Stephens S, Emtage S, Vetterlein O, Chaplin L, Bebbington C, Nesbitt A, Sopwith M, Athwal D, Novak C, Bodmer M
Celltech Therapeutics Ltd, Slough, Berkshire, UK.
Immunology. 1995 Aug;85(4):668-74.
A murine antibody to human tumour necrosis factor-alpha (TNF-alpha) (CB0010) was complementarity-determining region (CDR)-grafted using human IgG4 heavy and kappa light chain constant regions. In cynomolgus monkeys, the grafted antibody (CDP571) was eliminated with a half-life of 40-90 hr, two to three times longer than CB0010, and immunogenicity was reduced by > 90%. Responses to the constant regions were almost entirely eliminated and responses to the CDR loop (anti-idiotype) were lowered. CDP571 was given to 24 human volunteers in doses from 0.1 to 10.0 mg/kg. It was well tolerated, with a half-life of approximately 13 days. Anti-CDP571 antibodies were low or undetectable at higher doses. At lower doses, anti-CDP571 peaked at 2 weeks and then declined. The response was primarily IgM (in contrast to the cynomolgus monkey, where by 5 weeks IgG predominated) and was against a conformational epitope comprising heavy and light chain CDR loops. No antibodies were detected against the gamma 4/kappa domains or frameworks. The response had little or no effect on CDP571 binding to TNF-alpha or on plasma clearance.
一种针对人肿瘤坏死因子-α（TNF-α）的鼠源抗体（CB0010），利用人IgG4重链和κ轻链恒定区进行了互补决定区（CDR）移植。在食蟹猴中，移植后的抗体（CDP571）清除半衰期为40 - 90小时，比CB0010长两到三倍，免疫原性降低了90%以上。对恒定区的反应几乎完全消除，对CDR环（抗独特型）的反应降低。给24名人类志愿者注射了剂量为0.1至10.0 mg/kg的CDP571。它耐受性良好，半衰期约为13天。在较高剂量下，抗CDP571抗体水平较低或检测不到。在较低剂量下，抗CDP571抗体在2周时达到峰值，然后下降。反应主要为IgM（与食蟹猴相反，食蟹猴在5周时IgG占主导），且针对的是由重链和轻链CDR环组成的构象表位。未检测到针对γ4/κ结构域或框架的抗体。该反应对CDP571与TNF-α的结合或血浆清除几乎没有影响。
