A comprehensive engineering strategy improves potency and manufacturability of a near pan-neutralizing antibody against HIV

• DOI: 10.1016/j.str.2025.04.016
• Publication Date: 2025-05-14T14:37:26Z
• Authors: Mohammad M. Sajadi; Abdolrahim Abbasi; Zahra Rikhtegaran...; Christine Siska; Rutilio Clark; Woo Chi; Michael S. Seaman; Dieter Mielke; Kshitij Wagh; Qingbo Liu; Taylor Jumpa; Randal R. Ketchem; Dung N. Nguyen; William D. Tolbert; Brian G. Pierce; Ben Atkinson; Derrick Deming; Megan Sprague; Andrew Asakawa; David Ferrer; Yasmin Dunn; Sarah Calvillo; Rui Yin; Johnathan D. Guest; Bette Korber; Bryan T. Mayer; Alicia H. Sato; Xin Ouyang; Scott Foulke; Parham Habibzadeh; Maryam Karimi; Arash Aslanabadi; Mahsa Hojabri; Saman Saadat; Roza Zareidoodeji; Mateusz Kędzior; Edwin Pozharski; Alonso Heredia; Hegang Chen; David Montefiori; Guido Ferrari; Marzena Pazgier; George K. Lewis; Joseph G. Jardine; Paolo Lusso; Anthony DeVico

Anti-HIV envelope broadly neutralizing antibodies (bnAbs) are alternatives to conventional antiretrovirals with the potential prevent and treat infection, reduce latent reservoirs, and/or mediate a functional cure. Clinical trials "first-generation" bnAbs used alone or in combination show promising antiviral effects but also highlight that additional engineering of "enhanced" will be required for optimal clinical utility, while preserving enhancing Current Good Manufacturing Practices (cGMP) manufacturing capability. Here, we report an anti-CD4-binding site (CD4bs) bnAb, N49P9.3. Through series rational modifications, produced variant, N49P9.6-FR-LS, demonstrates enhanced potency, superior activity other bnAbs, low polyreactivity, longer circulating half-life. Additional final eN49P9, properties conducive cGMP production. Overall, these efforts demonstrate feasibility developing anti-CD4bs greatly improved as well translational value.