Cancer treatment with ror1 antibody immunoconjugates

Abstract

This article provides a method for treating cancer patients using immune conjugates, which comprise an anti-ROR1 antibody or its antigen-binding fragment and a pharmaceutical portion.

Description

[Previous Technology] Hematologic malignancies include diseases resulting from transformation events occurring in the immune or hematopoietic organs. Lymphomas arise from the accumulation of monoclonal tumor-like lymphocytes in lymph nodes and organs such as the blood, bone marrow, spleen, and liver. Variants of these cancers include non-Hodgkin 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), Richter transformation lymphoma (RTL), Burkitt lymphoma (BL), lymphoplasmacytic lymphoma (LPL), Waldenström macroglobulinemia (WM), acute lymphoblastic leukemia (ALL), and several types of T-cell lymphoma. Acute myeloid leukemia (AML) is caused by the accumulation of tumor-like myeloblastic cells in the bone marrow, blood, central nervous system, and other organs. Partly depending on the originating cells (B cells or T cells), NHL patients may experience disabling systemic symptoms, lymphadenopathy, and organ hypertrophy that can lead to life-threatening organ dysfunction, myelosuppression, and immunodeficiency that makes patients susceptible to infection and bleeding, and / or painful, intense itching, and disfiguring skin manifestations. LPL / WM patients overproduce immunoglobulin (IgM)-producing plasma cells, and due to the presence of this circulating monoclonal IgM protein (M-protein), they may exhibit excessively viscous plasma. In ALL or AML patients, the amplified selection of leukemic germ cells leading to dysfunction of normal bone marrow makes them susceptible to life-threatening infections and bleeding. Treatment for these diseases aims to induce tumor regression, slow tumor progression, control disease-related complications, and prolong life. Patients are typically given chemotherapy and / or immunotherapy agents. First-line therapy can provide long-term remission. However, many patients eventually experience disease relapse; further follow-up therapies are used to attempt to control disease presentation. Despite the use of agents with different mechanisms of action, progressive tumor resistance often occurs. Patients with multiple relapsing progressive diseases have a poor prognosis and may die from these cancers. Therefore, novel mechanisms of action are needed to safely provide new treatment options to patients with hematologic malignancies resistant to existing therapies. The orphan receptor 1 (ROR1), a tyrosine kinase-like receptor, is a cell surface protein that regulates signaling from its ligand, the secreted glycoprotein Wnt5a. Consistent with ROR1's role in influencing stem cell fate during embryogenesis, ROR1 expression is observed in aggressive malignancies that revert to embryonic transcriptional programs, but not in normal adult tissues. Therefore, ROR1 provides a favorable profile for therapeutic targeting. ROR1 is commonly found on malignant cells in patients with hematologic malignancies and is also present on the cell surface of various solid tumors, where it appears to be a marker for cancer stem cells. Given the unmet medical needs of many patients with hematologic malignancies and other cancers, and the role of ROR1 in cancer, there is a need for novel therapies that can improve patient outcomes by targeting ROR1, including patients who do not respond to existing therapies. [Summary of the Invention] This invention relates to a method for treating cancer patients using an immune conjugate having the structure shown below: [Figure] (Formula I) wherein the Ab is an antibody that specifically binds to the human receptor tyrosine kinase-like orphan receptor 1 (ROR1), wherein the heavy chain and light chain of the antibody comprise the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 2, respectively; and wherein the immune conjugate is administered to the patient at a dose of 0.25 to 4.00 mg / kg. As used herein, Formula I above is not intended to represent that each Ab can bind to only one replica of the drug moiety shown in the formula. In some embodiments, the number or replicas (DAR) of the drug moiety of each antibody is in the range of 1 to 7, wherein each drug moiety is bound to the antibody via a linker as shown in Formula I. In some embodiments, an immune conjugate is administered (e.g., intravenously) according to the dosing regimen described herein. For example, the immune conjugate may be 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 a particular embodiment, the immune conjugate may be administered over repeated three-week cycles (e.g., on day 1 or day 1 and day 8 of each cycle). In a particular embodiment, the immune conjugate may be administered over repeated four-week cycles (e.g., on day 1, day 8, and day 15 of each cycle). In some embodiments, the total number of cycles may be 3, 6, or more. In a particular embodiment, the immune conjugate may be administered as follows: weekly for the first three, four, six, or eight weeks, and then every three weeks thereafter; or once every three weeks for the first three, six, or nine weeks, and then weekly. In some embodiments, the immune conjugate is administered to a patient with a blood cancer such as lymphoma. In a particular embodiment, the cancer is selected from the group consisting of: CLL, SLL, MCL, FL, MZL, DLBCL, RTL, BL, LPL, WM, T-cell NHL, ALL, and AML. In a particular embodiment, the patient has previously received cancer treatment and / or has relapsed or refractory cancer (e.g., one or more existing cancer treatments, such as all existing treatments). In some embodiments, treatment with immune conjugates can induce tumor regression (e.g., cause complete tumor eradication); slow tumor progression; inhibit cancer metastasis; prevent cancer recurrence or residual disease; reduce the size of nodules or extranodal masses; reduce the number of malignant cells in the bone marrow and peripheral blood; reduce malignant splenomegaly or hepatomegaly; improve cancer-related anemia, neutropenia, or thrombocytopenia; improve skin appearance; reduce the likelihood of excessive viscosity symptoms in LPL / WM patients; improve disabling systemic symptoms; and / or prolong survival. This disclosure also provides an immune binder for use in the methods described herein to treat cancer in patients. Furthermore, this disclosure provides the use of the immune binder in the manufacture of a medicament for use in the treatment of cancer in patients using the methods described herein.

Implementation Method

Claims

1. Use of an immune conjugate for the preparation of a pharmaceutical product for the treatment of diffuse large B-cell lymphoma (DLBCL) or mantle cell lymphoma (MCL) in patients, wherein the immune conjugate is represented by formula (I) and comprises an antibody bound to a linker / load, (I) wherein: The Ab is an antibody that binds to ROR1, comprising: (i) a heavy chain variable region comprising: HCDR1 containing the amino acid sequence of SEQ ID NO: 5; HCDR2 containing the amino acid sequence of SEQ ID NO: 6; and HCDR3 containing the amino acid sequence of SEQ ID NO: 7; and (ii) a light chain variable region comprising: LCDR1 containing the amino acid sequence of SEQ ID NO: 8; LCDR2 containing the amino acid sequence of SEQ ID NO: 9; and LCDR3 containing the amino acid sequence of SEQ ID NO: 10; the linker / load has the following structure: wherein the number of the linker / load per antibody is 3 to 5, and the pharmaceutical product is intended to be administered to the patient at a dose of 1.50 to 4.00 mg / kg of the immunoconjugate; and wherein the patient has previously been treated for diffuse large B-cell lymphoma (DLBCL) or mantle cell lymphoma (MCL); and wherein: (i) The pharmaceutical product is intended to be administered in a three-week cycle, and on day 1 of each cycle; (ii) the pharmaceutical product is intended to be administered in a three-week cycle, and on day 1 and day 8 of each cycle at the dose; or (iii) the pharmaceutical product is intended to be administered in a four-week cycle, and on day 1, day 8 and day 15 of each cycle at the dose.

2. As claimed in claim 1, wherein the dose is 2.00, 2.25, 2.50 or 2.75 mg / kg.

3. As requested in claim 1, wherein the pharmaceutical product is intended to be administered on a three-week cycle, and is administered on the first day of each cycle.

4. As claimed in claim 1, wherein the medicine is to be administered in a three-week cycle, and is administered at the dose on day 1 and day 8 of each cycle.

5. As claimed in claim 1, wherein the medicine is to be administered in a four-week cycle, and is administered at the dose on day 1, day 8 and day 15 of each cycle.

6. As requested in any of items 1 to 5, wherein the number of cycles is 3 or more.

7. The use of any of the claims 1 to 5, wherein the medicine is intended for intravenous administration.

8. The use as claimed in any of claims 1 to 5, wherein the pharmaceutical product is for the treatment of diffuse large B-cell lymphoma (DLBCL).

9. The use of any of claims 1 to 5, wherein the DLBCL or MCL is relapsed or refractory.

10. For any of the uses described in claims 1 to 5, where treatment with the use of the pharmaceutical product results in one or more of the following: a) inducing tumor regression; b) delaying tumor progression; c) inhibiting cancer metastasis; d) preventing cancer recurrence or residual disease; e) reducing the size of nodules or extranodular masses; f) reducing the number of malignant cells in the bone marrow and peripheral blood; g) reducing malignant splenomegaly or hepatomegaly; h) improving cancer-related anemia, neutropenia, or thrombocytopenia; i) improving skin appearance; j) reducing the likelihood of hyperviscosity syndrome in LPL / WM patients; k) reducing disabling systemic symptoms; and l) prolonging survival.

11. For any of the uses in claims 1 to 5, wherein treatment with the use of the medicine results in the complete eradication of the tumor.

12. Use of a pharmaceutical composition for the preparation of a pharmaceutical product for the treatment of diffuse large B-cell lymphoma (DLBCL) or mantle cell lymphoma (MCL) in patients, wherein the pharmaceutical composition comprises one or more immune conjugates represented by formula (I), which comprises an antibody bound to a linker / load, (I) wherein: The Ab is an antibody that binds to ROR1, comprising: (i) a heavy chain variable region comprising: HCDR1 containing the amino acid sequence of SEQ ID NO: 5; HCDR2 containing the amino acid sequence of SEQ ID NO: 6; and HCDR3 containing the amino acid sequence of SEQ ID NO: 7; and (ii) a light chain variable region comprising: LCDR1 containing the amino acid sequence of SEQ ID NO: 8; LCDR2 containing the amino acid sequence of SEQ ID NO: 9; and LCDR3 containing the amino acid sequence of SEQ ID NO: 10; the linker / load has the following structure: wherein the number of the linker / load per antibody is 3 to 5; wherein the average number of linkers / loads linked to each antibody by all immunoconjugates in the composition is about 1 to about 7; and the pharmaceutical product is used at a concentration of 1.50 to 4.

00. The patient is given a dose of the immunoconjugate at a dose of mg / kg; and the patient has previously been treated for diffuse large B-cell lymphoma (DLBCL) or mantle cell lymphoma (MCL); and wherein: (i) the medicine is administered in a three-week cycle, and is administered on day 1 of each cycle; (ii) the medicine is administered in a three-week cycle, and is administered at the dose on day 1 and day 8 of each cycle; or (iii) the medicine is administered in a four-week cycle, and is administered at the dose on day 1, day 8 and day 15 of each cycle.

13. As claimed in claim 12, wherein the dose of the immunoconjugate in the pharmaceutical composition is 2.00, 2.25, 2.50 or 2.75 mg / kg.

14. As claimed in claim 13, wherein the dose is 2.25 or 2.50 mg / kg.

15. As requested in claim 12, wherein the pharmaceutical product is to be administered on a three-week cycle, and is administered on the first day of each cycle.

16. As claimed in claim 12, wherein the pharmaceutical product is to be administered in a three-week cycle, and is administered at the dose on day 1 and day 8 of each cycle.

17. As claimed in claim 12, wherein the medicine is to be administered in a four-week cycle, and is administered at the dose on day 1, day 8 and day 15 of each cycle.

18. As claimed in claim 12, wherein the medicine is intended for intravenous administration.

19. As claimed in claim 12, wherein the pharmaceutical product is used to treat diffuse large B-cell lymphoma (DLBCL).

Images