Antibodies binding C5 and uses thereof
An isolated monoclonal antibody that specifically binds human C5, or the antigen-binding portion thereof. A nucleic acid molecule encoding the antibody or the antigen-binding portion thereof, an expression vector, a host cell and a method for expressing the antibody or the antigen-binding portion thereof are also provided. Further provided are a bispecific molecule, an immunoconjugate, a chimeric antigen receptor, an oncolytic virus and a pharmaceutical composition comprising the antibody or the antigen-binding portion thereof, as well as a treatment method using an anti-C5 antibody or the antigen-binding portion thereof.
1 . An isolated monoclonal antibody, or an antigen-binding portion thereof, capable of binding to complement component 5, comprising
(i) a heavy chain variable region that comprises a V H CDR1 region, a V H CDR2 region and a V H CDR3 region; and
(ii) a light chain variable region that comprises a V L CDR1 region, a V L CDR2 region and a V L CDR3 region,
wherein the V H CDR1 region, the V H CDR2 region, the V H CDR3 region, the V L CDR1 region, the V L CDR2 region and the V L CDR3 region comprise amino acid sequences set forth in (1) SEQ ID NOs: 1, 7, 14, 20, 25 and 31, respectively; (2) SEQ ID NOs: 2, 8, 15, 20, 26 and 32, respectively; (3) SEQ ID NOs: 2, 8, 16, 20, 25 and 33, respectively; (4) SEQ ID NOs: 3, 9, 17, 21, 27 and 34, respectively; (5) SEQ ID NOs: 4, 10, 18, 22, 28 and 35, respectively; (6) SEQ ID NOs: 4, 11, 18, 22, 28 and 35, respectively; (7) SEQ ID NOs: 4, 12, 18, 23, 29 and 36, respectively; (8) SEQ ID NOs: 5, 12, 18, 23, 29 and 36, respectively; or (9) SEQ ID NOs: 6, 13, 19, 24, 30 and 37, respectively.
2 . The isolated monoclonal antibody, or the antigen-binding portion thereof, of claim 1 , wherein the heavy chain variable region comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NOs: 38, 39, 40, 41, 42 or 43,
wherein 29 th , 71 st , 102 nd and 107 th amino acid residues in SEQ ID NO: 39 are I, I, S and F, respectively; or L, M, G and L, respectively;
wherein 58 th and 60 th amino acid residues in SEQ ID NO: 41 are T and N respectively; or S and F, respectively,
wherein 74 th amino acid residue in SEQ ID NO: 42 is R or K.
3 . The isolated monoclonal antibody, or the antigen-binding portion thereof, of claim 1 , wherein the light chain variable region comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NOs: 44, 45, 46, 47, 48, or 59,
wherein 18 th , 92 nd and 106 th amino acid residues in SEQ ID NO: 44 are S, S and F, respectively; or T, H and I, respectively.
4 . The isolated monoclonal antibody, or the antigen-binding portion thereof, of claim 2 , wherein the heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to
(1) SEQ ID NOs: 38 and 44, respectively, wherein 18 th , 92 nd and 106 th amino acid residues in SEQ ID NO: 44 are S, S and F, respectively;
(2) SEQ ID NOs: 39 and 59, respectively, wherein 29 th , 71 st , 102 nd and 107 th amino acid residues in SEQ ID NO: 39 are I, I, S and F, respectively;
(3) SEQ ID NOs: 39 and 44, respectively, wherein 29 th 71 st , 102 nd and 107 th amino acid residues in SEQ ID NO: 39 are L, M, G and L, respectively, wherein 18 th , 92 nd and 106 th amino acid residues in SEQ ID NO: 44 are T, H and I, respectively;
(4) SEQ ID NOs: 40 and 45, respectively;
(5) SEQ ID NOs: 41 and 46, respectively, wherein 58 th and 60 th amino acid residues in SEQ ID NO: 41 are T and N respectively;
(6) SEQ ID NOs: 41 and 46, respectively, wherein 58 th and 60 th amino acid residues in SEQ ID NO: 41 are S and F, respectively;
(7) SEQ ID NOs: 42 and 47, respectively, wherein 74 th amino acid residue in SEQ ID NO: 42 is R;
(8) SEQ ID NOs: 42 and 47, respectively, wherein 74 th amino acid residue in SEQ ID NO: 42 is K; or
(9) SEQ ID NOs: 43 and 48, respectively.
5 . The isolated monoclonal antibody, or the antigen-binding portion thereof, of claim 1 , comprising a heavy chain constant region comprising an amino acid sequence of SEQ ID NO: 49, linked to the heavy chain variable region, and a light chain constant region comprising an amino acid sequence of SEQ ID NO: 50, linked to the light chain variable region.
6 . The isolated monoclonal antibody, or the antigen-binding portion thereof, of claim 1 , which is an IgG1, IgG2 or IgG4 isotype.
7 . The isolated monoclonal antibody, or the antigen-binding portion thereof, of claim 1 , which is able to (a) bind wild-type human C5; (b) bind human C5 carrying R885C mutation; (c) bind monkey C5; and (d) block complement-mediated hemolysis.
8 . The isolated monoclonal antibody, or the antigen-binding portion thereof, of claim 1 , which is a human antibody or antigen-binding portion thereof.
9 . A nucleotide encoding the isolated monoclonal antibody or the antigen-binding portion thereof of claim 1 .
10 . An expression vector comprising the nucleotide of claim 9 .
11 . A host cell comprising the expression vector of claim 10 .
12 . A pharmaceutical composition comprising the isolated monoclonal antibody, or antigen-binding portion thereof, of claim 1 , and a pharmaceutically acceptable carrier.
13 . The pharmaceutical composition of claim 12 , further comprising anti-inflammatory agent.
14 . A method for blocking complement-mediated hemolysis, comprising contacting red blood cells with the isolated monoclonal antibody or the antigen-binding portion thereof of claim 1 .
15 . An antibody, or an antigen-binding portion thereof, capable of binding to complement component 5, comprising a heavy chain variable region and a light chain variable region,
wherein the heavy chain variable region and the light chain variable region comprise amino acid sequences having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to
(1) SEQ ID NOs: 38 and 44, respectively, wherein 18 th , 92 nd and 106 th amino acid residues in SEQ ID NO: 44 are S, S and F, respectively;
(2) SEQ ID NOs: 39 and 59, respectively, wherein 29 th , 71 st , 102 nd and 107 th amino acid residues in SEQ ID NO: 39 are I, I, S and F, respectively;
(3) SEQ ID NOs: 39 and 44, respectively, wherein 29 th , 71 st , 102 nd and 107 th amino acid residues in SEQ ID NO: 39 are L, M, G and L, respectively, wherein 18 th , 92 nd and 106 th amino acid residues in SEQ ID NO: 44 are T, H and I, respectively;
(4) SEQ ID NOs: 40 and 45, respectively;
(5) SEQ ID NOs: 41 and 46, respectively, wherein 58 th and 60 th amino acid residues in SEQ ID NO: 41 are T and N respectively;
(6) SEQ ID NOs: 41 and 46, respectively, wherein 58 th and 60 th amino acid residues in SEQ ID NO: 41 are S and F, respectively;
(7) SEQ ID NOs: 42 and 47, respectively, wherein 74 th amino acid residue in SEQ ID NO: 42 is R;
(8) SEQ ID NOs: 42 and 47, respectively, wherein 74 th amino acid residue in SEQ ID NO: 42 is K; or
(9) SEQ ID NOs: 43 and 48, respectively.