title: Systemic administration of a bispecific antibody targeting EGFRvIII successfully treats intracerebral glioma.
abstract: Bispecific antibodies (bscAbs), particularly those of the bispecific T-cell engager (BiTE) subclass, have been shown to effectively redirect T cells against cancer. Previous efforts to target antigens expressed in both tumors and normal tissues have produced significant toxicity, however. Moreover, like other large molecules, bscAbs may be restricted from entry into the "immunologically privileged" CNS. A tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, is a constitutively activated tyrosine kinase not found in normal tissues but frequently expressed in glioblastomas and many other neoplasms. Because it is localized solely to tumor tissue, EGFRvIII presents an ideal target for immunotherapy. Here we report the preclinical evaluation of an EGFRvIII-targeted BiTE, bscEGFRvIIIxCD3. Our results show that bscEGFRvIIIxCD3 activates T cells to mediate potent and antigen-specific lysis of EGFRvIII-expressing gliomas in vitro (P < 0.001) at exceedingly low concentrations (10 ng/mL) and effector-to-target ratios (2.5:1). Treatment with i.v. bscEGFRvIIIxCD3 yielded extended survival in mice with well-established intracerebral tumors (P < 0.05) and achieved durable complete cure at rates up to 75%. Antitumor efficacy was significantly abrogated on blockade of EGFRvIII binding, demonstrating the need for target antigen specificity both in vitro and in vivo. These results demonstrate that BiTEs can be used to elicit functional antitumor immunity in the CNS, and that peptide blockade of BiTE-mediated activity may greatly enhance the safety profile for antibody-redirected T-cell therapies. Finally, bscEGFRvIIIxCD3 represents a unique advancement in BiTE technology given its exquisite tumor specificity, which enables precise elimination of cancer without the risk of autoimmune toxicity.
authors.affiliation: Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Choi
authors.forename: Chien-Tsun
authors.initials: CT
authors.lastname: Kuan
authors.forename: Mingqing
authors.initials: M
authors.lastname: Cai
authors.forename: Gary E
authors.initials: GE
authors.lastname: Archer
authors.forename: Duane A
authors.initials: DA
authors.lastname: Mitchell
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Gedeon
authors.forename: Luis
authors.initials: L
authors.lastname: Sanchez-Perez
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000008:administration & dosage / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000276:immunology; D002845:Chromatography; D004591:Electrophoresis, Polyacrylamide Gel; D066246:ErbB Receptors / Q000235:genetics / Q000276:immunology*; D004926:Escherichia coli; D005434:Flow Cytometry; D005910:Glioma / Q000188:drug therapy* / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D020349:Surface Plasmon Resonance; D013601:T-Lymphocytes / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D018033:Antibodies, Bispecific; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors