Demonstration of an in vivo generated sub-picomolar affinity fully human monoclonal antibody to interleukin-8
Demonstration of an in vivo generated sub-picomolar affinity fully human monoclonal antibody to interleukin-8
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DOI：
10.1016/j.bbrc.2005.07.002
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发表时间：
2005-09-09
影响因子：
3.1
通讯作者：
Babcook, J
中科院分区：
文献类型：
--
作者：
Rathanaswami, P;Roalstad, S;Babcook, J
单克隆抗体的高特异性和亲和力使其作为治疗剂具有吸引力。通常，报道为高亲和力的抗体的亲和力在高皮摩尔至低纳摩尔范围内，并且已经在体外亲和力成熟。已经提出在100 pM存在体内亲和力上限，并且产生对抗原具有高于估计上限的亲和力的抗体的B细胞在正常免疫应答期间在抗原诱导的亲和力成熟中不具有选择性优势。使用产生完全人抗体的转基因小鼠，我们常规地产生具有亚纳摩尔亲和力的抗体，经常拯救具有小于10 pM亲和力的抗体，并且现在描述存在具有亚皮摩尔平衡解离常数的体内产生的抗hIL-8抗体。这证实了可以在体内产生亲和力超过所提出的亲和力上限的抗体的预测。我们还描述了确定这种高亲和力的技术挑战。为了进一步理解亲和力对治疗的重要性，我们构建了一个数学模型，以IL-8作为模型抗原来预测抗体的亲和力与其体内效力之间的关系。(c)2005年爱思唯尔公司All rights reserved.
The high specificity and affinity of monoclonal antibodies make them attractive as therapeutic agents. In general, the affinities of antibodies reported to be high affinity are in the high picomolar to low nanomolar range and have been affinity matured in vitro. It has been proposed that there is an in vivo affinity ceiling at 100 pM and that B cells producing antibodies with affinities for antigen above the estimated ceiling would have no selective advantage in antigen-induced affinity maturation during normal immune responses. Using a transgenic mouse producing fully human antibodies, we have routinely generated antibodies with sub-nanomolar affinities, have frequently rescued antibodies with less than 10 pM affinity, and now describe the existence of an in vivo generated anti-hIL-8 antibody with a sub-picomolar equilibrium dissociation constant. This confirms the prediction that antibodies with affinities beyond the proposed affinity ceiling can be generated in vivo. We also describe the technical challenges of determining such high affinities. To further understand the importance of affinity for therapy, we have constructed a mathematical model to predict the relationship between the affinity of an antibody and its in vivo potency using IL-8 as a model antigen. (c) 2005 Elsevier Inc. All rights reserved.