophilin proteins.
A compound, having a molecular weight of less than 5 Kd and comprising from 2 to 3 ligands, each ligand of which independently comprises a macrocycle or portion thereof which binds to FKBP or cyclophilin, said units covalently joined together through a common linking group does not include an ester group in the backbone of the linker.
A compound, having a molecular weight less than 5 kd and comprising two or more ligands covalently joined through one or more linker groups, each ligand independently comprising a macrocycle or portion thereof which binds an FKBP or cyclophilin protein, wherein said compound has a reduced immunosuppressive effect in a Tag Jurkat cell mitogen activation assay.
A compound, having a molecular weight less than 5 kd and comprising two or more ligands covalently joined through one or more linker group, each ligand independently comprising a macrocycle or portion thereof which binds an FKBP or cyclophilin protein or mutagenized derivative thereof, wherein the compound is at least 100 fold less immunosuppressive than FK506, cyclosporin A or rapamycin.
Dependencies are inferred from the claim text.