title: Recombinant IgE antibodies for passive immunotherapy of solid tumours: from concept towards clinical application.
abstract: Therapeutic antibodies have revolutionised treatment of some cancers and improved prognosis for many patients. Over half of those available are approved for haematological malignancies, but efficacious antibodies for solid tumours are still urgently needed. Clinically available antibodies belong to the IgG class, the most prevalent antibody class in human blood, while other classes have not been extensively considered. We hypothesised that the unique properties of IgE, a class of tissue-resident antibodies commonly associated with allergies, which can trigger powerful immune responses through strong affinity for their particular receptors on effector cells, could be employed for passive immunotherapy of solid tumours such as ovarian and breast carcinomas. Our laboratory has examined this concept by evaluating two chimaeric antibodies of the same specificity (MOv18) but different isotype, an IgG1 and an IgE against the tumour antigen folate receptor α (FRα). The latter demonstrates the potency of IgE to mount superior immune responses against tumours in disease-relevant models. We identified Fcε receptor-expressing cells, monocytes/macrophages and eosinophils, activated by MOv18 IgE to kill tumour cells by mechanisms such as ADCC and ADCP. We also applied this notion to a marketed therapeutic, the humanised IgG1 antibody trastuzumab and engineered an IgE counterpart, which retained the functions of trastuzumab in restricting proliferation of HER2/neu-expressing tumour cells but also activated effector cells to kill tumour cells by different mechanisms. On-going efficacy, safety evaluations and future first-in-man clinical studies of IgE therapeutics constitute key metrics for this concept, providing new scope for antibody immunotherapies for solid tumours.
authors.affiliation: NIHR Biomedical Research Centre at Guy's and St Thomas's Hospitals and King's College London, London, UK. sophia.karagiannis@kcl.ac.uk
authors.forename: Sophia N
authors.initials: SN
authors.lastname: Karagiannis
authors.forename: Debra H
authors.initials: DH
authors.lastname: Josephs
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Karagiannis
authors.forename: Amy E
authors.initials: AE
authors.lastname: Gilbert
authors.forename: Louise
authors.initials: L
authors.lastname: Saul
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Rudman
authors.forename: Tihomir
authors.initials: T
authors.lastname: Dodev
authors.forename: Alexander
authors.initials: A
authors.lastname: Koers
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Blower
authors.forename: Christopher
authors.initials: C
authors.lastname: Corrigan
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Beavil
authors.forename: James F
authors.initials: JF
authors.lastname: Spicer
authors.forename: Frank O
authors.initials: FO
authors.lastname: Nestle
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: Gould
mesh_terms: D000818:Animals; D006801:Humans; D007116:Immunization, Passive / Q000379:methods*; D007073:Immunoglobulin E / Q000276:immunology* / Q000627:therapeutic use*; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D011961:Receptors, Fc / Q000276:immunology
chemical_list: D011961:Receptors, Fc; D007073:Immunoglobulin E