CN-122005838-A - CD 38-targeted antibody-drug conjugate and preparation method and application thereof

Abstract

The invention relates to the field of biopharmaceuticals, in particular to a CD 38-targeted antibody-drug conjugate, a preparation method and application thereof. The invention provides that the drug in the antibody-drug conjugate is a NAMPT inhibitor. The invention is based on the technology of a bisethylenesulfonamide linker and the antibody specifically targeting CD38 synthesizes an antibody-drug conjugate targeting CD38, wherein a payload NAMPT inhibitor is combined with the targeting CD38 antibody, so that ADCs with higher in-vivo and in-vitro biological activity can be generated.

Inventors

• JIANG BIAO
• CHEN HONGLI
• YIN QIANQIAN

Assignees

• 上海科技大学

Dates

Publication Date

20260512

Application Date

20241111

Claims (10)

1. 1. A CD 38-targeting antibody-drug conjugate, wherein the antibody-drug conjugate is a compound comprising formula I: In formula I, anti-CD38 represents an antibody targeting CD38, L represents a linker for linking the antibody and the NAMPT inhibitor, D represents the NAMPT inhibitor, n represents the molecular weight ratio of NAMPT inhibitor-antibody, and n is 1-20.
2. 2. The antibody-drug conjugate of claim 1, wherein the linker in the antibody-drug conjugate has any one of the following chemical structures:
3. 3. The antibody-drug conjugate of claim 1, wherein the antibody in the antibody-drug conjugate is selected from one or more of up to Lei Tuoyou mab, ai Shatuo mab, TJ202/MOR202, SG301 or HLX15, preferably the antibody is up to Lei Tuoyou mab.
4. 4. The antibody-drug conjugate of claim 1, wherein the NAMPT inhibitor in the antibody-drug conjugate is selected from one or more of FK866, KPT-9274, MBX-2982, or GMX 1777.
5. 5. The antibody-drug conjugate of claim 1, wherein the antibody-drug conjugate is a compound represented by formula A1 or A2, or a pharmaceutically acceptable salt thereof:
6. 6. A CD 38-targeting antibody-drug conjugate, wherein the antibody-drug conjugate is a compound comprising the formula A3:
7. 7. a method of preparing an antibody-drug conjugate according to any one of claims 1-6, comprising the steps of: a1 Reacting the compound 1 with thionyl chloride, and condensing the obtained compound with m-aminobenzoic acid to obtain a compound 2: a2 Compound 2, compound 3 are reacted in solution to give compound 4: a3 Compound 4, compound 5 are reacted in solution to give compound 6: a4 Carrying out a first shaking reaction on the antibody solution and the tris (2-carboxyethyl) phosphine solution, then adding the compound 6 solution for a second shaking reaction, and removing the small molecular compound to obtain an antibody-drug conjugate A1: or, the preparation method comprises the following steps: b1 Compound 7 and 4-nitrophenyl chloroformate in solution to give compound 8: b2 Compound 3, compound 8 are reacted in solution to give compound 9: b3 Compound 9, compound 5 are reacted in solution to give compound 10: b4 Carrying out a first shaking reaction on the antibody solution and the tris (2-carboxyethyl) phosphine solution, then adding the compound 10 solution for a second shaking reaction, and removing the small molecular compound to obtain an antibody-drug conjugate A2: or, the preparation method comprises the following steps: c1 Carrying out a first shaking reaction on the antibody solution and the tris (2-carboxyethyl) phosphine solution, then adding the compound 11 solution for a second shaking reaction, and removing the small molecular compound to obtain an antibody-drug conjugate A3:
8. 8. Use of an antibody-drug conjugate according to any one of claims 1-6 in the manufacture of a medicament for the treatment of a tumor.
9. 9. The use according to claim 8, wherein the tumour is selected from one or more of hematological cancer, skin cancer, head and neck cancer, lung cancer, liver cancer, stomach cancer, prostate cancer, oesophageal cancer, cervical cancer, uterine cancer, pancreatic cancer, breast cancer, kidney cancer, ureteral cancer, bladder cancer, pharyngeal squamous cell carcinoma, basal cell carcinoma, melanoma, tongue cancer, pharyngeal squamous cell carcinoma, malignant lymphoma, laryngeal squamous cell carcinoma, lung squamous cell, small cell carcinoma, oesophageal squamous cell carcinoma, cervical cancer, brain tumor; Preferably, the tumor is a hematological cancer.
10. 10. The use according to claim 9, wherein the hematological cancer is selected from one or more of acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphoblastic leukemia, burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, fahrenheit macroglobulinemia, or multiple myeloma.

Description

CD 38-targeted antibody-drug conjugate and preparation method and application thereof Technical Field The invention relates to the field of biopharmaceuticals, in particular to a CD 38-targeted antibody-drug conjugate, a preparation method and application thereof. Background CD38 is a multifunctional exonuclease that catalyzes the reversible hydrolysis of nicotinamide adenine dinucleotide (NAD+) to form cyclic adenosine diphosphate ribose (cADPR) and ADP-ribose, thereby playing an important role in regulating key biochemical processes. Modulation of nad+ metabolism by CD38 can affect tumor development and therapeutic efficacy. It is found that the abnormal expression of CD38 in various tumor cells is closely related to the occurrence and development of tumors, especially in multiple myeloma and leukemia, the CD38 is significantly up-regulated, so the CD38 has become a potential target point for cancer treatment. Tumor types with high expression of CD38 include Multiple Myeloma (MM), chronic Lymphocytic Leukemia (CLL), acute Myelogenous Leukemia (AML), acute Lymphoblastic Leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), mantle Cell Lymphoma (MCL), burkitt's Lymphoma (BL), and NK/T cell lymphoma (NKTCL) as well as some solid tumors such as liver cancer, breast cancer, lung cancer, and prostate cancer. Clinical studies have shown that the expression level of CD38 is associated with the progression and prognosis of various tumor type diseases. CD38 is not just a surface marker, it also participates in many important cellular functions. CD38 has nad+ glycosidase and ADPR cyclase activities, and its products such as cyclic ADP ribose (cADPR) and the like are involved in intracellular calcium (ca2+) regulation and energy metabolism. CD38 can activate downstream signaling pathways through interactions with different cell surface receptors, affecting cell proliferation, survival, migration, etc. In some cases, CD38 is also involved in regulating immune and inflammatory responses. Thus, CD38 can regulate and control excessive proliferation of tumor cells, imbalance of intracellular and extracellular metabolic pathways, formation of tumor microenvironment and the like through various mechanisms, thereby participating in occurrence and development of diseases. CD38 is also continuously advancing in the development of drugs targeting CD38 as a potential therapeutic target for anti-tumor therapy. CD38 monoclonal antibodies have been approved for the treatment of multiple myeloma, including up to Lei Tuoyou mab and i Sha Tuo mab, for the treatment of multiple myeloma. The problems faced at present include clinical studies that show that the clinical effect of monoclonal antibodies in multiple myeloma does not benefit from other tumor subtypes that are highly expressed and more aggressive in CD38, and that multiple myeloma faces drug resistance issues, thus requiring novel and effective therapeutic strategies. ADCs are composed of antibodies, connectors and load molecules, and the high-activity load molecules are specifically conveyed to target positions through targeting actions of the antibodies, so that the effects of improving the drug effect and reducing the toxicity are achieved. In the development of ADCs, not only is each component very important, but the mutual collocation of the components also has an important influence on the effect of the ADCs. The CD38 antibody-drug conjugate as an innovative anti-tumor treatment strategy has great research potential and clinical application prospect. Through research on CD38-ADCs, the method hopes to kill cancer cells more accurately and effectively, avoids serious side effects caused by traditional radiotherapy and chemotherapy, and further expands the broad prospect of CD38 as a therapeutic target. Disclosure of Invention In view of the above-mentioned drawbacks of the prior art, it is an object of the present invention to provide a CD 38-targeting antibody-drug conjugate, and a preparation method and use thereof, for solving the problems in the prior art. To achieve the above and other related objects, the present invention provides an antibody-drug conjugate, which is a compound comprising the formula I: In formula I, anti-CD38 represents a targeting ligand, preferably an antibody targeting CD38, and L represents a linker for linking the antibody and the NAMPT (nicotinamide ribosyl phosphate transferase) inhibitor. D represents a small molecule drug, preferably a NAMPT inhibitor. L comprises cleavable and non-cleavable linkers, n represents the molecular number ratio of NAMPT inhibitor-antibody, and n is 1-20, preferably 1-8. Preferably, the antibody in the antibody-drug conjugate is an anti-CD 38 antibody. The invention also provides a preparation method of the antibody-drug conjugate, which comprises the following steps: a1 Reacting the compound 1 with thionyl chloride, and condensing the obtained compound with m-aminobenzoic acid to obtain a compound 2: a2 Compo