Uses of immunoconjugates targeting CD138

Patent metadata

Field	Value
Publication number	US-10117932-B2
Application number	US-201213708014-A
Country	US
Kind code	B2
Filing date	Dec 7, 2012
Priority date	Dec 8, 2011
Publication date	Nov 6, 2018
Grant date	Nov 6, 2018

Abstract

Disclosed is a method and composition for treating a disease associated with target cells expressing CD138 in a multiple dose regimen. An immunoconjugate comprising an engineered targeting antibody targeting CD138 expressing cells and an effector molecule is administered in a multiple dose regimen. The multiple dose regimen comprises at least two doses and the aggregate dose administered within an active treatment cycle is an aggregate maximum tolerable dose (AMTD) or a fraction of the AMTD. The AMTD and/or said fraction exceeds the dose resulting in dose limiting toxicity (DLT) and/or exceeds the maximum tolerable dose (MTD) when the immunoconjugate is administered as a single dose, including as part of a multiple single dose regimen within said active treatment cycle.

First claim

What is claimed is:

1. A method for treating a disease associated with target cells expressing CD138 comprising:
administering to a subject in need thereof an immunoconjugate comprising at least one engineered targeting antibody targeting CD138 expressing cells, and
at least one maytansinoid, wherein said engineered targeting antibody is functionally attached to said maytansinoid to form said immunoconjugate, wherein at least a part of the engineered targeting antibody confers IgG4isotype properties, wherein
the immunoconjugate is administered in intervals of less than 11.1 days within a period of 21 days constituting a multiple dose regimen, wherein the aggregate dose administered within an active treatment cycle is an aggregate maximum tolerable dose (AMTD) or a fraction of the AMTD and wherein said AMTD and/or said fraction exceeds the dose resulting in dose limiting toxicity (DLT) when the immunoconjugate is administered as a single dose, including as part of a multiple single dose regimen and/or exceeds the maximum tolerable dose (MTD) when the immunoconjugate is administered as a single dose, including as part of a multiple single dose regimen within said active treatment cycle, wherein the active treatment cycle includes the administering being performed at least once a week for at least three weeks and the active treatment cycle is followed by a resting period of at least one week, which together define a treatment cycle of at least 28 days, and wherein, after one, two or more treatment cycles, at least stable disease is achieved.

2. The method of claim 1 , wherein the immunoconjugate is administered at least three times within said 21 days.

3. The method of claim 1 , wherein the immunoconjugate is administered in equal doses.

4. The method of claim 1 , wherein said multiple dose regimen lasts at least 3 weeks and is followed by a resting period.

5. The method of claim 4 , wherein progression free survival or stable disease is maintained during the resting period.

6. The method of claim 5 , wherein a level of said immunoconjugate in a body fluid of said subject, during said resting period is at least 0.5 μg/ml, at least 1 μg/ml, at least 2 μg/ml, at least 3 μg/ml, 4 μg/ml, 5 μg/ ml or 6 μg/ml and/or wherein more than 80%, more than 90%, more than 95% of the CD138 of isolated target cells are occupied by said immunoconjugate within four to twenty four hours after completion of administration of the immunoconjugate.

7. The method of claim 1 wherein the AMTD exceeds the dose of said DLT by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 80%, at least 90%, at least 100% or at least 120% and said MTD by at least 30%, at least 40at least 50%, at least 60%, at least 80%, at least 90at least 100%, at least 120% or at least 140%.

8. The method of claim 1 , wherein the AMTD is at least 240 mg/m 2 , 300 mg/m 2 , 360 mg/m 2 , or 420 mg/m 2 and the dose resulting in said DLT is 200 mg/m 2 or the AMTD is at least 240 mg/m 2 , 300 mg/m 2 , 360 mg/m 2 , or 420 mg/m 2 and said MTD is at least 160 mg/m 2 or at least 180 mg/m 2 .

9. The method of claim 1 , wherein at least stable disease is maintained during three, four, five, six, seven treatment cycles.

10. The method of claim 9 , wherein after reaching at least stable disease, the immunoconjugate is administered as a maintenance therapy less than twice within said active treatment cycle as a repeated single dose of between 60 mg/m 2 and 280 mg/m 2 , including about 70 mg/m 2 , about 80 mg/m 2 , about 90 mg/m 2 , about 100 mg/m 2 , about 110 mg/m 2 , about 120 mg/m 2 , about 130 mg/m 2 , about 140 mg/m 2 , 150 mg/m 2 , about 160 mg/m 2 , about 170 mg/m 2 , about 180 mg/m 2 , about 190 mg/m 2 , about 200 mg/m 2 , about 210 mg/m 2 , about 220 mg/m 2 , about 230 mg/m 2 , about 240 mg/m 2 , about 250 mg/m 2 , about 260 mg/m 2 and about 270 mg/m 2 .

11. The method of claim 10 , wherein the disease associated with target cells expressing CD138 is relapsed/refractory myeloma and wherein at least progression free survival, stable disease and or a minor response is obtained for more than 3 months during said maintenance therapy.

12. A method of claim 1 , wherein administration of said immunoconjugate as a repeated multiple dose in said active treatment cycle, results in an aggregate effective amount and a first level of the immunoconjugate in a body fluid of the subject and wherein, an amount equivalent to said aggregate effective amount is administered as a single dose or repeated single dose in said active treatment cycle, results in a second level of the immunoconjugate in a body fluid of said subject, wherein the first level is equal or below the second level.

13. The method of claim 12 , wherein the active treatment cycle lasts 21 days and/or the repeated multiple dose consists of 3 administrations of equal doses.

14. The method of claim 12 , wherein said aggregate effective amount is more than 200 mg/m 2 , about 220 mg/m 2 , about 240 mg/m 2 , about 260 mg/m 2 , or about 280 mg/m 2 .

15. The method of claim 1 , wherein administration of said immunoconjugate as a multiple dose regime results, 0-2 hours after completion of administration in a mean plasma level of at least 7 μg/ml, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60 or 70 μg/ml.

16. The method of claim 1 , further comprising determining 0-2 hours following a completion of administering an individual dose of said immunoconjugate or a pharmaceutical composition comprising the same, a level of said immunoconjugate in a body fluid, determining whether the level of the immunoconjugate is below or above 7 μg/m 2 , 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 μg/m 2 ,
increasing the individual dose in the next treatment cycle by at least 10 mg/m 2 , 20 mg/m 2 , about 30 mg/m 2 , about 40 mg/m 2 , about 50 mg/m 2 , about 60 mg/m 2 , 70 mg/m 2 , about 80 mg/m 2 , about 90 mg/m 2 or about 100 mg/m 2 if the level is below 7 μg/m 2 , 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 μg/m 2 , or
maintaining or decreasing by at least 10 mg/m 2 , 20 mg/m 2 , about 30 mg/m 2 , about 40 mg/m 2 , about 50 mg/m 2 , about 60 mg/m 2 , about 70 mg/m 2 , about 80 mg/m 2 , about 90 mg/m 2 or about 100 mg/m 2 , the individual dose in the next treatment cycle if the level is above 7 μg/m 2 , 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 μg/m 2 .

17. The method of claim 1 , wherein the at least one maytansinoid is N 2′ -(4-methyl-4-mercapto-1-oxopentyl)-maytansine (DM4) or N 2 -deacetyl-N 2 -(3-mercapto-1-oxopropyl)-maytansine (DM1).

18. The method of claim 17 , wherein the at least one maytansinoid is DM4.

19. A method for treating a disease associated with target cells expressing CD138, comprising:
administering to a patient in need thereof a pharmaceutical composition comprising an immunoconjugate and a pharmaceutically acceptable carrier in an active treatment cycle which is optionally followed by a resting period, wherein the immunoconjugate comprises
at least one targeting agent targeting CD138 expressing cells, and at least one maytansinoid, wherein said targeting agent is functionally attached to said effector molecule to form said immunoconjugate, and wherein the dose of the immunoconjugate administered at least once a week is about 20 mg/m 2 , about 30 mg/m 2 , about 40 mg/m 2 , about 50 mg/m 2 , about 60 mg/m 2 , 70 mg/m 2 , about 80 mg/m 2 , about 90 mg/m 2 , about 100 mg/m 2 , about 110 mg/m 2 , about 120 mg/m 2 , about 130 mg/m 2 , about 140 mg/m 2 , about 150 mg/m

Assignees

• Biotest Ag
• Immunogen Inc
• Immunogen Inc

Inventors

• Schulz Gregor
• Osterroth Frank
• Haeder Thomas
• Bruecher Christoph
• Niemann Gabriele
• Engling Andre
• Uherek Christoph
• Daelken Benjamin
• Wartenberg-Demand Andrea
• Zuber Chantal
• Gutscher Marcus
• Bernoester Katrin
• Koenig Martin

Classifications

• A61K47/6809

  Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin · CPC title

• A61K39/39558 Primary

  against tumor tissues, cells, antigens · CPC title

• A61K47/6851

  the antibody targeting a determinant of a tumour cell · CPC title

• A61K47/50

  the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates · CPC title

• A61P35/00

  Antineoplastic agents · CPC title