Detargeted adenovirus variants and related methods
AssigneeAdcure Biotechnologies, LLC.
InventorsDmitry M. Shayakhmetov, Nelson C. Di Paolo
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Abstract
The present disclosure describes the generation and the use of Ad variants (Ad) possessing any combination of mutations in genes that code for the hexon, penton, fiber, and non-structural proteins, where simultaneous modification of hexon and penton are made to avoid the trapping of Ad in the liver and to reduce toxicity after intravascular virus administration. Such liver de-targeted Ad can be useful tool for selective and specific gene delivery to extra-hepatic tissues and cells, including disseminated metastatic cancer cells.
Claims21
An isolated adenovirus with a mutation in the RGD motif of the penton protein, wherein the mutation causes reduced binding of β3 integrins of a host cell, and two mutations in the hexon hypervariable loops, wherein said mutations in the hexon hypervariable loops comprise a mutation in the HVR1 loop and a mutation in the HVR7 loop,
- wherein the mutation in the HVR1 loop of the hexon protein causes reduced virus trapping in Kupffer cells, and
- wherein the combination of the mutation in the RGD motif, the mutation in the HVR1 loop and the mutation in the HVR7 loop causes reduced liver sequestration of the adenovirus.
An isolated adenovirus with a mutation in the RGD motif of the penton protein, wherein the mutation causes reduced binding of β3 integrins of a host cell, and two mutations in the hexon hypervariable loops, wherein said mutations in the hexon hypervariable loops comprise a mutation in the HVR1 loop and a mutation in the HVR7 loop, wherein said adenovirus comprises a single virus genomic DNA molecule comprising a nucleotide sequence that encodes SEQ ID NO:3 or SEQ ID NO:4.
An isolated adenovirus comprising:
- (1) a mutation in the RGD motif of the penton protein, wherein the mutation causes reduced binding of β3 integrins of a host cell;
- (2) a mutation in the HVR1 region of the hexon protein, wherein the mutation causes reduced trapping of the adenovirus in Kupffer cells;
- and
- (3) a mutation in the HVR7 region of the hexon protein, wherein the mutation causes reduced binding of the adenovirus to a vitamin K dependent clotting factor,
- wherein the combination of the mutation in the RGD motif, the mutation in the HVR1 region and the mutation in the HVR7 region causes reduced liver sequestration of the adenovirus.
Dependencies are inferred from the claim text.