A Mixture of Functionally Oligoclonal Humanized Monoclonal Antibodies That Neutralize Clostridium difficile TcdA and TcdB with High Levels of In Vitro Potency Shows In Vivo Protection in a Hamster Infection Model
A Mixture of Functionally Oligoclonal Humanized Monoclonal Antibodies That Neutralize Clostridium difficile TcdA and TcdB with High Levels of In Vitro Potency Shows In Vivo Protection in a Hamster Infection Model
复制标题
DOI：
10.1128/cvi.00625-12
复制
发表时间：
2013-03-01
影响因子：
--
通讯作者：
Humphreys, David P.
中科院分区：
文献类型：
--
作者：
Davies, Nicola L.;Compson, Joanne E.;Humphreys, David P.
艰难梭菌感染是医院和护理机构患者中腹泻相关性腹泻的主要原因。尽管有有效的抗生素治疗，C。艰难梭菌感染（CDI）仍然是患者痛苦、死亡和大量医疗保健费用的主要原因。艰难梭菌通过两种蛋白质外毒素TcdA和TcdB的作用发挥其主要的病理作用，所述外毒素结合并破坏肠道组织。抗生素的目标是感染细菌，而不是外毒素。对接受抗生素治疗的患者施用针对TcdA和TcdB的中和抗体可能直接调节外毒素的作用。我们开发了三种人源化IgG1单克隆抗体（MAbs）的混合物，可中和TcdA和TcdB，以满足三种临床需求：降低腹泻的严重程度和持续时间，降低死亡率和降低复发率。与临床开发中的其他药物相比，UCB MAb混合物在各种体外结合和中和试验中显示出更高的效价（类似于10倍的改善），在CDI仓鼠模型中显示出更高的保护水平（28天时为82% vs 18%），以及更高的毒素结合效价（TcdA为12 vs 2，TcdB为3 vs 2）。单克隆抗体特性的比较也提供了一些洞察TcdA和TcdB在疾病过程中的潜在相对重要性。
Clostridium difficile infections are a major cause of antibiotic-associated diarrhea in hospital and care facility patients. In spite of the availability of effective antibiotic treatments, C. difficile infection (CDI) is still a major cause of patient suffering, death, and substantial health care costs. Clostridium difficile exerts its major pathological effects through the actions of two protein exotoxins, TcdA and TcdB, which bind to and disrupt gut tissue. Antibiotics target the infecting bacteria but not the exotoxins. Administering neutralizing antibodies against TcdA and TcdB to patients receiving antibiotic treatment might modulate the effects of the exotoxins directly. We have developed a mixture of three humanized IgG1 monoclonal antibodies (MAbs) which neutralize TcdA and TcdB to address three clinical needs: reduction of the severity and duration of diarrhea, reduction of death rates, and reduction of the rate of recurrence. The UCB MAb mixture showed higher potency in a variety of in vitro binding and neutralization assays (similar to 10-fold improvements), higher levels of protection in a hamster model of CDI (82% versus 18% at 28 days), and higher valencies of toxin binding (12 versus 2 for TcdA and 3 versus 2 for TcdB) than other agents in clinical development. Comparisons of the MAb properties also offered some insight into the potential relative importance of TcdA and TcdB in the disease process.