Combination therapy including an anti-CD19 antibody-drug conjugate and a PI3K inhibitor or second-line agent

Abstract

The present disclosure relates to combination therapies for the treatment of conditions such as cancer. In particular, the disclosure relates to combination therapies including treatment with an anti-CD19 antibody drug conjugate (anti-CD19 ADC) and a phosphoinositide 3-kinase (PI3K) inhibitor or second agent.

Description

[Technical Field]

[0001] Related Applications This application claims priority to two applications: (1) UK application GB1908233.8 filed on June 10, 2019, and (2) UK application GB1908234.6 filed on June 10, 2019.

[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 including treatment with an anti-CD19 antibody drug conjugate (anti-CD19 ADC) and a phosphoinositide 3-kinase (PI3K) inhibitor or second agent. [Background technology]

[0003] [Antibody therapy] Antibody therapy has been established as a targeted treatment for subjects with cancer, immunological, and angiogenic diseases (Non-Patent Document 1). Antibody-drug conjugates (ADCs), or immunoconjugates, are used to locally deliver cytotoxic or cytostatic agents, i.e., agents that kill or inhibit tumor cells in the treatment of cancer, targeting drug delivery to tumors and their intracellular accumulation there; however, systemic administration of the unconjugated drug can result in unacceptable levels of toxicity in normal cells (Non-Patent Documents 2-10).

[0004] [CD19] CD19 is a 95-kDa membrane receptor that is expressed early in B cell differentiation and remains expressed until the B cell is triggered to terminally differentiate (Non-Patent Documents 11 and 12). The CD19 extracellular domain contains two C2-type immunoglobulin (jG)-like domains separated by a smaller, potentially disulfide-bonded domain. The CD19 cytoplasmic domain is structurally unique but highly conserved among humans, mice, and guinea pigs (Non-Patent Document 13). CD19 is part of a protein complex found on the cell surface of B lymphocytes. This protein complex includes CD19, CD21 (complement receptor, type 2), CD81 (TAPA-1), and CD225 (Leu-13) (Non-Patent Document 13).

[0005] CD19 is a key regulator of transmembrane signaling in B cells. Increases or decreases in cell surface density of CD19 affect B cell development and function, leading to diseases such as autoimmunity and hypogammaglobulinemia. The CD19 complex enhances B cell responses to antigens in vivo by cross-linking two distinct signaling complexes present on the B cell membrane. The two signaling complexes bound to membrane IgM and CD19 activate phospholipase C (PLC) through distinct mechanisms. Cross-linking of CD19 with the B cell receptor reduces the number of IgM molecules required for PLC activation. CD19 also functions as an adaptor protein specialized for the amplification of Arc family kinases (Non-Patent Document 14).

[0006] CD19 binding has been shown to stimulate or inhibit B cell activation and proliferation, depending on the amount of cross-linking that occurs (Non-Patent Document 12). CD19 is expressed in more than 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 (anti-CD19-ADCs) comprising anti-CD19 antibodies, for example in the treatment of cancer, has been established (see, for example, Patent Documents 2 and 3). Research continues to further improve the efficacy, tolerability, and clinical usefulness of anti-CD19-ADCs. To this end, the present inventors have identified clinically advantageous combination therapies in which anti-CD19 ADCs are administered in combination with at least one PI3K inhibitor or secondary agent. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2014 / 05719 [Patent Document 2] International Publication No. 2014 / 057117 [Patent Document 3] International Publication No. 2016 / 166298 [Non-patent literature]

[0009] [Non-Patent Document 1] Carter, P. (2006) Nature Reviews Immunology 6:343-357 [Non-patent document 2] Xie et al(2006)Expert.Opin.Biol.Ther.6(3):281-291; [Non-patent document 3] Kovtun et al(2006)Cancer Res.66(6):3214-3121; [Non-patent document 4] Law et al(2006)Cancer Res.66(4):2328-2337; [Non-Patent Document 5] Wu et al(2005)Nature Biotech.23(9):1137-1145; [Non-patent document 6] Lambert J. (2005)Current Opin.in Pharmacol.5:543-549; [Non-Patent Document 7] Hamann P. (2005)Expert Opin.Ther.Patents15(9):1087-1103; [Non-patent document 8] Payne, G. (2003) Cancer Cell3:207-212; [Non-Patent Document 9] Trail et al(2003)Cancer Immunol.Immunother.52:328-337; [Non-Patent Document 10] Syrigos and Epenetos(1999)Anticancer Research19:605-614 [Non-Patent Document 11] Pezzutto et al (1987), J. Immunol 138:2793 [Non-Patent Document 12] Tedder et al (1994) lmmunol Today 15:437 [Non-Patent Document 13] Fujimoto et al (1998) Semin Immunol.10:267 [Non-Patent Document 14] Hasegawa et al (2001) J Immunol 167:3190 Summary of the Invention [Problem to be solved by the invention]

[0010] The present inventors have discovered that administering an anti-CD19 ADC in combination with a PI3K inhibitor or secondary agent to an individual provides unexpected clinical benefits. The present inventors have further discovered that administering an anti-CD19 ADC and a PI3K inhibitor or secondary agent to an individual who has been or is undergoing treatment with an anti-CD19 ADC synergistically enhances the therapeutic effect. [Means for solving the problem]

[0011] Thus, in a first aspect, the present disclosure provides a method for selecting an individual suitable for treatment with an anti-CD19 ADC, wherein the individual is selected for treatment with an anti-CD19 ADC if the individual has been or is undergoing treatment with a PI3K inhibitor or a second agent. The individual is selected for treatment with an anti-CD19 ADC if the individual has been or is undergoing treatment with a PI3K inhibitor or a second agent. refractory If so, they may be selected for treatment.

[0012] In another aspect, the disclosure provides a method of treating a condition in an individual, the method comprising selecting an individual suitable for treatment by the method of the first aspect, and then administering to the individual an effective amount of an anti-CD19 ADC, the method of treatment further comprising administering the anti-CD19 ADC in combination with a PI3K inhibitor or a second agent.

[0013] In another aspect, the disclosure provides a method of treating a condition in an individual, the method comprising administering to the individual an effective amount of an anti-CD19 ADC and a PI3K inhibitor or second agent, the individual may be selected for treatment by a method according to the first aspect.

[0014] The condition may be a proliferative disease, for example, non-Hodgkin's lymphoma, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic lymphoma (CLL), and marginal zone B-cell lymphoma (MZBL), and leukemia, such as hairy cell leukemia (HCL), hairy cell leukemia variant (HCL-v), and acute lymphoblastic leukemia (ALL), such as Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL).

[0015] The anti-CD19 ADC may be ADCX19 as described herein.

[0016] PI3K inhibitors include idelalisib, copanlisib, duvelisib, taselisib, bupalisib, alpelisib, umbralisib, dactolisib, and voxatalisib. Preferably, the PI3K inhibitor is idelalisib or copanlisib.

[0017] Second-line drugs include: (a) Bendamustine; (b) lenalidomide; (c) a proteasome inhibitor such as bortezomib, carfilzomib, ixazomib, oprozomib, or salinosporamide A; or (d) PARP inhibitors such as olaparib, CEP-9722, BMN-673 / talazoparib, rucaparib, iniparib / SAR24-550 / BSI-201, veliparib (ABT-888), niraparib / MK-4827, BGB-290, 3-aminobenzamide, and E7016; 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 (such as CD19+ infiltrating B cells).

[0018] In the disclosed methods, the anti-CD19 ADC may be administered prior to, concurrently with, or after administration of the PI3K inhibitor or secondary agent. The disclosed methods may further include administering a chemotherapeutic agent to the individual.

[0019] In another aspect, the disclosure provides anti-CD19 ADCs, or compositions comprising anti-CD19 ADCs, for use in the therapeutic methods described herein.

[0020] In one aspect, the disclosure provides a PI3K inhibitor or a secondary agent, or a composition comprising a PI3K inhibitor or a secondary 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 a PI3K inhibitor or a second agent in the manufacture of a medicament for treating a symptomatic disorder in an individual, wherein the treatment comprises a method of treatment described herein.

[0021] --------------------- In another aspect, the disclosure provides a first composition comprising an anti-CD19 ADC for use in a method of treating a condition in an individual, wherein the treatment comprises administering the first composition in combination with a second composition comprising a PI3K inhibitor or a second agent.

[0022] This embodiment also provides a first composition comprising a PI3K inhibitor or a second agent for use in a method of treating a disease in an individual, wherein the treatment comprises administering the first composition in combination with a second composition comprising an anti-CD19 ADC.

[0023] The condition may be a proliferative disease, for example, non-Hodgkin's lymphoma, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic lymphoma (CLL), and marginal zone B-cell lymphoma (MZBL), and leukemia, such as hairy cell leukemia (HCL), hairy cell leukemia variant (HCL-v), and acute lymphoblastic leukemia (ALL), such as Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL).

[0024] The anti-CD19 ADC may be ADCX19 as described herein.

[0025] PI3K inhibitors include idelalisib, copanlisib, duvelisib, taselisib, bupalisib, alpelisib, umbralisib, dactolisib, and voxatalisib. Preferably, the PI3K inhibitor is idelalisib or copanlisib.

[0026] Second-line drugs include: (a) Bendamustine; (b) lenalidomide; (c) a proteasome inhibitor such as bortezomib, carfilzomib, ixazomib, oprozomib, or salinosporamide A; or (d) PARP inhibitors such as olaparib, CEP-9722, BMN-673 / talazoparib, rucaparib, iniparib / SAR24-550 / BSI-201, veliparib (ABT-888), niraparib / MK-4827, BGB-290, 3-aminobenzamide, and E7016; 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 (such as CD19+ infiltrating B cells).

[0027] The first composition may be administered before, simultaneously with, or after the administration of the second composition.

[0028] The treatment may include administering a further chemotherapeutic agent to the individual.

[0029] --------------------- In a further aspect, the disclosure provides 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 administering the medicament in combination with a composition comprising a PI3K inhibitor or a second agent.

[0030] This embodiment also provides for the use of a PI3K inhibitor or a second agent in the manufacture of a medicament for treating a disease in an individual, wherein the medicament comprises a PI3K inhibitor or a second agent, and the treatment comprises administering the medicament in combination with a composition comprising an anti-CD19 ADC.

[0031] The condition may be a proliferative disease, for example, non-Hodgkin's lymphoma, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic lymphoma (CLL), and marginal zone B-cell lymphoma (MZBL), and leukemia, such as hairy cell leukemia (HCL), hairy cell leukemia variant (HCL-v), and acute lymphoblastic leukemia (ALL), such as Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL).

[0032] The anti-CD19 ADC may be ADCX19 as described herein.

[0033] PI3K inhibitors include idelalisib, copanlisib, duvelisib, taselisib, bupalisib, alpelisib, umbralisib, dactolisib, and voxatalisib. Preferably, the PI3K inhibitor is idelalisib or copanlisib.

[0034] Second-line drugs include: (a) Bendamustine; (b) lenalidomide; (c) a proteasome inhibitor such as bortezomib, carfilzomib, ixazomib, oprozomib, or salinosporamide A; or (d) PARP inhibitors such as olaparib, CEP-9722, BMN-673 / talazoparib, rucaparib, iniparib / SAR24-550 / BSI-201, veliparib (ABT-888), niraparib / MK-4827, BGB-290, 3-aminobenzamide, and E7016; 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 (such as CD19+ infiltrating B cells). The medicament may be administered before, simultaneously with, or after administration of the composition. The treatment may include administering a further chemotherapeutic agent to the individual.

[0035] --------------------- In another aspect of the present disclosure, First agents include anti-CD19 ADCs; a package insert containing instructions for administering said first agent in accordance with a method of treatment as disclosed herein; The kit may further comprise a second agent comprising a PI3K inhibitor or a secondary agent.

[0036] In another aspect of the present disclosure, First agents include anti-CD19 ADCs; a second agent comprising a PI3K inhibitor or a second agent; and optionally, a package insert containing instructions for administering said first agent in combination with a second agent to an individual for the treatment of a condition; A kit is provided, comprising:

[0037] This aspect further provides a kit comprising a pharmaceutical agent comprising a PI3K inhibitor or a second agent and a package insert comprising instructions for administering the pharmaceutical agent in combination with a composition comprising an anti-CD19 ADC to an individual for the treatment of a condition.

[0038] This aspect further provides a kit comprising a pharmaceutical agent comprising a PI3K inhibitor or a second agent and a package insert comprising instructions for administering the pharmaceutical agent in combination with a composition comprising an anti-CD19 ADC to an individual for the treatment of a condition.

[0039] The condition may be a proliferative disease, for example, non-Hodgkin's lymphoma, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic lymphoma (CLL), and marginal zone B-cell lymphoma (MZBL), and leukemia, such as hairy cell leukemia (HCL), hairy cell leukemia variant (HCL-v), and acute lymphoblastic leukemia (ALL), such as Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL).

[0040] The anti-CD19 ADC may be ADCX19 as described herein.

[0041] PI3K inhibitors include idelalisib, copanlisib, duvelisib, taselisib, bupalisib, alpelisib, umbralisib, dactolisib, and voxatalisib. Preferably, the PI3K inhibitor is idelalisib or copanlisib.

[0042] Second-line drugs include: (a) Bendamustine; (b) lenalidomide; (c) a proteasome inhibitor such as bortezomib, carfilzomib, ixazomib, oprozomib, or salinosporamide A; or (d) PARP inhibitors such as olaparib, CEP-9722, BMN-673 / talazoparib, rucaparib, iniparib / SAR24-550 / BSI-201, veliparib (ABT-888), niraparib / MK-4827, BGB-290, 3-aminobenzamide, and E7016; 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 (such as CD19+ infiltrating B cells).

[0043] The medicament or composition comprising the anti-CD19-ADC may be administered prior to, concurrently with, or after the administration of the medicament or composition comprising the PI3K inhibitor or secondary agent. The treatment may include administering to the individual an additional chemotherapeutic agent.

[0044] --------------------- In yet a further aspect, the disclosure provides a composition comprising an anti-CD19 ADC and a PI3K inhibitor or secondary agent.

[0045] This aspect of the disclosure further provides a method of treating a condition in an individual, the method comprising administering to the individual an effective amount of a composition comprising an anti-CD19 ADC and a PI3K inhibitor or second agent.

[0046] This aspect of the disclosure further provides a composition comprising an anti-CD19 ADC and a PI3K inhibitor or secondary agent for use in a method of treating a condition in an individual.

[0047] This aspect of the disclosure further provides the use of a composition comprising an anti-CD19 ADC and a PI3K inhibitor or second agent in the manufacture of a medicament for treating a condition in an individual.

[0048] This aspect of the disclosure further provides a kit comprising a composition comprising an anti-CD19 ADC and a PI3K inhibitor or secondary agent and a set of instructions for administering the agent to an individual for treatment of a condition.

[0049] The condition may be a proliferative disease, for example, non-Hodgkin's lymphoma, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic lymphoma (CLL), and marginal zone B-cell lymphoma (MZBL), and leukemia, such as hairy cell leukemia (HCL), hairy cell leukemia variant (HCL-v), and acute lymphoblastic leukemia (ALL), such as Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL).

[0050] The anti-CD19 ADC may be ADCX19 as described herein.

[0051] PI3K inhibitors include idelalisib, copanlisib, duvelisib, taselisib, bupalisib, alpelisib, umbralisib, dactolisib, and voxatalisib. Preferably, the PI3K inhibitor is idelalisib or copanlisib.

[0052] Second-line drugs include: (a) Bendamustine; (b) lenalidomide; (c) a proteasome inhibitor such as bortezomib, carfilzomib, ixazomib, oprozomib, or salinosporamide A; or (d) PARP inhibitors such as olaparib, CEP-9722, BMN-673 / talazoparib, rucaparib, iniparib / SAR24-550 / BSI-201, veliparib (ABT-888), niraparib / MK-4827, BGB-290, 3-aminobenzamide, and E7016; 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 (such as CD19+ infiltrating B cells). The treatment may include administering a further chemotherapeutic agent to the individual.

[0053] --------------------- [Brief explanation of the drawings]

[0054] [Figure 1] FIG. 10: Dose escalation. [Figure 2] This is the array number. DETAILED DESCRIPTION OF THE INVENTION

[0055] [Antibody-drug conjugates (ADC)] The present disclosure relates to improved efficacy of combinations of ADCs and PI3K inhibitors or second agents. ADCs can deliver drugs to target sites, which are preferably proliferating cell populations. In one embodiment, the antibody is directed against an antigen present on a proliferating cell population, and the antigen is absent from a non-proliferating cell population, or is present at a reduced level compared to the amount of antigen present in the proliferating cell population, e.g., a tumor cell population.

[0056] The ADC may include a linker that may be cleaved to release the drug at the target site. The drug may be a compound selected from RelA, RelB, RelC, RelD, or RelE. Thus, the conjugate may be used to selectively deliver the compound RelA, RelB, RelC, RelD, or RelE to a target site. The linker may be cleaved by an enzyme present at the target site. The present disclosure specifically relates to treatment with the anti-CD19 ADCs disclosed in US Pat. No. 6,223,999 and herein.

[0057] [ 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 ADC antibody and the drug component is a PBD warhead.

[0058] The ADC has the formula L-(D L ) p wherein D L is of formula I or II below:

[0059] [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 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 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)

[0060] [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 2~3alkynyl and cyclopropyl; R 12 the total number of carbon atoms in the group is 5 or less); (i.e.)

[0061] [ka] (In the formula, R 25a and R 25b one of which is H and the other is optionally substituted with a group selected from halo, methyl, methoxy 、 phenyl; Pyridyl ; and thiophenyl selected from); (if)

[0062] [ka] (In the formula, R 24 is H;C 1~3 Saturated alkyl; C 2~3 Alkenyl; C 2~3 alkynyl; cyclopropyl; optionally substituted with a group selected from halo, methyl, and methoxy. 、 phenyl; Pyridyl and thiophenyl; selected from the group consisting of: If there is a single bond between C2' and C3', R 12 is the following:

[0063] [ka] (In the formula, R 26a and R 26b are independently H, F, C 1~4 Saturated alkyl, C 2~3 alkenyl, wherein the alkyl and alkenyl groups are optionally selected from C 1~4 Alkylamide and C 1~4 alkyl esters; or R 26a and R26b When one of the groups is H, the other is a nitrile and C 1~4 alkyl esters); R 6 and R 9 is independently selected from H, R, OH, OR, SH, SR, NH, NHR, NRR′, nitro, MeSn, 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, NH, NHR, NRR′, nitro, MeSn, 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, NR N2 (where R N2 is H or C 1~4 alkyl), and / or may be interrupted by an aromatic ring, 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 and selected from the same groups as above; [Formula I] R L1’ is a linker that binds to the antibody (Ab); R 11a OH, OR A And R A is C 1~4 alkyl, and SOzM, where z is 2 or 3 and M is a monovalent pharmaceutically 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 H and R Cis selected from, where R C is a capping group; R 21 OH, OR A and SOzM; If there is a double bond between C2 and C3, 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 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)

[0064] [ka] (In the formula, R 11 , R 12 and R 13 are each independently H, C 1~3 Saturated alkyl, C 2~3 Alkenyl, C 2~3 alkynyl and cyclopropyl, wherein R 2 the total number of carbon atoms in the group is 5 or less); (i.e.)

[0065] [ka] (In the formula, R 15a and R 15b one of which is H and the other is optionally substituted with a group selected from halo, methyl, methoxy 、 phenyl; Pyridyl and thiophenyl; (if)

[0066] [ka] (In the formula, R 14 is H;C 1~3 Saturated alkyl; C 2~3 Alkenyl; C 2~3 alkynyl; cyclopropyl; optionally substituted with a group selected from halo, methyl, and methoxy. 、 phenyl; Pyridyl and thiophenyl)); selected from the group consisting of: If there is a single bond between C2 and C3, R 2 teeth,

[0067] [ka] (In the formula, R 16a and R 16b are independently H, F, C 1~4 Saturated alkyl, C 2~3 alkenyl, wherein the alkyl and alkenyl groups are optionally selected from C 1~4 Alkylamide and C 1~4 alkyl esters; or R 16a and R 16b When one of the groups is H, the other is a nitrile and C 1~4 alkyl esters); [Formula II] R 22 is of formula IIIa, IIIb or IIIc: (a)

[0068] [ka] (Wherein A is C 5~7 An aryl group, such as: (i)Q 1 is a single bond and Q 2 is a single bond and -Z-(CH2) n-, wherein 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 Q2 is a single bond; (b)

[0069] [ka] (In the formula, R C1 , R C2 and R C3 are independently H and unsubstituted C 1~2 selected from alkyl); (c)

[0070] [ka] (wherein Q is OR L2’ , S.R. L2’ and NR N -R L2’ Selected from R N is selected from H, methyl and ethyl; X is OR L2’ , S.R. L2’ , CO2-R L2’ , CO-R L2’ , NH-C(=O)-R L2’ , NHNH-R L2’ ,CONHNH-R L2’ ,

[0071] [ka] , N.R. N R L2’ wherein R N is H and C 1~4 selected from the group including alkyl; R L2’ is a linker that binds to an antibody (Ab); R 10 and R 11both 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 OH, OR A 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 OH, OR A and SOzM).

[0072] In one embodiment, LR L1’ or LR L2’ is the following group:

[0073] [ka] where the asterisk indicates the point of attachment to the PBD, Ab is the antibody, and L 1 is a cleavable linker and A is L 1 is a linking group that links the 2 is a covalent bond or, together with -OC(=O)-, forms a self-impermeable linker). In some such embodiments, L 1 can be cleaved enzymatically.

[0074] Such ADCs have previously been shown to be useful in treating CD19-expressing cancers (see, for example, Patent Document 2, which is incorporated herein by reference in its entirety).

[0075] The term "anti-CD19-ADC" includes any of the embodiments described in WO 2007 / 024990. In particular, in preferred embodiments, the ADC comprises one of the following:

[0076] [ka] (wherein the Ab is a CD19 antibody and the DAR is 1 to 8) It may have a chemical structure.

[0077] The antibody may comprise a VH domain having the sequence of any one of SEQ ID NOs: 1, 2, 3, 4, 5, or 6, and may optionally further comprise a VL domain having the sequence of any one of SEQ ID NOs: 7, 8, 9, 10, 11, or 12.

[0078] In certain embodiments, the antibody component of the anti-CD19 ADC is an antibody comprising VH and VL domains having the sequences of SEQ ID NO:1 and SEQ ID NO:7, SEQ ID NO:2 and SEQ ID NO:8, SEQ ID NO:3 and SEQ ID NO:9, SEQ ID NO:4 and SEQ ID NO:10, SEQ ID NO:5 and SEQ ID NO:11, or SEQ ID NO:6 and SEQ ID NO:12, respectively.

[0079] In a preferred embodiment, the antibody comprises a VH domain whose amino acid sequence is according to SEQ ID NO: 2. In a preferred embodiment, the antibody comprises a VL domain whose amino acid sequence is according to SEQ ID NO: 8. In a preferred embodiment, the antibody comprises a VH domain having the sequence of SEQ ID NO:2 and a VL domain having the sequence of SEQ ID NO:8. The VH and VL domains may pair to form the antibody antigen-binding site that links to CD19. In one embodiment, the antibody is an intact antibody comprising a VH domain and a VL domain, wherein the VH domain and VL domain have the sequences of SEQ ID NO:2 and SEQ ID NO:8.

[0080] In one embodiment, the antibody comprises a long chain having the sequence of SEQ ID NO:13 and a light chain having the sequence of 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. 6,239,999. 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 disclosed herein that has been humanized, deimmunized, or resurfaced.

[0081] A preferred anti-CD19 ADC for use in conjunction with this embodiment of the disclosure is ADCx19, described below. A second preferred anti-CD19 ADC for use in conjunction with this embodiment of the disclosure is ADCT-402 (loncastuximab tesirine).

[0082] 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, releasing free PBD dimers into the target cell. The released PBD dimers inhibit transcription in a sequence-selective manner, either by directly inhibiting RNA polymerase or by blocking the interaction of relevant transcription factors. PBD dimers do not distort the DNA double helix and produce covalent crosslinks that are not recognized by nucleotide excision repair factors, potentially resulting in longer-lasting effects (Hartley 2011). This involves:

[0083] [ka] It has a chemical structure.

[0084] Ab represents antibody RB4v1.2 (fully human monoclonal IgG1, K antibody with VH and VL sequences of SEQ ID NOs: 2 and 8, respectively). It was synthesized as described in patent application WO 2007 / 024990 (RB4v1.2-E) and typically has a DAR (drug-to-antibody ratio) of 2.0+ / -0.3.

[0085] CD19 binding As used herein, "binds to CD19" means that the antibody binds to CD19 with higher affinity than a nonspecific partner such as bovine serum albumin (BSA, Genbank Accession No. CAA76847, version number CAA76847.1GI:3336842, record updated January 7, 2011, 2:30 PM). In certain embodiments, the antibody has a binding constant that is at least 2, 3, 4, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, 1 ... 4 , 10 5 or 10 6 The antibodies of the present disclosure may bind to CD19 with high affinity. For example, in some embodiments, the antibodies bind to CD19 with an association constant (Ka) greater than 1×10 -6 , 10 -7 , 10 -8 , 10 -9 , 10 -10 , 10 -11 , 10 -12 , 10 -13 or 10 -14 Less than 1 of, about 10 -6 K equal to or less than M D It can bind to CD19.

[0086] In one embodiment, the CD19 polypeptide corresponds to Genbank Accession No. NP_001171569 Edition No. NP_001171569.1 GI:296010921; Record Last Updated September 10, 2012 at 12:43 AM. In one embodiment, the nucleic acid encoding the CD19 polypeptide corresponds to Genbank Accession No. NM_001178098, Edition No. NM_001178098.1 Gi:296010920; Recorded on September 10, 2012 at 12:43 AM. In an embodiment, the CD19 polypeptide corresponds to Uniprot / Swiss-Prot Accession No. P15391.

[0087] [PI3K inhibitors] The vertebrate class I PI 3-kinase enzyme family includes four distinct proteins of approximately 110 kDa (p110α, p110β, p110δ, and p110γ). All class I enzymes share most of their structural features and common substrate specificity (Rameh and Cantley, 1999; Fry, 2001; Katso et al., 2001). In vitro, all class I PI 3-kinases can phosphorylate PtdIns to PtdIns(3)P, PtdIns(4)P to PtdIns(3,4)P2, and PtdIns(4,5)P2 to PtdIns(3,4,5)P3. In vivo, PtdIns(4,5)P2 can be considered the preferred lipid substrate. Class I PI 3-kinases are primarily present in the cytoplasm at rest but are recruited to the membrane upon stimulation through interactions with receptors and adaptor proteins. They are thought to function primarily at the plasma membrane, although some class I PI 3-kinases have been reported to function at vesicle membranes and nuclear membranes (Rameh and Cantley, 1999; Fry, 2001; Katso et al., 2001). The cellular roles of class I PI 3-kinases are diverse, with evidence linking them to cell size, motility, survival, and proliferation in many different cell types and in response to numerous signaling pathways (Fry, 2001, Katso et al., 2001). The class I family can be further divided into two groups based on their regulatory partners and activation mechanisms.

[0088] Although PI3K was initially characterized 20 years ago as a RTK that binds to and activates oncogenes (reviewed in Zhao JJ et al., 2006), its relevance to human cancer was not established until the late 1990s, when the tumor suppressor PTEN was shown to act as a PI3-lipid phosphatase. Recent comprehensive cancer genome analyses have revealed that multiple components of the PI3K pathway are frequently mutated or altered in common human cancers, highlighting the importance of this pathway in cancer (see Wood LD, et al., Science, 2007; Samuels Y, et al., Science, 2004).

[0089] "Phosphoinositide 3-kinase inhibitor" (PI3K inhibitor) is used herein to mean any agent that specifically binds to and / or inhibits the biological activity of PI3K.

[0090] As used herein, "binds to PI3K" means that the agent binds to PI3K with higher affinity than a nonspecific partner such as bovine serum albumin (BSA, Genbank Accession No. CAA76847 version number CAA76847.1GI:3336842 record updated January 7, 2011 at 2:30 PM). In certain embodiments, the agent binds to PI3K with a ...00 PM). In certain embodiments, the agent binds to PI3K with a higher affinity than a nonspecific partner such as bovine serum albumin (BSA), as measured under physiological conditions. In certain embodiments, the agent binds to PI3K with a higher affinity than a nonspecific partner such as bovine serum albumin (BSA), as measured under physiological conditions. In certain embodiments, the agent binds to PI3K with a higher affinity than a nonspecific partner such as bovine serum albumin (BSA), as measured under physiological conditions. In certain embodiments, the agent binds to PI3K with a higher affinity than a nonspecific partner such as bovine serum albumin (BSA), as measured under physiological conditions. In certain embodiments, 4 , 10 5 or 10 6 The agent may bind to PI3K with high affinity. For example, in some embodiments, the agent may bind to PI3K 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 Less than 1 of, about 10 -6K equal to or less than M D It can bind to PI3K.

[0091] Suitable PI3K inhibitors for use in the present disclosure are as follows: a) Copanlisib

[0092] [ka] b) Idelalisib

[0093] [ka] c) Duvelisib

[0094] [ka] d) Taselisib

[0095] [ka] e) Buparlisib

[0096] [ka] f) Alpelisib

[0097] [ka] g) Umbralisib

[0098] [ka] h) Ductolisiv

[0099] [ka] i) Vuxtalisive

[0100] [ka] Preferably, the PI3K inhibitor is idelalisib or copanlisib. Most preferably, the PI3K inhibitor is idelalisib.

[0101] --------------------- [Secondary medication] The recent development of drugs that enhance antitumor immunity has rapidly transformed the treatment of a wide range of cancers. However, these treatments are not effective in all cancers, responses are often not durable, and many patients receive little or no benefit from treatment. In the oncology field, it is generally believed that only immunotherapy in combination with other treatment options can ultimately cure cancer patients.

[0102] ADCs are well tolerated and active across a variety of cancer types, and are likely to be a component of combination treatments that increase response rates and durability of treatment. The objective of this disclosure is to combine ADCs with second-line agents.

[0103] The secondary agents described herein may be immuno-oncology (IO) agents. Immuno-oncology (IO) agents are a type of cancer treatment that utilizes the body's immune system to fight cancer, which has been shown to improve the durability of anti-tumor responses. IO agents include, but are not limited to, PD1 inhibitors, PD-L1 inhibitors, CLTL4 inhibitors, GITR agonists, and OX40 agonists. Because a significant number of patients are not cured by single-agent immunotherapy and ultimately relapse, alternative IO agents or combination treatments with different therapeutic modalities are needed (see KS Peggs et al., 2009, Clinical and Experimental Immunology, 157:9-19 [doi:10.1111 / j.1365-2249.03912.x]; DM Pardol, 2012 [doi:10.1038 / nrc3239]).

[0104] Immunogenic cell death (ICD), a specialized form of cell death that stimulates an immune response against dead cell antigens (released by dying cells), is considered one of the best ways to induce adaptive immune responses and enhance the efficacy of anticancer drug therapy. However, this process can be suboptimal, necessitating combination strategies that attempt to fully restore the immunogenicity of cell death for therapeutic purposes. Anticancer drugs that induce ICD include anthracyclines (e.g., doxorubicin, epirubicin, idarubicin), alkylating agents (e.g., oxaliplatin, cyclophosphamide), the topoisomerase II inhibitor mitoxanthone, and the proteasome inhibitor bortezomib.

[0105] Antibody-drug conjugates containing PBD warheads may be particularly suitable as combination partners because they are more targeted than conventional chemotherapy and are expected to enhance antigen presentation to infiltrating T cells, as has been shown with auristatin-based ADCs.

[0106] Thus, when ADCs are combined with IOs, the ADCs directly kill target-expressing tumors, resulting in rapid antitumor activity, while the immunogenic cell death resulting from ADC-induced cell death may promote a stronger and more durable adaptive immune response compared with IOs administered alone.

[0107] To demonstrate that the anti-CD19 ADC functions synergistically with a second agent, a panel of CD19(+) cell lines is co-treated with varying concentrations of the anti-CD19 ADC and the second agent. As a negative control, the same panel of cell lines is treated with various concentrations of the second agent or various concentrations of the anti-CD19 ADC and vehicle. After incubation, two parameters are measured: the amount of surface CD19 (determined by flow cytometry) and in vitro cytotoxicity of the combination (determined by MTS assay). To measure cytotoxicity, cell viability is measured by adding MTS to each well and incubating at 37°C for 4 hours. Cell viability is calculated relative to the untreated control. Cytotoxicity synergy is calculated by converting cell viability data to fraction affected and calculating the combination index using the CalcuSyn analysis program. Second-line drugs include: (a) Bendamustine; (b) lenalidomide; (c) a proteasome inhibitor such as bortezomib, carfilzomib, ixazomib, oprozomib, or salinosporamide A; or (d) PARP inhibitors such as olaparib, CEP-9722, BMN-673 / talazoparib, rucaparib, iniparib / SAR24-550 / BSI-201, veliparib (ABT-888), niraparib / MK-4827, BGB-290, 3-aminobenzamide, and E7016; It may be.

[0108] Each of these classes of second-line agents is described in more detail below. bendamustine Bendamustine is a bifunctional mechlorethamine derivative that can form electrophilic alkyl groups that covalently bond to other molecules. Bendamustine acts as an alkylating agent, inducing intra- and interstrand crosslinks between DNA bases, leading to cell death. Bendamustine is active against both activated and quiescent cells. It is indicated for the treatment of chronic lymphocytic leukemia (CLL) and indolent B-cell non-Hodgkin's lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

[0109] [ka] Lenalidomide Lenalidomide is a thalidomide analogue with enhanced immunomodulatory and angiogenic properties, but with few of the adverse events specific to thalidomide. Lenalidomide is primarily used in the low-risk and intermediate-risk IPSS-1 setting in myelodysplastic syndromes (MDS). Several studies have demonstrated its ability to induce both red blood cell and cytogenetic responses in these disease groups. In clinical trials of patients with 5q chromosomal abnormalities, lenalidomide treatment resulted in red blood cell transfusion independence in 67% of patients. Furthermore, 45% of patients achieved complete cytogenetic remission, and 28% achieved minor cytogenetic remission. This outcome was independent of karyotype complexity. Lenalidomide may also induce long-term remission in del(5q) patients with increased medulloblast counts. In non-del(5q) patients with confirmed low-risk and intermediate-risk disease, 43% achieved transfusion independence or a reduction of pretreatment red blood cell transfusion volume of 50% or more.

[0110] Adverse events are common but manageable and include neutropenia, thrombocytopenia, pruritus, rash, and diarrhea. Lenalidomide has proven to be an essential agent for the treatment of MDS. Combinations with cytokines, demethylating agents, tyrosine kinase inhibitors, or chemotherapy are being investigated and may show additional benefit in both low-risk and high-risk MDS (see Giagounidis et al., Ther Clin Risk Manag. 2007 Aug;3(4):553-562).

[0111] [ka] Proteasome inhibitors The proteasome is a large protein complex that degrades intracellular proteins, requiring metabolic energy for its degradation. Ubiquitin polymerization, known to work in concert with the proteasome, functions as a degradation signal for many target proteins. Protein degradation is initiated by the covalent attachment of a chain consisting of several copies of ubiquitin (four or more ubiquitin molecules) to the proteasome through the coordinated action of a protein network, including E1 (ubiquitin-activating), E2 (ubiquitin-binding), and E3 (ubiquitin-ligating) enzymes. The polymerized ubiquitin chain then acts as a signal to transport the target protein to the proteasome, where the substrate is proteolyzed. To precisely select proteins, this cascade system recruits numerous enzymes (e.g., in humans, two E1 proteins, approximately 30 E2 proteins, and over 500 E3 proteins). The set of E3 proteins is highly diverse, as each E3 enzyme typically selectively recognizes protein substrates for ubiquitination (Tanaka 2009, Proc Jpn Acad Ser B Phys Biol Sci. 2009 Jan;85(1):12-36, and citations therein).

[0112] The ubiquitin-proteasome system (UPS) regulates almost all fundamental cellular processes, including cell cycle, signal transduction, cell death, immune response, metabolism, protein quality control, and development, by degrading short-lived regulatory proteins and structurally abnormal proteins.

[0113] These protein regulatory processes are also important in cancer, and the proteasome is a key regulator of carcinogenesis. According to the cancer stem cell hypothesis, cancers contain a variety of cells derived from a small subset of cancer stem cells (also known as tumor-initiating cells). These cells have the ability to propagate various cancers and constitute a subset that repopulates tumors after intravenous therapy. While the proteasome is involved in cancer stem cell cellular processes, its function has been shown to be reduced compared to other cancer cells. In particular, the proteasome has been reported to be involved in the proliferation and pluripotency that characterize cancer cells and cancer stem cells (see Voutadakis et al., Tumor Biology, Mar. 2017).

[0114] As used herein, the term "proteasome inhibitor" is used to mean any agent that specifically binds to and / or inhibits the biological activity of a proteasome component. As used herein, "binds to CD19" means that the agent binds to a proteasome component with higher affinity than a nonspecific partner such as bovine serum albumin (BSA, Genbank Accession No. CAA76847, version No. CAA76847.1GI:3336842, record updated January 7, 2011, 2:30 PM). In certain embodiments, the agent has a binding constant that is at least 2, 3, 4, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 100, 200, 50 ... 4 , 10 5 or 10 6 The antibodies of the present disclosure may bind to proteasome components with high affinity. For example, in some embodiments, the agent binds to proteasome components 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 Less than 1 of, about 10 -6 K equal to or less than M D can bind to proteasome components at

[0115] Suitable proteasome inhibitors for use in the present disclosure are: a) Bortezomib

[0116] [ka] b) Carfilzomib

[0117] [ka] c) Ixazomib

[0118] [ka] d) Oprozomib

[0119] [ka] e) Salinosporamide A

[0120] [ka] PARP inhibitors Poly(adenosine diphosphate [ADP]) ribose polymerase (PARP) is a family of enzymes involved in a wide range of cellular functions, including DNA transcription, DNA damage response, maintenance of genome stability, cell cycle control, and cell death. PARP-1 is the most abundant and best-characterized protein in this group. In oncology, its essential function in repairing single-strand DNA breaks (SSBs) via the base excision repair (BER) pathway has attracted considerable interest. Several PARP-1 inhibitors (PARPi) have been developed and are currently in clinical trials (including, but not limited to, olaparib, CEP-9722, talazoparib, rucaparib, iniparib, veliparib, and niraparib). In cancer therapy, PARPi primarily act by inhibiting DNA damage repair, ultimately leading to cell death.

[0121] PARP consists of four notable domains: a DNA-binding domain, a caspase-cleavage domain, an auto-modification domain, and a catalytic domain. The DNA-binding domain consists of two zinc finger motifs. The DNA-binding domain binds to damaged DNA (where base pairs are missing) and induces a conformational change. This binding has been shown to occur independently of other domains. This is essential for a programmed cell death model based on PARP's inhibition of caspase cleavage. The auto-modification domain functions to release the protein from DNA after catalysis and also plays an important role in inactivation by cleavage.

[0122] PARP resides in the cell nucleus. Its primary function is to detect metabolically, chemically, and radiation-induced single-strand DNA breaks (SSBs) and initiate an immediate cellular response by signaling the enzymatic machinery involved in SSB repair. Upon detecting a single-strand break, PARP binds to DNA, changes its structure, and initiates the synthesis of adenosine diphosphate ribose (poly(ADP)-ribose, PAR) chains, which act as a signal to other DNA repair enzymes. Target enzymes include DNA ligase III (LigIII), DNA polymerase beta (polβ), and scaffolding proteins such as X-ray cross-complementing gene 1 (XRCC1). After repair, the PAR chains are degraded via poly(ADP-ribose) glycohydrolase (PARG).

[0123] NAD+ is required as a substrate to generate ADP-ribose monomers. It has been thought that excessive PARP activation inhibits glucose oxidation, leading to intracellular NAD+ depletion, ATP depletion, and necrotic cell death. However, recent studies have suggested that inhibition of hexokinase activity leads to defective glycolysis (see Andrabi, PNAS 2014). As noted below, PARP is inactivated by cleavage by caspase-3 during programmed cell death.

[0124] PARP enzymes are essential for many cellular functions, including inflammatory gene expression. PARP1 is required for the induction of ICAM-1 gene expression by smooth muscle cells in response to TNF.

[0125] PBDs are a class of naturally occurring antitumor antibiotics discovered in actinomycetes. PBD dimers exert their cytotoxic effects by cross-linking two strands of DNA, thereby inhibiting replication and killing tumor cells. Importantly, the cross-links formed by PBD dimers do not distort DNA structure as much, thereby hiding DNA repair mechanisms that are often impaired in human tumors in contrast to normal tissues.

[0126] The combination of PBD-based ADCs with PARPi (including but not limited to olaparib, CEP-9722, talazoparib, rucaparib, iniparib, veliparib, and niraparib) is advantageous in that repair of DNA damage induced by PBD dimers is blocked by PARP inhibition, resulting in the accumulation of DNA damage that induces cell death in cancer cells.

[0127] To demonstrate additive or synergistic antitumor effects of treatment of solid tumor cell lines with a PBD-based ADC and a PARPi, a panel of solid tumor cell lines is treated with a range of concentrations of each ADC and PARPi. After incubation, the in vitro cytotoxicity of the combination (determined by CellTiter-Glo® or MTS assay) is measured. Cytotoxic synergy is calculated by converting cell viability data to fraction affected and calculating a combination index using the CalcuSyn analysis program.

[0128] By "PARP inhibitor" is meant a chemical compound or biological molecule that reduces PARP activity.

[0129] For example, to assess the degree of inhibition of PARP activity, a given sample or assay, e.g., containing a protein, gene, cell, or organism, is treated with a candidate activator or inhibitor and compared to a control sample treated with an inactive control molecule. The control sample is assigned a relative activity value of 100%. Inhibition is achieved when the relative activity value to the control is about 90% or less, usually 85% or less, more usually 80% or less, most usually 75% or less, generally 70% or less, more usually 65% ​​or less, most usually 60% or less, usually 55% or less, usually 50% or less, more usually 45% or less, most usually 40% or less, preferably 35% or less, more preferably 30% or less, even more preferably 25% or less, and most preferably 20% or less.

[0130] Suitable PARPi for use in the present disclosure are as follows: a) Olaparib

[0131] [ka] b) CEP-9722

[0132] [ka] c) BMN-673 / talazoparib

[0133] [ka] d) Rucaparib

[0134] [ka] e) Iniparib / SAR24-550 / BSI-201

[0135] [ka] f) Veliparib (ABT-888)

[0136] [ka] g) Niraparib / MK-4827

[0137] [ka] h) BGB-290

[0138] [ka] i) 3-aminobenzamide

[0139] [ka] j)E7016

[0140] [ka] Preferably, the second agent is olaparib or bendamustine.

[0141] --------------------- [ Advantageous Properties of the Combination of the Present Disclosure 〕 Both anti-CD19 ADCs and PI3K inhibitors or second-line agents have demonstrated clinical utility when used alone as single agents, e.g., in the treatment of cancer. However, as described herein, the combination of an anti-CD19 ADC and a PI3K inhibitor or second-line agent is expected to provide one or more of the following advantages over treatment with either an anti-CD19 ADC and a PI3K inhibitor or second-line agent alone: 1) Effective in treating a wider range of cancers 2) Effective treatment of individuals with resistant or intractable conditions, such as cancer, that have recurred after a period of remission; 3) improved response rates to treatment, and / or 4) Improved sustainability of treatment.

[0142] As used herein, effective treatment of a wider range of cancers means that complete responses are observed in a wider range of recognized cancer types following the combination treatment, i.e., complete responses are observed in cancer types that have previously been reported to be incompletely responsive to anti-CD19 ADC and PI3K inhibitor or second-line agent alone.

[0143] As used herein, effective treatment of a resistant, refractory, or recurrent condition means that, following the combination treatment, a complete response is observed in individuals who are partially or completely resistant or refractory to treatment with an anti-CD19 ADC and a PI3K inhibitor or a second-line agent alone (e.g., individuals who have no response or only a partial response following treatment with an anti-CD19 ADC and a PI3K inhibitor or a second-line agent alone, or individuals whose condition has recurred). In some embodiments, a complete response following treatment with the combination of an anti-CD19 ADC and a PI3K inhibitor or a second-line agent is observed in at least 10% of individuals who are partially or completely resistant or refractory to treatment with an anti-CD19 ADC and a PI3K inhibitor or a second-line agent alone. In some embodiments, a complete response following combination treatment with an anti-CD19 ADC and a PI3K inhibitor or second-line agent 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 partially or completely resistant or refractory to monotherapy with an anti-CD19 ADC and a PI3K inhibitor or second-line agent.

[0144] As used herein, improved response rate to treatment means that a higher proportion of individuals experience a complete response following combination treatment than is observed following treatment with an anti-CD19 ADC and a PI3K inhibitor or second-line agent alone. In some embodiments, a complete response following combination treatment with an anti-CD19 ADC and a PI3K inhibitor or second-line agent is observed in at least 10% of treated individuals. In some embodiments, a complete response following combination treatment with an anti-CD19 ADC and a PI3K inhibitor or second-line agent is observed in at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% of treated individuals.

[0145] As used herein, improved durability of treatment means that the mean duration of complete response in combination-treated individuals is longer than in individuals who achieve a complete response after treatment with an anti-CD19 ADC and a PI3K inhibitor or second-line agent alone. In some embodiments, the mean duration of complete response after combination treatment with an anti-CD19 ADC and a PI3K inhibitor or second-line agent is at least 6 months. In some embodiments, the mean duration of complete response after combination treatment with an anti-CD19 ADC and a PI3K inhibitor or second-line agent 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. As used herein, "complete response" means no clinical evidence of disease in an individual. Evidence can be assessed using any suitable method in the art, such as CT or PET scans, or biopsies, if appropriate. The number of doses required to achieve a complete response can be one, two, three, four, five, ten, or more. In some embodiments, the individual achieves a complete response within one year of administration of the first dose, such as within six months, three months, one month, two weeks, or one week after administration of the first dose.

[0146] [ Disease being treated 〕 Combination therapies described herein include those that utilize anti-cancer activity. In particular, in certain embodiments, the therapy includes an antibody covalently linked, i.e., via a linker, to a PBD drug moiety, i.e., a toxin. When the drug is not bound to the antibody, the PBD drug has a cytotoxic effect. The biological activity of the PBD drug moiety is modulated, i.e., upon binding to the antibody. The antibody-drug conjugates (ADCs) of the present disclosure achieve selective delivery of an effective amount of a cytotoxic drug to tumor tissue with greater selectivity, i.e., a lower effective dose.

[0147] Accordingly, in certain aspects, the present disclosure provides combination therapies that include administering an anti-CD19 ADC that binds CD19 for use in therapy, wherein the method includes selecting a subject based on expression of a target protein.

[0148] In one aspect, the disclosure provides a combination therapy comprising a label identifying the therapy as suitable for use in a subject determined to be suitable for such use. The label may identify the therapy as suitable for use in a subject expressing CD19, such as a subject overexpressing CD19. The label may identify the subject as having a particular type of cancer.

[0149] The cancer may be a lymphoma, such as non-Hodgkin's lymphoma. The label may identify the subject as having CD19+ lymphoma.

[0150] In a further aspect, there is also provided a combination therapy as described herein for use in treating a proliferative disorder. In another aspect of the present disclosure, there is provided the use of a conjugate in the manufacture of a medicament for the treatment of a proliferative disorder.

[0151] One of ordinary skill in the art can readily determine whether a candidate combination therapy treats a proliferative disorder of any particular cell type. For example, the following describes assays that can be conveniently used to evaluate the activity of a particular compound.

[0152] The combination therapies described herein can be used to treat proliferative disorders. The term "proliferative disorder" relates to unwanted or uncontrolled, excessive or abnormal cell proliferation, e.g., neoplastic or hyperplastic growth, whether in vitro or in vivo.

[0153] Examples of proliferative conditions include, but are not limited to, benign, pre-malignant, and malignant cell proliferations, including, but not limited to, neoplasias and tumors (e.g., histocytoma, glioma, astrocytoma, osteoma), cancer (e.g., lung cancer, small cell lung cancer, gastrointestinal cancer, colorectal cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma), lymphoma, leukemia, psoriasis, bone disease, fibroproliferative disorders (e.g., connective tissue), and atherosclerosis. Associated cancers include, but are not limited to, leukemia and ovarian cancer.

[0154] Any cell type may be treated, including, but not limited to, lung, gastrointestinal tract (including, for example, large intestine, colon), breast (mammary), ovary, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin.

[0155] Particularly relevant proliferative disorders include non-Hodgkin's lymphomas, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic lymphoma (CLL), and marginal zone B-cell lymphoma (MZBL), and leukemias such as hairy cell leukemia (HCL), hairy cell leukemia variant (HCL-v), and acute lymphoblastic leukemia (ALL), such as Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL). [Fielding A., Haematologica. 2010 Jan;95(1):8-12] It is contemplated that the combination therapy of the present disclosure may be used to treat a variety of diseases or conditions characterized, for example, by the overexpression of tumor antigens. Exemplary conditions or hyperproliferative disorders include benign or malignant tumors; leukemia, hematological malignancies, and lymphoid malignancies. Others include neuronal, glial, astrocytic, hypothalamic, glandular, macrophagal, epithelial, stromal, blastocytic, inflammatory, angiogenic, and immune disorders, including autoimmune disorders and graft-versus-host disease (GVHD).

[0156] Generally, the disease or condition to be treated is a hyperproliferative disease, such as cancer. Examples of cancers to be treated herein include, but are not limited to, carcinomas, lymphomas, blastomas, sarcomas, and leukemias or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinomas (e.g., epithelial squamous cell carcinomas), lung cancer, including small cell lung cancer and non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastrointestinal or gastric cancer, including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, renal carcinoma, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, and head and neck cancer.

[0157] Autoimmune diseases for which the combination therapy can be used to treat include rheumatic diseases (such as rheumatoid arthritis, Sjogren's syndrome, scleroderma, lupus including SLE and lupus nephritis, polymyositis / dermatomyositis, cryoglobulinemia, antiphospholipid syndrome, and psoriatic arthritis), osteoarthritis, autoimmune gastrointestinal and liver diseases (such as inflammatory bowel disease (such as ulcerative colitis and Crohn's disease), autoimmune gastritis and pernicious anemia, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and celiac disease), vasculitis (such as ANCA-associated vasculitis, Wegener's granulomatosis, and polyarthritis), autoimmune neuropathies (such as multiple sclerosis, myoclonus syndrome, myasthenia gravis, neuromyelitis optica, Parkinson's disease, and Alzheimer's disease), and autoimmune polyneuropathy, etc.), kidney disorders (glomerulonephritis, Goodpasture's syndrome, Berger's disease, etc.), autoimmune skin diseases (e.g., psoriasis, urticaria, hives, pemphigus vulgaris, bullous pemphigus, cutaneous lupus erythematosus, etc.), blood disorders (thrombocytopenic purpura, thrombotic thrombocytopenic purpura, post-transfusion purpura, autoimmune hemolytic anemia, etc.), arteriosclerosis, uveitis, autoimmune hearing diseases (e.g., inner ear disease and hearing loss, etc.), Behcet's disease, Raynaud's syndrome, organ transplantation, graft-versus-host disease (GVHD), and autoimmune endocrine diseases (diabetes-related autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM), Addison's disease, and autoimmune thyroid diseases (e.g., Graves' disease and thyroiditis)). More preferred examples of the disease include rheumatoid arthritis, ulcerative colitis, ANCA-associated vasculitis, lupus, multiple sclerosis, Sjogren's syndrome, Graves' disease, IDDM, pernicious anemia, thyroiditis, and glomerulonephritis.

[0158] In some embodiments, the subject has a proliferative disorder selected from non-Hodgkin's lymphoma, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic lymphoma (CLL), and marginal zone B-cell lymphoma (MZBL), and leukemia, such as hairy cell leukemia (HCL), hairy cell leukemia variant (HCL-v), and acute lymphoblastic leukemia (ALL), such as Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL). [Fielding A., Haematologica. 2010 Jan;95(1):8-12] In one embodiment, the subject has diffuse large B-cell lymphoma.

[0159] [ Patient selection 〕 In some embodiments, individuals believed to be suitable for treatment with the combination therapy are selected prior to administration of the therapy. As used herein, an individual considered suitable for treatment is an individual who is expected to benefit from or respond to the treatment. The individual may have, be suspected of, or be at risk of having cancer. The individual may have been diagnosed with cancer. In particular, the individual may have, be suspected of, or be at risk of having lymphoma. In some cases, the individual may have, be suspected of, or be at risk of having a solid cancer with tumor-associated non-tumor cells that express CD19, such as infiltrating cells that express CD19.

[0160] In some embodiments, individuals are selected based on the amount or pattern of CD19 expression, hi certain embodiments, the selection is based on cell surface expression of CD19.

[0161] In one embodiment, the target is PI3K. In one embodiment, the selection is based on expression of PI3K. In some embodiments, the selection is based on the levels of both CD19 and PI3K on the cell surface. In some cases, expression of the assay is measured in a specific tissue of interest, for example, in a sample of lymphoid or tumor tissue.

[0162] In some cases, the 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 embodiments, the individual is selected as suitable for treatment due to the presence of target expression in the sample, in which case individuals without target expression would be considered ineligible for treatment.

[0163] In other embodiments, the level of target expression is used to select individuals suitable for treatment: if the expression level of the target exceeds a threshold level, the individual is deemed suitable for treatment.

[0164] In some embodiments, the presence of CD19 in the sample and / or in the cells indicates that the individual is suitable for a combination treatment comprising an anti-CD19 ADC and a PI3K inhibitor or second agent. In other embodiments, the amount of CD19 and / or expression must exceed a threshold level to indicate that the individual is suitable for treatment. In some embodiments, the observation that CD19 and / or localization is altered in the sample compared to a control indicates that the individual is suitable for treatment.

[0165] In some embodiments, the 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.

[0166] In certain embodiments, a patient is deemed 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 disclosed herein, a patient is deemed suitable for treatment if at least 10% of the cells in the sample express CD 19.

[0167] 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 the total cells in the sample express CD 19. In some embodiments disclosed herein, a patient is determined to be suitable for treatment if at least 10% of the cells in the sample express CD 19.

[0168] In some embodiments, the individual is selected as suitable for treatment based on current or previous treatment regimes. In some embodiments, an individual is selected for treatment with an anti-CD19 ADC if the individual has previously been treated with a PI3K inhibitor or a second-line agent. In some embodiments, an individual is selected for treatment with an anti-CD19 ADC if the individual is currently being treated with a PI3K inhibitor or a second-line agent. In some cases, the individual is selected for treatment if the individual is resistant to treatment (or further treatment) with a PI3K inhibitor or second-line agent. In some cases, the PI3K inhibitor may be idelalisib or copanlisib. In some cases, the second-line agent may be bendamustine, bortezomib, lenalidomide, or olaparib. In embodiments where the individual is currently or has previously been treated with a PI3K inhibitor or second-line agent, the anti-CD19 ADC may be administered in combination with the PI3K inhibitor or second-line agent, or without continued administration of the PI3K inhibitor or second-line agent.

[0169] In some embodiments, the anti-CD19 ADC is administered to a selected individual in combination with a PI3K inhibitor or a second agent. In some embodiments, the anti-CD19 ADC may be administered to a selected individual without the ongoing administration of a PI3K inhibitor or a second agent. Preferably, the PI3K inhibitor is idelalisib or copanlisib. Preferably, the second agent is olaparib or bendamustine.

[0170] As used herein, the term "treatment (or further treatment) with a PI3K inhibitor (or second agent)" refers to to refractory " indicates that a condition (e.g., cancer) is more susceptible to PI3K inhibitors when administered as monotherapy. or has stopped responding to the administration of a second-line drug. In embodiments, the individual with refractory NHL is treated with the method described in Cheson at al. 2014 (So uth Asian J Cancer.2014Jan-Mar;3(1):66-7 0), in which non-responders are defined as: (i) A 50% increase in the sum of the diameters of previously identified abnormal nodules from the immediate nadir, or i) The appearance of any new lesions during or at the end of treatment; In some embodiments, an individual with refractory leukemia is defined as having received one complete cure. Individuals with stable or progressive disease who have completed two or more complete treatment cycles Patients are identified as those who achieve a partial response after multiple treatment cycles.

[0171] sample The sample may comprise or be derived from the following: a volume of blood; a volume of serum derived from an individual's blood, including the fluid portion of blood obtained after removal of fibrin clots and blood cells; a volume of pancreatic juice; a tissue sample or biopsy; or cells isolated from said individual.

[0172] The sample may be taken from any tissue or bodily fluid, hi certain aspects, the sample may be or be derived from a tissue sample, biopsy, resection, or cells isolated from the individual.

[0173] In some embodiments, the sample is a tissue sample. The sample may be a sample of tumor tissue, such as cancerous tumor tissue. The sample may be obtained by tumor biopsy. In some embodiments, the sample is a lymphoid tissue sample, such as a lymphoid lesion sample or a lymph node biopsy. In some embodiments, the sample is a skin biopsy.

[0174] In some embodiments, the sample is taken from a bodily fluid, more preferably a circulating bodily fluid. That is, the sample may be a blood sample or a lymphatic sample. In some embodiments, the sample is a urine sample or a saliva sample.

[0175] In some embodiments, the sample is a blood sample or a blood-derived sample, which may be a selected fraction of an individual's blood, such as a selected cell-containing fraction or a plasma or serum fraction.

[0176] The selected cell-containing fraction may contain relevant cell types, including white blood cells (WBCs), particularly peripheral blood mononuclear cells (PBCs) and / or granulocytes, and / or red blood cells (RBCs). That is, the method according to the present disclosure may comprise detecting a first target polypeptide or nucleic acid in blood in white blood cells, peripheral blood mononuclear cells, granulocytes and / or red blood cells.

[0177] The sample may be fresh or archived. For example, the archived tissue may be a biopsy taken at the time of an individual's initial diagnosis or at the time of recurrence. In certain embodiments, the sample is a fresh biopsy.

[0178] The first target polypeptide may be CD19.

[0179] Individual Status The individual may be an animal, mammal, viviparous mammal, marsupial (e.g., kangaroo, wombat), monocephaly (e.g., duck, platypus), rodent (e.g., guinea pig, hamster, rat, mouse), murine (e.g., mouse), lagomorph (e.g., rabbit), avian (e.g., bird), canine (e.g., dog), feline (e.g., cat), equine (e.g., horse), porcine (e.g., pig), ovine (e.g., sheep), bovine (e.g., cow), primate, ape (e.g., monkey, ape), primate (e.g., marmoset, baboon), ape (e.g., gorilla, chimpanzee, orangutan, geese), or human.

[0180] Furthermore, the individual may be in any form of development, for example, a fetus. In a preferred embodiment, the individual is a human. As used herein, the terms "subject," "patient," and "individual" are used interchangeably.

[0181] In some embodiments disclosed herein, the individual has been identified as having, suspected of having, or at risk for cancer. In some embodiments disclosed herein, the individual has already been diagnosed with cancer. The individual may have been diagnosed with non-Hodgkin's lymphoma, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic lymphoma (CLL), and marginal zone B-cell lymphoma (MZBL), and leukemia, such as hairy cell leukemia (HCL), hairy cell leukemia variant (HCL-v), and acute lymphoblastic leukemia (ALL), such as Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL). [Fielding A., Haematologica. 2010 Jan;95(1):8-12] In some cases, the individual may have been diagnosed with a leukemia such as non-Hodgkin's lymphoma, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic lymphoma (CLL), and marginal zone B-cell lymphoma (MZBL), and acute lymphoblastic leukemia (ALL), such as hairy cell leukemia (HCL), hairy cell leukemia variant (HCL-v), and Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL). [Fielding A., Haematologica. 2010 Jan;95(1):8-12] In some cases, the individual has been diagnosed with a solid tumor that contains infiltrating cells that express CD19+.

[0182] The individual is undergoing or has undergone therapeutic treatment for the cancer. The subject may or may not have previously taken ADCX19. In some cases, the cancer is lymphoma, including non-Hodgkin's lymphoma.

[0183] The individual is currently receiving or has previously received treatment with a PI3K inhibitor or a second-line agent. In some cases, the individual may be treated with a PI3K inhibitor or a second agent (or further treatment) refractory In some cases, the PI3K inhibitor is idelalisib or In some cases, second-line agents include bendamustine, bortezomib, and lenalidomide. The individual may be receiving treatment with a PI3K inhibitor or a second agent, such as olaparib. In embodiments that are receiving or have received, the anti-CD19 ADC may be administered with or have received a PI3K inhibitor. or in combination with a second-line agent, or without continued administration of a PI3K inhibitor or second-line agent It is okay to do so.

[0184] Control In some embodiments, 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.

[0185] In some cases, the control may be a control sample or a control dataset. The control may be a sample previously obtained from an individual with a known degree of compatibility. The control may be a dataset obtained by analyzing a control sample.

[0186] The control may be a positive control in which the target molecule is known to be present or expressed at high levels, or a negative control in which the target molecule is known to be absent or expressed at low levels.

[0187] The control may be a tissue sample taken from an individual known to benefit from the treatment. The tissue may be of the same species 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.

[0188] In some embodiments, the control may be a sample obtained from the same individual as the test sample, but may be a sample obtained from tissue known to be healthy. Thus, a sample of cancerous tissue from an individual may be compared to a non-cancerous tissue sample. In some cases, the control is a cell culture sample. In some cases, the test sample is analyzed prior to incubation with the antibody to determine the level of background staining inherent in the sample. In some cases, an isotype control is used, which uses an antibody of the same class as the target-specific antibody but which is not immunoreactive with the sample. This control is useful for distinguishing nonspecific interactions of the target-specific antibody.

[0189] The method may include interpretation of morphology and immunohistochemistry by a hematopathologist to ensure accurate interpretation of test results. For example, when analyzing expression levels of CD19 and / or PI3K, the method may include confirming that expression in the test sample is observed as membrane staining with cytoplasmic components. The method may also include confirming that the ratio of target signal to noise exceeds a threshold level, allowing specific background signals to be clearly distinguished from nonspecific background signals.

[0190] [ 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, e.g., inhibition of progression of the condition, and includes slowing the rate of progression, halting the rate of progression, regressing the condition, ameliorating the condition, and curing the condition. Treatment as a preventative measure (i.e., prophylaxis, prevention) is also included.

[0191] As used herein, the term "therapeutically effective amount" or "effective amount" means an amount of an active compound, or material, composition, or dosage containing an active compound, that, when administered in accordance with a desired treatment regimen, is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit / risk ratio. Similarly, as used herein, the term "prophylactically effective amount" means an amount of an active compound, or material, composition, or dosage containing an active compound, that, when administered in accordance with a desired treatment regimen, is effective for producing a desired prophylactic effect, commensurate with a reasonable benefit / risk ratio.

[0192] The present specification discloses methods of treatment. Also provided are methods of treatment comprising administering therapeutically effective amounts of an anti-CD19 ADC and a PI3K inhibitor or secondary agent to a subject in need of treatment. The term "therapeutically effective amount" refers to an amount sufficient to provide a benefit to the subject. The benefit may be at least an improvement in at least one symptom. The actual amount administered, as well as the rate and time course of administration, will depend on the nature and severity of the individual being treated. Prescribing a treatment, e.g., determining dosage, is within the responsibility of the medical practitioner or other physician. The subject may be tested to determine eligibility for treatment using the methods disclosed herein. The treatment method may include determining whether the subject is eligible for treatment using the methods disclosed herein.

[0193] The anti-CD19 ADC includes an anti-CD19 antibody. The anti-CD19 antibody may be an RB4v1.2 antibody. The ADC may include a drug that is a PBD dimer. The ADC may be ADCx19. The ADC may be the ADC disclosed in Patent Document 1.

[0194] PI3K inhibitors include idelalisib, copanlisib, duvelisib, taselisib, bupalisib, alpelisib, umbralisib, dactolisib, and voxatalisib. Preferably, the PI3K inhibitor is idelalisib or copanlisib.

[0195] Second-line drugs include: (a) Bendamustine; (b) lenalidomide; (c) a proteasome inhibitor such as bortezomib, carfilzomib, ixazomib, oprozomib, or salinosporamide A; or (d) PARP inhibitors such as olaparib, CEP-9722, BMN-673 / talazoparib, rucaparib, iniparib / SAR24-550 / BSI-201, veliparib (ABT-888), niraparib / MK-4827, BGB-290, 3-aminobenzamide, and E7016; It may be.

[0196] Treatment may include administering the anti-CD19 ADC / PI3K inhibitor or second agent combination alone or in further combination with other therapeutic agents, either simultaneously or sequentially, depending on the condition to be treated. Examples of combination treatments with anti-CD19 ADC + PI3K inhibitor include: (1) Identification of individuals who have been treated or are currently being treated with a PI3K inhibitor, such as idelalisib or copanlisib; (2) administering to the individual an anti-CD19 ADC, such as ADCx19; and, in some cases, (3) administering to the individual a PI3K inhibitor, such as idelalisib or copanlisib, in combination with an anti-CD19 ADC (e.g., simultaneously with or after the ADC); Examples include:

[0197] Examples of treatments combining anti-CD19 ADCs with second-line agents include the following: (1) Identification of individuals who have been treated or are currently being treated with second-line agents such as bendamustine, bortezomib, lenalidomide, or olaparib; (2) administering to the individual an anti-CD19 ADC, such as ADCx19; and, in some cases, (3) administering to the individual a second-line agent such as bendamustine, bortezomib, lenalidomide, or olaparib in combination with the anti-CD19 ADC (e.g., simultaneously with the ADC or after the ADC); Examples include:

[0198] Examples of treatments and therapies include, but are not limited to, chemotherapy (administration of active agents, including drugs such as chemotherapeutic agents); surgery; and radiation therapy. A "chemotherapeutic agent" is a chemical 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" as well as compounds used in conventional chemotherapy.

[0199] Examples of chemotherapeutic agents include: 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 Pharma), docetaxel (TAXOTERE®, Sanofi-Aventis), 5-FU (fluorouracil, CAS No. 51-21-8), gemcitabine (GEMZAR®, Lilly), PD-0325901 (CAS No. 391210-10-9, Pfizer), cisplatin (cis-diaminedichloroplatinum(II), CAS No. 15663-27-1), carboplatin (CAS No. 41575-94-4), paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton), trastuzumab (HERCEPTIN®, Genentech), temozolomide (4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo[4.3.0]nona-2,7,9-triene-9-carboxamide) CAS No. 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.

[0200] Further 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, Exelixi, WO 2007 / 04515), ARRY-886 (MeK inhibitor, AZD6244, Array BioPharma, AstraZeneca), SF-1126 (PI3K inhibitor, Semaphore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixi), PTK787 / ZK 222584 (Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin (folinic acid), rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, GlaxoSmithKline), lonafarinib (SARASAR®, SCH 66336, Schering-Plough), sorafenib (NEXAVAR®, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), irinotecan (CAMPTOSAR®, CPT-11, Pfizer), tipifarnib (ZARNESTRA™, Johnson & Johnson), ABRAXANE™ (Cremophor-Free),), albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumburg, IL), vandetanib (rINN, ZD6474, ZACTIMA®, AstraZeneca), chlorambucil, AG1478, AG1571 (SU 5271; Sugen), temsirolimus (TORISEL®, Wyeth), pazopanib (GlaxoSmithKline), canfosfamide (TELCYTA®, Teriq), thiotepa and cyclophosphamide (CYTOXAN®, NEOSAR®), alkyl sulfonates such as busulfan, imposulfan, and piposulfan;Azirines such as benzodopa, carboquone, metoledopa, and uredopa; ethylenimines and methylamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylmelamine; acetogenins (especially bullatacin and bullatacinone); camptothecins (including the synthetic analog topotecan); bryostatin; kallistatin; CC-1065 (including the synthetic analogs adzercin, carzercin, and biszercin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycins (synthetic analogs, KW-2189 and CB1-T M1); eleutherobin; pancratistatin; sarcoditin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride oxide, melphalan, nobeviquine, phenesterin, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and rannustine; enediyne antibiotics (e.g., antibodies such as calicheamicin, calicheamicin gamma 1I, and calicheamicin omega 1I (Angew Chem. Intl. Engl. 1994 33:183-186)); dynemicin, dynemicin A; bisphosphonates such as clodronate; esperamine;as well as neocarzinostatin chromophore and related chromoprotein enegin antibiotic chromophores), aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, Mitomycins such as esorubicin, idarubicin, nemorubicin, marcelomycin, and mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, queramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate; Purine analogues such as darabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calusterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilostane; furoic acid supplements such as furoic acid; aceglatone; aldophosphamide glycosides Do; aminolevulinic acid; eniluracil; amsacrine; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; epothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidanine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidanol; nitraelin; pentostatin; fenameth; pirarubicin; losantrone; podophyllic acid; 2-ethylhydrazide; procarbazine;PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; schizofiran; spirogermanium; tenuazonic acid; triazicon, 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veracrine A, roridin A, and anguidin); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16) Ifosfamide; Mitoxantrone; Vincristine; Vinorelbine (NAVELBINE®); Novantrone; Teniposide; Edatrexate; Daunomycin; Aminopterin; Capecitabine (XELOD®, Roche); Ibandronic acid; CPT-11; Topoisomerase inhibitor RFS2000; Difluoromethylornithine (DMFO); Retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids, and derivatives of any of the above. Drugs such as CHP (doxorubicin, prednisone, cyclophosphamide) or CHOP (doxorubicin, prednisone, cyclophosphamide, vincristine) may be used in combination.

[0201] The "chemotherapeutic agents" may be specified as follows: (i) antihormonal drugs that act to regulate or inhibit hormone action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including tamoxifen (including NOLVADEX®, tamoxifen citrate), raloxifene, droxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) enzymes that regulate estrogen production in the adrenal glands, such as tamoxifen, raloxifene, droxifene, 4-hydroxytamoxifen, ketoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); aromatase inhibitors that inhibit aromatase, such as 4(5)-imidazole, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane, Pfizer, formestany, famestany, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) flutamide, nilutamide, bicalutamide, leuprolide, goserelin, etc. (iv) protein kinase inhibitors such as MEK inhibitors (WO 2007 / 04515); (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation, such as PKC-α, Raf, and H-Ras, e.g., oblimersen (GENASENSENSE®, Genta Corporation); (vii) VEGF expression inhibitors (e.g., ANGIO (viii) gene therapy vaccines, e.g., ALLOVECTIN®, LEUCTIIN®, and VAXID®, PROLEUKIN® rIL-2, topoisomerase 1 inhibitors, e.g., LURTOTECAN®, ABARELIX® rmRH; (ix) anti-angiogenic agents, e.g., bevacizumab (AVASTIN®, Genentech), and pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0202] Also included within the specification of "chemotherapeutic agents" are therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech), cetuximab (ERBITUX®, ImClone), panitumumab (VECTIBIX®, Amgen), pertuzumab (PERJETM, OMNITARG™, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), MDX-060 (Medarex), and the antibody-drug conjugate gemtuzumab ozogamicin (MYLOTARG®, Wyeth).

[0203] Humanized monoclonal antibodies with therapeutic potential as chemotherapeutic agents for use in combination with the conjugates of the present disclosure include alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, cetolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, Examples include motavizumab, motovizumab, natalizumab, nimotuzumab, norobizumab, numavizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pertuzumab, pesetelizumab, ralizumab, reslizumab, resivizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tetribazumab, tocilizumab, toralizumab, trastuzumab, tucotuzumab, celmoleukin, tuxituzumab, umabituzumab, urtoxazumab, and visilituzumab.

[0204] The compositions according to the present disclosure are preferably pharmaceutical compositions. Pharmaceutical compositions according to and for use in the present disclosure may comprise the active ingredient, i.e., the conjugate compound, and pharmaceutically acceptable excipients, carriers, buffers, stabilizers, or other materials known to those skilled in the art. Such materials should be non-toxic and not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other materials will depend on the route of administration, whether oral, or by, for example, cutaneous, subcutaneous, or intravenous injection.

[0205] Pharmaceutical compositions for oral administration may be in tablet, capsule, powder, or liquid form. 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. Physiological saline, dextrose or other sugar solution, or glycols such as ethylene glycol, propylene glycol, or polyethylene glycol may be included. Capsules may contain a solid carrier such as gelatin.

[0206] For intravenous, cutaneous or subcutaneous injection, or injection into an affected area, the active ingredient will be 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 injection, lactated Ringer's injection, etc. Preservatives, stabilizers, buffers, antioxidants, and / or other additives may be included as needed.

[0207] [Dosage] Those skilled in the art will understand that appropriate dosages (doses) of anti-CD19 ADCs and / or PI3K inhibitors or secondary agents, and compositions containing these active ingredients, will vary from subject to subject. Determining the optimal dosage generally requires balancing the level of therapeutic benefit against risk or adverse side effects. The selected dosage 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 compound excretion, the duration of treatment, other drugs, compounds, and / or substances used concomitantly, the severity of the condition, and the subject's species, sex, age, weight, condition, general condition, and medical history. The amount and route of administration of the compound are ultimately at the discretion of the physician, veterinarian, or clinician, but generally, the dosage will be selected to achieve a local concentration at the site of action that achieves the desired effect without eliciting substantial adverse or dramatic side effects.

[0208] In certain embodiments, the dose of an anti-CD19 ADC is determined by the expression of CD19 observed in a sample obtained from a subject. That is, the level or location of CD19 expression in a sample can indicate the need for a higher or lower dose of the anti-CD19 ADC. For example, a high CD19 expression level can indicate that a higher dose of the anti-CD19 ADC is appropriate. In some cases, a high CD19 expression level can indicate the need for administration of an anti-CD19 ADC and another agent, such as combined administration of an anti-CD19 ADC with a chemotherapeutic agent. A high CD19 expression level suggests a more aggressive treatment regimen.

[0209] In some embodiments, the dosage of the PI3K inhibitor or secondary agent is determined by the expression observed in a sample obtained from the subject. That is, the level or location of expression in the sample can indicate that a higher or lower dose of the PI3K inhibitor or secondary agent is required. For example, a high expression level of PI3K can indicate that a higher dose of the PI3K inhibitor or secondary agent is appropriate. In some cases, a high expression level of PI3K can indicate the need for administration of a PI3K inhibitor or secondary agent and another agent. For example, the combined administration of a PI3K inhibitor or secondary agent and a chemotherapeutic agent. A high expression level of PI3K suggests a more aggressive treatment.

[0210] Administration can be via continuous or intermittent (e.g., in divided doses at appropriate intervals) administration in one dose throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the therapeutic purpose, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out, with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.

[0211] In general, a suitable dosage for each active compound ranges from 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, or the like, the dosage is calculated based on the parent compound, and the actual amount used is increased proportionately. In one embodiment, each active compound is administered to a human subject according to the following dosage regimen: about 100 mg, three times per day. In one embodiment, each active compound is administered to a human subject according to the following dosage regimen: about 150 mg, twice per day. In one embodiment, each active compound is administered to a human subject according to a regimen of about 200 mg, twice daily. However, in one embodiment, each conjugate compound is administered to a human subject according to the following dosing regimen: about 50 mg or about 75 mg, 3 or 4 times per day. In one embodiment, each conjugated compound is administered to a human subject according to a twice-daily dosing regimen of about 100 mg or about 125 mg.

[0212] For anti-CD19 ADCs that are PBD bearing ADCs, the dosages above can apply to an effective amount of the PBD compound that results in a conjugate (including the PBD moiety and a linker to the antibody) or the amount of compound released, e.g., after cleavage of the linker.

[0213] The anti-CD19 ADC includes an anti-CD19 antibody. The anti-CD19 antibody may be an RB4v1.2 antibody. The ADC may include a drug that is a PBD dimer. The ADC may be ADCx19. The ADC may be the ADC disclosed in Patent Document 1.

[0214] PI3K inhibitors include idelalisib, copanlisib, duvelisib, taselisib, bupalisib, alpelisib, umbralisib, dactolisib, and voxatalisib. Preferably, the PI3K inhibitor is idelalisib or copanlisib.

[0215] Second-line drugs include: (a) Bendamustine; (b) lenalidomide; (c) a proteasome inhibitor such as bortezomib, carfilzomib, ixazomib, oprozomib, or salinosporamide A; or (d) PARP inhibitors such as olaparib, CEP-9722, BMN-673 / talazoparib, rucaparib, iniparib / SAR24-550 / BSI-201, veliparib (ABT-888), niraparib / MK-4827, BGB-290, 3-aminobenzamide, and E7016; It may be. [ antibody 〕 The term "antibody" herein is used in the broadest sense and specifically encompasses monoclonal antibodies, polyclonal antibodies, dimers, multimers, multispecific antibodies (e.g., bispecific antibodies), intact antibodies (also referred to as "full-length" antibodies), and antibody fragments, so long as they exhibit the desired biological activity, e.g., the ability to bind to CD19. (Miller et al (2003) 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.

[0216] Antibodies are proteins produced by the immune system that can recognize and bind to specific antigens. (Janeway, C., Travers, P., Walport, M., Shlomchik (2001) Immuno Biology, 5th Ed., Garland Publishing, New York). A target antigen generally has multiple binding sites, also called epitopes, that are recognized by complementarity-determining regions (CDRs) on multiple antibodies. Antibodies that specifically bind to different epitopes have different structures; that is, a single antigen has more than one corresponding antibody. Antibodies may include full-length immunoglobulin molecules or immunologically active portions of full-length immunoglobulin molecules, i.e., molecules that contain an antigen-binding site or portion thereof that immunospecifically binds to an antigen of a relevant target, such as, but not limited to, cancer cells or cells that produce autoimmune antibodies associated with autoimmune disease. The immunoglobulin can be of any system (e.g., IgG, IgE, IgM, IgD, and IgA), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) or subclass, or allotype (e.g., human G1m1, G1m2, G1m3, non-G1m1 [i.e., any allotype other than G1m1], G1m17, G2m23, G3m21, G3m28, G3m11, G3m5, G3m13, G3m14, G3m10, G3m15, G3m16, G3m6, G3m24, G3m26, G3m27, A2m1, A2m2, Km1, Km2, Km2, and Km3) of immunoglobulin molecule. The immunoglobulins can be from any species, including from human, mouse, or rabbit.

[0217] "Antibody fragments" include portions of full-length antibodies, generally the antigen-binding or variable regions thereof. Examples of antibody fragments include Fab, Fab', F(ab')2, and scFv fragments; diabodies; linear antibodies; fragments produced by Fab expression libraries, anti-idiotypic (anti-Id) antibodies, CDRs (complementarity-determining regions), and epitope-binding fragments of any of the above that immunospecifically bind to cancer cell antigens, viral antigens, or microbial antigens, single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.

[0218] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible natural mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic epitope. Furthermore, in contrast to polyclonal antibody preparations which include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. Monoclonal antibodies are advantageous in their specificity and in their ability to be synthesized uncontaminated by other antibodies. The modifier "monoclonal" indicates the character of the antibody as being obtained from a population of substantially homogeneous antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present disclosure may be made by the hybridoma method first described by Kohler et al. (1975) Nature 256:495, or by recombinant DNA methods (see U.S. Pat. No. 4,816,567). The monoclonal antibodies may also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature, 352:624-628; Marks et al. (1991) J. Mol. Biol., 222:581-597, or from transgenic mice carrying a fully human immunoglobulin system (Lonberg (2008) Curr. Opinion 20(4):450-459).

[0219] The monoclonal antibodies herein specifically include "chimeric" antibodies, in which portions of the heavy and / or light chains are identical to or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chains are identical to or homologous to corresponding sequences in other antibodies derived from other species or belonging to other antibody classes or subclasses, so long as they exhibit the desired biological activity (U.S. Patent No. 4,816,567; and Morrison et al. (1984) Proc. Natl. Acad. Sci. USA, 81:6851-6855). Chimeric antibodies include "primatized" antibodies containing variable domain antigen-binding sequences derived from a non-human primate (e.g., an Old World monkey or ape) and human constant region sequences.

[0220] As used herein, a "complete antibody" comprises a VL domain and a VH domain, as well as a light chain constant domain (CL) and a heavy chain constant domain (CH1, CH2, and CH3). The constant domains may be native sequence constant domains (e.g., human native sequence constant domains) or amino acid sequence variants thereof. A complete antibody may have one or more "effector functions," which refer to biological activities attributable to the Fc region of an antibody (a native sequence Fc region or amino acid sequence variant Fc region). Examples of antibody effector functions include C1q binding; complement-dependent cytotoxicity; Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; and down-regulation of cell surface receptors such as the B cell receptor and BCR.

[0221] Depending on the amino acid sequence of the constant domain of their heavy chains, intact antibodies can be assigned to different "classes." There are five major classes of intact antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these can be further divided into "subclasses" (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA, and IgA2. The heavy chain constant domains that correspond to the different classes of antibodies are called α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.

[0222] BRIEF DESCRIPTION OF THE DRAWINGS Embodiments and experiments illustrating the principles of the present disclosure will now be discussed with reference to the accompanying drawings. The present disclosure includes combinations of the described aspects and preferred features unless such combinations are expressly disallowed or explicitly avoided. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. Aspects and embodiments of the present disclosure are illustrated by way of example with reference to the accompanying drawings. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this disclosure are incorporated herein by reference. Unless the context requires otherwise, throughout this specification, including the following claims, the term "comprises" and variations thereof are understood to mean the inclusion of a recited integer, step, or group of integers or steps, but not the exclusion of any integer, step, or group of integers or steps. As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Ranges can be expressed herein as "about" from one particular value and / or from another particular value. When such a range is expressed, another embodiment includes the one particular value and / or the other particular value. Similarly, when values ​​are expressed as approximations, using "about," it will be understood that the particular value forms another embodiment.

[0223] Some embodiments Several specific embodiments of the present disclosure are described below.

[0224] 1. Selecting an individual suitable for treatment with ADCx19, ADCT-402, or ADCT-402 a method of selecting a patient who has previously been treated with idelalisib or copanlisib, The individual is selected for treatment with ADCx19 or ADCT-402. 2. A method for selecting an individual suitable for treatment with ADCx19 or ADCT-402, , individuals currently receiving idelalisib or copanlisib were randomly assigned to receive ADCx19 or ADCT-402. The method of choice for treatment. 3. Treatment or further treatment with idelalisib or copanlisib refractory An individual who is 3. The method according to claim 1 or 2, selected from the group consisting of: 4. A method for treating a condition in an individual, said method comprising: (i) selecting an individual suitable for treatment by the method according to any one of 1 to 3; t (ii) administering to the individual an effective amount of ADCx19 or ADCT-402; A method comprising: 5. In addition, idelalisib or copanlisib in combination with ADCx19 or ADCT-402 5. The method of claim 4, comprising administering 6. A method for treating a condition in an individual, comprising administering to an individual an effective amount of ADCx19 or ADCT-402 and an injectable antibody. administering delalisib or copanlisib to said individual. 7. The method according to claim 6, wherein the individual is selected for treatment by the method according to any one of claims 1 to 3. How to post. 8. ADCx19 or The method according to any one of 5 to 7, comprising administering ADCT-402. 9. The method according to any one of 1 to 8, wherein the treatment further comprises administering a chemotherapeutic agent. method. 10. The method of any one of 1 to 9, wherein the individual is a human. 11. The individual has symptoms or has been diagnosed with symptoms, whichever is higher: 1-10 1. The method according to claim 1. 12. The individual is identified as having CD19 or CD19+ tumor-associated non-tumor cells (e.g., CD19+ infiltrating cells). 12. The method according to claim 11, wherein the patient has or has been determined to have a cancer that manifests. 13. The individual is currently undergoing treatment with idelalisib or copanlisib, any of 1 to 12. 10. The method according to claim 1. 14. Individual has received treatment with idelalisib or copanlisib, 1-13 10. The method according to any one of claims 1 to 9. 15. The individual is currently undergoing treatment or further treatment with idelalisib or copanlisib. refractory 15. The method according to any one of 1 to 14, wherein 16. Treatment is ADCx19 or ADCT-402 or idelalisib or copanlisib 16. The method according to any one of claims 1 to 15, wherein the efficacy of the method is higher than that of a monotherapy with either one of the anticoagulants or the anticoagulant. method. 17. The method of any one of 1 to 16, wherein the condition is a proliferative disease. 18. The method of claim 17, wherein the symptom is cancer. 19. The condition is a proliferative disorder, e.g., diffuse large B-cell lymphoma (DLBCL), Follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic lymphoma (CLL) Non-Hodgkin's lymphoma, including marginal zone B-cell lymphoma (MZBL), and Hairy Cell Leukemia (HCL), Hairy Cell Leukemia Variant (HCL-v), and Philadelphia Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL) 18 selected from the group including leukemias such as acute lymphoblastic leukemia (ALL) such as leukemias with ... The method described below. ADCx19 or ADCT-402 used in any of methods 20.4 to 19. 21. ADCx19 or ADC for use in the treatment method described in any one of paragraphs 4 to 19. A composition comprising T-402. 22. Idelalisib or copanlisib used in any of methods 5 to 19. 23. A composition containing idelalisib or copanlisib for use in any of methods 5 to 19. . 24. Use of ADCx19 or ADCT-402 in the manufacture of a medicament for treating a disease in an individual. The use, wherein the treatment includes any of the methods 4 to 19. 25. Use of idelalisib or copanlisib in the manufacture of a medicament for treating a disease in an individual. The treatment includes any one of methods 5 to 19. 26. The following: a first agent comprising ADCx19 or ADCT-402; instructions for administering the first drug by the method of any one of 1 or 4 to 19. A kit including: a package insert; 27. Furthermore, the following: 27. The kit of 26, comprising: a second agent comprising idelalisib or copanlisib. --------------------- The following paragraphs describe some specific aspects of the anti-CD19 ADC plus secondary agent of the present disclosure. The following describes an embodiment of the present invention: 1. Select individuals suitable for treatment with ADCx19, ADCT-402, or ADCT-402. 1. A method of selecting a therapeutically effective amount of bendamustine, bortezomib, lenalidomide, or copanli Individuals previously treated with sib were selected for treatment with ADCx19 or ADCT-402. A way to choose. 2. A method for selecting an individual suitable for treatment with ADCx19 or ADCT-402, , the individual is undergoing treatment with bendamustine, bortezomib, lenalidomide, or copanlisib and selected for treatment with ADCx19 or ADCT-402. 3. The individual has received treatment with bendamustine, bortezomib, lenalidomide, or copanlisib or the method according to 1 or 2, selecting said individual if resistant to further treatment. 4. A method for treating a condition in an individual, said method comprising: (i) selecting an individual suitable for treatment by the method according to any one of 1 to 3; t (ii) administering to the individual an effective amount of ADCx19 or ADCT-402; Including, a method. 5. In addition, bendamustine, bortezomib, lenalidomide or copanlisib and ADC 5. The method according to claim 4, further comprising administering in combination with x19 or ADCT-402. 6. A method for treating a condition in an individual, comprising administering an effective amount of ADCx19 or ADCT-402 and a vector. administering to said individual ramustine, bortezomib, lenalidomide or copanlisib. A method comprising: 7. The method according to claim 6, wherein the individual is selected for treatment by the method according to any one of claims 1 to 3. How to post. 8. Prior to, or after, bendamustine, bortezomib, lenalidomide, or copanlisib and then administering ADCx19 or ADCT-402. The method according to any one of claims 1 to 5. 9. The method according to any one of 1 to 8, wherein the treatment further comprises administering a chemotherapeutic agent. method. 10. The method of any one of 1 to 9, wherein the individual is a human. 11. The individual has symptoms or has been diagnosed with symptoms, whichever is higher: 1-10 1. The method according to claim 1. 12. The individual is identified as having CD19 or CD19+ tumor-associated non-tumor cells (e.g., CD19+ infiltrating cells). 12. The method according to claim 11, wherein the patient has or has been determined to have a cancer that manifests. 13. The individual has not received treatment with bendamustine, bortezomib, lenalidomide, or copanlisib. 13. The method according to any one of 1 to 12, wherein the patient is undergoing treatment with 14. The individual has not received treatment with bendamustine, bortezomib, lenalidomide, or copanlisib. 14. The method according to any one of 1 to 13, wherein the patient has been receiving treatment with 15. The individual has not received treatment with bendamustine, bortezomib, lenalidomide, or copanlisib. 15. The method according to any one of 1 to 14, wherein the patient is resistant to a previous or further treatment. 16. Treatment is ADCx19 or ADCT-402, or bendamustine, bortezomib, or Compared with monotherapy using either mirabegron, lenalidomide, or copanlisib alone 16. The method according to any one of 1 to 15, which has high efficacy. 17. The method of any one of 1 to 16, wherein the condition is a proliferative disease. 18. The method of claim 17, wherein the symptom is cancer. 19. The condition is a proliferative disorder, e.g., diffuse large B-cell lymphoma (DLBCL), Follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic lymphoma (CLL) Non-Hodgkin's lymphoma, including marginal zone B-cell lymphoma (MZBL), and Hairy Cell Leukemia (HCL), Hairy Cell Leukemia Variant (HCL-v), and Philadelphia Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL) 18 selected from the group including leukemias such as acute lymphoblastic leukemia (ALL) such as leukemias with ... The method described below. ADCx19 or ADCT-402 used in any of methods 20.4 to 19. 21. ADCx19 or ADCT-, used in the treatment method according to any one of 4 to 19. 402, a composition comprising: Bendamustine, bortezomib, lenalidomide or Copanlisib. 23. Bendamustine, bortezomib, lenalidomide, or A composition comprising copanlisib or copanlisib. 24. Use of ADCx19 or ADCT-402 in the manufacture of a medicament for treating a disease in an individual. The use, wherein the treatment includes any of the methods 4 to 19. 25. Bendamustine, bortezomib, lenalidomide in the manufacture of a medicament for treating a disease in an individual. Use of domide or copanlisib, wherein the treatment includes any of methods 5 to 19. use. 26. The following: a first agent comprising ADCx19 or ADCT-402; instructions for administering the first drug by the method of any one of 1 or 4 to 19. Includes package insert; Includes a kit. 27. In addition, one of the following: bendamustine, bortezomib, lenalidomide or copanlisib 27. The kit of 26, comprising a secondary agent comprising:

[0225] Description of the Invention (1) 1. A method for selecting an individual suitable for treatment with an anti-CD19 ADC, comprising: If the individual has been treated with a 3K agent, the individual is considered eligible for treatment with an anti-CD19 ADC. Choose, how. 2. A method for selecting an individual suitable for treatment with an anti-CD19 ADC, comprising: and selecting the individual for treatment with an anti-CD19 ADC if the individual is currently undergoing treatment with a 3K agent. . 3. The individual is undergoing treatment or further treatment with the anti-PI3K agent. refractory If 3. The method according to claim 1 or 2, wherein the method is selected for treatment. 4. A method for treating a condition in an individual, said method comprising: (i) selecting an individual suitable for treatment by the method according to any one of 1 to 3; t (ii) administering to the individual an effective amount of an anti-CD19 ADC; Including, a method. 5. The method of treatment further comprises administering the anti-CD19 ADC in combination with an anti-PI3K agent. , 4. 6. A method for treating a condition in an individual, comprising administering an effective amount of a CD19 ADC and an anti-PI3K agent to a subject. to said individual. 7. The method according to claim 6, wherein the individual is selected for treatment by the method according to any one of claims 1 to 3. How to post. 8. Administering an anti-CD19 ADC before, during, or after administration of an anti-PI3K agent The method according to any one of 5 to 7, comprising: 9. The method according to any one of 1 to 8, wherein the treatment further comprises administering a chemotherapeutic agent. method. 10. The method of any one of 1 to 9, wherein the individual is a human. 11. The individual has symptoms or has been diagnosed with symptoms, whichever is higher: 1-10 1. The method according to claim 1. 12. The individual is identified as having CD19 or CD19+ tumor-associated non-tumor cells (e.g., CD19+ infiltrating cells). 12. The method according to claim 11, wherein the patient has or has been determined to have a cancer that manifests. 13. The method of any one of 1 to 12, wherein the individual is undergoing treatment with an anti-PI3K agent. . 14. Any one of 1 to 13, in which the individual has previously received treatment with an anti-PI3K agent. The method described below. 15. The individual is currently undergoing treatment with an anti-PI3K agent or further treatment. refractory 1 to 14 10. The method according to any one of claims 1 to 9. 16. Treatment is monotherapy using either an anti-CD19 ADC or an anti-PI3K agent alone. 16. The method according to any one of 1 to 15, which has a higher efficacy compared to the method according to 1. 17. The method of any one of 1 to 3, wherein the anti-CD19 ADC is ADCx19. 17a. The method according to any one of 1 to 3, wherein the anti-CD19 ADC is ADCT-402. method. 18. The method of any one of 1 to 16, wherein the condition is a proliferative disease. 19. The method according to claim 18, wherein the symptom is cancer. 20. The condition is a proliferative disorder, e.g., diffuse large B-cell lymphoma (DLBCL), Follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic lymphoma (CLL) Non-Hodgkin's lymphoma, including marginal zone B-cell lymphoma (MZBL), and Hairy Cell Leukemia (HCL), Hairy Cell Leukemia Variant (HCL-v), and Philadelphia Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL) 19 selected from the group including leukemias such as acute lymphoblastic leukemia (ALL) such as leukemias with ... The method described below. 20a. The condition is diffuse large B-cell lymphoma (DLBCL), which may 20. The method according to 19, wherein the DLBCL is relapsed or refractory. 21. PI3K inhibitors include idelalisib, copanlisib, duvelisib, taselisib, and bromide. Palisib, alpelisib, umbralisib, dactolisib, or voxatalisib, 22. The method according to any one of 1 to 21. 22. The method of any one of 1 to 9, wherein the PI3K is idelalisib. 23. The method according to any one of 1 to 9, wherein the PI3K is copanlisib. 24. An anti-CD19 ADC for use in a treatment method according to any one of 4 to 23. 25. A composition comprising an anti-CD19-ADC for use in a treatment method according to any one of 4 to 23. Finished product. 26. An anti-PI3K agent used in a treatment method according to any one of items 5 to 23. 27. A composition comprising an anti-PI3K agent for use in a treatment method according to any one of claims 4 to 23. 28. Use of an anti-CD19 ADC in the manufacture of a medicament for treating a condition in an individual, comprising: The use, wherein the treatment comprises a method according to any one of 4 to 23. 29. Use of an anti-PI3K agent in the manufacture of a medicament for treating a condition in an individual, said treatment comprising: The use of the method according to any one of claims 5 to 23. 30. The following: First agents include anti-CD19 ADCs; a package insert containing instructions for administering the first drug by the method according to any one of claims 4 to 23. Appendix; Includes a kit. 31. Furthermore, the following: a second agent, including an anti-PI3K agent; 31. The kit according to 30, comprising:

[0226] Description of the Invention (2) 1. A method for selecting an individual suitable for treatment with an anti-CD19 ADC, comprising: If the individual has previously been treated with an anti-CD19 ADC, the individual is selected for treatment with the anti-CD19 ADC. How to do it. 2. A method for selecting an individual suitable for treatment with an anti-CD19 ADC, comprising: If the individual is currently undergoing treatment with an anti-CD19 ADC, the individual is selected for treatment with an anti-CD19 ADC. 3. The individual is not eligible for second-line or further treatment. refractory If so, it is selected for treatment. 3. The method according to claim 1 or 2, 4. A method for treating a condition in an individual, said method comprising: (i) selecting an individual suitable for treatment by the method according to any one of 1 to 3; t (ii) administering to the individual an effective amount of an anti-CD19 ADC; Including, a method. 5. The method of treatment further comprises administering the anti-CD19 ADC in combination with a second agent; The method described below. 6. A method for treating a condition in an individual, comprising administering an effective amount of an anti-CD19 ADC and a second agent. to said individual. 7. The method according to claim 6, wherein the individual is selected for treatment by the method according to any one of claims 1 to 3. How to post. 8. Administering an anti-CD19 ADC before, during, or after administration of a second agent The method according to any one of 5 to 7, comprising: 9. The method according to any one of 1 to 8, wherein the treatment further comprises administering a chemotherapeutic agent. method. 10. The method of any one of 1 to 9, wherein the individual is a human. 11. The individual has symptoms or has been diagnosed with symptoms, whichever is higher: 1-10 1. The method according to claim 1. 12. The individual is identified as having CD19 or CD19+ tumor-associated non-tumor cells (e.g., CD19+ infiltrating cells). 12. The method according to claim 11, wherein the patient has or has been determined to have a cancer that manifests. 13. The method of any one of 1 to 13, wherein the individual is undergoing treatment with a second agent. 14. The method of any one of 1 to 13, wherein the individual has been treated with a second agent. 15. The individual is not receiving treatment with a second-line drug or further treatment. refractory Any of 1 to 14 The method according to any one of claims 1 to 5. 16. Treatment is compared with monotherapy with either the anti-CD19 ADC or a second-line agent alone. 16. The method according to any one of 1 to 15, which has higher efficacy compared to the method according to 1. 17. The method of any one of 1 to 3, wherein the anti-CD19 ADC is ADCx19. 17a. The method according to any one of 1 to 3, wherein the anti-CD19 ADC is ADCT-402. method. 18. The method of any one of 1 to 16, wherein the condition is a proliferative disease. 19. The method according to claim 18, wherein the symptom is cancer. 20. The condition is a proliferative disorder, e.g., diffuse large B-cell lymphoma (DLBCL), Follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic lymphoma (CLL) Non-Hodgkin's lymphoma, including marginal zone B-cell lymphoma (MZBL), and Hairy Cell Leukemia (HCL), Hairy Cell Leukemia Variant (HCL-v), and Philadelphia Philadelphia chromosome-positive ALL (Ph+ALL) or Philadelphia chromosome-negative ALL (Ph-ALL) 19 selected from the group including leukemias such as acute lymphoblastic leukemia (ALL) such as leukemias with ... The method described below. 20a. The condition is diffuse large B-cell lymphoma (DLBCL), and in some cases 20. The method according to 19, wherein the DLBCL is relapsed or refractory. 21. The method of any one of 1-21, wherein the secondary agent is bendamustine. 22. The method of any one of 1-20, wherein the second agent is lenalidomide. 23. The method of any one of 1 to 20, wherein the secondary agent is a proteasome inhibitor. . 24. Proteasome inhibitors include bortezomib, carfilzomib, ixazomib, and opioids. 24. The method of 23, wherein the agent is lozomib or salinosporamide A. 25. The method according to 23, wherein the proteasome inhibitor is bortezomib. 26. The method of any one of claims 1 to 20, wherein the second agent is a PARP inhibitor (PARPi). How to do it. 27. PARPi include olaparib, CEP-9722, BMN-673 / talazoparib, Rucaparib, Iniparib / SAR24-550 / BSI-201, Veliparib (ABT- 888), niraparib / MK-4827, BGB-290, 3-aminobenzamide, and 26. The method according to claim 26, selected from E7016. 28. The method according to 26, wherein the proteasome inhibitor is olaparib. 29. An anti-CD19-ADC for use in a treatment method according to any one of 4 to 28. 30. A composition comprising an anti-CD19-ADC for use in a treatment method according to any one of 4 to 28. Finished product. 31. A secondary drug used in a treatment method according to any one of items 5 to 28. 32. A composition comprising a secondary agent for use in a treatment method according to any one of claims 4 to 28. 33. Use of an anti-CD19 ADC in the manufacture of a medicament for treating a condition in an individual, comprising: The use, wherein the treatment comprises a method according to any one of items 4 to 28. 34. Use of a secondary agent in the manufacture of a medicament for treating a condition in an individual, said treatment comprising: Use, including the method according to any one of items 5 to 28. 35. The following: First agents include anti-CD19 ADCs; instructions for administering the first drug by the method of any one of 1 or 4 to 28. Includes package insert; Includes a kit. 36.Furthermore, the following Secondary drugs, including secondary drugs; 36. The kit according to claim 35, comprising:

[0227] [Example] In the following examples: - CD19 expressing cell lines suitable for use in the examples include Ramos, Daudi, Raji, WSU-DLCL and NALM-6 cells. -Disease A-Diffuse large B-cell lymphoma / DLBC is an aggressive non-Hodgkin's lymphoma that arises from B cells in the lymphatic system. It is the largest subgroup of non-Hodgkin's lymphoma. -Disease B-mantle cell lymphoma / MCL is a rare B-cell NHL that most commonly affects men over 60 years of age. The disease is aggressive (fast growing), although in some patients it may progress in a more indolent (slow growing) manner. MCL accounts for approximately 5% of all NHL cases. -Disease C - Follicular lymphoma / FL is a fairly indolent form of NHL that has long survival times but is extremely difficult to cure and may transform into a more aggressive lymphoma. [Example]

[0228] In separate experiments, CD19-expressing cell lines are incubated for 0, 6, 24, and 48 hours with etoposide (negative control) and oxaliplatin (positive control), 1 μg / mL anti-CD19 ADC (CD19-targeting ADC with a PBD dimer warhead), 1 μg / mL anti-CD19 (antibody in the ADC), and 1 μg / mL B12-SG3249 (non-binding control ADC with the same PBD warhead as the anti-CD19 ADC). After incubation, the cells are washed and fed with human dendritic cells (DCs) for an additional 24 hours, after which DC activation is measured by increased surface expression of CD86 on the DC population (measured by flow cytometry) and by measuring DC-mediated release of IL-8 and MIP2. [Example]

[0229] The objective of this study is to evaluate the safety, tolerability, pharmacological and clinical activity of this combination treatment. The cancer types selected for study were: Disease A, Disease B, and Disease C. There is evidence that both drugs are effective as monotherapy, as follows: Anti-CD19 ADCs (see, for example, Patent Documents 1 and 3, WO 2014 / 057122 and WO 2016 / 166307) PI3K inhibitors or second-line agents (see K.S. Peggs et al. 2009, Clinical and Experimental Immunology, 157:9-19 [doi:10.1111 / j.1365-2249.2009.03912.x]) The primary goal of this study is to determine the safety of the drug combination and, if so, to identify appropriate doses and regimens for further testing. The study will also assess whether each combination induces pharmacological changes in tumors that suggest the possibility of clinical benefit. Furthermore, treatment with either an anti-CD19 ADC or a PI3K inhibitor or a second-line agent as a single agent will provide preliminary evidence that the combination may increase response rates and durability of response compared to published data. Each disease group will include a subset of patients previously treated with a PI3K inhibitor or second-line agent to explore whether combination treatments can overcome resistance to the PI3K inhibitor or second-line agent. For each disease group, excluding patients based on approved molecular diagnostic tests is not generally supported, and no specific molecular selection is intended.

[0230] Rationale for setting the anti-CD19 ADC starting dose The previously established RDE for the ADC (ug / kg given every 3 weeks) will be used for all patients in this study. To ensure patient safety, the starting dose used will be below the RDE, but it is the dose that still demonstrated patient benefit in Study ADC1, suggesting that patients enrolled at that dose will derive at least some benefit from participation.

[0231] Rationale for starting dose of PI3K inhibitor or second-line agent The previously established RDE for the PI3K inhibitor or second-line agent (µg / kg given every 3 weeks) will be used for all patients in this study. To ensure patient safety, the starting dose used will be below the RDE, but it is the dose that still demonstrated patient benefit in Study SA1, suggesting that patients enrolled at this dose will derive at least some benefit from participation.

[0232] Objectives and associated endpoints

[0233] [Table 1] [Research Plan] This Phase 1b, multicenter, open-label study will evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of EGFR in combination with an anti-PI3K agent or a second-line agent in patients with disease A, disease B, and disease C. The study will consist of a dose escalation portion followed by a second dose escalation portion. Dose escalation begins with a reduced starting dose of either the ADC and the anti-PI3K agent or second-line agent (compared to the respective recommended Phase II dose or approved dose) to ensure patient safety. The starting dose is 33% (or 50%) of the RDE of each compound. The dose of the anti-PI3K agent or second-line agent is then initially increased until the RDE or approved dose is reached, or a lower dose is administered if necessary for tolerability reasons. The dose of the ADC is then increased until the RDE of the combination treatment is reached. This is shown below:

[0234] [Table 2] If the combination is found to be safe, studies may be conducted in additional patients to confirm safety and tolerability at that dose. The dose of each compound may be further adjusted and / or the regimen may be modified.

[0235] Dose escalation of the combination treatment will be based on a Bayesian logistic regression model (BLRM) based on dose-limiting toxicities (DLTs) observed in the first (or first two) treatment cycles. The use of a BLRM is an established method for estimating the maximum tolerated dose (MTD) / extended recommended dose (RDE) in cancer patients. The adaptive BLRM follows the principle of overdose-controlled escalation (EWOC) to control for the risk of DLTs in future patients participating in the study. The use of Bayesian response adaptive models for small datasets has been approved by the FDA and EMEA (Guideline for Clinical Trials in Small Populations, February 1, 2007) and is supported by extensive literature (Babb et al., 1998; Neuenschwander et al., 2008).

[0236] The investigators and sponsors will decide on new dose combinations at the Dose Escalation Safety Call (DESC) based on a review of patient tolerability and safety information (including the BLRM summary of DLT risks, if applicable), and PK, PD, and preliminary activity information available at the time of the decision.

[0237] Once the MTD / RDE of the combination treatment is determined, an extension portion of this study may be initiated to further evaluate safety, tolerability, and preliminary efficacy.

[0238] Regarding combination with IO, changes in immune infiltration in tumors will also be characterized after combination treatment in the target disease state. Given the available clinical experience with the drugs in this study, it is believed that in many cases the dose of the combination drug can be identified without testing large dose levels or administration schedules. Patients will be instructed to undergo tumor biopsies at baseline and again after approximately two cycles of treatment to assess the pharmacodynamic activity of the combination treatment.

[0239] Regarding IO Combo: The degree of change in tumor infiltration by immune cells, including lymphocytes and macrophages, will contribute to decisions regarding potential benefit. [Dose escalation portion] During the dose-escalation phase of the study, patients will be treated with a fixed intravenous dose of the ADC and an increasing dose of the anti-PI3K agent or second-line agent, after which the ADC dose will be increased (in different cohorts) while the dose of the anti-PI3K agent or second-line agent is held constant.

[0240] Approximately 3-4 patients with Disease A, Disease B, or Disease C are treated in each escalation cohort until the MTD / RDE measurements are determined.

[0241] A 24-hour observation period will be conducted before the second patient is enrolled in dose level 1. The DLT observation period at each dose level is mandated by IO treatment authorities to be either one cycle (3 weeks) or two cycles (6 weeks), after which a decision will be made to move to the next dose level in the next cohort, remain at the current dose level, or taper to the previous dose level. There will be no tapers from dose level 1. Dose escalation will not be permitted.

[0242] Dose escalation will not be permitted at any dose level unless complete DLT information is available for at least two patients by the first cycle. Dose escalation will be determined using mCRM with a target DLT rate of 30% and an equivalence interval of 20% to 35%, with no dose escalation-overdose control (EWOC) or dose skipping.

[0243] Patients will be assigned to actively enrolling cohorts. Dose escalation will be performed for each combination treatment after one cycle of treatment. Safety assessments, including adverse events and laboratory values, will be closely monitored for all enrolled patients to identify DLTs. A single MTD / RDE will be identified; no disease-specific MTD / RDE will be established.

[0244] mCRM is performed for DE under the oversight of the Dose Escalation Steering Committee (DESC). The DESC reviews each escalated dose after reviewing all available safety data. PK data from patients at that dose level and the previous dose level also inform decision-making. The DESC may stop dose escalation prior to determining the MTD based on emerging PK, PD, toxicity, or response data.

[0245] If at least one patient in the study achieves at least a partial response, or if the DESC determines that further evaluation of PK or PD data is necessary to determine an RDE, additional patients may be enrolled to further evaluate safety and tolerability, regardless of dose.

[0246] Dose escalation will be stopped after three consecutive cohorts (or at least six patients) have been randomized to the same dose level. If the MTD is not reached, a recommended dose for escalation (RDE) will be determined. A minimum of six patients must be treated with the combination therapy before determining the MTD / RDE.

[0247] During dose escalation, patients are intended to undergo paired tumor biopsies, which may be analyzed to better understand the relationship between dose and pharmacodynamic activity of the combination treatment.

[0248] [Safety monitoring by the dose escalation steering committee] The DESC, comprised of ADC Therapeutics and the investigators, will continuously review patient safety during DE to determine whether modifications to the dose escalation schedule defined by the mCRM are necessary. In addition to safety observations, pharmacokinetic and / or pharmacodynamic data will also inform decision-making. Intermediate doses may be assigned with the agreement of ADC Therapeutics and the investigators. The DESC may continue to provide oversight during the second period. A formal Data Safety Monitoring Board (DSMB) will not be used.

[0249] [Dose expansion section] Once the MTD / RDE is declared, a dose expansion portion may be initiated. The primary purpose of the expansion portion is to further evaluate the safety and tolerability of the study drug at the MTD / RDE and to obtain a preliminary understanding of the efficacy of the combination treatment compared with existing data on the efficacy of the single agents.

[0250] One of the key exploratory objectives will be to evaluate changes in immune infiltrates within tumors responding to treatment. This will be assessed in paired tumor biopsies taken from patients treated at the MTD / RDE, combining at least 10 evaluable biopsies (biopsy specimens must contain sufficient tumor for analysis). If this is not possible, collection of such biopsies may be discontinued. At least 10-20 patients are planned to be treated in each study arm.

[0251] Multiple different study arms will be established for each disease. A total of nine study arms may be established for dose escalation. If enrollment into any of the arms is not possible, enrollment into that arm may be discontinued before the target of 10-20 cases is reached.

[0252] In each treatment group, there will be a maximum of approximately six patients who have been previously treated with an anti-PI3K or second-line agent and who have progressed on a previous monotherapy (i.e., not a combination therapy). This number could be increased if the combination has the potential to overcome prior resistance to a single dose of the anti-PI3K or second-line agent.

[0253] [Patient population] This study will be conducted in adult patients with advanced disease A, disease B, or disease C, as described above. The investigator or designee must ensure that only patients who meet all of the following inclusion criteria and none of the exclusion criteria will be treated in this study.

[0254] [Selection criteria] Patients eligible for this study must meet all of the following criteria: 1. Written consent must be obtained prior to any procedure 2. Age: 18 3.Patients with advanced / metastatic cancer and measurable disease according to RECIST 1.1 who have progressed despite or are intolerant to standard treatment, or for whom no standard treatment exists. Disease A Disease B Disease C must conform to one of the groups 4.ECOG Performance Status 0-1 (or 2 TBC) 5. TBC: Patients must have a lesion suitable for biopsy and be candidates for tumor biopsy according to the treatment institution's guidelines. Patients must be willing to undergo a new tumor biopsy at baseline and again during the treatment period of this study. 6. Prior treatment with an anti-PI3K agent or second-line agent or related compound (i.e., same MOA) is permitted.

[0255] [Exclusion criteria] Patients eligible for this study must not meet any of the following criteria: 1. History of severe hypersensitivity reaction to other monoclonal antibodies (monoclonal antibodies with the same scaffold as the ADC or the same IO monoclonal antibody, if applicable) 2. Known history of seropositive ADA to monoclonal antibody scaffolds, similar to ADCs 3. Central nervous system (CNS) disease only (if applicable) 4. Evidence of symptomatic CNS metastases or leptomeningeal disease (brain MRI or previously confirmed cerebrospinal fluid (CSF) cytology) Previously treated asymptomatic CNS metastases are permitted if last line of treatment (systemic anticancer therapy and localized radiation therapy) was completed ≥8 weeks prior to the start of treatment, except that the use of low-dose steroids is permitted.

[0256] Patients with isolated dural metastasis are eligible. 5.Patients with laboratory values ​​outside the following ranges: Serum creatinine ≤ 1.5 × ULN (upper limit of normal). If serum creatinine > 1.5, patients must have a creatinine clearance (calculated or measured using the Cockcroft-Gault formula) > 60 mL / min / 1.73 m 2 Eligible if Total bilirubin > 1.5 times ULN, except for cases where total bilirubin > 3.0 times ULN or direct bilirubin > 1.5 times ULN.

[0257] Patients with alanine aminotransferase (ALT) levels >3x ULN, excluding patients with liver tumor infiltration and ALT levels >5x ULN Patients with aspartate aminotransferase (AST) levels >3x ULN, excluding patients with tumor infiltration into the liver. Patients with AST levels >5x ULN are excluded. Absolute neutrophil count <1.0 × 10e9 / L Platelet count <75×10e9 / L Hemoglobin (Hgb) < 8 g / dL Potassium, magnesium, calcium, or phosphate abnormalities >CTCAE grade 1 despite appropriate replacement therapy 6. Cardiac dysfunction or clinically significant cardiac disease, including any of the following: Clinically significant and / or uncontrolled cardiac disease, such as congestive heart failure (NYHA grade III or IV) requiring treatment or uncontrolled hypertension as defined by a systolic blood pressure (SBP) of 160mmHg and / or a diastolic blood pressure (DBP) of 100mmHg, with or without antihypertensive medications Congenital long QT syndrome with QTcF >470 msec (women) or >450 msec (men) on the screening electrocardiogram using Fridericia correction Acute myocardial infarction or unstable angina less than 3 months ago (several months before study enrollment) Valvular disease with clinically significant cardiac dysfunction Symptomatic pericarditis Past or ongoing cardiomyopathy Left ventricular ejection fraction (LVEF) < 40% measured by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan History or presence of clinically significant cardiac arrhythmias, such as ventricular, supraventricular, nodal arrhythmias, or conduction abnormalities (TBC modifier: pacemaker required or not controlled by medical therapy) Atrial fibrillation instability (ventricular response rate >100 bpm) Note: Patients with stable atrial fibrillation may be enrolled if no other cardiac exclusion criteria are met. Complete left bundle branch block (LBBB), bifascicular block Any clinically significant ST-segment and / or T-wave abnormalities 7. Toxicity attributable to prior IO therapy that led to treatment discontinuation. Patients who were adequately treated with medication-associated skin rash or endocrine replacement therapy will not be excluded if the toxicity did not lead to treatment discontinuation. 8. Patients with known or suspected active autoimmune disease. Subjects with vitiligo, type 1 diabetes, residual hypothyroidism due to autoimmune disease requiring only hormone replacement, psoriasis not requiring systemic treatment, or disease not expected to recur in the absence of an external trigger will be permitted to enroll, provided that the trigger can be avoided. 9. Human immunodeficiency virus (HIV), active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection Testing is not required to be eligible. HCV testing should be considered if patients are at risk for undiagnosed HCV (e.g., history of injection drug use). 10. Malignant disease other than that treated in this study. Exceptions to this exclusion include curatively treated malignancies that have not recurred within 2 years prior to study treatment, completely resected basal cell carcinoma and squamous cell skin cancer, malignancies that were considered indolent and did not require treatment, and completely resected carcinoma in situ. 11. Systemic anti-cancer therapy within 2 weeks of the first dose of study drug. For cytotoxic agents with significant delayed toxicity, such as mitomycin C and nitrosoureas, a 4-week washout period is indicated. For patients receiving anti-cancer immunotherapy, such as CTLA-4 antagonists, a 6-week washout period is indicated. 12. Active diarrhea CTCAE grade 2 or diseases accompanied by chronic diarrhea (irritable bowel syndrome, inflammatory bowel disease, etc.) 13. Presence of CTCAE grade 2 toxicity (excluding alopecia, peripheral neuropathy, and ototoxicity; CTCAE grade 3 or higher is excluded) 14. Active infection requiring systemic antibiotic therapy 15. Active ulcer or gastrointestinal bleeding in the upper gastrointestinal tract 16. Active bleeding diathesis or oral antivitamin K drugs (excluding low-dose warfarin and aspirin or equivalent drugs, if INR is 2.0 or less) 17. Active autoimmune disease, motor neuron disease thought to be caused by autoimmunity, and other central nervous system autoimmune diseases 18.Patients who require concomitant use of immunosuppressants or long-term administration of corticosteroids: Replacement-dose steroids in symptoms of hypoadrenalism Topical steroids, inhalants, eye drops, eye drops 19. Use of live vaccines against infectious diseases (influenza, chickenpox, pneumococcus, etc.) within 4 weeks after starting administration of the study drug (use of live vaccines is not permitted throughout the study period) 20. Use of hematopoietic colony-stimulating factors (G-CSF, GMCSF, M-CSF, etc.) (less than 2 weeks before the start of study drug administration). Erythroid stimulating agents may be used as long as they are started at least 2 weeks before the first administration of study drug. 21. Major surgery within 2 weeks of first dose of study drug (NB mediastinoscopy, insertion of a central venous access device, or insertion of a feeding tube are not considered major surgery) 22. Radiation therapy within 2 weeks of the first dose of study drug, excluding palliative radiation therapy to a limited area, such as for the treatment of bone pain or locally painful tumors or masses. Patients must have measurable residual disease that has not been irradiated to allow for evaluation of response to treatment. 23.Participation in an interventional study within 2 weeks of the first administration of the study drug 24. A medical condition that, in the opinion of the investigator, would prevent the patient from participating in the clinical trial due to safety concerns, compliance with clinical trial procedures, or interpretation of study results. 25. Sexually active men who do not use condoms while taking study drug and for 90 days after stopping study treatment and who should not father children during this period. Men who have had a vasectomy should also use condoms to prevent semen-borne drug delivery. 26. Pregnant or lactating women, where pregnancy is defined as a woman's condition after conception until the end of pregnancy, who have a confirmed positive hCG test. In rare cases of endocrine tumors, patients may have hCG levels above the normal range but are not pregnant. In such cases, a repeat serum hCG test (with a non-elevated result) and vaginal / pelvic ultrasound should be performed to rule out pregnancy. After reviewing the results and discussing with medical personnel, the patient may be considered for enrollment in this study. 27. Females of childbearing potential, defined as any female of physiological reproductive potential who is not using a highly effective method of contraception during study drug administration and for 90 days after the last dose of study drug. Highly effective methods of contraception include: Total contraception (if this is consistent with the patient's desired normal lifestyle. Periodic abstinence (e.g., calendar, ovulation, symptom-temperature, post-ovulation methods) and pull-out are not acceptable methods of contraception. Female sterilization (bilateral surgical oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before receiving study treatment. In the case of oophorectomy alone, only if the woman's reproductive status was confirmed by postoperative assessment of hormone levels. Male sterilization (at least 6 months prior to screening). For female patients, the vasectomized male partner must be the patient's only partner. Use of hormonal therapy in combination with oral (estrogen and progesterone), injectable, or implantable intrauterine devices (IUDs) or intrauterine devices (IUSs) or other hormonal contraception of comparable efficacy (failure rate <1%), such as hormonal vaginal rings or transdermal hormonal contraceptive methods.

[0258] If using oral contraceptives, women must have been stable on the same pill for at least 3 months before receiving study medication.

[0259] Women with an appropriate clinical profile (e.g., appropriate age, history of vasomotor symptoms), who have had spontaneous amenorrhea for 12 months, or who have undergone bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks prior, are considered postmenopausal and not of childbearing potential. In the case of oophorectomy alone, women are considered not of childbearing potential only if follow-up evaluation of hormone levels confirms their reproductive status.

[0260] [Dose-limiting toxicity and dose modification guidelines] Dose-limiting toxicity (DLT) is defined as any of the following events that, in the opinion of the investigator, are at least possibly related to the ADC during the 21-day DLT evaluation period. Toxicities clearly and directly related to the primary disease or other etiology are excluded from this definition.

[0261] [Definition of DLT] Hematological DLTs are defined as follows: Grade 3 or 4 febrile neutropenia or neutropenic infection Grade 4 Neutropenia lasting more than 7 days Grade 4 Thrombocytopenia Grade 3 Thrombocytopenia with clinically significant bleeding or Grade 3 Thrombocytopenia requiring platelet transfusion Grade 3 Anemia requiring transfusion Grade 4 Anemia Non-hematological DLT is defined as follows: Grade 4 Non-hematological toxicity Grade 3 Persistence of non-hematological toxicity for more than 3 days despite optimal supportive therapy or medical intervention Hy's Law (when AST and / or ALT exceed 3 times the ULN, bilirubin exceeds 2 times the ULN, there are no initial findings of cholestasis (serum alkaline phosphatase (ALP) activity < 2 times the ULN), and there are no other reasons to explain the combined increase in transaminases and total serum bilirubin, such as viral hepatitis A, B, C, previous or acute liver disease, other drugs that may cause the observed injury, etc.) Grade 3 or higher Hypersensitivity / Transfusion-related reaction (regardless of pre-medication). Grade 3 hypersensitivity / transfusion-related reactions that disappear within 8 hours after onset with appropriate clinical management are not considered DLT A decrease in the ejection fraction of less than 40% or more than 20% from baseline Grade 4 Tumor lysis syndrome (Grade 3 TLS does not constitute DLT unless it leads to irreversible end-organ damage) The following conditions are not considered non-hematological DLT: Grade 3 Fatigue within 7 days Grade 3 Diarrhea, nausea or vomiting without pre-medication that responds to treatment and improves by one or more grades within 3 days for Grade 3 adverse events or within 7 days for Grade 1 or lower adverse events

[0262] An increase in AST or ALT is 5 times or more but 8 times or less the ULN, without an accompanying increase in bilirubin, and decreases to Grade 2 or lower within 5 days after onset

[0263] Grade 3: Serum lipase or serum amylase levels within 7 days without clinical signs or symptoms of pancreatitis Patients who have recovered from or become stable after DLT with appropriate medical management may continue treatment at the discretion of the investigator in consultation with the sponsor.

[0264] [Dose modification] Specific toxicity management guidelines are provided in the table below. The following may provide guidance to investigators for management of events not specified in the table.

[0265] [Table 3] [Example]

[0266] method MTT proliferation assays and IC50 calculations were performed on cell lines exposed to increasing concentrations of ADCx19 for 96 hours. Pearson correlation (r) was calculated for IC50 and cell surface CD19 expression levels (absolute fluorescence quantification using Quantum Simply Cellular microspheres; non-absolute, data from PMID 29298756) and RNA levels (Illumina HT-12 arrays and HTG EdgeSeq Oncology Biomarker Panel, data from PMID 29066507).

[0267] Synergy after 96 hours was assessed by the Chou-Talalay combination index (CI) (synergy CI<0.9, additive CI=0.9-1.1, synergy / no benefit CI>1.1) for two activated B-cell-like (ABC) DLBCLs (OCI-LY-3, TMD8) and two germinal center (GCB) DLBCLs (VAL, WSU-DLCL2).

[0268] result The ADCx19 median IC50 was 4 pM (95% CI, 2-10 pM) in 48 B-cell lymphoma lines and >800-fold higher in nine T-cell lymphoma lines (3.5 nM; 95% CI, 0.8-11 nM), as predicted based on CD19 expression patterns. Focusing on B-cell lymphomas, in vitro activity correlated with target expression measured at the cell surface protein level [(absolute quantification, n = 40, r -0.37 P 0.02; non-absolute quantification, n = 42, -0.48, P 0.001) and RNA level [(array, n = 39, -0.69 P < 0.001; HTG, n = 31, -0.73 P 0.001)]. In DLBCL, the presence of BCL2 and MYC translocations or TP53 inactivation did not affect sensitivity to ADCx19.

[0269] ADCx19 was then combined with either the PI3K inhibitors idelalisib or copanlisib in GCB and ABCDLBCL cell lines. The combination of ADCx19 and idelalisib resulted in synergistic activity in all cell lines. Synergy was observed with copanlisib (OCI-LY-3, VAL) in half of the cell lines tested.

[0270] The data is shown in the table below.

[0271] Combination treatment: ADCx19+idelalisib Cell line: OCI-LY3 RRID Cell Accession Identifier: CVCL_8800

[0272] [Table 4] Cell line: TMD8 RRID Cell Accession Identifier: CVCL_A442 Reference: Tohda et al., Leuk. Res. 30:1385-1390(52006)30:1385-1390(2006) Cell line: VAL RRID Cell Accession Identifier: CVCL_1819

[0273] [Table 5] Cell line: WSU-DLCL2 RRID cell accession identifier: CVCL_1902

[0274] [Table 6] Combination treatment: ADCx19 + copanlisib Cell line: OCI-LY3 RRID Cell Accession Identifier: CVCL_8800

[0275] [Table 7] Cell line: TMD8 RRID Cell Accession Identifier: CVCL_A442 Reference: Tohda et al., Leuk. Res. 30:1385-1390(2006) Cell line: VAL RRID Cell Accession Identifier: CVCL_1819

[0276] [Table 8] Cell line: WSU-DLCL2 RRID cell accession identifier: CVCL_1902

[0277] [Table 9] conclusion The potent single-agent in vitro anti-lymphoma activity of ADCx19 correlates with its target expression, supporting ongoing clinical trials in relapsed / refractory DLBCL. Data on the novel idelalisib and copanlisib combination demonstrate plausible clinical synergy. [Example]

[0278] method Cell lines were exposed to increasing concentrations of ADCx19 for 96 hours using MTT proliferation assays and IC50 values ​​were calculated. Pearson correlation (r) was calculated for IC50 values ​​and cell surface CD19 expression levels (absolute fluorescence quantification using Quantum Simply Cellular microspheres; non-absolute data, PMID 29298756) and RNA levels (Illumina HT-12 arrays and HTG EdgeSeq Oncology Biomarker Panel, PMID 29066507). Synergy after 96 hours was assessed by the Chou-Talalay combination index (CI) (synergy CI < 0.9, additive CI 0.9-1.1, synergy / futile CI > 1.1) for two activated B-cell-like (ABC) DLBCLs (OCI-LY-3, TMD8) and two germinal center (GCB) DLBCLs (VAL, WSU-DLCL2).

[0279] result The median IC50 of ADCx19 in 48 B-cell lymphoma lines was 4 pM (95% CI, 2-10 pM) and was over 800-fold higher in 9 T-cell lymphoma lines (3.5 nM; 95% CI, 0.8-11 nM), as expected based on the CD19 expression pattern. Focusing on B-cell lymphomas, the in vitro activity of ADCx19 correlated with target expression measured at both the cell surface protein level (absolute quantification, n = 40, r -0.37 P 0.02; non-absolute quantification, n = 42, - 0.48 P 0.001) and the RNA level (array, n = 39, - 0.69 P < 0.001; HTG, n = 31, - 0.73 P 0.001). In DLBCL, the presence of BCL2 and MYC translocations or TP53 inactivation did not affect sensitivity to ADCx19.

[0280] ADCx19 was then combined with the proteasome inhibitor bortezomib (ABC only), the chemotherapy agent bendamustine, and the PARP inhibitor olaparib in GCB and ABCDLBCL cell lines. Synergy with bendamustine was achieved in all cell lines except OCI-LY-3. Synergy was observed in half of the cell lines tested with olaparib (VAL, WSU-DLCL2). In two ABC DLBCLs (TMD8, OCI-LY-3), the addition of bortezomib and lenalidomide to ADCT-402 did not confer benefit.

[0281] The data is shown in the table below. Combination: ADCx19+bendamustine Cell line: OCI-LY3 RRID Cell Accession Identifier: CVCL_8800

[0282] [Table 10] Cell line: TMD8 RRID Cell Accession Identifier: CVCL_A442 Reference: Tohda et al., Leuk. Res. 30:1385-1390(2006)

[0283] [Table 11] Cell line: VAL RRID Cell Accession Identifier: CVCL_1819

[0284] [Table 12] Cell line: WSU-DLCL2 RRID cell accession identifier: CVCL_1902

[0285] [Table 13] Combination: ADCx19 + olaparib Cell line: OCI-LY3 RRID Cell Accession Identifier: CVCL_8800

[0286] [Table 14] Cell line: TMD8 RRID Cell Accession Identifier: CVCL_A442 Reference: Tohda et al., Leuk. Res. 30:1385-1390(2006) Cell line: VAL RRID Cell Accession Identifier: CVCL_1819

[0287] [Table 15] Cell line: WSU-DLCL2 RRID cell accession identifier: CVCL_1902

[0288] [Table 16] ADCx19 + bortezomib combination Cell line: OCI-LY3 RRID Cell Accession Identifier: CVCL_8800

[0289] [Table 17] Cell line: TMD8 RRID Cell Accession Identifier: CVCL_A442 Reference: Tohda et al., Leuk. Res. 30:1385-1390(2006)

[0290] [Table 18] ADCx19 + lenalidomide combination Cell line: OCI-LY3 RRID Cell Accession Identifier: CVCL_8800

[0291] [Table 19] Cell line: TMD8 RRID Cell Accession Identifier: CVCL_A442 Reference: Tohda et al., Leuk. Res. 30:1385-1390(2006)

[0292] [Table 20] conclusion The potent single-agent in vitro anti-lymphoma activity of ADCx19 correlates with its target expression and supports ongoing clinical trials in relapsed / refractory DLBCL. Data on the novel idelalisib and copanlisib combination demonstrate plausible clinical synergy.

Claims

1. A pharmaceutical composition comprising an anti-CD19 antibody-drug conjugate (ADC) for treating cancer in an individual, said treatment comprising administering to said individual effective amounts of an anti-CD19 ADC and a PI3K inhibitor or a PARP inhibitor; wherein the anti-CD19 ADC has the following structure: 【Chemical 1】 where Ab is an antibody that binds to CD19. where: the PI3K inhibitor is idelalisib or copanlisib; the PARP inhibitor is olaparib, and The pharmaceutical composition, wherein the cancer is B-cell lymphoma.

2. The anti-CD19 ADC comprises: (i) a VH domain having a sequence represented by SEQ ID NO: 1, 2, 3, 4, 5, or 6, and a VL domain having a sequence represented by SEQ ID NO: 7, 8, 9, 10, 11, or 12; (ii) a VH domain having the sequence represented by SEQ ID NO: 1 and a VL domain having the sequence represented by SEQ ID NO: 7; (iii) a VH domain having the sequence represented by SEQ ID NO: 2 and a VL domain having the sequence represented by SEQ ID NO: 8; (iv) a VH domain having the sequence represented by SEQ ID NO: 3 and a VL domain having the sequence represented by SEQ ID NO: 9; (v) a VH domain having the sequence represented by SEQ ID NO: 4 and a VL domain having the sequence represented by SEQ ID NO: 10; (vi) a VH domain having the sequence represented by SEQ ID NO: 5 and a VL domain having the sequence represented by SEQ ID NO: 11; or (vii) a VH domain having the sequence represented by SEQ ID NO: 6 and a VL domain having the sequence represented by SEQ ID NO: 12; The pharmaceutical composition of claim 1 , comprising an antibody having:

3. The pharmaceutical composition of claim 1, wherein the anti-CD19 ADC is ADCT-402.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein the treatment comprises administering the anti-CD19 ADC before, during, or after administration of the PI3K inhibitor or the PARP inhibitor.

5. The individual is: (i) has B-cell lymphoma or has been diagnosed with B-cell lymphoma; (ii) have or have been diagnosed with a B-cell lymphoma that expresses CD19 or CD19+ tumor-associated non-tumor cells; (iii) currently undergoing treatment with idelalisib, copanlisib, or olaparib; (iv) have previously received treatment with idelalisib, copanlisib, or olaparib; (v) is refractory to treatment with idelalisib, copanlisib, or olaparib or to further treatments; The pharmaceutical composition according to any one of claims 1 to 4.

6. The B-cell lymphoma is one of: (i) a non-Hodgkin's lymphoma selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic lymphoma (CLL), and marginal zone B-cell lymphoma (MZBL); or (ii) diffuse large B-cell lymphoma (DLBCL), optionally wherein the DLBCL is relapsed or refractory; The pharmaceutical composition according to any one of claims 1 to 5.

7. A pharmaceutical composition for treating B-cell lymphoma, comprising an anti-CD19-ADC, for use in combination with at least one compound selected from the group consisting of a PI3K inhibitor and a PARP inhibitor, wherein the anti-CD19-ADC and the PI3K inhibitor or the PARP inhibitor are defined in any one of claims 1 to 6, and the B-cell lymphoma is defined in claim 6.

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