JP-7855247-B2 - Pharmaceutical compositions for treating tumors

Inventors

• 朱▲シン▼懋
• 游▲約▼翔
• 田偉廷
• 張子文
• 林韋辰
• 程識軒

Assignees

• イミュンワーク インク．

Dates

Publication Date

20260508

Application Date

20240411

Priority Date

20230413

Claims (12)

1. A pharmaceutical composition for treating a tumor, comprising a molecular construct comprising an anti-CD38 antibody, a plurality of lenalidomide molecules or hydrolyzed lenalidomide molecules bound to the anti-CD38 antibody, and a linker unit , The aforementioned anti-CD38 antibody is A pair of CH2-CH3 segments of IgG, A pair of anti-CD38scFv is bonded to the N-terminuses of the pair of CH2-CH3 segments, A pair of binding peptides each attached to the C-terminus of the pair of CH2-CH3 segments, comprising a pair of binding peptides having a plurality of C residues, Equipped with, Each of the pair of binding peptides comprises the amino acid sequence "CGGHA" (SEQ ID NO: 1), "CPGHA" (SEQ ID NO: 2), "CGAHA" (SEQ ID NO: 3), "CPAHA" (SEQ ID NO: 4), "GCGGHA" (SEQ ID NO: 5), "ACPGHA" (SEQ ID NO: 6), or "GCPGHA" (SEQ ID NO: 7). Each of the plurality of lenalidomide molecules or hydrolyzed lenalidomide molecules is bound to the plurality of C residues of the pair of binding peptides. The aforementioned linker unit is A central core that is linear, 2 to 10 K residues, At least one filler independently positioned between two K residues, A terminal spacer having two ends, wherein one end is bound to the N-terminus of the first K residue or the C-terminus of the last K residue, and the other end is bound to the C residue of the binding peptide of the anti-CD38 antibody, Equipped with, Each of the filler and the terminal spacer independently comprises a central core having (1) 1 to 12 non-K amino acid residues or (2) PEGylated amino acids having 1 to 12 repeats of ethylene glycol (EG) units, A binding arm comprising 2 to 10 binding arms, wherein one end of each binding arm is bound to one of the K residues of the central core, and the other end of each binding arm is bound to each lenalidomide molecule or hydrolyzed lenalidomide molecule, Equipped with, The pharmaceutical composition is administered in an amount of about 0.1 to 10 mg/kg, wherein the administration of the pharmaceutical composition provides an effective amount of the lenalidomide molecule or the hydrolyzed lenalidomide molecule that is at least 1/1000th of the effective amount of the lenalidomide molecule used alone or in combination with the anti-CD38 antibody for the treatment of the tumor.
2. The pharmaceutical composition according to claim 1, wherein the effective amount of the lenalidomide molecule or the hydrolyzed lenalidomide molecule is about 1/10,000th of the effective amount of the lenalidomide molecule used alone or in combination with the anti-CD38 antibody for the treatment of the tumor.
3. The pharmaceutical composition described above is administered once every four weeks, as described in claim 1.
4. The pharmaceutical composition according to claim 1 , wherein each of the pair of binding peptides comprises the amino acid sequence "ACPGHA" (SEQ ID NO: 6).
5. The pharmaceutical composition according to claim 1 , wherein the terminal spacer comprises at least three negatively charged amino acid residues.
6. The pharmaceutical composition according to claim 5 , wherein the terminal spacer comprises the amino acid sequence "EDEDEAGG" (SEQ ID NO: 8), "EGEGEAGG" (SEQ ID NO: 9), or "EGEG" (SEQ ID NO: 10).
7. The pharmaceutical composition according to claim 6 , wherein the central core comprises the amino acid sequence "EDEDEGAGGGKGAGKGAGKG" (SEQ ID NO: 11).
8. The pharmaceutical composition according to claim 1 , wherein each of the binding arms comprises a polyethylene glycol (PEG) chain having 2 to 12 non-K amino acid residues, 2 to 24 repeats of an EG unit, or a combination thereof.
9. The pharmaceutical composition according to claim 1 , wherein each of the binding arms is bonded to the ε-amino group of the K residue.
10. The pharmaceutical composition according to claim 1, wherein the tumor is a solid tumor or a diffuse tumor.
11. The pharmaceutical composition according to claim 10, wherein the solid tumor is melanoma, esophageal cancer, gastric cancer, brain tumor, small cell lung cancer, non - small cell lung cancer, bladder cancer, breast cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, kidney cancer, hepatocellular carcinoma, ovarian cancer, prostate cancer, thyroid cancer, testicular cancer, or head and neck squamous cell carcinoma.
12. The pharmaceutical composition according to claim 10, wherein the diffuse tumor is acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), Hodgkin lymphoma, non-Hodgkin lymphoma, or multiple myeloma.

Description

Cross-reference of related applications: This application relates to and claims the interests of U.S. Provisional Patent Application No. 63/459249, filed on 13 April 2023, the contents of which this application is incorporated herein by reference in whole. This disclosure relates, in general, to the field of tumor treatment. More specifically, this disclosure relates to a method of treating tumors by using an anti-CD38 antibody and a molecular construct comprising multiple lenalidomide molecules or hydrolyzed lenalidomide molecules. Multiple myeloma (MM), also known as myeloma or plasma cell myeloma, is a type of bone marrow cancer in which cancerous plasma cells accumulate in the bone marrow, displacing normal blood cells and resulting in excessive monoclonal paraproteins (M proteins; abnormal antibodies), bone destruction, and replacement of other hematopoietic cell lines. Because cancerous plasma cells affect various parts of the body, the symptoms and signs of multiple myeloma vary greatly from patient to patient. Common symptoms and signs associated with multiple myeloma include bone pain, fractures, spinal cord compression, anemia, recurrent infections, hypercalcemia, abnormal bleeding, blood viscosity, fatigue, renal impairment, and neurological disorders. The RVd regimen, namely the combination of bortezomib (VELCADE®), lenalidomide (Revlimid®), and dexamethasone, is often used as a first-line treatment for multiple myeloma. Reports indicate that over 90% of myeloma patients respond well to this treatment. However, this treatment merely reduces the number of cancerous cells in the patient's bone marrow, thereby alleviating the symptoms of multiple myeloma; it does not cure the underlying disease. Furthermore, high doses of lenalidomide or other drugs in the combination regimen usually cause serious adverse effects (e.g., bleeding, dyspnea or labored breathing, thromboembolism, neutropenia, thrombocytopenia, fever, seizures, arrhythmias, speech and motor problems, and confusion). Since most multiple myeloma patients are elderly (50-70 years old), severe side effects are a concern. In light of the above, there is a need for novel methods for treating multiple myeloma in related technologies. The following provides a simplified overview of this disclosure to the reader for basic understanding. This overview is not a comprehensive overview of this disclosure, nor does it identify the main/essential elements of the invention, nor does it define the scope of the invention. Its sole purpose is to present some of the concepts disclosed herein in a simplified form as an introduction to the more detailed explanation that will follow. As concretely and extensively described herein, one aspect of this disclosure is directed to a method for treating a tumor in a subject. This method involves administering to a subject a molecular construct comprising an anti-CD38 antibody and a plurality of lenalidomide molecules or hydrolyzed lenalidomide molecules conjugated to the anti-CD38 antibody. According to certain embodiments of this disclosure, administration of a molecular construct delivers an effective amount of lenalidomide or hydrolyzed lenalidomide at least 1/1000th of the effective amount of lenalidomide used alone or in combination with an anti-CD38 antibody for the treatment of tumors. In certain preferred embodiments, the effective amount of lenalidomide or hydrolyzed lenalidomide is about 1/10,000th of the effective amount of lenalidomide used alone or in combination with an anti-CD38 antibody for the treatment of tumors. Preferably, the molecular construct is administered to the subject at a dose of approximately 0.01 to 100 mg/kg body weight per dose; more preferably, at approximately 0.1 to 10 mg/kg body weight per dose. According to some preferred embodiments, the molecular construct is administered to the subject once every four weeks. According to certain embodiments, the anti-CD38 antibody comprises a pair of CH2-CH3 segments of immunoglobulin G (IgG) and a pair of anti-CD38 single-strand variable fragments (scFv) conjugated to the N-terminuses of the pair of CH2-CH3 segments, respectively. In these embodiments, the pair of CH2-CH3 segments comprises a plurality of binding residues independently selected from the group consisting of lysine (K) residues and cysteine (C) residues, and a plurality of lenalidomide molecules or hydrolyzed lenalidomide molecules are conjugated to the plurality of binding residues, respectively. According to alternative embodiments, the anti-CD38 antibody comprises a pair of CH2-CH3 segments of IgG, a pair of anti-CD38scFv bound to the N-terminuses of the pair of CH2-CH3 segments, and a pair of binding peptides bound to the C-terminuses of the pair of CH2-CH3 segments. In these embodiments, each pair of binding peptides comprises multiple C residues and multiple lenalidomide molecules or hydrolyzed lenalidomide molecules bound to multiple C residues of each pair of binding