title: Efficacy and Tolerability of a GD2-Directed Trifunctional Bispecific Antibody in a Preclinical Model: Subcutaneous Administration Is Superior to Intravenous Delivery.
abstract: Trifunctional bispecific antibodies (trAb) are novel anticancer drugs that recruit and activate different types of immune effector cells at the targeted tumor. Thus, tumor cells are effectively eliminated and a long-lasting tumor-specific T-cell memory is induced. The trAb Ektomab is directed against human CD3 on T cells and the tumor-associated ganglioside GD2, which is an attractive target for immunotherapy of melanoma in humans. To optimize clinical applicability, we studied different application routes with respect to therapeutic efficacy and tolerability by using the surrogate trAb Surek (anti-GD2 × anti-murine CD3) and a murine melanoma engineered to express GD2. We show that subcutaneous injection of the trAb is superior to the intravenous delivery pathway, which is the standard application route for therapeutic antibodies. Despite lower plasma levels after subcutaneous administration, the same tumor-protective potential was observed in vivo compared with intravenous administration of Surek. However, subcutaneously delivered Surek showed better tolerability. This could be explained by a continuous release of the antibody leading to constant plasma levels and a delayed induction of proinflammatory cytokines. Importantly, the induction of counter-regulatory mechanisms was reduced after subcutaneous application. These findings are relevant for the clinical application of trifunctional bispecific antibodies and, possibly, also other immunoglobulin constructs. Mol Cancer Ther; 14(8); 1877-83. ©2015 AACR.
authors.affiliation: Helmholtz-Zentrum München, Institut für Molekulare Immunologie, Munich, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Deppisch
authors.affiliation: Trion Research GmbH, Martinsried, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Ruf
authors.affiliation: Helmholtz-Zentrum München, Institut für Molekulare Immunologie, Munich, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Eissler
authors.affiliation: Helmholtz-Zentrum München, Institut für Pathologie, Munich, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Neff
authors.affiliation: Ludwig-Maximilians-Universität München, Klinikum Großhadern, Medizinische Klinik III und Abteilung für Transfusionsmedizin, Munich, Germany.
authors.forename: Raymund
authors.initials: R
authors.lastname: Buhmann
authors.affiliation: Trion Research GmbH, Martinsried, Germany. Mocikat@helmholtz-muenchen.de Horst.Lindhofer@trionresearch.de.
authors.forename: Horst
authors.initials: H
authors.lastname: Lindhofer
authors.affiliation: Helmholtz-Zentrum München, Institut für Molekulare Immunologie, Munich, Germany. Mocikat@helmholtz-muenchen.de Horst.Lindhofer@trionresearch.de.
authors.forename: Ralph
authors.initials: R
authors.lastname: Mocikat
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D018033:Antibodies, Bispecific / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001682:Biological Availability; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005732:Gangliosides / Q000037:antagonists & inhibitors*; D007279:Injections, Subcutaneous; D008213:Lymphocyte Activation / Q000276:immunology; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D000970:Antineoplastic Agents; D016207:Cytokines; D005732:Gangliosides; C019403:ganglioside, GD2