Cancer treatment with ROR1 antibody immunoconjugates

Abstract

To provide new therapies, or methods for treating cancer patients, that can improve outcomes for the patients through targeting of ROR1.SOLUTION: Provided herein are methods for treating a cancer patient with immunoconjugates comprising an anti-ROR1 antibody or an antigen-fragment fragment thereof and a drug moiety.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Patent Application No. 62 / 800,187, filed February 1, 2019. No. 60 / 319,933, filed on Oct. 13, 2003, the disclosure of which is hereby incorporated by reference in its entirety. Be absorbed.

[0002] Sequence Listing This application contains a Sequence Listing which has been submitted electronically in ASCII format, which Sequence Listing is hereby incorporated by reference. The Sequence Listing created on January 29, 2020 is incorporated herein by reference in its entirety. The child copy is named 024651_WO003_SL.txt and has the following name: The size is 9,833 bytes. [Background technology]

[0003] Hematological malignancies are diseases resulting from transforming events occurring in the immune or hematopoietic organs. Lymphatic malignancies include those that occur in lymph nodes or in organs such as the blood, bone marrow, spleen, and liver. These cancers arise from the accumulation of monoclonal neoplastic lymphocytes in organs. and non-Hodgkin's lymphomas (NHLs), where non-Hodgkin's lymphoma includes chronic Chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma MCL, follicular lymphoma (FL), marginal zone lymphoma (MZL), diffuse large cell type DLBCL, Richter's transformed lymphoma (RTL), Burkitt's lymphoma Lymphoma (BL), Lymphoplasmacytic lymphoma (LPL), Waldenström macroglottoma WM, acute lymphoblastic leukemia (ALL) and several types of T-cell Acute myeloid leukemia (AML) is a type of cancer that affects the bone marrow, blood, central nervous system, and other organs. It occurs when neoplastic myeloblasts accumulate within the lining of the brain.

[0004] Patients with NHL depend in part on their cell of origin (B cell or T cell) for survival. Threatening organ dysfunction, bone marrow suppression and immunocompromise (which increases susceptibility to infection and bleeding) and / or may cause painful, severely pruritic and disfiguring may induce disabling systemic symptoms, lymphadenopathy and organ dysfunction Patients with LPL / WM may experience hypertrophy. The circulating monoclonal IgM protein (M protein) is produced by overproducing stromal cells. Patients with ALL or AML may develop plasma hyperviscosity due to the presence of erythropoietin (IL-1) and IL-2. In patients with leukemic blasts, the destruction of normal bone marrow function by the expansion of clones of leukemic blasts can be life-threatening. Become more susceptible to threatening infections and bleeding.

[0005] Treatment of these diseases involves inducing tumor regression, slowing tumor progression, and / or preventing the disease. The aim is to control complications associated with glaucoma and to prolong life. Patients are usually treated with chemotherapy and / or immunotherapy. However, many patients eventually experience recurrence of the disease. further treatments are used to try to control the symptoms of the disease. Progressive tumor resistance often occurs despite the use of different agents. Patients with advanced disease have a poor prognosis and may die from their cancer. To safely provide a new treatment option for patients with blood cancers that have become resistant to therapy To achieve this, new mechanisms of action are needed.

[0006] Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a ligand for It is a cell surface protein that mediates signals from the secretory glycoprotein Wnt5a. Embryonic development Consistent with its role in influencing stem cell fate during development, ROR1 expression is involved in the transcriptional processes of the embryo. It is observed in invasive malignant tumors of the gram-negative subtype but not in normal adult tissues. Thus, ROR1 offers a favorable selectivity profile as a therapeutic target. , is expressed on malignant cells in patients with hematological cancers, and on the cell surface of several solid tumors. There is, and it appears to be a marker for cancer stem cells. [Prior art documents] [Patent documents]

[0007] Patent document 1 WO2018 / 237335 Summary of the Invention [Problem to be solved by the invention]

[0008] High unmet medical need in many patients with hematological and other cancers In light of the role of ROR1 in cancer and the role of ROR1 in cancer, This includes new treatments that can improve outcomes for patients who do not respond to existing treatments. Treatment is required. [Means for solving the problem]

[0009] The present invention relates to a compound having the structure shown below: [ka]

[0010] and a method of treating a cancer patient using an immunoconjugate comprising the steps of: Here, Abs were specific for human receptor tyrosine kinase-like orphan receptor 1 (ROR1). wherein the heavy and light chains of the antibody are represented by SEQ ID NO: 1 and SEQ ID NO: 2, respectively. and wherein the immunoconjugate comprises an amino acid sequence of 0.25 to 4 As used herein, the above formula is administered to a patient at a dose of 0.00 mg / kg. I is a compound in which each Ab can be conjugated to only one copy of the drug moiety shown in the formula. In some embodiments, the number of drug moieties per antibody may be greater than or equal to 100. The number or copies of (DAR) ranges from 1 to 7, where each drug moiety is as shown in Formula I. The antibody is conjugated to the antibody via a linker as shown.

[0011] In some embodiments, the immunoconjugate is administered according to the dosing regimen described herein. Thus, the immunoconjugate is administered (e.g., intravenously). 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, In certain embodiments, the compound may be administered at a dose of 2.75 or 3.00 mg / kg. The immunoconjugates are administered in repeated 3-week cycles (e.g., 100 mg / cycle). In certain embodiments, the immunosuppressant may be administered on day 1, or on days 1 and 8. Noconjugates are administered in repeated 4-week cycles (e.g., 1 day per cycle) In some embodiments, the number of cycles may be administered. can total 3, 6 or more. In certain embodiments, the immunoconjugate can be administered as follows: every 3, 4, 6, or 8 weeks week, and every three weeks thereafter; or every three weeks for the first 3, 6, or 9 weeks, And every week thereafter.

[0012] In some embodiments, the immunoconjugate is directed to a patient suffering from a hematological cancer, such as a lymphoid malignancy. In certain embodiments, the cancer is CLL, SLL, MCL, FL , MZL, DLBCL, RTL, BL, LPL, WM, T-cell NHL, ALL and AML In certain embodiments, the patient has previously been treated for cancer. and / or recurrent or treated (e.g., one or more existing treatments for cancer, For example, they have cancer that is refractory to all existing treatments.

[0013] In some embodiments, treatment with the immunoconjugate induces tumor regression (e.g., ; slowing tumor progression; inhibiting cancer metastasis; preventing cancer recurrence Prevents recurrence or residual disease; reduces the size of nodal or extranodal tumor masses; reduces bone marrow and peripheral Decreasing the number of malignant cells in peripheral blood; Decreasing malignant splenomegaly or hepatomegaly; Cancer-related anemia , improves neutropenia or thrombocytopenia; improves skin symptoms; improves LPL / WM Reduces the likelihood of hyperviscosity syndrome in patients with the condition; improves disabling systemic symptoms and / or prolong survival.

[0014] The present disclosure also relates to methods for treating cancer in a patient with the methods described herein. Further, the present disclosure provides an immunoconjugate for use in US20130233633A1 - Immunoconjugates for the manufacture of drugs for treating cancer in a patient in a ... - Google Patents Provide for the use of. [Brief description of the drawings]

[0015] [Figure 1] Figure 1 is a graph showing plasma concentration-time curves recording the total plasma exposure of ADC-A (solid line) and MMAE (dotted line). C: cycle. D: day. LLQ: lower limit of quantification. [Diagram 2] Figure 2 is a series of graphs showing binding of ADC-A to ROR1 on circulating leukemic cells (top panel) and ADC-A and MMAE plasma concentrations (bottom panel) over time in two subjects with CLL. Subject 1: left. Subject 2: right. [Diagram 3] FIG. 3 is a graph showing the correlation between unoccupied ROR1 receptors and ADC-A plasma concentrations. [Figure 4] FIG. 4 is a graph showing pharmacokinetic simulations of ADC-A plasma concentrations over time using Q1 / 3W, Q2 / 3W and Q3 / 4W dosing regimens. [Diagram 5] Figure 5 is a graph showing best change in tumor size by ADC-A starting dose. TE: too early to evaluate. PR: partial response. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The present invention provides therapeutic regimens that use ROR1 immunoconjugates. The therapeutic regimen can be used to treat a variety of cancers, such as those predicted to express ROR1. It is possible.

[0017] 1. Immunoconjugates "Antibody drug conjugates" or "ADCs" or "immunoconjugates" are compounds that use a linker Covalently or non-covalently attached, with or without a linker, to one or more biologically active molecules. The immunoconjugate is an antibody molecule or an antigen-binding fragment thereof that is or a fragment thereof, wherein the antibody or fragment thereof is specific for human ROR1. and thus delivers its conjugated payload to cells (e.g., ROR1 positive In certain embodiments, the present invention can serve as an excellent targeting moiety for delivery to the host (e.g., reproductive cells). The immunoconjugates used in the therapeutic regimens of the invention are described in WO2018 / 237335. It is an immunoconjugate that has been described.

[0018] Shown below are the immunoconjugates described herein: The heavy and light chain complementarity determining regions (HCDRs and and LDCR), variable domains of the heavy and light chains (VH and VL) and heavy and light chains (HC and LC) are SEQ ID NOs: [Table 1]

[0019] In some embodiments, the antibody or antibody fragment in the immunoconjugate is a human R It specifically binds to OR1, and its heavy and light chains, respectively, comprise: (a) HCDR1-3 amino acid sequence in SEQ ID NO: 1 and LCDR1 in SEQ ID NO: 2 -3 amino acid sequence; (b) HCDR1-3 comprising the amino acid sequences of SEQ ID NOs: 5-7, respectively, and LCDR1-3 comprising the amino acid sequences of SEQ ID NOs:8-10; (c) HC comprising residues 26-33, 51-58 and 97-105 of SEQ ID NO:3, respectively. DR1-3, and residues 27-32, 50-52, and 89-97 of SEQ ID NO:4, respectively. LCDR1-3 including; (d) HC comprising residues 26-32, 52-57 and 99-105 of SEQ ID NO:3, respectively. DR1-3, and residues 24-34, 50-56, and 89-97 of SEQ ID NO:4, respectively. LCDR1-3 comprising: (e) HC comprising residues 31-35, 50-66 and 99-105 of SEQ ID NO:3, respectively. DR1-3, and residues 24-34, 50-56, and 89-97 of SEQ ID NO:4, respectively. LCDR1-3 including.

[0020] In certain embodiments of the immunoconjugates described herein, the antibody is In some embodiments, the cytotoxic drug can be conjugated to the cytotoxic drug via an anchor. The linker is a cleavable linker. A cleavable linker is a linker that contains a cleavable moiety. These examples show linkers that are typically susceptible to cleavage under in vivo conditions. In the form, the linker is a valine-citrulline (val-cit, or VC) linker. In certain embodiments, the linker may comprise a dipeptide such as is bonded to the group.

[0021] In some embodiments, the attachment of the linker / payload to the antibody or fragment is maleic. It can be formed via reaction with an imide group (which can also be referred to as a maleimide spacer). In certain embodiments, the maleimide group is maleimidocaproyl (mc); The linker / payload is a residue on the antibody or fragment and a mc in the linker precursor. The conjugated antibody or fragment is coupled to the antibody or fragment via a reaction between the group.

[0022] In some embodiments, the linker is a benzoic acid group or a benzyloxy group or a derivative thereof. In some embodiments, the linker can include para-amino-benzyl Contains an oxycarbonyl (PAB) group.

[0023] In some embodiments, the Ab and payload or drug (D) components of the immunoconjugate The bond between the moiety and the maleimide group, the peptide moiety, and / or the benzoic acid (e.g., PAB ) groups in any combination. In certain embodiments, the maleimide group is maleimidocaproyl (mc). In certain embodiments, the linker is Val- In certain embodiments, the attachment of the linker to the antibody or fragment comprises a Cit-PAB group. In certain embodiments, the antibody or flagyl group may be formed from a mc-Val-Cit group. The bond between the amine and the drug moiety can be formed from the mc-Val-Cit-PAB group.

[0024] Linkers can be conjugated to the anti-ROR1 antibodies and antigen-binding fragments of the disclosure in several ways. Generally, the linker and the cytotoxic moiety are attached to the antibody. One method for attaching the linker-drug conjugate to the antibody is to synthesize and attach the The method involves cleaving solvent-exposed disulfides with dithiothreitol (DTT) or Tris(2 -carboxyethyl)phosphine (TCEP), and then the resulting thiol was reacted with Maleimido-containing linker-drug moiety (e.g., 6-maleimidocaproyl-valine-citrate The compound was modified with phosphorus-p-aminobenzyloxycarbonyl (mc-VC-PAB). Native antibodies contain 4 interchain disulfide bonds and 12 intrachain disulfide bonds, and The antibody modified in this way therefore contains 100% unpaired cysteine ​​per antibody. In certain embodiments, the immunoconjugate may comprise multiple linker-drug moieties. The gates each have at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 linkers. In certain embodiments, the immunoconjugates each comprise one or more (For example, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or , 1-2) linker / drug moieties. The linker is branched, each of which can carry multiple drugs. When the drug moiety can be linked to the antibody, the ratio of the drug moiety to the antibody is preferably 0.01 to 0.1, and more preferably 0.01 to 0.1. is higher than when using

[0025] In some embodiments, the immunoconjugates described herein are Suitable cytotoxic drugs for use in the treatment of cancer include, for example, antitubulin drugs such as auristatins. In certain embodiments, the cytotoxic agent is monomethylauristatin E (MMAE). be.

[0026] In some embodiments, the immunoconjugates described herein are It has the following structure: [Table 2]

[0027] The anti-ROR1 antibody may be any of the anti-ROR1 antibodies described herein (e.g., SEQ ID NO:1). and a light chain amino acid sequence of SEQ ID NO: 2). do.

[0028] In certain embodiments, the immunoconjugates used in the treatment regimens of the invention have the following structure: Structure (I): [ka]

[0029] has.

[0030] In some embodiments, the antibody is Ab1, where Ab1 has a heavy chain amino acid sequence of SEQ ID NO:1. and the light chain amino acid sequence of SEQ ID NO:2 (Ab1); The compound can have a DAR of 3 to 6 and is referred to herein as "ADC-A." See also WO2018 / 237335. The payload is an antibody polypeptide. It is linked to Ab1 via a cysteine ​​residue in the tide chain.

[0031] 2. Treatment planning In some embodiments, the ROR1 immunoconjugates described herein (e.g., For example, ADC-A) is administered at a dose of 0.25 to 10 mg / kg, for example, 0.25 to 4 mg / kg. For example, the immunoconjugates may be administered in doses of 0.25, 0.5, 0.75, 1 , 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3. 5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 6.5, 7, 8, 9 or 10 mg / kg, or in the case of multiple doses, In certain embodiments, the immunoconjugates may be administered in any combination of doses. The gates are 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, and 2.00. , 2.25, 2.50, 2.75 or 3.00 mg / kg.

[0032] In some embodiments, the immunoconjugate comprises 1, 2, 3, 4, 5, 6, 7, 8, 9 The drug is administered in repeated cycles of 10, 11, 12, 13, 14, 15 or 16 weeks. In certain embodiments, the immunoconjugate is administered in three week cycles. In one embodiment, the immunoconjugate is administered in four-week cycles. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more cycles of administration (e.g., 3 or more cycles, or 4 In certain embodiments, the immunoconjugate may include cycles The administration days can be consecutive or or 1, 2, 3, 4, 5 or 6 days, 1 week, 2 weeks, 3 weeks or In certain embodiments, the immunoconjugate may be administered for one or more of the following periods: 1) for one or more weeks; Adjuvant is administered only on day 1 of each cycle (e.g., a 3-week cycle). In certain embodiments, the immunoconjugate is administered every cycle (e.g., every 3 week cycle). In certain embodiments, the immunoconjugate is administered on days 1 and 8 of each subgroup. The doses are administered on days 1, 8, and 15 of a cycle (eg, a 4 week cycle).

[0033] The immunoconjugate is initially administered according to the dosing regimen described herein. can then be administered in different dosing regimens (e.g., frequency of administration) as described herein. In some embodiments, the compound may be administered according to The immunoconjugate may be the first 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or It is administered weekly for 12 weeks, then every 3 weeks. In certain embodiments, The immunoconjugate is administered weekly for the first 2, 3, 4, 5, or 6 weeks, after which , every three weeks. In certain embodiments, the immunoconjugate is administered in the first It is administered weekly for 2, 3, 4, 5 or 6 weeks, then every 4 weeks. The conjugates can be administered, for example, as follows: · Every week for the first three weeks, then every three weeks; · Every week for the first 4 weeks, then every 3 weeks; · Every week for the first 6 weeks, then every 3 weeks; · Every week for the first 8 weeks, then every 3 weeks; · Every 3 weeks for the first 3 weeks, then weekly; · Every 3 weeks for the first 6 weeks, then weekly; Every 3 weeks for the first 9 weeks, then weekly thereafter.

[0034] In some embodiments, the dosing regimens described herein provide at least All are 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 μg / mL Immunoconjugates of plasma C max In some embodiments, the method described herein achieves the above-mentioned results. The dosing regimens described provide at least 500, 750, 1000, 125, 200, 300, 400, 500, 600, 750, 800, 900, 1000, 1250, 1400, 1600, 1800, 2000, 2200, 2400, 2800, 3 0, 1500, 1750, 2000, 2250, 2500, 2750, 3000, 325 Immunoconjugate plasma area under the concentration-time curve at 0 or 3500 h·μg / mL ( Achieve AUC.

[0035] In some embodiments, the dosing regimens described herein provide at least 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90% or 9 Maintains 5% immunoconjugate occupancy of the ROR1 receptor. In some embodiments, The dosing regimen described herein results in at least 50% immunoreactivity to ROR1 receptors. The occupancy rate of the indugegate shall be at least 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 300, 400, 500, 600, 700, 800, 1000, 15 ... In some embodiments, the dosing regimen described herein is maintained for 0 or 90% of the time. The study demonstrated that immunoconjugate occupancy of at least 75% of the ROR1 receptor was achieved over a short period of time. maintain the same level of activity for at least 20, 30, 40, 50, 60, 70, 80, or 90% of the time. In embodiments, the dosing regimens described herein target at least 90% of the ROR1 receptor. % immunoconjugate occupancy for at least 0.5, 1, 1.5, 2, 2 Maintain for .5, 3, 3.5, 4, 4.5 or 5%.

[0036] The immunoconjugates can be administered via parenteral administration. When used in a therapeutic approach, "parenteral administration" of an immunoconjugate involves physically invading the tissues of a subject. Breaking through the opening in the tissue and administering the immunoconjugate through the opening in the tissue. The term encompasses any route of administration characterized by the above-mentioned, and thus generally refers to administration into the bloodstream, into a muscle, or into the bloodstream. Parenteral administration thus includes, but is not limited to, administration directly to the internal organs. , administration of the immunoconjugate by injecting the immunoconjugate, or surgical incision. Administration of the immunoconjugate by administering the immunoconjugate through a tissue Immunoconjugates can be administered through a non-surgical wound penetrating the skin. In particular, parenteral administration includes, but is not limited to, the following: is intended to include: subcutaneous, intraperitoneal, intramuscular, intrasternal, intravenous, intraarterial intrathecal, intraventricular, intraurethral, ​​intracranial, intratumoral and intrasynovial injection or infusion; and renal In some embodiments, the injection is performed using a dialysis infusion technique. Regional perfusion is also contemplated. The drug may be administered by one route (e.g., intravenously) for one dose and then administered twice for subsequent doses. The drug may be administered by another route for

[0037] In certain embodiments, the immunoconjugate is administered by intravenous (IV) infusion. The IV infusion can be administered over a period of about 0.1 to about 4 hours (e.g., Approximately 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 7 0, 75, 80, 85, 90, 120 or 180). In certain embodiments, the infusion time is 3 0 minutes. Infusion times may be extended, if necessary, to accommodate individual patient tolerance. When the immunoconjugate is administered in two or more doses, some experiments have shown that In an embodiment, the infusion time for the first dose is longer than the infusion time for subsequent doses; and Alternatively, the infusion time for the first dose is shorter than the infusion time for subsequent doses.

[0038] In some embodiments, the immunoconjugate is administered as a monotherapy.

[0039] The treatment regimen of the present invention may be the treatment method described herein. The immunoglobulins described herein for use in the therapeutic regimens described herein. Conjugates or may be used in the treatment regimens described herein. of the immunoconjugates described herein for the manufacture of a medicament for use in It is understood that there may be uses.

[0040] 3. Patient Selection The treatment regimen of the present invention can be used to treat patients with cancer. In embodiments, the treatment regimens of the present invention are directed to a selected patient having a cancer as described herein. In certain embodiments, the patient has previously been treated for said cancer. and / or one or more (or all) of the recurrent or existing cancers associated with said cancer. ) cancer that is refractory to treatment.

[0041] "Treat," "treating," and "treatment" "treatment" refers to at least one of a biological disorder and / or its associated symptoms. Also indicates a method of reducing or eliminating 1. In this case, "alleviating" a disease, disorder, or condition means reducing or eliminating the severity and severity of the symptoms of the disease, disorder, or condition. Furthermore, the term "treatment" as used herein means to reduce the incidence and / or severity of the condition. References to include references to curative treatment, palliative treatment and prophylactic treatment. The treatment is intended to inhibit the growth of the cancer (which may result in partial or complete regression of the cancer). (including) inhibiting the progression or metastasis of cancer, preventing the recurrence or residual disease of cancer, and / or prolonging survival of the patient.

[0042] In some embodiments, the patient treated with the therapeutic regimen of the present invention has a cancer that expresses ROR1. Cancers expressing ROR1 can be identified by any suitable method to confirm gene or protein expression. By appropriate methods, e.g., histology, flow cytometry, radiopharmaceutical methods, RT-P The cancer cells used for the confirmation can be identified by CR or RNA-Seq. , can be obtained by tumor biopsy or by collection of circulating tumor cells. In this study, antibody-based assays such as flow cytometry or immunohistochemistry were used. When ROR1 is expressed, cancers that express ROR1 show higher anti-ROR1 antibody responses than isotype control antibodies. In certain embodiments, the RNA-based assay is any cancer having cells that exhibit the When used, ROR1-expressing cancers are compared with negative control cells or cancers that do not express ROR1. In comparison, cancers that exhibit elevated levels of ROR1 RNA.

[0043] In certain embodiments, the patient has a hematological malignancy, such as a lymphoid malignancy. In certain embodiments, the patient has a solid tumor, e.g., lymphoma, non-Hodgkin's Lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), marginal zone Lymphoma (MZL), marginal cell B-cell lymphoma, Burkitt lymphoma (BL), mantle Myocardial Infarction Lymphoma (MCL), Follicular Lymphoma (FL), Diffuse Large B-Cell Lymphoma (DLBCL), Richter-transformed non-Hodgkin's lymphoma, T-cell leukemia, T-cell Lymphoma (e.g., T-cell non-Hodgkin's lymphoma), lymphoplasmacytic lymphoma (LPL) , Waldenström's macroglobulinemia (WM), acute myeloid leukemia (AML), Acute lymphocytic leukemia (ALL), hairy cell leukemia (HCL), myeloma, multiple myeloma sarcoma (e.g., osteosarcoma, Ewing's sarcoma, rhabdomyosarcoma, soft tissue sarcoma, or , uterine sarcoma), brain tumor, glioblastoma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, neuroblastoma cancer, head and neck cancer, nasopharyngeal cancer, thyroid cancer, breast cancer (e.g., ER / PR-positive breast cancer, HER2- positive breast cancer or triple negative breast cancer), lung cancer (e.g., non-small cell lung cancer or small cell alveolar lung cancer), malignant mesothelioma, bile duct / gallbladder cancer (e.g., cholangiocarcinoma), colon cancer, colorectal cancer, esophageal cancer , gastric cancer, stomach cancer Gastrointestinal stromal tumor (GIST), liver (hepatocellular) cancer, pancreatic cancer, renal cell carcinoma, bladder cancer, prostate cancer, Cervical cancer, endometrial cancer, ovarian cancer, testicular cancer, epithelial squamous cell carcinoma, melanoma, adrenal cortical carcinoma, digestive Ductal carcinoid tumor, Insula cell tumor, Pancreatic neuroendocrine tumor, Cutaneous neuroendocrine carcinoma (Merkel cell In certain embodiments, the patient may have a cancer selected from the group consisting of bronchial asthma, ... and pheochromocytoma. Have a cancer that is refractory to therapy (eg, triple-negative breast cancer).

[0044] In certain embodiments, the patient is a patient with CLL / SLL, MCL, FL, MZL, DLBCL, Cancer selected from RTL, BL, LPL / WM, T-cell NHL, ALL, and AML In certain embodiments, the patient may have been previously treated for said cancer, and and / or one or more (e.g., all) existing treatments for the recurrent or recurrent cancer. have cancer that is refractory to

[0045] In some embodiments, the patient is receiving ibrutinib, acalabrutinib, autologous hematopoietic stem cell transplantation. , bendamustine, bortezomib, brentuximab vedotin, carmustine, chimeric antibody Carcinoma receptor T (CAR-T) cells, cisplatin, copanlisib, cyclophosphamide, cyclophosphamide Tarabin, daratumumab, dexamethasone, doxorubicin, etoposide, gemcitabine , idelalisib, lenalidomide, melphalan, methotrexate, methylprednisolone Ron, Mosnetuzumab, Obinutuzumab, Ofatumumab, Oxaliplatin, Pinutuzumab Mab, polatuzumab, rituximab, prednisone, radiation therapy, venetoclax, bin cristine or any combination thereof (e.g., prior treatment as seen in the Examples). is resistant to or relapses after treatment with any combination of drugs is.

[0046] In some embodiments, the treatment regimen comprises: (i) a histologically confirmed, aggressive hematological cancer or (ii) a compound known to provide clinical benefit; have malignancies unlikely to respond to established therapies or have a clinical benefit have become intolerant to established therapies known to provide A human patient, e.g., an adult patient (age 18 or older) having appropriate performance status and organ function. ), adolescent patients (ages 12-17), or pediatric patients (ages under 18). In an embodiment, the patient meets both criteria.

[0047] 4. Treatment results In some embodiments, treatment with the immunoconjugate also includes one or more of the following: Drop: Induce partial or complete tumor regression, which may be beneficial in some cases as a final therapeutic step. can persist beyond the amount; · Slowing tumor progression (e.g., by inhibiting tumor growth); · Preventing cancer recurrence or residual disease; Reduce the size of nodal or extranodal tumor masses (which may be painful and disfiguring) may be damaged or compressed); Reduces the number of malignant cells in the bone marrow and peripheral blood; · Reduce malignant splenomegaly or hepatomegaly; Cancer-related anemia, neutropenia, or thrombocytopenia (each of which may cause the patient to become fatigued) Improve the risk of irritation, infection or bleeding; Improve skin symptoms (which may be painful, extremely itchy or have external may spoil the view); · Reducing the likelihood of hyperviscosity syndrome in patients with LPL / WM; Improves disabling symptoms; and Extend survival.

[0048] The treatment may result in any combination of the above results.

[0049] In some embodiments, the treatment regimen of the present invention is to reduce the size of a patient's tumor to the sum of the products of the perpendicular diameters. (SPD) at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 8 In some embodiments, the treatment regimen of the present invention reduces the , the dimensions of the patient's tumor were to be reduced by at least 10%, 20%, 30%, or Reduce by 40%, 50%, 60%, 70%, 80% or 90%. In embodiments, the treatment regimen of the invention completely eradicates the tumor.

[0050] In some embodiments, the treatment regimens of the invention (e.g., for treating CLL and / or SLL) are The treatment plan for the or 7) result in: (a) There is no evidence of a new disease; (b) The absolute lymphocyte count (ALC) in peripheral blood was 4 × 10 9 / L; (c) all index nodular masses regress to ≤15 mm in longest diameter (LD); (d) Normal spleen size is 120 mm or less as measured by the longest vertical dimension (LVD). , and normal liver size is 180 mm or less on LVD imaging; (e) Regression of all nodular non-index disease to normal values ​​(e.g., 15 mm or less) and Resolution of all detectable non-nodal non-index disease; (f) Morphologically negative bone marrow is characterized by less than 30% lymphocytes and by age. defined as the absence of lymphoid nodules in bone marrow samples that are normal cells versus And, (g) Peripheral blood meeting all of the following criteria: (i) Absolute neutrophil count without exogenous growth factors within 2 weeks prior to the relevant blood count evaluation Number of balls (ANC)>1.5×10 9 / L; (ii) Exogenous growth factor or platelet transfusion within 2 weeks prior to the relevant blood count evaluation None, platelet count >100 × 10 9 / L; and (iii) The patient had received exogenous growth factors or red blood cell transfusions within 2 weeks prior to the relevant blood count evaluation. Hemoglobin >110 g / L (11.0 g / dL) without blood.

[0051] In certain embodiments, the treatment regimen results in all of (a)-(g) (a "complete response"). , and furthermore, 1×10 -4 Flow cytometry of bone marrow aspirates showing malignant cells: In some embodiments, this can result in a complete response with no measurable residual disease. The treatment regimens of the invention result in one or more of the following ("complete count recovery with incomplete count recovery"); Overall Response (%) (a) (a)-(f), (g)(ii) and (g)(iii), and absolute neutrophil count (ANC)≦1.5×10 9 / L or ANC ≥ 1.5 × 10 9 To maintain / L , requiring exogenous growth factors within 2 weeks prior to relevant blood count evaluation; (b) (a)-(f), (g)(i) and (g)(iii) and a platelet count of ≤10 0×10 9 / L or platelet count ≥ 100 × 10 9 To maintain / L, the relevant blood cells Requirement of exogenous growth factors or platelet transfusion within 2 weeks prior to evaluation; and (c) (a)-(f), (g)(i) and (g)(ii) and hemoglobin ≤ 1 10g / L (11.0g / dL), or hemoglobin ≥ 110g / L (11.0g / dL) L) within 2 weeks prior to the relevant blood count evaluation. Requires red blood cell transfusion.

[0052] In some embodiments, the treatment regimens of the invention (e.g., to treat CLL / SLL) include: results in one or more of the following (e.g., any 1, 2, 3, or 4): (a) There is no evidence of a new disease; (b) Lymphadenopathy alone if only lymphadenopathy is present at screening Two of the following criteria, except that improvement must be made to the extent specified below: A change in medical condition that meets one or more of the following: (i) A decrease of 50% or more in the absolute lymphocyte count (ALC) in peripheral blood from the time of screening ; (ii) The sum of product diameters (SPD) of the index nodular lesions increases by 50% from screening decrease by more than %; (iii) In subjects with splenomegaly at screening, the longest vertical A reduction of 50% or more in hypertrophy in LVD from screening (minimum 20 mm reduction) or reduction to 120 mm or less on imaging; (iv) In subjects with hepatic enlargement at screening, A reduction of 50% or more in hypertrophy from screening (minimum reduction of 20 mm) or Imaging reduced to 180 mm or less; and (v) CLL / SLL bone marrow infiltration or B lymphoid nodules within 50 days from screening decrease by more than %; (c) Deterioration of index disease, splenic disease, hepatic disease or is free of non-index diseases; and (d) Peripheral blood meeting one or more of the following criteria: (i) Absolute neutrophil count without exogenous growth factors within 2 weeks prior to the relevant blood count evaluation Number of balls (ANC)>1.5×10 9 / L or an increase of 50% or more from screening; (ii) Exogenous growth factor or platelet transfusion within 2 weeks prior to the relevant blood count evaluation None, platelet count >100 × 10 9 / L or an increase of 50% or more from screening; And, (iii) The patient had received exogenous growth factors or red blood cell transfusions within 2 weeks prior to the relevant blood count evaluation. Hemoglobin >110 g / L (>11.0 g / dL) or >11.0 g / dL from screening This is an increase of more than 50%.

[0053] In certain embodiments, the treatment regimen results in all of (a)-(d) ("partial response"). In certain embodiments, the treatment regimen comprises: (a), (b)(ii)-(b)(v), (c) and and (d) result in all of the following ("partial response with lymphocytosis").

[0054] In some embodiments, the treatment regimens of the invention (e.g., to treat CLL / SLL) include: This can result in one or both of the following: (a) there is no evidence of new diseases; and (b) There is no evidence of tumor growth.

[0055] In certain embodiments, the treatment regimen results in both (a) and (b) (“stable”).

[0056] In some embodiments, the treatment regimens of the invention (e.g., to treat CLL / SLL) include: Does not result in any of the following, which are signs of "progression": (a) Evidence of a new disease as determined by one or more of the following: (i) New nodules greater than 15 mm in any diameter; (ii) In subjects with a normal splenic LVD of 120 mm or less as measured by imaging at the nadir , splenic LVD >140 mm by imaging; (iii) In subjects with a normal liver LVD of 180 mm or less as measured by nadir imaging and hepatic LVD of >200 mm by imaging; (iv) Histologically confirmed new effusion, ascites, or other disease associated with CLL / SLL organ abnormalities; (v) new extranodal disease >10 mm; (vi) New findings consistent with lymphoma rather than another etiology (e.g., infection or inflammation) Fluorodeoxyglucose (FDG)-avid foci; and (vii) PET if a previous PET or bone marrow biopsy was negative for lymphoma or new or recurrent bone marrow involvement due to lymphoma by bone marrow biopsy; (b) Index lesion, splenic or hepatic disease, as determined by one or more of the following: or evidence of worsening of non-index illness: (i) Sum of products of diameters (SPD) of index lesions increased by 50% or more from nadir; (ii) An individual nodule or mass with a LD greater than 15 mm and an LPD greater than 10 mm. the longest diameter (LD) of the outer mass increases by more than 50% from the nadir; (iii) splenomegaly at screening or at the nadir of the splenic longest vertical dimension (LVD) A 50% or greater increase in splenic enlargement from nadir (minimum increase of 20 mm) in subjects with ; (iv) Subjects with hepatomegaly at screening or hepatic LVD nadir , an increase of 50% or more from the nadir of hepatic hypertrophy (minimum increase of 20 mm); (v) The apparent size of the effusion, ascites, or other organ abnormalities associated with CLL / SLL and (vi) conversion to more aggressive histology established by lymph node biopsy; (vii) The decrease in platelet count or hemoglobin due to CLL / SLL is due to autoimmune The disease was not due to a clonal CLL / SLL cell infiltration in bone marrow biopsies. It is confirmed that, (A) Your current platelet count is 100 × 10 9 / L or less, 50% above baseline has decreased by more than (B) Current hemoglobin is 110 g / L (11.0 g / dL) or less and baseline It has decreased by more than 20g / L (2g / dL) from the normal level.

[0057] In certain embodiments, the treatment produces none of the above results.

[0058] In some embodiments, a treatment regimen of the invention (e.g., for treating lymphoma) comprises the following: results in one or more of the following (e.g., any 1, 2, 3, 4, 5, 6, 7, or 8): (a) There is no evidence of a new disease; (b) all index nodular lesions regressed to ≤15 mm in LDi; (c) regression of all nodular nonindex disease to 15 mm or less; (d) resolution of all detectable extranodal index and nonindex disease; (e) Normal spleen size ≤130 mm as imaged in the longest vertical dimension (LVD) ; (f) If PET is performed, there is no evidence of residual disease – i.e., no evidence of residual disease on the Deauville scale The scores were 1 (no uptake above background), 2 (uptake ≤ mediastinum), and 3 (uptake ≤ mediastinum). or 3 (uptake >mediastinal, but ≤liver); (g) PET-avid tumor PET or morphological unilateral core biopsy Bone marrow evaluation is negative for lesions; if bone marrow biopsy is morphologically indeterminate, immunohistochemistry should be negative by chemistry; and (h) Absence of serum M protein by SIFE (in subjects with LPL / WM) ).

[0059] In certain embodiments, the treatment regimen results in all of (a)-(g) (a "complete response"). or all of (a)-(h) ("complete" in subjects with LPL / WM) "Response"), and further, 1 × 10 -4 Flow cytometry of bone marrow aspirate showing malignant cells: In certain embodiments, the patient may achieve a complete response with no measurable residual disease. The treatment plan will include all of (a)-(h) and baseline serum M protein concentrations. This results in a reduction of more than 90%.

[0060] In some embodiments, a treatment regimen of the invention (e.g., for treating lymphoma) comprises the following: results in one or more of the following (e.g., any 1, 2, 3, or 4): (a) There is no evidence of a new disease; (b) SPD of index nodal and extranodal disease was reduced by ≥50% from screening; (c) no increase in size of nonindex disease from its nadir; (d) In subjects with splenomegaly at screening, the extent to which splenomegaly persists for up to 1 year is unknown. A decrease of 50% or more from the screening point in vertical dimension (LVD) (minimum decrease of 20 mm), or reduced to 130 mm or less by imaging; (e) If PET is performed: (i) Typical FDG-avid lymphoma: A screening PET scan is performed. If the PET scan was not performed or was positive before treatment, the PET scan during treatment was Positive in ≥1 previously involved site - i.e., score 4 (medium) on the Deauville 5-point scale score 5 (significant uptake > liver) but not screened Screening PET was performed and was negative. If the PET scan is completed, there is no new PET evidence of disease. defined as a decrease of 25% or more in x; (ii) Variable FDG-avid lymphoma / FDG-avidity unknown: Pretreatment If a PET scan was not performed or if a pretreatment PET scan was not performed for lymphoma, If the test is negative, CT criteria should be used in the evaluation of the tumor during treatment. If pretreatment PET scan was positive, on-treatment PET should be performed to determine whether 1 or more previously involved sites were involved. positive in position; (f) Persistence of bone marrow disease in subjects meeting radiographic criteria for complete response (CR). Sex; and (g) A decrease of 50% but less than 90% from baseline in serum M protein concentration (LP subjects with L / WM).

[0061] In certain embodiments, the treatment regimen results in all of (a)-(f) (a "partial response"). or all of (a)-(g) (partial in subjects with LPL / WM) In certain embodiments, the treatment regimen results in all of (a)-(f), and Produce a 25% or greater but less than 50% decrease from baseline in serum M protein concentration ( “Minor response” in LPL / WM).

[0062] In some embodiments, a treatment regimen of the invention (e.g., for treating lymphoma) comprises the following: This results in one or more of the following: (a) There is no evidence of a new disease; (b) there is no evidence of tumor growth; and (c) A decrease of less than 25% and an increase of less than 25% from baseline in serum M protein concentration (in subjects with LPL / WM).

[0063] In certain embodiments, the treatment regimen of the invention provides both (a) and (b) ("stable "), or (a)-(c) ("stable" in subjects with LPL / WM) In certain embodiments, the treatment regimen of the present invention includes both (a) and (b), as well as serum Produce a 25% or greater but less than 50% decrease from baseline in M ​​protein concentration (LP "Minor response" in L / WM).

[0064] In some embodiments, the treatment regimen of the present invention includes the following (which are signs of "progression"): does not result in one or more of: (a) Evidence of a new disease as determined by one or more of the following: (i) New nodules greater than 15 mm in any diameter; (ii) healed (i.e., previously had a product of perpendicular diameters (PPD) of 0 mm 2 Assigned extranodal recurrence (previously unknown); (iii) new extranodal disease >10 mm; (iv) New non-index disease of any size clearly attributable to lymphoma (e.g., effusion) fluid, ascites, or other organ abnormalities) (e.g., PET, biopsy, cytology, or other non-radioactive assays) confirmed by); (v) Alternative etiology (e.g., infection or inflammation; there is uncertainty regarding the etiology of the new lesion) consistent with lymphoma rather than a biopsy or interval scan may be considered. New FDG-avid foci; and (vi) Previous PET or bone marrow biopsy performed as part of the study for lymphoma If negative, new or recurrent bone marrow involvement by PET or bone marrow biopsy to lymphoma; (b) Worsening of nodal or extranodal index lesions as determined by one or more of the following: evidence: (i) A 50% or greater increase from the nadir in the sum of the products of the diameters (SPD) of the index lesions addition; (ii) PP for individual nodules if the LD of the current nodule is greater than 15 mm D increased by 50% or more from the nadir, The LD or SD is 20 mm or less (LD or minimum dimension (SDi In the case of a lesion in the pelvis, the increase is 5 mm or more from the lowest point, or exceeds 20 mm (L D or SDi) In the case of a lesion, the increase is 10 mm or more from the lowest point. evidence of deterioration of individual index lymph nodes or nodal masses; (iii) a clear increase in the size of non-index disease; and (iv) in patients with splenic LVD >130 mm as measured by nadir imaging; Splenic swelling increased by 50% or more from the lowest point (minimum increase of 20 mm) or images at the lowest point Splenic LVD >150 mm in patients with splenic LVD ≤130 mm due to aging Visceral LVD; (c) more aggressive non-Hodgkin's lymphoma (NHL) established by lymph node biopsy; the shift to histology; (d) If PET was performed, the Deauville 5-point scale gave a score of 4 (moderate uptake > 4). liver) or score 5 (significant uptake > liver), consistent with disease progression (PD). There is an increase in effort compared to the nadir with concomitant anatomical increase in size. is defined as a 50% or greater increase in %ΔSUVmax; and (e) A 25% or greater increase from nadir in serum M protein concentration (with LPL / WM) (in subjects who

[0065] In certain embodiments, the treatment results in none of (a)-(d), or none of the above. does not result in any of the above outcomes.

[0066] In some embodiments, the treatment regimens of the invention (e.g., for treating acute lymphoblastic leukemia) include , resulting in one or more of the following (e.g., any 1, 2, or 3): (a) Leukemia that meets all of the following requirements: (i) Less than 5% myeloblasts (≥200 nucleated cells and the presence of bone marrow spicules) based on accompanying bone marrow aspirate / biopsy sample); (ii) absence of blasts in peripheral blood; (iii) Absence of extramedullary disease (this is defined as lymphadenopathy, splenomegaly, skin / gum involvement, testicular Mass involvement and absence of central nervous system involvement (i.e., achievement of CNS-1 status (cerebrospinal fluid There are no blast cells in it))); (b) Peripheral blood that meets all of the following requirements: (i) ANC ≥ 1.0 × 10 9 / L; (ii) Platelet count ≧100×10 9 / L; and (c) Mediastinal widening shows complete resolution as documented on radiograph.

[0067] In certain embodiments, the treatment regimen results in all of (a)-(c) (a "complete response"). , and further, 1×10 -4 Flow cytometry of bone marrow aspirates showing malignant cells: ("complete response with no measurable residual disease").

[0068] In some embodiments, the treatment regimens of the invention (e.g., for treating acute lymphoblastic leukemia) include , resulting in one or more of the following (e.g., any 1, 2, or 3): (a) Leukemia that meets all of the following requirements: (i) Less than 5% myeloblasts (≥200 nucleated cells and the presence of bone marrow spicules) based on accompanying bone marrow aspirate / biopsy sample); (ii) absence of blasts in peripheral blood; (iii) Absence of extramedullary disease (this is defined as lymphadenopathy, splenomegaly, skin / gum involvement, testicular Mass involvement and absence of central nervous system involvement (i.e., achievement of CNS-1 status (cerebrospinal fluid There are no blast cells in it))); (b) Peripheral blood that meets all of the following requirements: (i) ANC<1.0×10 9 / L; (ii) Platelet count<100×10 9 / L; and (c) Mediastinal widening was measured as the sum of the products of perpendicular diameters (SPD) as documented on radiographs. has regressed by more than 75%.

[0069] In certain embodiments, the treatment regimen results in all of (a)-(c) ("defective blood cell Complete response with multiple response recovery and / or unconfirmed complete response).

[0070] In some embodiments, the treatment regimens of the invention (e.g., for treating acute lymphoblastic leukemia) include , resulting in one or more of the following (e.g., any 1, 2, or 3): (a) A leukemia condition that meets any of the following requirements: (i) A 50% or greater decrease in myeloblasts to 5%-25% (>200 nucleated cells) based on bone marrow aspirate / biopsy samples with and the presence of bone marrow spicules); (ii) absence of blast cells in the peripheral blood; and (iii) Absence of new or worsening extramedullary disease (this includes lymphadenopathy, splenomegaly, Includes skin / gum infiltration, testicular mass, and no central nervous system involvement (e.g., CNS CNS-1 state (no blasts in the CNS fluid) and CNS-2 state (blasts in the CNS fluid) WBC < 5 × 10 9 / L) or CNS-3 status (blasts present in the cerebrospinal fluid and WB C ≥ 5 × 10 9 / L) or facial nerve palsy, brain / eye involvement, or hypothalamic syndrome. Not migrated)); (b) Peripheral blood that meets all of the following requirements: (i) ANC ≥ 1.0 × 10 9 / L; (ii) Platelet count ≧100×10 9 / L; and (c) Mediastinal widening was not observed unless the SPD had regressed by 50% or more, as documented by radiograph. There are.

[0071] In certain embodiments, the treatment regimen results in all of (a)-(c) ("partial response"). .

[0072] In some embodiments, the treatment regimens of the invention (e.g., for treating acute lymphoblastic leukemia) include , resulting in one or more of the following (e.g., 1, 2, or 3): (a) Sufficient improvement in ALL from baseline to qualify as a PR is also required to qualify as a DRP. There is also insufficient evidence of progression of ALL to be considered; (b) Absence of new or worsening extramedullary disease (this includes lymphadenopathy, splenomegaly, skin / Includes gingival involvement, testicular masses, and no central nervous system involvement (e.g., CNS-1 syndrome). CNS-1 state (no blasts in the CSF) and CNS-2 state (blasts in the CSF, WBC<5×10 9 / L) or CNS-3 status (blasts present in cerebrospinal fluid and WBC ≥ 5 ×10 9 / L) or progress to facial nerve palsy, brain / eye involvement, or hypothalamic syndrome. Not yet)); (c) No new mediastinal widening occurred and the SPD of existing mediastinal widening did not exceed 25% It has not increased.

[0073] In certain embodiments, the treatment regimen of the invention results in all of (a)-(c) ("stable ").

[0074] In some embodiments, the treatment regimens of the invention (e.g., for treating acute lymphoblastic leukemia) include , one or more of the following (which are signs of disease recurrence or progression, "DRPs"): For example, does not result in 1, 2, 3, 4, 5 or 6): (a) relapse of bone marrow blasts (to >5%) in subjects who experienced a CR; (b) recurrence of blasts in peripheral blood in subjects who experienced CR; (c) Myeloblasts increase by 25% to 20% or more (having 200 or more nucleated cells). based on bone marrow aspirate / biopsy sample with the presence of bone marrow spicules; (d) Peripheral blood blast count increased by 25% or more to 1 × 10 9 / L or more; (e) Development of new or worsening pre-existing extramedullary disease (this may include lymphadenopathy, splenomegaly, Include skin / gum infiltration, testicular mass, or include CNS involvement (e.g., CNS- CNS-1 state (no blasts in the cerebrospinal fluid) and CNS-2 state (blasts in the cerebrospinal fluid and WBC<5×10 9 / L) or CNS-3 status (blasts in cerebrospinal fluid and WBC ≧5×10 9 / L) or facial nerve palsy, brain / eye involvement, or hypothalamic syndrome development, (is transitioning); and (f) The occurrence of new mediastinal widening or an increase in the SPD of existing mediastinal widening of 25% or more.

[0075] In certain embodiments, the treatment does not result in any of (a)-(f).

[0076] In some embodiments, the treatment regimen of the invention (e.g., treating acute myeloid leukemia) comprises: This can result in one or both of the following: (a) Leukemia that meets all of the following requirements: (i) Less than 5% myeloblasts (≥200 nucleated cells and the presence of bone marrow spicules) based on accompanying bone marrow aspirate / biopsy sample); (ii) absence of blasts in peripheral blood; (iii) no blasts with Auer rods; and (iv) no extramedullary disease; and (b) Peripheral blood that meets both of the following requirements: (i) ANC ≥ 1.0 × 10 9 / L; (ii) Platelet count ≧100×10 9 / L.

[0077] In certain embodiments, the treatment regimen results in both (a) and (b) (a "complete response"). , and further, 1×10 -4 Flow cytometry of bone marrow aspirates showing malignant cells: ("complete response with no measurable residual disease").

[0078] In some embodiments, the treatment regimen of the invention (e.g., treating acute myeloid leukemia) comprises: This can result in one or both of the following: (a) Leukemia that meets all of the following requirements: (i) Less than 5% myeloblasts (≥200 nucleated cells and the presence of bone marrow spicules) based on accompanying bone marrow aspirate / biopsy sample); (ii) absence of blasts in peripheral blood; (iii) no blasts with Auer rods; and (iv) no extramedullary disease; and (b) Peripheral blood meeting only one of the following criteria: (i) ANC ≥ 1.0 × 10 9 / L; and (ii) Platelet count ≧100×10 9 / L.

[0079] In certain embodiments, the treatment regimen results in both (a) and (b) ("defective blood cell (Complete response with recovery of tumor counts).

[0080] In some embodiments, the treatment regimen of the invention (e.g., treating acute myeloid leukemia) comprises: This can result in one or both of the following: (a) Leukemia that meets all of the following criteria: (i) Less than 5% myeloblasts (≥200 nucleated cells and the presence of bone marrow spicules) based on accompanying bone marrow aspirate / biopsy sample); (ii) absence of blasts in peripheral blood; (iii) no blasts with Auer rods; and (iv) no extramedullary disease; and (b) Peripheral blood that meets both of the following criteria: (i) ANC≦1.0×10 9 / L; and (ii) Platelet count ≦100×10 9 / L.

[0081] In certain embodiments, the treatment regimen results in both (a) and (b) ("morphologic leukemia"). "freedom from disease").

[0082] In some embodiments, the treatment regimen of the invention (e.g., treating acute myeloid leukemia) comprises: This can result in one or both of the following: (a) A leukemia condition that meets any of the following requirements: (i) A 50% or greater decrease in myeloblasts to 5%-25% (>200 nucleated cells) based on bone marrow aspirate / biopsy samples with and the presence of bone marrow spicules); (ii) <5% myeloblasts but Auer rods are present (>200 based on bone marrow aspirate / biopsy sample with nucleated cells and the presence of bone marrow spicules); (iii) absence of blast cells in the peripheral blood; and (iv) No new or worsening extramedullary disease; and (b) Peripheral blood meeting both of the following criteria: (i) ANC ≥ 1.0 × 10 9 / L; and (ii) Platelet count ≧100×10 9 / L.

[0083] In certain embodiments, the treatment regimen results in both (a) and (b) (a "partial response").

[0084] In some embodiments, the treatment regimen of the invention (e.g., treating acute myeloid leukemia) comprises: This can result in one or both of the following: (a) CR MRD- Baseline for certification as CR, CRi, MLFS or PR There is neither sufficient improvement in AML from the initial phase nor sufficient evidence of AML deterioration to qualify as a DRP. and (b) There is no new or worsening extramedullary disease.

[0085] In certain embodiments, the treatment regimen of the invention results in both (a) and (b) ("stable ").

[0086] In some embodiments, the treatment regimen of the invention (e.g., treating acute myeloid leukemia) comprises: One or more of the following (which are signs of disease recurrence or progression, "DRPs"): Does not drip: (a) CR MRD- Bone marrow blasts in subjects who experienced CR, CRi, or MLFS recurrence (to >5%); (b) CR MRD- In the peripheral blood of subjects who experienced CR, CRi, MLFS, or PR, relapse of blast cells; (c) In subjects who experienced a PR, there was an absolute increase of 20% in bone marrow blasts to >25% (bone marrow aspirate / biopsy sample with 200 or more nucleated cells and the presence of bone marrow spicules) pull-based); (d) An absolute 20% increase in peripheral blasts to greater than 25% in subjects who experienced a PR and (e) Development of new or worsening of existing extramedullary disease.

[0087] In certain embodiments, the treatment does not result in any of (a)-(e).

[0088] In some embodiments, the therapeutic regimen of the invention (e.g., treating a solid tumor) comprises: This can result in one or both of the following: (a) Disappearance of all target lesions and no new measurable lesions (e.g., ≥1 dimension (maximum The longest diameter is recorded) and is >10 mm on a CT scan with a minimum slice thickness of 5 mm. Lesions that can be accurately measured by clinical examination or caliper measurement >10 mm, or >20 mm by chest x-ray); and (b) The target (e.g., in the short axis when assessed on a CT scan (minimum slice thickness 5 mm) 15mm or more) or non-target (e.g., 10mm or more but less than 15mm) Reduction in the short axis of any pathological lymph node to less than 10 mm, regardless of whether or not the node is metastatic.

[0089] In certain embodiments, the treatment plan provides both (a) and (b) (target lesions) (Complete response).

[0090] In some embodiments, the therapeutic regimens of the present invention (e.g., treating solid tumors) include those that are characterized by a diameter vector. Take the baseline total as the base line and any new measurements that may have emerged since the baseline A reduction of 30% or more in the sum of the diameters of the target lesions, including the possible lesions (referred to as the target lesion (Partial response, or

[0091] In some embodiments, the therapeutic regimens of the present invention (e.g., treating solid tumors) include those that are characterized by a diameter vector. Take the baseline total as the base line and any new measurements that may have emerged since the baseline A reduction of 30% or more in the sum of the diameters of the target lesions, including the possible lesions (referred to as the target lesion (Partial response, or

[0092] In some embodiments, the therapeutic regimens of the present invention (e.g., treating solid tumors) include those that are characterized by a diameter vector. did not produce sufficient shrinkage based on baseline sum to qualify as a partial response, or , nor does it result in a sufficient increase to qualify as progression based on the minimum sum of diameters during treatment. ("Stable" for target lesions).

[0093] In some embodiments, the therapeutic regimens of the invention (e.g., therapeutic regimens for treating solid tumors) are ) is the minimum post-baseline total (nadir tumor burden) or baseline total (if it is during treatment) The sum of the diameters of the target lesions (including new lesions) was calculated based on the smallest sum of the diameters of the target lesions (including new lesions). ≥20% increase (and ≥5mm absolute increase) in the target lesion (progression) Does not bring about

[0094] In some embodiments, the therapeutic regimen of the invention (e.g., treating a solid tumor) comprises: This results in one or more of the following: (a) Disappearance of all non-target lesions; (b) normalization of elevated tumor marker levels; and (c) All lymph nodes were nonpathological in size (<10 mm in short axis).

[0095] In certain embodiments, the treatment plan provides all of (a)-(c) (including those related to non-target lesions). In certain embodiments, the treatment regimen results in (b) and (c) but not (a "complete response"). does not result in (a), or results in (a) and (c) but not (b) (non-target "non-complete response / non-progression" for lesions).

[0096] In some embodiments, the therapeutic regimens of the present invention (e.g., treating solid tumors) are administered to existing non- Does not result in overt progression of target lesions ("progression" for non-target lesions).

[0097] In some embodiments, the therapeutic regimen of the invention (e.g., for treating solid tumors) comprises any one of the following: Brings about a physical response: - Absence of target lesions and new measurable lesions; absence of non-target lesions or tumor markers and absence of new non-measurable disease ("complete response"); - Absence of target lesions and new measurable lesions; and stable non-target lesions or tumors. marker("partial response"); - Absence of target lesions and new measurable lesions; and non-target lesions or tumor markers definite progression in the setting of CR ("partial response"); - A 30% or greater reduction in target lesions and new measurable lesions; and, Absence of markers, stable or unequivocal progression ("partial response"); or - <30% decrease to <20% increase in target lesions and new measurable lesions; and and absence of non-target lesions or tumor markers, stable disease or unequivocal progression ("stable disease").

[0098] In some embodiments, the therapeutic regimens of the invention (e.g., treating solid tumors) include target lesions. and a 20% or greater increase in new measurable lesions; and The study does not result in steady, stable or demonstrable progression ("progression").

[0099] In some embodiments, the treatment regimen of the invention is, for example, as defined above or in the Examples. have one or more of the following consequences: - CLL / SLL: CR, CRi, PR, or PR-L; - FL, MZL, MCL, DLBCL or BL:CR or PR; - LPL / WM:CR, VGPR, PR or MR; - ALL: CR, CRi / CRu or PR; - AML: CR, CRi, or PR; or - Solid tumors: CR or PR.

[0100] In some embodiments, the treatment regimen of the present invention comprises, in the first cycle of treatment, One or more of the following (e.g., any 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10): Not: (a) Grade 3 or greater febrile neutropenia; (b) Grade 4 or greater neutropenia; (c) grade 3 thrombocytopenia with grade 3 or greater bleeding; (d) thrombocytopenia of grade 4 or greater; (e) Grade 3, not resolving within 72 hours of onset, despite adequate prophylaxis Tumor lysis syndrome (TLS); (f) grade 4 or higher TLS despite appropriate precautions; (g) Grade 3 or greater despite recommended (or equivalent) antiemetic support vomiting; (h) Grade ≤1 or Grade ≥3 without improvement to baseline within 72 hours Abnormalities in the above non-hematological laboratory findings; (i) Other grade ≥ 3 non-hematologic treatment-emergent adverse events (TEAEs) (Grade ≥ 3) (excluding fatigue in step 3); and (j) The last TEAE of an immunoconjugate in that cycle occurred due to a drug-related TEAE. failure to recover to baseline for ≥21 days after dosing; All grades were determined using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. In certain embodiments, the treatment regimens of the present invention achieve any of the above outcomes. It won't let you.

[0101] In some embodiments, the treatment regimen of the invention includes one or more of the following (e.g., any one of the following): Does not result in 1, 2, 3, 4, 5 or 6): (a) As a result of a protocol-instructed procedure (e.g., venipuncture, ECG) complications; (b) A pre-existing condition that changes in severity or nature during or as a result of the administration of the drug. symptoms (e.g., increased pain, tumor flare reactions, worsening of symptoms of the underlying cancer such as TLS) ); (c) Injury or accident; (d) Requires clinical intervention or further investigation (beyond a repeat sequence or confirmatory test) Abnormalities in physiological examination or physical findings; (e) Lead to further investigation (beyond a repeat sequence or confirmatory testing) or Clinically significant adverse events that may lead to interruption or discontinuation of the investigational product, except when related to a clinical event that has been Laboratory (e.g., clinical chemistry, hematology, urinalysis) tests unrelated to the underlying disease that requires intervention ) or investigation (e.g., ECG, X-ray) abnormalities; and (f) Complications related to pregnancy or abortion.

[0102] In certain embodiments, the treatment regimens of the present invention achieve none of the above outcomes.

[0103] In some embodiments, the treatment regimen of the invention includes one or more of the following (e.g., any one of the following): Does not result in 1, 2, 3, 4, 5 or 6): (a) Death; (b) a life-threatening situation with an immediate risk of death; (c) Hospitalization or extension of existing hospitalization; (d) persistent or significant impairment / incapacity; (e) Congenital anomalies / birth defects in the offspring of subjects receiving the immunoconjugate Injury; and (f) Not immediately life-threatening or likely to cause death or hospitalization, but appropriate Based on medical and scientific judgment, to endanger the subject or prevent one of the outcomes listed above. A medically significant event that may require medical or surgical intervention to Allergic bronchospasm, new cancers or blood diseases requiring intensive care in a ward or at home (cachexia, convulsions not resulting in hospitalization, or the development of drug dependence or abuse).

[0104] In certain embodiments, the treatment regimens of the present invention achieve none of the above outcomes.

[0105] In some embodiments, the treatment regimen of the invention includes one or more of the following (e.g., one, two or more): does not yield 3): (a) Grade 3 or higher infusion reaction; (b) tumor lysis syndrome (TLS) of any grade; and (c) peripheral neuropathy grade 3 or greater; All grades were determined using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. It is defined using

[0106] In certain embodiments, the treatment regimens of the present invention achieve none of the above outcomes.

[0107] In some embodiments, the treatment regimen of the invention includes one or more of the following (e.g., any one of the following): 1, 2, 3, 4, 5, 6, 7, 8 or 9): urine, serum, Blood, systolic blood pressure, diastolic blood pressure, pulse, body temperature, blood oxygen saturation, and electrocardiogram (ECG) In certain embodiments, the treatment regimen of the present invention does not result in any of the above abnormalities. .

[0108] In some embodiments, the treatment regimens of the present invention provide detectable levels of circulating insulin in the serum of patients. Does not result in munoconjugate-reactive antibodies.

[0109] The treatment regimens described herein are also included in the methods of treatment described herein. The immunoconjugates described herein for use in the therapeutic regimens described herein. The present invention relates to a method for producing a conjugate or a medicament for the treatment regimen described herein. It is understood that the immunoconjugates described herein may be used.

[0110] 5. Premedication or Concomitant Medication Prevention of tumor lysis syndrome In some embodiments, patients treated with the treatment regimen of the present invention are selected from the group consisting of: To be assessed for risk of tumor lysis syndrome (TLS): CLL / SLL and NHL: (i) Low risk: serum lactate dehydrogenase (LDH) ≤ upper limit of normal (ULN), all measurable lymph nodes <5cm in diameter and ALC <25×10 9 / L; (ii) Medium risk: serum LDH >1 to ≤2×ULN, ≥1 measurable lymph node ≥5c m diameter but <10 cm diameter, or ALC ≥ 25 × 10 9 / L; (iii) High risk: serum LDH >2×ULN, 1 or more measurable lymph nodes ≥10c m diameter, or 1 or more measurable lymph nodes with LD ≥ 5 cm diameter but < 10 cm diameter And ALC≧25×10 9 / L; ALL: (i) Low risk: White blood cell count (WBC) < 20 × 10 9 / L and serum LDH level <2 ×ULN; (ii) Medium risk: WBC ≥ 20 × 10 9 / L~<100×10 9 / L and serum LD H level <2 × ULN; (iii) High risk: WBC ≥ 100 × 10 9 / L, or serum LDH level ≥ 2 × UL N; AML: (i) Low risk: serum LDH < 2 × ULN, serum uric acid < 5.5 mg / dL, and WBC <25×10 9 / L; (ii) Medium risk: serum LDH ≥ 2 × ULN, or serum uric acid ≥ 5.5 mg / dL and < 7 mg / dL or WBC ≥ 25 × 10 9 / L~<100×10 9 / L; (iii) High risk: serum uric acid ≥ 7 mg / dL or WBC ≥ 100 × 10 9 / L.

[0111] In some embodiments, if the patient is at moderate or high risk for TLS, and / or If TLS is observed during treatment, patients should be treated with allopurinol and Patients with hyperuricemia may also be administered rasburicase or febuxostat. For example, a patient may be administered the drug according to the dosing regimen described below. Can be administered: (i) Medium risk for TLS: Patients were required to receive ≥ 24-48 hours of PTCA before starting drug therapy and ≥ 8 Allopurinol may be administered orally at 100 to 300 mg every hour; The maximum daily dose of allopurinol is 800 mg. Doses of 300 mg or less should be taken in divided doses. and the dose should be reduced by at least 50% in subjects with renal insufficiency. Alternative medications (e.g., febuxostat) may be substituted when administered according to product labeling. In addition, patients with hyperuricemia can receive 3 to 4.5 mg of uric acid by IV infusion. Rasburicase may be administered.

[0112] (ii) High risk of TLS: Patients were required to initiate ≥24-48 hours prior to initiating drug therapy. Allopurinol may be administered orally at 100 to 300 mg every 8 hours; The maximum daily dose of allopurinol is 800 mg, and doses of 300 mg or less should be taken in divided doses. (although this may be insufficient for high-risk subjects) and renal failure In subjects with rheumatoid arthritis, the dose should be reduced by 50% or more. Alternative medications (e.g., febuxostat) may be used. tuxostat) may be substituted by administering according to the product label. High-risk patients should receive 3 to 4.5 mg of cefotaxime by IV infusion 3 to 4 hours before the first dose of drug. Rasburicase may be administered.

[0113] In some embodiments, patients are monitored with vital signs, AEs, and serum chemistry and hematology laboratories. The results of a laboratory study showed that TLS was not observed between cycle 1, day 1 (C1D1) and C1D3. and monitored.

[0114] Prevention of infusion reactions In some embodiments, the patient may receive fluid infusions prior to or during the treatment regimen of the present invention. Administer antipyretics and / or antihistamines to reduce the incidence and severity of reactions. In certain embodiments, the antipyretic agent may be administered by oral or IV route. For example, 650 to 1,000 ml of acetaminophen (paracetamol) g or equivalent. In certain embodiments, the antihistamine is administered orally or via IV. It can be administered by bronchoscopy and can be administered, for example, at 10 mg or equivalent of cetirizine. In some embodiments, one or both drugs may be administered at the same time for each immunoconjugate infusion. 30 to 60 minutes before the procedure. Nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., Ibuprofen or acetaminophen may be substituted. Corticosteroids (e.g., prednisolone) Zolone, 100 mg, or equivalent) may also be considered as a premedication.

[0115] Antiemetic prophylaxis In some embodiments, the patient experiences vomiting prior to or during treatment with the treatment regimen of the present invention. Antiemetics may be administered to treat vomiting and / or nausea.

[0116] Management of neutropenia In some embodiments, prior to or during the treatment of the present invention, the patient is To prevent or reduce induced neutropenic complications and promote neutrophil recovery, G- CSF (e.g., filgrastim, filgrastim-SND, PEG-filgrastim or may be administered lenograstim) or GM-CSF (eg, sargramostim).

[0117] Management of Hyperviscosity Syndrome (HVS) HVS suffers from LPL / WM due to the presence of high levels of circulating M protein It is a clinical feature in 10%-30% of patients. Immediate treatment of symptomatic HVS typically involves In some embodiments, prior to or after undergoing the treatment regimen of the present invention, During this time, patients can receive plasma exchange therapy to prevent or alleviate HVS. do.

[0118] 6. Products and Kits The present invention further provides the compounds described herein in the dosages described herein. Pharmaceutical compositions of immunoconjugates, optionally containing additional biologically active molecules (e.g., another therapeutic agent) and instructions for use in accordance with the treatment regimen described herein. A product (e.g., a kit) including the above containers (e.g., single-use containers or multi-use containers). The immunoconjugate and additional biologically active molecule are attached to a non-reactive glass substrate. together in suitable packing such as vials or ampoules made of glass or plastic. In some embodiments, the vials or ampoules may be packaged together or separately. Holds a liquid containing an immunoconjugate or a lyophilized powder containing an immunoconjugate the liquid or lyophilized powder may optionally contain additional therapeutic agents or biologically active molecules; In certain embodiments, the vial or ampoule contains the immunoconjugate and Optionally, concentrated stocks (e.g., 2x, 5x, 10x or more) of biologically active molecules may be used. In certain embodiments, the immunoconjugates described herein contain Pharmaceutical compositions of the gate (e.g., ADC-A) are available in doses of 50 mg, 100 mg, 150 mg, 2 00 mg, 250 mg or 300 mg of immunoconjugate (e.g., 0.50, 0. 75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2. Suitable for use at the doses described herein, such as 75 or 3.00 mg / kg. In certain embodiments, the product (e.g., The kit (e.g., a kit for administering the immunoconjugate and / or biologically active molecule) may be used in a method for administering the immunoconjugate and / or biologically active molecule. medical devices (e.g., syringes and needles); and / or a suitable diluent (e.g., sterile water and normal saline). The invention further includes a method of making the product.

[0119] Unless the context otherwise requires, the word "includes" is used throughout this specification and claims. "comprise" and its variations (e.g. "comprises" and "Comprising" has an open, inclusive meaning, i.e. "including but not limited to" The present specification and the appended claims are to be construed as meaning "without limitation." When used in this document, the singular forms "a," "an," and "the" are used where the context is clear. Unless expressly stated otherwise, the term "or" includes plural reference. Unless expressly stated otherwise, "and / or" is generally used in its inclusive sense. It should also be noted that, as used herein, the term "about" means Numerical ranges that are ±10%, ±5% or ±1% from the numerical value indicated within the context of a particular use Additionally, headings provided herein are for convenience only. These are merely illustrative and do not interpret the scope or meaning of the claimed embodiments.

[0120] All publications and patents referred to herein are incorporated by reference, for example, as to the invention currently being described. The present disclosure describes and describes the compositions and methodologies described therein that may be used in connection with the present disclosure. For purposes of disclosure, the entirety of the subject matter discussed herein is incorporated by reference. The publications cited herein are provided solely for their disclosure prior to the filing date of the present application. Nothing in this specification shall be construed as a presumption that the inventors of the present invention have invented such invention by virtue of prior invention or for any other reason. Nothing contained herein should be construed as an admission that there is no prior right to use the subject matter contained herein.

[0121] Unless otherwise defined, all technical and scientific terms used herein are generally understood by those skilled in the art to which the invention described herein pertains. Any similar or equivalent to those described herein. Methods, devices and materials may be used in the practice or testing of the invention described herein. It is possible. EXAMPLES

[0122] The following examples illustrate representative embodiments of the present invention and are not intended to be limiting in any way. It is not intended to be illustrated.

[0123] Example 1: Synthesis of ADC-A Conjugates of Ab1 and MC-VC-PAB-MMAE (ADC-A) were Similar results were obtained with kale (from 2 mg to 200 g). 00g of Ab1 (50mM sodium citrate, 10mg / mL trehalose, 0 Approximately 40 ml of 0.05 mM EDTA, 0.02% polysorbate 80, pH 5.2) g / mL) with 1.90 equivalents (eq) of tris(2-carboxyethyl)phosphine (TC The cells were treated with 5 mM EP and incubated at 20-24°C for 330 minutes. Add 6.5 eq of MC-VC-PAB-MMAE in acetamide (DMA) and mix. The mixture was kept at 22-23°C for an additional 60 min. The buffer was diluted to 10 mM by ultrafiltration / diafiltration (UF / DF) using The buffer was exchanged with sodium acetate (pH 4.8). The number of MAE drug molecules was confirmed using HIC-HPLC. HIC-HPLC, SE C-HPLC, RP-HPLC and UV / Vis data are summarized in Table 1 below. Consistent results were obtained at all scales, with DARs averaging 3.0–4.5%, depending on the methodology used. The range was .89 to 5.09. [Table 3]

[0124] Example 2: Dose Escalation Study of Anti-ROR1-MMAE Immunoconjugates Listed below are patients with previously treated relapsed or refractory CLL / SLL, M CL, FL, MZL, DLBCL, RTL, BL, LPL / WM, T cell NHL, ALL or ROR1 across a range of dose levels when administered to subjects with AML Safety, pharmacokinetics, pharmacodynamics, immunogenicity and efficacy of immunoconjugates (ADC-A) This is a protocol to evaluate the efficacy and safety of ADC-A in patients with refractory pulmonary edema. Repeated 3-week cycles (Q1 / 3W [Schedule 1]); 1 of each cycle Drug infusions were administered on days 1 and 8 in a repeated 3-week cycle (Q2 / 3W [schedule or repeated infusions on days 1, 8, and 15 of each cycle. The four-week cycle (Q3 / 4W [Schedule 3]) is conducted for approximately 30 minutes at a predetermined interval. It is administered intravenously (IV) over an infusion period that depends on the individual subject's therapeutic tolerance. It can be extended as needed to accommodate [Table 4]

[0125] Dose Levels The first cohort of subjects received ADC-A at 0.50 mg / kg Q1 / 3W. Cohorts of subjects will then be dosed Q1 / 3W, Q2 / 3W or Q3 / 4W. Subjects will be enrolled sequentially at progressively higher starting dose levels of ADC-A (Tables 2 and 3). If TEAEs are experienced that require a dose change below the starting level, a dose reduction is recommended. Initial dose of 0.25 mg / kg administered on a Q1 / 3W schedule to allow for minimal It is possible. [Table 5]

[0126] Accelerated Phase 3 Study in a Single Subject at Initial Dose Level Using a Q1 / 3W Schedule Dose escalation is planned. Cohorts of 3 to 6 subjects will then be enrolled sequentially to Using a standard 3+3 dose escalation design, each patient received progressively higher dose levels of ADC-A. Evaluate the dosing schedule. Patterns of dose-limiting toxicity (DTL) observed in cycle 1 Based on the dose schedule, titration will proceed to each dose schedule, which may be at the MTD or a lower dose within the tolerated dose range. A maximum tolerated dose (MTD) and recommended dosing regimen (RDR) are defined for each drug. is the highest dose level tested at which 6 or more subjects were treated, and 17 of the subjects % or less were associated with dose-limiting toxicity (DLT) in cycle 1. The RDR was the MTD. The choice of each RDR depends on the available drug doses. Based on consideration of short-term and long-term safety information along with kinetic, pharmacodynamic, and efficacy data. and supportive care (e.g., antiemetics or Once each RDR is established, the specific hematopoietic prophylaxis level can be defined. Further development is considered in liquid and / or solid tumors.

[0127] ADC-A administered to patients according to the provided dosing schedule was as follows according to disease type: Patients are expected to achieve an overall response (OR), defined as achieving the outcome: - CLL / SLL: Complete response (CR), complete response with incomplete blood count recovery (CRi ), partial response (PR), or partial response with lymphocytosis (PR-L); - NHL: CR or PR; - LPL / WM: CR, best partial response (VGPR), PR, or minor response (MPR) R); - ALL: CR, CRi, or unconfirmed complete response (CRu) (subjects with mediastinal disease (in the case of PR); and - AML: CR, CRi, morphologic leukemia free state (MLFS), or PR.

[0128] CR with no measurable residual disease (CR MRD- ) met all other criteria for CR plus 1 × 10 in the subject's bone marrow -4 Attainment of the following malignant cells (by flow cytometry) When provided according to the dosing regimen provided herein, ADC-A is a baseline study of the rate of change in tumor dimensions (sum of the products of the diameters (SPD) of index lesions). progression-free survival (PFS) (defined as the percentage change from baseline in The interval from the time of initial documentation of disease progression / recurrence or death from any cause. (defined as the time from the start of study treatment to death from any cause) and overall survival (OS) It is also expected to result in an improvement in the

[0129] The ADC-A dosing regimen also improved plasma concentrations of Wnt5a (as measured by immunoassay). changes (e.g., increases or decreases) in circulating plasma concentrations of ROR1 (immunoassays) assay) and circulating B Changes in the numbers of immune cells such as immune cells, T cells, and natural killer (NK) cells (e.g. It may also result in a change in the amount (e.g., increase or decrease) or activation state (e.g., increase or decrease). obtain.

[0130] Patient Selection In this study, patients 18 years of age or older; CLL / SLL, MCL, FL, MZL, DLBCL, RTL, BL, LPL / WM, T have been diagnosed with cellular NHL, ALL, or AML; Previously treated but progressed during or relapsed after previous systemic therapy or are unlikely to respond to established therapies known to provide clinical benefit or lack of evidence for an established therapy known to provide clinical benefit. have developed resistance; and All previous therapy to treat cancer (including surgery) was discontinued at least 1 week prior to the start of study therapy. have completed chemotherapy, radiation therapy, immunotherapy, or investigational therapy; The patient may be an adult.

[0131] Patients continuing immunosuppressive therapy other than corticosteroids may be excluded from treatment. At the time of initiating study therapy, subjects were required to receive at least one systemic corticosteroid (prednisone 0 mg / day or less or equivalent), or topical, inhaled or intra-articular corticosteroids. During study therapy, subjects may be taking systemic or Enteric, topical, inhaled, or intra-articular corticosteroids can be used (e.g. (e.g., for a concomitant medical condition or antiemetic prophylaxis).

[0132] Premedication To prevent tumor lysis syndrome (TLS), patients must be Allopurinol may be administered orally at 100 to 300 mg every 8 hours, starting before 24 hours. Alternative medications (e.g., febuxostat) may be substituted if administered according to the product label. In addition, subjects with hyperuricemia can receive 3–4 mg of uric acid via IV infusion. In addition, high-risk subjects may receive 0.5 mg of rasburicase at the first dose of the study drug. Rasburicase may be administered at 3-4.5 mg by IV infusion 3-4 hours prior to administration. .

[0133] If an infusion reaction is observed, subjects were asked to In addition, patients may be premedicated with antipyretics and antihistamines prior to ADC-A infusion. Oral or IV antipyretics (acetaminophen [paracetamol], 650-1,000 mg) g or equivalent) and oral or IV antihistamines (cetirizine, 10 mg or or equivalent), both of which are administered 30-60 minutes prior to each ADC-A injection. Nonsteroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, 400-800 mg) oral or equivalent) may be added to or substituted for acetaminophen. Premedication with corticosteroids (100 mg prednisolone, or equivalents) may be considered as appropriate.

[0134] Efficacy evaluation Chronic lymphocytic leukemia / small lymphocytic lymphoma Responses were defined as complete response (CR) with no measurable residual disease. MRD- ), complete response (CR) , complete response with incomplete blood count recovery (CRi), partial response (PR), and lymphocytosis. Patients are classified as partial response (PR-L), stable disease (SD) or progressive disease (PD). In situations where there was insufficient information to categorize response status, a response category of not evaluable (NE) was used. is provided.

[0135] Best overall response is identified. Best overall response is defined as the time from start of treatment to PD / relapse. The screening test is the best response recorded in a single dose. The nadir measurement is used as a reference for PD; The smallest measurement recorded, including the screening measurement, if this is the smallest measurement. When imaging data are available, these may be used to confirm tumor status. replaces physical examination data.

[0136] (1) Complete response with no measurable residual disease CR MRD- To meet the criteria, the following conditions must all be met: · All criteria for CR are met; Flow cytometry of bone marrow aspirates was performed at 1×10 -4 Showing malignant cells: (2) Complete response To meet the criteria for CR, all of the following conditions must be met: · No evidence of new diseases; ALC in peripheral blood was 4×10 9 / L or less; · All index nodular masses regressed to ≤15mm by LD; · Normal spleen and liver size; Regression of all nodal non-indicative disease to normal and regression of all detectable non-nodal non-indicative disease to normal Resolution of symptomatic disease; Morphologically negative bone marrow is characterized by less than 30% of nucleated cells being lymphocytes and by age. defined as the absence of lymphoid nodules in bone marrow samples that are normal cells versus normal cells; Peripheral blood meeting all of the following criteria: ANC>1 without exogenous growth factors within 2 weeks prior to relevant blood count evaluation .5×10 9 / L; No exogenous growth factor or platelet transfusions within 2 weeks prior to the relevant blood count evaluation , platelet count > 100 × 10 9 / L; and No exogenous growth factors or red blood cell transfusions within 2 weeks prior to the relevant blood count evaluation and hemoglobin >110 g / L (11.0 g / dL); (3) complete response with incomplete count recovery To meet the criteria for CRi, one or more of the following conditions must exist: All criteria for CR are met: ANC≦1.5×10 9 / L or ANC ≥ 1.5 × 10 9 Maintain / L requires exogenous growth factors within 2 weeks prior to relevant blood count evaluation to be effective; Platelet count ≤ 100 x 10 9 / L or platelet count ≥ 100 × 10 9 / L To maintain the condition, exogenous growth factors or platelet transfusions were required within 2 weeks prior to the relevant blood count evaluation. require; Hemoglobin ≤ 110 g / L (11.0 g / dL) or 2 weeks prior to relevant blood count evaluation to maintain ≥ 110 g / L (11.0 g / dL) the need for exogenous growth factors or red blood cell transfusions within 5 days; (4) Partial response To qualify for PR, all of the following conditions must be met: · No evidence of new diseases; If only lymphadenopathy is present at screening, Two of the following criteria, except that they must be improved to the extent specified below: A change in medical condition that meets the above criteria: A 50% or greater decrease in peripheral blood ALC from screening; A 50% or greater reduction in SPD of the index nodal lesion from screening; In subjects with enlarged spleens (>120 mm) at screening, LVD hypertrophy reduction of 50% or more from screening (minimum reduction of 20 mm) ), or reduced to 120 mm or less on imaging; In subjects with enlarged liver (>180 mm) at screening, LVD hypertrophy reduction of 50% or more from screening (minimum reduction of 20 mm) ), or reduced to 180 mm or less on imaging; CLL / SLL bone marrow infiltration or B lymphoid nodules 50% from screening decrease by more than; Deteriorating index disease, splenic disease, hepatic disease or non-index disease that meets the criteria for definite PD No disease; Peripheral blood meeting one or more of the following criteria: - The patient has not used exogenous growth factors (e.g., G-CSF) within 2 weeks prior to the relevant blood count evaluation. F) without, ANC>1.5×109 / L or 50% lower than at screening Increased over; No exogenous growth factor or platelet transfusions within 2 weeks prior to the relevant blood count evaluation , platelet count > 100 × 10 9 / L or a 50% or greater increase from screening addition; - The patient has not used exogenous growth factors (e.g., erythropoietin) within 2 weeks prior to the relevant blood count evaluation. Hemoglobin > 110 g / L (11.0 g / dL) without poietin or red blood cell transfusion or increased by 50% or more since screening; (5) Partial response with lymphocytosis To meet the criteria for PR-L, the following conditions must be met: · No evidence of new diseases; - Except for no decrease of 50% or more from screening in peripheral blood ALC All criteria for PR were achieved; (6) Stability To meet the criteria for SD, the following must be achieved: · No evidence of new diseases; Evidence of sufficient tumor shrinkage to qualify as PR or definitive PD no evidence of significant tumor growth; (7) Progress The occurrence of any of the following events indicates definite PD: Evidence of new diseases: · New nodules greater than 15mm in any diameter; Normal splenic LVD at the nadir (i.e., LVD ≤120 mm by imaging) splenic LVD >140 mm by imaging in subjects with; Normal liver LVD at the nadir (i.e., LVD ≤180 mm by imaging) hepatic LVD of >200 mm by imaging in subjects with; New non-index disease (e.g., effusion, ascites, or other organ systemic effusion related to CLL / SLL) organ abnormality); Evidence of index lesions, splenic or hepatic disease, or worsening of non-index disease: · ≥50% increase from nadir in SPD of index lesion; Individual nodal or extranodal mass with LD > 15 mm and LPD > 10 mm 50% or more increase from nadir in LD of In subjects with enlarged spleens (>120 mm) at screening, hypertrophy increases by more than 50% from the nadir (minimum increase of 20 mm); In subjects with enlarged liver (>180 mm) at screening, Increase of 50% or more from the time of leaning (minimum increase of 20 mm); Non-indicating disease (e.g., effusion, ascites, or other organ system related to CLL / SLL) a clear increase in size of the abnormality; Transition to more aggressive histology (e.g., RTL) established by lymph node biopsy Conversion (lymph node biopsy if subject has no prior objective documentation of CLL / SLL progression) date is considered the date of CLL / SLL progression); The decrease in platelet count or hemoglobin due to CLL / SLL is caused by an autoimmune phenomenon. This is not due to the presence of clonal CLL / SLL cells, as confirmed by bone marrow biopsy showing infiltration To be: Your current platelet count is 100 x 10 9 / L or less and at least 50% above baseline is decreasing; Your current hemoglobin level is 110g / L (11.0g / dL) or less, and your baseline It has decreased by more than 20 g / L (2 g / dL) since inception.

[0137] Lymphoma Responses were defined as complete response (CR) with no measurable residual disease. MRD- ), complete response (CR) , best partial response (VGPR; LPL / WM only), partial response (PR), minor response ( The disease is classified as MR; LPL / WM only), stable (SD) or progressive (PD). In situations where there was insufficient information to categorize response status, a response category of not evaluable (NE) was used. is provided.

[0138] Best overall response is identified. Best overall response is defined as the time from start of treatment to PD / relapse. The best response during treatment from screening recorded at the time of screening. The nadir measurement is used as a criterion for confirming response. This measurement is used as a screening measurement if it is the minimum measurement. For FDG-avid tumors, CR When assessing metabolic criteria for PET-CT response, the anatomical criteria for contrast-enhanced CT response are It takes precedence over academic criteria.

[0139] (1) Complete response with no measurable residual disease CR MRD- To meet the criteria, all of the following must be true: · All criteria for CR are met; Flow cytometry of bone marrow aspirates was performed at 1×10 -4 Showing malignant cells: (2) Complete response To meet the criteria for CR, all of the following conditions must be met: · No evidence of new diseases; · All index nodular lesions regressed to ≤15mm in LD; · Regression of all nodular non-index disease to 15mm or less; · Resolution of all detectable extranodal index and non-index disease; · Normal splenic size in LVD >130mm by imaging study; If PET is performed, there is no evidence of residual disease – i.e., Deauville 5-point scale The CT scan was scored as 1 (no uptake above background), 2 (uptake ≤ mediastinum), or , 3 (uptake > mediastinal, but ≤ liver); PET-avid: PET on tumors or morphological evaluation of unilateral core biopsies Therefore, bone marrow lesions are negative; if bone marrow biopsy is morphologically indeterminate, immunohistochemistry should be negative by chemistry; Absence of serum M protein by SIFE (in subjects with LPL / WM) ; (3) Best partial response (LPL / WM only) To meet the VGPR criteria, all of the following conditions must be met: · All anatomical criteria for CR are met; · Documented reduction of 90% or more from baseline in serum M protein concentration; (4) Partial response To qualify for PR, all of the following conditions must be met: · No evidence of new diseases; A 50% or greater reduction in SPD of index nodal and extranodal disease from screening; · No increase in size of non-index disease from its nadir; In subjects with splenomegaly at screening, the splenomegaly was Linear dimension (LVD) is reduced by 50% or more from the screening point (minimum reduction of 20 mm), or was reduced to less than 130 mm by imaging; If PET is performed: Typical FDG-avid lymphoma: screening PET scan performed If no PET scan was performed or if the PET scan was positive before treatment, the on-treatment PET scan was performed Positive in 1 or more sites involved in the uptake > liver) or score 5 (significant uptake > liver) at screening The uptake is decreased compared to the normal range. A screening PET scan was performed and was negative. In this case, there is no new PET evidence of disease. Decreased uptake is defined as a decrease of 25% or more; Variable FDG-avid lymphoma / FDG-avidity unknown: Pretreatment If a PET scan was not performed or if a pretreatment PET scan was performed for lymphoma If negative, CT criteria should be used in evaluating the tumor during treatment. If PET scan was positive at any one or more previously involved sites, on-treatment PET should be performed is positive; · Persistence of bone marrow disease in subjects who met radiographic criteria for CR; A decrease of 50% but less than 90% from baseline in serum M protein concentration (LPL / subjects with WM); (5) Minor response (LPL / WM only) To meet the MR criteria, all of the following conditions must be met: · Anatomical disease criteria for PR or SD are met; A 25% or greater but less than 50% decrease from baseline in serum M protein concentration was recorded Has been; (6) Stability To meet the criteria for SD, all of the following must be true: · No evidence of new diseases; Tumor shrinkage from screening sufficient to qualify as PR may also be considered PD. There is also no evidence of sufficient tumor growth to warrant treatment; If PET was performed, the results showed an increase in uptake compared to screening. There was no significant change in the liver and the Deauville 5-point scale showed a score of 4 (moderate uptake > liver) or indicates a score of 5 (significant uptake > liver); Less than a 25% decrease and less than a 25% increase from baseline in serum M protein concentration Addition (insurers with LPL / WM); (7) Progress The occurrence of any of the following events is indicative of PD: Evidence of new disease not present at screening: · New nodules greater than 15mm in any diameter; Healed (i.e., previously had a PPD of 0 mm 2 (extranodal disease) recurrence of the disorder; · New extranodal disease >10 mm; New non-index disease of any size clearly attributable to lymphoma (e.g., effusion, ascites or other organ abnormalities) (usually PET, biopsy, cytology, or other non-radiological confirmation is required); New FDG findings consistent with lymphoma rather than another etiology (e.g., infection or inflammation) -avid foci. If there is uncertainty regarding the etiology of new lesions, biopsy or in situ Turbulent scans may be considered; Previous PET or bone marrow biopsy performed as part of the study was negative for lymphoma If so, new or recurrent bone marrow involvement by PET or bone marrow biopsy to lymphoma; Evidence of progression of nodal or extranodal index lesions: · ≥ 50% increase from nadir in SPD of index lesion; If the LD of the current nodule is greater than 15 mm, the PPD for the individual nodule is Increased by 50% or more from the nadir PPD and LD or SDi is For lesions 20 mm or less (in LD or SDi), 5 mm or more from the lowest point Increased on; or 10m from the nadir for lesions >20mm (in LD or SDi) m increase, evidence of deterioration of individual index lymph nodes or nodal masses; · A clear increase in the size of non-index disease; Spleen in patients with splenic LVD >130 mm as measured by nadir imaging Swelling increases by 50% or more from the lowest point (minimum increase of 20 mm) or imaging at the lowest point is required. Splenic L > 150 mm by imaging in patients with splenic LVD ≤ 130 mm VD; · Conversion to more aggressive NHL histology established by lymph node biopsy; If PET was performed, Deauville 5-point scale score of 4 (moderate uptake > liver score 5 (significant uptake > liver) or score 5 (significant uptake > liver) and lesion size anatomy consistent with PD The increased uptake is due to the %ΔS defined as an increase of 50% or more in UVmax; A 25% or greater increase from nadir in serum M protein concentration (in patients with LPL / WM) (in subjects who

[0140] Acute lymphoblastic leukemia Responses were defined as complete response (CR) with no measurable residual disease. MRD- ), complete response (CR) , complete response with incomplete blood count recovery (CRi) (unconfirmed for subjects with mediastinal disease) Complete response (CRu) including complete response (CRu), partial response (PR), stable disease (SD), treatment failure (T The response status is further classified as disease recurrence or progression (DRP). In situations where there is insufficient information to assess efficacy, a response category of not evaluable (NE) is provided.

[0141] Best overall response is identified. Best overall response is defined as the time from start of treatment to DRP. The best response during treatment from baseline recorded. The baseline measurement is used to evaluate the response. The nadir measurement is used as a criterion for determining the DRP. the best measurement during the study is the baseline measurement if this is the measurement that meets this criterion. This constitutes the measure of least tumor involvement.

[0142] (1) Complete response with no measurable residual disease CR MRD- To meet the criteria, the following conditions must all be met: · All criteria for CR are met; Flow cytometry of bone marrow aspirates was performed at 1×10 -4 Showing malignant cells: (2) Complete response To meet the criteria for CR, all of the following conditions must be met: Leukemia that meets all of the following criteria: Fewer than 5% myeloblasts (≥200 nucleated cells and with the presence of bone marrow spicules) based on bone marrow aspirate / biopsy samples); · Absence of blast cells in peripheral blood; Extramedullary disease (this includes lymphadenopathy, splenomegaly, skin / gum involvement, testicular masses) and no central nervous system involvement [i.e., achievement of CNS-1 state {presence of blasts in cerebrospinal fluid, does not exist}] does not exist); Peripheral blood that meets all of the following requirements: ANC≧1.0×10 9 / L; Platelet count ≥ 100 x 10 9 / L; · Mediastinal widening shows complete resolution as documented on radiographs; (3) Complete response with incomplete blood count recovery and / or unconfirmed complete response To meet the CRi / CRu criteria, all of the following conditions must be met: Leukemia that meets all of the following criteria: Fewer than 5% myeloblasts (≥200 nucleated cells and with the presence of bone marrow spicules) based on bone marrow aspirate / biopsy samples); · Absence of blast cells in peripheral blood; Absence of extramedullary disease (this includes lymphadenopathy, splenomegaly, skin / gum involvement, testicular masses) and no central nervous system involvement [i.e., achievement of CNS-1 state {no buds in the cerebrospinal fluid} sphere does not exist}]); Peripheral blood that meets all of the following requirements: ANC<1.0×10 9 / L; Platelet count <100×10 9 / L; Mediastinal widening, as documented on radiographs, is the sum of the products of perpendicular diameters (SPD) has regressed by 75% or more; (4) Partial response To qualify for PR, all of the following conditions must be met: Leukemia that meets any of the following criteria: Reduce myeloblasts by 50% or more to 5%-25% (inclusive) (more than 200 Based on bone marrow aspirate / biopsy sample with nucleated cells and presence of bone marrow spicules); · Absence of blast cells in peripheral blood; No new or worsening extramedullary disease (this includes lymphadenopathy, splenomegaly, skin / Gingival infiltration, testicular mass, or central nervous system involvement [e.g., CNS-1 state {cerebrospinal fluid CNS-2 status {blasts present in cerebrospinal fluid, WBC < 5 × 10 9 / L} or CNS-3 status {blasts present in cerebrospinal fluid, WBC ≥ 5 × 10 9 / L}Also has not progressed to facial nerve palsy, brain / eye involvement, or hypothalamic syndrome] do); Peripheral blood that meets all of the following requirements: ANC≧1.0×10 9 / L; Platelet count ≥ 100 x 10 9 / L; Mediastinal widening was not observed unless the SPD had regressed by 50% or more, as documented by radiograph. r; (5) Stability / treatment failure To meet the criteria for SD, the following must be achieved: Sufficient improvement in ALL from baseline to qualify as PR is also required to qualify as DRP. There is also insufficient evidence of progression of ALL to warrant treatment; No new or worsening extramedullary disease (this includes lymphadenopathy, splenomegaly, skin / dental pedicle involvement, testicular mass, or central nervous system involvement [e.g., CNS-1 state {no blasts in CSF} to CNS-2 state {blasts in CSF, WBC<5×10 9 / L} or CNS-3 status {blasts present in cerebrospinal fluid, WBC ≥ 5 ×10 9 / L} or progress to facial nerve paralysis, brain / eye involvement, or hypothalamic syndrome. not yet]); No new mediastinal widening occurred, and the SPD of existing mediastinal widening did not increase by more than 25%. Not added; 18 weeks (for Schedule 1 and Schedule 2) or 16 weeks from the start of study treatment (For Schedule 3) by CR MRD- , CR, CRi / CRu or PR eligible Subjects without DRP are considered to be TF.

[0143] (6) Recurrence or progression of disease The occurrence of any of the following events is indicative of a DRP: · Relapse of bone marrow blasts (to >5%) in subjects who experienced a CR; recurrence of blasts in peripheral blood in subjects who experienced a CR; Increase in myeloblasts by 25% or more to 20% or more (having 200 or more nucleated cells) and based on bone marrow aspirate / biopsy samples with the presence of bone marrow spicules); Peripheral blood blast count increased by 25% to 1×10 9 / L or more; New or worsening existing extramedullary disease (this may include lymphadenopathy, splenomegaly, skin / dental pedicle involvement, testicular mass, or CNS involvement [e.g., CNS-1 status { CNS-2 status {blasts present in CSF, WBC <5×10 9 / L} or CNS-3 status {blasts present in cerebrospinal fluid, WBC ≥ 5 × 10 9 / L} or progression to facial nerve palsy, brain / eye involvement, or hypothalamic syndrome ]) onset; - The occurrence of new mediastinal widening or an increase in the SPD of existing mediastinal widening of 25% or more.

[0144] Acute myeloid leukemia Responses were defined as complete response (CR) with no measurable residual disease. MRD-), complete response (CR) , complete response with incomplete blood count recovery (CRi), morphologic leukemia-free status (MLFS) ), partial response (PR), stable disease (SD), treatment failure (TF), or disease recurrence or progression ( In addition, in situations where there is insufficient information to classify the response status, , and a response category of not evaluable (NE) is provided.

[0145] Best overall response is identified. Best overall response is defined as the number of patients with DRP or TCR who have not had any adverse events from the start of treatment. F is the best response from baseline recorded during treatment. , used as a criterion to confirm response. The best measurement under study is for DRP. Used as a criterion; the best measurement under study is if this is the measurement that meets this criterion This comprises a baseline measurement of the tumor lesions, which constitutes the measurement with the least tumor involvement.

[0146] (1) Complete response with no measurable residual disease CR MRD- To meet the criteria, the following conditions must all be met: · All criteria for CR are met; Flow cytometry of bone marrow aspirates was performed at 1×10 -4 Showing malignant cells: (2) Complete response To meet the criteria for CR, all of the following conditions must be met: Leukemia that meets all of the following criteria: Fewer than 5% myeloblasts (≥200 nucleated cells and with the presence of bone marrow spicules) based on bone marrow aspirate / biopsy samples); · Absence of blast cells in peripheral blood; Absence of blasts with Auer rods; · Absence of extramedullary disease; Peripheral blood that meets both of the following requirements: ANC≧1.0×10 9 / L; Platelet count ≥ 100 x 10 9 / L; (3) Complete response with incomplete blood count recovery To qualify for CRi, all of the following conditions must be met: Leukemia that meets all of the following criteria: Fewer than 5% myeloblasts (≥200 nucleated cells and with the presence of bone marrow spicules) based on bone marrow aspirate / biopsy samples); · Absence of blast cells in peripheral blood; Absence of blasts with Auer rods; · Absence of extramedullary disease; Peripheral blood meeting only one of the following criteria: ANC≧1.0×10 9 / L; Platelet count ≥ 100 x 10 9 / L; (4) Absence of morphological leukemia To meet the MLFS criteria, all of the following conditions must be met: Leukemia that meets all of the following criteria: Fewer than 5% myeloblasts (≥200 nucleated cells, ≥10% cellularity and based on bone marrow aspirate / biopsy sample with the presence of bone marrow spicules); · Absence of blast cells in peripheral blood; Absence of blasts with Auer rods; · Absence of extramedullary disease; Peripheral blood that meets both of the following criteria: ANC<1.0×10 9 / L; Platelet count <100×10 9 / L; (5) Partial response To qualify for PR, all of the following conditions must be met: Leukemia that meets any of the following criteria: Reduce myeloblasts by 50% or more to 5%-25% (inclusive) (more than 200 Based on bone marrow aspirate / biopsy sample with nucleated cells and presence of bone marrow spicules); <5% myeloblasts, but Auer rods are present (>200 Based on bone marrow aspirate / biopsy sample with nuclear cells and presence of bone marrow spicules); · Absence of blast cells in peripheral blood; · No new or worsening extramedullary disease; Peripheral blood meeting both of the following criteria: ANC≧1.0×10 9 / L; Platelet count ≥ 100 x 10 9 / L; (6) Stability / treatment failure To meet the criteria for SD, the following must be achieved: · CR MRD- Baseline for certification as CR, CRi, MLFS or PR There is neither sufficient improvement in AML since the onset of the disease nor sufficient evidence of AML deterioration to qualify as a DRP. ; · No new or worsening extramedullary disease; 18 weeks (for Schedule 1 and Schedule 2) or 16 weeks from the start of study treatment (For Schedule 3) by CR MRD- , CR, CRi, MLFS or PR qualification Subjects without DRP who had no DRP were considered to have TF.

[0147] (7) Recurrence or progression of disease The occurrence of any of the following events is indicative of a DRP: · CR MRD- 5% of myeloblasts in subjects who experienced CR, CRi, or MLFS recurrence until > %; · CR MRD-In peripheral blood of subjects who experienced CR, CRi, MLFS, or PR relapse of blast cells; In subjects who experienced a PR, there was an absolute 20% increase in bone marrow blasts to >25% ( Bone marrow aspirate / biopsy samples with 200 or more nucleated cells and the presence of bone marrow spicules Based on); · An absolute 20% increase in peripheral blasts to greater than 25% in subjects who experienced a PR; development of new or worsening extramedullary disease; Relapse or worsening of MRD as assessed by flow cytometry is not considered in the definition of DRP. will not be considered, but will be recorded.

[0148] Experimental and other evaluations The samples obtained and the parameters analyzed are shown in Table 4. [Table 6]

[0149] TIFF2025061126000009.tif222157

[0150] The severity grading of adverse events as applied herein is set forth in Table 5 below. is. [Table 7]

[0151] result I. Safety Data are from 12 subjects with MCL, 7 subjects with CLL / SLL, and D Two subjects with LBCL, two with FL, and one with MZL 25 subjects with hematological malignancies, including 1 subject with RTL The subjects were from four subjects who underwent hematopoietic stem cell transplantation (HSCT) and three subjects who underwent ESCC. Chimeric antigen receptor (CAR)-T cell or natural killer (NK) therapy in subjects Heavily pretreated with a median (range) of 4 (1-23) prior systemic chemotherapy regimens Was treated.

[0152] Ninety-six doses of ADC-A were administered, which consisted of 1, 1.0 and 20 mg / kg dose levels. 9 at the 1.5mg / kg dose level, 18 at the 2.25mg / kg dose level The study included 22 doses at 46 and 2.5 mg / kg dose levels. The number of cycles ranged from 1 to 10. All subjects received a Q1 / 3W dosing schedule. and received ADC-A (Table 2).

[0153] Treatment with ADC-A was generally well tolerated, with neutropenia being the major acute toxicity. No DLTs were observed at doses of 0.5, 1.0, and 1.5 mg / kg. The DLT of grade 4 neutropenia occurred in 1 of 7 patients with ADC-A 2.25 mg / kg. In addition, one subject receiving ADC-A 2.25 mg / kg experienced grade 3 neutropenia in C1 and was treated with ADC-A 2.25 mg / kg. One subject experienced grade 4 neutropenia at C2. In each case, neutropenia was observed around day 15 of the cycle. , responsive to granulocyte colony-stimulating factor (G-CSF) given reactively or as secondary prophylaxis Neutropenic fever and infections did not occur. The subject who initiated treatment experienced grade 4 thrombocytopenia at C1; however, this subject Subjects had a history of thrombocytopenia, including grade 2 thrombocytopenia at baseline, Post-baseline platelet abnormalities were apparently not drug-related, with ADC-A 2.5 mg / kg g, and C2 and C3 therapy was continued.

[0154] One subject experienced a Grade 2 event after five cycles of ADC-A 2.25 mg / kg. The patient had neuropathy of 1.5 mg / kg / dose; treatment was delayed for one cycle and then reduced to 1.5 mg / kg. Other adverse events, laboratory abnormalities, and ECG findings were mild, and treatment was resumed at a dose of or do not appear to be dependent on exposure and may be due to underlying cancer, comorbidities, concurrent diseases, or concomitant medications. No infusion reactions or tumor lysis syndrome were observed.

[0155] II. Pharmacokinetics Total ADC-A and MMAE over time for 16 patients receiving ADC-A Plasma concentrations are shown in Figure 1. Mean T max Immediately after the end of ADC infusion (30 min IV Occurred 0.5-2 hours after start of infusion and 48-89 hours after administration of MMAE. The pharmacokinetic (PK) parameters are shown in Table 6. [Table 8]

[0156] C max The increases in AUC were generally dose-proportional for ADC-A and MMAE The mean t 1 / 2 The value is independent of the dose. The range was 2.1 to 3.0 days.

[0157] Pharmacodynamic data from subjects with CLL suggest that ROR1 receptor agonists are involved in circulating CLL cells. The results showed that the ADC-A occupancy was dependent on the concentration and time of the antibody (Figure 2). , stained with LIVE / Dead reagent, and then CD19, CD5, UC961-PE and 4A5 stained with AlexaFluor647. 1.0 and 2.25 mg / kg At each ADC-A dose, only 22.7% and 12.8% of ROR1 receptors were activated at 30 min. By the end of the IV infusion, the unoccupied receptors were not occupied. showed a time-dependent return to baseline with a concomitant decrease in concentrations. At the kg dose level, target coverage decreased by day 8, consistent with a decrease in plasma ADC exposure. It seemed to be a little, then was lost by the 15th day.

[0158] As shown in Figure 3, the relationship between unoccupied ROR1 receptors and ADC-A plasma concentrations The correlation allows the establishment of target plasma concentration values. ADC-A plasma concentration of 1.7 μg / mL is required to maintain 75% To maintain receptor occupancy of 25% (25% unoccupied receptors), 5.8 μg / mL of ADC- A plasma concentration is required to maintain 90% receptor occupancy (10% unoccupied receptors). requires an ADC-A plasma concentration of 35 μg / mL.

[0159] Pharmacokinetic simulations were performed to further explore potential ADC-A dosing regimens. The simulations showed that weekly administration of ADC-A was more effective than once every three weeks. The weekly dosing regimen was chosen based on the results of the study and was repeated every 12 weeks prior to the next treatment cycle. Provides more sustained ADC-A exposure and ROR1 target occupancy while allowing bone marrow recovery and the induction regimen (e.g., Q2 / 3W or Q3 / 4W) and may be useful for a less frequent maintenance regimen (e.g., Q1 / 3W) following do. [Table 9]

[0160] III. Antitumor Response Antitumor activity was observed in patients with MCL( Heavily pretreated with AML (including 3 partial responses) and DLBCL (including 1 partial response) (Figure 5) This was observed in subjects who were

[0161] One subject with MCL had extensive preexisting disease with involvement of the palate, neck, chest, abdomen, and pelvis. The subjects were treated with R / methotrexate / cytarabine, rituximab, and eveloprapia. R-Hyper CVAD with rutinib, daratumumab, and lenalidomide-rituximab The patient had received heavy prior treatment and radiation therapy. The study showed evidence of demonstrable tumor response to treatment with ADC-A at 1 mg / kg. All nodule groups showed a decrease in tumor size, with a 53% decrease in SPD (sum of products of perpendicular diameters). In addition, the palatal lesions also decreased in size and tissue involvement. The magnitude of response was a partial response. Subjects appear to be eligible for PR. Subjects have no evidence of drug-related hematologic or non-hematologic toxicity. There were no signs of clinical toxicity.

[0162] Another subject with MCL presented with both a palatal mass and extranodal disease and had Rituki Cimab, rituximab / bortezomib, R-CHOP (rituximab, cyclophosphamide doxorubicin, vincristine and prednisone), BR (bendamustine and tuximab), R-hyper-CVAD with intrathecal prophylaxis, ibrutinib and mossene Subjects were heavily pretreated with izumab at 2.5 mg / kg for three cycles. Subjects demonstrated evidence of demonstrable tumor response to treatment with ADC-A. reported that their activity increased and fatigue was greatly reduced; furthermore, the size of the palatal lesions decreased by 85%. The magnitude of the response appears to qualify as a partial response (PR).

[0163] Another subject with MCL presented with orbital involvement and extranodal disease and was treated with R-CHOP , rituximab, ibrutinib-rituximab and rituximab-BEAM (carmustine) The subjects were heavily pretreated with cyclosporine, cytarabine, etoposide, and melphalan. showed that the tumor responded well to treatment with 2.5 mg / kg ADC-A for six cycles. Evidence of a response was seen with a 51% reduction in the SPD of tumor lesions. The magnitude of response was a partial response (P R) appears to qualify.

[0164] One subject with DLBCL presented with extranodal disease and was treated with R-CHOP, R- ESHAP (rituximab, etoposide, methylprednisolone, cytarabine and cisplatin) rituximab, gemcitabine and oxaliplatin), R-GEMOX (rituximab, gemcitabine and oxaliplatin), BE AM and autologous transplantation, pinatuzumab-rituximab, bendamustine-rituximab and fluoxetine The patient had been heavily pretreated with CAR-T cells along with Duranbine conditioning. Subjects were treated with ADC-A for six cycles (2.25 mg / kg in cycle 1, Reduced dose in cycle 2, 2.25 mg / kg in cycles 3-5, and 2.25 mg / kg in cycles 6 and 7. Both nodule groups measured showed evidence of demonstrable tumor response to 1.5 mg / kg of 10 ... The magnitude of response was partial response (PR), demonstrating a reduction in tumor size and a 68% reduction in SPD. appears to qualify as

[0165] Although preferred embodiments of the present invention have been shown and described herein, such It will be apparent to those skilled in the art that the above embodiments are provided by way of example only. Numerous variations, modifications, and substitutions will occur to those skilled in the art without departing from the spirit and scope of the present invention. Various alternatives to the embodiments of the invention described herein may be used in practicing the invention. It should be understood that this may be done. [Table 10]

Claims

1. Immunoconjugates comprising antibodies conjugated to drug moieties are used to treat cancer patients. The method of treating an allergic reaction, comprising administering to said subject a drug moiety having the formula (I): 【Chemistry 1】 and having the structure shown in wherein Ab in formula (I) is the antibody, and wherein the heavy and light chains of the antibody are comprising the amino acid sequences of SEQ ID NO:1 and SEQ ID NO:2, respectively; and wherein the immunoconjugate is administered to the patient at a dose of 0.25 to 4.00 mg / kg. Can be; The method.

2. The number of drug moieties (DAR) per antibody ranges from 1 to 7, and optionally from 3 to 5 or The method of claim 1, wherein is in the range of 3 to 6.

3. Doses of 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75 or 3.00 mg / kg according to claim 1 or 2. method.

4. The immunoconjugate is administered in three week cycles, and each cycle is administered at the doses listed above. The method according to any one of claims 1 to 3, wherein the administration is on day 1 of the first initiation of treatment.

5. The immunoconjugate is administered in three week cycles, and each cycle is administered at the doses listed above. The method according to any one of claims 1 to 3, wherein the administration is on days 1 and 8 of the first and second inhalation therapy.

6. The immunoconjugate is administered in four week cycles, and each cycle is administered at the doses listed above. The method according to any one of claims 1 to 3, wherein the administration is on days 1, 8 and 15 of 。

7. The method according to any one of claims 4 to 6, wherein the number of cycles is 3 or more.

8. The immunoconjugate is (a) weekly for the first 3 weeks, then every 3 weeks; (b) weekly for the first 4 weeks, then every 3 weeks; (c) weekly for the first 6 weeks, then every 3 weeks; (d) weekly for the first 8 weeks, then every 3 weeks; (e) every 3 weeks for the first 3 weeks, then weekly; (f) every 3 weeks for the first 6 weeks, then weekly; or (g) every 3 weeks for the first 9 weeks, then weekly; The method according to any one of claims 1 to 3, wherein the

9. The method according to any one of claims 1 to 8, wherein the immunoconjugate is administered intravenously. Law.

10. The method of any one of claims 1 to 9, wherein the cancer is a hematological cancer.

11. The method of any one of claims 1 to 9, wherein the cancer is a solid tumor.

12. Cancer: Chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), Cellular lymphoma (MCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), diffuse large intestine lymphoma (DCL), DLBCL, Richter's transformed lymphoma (RTL), Kitt's lymphoma (BL), lymphoplasmacytic lymphoma (LPL), Waldenström lymphoma WM macroglobulinemia, T-cell non-Hodgkin's lymphoma, acute lymphocytic leukemia ( 10. The method according to claim 1, wherein the cancer is selected from the group consisting of acute myeloid leukemia (AML), acute myeloid leukemia (ALL), and acute myeloid leukemia (AML). The method according to any one of claims 1 to 5.

13. The method according to any one of claims 1 to 12, wherein the patient has previously been treated for cancer. Law.

14. 14. The method of claim 1, wherein the cancer is recurrent or refractory to treatment. The method according to

15. Treatment with an immunoconjugate is (a) induces tumor regression; (b) slowing tumor progression; (c) inhibiting cancer metastasis; (d) preventing cancer recurrence or residual disease; (e) reducing the size of nodal or extranodal tumor masses; (f) reducing the number of malignant cells in the bone marrow and peripheral blood; (g) reducing malignant splenomegaly or hepatomegaly; (h) improving cancer-related anemia, neutropenia, or thrombocytopenia; (i) improving skin symptoms; (j) reducing the likelihood of hyperviscosity syndrome in patients with LPL / WM; (k) improving disabling systemic symptoms; and (l) prolonging survival; The method according to any one of claims 1 to 14, resulting in one or more of:

16. Any of claims 1 to 15, wherein treatment with the immunoconjugate completely eradicates the tumor.

2. The method according to claim 1.

17. An immunosuppressant for use in treating cancer in a patient according to the method of any one of claims 1 to 16. Conjugates

18. A method for producing a medicament for treating cancer in a patient according to any one of claims 1 to 16. Use of immunoconjugates.

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