Interleukin 15 Constructs and Methods of Use

Patent metadata

Field	Value
Publication number	US-2023357344-A1
Application number	US-202118245654-A
Country	US
Kind code	A1
Filing date	Sep 16, 2021
Priority date	Sep 16, 2020
Publication date	Nov 9, 2023
Grant date	—

Abstract

Provided arm IL15 constructs, a pharmaceutical composition comprising said IL15 constructs, and use of the IL15 constructs or the composition for treating a disease, such as cancer, infectious disease or an immune disorder.

First claim

1 . An interleukin 15 (IL15) construct comprising at least one IL15 molecule, at least one IL15 receptor alpha (IL15Ra) domain, at least one protease activatable moiety and at least one IgG1 Fc region.

2 . The interleukin 15 (IL15) construct of claim 1 , wherein the construct comprises a bivalent, homodimeric interleukin 15 (IL15) construct comprising from N-terminus to C-terminus:
a) an IL15 receptor alpha (IL15Ra) domain linked to; b) a first linker (L1) linked to; c) an IL15 domain, linked to; d) a second linker (L2) containing a protease activatable moiety linked to; e) an Interleukin 2 receptor beta (IL2Rb) domain; and f) an IgG1 Fc region, wherein the bivalent IL15 construct comprises:
(i) a homodimer set forth in SEQ ID NO:4 (M123);
(ii) a homodimer set forth in SEQ ID NO:5 (M135);
(iii) a homodimer set forth in SEQ ID NO:6 (M140);
(iv) a homodimer set forth in SEQ ID NO:7 (M145);
(v) a homodimer set forth in SEQ ID NO:8 (M175);
(vi) a homodimer set forth in SEQ ID NO:9 (M176);
(vii) a homodimer set forth in SEQ ID NO:10 (M177);
(viii) a homodimer set forth in SEQ ID NO:11 (M178);
(ix) a homodimer set forth in SEQ ID NO:12 (M207);
(x) a homodimer set forth in SEQ ID NO:13 (M231);
(xi) a homodimer set forth in SEQ ID NO:14 (M233);
(xii) a homodimer set forth in SEQ ID NO:15 (M234);
(xiii) a homodimer set forth in SEQ ID NO:16 (M238);
(xiv) a homodimer set forth in SEQ ID NO:17 (M239);
(xv) a homodimer set forth in SEQ ID NO:18 (M240);
(xvi) a homodimer set forth in SEQ ID NO:19 (M241);
(xvii) a homodimer set forth in SEQ ID NO:20 (M243);
(xviii) a homodimer set forth in SEQ ID NO:21 (M244);
(xix) a homodimer set forth in SEQ ID NO:22 (M245);
(xx) a homodimer set forth in SEQ ID NO:23 (M246);
(xxi) a homodimer set forth in SEQ ID NO:24 (M247);
(xxii) a homodimer set forth in SEQ ID NO:25 (M248);
(xxiii) a homodimer set forth in SEQ ID NO:26 (M249);
(xxiv) a homodimer set forth in SEQ ID NO:27 (M327);
(xxv) a homodimer set forth in SEQ ID NO:28 (M328);
(xxvi) a homodimer set forth in SEQ ID NO:29 (M329);
(xxvii) a homodimer set forth in SEQ ID NO:30 (M330);
(xxviii) a homodimer set forth in SEQ ID NO:31 (M331); or
(xxix) a homodimer set forth in SEQ ID NO:32 (M332).

3 . The interleukin 15 (IL15) construct of claim 1 , wherein the construct comprises a bivalent, heterodimeric interleukin 15 (IL15) construct comprising from N-terminus to C-terminus:
a) an Interleukin 2 receptor beta (IL2Rb) domain linked to; b) a first linker (L1) containing a protease activatable moiety, linked to; c) an IL15 domain,
comprising a first molecule and a second molecule comprising from N-terminus to C-terminus:
x) an IL15 receptor alpha (IL15Ra) domain; and
y) an IgG1 Fc region, wherein the heterodimeric IL15 construct comprises:
(i) a first molecule set forth in SEQ ID NO:33 (M43) and a second molecule set forth in SEQ ID NO:34 (M24);
(ii) a first molecule set forth in SEQ ID NO:35 (M61) and a second molecule set forth in SEQ ID NO:36 (M60); or
(iii) a first molecule set forth in SEQ ID NO:37 (M62) and a second molecule set forth in SEQ ID NO:38 (M60).

4 . The interleukin 15 (IL15) construct of claim 1 , wherein the construct comprises a bivalent, homodimeric interleukin 15 (IL15) construct comprising from N-terminus to C-terminus:
a) an IgG1 Fc region, linked to; b) a first linker (L1) linked to; c) an Interleukin 2 receptor beta (IL2Rb) domain linked to; d) a second linker (L2) containing a protease activatable moiety linked to; e) an IL15 receptor alpha (IL15Ra) domain linked to; f) a third linker (L3) linked to; g) an IL15 domain; and
wherein the bivalent IL15 construct comprises:
(i) a homodimer set forth in SEQ ID NO:42 (M232)
(ii) a homodimer set forth in SEQ ID NO:43 (M1001);
(iii) a homodimer set forth in SEQ ID NO:44 (M1002);
(vi) a homodimer set forth in SEQ ID NO:45 (M1003);
(v) a homodimer set forth in SEQ ID NO:46 (M1004);
(vi) a homodimer set forth in SEQ ID NO:47 (M1005); or
(vii) a homodimer set forth in SEQ ID NO:48 (M1006).

5 . The interleukin 15 (IL15) construct of claim 1 , wherein the construct comprises a monovalent, heterodimeric interleukin 15 (IL15) construct comprising from N-terminus to C-terminus:
a) an IL15 receptor alpha (IL15Ra) domain linked to; b) a first linker (L1) linked to; c) an IL15 domain linked to; d) a second linker (L2) containing a protease activatable moiety linked to; e) an Interleukin 2 receptor beta (IL2Rb) domain; and f) a first IgG1 Fc region,
as a first molecule and a second molecule comprising a second IgG1 Fc region, wherein the heterodimeric IL15 construct comprises a first molecule set forth in SEQ ID NO:49 (MK107) and a second molecule set forth in SEQ ID NO:50 (MH2).

6 . The interleukin 15 (IL15) construct of claim 1 , wherein the construct comprises a monovalent, heterodimeric interleukin 15 (IL15) construct comprising from N-terminus to C-terminus:
a) a first IgG1 Fc region linked to; b) a first linker (L1) linked to; c) an Interleukin 2 receptor beta (IL2Rb) domain linked to; d) a second linker (L2) containing a protease activatable moiety to; e) an IL15 receptor alpha (IL15Ra) domain linked to; f) a third linker (L3) linked to; g) an IL15 domain;
as a first molecule and a second molecule comprising a second IgG1 Fc region, wherein the monovalent, heterodimeric IL15 construct comprises:
(i) a first molecule set forth in SEQ ID NO:63 (M111) and a second molecule set forth in SEQ ID NO:64 (MH2);
(ii) a first molecule set forth in SEQ ID NO:65 (M2001) and a second molecule set forth in SEQ ID NO:52 (MH7); or
(iii) a first molecule set forth in SEQ ID NO:66 (M2002) and a second molecule set forth in SEQ ID NO:52 (MH7).

7 . The interleukin 15 (IL15) construct of claim 1 , wherein the construct comprises a monovalent, heterodimeric interleukin 15 (IL15) construct comprising from N-terminus to C-terminus:
a) an IL15 receptor alpha (IL15Ra) domain linked to; b) a first linker (L1) linked to; c) an IL15 domain linked to; d) a second linker (L2) containing a protease activatable moiety linked to; e) an Interleukin 2 receptor beta (IL2Rb) domain linked to; f) a third linker (L3) linked to; g) a first IgG1 Fc region,
as a first molecule and a second molecule comprising a second IgG1 Fc region, wherein the heterodimeric IL15 construct comprises:
(i) a first molecule set forth in SEQ ID NO:51 (MK114) and a second molecule set forth in SEQ ID NO:52 (MH7);
(ii) a first molecule set forth in SEQ ID NO:53 (MK115) and a second molecule set forth in SEQ ID NO:52 (MH7);
(iii) a first molecule set forth in SEQ ID NO:54 (MK117) and a second molecule set forth in SEQ ID NO:52 (MH7);
(iv) a first molecule set forth in SEQ ID NO:55 (MK118) and a second molecule set forth in SEQ ID NO:52 (MH7);
(v) a first molecule set forth in SEQ ID NO:56 (MK119) and a second molecule set forth in SEQ ID NO:52 (MH7);
(vi) a first molecule set forth in SEQ ID NO:57 (MK120) and a second molecule set forth in SEQ ID NO:52 (MH7);
(vii) a first molecule set forth in SEQ ID NO:58 (MK121) and a second molecule set forth in SEQ ID NO:52 (MH7);
(viii) a first molecule set forth in SEQ ID NO:59 (MK123) and a second molecule set forth in SEQ ID NO:52 (MH7);
(ix) a first molecule set forth in SEQ ID NO:60 (MK124) and a second molecule set forth in SEQ ID NO:52 (MH7);
(x) a first molecule set forth in SEQ ID NO:61 (MK125) and a second molecule set forth in SEQ ID NO:52 (MH7);
(xi) a first molecule set forth in SEQ ID NO:62 (MK126) and a second molecule set forth in SEQ ID NO:52 (MH7);
(xii) a first molecule set forth in SEQ ID NO:67 (MK136) and a second molecule set forth in SEQ ID NO:52 (MH7);

Assignees

• Beigene Ltd

Inventors

• Luan Xudong
• Liu Xuesong
• Lei Ming

Classifications

• C07K14/5443 Primary

  IL-15 · CPC title

• C07K14/7155

  for interleukins [IL] · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07K16/3076

  against structure-related tumour-associated moieties · CPC title

• C07K2319/30

  Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto · CPC title