Combination therapy

Abstract

The present disclosure relates to combinations of anti-CD19 antibody drug conjugates with anti-CD79b conjugates and their use in therapies, such as the treatment of proliferative diseases.

Description

[Technical field]

[0001] Application for incorporation This application claims priority to UK Application Nos. 2109373.7, filed June 29, 2021, 2109375.2, filed June 29, 2021, and 2109377.8, filed June 29, 2021, all of which are incorporated by reference in their entireties for all purposes as if fully set forth herein.

[0002] Technical Field The present disclosure relates to combination therapies for the treatment of pathological conditions such as cancer. In particular, the disclosure relates to combination therapies comprising treatment with an anti-CD19 antibody drug conjugate (anti-CD19 ADC) and an anti-CD79b agent. [Background technology]

[0003] antibody therapy Antibody therapy has been established for the targeted treatment of subjects suffering from cancer, immune disorders and angiogenic diseases. Antibody-drug conjugates (ADCs), i.e. immunoconjugates, are used for localized delivery of cytotoxic or cytostatic agents, i.e. drugs to kill or inhibit tumor cells in the treatment of cancer, to target the delivery of the drug moiety to and intracellular accumulation within tumors, whereas systemic administration of unconjugated drug agents can result in unacceptable levels of toxicity to normal cells.

[0004] CD19 CD19 is a 95 kDa membrane receptor that is expressed early in B cell differentiation and continues to be expressed until B cells undergo terminal differentiation. The CD19 extracellular domain contains two C2-type immunoglobulin (IG)-like domains separated by a smaller, potentially disulfide-linked domain. The CD19 cytoplasmic domain is a unique structure but is highly conserved between humans, mice, and guinea pigs. CD19 is part of a protein complex found on the cell surface of B lymphocytes. The protein complex includes CD19, CD21 (complement receptor, type 2), CD81 (TAPA-1), and CD225 (Leu 13).

[0005] CD19 is a key regulator of transmembrane signaling in B cells. Increased or decreased cell surface density of CD19 affects B cell development and function, resulting in diseases such as autoimmunity or hypogammaglobulinemia. The CD19 complex enhances the B cell response to antigens in vivo through cross-linking of two distinct signaling complexes found on the B cell membrane. The two signaling complexes associated with membrane IgM and CD19 activate phospholipase C (PLC) by different mechanisms. Cross-linking of CD19 with the B cell receptor reduces the number of IgM molecules required to activate PLC. CD19 also functions as a specialized adaptor protein for the amplification of Arc family kinases.

[0006] CD19 binding has been shown to enhance and inhibit B cell activation and proliferation, depending on the amount of cross-linking that occurs. CD19 is expressed on over 90% of B cell lymphomas and is predicted to affect lymphoma growth in vitro and in vivo.

[0007] Therapeutic Uses of Anti-CD19 ADCs The efficacy of antibody-drug conjugates containing anti-CD19 antibodies (anti-D19 antibodies) is shown as follows: For example, the inhibition of CD19-ADC in the treatment of cancer has been established; see, for example, Patent Documents 1 and 2. Research continues to further improve the efficacy, tolerability, and clinical utility of anti-CD19 ADCs. To this end, the inventors have identified clinically advantageous combination therapies in which anti-CD19 ADCs are administered in combination with at least one anti-CD79b agent. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2014 / 057117 [Patent Document 2] International Publication No. 2016 / 166298 Summary of the Invention [Problem to be solved by the invention]

[0009] The inventors have found that combining an anti-CD19 ADC and an anti-CD79b agent in an individual provides unexpected clinical benefit. The inventors have further found that administering an anti-CD19 ADC to an individual who has been treated or is being treated with an anti-CD79b agent provides a synergistic increase in therapeutic efficacy. [Means for solving the problem]

[0010] Thus, in a first aspect, the disclosure provides a method of selecting an individual suitable for treatment with an anti-CD19 ADC, where the individual is selected for treatment with an anti-CD19 ADC if the individual has been treated or is undergoing treatment with an anti-CD79b agent. If the individual is refractory to treatment with an anti-CD79b agent or to further treatment, the individual may optionally be selected for treatment.

[0011] In another aspect, the disclosure provides a method for treating a disease in an individual 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-CD19 ADC. The method of treatment may further comprise administering an anti-CD79b agent in combination with the anti-CD19 ADC.

[0012] In another aspect, the disclosure provides a method for treating a disease in an individual, comprising administering to the individual an effective amount of an anti-CD19 ADC and an anti-CD79b agent. Individuals for treatment can be selected according to the method according to the first aspect.

[0013] The disease may be a proliferative disease, e.g., cancer such as diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma, mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma, including Waldenstrom's macroglobulinemia (WM), and marginal zone B-cell lymphoma (MZBL), and leukemia, such as hairy cell leukemia (HCL), hairy cell leukemia variant (HCL-v), chronic lymphocytic leukemia (CLL), including Richter's syndrome, and acute lymphoblastic leukemia (ALL), such as Philadelphia chromosome positive ALL (Ph+ALL) or Philadelphia chromosome negative ALL (Ph-ALL).

[0014] The anti-CD19 ADC can be loncastuximab tesirine. The anti-CD19 ADC may be ADCx19 as described herein. The anti-CD79b agent can be polatuzumab vedotin.

[0015] The individual may be a human. The individual may have or be determined to have cancer. The individual may have or be determined to have CD19+ cancer or CD19+ tumor-associated non-tumor cells, e.g., CD19+ infiltrating B cells.

[0016] In the methods described herein, the anti-CD19 ADC may be administered prior to, simultaneously with, or following administration of an anti-CD79b agent. The methods described herein may further comprise administering a chemotherapeutic agent.

[0017] In other aspects, the disclosure provides anti-CD19 ADCs or compositions comprising anti-CD19 ADCs for use in the methods of treatment described herein. In one aspect, the disclosure provides an anti-CD79b agent, or a composition comprising an anti-CD79b agent, for use in the methods of treatment described herein. In a further aspect, the disclosure provides for the use of an anti-CD19 ADC or an anti-CD79b agent in the manufacture of a medicament for treating a disease in an individual, where the treatment comprises a method of treatment described herein.

[0018] ---------------------------- In another aspect, the disclosure provides a first composition comprising an anti-CD19 ADC for use in a method for treating a disease in an individual, the treatment comprising co-administration of the first composition with a second composition comprising an anti-CD79b agent. This aspect also provides a first composition comprising an anti-CD79b agent for use in a method for treating a disease in an individual, said treatment comprising co-administration of said first composition with a second composition comprising an anti-CD19 ADC. The disease may be a proliferative disease, e.g., cancer such as diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma, mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma, including Waldenstrom's macroglobulinemia (WM), and marginal zone B-cell lymphoma (MZBL), and leukemia, such as hairy cell leukemia (HCL), hairy cell leukemia variant (HCL-v), chronic lymphocytic leukemia (CLL), including Richter's syndrome, and acute lymphoblastic leukemia (ALL), such as Philadelphia chromosome positive ALL (Ph+ALL) or Philadelphia chromosome negative ALL (Ph-ALL).

[0019] The anti-CD19 ADC can be loncastuximab tesirine. The anti-CD19 ADC may be ADCx19 as described herein. The anti-CD79b agent can be polatuzumab vedotin.

[0020] The individual may be a human. The individual may have or be determined to have cancer. The individual may have or be determined to have CD19+ cancer or CD19+ tumor-associated non-tumor cells, e.g., CD19+ infiltrating B cells. The first composition may be administered prior to, simultaneously with, or after administration of the second composition. The treatment may include administering a further chemotherapeutic agent.

[0021] ---------------------------- In a further aspect, the disclosure provides the use of an anti-CD19 ADC in the manufacture of a medicament for treating a disease in an individual, wherein the medicament comprises an anti-CD19 ADC and the treatment comprises administration of the medicament in combination with a composition comprising an anti-CD79b agent. This aspect also includes the use of an anti-CD79b agent in the manufacture of a medicament for treating a disease in an individual, wherein the medicament comprises an anti-CD79b agent, and the treatment comprises co-administration of the medicament with a composition comprising an anti-CD19 ADC. The disease may be a proliferative disease, e.g., cancer such as diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma, mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma, including Waldenstrom's macroglobulinemia (WM), and marginal zone B-cell lymphoma (MZBL), and leukemia, such as hairy cell leukemia (HCL), hairy cell leukemia variant (HCL-v), chronic lymphocytic leukemia (CLL), including Richter's syndrome, and acute lymphoblastic leukemia (ALL), such as Philadelphia chromosome positive ALL (Ph+ALL) or Philadelphia chromosome negative ALL (Ph-ALL).

[0022] The anti-CD19 ADC can be loncastuximab tesirine. The anti-CD19 ADC may be ADCx19 as described herein. The anti-CD79b agent can be polatuzumab vedotin.

[0023] The individual may be a human. The individual may have or be determined to have cancer. The individual may have or be determined to have CD19+ cancer or CD19+ tumor-associated non-tumor cells, e.g., CD19+ infiltrating B cells. The medicament may be administered prior to, simultaneously with, or following administration of the composition. The treatment may include administering a further chemotherapeutic agent.

[0024] ---------------------------- In another aspect, the present disclosure provides a method for the preparation of a method for treating a cancer cell comprising: A first pharmaceutical agent comprising an anti-CD19 ADC and A package insert containing instructions for administering the first agent according to the methods of treatment described herein. A kit comprising: The kit may further comprise a second pharmaceutical agent comprising an anti-CD79b agent. In another aspect, the present disclosure provides a method for the preparation of a method for treating a cancer cell comprising: a first medicament comprising an anti-CD19 ADC; a second medicament comprising an anti-CD79b agent, and optionally, a package insert containing instructions for administering the first composition in combination with the second composition to treat a disease in an individual. A kit comprising: This embodiment also provides a kit that includes a package insert containing instructions for co-administration of an anti-CD19 ADC with an anti-CD79b agent to treat a disease in an individual. This embodiment further provides a kit comprising a medicament comprising an anti-CD79b agent and a package insert containing instructions for co-administration with an anti-CD19 ADC for the treatment of a disease in an individual. The disease may be a proliferative disease, e.g., cancer such as diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma, mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma, including Waldenstrom's macroglobulinemia (WM), and marginal zone B-cell lymphoma (MZBL), and leukemia, such as hairy cell leukemia (HCL), hairy cell leukemia variant (HCL-v), chronic lymphocytic leukemia (CLL), including Richter's syndrome, and acute lymphoblastic leukemia (ALL), such as Philadelphia chromosome positive ALL (Ph+ALL) or Philadelphia chromosome negative ALL (Ph-ALL).

[0025] The anti-CD19 ADC can be loncastuximab tesirine. The anti-CD19 ADC may be ADCx19 as described herein. The anti-CD79b agent can be polatuzumab vedotin.

[0026] The individual may be a human. The individual may have or be determined to have cancer. The individual may have or be determined to have CD19+ cancer or CD19+ tumor-associated non-tumor cells, e.g., CD19+ infiltrating B cells. A medicament or composition comprising an anti-CD19 ADC may be administered prior to, simultaneously with, or following administration of a medicament or composition comprising an anti-CD79b agent. The treatment may include administering a further chemotherapeutic agent.

[0027] ---------------------------- In other aspects, the disclosure provides compositions comprising an anti-CD19 ADC and an anti-CD79b agent, and uses of such compositions in the methods described herein. In this aspect, the disclosure also provides a method for treating a disease in an individual comprising administering to the individual an effective amount of a composition comprising an anti-CD19 ADC and an anti-CD79b agent. In this aspect, the disclosure also provides a composition comprising an anti-CD19 ADC and an anti-CD79b agent for use in treating a disease in an individual, comprising administering to the individual. In this aspect, the disclosure also provides for the use of a composition comprising an anti-CD19 ADC and an anti-CD79b agent in the manufacture of a medicament for treating a disease in an individual. In this aspect, the disclosure also provides a kit comprising a composition comprising an anti-CD19 ADC and an anti-CD79b agent, and a package insert containing directions for administration of the medicaments to treat a disease in an individual. The disease may be a proliferative disease, e.g., cancer such as diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma, mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma, including Waldenstrom's macroglobulinemia (WM), and marginal zone B-cell lymphoma (MZBL), and leukemia, such as hairy cell leukemia (HCL), hairy cell leukemia variant (HCL-v), chronic lymphocytic leukemia (CLL), including Richter's syndrome, and acute lymphoblastic leukemia (ALL), such as Philadelphia chromosome positive ALL (Ph+ALL) or Philadelphia chromosome negative ALL (Ph-ALL). The anti-CD19-ADC may be ADCX19 as described herein. The anti-CD79b agent can be polatuzumab vedotin.

[0028] The individual may be a human. The individual may have or be determined to have cancer. The individual may have or be determined to have CD19+ cancer or CD19+ tumor-associated non-tumor cells, e.g., CD19+ infiltrating B cells. The treatment may include administering to the individual a further chemotherapeutic agent.

[0029] The disclosure also relates more generally to the therapeutic methods described herein, including administering an antibody drug conjugate comprising a PBD dimer (e.g., a PBD described herein) as a warhead in combination with an antibody drug conjugate comprising monomethyl auristatin E as a warhead, and a combination of two antibody drug conjugates. The antibodies for each of the individual agents are selected to bind to different target molecules. An example of an antibody drug conjugate comprising monomethyl auristatin E is where the antibody targets anti-CD79b. Examples of antibody drug conjugates comprising PBD dimers are those that target CD19 as described above, as well as those that target CD25 or CD22 as described below.

[0030] Thus, in a further aspect, the disclosure provides for the combination of (i) an antibody-drug conjugate comprising a PBD dimer and (ii) an antibody-drug conjugate comprising monomethylauristatin E, wherein the antibody of (i) binds to a different target molecule (e.g., a different cell surface molecule, such as a protein, receptor, etc.) than the antibody of (ii). In a related aspect, the disclosure provides a method of treating an individual suffering from a proliferative disease by co-administering to the individual (i) an antibody-drug conjugate comprising a PBD dimer and (ii) an antibody-drug conjugate comprising monomethyl auristatin E, where the antibody of (i) binds to a different target molecule (e.g., a different cell surface molecule, such as a protein, receptor, etc.) than the antibody of (ii). Such administration may be simultaneous or separate. It will be appreciated by those skilled in the art that the further embodiments described in detail below for anti-CD19 ADCs and anti-CD79b ADCs, e.g., selection of PBDs, disease to be treated, patient selection and administration, may be applied mutatis mutandis to ADCs of (i) and (ii) that bind to different targets. Particular examples of other targets are CD25 and CD22, described in more detail below.

[0031] CD25 The type I transmembrane protein CD25 is present on activated T and B cells, some thymocytes, myeloid precursors, and oligodendrocytes. On activated T cells, it forms a heterodimer with the beta and gamma subunits (CD122 and CD132) and thus contains the high affinity receptor for IL-2. This ligand represents a survival factor for activated T cells, since removal of IL-2 leads to rapid cell death. In the case of B cells, CD25 is physiologically expressed in the early developmental stages of late pro-B cells and pre-B cells. Therefore, malignant tumors arising from this stage of B cell differentiation may also express CD25. Mast cell lesions are also positive for CD25, and therefore this is considered an important diagnostic criterion for the determination of systemic mastocytosis. In Hodgkin's lymphoma, it has been reported that CD25 is not expressed in Hodgkin / Reed-Sternberg in nodal lymphocyte-predominant Hodgkin's lymphoma (NLPHL). The general expression level has been reported to be lower than that of tumor-infiltrating lymphocytes (TIL), which may cause problems in showing CD25 tumor cells in these cases (Levi et al., Merz et al., 1995). Expression of the target antigen has also been reported for several B-cell and T-cell derived subtypes of non-Hodgkin's lymphoma, namely B-cell chronic lymphocytic leukemia, hairy cell leukemia, small cell lymphocytic lymphoma / chronic lymphocytic leukemia, as well as adult T-cell leukemia / lymphoma and anaplastic large cell lymphoma. CD25 is localized to the membrane, with low expression observed in the cytoplasm, and soluble CD25 can also be found outside the cell, including in serum.

[0032] Therapeutic Uses of Anti-CD25 ADCs For example, the efficacy of antibody-drug conjugates containing anti-CD25 antibodies (anti-CD25-ADCs) in the treatment of cancer has been established - see, e.g., International Publication Nos. WO 2014 / 057119, WO 2016 / 083468, WO 2016 / 166341, and WO 2019 / 224275. Research continues to further improve the efficacy, tolerability, and clinical utility of anti-CD25 ADCs. To this end, the inventors have identified a clinically advantageous combination therapy in which an anti-CD25 ADC is administered in combination with at least one anti-CD79b agent. Thus, in another aspect of the invention, instead of an anti-CD19-ADC in combination with an anti-CD 76b agent, an anti-CD25-ADC is used in combination with an anti-CD79b agent. Thus, all references to "anti-CD19-ADC" in the above embodiments may be replaced with "anti-CD25-ADC" in further embodiments.

[0033] CD22 CD22 is a 135 kDa type I transmembrane sialoglycoprotein of the immunoglobulin (Ig) superfamily. CD22 expression is specific to B cells and developmentally regulated such that expression is restricted to pro- and pre-B cells. As B cells mature, expression increases and CD22 localization shifts to the cell surface. CD22 is highly expressed on follicular, mantle, and marginal zone B cells, but is only faintly present on embryonic B cells. CD22 is an inhibitory coreceptor that downregulates B cell receptor (BCR) signaling by setting a signaling threshold that prevents overstimulation of B cells. Antibodies against CD22, such as epratuzumab (hLL2), have been used to treat various cancers and autoimmune diseases, including, but not limited to, acute lymphoblastic leukemia, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, systemic lupus erythematosus, and primary Sjogren's syndrome. Phase III clinical trials of epratuzumab in systemic lupus erythematosus are currently ongoing (see, e.g., ClinicalTrials.gov, "Study of Epratuzumab versus Placebo in Subjects with Moderate to Severe General Systemic Lupus Erythematosus (EMBODIMENT 1)"). CD22 regulates B-cell function and survival, and is therefore a key link for regulating humoral immunity and the growth of B-cell lymphomas, and is a target for therapeutic antibodies in cancer and autoimmune diseases.

[0034] Therapeutic Uses of Anti-CD22 ADCs The efficacy of antibody-drug conjugates containing anti-CD22 antibody (anti-C22 antibody) is as follows. For example, the use of CD22-ADC in the treatment of cancer has been established. It is described in International Publication No. 2014 / 057122 and International Publication No. 2016 / 166307, and Kantarjian et al., (2016, New Eng J Med). Research continues to further improve the efficacy, tolerability, and clinical utility of anti-CD22 ADCs. To this end, the inventors have identified clinically advantageous combination therapies in which anti-CD22 ADCs are administered in combination with at least one anti-CD79b agent. Thus, in another aspect of the invention, instead of an anti-CD19-ADC, an anti-CD22-ADC is combined with an anti-CD79b agent. Thus, all references to "anti-CD19-ADC" in the above embodiments can be replaced with "anti-CD22-ADC" in further embodiments.

[0035] ---------------------------- Antibody-Drug Conjugates (ADCs) The present disclosure relates to improving the efficacy of combinations of ADCs with anti-CD79b agents. The ADC can deliver a drug to a target location. The target location is preferably a proliferative cell population. The antibody is an antibody against an antigen present on the proliferative cell population. In one embodiment, the antigen is absent or present at a reduced level in non-humans. The amount of antigen represents the amount of the proliferative cell population compared to the amount of antigen present in the proliferative cell population, e.g., a tumor cell population. The ADC may include a linker that can be cleaved to release a drug at a target location. The drug may be a compound selected from RelA, RelB, RelC, RelD, or RelE. Thus, the conjugate can be used to selectively deliver the compound RelA, RelB, RelC, RelD, or RelE to a target location. The linker can be cleaved by an enzyme present at the target location. The present disclosure relates in particular to treatment with the anti-CD19 ADCs disclosed in US Pat. No. 6,399,433 and described herein.

[0036] Anti-CD19 ADC As used herein, the term "anti-CD19 ADC" or "CD19-ADC" refers to an ADC in which the antibody component is an anti-CD19 antibody. The term "PBD-ADC" refers to an ADC in which the drug component is a pyrrolobenzodiazepine (PBD) warhead. The term "anti-CD19-ADC" refers to an ADC in which the antibody component is an anti-CD19 antibody and the drug component is a PBD warhead.

[0037] The ADC may include a conjugate represented by the formula L-(DL)p, where DL is represented by formula I or II:

[0038] [ka] (In the formula, L is an antibody (Ab) that is an antibody that binds to CD19; If there is a double bond between C2' and C3', R 12is the following; (ia) optionally halo, nitro, cyano, ether, carboxy, ester, C 1~7 Alkyl, C 3~7 Heterocyclyl and bis-oxy-C 1~3 C, which may be substituted by one or more substituents selected from the group including alkylene 5~10 Aryl groups; (ib)C 1~5 Saturated fatty alkyl; (ic)C 3~6 Saturated cycloalkyl; (id)

[0039] [ka] (In the formula, R 21 , R 22 and R 23 are each independently H, C 1~3 Saturated alkyl, C 2~3 Alkenyl, C 2~3 alkynyl and cyclopropyl; R 12 the total number of carbon atoms in the group is 5 or less; (ie)

[0040] [ka] where R 25a and R 25b one of which is H and the other is selected from phenyl, which is optionally substituted with a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and (if)

[0041] [ka] (In the formula, R 24 is H;C 1~3 Saturated alkyl;C 2~3 Alkenyl; C 2~3alkynyl; cyclopropyl; phenyl, optionally substituted with a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; selected from the group consisting of; If there is a single bond between C2' and C3', R 12 The following:

[0042] [ka] (In the formula, R 26a and R 26b are independent, H, F, C 1~4 saturated alkyl, C2-3 alkenyl, wherein the alkyl and alkenyl groups are selected from C 1~4 Alkylamide and C 1~4 alkyl esters; or R 26a and R 26b One of them is H and the other is nitrile and C 1~4 selected from alkyl esters); R 6 and R 9 is independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR', nitro, Me3Sn, and halo; wherein R and R′ are independently optionally substituted C 1~12 Alkyl, C 3~20 Heterocyclyl and C 5~20 aryl groups; R 7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR', nitro, Me3Sn, and halo; R'' is C 3~12 It is an alkylene group, the chain of which may contain one or more heteroatoms, such as O, S, NRN2 (where N2 is H or C 1~4 alkyl), and / or may be interrupted by aromatic rings, such as benzene or pyridine; Y and Y' are selected from O, S, or NH; R 6 ', R7’ , R 9’ are R 6 , R 7 and R 9 is selected from the same group as [Formula I] R L1’ is a linker for connecting to an antibody (Ab); R 11a is OH, ORA (wherein RA is C 1~4 alkyl), and SOzM, where z is 2 or 3 and M is a monovalent pharma- ceutically acceptable cation; R 20 and R 21 both form a double bond between the nitrogen atom and the carbon atom to which they are attached, or R 20 is selected from H and R C, where R C is a capping group; R 21 is selected from OH, ORA, and SOzM; C 2 and C. 3 If there is a double bond between R 2 is the following; (ia) optionally halo, nitro, cyano, ether, carboxy, ester, C 1~7 Alkyl, C 3~7 Heterocyclyl and bis-oxy-C 1~3 C, which may be substituted by one or more substituents selected from the group including alkylene 5~10 Aryl groups; (ib)C 1~5 Saturated fatty alkyl; (ic)C 3~6 Saturated cycloalkyl; (id)

[0043] [ka] (In the formula, R 11 , R 12 and R 13 are each independently, are each independently, H, C 1~3 Saturated alkyl, C2~3 Alkenyl, C 2~3 alkynyl and cyclopropyl; R 2 the total number of carbon atoms in the group is 5 or less; (ie)

[0044] [ka] where R 15a and R 15b one of which is H and the other is selected from phenyl, which is optionally substituted with a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and (if)

[0045] [ka] (In the formula, R 14 is H;C 1~3 Saturated alkyl;C 2~3 Alkenyl; C 2~3 alkynyl; cyclopropyl; phenyl, optionally substituted with a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; selected from the group consisting of; If there is a single bond between C2 and C3, R 2 The following:

[0046] [ka] (In the formula, R 16a and R 16b are independent, H, F, C 1~4 saturated alkyl, C2-3 alkenyl, wherein the alkyl and alkenyl groups are selected from C 1~4 Alkylamide and C 1~4 alkyl esters; or R 16a and R 16b One of them is H and the other is nitrile and C 1~4selected from alkyl esters); [Chemical formula II] R 22 is represented by the following formula IIIa, IIIb or IIIc: (a)

[0047] [ka] (Wherein, A is C 5~7 is an aryl group, and (i)Q 1 is a single bond, and Q 2 is a single bond or -Z-(CH2) n -, where Z is selected from a single bond, O, S and NH, and n is 1 to 3; or (ii)Q 1 is -CH=CH- and Q 2 is a single bond; (b)

[0048] [ka] (In the formula, R C1 , R C2 and R C3 is independently H or unsubstituted C1-2 alkyl; (c)

[0049] [ka] (wherein Q is OR L2’ , S.R. L2’ and N.R. N -R L2’ Selected from R N is selected from H, methyl and ethyl X is OR L2’ , S.R. L2’ , CO2-R L2’ , C.O.R. L2’ , NH-C(=O)-R L2’ , NHNH-R L2’ , CONHNH-R L2’

[0050] [ka] NR N R L1’ , wherein R N is H or C 1~4 alkyl; R L2’ is a linker for attachment to an antibody (Ab); R 10 and R 11 both form a double bond between the nitrogen atom and the carbon atom to which they are attached, or R 10 is H and R 11 is selected from OH, ORA, and SOzM; R 30 and R 31 both form a double bond between the nitrogen atom and the carbon atom to which they are attached, or R 30 is H and R 31 is selected from OH, ORA and SOzM.

[0051] In one embodiment, the LR L2’ or L.R. L2’ below:

[0052] [ka] where the asterisk indicates the point of attachment to the PBD, Ab is an antibody, and L 1 is a cleavable linker, and A is L 1 is a linking group that links 2 is a covalent bond or forms a self-immolative linker together with -OC(=O)-) is the basis. In one embodiment, L 1 is enzymatically cleavable.

[0053] In one embodiment, the PBD has the following formula (III):

[0054] [ka] (In the formula, R LL is a linker for linking to Ab) It is expressed as: In other embodiments, the PBD has the following formula (IV):

[0055] [ka] (In the formula, R LL is a linker for linking to Ab, R LLA is a linker for attachment to Ab or a capping group RC It is expressed as:

[0056] Such ADCs have previously been shown to be useful in the treatment of CD19-expressing cancers (see, e.g., WO 2018 / 193105, and WO 2018 / 229222, which are incorporated by reference in their entireties).

[0057] The term "anti-CD19-ADC" may include any of the embodiments described in WO 2007 / 023111. In particular, in preferred embodiments, the ADC comprises one of the following:

[0058] [ka] (Wherein, Ab is a CD19 antibody and DAR is 1 to 8.) There is a chemical structure represented by the following formula:

[0059] The antibody may comprise a VH domain having a sequence as set forth in any one of SEQ ID NOs: 1, 2, 3, 4, 5 or 6, and optionally further comprises a VL domain having a sequence as set forth in any one of SEQ ID NOs: 7, 8, 9, 10, 11 or 12. In certain embodiments, the antibody components of the anti-CD19-ADCs are antibodies that comprise VH and VL domains having the sequences of SEQ ID NOs:1 and 7, SEQ ID NOs:2 and 8, SEQ ID NOs:3 and 9, SEQ ID NOs:4 and 10, SEQ ID NOs:5 and 11, or SEQ ID NOs:6 and 12, respectively. In one embodiment, the antibody has a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3, and comprises the CDR sequence of the VH domain having the sequence set forth in SEQ ID NO: 2. In one embodiment, the antibody has a VH domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, and comprises the CDR sequence of the VL domain having the sequence set forth in SEQ ID NO: 8. In a preferred embodiment, the antibody comprises a VH domain and a VL domain, The VH domain comprises a VH CDR1, a VH CDR2, and a VH CDR3, wherein the antibody comprises a CDR sequence of the VH domain having a sequence represented by SEQ ID NO:2; and The VL domain comprises a VL CDR1, a VL CDR2, and a VL CDR3, wherein the antibody comprises a CDR sequence of the VL domain having the sequence set forth in SEQ ID NO:8.

[0060] The CDRs of the antibody variable domains described herein may be identified by any suitable method known in the art, for example using any suitable antibody numbering scheme. The CDRs can be identified using either the Kabat numbering scheme (Kabat et al., USDepartment of Health and Human Services, 1991), the Chothia numbering scheme (Chothia C, Lesk A MJ Mol Biol. (1987) 196:901-17), or the IMGT numbering scheme (Giudicelli V, et al. Nucleic Acids Res. (1997) 25:206-11; Lefranc MP. Immunol Today (1997) 18:509). One of skill in the art will appreciate that these different CDR labeling systems may yield slightly different results, but in either case, the CDRs are readily identified by one of skill in the art.

[0061] In a preferred embodiment, the antibody comprises a VH domain having the sequence given in SEQ ID NO: 2. In a preferred embodiment, the antibody comprises a VL domain having the sequence given in SEQ ID NO:8. In a preferred embodiment, the antibody comprises a VH domain and a VL domain, wherein the VH domain has a sequence given in SEQ ID NO:2 and the VL domain has a sequence given in SEQ ID NO:8. The VH and VL domains can pair to form an antibody antigen-binding site that binds to CD19. In one embodiment, the antibody is a complete antibody comprising a VH domain and a VL domain, wherein the VH and VL domains have the sequences set forth in SEQ ID NOs:2 and 8. In one embodiment, the antibody is an antibody comprising a heavy chain having the sequence set forth in SEQ ID NO:13 and a light chain having the sequence set forth in SEQ ID NO:14. In one embodiment, the antibody is a fully human monoclonal IgG1 antibody, preferably IgG1,κ. In one embodiment, the antibody is the RB4v1.2 antibody described in US Pat. No. 5,399,633.

[0062] In some aspects, the antibody is an antibody described herein that has been modified (or further modified) as described below. In some embodiments, the antibody is an antibody described herein that has been humanized, deimmunized, or resurfaced. The most preferred anti-CD19 ADC for use with embodiments of the present disclosure is ADCx19, as described herein below. A second preferred anti-CD19 ADC for use with embodiments of the present disclosure is ADCT-402.

[0063] ADCx19 ADCx19 is an antibody-drug conjugate composed of a humanized antibody against human CD19 linked to a pyrrolobenzodiazepine (PBD) warhead via a cleavable linker. The mechanism of action of ADCX19 relies on CD19 binding. CD19-specific antibodies target the antibody-drug conjugate (ADC) to cells expressing CD19. Upon binding, the ADC is internalized and transported to lysosomes, where the protease-sensitive linker is cleaved and free PBD dimers are released into the target cell. The released PBD dimers inhibit transcription in a sequence-selective manner, either due to direct inhibition of RNA polymerase or due to inhibition of the interaction of associated transcription factors. The PBD dimers generate covalent crosslinks that do not distort the DNA double helix and are not recognized by nucleotide excision repair factors, resulting in a longer effective life (Hartley 2011).

[0064] It has the following chemical structure:

[0065] [ka] It is expressed as: Ab represents the antibody RB4v1.2 (an antibody with VH and VL sequences shown in SEQ ID NO:2 and SEQ ID NO:8, respectively), which was synthesized as described in WO 2005 / 023361 (RB4v1.2-E) and typically has, for example, a DAR (drug to antibody ratio) of 2+ / -0.5, + / -0.3.

[0066] CD19 binding As used herein, the term "binds to CD19" is used to mean that the antibody binds to CD19 with higher affinity than a non-specific partner, such as bovine serum albumin (BSA, Genbank Accession No. CAA76847, Version No. CAA76847.1 GI:3336842, Archive Last Updated: Jan. 7, 2011 02:30 PM). In certain embodiments, ... 4 , 10 5 or 10 6 The antibodies of the present invention can bind to CD19 with high affinity. For example, in one embodiment, the antibodies bind to CD19 with an association constant (Ka) that is about 10 times higher. -6 M or less, e.g., 1×10 -6 , 10 -7 , 10 -8 , 10 -9 , 10 -10 , 10 -11 , 10 -12 , 10 -13 or 10 -14 It can bind to CD19 with a KD of

[0067] In one embodiment, the CD19 polypeptide corresponds to Genbank Accession No. NP_001171569, Version No. NP_001171569.1 GI:296010921, Record Last Updated: 10 Sep. 2012, 12:43 AM. In one embodiment, the nucleic acid encoding the CD19 polypeptide corresponds to Genbank Accession No. NM_001178098, Version No. NM_001178098.1 GI:296010920, Record Last Updated: 10 Sep. 2012, 12:43 AM. In one embodiment, the CD19 polypeptide corresponds to Uniprot / Swiss-Prot Accession No. P15391.

[0068] The disclosure also relates more generally to the therapeutic methods described herein, including the co-administration of an antibody drug conjugate that includes a PBD dimer (such as a PBD described herein) as the warhead with an antibody drug conjugate that includes monomethyl auristatin E as the warhead, and the co-administration of two antibody drug conjugates, in which the antibodies for each of the individual agents are selected to bind to different target molecules. An example of an antibody drug conjugate that includes monomethyl auristatin E is where the antibody targets anti-CD79b. Examples of antibody drug conjugates that include PBD dimers are those that target CD19, as described above, as well as those that target CD25 or CD22, as described below. It will be appreciated by those skilled in the art that the further embodiments detailed throughout for anti-CD19 ADCs and anti-CD79b, e.g., selection of PBD, disease to be treated, patient selection and administration, may be applied mutatis mutandis to other ADCs described herein that bind to different targets. Particular examples of other targets are CD25 and CD22, described in more detail below.

[0069] Anti-CD25-ADC This disclosure also relates to treatment with the anti-CD25 ADCs disclosed in International Publication No. WO 2014 / 057119 and described herein. As used herein, the term "anti-CD25 ADC" or "CD25-ADC" refers to an ADC in which the antibody component is an anti-CD25 antibody. The term "PBD-ADC" refers to an ADC in which the drug component is a pyrrolobenzodiazepine (PBD) warhead. The term "anti-CD25-ADC" refers to an ADC in which the antibody component is an anti-CD25 antibody and the drug component is a PBD warhead. The ADC components are as defined above for anti-CD19-ADC.

[0070] In one embodiment, the antibody has a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3, and comprises the CDR sequence of the VH domain having the sequence set forth in SEQ ID NO: 25. In one embodiment, the antibody has a VH domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, and comprises the CDR sequence of the VL domain having the sequence set forth in SEQ ID NO: 26. In a preferred embodiment, the antibody comprises a VH domain and a VL domain, The VH domain comprises a VH CDR1, a VH CDR2, and a VH CDR3, wherein the antibody comprises a VH domain CDR sequence having a sequence represented by SEQ ID NO: 25; and The VL domain comprises a VL CDR1, a VL CDR2, and a VL CDR3, wherein the antibody comprises a CDR sequence of the VL domain having the sequence set forth in SEQ ID NO:26.

[0071] The antibody comprises a VH CDR1 having the amino acid sequence represented by SEQ ID NO:27, a VH CDR2 having the amino acid sequence represented by SEQ ID NO:28, and a VH CDR3 having the amino acid sequence represented by SEQ ID NO: The VH domain may comprise a VH CDR3 having the amino acid sequence represented by reference 29. In one aspect, the antibody component of the anti-CD25-ADC is an antibody that comprises a VH domain that comprises a VH CDR1 having the amino acid sequence set forth in SEQ ID NO: 27, a VH CDR2 having the amino acid sequence set forth in SEQ ID NO: 28, and a VH CDR3 having the amino acid sequence set forth in SEQ ID NO: 29. In one embodiment, the antibody comprises a VH domain having the sequence set forth in SEQ ID NO: 25. The antibody may further comprise a VL domain comprising a VL CDR1 having the amino acid sequence set forth in SEQ ID NO: 30, a VL CDR2 having the amino acid sequence set forth in SEQ ID NO: 31, and a VL CDR3 having the amino acid sequence set forth in SEQ ID NO: 32. In one embodiment, the antibody further comprises a VL domain having the sequence set forth in SEQ ID NO:26. In one embodiment, the antibody comprises a VH domain and a VL domain, wherein the VH and VL domain have a sequence set forth in SEQ ID NO:25 paired with SEQ ID NO:26. The VH and VL domains can pair to form an antibody antigen-binding site that binds to CD25.

[0072] In a preferred embodiment, the antibody is a complete antibody comprising a VH domain and a VL domain, the VH and VL domain having the sequences given in SEQ ID NO:25 and SEQ ID NO:26. In one embodiment, the antibody is a fully human monoclonal IgG1 antibody, preferably IgG1,κ. In one embodiment, the antibody is the AB12 antibody (Genmab A / S), described in WO 2004 / 045512.

[0073] In some aspects, the antibody is an antibody described herein that has been modified (or further modified) as described below. In some embodiments, the antibody is an antibody described herein that has been humanized, deimmunized, or resurfaced. The most preferred anti-CD25 ADC for use with embodiments of the present disclosure is ADCx25, as described herein below. Another preferred anti-CD25-ADC for use with embodiments of the present disclosure is camidanlumab tesirin.

[0074] ADCx25 ADCx25 is an antibody-drug conjugate composed of a human antibody against human CD25 linked to a pyrrolobenzodiazepine (PBD) warhead via a cleavable linker. The mechanism of action of ADCX25 relies on CD25 binding. CD25-specific antibodies target the antibody-drug conjugate (ADC) to cells expressing CD25. Upon binding, the ADC is internalized and transported to lysosomes, where the protease-sensitive linker is cleaved and free PBD dimers are released into the target cell. The released PBD dimers inhibit transcription in a sequence-selective manner, either due to direct inhibition of RNA polymerase or due to inhibition of the interaction of associated transcription factors. The PBD dimers generate covalent crosslinks that do not distort the DNA double helix and are not recognized by nucleotide excision repair factors, resulting in a longer effective life (Hartley 2011).

[0075] It has the following chemical structure:

[0076] [ka] It is expressed as: Ab refers to antibody AB12 (fully human monoclonal IgG1,κ antibody with VH and VL sequences shown in SEQ ID NO:25 and SEQ ID NO:26, respectively, also known as HuMax-TAC), which was synthesized as described in WO 2014 / 057119 (Conj AB12-E) and typically has, for example, a DAR (drug to antibody ratio) of 2.0+ / -0.3.

[0077] CD25 binding As used herein, the term "binds to CD25" is used to mean that an antibody binds to CD25 with higher affinity than a non-specific partner, such as bovine serum albumin (BSA, Genbank Accession No. CAA76847, Version No. CAA76847.1 GI:3336842, Archive Last Updated: Jan. 7, 2011 02:30 PM). In certain embodiments, the ... 4 , 10 5 or 10 6 The antibodies of the present disclosure can bind to CD25 with high affinity. For example, in one embodiment, the antibodies bind to CD25 with an association constant (Ka) that is about 10 times higher. -6 M or less, e.g., 1×10 -6 , 10 -7 , 10 -8 , 10 -9 , 10 -10 , 10 -11 , 10 -12 , 10 -13 or 10 -14 It can bind to CD25 with a KD of

[0078] In one embodiment, the CD25 polypeptide corresponds to Genbank Accession No. NP_000408, Version No. NP_000408.1 GI:4557667, Record Last Updated: September 09, 2012 04:59 PM. In one embodiment, the nucleic acid encoding the CD25 polypeptide corresponds to Genbank Accession No. NM_000417, Version No. NM_000417.2 GI:269973860, Record Last Updated: September 09, 2012 04:59 PM. In one embodiment, the CD25 polypeptide corresponds to Uniprot / Swiss-Prot Accession No. P01589.

[0079] Anti-CD22-ADC The present disclosure also relates to treatment with the anti-CD22 ADCs disclosed in International Publication No. WO 2014 / 057122 and described herein. As used herein, the term "anti-CD22 ADC" or "CD22-ADC" refers to an ADC in which the antibody component is an anti-CD22 antibody. The term "PBD-ADC" refers to an ADC in which the drug component is a pyrrolobenzodiazepine (PBD) warhead. The term "anti-CD22-ADC" refers to an ADC in which the antibody component is an anti-CD22 antibody and the drug component is a PBD warhead. The ADC components are as defined above for anti-CD19-ADC.

[0080] Antibody component of anti-CD22 ADC The antibody may comprise amino acid substitutions of the interchain cysteine ​​residues with non-cysteine ​​amino acids, and conjugation of the drug moiety to the antibody is made at the interchain cysteine ​​residue(s). The antibody preferably comprises: (i) a heavy chain having an amino acid substitution of each of the interchain cysteine ​​residues HC226 and HC229 according to the EU index as set forth in Kabat; (ii) a light chain having an amino acid substitution of the interchain cysteine ​​residues κLC214 or λLC213 according to the EU index as set forth in Kabat; and (iii) a heavy chain retaining an unsubstituted interchain cysteine ​​HC220 according to the EU index as set forth in Kabat. Preferably, the drug moiety is conjugated to unsubstituted interchain cysteine ​​HC220. Interchain cysteine ​​residues HC226 and HC229 may each be substituted with valine. Interchain cysteine ​​residues κLC214 or λLC213 may be substituted with serine.

[0081] In one embodiment, an antibody of the conjugate described herein comprises a light chain comprising the amino acid sequence of SEQ ID NO: 45, or a fragment thereof, wherein the cysteine ​​at position 105, if present, is replaced by a non-cysteine ​​amino acid. For example, SEQ ID NO: 46 discloses a light chain comprising the amino acid sequence of SEQ ID NO: 45, wherein the cysteine ​​at position 105 is replaced by a serine residue.

[0082] In one embodiment, an antibody of the conjugate described herein comprises a light chain comprising the amino acid sequence of SEQ ID NO: 47, or a fragment thereof, wherein the cysteine ​​at position 102, if present, is replaced by a non-cysteine ​​amino acid. For example, SEQ ID NO: 48 discloses a light chain comprising the amino acid sequence of SEQ ID NO: 47, wherein the cysteine ​​at position 102 is replaced by a serine residue. In one embodiment, the antibody comprises: (i) a heavy chain having an amino acid substitution at each of the interchain cysteine ​​residues HC226 and HC229 according to the EU index as set forth in Kabat, optionally wherein HC226 and HC229 are each replaced by a valine; (ii) a light chain having an amino acid substitution at the interchain cysteine ​​residue κLC214 or λLC213 according to the EU index as set forth in Kabat, optionally wherein κLC214 or λLC213 is replaced by serine; (iii) an antibody, or antigen-binding portion thereof, comprising a heavy chain retaining an unsubstituted interchain cysteine ​​HC220 according to the EU index as set forth in Kabat, and optionally a drug moiety conjugated to the cysteine ​​at HC220. In such embodiments, the antibody preferably further comprises a VH domain and a VL domain as defined herein below. The light chain may (i) comprise the amino acid sequence of SEQ ID NO:45, or a fragment thereof, wherein the cysteine ​​at position 105, if present, is replaced by a non-cysteine ​​amino acid (such as SEQ ID NO:46), or may comprise the amino acid sequence of SEQ ID NO:47, or a fragment thereof, wherein the cysteine ​​at position 102, if present, is replaced by a non-cysteine ​​amino acid (such as SEQ ID NO:48). The antibody may comprise a heavy chain comprising the amino acid sequence of SEQ ID NO:43, and a light chain comprising the amino acid sequence of SEQ ID NO:45 or SEQ ID NO:47; Each of the cysteines at positions 109 and 112 of SEQ ID NO:43 is replaced by a non-cysteine ​​amino acid; The cysteine ​​at position 105 of SEQ ID NO: 45 or the cysteine ​​at position 102 of SEQ ID NO: 47 is substituted with a non-cysteine ​​amino acid. Preferably, the drug moiety is conjugated to a cysteine ​​at position 103 of SEQ ID NO: 43. In some embodiments, the cysteines at positions 109 and 112 of SEQ ID NO: 43 are each substituted with a valine, such as in SEQ ID NO: 44. In some embodiments, the cysteine ​​at position 105 of SEQ ID NO: 45 or the cysteine ​​at position 102 of SEQ ID NO: 47 is substituted with a serine, such as in SEQ ID NOs: 46 and 48. In one embodiment, the antibody is a fully human monoclonal IgG1 antibody, preferably IgG1,κ.

[0083] VH and VL domains In one embodiment, the antibody has a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3, and the antibody comprises the CDR sequences of the VH domain having the sequence set forth in SEQ ID NO: 1. In one embodiment, the antibody has a VH domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, and the antibody comprises the CDR sequences of the VL domain having the sequence set forth in SEQ ID NO:34.

[0084] In a preferred embodiment, the antibody comprises a VH domain and a VL domain, The VH domain comprises a VH CDR1, a VH CDR2, and a VH CDR3, wherein the antibody comprises the CDR sequence of the VH domain having the sequence set forth in SEQ ID NO: 33; and The VL domain comprises a VL CDR1, a VL CDR2, and a VL CDR3, wherein the antibody comprises a VL domain CDR sequence having the sequence set forth in SEQ ID NO:34. The antibody may comprise a VH domain comprising a VH CDR1 having the amino acid sequence of SEQ ID NO:35, a VH CDR2 having the amino acid sequence of SEQ ID NO:36, and a VH CDR3 having the amino acid sequence of SEQ ID NO:37.

[0085] In one aspect, the antibody component of the anti-CD22-ADC is an antibody that comprises a VH domain that comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 35, a VH CDR2 having the amino acid sequence of SEQ ID NO: 36, and a VH CDR3 having the amino acid sequence of SEQ ID NO: 37. In one embodiment, the antibody comprises a VH domain having the sequence set forth in SEQ ID NO:22. The antibody may further comprise a VL domain comprising a VL CDR1 having the amino acid sequence of SEQ ID NO: 38, a VL CDR2 having the amino acid sequence of SEQ ID NO: 39, and a VL CDR3 having the amino acid sequence of SEQ ID NO: 40. In one embodiment, the antibody further comprises a VL domain having the sequence set forth in SEQ ID NO: 34. In one embodiment, the antibody comprises a VH domain and a VL domain, wherein the VH and VL domain have the sequence of SEQ ID NO:33 paired with SEQ ID NO:34. The VH and VL domains may pair to form an antibody antigen-binding site that binds CD22.

[0086] In one embodiment, the antibody component of the anti-CD22-ADC is an antibody that comprises a VH domain having the sequence set forth in SEQ ID NO:33. The antibody may further comprise a VL domain having the sequence set forth in SEQ ID NO:34. In some embodiments, the antibody comprises a VH domain and a VL domain as described herein below. a heavy chain having the sequence represented by SEQ ID NO:44; A light chain having the sequence represented by SEQ ID NO:46 A VH domain having the sequence represented by SEQ ID NO: 33; and It comprises a VL domain having the sequence represented by SEQ ID NO:32. Preferably, the drug moiety is conjugated to the cysteine ​​at position 103 of SEQ ID NO:44.

[0087] ---------------------------- In one embodiment, the antibody is the epratuzumab antibody described in WO 2014 / 057122. In one embodiment, the antibody comprises a heavy chain having the sequence set forth in SEQ ID NO: 47 and a light chain having the sequence set forth in SEQ ID NO: 48. Preferably, the drug moiety is conjugated to the cysteine ​​at position 219 of SEQ ID NO:47.

[0088] In some aspects, the antibody is an antibody described herein that has been modified (or further modified) as described below. In some embodiments, the antibody is an antibody described herein that has been humanized, deimmunized, or resurfaced. The most preferred anti-CD22 ADC for use with embodiments of the present disclosure is ADCx22, as described herein below.

[0089] ADCx22 ADCx22 is an antibody-drug conjugate composed of a human antibody against human CD22 linked to a pyrrolobenzodiazepine (PBD) warhead via a cleavable linker. The mechanism of action of ADCX22 relies on CD22 binding. CD22-specific antibodies target the antibody-drug conjugate (ADC) to cells expressing CD22. Upon binding, the ADC is internalized and transported to lysosomes, where the protease-sensitive linker is cleaved and free PBD dimers are released into the target cell. The released PBD dimers inhibit transcription in a sequence-selective manner, either due to direct inhibition of RNA polymerase or due to inhibition of the interaction of associated transcription factors. The PBD dimers generate covalent crosslinks that do not distort the DNA double helix and are not recognized by nucleotide excision repair factors, resulting in a longer effective life span (Hartley 2011).

[0090] It has the following chemical structure:

[0091] [ka] where Ab represents an antibody comprising a VH domain having the sequence of SEQ ID NO: 33 and a VL domain having the sequence of SEQ ID NO: 34. Typically, the antibody further comprises: (i) a heavy chain with an amino acid substitution (e.g., to valine) at each of interchain cysteine ​​residues HC226 and HC229 according to the EU index as set forth in Kabat; (ii) a light chain with an amino acid substitution (e.g., to serine) at interchain cysteine ​​residue kappa LC214 according to the EU index as set forth in Kabat; and (iii) a heavy chain retaining an unsubstituted interchain cysteine ​​HC220 according to the EU index as set forth in Kabat. Typically, a drug moiety is conjugated to the cysteine ​​at HC220. Thus, an antibody typically comprises a heavy chain having the sequence given in SEQ ID NO: 41 and a light chain having the sequence given in SEQ ID NO: 42. Linkage to the drug occurs on the inter-heavy chain cysteine ​​Cys220 (EU numbering). HC220 corresponds to position 219 of SEQ ID NO: 41.

[0092] Note that "having a sequence" has the same meaning as "comprising a sequence." In particular, in certain embodiments, the heavy chain of ADCx22 is expressed with an additional terminal "K" residue (thus terminating in SPGK), which is optionally post-translationally removed to improve the homogeneity of the final therapeutic ADC product.

[0093] CD22 binding As used herein, the term "binds to CD22" is used to mean that an antibody binds to CD22 with higher affinity than a non-specific partner, such as bovine serum albumin (BSA, Genbank Accession No. CAA76847, Version No. CAA76847.1 GI:3336842, Archive Last Updated: Jan. 7, 2011 02:30 PM). In certain embodiments, the ... 4 , 10 5 or 10 6The antibodies of the present invention can bind to CD22 with high affinity. For example, in one embodiment, the antibodies bind to CD22 with an association constant (Ka) that is about 10 times higher. -6 M or less, e.g., 1×10 -6 , 10 -7 , 10 -8 , 10 -9 , 10 -10 , 10 -11 , 10 -12 , 10 -13 or 10 -14 It can bind to CD22 with a KD of In certain embodiments, the CD22 polypeptide corresponds to Genbank Accession No. BAB15489, Version No. BAB15489.1 GI:10439338, Record Last Updated: September 11, 2006 at 11:24 PM. In one embodiment, the nucleic acid encoding the CD22 polypeptide corresponds to Genbank Accession No. AK026467, Version No. AK026467.1 GI:10439337, Record Last Updated: September 11, 2006 at 11:24 PM.

[0094] Anti-CD79b agents CD79b CD79 (composed of the subunits CD79a and CD79b) is a heterodimeric signaling component of the B cell receptor. CD79b membrane expression is restricted to the B cell compartment, ubiquitously expressed in mature B cell lymphomas, and located on the cell surface by the earliest committed B cell precursors before expression of immunoglobulin μ. Antibodies against CD79b induce negative cell signals and suppress responses to T cell-dependent antigens (Nakamura et al. 1996;64:39-46). However, unconjugated anti-CD79b antibodies induce modest B cell depletion and exhibit moderate, if any, antibody- and complement-dependent cytotoxicity (Fuh et al. 2017;174:628-640). Conversely, anti-CD79b ADCs induce long-term and sustained depletion of proliferating B cells (Fuh et al., ibid.), which are trafficked to lysosomal-like compartments in B cells as part of antigen presentation (Polson et al. 2007;110:616-623).

[0095] Anti-CD79b agents As used herein, the term "anti-CD79b agent" refers to any agent that specifically binds to CD79b and / or cells expressing CD79b. Preferably, the agent induces B cell depletion. As used herein, the term "specifically binds to CD79b" is used to mean that an agent binds to CD79b with higher affinity than a non-specific partner, such as bovine serum albumin (BSA, Genbank Accession No. CAA76847, Version No. CAA76847.1 GI:3336842, Record Last Updated: Jan. 7, 2011 02:30 PM). In certain embodiments, an agent binds to CD79b with an affinity that is at least 2, 3, 4, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 50 ... 4 , 10 5 or 10 6 The agent may bind to CD79b with high affinity. For example, in one embodiment, the agent binds to CD79b with an association constant (Ka) that is 1×10 -6 , 10 -7 , 10 -8 , 10 -9 , 10 -10 , 10 -11 , 10 -12 , 10 -13 or 10 -14 It can bind to CD79b with a KD of

[0096] Anti-CD79b ADC As used herein, the term "anti-CD79b ADC" refers to a conjugate comprising a moiety that specifically binds to CD79b conjugated to a payload. In one embodiment, the moiety that specifically binds to CD79b is an antibody. Optionally, the antibody is polatuzumab. In some embodiments, the payload comprises a drug, such as a cytotoxic drug. In some cases, the cytotoxic drug is an auristatin, such as monomethylauristatin. In some cases, the cytotoxic drug is monomethylauristatin (MMAE). In some cases, the payload comprises a linker moiety that conjugates the payload to a moiety that specifically binds to CD79b. In some embodiments, the payload is a drug-linker, where the drug-linker comprises a drug moiety and a linker moiety. The linker moiety may be cleavable by an enzyme, such as a protease. For example, in some embodiments, the linker is a dipeptide, such as valine-citrulline (val-cit, or vc).

[0097] In one embodiment, the ADC has the following structure:

[0098] [ka] where the asterisk indicates the point of attachment to the drug moiety, Ab is an antibody, and L 1 is a cleavable linker, and A is L 1 is a linking group that links 2 is a covalent bond or -OC(=O)- forms a self-immolative linker. There is.

[0099] ---------------------------- In a preferred embodiment, the ADC has formula (I): Ab-(DL)p(I) (In the formula, Ab is an antibody that binds to CD79b; DL is as follows

[0100] [ka] It is expressed as p is 1 to 8, for example 3 to 4, for example about 3.5. It may be a complex represented by the formula: In one embodiment, the antibody has a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3, and comprises the CDR sequence of the VH domain having the sequence set forth in SEQ ID NO: 17. In one embodiment, the antibody has a VH domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, and comprises the CDR sequence of the VL domain having the sequence set forth in SEQ ID NO: 18. In a preferred embodiment, the antibody comprises a VH domain and a VL domain, The VH domain comprises a VH CDR1, a VH CDR2, and a VH CDR3, wherein the antibody comprises a VH domain CDR sequence having a sequence represented by SEQ ID NO: 17; and The VL domain comprises a VL CDR1, a VL CDR2, and a VL CDR3, wherein the antibody comprises a CDR sequence of the VL domain having a sequence represented by SEQ ID NO: 18. In one embodiment, the antibody comprises a VH domain having a VH CDR3 having the amino acid sequence of SEQ ID NO: 21. In one embodiment, the VH domain further comprises a VH CDR2 having the amino acid sequence of SEQ ID NO: 20, and / or a VH CDR1 having the amino acid sequence of SEQ ID NO: 19. In one embodiment, the antibody comprises a VH domain having a VH CDR1 having the amino acid sequence of SEQ ID NO: 19, a VH CDR2 having the amino acid sequence of SEQ ID NO: 20, and a VH CDR3 having the amino acid sequence of SEQ ID NO: 21. In one embodiment, the antibody comprises a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3, and the CDR sequence of the VH domain has the sequence of SEQ ID NO: 17. In a preferred embodiment, the antibody comprises a VH domain having the sequence set forth in SEQ ID NO: 17.

[0101] The antibody may further comprise a VL domain. In certain embodiments, the antibody comprises a VL domain having a VL CDR3 having the amino acid sequence of SEQ ID NO: 24. In certain embodiments, the VL domain further comprises a VL CDR2 having the amino acid sequence of SEQ ID NO: 23, and / or a VL CDR1 having the amino acid sequence of SEQ ID NO: 22. In certain embodiments, the antibody comprises a VL domain having a VL CDR1 having the amino acid sequence of SEQ ID NO: 22, a VL CDR2 having the amino acid sequence of SEQ ID NO: 23, and a VL CDR3 having the amino acid sequence of SEQ ID NO: 24. In certain embodiments, the antibody comprises a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein the antibody comprises a CDR sequence of the VL domain having the sequence of SEQ ID NO: 18. In a preferred embodiment, the antibody comprises a VL domain having the sequence represented by SEQ ID NO: 18.

[0102] The CDRs of the antibody variable domains described herein can be identified by any suitable method known in the art, for example, using any suitable antibody numbering scheme. The CDRs can be identified using either the Kabat numbering scheme (Kabat et al., USDepartment of Health and Human Services, 1991), the Chothia numbering scheme (Chothia C, Lesk A MJ Mol Biol. (1987) 196:901-17), or the IMGT numbering scheme (Giudicelli V, et al. Nucleic Acids Res. (1997) 25:206-11; Lefranc MP. Immunol Today (1997) 18:509). Those skilled in the art will understand that these different CDR labeling systems may give slightly different results, but in each case the CDRs can be easily identified by those skilled in the art.

[0103] The VH and VL domains may form an antibody antigen-binding site that binds to CD79b. In one embodiment, the antibody is a complete antibody comprising a VH domain and a VL domain, wherein the VH and VL domain have the sequence of SEQ ID NO:17 paired with SEQ ID NO:18. In one embodiment, the antibody is a fully human monoclonal IgG1 antibody, preferably IgG1,κ.

[0104] In some aspects, the antibody is an antibody described herein that has been modified (or further modified) as described below. In some embodiments, the antibody is an antibody described herein that has been humanized, deimmunized, or resurfaced.

[0105] ---------------------------- The most preferred anti-CD79b agent is polatuzumab vedotin. Polatuzumab vedotin Polatuzumab vedotin (Polivy, Roche) is a CD79b-directed antibody-drug conjugate consisting of a humanized IgG1 anti-CD79b mAb conjugated to monoethyl auristatin E (MMAE) via the protease-cleavable linker vc (Val-Cit). Its chemical structure is:

[0106] [ka] It is expressed as: Ab represents the antibody polatuzumab (the antibody with the VH and VL sequences of SEQ ID NO: 17 and SEQ ID NO: 18, respectively), whose DAR (drug to antibody ratio) is typically 3.5.

[0107] ---------------------------- Advantageous Properties of the Disclosed Combination Both anti-CD19 ADCs (or anti-CD25 ADCs or anti-CD22 ADCs) and anti-CD79b agents have demonstrated clinical utility, for example, in the treatment of cancer, when used alone as single agents. However, as described herein, anti-CD19 ADCs and anti-CD79b agents offer the following advantages over the use of either anti-CD19 ADCs or anti-CD79b agents alone, relative to treatment with anti-CD19 b antibodies: 1) Effective treatment of a wider range of cancers 2) Effective treatment of individuals with resistant or refractory diseases, such as cancer, and those with cancer or other diseases that have relapsed after a period of remission 3) an increase in the response rate to treatment; and / or 4) Increased persistence of treatment may provide one or more of: As used herein, effective treatment of a broader range of cancers means that complete responses are observed in a broader range of recognized cancer types following treatment with the combination, i.e., cancer types that have not previously been reported to show complete responses to monotherapy with either anti-CD19 ADC or anti-CD79b. Without wishing to be bound by theory, in embodiments in which the anti-ADC and anti-ADC 79 b agents comprise different classes of cytotoxic agents with different modes of action (e.g., where the anti-ADC is loncastuximab tesillin and the anti-ADC 79 b agent is Pola-V, in some cases) (wherein the PBD dimer is a DNA crosslinker, whereas MMAE is a tubulin inhibitor), it is believed that cytotoxic agents acting via two different pathways contribute to additive or synergistic cytotoxicity. Furthermore, the fact that the two agents target two different cell surface antigens means that they are not competing for binding to the same antigen on the cell surface, facilitating delivery of the cytotoxic agent to the target cell.

[0108] As used herein, effective treatment of resistant, refractory, or relapsed disease means that a complete response is observed with the anti-CD19 ADC / anti-CD79b agent combination in individuals who are either partially or completely resistant or refractory to treatment with an anti-C1 antibody, to either anti-CD19 ADC or anti-CD79b monotherapy (e.g., individuals who show no response or only a partial response after treatment with either agent alone, or individuals with relapsed disease). In one embodiment, a complete response with the anti-CD19 ADC / anti-CD79b agent combination is observed in at least 10% of individuals following treatment who are either partially or completely resistant or refractory to either anti-CD19 ADC or anti-CD79b monotherapy. In certain embodiments, a complete response following treatment with an anti-CD19 ADC / anti-CD79b agent combination 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 who are either partially or completely resistant or refractory to treatment with an anti-C18 antibody or to treatment with either an anti-CD19 ADC or anti-CD79b alone. As used herein, increased response rate to a treatment means that a complete response following treatment with the combination is observed in a higher percentage of individuals than is observed following treatment with either anti-CD19 ADC or anti-CD79b alone. In certain embodiments, a complete response following treatment with the anti-CD19 ADC / anti-CD79b agent combination is observed in at least 10% of individuals treated with either anti-CD19 ADC or anti-CD79b alone. In certain embodiments, a complete response following treatment with the anti-CD19 ADC / anti-CD79b agent combination 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 treated with either anti-CD19 ADC or anti-CD79b alone. As used herein, increased durability of treatment refers to a longer mean duration of complete response in individuals treated with the combination versus monotherapy with either anti-CD19 ADC or anti-CD79b. In one embodiment, the mean duration of complete response following treatment with an anti-CD1 antibody is 1 week. The mean duration of complete response following treatment with an anti-CD19 ADC / anti-CD79b agent combination is at least 6 months. In one embodiment, the mean duration of complete response following treatment with an anti-CD19 ADC / anti-CD79b 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.

[0109] As used herein, "complete response" means that there is no clinical evidence of disease in an individual. Evidence can be assessed using any suitable method in the art, such as CT or PET scanning, or biopsy, if appropriate. The number of doses required to achieve a complete response may be 1, 2, 3, 4, 5, 10 or more. In some embodiments, an individual achieves a complete response within 1 year or less after the first dose, for example, within 6 months or less, 3 months or less, 1 month or less, 2 weeks or less, or 1 week or less after the first dose. References to anti-CD19 in this section and all following sections can be substituted with anti-CD22 and anti-CD25 in other embodiments, unless otherwise indicated.

[0110] Disease being treated Combination therapies described herein include those useful for anti-cancer activity. In particular, in certain embodiments, the treatments include antibodies conjugated to PBD drug moieties, i.e., toxins, i.e., covalently linked by a linker. When the drug is not conjugated to an antibody, the PBD drug has a cytotoxic effect. Thus, the biological activity of the PBD drug moiety is modulated by conjugation to an antibody. The antibody drug conjugates (ADCs) of the present disclosure selectively deliver an effective amount of a cytotoxic agent to tumor tissue, thereby allowing for greater selectivity, i.e., a lower effective dose, to be achieved. In one aspect, the disclosure provides a combination therapy comprising administering an anti-CD19 ADC that binds CD19 for use in treatment, comprising selecting a subject based on expression of a target protein. In one aspect, the present disclosure provides a combination therapy with a label that specifies that the combination therapy is suitable for use in a subject that is determined to be suitable for such use.The label may specify that the treatment is suitable for use in a subject that has expression of CD19, such as overexpression of CD19.The label may specify that the subject has a particular type of cancer. The cancer may be a lymphoma, such as non-Hodgkin's lymphoma. The label may specify that the subject has a CD19+ lymphoma. In a further aspect, there is also provided a combination therapy as described herein for use in treating a proliferative disease. Another aspect of the disclosure provides the use of a conjugate compound in the manufacture of a medicament for treating a proliferative disease. One of skill in the art can readily determine whether a candidate combination therapy treats a proliferative condition for any particular cell type. For example, assays that can be conveniently used to evaluate the activity provided by a particular compound are described below.

[0111] The combination therapies described herein can be used to treat proliferative disorders. The term "proliferative disorder" refers to undesired or uncontrolled cell proliferation, either in vitro or in vivo, of unwanted, excessive or abnormal cells, such as neoplastic or hyperplastic growth.

[0112] Examples of proliferative conditions include benign, premalignant and malignant cell proliferations, such as neoplasms and tumors (e.g., histocytoma, glioma, astrocyoma, 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 diseases (e.g., of connective tissue), and atherosclerosis. Cancers of interest include, but are not limited to, leukemia and ovarian cancer. Any type of cell can be treated, including, but not limited to, lung, gastrointestinal (including, e.g., intestine, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin.

[0113] Particularly interesting proliferative diseases include, but are not limited to, cancers such as diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma, mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), Waldenstrom's macroglobulinemia (WM), and non-Hodgkin's lymphomas, including marginal zone B-cell lymphoma (MZBL), and leukemias such as hairy cell leukemia (HCL), hairy cell leukemia variant (HCL-v), chronic lymphocytic leukemia (CLL), including Richter's syndrome, and acute lymphoblastic leukemia (ALL), such as Philadelphia chromosome positive ALL (Ph+ALL) or Philadelphia chromosome negative ALL (Ph-ALL). [Fielding A. 2010 January;95(1):8-12].

[0114] It is contemplated that the combination therapy of the present disclosure may be used to treat a variety of diseases or disorders characterized, for example, by overexpression of tumor antigens. Exemplary conditions or hyperproliferative disorders include benign or malignant tumors; leukemia, hematological, and lymphatic malignancies. Others include neuronal, glial, astrocyte, hypothalamic, glandular, macrophage, epithelial, stromal, blastocoel, inflammatory, angiogenic, and immunological, including autoimmune disorders and graft-versus-host disease (GVHD). Generally, 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 carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer, including small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous cell carcinoma of the lung, cancer of the peritoneum, hepatocellular carcinoma, gastric cancer or stomach cancer, including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney cancer or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, and head and neck cancer.

[0115] Autoimmune diseases for which the combination therapy may be used to treat include, but are not limited to, rheumatic diseases (e.g., rheumatoid arthritis, Sjogren's syndrome, scleroderma, lupus, such as SLE and lupus nephritis, polymyositis / dermatomyositis, cryoglobulinemia, antiphospholipid syndrome, and psoriatic arthritis), osteoarthritis, autoimmune gastrointestinal and liver diseases (e.g., inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), autoimmune gastritis and pernicious anemia, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and polyphlebitis), vasculitis (e.g., Churg-Strauss vasculitis, Wegener's granulomatosis, and cutaneous polyarteritis), autoimmune neurological diseases (e.g., psoriasis, opioid syndrome, and the like), and autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), autoimmune gastritis and pernicious anemia, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and polyphlebitis), vasculitis (e.g., Churg-Strauss vasculitis, Wegener's granulomatosis, and cutaneous polyarteritis), and autoimmune neurological diseases (e.g., psoriasis, opioid syndrome, and the like). Examples of autoimmune disorders include socronus-myoclonus syndrome, myasthenia gravis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, and cutaneous polyneuropathy, etc., blood disorders (e.g., thrombocytopenic purpura, thrombotic thrombocytopenic purpura, post-transfusion purpura, and autoimmune hemolytic anemia, etc.), atherosclerosis, uveitis, autoimmune hearing disorders (e.g., labyrinthitis and hearing loss, etc.), Behcet's disease, Raynaud's syndrome, organ transplantation, graft-versus-host disease (GVHD), and autoimmune endocrine disorders (e.g., diabetes-related autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM), Addison's disease, and autoimmune thyroid diseases (e.g., Graves' disease and thyroiditis)).

[0116] In certain aspects, the subject is afflicted with a proliferative disease selected from cancers such as diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma, mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma, including Waldenstrom's macroglobulinemia (WM), and marginal zone B-cell lymphoma (MZBL), and leukemias such as hairy cell leukemia (HCL), hairy cell leukemia variant (HCL-v), chronic lymphocytic leukemia (CLL), including Richter's syndrome, and acute lymphoblastic leukemia (ALL), such as Philadelphia chromosome positive ALL (Ph+ALL) or Philadelphia chromosome negative ALL (Ph-ALL).

[0117] CD25 The proliferative disorder may be characterized by the presence of a neoplasm that includes both CD25+ve cells and CD25-ve cells. The proliferative disorder may be characterized by the presence of a neoplasm that is composed of CD25-ve neoplastic cells, and in some cases, the CD25-ve neoplastic cells are associated with CD25+ve non-neoplastic cells, such as CD25+ve T cells. The target neoplasm or neoplastic cells may be all or part of a solid tumor. "Solid tumors" as used herein are understood to include solid hematological cancers such as lymphomas (Hodgkin's lymphoma or non-Hodgkin's T-cell lymphoma), which are discussed in more detail herein. A solid tumor may be a neoplasm, including a non-hematological cancer, that comprises or is composed of CD25+ve neoplastic cells. A solid tumor may be a neoplasm, including a non-hematological cancer, that is infiltrated with CD25+ve cells, such as CD25+ve T cells; such a solid tumor may lack expression of CD25 (i.e., may comprise or be composed of CD25-ve neoplastic cells). For example, the solid tumor may be a tumor with high levels of infiltrating T cells, such as infiltrating regulatory T cells (Treg; Meentier-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 Jan; 27(1):109-118). Thus, the solid tumor may be pancreatic, breast, colorectal, gastric and esophageal cancer, leukemia and lymphoma, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular carcinoma, renal cell carcinoma, and head and neck cancer.

[0118] Patient Selection In some embodiments, the individual is selected as suitable for treatment with the combination therapy before the treatment is administered. As used herein, an individual who is considered suitable for treatment is an individual who is expected to benefit from or respond to treatment. The individual may have, be suspected of, or be at risk of cancer. The individual may have been diagnosed with cancer. In particular, the individual may have, be suspected of, or be at risk of lymphoma. In some cases, the individual may have, be suspected of, or be at risk of solid cancer with tumor-associated non-tumor cells that express CD19 (e.g., infiltrating cells that express CD19). In some embodiments, individuals are selected based on the amount or pattern of expression of CD19. In some embodiments, the selection is based on cell surface expression of CD19. In certain embodiments, the target is CD79b. In certain embodiments, the selection is based on expression of CD79b. In one embodiment, the selection is based on the levels of both CD19 and CD79b at the cell surface. In some cases, expression of the target is determined in a particular tissue of interest, for example in a sample of lymphatic or tumor tissue. In some cases, systemic expression of the target is determined, for example in a sample of a circulating fluid such as blood, plasma, serum, or lymph. In some aspects, individuals are selected as suitable for treatment due to the presence of target expression in the sample. In these cases, individuals lacking target expression may be considered unsuitable for treatment. In other embodiments, the level of target expression is used to select individuals suitable for treatment: if the expression level of the target is above a threshold level, the individual is determined to be suitable for treatment. In certain embodiments, the presence of CD19 on cells in a sample and / or the presence of CD19 in cells indicates that the individual is suitable for a combination treatment comprising an anti-CD19 ADC and an anti-CD79b agent. In other embodiments, the amount and / or expression of CD19 must exceed a threshold level to indicate that the individual is suitable for the treatment. In certain embodiments, the observation of altered CD19 and / or localization in a sample compared to a control indicates that the individual is suitable for the treatment. In certain aspects, an individual is indicated as suitable for treatment if cells obtained from the lymph node or extranodal site react with antibodies to CD19 and / or as determined by IHC. In certain embodiments, 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 the total cells in the sample express CD 19. In certain embodiments described herein, a patient is determined to be suitable for treatment if at least 10% of the cells in the sample express CD 19. In some embodiments, 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 the gene. In some embodiments described herein, a patient is determined to be suitable for treatment if at least 10% of the cells in the sample express the gene. In certain aspects, an individual is selected as suitable for treatment based on their current or previous treatment regimen. In certain embodiments, if the individual has been treated with an anti-CD79b agent, the individual is selected for anti-CD19 ADC treatment. In certain embodiments, if the individual is undergoing treatment with an anti-CD79b agent, the individual is selected for anti-CD19 ADC treatment. In some cases, the individual is refractory to treatment (or further treatment) with an anti-CD79b agent and is optionally selected for treatment. In some cases, the anti-CD79b agent can be polatuzumab vedotin. In embodiments where the individual is undergoing or has undergone treatment with an anti-CD79b agent, the anti-CD19 ADC can be administered in combination with the anti-CD79b agent or without continued administration of the anti-CD79b agent.

[0119] In one embodiment, the anti-CD19 ADC is administered to the selected individual in combination with an anti-CD79b agent. In one embodiment, the anti-CD19 ADC is administered to the selected individual without continued administration of an anti-CD79b agent. The anti-CD79b agent is preferably polatuzumab vedotin. As used herein, the term "refractory to treatment (or further treatment) with an anti-CD79b agent" means that the disease (e.g., cancer) does not respond or has stopped responding to administration of an anti-CD79b agent when administered as a monotherapy. In one embodiment, an individual with refractory NHL is defined in Cheson at al. 2014 (South Asian J Cancer. 2014 Jan-Mar;3(1):66-70) as a non-responder is an individual who has either (i) a >50% increase from nadir in the sum product of the diameters of any previously identified abnormal nodules, or (ii) the appearance of any new lesions during or at the end of treatment. In one embodiment, an individual with refractory leukemia is identified as an individual with either stable or progressive disease who has completed one complete cycle of treatment, or an individual who has achieved a partial response after two or more complete cycles of treatment.

[0120] CD25 In certain aspects, the subject is selected based on having a neoplasm that includes both CD25+ve cells and CD25-ve cells. The neoplasm may be composed of CD25-ve neoplastic cells, and in some cases, the CD25-ve neoplastic cells are associated with CD25+ve non-neoplastic cells, such as CD25+ve Tregs. The neoplasm or neoplastic cells may be all or part of a solid tumor. The solid tumor may be partially or completely CD25-ve and may be infiltrated with CD25+ve cells, such as CD25+ve Tregs. In preferred aspects, the solid tumor is associated with high levels of CD25+ve infiltrating cells, e.g., Treg cells. In some aspects, the solid tumor is associated with low levels of CD25+ve infiltrating cells, e.g., Treg cells. In certain aspects, the solid tumor is not associated with CD25+ve infiltrating cells, such as Treg cells, e.g., the level of CD25+ve cells may be below the limit of detection.

[0121] sample The sample may comprise or be derived from a volume of blood; the fluid portion of blood obtained after removal of fibrin clots and blood cells; a volume of serum derived from an individual's blood; a volume of pancreatic juice; a tissue sample or biopsy; or cells isolated from said individual. The sample may be taken from any tissue or body fluid, hi certain aspects, the sample may comprise or be derived from a tissue sample, biopsy, resection or isolated cells from said individual. In some embodiments, the sample is a tissue sample. The sample may be a sample of tumor tissue, such as a cancerous tumor tissue. The sample may be obtained by tumor biopsy. In some embodiments, the sample is a lymphatic tissue sample, such as a lymphatic lesion sample or a lymph node biopsy. In some cases, the sample is a skin biopsy. In some embodiments, the sample is taken from a bodily fluid, more preferably a bodily fluid circulating in the body. Thus, the sample may be a blood sample or a lymphatic 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. A blood-derived sample may be a selected fraction of an individual's blood, such as a selected cell-containing fraction or a plasma or serum fraction. The selected cell-containing fraction may contain cell types of the subject, which may include white blood cells (WBCs), in particular peripheral blood mononuclear cells (PBCs) and / or granulocytes, and / or red blood cells (RBCs). Thus, the method according to the present disclosure may include detection of CD19 protein 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, archived tissue may be from a biopsy at the individual's initial diagnosis or at the time of recurrence. In some embodiments, the sample is a fresh biopsy.

[0122] Individual status The individual may be a mammal, a placental mammal, a marsupial (e.g., kangaroo, bat), a platypus (e.g., platypus), a rodent (e.g., guinea pig, hamster, rat, mouse), a murine (e.g., mouse), a lagomorph (e.g., rabbit), an avian (e.g., bird), a canine (e.g., dog), a feline (e.g., cat), an equine (e.g., horse), a porcine (e.g., pig), an ovine (e.g., sheep), a bovine (e.g., cow), a primate, an ape (e.g., monkey or ape-human), ape (e.g., marmoset, baboon), ape (e.g., gorilla, chimpanzee, orangutan, gibbon), or a human. Furthermore, an individual may be in any of its forms of development, such as a fetus. In one preferred embodiment, the individual is a human. The terms "subject," "patient," and "individual" are used interchangeably herein.

[0123] In some embodiments described herein, the individual is identified as having, suspected of having, or at risk of having cancer. In some embodiments described herein, the individual has already been diagnosed with cancer. The individual may have been diagnosed with cancer, such as diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma, mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma, including Waldenstrom's macroglobulinemia (WM), and marginal zone B-cell lymphoma (MZBL), and leukemia, such as hairy cell leukemia (HCL), hairy cell leukemia variant (HCL-v), chronic lymphocytic leukemia (CLL), including Richter's syndrome, and acute lymphoblastic leukemia (ALL), such as Philadelphia chromosome positive ALL (Ph+ALL) or Philadelphia chromosome negative ALL (Ph-ALL). In some cases, the individual has been diagnosed with cancer such as diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma, mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphomas including Waldenstrom's macroglobulinemia (WM), and marginal zone B-cell lymphoma (MZBL), and leukemia such as hairy cell leukemia (HCL), hairy cell leukemia variant (HCL-v), chronic lymphocytic leukemia (CLL) including Richter's syndrome, and acute lymphoblastic leukemia (ALL) such as Philadelphia chromosome positive ALL (Ph+ALL) or Philadelphia chromosome negative ALL (Ph-ALL) [Fielding A. 2010 Jan;95(1):8-12]. In some cases, the individual has been diagnosed with a solid tumor that contains CD19+ expressing infiltrating cells.

[0124] The individual may be undergoing or have undergone a therapeutic treatment for the cancer. The subject may or may not have previously received ADCX19. In some cases, the cancer is a lymphoma, including non-Hodgkin's lymphoma. The individual may be undergoing or may have undergone treatment with an anti-CD79b agent. In some cases, the individual may be refractory to treatment (or further treatment) with an anti-CD79b agent. In some cases, the anti-CD79b agent may be polatuzumab vedotin. In embodiments in which the individual is undergoing or has undergone treatment with an anti-CD79b agent, the anti-CD19 ADC may be administered in combination with the anti-CD79b agent or without continued administration of the anti-CD79b agent.

[0125] Control In one embodiment, target expression in an individual is compared to target expression in a control, which is useful for supporting the validity of staining and identifying experimental artifacts. In some cases, the control may be a reference sample or a reference data set. The reference may be a sample previously obtained from an individual with a known match. The reference may be a data set obtained from analyzing a reference sample. Controls may be positive controls, in which the target molecule is known to be present or expressed at high levels, or negative controls, 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 the 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 the treatment, such as an individual who has previously responded to the treatment. In some cases, the control may be a sample obtained from the same individual as the test sample, but from tissue known to be healthy, thus allowing a sample of cancerous tissue from an individual to be compared to a non-cancerous tissue sample. In some cases, the control is a cell culture sample.

[0126] Optionally, the test sample is analyzed prior to incubation with the antibody to determine the level of background staining inherent to the sample. In some cases, an isotype control is used. An isotype control uses an antibody of the same class as the target-specific antibody, but is not immunoreactive with the sample. Such controls are useful to distinguish non-specific interactions of the target-specific antibody. The method may include morphology interpretation by a hematopathologist and immunohistochemistry to ensure accurate interpretation of test results. The method may include confirmation that the pattern of expression correlates with the expected pattern. For example, if the amount of CD19 and / or CD79b expression is analyzed, the method may include confirmation that expression is observed in the test sample as membrane staining with cytoplasmic components. The method may include confirmation that the ratio of target signal to noise exceeds a threshold level, thereby allowing clear distinction between specific and non-specific background signals.

[0127] Treatment method The term "treatment" as used herein in the context of treating a condition generally relates to treatment and therapy, whether in humans or animals (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, such as inhibition of progression of the condition, including slowing the rate of progression, halting the rate of progression, regressing the condition, ameliorating the condition, and curing the condition. Treatment as a prophylactic measure (i.e., prevention, prophylaxis) is also included. The term "therapeutically effective amount" or "effective amount" as used herein relates to an amount of an active compound, or a material, composition or dosage form containing an active compound, that is effective to produce some desired therapeutic effect, commensurate with a reasonable benefit / risk ratio, when administered in accordance with a desired treatment regimen. Similarly, the term "prophylactically effective amount" as used herein relates to an amount of active compound, or a material, composition or dosage form containing an active compound, that is effective for producing some desired prophylactic effect, commensurate with a reasonable benefit / risk ratio, when administered in accordance with a desired treatment regimen. Disclosed herein are methods of treatment. Also provided are methods of treatment, comprising administering a therapeutically effective amount of an anti-T cell antibody to a subject in need of treatment. The term "therapeutically effective amount" is an amount sufficient to show benefit to the 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 what is being treated. Prescribing treatment, e.g., determining dosage, is within the responsibility of general practitioners and other medical doctors. The subject may be tested to determine eligibility to receive treatment according to the methods described herein. The methods of treatment may include a step of determining whether the subject is eligible for treatment using the methods described herein.

[0128] The anti-CD19 ADC comprises an anti-CD19 antibody. The anti-CD19 antibody may be an RB4v1.2 antibody. The ADC may comprise a drug that is a PBD dimer. The ADC may be an ADCx19. The ADC may be an ADC disclosed in US Pat. No. 6,399,636.

[0129] The anti-CD25 ADC comprises an anti-CD25 antibody. The anti-CD25 antibody may be HuMax-TAC™. The ADC may comprise a drug that is a PBD dimer. The ADC may be an anti-ADC, in particular ADCX25 or camidanlumab tesirin. The ADC may be an ADC disclosed in International Publication No. 2014 / 057119.

[0130] The anti-CD22 ADC comprises an anti-CD22 antibody. The anti-CD22 may be EMabC220. The ADC may comprise a drug that is a PBD dimer. The ADC may be an anti-CD22-ADC, such as ADCT-602 or ADCx22. The ADC may be an ADC disclosed in International Publication No. 2014 / 057122 or International Publication No. 2016 / 166307.

[0131] Typically, the individual to whom the treatment described herein is administered is in need of said treatment or has been identified or diagnosed as in need of treatment. The anti-CD79b agent can be polatuzumab vedotin. The treatment may include administration of an anti-B cell antibody. The anti-CD19 ADC / anti-CD79b agent may be used alone or in further combination with other treatments, either simultaneously or sequentially depending on the condition being treated.

[0132] Examples of treatment methods include the following: (1) Identifying the individual as having been treated or currently being treated with an anti-CD79b agent, such as polatuzumab vedotin; (2) administering to the individual an anti-CD19 ADC, e.g., ADCx19; and, in some cases, (3) Administering an anti-CD79b agent, such as polatuzumab vedotin, in combination with an anti-CD19 ADC (e.g., simultaneously with or after the ADC). Examples of treatments and procedures include, but are not limited to, chemotherapy (eg, administration of active agents including drugs such as chemotherapy agents); surgery; and radiation therapy.

[0133] A "chemotherapeutic agent" is a compound useful in the treatment of cancer, regardless of 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 compounds used in "targeted therapy" and conventional chemotherapy. Examples of chemotherapeutic agents include the following: lenalidomide (REVLIMID®, Celgene), vorinostat (ZOLINZA®, Merck), panobinostat (FARYDAK®, Novartis), mocetinostat (MGCD0103), everolimus (ZORTRESS®, CERTICAN®, Novartis), bendamustine (TREAKISYM®, RIBOMUSTIN®, LEVACT®, TREANDA®, Mundipharma International), erlotinib (TARCEVA®, Genentech / OSI), and rifabutinib (RIBA®, Genentech / OSI). Pharm.), docetaxel (TAXOTERE®, Sanofi Aventis), 5-FU (fluorouracil, 5-fluorouracil, CAS number 51-21-8), gemcitabine (GEMZAR®, Lilly), PD-0325901 (CAS number 391210-10-9, Pfizer), paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, NJ), trastuzumab (HERCEPTIN®, Genentech), temozolomide (4-methyl-5-oxo 23468-pentaazabicyclo[4.3.0]nona-279-triene 9-carboxamide, CAS number 85622-93-1, TEMODAR®, TEMODAL®, Schering Plough), tamoxifen ((Z)-2-[4-(1,2-diphenylbut-1-enyl)phenoxy]-N,N-dimethylethanamine, NOLVADEX®, ISTUBAL®, VALODEX®), and doxorubicin (ADRIAMYCIN®), Akti-1 / 2, HPPD, and rapamycin.

[0134] Examples of chemotherapeutic agents include oxaliplatin (Eloxatin®, Sanofi), bortezomib (VELCADE® Millennium Pharm), Sutent (SUNITINIB®, SU11248, Pfizer), letrozole (FEMARA® Novartis), imatinib mesylate (Gleevec®, Novartis), XL-518 (MeK inhibitor, Exelixis, International Publication No. 2007 / 044515), ARRY-886 (MeK inhibitor, AZD6244, Array BioPharma, AstraZeneca), SF-1126 (anti-CD79b agent, Semaphore Pharmaceuticals), BEZ-235 (anti-CD79b agent, Novartis), XL-147 (anti-CD79b agent, Exelixis), PTK787 / ZK 222584, fulvestrant (FASLODEX®, AstraZeneca), leucovorin (folinic acid), rapamycin (sirolimus, RAPAMNE®, Wyeth), lapatinib (TYKERB®, GSK572016, GlaxoSmithKline), lonafarnib (SARASAR™, SCH 66336 Schering-Plough), sorafenib (NEXAVAR®, BAY43-9006, Bayer Laboratories), gefitinib (IRESSA®, AstraZeneca), irinotecan (CAMPTOSAR®, CPT-11, Pfizer), tipifarnib (ZARNESTRA™, Johnson & Johnson), ABRAXANE™, an albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), vandetanib (rINN, ZD6474, ZACTIMA®, AstraZeneca), chlorambucil, AG1478, AG1571 (SU5271; Chongyuan), temsirolimus (VELCADE®, Millennium Pharm), pazopanib (GlaxoSmithKline), canfosfamide (SUNITINIB®, SU11248, Pfizer), thiotepa and cyclophosphamide (FEMARA®, Novartis); alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, metholedopa, and uredopa;Ethylenimines and methylamelanamines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylmelamine; acetogenins (especially bullatacin and bullatacinone); camptothecins (including the synthetic analogue topotecan); bryostatins; kallistatins; CC-1065 (including the synthetic analogues adozelesin, carzelesin, and bizeresin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (synthetic analogues, KW-2189, and CB1-TM1); eleutherobin pancratistatin; sarcodictin; spongiostatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine hydrochloride, melphalan, nobembitine, phenesterine, prednisolone, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as eneldin antibiotics (e.g., calicheamicin, calicheamicin gamma 1I, calicheamicin omega I1 (Angew Chem. Intl. Ed. Engl. (1994) 33:183-186); dynemicin, dynemicin A; bisphosphonates such as clodronate; esperamicin; neocarzinostatin chromophores and related chromoprotein enediyne antibiotic chromophores; aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo- xo-L-norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin, epirubicin, esorubicin, idarubicin, nemorubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, queramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin;antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calsterone, dromostanol propionate, epithiostanol, mepitiostane, and testoralactone; antiadrenal drugs such as aminoglutethimide, mitotane, and trilostane; florinic acid Folic acid supplements such as aceglatone, aldophosphamide glycosides, aminolevulinic acid, eniluracil, amsacrine, bestravcil, bisantrene, edatraxate, defoamine, demecolcine, diazicon, elfornitine, elliptinium acetate, epothilone, etoglucide, gallium nitrate, hydroxyurea, lentinan, lonidynin, maytansinoids such as maytansine and ansamitocin, mitoguazone, mitoxantrone, mopidanmol, nitraelin, pentostatin, phenamet, pirarubicin, rosoxantrone, podophyllic acid, 2-ethylhydrazide, procarbazine, PSK® polysaccharide complex (JHS Natural Products, Eugene or OR); Razoxane; Rhizoxin; Sizofiran; Spirogermanium; Tenuazonic acid; Triazicon; 2,2',2'-Trichlorotriethylamine; Trichothecenes (especially T-2 toxin, veracrine A, roridin A, and anguidin); Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitrol; Mitolactol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophos Famide; thiotepa; 6-thioguanine; mercaptopurine; methotrexate; platinum analogues such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine (Navelbine®); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (Xeloda®, Roche); ibandronate; CPT-11;Examples of the topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharma- ceutically acceptable salts, acids, and derivatives of any of these. Drugs such as CHP (doxorubicin, prednisone, cyclophosphamide) or CHOP (doxorubicin, prednisone, cyclophopsphamide, vincristine) can be used in combination.

[0135] The definition of "chemotherapeutic agent" also includes (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), e.g., tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxyphene, ketoxifene, LY117018, onapristone, and Fareston® (toremifine citrate); (ii) anti-estrogen agents that inhibit the action of hormones in the adrenal glands; aromatase inhibitors, which inhibit the enzyme aromatase that regulates aromatase production, such as 4(5)-imidazole, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestany, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) flutamide, nilutamide, bicalutamide, leuprolide , goserelin; and troxacitabine (a-1,3-dioxolane nucleoside cytosine analogue); (iv) protein kinase inhibitors such as MEK inhibitors (WO 2007 / 044515); (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes of signal transduction pathways involved in abnormal cell proliferation, e.g., PKC-α, Raf, H-Ras, e.g., oblimersen (GENASENSE®, Genta Corporation); (vii) VEGF expression inhibitors (e.g. , ANGIOZYME®), and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, e.g., ALLOVECTIN®, LEUVECTIN®, VAXID®; Proleukin® rIL-2; topoisomerase 1 inhibitors such as lutotecan®; Abarelix® rmRH; 9 angiogenesis inhibitors such as bevacizumab (AVASTIN®, Genentech); and pharmaceutically acceptable salts, acids, and derivatives of any of these.

[0136] The definition of "chemotherapeutic agent" also includes therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, ImClone); panitumumab (Vectibix®, Amgen), pertuzumab (PERJETA™, OMNITARG™, 2C4, Genentech), trastuzumab (Herceptin®, Genentech), MDX-060 (Medarex), and the antibody-drug conjugate gemtuzumab ozogamicin (Mylotarg®, Wyeth).

[0137] Humanized monoclonal antibodies that may be used as therapeutic chemotherapeutic agents in combination with the conjugates described herein include alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidofusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, and the like. zumab, motivizumab, natalizumab, nimotuzumab, norobizumab, numavizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resivizumab, rovelizumab, lupus Examples of these include tuximab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, trastuzumab, tucotuzumab celmoleukin, tuxituzumab, umavizumab, urtoxazumab, and visilizumab.

[0138] The composition according to the present disclosure is preferably a pharmaceutical composition. The pharmaceutical composition according to the present disclosure and for use according to the present disclosure may contain, in addition to the active ingredient, i.e. the conjugate compound, pharma- ceutically acceptable excipients, carriers, buffers, stabilizers or other materials 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 materials will depend on the route of administration, which may be oral or by injection, e.g., cutaneous, subcutaneous, or intravenous. The route of administration is via the skin, subcutaneous, or intravenous route. The pharmaceutical composition for oral administration may be in the form of a tablet, capsule, powder or liquid. Tablets may contain a solid carrier or adjuvant. Liquid pharmaceutical compositions generally contain a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. They may contain saline, glucose or other sugar solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol. Capsules may contain a solid carrier such as gelatin. For intravenous, cutaneous or subcutaneous injection, or injection into an affected area, the active ingredient is in the form of a parenterally acceptable aqueous solution that is pyrogen-free and has appropriate pH, isotonicity and stability. Those skilled in the art can prepare appropriate solutions using isotonic vehicles such as sodium chloride injection, Ringer's solution, lactated Ringer's solution, etc. Preservatives, stabilizers, buffers, antioxidants and / or other additives can be included as necessary.

[0139] dose Those skilled in the art will appreciate that appropriate doses of conjugated compounds, and compositions containing conjugated compounds, may vary from subject to subject. Determining optimal doses generally requires balancing the level of therapeutic benefit against any risk or adverse side effects. The selected dose level will depend on 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 treatment, other drugs, compounds, and / or materials used in combination, the severity of the condition, the species, sex, age, weight, condition, general health, and previous medical history of the subject. The amount of compound and the route of administration are ultimately at the discretion of the physician, veterinarian, or clinician, but generally, a dose will be selected to achieve a local concentration at the site of action that achieves the desired effect without causing substantial adverse or deleterious side effects.

[0140] In one embodiment, anti-CD19 ADC is determined by the expression of CD19 observed in a sample obtained from a subject. Thus, the level or location of CD19 expression in a sample may indicate that a higher or lower dose of anti-CD19 ADC is required. For example, a high expression level of CD19 indicates that a higher dose of anti-CD19 ADC is appropriate. In some cases, a high expression level of CD19 may indicate that administration of additional agents is required in addition to anti-CD19 ADC. For example, administration of a chemotherapy agent in combination with anti-CD19 ADC. A high expression level of CD19 may indicate that a more aggressive treatment is required.

[0141] In certain embodiments, the dosage of the anti-CD79b agent is determined by the 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-CD79b agent is required. For example, a high level of CD79b expression may indicate that a higher dose of the anti-CD79b agent is appropriate. In some cases, a high level of CD79b expression may indicate that administration of an additional agent in addition to the anti-CD79b agent is required, such as the combined administration of a chemotherapeutic agent and an anti-CD79b agent. A high level of CD79b expression may indicate that a more aggressive treatment is required.

[0142] Administration can be in a single dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the treatment period. Methods for determining the most effective means of administration and dosage are known to those of skill in the art and will vary with the formulation used for treatment, the purpose of the treatment, the cells of the subject being treated, and the subject being treated. Dosage levels and pattern will be selected by the treating physician, veterinarian, or clinician and can be administered in single or multiple doses. In general, a suitable dose of the active compound is in the range of about 100 ng to about 25 mg (more typically about 1 μg to about 10 mg) per kg of subject body weight per day. When the active compound is a salt, ester, amide, prodrug, etc., the dosage is calculated based on the parent compound, so the mass actually used will increase proportionately.

[0143] In one embodiment, each active compound is administered to a human subject at about 100 mg, three times daily, according to the following dosing schedule: In one embodiment, each active compound is administered to a human subject at about 150 mg twice daily according to the following dosing schedule: In one embodiment, each active compound is administered to a human subject at about 200 mg twice daily according to the following dosing schedule: However, in one embodiment, each conjugate compound is administered to a human subject at about 50 or about 75 mg, three or four times daily, according to the following dosing regimen: In one embodiment, each conjugate compound is administered to a human subject at about 100 or about 125 mg twice daily according to the following dosing schedule: In the case of anti-CD19 ADCs in which the ADC has a PBD, the dosages above apply to an effective amount of the conjugate (including the PBD moiety and the linker to the antibody) or PBD compound provided, e.g., the amount of compound releasable following cleavage of the linker.

[0144] The anti-CD19 ADC comprises an anti-CD19 antibody. The anti-CD19 antibody may be an RB4v1.2 antibody. The ADC may comprise a drug that is a PBD dimer. The anti-CD19-ADC may be ADCx19. The anti-CD19 ADC may be loncastuximab tesirine. The ADC may be an ADC disclosed in US Pat. No. 5,999,496. The anti-CD79b agent can be polatuzumab vedotin.

[0145] antibody As used herein, the term "antibody" is used in the broadest sense and includes monoclonal antibodies, polyclonal antibodies, dimers, multimers, multispecific antibodies (e.g., bispecific antibodies), complete antibodies (also referred to as "full-length" antibodies), and antibody fragments, so long as they exhibit the desired biological activity, such as the ability to bind CD19 (Miller et al (2003) J. Jour. of Immunology 170:4854-4861). Antibodies may be murine, human, humanized, chimeric, or derived from other species, such as rabbit, goat, sheep, horse or camel. BRIEF DESCRIPTION OF THE DRAWINGS Embodiments and experiments illustrating the principles of the present disclosure are now described with reference to the accompanying drawings. [Brief description of the drawings]

[0146] [Figure 1] 1 is a plot of median tumor volume showing the in vivo efficacy of the combination of ADCx19 and Pola-V. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0147] The present disclosure includes combinations of the described embodiments and preferred features except where such combinations are expressly not permitted or expressly 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, by way of example only, with reference to the accompanying drawings. Further 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 and the appended claims, unless the context requires otherwise, the term "comprise" and variations such as "comprises" and "comprising" are understood to mean the inclusion of recited elements, integers or steps, but not the exclusion of other unrecited elements, integers or steps. 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.

[0148] Description of the invention 1. A method for treating a disease in an individual, comprising administering to the individual an effective amount of an anti-CD19 ADC (or an anti-CD22 ADC or an anti-CD25 ADC) and an anti-CD79b agent. 2. The method of 1, wherein the individual is selected for treatment. 3. The method of 2, wherein the individual is selected for treatment with an anti-CD19 ADC (or an anti-CD22 ADC or an anti-CD25 ADC) if the individual has been treated with an anti-CD79b agent. 4. The method of 2, wherein the individual is selected for treatment with said anti-CD19 ADC (or anti-CD22 ADC or anti-CD25 ADC) if the individual is undergoing treatment with an anti-CD79b agent. 5. The method according to any one of the preceding claims, wherein the individual is selected for treatment if refractory to treatment with an anti-CD79b agent or to a further treatment.

[0149] 6. A method for treating a disease in an individual, comprising: (i) selecting an individual suitable for the treatment according to any one of 3 to 5 above; and (ii) administering to the individual an effective amount of the anti-CD19 ADC (or an anti-CD22 ADC or an anti-CD25 ADC); A method comprising: 7. The method of 6, further comprising co-administering the anti-CD19 ADC (or anti-CD22 ADC or anti-CD25 ADC) with an anti-CD79b agent. 8. The method of any one of 1-5 or 7, wherein treatment comprises administration of said ADC prior to, simultaneously with, or following administration of an anti-CD79b agent. 9. Any of the above methods, wherein the treatment further comprises administering a chemotherapeutic agent. 10. Any of the above methods, wherein the individual is a human. 11. Any of the above methods, wherein the individual is suffering from or has been determined to be suffering from a disease. 12. The method of claim 11, wherein the individual is suffering from or is determined to be suffering from a cancer expressing CD19 (or CD22 or CD25), CD19+ve (or CD22+ve or CD25+ve) tumor-associated non-tumor cells, or CD19+ve (or CD22+ve or CD25+ve) infiltrating cells.

[0150] 13. Any of the above methods, wherein the individual is undergoing treatment with an anti-CD79b agent. 14. Any of the above methods, wherein the individual has undergone treatment with an anti-CD79b agent. 15. Any of the above methods, wherein the individual is refractory to treatment with an anti-CD79b agent or to a further treatment. 16. Any of the above methods, wherein the treatment is more efficacious than monotherapy with an anti-CD19 ADC (or an anti-CD22 ADC or an anti-CD25 ADC) or an anti-CD79b agent alone. 17. Any of the above methods, wherein the disease is a proliferative disease. 18. The method of claim 17, wherein the disease is characterized by the presence of a neoplasm comprising CD19+ve (or CD22+ve or CD25+ve) tumor-associated non-tumor cells. 19. The method of claim 17, wherein the individual is determined to be suffering from or have been suffering from a disease characterized by the presence of a neoplasm comprising both CD25+ve cells and CD25-ve cells. 20. The method of claim 17, wherein the individual is determined to be suffering from or have been suffering from a disease characterized by the presence of a neoplasm comprising CD25-ve cells. 21. The method according to any one of 18 to 20, wherein the neoplasm is all or part of a solid tumor. 22. The method of claim 21, wherein the solid tumor is associated with CD25+ve infiltrating cells, and optionally, the solid tumor is associated with high levels of CD25+ve infiltrating cells. 23. The method of 21 or 22, wherein the solid tumor is selected from the group consisting of pancreatic cancer, breast cancer, colorectal cancer, gastric and esophageal cancer, leukemia and lymphoma, melanoma, non-small cell lung cancer, ovarian cancer, hepatocellular carcinoma, renal cell carcinoma, and head and neck cancer. 24. Any of the above methods, wherein the disease is cancer. 25. The method according to any of the above, wherein the disease is selected from the group consisting of cancers such as diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma, mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphomas including Waldenstrom's macroglobulinemia (WM) and marginal zone B-cell lymphoma (MZBL), and leukemias such as hairy cell leukemia (HCL), hairy cell leukemia variant (HCL-v), chronic lymphocytic leukemia (CLL) including Richter's syndrome, and acute lymphoblastic leukemia (ALL) such as Philadelphia chromosome positive ALL (Ph+ALL) or Philadelphia chromosome negative ALL (Ph-ALL). 26. Any of the above methods, wherein the anti-CD79b agent is an anti-CD79b ADC. 27. The CD79b ADC has the formula (I): Ab-(DL)p(I) (In the formula, Ab is an antibody that binds to CD79b; Download the following:

[0151] [ka] It is expressed as p is 1 to 8, for example 3 to 4, for example about 3.5. 26 methods, which are complexes represented by: 28. Any of the preceding methods, wherein the anti-CD79b agent or ADC has a VH domain comprising VH CDR1, VH CDR2, and VH CDR3, and comprises the CDR sequence of the VH domain having the sequence set forth in SEQ ID NO:17. 29. The method of 28, wherein the antibody has a VH domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, and the CDR sequence of the VL domain has the sequence set forth in SEQ ID NO:18. 30. The anti-CD79b agent or ADC comprises an antibody having a VH domain and a VL domain, the VH domain has a VH CDR1 having the amino acid sequence of SEQ ID NO: 19, a VH CDR2 having the amino acid sequence of SEQ ID NO: 20, and a VH CDR3 having the amino acid sequence of SEQ ID NO: 21; The VL domain has a VL CDR1 having the amino acid sequence of SEQ ID NO:22, a VL CDR2 having the amino acid sequence of SEQ ID NO:23, and a VL CDR3 having the amino acid sequence of SEQ ID NO:24. 27. The method according to any one of 1 to 27. 31. The method of any one of 1 to 27, wherein the anti-CD79b agent or ADC comprises an antibody having a VH domain having the sequence set forth in SEQ ID NO:17 and a VL domain having the sequence set forth in SEQ ID NO:18. 32. The method of any one of 1 to 27, wherein the anti-CD79b agent is polatuzumab vedotin. 33. The anti-CD19 ADC (or anti-CD22 ADC or anti-CD25 ADC) has the formula (I): Ab-(DL)p(I) (In the formula, DL is represented by the following formula I or II:

[0152] [ka] (In the formula, L is an antibody (Ab) that is an antibody that binds to CD19 (or CD22 or CD25); Where: If there is a double bond between C2' and C3', R 12 is the following; (ia) optionally halo, nitro, cyano, ether, carboxy, ester, C 1~7 Alkyl, C 3~7 Heterocyclyl and bis-oxy-C 1~3 C, which may be substituted by one or more substituents selected from the group including alkylene 5~10 Aryl groups; (ib)C 1~5 Saturated fatty alkyl; (ic)C 3~6 Saturated cycloalkyl; (id)

[0153] [ka] (In the formula, R 21 , R 22 and R 23 are each independently H, C 1~3 Saturated alkyl, C 2~3 Alkenyl, C 2~3 alkynyl and cyclopropyl; R 12 the total number of carbon atoms in the group is 5 or less; (ie)

[0154] [ka] where R 25a and R 25b one of which is H and the other is selected from phenyl, which is optionally substituted with a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and (if)

[0155] [ka] (In the formula, R 24 is H;C 1~3 Saturated alkyl;C 2~3 Alkenyl; C 2~3 alkynyl; cyclopropyl; phenyl, optionally substituted with a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; selected from the group consisting of; If there is a single bond between C2' and C3', R 12 The following:

[0156] [ka] (In the formula, R 26a and R 26b are independent, H, F, C1~4 saturated alkyl, C2-3 alkenyl, wherein the alkyl and alkenyl groups are selected from C 1~4 Alkylamide and C 1~4 alkyl esters; or R 26a and R 26b One of them is H and the other is nitrile and C 1~4 selected from alkyl esters); R 6 and R 9 is independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR', nitro, Me3Sn, and halo; wherein R and R′ are independently optionally substituted C 1~12 Alkyl, C 3~20 Heterocyclyl and C 5~20 aryl groups; R 7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR', nitro, Me3Sn, and halo; R'' is C 3~12 It is an alkylene group, the chain of which may contain one or more heteroatoms, such as O, S, NRN2 (where N2 is H or C 1~4 alkyl), and / or may be interrupted by aromatic rings, such as benzene or pyridine; Y and Y' are selected from O, S, or NH; R 6 ', R 7’ , R 9’ are R 6 , R 7 and R 9 is selected from the same group as [Formula I] R L1’ is a linker for connecting to an antibody (Ab); R 11a is OH, ORA (wherein RA is C 1~4 alkyl), and SOzM, where z is 2 or 3 and M is a monovalent pharma- ceutically acceptable cation; R 20 and R21 both form a double bond between the nitrogen atom and the carbon atom to which they are attached, or R 20 is selected from H and R C, where R C is a capping group; R 21 is selected from OH, ORA, and SOzM; C 2 and C. 3 If there is a double bond between R 2 is the following; (ia) optionally halo, nitro, cyano, ether, carboxy, ester, C 1~7 Alkyl, C 3~7 Heterocyclyl and bis-oxy-C 1~3 C, which may be substituted by one or more substituents selected from the group including alkylene 5~10 Aryl groups; (ib)C 1~5 Saturated fatty alkyl; (ic)C 3~6 Saturated cycloalkyl; (id)

[0157] [ka] (In the formula, R 11 , R 12 and R 13 are each independently, are each independently, H, C 1~3 Saturated alkyl, C 2~3 Alkenyl, C 2~3 alkynyl and cyclopropyl; R 2 the total number of carbon atoms in the group is 5 or less; (ie)

[0158] [ka] where R 15a and R 15bone of which is H and the other is selected from phenyl, which is optionally substituted with a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and (if)

[0159] [ka] (In the formula, R 14 is H;C 1~3 Saturated alkyl;C 2~3 Alkenyl; C 2~3 alkynyl; cyclopropyl; phenyl, optionally substituted with a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; selected from the group consisting of; If there is a single bond between C2 and C3, R 2 The following:

[0160] [ka] (In the formula, R 16a and R 16b are independent, H, F, C 1~4 saturated alkyl, C2-3 alkenyl, wherein the alkyl and alkenyl groups are selected from C 1~4 Alkylamide and C 1~4 alkyl esters; or R 16a and R 16b One of them is H and the other is nitrile and C 1~4 selected from alkyl esters); [Chemical formula II] R 22 is represented by the following formula IIIa, IIIb or IIIc: (a)

[0161] [ka] (Wherein, A is C 5~7 is an aryl group, and (i)Q 1 is a single bond, and Q 2 is a single bond or -Z-(CH2) n -, where Z is selected from a single bond, O, S and NH, and n is 1 to 3; or (ii)Q 1 is -CH=CH- and Q 2 is a single bond; (b)

[0162] [ka] (In the formula, R C1 , R C2 and R C3 is independently H or unsubstituted C1-2 alkyl; (c)

[0163] [ka] (wherein Q is OR L2’ , S.R. L2’ and N.R. N -R L2’ Selected from R N is selected from H, methyl and ethyl X is OR L2’ , S.R. L2’ , CO2-R L2’ , C.O.R. L2’ , NH-C(=O)-R L2’ , NHNH-R L2’ , CONHNH-R L2’

[0164] [ka] NR N R L1’ , wherein R N is H or C 1~4 alkyl; R L2’ is a linker for attachment to an antibody (Ab); R 10 and R 11 both form a double bond between the nitrogen atom and the carbon atom to which they are attached, or R 10 is H and R 11 is selected from OH, ORA, and SOzM; R 30 and R 31 both form a double bond between the nitrogen atom and the carbon atom to which they are attached, or R 30 is H and R 31 is selected from OH, ORA and SOzM Any of the above methods, comprising a complex represented by the formula: 34. 34. Anti-CD19 ADCs (or anti-CD22 ADCs or anti-CD25 ADCs) include the following:

[0165] [ka] (wherein Ab is an antibody that binds to CD19 (or CD22 or CD25), and p is 1 to 8). 34. The method according to claim 33, wherein the chemical structure is represented by: 35. Any of the preceding methods, wherein the anti-CD19 ADC has a VH domain comprising VH CDR1, VH CDR2, and VH CDR3, and comprises the CDR sequence of the VH domain having the sequence set forth in SEQ ID NO:2. 36. The method of 35, wherein the antibody further comprises a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, and the CDR sequence of the VL domain has the sequence set forth in SEQ ID NO:8. 37. Any of the above methods, wherein the anti-CD19 ADC comprises an antibody having a VH domain having the sequence set forth in SEQ ID NO:2. 38. The method of claim 37, wherein the anti-CD19 ADC further comprises an antibody having a VL domain having the sequence set forth in SEQ ID NO:8. 39. Any of the methods described above, wherein the anti-CD19 ADC comprises a heavy chain having the sequence represented by SEQ ID NO:13 and a light chain having the sequence represented by SEQ ID NO:14. 40. The method according to any of the above, wherein the anti-CD19 ADC is ADCx19. 41. The method of any one of 1 to 39, wherein the anti-CD19 ADC is loncastuximab tesirin. 42. An anti-CD19 ADC (or an anti-CD22 ADC or an anti-CD25 ADC) for use in any of the above methods of treatment. 43. A composition comprising an anti-CD19 ADC (or an anti-CD22 ADC or an anti-CD25 ADC) for use in any of the above methods of treatment. 44. A composition comprising an anti-CD19 ADC (or an anti-CD22 ADC or an anti-CD25 ADC) and an anti-CD79b agent. 45. An anti-CD19 ADC (or an anti-CD22 ADC or an anti-CD25 ADC) for use in 42, a composition for use according to 43, or a composition according to 44, wherein the anti-CD19 ADC is as defined in any one of 33 to 39 and / or the anti-CD79b agent is as defined in any one of 27 to 32. 46. ​​An anti-CD79b agent for use in any of the above-mentioned methods of treatment. 47. A composition comprising an anti-CD79b agent for use in any of the above methods of treatment. 48. An anti-CD79b agent for use in 46, or a composition for use in 42, wherein the anti-CD79b agent is polatuzumab vedotin. 49. Use of an anti-CD19 ADC (or an anti-CD22 ADC or an anti-CD25 ADC) in the manufacture of a medicament for treating a disease in an individual, said treating including any of the methods described above. 50. Use of an anti-CD19 ADC according to 49, wherein the anti-CD19 ADC is as defined in any one of 33 to 39. 51. Use of an anti-CD79b agent in the manufacture of a medicament for treating a disease in an individual, said treating including any of the methods described above. 52. The use of an anti-CD79b agent according to 51, wherein said anti-CD79b agent is polatuzumab vedotin. 53. A first medicament comprising an anti-CD19 ADC (or an anti-CD22 ADC or an anti-CD25 ADC); A package insert comprising instructions for administering the first medicament according to any one of the methods recited in any one of 1 to 41. Kit including: 54. The kit according to 53, wherein the anti-CD19 ADC is as defined in any one of 28 to 36. 55. The kit of 53 or 54, further comprising a second medicament comprising an anti-CD79b agent. 56. The kit of statement 55, wherein the anti-CD79b agent is polatuzumab vedotin. EXAMPLES

[0166] In vitro efficacy of ADCx19 in combination with Pola-V method MTT proliferation assays on cell lines exposed (120 h) to increasing concentrations of ADCx19 and Pola-V. Synergy at 120 h was assessed by Chou-Talalay combination index (CI) (synergy CI<0.9, additive CI=0.9-1.1, antagonism / no benefit CI>1.1) on activated B cell-like (ABC) DLBCL cell lines (TMD8), germinal center (GCB) DLBCL (WSU-DLCL2), and Burkitt's lymphoma (Ramos) cell lines.

[0167] result ADCx19 was combined with the anti-CD79b agent polatuzumab vedotin (Pola-V) in GCB and ABC-DLBCL cell lines and Burkitt's lymphoma cell lines. Synergy was achieved in Ramos and TMD8 cell lines combining ADCx19 with Pola-V (median CI 0.74 and 0.764, respectively), and WSU-DLCL2 showed additive efficacy (median CI 0.96). The data are shown in the table below (Fa=fraction affected). Table 1 Cell line: Ramos RRID cell accession identifier: CVCL_0597

[0168] [Table 1] Table 2 Cell line: TMD8 RRID cell accession identifier: CVCL_A442 Reference: Tohda et al., Leuk. Res. 30:1385-1390 (2006)

[0169] [Table 2] Table 3 Cell line: WSU-DLCL2 RRID cell accession identifier: CVCL_1902

[0170] [Table 3] EXAMPLES

[0171] In vivo efficacy of ADCx19 in combination with Pola-V method Female severe combined immunodeficient mice (Fox Chase SCID®, CB17 / Icr-Prkdcscid / IcrIcoCrl, Charles River) were 9 weeks old with body weights (BW) ranging from 17.3 to 24.1 g on day 1 of the study. On the day of transplantation, 1 × 10 7WSU-DLCL2 cells (0.1 mL suspension) were implanted subcutaneously into the right flank of each test animal and tumors were monitored as the tumor volume approached the target area. Ten days after tumor implantation, designated as study day 1, animals were cultured at 88–126 mm 3 Individual tumor volumes and 109-111 mm 3 The mice were then sorted into groups (n=10) with a mean tumor volume of 10. All vehicle and ADC doses were administered iv via tail vein injection once (qd x 1) on day 1. Dose volume was 0.2 mL per 20 grams of body weight (10 mL / kg) and adjusted to individual animal weight. Tumors were measured twice weekly using calipers and were 3 Each animal was euthanized when it reached the endpoint volume of 0.01 mg / kg or at the end of the study, whichever occurred first. The study was terminated on day 62. Tumors were measured in two dimensions with calipers and volumes were calculated using the following formula: Tumor volume (mm 3 )=w2×l / 2, where w=tumor width and l=tumor length (mm). Tumor weight is 1 mg per 1 mm 3 It can be estimated by assuming that it corresponds to

[0172] result In this study, Pola-V is the CD79bxADC used and loncastuximab tesirin is the CD19xADC used. Figure 1 shows a plot of median tumor volume. The table below shows a summary of study responses, where PR = partial response, CR = complete response, TFS = tumor free survivor.

[0173] [Table 4] EXAMPLES

[0174] In vivo efficacy of ADCx19 in combination with Pola-V Further in vivo studies were carried out similar to Example 2, but using the Ramos xenograft model. method Female severe combined immunodeficient mice (Fox Chase SCID®, CB17 / Icr-Prkdcscid / IcrIcoCrl, Charles River) were 8 weeks old with body weight (BW) range of 15.6-22.9 g on day 1 of the study. On the day of implantation, 1×107 Ramos cells (0.1 mL suspension) were implanted subcutaneously into the right flank of each test animal, and tumors were monitored as tumor volume approached the target area. All vehicle and ADC doses were administered iv via tail vein injection once (qd×1) on day 1. Dosing volume was 0.2 mL per 20 grams of body weight (10 mL / kg) and adjusted to the weight of individual animals. Fourteen days after tumor implantation, designated as study day 1, animals were cultured at 108–144 mm 3 Individual tumor volumes and tumor sizes between 130 and 134 mm 3 The mice were then sorted into groups (n=10) with a mean tumor volume of 10. Tumors were measured twice weekly using calipers and were 3 Each animal was euthanized when the endpoint volume of 0.01 mg / kg was reached or at the end of the study, whichever occurred first. The study was terminated on day 62.

[0175] result

[0176] [Table 5] In vivo, the combination of CD19xADC with CD79bxADC resulted in improved antitumor activity and better response rates in WSU-DLCL2 and Ramos xenograft models. The combination was well tolerated in both models. The translation of these preclinical data in the clinic is currently being investigated in a Phase I study evaluating the safety and tolerability of loncastuximab tesirine in combination with polatuzumab vedotin in patients with r / r NHL (NCT04970901). EXAMPLES

[0177] In vitro efficacy of the combination of SG3199 (PBD) and MMAE We tested the combination of the warheads used in CD19xADC (PBD SG3199) and CD79bxADC (monomethyl auristatin E (MMAE)) alone. This was performed essentially as in Example 1 in TMD8 cells. Cells were seeded at a density of 50000 cells / mL. We used SG3199 and MMAE using the following titrations: SG3199 - 7 point 1 vs 4 serial titrations from 230 pM to 0.06 pM; MMAE: 7 point 1 vs 3 serial titrations from 50 nM to 0.08 nM. Cells were incubated for 24 h and then viability was measured by CellTiterGlo assay. For analysis of the results, the data were first blank-corrected (the blank average of three replicates was subtracted from each data value). For GraphPad analysis, each replicate was normalized to untreated cells (average of three replicates). The data was analyzed by GraphPad Prism to generate dose-response curves with log drug concentration versus X(t). The axis indicates cell viability (%) and the Y axis indicates cell viability. For CalcuSyn analysis, the average of three replicates was normalized to untreated cells. The median Chou-Talalay combination index (CI) was 0.85 (<0.9 indicates synergy).

[0178] [Table 6]

[0179] [Table 7] EXAMPLES

[0180] In vitro efficacy of ADCx25 in combination with Pola-V method Synergy at 120 h in the MTT proliferation assay for cell lines exposed (120 h) to increasing concentrations of ADCx25 and Pola-V is assessed by the Chou-Talalay combination index (CI) (synergy CI<0.9, additive CI=0.9-1.1, antagonism / no benefit CI>1.1). EXAMPLES

[0181] In vivo efficacy of ADCx25 in combination with Pola-V method Female severe combined immunodeficient mice (Fox Chase SCID®, CB17 / Icr-Prkdcscid / IcrIcoCrl, Charles River) were 9 weeks old with body weight (BW) range of 17.3-24.1 g on day 1 of the study. This study is further carried out as in Examples 2 and 3. EXAMPLES

[0182] In vitro efficacy of ADCx22 in combination with Pola-V method MTT proliferation assay on cell lines exposed (120 h) to increasing concentrations of ADCx22 and Pola-V. Synergy at 120 h is assessed by Chou-Talalay combination index (CI) (synergy CI<0.9, additive CI=0.9-1.1, antagonism / no benefit CI>1.1) on germinal center (GCB) DLBCL (WSU-DLCL2) and Burkitt's lymphoma (Ramos) cell lines. EXAMPLES

[0183] In vivo efficacy of ADCx22 in combination with Pola-V method Female severe combined immunodeficient mice (Fox Chase SCID®, CB17 / Icr-Prkdcscid / IcrIcoCrl, Charles River) are implanted subcutaneously with either WSU-DLCL2 or Ramos cells into the right flank of each test animal and tumors are monitored as their volume approaches the target area. This study is further carried out as in Examples 2 and 3. ******* A number of publications are cited above in order to more fully describe and disclose the disclosure and state of the art to which the inventions herein may pertain. Each of the references mentioned in this disclosure is incorporated herein by reference in its entirety. Description of sequence listing

[0184] [Table 8]

[0185] [Table 9]

[0186] [Table 10]

[0187] [Table 11]

[0188] [Table 12]

Claims

1. An antibody-drug conjugate (ADC) comprising an anti-CD19 antibody and a pyrrolobenzodiazepine dimer (PBD) for use in a method for treating a disease in an individual, wherein the treatment comprises administering to the individual an effective amount of the ADC and polatuzumab vedotin, a pharmaceutical composition comprising the antibody-drug conjugate.

2. The antibody-drug conjugate according to claim 1, wherein the individual is a human.

3. The pharmaceutical composition according to claim 1, wherein the individual is undergoing treatment with polatuzumab vedotin.

4. The pharmaceutical composition according to claim 1, wherein the individual has received treatment with polatuzumab vedotin.

5. The pharmaceutical composition according to claim 1, wherein the individual is refractory to treatment with polatuzumab vedotin or further treatment.

6. The pharmaceutical composition according to claim 1, wherein the treatment has a higher efficacy compared to monotherapy using the ADC or polatuzumab vedotin alone.

7. The pharmaceutical composition according to claim 1, wherein the disease is a proliferative disease.

8. The pharmaceutical composition according to claim 7, wherein the disease is characterized by the presence of a neoplasm comprising CD19+ve cells.

9. The pharmaceutical composition according to claim 1, wherein the disease is cancer.

10. The pharmaceutical composition according to claim 1, wherein the individual has or is determined to have cancer expressing CD19 or CD19+ve tumor-associated non-tumor cells, or D19+ve infiltrating cells.

11. The pharmaceutical composition according to claim 1, wherein the disease is selected from the group consisting of non-Hodgkin lymphoma including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma, mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia (WM), and marginal zone B-cell lymphoma (MZBL), and leukemia including hairy cell leukemia (HCL), hairy cell leukemia variant (HCL-v), chronic lymphocytic leukemia (CLL) including Richter's syndrome, and Philadelphia chromosome-positive ALL (Ph+ALL), Philadelphia chromosome-negative ALL (Ph-ALL), acute lymphoblastic leukemia (ALL).

12. The pharmaceutical composition according to claim 1, wherein the antibody comprises the CDRs of SEQ ID NOs: 2 and 8.

13. The pharmaceutical composition according to claim 1, wherein the pyrrolobenzodiazepine dimer (PBD) is represented by the following formula (III): 【Chemical 1】 (wherein R ＬＬ is a linker for linking to an antibody) as represented, the pharmaceutical composition according to claim 1.

14. The following structure: [Chemical Formula 2] (wherein Ab is an anti-CD19 antibody) The pharmaceutical composition according to claim 1, represented by

15. Further comprising polatuzumab vedotin, wherein PBD is the PBD described in claim 13, and optionally, the anti-CD19 antibody comprises the CDRs of SEQ ID NOs: 2 and 8. The pharmaceutical composition according to claim 1.

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