A Comprehensive Engineering Strategy Improves Potency and Manufacturability of a Near Pan-neutralizing Antibody Against HIV

Mohammad M. Sajadi; Abdolrahim Abbasi; Zahra Rikhtegaran Tehrani; Christine C. Siska; Rutilio H. Clark; Woo Chi; Michael S. Seaman; Dieter Mielke; Kshitij Wagh; Qingbo Liu; Taylor Jumpa; Randal R. Ketchem; Dung Ngoc Pham Nguyen; William David Tolbert; Brian G. Pierce; Ben Atkinson; Derrick Deming; Megan Sprague; Andrew Asakawa; David Ferrer; Yasmin Dunn; Sarah Calvillo; Rui Ming Yin; Johnathan D. Guest; Bette Korber; Bryan T. Mayer; Alicia Sato; Xin Ouyang; Scott Foulke; Parham Habibzadeh

doi:10.1016/j.str.2025.04.016

BioengineeringStructureMay 14, 2025

Peer-reviewed journal article

A Comprehensive Engineering Strategy Improves Potency and Manufacturability of a Near Pan-neutralizing Antibody Against HIV

Mohammad M. Sajadi iD, Abdolrahim Abbasi, Zahra Rikhtegaran Tehrani iD, Christine C. Siska, Rutilio H. Clark, Woo Chi, Michael S. Seaman iD, Dieter Mielke iD, Kshitij Wagh iD, Qingbo Liu iD, Taylor Jumpa, Randal R. Ketchem iD, Dung Ngoc Pham Nguyen iD, William David Tolbert iD, Brian G. Pierce iD, Ben Atkinson, Derrick Deming, Megan Sprague, Andrew Asakawa, David Ferrer, Yasmin Dunn, Sarah Calvillo, Rui Ming Yin iD, Johnathan D. Guest iD, Bette Korber iD, , Anthony L. DeVico

Abstract

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 cGMP manufacturing capability. Here we report the engineering of an anti-CD4 binding-site (CD4bs) bnAb, N49P9.3, purified from the plasma of an HIV elite-neutralizer. Through a series of rational modifications we produced a variant 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.

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