Granted Patent
B1
US 12,616,723 · App. 18/508,194 · Granted May 5, 2026
Modified bacteria having improved pharmacokinetics and tumor colonization enhancing antitumor activity
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Abstract
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 antagonists 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 neoplastic diseases including solid tumors and lymphomas.
Claims (16)
1 . A tumor targeting, gram negative, lipid A mutant bacterium with suppressed virulence and suppressed tumor necrosis factor α (TNF-alpha) induction, which is genetically engineered for non-lethal administration to a mammal or human, comprising at least one inducible gene adapted to produce an antineoplastic active amino acid-degrading enzyme,
wherein the bacterium is further genetically engineered to secrete a peptide which inhibits at least one of programmed cell death protein 1 (PD1), programmed cell death ligand 1 (PD-L1), programmed cell death ligand 2 (PD-L2), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).
2 . The bacterium according to claim 1 , wherein the antineoplastic amino acid-degrading enzyme is effective to reduce levels of the amino acid in a tumor, and produce a toxic metabolite of the amino acid in the tumor.
3 . The bacterium according to claim 1 , wherein the antineoplastic amino acid-degrading enzyme comprises tryptophanase.
4 . The bacterium according to claim 1 , wherein the antineoplastic amino acid-degrading enzyme comprises tyrosinase.
5 . The bacterium according to claim 1 , wherein the antineoplastic amino acid-degrading enzyme comprises asparaginase.
6 . The bacterium according to claim 1 , wherein the at least one inducible gene has at least one of an arabinose promoter and an acetylsalicylic acid inducible promoter.
7 . The bacterium according to claim 1 , wherein the at least one inducible gene is heterologous to the bacterium.
8 . The bacterium according to claim 1 , wherein the bacterium is of a genus selected from the group consisting of Salmonella, Staphylococcus, Streptococcus, Listeria , Proprionibacteria, Escherechia, Bacteriodies, Bifidobacterium, Bacillus, Enterococcus, Neisseria, Shigella, Yersinia, Xenorhabdus, Photorhabdus, Lactobacillus, Lactococcus, Leuconostoc, Pediococcus , and Vibrio.
9 . The bacterium according to claim 1 , wherein the bacterium has a maximum size of growth of about 650 nm.
10 . The bacterium according to claim 1 , wherein the bacterium further comprises a second inducible gene which produces a heterologous flagellar antigen.
11 . The bacterium according to claim 1 , in an intravenous pharmaceutical dosage form.
12 . The bacterium according to claim 1 , further comprising a genetically engineered construct for transforming the tumor targeting bacterium with at least one gene encoding an inducible promoter lined to an active amino acid-degrading enzyme.
13 . The bacterium according to claim 1 , further comprising at least one gene adapted to produce a protease inhibitor.
14 . A tumor targeting, gram negative, lipid A mutant bacterium, which is genetically engineered for non-lethal administration to a mammal or human in an intravenous pharmaceutical dosage form, comprising at least one inducible gene adapted to produce an antineoplastic active amino acid-degrading enzyme,
wherein the bacterium is further genetically engineered to secrete a peptide which inhibits at least one of programmed cell death protein 1 (PD1), programmed cell death ligand 1 (PD-L1), programmed cell death ligand 2 (PD-L2), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).
Continuity (8)
Continuation
17093133
· Nov 9, 2020
Continuation
16983854
· Aug 3, 2020
Continuation
16659168
· Oct 21, 2019
Continuation
16410627
· May 13, 2019
Continuation
15679874
· Aug 17, 2017
Division
15482170
· Apr 7, 2017
Division
14858810
· Sep 18, 2015
Provisional Application
62052252
· Sep 18, 2014
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