title: A novel, blocking, Fc-silent anti-CD40 monoclonal antibody prolongs nonhuman primate renal allograft survival in the absence of B cell depletion.
abstract: CD40-CD154 pathway blockade prolongs renal allograft survival in nonhuman primates (NHPs). However, antibodies targeting CD154 were associated with an increased incidence of thromboembolic complications. Antibodies targeting CD40 prolong renal allograft survival in NHPs without thromboembolic events but with accompanying B cell depletion, raising the question of the relative contribution of B cell depletion to the efficacy of anti-CD40 blockade. Here, we investigated whether fully silencing Fc effector functions of an anti-CD40 antibody can still promote graft survival. The parent anti-CD40 monoclonal antibody HCD122 prolonged allograft survival in MHC-mismatched cynomolgus monkey renal allograft transplantation (52, 22, and 24 days) with accompanying B cell depletion. Fc-silencing yielded CFZ533, an antibody incapable of B cell depletion but still able to potently inhibit CD40 pathway activation. CFZ533 prolonged allograft survival and function up to a defined protocol endpoint of 98-100 days (100, 100, 100, 98, and 76 days) in the absence of B cell depletion and preservation of good histological graft morphology. CFZ533 was well-tolerated, with no evidence of thromboembolic events or CD40 pathway activation and suppressed a gene signature associated with acute rejection. Thus, use of the Fc-silent anti-CD40 antibody CFZ533 appears to be an attractive approach for preventing solid organ transplant rejection.
authors.affiliation: Department of Autoimmunity, Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Cordoba
authors.affiliation: Department of Autoimmunity, Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Wieczorek
authors.affiliation: Hôpital de Hautepierre, Strasbourg, France.
authors.forename: M
authors.initials: M
authors.lastname: Audet
authors.affiliation: Department of Autoimmunity, Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Roth
authors.affiliation: Department of Autoimmunity, Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: M A
authors.initials: MA
authors.lastname: Schneider
authors.affiliation: Department of Autoimmunity, Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Kunkler
authors.affiliation: Laboratory and Animal Services, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: N
authors.initials: N
authors.lastname: Stuber
authors.affiliation: Department of Autoimmunity, Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Erard
authors.affiliation: Department of Autoimmunity, Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Ceci
authors.affiliation: Laboratory and Animal Services, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Baumgartner
authors.affiliation: Department of Autoimmunity, Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Apolloni
authors.affiliation: Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Cattini
authors.affiliation: Department of Autoimmunity, Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Robert
authors.affiliation: Department of Autoimmunity, Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Ristig
authors.affiliation: Department of Autoimmunity, Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Munz
authors.affiliation: Department of Autoimmunity, Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Haeberli
authors.affiliation: Technical Research and Development, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Grau
authors.affiliation: Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Sickert
authors.affiliation: Department of Autoimmunity, Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Heusser
authors.affiliation: Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Espie
authors.affiliation: Department of Autoimmunity, Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Bruns
authors.affiliation: Department of Autoimmunity, Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Patel
authors.affiliation: Department of Autoimmunity, Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: J S
authors.initials: JS
authors.lastname: Rush
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology*; D016030:Kidney Transplantation / Q000009:adverse effects / Q000379:methods*; D008252:Macaca fascicularis; D008297:Male; D011897:Random Allocation; D013997:Time Factors; D014181:Transplantation Immunology / Q000502:physiology; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D023201:CD40 Ligand
keywords: B cell biology; costimulation; kidney (allograft) function/dysfunction; rejection: acute