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 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

doi:10.1016/j.str.2025.04.016

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 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 FerrerYasmin 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

^*Corresponding author for this work

Medicine

Research output: Contribution to journal › Article › peer-review

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 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.

Original language	English
Pages (from-to)	1150-1164.e8
Journal	Structure
Volume	33
Issue number	7
DOIs	https://doi.org/10.1016/j.str.2025.04.016
State	Published - 3 Jul 2025

Keywords

ADCC
CD4 binding site
HIV
HIV cure
bnAb
combination therapies
elite neutralizer
engineering
monoclonal antibody
neutralization

Access to Document

10.1016/j.str.2025.04.016

Cite this

Sajadi, M. M., Abbasi, A., Tehrani, Z. R., Siska, C., Clark, R., Chi, W., Seaman, M. S., Mielke, D., Wagh, K., Liu, Q., Jumpa, T., Ketchem, R. R., Nguyen, D. N., Tolbert, W. D., Pierce, B. G., Atkinson, B., Deming, D., Sprague, M., Asakawa, A., ... DeVico, A. (2025). A comprehensive engineering strategy improves potency and manufacturability of a near pan-neutralizing antibody against HIV. Structure, 33(7), 1150-1164.e8. https://doi.org/10.1016/j.str.2025.04.016

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

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 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.",

keywords = "ADCC, CD4 binding site, HIV, HIV cure, bnAb, combination therapies, elite neutralizer, engineering, monoclonal antibody, neutralization",

author = "Sajadi, {Mohammad M.} and Abdolrahim Abbasi and Tehrani, {Zahra Rikhtegaran} and Christine Siska and Rutilio Clark and Woo Chi and Seaman, {Michael S.} and Dieter Mielke and Kshitij Wagh and Qingbo Liu and Taylor Jumpa and Ketchem, {Randal R.} and Nguyen, {Dung N.} and Tolbert, {William D.} and Pierce, {Brian G.} and Ben Atkinson and Derrick Deming and Megan Sprague and Andrew Asakawa and David Ferrer and Yasmin Dunn and Sarah Calvillo and Rui Yin and Guest, {Johnathan D.} and Bette Korber and Mayer, {Bryan T.} and Sato, {Alicia H.} and Xin Ouyang and Scott Foulke and Parham Habibzadeh and Maryam Karimi and Arash Aslanabadi and Mahsa Hojabri and Saman Saadat and Roza Zareidoodeji and Mateusz K{\c e}dzior and Edwin Pozharski and Alonso Heredia and Hegang Chen and David Montefiori and Guido Ferrari and Marzena Pazgier and Lewis, {George K.} and Jardine, {Joseph G.} and Paolo Lusso and Anthony DeVico",

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month = jul,

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doi = "10.1016/j.str.2025.04.016",

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Sajadi, MM, Abbasi, A, Tehrani, ZR, Siska, C, Clark, R, Chi, W, Seaman, MS, Mielke, D, Wagh, K, Liu, Q, Jumpa, T, Ketchem, RR, Nguyen, DN, Tolbert, WD, Pierce, BG, Atkinson, B, Deming, D, Sprague, M, Asakawa, A, Ferrer, D, Dunn, Y, Calvillo, S, Yin, R, Guest, JD, Korber, B, Mayer, BT, Sato, AH, Ouyang, X, Foulke, S, Habibzadeh, P, Karimi, M, Aslanabadi, A, Hojabri, M, Saadat, S, Zareidoodeji, R, Kędzior, M, Pozharski, E, Heredia, A, Chen, H, Montefiori, D, Ferrari, G, Pazgier, M, Lewis, GK, Jardine, JG, Lusso, P & DeVico, A 2025, 'A comprehensive engineering strategy improves potency and manufacturability of a near pan-neutralizing antibody against HIV', Structure, vol. 33, no. 7, pp. 1150-1164.e8. https://doi.org/10.1016/j.str.2025.04.016

TY - JOUR

T1 - A comprehensive engineering strategy improves potency and manufacturability of a near pan-neutralizing antibody against HIV

AU - Sajadi, Mohammad M.

AU - Abbasi, Abdolrahim

AU - Tehrani, Zahra Rikhtegaran

AU - Siska, Christine

AU - Clark, Rutilio

AU - Chi, Woo

AU - Seaman, Michael S.

AU - Mielke, Dieter

AU - Wagh, Kshitij

AU - Liu, Qingbo

AU - Jumpa, Taylor

AU - Ketchem, Randal R.

AU - Nguyen, Dung N.

AU - Tolbert, William D.

AU - Pierce, Brian G.

AU - Atkinson, Ben

AU - Deming, Derrick

AU - Sprague, Megan

AU - Asakawa, Andrew

AU - Ferrer, David

AU - Dunn, Yasmin

AU - Calvillo, Sarah

AU - Yin, Rui

AU - Guest, Johnathan D.

AU - Korber, Bette

AU - Mayer, Bryan T.

AU - Sato, Alicia H.

AU - Ouyang, Xin

AU - Foulke, Scott

AU - Habibzadeh, Parham

AU - Karimi, Maryam

AU - Aslanabadi, Arash

AU - Hojabri, Mahsa

AU - Saadat, Saman

AU - Zareidoodeji, Roza

AU - Kędzior, Mateusz

AU - Pozharski, Edwin

AU - Heredia, Alonso

AU - Chen, Hegang

AU - Montefiori, David

AU - Ferrari, Guido

AU - Pazgier, Marzena

AU - Lewis, George K.

AU - Jardine, Joseph G.

AU - Lusso, Paolo

AU - DeVico, Anthony

PY - 2025/7/3

Y1 - 2025/7/3

N2 - 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.

AB - 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.

KW - ADCC

KW - CD4 binding site

KW - HIV

KW - HIV cure

KW - bnAb

KW - combination therapies

KW - elite neutralizer

KW - engineering

KW - monoclonal antibody

KW - neutralization

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U2 - 10.1016/j.str.2025.04.016

DO - 10.1016/j.str.2025.04.016

M3 - Article

AN - SCOPUS:105005274965

SN - 0969-2126

VL - 33

SP - 1150-1164.e8

JO - Structure

JF - Structure

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ER -