CN104892763A - Antibody-drug conjugate Pertuzumab-MCC-DM1, conjugate and Trastuzumab composition, and application of conjugate and composition - Google Patents
Antibody-drug conjugate Pertuzumab-MCC-DM1, conjugate and Trastuzumab composition, and application of conjugate and composition Download PDFInfo
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- A61K47/6855—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 the tumour determinant being from breast cancer cell
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- A61P35/02—Antineoplastic agents specific for leukemia
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- 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
- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
Abstract
The invention discloses a kind of antibody-drug conjugates Pertuzumab-MCC-DM1 (P-DM1) having the following structure, and the therapeutic agent compositions comprising P-DM1 and HER2 dimerisation inhibitor antibody, wherein, the therapeutic agent compositions include the P-DM1 of therapeutically effective amount and the HER2 dimerisation inhibitor antibody of therapeutically effective amount. The invention also discloses a kind of methods for treating hyperproliferative disease or illness, P-DM1 the and HER2 dimerisation inhibitor antibody agent including applying therapeutically effective amount to the mammal for needing such treatment or people. Pertuzumab and maytansine alkaloid DM1 is coupled by the present invention, the composition of the gained conjugate P-DM1 and HER2 dimerisation inhibitor antibody in vitro and in vivo show synergistic in inhibiting growth of cancer cells, can achieve the preferable therapeutic effect to the HER2 illness such as cancer mediated.
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Description
Technical field
The present invention relates to antibody-drug conjugates and the method by its treatment higher proliferation illness, be specifically related to the composition of a kind of antibody-drug conjugates Pertuzumab-MCC-DM1 (P-DM1) and the HER2 dimerisation inhibitor antibody trastuzumab with treatment significant quantity thereof, and use the method for described antibody-drug conjugates or composition treatment higher proliferation illness.
Background technology
HER2 (ErbB2) is the receptor tyrosine kinase being combined in surface of cell membrane, is encoded by proto-oncogene HER2/neu.Belong to Epidermal Growth Factor Receptor Family, this family comprises HER1(erbB1, EGFR), HER2(erbB2, NEU), HER3(erbB3) and HER4(erbB4).HER2 participates in the signal transduction path causing Growth of Cells and differentiation.The process LAN of HER2 is observed in the human breast carcinoma of about 25%-30%.Research display breast cancer wetting property when HER2 protein process LAN is strong, has more aggressive.And HER2 positive tumor is than not being the tumor growth of the HER2 positive and spreading faster.It is reported that HER2 positive breast cancer is 2.5 times of non-HER2 positive breast cancer recurrence rate.
Herceptin (Trastuzumab) is a kind of Humanized monoclonal antibodies for Her-2/neu Oncoprotein, and it is optionally combined in the region IV of HER2 (or HER2/neu) acceptor.Herceptin is by growing with HER2 protein bound inhibition tumor cell.1998, Herceptin (trade(brand)name: Trastuzumab, Herceptin) obtained U.S. food and FAD (Food and Drug Administration, FDA) approval listing, expresses positive breast cancer treatment for Her-2.Although the exploitation of Herceptin to the patient with HER2 positive tumor provide significantly will be good than independent chemotherapy result, but separately there is the Her-2 positive patient of 50% nearly to insensitive (the Singer CF of Herceptin treatment, Predicting the efficacy of Trastuzumab-based therapy in breast cancer:current standards and future strategies, Biochim Biophys Acta, 2008, 1786(2): 105-113), and most of Her2 positive patient is after the Herceptin treatment of 1 year, namely resistance can be produced to it.Therefore, still need for not responding Herceptin treatment or respond deficiency clinically, there is the tumour of process LAN HER2 or other develops the new cancer therapy for HER2 with the patient that HER2 expresses relevant disease.
Antibody-drug conjugates (antibody-drug conjugate, ADC) feature of specific antigen on monoclonal antibody specificity tumor cell is utilized, coupling small molecule chemotherapeutic medicine, can realize accurately antitumorigenic substance being delivered to the release of tumour target cell.In March, 2013, the ADC medicine T-DM1(Herceptin Trastuzumab of Roche company and maytenin DM1 coupling) obtain the accreditation of FDA for HER2 positive metastatic breast cancer treatment.T-DM1 at the Trastuzumab susceptibility of process LAN HER2 and Trastuzumab resistant tumor cell lines, and all demonstrates strong anti-tumor activity in the xenograft models of human breast carcinoma.The Study on mechanism display of T-DM1 is except the effect of small molecules DM1, also comprise effect and ADCC effect (the Trastuzumab Emtansine:A Unique Antibody-Drug Conjugate in Development for Human Epidermal Growth Factor Receptor2 – Positive Cancer of Trastuzumab itself, Clin Cancer Res, 2011,17 (20), 6437-6447).Handkerchief trastuzumab Pertuzumab is also a monoclonal antibody acting on HER dimerization.By in conjunction with HER2, block the assorted dimerization of HER2 and other HER receptor, caused mitogen activated protein kinases and PI3K path to be obstructed, and then occurred that growth of tumour cell is stagnated and apoptosis, thus slow down the growth of tumour.The difference of Pertuzumab and TTrastuzumab is the epitope binding region of light chain and heavy chain, and Pertuzumab is combined in the epi-position in the subdomain 2 of HER2, and the epi-position of TTrastuzumab is then positioned at subdomain 4.Pertuzumab, by blocking HER2 and other HER family member, comprises HERl(EGF-R ELISA; EGFR), HER3, and the combination of HER4 is worked.This combination is required for existing under part and signaling through map kinase and PI3 kinases.Therefore, Pertuzumab can suppress the Cellular Signaling Transduction Mediated that part starts.Suppress these signal transduction paths that retarded growth and tune can be caused respectively to die.T-DM1 and Pertuzumab coupling is demonstrated on cell and animal model the stronger anti-tumor activity of more single reagent (Dual targeting of HER2-positive cancer with Trastuzumab-emtansine (T-DM1) and pertuzumab:critical role for neuregulin blockade in anti-tumor response to combination therapy, Clin Cancer Res, Published Online First on October4,2013).But there is no at present about by Pertuzumab and the coupling of small molecule chemotherapeutic Medicine small molecule chemotherapeutics, treat the relevant report of the disease of HER2 mediation.
Summary of the invention
In order to overcome above-mentioned technical problem, the object of the present invention is to provide the composition of a kind of antibody-drug conjugates Pertuzumab-MCC-DM1 (P-DM1) and the HER2 dimerisation inhibitor antibody trastuzumab with treatment significant quantity thereof.
In order to reach foregoing invention object, the present invention adopts following technical scheme:
The invention provides a kind of antibody-drug conjugates Pertuzumab-MCC-DM1 (P-DM1) with following structure:
Wherein, mAb refers to handkerchief trastuzumab Pertuzumab, Pertuzumab is connected with maytenin alkaloid DM1 through difunctional linker reagent SMCC, in above formula, n represents drug-antibody ratio, and it ranges preferably from the round values between 1 to 8, wherein, 1,2,3,4,5,6,7 or 8 drug moiety covalently bind on antibody Pertuzumab.
The present invention also provides a kind of therapeutic agent compositions being used for the treatment of hyperproliferative disease or illness, and wherein, described therapeutic agent compositions comprises the P-DM1 for the treatment of significant quantity and the HER2 dimerisation inhibitor antibody for the treatment of significant quantity.
Further, described HER2 dimerisation inhibitor antibody is preferably Herceptin (Trastuzumab);
Further, the form that the P-DM1 of described treatment significant quantity and the HER2 dimerisation inhibitor antibody of described treatment significant quantity can be combined into preparaton is used or is alternately used.
The present invention also provides the method using described therapeutic agent compositions external and/or situ treatment mammalian cell, organism hyperproliferative disease or illness.Another aspect of the present invention also provides a kind of and uses therapeutic agent compositions of the present invention to treat the method for Mammals or people's hyperproliferative disease or illness (such as cancer comprises the disease regulated and controled by HER2 or KDR9 (vegf receptor 1)).
The present invention also provides a kind of method for the treatment of hyperproliferative disease or illness, comprises P-DM1 and the HER2 dimerisation inhibitor antibody agent to this type of Mammals treated of needs or people's administering therapeutic significant quantity.
Further, described P-DM1 and HER2 dimerisation inhibitor antibody agent is used with formulated in combination agent form;
Further, described P-DM1 and HER2 dimerisation inhibitor antibody agent is as therapeutic combination alternately (alternately, sequential administration) separate administration; Further, described P-DM1 and HER2 dimerisation inhibitor antibody agent be with about 3 weekly intervals or weekly 1 minor tick the patient with higher proliferation illness is used;
Further, described Mammals is HER2 positive patient; Further, described HER2 positive patient has accepted Trastuzumab and other chemotherapy agents therapy.
Another aspect of the present invention also provides antibody-drug conjugates P-DM1 of the present invention and the purposes of therapeutic agent compositions in the medicine for the preparation for the treatment of Mammals or people's hyperproliferative disease or illness (such as cancer, comprises and regulating and controlling by HER2).
Wherein, higher proliferation illness of the present invention is cancer, further, described higher proliferation illness expresses the cancer of HER2, further, described cancer is mammary cancer, cancer of the stomach, ovarian cancer, cervical cancer, prostate cancer, carcinoma of testis, genitourinary tract cancer, nonsmall-cell lung cancer, colorectal carcinoma, osteocarcinoma, carcinoma of the pancreas, colon-rectum, liver cancer and cholangiocarcinoma, skin carcinoma, the esophageal carcinoma, laryngocarcinoma, glioblastoma, neuroblastoma, gland cancer, oral carcinoma, thyroid carcinoma, lung cancer, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, kidney, carcinoma of small intestine, large bowel cancer, the rectum cancer, nasopharyngeal carcinoma, bladder cancer, melanoma, lip cancer, hair cell cancer, follicular carcinoma, brain and central nervous system cancer, Huo Qijin lymphatic cancer or leukemia, be preferably mammary cancer.
It is the method for effect prediction active drug combination in body from the efficacy data of body outer cell proliferation and in-vivo tumour xenograft experiments that another aspect of the present invention also provides by qualitative and quantitative analysis, and wherein said combination comprises P-DM1 and HER2 dimerisation inhibitor antibody.
The invention provides a kind of method for determining the compound that will combinationally use for cancer therapy, comprise: a) with the outer tumor cell line of the therapeutic combination handling body of Pertuzumab-MCC-DM1 and HER2 dimerisation inhibitor antibody, and b) measure collaborative or non-synergistic effect, be cancer therapy determination Synergistic treatment agent combination thus.
Further, the present invention also provides a kind of method for determining the compound that will combinationally use for cancer therapy, comprise: the breast cancer cell that (a) increases to HER2 or stomach cancer cell use the therapeutic combination of Pertuzumab-MCC-DM1 and HER2 dimerisation inhibitor antibody, (b) measuring the suppression of on cell proliferation, is cancer therapy determination Synergistic treatment agent combination thus.Wherein, with P-DM1 and the Trastuzumab combine measured combinatorial index (CI) of fixed concentration ratio, or combine the Trastuzumab combine measured combinatorial index (CI) of various concentration with the P-DM1 of fixed concentration.CI value is less than 0.9 instruction synergetic property; CI value indicates additivity between 0.9-1.1; And CI value is greater than 1.1 instruction Antagonisms.
Wherein, the breast cancer cell of described HER2 amplification is BT-474, SK-BR-3; The stomach cancer cell of described HER2 amplification is NCI-N87.
Antibody-drug conjugates of the present invention (P-DM1 can be prepared by the following method:
1) buffer-exchanged of antibody
Desalination chromatography (SephadexTM G25 desalting column) mode is utilized to replace handkerchief trastuzumab stoste in reaction buffer (potassium phosphate salt/NaCl/EDTA), and concentrated antibody, prepare handkerchief trastuzumab antibody;
2) preparation of MCC-DM1 mother liquor
Take MCC-DM1, fully dissolve with N,N-DIMETHYLACETAMIDE (DMA) and prepare mother liquor;
3) linked reaction
In the handkerchief trastuzumab prepared by step (1), add the MCC-DM1 mother liquor that step (2) prepares carry out conjugation reaction.At first with some excessive MCC-DM1 titrated antibody to measure DM1: mAb ratio of hope.Then the SMCC-DM1 mother liquor adding 8-10 times of excess molar ratio reacts;
4) purifying
Adopt gel-filtration column (Superdex200) by gel-filtration purified for linked reaction mixture sodium succinate/NaCl damping fluid, collect peak sample according to UV280 ultraviolet absorption value, or ultrafiltration number time.
In the present invention, make as given a definition:
Term " treatment " or " process " refer to both therapeutic treatment and preventative or precaution measure, and wherein target is prevention or slows down (alleviating) undesired physiology change or illness, the such as growth of higher proliferation situation such as cancer, is formed or propagates.In order to the present invention, clinical effectiveness that is favourable or that expect includes but not limited to: relief of symptoms, weaken the degree of disease, morbid state stablizes (namely not worsening), postpone or slow down disease progression, improve or the state that palliates a disease, and rehabilitation (no matter be part or completely), no matter be detectable or undetectable." treatment " or " process " can also refer to survive with not connecing to extend compared with subject expection survival.Need the experimenter for the treatment of to comprise the experimenter that suffers from disease or illness for a long time and tend to be attacked by a disease or illness experimenter or the experimenter of situation or illness will be prevented.
Term " treatment significant quantity " refers to the amount of the compounds of this invention, it (i) treats specified disease described herein, situation, or illness, (ii) alleviate, improve, or eliminate specified disease, situation, or one or more symptoms of illness, or (iii) prevent or postpone specified disease, situation, or the outbreak of one or more symptoms of illness.When cancer, the treatment significant quantity of medicine can reduce cancer cells number; Reduce gross tumor volume; Suppress (i.e. slowing down to a certain degree preferably stops) cancer cell infiltration in peripheral organs; Suppress (i.e. slowing down to a certain degree preferably stops) metastases; Tumor suppression growth to a certain degree; And/or to a certain degree alleviate one or more symptoms with related to cancer.With regard to medicine can anticancer growth and/or kill existing cancer cells degree with regard to, it can be T suppression cell and/or cytotoxinic.For cancer therapy, such as effect can be measured by the time (TTP) and/or mensuration responsiveness (RR) of evaluating distance disease progression.
" higher proliferation illness " refers to tumour, cancer, and true tumor tissue, comprises before cancerating and the non-true tumor stage, but also comprises psoriatic, endometriosis, polyp and fibroadenoma.
Term " cancer " and " carcinous " are pointed to or describe feature in Mammals and be generally the not modulated physiological situation of Growth of Cells." tumour " comprises one or more cancerous cells.The example of cancer includes but not limited to cancer, lymphoma, blastoma, sarcoma and leukemia or lymphoid malignancies.The more specifically example of this type of cancer comprises squamous cell carcinoma (such as epithelial squamous cell cancer), and lung cancer (comprises small cell lung cancer, nonsmall-cell lung cancer, the gland cancer of lung, and the squama cancer of lung), peritoneal cancer, hepatocellular carcinoma, cancer of the stomach (comprising gastrointestinal cancer), film gland cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, the dirty cancer of wing, hepatoma, mammary cancer, colorectal carcinoma, the rectum cancer, colorectal carcinoma, carcinoma of endometrium or uterus carcinoma, salivary-gland carcinoma, kidney, prostate cancer, carcinoma vulvae, thyroid carcinoma, liver cancer, anus cancer, penile cancer, and head and neck cancer.
Term " pharmacy is acceptable " indicate this material or composition must be in chemistry and/or toxicology with other composition forming preparaton and/or the Mammals treated with it compatible.
What term used herein " collaborative " referred to medicament more single than two or more adds the more effective therapeutic combination with effect.The determination of the cooperative interaction between the antibody of P-DM1 and HER2 dimerisation inhibitor can based on the result obtained from assay method described herein.
Combination treatment can provide " synergetic property " and prove " working in coordination with ", namely uses the effect realized during activeconstituents to be greater than together and separately uses caused effect sum.Synergistic effect can be obtained: (1) is prepared altogether with the dosage unit formulations combined and used simultaneously or send when activeconstituents is as described below; (2) as the preparaton alternate delivery separated; Or (3) provide some other schemes.When sending in rotational therapy, when compound is sequential use or limit send time (such as by the difference injection in syringe separately) can synergistic effect be obtained.Generally speaking, during rotational therapy, sequentially (namely on the time continuously) use often kind of activeconstituents of effective dose.
Beneficial effect:
In of the present invention, by Pertuzumab and small molecule chemotherapeutic drug coupling, the composition of P-DM1 and HER2 dimerisation inhibitor antibody is show synergistic in anticancer growth in vitro and in vivo, can reach the illness of HER2 mediation as the better result for the treatment of of cancer.Antibody-drug conjugates P-DM1 of the present invention and considerably improve result for the treatment of with the combination of antibody trastuzumab, provides illness as more effective in the cancer method for the treatment of based on HER2 mediation.
Additional advantage of the present invention and novel characteristic are listed in the following description, are for those skilled in the art apparently maybe to be learned by practice of the present invention after the specification sheets of part below checking.Can be familiar with and obtain advantage of the present invention by means of the means/instrument particularly pointed out in claims, combination, composition and method.
Accompanying drawing explanation
Fig. 1 shows the Pertuzumab-MCC-DM1(P-DM1 of independent various concentration), P-DM1 and the Trastuzumab combined treatment of Trastuzumab and fixed concentration ratio (1:1) after 5 days to the effect of BT-474 cells in vitro cell inhibitory effect.
Fig. 2 shows the Pertuzumab-MCC-DM1(P-DM1 of various fixed concentration) combine Trastuzumab, and the Trastuzumab process of independent various concentration after 5 days to the effect of BT-474 cells in vitro cell inhibitory effect.
Fig. 3 shows the Pertuzumab-MCC-DM1(P-DM1 of independent various concentration), P-DM1 and the Trastuzumab combined treatment of Trastuzumab and fixed concentration ratio (1:10) after 5 days to the effect of NCI-N87 cells in vitro cell inhibitory effect.
Fig. 4 shows the Pertuzumab-MCC-DM1(P-DM1 of various fixed concentration) combine Trastuzumab, and the Trastuzumab process of independent various concentration after 5 days to the effect of NCI-N87 cells in vitro cell inhibitory effect.
Fig. 5 shows the Pertuzumab-MCC-DM1(P-DM1 of independent various concentration), the P-DM1 of Trastuzumab and various fixed concentration combines Trastuzumab combined treatment after 5 days to the effect of SK-BR-3 cells in vitro cell inhibitory effect.
Fig. 6 (A) shows the Pertuzumab-MCC-DM1(P-DM1 of independent various concentration) process 5 days after to the effect of Calcu-3 cells in vitro cell inhibitory effect, (B) show various fixed concentration P-DM1 combine Trastuzumab, and the Trastuzumab(+ solvent of independent various concentration) process 5 days after to the effect of Calu-3 cells in vitro cell inhibitory effect.
Fig. 7 (A) shows the Pertuzumab-MCC-DM1(P-DM1 of independent various concentration) process 3 days after to the effect of DU-145 cells in vitro cell inhibitory effect, (B) show various fixed concentration P-DM1 combine Trastuzumab, and the Trastuzumab(+ solvent of independent various concentration) process 3 days after to the effect of DU-145 cells in vitro cell inhibitory effect.
Fig. 8 (A) shows the Pertuzumab-MCC-DM1(P-DM1 of independent various concentration) process 3 days after to the effect of SKOV-3 cells in vitro cell inhibitory effect, (B) show various fixed concentration P-DM1 combine Trastuzumab, and the Trastuzumab(+ solvent of independent various concentration) process 3 days after to the effect of SKOV-3 cells in vitro cell inhibitory effect.
Fig. 9 shows below the time dependent figure of gross tumor volume average to Herceptin-resistance human breast carcinoma BT-474/T721 Nude Mice after administration: (l) solvent control; (2) P-DM1 3mg/kg; (3) P-DM1 10mg/kg; (4) P-DM1 3mg/kg+Trastuzumab 10mg/kg.
Embodiment
Certain embodiments of the present invention are addressed in detail, exemplified with their example in appended structure and formula at this.Although the present invention will be described together with cited embodiment, be to be understood that they are not intended to limit the invention to those embodiments.On the contrary, the present invention is intended to contain all alternativess, amendment and equivalent, and it can be included in the scope of the invention that claim limits.Those skilled in the art can understand many methods that are similar with material with method described herein or that be equal to and material can be used for implementing the present invention.The present invention is limited to absolutely not described method and material.If the document taken in, patent are different from the application with similar material or contradiction, include but not limited to defined term, the usage of term, described technology, like this, be as the criterion with the application.
Embodiment
In order to illustrate the present invention, comprise the following example.But, should be appreciated that these embodiments do not limit the present invention, and be intended to prompting enforcement method of the present invention.
Embodiment 1:Pertuzumab-MCC-DM1(P-DM1) preparation
Preparation process is as follows:
1) buffer-exchanged of antibody
Utilize desalination chromatography (SephadexTM G25 desalting column) mode to replace handkerchief trastuzumab stoste in reaction buffer (50mM potassium phosphate salt/50mM NaCl/2mM EDTA, pH7.5), and concentrated antibody concentration is to 5mg/ml, prepares handkerchief trastuzumab antibody;
2) preparation of MCC-DM1 mother liquor
Take MCC-DM1, fully dissolve the MCC-DM1 mother liquor of preparation 10mg/ml with N,N-DIMETHYLACETAMIDE (DMA);
3) linked reaction
In the handkerchief trastuzumab prepared by step (1), add the MCC-DM1 mother liquor that step (2) configures carry out conjugation reaction.At first with some excessive MCC-DM1 titrated antibody to measure DM1: the mAb ratio of wishing, be 6-10 times of molar excess for people's antibody this scope usual.In reaction, DMA is within 5%v/v.Temperature of reaction is 25 DEG C, and the reaction times is 1.5 to about 20 hours.Reaction is divided into three groups to carry out:
A) the SMCC-DM1 mother liquor of 8 times of excess molar ratio is added in reaction;
B) the SMCC-DM1 mother liquor of 9 times of excess molar ratio is added in reaction;
C) the SMCC-DM1 mother liquor of 10 times of excess molar ratio is added in reaction;
4) purifying
Adopt gel-filtration column (Superdex200) by gel-filtration purified for the sodium succinate of linked reaction mixture pH5.0/150mM NaCl damping fluid, collect peak sample according to UV280 ultraviolet absorption value, or ultrafiltration number time.By measure conjugate 252 and 280nm absorbancy and use DM1 and antibody to measure the number (calculation formula is such as formula 1) of the DM1 molecule of each Ab antibody molecule in final conjugate at the known optical extinction coefficient of these two wavelength.Use the Conjugate ratio of mass spectrometry counting yield simultaneously, and contrast.Data are in table 1.
Formula 1
Table 1 feed ratio is on the impact of Conjugate ratio
The measuring method of Conjugate ratio in this experiment: measure Conjugate ratio and refer to the quantity measuring and each monoclonal antibody molecule is connected with small-molecule drug, i.e. the mol ratio of conjugate Chinese traditional medicine and antibody.Ultraviolet spectrophotometry and mass spectrometry two kinds of methods can be adopted to measure.Ultraviolet spectrophotometry: by measuring the ultraviolet absorption value of conjugate at 252nM and 280nM place, and undertaken calculating Conjugate ratio (DAR) by langbobier law; Mass spectrometry: antagonist-maytenin alkaloid conjugate carries out ESI-MS analysis, can obtain the peak type figure connected without number medicine, carry out calculating Conjugate ratio according to the area at each peak.The Conjugate ratio obtained by two kinds of methods has good consistence.
Conjugate concentration determination in this experiment: adopt ultraviolet spectrophotometry, be determined at the ultraviolet absorption value at 252nM and 280nM place, by the concentration of langbobier law calculating antibody and medicine; Conjugate concentration described in the present invention is monoclonal antibody concentration and the summation being connected to maytenin alkaloid (DM1) medicine on monoclonal antibody.
Embodiment 2: body outer cell proliferation measures biological activity test
Below in experiment, experiment material used derives from: DMEM substratum, F12K substratum, RPMI1640 substratum, 0.25% trypsinase-EDTA, foetal calf serum, 100 × Sodium.alpha.-ketopropionate, 100 × mycillin are purchased from Gibco company.Sulforhodamine B (Sulforhodamine B, SRB) available from Sigma.BT-474 breast cancer cell and NCI-N87 stomach cancer cell are from Chinese Academy of Sciences's Kunming cell bank, SK-BR-3 breast cancer cell is from Bo Gu bio tech ltd, Shanghai, Calu-3 lung carcinoma cell is from Shanghai Inst. of Life Science, CAS cell bank, and SKOV-3 ovarian cancer cell and DU-145 prostate cancer cell are from American type culture collection (ATCC).Other reagent are all analytical pure.96 hole flat-bottomed polystyrene (Corning, catalog number 3599).Synergy2 microplate reader (Bio-Tek).
In the present embodiment, have studied Pertuzumab-MCC-DM1(P-DM1) separately or combine with Trastuzumab the effect that tumor cell line is bred.
The present embodiment uses Sulforhodamine B (SRB) colorimetry to evaluate the antiproliferative effect of drug regimen.SRB is a kind of pink anionic dyestuff, soluble in water, in acid condition can specifically in cell the basic aminoacids of constitutive protein matter be combined; Under 510nm wavelength, produce absorption peak, light absorption value and the linear positive correlation of cell concentration, therefore can be used as the detection by quantitative of cell count.
The clone that the present embodiment is selected has: BT-474, SK-BR-3 breast cancer cell, NCI-N87 stomach cancer cell, Calu-3 lung carcinoma cell, SKOV-3 ovarian cancer cell and DU-145 prostate cancer cell.
BT-474, SK-BR-3, NCI-N87 cell is in 1640 substratum containing 10% foetal calf serum, Calu-3, SKOV-3, DU-145 cell is in the DMEM substratum containing 10% foetal calf serum, in 37 DEG C, logarithmic phase is cultured in 5%CO2 incubator, the above-mentioned cell being in logarithmic phase is seeded to 96 well culture plates with the density of 2 × 103 ~ 9 × 103 cell per well respectively, every hole 100 μ L, cultivate after 24 hours, the medicine adding different concns acts on 3 days or 5 days respectively, respectively with 3, 4 or 5 times of dilution preparations, 9 concentration, each concentration establishes multiple hole, to make all medicinal composition treatment group at same plate, and establish Vehicle controls and the cell-free medium hole of respective concentration.After effect terminates, attached cell inclines nutrient solution, adds the solution of trichloroacetic acid (30% of 4 DEG C of precoolings, w/v) 100 μ l, fix 1 hour in 4 DEG C, use deionized water rinsing subsequently 5 times, after drying at room temperature, every hole adds the SRB dye liquor (Sigma of 0.4% (w/v), 1% glacial acetic acid preparation) 100 μ L, after incubated at room temperature dyeing 30min, rinse 4 times with 1% glacial acetic acid, remove unconjugated dyestuff, room temperature is dried.Every hole adds 10mM Tris solution 100 μ L, after incubated at room temperature dyeing 15min, rinse five times with 1% glacial acetic acid and wash away unconjugated SRB, after drying at room temperature, every hole adds 10mM Tris damping fluid (pH=10.5) and dissolves the dyestuff be combined with cell protein, adopt Synergy2 microplate reader (Bio-Tek) wavelength 510nm and 690nm place to measure absorbance value (OD value), and obtain A=OD510-OD690.
Inhibiting rate (%)=(A contrasts-A administration)/A contrasts × 100%.
Use Chou and Talalay combined method with CalcuSyn software program, determine combinatorial index (CI) by isoboles CI=(D) 1/ (Dx) 1+ (D) 2/ (Dx) 2 that solve an equation.When the suppression X% that medicine 1 (D) 1 and medicine 2 (D) 2 combines, (Dx) 1 and (Dx) 2 are suppression X% be used alone medicine 1 and medicine 2 time concentration.For each compound, use the growth % value under each concentration recorded by SRB assay method.
This experiment uses Pertuzumab-MCC-DM1(P-DM1) alone or in combination the tumor cell line of Trastuzumab to multiple HER2 process LAN carried out the research of Cell culture invitro proliferation function, also the tumor cell line of non-HER2 process LAN has been carried out to the research of Cell culture invitro proliferation function simultaneously.Use Chou & Talalay methods analyst data, with P-DM1 and the Trastuzumab combine measured combinatorial index (CI) of fixed concentration ratio, or combine the Trastuzumab combine measured combinatorial index (CI) of various concentration with the P-DM1 of fixed concentration.CI value is less than 0.9 instruction synergetic property; CI value indicates additivity between 0.9-1.1; And CI value is greater than 1.1 instruction Antagonisms.P-DMl individual curing all can produce anti-tumour cell proliferative activity, and as shown in Figure 1, the BT-474 cell for HER2 process LAN uses P-DM1 and the Trastuzumab of fixed concentration ratio (1:1) combination to cause the antiproliferation of working in coordination with.Murine xenogralt research shows similar result, and P-DM1 combines Trastuzumab and causes and the antitumor efficacy (Fig. 9) greatly strengthened compared with independent pharmaceutical treatment.As shown in Figure 3, the antiproliferation that the NCI-N87 cell of HER2 process LAN uses P-DM1 and the Tastuzumab of fixed concentration ratio to combine (P-DM1:Tastuzumab is 1:10) also to cause working in coordination with, except the combination of the highest (10 μ g/mL P-DM1 and 100 μ g/mL Trastuzumab) or minimum (0.0256ng/mL P-DM1 and 0.256ng/mL Trastuzumab) concentration.As in Figure 3-5, in NCI-N87, SK-BR-3 cell of HER2 process LAN, the Trastuzumab of various concentration and the P-DM1 of multiple fixed concentration combines the antiproliferation all causing working in coordination with.As shown in Figure 2, in BT-474 cell, the Trastuzumab of various concentration and the P-DM1 of multiple fixed concentration combines the antiproliferation all causing working in coordination with, Trastuzumab(25 or 100 μ g/mL except with high density) combination.As shown in Figure 6, to the Calu-3 cell of HER2 process LAN, the P-DM1(0.5 of fixed concentration or 5 μ g/mL) with the Trastuzumab(0.1 ~ 6.5 μ g/mL of finite concentration scope) combine the antiproliferation causing working in coordination with.As shown in Figure 7, to the DU-145 cell of non-HER2 process LAN, the Trastuzumab of various concentration and the P-DM1(7 of fixed concentration or 10 μ g/mL) combine the antiproliferation causing working in coordination with.As shown in Figure 8, to the SKOV-3 cell of non-HER2 process LAN, independent P-DMl produces inhibition tumor cell proliferation function; P-DMl and the Trastuzumab combination of fixed concentration is more effective unlike independent P-DMl.
Embodiment 3: anti-tumor in vivo effect determination experiment:
Effect of combination of the present invention can be measured in vivo, in rodent, namely implant allograft or the heterograft of cancer cells, and by described combined treatment tumour.By test mice medicine or control treatment, and monitor several weeks or longer time with measures arrive tumour double time, log cell kills and wounds, and tumor suppression.
1) laboratory animal
BALB/cA-nude nude mouse, 6-7 week, male, purchased from Shanghai Slac Experimental Animal Co., Ltd..Conformity certification number: SCXK(Shanghai) 2012-0002.Feeding environment: SPF level.
2) experimental procedure
Nude mouse subcutaneous vaccination human breast carcinoma BT-474/T721 cell, after tumor growth to 100-200mm3, by animal random packet (D0).Dosage and dosage regimen are in table 2.Survey 2 knurl volumes weekly, claim mouse heavy, record data.Gross tumor volume (V) calculation formula is:
V=1/2 × a × b2 wherein a, b represents length and width respectively.
T/C (%)=(T-T
0)/(C-C
0) × 100, wherein T, C are the gross tumor volume at the end of experiment; T
0, C
0for gross tumor volume when experiment starts.
Table 2 dosage and dosage regimen
D0: administration time for the first time; IV: intravenously administrable;
Mouse number when experiment starts: control group n=10, treatment group n=6.
3) experimental result
Fig. 9 shows the curative effect to Herceptin-resistance human breast carcinoma BT-474/T721 Nude Mice after following administration: (l) solvent control; (2) P-DM1 3mg/kg; (3) P-DM1 10mg/kg; (4) P-DM1 3mg/kg+Trastuzumab10mg/kg.Result shows, P-DM1(3,10mg/kg, IV, 1 time weekly, totally 3 times) the obvious growth suppressing BT-474/T721 nude mouse subcutaneous transplantation knurl, tumour inhibiting rate is respectively 72% and 97%, and wherein high dose group has 1/6 tumor partial regression; Trasutuzumab(10mg/kg, IV, 1 time weekly, totally 3 times) antitumor action of notable synergistic P-DM1, make tumour inhibiting rate bring up to 127% from 72% during alone P-DM1 3mg/kg, and have 5/6 tumor partial regression, during synergy, toxicity is not significantly increased.Therefore, P-DM1(3,10mg/kg, IV, 1 time weekly, totally 3 times) dose-dependently obviously suppress the growth of Herceptin-anti-medicine human breast carcinoma BT-474/T721 nude mouse subcutaneous transplantation knurl, cause tumor partial regression; Trastuzumab(10mg/kg, IV, 1 time weekly, totally 3 times) antitumor action of notable synergistic P-DM1.
In sum, antibody-drug conjugates P-DM1 of the present invention and considerably improve result for the treatment of with the combination of antibody trastuzumab, The inventive process provides illness as more effective in the cancer method for the treatment of based on HER2 mediation.
Claims (10)
1. there is an antibody-drug conjugates Pertuzumab-MCC-DM for following structure, i.e. P-DM1:
Wherein, mAb refers to handkerchief trastuzumab Pertuzumab, and Pertuzumab is connected with maytenin alkaloid DM1 through difunctional linker reagent SMCC, and in above formula, n represents drug-antibody ratio.
2. antibody-drug conjugates P-DM1 according to claim 1, is characterized in that, described drug-antibody is the round values between 1 to 8 than the scope of n, and wherein, 1,2,3,4,5,6,7 or 8 drug moiety covalently bind on antibody Pertuzumab.
3. the therapeutic agent compositions of medicine for the preparation for the treatment of hyperproliferative disease or illness, it is characterized in that, described therapeutic agent compositions comprises the antibody-drug conjugates P-DM1 according to claim 1 and 2 for the treatment of significant quantity and the HER2 dimerisation inhibitor antibody for the treatment of significant quantity.
4. therapeutic agent compositions according to claim 3, is characterized in that, described HER2 dimerisation inhibitor antibody is Herceptin Trastuzumab.
5. the therapeutic agent compositions according to claim 3 or 4, it is characterized in that, the form that the antibody-drug conjugates P-DM1 of described treatment significant quantity and the HER2 dimerisation inhibitor antibody of described treatment significant quantity can be combined into preparaton is used or is alternately used.
6. the therapeutic agent compositions according to claim 3 or 4, is characterized in that, described higher proliferation illness is cancer.
7. the therapeutic agent compositions according to claim 3 or 4, is characterized in that, described higher proliferation illness expresses the cancer of HER2.
8. therapeutic agent compositions according to claim 7, it is characterized in that, described cancer is mammary cancer, cancer of the stomach, ovarian cancer, cervical cancer, prostate cancer, carcinoma of testis, genitourinary tract cancer, nonsmall-cell lung cancer, colorectal carcinoma, osteocarcinoma, carcinoma of the pancreas, colon-rectum, liver cancer and cholangiocarcinoma, skin carcinoma, the esophageal carcinoma, laryngocarcinoma, glioblastoma, neuroblastoma, gland cancer, oral carcinoma, thyroid carcinoma, lung cancer, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, kidney, carcinoma of small intestine, large bowel cancer, the rectum cancer, nasopharyngeal carcinoma, bladder cancer, melanoma, lip cancer, hair cell cancer, follicular carcinoma, brain and central nervous system cancer, Huo Qijin lymphatic cancer or leukemia.
9. therapeutic agent compositions according to claim 8, is characterized in that, described cancer is mammary cancer or cancer of the stomach.
10. the application of the P-DM1 described in claim 1 or 2 in the medicine for the preparation for the treatment of hyperproliferative disease or illness.
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| PCT/CN2015/073629 WO2015131822A1 (en) | 2014-03-05 | 2015-03-04 | Antibody-drug conjugate pertuzumab-mcc-dm1, composition of pertuzumab-mcc-dm1 and trastuzumab and uses thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017088734A1 (en) * | 2015-11-23 | 2017-06-01 | 四川科伦博泰生物医药股份有限公司 | Anti-erbb2 antibody-drug conjugate and composition thereof, preparation method therefor, and application thereof |
| CN106938051A (en) * | 2016-08-22 | 2017-07-11 | 复旦大学 | Target the antibody drug conjugates of tissue factor |
| CN107012116A (en) * | 2017-05-09 | 2017-08-04 | 华东师范大学 | A kind of construction method of small intestine 3D organoids research BCRP mediate drug transshipment models and application |
| CN116407540A (en) * | 2023-02-17 | 2023-07-11 | 杭州邦顺制药有限公司 | Application of medicine in preventing and treating HER2 expression positive solid tumor |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103288957A (en) * | 2012-12-21 | 2013-09-11 | 百奥泰生物科技(广州)有限公司 | Antibody drug derivative inhibiting tumor growth, its preparation method and use |
| CN103476407A (en) * | 2010-12-09 | 2013-12-25 | 霍夫曼-拉罗奇有限公司 | Treatment of HER2-positive cancer with paclitaxel and trastuzumab-MCC-DM1 |
-
2014
- 2014-03-05 CN CN201410079082.3A patent/CN104892763A/en active Pending
-
2015
- 2015-03-04 WO PCT/CN2015/073629 patent/WO2015131822A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103476407A (en) * | 2010-12-09 | 2013-12-25 | 霍夫曼-拉罗奇有限公司 | Treatment of HER2-positive cancer with paclitaxel and trastuzumab-MCC-DM1 |
| CN103288957A (en) * | 2012-12-21 | 2013-09-11 | 百奥泰生物科技(广州)有限公司 | Antibody drug derivative inhibiting tumor growth, its preparation method and use |
Non-Patent Citations (1)
| Title |
|---|
| JOHN M. CASSADY等: "Recent Developments in the Maytansinoid Antitumor Agents", 《CHEM. PHARM. BULL.》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017088734A1 (en) * | 2015-11-23 | 2017-06-01 | 四川科伦博泰生物医药股份有限公司 | Anti-erbb2 antibody-drug conjugate and composition thereof, preparation method therefor, and application thereof |
| CN107921124A (en) * | 2015-11-23 | 2018-04-17 | 四川科伦博泰生物医药股份有限公司 | Anti-ErbB 2 antibodies drug conjugates and combinations thereof, preparation method and application |
| EA039757B1 (en) * | 2015-11-23 | 2022-03-10 | Сычуань Кэлунь-Байотек Байофармасьютикал Ко., Лтд. | ANTI-ErbB2 ANTIBODY-DRUG CONJUGATE AND COMPOSITION THEREOF, PREPARATION METHOD THEREFOR AND APPLICATION THEREOF |
| US11903948B2 (en) | 2015-11-23 | 2024-02-20 | Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. | Anti-ErbB2 antibody-drug conjugate and composition thereof, preparation method therefor, and use thereof |
| CN106938051A (en) * | 2016-08-22 | 2017-07-11 | 复旦大学 | Target the antibody drug conjugates of tissue factor |
| CN106938051B (en) * | 2016-08-22 | 2019-10-11 | 复旦大学 | Target the antibody-drug conjugates of tissue factor |
| CN107012116A (en) * | 2017-05-09 | 2017-08-04 | 华东师范大学 | A kind of construction method of small intestine 3D organoids research BCRP mediate drug transshipment models and application |
| CN116407540A (en) * | 2023-02-17 | 2023-07-11 | 杭州邦顺制药有限公司 | Application of medicine in preventing and treating HER2 expression positive solid tumor |
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