SPECIFIC ANTIBODY-DRUG-CONJUGATES (ADCS) WITH KSP INHIBITORS AND ANTI-CD123-ANTIBODIES

• US 20190330357A1
• Filed: 06/08/2017
• Published: 10/31/2019
• Est. Priority Date: 06/15/2016
• Status: Active Grant

• Current Assignee: Bayer Pharma AG (Bayer AG)
• Original Assignee: Bayer Pharma AG (Bayer AG)
• Inventors: LERCHEN, Hans-Georg, REBSTOCK, Anne-Sophie, CANCHO GRANDE, Yolanda, WITTROCK, Sven, STELTE-LUDWIG, Beatrix, KIRCHHOFF, Dennis, MAHLERT, Christoph, GREVEN, Simone, MARSCH, Stephan
• Granted Patent: US 11,001,636 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6851 the antibody targeting a determinant of a tumour cell
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/2866 against receptors for cytokines, lymphokines, interferons
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/77 Internalization into the cell

Abstract

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.

Claims

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)

2. :

The conjugate according to claim 1, wherein

X is —

CH₂—

;

L is (—

CH₂—

CH₂—

O—

)_m—

CH₂—

CH₂—

;

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;

122, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO;

123, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO;

124, and

a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO;

126, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO;

127, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO;

128;

or

a variable heavy chain comprising the variable CDR1 sequence of the heavy chain, as shown in SEQ ID NO;

202, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO;

203, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO;

204, and

a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO;

206, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO;

207, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO;

208;

or

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,

or a salt, a solvate, a salt of a solvate, or an epimer thereof.

3. :

The conjugate according to claim 1, wherein

X is —

CH₂—

;

L is (—

CH₂—

CH₂—

O—

)_m—

CH₂—

CH₂—

;

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;

122, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO;

123, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO;

124, and

a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO;

126, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO;

127, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO;

128;

or

a variable heavy chain comprising the variable CDR1 sequence of the heavy chain, as shown in SEQ ID NO;

202, the variable CDR2 sequence of the heavy chain, as shown in SEQ ID NO;

203, and the variable CDR3 sequence of the heavy chain, as shown in SEQ ID NO;

204, and

a variable light chain comprising the variable CDR1 sequence of the light chain, as shown in SEQ ID NO;

206, the variable CDR2 sequence of the light chain, as shown in SEQ ID NO;

207, and the variable CDR3 sequence of the light chain, as shown in SEQ ID NO;

208;

or

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,

or a salt, a solvate, a salt of a solvate, or an epimer thereof.

4. :

The conjugate according to claim 1, wherein the conjugate has the structure;

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;

121, and a variable sequence of the light chain, as shown in SEQ ID NO;

125;

or

a variable sequence of the heavy chain, as shown in SEQ ID NO;

201, and a variable sequence of the light chain, as shown in SEQ ID NO;

205;

or

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;

129, and a sequence of the light chain, as shown in SEQ ID NO;

13;

or

a sequence of the heavy chain, as shown in SEQ ID NO;

209, and a sequence of the light chain, as shown in SEQ ID NO;

210;

or

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 or prophylaxis of diseases, comprising administering to a patient in need thereof a conjugate according to claim 1.

11. :

A method for treatment of hyperproliferative or angiogenic disorders, comprising administering to a patient in need thereof an effective amount of a conjugate according to claim 1.

12. :

A method for treatment or prophylaxis of hyperproliferative or angiogenic disorders in humans and animals in need thereof, comprising administering an effective amount of at least one conjugate according to claim 1.

13. :

A method for treatment of hyperproliferative or angiogenic disorders, comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition according to claim 9.