About this item:

92 Views | 47 Downloads

Author Notes:

pls47@case.edu or dmitryshay@emory.edu

We are thankful to Eric Irons (Buffalo University) for analyzing in vitro properties of Ad5-Lam1 virus and Neetu M. Gulati for assistance with preparing Ad5-3M cryo-EM grids.

D.M.S. has equity interest and is a chief scientific officer of AdCure Bio, which develops adenovirus technologies for therapeutic use. D.M.S. is an inventor on issued US patents No. 9,982,276, Penton-mutated, integrin-retargeted adenovirus vectors with reduced toxicity and their use; and No.10,376,549, Detargeted adenovirus variants and related methods; and pending US patent application 16/460,160 and European patent application 16740545.5, Detargeted adenovirus variants and related methods, submitted by AdCure Bio. All other authors declare that they have no competing interests.

Subjects:

Research Funding:

The authors acknowledge the use of instruments at the Electron Imaging Center for NanoMachines supported by NIH (1S10RR23057, 1S10OD018111, and 1U24GM116792), NSF (DBI-1338135) and CNSI at UCLA. We thank the Case Western Reserve University High Performance Computing staff for their assistance with campus computing resources. Preliminary image processing was performed using the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation grant number ACI-1548562. This work used the XSEDE Large Memory Nodes (Bridges Large) at the Pittsburgh Supercomputing Center through allocation MCB170163.

This work was supported by NIH grant AI107960 to D.M.S and P.L.S. and by NIH grant AI065429, David C. Lowance Endowment Fund, and Children’s Healthcare of Atlanta Research Trust to D.M.S. C.C.E. acknowledges support from the NIH T32 GM008803 training grant. The analysis of Ad5/35-3M was supported by funding from AdCure Bio to D.M.S.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • MOLECULAR-DYNAMICS
  • NATURAL ANTIBODIES
  • VECTORS
  • VIRUS
  • TOXICITY
  • HEXON
  • VISUALIZATION
  • MACROPHAGES
  • CLEARANCE
  • RECEPTORS

Systemic cancer therapy with engineered adenovirus that evades innate immunity

Tools:

Journal Title:

SCIENCE TRANSLATIONAL MEDICINE

Volume:

Volume 12, Number 571

Publisher:

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Oncolytic virus therapy is a cancer treatment modality that has the potential to improve outcomes for patients with currently incurable malignancies. Although intravascular delivery of therapeutic viruses provides access to disseminated tumors, this delivery route exposes the virus to opsonizing and inactivating factors in the blood, which limit the effective therapeutic virus dose and contribute to activation of systemic toxicities. When human species C adenovirus HAdv-C5 is delivered intravenously, natural immunoglobulin M (IgM) antibodies and coagulation factor X rapidly opsonize HAdv-C5, leading to virus sequestration in tissue macrophages and promoting infection of liver cells, triggering hepatotoxicity. Here, we showed that natural IgM antibody binds to the hypervariable region 1 (HVR1) of the main HAdv-C5 capsid protein hexon. Using compound targeted mutagenesis of hexon HVR1 loop and other functional sites that mediate virus-host interactions, we engineered and obtained a high-resolution cryo-electron microscopy structure of an adenovirus vector, Ad5-3M, which resisted inactivation by blood factors, avoided sequestration in liver macrophages, and failed to trigger hepatotoxicity after intravenous delivery. Systemic delivery of Ad5-3M to mice with localized or disseminated lung cancer led to viral replication in tumor cells, suppression of tumor growth, and prolonged survival. Thus, compound targeted mutagenesis of functional sites in the virus capsid represents a generalizable approach to tailor virus interactions with the humoral and cellular arms of the immune system, enabling generation of “designer” viruses with improved therapeutic properties.

Copyright information:

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/rdf).
Export to EndNote