Frontier of therapeutic antibody discovery:The challenges and how to face them  

作　　者：Zhi-Jian Lu Su-Jun Deng Da-Gang Huang Yun He Ming Lei Li Zhou Pei Jin 

机构地区：[1]China Novartis Institutes for Biomedical Research,Zhangjiang Hi-Tech Park [2]Novartis Institutes for Biomedical Research,Inc.,250 Massachusetts Avenue

出　　处：《World Journal of Biological Chemistry》2012年第12期187-196,共10页世界生物化学杂志（英文版）（电子版）

摘　　要：Therapeutic monoclonal antibodies have become an important class of modern medicines.The established technologies for therapeutic antibody discovery such as humanization of mouse antibodies,phage display of human antibody libraries and transgenic animals harboring human IgG genes have been practiced successfully so far,and many incremental improvements are being made constantly.These methodologies are responsible for currently marketed therapeutic antibodies and for the biopharma industry pipeline which are concentrated on only a few dozen targets.A key challenge for wider application of biotherapeutic approaches is the paucity of truly validated targets for biotherapeutic intervention.The efforts to expand the target space include taking the pathway approach to study the disease correlation.Since many new targets are multi-spanning and multimeric membrane proteins there is a need to develop more effective methods to generate antibodies against these difficult targets.The pharmaceutical properties of therapeutic antibodies are an active area for study concentrating on biophysical characteristics such as thermal stability and aggregation propensity.The immunogenicity of biotherapeutics in humans is a very complex issue and there are no truly predictive animal models to rely on.The in silico and T-cell response approaches identify the potential for immunogenicity;however,one needs contingency plans for emergence of antiproduct antibody response for clinical trials.Therapeutic monoclonal antibodies have become an important class of modern medicines. The established technologies for therapeutic antibody discovery such as humanization of mouse antibodies, phage display of human antibody libraries and transgenic animals harboring human IgG genes have been practiced successfully so far, and many incremental improvements are being made constantly. These methodologies are responsible for currently marketed therapeutic antibodies and for the biopharma industry pipeline which are concentrated on only a few dozen targets. A key challenge for wider application of biotherapeutic approaches is the paucity of truly validated targets for biotherapeutic intervention. The efforts to expand the target space include taking the pathway approach to study the disease correlation. Since many new targets are multi-spanning and multimeric membrane proteins there is a need to develop more effective methods to generate antibodies against these difficult targets. The pharmaceutical properties of therapeutic antibodies are an active area for study concentrating on biophysical characteristics such as thermal stability and aggregation propensity. The immunogenicity of biotherapeutics in humans is a very complex issue and there are no truly predictive animal models to rely on. The in silico and T-cell response approaches identify the potential for immunogenicity; however, one needs contingency plans for emergence of anti-product antibody response for clinical trials.

关 键 词：Antibody BIOTHERAPEUTICS BIOPHYSICAL property BISPECIFIC HUMANIZATION Immunogenicity Transgenic RODENT PHAGE display Yeast 

分 类 号：R96[医药卫生—药理学]