US 2019/0161555 A1 · Bispecific Antibodies Directed Against OX40 and a Tumor-Associated Antigen

Abstract

The invention provides bispecific polypeptides comprising a first binding domain, designated B1, which is capable of binding specifically to OX40, and a second binding domain, designated B2, which is capable of specifically binding to a tumour cell-associated antigen. Also provided are pharmaceutical compositions of such bispecific polypeptides and uses of the same in medicine.

Claims88

Dependent claims

A bispecific polypeptide comprising a first binding domain, designated B1, which is capable of binding specifically to OX40, and a second binding domain, designated B2, which is capable of specifically binding to a tumour cell-associated antigen.

A polypeptide according to any one of the preceding claims wherein binding domain B1 and binding domain B2 are fused directly to each other.

A polypeptide according to any one of the preceding claims, wherein the polypeptide is incapable of inducing antibody dependent cell cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and/or complement-dependent cytotoxicity (CDC).

A polypeptide according to any one of the preceding claims, wherein the polypeptide is capable of inducing tumour immunity.

A polypeptide according to any one of the preceding claims, wherein the polypeptide is capable of inducing:

(a) activation of cytotoxic T cells, i.e. CD8+ T cells;
(b) activation of helper T cells, i.e. CD4+ T cells;
(c) activation of dendritic cells;
and/or
(d) activation of natural killer cells;
and/or
(e) reprogramming of Tregs into effector T cells.

4 more elements

A polypeptide according to any one of the preceding claims wherein binding domain B1 binds to human OX40 with a KD of less than 50×10−10M or less than 25×10−10M, more preferably less than 10, 9, 8, 7, or 6×10−10M, most preferably less than 5×10−10M.

A polypeptide according to any one of the preceding claims, wherein B1 exhibits at least one of the following functional characteristics when present independently of B2:

I. binding to human OX40 with a KD value which is less than 10×10−10M, more preferably less than 5×10−10M;
II. does not bind to murine OX40;
and
III. does not bind to other human TNFR superfamily members, for example human CD137 or CD40

1 more element

A polypeptide according to any one of the preceding claims, wherein B1 comprises any one, two, three, four, five or all six features independently selected from the following:

(a) a heavy chain CDR1 sequence which is 8 amino acids in length and comprises the consensus sequence:
“G, F, T, F, G/Y/S, G/Y/S, Y/S, Y/S/A”;
(b) a heavy chain CDR2 sequence which is 8 amino acids in length and comprises the consensus sequence:
“I, G/Y/S/T, G/S/Y, S/Y, G/S/Y, G/S/Y, G/S/Y, T”;
(c) a heavy chain CDR3 sequence which is 9 to 17 amino acids in length and which comprises the consensus sequence of:
“A, R, G/Y/S/H, G/Y/F/V/D, G/Y/P/F, -/H/S, -/N/D/H, -/Y/G, -/Y, -/Y, -/W/A/V, -/A/Y, -/D/A/Y/G/H/N, Y/S/W/A/T, L/M/I/F, D, Y”
(d) a light chain CDR1 sequence which consists of the sequence:
“Q, S, I, S, S, Y”;
(e) a light chain CDR2 sequence which consists of the sequence:
“A, A, S”;
(f) a light chain CDR3 sequence which is 8 to 10 amino acids in length and comprises the consensus sequence:
“Q,Q, S/Y/G, -/Y/H/G, -/S/Y/G/D, S/Y/G/D, S/Y/G/T, P/L, Y/S/H/L/F, T”;
wherein the heavy chain CDR3 sequence of (c) is preferably a sequence of 10 amino acids in length which comprises the consensus sequence “A, R, Y/H, D, Y, A/Y/G, S/W/A, M/L, D, Y” or a CDR3 sequence of 11 amino acids in length which comprises the consensus sequence “A, R, G/Y, V/F/Y, P, H, G/Y/H, Y, F/I, D, Y”;
and
the light chain CDR3 sequence of (f) preferably consists of the sequence “Q, Q, S, Y, S, T, P, Y, T”.

12 more elements

A polypeptide according to any one of the preceding claims, wherein B1 comprises all three heavy chain CDR sequences of a VH sequence as shown in Table C(1) and/or all three light chain CDR sequences of a VL sequence as shown in Table C(2), or wherein B1 comprises a heavy chain VH sequence and/or a light chain VL sequence as shown in Table D.

A polypeptide according to any one of the preceding claims wherein binding domain B1 comprises:

(a) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1166/1167 (SEQ ID NOs:
32, 40 and 49 and/or SEQ ID NOs:
26, 27 and 60);
(b) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1170/1171 (SEQ ID NOs:
32, 41 and 50 and/or SEQ ID NOs:
26, 27 and 61);
(c) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1164/1135 (SEQ ID NOs:
33, 42 and 51 and/or SEQ ID NOs:
26, 27 and 62);
(d) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1168/1135 (SEQ ID NOs:
34, 43 and 52 and/or SEQ ID NOs:
26, 27 and 62);
(e) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1482/1483 (SEQ ID NOs:
35, 44 and 53 and/or SEQ ID NOs:
26, 27 and 63);
(f) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1490/1135 (SEQ ID NOs:
35, 43 and 54 and/or SEQ ID NOs:
26, 27 and 62);
(g) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1514/1515 (SEQ ID NOs:
36, 45 and 55 and/or SEQ ID NOs:
26, 27 and 64);
(h) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1520/1135 (SEQ ID NOs 35, 40 and 56 and/or SEQ ID NOs:
26, 27 and 62);
(i) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1524/1525 (SEQ ID NOs:
37, 46 and 57 and/or SEQ ID NOs:
26, 27 and 65);
(j) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1526/1527 (SEQ ID NOs:
38, 47 and 58 and/or SEQ ID NOs:
26, 27 and 66);
(k) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1542/1135 (SEQ ID NOs:
39, 48 and 59 and/or SEQ ID NOs:
26, 27 and 62);
or
(l) the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1170/1167 (SEQ ID NOs:
32, 41 and 50 and/or SEQ ID NOs:
26, 27 and 60).

33 more elements

A polypeptide according to any one of the preceding claims wherein binding domain B1 comprises:

(a) the heavy chain variable region and/or the light chain variable region of antibody 1166/1167 (SEQ ID NO:
69 and/or SEQ ID NO:
67);
(b) the heavy chain variable region and/or the light chain variable region of antibody 1170/1171 (SEQ ID NO:
73 and/or SEQ ID NO:
71);
(c) the heavy chain variable region and/or the light chain variable region of antibody 1164/1135 (SEQ ID NO:
77 and/or SEQ ID NO:
75);
(d) the heavy chain variable region and/or the light chain variable region of antibody 1168/1135 (SEQ ID NO:
79 and/or SEQ ID NO:
75);
(e) the heavy chain variable region and/or the light chain variable region of antibody 1482/1483 (SEQ ID NO:
83 and/or SEQ ID NO:
81);
(f) the heavy chain variable region and/or the light chain variable region of antibody 1490/1135 (SEQ ID NO:
85 and/or SEQ ID NO:
75);
(g) the heavy chain variable region and/or the light chain variable region of antibody 1514/1515 (SEQ ID NO:
89 and/or SEQ ID NO:
87);
(h) the heavy chain variable region and/or the light chain variable region of antibody 1520/1135 (SEQ ID NO:
91 and/or SEQ ID NO:
75);
(i) the heavy chain variable region and/or the light chain variable region of antibody 1524/1525 (SEQ ID NO:
95 and/or SEQ ID NO:
93);
(j) the heavy chain variable region and/or the light chain variable region of antibody 1526/1527 (SEQ ID NO:
99 and/or SEQ ID NO:
97);
(k) the heavy chain variable region and/or the light chain variable region of antibody 1542/1135 (SEQ ID NO:
101 and/or SEQ ID NO:
75);
(l) the heavy chain variable region and/or the light chain variable region of antibody 1170/1167 (SEQ ID NO:
73 and/or SEQ ID NO:
67);
or
(m) variants of said heavy chain variable regions and/or said heavy chain variable regions having at least 90% sequence identity thereto.

35 more elements

A polypeptide according to any one of the preceding claims wherein binding domain B1 comprises:

(a) the light chain and/or the heavy chain of antibody 1166/1167;
(b) the light chain and/or the heavy chain of antibody 1170/1171;
(c) the light chain and/or the heavy chain of antibody 1164/1135;
(d) the light chain and/or the heavy chain of antibody 1168/1135;
(e) the light chain and/or the heavy chain of antibody 1482/1483;
(f) the light chain and/or the heavy chain of antibody 1490/1135;
(g) the light chain and/or the heavy chain of antibody 1514/1515;
(h) the light chain and/or the heavy chain of antibody 1520/1135;
(i) the light chain and/or the heavy chain of antibody 1524/1525;
(j) the light chain and/or the heavy chain of antibody 1526/1527;
(k) the light chain and/or the heavy chain of antibody 1542/1135;
or
(l) the light chain and/or the heavy chain of antibody 1170/1167.

10 more elements

A polypeptide according to any one of the preceding claims wherein binding domain B1 comprises the heavy chain variable region and/or the light chain variable region of antibody 1170/1171 (SEQ ID NO:

73 and/or SEQ ID NO:
71)

A polypeptide according to any one of the preceding claims wherein binding domain B1 comprises the heavy chain variable region and/or the light chain variable region of antibody 1526/1527 (SEQ ID NO:

99 and/or SEQ ID NO:
97).

A polypeptide according to any one of the preceding claims wherein binding domain B1 comprises the heavy chain variable region and/or the light chain variable region of antibody 1168/1135 (SEQ ID NO:

79 and/or SEQ ID NO:
75).

A polypeptide according to any one of the preceding claims wherein binding domain B2 binds to a tumour cell-associated antigen selected from the group consisting of:

(a) products of mutated oncogenes and tumour suppressor genes;
(b) overexpressed or aberrantly expressed cellular proteins;
(c) tumour antigens produced by oncogenic viruses;
(d) oncofetal antigens;
(e) altered cell surface glycolipids and glycoproteins;
(f) cell type-specific differentiation antigens;
(g) hypoxia-induced antigens;
(h) tumour peptides presented by MHC class I;
(i) epithelial tumour antigens;
(j) haematological tumour-associated antigens;
(k) cancer testis antigens;
and
(l) melanoma antigens.

10 more elements

A polypeptide according to any one of the preceding claims wherein the tumour cell-associated antigen is an oncofetal antigen.

A polypeptide according to any one of the preceding claims wherein the tumour cell-associated antigen is 5T4.

A polypeptide according to any one of the preceding claims wherein binding domain B2 binds to the tumour cell-associated antigen with a KD of less than 10×10−9M, for example less than 4×10−9M or less than 1.2×10−9M.

A polypeptide according to any one of the preceding claims wherein binding domain B2 comprises:

(a) the three CDRs of the light chain and/or the three CDRs of the heavy chain of antibody 1206/1207 (SEQ ID NOs:
26, 27 and 28 and/or SEQ ID NOs:
17, 19 and 22);
(b) the three CDRs of the light chain and/or the three CDRs of the heavy chain of antibody 1208/1135 (SEQ ID NOs:
26, 27 and 29 and/or SEQ ID NOs:
18, 20 and 23);
(c) the three CDRs of the light chain and/or the three CDRs of the heavy chain of antibody 1210/1211 (SEQ ID NOs:
26, 27 and 30 and/or SEQ ID NOs:
18, 20 and 24);
and
(d) the three CDRs of the light chain and/or the three CDRs of the heavy chain of antibody 1212/1213 (SEQ ID NOs:
26, 27 and 31 and/or SEQ ID NOs:
18, 21 and 25).

10 more elements

A polypeptide according to any one of the preceding claims wherein binding domain B2 comprises:

(a) the light chain variable region and/or the heavy chain variable region of antibody 1206/1207 (SEQ ID NO:
3 and/or SEQ ID NO:
1);
(b) the light chain variable region and/or the heavy chain variable region of antibody 1208/1135 (SEQ ID NO:
7 and/or SEQ ID NO:
5);
(c) the light chain variable region and/or the heavy chain variable region of antibody 1210/1211 (SEQ ID NO:
11 and/or SEQ ID NO:
9);
(d) the light chain variable region and/or the heavy chain variable region of antibody 1212/1213 (SEQ ID NO:
15 and/or SEQ ID NO:
13);
or
(e) variants of said light chain variable regions and/or said heavy chain variable regions having at least 90% sequence identity thereto.

11 more elements

A polypeptide according to any one of the preceding claims wherein binding domain B2 comprises:

(a) the light chain and/or the heavy chain of antibody 1206/1207;
(b) the light chain and/or the heavy chain of antibody 1208/1135;
(c) the light chain and/or the heavy chain of antibody 1210/1211;
or
(d) the light chain and/or the heavy chain of antibody 1212/1213.

2 more elements

A polypeptide according to any one of the preceding claims wherein binding domain B2 comprises the light chain variable region and the heavy chain variable region of antibody 1208/1135 (SEQ ID NO:

7 and SEQ ID NO:
5).

A polypeptide according to any one of the preceding claims wherein binding domain B1 is an IgG and binding domain B2 is an scFv.

A polypeptide according to any one of the preceding claims wherein:

(a) B1 comprises the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1170/1167 (SEQ ID NOs:
32, 41 and 50 and/or SEQ ID NOs:
26, 27 and 60) and B2 comprises the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1210/1211 (SEQ ID NOs:
18, 20 and 24 and/or SEQ ID NOs:
26, 27 and 30);
(b) B1 comprises the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1482/1483 (SEQ ID NOs:
35, 44 and 53 and/or SEQ ID NOs:
26, 27 and 63) and B2 comprises the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1210/1211 (SEQ ID NOs:
18, 20 and 24 and/or SEQ ID NOs:
26, 27 and 30);
(c) B1 comprises the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1170/1167 (SEQ ID NOs:
32, 41 and 50 and/or SEQ ID NOs:
26, 27 and 60) and B2 comprises the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1208/1135 (SEQ ID NOs:
18, 20 and 23 and/or SEQ ID NOs:
26, 27 and 29);
(d) B1 comprises the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1482/1483 (SEQ ID NOs:
35, 44 and 53 and/or SEQ ID NOs:
26, 27 and 63) and B2 comprises the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1208/1135 (SEQ ID NOs:
18, 20 and 23 and/or SEQ ID NOs:
26, 27 and 29);
(e) B1 comprises the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1166/1167 (SEQ ID NOs:
32, 40 and 49 and/or SEQ ID NOs:
26, 27 and 60) and B2 comprises the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1210/1211 (SEQ ID NOs:
18, 20 and 24 and/or SEQ ID NOs:
26, 27 and 30);
(f) B1 comprises the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1170/1171 (SEQ ID NOs:
32, 41 and 50 and/or SEQ ID NOs:
26, 27 and 61) and B2 comprises the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1210/1211 (SEQ ID NOs:
18, 20 and 24 and/or SEQ ID NOs:
26, 27 and 30);
(g) B1 comprises the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1166/1167 (SEQ ID NOs:
32, 40 and 49 and/or SEQ ID NOs:
26, 27 and 60) and B2 comprises the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1208/1135 (SEQ ID NOs:
18, 20 and 23 and/or SEQ ID NOs:
26, 27 and 29);
(h) B1 comprises the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1170/1171 (SEQ ID NOs:
32, 41 and 50 and/or SEQ ID NOs:
26, 27 and 61) and B2 comprises the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1208/1135 (SEQ ID NOs:
18, 20 and 23 and/or SEQ ID NOs:
26, 27 and 29);
(i) B1 comprises the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1526/1527 (SEQ ID NOs:
38, 47 and 58 and/or SEQ ID NOs:
26, 27 and 66) and B2 comprises the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1210/1211 (SEQ ID NOs:
18, 20 and 24 and/or SEQ ID NOs:
26, 27 and 30);
or
(j) B1 comprises the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1526/1527 (SEQ ID NOs:
38, 47 and 58 and/or SEQ ID NOs:
26, 27 and 66) and B2 comprises the three CDRs of the heavy chain and/or the three CDRs of the light chain of antibody 1208/1135 (SEQ ID NOs:
18, 20 and 23 and/or SEQ ID NOs:
26, 27 and 29)

48 more elements

A polypeptide according to any one of the preceding claims wherein:

(a) B1 comprises the heavy chain variable region and/or the light chain variable region of antibody 1170/1167 (SEQ ID NO:
73 and/or SEQ ID NO:
67) and B2 comprises the heavy chain variable region and/or the light chain variable region of antibody 1210/1211 (SEQ ID NO:
9 and/or SEQ ID NO:
11);
(b) B1 comprises the heavy chain variable region and/or the light chain variable region of antibody 1482/1483 (SEQ ID NO:
83 and/or SEQ ID NO:
81) and B2 comprises the heavy chain variable region and/or the light chain variable region of antibody 1210/1211 (SEQ ID NO:
9 and/or SEQ ID NO:
11);
(c) B1 comprises the heavy chain variable region and/or the light chain variable region of antibody 1170/1167 (SEQ ID NO:
73 and/or SEQ ID NO:
67) and B2 comprises the heavy chain variable region and/or the light chain variable region of antibody 1208/1135 (SEQ ID NO:
5 and/or SEQ ID NO:
7);
(d) B1 comprises the heavy chain variable region and/or the light chain variable region of antibody 1482/1483 (SEQ ID NO:
83 and/or SEQ ID NO:
81) and B2 comprises the heavy chain variable region and/or the light chain variable region of antibody 1208/1135 (SEQ ID NO:
5 and/or SEQ ID NO:
7);
(e) B1 comprises the heavy chain variable region and/or the light chain variable region of antibody 1166/1167 (SEQ ID NO:
69 and/or SEQ ID NO:
67) and B2 comprises the heavy chain variable region and/or the light chain variable region of antibody 1210/1211 (SEQ ID NO:
9 and/or SEQ ID NO:
11);
(f) B1 comprises the heavy chain variable region and/or the light chain variable region of antibody 1170/1171 (SEQ ID NO:
73 and/or SEQ ID NO:
71) and B2 comprises the heavy chain variable region and/or the light chain variable region of antibody 1210/1211 (SEQ ID NO:
9 and/or SEQ ID NO:
11);
(g) B1 comprises the heavy chain variable region and/or the light chain variable region of antibody 1166/1167 (SEQ ID NO:
69 and/or SEQ ID NO:
67) and B2 comprises the heavy chain variable region and/or the light chain variable region of antibody 1208/1135 (SEQ ID NO:
5 and/or SEQ ID NO:
7);
(h) B1 comprises the heavy chain variable region and/or the light chain variable region of antibody 1170/1171 (SEQ ID NO:
73 and/or SEQ ID NO:
71) and B2 comprises the heavy chain variable region and/or the light chain variable region of antibody 1208/1135 (SEQ ID NO:
5 and/or SEQ ID NO:
7);
(i) B1 comprises the heavy chain variable region and/or the light chain variable region of antibody 1526/1527 (SEQ ID NO:
99 and/or SEQ ID NO:
97);
and B2 comprises the heavy chain variable region and/or the light chain variable region of antibody 1210/1211 (SEQ ID NO:
9 and/or SEQ ID NO:
11);
(j) B1 comprises the heavy chain variable region and/or the light chain variable region of antibody 1526/1527 (SEQ ID NO:
99 and/or SEQ ID NO:
97);
and B2 comprises the heavy chain variable region and/or the light chain variable region of antibody 1208/1135 (SEQ ID NO:
5 and/or SEQ ID NO:
7);
or
(k) variants of said light chain variable regions and/or said heavy chain variable regions having at least 90% sequence identity thereto.

51 more elements

Dependencies are inferred from the claim text.

Facts

Application

16/312,374Filed 30 Jun 2017

Priority

GB 1611530.51 Jul 2016

Published

30 May 2019

Term ends

Not estimatedThe source records don’t support an estimate.

Classification18 codes

C07K 16/2878
Against receptors, cell surface antigens or cell surface determinants: against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
A61P 35/00
Antineoplastic agents
C07K 16/30
Against receptors, cell surface antigens or cell surface determinants: from tumour cells
C12N 15/62
DNA or RNA fragments; Modified forms thereof ; Non-coding nucleic acids having a biological activity: dNA sequences coding for fusion proteins

Bispecific Antibodies Directed Against OX40 and a Tumor-Associated Antigen

Life of this patent

Abstract

Claims88

Bispecific Antibodies Directed Against OX40 and a Tumor-Associated Antigen

Life of this patent

Abstract

Claims88