IP Library › Granted Patent US 12,371,683
Granted Patent B2
US 12,371,683 · App. 16/628,258 · Granted Jul 29, 2025

Hyaluronidase variants and pharmaceutical composition comprising the same

Inventors: Soon Jae Park (Daejeon, KR); Hye-Shin Chung (Daejeon, KR); Seung Joo Lee (Daejeon, KR); Sun-Ah You (Daejeon, KR); Hyung-Nam Song (Daejeon, KR); Chang Woo Lee (Daejeon, KR)
Assignee: ALTEOGEN Inc.
C12N9/2402A61K45/06C07K14/00C12Y302/01035
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Quick Facts
Patent No.
US 12,371,683
App. No.
16/628,258
Granted
Jul 29, 2025
Kind
B2
Abstract

The present invention is related to the field of protein engineering technology which increases the enzymatic activity and thermal stability of human hyaluronidase which is an enzyme that hydrolyzes hyaluronic acid; and more particularly to hyaluronidase PH20 variants or fragments thereof, which comprise one or more amino acid residue substitutions in the region corresponding to the alpha-helix region and its linker region in the amino acid sequence of wild-type PH20 of SEQ ID NO: 1 and in which one or more amino acid residues at the N-terminus and/or the C-terminus are selectively cleaved additionally. Specifically, the present invention relates to PH20 variants or fragments thereof, which comprise one or more amino acid residue substitutions selected from the group consisting of T341A, T341C, T341G, S343E, M345T, K349E, L353A, L354I, N356E and I361T in wild-type PH20 having the amino acid sequence of SEQ ID NO: 1, and additionally comprise the substitution of amino acids located in the alpha-helix 8 region and/or a linker region between alpha-helix 7 and alpha-helix 8 in the amino acid sequence of wild-type PH20, and in which one or more amino acids located at the N-terminal and C-terminal regions are deleted.

Claims (87)

1. A PH20 variant, wherein the amino acid sequence of the PH20 variant is SEQ ID NO: 1 with modifications consisting of:

(a) amino acid residue substitutions M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D and I361T relative to SEQ ID NO: 1, and one or more amino acid residue substitutions selected from the group consisting of T341A, T341G, T341S, L342W, S343E, I344N and N363G relative to SEQ ID NO: 1;

(b) an N-terminus deletion of amino acid residues M1 to T35, M1 to L36, M1 to N37, M1 to F38, M1 to R39, or M1 to A40 of SEQ ID NO: 1; and

(c) a C-terminus deletion, wherein the C-terminus of the PH20 variant ends with an amino acid residue selected from any one of I465 to S490 of SEQ ID NO: 1.

2. The PH20 variant of claim 1 , wherein the amino acid residue substitutions relative to SEQ ID NO: 1 consist of the amino acid residue substitutions in any one of the following groups of amino acid residue substitutions:

(a) T341S, L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D and I361T;

(b) L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D and I361T;

(c) M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D, I361T and N363G;

(d) T341G, L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D and I361T;

(e) T341A, L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D and I361T;

(f) I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D and 1361T; and

(g) S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D and I361T.

3. The PH20 variant of claim 1 , wherein the C-terminus of the PH20 variant ends with amino acid residue I465, D466, A467, F468, K470, P471, P472, M473, E474, T475, E476, P478, 1480, Y482, A484, P486, T488, or S490 of SEQ ID NO: 1.

4. A PH20 variant comprising the amino acid sequence of any one of the amino acid sequences of SEQ ID NOs: 60, 63 to 69, 71 to 74, 77 to 80, 82, and 87 to 115.

5. A PH20 variant comprising the amino acid sequence of SEQ ID NO: 99.

6. The PH20 variant of claim 4 , wherein the amino acid sequence of the PH20 variant consists of any one of the amino acid sequences of SEQ ID NOs: 60, 63 to 69, 71 to 74, 77 to 80, 82, and 87 to 115.

7. A PH20 variant, wherein the amino acid sequence of the PH20 variant consists of the amino acid sequence of SEQ ID NO:99.

8. A PH20 variant, wherein the amino acid sequence of the PH20 variant is SEQ ID NO: 1 with modifications consisting of:

(a) amino acid residue substitutions consisting of T341S, L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D, and I361T relative to SEQ ID NO: 1;

(b) an N-terminus deletion of amino acid residues M1 to T35, M1 to L36, M1 to N37, M1 to F38, M1 to R39, or M1 to A40; and

(c) a C-terminus deletion, wherein the C-terminus of the PH20 variant ends with an amino acid residue selected from any one of I465 to S490 of SEQ ID NO: 1.

9. The PH20 variant of claim 8 , wherein the N-terminus deletion is a deletion of amino acid residues M1 to T35, M1 to L36, M1 to N37, or M1 to F38 of SEQ ID NO: 1.

10. The PH20 variant of claim 8 , wherein the N-terminus deletion is a deletion of amino acid residues M1 to T35, M1 to L36, M1 to N37, or M1 to F38 of SEQ ID NO: 1, and the C-terminus of the PH20 variant ends with amino acid residue I465, D466, A467, F468, K470, P471, P472, M473, E474, T475, E476, P478, I480, Y482, A484, P486, T488, or S490 of SEQ ID NO: 1.

11. The PH20 variant of claim 8 , wherein the N-terminus deletion is a deletion of amino acid residues M1 to T35, M1 to L36, M1 to N37, or M1 to F38 of SEQ ID NO: 1, and the C-terminus of the PH20 variant ends with amino acid residue I465, F468, or P471 of SEQ ID NO: 1.

12. The PH20 variant of claim 8 , wherein the N-terminus deletion is a deletion of amino acid residues M1 to T35, M1 to L36, M1 to N37, M1 to F38, or M1 to R39 of SEQ ID NO: 1, and the C-terminus of the PH20 variant ends with amino acid residue F468 of SEQ ID NO: 1.

13. The PH20 variant of claim 12 , wherein the N-terminus deletion is a deletion of amino acid residues M1 to T35, M1 to L36, M1 to N37, or M1 to F38 of SEQ ID NO: 1.

14. A PH20 variant, wherein the amino acid sequence of the PH20 variant is SEQ ID NO: 1 with modifications consisting of:

(a) amino acid residue substitutions, wherein the amino acid residue substitutions consist of amino acid residue substitutions in the region T341 to I361 of SEQ ID NO: 1, wherein the amino acid residue substitutions in the region T341 to 1361 comprise amino acid residue substitutions M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D, and I361T relative to SEQ ID NO: 1, and one or more amino acid residue substitutions selected from the group consisting of T341A, T341C, T341D, T341G, T341S, L342W, and S343E relative to SEQ ID NO: 1, and wherein the amino acid residue substitutions in the region do not comprise an amino acid residue substitution at amino acid residue C351 or Y357 relative to SEQ ID NO: 1;

(b) an N-terminus deletion of amino acid residues M1 to T35, M1 to L36, M1 to N37, M1 to F38, M1 to R39, or M1 to A40 of SEQ ID NO: 1; and

(c) a C-terminus deletion, wherein the C-terminus of the PH20 variant ends with an amino acid residue selected from any one of I465 to S490 of SEQ ID NO: 1.

15. The PH20 variant of claim 14 , wherein the one or more amino acid residue substitutions is selected from the group consisting of T341A, T341G, T341S, L342W, and S343E relative to SEQ ID NO: 1.

16. The PH20 variant of claim 14 , wherein the amino acid residue substitutions in the region consist of the amino acid residue substitutions in any one of the following groups of amino acid residue substitutions:

(a) T341S, L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D, and I361T;

(b) L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D, and I361T;

(c) T341D, L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D, and 1361T;

(d) T341G, L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D, and I361T;

(e) T341A, L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D, and I361T;

(f) T341C, L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D, and I361T; and

(g) S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D, and I361T.

17. The PH20 variant of claim 1 , wherein the C-terminus of the PH20 variant ends with an amino acid residue selected from any one of D466 to S490 of SEQ ID NO: 1.

18. The PH20 variant of claim 1 , wherein the one or more amino acid residue substitutions is selected from the group consisting of T341S, L342W, S343E, I344N, and N363G relative to SEQ ID NO: 1.

19. A PH20 variant comprising the amino acid sequence of SEQ ID NO: 60, 63, 64, 65, 66, 67, 68, 69, 71, 72, 73, 74, 77, 78, 79, 80, 82, 87, 88, 89, 90, 91, 92, 93, 94, 95, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 112, 113, 114, or 115.

20. The PH20 variant of claim 19 , wherein the amino acid sequence of the PH20 variant consists of the amino acid sequence of SEQ ID NO: 60, 63, 64, 65, 66, 67, 68, 69, 71, 72, 73, 74, 77, 78, 79, 80, 82, 87, 88, 89, 90, 91, 92, 93, 94, 95, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 112, 113, 114, or 115.

21. The PH20 variant of claim 1 , wherein the C-terminus of the PH20 variant ends with amino acid residue I465, D466, A467, F468, K470, P471, P472, M473, E474, T475, E476, P478, 1480, or Y482 of SEQ ID NO: 1.

22. The PH20 variant of claim 1 , wherein the N-terminus deletion is a deletion of amino acid residues M1 to T35, M1 to L36, M1 to N37, or M1 to F38 of SEQ ID NO: 1, and wherein the C-terminus of the PH20 variant ends with amino acid residue I465, D466, A467, F468, K470, P471, P472, M473, E474, T475, E476, P478, 1480, or Y482 of SEQ ID NO: 1.

23. The PH20 variant of claim 8 , wherein the N-terminus deletion is a deletion of amino acid residues M1 to T35, M1 to L36, M1 to N37, or M1 to F38 of SEQ ID NO: 1, and wherein the C-terminus of the PH20 variant ends with amino acid residue I465, D466, A467, F468, K470, P471, P472, M473, E474, T475, E476, P478, 1480, or Y482 of SEQ ID NO: 1.

24. The PH20 variant of claim 8 , wherein the N-terminus deletion is a deletion of amino acid residues M1 to T35, M1 to L36, M1 to N37, M1 to F38, or M1 to R39 of SEQ ID NO: 1.

25. The PH20 variant of claim 8 , wherein the C-terminus of the PH20 variant ends with amino acid residue F468 of SEQ ID NO: 1.

26. The PH20 variant of claim 2 , wherein the C-terminus of the PH20 variant ends with amino acid residue F468 of SEQ ID NO: 1.

27. The PH20 variant of claim 8 , wherein the C-terminus of the PH20 variant ends with amino acid residue Y482 of SEQ ID NO: 1.

28. The PH20 variant of claim 24 , wherein the C-terminus of the PH20 variant ends with amino acid residue Y482 of SEQ ID NO: 1.

29. The PH20 variant of claim 8 , wherein the C-terminus of the PH20 variant ends with amino acid residue I465, D466, A467, F468, K470, or P471 of SEQ ID NO: 1.

30. The PH20 variant of claim 24 , wherein the C-terminus of the PH20 variant ends with amino acid residue I465, D466, A467, F468, K470, or P471 of SEQ ID NO: 1.

31. A PH20 variant, wherein the amino acid sequence of the PH20 variant is SEQ ID NO: 1 with modifications consisting of:

(a) amino acid residue substitutions consisting essentially of amino acid residue substitutions in the region T341 to 1361 of SEQ ID NO: 1, wherein the amino acid residue substitutions in the region T341 to 1361 comprise amino acid residue substitutions M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D, and I361T relative to SEQ ID NO: 1, and one or more amino acid residue substitutions selected from the group consisting of T341A, T341C, T341D, T341G, T341S, L342W, and S343E relative to SEQ ID NO: 1, and wherein the amino acid residue substitutions in the region do not comprise an amino acid residue substitution at amino acid residue C351 or Y357 relative to SEQ ID NO: 1;

(b) an N-terminus deletion of amino acid residues M1 to T35, M1 to L36, M1 to N37, M1 to F38, M1 to R39, or M1 to A40 of SEQ ID NO: 1; and

(c) a C-terminus deletion, wherein the C-terminus of the PH20 variant ends with an amino acid residue selected from any one of 1465 to S490 of SEQ ID NO: 1.

32. The PH20 variant of claim 31 , wherein the one or more amino acid residue substitutions is selected from the group consisting of T341A, T341G, T341S, L342W, and S343E relative to SEQ ID NO: 1.

33. The PH20 variant of claim 31 , wherein the amino acid residue substitutions in the region consist of the amino acid residue substitutions in any one of the following groups of amino acid residue substitutions:

(a) T341S, L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D, and I361T;

(b) L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D, and I361T;

(c) T341D, L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D, and I361T;

(d) T341G, L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D, and I361T;

(e) T341A, L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D, and I361T;

(f) T341C, L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D, and I361T; and

(g) S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D, and I361T.

34. The PH20 variant of claim 31 , wherein the amino acid residue substitutions in the region consist of T341S, L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D, and I361T relative to SEQ ID NO: 1.

35. The PH20 variant of claim 31 , wherein the amino acid residue substitutions in the region consist of T341S, L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D, and I361T relative to SEQ ID NO: 1, and the N-terminus deletion is a deletion of amino acid residues M1 to T35, M1 to L36, M1 to N37, or M1 to F38 of SEQ ID NO: 1.

36. A PH20 variant, wherein the amino acid sequence of the PH20 variant is SEQ ID NO: 1 with modifications consisting of:

(a) amino acid residue substitutions relative to SEQ ID NO: 1, wherein the amino acid residue substitutions consist essentially of:

amino acid residue substitutions M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D and I361T relative to SEQ ID NO: 1, and

one or more amino acid residue substitutions selected from the group consisting of T341A, T341G, T341S, L342W, S343E, I344N and N363G relative to SEQ ID NO: 1;

(b) an N-terminus deletion of amino acid residues M1 to T35, M1 to L36, M1 to N37, M1 to F38, M1 to R39, or M1 to A40 of SEQ ID NO: 1; and

(c) a C-terminus deletion, wherein the C-terminus of the PH20 variant ends with an amino acid residue selected from any one of 1465 to S490 of SEQ ID NO: 1.

37. The PH20 variant of claim 36 , wherein the C-terminus of the PH20 variant ends with amino acid residue I465, D466, A467, F468, K470, P471, P472, M473, E474, T475, E476, P478, 1480, Y482, A484, P486, T488, or S490 of SEQ ID NO: 1.

38. The PH20 variant of claim 36 , wherein the C-terminus of the PH20 variant ends with an amino acid residue selected from any one of D466 to S490 of SEQ ID NO: 1.

39. The PH20 variant of claim 36 , wherein the one or more amino acid residue substitutions is selected from the group consisting of T341S, L342W, S343E, I344N, and N363G relative to SEQ ID NO: 1.

40. The PH20 variant of claim 36 , wherein the C-terminus of the PH20 variant ends with amino acid residue I465, D466, A467, F468, K470, P471, P472, M473, E474, T475, E476, P478, 1480, or Y482 of SEQ ID NO: 1.

41. The PH20 variant of claim 36 , wherein the N-terminus deletion is a deletion of amino acid residues M1 to T35, M1 to L36, M1 to N37, or M1 to F38 of SEQ ID NO: 1, and wherein the C-terminus of the PH20 variant ends with amino acid residue I465, D466, A467, F468, K470, P471, P472, M473, E474, T475, E476, P478, 1480, or Y482 of SEQ ID NO: 1.

42. A protein comprising the PH20 variant of claim 1 .

43. A protein comprising the PH20 variant of claim 2 .

44. A protein comprising the PH20 variant of claim 8 .

45. A protein comprising the PH20 variant of claim 14 .

46. A protein comprising the PH20 variant of claim 16 .

47. A protein comprising the PH20 variant of claim 31 .

48. A protein comprising the PH20 variant of claim 33 .

49. A protein comprising the PH20 variant of claim 36 .

Assignments (2)
CORRECTIVE ASSIGNMENT TO CORRECT THE THE NAME OF THE ASSIGNEE PREVIOUSLY RECORDED AT REEL: 51479 FRAME: 634. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Recorded Nov 15, 2024
From: PARK, SOON JAE; CHUNG, HYE-SHIN; LEE, SEUNG JOO; YOU, SUN-AH; SONG, HYUNG-NAM; LEE, CHANG WOO
To: ALTEOGEN INC.
Reel/Frame 070343/0657 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 10, 2020
From: PARK, SOON JAE; CHUNG, HYE-SHIN; LEE, SEUNG JOO; YOU, SUN-AH; SONG, HYUNG-NAM; LEE, CHANG WOO
To: ALTEOGEN, INC.
Reel/Frame 051479/0634 →
Priority Claims (2)
KR 10-2018-0086308 · Jul 25, 2018 · national
KR 10-2019-0029758 · Mar 15, 2019 · national
Continuity (1)
Related Publication 20210155913A1 · May 27, 2021
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Swiss Model Printout of PH20 Model, printed Nov. 10, 2024 (Exhibit 1069 in PGR2025-00003). [cited by applicant]
Swiss Model Printout of PH20 Model with D320K Mutation, printed Nov. 9, 2024 (Exhibit 1070 in PGR2025-00003). [cited by applicant]
Swiss Model Printout of PH20 Model with D320H Mutation, printed Nov. 9, 2024 (Exhibit 1071 in PGR2025-00003). [cited by applicant]
Swiss Model Printout of PH20 Model with D320R Mutation, printed Nov. 9, 2024 (Exhibit 1072 in PGR2025-00003). [cited by applicant]
Swiss Model Printout of PH20 Model with D320S Mutation, printed Nov. 9, 2024 (Exhibit 1073 in PGR2025-00003). [cited by applicant]
Cited By (1)
US 12,678,492