Monoclonal antibody humanness score and its applications
Monoclonal antibody humanness score and its applications
复制标题
DOI：
10.1186/1472-6750-13-55
复制
发表时间：
2013-07-05
影响因子：
3.5
通讯作者：
Adler, Adam S.
中科院分区：
文献类型：
--
作者：
Gao, Sean H.;Huang, Kexin;Adler, Adam S.
背景：单克隆抗体疗法在治疗从癌症到自身免疫性疾病和神经系统疾病等多种疾病方面迅速普及。目前使用多种形式的抗体疗法，其恒定区和可变区中存在的人类序列数量不同，其中更像人类的抗体在临床试验中通常会降低免疫原性。结果：在这里，我们提出了一种量化单克隆抗体可变区的人源性的方法，并表明该方法能够以优异的特异性清楚地区分人类和非人类抗体。在创建并分析了人类抗体序列数据库后，我们对治疗性抗体的人性进行了深入分析，发现人性评分的增加与抗体免疫原性的降低相关。我们进一步发现，基于人性评分，全人源抗体和更像人的人源化抗体的免疫原性具有惊人的相似性。结论：我们的结果表明，在大多数情况下，将抗体人源化并确认最终形式的人源性可能足以消除免疫原性问题，其程度与使用全人源抗体相同。我们创建了一个公共网站，根据我们的人类抗体数据库计算任何输入抗体序列的人类分数。该工具在新的单克隆抗体疗法的临床前药物开发过程中将具有巨大的价值。
Background: Monoclonal antibody therapeutics are rapidly gaining in popularity for the treatment of a myriad of diseases, ranging from cancer to autoimmune diseases and neurological diseases. Multiple forms of antibody therapeutics are in use today that differ in the amount of human sequence present in both the constant and variable regions, where antibodies that are more human-like usually have reduced immunogenicity in clinical trials.Results: Here we present a method to quantify the humanness of the variable region of monoclonal antibodies and show that this method is able to clearly distinguish human and non-human antibodies with excellent specificity. After creating and analyzing a database of human antibody sequences, we conducted an in-depth analysis of the humanness of therapeutic antibodies, and found that increased humanness score is correlated with decreased immunogenicity of antibodies. We further discovered a surprisingly similarity in the immunogenicity of fully human antibodies and humanized antibodies that are more human-like based on their humanness score.Conclusions: Our results reveal that in most cases humanizing an antibody and confirming the humanness of the final form may be sufficient to eliminate immunogenicity issues to the same extent as using fully human antibodies. We created a public website to calculate the humanness score of any input antibody sequence based on our human antibody database. This tool will be of great value during the preclinical drug development process for new monoclonal antibody therapeutics.