8FIS

Structure of Bispecific CAP256V2LS-J3 Fab in complex with BG505 DS-SOSIP.664

Summary for 8FIS

• Entry DOI: 10.2210/pdb8fis/pdb
• EMDB information: 29209
• Descriptor: Envelope glycoprotein gp41, 2-acetamido-2-deoxy-beta-D-glucopyranose, Envelope glycoprotein gp120, ... (10 entities in total)
• Functional Keywords: cd4, hiv-1, sosip, vaccine, immune system, llama, v2 apex, therapeutic, viral protein, cap256, vrc26.25
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 10
• Total formula weight: 381232.65

Authors

Gorman, J.,Kwong, P.D. (deposition date: 2022-12-16, release date: 2023-02-01, Last modification date: 2024-11-13)

Primary citation

Zhang, B.,Gorman, J.,Kwon, Y.D.,Pegu, A.,Chao, C.W.,Liu, T.,Asokan, M.,Bender, M.F.,Bylund, T.,Damron, L.,Gollapudi, D.,Lei, P.,Li, Y.,Liu, C.,Louder, M.K.,McKee, K.,Olia, A.S.,Rawi, R.,Schon, A.,Wang, S.,Yang, E.S.,Yang, Y.,Carlton, K.,Doria-Rose, N.A.,Shapiro, L.,Seaman, M.S.,Mascola, J.R.,Kwong, P.D.
Bispecific antibody CAP256.J3LS targets V2-apex and CD4-binding sites with high breadth and potency.
Mabs, 15:2165390-2165390, 2023

PubMed Abstract: Antibody 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 (IC) 0.079 μg/ml) and 100% of a 100-virus clade C panel (geometric mean IC of 0.05 μg/ml), suggesting its anti-HIV utility especially in regions where clade C dominates.

PubMed: 36729903
DOI: 10.1080/19420862.2023.2165390

Experimental method

ELECTRON MICROSCOPY (3.18 Å)