US 2019/0194309 A1 · MACROPHAGE STIMULATING PROTEIN RECEPTOR (OR RON - RECEPTEUR D' ORIGINE NANTAIS) ANTIBODIES AND USES THEREOF

Abstract

Disclosed are monoclonal antibodies that bind specifically to macrophage stimulating protein receptor (or RON—Recepteur d' Origine Nantais). Also provided are the chimeric antigen receptors, bispecific antibodies, bivalent antibodies and biTE thereof, as well as pharmaceutical compositions and uses of said antibodies for the treatment of cancer and fibrosis and an ex vivo method of evaluating the status of a cancer patient using said antibodies. In particular, two monoclonal antibodies, 7G8 and 6D4, demonstrating good therapeutic efficacy in inhibiting tumour growth in human xenograft mice models and sensitivity in human xenograft mouse tumour imaging models are provided.

Claims21

Dependent claims

-31. (canceled)

A antigen binding domain comprising the heavy chain CDRs of CDRH1, CDRH2, and CDRH3 and the light chain CDRs of CDRL1, CDRL2, and CDRL3, wherein

(a) CDRH1 is selected from the group consisting of SEQ ID NO:
1, SEQ ID NO:
27, SEQ ID NO:
45, SEQ ID NO:
56, SEQ ID NO:
73, SEQ ID NO:
89, SEQ ID NO:
100, SEQ ID NO:
116, and SEQ ID NO:
135 or a CDRH1 sequence differing 1 or 2 amino acids therefrom;
(b) CDRH2 is selected from the group consisting of SEQ ID NO:
2, SEQ ID NO:
28, SEQ ID NO:
46, SEQ ID NO:
57, SEQ ID NO:
74, SEQ ID NO:
90, SEQ ID NO:
101, SEQ ID NO:
117, and SEQ ID NO:
136;
or a CDRH2 sequence differing 1 or 2 amino acids therefrom;
(c) CDRH3 is selected from the group consisting of SEQ ID NO:
3, SEQ ID NO:
29, SEQ ID NO:
47, SEQ ID NO:
58, SEQ ID NO:
75, SEQ ID NO:
91, SEQ ID NO:
102, and SEQ ID NO:
137;
or a CDRH3 sequence differing 1 or 2 amino acids therefrom;
(d) CDRL1 is selected from the group consisting of SEQ ID NO:
18, SEQ ID NO:
36, SEQ ID NO:
65, SEQ ID NO:
81, SEQ ID NO:
108, and SEQ ID NO:
144;
or a CDRL1 sequence differing 1 or 2 amino acids therefrom;
(e) CDRL2 is selected from the group consisting of SEQ ID NO:
19, SEQ ID NO:
37, SEQ ID NO:
66, SEQ ID NO:
82, and SEQ ID NO:
109;
or a CDRL2 sequence differing 1 or 2 amino acids therefrom;
and
CDRL3 is selected from the group consisting of SEQ ID NO:
20, SEQ ID NO:
38, SEQ ID NO:
67, SEQ ID NO:
83, SEQ ID NO:
110, SEQ ID NO:
123, and SEQ ID NO:
145;
or a CDRL3 sequence differing 1 or 2 amino acids therefrom;
or an antigen specific binding domain comprising CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, wherein:
i. CDRH1 is selected from the group consisting of SEQ ID NO:
1, SEQ ID NO:
27, SEQ ID NO:
45, SEQ ID NO:
56, SEQ ID NO:
73, SEQ ID NO:
89, and SEQ ID NO:
100, SEQ ID NO:
116, SEQ ID NO:
135 and a CDRH1 differing from any one of the same in that 1 or 2 amino acids are replaced, deleted or added;
ii. CDRH2 is selected from the group consisting of SEQ ID NO:
2, SEQ ID NO:
28, SEQ ID NO:
46, SEQ ID NO:
57, SEQ ID NO:
74, SEQ ID NO:
90, and SEQ ID NO:
101, SEQ ID NO:
117, SEQ ID NO:
136 and a CDRH2 differing from any one of the same in that 1 or 2 amino acids are replaced, deleted or added;
iii. CDRH3 is selected from the group consisting of SEQ ID NO:
3, SEQ ID NO:
29, SEQ ID NO:
47, SEQ ID NO:
58, SEQ ID NO:
75, SEQ ID NO:
91, and SEQ ID NO:
102, SEQ ID NO:
137 and a CDRH3 differing from any one of the same in that 1 or 2 amino acids are replaced, deleted or added;
iv. CDRL1 is selected from the group consisting of SEQ ID NO:
18, SEQ ID NO:
36, SEQ ID NO:
65, SEQ ID NO:
81, SEQ ID NO:
108, SEQ ID NO:
144 and a CDRL1 differing from any one of the same in that 1 or 2 amino acids are replaced, deleted or added;
v. CDRL2 is selected from the group consisting of SEQ ID NO:
19, SEQ ID NO:
37, SEQ ID NO:
66, SEQ ID NO:
82, SEQ ID NO:
109 and a CDRL2 differing from any one of the same in that 1 or 2 amino acids are replaced, deleted or added;
and
(f) CDRL3 is selected from the group consisting of SEQ ID NO:
20, SEQ ID NO:
38, SEQ ID NO:
67, SEQ ID NO:
83, SEQ ID NO:
110, SEQ ID NO:
123, SEQ ID NO:
145 and a CDRL3 differing from any one of the same in that 1 or 2 amino acids are replaced, deleted or added.

105 more elements

An isolated antibody comprising an antigen binding domain comprising the heavy chain CDRs of CDRH1, CDRH2, and CDRH3 and the light chain CDRs of CDRL1, CDRL2, and CDRL3, wherein

(a) CDRH1 is selected from the group consisting of SEQ ID NO:
1, SEQ ID NO:
27, SEQ ID NO:
45, SEQ ID NO:
56, SEQ ID NO:
73, SEQ ID NO:
89, SEQ ID NO:
100, SEQ ID NO:
116, and SEQ ID NO:
135 or a CDRH1 sequence differing 1 or 2 amino acids therefrom;
(b) CDRH2 is selected from the group consisting of SEQ ID NO:
2, SEQ ID NO:
28, SEQ ID NO:
46, SEQ ID NO:
57, SEQ ID NO:
74, SEQ ID NO:
90, SEQ ID NO:
101, SEQ ID NO:
117, and SEQ ID NO:
136;
or a CDRH2 sequence differing 1 or 2 amino acids therefrom;
(c) CDRH3 is selected from the group consisting of SEQ ID NO:
3, SEQ ID NO:
29, SEQ ID NO:
47, SEQ ID NO:
58, SEQ ID NO:
75, SEQ ID NO:
91, SEQ ID NO:
102, and SEQ ID NO:
137;
or a CDRH3 sequence differing 1 or 2 amino acids therefrom;
(d) CDRL1 is selected from the group consisting of SEQ ID NO:
18, SEQ ID NO:
36, SEQ ID NO:
65, SEQ ID NO:
81, SEQ ID NO:
108, and SEQ ID NO:
144;
or a CDRL1 sequence differing 1 or 2 amino acids therefrom;
(e) CDRL2 is selected from the group consisting of SEQ ID NO:
19, SEQ ID NO:
37, SEQ ID NO:
66, SEQ ID NO:
82, and SEQ ID NO:
109;
or a CDRL2 sequence differing 1 or 2 amino acids therefrom;
and
CDRL3 is selected from the group consisting of SEQ ID NO:
20, SEQ ID NO:
38, SEQ ID NO:
67, SEQ ID NO:
83, SEQ ID NO:
110, SEQ ID NO:
123, and SEQ ID NO:
145;
or a CDRL3 sequence differing 1 or 2 amino acids therefrom;
or an antigen specific binding domain comprising CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, wherein:
i. CDRH1 is selected from the group consisting of SEQ ID NO:
1, SEQ ID NO:
27, SEQ ID NO:
45, SEQ ID NO:
56, SEQ ID NO:
73, SEQ ID NO:
89, and SEQ ID NO:
100, SEQ ID NO:
116, SEQ ID NO:
135 and a CDRH1 differing from any one of the same in that 1 or 2 amino acids are replaced, deleted or added;
ii. CDRH2 is selected from the group consisting of SEQ ID NO:
2, SEQ ID NO:
28, SEQ ID NO:
46, SEQ ID NO:
57, SEQ ID NO:
74, SEQ ID NO:
90, and SEQ ID NO:
101, SEQ ID NO:
117, SEQ ID NO:
136 and a CDRH2 differing from any one of the same in that 1 or 2 amino acids are replaced, deleted or added;
iii. CDRH3 is selected from the group consisting of SEQ ID NO:
3, SEQ ID NO:
29, SEQ ID NO:
47, SEQ ID NO:
58, SEQ ID NO:
75, SEQ ID NO:
91, and SEQ ID NO:
102, SEQ ID NO:
137 and a CDRH3 differing from any one of the same in that 1 or 2 amino acids are replaced, deleted or added;
iv. CDRL1 is selected from the group consisting of SEQ ID NO:
18, SEQ ID NO:
36, SEQ ID NO:
65, SEQ ID NO:
81, SEQ ID NO:
108, SEQ ID NO:
144 and a CDRL1 differing from any one of the same in that 1 or 2 amino acids are replaced, deleted or added;
v. CDRL2 is selected from the group consisting of SEQ ID NO:
19, SEQ ID NO:
37, SEQ ID NO:
66, SEQ ID NO:
82, SEQ ID NO:
109 and a CDRL2 differing from any one of the same in that 1 or 2 amino acids are replaced, deleted or added;
and
(f) CDRL3 is selected from the group consisting of SEQ ID NO:
20, SEQ ID NO:
38, SEQ ID NO:
67, SEQ ID NO:
83, SEQ ID NO:
110, SEQ ID NO:
123, SEQ ID NO:
145 and a CDRL3 differing from any one of the same in that 1 or 2 amino acids are replaced, deleted or added.

105 more elements

A method of preventing or treating cancer or fibrosis in a patient comprising administering a therapeutically effective amount of an antigen binding domain according to the patient in need thereof, wherein the antigen binding domain comprises the heavy chain CDRs of CDRH1, CDRH2, and CDRH3 and the light chain CDRs of CDRL1, CDRL2, and CDRL3, wherein

(a) CDRH1 is selected from the group consisting of SEQ ID NO:
1, SEQ ID NO:
27, SEQ ID NO:
45, SEQ ID NO:
56, SEQ ID NO:
73, SEQ ID NO:
89, SEQ ID NO:
100, SEQ ID NO:
116, and SEQ ID NO:
135 or a CDRH1 sequence differing 1 or 2 amino acids therefrom;
(b) CDRH2 is selected from the group consisting of SEQ ID NO:
2, SEQ ID NO:
28, SEQ ID NO:
46, SEQ ID NO:
57, SEQ ID NO:
74, SEQ ID NO:
90, SEQ ID NO:
101, SEQ ID NO:
117, and SEQ ID NO:
136;
or a CDRH2 sequence differing 1 or 2 amino acids therefrom;
(c) CDRH3 is selected from the group consisting of SEQ ID NO:
3, SEQ ID NO:
29, SEQ ID NO:
47, SEQ ID NO:
58, SEQ ID NO:
75, SEQ ID NO:
91, SEQ ID NO:
102, and SEQ ID NO:
137;
or a CDRH3 sequence differing 1 or 2 amino acids therefrom;
(d) CDRL1 is selected from the group consisting of SEQ ID NO:
18, SEQ ID NO:
36, SEQ ID NO:
65, SEQ ID NO:
81, SEQ ID NO:
108, and SEQ ID NO:
144;
or a CDRL1 sequence differing 1 or 2 amino acids therefrom;
(e) CDRL2 is selected from the group consisting of SEQ ID NO:
19, SEQ ID NO:
37, SEQ ID NO:
66, SEQ ID NO:
82, and SEQ ID NO:
109;
or a CDRL2 sequence differing 1 or 2 amino acids therefrom;
and
CDRL3 is selected from the group consisting of SEQ ID NO:
20, SEQ ID NO:
38, SEQ ID NO:
67, SEQ ID NO:
83, SEQ ID NO:
110, SEQ ID NO:
123, and SEQ ID NO:
145;
or a CDRL3 sequence differing 1 or 2 amino acids therefrom;
or an antigen specific binding domain comprising CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, wherein:
i. CDRH1 is selected from the group consisting of SEQ ID NO:
1, SEQ ID NO:
27, SEQ ID NO:
45, SEQ ID NO:
56, SEQ ID NO:
73, SEQ ID NO:
89, and SEQ ID NO:
100, SEQ ID NO:
116, SEQ ID NO:
135 and a CDRH1 differing from any one of the same in that 1 or 2 amino acids are replaced, deleted or added;
ii. CDRH2 is selected from the group consisting of SEQ ID NO:
2, SEQ ID NO:
28, SEQ ID NO:
46, SEQ ID NO:
57, SEQ ID NO:
74, SEQ ID NO:
90, and SEQ ID NO:
101, SEQ ID NO:
117, SEQ ID NO:
136 and a CDRH2 differing from any one of the same in that 1 or 2 amino acids are replaced, deleted or added;
iii. CDRH3 is selected from the group consisting of SEQ ID NO:
3, SEQ ID NO:
29, SEQ ID NO:
47, SEQ ID NO:
58, SEQ ID NO:
75, SEQ ID NO:
91, and SEQ ID NO:
102, SEQ ID NO:
137 and a CDRH3 differing from any one of the same in that 1 or 2 amino acids are replaced, deleted or added;
iv. CDRL1 is selected from the group consisting of SEQ ID NO:
18, SEQ ID NO:
36, SEQ ID NO:
65, SEQ ID NO:
81, SEQ ID NO:
108, SEQ ID NO:
144 and a CDRL1 differing from any one of the same in that 1 or 2 amino acids are replaced, deleted or added;
v. CDRL2 is selected from the group consisting of SEQ ID NO:
19, SEQ ID NO:
37, SEQ ID NO:
66, SEQ ID NO:
82, SEQ ID NO:
109 and a CDRL2 differing from any one of the same in that 1 or 2 amino acids are replaced, deleted or added;
and
(f) CDRL3 is selected from the group consisting of SEQ ID NO:
20, SEQ ID NO:
38, SEQ ID NO:
67, SEQ ID NO:
83, SEQ ID NO:
110, SEQ ID NO:
123, SEQ ID NO:
145 and a CDRL3 differing from any one of the same in that 1 or 2 amino acids are replaced, deleted or added.

105 more elements

Dependencies are inferred from the claim text.

Facts

Application

16/328,711Filed 28 Aug 2017

Priority

SG 10201607147P26 Aug 2016

Published

27 Jun 2019

Term ends

Not estimatedThe source records don’t support an estimate.

Classification18 codes

C07K 16/22
Against material from animals or humans: against growth factors ; against growth regulators
A61K 47/6845
The modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site: the antibody targeting a cytokine, e.g.…
A61P 35/00
Antineoplastic agents
C07K 16/2863
Against receptors, cell surface antigens or cell surface determinants: against receptors for growth factors, growth regulators

Macrophage stimulating protein receptor (or ron - recepteur d' origine nantais) antibodies and uses thereof

Life of this patent

Macrophage stimulating protein receptor (or ron - recepteur d' origine nantais) antibodies and uses thereof

Life of this patent

Abstract

Claims21