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EP0090025A1 - Kennzeichnung einer spezifischen brustdrüse - Google Patents

Kennzeichnung einer spezifischen brustdrüse

Info

Publication number
EP0090025A1
EP0090025A1 EP82903200A EP82903200A EP0090025A1 EP 0090025 A1 EP0090025 A1 EP 0090025A1 EP 82903200 A EP82903200 A EP 82903200A EP 82903200 A EP82903200 A EP 82903200A EP 0090025 A1 EP0090025 A1 EP 0090025A1
Authority
EP
European Patent Office
Prior art keywords
mammary
host
radionuclide
labelled
fab
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.)
Withdrawn
Application number
EP82903200A
Other languages
English (en)
French (fr)
Other versions
EP0090025A4 (de
Inventor
Roberto Luis Dr. Ceriani
Jerry Arthur Peterson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of EP0090025A1 publication Critical patent/EP0090025A1/de
Publication of EP0090025A4 publication Critical patent/EP0090025A4/de
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1045—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants
    • A61K51/1051—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants the tumor cell being from breast, e.g. the antibody being herceptin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3015—Breast
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • Monoclonal and polyclonal antibodies offer many opportunities for distinguishing between different antigens or antigenic sites.
  • the anti ⁇ bodies may have specific binding sites, because of the large number of determinants present in the system of interest, the potential for a variety of amino acid sequences to assume similar polar and spatial confirmations, and various degrees of non-specific binding, even injected antisera specific for a particular epitope may be widely distributed in a host.
  • injected antisera specific for a particular epitope may be widely distributed in a host.
  • injected antisera specific for a particular epitope may be widely distributed in a host.
  • there is a substantial challenge in developing antibodies which will •provide a high level of discrimination between the site of interest and the large number of other sites which are present in the host.
  • An area of particular interest is detection of breast cancer and its metastases.
  • For appropriate therapy for breast cancer there must be reliable detection and tumor staging.
  • the ability to detect hitherto unknown metastases and more accurately determine the extent of lymph node involvement can radically change the therapeutic approach.
  • the present techniques are of limited applica ⁇ tion, permitting detection of only certain metastases based on limitations imposed by size, depth and vascularity.
  • the present techniques have the further failure of being non- specific in not being able to distinguish between the source of the tumor as well as between a tumor and a cyst, abcess or inflammatory site.
  • 80,000 daltons specific for mammary epithelial cells are employed for site directed localization or imaging of mam ⁇ mary neoplastic tissue, whether the tissue is associated with the breast or other organ.
  • poly- or monoclonal Fab fragments labelled with radionuclides speci ⁇ fic for normal mammary epithelial cell surface antigens are introduced into a host for selective specific binding to mammary epithelial tissue, providing a high ratio of speci- fie binding to background, while allowing for rapid elimina tion of the radionuclide labelled fragment.
  • back- ground values can be obtained which permit accurate detec ⁇ tion of neoplastic mammary tissue.
  • the subject invention provides methods and composi tions for specifically localizing or imaging mammary tissue, particularly detecting neoplastic mammary tissue, regardless of the aggregation site of the mammary epithelial cells. High specificity is achieved by obtaining antibodies to antigenic sites of normal mammary epithelial cells, where the antibodies bind to both normal and neoplastic cells.
  • the subject invention permits localization, not only of carcinomas located at the breast but also metastatic carcinomas from a primary breast carcinoma of origin. Thus, •even after a breast cancer is removed, where cancerous colonies have developed from the primary breast carcinoma, these will be readily imageable.
  • the hosts of interest for mammary carcinoma detec ⁇ tion are mammals, which includes research animals, domestic animals, including pets and farm animals, as well as humans.
  • Antibodies may be obtained by employing as an immunogen delipidated milk fat globules containing mammary surface epithelial antigens.
  • whole cells, lysates, surface antigens or determinant portions of surface antigens may be employed as a source of normal surface antigens to serve as immunogens.
  • various tech ⁇ niques can be employed for producing the antibody fragments.
  • milk is obtained from a nursing host, the cream fraction isolated, milk fat globules in the cream fraction freed of the fat employing organic solvents e.g. chloroform and ether, and the residue lyophilized.
  • the lyophilized powder may then be used as an immunogen in a host different from the host source of the milk.
  • surface antigens or fragments thereof obtained from whole cells may be used for the preparation of poly- clonal or monoclonal antibodies.
  • Surface antigens may be isolated from defatted fat globules or by lysing mammary epithelial cells and using an affinity column, employing antibodies specific for the mammary epithelial surface antigens for separation of the surface antigen. Individual surface antigens may be freed from the affinity column and separated by various techniques, such as chromatography, electrophoresis, isopycnic separation, gradient density, or other conventional techniques.
  • the individual surface antigen may then be employed as an immunogen or the protein partially digested and the resulting fragments obtained and employed for affinity chromatography using the antibodies described above to isolate peptides providing the desired determinant sites.
  • These antigens or fragments thereof may be injected into a host other than the host source of the antigen or may be combined, either covalently or noncovalently, to an immuno ⁇ gen foreign to the host source and then injected into the host source for production of antisera.
  • the technique employed will be for prepara ⁇ tion of monoclonal antibodies.
  • monoclonal antibodies a wide variety of conventional techniques may be employed, primarily based on the seminal work of Kohler and Milstein.
  • the monoclonal antibodies usually other than the whole cell will be em ⁇ ployed, normally either the antigen or a fragment having a desired determinant, site.
  • the monoclonal antibodies may be obtained by injecting the antigen, immunogenic fragment of an antigen or an haptenic fragment bound to an immunogen, into a host different from the host source of the antigen with an appropriate adjuvant, repeating the injection about two to four weeks later.
  • spleen This is followed by isolation of the spleen and fusing of the splenocytes with an appropriate fusion partner e.g. a myeloma or lymphoma cell, from the same or different
  • the resulting hybridomas may then be screened for antibodies which bind to the deter ⁇ minant site(s) of interest.
  • peripheral blood cells or lymphocytes may be immunized in vitro and used as the partner for fusion with the immortalized cell line.
  • the immunoglobulin will then be harvested in conven ⁇ tional ways and treated to provide specific binding fragments.
  • the IgG will be purified followed by digestion to provide a frag ⁇ ment.
  • Various fragments may be obtained by conventional techniques, such as Fab, F(ab) 2 , Fd or Fv.
  • pep- tidases have been reported which cleave antibodies at speci ⁇ fic sites or controlled proteolytic degradation can be employed. Each of these fractions may have advantages in providing the desired degree of affinity, rate of elimina ⁇ tion, ' acceptable degree of immunogenicity, or the like.
  • Various proteases may be employed for digesting the antisera and removing undesired fragments to leave the binding por- tion, normally having a single binding site.
  • the resulting digested antibody fragment will be purified further, either before or after labelling, normally before labelling, by absorption with host source cells other than the mammary epithelial cells, to remove cross-reacting antibody fragments.
  • host source cells other than the mammary epithelial cells
  • red blood cells, liver homogenates, fetal fibroblasts and var ⁇ ious cell lines e.g. HeLa, colorectal carcinoma, etc. may be employed to further insure the specificity of the anti ⁇ body fragments which are used.
  • various components from the cells may be secreted or be leached into the anti ⁇ serum composition.
  • the antibody fragment compo- sition is combined with the complementary binding member insolubilized to a support to provide an in ⁇ olubilized phase pair member and the specific antibody fragments are then bound to the insolubilized phase.
  • the insolubilized phase is then washed thoroughly to remove any non-specifically bound components and the purified antibody fragments released using a solution such as 2M sodium isocyanate, followed by rapid dialysis.
  • radionuclides may by employed for therapy, in vivo diagnosis, physiological studies, or the like.
  • Various radionuclides may be employed, commonly radioactive iodine e.g. 131 I 125 I, 123 I, and 99m Tc.
  • Conventional labeling techniques are employed, conveniently the chloramine-T method for iodine of Greenwood and Hunter, Biochem. J. (1963) 89:114-123 or lactoperoxidase.
  • Other labels include fluorescers which may be covalently conjugated through carboxyl groups, isothiocyanate, thio groups, activated olefins, or the like.
  • Other labels may also be useful as imaging detection techniques are evolved.
  • the resulting labelled composition may then be injected intravenously into the host in an appropriate physiologically acceptable vehicle.
  • phosphate buffered saline, saline, Ringer's solution or other aqueous buffered medium may be employed.
  • about 5 to 30 ⁇ Ci, more usually about 10 to 25 ⁇ Ci, will be injected per kilogram of host where a radionuclide is employed for imaging of a carcinoma.
  • a different radionuclide will be injected into the host to provide for a background control so that the concentration of the labeled antibody fragment is determined by the ratio of the emission from the radionuclide label divided by the emission from the background radionuclide.
  • the scanning of the distribution of the radionuclide will be made from about 6 to 48 hrs. after injection.
  • 1 ⁇ l instruments may be used for scanning of the radionuclide distribution.
  • compositions employing the antibody fragments may be formulated and supplied labelled with a moderately long half-lived radionuclide e.g. 131I or sup ⁇ plied unlabelled to be labelled prior to use.
  • the formu ⁇ lated product may be provided as a concentrate, at concen ⁇ trations 1.5 to 10 times the concentration to be employed ⁇ for administration or may be provided at the desired con- centration.
  • the dosage will vary. Since humans will be the most commonly treated, the indicated dosages are primarily for humans.
  • compositions of the labelled antibody fragment may be preprepared or be prepared for use shortly before injec- tion, e.g. intravenously . These compositions will contain from about 10 to 300 ⁇ g protein/ml of the labelled antibody
  • QQ ⁇ n Tc-pertechnetate may be added to the composition prior to injection.
  • the technecium provides for a background level of radiation which can be distinguished from the emission from radioactive iodine so as to give a measured natural variation in distribution of the radionuclide.
  • preservatives such as benzyl alcohol, buffers e.g. phos ⁇ phate, salt (NaCl), inert protein e.g. serum albumins.
  • the concentration of the buffer will generally by 0.03 to 0.07M, while the concentration of the salt will generally be 0.11 to 0.18M, while the amounts of the other materials may be varied widely, the inert proteins generally range from about 0.1 to 2 weight percent and the additives generally ranging from about 0.0001 to about 0.1 weight percent, when present.
  • the pH will generally be in the range of about 7 to 7.8.
  • OMPI Antisera were prepared essentially as described in Ceriani and Peterson, supra. After an injection of oxytocin, mouse milk was collected by suction from nursing mice separated from their pups overnight. The cream frac- tion was collected after centrifugation (13,000 g) and washed three times with phosphate-buffered saline (PBS). The final cream fraction consisting of the milk fat globules (MFG) was suspended in water and washed three times with chloroform and three times with ether to remove the fat and then lyophilized. New Zealand white rabbits were immunized with a 5-mg injection of this defatted MFG membrane prepara ⁇ tion followed by an injection 3 weeks later of 3 g.
  • PBS phosphate-buffered saline
  • Serum was collected 10 days after the second injection and the serum globulins were precipitated by 40% saturated ammonium sulfate. The globulins were redissolved in PBS, dialysed against PBS, and then heated at 60C for 30 min. to destroy complement before sodium azide was added. The globulins -were stored frozen at -20°C.
  • the IgG was first purified from the stored globulin fraction by gel filtration chromatography on a 27x2.5-cm diameter Sephadex G-200 column with 0.1m Tris, pH 8.0, 0.15 NaCl, 0.1% sodium azide. One hundred 2 ml fractions were collected at room temperature during the five hour elution period and the peak fractions determined by optical density at 280 ⁇ m. The IgG came off the column as a single peak separated from and after the void volume. The fractions of this peak were pooled.
  • the digestion of IgG with papain was a modifica- tion of the method of Porter, Biochem. J. (1959) 73:119-127. After its protein concentration was determined (Lowry) the IgG fraction was dialyzed against 0.1 m phosphate, pH 7.5, 0.002 m ethylenediaminotetraacetic acid diluted by an appro ⁇ priate factor necessary to retain these molarities after later concentrating the IgG to 15 mg/ml. (All dialyses were done at 4°C.) After dialysis, the IgG solution in the tubing was concentrated by dehydration until the appropriate concentration was achieved.
  • MME MME
  • Fab absorbed in this way bound specifically to mouse mammary epithelial cells and not to cells from other tissues of the mouse as revealed by immunofluorescence techniques, as was the case for the intact anti-MME.
  • the labeled, absorbed anti-MME (Fab) was stored at 4°C and used within 10 days.
  • Nonspecific Fab of a nonimmunized rabbit was pre ⁇ pared, labeled and absorbed in the same manner as the speci ⁇ fic anti-MME (Fab).
  • Monoclonal antibodies specific for normal mammary, epithelial cell surface antigens may be prepared as follows. Delipidated human milk fat globules (HMFG) or specific purified components are injected into BALB/c mice and receive at least one booster from two to three week inter ⁇ vals. Three to four days after the last booster injection, the immunized mouse spleen cells are fused with mouse myeloma cells in the presence of PEG6000 and then plated in 600 microwells plus feeder layers. HAT medium is added and the supernatants from HAT resistant clones screened for binding to insolubilized HMFG.
  • HMFG Delipidated human milk fat globules
  • specific purified components are injected into BALB/c mice and receive at least one booster from two to three week inter ⁇ vals. Three to four days after the last booster injection, the immunized mouse spleen cells are fused with mouse myeloma cells in the presence of PEG6000 and then plated in 600 microwell
  • HMFG positive clones are screened by adding the supernatants to microtiter wells to which are bound cell membranes from the following cell types: HeLa, HT-29, human mammary fibroblasts, and human lymphoma (Bristol-8). Antibodies which specifically bind to the above membranes may be detected with radio- or other labelled anti(mouse Ig).
  • the desired clones are those that bound to HMFG, but not to membranes of HeLa, colon carci ⁇ noma, human fibroblasts and human lymphoma cell membranes.
  • the monoclonal antibodies may then be produced by injecting the selected hybridoma cells into BALB/c mice to produce ascites fluid or growing the cells and harvesting the media in which the hybridomas are grown.
  • the monoclonal anti ⁇ bodies are then purified with affinity columns containing anti(mouse Ig) on the solid phase.
  • the two transplantable mammary tumors 3910-30 (Ceriani et al, (1978) supra) and HOG (Medina and DeOme, J. Natl. Cancer Inst. (1970) 45:353-363) were maintained in BALB/c mice by subcutaneous transplantation. Both were spontaneous mammary tumors that arose in BALB/c and have shown no mouse mammary tumor virus particles upon electron microscopic examination.
  • the two lines that were non- mammary lines (Ceriani et al, (1976) supra) arose in C57/BL mice and were maintained in that strain.
  • mammary-tumor-bearing mice were injected intravenously with 0.25 ⁇ Ci of the 125I labeled preparation in 0.1 ml PBS.
  • the mice were dissected after 24 hours and samples of blood, urine, and tumor taken, along with the brain, liver, lung, kidneys, and the muscle and bone of one hind leg.
  • the tissue pieces were weighed and counted on a Packard Scintillation Counter. Values of cpm per gram obtained by similar injections of 125I-labeled BSA were subtracted to account for blood content of each tissue.
  • mice to be imaged were given 1 ml KI in 0.1 ml PBS to block 131I uptake by the thyroid, followed by an mtra-
  • An on-line PDP 11-34 computer controlled the data acquisition and displayed the images on black and white and color television monitors.
  • the 131I images could be normal ⁇ ized to the "'TC images by a program that divided the 131. counts by the xc counts for each imaging element. Syringes filled with ⁇ c were used as fiducial markers to reference the image to actual photographs of the animals. Mice carrying transplanted mammary tumors were injected intravenously with 0.25 ⁇ Ci of labeled, absorbed anti-MME(Fab) . Twenty-four hr. later, they were sacrificed and the amount of label in various tissues was determined.
  • tissue levels were lower than those found previously with whole gamma globulin.
  • the entire blood pool of the animals was calculated to contain only 1% of the injected dose at 24 hrs.
  • Time-course studies showed tissue levels to drop rapidly toward background levels by 2 days. This was in marked contrast to the radio- iodinated gamma globulin preparation, which showed increas ⁇ ing accumulation of label in the liver for at least three days.
  • the kinetics of appearance of Fab in the urine indi- cated that by 19 hr. , 99% of it had been excreted.
  • the labeled Fab appeared to pass intact through the kidneys into the urine, since 96% of the 125I recovered in the urine was associated with protein.
  • the labeled Fab preparations were found to consist of a molecule of 50,000 daltons, the molecular weight expected for a rabbit Fab fragment, along with its apparent dimer of about 100,000 daltons.
  • the labeled mater ⁇ ial in urine had a nearly identical electrophoretic profile..
  • Treatment of both the labeled Fab and urine with the reduc- ing agent ⁇ -mercaptoethanol yielded subunits of 26,000 daltons, the size expected for the polypeptides that make up the Fab fragment.
  • mice similar to those used for tissue distribution studies were given intravenous injections of 70 ⁇ Ci of
  • the iodine images from the germanium camera typically contained 5,000-10,000 counts, accumulated over a 45-60 min. period. Technecium images, containing about 100,000 counts, were obtained over a 5-10 in. period.
  • the prominent area of concentration at the midportion of the mice is most likely the blood-filled liver and spleen, and accumulation in the stomach. Some ⁇ times, a concentration of "'Tc also remained at the site of its injection.
  • the 131I image of nonmammary tumor-bearing animals showed relatively even distribution of the label throughout the animal's body and over the tumor with slightly concen ⁇ trated areas over the liver, and sometimes over the bladder as was also the case with nonspecific Fab used in mice with mammary tumors.
  • the 131I images of mammary tumor-bearing animals injected with anti-MME (Fab) showed concentration of the label over the tumor at levels distinctly higher than those of other tissue of the animal.
  • a normalized image was generated consisting of the ratios of I to ⁇ c at each imaging element.
  • the nor ⁇ malization procedure allows an increase in the specificity of the 131I imaging by compensating for differences in extracellular and intravascular spaces in each individual mouse, with the reservation that areas of physiological accumulation, such as the stomach and bladder are not in ⁇ cluded when comparing the density of label in different areas of the mouse.
  • the normalized ( 1/ ⁇ c) images there were usually a few hot spots outside of the body of the mice. These are artifacts of the normalization process that occur as a result of the very low counts in these areas and their resulting poor statistics.
  • the mice carrying mammary tumors had a clearly defined concentration of label over their tumors.
  • the visual ambiguities of the 1-64 scale were eliminated by using a printed matrix of the counts in each imaging element, to quantitate results. Projection of the photograph of the mouse on this matrix permitted determining the average counts per imaging element in the area of the tumor and over a comparable area on the opposite side of the mouse. From the average counts per imaging element the localization ratio (tumor/opposite side) was determined for the 99m Tc, 131 I and 131 I/ 99m Tc images.
  • the localization ratio is found by dividing the average counts per imaging element of the germanium camera image. over the tumor by the average counts over a comparable area on the opposite side of the mouse.
  • 131 1/99mTc are close to 1.0 or even less indicating no non- speci .fi.c accumulation of 131I-Fab m the tumor. It is evident from the above results, that by using antibody fragments specific for normal mammary epithelial cells, a rapid accurate imaging of tumors can be Obtained regardless of the site of the tumor. The fragments are rapidly eliminated, so that there are minimal effects from the radiation resulting from the radionuclide label.
  • the antibody fragments still retain sufficient binding affinity to rapidly accumulate in the host by primarily specific binding to normal mammary epithelial tissue to allow for sharp discrimination between mammary epithelial tissue and other tissues present in the host.
  • labelled antibody fragments which are specific for normal mammary epithelial cell surface antigen determinant sites localization is achieved wherever neoplastic mammary tissue exists in the host. Thus, not only are tumors located throughout the host, but the primary carcinoma of origin is also determined, where the primary carcinoma of origin was a mammary carcinoma.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Cell Biology (AREA)
  • Oncology (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
EP19820903200 1981-09-28 1982-09-20 Kennzeichnung einer spezifischen brustdrüse. Withdrawn EP0090025A4 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US30643981A 1981-09-28 1981-09-28
US306439 1989-02-03

Publications (2)

Publication Number Publication Date
EP0090025A1 true EP0090025A1 (de) 1983-10-05
EP0090025A4 EP0090025A4 (de) 1984-01-12

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EP19820903200 Withdrawn EP0090025A4 (de) 1981-09-28 1982-09-20 Kennzeichnung einer spezifischen brustdrüse.

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EP (1) EP0090025A4 (de)
WO (1) WO1983001004A1 (de)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4649039A (en) * 1984-07-03 1987-03-10 E. I. Du Pont De Nemours And Company Radiolabeling of methionine-containing proteins and peptides
US4837003A (en) * 1984-09-13 1989-06-06 Mallinckrodt, Inc. Radiolabeled antibody fragments
US6222020B1 (en) * 1987-01-07 2001-04-24 Imperial Cancer Research Technology Limited Antigens derived from the core protein of the human mammary epithelial mucin
US5683674A (en) * 1987-01-07 1997-11-04 Imperial Cancer Research Technology Ltd. Antibody against human mucin core protein and method of preparing and using same
RU2626123C1 (ru) * 2016-07-12 2017-07-21 государственное бюджетное учреждение здравоохранения "Санкт-Петербургский клинический научно-практический центр специализированных видов медицинской помощи (онкологический)" Способ дифференциальной диагностики опухолей аногенитальных маммароподобных желез
CN111760039A (zh) * 2020-07-17 2020-10-13 王永胜 放射性核素靶向乳腺癌前哨淋巴结转移示踪剂及制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3927193A (en) * 1973-05-18 1975-12-16 Hoffmann La Roche Localization of tumors by radiolabelled antibodies
FR2310748A1 (fr) * 1975-05-15 1976-12-10 Abramovici J Procede de marquage de proteines a l'aide du technetium

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4229426A (en) * 1978-02-22 1980-10-21 Duke University, Inc. Breast cyst fluid protein assay
US4232001A (en) * 1978-09-22 1980-11-04 University Patents, Inc. Methods and materials for detection of estrophilin
US4311688A (en) * 1979-10-29 1982-01-19 Serono Laboratories Inc. Composition and method for cancer detection in humans
US4331647A (en) * 1980-03-03 1982-05-25 Goldenberg Milton David Tumor localization and therapy with labeled antibody fragments specific to tumor-associated markers

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3927193A (en) * 1973-05-18 1975-12-16 Hoffmann La Roche Localization of tumors by radiolabelled antibodies
FR2310748A1 (fr) * 1975-05-15 1976-12-10 Abramovici J Procede de marquage de proteines a l'aide du technetium

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO8301004A1 *

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EP0090025A4 (de) 1984-01-12
WO1983001004A1 (en) 1983-03-31

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