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Author: Pereboev, Alexander ; Belousova, Natalya ; Krasnykh, Victor ; Triozzi, Pierre L. ; Krendelshchikov, Alexander ; Simonenko, Vera ; Aldrich, Wayne A. ; Gillies, Stephen D. ; Lo, Kin-Ming ; Curiel, David T. ; Douglas, Joanne T. ; Mikheeva, Galina ; Korokhov, Nikolay ; Kotova, Olga ; Kotov, Alexander ; Krendelshchikova, Valentina ; Banerjee, Papia T.

ABSTRACTA potential barrier to the development of genetically targeted adenovirus (Ad) vectors for cell-specific delivery of gene therapeutics lies in the fact that several types of targeting protein ligands require posttranslational modifications, such as the formation of disulfide bonds, which are not available to Ad capsid proteins due to their nuclear localization during assembly of the virion. To overcome this problem, we developed a new targeting strategy, which combines genetic modifications of the Ad capsid with a protein bridge approach, resulting in a vector-ligand targeting complex. The components of the complex associate by virtue of genetic modifications to both the Ad capsid and the targeting ligand. One component of this mechanism of association, the Fc-binding domain ofStaphylococcus aureusprotein A, is genetically incorporated into the Ad fiber protein. The ligand is comprised of a targeting component fused with the Fc domain of immunoglobulin, which serves as a docking moiety to bind to these genetically modified fibers during the formation of the Ad-ligand complex. The modular design of the ligand solves the problem of structural and biosynthetic compatibility with the Ad and thus facilitates targeting of the vector to a variety of cellular receptors. Our study shows that targeting ligands incorporating the Fc domain and either an anti-CD40 single-chain antibody or CD40L form stable complexes with protein A-modified Ad vectors, resulting in significant augmentation of gene delivery to CD40-positive target cells. Since this gene transfer is independent of the expression of the native Ad5 receptor by the target cells, this strategy results in the derivation of truly targeted Ad vectors suitable for tissue-specific gene therapy.

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100 Translational Medicine associated with EMD Lexigen Research Center Corp.

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Pipeline

Pipeline Snapshot as of 18 Dec 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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