JPWO2021155042A5

JPWO2021155042A5 -

Info

Publication number: JPWO2021155042A5
Application number: JP2022544745A
Authority: JP
Publication date: 2024-02-05

Claims

(a) treating a solid tumor in a subject in need of treatment ;
(b) inducing proliferation of CD8 ⁺ effector memory T cells;
(c) inducing proliferation of NK cells;
(d) inducing proliferation of CD8 ⁺ effector memory T cells and NK cells; or
(e) inducing IFNγ production in the subject;
A heterodimeric protein for use in
The heterodimeric protein is (i) a first monomer comprising an IL-15 protein and a first Fc domain, wherein the IL-15 protein is covalently linked to the N-terminus of the first Fc domain. (ii) a second monomer comprising a sushi domain of an IL-15Rα protein and a second Fc domain, wherein the sushi domain of the IL-15Rα protein is a second monomer covalently attached to the N-terminus of a second Fc domain , the IL-15 protein comprising an N65D amino acid substitution selected from the group consisting of N4D, D30N, and E64Q. one or more amino acid substitutions.

(a) treating a solid tumor in a subject in need of treatment;
(b) inducing proliferation of CD8 ⁺ effector memory T cells ;
(c) inducing proliferation of NK cells;
(d) inducing proliferation of CD8 ⁺ effector memory T cells and NK cells; or
(e) inducing IFNγ production in the subject;
1. The use of a heterodimeric protein in the manufacture of a medicament for
A heterodimeric protein is a first monomer comprising (i) an IL-15 protein and a first Fc domain, wherein the IL-15 protein shares an N-terminus with the first Fc domain. (ii) a second monomer comprising a sushi domain of an IL-15Rα protein and a second Fc domain, wherein the sushi domain of the IL-15Rα protein is bound to a first monomer; a second monomer covalently attached to the N-terminus of the second Fc domain , the IL-15 protein having an N65D amino acid substitution selected from the group consisting of N4D, D30N, E64Q. one or more amino acid substitutions .

2. Each of the first Fc domain and the second Fc domain is a heterozygous compound for use according to claim 1, wherein each of the first Fc domain and the second Fc domain comprises the amino acid substitutions E233P, L234V, L235A, G236del, and S267K (according to EU numbering). meric protein, or the use according to claim 2.

4. The use according to claim 1 or 3 , wherein the first Fc domain further comprises amino acid substitutions L368D and K370S and the second Fc domain further comprises amino acid substitutions S364K and E357Q (according to EU numbering). or the use according to claim 2 or 3 .

Any of claims 1, 3 and 4 , wherein the first Fc domain further comprises amino acid substitutions S364K and E357Q, and the second Fc domain further comprises amino acid substitutions L368D and K370S (according to EU numbering). A heterodimeric protein for the use according to claim 1 or the use according to any one of claims 2 to 4 .

Heterodimer for use according to any one of claims 1 and 3 to 5, wherein the first Fc domain further comprises the amino acid substitutions Q295E, N384D, Q418E and N421D (according to EU numbering). Protein or the use according to any one of claims 2 to 5 .

Heterodimer for use according to any one of claims 1 and 3 to 6, wherein the second Fc domain further comprises the amino acid substitutions Q295E, N384D, Q418E and N421D (according to EU numbering). Protein or the use according to any one of claims 2 to 6 .

A heterodimeric protein for use according to any one of claims 1 and 3 to 7, or claim 2, wherein said second Fc domain further comprises the amino acid substitution K246T (according to EU numbering). Use as described in any one of items 7 to 7 .

A heterodimeric protein for use according to any one of claims 1 and 3 to 8, or any one of claims 2 to 8, wherein the IL-15 protein comprises amino acid substitutions D30N, E64Q and N65D. The use described in paragraph (1) above .

The heterodimeric protein for use according to any one of claims 1 and 3 to 9, or the heterodimeric protein of claims 2 to 9, wherein the IL-15 protein comprises the amino acid sequence shown in SEQ ID NO: 5. Uses as described in any one of the clauses .

A heterodimeric protein for use according to any one of claims 1 and 3 to 10, or claim 2, wherein the sushi domain of the IL-15Rα protein comprises the amino acid sequence shown in SEQ ID NO: 4. The use according to any one of items 1 to 10 .

A heterodimer for use according to any one of claims 1 and 3 to 11 , wherein the IL-15 protein is covalently linked to the N-terminus of the first Fc domain via a first linker. body protein or the use according to any one of claims 2 to 11 .

A heterodimer for use according to any one of claims 1 and 3 to 12 , wherein the IL-15Rα protein is covalently linked to the N-terminus of the second Fc domain via a second linker. body protein, or the use according to any one of claims 2 to 12 .

The IL-15 protein is covalently linked to the N-terminus of the first Fc domain via a first linker, and the IL-15Rα protein is linked to the N-terminus of the second Fc domain via a second linker. A heterodimeric protein for the use according to any one of claims 1 and 3 to 13, or the use according to any one of claims 2 to 13, which is covalently linked .

A heterodimeric protein for use according to any one of claims 1 and 3 to 14, wherein the first linker and/or the second linker are independently variable length Gly-Ser linkers. , or the use according to any one of claims 2 to 14 .

The first linker and/or the second linker are independently (Gly-Gly-Gly-Gly-Ser)n (SEQ ID NO: 39), (Ser-Ser-Ser-Ser-Gly)n (SEQ ID NO: 40), (Gly-Ser-Ser-Gly-Gly) n (SEQ ID NO: 41), and (Gly-Gly-Ser-Gly-Gly) n (SEQ ID NO: 42), 16. A heterodimeric protein for use or use according to claim 15 , wherein n is an integer between 1 and 5.

Any one of claims 1 and 3 to 16 , wherein the first monomer comprises the amino acid sequence shown in SEQ ID NO: 9, and the second monomer comprises the amino acid sequence shown in SEQ ID NO: 10. or the use according to any one of claims 2 to 16 .

Any one of claims 1 and 3 to 16, wherein the first monomer comprises the amino acid sequence shown in SEQ ID NO: 9, and the second monomer comprises the amino acid sequence shown in SEQ ID NO: 16. or the use according to any one of claims 2 to 16 .

A heterodimeric protein for use according to any one of claims 1 and 3 to 18, or claims 2 to 18, wherein the solid tumor is locally advanced, recurrent or metastatic. Uses as described in any one of the following .

The solid tumor is squamous cell carcinoma, cutaneous squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, gastric cancer, pancreatic cancer, glioblastoma, cervical cancer, Ovarian cancer, liver cancer, bladder cancer, liposarcoma, soft tissue sarcoma, urothelial cancer, ureter and renal pelvis, multiple myeloma, osteosarcoma, hepatocellular carcinoma, melanoma, stomach cancer , breast cancer, colon cancer, colorectal cancer, endometrial cancer, salivary gland cancer, renal cell cancer, liver cancer, esophageal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, Merkel cell cancer 20. Heterogeneous cancer for use according to any one of claims 1 and 3 to 19 , selected from the group consisting of cancer, germ cell cancer, frequent microsatellite instability cancer, and head and neck squamous cell carcinoma. meric protein, or the use according to any one of claims 2 to 19 .

The target is
(i) has not previously received a drug to treat a solid tumor ;
(ii) currently receiving a checkpoint inhibitor; or
(iii) have previously received a checkpoint inhibitor;
A heterodimeric protein for use according to any one of claims 1 and 3 to 20, or a use according to any one of claims 2 to 20 .

22. A heterodimeric protein for use or use according to claim 21 , wherein the checkpoint inhibitor targets PD-1 , PD-L1 or CTLA-4 .

The heterodimeric protein has a body weight of about 0.0025 mg/kg, about 0.005 mg/kg, about 0.01 mg/kg, about 0.015 mg/kg, about 0.02 mg/kg, about 0. 025mg/kg, about 0.03mg/kg, about 0.04mg/kg, about 0.05mg/kg, about 0.06mg/kg, about 0.08mg/kg, about 0.1mg/kg, about 0.12mg /kg, about 0.16 mg/kg, about 0.2 mg/kg, about 0.24 mg/kg , and about 0.32 mg/kg. A heterodimeric protein for the use according to any one of claims 1 and 3 to 22, or the use according to any one of claims 2 to 22 .

24. Any one of claims 1 and 3-23 , wherein the heterodimeric protein is formulated to be administered at a frequency selected from the group consisting of Q1W, Q2W, Q3W, Q4W, Q5W and Q6W. or the use according to any one of claims 2 to 23 .

25. The heterodimeric protein according to any one of claims 1 and 3 to 24, wherein the heterodimeric protein is formulated to be administered in combination with an agent that targets the PD-L1/PD-1 axis. A heterodimeric protein for use or a use according to any one of claims 2 to 24 .

The drug targeting the PD-L1/PD-1 axis,
(i) an anti-PD-1 antibody , optionally selected from nivolumab, pembrolizumab, pidilizumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, tripalimab, MDX-1106, AMP-514 and AMP-224; be done; or
(ii) an anti-PD-L1 antibody, optionally selected from avelumab, durvalumab, atezolizumab, BMS-936559, BMS-39886, KN035, CK-301 and MSB0010718C;
Heterodimeric protein for use or use according to claim 25 .