Antigen binding polypeptides
The invention relates to a platform technology for production of antigen binding polypeptides having specificity for a desired target antigen which is based on the conventional antibody repertoire of species in the family Camelidae, and to antigen binding polypeptides obtained using this technology platform. In particular, the invention provides an antigen binding polypeptide comprising a VH domain and a VL domain, wherein at least one hypervariable loop or complementarity determining region (CDR) in the VH domain or the VL domain is obtained from a VH or VL domain of a species in the family Camelidae.
1. A chimeric antigen binding polypeptide that specifically binds to a human target antigen, said polypeptide comprising a VH domain and a VL domain, said VH domain comprising hypervariable loops H1, H2 and H3, wherein said VH domain polypeptide is paired with a VL domain comprising hypervariable loops L1, L2 and L3, wherein said VH domain and said VL domain are each fused to one or more IgG constant domains of a human antibody, wherein each of the hypervariable loops H1-H3 and L1-L3 are obtained from a conventional antibody of a Lama species by active immunization of the Lama species with the human target antigen, wherein said conventional antibody is a heterotetrameric IgG antibody composed of two identical light chains and two identical heavy chains, and wherein at least one of the hypervariable loops H1, H2, L1, L2 and L3 exhibits a predicted or actual canonical fold structure which is identical or substantially identical to a canonical fold structure of a corresponding H1, H2, L1, L2 or L3 hypervariable loop which occurs in a human antibody.
2. The chimeric polypeptide of claim 1 , wherein hypervariable loops H1 and H2 each exhibit a predicted or actual canonical fold structure which is identical or substantially identical to the canonical fold structure of the corresponding H1 and H2 hypervariable loops which occur in human antibodies.
3. The chimeric polypeptide of claim 1 , wherein hypervariable loops L1, L2 and L3 each exhibit a predicted or actual canonical fold structure which is identical or substantially identical to the canonical fold structure of the corresponding L1, L2 and L3 hypervariable loops which occur in human antibodies.
4. The chimeric polypeptide of claim 1 , wherein hypervariable loops H1, H2, L1, L2 and L3 each exhibit a predicted or actual canonical fold structure which is identical or substantially identical to the canonical fold structure of the corresponding H1, H2, L1, L2 and L3 hypervariable loops which occur in human antibodies.
5. A chimeric antigen binding polypeptide that specifically binds to a human target antigen, said polypeptide comprising a VH domain and a VL domain, said VH domain comprising hypervariable loops H1, H2 and H3, wherein said VH domain polypeptide is paired with a VL domain comprising hypervariable loops L1, L2 and L3, wherein said VH domain and said VL domain are each fused to one or more IgG constant domains of a human antibody, wherein each of hypervariable loops H1-H3 and L1-L3 of the polypeptide are obtained from a conventional antibody of a Lama species by active immunization of the Lama species with the human target antigen, wherein said conventional antibody is a heterotetrameric IgG antibody composed of two identical light chains and two identical heavy chains, and wherein the hypervariable loops H1 and H2 form a combination of predicted or actual canonical fold structures which is identical or substantially identical to a combination of canonical fold structures known to occur in corresponding hypervariable loops of a human germline VH domain.
6. The chimeric polypeptide of claim 5 , wherein the combination of canonical fold structures occurring in the human VH domain is selected from the group consisting of 1-1, 1-2, 1-3, 1-4, 1-6, 2-1, 3-1 and 3-5.
7. The chimeric polypeptide of claim 5 , wherein hypervariable loops L1 and L2 in the VL domain of the polypeptide form a combination of predicted or actual canonical fold structures which is identical or substantially identical to a combination of canonical fold structures known to occur in corresponding hypervariable loops of a human germline VL domain.
8. The chimeric polypeptide of claim 7 , wherein the combination of canonical fold structures occurring in the human VL domain is selected from the group consisting of 11-7, 13-7(A,B,C), 14-7 A,B), 12-11, 14-11, 12-12, 2-1, 3-1, 4-1 and 6-1.
9. The chimeric polypeptide of claim 7 wherein the VL domain of the polypeptide exhibits a sequence identity of 90% or greater with one or more human VL domains across framework regions FR1, FR2, FR3 and FR4.
10. The chimeric polypeptide of claim 1 or 5 , wherein the VH domain of the polypeptide exhibits a sequence identity of 90% or greater with one or more human VH domains across framework regions FR1, FR2, FR3 and FR4.
11. The chimeric polypeptide of claim 1 or 5 , wherein the VH domain of the polypeptide exhibits a sequence identity of 95% or greater with one or more human VH domains across framework regions FR1, FR2, FR3 and FR4.
12. The chimeric polypeptide of claim 11 , wherein the VL domain of the polypeptide exhibits a sequence identity of 95% or greater with one or more human VL domains across framework regions FR1, FR2, FR3 and FR4.
13. The chimeric polypeptide of claim 1 or 5 , wherein the VH domain of the polypeptide exhibits a sequence identity of 97% or greater with one or more human VH domains across framework regions FR1, FR2, FR3 and FR4.
14. The chimeric polypeptide of claim 13 , wherein the VL domain of the polypeptide exhibits a sequence identity of 97% or greater with one or more human VL domains across framework regions FR1, FR2, FR3 and FR4.
15. The chimeric polypeptide of claim 1 or 5 , wherein the at least one hypervariable loop in the VH domain or the VL domain of the polypeptide contains at least one amino acid substitution as compared to the corresponding hypervariable loop in the conventional antibody.
16. The chimeric polypeptide of claim 1 or 5 , wherein both of the VH and VL domains of the polypeptide comprise a total of between 1 and 10 amino acid substitutions across the framework regions FR1, FR2, FR3 and FR4 as compared to corresponding VH and VL domains of the conventional antibody.
17. The chimeric polypeptide of claim 1 or 5 , wherein the VH or VL domain of the polypeptide comprises a total of between 1 and 10 amino acid substitutions across the framework regions FR1, FR2, FR3 and FR4 as compared to corresponding VH or VL domains of the conventional antibody.
18. The chimeric polypeptide of claim 1 or 5 , wherein the Lama species is llama ( Lama glama ) or alpaca ( Lama pacos ).
19. The chimeric polypeptide of claim 1 or 5 , wherein the antigen binding polypeptide is an antibody or an antigen binding fragment thereof.