阅读说明：本技术 使用ror1抗体免疫缀合物的癌症治疗 (Cancer treatment using ROR1 antibody immunoconjugates ) 是由 L·米勒 B·兰努蒂 K·杰森 于 2020-02-01 设计创作，主要内容包括：本申请提供了用包含ROR1抗体或其抗原片段片段和药物部分的免疫缀合物治疗癌症患者的方法。(The present application provides methods of treating cancer patients with an immunoconjugate comprising a ROR1 antibody, or antigenic fragment thereof, and a drug moiety.)

1. A method of treating a cancer patient using an immunoconjugate comprising an antibody conjugated to a drug moiety, wherein the drug moiety has the structure shown in formula (I):

wherein Ab in formula (I) is an antibody, wherein the heavy and light chains of the antibody comprise SEQ ID NO: 1 and SEQ ID NO: 2; and is

Wherein the immunoconjugate is administered to the patient at a dose of 0.25 to 4.00 mg/kg.

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

3. The method of claim 1 or 2, wherein the dose is 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.

4. The method of any one of claims 1-3, wherein the immunoconjugate is administered in a three week cycle and at the dose on day 1 of each cycle.

5. The method of any one of claims 1-3, wherein the immunoconjugate is administered in a three week cycle and at the dose on days 1 and 8 of each cycle.

6. The method of any one of claims 1-3, wherein the immunoconjugate is administered in a four week cycle and at the dose on days 1, 8, and 15 of each cycle.

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

8. The method of any one of claims 1-3, wherein the immunoconjugate is administered as follows:

a) once per week for the first three weeks, then once per three weeks;

b) once per week for the first four weeks, then once per three weeks;

c) once per week for the first six weeks, then once per three weeks;

d) once per week for the first eight weeks, then once per three weeks;

e) once every three weeks for the first three weeks, then once every week;

f) once every three weeks for the first six weeks, then once every week; or

g) Every three weeks for the first nine weeks, then once a week.

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

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

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

12. The method of any one of claims 1-9, wherein the cancer is selected from Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), Mantle Cell Lymphoma (MCL), Follicular Lymphoma (FL), Marginal Zone Lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), Rickett's Transition Lymphoma (RTL), Burkitt's Lymphoma (BL), lymphoplasmacytoid lymphoma (LPL), Waldenstrom Macroglobulinemia (WM), T-cell non-hodgkin's lymphoma, Acute Lymphocytic Leukemia (ALL), and Acute Myeloid Leukemia (AML).

13. The method of any one of claims 1-12, wherein the patient has previously received treatment for the cancer.

14. The method of any one of claims 1-13, wherein the cancer is relapsed or refractory.

15. The method of any one of claims 1-14, wherein treatment with the immunoconjugate results in one or more of:

a) Inducing tumor regression;

b) the tumor progression is delayed;

c) inhibiting cancer metastasis;

d) preventing cancer recurrence or residual disease;

e) reducing the size of the nodules or extranodal tumor masses;

f) reducing the number of malignant cells in bone marrow and peripheral blood;

g) relieving malignant splenomegaly or hepatomegaly;

h) ameliorating anemia, neutropenia, or thrombocytopenia associated with cancer;

i) improving skin performance;

j) the possibility of the LPL/WM patient to generate high viscous blood syndrome is reduced;

k) improving disabling systemic symptoms; and

l) prolonged survival.

16. The method of any one of claims 1-15, wherein treatment with the immunoconjugate results in complete eradication of the tumor.

17. An immunoconjugate for use in treating cancer in a patient in the method of any one of claims 1-16.

18. Use of an immunoconjugate in the manufacture of a medicament for treating cancer in a patient in a method of any one of claims 1-16.

Background

Hematological malignancies include diseases caused by transitional events that occur in immune or hematopoietic organs. Lymphoid malignancies arise from the accumulation of monoclonal neoplastic lymphocytes in lymph nodes and organs such as blood, bone marrow, spleen and liver. Variants of these cancers include non-hodgkin's lymphoma (NHL), including Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), Mantle Cell Lymphoma (MCL), Follicular Lymphoma (FL), Marginal Zone Lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), rickett-transformed lymphoma (RTL), Burkitt's Lymphoma (BL), lymphoplasmacytoid lymphoma (LPL), Waldenstrom Macroglobulinemia (WM), Acute Lymphocytic Leukemia (ALL), and several types of T-cell lymphoma. Acute Myeloid Leukemia (AML) is caused by the accumulation of neoplastic myeloid blasts (blasts) in the bone marrow, blood, central nervous system and other organs.

Depending in part on the cell of origin (B-cell or T-cell), NHL patients may experience disabling systemic symptoms, lymphadenopathy, and organ megaly that may lead to life-threatening organ dysfunction, bone marrow depression and immune hypofunction that may be susceptible to infection and bleeding, and/or skin manifestations that may be painful, severe itching, and disfiguring. LPL/WM patients produce excessive immunoglobulin (Ig) M-producing plasma cells and may develop plasma hyperviscosity due to the presence of this circulating monoclonal IgM protein (M-protein). For ALL or AML patients, the expanding clones of leukemic blasts disrupt normal bone marrow function, rendering them susceptible to life-threatening infections and hemorrhage.

Treatment of these diseases aims to induce tumor regression, delay tumor progression, control disease-related complications and prolong life. Chemotherapy and/or immunotherapy agents are typically administered to patients. First line therapy can provide sustained regression. However, many patients eventually experience disease recurrence; further sequential therapies are used in an attempt to control disease manifestations. Despite the use of drugs with different mechanisms of action, progressive tumor resistance often occurs. Patients with progressive disease with multiple relapses have a poor prognosis and are likely to die of cancer. Therefore, new mechanisms of action are needed to safely provide new treatment options for hematological cancer patients who develop resistance to existing therapies.

Receptor tyrosine kinase-like orphan receptor 1(ROR1) is a cell surface protein that mediates signaling from its ligand, the secreted glycoprotein Wnt5 a. Consistent with its role in affecting stem cell fate during embryogenesis, ROR1 expression was observed in aggressive malignancies reverting to the embryonic transcriptional program, but ROR1 expression was not observed in normal adult tissues. Thus, ROR1 provides advantageous selectivity as a therapeutic target. ROR1 is commonly expressed on malignant cells in hematological cancer patients, and is also present on the cell surface of a variety of solid tumors, and appears to be a marker for cancer stem cells.

In view of the highly unmet medical needs of many patients with hematologic and other cancers and the role of ROR1 in cancer, there is a need for new therapies that can improve the outcome of patients (including patients who do not respond to existing therapies) by targeting ROR 1.

Disclosure of Invention

The present invention relates to a method of treating a cancer patient with an immunoconjugate having the structure shown below:

wherein Ab is an antibody that specifically binds human receptor tyrosine kinase-like orphan receptor 1(ROR1), wherein the heavy and light chains of the antibody comprise SEQ ID NO: 1 and SEQ ID NO: 2; and wherein the immunoconjugate is administered to the patient at a dose of 0.25-4.00 mg/kg. As used herein, formula I above is not intended to indicate that each Ab may only be conjugated to one copy of the drug moiety shown in the formula. In some embodiments, the drug moiety copy number (DAR) per antibody is from 1 to 7, wherein each drug moiety is conjugated to the antibody through a linker as shown in formula 1.

In some embodiments, the immunoconjugate is administered (e.g., intravenously) according to the dosage regimen described herein. The immunoconjugate may be administered, for example, at a dose 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. In certain embodiments, the immunoconjugate may be administered in repeated three-week cycles (e.g., on day 1 or day 1 and day 8 of each cycle). In certain embodiments, the immunoconjugate may be administered in repeated four week cycles (e.g., on days 1, 8, and 15 of each cycle). In some embodiments, the number of cycles may be a total of 3, 6, or more. In particular embodiments, the immunoconjugate may be administered as follows: once per week for the first three, four, six or eight weeks, then once per three weeks; or once every three weeks for the first three, six or nine weeks, and then once a week.

In some embodiments, the immunoconjugate is administered to a patient having a hematologic cancer, e.g., a lymphoid malignancy. In certain embodiments, the cancer is selected from CLL, SLL, MCL, FL, MZL, DLBCL, RTL, BL, LPL, WM, T cell NHL, ALL, and AML. In particular embodiments, the patient has previously received a cancer treatment (e.g., one or more existing cancer treatments, e.g., all existing treatments), and/or has a relapsed or refractory cancer.

In some embodiments, the immunoconjugate treatment induces tumor regression (e.g., resulting in complete tumor eradication); the tumor progression is delayed; inhibiting cancer metastasis; preventing cancer recurrence or residual disease; reducing the size of nodules or extranodal tumor masses; reducing the number of malignant cells in bone marrow and peripheral blood; relieving malignant splenomegaly or hepatomegaly; ameliorating anemia, neutropenia, or thrombocytopenia associated with cancer; improving skin performance; the possibility of the LPL/WM patient to generate high viscosity blood is reduced; alleviating disabling systemic symptoms; and/or extending survival.

The present application also provides an immunoconjugate for use in treating cancer in a patient in a method described herein. In addition, the application provides the use of an immunoconjugate for the preparation of a medicament for treating cancer in a patient in a method described herein.

Drawings

Figure 1 is a graph showing plasma concentration-time curves recording total ADC-a (solid line) and MMAE (dashed line) plasma exposure. C: and (4) period. D: and (5) day. LLQ: lower quantization limit.

FIG. 2 is a set of graphs showing the binding of ADC-A to ROR1 on circulating leukemia cells over time (upper panel) and the plasma concentrations of ADC-A and MMAE (lower panel) in two individuals with CLL. Individual 1: and (4) left. Individual 2: and (4) right.

FIG. 3 is a graph showing the correlation of unoccupied ROR1 receptor with ADC-A plasma concentration.

FIG. 4 is a graph depicting the results of a pharmacokinetic simulation of ADC-A plasma concentrations over time using the Q1/3W, Q2/3W and Q3/4W administration regimens.

FIG. 5 is a graph showing the optimal change in tumor size caused by the initial dose of ADC-A. TE: the evaluation was also premature. PR: and (4) partially reacting.

Detailed Description

The present invention provides therapeutic regimens using ROR1 immunoconjugates. These treatment regimens are useful for treating a variety of cancers, such as cancers that are expected to express ROR 1.

1. Immunoconjugates

An "antibody-drug conjugate" or "ADC" or "immunoconjugate" refers to an antibody molecule or antigen-binding fragment thereof that is covalently or non-covalently bound to one or more biologically active molecules, with or without a linker. The present immunoconjugates comprise human ROR 1-specific antibodies or fragments thereof, and thus can be used as excellent targeting moieties to deliver conjugated payloads to cells (e.g., ROR1 positive cells). In certain embodiments, the immunoconjugate used in the therapeutic regimen of the present invention is the immunoconjugate described in WO 2018/237335.

The SEQ ID NO numbers for the amino acid sequences of the heavy and light chain complementarity determining regions (HCDR and LCDR), the heavy and light chain variable domains (VH and VL), and the heavy and light chains (HC and LC) of the exemplary ROR1 antibody used in the immunoconjugates described herein are shown below:

HCDR1	HCDR2	HCDR3	VH	HC	LCDR1	LCDR2	LCDR3	VL	LC
										5	6	7	3	1	8	9	10	4	2

in some embodiments, the antibody or antibody fragment in the immunoconjugate specifically binds human ROR1, whose heavy and light chains comprise, respectively:

a) SEQ ID NO: 1 and the amino acid sequence of HCDR1-3 in SEQ ID NO: 2, LCDR1-3 amino acid sequence;

b) comprises SEQ ID NO: 5-7 and HCDR1-3 comprising the amino acid sequences of SEQ ID NOs: LCDR1-3 of the amino acid sequence of 8-10;

c) comprises SEQ ID NO: 3, residues 26-33, 51-58, and 97-105, and HCDR1-3 comprising SEQ ID NO: 4 residues 27-32, 50-52 and 89-97 LCDR 1-3;

d) comprises SEQ ID NO: 3, residues 26-32, 52-57, and 99-105, and HCDR1-3 comprising SEQ ID NO: 4, residues 24-34, 50-56, and 89-97 LCDR 1-3; or

e) Comprises SEQ ID NO: 3, residues 31-35, 50-66, and 99-105, and HCDR1-3 comprising SEQ ID NO: 4, residues 24-34, 50-56, and 89-97 of LCDR 1-3.

In certain embodiments of the immunoconjugates described herein, the antibody can be conjugated to the cytotoxic agent through a linker. In some embodiments, the linker is a cleavable linker. A cleavable linker refers to a linker that comprises a cleavable moiety and is typically susceptible to cleavage under in vivo conditions. In exemplary embodiments, the linker may comprise a dipeptide, such as a valine-citrulline (val-cit or VC) linker. In certain embodiments, the linker is attached to a cysteine residue on the antibody.

In some embodiments, conjugation of the linker/payload to the antibody or fragment may be formed by reaction with a maleimide group (which may also be referred to as a maleimide spacer). In certain embodiments, the maleimide group is maleimide hexanoyl (mc); thus, the linker/payload is conjugated to the antibody or fragment by reaction between residues on the antibody or fragment and the mc group in the linker precursor.

In some embodiments, the linker may comprise benzoic acid or benzyloxy, or a derivative thereof. In some embodiments, the linker comprises a p-amino-benzyloxycarbonyl (PAB) group.

In some embodiments, the linkage between the Ab and the payload or drug (D) component of the immunoconjugate may be formed by reacting the components in any combination with a linker comprising a maleimide group, a peptide moiety, and/or a benzoic acid (e.g., PAB) group. In certain embodiments, the maleimide group is maleimidocaproyl (mc). In certain embodiments, the peptide group is Val-cit (vc). In certain embodiments, the linker comprises a Val-Cit-PAB group. In certain embodiments, conjugation of the linker to the antibody or fragment may be formed from the mc-Val-Cit group. In certain embodiments, the linkage between the antibody or fragment and the drug moiety may be formed by the mc-Val-Cit-PAB group.

The linker can be conjugated to the anti-ROR 1 antibodies and antigen-binding fragments of the present application in a variety of ways. Typically, the linker and cytotoxic moiety are synthesized and conjugated prior to attachment to the antibody. One method of attaching linker-drug conjugates to antibodies includes reducing solvent-exposed disulfide bonds with Dithiothreitol (DTT) or tris (2-carboxyethyl) phosphine (TCEP), followed by modification of the resulting thiol with a maleimide-containing linker-drug moiety (e.g., 6-maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-VC-PAB)). The native antibody contains 4 interchain disulfide bonds and 12 intrachain disulfide bonds, as well as unpaired cysteines. Thus, antibodies modified in this manner may comprise more than one linker-drug moiety per antibody. In certain embodiments, each immunoconjugate comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 linker/drug moieties. In certain embodiments, each immunoconjugate comprises one or more (e.g., 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2) linker/drug moieties. In the case where the linkers are branched and each linker can link multiple drug moieties, the ratio of drug moieties to antibody will be higher than if unbranched linkers are used.

In some embodiments, a suitable cytotoxic agent for use in the immunoconjugates described herein can be, for example, an anti-tubulin agent, such as an auristatin (auristatin). In certain embodiments, the cytotoxic agent is monomethyl auristatin e (mmae).

In some embodiments, the immunoconjugates described herein are constructed by:

MAL: maleimide chemistry (MAL).

The ROR1 antibody can be an anti-ROR 1 antibody described herein, e.g., having the amino acid sequence of SEQ ID NO: 1 and the heavy chain amino acid sequence of SEQ ID NO: 2, or a light chain amino acid sequence of seq id No. 2.

In particular embodiments, the immunoconjugates used in the treatment regimens of the invention have the following structure (I):

in some embodiments, the antibody is Ab1, which has the amino acid sequence of SEQ ID NO: 1 and the heavy chain amino acid sequence of SEQ ID NO: 2 (Ab 1); the immunoconjugate may have a DAR of 3-6, and is referred to herein as "ADC-a". See also WO 2018/237335. The payload is conjugated to Ab1 through a cysteine residue in the antibody polypeptide chain.

2. Treatment regimens

In some embodiments, the ROR1 immunoconjugate described herein (e.g., ADC-a) is administered at a dose of 0.25 to 10mg/kg, e.g., 0.25 to 4 mg/kg. For example, the immunoconjugate may be administered at a dose 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 10mg/kg, or any combination thereof, for multiple administrations. In certain embodiments, the immunoconjugate is administered at a dose 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.

In some embodiments, the immunoconjugate is administered in a repeated cycle of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In certain embodiments, the immunoconjugate is administered in a three week cycle. In certain embodiments, the immunoconjugate is administered in a four week cycle. A treatment regimen can include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more administration cycles (e.g., 3 or more cycles, or 4 or more cycles). In certain embodiments, the immunoconjugate is administered on day 1, 2, 3, 4, 5, 6, or 7 of the cycle. The number of days of administration may be consecutive, or there may be one, two, three, four, five or six days, one week, two weeks, three weeks or four weeks between them, or any combination thereof. In particular embodiments, the immunoconjugate is administered only on day 1 of each cycle (e.g., a three-week cycle). In particular embodiments, the immunoconjugate is administered on days 1 and 8 of each cycle (e.g., a three-week cycle). In particular embodiments, the immunoconjugate is administered on days 1, 8, and 15 of each cycle (e.g., 4-week cycle).

The immunoconjugate may be administered initially according to an administration regimen described herein, followed by administration according to a different administration regimen described herein (e.g., increasing or decreasing the frequency of administration). In some embodiments, the immunoconjugate is administered once weekly for the first 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks, followed by once every 3 weeks. In certain embodiments, the immunoconjugate is administered once weekly for the first 2, 3, 4, 5, or 6 weeks, followed by once every 3 weeks. In certain embodiments, the immunoconjugate is administered once weekly for the first 1, 2, 3, 4, 5, or 6 weeks, followed by once every 4 weeks. For example, the immunoconjugate may be administered as follows:

-once a week for the first three weeks, then once every three weeks;

-once weekly for the first four weeks and then once every three weeks;

-once a week for the first six weeks, then once every three weeks;

-once a week for the first eight weeks, then once every three weeks;

-once every three weeks for the first three weeks and then once a week;

-once every three weeks for the first six weeks and then once a week; or

Once every three weeks for the first nine weeks, then once a week.

In some embodiments, the administration regimen described herein achieves an immunoconjugate plasma Cmax of at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 μ g/mL in a patient _max. In some embodiments, the administration regimen described herein achieves an area under the plasma concentration-time curve (AUC) of the immunoconjugate of at least 500, 750, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, 3000, 3250, or 3500 hr · μ g/mL in the patient.

In some embodiments, the administration regimen described herein maintains an immunoconjugate occupancy of the RORl receptor in the patient of at least 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95%. In some embodiments, the administration regimens described herein maintain at least 50% of the immunoconjugate occupancy of ROR1 receptor for at least 20, 30, 40, 50, 60, 70, 80, or 90% of the time. In some embodiments, the administration regimens described herein maintain at least 75% of the immunoconjugate occupancy of ROR1 receptor for at least 20, 30, 40, 50, 60, 70, 80, or 90% of the time. In some embodiments, the administration regimen described herein maintains at least 90% of the immunoconjugate occupancy of ROR1 receptor for at least 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5% of the time.

The immunoconjugate may be administered by parenteral administration. As used herein, "parenteral administration" of an immunoconjugate includes any route of administration characterized by physical disruption of a tissue of an individual as well as administration of the immunoconjugate through a breach in the tissue, thus typically resulting in direct administration into the bloodstream, into muscle, or into an internal organ. Thus, parenteral administration includes, but is not limited to, administration of the immunoconjugate by injection, administration of the immunoconjugate by surgical incision, administration of the immunoconjugate by tissue penetrating non-surgical wound, and the like. In particular, parenteral administration includes, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intrasternal, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, intracranial, intratumoral, and intrasynovial injection or infusion; and renal dialysis infusion techniques. Regional infusion is also contemplated. In some embodiments, infusion may be by administration of an initial dose by one route (e.g., intravenously) followed by administration of a subsequent dose by another route.

In certain embodiments, the immunoconjugate is administered by Intravenous (IV) infusion. An IV infusion may be performed for about 0.1 to about 4 hours (e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 120, or 180). In a particular embodiment, the infusion time is 30 minutes. The infusion time may be extended as needed to accommodate the tolerance of the individual patient to the treatment. When the immunoconjugate is administered in more than one dose, in some embodiments, the infusion time of the first dose is longer than the infusion time of the subsequent dose, or the infusion time of the first dose is shorter than the infusion time of the subsequent dose.

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

It will be appreciated that the treatment regimen of the invention may be the method of treatment described herein, the immunoconjugate described herein for use in the treatment regimen described herein, or the use of the immunoconjugate described herein for the manufacture of a medicament for use in the treatment regimen described herein.

3. Patient selection

The treatment regimens of the invention can be used to treat cancer patients. In some embodiments, the treatment regimen of the invention comprises the step of selecting a patient having a cancer as described herein. In certain embodiments, the patient may have previously received treatment for the cancer, and/or has a recurrent cancer or a cancer as follows: one or more (or all) of the existing treatments for this cancer are refractory to treatment.

"treating", "treating" and "treatment" refer to a method of reducing or eliminating a biological disease and/or at least one symptom associated therewith. As used herein, "alleviating" a disease, disorder, or condition refers to reducing the severity and/or frequency of symptoms of the disease, disorder, or condition. Further, references herein to "treatment" include references to curative, palliative and prophylactic treatment. Cancer treatment includes inhibiting cancer growth (including causing partial or complete regression of cancer), inhibiting cancer progression or metastasis, preventing cancer recurrence or residual disease, and/or prolonging patient survival.

In some embodiments, a patient treated with a therapeutic regimen of the invention has a cancer that expresses ROR 1. Cancer expressing ROR1 can be determined by any suitable method of determining gene or protein expression, for example, by histology, flow cytometry, radiopharmaceutical methods, RT-PCR, or RNA-Seq. Cancer cells for assay can be obtained by tumor biopsy or by collection of circulating tumor cells. In certain embodiments, if an antibody-based assay is used, such as flow cytometry or immunohistochemistry, the cancer expressing ROR1 is any cancer having cells that exhibit greater ROR1 antibody reactivity than isotype control antibodies. In certain embodiments, if an RNA-based assay is used, the ROR 1-expressing cancers are those that exhibit elevated levels of ROR1 RNA compared to negative control cells or cancers that do not express ROR 1.

In certain embodiments, the patient has a hematological malignancy, such as a lymphoid malignancy. In certain embodiments, the patient has a solid tumor. The patient may have a disease selected from, for example, lymphoma, non-hodgkin's lymphoma, Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), Marginal Zone Lymphoma (MZL), marginal cell B-cell lymphoma, Burkitt's Lymphoma (BL), Mantle Cell Lymphoma (MCL), Follicular Lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), non-hodgkin's lymphoma undergoing a rikt transition, T-cell leukemia, T-cell lymphoma (e.g., T-cell non-hodgkin's lymphoma), lymphoplasmacytoid lymphoma (LPL), Waldenstrom's Macroglobulinemia (WM), Acute Myeloid Leukemia (AML), Acute Lymphocytic Leukemia (ALL), Hairy Cell Leukemia (HCL), myeloma, Multiple Myeloma (MM), sarcoma (e.g., osteosarcoma, ewing sarcoma, rhabdomyosarcoma, soft tissue sarcoma, or uterine sarcoma), Brain cancer, glioblastoma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, neuroblastoma, 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 lung cancer), malignant mesothelioma, bile duct/gallbladder cancer (e.g., cholangiocarcinoma), colon cancer, colorectal cancer, esophageal cancer, gastric cancer (stomach cancer), cancers such as gastric cancer (gastic cancer), gastrointestinal stromal tumor (GIST), liver cancer (hepatocellular) cancer, pancreatic cancer, renal cell carcinoma, bladder cancer, prostate cancer, cervical cancer, endometrial cancer, ovarian cancer, testicular cancer, epithelial squamous cell carcinoma, melanoma, adrenocortical carcinoma, gastrointestinal carcinoids, islet cell tumors, pancreatic neuroendocrine tumors, cutaneous neuroendocrine cancer (Merkel cell carcinoma), and pheochromocytoma. In certain embodiments, the patient has a cancer refractory to other therapeutic agents (e.g., triple negative breast cancer).

In a particular embodiment, the patient has a cancer selected from the group consisting of CLL/SLL, MCL, FL, MZL, DLBCL, RTL, BL, LPL/WM, T cell NHL, ALL and AML. In certain embodiments, the patient may have previously received treatment for the cancer, and/or has a recurrent or following cancer: one or more (e.g., all) of the existing treatments for such cancers are refractory to treatment.

In some embodiments, the patient is resistant to or relapsed under the following treatments: ibrutinib, alcalitinib (acarabutinib), autologous hematopoietic stem cell transplantation, bendamustine, bortezomib, weibull's eye-xib (brentuximab vedotin), carmustine, chimeric antigen receptor T (CAR-T) cells, cisplatin, coppanisib (copanlisib), cyclophosphamide, cytarabine, daratumumab (daratumab), dexamethasone, doxorubicin, etoposide, gemcitabine, idelalisib (idelalisib), lenalidomide, melphalan, methotrexate, methylprednisolone, mostuzumab, orinituzumab (obium), ofatumumab, oxaliplatin, pintuzumab (pinatuzumab), polatuzumab (polatuzumab), rituximab, prednisone, radiation therapy, vinorelbine (vincalex), vincalexan (any combination thereof, for example, any combination thereof.

In some embodiments, the treatment regimen is administered to a human patient with sufficient physical performance status and organ function, such as an adult patient (>18 years), an adolescent patient (>12 to 17 years), or a pediatric patient (<18 years), who (i) has a histologically confirmed advanced hematological cancer or solid tumor; and/or (ii) having a malignancy that is less likely to respond to, or is resistant to, established therapies known to provide clinical benefit. In certain embodiments, the patient meets both criteria.

4. Therapeutic results

In some embodiments, treatment with the immunoconjugate results in one or more of:

induction of partial or complete tumor regression, possibly in some cases lasting until after the last dose of treatment;

delay of tumor progression (e.g., by inhibiting tumor growth);

-preventing cancer recurrence or residual disease;

-reducing the size of nodules or extranodal tumor masses (which may be painful, destructible or compressive);

-reduction of the number of malignant cells in bone marrow and peripheral blood;

-alleviating malignant splenomegaly or hepatomegaly;

ameliorating anemia, neutropenia or thrombocytopenia associated with cancer (which exposes the patient to the risk of fatigue, infection or bleeding, respectively);

-improvement of skin appearance (which may be painful, intense pruritic or disfiguring);

-reducing the likelihood of occurrence of high viscosity syndrome in LPL/WM patients;

-ameliorating disabling systemic symptoms; and

-prolongation of survival.

Treatment may result in any combination of the above results.

In some embodiments, the treatment regimens of the invention reduce the tumor size of the patient, wherein the sum of perpendicular diameter products (SPD) is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, a treatment regimen of the invention reduces the size of a tumor in a patient, wherein the sum of the longest diameters of the target lesions is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the treatment regimens of the invention completely eradicate the tumor.

In some embodiments, a treatment regimen of the invention (e.g., to treat CLL and/or SLL) results in one or more (e.g., any one, two, three, four, five, six, or seven) of the following:

a) no evidence of new disease;

b) absolute Lymphocyte Count (ALC) in peripheral blood<4×10⁹/L；

c) The Longest Diameter (LD) of all index nodule lumps disappears to be less than or equal to 15 mm;

d) Measuring the normal spleen size with the Longest Vertical Dimension (LVD) less than or equal to 120mm through imaging, and measuring the normal liver size with the LVD less than or equal to 180mm through imaging;

e) all nodular non-index disease regresses to normal (e.g., ≦ 15mm) and all detectable non-nodular, non-index disease disappears;

f) morphologically negative bone marrow defined as < 30% of nucleated cells in normal-age bone marrow samples are lymphocytes and no lymphoid nodules; and

g) peripheral blood that meets all of the following criteria:

i) absolute Neutrophil Count (ANC) with no exogenous growth factor for 2 weeks before assessment of relevant blood counts>1.5×10⁹/L；

ii) platelet count without exogenous growth factor or platelet infusion 2 weeks or less prior to assessment of relevant blood count>100×10⁹L; and

iii) hemoglobin >110g/L (11.0g/dL) without exogenous growth factor or erythrocyte infusion 2 weeks before relevant blood count assessment.

In certain embodiments, the treatment regimen results in all of a) -g) ("complete response"), and may further result in bone marrow puncture flow cytometry exhibiting ≦ 1 × 10^-4Individual malignant cells ("no complete response to detectable residual disease"). In some embodiments, the treatment regimen of the present invention results in one or more of the following ("incomplete response of count recovery"):

a) a) to f), g) (ii) and g) (iii), and an Absolute Neutrophil Count (ANC). ltoreq.1.5X 10⁹/L or requires exogenous growth factors to maintain ANC ≧ 1.5X 10⁹/L；

b) a) to f), g) (i) and g) (iii) and a platelet count of ≤ 100 × 10⁹/L or exogenous growth factor or platelet infusion required to maintain a platelet count of 100X 10 or more before 2 weeks before assessment of relevant blood counts⁹L; and

c) a) -f), g) (i) and g) (ii), and hemoglobin ≦ 110g/L (11.0g/dL) or 2 weeks prior to relevant cytometry evaluation requiring exogenous growth factor or red blood cell infusion to maintain hemoglobin ≦ 110g/L (11.0 g/dL).

In some embodiments, a treatment regimen of the invention (e.g., to treat CLL/SLL) results in one or more (e.g., any one, two, three, or four) of:

a) no evidence of new disease;

b) changes in disease status that meet two or more of the following criteria (with the exception that if lymphadenopathy is present at the time of screening, then only lymphadenopathy must improve to the extent specified below):

i) absolute Lymphocyte Count (ALC) in peripheral blood was reduced by more than or equal to 50% compared to screening;

ii) the sum of the diameter products (SPD) of the index nodular lesions is reduced by more than or equal to 50% compared with that in screening;

iii) in individuals with enlarged spleens at screening, the Longest Vertical Dimension (LVD) of enlargement of the spleens is reduced by more than or equal to 50% (minimum reduction by 20mm) or to less than or equal to 120mm as compared to screening, as measured by imaging;

iv) in individuals with enlarged liver at screening, the LVD with enlarged liver is reduced by more than or equal to 50% (minimum 20mm) or reduced to less than or equal to 180mm compared to that at screening, as measured by imaging; and

v) CLL/SLL marrow infiltration or B lymph node reduction by more than or equal to 50% compared to screening;

c) no index meeting clear Progressive Disease (PD) criteria, worsening of spleen, liver or non-index disease; and

d) peripheral blood meeting one or more of the following criteria:

i) absolute Neutrophil Count (ANC) with no exogenous growth factors for ≦ 2 weeks prior to assessment of relevant blood counts>1.5×10⁹The increase of/L or phase compared with the screening is more than or equal to 50 percent;

ii) platelet count without exogenous growth factor or platelet infusion 2 weeks or less prior to assessment of relevant blood count>100×10⁹The increase of/L or phase compared with the screening is more than or equal to 50 percent; and

iii) hemoglobin >110g/L (11.0g/dL) or an increase of > 50% compared to screening without exogenous growth factor or erythrocyte infusion before < 2 weeks of relevant blood count assessment.

In certain embodiments, the method of treatment results in a complete (partial response) of a) -d). In certain embodiments, the method of treatment results in all of a), b) ii) -b) v), c) and d) ("partial response to lymphadenopathy")

In some embodiments, a treatment regimen of the invention (e.g., to treat CLL/SLL) results in one or both of:

a) no evidence of new disease; and

b) there was no evidence of tumor growth.

In certain embodiments, the treatment regimen results in both a) and b) ("stable disease").

In some embodiments, a treatment regimen of the invention (e.g., to treat CLL/SLL) does not result in the outcome of any of the following (which is a sign of "progressive disease"):

a) evidence of any new disease determined by one or more of:

i) new nodules >15mm in any diameter were measured;

ii) splenic LVD > 140mm as measured by imaging in individuals with normal splenic LVD ≦ 120mm as measured by imaging at nadirs;

iii) liver LVD > 200mm as measured by imaging in individuals with normal liver LVD ≦ 180mm as measured by imaging at nadir;

iv) histologically confirmed new exudate, ascites or other CLL/SLL-associated organ abnormalities;

v) new extranodal foci >10 mm;

vi) new avid Fluorodeoxyglucose (FDG) foci consistent with lymphoma but not other etiologies (e.g., infection or inflammation); and

vii) lymphoma was previously negative by PET or bone marrow biopsy, but new or recurrent lymphoma bone marrow involvement was found by PET or bone marrow biopsy;

b) evidence of worsening of the index lesion, spleen or liver or non-index disease determined by one or more of:

i) the increase of the sum of the index focus diameter products (SPD) is more than or equal to 50 percent compared with the lowest point;

ii) the Longest Diameter (LD) of a single nodule or extranodal mass is increased by more than or equal to 50% compared to the nadir, now LD >15mm, LPD >10 mm;

iii) splenic enlargement is greater than or equal to 50% greater than the nadir (least 20mm increase) in individuals with splenic enlargement at screening or at the lowest point of the Longest Vertical Dimension (LVD);

iv) liver enlargement is increased by > 50% compared to nadir (minimum 20mm increase) at screening or in individuals with hepatomegaly at the Longest Vertical Dimension (LVD) nadir;

v) a definite increase in the size of fluid accumulation, ascites or other organ abnormalities associated with CLL/SLL; and

vi) more aggressive histology to transition to by lymph node biopsy;

vii) the decrease in platelet count or hemoglobin is due to CLL/SLL, as confirmed by a bone marrow biopsy showing clonal CLL/SLL cell infiltration, but not to an autoimmune phenomenon, wherein

A) The current platelet count is less than or equal to 100X 10⁹a/L, and a decrease of greater than or equal to 50% from baseline; and

B) current hemoglobin < 110g/L (11.0g/dL) and decreases by >20g/L (2g/dL) relative to baseline.

In certain embodiments, the treatment does not result in any of the above-described results.

In some embodiments, a treatment regimen of the invention (e.g., to treat lymphoma) results in one or more (e.g., any one, two, three, four, five, six, seven, or eight) of:

a) no evidence of new disease;

b) the nodular lesions of all indexes in the LDi are subsided to be less than or equal to 15 mm;

c) all nodular non-index diseases disappear to be less than or equal to 15 mm;

d) disappearance of all detectable extranodal and non-indicative diseases;

e) normal spleen size of less than or equal to 130mm Longest Vertical Dimension (LVD) as measured by imaging;

f) if PET is performed, there is no evidence of residual disease-i.e., the Deauville5 subscale scores 1 (no uptake above background), 2 (uptake ≦ mediastinum), or 3 (uptake > mediastinum but ≦ liver);

g) bone marrow involvement was negative as measured by morphological assessment of PET (for PET-philic tumors) or unilateral core biopsy; immunohistochemistry should be negative if bone marrow biopsy morphology cannot be determined; and

h) No serum M protein was detected by SIFE (in individuals with LPL/WM).

In certain embodiments, the treatment regimen results in all of a) -g) ("complete response") or all of a) -h) (LPL/WM individuals, "complete response"), and may further result in bone marrow puncture flow cytometry exhibiting ≦ 1 × 10^-4A malignant cell (complete response to no detectable residual disease) "). In some embodiments, the treatment regimens of the invention result in a decrease of > 90% in all of a) -h) and serum M protein concentration compared to baseline.

In some embodiments, a treatment regimen of the invention (e.g., to treat lymphoma) results in one or more (e.g., any one, two, three, or four) of:

a) there is no evidence of a new disease

b) The indexes of the SPD of the nodules and the extranodal lesions are reduced by more than or equal to 50 percent compared with the SPD in screening;

c) the size of the non-index disease was not increased compared to the nadir;

d) in individuals with enlarged spleens at screening, the Longest Vertical Dimension (LVD) of enlargement of the spleens as measured by imaging was reduced by greater than or equal to 50% (minimum reduction of 20mm) or less than or equal to 130mm as compared to at screening;

e) if PET is performed:

i) typical FDG-philic lymphomas: if no screening PET scan was performed before treatment or the PET scan was positive, the on-treatment (on-treatment) PET was positive at ≧ 1 previously affected site, i.e., the Deauville 5 scale scored 4 (moderate intake) >Liver) or 5 points (significant intake)>Liver) but with reduced uptake compared to the screening. If a screening PET is performed and the result is negative, there is no evidence of new PET disease. Uptake reduction was defined as% Δ SUV_maxThe reduction is more than or equal to 25 percent;

ii) variable FDG-philic lymphoma/FDG affinity unknown: if a PET scan is not performed before treatment or if lymphoma is negative as determined by a pre-treatment PET scan, the tumor should be assessed using CT criteria during treatment. If PET scanning before treatment is positive, PET is positive at more than or equal to 1 previous affected part during treatment;

f) the involvement of bone marrow in the individual that meets the radiological criteria for a Complete Response (CR) persists; and

g) serum M protein concentration (in individuals with LPL/WM) decreased by > 50% but < 90% from baseline.

In certain embodiments, the treatment regimen results in all of a) -f) ("partial response") or all of a) -g) (partial response "in LPL/WM individuals). In certain embodiments, the treatment regimen results in a decrease in all and serum M protein concentrations in a) -f) by ≧ 25% but < 50% from baseline (a "mild response" in LPL/WM).

In some embodiments, a treatment regimen of the invention (e.g., to treat lymphoma) results in one or more of the following:

a) No evidence of new disease;

b) no evidence of tumor growth; and

c) serum M protein concentration (in individuals with LPL/WM) was decreased by < 25% and increased by < 25% compared to baseline.

In certain embodiments, a treatment regimen of the invention results in a) and b) ("stable disease") or a) -c) (stable disease "in LPL/WM individuals). In certain embodiments, the treatment regimens of the invention result in a decrease of a) and b) and serum M protein concentration by ≧ 25% but < 50% from baseline (the "mild response" in LPL/WM).

In some embodiments, the treatment regimen of the present invention does not result in one or more of the following (which are indicative of "progressive disease") outcomes:

a) evidence of any new disease determined by one or more of:

i) new nodules of any diameter measuring >15 mm;

ii) resolved extranodal lesions (i.e., a Product of Perpendicular Diameters (PPD) of 0mm has been previously assigned²) Reappearance;

iii) new extranodal foci >10 mm;

iv) new non-indicative diseases of any size (e.g., effusion, ascites, or other organ abnormalities) that can be definitively attributed to lymphoma (e.g., as confirmed by PET, biopsy, cytology, or other non-radiological testing);

v) lymphoma but not other etiologies (e.g., infection or inflammation; biopsy or space scan may be considered if the cause of the new lesion is uncertain) a matching new FDG-parent lesion; and

vi) if a PET or bone marrow biopsy previously performed as part of the study is negative for lymphoma, finding new or recurrent lymphoma bone marrow involvement by the PET or bone marrow biopsy;

b) evidence of lesion deterioration of a nodule or extranodal marker determined by one or more of:

i) the increase of the sum of the index focus diameter products (SPD) is more than or equal to 50 percent compared with the lowest point;

ii) evidence of single index lymph node or nodal lump deterioration, wherein the PPD of any single nodule increases by > 50% compared to nadir, by > 50% compared to nadir if the nodule now has an LD of >15mm, by > 5mm compared to nadir for lesions measured at < 20mm (LD or shortest Size (SDi)), or by > 10mm for lesions measured at >20mm (LD or SDi).

iii) a clear increase in non-index disease size; and

iv) splenic enlargement is increased by ≥ 50% compared to nadir (minimum increase of 20mm) in patients with splenic LVD >130mm with nadir as measured by imaging, or splenic LVD >150mm as measured by imaging in patients with splenic LVD >130mm with nadir as measured by imaging;

c) Determination of a shift to more aggressive non-hodgkin lymphoma (NHL) histology by lymph node biopsy;

d) if PET is performed, the Deauville 5 scale scores 4 points (moderate intake > liver) or 5 points (significant intake > liver), with increased intake compared to nadir and with an increase in lesion size consistent with Progressive Disease (PD). Increased uptake is defined as an increase of > 50% in% Δ SUVax;

e) serum M protein concentrations increased by > 25% compared to nadir (in individuals with LPL/WM).

In certain embodiments, the treatment does not result in any of a) -d), or any of the results described above.

In some embodiments, a treatment regimen of the invention (e.g., to treat acute lymphocytic leukemia) results in one or more (e.g., any one, two, or three) of:

a) the leukemia state meets all of the following requirements:

i) < 5% bone marrow primary cells (bone marrow needle-like structures present based on bone marrow aspirate/biopsy samples with ≧ 200 nucleated cells);

ii) there are no blasts in the peripheral blood; and

iii) extramedullary disease (including lymphadenectasis, splenomegaly, skin/gum infiltration, testicular mass, and absence of central nervous system involvement (i.e., CNS-1 state is achieved (no primary cells in cerebrospinal fluid));

b) Peripheral blood meets all of the following requirements:

i)ANC≥1.0×10⁹/L；

ii) platelet count ≥ 100X 10⁹L; and

c) any mediastinal enlargement was shown to be completely resolved as recorded by radiology.

In certain embodiments, the treatment regimen results in all of a) -c) ("complete response"), and may further result in a bone marrow puncture flow cytometry that exhibits ≦ 1 × 10^-4Individual malignant cells ("complete response with no detectable residual lesions").

In some embodiments, a treatment regimen of the invention (e.g., to treat acute lymphocytic leukemia) results in one or more (e.g., any one, two, or three) of:

a) the leukemia state meets all of the following requirements:

i) < 5% bone marrow primary cells (bone marrow needle-like structures present based on bone marrow aspirate/biopsy samples with ≧ 200 nucleated cells);

ii) there are no blasts in the peripheral blood; and

iii) extramedullary disease (including lymphadenectasis, splenomegaly, skin/gum infiltration, testicular mass, and absence of central nervous system involvement (i.e., CNS-1 state is achieved (no primary cells in cerebrospinal fluid));

b) peripheral blood meets all of the following requirements:

i)ANC＜1.0×10⁹/L；

ii) platelet count less than 100X 10⁹L; and

c) as recorded radiologically, the sum of the products of the perpendicular diameters of any mediastinal enlargement (SPD) had resolved by > 75%.

In certain embodiments, the treatment regimen results in all of (a) "incomplete complete response to recovery of blood counts" and/or "unidentified complete response") in a) -c).

In some embodiments, a treatment regimen of the invention (e.g., to treat acute lymphocytic leukemia) results in one or more (e.g., any one, two, or three) of:

a) the leukemia state meets any one of the following requirements:

i) bone marrow blasts were greater than or equal to 50% reduced to 5% -25% (bone marrow needle formation present based on bone marrow aspirate/biopsy samples with greater than or equal to 200 nucleated cells);

ii) there are no blasts in the peripheral blood; and

iii) absence of new or worsening extramedullary disease (including lymphadenectasis, splenomegaly, skin/gum infiltration, testicular mass, and absence of central nervous system involvement (e.g., CNS-1 state (absence of primitive cells in cerebrospinal fluid) that has not yet transitioned to CNS-2 state (WBC)<5×10⁹/L, presence of primitive cells in cerebrospinal fluid), or CNS-3 status (WBC ≧ 5X 10⁹L, presence of primitive cells in cerebrospinal fluid) or development of facioplegia, brain/eye involvement, or hypothalamic syndrome));

b) peripheral blood meets all of the following requirements:

i)ANC≥1.0×10⁹/L；

ii) platelet count ≥ 100X 10 ⁹L; and

c) as recorded by radiology, any mediastinal enlargement resolved > 50% of SPD.

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

In some embodiments, a treatment regimen of the invention (e.g., with a treated acute lymphoblastic leukemia) results in one or more (e.g., one, two, or three) of the following:

a) the improvement of ALL compared to baseline was not sufficient to comply with PR, and evidence of ALL worsening was not sufficient to comply with DRP;

b) no new or worsening extramedullary disease (including lymphadenectasis, splenomegaly, skin/gum infiltration, testicular mass, and no central nervous system involvement (e.g., CNS-1 status (no primitive cells in cerebrospinal fluid) that has not yet transitioned to CNS-2 status (WBC)<5×10⁹/L, presence of primitive cells in cerebrospinal fluid), or CNS-3 status (WBC ≧ 5X 10⁹/L, presence of primitive cells in cerebrospinal fluid) or progression to facioplegia, brain/eye involvement, or hypothalamic syndrome);

c) no new mediastinal enlargement occurs, and the increase of SPD of the existing mediastinal enlargement is not more than 25%.

In certain embodiments, the treatment regimens of the invention result in all of a) -c) ("stable disease").

In some embodiments, a treatment regimen of the invention (e.g., to treat acute lymphocytic leukemia) does not result in one or more of the following (e.g., one, two, three, four, five, or six) outcomes that are indicative of disease recurrence or progression ("DRP"):

a) bone marrow blasts reappeared in individuals experiencing CR (to > 5%);

b) reappearance of primary cells in peripheral blood of individuals who have undergone CR;

c) bone marrow blasts increased by > 25% to > 20% (bone marrow needles present based on bone marrow aspirate/biopsy samples with > 200 nucleated cells);

d) the initial cell increase in peripheral blood is not less than 25%, and increases to>1×10⁹/L；

e) New extramedullary diseases or existing extramedullary disease progression (including lymph node enlargement, splenomegaly, skin/gum infiltration, testicular mass and absence of central nervous system involvement (e.g., CNS-1 status (absence of primitive cells in cerebrospinal fluid)) have been shifted to CNS-2 status (WBC)<5×10⁹/L, presence of primitive cells in cerebrospinal fluid), or CNS-3 status (WBC ≧ 5X 10⁹/L, presence of primitive cells in cerebrospinal fluid) or development of facial paralysis, brain/eye disordersTired, or hypothalamic syndrome); and

f) the new mediastinal swelling appears, or the SPD increase of the existing mediastinal swelling is more than or equal to 25 percent.

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

In some embodiments, a treatment regimen of the invention (e.g., to treat acute myeloid leukemia) results in one or both of:

a) the leukemia state meets all of the following requirements:

i) < 5% bone marrow primary cells (bone marrow needle present based on bone marrow aspiration/biopsy samples with ≧ 200 nucleated cells);

ii) primitive cells are absent from peripheral blood;

iii) is free of primary cells and Auer bodies; and

iv) extramedullary disease; and

b) peripheral blood meets the following two requirements:

i)ACN≥1.0×10⁹/L；

ii) platelet count ≥ 100X 10⁹/L。

In certain embodiments, the treatment regimen results in a) and b) ("complete response"), and may further result in flow cytometry results in bone marrow aspiration exhibiting ≦ 1 × 10^-4Individual malignant cells ("complete response with no detectable residual lesions").

In some embodiments, a treatment regimen of the invention (e.g., to treat acute myeloid leukemia) results in one or both of:

a) the leukemia state meets all of the following requirements:

i) < 5% bone marrow primary cells (bone marrow needle present based on bone marrow aspiration/biopsy samples with ≧ 200 nucleated cells);

ii) primitive cells are absent from peripheral blood;

iii) is free of primary cells and Auer bodies; and

iv) extramedullary disease; and

b) peripheral blood meets only one of the following two criteria:

i)ACN≥1.0×10⁹/L；

ii) platelet count ≥ 100X 10⁹/L。

In certain embodiments, the treatment regimen results in a) and b) ("complete response with incomplete recovery of blood counts").

In some embodiments, a treatment regimen of the invention (e.g., to treat acute myeloid leukemia) results in one or both of the following outcomes:

a) the leukemia state meets all of the following requirements:

i) < 5% bone marrow primary cells (bone marrow needle present based on bone marrow aspiration/biopsy samples with ≧ 200 nucleated cells);

ii) primitive cells are absent from peripheral blood;

iii) is free of primary cells and Auer bodies; and

iv) extramedullary disease; and

b) peripheral blood meets the following two requirements:

i)ACN≤1.0×10⁹/L；

ii) platelet count ≤ 100 × 10⁹/L。

In certain embodiments, the treatment regimen results in a) and b) ("morphological leukemia free status").

In some embodiments, a treatment regimen of the invention (e.g., to treat acute myeloid leukemia) results in one or both of the following outcomes:

a) the leukemia state meets one of all the following requirements:

i) bone marrow blasts were reduced by > 50% to 5-25% (based on bone marrow aspirate/biopsy samples with > 200 nucleated cells, bone marrow needles were present);

ii) < 5% bone marrow primary cells but Auer corpuscles were present (bone marrow needles were present based on bone marrow aspirate/biopsy samples with ≧ 200 nucleated cells);

iii) primitive cells are absent from peripheral blood; and

iv) no new or worsening extramedullary disease; and

b) peripheral blood meets the following two requirements:

i)ACN≥1.0×10⁹l; and

ii) platelet count ≥ 100X 10⁹/L。

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

In some embodiments, a treatment regimen of the invention (e.g., to treat acute myeloid leukemia) results in one or both of the following outcomes:

a) the improvement in AML compared to baseline was not sufficient to meet CR_MRD-CR, CRi, MLFS or PR, and evidence of AML deterioration is insufficient to comply with DRP; and

b) there was no new or worsening extramedullary disease.

In certain embodiments, a treatment regimen of the invention results in a) and b) ("stable disease").

In some embodiments, a treatment regimen of the invention (e.g., to treat acute myeloid leukemia) does not result in one or more of the following as a result of a sign of disease recurrence or progression ("DRP"):

a) subject to CR_MRD-Bone marrow blasts (to) in individuals with CR, CRi or MLFS>5％)；

b) Has undergone CR _MRD-Re-appearance of primitive cells in peripheral blood of individuals CR, CRi, MLFS or PR;

c) bone marrow blasts in individuals who have undergone PR are increased by an absolute 20% to > 25% (bone marrow needles present based on bone marrow aspirate/biopsy samples with > 200 nucleated cells);

d) absolute 20% increase in peripheral blood blasts to > 25% in individuals who have undergone PR;

e) new extramedullary disease or worsening of existing extramedullary disease occurs.

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

In some embodiments, a treatment regimen of the invention (e.g., to treat a solid tumor) results in one or both of the following:

a) all target lesions disappeared and no new detectable lesions (e.g., lesions accurately measured at ≧ 1 size (dimension) (longest diameter recorded) as measured in a CT scan with a minimum slice thickness of 5mm >10mm, or a caliper measurement of >10mm as measured by clinical examination, or >20mm by chest X-ray examination); and

b) the short axis of any pathological lymph node is reduced to <10mm, whether targeted (e.g., short axis ≧ 15mm at CT scan evaluation (5 mm minimum slice thickness)) or non-targeted (e.g., >10mm but <15 mm).

In certain embodiments, the treatment regimen results in a "complete response" of a) and b) (the target lesion).

In some embodiments, a treatment regimen of the invention (e.g., to treat a solid tumor) results in a reduction in the sum of target lesion diameters by ≧ 30% (referenced to the sum of baseline diameters), including any newly detectable lesions that may have occurred since baseline (a "partial response" of the target lesion).

In some embodiments, a treatment regimen of the invention (e.g., to treat a solid tumor) results in a reduction of the sum of the diameters of the target lesions by ≧ 30% (referenced to the sum of baseline diameters), including any newly detectable lesions that may have occurred since baseline (target lesion "partial response").

In some embodiments, a treatment regimen of the invention (e.g., to treat a solid tumor) results in neither a sufficient reduction in compliance with partial response (referenced to the sum of baseline diameters) nor a sufficient increase in compliance with disease progression (referenced to the sum of baseline diameters) during treatment (target lesion "stable").

In some embodiments, a treatment regimen of the invention (e.g., to treat a solid tumor) does not result in a greater than or equal to 20% increase in the sum of target lesion diameters (absolute increase greater than or equal to 5mm) during treatment, referenced to the sum of post-minimal baseline (post-baseline) (tumor nadir) or the sum of baseline (if it is minimal) (target lesion "disease progression").

In some embodiments, a treatment regimen of the invention (e.g., to treat a solid tumor) results in one or more of the following:

a) all non-target lesions disappeared;

b) normalization of elevated tumor marker levels; and

c) all lymph nodes were non-pathological in size (minor axis <10 mm).

In certain embodiments, the treatment regimen results in a "complete response" of all (non-target lesions) in a) -c). In certain embodiments, the treatment regimen results in b) and c) but not a), or results in a) and c) but not b) (non-target lesions "incomplete response/non-disease progression").

In some embodiments, a treatment regimen of the invention (e.g., to treat a solid tumor) does not result in a clear progression of an existing non-target lesion (non-target lesion "disease progression").

In some embodiments, the treatment regimens of the invention (e.g., to treat a solid tumor) result in an overall response:

-no target lesion and a new detectable lesion; no non-target lesion or tumor marker; and no new, undetectable lesions ("complete reactions");

-no target lesion and a new detectable lesion; stable non-target lesion or tumor markers ("partial response");

-no target lesion and a new detectable lesion; unambiguous progression of non-target lesion or tumor markers ("partial response");

-a reduction of the target lesion by more than or equal to 30% and a new detectable lesion; the presence, stable or clear progression of non-target lesion or tumor markers ("partial response"); or

-a decrease < 30% to an increase < 20% of target lesions and new detectable lesions; absence, stable or clear progression of non-target lesions or tumor markers ("stable disease").

In some embodiments, a treatment regimen of the invention (e.g., to treat a solid tumor) does not result in an increase in target lesions of ≧ 20% and newly detectable lesions; and does not exist, stably or clearly progress at non-target lesions or tumor markers ("disease progression").

In some embodiments, a treatment regimen of the invention results in one or more of the following results, for example, as defined above or in the examples:

-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.

In some embodiments, a treatment regimen of the invention does not result in one or more (e.g., any one, two, three, four, five, six, seven, eight, nine, or ten) of the following in the first treatment cycle:

a) Grade 3 or more febrile neutrophilic granulocytopenia;

b) grade 4 or more neutropenia;

c) grade 3 thrombocytopenia with grade 3 or more bleeding;

d) grade 4 or more thrombocytopenia;

e) grade 3 Tumor Lysis Syndrome (TLS), which, despite adequate precautions, remains unresolved within 72 hours after onset;

f) TLS is greater than or equal to grade 4 despite adequate precautions;

g) despite the recommended (or equivalent) antiemetic support, grade 3 emesis occurs;

h) grade 3 or more non-hematologic laboratory abnormalities that do not improve to grade 1 or baseline within 72 hours;

i) other adverse events (TEAE) with grade 3 non-hematological treatment (except for grade 3 fatigue); and

j) due to drug-related TEAE, failed to return to baseline after more than 21 days from the last dose of immunoconjugate in the cycle,

wherein all grades are defined using the common terminology for adverse events standard (CTCAE) version 5.0. In certain embodiments, the treatment regimens of the invention do not result in any of the described results.

In some embodiments, a treatment regimen of the invention does not result in one or more (e.g., any one, two, three, four, five, or six) of the following:

a) Any complications that occur from protocol-specific procedures (e.g., venipuncture, ECG);

b) any pre-existing condition that increases in severity or changes in nature during or as a result of administration (e.g., worsening manifestations of underlying cancer, such as increased pain, tumor flare response, TLS, etc.);

c) any injury or accident;

d) any abnormalities in physiological or physical examination findings that require clinical intervention or further investigation (beyond the requirement for repeat testing or confirmation testing);

e) any laboratory (e.g., clinical chemistry, hematology, urinalysis) or research (e.g., ECG, X-ray) abnormality independent of the underlying medical condition that requires clinical intervention or results in further investigation (beyond ordering repeat or confirmation tests), or results in discontinuation or discontinuation of research drug unless it is associated with a reported clinical event; and

f) complications associated with pregnancy or termination of pregnancy.

In certain embodiments, the treatment regimens of the invention do not result in any of the described results.

In some embodiments, a treatment regimen of the invention does not result in one or more (e.g., any one, two, three, four, five, or six) of the following:

a) Death;

b) life threatening situations with direct risk of death;

c) hospitalization or extension of existing hospitalization;

d) persistent or severe disability/incapacity;

e) progeny of individuals receiving the immunoconjugate have congenital abnormalities/birth defects; and

f) medically significant events, which may not be immediately life threatening or result in death or hospitalization, but which, based on appropriate medical and scientific judgment, may be endangering the individual or may require medical or surgical intervention to prevent one of the above outcomes (e.g., allergic bronchospasm requiring intensive treatment in an emergency room or at home, new cancer or hematological cachexia, tics that do not result in hospitalization, or development of drug dependence or abuse).

In certain embodiments, the treatment regimens of the invention do not result in any of the described results.

In some embodiments, a treatment regimen of the invention does not result in one or more (e.g., one, two, or three) of the following:

a) infusion reaction of grade more than or equal to 3;

b) tumor Lysis Syndrome (TLS) at any level; and

c) grade 3 or more peripheral nerve lesions;

wherein all grades are defined using the common terminology for adverse events standard (CTCAE) version 5.0.

In certain embodiments, the treatment regimens of the invention do not result in any of the described results.

In some embodiments, a treatment regimen of the invention does not result in an abnormality of one or more (e.g., any one, two, three, four, five, six, seven, eight, or nine) of: urine, serum, blood, systolic pressure, diastolic pressure, pulse, body temperature, blood oxygen saturation, and Electrocardiogram (ECG) readings. In certain embodiments, the treatment regimens of the invention do not result in any of the above abnormalities.

In some embodiments, the treatment regimens of the invention do not produce detectable levels of circulating immunoconjugate-reactive antibodies in the serum of the patient.

It will be appreciated that the treatment regimen described herein may be the treatment method described herein, the immunoconjugate described herein for the treatment regimen described herein, or the use of the immunoconjugate described herein for the manufacture of a medicament for the treatment regimen described herein.

5. Before or simultaneously applying

Prevention of tumor lysis syndrome

In some embodiments, the patient to be treated with a treatment regimen of the invention is assessed for risk of Tumor Lysis Syndrome (TLS) using the following criteria:

CLL/SLL and NHL:

(i) low risk: serum Lactate Dehydrogenase (LDH) is less than or equal to the Upper Limit of Normal (ULN), and all detectable lymph node diameters<5cm，ALC<25×10⁹/L。

(ii) Moderate risk: serum LDH>1 to less than or equal to 2 × ULN, 1 or more and 5 or more diameters<Measurable lymph nodes 10cm, or ALC ≥ 25 × 10⁹/L。

(iii) High risk: serum LDH>2 × ULN, the diameter of more than or equal to 1 measurable lymph node is more than or equal to 10cm, or more than or equal to 1 measurable lymph node LD is more than or equal to 5 but the diameter<10cm and ALC is more than or equal to 25 multiplied by 10⁹/L。

ALL：

(i) Low risk: white blood cell count (WBC)<20×10⁹/L and serum LDH levels<2×ULN

(ii) Moderate risk: WBC ≥ 20 × 10⁹L to<100×10⁹/L and serum LDH levels<2×ULN

(iii) High risk: WBC ≥ 100 × 10⁹/L or serum LDH level is more than or equal to 2 multiplied by ULN

AML：

(i) Low risk: serum LDH<2 × ULN, serum uric acid<5.5mg/dL, and WBC<25×10⁹/L。

(ii) Moderate risk: serum LDH is more than or equal to 2 multiplied by ULN, or serum uric acid is more than or equal to 5.5mg/dL and<7mg/dL, or WBC ≥ 25X 10⁹L to<100×10⁹/L。

(iii) High risk: serum uric acid is more than or equal to 7mg/dL or WBC is more than or equal to 100 multiplied by 10⁹/L。

In some embodiments, if the patient is at moderate or high TLS risk, and/or if TLS is observed during treatment, the patient may receive allopurinol and/or febuxostat before or during treatment. Patients with hyperuricemia may additionally receive labyrinase. For example, the patient may receive the drug according to the following protocol:

(i) TLS moderate risk: the patient can start more than or equal to 24 to 48 hours before starting the drug treatment, and 100 to 300mg of allopurinol is orally taken every 8 hours; it is noted that the maximum daily allopurinol dosage is 800mg, the dosage less than or equal to 300mg does not need to be divided into several doses, and the dosage of patients with renal insufficiency is reduced by more than or equal to 50%. Substitutions may be made in place of drugs (e.g., febuxostat), which are administered according to product labeling. In addition, patients with hyperuricemia may be infused intravenously with 3 to 4.5mg of labyrinase.

(ii) TLS high risk: the patient can take 100 to 300mg allopurinol every 8 hours beginning at more than or equal to 24 to 48 hours before starting the drug treatment; it is noteworthy that the maximum daily allopurinol dose is 800mg, the dose ≦ 300mg need not be divided into several doses (but may not be sufficient for high risk individuals), and individuals with renal insufficiency should be reduced by a dose of ≧ 50%. Replacement drugs (e.g., febuxostat) can be used instead, applied according to product labeling. In addition, patients with hyperuricemia may be infused intravenously with 3 to 4.5mg of labyrinase, administered 3 to 4 hours prior to the first dose of the drug.

In some embodiments, patients are monitored for TLS during cycle 1, day 1 (C1D1) to C1D3, vital signs, Adverse Events (AEs), and serum chemistry and hematology laboratory studies are evaluated.

Infusion reaction prevention measures

In some embodiments, prior to or concurrently with the treatment regimens of the present invention, the patient may receive an antipyretic and/or antihistamine to reduce the incidence and severity of infusion reactions. In certain embodiments, the antipyretic may be administered by the oral or IV route and may be, for example, acetaminophen (paracetamol), 650 to 1000mg or an equivalent. In certain embodiments, the antihistamine can be administered by the oral or IV route and can be, for example, cetirizine, 10mg or equivalent. In some embodiments, one or both drugs are administered 30 to 60 minutes prior to each immunoconjugate infusion. Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, may be added, or used in place of acetaminophen, 400 to 800mg orally or an equivalent. Corticosteroids, such as prednisolone, 100mg or equivalent, may also be considered as a pre-operative drug.

Antiemetic prophylactic measures

In some embodiments, prior to or concurrently with the treatment regimens of the invention, the patient may receive an antiemetic agent to treat nausea and/or vomiting.

Neutropenia management

In some embodiments, prior to or concurrently with receiving a treatment regimen of the present invention, the patient may receive G-CSF (e.g., filgrastim, fagrastim-SND, PEG-filgrastim or lenograstim) or GM-CSF (e.g., sargrastim) to prevent or alleviate neutropenic complications caused by the drug and to promote recovery of neutrophils.

High Viscous Syndrome (HVS) management

HVS is a clinical feature of 10% to 30% of LPL/WM patients due to the presence of high levels of circulating M protein. Immediate treatment of symptomatic HVS is usually plasmapheresis. In some embodiments, prior to or concurrently with receiving a treatment regimen of the present invention, the patient may receive plasmapheresis to prevent or reduce HVS.

6. Article and kit

The invention also provides an article of manufacture (e.g., a kit) comprising one or more containers (e.g., single-use or multi-use containers) containing a dosage of a pharmaceutical composition of an immunoconjugate described herein, optionally an additional biologically active molecule (e.g., another therapeutic agent), and instructions for use according to a treatment regimen described herein. The immunoconjugate and the additional biologically active molecule may be packaged together or separately in a suitable package, such as a vial or ampoule made of non-reactive glass or plastic. In some embodiments, the vial or ampoule contains a liquid containing the immunoconjugate or a lyophilized powder containing the immunoconjugate; the liquid or lyophilized powder may optionally include additional therapeutic agents or bioactive molecules. In certain embodiments, the vial or ampoule contains a concentrated stock solution (e.g., 2 ×, 5 ×, 10 × or more times) of the immunoconjugate and optionally the biologically active molecule. In particular embodiments, the pharmaceutical compositions of the immunoconjugates described herein (e.g., ADC-a) are packaged in a disposable glass vial (e.g., suitable for use at the dosages described herein, e.g., 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75, or 3.00mg/kg) containing 50mg, 100mg, 150mg, 200mg, 250mg, or 300mg of the immunoconjugate. In certain embodiments, articles of manufacture, such as kits, include medical devices (e.g., syringes and needles) for administering immunoconjugates and/or bioactive molecules; and/or suitable diluents (e.g., sterile water and saline). The invention also includes a method of making the article.

Unless the context requires otherwise, throughout the description and the claims, the word "comprise", and variations such as "comprises" and "comprising", will be interpreted in an open, inclusive sense, i.e., as "including but not limited to". As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally employed in its sense including "and/or" unless the content clearly dictates otherwise. As used herein, the term "about" refers to a range of values to which 10%, 5%, or 1% is added or subtracted from the recited value, in the context of particular usage. Furthermore, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed embodiments.

All publications and patents mentioned herein are incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the constructs and methodologies described in the publications, which might be used in combination with the presently described invention. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or any other reason.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention described herein belongs. Any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the inventions described herein.

Examples

The following examples illustrate representative embodiments of the invention and are not meant to be limiting in any way.

Example 1: synthesis of ADC-A

Conjugation of Ab1 to MC-VC-PAB-MMAE (ADC-a) was performed on multiple scales (2mg to 200g) with similar results. At large scale, about 200g Ab1 (about 40mg/mL in 50mM sodium citrate, 10mg/mL trehalose, 0.05mM EDTA, 0.02% polysorbate 80, pH5.2) was treated with 1.90 equivalents (eq) of tris (2-carboxyethyl) phosphine (TCEP, 5mM) and held at 20-24 ℃ for 330 minutes. Next, 6.5eq of MC-VC-PAB-MMAE in N, N-Dimethylacetamide (DMA) was added and the mixture was held at 22-23 ℃ for an additional 60 minutes. The buffer was exchanged for 10mM sodium acetate, pH4.8 by ultrafiltration/diafiltration (UF/DF) using a 30kD UF membrane cassette. The number of MMAE drug molecules attached per antibody molecule (DAR) was determined using HIC-HPLC. Data from HIC-HPLC, SEC-HPLC, RP-HPLC and UV/Vis are summarized in Table 1 below. Consistent results were obtained at all scales, with DAR averaging 3.89 to 5.09, depending on the method used.

TABLE 1 ADC-A drug-antibody ratio (DAR)

D0: unconjugated antibody.

Example 2: dose escalation study of anti-ROR 1-MMAE immunoconjugates

Described below are protocols for assessing the safety, pharmacokinetics, pharmacodynamics, immunogenicity, and efficacy of RORl immunoconjugates (ADC-a) at a range of dose levels when administered to individuals with previously treated relapsed or refractory CLL/SLL, MCL, FL, MZL, DLBCL, RTL, BL, LPL/WM, T cell NHL, ALL, or AML. ADC-a was administered Intravenously (IV) in repeated 3-week cycles with drug infusion on day 1 of each cycle (Q1/3W [ protocol 1 ]); administered in repeated 3-week cycles with drug infusions on days 1 and 8 of each cycle (Q2/3W [ scheme 2 ]); or in repeated 4-week cycles with drug infusions on days 1, 8 and 15 of each cycle (Q3/4W [ protocol 3]), with a planned infusion time of about 30 minutes. The infusion time can be extended as needed to accommodate the tolerance of each individual to treatment.

TABLE 2 ADC-A dosing regimen

Dosage level

The initial group of subjects will be prescribed as follows: ADC-A, 0.50mg/kgQ 1/3W. Thereafter, groups of subjects will be recruited in sequence to gradually increase the initial dosage level of ADC-A for administration at Q1/3W, Q2/3W or Q3/4W (tables 2 and 3). An initial dose of 0.25mg/kg may be administered in a Q1/3W regimen to allow for dose reduction (when a subject is undergoing TEAE, the dose needs to be adjusted to a level below the initial level).

TABLE 3 ADC-A dose levels

Dose escalation is planned to be accelerated at the initial dose level in a single subject using the Q1/3W regimen. Thereafter, groups of 3 to 6 subjects will be enrolled in turn, evaluating each dosing regimen of ADC-a at progressively higher dose levels using a standard 3+3 dose escalation design. Based on the dose-limiting toxicity (DTL) pattern observed in cycle 1, escalation was performed to define a Maximum Tolerated Dose (MTD) and a Recommended Dosing Regimen (RDR), which may be the MTD or a lower dose within the tolerable dose range, for each administration regimen. MTD is the highest tested dose level, ≧ 6 subjects receive treatment for the highest tested dose level, and the highest tested dose level in ≦ 17% of subjects is associated with cycle 1 dose-limiting toxicity (DLT). The RDR may be the MTD or may be a lower dose within a tolerable dose range. The choice of each RDR will be based on considerations of short-term and long-term safety information as well as available pharmacokinetic, pharmacodynamic and efficacy data, and may be defined in the context of supportive care (e.g., antiemetic or hematopoietic prophylaxis) provided to the subject to achieve the level of RDR. Once each RDR is determined, further development in specific hematologic cancers and/or solid tumors will be considered.

It is expected that administration of ADC-a to a patient according to the provided administration regimen will achieve an Overall Response (OR), defined by disease type, to achieve the following results:

-CLL/SLL: a Complete Response (CR), a complete response with incomplete recovery of blood Counts (CRi), a Partial Response (PR), or a partial response with lymphocytosis (PR-L);

-NHL: CR or PR;

-LPL/WM: CR, Very Good Partial Reaction (VGPR), PR, or Mild Reaction (MR);

-ALL: CR, CRi or unidentified complete response (CRu) (for individuals with mediastinal disease), or PR; and

-AML: CR, CRi, Morphological Leukemia Free Status (MLFS) or PR.

CR (CR) without detectable residual lesions_MRD-) Defined as meeting the criteria of CR in all other individuals in the bone marrow to ≦ 1X 10 malignant cells^-4And (assessed by flow cytometry). It is also expected that ADC-a when provided according to the dosing regimen provided herein will result in improvements in: percent change in tumor size (defined as the percent change from baseline in the sum of the index lesion diameter products (SPD)), Progression Free Survival (PFS) (defined as the time interval from the initiation of study treatment to early time when disease progression/recurrence or death from any cause is first recorded), and Overall Survival (OS) (defined as the time interval from initiation of study treatment to death from any cause) Time interval of death caused).

ADC-a dosing regimens may also result in a change (e.g., an increase or a decrease) in Wnt5a plasma concentration (as assessed by an immunoassay), a change (e.g., an increase or a decrease) in the plasma concentration of circulating RORl (as assessed by an immunoassay), and a change (e.g., an increase or a decrease) in the number or a change (e.g., an increase or a decrease) in the activation state of immune cells, such as circulating B cells, T cells, and Natural Killer (NK) cells.

Patient selection

In this study, patients may be adult patients over 18 years of age; has been diagnosed as CLL/SLL, MCL, FL, MZL, DLBCL, RTL, BL, LPL/WM, T cell NHL, ALL or AML; previously treated, but progressed during or recurred after previous systemic treatment, or are less likely to respond to, or develop resistance to, established therapies known to provide clinical benefit; all previous treatments (including surgery, radiation, chemotherapy, immunotherapy or research treatments) used to treat cancer were completed more than 1 week before study treatment began.

Patients undergoing immunosuppressive therapy other than corticosteroids may be excluded from the treatment. At the start of the study treatment, the subject may be using a systemic corticosteroid (prednisone or equivalent at a dose ≦ 10 mg/day), or a topical, inhaled, or intra-articular corticosteroid. During study treatment, subjects may use systemic, enteric, topical, inhalation, or intra-articular corticosteroids as needed (e.g., for concurrent medical conditions or antiemetic prophylaxis).

Preoperative drug

To prevent Tumor Lysis Syndrome (TLS), 100 to 300mg of allopurinol can be administered orally to a patient every 8 hours starting at ≧ 24 to 48 hours prior to the start of study drug treatment. Alternative drugs (e.g., febuxostat) may be administered instead, following product labeling. Furthermore, subjects with hyperuricemia may receive 3 to 4.5mg of labyrinase by intravenous infusion. Furthermore, high risk subjects may receive an intravenous infusion of labyrinase at 3 to 4.5mg administered 3 to 4 hours prior to the first dose of study drug.

If an infusion response is observed, the subject may be pre-administered with an antipyretic and an antihistamine prior to ADC-A infusion to reduce the incidence and severity of infusion responses. The regimen may be oral or intravenous administration of an antipyretic (acetaminophen [ paracetamol ], 650 to 1000mg or equivalent) and oral or intravenous administration of an antihistamine (cetirizine, 10mg or equivalent), each 30 to 60 minutes prior to each ADC-a infusion. Non-steroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, 400 to 800mg orally or equivalent) may be added or substituted for acetaminophen. If desired, it is contemplated to use a corticosteroid (100mg prednisolone or equivalent) as a pre-operative drug.

Efficacy assessment

Chronic lymphocytic leukemia/small lymphocytic lymphoma

The reaction will be classified as a complete reaction without detectable residual lesions (CR)_MRD-) Complete Response (CR), complete response with incomplete recovery of blood cell Count (CRi), Partial Response (PR), partial response with lymphocytosis (PR-L)), stable disease State (SD), or disease Progression (PD). Furthermore, for the case where there is insufficient information to classify the reaction status, an unevaluable (NE) reaction category is also provided.

The optimal overall response will be determined. The best overall response is the best response recorded from the start of treatment to PD/relapse. The screening measurements will serve as a reference for determining the response. The nadir measurement will be a reference for PD; the nadir measurement constitutes the smallest measurement recorded, and the nadir measurement comprises the screening measurement if the screening measurement is the smallest measurement. Where imaging data is available, such data will replace physical examination data in determining the tumor status.

(1) Complete reaction without detectable residual lesions

To satisfy CR_MRD-Must satisfy all of the following conditions:

● satisfy all criteria for CR

● boneFlow cytometry of medullary puncture showed ≤ 1 × 10 ^-4A malignant cell

(2) Complete reaction

To meet the criteria for CR, all of the following conditions must be met:

● No evidence of New disease

● peripheral blood ALC<4×10⁹/L

● all index nodule lump subsides to normal size with LD less than or equal to 15mm

● Normal spleen and liver size

● all nodular non-index diseases return to normal, all detectable non-nodular, non-index diseases disappear

● morphologically negative bone marrow, which is defined as < 30% of nucleated cells in normal-age bone marrow samples are lymphocytes and no lymphoid nodules

● peripheral blood meets all of the following criteria:

● ANC in the absence of exogenous growth factors 2 weeks before assessment of relevant blood counts>1.5×10⁹/L；

● platelet count with no exogenous growth factor or platelet infusion at 2 weeks or less before assessment of relevant blood count>100×10⁹L; and

● hemoglobin >110g/L (11.0g/dL) with no exogenous growth factor or erythrocyte infusion until 2 weeks before relevant blood count evaluation.

(3) Complete reaction with incomplete recovery of counts

To meet the criteria of CRi, all criteria of CR are met except for the presence of ≧ 1:

●ANC≤1.5×10⁹/L or requires exogenous growth factors to maintain ANC ≧ 1.5X 10 ⁹/L

● platelet count ≤ 100 × 10⁹/L or exogenous growth factor or platelet infusion required to maintain a platelet count of 100X 10 or more before 2 weeks before assessment of relevant blood counts⁹/L

● hemoglobin 110g/L (11.0g/dL) or 2 weeks before relevant cytometry evaluation requires exogenous growth factors or red blood cell infusions to maintain hemoglobin 110g/L (11.0 g/dL).

(4) Partial reaction

To meet the criteria for PR, all of the following conditions must be met:

● No evidence of New disease

● the change in disease status meets ≧ 2 of the following criteria, with the exception that if lymphadenopathy is present at the time of screening, then only lymphadenopathy must be ameliorated to the extent specified below:

● peripheral blood ALC is reduced by more than or equal to 50 percent compared with that in screening

● index the SPD of nodular lesions is reduced by more than or equal to 50 percent compared with that in screening

● in individuals with enlarged spleens at the time of screening, the LVD with enlarged spleens was reduced by more than or equal to 50% (minimum 20mm) or reduced to less than or equal to 120mm as compared to the LVD at the time of screening as measured by imaging

● in individuals with enlarged liver at screening, the LVD of increased liver was reduced by more than or equal to 50% (minimum 20mm) or reduced to less than or equal to 180mm as measured by imaging compared to screening

● CLL/SLL marrow infiltration or B lymph node is reduced by more than or equal to 50% compared with screening

● no index meeting clear PD criteria, worsening of spleen, liver or non-index disease

● the peripheral blood meets the following standard of more than or equal to 1:

● ANC in the absence of exogenous growth factors 2 weeks before assessment of relevant blood counts>1.5×10⁹The increase of/L is more than or equal to 50 percent compared with the increase in screening

● platelet count with no exogenous growth factor or platelet infusion at 2 weeks or less before assessment of relevant blood count>100×10⁹The increase of/L is more than or equal to 50 percent compared with the increase in screening

● hemoglobin >110g/L (11.0g/dL) or increased by > 50% without exogenous growth factor or erythrocyte infusion 2 weeks before assessment of relevant blood counts

(5) Partial response to lymphocytosis

To meet the criteria of PR-L, the following must be met:

● No evidence of New disease

● all standards for PR have been met except that peripheral blood ALC has not been reduced by more than or equal to 50% compared to screening

(6) Stable state of illness

To meet the SD standard, the following conditions must be met:

● No evidence of New disease

● there is neither sufficient evidence that tumor shrinkage corresponds to PR, nor sufficient evidence that tumor growth corresponds to definite PD

(7) Progression of disease

The occurrence of any of the following events indicates unambiguous PD:

● evidence of any new disease:

● to any new nodule with a diameter >15mm

● in individuals with normal splenic LVD at nadir (i.e., LVD measured by imaging ≦ 120mm), splenic LVD measured by imaging > 140mm

● liver LVD > 200mm as measured by imaging in individuals with normal liver LVD at nadir (i.e., LVD ≦ 180mm as measured by imaging)

● New non-index diseases (e.g., effusion, ascites, or other organ abnormalities associated with CLL/SLL)

● evidence of worsening of index lesions, spleen or liver or non-index disease:

● index SPD of focus is increased by more than or equal to 50 percent compared with the lowest point

● Single nodule or extranodal mass, which now has an LD of >15mm, an LPD of >10mm, has an LD increase of > 50% compared to nadir

● in individuals with enlarged spleen (> 120mm) at screening, the increase in enlarged spleen compared to nadir was > 50% (minimum 20mm increase)

● liver enlargement (> 180mm) in individuals with liver enlargement at screening greater than or equal to 50% from nadir (minimum 20mm increase)

● clear increase in size of non-index disease (e.g., effusion, ascites, or other organ abnormalities associated with CLL/SLL)

● transition to more aggressive histology (e.g., RTL) as determined by lymph node biopsy (if the subject does not have an earlier objective record of CLL/SLL progression, the date of lymph node biopsy is considered to be the date of CLL/SLL progression)

● the decrease in platelet count or hemoglobin is caused by CLL/SLL, but not by autoimmune phenomena, as evidenced by a bone marrow biopsy showing clonal CLL/SLL cell infiltration

● the current platelet count is less than or equal to 100X 10⁹/L, decreased by more than or equal to 50% compared with the base line

● Current hemoglobin ≦ 110g/L (11.0g/dL), >20g/L (2g/dL) drop from baseline

Lymphoma (lymphoma)

The reaction will be classified as a complete reaction without detectable residual lesions (CR)_MRD-) Complete Reaction (CR), very good partial reaction (VGPR, LPL/WM only), Partial Reaction (PR), mild reaction (MR; LPL/WM only), Stable Disease (SD) or disease Progression (PD). Furthermore, for the case where there is insufficient information to classify the reaction status, an unevaluable (NE) reaction category is also provided.

The optimal overall response will be determined. The best overall response is the best response recorded from the start of treatment to PD/relapse since screening. The screening measurements will serve as a reference for determining the response. The nadir measurement will be a reference for PD; the nadir measurement constitutes a minimum measurement recorded, the nadir measurement comprising the screening measurement if the screening measurement is the minimum measurement. For FDG-philic tumors, metabolic criteria for response measured by PET-CT will be prioritized over anatomical criteria for response measured by enhanced CT when CR is assessed.

(1) Complete reaction without detectable residual lesions

To satisfy CR_MRD-Must satisfy all of the following conditions:

● satisfy all criteria for CR

● flow of bone marrow punctureFormula cytometry shows ≤ 1 × 10^-4A malignant cell

(2) Complete reaction

To meet the criteria for CR, all of the following conditions must be met:

● No evidence of New disease

● all index nodular lesions subside to LD less than or equal to 15mm

● all nodose non-index diseases subside to less than or equal to 15mm

● disappearance of all detectable extranodal and non-indicative diseases

● Normal spleen size with LVD >130mm was measured by imaging studies

● if PET is performed, there is no evidence of residual disease-i.e., the Deauville 5 subscale scored 1 (no uptake above background), 2 (uptake ≦ mediastinum), or 3 (uptake > mediastinum but ≦ liver)

● bone marrow involvement was determined to be negative by PET (for PET-philic tumors) or by morphological assessment of unilateral core biopsies; if the bone marrow biopsy is morphologically indeterminate, it should be determined to be negative by immunohistochemistry

● serum-free M protein by SIFE (in LPL/WM subjects)

(3) Very good partial reaction (LPL/WM only)

To meet the criteria of VGPR, all of the following conditions must be met:

● satisfy all anatomical criteria for CR

● recorded a decrease in serum M protein concentration of > 90% compared to baseline

(4) Partial reaction

To meet the criteria for PR, all of the following conditions must be met:

● No evidence of New disease

● index the SPD of nodules and extranodal lesions is reduced by more than or equal to 50 percent compared with that in screening

● size of non-index disease is not increased compared to nadir

● in subjects with enlarged spleen at screening, the Longest Vertical Dimension (LVD) of enlarged spleen as measured by imaging decreased by ≥ 50% (minimum 20mm) or to <130mm at screening

● if PET:

● typical FDG-philic lymphomas: if no screening PET scan is performed before treatment or the PET scan is positive, the PET is positive at ≥ 1 previously affected part during treatment, i.e. the Deauville 5 scale score is 4 (moderate intake)>Liver) or 5 points (significant intake)>Liver) but with reduced uptake compared to the screening. If a screening PET is performed and the result is negative, there is no evidence of new PET disease. Uptake reduction was defined as% Δ SUV_maxThe reduction is more than or equal to 25 percent;

● variable FDG-philic lymphoma/FDG affinity is unknown: if a PET scan is not performed before treatment or if lymphoma is negative as determined by a pre-treatment PET scan, the tumor should be assessed using CT criteria during treatment. If PET scanning before treatment is positive, PET in treatment is positive at more than or equal to 1 previous affected part;

● the persistence of bone marrow involvement in individuals meeting the radiological criteria for CR

● serum M protein concentration (in individuals with LPL/WM) decreased by > 50% but < 90% from baseline

(5) Slight reaction (LPL/WM only)

To meet the MR criteria, all of the following conditions must be met:

● meets anatomical disease criteria for PR or SD

● recorded a decrease in serum M protein concentration of > 25% but < 50% from baseline

(6) Stable state of illness

To meet the SD standard, all of the following conditions must be met:

● No evidence of New disease

● tumor shrinkage relative to screening was insufficient to meet PR and evidence of tumor growth was insufficient to meet PD

● if PET was performed, the results showed that the Deauville 5 scale scored 4 (moderate intake > liver) or 5 (significant intake > liver) with no significant change in intake compared to the screen

● serum M protein concentration decreased < 25% and increased < 25% compared to baseline (in subjects with LPL/WM)

(7) Progression of disease

PD is indicated by the occurrence of any of the following events:

● evidence of any new disease not present at the time of screening:

● New nodule with any diameter measurement >15mm

● resolved extranodal lesions (i.e., previously designated PPD as 0 mm) ²) Reappear

● New extranodal focus >10mm

● can be unambiguously attributed to a new non-indicative disease of any size of lymphoma (e.g., effusion, ascites, or other organ abnormalities) (PET, biopsy, cytology, or other non-radiologic confirmation is typically required to confirm the disease attributed to lymphoma).

● novel FDG-philic foci consistent with lymphoma but not other etiologies (e.g., infection or inflammation). If the cause of the new lesion is uncertain, a biopsy or interval scan may be considered.

● if a PET or bone marrow biopsy previously performed as part of the study is negative for lymphoma, new or recurrent lymphoma bone marrow involvement is found by the PET or bone marrow biopsy.

● evidence of lesion degeneration of nodules or extranodal markers:

● index the increase of SPD in focus is more than or equal to 50% compared with the lowest point;

● evidence of single index lymph node or nodal lump deterioration, where PPD of any single node increased by > 50% compared to nadir, if the node now has an LD >15mm, increased by > 50% compared to nadir PPD, with LD or SDi increasing from nadir:

● for the focus with the measurement result less than or equal to 20mm (LD or SDi), the increase is more than or equal to 5mm, or

● for the focus with the measuring result of less than 20mm (LD or SDi), the increase is more than or equal to 10mm

● clear increase in size of non-index disease

● splenic enlargement increased by ≧ 50% compared to nadir (least 20mm increase) in patients with splenic LVD >130mm as measured by imaging at nadir, or splenic LVD >150mm as measured by imaging in patients with splenic LVD ≦ 130mm as measured by imaging at nadir;

● confirmation of transition to more aggressive NHL histology by lymph node biopsy

● if PET is performed, the Deauville 5 scale scores 4 points (moderate intake > liver) or 5 points (significant intake > liver), with increased intake compared to nadir and increased lesion size consistent with PD. Increased uptake is defined as an increase in% Δ SUVax of > 50%

● serum M protein concentration increased by more than or equal to 25% compared to nadir (in individuals with LPL/WM)

Acute lymphatic leukemia

The response was classified as Complete (CR) with no detectable residual lesions_MRD-) Complete Response (CR), complete response with incomplete recovery of blood Counts (CRi) (unconfirmed complete response [ CRu ] is also included in subjects with mediastinal disease]) Partial Response (PR), Stable Disease (SD), Treatment Failure (TF), or disease recurrence or progression (DRP). Furthermore, for the case where there is insufficient information to classify the reaction status, an unevaluable (NE) reaction category is also provided.

The optimal overall response will be determined. The optimal overall response is the optimal in-treatment response compared to baseline from the start of treatment to the DPR recording. The baseline measurement will serve as a reference for determining the response. The nadir measurement will be used as a reference for DPR; the best in-study measurement constitutes the measurement with the least tumor involvement, which includes the baseline measurement if it is the measurement that meets this criterion.

(1) Complete reaction without detectable residual lesions

To satisfy CR_MRD-Must satisfy all of the following conditions:

● satisfy all criteria for CR

● flow cytometry of bone marrow puncture showed ≤ 1 × 10^-4A malignant cell

(2) Complete reaction without detectable residual lesions

To meet the criteria for CR, all of the following conditions must be met:

● leukemia status meets all of the following requirements:

o < 5% bone marrow blasts (based on bone marrow aspiration with ≥ 200 nucleated cells ≥ 5%

Biopsy sample, needle like structure of bone marrow

Lack of primary cells in peripheral blood

Anucleate extramedullary diseases (including lymphadenectasis, splenomegaly, skin/gum infiltration, testicular mass and no central nervous system involvement [ i.e. CNS-1 state is reached { no primitive cells in cerebrospinal fluid } ]);

● peripheral blood meets all of the following requirements:

○ANC≥1.0×10⁹/L

platelet count ≥ 100X 10⁹/L

● any mediastinal enlargement was shown to be completely resolved as recorded by radiology

(3) Complete responses with incomplete recovery of blood counts and/or unidentified complete responses to meet the criteria of CRi/CRu must meet all of the following requirements:

● leukemia status meets all of the following requirements:

o < 5% bone marrow primary cells (bone marrow aspiration/biopsy specimens with ≥ 200 nucleated cells, presence of bone marrow needle-like structure)

Lack of primary cells in peripheral blood

Anucleate extramedullary diseases (including lymphadenectasis, splenomegaly, skin/gum infiltration, testicular mass and no central nervous system involvement [ i.e. CNS-1 state is reached { no primitive cells in cerebrospinal fluid } ]);

● peripheral blood meets all of the following requirements:

○ANC＜1.0×10⁹/L

platelet count less than 100X 10⁹/L

● the sum of the products of the perpendicular diameters (SPD) of any mediastinal enlargement had resolved by 75% or more as recorded by radiology.

(4) Partial reaction

To meet the criteria for PR, all of the following requirements must be met:

● the leukemia state meets one of the following requirements:

bone marrow primary cell reduction ≥ 50%, from 5% -25% (based on bone marrow aspiration/biopsy specimens with ≥ 200 nucleated cells, presence of bone marrow needle-like structure)

Lack of primary cells in peripheral blood

No new or worsening extramedullary disease (including lymphadenectasis, splenomegaly, skin/gum infiltration, testicular mass, and no central nervous system involvement [ e.g., CNS-1 state without primitive cells in cerebrospinal fluid, which has not yet been transformed into CNS-2 state { WBC })<5×10⁹/L, presence of primary cells in cerebrospinal fluid, or CNS-3 status { WBC ≧ 5X 10⁹L, presence of primitive cells in cerebrospinal fluid } or development of facioplegia, brain/eye involvement, or hypothalamic syndrome)

● peripheral blood meets all of the following requirements:

○ANC≥1.0×10⁹/L

i platelet count ≥ 100X 10⁹/L

● any mediastinal enlargement resolved > 50% SPD as recorded by radiology.

(5) Stable disease/failure of treatment

To meet the standard for SD, all of the following conditions must be met:

● ALL is not improved enough from baseline to meet PR requirements, and evidence of ALL deterioration is not enough to meet DRP requirements;

● absence of new or worsening extramedullary disease (including lymphadenectasis, splenomegaly, skin/gum infiltration, testicular mass, and absence of central nervous system involvement [ e.g., CNS-1 state { absence of primitive cells in cerebrospinal fluid } that has not yet transitioned to CNS-2 state { WBC < 5X 109/L, presence of primitive cells in cerebrospinal fluid }, or CNS-3 state { WBC ≧ 5X 109/L, presence of primitive cells in cerebrospinal fluid } or progression to facioplegia, brain/eye involvement, or hypothalamic syndrome)

● no new mediastinal enlargement and no more than 25% increase in SPD with existing mediastinal enlargement.

Failure to CR from study treatment initiation until 18 weeks (for protocol 1 and protocol 2) or 16 weeks (for protocol 3)_MRD-Subjects who were CR, CRi/CRu or PR, and who also did not have a DRP were considered to have TF.

(6) Disease recurrence or progression

The occurrence of any of the following events indicates a DRP:

● bone marrow blasts reappeared in individuals experiencing CR (to > 5%)

● Re-emergence of primary cells from peripheral blood of individuals who have undergone CR

● bone marrow blasts increased by > 25% to > 20% (based on bone marrow aspiration/biopsy specimens with > 200 nucleated cells, presence of bone marrow needles)

● increase of primary cells in peripheral blood by 25% or more>1×10⁹/L

● New extramedullary disease or existing extramedullary disease aggravation (including lymph node enlargement, splenomegaly, skin/gum infiltration, testis lump and no central nervous system involvement [ e.g. CNS-1 state [ without primitive cells in cerebrospinal fluid ] has been converted into CNS-2 state { WBC [)<5×10⁹/L, presence of primary cells in cerebrospinal fluid, or CNS-3 status { WBC ≧ 5X 10⁹L, presence of primitive cells in cerebrospinal fluid } or development of facioplegia, brain/eye involvement, or hypothalamic syndrome)

● the swelling of new mediastinum occurs, or the SPD increase of the swelling of the existing mediastinum is more than or equal to 25%.

Acute myeloid leukemia

The response will be classified as a complete response with no detectable residual lesions (CR)_MRD-) Complete Response (CR), complete response with incomplete recovery of blood cell Count (CRi), morphological leukemia-free state (MLFS), Partial Response (PR), Stable Disease (SD), Treatment Failure (TF), or disease recurrence or progression (DRP). In addition, for situations where there is insufficient information to classify the classification status, an unevaluable (NE) response category is also provided.

The optimal overall response will be determined. The optimal overall response is the optimal in-treatment response compared to baseline from the start of treatment to the DPR or TF record. The baseline state will be used as a reference for determining the response. The measurement results in the best study will be used as reference for DPR; the best in-study measurement constitutes the measurement with the least tumor involvement, which includes the baseline measurement if it is the measurement that meets this criterion.

(1) Complete reaction without detectable residual lesions

To satisfy CR_MRD-Must satisfy all of the following conditions:

● satisfy all criteria for CR

● flow cytometry of bone marrow puncture showed ≤ 1 × 10 ^-4A malignant cell

(2) Complete reaction

To meet the criteria for CR, all of the following conditions must be met:

● leukemia status meets all of the following requirements:

o.i) < 5% bone marrow primary cells (based on bone marrow aspiration/biopsy specimens with ≧ 200 nucleated cells, presence of bone marrow needles)

O ii) absence of primitive cells in peripheral blood

O iii) absence of primary cells and Auer corpuscles

O iv) extramedullary disease

● peripheral blood meets the following two requirements:

○ACN≥1.0×10⁹/L

platelet count ≥ 100X 10⁹/L

(3) Complete reaction of incomplete recovery of blood cell count

To meet the CRi criteria, all of the following conditions must be met:

● leukemia status meets all of the following requirements:

o < 5% bone marrow blasts (based on bone marrow aspiration with ≥ 200 nucleated cells ≥ 5%

Biopsy sample, presence of bone marrow needles)

O peripheral blood without primitive cells

O.cell-free and Auer corpuscle

Anucleate extramedullary disease

● peripheral blood meets the following two requirements:

○ACN≥1.0×10⁹/L

platelet count ≥ 100X 10⁹/L

(4) Morphological non-leukemic state

To meet the MLFS criteria, all of the following conditions must be met:

● leukemia status meets all of the following requirements:

o < 5% bone marrow blasts (based on bone marrow aspiration with ≥ 200 nucleated cells ≥ 5%

Biopsy sample, presence of bone marrow needles)

O peripheral blood without primitive cells

O.cell-free and Auer corpuscle

Anucleate extramedullary disease

● peripheral blood meets the following two requirements:

○ACN＜1.0×10⁹/L；

platelet count < 100X 10⁹/L。

(5) Partial reaction

To meet the criteria for PR, all of the following conditions must be met:

● leukemia status meets one of all the following requirements:

increase in bone marrow primary cells by 50% or more and 5-25% (based on bone marrow aspiration/biopsy specimens with 200 or more nucleated cells, presence of bone marrow needles)

O < 5% bone marrow primary cells but Auer corpuscles present (bone marrow aspiration/biopsy specimens with ≧ 200 nucleated cells, presence of bone marrow needles)

O peripheral blood without primitive cells

non-New or worsening extramedullary disease

● peripheral blood meets the following two requirements:

○ACN≥1.0×10⁹/L；

platelet count ≥ 100X 10⁹/L。

(6) Stable disease/failure of treatment

To meet the standard for SD, all of the following conditions must be met:

● AML is not improved enough compared to baseline to meet CR_MRD-CR, CRi, MLFS or PR, and evidence of AML deterioration is insufficient to meet DRP

● No New or aggravated extramedullary disease

Failure to CR from study treatment initiation until 18 weeks (for protocol 1 and protocol 2) or 16 weeks (for protocol 3) _MRD-Subjects who were CR, CRi/CRu or PR, and who also did not have a DRP were considered to have TF.

(7) Disease recurrence or progression

The occurrence of any of the following events indicates a DRP:

● experience CR_MRD-Bone marrow blasts (to > 5%) reappeared in individuals with CR, CRi or MLFS

● has experienced CR_MRD-Reappearance of primitive cells in peripheral blood of individuals CR, CRi, MLFS or PR

● individuals who have undergone PR had an absolute 20% increase in bone marrow blasts to > 25% (bone marrow needles present based on bone marrow aspirate/biopsy samples with ≧ 200 nucleated cells);

● the absolute increase in primary cells in peripheral blood of individuals who have undergone PR is 20%, up to > 25%;

● new extramedullary disease or worsening of existing extramedullary disease.

Recurrence or exacerbation of MRD assessed by flow cytometry is not taken into account in the definition of DRP, but will be recorded.

Laboratory and other evaluations

The samples to be obtained and the parameters to be analyzed are shown in table 4.

TABLE 4 laboratory parameters to be evaluated and other parameters

Abbreviations: ADA ═ antidrag antibody, ALL ═ acute lymphoblastic leukemia, ALP ═ alkaline phosphatase, ALT ═ alanine aminotransferase, AML ═ acute myeloid leukemia, aPTT ═ activated partial thromboplastin time, AST ═ aspartate aminotransferase, BUN ═ haematurin nitrogen, CCL ═ chemokine (C-C motif) ligand, CD ═ cluster of differentiation, CK ═ creatine kinase, CLL ═ chronic lymphocytic leukemia, CT ═ computed tomography, CXCL ═ chemokine (C-X-C motif) ligand, DAR ═ drug-antibody ratio, DLBCL ═ diffuse large B cell lymphoma, DNA ═ deoxyribonucleic acid, ECG ═ electrocardiogram, FDG ═ fluorodeoxyglucose, FISH ═ fluorescent in situ hybridization, HBc ═ anti-core antibody, HBsAg ═ anti-hepatitis B virus, HIV-surface antigen, HIV hepatitis B virus, hepatitis B virus antigen, hepatitis B virus in situ hepatitis B virus, IFN γ ═ γ interferon, IL ═ interleukins, LDH ═ lactate dehydrogenase, LPL/WM ═ lymphoplasmacytoid lymphoma/waldenstrom macroglobulinemia, M protein ═ monoclonal immunoglobulin M protein, MMAE ═ monomethyl auristatin E, MRD ═ detectable residual disease, MRI ═ magnetic resonance imaging, NGS ═ next generation sequencing, NK ═ natural killer (cell), PET ═ positron emission tomography, PCR ═ polymerase chain reaction, PT ═ prothrombin time, RNA ═ ribonucleic acid, ROR1 ═ receptor tyrosine kinase-like orphan receptor 1, SIFE ═ serum immunosuppresion, SPEP ═ serum protein electrophoresis, TNF α ═ tumor necrosis factor, β -HCG ═ β -human chorionic gonadotropin

Adverse event severity ratings as used herein are described in table 5 below

Results

I. Security

Data has been obtained from 25 subjects with hematological malignancies, including 12 subjects with MCL, 7 subjects with CLL/SLL, 2 subjects with DLBCL, 2 subjects with FL, 1 subject with MZL, and 1 subject with RTL. Subjects received an over-pretreatment (median (range) of 4(1-23) previous systemic chemotherapy regimens) including Hematopoietic Stem Cell Transplantation (HSCT) treatment in 4 subjects, Chimeric Antigen Receptor (CAR) -T cell or natural killer cell (NK) treatment in 3 subjects.

96 doses of ADC-A were administered, including 1 dose at a 0.5mg/kg dose level, 9 doses at a 1.0mg/kg dose level, 18 doses at a 1.5mg/kg dose level, 46 doses at a 2.25mg/kg dose level, and 22 doses at a 2.5mg/kg dose level. The number of cycles of treatment received is from 1 to 10. All subjects received ADC-A following the Q1/3W dosing regimen (Table 2).

ADC-a treatment is generally well tolerated and neutropenia is the major acute toxicity. No DLT was observed at doses of 0.5, 1.0 and 1.5 mg/kg. At ADC-A2.25 mg/kg, 1 of 7 subjects in C1 exhibited grade 4 neutropenic DLT. Furthermore, 1 subject receiving 2.25mg/kg of ADC-A experienced grade 3 neutropenia in C1, while 1 subject receiving 2.25mg/kg of ADC-A experienced grade 4 neutropenia in C2. In each of these 3 cases, neutropenia was observed at approximately day 15 of the cycle. Neutropenia is responsive to granulocyte colony stimulating factor (G-CSF) administered postcognitively or as a secondary prophylactic measure. Reduced neutrophil fever or infection did not occur. Subjects who started with ADC-a 2.5mg/kg experienced grade 4 thrombocytopenia in C1; however, the subject had a history of thrombocytopenia, including grade 2 thrombocytopenia at baseline, her post-baseline platelet abnormalities were not clearly drug related, and she continued to receive treatment with C2 and C3 at 2.5mg/kg ADC-A.

One subject had grade 2 neuropathy after 5 cycles of ADC-a 2.25mg/kg dosing; treatment was delayed for 1 cycle and treatment was resumed at a dose of 1.5 mg/kg. Other adverse events, laboratory abnormalities and low ecg results appear to be dose or exposure independent and may be caused by underlying cancer, complications or concomitant medications. No infusion reactions or tumor lysis syndromes were observed.

Pharmacokinetics

The plasma concentrations of total ADC-A and MMAE in 16 patients administered ADC-A as a function of time are shown in FIG. 1. Mean T occurs shortly after the end of ADC infusion (0.5 to 2 hours from the start of 30 min IV infusion) and 48 to 89 hours after MMAE administration_max. The corresponding Pharmacokinetic (PK) parameters are shown in table 6.

TABLE 6 ADC-A pharmacokinetic parameters

a AUC of Total ADC_lastDivided by AUC of total antibody_last

Abbreviations: ADC ═ antibody-drug conjugate, AUC_lastArea under the concentration-time curve until the last detectable concentration, CL ═ clearance, C_maxMaximum concentration, MMAE monomethylauristatin E, SD standard deviation, t_1/2Half-life, T_maxTime to reach maximum concentration, V_zVolume of distribution

For ADC-A, C_maxAnd increase in AUC is generally dose-proportional, whereas for MMAE, C _maxAnd increase in AUC was somewhat dose-independent. Average t of ADC-A_1/2Values ranged from 2.1 to 3.O days, independent of the dose administered.

Pharmacodynamic data from subjects with CLL showed that ADC-a occupancy of ROR1 receptor in circulating CLL cells was concentration and time dependent (figure 2). Cells were isolated by Ficoll, stained with LIVE/Dead reagent, and then stained with CD19, CD5, UC961-PE, and 4A5AlexaFluor 647. At ADC-A doses of 1.0 and 2.25mg/kg, respectively, only 22.7% and 12.8% of the ROR1 receptors were unoccupied at the end of the 30 minute IV infusion. Unoccupied receptors showed time-dependent regression towards baseline, which corresponds to a simultaneous decrease in ADC-a plasma concentration. At the 2.25mg/kg dose level, the target coverage appeared to decrease at day 8 and disappear at day 15, consistent with a decrease in plasma ADC exposure.

The correlation of unoccupied ROR1 receptor with ADC-a plasma concentration as shown in figure 1 enables the establishment of target plasma concentration values. A plasma concentration of ADC-A of 1.7. mu.g/mL was required to maintain 50% receptor occupancy (50% of the unoccupied receptors). A plasma concentration of 5.8. mu.g/mL ADC-A was required to maintain 75% receptor occupancy (25% of unoccupied receptors). A plasma concentration of ADC-A of 35. mu.g/mL was required to maintain 90% receptor occupancy (10% of the unoccupied receptors).

Pharmacokinetic simulations were performed to further explore potential ADC-a dosing regimens. Simulations indicate that administration of ADC-a once a week may be more effective than once every three weeks (fig. 4 and table 7). The once weekly dosing regimen may provide more continuous ADC-a exposure and ROR1 target occupancy while allowing bone marrow recovery prior to the next treatment cycle, and may be useful for subsequent induction regimens (e.g., Q2/3W or Q3/4W) of maintenance regimens (e.g., Q1/3W) with less frequent drug use.

TABLE 7.12 maintenance of ROR1 occupancy within weeks

Anti-tumor response

After treatment with ADC-a using the Q1/3W dosing regimen, anti-tumor activity was observed in subjects with MCL (including three partial responses) and DLBCL (including one partial response) who had been over-pretreated (fig. 5).

One subject with MCL showed extensive pre-existing disease with lesions in the palate, neck, chest, abdomen and pelvis. The subject had previously been receiving over-treatment: R-hyper-CVAD and R/methotrexate/cytarabine, rituximab, ibrutinib, daratumab, lenalidomide-rituximab and radiation. Subjects showed evidence of objective tumor response to 2.25mg/kg ADC-a treatment over three cycles. All the nodule groups measured showed a reduction in tumor size with a 53% reduction in SPD (sum of perpendicular diameter products). In addition, the size and tissue infiltration of palatal lesions are also reduced. The magnitude of the response appears to correspond to the Partial Response (PR). The subject did not show any signs of hematologic or non-hematologic toxicity associated with the drug.

Another subject with MCL showed a palate mass and extranodal disease and had received excessive prior treatment: rituximab, rituximab/bortezomib, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone), BR (bendamustine and rituximab), R-hyper-CVAD and intrathecal precautions, ibrutinib and mosuetuzumab. Subjects showed evidence of objective tumor response to 2.5mg/kg ADC-a treatment over three cycles. The subject reported that his activity increased and fatigue was substantially resolved; furthermore, the size of the palatal lesion was reduced by 85%. The magnitude of the response appears to correspond to the Partial Response (PR).

Another subject with MCL showed orbital and extranodal disease and had previously received overtreatment: R-CHOP, rituximab, ibrutinib-rituximab and rituximab-BEAM (carmustine, cytarabine, etoposide and melphalan). Subjects showed evidence of an objective tumor response to 2.5mg/kg ADC-a treatment over six cycles with 51% reduction in SPD of tumor lesions. The magnitude of the response appears to correspond to the Partial Response (PR).

One subject with DLBCL exhibited extranodal disease and had received excessive prior treatment: R-CHOP, R-ESHAP (rituximab, etoposide, methylprednisolone, cytarabine and cisplatin), R-GEMOX (rituximab, gemcitabine and oxaliplatin), BEAM plus autograft, pinatuzumab-rituximab, bendamustine-rituximab and CAR-T cells are opsonized with fludarabine. Subjects showed evidence of objective tumor response to six cycles of ADC-A treatment (cycle 12.25 mg/kg, cycle 2 dose reduction, cycle 3-52.25 mg/kg, cycle 6-72.5 mg/kg). Both measured nodule groups showed a reduction in tumor size and a 68% reduction in SPD. The magnitude of the response appears to correspond to the Partial Response (PR).

While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention.

The amino acid sequences described herein are shown in table 8 below.

TABLE 8 sequence listing

*SEQ：SEQ ID NO。