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CN112843262A - Antibodies or ligands to human ABCA1 that bind radionuclides and uses thereof - Google Patents

Antibodies or ligands to human ABCA1 that bind radionuclides and uses thereof Download PDF

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CN112843262A
CN112843262A CN202011263638.6A CN202011263638A CN112843262A CN 112843262 A CN112843262 A CN 112843262A CN 202011263638 A CN202011263638 A CN 202011263638A CN 112843262 A CN112843262 A CN 112843262A
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antibody
glioma
drug conjugate
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drug
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CN112843262B (en
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刘阳
张红
柄志桐
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Institute of Modern Physics of CAS
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    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
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    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1018—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against material from animals or humans
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    • 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
    • A61K47/6843—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 material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans

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Abstract

The present invention relates to antibodies or ligands against human ABCA1 that bind radionuclides and uses thereof. The drug conjugates of the present invention are capable of diagnosing neoplastic conditions, either alone or in combination with other active ingredients. The present invention provides another viable option for better diagnosis of tumors.

Description

Antibodies or ligands to human ABCA1 that bind radionuclides and uses thereof
Technical Field
The invention belongs to the field of biopharmaceuticals, and particularly relates to an antibody or ligand against human ABCA1, which binds to a radionuclide, and uses thereof, particularly uses thereof in targeted therapy of glioma (LGG) or glioblastoma multiforme (GBM).
Background
Gliomas are one of the most common and serious types of neurological tumors. Gliomas are often very unfriendly in prognosis and are life-threatening diseases.
Gliomas are generally classified by cell type, grade and location, and most often by specific types of cells, as glioma cells share many histological features with these specific types of cells. It should be noted that the particular type of cell described above is not necessarily the type of cell that is the primary of the glioma. Currently, the main types of glioma and the corresponding specific types of cells are as follows: ependymomas (ependymal cells), astrocytomas (astrocytes), oligodendrogliomas (oligodendrocytes), brain stem gliomas (brainstem), optic gliomas (cells within or around the optic nerve) and mixed gliomas (cells from different types of glial cells). Of course, the specific cell types corresponding to these can be classified into optic glioma (which may cause visual impairment or visual loss) and myeloglioma, etc.
On the other hand, according to WHO, gliomas were also further classified. Grade I is the lowest grade with the earliest stage of glioma development and the best prognosis, and grade I gliomas are generally considered benign. Grade II is a grade only higher than the lowest grade described above, in which gliomas are highly differentiated, not undifferentiated carcinomas. Grade III and IV are undifferentiated or anaplastic cancers and are clearly malignant. The prognosis for grades III and IV is very poor. However, it is noted that grade I and II have a better prognosis, but over time, these grades of glioma change, for example, with increasing incurability and a tendency to increase in grade.
Depending on the location of the glioma, it is particularly whether they are above or below the dural septum. Supraseptal gliomas are more common in adults, while subintimal gliomas are more common in the lower ages.
The symptoms of glioma patients vary with the size, growth rate, location of the disease and the like of the tumor. Usually, patients with glioma are accompanied mainly by convulsion, headache or migraine, neurological dysfunction (e.g., memory and speech problems), and poor mental condition.
Treatment of gliomas typically involves surgical resection followed by radiation and chemotherapy. Glioblastoma is a more common type of tumor than other major types of central nervous system tumors. It can be treated with temozolomide in combination with radiation therapy followed by adjuvant therapy, but the median survival of this therapy is not long.
The exact cause of glioma is not known. Current studies indicate that glioma development is associated with genetic mutations, such as DNA repair genes ERGC1, ERGC2, XRCC1, isocitrate dehydrogenase genes IDH1 and IDH2, p53, PTEN, and the like.
In fact, gliomas are rarely curable and the prognosis for patients with high grade gliomas is generally worse. Therefore, improved treatments for gliomas are highly desirable.
ATP-binding cassette transporter a1(ATP-binding Gassette transporter a1, ABCA1) is an ATP-dependent transporter that mediates efflux of cholesterol and phospholipids to extracellular lipid-deficient HDL particles. ABCA1 acts as a key regulator of lipid efflux from cells to apolipoproteins and is therefore involved in reducing the risk of atherosclerosis. Further, ABCA1 is a key molecule affecting HDL levels in plasma. In the liver and small intestine, human ABCA1 produces most of the circulating HDL.
The radioisotope drug is an important component of nuclear medicine, and is widely applied to diagnosis and treatment of cancer, myocardial imaging and diagnosis of heart diseases, and state monitoring of neurodegenerative diseases. Radiopharmaceuticals refer to a class of special pharmaceuticals that contain radioisotopes for use in medical diagnosis and therapy. A compound or biological agent comprising a radioisotope label for use in medical diagnosis or treatment in vivo. Radiopharmaceuticals are classified into diagnostic radiopharmaceuticals and therapeutic radiopharmaceuticals according to their use. The targeted radioisotope medicine adopting internal irradiation has good treatment effect and low side effect, has better internal irradiation treatment effect particularly on diffuse cancer and micrometastasis cancer, forms perfect complementation with ion beam tumor treatment, and has become a new trend of radioactive tumor treatment medicine development in European and American countries. Although isotope imaging and treatment have obvious advantages and application prospects, the isotope imaging and treatment also have some problems, such as lack of high-specificity targeting on a focus part, organ damage caused by enrichment in normal organs, mismatch of blood circulation time and half-life period and the like, and further application of the isotope imaging and treatment in clinic is hindered. The development of isotopes for targeted diagnosis and treatment is urgently needed, the treatment efficiency is improved, and the toxic and side effects are reduced.
Disclosure of Invention
In order to better cure or provide another viable option for treating gliomas, improving the prognosis or quality of life of patients, the inventors of the present invention have undergone extensive and diligent screening to find nuclides that can be conjugated to antibodies or ligands against human ABCA1 to treat gliomas.
Accordingly, in one aspect, the invention provides anti-ABCA1 antibodies and antigen binding fragments thereof. Further, the antigen binding fragment of the present invention may be selected from the group consisting of: camel Ig, Ig NAR, Fab fragment, Fab 'fragment, F (ab)'2Fragment, F (ab)'3Fragment, Fv, scFv, bis-scFv, (scFv)2A minibody, a diabody, a triabody, a tetrabody, a disulfide stabilized Fv protein, and a single domain antibody (sdAb, nanobody), a bispecific antibody, or a trispecific antibody, and the like.
Further, the present invention also provides a fusion protein comprising the above antibody or antigen-binding fragment.
Illustratively, the fusion protein described in the present invention may further comprise a tag sequence (e.g., Poly-His, Hemagglutenin, c-Myc, GST, Flag-tag, etc.) or an IgG1-Fc protein sequence.
The invention also provides an antibody-drug conjugate comprising an antibody or antigen-binding fragment described herein.
Illustratively, in the antibody-drug conjugate of the present invention, the drug is selected from the following: radionuclides (preferably alpha-emitting nuclides 211At, 225Ac, 223Ra),32P、35S, fluorescent dye, electron dense reagent, enzyme, biotin, streptavidin, digoxigenin, hapten and immunityAn immunogenic protein, a nucleic acid molecule having a sequence complementary to a target, or a combination of any of the foregoing; or immunomodulatory compounds, anti-cancer agents, anti-viral agents, antibacterial agents, antifungal agents, and antiparasitic agents, or a combination of any of the foregoing.
One aspect of the present invention relates to a drug for treating glioma, comprising the drug conjugate of the present invention. Optionally, the medicament of the present invention further comprises a pharmaceutically acceptable carrier.
Preferably, the medicament for treating glioma of the present invention further comprises other active ingredients for treating glioma.
A second aspect of the invention provides the use of an antibody of the invention or a drug conjugate of the invention in the manufacture of a medicament for the treatment of glioma. Optionally, the medicament for treating glioma further comprises a pharmaceutically acceptable carrier. Preferably, the medicament for treating glioma further comprises other active ingredients for treating glioma.
A third aspect of the invention provides a method of treating a glioma in a subject comprising administering to said subject an effective amount of a drug conjugate of the invention.
Illustratively, the other active ingredient described in the present invention may be, for example, temozolomide.
For the subject of the present invention, it is preferably a mammal, more preferably a human.
Any modification of the drug conjugates of the present invention may be made by those skilled in the art, provided that the modification does not adversely affect their activity. For example, multiple radionuclides may be conjugated in a drug conjugate to enhance its therapeutic activity in vivo; or may be linked to known penetration peptides to facilitate transdermal absorption of the compounds of the invention or crossing the blood brain barrier, etc. In summary, the drug conjugates of the present invention can be variously modified by those skilled in the art to enhance delivery efficiency or for other purposes and maintain their activity. Such modifications are also within the scope of the present invention.
In the present invention, the methods, uses and products of the invention may comprise, in addition to the active ingredient, suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active ingredient into preparations, for example suitable for injection or infusion.
Formulations suitable for injection or infusion may include aqueous and non-aqueous sterile injection solutions, which may optionally contain anti-oxidants, buffers, bacteriostats and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
The various cytokine active ingredients of the invention may optionally be combined with solid excipients and the resulting mixture is optionally ground and, if desired, after addition of suitable auxiliaries, the mixture of granules is processed to give the desired dosage form. Suitable excipients are in particular fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose or starch preparations, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents, such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate, may be added.
In the present invention, the amount of administration of the drug conjugate of the present invention can be any amount that is capable of treating glioma or inhibiting the proliferation of glioma cells in a subject.
In the present invention, the determination of an effective amount to administer, as well as the appropriate unit dose, is within the ability of those skilled in the art, particularly in light of the disclosure provided herein.
According to the present invention, the pharmaceutical agent of the present invention can be administered to a subject in any effective dose. Preferably, the medicament of the invention may be administered in multiple doses, for example from about 5 to about 15 doses, more preferably about 6-10 doses, most preferably about 8 doses. In a particularly preferred embodiment, the medicament of the invention is administered to the subject during the course of administration, e.g. by injection, infusion or orally, at a frequency of about once every two weeks. In a particularly preferred embodiment, the administration is by intravenous injection.
It will be appreciated that the medicament of the invention may be formulated in any suitable manner for administration by any suitable route.
Dosage units of the medicaments of the invention are based on conventional administration to a subject. For example, the dosage unit can be determined daily, weekly, monthly, etc., based on the frequency of administration. Dosage units may also be determined on a two/week, three/week basis, and the like.
As used herein, "comprising" is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional unrecited elements or method steps. The term "comprising" in any of the expressions herein, particularly in describing the method, use or product of the invention, is to be understood as including those products, methods and uses which consist essentially of and consist of the recited components or elements or steps. The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein.
The pharmaceutical product of the present invention may contain instructions relating to the pharmaceutical product, and the instructions may contain the following: indications (e.g., gliomas), dosages (e.g., as exemplified above), and possible side effects, among others.
The terms and expressions which have been employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.
Drawings
FIG. 1 shows an intravenous injection68Transverse position PET-CT image 30min after Ga-DOTA-NCS-ABCA1 probe. The tumor site is shown in the red circle.
FIG. 2 is an intravenous injection68Ga-DOTA-NCS-ABCA 130 nin, 60min, ratio of the amount of HepG2 tumor to tumor-bearing mouse muscle radioactive probe aggregate (T/M) after 90 min.
FIG. 3 is an intravenous injection68Ga-DOTA-NCS-ABCA 130 nin, 60min, ratio of MDA-MD-231 tumor to tumor-bearing mouse muscle radioactive probe aggregation amount (T/M) after 90 min.
For a more clear illustration of the invention, reference is now made in detail to the following examples, which are intended to be purely exemplary of the invention and are not to be interpreted as limiting the application.
The atp-binding cassette transporter a1(ABCA1) is one of the important members of the triphosphate-binding cassette transporter superfamily, and plays an extremely important regulatory role in reverse cholesterol transport, cholesterol metabolism, and High Density Lipoprotein (HDL) metabolism. Mutations in the ABCA1 gene induce Tangier disease and familial HDL deficiency. In recent years, researches show that the cholesterol efflux function mediated by ABCA1 has anti-tumor activity, and ABCA1 is expected to become a new target for tumor treatment.
Liver cancer, a malignant tumor of the liver, can be divided into primary and secondary types. The primary liver malignant tumor originates from the epithelium or mesenchymal tissue of the liver, the former is called primary liver cancer, which is a highly-developed malignant tumor with great harm in China; the latter is called sarcoma, and is less common than primary liver cancer. Secondary or metastatic liver cancer refers to the invasion of malignant tumors of multiple organ origins in the whole body to the liver. Liver metastasis of malignant tumors of stomach, biliary tract, pancreas, colon, ovary, uterus, lung, and breast is common.
The clinical manifestation of triple negative breast cancer is an invasive course, and has higher distant metastasis risk, higher visceral metastasis chance than bone metastasis and higher brain metastasis probability. The risk of distant metastasis of triple negative breast cancer peaks at 3 years and may decline thereafter. Median tumor size of triple negative breast cancer was 2cm with lymph node metastasis in 50%. The breast cancer has a histological grade of 3 and a high cell proliferation rate.
1 reasons for selection of test systems
According to the guiding principle of the research technology of the non-clinical pharmacokinetics of drugs, the nude mice are congenital thymus gland defects, and the nude mice are externally shown to be hairless and lack normal thymus gland. Its characteristics include T cell deficiency, so that it can accept externally transplanted cells, has less immunological rejection and is suitable for xenotransplantation.
Animal tagging and identification
The quarantine adaptation period is marked by animal ID number inherent to the animal, and the animal number is used after grouping. In the experimental process, each animal has a unique animal number, and a cage card is attached to an animal cage, and the cage card is provided with information such as special numbers, animal ID numbers, groups, sexes and the like.
Quarantine and adaptive breeding
All animals received at least 7 days of quarantine and acclimatization, and the feeding conditions were: the temperature is 20-27 ℃, the humidity is 45-75%, and the illumination is performed for 12 hours with alternating light and shade.
Cage utensil
Animals were housed in independent air supply systems IVC with no more than 5 animals per cage.
Test animal feed
The types of the feed are as follows: mouse maintenance feed
Production unit: jiangsu cooperative medical bioengineering Limited liability company
Production license number: suzuo Fed certificate (2014)01008, SCXK (Jing) 2014-0010
The feed batch number is as follows: 20180530, respectively; 18068221
The validity period is as follows: 20190529
Storage conditions are as follows: low temperature, dry and sanitary
The feeding method comprises the following steps: free diet
And (3) feed detection: each batch of feed is proved to be qualified by the quality provided by a manufacturer; the feed is subjected to 1 time of conventional nutrient component index, chemical pollutant index and microorganism index detection by a professional detection unit qualified by a third party every year.
Drinking water for experimental animals
The feed is fed through a kettle in the cage and can be freely taken, and the drinking water is sterilized purified water.
Radiolabelling
NOTA-ABCA1 preparation
1mg of NOTA-NCS was dissolved in 1mL of H2To O, 50uL (50ug, 62nmol) was added to reconstituted ABCA1 antibody (1mg, 74nmol, Anti-ABCA1 antibody [ AB.H10 ]]Purchased from abcam and is a mouse monoclonal antibody [ AB.H10 ]]to ABCA1, immunogen: combbinant fragment correlation to Human ABCA1 aa 1800-2260, Database link: 095477), the ratio of the antibody to NOTA-NCS is 1: 1, and 20uL of 0.1M NaHCO3 solution is added at the same time, protected from light, and the reaction is performed with shaking at 25 ℃ for 0.5 h.
68Preparation of Ga ions
The germanium-gallium generator was rinsed with 5mL of 0.1M HCl, the hydrochloric acid eluent was collected in stages, and 500uL of sodium acetate buffer (0.1mol/L, PH 4.3) was added to the highest active fraction (7mCi, 0.5mL) in the middle.
68Preparation of Ga-DOTA-NCS-ABCA1
Adding prepared DOTA-NCS-ABCA1 solution68Ga3+In a sodium acetate buffer solution, and reacting at 40 ℃ for 30 min.
Separating and purifying
Pre-activating a PD-10 desalting column, diluting a product, loading 2.5mL of the diluted product, filling buffer solution after emptying, starting to collect samples, connecting 10 tubes to each 10 drops (about 0.35mL) of tube, testing the radioactivity by an activity meter, and taking the highest tube in the front section of activity for experiment
Radiochemical purity determination
TLC detection, using Xinhua No. one paper, and developing agent is sodium acetate buffer solution.
Tumor model establishment
Cell culture
Performing conventional culture amplification on HepG2 and MDA-MD-231 cell strains, replacing fresh culture medium one day before inoculation, and discarding cultureThe medium in the flask was washed twice with PBS, digested by adding 1mL of 0.25% trypsin containing EDTA, observed under a microscope for cell curling and rounding, tapped on the cell culture flask to allow the cells to slough off, then digested by adding complete medium, and centrifuged at 800rpm for 5 min. The cells were resuspended in serum-free medium, and the cell concentration of the resuspended cells was adjusted to 1X 107Per mL;
cell seeding
0.1mL of the vaccine was inoculated to the right underarm of each nude mouse. When the tumor grows to 150-3Used for formal experimental study.
Micro-PET/CT scanning
1) Preheating the Micro-PET/CT, and calibrating daily;
2) animals were weighed and nude mice were anesthetized with isoflurane;
3) static scanning: after the animal positive reflection disappears, injecting imaging agent into tail vein, each about 60uci, with volume of 0.1mL, anesthetizing and fixing to scanning bed 30min, 60min and 90min after injection, performing PET static scanning for 10min, and performing CT scanning.
Administration related information and dosage design
The administration route and the method are as follows: tail vein injection
Reasons for the choice of route of administration: is consistent with the clinical planned administration mode
Frequency and duration of administration: single administration
Administration volume: 0.1mL
Image analysis
And (3) carrying out Micro-PET/CT scanning data analysis through Siemens self-contained software, quantifying the uptake of animal tumor and muscle, and determining the tumor muscle ratio.
As a result:
the probe is rapidly cleared from the blood and excreted primarily through the kidney. The probe was clearly clustered in both tumors (FIG. 1). To pair68The T/NT values of the Ga-DOTA-NCS-ABCA1 probe visualized at 90min after injection are shown below. In HepG2 cells, the T/NT value of tumor/muscle was maximal at 90min, 2.27. + -. 0.18 (FIG. 2). In MDA-MD-231 cells, the T/NT value of tumor/muscle was maximal at 30min, 3.36. + -. 0.30 (FIG. 3).

Claims (10)

1. An antibody-drug conjugate comprising an antibody or antigen-binding fragment directed to human ABCA1, wherein the drug is selected from the group consisting of: radionuclides (preferably alpha-emitting nuclides 211At, 225Ac, 223Ra),32P、35S、68Ga. A fluorescent dye, an electron-dense reagent, an enzyme, biotin, streptavidin, digoxigenin, a hapten, an immunogenic protein, a nucleic acid molecule having a sequence complementary to a target, or a combination of any of the foregoing; or immunomodulatory compounds, anti-cancer agents, anti-viral agents, antibacterial agents, antifungal agents, and antiparasitic agents, or a combination of any of the foregoing.
2. The antibody-drug conjugate of claim 1, wherein the radionuclide is a nuclide of alpha rays and is selected from any one of 211At, 225Ac, 223Ra, or a combination thereof; and/or said antigen binding fragment is selected from the group consisting of: camel Ig, Ig NAR, Fab fragment, Fab 'fragment, F (ab)'2Fragment, F (ab)'3Fragment, Fv, scFv, bis-scFv, (scFv)2Minibody, diabody, triabody, tetrabody, disulfide stabilized Fv protein and single domain antibody (sdAb, nanobody), bispecific antibody or trispecific antibody, preferably camel Ig, most preferably the structure of the conjugate is:68Ga-DOTA-NCS-ABCA1。
3. a probe for diagnosing tumors, which comprises the drug conjugate of claim 1 or 2, and optionally, the drug further comprises a pharmaceutically acceptable carrier, preferably, the drug is in a dosage form suitable for injection, infusion or oral administration; or preferably, the glioma is selected from the group consisting of ependymoma, astrocytoma, oligodendroglioma, brain stem glioma and mixed glioma, and glioblastoma multiforme (GBM), breast cancer, liver cancer.
4. The probe of claim 3, further comprising an additional tumor diagnostic probe.
5. Use of a drug conjugate according to claim 1 or 2 for the preparation of a formulation for use in diagnosis, optionally for use in a medicament further comprising a pharmaceutically acceptable carrier, preferably the medicament is in a dosage form suitable for injection, infusion or oral administration; or preferably, the glioma is selected from the group consisting of ependymomas, astrocytomas, oligodendrogliomas, brain stem gliomas, and mixed gliomas, and glioblastoma multiforme (GBM).
6. The use according to claim 5, wherein the preparation for the therapeutic diagnosis of tumors also contains other active ingredients for the diagnosis of tumors.
7. A method of diagnosing a tumor in a subject comprising administering to the subject an effective amount of the drug conjugate of claim 1 or 2, or the probe of claim 3 or 4.
8. The method according to claim 7, wherein the subject is a mammal, preferably a human.
9. A method of preparing a drug conjugate for diagnosing a tumor, comprising conjugating a radionuclide (preferably the nuclide 211At, 225Ac, 223Ra of alpha rays,68Ga)。
10. a CAR-T, CAR-B or CAR-NK cell targeted for treatment of glioma, comprising an antibody or antigen-binding fragment (e.g., nanobody) against ABCA 1.
CN202011263638.6A 2019-11-12 2020-11-12 Antibodies or ligands against human ABCA1 that bind radionuclides and uses thereof Active CN112843262B (en)

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