title: Preclinical efficacy and immunological safety of FR104, an antagonist anti-CD28 monovalent Fab' antibody.
abstract: Antagonist anti-CD28 antibodies prevent T cell costimulation and differentiate from CTLA4Ig since they cannot block CTLA-4 and PDL-1 coinhibitory signals. They demonstrated efficacy in suppressing effector T cells while enhancing regulatory T cells function and immune tolerance. However, anti-CD28 antibodies devoid of immunotoxicity and with a good pharmacokinetic profile have not yet been developed. Here, we describe FR104, a novel humanized pegylated anti-CD28 Fab' antibody fragment presenting a long elimination half-life in monkeys. In vitro, FR104 failed to induce human T cell proliferation and cytokines secretion, even in the presence of anti-CD3 antibodies or when cross-linked with secondary antibodies. Furthermore, in humanized NOD/SCID mice adoptively transferred with human PBMC, whereas superagonist and divalent antibodies elicited rapid cytokines secretion and human T cell activation, FR104 did not. These humanized mice developed a florid graft-versus-host disease, which was prevented by administration of FR104 in a CTLA4-dependent manner. Interestingly, administration of high doses of CTLA4-Ig was ineffective to prevent GVHD, whereas administration of low doses was partially effective. In conclusion, we demonstrated that FR104 is devoid of agonist activity on human T cells and thus compatible with a clinical development that might lead to higher therapeutic indexes, by sparing CTLA-4, as compared to CD80/CD86 antagonists.
authors: Institut National de la Santé Et de la Recherche Médicale Unité Mixte de Recherche 1064, Nantes, France.
authors: N
authors: N
authors: Poirier
authors: C
authors: C
authors: Mary
authors: N
authors: N
authors: Dilek
authors: J
authors: J
authors: Hervouet
authors: D
authors: D
authors: Minault
authors: G
authors: G
authors: Blancho
authors: B
authors: B
authors: Vanhove
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000276:immunology; D004353:Drug Evaluation, Preclinical; D005434:Flow Cytometry; D007140:Immunoglobulin Fab Fragments / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID
chemical_list: D018106:CD28 Antigens; D060908:CTLA-4 Antigen; D007140:Immunoglobulin Fab Fragments