title: The human agonistic CD40 antibody ADC-1013 eradicates bladder tumors and generates T-cell-dependent tumor immunity.
abstract: OBJECTIVE
  Local administration of immune-activating antibodies may increase the efficacy and reduce the immune-related adverse events associated with systemic immunotherapy of cancer. Here, we report the development and affinity maturation of a fully human agonistic CD40 antibody (IgG1), ADC-1013.
  
  
  METHODS
  We have used molecular engineering to generate an agonistic antibody with high affinity for CD40. The functional activity of ADC-1013 was investigated in human and murine in vitro models. The in vivo effect was investigated in two separate bladder cancer models, both using human xenograft tumors in immune deficient NSG mice and using a syngeneic bladder cancer model in a novel human CD40 transgenic mouse.
  
  
  RESULTS
  Activation of dendritic cells (DC) by ADC-1013 results in upregulation of the costimulatory molecules CD80 and CD86, and secretion of IL12. ADC-1013 also activates DCs from human CD40 transgenic mice, and peptide-pulsed and ADC-1013-stimulated DCs induce antigen-specific T-cell proliferation in vitro. In vivo, treatment with ADC-1013 in a syngeneic bladder cancer model, negative for hCD40, induces significant antitumor effects and long-term tumor-specific immunity. Furthermore, ADC-1013 demonstrates significant antitumor effects in a human bladder cancer transplanted into immunodeficient NSG mice.
  
  
  CONCLUSIONS
  Our data demonstrate that ADC-1013 induces long-lasting antitumor responses and immunologic memory mediated by CD40 stimulation. To the best of our knowledge, ADC-1013 represents the first immunomodulatory antibody developed for local immunotherapy of cancer.
authors.affiliation: Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Mangsbo
authors.affiliation: Department of Immunotechnology, Lund University, Lund, Sweden.
authors.forename: Sissela
authors.initials: S
authors.lastname: Broos
authors.affiliation: Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Erika
authors.initials: E
authors.lastname: Fletcher
authors.affiliation: Alligator Bioscience AB, Lund, Sweden.
authors.forename: Niina
authors.initials: N
authors.lastname: Veitonmäki
authors.affiliation: Alligator Bioscience AB, Lund, Sweden.
authors.forename: Christina
authors.initials: C
authors.lastname: Furebring
authors.affiliation: Alligator Bioscience AB, Lund, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Dahlén
authors.affiliation: Alligator Bioscience AB, Lund, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Norlén
authors.affiliation: Department of Immunotechnology, Lund University, Lund, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Lindstedt
authors.affiliation: Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Tötterman
authors.affiliation: Department of Immunotechnology, Lund University, Lund, Sweden. Alligator Bioscience AB, Lund, Sweden. pek@alligatorbioscience.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Ellmark
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D019013:CD40 Antigens / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects / Q000276:immunology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D019013:CD40 Antigens; C000602878:mitazalimab