Product and method for treatment of conditions associated with receptor-desensitization
Particular members of the multisubunit immune recognition receptor (MIRR) family of receptors, specifically, the B cell antigen receptor (BCR), the pre-B cell receptor (pre-BCR), the pro-B cell receptor (pro-BCR), Ig Fc receptors (FcR), and NK receptors, can be physically uncoupled from their associated transducers. The invention describes regulatory compounds and methods for mimicking such dissociation/destabilization for the purposes of receptor desensitization and for treatment of conditions in which receptor desensitization or alternatively, enhanced or prolonged receptor sensitization, is desirable. Compounds and methods for enhancing or prolonging receptor sensitization are also disclosed, as are methods for identifying regulatory compounds suitable for use in the present methods.
1. An isolated regulatory compound that desensitizes a B cell antigen receptor, receptor,
wherein the isolated regulatory compound is an antibody or antigen-binding fragment thereof,
wherein said receptor has an extracellular ligand binding component and a transducer component,
wherein said antibody or fragment thereof is identified by its ability to selectively bind to said transducer component consisting of Igα and Igβ of said receptor and upon said binding: (1) induces said extracellular ligand binding component to dissociate from said transducer component; and/or (2) inhibits said extracellular ligand binding component from associating with said transducer component
and wherein said antibody or fragment thereof does not substantially stimulate said receptor.
2. The isolated regulatory compound of claim 1 , wherein said antibody or fragment thereof is monovalent.
3. The isolated regulatory compound of claim 1 , wherein said antibody is a bi-specific antibody comprising: a) a first portion which binds to said receptor and: (1) causes a dissociation of said extracellular ligand binding component from said transducer component when said components are associated with each other prior to contact with said compound; or (2) inhibits association of said extracellular ligand binding component with said transducer component when said components are dissociated from each other prior to contact with said compound; and b) a second portion which selectively binds to a cell surface molecule expressed by a cell which expresses said receptor.
4. The isolated regulatory compound of claim 1 , wherein said receptor is a B cell antigen receptor, and wherein said antibody or fragment thereof binds to a transducer component selected from the group consisting of Igα and Igβ.
5. The isolated regulatory compound of claim 1 , wherein said antibody or fragment thereof binds to a portion of said transducer component that contacts a portion of said extracellular ligand binding component when said receptor is bound by its natural ligand, thereby inhibiting contact of said transducer component with said extracellular ligand binding component.
6. The isolated regulatory compound of claim 1 , wherein said antibody or fragment thereof binds to a portion of said transducer component which contacts a portion of said extracellular ligand binding component that is phosphorylated when said receptor is bound by its natural ligand, thereby inhibiting phosphorylation of said extracellular ligand binding component.
7. The isolated regulatory compound of claim 1 , wherein said antigen-binding fragment is selected from the group consisting of Fab, F(ab′)2, Fab′ and scFv.