Sajadi Mohammad M, Abbasi Abdolrahim, Tehrani Zahra Rikhtegaran, Siska Christine, Clark Rutilio, Chi Woo, Seaman Michael S, Mielke Dieter, Wagh Kshitij, Liu Qingbo, Jumpa Taylor, Ketchem Randal R, Nguyen Dung N, Tolbert William D, Pierce Brian G, Atkinson Ben, Deming Derrick, Sprague Megan, Asakawa Andrew, Ferrer David, Dunn Yasmin, Calvillo Sarah, Yin Rui, Guest Johnathan D, Korber Bette, Mayer Bryan T, Sato Alicia H, Ouyang Xin, Foulke Scott, Habibzadeh Parham, Karimi Maryam, Aslanabadi Arash, Hojabri Mahsa, Saadat Saman, Zareidoodeji Roza, Kędzior Mateusz, Pozharski Edwin, Heredia Alonso, Chen Hegang, Montefiori David, Ferrari Guido, Pazgier Marzena, Lewis George K, Jardine Joseph G, Lusso Paolo, DeVico Anthony
Divisions of Vaccine Research and Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Medicine, Maryland VA Healthcare System, Baltimore, MD, USA.
Divisions of Vaccine Research and Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA.
Structure. 2025 Jul 3;33(7):1150-1164.e8. doi: 10.1016/j.str.2025.04.016. Epub 2025 May 14.
Anti-HIV envelope broadly neutralizing antibodies (bnAbs) are alternatives to conventional antiretrovirals with the potential to prevent and treat infection, reduce latent reservoirs, and/or mediate a functional cure. Clinical trials with "first-generation" bnAbs used alone or in combination show promising antiviral effects but also highlight that additional engineering of "enhanced" antibodies will be required for optimal clinical utility, while preserving or enhancing Current Good Manufacturing Practices (cGMP) manufacturing capability. Here, we report the engineering of an anti-CD4-binding site (CD4bs) bnAb, N49P9.3. Through a series of rational modifications, we produced a variant, N49P9.6-FR-LS, that demonstrates enhanced potency, superior antiviral activity in combination with other bnAbs, low polyreactivity, and longer circulating half-life. Additional engineering for manufacturing produced a final variant, eN49P9, with properties conducive to cGMP production. Overall, these efforts demonstrate the feasibility of developing enhanced anti-CD4bs bnAbs with greatly improved antiviral properties as well as potential translational value.
抗HIV包膜广泛中和抗体（bnAbs）是传统抗逆转录病毒药物的替代物，具有预防和治疗感染、减少潜伏库以及/或者介导功能性治愈的潜力。单独使用或联合使用“第一代”bnAbs的临床试验显示出有前景的抗病毒效果，但也突出表明，为了实现最佳临床效用，同时保留或提高现行药品生产质量管理规范（cGMP）生产能力，将需要对“增强型”抗体进行更多工程改造。在此，我们报告了一种抗CD4结合位点（CD4bs）bnAb，即N49P9.3的工程改造。通过一系列合理修饰，我们产生了一个变体N49P9.6-FR-LS，它表现出增强的效力、与其他bnAbs联合使用时具有卓越的抗病毒活性、低多反应性以及更长的循环半衰期。为生产进行的进一步工程改造产生了最终变体eN49P9，其特性有利于cGMP生产。总体而言，这些研究工作证明了开发具有大大改善的抗病毒特性以及潜在转化价值的增强型抗CD4bs bnAbs的可行性。
Protein Sci. 2023-11
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