CN1905900A - Targeting of ERB antigens - Google Patents
Targeting of ERB antigens Download PDFInfo
- Publication number
- CN1905900A CN1905900A CN 200480041118 CN200480041118A CN1905900A CN 1905900 A CN1905900 A CN 1905900A CN 200480041118 CN200480041118 CN 200480041118 CN 200480041118 A CN200480041118 A CN 200480041118A CN 1905900 A CN1905900 A CN 1905900A
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- China
- Prior art keywords
- conjugate
- antibody
- biotin
- preferred
- erb
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
A conjugate comprising a) a trifunctional cross-linking moiety, to which is coupled b) an affinity ligand via a linker 1, c) a cytotoxic agent, optionally via a linker 2, and d) an anti Erb antibody or variants thereof having the ability to bind to Erb antigens expressed on mammalian tumour surfaces with an affinity-binding constant of at least 5x10<6>M<-1>, wherein the affinity ligand is biotin, or a biotin derivative having essentially the same binding function to avidin or streptavidin as biotin, wherein stability towards enzymatic cleavage of the biotinamide bond has been introduced in linker 1.
Description
The invention technical field
The present invention relates to new and the bonded conjugate of mammal Erb gene outcome and comprise the pharmaceutical composition of described conjugate, relate to the medicine box that comprises this pharmaceutical composition and external device, and relate to the method for cancer for the treatment of and/or diagnosing expression Erb gene outcome.
Background technology
The proto-oncogene of coding somatomedin and receptor thereof impels the development (Aronson, SA, Science, 254:1146-1153 (1991)) of breast carcinoma and other human malignancies, is the potential target spot of new therapeutic strategy therefore.Particularly, having observed this expression of gene in more dangerous breast carcinoma, bladder cancer, pulmonary carcinoma and gastric cancer strengthens.
Human epidermal growth factor acceptor-2 (HER2) Codocyte surface receptor, and participation causes signal transduction pathway (the DiAgustine R﹠amp of normal cell growth and differentiation; Richards RG, J.MammaryGland Biol Neoplasia 2:109-118 (1997)).Yet the HER2 receptor is crossed in the human breast carcinoma of 15-25% and is expressed (Hynes NE﹠amp; Stern DF, 1198:165-184 (1994), people such as Revillion F, Eur.J.Cancer 34:791-808 (1998)), and this cross to express with the women who suffers from the positive and lymph node disease-negative of lymph node in poor clinical result, comprise the anosis rate of reduction and total relevant (the Hynes NE﹠amp of survival rate; Stern DF, Biochim.Biophys.Acta, 1198:165-184 (1994); People such as Slamon DJ, Science, 244:707-712; Ravdin PM﹠amp; ChamnessGC, Gene, 159:19-27 (1995); Bell R.Oncology, 63 (supplementary issue 1): 39-46 (2002)).In addition, evidence suggests that at present HER2 has indicated replying the standard anticancer therapy.Also referring to PCT/US 00/18283; PCT/US 97/18385; PCT/US 98/26266; EP 1 106 183; PCT/US 00/12552 and PCT/US 00/17366.
HER-2 is the member of erbB epidermal growth factor recipient tyrosine kinase family.Early stage in the eighties in 20th century, when finding the highly homologous oncogene of AEB oncovirus coding and human epidermal growth factor acceptor (HER-1 claims ErbB1 and EGFR again), begin erbB receptor tyrosine kinase and cancer are interrelated.From the rat neuroblastoma of chemical induction, identify the gene of a kind of neu of being called subsequently, it can make the fibroblast distortion in the culture medium, and be proved to be relevant but different (Shih with it with the HER-1 gene, people such as C, Nature, 290:261-264 (1981), people such as Schechter, Nature, 312:513-516 (1984)).Almost at the same time, other 2 groups isolate the relevant proto-oncogene of people erbB and independently of one another with its called after HER-2 people such as (, Science, 230:1132-1139 (1985)) Coussens and c-erbB2 (people such as Semba, PNAS, 82:6497-6501 (1985)).It is identical with neu that these genes are proved to be subsequently.King and colleague thereof also identify a kind of EGFR related gene of crossing amplification in human breast cancer cell system; This gene also is found identical with the HER-2/neu/erbB2 gene (King, people such as CR, Science, 229:974-976 (1985)).
HER-1 has many different with HER-2: the HER-2 gene is positioned at chromosome 17 and the HER-1 gene is positioned at chromosome 7, the varying in size of HER-2mRNA and albumen and HER-1 gene outcome.ErbB receptor tyrosine kinase family also has two other member, HER-3 and HER-4 (erbB4), these 4 kinds of receptors are shared a complete membrane structure of striding, and this structure is by extracellular component and stride membrane component and comprise the intracellular region that the side has the kinase domain of tyrosine autophosphorylation action site and form jointly.
Domain different family members has many functional differences.For example, as if HER-2 does not have direct part and HER-3 does not have the endogenous kinase activity, therefore the many complex interactions that comprise dimerization between different family members be signal needed.The HER-2 receptor can signal by forming heterodimer with other HER family member who is incorporated into part, and perhaps two HER-2 molecules can have the homodimer of endogenous kinase activity in conjunction with formation.The generation that causes homodimer and heterodimer activate constituent is expressed in crossing of HER-2.ErbB receptor kinase activation is supplemented to cytoplasmic domain with a large amount of adaptins, thereby triggers a large amount of downstream signal cascades.The end product of HER-2 activation is that cell growth, division, differentiation, migration and absorption exert an influence/summarize referring to Yarden, Y﹠amp; Sliwkowski, MX, Nature Reviews in Molecular and Cellular Biology, 2:127-137 (2001).
Slamon and colleague be report at first, and the HER-2 receptor is crossed in the human breast carcinoma of 20-30% and expressed (Slamon, people such as DJ, Science 235:177-182 (1987)).In most of the cases cross to express and cause (Pauletti, people such as G, Oncogene, 13:63-72 (1996)) by HER-2 gene amplification.The amplification of people HER2 gene and/or cross prognosis mala relevant (Slamon, people such as DJ, Science, the 235:177-182 (1987) of expression and breast carcinoma and ovarian cancer; And Slamon, people such as DJ, Science, 244:707-712 (1989)).HER2 cross to express also with other cancer, comprises that gastric cancer, carcinoma of endometrium, salivary-gland carcinoma, pulmonary carcinoma, renal carcinoma, colon cancer and bladder cancer are relevant.HER-2 gene amplification causes mRNA level increase that is detected by northern blot (Northern blot) and the HER-2 acceptor levels that is detected by immunohistochemistry (IHC) or western blot analysis (Western blot) to increase.In the time can seeing multiple the duplicating of HER-2 gene in the nucleus at infection cell, adopt fluorescence in situ hybridization (FISH) can see the excessive amplification of gene the most significantly.This technology has become the effective ways that detect HER-2 gene amplification in clinical sample.
Another related gene that is called erbB3 or HER3 has also been described.Referring to U.S. Pat 5,183,884 and 5,480,968; People such as Plowman, Proc.Natl.Acad.Sci.USA, 87:4905-4909 (1990); People such as Kraus, Proc.Natl.Acad.Sci.USA, 86:9193-9197 (1989); European patent application EP 444,961 A1; With people such as Kraus, Proc.Natl.Acad.Sci.USA, 90:2900-2904 (1993).People such as Kraus (1989) find that the level of erbB3 mRNA in some HBT's cell line significantly improves, and show erbB3, are similar to erbB1 and erbB2, may work in some human malignancies.These studies show that some breast tumor cell lines have shown the remarkable rising of stable state ErbB3 tyrosine phosphorylation, and further specifying this receptor may work in human malignancies.Therefore, use the diagnosis bioassay with the bonded antibody of ErbB3 to be described in U.S. Pat 5,183, in 884 and 5,480,968 by people such as Kraus.
The effect of erbB3 in cancer is also existing, and other people explored.Have been found that it is breast carcinoma (people such as Lemoine, Br.J.Cancer, 66:1116-1121 (1992)), human primary gastrointestinal cancers (people such as Poller, J.Pathol., 168:275-280 (1992), people such as Rajkumer, J.Pathol., people such as 170:271-278 (1993) and Sanidas, Int.J.Cancer.54:935-940 (1993)) and cancer of pancreas (people such as Lemoine, J.Pathol., people such as 168:269-273 (1992) and Friess, ClinicalCancer Research, 1:1413-1420 (1995)) middle expression excessively.
ErbB3 is unique in the ErbB receptor family, because it has seldom or does not have endogenous tyrosine kinase activity (people such as Guy, Proc.Natl.Acad.Sci. people such as USA 91:8132-8136 (1994) and Kim, J.Biol.Chem.269:24747-55 (1994)).When Erb3 and ErbB2 coexpression, form active signal complex, can destroy this complex (people such as Sliwkowski, J.Biol.Chem., 269 (20): 14661-14665 (1994)) to the antibody of anti-ErbB.In addition, when with the ErbB2 coexpression, ErbB3 is enhanced to higher affine state with the affinity of transferring albumen (HRG).About the ErbB2-ErbB3 albumen composition also referring to people such as Levi, Journal ofNeuroscience 15:1329-1340 (1995): people such as Morrissey, Proc.Natl.Acad.Sci.USA 92:1431-1435 (1995); People such as Lewis, Cancer Res., 56:1457-1465 (1996).
People such as Rajkumar (British Journal Cancer.70 (3): 459-465 (1994)) have researched and developed the monoclonal antibody of a kind of anti-ErbB3, and its no anchorage dependence growth to the cell line of expressing this receptor has antagonism.
1 grade of subfamily of growth factor receptor protein tyrosine kinase is further extended to comprising that the HER4/p180erbB4 receptor is (referring to European patent application EP 599,274; People such as Plowman, Proc.Natl.Acad.Sci.USA, people such as 90:1746-1750 (1993) and Plowman, Nature, 366:473-475 (1993)).People such as Plowman find that the HER4 that increases expresses with some cancer of epithelium genesis, comprises that breast carcinoma is closely related.Therefore, expressing the diagnostic method that detects human neoplasia disease (particularly breast carcinoma) by evaluation HER4 is described in the European patent application EP 599,274.
The discovery that the research of activation of HER2 oncogene has been caused transferring protein polypeptide family.As if these protein derive from the monogenic alternative splicing that is positioned on human chromosome 8 galianconism, referring to people such as Lee, and Genomics, 16:790-791 (1993); With people such as Orr-Urtreger, Proc.Natl.Acad.Sci.USA, the 90th volume, 1867-1871 page or leaf (1993); PCT/US 79/03546 and PCT/US97/11825.
HER-2 crosses expression in the human breast carcinoma of only a few and the significantly bad discovery of prognosis points out software engineering researchers invent with the medicine of HER-2 as the treatment target spot.Comprise that some seminar of the worker of Genentech Inc. have cultivated the mouse monoclonal antibody of HER-2 ectodomain, and prove that the part in these antibody can suppress the growth (Hudziak of the cell line of expressed receptor, people such as RM, Molecular Cell Biology, 9:1165-1172 (1989); Fendly, people such as BM, CancerResearch 50:1550-1558 (1990)).This effect also sees in the human breast carcinoma xenograft that HER-2-crosses expression, wherein the antibody effect be found can with antineoplastic agent such as cisplatin collaborative (Pietras, people such as RJ, Cancer Research, 9:1829-1838 (1994); Harris, M﹠amp; Smith, I, Endocrine-Related Cancer, 9:75-85 (2002)).
Genentech researchers have developed one group can suppress HER-2
+The mouse monoclonal antibody of cell line; MuMAb 4D5 the most effectively wherein.Find that this antibody can suppress to express the cell line proliferation of HER-2, but the cell that the HER-2 level is not had to raise has or not influence (Sarup, people such as JC, Growth Regulation, 1:72-82 (1991)) very little.Someone finds that 4D5 is effective inhibitor (Beselga﹠amp of people's breast carcinoma xenograft growth; Mendelsohn, Pharmacology Therapy, 64:127-154 (1994) and therefore selectedly carry out further clinical development.
In order to reduce the probability that produces the anti-Mus immunne response of people, subsequently with the 4D5 Humanization of murine monoclonal antibody.Carter and colleague are with the hypervariable region sub-clone of the antibody plasmid to encode human kappa light chain and IgG1 constant region, to produce the carrier of coding chimeric antibody, it is subsequently by site directed mutagenesis quilt further humanization (Carter, people such as P, PNAS:89,4285-4289 (1992)).With carrier transduction to Chinese hamster ovary (CHO) cell subsequently secretory antibody to culture medium and purification therefrom.The chimeric antibody that is called trastuzumab is 95% people and 5% Mus and keeps high-affinity to the HER-2 antigenic determinant of parental generation antibody.
Trastuzumab to 3 times of the affinitys of HER-2 to its parental generation murine antibody 4D5.Verified it and 4D5 are similar, and HER-2 overexpressing cell cording is had significant antiproliferative effect and to the effect very little (Carter, people such as P, PNAS:89,4285-4289 (1992)) of the cell of not expressing HER-2.This antiproliferative effect is also by proving that the growth of the BT-474 tumor xenogeneic graft of setting up in this experiment is suppressed by trastuzumab in the Baselga and the breast carcinoma xenograft experiment of working together in vivo.When dosage was less than 1mg/kg, growth was dose dependent ground and suppresses, and in the next not growth (Baselga, people such as J, Cancer Research, 58:2825-2831 (1998)) fully of higher dosage.In same research, research worker tries trastuzumab is added in paclitaxel or the doxorubicin.Separately chemotherapy is proved to be the anti-tumor activity that has only appropriateness, and causes chemotherapeutic effect significantly to strengthen with the combination treatment of trastuzumab, adopts paclitaxel and trastuzumab to can be observed maximum growth and suppresses.
Pegram and colleague have investigated the effect of trastuzumab to many other chemotherapeutics in HER-2 transfection MCF7 xenograft models.Synergistic interaction sees cisplatin, docetaxel, plug for group, cyclophosphamide, vinorelbine and etoposide.Superposition sees doxorubicin, paclitaxel, vinblastine and methotrexate, and finds that the combination of trastuzumab and 5-fluorouracil (5-FU) is antagonism (Pegram, people such as M, Oncogene, 18:2241-2251 (1999); Konecny, people such as G, Breast Cancer Research and Treatment, 69:53-63 (2001) summarizes referring to Pegram people such as MD, Seminars in Oncology, 27:21-25 (2000)).Observed synergism has caused the clinical trial exploration of trastuzumab and chemotherapeutic combination in these body inner models.
Proved trastuzumab (Herceptin
) (people such as Cobleigh MA, J.Clin.Oncol.17:2639-2648 (1999) when shifting the mastopathy patient with administered as monotherapy to HER-2 is positive; (people such as Slamon DJ, N.Engl.J.Med.344:783-792 (2001)) has significant clinical advantages during people such as Vogel CL.Et, J.Clin.Oncol. 20:719-726 (2002)) or with the chemotherapy combination medicine-feeding.Trastuzumab treatment has impressive survival advantage (people such as Vogel CL, J.Clin.Oncol.20:719-726 (2002); People such as Slamon DJ, N.Engl.J.Med.344:783-792 (2001)), such advantage comprises: compare with chemotherapy only, when proving that by immunohistochemistry (IHC) its tumor has IHC 3+ albumen to cross in patient's the chemotherapy of expression and adds trastuzumab, make the half survival increase by 45% (individual month of 29 vs20, (Smith IE, Anticancer Drugs 12 (supplementary issue .4): S3-S10 (2001) respectively).Illustrated as these supplementary issue other parts, the evidence of cross-over experiment contrast shows that the clinical advantages that is reached by trastuzumab is than the treatment that gives a little earlier better (Bell R.Oncology, 63 (supplementary issue 1:39-46 (2002)) under the transfer environment.
WO 03/03511 (AB WARF) discloses and has been used for the multiple medicines thing multiple ligand conjugate that targeted drug transmits, and wherein the EGF-R ELISA of identification polypeptide, monoclonal antibody or its part can be used as target molecule.
(Genentech Inc.) discloses the Therapeutic Method that uses anti-ErbB antibody-maytansinoid conjugate to WO 01/00244, wherein direct the and anti-ErbB antibodies of maytansinoid.
WO 00/02050 (Mitra Medical Technology AB and radiation oncology system of University of Washington) discloses a kind of three function reagent of puting together with biomolecule.
In 2003, estimating had 211,300 American Women the wellability breast carcinoma newly to occur approximately.The women is the most normal to diagnose out non-skin cancer.The sustainable growth since nineteen eighty of breast carcinoma sickness rate is although rate of increase decreased in the eighties in the nineties in 20th century than 20th century.In addition, in nearest a period of time, the breast carcinoma sickness rate only increases in 50 years old and above crowd.In 2003,1,300 cancer of male breast new case will appear in expectation.
Except that the wellability breast carcinoma, in the women, estimated 55,700 original position breast carcinoma new cases will be taken place in 2003.Wherein, about 85% will be ductal carcinoma in situ(DCIS) (DCIS).The increase that the DCIS case detects is that the direct result that increases is used in the mastography screening, and (promptly before can being felt) detects the wellability breast carcinoma before can touching.
Die from breast carcinoma (39,800 women, 400 male) in respect of about 40,200 patients in advance, in women's cancer mortality, be in the 2nd.According to latest data, along with the young woman of white man and non-descendants' American philtrum reduces in a large number, mortality rate is annual in the period of 1989-1995 to descend 1.4%, annually subsequently descends 3.2%.This minimizing is likely and detects in early days and improve both result of treatment.
Although remove tumor by operation, there is the danger of recurrence all the time, because have the position that microscopic cancerous cell has been diffused into distant place in the health.In order to reduce the danger of patient's recurrence, many patients with mastocarcinoma are accepted chemotherapy.Chemotherapy is used the cancer therapy drug that spreads all over whole body.
Many different chemotherapeutics are arranged, they usually behind corrective surgery combination medicine-feeding 3 to 6 months.According to the kind of the chemotherapy regimen of being accepted, Drug therapy can give in per 3 to 4 weeks, and many medicines need the whole body administration.Modal 2 kinds of schemes are AC (doxorubicin and cyclophosphamide) administration 3 months or CMF (cyclophosphamide, methotrexate and fluorouracil) administration 6 months.
Sometimes patient's cancer can recur, and perhaps develops into the outer disease of IV phase breast.These patients need chemotherapy, and may attempt many kinds of different pharmaceuticals up to producing response.Sometimes chemotherapy gives before operation, for example new adjuvant chemotherapy.It is generally used for need be before can performing the operation the cancer in reduced very late period.
Breast carcinoma is accepted the high-energy radiotherapy usually, and this treatment requires the patient to have 5 days to go to the radiotherapy center in one week, adds up for 6 weeks.Radiation is very important for the danger that reduces local recurrence, and through being usually used in later phase case to kill the tumor cell that may be positioned at lymph node.
Can increase " mean survival time " of expressing the HER-2 patients with mastocarcinoma although proved trastuzumab (Herceptin), when its most significant effect betides and makes up with chemotherapy.Yet these combined therapies have serious adverse, particularly fatal in some cases ventricular dysfunction and congestive heart failure.The sickness rate of cardiac dysfunction and severity are especially high in the patient who accepts Herceptin and anthracycline antibiotics and cyclophosphamide combined therapy.
For a large amount of cancer indications, radioimmunotherapy is proved to be than more effective (the Goldenberg D.M.﹠amp of naked antibody; Nabi, H.A., Cancer 89:104-113,2000).
The effectiveness of " yet naked antibody " depends on the ability of inducing host's tumor response through antibody dependent cellular cytotoxicity (ADCC) and complement activation, perhaps the ability of blocking and may preventing further growth by the interruption of growth signal when for trastuzumab (Herceptin).On the other hand, come the kill tumor cell through radiolabeled antibody by the emission radioactive particle, therefore even when the host immune effector function is impaired also possibility is effective.In addition, based on the characteristic of radionuclide, radioimmunotherapy can destroy the cell (interference of interchannel) away from immune target cell.Therefore, even also can treat xenograft tumor (expressing the tumor of multiple antigen degree), because not all cell is all by targeting.Therefore the antibody that carries radionuclide is brought into play it and is killed cytosis and only need the tumour-specific binding site.Yet the radioimmunity targeting also can use with naked antibodies and/or with chemotherapy or external exposure.
The use of radioimmunity targeting in breast carcinoma explored in some researchs.The antigen target mainly comprises CEA, MUC1 and U6.These and other is used for the antibody of breast carcinoma recently by summary (GoldenbergD.M.﹠amp; Nabi, H.A., Cancer 89:104-113,2000).
Yet, but normal organ toxicity has limited the live vol of safely use in the patient, thus limited the tumor absorbed dose.Primary dose limitation organ is a bone marrow.Hematologic cancers such as local B cell lymphoma can be 30 to 44Gy external beam X-ray therapy healing by dosage.The dosage that is reached by conventional planning immunization therapy (not using stem cell to support) is lower.People such as Wiseman have reported the median doses 15Gy (people such as Wiseman G, Critical reviews inOncology/Hematology 39 (2001) 181-194) that the B cell lymphoma III phase tests.Responsiveness is that 80% objective response and 34% responds fully.The Seattle group that uses stem cell to support has reported that the highest remission rate is 80% to alleviate people such as (, J.Clin.Oncol.16 (10): 3270-3278,1998) Liu Steven Y fully.They estimate that knub position reaches 27 to 92Gy.
Non-hematology's dose limitation toxicity is the reversibility pulmonary incompetence, when this betides lung dosage more than or equal to 27Gy.Although research is not very to have comparability, they have pointed out the dose-effect relationship among the RIT.If there is dose relationship, then high dose just may make effect strengthen if can transmit more to tumor.This may be clinical maximally related, because alleviating fully behind the RIT has the longer alleviation persistent period people such as (, J.Nucl.Med.39:21S-26S, 1998) Wahl.
To this a radiosensitivity that obstacle is a bone marrow.The absorbed dose of bone marrow are higher may to cause the severe bone marrow depression.Therefore, the essential dosage that reaches more effective treatment is hindered by the gathering of the radioactivity in the blood circulation, causes the toxicity to normal organ such as bone marrow.Reported and multiplely behind intravenously administrable, removed the method (as therapeutic or diagnostic monoclonal antibody) that blood makes it not contain cell toxicant target biology molecule (summary is referring to Schriber G.J. and Kerr D.E., Current Medical Chemistry2:616-629, (1995); Goldenberg D.M., people such as J.Nucl.Med 43:693-713 (2002) and Carlsson, Radiotherapy and Oncology 66:107-117 (2003)).
Having proposed several different methods removes through radiolabeled antibody from blood circulation after with the immunoconjugates that gathers the amount that is enough to diagnose or treats in tumor fast.Wherein used certain methods comprises by forming immune complex comes enhancing body self purge mechanism.The blood clearance increase of radiolabelled antibody can obtain by using the molecule with the treatment antibodies, and for example other points to monoclonal antibody (people such as Klibanov, the J.Nucl.Med 29:1951-1956 (1988) of treatment antibody; People such as Marshall, Br.J.Cancer 69:502-507 (1994); People such as Sharkey, Bioconjugate Chem.8:595-604, (1997)), avidin/Succ-PEG-DSPE (people such as Sinitsyn, J.Nucl.Med.30:66-69 (1989), people such as Marshall, Br.J.Cancer 71:18-24 (1995)) or the chemical compound that contains glycosyl (Ashwell and Morell, Adv.Enzymol.41:99-128 (1974)) that can remove by the hepatocyte receptor.
In so-called avidin tracking pattern, when having assembled the antibody of q.s in the tumor, the whole body administration after using the treatment that has been combined with biotin on it or diagnosing antibody of avidin or Succ-PEG-DSPE.Avidin or Succ-PEG-DSPE will link to each other with antibody, and so the immune complex that forms will be removed from blood circulation and remove in patient's body via liver via reticuloendothelial system (RES).These processes will improve the clearance rate of biotinylated cytotoxic antibody.The optional method that reaches same purpose is to use anti-idiotype antibody.Yet all these methods depend on the blood of liver or kidney and remove, and therefore make any one of these vitals or the cytotoxicity that both and bladder contact high dose.
Another major defect of these methods is the immunogenicity of these medicines, particularly Succ-PEG-DSPE, in a single day this immunogenicity stops repetitive therapy when immunne response taking place.
The ex vivo technique that blood is removed is widely used in the kidney dialysis, there because the renal function deficiency causes toxic substance to accumulate in blood.Other medical applications of available device outside comprises: the removal of radioactive substance; The removal of the metal of poisoning level; The removal of the toxin that antibacterial or virus produce; The removal of the medicine of poisoning level; Remove (as cancerous cell, specific hematopoietic cell is as B-, T-or NK-cell) with whole cell; The perhaps removal of antibacterial and virus.
The ex vivo technique that is used for removing from blood circulation medicine is especially attractive, because toxicant is removed from health fast.
Existing (Henry, the ChemicalAbstract 18:565 (1991) of describing of the application of these methods in the context of immunity targeting; People such as Hofheinze D, Proc.Am.Assoc.Cancer Res.28:391 (1987); People such as Lear J.K., Antibody Immunoconj. Radiopharm.4:509 (1991); People such as Dienhart D.G., Antibody Immunoconj.Radiopharm.7:225 (1991); People such as DeNardo S.J., J.Nucl.Med 33:862-863 (1992); People such as DeNardo G.L., J.Nucl.Med 34:1020-1027 (1993); DeNardo G.L., J.Nucl.Med 33:863-864 (1992); With U.S. Pat 5,474,772 (Therapeutic Method that carry out with medicine)).
In order to make blood remove more effective and can to handle whole blood and be not only the blood plasma of mentioning as above-mentioned method, medicine (as carry the cytocide thing of tumour-specific monoclonal antibody or be used for the radionuclide of tumor-localizing) is removed by biotinylation and by the avidin 9 albefaction adsorbent on the base for post matter.Many publications provide data, illustrate that this technology to the removing of the tumor specific antibody of biotinylated and radioisotope labeling not only effectively but also practical (people such as Norrgren K, AntibodyImmunoconj.Radiopharm.4:54 (1991); People such as Norrgren K, J.Nucl.Med 34:448-454 (1993); People such as Garkavij M, Acta Oncologica 53:309-312 (1996); People such as Garkavij M, J.Nucl.Med.38:895-901 (1997)).
This technology also has description in EP 0 567 514 and US 6,251,394.The device MitraDep of Mitra MedicalTechnology AB (Lund, Sweden) exploitation and manufacturing is promptly based on this technology.By using the bag that connects biotin labeled therapeutic antibodies by the filter of avidin, the blood clearance technique is advantageously applied to chimeric antibody or full-length human antibody equally.Experimental data is presented in 3 hours absorption processes, and the circulating biological elementization antibody more than 90% can be removed (Clinical Investigator ' s Brochure-MitraDep ) by MitraDep system.These are proved in up-to-date clinical research.
In order to be absorbed into external filter, before being applied to the patient, the clone's monoclonal antibody body that carries cytotoxic agent (as radionuclide) need be by biotinylation (the avidin irreversible fixation in biotin and the filter).The quantitative range of the biotinyl of each IgG molecule part is 3-6, normally 4.
Yet, in most of the cases adopt the functional group of the same type (epsilon-amino) of antibody to come coupling chelation group and biotin group, cause the competition in accessible site.
The chelation of antibody and/or biotin function produce the allos prepared product, if for example average each antibody of chelating antibody has 3 chelating agen, then in fact prepared product comprises the mixtures of antibodies of 1 chelating agen/antibody to 7 chelating agen/antibody.Because chelating agen and biotin are connected the same part of antibody, so some antibody with a greater number chelating agen will contain the biotin molecule that hangs down quantity, and some have the antibody of high quantity chelating agen will not have biotin at all.
This means statistically, carries radionuclide and the antibody of inanimate object element will circulate in blood, and these antibody will can not removed by MitraDep filter.
For the labelling that promotes therapeutic or the naked antibody of diagnostic with guarantee that biotin and radiolabeled ratio are 1 to 1, Mitra Medical Technology AB (Lund, Sweden) has developed a series of new water-soluble structure that comprises two class functional groups (Tag-reagent; MitraTag
TM), make thus chelation group (being used for radioactive label) and biotin group can be simultaneously and regiospecificity ground put together.
This new method is compared with biotinylization with the continued labelling of radionuclide has many advantages, under the situation that naked (non-chelating) antibody is provided to hospital, and except that the radioactive label step under chelation group and the biotin group is had to antibody is connected the situation, this method is especially attractive.
The further development and application of these medicines has description: US 6 251 394 in following document; PCT/SE 98/01345; PCT/SE 99/01241; PCT/SE 99/01241; US 09/,519 998; US 09/750,280; PCT/SE 02/01191 and Wilbur, people such as S.D, BioconjugateChemistry, 13:1079-1092 (2002).
The Tag-reagent of chelation group DOTA labelling is called as MitraTag
TM-1033, also state in the definitional part hereinafter.
Summary of the invention
What the objective of the invention is to solve above-mentioned discussion expresses the relevant problem of some Cancerous disease of proto-oncogene Erb with treatment.This purpose is by finishing as the present invention who defines in claims and the following explanation.
The present invention includes the conjugate that comprises anti-Erb antibody, comprise the described medical composition that comprises the conjugate of anti-Erb antibody, comprise the medicine box of this medical composition, and treatment and/or diagnosis are expressed the cancer of oncogene protein HER, promptly specifically are the several different methods of breast carcinoma and ovarian cancer.
More precisely, one aspect of the present invention relates to conjugate, and this conjugate comprises:
A) three function crosslink parts, its coupling has
B) affinity ligand connects via connecting 1;
C) cytotoxic agent, optional via connecting 2 connections; With
D) anti-Erb antibody or its variant, it can combine with the Erb antigen of expressing on the mammal tumor surface, and affine binding constant is at least 5 * 10
6M
-1,
Wherein affinity ligand is a biotin, or has the biotin derivative of identical substantially with the biotin function in conjunction with avidin or Succ-PEG-DSPE, and wherein the stability of the enzymatic lysis of preferred biotinamide bond is introduced connecting in 1.
On the other hand, the present invention relates to comprise the medical composition of described conjugate and pharmaceutically acceptable excipient.
On the other hand, the present invention relates to medicine box, this medicine box is used for externally removing or being the concentration of the medical composition that comprises conjugate that reduces the not conjunctive tissue of the blood plasma of mammalian hosts or whole blood at least, wherein said medical composition is introduced in the described mammalian hosts body in advance and is kept a period of time therein, to be concentrated into particular organization or cell on it by adhering to, described medicine box comprises:
A) described medical composition and
B) comprise the device outside of sessile receptor, the affinity ligand of reagent combines with described sessile receptor.
On the other hand, the present invention relates to the method for cancer that is used for the treatment of and/or diagnoses expression Erb gene outcome on the mammalian hosts surface of tumor cells of claim 33-45, wherein medical composition is applied to the mammal that needs it.
Other advantage of the present invention and purpose will more at large be described, and describe especially with reference to the accompanying drawings.
The accompanying drawing summary
Fig. 1 shows that " cold " (unmarked, no 1033-conjugate) trastuzumab is right
111The 1033-trastuzumab of In labelling and the bonded competitive inhibition of SKBR-3 cell.
Fig. 2 shows injection
111In-1033-trastuzumab (solid triangle) or
111The comparison of the radioactivity CLTB of the rat of In-1033-Rituximab (closed square) antibody conjugates is represented with percentage ratio ± standard deviation.Data are through radioactive decay and background correction.
Fig. 3 shows injection
111In-1033-trastuzumab (solid triangle) or
111The comparison of the total blood clearance of radioactivity of the rat of In-1033-Rituximab (closed square) antibody conjugates is represented with the % ± standard deviation that accounts for initial activity.Data are through radioactive delay correction.
Fig. 4 shows in the rat
111The bio distribution of In-1033-trastuzumab is represented with the % ± standard deviation that accounts for every gram tissue injection dosage.The result is through radioactive delay correction.
Fig. 5 shows in the rat
111The bio distribution of In-1033-Rituximab is represented with the % ± standard deviation difference that accounts for every gram tissue injection dosage.The result is through radioactive delay correction.
The description of preferred embodiment
Definition:
" naked antibody " means antibody, antibody fragment, " scFv " antibody fragment when being used for this paper Or " double antibody ", they do not carry any reagent that is connected with immunoglobulin structure or structure to strengthen The antibody effect is so naked antibody need to depend on the inherence effect of antibody itself to the effect of tumour cell.
As used herein term " monoclonal antibody " refer to from the antibody population of homogeneity basically obtain anti-Body namely, comprises except the sudden change of the natural generation that may exist with minimum all identical antibody population Single antibody. Monoclonal antibody high special and resist single antigen site. And, and generally include Resist routine (polyclone) the antibody preparations phase of the different antibodies of different determinants (antigen deciding section) Instead, to be them synthetic and be not subjected to other immune globulin by the hybridoma culture for the advantage of each monoclonal antibody White pollution. Qualifier " monoclonal " shows the feature of the antibody that obtains from the antibody population of homogeneity basically, Need to produce antibody by any ad hoc approach and should not be construed as. For example, wish is used according to the present invention Monoclonal antibody can by by people such as Kohler at Nature, describe first among the 256:495 (1975) The hybridoma method prepare, perhaps prepare (referring to for example United States Patent (USP) by the recombinant DNA method 4,816,567). Monoclonal antibody also can be described in such as use the people such as Clackson, Nature, and 352: The people such as 624-628 (1991) and Marks, J.Mol.Biol., the technology among the 222:581-597 (1991) from Separate in the phage antibody library.
The monoclonal antibody of this paper is particularly including " chimeric " antibody (immunoglobulin (Ig)), and wherein a part is heavy Chain and/or light chain and from specific kind or belong to corresponding order in the antibody of specific antibody class or subclass Row are equal to or homology with it, and the remainder of chain with from other kind or belong to other antibody class or Corresponding order in the antibody of subclass and the fragment of these antibody (as long as they demonstrate required biologically active) Row are equal to or homology (United States Patent (USP) 4,816,567 with it; The people such as Morrison, Proc.Natl.Acad. Sci.USA, 81:6851-6855 (1984)).
" humanization " form of inhuman (for example mouse) antibody is gomphosis immunoglobulin. Contain foreword The immunoglobulin chain of row or its fragment (for example Fv, Fab, Fab ', F (ab ')2Or other of antibody is anti-Former in subsequence) derived from non-human immunoglobulin. For most of, humanized antibody is that the people exempts from Epidemic disease globulin (acceptor (recipient) antibody), wherein the residue quilt of the complementarity-determining region of acceptor (CDR) Has the inhuman kind (donor antibody) of expection specificity, affinity and capacity such as mouse, rat or rabbit The residue of CDR replace. In some instances, Fv framework region (FR) residue of human immunoglobulin(HIg) Replaced by corresponding inhuman residue. And humanized antibody can comprise neither and also not exist at receptor antibody The CDR that introduces or the residue in the frame sequence. Can make these modifies with further refining and optimum Change the antibody performance.
Usually, humanized antibody comprise basically all or at least one, generally be two variable knots The structure territory, wherein all or basically all CDR district corresponding to the CDR district of non-human immunoglobulin, All or basically all FR district be the FR district of human immunoglobulin(HIg) sequence. Humanized antibody Well also comprise at least a portion constant region for immunoglobulin (Fc), be generally the constant of human immunoglobulin(HIg) District (Fc). More details are referring to people such as Jones, Nature, 321:522-525 (1986): Reichmann Deng the people, Nature.332:323-329 (1988) and Presta, Curr.Op.Struct.Biol., 2: 593-596 (1992). Humanized antibody is by preparing the macaque immunity with interested antigen.
" antigen fragment " comprises the part of complete antibody, generally is the antigen binding domain of complete antibody Or variable region. The example of antibody fragment comprises Fab, Fab ', F (ab ')2With the Fv fragment; Double antibody; The single-chain antibody molecule; With the multi-specificity antibody that is formed by antibody fragment.
" scFv " antibody fragment comprises VH and the VL domain of antibody, wherein these domains Be present in the wall scroll polypeptide chain. Usually, the Fv polypeptide also comprises and is between VH and the VL domain Polypeptide connects, and it makes sFv form antigen in conjunction with required structure. The summary of sFv is referring to Pluckthun The Pharmacology of Monoclonal Antibodies, the 113rd the volume, Rosenbourg and Moore edits, Springer-Verlag, New York, 269-315 page or leaf (1994).
Term " double antibody " refers to have the little antibody fragment of 2 antigen binding sites, and this fragment is included in The weight chain variable domain (VH) that connects in the same polypeptide chain and light chain variable domain (VL) (VH-VL). By using too short so that allow the connection between two domains of same chain, match, Make the complementary structure territory pairing of domain and another chain and produce 2 antigen binding sites. Double antibody At for example EP 404,097; WO 93/11161; With the people such as Hollinger, Proc.Natl.Acad.Sci. USA, 90:6444-6448 has more complete description in (1993).
Term used herein " anti-Erb antibody " is intended to refer to such antibody, and its various types of mammal erb gene outcome specificitys that can express on tumour cell are combined, and affine binding constant is at least 5 * 106M
-1 This term includes but not limited to anti-erb1, erb2, erb3 and erb4 antibody.
Term erb or erb antigen relate in this application various types of mammal erb genes and produce Thing, particularly these gene outcomes are as the purposes of the target spot of anti-tumour antibody.
As used herein " variant " of the anti-Erb antibody of term mean any when with the Erb antigen molecule in conjunction with the time have the affine binding constant of identical or basic simlarity, affine binding constant is at least 5 * 10-6M
-1Its distortion, fragment or derivative.
In order to optimize half-life in body fluid and antibody or antibody fragment or derivative in the tumour tissue Delay, any these variants can be by repairing from the polyglycol chain coupling of different numbers Decorations. In most preferred application, antibody or antibody derivatives should allow to adhere to the biology of enough numbers Plain residue to be being used for by coming external elimination with the fixing interaction of avidin, and not significantly Reduce target reagent in conjunction with character.
" treatment " relates to therapeutic handling and prevention or preventive means. Need the patient for the treatment of to comprise Ill patient and wherein disease want the patient that prevented.
" mammal " that be used for the treatment of purpose refers to any mammiferous animal that is categorized as, comprise the people, raise and train and agricultural animal, and zoo, motion or pet animals, for example Canis familiaris L., horse, cat, cattle or the like.Preferred mammal is the people.
" disorder " be any can be from the disease that benefits with anti-Erb Antybody therapy.This comprises chronic and acute disorder or disease, comprises making mammal easily suffer from the pathological condition of described disorder.The limiting examples of the disorder of this paper institute desire treatment comprises optimum and malignant tumor; Leukemia and lymph malignant tumor; Neuron, neuroglia, spider cell, hypothalamus and other body of gland, macrophage, epithelium, a matter and blastocelic disease; And disease inflammatory, angiogenesis and immunity (immologic).
Term " cancer " and " cancer " relate to or describe out of control with the cell growth usually in the mammal is the physiological situation of feature.The example of cancer includes but not limited to cancer, lymphoma, blastoma, sarcoma and leukemia.The example more specifically of these cancers comprises squamous cell carcinoma, small cell lung cancer, nonsmall-cell lung cancer, human primary gastrointestinal cancers, cancer of pancreas, glioblastoma, cervical cancer, ovarian cancer, hepatocarcinoma, bladder cancer, hepatoma, breast carcinoma, colon cancer, colorectal carcinoma, carcinoma of endometrium, salivary-gland carcinoma, renal carcinoma, renal cancer, carcinoma of prostate, carcinoma vulvae, thyroid carcinoma, liver cancer and various H﹠N cancer.
Term " cytotoxic agent " material that refers to suppress or stop cell function and/or cause cytoclasis as used herein.This term is intended to comprise radiosiotope (for example I, Y, Lu), chemotherapeutics and toxin (such as but not limited to active toxin or its fragment of antibacterial, fungus, plant or animal origin).Some radionuclides such as indium-111 used with low activity as diagnostic agent and itself, if but giving higher dosage also can be used for therapeutic purposes, and also be the cytotoxic agent of this paper therefore.
" chemotherapeutics " is the chemical compound that can be used for treating cancer.The example of chemotherapeutics comprises amycin, doxorubicin, 5-fluorouracil, cytosine arabinoside (" Ara-C "), cyclophosphamide, plug is for group, busulfan, Cytoxin, paclitaxel, methotrexate, cisplatin, melphalan, vinblastine, bleomycin, etoposide, ifosfamide, ametycin, mitoxantrone, vincristine, vinorelbine, carboplatin, teniposide, Duanomysin, carminomycin, aminopterin-induced syndrome, actinomycin D, mitomycin, Esperamicins is (referring to United States Patent (USP) 4,675,187), Maytansinoid, the relevant chlormethine of melphalan with other.
Term " MitraTag as used herein
TM-1033 ", also abbreviate " 1033 " as, refer to chemical compound 3-(13 '-the trioxa diamidogen-1-of the thiourea benzyl-DOTA) (13 " trioxa diamidogen-5-isocyanide sulfenyl-amino isophthalic esters of biotin-Asp-OH).
Following embodiment of the present invention also is used to explain details of the present invention.
The cancer in tumor cell surface expression Erb gene outcome of all kinds all is suitable for adopting medical composition of the present invention, medicine box or method to treat.In preferred embodiments, medical composition, medicine box or method are applicable to breast carcinoma or ovarian cancer.Most preferred application is so-called HER-2 type breast carcinoma, promptly crosses and expresses the breast carcinoma of HER-2.This type also is called Erb-B2 or c-erb-2.
The present invention treats the particularly breast carcinoma and the ovarian cancer of particular type for the medical composition that makes new advances.
And, adopt the present invention, by behind the dosed cells toxic agent, reduce cytotoxic agent in blood circulation concentration and may adopt higher dosage thus and therefore obtain more effective therapeutic scheme and need not make vitals and contact, tumor and non-tumor ratio that may raising cell toxicant targeting agent in dispersivity cancer, the particularly breast carcinoma of treatment expression proto-oncogene Erb and ovarian cancer than high toxicity.
In one embodiment, give with single dose by bone marrow transplantation or other known method by this area through radiolabeled anti-Erb antibody, this dosage is subject to patient's tolerance dose and does not have the reconstruct of hemopoietic function.
90The dosage range of the anti-Erb antibody of Y-(" low dosage ") is the 10-20MBq/kg body weight, preferred 11-15MBq/kg, and purpose is localized
111The scope of the anti-Erb antibody of In-is 50-200MBq/m
2Body surface, preferred 100-150MBq/m
2Body surface.In this embodiment, unconjugated external removing through radiolabeled treatment or diagnosis antibody is chosen wantonly.
In another embodiment, give with single dose through radiolabeled anti-Erb antibody, this single dose is used for sending a large amount of radioactivity to patient.This " high dose method " must or reduce method combination to the radiation effect of bone marrow with reconstruct bone marrow, preferably by using MitraDep
System.Right
90The anti-Erb antibody of Y-, " high dose " refers to that single dose surpasses the 20MBq/kg body weight.
In a preferred embodiment,
111The anti-Erb antibody of In-is with 100-150MBq/m
2The dosage of body surface and " high dose " (>20MBq/kg body weight)
90The anti-Erb antibody combination of Y-gives successively or gives simultaneously with 6-8 days intervals.
In one embodiment, give with single dose by bone marrow transplantation or other known method by this area through radiolabeled anti-Erb antibody, this dosage is subject to patient's tolerance dose and does not have the reconstruct of hemopoietic function.
177The dosage range of the anti-Erb antibody of Lu-(" low dosage ") is 555-2220MBq/m
2Body surface, preferred 1000-2000MBq/m
2In this embodiment, unconjugated external removing through radiolabeled treatment or diagnosis antibody is chosen wantonly.
In another embodiment, give with single dose through radiolabeled anti-Erb antibody, this single dose is used for sending a large amount of radioactivity to patient.This " high dose method " must or reduce methods known in the art combination to the radiation effect of bone marrow with reconstruct bone marrow, preferably by using MitraDep
System.Right
177The anti-Erb antibody of Lu-, " high dose " refers to that single dose surpasses 2220MBq/m
2Body surface.
177Lu with
90It is as follows that Y compares its advantage:
90Y is pure radiator beta-ray, can not therefore need to use by outside gammacamera imaging (immunoscintigraphy)
111In comes imaging.On the contrary,
177Lu also launches gamma-rays except that the β emission of ions.Therefore,
177But the Lu direct imaging and do not need with
111The In combination.Therefore, work as use
177Only need a kind of radiopharmaceutical to be used for location and treatment during Lu, this has simplified therapeutic scheme and has reduced cost, but also has reduced patient's radiation load.
With
177Lu compares,
90Lack (2.67 days) and range the physical half time of Y and grow (12.0mm).
177The half-life of Lu is grown (6.7 days) and range, and to lack the benefit of (2.2mm) be to allow antibody-radionuclide to concentrate on the tumor long period, and the long half-life makes in the cell half-life longer well.In addition,
177The shorter range of Lu can cause the less onlooker's radiation (cross-fire) of organizing to contiguous tumor tissues, and possible cost is lower to the effectiveness than macrolesion.
90The more long range advantage of Y is to shine than macrolesion preferably.
Based on prognosis breast carcinoma is divided into 5 different phases.When breast begins to grow out of control and invades adjacent tissue subsequently or diffusion when spreading all over whole body, breast carcinoma appears.The tumor that can diffuse to whole body or intrusion adjacent tissue is considered to cancer, is called malignant tumor.In theory, organizing all of any kind can form cancer in the breast, but forms from milk duct or mammary gland usually.
In order to instruct some experiences for the treatment of and prognosis being provided, breast carcinoma is divided into 5 different phases.
0 phase (being called cancer in situ)
Lobular carcinoma in situ (LCIS) refers to along the abnormal cell of mammary gland arrangement.This is that future development is the risk factor of cancer, but this does not represent cancer itself.
Ductal carcinoma in situ(DCIS) (DCIS) refers to along the abnormal cell of conduit arrangement.The women who suffers from DCIS suffers from the danger increase of wellability breast carcinoma.Therapeutic scheme is similar to I phase patients with mastocarcinoma.
I phase---early-stage breast cancer, wherein diameter of tumor is less than 2cm and do not diffuse out breast.
II phase---early-stage breast cancer, wherein diameter of tumor is less than 2cm and diffused to axillary lymph knot, perhaps diameter of tumor 2-5cm (diffusion or do not diffuse to the axillary lymph knot), perhaps diameter of tumor is greater than 5cm and do not diffuse out breast.
The III phase---local late period breast carcinoma, wherein diameter of tumor is greater than 5cm and diffused to the axillary lymph knot, perhaps cancer is distributed widely in the axillary lymph knot, perhaps cancer has diffused to the lymph node of contiguous breastbone or other tissue of contiguous breast.
IV phase---transitivity breast carcinoma, wherein cancer has been scattered out other organ that breast is transferred to health.
Although all patients of 5 groups all are fit to treatment of the present invention, malignant tumor is represented III phase and IV phase in the most preferred embodiment.
In the present invention, immune targeting agent (immunoconjugates) is the reagent that carries the cytotoxic moiety that is different from the ordinary cells cytotoxic drug, and it combines with the tumor cell specific of expressing proto-oncogene Erb with higher affinity, can be applied to the people.In a preferred application, immune targeting agent is an antibody, and it can have different isotypes and can derive from any kind.Preferred antibody is Humanized monoclonal antibodies.And interested especially is also with at least about 50nM, more preferably at least about those of the affinity of 10nM and erb receptors bind except having above-mentioned character.
Interested especially is the monoclonal antibody derivant.The latter comprises fragment such as Fab, Fab ', F (ab ')
2, F (ab ") and Fv fragment or the like.They also comprise specific genetic engineering hybrid or chemical synthesising peptide based on the antigen binding domain of one or more target-specific monoclonal antibodies (for example chimeric antibody or humanized antibody, single-chain antibody or the like).Biomolecule bound fraction (IgG reactivity part) covalently or non-covalently combines with anti-Erb antibody or puts together, and affine binding constant is at least 5 * 10
8M
-1
For potentiation or introducing diagnostic properties, use the carrier (immunoconjugates) of tumour-specific monoclonal antibody as the various kinds of cell toxic agent, described cytotoxic agent is such as but not limited to radionuclide, chemotherapeutics, the toxin of synthetic or natural generation, immunosuppressant or immunostimulant, radiosensitizer, X ray or MRI or ultransonic reinforcing agent, after being focused to specific cells or tissue, the anti-Erb antibody that is loaded with non radioactive element can be converted to this non radioactive element of radioelement by external exposure, perhaps light-sensitive compound or be used for the chemical compound of photo imaging or photodynamic therapy, any other molecule that perhaps directly or indirectly cancerous cell or cancerous tissue is had same or similar effect, and used enzyme in the preceding regimen.Cytotoxic agent is radionuclide preferably, for example gamma ray radiator such as iodine-131 or metal ion conjugate, and wherein metal is selected from the beta particle radioactive source, as yttrium, lutecium or rhenium.People's such as Gansow United States Patent (USP) 4,472,509 discloses diethylene-triamine pentaacetic acid (DTPA) chelating agen and has been used for radioactive metal and the bonded purposes of monoclonal antibody.This patent still is used to explain the scheme of preparation well known in the art through the antibody of radioisotope labeling especially at the purification technique that is used for removing from radiopharmaceutical the metal of non-binding and accidental combination (non-chelating).
According to such general step, making has antigenic target tissue that active antibody of specific reaction and a certain amount of selected bifunctional chelating agent reaction with protein bound functional group and melts combine functional group are arranged to uniting, with preparation chelating agen/antibody conjugates.In the puting together of antibody and chelating agen, excessive chelating agen and antibody response, its concrete ratio depends on the character and the required chelating agen number of every antibody of reactant.Requirement is that radionuclide is combined by chelating (for metal) or covalent bond in such a way: under the condition of using biomolecule conjugate (for example being used for the patient), they can not isolated from biotinylation/radiolabeled chemical compound.
When cytotoxic agent be radionuclide, particularly during the metal radionuclide, it combines with three function crosslink parts by the cytotoxic agent bound fraction.
Therefore, preferably stable chelated agent or covalent bond scheme.The example of this combination/bonding part (being the cytotoxic agent bound fraction) forms aryl halide and vinyl halide to the halogen radionuclide; And Tc and Re radionuclide are comprised N
2S
2And N
3The S chelating agen; For In, Y, Pb, Bi, Cu, Sm and Lu radionuclide, amino-carboxy derivatives such as EDTA, triethylenetetraaminehexaacetic acid and DTPA or derivatives thereof, described DTPA derivant is Me-DTPA, CITC-DTPA and cyclohexyl-DTPA, and cyclammonium, as NOTA, DOTA and TETA, and derivant (Yuangfang and Chuanchu, Pure﹠amp; Appl.Chem.63,427-463,1991).
The β ray irradiation source that can be used as cytotoxic agent comprises radionuclide such as scandium-46, scandium-47, scandium-48, copper-67, gallium-72, gallium-73,90Y, ruthenium-97, palladium-100, rhodium-101, palladium-109, samarium-153, lutecium-177, rhenium-186, rhenium-188, rhenium-189, gold-198 and radium-212.The most useful gamma ray radiator is iodine-131 and indium-m114.Can be used for other metal ion of the present invention and comprise alpha ray radioactive source such as bismuth-212, bismuth-213 and astatine-211, and positron emission source such as gallium-68 and zirconium-89.
In another embodiment of the present invention, not only can be used for treatment through the targeting agent of radioisotope labeling and express the antigenic cancer of erb, but also can be used for the imaging of this class cancer.Imaging can be finished by the beta-emitting radionuclide of utilization employing bremsstrahlung or by the gamma ray activity nucleic that is used for imaging.In another preferred embodiment, be β and gamma ray radiator simultaneously
177Lu is used as the cytotoxic agent of treatment and cancer diagnosis.
In preferred embodiments, conjugate, preferred MitraTag
TMAverage 2-4 the molecule of a)-c) part combine with each anti-Erb antibody molecule, in the most preferred embodiment, the average mark subnumber of whenever anti-Erb antibody is that 2.5-3.5 is individual.
Suitable time after administration, " agent of cell toxicant targeting " will remove from blood system by in vitro method.For external elimination is become easily, the device that will be used for whole blood or blood plasma extracorporeal circulation links to each other with the patient with the blood access device by pipe line.This device should provide and blood is transported to the conduit of adsorbent equipment and will handle back blood or blood plasma feeds back conduit to the patient.Under the situation that this blood plasma is handled by adsorbent equipment, the means that also need plasma separating unit and blood plasma after concentrate blood and the processing is mixed.The latter is undertaken by two kinds of components are imported the gas-proofing apparatus that mixes usefulness usually.
Under the processed situation of whole blood, conventional dialysis machine can constitute the basis of this device.Dialysis machine is equipped with all essential safety equipment and monitoring equipment usually with the safety need of satisfying the patient and make system simple to operate.Therefore, in preferred scheme, handle whole blood, and standard dialysis machines is only used by hardware being made less change back.Then, this device need be suitable for the new procedures of new intended purposes.
Except installing, also need to be suitable for estimating flow and specific blood line from the patient to the machine distance.These pipe lines can by with blood or the compatible any material manufacture of blood plasma, comprise the used material of conventional conduit used in the dialysis.
Blood access can be finished by peripheral venous catheter, perhaps if finish by central venous catheter need be than high blood flow the time, such as but not limited to clavicle down or femoral catheter.
For affinity adsorbent, substrate can have multiple shape and chemical composition.For example, it can constitute the cylindrical space of filling with natural origin or made microparticle polymer.But the granule macropore or its surface be grafted (grafted), the latter be for enlarged surface long-pending.Granule is spherical or granular, based on the combination or the analog material of polysaccharide, ceramic material, glass, silicon dioxide, plastics or any of these.The combination of these materials can for example be the solid particle that is coated with natural origin or made suitable polymer.Also can use synthetic membrane.These films can be the planar films by the material manufacture of cellulose, polyamide, polysulfones, polypropylene or other type, and the enough inertia of the material of described other type, bio-compatible and nontoxic and receptor can be directly or be fixed thereon after chemical modification is carried out on the film surface.Also can use capillary-pipe film (as the hollow fibre of making by cellulose), polypropylene or be suitable for other material of this type of film.Embodiment preferred is based on agarose and is suitable for the microparticle material of external application.
In one embodiment, use molecularly imprinted polymer (MIP).In the case, conjugate does not comprise any affinity ligand.The cross linked polymer that they normally prepare in the presence of template molecule.Template can be the molecular structure of puting together with target molecule (chelate group such as DOTA or DTPA derivant), or target molecule is had more or less specific ad hoc structure (for example antibody structure).
In another embodiment, substrate is by the part coating, and this part shows the reagent of removing with desire (for example anti-Erb antibody of radioactivity) from blood circulation specificity interacts.This part can be selected from monoclonal antibody (comprising its fragment or through engineering approaches homologue), fit, peptide, oligomerization deoxynucleoside (comprising its fragment), intercalating agent comprise dyestof, oligosaccharide and with the chelate group that is incorporated into the metal interaction of desiring to remove reagent.
In another embodiment, affinity ligand is connected with anti-Erb antibody, and adsorbent equipment comprises and the bonded sessile receptor of affinity ligand specificity.The combination of the affinity ligand of any kind/sessile receptor as " antibody and antigen/-hapten " and " protein and cofactor " can be used for the application, condition is, they demonstrate sufficiently high affinity and selectivity to tumor marker, and affinity ligand-acceptor interaction is not touched the blood of immune targeting agent and/or device or other body fluid or tissue and disturbs.
In one of most preferred application, affinity ligand/sessile receptor combination is biotin or biotin derivative and biotin binding molecule, particularly, wherein affinity ligand is that biotin or derivatives thereof and sessile receptor are avidin or Succ-PEG-DSPE or any other biotin binding molecule.The affinity ligand of biotin/avidin and biotin/streptavidin is to using with biomolecule usually.The very strong interaction of biotin and avidin and Succ-PEG-DSPE (is K=10
13-10
15M
-1) (Green, Methods Enzymol.184,51-67,1990; Green, Adv.Prot.Chem.29,85-133,1975) application foundation in the purposes that is them in a large amount of external or bodies.Other application of the present invention is to remove multiple different biotinylated " cancer therapy drug " simultaneously by identical external step.
An embodiment part of conjugate of the present invention is as shown below, and wherein anti-Erb reactivity partly is a trastuzumab.
The structural requirement of this 1033-conjugate comprises that containing being connected between biotin moiety (affinity ligand), biotin and the molecule remainder is connected 2 between 1, three function crosslink parts, cytotoxic agent bound fraction, cell toxicant bound fraction and the molecule remainder.The structural requirement of 1033-conjugate can be divided into three parts based on functional requirement.These three parts are to contain biotin moiety, cytotoxic agent bound fraction and three function crosslink parts.Formula I has shown the general formula of conjugate of the present invention (not being combined with any cytotoxic agent on it).
Formula I: what be used for the bond radionuclide comprises the general formula of trastuzumab as the conjugate of the present invention of anti-Erb antibody
The structural requirement that contains biotin moiety: in this article, having the biotin moiety (being affinity ligand) that contains of said structure, three aspects are arranged is important.They are: the blocking-up of (1) biotin amide enzymatic lysis; (2) reservation of homobiotin binding affinity; (3) reasonable water miscible acquisition.For these attributes are provided, biotin conjugate must comprise biotin molecule and be coupled to the suitable of crosslink part and be connected.
Biotin conjugate must by with valeric acid side chain (n=3) on prepare puting together of formic acid ester group.Put together in other position of biotin molecule and then to cause to combine with avidin and Succ-PEG-DSPE fully.This can make that biotin molecule is useless to the application.The preferred form of puting together is to form amido bond (described in general formula) with the formic acid ester group.Because being combined in the dark pocket (for example 9 ) of biotin and avidin and Succ-PEG-DSPE takes place, shortening (n<3) or growth (n>3) valeric acid side chain then cause binding affinity lower, and this is not that the application is desired.
The blocking-up of biotin amide enzymatic activity (promptly is respectively R by be connected suitable substituent group on the atom of the amino of biotin amide or contiguous with this amino (promptly distance is less than 3 carbon atoms)
1And R
2) finish.Biotin amide enzyme is the enzyme of the amido bond of cracking (hydrolysis) biotin carboxylate conjugate.This kind of enzyme is extremely important in animal and human's biotin recirculation.The metabolism of biotin in (some differences) protein carboxylase discharges biotin-ε-N-lysine (biotin complex of yeast .), and biotin amide enzyme spcificity cracking amido bond is to discharge free biotin.Biotin amide enzyme can also other biotinamide bond of cracking (non-specific).In this application, biotin amide enzyme not from conjugate cracking to go out biotin be very important because otherwise can't obtain required effect.Therefore, (the R of functional group of the enzymatic activity of useful biotin conjugate structure adding blocking-up biotin amide enzyme
1Or R
2).Though to R
1, any structure all may be blocked biotin amide enzyme, but its structure is restricted to methyl (CH usually
3), because this group is blocked biotin amide enzymatic activity fully.The N-methyl significantly reduces the binding affinity of biotin and avidin and Succ-PEG-DSPE, but still can be used for the application.To R
1, than macoradical (as ethyl, aryl etc.) because forfeiture binding affinity but useless.Has substituent R
1Alternative be on the atom (as methylene) of the amino of contiguous biotin amide, to have substituent R
2Volume is bigger and change that more substituent group can be used for this position and the binding affinity of biotin is not made significant difference.Work as R
2Be CH
3Or CH
2CH
3The time biotin amide enzyme not exclusively be blocked, although heating rate is slowed down largely (for example slowing to 25% and 10% respectively).Work as R
2Be-CH
2OH and-CO
2Biotin amide enzymatic activity is blocked fully during H functional group.When being-CH
2During OH (methylol) functional group, can finish this blocking-up by introducing seryl-.When being CO
2During H (carboxyl) functional group, can finish this blocking-up by introducing α or β aspartyl.Important opinion is, when introducing these groups as R
2The time binding affinity do not reduce.Also can use big functional group as R
2Block biotin amide enzymatic activity, but can reduce binding affinity.If big functional group is as R
2The binding affinity that causes during introducing reduces not to be higher than works as R
1Be CH
3The binding affinity of Shi Yinqi reduces, and then they can be used for the application.
The influence that the biotin affinity of biotin moiety and water solublity are subjected to used coupling part in the formula I structure.The character that the length of coupling part (connecting 1) and character depend on the molecule of puting together with it to a certain extent.The coupling part can be used for providing the interval between biotin moiety and the conjugate remainder, so that biotin is in conjunction with not being subjected to the sterically hindered influence of protein (or other puts together molecule).Connect 1 length (atom number of linear chain) can by o=4-20 (for the conjugate of micromolecule such as steroid) be changed to o>20 (for macromole conjugate such as IgG molecule).The atomic property that also can change (in its linear chain or its side chain) in the connection 1 is to increase water solublity.For example, by introducing oxygen or sulphur atom (forming ether or thioether) or improving the connection that contains more than 4 MU (methylene unit) by connecting ionizable functional group (for example sulfonate radical, formate, amino or ammonium).
The structural requirement of cytotoxic agent bound fraction: multiple radionuclide chelators and bonding agent can be used for formula I structure.In formula I, use " benzyl-DOTA " part as an example.According to the character of cytotoxic agent bound fraction, need coupling part (connecting 2).Some radionuclide chelatings and/or bonding part are divided into low aqueous solubility, are important so adding comprises the link molecule that improves water miscible functional group.In the DOTA chelating agen, the major function of coupling part is to improve the water solublity of puting together molecule.Change the atomic property that connects 2 (in its linear chain or its side chains) and increase water solublity.For example, by introducing oxygen or sulphur atom (forming ether or thioether) or improving the connection that contains more than 4 MU (methylene unit) by connecting ionizable functional group (for example sulfonate radical, formate, amino or ammonium).The length (atom number of linear chain) of connection 2 also can change (for example p=1-20) according to the character of hetero atom of wherein introducing or the functional group that connects on straight chain.
The structural requirement of three function crosslink parts: multiple three functional moleculars can be used as crosslink part.Any have three can be connected (connect 1 and 2) go up and protein on the molecule of functional group of functional group reactions all be the alternative of three function crosslink parts.Except that three function crosslink parts are not for example given the indissolubility of formula I structure in aqueous solution, other unique structural limitations to three function corsslinking moleculars is, this structure should be the structure that can modify by this way: allow to add successively and contain biotin moiety, cytotoxic agent bound fraction, and put together with anti-Erb antibody.For example, in 1033 structures, use three functionalization phenyl ring (amino M-phthalic acid).
Preferred structure, the 1033-trastuzumab, shown in II, wherein n=3, o=3, p=3, R
1=H and R
2=COOH (not in conjunction with any cytotoxic agent).
The concrete structure of formula II:1033-trastuzumab
The instantiation of conjugate of the present invention is
177The Lu-1033-trastuzumab, promptly
177Lu-3-(the trioxa diamidogen-1-of 13 '-thiourea benzyl-DOTA) (13 "-the trioxa diamidogen-5-isocyanide sulfenyl-amino isophthalic ester-trastuzumab of biotin-Asp-OH);
90The Y-1033-trastuzumab;
111The In-1033-trastuzumab; The 1033-trastuzumab, wherein thiourea benzyl-DOTA is replaced by maytansinoid; With the 1033-trastuzumab, wherein thiourea benzyl-DOTA is replaced by doxorubicin.
In another embodiment of the present invention, comprise more than one, preferred two affinity ligands and/or more than one, preferred two cytotoxic agents in the conjugate.In the case, crosslink part three functional groups not just.
Embodiment
Following embodiment should not be interpreted as limiting the present invention, and should be counted as the evidence of exploitativeness of the present invention.
Embodiment 1: the puting together and radioactive label of trastuzumab
In present embodiment and embodiment subsequently, indium-111 is used to replace 90Y under some examples, because the former is γ-radioactive source and has the radiation hazard littler than 90Y.With monoclonal antibody trastuzumab and 3-(the trioxa diamidogen-1-of 13 '-thiourea benzyl-DOTA) (13 "-the trioxa diamidogen-5-isocyanide sulfenyl-amino isophthalic ester (MitraTag of biotin-Asp-OH)
TM-1033) (hereinafter also abbreviate 1033 as) and adopt people such as Wilbur D.S at Bioconjuagte Chem.13:1079-1092, the method described in 2002 is puted together.1 liter of metal-free HEPES of 10mg monoclonal anti body and function in 4 ℃ of dialysis 3 days, is changed 3 times buffer.Preparation MitraTag
TMThe aqueous solution of-1033 (800 μ g) adds in the antibody-solutions.After room temperature is incubated overnight, antibody conjugates was dialysed 4 buffer of minimum replacing with 1 liter of metal-free 250mM acetic acid solution buffer (pH5.3) 4 days in 4 ℃.Measure the MitraTag of every monoclonal antibody by the HABA method
TM-1033 average number are 2.2.The antibody of puting together of metallization removal is stored in 4-8 ℃ and is used for radioactive label test.
Will (400 μ l) the 1033-antibody of the 2mg in the 250mM ammonium acetate (pH5.3) and 30 μ l be dissolved in radionuclide to be studied in the 40mM hydrochloric acid (
111InCl
3 90YCl
3 177LuCl
3) mix.Carried out labelling 15 minutes in 45 ℃.Add 43 μ l DTPA with cessation reaction.Measure the amount of radioactivity conjugate by TLC and HPLC.
The trastuzumab that embodiment 2:1033-puts together combines with the avidin adsorbent
Adopt the avidin adsorbent that adopts in micro-column analysis and the MitraDep device bonded
111The 1033-trastuzumab radioactivity conjugate fraction of In-labelling.97% radioactivity of having an appointment in radiolabeled 1033-conjugate sample combines with micro-column by the avidin adsorbent.
Embodiment 3: with the bonded affinity analysis of target antigen
Adopt competitive inhibition to analyze and research and put together the influence of process the affinity (intensity) of trastuzumab and target antigen.In brief, with the trastuzumab of recruitment and constant basis
111The 1033-trastuzumab of In-labelling mixes.Mixture is added in the fixedly SK-BR3 cell in 96 orifice plates.After 2 hours, washing hole is being measured and the bonded radioactivity of cell in NaI (T1) the flicker cell counter automatically in the room temperature incubation.
Bonded radioactive amount to trastuzumab concentration mapping (Fig. 1), is calculated 50% and suppressed required concentration (IC
50).IC
50Be the tolerance of the relative affinity of institute's test antibody; The affinity reduction is counted as IC
50Concentration increases.The significant change of affinity shows IC usually
50Difference should be at least 10-doubly.
1 μ g/ml (6.7nM)
111The In-1033-trastuzumab is suppressed by the trastuzumab of not puting together of 0.03-500 μ g/ml " cold ".The IC that is measured
50Be 0.4 μ g/ml (2.5nM).By IC
50The calculating dissociation constant is 0.3nM.According to the information that the manufacturer of trastuzumab publishes, dissociation constant is 0.1nM.
The reduction slightly of affinity is counted as because 1033-trastuzumab conjugate.Prove in clinical research that the 10-of affinity times difference can not cause any significant difference of tumor uptake.Therefore, draw as drawing a conclusion: every antibody at the most 2.2 conjugates trastuzumab put together will can not cut down antibody body in conjunction with character.
Embodiment 4: the MitraTag of trastuzumab
TMThe pharmacokinetics of-1033 conjugates
Will
111The pharmacokinetics of In-1033-trastuzumab and bio distribution data and usefulness
111The data that the In-1033-Rituximab is obtained compare, the clinical data that can get as this radioactivity conjugate.With these two kinds of antibody humanizations is human monoclonal IgG1 antibody.
The 3-4MBq that uses with the about 100 μ g/ rats of injection in 15 Spraque Dawley strain rat veins
111The 1033-antibody conjugates of In labelling.
Employing be furnished with the medium energy collimator scintillation camera (General Electric 400T, GE, the Milwaukee, WI USA) carries out whole body (WB) imaging.Image is preserved and analyzed with Nuclear MAC2.7 software.Obtain the grand total of whole body by this image.Behind radioactive delay correction and subtracting background, counting is used to calculate the activity delay (%) of health.See Fig. 2.
Work as handle
111The WBR of In-1033-trastuzumab with
111When the WBR of In-1033-Rituximab is compared, do not observe significant difference.
In order to define
111The pharmacokinetics of In-1033-trastuzumab and with
111The In-1033-Rituximab relatively, the following time from the about 0.2ml blood sample of eye socket vein treating the preponderant disease instead of the secondary disease: injected back 10 minutes, 2.5 hours, 8 hours, 24 hours, 48 hours and 96 hours.Automatically measure radioactivity in NaI (T1) scintillation well counter, injected active percent/gram blood (%/g) expression to account for, warp
111In decay correction (Fig. 3).Work as handle
111The blood clearance rate of In-1033-trastuzumab with
111When the blood clearance rate of In-1033-Rituximab is compared, do not observe significant difference.
Embodiment 5: the bio distribution of conjugate in organ and tissue
After injection, dissected in 2.5,8,24,48 and 96 hours, remove interested organ and tissue, weigh and measure contamination.Measuring radioactivity in NaI (T1) scintillation well counter automatically, will count through decay correction.With the distribution of each organ with
111The In-1033-Rituximab is compared.The active distribution of injecting such as Fig. 4 (
111The In-1033-trastuzumab) and Fig. 5 (
111The In-1033-Rituximab) shown in.
111The In-1033-trastuzumab with
111The In-1033-Rituximab is compared, and observing has higher picked-up in kidney and lung, at lung low picked-up is arranged.
111The higher picked-up of In-1033-trastuzumab in lung mainly observed after injection soon, finishes during same level approximately after 48 hours.
Embodiment 6: use according to the preferred embodiments of the invention
90Y/
111The scheme of the breast carcinoma of HER-2 is expressed in the treatment of In-trastuzumab
At the 0th day, all patients accepted the trastuzumab of 1-4mg/kg body weight, the dosage of immediately receiving treatment
90Y-1033-trastuzumab (>10MBq/kg body weight).The patient can choose wantonly and use 100-150MBq/m
2Body surface (1.1-3.9mCi/m
2Body surface) dosage
111The In-1033-trastuzumab, it will be used for imaging and dosiology.
A period of 1-3 days, the patient handled with MitraDep , makes at least 3 blood volumes pass MitraDep device.
Optional and be to use as a kind of safety measure
90Before the Y-1033-trastuzumab, collect bone marrow so that allow the bone marrow recovery if necessary.
Optional is to use in 1 year
90Y-1033-trastuzumab repetitive therapy 2-6 time, 1 year repeats 2-4 time in the most preferred embodiment, prerequisite be do not occur dose-limiting toxicity and patient with regard to radiotoxicity from before treatment recover.
Optional is that the patient is accepting
90Receive treatment before or after the Y-1033-trastuzumab and the trastuzumab (Herceptin) of inferior therapeutic dose and/or trastuzumab (Herceptin) give with
90Using of Y-1033-trastuzumab accompanied.
Embodiment 7: use according to another preferred embodiment of the present invention
177The scheme of the breast carcinoma of HER-2 is expressed in the treatment of Lu-trastuzumab
At the-7 to-1 days, all patients once accepted the trastuzumab of 6-8mg/kg body weight.
At the 0th day, patient's dosage of receiving treatment
177Lu-1033-trastuzumab (>555MBq/m
2Body surface).For imaging and dosiology, the patient can choose wantonly by immune scintigraphy and study.
A period of 1-4 days, the patient handled with MitraDep , makes at least 3 blood volumes pass MitraDep device.
Optional and be to use as a kind of safety measure
177Before the Lu-1033-trastuzumab, collect bone marrow so that allow the bone marrow recovery if necessary.
Optional is to use in 1 year
177Lu-1033-trastuzumab repetitive therapy 2-6 time, 1 year repeats 2-4 time in the most preferred embodiment, prerequisite be do not occur dose-limiting toxicity and patient with regard to radiotoxicity from before treatment recover.
Optional is that the patient is accepting
177Receive treatment before or after the Lu-1033-trastuzumab and the trastuzumab (Herceptin) of inferior therapeutic dose and/or trastuzumab (Herceptin) give with
177Using directly of Lu-1033-trastuzumab accompanied.
Claims (45)
1. conjugate comprises:
A) three function crosslink parts, its coupling has
B) affinity ligand connects via connecting 1;
C) cytotoxic agent, optional via connecting 2 connections; With
D) anti-Erb antibody or its variant, it can combine with the Erb antigen of expressing on the mammal tumor surface, and affine binding constant is at least 5 * 10
6M
-1,
Wherein affinity ligand is a biotin, or has the biotin derivative of identical substantially with the biotin function in conjunction with avidin or Succ-PEG-DSPE, and wherein the stability of the enzymatic lysis of relevant biotin acyl hydrogen bond is introduced connecting in 1.
2. according to the conjugate of claim 1, wherein anti-Erb antibody or its variant are at Erb1, Erb2, Erb3 and/or the Erb4 antigen of mammal tumor surface expression.
3. according to the conjugate of claim 1 or 2, wherein anti-Erb antibody variants be when with Erb antigen in conjunction with the time have and identical or similar substantially be at least 5 * 10
6M
-1Distortion, fragment or the derivant of any anti-Erb antibody of affine binding constant, described fragment comprises Fab, Fab ', F (ab ')
2, F (ab ") and Fv fragment; Double antibody; The single-chain antibody molecule; With the multi-specificity antibody that forms by antibody fragment.
4. according to each conjugate in the aforementioned claim, wherein anti-Erb antibody is through connecting 3 and three function crosslink part couplings, and wherein connect 3 and anti-Erb antibody between the key that forms be covalent bond or non-covalent bond, affine binding constant is at least 5 * 10
8M
-1
5. according to each conjugate in the aforementioned claim, wherein cytotoxic agent is a radionuclide, chemotherapeutics, the toxin of synthetic or natural generation, immunosuppressant or immunostimulant, radiosensitizer, X ray or MRI or ultransonic reinforcing agent, after being focused to specific cells or tissue, the anti-Erb antibody that is loaded with non radioactive element can be converted to this non radioactive element of radioelement by external exposure, perhaps light-sensitive compound or be used for the chemical compound of photo imaging or photodynamic therapy perhaps directly or indirectly has any other molecule of same or similar effect to cancerous cell or cancerous tissue.
6. according to each conjugate in the aforementioned claim, wherein cytotoxic agent is radionuclide, chemotherapeutics or toxin.
7. according to the conjugate of claim 6, wherein cytotoxic agent is radionuclide and combines with three function crosslink parts through the cytotoxic agent bound fraction.
8. according to the conjugate of claim 7, wherein the cytotoxic agent bound fraction forms aryl halide and vinyl halide to the halogen radionuclide, and Tc and Re radionuclide are comprised N
2S
2And N
3The S chelating agen, for In, Y, Pb, Bi, Cu, Sm and Lu radionuclide, amino-carboxy derivatives, preferred EDTA, triethylenetetraaminehexaacetic acid and DTPA or derivatives thereof, wherein the DTPA derivant is Me-DTPA, CITC-DTPA and cyclohexyl-DTPA, and cyclammonium, preferred NOTA, DOTA and TETA, and derivant, or can form any other radionuclide of complex with described chelating.
9. according to the conjugate of claim 7 and 8, wherein in the cytotoxic agent bound fraction, comprise DOTA, and cytotoxic agent is used for the treatment of application
90Y or be used for diagnostic application
111In.
10. according to the conjugate of claim 6 and 7, wherein the cytotoxic agent bound fraction comprises DOTA, and cytotoxic agent is used to diagnose and treats and use both
177Lu.
11. conjugate according to claim 10, wherein radionuclide is β ray irradiation source, preferred scandium-46, scandium-47, scandium-48, copper-67, gallium-72, gallium-73,90Y, ruthenium-97, palladium-100, rhodium-101, palladium-109, samarium-153, lutecium-177, rhenium-186, rhenium-188, rhenium-189, gold-198 and radium-212; Gamma ray radiator, preferred iodine-131, lutecium-177 and indium-m 114; Perhaps alpha ray radioactive material, preferred bismuth-212, bismuth-213 and astatine-211; And the positron emission source, preferred gallium-68 and zirconium-89; Wherein chemotherapeutics is an amycin, doxorubicin, 5-fluorouracil, cytosine arabinoside (" Ara-C "), cyclophosphamide, plug is for group, busulfan, Cytoxin, paclitaxel, methotrexate, cisplatin, melphalan, vinblastine, bleomycin, etoposide, ifosfamide, ametycin, mitoxantrone, vincristine, vinorelbine, carboplatin, teniposide, Duanomysin, carminomycin, aminopterin-induced syndrome, actinomycin D, mitomycin, Esperamicins, Maytansinoid, the relevant chlormethine of melphalan with other; And wherein toxin is active toxin or its fragment of antibacterial, fungus, plant or animal origin.
12. according to each conjugate in the aforementioned claim, wherein affinity ligand is and the bonded part of following part specificity: any other derivant, mutant or the fragment of avidin, Succ-PEG-DSPE or avidin or Succ-PEG-DSPE, wherein said any other derivant, mutant or fragment have essentially identical and the bonded function of this affinity ligand.
13. according to each conjugate in the aforementioned claim, wherein biotin derivative is selected from norbiotin (norbiotin), homobiotin, oxybiotin, imino group biotin, desthiobiotin (destibiotin), dihydro base biotin, biotinylsulfoxide and biotin-sulfone, and perhaps it has essentially identical combined function, preferred affine binding constant is at least 10
9M
-1The derivant of combined function.
14. according to each conjugate in the aforementioned claim, wherein three function crosslink parts are selected from triaminobenzene, three carboxyl benzene, dicarboxyl aniline and diaminobenzoic acid.
15. according to each conjugate in the aforementioned claim, wherein connect 1 as coupling part and interval between three function crosslink parts and affinity ligand, the preferred biotin moiety, so as with avidin or Succ-PEG-DSPE or arbitrarily not combining of other biotin bound fraction weakened by steric hindrance.
16. according to each conjugate in the aforementioned claim, wherein connect 1 atom that contains hydrogen bonding, preferred ether or thioether, perhaps ionogen, preferable formic acid root, sulfonate radical or ammonium are to help the water solublity of biotin moiety.
17. according to each conjugate in the aforementioned claim, wherein about the enzymatic lysis of biotinamide bond, preferably the plain amidase cracking of antibiont with the stability that discharges biotin by introduce on the amino of biotin amide methyl or with the atom that amino is contiguous, preferred distance is less than 3 carbon atoms of biotin amide on introduce α formic acid ester group, methylol or methyl and provide.
18. according to each conjugate in the aforementioned claim, wherein connecting 2, length is provided is 1-25, the interval of preferred 6-18 atom.
19. according to the conjugate of claim 18, wherein connect 2 atoms that contain hydrogen bonding, preferred ether or thioether, perhaps ionogen is to help water solublity.
20., wherein connect 2 and be excluded according to each conjugate among the claim 1-17.
21. according to each conjugate in the aforementioned claim, wherein connecting 3, length is provided is the interval of 1-25, preferred 6-18 atom or atomic group.
22. according to the conjugate of claim 21, wherein connect 3 atoms that contain hydrogen bonding, preferred ether or thioether, perhaps ionogen, preferable formic acid root, sulfonate radical or ammonium are to help water solublity.
23., wherein connect 3 and be excluded according to each conjugate among claim 1-3 and the 5-20.
24. according to each conjugate in the aforementioned claim, wherein also in conjunction with more than one, preferred two affinity ligands and/or more than one, preferred two cytotoxic agents.
25. according to each conjugate in the aforementioned claim, wherein average 2-4 of a)-c) part of conjugate, preferred 2.5-3.5 molecule are connected with each anti-Erb antibody.
27. according to each conjugate among the claim 1-25, wherein it is
177The Lu-1033-trastuzumab, promptly
177Lu-3-(the trioxa diamidogen-1-of 13 '-thiourea benzyl-DOTA) (13 "-the trioxa diamidogen-5-isocyanide sulfenyl-amino isophthalic ester-trastuzumab of biotin-Asp-OH);
90The Y-1033-trastuzumab;
111The In-1033-trastuzumab; The 1033-trastuzumab, wherein thiourea benzyl-DOTA is replaced by maytansinoid; With the 1033-trastuzumab, wherein thiourea benzyl-DOTA is replaced by doxorubicin.
28. medical composition, wherein it comprises among the claim 1-27 each conjugate and pharmaceutically acceptable excipient.
29. according to the medical composition of claim 28, wherein excipient is to be used for the solution using outside gastrointestinal tract, preferably use through intravenous.
30. medicine box, be used for external remove or be at least reduce the blood plasma of mammalian hosts or whole blood not conjunctive tissue as each defined medical composition in claim 28 and 29, wherein said medical composition comprises among the claim 1-26 each conjugate, and wherein said medical composition is introduced in the body of described mammalian hosts in advance and is kept a period of time therein, to be concentrated into particular organization or cell on it by adhering to, described medicine box comprises
A) described medical composition and
B) comprise the device outside of sessile receptor, the affinity ligand of conjugate combines with described sessile receptor.
31. medicine box according to claim 30, wherein it comprises antibody and antigen/hapten or protein and cofactor as affinity ligand/sessile receptor combination, preferred biotin or biotin derivative as affinity ligand and avidin or Succ-PEG-DSPE as sessile receptor.
32. according to the medicine box of claim 30, wherein do not have affinity ligand in the conjugate of medical composition, and sessile receptor is and the interactional molecularly imprinted polymer of conjugate.
33. each medical composition in the method for cancer of the tumor cell surface expression Erb of mammalian hosts gene outcome, is wherein given in the administration claim 28 and 29 that needs it in treatment.
34. according to the method for claim 33, wherein said cancer is breast carcinoma or ovarian cancer.
35. according to the method for claim 33 and 34, wherein said cancer is a breast carcinoma, preferably Erb2 type breast carcinoma.
36. each method among the claim 33-35 is wherein used to mammalian hosts with the dosage of 10-20MBq/kg body weight, preferred 11-15MBq/kg body weight and is contained
90Y is as the claim 28 of cytotoxic agent and 29 medical composition.
37. according to each method among the claim 33-35, wherein dosage is higher than containing of 20MBq/kg body weight
90Y as the medicament administration of the claim 28 of cytotoxic agent and 29 in mammalian hosts, together with adopting reconstruct bone marrow or reducing method to the radiation effect of bone marrow.
38. diagnosis is in the method for cancer of the tumor cell surface expression Erb of mammalian hosts gene outcome, wherein uses in claim 28 and 29 each medical composition to mammalian hosts.
39. according to the method for claim 38, wherein said cancer is breast carcinoma or ovarian cancer.
40. according to the method for claim 38 and 39, wherein said cancer is a breast carcinoma, preferably Erb2 type breast carcinoma.
41. according to each method among the claim 38-40, wherein
111In is with 50-200MBq/m
2Body surface, preferred 100-150MBq/m
2The dosage of body surface is applied to mammalian hosts.
42. treatment and diagnosis are in the method for cancer of the tumor cell surface expression Erb of mammalian hosts gene outcome, wherein giving the mammalian hosts application dosage is 50-200MBq/m
2Body surface, preferred 100-150MBq/m
2Containing of body surface
111The claim 28 of In and 29 medical composition and dosage are containing of 10-20MBq/kg body weight, preferred 11-15MBq/kg body weight
90Y is as the claim 28 of cytotoxic agent and 29 medical composition.
43. treatment and diagnosis are in the method for cancer of the tumor cell surface expression Erb of mammalian hosts gene outcome, wherein giving the mammalian hosts application dosage is 100-150MBq/m
2Containing of body surface
111Containing of the claim 28 of In and 29 medical composition and dosage>20MBq/kg body weight
90Y uses successively or uses simultaneously with described sequence interval 6-8 days as the claim 28 of cytotoxic agent and 29 medical composition.
44. treatment and diagnosis are in the method for cancer of the tumor cell surface expression Erb of mammalian hosts gene outcome, wherein using single dose to mammalian hosts is 555-2220MBq/m
2Body surface, preferred 1000-2000MBq/m
2Containing of body surface
177Lu is as the claim 28 of cytotoxic agent and 29 medical composition.
45. treatment and diagnosis are in the method for cancer of the tumor cell surface expression Erb of mammalian hosts gene outcome, wherein single dose is higher than 2220MBq/m
2Containing of body surface
177Lu is applied to mammalian hosts as the claim 28 of cytotoxic agent and 29 medical composition, together with the method that adopts reconstruct bone marrow or reduction to the radiation effect of bone marrow.
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Cited By (4)
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CN107250104A (en) * | 2014-10-16 | 2017-10-13 | 墨尔本大学 | New image forming composition and application thereof |
CN108570081A (en) * | 2018-05-25 | 2018-09-25 | 西南医科大学附属医院 | The ligand compound and preparation of a kind of glucose diagnostic imaging and treatment and application |
WO2020019232A1 (en) * | 2018-07-26 | 2020-01-30 | Tayu Huaxia Biotech Medical Group Co., Ltd. | Compositions and methods for imaging |
US11987629B2 (en) | 2018-06-01 | 2024-05-21 | Tayu Huaxia Biotech Medical Group Co., Ltd. | Compositions and uses thereof for treating disease or condition |
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CN107250104A (en) * | 2014-10-16 | 2017-10-13 | 墨尔本大学 | New image forming composition and application thereof |
CN107250104B (en) * | 2014-10-16 | 2019-08-16 | 墨尔本大学 | Novel image forming composition and application thereof |
CN110357967A (en) * | 2014-10-16 | 2019-10-22 | 墨尔本大学 | Novel image forming composition and application thereof |
CN110357967B (en) * | 2014-10-16 | 2023-04-14 | 墨尔本大学 | Novel imaging compositions and uses thereof |
CN108570081A (en) * | 2018-05-25 | 2018-09-25 | 西南医科大学附属医院 | The ligand compound and preparation of a kind of glucose diagnostic imaging and treatment and application |
US11987629B2 (en) | 2018-06-01 | 2024-05-21 | Tayu Huaxia Biotech Medical Group Co., Ltd. | Compositions and uses thereof for treating disease or condition |
WO2020019232A1 (en) * | 2018-07-26 | 2020-01-30 | Tayu Huaxia Biotech Medical Group Co., Ltd. | Compositions and methods for imaging |
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