Novel anti adam17 antibody and its use for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-2016326257-A1
Application number	US-201415107848-A
Country	US
Kind code	A1
Filing date	Dec 24, 2014
Priority date	Dec 24, 2013
Publication date	Nov 10, 2016
Grant date	—

Abstract

The present invention relates to a novel antibody capable of binding to ADAM17 and also the amino and nucleic acid sequences coding for said antibody. From one aspect, the invention relates to a novel antibody, or antigen-binding fragments, capable of binding to ADAM17 with anti-tumour activities. The invention also comprises the use of said antibody as a drug for the treatment of cancer. Finally, the invention comprises compositions comprising said antibody, alone or in combination or conjugation with other anti-cancer compounds, and the use of same for the treatment of cancer.

First claim

1 . A monoclonal antibody, or an antigen-binding fragment thereof, that binds to an ADAM17 epitope and that inhibits the shedding of at least one substrate of ADAM17, characterized in that said ADAM17 epitope consists of an epitope comprised within the membrane proximal domain (MPD) of sequence SEQ ID No. 32.

2 . The antibody according to claim 1 , characterized in that it inhibits the shedding of at least one substrate of ADAM17 with an IC 50 of 500 pM or less, preferentially 200 pM or less and more preferentially 100 pM or less.

3 . The antibody of claim 1 or 2 , characterized in that said at least one substrate of ADAM17 is selected from TNF-α, TGF-α, AREG and HB-EGF.

4 . The antibody according to one of claims 1 to 3 , characterized in that it binds to an ADAM17 epitope with a Kd of about 10 nM or less, preferentially of about 5 nM or less, as determined by surface plasmon resonance (SPR).

5 . A monoclonal antibody, or an antigen-binding fragment thereof, that binds to an ADAM17 epitope, characterized in that it comprises:
i) a heavy chain comprising CDR-H1, CDR-H2 and CDR-H3 of amino acid sequences SEQ ID Nos. 1, 2 and 3, respectively; and ii) a light chain comprising CDR-L1, CDR-L2 and CDR-L3 of amino acid sequences SEQ ID Nos. 4, 5 and 6, respectively.

6 . The antibody according to claim 5 , characterized in that the CDR-H1 is of amino acid sequence SEQ ID Nos. 7.

7 . The antibody according to claim 5 , characterized in that the CDR-H1 is of amino acid sequences SEQ ID Nos. 8.

8 . The antibody according to claim 5 , characterized in that it comprises a heavy chain variable domain of sequence comprising the amino acid sequence SEQ ID No. 9, 11 or 12.

9 . The antibody according to claim 5 , characterized in that it comprises a light chain variable domain of sequence comprising the amino acid sequence SEQ ID No. 10.

10 . The antibody according to claim 5 , characterized in that it comprises a heavy chain variable domain of sequence comprising the amino acid sequence SEQ ID No. 9, 11 or 12; and a light chain variable domain of sequence comprising the amino acid sequence SEQ ID No. 10.

11 . A monoclonal antibody, or an antigen-binding fragment thereof, characterized in that it consists of the monoclonal antibody 1022C3 obtained from the hybridoma 1-4686 deposited at the CNCM, Institut Pasteur, France, on the 18 Oct. 2012.

12 . The antibody according to one of claims 5 to 11 characterized in that it is capable of binding to a single epitope of ADAM17 comprised within the membrane proximal domain (MPD) of sequence SEQ ID No. 32.

13 . The antibody according to claim 12 , characterized in that it inhibits the shedding of at least one substrate of ADAM17 with an IC 50 of 500 pM or less, preferentially 200 pM or less and more preferentially 100 pM or less.

14 . The antibody of claim 13 , characterized in that said at least one substrate of ADAM17 is selected from TNF-α, TGF-α, AREG and HB-EGF.

15 . The antibody according to claim 12 , characterized in that it binds to an ADAM17 epitope with a Kd of about 10 nM or less, preferentially of about 5 nM or less, as determined by surface plasmon resonance (SPR).

16 . The antibody according to one of claims 1 to 15 for use in a method of inhibiting the growth and/or the proliferation of tumour cells.

17 . The antibody according to claim 16 , characterized in that said tumour cells are selected from tumour cells expressing ADAM17.

18 . The murine hybridoma 1-4686 deposited at the CNCM, Institut Pasteur, France, on the 18 Oct. 2012.

19 . An isolated nucleic acid, characterized in that it is chosen from the following nucleic acids:
a) a DNA or RNA, coding for an antibody, or an antigen-binding fragment thereof, according to one of claims 1 to 15 ; and b) a DNA comprising at least one of the sequence selected from the group consisting of the sequences SEQ ID No. 13-28 and 36 to 38.

20 . A vector comprising a nucleic acid according to claim 19 .

21 . A host cell comprising a vector according to claim 20 .

22 . A transgenic animal with the exception of human comprising at least one cell transformed by a vector according to claim 20 .

23 . A process for production of an antibody, or an antigen-binding fragment thereof, according to one of claims 1 to 15 , characterized in that it comprises the following stages:
a) the culture in a medium and appropriate culture conditions of a cell according to claim 21 ; and
b) the recovery of said antibody, or antigen-binding fragment thereof, thus produced starting from the culture medium or said cultured cells.

24 . A composition comprising the antibody according to one of claims 1 to 15 .

25 . The composition according to claim 24 , characterized in that it further comprises, as a combination product, a cytotoxic agent.

26 . The composition according to claim 24 , characterized in that it further comprises, as a conjugation product, a cytotoxic agent.

27 . The composition according to one of claims 24 to 26 , characterized in that the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable vehicle.

28 . The composition according to one of claims 24 to 27 for use in a method of inhibiting the growth and/or the proliferation of tumour cells.

29 . The use of an antibody according to one of claims 1 to 15 , or obtained by the process of claim 23 , or of a composition according to one of claims 24 to 27 for the treatment of cancer.

30 . The use according to claim 29 , characterized in that said cancer is a cancer chosen from cancers expressing ADAM17.

31 . The use according to claim 29 or 30 , characterized in that said cancer is a cancer chosen from ovarian cancer, breast cancer, kidney cancer, liver cancer, pancreatic cancer, lung cancer, head and neck cancer and epidermoid carcinoma.

Assignees

• Pf Medicament

Inventors

• Lowe Peter

Classifications

• C07K16/40

  against enzymes · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title

• C07K2317/56

  variable (Fv) region, i.e. VH and/or VL · CPC title