IP Library › Granted Patent US 12,239,688
Granted Patent B2
US 12,239,688 · App. 17/209,047 · Granted Mar 4, 2025

IL-15/IL-15RA heterodimeric Fc fusion proteins and uses thereof

Inventors: Matthew Bernett (Monrovia, CA); John Desjarlais (Pasadena, CA); Rumana Rashid (Temple City, CA); Rajat Varma (Monrovia, CA); Christine Bonzon (Los Angeles, CA)
Assignee: Xencor, Inc.
A61K38/2086A61K38/1793A61K39/3955A61P35/00C07K14/5443C07K14/7155C07K16/2818C07K16/28C07K2317/21C07K2317/24C07K2319/30
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Quick Facts
Patent No.
US 12,239,688
App. No.
17/209,047
Granted
Mar 4, 2025
Kind
B2
Abstract

The present invention is directed to novel IL-15/IL-15Rα heterodimeric Fc fusion proteins and uses thereof. The IL-15/IL-15Rα heterodimeric Fc fusion proteins can be administered to a patient to treat cancer. In some cases, the IL-15/IL-15Rα heterodimeric Fc fusion protein is administered in combination with a checkpoint blockage antibody such as a PD-1 antibody.

Claims (31)

1. A method of inducing T cell expansion in a patient comprising administering:

a therapeutically effective amount of an IL-15/IL-15Rα heterodimeric Fc fusion protein comprising:

a) a first monomer comprising, from N- to C-terminal:

i) an IL-15 receptor alpha (IL-15Rα) sushi domain;

ii) a first domain linker; and

iii) a first variant Fc domain comprising CH2-CH3; and

b) a second monomer comprising from N- to C-terminal:

i) a variant IL-15 domain comprising the amino acid sequence of SEQ ID NO:2 and any one of the amino acid substitutions selected from the group consisting of N4D/N65D, D30N/N65D, and D30N/E64Q/N65D;

ii) a second domain linker; and

iii) a second variant Fc domain comprising CH2-CH3;

wherein the first and second variant Fc domains are variants of a human IgG1 Fc domain and have a set of amino acid substitutions selected from the group consisting of S267K/L368D/K370S:S267K/S364K/E357Q; S364K/E357Q:L368D/K370S; L368D/K370S:S364K; L368E/K370S:S364K; T411E/K360E/Q362E:D401K; L368D/K370S:S364K/E357L and K370S:S364K/E357Q, according to EU numbering; and

a therapeutically effective amount of an anti-PD-L1 antibody.

2. The method according to claim 1 , wherein the variant IL-15 domain comprises the amino acid sequence of SEQ ID NO: 2 and the amino acid substitutions D30N/E64Q/N65D.

3. The method according to claim 1 , wherein the IL-15Rα sushi domain comprises the amino acid sequence of SEQ ID NO:4.

4. The method according to claim 1 , wherein the first and second variant Fc domains have S364K/E357Q: L368D/K370S substitutions.

5. The method according to claim 1 , wherein the first variant Fc domain has S364K/E357Q substitutions and the second variant Fc domain has L368D/K370S substitutions.

6. The method according to claim 1 , wherein the first and second variant Fc domains each comprise M428L/N434S substitutions.

7. The method according to claim 1 , wherein the first and second variant Fc domains each comprise E233P/L234V/L235A/G236del/S267K substitutions.

8. The method according to claim 1 , wherein the IL-15/IL-15Rα heterodimeric Fc fusion protein and the anti-PD-L1 antibody are administered concomitantly or sequentially.

9. The method according to claim 1 , wherein the anti-PD-L1 antibody is atezolizumab, avelumab, or durbalumab.

10. The method according to claim 1 , wherein the IL-15/IL-15Rα heterodimeric Fc fusion protein comprises the amino acid sequences of i) SEQ ID NOs 253 and 254 or ii) SEQ ID NOs: 204 and 205.

11. The method according to claim 10 , wherein the IL-15/IL-15Rα heterodimeric Fc fusion protein comprises the amino acid sequences of SEQ ID NOs: 253 and 254, and the anti-PD-L1 antibody is atezolizumab.

12. The method according to claim 10 , wherein the IL-15/IL-15Rα heterodimeric Fc fusion protein comprises the amino acid sequences of SEQ ID NOs: 253 and 254, and the anti-PD-L1 antibody is avelumab.

13. The method according to claim 10 , wherein the IL-15/IL-15Rα heterodimeric Fc fusion protein comprises the amino acid sequences of SEQ ID NOs: 253 and 254, and the anti-PD-L1 antibody is durbalumab.

14. The method according to claim 10 , wherein the IL-15/IL-15Rα heterodimeric Fc fusion protein comprises the amino acid sequences of SEQ ID NOs: 204 and 205, and the anti-PD-L1 antibody is atezolizumab.

15. The method according to claim 10 , wherein the IL-15/IL-15Rα heterodimeric Fc fusion protein comprises the amino acid sequence of SEQ ID NOs: 204 and 205, and the anti-PD-L1 antibody is avelumab.

16. The method according to claim 10 , wherein the IL-15/IL-15Rα heterodimeric Fc fusion protein comprises the amino acid sequence of SEQ ID NOs: 204 and 205, and the anti-PD-L1 antibody is durbalumab.

17. The method according to claim 1 , wherein the level of vascular leakage ranges from a 20% reduction or less in serum albumin in the patient following administration.

18. The method according to claim 1 , wherein the T cell expansion is at least a 2-fold increase in T cells.

19. The method according to claim 1 , wherein the T cell expansion ranges from a 2-fold to a 15-fold increase in T cells.

20. The method according to claim 1 , wherein the T cells comprise tumor infiltrating lymphocytes.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 30, 2026
From: LIU, KE
To: XENCOR, INC.
Reel/Frame 075473/0440 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 17, 2021
From: BERNETT, MATTHEW J.; RASHID, RUMANA; DESJARLAIS, JOHN; VARMA, RAJAT; BONZON, CHRISTINE
To: XENCOR, INC.
Reel/Frame 057202/0928 →
Continuity (6)
Continuation 16388174 · Apr 18, 2019
Provisional Application 62756800 · Nov 7, 2018
Provisional Application 62724396 · Aug 29, 2018
Provisional Application 62684143 · Jun 12, 2018
Provisional Application 62659563 · Apr 18, 2018
Related Publication 20220040264A1 · Feb 10, 2022
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