title: Advantages of Papio anubis for preclinical testing of immunotoxicity of candidate therapeutic antagonist antibodies targeting CD28.
abstract: Antagonist anti-CD28 antibodies prevent T-cell costimulation and are functionally different from CTLA4Ig since they cannot block CTLA-4 and PDL-1 co-inhibitory signals. They demonstrated preclinical efficacy in suppressing effector T cells while enhancing immunoregulatory mechanisms. Because a severe cytokine release syndrome was observed during the Phase 1 study with the superagonist anti-CD28 TGN1412, development of other anti-CD28 antibodies requires careful preclinical evaluation to exclude any potential immunotoxicity side-effects. The failure to identify immunological toxicity of TGN1412 using macaques led us to investigate more relevant preclinical models. We report here that contrary to macaques, and like in man, all baboon CD4-positive T lymphocytes express CD28 in their effector memory cells compartment, a lymphocyte subtype that is the most prone to releasing cytokines after reactivation. Baboon lymphocytes are able to release pro-inflammatory cytokines in vitro in response to agonist or superagonist anti-CD28 antibodies. Furthermore, we compared the reactivity of human and baboon lymphocytes after transfer into non obese diabetic/severe combined immunodeficiency (NOD/SCID) interleukin-2rγ knockout mice and confirmed that both cell types could release inflammatory cytokines in situ after injection of agonistic anti-CD28 antibodies. In contrast, FR104, a monovalent antagonistic anti-CD28 antibody, did not elicit T cell activation in these assays, even in the presence of anti-drug antibodies. Infusion to baboons also resulted in an absence of cytokine release. In conclusion, the baboon represents a suitable species for preclinical immunotoxicity evaluation of anti-CD28 antibodies because their effector memory T cells do express CD28 and because cytokine release can be assessed in vitro and trans vivo.
authors.affiliation: Institut National de la Santé Et de la Recherche Médicale Unité Mixte de Recherche; Institut de Transplantation Urologie Néphrologie (ITUN) ; Université de Nantes; Nantes, France; Effimune SAS; Nantes, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Poirier
authors.affiliation: Institut National de la Santé Et de la Recherche Médicale Unité Mixte de Recherche; Institut de Transplantation Urologie Néphrologie (ITUN) ; Université de Nantes; Nantes, France; Effimune SAS; Nantes, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Mary
authors.affiliation: Institut National de la Santé Et de la Recherche Médicale Unité Mixte de Recherche; Institut de Transplantation Urologie Néphrologie (ITUN) ; Université de Nantes; Nantes, France; Centre Hospitalier Universitaire; Nantes, France.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Le Bas-Bernardet
authors.affiliation: Institut National de la Santé Et de la Recherche Médicale Unité Mixte de Recherche; Institut de Transplantation Urologie Néphrologie (ITUN) ; Université de Nantes; Nantes, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Daguin
authors.affiliation: Institut National de la Santé Et de la Recherche Médicale Unité Mixte de Recherche; Institut de Transplantation Urologie Néphrologie (ITUN) ; Université de Nantes; Nantes, France.
authors.forename: Lyssia
authors.initials: L
authors.lastname: Belarif
authors.affiliation: Institut National de la Santé Et de la Recherche Médicale Unité Mixte de Recherche; Institut de Transplantation Urologie Néphrologie (ITUN) ; Université de Nantes; Nantes, France.
authors.forename: Melanie
authors.initials: M
authors.lastname: Chevalier
authors.affiliation: Institut National de la Santé Et de la Recherche Médicale Unité Mixte de Recherche; Institut de Transplantation Urologie Néphrologie (ITUN) ; Université de Nantes; Nantes, France.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hervouet
authors.affiliation: Institut National de la Santé Et de la Recherche Médicale Unité Mixte de Recherche; Institut de Transplantation Urologie Néphrologie (ITUN) ; Université de Nantes; Nantes, France.
authors.forename: David
authors.initials: D
authors.lastname: Minault
authors.affiliation: Institut National de la Santé Et de la Recherche Médicale Unité Mixte de Recherche; Institut de Transplantation Urologie Néphrologie (ITUN) ; Université de Nantes; Nantes, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Ville
authors.affiliation: Institut National de la Santé Et de la Recherche Médicale Unité Mixte de Recherche; Institut de Transplantation Urologie Néphrologie (ITUN) ; Université de Nantes; Nantes, France.
authors.forename: Vianney
authors.initials: V
authors.lastname: Charpy
authors.affiliation: Institut National de la Santé Et de la Recherche Médicale Unité Mixte de Recherche; Institut de Transplantation Urologie Néphrologie (ITUN) ; Université de Nantes; Nantes, France; Centre Hospitalier Universitaire; Nantes, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Blancho
authors.affiliation: Institut National de la Santé Et de la Recherche Médicale Unité Mixte de Recherche; Institut de Transplantation Urologie Néphrologie (ITUN) ; Université de Nantes; Nantes, France; Effimune SAS; Nantes, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Vanhove
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology / Q000633:toxicity*; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000633:toxicity*; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000633:toxicity; D018106:CD28 Antigens / Q000037:antagonists & inhibitors* / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D008252:Macaca fascicularis; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D023421:Models, Animal; D048530:Papio anubis / Q000276:immunology*; D013045:Species Specificity; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018106:CD28 Antigens; D016207:Cytokines; C509303:TGN-1412
keywords: CD28; FR104; cytokines; humanized mice; immunotoxicity; primate