Breast cancer antibody drug conjugate based on targeted HER2 receptor and application of breast cancer antibody drug conjugate

Abstract

The invention discloses a breast cancer antibody drug conjugate based on a targeted HER2 receptor and application of the breast cancer antibody drug conjugate in the technical field of antibody drug conjugates, the breast cancer antibody drug conjugate comprises a monoclonal antibody, the monoclonal antibody is coupled with a cytotoxic drug through a polymer, the monoclonal antibody is trastuzumab, and the monoclonal antibody is an HER2 receptor. The cytotoxic drug is maytansine DM1 with a tubulin synthesis inhibition effect, the polymer comprises a polyaspartic acid chain, a plurality of maleimide groups are grafted on side branch carboxyl of the polyaspartic acid chain, and Fc-III-4C peptide in the polymer is combined with an Fc segment of trastuzumab through a high affinity effect, so that the polymer can be used for inhibiting microtubulin synthesis. And the monoclonal antibody-polymer-cytotoxic drug conjugate T-NPLA-DM1 is formed by using the monoclonal antibody-polymer-cytotoxic drug conjugate. The antibody drug conjugate is novel and effective, and the drug loading capacity of a single drug molecule is improved by using the polyamino acid as the drug conjugate, so that the drug-antibody ratio of the antibody drug conjugate is improved, and the lethality of an anti-tumor drug to HER2 positive breast cancer tumor cells is enhanced.

Description

Technical Field

[0001] The present invention belongs to the technical field of antibody-drug conjugates, and in particular is a breast cancer antibody-drug conjugate based on targeting HER2 receptor and its application. Background Art

[0002] Antibody-drug conjugates (ADCs) are an innovative treatment that combines the dual advantages of highly specific targeting monoclonal antibodies and highly active small molecule cytotoxic drugs. ADCs drugs usually consist of three parts: monoclonal antibodies targeting receptors, highly active small molecule cytotoxic drugs, and linkers that connect the two. When ADCs drugs enter the human body, their antibody part specifically recognizes and binds to positive cancer cells. Subsequently, inside the cancer cells, the linker is degraded, releasing the cytotoxic drug, thereby accurately killing cancer cells with less impact on normal cells.

[0003] T-DM1 is the world's first ADCs drug for solid tumors. It is composed of the anti-HER2 monoclonal antibody trastuzumab and the cytotoxic drug DM1 coupled through a non-cleavable thioether linker. Its drug-antibody ratio (DAR) is 3.5. Maytansine (DM1) is a powerful anti-microtubule drug that can effectively inhibit tubulin polymerization and induce cell apoptosis. Although T-DM1 has a good therapeutic effect on HER2-positive breast cancer, the optimization of the delivery efficiency of maytansine is still worth studying.

[0004] Recent studies have shown that high DAR ADCs have the potential to improve tumor killing ability, and a certain tumor antigen density value is a prerequisite for ADCs to work. Therefore, it is necessary to propose a breast cancer antibody-drug conjugate based on targeting HER2 receptors that can improve the drug-antibody ratio and enhance the killing ability of HER2-positive breast cancer tumor cells. Summary of the invention

[0005] In order to solve the above problems, the purpose of the present invention is to provide a breast cancer antibody-drug conjugate based on targeting HER2 receptor and its application, by using polyamino acids as drug conjugates to increase the drug loading capacity of single drug molecules, thereby improving the drug-antibody ratio of antibody-drug conjugates and enhancing the killing ability of anti-tumor drugs on HER2-positive breast cancer tumor cells.

[0006] In order to achieve the above object, the technical scheme of the present invention is as follows: a monoclonal antibody is coupled to a cytotoxic drug through a polymer, the monoclonal antibody is trastuzumab, and the cytotoxic drug is maytansine DM1 having a microtubule synthesis inhibitory effect.

[0007] The principle of the basic regimen is that trastuzumab is a humanized monoclonal antibody that can specifically recognize and bind to the HER2 receptor. The HER2 receptor is overexpressed in a variety of malignant tumors, including breast cancer, gastric cancer, ovarian cancer, etc., so trastuzumab is widely used in the treatment of these tumors.

[0008] Maytansine DM1 is a tubulin inhibitor with a strong ability to inhibit tumor cell proliferation. It binds to tubulin and inhibits the dynamics of microtubules, thereby blocking the formation of spindles during cell mitosis and leading to cell apoptosis. Due to the high cytotoxicity of maytansine DM1, it is often used as the payload part of ADCs drugs to achieve precise killing of tumor cells.

[0009] Trastuzumab is coupled to maytansine DM1 through a polymer. This coupling method allows ADCs drugs to maintain their dual advantages of targeting and cytotoxicity. When ADCs drugs enter the human body, their antibody part (trastuzumab) will specifically recognize and bind to HER2-positive cancer cells. Subsequently, inside the cancer cells, the polymer linker is degraded, releasing maytansine DM1, thereby accurately killing cancer cells.

[0010] The beneficial effects of the basic scheme are: 1. ADCs drugs can accurately identify and bind to HER2-positive cancer cells, enter the cancer cells through endocytosis, and release maytansine DM1 under specific conditions to achieve precise killing of cancer cells. This efficient and precise killing mechanism significantly improves the targetedness and effectiveness of treatment.

[0011] 2. The targeting of ADCs drugs enables them to reduce the killing of normal cells, thereby significantly reducing the side effects of treatment. This is of great significance for improving the quality of life of patients and alleviating the pain during treatment. Due to the high efficiency and accuracy of ADCs drugs, doctors can adjust the drug dosage according to the specific conditions of patients, reduce unnecessary drug use, and further reduce the occurrence of side effects.

[0012] 3. ADCs have fewer side effects and can reduce the pain, nausea, vomiting and other discomfort symptoms that patients experience during treatment, improving their comfort. Compared with traditional chemotherapy drugs, ADCs cause less damage to normal cells, can maintain the patient's body functions and immunity, and reduce the risk of physical weakness and infection caused by treatment.

[0013] Furthermore, the polymer comprises a polyaspartic acid chain having a plurality of maleimide groups grafted to the polyaspartic acid chain via a pendant carboxyl group.

[0014] The beneficial effects of the basic scheme are: 1. As a polymer with good biocompatibility, the multiple carboxyl groups in the structure of the polyaspartic acid chain provide abundant sites for the grafting of maleimide groups. By covalently coupling the maleimide group with the thiol group in the cytotoxic drug (such as maytansine DM1), the amount of drug that can be carried by a single antibody molecule, i.e., the drug-antibody ratio (DAR), can be significantly increased. A higher DAR means that each ADCs molecule can release more drug molecules, thereby enhancing the killing power of tumor cells.

[0015] 2. Polyaspartic acid chains have good water solubility and biological stability, which helps maintain the stability and activity of ADCs drugs in the body. The coupling reaction between maleimide groups and thiol groups is a relatively stable chemical bond that can remain stable for a long time in the body environment, ensuring the effective release of drugs.

[0016] 3. The design and selection of polymer linkers are crucial to the release rate and location of ADCs drugs. The degradation rate of the polyaspartic acid chain can be regulated by adjusting its chain length and the type of side branch groups, thereby achieving precise control of the drug release rate. This controllable release mechanism helps ensure the effective accumulation of drugs at the tumor site while reducing distribution in normal tissues, further reducing side effects.

[0017] 4. By optimizing the structure and properties of the polymer, the bioavailability of ADCs drugs in the body can be improved. The biocompatibility and degradability of the polyaspartic acid chain help reduce the clearance rate of ADCs drugs in the body and extend their half-life in the body. This not only helps to improve the efficacy of the drug, but also reduces the frequency of administration and improves patient compliance.

[0018] Furthermore, the polyaspartic acid chain is poly-L-aspartic acid having a front-end azide group, namely, NPLA.

[0019] Furthermore, the degree of polymerization of the polyaspartic acid chain is at least greater than 200.

[0020] The beneficial effects of the basic scheme are: 1. As the degree of polymerization increases, the polyaspartic acid chain can provide more coupling sites, thereby allowing more drug molecules (such as maytansine DM1) to be coupled to the antibody. This not only increases the drug loading capacity of the ADC (i.e., the drug-antibody ratio), but also enhances the overall stability of the ADC molecule. The polyaspartic acid chain with a high degree of polymerization has better molecular chain rigidity, which helps to resist the damage of the external environment to the ADC molecule, thereby extending the half-life of the drug in vivo and improving the bioavailability of the drug.

[0021] 2. Poly-L-aspartic acid is a natural amino acid polymer with good biocompatibility and degradability. High-polymerization poly-aspartic acid chains as polymer linkers of ADCs drugs can further reduce the toxic effects of drugs on normal cells and reduce the risk of immune and allergic reactions. The degradation products of high-polymerization poly-aspartic acid chains in the body are amino acids, which can be absorbed and utilized by the human body and will not cause harm to the human body.

[0022] 3. High-polymerization polyaspartic acid chains as polymer linkers can ensure the stability and activity of ADCs drugs in the body. This helps to improve the efficacy of ADCs drugs and prolong their duration of action. Since high-polymerization polyaspartic acid chains have better molecular chain rigidity, this helps the transportation and distribution of ADCs drugs in the body, allowing them to reach the tumor site more effectively and exert their therapeutic effects.

[0023] Furthermore, the maleimide groups all underwent click chemistry reactions with DM1 to generate thiol groups and form the polymer prodrug NPLA-DM1.

[0024] Furthermore, the front-end azide group of the polymer prodrug undergoes a click chemistry reaction with the Fc-III-4C peptide modified with dibenzocyclooctyne to form a polymer-cytotoxic drug, Fc-NPLA-DM1.

[0025] The beneficial effect of the basic scheme is that through the click chemistry reaction, the front azide group is firmly connected to the DBCO-modified Fc-III-4C peptide to form a stable chemical bond, thereby enhancing the stability of Fc-NPLA-DM1 in vivo. This stability helps to reduce the degradation and inactivation of the drug during transportation and storage, ensuring that the drug can reach the target site and exert its therapeutic effect.

[0026] Furthermore, the Fc-III-4C peptide in the polymer binds to the Fc segment of trastuzumab through high affinity to form a monoclonal antibody-polymer-cytotoxic drug conjugate T-NPLA-DM1, which is used to treat SKBR-3 breast cancer that highly expresses HER2 protein.

[0027] The beneficial effects of the basic regimen are: 1. T-NPLA-DM1 combines the high specificity and affinity of trastuzumab for HER2 protein, and can accurately target SKBR-3 breast cancer cells that highly express HER2 protein. This precise targeting helps reduce the toxic effects of the drug on non-target cells and improve the efficacy and safety of the drug.

[0028] 2. Through the high affinity of Fc-III-4C peptide and trastuzumab Fc segment, T-NPLA-DM1 can selectively bind to HER2-positive breast cancer cells. This selectivity helps reduce the side effects of the drug while enhancing the killing effect on tumor cells.

[0029] 3. Since T-NPLA-DM1 combines the targeting of trastuzumab and the killing effect of the cytotoxic drug DM1, it has a higher efficacy. In SKBR-3 breast cancer cells that highly express HER2 protein, T-NPLA-DM1 can significantly inhibit the growth and proliferation of tumor cells, and even cause apoptosis of tumor cells.

[0030] 4. Due to its precise targeting and selectivity, T-NPLA-DM1 can reduce the toxic effects of drugs on non-target cells. This helps to reduce the systemic toxicity of drugs and reduce side effects and discomfort for patients.

[0031] Furthermore, the highest drug-to-resistance ratio of DM1-loaded T-NPLA-DM1 can reach 30.

[0032] The beneficial effects of the basic scheme are: 1. A high drug-to-antibody ratio means that each antibody molecule can carry more drug molecules (DM1). This increases the overall drug loading of the T-NPLA-DM1 drug, thereby improving its ability to kill tumor cells.

[0033] 2. High drug-to-resistance ratio helps to prolong the half-life of T-NPLA-DM1 in the body. This allows the drug to be released continuously for a longer period of time and maintain its killing effect on tumor cells.

[0034] 3. Compared with traditional chemotherapy drugs, T-NPLA-DM1 has lower side effects and higher safety. The high drug-to-resistance ratio allows the dosage to be reduced while maintaining the same efficacy, further reducing the side effects and discomfort of patients.

[0035] 4. The high drug-to-resistance ratio allows for flexible adjustment of drug loading in individualized treatment based on factors such as the patient's tumor load and drug resistance to achieve the best therapeutic effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 Schematic diagram of the structure of the monoclonal antibody-polymer-cytotoxic drug conjugate T-NPLA-DM1 in an embodiment of the present invention.

[0037] Figure 2 Schematic diagram of the reaction of generating NPLA by the ring-opening polymerization of NCA in an embodiment of the present invention.

[0038] Figure 3Schematic diagram of the reaction for producing NPLA-Mal in an embodiment of the present invention.

[0039] Figure 4 Schematic diagram of the generation of NPLA-DM1 by the thiol-maleimide click chemistry reaction in an embodiment of the present invention.

[0040] Figure 5 Schematic diagram of the reaction for producing Fc-NPLA-DM1 in an embodiment of the present invention.

[0041] Figure 6 Schematic diagram of the reaction for producing T-NPLA-DM1 in an embodiment of the present invention. DETAILED DESCRIPTION

[0042] The following is further described in detail through specific implementation methods:

[0043] Example 1

[0044] Basically as attached Figure 1 , Figure 2 , Figure 3 , Figure 4 , Figure 5 and Figure 6 Shown is a breast cancer antibody-drug conjugate based on targeting HER2 receptor, including a monoclonal antibody, which is coupled to a cytotoxic drug via a polymer. The monoclonal antibody is trastuzumab, and the cytotoxic drug is maytansine DM1 with microtubule synthesis inhibitory effect.

[0045] The polymer includes a polyaspartic acid chain, which is poly-L-aspartic acid with a front-end azide group, namely NPLA. The degree of polymerization of the polyaspartic acid chain is at least greater than 200. The side carboxyl groups of the polyaspartic acid chain are grafted with a number of maleimide groups. The maleimide groups undergo click chemical reactions with DM1 to generate thiol groups and form a polymer prodrug NPLA-DM1.

[0046] The front-end azide group of the polymer prodrug undergoes a click chemistry reaction with the Fc-III-4C peptide modified with dibenzocyclooctyne to form a polymer-cytotoxic drug, Fc-NPLA-DM1. The Fc-III-4C peptide in the polymer binds to the Fc segment of trastuzumab through high affinity to form a monoclonal antibody-polymer-cytotoxic drug conjugate T-NPLA-DM1, which is used to treat SKBR-3 breast cancer that highly expresses HER2 protein. The highest drug-to-antibody ratio of the DM1-loaded T-NPLA-DM1 drug can reach 30.

[0047] The specific implementation process is as follows: Preparation of breast cancer antibody-drug conjugates targeting HER2 receptors.

[0048] 1. L-aspartic acid was polymerized using the NCA ring-opening polymerization method. The ring-opening polymerization of L-aspartic acid-4-benzyl ester-N-carboxyl cyclic anhydride (BLA-NCA) was initiated by azidotriethylene glycol amino (N3-PEG3-NH2) to prepare poly (L-aspartic acid benzyl ester) (NPBLA) with an azide terminal group. Subsequently, the benzyl ester group on its side chain was deprotected to obtain poly (L-aspartic acid) (NPLA) with an azide terminal group.

[0049] The specific operation is to take a 500mL round-bottom flask and a connecting device, add 10.0g BLA-NCA (40.1mmol) to fully dissolve it in 200mL anhydrous dichloromethane (DCM) while ensuring that there is no water and oxygen. After the solution is clarified, add 78.1mg N3-PEG3-NH2 (0.2mmol) as an initiator to the solution, then put on a balloon filled with high-purity argon to buffer the pressure in the reaction bottle, and react in a water bath at 30°C for 72 hours, and then use 193.6mg acetic anhydride (1.9mmol) for end-capping to prevent the amino group at the end of the main chain of NPLA from affecting the subsequent reaction.

[0050] After the end-capping, the reaction was continued at 30°C for 24 hours, and the reaction solution was dripped into 2L of anhydrous ether to precipitate to obtain white solid NPBLA. NPBLA was completely dissolved in 100mL of dichloroacetic acid, and 38mL of a mixed solution of hydrobromic acid / acetic acid (33.0wt.%) was slowly dripped at 30°C, reacted for 1 hour, and then precipitated with 1L of anhydrous ether. The obtained precipitate was re-dissolved in DMF and transferred to a dialysis bag with a molecular weight cutoff (MWCO) of 3500Da. The dialysis bag was boiled in boiling distilled water for 10 minutes to remove impurities. After dialysis in distilled water for 72 hours, the product was freeze-dried using a freeze dryer to obtain white solid NPLA (yield: 91%).

[0051] 2. Some side chain carboxyl groups of NPLA were functionalized with maleimide groups by reacting the carboxyl groups of NPLA with Mal-C2H4-NH2·HCl.

[0052] The specific operation is to first dissolve 94.0 mg NPLA (1.0 mmol) in 8 mL anhydrous DMF, add 30.8 mg EDCI (50.0 mmol) and 20.2 mg NHS (55.0 mmol), and then stir at 30 ° C for 2 hours. Then add 28.1 mg Mal-C2H4-NH2·HCl (50.0 mmol) and 2.1 mg DIPEA (, 5.0 mmol) to the solution, and then stir at 30 ° C for 24 hours. Finally, the above solution is transferred to a pretreated dialysis bag (MWCO = 7000 Da) and dialyzed with distilled water for 72 hours. After freeze drying in a freeze dryer, NPLA-Mal (yield: 92%) is obtained.

[0053] 3. Synthesis of NPLA-DM1 30 .

[0054] The specific operation is as follows: 48.3 mg NPLA-Mal (1.0 mmol) was completely dissolved in 10 mL of anhydrous DMF. 35.9 mg DM1 (40.0 mmol) and 0.6 mg DIPEA (4.0 mmol) were dissolved in 3 mL of anhydrous acetonitrile, and the resulting mixture was stirred at 30°C in the dark for 12 hours. The reaction solution was transferred to a pretreated dialysis bag (MWCO = 7000 Da) and dialyzed with distilled water for 72 hours. NPLA-DM1 30 After freeze drying, it was a yellow solid (yield: 93%). The drug loading (DLC) of NPLA-DM130 was measured using an ultraviolet / visible light (UV / vis) spectrometer (Lambda 365) and calculated according to the following formula:

[0055] Drug loading (wt.%) = (mass of encapsulated drug / total mass of encapsulated drug and polymer) × 100%

[0056] 4. Synthesis of Fc-NPLA-DM1 30 .

[0057] The specific steps are: 36.8 mg NPLA-DM1 30 (1.0 mmol) and 3.1 mg Fc-DBCO (1.2 mmol) were dissolved in 10 mL of anhydrous DMF and stirred at 30 °C in a dark environment for 48 hours. The resulting mixture was then transferred to a pretreated dialysis bag (MWCO = 7000 Da), dialyzed with distilled water for 72 hours, and freeze-dried to obtain Fc-NPLA-DM1. 30 .

[0058] 5. Synthesis of T-NPLA-DM1 30 .

[0059] 1.6 mg Fc-NPLA-DM1 30 (1.0 mmol) was dissolved in 1.0 mL Tris-HCl buffer (pH = 7.4, 50 mM), and 4.0 mg trastuzumab (0.9 mmol) was added to the solution, stirred for 2 hours in a 4 ° C water bath, and then ultrafiltered using a 100 kDa ultrafiltration column to remove unconnected conjugates. The filtrate and purified T-NPLA-DM1 were measured using UV / visible spectroscopy. 30 The drug concentration in the medium was 0.0447 μg / mL, and a transparent colorless liquid T-NPLA-DM1 was obtained. 30 .

[0060] Example 2

[0061] The difference from the above embodiment is that, as shown in Table 1: the dynamic light scattering (DLS) method was used to determine the expression of trastuzumab, NPLA-DM1 30 and Fc-NPLA-DM1 30 The particle sizes (diameters) of T-NPLA-DM1 were 10.72±0.4 nm (polydispersity index [PDI] = 0.31), 14.42±2.4 nm (PDI = 0.16), and 108.0±6.6 nm (PDI = 0.18), respectively. 30 The particle size is 122.6±0.4nm (PDI=0.22). The results are shown in the following table. 30 No unbound mAb was found in the particle size curve, indicating that trastuzumab was successfully coupled to Fc-NPLA-DM1 with high efficiency. 30 .

[0062] The experimental data were expressed as mean ± standard deviation (SD), and statistical significance was determined using GraphPad Prism 8.0 and OriginPro 8.0 software.

[0063] Table 1. Particle size and polydispersity index of the products in each step of Example 1

[0064]

[0065] Compared with the control group, *P<0.05.

[0066] Example 3

[0067] The difference from the above embodiment is that, as shown in Table 2, the zeta potential of the materials in each step was measured, and it was found that trastuzumab, NPLA-DM1 30 、Fc-NPLA-DM1 30 and T-NPLA-DM1 30The zeta potentials are shown in the table below, which are -3.44±0.2mV, -14.6±1.6mV, -14.2±0.4mV and -8.04±0.3mV respectively. These negative charges are caused by the presence of a large number of carboxyl groups in poly-L-aspartic acid.

[0068] Table 2. Zeta potential of the products in each step of Example 1

[0069]

[0070] Compared with the control group, *P<0.05.

[0071] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device.

[0072] The above is only an embodiment of the present invention. The common sense such as the known specific structure and characteristics in the scheme is not described in detail here. The ordinary technicians in the relevant field know all the common technical knowledge in the technical field of the invention before the application date or priority date, can obtain all the existing technologies in the field, and have the ability to apply the conventional experimental means before that date. The ordinary technicians in the relevant field can improve and implement this scheme in combination with their own abilities under the enlightenment given by this application. Some typical known structures or known methods should not become obstacles for ordinary technicians in the relevant field to implement this application. It should be pointed out that for those skilled in the art, without departing from the structure of the present invention, several deformations and improvements can be made, which should also be regarded as the protection scope of the present invention, which will not affect the effect of the implementation of the present invention and the practicality of the patent. The protection scope required by this application shall be based on the content of its claims, and the specific implementation methods and other records in the specification can be used to interpret the content of the claims.

Claims

1. A breast cancer antibody-drug conjugate targeting HER2 receptor, comprising a monoclonal antibody, characterized in that: The monoclonal antibody is coupled to a cytotoxic drug through a polymer. The monoclonal antibody is trastuzumab, and the cytotoxic drug is maytansine DM1 which has a microtubule synthesis inhibitory effect.

2. The breast cancer antibody-drug conjugate targeting HER2 receptor according to claim 1, characterized in that: The polymer comprises a polyaspartic acid chain having a plurality of maleimide groups grafted to the polyaspartic acid chain with pendant carboxyl groups.

3. The breast cancer antibody-drug conjugate targeting HER2 receptor according to claim 1, characterized in that: The polyaspartic acid chain is poly-L-aspartic acid with a front azide group, namely NPLA.

4. The breast cancer antibody-drug conjugate targeting HER2 receptor according to claim 2, characterized in that: The degree of polymerization of the polyaspartic acid chain is at least greater than 200.

5. The breast cancer antibody-drug conjugate targeting HER2 receptor according to claim 1, characterized in that: The maleimide groups all undergo click chemistry reactions with DM1 to generate thiol groups and form the polymer prodrug NPLA-DM1.

6. The breast cancer antibody-drug conjugate targeting HER2 receptor according to claim 1, characterized in that: The front-end azide group of the polymer prodrug undergoes a click chemistry reaction with the Fc-III-4C peptide modified with dibenzocyclooctyne to form a polymer-cytotoxic drug, Fc-NPLA-DM1.

7. The breast cancer antibody-drug conjugate targeting HER2 receptor according to claim 1, characterized in that: The Fc-III-4C peptide in the polymer binds to the Fc segment of trastuzumab through high affinity to form the monoclonal antibody-polymer-cytotoxic drug conjugate T-NPLA-DM1, which is used to treat SKBR-3 breast cancer with high expression of HER2 protein.

8. The breast cancer antibody-drug conjugate targeting HER2 receptor according to claim 7, characterized in that: The highest drug-to-resistance ratio of DM1-loaded T-NPLA-DM1 can reach 30.

9. The use of the antibody-drug conjugate according to claim 7, characterized in that: Used for the preparation of anti-tumor drugs.

10. The use of the antibody-drug conjugate according to claim 9, characterized in that: It involves administering an antibody-drug conjugate, or T-NPLA-DM1, to patients with HER-positive breast cancer.

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