Bispecific antibody CAP256.J3LS targets V2-apex and CD4-binding sites with high breadth and potency

Baoshan Zhang; Jason Gorman; Young D. Kwon; Amarendra Pegu; Cara W. Chao; Tracy Liu; Mangaiarkarasi Asokan; Michael F. Bender; Tatsiana Bylund; Leland Damron; Deepika Gollapudi; Paula Lei; Yile Li; Cuiping Liu; Mark K. Louder; Krisha McKee; Adam S. Olia; Reda Rawi; Arne Schön; Shuishu Wang; Eun Sung Yang; Yongping Yang; Kevin Carlton; Nicole A. Doria-Rose; Lawrence Shapiro; Michael S. Seaman; John R. Mascola; Peter D. Kwong

doi:10.1080/19420862.2023.2165390

mAbs (Dec 2023)

Bispecific antibody CAP256.J3LS targets V2-apex and CD4-binding sites with high breadth and potency

Baoshan Zhang,
Jason Gorman,
Young D. Kwon,
Amarendra Pegu,
Cara W. Chao,
Tracy Liu,
Mangaiarkarasi Asokan,
Michael F. Bender,
Tatsiana Bylund,
Leland Damron,
Deepika Gollapudi,
Paula Lei,
Yile Li,
Cuiping Liu,
Mark K. Louder,
Krisha McKee,
Adam S. Olia,
Reda Rawi,
Arne Schön,
Shuishu Wang,
Eun Sung Yang,
Yongping Yang,
Kevin Carlton,
Nicole A. Doria-Rose,
Lawrence Shapiro,
Michael S. Seaman,
John R. Mascola,
Peter D. Kwong

Affiliations

Baoshan Zhang: Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
Jason Gorman: Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
Young D. Kwon: Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
Amarendra Pegu: Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
Cara W. Chao: Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
Tracy Liu: Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
Mangaiarkarasi Asokan: Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
Michael F. Bender: Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
Tatsiana Bylund: Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
Leland Damron: Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
Deepika Gollapudi: Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
Paula Lei: Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
Yile Li: Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
Cuiping Liu: Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
Mark K. Louder: Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
Krisha McKee: Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
Adam S. Olia: Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
Reda Rawi: Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
Arne Schön: Department of Biology, Johns Hopkins University, Baltimore, MD, USA
Shuishu Wang: Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
Eun Sung Yang: Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
Yongping Yang: Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
Kevin Carlton: Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
Nicole A. Doria-Rose: Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
Lawrence Shapiro: Department of Biochemistry, Columbia University, New York, NY, USA
Michael S. Seaman: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
John R. Mascola: Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
Peter D. Kwong: Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA

DOI: https://doi.org/10.1080/19420862.2023.2165390
Journal volume & issue: Vol. 15, no. 1

Abstract

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ABSTRACTAntibody CAP256-VRC26.25 targets the second hypervariable region (V2) at the apex of the HIV envelope (Env) trimer with extraordinary neutralization potency, although less than optimal breadth. To improve breadth, we linked the light chain of CAP256V2LS, an optimized version of CAP256-VRC26.25 currently under clinical evaluation, to the llama nanobody J3, which has broad CD4-binding site-directed neutralization. The J3-linked bispecific antibody exhibited improved breadth and potency over both J3 and CAP256V2LS, indicative of synergistic neutralization. The cryo-EM structure of the bispecific antibody in complex with a prefusion-closed Env trimer revealed simultaneous binding of J3 and CAP256V2LS. We further optimized the pharmacokinetics of the bispecific antibody by reducing the net positive charge of J3. The optimized bispecific antibody, which we named CAP256.J3LS, had a half-life similar to CAP256V2LS in human FcRn knock-in mice and exhibited suitable auto-reactivity, manufacturability, and biophysical risk. CAP256.J3LS neutralized over 97% of a multiclade 208-strain panel (geometric mean concentration for 80% inhibition (IC80) 0.079 μg/ml) and 100% of a 100-virus clade C panel (geometric mean IC80 of 0.05 μg/ml), suggesting its anti-HIV utility especially in regions where clade C dominates.

Published in mAbs

ISSN: 1942-0862 (Print); 1942-0870 (Online)
Publisher: Taylor & Francis Group
Country of publisher: United Kingdom
LCC subjects: Medicine: Therapeutics. Pharmacology; Medicine: Internal medicine: Specialties of internal medicine: Immunologic diseases. Allergy
Website: https://www.tandfonline.com/journals/kmab

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