WO1994022478A1 - PREVENTION DE TUMEURS AVEC DES ANTICORPS MONOCLONAUX DIRIGES CONTRE L'ONCOGENE $i(NEU) - Google Patents

PREVENTION DE TUMEURS AVEC DES ANTICORPS MONOCLONAUX DIRIGES CONTRE L'ONCOGENE $i(NEU) Download PDF

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Publication number
WO1994022478A1
WO1994022478A1 PCT/US1994/003528 US9403528W WO9422478A1 WO 1994022478 A1 WO1994022478 A1 WO 1994022478A1 US 9403528 W US9403528 W US 9403528W WO 9422478 A1 WO9422478 A1 WO 9422478A1
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WIPO (PCT)
Prior art keywords
antibody
neu
tumors
individual
group
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PCT/US1994/003528
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English (en)
Inventor
Mark I. Greene
Makoto Katsumato
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The Trustees Of The University Of Pennsylvania
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.)
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Publication date
Application filed by The Trustees Of The University Of Pennsylvania filed Critical The Trustees Of The University Of Pennsylvania
Priority to US08/525,800 priority Critical patent/US6733752B1/en
Priority to AU65278/94A priority patent/AU6527894A/en
Publication of WO1994022478A1 publication Critical patent/WO1994022478A1/fr
Priority to US12/316,299 priority patent/US20090104191A1/en
Priority to US12/589,053 priority patent/US20100040618A1/en
Priority to US12/804,419 priority patent/US20110020332A1/en
Priority to US13/186,299 priority patent/US20110274688A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to methods of preventing the transformation of normal mammalian cells into tumor cells.
  • Tumor cells display a variety of characteristics that distinguish them from normal cells. Recent studies in the molecular genetics of cancer indicate that certain genes known as oncogenes may play a role in the transformation of some cells from their normal condition to a cancerous condition.
  • neu An oncogene which encodes a protein that exposes antigenic sites on the surface of transformed cells has been identified by transfection of DNA from ethyl nitrosourea- induced rat neuroblastomas into NIH3T3 cells. This oncogene has been termed neu .
  • the neu gene has been found to be amplified in some human tumors, particularly those of the breast, suggesting that this gene may play a role in the etiology of human cancer.
  • the neu oncogene encodes a cell surface protein on rat cells transformed by it.
  • the protein encoded by the neu oncogene is a 185kDa transmembrane glycoprotein with tyrosine kinase activity, generally known by the name pl85.
  • the neu gene is closely related to the epidermal growth factor (EGF) receptor gene in structure.
  • the neu oncogene and pl85 have also been found active in human adenocarcinomas including breast, lung, salivary gland and kidney adenocarcinomas, as well as prostate neuroblastoma. In human primary breast cancers, amplification of the neu oncogene was found in about 30% of all malignant tumors examined.
  • the present invention provides methods for the prevention of tumor cells which express a translation product of the neu oncogene on their surfaces.
  • a prophylactic amount of an antibody that specifically binds to pl85 is administered to an individual.
  • the present invention provides methods of preventing the transformation of normal human cells into tumors cells which express a translation product of the neu oncogene on their surfaces.
  • a prophylactic amount of an antibody that specifically binds to pl85 is administered to an individual.
  • the present invention provides methods for the prevention of the origination of genetically induced mammalian tumor cells which express a translation product of the neu oncogene on their surfaces by interfering with a transforming event.
  • a prophylactic amount of an antibody that specifically binds to pl85 is administered to an individual.
  • neu-associated cancer and ".neu-associated tumors” are meant to refer to tumor cells and neoplasms which express the neu gene to produce pl85.
  • the translation product of the neu oncogene is pl85, a transmembrane glycoprotein having tyrosine kinase activity and a molecular weight of about 185,000 daltons as determined by carrying out electrophoresis on the glycoprotein and comparing its movement with marker proteins of known molecular weight.
  • anti-pl85 antibodies selectively inhibit the neoplastic development in animals susceptible to developing neu transformed tumors.
  • mammalian tumors cells which express a translation product of the neu oncogene on their surfaces can be prevented by administration of antibodies which bind to pl85.
  • a prophylactic amount of an antibody that specifically binds to pl85 is administered to an individual who is identified as being susceptible to neu-associated tumors.
  • the present invention is particularly useful to prophylactically treat an individual who is predisposed to develop neu-associated tumors or who has had neu-associated tumors and is therefore susceptible to a relapse or recurrence.
  • the term "high risk individual” is meant to refer to an individual who has had a neu-associated tumor either removed or enter remission and who is therefore susceptible to a relapse or recurrence.
  • the individual can be prophylactically treated against the neu-associated tumors that they have been diagnosed as having had in order to combat a recurrence.
  • the individual can be treated according to the present invention to prevent normal cells from transforming into tumor cells.
  • Prophylactic compositions for prevention of neu- associated tumors comprise an antibody specific for the pl85 molecule and a pharmaceutically acceptable carrier. According to preferred embodiments, the prophylactic compositions for prevention of neu-associated tumors are injectable. The compositions comprise an antibody specific for the pl85 molecule and a pharmaceutically acceptable carrier or injection vehicle.
  • the antibodies are chosen from antibodies made according to the procedures described in detail below or other conventional methods for producing monoclonal antibodies.
  • the carrier be selected from those well known to persons having ordinary skill in the art.
  • An example of a carrier is sterile saline.
  • monoclonal antibodies which specifically bind to pl85 and are useful in prophylactic anti-tumor compositions using standard techniques and readily available starting materials.
  • the techniques for producing monoclonal antibodies are outlined in Harlow, E. and D. Lane, (1988) ANTIBODIES: A Laboratory Manual , Cold Spring Harbor Laboratory, Cold Spring Harbor NY, which is incorporated herein by reference, provide detailed guidance for the production of hybridomas and monoclonal antibodies which specifically bind to target proteins.
  • the protein of interest rodent or human pl85 for example, is injected into mice.
  • the spleen of the mouse is removed, the spleen cells are isolated and fused with immortalized mouse cells.
  • the hybrid cells, or hybridomas, are cultured and those cells which secrete antibodies are selected.
  • the antibodies are analyzed and, if found to specifically bind to the protein of interest, the hybridoma which produces them is cultured to produce a continuous supply of antigen specific antibodies.
  • antibodies specific for either rodent, particularly rat, pl85 or the corresponding human pl85 may be used in prophylactic compositions. Accordingly, either rodent pl85 or human pl85 is used to generate hybridomas. In both cases, the genes which encode these proteins are widely known and readily available to those having ordinary skill in the art. Thus, one having ordinary skill in the art can make antibodies useful to practice the present invention.
  • the present invention relates to human antibodies, humanized antibodies, Fabs and chimeric antibodies and Fabs which bind to pl85 which may be produced routinely by those having ordinary skill in the art.
  • the prophylactic composition comprises monoclonal antibodies designated 7.5.5, 7.9.5, 7.16.4 and 7.21.2. In some preferred embodiments of the present invention, the prophylactic composition comprises humanized monoclonal antibodies or Fabs which contain complementarity determining regions from antibodies designated 7.5.5, 7.9.5, 7.16.4 and 7.21.2. In some preferred embodiments of the present invention, the prophylactic composition comprises humanized monoclonal antibodies or Fabs which contain variable regions from antibodies designated 7.5.5, 7.9.5, 7.16.4 and 7.21.2. Patient population
  • the present invention may be used to prevent tumors in any patient population identified as being susceptible to neu-associated tumors, it is particularly useful in high risk individuals who, for example, have a family history of neu-associated cancer or show a genetic predisposition. Additionally, the present invention is particularly useful to prevent neu-associated tumors in patients who have had neu-associated tumors removed by surgical resection or who have been diagnosed as having neu- associated cancer in remission.
  • compositions may include additional components to render them more effective.
  • a prophylactic composition of the invention may comprise multiple anti-pl85 antibodies including antibodies specific for different epitopes of pl85.
  • the prophylactic compositions may include other anti-cancer agents such as, for example, cis-platin.
  • chemotherapeutics may be administered prophylactically to patients who have treated for neu-associated cancer by surgery or radiation treatment and who have had removal or remission. Administration regimen
  • antibody About 5 ⁇ g to 5000 mg of antibody may be administered. In some preferred embodiments, 50 ⁇ g to 500 mg of antibody may be administered. IN other preferred embodiments, 500 ⁇ g to 50 mg of antibody may be administered.
  • 5 mg of antibody is administered.
  • Prophylactic compositions may be administered by an appropriate route such as, for example, by oral, intranasal, intramuscular, intraperitonealor subcutaneousadministration.
  • intravenous administration is preferred.
  • C3H and [C3H x DBA/2] Fl (C3D2 Fl) mice were obtained from the Jackson Laboratory, Bar Harbor, ME.
  • Inbred congenitally athymic Balb/c nude (nu/nu) mice were obtained from the National Cancer Institute animal colony (San Diego, CA) . Animals used in the experiments are maintained in accordance with the guidelines of the Committee on' Care and Use of Laboratory Animals of the Institute of Animal Resources, National Research Council (DHEW publication number (NIH) 78-23, revised 1978). Isolation of hybridomas that secrete monoclonal antibodies that are reactive with new-transformed cells
  • C3H/HeJ mice are repeatedly immunized with NIH 3T3 transfectants transformed by the neu oncogene (cell line B104- 1-1), emulsified in Freund's adjuvant.
  • Spleens from immune mice are fused with the aminopterin-sensitive NS-1 myeloma line, and hybridomas are selected in hypoxanthine-aminopterin- thymidine media.
  • Culture supernatants from growing hybridomas are initially screened for the presence of antibody capable of binding B104-1-1 cells by indirect immunofluorescence using fluorescence activated cell sorting (FACS) .
  • FACS fluorescence activated cell sorting
  • the heavy chain isotypes of the monoclonal antibodies characterized here are determined by double immunodiffusion in agar according to the method of Ouchterlony, in Hudson, L and F.C.Hay, eds. , Practical Immunology, Blackwell Scientific Publications, London, p.117, which is specifically incorporated herein. Purification of monoclonal antibodies
  • Hybridoma cells are washed several times in HBSS and injected into pristine primed, 400 rad irradiated, C3D2F1 mice to induce ascites fluid production.
  • the fluid is removed by aspiration with a 19 gauge needle and hybridoma cells and debris are removed by centrifugation at 1000 x g.
  • the clarified ascites fluid is then stored at -70°C prior to purification, or is purified immediately. Purification is performed according to the method of Drebin et al . in Immunology and Cancer (M.L. Kripke and P. Frost, eds.) University of Texas Press, Austin, TX, p. 277 which is specifically incorporated herein.
  • Flow cytometry Cells are removed from dishes with buffered EDTA (Versene; Gibco) and washed twice in FACS medium (Hank's balanced salt solution(HBBS; Gibco) supplemented with 2% fetal calf serum (FCS) , 0.1% sodium azide and lOmM HEPES) ; 1 x 10 6 cells in 0.1 ml FACS medium are incubated with 0.1 ml of hybridoma culture supernatant for 1 hr at 4°C.
  • CNBr-activated Sepharose 4B beads are swollen in ImM HC1, and then mixed with purified antibodies in coupling buffer (0.5 M NaCl, 0.1 M NaHC0 3 , pH 8.3) at a ratio of 2 mg immunoglobulin (lmg per ml) per ml of activated beads. The mixture is rotated overnight on an end-over-end mixture at 4°C, and then unreacted sites are blocked with 0.2 M glycine pH 8.0 for 2 hours at room temperature. The beads are then poured onto a sintered glass filter and washed with three cycles of 100 bead volumes of coupling buffer, 10 bead volumes of 3.5 M MgCl 2 , 100 bead volumes of coupling buffer to wash away excess adsorbed proteins.
  • coupling buffer 0.5 M NaCl, 0.1 M NaHC0 3 , pH 8.3
  • Non-specific protein binding to the antibody coupled beads is blocked by a brief wash in sterile DMEM containing 10% fetal calf serum. The beads are then washed in PBS and stored in PBS containing 0.1% sodium azide at 4°C until they are used in immunoprecipitation experiments. All of the monoclonal antibodies which specifically bind to the surface of neu-transformed cells are reactive with the p-185 molecule encoded by the neu oncogene. These monoclonal antibodies specifically precipitate pl85 from metabolically labeled lysates of neu-transformed cells.
  • 3 x 10 5 cells are seeded in 60-mm tissues culture dishes and incubated for 18 hr in 0.8 ml phosphate-free Dulbecco-Vogt modified Eagle's medium containing 4% fetal calf serum and 0.4 mCi 2 P (carrier-free; NEN) .
  • Cells are lysed in phosphate-buffered RIPA buffer containing ImM ATP, 2mM EDTA and 20mM sodium fluoride, and immunoprecipitates are prepared and washed according to Sefton et al . (1979) Virology 28:957-971 (1979), which is specifically incorporated herein.
  • Rat and human neu oncogene DNA sequences are similar and the two genes share some sequences as can be shown by computer-aided analysis of the structure of the genes.
  • Antibodies to the human gene can be produced by following the procedure as set forth above for making antibodies to the rat neu oncogene and using the rat neu oncogene sequences which are shared with human neu oncogene instead of the rat neu oncogene.
  • domain 1 antibodies 7.5.5, 7.9.5 and All were found to bind to domain 2
  • antibody 7.21.2 was found to bind to domain 3.
  • the denominations of domains 1, 2, and 3 are arbitrary and are used as a short hand to group antibodies that competitively bind to pl85 into the same group.
  • Antibodies placed into any one group competitively bind with other antibodies of the same group to pl85, but do not to any substantial extent inhibit binding of antibodies to other portions of pl85.
  • Isotype analysis of the antibodies provided the following isotypes for the antibodies: IgGl-antibody 7.9.5; IgG2a- antibodies All and 7.16.4; IgG2B - antibody 7.5.5; and IgGl - antibody 7.21.2.
  • Hybridoma cell line producing monoclonal antibody 7.9.5 was deposited in the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Maryland, 20852-1776 on July 3, 1990 and has accession number HB10492.
  • Hybridoma cell line producing monoclonal antibody 7.16.4 was deposited in the American Type Culture Collection 12301 Parklawn Drive, Rockville, Maryland, 20852-1776 on July 3, 1990 and has accession number HB10493.
  • Oncogenic rat neu fneuT differs from wild type neu by a point mutation within the transmembrane domain of the coding sequence.
  • Certain strains of transgenic mice that express the neuT oncogene (L. Bouchard, et al. Cell 57, 931 (1989)) develop breast tumors at an average of forty four weeks of age.
  • Intraperitoneal injection of a monoclonal antibody against pl ⁇ s"*" 1 dramatically affected tumor development in these transgenic mice. A significant proportion (50%) of mice did not develop tumors even after ninety weeks of age when injected with monoclonal antibodies. This demonstrates for the first time that immunological manipulations of piss" 6 " can effectively prevent the development of genetically induced breast tumors in a rodent model.
  • This transgenic mouse model has certain important characteristics; 1) the expressed oncogene is genetically programmed and is activated in a predictable manner in conjunction with tissue specific promoter/enhancer elements; 2) the stochastic appearance of tumors suggests that involvement of other oncogenes or oncogenic factors is necessary for full development of tumors, a situation clearly analogous to naturally occurring tumors; and 3) the immunological interactions between the tumors and the host transgenic animal can be examined, since the host immune system was intact. Finally, the effect of distinct treatments could be assessed on tumors prior to or after their predicted development.
  • mice of line MN-10 on the BALB/c background. These mice became pregnant frequently and were able to nurse their litters during the treatment period.
  • the average tumor onset periods of these two sets of control mice were 42.8+ 3.2 (SEM) and 45.0 + 3.0 weeks, respectively.
  • the average tumor onset period was significantly delayed by 7.9 weeks between the low dosage group and its associated control mice (p ⁇ 0.05)
  • the difference between the low dosage group and the second control mice was marginally insignificant (0.05 ⁇ p ⁇ 0.1).
  • the high dose treatment group of mice developed tumors after 45.6 weeks of age. However, 6 of 12 mice in this group (50%) remained free of tumors at more than 90 weeks of age. This indicates that treatment of transgenic mice with MAb 7.16.4 10 ⁇ g twice weekly can effectively suppress tumor development in a large fraction of these mice for almost their entire life span (about 100 weeks) . Nearly half of the mice in both control groups and in the low dosage group developed two to five independent tumors within a six week period after the first tumor became visible. In contrast, all animals that developed malignancy in the high dosage group had only a single tumor. The tumor volume of the high dosage group at a given point after tumor appearance was always smaller than that of control mice at the same point.
  • mice The histology of the MMTV/neuT transgenic mice used in the present experiment have been previously characterized in detail (L. Bouchard et al. Cell 57, 931 (1989)) which is incorporated herein by reference. All untreated mice developed moderately to poorly differentiated ductal adenocarcinomas of the breast. A small proportion of these mice also developed salivary gland and Harderian gland tumors consistent with previous observations. The breast tumors which arose in mice treated with MAb 7.16.4 were moderately to poorly differentiated adenocarcinomas (Fig. 2A and B) which were histologically indistinguishable from that of untreated mice. Occasionally single tumors displayed both poorly and moderately differentiated areas.
  • the non-tumor breast tissue of the high dosage treated mice was histologically similar to that of the untreated mice, even after 70 weeks of treatment No ductal epithelial hyperplasia, ductal destruction or lymphoid infiltration was observed. There is no indication that the suppression of tumor development in MAb treated mice involves host immune mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) . Similarly, studies using tumor implant model of MAb therapy found no decisive contribution of host immune elements to the elimination of established tumors expressing neuT.
  • ADCC antibody-dependent cellular cytotoxicity
  • pl85c ⁇ rB ⁇ 2 overexpression usually associated with gene amplification, and it is relevant that the overexpression of pl85 c"erbB"2 can be observed in early stages of human breast tumors.
  • the data indicates that continuous down-regulation of the pl ⁇ " * " 1 molecule leads to tumor growth suppression in a dose-dependent manner.
  • the antibody mediated dose-dependent tumor suppression shown here suggests that the continuous down- regulation of pies" 60 ! diminishes the activity of necessary oncogenic factors in tumorigenesis. Prevention of metastasis or recurrence is feasible by administering anti-pl85 antibodies.

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Abstract

On décrit des procédés pour empêcher la transformation d'une cellule normale en cellule tumorale portant la glycoprotéine p185 sur sa surface. Les procédés consistent à administrer un anticorps qui se lie spécifiquement à la glycoprotéine p185. On décrit des procédés pour prévenir la transformation de cellules normales en cellules tumorales portant la glycoprotéine p185 sur leur surface chez un individu présentant un risque élevé de développement de tumeurs.
PCT/US1994/003528 1993-03-30 1994-03-30 PREVENTION DE TUMEURS AVEC DES ANTICORPS MONOCLONAUX DIRIGES CONTRE L'ONCOGENE $i(NEU) WO1994022478A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US08/525,800 US6733752B1 (en) 1994-03-30 1994-03-30 Prevention of tumors with monoclonal antibodies against neu
AU65278/94A AU6527894A (en) 1993-03-30 1994-03-30 Prevention of tumors with monoclonal antibodies against (neu)
US12/316,299 US20090104191A1 (en) 1993-03-30 2008-12-10 Prevention of tumors with monoclonal antibodies against neu
US12/589,053 US20100040618A1 (en) 1993-03-30 2009-10-15 Prevention of tumors with monoclonal antibodies against neu
US12/804,419 US20110020332A1 (en) 1993-03-30 2010-07-21 Prevention of tumors with monoclonal antibodies against neu
US13/186,299 US20110274688A1 (en) 1993-03-30 2011-07-19 Prevention of tumors with monoclonal antibodies against neu

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US3849893A 1993-03-30 1993-03-30
US08/038,498 1993-03-30

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US10/833,707 Continuation US20040202664A1 (en) 1993-03-30 2004-04-27 Prevention of tumors with monoclonal antibodies against neu

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