Method of decreasing cytotoxic side-effects and improving efficacy of immunoconjugates

• US 9,011,864 B2
• Filed: 12/23/2008
• Issued: 04/21/2015
• Est. Priority Date: 12/26/2007
• Status: Active Grant

• Current Assignee: Biotest AG (OGEL GmbH)
• Original Assignee: ImmunoGen Incorporated, Biotest AG (OGEL GmbH)
• Inventors: Schulz, Gregor, Bruecher, Christoph, Osterroth, Frank, Zeng, Steffen, Uherek, Christoph, Aigner, Silke, Daelken, Benjamin, Ruehle, Markus, Kraus, Elmar
• Primary Examiner(s): Sang, Hong
• Application Number:
  US12/342,180
• Publication Number:
  US 20090181038A1
• Time in Patent Office: 2,310 Days
• Field of Search: None
• US Class Current: 424/178.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• 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: A61K 47/6891 Pre-targeting systems involving an antibody for targeting specific cells
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues

Abstract

Disclosed are methods, compositions and kits for improving targeting, in particular tumor targeting, of immunoconjugates. The method and composition relies on the sequestration of non-target cells that also express the antigen the immunoconjugate targets. Sequestration of those non-target cells in a variety of ways is disclosed. The methods, compositions and kits allow appropriate sequestration of non-target cells while maintaining a high degree of effectiveness of the immunoconjugates against target cells.

Claims

1. A method for improving tumor targeting, of immunoconjugates targeting cell bound CD138 antigen expressed on target cells comprising:

(a) administering to a patient in need thereof an unconjugated antibody, wherein said unconjugated antibody binds to a linear epitope between residues 90-95 of the core protein on human CD138 wherein CD138 is, in the blood of said patient, cell bound on target cells and non-target cells and is also present in soluble form (soluble antigen) and wherein said target cells are cancer cells and;

(b) sequestering in said patient cell bound CD138 antigen on target and non-target cell, optionally soluble antigen, and optionally CD138 antigen expressing cells, wherein the cell bound CD138 antigen and soluble CD138 antigen are different configurations of the same CD138 antigen,

(c) administering an immunoconjugate targeting said cell bound CD138 antigen expressed on target cells comprising a targeting antibody for said cell bound CD138 antigen that is functionally attached to an effector molecule, wherein said sequestering in (b) improves tumor targeting of said immunoconjugate.

2. The method of claim 1, wherein the unconjugated antibody sequesters said cell bound CD138 antigen, soluble antigen and/or said antigen expressing cells.

3. The method of claim 1, wherein the cell bound CD138 antigen is internalized upon binding to the immunoconjugate and/or is subject to shedding.

4. The method of claim 1, wherein said non-target cells comprise not readily regenerating cells.

5. The method of claim 2, wherein a relative sequestration of CD138 expressing non-target cells to CD138 expressing target cells is higher than 5 or higher than 10.

6. The method of claim 2, wherein a ratio of the unconjugated antibody to the immunoconjugate provided is about 10:

1 to about 1;

2.

7. The method of claim 2, wherein a vasodilatory agent is provided prior to or concomitant with the unconjugated antibody.

8. The method of claim 1, wherein said immunoconjugate targeting cell bound CD138 is administered concurrently with or subsequent to said unconjugated CD138 antibody.

9. The method of claim 8, wherein said sequestering in (b) and administering in (c) is separated by a time interval.

10. The method of claim 9, wherein the time interval is at least 20 minutes.

11. The method of claim 1, wherein said targeting antibody in (c) is antibody B-B4.

12. The method of claim 1, wherein said unconjugated antibody is nBT062.

13. The method of claim 4, wherein the not readily regenerating cells are epithelial cells, brain, heart, kidney or liver cells.

14. The method of claim 7, wherein the vasodilatory agent is prazosin, terazosin or doxazosin.

15. The method of claim 1, wherein said targeting antibody comprises HCDR1, HCDR2 and HCDR3 and LCDR1, LCDR2 and LCDR3 of the B-B4 antibody.

16. The method of claim 1, wherein said non-target cells are epithelial cells or liver cells.

17. The method of claim 5, wherein the relative sequestration of CD138 expressing non-target cells to CD138 expressing target cells obtained is higher than 20or higher than 30.

18. The method of claim 6, wherein the ratio of the unconjugated antibody to the immunoconjugate provided is about 5:

1 to 2;

1.