CN118141945A - HER2 nanobody drug conjugates - Google Patents

HER2 nanobody drug conjugates Download PDF

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Publication number
CN118141945A
CN118141945A CN202410267538.2A CN202410267538A CN118141945A CN 118141945 A CN118141945 A CN 118141945A CN 202410267538 A CN202410267538 A CN 202410267538A CN 118141945 A CN118141945 A CN 118141945A
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cancer
antibody
carcinoma
drug conjugate
antibody drug
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杨梦甦
谭贤文
周小钰
侯旭华
王珊
邱佳
曾一哲
张思月
李连欣
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Shenzhen Futian Research Institute Of City University Of Hong Kong
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Shenzhen Futian Research Institute Of City University Of Hong Kong
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • Proteomics, Peptides & Aminoacids (AREA)
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  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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Abstract

The invention belongs to the field of biological medicine, and particularly relates to a HER2 nano antibody drug conjugate. Specifically, the invention provides an antibody drug conjugate or pharmaceutically acceptable salt thereof, wherein the antibody drug conjugate is formed by conjugation of an antibody and Auristatin or a functional peptide analogue or derivative thereof through a connector, and the sequence of the antibody is shown as SEQ ID NO. 1.

Description

HER2 nanobody drug conjugates
Technical Field
The invention belongs to the field of biological medicine, and particularly relates to a HER2 nano antibody drug conjugate.
Background
Antibody drug conjugates (antibody drug conjugate), also known as ADCs, are a new class of therapeutic drugs that combine monoclonal antibody specificity with chemotherapeutic drug toxicity, and have become a promising strategy for cancer treatment, particularly those that are resistant to traditional therapies.
The ADC consists of a monoclonal antibody, a linking molecule and a toxic drug. Monoclonal antibodies are directed against and specifically bind to the surface antigen portion of cancer cells, the choice of which depends on the level of expression, distribution and rate of internalization of the antigen. The linker molecule is a bridge linking the antibody and the drug, and the linker should be stable in circulation, prevent premature release of the drug, and be cleavable within the target cell to enable drug delivery. The linker molecules are divided into cleavable and non-cleavable ones. The cleavable linker molecule may be hydrolyzed by an enzyme, pH, or reduction reaction. The non-cleavable linker molecule relies on lysosomal antibody-drug complex degradation. Toxic drugs are cytotoxic agents that kill cancer cells. The drug should have high toxic potency, low molecular weight, and suitable chemistry for coupling. A wide variety of toxic drugs used in ADCs include microtubule inhibitors, DNA damaging agents, and RNA polymerase inhibitors. The mechanism of action of ADC is as follows, first, ADC binds to target antigen on the surface of cancer cells; second, the ADC is internalized into the endosome via antigen-mediated endocytosis. Third, depending on the type of linker, the drug is released from the ADC either in the endosome or escapes into the cytoplasm. Fourth, drugs exert cytotoxic processes by interfering with a variety of cells, such as microtubule polymerization, DNA synthesis, or RNA transcription. Finally, toxic drugs can induce apoptosis, necrosis or autophagy of tumor cells, resulting in cell death.
Nanobodies, which are a small and stable camelid antibody fragment, are also a good choice for future ADCs. It consists of a single variable domain (VHH) that retains the antigen's binding capacity of conventional antibodies. Its size (12-15 kDa) is smaller than conventional antibodies (150 kDa), which can better penetrate and distribute in solid tumors. The nano antibody has higher stability than the traditional antibody, so that the shelf life is longer and the nano antibody is easier to store.
Disclosure of Invention
Aiming at the problem of poor permeation and retention of ADC in solid tumors, a mode of taking a tumor surface antigen HER2 as a target point, synthesizing HER2 nanobody and connecting a toxic drug, namely methyl reoxetine E (monomethyl auristatin E) is selected to prepare a novel nanobody drug conjugate.
Specifically, the invention provides the following technical scheme:
In one aspect, the invention provides an antibody drug conjugate or pharmaceutically acceptable salt thereof, wherein the antibody drug conjugate is formed by conjugation of an antibody and Auristatin or a functional peptide analogue or derivative thereof through a connector, and the sequence of the antibody is shown as SEQ ID NO. 1.
Preferably, the Auristatin is methyl reoxetine E (monomethyl auristatinE, MMAE, monomethyl auristatin E).
The Auristatin of the present invention has activities that interfere with microtubule dynamics, GTP hydrolysis, nuclear and cell division, and antifungal activity. Auristatin the drug moiety may be linked to the antibody via a linker.
Preferably, the linker comprises a cleavable or non-cleavable linker comprising one or more PAB, amino acid or peptide; preferably, the peptide may be a dipeptide, tripeptide, tetrapeptide, pentapeptide.
Exemplary dipeptides include, but are not limited to, alanine-alanine (ala-ala), valine-citrulline (vc or val-cit), alanine-phenylalanine (af or ala-phe); phenylalanine-lysine (fk or phe-lys); phenylalanine-homolysine (phe-homolys); and N-methyl-valine-citrulline (Me-val-cit). Exemplary tripeptides include, but are not limited to, glycine-valine-citrulline (gly-val-cit) and glycine-glycine (gly-gly-gly).
Preferably, the peptide may comprise naturally occurring and/or non-natural amino acid residues. The term "naturally occurring amino acid" refers to Ala, asp, cys, glu, phe, gly, his, he, lys, leu, met, asn, pro, gin, arg, ser, thr, val, trp and Tyr. "unnatural amino acid" includes homoserine, homoarginine, citrulline, phenylglycine, taurine, iodotyrosine, selenocysteine, norleucine (Nle), norvaline (Nva), beta-alanine, L-naphthylalanine or D-naphthylalanine, ornithine (Orn), and the like.
Preferably, the linker is a valine-citrulline (Val-Cit) linker. Examples of structures of Val-Cit linkers include, but are not limited to, MC-vc-PAB, MC-vc-GABA, described below, where MC is an abbreviation for maleimidocaproyl, vc is an abbreviation for Val-Cit, and PAB is an abbreviation for p-aminobenzyl carbamate.
In another aspect, the invention provides a method of preparing an antibody drug conjugate comprising contacting an antibody having the sequence shown in SEQ ID NO.1 with VcMMAE (mc-vc-PAB-MMAE) under partially or fully reducing conditions.
More specifically, the preparation method comprises contacting an antibody having the sequence shown in SEQ ID NO.1 with VcMMAE in the presence of a reducing agent.
Preferably, the reducing agent is Dithiothreitol (DTT) or tricarbonyl ethyl phosphine (TCEP).
Preferably, the reducing agent is tricarbonyl ethyl phosphine.
Preferably, the preparation method is to add a sufficient amount (1-20 times the molar amount of the antibody) of TCEP to the antibody solution, then add a sufficient amount (1-5 times the molar amount of the antibody) of VcMMAE, and then screen through a molecular sieve after the reaction at room temperature.
Specifically, the 1-20 includes 1,2,3, 4, 5, 6,7,8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, and the 1-5 includes 1,2,3, 4, 5.
Preferably, the preparation method is to add VcMMAE times the molar amount of the antibody to the antibody solution after adding sufficient TCEP, and to screen the solution by molecular sieves after reacting at room temperature.
More specifically, 3000 daltons.
More preferably, the reaction products screened through the molecular sieve are reconstituted in a suitable solution comprising borate, bicarbonate, tris-HCl, citrate, phosphate or other organic acid solution, in particular embodiments of the invention in Phosphate Buffered Saline (PBS).
In another aspect, the invention provides antibody drug conjugates prepared by the above preparation method.
In another aspect, the invention provides a pharmaceutical composition comprising the antibody drug conjugate described above.
Pharmaceutical compositions may be formulated with pharmaceutically acceptable carriers or diluents and any other known adjuvants and excipients, according to conventional techniques.
Pharmaceutically acceptable carriers or diluents and any other known adjuvants and excipients should be suitable for the antibody drug conjugates of the invention and the mode of administration selected. The suitability of the carrier and other components of the pharmaceutical composition is determined based on the absence of significant negative impact upon antigen binding on the desired biological properties of the selected compounds or pharmaceutical compositions of the invention.
Specifically, the carrier is solid, gel or liquid, the solid carrier is lactose, clay, sucrose, talcum, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid or a soluble polymer, the liquid carrier is phosphate buffer salt solution, syrup, oil, water, emulsion, wetting agent or sterile solution, and the diluent is distilled water, physiological saline, ringer's solution, glucose solution, PBS solution or Hank's solution.
Preferably, the pharmaceutical composition may be in the form of a tablet, pill, powder, granule, capsule, lozenge, syrup, emulsion, suspension, controlled release preparation, aerosol, film, injection, intravenous drip, transdermal absorption preparation, ointment, lotion, adhesive preparation, suppository, nasal preparation, pulmonary preparation or eye drop.
The pharmaceutical composition of the present invention may be administered by any of the following means: oral, spray inhalation, rectal, nasal, buccal, topical, parenteral, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intracardiac, intrasternal or intravenous administration.
The pharmaceutical compositions of the invention may also be administered in combination therapy, i.e., in combination with other therapeutic agents associated with the disease or condition to be treated. Thus, in one embodiment, the pharmaceutical compositions of the invention are for use in combination with one or more additional therapeutic agents (e.g., cytotoxic, chemotherapeutic or anti-angiogenic agents).
The administration of such combinations may be simultaneous, separate or sequential. For simultaneous administration, the drugs may be administered as one composition or as separate compositions, as the case may be. The present invention thus also provides a method of treatment for the treatment of cancer according to the invention, which method comprises administering a pharmaceutical composition according to the invention in combination with one or more additional therapeutic agents as described below: doxorubicin, vincristine, vinorelbine, paclitaxel, cisplatin, actinomycin, bleomycin, busulfan, capecitabine, carboplatin, glibenc, hydroxycamptothecin, lapatinib (Tykerb, lapatinib), torisel (temsirolimus), sunitinib (Sunitinib, sutent), iressa, gefitinib tablet, tarceva (Tarceva ), herceptin (Herceptin, trastuzumab), avastin (avastin), arsenic trioxide, trans-retinoic acid, velcade (Velcade, bortezomib), temozolomide (Temodar), erbitux (cetuximab), dasatinib (dasatinib Sprycel), sorafenib (sorafenib, neuar), towel Bai Nishan anti (vectifix, panitumab), tet (TS-1), and (TS-Ixempra (ixabepilone)).
In another aspect, the invention provides the use of the above antibody drug conjugate in the preparation of a cancer drug.
Preferably, the cancer is such as melanoma, fibrosarcoma, myxosarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelioma, synovial carcinoma, mesothelioma, ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat adenoma, sebaceous gland carcinoma, papillary adenocarcinoma, cystic adenocarcinoma, medullary carcinoma, bronchi carcinoma, renal cell carcinoma, liver cancer, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, wilms' tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, neuroblastoma, craniopharyngema, ventricular omenings tumor, pineal tumor, angioblastoma, auditory glioma, oligodendroglioma, meningioma, neuroblastoma, gastric carcinoma, and anterior carcinoma.
Preferably, the cancer is a HER2 positive cancer.
Preferably, the cancer is HER2 positive breast cancer.
In another aspect, the invention provides a method of treating cancer comprising administering to a patient the aforementioned therapeutically effective amount of an antibody drug conjugate.
The term "therapeutically effective amount" or "effective amount" refers to an amount of one or more agents or compositions as described herein sufficient to delay, terminate or reverse cancer progression or prolong patient survival in an individual. A therapeutically effective amount may refer to a target serum concentration that has been shown to be effective, for example, in slowing disease progression. When the term "therapeutically effective amount" is used to refer to a combination therapy, it refers to the amount of agents that, in combination, are such that the combined effect elicits the desired biological or medical response. Efficacy can be measured in a conventional manner, depending on the condition to be treated. For example, in neoplastic diseases, potency can be measured by assessing time to disease progression (TTP) or determining Reaction Rate (RR).
For therapeutic purposes, the term "subject" or "patient" as used herein refers to any animal, particularly animals classified as mammals, including humans, domestic animals and farm animals, as well as zoo, sports or pet animals, such as dogs, horses, cats, cattle and the like. Preferably, the patient is a human.
The antibody drug conjugate (antibody drug conjugate, ADC) is prepared by connecting a monoclonal antibody or an antibody fragment with cytotoxin with biological activity or a small molecular drug with cell killing activity through a stable chemical joint compound, fully utilizing the specificity of the antibody on tumor cell specificity or high expression antigen binding and the high efficiency of cytotoxin, and avoiding toxic and side effects on normal cells.
Drawings
FIG. 1 is a graph of the Mass Spectrum (MS), SDS-PAGE and SEC-HPLC identification of HER2 nanobody. Fig. 2 is a graph of experimental results of the biological thin film interference assay for determining affinity of HER2 nanobody and trastuzumab for HER2 protein.
FIG. 3 is a graph showing the results of flow cytometry detection of HER2 expression in SK-BR-3 (+) and MDA-MB-231 (-) cell lines.
FIG. 4 is a graph showing the results of fluorescence microscopy of HER2 expression in SK-BR-3 (+) and MDA-MB-231 (-) cell lines.
FIG. 5 is a graph of the toxicity results of antibody drug conjugates on SK-BR-3 (+) and MDA-MB-231 (-).
Detailed Description
The present invention will be further described with reference to specific embodiments, but the scope of the present invention is not limited thereto, and any person skilled in the art, who is within the scope of the present invention, should make equivalent substitutions or modifications according to the technical scheme of the present invention and the inventive concept thereof, and should be covered by the scope of the present invention.
Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
Example one, affinity detection
The nanometer antibody with the sequence shown in SEQ ID NO.1 is expressed in large scale and high quality by using a Chinese Hamster Ovary (CHO) cell system, and the molecular weight of the nanometer antibody obtained after purification and identification is 14506 daltons, and the purity is 93% (figure 1). We also determined that HER2 nanobody and HER2 protein had Kd values of 1.83 x 10 -9 by biofilm interferometry, trastuzumab (MedChemExpress) had Kd values of 1.03 x 10 -8 by biofilm interferometry.
The SEQ ID NO.1 sequence is QVQLQESGGGSVQAGETLRLSCTASGFTFDDS DMGWYRQAPGNECELVSTISADGSTFYADSVKGRFTISQDNAKNTVYLQMN SLKPEDTAVYYCASPENEYELGTCEALDYWGQGTQVTVSSHHHHHHHHC., wherein CDR1 is GFTFDDSDMG, CDR2 is ISADGTS, and CD3 is ASPENEYELGT CEALDY (hereinafter referred to as nanobody of the invention).
That is, the nanobody of the present invention has a stronger affinity for HER2 protein than trastuzumab commercialized.
Example two, synthesis of antibody drug conjugates and detection of cytotoxicity
The C-terminal modification of the nano antibody is added with cysteine for binding and connection, and the subsequent steps are as follows:
1) Synthesis of nanobody drug conjugate according to the present invention
① Adding 10 times mole amount of TCEP to the nano antibody solution;
② VcMMAE (mc-vc-PAB-MMAE, medChemExpress) was added in an amount 2 times the molar amount of HER2 nanobody and reacted for 2 hours at room temperature;
③ Centrifuging the reaction mixture with a molecular sieve with molecular retention of 3000 daltons at 4500rpm for 30 min;
④ PBS redissolves the reaction product retained by the molecular sieve (hereinafter abbreviated as NDC).
2) Synthesis of trastuzumab drug conjugates
① Adding 10 times mole amount of TCEP to trastuzumab solution;
② Adding VcMMAE (mc-vc-PAB-MMAE, medChemExpress) which is 4 times of the molar quantity of the trastuzumab, and reacting for 2 hours at room temperature;
③ Centrifuging the reaction mixture with molecular sieve with molecular retention of 10000 dalton at 4500rpm for 30 min;
④ PBS redissolved the reaction product (trastuzumab drug conjugate) entrapped by the above molecular sieve, and this conventional ADC was used as a control group (hereinafter abbreviated as ADC).
Cytotoxicity experiments were performed by selecting a HER2 high-expression positive cell line SK-BR-3 and a HER2 low-expression negative cell line MDA-MB-231 (the cell surface HER2 expression of which is shown in the results of flow cytometry and fluorescence microscopy verification shown in fig. 3-4), detecting concentration ranges of NDC, ADC and VcMMAE are 100-500000pM, incubation time is 72 hours, and cell viability detection is performed by using a cytotoxicity kit.
As shown in FIG. 5, in SK-BR-3 (+) the nanobody set and the common antibody set of the present invention both exhibit targeting ability and increase drug sensitivity. The nano antibody also shows obvious targeting difference in SK-BR-3 (+) and MDA-MB-231 (-).
The results show that the nano antibody drug conjugate has better targeting and tumor cytotoxicity.

Claims (10)

1. An antibody drug conjugate or pharmaceutically acceptable salt thereof, wherein the antibody drug conjugate is formed by conjugation of an antibody and Auristatin through a connector, and the sequence of the antibody is shown as SEQ ID NO. 1;
preferably, the Auristatin includes an analog or derivative of Auristatin;
Preferably, the Auristatin is monomethyl auristatin E.
2. The antibody drug conjugate of claim 1, wherein the linker comprises a cleavable or non-cleavable linker comprising one or more PAB, amino acid or peptide;
preferably, the peptide comprises a dipeptide, tripeptide, tetrapeptide, pentapeptide;
preferably, the linker comprises valine-citrulline, alanine-alanine, alanine-phenylalanine, phenylalanine-lysine, phenylalanine-homolysine, N-methyl-valine-citrulline, glycine-glycine;
Preferably, the linker is valine-citrulline.
3. A method of preparing an antibody drug conjugate, the method comprising contacting an antibody having the sequence shown in SEQ ID No.1 with VcMMAE under partially or fully reducing conditions;
Preferably, the reducing agent is TCEP;
preferably, the preparation method is to add a sufficient amount of TCEP to the antibody solution, then add a sufficient amount of VcMMAE in the molar amount of the antibody, and then screen the antibody solution by a molecular sieve after the reaction at room temperature.
4. The method of claim, wherein the amount of TCEP added to the antibody solution is about 2 times the molar amount of VcMMAE, and the antibody solution is subjected to a reaction at room temperature and then screened by a molecular sieve;
Preferably, through a molecular sieve of 3000 daltons;
preferably, the reaction product screened by the molecular sieve is reconstituted in phosphate buffer for use.
5. An antibody drug conjugate prepared by the method of claim 3.
6. A pharmaceutical composition comprising the antibody drug conjugate of claim 1 or 4;
Preferably, the pharmaceutical composition further comprises other cancer therapeutic agents and/or pharmaceutically acceptable carriers or diluents.
7. The pharmaceutical composition of claim 5, wherein the cancer therapeutic comprises doxorubicin, vincristine, vinorelbine, paclitaxel, cisplatin, actinomycin, bleomycin, busulfan, capecitabine, carboplatin, glifebridine, hydroxycamptothecin, lapatinib, torisel, sunitinib, iressa, tazicar, herceptin, avastin, arsenic trioxide, trans-retinoic acid, velcade, temozolomide, erbitux, dasatinib, sorafenib, towel Bai Nishan resistance, tigloy, ixempra.
8. Use of the antibody drug conjugate of claim 1, the antibody drug conjugate of claim 5 or the pharmaceutical composition of claim 6 for the preparation of a medicament for treating cancer, said cancer being a HER2 positive cancer.
9. The use of claim 8, wherein the cancer comprises melanoma, fibrosarcoma, myxosarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphatic endothelial sarcoma, synovial carcinoma, mesothelioma, ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat adenoma, sebaceous gland carcinoma, papillary adenocarcinoma, cystic adenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, liver carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, wilms' tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyoma, ependymoma, pineal tumor, angioblastoma, auditory glioma, oligodendroglioma, meningioma, neuroblastoma, gastric cancer, retinoblastoma, gastric cancer, and anterior carcinoma.
10. The use of claim 8, wherein the cancer is HER2 positive gastric or breast cancer.
CN202410267538.2A 2024-03-08 2024-03-08 HER2 nanobody drug conjugates Pending CN118141945A (en)

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