Lazar Greg A, Desjarlais John R, Jacinto Jonathan, Karki Sher, Hammond Philip W
Xencor, 111 W. Lemon Avenue, Monrovia, CA 91016, USA.
Mol Immunol. 2007 Mar;44(8):1986-98. doi: 10.1016/j.molimm.2006.09.029. Epub 2006 Oct 31.
We introduce a new method of humanization based on a novel and immunologically relevant metric of antibody humanness, termed human string content (HSC), that quantifies a sequence at the level of potential MHC/T-cell epitopes. Use of this quantity rather than global identity as an optimization goal enables the sampling of human diversity from distinct human germline sequences across the framework and CDR regions, and allows for the generation of multiple diverse candidate sequences. As a result engineering is carried out at finer sequence resolution relative to standard CDR grafting methods, providing for the optimization of antibody properties beyond immunogenicity such as antigen affinity and solution behavior. We have applied this method to the humanization of four antibodies with different antigen specificities. The resulting variable domains differ fundamentally from CDR-grafted antibodies in that they are immunologically more human and their humanness is derived from several discrete germline sequences. Furthermore, these antibodies bind their respective antigens better than or comparable to those of the parent antibodies without the need for affinity maturation.
我们基于一种新的、与免疫相关的抗体人源化指标——人源序列含量（HSC），引入了一种新的人源化方法。该指标在潜在的MHC/T细胞表位水平上对序列进行量化。使用这个量而非全局同一性作为优化目标，能够从框架区和互补决定区（CDR）的不同人类种系序列中对人类多样性进行采样，并允许生成多个不同的候选序列。因此，相对于标准的CDR移植方法，工程操作是在更精细的序列分辨率下进行的，从而实现了除免疫原性之外的抗体特性优化，如抗原亲和力和溶液行为。我们已将此方法应用于四种具有不同抗原特异性的抗体的人源化。所得的可变区与CDR移植抗体有根本区别，因为它们在免疫方面更具人源化，且其人源化源自几个离散的种系序列。此外，这些抗体与其各自抗原的结合能力优于或等同于亲本抗体，且无需亲和力成熟。
