Preclinical Efficacy and Immunological Safety of FR104, an Antagonist Anti-CD28 Monovalent Fab′ Antibody
Résumé
Antagonist anti-CD28 antibodies prevent T cell cos-timulation 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 pharma-cokinetic 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.
Domaines
Médecine humaine et pathologie
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