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  • C07K16/32—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/10—Drugs for disorders of the urinary system of the bladder
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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  • A61P17/00—Drugs for dermatological disorders
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  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
  • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
  • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

• Protein tyrosine kinases are enzymes that are involved in this process. Receptor protein tyrosine kinases are believed to direct cellular growth via ligand-stimulated tyrosine phosphorylation of intracellular substrates.
• the class I subfamily of growth factor receptor protein tyrosine kinases includes the 170 kDa epidermal growth factor receptor (EGFR) encoded by the erbB ⁇ gene. erbBl has been causally implicated in human malignancy. In particular, increased expression of this gene has been observed in carcinomas of the breast, bladder, lung, head, neck and stomach.
• the antibodies will bind to the ErbB2 epitope bound by the 7C2 and/or 7F3 antibodies described herein.
• Preferred antibodies are monoclonal antibodies e.g. humanized antibodies.
• Antibodies of particular interest are those which, in addition to the above-described properties, bind the ErbB2 receptor with an affinity of at least about lOnM, more preferably at least about InM.
• the invention also provides: an isolated nucleic acid molecule encoding the antibody of the preceding paragraphs which may further comprise a promoter operably linked thereto; an expression vector comprising the nucleic acid molecule operably linked to control sequences recognized by a host cell transformed with the vector, a host cell comprising the nucleic acid (e g a hyb ⁇ doma cell line), and a process for making the antibody comprising cultu ⁇ ng a cell comprising the nucleic acid so as to express the ant ⁇ -ErbB2 antibody and, optionally, recovering the antibody from the host cell culture and, preferably, the host cell culture medium
• the invention also provides methods for using the ant ⁇ -ErbB2 antibodies disclosed herein
• the invention provides a method for inducing cell death comprising exposmg a cell, such as a cancer cell which overexpresses ErbB2, to ant ⁇ -ErbB2 antibody described herein in an amount effective to induce cell death
• the cell may be in cell culture or in
• the monoclonal antibodies herein specifically include "chime ⁇ c" antibodies (immunoglobulins) in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the cha ⁇ n(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U S Patent No 4,816,567, Morrison et al , Proc Natl Acad Sci USA, 81 6851-6855 (1984))
• the prodrugs of this invention include, but are not limited to, phosphate-containing prodrugs, thiophosphate-containing prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs, D-amino acid-modified prodrugs, glycosylated prodrugs, ⁇ -lactam- containing prodrugs, optionally substituted phenoxyacetamide-containing prodrugs or optionally substituted phenylacetamide-containing prodrugs, 5-fluorocytosine and other 5-fluorouridine prodrugs which can be converted into the more active cytotoxic free drug.
• Eukaryotic cells are known to utilize promoters, polyadenylation signals, and enhancers.
• Nucleic acid is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence.
• DNA for a presequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide;
• a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation.
• Antibodies with more than two valencies are contemplated
• t ⁇ specific antibodies can be prepared ⁇ utt et al J Immunol 147 60 (1991)
• the early and late promoters of the SV40 virus are conveniently obtained as an SV40 restriction fragment that also contains the SV40 viral origin of replication
• the immediate early promoter of the human cytomegalovirus is conveniently obtained as a Hmdlll E restriction fragment
• a system for expressing DNA in mammalian hosts using the bovine papilloma virus as a vector is disclosed in U S Patent No 4,419,446
• a modification of this system is described in U S Patent No 4,601,978 See also Reyes et al , Nature 297 598-601 (1982) on expression of human ⁇ -mterferon cDNA in mouse cells under the control of a thymidine kinase promoter from he ⁇ es simplex virus
• the rous sarcoma virus long terminal repeat can be used as the promoter (v) Enhancer element component
• the antibody can be produced lntracellularly, in the periplasmic space, or directly secreted into the medium If the antibody is produced lntracellularly, as a first step, the particulate debris, either host cells or lysed fragments, is removed, for example, by centrifugation or ultrafiltration Carter et al , Bio/Technology 10 163- 167 ( 1992) describe a procedure for isolating antibodies which are secreted to the periplasmic space of £ coli Briefly, cell paste is thawed in the presence of sodium acetate (pH 3 5), EDTA, and phenylmethylsulfonylfluo ⁇ de (PMSF) over about 30 mm Cell debris can be removed by centrifugation Where the antibody is secreted into the medium, supematants from such expression systems are preferably first concentrated using a commercially available protem concentration filter, for example, an Amicon or Millipore Pellicon ultrafiltration unit A protease
• Suitable dosages for the growth inhibitory agent are those presently used and may be lowered due to the combined action (synergy) of the growth inhibitory agent and anti-ErbB2 antibody.
• the appropriate dosage of antibody will depend on the type of disease to be treated, as defined above, the severity and course of the disease, whether the antibody is administered for preventive or therapeutic pu ⁇ oses, previous therapy, the patient's clinical history and response to the antibody, and the discretion of the attending physician.
• the antibody is suitably administered to the patient at one time or over a series of treatments.
• the data from 1 x 10 4 cells were collected and stored using LYSYS IITM software and analyzed using PAINT-A-GATETM software (Becton Dickinson) (Darzynkiewica et al. Cytometry 13:795-808 (1992) and Picker et al. J. Immunol. 150(3):1 105-1121 (1993)).
• the viability and percentage of cells in each stage of the cell cycle were determined on gated single cells using 7AAD and Hoechst staining, respectively. (Cell doublets were excluded by pulse analysis of width vs. area of the Hoechst signal.) Cell numbers were determined using a hemocytometer. DNA synthesis.
• the binding affinities of anti-ErbB2 antibodies (7C2 and 4D5) were determined by Scatchard analysis.
• the binding constants (K d ) were 6.5 x 10 "9 M (4D5) and 2.9 x 10 "9 M (7C2).
• Blocking experiments were carried out using unlabelled antibodies followed by FITC-7C2.
• 4D5 reacts with a different epitope than 7C2.
• the effect of these antibodies on the growth of the BT474 human breast cancer cells which overexpress ErbB2 was then investigated.
• Fig. 3A shows the results of flow cytometric analysis of cells incubated with an isotype-matched control. 10-12% of the cells were dead and 28% of the viable cells were in the S-G2-M phases of the cell cycle.
• Irrelevant antibody ( ⁇ gpl20) (isotype matched) - lOmg/kg in 100 ⁇ l IP twice weekly

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