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TitleIdentification and engineering of potent bispecific antibodies that protect against herpes simplex virus recurrent disease.
Journal, issue, pagesCell Rep, Vol. 44, Issue 8, Page 116063, Year 2025
Publish dateJul 26, 2025
AuthorsChingwei V Lee / Hector Viadiu / Apurva Kalamkar / David I Bernstein / Andrew Pae / Xinchao Yu / Sylvia Wong / Fernando J Bravo / Sheng Ding / Elbert Seto / Magdeleine Hung / Yu Yu / Weimei Xing / Giuseppe A Papalia / Wei Kan / Brian Carr / Majlinda Thomas / Leah Tong / Priyanka Desai / Nadine Jarrousse / Alexandre Mercier / Meghan M Holdorf / Simon P Fletcher / Emma Abernathy /
PubMed AbstractHerpes simplex virus (HSV) causes lifelong infections, including oral and genital herpes. There is no vaccine, and current antivirals are only partially effective at reducing symptoms and ...Herpes simplex virus (HSV) causes lifelong infections, including oral and genital herpes. There is no vaccine, and current antivirals are only partially effective at reducing symptoms and transmission. Therapeutic antibodies offer a potentially long-acting treatment option, although efforts to pursue this have been limited. We performed an alpaca immunization campaign and discovered high-affinity antibodies that both neutralized and completely blocked cell-to-cell spread (CCS), a key mechanism by which HSV evades neutralizing antibodies. Unexpectedly, we found that engineering antibodies into a bispecific format targeting two viral glycoproteins dramatically increased antiviral potency. Solving the structures of three antibodies using cryo-electron microscopy (cryo-EM) revealed a mechanistic understanding of how the bispecific format could enhance potency. Lastly, these bispecific antibodies significantly reduced lesion development in the guinea pig model of genital herpes, demonstrating that delayed dosing after latency establishment can reduce disease and confirming their potential as a transformative treatment option.
External linksCell Rep / PubMed:40716063
MethodsEM (single particle)
Resolution2.1 - 2.3 Å
Structure data

EMDB-48671, PDB-9mvu:
C6 Herpes Virus Simplex Neutralizing Nanobody Bound to HSV Glycoprotein gB
Method: EM (single particle) / Resolution: 2.2 Å

EMDB-48677, PDB-9mw5:
D1 Herpes Virus Simplex Neutralizing Nanobody Bound to HSV Glycoprotein gB
Method: EM (single particle) / Resolution: 2.1 Å

EMDB-48730, PDB-9my8:
D7 Herpes Virus Simplex Neutralizing Nanobody Bound to HSV Glycoprotein gD
Method: EM (single particle) / Resolution: 2.3 Å

Chemicals

ChemComp-HOH:
WATER

ChemComp-NA:
Unknown entry

Source
  • homo sapiens (human)
  • human herpesvirus 1 (strain 17)
  • lama glama (llama)
  • human herpesvirus 2
KeywordsANTIVIRAL PROTEIN / Neutralizing Antibody

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