Antibodies that are cross-reactive for macrophage migration inhibitory factor (MIF) and D-dopachrome tautomerase (D-DT)
The present disclosure relates to antigen-binding moieties that specifically bind to MIF and D-DT and compositions and methods of use thereof.
1. An isolated antigen-binding moiety, wherein the antigen-binding moiety specifically binds human MIF and human D-DT,
wherein the antigen-binding moiety recognizes an epitope of MIF,
wherein a similar epitope is present in D-DT and
wherein said isolated antigen-binding moiety recognizes both epitopes,
said epitopes in MIF and D-DT comprise an amino acid shown in FIG. 1 that
is identical in human MIF and human D-DT.
2. The isolated antigen-binding moiety of claim 1 , wherein the isolated antigen-binding moiety binds to MIF and to D-DT with an EC 50 concentration of less than 100 nM.
3. The isolated antigen-binding moiety of claim 1 , wherein the isolated antigen-binding moiety binds to MIF and to D-DT with a dissociation constant (K D ) of less than 1×10 7 M −1 .
4. The isolated antigen-binding moiety of claim 1 , wherein the isolated antigen-binding moiety is an antibody, a fragment thereof, a single domain antibody, a maxibody, a minibody, an intrabody, a diabody, a triabody, a tetrabody, a v-NAR, a camelid antibody, or a domain antibody.
5. The antibody or fragment thereof of claim 4 , wherein said antibody or fragment thereof is a monoclonal antibody or a polyclonal antibody.
6. The antibody or fragment thereof of claim 4 , wherein said antibody is a human, humanized or chimeric antibody.
7. The antibody or fragment thereof of claim 4 , wherein said antibody or fragment thereof is of the IgG isotype.
8. The antibody or fragment thereof of claim 4 , wherein said antibody fragment thereof is selected from the group consisting of a Fab, F(ab2)′, F(ab)2′, scFV.
9. An antibody-derived scaffold comprising the antigen binding moiety of claim 1 , wherein said antibody-derived scaffold is a bispecific antibody-derived scaffold selected from the group consisting of a bispecific-scFv, a tetravalent bispecific antibody, a cross-linked Fab or a bispecific IgG.
10. A pharmaceutical composition comprising an antigen binding moiety according to claim 1 , and a pharmaceutically acceptable carrier.
11. An isolated antigen-binding moiety of claim 1 that cross-competes with an isolated antibody or fragment thereof, comprising heavy chain variable region CDR1 of SEQ ID NO: 1; CDR2 of SEQ ID NO: 2; CDR3 of SEQ ID NO: 3; and a light chain variable region CDR1 of SEQ ID NO: 4; CDR2 of SEQ ID NO: 5; and CDR3 of SEQ ID NO: 6.
12. An isolated antigen-binding moiety of claim 11 that binds to the same epitope as an isolated antibody or fragment thereof, comprising heavy chain variable region CDR1 of SEQ ID NO: 1; CDR2 of SEQ ID NO: 2; CDR3 of SEQ ID NO: 3; and a light chain variable region CDR1 of SEQ ID NO: 4; CDR2 of SEQ ID NO: 5; and CDR3 of SEQ ID NO: 6.
13. An isolated antigen-binding moiety of claim 1 that cross-competes with an isolated antibody or fragment thereof, comprising a heavy chain variable region CDR1 of SEQ ID NO: 17; CDR2 of SEQ ID NO: 18; CDR3 of SEQ ID NO: 19; and a light chain variable region CDR1 of SEQ ID NO: 20; CDR2 of SEQ ID NO: 21; and CDR3 of SEQ ID NO: 22.
14. An isolated antigen-binding moiety of claim 13 that binds to the same epitope as an isolated antibody or fragment thereof, comprising a heavy chain variable region CDR1 of SEQ ID NO: 17; CDR2 of SEQ ID NO: 18; CDR3 of SEQ ID NO: 19; and a light chain variable region CDR1 of SEQ ID NO: 20; CDR2 of SEQ ID NO: 21; and CDR3 of SEQ ID NO: 22.
15. An isolated antigen-binding moiety of claim 1 that cross-competes with an isolated antibody or fragment thereof, comprising a heavy chain variable region CDR1 of SEQ ID NO: 33; CDR2 of SEQ ID NO: 34; CDR3 of SEQ ID NO: 35; and a light chain variable region CDR1 of SEQ ID NO: 36; CDR2 of SEQ ID NO: 37; and CDR3 of SEQ ID NO: 38.
16. An isolated antigen-binding moiety of claim 15 that binds to the same epitope as an isolated antibody or fragment thereof, comprising a heavy chain variable region CDR1 of SEQ ID NO: 33; CDR2 of SEQ ID NO: 34; CDR3 of SEQ ID NO: 35; and a light chain variable region CDR1 of SEQ ID NO: 36; CDR2 of SEQ ID NO: 37; and CDR3 of SEQ ID NO: 38.
17. An isolated antigen-binding moiety of claim 1 , comprising an antibody or fragment thereof having at least 95% sequence identity to an antibody or fragment thereof comprising the heavy chain variable region CDR1 of SEQ ID NO: 1; CDR2 of SEQ ID NO: 2; CDR3 of SEQ ID NO: 3; and a light chain variable region CDR1 of SEQ ID NO: 4; CDR2 of SEQ ID NO: 5; and CDR3 of SEQ ID NO: 6.
18. An isolated antibody or fragment thereof of claim 17 , comprising a heavy chain variable region CDR1 of SEQ ID NO: 1; CDR2 of SEQ ID NO: 2; CDR3 of SEQ ID NO: 3; and a light chain variable region CDR1 of SEQ ID NO: 4; CDR2 of SEQ ID NO: 5; and CDR3 of SEQ ID NO: 6.
19. An isolated antibody or fragment thereof of claim 18 which antibody comprises a VH comprising SEQ ID NO: 14 and a VL comprising SEQ ID NO: 13.
20. An isolated antigen-binding moiety of claim 1 , comprising an antibody or fragment thereof having at least 95% sequence identity to an antibody or fragment thereof comprising a heavy chain variable region CDR1 of SEQ ID NO: 17; CDR2 of SEQ ID NO: 18; CDR3 of SEQ ID NO: 19; and a light chain variable region CDR1 of SEQ ID NO: 20; CDR2 of SEQ ID NO: 21; and CDR3 of SEQ ID NO: 22.
21. An isolated antibody or fragment thereof of claim 20 , comprising a heavy chain variable region CDR1 of SEQ ID NO: 17; CDR2 of SEQ ID NO: 18; CDR3 of SEQ ID NO: 19; and a light chain variable region CDR1 of SEQ ID NO: 20; CDR2 of SEQ ID NO: 21; and CDR3 of SEQ ID NO: 22.
22. An isolated antibody or fragment thereof of claim 21 , which antibody comprises a VH comprising SEQ ID NO: 30 and a VL comprising SEQ ID NO: 29.
23. An isolated antigen-binding moiety of claim 1 , comprising an antibody or fragment thereof having at least 95% sequence identity to an antibody or fragment thereof, comprising a heavy chain variable region CDR1 of SEQ ID NO: 33; CDR2 of SEQ ID NO: 34; CDR3 of SEQ ID NO: 35; and a light chain variable region CDR1 of SEQ ID NO: 36; CDR2 of SEQ ID NO: 37; and CDR3 of SEQ ID NO: 38.
24. An isolated antibody or fragment thereof of claim 23 , comprising a heavy chain variable region CDR1 of SEQ ID NO: 33; CDR2 of SEQ ID NO: 34; CDR3 of SEQ ID NO: 35; and a light chain variable region CDR1 of SEQ ID NO: 36; CDR2 of SEQ ID NO: 37; and CDR3 of SEQ ID NO: 38.
25. An isolated antibody or fragment thereof of claim 24 which antibody comprises a VH comprising SEQ ID NO: 46 and a VL comprising SEQ ID NO: 45.
26. A nucleic acid encoding an isolated antigen-binding moiety according to claim 1 .
27. A vector comprising a nucleic acid of claim 26 .
28. An isolated host cell comprising a vector according to claim 27 .
29. An isolated host cell according to claim 28 wherein the host cell is a mammalian cell.
30. An isolated host cell according to claim 28 wherein the host cell is a human cell.
31. A nucleic acid sequence encoding an isolated antigen-binding moiety according to claim 1 , said antigen-binding moiety comprising an antibody or fragment thereof having at least 95% sequence identity to an antibody or fragment thereof encoded by the nucleic acids selected from the group consisting of
1) SEQ ID NO: 15 encoding a variable light chain, and SEQ ID NO: 16 encoding a variable heavy chain;
2) SEQ ID NO: 31 encoding a variable light chain, and SEQ ID NO: 32 encoding a variable heavy chain; and
3) SEQ ID NO: 47 encoding a variable light chain, and SEQ ID NO: 48 encoding a variable heavy chain.
32. A nucleic acid encoding an isolated antibody or fragment thereof of claim 31 , wherein the nucleic acid encoding the VH comprises SEQ ID NO: 16 and the nucleic acid encoding the VL comprises SEQ ID NO: 15.
33. A nucleic acid encoding an isolated antibody or fragment thereof of claim 31 , wherein the nucleic acid encoding the VH comprises SEQ ID NO: 32 and the nucleic acid encoding the VL comprises SEQ ID NO: 31.
34. A nucleic acid encoding an isolated antibody or fragment thereof of claim 31 , wherein the nucleic acid encoding the VH comprises SEQ ID NO: 48 and the nucleic acid encoding the VL comprises SEQ ID NO: 47.