WO1995020045A1 - Antibodies to egf receptor and their antitumour effect - Google Patents
Antibodies to egf receptor and their antitumour effect Download PDFInfo
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- WO1995020045A1 WO1995020045A1 PCT/GB1995/000118 GB9500118W WO9520045A1 WO 1995020045 A1 WO1995020045 A1 WO 1995020045A1 GB 9500118 W GB9500118 W GB 9500118W WO 9520045 A1 WO9520045 A1 WO 9520045A1
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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
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- This invention relates to the development of agents and methods for treating tumour cells. More particularly, it is concerned with antibodies against the epidermal growth factor receptor (EGFR) , which have been found to exhibit an antitu our effect.
- EGFR epidermal growth factor receptor
- EGFR epidermal growth factor receptor
- This receptor is a 170 D transmembrane glycoprotein with tyrosine kinase activity which transmits the mitogenic action of the EGF family of growth factors including EGF, TGF ⁇ and amphiregulin.
- EGF epidermal growth factor receptor
- TGF ⁇ TGF ⁇
- amphiregulin The binding of these ligands to the external domain of the EGF receptor initiates a number of early and delayed responses in the target cells leading ultimately to DNA synthesis and cell division.
- Over-expression of the EGFR has been reported in a number of human malignancies including cancer of the breast, brain, bladder, head and neck, pancreas and lung (1,9-12) .
- ICR64 directed against epitope D
- ICR16 IgG2a
- ICR62 IgG2b
- the present invention provides antibodies to EGF receptor, and fragments thereof, for therapeutic use. Included in this aspect of the invention are those antibodies identified herein, and their functional equivalents, mutants and derivatives.
- the antibodies may be murine (rat or mouse) , but preferably have framework regions and/or constant regions based on or derived from human antibodies.
- the antibodies may be complete immunoglobulin molecules, but they may be Ig fragments, for example monovalent or divalent Ig entities such as Fab fragments, single chain Fv molecules etc.
- the present invention discloses the use of antibodies to the EGFR, or fragments thereof, in the preparation of a medicament for inducing terminal differentiation in tumour cells, especially those which are characterised by over-expressing EGFR.
- the present invention provides DNA encoding the above antibodies, expression vectors comprising that DNA and host cells transformed with the expression vectors.
- the present invention provides pharmaceutical compositions comprising one or more of the above antibodies, for example selected from antibodies ICR16, ICR62 and ICR64.
- the amounts of the antibodies used in the compositions can be determined by the skilled person, and will be typically in the range 1 to 300mg.
- the above antibodies or fragements can be conjugated to a label, toxin or drug.
- the antibodies could be used to target an active agent administered in a precursor form to cells, for conversion to the active form by an activating agent produced in, or targeted to, the cells to be treated. This type of approach is sometimes known as ADEPT (see for example, EP-A-415731 and WO 90/07936) .
- peptide or mimetic molecules which mimic the antibody binding to EGFR and likewise induce terminal differentiation of tumour cells.
- the present invention also includes the use of the above antibodies in the design or synthesis of these mimetics.
- EGF receptor antibodies are primarily of interest in the treatment of tumour cells, they may also find applications in the treatment of other disorders, eg arthritis, psoriasis, atherosclerosis, S E, inflammation or other proliferative disorders.
- the antibodies described above can altered in a variety of ways using recombinant DNA technology coupled with advances in the field of monoclonal antibody and protein engineering. This has enabled access to a large selection of antibodies and antibody fragments with different properties and structures to natural antibodies.
- Monoclonal antibodies can be subjected to the techniques of recombinant DNA technology to produce other antibodies or chimeric molecules which retain the specificity of the original antibody. Such techniques may involve introducing DNA encoding the immunoglobulin variable region, or the complementarity determining regions (CDRs) , of an antibody to the constant regions, or constant regions plus framework regions, of a different immunoglobulin. See, for instance, EP-A-184187, GB 2188638A or EP-A-239400.
- a hybridoma producing a monoclonal antibody may be subject to genetic mutation or other changes, which may or may not alter the binding specificity of antibodies produced.
- an antibody specific for a protein may be obtained from a recombinantly produced library of expressed immunoglobulin variable domains, eg using lambda bacteriophage or filamentous bacteriophage which display functional immunoglobulin binding domains on their surfaces; for instance see WO92/01047.
- the library may be naive, that is constructed from sequences obtained from an organism which has not been immunised with the target, or may be one constructed using sequences obtained from an organism which has been exposed to the antigen of interest
- Antibodies may be modified in a number of ways. Indeed the term “antibody” should be construed as covering any specific binding substance having an binding domain with the required specificity. Thus this term covers antibody fragments, derivatives, functional equivalents and homologues of antibodies, including any polypeptide comprising an immunoglobulin binding domain, whether natural or synthetic. Chimaeric molecules comprising an immunoglobulin binding domain, or equivalent, fused to another polypeptide are therefore included. Cloning and expression of chimaeric antibodies are described in EP-A- 0120694 and EP-A-0125023.
- binding fragments are (i) the Fab fragment consisting of VL, VH, CL and CHI domains; (ii) the Fd fragment consisting of the VH and CHI domains; (iii) the Fv fragment consisting of the VL and VH domains of a single antibody; (iv) the dAb fragment (Ward, E.S. et al.
- Diabodies are multimers of polypeptides, each polypeptide comprising a first domain comprising a binding region of an immunoglobulin light chain and a second domain comprising a binding region of an immunoglobulin heavy chain, the two domains being linked (eg by a peptide linker) but unable to associate with each other to form an antigen binding site: antigen binding sites are formed by the association of the first domain of one polypeptide within the multimer with the second domain of another polypeptide within the multimer (WO94/13804) .
- bispecific antibodies may be conventional bispecific antibodies, which can be manufactured in a variety of ways (Holliger, P. and Winter G. Current Opinion Biotechnol.
- Diabodies and scFv can be constructed without an Fc region, using only variable domains, potentially reducing the effects of anti-idiotypic reaction.
- Other forms of bispecific antibodies include the single chain "Janusins" described in Traunecker et al, Embo Journal, 10, 3655-3659, (1991) .
- Bispecific diabodies, as opposed to bispecific whole antibodies, are also particularly useful because they can be readily constructed and expressed in E. coli .
- phage display WO94/13804
- one arm of the diabody is to be kept constant, for instance, with a specificity directed against antigen X, then a library can be made where the other arm is varied and an antibody of appropriate specificity selected.
- bispecific antibodies incorporating a specificity for the T-cell co-receptor CD3 have been shown to inhibit tumour growth (Titus, J. A. et al. , J. Immunol. 138, 4018-4022 (1987)) and to cure lymphoma (Brissinck J. et al, J. Immunol. 174, 4019-4026 (1991)).
- humanise non-human (eg murine) antibodies to provide antibodies having the antigen binding properties of the non-human antibody, while minimising the immunogenic response of the antibodies, eg when they are used in human therapy.
- humanised antibodies comprise framework regions derived from human immunoglobulins
- acceptor antibody in which residues from one or more complementary determining regions (CDR's) are replaced by residues from CDR's of a non-human species (donor antibody) such as mouse, rat or rabbit antibody having the desired properties, eg specifici .y, affinity or capacity.
- donor antibody such as mouse, rat or rabbit antibody having the desired properties, eg specifici .y, affinity or capacity.
- Some of the framework residues of the human antibody may also be replaced by corresponding non-human residues, or by residues not present in either donor or acceptor antibodies.
- Figures 1 and 2 show flow cytometric analysis of DNA in nuclei obtained from HN5 cells following four days incubation in vitro in DMEM-2%FCS alone or in DMEM-2%FP" containing anti-EGFR mAbs (156nM) or EGF (lOnM) .
- Fi_ shows DNA histograms;
- Fig 2 shows the percentage of cells in each phase.
- Figures 3 and 4 show the influence of antibodies to the EGFR or their Fab fragments on the binding of 125 I-EGF (Fig 3) or 125 I-TGF ⁇ (Fig 4) to the human bladder carcinoma cell line EJ.
- Figures 5 and 6 show Scatchard plots of 12S I-EGF binding to EJ cells in the absence or presence of monovalent and divalent mAbs ICR9 (Fig 5) and ICR62 (Fig 6) .
- Figures 7-9 show the effect of treatment with antibodies to the EGFR or their Fab fragments on the growth in vitro of HN6 cells (Figs 7) , other head and neck carcinoma cell lines overexpres ⁇ ing the EGF receptor (Fig 8) , and the TGF ⁇ induced proliferation of quiescent human foreskin fibroblasts (Fig 9) .
- Figure 10 shows titration curves showing the inhibition of binding of 1251-EGF to EJ cells by serum taken at the times indicated.
- A patient 8 (20mg) ;
- B patient 10 (40mg) ; or
- C patient 13 (lOOmg) .
- the starting concentration of the ICR62 standard was lOug/ml.
- Figure 11 shows the development of human anti-rat antibodies in the serum of patient number 9 following injection of 20mg ICR62 shown by binding to intact ICR62 (A) , Fab ICR62 (B) and scFv ICR62 (C) .
- Figure 12 the development of human anti-rat antibodies in the serum of patient number 11 following injection of 40mg of ICR62 shown by binding to intact ICR62 (A) , Fab ICR62 (B) but not scFv ICR62 (C) .
- sequence listings show the DNA and deduced amino acid sequences of the variable regions of the heavy and light chains of ICR62 and ICR64, with the CDRs indicated in square brackets.
- the head and neck carcinoma cell line LICR-LON-HN5 and the breast carcinoma cell line MDA-MB 468 were cultured routinely in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% foetal calf serum (FCS) and the antibiotics penicillin, streptomycin and neomycin.
- DMEM Dulbecco's modified Eagle's medium
- FCS foetal calf serum
- concentration of FCS in medium was reduced to 2% to minimize the effects of any growth factors present.
- Isotype matched control antibodies included ALN/ll/53 (IgG2a) and 11/160 (IgG2b) which are directed against a specific antigen on the rat sarcoma HSN (27) , or RCI/4/74 (IgGl) an antibody directed against an idiotopic determinant on ICR16 (unpublished data) .
- Monoclonal antibody to cytokeratin 10 (R SE-60) was obtained from EuroPath Ltd, Cornwall.
- Mouse monoclonal antibody to involucrin (28) was a gift from Dr Fiona Watt (Imperial Cancer Research Fund, London) .
- mice bearing human tumour xenografts Treatment of mice bearing human tumour xenografts with antibodies to the EGFR.
- Xenografts of human tumours were established in athymic (nu/nu) mice and treated with antibodies as described previously (29,39) . Briefly, the protocols used were as follows.
- HN5 tumour xenografts Since treatment of athymic mice with antibody initiated at the time of tumour inoculation results in complete and permanent regression of these tumours (39) , HN5 tumour xenografts were set up as described above but the commencement of treatment with antibodies to the EGFR was delayed until the tumours had reached a mean diameter of about 0.5cm. In this experiment groups of four to five mice were treated with antibodies ICR61 or ICR64, or with combinations of ICR61 plus ICR62 or ICR64 plus ICR62; pairs which do not compete for binding to the EGFR. In each case a second group of mice was treated with control antibodies or saline.
- Treatment with antibodies was for five consecutive days and thereafter three times weekly until the day indicated in each experiment (total dose 2.2mg/mouse) . Animals were observed for up to 100 days or killed when the tumours reached a mean diameter of 0.8-1.0cm.
- tumours were excised and samples were fixed in Methacarn and then embedded in paraffin. Four micron sections were cut and stained with haematoxylin and eosin (H & E) .
- DAB [lOOmg DAB in 100ml of 0.1 M Tris buffer pH7.2, 100ml H 2 0, 66 ⁇ l H 2 0 2 ] .
- the sections were washed twice in DDW, counterstained in Mayer's haemalum for 1 minute, dehydrated by passing through graded alcohols then mounted in DPX.
- staining of the frozen sections was performed as above but without incubation in the primary antibody in order to visualize the presence of any remaining therapeutic mAb.
- HN5 cells (7.5 x 10 s ) were seeded into 25cm 2 Nunc flasks (Gibco Europe Ltd, Scotland) containing 15ml DMEM plus 2%
- FCS Monoclonal antibody (25 ⁇ g/ml) , EGF (lOnM) or the equivalent amount of medium only was then added and the cultures were incubated for four days at 37°C.
- Flow cytometric analysis of the nuclei prepared from these cells was performed essentially as described by Ormerod et al (30) . Briefly, a suspension of single cells from each flask was prepared in 200 ⁇ l of PBS and this was followed by the vigorous addition of 2ml ice cold 70% ethanol-30% PBS. The cells were incubated for at least 30 minutes at 4°C, harvested by centrifugation and resuspended in 700 ⁇ l PBS.
- RNAse lmg/ml, Sigma
- propidium iodide lOO ⁇ g/ml, Sigma
- 5xl0 4 HN5 cells were plated onto glass cover slips in 24 well plates containing 1ml DMEM plus 2%FCS. Following overnight incubation at 37°C, specific or control antibodies (25 ⁇ g/ml) or medium alone were added to the cultures and the cells were incubated for a further three to four days at 37°C. After two washes with PBS, the cells were fixed for 5 minutes in ice-cold methanol then washed by incubation in PBS for 30 minutes. Mouse anti-cytokeratin 10 or anti-involucrin mAb diluted in PBS-0.5% BSA was added and the coverslips were incubated at 4°C for 1 hour.
- HN5 tumour xenografts following treatment with one, or a combination of two anti-EGFR mAbs that bind to two distinct epitopes on the external domain of the human EGF receptor.
- ICR62 plus ICR64 total dose 2.2mg/mouse
- HN5 tumour xenografts were treated from day 5-24 with antibody ICR61, 2/8 tumours had disappeared completely when the experiment was terminated on day 75 (29) .
- Examination of the nodules remaining also showed that few if any viable cells were present and the lesions were similar in appearance to those described above.
- An H & E stained section of an HN5 nodule remaining after treatment from day 7-24 with a combination of ICR61 plus ICR62 (total dose 2.2mg/mouse) showed that zones of keratinisation and apparent squamous differentiation were present. Indeed, keratinized areas could be found in all of the tumour lesions remaining in mice that had undergone treatment with the specific antibodies used either alone or in combination.
- tumours were excised, cryosections were prepared and stained with peroxidase conjugated F(ab') 2 rabbit anti-rat IgG.
- the uniform staining of the tumour cell membranes with the second antibody shows that all of the tumour cells were coated with specific rat antibody at this time.
- the total area of tumour remaining was smaller in the mice treated with ICR62 (mean tumour diameter 27.5% of control) however, compared with those treated with ICR16 (mean tumour diameter 86% of control) .
- the ICR62 treated tumours showed a more extensive host cell infiltrate surrounding the remaining viable tumour cells.
- HN5 cells treated with antibodies to the EGFR undergo terminal differentiation.
- Antibody ICR62 which binds to epitope C on the EGFR inhibits (a) the binding of ligand to the receptor, (b) the
- a on the EGF receptor increases the binding of ligand (EGF and TGF ⁇ ) to the EGF receptor, (b) enhances the
- EGF EGF induced proliferation of human fibroblasts, and (c) stimulates the growth of tumours over-expressing the EGF receptor (25) .
- our aim was to discover if the monovalent Fab fragments of these mAbs were as effective as the bivalent mAbs in inducing these effects or if bivalent antibody was essential for their activity ( 2 , 3 , 5 , 7 , 44 , 45 ) .
- a competitive RIA was used to determine the effect of the mAbs and their Fab fragments on the binding of 125 I-EGF and 125 I-TGF ⁇ to the EGFR on EJ cells as described (26) .
- the rat mAbs 11/160 and ALN/11/53 directed against an irrelevant antigen (27) were used as controls.
- 125 I-EGF was prepared as described above. EJ cells were seeded into 96 well plates (2xl0 4 cells/well) in DMEM containing 10% FCS. Following 48 hours incubation at 37°C, the cells were washed twice with ice cold binding buffer (DMEM, 15mM Hepes containing 0.1% BSA) and incubated with 20 ⁇ l of ICR9, Fab ICR9, ICR62 or Fab ICR62 (20 ⁇ g/ml) or medium alone for 30 minutes on ice prior to addition of 30 ⁇ l of 125 I-EGF (0.86-104nM) .
- DMEM ice cold binding buffer
- HSC-1, HSC-2, HSC-4, Ca9-22, LICR-L0N-HN5 and LICR-LON-HN6 cell lines (6,9) were grown in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% foetal calf serum (FCS) and the antibiotics penicillin, streptomycin and neomycin.
- DMEM Dulbecco's modified Eagle's medium
- FCS foetal calf serum
- DE532 cells (Flow Laboratories) seeded at 4 x 10 4 cells/ml in EMEM-10% FCS into 24-well plates were grown to confluence then the medium was replaced with EMEM-1%FCS. After 48 hours in this medium, 50 ⁇ l aliquot ⁇ of mAb or Fab fragment (25 ⁇ g/ml) and/or TGF ⁇ (5ng/ml) were added to triplicate wells and the cells were incubated overnight at 37°C then pulsed for 6 hours with 2 ⁇ Ci/well of 3 H-thymidine. The acid insoluble radioactivity incorporated into DNA was determined in a liquid scintillation counter.
- Photomicrographs of HN5 tumour cells were taken following treatment for four days with 156nM of ICR62, ICR62 Fab fragment or control antibody 11/160 (27) , and viewed alternatively by phase contrast illumination or by immunofluorescent staining for expression of cytokeratin 10.
- 5 x 10 4 HN5 cells were plated onto glass cover slips and placed in 24 well plates containing lml DMEM-2% FCS/well. Following overnight incubation at 37°C, specific or control antibodies (25 ⁇ g/ml) were added to the cultures and the cells were incubated for a further four days at 37°C.
- the monovalent ICR62 inhibited the growth of five other head and neck tumour cell lines (HN5, HSC-1, HSC-2, HSC-4 and Ca9-22) (6,9) which overexpress the EGF receptor (figure 8) .
- HN5 head and neck tumour cell lines
- HSC-1, HSC-2, HSC-4 and Ca9-22 overexpress the EGF receptor
- monovalent Fab fragments of this antibody also inhibited completely the TGF ⁇ induced proliferation of quiescent human foreskin fibroblasts ( Figure 9) .
- the Fab of ICR62 was as effective as the bivalent antibody in inducing the differentiation of HN5 cells.
- antigenic modulation wa ⁇ not a ⁇ ignificant factor in the escape of viable cells from antibody treatment and, providing antibody access wa ⁇ ⁇ ati ⁇ factory, the ⁇ e cells might be ⁇ u ⁇ ceptible to further treatment with antibody.
- the intramolecular model suggests that binding of EGF to the EGF receptor induces a conformational change in the extracellular domain of a receptor monomer which is propagated across the plasma membrane to the cytoplasmic kinase domain leading to its activation (46,49).
- the intermolecular model (2,3,48) on the other hand, propo ⁇ e ⁇ that receptor dimerization following ligand binding trigger ⁇ pho ⁇ phorylation by the cytopla ⁇ mic tyrosine kinase.
- the second model it wa ⁇ expected that bivalent antibody would block activation by preventing receptor dimerization (3,7,8,44).
- CDRs complementary determining regions
- FR ⁇ framework regions
- the ⁇ e CDRs can be grafted into the FRs of human antibodies, optionally with retention of selected murine re ⁇ idues in the FRs, according to well establi ⁇ hed principle ⁇ di ⁇ cus ⁇ ed above(see for example, Winter GB-A-2188638, Harris et al WO92/04381 and Queen et al, PNAS (1989), 86:10029-33) to create corresponding humanised antibodies which may be more appropriate for the treatment of humans.
- tumours which expres ⁇ 10 s or le ⁇ receptor ⁇ are much le ⁇ ⁇ en ⁇ itive to antibody treatment than are the EGFR overexpressing tumour cells (1,26) .
- Mendelsohn and colleagues in a preclinical study with chimpanzees have reported that treatment with a total dose of 650mg of antibody produced no toxicity (41) .
- the aims of this clinical study were to (a) monitor patients for any possible signs of toxicity, (b) investigate if therapeutic antibody had localised specifically to tumour cell ⁇ in meta ⁇ tatic le ⁇ ion ⁇ , (c) determine the level of ICR62 remaining in circulation following treatment and (d) di ⁇ cover if the patient ⁇ mounted a human anti-rat antibody (HARA) re ⁇ pon ⁇ e.
- HAA human anti-rat antibody
- Patient ⁇ were con ⁇ idered eligible for inclu ⁇ ion in thi ⁇ trial who had i) inoperable hi ⁇ tologically or cytologically confirmed diagnosis of squamou ⁇ cell carcinoma of the lung or head and neck, ii) immunocytochemically proven expre ⁇ sion of the EGF receptor, iii) an ECOCG performance status of 0-2, iv) no known history of allergy or atopy, v) no immunological therapy within the previous 4 week ⁇ , vi) no significant abnormalities of renal, hepatic, or bone marrow function ( haemoglobin > lOg/dl, white count > 3xl0 9 /l / platelet > 120, creatinine ⁇ 130, liver enzymes and bilirubin ⁇ x2 normal) .
- tumour grade and the previou ⁇ treatments that the patient ⁇ had received are ⁇ ummari ⁇ ed in Table 1.
- Patient ⁇ were ⁇ kin te ⁇ ted (lOug intradermally) lhr before antibody wa ⁇ admini ⁇ tered and no patient was found to give an adverse respon ⁇ e.
- Antibody in pho ⁇ phate buffered ⁇ aline pH 7.4 wa ⁇ given intravenou ⁇ ly a ⁇ a single bolus injection over a period of 30-60 minutes.
- Groups of three patients were treated with 2.5, 10, 20, or 40mg of ICR62 and a further eight patients were given lOOmg of this antibody. All patients were evaluated for ⁇ igns of toxicity.
- the amount of free mAb ICR62 pre ⁇ ent in ⁇ erum wa ⁇ determined by its ability to inhibit the binding of EGF or TGF to the bladder carcinoma cell line EJ as described previously (27) .
- Doubling dilutions of serum (50 ⁇ l) were mixed with an equal volume of 125 I-EGF (4xl0 4 cpm) or 125 i- TGF (4xl0 4 cpm) .
- Standards containing known concentrations of ICR62 were set up in the same way. Aliquots of 90 ⁇ l of each mixture were then transfered to monolayers of EJ cells grown to confluency in 96 well plates.
- tumour biopsies were snap frozen in liquid nitrogen then mounted in OCT medium and sections of 5 ⁇ m thicknes ⁇ cut.
- a second sample was fixed in acetone at 4°C for 10 minutes, then after wa ⁇ hing briefly in PBS the ⁇ ection wa ⁇ incubated with mAb ICR62 (lOO ⁇ g/ml, for 1 hour. Following washing in PBS for 5 minutes, the sections were incubated with a 1:100 dilution of sheep anti-rat F(ab')2 conjugated to horse radish peroxidase (Amersham) for 45 minutes.
- Peroxidase staining was demonstrated by incubating the section ⁇ for 10 minute ⁇ in a ⁇ olution containing 0.05% diaminobenzidine (Sigma), 0.1% hydrogen peroxide (Merck) and 0.07% imidazole (Merck) . After wa ⁇ hing in running tap water for 5 minute ⁇ , the sections were counterstained in Mayer' ⁇ Haematoxylin (HD Supplier ⁇ ) for 30 seconds. Finally the section ⁇ were dehydrated, cleared and mounted.
- biopsie ⁇ were taken from metastatic sites, 24 hours after the antibody was administered, then frozen sections were cut and stained with sheep anti-rat antibody alone.
- serial section ⁇ taken from the ⁇ ame biop ⁇ ies were stained first with ICR62 followed by the peroxidase conjugated sheep anti rat F(ab')2 so that all EGFR expressing cells were stained.
- Patient ⁇ were admitted to ho ⁇ pital on the day before the admini ⁇ tration of antibody and their biochemical and haematological parameters were monitored. Following intravenou ⁇ injection of the antibody some of the patients exhibited mild rigors and fever or hypotension (Table 1) . The symptom ⁇ which were not related to the do ⁇ e of antibody admini ⁇ tered were readily controlled. In no ca ⁇ e were any ⁇ evere toxicitie ⁇ observed. The patients were released from hospital 24 hours after the injection of antibody and they were seen at weekly intervals for up to six weeks. None of the patients reported any untoward effects of their treatment during the follow-up period.
- the level of ICR62 remaining in circulation wa ⁇ found to be highe ⁇ t in patient ⁇ recieving lOOmg of ICR62. In one patient, about half of the antibody admini ⁇ tered wa ⁇ in circulation on day 3 but no free mAb could be detected in the blood at 7 days post ICR62 treatment.
- Injected ICR62 binds to the EGFR on tumour cell membranes
- Biopsie ⁇ were taken of meta ⁇ tatic le ⁇ ions from six patient ⁇ , 24 hours after treatment of the patients with 40mg or lOOmg of ICR62. Frozen ⁇ ections were examined for the presence of cell bound antibody by staining directly with a peroxidase-conjugated second antibody reagent. Two of the biopsie ⁇ were found to con ⁇ ist largely of necrotic material and were discarded but four yielded well defined regions containing infiltrating tumour. The sections illustrated in figure 2a show that 24 hours after treatment of two patients with 40mg of ICR62, the antibody had localized to the membranes of tumour cells in the metastatic sites and the proliferating cells at the periphery of the tumour were strongly stained.
- ICR62 ( Table 1, Figure 4) .
- Sera from two out of the eight patient ⁇ treated with lOOmg of ICR62 (patients 16 and 19) contained antibodies directed against determinants on the constant region since they bound to the Fab and intact antibody but not to the ICR62 scFv (Table 1, Figure 5) .
- the results obtained with the serum taken before treatment indicated that antibodies which bound to rat IgG were present in the sera before ICR62 was administered but test ⁇ were not done to determine if binding wa ⁇ ⁇ pecific or due to the presence of autoantibodies such as rheumatoid factor.
- mice antibodies have undergone clinical evaluation in Phase I and Phase II ⁇ tudies in patients with head and neck, lung or brain cancers including mAb EGFR1 (52,53), mAbs 225 and 528 (42,54), mAb 425 (EMD 55900 E Merk, 55-59) and mAb RG83852 (60) .
- the aim of these studie ⁇ like the one pre ⁇ ented here, wa ⁇ to determine whether treatment of cancer patient ⁇ with anti- EGFR mAbs produced life threatening toxicities by binding to the EGFR expre ⁇ sed by normal tis ⁇ ue ⁇ including liver and ⁇ kin.
- the re ⁇ ult ⁇ of the ⁇ e ⁇ tudie ⁇ have ⁇ hown that mouse antibodies to the EGFR can be given safely to patients without toxicity.
- Divigi and colleagues have treated patients with advanced ⁇ quamou ⁇ cell carcinoma of the lung with ⁇ ingle do ⁇ e ⁇ of up to 300mg of mAb 225, including 4mg of indium Ill-labeled 225, without any sign of toxicity (42) .
- mAb ICR62 for a phase I clinical study since it was the most effective of a large number of rat mAbs we had made again ⁇ t the human EGFR, at inducing the regre ⁇ ion of xenograft ⁇ of head and neck, vulva and breast carcinomas grown in athymic mice (39,50,51) .
- the results of this Phase I clinical study has indicated that mAb ICR62 can be given safely, at doses up to lOOmg, to cancer patients without any life threatening toxicities. This finding is in agreement with the re ⁇ ult ⁇ of studies with mouse antibodies to the EGFR described above.
- the results of this Phase I dose escalation study has indicated that the rat mAb ICR62, which acts as an EGF and TGF antagonist, a) can be adminstered safely in patients with squamou ⁇ cell carcinoma, b) localize ⁇ efficently to meta ⁇ tatic sites in patients with squamous cell carcinoma, and c) may therefore be useful in the treatment of a significant number of cancer patient ⁇ who ⁇ e tumour ⁇ overexpre ⁇ the EGF receptor. From the re ⁇ ult ⁇ of our preclinical ⁇ tudie ⁇ in athymic mice, we have noted that to achieve tumour de ⁇ truction repeated admin ⁇ tration of EGFR mAb ⁇ may be required. For thi ⁇ rea ⁇ on, a phase II clinical study is planned using multiple do ⁇ e ⁇ of mAb ICR62.
- EGFR in human esophageal carcinoma cells act as ' a autocrine growth factor.
- Bilzer T Stassiecki P
- Vega F et al : Immunotherapy of malignant gliomas with the anti-EGFR monoclonal antibody. Proc Annu Meet Am Assoc Cancer Res,
- AAG TTC AAG AGC AAG GCC ACA TTG ACT GCA GAC AAA TCC ACC GAT ACA GCC TAT ATG GAG
- GGA GAA GCT CCC AAA CGC CTG ATA TAT : AAT ACA AAC AAT TTG CAA ACA GGC ATC CCA TCA Gly Glu Ala Pro Lys Arg Leu He Tyr Asn Thr Asn Asn Leu Gin Thr Gly He Pro Ser
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Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP95906400A EP0737251A1 (en) | 1994-01-21 | 1995-01-23 | Antibodies to egf receptor and their antitumour effect |
AU14601/95A AU691865B2 (en) | 1994-01-21 | 1995-01-23 | Antibodies to egf receptor and their antitumour effect |
JP7519421A JPH09510605A (en) | 1994-01-21 | 1995-01-23 | Antibody against EGF receptor and antitumor effect thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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GB9401182.2 | 1994-01-21 | ||
GB9401182A GB9401182D0 (en) | 1994-01-21 | 1994-01-21 | Antibodies to EGF receptor and their antitumour effect |
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WO1995020045A1 true WO1995020045A1 (en) | 1995-07-27 |
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PCT/GB1995/000118 WO1995020045A1 (en) | 1994-01-21 | 1995-01-23 | Antibodies to egf receptor and their antitumour effect |
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EP (1) | EP0737251A1 (en) |
JP (1) | JPH09510605A (en) |
AU (1) | AU691865B2 (en) |
CA (1) | CA2180834A1 (en) |
GB (1) | GB9401182D0 (en) |
WO (1) | WO1995020045A1 (en) |
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JPH09510605A (en) | 1997-10-28 |
AU1460195A (en) | 1995-08-08 |
EP0737251A1 (en) | 1996-10-16 |
GB9401182D0 (en) | 1994-03-16 |
AU691865B2 (en) | 1998-05-28 |
CA2180834A1 (en) | 1995-07-27 |
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