Phase I trial of a humanized, Fc receptor nonbinding anti-CD3 antibody, hu12F6mu in patients receiving renal allografts.
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.
Li
Jing
J
PLA Postgraduate School of Medicine; Second Military Medical University; National Engineering Research Center of Antibody Medicine, China.
Zhou
Bo
B
PLA Postgraduate School of Medicine; Second Military Medical University; National Engineering Research Center of Antibody Medicine, China.
Shentu
Jianzhong
J
Zhejiang University, Hangzhou, China.
Du
Li
L
PLA Postgraduate School of Medicine; Second Military Medical University, China.
Tan
Min
M
PLA Postgraduate School of Medicine; Second Military Medical University, China.
Hou
Sheng
S
PLA Postgraduate School of Medicine; Second Military Medical University; National Engineering Research Center of Antibody Medicine, China.
Qian
Weizhu
W
PLA Postgraduate School of Medicine; Second Military Medical University; National Engineering Research Center of Antibody Medicine, China.
Li
Bohua
B
PLA Postgraduate School of Medicine; Second Military Medical University; National Engineering Research Center of Antibody Medicine, China.
Zhang
Dapeng
D
PLA Postgraduate School of Medicine; Second Military Medical University; National Engineering Research Center of Antibody Medicine, China.
Dai
Jianxin
J
PLA Postgraduate School of Medicine; Second Military Medical University; National Engineering Research Center of Antibody Medicine, China.
Wang
Hao
H
PLA Postgraduate School of Medicine; Second Military Medical University; National Engineering Research Center of Antibody Medicine, China.
Zhang
Xu
X
PLA Postgraduate School of Medicine, China.
Chen
Jianghua
J
Zhejiang University, Hangzhou, China.
Guo
Yajun
Y
PLA Postgraduate School of Medicine; Second Military Medical University; National Engineering Research Center of Antibody Medicine, China.
D061605:Administration, Intravenous; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics; D017252:CD3 Complex / Q000276:immunology; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000209:etiology / Q000517:prevention & control*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D016130:Immunophenotyping; D007167:Immunotherapy / Q000379:methods*; D016030:Kidney Transplantation; D018655:Lymphocyte Count; D009154:Mutation / Q000235:genetics; D011183:Postoperative Complications / Q000517:prevention & control*; D011485:Protein Binding / Q000235:genetics; D015202:Protein Engineering; D011961:Receptors, Fc / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D007141:Immunoglobulin Fc Fragments; D011961:Receptors, Fc