title: Harnessing engineered antibodies of the IgE class to combat malignancy: initial assessment of FcɛRI-mediated basophil activation by a tumour-specific IgE antibody to evaluate the risk of type I hypersensitivity.
abstract: BACKGROUND
  IgE antibodies, sequestered into tissues and retained locally by the high-affinity IgE receptor, FcɛRI, on powerful effector cells such as mast cells, macrophages and eosinophils, may offer improvements in the therapy of solid tumours. The chimeric antibody, MOv18 IgE, against the human ovarian carcinoma antigen, folate receptor α (FRα), is more effective than its IgG1 counterpart in xenograft models of ovarian cancer. Although MOv18 IgE binds to a single epitope on FRα and cannot cross-link IgE receptors on basophils, there remains a risk that components in the circulation of ovarian cancer patients might cross-link FRα-MOv18-IgE-receptor-FcɛRI complexes on basophils to cause type I hypersensitivity.
  
  
  OBJECTIVE
  To assess the propensity for MOv18 used in a therapeutic setting to cause FcɛRI-mediated type I hypersensitivity.
  
  
  METHODS
  As validated readouts of the potential for MOv18 to cause FcɛRI-mediated type I hypersensitivity we measured release of a granule-stored mediator from a rat basophilic leukaemia cell line RBL SX-38 stably transfected with human tetrameric (αβγ2) FcɛRI, and induction of CD63 on blood basophils from patients with ovarian carcinoma and healthy controls ex vivo.
  
  
  RESULTS
  Serum FRα levels were increased in ovarian cancer patients compared with healthy controls. MOv18 IgE alone, or in the presence of its antigen recombinant human FRα, or of healthy volunteer (n=14) or ovarian carcinoma patient (n=32) sera, did not induce RBL SX-38 cell degranulation. Exposure to FRα-expressing ovarian tumour cells at target-to-effector ratios expected within tumours induced degranulation. MOv18 IgE did not induce expression of CD63 in blood basophils from either healthy volunteers (n=6), or cancer patients, despite detectable levels of circulating FRα (n=5).
  
  
  CONCLUSIONS
  These encouraging data are compatible with the hypothesis that, when ovarian carcinoma patients are treated with MOv18, FcɛRI-mediated activation of effector cells occurs within the tumour mass but not in the circulation mandating, with due caution, further pre-clinical studies.
authors.affiliation: NIHR Biomedical Research Centre at Guy's and St Thomas's Hospitals and King's College London, Cutaneous Medicine & Immunotherapy Unit, St John's Institute of Dermatology, Division of Genetics & Molecular Medicine, King's College London School of Medicine, Guy's Hospital, King's College London, London, UK.
authors.forename: S M
authors.initials: SM
authors.lastname: Rudman
authors.forename: D H
authors.initials: DH
authors.lastname: Josephs
authors.forename: H
authors.initials: H
authors.lastname: Cambrook
authors.forename: P
authors.initials: P
authors.lastname: Karagiannis
authors.forename: A E
authors.initials: AE
authors.lastname: Gilbert
authors.forename: T
authors.initials: T
authors.lastname: Dodev
authors.forename: J
authors.initials: J
authors.lastname: Hunt
authors.forename: A
authors.initials: A
authors.lastname: Koers
authors.forename: A
authors.initials: A
authors.lastname: Montes
authors.forename: L
authors.initials: L
authors.lastname: Taams
authors.forename: S
authors.initials: S
authors.lastname: Canevari
authors.forename: M
authors.initials: M
authors.lastname: Figini
authors.forename: P J
authors.initials: PJ
authors.lastname: Blower
authors.forename: A J
authors.initials: AJ
authors.lastname: Beavil
authors.forename: C F
authors.initials: CF
authors.lastname: Nicodemus
authors.forename: C
authors.initials: C
authors.lastname: Corrigan
authors.forename: S B
authors.initials: SB
authors.lastname: Kaye
authors.forename: F O
authors.initials: FO
authors.lastname: Nestle
authors.forename: H J
authors.initials: HJ
authors.lastname: Gould
authors.forename: J F
authors.initials: JF
authors.lastname: Spicer
authors.forename: S N
authors.initials: SN
authors.lastname: Karagiannis
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000009:adverse effects* / Q000235:genetics / Q000276:immunology; D000918:Antibody Specificity; D000951:Antigens, Neoplasm / Q000276:immunology; D001491:Basophils / Q000276:immunology*; D002277:Carcinoma / Q000276:immunology / Q000628:therapy*; D015550:Cell Degranulation; D045744:Cell Line, Tumor; D005260:Female; D058975:Folate Receptor 1 / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000209:etiology* / Q000276:immunology; D007073:Immunoglobulin E / Q000235:genetics / Q000276:immunology; D010051:Ovarian Neoplasms / Q000276:immunology / Q000628:therapy*; D015202:Protein Engineering; D051381:Rats; D017455:Receptors, IgE / Q000276:immunology*; D060149:Tetraspanin 30 / Q000378:metabolism
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000951:Antigens, Neoplasm; C554586:CD63 protein, human; D058975:Folate Receptor 1; C424863:MOv18 monoclonal antibody; D017455:Receptors, IgE; D060149:Tetraspanin 30; D007073:Immunoglobulin E