CN114302746A - Combination therapy comprising an anti-CD 25 antibody drug conjugate and another agent - Google Patents

Combination therapy comprising an anti-CD 25 antibody drug conjugate and another agent Download PDF

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CN114302746A
CN114302746A CN202080043019.8A CN202080043019A CN114302746A CN 114302746 A CN114302746 A CN 114302746A CN 202080043019 A CN202080043019 A CN 202080043019A CN 114302746 A CN114302746 A CN 114302746A
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agent
treatment
individual
cancer
bcl
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F·扎马尔基
F·贝尔托尼
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ADC Therapeutics SA
MedImmune Ltd
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ADC Therapeutics SA
MedImmune Ltd
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Priority claimed from GBGB1908231.2A external-priority patent/GB201908231D0/en
Priority claimed from GBGB1908227.0A external-priority patent/GB201908227D0/en
Priority claimed from GBGB1908232.0A external-priority patent/GB201908232D0/en
Application filed by ADC Therapeutics SA, MedImmune Ltd filed Critical ADC Therapeutics SA
Publication of CN114302746A publication Critical patent/CN114302746A/en
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Abstract

The present disclosure relates to combination therapies for treating pathological conditions such as cancer. In particular, the disclosure relates to combination therapies comprising treatment with an anti-CD 25 antibody drug conjugate (anti-CD 25ADC) and an anti-BCL-2 agent, an mTOR inhibitor, or a second agent.

Description

Combination therapy comprising an anti-CD 25 antibody drug conjugate and another agent
Application of earlier filing
The present application claims priority from three applications: (1) uk application GB1908227.0 filed on 10.6.2019; (2) uk application GB1908231.2 filed on 10.6.2019; and (3) uk application GB1908232.0 filed on 10.6.2019.
Technical Field
The present disclosure relates to combination therapies for treating pathological conditions, such as cancer. In particular, the disclosure relates to combination therapies comprising treatment with an anti-CD 25 antibody drug conjugate (anti-CD 25ADC) and an anti-BCL-2 agent, mTOR inhibitor, or second agent.
Background
Antibody therapy
Antibody therapies for the targeted treatment of subjects with cancer, immune and angiogenic disorders have been established (Carter, P. (2006) Nature Reviews Immunology 6: 343-. Local delivery of cytotoxic or cytostatic agents (i.e., drugs used to kill or inhibit tumor cells in cancer therapy) using antibody-drug conjugates (ADCs) (i.e., immunoconjugates) to target the delivery of the drug moiety to the tumor and intracellular accumulation therein, whereas systemic administration of these unconjugated drug agents may result in unacceptable levels of toxicity to normal cells (Xie et al (2006) Expert. Opin. biol. The.6 (3): 281-291; Kovtun et al (2006) Cancer Res.66(6): 3214-3121; Law et al (2006) Cancer Res.66(4):2328 2337; Wu et al (2005) Nature Biotech.23(9): 1137-1145; Lambert J. (2005) Current Optin. in Pharmacol.5: 543; Hamann P. (2005) Expert. The. Patents 15(9): 1087-1103; Payne, G. (2003) Cancer 3: 207-212; Traceil et al (2003) Cancer 19: 69; Syrian et al (1999).
CD25
The type I transmembrane protein CD25 is present on activated T and B cells, some thymocytes, bone marrow precursor cells, and oligodendrocytes. On activated T cells, it forms heterodimers (CD122 and CD132) with the β and γ subunits, and thus contains a high affinity receptor for IL-2. This ligand represents a survival factor for activated T cells, as removal of IL-2 causes these cells to die immediately.
In the case of B cells, CD25 is physiologically expressed at an early developmental stage in late progenitor B cells and pre B cells. Thus, malignancies arising from this stage of B cell differentiation may also express CD 25. Mast cell pathology was also CD25 positive, which is therefore considered to be the primary diagnostic criteria for determining systemic mastocytosis. Among Hodgkin lymphomas, CD25 was reported to be not expressed in Hodgkin-/Reed-starberg cells (Hodgkin-/Reed-Sternberg cells) in Hodgkin lymphoma (NLPHL) of which nodular lymphocytes are the major type, whereas the same cell type expresses CD25 at different levels in classical Hodgkin lymphomas of mixed cell types. The overall expression level was reported to be lower than in Tumor Infiltrating Lymphocytes (TILs), which may create problems with the development of CD25 tumor cells under these conditions (Levi et al, Merz et al, 1995).
Expression of target antigens has also been reported for non-hodgkin-lymphomas of several B-cell and T-cell derived subtypes, namely B-cell chronic lymphocytic leukemia, hairy cell leukemia, small cell lymphocytic lymphoma/chronic lymphocytic leukemia, and adult T-cell leukemia/lymphoma and anaplastic large cell lymphoma.
CD25 could be localized on the membrane and some expression was observed in the cytoplasm. Soluble CD25 can also be observed extracellularly (such as in serum).
Therapeutic use of anti-CD 25ADC
The efficacy of antibody drug conjugates comprising anti-CD 25 antibodies (anti-CD 25-ADC) in the treatment of, for example, cancer has been determined, see, for example, WO2014/057119, WO2016/083468, and WO 2016/166341.
Studies were continued to further improve the efficacy, tolerability, and clinical utility of anti-CD 25 ADCs. To this end, the authors have identified clinically advantageous combination therapies in which an anti-CD 25ADC is administered in combination with at least one anti-BCL-2 agent, mTOR inhibitor, or second agent.
Disclosure of Invention
The present authors have determined that administration of anti-CD 25ADC in combination with an anti-BCL-2 agent, mTOR inhibitor, or second agent to an individual results in an unexpected clinical advantage. The authors also determined that administration of anti-CD 25ADC and an anti-BCL-2 agent, mTOR inhibitor, or second agent to an individual who has been treated with, or is being treated with, an anti-BCL-2 agent, mTOR inhibitor, or second agent results in a synergistic increase in the efficacy of the treatment.
Accordingly, in a first aspect, the present disclosure provides a method of selecting an individual suitable for treatment with an anti-CD 25ADC, wherein an individual is selected for treatment with an anti-CD 25ADC if the individual has been treated or is being treated with an anti-BCL-2 agent, mTOR inhibitor, or second agent. An individual may be selected for treatment if the individual is refractory to treatment with an anti-BCL-2 agent, mTOR inhibitor, or second agent, or further treatment.
In another aspect, the present disclosure provides a method for treating a disorder in an individual, the method comprising selecting an individual suitable for treatment by the method of the first aspect, and then administering to the individual an effective amount of an anti-CD 25 ADC. The method of treatment may further comprise administering an anti-BCL-2 agent, mTOR inhibitor, or a second agent in combination with an anti-CD 25 ADC.
In another aspect, the present disclosure provides a method for treating a disorder in an individual, the method comprising administering to the individual an effective amount of an anti-CD 25ADC and an anti-BCL-2 agent, an mTOR inhibitor, or a second agent. The individual may be selected for treatment according to a method according to the first aspect.
The disorder can be a proliferative disease, e.g., cancer, such as hodgkin's and non-hodgkin's lymphomas, including diffuse large B-cell lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Lymphoma (CLL), marginal zone B-cell lymphoma (MZBL); and leukemias, such as Hairy Cell Leukemia (HCL), variant hairy cell leukemia (HCL-v), Acute Myeloid Leukemia (AML), Anaplastic Large Cell Lymphoma (ALCL), and Acute Lymphoblastic Leukemia (ALL), such as Philadelphia chromosome positive ALL (Ph + ALL) or Philadelphia chromosome negative ALL (Ph-ALL).
Proliferative diseases may be characterized by the presence of a neoplasm comprising CD25+ ve and CD25-ve cells.
A proliferative disease can be characterized by the presence of a neoplasm consisting of CD25-ve neoplastic cells, optionally wherein CD25-ve neoplastic cells are associated with CD25+ ve non-neoplastic cells (such as CD25+ ve T cells).
The target neoplasm or neoplastic cell may be all or a portion of a solid tumor.
A "solid tumor" will be understood herein to include solid hematological cancers, such as lymphomas discussed in more detail herein (hodgkin's lymphoma or non-hodgkin's lymphoma). The solid tumor can be an advanced solid tumor.
A solid tumor can be a neoplasm comprising or consisting of CD25+ ve neoplastic cells, including non-hematologic cancers. A solid tumor may be a neoplasm infiltrating CD25+ ve cells (such as CD25+ ve T cells), including non-hematologic cancers; such solid tumors can lack CD25 expression (in other words, comprise or consist of CD25-ve neoplastic cells).
For example, a solid tumor can be a tumor with high levels of infiltrating T cells (such as infiltrating regulatory T cells, Treg; Menterier-Caux, C. et al, Targ Oncol (2012)7: 15-28; Arce Vargas et al, 2017, Immunity 46, 1-10; Tanaka, A. et al, Cell Res.2017, 1 month 27(1): 109-118). Thus, the solid tumor can be pancreatic cancer, breast cancer, colorectal cancer, gastric and esophageal cancer, leukemia and lymphoma, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular cancer, renal cell carcinoma, and head and neck cancer.
The anti-CD 25-ADC may be ADCx25 described herein.
The anti-CD 25-ADC can be ADCT-301.
The anti-BCL-2 agent can be Venetock (Venetocalax) (ABT-199), Naviotmax (Avitoclax) (ABT-263), ABT-737, S55746/BCL201, and Olimersen (oblimersen) (G3139). Preferably, the anti-BCL-2 agent is Venetok (ABT-199).
The mTOR inhibitor may be everolimus (RAD001), sirolimus (sirolimus) (Rapamycin (Rapamycin)), CCI-779 (temsirolimus), ridaforolimus (ridaforolimus) (AP-23573), NVP-BEZ235 (Datolisib)), BGT226, SF1126, Gedatolisib, Omeiisib, XL765, Ku-0063794, oleuropein, AZD8055, AZD2014, AZD3147, Sadaparissib (INK128/MLN0128), Lin027, torin 1, torin 2, trinib (kintoronib) (PP242), WYE687, ETP45658, Rapamipi 84, Lin 0435309, 123 eCF309, OSI-691 388, or Rapamicin.
The second agent may be:
(a) bendamustine (Bendamustine);
(b) phosphatidylinositol 3-kinase inhibitors such as copanlisib, idelalisib, duviraib, taseliib, bupaliib, apetilib, ubuliib (Umbralisib), daptomicib, and ortaliib (voxtaliib);
(c) proteasome inhibitors such as bortezomib (bortezomib), carfilzomib (carfilzomib), ixazoib (ixazoib), Oprozomib (oprazoib), and salinosporamide a;
(d) antifolates such as pralatrexate, methotrexate (methotrexate), pemetrexed (pemetrexed), and raltitrexed (raltitrexed); or
(e) HDAC inhibitors such as romidepsin (romidepsin), vorinostat (vorinostat), aberestat (Abexinostat), belinostat (belinostat) (PXD101), LAQ824, panobinostat (panobinostat) (LBH589), entinostat (MS-275), tacrine (tacedinine) (CI994) and moxidestat (MGCD 0103).
The subject may be a human. The individual may have cancer, or may have been determined to have cancer. The subject may have or have been determined to have CD25+ cancer or to have or have been determined to have CD25+ tumor-associated non-tumor cells, such as CD25+ infiltrating T cells.
In the disclosed methods, the anti-CD 25ADC may be administered prior to, simultaneously with, or after the anti-BCL-2 agent, mTOR inhibitor, or second agent. The disclosed methods can include administering another chemotherapeutic agent to the subject.
In another aspect, the present disclosure provides an anti-CD 25ADC or a composition comprising an anti-CD 25ADC for use in a method of treatment as described herein.
In one aspect, the present disclosure provides an anti-BCL-2 agent, mTOR inhibitor, or second agent, or a composition comprising an anti-BCL-2 agent, mTOR inhibitor, or second agent, for use in a method of treatment as described herein
In another aspect, the present disclosure provides the use of an anti-CD 25ADC or an anti-BCL-2 agent, mTOR inhibitor, or second agent in the manufacture of a medicament for the treatment of a disorder in an individual, wherein the treatment comprises a method of treatment as described herein.
---------------------------------
In another aspect, the present disclosure provides a first composition comprising an anti-CD 25ADC for use in a method of treating a disorder in an individual, wherein the treatment comprises administering the first composition in combination with a second composition comprising an anti-BCL-2 agent, an mTOR inhibitor, or a second agent.
This aspect also provides a first composition comprising an anti-BCL-2 agent, an mTOR inhibitor, or a second agent for use in a method of treating a disorder in an individual, wherein the treatment comprises administering the first composition in combination with a second composition comprising an anti-CD 25 ADC.
The disorder can be a proliferative disease, e.g., a cancer, such as non-hodgkin's lymphoma, including diffuse large B-cell lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Lymphoma (CLL), and marginal zone B-cell lymphoma (MZBL); and leukemias, such as Hairy Cell Leukemia (HCL), variant hairy cell leukemia (HCL-v), Anaplastic Large Cell Lymphoma (ALCL), and Acute Lymphoblastic Leukemia (ALL), such as philadelphia chromosome positive ALL (Ph + ALL) or philadelphia chromosome negative ALL (Ph-ALL).
The anti-CD 25-ADC may be ADCX25 described herein.
The anti-CD 25-ADC can be ADCT-301.
The anti-BCL-2 agent can be Venetok (ABT-199), Navietok (ABT-263), ABT-737, S55746/BCL201, and Orlemison (G3139). Preferably, the anti-BCL-2 agent is Venetok (ABT-199).
The mTOR inhibitor can be everolimus (RAD001), sirolimus (rapamycin), CCI-779 (temsirolimus), ridaforolimus (AP-23573), NVP-BEZ235 (daptomixb), BGT226, SF1126, jidalisel, omithizamide, XL765, Ku-0063794, oleuropein, AZD8055, AZD2014, AZD3147, sapercetin (INK128/MLN0128), OSI027, torein 1, torein 2, Turkonib (PP242), WYE687, ETP45658, PF 12305284, PF04691502, XL388, 35309, Rapalink-1, or Rapalink-2.
The second agent may be:
(a) bendamustine;
(b) phosphatidylinositol 3-kinase inhibitors such as copaipamide, idalarix, duviraxib, taselib, buparib, apidrix, ubulalix, daprolib, and ortalib;
(c) proteasome inhibitors such as bortezomib, carfilzomib, ixazoib, oprozomib, and salinosporamide a;
(d) antifolates such as pralatrexate, methotrexate, pemetrexed, and raltitrexed; or
(e) HDAC inhibitors such as romidepsin, vorinostat, Abistal, belinostat (PXD101), LAQ824, panobinostat (LBH589), entinostat (MS-275), tacroline (CI994) and moxidestat (MGCD 0103).
The subject may be a human. The individual may have cancer, or may have been determined to have cancer. The subject may have or have been determined to have CD25+ cancer or to have or have been determined to have CD25+ tumor-associated non-tumor cells, such as CD25+ infiltrating T cells.
The first composition may be administered before, simultaneously with, or after the second composition. The treatment may comprise administering another chemotherapeutic agent to the individual.
---------------------------------
In another aspect, the present disclosure provides a use of an anti-CD 25ADC in the manufacture of an agent for treating a disorder in an individual, wherein the agent comprises an anti-CD 25ADC, and wherein treatment comprises administering the agent in combination with a composition comprising an anti-BCL-2 agent, an mTOR inhibitor, or a second agent.
This aspect also provides for the use of an anti-BCL-2 agent in the manufacture of an agent for treating a disorder in an individual, wherein the agent comprises the anti-BCL-2 agent, an mTOR inhibitor, or a second agent, and wherein the treatment comprises administering the agent in combination with a composition comprising an anti-CD 25 ADC.
The disorder can be a proliferative disease, e.g., cancer, such as hodgkin's and non-hodgkin's lymphomas, including diffuse large B-cell lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Lymphoma (CLL), marginal zone B-cell lymphoma (MZBL); and leukemias, such as Hairy Cell Leukemia (HCL), variant hairy cell leukemia (HCL-v), Acute Myeloid Leukemia (AML), Anaplastic Large Cell Lymphoma (ALCL), and Acute Lymphoblastic Leukemia (ALL), such as Philadelphia chromosome positive ALL (Ph + ALL) or Philadelphia chromosome negative ALL (Ph-ALL).
Proliferative diseases may be characterized by the presence of a neoplasm comprising CD25+ ve and CD25-ve cells.
A proliferative disease can be characterized by the presence of a neoplasm consisting of CD25-ve neoplastic cells, optionally wherein CD25-ve neoplastic cells are associated with CD25+ ve non-neoplastic cells (such as CD25+ ve T cells).
The target neoplasm or neoplastic cell may be all or a portion of a solid tumor.
A "solid tumor" will be understood herein to include solid hematological cancers, such as lymphomas discussed in more detail herein (hodgkin's lymphoma or non-hodgkin's lymphoma). The solid tumor can be an advanced solid tumor.
A solid tumor can be a neoplasm comprising or consisting of CD25+ ve neoplastic cells, including non-hematologic cancers. A solid tumor may be a neoplasm infiltrating CD25+ ve cells (such as CD25+ ve T cells), including non-hematologic cancers; such solid tumors can lack CD25 expression (in other words, comprise or consist of CD25-ve neoplastic cells).
For example, a solid tumor can be a tumor with high levels of infiltrating T cells (such as infiltrating regulatory T cells, Treg; Menterier-Caux, C. et al, Targ Oncol (2012)7: 15-28; Arce Vargas et al, 2017, Immunity 46, 1-10; Tanaka, A. et al, Cell Res.2017, 1 month 27(1): 109-118). Thus, the solid tumor can be pancreatic cancer, breast cancer, colorectal cancer, gastric and esophageal cancer, leukemia and lymphoma, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular cancer, renal cell carcinoma, and head and neck cancer.
The anti-CD 25ADC may be ADCX25 as described herein.
The anti-CD 25-ADC can be ADCT-301.
The anti-BCL-2 agent can be Venetok (ABT-199), Navietok (ABT-263), ABT-737, S55746/BCL201, and Orlemison (G3139). Preferably, the anti-BCL-2 agent is Venetok (ABT-199).
The mTOR inhibitor can be everolimus (RAD001), sirolimus (rapamycin), CCI-779 (temsirolimus), ridaforolimus (AP-23573), NVP-BEZ235 (daptomixb), BGT226, SF1126, jidalisel, omithizamide, XL765, Ku-0063794, oleuropein, AZD8055, AZD2014, AZD3147, sapercetin (INK128/MLN0128), OSI027, torein 1, torein 2, Turkonib (PP242), WYE687, ETP45658, PF 12305284, PF04691502, XL388, 35309, Rapalink-1, or Rapalink-2.
The second agent may be:
(a) bendamustine;
(b) phosphatidylinositol 3-kinase inhibitors such as copaipamide, idalarix, duviraxib, taselib, buparib, apidrix, ubulalix, daprolib, and ortalib;
(c) proteasome inhibitors such as bortezomib, carfilzomib, ixazoib, oprozomib, and salinosporamide a;
(d) antifolates such as pralatrexate, methotrexate, pemetrexed, and raltitrexed; or
(e) HDAC inhibitors such as romidepsin, vorinostat, Abistal, belinostat (PXD101), LAQ824, panobinostat (LBH589), entinostat (MS-275), tacroline (CI994) and moxidestat (MGCD 0103).
The subject may be a human. The individual may have cancer, or may have been determined to have cancer. The subject may have or have been determined to have CD25+ cancer or to have or have been determined to have CD25+ tumor-associated non-tumor cells, such as CD25+ infiltrating T cells.
The agent may be administered prior to, simultaneously with, or after the composition. The treatment may comprise administering another chemotherapeutic agent to the individual.
---------------------------------
Another aspect of the disclosure provides a kit comprising:
a first agent comprising an anti-CD 25 ADC;
a package insert comprising instructions for administering the first agent according to the method of treatment as disclosed herein. The kit may further comprise a second agent comprising an anti-BCL-2 agent, an mTOR inhibitor, or a second agent.
Another aspect of the disclosure provides a kit comprising:
a first agent comprising an anti-CD 25ADC, an mTOR inhibitor, or a second agent;
a second agent comprising an anti-BCL-2 agent, an mTOR inhibitor, or a second agent; and optionally also (c) a second set of one or more of,
a package insert comprising instructions for administering the first agent in combination with the second agent to an individual to treat a disorder.
This aspect also provides a kit comprising an agent comprising an anti-CD 25 ADC; and a package insert comprising instructions for administering the agent to the individual in combination with a composition comprising an anti-BCL-2 agent, an mTOR inhibitor, or a second agent, for treating the disorder.
This aspect also provides a kit comprising an agent comprising an anti-BCL-2 agent, an mTOR inhibitor, or a second agent; and a package insert comprising instructions for administering the agent to an individual in combination with a composition comprising an anti-CD 25ADC for treatment of a disorder.
The disorder can be a proliferative disease, e.g., cancer, such as hodgkin's and non-hodgkin's lymphomas, including diffuse large B-cell lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Lymphoma (CLL), marginal zone B-cell lymphoma (MZBL); and leukemias, such as Hairy Cell Leukemia (HCL), variant hairy cell leukemia (HCL-v), Acute Myeloid Leukemia (AML), Anaplastic Large Cell Lymphoma (ALCL), and Acute Lymphoblastic Leukemia (ALL), such as Philadelphia chromosome positive ALL (Ph + ALL) or Philadelphia chromosome negative ALL (Ph-ALL).
Proliferative diseases may be characterized by the presence of a neoplasm comprising CD25+ ve and CD25-ve cells.
A proliferative disease can be characterized by the presence of a neoplasm consisting of CD25-ve neoplastic cells, optionally wherein CD25-ve neoplastic cells are associated with CD25+ ve non-neoplastic cells (such as CD25+ ve T cells).
The target neoplasm or neoplastic cell may be all or a portion of a solid tumor.
A "solid tumor" will be understood herein to include solid hematological cancers, such as lymphomas discussed in more detail herein (hodgkin's lymphoma or non-hodgkin's lymphoma). The solid tumor can be an advanced solid tumor.
A solid tumor can be a neoplasm comprising or consisting of CD25+ ve neoplastic cells, including non-hematologic cancers. A solid tumor may be a neoplasm infiltrating CD25+ ve cells (such as CD25+ ve T cells), including non-hematologic cancers; such solid tumors can lack CD25 expression (in other words, comprise or consist of CD25-ve neoplastic cells).
For example, a solid tumor can be a tumor with high levels of infiltrating T cells (such as infiltrating regulatory T cells, Treg; Menterier-Caux, C. et al, Targ Oncol (2012)7: 15-28; Arce Vargas et al, 2017, Immunity 46, 1-10; Tanaka, A. et al, Cell Res.2017, 1 month 27(1): 109-118). Thus, the solid tumor can be pancreatic cancer, breast cancer, colorectal cancer, gastric and esophageal cancer, leukemia and lymphoma, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular cancer, renal cell carcinoma, and head and neck cancer.
The anti-CD 25ADC may be ADCX25 as described herein.
The anti-CD 25-ADC can be ADCT-301.
The anti-BCL-2 agent can be Venetok (ABT-199), Navietok (ABT-263), ABT-737, S55746/BCL201, and Orlemison (G3139). Preferably, the anti-BCL-2 agent is Venetok (ABT-199).
The mTOR inhibitor can be everolimus (RAD001), sirolimus (rapamycin), CCI-779 (temsirolimus), ridaforolimus (AP-23573), NVP-BEZ235 (daptomixb), BGT226, SF1126, jidalisel, omithizamide, XL765, Ku-0063794, oleuropein, AZD8055, AZD2014, AZD3147, sapercetin (INK128/MLN0128), OSI027, torein 1, torein 2, Turkonib (PP242), WYE687, ETP45658, PF 12305284, PF04691502, XL388, 35309, Rapalink-1, or Rapalink-2.
The second agent may be:
(a) bendamustine;
(b) phosphatidylinositol 3-kinase inhibitors such as copaipamide, idalarix, duviraxib, taselib, buparib, apidrix, ubulalix, daprolib, and ortalib;
(c) proteasome inhibitors such as bortezomib, carfilzomib, ixazoib, oprozomib, and salinosporamide a;
(d) antifolates such as pralatrexate, methotrexate, pemetrexed, and raltitrexed; or
(e) HDAC inhibitors such as romidepsin, vorinostat, Abistal, belinostat (PXD101), LAQ824, panobinostat (LBH589), entinostat (MS-275), tacroline (CI994) and moxidestat (MGCD 0103).
The subject may be a human. The individual may have cancer, or may have been determined to have cancer. The subject may have or have been determined to have CD25+ cancer or to have or have been determined to have CD25+ tumor-associated non-tumor cells, such as CD25+ infiltrating T cells.
The agent or composition comprising an anti-CD 25ADC may be administered prior to, simultaneously with or after the agent or composition comprising an anti-BCL-2 agent, mTOR inhibitor, or second agent. The treatment may comprise administering another chemotherapeutic agent to the individual.
---------------------------------
In another aspect, the present disclosure provides a composition comprising an anti-CD 25ADC and an anti-BCL-2 agent, mTOR inhibitor, or second agent.
Also provided in this aspect of the disclosure is a method of treating a disorder in an individual, the method comprising administering to the individual an effective amount of a composition comprising an anti-CD 25ADC and an anti-BCL-2 agent, an mTOR inhibitor, or a second agent.
Also provided in this aspect of the disclosure is a composition comprising an anti-CD 25ADC and an anti-BCL-2 agent, an mTOR inhibitor, or a second agent for use in a method of treating a disorder in an individual.
Also provided in this aspect of the disclosure is the use of a composition comprising an anti-CD 25ADC and an anti-BCL-2 agent, an mTOR inhibitor, or a second agent in the manufacture of a medicament for treating a disorder in an individual.
Also provided in this aspect of the disclosure is a kit comprising a composition comprising an anti-CD 25ADC and an anti-BCL-2 agent, an mTOR inhibitor, or a second agent; and a set of instructions for administering the agent to the subject to treat the disorder.
The disorder can be a proliferative disease, e.g., cancer, such as hodgkin's and non-hodgkin's lymphomas, including diffuse large B-cell lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Lymphoma (CLL), marginal zone B-cell lymphoma (MZBL); and leukemias, such as Hairy Cell Leukemia (HCL), variant hairy cell leukemia (HCL-v), Acute Myeloid Leukemia (AML), Anaplastic Large Cell Lymphoma (ALCL), and Acute Lymphoblastic Leukemia (ALL), such as Philadelphia chromosome positive ALL (Ph + ALL) or Philadelphia chromosome negative ALL (Ph-ALL).
Proliferative diseases may be characterized by the presence of a neoplasm comprising CD25+ ve and CD25-ve cells.
A proliferative disease can be characterized by the presence of a neoplasm consisting of CD25-ve neoplastic cells, optionally wherein CD25-ve neoplastic cells are associated with CD25+ ve non-neoplastic cells (such as CD25+ ve T cells).
The target neoplasm or neoplastic cell may be all or a portion of a solid tumor.
A "solid tumor" will be understood herein to include solid hematological cancers, such as lymphomas discussed in more detail herein (hodgkin's lymphoma or non-hodgkin's lymphoma).
A solid tumor can be a neoplasm comprising or consisting of CD25+ ve neoplastic cells, including non-hematologic cancers. A solid tumor may be a neoplasm infiltrating CD25+ ve cells (such as CD25+ ve T cells), including non-hematologic cancers; such solid tumors can lack CD25 expression (in other words, comprise or consist of CD25-ve neoplastic cells).
For example, a solid tumor can be a tumor with high levels of infiltrating T cells (such as infiltrating regulatory T cells, Treg; Menterier-Caux, C. et al, Targ Oncol (2012)7: 15-28; Arce Vargas et al, 2017, Immunity 46, 1-10; Tanaka, A. et al, Cell Res.2017, 1 month 27(1): 109-118). Thus, the solid tumor can be pancreatic cancer, breast cancer, colorectal cancer, gastric and esophageal cancer, leukemia and lymphoma, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular cancer, renal cell carcinoma, and head and neck cancer.
The anti-CD 25ADC may be ADCX25 as described herein.
The anti-CD 25-ADC can be ADCT-301.
The anti-BCL-2 agent can be Venetok (ABT-199), Navietok (ABT-263), ABT-737, S55746/BCL201, and Orlemison (G3139). Preferably, the anti-BCL-2 agent is Venetok (ABT-199).
The mTOR inhibitor can be everolimus (RAD001), sirolimus (rapamycin), CCI-779 (temsirolimus), ridaforolimus (AP-23573), NVP-BEZ235 (daptomixb), BGT226, SF1126, jidalisel, omithizamide, XL765, Ku-0063794, oleuropein, AZD8055, AZD2014, AZD3147, sapercetin (INK128/MLN0128), OSI027, torein 1, torein 2, Turkonib (PP242), WYE687, ETP45658, PF 12305284, PF04691502, XL388, 35309, Rapalink-1, or Rapalink-2.
The second agent may be:
(a) bendamustine;
(b) phosphatidylinositol 3-kinase inhibitors such as copaipamide, idalarix, duviraxib, taselib, buparib, apidrix, ubulalix, daprolib, and ortalib;
(c) proteasome inhibitors such as bortezomib, carfilzomib, ixazoib, oprozomib, and salinosporamide a;
(d) antifolates such as pralatrexate, methotrexate, pemetrexed, and raltitrexed; or
(e) HDAC inhibitors such as romidepsin, vorinostat, Abistal, belinostat (PXD101), LAQ824, panobinostat (LBH589), entinostat (MS-275), tacroline (CI994) and moxidestat (MGCD 0103).
The subject may be a human. The individual may have cancer, or may have been determined to have cancer. The subject may have or have been determined to have CD25+ cancer or to have or have been determined to have CD25+ tumor-associated non-tumor cells, such as CD25+ infiltrating T cells.
The treatment may comprise administering another chemotherapeutic agent to the individual.
Detailed Description
Antibody Drug Conjugates (ADC)
The present disclosure relates to improved efficacy of ADC in combination with an anti-BCL-2 agent, an mTOR inhibitor, or a second agent.
The ADC may deliver the drug to the target site. The target site is preferably a population of proliferating cells. Antibodies are antibodies to antigens present on a population of proliferating cells. In one aspect, the antigen is absent or present at a reduced level in a non-proliferating cell population as compared to the amount of antigen present in a proliferating cell population (e.g., a tumor cell population).
The ADC may comprise a linker that is cleavable to release the drug at the target site. The drug may be a compound selected from RelA, RelB, RelC, RelD or RelE. Thus, the conjugates can be used to selectively provide compounds RelA, RelB, RelC, RelD, or RelE to a target location.
The linker may be cleaved by an enzyme present at the target site.
The present disclosure specifically relates to treatment with anti-CD 25 ADCs disclosed in WO2014/057119 and as described herein.
anti-CD 25ADC
As used herein, the term "CD 25-ADC" refers to an ADC in which the antibody component is an anti-CD 25 antibody. The term "PBD-ADC" refers to an ADC in which the drug component is a Pyrrolobenzodiazepine (PBD) warhead. The term "anti-CD 25-ADC" refers to an ADC in which the antibody component is an anti-CD 25 antibody and the drug component is a PBD warhead.
The ADC may comprise the formula L- (D)L)pThe conjugate of (1), wherein DLHas the formula I or II:
Figure BDA0003405210870000161
wherein:
l is an antibody (Ab) that binds to CD 25;
when there is a double bond between C2 'and C3', R12Selected from the group consisting of:
(ia) C optionally substituted by one or more substituents selected from the group comprising5-10Aryl: halogen, nitro, cyano, ether, carboxyl, ester, C1-7Alkyl radical, C3-7Heterocyclyl and dioxy-C1-3An alkylene group;
(ib)C1-5a saturated aliphatic alkyl group;
(ic)C3-6a saturated cycloalkyl group;
(id)
Figure BDA0003405210870000162
wherein R is21、R22And R23Each of which is independently selected from H, C1-3Saturated alkyl radical, C2-3Alkenyl radical, C2-3Alkynyl and cyclopropyl, wherein R12The total number of carbon atoms in the group is not more than 5;
(ie)
Figure BDA0003405210870000163
wherein R is25aAnd R25bOne of H and the other selected from: phenyl radical ofPhenyl optionally substituted with a group selected from halo, methyl, methoxy; a pyridyl group; and a phenylthio group; and
(if)
Figure BDA0003405210870000171
wherein R is24Selected from: h; c1-3A saturated alkyl group; c2-3An alkenyl group; c2-3An alkynyl group; a cyclopropyl group; phenyl optionally substituted with a group selected from halo, methyl, methoxy; a pyridyl group; and a phenylthio group;
when a single bond is present between C2 'and C3',
R12is composed of
Figure BDA0003405210870000172
Wherein R is26aAnd R26bIndependently selected from H, F, C1-4Saturated alkyl radical, C2-3Alkenyl, said alkyl and alkenyl optionally selected from C1-4Alkylamide group and C1-4Alkyl ester group substitution; or when R is26aAnd R26bWhen one of them is H, the other is selected from nitrile and C1-4An alkyl ester;
R6and R9Independently selected from H, R, OH, OR, SH, SR, NH2NHR, NRR', nitro, Me3Sn and a halogen group;
wherein R and R' are independently selected from optionally substituted C1-12Alkyl radical, C3-20Heterocyclic group and C5-20An aryl group;
R7selected from H, R, OH, OR, SH, SR, NH2NHR, NHRR', nitro, Me3Sn and a halogen group;
r' is C3-12Alkylene, the chain possibly being interrupted by one or more hetero atoms (e.g. O, S, NR)N2(wherein R isN2Is H or C1-4Alkyl)) to an intercross; and/or aromatic rings, such as benzene or pyridine;
y and Y' are selected from O, S or NH;
R6’、R7’、R9’is selected from the group consisting of6、R7And R9The same group;
[ formula I ]
RL1’Is a linker for attachment to an antibody (Ab);
R11aselected from OH, ORA(wherein R isAIs C1-4Alkyl) and SOzM, wherein z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;
R20and R21Together form a double bond with the nitrogen and carbon atoms to which they are bound; or
R20Selected from H and RCWherein R isCIs a capping group;
R21selected from OH, ORAAnd SOzM；
When there is a double bond between C2 and C3, R2Selected from the group consisting of:
(ia) C optionally substituted by one or more substituents selected from the group comprising5-10Aryl: halogen, nitro, cyano, ether, carboxyl, ester, C1-7Alkyl radical, C3-7Heterocyclyl and dioxy-C1-3An alkylene group;
(ib)C1-5a saturated aliphatic alkyl group;
(ic)C3-6a saturated cycloalkyl group;
(id)
Figure BDA0003405210870000181
wherein R is11、R12And R13Each of which is independently selected from H, C1-3Saturated alkyl radical, C2-3Alkenyl radical, C2-3Alkynyl and cyclopropyl, wherein R2The total number of carbon atoms in the group is not more than 5;
(ie)
Figure BDA0003405210870000182
wherein R is15aAnd R15bOne of which is H and the other isSelected from: phenyl optionally substituted with a group selected from halo, methyl, methoxy; a pyridyl group; and a phenylthio group; and
(if)
Figure BDA0003405210870000183
wherein R is14Selected from: h; c1-3A saturated alkyl group; c2-3An alkenyl group; c2-3An alkynyl group; a cyclopropyl group; phenyl optionally substituted with a group selected from halo, methyl, methoxy; a pyridyl group; and a phenylthio group;
when there is a single bond between C2 and C3,
R2is composed of
Figure BDA0003405210870000184
Wherein R is16aAnd R16bIndependently selected from H, F, C1-4Saturated alkyl radical, C2-3Alkenyl, said alkyl and alkenyl optionally selected from C1-4Alkylamide group and C1-4Alkyl ester group substitution; or when R is16aAnd R16bWhen one of them is H, the other is selected from nitrile and C1-4An alkyl ester;
[ formula II ]
R22Having formula IIIa, formula IIIb, or formula IIIc:
(a)
Figure BDA0003405210870000191
wherein A is C5-7Aryl radical, and
(i)Q1is a single bond, and Q2Selected from the group consisting of single bonds and-Z- (CH)2)n-, wherein Z is selected from the group consisting of a single bond, O, S and NH and n is 1 to 3; or
(ii)Q1is-CH ═ CH-, and Q2Is a single bond;
(b)
Figure BDA0003405210870000192
wherein;
RC1、RC2and RC3Independently selected from H and unsubstituted C1-2An alkyl group;
(c)
Figure BDA0003405210870000193
wherein Q is selected from O-RL2'、S-RL2' and NRN-RL2', and RNSelected from H, methyl and ethyl
X is selected from the group comprising: O-RL2’、S-RL2’、CO2-RL2’、CO-RL2’、NH-C(＝O)-RL2’、NHNH-RL2’、CONHNH-RL2’、
Figure BDA0003405210870000194
NRNRL2’Wherein R isNSelected from the group consisting of H and C1-4A group of alkyl groups;
RL2’is a linker for attachment to an antibody (Ab);
R10and R11Together form a double bond with the nitrogen and carbon atoms to which they are bound; or
R10Is H and R11Selected from OH, ORAAnd SOzM；
R30And R31Together form a double bond with the nitrogen and carbon atoms to which they are bound; or
R30Is H and R31Selected from OH, ORAAnd SOzM。
In some embodiments, L-RL1’Or L-RL2’Is the following group:
Figure BDA0003405210870000201
wherein the asterisk indicates the point of attachment to the PBD, Ab is an antibody, L1To cleave the linker, A is1Linking group to an antibody, L2Is a covalent bond or forms a self-immolative linker together with-OC (═ O) -.
In some of these embodiments, L1Is enzymatically cleavable.
Such ADCs have previously been demonstrated to be useful in the treatment of cancers that express CD25 (see, e.g., WO2014/057119, which is incorporated herein by reference in its entirety).
The term anti-CD 25-ADC may include any of the embodiments described in WO 2014/057119. In particular, in a preferred embodiment, the ADC may have the following chemical structure:
Figure BDA0003405210870000202
wherein Ab is a CD25 antibody and DAR is between 1 and 8.
The antibody may comprise a VH domain comprising VH CDR1 of amino acid sequence SEQ ID No.3, VH CDR2 of amino acid sequence SEQ ID No.4 and VH CDR3 of amino acid sequence SEQ ID No. 5.
In some aspects, the antibody component of the anti-CD 25-ADC is an antibody comprising a VH domain comprising VH CDR1 having the amino acid sequence of SEQ ID No.3, VH CDR2 having the amino acid sequence of SEQ ID No.4, and VH CDR3 having the amino acid sequence of SEQ ID No. 5. In some embodiments, the antibody comprises a VH domain having a sequence according to SEQ ID No. 1.
The antibody may further comprise a VL domain comprising a VL CDR1 having the amino acid sequence of SEQ ID No.6, a VL CDR2 having the amino acid sequence of SEQ ID No.7 and a VL CDR3 having the amino acid sequence of SEQ ID No. 8. In some embodiments, the antibody further comprises a VL domain having a sequence according to SEQ ID No. 2.
In some embodiments, the antibody comprises a VH domain and a VL domain having the sequence of SEQ ID No.1 paired with SEQ ID No. 2.
The one or more VH and VL domains may pair to form an antibody antigen-binding site that binds CD 25.
In a preferred embodiment, the antibody is a complete antibody comprising a VH domain and a VL domain having the sequences of SEQ ID No.1 and SEQ ID No. 2.
In some embodiments, the antibody is a fully human monoclonal IgG1 antibody, preferably an IgG1, κ.
In some embodiments, the antibody is an AB12 antibody (Genmab A/S) as described in WO 2004/045512.
In one aspect, the antibody is an antibody as described herein that has been modified (or further modified) as described below. In some embodiments, the antibody is a humanized, exempt, or resurfaced version of the antibody disclosed herein.
As described herein below, a preferred anti-CD 25-ADC for use in aspects of the present disclosure is ADCX 25.
Another preferred anti-CD 25-ADC for use in aspects of the present disclosure is ADCT-301.
ADCx25
ADCx25 is an antibody drug conjugate consisting of a human antibody against human CD25 linked via a cleavable linker to a Pyrrolobenzodiazepine (PBD) warhead. The mechanism of action of ADCX25 is dependent on CD25 binding. The CD 25-specific antibody targets the Antibody Drug Conjugate (ADC) to cells expressing CD 25. Upon binding, the ADC is internalized and transported to lysosomes, where the protease-sensitive linker is cleaved and the free PBD dimer is released inside the target cell. The released PBD dimers inhibit transcription in a sequence selective manner due to direct inhibition of RNA polymerase or inhibition of the interaction of the associated transcription factors. The PBD dimer creates covalent crosslinks that do not distort the DNA duplex and are not recognized by nucleotide excision repair factors, allowing for a longer lifetime (Hartley 2011).
It has the following chemical structure:
Figure BDA0003405210870000221
ab denotes antibody AB12 (fully human monoclonal IgG1, K antibody having VH and VL sequences SEQ ID NO.1 and SEQ ID NO.2, respectively, also known as HuMax-TAC). It was synthesized as described in WO2014/057119 (Conj AB12-E) and typically had a DAR (drug to antibody ratio) of 2.0 +/-0.3.
CD25 binding
As used herein, the "first target protein" (FTP) is preferably CD 25.
As used herein, "binds CD 25" is used to mean that the antibody binds CD25 with higher affinity than a non-specific partner (such as bovine serum albumin, BSA, Genbank accession number CAA76847, version number CAA76847.1GI:3336842, record update date: 2011, 1,7, p.m. 02: 30). In some embodiments, the antibody has an association constant for BSA that is at least 2,3,4, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, 10 higher than the antibody's association constant for BSA, when measured under physiological conditions4、105Or 106Multiple association constant (K)a) Binds to CD 25. The antibodies of the present disclosure can bind CD25 with high affinity. For example, in some embodiments, the antibody may be equal to or less than about 10-6M (such as equal to or less than 1x10-6、10-7、10-8、10-9、10-10、10-11、10-12、10-13Or 10-14One of) KDBinds to CD 25.
In some embodiments, the CD25 polypeptide corresponds to Genbank accession No. NP _000408, version number NP _000408.1GI:4557667, record update date: 9/2012 in the afternoon 04: 59. In one embodiment, the nucleic acid encoding a CD25 polypeptide corresponds to Genbank accession No. NM _000417, version No. NM _000417.2GI:269973860, record update date: 9/2012 in the afternoon 04: 59. In some embodiments, the CD25 polypeptide corresponds to Uniprot/Swiss-Prot accession number P01589.
anti-BCL-2 agents
Suitable anti-BCL-2 agents include Venetok (ABT-199), Navietok (ABT-263), ABT-737, S55746/BCL201, and Orimeson (G3139). Preferably, the anti-BCL-2 agent is Venetok (ABT-199).
BCL-2 is localized to the outer membrane of mitochondria, where it plays an important role in promoting cell survival and inhibiting the action of pro-apoptotic proteins. Pro-apoptotic proteins in the BCL-2 family, including Bax and Bak, generally act on the mitochondrial membrane to promote the permeabilization and release of cytochrome C and ROS, which are important signals in the apoptotic cascade. These pro-apoptotic proteins are in turn activated by the BH 3-only protein and are inhibited by the function of BCL-2 and its associated BCL-Xl. The dynamic effects of pro-and anti-apoptotic proteins, as well as other proteins, may alter the significance of increased BCL-2 expression in human diseases. However, a wide variety of cancer types (hematological and non-hematological solid tumors) associated with aberrant expression of BCL-2 are consistent with their role as regulators of apoptosis (see Hanada M. et al, blood.1993; 82: 1820-.
"anti-BCL-2 agent" is used herein to mean any agent that specifically binds to BCL-2 and/or inhibits the biological activity thereof.
As used herein, "specifically binds BCL-2" is used to mean that the agent binds BCL-2 with higher affinity compared to a non-specific partner (such as bovine serum albumin, BSA, Genbank accession No. CAA76847, version number CAA76847.1GI:3336842, record update date: 2011, 1,7, p.m. 02: 30). In some embodiments, the agent has an association constant for BSA that is at least 2,3,4, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, 10 higher than the agent's association constant for BSA, when measured under physiological conditions4、105Or 106Multiple association constant (K)a) Binds to BCL-2. The agent can bind BCL-2 with high affinity. For example, in some embodiments, the agent may be equal to or less than about 10-6M (such as 1x 10)-6、10-7、10-8、10-9、10-10、10-11、10-12、10-13Or 10-14) K ofDBinds to BCL-2.
In some embodiments, the BCL-2 polypeptide corresponds to Genbank accession No. AAB72092, version number AAB72092.1, record update date: 2016, 7, 24, p.m. 02/22 in the afternoon. In one embodiment, the nucleic acid encoding a BCL-2 polypeptide corresponds to Genbank accession No. AF021792, version number AF021792.1, record update date: 2016, 7, 24, p.m. 02/22 in the afternoon. In some embodiments, the BCL-2 polypeptide corresponds to Uniprot/Swiss-Prot accession number Q92934.
To demonstrate that anti-CD 25ADC works synergistically with anti-BCL-2 agents, a panel of CD25(+) cell lines will be co-treated with a range of concentrations of anti-CD 25ADC and anti-BCL-2 agents. As negative controls, the same set of cell lines will be treated with a range of concentrations of anti-BCL-2 agent or with a range of concentrations of anti-CD 25ADC and vehicle. After incubation, two parameters will be measured: the amount of surface CD25 (as determined by flow cytometry) and the combined in vitro cytotoxicity (as determined by MTS assay). To determine cytotoxicity, cell viability was measured by adding MTS to each well and incubating for 4 hours at 37 ℃. Percent cell viability was calculated and compared to untreated controls. Cytotoxicity synergy was calculated by converting cell viability data to affected scores and calculating combination indices using the CalcuSyn analysis program.
anti-CBCL-2 agents suitable for use in the present disclosure include:
a) veneton gram (ABT-199)
CAS number → 1257044-40-8
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB11581
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → N54AIC43PW
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000251
Formula I: venetong vitamin
b) Navitoke (ABT-263)
CAS number → 923564-51-6
(see http:// www.cas.org/content/chemical-substances/faqs)
Unique identification code (UNII) → XKJ5VVK2WD
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000252
Formula II: navitox
c)ABT-737
CAS number → 852808-04-9
(seehttp://www.cas.org/content/chemical-substances/faqs)
Unique identification code (UNII) → Z5NFR173NV
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000261
Formula III: ABT-737
d)S55746/BCL201
CAS number → 1448584-12-0
(seehttp://www.cas.org/content/chemical-substances/faqs)
Figure BDA0003405210870000262
Formula IV: SS55746
e) Olimoesen (G3139)
CAS number → 190977-41-4
(seehttp://www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB06650
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → 85J5ZP6YSL
(seehttp://www.fda.gov/ForIndustry/DataStandards/ SubstanceRegistrationSystem-UniqueIngredientIdentifierUNII/default.htm)
Oligonucleotide structure: d (P-thio) (T-C-T-C-C-A-G-C-G-T-G-C-G-C-C-A-T)
----------------------------------
anti-mTOR agents
Suitable mTOR inhibitors include everolimus (RAD001), sirolimus (rapamycin), CCI-779 (temsirolimus), ridaforolimus (AP-23573), NVP-BEZ235 (dapoxib), BGT226, SF1126, jidalisel, omithizamide, XL765, Ku-0063794, oleuropein, AZD8055, AZD2014, AZD3147, sapercetin (INK128/MLN0128), OSI027, torein 1, torein 2, troxanib (PP242), WYE687, ETP45658, PF05212384, PF 69104691502, XL388, 35309, Rapalink-1, or Rapalink-2. Preferably, the mTOR inhibitor is everolimus.
By "mTOR inhibitor" is used herein to mean any agent that specifically binds to mTOR and/or inhibits its biological activity.
As used herein, "specifically binds mTOR" is used to mean that the agent binds mTOR with a higher affinity than a non-specific partner (such as bovine serum albumin, BSA, Genbank accession number CAA76847, version number CAA76847.1GI:3336842, record update date: 2011 1 month 7 afternoon 02: 30). In some embodiments, the agent has an association constant for BSA that is at least 2,3,4, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, 10 higher than the agent's association constant for BSA, when measured under physiological conditions4、105Or 106Multiple association constant (K)a) Binds mTOR. The agent can bind mTOR with high affinity. For example, in some embodiments, the agent may be equal to or less than about 10-6M (such as 1x 10)-6、10-7、10-8、10-9、10-10、10-11、10-12、10-13Or 10-14) K ofDBinds mTOR.
In some embodiments, the mTOR polypeptide corresponds to Genbank accession No. AAA58486, version number AAA58486.1, record update date: on 6/23/2010, 09 am: 02. In one embodiment, the nucleic acid encoding an mTOR polypeptide corresponds to Genbank accession No. L34075, version No. L34075.1, the date of record update: on 6/23/2010, 09 am: 02. In some embodiments, the mTOR polypeptide corresponds to Uniprot/Swiss-Prot accession number P42345-1.
To demonstrate that anti-CD 25ADC and mTOR inhibitor work synergistically, a panel of CD25(+) cell lines will be co-treated with a range of concentrations of anti-CD 25ADC and mTOR inhibitor. As negative controls, the same set of cell lines will be treated with a range of concentrations of mTOR inhibitor or with a range of concentrations of anti-CD 25ADC and vehicle. After incubation, two parameters will be measured: the amount of surface CD25 (as determined by flow cytometry) and the combined in vitro cytotoxicity (as determined by MTS assay). To determine cytotoxicity, cell viability was measured by adding MTS to each well and incubating for 4 hours at 37 ℃. Percent cell viability was calculated and compared to untreated controls. Cytotoxicity synergy was calculated by converting cell viability data to affected scores and calculating combination indices using the CalcuSyn analysis program.
Suitable mTor inhibitors for use in the present disclosure include:
a) everolimus
CAS number → 159351-69-6
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB01590
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → 9HW64Q8G6G
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000281
Formula V: everolimus, dihydroxy-12- [ (2R) -1- [ (1S,3R,4R) -4- (2-hydroxyethoxy) -3-methoxycyclohexyl ] propan-2-yl ] -19, 30-dimethoxy-15, 17,21,23,29, 35-hexamethyl-11, 36-dioxa-4-azatricyclo [30.3.1.0 trihexa-16, 24,26, 28-tetraene-2, 3,10,14, 20-pentanone
b) Sirolimus (rapamycin)
CAS number → 53123-88-9
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB00877
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → W36ZG6FT64
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000291
Formula VI: sirolimus, (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R) -1, 18-dihydroxy-12- { (2R) -1- [ (1S,3R,4R) -4-hydroxy-3-methoxycyclohexyl ] -2-propyl } -19, 30-dimethoxy-15, 17,21,23,29, 35-hexamethyl-11, 36-dioxa-4-azatricyclo [ 30.3.1.0-4, 9- ] trihexaxadecyl-16, 24,26, 28-tetraene-2, 3,10,14, 20-pentanone
c) Tesirolimus (CCI-779)
CAS number → 162635-04-3
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB06287
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → 624KN6GM2T
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000301
Formula VII, temsirolimus: 3-hydroxy-2- (hydroxymethyl) -2-methylpropionic acid (1R,2R,4S) -4- { (2R) -2- [ (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS) -9, 27-dihydroxy-10, 21-dimethoxy-6, 8,12,14,20, 26-hexamethyl-1, 5,11,28, 29-pentaoxo-1, 4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,34,34 a-eicosahydro-3H-23, 27-epoxypyrido [2,1-c ] [1,4] Oxazacyclotriundec-3-yl propyl } -2-methoxycyclohexyl ester
d) The earth phospholimus (AP-23573),
CAS number → 572924-54-0
(see http:// www.cas.org/content/chemical-substances/faqs)
Unique identification code (UNII) → 48Z35KB15K
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000302
Formula VIII, ridaforolimus: (1R,2R,4S) -4- [ (2R) -2- [ (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R) -1, 18-dihydroxy-19, 30-dimethoxy-15, 17,21,23,29, 35-hexamethyl-2, 3,10,14, 20-pentaoxo-11, 36-dioxa-4-azatricyclo [30.3.1.04,9] thirty-six-16, 24,26, 28-tetraen-12-yl ] propyl ] -2-methoxycyclohexyl diphosphonite
e) Dapoxib (NVP-BEZ235)
CAS number → 915019-65-7
(see http:// www.cas.org/content/chemical-substances/faqs)
Unique identification code (UNII) → RUJ6Z9Y0DT
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000311
Formula IX, dapoxib: 2-methyl-2- {4- [ 3-methyl-2-oxo-8- (quinolin-3-yl) -2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl ] phenyl } propionitrile
f)BGT226
CAS number → 1245537-68-1
(see http:// www.cas.org/content/chemical-substances/faqs)
Figure BDA0003405210870000312
Formula X, BGT 226: 1, 3-dihydro-8- (6-methoxy-3-pyridinyl) -3-methyl-1- [4- (1-piperazinyl) -3- (trifluoromethyl) phenyl ] -2H-imidazo [4,5-c ] quinolin-2-one, (2Z) -2-butenedioic acid ester
g)SF1126
CAS number → 936487-67-1
(see http:// www.cas.org/content/chemical-substances/faqs)
Figure BDA0003405210870000321
Formula XI, SF 1126: (8S,14S,17S) -14- (carboxymethyl) -8- (3-guanidinopropyl) -17- (hydroxymethyl) -3,6,9,12, 15-pentaoxo-1- (4- (4-oxo-8-phenyl-4H-chroman-2-yl) morpholinyl-4-ium) -2-oxa-7, 10,13, 16-tetraazaoctadeca-18-oic acid ester
h) Jedary plug
CAS number → 1197160-78-3
(see http:// www.cas.org/content/chemical-substances/faqs)
Unique identification code (UNII) → 96265TNH2R
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000322
Formula XII, jidalisei: 1- [4- [4- (dimethylamino) piperidine-1-carbonyl ] phenyl ] -3- [4- (4, 6-dimorpholin-4-yl-1, 3, 5-triazin-2-yl) phenyl ] urea
i) Omeliser
CAS number → 1086062-66-9
(see http:// www.cas.org/content/chemical-substances/faqs)
Unique identification code (UNII) → 1X8F5A3NA0
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000331
Formula XIII: 2, 4-difluoro-N- [ 2-methoxy-5- (4-pyridazin-4-ylquinolin-6-yl) pyridin-3-yl ] benzenesulfonamide
j)XL765
CAS number → 934493-76-2
(see http:// www.cas.org/content/chemical-substances/faqs)
Figure BDA0003405210870000332
Formula X: XL765
k)Ku-0063794
CAS number → 938440-64-3
(see http:// www.cas.org/content/chemical-substances/faqs)
Figure BDA0003405210870000341
Formula XIV: rel-5- [2- [ (2R,6S) -2, 6-dimethyl-4-morpholinyl ] -4- (4-morpholinyl) pyrido [2,3-d ] pyrimidin-7-yl ] -2-methoxybenzyl alcohol
l) Oleuropein
CAS number → 31773-95-2
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference →
(see https:// www.drugbank.ca /)
Unique identification code (UNII) →
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000342
Formula XV: (4S,5E,6R) -4- [2- [2- (3, 4-dihydroxyphenyl) ethoxy ] -2-oxoethyl ] -5-ethylene-6-hydroxy-4H-pyran-3-carboxylic acid methyl ester
m)AZD8055
CAS number → 1009298-09-2
(see http:// www.cas.org/content/chemical-substances/faqs)
Figure BDA0003405210870000351
Formula XVI: 5- [2, 4-bis [ (3S) -3-methyl-4-morpholinyl ] pyrido [2,3-d ] pyrimidin-7-yl ] -2-methoxy-benzyl alcohol
n)AZD2014
CAS number → 1009298-59-2
(see http:// www.cas.org/content/chemical-substances/faqs)
Figure BDA0003405210870000352
Formula XVII: AZD2014
o)AZD 3147
CAS number → 1101810-02-9
(see http:// www.cas.org/content/chemical-substances/faqs)
Figure BDA0003405210870000353
Formula XVIII: n- [4- [4- [1- (cyclopropylsulfonyl) cyclopropyl ] -6- [ (3S) -3-methyl-4-morpholinyl ] -2-pyrimidinyl ] phenyl ] -N' - (2-hydroxyethyl) thiourea
p) Sapparatus (INK128/MLN0128)
CAS number → 1224844-38-5
(see http:// www.cas.org/content/chemical-substances/faqs)
Figure BDA0003405210870000361
Formula XIX: 5- (4-amino-1-propan-2-ylpyrazolo [3,4-d ] pyrimidin-3-yl) -1, 3-benzoxazol-2-amine
q)OSI027
CAS number → 936890-98-1
(see http:// www.cas.org/content/chemical-substances/faqs)
Unique identification code (UNII) → 25MKH1SZ0M
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000362
Formula XX: 4- [ 4-amino-5- (7-methoxy-1H-indol-2-yl) imidazo [5,1-f ] [1,2,4] triazin-7-yl ] cyclohexane-1-carboxylic acid
r)Torin 1
CAS number → 1222998-36-8
(see http:// www.cas.org/content/chemical-substances/faqs)
Figure BDA0003405210870000371
Formula XXI: 1- [4- [4- (1-oxopropyl) -1-piperazinyl ] -3- (trifluoromethyl) phenyl ] -9- (3-quinolinyl) -benzo [ H ] -1, 6-naphthyridin-2 (1H) -one
s)Torin 2
CAS number → 1223001-51-1
(see http:// www.cas.org/content/chemical-substances/faqs)
Figure BDA0003405210870000372
Formula XXII: 9- (6-amino-3-pyridyl) -1- [3- (trifluoromethyl) phenyl ] -benzo [ H ] -1, 6-naphthyridine-2 (1H)
-ketones
t) Tuokennib (PP242)
CAS number → 1092351-67-1
(see http:// www.cas.org/content/chemical-substances/faqs)
Figure BDA0003405210870000373
Formula XXIII: 2- (4-amino-1-isopropyl-1H-pyrazolo [3,4-d ] pyrimidin-3-yl) -1H-indol-5-ol
u)WYE687
CAS number → 1062161-90-3
(see http:// www.cas.org/content/chemical-substances/faqs)
Figure BDA0003405210870000381
Formula XXIV: n- [4- [4- (4-morpholinyl) -1- [1- (3-pyridylmethyl) -4-piperidinyl ] -1H-pyrazolo [3,4-d ] pyrimidin-6-yl ] phenyl ] -carbamic acid methyl ester hydrochloride
v)ETP45658
CAS number → 1198357-79-7
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference →
(see https:// www.drugbank.ca /)
Unique identification code (UNII) →
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000382
Formula XXV: 3- [ 1-methyl-4- (4-morpholinyl) -1H-pyrazolo [3,4-d ] pyrimidin-6-ylphenol
w)PF05212384
CAS number → 1197160-78-3
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB11896
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → 96265TNH2R
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000391
Formula XXVI: n- [4- [ [4- (dimethylamino) -1-piperidinyl ] carbonyl ] phenyl ] -N' - [4- (4, 6-di-4-morpholinyl-1, 3, 5-triazin-2-yl) phenyl ] urea
x)PF04691502
CAS number → 1013101-36-4
(see http:// www.cas.org/content/chemical-substances/faqs)
Figure BDA0003405210870000392
Formula XXVII: amino-8- [ trans-4- (2-hydroxyethoxy) cyclohexyl ] -6- (6-methoxy-3-pyridyl) -4-methyl-pyrido [2,3-d ] pyrimidin-7 (8H) -one
y)XL388
CAS number → 1251156-08-7
(see http:// www.cas.org/content/chemical-substances/faqs)
Figure BDA0003405210870000401
Formula XXVIII: [7- (6-amino-3-pyridinyl) -2, 3-dihydro-1, 4-benzoxazepin-4 (5H) -yl ] [ 3-fluoro-2-methyl-4- (methylsulfonyl) phenyl ] -methanone
z)eCF309
CAS number → 2001571-40-8
(see http:// www.cas.org/content/chemical-substances/faqs)
Figure BDA0003405210870000402
Formula XXIX: 3- (2-amino-5-benzoxazolyl) -1- (2, 2-diethoxyethyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine
aa)RapaLink-1
CAS number → 1887095-82-0
(see http:// www.cas.org/content/chemical-substances/faqs)
Figure BDA0003405210870000411
Formula XXXI: 40-O- (2- ((1- (32- (4-amino-3- (2-aminobenzo [ d ] oxazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -27-oxo-3, 6,9,12,15,18,21, 24-octaoxa-28-azatridodecyl) -1H-1,2, 3-triazol-4-yl) methoxy) ethyl) -rapamycin
bb)Rapalink-2
Figure BDA0003405210870000412
Formula XXXII: 40-O- (2- ((1- (32- (4-amino-3- (2-aminobenzo [ d ] oxazol-5-yl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -27-oxo-3, 6,9,12,15,18,21, 24-heptaoxa-28-azatridodecyl) -1H-1,2, 3-triazol-4-yl) methoxy) ethyl) -rapamycin
----------------------------------
Second agent
Recent developments in agents that enhance anti-tumor immunity have rapidly changed the treatment of a wide range of cancers. However, these treatments are not effective in all cancer types, the response is often not persistent, and many patients receive little benefit from treatment. The prevailing hypothesis in the field of oncology is that only a combination of immunotherapy with other treatment options will ultimately be able to cure cancer patients.
ADCs are fully tolerated and active in a range of cancer types and will likely be a component of combination therapies that increase response rates and treatment persistence. It is an object of the present disclosure to combine an ADC with a second agent.
The second agent as described herein may be an immuno-oncology (IO) drug.
Immune-oncology (IO) drugs, a cancer therapy that relies on the body's immune system to help fight cancer, have shown enhanced persistence of anti-tumor responses. There are different types of IO including, but not limited to, PD1 inhibitors, PD-L1 inhibitors, CLTL4 inhibitors, GITR agonists, and OX40 agonists. Since a significant proportion of patients are not cured by single-dose immunotherapy and eventually relapse, combination therapy with alternative IO drugs or different treatment modalities is required (see KS Peggs et al 2009, Clinical and Experimental Immunology,157: 9-19 [ doi:10.1111/j.1365-2249.2009.03912.x ]; DM pardol 2012[ doi:10.1038/nrc3239 ]).
Immunogenic Cell Death (ICD) is a specific form of cell death that stimulates the immune response to dead cell antigens (released by dying cells) and it is considered one of the best ways to induce an adaptive immune response and improve the efficacy of anti-cancer therapies. This approach is often suboptimal, requiring the use of a combinatorial strategy that attempts to restore the full immunogenicity of cell death for therapeutic purposes. There are several anti-neoplastic agents that can induce ICDs, such as various anthracyclines (including doxorubicin (doxorubicin), epirubicin (epirubicin), and idarubicin (idarubicin)), alkylating agents (including oxaliplatin (oxapilatin) and cyclophosphamide), the topoisomerase II inhibitor mitoxantrone (mitoxantrone), and the proteasome inhibitor bortezomib.
Antibody-drug conjugates, including those with PBD warheads, may be particularly suitable as combination partners because they are more targeted than conventional chemotherapy and are expected to result in increased antigen presentation to infiltrating T cells as demonstrated for auristatin-based ADCs.
Combining an ADC with IO thus provides dual benefits: on the one hand, ADCs will directly kill the tumor expressing the target, providing immediate anti-tumor activity, and on the other hand, immunogenic cell death induced by ADC-mediated cell killing may promote a stronger and more durable adaptive immune response than when IO is administered as a single agent.
To demonstrate that the anti-CD 25ADC works synergistically with the second agent, a panel of CD25(+) cell lines will be co-treated with a range of concentrations of anti-CD 25ADC and the second agent. As a negative control, the same set of cell lines will be treated with a range of concentrations of the second agent or with a range of concentrations of anti-CD 25ADC and vehicle. After incubation, two parameters will be measured: the amount of surface CD25 (as determined by flow cytometry) and the combined in vitro cytotoxicity (as determined by MTS assay). To determine cytotoxicity, cell viability was measured by adding MTS to each well and incubating for 4 hours at 37 ℃. Percent cell viability was calculated and compared to untreated controls. Cytotoxicity synergy was calculated by converting cell viability data to affected scores and calculating combination indices using the CalcuSyn analysis program.
The second agent may be:
(a) bendamustine;
(b) phosphatidylinositol 3-kinase inhibitors such as copaipamide, idalarix, duviraxib, taselib, buparib, apidrix, ubulalix, daprolib, and ortalib;
(c) proteasome inhibitors such as bortezomib, carfilzomib, ixazoib, oprozomib, and salinosporamide a;
(d) antifolates such as pralatrexate, methotrexate, pemetrexed, and raltitrexed; or
(e) HDAC inhibitors such as romidepsin, vorinostat, Abistal, belinostat (PXD101), LAQ824, panobinostat (LBH589), entinostat (MS-275), tacroline (CI994) and moxidestat (MGCD 0103).
Each of these classes of second agents is described in more detail below.
Bendamustine
Bendamustine is a bifunctional dichloromethyldiethanamine derivative capable of forming electrophilic alkyl groups covalently bonded to other molecules. By this function as an alkylating agent, bendamustine causes intra-and inter-strand cross-linking between DNA bases, leading to cell death. It is active against both living and dormant cells.
Bendamustine has been indicated for the treatment of Chronic Lymphocytic Leukemia (CLL) and indolent B-cell non-hodgkin's lymphoma (NHL), which has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.
CAS number → 16506-27-7
(see http:// www.cas.org/content/chemical-substances/faqs)
Unique identification code (UNII) → 9266D9P3PQ
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000441
Formula XXXIII: bendamustine, 4- [5- [ bis (2-chloroethyl) amino ] -1-methylbenzimidazol-2-yl ] butanoic acid
Phosphatidylinositol 3-kinase inhibitors
The class I family of PI 3-kinase enzymes in vertebrates contains four distinct protein species (p110 α, p110 β, p110 δ, and p110 γ) of about 110 kDa. Most structural features of all class I enzymes are common and have common substrate specificity (Rameh and Cantley, 1999; Fry, 2001; Katso et al, 2001). In vitro, all class I PI 3-kinases are capable of phosphorylating PtdIns to PtdIns (3) P, phosphorylating PtdIns (4) P to PtdIns (3,4) P2 and phosphorylating PtdIns (4,5) P2 to PtdIns (3,4,5) P3, with PtdIns (4,5) P2 being considered as a preferred lipid substrate in vivo. Class I PI 3-kinases are predominantly cytoplasmic in resting cells, but recruit to the membrane via interaction with receptors or adaptor proteins upon stimulation. They are thought to function primarily at the plasma membrane, but class I PI 3-kinases have been reported to be associated with vesicles and nuclear membranes (Rameh and Cantley, 1999; Fry, 2001; Katso et al, 2001). The cellular roles of class I PI 3-kinases are diverse, with evidence linking them to cell size, viability, survival and proliferation in response to many signaling systems in many different cell types (Fry, 2001; Katso et al, 2001). The class I family is further subdivided into two groups based on their regulatory partners and activation mechanisms.
Although PI3K was first characterized two decades ago via binding to oncogenes and activated RTKs (reviewed in Zhao JJ et al, 2006), its association with human cancer was not established until the late 90 s of the 20 th century when the tumor suppressor PTEN was demonstrated to act as a PI 3-lipid phosphatase. Current comprehensive genomic analysis of cancer has revealed that in common human cancers, multiple components of the PI3K pathway are often mutated or altered, underscoring the importance of this pathway in cancer (see Wood LD et al science.2007; Samuels Y et al science.2004).
"phosphatidylinositol 3-kinase inhibitor" (PI3K inhibitor) is used herein to mean any agent that specifically binds to PI3K and/or inhibits its biological activity.
As used herein, "specifically binds PI 3K" is used to mean that the agent binds PI3K with higher affinity than a non-specific partner (such as bovine serum albumin, BSA, Genbank accession number CAA76847, version number CAA76847.1GI:3336842, record update date: 2011, 1,7, p.m. 02: 30). In some embodiments, the agent has an association constant for BSA that is at least 2,3,4, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, 10 higher than the agent's association constant for BSA, when measured under physiological conditions4、105Or 106Multiple association constant (K)a) Binds PI 3K. The agent can bind PI3K with high affinity. For example, in some embodiments, the agent may be equal to or less than about 10-6M (such as 1x 10)-6、10-7、10-8、10-9、10-10、10-11、10-12、10-13Or 10-14) K ofDBinds PI 3K.
PI3K inhibitors suitable for use in the present disclosure include:
a) kaempferi
CAS number → 1032568-63-0
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB12483
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → WI6V529FZ9
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000461
Formula XXXIV: copailisib, 2-amino-N- [ 7-methoxy-8- (3-morpholin-4-ylpropoxy) -2, 3-dihydroimidazo [1,2-c ] quinazolin-5-yl ] pyrimidine-5-carboxamide
b) Idelalisib
CAS number → 870281-82-6
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB09054
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → YG57I8T5M0
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000462
Formula XXXV: elatrilisib, 5-fluoro-3-phenyl-2- [ (1S) -1- (7H-purin-6-ylamino) propyl ] -4
(3H) -quinazolinones
c) Duvirisib
CAS number → 1201438-56-3
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB11952
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → 610V23S0JI
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000471
Formula XXXVI: duvirisib, 8-chloro-2-phenyl-3- [ (1S) -1- (3H-purin-6-ylamino) ethyl ] -1(2H) -isoquinolinone
d) Tasaili cloth
CAS number → 1282512-48-4
(see http:// www.cas.org/content/chemical-substances/faqs)
Unique identification code (UNII) → L08J2O299M
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000481
Formula XXXVII: taselib, 2- {4- [2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydroimidazo [1,2-d ] [1,4] benzoxazepin-9-yl ] -1H-pyrazol-1-yl } -2-methylpropanamide
e) Bupalib
CAS number → 944396-07-0
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB11666
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → 0ZM2Z182GD
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000482
Formula XXXVIII: buparvillea, 5- [2, 6-bis (morpholin-4-yl) pyrimidin-4-yl ] -4- (trifluoromethyl) pyridin-2-amine
f) Asperigis
CAS number → 1217486-61-7
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference →
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → 08W5N2C97Q
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000491
Formula XXXIX: albizinil, (2S) -1-N- [ 4-methyl-5- [2- (1,1, 1-trifluoro-2-methylpropan-2-yl) pyridin-4-yl ] -1, 3-thiazol-2-yl ] pyrrolidine-1, 2-dicarboxamide
g) Ubberelline
CAS number → 1532533-67-7
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB14989
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → 38073MQB2A
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000492
Formula XL: ulipristal, (S) -2- (1- (4-amino-3- (3-fluoro-4-isopropoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) ethyl) -6-fluoro-3- (3-fluorophenyl) -4H-chroman-4-one
h) Dapoxib
CAS number → 915019-65-7
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB11651
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → RUJ6Z9Y0DT
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000501
Formula XLI: dapoxib, 2-methyl-2- {4- [ 3-methyl-2-oxo-8- (quinolin-3-yl) -2, 3-dihydro-1H-imidazo [4,5-c ] quinolin-1-yl ] phenyl } propionitrile
i) Wotalix
CAS number → 934493-76-2
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB12400
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → CVL1685GPH
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000502
Formula XLII:
2-amino-8-ethyl-4-methyl-6- (1H-pyrazol-5-yl) -7H, 8H-pyrido [2,3-d ] pyrimidin-7-one
Proteasome inhibitors
Proteasomes are large protein complexes responsible for the degradation of intracellular proteins, a process requiring metabolic energy. Polymerization of the major molecule ubiquitin, which is known to work in concert with the proteasome, serves as a degradation signal for many target proteins; disruption of proteins is initiated by covalent attachment of chains consisting of several copies of ubiquitin (more than four ubiquitin molecules) by the synergistic action of the network of proteins including E1 (ubiquitin activation), E2 (ubiquitin conjugation), and E3 (ubiquitin conjugating) enzymes. The polymerized ubiquitin chains serve as a signal for shuttling the target protein to the proteasome, where the substrate is proteolytically cleaved. To select proteins accurately, many enzymes are regulated in this cascade case (e.g., 2E 1 proteins in humans, about 30E 2 proteins, and over 500 different species of E3). The collection of E3 proteins is highly diverse, as each E3 enzyme typically selectively recognizes one protein substrate for ubiquitination (see Tanaka 2009, Proc Jpn Acad Ser B Phys Biol Sci.2009, 1 month; 85(1): 12-36 and the cited materials therein).
The ubiquitin-proteasome system (UPS) controls almost all basic cellular processes, such as progression through cell cycle progression, signal transduction, cell death, immune responses, metabolism, protein quality control, and development, by degrading short-lived regulatory or structurally abnormal proteins.
These protein regulatory processes are also important in cancer, and thus, proteasomes are important regulators of carcinogenesis. Cancer includes a variety of cells that originate from a small percentage of cancer stem cells or are referred to as tumor initiating cells, according to cancer stem cell theory. These cells constitute a subset of the capacity to proliferate a wide variety of cancers and allow tumor recovery after cytostatic therapy. The proteasome functions in cellular processes in cancer stem cells, but it has been found to have reduced function in cancer stem cells compared to the remaining cancer cells. In particular, proteasomes have been reported to play a role in proliferation and pluripotency, which are characteristic of established cancer cells and cancer stem cells (see Voutsadakis et al, tomor Biology, 3 months 2017).
"proteasome inhibitor" is used herein to mean any agent that specifically binds to a proteasome component and/or inhibits a biological activity thereof.
As used herein, "specifically binds a proteasome component" is used to mean that the agent binds a proteasome component with higher affinity than a non-specific partner (such as bovine serum albumin, BSA, Genbank accession number CAA76847, version number CAA76847.1GI:3336842, record update date: 2011, 1,7, p.m. 02: 30). In some embodiments, the agent has an association constant for BSA that is at least 2,3,4, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, 10 higher than the agent's association constant for BSA, when measured under physiological conditions4、105Or 106Multiple association constant (K)a) Binding to a proteasome component. The agents can bind proteasome components with high affinity. Examples of such applications areFor example, in some embodiments, the agent may be equal to or less than about 10-6M (such as 1x 10)-6、10-7、10-8、10-9、10-10、10-11、10-12、10-13Or 10-14) K ofDBinding to a proteasome component.
Inhibitors of proteasome components suitable for use in the present disclosure include:
a) bortezomib
CAS number → 179324-69-7
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB00188
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → 69G8BD63PP
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000521
Formula XLIII: bortezomib, [ (1R) -3-methyl-1- ({ (2S) -3-phenyl-2- [ (pyrazin-2-ylcarbonyl) amino ] propanoyl } amino) butyl ] boronic acid
b) Carfilzomib
CAS number → 868540-17-4
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB08889
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → 72X6E3J5AR
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000531
Formula XLIV: carfilzomib, (2S) -4-methyl-N- [ (2S) -1- [ [ (2S) -4-methyl-1- [ (2R) -2-methyloxiran-2-yl ] -1-oxopent-2-yl ] amino ] -1-oxo-3-phenylprop-2-yl ] -2- [ [ (2S) -2- [ (2-morpholin-4-ylacetyl) amino ] -4-phenylbutyryl ] amino ] pentanamide
c) Ixazomib
CAS number → 1072833-77-2
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB09570
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → 71050168a2
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000532
Formula XLV: ixazomib, N2- (2, 5-dichlorobenzoyl) -N- [ (1R) -1- (borono) -3-methylbutyl ] glycinamide
d) Oprozomib
CAS number → 935888-69-0
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB11991
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → MZ37792Y8J
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000541
Formula XLVI: oprozomib, N- [ (2S) -3-methoxy-1- [ [ (2S) -1- [ (2R) -2-methyloxiran-2-yl ] -1-oxo-3-phenylpropan-2-yl ] amino ] -1-oxopropan-2-yl ] -2-methyl-1, 3-thiazole-5-carboxamide
e) Salicosporine amide A
CAS number → 437742-34-2
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB11762
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → 703P9YDP7F
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000542
Formula XLVII: salicosporamide A, (4R,5S) -4- (2-chloroethyl) -1- ((1S) -cyclohex-2-enyl (hydroxy) methyl) -5-methyl-6-oxa-2-azabicyclo [3.2.0] heptane-3, 7-dione
Antifolic agent
Antifolates were the first group of antimetabolites to enter the clinic 65 years ago. The mechanism of action is due to disruption of the metabolic pathway that requires a carbon moiety supplied by the B9 folate vitamin similar thereto. While newer bone marrow and intestinal tissues are also folate dependent and are sites of antifolate toxicity, the clinical utility of antifolates is determined and dosages and time courses of administration are identified that provide sufficient selectivity to render these drugs effective in the treatment of cancer as well as inflammatory disorders.
The early antifolate drug was methotrexate. However, despite its early clinical success, understanding of the mechanism of action of methotrexate is slow. Likewise, the efficacy and selectivity of the folinic acid "rescue" that allows for the safe administration of high doses of methotrexate is well empirically determined, and even today, the basis for the selectivity of this regimen is not widely understood or well understood. The lack of a fundamental understanding of the biochemistry and molecular pharmacology of methotrexate has hampered the development of successive generations of antifolates that will enable the full clinical potential of such drugs to be achieved. Thus, over fifty years after the introduction of methotrexate, the second antifolate pemetrexed was approved in 2004 for the treatment of mesothelioma and subsequent non-small cell lung cancer. Pralatrexate was approved for the treatment of cutaneous T cell lymphoma in 2009 thereafter.
By "antifolate" is used herein to mean any agent that specifically binds to a component of the folate metabolic pathway and/or inhibits its biological activity.
As used herein, "specifically binds to a folate metabolic pathway component" is used to mean that the agent binds to a folate metabolic pathway component with a higher affinity than to a non-specific partner (such as bovine serum albumin, BSA, Genbank accession number CAA76847, version number CAA76847.1GI:3336842, record update date: 2011, 1,7, p.m. 02: 30). In some embodiments, the agent has an association constant for BSA that is at least 2,3,4, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, 10 higher than the agent's association constant for BSA, when measured under physiological conditions4、105Or 106Multiple association constant (K)a) Binding to a folate metabolic pathway component. The agent can bind folate metabolic pathway components with high affinity. For example, in some embodiments, the agent may be equal to or less than about 10-6M (such as 1x 10)-6、10-7、10-8、10-9、10-10、10-11、10-12、10-13Or 10-14) K ofDBinding to a folate metabolic pathway component.
Antifolates suitable for use in the present disclosure include:
a) pralatrexate
CAS number → 146464-95-1
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB06813
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → A8Q8I19Q20
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Formula XLVIII: pralatrexate, N- (4- {1- [ (2, 4-diaminopteridin-6-yl) methyl ] but-3-yn-1-yl } benzoyl) -L-glutamic acid
Figure BDA0003405210870000561
b) Methotrexate (MTX)
CAS number → 59-05-2
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB00563
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → YL5FZ2Y5U1
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000571
Formula XLIX: methotrexate, (2S) -2- [ (4- { [ (2, 4-diaminopteridin-6-yl) methyl ] (methyl) amino } benzoyl) amino ] glutarate
c) Pemetrexed
CAS number → 137281-23-3
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB00642
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → 04Q9AIZ7NO
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000572
Formula L: pemetrexed, (2S) -2- { [4- [2- (2-amino-4-oxo-1, 7-dihydropyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoyl ] amino } pentanedioic acid
d) Raltitrexed
CAS number → 112887-68-0
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB00293
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → FCB9EGG971
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000581
Formula LI: raltitrexed, N- [ (5- { methyl [ (2-methyl-4-oxo-1, 4-dihydroquinazolin-6-yl) methyl ] amino } -2-thienyl) carbonyl ] -L-glutamic acid
HDAC inhibitors
Many studies have demonstrated a key role for epigenetic mechanisms in cancer development. Carcinogenesis can not only be explained by genetic alterations, but also involves epigenetic processes (DNA methylation, histone modification, and noncoding RNA deregulation). Histone modifications include H3 and H4 histone lysine deacetylation leading to chromatin decondensation. These changes affect gene transcription, including upregulation of several anti-cancer genes and DNA repair genes. Thus, epigenetic processes have become novel therapeutic targets in many studies.
Studies in which members of class I HDACs have been knocked out using mice have demonstrated the importance of Histone Deacetylases (HDACs) in organisms. HDAC 1-nude mice died prenatally due to severe proliferation defects and overall growth arrest; HDAC 2-nude mice died the first day after birth due to cardiac malformation; and HDAC 3-nude mice died prenatally due to defects in gastrulation. HDACs appear to be important for gene expression. Its levels vary greatly in cancer cells and have been described several times, varying according to tumor type. HDAC1 is highly expressed in prostate, gastric, lung, esophageal, colon, and breast cancers. High levels of HDAC2 were found in colorectal, cervical and gastric cancers. Furthermore, HDAC3 was overexpressed in colon and breast tumors, whereas HDAC6 was highly expressed in breast tumors, HDAC8 was overexpressed in neuroblastoma cells, and HDAC11 was mainly localized in rhabdomyosarcoma. Increased expression and/or histone hyperacetylation of different HDACs in different cancers is caused by different mechanisms that can affect the effect of individual HDAC inhibitors (see Eckschlager et al, Int J Mol sci.2017, 7 months; 18(7): 1414; and references cited therein).
"HDAC inhibitor" is used herein to mean any agent that specifically binds to HDACs and/or inhibits the biological activity thereof.
As used herein, "specifically binds to HDACs" is used to mean that the agent binds HDACs with higher affinity than non-specific partners (such as bovine serum albumin, BSA, Genbank accession number CAA76847, version number CAA76847.1GI:3336842, record update date: 2011, 1,7, p.m. 02: 30). In some embodiments, the agent has an association constant for BSA that is at least 2,3,4, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, 10 higher than the agent's association constant for BSA, when measured under physiological conditions4、105Or 106Multiple association constant (K)a) Binds to HDAC. The agent can bind HDACs with high affinity. For example, in some embodiments, the agent may be equal to or less than about 10-6M (such as 1x 10)-6、10-7、10-8、10-9、10-10、10-11、10-12、10-13Or 10-14) K ofDBinds to HDAC.
HDAC inhibitors suitable for use in the present disclosure include:
a) romidepsin
CAS number → 128517-07-7
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB06176
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → CX3T89XQBK
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000601
Formula LII: romidepsin, (1S,4S,7Z,10S,16E,21R) -7-ethylene-4, 21-diisopropyl-2-oxa-12, 13-dithio-5, 8,20, 23-tetraazabicyclo [8.7.6] ditridecyl-16-ene-3, 6,9,19, 22-pentanone
b) Vorinostat
CAS number → 149647-78-9
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB02546
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → 58IFB293JI
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000602
Formula LIII: N-hydroxy-N' -phenyloctane diamides
c) Abelstat
CAS number → 783355-60-2
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB12565
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → IYO470654U
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000611
Formula LIV: abbestat, 3- [ (dimethylamino) methyl ] -N- {2- [4- (hydroxycarbamoyl) phenoxy ] ethyl } -1-benzofuran-2-carboxamide
d) Belinostat (PXD101)
CAS number → 866323-14-0
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB05015
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → F4H96P17NZ
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000612
Formula LV: belinostat, (2E) -N-hydroxy-3- [3- (phenylaminosulfonyl) phenyl ] prop-2-enamide
e)LAQ824
CAS number → 404951-53-7
(see http:// www.cas.org/content/chemical-substances/faqs)
Unique identification code (UNII) → V10P524501
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000621
Formula LVI: LAQ824, (2E) -N-hydroxy-3- [4- [ [ (2-hydroxyethyl) [2- (1H-indol-3-yl) ethyl ] amino ] methyl ] phenyl ] -2-propenamide
f) Panobinostat (LBH589)
CAS number → 404950-80-7
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB06603
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → 9647FM7Y3Z
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000622
Formula LVII: panobinostat, N-hydroxy (2E) -3- [4- ({ [2- (2-methyl-1H-indol-3-yl) ethyl ] amino } methyl) phenyl ] prop-2-eneimidic acid
g) Entinostat (MS-275)
CAS number → 209783-80-2
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB11841
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → 1ZNY4FKK9H
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000631
Formula LVIII: entinostat, N- [ [4- [ (2-aminophenyl) carbamoyl ] phenyl ] methyl ] carbamic acid pyridin-3-ylmethyl ester
h) Taike dinaline (CI994)
CAS number → 112522-64-2
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB12291
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → UMF554N5FG
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000632
Formula LIX: tacrine, N- (2-aminophenyl) -4-acetamidobenzamide
i) Moxistat (MGCD0103)
CAS number → 726169-73-9
(see http:// www.cas.org/content/chemical-substances/faqs)
Drug bank reference → DB11830
(see https:// www.drugbank.ca /)
Unique identification code (UNII) → A6GWB8T96J
(see http:// www.fda.gov/ForIndustry/DataStandards/Presence registration System-uniqueIngredientIdentifier UNII/default. htm)
Figure BDA0003405210870000641
Formula LX: moxistat, N- (2-aminophenyl) -4- ({ [4- (pyridin-3-yl) pyrimidin-2-yl ] amino } methyl) benzamide
----------------------------------
Advantageous properties of the combinations described
anti-CD 25ADC has demonstrated clinical utility when used alone as a single agent with an anti-BCL-2 agent, mTOR inhibitor, or second agent, for example in the treatment of cancer. However, as described herein, the combination of an anti-CD 25ADC and an anti-BCL-2 agent, mTOR inhibitor, or second agent is expected to provide one or more of the following advantages over treatment with anti-CD 25ADC alone or an anti-BCL-2 agent, mTOR inhibitor, or second agent:
1) effective treatment of a wider range of cancers;
2) effective treatment of resistant or refractory forms of disorders (such as cancer) and individuals with disorders such as cancer who relapse after a period of remission;
3) increased response rate to treatment; and/or
4) Increased treatment duration.
Effective treatment of a broader range of cancers as used herein means that a complete response is observed in a wider range of identified cancer types after treatment with the combination. In other words, complete response is observed from cancer types that have not previously reported complete response to anti-CD 25ADC alone or anti-BCL-2 agent, mTOR inhibitor, or second agent.
Effective treatment in the form of resistance, refractory or relapse as used herein means that after treatment with the combination, a complete response is observed in individuals who are partially or completely resistant or refractory to treatment with anti-CD 25ADC or anti-BCL-2 agent, mTOR inhibitor or second agent alone (e.g., individuals who show no response or only partial response after treatment with either agent alone, or individuals whose condition recurs). In some embodiments, a complete response is observed in at least 10% of individuals who are partially or completely resistant or refractory to treatment with anti-CD 25ADC alone or an anti-BCL-2 agent, mTOR inhibitor, or a second agent, following treatment with the anti-CD 25 ADC/anti-BCL-2 agent, mTOR inhibitor, or second agent combination. In some embodiments, a complete response is observed in at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% of individuals that are partially or completely resistant or refractory to treatment with anti-CD 25ADC alone or an anti-BCL-2 agent, an mTOR inhibitor, or a second agent, following treatment with the anti-CD 25 ADC/anti-BCL-2 agent, mTOR inhibitor, or second agent combination.
Increased response rate to treatment as used herein means that a complete response is observed in a greater proportion of individuals after treatment with the combination than is observed after treatment with either anti-CD 25ADC alone or anti-BCL-2 agent, mTOR inhibitor, or second agent. In some embodiments, a complete response is observed in at least 10% of treated individuals following treatment with the anti-CD 25 ADC/anti-BCL-2 agent, mTOR inhibitor, or second agent combination. In some embodiments, a complete response is observed in at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% of treated individuals following treatment with the anti-CD 25 ADC/anti-BCL-2 agent, mTOR inhibitor, or second agent combination.
Increased treatment durability as used herein means a longer average duration of complete response in an individual treated with the combination than in an individual achieving a complete response after treatment with either the anti-CD 25ADC or the anti-BCL-2 agent, mTOR inhibitor, or second agent alone. In some embodiments, the average duration of complete response after combined treatment with the anti-CD 25 ADC/anti-BCL-2 agent, mTOR inhibitor, or second agent is at least 6 months. In some embodiments, the average duration of complete response after treatment with the anti-CD 25 ADC/anti-BCL-2 agent, mTOR inhibitor, or second agent combination is at least 12 months, at least 18 months, at least 24 months, at least 3 years, at least 4 years, at least 5 years, at least 6 years, at least 7 years, at least 8 years, at least 9 years, at least 10 years, at least 15 years, or at least 20 years.
By 'complete response' is used herein to mean the absence of any clinical evidence of disease in an individual. Evidence can be assessed using appropriate methods in the art (e.g., CT or PET scans) or biopsy (as appropriate). The number of doses required to achieve a complete response can be one, two, three, four, five, ten or more. In some embodiments, the subject achieves a complete response no more than one year after administration of the first dose (such as no more than 6 months, no more than 3 months, no more than one month, no more than two weeks, or no more than one week after administration of the first dose).
The disorder treated
The combination therapies described herein include those with utility against anticancer activity. In particular, in certain aspects, the therapies comprise an antibody conjugated (i.e., covalently linked) to a PBD drug moiety (i.e., a toxin) through a linker. PBD drugs have cytotoxic effects when the drug is not conjugated to an antibody. The biological activity of the PBD drug moiety is thus modulated by conjugation to an antibody. The antibody-drug conjugates (ADCs) of the present disclosure selectively deliver an effective dose of a cytotoxic agent to tumor tissue, whereby greater selectivity, i.e., a lower effective dose, can be achieved.
Accordingly, in one aspect, the present disclosure provides a combination therapy comprising administering an anti-CD 25ADC that binds CD25 for use in therapy, wherein the method comprises selecting a subject based on expression of a target protein.
In one aspect, the present disclosure provides a combination therapy and a label indicating that the therapy is suitable for a subject determined to be suitable for such use. The label may indicate that the therapy is suitable for use in a subject having expression of CD25 (such as overexpression of CD 25). The tag may indicate that the subject has a particular type of cancer.
In another aspect, there is also provided a combination therapy as described herein for the treatment of a proliferative disease. Another aspect of the disclosure provides the use of a conjugate compound in the manufacture of a medicament for the treatment of a proliferative disease.
One skilled in the art can readily determine whether a candidate combination therapy for any particular cell type treats a proliferative disorder. For example, the following description may be suitably used in assays to assess the activity provided by a particular compound.
The combination therapies described herein can be used to treat proliferative diseases. The term "proliferative disease" is an unwanted or uncontrolled cellular proliferation, such as neoplastic or proliferative growth, involving an unwanted excess or abnormal cells in vitro or in vivo.
Examples of proliferative disorders include, but are not limited to, benign, pre-malignant, and malignant cell proliferation, including, but not limited to, neoplasms and tumors (e.g., histiocytoma, glioma, astrocytoma, osteoma), cancer (e.g., lung cancer, small cell lung cancer, gastrointestinal cancer, intestinal cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma), lymphoma, leukemia, psoriasis, bone disease, fibroproliferative disorders (e.g., fibroproliferative disorders of connective tissue), and atherosclerosis. Cancers of interest include, but are not limited to, leukemia and ovarian cancer.
Any cell type that can be treated includes, but is not limited to, lung, gastrointestinal tract (including, e.g., intestine, colon), breast (mammary gland cells), ovary, prostate, liver (liver cells), kidney (kidney cells), bladder, pancreas, brain, and skin.
Proliferative disorders of particular interest include, but are not limited to, non-hodgkin's lymphomas, including diffuse large B-cell lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Lymphoma (CLL), and marginal zone B-cell lymphoma (MZBL); and leukemias, such as Hairy Cell Leukemia (HCL), variant hairy cell leukemia (HCL-v), Anaplastic Large Cell Lymphoma (ALCL), and Acute Lymphoblastic Leukemia (ALL), such as philadelphia chromosome positive ALL (Ph + ALL) or philadelphia chromosome negative ALL (Ph-ALL). [ Fielding A., 1 month of Haematologica.2010; 95(1):8-12].
Proliferative diseases may be characterized by the presence of a neoplasm comprising CD25+ ve and CD25-ve cells.
A proliferative disease can be characterized by the presence of a neoplasm consisting of CD25-ve neoplastic cells, optionally wherein CD25-ve neoplastic cells are associated with CD25+ ve non-neoplastic cells (such as CD25+ ve T cells).
The target neoplasm or neoplastic cell may be all or a portion of a solid tumor.
A "solid tumor" will be understood herein to include solid hematological cancers, such as lymphomas discussed in more detail herein (hodgkin's lymphoma or non-hodgkin's lymphoma). The solid tumor can be an advanced solid tumor.
A solid tumor can be a neoplasm comprising or consisting of CD25+ ve neoplastic cells, including non-hematologic cancers. A solid tumor may be a neoplasm infiltrating CD25+ ve cells (such as CD25+ ve T cells), including non-hematologic cancers; such solid tumors can lack CD25 expression (in other words, comprise or consist of CD25-ve neoplastic cells).
For example, a solid tumor can be a tumor with high levels of infiltrating T cells (such as infiltrating regulatory T cells, Treg; Menterier-Caux, C. et al, Targ Oncol (2012)7: 15-28; Arce Vargas et al, 2017, Immunity 46, 1-10; Tanaka, A. et al, Cell Res.2017, 1 month 27(1): 109-118). Thus, the solid tumor can be pancreatic cancer, breast cancer, colorectal cancer, gastric and esophageal cancer, leukemia and lymphoma, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular cancer, renal cell carcinoma, and head and neck cancer.
In some embodiments, the proliferative disorder is T-cell lymphoma. In some cases, the disorder is Anaplastic Large Cell Lymphoma (ALCL), such as ALK-positive or ALK-negative ALCL.
It is contemplated that the combination therapies of the present disclosure may be used to treat a variety of diseases or disorders characterized, for example, by overexpression of a tumor antigen. Exemplary conditions or hyperproliferative disorders include benign or malignant tumors; leukemia, hematologic malignancies, and lymphoid malignancies. Other diseases include neuronal, glial, astrocyte, hypothalamic, glandular, macrophage, epithelial, stromal, blastocoel, inflammatory, angiogenic, and immunological diseases, including autoimmune disorders and graft-versus-host disease (GVHD).
Typically, the disease or disorder to be treated is a hyperproliferative disease, such as cancer. Examples of cancers to be treated herein include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More specific examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer (including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung), cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer (including cancer of the gastrointestinal tract), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, and head and neck cancer.
Autoimmune diseases in which combination therapy may be used include rheumatic disorders (such as rheumatoid arthritis, Shegarand's syndrome: (A))
Figure BDA0003405210870000691
syndrome), scleroderma, lupus (such as SLE and lupus nephritis), polymyositis/dermatomyositis, cryoglobulinemia, antiphospholipid antibody syndrome and psoriatic arthritis), osteoarthritis, autoimmune gastrointestinal and liver disorders (such as inflammatory bowel diseases (e.g. ulcerative colitis and Crohn's disease), autoimmune gastritis and pernicious anemia, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis and celiac disease), vasculitis (such as ANCA-associated vasculitis including charg-schert's vasculitis (Churg-Strauss vasculitis), Wegener's granulomatosis and polyarteritis), autoimmune neurological disorders (such as multiple sclerosis, ocular clonus myoclonus syndrome, myasthenia gravis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease and autoimmune polyneuropathy), kidney disorders (such as glomerulonephritis, Goodpasture's syndrome and Berger's disease), autoimmune skin disorders (such as psoriasis, urticaria, rubella, pemphigus vulgaris, bullous pemphigoid and cutaneous lupus erythematosus), hematologic disorders (such as thrombocytopenic purpura, thrombotic thrombocytopenic purpura, post-transfusion purpura and autoimmuneHemolytic anemia), atherosclerosis, uveitis, autoimmune hearing diseases (such as inner ear disease and hearing loss), Behcet's disease, Raynaud's syndrome, organ transplantation, graft-versus-host disease (GVHD), and autoimmune endocrine disorders (such as diabetes-related autoimmune diseases, such as insulin-dependent diabetes mellitus (IDDM), Addison's disease, and autoimmune thyroid diseases (e.g., Graves' disease and thyroiditis)). More preferred such diseases include, for example, rheumatoid arthritis, ulcerative colitis, ANCA-associated vasculitis, lupus, multiple sclerosis, heulan syndrome, graves' disease, IDDM, pernicious anemia, thyroiditis and glomerulonephritis.
In some aspects, the subject has a proliferative disorder selected from: (classical) hodgkin lymphomas with mixed cell types (hodgkin-/reed-scherger cells: CD25+/-), or non-hodgkin lymphomas, including B-cell chronic lymphocytic leukemia, diffuse large B-cell lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Lymphoma (CLL), marginal zone B-cell lymphoma (MZBL); and leukemias, such as Hairy Cell Leukemia (HCL), variant hairy cell leukemia (HCL-v), Acute Myeloid Leukemia (AML), Anaplastic Large Cell Lymphoma (ALCL), Acute Lymphoblastic Leukemia (ALL), such as philadelphia chromosome positive ALL (Ph + ALL) or philadelphia chromosome negative ALL (Ph-ALL) [ Fielding a., haematologic.2010 for 1 month; 95(1) 8-12), small cell lymphocytic lymphoma, adult T cell leukemia/lymphoma or anaplastic large cell lymphoma.
In some aspects, the subject has a proliferative disease characterized by the presence of a neoplasm comprising CD25+ ve and CD25-ve cells.
A proliferative disease can be characterized by the presence of a neoplasm consisting of CD25-ve neoplastic cells, optionally wherein CD25-ve neoplastic cells are associated with CD25+ ve non-neoplastic cells (such as CD25+ ve T cells).
The target neoplasm or neoplastic cell may be all or a portion of a solid tumor.
A solid tumor can be a neoplasm comprising or consisting of CD25+ ve neoplastic cells, including non-hematologic cancers. A solid tumor may be a neoplasm infiltrating CD25+ ve cells (such as CD25+ ve T cells), including non-hematologic cancers; such solid tumors can lack CD25 expression (in other words, comprise or consist of CD25-ve neoplastic cells). The solid tumor can be an advanced solid tumor.
For example, a solid tumor can be a tumor with high levels of infiltrating T cells (such as infiltrating regulatory T cells, Treg; Menterier-Caux, C. et al, Targ Oncol (2012)7: 15-28; Arce Vargas et al, 2017, Immunity 46, 1-10; Tanaka, A. et al, Cell Res.2017, 1 month 27(1): 109-118). Thus, the solid tumor can be pancreatic cancer, breast cancer, colorectal cancer, gastric and esophageal cancer, leukemia and lymphoma, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular cancer, renal cell carcinoma, and head and neck cancer.
Classical hodgkin lymphomas include nodular sclerosing, lymphocyte predominant, lymphocyte depleting, and mixed cell subtypes. The hodgkin lymphoma subtype may not be determined. In certain aspects, patients tested according to the methods herein suffer from hodgkin's lymphoma of nodular sclerosing and mixed-cell subtypes.
In certain aspects, the subject has diffuse large B-cell lymphoma or peripheral T-cell lymphoma, including anaplastic large-cell lymphoma and angioimmunoblastic T-cell lymphoma subtypes.
Patient selection
In certain aspects, an individual is selected for treatment with a combination therapy prior to administration of the treatment.
As used herein, individuals considered suitable for treatment are those expected to benefit from or respond to treatment. The subject may have or be suspected of having cancer or be at risk of having cancer. The individual may have received a diagnosis of cancer. In particular, the individual may have or be suspected of having lymphoma or at risk of having lymphoma. In some cases, an individual may have or be suspected of having or at risk of having a solid cancer with tumor-associated non-tumor cells that express CD25, such as infiltrating cells that express CD 25.
In some aspects, the subject is selected based on the amount or pattern of expression of CD 25. In some aspects, the selection is based on CD25 expression at the cell surface in the tissue or structure of interest. Thus, in some cases, a subject is selected based on having, being at risk of having, or having received a diagnosis of a proliferative disease characterized by the presence of, a neoplasm comprising or associated with cells having surface CD25 expression or cells having surface CD25 expression. A neoplasm may consist of cells having surface CD25 expression.
In some aspects, the subject is selected based on having a neoplasm comprising CD25+ ve and CD25-ve cells. A neoplasm may consist of CD25-ve neoplastic cells, optionally wherein CD25-ve neoplastic cells are associated with CD25+ ve non-neoplastic cells (such as CD25+ ve tregs). The neoplastic or neoplastic cells may be all or a portion of a solid tumor. Solid tumors can be partially or completely CD25-ve, and can infiltrate CD25+ ve cells, such as CD25+ ve tregs. In a preferred aspect, the solid tumor is associated with high levels of CD25+ ve infiltrating cells (such as Treg cells). In some aspects, a solid tumor is associated with low levels of CD25+ ve infiltrating cells (such as Treg cells). In some aspects, a solid tumor is not associated with CD25+ ve infiltrating cells (such as Treg cells); for example, the level of CD25+ ve cells may be below the detection limit. The solid tumor can be an advanced solid tumor.
In some cases, expression of CD25 in a particular tissue of interest is determined. For example, in a sample of tumor tissue. In some cases, systemic expression of CD25 was determined. For example, in samples of circulating fluids such as blood, plasma, serum or lymph.
In some aspects, the subject is selected as suitable for treatment due to the presence of CD25 expression in the sample. In such cases, subjects without CD25 expression may be considered to be unsuitable for treatment.
In other aspects, the level of CD25 expression is used to select subjects suitable for treatment. The subject is determined to be suitable for treatment when the expression level of the target is above a threshold level.
In some aspects, if cells obtained from the tumor react with an antibody against CD25 as determined by IHC, the subject is indicated as suitable for treatment.
In some aspects, a subject is determined to be suitable for treatment if at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more of all cells in the sample express CD 25. In some aspects disclosed herein, a subject is determined to be suitable for treatment if at least 5% of the cells in the sample express CD 25.
In certain aspects, the target is BCL-2, mTOR, or a secondary target protein. In some aspects, the selection is based on expression of BCL-2, mTOR, or a secondary target protein.
In some aspects, the selection is based on the level of CD25 and BCL-2, mTOR, or a secondary target protein on the cell surface.
In some aspects, the presence of CD25 in cells in the sample and/or the individual is indicated as being eligible for treatment with a combination comprising an anti-CD 25ADC and an anti-BCL-2 agent, an mTOR inhibitor, or a second agent. In other aspects, the amount and/or expression of CD25 must be above a threshold level to indicate that the individual is eligible for treatment. In some aspects, an observed change in CD25 and/or localization in the sample as compared to the control indicates that the individual is eligible for treatment.
In some aspects, if cells obtained from a lymph node or an extranodal site react with an antibody to CD25 and/or as determined by IHC, the individual is indicated as being eligible for treatment.
In some aspects, a patient is determined to be suitable for treatment if at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more of all cells in the sample express CD 25. In some aspects disclosed herein, a patient is determined to be suitable for treatment if at least 10% of the cells in the sample express CD 25.
In some aspects, a patient is determined to be suitable for treatment if at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more of all cells in the sample are expressed. In some aspects disclosed herein, a patient is determined to be suitable for treatment if at least 10% of the cells in the sample are expressed.
In some aspects, an individual suitable for treatment is selected based on a current or previous treatment regimen. In some embodiments, if the individual has been treated with an anti-BCL-2 agent, an mTOR inhibitor, or a second agent, the individual is selected for treatment with an anti-CD 25 ADC. In some embodiments, if the individual is being treated with an anti-BCL-2 agent, an mTOR inhibitor, or a second agent, the individual is selected for treatment with the anti-CD 25 ADC. In some cases, an individual is selected for treatment if the individual is refractory to treatment (or further treatment) with an anti-BCL-2 agent, mTOR inhibitor, or a second agent. In some cases, the anti-BCL-2 agent may be tenettol. In some cases, the mTOR inhibitor may be everolimus. In some cases, the second agent can be bortezomib, and in some cases, the second agent can be bendamustine, copaizis, idazolis, pralatrexate, romidepsin, or vorinostat. In embodiments where the individual is undergoing or has undergone treatment with an anti-BCL-2 agent, mTOR inhibitor, or second agent, the anti-CD 25ADC may be administered in combination with the anti-BCL-2 agent, mTOR inhibitor, or second agent, or administration of the anti-BCL-2 agent, mTOR inhibitor, or second agent may not be continued.
In some embodiments, the anti-CD 25ADC is administered to the selected individual in combination with an anti-BCL-2 agent, mTOR inhibitor, or a second agent. In some embodiments, the anti-CD 25ADC is administered to the selected individual without continuing to administer the anti-BCL-2 agent, mTOR inhibitor, or second agent. Preferably, the anti-BCL-2 agent is Venetok. The mTOR inhibitor is preferably everolimus. In some cases, the second agent can be bortezomib, and in some cases, the second agent can be bendamustine, copaizis, idazolis, pralatrexate, romidepsin, or vorinostat.
The term 'treated (or further treated) with an anti-BCL-2 agent, mTOR inhibitor, or second agent as refractory' is used herein to mean that when administered as monotherapy, the disorder, such as cancer, is not responsive to, or has ceased to be responsive to, administration of the anti-BCL-2 agent, mTOR inhibitor, or second agent. In some embodiments, individuals with refractory NHL are identified using the response criteria disclosed in Cheson et al, 2014(South Asian J cancer. 2014.1-3 months; 3(1): 66-70). In the document, non-responders are defined as individuals who (i) had a > 50% increase in nadir compared to the sum of the diameters of any previously identified abnormal nodules, or (ii) had any new lesions appeared during or at the end of treatment. In some embodiments, an individual with refractory leukemia is identified as an individual with stable or progressive disease who has completed one complete treatment cycle, or who achieves a partial response after two or more complete treatment cycles.
Sample (I)
The sample may comprise or may be derived from: a quantity of blood; an amount of serum derived from blood of an individual and which may comprise a fluid portion of the blood obtained after removal of fibrin clots and blood cells; a quantity of pancreatic juice; a tissue sample or biopsy; or a cell isolated from the individual.
The sample may be taken from any tissue or body fluid. In certain aspects, the sample may comprise or may be derived from a tissue sample, a biopsy, an excision, or cells isolated from an individual.
In certain aspects, the sample is a tissue sample. The sample can be a sample of tumor tissue (such as cancerous tumor tissue). The sample may have been obtained by tumor biopsy. In some aspects, the sample is a lymphatic tissue sample, such as a lymphatic system lesion sample or a lymph node biopsy. In some cases, the sample is a skin biopsy.
In some aspects, the sample is taken from a bodily fluid, more preferably a bodily fluid that circulates in the body. Thus, the sample may be a blood sample or a lymph sample. In some cases, the sample is a urine sample or a saliva sample.
In some cases, the sample is a blood sample or a blood-derived sample. The blood-derived sample can be a selected portion of the blood of the subject, such as a selected cell-containing fraction or a plasma or serum fraction.
The selected cell-containing fraction may contain cell types of interest, which may include White Blood Cells (WBCs), particularly peripheral blood mononuclear cells (PBCs) and/or granulocytes, and/or Red Blood Cells (RBCs). Thus, methods according to the present disclosure may involve detecting a first target polypeptide or nucleic acid in blood, white blood cells, peripheral blood mononuclear cells, granulocytes, and/or red blood cells.
The sample may be fresh or archived. For example, the archived tissue may be from the first diagnosis of the individual, or a biopsy at the time of relapse. In certain aspects, the sample is a fresh biopsy.
The first target polypeptide may be CD 25.
Individual condition
The subject can be an animal, a mammal, a placental mammal, a marsupial (e.g., kangaroo, satchel), a monocellular animal (e.g., duckbilled), a rodent (e.g., guinea pig, hamster, rat, mouse), a murine (e.g., mouse), a lagomorph (e.g., rabbit), a avian (e.g., bird), a canine (e.g., dog), a feline (e.g., cat), a equine (e.g., horse), a porcine (e.g., pig), a ovine (e.g., sheep), a bovine (e.g., cow), a primate, an simian (e.g., monkey or ape), a simian (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutan, gibbon), or a human.
Furthermore, the individual may be any of its developmental forms, such as a fetus. In a preferred embodiment, the individual is a human. The terms "subject", "patient" and "individual" are used interchangeably herein.
In some aspects disclosed herein, the subject has or is suspected of having cancer or has been identified as being at risk for cancer. In some aspects disclosed herein, the individual has received a diagnosis of cancer. Individuals may have been diagnosed with a proliferative disease characterized by the presence of a neoplasm comprising CD25+ ve and CD25-ve cells.
A proliferative disease can be characterized by the presence of a neoplasm consisting of CD25-ve neoplastic cells, optionally wherein CD25-ve neoplastic cells are associated with CD25+ ve non-neoplastic cells (such as CD25+ ve T cells).
In some cases, the individual has received a diagnosis of a solid tumor containing infiltrating cells that express CD25 +.
A solid tumor can be a neoplasm comprising or consisting of CD25+ ve neoplastic cells, including non-hematologic cancers. A solid tumor may be a neoplasm infiltrating CD25+ ve cells (such as CD25+ ve T cells), including non-hematologic cancers; such solid tumors can lack CD25 expression (in other words, comprise or consist of CD25-ve neoplastic cells). The solid tumor can be an advanced solid tumor.
For example, a solid tumor can be a tumor with high levels of infiltrating T cells (such as infiltrating regulatory T cells, Treg; Menterier-Caux, C. et al, Targ Oncol (2012)7: 15-28; Arce Vargas et al, 2017, Immunity 46, 1-10; Tanaka, A. et al, Cell Res.2017, 1 month 27(1): 109-118). Thus, the solid tumor can be pancreatic cancer, breast cancer, colorectal cancer, gastric and esophageal cancer, leukemia and lymphoma, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular cancer, renal cell carcinoma, and head and neck cancer.
The individual may be undergoing or have undergone therapeutic treatment for the cancer. The subject may or may not have previously received ADCX 25. In some cases, the cancer is lymphoma, including non-hodgkin's lymphoma.
The individual may be undergoing or have undergone treatment with an anti-BCL-2 agent, an mTOR inhibitor, or a second agent. In some cases, the individual may be refractory to treatment (or further treatment) with an anti-BCL-2 agent, mTOR inhibitor, or a second agent. In some cases, the anti-BCL-2 agent may be tenettol. In some cases, the mTOR inhibitor may be everolimus. In some cases, the second agent can be bortezomib, and in some cases, the second agent can be bendamustine, copaizis, idazolis, pralatrexate, romidepsin, or vorinostat. In embodiments where the individual is undergoing or has undergone treatment with an anti-BCL-2 agent, mTOR inhibitor, or second agent, the anti-CD 25ADC may be administered in combination with the anti-BCL-2 agent, mTOR inhibitor, or second agent, or administration of the anti-BCL-2 agent, mTOR inhibitor, or second agent may not be continued.
Control
In some aspects, target expression in an individual is compared to target expression in a control. Controls can be used to support the effectiveness of the staining and to identify experimental artifacts.
In some cases, the control may be a reference sample or reference dataset. The reference may be a sample that has been previously obtained from an individual with a known degree of fitness. The reference may be a data set obtained from analysis of a reference sample.
The control may be a positive control, wherein the target molecule is known to be present, or expressed at a high level; or a negative control in which the target molecule is known to be absent or expressed at low levels.
The control may be a sample of tissue from an individual known to benefit from treatment. The tissue may be of the same type as the sample being tested. For example, a sample of tumor tissue from an individual may be compared to a control sample of tumor tissue from an individual known to be suitable for treatment, such as an individual that has previously responded to treatment.
In some cases, the control may be a sample obtained from the same individual as the test sample but from a tissue that is known to be healthy. Thus, a sample of cancerous tissue from an individual may be compared to a sample of non-cancerous tissue.
In some cases, the control is a cell culture sample.
In some cases, the test sample is analyzed prior to incubation with the antibody to determine the background staining level inherent to the sample.
In some cases, isotype controls were used. Isotype controls use the same class of antibodies as the target-specific antibodies, but are not immunoreactive with the sample. Such controls can be used to distinguish between non-specific interactions of target-specific antibodies.
The method may include morphological and immunohistochemical interpretation by a hematopathologist to ensure accurate interpretation of test results. The method may involve confirming that the expression pattern is related to an expected pattern. For example, where the amount of CD25 and/or BCL-2, mTOR, or secondary target protein expression is analyzed, the method may involve confirming that expression is observed as membrane staining with cytoplasmic components in the test sample. The method may involve confirming that the ratio of target signal to noise is above a threshold level, thereby allowing clear discrimination between specific and non-specific background signals.
Method of treatment
As used herein, the term "treatment" in the context of treating a condition is generally related to treatment and therapy of a human or animal (e.g., in veterinary applications) that achieves a desired therapeutic effect (e.g., inhibits progression of the condition), and includes decreasing the rate of progression, arresting the rate of progression, resolution of the condition, amelioration of the condition, and healing of the condition. Treatment as a prophylactic measure (i.e., prevention, prophylaxis) is also included.
As used herein, the term "therapeutically effective amount" or "effective amount" is an amount that is effective in relation to the active compound or a material, composition or dosage form comprising the active compound to produce a certain desired therapeutic effect when administered according to a desired therapeutic regimen and to meet a reasonable benefit/risk ratio.
Similarly, as used herein, the term "prophylactically effective amount" is an amount related to an active compound or a material, composition or dosage form containing an active compound that is effective to produce some desired prophylactic effect when administered according to a desired treatment regimen, and to meet a reasonable benefit/risk ratio.
Methods of treatment are disclosed herein. Also provided is a method of treatment comprising administering to a subject in need thereof a therapeutically effective amount of an anti-CD 25ADC and an anti-BCL-2 agent, an mTOR inhibitor, or a second agent. The term "therapeutically effective amount" is an amount sufficient to exhibit a benefit to a subject. Such benefit may be at least an improvement in at least one symptom. The actual amount administered, as well as the rate and time course of administration, will depend on the nature and severity of the target being treated. Prescription of treatment (e.g., determination of dosage) is within the responsibility of general practitioners and other physicians. The subjects may have been tested to determine that they are eligible to receive treatment according to the methods disclosed herein. A method of treatment may comprise the step of determining whether a subject is eligible for treatment using the methods disclosed herein.
The anti-CD 25ADC comprises an anti-CD 25 antibody. The anti-CD 25 antibody can be HuMax-TACTM. The ADC may comprise a drug that is a PBD dimer. The ADC may be an anti-CD 25-ADC, and in particular ADCX25 or ADCT-301 (Terlin-Caliluzumab tesiline). The ADC may be the ADC disclosed in WO 2014/057119.
The anti-BCL-2 agent can be Venetok (ABT-199), Navietok (ABT-263), ABT-737, S55746/BCL201, and Orlemison (G3139). Preferably, the anti-BCL-2 agent is Venetok (ABT-199).
The mTOR inhibitor can be everolimus (RAD001), sirolimus (rapamycin), CCI-779 (temsirolimus), ridaforolimus (AP-23573), NVP-BEZ235 (daptomixb), BGT226, SF1126, jidalisel, omithizamide, XL765, Ku-0063794, oleuropein, AZD8055, AZD2014, AZD3147, sapercetin (INK128/MLN0128), OSI027, torein 1, torein 2, Turkonib (PP242), WYE687, ETP45658, PF 12305284, PF04691502, XL388, 35309, Rapalink-1, or Rapalink-2.
The second agent may be:
(a) bendamustine;
(b) phosphatidylinositol 3-kinase inhibitors such as copaipamide, idalarix, duviraxib, taselib, buparib, apidrix, ubulalix, daprolib, and ortalib;
(c) proteasome inhibitors such as bortezomib, carfilzomib, ixazoib, oprozomib, and salinosporamide a;
(d) antifolates such as pralatrexate, methotrexate, pemetrexed, and raltitrexed; or
(e) HDAC inhibitors such as romidepsin, vorinostat, Abistal, belinostat (PXD101), LAQ824, panobinostat (LBH589), entinostat (MS-275), tacroline (CI994) and moxidestat (MGCD 0103).
Treatment may involve administration of an anti-CD 25 ADC/anti-BCL-2 agent combination alone or in further combination with other treatments, either simultaneously or sequentially depending on the condition to be treated.
An example of a method of combination therapy with anti-CD 25ADC plus anti-BCL 2 involves:
(1) identifying an individual that has been treated with an anti-BCL-2 agent (such as venetock) or is being treated with an anti-BCL-2 agent;
(2) administering to the individual an anti-CD 25ADC, such as ADCx 25; and optionally
(3) An anti-BCL-2 agent, such as venetock, is administered to the individual in combination with (e.g., simultaneously with, or subsequent to) the anti-CD 25 ADC.
An example of a method of combination therapy with anti-CD 25ADC plus mTOR inhibitor involves:
(1) identifying an individual who has been treated or is being treated with an mTOR inhibitor (such as everolimus);
(2) administering to the individual an anti-CD 25ADC, such as ADCx 25; and optionally
(3) Administering to the individual an mTOR inhibitor, such as everolimus, in combination with (e.g., simultaneously with, or subsequent to) the anti-CD 25 ADC.
An example of a method of combination therapy with anti-CD 25ADC plus a second agent involves:
(1) identifying an individual who has been treated with, or is being treated with, a second agent (such as bendamustine, copaidine, idazolidine, bortezomib, pralatrexate, romidepsin, or vorinostat);
(2) administering to the individual an anti-CD 25ADC, such as ADCx 25; and optionally
(3) Administering to the individual a second agent, such as bendamustine, copaipamide, idazolide, bortezomib, pralatrexate, romidepsin, or vorinostat, in combination with (e.g., simultaneously with, or subsequent to) the anti-CD 25 ADC.
Examples of treatments and therapies include, but are not limited to, chemotherapy (administration of active agents, including, for example, drugs, such as chemotherapeutic agents); performing surgery; and radiation therapy.
"chemotherapeutic agents" are compounds that can be used to treat cancer, regardless of the mechanism of action. Classes of chemotherapeutic agents include, but are not limited to: alkylating agents, antimetabolites, spindle poison plant alkaloids, cytotoxic/antitumor antibiotics, topoisomerase inhibitors, antibodies, photosensitizers, and kinase inhibitors. Chemotherapeutic agents include "targeted therapies" and compounds used in conventional chemotherapy.
Examples of chemotherapeutic agents include: lenalidomide (A)
Figure BDA0003405210870000801
Celgene), vorinostat (
Figure BDA0003405210870000802
Merck), panobinostat (C)
Figure BDA0003405210870000803
Novartis), moxystat (MGCD0103), everolimus (
Figure BDA0003405210870000804
Novartis), bendamustine (TRE)
Figure BDA0003405210870000805
Mundicharma International), erlotinib (
Figure BDA0003405210870000806
Genentech/OSI Pharm), docetaxel (TA)
Figure BDA0003405210870000807
Sanofi-Aventis), 5-FU (fluorouracil, 5-fluorouracil, CAS number 51-21-8), gemcitabine (Gemcitabine)
Figure BDA0003405210870000808
Lilly), PD-0325901(CAS number 391210-10-9, Pfizer), cisplatin (cis-diamine, dichloroplatinum (II), CAS number 15663-27-1),Carboplatin (CAS number 41575-94-4), paclitaxel (paclitaxel) ((R))
Figure BDA0003405210870000809
Bristol-Myers Squibb Oncology, Princeton, N.J.), Trastuzumab (R) (R.B.C.)
Figure BDA00034052108700008010
Genentech), temozolomide (4-methyl-5-oxo-2, 3,4,6, 8-pentaazabicyclo [4.3.0]Nonane-2, 7, 9-triene-9-carboxamide, CAS number 85622-93-1,
Figure BDA00034052108700008011
schering Plough), tamoxifen ((Z) -2- [4- (1, 2-diphenylbut-1-enyl) phenoxy]-N, N-dimethylethylamine,
Figure BDA00034052108700008012
ISTUB
Figure BDA0003405210870000811
) And doxorubicin
Figure BDA0003405210870000812
Akti-1/2, HPPD and rapamycin.
Further examples of chemotherapeutic agents include: oxaliplatin (A)
Figure BDA0003405210870000813
Sanofi), bortezomib (
Figure BDA0003405210870000814
Millennium Pharm.), sultan (sutent), (II)
Figure BDA0003405210870000815
SU11248, Pfizer), letrozole (I), (II), (III), (IV), (V), (
Figure BDA0003405210870000816
Novartis), imatinib mesylate (imatinib mesylate), (I) and (II) a pharmaceutically acceptable salt thereof
Figure BDA0003405210870000817
Novartis), XL-518(Mek inhibitor, Exelixis, WO 2007/044515), ARRY-886(Mek inhibitor, AZD6244, Array BioPharma, Astra Zeneca), SF-1126(PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235(PI3K inhibitor, Novartis), XL-147(PI3K inhibitor, Exelixis), PTK787/ZK 222584(Novartis), fulvestrant (fulvestrant) ((fulvestrant)
Figure BDA0003405210870000818
AstraZeneca), leucovorin (leucovorin), rapamycin (sirolimus,
Figure BDA0003405210870000819
wyeth), lapatinib (TYKE)
Figure BDA00034052108700008110
GSK572016 (Glaxo Smith Kline), Lonafanib (Lonafarnib) (SARASAR)TMSCH 66336, Schering Plough), Sorafenib (sorafenib) ((Schering Plough)
Figure BDA00034052108700008111
BAY43-9006, Bayer Labs), gefitinib (gefitinib) ((B)
Figure BDA00034052108700008112
AstraZeneca), irinotecan (irinotecan), (
Figure BDA00034052108700008113
CPT-11, Pfizer), tipifarnib (ZARNESTRA)TM，Johnson&Johnson)、ABRAXANETMAlbumin engineered nanoparticle formulations of paclitaxel (without Cremophor), paclitaxel (American Pharmaceutical Partners, Schaumberg, Il), vandetanib (rINN, ZD6474, ZACTI)
Figure BDA00034052108700008114
AstraZeneca), chlorambucil (chlorambucil), AG1478, AG1571(SU 5271; sugen), temsirolimus (
Figure BDA00034052108700008115
Wyeth), pazopanib (pazopanib) (GlaxoSmithKline), canfosfamide (canfosfamide) (Wyeth)), pazopanib (pazopanib) (GlaxoSmithKline), and canfosfamide (canfosfamide) ((C-A-B-C-A-C
Figure BDA00034052108700008116
Telik), thiotepa (thiotepa) and cyclophosphamide
Figure BDA00034052108700008117
Alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodidopa (benzodipa), carboquone (carboquone), metodopa (meteedopa), and urodopa (uredopa); ethyleneimine and methylmelamine including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; annonaceous acetogenin (especially bullatacin and bullatacin); camptothecin (including the synthetic analogue topotecan); statstatins (bryostatin); a caristatin (callystatin); CC-1065 (including its adozelesin (adozelesin), carvelesin (carzelesin), and bizelesin (bizelesin) synthetic analogs); nostoc (especially nostoc 1 and nostoc 8); dolastatin (dolastatin); duocarmycin (duocarmycin) (including the synthetic analogs KW-2189 and CB1-TM 1); eislobin (eleutherobin); (ii) coprinus atramentarius alkali; alcohol of coral tree; sponge chalone; nitrogen mustards such as chlorambucil, naphazoline, cholorophosphamide, estramustine (estramustine), ifosfamide, dichloromethyl diethylamine oxide hydrochloride, melphalan (melphalan), neonebivhin (novembichin), benzene mustarne cholesterol, prednimustine (prednimustine), trofosfamide, uracil mustard; nitrosoureas such as carmustine (carmustine), chlorourethrin, fotemustine (Fotemustine), lomustine (lomustine), nimustine (nimustine), and ramustine (ranimustine); antibiotics, such as enediyne antibiotics (e.g., calicheamicin (calicheamicin), calicheamicin gamma 1l, calicheamicin omega I1(Angew chem. Intl. Ed. Engl. (1994)33: 183-). 186); dactinomycinEndomycin (dynemicin), dalinomycin a; bisphosphonates, such as clodronate; esperamicin (esperamicin); and neocarzinostain chromophore and related chromoprotein enediyne antibiotic chromophore), aclacinomycin (aclacinomycin), actinomycin (actinomycin), amphenomycin (aurramycin), azaserine, bleomycin (bleomycin), actinomycin C, carabicin (carabicin), carminomycin (carminomycin), carzinomycin, chromomycin, dactinomycin (dactinomycin), daunorubicin (daunorubicin), ditorelbicin (detorubicin), 6-diazo-5-oxo-L-norleucine, morpholinyl-doxorubicin, cyanomorpholinyl-doxorubicin, 2-pyrrolinyl-doxorubicin and deoxydoxorubicin, epirubicin, esorubicin (idarubicin), idarubicin, nemorubicin (nemorubicin), nemorubicin (nemulin), maculomycin (marcycin), mitomycin (such as mitomycin C), calicheamicin (gentamycin), mycins (gentamycin C (gentamycin), myceliomycin (myceliophytin C), actinomycin C, carabinicin (norubicin), and doxorubicin, and a pharmaceutically acceptable salts thereof, Olivomycin, pelomomycin (peplomycin), pofiomycin (porfiromycin), puromycin, triiron doxorubicin, rodobicin (rodorubicin), streptonigrin (streptonigrin), streptozocin (streptozocin), tubercidin, ubenimex (ubenimex), stastatin (zinostatin), zorubicin (zorubicin); antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin (pteropterin), trimetrexate (trimetrexate); purine analogs such as fludarabine (fludarabine), 6-mercaptopurine, thiamine, thioguanine; pyrimidine analogs such as cyclocytidine, azacitidine (azacitidine), 6-azauridine, carmofur (carmofur), cytarabine, dideoxyuridine, deoxyfluorouridine (enocitabine), fluorouridine; androgens such as carposterone (calusterone), dromostanolone propionate, epitioandrostanol, mepiquantene (mepiquantene), testolactone; anti-adrenal agents such as aminoglutethimide (aminoglutethimide), mitotane (mitotane), trostane (trilostane); folic acid replenisher such as folinic acid; acetyl glucurolactone; an aldehydic phosphoramide glycoside; (ii) aminolevulinic acid; eniluracil (eniluracil); amsacrine (amsacrine); doubly-branched betuzucil; bisantrene;edatrexate (edatraxate); polyfluoroamide (defofamine); dimecorsine (demecolcine); diazaquinone (diaziqutone); efletiri powder (elfornitine); ammonium etitanium acetate; epothilone (epothilone); etoglut (etoglucid); gallium nitrate; a hydroxyurea; lentinan; lonidamine (lonidainine); maytansinoids (maytansinoids), such as maytansine (maytansine) and ansamitocins (ansamitocins); mitoguazone (mitoguzone); mitoxantrone (mitoxantrone); mopidanol (mopidanmol); nitrerine (nitrarine); pentostatin (pentostatin); methionine; pirarubicin (pirarubicin); losoxantrone (losoxantrone); pedicellonic acid; 2-ethylhydrazine; procarbazine (procarbazine);
Figure BDA0003405210870000833
polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane (rizoxane); rhizomycin; sizofuran (sizofiran); a germanium spiroamine; alternarionic acid; a tri-imine quinone; 2,2' -trichlorotriethylamine; trichothecenes (especially T-2 toxin, verrucin A (verracurin A), bacillocin A and serpentin); urethane (urethan); vindesine (vindesine); dacarbazine (dacarbazine); mannitol mustard; dibromomannitol; dibromodulcitol; pipobromane (pipobroman); gatifloxacin (gacytosine); arabinoside ("Ara-C"); cyclophosphamide; thiotepa; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine
Figure BDA0003405210870000831
(ii) a hydroxyanthraquinone; teniposide (teniposide); edatrexae; daunomycin; aminopterin; capecitabine (capecitabine) (capecitabine)
Figure BDA0003405210870000832
Roche); ibandronate (ibandronate); CPT-11; topoisomerase inhibitor RFS 2000; difluoromethyl ornithine (DMFO); retinoids such as retinoic acid; and of any of the abovePharmaceutically acceptable salts, acids and derivatives. Combinations of agents may be used, such as CHP (doxorubicin, prednisone, cyclophosphamide) or CHOP (doxorubicin, prednisone, cyclophosphamide, vincristine).
Also included in the definition of "chemotherapeutic agent" are: (i) anti-hormonal agents which act to modulate or inhibit the action of hormones on tumours, such as anti-oestrogens and selective oestrogen receptor modulators (SERMs), including for example tamoxifen (including
Figure BDA0003405210870000841
Tamoxifen citrate), raloxifene (raloxifene), droloxifene (droloxifene), 4-hydroxytamoxifene, troloxifene (trioxifene), naloxifene (keoxifene), LY117018, onapristone (onapristone), and
Figure BDA0003405210870000842
(toremifene citrate); (ii) aromatase inhibitors which inhibit aromatase which regulates estrogen production in the adrenal gland, such as 4(5) -imidazole, aminoglutethimide,
Figure BDA0003405210870000843
(megestrol acetate),
Figure BDA0003405210870000844
(exemestane; Pfizer), fulvestrant (formestanine), fadrozole (fadrozole),
Figure BDA0003405210870000845
(vorozole)), (vorozole) (vorozole))),
Figure BDA0003405210870000846
(letrozole; Novartis), and
Figure BDA0003405210870000847
(anastrozole; AstraZeneca); (iii) antiandrogens, such as flutamide, nilutamide, bicalutamidede), leuprolide (leuprolide) and goserelin (goserelin); and troxacitabine (troxacitabine) (1, 3-dioxolane nucleoside cytosine analogues); (iv) protein kinase inhibitors such as MEK inhibitors (WO 2007/044515); (v) a lipid kinase inhibitor; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes involved in signaling pathways involved in abnormal cell proliferation (e.g., PKC- α, Raf, and H-Ras), such as Orimerson (R) ((R))
Figure BDA0003405210870000848
Genta Inc.); (vii) ribozymes, such as VEGF expression inhibitors (e.g.
Figure BDA0003405210870000849
) And inhibitors of HER2 expression; (viii) vaccines, such as gene therapy vaccines, e.g.
Figure BDA00034052108700008410
LEUVECT
Figure BDA00034052108700008411
And
Figure BDA00034052108700008412
rIL-2; topoisomerase 1 inhibitors, such as LU
Figure BDA00034052108700008413
rmRH; (ix) anti-angiogenic agents, such as bevacizumab (bevacizumab) ((r))
Figure BDA00034052108700008414
Genentech); and pharmaceutically acceptable salts, acids and derivatives of any of the above.
Also included in the definition of "chemotherapeutic agent" are therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (r) ((r))
Figure BDA0003405210870000851
Genentech); cetuximab (cetuximab) (E)
Figure BDA0003405210870000852
Imclone); panitumumab (panitumumab)
Figure BDA0003405210870000853
Amgen), pertuzumab (pertuzumab) (PERJETA)TM、OMNITARGTM2C4, Genentech), trastuzumab (
Figure BDA0003405210870000854
Genentech), MDX-060(Medarex) and the antibody drug conjugate otacin gemtuzumab (gemtuzumab ozogamicin) (
Figure BDA0003405210870000855
Wyeth)。
Humanized monoclonal antibodies having therapeutic potential as chemotherapeutic agents in combination with the conjugates of the present disclosure include: alemtuzumab, aprezumab (apiolizumab), aselizumab (aselizumab), alemtuzumab (atlizumab), bambizumab (bapineuzumab), bevacizumab, moxin bivatuzumab (bivatuzumab mertansine), moxin-trastuzumab (cantuzumab), ceduzumab (ceduzumab), velizumab), gorto cetuzumab (certolizumab pegol), cefdituzumab (ciduzumab), ceduzumab (ciduzumab), eculizumab (eculizumab), efuzumab (efuzumab), epratuzumab (epratuzumab), eprezuzumab (erbuzumab), non-philippib (apituzumab), aromatuzumab (aromatuzumab), eprezuzumab), epratuzumab (epratuzumab), epratuzumab (airuzumab), epratuzumab (erbuzumab), epratuzumab (airuzumab), epratuzumab (erbuzumab), epratuzumab (erbitumumab (erbuzumab), epratuzumab (erbitumumab), epratuzumab (erbitumumab), or erbitumumab (erbitumumab), or-tuzumab (erbitumumab), or hertuzumab (erbitumumab), or a (erbitumumab), or-tuzumab (erbitumumab), or hertuzumab (erbitumumab), or, Momuzumab (motavizumab), motozumab (motavizumab), natalizumab (natalizumab), nimotuzumab (nimotuzumab), norovalizumab (nolovizumab), numalizumab (numavizumab), omalizumab (omalizumab), palivizumab (palivizumab), paclobutrazumab (paclobulizumab), pefurtuzumab (paclobulizumab), pembrolizumab (pembrolizumab), pertuzumab (pericentruzumab), pertuzumab (pertuzumab), pertuzumab (rallizumab), ranibizumab (ranibizumab), rayleigh mab (resivizumab), rayleigh mab (reslizumab), rivuzumab (reslizumab), lexed antibody (resazulizumab), rituzumab (rituzumab), rituximab (ranibizumab (rit-castuzumab), rituzumab (retalizumab), rituzumab (resluruzumab), rituzumab (rexib (rituzumab), rituximab (retab (retalizumab), rituximab (retab), rituximab (rex), rituximab (rex), ritub), rituximab (rex), rex (rex), rezex (rex), rex (rezex), rex (rex), rex (rezex (rex), rex (rex), rex (rex), rex (rex), rex (rex), rex (rex-rex (rex), rex (rex-Refatuzumab), rex-trastux-rex), rex-Refatuzumab), rex-Refatten), rex-rex), rex-Rey), rex-, Tollizumab (toralizumab), trastuzumab, tuotuzumab (tutuzumab) simon, tukucistuzumab (tucusituzumab), enzuzumab (umavivizumab), ubuzumab (urotuximab), and vislizumab (visulizumab).
The composition according to the present disclosure is preferably a pharmaceutical composition. In addition to the active ingredient (i.e., the conjugate compound), the pharmaceutical compositions according to the present disclosure and for use according to the present disclosure may also comprise pharmaceutically acceptable excipients, carriers, buffers, stabilizers, or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The exact nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, for example transdermally, subcutaneously or intravenously.
Pharmaceutical compositions for oral administration may be in the form of tablets, capsules, powders or liquids. Tablets may contain solid carriers or adjuvants. Liquid pharmaceutical compositions typically comprise a liquid carrier, such as water, petroleum, animal or vegetable oil, mineral oil, or synthetic oil. Physiological saline solution, dextrose or other sugar solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included. Capsules may contain a solid carrier, such as gelatin.
For intravenous, transdermal or subcutaneous injection or injection at the site of affliction, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability. Those skilled in the art are fully enabled to prepare suitable solutions, such as sodium chloride Injection, Ringer's Injection, lactated Ringer's Injection, using, for example, isotonic vehicles. Preservatives, stabilizers, buffers, antioxidants and/or other additives may be included as desired.
Dosage form
One skilled in the art will appreciate that the appropriate dosage of the anti-CD 25ADC and/or anti-BCL-2 agent, mTOR inhibitor, or second agent, and compositions comprising these active elements, may vary from subject to subject. Determining the optimal dosage will generally involve balancing the level of therapeutic benefit with any risk or deleterious side effects. The selected dosage level will depend upon a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, the other drugs, compounds and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and current medical history of the subject. The amount of compound and the route of administration will ultimately be at the discretion of the physician, veterinarian or clinician, although generally the dosage will be selected to achieve a local concentration at the site of action that achieves the desired effect without causing substantial deleterious or adverse side effects.
In certain aspects, the dose of anti-CD 25ADC is determined by the expression of CD25 observed in a sample obtained from the subject. Thus, the level or location of CD25 expression in a sample may indicate that a higher or lower dose of anti-CD 25ADC is required. For example, a high CD25 expression level may indicate that a higher dose of anti-CD 25ADC would be suitable. In some cases, a high level of CD25 expression may indicate that another agent other than anti-CD 25ADC needs to be administered. For example, anti-CD 25ADC is administered in combination with a chemotherapeutic agent. High CD25 expression levels may indicate a more aggressive therapy.
In certain aspects, the dosage of the anti-BCL-2 agent, mTOR inhibitor, or second agent is determined by expression observed in a sample obtained from the subject. Thus, the level or location of expression in the sample may indicate that a higher or lower dose of the anti-BCL-2 agent, mTOR inhibitor, or second agent is required. For example, a high BCL-2, mTOR, or secondary target protein expression level may indicate that a higher dose of the anti-BCL-2 agent, mTOR inhibitor, or second agent would be suitable. In some cases, a high BCL-2, mTOR, or secondary target protein expression level may indicate a need to administer another agent in addition to the anti-BCL-2 agent, mTOR inhibitor, or second agent. For example, an anti-BCL-2 agent, mTOR inhibitor, or second agent is administered in combination with a chemotherapeutic agent. High levels of BCL-2, mTOR, or secondary target protein expression may indicate a more aggressive therapy.
Administration may be effected in one dose, continuously or intermittently (e.g., in separate doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those skilled in the art and will vary with the formulation used in therapy, the purpose of the therapy, the target cell or cells being treated and the subject being treated. Single or multiple administrations may be carried out and the dose level and pattern selected by the treating physician, veterinarian or clinician.
In general, suitable dosages for each active compound range from about 100ng to about 25mg per kilogram body weight of the subject per day (more typically from about 1 μ g to about 10 mg). Where the active compound is a salt, ester, amide, prodrug, or the like, the amount administered is calculated based on the parent compound and thus the actual weight used is scaled up.
In one embodiment, each active compound is administered to a human subject according to the following dosage regimen: about 100mg, 3 times daily.
In one embodiment, each active compound is administered to a human subject according to the following dosage regimen: about 150mg, 2 times daily.
In one embodiment, each active compound is administered to a human subject according to the following dosage regimen: about 200mg, 2 times daily.
However, in one embodiment, each conjugate compound is administered to the human subject according to the following dosage regimen: about 50 or about 75mg, 3 or 4 times daily.
In one embodiment, each conjugate compound is administered to a human subject according to the following dosage regimen: about 100 or about 125mg 2 times daily.
For anti-CD 25ADC, where it is a PBD-bearing ADC, the dosages described above may be applied to the conjugate (comprising the PBD moiety and the linker to the antibody) or to the effective amount of PBD compound provided, e.g. the amount of compound that is releasable after cleavage of the linker.
The anti-CD 25ADC comprises an anti-CD 25 antibody. The anti-CD 25 antibody can be HuMax-TACTM. The ADC may comprise a drug that is a PBD dimer. The ADC may be an anti-CD 25-ADC, and in particular, ADCX25 or ADCT-301. The ADC may be the ADC disclosed in WO 2014/057119.
The anti-BCL-2 agent can be Venetok (ABT-199), Navietok (ABT-263), ABT-737, S55746/BCL201, and Orlemison (G3139). Preferably, the anti-BCL-2 agent is Venetok (ABT-199).
The mTOR inhibitor can be everolimus (RAD001), sirolimus (rapamycin), CCI-779 (temsirolimus), ridaforolimus (AP-23573), NVP-BEZ235 (daptomixb), BGT226, SF1126, jidalisel, omithizamide, XL765, Ku-0063794, oleuropein, AZD8055, AZD2014, AZD3147, sapercetin (INK128/MLN0128), OSI027, torein 1, torein 2, Turkonib (PP242), WYE687, ETP45658, PF 12305284, PF04691502, XL388, 35309, Rapalink-1, or Rapalink-2.
The second agent may be:
(a) bendamustine;
(b) phosphatidylinositol 3-kinase inhibitors such as copaipamide, idalarix, duviraxib, taselib, buparib, apidrix, ubulalix, daprolib, and ortalib;
(c) proteasome inhibitors such as bortezomib, carfilzomib, ixazoib, oprozomib, and salinosporamide a;
(d) antifolates such as pralatrexate, methotrexate, pemetrexed, and raltitrexed; or
(e) HDAC inhibitors such as romidepsin, vorinostat, Abistal, belinostat (PXD101), LAQ824, panobinostat (LBH589), entinostat (MS-275), tacroline (CI994) and moxidestat (MGCD 0103).
Antibodies
The term "antibody" is used herein in a broad sense and specifically encompasses monoclonal antibodies, polyclonal antibodies, dimers, multimers, multispecific antibodies (e.g., bispecific antibodies), intact antibodies (also described as "full length" antibodies), and antibody fragments, so long as they exhibit the desired biological activity, e.g., the ability to bind CD25 (Miller et al (2003) journal.of Immunology 170: 4854-4861). The antibody may be a murine antibody, a human antibody, a humanized antibody, a chimeric antibody or derived from other species, such as rabbit, goat, sheep, horse or camel.
Antibodies are proteins produced by the immune system that are capable of recognizing and binding to a specific antigen. (Janeway, C., Travers, P., Walport, M., Shlomchik (2001) Immuno Biology, 5 th edition, Garland Publishing, New York). Target antigens typically have a number of binding sites, also referred to as epitopes, that are recognized by Complementarity Determining Regions (CDRs) on multiple antibodies. Each antibody that specifically binds to a different epitope has a different structure. Thus, one antigen may have more than one corresponding antibody. The antibody may comprise a full-length immunoglobulin molecule or an immunologically active portion of a full-length immunoglobulin molecule, i.e., a molecule or portion thereof that contains an antigen binding site that immunospecifically binds to an antigen of a target of interest, such targets including, but not limited to, cancer cells or cells that produce autoimmune antibodies associated with autoimmune diseases. The immunoglobulin may be of any class (e.g., IgG, IgE, IgM, IgD, and IgA) of immunoglobulin molecule, class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) or subclass or allotype (e.g., human G1m1, non-G1 m1[ i.e., any allotype other than G1m1 ], G1m1, G2m 1, G3m1, A2m1, k1, and k 1). The immunoglobulin may be derived from any species, including from human, murine or rabbit.
An "antibody fragment" comprises a portion of a full-length antibody, typically an anti-human antibody thereofThe primary binding domain or the variable domain. Examples of antibody fragments include Fab, Fab ', F (ab')2And a scFv fragment; a diabody; a linear antibody; fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies, CDRs (complementarity determining regions) and epitope-binding fragments of any of the above that immunospecifically bind to a cancer cell antigen, a viral antigen, or a microbial antigen, single chain antibody molecules; and multispecific antibodies formed from antibody fragments.
The term "monoclonal antibody" as used herein refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, each monoclonal antibody is directed against a single determinant on the antigen, in contrast to polyclonal antibody preparations comprising different antibodies directed against different determinants (epitopes). In addition to their specificity, monoclonal antibodies are advantageous because they can be synthetic, uncontaminated by other antibodies. The modifier "monoclonal" indicates that the antibody is characterized as being obtained from a substantially homogeneous population of antibodies, and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies to be used according to the present disclosure can be prepared by the hybridoma method first described by Kohler et al (1975) Nature 256:495, or can be prepared by recombinant DNA methods (see US 4816567). Clackson et al (1991) Nature,352: 624-; the technique described in Marks et al (1991) J.mol.biol.,222: 581-.
Monoclonal antibodies herein specifically include "chimeric" antibodies in which a portion of the heavy and/or light chain is identical or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remaining chain(s) is identical or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (US 4816567; and Morrison et al (1984) Proc. Natl.Acad. Sci. USA,81: 6851-6855). Chimeric antibodies include "primatized" antibodies comprising variable domain antigen binding sequences derived from a non-human primate (e.g., old world monkey or ape) and human constant region sequences.
An "intact antibody" herein is an antibody comprising VL and VH domains, as well as a light chain constant domain (CL) and heavy chain constant domains CH1, CH2, and CH 3. The constant domain may be a native sequence constant domain (e.g., a human native sequence constant domain) or an amino acid sequence variant thereof. An intact antibody may have one or more "effector functions," which refer to those biological activities attributable to the Fc region of the antibody (either the native sequence Fc region or the amino acid sequence variant Fc region). Examples of antibody effector functions include C1q binding; complement-dependent cytotoxicity; fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); performing phagocytosis; and down-regulating cell surface receptors, such as B cell receptors and BCRs.
Depending on the amino acid sequence of the constant domain of the heavy chain, the intact antibody can be assigned to different "classes". There are five main classes of intact antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these major classes can be further divided into "subclasses" (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA, and IgA 2. The heavy chain constant domains corresponding to different antibody classes are called α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
Drawings
Embodiments and experiments illustrating the principles of the present disclosure will now be discussed with reference to the accompanying drawings, in which:
FIG. 1 sequence
The present disclosure includes combinations of the described aspects and preferred features unless such combinations are clearly not allowed or explicitly avoided.
The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
Aspects and embodiments of the present disclosure will now be described, for example, with reference to the accompanying drawings. Other aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.
Throughout this specification including the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment.
Some embodiments
The following paragraphs describe some specific embodiments of the anti-CD 25ADC plus anti-BCL-2 agent aspect of the present disclosure:
1. a method of selecting an individual suitable for treatment with ADCx25 or ADCT-301, wherein if the individual has been treated with venetork, the individual is selected for treatment with ADCx25 or ADCT-301.
2. A method of selecting an individual suitable for treatment with ADCx25 or ADCT-301, wherein if the individual is being treated with venetork, the individual is selected for treatment with ADCx25 or ADCT-301.
3. The method of any one of the preceding paragraphs, wherein the individual is selected for treatment if the individual is refractory to treatment with tenecter's therapy or further treatment.
4.A method for treating a disorder in an individual, the method comprising:
(i) selecting an individual suitable for treatment by a method according to any of paragraphs 1 to 3; and
(ii) administering to the individual an effective amount of ADCx25 or ADCT-301.
5. The method of paragraph 4, further comprising administering a combination of Venetock and ADCx25 or ADCT-301.
6. A method for treating a disorder in an individual, the method comprising administering to the individual an effective amount of ADCx25 or ADCT-301 and venetock.
7. The method according to paragraph 6, wherein the individual is selected for treatment according to the method according to any one of paragraphs 1 to 3.
8. The method of any of paragraphs 5 to 7, wherein the treatment comprises administration of ADCx25 or ADCT-301 prior to, simultaneously with, or after venetork.
9. The method of any preceding paragraph, wherein the treatment further comprises administering a chemotherapeutic agent.
10. The method of any preceding paragraph, wherein the individual is a human.
11. The method of any preceding paragraph, wherein the individual has a disorder or has been determined to have a disorder.
12. The method of paragraph 11, wherein the individual has or has been determined to have cancer expressing CD25 or CD25+ tumor-associated non-tumor cells, such as CD25+ infiltrating cells.
13. The method of any preceding paragraph, wherein the subject is undergoing treatment with venetork.
14. The method of any preceding paragraph, wherein the subject has undergone treatment with venetork.
15. The method of any preceding paragraph, wherein the individual is refractory to treatment with vinatork or further treatment.
16. The method of any one of the preceding paragraphs, wherein the treatment has increased efficacy compared to monotherapy with ADCx25 or ADCT-301 or venetokay alone.
17. The method of any preceding paragraph, wherein the disorder is a proliferative disease.
18. The method of paragraph 17, wherein said disorder is cancer.
19. The method of paragraph 18, wherein said disorder is selected from the group comprising: non-hodgkin's lymphomas, including diffuse large B-cell lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Lymphoma (CLL), and marginal zone B-cell lymphoma (MZBL); and leukemias, such as Hairy Cell Leukemia (HCL), variant hairy cell leukemia (HCL-v), Anaplastic Large Cell Lymphoma (ALCL), and Acute Lymphoblastic Leukemia (ALL), such as philadelphia chromosome positive ALL (Ph + ALL) or philadelphia chromosome negative ALL (Ph-ALL).
ADCx25 or ADCT-301 for use in a method of treatment according to any of paragraphs 4 to 19.
21. A composition comprising ADCx25 or ADCT-301 for use in a method of treatment according to any one of paragraphs 4 to 19.
22. Venetork for use in a method of treatment according to any one of paragraphs 5 to 19.
23. A composition comprising vinatork for use in a method of treatment according to any one of paragraphs 5 to 19.
Use of ADCx25 or ADCT-301 in the manufacture of a medicament for treating a disorder in a subject, wherein the treatment comprises the method of any of paragraphs 4 to 19.
25. Use of Venetork in the manufacture of a medicament for treating a disorder in a subject, wherein the treatment comprises the method of any one of paragraphs 5 to 19.
26. A kit, comprising:
a first agent comprising ADCx25 or ADCT-301;
a package insert comprising instructions for administering the first agent according to the method of any of paragraphs 4 to 19.
27. The kit of paragraph 26, further comprising:
a second agent comprising vernetorks.
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The following paragraphs describe some specific embodiments of the anti-CD 25ADC plus mTOR inhibitor aspects of the present disclosure:
1. a method of selecting an individual suitable for treatment with ADCx25 or ADCT-301, wherein if the individual has been treated with everolimus, then the individual is selected for treatment with ADCx25 or ADCT-301.
2. A method of selecting an individual eligible for treatment with ADCx25 or ADCT-301, wherein if the individual is being treated with everolimus, then selecting the individual for treatment with ADCx25 or ADCT-301.
3. The method of any one of the preceding paragraphs, wherein the subject is selected for treatment if the subject is refractory to treatment with everolimus or further treatment.
4.A method for treating a disorder in an individual, the method comprising:
(i) selecting an individual suitable for treatment by a method according to any of paragraphs 1 to 3; and
(ii) administering to the individual an effective amount of ADCx25 or ADCT-301.
5. The method of paragraph 4, further comprising administering everolimus in combination with ADCx25 or ADCT-301.
6. A method for treating a disorder in an individual, the method comprising administering to the individual an effective amount of ADCx25 or ADCT-301 and everolimus.
7. The method according to paragraph 6, wherein the individual is selected for treatment according to the method according to any one of paragraphs 1 to 3.
8. The method of any of paragraphs 5 to 7, wherein the treatment comprises administration of ADCx25 or ADCT-301 before, simultaneously with or after everolimus.
9. The method of any preceding paragraph, wherein the treatment further comprises administering a chemotherapeutic agent.
10. The method of any preceding paragraph, wherein the individual is a human.
11. The method of any preceding paragraph, wherein the individual has a disorder or has been determined to have a disorder.
12. The method of paragraph 11, wherein the individual has or has been determined to have cancer expressing CD25 or CD25+ tumor-associated non-tumor cells, such as CD25+ infiltrating cells.
13. The method of any preceding paragraph, wherein the subject is undergoing treatment with everolimus.
14. The method of any preceding paragraph, wherein the subject has undergone treatment with everolimus.
15. The method of any preceding paragraph, wherein the subject is refractory to treatment with everolimus or further treatment.
16. The method of any one of the preceding paragraphs, wherein the treatment has increased efficacy compared to monotherapy with ADCx25 or ADCT-301 or everolimus alone.
17. The method of any preceding paragraph, wherein the disorder is a proliferative disease.
18. The method of paragraph 17, wherein said disorder is cancer.
19. The method of paragraph 18, wherein said disorder is selected from the group comprising: non-hodgkin's lymphomas, including diffuse large B-cell lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Lymphoma (CLL), and marginal zone B-cell lymphoma (MZBL); and leukemias, such as Hairy Cell Leukemia (HCL), variant hairy cell leukemia (HCL-v), Anaplastic Large Cell Lymphoma (ALCL), and Acute Lymphoblastic Leukemia (ALL), such as philadelphia chromosome positive ALL (Ph + ALL) or philadelphia chromosome negative ALL (Ph-ALL).
ADCx25 or ADCT-301 for use in a method of treatment according to any of paragraphs 4 to 19.
21. A composition comprising ADCx25 or ADCT-301 for use in a method of treatment according to any one of paragraphs 4 to 19.
22. Everolimus for use in a method of treatment according to any one of paragraphs 5 to 19.
23. A composition comprising everolimus for use in a method of treatment according to any one of paragraphs 5 to 19.
Use of ADCx25 or ADCT-301 in the manufacture of a medicament for treating a disorder in a subject, wherein the treatment comprises the method of any of paragraphs 4 to 19.
25. Use of everolimus in the manufacture of a medicament for treating a disorder in a subject, wherein the treatment comprises the method of any one of paragraphs 5 to 19.
26. A kit, comprising:
a first agent comprising ADCx25 or ADCT-301;
a package insert comprising instructions for administering the first agent according to the method of any of paragraphs 4 to 19.
27. The kit of paragraph 26, further comprising:
a second agent comprising everolimus.
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The following paragraphs describe some specific embodiments of the anti-CD 25ADC plus second agent aspect of the present disclosure:
1. a method of selecting an individual suitable for treatment with ADCx25 or ADCT-301, wherein the individual is selected for treatment with ADCx25 or ADCT-301 if the individual has been treated with bendamustine, copaipamil, idalisib, pralatrexate, romidepsin or vorinostat.
2. A method of selecting an individual suitable for treatment with ADCx25 or ADCT-301, wherein the individual is selected for treatment with ADCx25 or ADCT-301 if the individual is being treated with bendamustine, copaipamil, idalisib, pralatrexate, romidepsin or vorinostat.
3. The method of any one of the preceding paragraphs, wherein the individual is selected for treatment if the individual is refractory to treatment with bendamustine, copaimliside, idalais, pralatrexate, romidepsin, or vorinostat, or further treatment.
4.A method for treating a disorder in an individual, the method comprising:
(i) selecting an individual suitable for treatment by a method according to any of paragraphs 1 to 3; and
(ii) administering to the individual an effective amount of ADCx25 or ADCT-301.
5. The method of paragraph 4, further comprising administering bendamustine, copaipamide, idalais, pralatrexate, romidepsin, or vorinostat in combination with ADCx25 or ADCT-301.
6. A method for treating a disorder in a subject, the method comprising administering to the subject an effective amount of ADCx25 or ADCT-301 and bendamustine, copaipamil, idalais, pralatrexate, romidepsin, or vorinostat.
7. The method according to paragraph 6, wherein the individual is selected for treatment according to the method according to any one of paragraphs 1 to 3.
8. The method of any of paragraphs 5 to 7, wherein the treatment comprises administration of ADCx25 or ADCT-301 prior to bendamustine, copaimlisis, idalais, pralatrexate, romidepsin or vorinostat, simultaneously with bendamustine, copaimlisis, idalais, pralatrexate, romidepsin or vorinostat, or after bendamustine, copaimlisis, idalais, pralatrexate, romidepsin or vorinostat.
9. The method of any preceding paragraph, wherein the treatment further comprises administering a chemotherapeutic agent.
10. The method of any preceding paragraph, wherein the individual is a human.
11. The method of any preceding paragraph, wherein the individual has a disorder or has been determined to have a disorder.
12. The method of paragraph 11, wherein the individual has or has been determined to have cancer expressing CD25 or CD25+ tumor-associated non-tumor cells, such as CD25+ infiltrating cells.
13. The method of any preceding paragraph, wherein the individual is undergoing treatment with bendamustine, copaizide, idalaisins, pralatrexate, romidepsin, or vorinostat.
14. The method of any preceding paragraph, wherein the individual has undergone treatment with bendamustine, copaimliside, idalais, pralatrexate, romidepsin, or vorinostat.
15. The method of any preceding paragraph, wherein the individual is refractory to treatment or further treatment with bendamustine, copaipamil, idalaix, pralatrexate, romidepsin, or vorinostat.
16. The method of any one of the preceding paragraphs, wherein the treatment has increased efficacy compared to monotherapy with ADCx25 or ADCT-301 or bendamustine, copaiparental, idazolis, pralatrexate, romidepsin, or vorinostat alone.
17. The method of any preceding paragraph, wherein the disorder is a proliferative disease.
18. The method of paragraph 17, wherein said disorder is cancer.
19. The method of paragraph 18, wherein said disorder is selected from the group comprising: non-hodgkin's lymphomas, including diffuse large B-cell lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Lymphoma (CLL), and marginal zone B-cell lymphoma (MZBL); and leukemias, such as Hairy Cell Leukemia (HCL), variant hairy cell leukemia (HCL-v), Anaplastic Large Cell Lymphoma (ALCL), and Acute Lymphoblastic Leukemia (ALL), such as philadelphia chromosome positive ALL (Ph + ALL) or philadelphia chromosome negative ALL (Ph-ALL).
ADCx25 or ADCT-301 for use in a method of treatment according to any of paragraphs 4 to 19.
21. A composition comprising ADCx25 or ADCT-301 for use in a method of treatment according to any one of paragraphs 4 to 19.
22. Bendamustine, copaix, idalais, pralatrexate, romidepsin or vorinostat for use in a method of treatment according to any one of paragraphs 5 to 19.
23. A composition comprising bendamustine, copaix, idalais, pralatrexate, romidepsin, or vorinostat for use in a method of treatment according to any one of paragraphs 5 to 19.
Use of ADCx25 or ADCT-301 in the manufacture of a medicament for treating a disorder in a subject, wherein the treatment comprises the method of any of paragraphs 4 to 19.
25. Use of bendamustine, copaidine, idalais, pralatrexate, romidepsin, or vorinostat in the manufacture of a medicament for treating a disorder in a subject, wherein the treatment comprises the method of any one of paragraphs 5 to 19.
26. A kit, comprising:
a first agent comprising ADCx25 or ADCT-301;
a package insert comprising instructions for administering the first agent according to the method of any of paragraphs 4 to 19.
27. The kit of paragraph 26, further comprising:
a second agent comprising bendamustine, copaix, idazolis, pralatrexate, romidepsin, or vorinostat.
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The following paragraphs describe some specific embodiments of the anti-CD 25ADC plus second agent aspect of the present disclosure:
1. a method of selecting an individual suitable for treatment with ADCx25 or ADCT-301, wherein if the individual has been treated with bortezomib, then the individual is selected for treatment with ADCx25 or ADCT-301.
2. A method of selecting an individual eligible for treatment with ADCx25 or ADCT-301, wherein if the individual is being treated with bortezomib, then the individual is selected for treatment with ADCx25 or ADCT-301.
3. The method of any one of the preceding paragraphs, wherein the individual is selected for treatment if the individual is refractory to treatment with bortezomib or further treatment.
4.A method for treating a disorder in an individual, the method comprising:
(i) selecting an individual suitable for treatment by a method according to any of paragraphs 1 to 3; and
(ii) administering to the individual an effective amount of ADCx25 or ADCT-301.
5. The method of paragraph 4, further comprising administering bortezomib in combination with ADCx25 or ADCT-301.
6. A method for treating a disorder in an individual, the method comprising administering to the individual an effective amount of ADCx25 or ADCT-301 and bortezomib.
7. The method according to paragraph 6, wherein the individual is selected for treatment according to the method according to any one of paragraphs 1 to 3.
8. The method of any of paragraphs 5 to 7, wherein the treatment comprises administration of ADCx25 or ADCT-301 prior to, simultaneously with, or after bortezomib.
9. The method of any preceding paragraph, wherein the treatment further comprises administering a chemotherapeutic agent.
10. The method of any preceding paragraph, wherein the individual is a human.
11. The method of any preceding paragraph, wherein the individual has a disorder or has been determined to have a disorder.
12. The method of paragraph 11, wherein the individual has or has been determined to have cancer expressing CD25 or CD25+ tumor-associated non-tumor cells, such as CD25+ infiltrating cells.
13. The method of any preceding paragraph, wherein the subject is undergoing treatment with bortezomib.
14. The method of any preceding paragraph, wherein the subject has undergone treatment with bortezomib.
15. The method of any preceding paragraph, wherein the subject is refractory to treatment with bortezomib or further treatment.
16. The method of any one of the preceding paragraphs, wherein the treatment has increased efficacy compared to monotherapy with ADCx25 or ADCT-301 or bortezomib alone.
17. The method of any preceding paragraph, wherein the disorder is a proliferative disease.
18. The method of paragraph 17, wherein said disorder is cancer.
19. The method of paragraph 18, wherein said disorder is selected from the group comprising: non-hodgkin's lymphomas, including diffuse large B-cell lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Lymphoma (CLL), and marginal zone B-cell lymphoma (MZBL); and leukemias, such as Hairy Cell Leukemia (HCL), variant hairy cell leukemia (HCL-v), Anaplastic Large Cell Lymphoma (ALCL), and Acute Lymphoblastic Leukemia (ALL), such as philadelphia chromosome positive ALL (Ph + ALL) or philadelphia chromosome negative ALL (Ph-ALL).
ADCx25 or ADCT-301 for use in a method of treatment according to any of paragraphs 4 to 19.
21. A composition comprising ADCx25 or ADCT-301 for use in a method of treatment according to any one of paragraphs 4 to 19.
22. Bortezomib for use in a method of treatment according to any one of paragraphs 5 to 19.
23. A composition comprising bortezomib for use in a method of treatment according to any of paragraphs 5 to 19.
Use of ADCx25 or ADCT-301 in the manufacture of a medicament for treating a disorder in a subject, wherein the treatment comprises the method of any of paragraphs 4 to 19.
25. Use of bortezomib in the manufacture of a medicament for treating a disorder in a subject, wherein said treatment comprises the method of any of paragraphs 5 to 19.
26. A kit, comprising:
a first agent comprising ADCx25 or ADCT-301;
a package insert comprising instructions for administering the first agent according to the method of any of paragraphs 4 to 19.
27. The kit of paragraph 26, further comprising:
a second agent comprising bortezomib.
Statement of the invention (1)
1. A method of selecting an individual suitable for treatment with an anti-CD 25ADC, wherein if the individual has been treated with an anti-BCL-2 agent, the individual is selected for treatment with the anti-CD 25 ADC.
2. A method of selecting an individual suitable for treatment with an anti-CD 25ADC, wherein if the individual is being treated with an anti-BCL-2 agent, the individual is selected for treatment with the anti-CD 25 ADC.
3. The method of any one of the preceding paragraphs, wherein the individual is selected for treatment if the individual is refractory to treatment with the anti-BCL-2 agent or further treatment.
4.A method for treating a disorder in an individual, the method comprising:
(i) selecting an individual suitable for treatment by a method according to any of paragraphs 1 to 3; and
(ii) administering to the individual an effective amount of the anti-CD 25 ADC.
5. The method of paragraph 4, further comprising administering an anti-BCL-2 agent in combination with the anti-CD 25 ADC.
6. A method for treating a disorder in an individual, the method comprising administering to the individual an effective amount of an anti-CD 25ADC and an anti-BCL-2 agent.
7. The method according to paragraph 6, wherein the individual is selected for treatment according to the method according to any one of paragraphs 1 to 3.
8. The method of any one of paragraphs 5 to 7, wherein the treatment comprises administration of the anti-CD 25ADC prior to the anti-BCL-2 agent, simultaneously with the anti-BCL-2 agent, or after the anti-BCL-2 agent.
9. The method of any preceding paragraph, wherein the treatment further comprises administering a chemotherapeutic agent.
10. The method of any preceding paragraph, wherein the individual is a human.
11. The method of any preceding paragraph, wherein the individual has a disorder or has been determined to have a disorder.
12. The method of paragraph 11, wherein the individual has or has been determined to have cancer expressing CD25 or CD25+ tumor-associated non-tumor cells, such as CD25+ infiltrating cells.
13. The method of any preceding paragraph, wherein the individual is undergoing treatment with an anti-BCL-2 agent.
14. The method of any preceding paragraph, wherein the individual has undergone treatment with an anti-BCL-2 agent.
15. The method of any preceding paragraph, wherein the subject is refractory to treatment or further treatment with the anti-BCL-2 agent.
16. The method of any one of the preceding paragraphs, wherein the treatment has increased efficacy compared to monotherapy with the anti-CD 25ADC or anti-BCL-2 agent alone.
17. The method of any preceding paragraph, wherein the anti-CD 25ADC is ADCx25 or ADCT-301.
18. The method of any preceding paragraph, wherein the disorder is a proliferative disease.
19. The method of paragraph 18, wherein said disorder is cancer.
20. The composition, method, use or kit of any preceding paragraph, wherein the subject has or has been determined to have a disorder characterized by the presence of a neoplasm comprising CD25+ ve and CD25-ve cells.
21. The composition, method, use or kit of any preceding paragraph, wherein the subject has or has been determined to have a disorder characterized by the presence of a neoplasm comprising or consisting of CD25-ve neoplastic cells.
22. The composition, method, use or kit of any one of paragraphs 20 or 21, wherein the neoplasm is all or a portion of a solid tumor.
23. The method of statement 22, wherein the solid tumor is associated with CD25+ ve infiltrating cells;
optionally wherein the solid tumor is associated with high levels of CD25+ ve infiltrating cells.
24. The method of statement 23, wherein the solid tumor is selected from the group consisting of: pancreatic cancer, breast cancer (including triple negative breast cancer), colorectal cancer, gastric and esophageal cancer, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular cancer, renal cell carcinoma, bladder cancer, and head and neck cancer.
25. The composition, method, use or kit of any preceding paragraph, wherein the disorder is selected from the group comprising:
hodgkin's and non-hodgkin's lymphomas, including diffuse large B-cell lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Lymphoma (CLL), marginal zone B-cell lymphoma (MZBL);
leukemias, such as Hairy Cell Leukemia (HCL), variant hairy cell leukemia (HCL-v), Acute Myeloid Leukemia (AML), Anaplastic Large Cell Lymphoma (ALCL), and Acute Lymphoblastic Leukemia (ALL), such as philadelphia chromosome positive ALL (Ph + ALL) or philadelphia chromosome negative ALL (Ph-ALL);
pancreatic cancer, breast cancer, colorectal cancer, gastric and esophageal cancer, leukemia and lymphoma, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular cancer, renal cell carcinoma, and head and neck cancer.
26. The method of any preceding paragraph, wherein the anti-BCL-2 agent is selected from the group consisting of: venetok (ABT-199), Navitoxk (ABT-263), ABT-737, S55746/BCL201, and Olimoeson (G3139).
27. The method of any preceding paragraph, wherein the anti-BCL-2 agent is tenettog.
28. An anti-CD 25ADC for use in a method of treatment according to any of paragraphs 4 to 27.
29. A composition comprising an anti-CD 25ADC for use in a method of treatment according to any one of paragraphs 4 to 27.
30. An anti-BCL-2 agent for use in a method of treatment according to any one of paragraphs 5 to 27.
31. A composition comprising an anti-BCL-2 agent for use in a method of treatment according to any one of paragraphs 5 to 27.
32. Use of an anti-CD 25ADC in the manufacture of a medicament for treating a disorder in a subject, wherein the treatment comprises the method of any one of paragraphs 4 to 27.
33. Use of an anti-BCL-2 agent in the manufacture of a medicament for treating a disorder in a subject, wherein the treatment comprises the method of any one of paragraphs 5 to 27.
34. A kit, comprising:
a first agent comprising an anti-CD 25 ADC;
a package insert comprising instructions for administering the first agent according to the method of any of paragraphs 4 to 27.
35. The kit of paragraph 34, further comprising:
a second agent comprising an anti-BCL-2 agent.
Statement of the invention (2)
1. A method of selecting an individual suitable for treatment with an anti-CD 25ADC, wherein if the individual has been treated with an mTOR inhibitor, the individual is selected for treatment with the anti-CD 25 ADC.
2. A method of selecting an individual suitable for treatment with an anti-CD 25ADC, wherein if the individual is being treated with an mTOR inhibitor, the individual is selected for treatment with the anti-CD 25 ADC.
3. The method of any of the preceding paragraphs, wherein the individual is selected for treatment if the individual is refractory to treatment or further treatment with the mTOR inhibitor.
4.A method for treating a disorder in an individual, the method comprising:
(i) selecting an individual suitable for treatment by a method according to any of paragraphs 1 to 3; and
(ii) administering to the individual an effective amount of the anti-CD 25 ADC.
5. The method of paragraph 4, further comprising administering a mTOR inhibitor in combination with the anti-CD 25 ADC.
6. A method for treating a disorder in an individual, the method comprising administering to the individual an effective amount of an anti-CD 25ADC and an mTOR inhibitor.
7. The method according to paragraph 6, wherein the individual is selected for treatment according to the method according to any one of paragraphs 1 to 3.
8. The method of any of paragraphs 5 to 7, wherein the treatment comprises administration of the anti-CD 25ADC prior to, simultaneously with or after the mTOR inhibitor.
9. The method of any preceding paragraph, wherein the treatment further comprises administering a chemotherapeutic agent.
10. The method of any preceding paragraph, wherein the individual is a human.
11. The method of any preceding paragraph, wherein the individual has a disorder or has been determined to have a disorder.
12. The method of paragraph 11, wherein the individual has or has been determined to have cancer expressing CD25 or CD25+ tumor-associated non-tumor cells, such as CD25+ infiltrating cells.
13. The method of any preceding paragraph, wherein the individual is undergoing treatment with an mTOR inhibitor.
14. The method of any preceding paragraph, wherein the individual has undergone treatment with an mTOR inhibitor.
15. The method of any preceding paragraph, wherein the individual is refractory to treatment or further treatment with the mTOR inhibitor.
16. The method of any one of the preceding paragraphs, wherein the treatment has increased efficacy compared to a monotherapy using the anti-CD 25ADC or mTOR inhibitor alone.
17. The method of any preceding paragraph, wherein the anti-CD 25ADC is ADCx25 or ADCT-301.
18. The method of any preceding paragraph, wherein the disorder is a proliferative disease.
19. The method of paragraph 18, wherein said disorder is cancer.
20. The method of any preceding paragraph, wherein the individual has, or has been determined to have, a condition characterized by the presence of a neoplasm comprising CD25+ ve and CD25-ve cells.
21. The method of any preceding paragraph, wherein the individual has, or has been determined to have, a disorder characterized by the presence of a neoplasm comprising or consisting of CD25-ve neoplastic cells.
22. The method of any of paragraphs 20 or 21, wherein the neoplasm is all or a portion of a solid tumor.
23. The method of statement 22, wherein the solid tumor is associated with CD25+ ve infiltrating cells;
optionally wherein the solid tumor is associated with high levels of CD25+ ve infiltrating cells.
24. The method of statement 23, wherein the solid tumor is selected from the group consisting of: pancreatic cancer, breast cancer (including triple negative breast cancer), colorectal cancer, gastric and esophageal cancer, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular cancer, renal cell carcinoma, bladder cancer, and head and neck cancer.
25. The method of any preceding paragraph, wherein the disorder is selected from the group comprising:
hodgkin's and non-hodgkin's lymphomas, including diffuse large B-cell lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Lymphoma (CLL), marginal zone B-cell lymphoma (MZBL);
leukemias, such as Hairy Cell Leukemia (HCL), variant hairy cell leukemia (HCL-v), Acute Myeloid Leukemia (AML), Anaplastic Large Cell Lymphoma (ALCL), and Acute Lymphoblastic Leukemia (ALL), such as philadelphia chromosome positive ALL (Ph + ALL) or philadelphia chromosome negative ALL (Ph-ALL);
pancreatic cancer, breast cancer, colorectal cancer, gastric and esophageal cancer, leukemia and lymphoma, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular cancer, renal cell carcinoma, and head and neck cancer.
26. The method of any preceding paragraph, wherein the mTOR inhibitor is everolimus (RAD001), sirolimus (rapamycin), CCI-779 (temsirolimus), ridaforolimus (AP-23573), NVP-BEZ235 (daptomixb), BGT226, SF1126, Gedalisel, Omeilisib, XL765, Ku-0063794, oleuropein, AZD8055, AZD2014, AZD3147, Sappacrophan (INK128/MLN0128), OSI027, torein 1, torein 2, Tukinib (PP242), WYE687, ETP 658, PF05212384, PF04691502, XL388, eCF309, Rapalink-1, or Rapalink-2.
27. The method of any preceding paragraph, wherein the mTOR inhibitor is everolimus.
28. An anti-CD 25ADC for use in a method of treatment according to any of paragraphs 4 to 27.
29. A composition comprising an anti-CD 25ADC for use in a method of treatment according to any one of paragraphs 4 to 27.
30. An mTOR inhibitor for use in a method of treatment according to any of paragraphs 5 to 27.
31. A composition comprising an mTOR inhibitor for use in a method of treatment according to any of paragraphs 5 to 27.
32. Use of an anti-CD 25ADC in the manufacture of a medicament for treating a disorder in a subject, wherein the treatment comprises the method of any one of paragraphs 4 to 27.
Use of an mTOR inhibitor in the manufacture of a medicament for treating a disorder in an individual, wherein the treatment comprises the method of any of paragraphs 5 to 27.
34. A kit, comprising:
a first agent comprising an anti-CD 25 ADC;
a package insert comprising instructions for administering the first agent according to the method of any of paragraphs 4 to 27.
35. The kit of paragraph 34, further comprising:
a second agent comprising an mTOR inhibitor.
Statement of the invention (3)
1. A method of selecting an individual suitable for treatment with an anti-CD 25ADC, wherein if the individual has been treated with a second agent, the individual is selected for treatment with the anti-CD 25 ADC.
2. A method of selecting an individual suitable for treatment with an anti-CD 25ADC, wherein if the individual is being treated with a second agent, the individual is selected for treatment with the anti-CD 25 ADC.
3. The method of any one of the preceding paragraphs, wherein the individual is selected for treatment if the individual is refractory to treatment with the second agent or further treatment.
4.A method for treating a disorder in an individual, the method comprising:
(i) selecting an individual suitable for treatment by a method according to any of paragraphs 1 to 3; and
(ii) administering to the individual an effective amount of the anti-CD 25 ADC.
5. The method of paragraph 4, further comprising administering a second agent in combination with the anti-CD 25 ADC.
6. A method for treating a disorder in an individual, the method comprising administering to the individual an effective amount of an anti-CD 25ADC and a second agent.
7. The method according to paragraph 6, wherein the individual is selected for treatment according to the method according to any one of paragraphs 1 to 3.
8. The method of any one of paragraphs 5 to 7, wherein the treatment comprises administration of the anti-CD 25ADC prior to, concurrently with, or after the second agent.
9. The method of any preceding paragraph, wherein the treatment further comprises administering a chemotherapeutic agent.
10. The method of any preceding paragraph, wherein the individual is a human.
11. The method of any preceding paragraph, wherein the individual has a disorder or has been determined to have a disorder.
12. The method of paragraph 11, wherein the individual has or has been determined to have cancer expressing CD25 or CD25+ tumor-associated non-tumor cells, such as CD25+ infiltrating cells.
13. The method of any preceding paragraph, wherein the individual is undergoing treatment with a second agent.
14. The method of any preceding paragraph, wherein the individual has undergone treatment with a second agent.
15. The method of any preceding paragraph, wherein the subject is refractory to treatment with the second agent or further treatment.
16. The method of any one of the preceding paragraphs, wherein the treatment has increased efficacy compared to monotherapy with the anti-CD 25ADC or a second agent alone.
17. The method of any preceding paragraph, wherein the anti-CD 25ADC is ADCx25 or ADCT-301.
18. The method of any preceding paragraph, wherein the disorder is a proliferative disease.
19. The method of paragraph 18, wherein said disorder is cancer.
20. The method of any preceding paragraph, wherein the individual has, or has been determined to have, a condition characterized by the presence of a neoplasm comprising CD25+ ve and CD25-ve cells.
21. The method of any preceding paragraph, wherein the individual has, or has been determined to have, a disorder characterized by the presence of a neoplasm comprising or consisting of CD25-ve neoplastic cells.
22. The method of any of paragraphs 20 or 21, wherein the neoplasm is all or a portion of a solid tumor.
23. The method of statement 22, wherein the solid tumor is associated with CD25+ ve infiltrating cells;
optionally wherein the solid tumor is associated with high levels of CD25+ ve infiltrating cells.
24. The method of statement 23, wherein the solid tumor is selected from the group consisting of: pancreatic cancer, breast cancer (including triple negative breast cancer), colorectal cancer, gastric and esophageal cancer, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular cancer, renal cell carcinoma, bladder cancer, and head and neck cancer.
25. The method of any preceding paragraph, wherein the disorder is selected from the group comprising:
hodgkin's and non-hodgkin's lymphomas, including diffuse large B-cell lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Lymphoma (CLL), marginal zone B-cell lymphoma (MZBL);
leukemias, such as Hairy Cell Leukemia (HCL), variant hairy cell leukemia (HCL-v), Acute Myeloid Leukemia (AML), Anaplastic Large Cell Lymphoma (ALCL), and Acute Lymphoblastic Leukemia (ALL), such as philadelphia chromosome positive ALL (Ph + ALL) or philadelphia chromosome negative ALL (Ph-ALL);
pancreatic cancer, breast cancer, colorectal cancer, gastric and esophageal cancer, leukemia and lymphoma, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular cancer, renal cell carcinoma, and head and neck cancer.
26. The method of any of paragraphs 1 to 25, wherein the second agent is bendamustine.
27. The method of any of paragraphs 1 to 25, wherein the second agent is a phosphatidylinositol 3-kinase inhibitor.
28. The method of paragraph 27, wherein the phosphatidylinositol 3-kinase inhibitor is copaipamil, idarilib, duviraib, taselib, bupariib, apidrib, ubularicib, daptomib, or ortalib.
29. The method of paragraph 27, wherein the phosphatidylinositol 3-kinase inhibitor is copaix or idelalisix.
30. The method of any of paragraphs 1 to 25, wherein the second agent is a proteasome inhibitor.
31. The method of paragraph 30, wherein the proteasome inhibitor is bortezomib, carfilzomib, ixazoib, oprozomib, or salinosporamide a.
32. The method of paragraph 30, wherein the proteasome inhibitor is bortezomib.
33. The method of any of paragraphs 1 to 25, wherein the second agent is an antifolate.
34. The method of paragraph 33, wherein the antifolate is pralatrexate, methotrexate, pemetrexed, or raltitrexed.
35. The method of paragraph 33, wherein the antifolate is pralatrexate.
36. The method of any of paragraphs 1 to 25, wherein the second agent is an HDAC inhibitor.
37. The method of paragraph 36, wherein the HDAC inhibitor is romidepsin, vorinostat, abbestat, belinostat (PXD101), LAQ824, panobinostat (LBH589), entinostat (MS-275), tacroline (CI994), or moxidestat (MGCD 0103).
38. The method of paragraph 36, wherein the HDAC inhibitor is romidepsin or vorinostat.
39. An anti-CD 25ADC for use in a method of treatment according to any of paragraphs 4 to 38.
40. A composition comprising an anti-CD 25ADC for use in a method of treatment according to any one of paragraphs 4 to 38.
41. A second agent for use in a method of treatment according to any one of paragraphs 5 to 38.
42. A composition comprising a second agent for use in a method of treatment according to any one of paragraphs 5 to 38.
43. Use of an anti-CD 25ADC in the manufacture of a medicament for treating a disorder in a subject, wherein the treatment comprises the method of any one of paragraphs 4 to 38.
44. Use of a second agent in the manufacture of a medicament for treating a disorder in a subject, wherein the treatment comprises the method of any one of paragraphs 5 to 38.
45. A kit, comprising:
a first agent comprising an anti-CD 25 ADC;
a package insert comprising instructions for administering the first agent according to the method of any of paragraphs 4 to 38.
46. The kit of paragraph 45, further comprising:
a second agent comprising a second agent.
Examples
Example 1
Introduction to the design reside in
Terilin-california (ADCT-301) is an anti-CD 25 antibody-drug conjugate (ADC) conjugated to SG3199 via a protease cleavable linker, SG3199 is a highly cytotoxic DNA minor groove cross-linked pyrrolobenzodiazepine dimer (Flynn et al Mol Cancer Ther 2016, and as described herein).
ADCT-301 is currently in phase I as a single dose in relapsed/refractory lymphoma (NCT02432235), advanced solid tumors (NCT03621982), and acute myeloid leukemia (NCT 02588092). It has preclinical activity as a single agent in 57 lymphoma cell lines and in combination with the selected drug in T cell lymphoma derived cell lines.
Method
Cell lines were exposed to increasing concentrations of ADCT-301 for 96h, followed by MTT proliferation assays. CD25 expression was measured at the cell surface level via fluorescence quantification (Quantum simple Cellular microspheres) and at the RNA level (Illumina HT-12 array and HTG EdgeSeq tumor biomarker panel). The combined study of dose escalated ADCT-301 and dose escalated other drugs was evaluated by MTT proliferation assay in FE-PD, Karpas-299, KI-JK and MAC1 cell lines over 96 h.
The median Combination Index (CI) was calculated using the weekly tower method (Chou-Talalay method) (synergy CI <0.9, additive CI ═ 0.9-1.1, antagonism/no benefit CI > 1.1).
Results
ADCT-301 exhibited much stronger activity in T-cell lymphomas (n-9, median IC 50-4 pM; 95% c.i., 1.6pM-0.9nM) compared to B-cell lymphomas (n-48, 0.7 nM; 95% c.i., 0.4-2.6nM) (P-0.047). At the cell surface level (n-53, Pearson r-0.50, P-0.0001) and RNA level (n-53, Pearson r-0.52, P <0.0001), in vitro activity was highly correlated with CD25 expression. CD25 is also more highly expressed in T cell lymphomas compared to B cell lymphomas (P <0.0001), consistent with differences in IC50, and remains relevant within subgroups (T cell lymphomas with a pearson coefficient r ═ 0.90, P ═ 0.0021; B cell lymphomas with a pearson coefficient r ═ 0.3, P ═ 0.05).
Based on higher activity in T-cell lymphomas, ADCT-301-containing combinations were evaluated in 4 cell lines derived from peripheral T-cell lymphomas: anaplastic Large Cell Lymphoma (ALCL) which is (n ═ 1), ALK-positive (n ═ 2) or ALK-negative (n ═ 1) is not specified separately.
ADCT-301 plus the BCL2 inhibitor, vinatock, was synergistic in all but one cell line. As shown by the data table shown below.
Cell line: FE-PD
RRID cell entry identity: CVCL _ H614
Reference documents: del Mistro et al, Leukemia, month 7 1994; 8(7) pages 1214-9.
Figure BDA0003405210870001141
Figure BDA0003405210870001151
Cell line: karpas-299
RRID cell entry identity: CVCL _1324
Reference documents: fischer et al, Blood, 7 months 1988; 72(1) pages 234-40.
Figure BDA0003405210870001152
Cell line: Ki-JK
RRID cell entry identity: CVCL _2093
Reference documents: shimakage et al, Intervirology, 1993; 36(4) pages 215-24.
Figure BDA0003405210870001153
Figure BDA0003405210870001161
Cell line: mac-1
RRID cell entry identity: CVCL _ H631
Reference documents: su et al, Am J Pathol, 8 months 1988; 132(2) pages 192-8.
Figure BDA0003405210870001162
Figure BDA0003405210870001171
Conclusion
The strong single agent anti-lymphoma activity and observed in vitro synergy with the targeting agent supports current ADCT-301 clinical development and identifies potential combination partners for future clinical studies.
Example 2
Introduction to the design reside in
Terilin-california (ADCT-301) is an anti-CD 25 antibody-drug conjugate (ADC) conjugated to SG3199 via a protease cleavable linker, SG3199 is a highly cytotoxic DNA minor groove cross-linked pyrrolobenzodiazepine dimer (Flynn et al Mol Cancer Ther 2016, and as described herein).
ADCT-301 is currently in phase I as a single dose in relapsed/refractory lymphoma (NCT02432235), advanced solid tumors (NCT03621982), and acute myeloid leukemia (NCT 02588092). It has preclinical activity as a single agent in 57 lymphoma cell lines and in combination with the selected drug in T cell lymphoma derived cell lines.
Method
Cell lines were exposed to increasing concentrations of ADCT-301 for 96h, followed by MTT proliferation assays. CD25 expression was measured at the cell surface level via fluorescence quantification (Quantum simple Cellular microspheres) and at the RNA level (Illumina HT-12 array and HTG EdgeSeq tumor biomarker panel). The combined study of dose escalated ADCT-301 and dose escalated other drugs was evaluated by MTT proliferation assay in FE-PD, Karpas-299, KI-JK and MAC1 cell lines over 96 h.
The median Combination Index (CI) was calculated using the weekly tower method (Chou-Talalay method) (synergy CI <0.9, additive CI ═ 0.9-1.1, antagonism/no benefit CI > 1.1).
Results
ADCT-301 exhibited much stronger activity in T-cell lymphomas (n-9, median IC 50-4 pM; 95% c.i., 1.6pM-0.9nM) compared to B-cell lymphomas (n-48, 0.7 nM; 95% c.i., 0.4-2.6nM) (P-0.047). At the cell surface level (n-53, Pearson r-0.50, P-0.0001) and RNA level (n-53, Pearson r-0.52, P <0.0001), in vitro activity was highly correlated with CD25 expression. CD25 is also more highly expressed in T cell lymphomas compared to B cell lymphomas (P <0.0001), consistent with differences in IC50, and remains relevant within subgroups (T cell lymphomas with a pearson coefficient r ═ 0.90, P ═ 0.0021; B cell lymphomas with a pearson coefficient r ═ 0.3, P ═ 0.05).
Based on higher activity in T-cell lymphomas, ADCT-301-containing combinations were evaluated in 4 cell lines derived from peripheral T-cell lymphomas: anaplastic Large Cell Lymphoma (ALCL) which is (n ═ 1), ALK-positive (n ═ 2) or ALK-negative (n ═ 1) is not specified separately.
As shown by the data table shown below, ADCT-301 plus the mTOR inhibitor everolimus showed synergy in the 4/4 cell line.
Cell line: FE-PD
RRID cell entry identity: CVCL _ H614
Reference documents: del Mistro et al, Leukemia, month 7 1994; 8(7) pages 1214-9.
Figure BDA0003405210870001181
Figure BDA0003405210870001191
Cell line: karpas-299
RRID cell entry identity: CVCL _1324
Reference documents: fischer et al, Blood, 7 months 1988; 72(1) pages 234-40.
Figure BDA0003405210870001192
Cell line: Ki-JK
RRID cell entry identity: CVCL _2093
Reference documents: shimakage et al, Intervirology, 1993; 36(4) pages 215-24.
Figure BDA0003405210870001201
Cell line: mac-1
RRID cell entry identity: CVCL _ H631
Reference documents: su et al, Am J Pathol, 8 months 1988; 132(2) pages 192-8.
Figure BDA0003405210870001202
Figure BDA0003405210870001211
Conclusion
The strong single agent anti-lymphoma activity and observed in vitro synergy with the targeting agent supports current ADCT-301 clinical development and identifies potential combination partners for future clinical studies.
Example 3
Introduction to the design reside in
Terilin-california (ADCT-301) is an anti-CD 25 antibody-drug conjugate (ADC) conjugated to SG3199 via a protease cleavable linker, SG3199 is a highly cytotoxic DNA minor groove cross-linked pyrrolobenzodiazepine dimer (Flynn et al Mol Cancer Ther 2016, and as described herein).
ADCT-301 is currently in phase I as a single dose in relapsed/refractory lymphoma (NCT02432235), advanced solid tumors (NCT03621982), and acute myeloid leukemia (NCT 02588092). It has preclinical activity as a single agent in 57 lymphoma cell lines and in combination with the selected drug in T cell lymphoma derived cell lines.
Method
Cell lines were exposed to increasing concentrations of ADCT-301 for 96h, followed by MTT proliferation assays. CD25 expression was measured at the cell surface level via fluorescence quantification (Quantum simple Cellular microspheres) and at the RNA level (Illumina HT-12 array and HTG EdgeSeq tumor biomarker panel). The combined study of dose escalated ADCT-301 and dose escalated other drugs was evaluated by MTT proliferation assay in FE-PD, Karpas-299, KI-JK and MAC1 cell lines over 96 h.
The median Combination Index (CI) was calculated using the weekly tower method (Chou-Talalay method) (synergy CI <0.9, additive CI ═ 0.9-1.1, antagonism/no benefit CI > 1.1).
Results
ADCT-301 exhibited much stronger activity in T-cell lymphomas (n-9, median IC 50-4 pM; 95% c.i., 1.6pM-0.9nM) compared to B-cell lymphomas (n-48, 0.7 nM; 95% c.i., 0.4-2.6nM) (P-0.047). At the cell surface level (n-53, Pearson r-0.50, P-0.0001) and RNA level (n-53, Pearson r-0.52, P <0.0001), in vitro activity was highly correlated with CD25 expression. CD25 is also more highly expressed in T cell lymphomas compared to B cell lymphomas (P <0.0001), consistent with differences in IC50, and remains relevant within subgroups (T cell lymphomas with a pearson coefficient r ═ 0.90, P ═ 0.0021; B cell lymphomas with a pearson coefficient r ═ 0.3, P ═ 0.05).
Based on higher activity in T-cell lymphomas, ADCT-301-containing combinations were evaluated in 4 cell lines derived from peripheral T-cell lymphomas: anaplastic Large Cell Lymphoma (ALCL) which is (n ═ 1), ALK-positive (n ═ 2) or ALK-negative (n ═ 1) is not specified separately.
ADCT-301 plus the PI3K inhibitor copaix was synergistic in all but one cell line.
ADCT-301 plus the HDAC inhibitor vorinostat is also synergistic in all but one cell line.
ADCT-301 plus the HDAC inhibitor romidepsin produced a synergistic effect in the 2/4 cell line.
The combination of ADCT-301 with the antifolate pralatrexate was synergistic in the ALK-positive ALCL cell line of 2/2.
The combination of ADCT-301 with the proteasome inhibitor bortezomib resulted in a synergistic effect in the cell line of 2/4.
Finally, the combination of ADCT-301 with bendamustine achieved synergy in the 1/4 cell line.
The data are shown in the following table.
Combining: ADCT-301+ copal lyssodexide
Cell line: FE-PD
RRID cell entry identity: CVCL _ H614
Reference documents: del Mistro et al, Leukemia, month 7 1994; pages 1214-9 in 8 (7).
Figure BDA0003405210870001231
Cell line: karpas-299
RRID cell entry identity: CVCL _1324
Reference documents: fischer et al, Blood, 7 months 1988; 72(1) pages 234-40.
Figure BDA0003405210870001232
Figure BDA0003405210870001241
Cell line: Ki-JK
RRID cell entry identity: CVCL _2093
Reference documents: shimakage et al, Intervirology, 1993; 36(4) pages 215-24.
Figure BDA0003405210870001242
Figure BDA0003405210870001251
Cell line: mac-1
RRID cell entry identity: CVCL _ H631
Reference documents: su et al, Am J Pathol, 8 months 1988; 132(2) pages 192-8.
Figure BDA0003405210870001252
Figure BDA0003405210870001261
Combining: ADCT-301+ vorinostat
Cell line: FE-PD
RRID cell entry identity: CVCL _ H614
Reference documents: del Mistro et al, Leukemia, month 7 1994; 8(7) pages 1214-9.
Figure BDA0003405210870001262
Cell line: karpas-299
RRID cell entry identity: CVCL _1324
Reference documents: fischer et al, Blood, 7 months 1988; 72(1) pages 234-40.
Figure BDA0003405210870001263
Figure BDA0003405210870001271
Cell line: Ki-JK
RRID cell entry identity: CVCL _2093
Reference documents: shimakage et al, Intervirology, 1993; 36(4) pages 215-24.
Figure BDA0003405210870001272
Figure BDA0003405210870001281
Cell line: mac-1
RRID cell entry identity: CVCL _ H631
Reference documents: su et al, Am J Pathol, 8 months 1988; 132(2) pages 192-8.
Figure BDA0003405210870001282
Figure BDA0003405210870001291
Combining: ADCT-301+ Romidepsin
Cell line: FE-PD
RRID cell entry identity: CVCL _ H614
Reference documents: del Mistro et al, Leukemia, month 7 1994; 8(7) pages 1214-9.
Figure BDA0003405210870001292
Cell line: karpas-299
RRID cell entry identity: CVCL _1324
Reference documents: fischer et al, Blood, 7 months 1988; 72(1) pages 234-40.
Figure BDA0003405210870001301
Cell line: Ki-JK
RRID cell entry identity: CVCL _2093
Reference documents: shimakage et al, Intervirology, 1993; 36(4) pages 215-24.
Figure BDA0003405210870001302
Cell line: mac-1
RRID cell entry identity: CVCL _ H631
Reference documents: su et al, Am J Pathol, 8 months 1988; 132(2) pages 192-8.
Figure BDA0003405210870001303
Figure BDA0003405210870001311
Combining: ADCT-301+ pralatrexate
Cell line: karpas-299
RRID cell entry identity: CVCL _1324
Reference documents: fischer et al, Blood, 7 months 1988; 72(1) pages 234-40.
Figure BDA0003405210870001312
Figure BDA0003405210870001321
Cell line: Ki-JK
RRID cell entry identity: CVCL _2093
Reference documents: shimakage et al, Intervirology, 1993; 36(4) pages 215-24.
Figure BDA0003405210870001322
Combining: ADCT-301+ bortezomib
Cell line: FE-PD
RRID cell entry identity: CVCL _ H614
Reference documents: del Mistro et al, Leukemia, month 7 1994; 8(7) pages 1214-9.
Figure BDA0003405210870001323
Figure BDA0003405210870001331
Cell line: karpas-299
RRID cell entry identity: CVCL _1324
Reference documents: fischer et al, Blood, 7 months 1988; 72(1) pages 234-40.
Figure BDA0003405210870001332
Figure BDA0003405210870001341
Cell line: Ki-JK
RRID cell entry identity: CVCL _2093
Reference documents: shimakage et al, Intervirology, 1993; 36(4) pages 215-24.
Figure BDA0003405210870001342
Cell line: mac-1
RRID cell entry identity: CVCL _ H631
Reference documents: su et al, Am J Pathol, 8 months 1988; 132(2) pages 192-8.
Figure BDA0003405210870001343
Figure BDA0003405210870001351
Combining: ADCT-301+ bendamustine
Cell line: FE-PD
RRID cell entry identity: CVCL _ H614
Reference documents: del Mistro et al, Leukemia, month 7 1994; 8(7) pages 1214-9.
Figure BDA0003405210870001352
Figure BDA0003405210870001361
Cell line: karpas-299
RRID cell entry identity: CVCL _1324
Reference documents: fischer et al, Blood, 7 months 1988; 72(1) pages 234-40.
Figure BDA0003405210870001362
Figure BDA0003405210870001371
Cell line: Ki-JK
RRID cell entry identity: CVCL _2093
Reference documents: shimakage et al, Intervirology, 1993; 36(4) pages 215-24.
Figure BDA0003405210870001372
Figure BDA0003405210870001381
Cell line: mac-1
RRID cell entry identity: CVCL _ H631
Reference documents: su et al, Am J Pathol, 8 months 1988; 132(2) pages 192-8.
Figure BDA0003405210870001382
Conclusion
The strong single agent anti-lymphoma activity and observed in vitro synergy with the targeting agent supports current ADCT-301 clinical development and identification of combination partners for future clinical treatment.
Example 4
The purpose of this proposed study was to pre-evaluate the safety, tolerability, pharmacological and clinical activity of this combination
The following cancer types have been selected for study: disease A, disease B and disease C
There is evidence for the efficacy of both drugs as a single dose:
● anti-CD 25ADC (see, e.g., WO2014/057119, WO2016/083468, and WO2016/166341)
● anti-BCL-2 agent, mTOR inhibitor or second agent (see KS Peggs et al 2009, Clinical and Experimental Immunology,157: 9-19 [ doi:10.1111/j.1365-2249.2009.03912.x ])
This primary objective of this study was to explore whether these agents could be safely combined, and if so, one or more doses and regimens would be identified as suitable for further study. The study will also assess whether each combination induces a pharmacological change in the tumor that would indicate potential clinical benefit.
Furthermore, it will provide preliminary evidence that the combination can increase response rate and persistence of response compared to published data for treatment with a single dose of anti-CD 25ADC or anti-BCL-2 agent, mTOR inhibitor, or second agent.
Each disease group may include a subset of patients previously treated with an anti-BCL-2 agent, mTOR inhibitor, or second agent to explore whether the combination therapy can overcome resistance to the anti-BCL-2 agent, mTOR inhibitor, or second agent therapy. For each disease, no specific molecular selection is intended to be applied, as currently available data based on approved molecular diagnostics generally does not support test exclusion of patients.
Basic principles of anti-CD 25ADC initial dose
All patients in this study will use the RDE (micrograms administered per kilogram per three weeks) that has been established for ADC. To ensure patient safety, a starting dose lower than RDE will be used; the starting dose level will be one that can still exhibit patient benefit in study ADC1, indicating that patients enrolled at such dose levels will receive at least some benefit from participation.
Rationale for starting doses of anti-BCL-2 agent, mTOR inhibitor, or second agent
All patients in this study will use the established RDE (micrograms administered per kilogram per three weeks) for the anti-BCL-2 agent, mTOR inhibitor, or second agent. To ensure patient safety, a starting dose lower than RDE will be used; the starting dose level will be one that can still exhibit patient benefit in study SA1, indicating that patients enrolled at such dose levels will receive at least some benefit from participation.
Targets and associated endpoints
Figure BDA0003405210870001401
Design of research
This phase Ib, multicenter, open label study, is used to characterize the safety, tolerability, Pharmacokinetics (PK), Pharmacodynamics (PD), and antitumor activity of the combination of ADC with an anti-BCL-2 agent, mTOR inhibitor, or a second agent in patients with disease a, disease B, and disease C.
The study included a dose escalation portion and a dose enlargement portion in that order.
For both ADC and anti-BCL-2 agent, mTOR inhibitor, or second agent, dose escalation will begin with a reduced initial dose (compared to their respective recommended phase 2 or approved dose levels) to ensure patient safety. For each compound, the starting dose will be 33% (or 50%) of the RDE. Subsequently, the dose of the anti-BCL-2 agent, mTOR inhibitor, or second agent will first be escalated until either the RDE or approved dose has been reached, or a lower dose if necessary for tolerability reasons. The dose of ADC will then be escalated until the RDE of the combination therapy is reached. This is visualized in the following figures:
Figure BDA0003405210870001411
if the dose combination is determined to be safe, it can be tested in other patients to confirm safety and tolerability at the dose level. The dosage of each compound can be further tailored, and/or the regimen can be modified.
Dose escalation of the combination will be guided by a Bayesian Logistic Regression Model (BLRM) based on any dose-limiting toxicity (DLT) observed during the first (or first two, TBC) therapy cycle. BLRM is a well-established method for estimating the Maximum Tolerated Dose (MTD)/recommended escalation dose (RDE) in cancer patients. Adaptive BLRM will be guided by the principle of controlling over-medication (EWOC) to Control the risk of DLT in future patients under study. The use of bayesian response adaptive models for small datasets has been accepted by the FDA and EMEA ("guidelines for small group clinical trials in small publications", 2.1.2007) and approved by a number of publications (Babb et al 1998, Neuenschwander et al 2008).
New dose combinations were determined by investigators and sponsoring researchers in Dose Escalation Safety Calls (DESC) based on review of patient tolerance and safety information (BLRM summary including DLT risk where applicable) and PK, PD and preliminary activity information available at the time of decision.
After one or more MTDs/RDEs for the combination are determined, an expanded portion of the study can be initiated to further assess safety, tolerability, and primary efficacy.
■ for combinations with IO, changes in immune infiltration in tumors will also be characterized after combination therapy in the disease indication of interest.
In view of the available prior clinical experience with the agents in this study, it is expected that in most cases the combined dose can be determined without testing on a large number of dose levels or time courses. To assess the pharmacodynamic activity of the combination, the patient would be required to undergo a tumor biopsy at baseline and again after about two therapy cycles.
■ for IO combining: the varying degree of tumor infiltration by immune cells including lymphocytes and macrophages will aid in the determination of any potential benefit.
Dose escalation section
During the dose escalation portion of the study, patients will be treated with a fixed dose of ADC administered intravenously, and an increasing dose of an anti-BCL-2 agent, mTOR inhibitor, or second agent, until the RDE of the anti-BCL-2 agent, mTOR inhibitor, or second agent has been reached. Subsequently, the dosage of ADC was increased (in different cohorts) while keeping the dosage of the anti-BCL-2 agent, mTOR inhibitor, or second agent constant.
Two to about 3 or 4 patients with disease a, disease B, or disease C will be treated in each ascending cohort until one or more MTDs/one or more RDEs are determined.
A 24 hour observation will be made before the second patient at dose level 1 is enrolled. The DLT observation period for each dose level is 1 cycle (3 weeks) or 2 cycles (6 weeks) as required by the relevant authorities for IO therapy, after which it will be determined whether the next cohort is to be incremented to the next dose level, held at the current dose level or decremented to the previous dose level. There will be no decrementing from dose level 1. Dose escalation in patients is not allowed.
Dose escalation is not tolerated unless 2 or more patients have complete DLT information in the first cycle at any given dose level. Dose escalation will be determined by using mCRM with target DLT rate of 30% and equivalence interval of 20% to 35% and using escalation to control over overdose (EWOC) and no dose jump.
Patients will be assigned to the queue for active recruitment. Dose escalation will be performed in each combination after completion of one treatment cycle. Safety assessments including Adverse Events (AEs) and laboratory values of all enrolled patients will be closely monitored to identify any DLTs. A single MTD/RDE will be determined; disease-specific MTD/RDE will not be established.
mCRM will be administered for DE under the supervision of the dose escalation guide committee (DESC). DESC will confirm each incremental dose level after reviewing all available safety data. PK data for the patient at the dose level and previous dose levels may also provide a basis for decision making. Dose escalation can be stopped by DESC based on PK, PD, toxicity or response data generated prior to determination of MTD.
If at least 1 patient in the study has achieved a partial response or better, or if the DESC deems it necessary to further evaluate PK or PD data to determine RDE, then other patients may be included at any dose level to further evaluate safety and tolerability.
Dose escalation will be stopped after successively assigning 3 cohorts (or at least 6 patients) to the same dose level. If the MTD is not reached, then a recommended escalation dose (RDE) will be determined. A minimum of 6 patients must be treated with the combination prior to determination of MTD/RDE.
It is expected that paired tumor biopsies will be obtained from the patient during dose escalation. Analysis of these biopsies will help to better understand the relationship between dose and pharmacodynamic activity of the combination.
Safety supervision of the dose escalation guidance committee
DESC containing ADC Therapeutics and investigators will continue to investigate patient safety during DE to determine if the dose escalation schedule specified by mCRM requires modification. In addition to security observations, PK and/or PD data may also provide basis for decision making. Intermediate doses may be dispensed after agreement between ADC Therapeutics and the investigator. During part 2, the DESC may continue to provide supervision. The official data security monitoring committee (DSMB) is not used.
Dose enlarging portion
After the MTD/RDE has been declared, the dose enlargement portion may begin. The main objective of the expanded section is to further evaluate the safety and tolerability of the study treatment at MTD/RDE and to obtain a preliminary understanding of the efficacy of the combination compared to historical single agent efficacy data.
An important exploratory goal is to assess the change in immune infiltration in tumors in response to treatment. This will be evaluated in paired tumor biopsies collected from patients, with a minimum of ten pairs of evaluable biopsies in patients treated under MTD/RDE (biopsy samples must contain enough tumor for analysis). If this is not feasible, collection of these biopsies can be stopped. A minimum of 10 to 20 patients were scheduled for treatment in each study group.
Several different research experimental groups will be opened, one for each disease. A total of nine investigational experimental groups can be run in dose escalation. If registration as either of these groups is not feasible, registration to the group may be turned off before the goals of 10-20 patients are met.
In each treatment group, up to about six patients who have received prior single administration (i.e., not combined) of anti-BCL-2 agent, mTOR inhibitor, or second agent therapy and progressed will be allowed to be treated. This number can be increased if the combination shows promise to overcome resistance to prior treatment with a single administration of an anti-BCL-2 agent, mTOR inhibitor, or second agent.
Patient population
The study will be conducted in adult patients with advanced disease a, disease B or disease C as outlined above. The investigator or assigner must ensure that only patients who meet all of the following inclusion criteria and do not meet any exclusion criteria are provided treatment in the study.
Incorporation guidelines
Patients eligible for inclusion in this study must meet all of the following criteria:
1. written informed consent must be obtained prior to any procedure
2. The age was 18 years.
3. Patients with advanced/metastatic cancer with measurable disease as determined by RECIST version 1.1 have progressed despite standard therapy, or are intolerant to standard therapy, or are absent standard therapy. The patient must meet one of the following groups:
● disease A
● disease B
● disease C
ECOG physical Performance status 0-1 (or 2TBC)
TBC: the patient must have a disease site that facilitates biopsy and be a candidate for tumor biopsy according to guidelines of the treatment facility. The patient must be willing to undergo a new tumor biopsy at baseline and again during treatment at the time of this study.
6. Allowing prior treatment with an anti-BCL-2 agent, an mTOR inhibitor, or a second agent or related compound (i.e., the same MOA)
Incorporation guidelines
Patients eligible for this study failed to meet any of the following criteria:
1. there was a history of severe anaphylactic reactions to other mAbs (or to mAbs of the same backbone as in ADC or, where applicable, to the same IOmAb)
2. It is known that there is a positive serum human ADA history to the mAb backbone as in ADC
3. Only Central Nervous System (CNS) diseases (when applicable)
4. Evidence of symptomatic CNS metastasis or leptomeningeal disease (brain MRI or previously recorded cerebrospinal fluid (CSF) cytology)
Figure BDA0003405210870001451
Previously treated asymptomatic CNS metastases are tolerated provided that the final treatment (systemic anti-cancer therapy and or local radiotherapy) is completed by week 8 before administration on day 1, except to allow for gradual reduction of low dose steroids)
Figure BDA0003405210870001461
Patients with discrete dural metastases were eligible.
5. The patient's laboratory values out of range are defined as:
● serum creatinine < (1.5 x ULN). If serum creatinine > 1.5, then the patient is eligible, creatinine clearance (calculated or measured using the Cockcroft-Gault formula) must be > 60mL/min/1.73m2
● Total bilirubin > 1.5 XULN, except Gilbert's syndrome patients were excluded if Total bilirubin > 3.0 XULN or direct bilirubin > 1.5 XULN
● alanine Aminotransferase (ALT) >3 XULN, except patients with tumor-associated liver were excluded if ALT >5 XULN
● aspartate Aminotransferase (AST) >3 XULN, except patients with tumor involvement of the liver were excluded if AST >5 XULN
● Absolute neutrophil count <1.0x 10e9/L
● platelet count <75 x10 e9/L
● hemoglobin (Hgb) <8g/dL
● abnormal potassium, magnesium, calcium or phosphate > CTCAE grade 1 despite appropriate replacement therapy
6. Impaired cardiac function or clinically significant cardiac disease, including any of the following:
● clinically significant and/or uncontrolled heart disease, such as congestive heart failure in need of treatment (NYHA class III or IV) or uncontrolled hypertension as defined by Systolic Blood Pressure (SBP)160mm Hg and/or Diastolic Blood Pressure (DBP)100mm Hg with or without the use of antihypertensive drugs.
● female QTcF >470 ms or male QTcF >450 ms in screening ECG for congenital long QT syndrome using Friderick's correction (Fridericia's correction)
● acute myocardial infarction or unstable angina pectoris < 3 months (months before study entry)
● clinically significant valvular disease and impairment of cardiac function was noted
● symptomatic pericarditis
● history of cardiomyopathy or cardiomyopathy being recorded
● Left Ventricular Ejection Fraction (LVEF) < 40% as determined by Echocardiogram (ECHO) or multi-gated acquisition (MUGA) scans
● history of arrhythmia or the presence of any clinically significant arrhythmia, such as ventricular, supraventricular, nodal arrhythmia or conduction abnormalities (TBC modifier: … … pacemaker required or drug uncontrolled)
● unstable atrial fibrillation exists (ventricular response rate >100 bpm).
Figure BDA0003405210870001471
Note that: patients with stable atrial fibrillation may be recruited if they do not meet other cardiac exclusion criteria.
● complete Left Bundle Branch Block (LBBB), double branch block
● any clinically significant ST-segment and/or T-wave abnormalities
7. Treatment discontinuation was caused by toxicity due to prior IO therapy. Patients appropriately treated for drug-related rashes or for endocrinopathies using alternative therapies are not excluded provided that these toxicities do not result in discontinuation of prior treatments.
8. The patient has an active, known or suspected autoimmune disease. Subjects with leukoderma, type I diabetes, residual hypothyroidism due to autoimmune disorders requiring only hormone replacement, psoriasis without the need for systemic treatment, or disorders expected to not recur in the absence of external triggers are allowed to be recruited, provided that triggers can be avoided.
9. Infection with Human Immunodeficiency Virus (HIV) or active Hepatitis B (HBV) or Hepatitis C (HCV)
Figure BDA0003405210870001472
The test is not mandatory to be qualified. If a patient is at risk of having an undiagnosed HCV (e.g., has a history of drug use), then tests for HCV should be considered.
10. Malignant diseases other than those being treated in this study. Exceptions to this exclusion include the following: malignancies that were cured and did not recur within 2 years prior to study treatment; completely resected basal cell and squamous cell skin cancer; any malignancy that is considered inert and never requires treatment; and any type of carcinoma in situ that is completely resected.
11. Systemic anti-cancer therapy was performed within 2 weeks of the first dose of study treatment. For cytotoxic agents with significant delayed toxicity, such as mitomycin C and nitrosoureas, a clearance period of 4 weeks is indicated. For patients receiving anti-cancer immunotherapy (such as CTLA-4 antagonists), 6 weeks are indicated as washout periods.
12. Active diarrhea CTCAE grade 2 or medical conditions associated with chronic diarrhea (such as irritable bowel syndrome, inflammatory bowel disease)
13. There are 2: CTCAE grade 2 toxicity due to previous cancer therapies (except alopecia, peripheral neuropathy, and ototoxicity were excluded if ═ CTCAE grade 3).
14. Systemic antibiotic therapy is required for active infections.
15. Active ulceration of the upper gastrointestinal tract or bleeding of the gastrointestinal tract
16. Active hemorrhagic diathesis or the use of oral anti-vitamin K drugs (except for low doses of warfarin and aspirin or equivalent, provided INR < (2.0))
17. Active autoimmune diseases, motor neuropathy believed to be of autoimmune origin, and other CNS autoimmune diseases
18. Patients need long-term treatment with immunosuppressive agents or with corticoids in addition to:
Figure BDA0003405210870001482
alternative doses of steroids in the context of adrenal insufficiency
Figure BDA0003405210870001481
Allowing topical, inhalation, nasal and ophthalmic steroids
19. Any live vaccine against infectious diseases (e.g. influenza, chicken pox, pneumococcus) was used within 4 weeks of the initial study treatment (note that live vaccine was not allowed for the entire duration of the study)
20. Hematopoietic colony stimulating growth factors (e.g., G-CSF, GMCSF, M-CSF) were used <2 weeks before starting study drug use. The use of a red blood cell stimulator is permitted as long as it begins at least 2 weeks prior to the first dose of study treatment.
21. There was major surgery within 2 weeks of the first dose of study treatment (note that mediastinoscopy, insertion of a central venous access device, or insertion of a feeding tube were not considered major surgery).
22. Radiation therapy was used within 2 weeks of the first dose of study drug, except palliative radiation therapy for limited areas, such as tumor masses for treatment of skeletal or local pain. To allow assessment of response to treatment, the patient must have the remaining unmeasured disease not yet irradiated
23. Interventional, investigational studies were enrolled during the first dose of study treatment, 2 weeks.
24. Researchers judge any medical condition that would prevent patients from participating in a clinical study due to safety concerns, adherence to clinical study procedures, or interpretation of study results.
25. Sexually active men, except they used condoms during intercourse while taking the drug and continued for 90 days after discontinuing study treatment, and should not gestate their children during this period. Men who excise vas deferens also need to use condoms to prevent drug delivery via semen.
26. Pregnancy or a female in lactation was confirmed by positive hCG laboratory tests, wherein pregnancy is defined as the state after pregnancy and until termination of pregnancy. In the rare case of endocrine gland-secreting tumors, hCG levels can be above normal limits in patients, but without pregnancy. In these cases, repeated serum hCG tests (no increase in results) and vaginal/pelvic ultrasound will be performed to rule out pregnancy. After confirming the results and discussing with a medical representative, these patients may be entered into the study.
27. Women with fertility potential, defined as all women that are physiologically capable of conception, unless they use a highly effective contraceptive method during the study treatment and for 90 days after any of the last doses of the study treatment. Highly effective methods of contraception include:
● full abstinence (when this is consistent with the patient's preferred and normal lifestyle, regular abstinence (e.g. calendar, ovulation, symptomatic temperature, post-ovulation) and withdrawal are unacceptable contraceptive regimens
● female sterilization (with surgical bilateral ovariectomy with or without hysterectomy), total hysterectomy, or tubal ligation was performed at least 6 weeks prior to study treatment. In the case of ovariectomy alone, the reproductive status of women has only been confirmed by follow-up hormone level assessment
● Male is sterilized (at least 6 months prior to screening). For a female patient in the study, the male partner from which the vas deferens was excised should be the only partner for the patient.
● use oral (estrogen and progesterone), injected or implanted combined hormone contraceptive methods or placement of intrauterine devices (IUDs) or intrauterine systems (IUSs) or other forms of hormonal contraception with similar efficacy (failure rate < 1%), such as hormonal pessaries or transdermal hormone contraception.
Figure BDA0003405210870001501
In the case of oral contraception, women should be stable to the same pill for a minimum of 3 months prior to study treatment.
Figure BDA0003405210870001502
Women are considered postmenopausal and do not have fertility potential if they have a natural (natural) amenorrhea of the appropriate clinical type (e.g. appropriate age, history of vasomotor symptoms) for 12 months or have had a surgical bilateral ovariectomy (with or without hysterectomy) or tubal ligation at least 6 weeks ago. In the case of ovariectomy alone, a woman is considered to have no fertility potential only if her reproductive status has been confirmed by follow-up hormone level assessment.
Dose limiting toxicity and dose modification guidelines
Dose-limiting toxicity (DLT) is defined as any of the following events occurring during the 21-day DLT evaluation period that are considered at least likely to be related to ADC, according to the judgment of the investigator. Toxicity that is apparent and directly related to the primary disease or to another etiology is excluded from this definition.
DLT definition
Hematology DLT is defined as:
■ 3 grade 3 or 4 febrile neutropenia or neutropenic infection
■ 4 grade 4 neutropenia persists for >7 days
■ 4 grade thrombocytopenia
■ grade 3 thrombocytopenia with clinically significant bleeding, or grade 3 thrombocytopenia requiring platelet infusion
■ grade 3 anemia requiring transfusion
Grade ■ 4 anemia
Non-hematologic DLT is defined as:
■ 4 grade non-hematologic toxicity
■ grade 3 non-hematologic toxicity lasting >3 days despite best supportive care or medical intervention
■ cases of Hei's law (Hy's law) (AST and/or ALT > 3x ULN)And isBilirubin is > 2xULN,and isInitially no cholestasis was found (serum alkaline phosphatase (ALP) activity < 2x ULN)And isNo other reason could explain that increased transaminase in combination with serum total bilirubin (such as viral hepatitis A, B or C, pre-existing or acute liver disease) or another drug could cause the damage observed)
■ 3 grade 3 or higher hypersensitivity/infusion related reactions (not related to pre-operative medication). Grade 3 hypersensitivity/infusion related reactions that resolve within 8 hours after onset under appropriate clinical management are not suitable as DLT.
■ LVEF to < 40% or > 20% decrease from baseline
■ 4 grade oncolytic syndrome (grade 3 TLS will not constitute DLT unless it causes irreversible end organ damage)
The following disorders are not considered non-hematological DLTs:
● 3 grade fatigue lasts less than or equal to 7 days
● grade 3 diarrhea, nausea or vomiting in the absence of preoperative medication, which responded to therapy and grade 3 events improved by at least 1 grade within 3 days or reached grade ≦ 1 grade within 7 days.
● AST or ALT increased by 5x ULN but 8x ULN, while bilirubin did not increase at the same time, and it decreased to grade 2 within 5 days after onset.
● if there is no clinical sign or symptom of pancreatitis, the level 3 serum lipase or serum amylase lasts less than 7 days
Patients who experience a DLT that resolves or stabilizes with appropriate medical management may continue treatment at the discretion of the researcher and sponsor negotiation.
Dose modification
Guidelines for managing specific toxicities are detailed in the table below. For the management of events not specified in the table, the following can be used as a guide for the investigator:
Figure BDA0003405210870001511
Figure BDA0003405210870001521
SEQUENCE LISTING
<110> ADC treatment Co., Ltd (ADC THERAPEUTICS SA)
Immunomedical Co., Ltd (MEDIMUNE LIMITED)
<120> combination therapy comprising an anti-CD 25 antibody drug conjugate and another agent
<130> P21119424WP
<150> GB 1908227.0
<151> 2019-06-10
<150> GB 1908232.0
<151> 2019-06-10
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Gly Arg Ile Ile Pro Ile Leu Gly Val Glu Asn Tyr Ala Gln Lys Phe
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Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
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Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly
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Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
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Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro Leu
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Claims (50)

1. A method of selecting an individual suitable for treatment with an anti-CD 25ADC, wherein if the individual has been treated with an anti-BCL-2 agent, an mTOR inhibitor, or a second agent, the individual is selected for treatment with the anti-CD 25 ADC.
2. A method of selecting an individual suitable for treatment with an anti-CD 25ADC, wherein if the individual is being treated with an anti-BCL-2 agent, an mTOR inhibitor, or a second agent, the individual is selected for treatment with the anti-CD 25 ADC.
3. The method of any one of the preceding claims, wherein the individual is selected for treatment if the individual is refractory to treatment or further treatment with the anti-BCL-2 agent, the mTOR inhibitor, or the second agent.
4.A method for treating a disorder in an individual, the method comprising:
(i) selecting an individual suitable for treatment by a method according to any one of claims 1 to 3; and
(ii) administering to the individual an effective amount of the anti-CD 25 ADC.
5. The method of claim 4, further comprising administering an anti-BCL-2 agent, an mTOR inhibitor, or a second agent in combination with the anti-CD 25 ADC.
6. A method for treating a disorder in an individual, the method comprising administering to the individual an effective amount of an anti-CD 25ADC and an anti-BCL-2 agent, an mTOR inhibitor, or a second agent.
7. The method of claim 6, wherein the individual is selected for treatment according to the method of any one of claims 1 to 3.
8. The method of any one of claims 5-7, wherein the treatment comprises administering the anti-CD 25ADC prior to the anti-BCL-2 agent, the mTOR inhibitor, or the second agent, concurrently with the anti-BCL-2 agent, the mTOR inhibitor, or the second agent, or after the anti-BCL-2 agent, the mTOR inhibitor, or the second agent.
9. The method of any preceding claim, wherein the treatment further comprises administration of a chemotherapeutic agent.
10. The method of any preceding claim, wherein the individual is a human.
11. The method of any preceding claim, wherein the individual has a disorder or has been determined to have a disorder.
12. The method of claim 11, wherein the individual has or has been determined to have a CD25 expressing cancer or has been determined to have CD25+ tumor-associated non-tumor cells, such as CD25+ infiltrating cells.
13. The method of any preceding claim, wherein the individual is undergoing treatment with an anti-BCL-2 agent, an mTOR inhibitor, or a second agent.
14. The method of any preceding claim, wherein the individual has undergone treatment with an anti-BCL-2 agent, an mTOR inhibitor, or a second agent.
15. The method of any preceding claim, wherein the individual is refractory to treatment or further treatment with the anti-BCL-2 agent, the mTOR inhibitor, or the second agent.
16. The method of any one of the preceding claims, wherein the treatment has increased efficacy compared to a monotherapy using the anti-CD 25ADC or the anti-BCL-2 agent, the mTOR inhibitor, or the second agent alone.
17. The method of any preceding claim, wherein the anti-CD 25ADC is ADCx25 or ADCT-301.
18. The method of any preceding claim, wherein the disorder is a proliferative disease.
19. The method of claim 18, wherein the disorder is cancer.
20. The method of any preceding claim, wherein the individual has, or has been determined to have, a condition characterised by the presence of a neoplasm comprising CD25+ ve and CD25-ve cells.
21. The method of any preceding claim, wherein the subject has, or has been determined to have, a disorder characterized by the presence of a neoplasm comprising or consisting of CD25-ve neoplastic cells.
22. The method of any one of claims 20 or 21, wherein the neoplasm is all or a portion of a solid tumor.
23. The method of statement 22, wherein the solid tumor is associated with CD25+ ve infiltrating cells;
optionally wherein the solid tumor is associated with high levels of CD25+ ve infiltrating cells.
24. The method of statement 23, wherein the solid tumor is selected from the group consisting of: pancreatic cancer, breast cancer (including triple negative breast cancer), colorectal cancer, gastric and esophageal cancer, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular cancer, renal cell carcinoma, bladder cancer, and head and neck cancer.
25. The method of any preceding claim, wherein the disorder is selected from the group comprising:
hodgkin's and non-hodgkin's lymphomas, including diffuse large B-cell lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Lymphoma (CLL), marginal zone B-cell lymphoma (MZBL);
leukemias, such as Hairy Cell Leukemia (HCL), variant hairy cell leukemia (HCL-v), Acute Myeloid Leukemia (AML), Anaplastic Large Cell Lymphoma (ALCL), and Acute Lymphoblastic Leukemia (ALL), such as philadelphia chromosome positive ALL (Ph + ALL) or philadelphia chromosome negative ALL (Ph-ALL);
pancreatic cancer, breast cancer, colorectal cancer, gastric and esophageal cancer, leukemia and lymphoma, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular cancer, renal cell carcinoma, and head and neck cancer.
26. The method of any one of claims 1 to 25, wherein the second agent is bendamustine.
27. The method of any one of claims 1-25, wherein the second agent is a phosphatidylinositol 3-kinase inhibitor.
28. The method of claim 27, wherein the phosphatidylinositol 3-kinase inhibitor is copaipamil, idelalisib, duviraib, taselib, buparib, apidrib, ubularicib, daptomib, or ortalib.
29. The method of claim 27, wherein the phosphatidylinositol 3-kinase inhibitor is copaipamil or esalalix.
30. The method of any one of claims 1-25, wherein the second agent is a proteasome inhibitor.
31. The method of claim 30, wherein the proteasome inhibitor is bortezomib, carfilzomib, ixazoib, oprozomib, or salinosporamide a.
32. The method of claim 30, wherein the proteasome inhibitor is bortezomib.
33. The method of any one of claims 1 to 25, wherein the second agent is an antifolate.
34. The method of claim 33, wherein the antifolate is pralatrexate, methotrexate, pemetrexed, or raltitrexed.
35. The method of claim 33, wherein said antifolate is pralatrexate.
36. The method of any one of claims 1 to 25, wherein the second agent is an HDAC inhibitor.
37. The method of claim 36, wherein the HDAC inhibitor is romidepsin, vorinostat, abbestat, belinostat (PXD101), LAQ824, panobinostat (LBH589), entinostat (MS-275), tacroline (CI994), or moxidestat (MGCD 0103).
38. The method of claim 36, wherein the HDAC inhibitor is romidepsin or vorinostat.
39. The method according to any one of claims 1 to 25, wherein the anti-BCL-2 agent is selected from the group consisting of: venetok (ABT-199), Navitoxk (ABT-263), ABT-737, S55746/BCL201, and Olimoeson (G3139).
40. The method of claim 39, wherein the anti-BCL-2 agent is Venetork.
41. The method of any one of claims 1-25, wherein the mTOR inhibitor is everolimus (RAD001), sirolimus (rapamycin), CCI-779 (temsirolimus), ridaforolimus (AP-23573), NVP-BEZ235 (dapoxib), BGT226, SF1126, jidalisel, omithizamide, XL765, Ku-0063794, oleuropein, AZD8055, AZD2014, AZD3147, sapercetin (INK128/MLN0128), OSI027, torein 1, torein 2, cotonib (PP242), WYE687, ETP45658, PF 12305284, 04691502, XL388, eCF309, rapak-1, or RapaLink-2.
42. The method of claim 41, wherein the mTOR inhibitor is everolimus.
43. An anti-CD 25ADC for use in a method of treatment according to any one of claims 4 to 42.
44. A composition comprising an anti-CD 25ADC for use in a method of treatment according to any one of claims 4 to 42.
45. An anti-BCL-2 agent, an mTOR inhibitor, or a second agent for use in the method of treatment according to any one of claims 5-42.
46. A composition comprising an anti-BCL-2 agent, an mTOR inhibitor, or a second agent, for use in a method of treatment according to any one of claims 5 to 42.
47. Use of an anti-CD 25ADC in the manufacture of a medicament for treating a disorder in a subject, wherein the treatment comprises the method of any one of claims 4 to 42.
48. Use of an anti-BCL-2 agent, an mTOR inhibitor, or a second agent in the manufacture of a medicament for treating a disorder in an individual, wherein the treatment comprises the method of any one of claims 5-42.
49. A kit, comprising:
a first agent comprising an anti-CD 25 ADC;
a package insert comprising instructions for administering the first agent according to the method of any one of claims 4-42.
50. The kit of claim 49, further comprising:
a second agent comprising an anti-BCL-2 agent, an mTOR inhibitor, or a second agent.
CN202080043019.8A 2019-06-10 2020-06-08 Combination therapy comprising an anti-CD 25 antibody drug conjugate and another agent Pending CN114302746A (en)

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