Combination of Novel Anti-CD45RB and Anti-CD40 Chimeric Antibodies Promotes Operational Tolerance and Induction of T Regulatory Cells in Cynomolgus Monkey Renal Allograft Recipients.

Peripheral tolerance in primates receiving solid organ allografts remains elusive. Based on our previous results in which a human-mouse chimeric α-CD45RB mAb (6G3) modestly prolonged renal transplant graft survival (GS) in cynomolgus monkeys (cynos), we examined a combination of recently created rhesus-mouse chimeric α-CD45RB (r6G3R1) and α-CD40 (r2C10R4) mAbs. Chinese and Mauritius cyno renal transplant recipients were treated with α-CD45RB (r6G3R1 [IgG1] given as 10®5 mg/kg iv on d-1,0,7, then 2x/wk until d29) and/or α-CD40 (r2C10R4 [IgG4] dosed at 20®5 mg/kg iv, d-1,0,5,7, then 2x/wk until d58). Donor/recipients were highly mismatched, sharing 2-4/16 microsatellite markers, and Class I MHC sequencing of 6/9 cynos revealed no shared alleles. Treatment with α-CD40 alone prolonged GS (n=3; POD 99, 111, 119) but was associated with increasing sCr from POD ≥65, as well as acute and chronic rejection (biopsies POD 56, 82, 87). In contrast, the combination of α-CD45RB and α-CD40 could induce long-term GS/operational tolerance (n=6; POD 52, 53, 64, 148, >794, >1083). Moreover, both operationally tolerant recipients continue to exhibit normal sCr levels (95-121 mmol/L) as of POD 794 and 1083, exhibiting no adverse effects and nearly normal renal biopsies (POD 89, 434, 723). α-CD40 monotherapy notably reduced expression of CD40, and CD80 and CD86 activation markers on B cells and DCs. Addition of α-CD45RB to the regimen induced a dramatic shift in CD45RB isoform expression on T cells and increased the frequency of CD4+CD25+Foxp3+ T cells (>2-fold vs. Pre-Tx) that was not observed with α-CD40 alone. When tested in vitro, only PBMCs from cynos receiving combination therapy exhibited reduced MLR activity and a concomitant increase in allo-specific CD25+ Treg proliferation in both operationally tolerant cynos and two others during stable engraftment. We continue to test these novel chimeric mAbs, since their ability to downregulate T and B cell activation, promote regulatory T cell induction, and prolong GS without further immunosuppression, holds significant promise for future clinical application. DISCLOSURE:Reimann, K.: Other, chimeric Ab r2C10R4, FCOI management plan @ University of Massachusett.

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