Anti-HER2 antibodies and their uses
View Patent ↗The present disclosure relates to antibodies directed to HER2 and uses of such antibodies, for example to treat diseases associated with the activity and/or overproduction of HER2.
1. An anti-HER2 antibody or an anti-HER2 binding fragment of an antibody which comprises a VH having positions 1 to 117 of SEQ ID NO:1 and a VL having positions 1 to 103 of SEQ ID NO:2 that have one or more amino acid substitutions or combinations of amino acid substitutions as compared to an antibody having a VH comprising an amino acid sequence corresponding to positions 1 to 117 of SEQ ID NO:1 and a VL comprising an amino acid sequence corresponding to positions 1 to 103 of SEQ ID NO:2, wherein said one or more amino acid substitutions or combinations of amino acid substitutions are selected from:
(i) the third framework of the VH chain (FR-H3) substitution R83K as compared to a VH of SEQ ID NO: 1;
(ii) the first CDR of the VL chain (CDR-L1) substitution D28L as compared to a VL of SEQ ID NO:2;
(iii) the first CDR of the VL chain (CDR-L1) substitution A34D as compared to a VL of SEQ ID NO:2;
(iv) the first CDR of the VL chain (CDR-L 1) substitution A34V as compared to a VL of SEQ ID NO:2;
(v) the first CDR of the VH chain (CDR-H 1) substitution D31T as compared to a VH of SEQ ID NO: 1;
(vi) the first CDR of the VH chain (CDR-H 1) substitution D31H as compared to a VH of SEQ ID NO: 1;
(vii) the second CDR of the VH chain (CDR-H2) substitution Y52K as compared to a VH of SEQ ID NO: 1; and
(viii) the third CDR of the VH chain (CDR-H3) substitution W95F as compared to a VH of SEQ ID NO: 1.
2. The anti-HER2 antibody or anti-HER2 binding fragment of an antibody of claim 1 , wherein FR-H3 includes the substitution R83K as compared to a VH of SEQ ID NO:1.
3. The anti-HER2 antibody or anti-HER2 binding fragment of an antibody of claim 1 , wherein CDR-H3 includes the substitution W95F as compared to CDR-H3 of a VH of SEQ ID NO:1.
4. The anti-HER2 antibody or anti-HER2 binding fragment of an antibody of claim 1 , wherein CDR-L1 includes the substitution Q27S as compared to CDR-L1 of a VL of SEQ ID NO:2.
5. The anti-HER2 antibody or anti-HER2 binding fragment of an antibody of claim 1 , wherein CDR-L1 includes the substitution A34V as compared to CDR-L1 of a VL of SEQ ID NO:2.
6. The anti-HER2 antibody or anti-HER2 binding fragment of an antibody of claim 1 , wherein CDR-L1 includes at least one of the combination of substitutions selected from D28N +A34D and D28L +A34D as compared to CDR-L1 of a VL of SEQ ID NO:2.
7. The anti-HER2 antibody or anti-HER2 binding fragment of an antibody of claim 1 , wherein CDR-L1 includes at least one of the combination of substitutions selected from Q27S +A34D , Q27L +A34V, and Q27F +A34D as compared to CDR-L1 of a VL of SEQ ID NO:2.
8. The anti-HER2 antibody or anti-HER2 binding fragment of an antibody of claim 1 which has increased affinity to HER2 as compared to an antibody having a VH comprising an amino acid sequence corresponding to positions 1 to 117 of SEQ ID NO:1 and a VL comprising an amino acid sequence corresponding to positions 1 to 103 of SEQ ID NO:2.
9. The anti-HER2 antibody or anti-HER2 binding fragment of claim 8 which has an affinity to HER-2 that is at least 1.1-fold that of an antibody having a VH comprising an amino acid sequence corresponding to positions 1 to 117 of SEQ ID NO:1 and a VL comprising an amino acid sequence corresponding to positions 1 to 103 of SEQ ID NO:2, as assayed by BIAcore, AlphaLISA or by FACS.
10. The anti-HER2 antibody or anti-HER2 binding fragment of claim 9 which has
(i) at least one VL substitution selected from: T22G and A34V as compared a VL of SEQ ID NO:2;
(ii) at least one VL substitution selected from: T22G, T22S, C23A, R24H, R24C, R24V, A25C, A25G, A25P, Q27V, D28A, V29A, V29S, A34D, A34G, A51S, S52W, S52M, S52Q, S52H, S52G, S52R, L54I, L54G, L54V, S56A, S56P, S56G, S56H, S56Y, S56F, S56N, S56M, R66K, Y92M, T93L, T93M, T93V, and P96G as compared a VL of SEQ ID NO:2 and/or at least one VH substitution selected from D31H, Y52K, T53R, K64S, A88E, V89Y, S93D, D98L, D98M and D98V as compared a VH of SEQ ID NO:1;
(iii) at least one VL substitution selected from: T22G, L54I, and S56Y as compared a VL of SEQ ID NO:2; and/or at least one VH substitution selected from D31H, D31T, Y52K, D98M and D98W, as compared to SEQ ID NO:1;
(iv) at least one VL substitution selected from: T22G, L54I, and S56Y as compared a VL of SEQ ID NO:2; and/or at least one VH substitution selected from D31H, D31T, Y52K and D98M, as compared to SEQ ID NO:1; or
(v) at least one VL substitution selected from: T22G, T22S, C23A, R24H, R24C, R24V, A25C, A25G, A25P, Q27V, D28A, V29A, V29S, A34D, A34G, A51S, S52W, S52M, S52Q , S52H, S52G, S52R, L54I, L54G, L54V, S56A, S56P, S56G, S56H, S56Y, S56F, S56N, S56M, R66K, Y92M, T93L, T93M, T93V, and P96G as compared a VL of SEQ ID NO:2 and/or at least one VH substitution selected from D31H, Y52K, T53R, K64S, A88E, V89Y, S93D, D98L and D98V as compared a VH of SEQ ID NO:1.
11. The anti-HER2 antibody or anti-HER2 binding fragment of claim 1 which is a monoclonal antibody or anti-HER2 binding fragment of a monoclonal antibody, respectively.
12. The anti-HER2 antibody or anti-HER2 binding fragment of claim 1 which is a human or humanized antibody, or anti-HER2 binding fragment of a human or humanized antibody, respectively.
13. An antibody-drug conjugate comprising an anti-HER2 antibody or anti-HER2 binding fragment according to claim 1 .
14. A pharmaceutical composition comprising an anti-HER2 antibody or anti-HER2 binding fragment according to claim 1 and a pharmaceutically acceptable carrier.
15. An anti-HER2 antibody or an anti-HER2 binding fragment of an antibody which comprises six CDRs having amino acid sequences of SEQ ID NO: 3 (CDR-H1), SEQ ID NO:4 (CDR-H2), SEQ ID NO: 5 (CDR-H3), SEQ ID NO:104 (CDR-L1), SEQ ID NO:7 (CDR-L2), and SEQ ID NO:8 (CDR-L3) that have one or more amino acid substitutions or combinations of substitutions as compared to an antibody comprising CDRs having amino acid sequences of SEQ ID NO:3 (CDR-H1), SEQ ID NO:4 (CDR-H2), SEQ ID NO:5 (CDR-H3), SEQ ID NO:104 (CDR-L1), SEQ ID NO:7 (CDR-L2), and SEQ ID NO:8 (CDR-L3), wherein said one or more amino acid substitutions or combinations of amino acid substitutions are selected from:
(i) the CDR-L1 substitution D28L;
(ii) the CDR-L1 substitution A34D;
(iii) the CDR-L1 substitution A34V;
(iv) the CDR-H1 substitution D31T;
(v) the CDR-H1 substitution D31H;
(vi) the CDR-H2 substitution Y52K; and
(vi) the CDR-H3 substitution W95F.
16. The anti-HER2 antibody or anti-HER2 binding fragment of an antibody of claim 15 , wherein the antibody or anti-HER2 binding fragment further comprises a VH that has the amino acid substitution R83K as compared to the VH of SEQ ID NO:1.