Claims for Patent: 9,289,509

Summary for Patent: 9,289,509

Title:	Uses of immunoconjugates targeting CD138
Abstract:	Disclosed are methods and treatment regimes that include the administration of immunconjugates targeting CD138 to combat diseases. The immunoconjugate is either used as the sole active ingredient, as part of a treatment regime or as part of an anticancer combination.
Inventor(s):	Osterroth; Frank (Dietzenbach, DE), Uherek; Christoph (Seligenstadt, DE), Bruecher; Christoph (Eschborn, DE), Daelken; Benjamin (Frankfurt am Main, DE), Engling; Andre (Frankfurt, DE), Haeder; Thomas (Dreieichenhain, DE), Wartenberg-Demand; Andrea (Linden, DE), Niemann; Gabriele (Karlsruhe, DE), Zuber; Chantal (Frankfurt, DE), Czeloth; Niklas (Dreieich, DE), Aigner; Silke (Frankenthal, DE), Zeng; Steffen (Muenster, DE), Schulz; Gregor (Umkirch, DE)
Assignee:	Biotest AG (Dreieich, DE) Immunogen Inc. (Waltham, MA)
Application Number:	12/774,705
Patent Claims:	1. A method for treating a subject with cancer having target cells expressing CD138, wherein said subject has a refractory disease phenotype, comprising: (i) identifying said subject as not responding, or responding poorly, to treatment with one or more cytotoxic agents, and (ii) administering to said subject that does not respond, or responds poorly, to treatment with one or more cytotoxic agents an effective amount of an immunoconjugate comprising at least one targeting antibody targeting CD138 expressing cells, and at least one maytansinoid effector molecule, wherein said targeting antibody is functionally attached to said effector molecule to form said immunoconjugate, wherein said immunoconjugate is BT062 or has a light chain having at least about 70% sequence identity with SEQ ID No: 2 and a heavy chain having at least about 70% sequence identity with SEQ ID No: 1, wherein said immunoconjugate comprises residues 24-34 (CDR1), residues 50-56 (CDR2) and residues 89-97 (CDR3) of SEQ ID NO: 2 as well as residues 31-35 (CDR1), residues 51-68 (CDR2) and residues 99-111(CDR3) of SEQ ID No:1. 2. The method of claims 1, wherein the immunoconjugate is administered to the subject in an amount from 20 mg/m.sup.2 to 200 mg/m.sup.2 or a pharmacokinetic equivalent of 20 mg/m.sup.2 to 200 mg/m.sup.2 when administered in combination with an agent for treating adverse side effects. 3. The method of claim 1, wherein a maximum concentration of the immunoconjugate in the subject's plasma between 0 to 2 hours after an end of said first intravenous administration is less than 40% of the theoretical maximum concentration for said immunoconjugate. 4. The method of claim 1, wherein the immunoconjugate is intravenously administered at least four times and a maximum concentration of the immunoconjugate in the subject's plasma between 0 to 2 hours after an end of each of said administrations is less than 55% of the theoretical maximum concentration for said immunoconjugate. 5. The method of claim 1, wherein said immunoconjugate is administered in a repeated single dose, of not more than about 120 mg/m.sup.2, an average daily dose of about 400 .mu.g/m.sup.2 to about 6 mg/m.sup.2, and/or an average weekly dose of about 3 mg/m.sup.2 to about 40 mg/m.sup.2. 6. The method according to claim 1, wherein for about 20, 30, 40, 50, 60, 70, 80, 90 100, 120, 140, 160, 180, 190, 200, 210 or more days stable disease is maintained. 7. The method according to claim 1, wherein for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 treatment cycles each of about three weeks stable disease is maintained. 8. The method of claim 7, wherein at least stable disease is maintained for 5, 6, 7, 8, 9 or 10 treatment cycles at 20 mg/m.sup.2. 9. The method of claim 8, wherein a minor response is observed after up to 8 treatment cycles. 10. The method of claim 1, wherein said method results in a minor response, a partial response, a very good partial response, a stringent complete response or a complete response durable for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 treatment cycles or more wherein said treatment cycles each comprise about 3 weeks with an administration of said immunoconjugate on day 1 of each said treatment cycle or for 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77 or 82 days, respectively. 11. The method of claim 1, wherein the immunoconjugate is administered to the subject in an amount from 5 mg/m.sup.2 or 10 m g/m.sup.2 to less than 160 mg/m.sup.2. 12. The method of claim 3, wherein said maximum concentration is less than 3 .mu.g/ml for 10 mg/m.sup.2, less than 8 .mu.g/ml for 20 mg/m.sup.2, less than 15 .mu.g/ml for 40 mg/m.sup.2, less than 25 .mu.g/ml for 80 mg/m.sup.2, less than 30 .mu.g/ml for 120 mg/m.sup.2. 13. The method of claim 4, wherein said maximum concentration is less than 14 .mu.g/ml for 20 mg/m.sup.2, less than 15 .mu.g/ml for 40 mg/m.sup.2 or less than 25 .mu.g/ml for 80 mg/m.sup.2. 14. The method of claim 1, wherein said CD138 is, in said subject, expressed on said target cells and on non-target cells, wherein said non-target cells expressing CD138 including epithelial cells, are substantially unaffected. 15. The method of claim 14, wherein expression level of CD138 on said target and non-target cells expressing CD138 is comparable. 16. The method of claim 14 or 15, wherein said immunoconjugate is administered to the subject as a single dose, a repeated single dose or in multiple doses in an amount from 5 mg/m.sup.2 to 200 mg/m.sup.2 or a pharmacokinetic equivalent of 5 mg/m.sup.2 to 200 mg/m.sup.2 when administered in combination with an agent for treating adverse side effects and wherein said administering results in a response in said subject, after less than 40, 30, 20, 15, 10, 9, 8, 7, 6, 5 hours. 17. The method of claim 16, wherein said effective amount is more than 120 mg/m.sup.2. 18. The method of claim 14, wherein said effective amount is administered as a single dose, a repeated single dose or in multiple doses. 19. The method of claim 18, wherein a cmax value after each administration is more than 55% of a theoretical cmax value. 20. The method of claim 14, wherein said administration results in at least stable disease, a minor response or a partial response in said subject after a first administration. 21. The method of claim 1, wherein said immunoconjugate comprises nBT062 or a targeting antibody having at least 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity with nBT062. 22. The method of claim 1, wherein the method consists essentially of administering a pharmaceutical composition comprising said immunoconjugate and a pharmaceutically acceptable carrier, wherein an active ingredient of said composition consists essentially of said immunoconjugate. 23. The method of claim 1, wherein the immunoconjugate is administered intravenously. 24. The method of claim 23, wherein the immunoconjugate is administered intravenously in a repeated single dose. 25. The method of claim 1 or 2, wherein said cancer is selected from the group consisting of renal cell carcinoma, endometrial cancer, cervical cancer, prostate adenocarcinoma, pancreatic carcinoma, gastric cancer, bladder cancer, mammary carcinoma, hepato-carcinoma, colorectal carcinoma, colon carcinoma, squamous cell carcinoma, lung cancer including squamous cell lung carcinoma, non Hodgkin lymphoma, thymus, uterus, urinary or ovarian carcinoma. 26. The method according to claim 1, wherein the cancer is associated with bone pains and/or bone complications and wherein administration of said immunoconjugate reduces said bone pains and/or bone complications to an acceptable level. 27. The method of claim 1, wherein the immunoconjugate overcomes the refractory phenotype. 28. A method of treating a patient with cancer having target cells expressing CD138, comprising (i) identifying said cancer of said patient as being associated with target cells expressing CD138, including multiple myeloma and as not responding, or responding poorly, to treatment with one or more cytotoxic agents including immunomodulators and/or proteasome inhibitors, and (ii) administering to said patient that does not respond, or responds poorly, to treatment with one or more cytotoxic agents including immunomodulators and/or proteasome inhibitors, intravenously an effective amount of an immunoconjugate comprising nBT062 or a targeting antibody having at least 70%, 80%, 85%, 90%, 95%, 98%, 99% or 100% sequence identity with nBT062, wherein said immunoconjugate comprises residues 24-34 (CDR1), residues 50-56 (CDR2) and residues 89-97 (CDR3) of SEQ ID NO: 2 as well as residues 31-35 (CDR1), residues 51-68 (CDR2) and residues 99-111 (CDR3) of SEQ ID No: 1 and wherein said cancer is treated. 29. The method of claim 28, wherein said cancer is relapsed or refractory multiple myeloma. 30. The method of claim 28, wherein the patient displays levels of sCD138 of more than 50 ng/ml, more than 60 ng/ml, more than 70 ng/ml more than 80 ng/ml, more than 100 ng/ml, more than 150 ng/ml, more than 200 ng/ml, more than 200, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500 ng/ml, and wherein an amount of the immunoconjugate as low as 20 mg/m.sup.2 or as low as 40 mg/m.sup.2 is effective to provide a minor response. 31. The method of claim 30, wherein said patient is displaying levels of sCD138 of more than 1000ng/ml. 32. The method of claim 30, wherein the cytotoxic agents to which the patient did not respond or responded poorly were lenalidomide and/or bortezomib. 33. The method of claim 1, comprising: administering to the subject an effective amount of an anticancer combination comprising at least one cytotoxic agent and the at least one immunoconjugate. 34. A method for treating a non-plasmaproliferative cancer expressing CD138 in a subject, said subject having a refractory disease phenotype, comprising: (i) identifying said subject as not responding, or responding poorly, to treatment with one or more cytotoxic agents, and (ii) administering to said subject that does not respond, or responds poorly, to treatment with one or more cytotoxic agent an effective amount of an immunoconjugate comprising at least one antibody targeting CD138 expressing cells, and at least one maytansinoid effector molecule, wherein said antibody is functionally attached to said effector molecule to form said immunoconjugate, wherein said CD138 is, in said subject, expressed on said target cells and on non-target cells at comparable levels or wherein said CD138 is, in said subject, expressed on said target cells at levels below that of said non-target cells expressing CD138, wherein said immunoconjugate is administered to the subject in an amount from 5 mg/m.sup.2 to 200 mg/m.sup.2 or a pharmacokinetic equivalent of 5 mg/m.sup.2 to 200 mg/m.sup.2 when administered in combination with an agent for treating adverse side effects, wherein a maximum concentration of the immunoconjugate in the subject's plasma, based on a measurement between 0 to 2 hours after an end of a first intravenous administration, of less than 50% of a theoretical maximum concentration and wherein the theoretical maximum concentration (in (.mu.g/ml)) is calculated as follows: .times..times..times..times..times..times. .times..times..times..times..times..times..times..times..times..times..ti- mes..times..times..times..times..times..times..times..times..times..times.- .times..times..times..times..times..times..times..times..times..times..tim- es. ##EQU00003## wherein the immunoconjugate is administered in a single dose, a repeated single dose or in multiple doses and wherein the immunoconjugate overcomes the refractory phenotype, wherein said immunoconjugate comprises residues 24-34 (CDR1), residues 50-56 (CDR2) and residues 89-97 (CDR3) of SEQ ID NO: 2 as well as residues 31-35 (CDR1), residues 51-68 (CDR2) and residues 99-111 (CDR3) of SEQ ID No: 1. 35. The method of claim 33, wherein said non-target cells expressing CD138 are epithelium cells. 36. The method of claim 33, wherein said target cells of said cancer shed CD138 over a period of 24 hours, 2, 3, 4, 5, 6 days. 37. The method of claim 36, wherein said cancer is mammary carcinoma. 38. The method of claim 33 or 34, wherein immunoconjugate induces remission of a solid tumor. 39. The method of claim 38, wherein solid tumor is a pancreatic carcinoma or a mammary carcinoma. 40. The method of claim 38, wherein said remission is followed by time interval which is free of re-growth of said tumor. 41. The method of claim 33 or 34, wherein said cancer is renal cell carcinoma, endometrial cancer, cervical cancer, prostate adenocarcinoma, pancreatic carcinoma, gastric cancer, bladder cancer, mammary carcinoma, hepato-carcinoma, colorectal carcinoma, colon carcinoma, squamous cell carcinoma, lung cancer in particular squamous cell lung carcinoma, non Hodgkin lymphoma, thymus, uterus, urinary or ovarian carcinoma. 42. The method of claim 38, wherein the tumor is a mammary carcinoma, which is estrogen receptor negative and/or progesterone receptor negative and/or trastuzumab resistant. 43. The method according to claim 1, wherein the targeting antibody is an engineered antibody. 44. A method of claim 33, wherein the cytotoxic agent is bortezomib, thalidomide, pomalidomide, lenalidomide, melphalan or a mixture of two or more thereof. 45. The method of claim 1, further comprising measuring a maximum concentration of the immunoconjugate in the subject's plasma, based on a measurement between 0 to 2 hours after an end of a first intravenous administration, is less than 50% of a theoretical maximum concentration and wherein the theoretical maximum concentration (in (.mu.g/ml)) is calculated as follows: .times..times..times..times..times..times. .times..times..times..times..times..times..times..times..times..times..ti- mes..times..times..times..times..times..times..times..times..times..times.- .times..times..times..times..times..times..times..times..times..times..tim- es. ##EQU00004## and wherein the theoretical maximum concentration is calculated as follows: .times..times..times. .times..times..times..times..times..times. ##EQU00005## 46. The method of claim 1, wherein said immunoconjugate comprises a chimeric antibody comprising amino acids 1 to 107 of SEQ ID NO. 2 and amino acids 1 to 120 of SEQ ID NO: 1. 47. The method of claim 29, wherein said cancer is relapsed myeloma. 48. The method of claim 29, wherein said cancer is relapsed/refractory or refractory multiple myeloma. 49. The method of claim 44, wherein the cytotoxic agents are lenalidomide and/or pomalidomide.

Details for Patent 9,289,509

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2029-05-06
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2029-05-06
Genentech, Inc.	HERCEPTIN HYLECTA	trastuzumab and hyaluronidase-oysk	Injection	761106	02/28/2019		2029-05-06