PD-1 targeted IL-15/IL-15RALPHA fc fusion proteins and uses in combination therapies thereof

Patent metadata

Field	Value
Publication number	US-11377477-B2
Application number	US-201916600236-A
Country	US
Kind code	B2
Filing date	Oct 11, 2019
Priority date	Oct 12, 2018
Publication date	Jul 5, 2022
Grant date	Jul 5, 2022

Abstract

The present invention is directed to novel PD-1 targeted heterodimeric Fc fusion proteins comprising an IL-15/IL-15Rα Fc-fusion protein and a PD-1 antibody fragment-Fc fusion protein. In some embodiments, the PD-1 targeted IL-15/Rα-Fc fusion proteins are administered to a patient to treat cancer. In some embodiments, the PD-1 targeted IL-15/Rα-Fc fusion proteins are administered in combination with a PD-1 blockade antibody such as nivolumab and/or pembrolizumab. In some embodiments, the PD-1 targeted IL-15/Rα-Fc fusion proteins do not compete with a PD-1 blockade antibody such as nivolumab and/or pembrolizumab for antigen binding.

First claim

What is claimed is:

1. A PD-1 targeted IL-15/Rα heterodimeric Fc fusion protein comprising:
a) a first monomer comprising, from N- to C-terminal:
i) a IL-15 Rα sushi domain protein;
ii) a first domain linker;
iii) an IL-15 protein; and
iv) a first variant Fc domain; and

b) a second monomer comprising a heavy chain comprising VH-CH1-hinge-CH2-CH3, wherein said CH2-CH3 is a second variant Fc domain;
c) a third monomer comprising a light chain comprising VL-CL; wherein said VH and VL domains form an antigen binding domain that binds to human PD-1 and does not compete for said human PD-1 with nivolumab and/or pembrolizumab; wherein said VH domain has at least 95% amino acid sequence identity with SEQ ID NO:5 and said VL domain has at least 95% amino acid sequence identity with SEQ ID NO:6;
wherein said first variant Fc domain and said second variant Fc domain are each a variant of a human IgG Fc domain.

2. The PD-1 targeted IL-15/Rα heterodimeric Fc fusion protein according to claim 1 wherein said VH domain is a variant of SEQ ID NO:5 comprising the amino acid substitution F32L and said VL domain is a variant of SEQ ID NO:6 comprising the amino acid substitution N31H.

3. The PD-1 targeted IL-15/Rα heterodimeric Fc fusion protein according to claim 2 wherein said VL domain further comprises the amino acid substitutions K36Y/S99T.

4. The PD-1 targeted IL-15/Rα heterodimeric Fc fusion protein according to claim 1 wherein said VH is SEQ ID NO:5 and said VL is SEQ ID NO:6.

5. The PD-1 targeted IL-15/Rα heterodimeric Fc fusion protein according to claim 1 wherein said IL-15 protein is a variant human IL-15 protein comprising amino acid substitution(s) selected from the group of D30N/E64Q/N65D; D30N/N65D; N1D; N4D; D8N; D30N; D61N; E64Q; N65D; Q108E; N1D/N4D/D8N; N1D/N4D/N65D; N1D/D30N; N1D/D61N; N1D/D61N/E64Q/Q108E; N1D/E64Q; N1D/N65D; N1D/Q108E; N4D; N4D/D30N; N4D/D61N; N4D/D61N/N65D; N4D/D61N/E64Q/Q108E; N4D/E64Q; N4D/N65D; D8N/D61N; D8N/E64Q; D30N/E64Q; D30N/Q180E; D61N/E64Q/N65D; E64Q; E64Q/N65D; E64Q/Q108E; and N65D/Q108E.

6. The PD-1 targeted IL-15/Rα heterodimeric Fc fusion protein according to claim 1 , wherein said IL-15 protein is a variant human IL-15 protein comprising amino acid substitution(s) selected from the group of N4D/N65D; D30N; D30N/E64Q; D30N/N65D; and D30N/E64Q/N65D.

7. The PD-1 targeted IL-15/Rα heterodimeric Fc fusion protein according to claim 1 , wherein said first variant Fc domain and said second variant Fc domain are each a variant of a human IgG1, IgG2, or IgG4 Fc domain and comprise amino acid substitutions L368D/K370S:S364K/E357Q, according to EU numbering.

8. The PD-1 targeted IL-15/Rα heterodimeric Fc fusion protein of according to claim 1 , wherein said first variant Fc domain and said second variant Fc domain are each a variant of a human IgG1 Fc domain and each comprise amino acid substitutions M428L/N434S, according to EU numbering.

9. The PD-1 targeted IL-15/Rα heterodimeric Fc fusion protein according to claim 1 wherein said VH is SEQ ID NO:5 and said VL is a variant of SEQ ID NO:6 comprising the amino acid substitution N31H.

10. A nucleic acid composition comprising:
a) a first nucleic acid encoding the first monomer according to claim 1 ;
b) a second nucleic acid encoding the second monomer according to claim 1 ; and
c) a third nucleic acid encoding the third monomer according to claim 1 ; respectively.

11. An expression vector composition comprising:
a) an expression vector comprising the first nucleic acid of claim 10 ;
b) an expression vector comprising the second nucleic acid of claim 10 ; and
c) an expression vector comprising the third nucleic acid of claim 10 .

12. A host cell comprising the expression vector composition according to claim 11 .

13. A method of producing a targeted IL-15/Rα heterodimeric Fc fusion protein, the method comprising: culturing the host cell of claim 12 under conditions where said targeted IL-15/Rα heterodimeric Fc fusion protein is expressed; and recovering said protein.

Assignees

• Xencor Inc

Inventors

• Bernett Matthew
• Desjarlais John R
• Hedvat Michael
• Schubbert Suzanne
• Bonzon Christine
• Rashid Rumana
• Varma Rajat

Classifications

• C07K2317/53

  Hinge · CPC title

• C07K14/5443 Primary

  IL-15 · CPC title

• C07K2319/32

  fusions with soluble part of a cell surface receptor, "decoy receptors" · CPC title

• C07K2317/33

  Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity · CPC title

• A61P35/00

  Antineoplastic agents · CPC title