US 2019/0194315 A1 · ANTIBODY DRUG CONJUGATES

Abstract

This application discloses anti-P-cadherin antibodies, antigen binding fragments thereof, and antibody drug conjugates of said antibodies or antigen binding fragments, particularly antibody drug conjugates comprising anti-P-cadherin antibodies conjugated to auristatin analogs. The invention also relates to methods of treating cancer using the antibody drug conjugates. Also disclosed herein are methods of making the antibodies, antigen binding fragments, and antibody drug conjugates, and methods of using the antibodies and antigen binding fragments as diagnostic reagents.

An antibody that binds human P-cadherin selected from any one of the following:

a. An antibody or antigen binding fragment thereof comprising a heavy chain variable region that comprises a VH CDR1 of SEQ ID NO:
1, a VH CDR2 of SEQ ID NO:
2, and a VH CDR3 of SEQ ID NO:
3, wherein the CDR is defined in accordance with the Kabat definition;
and a light chain variable region that comprises a VL CDR1 of SEQ ID NO:
11, a VL CDR2 of SEQ ID NO:
12, and a VL CDR3 of SEQ ID NO:
13, wherein the CDR is defined in accordance with the Kabat definition, and a modified heavy chain constant region comprising cysteine at positions 152 and 375, wherein said cysteine positions are numbered according to the EU system;
b. An antibody or antigen binding fragment thereof comprising a heavy chain variable region that comprises a VH CDR1 of SEQ ID NO:
21, a VH CDR2 of SEQ ID NO:
22, and a VH CDR3 of SEQ ID NO:
23, wherein the CDR is defined in accordance with the Kabat definition;
and a light chain variable region that comprises a VL CDR1 of SEQ ID NO:
31, a VL CDR2 of SEQ ID NO:
32, and a VL CDR3 of SEQ ID NO:
33, wherein the CDR is defined in accordance with the Kabat definition, and a modified heavy chain constant region comprising cysteine at positions 152 and 375, wherein said cysteine positions are numbered according to the EU system;
c. An antibody or antigen binding fragment thereof comprising a heavy chain variable region that comprises a VH CDR1 of SEQ ID NO:41, a VH CDR2 of SEQ ID NO:42, and a VH CDR3 of SEQ ID NO:43, wherein the CDR is defined in accordance with the Kabat definition;
and a light chain variable region that comprises a VL CDR1 of SEQ ID NO:51, a VL CDR2 of SEQ ID NO:52, and a VL CDR3 of SEQ ID NO:53, wherein the CDR is defined in accordance with the Kabat definition, and a modified heavy chain constant region comprising cysteine at positions 152 and 375, wherein said cysteine positions are numbered according to the EU system;
d. An antibody or antigen binding fragment thereof comprising a heavy chain variable region that comprises a VH CDR1 of SEQ ID NO:61, a VH CDR2 of SEQ ID NO:62, and a VH CDR3 of SEQ ID NO:63, wherein the CDR is defined in accordance with the Kabat definition;
and a light chain variable region that comprises a VL CDR1 of SEQ ID NO:71, a VL CDR2 of SEQ ID NO:72, and a VL CDR3 of SEQ ID NO:73, wherein the CDR is defined in accordance with the Kabat definition, and a modified heavy chain constant region comprising cysteine at positions 152 and 375, wherein said cysteine positions are numbered according to the EU system;
e. An antibody or antigen binding fragment thereof comprising a heavy chain variable region that comprises a VH CDR1 of SEQ ID NO:81, a VH CDR2 of SEQ ID NO:82, and a VH CDR3 of SEQ ID NO:83, wherein the CDR is defined in accordance with the Kabat definition;
and a light chain variable region that comprises a VL CDR1 of SEQ ID NO:91, a VL CDR2 of SEQ ID NO:92, and a VL CDR3 of SEQ ID NO:93, wherein the CDR is defined in accordance with the Kabat definition, and a modified heavy chain constant region comprising cysteine at positions 152 and 375, wherein said cysteine positions are numbered according to the EU system;
f. An antibody or antigen binding fragment thereof comprising a heavy chain variable region that comprises a VH CDR1 of SEQ ID NO:101, a VH CDR2 of SEQ ID NO:102, and a VH CDR3 of SEQ ID NO:103, wherein the CDR is defined in accordance with the Kabat definition;
and a light chain variable region that comprises a VL CDR1 of SEQ ID NO:111, a VL CDR2 of SEQ ID NO:112, and a VL CDR3 of SEQ ID NO:113, wherein the CDR is defined in accordance with the Kabat definition, and a modified heavy chain constant region comprising cysteine at positions 152 and 375, wherein said cysteine positions are numbered according to the EU system;
g. An antibody or antigen binding fragment thereof comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:7, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:17, and a modified heavy chain constant region comprising cysteine at positions 152 and 375, wherein said cysteine positions are numbered according to the EU system;
h. An antibody or antigen binding fragment thereof comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:27, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:37, and a modified heavy chain constant region comprising cysteine at positions 152 and 375, wherein said cysteine positions are numbered according to the EU system;
i. An antibody or antigen binding fragment thereof comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:47, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:57, and a modified heavy chain constant region comprising cysteine at positions 152 and 375, wherein said cysteine positions are numbered according to the EU system;
j. An antibody or antigen binding fragment thereof comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:67, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:77, and a modified heavy chain constant region comprising cysteine at positions 152 and 375, wherein said cysteine positions are numbered according to the EU system;
k. An antibody or antigen binding fragment thereof comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:87, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:97, and a modified heavy chain constant region comprising cysteine at positions 152 and 375, wherein said cysteine positions are numbered according to the EU system;
l. An antibody or antigen binding fragment thereof comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:107, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:117, and a modified heavy chain constant region comprising cysteine at positions 152 and 375, wherein said cysteine positions are numbered according to the EU system;
m. An antibody or antigen binding fragment thereof comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:130, and a light chain comprising the amino acid sequence of SEQ ID NO:19;
n. An antibody or antigen binding fragment thereof comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:133, and a light chain comprising the amino acid sequence of SEQ ID NO:39;
o. An antibody or antigen binding fragment thereof comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:136, and a light chain comprising the amino acid sequence of SEQ ID NO:59;
p. An antibody or antigen binding fragment thereof comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:139, and a light chain comprising the amino acid sequence of SEQ ID NO:79;
q. An antibody or antigen binding fragment thereof comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:142, and a light chain comprising the amino acid sequence of SEQ ID NO:99;
r. An antibody or antigen binding fragment thereof comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:145, and a light chain comprising the amino acid sequence of SEQ ID NO:119;
s. An antibody or antigen binding fragment thereof comprising a heavy chain variable region that comprises a VH CDR1 of SEQ ID NO:
1, a VH CDR2 of SEQ ID NO:
2, and a VH CDR3 of SEQ ID NO:
3, wherein the CDR is defined in accordance with the Kabat definition;
and a light chain variable region that comprises a VL CDR1 of SEQ ID NO:
11, a VL CDR2 of SEQ ID NO:
12, and a VL CDR3 of SEQ ID NO:
13, wherein the CDR is defined in accordance with the Kabat definition, and a modified heavy chain constant region comprising cysteine at position 360, and a modified light chain constant region comprising cysteine at position 107, wherein said cysteine positions are numbered according to the EU system;
t. An antibody or antigen binding fragment thereof comprising a heavy chain variable region that comprises a VH CDR1 of SEQ ID NO:
21, a VH CDR2 of SEQ ID NO:
22, and a VH CDR3 of SEQ ID NO:
23, wherein the CDR is defined in accordance with the Kabat definition;
and a light chain variable region that comprises a VL CDR1 of SEQ ID NO:
31, a VL CDR2 of SEQ ID NO:
32, and a VL CDR3 of SEQ ID NO:
33, wherein the CDR is defined in accordance with the Kabat definition, and a modified heavy chain constant region comprising cysteine at position 360, and a modified light chain constant region comprising cysteine at position 107, wherein said cysteine positions are numbered according to the EU system;
u. An antibody or antigen binding fragment thereof comprising a heavy chain variable region that comprises a VH CDR1 of SEQ ID NO:41, a VH CDR2 of SEQ ID NO:42, and a VH CDR3 of SEQ ID NO:43, wherein the CDR is defined in accordance with the Kabat definition;
and a light chain variable region that comprises a VL CDR1 of SEQ ID NO:51, a VL CDR2 of SEQ ID NO:52, and a VL CDR3 of SEQ ID NO:53, wherein the CDR is defined in accordance with the Kabat definition, and a modified heavy chain constant region comprising cysteine at position 360, and a modified light chain constant region comprising cysteine at position 107, wherein said cysteine positions are numbered according to the EU system;
v. An antibody or antigen binding fragment thereof comprising a heavy chain variable region that comprises a VH CDR1 of SEQ ID NO:61, a VH CDR2 of SEQ ID NO:62, and a VH CDR3 of SEQ ID NO:63, wherein the CDR is defined in accordance with the Kabat definition;
and a light chain variable region that comprises a VL CDR1 of SEQ ID NO:71, a VL CDR2 of SEQ ID NO:72, and a VL CDR3 of SEQ ID NO:73, wherein the CDR is defined in accordance with the Kabat definition, and a modified heavy chain constant region comprising cysteine at position 360, and a modified light chain constant region comprising cysteine at position 107, wherein said cysteine positions are numbered according to the EU system;
w. An antibody or antigen binding fragment thereof comprising a heavy chain variable region that comprises a VH CDR1 of SEQ ID NO:81, a VH CDR2 of SEQ ID NO:82, and a VH CDR3 of SEQ ID NO:83, wherein the CDR is defined in accordance with the Kabat definition;
and a light chain variable region that comprises a VL CDR1 of SEQ ID NO:91, a VL CDR2 of SEQ ID NO:92, and a VL CDR3 of SEQ ID NO:93, wherein the CDR is defined in accordance with the Kabat definition, and a modified heavy chain constant region comprising cysteine at position 360, and a modified light chain constant region comprising cysteine at position 107, wherein said cysteine positions are numbered according to the EU system;
x. An antibody or antigen binding fragment thereof comprising a heavy chain variable region that comprises a VH CDR1 of SEQ ID NO:101, a VH CDR2 of SEQ ID NO:102, and a VH CDR3 of SEQ ID NO:103, wherein the CDR is defined in accordance with the Kabat definition;
and a light chain variable region that comprises a VL CDR1 of SEQ ID NO:111, a VL CDR2 of SEQ ID NO:112, and a VL CDR3 of SEQ ID NO:113, wherein the CDR is defined in accordance with the Kabat definition, and a modified heavy chain constant region comprising cysteine at position 360, and a modified light chain constant region comprising cysteine at position 107, wherein said cysteine positions are numbered according to the EU system;
y. An antibody or antigen binding fragment thereof comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:7, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:17, and a modified heavy chain constant region comprising cysteine at position 360, and a modified light chain constant region comprising cysteine at position 107, wherein said cysteine positions are numbered according to the EU system;
z. An antibody or antigen binding fragment thereof comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:27, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:37, and a modified heavy chain constant region comprising cysteine at position 360, and a modified light chain constant region comprising cysteine at position 107, wherein said cysteine positions are numbered according to the EU system;
aa. An antibody or antigen binding fragment thereof comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:47, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:57, and a modified heavy chain constant region comprising cysteine at position 360, and a modified light chain constant region comprising cysteine at position 107, wherein said cysteine positions are numbered according to the EU system;
bb. An antibody or antigen binding fragment thereof comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:67, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:77, and a modified heavy chain constant region comprising cysteine at position 360, and a modified light chain constant region comprising cysteine at position 107, wherein said cysteine positions are numbered according to the EU system;
cc. An antibody or antigen binding fragment thereof comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:87, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:97, and a modified heavy chain constant region comprising cysteine at position 360, and a modified light chain constant region comprising cysteine at position 107, wherein said cysteine positions are numbered according to the EU system;
dd. An antibody or antigen binding fragment thereof comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:107, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:117and a modified heavy chain constant region comprising cysteine at position 360, and a modified light chain constant region comprising cysteine at position 107, wherein said cysteine positions are numbered according to the EU system;
ee. An antibody or antigen binding fragment thereof comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:131, and a light chain comprising the amino acid sequence of SEQ ID NO:132;
ff. An antibody or antigen binding fragment thereof comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:134, and a light chain comprising the amino acid sequence of SEQ ID NO:135;
gg. An antibody or antigen binding fragment thereof comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:137, and a light chain comprising the amino acid sequence of SEQ ID NO:138;
hh. An antibody or antigen binding fragment thereof comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:140, and a light chain comprising the amino acid sequence of SEQ ID NO:141;
ii. An antibody or antigen binding fragment thereof comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:143, and a light chain comprising the amino acid sequence of SEQ ID NO:144;
or
jj. An antibody or antigen binding fragment thereof comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:146, and a light chain comprising the amino acid sequence of SEQ ID NO:147.

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Antibody drug conjugates

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Antibody drug conjugates

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Abstract

Claims48