title: Preclinical evaluation of light-activatable, bispecific anti-human CD3 antibody conjugates as anti-ovarian cancer therapeutics.
abstract: The administration of anti-CD3 antibodies, either unmodified or in bispecific formats, has been shown to kill tumors. However, their activity needs to be carefully controlled. We have approached this problem by inhibiting their anti-CD3 activity until it is required. Folated anti-human CD3 antibody bispecific conjugates were therefore synthesised in which the folate portion of the conjugates remained free to bind to folate receptor (FR) expressing cancer cells, whilst their anti-CD3 activity was reversibly inhibited. On irradiation with UV-A light, the T-cell binding activity of the anti-CD3 antibody can be restored only when and where it is required, i.e., adjacent to a tumor. Conjugate bound to FR expressed on normal tissues in other parts of the body remains inactive. This report describes the preclinical in vivo testing of these conjugates in transgenic mice whose T-cells express human CD3 molecules. When the 'cloaked' conjugates were reactivated in the region of the primary tumor, both primary tumor growth and liver metastasis were markedly reduced. That the deliberate targeting of T-cell activity locally to the primary tumor also resulted in reduced distant metastatic growth was a key finding. Light-activatable bispecific antibody conjugates similar to those described here offer a means to control T-cell targeting with a much higher degree of specificity to tumors because they minimize potentially dangerous and unwanted side effects in non-illuminated areas. The addition of light-specific targeting to the inherent tumor specific targeting of therapeutic antibody conjugates could result in the development of safer treatments for patients.
authors.affiliation: Diagnostic and Therapeutic Technologies, Institute of Cellular Medicine, Newcastle University, The Medical School, Newcastle upon Tyne NE2 4HH, UK. stephen.thompson@ncl.ac.uk
authors.forename: Stephen
authors.initials: S
authors.lastname: Thompson
authors.forename: John
authors.initials: J
authors.lastname: Dessi
authors.forename: Colin H
authors.initials: CH
authors.lastname: Self
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D017252:CD3 Complex / Q000276:immunology / Q000627:therapeutic use; D002352:Carrier Proteins; D004353:Drug Evaluation, Preclinical; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D006801:Humans; D008027:Light; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000276:immunology; D011956:Receptors, Cell Surface; D013601:T-Lymphocytes
chemical_list: D018033:Antibodies, Bispecific; D017252:CD3 Complex; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D011956:Receptors, Cell Surface