Ligant (ACT-4-L) to a receptor on the surface of activated CD4+T-cells
AssigneeThe Board of Trustees of the Leland Stanford Junior University
InventorsWayne Godfrey, Edgar G. Engleman
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Abstract
The invention provides ligands and fragments thereof to a receptor on the surface of activated CD4+ T-cells. An exemplary ligand is designated ACT-4-L-h-1. Preferred fragments include purified extracellular domains of ligands. The invention also provides humanized and human antibodies to the ligand. The invention further provides methods of using the ligand and the antibodies in treatment of diseases and conditions of the immune system. The invention also provides methods of monitoring activated CD4+ T-cells using the ligands or fragments thereof.
Claims50
A purified ACT-4-L ligand polypeptide having a segment between 5 and 160 contiguous amino acids from an amino acid sequence shown in FIG. 10.
A purified extracellular domain of an ACT-4-L ligand comprising at least five contiguous amino acids from the full-length ACT-4-L-h-1 extracellular domain.
An ACT-4 receptor polypeptide consisting essentially of a domain that specifically binds to the ACT-4-L-h-1 ligand.
A humanized monoclonal antibody comprising a humanized heavy chain and a humanized light chain:
- (1) the humanized light chain comprising three complementarity determining regions (CDR1, CDR2 and CDR3) having amino acid sequences from the corresponding complementarity determining regions of a light chain of a nonhuman antibody that specifically binds to an extracellular domain of the ACT-4-L-h-1 ligand, and having a variable region framework sequence substantially identical to a human light chain variable region framework sequence;
- and
- (2) the humanized heavy chain comprising three complementarity determining regions (CDR1, CDR2 and CDR3) having amino acid sequences from the corresponding complementarity determining regions a heavy chain of the nonhuman antibody, and having a variable region framework sequence substantially identical to a human heavy chain variable region framework sequence;
- wherein the humanized antibody specifically binds to the extracellular domain of the ACT-4-L-h-1 ligand with a binding affinity having a lower limit of 107 M−1 and an upper limit that is within five-fold of the binding affinity of the nonhuman antibody.
A human monoclonal antibody that specifically binds to an extracellular domain of the ACT-4-L-h-1 ligand.
A purified nucleic acid segment having between 15 and 500 contiguous nucleotides from the sequence shown in FIG. 10.
An isolated population of cells substantially enriched in B-cells expressing an ACT-4-L ligand on their surface.
An isolated stable cell line expressing an ACT-4-L ligand on its surface.
A pharmaceutical composition comprising a pharmaceutically active carrier and an agent that specifically binds to an extracellular domain of the ACT-4-L-h-1 ligand.
A method of suppressing an immune response in a patient having an immune disease or condition, the method comprising administering an effective amount of a pharmaceutical composition comprising a pharmaceutically active carrier and an agent that specifically binds to the ACT-4-L-h-1 ligand.
A method of suppressing an immune response in a patient having an immune disease or condition, the method comprising administering an effective amount of a pharmaceutical composition comprising a pharmaceutically active carrier and an agent that competes with the ACT-4-L ligand for specific binding to the ACT-4-h-1 receptor.
A method of screening for immunosuppressive agents, the method comprising:
- contacting an ACT-4-L-h-1 ligand polypeptide with a potential immunosuppressive agent;
- and
- detecting specific binding between the ACT-4-L-h-1 ligand polypeptide and the agent, the specific binding indicative of immunosuppressive activity.
A method of monitoring activated CD4+ T-cells, the method comprising:
- contacting a tissue sample from a patient with an ACT-4-L ligand polypeptide that specifically binds to an extracellular domain of the ACT-4-h-1 receptor;
- and
- detecting specific binding between the ACT-4-L ligand polypeptide and the tissue sample to indicate the presence of the activated CD4+ T-cells.
A method of inhibiting infection of CD4+ T-cells by a human immune deficiency virus, the method comprising contacting the CD4+ T-cells with an antibody that specifically binds to an extracellular domain of the ACT-4 receptor.
Dependencies are inferred from the claim text.