Targeted heterodimeric Fc fusion proteins containing IL-15/IL-15RA and NKG2D antigen binding domains

Patent metadata

Field	Value
Publication number	US-11618776-B2
Application number	US-201916724118-A
Country	US
Kind code	B2
Filing date	Dec 20, 2019
Priority date	Dec 20, 2018
Publication date	Apr 4, 2023
Grant date	Apr 4, 2023

Abstract

The present invention is directed to a novel targeted heterodimeric Fc fusion proteins comprising an IL-15/IL-15Rα Fc fusion protein and an NKG2D antigen binding domain Fc fusion proteins.

First claim

What is claimed is:

1. A targeted heterodimeric protein comprising:
a) a first monomer comprising, from N- to C-terminal:
i) a human IL-15Rα(sushi) domain;
ii) a first domain linker;
iii) a variant of human IL-15 comprising the amino acid sequence of SEQ ID NO:2 and one or more amino acid substitutions selected from the group consisting of N1D, N4D, D8N, D30N, D61N, E64Q, N65D, and Q108E;
iv) a second domain linker; and
v) a first variant Fc domain; and

b) a second monomer comprising, from N- to C-terminal:
i) a NKG2D antigen binding domain (ABD); and
ii) a second variant Fc domain,

wherein said first Fc domain and said second Fc domain have a set of amino acid substitutions selected from the group consisting of: (i) S267K/L368D/K370S:S267K/S364K/E357Q; (ii) S364K/E357Q:L368D/K370S; (iii) L368D/K370S:S364K; (iv) L368E/K370S:S364K; (v) T411E/E360E/Q362E:D401K; (vi) L368D/K370S:S364K/E357Q, and (vii) K370S:S364K/E357Q, according to EU numbering; and
wherein said NKG2D ABD comprises a variable heavy and light domain pair selected from the group consisting of MS[NKG2D]_H0L0 (variable domain of SEQ ID NO: 931 and variable domain of SEQ ID NO: 932), KYK-1.0[NKG2D]_H1L1 (SEQ ID NO: 1042 and SEQ ID NO: 1043), KYK-2.0[NKG2D]_H0L0 (SEQ ID NO: 1044 and 1045), 1D7B4[NKG2D]_H1L1 (SEQ ID NO: 1040 and SEQ ID NO: 1041), 6E5A7[NKG2D]_H0L0 (SEQ ID NO: 1048 and SEQ ID NO: 1049), 6H7E7[NKG2D]_H0L0 (SEQ ID NO: 1050 and SEQ ID NO: 1051), 11B2D10[NKG2D]_H0L0 (SEQ ID NO: 1046 and SEQ ID NO: 1047), 16F31[NKG2D]_H1L1 (SEQ ID NO: 1054 and SEQ ID NO: 1055), mAb A[NKG2D]_H1L1 (SEQ ID NO: 1060 and SEQ ID NO: 1062), mAb A[NKG2D]_H1L2 (SEQ ID NO: 1060 and SEQ ID NO: 1063), mAb A[NKG2D]_H2L1 (SEQ ID NO: 1061 and SEQ ID NO: 1062), mAb A[NKG2D]_H2L2 (SEQ ID NO: 1061 and SEQ ID NO: 1063), mAb B[NKG2D]_H1L1 (SEQ ID NO: 1064 and SEQ ID NO: 1067), mAb B[NKG2D]_H1L1.1 (SEQ ID NO: 1064 and SEQ ID NO: 1068), mAb B[NKG2D]_H1L2 (SEQ ID NO: 1064 and SEQ ID NO: 1069), mAb B[NKG2D]_H2L1 (SEQ ID NO: 1065 and SEQ ID NO: 1067), mAb B[NKG2D]_H2L1.1 (SEQ ID NO: 1065 and SEQ ID NO: 1068), mAb B[NKG2D]_H2L2 (SEQ ID NO: 1065 and SEQ ID NO: 1069), mAb B[NKG2D]_H3L1 (SEQ ID NO: 1066 and SEQ ID NO: 1067), mAb B[NKG2D]_H3L1.1 (SEQ ID NO: 1066 and SEQ ID NO: 1068), mAb B[NKG2D]_H3L2 (SEQ ID NO: 1066 and SEQ ID NO: 1069), mAb C[NKG2D]_H1L1 (SEQ ID NO: 1070 and SEQ ID NO: 1072), mAb C[NKG2D]_H1L2 (SEQ ID NO: 1070 and SEQ ID NO: 1073), mAb C[NKG2D]_H2L1 (SEQ ID NO: 1071 and SEQ ID NO: 1072), mAb C[NKG2D]_H2L2 (SEQ ID NO: 1071 and SEQ ID NO: 1073), mAb D[NKG2D]_H1L1 (SEQ ID NO: 1056 and SEQ ID NO: 1057), and mAb E[NKG2D]_H1L1 (SEQ ID NO: 1052 and SEQ ID NO: 1053).

2. The targeted heterodimeric protein of claim 1 , wherein said variant of human IL-15 has amino acid substitutions selected from the group consisting of N4D/N65D, D30N/N65D, D30N/E64Q/N65D, N1D, N4D, D8N, D30N, D61N, E64Q, N65D, Q108E, N1D/D61N, N1D/E64Q, N4D, D61N, N4D/E64Q, D8N/D61N, D8N/E64Q, D61N/E64Q, E64Q/Q108E, N1D/N4D/D8N, D61N/E64Q/N65Q, N1D/D61N/E64Q/Q108E, N4D/D61N/E64Q/Q108E, N1D/N65D, D30N/Q108E, N65D/Q108E, E64Q/N65D, N1D/N4D/N65D, and N4D/D61N/N65D.

3. The targeted heterodimeric protein of claim 1 , wherein said human IL-15Rα(sushi) domain comprises the amino acid sequence of SEQ ID NO:4.

4. The targeted heterodimeric protein of claim 1 , wherein said NKG2D antigen binding domain is a single chain variable fragment (scFv) or a Fab fragment.

5. The targeted heterodimeric protein of claim 1 , wherein said first or said second Fc domains have an additional amino acid substitution comprising Q295E/N384D/Q418E/N421D, according to EU numbering.

6. The targeted heterodimeric protein of claim 1 , wherein said first and 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.

7. The targeted heterodimeric protein of claim 1 , wherein said first and said second Fc domains have an additional set of amino acid substitutions M428L/N434S.

Assignees

• Xencor Inc

Inventors

• Bernett Matthew J
• Desjarlais John R
• Varma Rajat
• Moore Gregory
• Diaz Juan
• Nisthal Alex
• Liu Ke
• Rashid Rumana
• Chang Eric

Classifications

• C07K2317/94

  Stability, e.g. half-life, pH, temperature or enzyme-resistance · CPC title

• C07K2317/31

  multispecific · CPC title

• C07K2317/55

  Fab or Fab' · CPC title

• C07K2317/35

  Valency · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title