Phase I trial of a humanized, Fc receptor nonbinding anti-CD3 antibody, hu12F6mu in patients receiving renal allografts

Abstract

Hu12F6mu is an Fc-mutated, humanized anti-CD3 antibody developed in our lab. The aim of this study was to assess single dose escalation pharmacokinetics (PK) and safety profile of hu12F6mu and to measure the effects of the antibody on levels of circulating T cells over time. Twenty-seven patients receiving renal allografts were randomized to receive hu12F6mu intravenously at a single-dose of 2.5, 5 or 10 mg. The concentration-time data obtained by a validated ELISA method were subjected to non-compartmental PK analysis by DAS 2.1 software. Subgroups of CD2(+), CD3(+), CD4(+) and CD8(+) lymphocytes were monitored periodically by flow cytometry. Our results showed that hu12F6mu exhibited linear PK over the dose range of 2.5 to 10 mg. A significant decline in the proportion of T cells was observed immediately after the infusion, followed by a progressive increase occurring over the ensuing days of therapy. A significant negative correlation was observed between serum concentration of hu12F6mu and CD3(+) cell proportion. Intravenous infusion of hu12F6mu was well-tolerated in patients receiving renal allografts. These results suggest that hu12F6mu may have potential as a therapeutic agent, although further studies are needed.

Figure 1

Concentration-time curves of hu12F6mu after a single intravenous infusion of 2.5 mg (■, n = 9), 5 mg (●, n = 9) and 10 mg (▲, n = 9) antibody in kidney transplantation recipients. Data are expressed as mean ± SD.

Figure 2

Mean proportion (%) of CD2⁺ subset in three groups. Data represent mean ± SD values for different subjects in 2.5 mg (■, n = 9), 5 mg (●, n = 9) and 10 mg (▲, n = 9) group.

Figure 3

Mean proportion (%) of CD3⁺ subset in three groups. Data represent mean ± SD values for different subjects in 2.5 mg (■, n = 9), 5 mg (●, n = 9) and 10 mg (▲, n = 9) group.

Figure 4

Mean proportion (%) of CD4⁺ subset in three groups. Data represent mean ± SD values for different subjects in 2.5 mg (■, n = 9), 5 mg (●, n = 9) and 10 mg (▲, n = 9) group.

Figure 5

Mean proportion (%) of CD8⁺ subset in three groups. Data represent mean ± SD values for different subjects in 2.5 mg (■, n = 9), 5 mg (●, n = 9) and 10 mg (▲, n = 9) group.

Figure 6

Mean blood lymphocyte counts (×10⁹/L) in three groups. Data represent mean ± SD values for different subjects in 2.5 mg (■, n = 9), 5 mg (●, n = 9) and 10 mg (▲, n = 9) group.

Figure 7

The concentration-effect plots display the coherence between hu12F6mu serum concentration and CD3⁺ cell proportion (%) after administration of 10 mg of antibody. ■, CD3⁺ proportion (%); ●, hu12F6mu serum concentration (ng·L⁻¹).