Specific antibody-drug-conjugates (ADCs) with KSP inhibitors and anti-CD123-antibodies
The invention relates to specific Antibody-Drug-Conjugates (ADCs) with KSP inhibitors and anti-CD 123-antibodies, to the use of these conjugates for the treatment and/or prophylaxis of diseases and to the use of these conjugates for preparing medicaments for treatment and/or prevention of diseases, in particular hyperproliferative and/or angiogenic disorders such as, for example, cancer diseases. Such treatments can be carried out as monotherapy or else in combination with other medicaments or further therapeutic measures.
1. A conjugate of an antibody or a functional fragment thereof (AK) together with one or more chemical compound(s) as defined in formula (I), or a salt, a solvate, a salt of a solvate, or an epimer of one or more chemical compound(s) as defined in formula (I)
wherein
X is —CH 2 — or —CH 2 —CH 2 —;
L is (—CH 2 —CH 2 —O—) m —CH 2 —CH 2 —;
m is 1 to 20;
n is 1 to 8; and
AK is an anti-CD123 antibody or a functional fragment thereof,
wherein the antibody or the functional fragment thereof is attached via a cysteine residue and wherein said antibody or functional fragment thereof comprises:
a variable heavy chain comprising the variable CDR1 sequence of the heavy chain, as shown in SEQ ID NO: 132, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO: 133, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO: 134, and
a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO: 136, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO: 137, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO: 138; or
a variable heavy chain comprising the variable CDR1 sequence of the heavy chain, as shown in SEQ ID NO: 192, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO: 193, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO: 194, and
a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO: 196, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO: 197, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO: 198.
2. The conjugate according to claim 1 , wherein
X is —CH 2 —;
L is (—CH 2 —CH 2 —O—) m —CH 2 —CH 2 —;
m is 1 to 20;
n is 1 to 8; and
AK is an anti-CD123 antibody or a functional fragment thereof,
wherein the antibody or the functional fragment thereof is attached via a cysteine residue and wherein said antibody or functional fragment thereof comprises:
a variable heavy chain comprising the variable CDR1 sequence of the heavy chain, as shown in SEQ ID NO: 132, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO: 133, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO: 134, and
a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO: 136, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO: 137, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO: 138; or
a variable heavy chain comprising the variable CDR1 sequence of the heavy chain, as shown in SEQ ID NO: 192, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO: 193, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO: 194, and
a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO: 196, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO: 197, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO: 198.
3. The conjugate according to claim 1 , wherein
X is —CH 2 —;
L is (—CH 2 —CH 2 —O—) m —CH 2 —CH 2 —;
m is 2 to 8;
n is 1 to 8; and
AK is an anti-CD123 antibody or a functional fragment thereof,
wherein the antibody or the functional fragment thereof is attached via a cysteine residue and wherein said antibody or functional fragment thereof comprises:
a variable heavy chain comprising the variable CDR1 sequence of the heavy chain, as shown in SEQ ID NO: 132, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO: 133, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO: 134, and
a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO: 136, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO: 137, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO: 138; or
a variable heavy chain comprising the variable CDR1 sequence of the heavy chain, as shown in SEQ ID NO: 192, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO: 193, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO: 194, and
a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO: 196, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO: 197, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO:198.
4. The conjugate according to claim 1 , wherein the conjugate has the structure:
wherein
n is 1 to 8; and
AK is an anti-CD123 antibody or a functional fragment thereof,
wherein the antibody or the functional fragment thereof is attached via a cysteine residue and wherein said antibody or functional fragment thereof comprises:
a variable heavy chain comprising the variable CDR1 sequence of the heavy chain, as shown in SEQ ID NO: 132, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO: 133, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO: 134, and
a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO: 136, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO: 137, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO: 138; or
a variable heavy chain comprising the variable CDR1 sequence of the heavy chain, as shown in SEQ ID NO: 192, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO: 193, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO: 194, and
a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO: 196, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO: 197, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO: 198.
5. The conjugate according to claim 1 , wherein n is 2 to 6.
6. The conjugate according to claim 1 , wherein the anti-CD123 antibody or the functional fragment thereof comprises:
a variable sequence of the heavy chain, as shown in SEQ ID NO:131, and
a variable sequence of the light chain, as shown in SEQ ID NO:135; or
a variable sequence of the heavy chain, as shown in SEQ ID NO:191, and
a variable sequence of the light chain, as shown in SEQ ID NO:195.
7. The conjugate according to claim 1 , wherein the anti-CD123 antibody is an IgG antibody and wherein the functional fragment thereof is an scFv, Fab, Fab′ fragment or a F(ab)2 fragment.
8. The conjugate according to claim 1 , wherein the anti-CD123 antibody comprises:
a sequence of the heavy chain, as shown in SEQ ID NO:139, and a sequence of the light chain, as shown in SEQ ID NO:140; or
a sequence of the heavy chain, as shown in SEQ ID NO:199, and a sequence of the light chain, as shown in SEQ ID NO:200.
9. A pharmaceutical composition comprising a conjugate according to claim 1 in combination with an inert non-toxic pharmaceutically suitable auxiliary.
10. A method for treatment of cancer which expresses CD123, comprising administering to a patient in need thereof an effective amount of a conjugate according to claim 1 .
11. A method for treatment of cancer which expresses CD123 in humans and animals in need thereof, comprising administering an effective amount of at least one conjugate according to claim 1 .
12. A method for treatment of cancer which expresses CD123, comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition according to claim 9 .
13. The method of claim 10 , wherein the cancer is lung cancer or leukemia.
14. The method of claim 11 , wherein the cancer is lung cancer or leukemia.
15. The method of claim 12 , wherein the cancer is lung cancer or leukemia.