US 2023/0146646 A1 · ANTI-MERTK AGONISTIC ANTIBODIES AND USES THEREOF

Abstract

The present disclosure provides antibody-drug conjugates comprising (i) antibodies that specifically bind to Mer Tyrosine Kinase (MERTK) (e.g., human MERTK, or both human and mouse MERTK), and (ii) cytotoxic agents conjugated directly to the antibodies or conjugated to the antibodies via linkers, and compositions comprising such antibody-drug conjugates, wherein the antibodies contained in the antibody-drug conjugates agonize MERTK signaling of endothelial cells. The present disclosure also provides methods for treating cancer, by administering an antibody-drug conjugate that comprises (i) an antibody that specifically binds to MERTK and agonizes MERTK signaling of endothelial cells, and (ii) a cytotoxic agent conjugated directly to the antibody or conjugated to the antibody via a linker.

Claims22

Dependent claims

1-78. (canceled)

A method of producing an antibody-drug conjugate, said antibody-drug conjugate comprising (a) an antibody moiety that is an antibody or antigen-binding fragment thereof that specifically binds to human MERTK;

and (b) one or more drug moieties, each drug moiety being a cytotoxic agent;
wherein the cytotoxic agent is conjugated directly to the antibody moiety;
wherein said antibody or antigen-binding fragment comprises a heavy chain variable region (VH) and a light chain variable region (VL), and wherein
(i) the VH comprises a CDR 1 of SEQ ID NO:
1, a CDR2 of SEQ ID NO:
6, and a CDR3 of SEQ ID NO:
11;
and the VL comprises a CDR1 of SEQ ID NO:
15, a CDR2 of SEQ ID NO:
19, and a CDR3 of SEQ ID NO:
22;
or
(ii) the VH comprises a CDR1 of SEQ ID NO:
2, a CDR2 of SEQ ID NO:
7, and a CDR3 of SEQ ID NO:
12;
and the VL comprises a CDR1 of SEQ ID NO:
16, a CDR2 of SEQ ID NO:
20, and a CDR3 of SEQ ID NO:
23;
or
(iii) the VH comprises a CDR1 of SEQ ID NO:
3, a CDR2 of SEQ ID NO:
8, and a CDR3 of SEQ ID NO:
11;
and the VL comprises a CDR1 of SEQ ID NO:
15, a CDR2 of SEQ ID NO:
19 and a CDR3 of SEQ ID NO:
22;
or
(iv) the VH comprises a CDR1 of SEQ ID NO:
4, a CDR2 of SEQ ID NO:
9, and a CDR3 of SEQ ID NO:
13;
and the VL comprises a CDR1 of SEQ ID NO:
17, a CDR2 of SEQ ID NO:
21, and a CDR3 of SEQ ID NO:
24;
or
(v) the VH comprises a CDR1 of SEQ ID NO:
5, a CDR2 of SEQ ID NO:
10, and a CDR3 of SEQ ID NO:
14;
and the VL comprises CDR1 of SEQ ID NO:
18, a CDR2 of SEQ ID NO:
20, and a CDR3 of SEQ ID NO:
22;
or
(vi) the VH comprises a CDR1 of SEQ ID NO:
3, a CDR2 of SEQ ID NO:
6, and a CDR3 of SEQ ID NO:
11;
and the VL comprises a CDR1 of SEQ ID NO:
15, a CDR2 of SEQ ID NO:
19 and a CDR3 of SEQ ID NO:
22;
or
(vii) the VH comprises a CDR1 of SEQ ID NO:
25, a CDR2 of SEQ ID NO:
30, and a CDR3 of SEQ ID NO:
35;
and the VL comprises a CDR1 of SEQ ID NO:
39, a CDR2 of SEQ ID NO:
43, and a CDR3 of SEQ ID NO:46;
(viii) the VH comprises a CDR1 of SEQ ID NO:
26, a CDR2 of SEQ ID NO:
31, and a CDR3 of SEQ ID NO:
36;
and the VL comprises a CDR1 of SEQ ID NO:
40, a CDR2 of SEQ ID NO:
44, and a CDR3 of SEQ ID NO:
47;
or
(ix) the VH comprises a CDR1 of SEQ ID NO:
27, a CDR2 of SEQ ID NO:
32, and a CDR3 of SEQ ID NO:
35;
and the VL comprises a CDR1 of SEQ ID NO:
39, a CDR2 of SEQ ID NO:
43, and a CDR3 of SEQ ID NO:
46;
or
(x) the VH comprises a CDR1 of SEQ ID NO:
28, a CDR2 of SEQ ID NO:
33, and a CDR3 of SEQ ID NO:
37;
and the VL comprises a CDR1 of SEQ ID NO:
41, a CDR2 of SEQ ID NO:
45, and a CDR3 of SEQ ID NO:
48;
or
(xi) the VH comprises a CDR1 of SEQ ID NO:
29, a CDR2 of SEQ ID NO:
34, and a CDR3 of SEQ ID NO:
38;
and the VL comprises a CDR1 of SEQ ID NO:
42, a CDR2 of SEQ ID NO:
44, and a CDR3 of SEQ ID NO:
46;
or
(xii) the VH comprises a CDR1 of SEQ ID NO:
27, a CDR2 of SEQ ID NO:
30, and a CDR3 of SEQ ID NO:
35;
and the VL comprises a CDR1 of SEQ ID NO:
39, a CDR2 of SEQ ID NO:
43, and a CDR3 of SEQ ID NO:
46,
said method comprising:
(a) conjugating the cytotoxic agent directly to the antibody moiety to produce the antibody-drug conjugate;
and (b) purifying the antibody-drug conjugate.

108 more elements

(b) one or more drug moieties, each drug moiety being a cytotoxic agent and (c) a linker;
wherein the cytotoxic agent is conjugated to the antibody moiety via the linker;
wherein said antibody or antigen-binding fragment comprises a heavy chain variable region (VH) and a light chain variable region (VL), and wherein
(i) the VH comprises a CDR 1 of SEQ ID NO:
1, a CDR2 of SEQ ID NO:
6, and a CDR3 of SEQ ID NO:
11;
and the VL comprises a CDR1 of SEQ ID NO:
15, a CDR2 of SEQ ID NO:
19, and a CDR3 of SEQ ID NO:
22;
or
(ii) the VH comprises a CDR1 of SEQ ID NO:
2, a CDR2 of SEQ ID NO:
7, and a CDR3 of SEQ ID NO:
12;
and the VL comprises a CDR1 of SEQ ID NO:
16, a CDR2 of SEQ ID NO:
20, and a CDR3 of SEQ ID NO:
23;
or
(iii) the VH comprises a CDR1 of SEQ ID NO:
3, a CDR2 of SEQ ID NO:
8, and a CDR3 of SEQ ID NO:
11;
and the VL comprises a CDR1 of SEQ ID NO:
15, a CDR2 of SEQ ID NO:
19 and a CDR3 of SEQ ID NO:
22;
or
(iv) the VH comprises a CDR1 of SEQ ID NO:
4, a CDR2 of SEQ ID NO:
9, and a CDR3 of SEQ ID NO:
13;
and the VL comprises a CDR1 of SEQ ID NO:
17, a CDR2 of SEQ ID NO:
21, and a CDR3 of SEQ ID NO:
24;
or
(v) the VH comprises a CDR1 of SEQ ID NO:
5, a CDR2 of SEQ ID NO:
10, and a CDR3 of SEQ ID NO:
14;
and the VL comprises CDR1 of SEQ ID NO:
18, a CDR2 of SEQ ID NO:
20, and a CDR3 of SEQ ID NO:
22;
or
(vi) the VH comprises a CDR1 of SEQ ID NO:
3, a CDR2 of SEQ ID NO:
6, and a CDR3 of SEQ ID NO:
11;
and the VL comprises a CDR1 of SEQ ID NO:
15, a CDR2 of SEQ ID NO:
19 and a CDR3 of SEQ ID NO:
22;
or
(vii) the VH comprises a CDR1 of SEQ ID NO:
25, a CDR2 of SEQ ID NO:
30, and a CDR3 of SEQ ID NO:
35;
and the VL comprises a CDR1 of SEQ ID NO:
39, a CDR2 of SEQ ID NO:
43, and a CDR3 of SEQ ID NO:46;
(viii) the VH comprises a CDR1 of SEQ ID NO:
26, a CDR2 of SEQ ID NO:
31, and a CDR3 of SEQ ID NO:
36;
and the VL comprises a CDR1 of SEQ ID NO:
40, a CDR2 of SEQ ID NO:
44, and a CDR3 of SEQ ID NO:
47;
or
(ix) the VH comprises a CDR1 of SEQ ID NO:
27, a CDR2 of SEQ ID NO:
32, and a CDR3 of SEQ ID NO:
35;
and the VL comprises a CDR1 of SEQ ID NO:
39, a CDR2 of SEQ ID NO:
43, and a CDR3 of SEQ ID NO:
46;
or
(x) the VH comprises a CDR1 of SEQ ID NO:
28, a CDR2 of SEQ ID NO:
33, and a CDR3 of SEQ ID NO:
37;
and the VL comprises a CDR1 of SEQ ID NO:
41, a CDR2 of SEQ ID NO:
45, and a CDR3 of SEQ ID NO:
48;
or
(xi) the VH comprises a CDR1 of SEQ ID NO:
29, a CDR2 of SEQ ID NO:
34, and a CDR3 of SEQ ID NO:
38;
and the VL comprises a CDR1 of SEQ ID NO:
42, a CDR2 of SEQ ID NO:
44, and a CDR3 of SEQ ID NO:
46;
or
(xii) the VH comprises a CDR1 of SEQ ID NO:
27, a CDR2 of SEQ ID NO:
30, and a CDR3 of SEQ ID NO:
35;
and the VL comprises a CDR1 of SEQ ID NO:
39, a CDR2 of SEQ ID NO:
43, and a CDR3 of SEQ ID NO:
46,
said method comprising the following steps in the order stated:
(a) conjugating the linker directly to the antibody moiety to produce a linker-antibody moiety;
(b) conjugating the linker of the linker-antibody moiety directly to the cytotoxic agent to produce the antibody-drug conjugate;
and
(c) purifying the antibody-drug conjugate.

110 more elements

A method of treating cancer in a subject in need thereof, comprising administering to said subject an antibody-drug conjugate and an additional therapeutic agent,

wherein the antibody-drug conjugate comprises (a) an antibody moiety that is an antibody or antigen-binding fragment thereof that specifically binds to human MERTK;
(b) one or more drug moieties, each drug moiety being a cytotoxic agent and (c) optionally a linker;
wherein the cytotoxic agent is conjugated directly to the antibody moiety or is conjugated to the antibody moiety via the linker;
wherein said antibody or antigen-binding fragment comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein
(i) the VH comprises a CDR 1 of SEQ ID NO:
1, a CDR2 of SEQ ID NO:
6, and a CDR3 of SEQ ID NO:
11;
and the VL comprises a CDR1 of SEQ ID NO:
15, a CDR2 of SEQ ID NO:
19, and a CDR3 of SEQ ID NO:
22;
or
(ii) the VH comprises a CDR1 of SEQ ID NO:
2, a CDR2 of SEQ ID NO:
7, and a CDR3 of SEQ ID NO:
12;
and the VL comprises a CDR1 of SEQ ID NO:
16, a CDR2 of SEQ ID NO:
20, and a CDR3 of SEQ ID NO:
23;
or
(iii) the VH comprises a CDR1 of SEQ ID NO:
3, a CDR2 of SEQ ID NO:
8, and a CDR3 of SEQ ID NO:
11;
and the VL comprises a CDR1 of SEQ ID NO:
15, a CDR2 of SEQ ID NO:
19 and a CDR3 of SEQ ID NO:
22;
or
(iv) the VH comprises a CDR1 of SEQ ID NO:
4, a CDR2 of SEQ ID NO:
9, and a CDR3 of SEQ ID NO:
13;
and the VL comprises a CDR1 of SEQ ID NO:
17, a CDR2 of SEQ ID NO:
21, and a CDR3 of SEQ ID NO:
24;
or
(v) the VH comprises a CDR1 of SEQ ID NO:
5, a CDR2 of SEQ ID NO:
10, and a CDR3 of SEQ ID NO:
14;
and the VL comprises CDR1 of SEQ ID NO:
18, a CDR2 of SEQ ID NO:
20, and a CDR3 of SEQ ID NO:
22;
or
(vi) the VH comprises a CDR1 of SEQ ID NO:
3, a CDR2 of SEQ ID NO:
6, and a CDR3 of SEQ ID NO:
11;
and the VL comprises a CDR1 of SEQ ID NO:
15, a CDR2 of SEQ ID NO:
19 and a CDR3 of SEQ ID NO:
22;
or
(vii) the VH comprises a CDR1 of SEQ ID NO:
25, a CDR2 of SEQ ID NO:
30, and a CDR3 of SEQ ID NO:
35;
and the VL comprises a CDR1 of SEQ ID NO:
39, a CDR2 of SEQ ID NO:
43, and a CDR3 of SEQ ID NO:46;
(viii) the VH comprises a CDR1 of SEQ ID NO:
26, a CDR2 of SEQ ID NO:
31, and a CDR3 of SEQ ID NO:
36;
and the VL comprises a CDR1 of SEQ ID NO:
40, a CDR2 of SEQ ID NO:
44, and a CDR3 of SEQ ID NO:
47;
or
(ix) the VH comprises a CDR1 of SEQ ID NO:
27, a CDR2 of SEQ ID NO:
32, and a CDR3 of SEQ ID NO:
35;
and the VL comprises a CDR1 of SEQ ID NO:
39, a CDR2 of SEQ ID NO:
43, and a CDR3 of SEQ ID NO:
46;
or
(x) the VH comprises a CDR1 of SEQ ID NO:
28, a CDR2 of SEQ ID NO:
33, and a CDR3 of SEQ ID NO:
37;
and the VL comprises a CDR1 of SEQ ID NO:
41, a CDR2 of SEQ ID NO:
45, and a CDR3 of SEQ ID NO:
48;
or
(xi) the VH comprises a CDR1 of SEQ ID NO:
29, a CDR2 of SEQ ID NO:
34, and a CDR3 of SEQ ID NO:
38;
and the VL comprises a CDR1 of SEQ ID NO:
42, a CDR2 of SEQ ID NO:
44, and a CDR3 of SEQ ID NO:
46;
or
(xii) the VH comprises a CDR1 of SEQ ID NO:
27, a CDR2 of SEQ ID NO:
30, and a CDR3 of SEQ ID NO:
35;
and the VL comprises a CDR1 of SEQ ID NO:
39, a CDR2 of SEQ ID NO:
43, and a CDR3 of SEQ ID NO:
46.

106 more elements

Dependencies are inferred from the claim text.

Anti-mertk agonistic antibodies and uses thereof

Life of this patent

Anti-mertk agonistic antibodies and uses thereof

Life of this patent

Abstract

Claims22