*Purpose: Co-stimulation blockade (CoB) has emerged as a promising immunosuppression strategy with the advent of Belatacept, a novel CTLA4-Ig fusion protein that blocks CD28-mediated T cell co-stimulation. Compared to traditional calcineurin inhibitor-based immunosuppression, Belatacept confers improved graft survival, graft function, and overall survival in renal transplant recipients. However, it is also associated with increased rates of early acute rejection, termed CoB-resistant rejection (CoBRR). The purpose of this study was to examine the role of NOTCH pathway inhibition on CoBRR.

*Methods: Murine and non-human primate (NHP) transplant models were used to investigate the role of NOTCH pathway inhibition via blockade of Delta-like ligand 4 (DLL4) on CoBRR.

*Results: In a model of Balb/C to C57BL/6 skin transplantation, combined CoB (CTLA-4Ig + anti-CD154) and anti-DLL4 blockade significantly prolonged skin graft survival compared to CoB alone (MST 85 vs. 32 days, p = 0.001**). Anti-DLL4 blockade inhibited T cell activation and suppressed the formation of anti-donor antibody. Donor-specific T cell responses were also assessed in recipients of mOVA skin grafts following adoptive transfer of Thy1.1+ ovalbumin-specific OT-I T cells. Combined CTLA-4Ig and anti-DLL4 blockade suppressed donor-specific CD8+ T cell effector function via IFN-γ and TNF-α production. We then evaluated the effect of anti-DLL4 blockade in a NHP model of MHC mismatched renal transplantation. REGN421, a fully human IgG1 DLL4 monoclonal antibody, synergized with Belatacept to significantly prolong renal allograft survival compared to Belatacept alone (MST 151 vs. 38 days, p = 0.05*).

*Conclusions: These data demonstrate that anti-DLL4 blockade is a promising therapy to suppress co-stimulation resistant alloreactivity and may help facilitate clinical translation of anti-DLL4 therapies in conjunction with Belatacept.

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