Modified bacteria having improved pharmacokinetics and tumor colonization enhancing antitumor activity

摘要

Bacterial strains are provided having at least one of a reduced size, a sialic acid coat, inducibly altered surface antigens, and expression of PD-L1 or CTLA-4 agonists and/or tryptophanase. The bacteria may have improved serum half-life, increased penetration into tumors, increased tumor targeting and increased antitumor activity. The bacteria are useful for delivery of therapeutic agents that treat of neoplastic diseases including solid tumors and lymphomas.

主权项

1. A live genetically engineered Salmonella bacterium, comprising:
at least one first gene, producing at least one secreted first gene product comprising a sialic acid O-acyl transferase under control of at least one heterologous first inducible promoter; and at least one second gene, producing a secreted functional antitumor enzyme gene product under control of a second heterologous inducible promoter, the at least one first gene being distinct from the at least one second gene, the at least one heterologous first inducible promoter being distinct from the at least one heterologous second inducible promoter; the live genetically engineered Salmonella bacterium being adapted for:
administration to a human or animal and colonization of at least one tissue under non-lethal conditions,after colonization of the at least one tissue, secretion of the sialic acid O-acyl transferase under control of the first inducible promoter, for action on external components of the live genetically engineered Salmonella bacterium, andafter colonization of the at least one tissue, secretion of the secreted functional antitumor enzyme gene product under control of the second inducible promoter, for action against tumor cells.