The human antibody sequence space and structural design of the V, J regions, and CDRH3 with Rosetta.
The human antibody sequence space and structural design of the V, J regions, and CDRH3 with Rosetta.
复制标题
DOI：
10.1080/19420862.2022.2068212
复制
发表时间：
2022-01
期刊：
影响因子：
5.3
通讯作者：
Meiler, Jens
中科院分区：
文献类型：
--
作者：
Schmitz, Samuel;Schmitz, Emily A.;Crowe, James E., Jr.;Meiler, Jens
人类的适应性免疫反应使得抗原表位能够以高特异性靶向病原体。病原体感染诱导体细胞超突变和b细胞选择过程，控制抗体序列景观的形状和多样性。到目前为止，即使是通过下一代测序获得的最大的适应性免疫受体免疫组库也不能完全捕获单个个体的巨大抗体序列空间，据估计至少有1012个潜在序列。遗传密码的简并性意味着可能的核苷酸三联体数量（64个）大于规范氨基酸的数量（20个），导致一些氨基酸被多个三联体编码，不同的氨基酸在三联体中的1或2个位置共享相同的核苷酸。我们假设遗传密码的简并性可以用来统计建模一个扩大的人类抗体氨基酸序列空间，以适应观察到的和假设的抗体序列空间之间的差异。在贝叶斯统计和免疫组库聚类的帮助下，我们从单核苷酸频率计算氨基酸概率，推断出人类氨基酸序列空间，用于设计Rosetta类人抗体。我们发现，与没有约束的Rosetta设计相比，用我们的约束设计的抗体在V区和J区平均比没有约束的Rosetta设计的抗体更像人类16.6%。与具有相似突变数的Rosetta设计相比，27种抗体中有8种的重链CDR3区域（CDRH3）的人源性得到提高，并可成功应用于小家鼠抗体，证明其人源化。
The human adaptive immune response enables the targeting of epitopes on pathogens with high specificity. Infection with a pathogen induces somatic hyper-mutation and B-cell selection processes that govern the shape and diversity of the antibody sequence landscape. To date, even the largest immunome repertoires of adaptive immune receptors acquired by next-generation sequencing cannot fully capture the vast antibody sequence space of a single individual, which is estimated to be at least 1012 potential sequences. Degeneracy of the genetic code means that the number of possible nucleotide triplets (64) is greater than the number of canonical amino acids (20), resulting in some amino acids being encoded by multiple triplets and different amino acids sharing the same nucleotide in 1 or 2 positions in the triplet. We hypothesize that the degeneracy of the genetic code can be used to statistically model an enlarged space of human antibody amino acid sequences, accommodating for the discrepancy between the observed and the hypothesized antibody sequence space. Facilitated by Bayesian statistics and immunome repertoire clustering, we calculated amino acid probabilities from single nucleotide frequencies to infer a human amino acid sequence space that is used to design human-like antibodies with Rosetta. We show that antibodies designed with our restraints are on average up to 16.6% more human-like in the V and J regions compared to the Rosetta designs produced without constraints. The human-likeness of the heavy-chain CDR3 region (CDRH3) could be increased for 8 of 27 antibodies compared to Rosetta designs with a similar number of mutations and could be successfully applied on Mus musculus antibodies to demonstrate humanization.
登录
查看更多内容
影响因子：
5.3
作者：
Kaplon, Helene;Reichert, Janice M.
通讯作者：
Reichert, Janice M.
影响因子：
3.7
作者：
Seeliger D
通讯作者：
Seeliger D
影响因子：
4.3
作者：
Sevy AM;Jacobs TM;Crowe JE Jr;Meiler J
通讯作者：
Meiler J
影响因子：
4.3
作者：
Adolf-Bryfogle, Jared;Kalyuzhniy, Oleks;Dunbrack, Roland L., Jr.
通讯作者：
Dunbrack, Roland L., Jr.
DOI：
10.1016/j.jpba.2009.07.013
发表时间：
2010-01-05
影响因子：
3.4
作者：
Nechansky, Andreas
通讯作者：
Nechansky, Andreas