US2023220081A1PendingUtilityA1

BISPECIFIC HETERODIMERIC FUSION PROTEINS CONTAINING IL-15 - IL-15Ralpha Fc-FUSION PROTEINS AND IMMUNE CHECKPOINT ANTIBODY FRAGMENTS

Assignee: XENCOR INCPriority: Oct 14, 2016Filed: Dec 13, 2022Published: Jul 13, 2023

Est. expiryOct 14, 2036(~10.2 yrs left)· nominal 20-yr term from priority

Inventors:Matthew J. Bernett Rumana Rashid John Desjarlais Rajat Varma Christine Bonzon

A61K 38/00C07K 2317/94C07K 2317/622C07K 2317/526C07K 2317/24A61P 35/00C07K 2319/30C07K 2317/73C07K 2317/53C07K 2317/31C12N 15/63C07K 14/7155A61K 2039/505C07K 2317/92C07K 2317/565C07K 2317/524C07K 14/5443C07K 2319/32C07K 2317/74C07K 2317/55C07K 2317/35C07K 16/2818

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Claims

Abstract

The present invention is directed to novel bispecific heterodimeric Fc fusion proteins comprising an IL-15/IL-15Rα Fc-fusion protein and a PD-1 antibody fragment-Fc fusion protein.

Claims

exact text as granted — not AI-modified

What is claimed is:

1 . A bispecific heterodimeric protein comprising:
a) a fusion protein comprising a first protein domain, a second protein domain, and a first Fc domain, wherein said first protein domain is covalently attached to the N-terminus of said second protein domain using a first domain linker, wherein said second protein domain is covalently attached to the N-terminus of said first Fc domain using a second domain linker, and wherein said first protein domain comprises an IL-15Rα protein and said second protein domain comprises an IL-15 protein; and b) an antibody fusion protein comprising a PD-1 antigen binding domain (ABD) and a second Fc domain, wherein said PD-1 antigen binding domain is covalently attached to the N-terminus of said second Fc domain, and said PD-1 antigen binding domain is a single chain variable fragment (scFv) or a Fab fragment;
wherein said first and said second Fc domains have a set of amino acid substitutions selected from the group consisting of S267K/L368D/K370S:S267K/LS364K/E357Q; S364K/E357Q:L368D/K370S; L368D/K370S:S364K; L368E/K370S:S364K; T411T/E360E/Q362E:D401K; L368D/K370S:S364K/E357L and K370S:S364K/E357Q, according to EU numbering.

2 . The bispecific heterodimeric protein according to claim 1 , wherein said first and/or said second Fc domains have an additional set of amino acid substitutions comprising Q295E/N384D/Q418E/N421D, according to EU numbering.

3 . The bispecific heterodimeric protein according to claim 1 or 2 , wherein said first and/or said second Fc domains have an additional set of amino acid substitutions consisting of G236R/L328R, E233P/L234V/L235A/G236del/S239K, E233P/L234V/L235A/G236del/S267K, E233P/L234V/L235A/G236del/S239K/A327G, E233P/L234V/L235A/G236del/S267K/A327G and E233P/L234V/L235A/G236del, according to EU numbering.

4 . The bispecific heterodimeric protein according to any one of claims 1 to 3 , wherein said IL-15 protein has a polypeptide sequence selected from the group consisting of SEQ ID NO:1 (full-length human IL-15) and SEQ ID NO:2 (truncated human IL-15), and said IL-15Rα protein has a polypeptide sequence selected from the group consisting of SEQ ID NO:3 (full-length human IL-15Rα) and SEQ ID NO:4 (sushi domain of human IL-15Rα).

5 . The bispecific heterodimeric protein according to any one of claims 1 to 4 , wherein said IL-15 protein and said IL-15Rα protein have a set of amino acid substitutions selected from the group consisting of E87C:D96/P97/C98; E87C:D96/C97/A98; V49C: 540C; L52C: 540C; E89C:K34C; Q48C:G38C; E53C:L42C; C42S:A37C; and L45C:A37C, respectively.

6 . The bispecific heterodimeric protein according to any one of claims 1 to 5 , wherein said PD-1 antigen binding domain comprises an anti-PD-1 scFv or an anti-PD-1 Fab.

7 . The bispecific heterodimeric protein according to any one of claims 1 to 6 , wherein said first fusion protein has a polypeptide sequence of SEQ ID NO: XX (16478) and said scFv of the PD-1 antigen binding domain has a polypeptide sequence of SEQ ID NO: XX (15110).

8 . The bispecific heterodimeric protein according to any one of claims 1 to 6 , wherein said first fusion protein has a polypeptide sequence of SEQ ID NO: XX (16478) and said Fab of the PD-1 antigen binding domain has polypeptide sequences of SEQ ID NO: XX (14833) and SEQ ID NO: XX (14812).

9 . The bispecific heterodimeric protein according to any one of claims 1 to 8 , wherein said heterodimeric protein is XENP21480, XENP22022, XENP25850, or XENP25937.

10 . A nucleic acid composition encoding the fusion protein of any one of claims 1 to 9 .

11 . A nucleic acid composition encoding the antibody fusion protein of any one of claims 1 to 9 .

12 . An expression vector comprising the nucleic acid composition of claim 10 .

13 . An expression vector comprising the nucleic acid composition of claim 11 .

14 . The expression vector of claim 13 , further comprising the nucleic acid composition of claim 10 .

15 . A host cell comprising one or two expression vectors of any one of claims 12 to 14 .

16 . A bispecific heterodimeric protein comprising:
a) a fusion protein comprising a first protein domain and a first Fc domain, wherein said first protein domain is covalently attached to the N-terminus of said first Fc domain using a domain linker and said first protein domain comprises an IL-15Rα protein; b) a second protein domain noncovalently attached to said first protein domain, said second protein domain comprises an IL-15 protein; and c) an antibody fusion protein comprising an PD-1 antigen binding domain and a second Fc domain, wherein said PD-1 antigen binding domain is covalently attached to the N-terminus of said second Fc domain and said PD-1 antigen binding domain is a single chain variable fragment (scFv) or a Fab fragment;
wherein said first and said second Fc domains have a set of amino acid substitutions selected from the group consisting of S267K/L368D/K370S:S267K/LS364K/E357Q; S364K/E357Q:L368D/K370S; L368D/K370S:S364K; L368E/K370S:S364K; T411T/E360E/Q362E:D401K; L368D/K370S:S364K/E357L and K370S:S364K/E357Q, according to EU numbering.

17 . The bispecific heterodimeric protein according to claim 16 , wherein said first and/or said second Fc domains have an additional set of amino acid substitutions comprising Q295E/N384D/Q418E/N421D, according to EU numbering.

18 . The bispecific heterodimeric protein according to claim 16 or 17 , wherein said first and/or said second Fc domains have an additional set of amino acid substitutions consisting of G236R/L328R, E233P/L234V/L235A/G236del/S239K, E233P/L234V/L235A/G236del/S267K, E233P/L234V/L235A/G236del/S239K/A327G, E233P/L234V/L235A/G236del/S267K/A327G and E233P/L234V/L235A/G236del, according to EU numbering.

19 . The bispecific heterodimeric protein according to any one of claims 16 to 18 , wherein said IL-15 protein has a polypeptide sequence selected from the group consisting of SEQ ID NO:1 (full-length human IL-15) and SEQ ID NO:2 (truncated human IL-15), and said IL-15Rα protein has a polypeptide sequence selected from the group consisting of SEQ ID NO:3 (full-length human IL-15Rα) and SEQ ID NO:4 (sushi domain of human IL-15Rα).

20 . The bispecific heterodimeric protein according to any one of claims 16 to 19 , wherein said IL-15 protein and said IL-15Rα protein have a set of amino acid substitutions selected from the group consisting of E87C:D96/P97/C98; E87C:D96/C97/A98; V49C:S40C; L52C:S40C; E89C:K34C; Q48C:G38C; E53C:L42C; C42S:A37C; and L45C:A37C, respectively.

21 . The bispecific heterodimeric protein according to any one of claims 16 to 20 , wherein said PD-1 antigen binding domain comprises an anti-PD-1 scFv or an anti-PD-1 Fab.

22 . The bispecific heterodimeric protein according to any one of claims 16 to 21 , wherein said fusion protein has a polypeptide sequence selected from the group consisting of SEQ ID NO: XX (16481), said second protein domain has a polypeptide sequence of SEQ ID NO: XX (16484), and said Fab of the PD-1 antigen binding domain has polypeptide sequences of SEQ ID NO: XX (14833) and SEQ ID NO: XX (14812).

23 . The bispecific heterodimeric protein according to any one of claims 16 to 21 , wherein said fusion protein has a polypeptide sequence selected from the group consisting of SEQ ID NO: XX (17584), said second protein domain has a polypeptide sequence of SEQ ID NO: XX (17074), and said Fab of the PD-1 antigen binding domain has polypeptide sequences of SEQ ID NO: XX (14833) and SEQ ID NO: XX (14812).

24 . The bispecific heterodimeric protein according to any one of claims 16 to 23 , wherein said heterodimer protein is selected from the group consisting of XENP22112 and XENP22641.

25 . A nucleic acid composition encoding the fusion protein of any one of claims 16 to 24 .

26 . A nucleic acid composition encoding the antibody fusion protein of any one of claims 16 to 24 .

27 . An expression vector comprising the nucleic acid composition of claim 25 .

28 . An expression vector comprising the nucleic acid composition of claim 26 .

29 . The expression vector of claim 28 , further comprising the nucleic acid composition of claim 25 .

30 . The expression vector of any one of claims 27 to 29 , further comprising a nucleic acid composition encoding said second protein domain.

31 . A host cell comprising one or more expression vectors of any one of claims 27 to 30 .

32 . A bispecific heterodimeric protein comprising:
a) a first antibody fusion protein comprising a first PD-1 antigen binding domain and a first Fc domain, wherein said first PD-1 antigen binding domain is covalently attached to the N-terminus of said first Fc domain via a first domain linker, and said first PD-1 antigen binding domain is a single chain variable fragment (scFv) or a Fab fragment; b) a second antibody fusion protein comprising a second PD-1 antigen binding domain, a second Fc domain, and a first protein domain, wherein said second PD-1 antigen binding domain is covalently attached to the N-terminus of said second Fc domain via a second domain linker, said first protein domain is covalently attached to the C-terminus of said second Fc domain via a third domain linker, said second PD-1 antigen binding domain is a single chain variable fragment (scFv) or a Fab fragment, and said first protein domain comprises an IL-15Rα protein; and (c) a second protein domain noncovalently attached to said first protein domain of said second antibody fusion protein and comprising an IL-15 protein,
wherein said first and said second Fc domains have a set of amino acid substitutions selected from the group consisting of S267K/L368D/K370S:S267K/LS364K/E357Q; S364K/E357Q:L368D/K370S; L368D/K370S:S364K; L368E/K370S:S364K; T411T/E360E/Q362E:D401K; L368D/K370S:S364K/E357L and K370S:S364K/E357Q, according to EU numbering.

33 . The bispecific heterodimeric protein according to claim 32 , wherein said first and/or said second Fc domains have an additional set of amino acid substitutions comprising Q295E/N384D/Q418E/N421D, according to EU numbering.

34 . The bispecific heterodimeric protein according to claim 32 or 33 , wherein said first and/or said second Fc domains have an additional set of amino acid substitutions consisting of G236R/L328R, E233P/L234V/L235A/G236del/S239K, E233P/L234V/L235A/G236del/S267K, E233P/L234V/L235A/G236del/S239K/A327G, E233P/L234V/L235A/G236del/S267K/A327G and E233P/L234V/L235A/G236del, according to EU numbering.

35 . The bispecific heterodimeric protein according to any one of claims 32 to 34 , wherein said IL-15 protein has a polypeptide sequence selected from the group consisting of SEQ ID NO:1 (full-length human IL-15) and SEQ ID NO:2 (truncated human IL-15), and said IL-15Rα protein has a polypeptide sequence selected from the group consisting of SEQ ID NO:3 (full-length human IL-15Rα) and SEQ ID NO:4 (sushi domain of human IL-15Rα).

36 . The bispecific heterodimeric protein according to any one of claims 32 to 35 , wherein said IL-15 protein and said IL-15Rα protein have a set of amino acid substitutions selected from the group consisting of E87C:D96/P97/C98; E87C:D96/C97/A98; V49C: 540C; L52C: 540C; E89C:K34C; Q48C:G38C; E53C:L42C; C42S:A37C; and L45C:A37C, respectively.

37 . The bispecific heterodimeric protein according to any one of claims 32 to 36 , wherein said first PD-1 antigen binding domain comprises an anti-PD-1 scFv or an anti-PD-1 Fab.

38 . The bispecific heterodimeric protein according to any one of claims 32 to 37 , wherein said second PD-1 antigen binding domain comprises an anti-PD-1 scFv or an anti-PD-1 Fab.

39 . The bispecific heterodimeric protein according to any one of claims 32 to 37 , wherein said first antibody fusion protein has polypeptide sequences of SEQ ID NO: XX (17599) and SEQ ID NO: XX (9016), said second antibody fusion protein has polypeptide sequence of SEQ ID NO: XX (16478) and SEQ ID NO: XX (9016), and said second protein domain has a polypeptide sequence of SEQ ID NO: XX (16484).

40 . The bispecific heterodimeric protein according to any one of claims 32 to 37 , wherein said first antibody fusion protein has polypeptide sequences of SEQ ID NO: XX (17601) and SEQ ID NO: XX (9016), said second antibody fusion protein has polypeptide sequence of SEQ ID NO: XX (9018) and SEQ ID NO: XX (9016), and said second protein domain has a polypeptide sequence of SEQ ID NO: XX (17074).

41 . The bispecific heterodimeric protein according to any one of claims 32 to 40 , wherein said heterodimeric protein is XENP22642 or XENP22644.

42 . A nucleic acid composition encoding the first antibody fusion protein of any one of claims 32 to 41 .

43 . A nucleic acid composition encoding the second antibody fusion protein of any one of claims 32 to 41 .

44 . A nucleic acid composition encoding the second protein domain of any one of claims 32 to 41 .

45 . An expression vector comprising the nucleic acid composition of claim 42 .

46 . An expression vector comprising the nucleic acid composition of claim 43 .

47 . An expression vector comprising the nucleic acid composition of claim 44 .

48 . The expression vector of claim 45 , further comprising the nucleic acid composition of claim 43 and/or 44 .

49 . A host cell comprising one or more expression vectors of any one of claims 45 to 48 .

50 . The bispecific heterodimeric protein according to any one of claims 1 to 9 , 16 to 24 , and 32 - 41 , wherein said IL-15 protein has one or more amino acid substitutions selected from the group consisting of N1D, N4D, D8N, D30N, D61N, E64Q, N65D, and Q108E.

51 . A bispecific heterodimeric protein selected from the group consisting of XENP21480, XENP22022, XENP22112, XENP22641, XENP22642, XENP22644, XENP25850, and XENP25937.

52 . A nucleic acid composition comprising one or more nucleic acids encoding a bispecific heterodimeric protein selected from the group consisting of XENP21480, XENP22022, XENP22112, XENP22641, XENP22642, XENP22644, XENP25850, and XENP25937.

53 . An expression vector composition comprising one or more expression vectors each comprising a nucleic acid such that the one or more expression vectors encode a bispecific heterodimeric protein selected from the group consisting of XENP21480, XENP22022, XENP22112, XENP22641, XENP22642, XENP22644, XENP25850, and XENP25937.

54 . A host cell comprising the nucleic acid composition of claim 52 .

55 . A host cell comprising the expression vector composition of claim 53 .

56 . A method of producing the bispecific heterodimeric protein of claim 51 comprising culturing the host cell claim 54 or 55 under suitable conditions wherein said bispecific heterodimeric protein is expressed, and recovering said protein.

57 . A method of treating cancer in a patient in need thereof comprising administering a therapeutically effective amount of the bispecific heterodimeric protein of claim 51 to said patient.

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