Application of CD203a as a therapeutic target for triple-negative breast cancer stem cell membranes

Abstract

The present invention discloses the application of CD203a as a target for triple-negative breast cancer stem cell membrane therapy. The inventor verified in vivo and in vitro through a series of functional experiments that CD203a enriches BCSC in TNBC. At the same time, clinical specimen analysis shows that the expression of CD203a is highly correlated with triple-negative breast cancer and has a significant impact on the survival prognosis of breast cancer patients. The development of drugs targeting CD203a, such as ADC drugs targeting CD203a, can significantly inhibit the viability of BCSCs, achieve a killing effect on TNBC, and achieve the effect of effectively treating triple-negative breast cancer.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and specifically relates to the application of CD203a as a therapeutic target for triple-negative breast cancer stem cell membrane. Background Art

[0002] Breast cancer is the leading cause of tumor-related morbidity and mortality among women worldwide. It is a heterogeneous disease that is divided into different subtypes based on the expression of markers such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Among them, triple-negative breast cancer (TNBC) accounts for 10-20% of all breast cancers. [1] , it does not express ER, PR, and HER2 proteins, and only a few targeted drugs are used in clinical treatment [2] Compared with hormone receptor-positive or HER2-amplified breast cancer, TNBC patients are more likely to spread outside the breast and relapse after treatment. The molecular mechanism of TNBC recurrence has not been fully elucidated, and currently only a few targeted drugs (PARP inhibitors (olaparib), PD1 / PD-L1 blocking antibodies) have improved the prognosis of TNBC in clinical treatment. [3,4] The study reported that some TNBC subgroups (carrying germline BRCA1 / 2 mutations) benefited from olaparib treatment [5,6] Immune checkpoint inhibition monotherapy also benefits only a small subset of patients [7] Therefore, the inventors urgently need to find new therapeutic targets to intervene in TNBC.

[0003] Increasing evidence suggests that breast cancer contains a heterogeneous population of breast cancer stem cells (BCSCs), which can generate progeny of non-stem tumor cells and only BCSCs are capable of tumor regeneration. Frequent tumor recurrence and poor prognosis are believed to be the result of BCSCs becoming resistant to currently available targeted therapies. [8] Currently, more than 60% of approved drugs target membrane proteins, such as transporters and receptors, that play key roles in physiological and pathological processes. [9] Despite decades of research, the key cell surface proteins of BCSCs are still not fully understood. At the same time, many drugs targeting BCSCs have shown significant effects on TNBC. [2] Although membrane proteins make up only one-third of human protein-coding genes, they account for two-thirds of known drug targets.

[10] Therefore, profiling the BCSC cell surface proteome will be an ideal method to identify new BCSC markers and therapeutic targets. The most effective method to separate and identify cancer cells (CC) and cancer stem cells (CSC) is to analyze the differential expression of cell surface proteins in CSCs and CCs.

[11] The development of effective treatments for TNBC relies on identifying BCSCs cell surface markers that are lowly expressed in normal tissues. These differentially expressed membrane proteins can not only serve as molecular markers for CSC enrichment, but also are ideal candidate proteins for therapeutic targets.

[12] . The immune-based antibody-drug conjugate (ADC) combines the targeting ability of monoclonal antibodies with the anti-cancer ability of cytotoxic drugs, providing a new treatment strategy for TNBC. In 2020, the U.S. Food and Drug Administration (FDA) approved the first ADC targeting Trop-2 (sacituzumab govitcan) for metastatic TNBC and demonstrated its clinically significant efficacy.

[13] .

[0004] CD203a is a type II transmembrane glycoprotein that catalyzes the hydrolysis of ATP / GTP into AMP / GMP and inorganic pyrophosphates (PPi), and is considered to be a central regulator of mammalian bone and cartilage development. Its encoding gene is ectonucleotide pyrophosphatase / phosphodiesterase family member 1, ENPP1 . No studies have shown its role in triple-negative breast cancer. Summary of the invention

[0005] The purpose of the present invention is to overcome at least one deficiency of the prior art and provide an application of CD203a as a therapeutic target for triple-negative breast cancer stem cell membranes.

[0006] The technical solution adopted by the present invention is:

[0007] The first aspect of the present invention provides:

[0008] Application of CD203a as a therapeutic target for triple-negative breast cancer stem cell membranes.

[0009] The second aspect of the present invention provides:

[0010] The invention discloses an application of a compound in preparing a drug for targeted killing of breast tumor stem cells. The compound can target CD203a and has a cell killing effect.

[0011] In some application examples, the compound is an antibody-drug conjugate.

[0012] In some application examples, the antibody of the antibody-drug conjugate is an anti-CD203a antibody.

[0013] In some application examples, the antibody-drug conjugate is a small molecule that has a cell-killing effect selected from maytansine, monomethyl auristatin E, SN-38, DM4 or eribulin.

[0014] In some application examples, the small molecule is coupled to the antibody via a linker.

[0015] In some application examples, the antibody-drug conjugate is selected from anti-CD203a antibody-SMCC-DM1, anti-CD203a antibody-drutecan or anti-CD203a antibody-SMCC-DM4.

[0016] The third aspect of the present invention provides:

[0017] The invention discloses an application of an antibody-drug conjugate in the preparation of a drug for treating triple-negative breast cancer. The antibody-drug conjugate comprises an anti-CD203a antibody and a small molecule having a killing effect on cells.

[0018] In some application examples, the small molecule having a killing effect on cells is selected from maytansine, monomethyl auristatin E, SN-38, DM4 or eribulin.

[0019] In some application examples, the small molecule is coupled to the antibody via a linker.

[0020] In some application examples, the antibody-drug conjugate is selected from anti-CD203a antibody-SMCC-DM1, anti-CD203a antibody-drutecan or anti-CD203a antibody-SMCC-DM4.

[0021] A fourth aspect of the present invention provides:

[0022] An antibody-drug conjugate for treating triple-negative breast cancer comprises a small molecule having a cell-killing effect, wherein the small molecule is conjugated to an anti-CD203a antibody.

[0023] In some examples of antibody-drug conjugates, the small molecule having a cell-killing effect is selected from maytansine, monomethyl auristatin E, SN-38, DM4 or eribulin.

[0024] In some examples of antibody-drug conjugates, the antibody-drug conjugate is selected from anti-CD203a antibody-SMCC-DM1, anti-CD203a antibody-drutecan or anti-CD203a antibody-SMCC-DM4.

[0025] The beneficial effects of the present invention are:

[0026] The inventors verified in vivo and in vitro through a series of functional experiments that CD203a enriched BCSCs in TNBC. At the same time, clinical specimen analysis showed that the expression of CD203a was highly correlated with triple-negative breast cancer and had a significant impact on the survival prognosis of breast cancer patients. The development of drugs targeting CD203a, such as ADC drugs targeting CD203a, can significantly inhibit the viability of BCSCs, achieve a killing effect on TNBC, and achieve the effect of effectively treating triple-negative breast cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 It is a multi-omics screening method to discover membrane targets of triple-negative breast cancer stem cells;

[0028] Figure 2 It is the verification that CD203a is localized on the cell membrane of triple-negative breast cancer;

[0029] Figure 3 It is the validation of CD203a enrichment of triple-negative breast cancer stem cells;

[0030] Figure 4 This is an analysis of the relationship between CD203a and poor prognosis of breast cancer;

[0031] Figure 5 It is the preparation of anti-CD203a conjugate drug;

[0032] Figure 6 It is the killing effect of anti-CD203a conjugate drugs on triple-negative breast cancer cells and tumor stem cells. DETAILED DESCRIPTION

[0033] The first aspect of the present invention provides:

[0034] Application of CD203a as a therapeutic target for triple-negative breast cancer stem cell membranes.

[0035] The second aspect of the present invention provides:

[0036] The invention discloses an application of a compound in preparing a drug for targeted killing of breast tumor stem cells. The compound can target CD203a and has a cell killing effect.

[0037] In some application examples, the compound is an antibody-drug conjugate (ADC). ADC has been proven to be an effective targeted drug development strategy, which can effectively reduce the difficulty of developing targeted killing drugs.

[0038] In some application examples, the antibody of the antibody-drug conjugate is an anti-CD203a antibody, which can better target breast tumor stem cells expressing membrane CD203a and reduce side effects.

[0039] The small molecule that has a killing effect on cells can be various known small molecules, especially small molecules that have been experimentally verified to have relevant effects, and there is no particular requirement for the type. In some application examples, the antibody-drug conjugate that has a killing effect on cells is selected from maytansine, monomethyl auristatin E, SN-38, DM4 or eribulin.

[0040] In some application examples, the small molecule is coupled to the antibody via a linker.

[0041] In some application examples, the antibody-drug conjugate is selected from anti-CD203a antibody-SMCC-DM1, anti-CD203a antibody-drutecan or anti-CD203a antibody-SMCC-DM4.

[0042] The third aspect of the present invention provides:

[0043] The invention discloses an application of an antibody-drug conjugate in the preparation of a drug for treating triple-negative breast cancer. The antibody-drug conjugate comprises an anti-CD203a antibody and a small molecule having a killing effect on cells.

[0044] In some application examples, the small molecules (without linkers) that have a killing effect on cells include: Maytansine, monomethyl auristatin E (MMAE), SN-38, DM4, Eribulin, etc.

[0045] In some application examples, the small molecule is coupled to the antibody via a linker. By using a linker, the cell-killing effect of the small molecule can be better exerted.

[0046] In some application examples, the antibody-drug conjugate is selected from anti-CD203a antibody-SMCC-DM1, anti-CD203a antibody-drutecan or anti-CD203a antibody-SMCC-DM4.

[0047] A fourth aspect of the present invention provides:

[0048] An antibody-drug conjugate for treating triple-negative breast cancer comprises a small molecule having a cell-killing effect, wherein the small molecule is conjugated to an anti-CD203a antibody.

[0049] In some examples of antibody-drug conjugates, the small molecules (without a linker) that have a killing effect on cells include: Maytansine, Monomethyl auristatin E (MMAE), SN-38, DM4, Eribulin, etc.

[0050] In some examples of antibody-drug conjugates, the antibody-drug conjugate is selected from anti-CD203a antibody-SMCC-DM1, anti-CD203a antibody-drutecan or anti-CD203a antibody-SMCC-DM4.

[0051] The technical solution of the present invention is further explained below in conjunction with experiments.

[0052] 1. Multi-omics screening found CD203a as a potential therapeutic target for cancer stem cells in triple-negative breast cancer

[0053] To identify cell membrane proteins that are potential therapeutic targets for breast cancer stem cells (BCSC) in triple-negative breast cancer (TNBC), the inventors used a multi-omics approach to screen for differentially expressed cell surface proteins between sphere-cultured and adherent-cultured TNBC cells (MDA-MB-231). The inventors first performed glycosylated peptide enrichment and quantitative mass spectrometry (MS) based on isobaric tags for relative and absolute quantitation (iTRAQ), and quantitatively analyzed the glycosylated proteome with three technical replicates ( Figure 1 a). The inventors quantified 235 N-glycopeptides (corresponding to 154 N-glycoproteins) and identified 12 upregulated (>2-fold) glycoproteins in spheroid cells ( Figure 1 a). To narrow down the list of 12 proteins, the inventors also looked at their transcription levels. Super-enhancers (SEs) are considered key drivers of gene transcription that control and maintain cancer cell properties.

[14] Therefore, the inventors attempted to identify the specific SEs of BCSCs in TNBC. Due to the lack of a BCSC enhancer database, the inventors performed chromatin immunoprecipitation sequencing (ChIP-seq) on histone H3 acetylation modification at Lys 27 (H3K27ac) and analyzed SEs in the genomes of spheroid and adherent TNBC cells. The inventors identified 1284 and 1457 SEs in spheroid cells and adherent cells, respectively ( Figure 1 b). To identify specific genes driven by SE in spheroid cells, we further performed RNA sequencing (RNA-seq) analysis to comprehensively explore genes with differential expression (>2-fold, p-value <0.05) ( Figure 1 c). The inventors then intersected the genes with elevated expression in spheroid cells with a list of genes predicted to encode membrane proteins (n=5520) that contain at least one predicted transmembrane (TM) segment (www.proteinatlas.org / humanproteome / tissue / secretome). Combined, the inventors eventually narrowed the list of target genes to only two candidate genes ( ENPP1 and CDCP1 )( Figure 1 d).

[0054] Research shows CDCP1 A new tumor stem cell marker

[15] , and promotes the metastasis of TNBC via homodimerization and metabolic reprogramming [16,17] Antibody-drug conjugates (ADCs) targeting CDCP1 have been used in ovarian cancer

[18] According to reports, ENPP1 Can activate BCSC characteristics

[19] , and promote breast cancer metastasis and immune evasion via extracellular cGAMP hydrolysis

[20] .However, ENPP1 The causal relationship of maintaining breast cancer stem cells is still unclear, and it has not been explored as a therapeutic target for breast cancer stem cells (CSCs) so far. Therefore, the inventors will next use CD203a ( ENPP1 The encoded protein) is used as a potential therapeutic target to study its drugability.

[0055] In previous reports, CD203a is a single-pass transmembrane protein with a very large extracellular domain (100-925 amino acids)

[21] , providing a potential epitope for targeted therapy. In order to explore the subcellular localization of CD203a in TNBC, the inventors performed cell component separation-immunoblotting (western blotting, WB) and flow cytometry analysis to show that CD203a is localized on the cell membrane ( Figure 2 a, b). Therefore, CD203a is a preferred choice for further study of BCSC as a drug target in TNBC.

[0056] 2. CD203a maintains the stemness of triple-negative breast cancer cells

[0057] The inventors first verified their screening by WB analysis. Compared with adherent cells, spheroid cells significantly overexpressed CD203a ( Figure 3 a). In addition, not only TNBC (MDA-MB-231 and BT549) but also luminal breast cancer (MCF7) highly expressed CD203a in spheroid cells, suggesting that CD203a has a wide range of applications as a BCSC therapeutic target ( Figure 3 a). Because the inventors mainly focused on improving the prognosis of TNBC, the inventors used three sgRNAs (sg1, sg2 sg3; collectively referred to as sgENPP1 below) and Cas9 to transiently knock out the ENPP1 gene in TNBC cells. To determine the role of CD203a in the self-renewal function of BCSCs, the inventors compared WT and ENPP1 Role of missing cells in mammary gland spheroidization, a widely used assay to determine self-renewal capacity

[22] The results showed that sgENPP1 significantly reduced the number of TNBC cell spheres ( Figure 3 b), indicating that CD203a is involved in maintaining the CSC phenotype of triple-negative breast cancer cells.

[0058] 3. High expression of CD203a is associated with poor clinical prognosis

[0059] The inventors used GEPIA2 (http: / / gepia2.cancer-pku.cn / ) to analyze TCGA data and found that breast cancer is the most common cancer among all cancers. ENPP1 The highest expression level ( Figure 4 a). To investigate whether the expression of ENPP1 / CD203a in breast cancer is clinically relevant, the inventors found in TCGA and GTEx data ENPP1 The expression of mRNA in breast cancer is higher than that in normal breast tissue ( Figure 4 b), which is consistent with the inventor's preparation of drugs with CD203a as a therapeutic target. Survival analysis showed ENPP1 There are significant differences between high- and low-expressing breast cancers ( Figure 4c). In short, CD203a is a cell surface molecule that is differentially expressed compared with normal tissues, contains a potential epitope for immunoconjugate-based therapy of TNBC, and can predict worse clinical outcomes.

[0060] 4. Preparation of anti-CD203a conjugate drugs and their killing effects on triple-negative breast cancer

[0061] Antibody-drug conjugates (ADCs) targeting tumor cell surface proteins show significantly improved outcomes in patients with neuroblastoma [23–25] The inventors also wanted to determine whether ADC targeting CD203a could achieve this goal. The inventors used a commercial CD203a antibody (FAB6136G, R&D Systems) conjugated with a drug called SMCC-DM1, where SMCC is a protein crosslinker and DM1 is a highly effective microtubule-disrupting drug ( Figure 5 a). The inventors evaluated the drug to antibody ratio (DAR) using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) and found that in the ADC named "anti-CD203a-DM1" by the inventors, about 5% of the anti-CD203a antibody was conjugated to SMCC-DM1 ( Figure 5 b). The inventors evaluated the microtubule-disrupting effect of the ADC on cancer cells expressing GFP-fused tubulin by confocal microscopy. The inventors found that 55% (N=100) of the cells treated with anti-CD203a-DM1 had disrupted microtubule networks, while 0% (N=250; Figure 5 c). Finally, the inventors tested the killing effect of the ADC on TNBC cells and BCSC. In the MTT cytotoxicity assay, anti-CD203a-DM1 had a dose-dependent cytotoxicity against TNBC cells; in contrast, the unconjugated parent anti-CD203a antibody and the isotype antibody-DM1 ADC showed no significant cytotoxicity ( Figure 6 a). The inventors treated TNBC cells with 0.5 μg / ml ADC or other control groups for 30 min, then performed a clone formation test and cultured them in fresh culture medium for one week to observe the inhibitory effect of anti-CD203a-DM1 on TNBC cell growth. Compared with the anti-CD203a antibody and isotype antibody-DM1ADC groups, the clone cell growth in the anti-CD203a-DM1 treatment group was weakened ( Figure 6b). Since CD203a is highly expressed in BCSCs, the inventors next evaluated the effect of ADC in the sphere formation assay. To the inventors' surprise, anti-CD203a-DM1 treatment specifically and significantly led to a decrease in the number of spheres ( Figure 6 c).

[0062] To summarize the above, it can be foreseen that ADCs (such as anti-CD203a-DM1) that specifically target BCSCs and mediate breast cancer cytotoxicity in an antigen-specific and concentration-dependent manner in vitro are expected to be targeted for the treatment of triple-negative breast cancer.

[0063] The above is a further detailed description of the present invention, which should not be regarded as a limitation on the specific implementation of the present invention. For ordinary technicians in the technical field to which the present invention belongs, simple deduction or replacement without departing from the concept of the present invention is within the protection scope of the present invention.

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Claims

1. Use of a compound in the preparation of a drug for targeted killing of triple-negative breast cancer stem cells, characterized in that: The compound targets CD203a and has a cell-killing effect. The compound is an antibody-drug conjugate, the antibody of the antibody-drug conjugate is an anti-CD203a antibody, the small molecule of the antibody-drug conjugate that has a cell-killing effect is SMCC-DM1, and the antibody-drug conjugate is an anti-CD203a antibody-SMCC-DM1.

2. The use of an antibody-drug conjugate in the preparation of a drug for treating triple-negative breast cancer, characterized in that: The antibody-drug conjugate comprises an anti-CD203a antibody and a small molecule having a killing effect on cells, wherein the small molecule is SMCC-DM1, and the antibody-drug conjugate targets and kills triple-negative breast tumor stem cells.

3. An antibody-drug conjugate for treating triple-negative breast cancer, comprising a small molecule that has a killing effect on cells, characterized in that: The small molecule is coupled to an anti-CD203a antibody, the small molecule is SMCC-DM1, and the antibody-coupled drug targets and kills triple-negative breast cancer stem cells.

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