Recombinant fusion protein containing an anti-PD-L1 antibody
View Patent ↗The present invention provides a recombinant fusion protein containing an anti-PD-L1 antibody, with at least one paratope of the anti-PD-L1 antibody linked via a linker to an extracellular Ig-like domain of a signal-regulator protein (SIRP) at N-terminus of a heavy chain or a light chain, wherein the recombinant fusion protein can bind to CD47, PD-L1 and FcR simultaneously. The present invention also provides a polynucleotide encoding the recombinant fusion protein, an expression vector containing the polynucleotide, a method for producing the recombinant protein and a method for treating a disease caused by over expression of CD47 and/or PD-L1 using the recombinant protein.
1. A recombinant fusion protein, comprising an anti-PD-LI antibody and two signal-regulator proteins (SIRP),
wherein the anti-PD-L1 antibody comprises two heavy chains, two light chains, and a fragment crystallizable region (Fc region),
wherein each heavy chain has an amino acid sequence of SEQ ID NO: 6,
wherein each light chain has an amino acid sequence of SEQ ID NO: 8,
wherein each SIRP comprises an extracellular Ig-like domain,
wherein each SIRP is SIRPα,
wherein the extracellular Ig-like domain of SIRPα is SIRPαD1 having an amino acid sequence of SEQ ID NO. 2,
wherein at least one paratope of the anti-PD-L1 antibody is linked via a linker to SIRPαD1 at an N-terminus of the heavy chain,
wherein the linker is -(Gly-Gly-Gly-Gly-Ser) 3 - (SEQ ID NO: 4); and
wherein the recombinant fusion protein simultaneously binds to CD47 via the SIRP, PD-L1 via at least one paratope of the anti-PD-L1 antibody, and FcR via the Fc region of the anti-PD-L1 antibody.
2. The recombinant fusion protein of claim 1 , wherein one paratope of the anti-PDL1 antibody is linked to SIRPαD1 at the N-terminus of the heavy chain.
3. The recombinant fusion protein of claim 1 , wherein two paratopes of the anti-PD-L1 antibody are linked to SIRPαD1 at the N-terminus of the heavy chain.
4. A pharmaceutical composition, comprising the recombinant fusion protein of claim 1 , and at least one pharmaceutically acceptable excipient.
5. The pharmaceutical composition of claim 4 , further comprising at least one pharmaceutically acceptable adjuvant.
6. A method for treating a cancer caused by over-expression of CD47 and/or PD-L1, comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 4 .
7. The method of claim 6 , wherein the cancer is selected from the group consisting of acute myelocytic leukemia (AML), chronic myelocytic leukemia (CML), acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), bladder cancer, prostate cancer, lung cancer, colon cancer, breast cancer, pancreatic cancer, and renal cell carcinoma.
8. The method of claim 7 , wherein the cancer is non-Hodgkin's lymphoma.