Biotherapeutics Discovery, Boehringer Ingelheim, Ridgefield, CT 06877.
Biotherapeutics Discovery, Boehringer Ingelheim, Ridgefield, CT 06877
Proc Natl Acad Sci U S A. 2021 Sep 14;118(37). doi: 10.1073/pnas.2020577118.
Feeding biopharma pipelines with biotherapeutic candidates that possess desirable developability profiles can help improve the productivity of biologic drug discovery and development. Here, we have derived an in silico profile by analyzing computed physicochemical descriptors for the variable regions (Fv) found in 77 marketed antibody-based biotherapeutics. Fv regions of these biotherapeutics demonstrate significant diversities in their germlines, complementarity determining region loop lengths, hydrophobicity, and charge distributions. Furthermore, an analysis of 24 physicochemical descriptors, calculated using homology-based molecular models, has yielded five nonredundant descriptors whose distributions represent stability, isoelectric point, and molecular surface characteristics of their Fv regions. Fv regions of candidates from our internal discovery campaigns, human next-generation sequencing repertoires, and those in clinical-stages (CST) were assessed for similarity with the physicochemical profile derived here. The Fv regions in 33% of CST antibodies show physicochemical properties that are dissimilar to currently marketed biotherapeutics. In comparison, physicochemical characteristics of ∼29% of the Fv regions in human antibodies and ∼27% of our internal hits deviated significantly from those of marketed biotherapeutics. The early availability of this information can help guide hit selection, lead identification, and optimization of biotherapeutic candidates. Insights from this work can also help support portfolio risk assessment, in-licensing, and biopharma collaborations.
利用具有理想开发特性的治疗性候选物为生物制药管道提供营养，可以帮助提高生物药物发现和开发的生产力。在这里，我们通过分析 77 种市售基于抗体的治疗性生物制剂中发现的可变区 (Fv) 的计算物理化学描述符，得出了一个计算模型。这些治疗性生物制剂的 Fv 区域在其胚系、互补决定区环长度、疏水性和电荷分布方面表现出显著的多样性。此外，对使用同源建模计算的 24 个物理化学描述符进行分析，得到了 5 个非冗余描述符，其分布代表了 Fv 区域的稳定性、等电点和分子表面特征。对我们内部发现的候选物的 Fv 区域、人类下一代测序库中的候选物和处于临床阶段 (CST) 的候选物进行了评估，以确定与这里推导的物理化学特征的相似性。在 CST 抗体中，有 33%的 Fv 区域显示出与目前市售生物治疗剂不同的物理化学特性。相比之下，人类抗体中约 29%的 Fv 区域和约 27%的内部命中的物理化学特征与市售生物治疗剂显著不同。该信息的早期可用性可以帮助指导命中选择、先导物识别和治疗性候选物的优化。这项工作的见解还可以帮助支持投资组合风险评估、引进许可和生物制药合作。
