Phase I trial of HuM291, a humanized anti-CD3 antibody, in patients receiving renal allografts from living donors

Background. HuM291 is a humanized anti-CD8 monoclonal antibody engineered t o reduce binding to Fc gamma receptors and complement fixation, HuM291 has a long serum half-life and mediated profound depletion of circulating T cel ls in chimpanzees; HuM291 also has significantly less mitogenic and cytokin e-releasing activity than OKT3 in vitro. Methods. A phase I dose-escalation study was conducted in 15 end-stage rena l disease patients scheduled for renal allografts from living donors, Patie nts received one i,v, HuM291 injection before transplanta- tion, Five doses were tested: 0.015 mug/kg, 0.15 mug/kg, 0.0015 mg/kg, 0.0045 mg/kg, and 0. 015 mg/kg, Patients were followed for adverse events, laboratory abnormalit ies, serum cytokine levels, pharmacokinetics, and CD2(+), CD3(+), CD4(+), a nd CD8(+) T cell counts. Results. HuM291 was well tolerated; most adverse events were mild to modera te in severity and included headache, nausea, chills, and fever. These occu rred within the first few hours after HuM291 administration, resolved withi n 24 to 48 hr, and were likely related to cytokine release. In general, pea k tumor necrosis factor-alpha, interferon-gamma, and interleukin-g levels w ere detected 1 to 6 hr postdosing only at the three highest doses and were generally undetectable by 24-hr postdosing, Serious adverse events possibly related to HuM291 included clotting of a fistula (two patients), chemical cellulitis tone patient), and increased serum creatinine/decreased hematocr it tone patient). At doses greater than or equal to0.0015 mg/kg (0.1 mg/70 kg), HuM291 induced rapid, marked depletion of peripheral T cells within 2 hr; duration of T cell depletion was dose dependent. At the two highest dos e levels, T cells remained depleted for approximately 1 week. Conclusions. A single HuM291 dose rapidly depleted circulating T cells in a dose-dependent manner and was associated with only mild to moderate sympto ms of cytokine release.