Microtubule-modifying compound

Patent metadata

Field	Value
Publication number	US-9695239-B2
Application number	US-201314436568-A
Country	US
Kind code	B2
Filing date	Oct 24, 2013
Priority date	Oct 24, 2012
Publication date	Jul 4, 2017
Grant date	Jul 4, 2017

Abstract

A compound formed from at least one component A comprising a binding domain for extra-cellular surface structures of a diseased proliferating cell that internalized upon binding of component A of said compound, and at least one component B, characterized in that component B is a polypeptide which amino acid sequence comprises a microtubule-associated protein (MAP) or comprises at least a partial sequence of the MAP, the partial sequence having maintained the binding function of the MAP to a microtubule.

First claim

The invention claimed is:

1. A compound formed from at least one component A comprising a binding domain for extra-cellular surface structures of a diseased proliferating cell that is internalized upon binding of component A of said compound, wherein said extra-cellular surface structures are selected from the group consisting of CD64, EGFR, AchR, EpCAM, and CD30, and at least one component B, characterized in that component B is a polypeptide whose amino acid sequence comprises a microtubule-associated protein (MAP).

2. The compound according to claim 1 , wherein component A is selected from the group of internalizing cell surface receptor binding structures consisting of antibodies or fragments thereof which retain antigen binding function and specificity of a parent antibody.

3. The compound according to claim 1 , wherein component A has higher valency by comprising one or more binding structures selected from any one of those listed in claim 2 .

4. The compound according to claim 1 , wherein component B is selected from the group consisting of microtubule-associated proteins (MAPs), Kinesins, KIFC1-3, Dyneins, DNAI1 and 2, DNAL1 and 4, Tau protein, Dynactin DCTN1, Tubulins, Stathmin, Gephyrin, Tektins, and Dynamins.

5. The compound according to claim 1 formed by component A and KIF1, component A and KIF2A, component A and KIF4A, component A and KIF5A, component A and KIF5B, component A and KIF6, component A and KIF7, component A and KIF9, component A and KIF10, component A and KIF11, component A and KIF12, component A and KIF13B, component A and KIF14, component A and KIF15, component A and KIF17, component A and KIF19, component A and KIF22, component A and KIF23, component A and KIF24, component A and KIF25, component A and KIF26, component A and KIF27, component A and KIFC1, component A and KIFC2, component A and KIFC3, component A and DNAH1, component A and DNAH2, component A and DNAH3, component A and DNAH5, component A and DNAH6, component A and DNAH7, component A and DNAH8, component A and DNAH9, component A and DNAH10, component A and DNAH11, component A and DNAH12, component A and DNAH14, component A and DNAI1, component A and DNAI2, component A and DNAL1, component A and DNAL4, component A and Tau, component A and Stathmin, component A and Gephyrin, component A and MAP1a, component A and MAP1b, component A and MAP2, component A and MAP4, component A and XMAP5, component A and MAP6, component A and MAP7, component A and MAP5, component A and MAP5, component A and DCTN1, component A and TUBA1, component A and TUBA2, component A and TUBA3, component A and TUBA4, component A and TUBA6, component A and TUBA8, component A and TEKT1, component A and TEKT2, component A and TEKT3, component A and TEKT4, component A and TEKT5, component A and DNM1, component A and DNM2, or component A and DNM3.

6. The compound according to claim 1 , wherein the components are chemically coupled or fused to each other by genetic engineering.

7. A compound formed from at least one component A comprising a binding domain for extra-cellular surface structures of a diseased proliferating cell that is internalized upon binding of component A of said compound, wherein said extra-cellular surface structures are selected from the group consisting of CD64, EGFR, AchR, EpCAM, and CD30, and at least one component B, characterized in that component B is a polypeptide whose amino acid sequence comprises a microtubule-associated protein (MAP) or comprises at least a partial sequence of the MAP, the partial sequence having maintained the binding function of the MAP to a microtubule;
wherein the compound is encoded by a polynucleotide having the nucleotide sequences of SEQ ID NO: 3, 11 and/or 13.

8. A polynucleotide encoding the compound of claim 1 , having the SEQ ID NO: 3, 11 and/or 13.

9. A process for manufacturing the fused compound of claim 6 comprising
cloning a component B to yield a polynucleotide;
fusing said polynucleotide coding for component B with a polynucleotide coding for a protein of component A to yield a polynucleotide coding for the compound of claim 1 ;
expressing said polynucleotide coding for the compound of claim 1 in suitable host; and
isolating and purifying the compound of claim 1 .

10. A vector comprising at least one polynucleotide of claim 8 .

11. A cell comprising the vector of claim 10 .

12. A medicament comprising a compound of claim 1 .

13. A method for treating a cancer or a proliferating disease, wherein a cell of the cancer or the proliferating disease expresses a receptor selected from the group consisting of CD64, EGFR, AchR, EpCam and CD30, said method comprising administering to a subject having the cancer or proliferating disease an effective amount of a compound of claim 1 .

14. The compound according to claim 2 , wherein
the antibody fragment is a scFv.

15. The compound according to claim 4 , wherein
a. the MAP has one of SEQ ID NOs: 57-65;
b. the kinesin is KIF1-27 having SEQ ID NO: 14 or SEQ ID NO: 35;
c. the KIFC1-3 has one of SEQ ID NOs: 36-38;
d. the dynein is DNAH1-14 having one of SEQ ID NOs: 39-50;
e. the DNAI1 and 2 have SEQ ID NOs: 51 or 52, respectively;
f. the DNAL1 and 4 have SEQ ID NOs: 53 or 54, respectively;
g. the Tau protein is a Tau protein having deleted phosphorylation sites, wherein said Tau protein is encoded by SEQ ID NO: 1;
h. the Dynactin is DCTN1 having SEQ ID NO: 66;
i. the Tubulin is TUBA1-8 having one of SEQ ID NOs: 67-72;
j. the Stathmin has SEQ ID NO: 55;
k. the Gephyrin has SEQ ID NO: 56;
l. the Tektin is TEKT1-5 having one of SEQ ID NOs: 73-77; and
m. the Dynamin is DNM1-3 having one of SEQ ID NOs: 78-80.

16. The compound according to claim 1 , wherein component A is an H22(scFv) encoded by a polynucleotide having the SEQ ID NO: 2.

Assignees

• Fraunhofer Ges Forschung

Inventors

• Barth Stefan
• Thepen Theopilus
• Hristodorov Dmitrij
• Mladenov Radoslav

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07K14/47

  from mammals · CPC title

• C07K2319/21

  containing a His-tag · CPC title

• C07K16/2878

  against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 · CPC title

• C07K14/54

  Interleukins [IL] · CPC title