Anti-podocalyxin antibodies and methods of using the same

Patent metadata

Field	Value
Publication number	US-2016264663-A1
Application number	US-201415031244-A
Country	US
Kind code	A1
Filing date	Oct 21, 2014
Priority date	Oct 21, 2013
Publication date	Sep 15, 2016
Grant date	—

Abstract

The present invention is directed to compositions of matter useful for the treatment of cancer in mammals and to methods of using those compositions of matter for the same. Antibodies specific for podocalyxin designated Ab1 and 3G2 are disclosed, as is the use of said antibodies for the inhibition of growth of a tumor that expresses podocalyxin, and the use of said antibodies for targeting tumour endothelial cells that express podocalyxin.

First claim

What is claimed is:

1 . An anti-podocalyxin antibody comprising at least one HVR sequence selected from the group:
(i) HVR-L1 comprising QASQSISNYLA (SEQ ID NO: 9) or QSISNY (SEQ ID NO: 17); (ii) HVR-L2 comprising RASTLAS (SEQ ID NO: 10) or RAS (SEQ ID NO:18); (iii) HVR-L3 comprising QQGYVSNNLDNIFGGGTEVVVK (SEQ ID NO: 11); (iv) HVR-H1 comprising SYAMG (SEQ ID NO: 6), GIDLSSYAMG (SEQ ID NO:12), or GIDLSSYA (SEQ ID NO: 13); (v) HVR-H2 comprising FIYASGSIFYASWAKG (SEQ ID NO: 7), FIYASGSI (SEQ ID NO: 14), or IYASGSI (SEQ ID NO: 15); and (vi) HVR-H3 comprising AGYYFGGNYDLNLWGQGTLVTVSS (SEQ ID NO: 8) or ARAGYYFGGNYDLNL (SEQ ID NO: 16).

2 . An anti-podocalyxin antibody comprising at least one HVR sequence selected from the group:
(i) HVR-L1 comprising SANSNVRYIH (SEQ ID NO: 27) or SNVRY (SEQ ID NO: 28); (ii) HVR-L2 comprising DTSKLSS (SEQ ID NO: 29) or DTS (SEQ ID NO: 30); (iii) HVR-L3 comprising QQWISNPLT (SEQ ID NO: 31); (iv) HVR-H1 comprising SYVMH (SEQ ID NO: 19), GYTFTSYVMN (SEQ ID NO: 20), or GYTFTSYV (SEQ ID NO: 21); (v) HVR-H2 comprising YIHPYNDGTNYNEKFKG (SEQ ID NO: 22), YIHPYNDGT (SEQ ID NO: 23), or IHPYNDGT (SEQ ID NO: 24); AND (vi) HVR-H3 comprising SWDWYFDV (SEQ ID NO: 25) or ARSWDWYFDV (SEQ ID NO: 26).

3 . The antibody of claim 1 or 2 , wherein the antibody is a chimeric, humanized, or human antibody.

4 . The antibody of claim 1 or 2 , wherein at least a portion of the framework sequence is a human consensus framework sequence.

5 . The antibody of claim 1 or 2 , wherein the antibody is a monoclonal antibody.

6 . The antibody of claim 5 , wherein the antibody is humanized.

7 . The antibody of claim 5 , which is an antibody fragment.

8 . The antibody of claim 7 , wherein the antibody fragment is selected from a Fab, Fab′-SH, Fv, scFv or (Fab′) 2 fragment.

9 . The antibody of any one of claims 1 - 6 , where the antibody comprises an Fc region.

10 . An anti-podocalyxin antibody, wherein the antibody
(i) binds substantially to the same epitope as an anti-podocalyxin antibody comprising a heavy chain variable domain selected from the group SEQ ID NO: 3, SEQ ID NO: 39, SEQ ID NO: 35, and SEQ ID NO: 37, and a light chain variable domain selected from the group SEQ ID NO:5, SEQ ID NO: 41, and SEQ ID NO: 33; and/or (ii) competes for binding to the same epitope as an anti-podocalyxin antibody comprising a heavy chain variable domain selected from the group SEQ ID NO: 3, SEQ ID NO: 39, SEQ ID NO: 35, and SEQ ID NO: 37, and a light chain variable domain selected from the group SEQ ID NO:5, SEQ ID NO: 41, and SEQ ID NO: 33.

11 . An anti-podocalyxin antibody made by the process of:
(a) culturing a cell expressing an antibody selected from the group (i) an antibody comprising a heavy chain variable domain of SEQ ID NO: 3 and a light chain variable domain of SEQ ID NO: 5; (ii) an antibody comprising a heavy chain variable domain of SEQ ID NO: 39 and a light chain variable domain of SEQ ID NO: 41; (iii) an antibody comprising a heavy chain variable domain of SEQ ID NO: 35 and a light chain variable domain of SEQ ID NO: 33; and (iv) an antibody comprising a heavy chain variable domain of SEQ ID NO: 37 and a light chain variable domain of SEQ ID NO: 33; and (b) isolating the antibody from said cultured cell.

12 . An antibody that binds to podocalyxin, wherein the antibody comprises a heavy chain variable domain having a least 90% sequence identity to the amino acid sequence selected from the group SEQ ID NO: 3, SEQ ID NO: 39, SEQ ID NO: 35, and SEQ ID NO: 37, and a light chain variable domain having at least 90% sequence identity to the amino acid sequence selected from the group SEQ ID NO: 5, SEQ ID NO: 41, and SEQ ID NO: 33.

13 . An anti-podocalyxin antibody selected from:
(i) an antibody comprising a heavy chain variable domain comprising SEQ ID NO: 3 and/or a light chain variable domain comprising SEQ ID NO: 5; (ii) an antibody comprising a heavy chain variable domain comprising SEQ ID NO:39 and/or a light chain variable domain comprising SEQ ID NO: 41; (iii) an antibody comprising a heavy chain variable domain comprising SEQ ID NO: 35 and/or a light chain variable domain comprising SEQ ID NO: 33; and (iv) an antibody comprising a heavy chain variable domain comprising SEQ ID NO: 37 and/or a light chain variable domain comprising SEQ ID NO: 33.

14 . An anti-podocalyxin antibody selected from:
(i) an antibody comprising a heavy chain variable region amino acid sequence depicted in FIG. 10F and/or a light chain variable region amino acid sequence depicted in FIG. 10B ; (ii) an antibody comprising a heavy chain variable region amino acid sequence depicted in FIG. 10H or J and/or a light chain variable region amino acid sequence depicted in FIG. 10D ; (iii) an antibody comprising a heavy chain variable region amino acid sequence depicted in FIG. 11B and/or a light chain variable region amino acid sequence depicted in FIG. 11D ; (iv) an antibody comprising a heavy chain variable region amino acid sequence selected from a sequence shown in FIG. 11F or H and/or a light chain variable region amino acid sequence depicted in FIG. 11J ; and (v) an antibody comprising a heavy chain variable region amino acid sequence selected from a sequence shown in FIG. 12A and/or a light chain variable region amino acid sequence depicted in FIG. 12C .

15 . A polynucleotide encoding the heavy chain variable region and/or the light chain variable region of any one of the preceding claims.

16 . The polynucleotide of claim 15 , wherein the polynucleotide is selected from SEQ ID NOs: 2, 4, 32, 34, 36, 38, and 40.

17 . A vector comprising the polynucleotide of claim 16 .

18 . A host cell comprising the vector of claim 17 .

19 . An anti-podocalyxin antibody, which
(i) binds substantially to the same epitope as an anti-podocalyxin antibody according to any one of claims 1 , 2 , 13 or 14 ; and/or (ii) competes for binding to the same epitope as an anti-podocalyxin antibody according to claim 1 , 2 , 13 , or 14 .

20 . A method of inhibiting the growth of a tumor that expresses podocalyxin in vivo, said method comprising administering an antibody of any one of claim 1 - 14 or 19 to a patient having said tumour, thereby causing one or more of (i) inhibition of growth or proliferation of a cell to which said antibody binds; (ii) induction of death of a cell to which said antibody binds; (iii) inhibition of delamination of a cell to which said antibody binds; (iv) inhibition of the metastasis of a cell to which it binds; and (v) inhibition of the vascularization of said tumor.

21 . A pharmaceutical composition comprising an antibody according to any one of claim 1 - 14 or 19 and a pharmaceutically acceptable carrier.

22 . A method of treating a subject having cancer, said method comprising administering to the subject the pharmaceutical composition of claim 21 .

23 . The method of claim 22 , wherein the subject is human.

24 . The method of claim 22 or 23 , wherein the cancer is selected from the group consisting of breast cancer, kidney cancer, ovarian cancer, lung cancer, prostate cancer, liver cancer, pancreatic cancer, colon cancer, bladder cancer, heamtopeietic cancer, and brain cancer.

25 . Use of an antibody according to any one of claims 1 - 14 or 19 in the preparation of a medicament for the treatment of cancer.

26 .

Assignees

• The Centre For Drug Res And Dev
• Univ British Columbia

Inventors

• Babcook John Stephen
• Mcnagny Kelly Marshall
• Roskelley Calvin D
• Hedberg Bradley John
• Snyder Kimberly Ashely
• Hughes Michael R

Classifications

• C07K16/30

  from tumour cells · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07K2317/33

  Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• A61K2039/505

  comprising antibodies · CPC title