IP Library › Granted Patent US 12,311,032
Granted Patent B2
US 12,311,032 · App. 18/457,861 · Granted May 27, 2025

Anti-Ror2 antibodies, antibody fragments, their immunoconjugates and uses thereof

Inventors: Jay M. Short (Jackson, WY); Hwai Wen Chang (San Marcos, CA); Gerhard Frey (San Diego, CA)
Assignee: BioAlta, Inc.
A61K47/6849A61K38/07A61K39/3955A61K47/6803A61K47/68031A61K47/6811A61P35/00C07K16/28C07K16/2803A61K2039/505C07K2317/24C07K2317/33
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Quick Facts
Patent No.
US 12,311,032
App. No.
18/457,861
Granted
May 27, 2025
Kind
B2
Abstract

An antibody or antigen-binding antibody fragment having a heavy chain variable region and/or a light chain variable region that specifically binds to Ror2 antigen, as well as immunoconjugates containing the heavy chain variable region and/or the light chain variable region that bind to Ror2 antigen, are provided. Pharmaceutical compositions and kits comprising the polypeptide or antibodies and antibody fragments containing the polypeptide are also provided.

Claims (116)

1. A method of treating cancer comprising administering to a subject in need of such treatment,

(i) an antibody or antigen-binding fragment thereof that specifically binds to ROR2 protein, said antibody or antigen-binding fragment thereof comprising:

a heavy chain variable region including three complementarity determining regions, said regions having H1, H2, and H3 sequences, wherein:

the H1 sequence is GYTX 1 TEX 2 X 3 X 4 H (SEQ ID NO: 1);

the H2 sequence is X 5 X 6 X 7 X 8 NNGGTGYNQKFKG (SEQ ID NO: 2); and

the H3 sequence is X 9 X 10 X 11 SX 12 YX 13 YX 14 X 15 SYFX 16 X 17 X 18 (SEQ ID NO: 3);

wherein

X 1 is F or E,

X 2 is Y or D,

X 3 is T or C,

X 4 is M or D or E or Y,

X 5 is G or S,

X 6 is I or E,

X 7 is N or C or L or V,

X 8 is T or D or E,

X 9 is A or M or T,

X 10 is R or H,

X 11 is G,

X 12 is L or F,

X 13 is S,

X 14 is G,

X 15 is N or E,

X 16 is D or L,

X 17 is Y or T, and

X 18 is W or L; and

a light chain variable region including three complementarity determining regions, said regions having L1, L2, and L3 sequences, wherein:

the L1 sequence is SATSSX 19 X 20 X 21 MX 22 (SEQ ID NO: 7);

the L2 sequence is X 23 TSNLAS (SEQ ID NO: 8); and

the L3 sequence is QX 24 X 25 SX 26 YPFX 27 X 28 (SEQ ID NO: 9);

wherein

X 19 is V or E,

X 20 is S or D,

X 21 is Y or C or D,

X 22 is H or G or L,

X 23 is G or C or H or P,

X 24 is Q or E,

X 25 is R or H,

X 26 is S or G or I or Q,

X 27 is T or D, and

X 28 is F or D or E,

wherein the antibody or antigen-binding fragment thereof has a total of one or two mutations in the heavy chain and light chain complementarity determining regions H1, H2, H3, L1, L2, and L3, and the one or two mutations are determined in comparison with the complementarity determining regions H1, H2, H3, L1, L2, and L3 of the parental antibody or antigen-binding fragment thereof in which X 1 to X 28 are F, Y, T, M, G, I, N, T, A, R, G, L, S, G, N, D, Y, W, V, S, Y, H, G, Q, R, S, T, and F, respectively; and

wherein the antibody or antigen-binding fragment thereof has a ratio of binding affinity to the ROR2 protein at pH 6.0 to binding affinity to the ROR2 protein at pH 7.4 of at least 1.5; and

(ii) at least one of external beam radiotherapy and brachytherapy.

2. The method of claim 1 , wherein the heavy chain variable region has an amino acid sequence selected from SEQ ID NOs: 18 and 20-22.

3. The method of claim 1 , wherein the light chain variable region has an amino acid sequence selected from SEQ ID NOs: 13, 15 and 16.

4. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof has a ratio of binding affinity to the ROR2 protein at pH 6.0 to binding affinity to the ROR2 protein at pH 7.4 of at least 2 to 1.

5. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof has a ratio of binding affinity to the ROR2 protein at pH 6.0 to binding affinity to the ROR2 protein at pH 7.4 of at least 3 to 1.

6. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof has a ratio of binding affinity to the ROR2 protein at pH 6.0 to binding affinity to the ROR2 protein at pH 7.4 of at least 4 to 1.

7. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof has a ratio of binding affinity to the ROR2 protein at pH 6.0 to binding affinity to the ROR2 protein at pH 7.4 of at least 7 to 1.

8. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof has a ratio of binding affinity to the ROR2 protein at pH 6.0 to binding affinity to the ROR2 protein at pH 7.4 of at least 10 to 1.

9. A method of treating cancer comprising administering to a subject in need of such treatment,

(i) an immunoconjugate comprising an antibody or antigen-binding fragment thereof of claim 1 conjugated to at least one auristatin; and

(ii) af least one of external beam radiotherapy and brachytherapy.

10. A method of treating cancer comprising administering to a subject in need of such treatment,

(i) an immunoconjugate comprising an anti-ROR2 antibody or antigen-binding fragment thereof having:

(a) a heavy chain variable region of SEQ ID NO: 20 and a light chain variable region of SEQ ID NO: 15;

(b) a heavy chain variable region of SEQ ID NO: 21 and a light chain variable region of SEQ ID NO: 16; or

(c) a heavy chain variable region of SEQ ID NO: 22 and a light chain variable region of SEQ ID NO: 16,

conjugated to at least one agent selected from maytansinoids, auristatins, dolastatins, calicheamicin, pyrrolobenzodiazepines and anthracyclines; and

(ii) at least one of external beam radiotherapy and brachytherapy.

11. The method of claim 10 , wherein the heavy chain variable region is SEQ ID NO: 20 and the light chain variable region is SEQ ID NO: 15.

12. The method of claim 10 , wherein the heavy chain variable region is SEQ ID NO: 21 and the light chain variable region is SEQ ID NO: 16.

13. The method of claim 10 , wherein the heavy chain variable region is SEQ ID NO: 22 and the light chain variable region is SEQ ID NO: 16.

14. The method of claim 10 , wherein the at least one agent is an auristatin.

15. The method of claim 14 , wherein the auristatin comprise monomethyl auristatin E (MMAE).

16. A method of treating cancer comprising administering to a subject in need of such treatment,

(i) an immunoconjugate that specifically binds to ROR2 protein, said immunoconjugate comprising an anti-ROR2 antibody or antigen-binding fragment thereof comprising:

a heavy chain variable region including three complementarity determining regions, said regions having H1, H2, and H3 sequences, wherein:

the H1 sequence is GYTX 1 TEX 2 X 3 X 4 H (SEQ ID NO: 1);

the H2 sequence is X 5 X 6 X 7 X 8 NNGGTGYNQKFKG (SEQ ID NO: 2); and

the H3 sequence is X 9 X 10 X 11 SX 12 YX 13 YX 14 X 15 SYFX 16 X 17 X 18 (SEQ ID NO: 3);

wherein

X 1 is F or E,

X 2 is Y or D,

X 3 is T or C,

X 4 is M or D or E or Y,

X 5 is G or S,

X 6 is I or E,

X 7 is N or C or L or V,

X 8 is T or D or E,

X 9 is A or M or T,

X 10 is R or H,

X 11 is G,

X 12 is L or F,

X 13 is S,

X 14 is G,

X 15 is N or E,

X 16 is D or L,

X 17 is Y or T, and

X 18 is W or L; and

a light chain variable region including three complementarity determining regions, said regions having L1, L2, and L3 sequences, wherein:

the L1 sequence is SATSSX 19 X 20 X 21 MX 22 (SEQ ID NO: 7);

the L2 sequence is X 23 TSNLAS (SEQ ID NO: 8); and

the L3 sequence is QX 24 X 25 SX 26 YPFX 27 X 28 (SEQ ID NO: 9);

wherein

X 19 is V or E,

X 20 is S or D,

X 21 is Y or C or D,

X 22 is H or G or L,

X 23 is G or C or H or P,

X 24 is Q or E,

X 25 is R or H,

X 26 is S or G or I or Q,

X 27 is T or D, and

X 28 is F or D or E, and

wherein the antibody or antigen-binding fragment thereof has a total of one or two mutations in the heavy chain and light chain complementarity determining regions H1, H2, H3, L1, L2, and L3, and the one or two mutations are determined in comparison with the complementarity determining regions H1, H2, H3, L1, L2, and L3 of the parental antibody or antigen-binding fragment thereof in which X 1 to X 28 are F, Y, T, M, G, I, N, T, A, R, G, L, S, G, N, D, Y, W, V, S, Y, H, G, Q, R, S, T, and F, respectively; and

wherein the immunoconjugate has a ratio of binding affinity to the ROR2 protein at pH 6.0 to binding affinity to the ROR2 protein at pH 7.4 of at least 1.5; and

(ii) at least one of external beam radiotherapy and brachytherapy.

17. The method of claim 16 , wherein the immunoconjugate has a ratio of binding affinity to the ROR2 protein at pH 6.0 to binding affinity to the ROR2 protein at pH 7.4 of at least 2 to 1.

18. The method of claim 16 , wherein the immunoconjugate has a ratio of binding affinity to the ROR2 protein at pH 6.0 to binding affinity to the ROR2 protein at pH 7.4 of at least 3 to 1.

19. The method of claim 16 , wherein the immunoconjugate has a ratio of binding affinity to the ROR2 protein at pH 6.0 to binding affinity to the ROR2 protein at pH 7.4 of at least 4 to 1.

20. The method of claim 16 , wherein the immunoconjugate has a ratio of binding affinity to the ROR2 protein at pH 6.0 to binding affinity to the ROR2 protein at pH 7.4 of at least 7 to 1.

21. The method of claim 16 , wherein the immunoconjugate has a ratio of binding affinity to the ROR2 protein at pH 6.0 to binding affinity to the ROR2 protein at pH 7.4 of at least 10 to 1.

22. The method of claim 16 , wherein the immunoconjugate comprises at least one agent selected from a chemotherapeutic agent, a cytostatic agent, and a cytotoxic agent.

23. The method of claim 22 , wherein the at least one agent is selected from maytansinoids, auristatins, dolastatins, calicheamicin, pyrrolobenzodiazepines, and anthracyclines.

24. The method of claim 23 , wherein the auristatins comprise monomethyl auristatin E (MMAE).

Continuity (5)
Continuation 17533852 · Nov 23, 2021
Continuation 16088769
Provisional Application 62447218 · Jan 17, 2017
Provisional Application 62335719 · May 13, 2016
Related Publication 20240092901A1 · Mar 21, 2024
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