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OwnerYunbiao Luinventor
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The present invention provides an active form (BY-001) of a homomultimeric chimeric protein PD-L1/Fc-gamma1, which may have a composition of 25% dimer, 30% tetramer and 45% hexamer. BY-001 consists of two distinct functional domains at the aggregated state, one is the extracellular domain of PD-L1 and another one is the IgG1 Fc region. Accordingly, the first functional domain of PD-L1 at its aggregated state is more effective in suppressing the activity of CD3+ and CD28+ T cells; while, on the other hand, the second functional domain of FC-gamma1 at its aggregated state exerts only the suppressive effects on the immune cell bearing the Fc-gamma receptors. Thus, the features provided in present invention indicate that BY-001 regulates the functions of immune cells subsets that are responsible for the peripheral immune tolerance, which makes BY-001 potential to help restore or maintain the peripheral immune tolerance in patients with autoimmune diseases or in recipients of allografts.
1. An active composition (BY-001) of homomultimeric forms of chimeric protein PD-L1/Fc-gamma1 comprising the forms of dimer, tetramer and Hexamer, wherein the probable ratio of the forms is at 25% of dimer, 30% of tetramer and 45% of hexamer respectively (FIG. 2).
2. A form of homomultimeric chimeric protein PD-L1/Fc-gamma1 in advanced structure consisting of multiple monomer of chimeric protein PD-L1/ Fc-gamma1, wherein the monomer of chimeric protein PD-L1/Fc-gamma1 contains two distinct function domains.
3. The two distinct function domains in the monomeric chimeric protein PD-L1/ Fc-gamma1 according to claim 2 consisting of the PD-L1 domain (extracellular domain of human PD-L1) and the Fc-gamma1 domain (region of human IgG1 Fc), wherein the PD-L1 domain contains the portions of immunoglobulin V like region (V-set region, 19˜127 amino-acids, exon-2) and immunoglobulin constant like region (C-set region, 128˜220 amino-acids, exon 3), and the Fc-gamma1 domain contains the regions of hinge, CH2 and CH3 in human IgG1 heavy chain (FIG. 1).
4. BY-001 (a composition of bifunctional homomultimeric forms of chimeric protein PD-L1/Fc-gamma1) according to claims 1 and 3 comprising the polypeptide PD-L1, wherein the aggregated form of PD-L1 portion bind to and trigger PD-1 (CD279) expressed on T cells.
5. BY-001 (a composition of bifunctional homomultimeric forms of chimeric protein PD-L1/Fc-gamma1) according to claim1 and 3 comprising the polypeptide Fc-gamma1, wherein the aggregated form of Fc-gamma1 portion bind to Fc-gammaRIIA/B and trigger the suppressive function of Fc-gammaRII expressed on monocyte/macrophages or progenitor of erythrocyte.
6. A method of treating CD3+ CD28+ immune cells comprising administering effective amount of BY-001 according to claim 4, wherein aggregated PD-L1 portion of BY-001 suppresses the activity of T cell (FIG. 3).
7. A method of treating human peripheral blood monocyte (hPBMC) comprising administering effective amount of BY-001 according to claim 4, wherein aggregated PD-L1 portion of BY-001 suppresses the activation of PD-1 bearing lymphocytes among the PBMC (FIG. 4).
8. A method of treating immune cells bearing Fc-gammaRII only comprising administering effective amount of BY-001 according to claim 4, wherein the homomultimeric Fc-gamma1 of BY-001 bind to and trigger the Fc-gammaRIIA/B on immune cells to suppress the cytokines production (FIG. 5).
9. A method of treating immune cells comprising immune cells bearing Fc-gammaRI and Fc-gammaRII administering effective amount of BY-001 according to claim 4, wherein the homomultimeric Fc-gamma1 of BY-001 bind to and trigger the Fc-gammaRIIA/B on immune cells to suppress the cytokines production (FIG. 6).
10. The bifunctional proof of the domains contained in BY-001 according to claims 6, 7, 8 and 9 comprising the features of triggering the pathways of PD-1/PD-L1 and Fc-gamma1RIIB/Fc-gamma, wherein the features inherit the characteristics in vitro and in vivo that have been published in highly recognized scientific journals as mention in the part of background.
11. BY-001 according to claim 10 comprising a pharmaceutical composition for the treatment of immune diseases or protection of allografts, wherein the therapeutic potential of BY-001 is indicated