Treatment with saturating dose of conventional anti-CD28 monoclonal antibody well tolerated in pig acute myocardial infarction model

Abstract

CD4+ Foxp3+ regulatory T cells (Treg) efficiently foster wound healing after myocardial infarction (MI). Therapeutically shifting the balance between CD4+ Foxp3- conventional T cells (Tconv) and Treg towards Tregs enhanced survival in a mouse model of MI. Due to species-specific differences in cardiac wound healing and remodelling, it remains, however, unclear whether these findings can be translated into novel immunotherapies for human patients after MI. Therefore, we studied pigs whose cardiac wound healing after MI and the composition of the immune system are very close to humans. This includes the relevant complication of developing a cytokine release syndrome (CRS) after infusion of saturating amounts of a superagonistic anti-CD28 monoclonal antibody (mAb). To achieve the intended shift in the Treg/Tconv balance, we treated pigs three days after interventional MI induction with a non-superagonistic, i.e. conventional, anti-CD28 mAb, clone 3D11. Infusion of a saturating dose (1 mg/kg body weight) of mAb 3D11 was clinically well tolerated without signs of CRS induction or any other complications. Molecularly, mAb 3D11 infusion led to a downmodulation of CD28 expression on porcine T cells in vivo with the remaining CD28 molecules blocked from binding natural ligand proteins CD80 and CD86, as we show in this publication. Apart from modulating CD28 expression, treatment with mAb 3D11 did not induce any overt changes in the peripheral T cell compartment. However, after mAb 3D11 treatment, we observed Treg accumulation in the infarcted heart, particularly the border zone, on day 7 post-MI using immunofluorescence histology. Our findings thus suggest that even saturating doses of conventional anti-CD28 monoclonal antibodies could potentially be safely administered in patients to therapeutically shift the Treg/Tconv balance in the infarcted myocardium. This might be sufficient to enhance cardiac wound healing in patients short-term and prevent adverse remodelling long-term.