Non-immunogenic single domain antibodies

Inventors: Brendan P. Eckelman (La Jolla, CA); John C. Timmer (La Jolla, CA); Quinn Deveraux (La Jolla, CA)

Assignee: Inhibrx, Inc.

C07K16/00 C07K16/4283 C07K2317/24 C07K2317/56 C07K2317/567 C07K2317/569

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Quick Facts

Patent No.: US 10,526,397
App. No.: 15/003,234
Granted: Jan 7, 2020
Kind: B2

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Abstract

The invention provides modifications within human or humanized single domain antibody fragments (sdAbs) that prevent recognition by pre-existing antibodies, to isolated polypeptides that include these modifications, and to methods and uses thereof.

Claims (24)

1. A single domain antibody (sdAb) comprising a mutation at position Leu11 according to Kabat, wherein the mutation at position Leu11 is Leu11Lys (L11K), Leu11Arg (L11R), Leu11Asp (L11D), or Leu11Glu (L11E), and wherein the carboxy terminus comprises an amino acid sequence selected from TVE, TVK, LVTVS (SEQ ID NO: 7), LVTVSS (SEQ ID NO: 113), TVSE (SEQ ID NO: 24), TVEG (SEQ ID NO: 25), TVSEG (SEQ ID NO: 26), TVSK (SEQ ID NO: 27), TVKG (SEQ ID NO: 28), TVSKG (SEQ ID NO: 29), TVSKPG (SEQ ID NO: 44), TVSKPGG (SEQ ID NO: 45), TVKP (SEQ ID NO: 46), TVKPG (SEQ ID NO: 47), TVKPGG (SEQ ID NO: 48), TVRP (SEQ ID NO: 49), TVRPG (SEQ ID NO: 50), TVRPGG (SEQ ID NO: 51), TVEP (SEQ ID NO: 52), TVEPG (SEQ ID NO: 53), TVEPGG (SEQ ID NO: 54), TVDP (SEQ ID NO: 55), TVDPG (SEQ ID NO: 56), and TVDPGG (SEQ ID NO: 57).

2. The single domain antibody of claim 1 , wherein the carboxy terminus comprises an amino acid sequence selected from SEQ ID NOs: 2-10 and 30-43.

3. The single domain antibody of claim 1 , wherein the mutation at position Leu11 is Leu11Lys (L11K) and the carboxy terminus comprises an amino acid sequence selected from TVE, TVSE (SEQ ID NO: 24), TVEG (SEQ ID NO: 25), TVSEG (SEQ ID NO: 26), TVEP (SEQ ID NO: 52), TVEPG (SEQ ID NO: 53), TVEPGG (SEQ ID NO: 54), TVDP (SEQ ID NO: 55), TVDPG (SEQ ID NO: 56), and TVDPGG (SEQ ID NO: 57).

4. The single domain antibody of claim 1 , wherein the mutation at position Leu11 is Leu11Glu (L11E) and the carboxy terminus comprises an amino acid sequence selected from TVK, TVSK (SEQ ID NO: 27), TVKG (SEQ ID NO: 28), TVSKG (SEQ ID NO: 29), TVSKPG (SEQ ID NO: 44), TVSKPGG (SEQ ID NO: 45), TVKP (SEQ ID NO: 46), TVKPG (SEQ ID NO: 47), TVKPGG (SEQ ID NO: 48), TVRP (SEQ ID NO: 49), TVRPG (SEQ ID NO: 50), and TVRPGG (SEQ ID NO: 51).

5. The single domain antibody of claim 1 , wherein the mutation at position Leu11 is Leu11Glu (L11E) and the carboxy terminus comprises an amino acid sequence selected from TVE, TVSE (SEQ ID NO: 24), TVEG (SEQ ID NO: 25), TVSEG (SEQ ID NO: 26), TVEP (SEQ ID NO: 52), TVEPG (SEQ ID NO: 53), TVEPGG (SEQ ID NO: 54), TVDP (SEQ ID NO: 55), TVDPG (SEQ ID NO: 56), and TVDPGG (SEQ ID NO: 57).

6. The single domain antibody of claim 1 , wherein the mutation at position Leu11 is Leu11Lys (L11K) and the carboxy terminus comprises an amino acid sequence selected from TVK, TVSK (SEQ ID NO: 27), TVKG (SEQ ID NO: 28), TVSKG (SEQ ID NO: 29), TVSKPG (SEQ ID NO: 44), TVSKPGG (SEQ ID NO: 45), TVKP (SEQ ID NO: 46), TVKPG (SEQ ID NO: 47), TVKPGG (SEQ ID NO: 48), TVRP (SEQ ID NO: 49), TVRPG (SEQ ID NO: 50), and TVRPGG (SEQ ID NO: 51).

7. The single domain antibody of claim 1 , wherein the mutation at position Leu11 is Leu11Glu (L11E) and the carboxy terminus of the single domain antibody comprises the amino acid sequence of SEQ ID NO: 48 or SEQ ID NO: 34.

8. The single domain antibody of claim 1 , wherein the mutation at position Leu11 is Leu11Glu (L11E) and the carboxy terminus of the single domain antibody comprises the amino acid sequence of SEQ ID NO: 47 or SEQ ID NO: 33.

9. The single domain antibody of claim 1 , wherein the mutation at position Leu11 is Leu11Arg (L11R) and the carboxy terminus comprises an amino acid sequence selected from TVE, TVSE (SEQ ID NO: 24), TVEG (SEQ ID NO: 25), TVSEG (SEQ ID NO: 26), TVEP (SEQ ID NO: 52), TVEPG (SEQ ID NO: 53), TVEPGG (SEQ ID NO: 54), TVDP (SEQ ID NO: 55), TVDPG (SEQ ID NO: 56), and TVDPGG (SEQ ID NO: 57).

10. The single domain antibody of claim 1 , wherein the mutation at position Leu11 is Leu11Arg (L11R) and the carboxy terminus comprises an amino acid sequence selected from TVK, TVSK (SEQ ID NO: 27), TVKG (SEQ ID NO: 28), TVSKG (SEQ ID NO: 29), TVSKPG (SEQ ID NO: 44), TVSKPGG (SEQ ID NO: 45), TVKP (SEQ ID NO: 46), TVKPG (SEQ ID NO: 47), TVKPGG (SEQ ID NO: 48), TVRP (SEQ ID NO: 49), TVRPG (SEQ ID NO: 50), and TVRPGG (SEQ ID NO: 51).

11. The single domain antibody of claim 1 , wherein the mutation at position Leu11 is Leu11Asp (L11D) and the carboxy terminus comprises an amino acid sequence selected from TVE, TVSE (SEQ ID NO: 24), TVEG (SEQ ID NO: 25), TVSEG (SEQ ID NO: 26), TVEP (SEQ ID NO: 52), TVEPG (SEQ ID NO: 53), TVEPGG (SEQ ID NO: 54), TVDP (SEQ ID NO: 55), TVDPG (SEQ ID NO: 56), and TVDPGG (SEQ ID NO: 57).

12. The single domain antibody of claim 1 , wherein the mutation at position Leu11 is Leu11Asp (L11D) and the carboxy terminus comprises an amino acid sequence selected from TVK, TVSK (SEQ ID NO: 27), TVKG (SEQ ID NO: 28), TVSKG (SEQ ID NO: 29), TVSKPG (SEQ ID NO: 44), TVSKPGG (SEQ ID NO: 45), TVKP (SEQ ID NO: 46), TVKPG (SEQ ID NO: 47), TVKPGG (SEQ ID NO: 48), TVRP (SEQ ID NO: 49), TVRPG (SEQ ID NO: 50), and TVRPGG (SEQ ID NO: 51).

13. The single domain antibody of claim 1 , wherein the mutation at position Leu11 is Leu11Glu (L11E) and the carboxy terminus of the single domain antibody comprises the amino acid sequence TVKP (SEQ ID NO: 46).

14. The single domain antibody of claim 1 , wherein the mutation at position Leu11 is Leu11Glu (L11E) and the carboxy terminus of the single domain antibody comprises the amino acid sequence TVK.

15. The single domain antibody of claim 1 , wherein the mutation at position Leu11 is Leu11Glu (L11E) and the carboxy terminus of the single domain antibody comprises the amino acid sequence TVRP (SEQ ID NO: 49), TVRPG (SEQ ID NO: 50), or TVRPGG (SEQ ID NO: 51).

16. The single domain antibody of claim 1 , wherein the mutation at position Leu11 is Leu11Asp (L11D) and the carboxy terminus of the single domain antibody comprises the amino acid sequence of TVKPGG (SEQ ID NO: 48).

17. The single domain antibody of claim 1 , wherein the mutation at position Leu11 is Leu11Asp (L11D) and the carboxy terminus of the single domain antibody comprises the amino acid sequence of TVKPG (SEQ ID NO: 47).

18. The single domain antibody of claim 1 , wherein the mutation at position Leu11 is Leu11Asp (L11D) and the carboxy terminus of the single domain antibody comprises the amino acid sequence TVKP (SEQ ID NO: 46).

19. The single domain antibody of claim 1 , wherein the mutation at position Leu11 is Leu11Asp (L11D) and the carboxy terminus of the single domain antibody comprises the amino acid sequence TVK.

20. The single domain antibody of claim 1 , wherein the mutation at position Leu11 is Leu11Asp (L11D) and the carboxy terminus of the single domain antibody comprises the amino acid sequence TVRP (SEQ ID NO: 49), TVRPG (SEQ ID NO: 50), or TVRPGG (SEQ ID NO: 51).

21. The single domain antibody of claim 1 , wherein the mutation at position Leu11 is Leu11Lys (L11K) and the carboxy terminus of the single domain antibody comprises the amino acid sequence TVE, TVEP (SEQ ID NO: 52), TVEPG (SEQ ID NO: 53), or TVEPGG (SEQ ID NO: 54).

22. The single domain antibody of claim 1 , wherein the mutation at position Leu11 is Leu11Lys (L11K) and the carboxy terminus of the single domain antibody comprises the amino acid sequence TVDP (SEQ ID NO: 55), TVDPG (SEQ ID NO: 56), or TVDPGG (SEQ ID NO: 57).

23. The single domain antibody of claim 1 , wherein the mutation at position Leu11 is Leu11Arg (L11R) and the carboxy terminus of the single domain antibody comprises the amino acid sequence TVE, TVEP (SEQ ID NO: 52), TVEPG (SEQ ID NO: 53), or TVEPGG (SEQ ID NO: 54).

24. The single domain antibody of claim 1 , wherein the mutation at position Leu11 is Leu11Arg (L11R) and the carboxy terminus of the single domain antibody comprises the amino acid sequence TVDP (SEQ ID NO: 55), TVDPG (SEQ ID NO: 56), or TVDPGG (SEQ ID NO: 57).

Assignments (8)

SECURITY INTEREST Recorded Jan 14, 2025

From: INHIBRX BIOSCIENCES, INC.

To: OXFORD FINANCE LLC; OXFORD FINANCE LLC

Reel/Frame 069894/0045 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 10, 2024

From: INHIBRX, INC.

To: INHIBRX BIOSCIENCES, INC.

Reel/Frame 067680/0770 →

RELEASE OF SECURITY INTEREST Recorded Jun 3, 2024

From: OXFORD FINANCE LLC, AS COLLATERAL AGENT

To: INHIBRX, INC.