This disclosure relates to an immunoglobulin
single variable domain (ISVD)-containing modulator that allosterically binds to a three-dimensional (3D)
epitope of a
protein complex comprising at least one inhibitory
immune receptor and at least one corresponding ligand. The modulator regulates
cooperativity within such complexes, thereby affecting the binding affinity and downstream signaling pathways. Specifically, the
allosteric modulator of this invention induces positive
cooperativity in immunoinhibitory
receptor-ligand complexes, thus suppressing immune responses in a spatiotemporally restricted manner. Accordingly, these allosteric modulators are useful as therapeutic agents for inflammatory diseases, such as autoimmune diseases, allergic diseases, or graft-versus-
host disease (GVHD). Moreover, this disclosure pertains to methods for identifying, selecting, and producing said allosteric modulators.