Dosage regimes for administration of Anti-CD19 ADC

Abstract

To provide a pharmaceutical composition for treating CD19-positive lymphoma.SOLUTION: The present invention provides a pharmaceutical composition comprising an ADC which binds to CD19 (CD19-ADC) and rituximab, where the CD19-ADC is a compound of formula I bound to an antibody that binds to CD19 (RL1' is a linker for connection to the antibody).SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to novel dosing regimens for treating pathological conditions such as cancer with antibody drug conjugates (ADCs). In particular, the disclosure relates to the administration of ADCs that bind to CD19 (CD19-ADCs). [Background technology]

[0002] antibody therapy Antibody therapy has been established to provide targeted treatment for cancer, immune disorders, and angiogenic disorders (Carter, P. (2006) Nature Reviews Immunology 6:343-357). The use of antibody-drug conjugates (ADCs), i.e., immunoconjugates, for the local delivery of cytotoxic or cytostatic agents, i.e., drugs that kill or inhibit tumor cells, in the treatment of cancer aims to deliver the drug moiety to the tumor and accumulate within the tumor cells, but systemic administration of these unconjugated agents can result in unacceptable levels of toxicity to normal cells (Xie et al (2006) Expert. Opin. Biol. Ther. 6(3):281-291; Kovtun et al (2006) Cancer Res. 66(6):3214-3121; Law et al (2006) Cancer Res. 66(4):2328-2337; Wu et al (2005) Nature Biotech. 23(9):1137-1145; Lambert J. (2005) Current Opin. in Pharmacol. 5:543-549; Hamann P. (2005) Expert Opin. Ther. Patents 15(9):1087-1103, Payne, G. (2003) Cancer Cell 3:207-212, Trail et al (2003) Cancer Immunol. Immunother.52:328-337, Syrigos and Epenetos (1999) Anticancer Research 19:605-614).

[0003] CD19 CD19 is a 95 kDa membrane receptor that is expressed early during B cell differentiation and continues to be expressed until B cells are induced to terminally differentiate (Pezzutto et al. (1987), J. Immunol 138:2793; Tedder et al (1994) Immunol Today 15:437). The CD19 extracellular domain contains two C2-type immunoglobulin (IG)-like domains separated by a smaller disulfide-bonded domain. The CD19 cytoplasmic domain is structurally unique but highly conserved among humans, mice, and guinea pigs (Fujimoto et al., (1998) Semin Immunol. 10:267). CD19 is part of a protein complex found on the cell surface of B lymphocytes. The protein complex includes CD19, CD21 (complement receptor, type 2), CD81 (TAPA-1) and CD225 (Leu-13) (Fujimoto, supra).

[0004] CD19 is a key regulator of transmembrane signaling in B cells. Increases and decreases in cell surface density of CD19 affect B cell development and function, leading to autoimmune or hypogammaglobulinemia diseases. The CD19 complex facilitates B cell responses to antigens in vivo through cross-linking of two distinct signaling complexes found in the membrane of B cells. The two signaling complexes associated with membrane IgM and CD19 activate phospholipase C (PLC) by different mechanisms. Cross-linking of CD19 and the B cell receptor reduces the number of IgM molecules required for PLC activation. CD19 also functions as a specialized adaptor protein for the amplification of Arc family kinases (Hasegawa et al., (2001) J Immunol 167:3190).

[0005] Binding of CD19 has been shown to both enhance and inhibit B cell activation and proliferation, depending on the amount of cross-linking that occurs (Tedder, 1994, Immunol. Today 15:437). CD19 is expressed on over 90% of B cell lymphomas and is predicted to affect lymphoma growth in vitro and in vivo.

[0006] Therapeutic Uses of Anti-CD19 ADCs For example, the efficacy of antibody drug conjugates comprising anti-CD19 antibodies (anti-CD19-ADCs) in the treatment of cancer has been disclosed, see, e.g., WO2014 / 057117 and WO2016 / 166298.

[0007] Research is ongoing with the goal of further improving the efficacy, tolerability, and clinical utility of anti-CD19 ADCs. To this end, the authors have identified clinically beneficial dosing regimens for administering anti-CD19 ADCs. Summary of the Invention

[0008] The authors have developed dosing regimens that improve the efficacy, efficiency and / or tolerability of CD19-ADC treatment in subjects treated with CD19-ADC.Interestingly, it has become clear that the parameters required for optimal efficacy, efficiency and / or tolerability of treatment differ across indication subsets.

[0009] Lymphoma The authors noted that while treating a cohort of subjects with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL) with a single dose of CD19-ADC per 3-week treatment cycle, as described below, repeat dosing every 3 weeks was not well tolerated or was unnecessary at doses of 120 μg / kg or greater. Of 6 responding patients treated with -120 μg / kg (4 complete response, 2 partial response), 4 required at least one dose delay during treatment (3 to 7 treatment cycles) and 2 discontinued treatment due to adverse events. Three patients who were treated with CD19-ADC at 150 μg / kg for 2–3 treatment cycles required dose delays before experiencing side effects, and ultimately were removed from the study due to persistent toxicity. Of six patients treated with -200 μg / kg, five achieved a complete response and one achieved a partial response, although all patients had some evidence of toxicity at the end of the second or third treatment cycle.

[0010] In addition, pharmacokinetic studies have shown that the CD19 ADCs are not rapidly cleared from the bloodstream, and trough concentrations at the end of each 3-week treatment cycle remain at relatively high levels or even increase gradually with each treatment cycle.

[0011] Therefore, the authors speculated that tapering the dose of CD19-ADC and / or increasing the length of each treatment cycle could allow for more effective long-term treatment of lymphoma subjects by providing rational exposure to CD19-ADC to provide efficacy while maximizing long-term tolerability through reduced accumulation of CD19-ADC.

[0012] Thus, part of the subject matter of this disclosure relates to the use of CD19-ADCs in tapered and / or extended dosing regimens to treat proliferative diseases, which are expected to be associated with various clinical advantages, including reduced toxicity and side effects, and thus expanding the treatable population to include subjects who cannot tolerate the side effects of known dosing regimens.

[0013] Preferably, the tapering and / or extended dosing regimes described herein are employed when the proliferative disease is lymphoma. For example, the proliferative disease may be diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic lymphoma (CLL), non-Hodgkin's lymphoma such as Waldenstrom's macroglobulinemia, Burkitt's lymphoma, and marginal zone B-cell lymphoma (MZBL).

[0014] In a first aspect, the disclosure provides a method of treating a proliferative disease in a subject, the method comprising administering to the subject a CD19-ADC, wherein the CD19-ADC is administered to the subject in a tapering and / or extended dosing regimen.

[0015] The CD19-ADC may be an ADCx19 as described herein.

[0016] The term "tapering dosing regimen" is used herein to describe a dosing regimen in which the total dose of CD19-ADC administered in a first treatment cycle (hereinafter referred to as the "starting dose") is greater than the total dose of CD19-ADC administered in one or more subsequent treatment cycles. A tapering dosing regimen is in contrast to a fixed dosing regimen in which the starting dose is the same as the total dose administered in each subsequent treatment cycle (see "Fixed" in Table 1 below).

[0017] In some cases, the dosage is reduced only if the subject has achieved at least stable disease [SD] (i.e., SD or better, such as PR or CR) at the end of the previous treatment cycle.

[0018] Preferably, the starting dose is reduced no more than once during treatment of a subject, in which case the total dose after the dose reduction is referred to hereinafter as the "reduced dose."

[0019] In some cases, the dose is reduced after the first treatment cycle, i.e., the starting dose is administered in the first treatment cycle and the reduced dose is administered in the second or subsequent treatment cycles. The "Tapering 6" dosing regimen in Table 1 is an example of such a dosing regimen.

[0020] In some cases, the dose is reduced after the second treatment cycle, i.e., the starting dose is administered for each of the first and second treatment cycles, and the reduced dose is administered for each of the third and subsequent treatment cycles. The dosing regimes "Taper 3", "Taper 4", "Taper 5" and "Taper 7" in Table 1 are examples of such dosing regimes.

[0021] In some cases, the starting dose is at least 120 μg / kg. In some cases, the starting dose is at least 150 μg / kg (such as at least 200 μg / kg). In some cases, the starting dose is about 120 μg / kg, 150 μg / kg, or 200 μg / kg. In some cases, the reduced dose is about 50% of the starting dose. In some cases, the reduced dose is about 60 μg / kg. In some cases, the reduced dose is about 75 μg / kg. In some cases, the starting dose is about 200 μg / kg and the reduced dose is about 60 μg / kg. In some cases, the starting dose is about 140-160 μg / kg and the reduced dose is about 70-80 μg / kg. In some cases, the starting dose is about 150 μg / kg and the reduced dose is about 75 μg / kg.

[0022] In some cases, each treatment cycle is three weeks in length.

[0023] In some cases, each treatment cycle is six weeks in length.

[0024] The term "extended dosing regimen" is used herein to describe a dosing regimen in which the length of the first treatment cycle (hereinafter "initial cycle length") is shorter than the length of one or more subsequent treatment cycles. An extended dosing regimen is in contrast to a fixed dosing regimen in which the initial cycle length is the same as the length of each subsequent treatment cycle (see "Fixed" in Table 2 below).

[0025] In some cases, the length of a treatment cycle is extended only if the subject achieved at least stable disease [SD] at the end of the previous treatment cycle.

[0026] Preferably, the treatment cycle length is extended no more than once during treatment of a subject, in which case the length of the treatment cycle after extension is referred to hereinafter as the "extended cycle length."

[0027] In some cases, after the first treatment cycle, the cycle length is extended, i.e., the first treatment cycle is the initiation cycle length and each subsequent treatment cycle is an extended cycle length. The "Extended 4" dosing regimen in Table 2 is an example of such a dosing regimen.

[0028] In some cases, after the second treatment cycle, the cycle length is extended, i.e., the first and second treatment cycles are each an initiation cycle length, and each subsequent treatment cycle is an extended cycle length. The "Extended 3" dosing regimen in Table 2 is an example of such a dosing regimen.

[0029] In some cases, the initiation cycle length is 3 weeks. In some cases, the extension cycle length is 6 weeks.

[0030] Preferably, in a tapered and extended dosing regimen, the starting dose is reduced no more than once and the length of the treatment cycle is extended no more than once during the treatment of a subject.

[0031] In some cases, the dosage is reduced and / or the cycle length is extended only if the subject has achieved at least stable disease [SD] at the end of the previous treatment cycle.

[0032] In some cases, the second treatment cycle is followed by a reduced dose and extended cycle length, i.e., the first and second treatment cycles are each at an initial dose and initial cycle length, and each subsequent treatment cycle is at a reduced dose and extended cycle length.

[0033] In some cases, the starting dose is at least 120 μg / kg. In some cases, the starting dose is at least 150 μg / kg (such as at least 200 μg / kg). In some cases, the starting dose is about 120 μg / kg, 150 μg / kg, or 200 μg / kg. In some cases, the reduced dose is about 75 μg / kg. In some cases, the reduced dose is about 60 μg / kg. In some cases, the starting cycle length is 3 weeks and the extended cycle length is 6 weeks. In some cases, the starting dose is about 120 μg / kg, the starting cycle length is 3 weeks, the reduced dose is about 60 μg / kg, and the extended cycle length is 6 weeks. In some cases, the starting dose is about 150 μg / kg, the starting cycle length is 3 weeks, the reduced dose is about 60 μg / kg, and the extended cycle length is 6 weeks. In some cases, the starting dose is about 140-160 μg / kg, the starting cycle length is 3 weeks, the reduced dose is about 70-80 μg / kg, and the extended cycle length is 3 weeks. In some cases, the starting dose is about 150 μg / kg, the starting cycle length is 3 weeks, the reduced dose is about 75 μg / kg, and the extended cycle length is 3 weeks.

[0034] The subject of the present disclosure may be a human.

[0035] The subject of the present disclosure may be cancer or may be determined to be cancer. The subject of the present disclosure may be CD19+ cancer or have CD19+ non-tumor cells (such as CD19+ infiltrating T cells) associated with the tumor, or may be CD19+ cancer or have CD19+ non-tumor cells (such as CD19+ infiltrating cells) associated with the tumor.

[0036] Preferably, the tapering and / or extended dosing regimen described herein is employed when the subject has, is suspected of, or has been diagnosed with lymphoma. For example, the subject may have, is suspected of, or has been diagnosed with non-Hodgkin's lymphoma, such as diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic lymphoma (CLL), Waldenstrom's macroglobulinemia, Burkitt's lymphoma, and marginal zone B-cell lymphoma (MZBL).

[0037] In alternative, less preferred embodiments, the subject may have, be suspected of, or be diagnosed with leukemia, such as hairy cell leukemia (HCL), hairy cell leukemia subtype (HCL-v), and acute lymphoblastic leukemia (ALL), such as Philadelphia chromosome positive ALL (Ph+ALL) or Philadelphia chromosome negative ALL (Ph-ALL).

[0038] The proliferative diseases of the present disclosure may be resistant, relapsed or refractory.

[0039] The subject may have, or may be determined to have, relapsed or refractory B-cell non-Hodgkin's lymphoma (B-NHL).

[0040] In some cases, the subject has been diagnosed with a proliferative disorder of the present disclosure prior to the initiation of treatment with the CD19-ADC.

[0041] In some cases, the methods of the disclosure further include administering a second anti-cancer compound in combination with the CD19-ADC.

[0042] Specifically contemplated are combinations of CD19-ADC and ibrutinib, CD19-ADC and durvalumab, CD19-ADC and rituximab, CD19-ADC and cytarabine, and CD19-ADC and rituximab and cytarabine.

[0043] In some cases, the tapering and / or extended dosing regimes of the present disclosure reduce the toxicity or side effects of treatment as compared to fixed dose level and cycle length regimes.

[0044] In some cases, the tapering and / or extended dosing regimes of the present disclosure improve the efficacy of treatment as compared to fixed dose level and cycle length regimes.

[0045] In some cases, the CD19-ADC is administered intravenously.

[0046] In a second aspect, the disclosure provides a method of reducing toxicity and / or side effects associated with administration of a CD19-ADC to a subject, the method comprising administering the CD19-ADC in a tapering and / or extended dosing regimen as defined herein.

[0047] In a third aspect, the disclosure provides a method of improving the efficacy of a treatment associated with administration of a CD19-ADC to a subject, the method comprising administering the CD19-ADC in a tapering and / or extended dosing regimen as defined herein.

[0048] In a fourth aspect, the present disclosure provides a method for selecting a subject for treatment with a tapering and / or extended dosing regime as described herein, comprising selecting a subject for treatment that expresses CD19 in a tissue of interest.

[0049] In a fifth aspect, the disclosure provides a packaged pharmaceutical comprising a CD19-ADC as described herein, in association with a label or insert that informs the patient that the CD19-ADC should be administered in a tapering and / or extended dosing regimen.

[0050] The present disclosure relates to a first medicament comprising a CD19-ADC, and optionally A package insert or label containing instructions for administering the CD19-ADC in a tapering and / or extended dosing regimen as described herein. Also provided is a kit comprising:

[0051] In a sixth aspect, the present disclosure provides a CD19-ADC as defined herein, for use in a method of treatment as described herein.

[0052] In a seventh aspect, the disclosure provides for the use of a CD19-ADC as defined herein in the preparation of a medicament for use in a method of treatment as described herein.

[0053] leukemia The authors, while treating a cohort of human subjects with relapsed or refractory acute lymphoblastic leukemia (ALL) with a single dose of CD19-ADC in a 3-week treatment cycle, found that in the majority of patients, the plasma concentrations of the ADC were near the lower limit of quantification and that pharmacokinetic (PK) parameters were indistinguishable. These patients showed rapid elimination of the drug early in the course of time. These observations were coupled with the observation that many patients who achieved complete recovery (CR) showed slower elimination of the ADC from plasma, evident by treatment cycle 2.

[0054] The authors therefore sought to modify the dosing regimen to improve the efficacy of treatment with CD19-ADC. Data collected from a wide variety of mouse xenograft models of CD19+ proliferative disease demonstrated that administration of a single dose of CD19-ADC on day 1 of a treatment cycle resulted in effective treatment, whereas administration of the same total dose of AD19-ADC divided into a series of smaller doses resulted in improved levels of mortality (see Figures 2 and 3).

[0055] However, the authors speculated that fractionating the CD19-ADC dose and administering it at shorter intervals throughout the treatment cycle would (1) maintain a more consistent and effective ADC exposure throughout the treatment cycle, and (2) use a higher total dose but with lower peak levels, thereby reducing the toxicity associated with peak exposure levels.

[0056] Without intending to be bound by theory, the use of such split-dose regimens may be particularly beneficial in diseases such as acute leukemia, where the rapid production of circulating blasts acts as an antigen sink for CD19-ADC. This is consistent with several other cases treating leukemia subjects that have explored or adopted split-dose regimens (Frey F, et al. Abstract 7002. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago; Aue G, et al. Haematologica February 2010 95:329-332; Taksin A, et al. Leukemias (2007) 21, 66-71. Published online 19 October 2006).

[0057] Thus, part of the subject matter of this disclosure relates to the use of CD19-ADCs in split-dose regimens for the treatment of proliferative diseases, particularly leukemias. These split-dose regimens are expected to result in a variety of clinical advantages, including improved efficacy, reduced toxicity and side effects, and the resulting expansion of the treatable population to include subjects who cannot tolerate the side effects of known, more adverse dosing regimens.

[0058] Preferably, the split-dose regimens described herein are employed when the proliferative disease is a leukemia, such as hairy cell leukemia (HCL), hairy cell leukemia subtype (HCL-v), and acute lymphoblastic leukemia (ALL), such as Philadelphia chromosome positive ALL (Ph+ALL) or Philadelphia chromosome negative ALL (Ph-ALL).

[0059] In an eighth aspect, the disclosure provides a method of treating a proliferative disease in a subject, the method comprising administering to the subject a CD19-ADC, wherein the CD19-ADC is administered to the subject in a split dose regimen.

[0060] The CD19-ADC may be ADCX19 as described herein.

[0061] The term "split-dose regimen" is used herein to describe a dosing regimen in which the total dose of CD19-ADC administered during a treatment cycle is administered in a series of two or more separate doses during the treatment cycle. The term "split-dose" is used herein to indicate an ADC dose that is a portion of the total ADC dose administered in a treatment cycle. The sum of all split doses delivered in a treatment cycle equals the total dose. A split-dose regimen is in contrast to a "single-dose" dosing regimen in which the total dose of CD19-ADC administered during a treatment cycle is administered as a single dose at the beginning of the treatment cycle.

[0062] Preferably, the total dose of CD19-ADC is administered as equally divided doses at equal intervals throughout the entire treatment cycle. Particularly preferred is administration to subjects once a week. In some cases, the total dose of CD19-ADC is administered in three equally divided doses over a three-week treatment cycle (one divided dose administered once a week). For example, one divided dose is administered on the first, eighth and fifteenth days of the three-week treatment cycle. Further features of the divided administration regime are discussed herein.

[0063] The subject of the present disclosure may be a human. The subject may have or be considered to have cancer. The subject may have CD19+ cancer or have CD19+ non-tumor cells (such as CD19 infiltrating T cells) associated with the tumor, or may have CD19+ cancer or have CD19+ non-tumor cells associated with the tumor.

[0064] Preferably, the split-dose regimens described herein are employed when a subject has, is suspected of, or has been diagnosed with leukemia. For example, the subject may have, is suspected of, or has been diagnosed with hairy cell leukemia (HCL), hairy cell leukemia subtype (HCL-v), and acute lymphoblastic leukemia (ALL), such as Philadelphia chromosome positive ALL (Ph+ALL) or Philadelphia chromosome negative ALL (Ph-ALL).

[0065] In another, less preferred embodiment, the subject may have, suspected or diagnosed with lymphoma, e.g., non-Hodgkin's lymphoma such as diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic lymphoma (CLL), Waldenstrom's macroglobulinemia, Burkitt's lymphoma and marginal zone B-cell lymphoma (MZBL).

[0066] The proliferative disease may be resistant, relapsed or refractory.

[0067] The subject of the present disclosure may have or be considered to have relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).

[0068] In some cases, the subject has been diagnosed with a proliferative disorder of the present disclosure prior to the initiation of treatment with the CD19-ADC.

[0069] In some cases, the methods of the disclosure further include administering a second anti-cancer compound in combination with the CD19-ADC.

[0070] In some cases, the split dosing regimens of the present disclosure reduce the toxicity or side effects of treatment as compared to a single dose per treatment cycle regime.

[0071] In some cases, the split dosing regimes of the present disclosure improve the efficacy of treatment as compared to a single dose per treatment cycle regime.

[0072] In some cases, the CD19-ADC is administered intravenously.

[0073] In a ninth aspect, the disclosure provides a method of reducing toxicity and / or side effects associated with administration of a CD19-ADC to a subject, the method comprising administering the CD19-ADC in a split dose regimen as defined herein.

[0074] In a tenth aspect, the disclosure provides a method of improving the efficacy of a treatment associated with administration of a CD19-ADC to a subject, the method comprising administering the CD19-ADC in a split dose regimen as defined herein.

[0075] In an eleventh aspect, the present disclosure provides a method for selecting a subject for treatment with a split-dose regimen as described herein, comprising selecting a subject that expresses CD19 in a tissue of interest.

[0076] In a twelfth aspect, the disclosure provides a packaged pharmaceutical comprising a CD19-ADC as described herein, in association with a label or insert that informs the patient that the CD19-ADC should be administered in a split dose regimen.

[0077] The present disclosure relates to a first medicament comprising a CD19-ADC, and optionally A package insert or label containing instructions for administering the CD19-ADC in a split-dose regimen as described herein. Also provided is a kit comprising:

[0078] In a thirteenth aspect, the present disclosure provides a CD19 ADC as defined herein for use in a method of treatment as described herein.

[0079] In a fourteenth aspect, the disclosure provides for the use of a CD19-ADC as defined herein in the preparation of a medicament for use in a method of treatment as described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0080] As described in more detail below, the authors hypothesize that CD19-ADCs as defined herein, when administered in tapering and / or extended dosing regimes in the treatment of lymphoma, may exhibit improved efficacy and / or reduced toxicity compared to the efficacy and / or toxicity observed when the ADCs are administered in fixed dose size and treatment cycle length regimes.

[0081] Accordingly, in a first aspect, the disclosure provides a method of treating a proliferative disease in a subject, comprising administering to the subject a CD19-ADC, wherein the CD19-ADC is administered to the subject in a tapering and / or extended dosing regimen.

[0082] Furthermore, the authors speculate that CD19-ADCs as defined herein, when administered in a split dose regimen, may exhibit improved efficacy and / or reduced toxicity in the treatment of leukemia compared to the efficacy and / or toxicity observed when a comparable dose of the ADC is administered as a single dose.

[0083] Accordingly, in an eighth aspect, the disclosure provides a method of treating a proliferative disease in a subject, the method comprising administering to the subject a CD19-ADC, wherein the CD19-ADC is administered to the subject in a split dose regimen.

[0084] These findings provide further utility for CD19-ADCs as described above and suggest new therapeutic contexts for use, for example, in association with patient populations that are more sensitive to CD19-ADC toxicity or that require higher doses of CD19-ADC to be effectively treated.

[0085] Anti-CD19 ADC As used herein, the term "CD19-ADC" refers to an ADC in which the antibody moiety is an anti-CD19 antibody. The term "PBD-ADC" refers to an ADC in which the drug moiety is a pyrrolobenzodiazepine (PBD) warhead. The term "anti-CD19-ADC" refers to an ADC in which the antibody moiety is an anti-CD19 antibody and the drug moiety is a PBD warhead.

[0086] The ADC is L-(D L ) p wherein D L is a group of formula I or II: [ka] [ka] During the ceremony, L is an antibody (Ab) that is an antibody that binds to CD19, When there is a double bond between C2' and C3', R 12teeth, (ia) optionally, halo, nitro, cyano, ether, carboxy, ester, C 1-7 Alkyl, C 3-7 Heterocyclyl and bis-oxy-C 1-3 C substituted with one or more substituents selected from the group consisting of alkylene 5-10 Aryl groups, (ib)C 1-5 Saturated aliphatic alkyl, (ic)C 3-6 saturated cycloalkyl, (id) a group: [ka] R 21 , R 22 and R 23 Each of these is independent of H, C 1-3 Saturated alkyl, C 2-3 Alkenyl, C 2-3 alkynyl and cyclopropyl; R 12 A group having a total of 5 or less carbon atoms in the group, (ie) a group [ka] R 25a and R 25b one of which is H and the other is phenyl, optionally substituted by a group selected from halo, methyl, methoxy, pyridyl, and thiophenyl; and (if) the group [ka] R 24 But, H, C 1-3 Saturated alkyl, C 2-3 Alkenyl, C 2-3 A group selected from alkynyl, cyclopropyl, phenyl, optionally substituted by a group selected from halo, methyl, methoxy, pyridyl, and thiophenyl. is selected from the group consisting of When there is a single bond between C2' and C3', R 12 is the following group: [ka] R 26a and R 26b are independent, H, F, C 1-4 Saturated alkyl, C 2-3 alkenyl, the alkyl and alkenyl groups being optionally selected from 1-4 Alkylamide and C 1-4 or R 26a and R 26b When one of the groups is H, the other group is a nitrile and C 1-4 alkyl esters, R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR', nitro, Me3Sn, and halo; R and R′ are independently optionally substituted C 1-12 Alkyl group, C 3-20 Heterocyclyl groups and C 5-20 aryl groups; R 7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR', nitro, Me3Sn, and halo; R” is C 3-12 It is an alkylene group, the chain of which may contain one or more heteroatoms, e.g., O, S, NR N2 (R N2 is H or C 1-4 alkyl), and / or may be interrupted by aromatic rings, e.g. benzene or pyridine, Y and Y' are selected from O, S or NH; R 6’ is R 6 And, R 7’ is R 7 And, R9’ is R 9 are selected from the same group as In formula I, R L1’ is a linker for linking to an antibody (Ab), R 11a OH, OR A (R A is C 1-4 alkyl), and SO z M, z is 2 or 3, and M is a pharma- ceutically acceptable monovalent cation; R 20 and R 21 are taken together to form a double bond between the nitrogen atom and the carbon atom to which they are attached, or R 20 H and R C are selected from R C is a capping group, R 21 OH, OR A and S.O. z M is selected from When a double bond exists between C2 and C3, R 2 teeth, (ia) optionally, halo, nitro, cyano, ether, carboxy, ester, C 1-7 Alkyl, C 3-7 Heterocyclyl and bis-oxy-C 1-3 C substituted with one or more substituents selected from the group consisting of alkylene 5-10 Aryl groups, (ib)C 1-5 Saturated aliphatic alkyl, (ic)C 3-6 saturated cycloalkyl, (id) a group: [ka] R 11 , R 12 and R 13 Each of these is independent of H, C 1-3 Saturated alkyl, C 2-3Alkenyl, C 2-3 alkynyl and cyclopropyl; R 2 A group having a total of 5 or less carbon atoms in the group, (ie) a group [ka] R 15a and R 15b one of which is H and the other is phenyl, optionally substituted by a group selected from halo, methyl, methoxy, pyridyl, and thiophenyl; and (if) the group [ka] R 14 But, H, C 1-3 Saturated alkyl, C 2-3 Alkenyl, C 2-3 A group selected from alkynyl, cyclopropyl, phenyl, optionally substituted by a group selected from halo, methyl, methoxy, pyridyl, and thiophenyl. is selected from the group consisting of When there is a single bond between C2 and C3, R 2 is the following group: [ka] R 16a and R 16b are independent, H, F, C 1-4 Saturated alkyl, C 2-3 alkenyl, the alkyl and alkenyl groups being optionally selected from 1-4 Alkylamide and C 1-4 or R 16a and R 16b When one of the groups is H, the other group is a nitrile and C 1-4 alkyl esters, In formula II, R 22 is a group of formula IIIa, IIIb or IIIc: (a) [ka] (Wherein, A is C 5-7 is an aryl group, (i)Q 1 is a single bond, and Q 2 is a single bond and -Z-(CH2) n -, where Z is selected from a single bond, O, S and NH, and n is 1 to 3; or (ii)Q 1 is -CH=CH-, and Q 2 is a single bond) (b) [ka] (In the formula, R C1 , R C2 and R C3 are independently H and unsubstituted C 1-2 alkyl) (c) [ka] (wherein Q is OR L2’ , S.R. L2’ and N.R. N -R L2’ are selected from R N is selected from H, methyl and ethyl X is OR L2’ , S.R. L2’ , CO2-R L2’ , C.O.R. L2’ , NH-C(=O)-R L2’ , NHNH-R L2’ , CONHNH-R L2’ , [ka] , [ka] , NR N R L2’ and R is selected from the group including N H and C 1-4 is selected from the group consisting of alkyl, R L2’ is a linker for linking to an antibody (Ab), R 10 and R 11 are taken together to 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 S.O. z M is selected from R 30 and R 31 are taken together to 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 S.O. z It is selected from M.

[0087] In some embodiments, LR L1’ or L-R L2’ is the following group, [ka] where the asterisk indicates the binding position to the PBD, Ab is an antibody, and L 1 is a cleavable linker, and A is L 1 is a linking group that links 2 is a covalent bond or together with -OC(=O)- to form a self-immolative linker.

[0088] In some of these embodiments, L 1is enzymatically cleavable.

[0089] Such ADCs have previously been shown to be useful for the treatment of CD19-expressing cancers (see, e.g., WO2014 / 057117, which is incorporated by reference in its entirety).

[0090] The term "anti-CD19-ADC" may include any of the embodiments described in WO2014 / 057117. In particular, in preferred embodiments, an ADC of the disclosure may have the following chemical structure: [ka] In the formula, Ab is a CD19 antibody and DAR is 1 to 8.

[0091] The antibodies of the disclosure may comprise a VH domain having a sequence according to any one of SEQ ID NOs: 1, 2, 3, 4, 5 or 6, and optionally further comprise a VL domain having a sequence according to any one of SEQ ID NOs: 7, 8, 9, 10, 11 or 12.

[0092] In some embodiments, the antibody portion of the anti-CD19-ADC is an antibody comprising a VH domain having the sequence of SEQ ID NO:1 and a VL domain having the sequence of SEQ ID NO:7, a VH domain having the sequence of SEQ ID NO:2 and a VL domain having the sequence of SEQ ID NO:8, a VH domain having the sequence of SEQ ID NO:3 and a VL domain having the sequence of SEQ ID NO:9, a VH domain having the sequence of SEQ ID NO:4 and a VL domain having the sequence of SEQ ID NO:10, a VH domain having the sequence of SEQ ID NO:5 and a VL domain having the sequence of SEQ ID NO:11, or a VH domain having the sequence of SEQ ID NO:6 and a VH domain having the sequence of SEQ ID NO:12.

[0093] In a preferred embodiment, an antibody of the present disclosure comprises a VH domain having a sequence according to SEQ ID NO: 2. In a preferred embodiment, an antibody of the present disclosure comprises a VL domain having a sequence according to SEQ ID NO: 8.

[0094] In a preferred embodiment, an antibody of the disclosure comprises a VH domain and a VL domain, wherein the VH domain has the sequence of SEQ ID NO:2 and the VL domain has the sequence of SEQ ID NO:8.

[0095] The VH domain and VL domain(s) may pair to form an antibody antigen-binding site that binds CD19.

[0096] In some embodiments, the antibodies of the disclosure are intact antibodies comprising a VH domain and a VL domain, wherein the VH and VL domains have the sequences of SEQ ID NO:2 and SEQ ID NO:8.

[0097] In some embodiments, the antibody of the disclosure is an antibody comprising a heavy chain having the sequence of SEQ ID NO:13 and a light chain having the sequence of SEQ ID NO:14.

[0098] In some embodiments, the antibodies of the disclosure are fully human monoclonal IgG1 antibodies, preferably IgG1, κ.

[0099] In some embodiments, the antibody of the disclosure is the RB4v1.2 antibody described in WO2014 / 057117.

[0100] In one aspect, the antibodies of the disclosure are as described herein, modified (or further modified) as described below. In some embodiments, the antibodies of the disclosure are humanized, deimmunized, or resurfaced versions of the antibodies disclosed in the present invention.

[0101] The most preferred anti-CD19 ADC for use in embodiments of the present disclosure is ADCX19, as described herein below.

[0102] 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 binding to CD19. This CD19-specific antibody directs 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 within the target cell. The released PBD dimers inhibit transcription in a sequence-selective manner, either by direct inhibition of RNA polymerase or by blocking the interaction of associated transcription factors. The PBD dimers form covalent crosslinks that do not distort the DNA double helix and are not recognized by nucleotide excision repair factors, thereby allowing for a longer shelf life (Hartley 2011). When DNA replication forks reach these DNA cross-links, they cause strand breaks, leading to the induction of apoptosis.

[0103] ADCx19 has the following chemical structure: [ka]

[0104] Ab represents the RB4v1.2 antibody (an antibody having the VH sequence of SEQ ID NO: 2 and the VL sequence of SEQ ID NO: 8). ADCx19 was synthesized as described in WO2014 / 057117 (RB4v1.2-E) and has a DAR (drug antibody ratio) of typically 2±0.3.

[0105] Binding to CD19 As used herein, "binds to CD19" is used to refer to an antibody of the disclosure that binds to CD19 with higher affinity than a non-specific partner such as bovine serum albumin (BSA, GenBank Accession No. CAA76847, Version No. CAA76847.1 GI:3336842, Archive Last Updated: Jan. 7, 2011 at 2:30 PM). In some embodiments, an antibody of the disclosure has a binding constant (K a ) at least 2x, 3x, 4x, 5x, 10x, 20x, 50x, 100x, 200x, 500x, 1000x, 2000x, 5000x, 10 4 Double, 10 5 Double or 10 6 The antibodies of the present disclosure can bind to CD19 with high affinity. For example, in some embodiments, the antibodies of the present disclosure bind to CD19 with an affinity constant that is about 10 times higher. -6 M or less (1×10 -6 Below, 1×10 -7 Below, 1×10 -8 Below, 1×10 -9 Below, 1×10 -10 Below, 1×10 -11 Below, 1×10 -12 Below, 1×10- 13 Less than or equal to 10 -14 (e.g.) K D and can bind to CD19.

[0106] In some embodiments, the CD19 polypeptide corresponds to GenBank Accession No. NP_001171569, Version No. NP_001171569.1 GI:296010921 (Record Last Updated: 10 Sep. 2012 at 12:43 AM). In one embodiment, the nucleic acid encoding the CD19 polypeptide corresponds to GenBank Accession No. NM_001178098, Version No. NM_001178098.1 GI:296010920 (Record Last Updated: 10 Sep. 2012 at 12:43 AM). In some embodiments, the CD19 polypeptide corresponds to Uniprot / Swiss-Prot Accession No. P15391.

[0107] Tapering and / or extended dosing regimens The term "tapering dosing regimen" is used herein to describe a dosing regimen in which the total dose of CD19-ADC administered in a first treatment cycle (hereinafter referred to as the "starting dose") is greater than the total dose of CD19-ADC administered in one or more subsequent treatment cycles. A tapering dosing regimen is in contrast to a fixed dosing regimen (see "Fixed" in Table 1 below) in which the starting dose is the same as the total dose administered in each subsequent treatment cycle.

[0108] As used herein, the term "total dose" is used to describe the total amount of ADC administered during one treatment cycle.

[0109] A subject's tapering dosing regimen may consist of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more treatment cycles. In some cases, a dosing regimen is terminated when a subject achieves CR. In some cases, a dosing regimen is terminated when a subject experiences DLT. In some cases, a dosing regimen is considered to be terminated when dosing needs to be delayed beyond the length of the previous treatment cycle.

[0110] In tapering dosing regimes, the starting dose may be reduced no more than once, no more than twice, or no more than three times during the dosing regime. In cases where the starting dose is reduced more than once, each reduction may be the same or different amount. The total dose may be kept constant for one, two, three or more treatment cycles before the dose reduction (see, e.g., Table 1 below). [Table 1] Table 1

[0111] In some cases, the dosage is reduced only if the subject has achieved at least stable disease [SD] at the end of the previous treatment cycle.

[0112] In some cases, the starting dose is at least about 10 μg / kg, 20 μg / kg, 30 μg / kg, 40 μg / kg, 50 μg / kg, 60 μg / kg, 70 μg / kg, 80 μg / kg, 90 μg / kg, 100 μg / kg, 110 μg / kg, 120 μg / kg, 130 μg / kg, 140 μg / kg, 150 μg / kg, 160 μg / kg, 170 μg / kg, 180 μg / kg, 190 μg / kg, or 200 μg / kg. In some cases, the starting dose is at least 120 μg / kg. In some cases, the starting dose is at least 150 μg / kg (such as at least 200 μg / kg).

[0113] In some cases, the starting dose is about 10 μg / kg, 20 μg / kg, 30 μg / kg, 40 μg / kg, 50 μg / kg, 60 μg / kg, 70 μg / kg, 80 μg / kg, 90 μg / kg, 100 μg / kg, 120 μg / kg, 150 μg / kg, 200 μg / kg, 250 μg / kg, 300 μg / kg, 350 μg / kg, 400 μg / kg, 450 μg / kg, 500 μg / kg, 550 μg / kg or 600 μg / kg. In some cases, the starting dose is 1-10 μg / kg, 11-20 μg / kg, 21-30 μg / kg, 31-40 μg / kg, 41-50 μg / kg, 51-60 μg / kg, 61-70 μg / kg, 71-80 μg / kg, 81-90 μg / kg, 91-100 μg / kg, 101-120 μg / kg, 121-140 μg / kg, 141-160 μg / kg, 161-180 μg / kg, 181-200 μg / kg, 201-220 μg / kg, 221-240 μg / kg, 241-260 μg / kg, 251-260 μg / kg, 261-270 μg / kg, 271-280 μg / kg, 281-290 μg / kg, 291-300 μg / kg, 311-320 μg / kg, 331-340 μg / kg, 341-360 μg / kg, 351-370 μg / kg, 361-380 μg / kg, 371-390 μg / kg, 381-400 μg / kg, 391-410 μg / kg, 421-420 μg / kg, 431-440 μg / kg, 441-450 μg / kg, 451-460 μg / kg, 471-480 μg / kg, 471-490 μg / kg, 481-490 μg / kg, 491-500 μg / kg, 511-520 μg / kg, 53 kg, 261~280μg / kg, 281~300μg / kg, 301~320μg / kg, 321~340μg / kg, 341~360μg / kg, 361~380μg / kg, 381~400μg / kg, 401~420μg / kg, 421~440 μg / kg, 441-460μg / kg, 461-480μg / kg, 481-500μg / kg, 501-520μg / kg, 521-540μg / kg, 541-560μg / kg, 561-580μg / kg or 581-600μg / kg.

[0114] In some cases, the starting dose is about 120 μg / kg, 150 μg / kg, or 200 μg / kg. In some cases, the starting dose is about 140-160 μg / kg. In some cases, the starting dose is about 150 μg / kg.

[0115] In some cases, each dose reduction reduces the dosage by at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or at least 95%. In some cases, each dose reduction reduces the dosage by about 50%.

[0116] Preferably, the starting dose is reduced no more than once during treatment of a subject, in which case the total dose after the dose reduction is hereinafter referred to as the "reduced dose."

[0117] In some cases, the dose is reduced after the first treatment cycle, i.e., the starting dose is administered in the first treatment cycle and the reduced dose is administered in the second or subsequent treatment cycles. The "Tapering 6" dosing regimen in Table 1 is an example of such a dosing regimen.

[0118] In some cases, the dose is reduced after the second treatment cycle, i.e., the starting dose is administered for each of the first and second treatment cycles, and the reduced dose is administered for each of the third and subsequent treatment cycles. The dosing regimes "Taper 3", "Taper 4", "Taper 5" and "Taper 7" in Table 1 are examples of such dosing regimes.

[0119] In some cases, the reduced dose is about 10 μg / kg, 15 μg / kg, 20 μg / kg, 25 μg / kg, 30 μg / kg, 35 μg / kg, 40 μg / kg, 45 μg / kg, 50 μg / kg, 55 μg / kg, 60 μg / kg, 65 μg / kg, 70 μg / kg, 75 μg / kg, 80 μg / kg, 85 μg / kg, 90 μg / kg, 95 μg / kg, 100 μg / kg, 120 μg / kg, 150 μg / kg, 200 μg / kg, 250 μg / kg or 300 μg / kg. In some cases, the reduced dose is 1-10 μg / kg, 11-20 μg / kg, 21-30 μg / kg, 31-40 μg / kg, 41-50 μg / kg, 51-60 μg / kg, 61-70 μg / kg, 71-80 μg / kg, 81-90 μg / kg, 91-100 μg / kg, 101-120 μg / kg, 121-140 μg / kg, 141-160 μg / kg, 161-180 μg / kg, 181-200 μg / kg, 201-220 μg / kg, 221-240 μg / kg, 241-260 μg / kg, 261-280 μg / kg, or 281-300 μg / kg.

[0120] In some cases, the reduced dose is 60 μg / kg.

[0121] In some cases, the reduced dose is about 70-80 μg / kg, in some cases, the reduced dose is 75 μg / kg.

[0122] In some cases, the length of each treatment cycle is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks or 9 weeks.

[0123] In some cases, each treatment cycle is 3 weeks in length. In some cases, each treatment cycle is 6 weeks in length.

[0124] The term "extended dosing regimen" is used herein to describe a dosing regimen in which the length of the first treatment cycle (hereinafter referred to as the "initial cycle length") is shorter than the length of one or more subsequent treatment cycles. An extended dosing regimen is in contrast to a fixed dosing regimen (see "Fixed" in Table 2 below) in which the initial cycle length is the same as the length of each subsequent treatment cycle.

[0125] A subject's tapering dosing regimen may consist of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 treatment cycles. In some cases, a dosing regimen is terminated when a subject achieves CR. In some cases, a dosing regimen is terminated when a subject experiences DLT. In some cases, a dosing regimen is considered terminated when dosing needs to be delayed beyond the length of the previous treatment cycle.

[0126] In an extended dosing regimen, the treatment cycle length may be extended no more than once, no more than twice, or no more than three times during the dosing regimen. In cases where the cycle length is extended more than once, the length of the extensions may be the same or different each time. The treatment cycle length may be kept constant for one, two, three or more treatment cycles prior to the extension (see, for example, Table 2 below). [Table 2] Table 2

[0127] In some cases, the treatment cycle length is extended only if the subject achieved at least stable disease [SD] at the end of the previous treatment cycle.

[0128] Preferably, the dose is administered as a single dose on day 1 of a treatment cycle. Thus, for example, a subject beginning a "fixed" dosing regimen as described above may be dosed on days 1, 22, 43, etc., until the regimen is discontinued.

[0129] Following this pattern, subjects beginning the "Extended 3" dosing regimen described above may be dosed on Day 1-(+3 weeks) → Day 22-(+3 weeks) → Day 43-(+6 weeks) → Day 85-(+6 weeks) → Day 127, etc., until the regimen is discontinued. However, preferably, "Day 1" of the first treatment cycle of the extended cycle length is delayed so that the time elapsed between "Day 1" of the last cycle of the short treatment cycles and "Day 1" of the first treatment cycle of the extended cycle length is the same as the length of the extended treatment cycle. Thus, in a preferred dosing pattern for the "Extended 3" dosing regimen, subjects are dosed on Day 1-(+3 weeks) → Day 22-(+3 weeks) → -(delayed by +3 weeks) → Day 64-(+6 weeks) → Day 106-(+6 weeks) → Day 148, etc., until the regimen is discontinued.

[0130] In some cases, the initiation cycle length is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks or 9 weeks.

[0131] In some cases, the initial cycle length is 3 weeks.

[0132] In some cases, each extension of the cycle length extends the treatment cycle length by at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or at least 100%. In some cases, each extension of the cycle length extends the treatment cycle length by 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks or 6 weeks.

[0133] Preferably, the treatment cycle length is extended no more than once during treatment of a subject, in which case the treatment cycle length after extension is referred to hereinafter as the "extended cycle length."

[0134] In some cases, after the first treatment cycle, the cycle length is extended, i.e., the first treatment cycle is the initiation cycle length and each subsequent treatment cycle is an extended cycle length. The "Extended 4" dosing regimen in Table 2 is an example of such a dosing regimen.

[0135] In some cases, after the second treatment cycle, the cycle length is extended, i.e., each of the first and second treatment cycles is an initiation cycle length, and each treatment cycle thereafter is an extended cycle length. The "Extended 3" dosing regimen in Table 2 is an example of such a dosing regimen.

[0136] In some cases, the extended cycle length is 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks or 12 weeks.

[0137] In some cases, the initiation cycle length is 3 weeks. In some cases, the extended cycle length is 6 weeks. In some cases, the initiation cycle length is 3 weeks and the extended cycle length is 6 weeks.

[0138] The dosing regime may be tapered, extended, or both tapered and extended.

[0139] Tapering and extending dosing regimens incorporate both of these elements as described herein.

[0140] In some cases, the dosage is reduced and / or the length of a treatment cycle is extended only if the subject has achieved at least stable disease [SD] at the end of the previous treatment cycle.

[0141] Preferably, in a tapered and extended dosing regimen, the starting dose is reduced no more than once and the treatment cycle length is extended no more than once during treatment of a subject.

[0142] In some cases, the first treatment cycle is followed by a reduced dose and extended cycle length, i.e., a starting dose and initial cycle length for the first treatment cycle, and a reduced dose and extended cycle length for each subsequent treatment cycle.

[0143] In some cases, the second treatment cycle is followed by a reduced dose and extended cycle length, i.e., an initial dose and initial cycle length for each of the first and second treatment cycles, and a reduced dose and extended cycle length for each treatment cycle thereafter.

[0144] In some cases, the starting dose is at least about 10 μg / kg, 20 μg / kg, 30 μg / kg, 40 μg / kg, 50 μg / kg, 60 μg / kg, 70 μg / kg, 80 μg / kg, 90 μg / kg, 100 μg / kg, 110 μg / kg, 120 μg / kg, 130 μg / kg, 140 μg / kg, 150 μg / kg, 160 μg / kg, 170 μg / kg, 180 μg / kg, 190 μg / kg, or 200 μg / kg. In some cases, the starting dose is at least 120 μg / kg. In some cases, the starting dose is at least 150 μg / kg (such as at least 200 μg / kg).

[0145] In some cases, the starting dose is about 10 μg / kg, 20 μg / kg, 30 μg / kg, 40 μg / kg, 50 μg / kg, 60 μg / kg, 70 μg / kg, 80 μg / kg, 90 μg / kg, 100 μg / kg, 120 μg / kg, 150 μg / kg, 200 μg / kg, 250 μg / kg, 300 μg / kg, 350 μg / kg, 400 μg / kg, 450 μg / kg, 500 μg / kg, 550 μg / kg or 600 μg / kg. In some cases, the starting dose is 1-10 μg / kg, 11-20 μg / kg, 21-30 μg / kg, 31-40 μg / kg, 41-50 μg / kg, 51-60 μg / kg, 61-70 μg / kg, 71-80 μg / kg, 81-90 μg / kg, 91-100 μg / kg, 101-120 μg / kg, 121-140 μg / kg, 141-160 μg / kg, 161-180 μg / kg, 181-200 μg / kg, 201-220 μg / kg, 221-240 μg / kg, 241-260 μg / kg, 251-260 μg / kg, 261-270 μg / kg, 271-280 μg / kg, 281-290 μg / kg, 291-300 μg / kg, 311-320 μg / kg, 331-340 μg / kg, 341-360 μg / kg, 351-370 μg / kg, 361-380 μg / kg, 371-390 μg / kg, 381-400 μg / kg, 391-410 μg / kg, 421-420 μg / kg, 431-440 μg / kg, 441-450 μg / kg, 451-460 μg / kg, 471-480 μg / kg, 471-490 μg / kg, 481-490 μg / kg, 491-500 μg / kg, 511-520 μg / kg, 53 kg, 261~280μg / kg, 281~300μg / kg, 301~320μg / kg, 321~340μg / kg, 341~360μg / kg, 361~380μg / kg, 381~400μg / kg, 401~420μg / kg, 421~440 μg / kg, 441-460μg / kg, 461-480μg / kg, 481-500μg / kg, 501-520μg / kg, 521-540μg / kg, 541-560μg / kg, 561-580μg / kg or 581-600μg / kg.

[0146] In some cases, the reduced dose is about 10 μg / kg, 15 μg / kg, 20 μg / kg, 25 μg / kg, 30 μg / kg, 35 μg / kg, 40 μg / kg, 45 μg / kg, 50 μg / kg, 55 μg / kg, 60 μg / kg, 65 μg / kg, 70 μg / kg, 75 μg / kg, 80 μg / kg, 85 μg / kg, 90 μg / kg, 95 μg / kg, 100 μg / kg, 120 μg / kg, 150 μg / kg, 200 μg / kg, 250 μg / kg or 300 μg / kg. In some cases, the reduced dose is 1-10 μg / kg, 11-20 μg / kg, 21-30 μg / kg, 31-40 μg / kg, 41-50 μg / kg, 51-60 μg / kg, 61-70 μg / kg, 71-80 μg / kg, 81-90 μg / kg, 91-100 μg / kg, 101-120 μg / kg, 121-140 μg / kg, 141-160 μg / kg, 161-180 μg / kg, 181-200 μg / kg, 201-220 μg / kg, 221-240 μg / kg, 241-260 μg / kg, 261-280 μg / kg, or 281-300 μg / kg.

[0147] In some cases, the initiation cycle length is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks or 9 weeks.

[0148] In some cases, the extended cycle length is 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks or 12 weeks.

[0149] In some cases, the starting dose is about 120 μg / kg, 150 μg / kg, or 200 μg / kg. In some cases, the starting dose is about 140-160 μg / kg. In some cases, the starting dose is about 150 μg / kg. In some cases, the reduced dose is about 60 μg / kg. In some cases, the reduced dose is about 70-80 μg / kg. In some cases, the reduced dose is about 75 μg / kg. In some cases, the starting cycle length is 3 weeks and the extended cycle length is 6 weeks. In some cases, the starting dose is about 120 μg / kg, the starting cycle length is 3 weeks, the reduced dose is about 60 μg / kg, and the extended cycle length is 6 weeks. In some cases, the starting dose is about 150 μg / kg, the starting cycle length is 3 weeks, the reduced dose is about 60 μg / kg, and the extended cycle length is 6 weeks.

[0150] In some particularly preferred cases, the starting dose is about 140-160 μg / kg, the starting cycle length is 3 weeks, the reduced dose is about 70-80 μg / kg, and the extended cycle length is 3 weeks (i.e., the regime is tapered but not extended).

[0151] In some particularly preferred cases, the starting dose is about 150 μg / kg, the starting cycle length is 3 weeks, the reduced dose is about 75 μg / kg, and the extended cycle length is 3 weeks (i.e., the regime is tapered but not extended).

[0152] In some particularly preferred cases, the dosing regimens of the present disclosure are as shown in the table below, where [+21] indicates that a reduced dose of 75 μg / kg may be repeated every 3 weeks for as many treatment cycles as deemed appropriate by the medical practitioner administering the ADC. [Table 3]

[0153] Split-dose regimens The term "split-dose regimen" is used herein to describe a dosing regimen in which the total dose of CD19-ADC administered during a treatment cycle is administered in a series of two or more separate doses during the treatment cycle. The term "split-dose" is used herein to indicate an ADC dose that is a portion of the total ADC dose administered in a treatment cycle. The sum of all split doses delivered in a treatment cycle equals the total dose. A split-dose regimen is in contrast to a "single-dose" dosing regimen in which the total dose of CD19-ADC administered during a treatment cycle is administered as a single dose at the beginning of the treatment cycle.

[0154] For example, in an example of a single dose administration regimen of CD19-ADC, 100% of the total dose of CD19-ADC administered during a treatment cycle is administered on day 1 of a three-week treatment cycle. The subject is then monitored throughout the cycle, and the subject's response level is used to determine whether the treatment cycle should be repeated, discontinued, or modified. In contrast, a split administration regimen may include administering only 33% of the total dose of ADC administered during a treatment cycle on day 1 of a three-week treatment cycle, followed by 33% on day 8, and the final 33% on day 15.

[0155] The total administered dose may be divided into any number of doses, which number is determined according to the clinical requirements of the subject. For example, the total administered dose may be divided into 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses.

[0156] The CD19-ADC dose in each split administration may be the same or different. Thus, for example, a total dose of 100 units of ADC may be delivered in three split doses, which may be delivered as (1×50 units, 1×30 units, and 1×20 units) or (3×33 1 / 3 units). Preferably, all split doses contain the same amount of CD19-ADC, i.e., all split doses are of equal magnitude.

[0157] The time interval between each divided dose and the next divided dose may be the same as or different from the time interval between the previous divided dose and the current divided dose.Preferably, the time interval between each divided dose and the next divided dose is the same as the time interval between the previous divided dose and the current divided dose.That is, preferably, the administration of the divided doses is equally spaced throughout the entire treatment cycle.An example of such periodic administration is administration of three divided doses on days 1, 8 and 15 of a three-week (i.e., 21-day) treatment cycle.

[0158] The length of the treatment cycle can vary depending on the pharmacokinetics (PK) of the CD19-ADC and the clinical requirements of the subject. The treatment cycle can be 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or 9 weeks. Preferably, the treatment cycle is 3 weeks or 6 weeks, with 3 weeks being particularly preferred.

[0159] The total dose of CD19-ADC administered during a treatment cycle can vary according to the clinical requirements of the subject.For example, the total dose can be about 10 μg / kg, 20 μg / kg, 30 μg / kg, 40 μg / kg, 50 μg / kg, 60 μg / kg, 70 μg / kg, 80 μg / kg, 90 μg / kg, 100 μg / kg, 120 μg / kg, 150 μg / kg, 200 μg / kg, 250 μg / kg, 300 μg / kg, 350 μg / kg, 400 μg / kg, 450 μg / kg, 500 μg / kg, 550 μg / kg or 600 μg / kg. In some cases, the total dose is 1-10 μg / kg, 11-20 μg / kg, 21-30 μg / kg, 31-40 μg / kg, 41-50 μg / kg, 51-60 μg / kg, 61-70 μg / kg, 71-80 μg / kg, 81-90 μg / kg, 91-100 μg / kg, 101-120 μg / kg, 121-140 μg / kg, 141-160 μg / kg, 161-180 μg / kg, 181-200 μg / kg, 201-220 μg / kg, 221-240 μg / kg, 241-260 μg / kg, 251-260 μg / kg, 261-270 μg / kg, 271-280 μg / kg, 281-290 μg / kg, 291-300 μg / kg, 311-320 μg / kg, 331-340 μg / kg, 341-360 μg / kg, 351-370 μg / kg, 361-380 μg / kg, 371-390 μg / kg, 381-400 μg / kg, 391-410 μg / kg, 391-420 μg / kg, 391-430 μg / kg, 391-440 μg / kg, 391-450 μg / kg, 391-460 μg / kg, 391-470 μg / kg, 391-480 μg / kg, 391-490 μg / kg, 391-500 μg / kg, 39 g, 261~280μg / kg, 281~300μg / kg, 301~320μg / kg, 321~340μg / kg, 341~360μg / kg, 361~380μg / kg, 381~400μg / kg, 401~420μg / kg, 421~440μ g / kg, 441-460μg / kg, 461-480μg / kg, 481-500μg / kg, 501-520μg / kg, 521-540μg / kg, 541-560μg / kg, 561-580μg / kg or 581-600μg / kg.

[0160] The size of the split doses will depend on the total dose of CD19-ADC administered during a treatment cycle, the number of split doses into which the total dose is divided, and the relative size of the split doses. In some cases, each split dose is an equal size dose. In some cases, the split dose is about 3 μg / kg, 10 μg / kg, 20 μg / kg, 30 μg / kg, 40 μg / kg, 50 μg / kg, 60 μg / kg, 70 μg / kg, 80 μg / kg, 90 μg / kg, 100 μg / kg, 110 μg / kg, 120 μg / kg, 130 μg / kg, 140 μg / kg, 150 μg / kg, 160 μg / kg, 170 μg / kg, 180 μg / kg, 190 μg / kg, or 200 μg / kg. In some cases, the divided doses are 1-10 μg / kg, 11-20 μg / kg, 21-30 μg / kg, 31-40 μg / kg, 41-50 μg / kg, 51-60 μg / kg, 61-70 μg / kg, 71-80 μg / kg, 81-90 μg / kg, 91-100 μg / kg, 101-110 μg / kg, 111-120 μg / kg, 121-130 μg / kg, 131-140 μg / kg, 141-150 μg / kg, 151-160 μg / kg, 161-170 μg / kg, 171-180 μg / kg, 181-190 μg / kg, or 191-200 μg / kg.

[0161] Preferably, the total dose of CD19-ADC is administered as equally divided doses at equal intervals throughout the treatment cycle. It is particularly preferred that the subject is administered once a week. In a preferred case, each divided dose is 40-60 μg / kg, such as 45-55 μg / kg. In a particularly preferred case, each divided dose is 50 μg / kg.

[0162] In some cases, the total dose of CD19-ADC is administered in three equal divided doses over a three week treatment cycle, with the divided doses administered once a week, e.g., on days 1, 8, and 15 of the three week treatment cycle.

[0163] Disorders to be treated Therapies described herein include those that have the utility of anti-cancer therapy. In particular, in certain embodiments, the therapies of the present disclosure include antibodies conjugated to PBD drug moieties, i.e., toxins, i.e., antibodies covalently linked by linkers. When the drug is not conjugated to an antibody, the PBD drug has cytotoxic activity. Thus, the biological activity of the PBD drug moiety is modulated by conjugation to an antibody. The antibody drug conjugates (ADCs) of the present disclosure can selectively deliver an effective dose of a cytotoxic agent to tumor tissue, thereby improving selectivity, i.e., expanding the therapeutic window.

[0164] Thus, in one aspect, the disclosure provides a method of therapy comprising administering a therapeutic ADC that binds CD19, comprising selecting a subject based on expression of CD19.

[0165] In one aspect, the disclosure provides a packaged ADC for use in a therapy, the packaged ADC comprising a label specifying that the therapy is suitable for use in a subject determined to be suitable for such use. The label may specify that the therapy is suitable for use in a subject who expresses CD19, i.e., is CD19+.

[0166] The label may specify that the ADC is administered in tapered and / or extended dosing regimens as described herein. The label may specify that the subject has a particular type of cancer, such as a lymphoma, such as B-cell non-Hodgkin's lymphoma (B-NHL), and optionally, the lymphoma is relapsed or refractory. Examples of NHL lymphomas include diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic lymphoma (CLL), Waldenstrom's macroglobulinemia, Burkitt's lymphoma, and marginal zone B-cell lymphoma (MZBL).

[0167] The label may specify that the ADC is administered in a split-dose regimen as described herein. The label may specify that the subject has a particular type of cancer, such as a hematologic disease, and optionally, the B-ALL is relapsed or refractory. Examples of leukemia include hairy cell leukemia (HCL), hairy cell leukemia subtype (HCL-v), and acute lymphoblastic leukemia (ALL), such as Philadelphia chromosome positive ALL (Ph+ALL) or Philadelphia chromosome negative ALL (Ph-ALL), B-cell lineage acute lymphoblastic leukemia (B-ALL).

[0168] The proliferative disease treated by the methods disclosed herein may be CD19+. However, as described herein, in the practice of the present disclosure, at least some of the cells at the target location (typically a neoplasm) may be CD19-positive, or may be CD19-positive at low levels. For example, in the target neoplasm, for example, less than 80%, 70%, 60%, 50%, 30%, 20%, 10%, or 5% of the cells may be CD19-positive. In some cases where the disease is a leukemia, such as B-ALL, CD19+ is defined as 5% or more of the leukemic blast cells in the bone marrow (aspirate or biopsy specimen) expressing CD19, as determined by an approved clinical laboratory.

[0169] In some cases, the CD19+ve cells are tumor infiltrating cells. In some cases, the neoplasm or neoplastic cells are or are present in a blood cancer. In some cases, the neoplasm or neoplastic cells are or are present in a solid tumor. It is understood that "solid tumor" in this disclosure includes solid blood cancers such as lymphoma (Hodgkin's lymphoma or non-Hodgkin's lymphoma), which are discussed in more detail below.

[0170] Other solid tumors may be neoplasms (including non-hematological cancers) infiltrated by CD-19 positive cells.

[0171] In some cases, the neoplasm or neoplastic cells are malignant. In some cases, the neoplasm or neoplastic cells are metastatic.

[0172] The therapies described herein may be used to treat proliferative disorders. The term "proliferative disorder" refers to unwanted or uncontrolled cell proliferation of unwanted, excessive or abnormal cells, such as neoplastic or hypertrophic growth, whether in vitro or in vivo.

[0173] Any type of cell may be treated, including, but not limited to, cells of the lung, gastrointestinal tract (including, e.g., intestine, colon), breast (breast), ovary, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin. It is contemplated that the therapy of the present disclosure may be used to treat various diseases or disorders characterized by, for example, overexpression of tumor antigens. Exemplary conditions of hyperproliferative disorders include benign or malignant tumors, leukemia, hematological malignancies, and lymphatic malignancies. Others include neuronal disorders, glial cell disorders, astroglial cell disorders, hypothalamic disorders, glandular disorders, macrophage disorders, epithelial disorders, stromal disorders, blastocoel disorders, inflammatory disorders, angiogenic disorders, and immune disorders, including autoimmune disorders and graft-versus-host disease (GVHD).

[0174] Generally, the disease or disorder to be treated is a hyperproliferative disease such as cancer. Examples of cancers to be treated by the present invention include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More specifically, examples of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer (including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma), peritoneal cancer, hepatocellular carcinoma, gastric or abdominal cancer (including gastrointestinal cancer), pancreatic cancer, gliosarcoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, uterine or uterine cancer, salivary gland cancer, kidney cancer or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, melanoma, sarcoma, osteosarcoma, and head and neck cancer.

[0175] Autoimmune diseases that may be treated with a combination therapy include rheumatic disorders (e.g., rheumatoid arthritis, Sjogren's syndrome, scleroderma, lupus, such as SLE and lupus nephritis, polymyositis / dermatomyositis, cryoglobulinemia, antiphospholipid syndrome, and psoriatic arthritis), osteoarthritis, autoimmune gastrointestinal and liver disorders (e.g., inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), autoimmune gastritis and pernicious anemia, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and celiac disease), vasculitis (e.g., ANCA-associated vasculitis, including Churg-Strauss vasculitis, Wegener's granulomatosis, and polyarteritis), autoimmune neuropathies (e.g., multiple sclerosis, opsoclonus-myoclonus syndrome, myasthenia gravis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, and the like). and autoimmune polyneuropathy), kidney disorders (e.g., glomerulonephritis, Goodpasture's syndrome, and Berger's disease), autoimmune skin disorders (e.g., psoriasis, urticaria, hives, pemphigus vulgaris, bullous pemphigoid, and cutaneous lupus erythematosus), blood disorders (e.g., thrombocytopenic purpura, thrombotic thrombocytopenic purpura, post-transfusion purpura, and autoimmune hemolytic anemia), atherosclerosis, uveitis, autoimmune hearing disorders (e.g., inner ear disease and hearing loss), Behcet's disease, Raynaud's syndrome, organ transplantation, graft-versus-host disease (GVHD), and autoimmune endocrine disorders (e.g., diabetes-related autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM), Addison's disease, and autoimmune thyroid diseases (e.g., Graves' disease and thyroiditis)). Among such diseases, more preferred ones include, for example, rheumatoid arthritis, ulcerative colitis, ANCA-associated vasculitis, lupus, multiple sclerosis, Sjogren's syndrome, Graves' disease, IDDM, pernicious anemia, thyroiditis and glomerulonephritis.

[0176] Particularly targeted proliferative disorders include, but are not limited to, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma (BL), mantle cell lymphoma (MCL), chronic lymphocytic lymphoma (CLL), non-Hodgkin's lymphomas including Waldenstrom's macroglobulinemia, Burkitt's lymphoma 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].

[0177] In certain aspects, the subject has diffuse large B-cell lymphoma, or peripheral T-cell lymphoma (including subtypes of anaplastic large cell lymphoma and angioimmunoblastic T-cell lymphoma).

[0178] The diseases of the present disclosure may be resistant, recurrent or refractory. As used herein, recurrent disease refers to a condition in which a previously treated tumor becomes undetectable by conventional imaging techniques and becomes detectable again, and refractory disease refers to a condition in which the cancer continues to grow despite anti-tumor therapy.

[0179] Preferably, when the proliferative disease is lymphoma, the tapering and / or extended dosing regimen described herein is employed.For example, the proliferative disease can be diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic lymphoma (CLL), non-Hodgkin's lymphoma, such as Waldenstrom's macroglobulinemia, Burkitt's lymphoma and marginal zone B-cell lymphoma (MZBL).In some cases, the proliferative disease is relapsed or refractory B-cell non-Hodgkin's lymphoma (B-NHL).

[0180] Preferably, the split-dose regimen described herein is employed when the proliferative disease is a leukemia, such as hairy cell leukemia (HCL), hairy cell leukemia subtype (HCL-v), and acute lymphoblastic leukemia (ALL), such as Philadelphia chromosome positive ALL (Ph+ALL) or Philadelphia chromosome negative ALL (Ph-ALL). In some cases, the proliferative disease is relapsed or refractory B-cell lineage acute lymphoblastic leukemia (B-ALL). In some cases, the proliferative disease is CD19+ acute lymphoblastic leukemia.

[0181] Reduced toxicity and increased efficacy Lymphoma The present disclosure provides a method of reducing toxicity and / or side effects associated with administration of a CD19-ADC to a subject, the method comprising administering the CD19-ADC in a tapering and / or extended dosing regimen as defined herein.

[0182] In some cases, the reduction in toxicity is measured in comparison to a dosing regimen in which the dose level and cycle length are constant. The dose level and cycle length of the fixed comparator regimen may be the same as the starting dose and starting cycle length of the tapering and / or extending regimen.

[0183] In some cases, the level of toxicity is measured as the number of treatment-emergent adverse events (TEAEs) occurring after one treatment cycle with a given total dose of CD19-ADC. A treatment-emergent adverse event (TEAE) is defined as any event not seen before exposure to CD19-ADC or any event that was already seen but worsened in either intensity or frequency after exposure to CD19-ADC. The number of AEs occurring in tapering and / or extended dosing regimes can be 95% or less (e.g., 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, or 5% or less) of the number of AEs occurring in the corresponding fixed dose level and cycle length regime. Adverse events will be adjudicated according to CTCAE Version 4.0 (v4.03, published June 14, 2010, NIH Publication No. 09-5410).

[0184] For example, if in 100 subjects, one treatment cycle of a single dose regimen results in 10 AEs and one treatment cycle of a corresponding tapering and / or extended regimen results in 5 AEs, then the number of AEs in the tapering and / or extended regimen is 50% of the number of AEs in the corresponding fixed dose level and cycle length regimen.

[0185] In some cases, the level of toxicity is measured as the number of serious adverse events (SAEs) that occur after one treatment cycle with a given total dose of CD19-ADC. A serious adverse event (SAE) is defined as any event that results in death, is immediately life-threatening, requires hospitalization or prolongs an existing hospitalization, results in persistent or significant disability / incapacity, or is a congenital anomaly / birth defect. Hospitalization for elective procedures or protocol compliance is not considered an SAE. Serious medical events that may not result in death, are life-threatening, or require hospitalization may be considered an SAE when, based on appropriate medical judgment, they may threaten the patient or require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive care in the emergency room or at home, blood disorders or convulsions that do not result in hospitalization, or the development of drug dependence or abuse. The incidence of SAEs in tapering and / or extended dosing regimens may be 95% or less (e.g., 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, or 5% or less) of the incidence of SAEs in the corresponding fixed dose level and cycle length regimen. Adverse events will be adjudicated according to CTCAE Version 4.0 (v4.03, published June 14, 2010, NIH Publication No. 09-5410).

[0186] In some cases, the level of toxicity is measured as the number of dose-limiting toxicities (DLTs) occurring after one treatment cycle with a given total dose of CD19-ADC. The incidence of DLTs in tapering and / or extended dosing regimens can be 95% or less (e.g., 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, or 5% or less) of the incidence of DLTs in a corresponding fixed dose level and cycle length regimen.

[0187] For example, if in 100 subjects, one treatment cycle of a single dose regimen results in 10 DLTs and one treatment cycle of a corresponding tapered and / or extended regimen results in 5 DLTs, then the incidence of DLTs in the tapered and / or extended regimen is 50% of the incidence of DLTs in the corresponding fixed dose level and cycle length regimen.

[0188] A DLT, as used herein, is defined as any of the following events, except those clearly attributable to the underlying disease or exogenous causes: Hematological DLT is 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 associated with clinically significant bleeding or requiring platelet transfusion Grade 4 anemia Non-hematological DLTs are defined as follows: Grade 4 tumor lysis syndrome (Grade 3 tumor lysis syndrome is not considered a DLT unless it leads to irreversible end-organ damage.) Grade ≥ 3 AEs (including nausea, vomiting, diarrhea, and electrolyte imbalance lasting > 48 hours despite optimal treatment, excluding alopecia of any grade). Hypersensitivity reactions of grade 3 or higher (regardless of prior medication) Skin ulcers of grade 2 or higher

[0189] The above adverse events will be judged according to CTCAE Version 4.0 (v4.03, published June 14, 2010, NIH Publication No. 09-5410).

[0190] The disclosure also provides a method of improving the efficacy of a treatment associated with administration of a CD19-ADC to a subject, the method comprising administering the CD19-ADC in a tapering and / or extended dosing regimen as defined herein.

[0191] In some cases, this improved efficacy is measured in comparison to a dosing regimen in which the dose level and cycle length are constant, where the dose level and cycle length of the fixed comparator regimen may be the same as the starting dose and starting cycle length of the tapering and / or extending regimen.

[0192] In some cases, the level of efficacy is measured as the proportion of subjects who achieve at least stable disease [SD] (i.e., the proportion of subjects who achieve either stable disease [SD], partial response [PR], or complete response [CR]) after one treatment cycle with a given total dose of the ADC. The proportion of subjects who achieve at least SD can be at least 110% (such as at least 120%, at least 130%, at least 140%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, or at least 200%) of the proportion of subjects who achieve at least stable disease [SD] at a corresponding fixed dose level and cycle length regimen.

[0193] For example, if in 100 subjects, a single-dose regimen results in at least SD in 50 subjects and a corresponding tapered and / or extended regimen results in at least SD in 80 subjects, then the proportion of subjects who achieve at least SD with the tapered and / or extended regimen is 160% of the proportion of subjects who achieve at least a partial response [SD] with the corresponding fixed dose level and cycle length regimen.

[0194] Assessment of response to treatment with ADC may be based on bone marrow samples (aspirates or biopsy specimens if aspirates are not available) taken before and after the end of each treatment cycle, e.g., on day 19 (± 3 days) of a 21-day treatment cycle. Subject response to ADC may be classified as CR, PR, SD, or PD according to the 2014 Lugano Classification Criteria (using the New "Cheson" Criteria) as follows: ●Complete response (CR) is defined as achievement of each of the following: Nodular disease with LDi less than 1.5 cm Extranodal disease: None seen ○Spleen: Atrophy to normal ○No new lesions observed. Bone marrow: morphology is normal. In uncertain cases, IHC is negative. ●Partial response (PR) is defined as achievement of each of the following: Nodal disease: SPD of all target lesions is reduced by 50% or more from baseline. No non-targeted increase is observed. Spleen: The enlarged area of ​​the spleen has decreased by more than 50% from baseline (greater than 13 cm). ○No new lesions observed. Stable disease (SD) is defined as achievement of each of the following: Nodal disease: SPD of all target lesions is reduced by >50% from baseline. o The criteria for nodal PD are not met.  No non-target progression observed.  No progression of splenomegaly is observed. No new lesions were observed. Criteria for nodular PD: An individual nodule / lesion should be considered abnormal if: LDi is greater than 1.5 cm, and PPD has increased by 50% or more from the lowest value, and ●LDi or SDi has increased from the lowest value as shown below. For lesions 2 cm or less, 0.5 cm or more For lesions over 2 cm, 1.0 cm or more

[0195] leukemia The present disclosure provides a method of reducing toxicity and / or side effects associated with administration of a CD19-ADC to a subject, the method comprising administering the CD19-ADC in a split dose regimen as defined herein.

[0196] In some cases, the reduction in toxicity is measured in comparison to a single dose administration regimen with the same total administered dose and length of the treatment cycle, in which the total dose of the CD19-ADC is administered as a single dose at the start of the treatment cycle.

[0197] In some cases, the level of toxicity is measured as the number of treatment-emergent adverse events (TEAEs) occurring after one treatment cycle with a given total dose of CD19-ADC. A treatment-emergent adverse event (TEAE) is defined as any event not seen before exposure to CD19-ADC or any event that was already seen but worsened in either intensity or frequency after exposure to CD19-ADC. The number of AEs occurring in a split-dose regimen can be 95% or less (e.g., 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, or 5% or less) of the number of AEs occurring in a corresponding single-dose regimen. Adverse events will be adjudicated according to CTCAE Version 4.0 (v4.03, published June 14, 2010, NIH Publication No. 09-5410).

[0198] For example, in 100 subjects, if one treatment cycle of a single-dose regimen results in 10 AEs and one treatment cycle of the corresponding fractionated regimen results in 5 AEs, the number of AEs with the fractionated regimen is 50% of the number of AEs with the corresponding single-dose regimen.

[0199] In some cases, the level of toxicity is measured as the number of serious adverse events (SAEs) that occur after one treatment cycle with a given total dose of CD19-ADC. A serious adverse event (SAE) is defined as any event that results in death, is immediately life-threatening, requires hospitalization or prolongs an existing hospitalization, results in persistent or significant disability / incapacity, or is a congenital anomaly / birth defect. Hospitalization for elective procedures or protocol compliance is not considered an SAE. Serious medical events that may not result in death, are life-threatening, or require hospitalization may be considered an SAE when, based on appropriate medical judgment, they may threaten the patient or require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive care in the emergency room or at home, blood disorders or convulsions that do not result in hospitalization, or the development of drug dependence or abuse. The incidence of SAEs in a split-dose regimen can be 95% or less (e.g., 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, or 5% or less) of the incidence of SAEs in the corresponding single-dose regimen. Adverse events will be adjudicated according to CTCAE Version 4.0 (v4.03, published June 14, 2010, NIH Publication No. 09-5410).

[0200] In some cases, the level of toxicity is measured as the number of dose-limiting toxicities (DLTs) that occur after one treatment cycle with a given total dose of CD19-ADC. The number of DLTs occurring in a split-dose regimen can be 95% or less (e.g., 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, or 5% or less) of the number of DLTs occurring in a corresponding single-dose regimen.

[0201] For example, if, in 100 subjects, one treatment cycle of a single-dose regimen results in 10 DLTs and one treatment cycle of the corresponding fractionated regimen results in 5 DLTs, the number of DLTs with the fractionated regimen is 50% of the number of DLTs with the corresponding single-dose regimen.

[0202] A DLT, as used herein, is defined as any of the following events, except those clearly attributable to the underlying disease or exogenous causes: Hematological DLT is defined as follows: Grade 3 or higher events of neutropenia and / or thrombocytopenia or grade 4 anemia with hypoplastic bone marrow and no residual leukemia (i.e., <5% blasts) for at least 6 weeks from the start of the cycle. In cases of normoplastic bone marrow with <5% blasts, an 8 week period of grade 3 or higher pancytopenia will be considered a DLT. Non-hematological DLTs are defined as follows: Grade 4 tumor lysis syndrome (Grade 3 tumor lysis syndrome is not considered a DLT unless it leads to irreversible end-organ damage.) Grade ≥ 3 AEs (including nausea, vomiting, diarrhea, and electrolyte imbalance lasting > 48 hours despite optimal treatment; excluding alopecia of any grade) Hypersensitivity reaction of CTCAE grade 3 or higher (regardless of premedication) Skin ulcers of CTCAE grade 3 or higher

[0203] The above adverse events will be judged according to CTCAE Version 4.0 (v4.03, published June 14, 2010, NIH Publication No. 09-5410).

[0204] The disclosure also provides a method of improving the efficacy of a treatment associated with administration of a CD19-ADC to a subject, the method comprising administering the CD19-ADC in a split dose regimen as defined herein.

[0205] In some cases, this improved efficacy is measured in comparison to a single dose administration regimen of the same total administered dose and length of treatment cycle, in which the total dose of the ADC is administered as a single dose at the start of a treatment cycle.

[0206] In some cases, the level of efficacy is measured as the proportion of subjects who achieve at least a partial response [PR] (i.e., the proportion of subjects who achieve either a partial response [PR], a complete response with incomplete blood count recovery [CRi], or a complete response [CR]) after one treatment cycle with a given total dose of the ADC. The proportion of subjects who achieve at least a PR can be at least 110% (such as at least 120%, at least 130%, at least 140%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, or at least 200%) of the proportion of subjects who achieve at least a partial response [PR] in the corresponding single dose regimen.

[0207] For example, if in 100 subjects, a single-dose regimen results in at least PR in 50 subjects and a corresponding fractionated regimen results in at least PR in 80 subjects, then the proportion of subjects achieving at least PR with the fractionated regimen is 160% of the proportion of subjects achieving at least a partial response [PR] with the corresponding single-dose regimen.

[0208] Assessment of response to treatment with ADC may be based on bone marrow samples (aspirate or biopsy specimen if aspirate is not available) taken before and after the end of each treatment cycle, e.g., on day 19 (± 3 days) of a 21-day treatment cycle. A subject's response to ADC may be classified as CR, CRi, PR, PD, or NR according to the following criteria: ●Complete response (CR) is defined as achievement of each of the following: In the bone marrow image, the number of blast cells is less than 5%, and no blast cells with Auer rods are observed. Absolute neutrophil count is 1.0 × 109 / L or more and platelet count is 100 × 109 / L or more. o No extramedullary disease is observed. o The patient is not under the influence of red blood cell (RBC) transfusion. A complete response (CRi) is when blood counts are not fully recovered, with an ANC value of 1.0 x 10 9 / L and / or platelet counts below 100×10 9 / L. ●Partial response (PR) is defined as meeting each of the following: Absolute neutrophil count is 1.0 x 109 / L or more and platelet count is 100 x 109 / L or more. - In the bone marrow image, the percentage of bone marrow blasts has decreased by 50% or more from baseline to a level greater than 5% and less than 25%, or the bone marrow image shows less than 5% blasts and Auer rods. ● No response (NR) is defined as not achieving CR, CRi or PR. ●Disease progression (PD) is defined as follows: For patients in CR or CRi, the first day of reappearance of blast cells in the bone marrow and / or peripheral blood to a level of 5% or more or the first appearance of extramedullary disease In patients with PR, the first day that blast cells increased in bone marrow and / or peripheral blood and the patient no longer met the criteria for PR

[0209] Patient Selection In certain cases, subjects are selected prior to initiating treatment as suitable for treatment with either (a) tapering and / or extended dosing regimes, or (b) split dosing regimes.

[0210] Preferably, a subject has, is suspected of, or has been diagnosed with lymphoma and is selected for treatment with the tapering and / or extended dosing regimens described. For example, the lymphoma may be diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic lymphoma (CLL), non-Hodgkin's lymphoma such as Waldenstrom's macroglobulinemia, Burkitt's lymphoma, and marginal zone B-cell lymphoma (MZBL).

[0211] Preferably, a subject is selected for treatment with the described split-dose regimen if the subject has, has, is suspected of, or has been diagnosed with leukemia, for example, the leukemia may be hairy cell leukemia (HCL), hairy cell leukemia subtype (HCL-v), and acute lymphoblastic leukemia (ALL), such as Philadelphia chromosome positive ALL (Ph+ALL) or Philadelphia chromosome negative ALL (Ph-ALL).

[0212] As used herein, the subject that is considered suitable for treatment is the subject that is expected to benefit from or respond to treatment. The subject may have cancer, be suspected of cancer, or be at risk of cancer. The subject may have been diagnosed with cancer. In particular, the subject may have lymphoma, be suspected of lymphoma, or be at risk of lymphoma. In some cases, the subject may have solid cancer, be suspected of solid cancer, or be at risk of solid cancer with tumor-associated non-tumor cells that express CD19, such as infiltrating cells that express CD19.

[0213] In some cases, the subject is selected based on the amount or pattern of expression of CD19. In some cases, the selection is based on expression of CD19 on the cell surface.

[0214] In some cases, expression of CD19 in a particular tissue of interest, e.g., lymphoid or tumor tissue, is determined in a sample. In some cases, systemic expression of CD19 is determined in a sample of a circulating fluid, e.g., blood, plasma, serum, or lymph.

[0215] In some cases, subjects are selected as suitable for treatment by the presence of CD19 expression in the sample. In these cases, subjects lacking CD19 expression may be considered ineligible for treatment.

[0216] In other cases, the level of CD19 expression is used to select a subject as suitable for treatment. If the expression level of CD19 is above a threshold level, the subject is deemed suitable for treatment.

[0217] In some cases, the presence of CD19+ on cells in a sample indicates that the subject is suitable for treatment with a combination drug that includes an ADC. In other cases, CD19 expression must be above a threshold level to indicate that the subject is suitable for treatment. In some cases, the observation that CD19 localization is altered in a sample compared to a control indicates that the subject is suitable for treatment.

[0218] In some cases, a subject is indicated as suitable for treatment if cells taken from the lymph node or extranodal site react with antibodies to CD19, as determined by IHC.

[0219] In some cases, 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 some cases disclosed herein, a patient is deemed suitable for treatment if at least 5% of the cells in the sample express CD 19.

[0220] In some cases, patients are deemed suitable for treatment if they have experienced DLT after a single previous treatment cycle with an ADC.

[0221] In some cases, patients are deemed suitable for treatment if they have shown any signs of ADC-induced toxicity during a previous single-dose treatment cycle with the ADC.

[0222] In some cases, patients are deemed suitable if they have increased susceptibility to ADC-induced toxicity.

[0223] In some cases, patients are deemed suitable for treatment if their disease is relapsed or refractory.

[0224] In some cases, subjects undergo a neurological examination prior to treatment with an ADC. Preferably, the neurological examination includes testing of strength, sensation, and deep tendon reflexes.

[0225] In some cases, a subject is deemed ineligible for treatment with ADC if he / she has a neurological disorder or has recently developed a neurological disorder. Examples of such disorders include polio and multiple sclerosis. In general, a subject is not deemed ineligible for treatment with ADC due to a neurological disorder that is explained by the subject's past medical history and is known not to be related to treatment with ADC or a risk factor for treatment with ADC. An example of such a disorder is left-sided weakness that is known to be due to a previous cerebrovascular accident, such as cerebral infarction.

[0226] Neuropathy as discussed herein may be polyradiculopathy (including acute inflammatory demyelinating polyradiculopathy (AIDP)), Guillain-Barré syndrome (GBS), myasthenia gravis, or a neuropathy (e.g., ascending (bilateral) sensory loss and / or motor weakness) associated with or that is an early indicator of polyradiculitis, GBS or myasthenia gravis.

[0227] In some cases, the subject undergoes a neurological examination after administration of the ADC. In some cases, the results of the subject's neurological examination after administration of the ADC are compared with those obtained before administration of the ADC to evaluate any changes in the neurological parameters examined. In some cases, if the subject experiences neurotoxicity, treatment with the ADC is reduced, interrupted, or permanently discontinued.

[0228] Neurotoxicity as discussed herein may be polyradiculopathy (including acute inflammatory demyelinating polyradiculopathy (AIDP)), Guillain-Barré syndrome (GBS), myasthenia gravis, or neuropathy (e.g., ascending (bilateral) sensory loss and / or motor weakness) associated with or that is an early indicator of polyradiculitis, GBS or myasthenia gravis.

[0229] In some cases, the subject undergoes a neurological examination after each administration of the ADC. In some cases, the results of the subject's neurological examination after each administration of the ADC are compared to results obtained before the most recent administration of the ADC to assess any changes in the neurological parameters examined. In some cases, the results of the subject's neurological examination after each administration of the ADC are compared to results obtained before the first administration of the ADC to assess any changes in the neurological parameters examined.

[0230] In some cases, subjects undergo a neurological examination if they experience neurotoxicity following administration of the ADC.

[0231] In some cases, if a subject has neuropathy or experiences neurotoxicity, ADC treatment may be reduced, interrupted, or permanently discontinued. For example, ADC treatment may be reduced or interrupted if a subject experiences grade 1 or higher neurotoxicity (such as grade 1 neurotoxicity (e.g., ascending (bilateral) sensory loss and / or motor weakness) that is related to or is an early indicator of polyradiculitis). In some cases, ADC treatment may be permanently discontinued if a subject experiences grade 2 or higher neurotoxicity (e.g., grade 2 polyradiculitis or GBS).

[0232] Adverse events will be adjudicated according to CTCAE Version 4.0 (v4.03, published June 14, 2010, NIH Publication No. 09-5410).

[0233] In some cases, the ADC treatment is decreased by reducing the dose of ADC administered to the subject for each subsequent treatment cycle. In some cases, the ADC treatment is decreased by extending the length of each subsequent treatment cycle, for example from a 3-week cycle to a 6-week cycle. In some cases, the ADC treatment is decreased by reducing the dose of ADC administered to the subject for each subsequent treatment cycle and extending the cycle length for each subsequent treatment cycle.

[0234] In some cases, ADC treatment is interrupted by stopping ADC treatment until toxicity resolves. In some cases, ADC treatment is resumed after toxicity resolves to baseline. Subjects may be monitored once a week until neurotoxicity resolves. In some cases, treatment is suspended for up to 3 weeks (21 days).

[0235] For example, in some cases, subjects undergo a neurological examination if they experience grade 1 or higher neurotoxicity (such as grade 1 neurotoxicity (e.g., ascending (bilateral) sensory loss and / or motor weakness) that is related to or an early indicator of polyradiculitis). In some cases, if a subject experiences grade 1 or higher neurotoxicity (e.g., grade 1 polyradiculitis or GBS), treatment with the ADC is resumed after toxicity has resolved to baseline. Subjects may be monitored weekly until neurotoxicity has resolved.

[0236] In some cases, treatment with the ADC is permanently discontinued if a subject experiences grade 2 or higher neurotoxicity (eg, grade 2 polyradiculitis or GBS).

[0237] In some cases, a subject is deemed ineligible for treatment with an ADC if they have, or have recently had, an infection caused by a pathogen that may be associated with a neurological and / or immune-related disease, such as HSV1, HSV2, VZV, EBV, CMV, measles, influenza A, Zika virus, chikungunya virus, Mycoplasma pneumonia, Campylobacter jejuni, or enterovirus D68.

[0238] In some cases, treatment with the ADC is reduced, interrupted, or permanently discontinued if the subject experiences, is, or acquires an infection caused by a pathogen that may be associated with a neurological and / or immune-related disease. Examples of such pathogens include HSV1, HSV2, VZV, EBV, CMV, measles, influenza A, Zika virus, chikungunya virus, Mycoplasma pneumonia, Campylobacter jejuni, or enterovirus D68. In some cases, treatment with the ADC is discontinued until at least 4 weeks after the symptoms of the infection have resolved.

[0239] Examples of immune-related diseases include rheumatoid arthritis, progressive systemic sclerosis [scleroderma], systemic lupus erythematosus, Sjogren's syndrome, and autoimmune vasculitis [e.g. Wegener's granulomatosis].

[0240] In some cases, treatment with the ADC is reduced, interrupted, or permanently discontinued if a subject experiences grade 1 or greater autoimmune toxicity (eg, endocrinopathy).

[0241] sample A sample of the present disclosure may include or be derived from a quantity of blood drawn from the subject, a quantity of serum derived from the subject's blood (which may include the fluid portion of blood obtained after removal of fibrin clots and blood cells), a quantity of pancreatic juice or bodily fluids obtained from a spinal tap, a tissue sample or biopsy specimen, or isolated cells.

[0242] The sample may be taken from any tissue or body fluid, in certain cases the sample may comprise or be derived from a tissue sample, a biopsy, a section or isolated cells taken from the subject.

[0243] In certain cases, the sample is a tissue sample. The sample may be a sample of tumor tissue, such as a cancerous tumor tissue. The sample may be obtained by tumor biopsy. In some cases, the sample is a lymphatic tissue sample, such as a lymphatic lesion sample or a lymph node biopsy specimen. In some cases, the sample is a skin biopsy specimen.

[0244] In some cases, the sample is taken from a bodily fluid, more preferably from a bodily fluid that circulates throughout the body. Thus, the sample may be a blood sample or a lymphatic sample. In some cases, the sample is a urine sample or a saliva sample.

[0245] In some cases, the sample is a blood sample or a blood-derived sample. The blood-derived sample may be a selected fraction of the subject's blood, such as a selected cell-containing fraction, a plasma fraction, or a serum fraction.

[0246] The selected cell-containing fraction may comprise the relevant cell type, which may include white blood cells (WBCs), in particular peripheral blood mononuclear cells (PBCs) and / or granulocytes and / or red blood cells (RBCs). Thus, the method according to the present disclosure may involve detection of CD19 polypeptide or nucleic acid in blood, white blood cells, peripheral blood mononuclear cells, granulocytes and / or red blood cells.

[0247] The sample can be a fresh sample or a preserved sample.For example, the preserved tissue can be from the subject's first diagnosis or a biopsy specimen at the time of recurrence.In certain cases, the sample is a fresh biopsy specimen.

[0248] Target status The subject of the present disclosure may be an animal, a mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a monotreme (e.g., platypus), a rodent (e.g., guinea pig, hamster, rat, mouse), a murine (e.g., mouse), a lagomorph (e.g., rabbit), an avian (e.g., bird), a canine (e.g., dog), a feline (e.g., cat), an equine (e.g., horse), a porcine (e.g., pig), an ovine (e.g., sheep), a bovine (e.g., cow), a primate, a simian (e.g., monkey or ape), ape (e.g., marmoset, baboon), ape (e.g., gorilla, chimpanzee, orangutan, gibbon), or a human.

[0249] Furthermore, the subject may be in any of its forms of development, such as a fetus. In a preferred embodiment, the subject is a human. The terms "subject," "patient," and "individual" are used interchangeably herein.

[0250] In some cases disclosed herein, the subject has been identified as having, suspected of having, or at risk for cancer. In some cases disclosed herein, the subject has already been diagnosed with cancer.

[0251] The subject may have, be suspected of, be identified as at risk of, or have been diagnosed with a lymphoma, such as diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic lymphoma (CLL), non-Hodgkin's lymphoma, including Waldenstrom's macroglobulinemia, Burkitt's lymphoma, and marginal zone B-cell lymphoma (MZBL). Such subjects are preferably treated with tapering and / or extended dosing regimes as disclosed herein.

[0252] The subject may have, be suspected of having, be identified as at risk for, or have already been diagnosed with leukemia, such as hairy cell leukemia (HCL), hairy cell leukemia subtype (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]. Such subjects are preferably treated with a split-dose regimen as disclosed herein.

[0253] In some cases, the subject has been diagnosed with a solid tumor that comprises CD19+ expressing infiltrating T cells.

[0254] The subject may be undergoing or have undergone therapeutic treatment for the cancer. The subject may or may not have been previously administered ADCX19. In some cases, the cancer is leukemia or lymphoma, including non-Hodgkin's lymphoma.

[0255] control In some cases, CD19 expression in a subject is compared to the expression of the target in a control. Controls are useful to verify the validity of staining and to identify experimental artifacts.

[0256] In some cases, the control may be a control sample or a control data set. The control may be a sample previously collected from a subject of known suitability. The control may be a data set obtained by analysis of a control sample.

[0257] A 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.

[0258] The control may be a tissue sample from a subject known to benefit from the treatment. The tissue may be the same type of sample as the sample being tested. For example, a tumor tissue sample taken from a subject may be compared with a control sample of tumor tissue taken from a subject known to be suitable for the treatment (such as a subject who has previously responded to the treatment).

[0259] In some cases, the control may be a sample taken from the same subject as the test sample, but of tissue known to be normal. Thus, a sample of cancerous tissue taken from a subject may be compared to a non-cancerous tissue sample.

[0260] In some cases, the control is a cell culture sample.

[0261] In some cases, the test sample is analyzed prior to incubation with the antibody to determine the level of background staining inherent to the sample.

[0262] In some cases, isotype controls are used that are of the same class as the target-specific antibody but that do not immunoreact with the sample. Such controls are useful to distinguish non-specific interactions of the target-specific antibody.

[0263] The disclosed method may include morphology and immunohistochemistry interpretation by a hematopathologist to ensure accurate interpretation of test results. The disclosed method may include confirming that the pattern of expression correlates with the expected pattern. For example, when analyzing CD19 expression levels, the disclosed method may include confirming that expression is observed in the test sample as membrane staining along with cytoplasmic components. The disclosed method may include confirming that the ratio of target signal to noise is above a threshold level, thereby allowing specific signals to be clearly distinguished from non-specific background signals.

[0264] Treatment method The term "treatment", as used herein, in reference to the treatment of a condition, generally relates to treatments and therapies, whether in humans or animals (e.g., veterinary applications), that have some desired therapeutic effect (e.g., inhibition of progression of the condition), including slowing the rate of progression, halting the rate of progression, regressing the condition, ameliorating the condition, and curing the condition. Treatment as a preventative measure (i.e., prophylaxis, prevention) is also included.

[0265] The term "therapeutically effective amount" or "effective amount," as used herein, refers to an amount of an active compound, or a substance, composition, or dosage form containing an active compound, that is effective to produce some desired therapeutic effect when administered in accordance with a desired treatment regimen, commensurate with a reasonable benefit / risk ratio. Generally, when methods of treatment describe the use of an ADC, it is intended that the ADC be used in a therapeutically effective amount.

[0266] The actual amount administered, and the rate and time course of administration, will depend on the nature and severity of the condition being treated. Judgments regarding prescription of treatment, e.g., dosage, are within the scope of ordinary medical practitioners and other physicians. The subject may be examined to determine suitability for treatment with the methods disclosed herein. The treatment methods of the present disclosure may include a step of determining whether the subject is suitable for treatment using the methods disclosed herein.

[0267] Similarly, the term "prophylactically effective amount," as used herein, relates to an amount of an active compound, or a substance, composition or dosage form containing an active compound, that is effective for producing some desired prophylactic effect, commensurate with a reasonable benefit / risk ratio, when administered in accordance with a desired treatment regimen.

[0268] Disclosed in the present invention are therapeutic methods, including administering to a subject in need of treatment a therapeutically effective amount of an ADC in a tapering and / or extended dosing regimen.

[0269] The ADC may comprise an anti-CD19 antibody. The anti-CD19 antibody may be RB4v1.2. The ADC may comprise a drug that is a PBD dimer. The ADC may be an anti-CD19-ADC, in particular ADCX19. The ADC may be an ADC disclosed in WO2014 / 057117.

[0270] Treatments of the present disclosure may include administration of the ADC alone or in combination with other treatments, either simultaneously or sequentially, depending on the condition being treated. Sequential administration involves administration of the ADC in some cases prior to the other treatment and in other cases after the other treatment. Examples of treatments and therapies include, but are not limited to, chemotherapy (e.g., administration of active agents including drugs such as chemotherapeutic agents), immunotherapy, surgery, and radiation therapy.

[0271] 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", immuno-oncology agents such as checkpoint inhibitors, and conventional chemotherapy agents.

[0272] 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), and rifabutinib (RIBA®, Genentech / OSI). Pharm.), docetaxel (TAXOTERE®, Sanofi-Aventis), 5-FU (fluorouracil, 5-fluorouracil, CAS number 51-21-8), gemcitabine (GEMZAR®, Lilly), PD-0325901 (CAS number 391210-10-9, Pfizer), cisplatin (cis-diamine, dichloroplatinum(II), CAS number 15663-27-1), carboplatin (CAS number 41575-94-4), paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, NJ), 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 number 85622-93-1, TEMODAR®, TEMODAL®, Schering Plough), tamoxifen ((Z)-2-[4-(1,2-diphenylbut-1-enyl)phenoxy]-N,N-dimethylethanamine, NOLVADEX®, ISTUBAL®, VALODEX®), doxorubicin (ADRIAMYCIN®), Akti-1 / 2, HPPD, and rapamycin.

[0273] 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, Exelixis, WO2007 / 044515), ARRY-886 (Mek inhibitor, AZD6244, Array BioPharma, Astra Zeneca), SF-1126 (PI3K inhibitor, Semaphores), and EGFR inhibitor (EGFR inhibitor, ... Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787 / ZK222584 (Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin (folinic acid), rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), lonafarnib (SARASAR™, SCH66336, Schering Plough), sorafenib (NEXAVAR®, BAY43-9006, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), irinotecan (CAMPTOSAR®, CPT-11, Pfizer), tipifarnib (ZARNESTRA™, Johnson & Johnson), ABRAXANE™ (Cremophor-free), an albumin-modified nanoparticulate formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), vandetanib (rINN, ZD6474, ZACTIMA®, AstraZeneca), chlorambucil, AG1478, AG1571 (SU5271, Sugen), temsirolimus (TORISEL®, Wyeth), pazopanib (GlaxoSmithKline), canfosfamide (TELCYTA®, Telik),thiotepa and cyclophosphamide (CYTOXAN®, NEOSAR®), alkyl sulfonates such as busulfan, improsulfan and piposulfan, aziridines such as benzodopa, carboquone, meturedopa and uredopa, ethylenimines and methylmelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelanin, acetogenins (particularly bullatacin and bullatacinone), camptothecins (including the synthetic analog topotecan), bryostatin, kallistatin, CC-1065 (including its synthetic analogs adozelesin, carzelesin and bizelesin), cryptophycins (particularly cryptophycin 1 and cryptophycin 2), Antibiotics such as dolastatins, duocarmycins (including the synthetic analogs KW-2189 and CB1-TM1), eleutherobin, pancratistatin, sarcodictine, spongiostatin, chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembitine, phenesterine, prednimustine, trofosfamide, nitrogen mustards such as uracil mustard, nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine, enediyne antibiotics (e.g., calicheamicin, calicheamicin gamma 1I, calicheamicin omega 11 (Angew Chem. Intl. Ed. Engl. (1994) 33:183-186), dynemicin, dynemicin A, bisphosphonates such as clodronate, esperamicin, neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomycin, actinomycin, ausramycin, 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, esorubicin, idarubicin,Mitomycins such as nemorubicin, marcelomycin, mitomycin C; mycophenolic acid; nogalamycin; olivomycin; peplomycin; porfiromycin; puromycin; chelamycin; rodorubicin; streptonigrin; streptozocin; tubercidin; ubenimex; zinostatin; zorubicin; methotrexate; and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; ancitabine; azacitidine; 6-azauridine; carmofur; cytarabine; dideoxyuridine; doxifluridine; enocitabine; floxuridine; calsterone; dromostate propionate. androgens such as nolon, epithiostanol, mepitiostane, testolactone; antiadrenal agents such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as floric acid; aceglatone, aldophosphamide glycosides, aminolevulinic acid, eniluracil, amsacrine, bestravcil, bisantrene, edatrexate, defofamine, demecolcine, diaziquone, elfornitine, elliptinium acetate, epothilone, etoglucide, gallium nitrate, hydroxyurea, lentinan, lonidamine, maytansinoids such as maytansine and ansamitocin; mitoguazone, mitoxantrone, mopidamol, nitramine, pentostatin, phenamet, pirarubicin, losoxantrone, 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, veraculin A, roridin A, and anguidine), urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside ("Ara-C"), cyclophosphamide, thiotepa, 6-thioguanine, mercaptopurine, methotrexate,Platinum analogues such as cisplatin and carboplatin, vinblastine, etoposide (VP-16), ifosfamide, mitoxantrone, vincristine, vinorelbine (NAVELBINE®), novantrone, teniposide, edatrexate, daunomycin, aminopterin, capecitabine (XELODA®, Roche), ibandronate, CPT-11, topoisomerase inhibitor RFS2000, difluoromethylornithine (DMFO), retinoids such as retinoic acid, and pharma- ceutical acceptable salts, acids, and derivatives of any of the above. Combinations of drugs may also be used, such as CHP (doxorubicin, prednisone, cyclophosphamide) or CHOP (doxorubicin, prednisone, cyclophosphamide, vincristine).

[0274] The definition of "chemotherapeutic agent" includes (i) anti-hormonal agents that act to regulate or inhibit the action of hormones on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®, tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxyphene, ketoxifene, LY117018, onapristone, and FARESTON® (toremifene citrate); (ii) anti-hormonal agents that act to regulate or inhibit the action of hormones on tumors, such as, for example, 4(5)-imidazole, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane, Pfizer), formstane, fadrozole. (iii) aromatase inhibitors, which inhibit aromatase, an enzyme that regulates the production of estrogen in the adrenal glands, such as RIVISOR® (vorozole), FEMARA® (letrozole, Novartis) and ARIMIDEX® (anastrozole, AstraZeneca); (iv) antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide, goserelin and troxacitabine (1,3-dioxolane nucleoside cytosine analogues); (v) protein kinase inhibitors, such as MEK inhibitors (WO 2007 / 044515); (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, in particular oblimersen (GENASENSE®, Genta Inc.Also included are antisense oligonucleotides that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation, e.g., PKCα, Raf, and H-Ras, such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors, (viii) gene therapy vaccines, e.g., vaccines such as ALLOVECTIN®, LEUVECTIN®, and VAXID®, topoisomerase 1 inhibitors such as PROLEUKIN® rIL-2, LURTOTECAN®, ABARELIX® rmRH, (ix) angiogenesis inhibitors such as bevacizumab (AVASTIN®, Genentech), as well as pharmacologic acceptable salts, acids, and derivatives of any of the above.

[0275] Also included within the definition of "chemotherapeutic agent" are therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech), cetuximab (ERBITUX®, Imclone), panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech / Biogen Idec), ofatumumab (ARZERRA®, GSK), pertuzumab (PERJETA™, OMNITARG™, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), MDX-060 (Medarex), and the antibody drug conjugate gemtuzumab ozogamicin (MYLOTARG®, Wyeth).

[0276] Humanized monoclonal antibodies with potential therapeutic potential as chemotherapeutic agents to be combined with the conjugates of the present disclosure include alemtuzumab, apolizumab, acelizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidofusituzumab, cidofusituzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlotinib, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motavizumab, Natalizumab, nimotuzumab, norobizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resivizumab, rovelizumab, ruplizumab, sibrotuzumab , siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, trastuzumab, tucotuzumab celmoleukin, tucituzumab, umavizumab, urtoxazumab, nivolumab, pembrolizumab, durvalumab, and visilizumab.

[0277] In some cases, the ADC is administered to the subject in combination with, among others, steroids, ibrutinib, durvalumab, rituximab, and / or cytarabine.

[0278] Use in combination with steroids In developing the ADC dosing regimens described herein, it was observed that administration of a steroid, such as dexamethasone, reduced the frequency and / or severity of subject-reported toxic symptoms.

[0279] Thus, in a preferred embodiment, the ADC is administered in combination with a steroid, such as dexamethasone.

[0280] Preferably, the steroid is dexamethasone. Other suitable steroids are found in the class of corticosteroids, such as glucocorticoids. Examples of glucocorticoids are cortisol (hydrocortisone), cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, fludrocortisone acetate, and deoxycorticosterone acetate.

[0281] Specifically, embodiments are contemplated in which CD19-ADC is administered in combination with steroids such as dexamethasone.Preferably, a first dose of steroid is administered before CD19-ADC is administered, for example, at least 2 hours before ADC is administered.An additional dose of steroids such as dexamethasone can be administered to the subject on the day after ADC is administered.Optionally, an additional dose of steroids such as dexamethasone can be administered to the subject on the day before ADC is administered.

[0282] The steroid may be administered prior to administration of the ADC, for example at least 2 hours, at least 6 hours, at least 12 hours, or the day before administration of the ADC.

[0283] In some embodiments, a first dose of steroid is administered on the day before the ADC is administered. A second dose of steroid may then be administered on the day the ADC is administered, preferably prior to administration of the ADC (e.g., at least 2 hours prior to administration of the ADC). A third dose of steroid may then be administered on the day after the ADC is administered. In dosing regimes that include one or more administrations of an ADC per treatment cycle (e.g., split dosing regimes), the steroid is preferably administered in conjunction with only the first administration of the ADC in each treatment cycle.

[0284] In some embodiments, a first dose of steroid is administered on the day the ADC is administered, preferably prior to administration of the ADC (e.g., at least 2 hours prior to administration of the ADC), and a second dose of steroid is administered the day after the ADC is administered. In dosing regimes that include more than one administration of an ADC per treatment cycle (e.g., split dosing regimes), the steroid is preferably administered in conjunction with only the first administration of the ADC in each treatment cycle.

[0285] The steroid may be administered by any method known in the art, such as orally, parenterally (e.g., intravenously, intramuscularly, or intrathecally), by inhalation, or topically. Preferably, the steroid is administered orally.

[0286] Steroids can be administered in various dosage regimes.For example, daily steroid dosage can be administered as a single dose, two divided doses, three divided doses or more than three divided doses.Preferably, the divided doses are equal-sized doses.Preferably, daily steroid dosage is administered as two equal divided doses.

[0287] Each dose of steroid may be 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg or 30 mg.

[0288] Each divided dose of the steroid may be 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg or 15 mg.

[0289] In some embodiments, dexamethasone is administered orally at 4 mg twice daily (i) the day before the ADC is administered, (ii) the day the ADC is administered, and (iii) the day after the ADC is administered. Steroids are only administered in conjunction with the ADC administered on day 1 of week 1 of each cycle, regardless of the ADC treatment schedule.

[0290] In some embodiments, dexamethasone is administered orally at 4 mg twice daily (i) on the day the ADC is administered, at least 2 hours prior to the ADC, and (ii) on the day following the ADC administration. Steroids are only administered in conjunction with the ADC administered on day 1 of week 1 of each cycle, regardless of the ADC treatment schedule.

[0291] In some embodiments, dexamethasone is administered orally at 8 mg twice daily (i) the day before the ADC is administered, (ii) the day the ADC is administered, preferably at least 2 hours before the ADC, and (iii) the day after the ADC is administered. Steroids are only administered in conjunction with the ADC administered on day 1 of week 1 of each cycle, regardless of the ADC treatment schedule.

[0292] In some embodiments, dexamethasone is administered orally at 8 mg twice daily (i) on the day the ADC is administered, preferably at least 2 hours prior to the ADC, and (ii) the day after the ADC is administered. Steroids are only administered in conjunction with the ADC administered on day 1 of week 1 of each cycle, regardless of the ADC treatment schedule.

[0293] Dexamethasone: Dexamethasone: (i)CAS number→50-02-2 (See http: / / www.cas.org / content / chemical-substances / faqs)

[0294] (ii)Unique Ingredient Identifier(UNII)→7S5I7G3JQL (See http: / / www.fda.gov / ForIndustry / DataStandards / SubstanceRegistrationSystem-UniqueIngredientIdentifierUNII / default.htm)

[0295] (iii) IUPAC name→ (8S,9R,10S,11S,13S,14S,16R,17R)-9-Fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one

[0296] (iv) Structure→ [ka]

[0297] Combination with ibrutinib In particular, in embodiments in which the proliferative disorder is lymphoma, administration of a CD19-ADC in combination with ibrutinib is contemplated.

[0298] Ibrutinib may be administered to a subject before, in combination with, or after a CD19-ADC. Preferably, the CD19-ADC and ibrutinib are administered in combination. For example, in some cases, administration of ibrutinib begins on day 1 of treatment cycle 1 of the CD19-ADC administration regime described herein.

[0299] When administered in combination with ibrutinib, the CD19-ADC is preferably administered in a dosing regimen consisting of two Q3W (once every three weeks) treatment cycles. Preferably, the dose of each of the two treatment cycles is the same. Alternatively, the second dose may be a reduced dose, i.e., the dosing regimen may be a tapered dosing regimen as defined herein.

[0300] When administered in combination with ibrutinib, the starting dose may be about 60 μg / kg, about 90 μg / kg, about 120 μg / kg, or about 150 μg / kg. In some embodiments, when administered in combination with ibrutinib, the starting dose of CD19-ADC may be about 140-160 μg / kg.

[0301] In some cases, the CD19-ADC and ibrutinib are administered sequentially, for example, in some cases, administration of ibrutinib begins after completion of treatment with the CD19-ADC.

[0302] In some cases, administration of ibrutinib is discontinued upon completion of treatment with a CD19-ADC. Typically, however, administration of ibrutinib continues after completion of treatment with a CD19-ADC. In some cases, administration of ibrutinib continues for up to one year after completion of treatment with a CD19-ADC.

[0303] If a subject achieves a CR after initial treatment with a CD19-ADC in combination with ibrutinib, then typically no further administration of CD19-ADC is administered to the subject, and in these cases, administration of ibrutinib is typically continued for up to one year after completion of treatment with the CD19-ADC.

[0304] If the subject achieves SD or PR after initial treatment with a CD19-ADC in combination with ibrutinib, then an additional CD19-ADC may be administered to the subject. In these cases, administration of ibrutinib is typically continued after initial treatment with a CD19-ADC in combination with ibrutinib. If the subject does not achieve CR within 3 months of completing initial treatment with a CD19-ADC, then an additional CD19-ADC may be administered to the subject.

[0305] The additional CD19-ADC may be administered in a dosing regimen consisting of two Q3W treatment cycles.Preferably, the dose of each of the two treatment cycles is the same.Alternatively, the second dose may be a reduced dose, i.e., the dosing regimen may be a tapering dosing regimen as defined herein.Typically, the additional CD19-ADC is administered in combination with treatment with ibrutinib.

[0306] Ibrutinib may be administered in a QD (once a day) dosing regimen, i.e., ibrutinib may be administered once a day. Preferably, the dose of ibrutinib is about 550-570 mg / day (such as about 560 mg / day). Reduced daily doses are about 420 mg / day and about 280 mg / day, and reduced doses may be administered if the subject exhibits, for example, treatment-related toxicity.

[0307] In some cases in which a CD19-ADC is administered in combination with ibrutinib, the subject has, is suspected of having, has been identified as at risk for, or has been diagnosed with cancer, such as diffuse large B-cell lymphoma (DLBCL) or mantle cell lymphoma (MCL).

[0308] Ibrutinib (Imbruvica): (i)CAS number→936563-96-1 (See http: / / www.cas.org / content / chemical-substances / faqs)

[0309] (ii) Unique Ingredient Identifier (UNII) → 1X70OSD4VX (see http: / / www.fda.gov / ForIndustry / DataStandards / SubstanceRegistrationSystem-UniqueIngredientIdentifierUNII / default.htm)

[0310] (iii) IUPAC name → 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one

[0311] (iv) Structure → [ka]

[0312] Combination with durvalumab In particular, in embodiments in which the proliferative disorder is lymphoma, administration of a CD19-ADC in combination with durvalumab is contemplated.

[0313] Durvalumab may be administered to the subject before, in combination with, or after the CD19-ADC. Preferably, the CD19-ADC and durvalumab are administered concomitantly, i.e., the CD19-ADC and durvalumab are administered as part of the same treatment cycle. In some cases, the CD19-ADC and durvalumab are not administered on the same day of a treatment cycle. For example, in some cases, the CD19-ADC is administered on day 1 of a treatment cycle and durvalumab is administered on day 8 of a treatment cycle.

[0314] When administered in combination with durvalumab, the CD19-ADC is preferably administered in a dosing regimen consisting of two Q3W treatment cycles. Preferably, the CD19-ADC dose in each of the two treatment cycles is the same. Alternatively, the second dose may be a reduced dose, i.e., the dosing regimen may be a tapered dosing regimen as defined herein.

[0315] Durvalumab, when administered in combination with a CD19-ADC, is preferably administered in a Q3W dosing regimen. In some embodiments, the dose of durvalumab is about 1400-1600 mg. The dose of durvalumab is preferably 1500 mg.

[0316] In some cases where CD19-ADC is administered in combination with durvalumab, the starting dose is about 90 μg / kg, about 120 μg / kg, or about 150 μg / kg. In some embodiments, when administered in combination with durvalumab, the starting dose of CD19-ADC may be about 140-160 μg / kg.

[0317] In some cases, the CD19-ADC and durvalumab are administered sequentially, for example, in some cases, administration of durvalumab begins after completion of treatment with the CD19-ADC.

[0318] In some cases, durvalumab administration is discontinued upon completion of CD19-ADC therapy. Typically, however, durvalumab administration continues after completion of CD19-ADC therapy. In some cases, durvalumab administration continues for up to one year after completion of CD19-ADC therapy.

[0319] Durvalumab is preferably administered in a Q4W dosing regimen when administered following completion of treatment with CD19-ADC. In some embodiments, the administered dose of durvalumab is about 1400-1600 mg. The administered dose of durvalumab is preferably 1500 mg.

[0320] If a subject achieves a CR after initial treatment with a CD19-ADC in combination with durvalumab, then typically no further CD19-ADC is administered to the subject, and in these cases durvalumab administration typically continues for up to one year after completion of treatment with the CD19-ADC.

[0321] If the subject achieves SD or PR after initial treatment with a CD19-ADC in combination with durvalumab, then an additional CD19-ADC may be administered to the subject. In these cases, administration of durvalumab typically continues after initial treatment with a CD19-ADC in combination with durvalumab. If the subject does not achieve CR within 3 months of completing initial treatment with a CD19-ADC, then an additional CD19-ADC may be administered to the subject.

[0322] The additional CD19-ADC may be administered in a dosing regimen consisting of two Q3W treatment cycles. Preferably, the dose of each of the two treatment cycles is the same. Alternatively, the second dose may be a reduced dose, i.e., the dosing regimen may be a tapering dosing regimen as defined herein. Typically, the additional CD19-ADC is administered in combination with treatment with durvalumab.

[0323] In some cases in which the CD19-ADC is administered in combination with durvalumab, the subject has, is suspected of having, has been identified as at risk for, or has been diagnosed with the following cancers: diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL) or non-Hodgkin lymphoma (FL).

[0324] Durvalumab / MEDI4736: (i)CAS number→1428935-60-7 (See http: / / www.cas.org / content / chemical-substances / faqs)

[0325] (ii) Unique Ingredient Identifier (UNII) → 28X28X9OKV (see http: / / www.fda.gov / ForIndustry / DataStandards / SubstanceRegistrationSystem-UniqueIngredientIdentifierUNII / default.htm)

[0326] (iii) VH sequence (outside 1) TIFF2025024041000024.tif17137

[0327] (iv) VL sequence (outside 2) TIFF2025024041000025.tif17137

[0328] In combination with rituximab In particular, in embodiments in which the proliferative disorder is lymphoma, administration of the CD19-ADC in combination with rituximab is contemplated.

[0329] Rituximab may be administered to the subject prior to, in combination with, or after the CD19-ADC. Preferably, the CD19-ADC and rituximab are administered in combination. For example, in some cases, administration of rituximab and CD19-ADC begins on day 1 of treatment cycle 1 of the described CD19-ADC administration regime.

[0330] In some cases, the CD19-ADC and rituximab are administered sequentially, for example, in some cases, administration of rituximab begins after completion of treatment with the CD19-ADC.

[0331] Rituximab may be administered on a Q3W dosing regimen. In some embodiments, the dose of rituximab is 325-425 mg / m2. Preferably, the dose of rituximab is 375 mg / m2 or less. 2 It is.

[0332] Preferably, when administering CD19-ADC in combination with rituximab, the starting dose is about 90 μg / kg, about 120 μg / kg, or about 150 μg / kg. In some embodiments, the starting dose of CD19-ADC when administered in combination with rituximab may be about 140-160 μg / kg.

[0333] In some cases in which the CD19-ADC is administered in combination with rituximab, the subject has, is suspected of having, has been identified as at risk for, or has been diagnosed with non-Hodgkin's lymphoma, such as diffuse large B-cell lymphoma (DLBCL).

[0334] In some cases where the CD19-ADC is administered in combination with rituximab, the subject may be undergoing or have undergone treatment with rituximab. In some cases, the individual may be refractory to treatment (or further treatment) with rituximab. In embodiments where the individual is undergoing or has undergone treatment with rituximab, the anti-CD19 ADC may be administered in combination with rituximab or without continued administration of rituximab.

[0335] Rituximab: (i)CAS number→174722-31-7 (See http: / / www.cas.org / content / chemical-substances / faqs)

[0336] (ii) Drugbank reference number: DB00073 (See https: / / www.drugbank.ca / )

[0337] (iii) Unique Ingredient Identifier (UNII) → 4F4X42SYQ6 (see http: / / www.fda.gov / ForIndustry / DataStandards / SubstanceRegistrationSystem-UniqueIngredientIdentifierUNII / default.htm)

[0338] (iv) Heavy chain sequence: QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWG AGTTVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKAEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0339] Light chain sequence: QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0340] Combination with cytarabine In particular, in embodiments in which the proliferative disorder is lymphoma, administration of the CD19-ADC in combination with cytarabine is contemplated.

[0341] Cytarabine may be administered to the subject prior to, concomitantly with, or after the CD19-ADC. Preferably, the CD19-ADC and cytarabine are administered concomitantly.

[0342] In a preferred embodiment, the CD19-ADC is administered in a Q3W regimen, preferably on day 2 of a treatment cycle. Preferably, the CD19-ADC is administered at an initial dose for two treatment cycles, followed by a reduced dose of 50% of the initial dose in subsequent cycles. In some embodiments, the initial dose is about 140-160 μg / kg and the reduced dose is about 70-80 μg / kg. Preferably, the initial dose is about 150 μg / kg and the reduced dose is about 75 μg / kg.

[0343] In a preferred embodiment, cytarabine is administered in a Q3W regimen, preferably as 5 divided doses, 1 divided dose per day on days 1-5 of each cycle. Preferably, cytarabine is administered as 5 equal divided doses. The divided doses are about 100 mg / m 2 , about 200mg / m 2 , about 300mg / m 2 or about 400 mg / m 2 It may be.

[0344] In some cases in which a CD19-ADC is administered in combination with cytarabine, the subject has, is suspected of having, has been identified as at risk for, or has been diagnosed with non-Hodgkin's lymphoma, such as diffuse large B-cell lymphoma (DLBCL).

[0345] Cytarabine: (i) CAS number: 147-94-4 (see http: / / www.cas.org / content / chemical-substances / faqs)

[0346] (ii) Unique Ingredient Identifier (UNII) → 04079A1RDZ (see http: / / www.fda.gov / ForIndustry / DataStandards / SubstanceRegistrationSystem-UniqueIngredientIdentifierUNII / default.htm)

[0347] (iii) IUPAC name: 4-amino-1-[(2R,3S,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one

[0348] (iv) Structure→ [ka]

[0349] Combination with cytarabine and rituximab In particular, in embodiments in which the proliferative disorder is lymphoma, administration of the CD19-ADC in combination with cytarabine and rituximab is contemplated.

[0350] Cytarabine and rituximab may be administered to the subject prior to, in combination with, or after the CD19-ADC. Preferably, the CD19-ADC, cytarabine, and rituximab are administered in combination. For example, in some cases, administration of cytarabine, rituximab, and CD19-ADC begins on day 1 of treatment cycle 1 of the described CD19-ADC administration regime.

[0351] In a preferred embodiment, rituximab is administered in a Q3W regimen, preferably on day 1 of a treatment cycle. In some embodiments, the administered dose of rituximab is 325-425 mg / m2. Preferably, the administered dose of rituximab is 375 mg / m2 or less. 2 It is.

[0352] In a preferred embodiment, the CD19-ADC is administered in a Q3W regimen, preferably on day 2 of a treatment cycle. Preferably, the CD19-ADC is administered at an initial dose for two treatment cycles, followed by a reduced dose of 50% of the initial dose in subsequent cycles. In some embodiments, the initial dose is about 140-160 μg / kg and the reduced dose is about 70-80 μg / kg. Preferably, the initial dose is about 150 μg / kg and the reduced dose is about 75 μg / kg.

[0353] In a preferred embodiment, cytarabine is administered in a Q3W regimen, preferably as 5 divided doses, 1 divided dose per day on days 1-5 of each cycle. Preferably, cytarabine is administered as 5 equal divided doses. The divided doses are about 100 mg / m 2 , about 200mg / m 2 , about 300mg / m 2 or about 400 mg / m 2 It may be.

[0354] In some cases in which the CD19-ADC is administered in combination with rituximab and cytarabine, the subject has, is suspected of having, has been identified as at risk for, or has been diagnosed with non-Hodgkin's lymphoma, such as diffuse large B-cell lymphoma (DLBCL).

[0355] In some cases where a CD19-ADC is administered in combination with cytarabine and rituximab, the subject may be undergoing or have undergone treatment with rituximab. In some cases, the individual may be refractory to treatment (or further treatment) with rituximab. In embodiments where the individual is undergoing or has undergone treatment with rituximab, the anti-CD19 ADC may be administered in combination with rituximab or without continued administration of rituximab.

[0356] Specifically contemplated are embodiments in which a CD19-ADC is administered in combination with a diuretic, such as spironolactone, which may be administered to a subject receiving a CD19-ADC who experiences weight gain, edema, or pleural effusion.

[0357] Specifically contemplated are embodiments in which the CD19-ADCs are administered in combination with intrathecal medications for CNS prophylaxis.

[0358] The composition according to the present disclosure is preferably a pharmaceutical composition.The pharmaceutical composition according to the present disclosure and intended for use according to the present disclosure may contain, in addition to the active ingredient, i.e., the conjugate compound, pharma- ceutical acceptable excipients, carriers, buffers, stabilizers or other substances known to those skilled in the art. Such substances must be non-toxic and must not impair the efficacy of the active ingredient. The exact nature of the carrier or other substances will depend on the route of administration, which may be oral or by injection, for example, cutaneous, subcutaneous or intravenous.

[0359] The pharmaceutical composition for oral administration may be in the form of a tablet, capsule, powder or liquid. Tablets may contain a solid carrier or adjuvant. Liquid pharmaceutical compositions generally contain a liquid carrier such as water, petroleum-based, animal oil, vegetable oil, mineral oil or synthetic oil. They may contain saline, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol. Capsules may contain a solid carrier such as gelatin.

[0360] For intravenous injection, cutaneous injection, subcutaneous injection or injection into affected area, the active ingredient is in the form of a parenterally acceptable aqueous solution that is pyrogen-free and has suitable pH, isotonicity and stability.Those skilled in the art can fully prepare suitable solutions using isotonic vehicles such as sodium chloride injection, Ringer's injection, lactated Ringer's injection.Preservatives, stabilizers, buffers, antioxidants and / or other additives may be included as necessary.

[0361] dose It will be apparent to those skilled in the art that appropriate dosages of ADCs and compositions containing their active ingredients may vary from subject to subject. Determining the optimal dosage will generally involve balancing the level of therapeutic benefit with any 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 excretion of the compound, the duration of treatment, other drugs, compounds and / or substances used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health and past medical history of the subject. The dosage and route of administration of the compound will ultimately be at the discretion of the physician, veterinarian or clinician, but will generally be selected to achieve a local concentration at the site of action that will produce the desired effect without causing significant dangerous or adverse side effects.

[0362] In certain embodiments, the dose of ADC is determined by the expression of CD19 in the sample taken from the subject.Therefore, the level or localization of the expression of CD19 in the sample may indicate that a high or low dose of ADC is required.For example, a high expression level of CD19 may indicate that a high dose of ADC is suitable.In some cases, a high expression level of CD19 may indicate the need to administer another agent in addition to ADC.For example, administer ADC in conjunction with a chemotherapeutic agent.A high expression level of CD19 may indicate the need for more aggressive therapy.

[0363] In general, the suitable dose of each active compound is in the range of about 100 ng to about 25 mg (more typically about 1 μg to about 10 mg) per kg of subject body weight per day. When the active compound is a salt, ester, amide, prodrug, etc., the dosage is calculated based on the parent compound, so the actual weight used will increase proportionately.

[0364] In some situations, standardizing the dose based on a body size parameter, such as body surface area (BSA), rather than based on body weight, takes into account inter-subject variability in the pharmacokinetics (e.g., clearance rate) of the ADC. In these situations, calculating dose levels using the body size parameter provides more accurate dosing.

[0365] Thus, in some embodiments, the dose of the ADC administered to a subject is standardized to the subject's size (i.e., not to the subject's weight). In some cases, the dose of the ADC administered to a subject is standardized to the subject's body surface area (BSA). Preferably, the dose of the ADC is standardized to BSA using the Dubois formula (e.g., as disclosed in Japanese Journal of Clinical Oncology, Volume 33, Issue 6, 1 June 2003, Pages 309-313, https: / / doi.org / 10.1093 / jjco / hyg062).

[0366] antibody The term "antibody" is used herein in the broadest sense and specifically encompasses monoclonal antibodies, polyclonal antibodies, dimers, multimers, multispecific antibodies (e.g., bispecific antibodies), intact antibodies (also described as "full-length" antibodies) and antibody fragments (provided that they exhibit the desired biological activity, e.g., the ability to bind to a first target protein) (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.

[0367] An antibody is a protein produced by the immune system that can recognize and bind to a specific antigen (Janeway, C., Travers, P., Walport, M., Shlomchik (2001) Immuno Biology, 5th Ed., Garland Publishing, New York). A target antigen generally has numerous binding sites (also called epitopes) that are recognized by the complementarity determining regions (CDRs) of multiple antibodies. Each antibody that specifically binds to a different epitope has a different structure. Thus, one antigen may have more than one corresponding antibody. An antibody may include a full-length immunoglobulin molecule or an immunologically active portion of a full-length immunoglobulin molecule, i.e., a molecule that contains an antigen binding site that immunospecifically binds to an antigen or a portion thereof of a target of interest, such as, but not limited to, a cancer cell or a cell that produces an autoimmune antibody associated with an autoimmune disease. The immunoglobulin can be an immunoglobulin molecule of any type (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 [any allotype other than G1m1], G1m17, G2m23, G3m21, G3m28, G3m11, G3m5, G3m13, G3m14, G3m10, G3m15, G3m16, G3m6, G3m24, G3m26, G3m27, A2m1, A2m2, Km1, Km2, and Km3). The immunoglobulin can be from any species, including from human, mouse, or rabbit.

[0368] An "antibody fragment" comprises a portion of a full-length antibody, generally the antigen-binding or variable region thereof. Examples of antibody fragments include Fab, Fab', F(ab')2 and scFv fragments, diabodies, linear antibodies, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies, CDRs (complementarity determining regions), and epitope-binding fragments of any of the above that immunospecifically bind to cancer cell antigens, viral antigens or microbial antigens, single-chain antibody molecules, and multispecific antibodies formed from antibody fragments.

[0369] The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies constituting the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed to a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations that include different antibodies directed to different determinants (epitopes), each monoclonal antibody is directed to a single determinant on the antigen. In addition to their specificity, monoclonal antibodies are advantageous in that they may be synthesized free of contaminating other antibodies. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and should not be construed as requiring the antibody to be produced by any particular method. For example, monoclonal antibodies for use in accordance with the present disclosure may be produced by the hybridoma method first described by Kohler et al (1975) Nature 256:495, or may be produced by recombinant DNA methods (see US 4816567). Monoclonal antibodies may 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).

[0370] Monoclonal antibodies herein specifically include "chimeric" antibodies, in which a portion of the heavy and / or light chain is identical or homologous to the corresponding sequence of an antibody derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical or homologous to the corresponding sequence of an antibody derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, provided that they exhibit the desired biological activity (US4816567 and Morrison et al (1984) Proc. Natl. Acad. Sci. USA, 81:6851-6855). Chimeric antibodies include "primatized" antibodies that contain antigen-binding sequences of variable domains derived from a non-human primate (e.g., Old World Monkey or Ape-Man) and human constant region sequences.

[0371] An "intact antibody" herein is an antibody comprising a VL domain, a VH domain, and a light chain constant domain (CL), a heavy chain constant domain CH1, CH2 and CH3. The constant domain may be a native sequence constant domain (e.g., a human native sequence constant domain) or an amino acid sequence variant thereof. An intact antibody may have one or more "effector functions", which refer to the biological activities attributable to the Fc region of an antibody (a native sequence Fc region or an amino acid sequence variant Fc region). Examples of antibody effector functions include binding of C1q, complement dependent cytotoxicity, binding of Fc receptors, antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, and down-regulation of cell surface receptors such as the B cell receptor, i.e., BCR.

[0372] Intact antibodies can be assigned to different "classes" depending on the amino acid sequence of the constant domain of their heavy chains. There are five main classes of intact antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these can be further divided into "subclasses" (isotypes), e.g., 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 the different classes of immunoglobulins are well known.

[0373] In the following, embodiments and experiments illustrating the principles of the present disclosure will be discussed with reference to the accompanying drawings. [Brief description of the drawings]

[0374] [Figure 1A] array [Figure 1B] array [Diagram 2] Ramos-e222 Subcutaneous Model - Mouse Xenograft [Diagram 3] NALM-6 tumor cell inoculation model - mouse xenograft [Figure 4] Total antibody and ADCx19 concentrations over time by patient and dose (Cycle 1)

[0375] This disclosure includes any combination of the illustrative and preferred features described except where expressly impermissible or expressly avoided.

[0376] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0377] Examples and embodiments of the present disclosure are illustrated below by way of example with reference to the accompanying drawings. Further examples and embodiments will be apparent to those skilled in the art. All documents mentioned in this specification are incorporated herein by reference.

[0378] Throughout this specification, including the appended claims, unless the context otherwise requires, the words "comprise" and variations such as "comprises" and "comprising" shall be understood to indicate the inclusion of a stated integer, step, group of integers or group of steps but not the exclusion of any other integer, step, group of integers or group of steps.

[0379] It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as having a particular lower limit, and / or as having a particular upper limit, preceded by "about." When such a range is stated, another embodiment includes the particular lower limit and / or the particular upper limit. Similarly, when values ​​are stated as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment.

[0380] Some embodiments Lymphoma The disclosure provides a method of treating a proliferative disease in a subject, comprising administering to the subject a CD19-ADC, wherein the CD19-ADC is administered to the subject in a tapering and / or extended dosing regimen.

[0381] In some cases, the dosing regimen involves administering about 120 μg / kg every 3 weeks for two cycles, followed by a reduced dose of about 60 μg / kg for the third and subsequent cycles, followed by subsequent treatment every 6 weeks (starting 6 weeks after administration of the second cycle). Preferably, only subjects who achieve at least SD after the second cycle will continue at the reduced dose and extended cycle length.

[0382] In some cases, the dosing regimen involves administering about 150 μg / kg every 3 weeks for two cycles, followed by a reduced dose of about 60 μg / kg for the third and subsequent cycles, followed by subsequent treatment every 6 weeks (starting 6 weeks after the second cycle). Preferably, only subjects who achieve at least SD after the second cycle will continue at the reduced dose and extended cycle length.

[0383] In some preferred cases, the dosing regimen involves administering about 140-160 μg / kg every 3 weeks for two cycles, followed by subsequent treatments every 3 weeks at a reduced dose of about 70-80 μg / kg for the third and subsequent cycles (starting 3 weeks after the second cycle). Preferably, only subjects who achieve at least SD after the second cycle will continue at the reduced dose.

[0384] In some particularly preferred cases, the dosing regimen involves administration of about 150 μg / kg every 3 weeks for two cycles, followed by subsequent treatment every 3 weeks at a reduced dose of about 75 μg / kg for the third and subsequent cycles (starting 3 weeks after administration of the second cycle). Preferably, only subjects who achieve at least SD after the second cycle will continue at the reduced dose.

[0385] In some cases, the dosing regimen involves administration of about 200 μg / kg every 6 weeks for two cycles, followed by a reduced dose of about 60 μg / kg for the third and subsequent cycles, followed by subsequent treatment every 6 weeks (starting 6 weeks after administration of the second cycle). Preferably, only subjects who achieve at least SD after the second cycle will continue at the reduced dose.

[0386] In some cases, the dosing regimen involves administration of about 200 μg / kg every 6 weeks for one cycle, followed by subsequent treatments every 6 weeks at a reduced dose of about 60 μg / kg for the second or subsequent cycles (starting 6 weeks after administration of the first cycle). Preferably, only subjects who achieve at least SD after the first cycle will continue at the reduced dose.

[0387] In some cases, the dosing regimen includes administering about 45 μg / kg every 3 weeks for up to 4 treatment cycles, followed by subsequent treatment with a reduced dose of about 30 μg / kg or about 20 μg / kg (e.g., 20-30 μg / kg) every 3 weeks. In some cases, the dose is reduced after administering a starting dose of 45 μg / kg for only 1 treatment cycle. In some cases, the dose is reduced after administering a starting dose of 45 μg / kg for only 2 treatment cycles. In some cases, the dose is reduced after administering a starting dose of 45 μg / kg for only 3 treatment cycles. In some cases, the dose is reduced after administering a starting dose of 45 μg / kg for 4 treatment cycles.

[0388] Preferably, the CD19-ADC is administered as a single dose on day 1 of each cycle, unless otherwise specified.

[0389] Preferably, the CD19-ADC is ADCx19 as described herein.

[0390] Preferably, the proliferative disease is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic lymphoma (CLL), B-cell lineage non-Hodgkin's lymphoma (B-NHL) such as Waldenstrom's macroglobulinemia, Burkitt's lymphoma and marginal zone B-cell lymphoma (MZBL). The disease may be relapsed or refractory.

[0391] Preferably, the subject is a human.

[0392] Preferably, the CD19-ADC is administered in combination with dexamethasone, as described herein.

[0393] Combination with ibrutinib In embodiments in which a CD19-ADC is administered in combination with ibrutinib, the CD19-ADC is preferably administered in a dosing regimen consisting of two equal Q3W treatment cycles.

[0394] Preferably, the starting dose of CD19-ADC is about 60 μg / kg, about 90 μg / kg, about 120 μg / kg or about 150 μg / kg.

[0395] Ibrutinib is preferably administered in combination with a CD19-ADC in a QD regimen. The dose of ibrutinib is preferably about 560 mg / day.

[0396] Preferably, administration of ibrutinib continues after completion of treatment with the CD19-ADC.

[0397] If a subject achieves a CR after initial treatment with a combination of a CD19-ADC and ibrutinib, then preferably the subject is not further administered with a CD19-ADC.

[0398] If the subject achieves SD or PR after initial treatment with a combination of CD19-ADC and ibrutinib, then administration of ibrutinib is preferably continued after completion of treatment with the CD19-ADC.If the subject does not achieve CR within 3 months of completing initial treatment with the CD19-ADC, then an additional CD19-ADC is preferably administered to the subject.

[0399] Preferably, the additional CD19-ADC is administered in combination with ibrutinib, as described above, in a dosing regimen consisting of two equal Q3W treatment cycles.

[0400] Combination with durvalumab In embodiments in which a CD19-ADC is administered in combination with durvalumab, the CD19-ADC is preferably administered in a dosing regimen consisting of two equal Q3W treatment cycles.

[0401] Preferably, the starting dose of CD19-ADC is about 90 μg / kg, about 120 μg / kg or about 150 μg / kg.

[0402] Durvalumab is preferably administered in combination with a CD19-ADC on a Q3W regimen. The dose of durvalumab is preferably about 1500 mg.

[0403] When administered in combination in a Q3W regimen, preferably, the CD19-ADC is administered on day 1 of the Q3W cycle and durvalumab is administered on day 8 of the Q3W cycle.

[0404] Preferably, administration of durvalumab continues after completion of treatment with CD19-ADC. When administered after completion of treatment with CD19-ADC, durvalumab is preferably administered on a Q4W dosing regimen. The dose of durvalumab administered is preferably about 1500 mg.

[0405] If a subject achieves a CR after initial treatment with a CD19-ADC in combination with durvalumab, then preferably the subject is not further administered CD19-ADC.

[0406] If the subject achieves SD or PR after initial treatment with a CD19-ADC in combination with durvalumab, then administration of durvalumab is preferably continued after completion of treatment with the CD19-ADC. If the subject does not achieve CR within 3 months of completing initial treatment with a CD19-ADC, then the subject is preferably administered an additional CD19-ADC.

[0407] Preferably, the additional CD19-ADC is administered in combination with durvalumab in a dosing regimen consisting of two equal Q3W treatment cycles, as described above.

[0408] In combination with rituximab In some embodiments in which a CD19-ADC is administered in combination with rituximab, the CD19-ADC is administered in a dosing regimen comprising about 140-160 μg / kg administered every 3 weeks for two cycles, followed by a reduced dose of about 70-80 μg / kg for the third and subsequent cycles with subsequent treatments every 3 weeks (starting 3 weeks after the second cycle dosing).

[0409] In some preferred embodiments in which a CD19-ADC is administered in combination with rituximab, the CD19-ADC is preferably administered in a dosing regimen comprising about 150 μg / kg administered every three weeks for two cycles, followed by a reduced dose of about 75 μg / kg for the third and subsequent cycles, with subsequent treatments every three weeks (starting three weeks after administration of the second cycle).

[0410] Rituximab is preferably administered in combination with a CD19-ADC on a Q3W regimen, e.g., both are administered on day 1 of each treatment cycle. In some embodiments, the dose of rituximab is about 325-425 mg / m 2 The dose of rituximab is preferably about 375 mg / m 2 It is.

[0411] Combination with cytarabine In some embodiments in which a CD19-ADC is administered in combination with cytarabine, the CD19-ADC is administered in a dosing regimen comprising about 140-160 μg / kg administered every 3 weeks for two cycles, followed by a reduced dose of about 70-80 μg / kg for the third and subsequent cycles, with subsequent treatments every 3 weeks (starting 3 weeks after the second cycle dosing).

[0412] In some preferred embodiments in which a CD19-ADC is administered in combination with cytarabine, the CD19-ADC is preferably administered in a dosing regimen comprising about 150 μg / kg administered every three weeks for two cycles, followed by a reduced dose of about 75 μg / kg for the third and subsequent cycles, with subsequent treatment every three weeks (starting three weeks after administration of the second cycle).

[0413] Preferably, the CD19-ADC is administered on day 2 of each Q3W treatment cycle.

[0414] Cytarabine is preferably administered in combination with CD19-ADC in a Q3W regimen. Preferably, cytarabine is administered as 5 equal doses, one divided dose per day on days 1-5 of each cycle. The divided dose levels are about 100 mg / m per divided dose. 2 , about 200mg / m 2 , about 300mg / m 2 or about 400 mg / m 2 It may be.

[0415] Combination with cytarabine and rituximab In some embodiments in which a CD19-ADC is administered in combination with cytarabine and rituximab, the CD19-ADC is administered in a dosing regimen comprising about 140-160 μg / kg administered every 3 weeks for two cycles, followed by a reduced dose of about 70-80 μg / kg for the third and subsequent cycles, with subsequent treatments every 3 weeks (starting 3 weeks after the second cycle dosing).

[0416] In some preferred embodiments in which a CD19-ADC is administered in combination with cytarabine and rituximab, the CD19-ADC is preferably administered in a dosing regimen comprising about 150 μg / kg administered every three weeks for two cycles, followed by a reduced dose of about 75 μg / kg for the third and subsequent cycles, followed by treatment every three weeks (starting three weeks after administration of the second cycle).

[0417] Preferably, the CD19-ADC is administered on day 2 of each Q3W treatment cycle.

[0418] Rituximab is preferably administered in combination with a CD19-ADC on a Q3W regimen. In some embodiments, the dose of rituximab is about 325-425 mg / m 2 The dose of rituximab is preferably about 375 mg / m 2 It is.

[0419] Preferably, rituximab is administered on day 1 of each Q3W treatment cycle.

[0420] Cytarabine is preferably administered in combination with CD19-ADC in a Q3W regimen. Preferably, cytarabine is administered as 5 equal doses, one divided dose per day on days 1-5 of each cycle. The divided dose levels are about 100 mg / m per divided dose. 2 , about 200mg / m 2 , about 300mg / m 2 or about 400 mg / m 2 It may be.

[0421] leukemia Split dosing regimes in which divided doses are administered once a week, for example, on days 1, 8, and 15 of a 21 day (3 week) treatment cycle, are specifically contemplated.

[0422] Preferably, each sub-dose is of equal magnitude, ie, each sub-dose delivers the same amount of CD19-ADC to the subject.

[0423] Preferably, each divided dose is 40-60 μg / kg (such as 45-55 μg / kg). In particularly preferred cases, each divided dose is 50 μg / kg.

[0424] Preferably, the CD19-ADC is ADCx19 as described herein.

[0425] Preferably, the subject is a human.

[0426] Preferably, the proliferative disease is a leukemia, such as hairy cell leukemia (HCL), hairy cell leukemia subtype (HCL-v), and acute lymphoblastic leukemia (ALL), such as Philadelphia chromosome positive ALL (Ph+ALL) or Philadelphia chromosome negative ALL (Ph-ALL). The disease may be relapsed or refractory.

[0427] The use of this type of split-dose regimen to treat hematological cancers such as ALL is a particularly interesting embodiment, which is preferably CD19+ and may be of the relapsed or refractory type.

[0428] Preferably, the CD19-ADC is administered in combination with dexamethasone, as described herein.

[0429] Disclosure Statement Lymphoma 1. A method of treating a proliferative disease in a subject, comprising administering to the subject a CD19-ADC, the CD19-ADC comprising administering to the subject an L-(D L ) p wherein D L is a group of formula I or II: [ka] [ka] During the ceremony, L is an antibody (Ab) that is an antibody that binds to CD19, When there is a double bond between C2' and C3', R 12 but, (ia) optionally, halo, nitro, cyano, ether, carboxy, ester, C 1-7 Alkyl, C 3-7 Heterocyclyl and bis-oxy-C 1-3 C substituted with one or more substituents selected from the group consisting of alkylene 5-10 Aryl groups, (ib)C 1-5 Saturated aliphatic alkyl, (ic)C 3-6 saturated cycloalkyl, (id) a group: [ka] In the formula, R 21 , R 22 and R 23 Each of these is independent of H, C 1-3 Saturated alkyl, C 2-3 Alkenyl, C 2-3 alkynyl and cyclopropyl; R 12 A group having a total of 5 or less carbon atoms in the group, (ie) a group [ka] In the formula, R 25a and R 25b one of which is H and the other is phenyl, optionally substituted by a group selected from halo, methyl, methoxy, pyridyl, and thiophenyl; and (if) a group [ka] R 24 But, H, C 1-3 Saturated alkyl, C 2-3 Alkenyl, C 2-3 A group selected from alkynyl, cyclopropyl, phenyl, optionally substituted by a group selected from halo, methyl, methoxy, pyridyl, and thiophenyl. is selected from the group consisting of When there is a single bond between C2' and C3', R 12 is the following group: [ka] R 26aand R 26b are independent, H, F, C 1-4 Saturated alkyl, C 2-3 alkenyl, the alkyl and alkenyl groups being optionally selected from 1-4 Alkylamide and C 1-4 or R 26a and R 26b When one of the groups is H, the other group is a nitrile and C 1-4 alkyl esters, R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR', nitro, Me3Sn, and halo; R and R' are independently optionally substituted C 1-12 Alkyl group, C 3-20 Heterocyclyl groups and C 5-20 aryl groups; R 7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR', nitro, Me3Sn, and halo; R” is C 3-12 An alkylene group, the chain of which may contain one or more heteroatoms, e.g., O, S, NR N2 (R N2 is H or C 1-4 alkyl), and / or may be interrupted by aromatic rings, e.g. benzene or pyridine, Y and Y' are selected from O, S or NH; R 6’ R 6 And, R 7’ R 7 And, R 9’ R 9 are selected from the same group as In formula I, R L1’ is a linker for linking to an antibody (Ab), R 11a But, OH, OR A (RA is C 1-4 alkyl), and SO z M, z is 2 or 3, and M is a pharma- ceutically acceptable monovalent cation; R 20 and R 21 together form a double bond between the nitrogen atom and the carbon atom to which they are attached, or R 20 But H and R C are selected from R C is a capping group, R 21 But, OH, OR A and S.O. z M is selected from When a double bond exists between C2 and C3, R 2 but, (ia) optionally, halo, nitro, cyano, ether, carboxy, ester, C 1-7 Alkyl, C 3-7 Heterocyclyl and bis-oxy-C 1-3 C substituted with one or more substituents selected from the group consisting of alkylene 5-10 Aryl groups, (ib)C 1-5 Saturated aliphatic alkyl, (ic)C 3-6 saturated cycloalkyl, (id) a group: [ka] R 11 , R 12 and R 13 Each of these is independent of H, C 1-3 Saturated alkyl, C 2-3 Alkenyl, C 2-3 alkynyl and cyclopropyl; R 2 A group having a total of 5 or less carbon atoms in the group, (ie) a group [ka] R 15a and R 15b one of which is H and the other is phenyl, optionally substituted by a group selected from halo, methyl, methoxy, pyridyl, and thiophenyl; and (if) a group [ka] R 14 But, H, C 1-3 Saturated alkyl, C 2-3 Alkenyl, C 2-3 A group selected from alkynyl, cyclopropyl, phenyl, optionally substituted by a group selected from halo, methyl, methoxy, pyridyl, and thiophenyl. is selected from the group consisting of When there is a single bond between C2 and C3, R 2 is the following group, [ka] R 16a and R 16b are independent, H, F, C 1-4 Saturated alkyl, C 2-3 alkenyl, the alkyl and alkenyl groups being optionally selected from 1-4 Alkylamide and C 1-4 or R 16a and R 16b When one of the groups is H, the other group is a nitrile and C 1-4 alkyl esters, In formula II, R 22 is a group of formula IIIa, IIIb or IIIc: (a) [ka] (Wherein, A is C5-7 is an aryl group, (i)Q 1 is a single bond, and Q 2 is a single bond and -Z-(CH2) n -, where Z is selected from a single bond, O, S and NH, and n is 1 to 3; or (ii)Q 1 is -CH=CH-, and Q 2 is a single bond) (b) [ka] (In the formula, R C1 , R C2 and R C3 are independently H and unsubstituted C 1-2 alkyl) (c) [ka] (wherein Q is OR L2’ , S.R. L2’ and N.R. N -R L2’ are selected from R N is selected from H, methyl and ethyl X is OR L2’ , S.R. L2’ , CO2-R L2’ , C.O.R. L2’ , NH-C(=O)-R L2’ , NHNH-R L2’ , CONHNH-R L2’ , [ka] , [ka] , NR N R L2’ and R is selected from the group including N But H and C 1-4is selected from the group consisting of alkyl, R L2’ is a linker for linking to an antibody (Ab), R 10 and R 11 together 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 But, OH, OR A and S.O. z M is selected from R 30 and R 31 together 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 But, OH, OR A and S.O. z The method according to any one of claims 1 to 5, wherein said method is selected from M.

[0430] 2. The method of the first statement, wherein the CD19-ADC is administered to the subject in a tapering and / or extended dosing regimen.

[0431] 3. The CD19-ADC has the following chemical structure: [ka] 2. The method of any one of the first or second statements, wherein Ab is a CD19 antibody and the DAR is 1-8.

[0432] 4. The method according to any one of the first to third statements, wherein the Ab comprises a VH domain having the sequence of SEQ ID NO:2 and a VL domain having the sequence of SEQ ID NO:8.

[0433] 5. The method according to any one of the first to fourth statements, wherein the Ab comprises a heavy chain having the sequence of SEQ ID NO:13 and a light chain having the sequence of SEQ ID NO:14.

[0434] 6. The method of any one of claims 1 to 5, wherein the CD19-ADC is ADCx19.

[0435] 7. The method of any of the preceding statements, wherein the starting dose of CD19-ADC is reduced no more than twice during the dosing regimen.

[0436] 8. The method of any of the preceding statements, wherein the starting dose of CD19-ADC is reduced no more than once during the dosing regimen.

[0437] 9. The method of any of the preceding statements, wherein the dosage is reduced after the first treatment cycle.

[0438] 10. The method of any of the preceding statements, wherein the dosage is reduced after the second treatment cycle.

[0439] 11. The method of any of the preceding statements, wherein the dosage is reduced after the third treatment cycle.

[0440] 12. The method of any of the preceding statements, wherein the dosage is reduced after the fourth treatment cycle.

[0441] 13. The method of any of the preceding statements, wherein the dose is reduced only if the subject has achieved at least stable disease [SD] at the end of the immediately preceding treatment cycle.

[0442] 14. The method of any of the preceding statements, wherein the starting dose is 40-50 μg / kg (such as about 45 μg / kg).

[0443] 15. The method of any of the preceding statements, wherein the starting dose is at least 60 μg / kg.

[0444] 16. The method of any of the preceding statements, wherein the starting dose is about 60 μg / kg.

[0445] 17. The method of any of the preceding statements, wherein the starting dose is at least 90 μg / kg.

[0446] 18. The method of any of the preceding statements, wherein the starting dose is about 90 μg / kg.

[0447] 19. The method of any of the preceding statements, wherein the starting dose is at least 120 μg / kg.

[0448] 20. The method of any of the preceding statements, wherein the starting dose is about 120 μg / kg.

[0449] 21. The method of any of the preceding statements, wherein the starting dose is at least 150 μg / kg.

[0450] 22. The method of any of the preceding statements, wherein the starting dose is about 140-160 μg / kg (such as 150 μg / kg).

[0451] 23. The method of any of the preceding statements, wherein the starting dose is at least 200 μg / kg.

[0452] 24. The method of any of the preceding statements, wherein the starting dose is about 200 μg / kg.

[0453] 25. The method of any of the preceding statements, wherein the reduced dose is about 50% of the starting dose.

[0454] 26. The method of any of the preceding statements, wherein the reduced dose is about 60 μg / kg.

[0455] 27. The method of any of the preceding statements, wherein the reduced dose is about 70-80 μg / kg, optionally, the reduced dose is 75 μg / kg.

[0456] 28. The method of any of the preceding statements, wherein the reduced dose is 15-35 μg / kg (such as about 20 μg / kg or about 30 μg / kg).

[0457] 29. The method of any of the preceding statements, wherein each treatment cycle is the same length.

[0458] 30. The method of claim 29, wherein each treatment cycle is 3 weeks.

[0459] 31. The method of claim 29, wherein each treatment cycle is 6 weeks.

[0460] 32. Approximately 200 μg / kg of CD19-ADC is administered for two 6-week treatment cycles, followed by The method of claim 31, wherein a subsequent 6-week cycle of 60 μg / kg is initiated 6 weeks after administration of the second cycle.

[0461] 33. Approximately 200 μg / kg of CD19-ADC is administered in one 6-week treatment cycle, followed by The method of claim 31, wherein a subsequent 6-week cycle of 60 μg / kg is initiated 6 weeks after administration of the first cycle.

[0462] 34. Approximately 140-160 μg / kg of CD19-ADC is administered for two 3-week treatment cycles, followed by Three weeks after the second cycle, a subsequent 3-week cycle of 70-80 μg / kg was started. Optionally, about 150 μg / kg of CD19-ADC is administered for two 3-week treatment cycles, followed by The method of claim 30, wherein a subsequent 3-week cycle of 75 μg / kg is initiated 3 weeks after administration of the second cycle.

[0463] 35. The method of any one of claims 1 to 27, wherein the length of the treatment cycle is extended no more than twice during the administration regime.

[0464] 36. The method of any one of claims 1 to 27 or 31, wherein the length of the treatment cycle is extended by no more than one time during the dosing regimen.

[0465] 37. The method of any one of claims 1-27 or 35-36, wherein after the first treatment cycle, the length of the treatment cycle is extended.

[0466] 38. The method of any one of claims 1 to 27 or 35 to 37, wherein after the second treatment cycle, the length of the treatment cycle is extended.

[0467] 39. The method of any one of claims 1 to 27 or 35 to 38, wherein the cycle length is extended only if the subject achieved at least stable disease [SD] at the end of the immediately preceding treatment cycle.

[0468] 40. A method according to any one of statements 1 to 27 or 35 to 39, wherein "day 1" of the first treatment cycle of the extended cycle length is delayed so that the time elapsed between "day 1" of the last cycle of the shorter treatment cycles and "day 1" of the first treatment cycle of the extended cycle length is the same as the length of the extended treatment cycle.

[0469] 41. The method of any one of claims 1 to 27 or 35 to 40, wherein the initiation cycle length is 3 weeks.

[0470] 42. The method according to any one of claims 1 to 27 or 35 to 41, wherein the extended cycle length is 6 weeks.

[0471] 43. Approximately 150 μg / kg of CD19-ADC is administered for two 3-week treatment cycles, followed by The method of claim 42, wherein a subsequent 6-week cycle of 60 μg / kg is initiated 6 weeks after administration of the second cycle.

[0472] 44. Approximately 120 μg / kg of CD19-ADC is administered for two 3-week treatment cycles, followed by The method of claim 42, wherein a subsequent 6-week cycle of 60 μg / kg is initiated 6 weeks after administration of the second cycle.

[0473] 45. The method of any of the preceding statements, wherein the CD19-ADC is administered as a single dose.

[0474] 46. ​​The method of any of the preceding statements, wherein the dose of CD19-ADC is administered on day 1 of a treatment cycle.

[0475] 47. The method of any of the preceding statements, wherein the proliferative disorder is characterized by the presence of a neoplasm comprising CD19+ve cells.

[0476] 48. The method of any of the preceding statements, wherein the subject has been diagnosed with the proliferative disease prior to initiation of treatment with CD19-ADC.

[0477] 49. The method of any of the preceding statements, wherein the disease is B-cell non-Hodgkin's lymphoma (B-NHL).

[0478] 50. A method according to any preceding statement, comprising selecting a subject for treatment based on expression of CD19.

[0479] 51. The method of claim 50, wherein the subject is selected if at least 5% of the neoplastic cells express CD19.

[0480] 52. The method of any of the preceding statements, wherein the proliferative disease is a leukemia such as diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic lymphoma (CLL), non-Hodgkin's lymphoma including Waldenstrom's macroglobulinemia, Burkitt's lymphoma and marginal zone B-cell lymphoma (MZBL), and 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)).

[0481] 53. The method of any of the preceding statements, wherein the proliferative disease is B-cell non-Hodgkin's lymphoma (B-NHL).

[0482] 54. The method of any of the preceding statements, wherein the proliferative disease is resistant, relapsed or refractory.

[0483] 55. The method of any of the preceding statements, wherein the subject is a human.

[0484] 56. The method of any of the preceding statements, wherein the CD19-ADC is administered intravenously.

[0485] 57. The method of any preceding claim, further comprising administering a chemotherapeutic agent in combination with the CD19-ADC.

[0486] 58. The method of claim 57, wherein the chemotherapeutic agent is a checkpoint inhibitor.

[0487] 59. The method of claim 57, wherein the checkpoint inhibitor is ibrutinib.

[0488] 60. The method of claim 59, wherein the ibrutinib is administered in combination with a CD19-ADC.

[0489] 61. The method of any one of claims 59 or 60, wherein the ibrutinib is administered in a QD dosing regimen.

[0490] 62. The method according to any one of claims 59 to 61, wherein the dosage of ibrutinib is 560 mg / day, 420 mg / day or 280 mg / day.

[0491] 63. The method according to any one of claims 59 to 61, wherein the dosage of ibrutinib is 560 mg / day.

[0492] 64. The method of any one of statements 59 to 63, wherein the CD19-ADC is administered to the subject in two Q3W cycles.

[0493] 65. The method of claim 64, wherein the dose of CD19-ADC in each of the two 3-week treatment cycles is the same.

[0494] 66. The method of any one of claims 59 to 65, wherein the dose of CD19-ADC is about 60 μg / kg, about 90 μg / kg, about 120 μg / kg, about 140-160 μg / kg or about 150 μg / kg.

[0495] 67. The method of any one of statements 59 to 66, wherein administration of ibrutinib is continued after completion of treatment with CD19-ADC.

[0496] 68. The method of any one of claims 64 to 67, wherein the CD19-ADC is administered to the subject for two further three-week treatment cycles.

[0497] 69. The method of claim 68, wherein if the subject has not achieved CR 3 months after completion of the first two 3-week treatment cycles, two additional treatment cycles of the CD19-ADC are administered.

[0498] 70. The method of any one of claims 59 to 69, wherein the subject has, is suspected of, has been identified as at risk for, or has been diagnosed with a non-Hodgkin's lymphoma, such as diffuse large B-cell lymphoma (DLBCL) or mantle cell lymphoma (MCL).

[0499] 71. The method of claim 57, wherein the chemotherapeutic agent is durvalumab.

[0500] 72. The method of claim 71, wherein the durvalumab is administered in combination with a CD19-ADC.

[0501] 73. The method of any one of statements 71 or 72, wherein the durvalumab is administered in a Q3W dosing regimen.

[0502] 74. The method of any one of claims 71 to 73, wherein the dose of durvalumab is 1500 mg.

[0503] 75. The method of any one of claims 71 to 74, wherein the CD19-ADC is administered to the subject in two 3-week treatment cycles.

[0504] 76. The method of claim 75, wherein the dose of CD19-ADC in each of the two 3-week treatment cycles is the same.

[0505] 77. The method of any one of statements 71 to 76, wherein the dose of CD19-ADC is about 90 μg / kg, about 120 μg / kg, about 140-160 μg / kg or about 150 μg / kg.

[0506] 78. The method of any one of statements 71 to 77, wherein administration of durvalumab is continued after completion of treatment with CD19-ADC.

[0507] 79. The method of claim 78, wherein the durvalumab is administered in a Q4W dosing regimen following completion of treatment with the CD19-ADC.

[0508] 80. The method of any one of claims 75 to 79, wherein the CD19-ADC is administered to the subject for two additional three-week treatment cycles.

[0509] 81. The method of claim 80, wherein if the subject has not achieved CR 3 months after completion of the first two 3-week treatment cycles, two additional treatment cycles of the CD19-ADC are administered.

[0510] 82. The method of any one of claims 59 to 69, wherein the subject has, is suspected of, has been identified as being at risk for, or has been diagnosed with a non-Hodgkin's lymphoma, such as diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) or mantle cell lymphoma (MCL).

[0511] 83. The method of claim 57, wherein the chemotherapeutic agent is rituximab.

[0512] 84. The method of claim 83, wherein the rituximab is administered in combination with a CD19-ADC.

[0513] 85. The method of any one of statements 83 or 84, wherein the rituximab is administered in a Q3W dosing regimen.

[0514] 86. The dose of rituximab is 325-425 mg / m 2 and Optionally, the administered dose of rituximab is 375 mg / m 2 The method according to any one of claims 83 to 85,

[0515] 87. The method of any one of statements 83 to 86, wherein the dose of CD19-ADC is about 90 μg / kg, about 120 μg / kg, about 140-160 μg / kg or about 150 μg / kg.

[0516] 88. The method of any one of claims 83 to 87, wherein the subject has, is suspected of, has been identified as being at risk for, or has been diagnosed with a non-Hodgkin's lymphoma, such as diffuse large B-cell lymphoma (DLBCL).

[0517] 89. The method of claim 57, wherein the chemotherapy agent is cytarabine.

[0518] 90. The method of claim 89, wherein the cytarabine is administered in combination with a CD19-ADC.

[0519] 91. The method of any one of statements 89 or 90, wherein the CD19-ADC is administered on day 2 of each Q3W treatment cycle.

[0520] 92. The method of any one of statements 89 to 91, wherein the cytarabine is administered in a Q3W dosing regimen.

[0521] 93. The method of claim 92, wherein the cytarabine is administered as 5 divided doses, 1 divided dose per day on days 1 to 5 of each cycle.

[0522] 94. Each divided dose of cytarabine is 100 mg / m 2 , 200 mg / m 2 , 300 mg / m 2 or 400 mg / m 2 The method according to claim 93,

[0523] 95. The method of any one of claims 89 to 94, wherein the subject has, is suspected of, has been identified as being at risk for, or has been diagnosed with a non-Hodgkin's lymphoma, such as diffuse large B-cell lymphoma (DLBCL).

[0524] 96. The method of any one of statements 89 to 95, wherein the cytarabine is administered in further combination with rituximab as described in any one of statements 84 to 88.

[0525] 97. The method of claim 57 or claim 58, wherein the chemotherapeutic agent is administered to the subject prior to, simultaneously with, or after the CD19-ADC.

[0526] 98. The method of any of the preceding statements, wherein the CD19-ADC is administered in combination with a steroid.

[0527] 99. The method of claim 98, wherein the first dose of steroid is administered on the same day as the ADC.

[0528] 100. The method of claim 99, wherein the first dose of steroid is administered at least 2 hours prior to the ADC.

[0529] 101. The method of any one of claims 98 or 99, wherein a second dose of steroid is administered the day after the ADC.

[0530] 102. The method of claim 98, wherein the first dose of steroid is administered the day before the ADC.

[0531] 103. The method of claim 102, wherein a second dose of steroid is administered on the same day as the ADC.

[0532] 104. The method of claim 103, wherein a second dose of steroid is administered at least 2 hours prior to the ADC.

[0533] 105. The method according to any one of claims 103 or 104, wherein a third dose of steroid is administered the day after the ADC.

[0534] 106. The method according to any one of statements 98 to 105, wherein a steroid or multiple doses of a steroid are administered in conjunction with only the first administration of the ADC in each treatment cycle.

[0535] 107. The method according to any one of claims 98 to 106, wherein the steroid is administered orally.

[0536] 108. The method according to any one of claims 98 to 107, wherein each dose of the steroid is 8 mg.

[0537] 109. The method according to any one of claims 98 to 108, wherein each dose of the steroid is 16 mg.

[0538] 110. The method according to any one of claims 98 to 109, wherein each dose of steroid is administered as two equally divided doses.

[0539] 111. The method according to any one of claims 98 to 110, wherein each divided dose is 4 mg.

[0540] 112. The method according to any one of claims 96 to 111, wherein each divided dose is 8 mg.

[0541] 113. The method according to any one of claims 96 to 112, wherein the steroid is dexamethasone.

[0542] 114. The method of claim 98, wherein 4 mg or 8 mg of dexamethasone is administered orally twice daily (i) on the day before the ADC is administered on day 1 of week 1 of the treatment cycle, (ii) on the day the ADC is administered on day 1 of week 1 of the treatment cycle, and (iii) on the day after the ADC is administered on day 1 of week 1 of the treatment cycle.

[0543] 115. The method of claim 98, wherein 4 mg or 8 mg of dexamethasone is administered orally twice daily (i) on the day that the ADC is administered on day 1 of week 1 of the treatment cycle, and (ii) on the day following administration of the ADC on day 1 of week 1 of the treatment cycle.

[0544] 116. The method of any one of statements 114 and 115, wherein dexamethasone administered on the same day as the ADC is administered at least 2 hours before the ADC.

[0545] 117. The method according to any one of statements 114 to 115, wherein the dexamethasone is administered in conjunction with only the first administration of the ADC in each treatment cycle.

[0546] 118. The method of any of the preceding statements, wherein the toxicity of the tapering and / or extended dosing regimen is lower than a single dose dosing regimen at a constant dose level and cycle length, and optionally, the constant dose level and cycle length of the comparative regimen are the same as the starting dose and starting cycle length of the tapering and / or extended regimen.

[0547] 119. The method of claim 98, wherein the incidence of TEAEs in the tapering and / or extended dosing regime is 50% or less than the incidence of TEAEs in a fixed dose level and cycle length regime.

[0548] 120. The method of claim 119, wherein the incidence of SAEs in the tapering and / or extended dosing regime is 50% or less than the incidence of SAEs in a fixed dose level and cycle length regime.

[0549] 121. The method of claim 98, wherein the incidence of DLT in the tapering and / or extended dosing regime is 50% or less than the incidence of DLT in a fixed dose level and cycle length regime.

[0550] 122. A method according to any of the preceding statements, wherein the efficacy of the tapered and / or extended dosing regime is greater than a dosing regime having a constant dose level and cycle length, and optionally, the constant dose level and cycle length of the comparative regime are the same as the starting dose and starting cycle length of the tapered and / or extended regime.

[0551] 123. The method of claim 122, wherein the proportion of subjects achieving at least PR with the tapering and / or extended dosing regimen is at least 150% of the proportion of subjects achieving at least a partial response [PR] with a fixed dose level and cycle length regimen.

[0552] 124. The method of any of the preceding statements, wherein the subject undergoes a neurological examination prior to treatment with the ADC.

[0553] 125. The method of any of the preceding statements, wherein the subject undergoes a neurological examination after administration of the ADC.

[0554] 126. The method of any of the preceding statements, wherein the subject undergoes a neurological examination after each administration of the ADC.

[0555] 127. The method of any of the preceding statements, wherein if the subject experiences neurotoxicity following administration of the ADC, the subject undergoes a neurological examination.

[0556] 128. The method of any one of statements 124 to 127, wherein the neurological examination includes testing of strength, sensation and / or deep tendon reflexes.

[0557] 129. The method of any of the preceding statements, wherein treatment with the ADC is reduced, interrupted, or permanently discontinued if the subject has a neuropathy or experiences neurotoxicity.

[0558] 130. The method of any of the preceding statements, wherein treatment with the ADC is reduced or discontinued in the subject if grade 1 neurotoxicity is observed.

[0559] 131. The method of any of the preceding statements, wherein the subject permanently discontinues treatment with the ADC if grade 2 neurotoxicity occurs.

[0560] 132. The method of any one of statements 129 to 131, wherein treatment with an ADC is decreased by reducing the dose of the ADC administered to the subject in each treatment cycle after the second and / or by extending the length of each treatment cycle after the second and / or subsequent cycles.

[0561] 133. A method for selecting a subject for treatment by the method according to any one of claims 1 to 129, comprising determining whether the subject has or has recently become neuropathy, and determining that the subject is not suitable for treatment with the ADC if the subject has or has recently become neuropathy.

[0562] 134. A method for selecting a subject for treatment by a method according to any one of statements 1 to 132, comprising determining whether the subject has or has recently had an infectious disease caused by a pathogen that may be associated with a neurological disease and / or an immune-related disease, and determining that the subject is not suitable for treatment with the ADC if the subject has or has recently had such an infectious disease and / or an immune-related disease.

[0563] 135. The method of any one of statements 127 to 134, wherein the neuropathy or neurotoxicity is polyradiculopathy, acute inflammatory demyelinating polyradiculopathy (AIDP), Guillain-Barré syndrome (GBS), myasthenia gravis, or neuropathy (such as ascending sensory loss and / or motor weakness) related to or an early indicator of polyradiculitis, GBS, or myasthenia gravis.

[0564] 136. The method of any one of statements 125 to 132, wherein the neurological disorder or neurotoxicity is Guillain-Barré syndrome (GBS).

[0565] 137. A method for reducing toxicity and / or side effects associated with administration of a CD19-ADC to a subject, comprising administering the CD19-ADC according to any of the methods described in the preceding paragraphs.

[0566] 138. A method of improving the efficacy of a treatment associated with administration of a CD19-ADC to a subject, comprising administering the CD19-ADC according to any of the methods described in the preceding paragraphs.

[0567] 139. A method for selecting a subject for treatment with a method according to any one of statements 1 to 138, comprising selecting a subject for treatment that expresses CD19 in a tissue of interest.

[0568] 140. The method of claim 139, wherein the subject is selected if at least 5% of the cells in the relevant tissue sample express CD19.

[0569] 141. The method of any one of claims 139 and 140, wherein the tissue in question is lymphatic tissue or tumor tissue.

[0570] 142. The method of any one of claims 139 to 141, wherein the subject has experienced DLT during a fixed dose and / or fixed cycle length administration regime of the CD19-ADC.

[0571] 143. A packaged drug product that includes, in conjunction with a CD19-ADC as defined in any one of statements 1 through 5, a label or insert that informs the patient that the CD19-ADC should be administered in accordance with the method of any one of statements 1 through 92.

[0572] 144. A first medicament comprising a CD19-ADC as defined in any one of claims 1 to 6, and optionally A package insert or label containing instructions for administering the CD19-ADC according to any one of claims 1 to 136. Kit including:

[0573] 145. A CD19-ADC as defined in any one of statements 1 to 6 for use in a method according to any one of statements 1 to 136.

[0574] 146. A pharmaceutical composition comprising a CD19-ADC as defined in any one of statements 1 to 6, optionally in combination with a pharma- ceutical acceptable excipient, for use in a method according to any one of statements 1 to 136.

[0575] 147. Use of a CD19-ADC as defined in any one of statements 1 to 6 in the preparation of a medicament for use in any one of the methods of statements 1 to 136.

[0576] leukemia 1. A method of treating a proliferative disorder in a subject, comprising administering to the subject a CD19-ADC, wherein the CD19-ADC is administered to the subject in a split dose regimen; The CD19-ADC was L ) p wherein D L is a group of formula I or II: [ka] [ka] During the ceremony, L is an antibody (Ab) that is an antibody that binds to CD19, When there is a double bond between C2' and C3', R 12 but, (ia) optionally, halo, nitro, cyano, ether, carboxy, ester, C 1-7 Alkyl, C 3-7 Heterocyclyl and bis-oxy-C 1-3 C substituted with one or more substituents selected from the group consisting of alkylene 5-10 Aryl groups, (ib)C 1-5 Saturated aliphatic alkyl, (ic)C 3-6 saturated cycloalkyl, (id) a group: [ka] R 21 , R 22 and R 23 Each of these is independent of H, C 1-3 Saturated alkyl, C 2-3 Alkenyl, C 2-3 alkynyl and cyclopropyl; R 12 A group having a total of 5 or less carbon atoms in the group, (ie) a group [ka] R 25a and R 25b one of which is H and the other is phenyl, optionally substituted by a group selected from halo, methyl, methoxy, pyridyl, and thiophenyl; and (if) a group [ka] R 24 But, H, C 1-3 Saturated alkyl, C2-3 Alkenyl, C 2-3 A group selected from alkynyl, cyclopropyl, phenyl, optionally substituted by a group selected from halo, methyl, methoxy, pyridyl, and thiophenyl. is selected from the group consisting of When there is a single bond between C2' and C3', R 12 is the following group: [ka] R 26a and R 26b are independent, H, F, C 1-4 Saturated alkyl, C 2-3 alkenyl, the alkyl and alkenyl groups being optionally selected from 1-4 Alkylamide and C 1-4 or R 26a and R 26b When one of the groups is H, the other group is a nitrile and C 1-4 alkyl esters, R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR', nitro, Me3Sn, and halo; R and R' are independently optionally substituted C 1-12 Alkyl group, C 3-20 Heterocyclyl groups and C 5-20 aryl groups; R 7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR', nitro, Me3Sn, and halo; R” is C 3-12 An alkylene group, the chain of which may contain one or more heteroatoms, e.g., O, S, NR N2 (R N2 is H or C 1-4alkyl), and / or may be interrupted by aromatic rings, e.g. benzene or pyridine, Y and Y' are selected from O, S or NH; R 6’ R 6 And, R 7’ R 7 And, R 9’ R 9 are selected from the same group as In formula I, R L1’ is a linker for linking to an antibody (Ab), R 11a But, OH, OR A (R A is C 1-4 alkyl), and SO z M, z is 2 or 3, and M is a pharma- ceutically acceptable monovalent cation; R 20 and R 21 together form a double bond between the nitrogen atom and the carbon atom to which they are attached, or R 20 But H and R C are selected from R C is a capping group, R 21 But, OH, OR A and S.O. z M is selected from When a double bond exists between C2 and C3, R 2 but, (ia) optionally, halo, nitro, cyano, ether, carboxy, ester, C 1-7 Alkyl, C 3-7 Heterocyclyl and bis-oxy-C 1-3 C substituted with one or more substituents selected from the group consisting of alkylene 5-10 Aryl groups, (ib)C 1-5 Saturated aliphatic alkyl, (ic)C 3-6 saturated cycloalkyl, (id) a group: [ka] R 11 , R 12 and R 13 Each of these is independent of H, C 1-3 Saturated alkyl, C 2-3 Alkenyl, C 2-3 alkynyl and cyclopropyl; R 2 A group having a total of 5 or less carbon atoms in the group, (ie) a group [ka] R 15a and R 15b one of which is H and the other is phenyl, optionally substituted by a group selected from halo, methyl, methoxy, pyridyl, and thiophenyl; and (if) a group [ka] R 14 But, H, C 1-3 Saturated alkyl, C 2-3 Alkenyl, C 2-3 A group selected from alkynyl, cyclopropyl, phenyl, optionally substituted by a group selected from halo, methyl, methoxy, pyridyl, and thiophenyl. is selected from the group consisting of When there is a single bond between C2 and C3, R 2 is the following group, [ka] R 16a and R 16b are independent, H, F, C 1-4 Saturated alkyl, C 2-3 alkenyl, the alkyl and alkenyl groups being optionally selected from1-4 Alkylamide and C 1-4 or R 16a and R 16b When one of the groups is H, the other group is a nitrile and C 1-4 alkyl esters, In formula II, R 22 is a group of formula IIIa, IIIb or IIIc: (a) [ka] (Wherein, A is C 5-7 is an aryl group, (i)Q 1 is a single bond, and Q 2 is a single bond and -Z-(CH2) n -, where Z is selected from a single bond, O, S and NH, and n is 1 to 3; or (ii)Q 1 is -CH=CH-, and Q 2 is a single bond) (b) [ka] (In the formula, R C1 , R C2 and R C3 are independently H and unsubstituted C 1-2 alkyl) (c) [ka] (wherein Q is OR L2’ , S.R. L2’ and N.R. N -R L2’ are selected from R N is selected from H, methyl and ethyl X is OR L2’ , S.R. L2’ , CO2-RL2’ , C.O.R. L2’ , NH-C(=O)-R L2’ , NHNH-R L2’ , CONHNH-R L2’ , [ka] , [ka] NR N R L2’ and R is selected from the group including N But H and C 1-4 is selected from the group consisting of alkyl, R L2’ is a linker for linking to an antibody (Ab), R 10 and R 11 together 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 But, OH, OR A and S.O. z M is selected from R 30 and R 31 together 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 S.O. z The method according to any one of claims 1 to 5, wherein said method is selected from M.

[0577] 2. The CD19-ADC has the following chemical structure: [ka] The method of claim 1, wherein Ab is a CD19 antibody and the DAR is 1 to 8.

[0578] 3. The method of any one of the first and second statements, wherein the Ab comprises a VH domain having the sequence of SEQ ID NO:2 and a VL domain having the sequence of SEQ ID NO:8.

[0579] 4. The method according to any one of the first to third statements, wherein the Ab comprises a heavy chain having the sequence of SEQ ID NO:13 and a light chain having the sequence of SEQ ID NO:14.

[0580] 5. The method of any one of claims 1 to 4, wherein the CD19-ADC is ADCx19.

[0581] 6. The method of any of the preceding statements, wherein the total dose of CD19-ADC administered during a treatment cycle is administered as a series of two or more separate doses during the treatment cycle.

[0582] 7. The method of any of the preceding statements, wherein split doses of the CD19 ADC are administered at equally spaced intervals throughout a treatment cycle.

[0583] 8. The method of any of the preceding statements, wherein split doses of the CD19-ADC are administered to the subject once a week.

[0584] 9. The method of any of the preceding statements, wherein the length of the treatment cycle is 3 weeks.

[0585] 10. The method of any of the preceding statements, wherein the length of the treatment cycle is 6 weeks.

[0586] 11. The method of any of the preceding statements, wherein split doses of the CD19-ADC are administered once a week for a 3-week treatment cycle.

[0587] 12. The method of any of the preceding statements, wherein split doses of the CD19-ADC are administered on days 1, 8, and 15 of a 3-week treatment cycle.

[0588] 13. The method of any of the preceding statements, wherein a total dose of about 10 μg / kg of CD19-ADC is administered during a treatment cycle.

[0589] 14. The method of any of the preceding statements, wherein a total dose of about 20 μg / kg of CD19-ADC is administered during a treatment cycle.

[0590] 15. The method of any of the preceding statements, wherein a total dose of about 30 μg / kg of CD19-ADC is administered during a treatment cycle.

[0591] 16. The method of any of the preceding statements, wherein a total dose of about 40 μg / kg of CD19-ADC is administered during a treatment cycle.

[0592] 17. The method of any of the preceding statements, wherein a total dose of about 50 μg / kg of CD19-ADC is administered during a treatment cycle.

[0593] 18. The method of any of the preceding statements, wherein a total dose of about 60 μg / kg of CD19-ADC is administered during a treatment cycle.

[0594] 19. The method of any of the preceding statements, wherein a total dose of about 70 μg / kg of CD19-ADC is administered during a treatment cycle.

[0595] 20. The method of any of the preceding statements, wherein a total dose of about 80 μg / kg of CD19-ADC is administered during a treatment cycle.

[0596] 21. The method of any of the preceding statements, wherein a total dose of about 90 μg / kg of CD19-ADC is administered during a treatment cycle.

[0597] 22. The method of any of the preceding statements, wherein a total dose of about 100 μg / kg of CD19-ADC is administered during a treatment cycle.

[0598] 23. The method of any of the preceding statements, wherein a total dose of about 120 μg / kg of CD19-ADC is administered during a treatment cycle.

[0599] 24. The method of any of the preceding statements, wherein a total dose of about 140-160 μg / kg (such as about 150 μg / kg) of CD19-ADC is administered during a treatment cycle.

[0600] 25. The method of any of the preceding statements, wherein a total dose of about 200 μg / kg of CD19-ADC is administered during a treatment cycle.

[0601] 26. The method of any of the preceding statements, wherein a total dose of about 250 μg / kg of CD19-ADC is administered during a treatment cycle.

[0602] 27. The method of any of the preceding statements, wherein a total dose of about 300 μg / kg of CD19-ADC is administered during a treatment cycle.

[0603] 28. The method of any of the preceding statements, wherein a total dose of about 350 μg / kg of CD19-ADC is administered during a treatment cycle.

[0604] 29. The method of any of the preceding statements, wherein a total dose of about 400 μg / kg of CD19-ADC is administered during a treatment cycle.

[0605] 30. The method of any of the preceding statements, wherein a total dose of about 450 μg / kg of CD19-ADC is administered during a treatment cycle.

[0606] 31. The method of any of the preceding statements, wherein a total dose of about 500 μg / kg of CD19-ADC is administered during a treatment cycle.

[0607] 32. The method of any of the preceding statements, wherein a total dose of about 550 μg / kg of CD19-ADC is administered during a treatment cycle.

[0608] 33. The method of any of the preceding statements, wherein a total dose of about 600 μg / kg of CD19-ADC is administered during a treatment cycle.

[0609] 34. The method of any of the preceding statements, wherein a total dose of 1-10 μg / kg of CD19-ADC is administered during a treatment cycle.

[0610] 35. The method of any of the preceding statements, wherein a total dose of 11-20 μg / kg of CD19-ADC is administered during a treatment cycle.

[0611] 36. The method of any of the preceding statements, wherein a total dose of 21-30 μg / kg of CD19-ADC is administered during a treatment cycle.

[0612] 37. The method of any of the preceding statements, wherein a total dose of 31-40 μg / kg of CD19-ADC is administered during a treatment cycle.

[0613] 38. The method of any of the preceding statements, wherein a total dose of 41-50 μg / kg of CD19-ADC is administered during a treatment cycle.

[0614] 39. The method of any of the preceding statements, wherein a total dose of 51-60 μg / kg of CD19-ADC is administered during a treatment cycle.

[0615] 40. The method of any of the preceding statements, wherein a total dose of 61-70 μg / kg of CD19-ADC is administered during a treatment cycle.

[0616] 41. The method of any of the preceding statements, wherein a total dose of 71-80 μg / kg of CD19-ADC is administered during a treatment cycle.

[0617] 42. The method of any of the preceding statements, wherein a total dose of 81-90 μg / kg of CD19-ADC is administered during a treatment cycle.

[0618] 43. The method of any of the preceding statements, wherein a total dose of 91-100 μg / kg of CD19-ADC is administered during a treatment cycle.

[0619] 44. The method of any of the preceding statements, wherein a total dose of 101-120 μg / kg of CD19-ADC is administered during a treatment cycle.

[0620] 45. The method of any of the preceding statements, wherein a total dose of 121-140 μg / kg of CD19-ADC is administered during a treatment cycle.

[0621] 46. ​​The method of any of the preceding statements, wherein a total dose of 141-160 μg / kg of CD19-ADC is administered during a treatment cycle.

[0622] 47. The method of any of the preceding statements, wherein a total dose of 161-180 μg / kg of CD19-ADC is administered during a treatment cycle.

[0623] 48. The method of any of the preceding statements, wherein a total dose of 181-200 μg / kg of CD19-ADC is administered during a treatment cycle.

[0624] 49. The method of any of the preceding statements, wherein a total dose of 201-220 μg / kg of CD19-ADC is administered during a treatment cycle.

[0625] 50. The method of any of the preceding statements, wherein a total dose of 221-240 μg / kg of CD19-ADC is administered during a treatment cycle.

[0626] 51. The method of any of the preceding statements, wherein a total dose of 241-260 μg / kg of CD19-ADC is administered during a treatment cycle.

[0627] 52. The method of any of the preceding statements, wherein a total dose of 261-280 μg / kg of CD19-ADC is administered during a treatment cycle.

[0628] 53. The method of any of the preceding statements, wherein a total dose of 281-300 μg / kg of CD19-ADC is administered during a treatment cycle.

[0629] 54. The method of any of the preceding statements, wherein a total dose of 301-320 μg / kg of CD19-ADC is administered during a treatment cycle.

[0630] 55. The method of any of the preceding statements, wherein a total dose of 321-340 μg / kg of CD19-ADC is administered during a treatment cycle.

[0631] 56. The method of any of the preceding statements, wherein a total dose of 341-360 μg / kg of CD19-ADC is administered during a treatment cycle.

[0632] 57. The method of any of the preceding statements, wherein a total dose of 361-380 μg / kg of CD19-ADC is administered during a treatment cycle.

[0633] 58. The method of any of the preceding statements, wherein a total dose of 381-400 μg / kg of CD19-ADC is administered during a treatment cycle.

[0634] 59. The method of any of the preceding statements, wherein a total dose of 401 to 420 μg / kg of CD19-ADC is administered during a treatment cycle.

[0635] 60. The method of any of the preceding statements, wherein a total dose of 421 to 440 μg / kg of CD19-ADC is administered during a treatment cycle.

[0636] 61. The method of any of the preceding statements, wherein a total dose of 441-460 μg / kg of CD19-ADC is administered during a treatment cycle.

[0637] 62. The method of any of the preceding statements, wherein a total dose of 461-480 μg / kg of CD19-ADC is administered during a treatment cycle.

[0638] 63. The method of any of the preceding statements, wherein a total dose of 481-500 μg / kg of CD19-ADC is administered during a treatment cycle.

[0639] 64. The method of any of the preceding statements, wherein a total dose of 501-520 μg / kg of CD19-ADC is administered during a treatment cycle.

[0640] 65. The method of any of the preceding statements, wherein a total dose of 521-540 μg / kg of CD19-ADC is administered during a treatment cycle.

[0641] 66. The method of any of the preceding statements, wherein a total dose of 541-560 μg / kg of CD19-ADC is administered during a treatment cycle.

[0642] 67. The method of any of the preceding statements, wherein a total dose of 561-580 μg / kg of CD19-ADC is administered during a treatment cycle.

[0643] 68. The method of any of the preceding statements, wherein a total dose of 581-600 μg / kg of CD19-ADC is administered during a treatment cycle.

[0644] 69. The method of any of the preceding statements, wherein the divided dose is about 10 μg / kg.

[0645] 70. The method of any of the preceding statements, wherein the divided dose is about 20 μg / kg.

[0646] 71. The method of any of the preceding statements, wherein the divided dose is about 30 μg / kg.

[0647] 72. The method of any of the preceding statements, wherein the divided dose is about 40 μg / kg.

[0648] 73. The method of any of the preceding statements, wherein the divided dose is about 50 μg / kg.

[0649] 74. The method of any of the preceding statements, wherein the divided dose is about 60 μg / kg.

[0650] 75. The method of any of the preceding statements, wherein the divided dose is about 70 μg / kg.

[0651] 76. The method of any of the preceding statements, wherein the divided dose is about 80 μg / kg.

[0652] 77. The method of any of the preceding statements, wherein the divided dose is about 90 μg / kg.

[0653] 78. The method of any of the preceding statements, wherein the divided dose is about 100 μg / kg.

[0654] 79. The method of any of the preceding statements, wherein the divided dose is about 110 μg / kg.

[0655] 80. The method of any of the preceding statements, wherein the divided dose is about 120 μg / kg.

[0656] 81. The method of any of the preceding statements, wherein the divided dose is about 130 μg / kg.

[0657] 82. The method of any of the preceding statements, wherein the divided dose is about 140 μg / kg.

[0658] 83. The method of any of the preceding statements, wherein the divided dose is about 150 μg / kg.

[0659] 84. The method of any of the preceding statements, wherein the divided dose is about 160 μg / kg.

[0660] 85. The method of any of the preceding statements, wherein the divided dose is about 170 μg / kg.

[0661] 86. The method of any of the preceding statements, wherein the divided dose is about 180 μg / kg.

[0662] 87. The method of any of the preceding statements, wherein the divided dose is about 190 μg / kg.

[0663] 88. The method of any of the preceding statements, wherein the divided dose is about 200 μg / kg.

[0664] 89. The method of any of the preceding statements, wherein the divided dose is 1-10 μg / kg.

[0665] 90. The method of any of the preceding statements, wherein the divided dose is 11-20 μg / kg.

[0666] 91. The method of any of the preceding statements, wherein the divided dose is 21-30 μg / kg.

[0667] 92. The method of any of the preceding statements, wherein the divided dose is 31-40 μg / kg.

[0668] 93. The method of any of the preceding statements, wherein the divided dose is 41-50 μg / kg.

[0669] 94. The method of any of the preceding statements, wherein the divided dose is 51-60 μg / kg.

[0670] 95. The method of any of the preceding statements, wherein the divided dose is 61-70 μg / kg.

[0671] 95a. The method of any of the preceding statements, wherein the divided dose is about 40-60 μg / kg (such as about 45-55 μg / kg).

[0672] 96. The method of any of the preceding statements, wherein the divided dose is 71-80 μg / kg.

[0673] 97. The method of any of the preceding statements, wherein the divided dose is 81-90 μg / kg.

[0674] 98. The method of any of the preceding statements, wherein the divided dose is 91-100 μg / kg.

[0675] 99. The method of any of the preceding statements, wherein the divided dose is 101-110 μg / kg.

[0676] 100. The method of any of the preceding statements, wherein the divided dose is 111-120 μg / kg.

[0677] 101. The method of any of the preceding statements, wherein the divided dose is 121-130 μg / kg.

[0678] 102. The method of any of the preceding statements, wherein the divided dose is 131-140 μg / kg.

[0679] 103. The method of any of the preceding statements, wherein the divided dose is 141-150 μg / kg.

[0680] 104. The method of any of the preceding statements, wherein the divided dose is 151-160 μg / kg.

[0681] 105. The method of any of the preceding statements, wherein the divided dose is 161-170 μg / kg.

[0682] 106. The method of any of the preceding statements, wherein the divided dose is 171-180 μg / kg.

[0683] 107. The method of any of the preceding statements, wherein the divided dose is 181-190 μg / kg.

[0684] 108. The method of any of the preceding statements, wherein the divided dose is 191-200 μg / kg.

[0685] 109. The method of any of the preceding statements, wherein the amount of CD19-ADC in each divided dose is the same.

[0686] 110. The method of any of the preceding statements, wherein the proliferative disorder is characterized by the presence of a neoplasm comprising CD19+ve cells.

[0687] 111. The method of any of the preceding statements, wherein the subject has been diagnosed with the proliferative disease prior to initiation of treatment with CD19-ADC.

[0688] 112. The method according to claim 111, wherein the disease is CD19+ ALL.

[0689] 113. A method according to any preceding statement, comprising selecting a subject for treatment based on expression of CD19.

[0690] 114. The method of claim 113, wherein the subject is selected if at least 5% of the neoplastic cells express CD19.

[0691] 115. The method of any of the preceding statements, wherein the proliferative disease is a leukemia such as diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic lymphoma (CLL), non-Hodgkin's lymphoma including Waldenstrom's macroglobulinemia, Burkitt's lymphoma and marginal zone B-cell lymphoma (MZBL), and 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 (Ph-ALL)).

[0692] 116. The method of any of the preceding statements, wherein the proliferative disease is CD19+ ALL.

[0693] 117. The method of any of the preceding statements, wherein the proliferative disease is resistant, relapsed or refractory.

[0694] 118. The method of any of the preceding statements, wherein the subject is a human.

[0695] 119. The method of any of the preceding statements, wherein the CD19-ADC is administered intravenously.

[0696] 120. The method of any preceding claim, further comprising administering a chemotherapeutic agent in combination with the CD19-ADC.

[0697] 121. The method of claim 120, wherein the chemotherapeutic agent is administered to the subject prior to, simultaneously with, or after the CD19-ADC.

[0698] 122. The method of any of the preceding statements, wherein the CD19-ADC is administered in combination with a steroid.

[0699] 123. The method of claim 122, wherein the first dose of steroid is administered on the same day as the ADC.

[0700] 124. The method of claim 123, wherein the first dose of steroid is administered at least 2 hours prior to the ADC.

[0701] 125. The method of any one of claims 123 or 124, wherein a second dose of steroid is administered the day after the ADC.

[0702] 126. The method of claim 122, wherein the first dose of steroid is administered the day before the ADC.

[0703] 127. The method of claim 126, wherein a second dose of steroid is administered on the same day as the ADC.

[0704] 128. The method of claim 127, wherein a second dose of steroid is administered at least 2 hours prior to the ADC.

[0705] 129. The method of any one of claims 127 or 128, wherein a third dose of steroid is administered the day after the ADC.

[0706] 130. The method of any one of statements 122 to 129, wherein the steroid or multiple doses of steroid are administered in conjunction with only the first administration of the ADC in each treatment cycle.

[0707] 131. A method according to any one of claims 122 to 130, wherein the steroid is administered orally.

[0708] 132. The method according to any one of statements 122 to 131, wherein each dose of the steroid is 8 mg.

[0709] 133. The method according to any one of claims 122 to 132, wherein each dose of the steroid is 16 mg.

[0710] 134. The method according to any one of statements 122 to 133, wherein each dose of steroid is administered as two equally divided doses.

[0711] 135. The method according to any one of statements 122 to 134, wherein each divided dose is 4 mg.

[0712] 136. The method according to any one of statements 122 to 135, wherein each divided dose is 8 mg.

[0713] 137. The method according to any one of statements 122 to 136, wherein the steroid is dexamethasone.

[0714] 138. The method of claim 122, wherein 4 mg of dexamethasone is administered orally twice daily: (i) on the day before the ADC is administered on day 1 of week 1 of the treatment cycle, (ii) on the day on which the ADC is administered on day 1 of week 1 of the treatment cycle, and (iii) on the day after the ADC is administered on day 1 of week 1 of the treatment cycle.

[0715] 139. The method of claim 122, wherein 4 mg of dexamethasone is administered orally twice daily (i) on the day that the ADC is administered on day 1 of week 1 of the treatment cycle, and (ii) on the day following administration of the ADC on day 1 of week 1 of the treatment cycle.

[0716] 140. The method of any one of statements 138 and 139, wherein dexamethasone administered on the same day as the ADC is administered at least 2 hours before the ADC.

[0717] 141. The method of any one of statements 138 to 140, wherein the dexamethasone is administered in conjunction with only the first administration of the ADC in each treatment cycle.

[0718] 142. The method of any of the preceding statements, wherein the toxicity of the split dose regimen is lower than that of a single dose regimen for the same total administered dose and treatment cycle length.

[0719] 143. The method of claim 142, wherein the incidence of TEAEs in the split dose regimen is 50% or less than the incidence of TEAEs in the single dose regimen.

[0720] 144. The method of claim 142, wherein the incidence of SAEs in the split dose regimen is 50% or less than the incidence of SAEs in the single dose regimen.

[0721] 145. The method of claim 142, wherein the incidence of DLT in the split dose regimen is 50% or less than the incidence of DLT in the single dose regimen.

[0722] 146. The method of any of the preceding statements, wherein the efficacy of the split dose regimen is greater than a single dose administration regimen for the same total administered dose and the same treatment cycle length.

[0723] 147. The method of claim 146, wherein the proportion of subjects achieving at least a PR in the split-dose regimen is at least 150% of the proportion of subjects achieving at least a partial response [PR] in the single-dose regimen.

[0724] 148. A method for reducing toxicity and / or side effects associated with administration of a CD19-ADC to a subject, comprising administering the CD19-ADC according to any of the methods described in the preceding paragraphs.

[0725] 149. A method of improving the efficacy of a treatment associated with administration of a CD19-ADC to a subject, comprising administering the CD19-ADC according to any of the methods described in the preceding paragraphs.

[0726] 150. A method for selecting a subject for treatment with a method according to any one of claims 1 to 141, comprising selecting a subject expressing CD19 in a tissue of interest.

[0727] 151. The method of claim 150, wherein the subject is selected if at least 5% of the cells in the relevant tissue sample express CD19.

[0728] 152. The method of any one of claims 150 and 151, wherein the tissue in question is lymphatic tissue or tumor tissue.

[0729] 153. The method of any one of claims 150 to 152, wherein the subject has experienced DLT during a single dose administration regimen of the CD19-ADC.

[0730] 154. A packaged drug product that includes, in conjunction with a CD19-ADC as defined in any one of statements 1 through 5, a label or insert that informs the patient that the CD19-ADC should be administered in accordance with the method of any one of statements 1 through 151.

[0731] 155. A first medicament comprising a CD19-ADC as defined in any one of the first to fifth statements, and optionally A package insert or label containing instructions for administering the CD19-ADC according to any one of claims 1 to 151. Kit including:

[0732] 156. A CD19-ADC as defined in any one of statements 1 to 5, for use in a method according to any one of statements 1 to 151.

[0733] 157. A pharmaceutical composition comprising a CD19-ADC as defined in any one of statements 1 to 5, optionally in combination with a pharma- ceutical acceptable excipient, for use in a method according to any one of statements 1 to 151.

[0734] 158. Use of a CD19-ADC as defined in any one of statements 1 to 5 in the preparation of a medicament for use in any one of the methods of statements 1 to 151. EXAMPLES

[0735] Example 1: Pharmacokinetics of ADCx19 in ALL patients Forty-eight patients with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL) received at least one dose of ADCx19 (4 at 15 μg / kg, 4 at 30 μg / kg, 4 at 60 μg / kg, 5 at 90 μg / kg, 12 at 120 μg / kg, 3 at 150 μg / kg, and 17 at 200 μg / kg). The 120 μg / kg and 200 μg / kg cohorts were expanded to further explore the early efficacy signals seen at these dose levels.

[0736] Emerging safety, pharmacokinetic, and efficacy data suggest that at doses ≥120 μg / kg, repeated dosing every 3 weeks is either not well tolerated or not necessary. Twelve patients (10 with DLBCL, 1 with FL, and 1 with MCL) were treated with 120 μg / kg, with 4 patients achieving complete remission (CR) and 2 achieving partial remission (PR). Six responders received 3–7 infusions of ADCx19, and 4 of these patients had at least 1 dose delayed due to adverse events (fatigue (2), edema (3), muscle pain (2), rash (1), and increased GGT and alkaline phosphatase (1)). In this cohort, 2 patients discontinued treatment due to adverse events (both achieved CR).

[0737] At 150 μg / kg, the first three patients received either two or three cycles of ADCTx19 before requiring dose delays due to side effects and were ultimately removed from the study due to persistent toxicity.

[0738] The first six evaluable patients treated in the 200 μg / kg cohort (dosed every 3 weeks) achieved CR (5) or PR (1) at the first restaging at the end of cycle 2 (after the second dose). However, all patients had some signs of toxicity at the end of cycle 2 (4 patients) or cycle 3 (1 patient). Pharmacokinetic profiles for the first two cycles in the first three patients treated in the 200 μg / kg cohort showed that the AUC and Cmax at the 200 μg / kg dose level were significantly higher than those seen at the lower doses. Trough concentrations at the end of cycle 1 were seen to be in the range of 500-1000 ng / ml.

[0739] In light of the identified safety profile, it is proposed that in future subjects receiving doses of 120 μg / kg or greater, the dosing regimen be modified to include tapering and / or extended dosing regimens as described herein, in particular using the following tapering and extended dosing regimens:

[0740] A. 120 μg / kg: Administered every 3 weeks for 2 cycles. Patients with at least SD after the second cycle continue treatment at a reduced dose of 60 μg / kg every 6 weeks (starting 6 weeks after the cycle 2 infusion). B. 150 μg / kg: Administered every 3 weeks for 2 cycles. Patients with at least SD after the second cycle continue treatment at a reduced dose of 60 μg / kg every 6 weeks (starting 6 weeks after the cycle 2 infusion). C. 200 μg / kg: Administered every 6 weeks for 2 cycles. Patients with at least SD 6 weeks after Cycle 2 will continue treatment at a reduced dose of 60 μg / kg every 6 weeks (starting 6 weeks after the Cycle 2 infusion). D. 200 μg / kg: given every 6 weeks. Patients with at least SD after 6 weeks of Cycle 1 will continue treatment at a reduced dose of 60 μg / kg every 6 weeks (starting 6 weeks after the Cycle 1 infusion). E. 150 μg / kg: Administered every 3 weeks for 2 cycles. Patients with at least SD after the second cycle continue treatment at a reduced dose of 75 μg / kg every 3 weeks (starting 3 weeks after the cycle 2 infusion).

[0741] The complete clinical trial protocol for the 3-week treatment cycle with a single dose administered on day 1 is publicly available at www.clinical trials.gov and the unique ClinicalTrials.gov identifier is NCT02669017 (updated April 25, 2017).

[0742] Example 2: Summary of Tapering and / or Extended Dosing Protocols Indications Patients with relapsed or refractory B-cell non-Hodgkin's lymphoma (B-NHL) who have failed or are intolerant to any established therapy or for whom, in the investigator's opinion, no other treatment options are available

[0743] The Dose Escalation Steering Committee (DESC) will determine which histologic subtypes will be examined in Part 2 of the study based on the efficacy and tolerability profile emerging from Part 1.

[0744] B-cell NHL is defined as: Diffuse large B-cell lymphoma (DLBCL) Follicular lymphoma (FL) Chronic lymphocytic leukemia (CLL) Mantle cell lymphoma (MCL) Marginal zone B-cell lymphoma (MZBCL) Burkitt lymphoma (BL) Lymphoplasmacytic lymphoma (Waldenström macroglobulinemia [WM])

[0745] the purpose Primary Objectives: -Evaluate the safety and tolerability of ADCx19 in patients with relapsed or refractory B-cell NHL and, where appropriate, define the maximum tolerated dose (MTD) (Part 1). -Define the recommended dose(s) of ADCx19 for Part 2 (expansion). - Part 2 (expansion) will evaluate the safety and tolerability of ADCx19 at the dose level(s) recommended in Part 1.

[0746] Secondary Objectives: -To evaluate the clinical activity of ADCx19 as measured by overall response rate (ORR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS). - Characterize the pharmacokinetic (PK) profiles of ADCx19 (total antibody, drug-to-antibody ratio [DAR] >= 0), PBD-conjugated antibody (DAR >= 1) and free warhead. - Assess circulating anti-drug antibodies (ADA) before, during, and after treatment with ADCx19.

[0747] Efficacy evaluation Disease assessments will occur within 6 days prior to day 1 of cycles 3 and 5, and then every 3 cycles thereafter (i.e., cycles 8, 11, 14, etc.) until disease progression, or more frequently if clinically indicated. All subsequent evaluations should uniformly use the same methods used at screening to identify the site of disease. If PET-CT is positive, then subsequent diagnostic CT and MRI are not required unless clinically indicated. If the screening PET-CT exam is negative, then PET-CT is not required.

[0748] In patients on a 6-week schedule with reduced dosing frequency, disease evaluation should occur approximately 6 and 12 weeks after Day 1 of Cycle 1, and at least every 12 weeks thereafter. It is understood that there is a ±6 day window for restaging these patients.

[0749] Patient response to treatment will be defined by the investigator as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) based on the 2014 Lugano Classification Criteria.

[0750] Penalty rating Validated bioanalytical method measurements will be used to assess the PK profiles of ADCT-402 (whole antibody, DAR > 0), PBD-conjugated antibody (DAR > 1) and free warhead SG3199. The PK profiles will include quantification of standard PK parameters (e.g., maximum plasma concentration [Cmax], time to Cmax [Tmax]).

[0751] The study will include the following pharmacodynamic and other exploratory evaluations at various time points: Immunohistochemistry for CD19 protein expression (archived tumor tissue or pretreatment tumor biopsy specimens from consenting patients) - Serum levels of ADA for ADCx19 -Analysis of peripheral WBC populations and CD marker panel expression (CD19, CD20, CD21, CD22) before, during, and after treatment with ADCx19 (US only) - Serum concentrations of ADCx19 and free warhead will be determined. QT interval will also be measured.

[0752] Safety assessment Safety will be assessed based on evaluation of adverse events (AEs), serious AEs (SAEs), treatment discontinuation due to AEs, dose-limiting toxicity(s) (DLTs), periodic 12-lead electrocardiogram (ECG) recordings, physical examination, vital sign measurements, ECOG performance status, and results of hematology, coagulation panel, pregnancy test (for women of childbearing potential), biochemistry, and urinalysis obtained at various times during the study. Adverse events will be adjudicated according to CTCAE Version 4.0 (v4.03, published June 14, 2010, NIH Publication No. 09-5410).

[0753] Product Dosage and Method of Administration ADCx19 is a sterile formulation containing a PBD-conjugated humanized monoclonal IgG1 antibody (DAR>1), a humanized monoclonal IgG1 antibody (DAR=0) and SG3249. ADCx19 is supplied preformulated in 10 mL disposable glass vials, containing approximately 16 mg of ADCx19 per vial (deliverable volume: 3.2 mL at 5 mg / mL plus an additional overfill of 0.3 mL).

[0754] Patients will receive a 1-hour intravenous (IV) infusion of ADCx19 on Day 1 of Cycle 1. If ADCx19 is well tolerated after the first infusion, the infusion duration may be shortened to 30 minutes for that patient's subsequent cycles, at the investigator's discretion.

[0755] Dose escalation design In Part 1, patients will be assigned to treatment with ADCT-402 at escalating doses in a 3+3 study design. The initial dose of ADCT-402 will be 15 μg / kg (dose level 1) and the maximum tolerated dose will be 300 μg / kg.

[0756] Additional dose levels and schedules to be evaluated include the following: A. 120 μg / kg: Administered every 3 weeks for 2 cycles. Patients with at least SD after the second cycle continue treatment at a reduced dose of 60 μg / kg every 6 weeks (starting 6 weeks after the cycle 2 infusion). B. 150 μg / kg: Administered every 3 weeks for 2 cycles. Patients with at least SD after the second cycle continue treatment at a reduced dose of 60 μg / kg every 6 weeks (starting 6 weeks after the cycle 2 infusion). C. 200 μg / kg: Administered every 6 weeks for 2 cycles. Patients with at least SD 6 weeks after Cycle 2 will continue treatment at a reduced dose of 60 μg / kg every 6 weeks (starting 6 weeks after the Cycle 2 infusion). D. 200 μg / kg: given every 6 weeks. Patients with at least SD after 6 weeks of Cycle 1 will continue treatment at a reduced dose of 60 μg / kg every 6 weeks (starting 6 weeks after the Cycle 1 infusion). E. 150 μg / kg: Administered every 3 weeks for 2 cycles. Patients with at least SD after the second cycle continue treatment at a reduced dose of 60 μg / kg every 6 weeks (starting 6 weeks after the cycle 2 infusion).

[0757] The first patient enrolled in the study at 15 μg / kg (dose level 1) must be observed for the occurrence of AEs for 7 days before treating the second patient in the study. The DLT observation period during dose escalation is 1 cycle.

[0758] At each dose level, if the first three patients do not experience a DLT at that level, the next higher dose level may be used for new patients. If one of the three patients experiences a DLT, up to three additional patients will be treated at the same dose level. If the additional three patients do not experience a DLT at that dose level, the next higher dose level may be used for new patients. However, if one or more of the additional three patients experience a DLT, no further patients will be initiated at that dose level, and the previous dose will be set as the MTD. The MTD is therefore defined as the highest dose level at which either no DLT is observed in the first three treated patients or no more than one DLT is observed in the first six treated patients.

[0759] The study will be continuously monitored for safety and early discontinuation so that the MTD can be better defined.

[0760] Dose-expansion design In Part 2 (expansion), patients will be assigned to the dose level(s) and / or schedule(s) of ADCT-402 specified in Part 1 based on the safety, efficacy, and pharmacokinetic data derived.

[0761] The population in Part 2 (expansion) may be restricted to specific histologies based on both the activity signal and safety observed in Part 1.

[0762] Additionally, dose levels and schedules evaluated in Part 2 may include Regimens A, B, C, and D as described above for Part 1.

[0763] Example 3: Overview of safety and efficacy studies of ADCx19 treatment Study design Serum concentrations of PBD-conjugated Ab were determined using a validated electrochemiluminescence immunoassay. Data were analyzed by population PK methods using NONMEM (version 7.3, conditional first-order approximation).

[0764] The Bayesian PK analysis employed a two-compartment open model and a zero-order infusion rate with a log-transformation approach on both sides. Area under the curve (AUC) values ​​were estimated from individual patient posterior Bayesian estimates.

[0765] The effects of various covariates on PK variability were evaluated, including age, sex, race, body surface area (BSA), body mass index, weight, albumin, alanine aminotransferase, aspartate aminotransferase, bilirubin, creatinine clearance, and hemoglobin (Hb).

[0766] Graphical trends in PK exposure values ​​were examined along with maximum severity of early (cycle 1) and late (all cycles) TEAEs of any grade, anemia, platelets, neutrophils, Hb, fatigue, edema, and pleural effusion.

[0767] Logistic regression was used to quantitatively assess apparent trends for the AUC and odds of the following dichotomous outcome variables in association with demographic factors (age, sex, weight, BSA, and maximum Eastern Cooperative Oncology Group status): - Grade 3 or greater maximum severity TEAE Grade ≥ 3 thrombocytopenia - Grade 1 or greater edema or pleural effusion.

[0768] Dose and PK were correlated with maximum change from baseline tumor size to identify potential relationships between exposure and activity (at least 50% reduction, complete response, and partial response).

[0769] result Patient characteristics Data on 77 patients (53 men and 24 women) containing 1138 observations were included in the population PK model.

[0770] Final population PK model The final population PK model parameters are presented in the table below.

[0771] Strong correlations were found between observed and estimated serum drug concentrations. Exposure values, and associated intersubject variability, increased with dose. Apparent terminal half-life values ​​were large but moderately variable.

[0772] Repeated dosing resulted in moderate drug accumulation.

[0773] BSA had a significant effect on the volume of distribution.

[0774] No other significant covariates were identified.

[0775] [Table 4] BSA: body surface area, CL: total body clearance, CV: coefficient of variation, IIV: interindividual variability of each pharmacokinetic parameter, Q1: intercompartmental clearance, SE: standard error, Vc: volume of distribution in the central compartment, Vp: volume of distribution in the peripheral compartment

[0776] Relationship between exposure and safety Increasing PBD-conjugated Ab exposure (AUC) was associated with the odds of grade ≥3 thrombocytopenia in cycle 1 (p=0.0067) and any grade ≥3 TEAE during cycle 1 and all cycles (both p=0.031) (see table below). Men appeared to be more susceptible than women to any grade ≥3 TEAE. There was a clear visual trend of increasing AUC with the odds of grade ≥1 edema or pleural effusion. [Table 5]

[0777] Relationship between exposure and efficacy Dose escalation of ADCx19 was significantly associated with an increased probability of objective response (p=0.0439).

[0778] Increasing PBD-conjugated Ab exposure (AUC) was significantly associated with increased odds of objective response (p=0.0292).

[0779] conclusion A linear 2-compartment model was used to describe the PK profile of the PBD-conjugated Ab following administration of ADCx19.

[0780] BSA was a significant covariate of volume of distribution.

[0781] A significant positive correlation was observed between PBD conjugate Ab exposure values ​​(AUC) and the incidence of grade ≥3 TEAEs (cycle 1 and all cycles) and grade ≥3 thrombocytopenia in cycle 1.

[0782] Since the frequency of grade 3 or higher TEAEs increased with continuous administration, it appears that limiting the number of administration cycles may control the rate of serious adverse events.

[0783] Men may be more susceptible to serious adverse events than women.

[0784] A trend toward an association was evident between AUC and grade ≥1 edema or pleural effusion.

[0785] Interim efficacy evaluations demonstrated significant dose- and exposure-response relationships for ADCx19 when administered on a q3w schedule.

[0786] Example 4: Efficacy of ADCx19 treatment in a mouse xenograft in vivo model Ramos-e222 Subcutaneous Model Female severe combined immunodeficient mice (Fox Chase SCID®, CB-17 / Icr-Prkdcscid, Charles River) were 8 weeks old and ranged in body weight (BW) from 117.5 to 25.6 grams on day 1 of the study.

[0787] On the day of tumor implantation, Ramos cells were harvested in logarithmic growth phase and resuspended in phosphate-buffered saline. Xenografts were initiated by subcutaneously implanting 1 x 107 Ramos cells (0.1 mL suspension) into the right flank of each test mouse, and tumors were monitored as tumor volumes approached the target range of 100-150 mm3. Tumors were measured in two dimensions using calipers, and volumes were calculated using the following formula: Tumor volume (mm3) = w2 × l / 2 where w is the width and l is the length of the tumor in mm. Tumor weight can be estimated assuming that 1 mg corresponds to 1 mm3 of tumor volume.

[0788] Thirteen days after tumor implantation (day 1 of the study), the mice were divided into groups, each of which consisted of 10 mice, with individual tumor volumes ranging from 108 to 172 mm. 3 and the mean tumor volume of the group was 120 mm 3All drugs were administered intravenously (iv) via tail vein injection at a dose volume of 0.2 mL per 20 grams of body weight (10 mL / kg) (weighed to the weight of each individual mouse) once on day 1. Tumors were measured twice weekly using calipers, and each mouse was euthanized when its tumor reached an endpoint volume of 2000 mm3 or at the end of the study, whichever occurred first.

[0789] One group of mice received a single dose of 1 mg / kg ADCx19 on day 1 (qd x 1).

[0790] In two other groups, the same dose of ADCx19 was administered in three divided doses, i.e., three doses of 0.33 mg / kg each: in one group, the doses were administered one week apart (qwk×3), and in the second group, the doses were administered four days apart (q4d×3).

[0791] In both divided dose groups, a steady growth in tumor size was observed beginning around day 20. In contrast, the group that received a single dose on day 1 did not show any significant tumor mass by the end of the study (see Figure 2).

[0792] NALM-6 tumor cell inoculation model Human B-cell leukemia NALM-6 was used as an intravenous xenograft model. NALM-6 culture medium from passage 12 was used for inoculation of tumor cells. The survival rate of inoculated cells was 90%.

[0793] At the start of the experiment, adult female NOG mice were 5-8 weeks old with an average body weight of 17.2 g. After a 7-day acclimation period, each female NOG mouse was inoculated intravenously with 1x107 tumor cells obtained from in vitro passage (day 0).

[0794] Treatment began 3 days after inoculation with NALM-6. Body weights were measured three times a week, and the general health of all mice was checked daily.

[0795] Each mouse was sacrificed and necropsied if it developed hind leg paralysis and / or lost more than 20% of its body weight. The study was terminated on day 90.

[0796] One group of mice received a single dose of 1 mg / kg ADCx19 on day 1 (qd x 1).

[0797] In the other group, the same dose of ADCx19 was administered in three divided doses, i.e., 0.33 mg / kg each for three doses, 4 days apart (q4d×3).

[0798] In the group that received the split dose, some deaths were observed toward the end of the study, in contrast to the group that received a single dose on day 1, where no deaths occurred toward the end of the study (see Figure 3).

[0799] Example 5: Pharmacokinetics of ADCx19 in ALL patients Nineteen patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) comprising three dose cohorts (15 μg / kg, 30 μg / kg, and 60 μg / kg) received ADCx19 using a 3-week treatment cycle with a single dose administered on day 1.

[0800] Preliminary pharmacokinetic (PK) information from seven patients (n=4 at 15 μg / kg, n=2 at 30 μg / kg, n=1 at 60 μg / kg) shows interpatient variability. In most patients, concentrations were near the lower limit of quantification and PK parameters were not discernible. These patients demonstrated rapid elimination of drug early in the study. Patients who achieved a CR demonstrated slower elimination by cycle 2 than other patients.

[0801] The complete clinical trial protocol for the 3-week treatment cycle administered as a single dose on day 1 is publicly available at www.clinical trials.gov and has the ClinicalTrials.gov unique identifier NCT02669264 (updated February 21, 2017).

[0802] Example 6: Overview of split dose protocol Indications Patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) who have failed or are intolerant to any established therapy or for whom other treatment options are unavailable.

[0803] the purpose Primary Objectives: -To evaluate the safety and tolerability of ADCx19 and determine the maximum tolerated dose (MTD) in patients with relapsed or refractory B-ALL (Part 1). - Determine the recommended ADCx19 dose for Part 2 (expansion). -Part 2 (expansion) will evaluate the safety and tolerability of ADCx19 at the dose level recommended in Part 1.

[0804] Secondary Objectives: The secondary objectives of Parts 1 and 2 of the study are to: -Evaluate the clinical activity of ADCx19 based on determination of patient response to treatment (complete response [CR], CR with incomplete blood count recovery [CRi], partial response [PR], progressive disease [PD], no response [NR]), as well as overall response rate (ORR), duration of response (DOR), overall survival (OS), and progression-free survival (PFS). - Characterize the pharmacokinetic (PK) profiles of ADCx19 (total antibody, drug-to-antibody ratio [DAR] >= 0), PBD-conjugated antibody (DAR >= 1) and free warhead. - Assess anti-drug antibodies (ADA) to ADCx19 in serum before, during, and after treatment with ADCx19.

[0805] Efficacy evaluation Assessment of response to treatment with ADCx19 will be based on bone marrow samples (aspirate or biopsy specimen if aspirate is not available). ADCx19 activity will be assessed based on investigator assessment of the patient's response to ADCx19 as CR, CRi, PR, PD, or NR, as defined herein.

[0806] Penalty rating The PK profiles of ADCx19 (whole antibody, DAR>0), PBD-conjugated antibody (DAR>1), and free warhead will be evaluated primarily in cycles 1 and 2. The PK profiles will include determination of standard PK parameters (e.g., maximum plasma concentration [Cmax], time to Cmax [Tmax]). The following PD and other exploratory assessments will be performed at various time points during the study: - Flow cytometric assessment of CD19 and other CD marker expression in mononuclear cells (MNC) isolated from bone marrow aspirates and whole blood (WB) (retrospectively tested by a central laboratory on samples taken prior to treatment with ADCx19) - Serum levels of ADA to ADCx19 before, during and after treatment with ADCx19 - Analysis of peripheral WBC populations and CD marker panel expression (e.g., CD19, CD20, CD21, CD22) by flow cytometry in WB before, during, and after treatment with ADCx19 (cycles 1 and 2) - Serum concentrations of ADCx19 and free warfarin, and QT interval - Measurement of MRD by flow cytometry in bone marrow

[0807] Safety assessment Safety will be assessed based on AEs, serious AEs (SAEs), treatment discontinuations due to AEs, DLTs (as defined herein), serum cytokine measurements, periodic 12-lead electrocardiogram (ECG) recordings, physical examination, vital sign measurements, ECOG performance status, and results of hematology, biochemistry, coagulation panels, pregnancy tests (for women of childbearing potential), and urinalysis. Adverse events will be adjudicated according to CTCAE Version 4.0 (v4.03, published June 14, 2010, NIH Publication No. 09-5410).

[0808] Product Dosage and Method of Administration ADCx19 is a sterile formulation containing a PBD-conjugated humanized monoclonal IgG1 antibody (DAR>1), a humanized monoclonal IgG1 antibody (DAR=0) and SG3249. ADCx19 is supplied preformulated in 10 mL single-use glass vials, containing approximately 16 mg of ADCx19 per vial (deliverable volume: 3.2 mL at 5 mg / mL plus an additional overfill of 0.3 mL). Patients will receive a 1-hour intravenous (IV) infusion of ADCx19 on Day 1 of Cycle 1. If ADCx19 is well tolerated after the first infusion, the infusion duration may be shortened to 30 minutes for the patient's second and subsequent cycles at the discretion of the investigator.

[0809] The dosing schedule for the investigational product is as follows:

[0810] Patients will receive ADCx19 on days 1, 8, and 15 (once weekly [QW]) of each 3-week (21 day) treatment cycle.

[0811] Patients will maintain the same treatment schedule throughout the study.

[0812] Once a patient achieves CR / CRi, frequency or dose may be adjusted by DESC based on the emerging safety, efficacy and PK profile.

[0813] The study will continue to be monitored for any emerging safety, efficacy and / or PK profiles and the DESC will determine whether it is appropriate to maintain the QW schedule, revert to an every 3 weeks (Q3W) schedule, or test other dosing regimens.

[0814] Dose escalation design Dose escalation (Part 1) will follow a 3+3 design. The starting dose of ADCx19 will be 15 μg / kg (dose level 1) and the maximum tolerated dose will be 600 μg / kg.

[0815] The DLT observation period during dose escalation will be one cycle. Patients will progress sequentially to each dose level.

[0816] At each dose level, if no DLT is observed in the first three patients at that level, the next higher dose level may be used for new patients. If one of the three patients experiences a DLT, up to three additional patients will be treated at the same dose level. If no DLT is observed in the three additional patients at that dose level, the next higher dose level may be used for new patients. However, if one or more of the three additional patients experience a DLT, no further patients will be added at that dose level, and the previous dose will be defined as the MTD. The MTD is therefore defined as the highest dose level at which no DLT is observed in the first three treated patients or no more than one DLT is observed in the first six treated patients.

[0817] During Part 1, the Dose Escalation Steering Committee (DESC) may expand enrollment at doses below the current dose level as part of the dose escalation process. Additional patients may be added at a reduced dose level only if there is at least one patient who achieves PR (or better). No more than 10 patients total can be treated at any dose level unless 3 or more of the 10 patients achieve PR or better.

[0818] During dose expansion, patients will be monitored for safety using the same DLT criteria used during dose escalation. If more than 30% of patients experience a safety event during treatment that meets the criteria for defining a DLT during the dose escalation phase of the study, enrollment in the expansion cohort(s) may be halted and the study data reviewed to determine whether additional monitoring or other measures (e.g., changes in dose levels) should be evaluated prior to further enrollment.

[0819] Example 7: Overview of safety and efficacy studies of ADCx19 treatment Study design A phase 1, open-label, multicenter, dose-escalation study (part 1) and dose-expansion study (part 2) in the United States is enrolling patients with R / R B-ALL.

[0820] In Part 1, patients will be assigned to treatment with a 3+3 dose escalation design to determine the maximum tolerated dose (MTD). The initial dose of ADCx19 was 15 μg / kg (dose level 1). Patients treated every 3 weeks will receive ADCx19 intravenously on day 1 of each 21-day cycle, and patients assigned to the weekly regimen will receive ADCx19 on days 1, 8, and 15.

[0821] Part 2 will further evaluate the safety, tolerability, PK, and clinical activity of ADCx19 at the dose recommended by Part 1. A complete response will be defined as achievement of each of the following: - Fewer than 5% blast cells are seen in the bone marrow. -Absolute neutrophil count ≥ 1.0 x 109 / L and platelet count ≥ 100 x 109 / L. -No extramedullary disease observed. - The patient is not undergoing red blood cell transfusion. [Table 6]

[0822] result Patient characteristics As of October 30, 2017, 29 B-ALL patients (18 men, 11 women) were treated with ADCx19.

[0823] Patients had received a median of two prior chemotherapy regimens (minimum 1, maximum 12). Eleven (37.9%) patients had received prior allogeneic stem cell transplant. No dose-limiting toxicities (DLTs) were observed up to the maximum evaluated dose of 150 μg / kg once every 3 weeks (q3w). The most recent treatment cohort received ADCx19 at a dose of 50 μg / kg once weekly.

[0824] Penalty data PK data showed that PBD-conjugated antibody concentrations were below quantifiable levels of 5.0 ng / L and total antibody concentrations were below quantifiable levels of 20 ng / L well before the end of the 21-day treatment cycle (see Figure 4). PBD dimer concentrations remained well below measurable levels over the entire time course, justifying a change to weekly dosing.

[0825] Safety Data No DLTs were observed. Treatment-emergent adverse events (TEAEs) were reported by 28 of 29 patients (96.6%), for a total of 265 TEAEs. Twelve (41.4%) patients reported adverse events considered possibly or likely related to ADCx19. The most common TEAEs were: -Nausea (n=9) - Fatigue (n=7) -Febrile neutropenia (n=7) - Headache (n=7)

[0826] Grade ≥3 TEAEs were reported in 24 of 29 patients (82.8%), with febrile neutropenia (n=7) and neutropenia (n=4) being the most common (see table below).

[0827] Two patients experienced fatal TEAEs (pulmonary infection and sepsis), both in the 120 μg / kg q3w group. Four patients experienced TEAEs that led to dose delays or reductions, but none led to treatment discontinuation. Seven patients reported hepatotoxic events, one of which led to dose delays (due to hyperbilirubinemia). Four patients experienced grade 3 hepatotoxic events, including during cycle 1, all of which were reversible (median duration [range]: 11.5 days [5-36 days]) and unrelated to veno-occlusive disease. Three infusion-related reactions were reported, including one infusion-related grade 2 reaction, one cytokine release syndrome, and one grade 1 tachycardia.

[0828] The MTD has not yet been reached.

[0829] Grade ≥3 TEAEs by preferred category (safety analysis set, dose unit: ug / kg): [Table 7]

[0830] Efficacy Data Two patients achieved a complete response with no minimal residual disease (MRD) after five treatment cycles at a dose of 30 μg / kg q3w and after two treatment cycles at a dose of 120 μg / kg q3w.

[0831] All responders had previously received blinatumomab.

[0832] A third patient achieved a complete response with MRD positivity at a dose of 150 μg / kg q3w.

[0833] The fourth patient achieved a complete bone marrow response with incomplete blood count response and progression of extramedullary disease at a dose of 150 μg / kg q3w.

[0834] conclusion In this phase 1 study in patients with R / R B-ALL, single-agent ADCx19 was well tolerated with no DLTs and 2 MRD-negative complete responses in a heavily pretreated population.

[0835] The full dose will be continued to find the MTD for the once weekly regimen.

[0836] A dose-expansion phase in Part 2 of the study is planned to further evaluate the tolerability, safety, PK, and activity of ADCx19.

Claims

1. 1. A pharmaceutical composition for treating CD19-positive lymphoma in a subject, comprising a CD19-antibody drug conjugate (ADC), the pharmaceutical composition is for administration to the subject in combination with rituximab; the CD19-ADC is administered to the subject in a dose-reducing dosing regimen comprising multiple treatment cycles; the dose of the CD19-ADC is reduced after the second treatment cycle; the starting dose of the CD19-ADC is about 120 μg / kg to about 200 μg / kg; The CD19-ADC has the following structure: 【Chemistry 1】 It is a structure represented by The Ab comprises a VH domain having the amino acid sequence represented by SEQ ID NO:2 and a VL domain having the amino acid sequence represented by SEQ ID NO:8; the CD19-ADC has a drug-to-antibody (Ab) ratio (DAR) of 1 to 8; The pharmaceutical composition is administered by intravenous injection.

2. 1. A pharmaceutical composition for treating B-cell non-Hodgkin's lymphoma (B-NHL) in a subject, comprising a CD19-antibody drug conjugate (ADC), the pharmaceutical composition is for administration to the subject in combination with rituximab; the CD19-ADC is administered to the subject in a dose-reducing dosing regimen comprising multiple treatment cycles; the dose of the CD19-ADC is reduced after the second treatment cycle; the starting dose of the CD19-ADC is about 120 μg / kg to about 200 μg / kg; The CD19-ADC has the following structure: 【Chemistry 2】 It is a structure represented by The Ab comprises a VH domain having the amino acid sequence represented by SEQ ID NO:2 and a VL domain having the amino acid sequence represented by SEQ ID NO:8; the CD19-ADC has a drug-to-antibody (Ab) ratio (DAR) of 1 to 8; The pharmaceutical composition is administered by intravenous injection.

3. 1. A pharmaceutical composition for treating diffuse large B-cell lymphoma (DLBCL) in a subject, comprising a CD19-antibody drug conjugate (ADC), the pharmaceutical composition is for administration to the subject in combination with rituximab; the CD19-ADC is administered to the subject in a dose-reducing dosing regimen comprising multiple treatment cycles; the dose of the CD19-ADC is reduced after the second treatment cycle; the starting dose of the CD19-ADC is about 120 μg / kg to about 200 μg / kg; The CD19-ADC has the following structure: 【Transformation 3】 It is a structure represented by The Ab comprises a VH domain having the amino acid sequence represented by SEQ ID NO:2 and a VL domain having the amino acid sequence represented by SEQ ID NO:8; the CD19-ADC has a drug-to-antibody (Ab) ratio (DAR) of 1 to 8; The pharmaceutical composition is administered by intravenous injection.

4. 1. A pharmaceutical composition for treating follicular lymphoma (FL) in a subject, comprising a CD19-antibody drug conjugate (ADC), the pharmaceutical composition is for administration to the subject in combination with rituximab; the CD19-ADC is administered to the subject in a dose-reducing dosing regimen comprising multiple treatment cycles; the dose of the CD19-ADC is reduced after the second treatment cycle; the starting dose of the CD19-ADC is about 120 μg / kg to about 200 μg / kg; The CD19-ADC has the following structure: 【Chemistry 4】 It is a structure represented by The Ab comprises a VH domain having the amino acid sequence represented by SEQ ID NO:2 and a VL domain having the amino acid sequence represented by SEQ ID NO:8; the CD19-ADC has a drug-to-antibody (Ab) ratio (DAR) of 1 to 8; The pharmaceutical composition is administered by intravenous injection.

5. 5. The pharmaceutical composition of claim 1, 2, 3, or 4, wherein the starting dose of the CD19-ADC is reduced once in the dosing regimen.

6. 5. The pharmaceutical composition of claim 1, 2, 3, or 4, wherein the starting dose of the CD19-ADC is about 140 μg / kg to about 160 μg / kg.

7. 5. The pharmaceutical composition of claim 1, 2, 3, or 4, wherein the starting dose of the CD19-ADC is about 120 μg / kg, about 150 μg / kg, or about 180 μg / kg.

8. 5. The pharmaceutical composition of claim 1, 2, 3 or 4, wherein each treatment cycle is three weeks long.

9. 5. The pharmaceutical composition of claim 1, 2, 3, or 4, wherein the dose of the CD19-ADC is reduced to about 50% of the starting dose.

10. The amount of rituximab administered is about 375 mg / m ２ ~About 425mg / m ２ 5. The pharmaceutical composition according to claim 1, 2, 3 or 4, wherein

11. The amount of rituximab administered is about 375 mg / m ２ The pharmaceutical composition of claim 10, wherein

12. 12. The pharmaceutical composition of claim 11, wherein rituximab is administered in a Q3W (once every three weeks) dosing regimen.

13. 2. The pharmaceutical composition of claim 1, wherein the subject has, is suspected of, is identified as being at risk for, or has been diagnosed with CD19-positive lymphoma.

14. 3. The pharmaceutical composition of claim 2, wherein the subject has, is suspected of, is identified as being at risk for, or has been diagnosed with B-cell non-Hodgkin's lymphoma (B-NHL).

15. 4. The pharmaceutical composition of claim 3, wherein the subject has, is suspected of having, is identified as being at risk for, or has been diagnosed with diffuse large B-cell lymphoma (DLBCL).

16. 5. The pharmaceutical composition of claim 4, wherein the subject has, is suspected of having, is identified as being at risk for, or has been diagnosed with follicular lymphoma (FL).

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