Anti-5T4 antibodies and antibody-drug conjugates
The present disclosure relates to CDR defined antibodies targeting the 5T4 oncofoetal antigen (TPBG, 5T4, Wnt Activated Inhibitory Factor 1, WAIF1) which exhibit a binding affinity for human 5T4 antigen which is in the same order of magnitude as their affinity for cynomolgus monkey 5T4. Antibody-drug conjugates (ADCs), and their use in the treatment of human solid tumours and haematological malignancies are claimed.
1. An antibody-drug conjugate comprising an anti-5T4 antibody having a linker drug conjugated thereto:
wherein said antibody comprises a heavy chain (HC) and light chain (LC) variable region (VR) complementarity determining, regions (CDRs) selected from the group consisting of:
a. CDR1, CDR2, and CDR3 as shown in SEQ ID NO:1 and CDR1, CDR2, and CDR3 as shown in SEQ ID NO:2;
b. CDR1, CDR2, and CDR3 as shown in SEQ ID NO:5 and CDR1, CDR2, and CDR3 as shown in SEQ ID NO:6;
c. CDR1, CDR2, and CDR3 as shown in SEQ ID NO:7 and CDR1, CDR2, and CDR3 as shown in SEQ ID NO:8;
d. CDR1, CDR2, and CDR3 as shown in SEQ ID NO:11 and CDR1, CDR2, and CDR3 as shown in SEQ ID NO:12;
e. CDR1, CDR2, and CDR3 as shown in SEQ ID NO:13 and CDR1, CDR2, and CDR3 as shown in SEQ ID NO:14;
f. CDR1, CDR2, and CDR3 as shown in SEQ ID NO:17 and CDR1, CDR2, and CDR3 as shown in SEQ ID NO:18;
g. CDR1, CDR2, and CDR3 as shown in SEQ ID NO:19 and CDR1, CDR2, and CDR3 as shown in SEQ ID NO 20;
h. CDR1, CDR2, and CDR3 as shown in SEQ ID NO:25 and CDR1, CDR2, and CDR3 as shown in SEQ ID NO:26.
2. The antibody-drug conjugate according to claim 1 , wherein said linker drug is site-specifically conjugated to the antibody through at least one engineered cysteine.
3. The antibody-drug conjugate according to claim 1 , wherein said conjugate is of formula (I)
wherein Antibody represents said anti-5T4 antibody,
n is 0-3,
m represents an average DAR of from 1 to 6,
R 1 is selected from
y is 1-16, and
R 2 is selected from
4. The antibody-drug conjugate according to claim 3 , wherein
n is 0-1,
m represents an average DAR of from 1.5 to 2,
R 1 is
y is 1-4, and
R 2 is selected from
5. The antibody-drug conjugate according to claim 1 , wherein said conjugate is of formula (II)
wherein Antibody represents said anti-5T4 antibody.
6. The antibody-drug conjugate according to claim 1 , wherein the anti-5T4 antibody is a humanized antibody comprising HCVR and LCVR selected from the group consisting of:
a. HCVR amino acid sequence of SEQ ID NO:61 and LCVR amino acid sequence of SEQ ID NO:51;
b. HCVR amino acid sequence of SEQ ID NO:62 and LCVR amino acid sequence of SEQ ID NO:51;
c. HCVR amino acid sequence of SEQ ID NO:63 and LCVR amino acid sequence of SEQ ID NO:49;
d. HCVR amino acid sequence of SEQ ID NO:64 and LCVR amino acid sequence of SEQ ID NO:50;
e. HCVR amino acid sequence of SEQ ID NO:59 and LCVR amino acid sequence of SEQ ID NO:47; and
f. HCVR amino acid sequence of SEQ ID NO:60 and LCVR amino acid sequence of SEQ ID NO:48;
wherein the linker drug is site-specifically conjugated to the anti-5T4 antibody through the engineered cysteine at heavy chain position 41 (according to Kabat numbering).
7. A pharmaceutical composition comprising the antibody-drug conjugate according to claim 1 and one or more pharmaceutically acceptable excipients.
8. The pharmaceutical composition according to claim 7 , wherein said composition is a lyophilized powder.
9. The antibody-drug conjugate according to claim 3 , wherein the anti-5T4 antibody is a humanized antibody comprising HCVR and LCVR selected from the group consisting of:
a. HCVR amino acid sequence of SEQ ID NO:61 and LCVR amino acid sequence of SEQ ID NO:51;
b. HCVR amino acid sequence of SEQ ID NO:62 and LCVR amino acid sequence of SEQ ID NO:51;
c. HCVR amino acid sequence of SEQ ID NO:63 and LCVR amino acid sequence of SEQ ID NO:49;
d. HCVR amino acid sequence of SEQ ID NO:64 and LCVR amino acid sequence of SEQ ID NO:50;
e. HCVR amino acid sequence of SEQ ID NO:59 and LCVR amino acid sequence of SEQ ID NO:47; and
f. HCVR amino acid sequence of SEQ ID NO:60 and LCVR amino acid sequence of SEQ ID NO:48;
wherein the linker drug is site-specifically conjugated to the anti-5T4 antibody through the engineered cysteine at heavy chain position 41 (according to Kabat numbering).
10. The antibody-drug conjugate according to claim 5 , wherein the anti-5T4 antibody is a humanized antibody comprising HCVR and LCVR selected from the group consisting of:
a. HCVR amino acid sequence of SEQ ID NO:61 and LCVR amino acid sequence of SEQ ID NO:51;
b. HCVR amino acid sequence of SEQ ID NO:62 and LCVR amino acid sequence of SEQ ID NO:51;
c. HCVR amino acid sequence of SEQ ID NO:63 and LCVR amino acid sequence of SEQ ID NO:49;
d. HCVR amino acid sequence of SEQ ID NO:64 and LCVR amino acid sequence of SEQ ID NO:50;
e. HCVR amino acid sequence of SEQ ID NO:59 and LCVR amino acid sequence of SEQ ID NO:47; and
f. HCVR amino acid sequence of SEQ ID NO:60 and LCVR amino acid sequence of SEQ ID NO:48;
wherein the linker drug is site-specifically conjugated to the anti-5T4 antibody through the engineered cysteine at heavy chain position 41 (according to Kabat numbering).
11. The antibody-drug conjugate according to claim 2 , wherein the at least one engineered cysteine is present at one or more positions of said antibody selected from
heavy chain 40, 41 and 89 (according to Kabat numbering); and
light chain 40 and 41 (according to Kabat numbering).
12. The antibody-drug conjugate according to claim 11 , wherein the at least one engineered cysteine is present at heavy chain position 41 (according to Kabat numbering).
13. The antibody-drug conjugate according to claim 12 , wherein said antibody comprises a heavy chain (HC) and light chain (LC) variable region (VR) complementarity determining regions (CDRs) selected from the group consisting of:
a. CDR1, CDR2, and CDR3 as shown in SEQ ID NO:1 and CDR1, CDR2, and CDR3 as shown in SEQ ID NO:2;
b. CDR1, CDR2, and CDR3 as shown in SEQ ID NO:5 and CDR1, CDR2, and CDR3 as shown in SEQ ID NO:6; and
c. CDR1, CDR2, and CDR3 as shown in SEQ ID NO:11 and CDR1, CDR2, and CDR3 as shown in SEQ ID NO:12.
14. The antibody-drug conjugate according to claim 12 , wherein said linker drug comprises a cytotoxic drug selected from the group consisting of duocarmycins, calicheamicins, pyrrolobenzodiazepine dimers, maytansinoids, and auristatins.
15. The antibody-drug conjugate according to claim 10 , wherein the anti-5T4 antibody is a humanized antibody comprising HCVR amino acid sequence of SEQ ID NO:61 and LCVR amino acid sequence of SEQ ID NO:51.
16. The antibody-drug conjugate according to claim 10 , wherein the anti-5T4 antibody is a humanized antibody comprising HCVR amino acid sequence of SEQ ID NO:62 and LCVR amino acid sequence of SEQ ID NO:51.
17. The antibody-drug conjugate according to claim 10 , wherein the anti-5T4 antibody is a humanized antibody comprising HCVR amino acid sequence of SEQ ID NO:63 and LCVR amino acid sequence of SEQ ID NO:49.
18. The antibody-drug conjugate according to claim 10 , wherein the anti-5T4 antibody is a humanized antibody comprising HCVR amino acid sequence of SEQ ID NO:64 and LCVR amino acid sequence of SEQ ID NO:50.
19. The antibody-drug conjugate according to claim 10 , wherein the anti-5T4 antibody is a humanized antibody comprising HCVR amino acid sequence of SEQ ID NO:59 and LCVR amino acid sequence of SEQ ID NO:47.
20. The antibody-drug conjugate according to claim 10 , wherein the anti-5T4 antibody is a humanized antibody comprising HCVR amino acid sequence of SEQ ID NO:60 and LCVR amino acid sequence of SEQ ID NO:48.