Other

Vion Pharmaceuticals, Inc.

Yale University

Aviex Technologies LLC

Aviex Textnologies LLC

Theobald Therapeutics LLC

David Gordon Bermudes

Kenneth Brooks Low

David Quintero

John M Pawelek

Ivan C King

Michael Belcourt

Caroline A Clairmont

Stanley L Lin

Martina Ittensohn

Bacteria with tumor-targeting capability express, surface displayed, secreted and/or released modified chimeric therapeutic proteins with enhanced therapeutic activity against a neoplastic tissue including solid tumors, lymphomas and leukemias. The bacteria may be attenuated, non-pathogenic, low pathogenic or a probiotic. The chimeric proteins may be protease sensitive and may optionally be further accompanied by co-expression of a secreted protease inhibitor as a separate molecule or as a fusion.

Chimeric protein toxins for expression by therapeutic bacteria

Bacterial strains are provided having at least one enhanced mechanism to sequester, bind, precipitate, chemically oxidize or reduce copper ions or other toxic divalent transition metals. The bacteria may also have optional copper resistance mechanisms. The bacteria reduce the amount of available copper to tissues, which may be cancerous tissues, and reduce tumor growth, angiogenesis and/or metastasis, or tissues subject to excess copper due to host defects in copper metabolism. The bacteria are useful for treatment of neoplastic diseases including solid tumors and lymphomas, as well as Wilson's Disease, Menke's Disease, and possible Alzheimer's Disease, Parkinson's Disease, and Creutzfeld-Jakob Disease.

Copper chelation therapeutics

The present invention uses co-expression of protease inhibitors and protease sensitive therapeutic agents including phage and phagemids delivering peptides, therapeutic antibodies, DNA and RNA-based therapeutics that results in treating inflammation of a variety of disorders including psoriasis, atopic dermatitis and inflammatory bowel disease. The invention also provides bacteria that inhibit the growth of intestinal parasites such as worms, and deliver siRNA or miRNA that have specific anti-parasitic effects that results in the reduction or elimination of the parasite.

Bacteria carrying bacteriophage and protease inhibitors for the treatment of disorders and methods of treatment

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 of neoplastic diseases including solid tumors and lymphomas.

Modified bacteria having improved pharmacokinetics and tumor colonization enhancing antitumor activity

A genetically engineered live bacterium which is adapted to selectively replicate in and colonize a selected tissue type within the mammal, and concurrently produce within the selected tissue type at least one protease-sensitive cytotoxic molecule which is degradable by proteases within the selected tissue type, and at least one protease inhibitor peptide to inhibit the proteases within the selected tissue type from proteolytically degrading the protease sensitive cytotoxic molecule. The combination results in higher concentrations of the cytotoxic molecule local to the colonization, while permitting protease degradation of the cytotoxic molecule further away from the colonization.

Protease inhibitor:protease sensitive expression system and method improving the therapeutic activity and specificity of proteins and phage and phagemids delivered by bacteria

Bacterial strains are provided having at least one enhanced mechanism to sequester, bind, precipitate, chemically oxidize or reduce copper ions or other toxic divalent transition metals. The bacteria may also have optional copper resistance mechanisms. The bacteria reduce the amount of available copper to tissues, which may be cancerous tissues, and reduce tumor growth, angiogenesis and/or metastasis, or tissues subject to excess copper due to host defects in copper metabolism. The bacteria are useful for treatment of neoplastic diseases including solid tumors and lymphomas, as well as Wilson's Disease, Menke's Disease, and possible Alzheimer's Disease, Parkinson's Disease, and Creutzfeldt-Jakob Disease.

A live genetically engineered bacterium, comprising a genetically engineered construct comprising a nucleic acid sequence encoding at least one portion of a SARS-CoV-2 antigen, the live genetically engineered bacterium being adapted for administration to a human or animal and colonization of at least one tissue under non-lethal conditions. The antigen is preferably the SARS-CoV-2 spike protein. The nucleic acid sequence preferably includes an associated promoter.

Expression of SARS-CoV-2 spike protein receptor binding domain in attenuatedas a vaccine

Bacteria which co-express protease inhibitors and protease sensitive therapeutic agents, which are surface displayed, secreted and/or released and result in their localized production and maintenance within a target tissue and inactivation outside of the target tissue, thereby increasing therapeutic activity and reducing the systemic toxicity. The bacteria may be attenuated, non-pathogenic, low pathogenic or a probiotic. Protease sensitivity may be further accomplished by engineering protease degradation sites within the therapeutic agents, further enhancing the inactivation outside of the target tissue while retaining activity within the target tissue through co-expression of a protease inhibitor. Novel chimeric proteins secreted by bacteria, including chimeric toxins targeted to neoplastic cells, tumor matrix cells and cells of the immune system, and combination therapies of these protease inhibitor:chimeric toxin-expressing bacteria together with small-molecule and biologic agents are also described. Non-conjugative bacteria limiting exchange of genetic material, and antibody resistant bacteria are also provided.

Protease inhibitor:protease sensitive expression system, composition and methods for improving the therapeutic activity and specificity of proteins delivered by bacteria

Bacteria with tumor-targeting capability express, surface displayed, secreted and/or released modified chimeric therapeutic proteins with enhanced therapeutic activity against a neoplastic tissue including solid tumors, lymphomas and leukemias. The bacteria may also express, surface display, secrete and/or release a tumor-penetrating peptide. The bacteria may be attenuated, non-pathogenic, low pathogenic or a probiotic. The chimeric proteins may be protease sensitive and may optionally be further accompanied by co-expression of a secreted protease inhibitor as a separate molecule or as a fusion.

Saccharide binding, tumor penetration, and cytotoxic antitumor chimeric peptides from therapeutic bacteria

Expression of SARS-CoV-2 spike protein receptor binding domain in attenuated salmonella as a vaccine

Chimeric proteins are expressed, secreted or released by a bacterium to immunize against or treat a parasite, infectious disease or malignancy. The delivery vector may also be attenuated, non-pathogenic, low pathogenic, or a probiotic bacterium. The chimeric proteins include chimeras of, e.g., phage coat and/or colicin proteins, bacterial toxins and/or enzymes, autotransporter peptides, lytic peptides, multimerization domains, and/or membrane transducing (ferry) peptides. The active portion of the immunogenic chimeric proteins can include antigens against a wide range of parasites and infectious agents, cancers, Alzheimer's and Huntington's diseases, and have enhanced activity when secreted or released by the bacteria, and/or have direct anti-parasite or infectious agent activity. The activity of the secreted proteins is further increased by co-expression of a protease inhibitor that prevents degradation of the effector peptides. Addition of an antibody binding or antibody-degrading protein further prevents the premature elimination of the vector and enhances the immune response.

Immunization and/or treatment of parasites and infectious agents by live bacteria

Protease inhibitors together with protease sensitive therapeutics or diagnostics are provided, which may be ionically or covalently bound, or unbound. The protease inhibitors and/or protease sensitive moiety may be provided in monomeric, homopolymeric, heteropolymeric (for each of the protease and agent) and/or block copolymeric (combining polymers of agent and inhibitor) form. The inhibitors may be native active or e.g., protease activated. Multiple protease inhibitor peptides may be used in-frame with multiple protease cleavage signals (polymeric protease activated protease inhibitors). Combination with the protease inhibitors with the protease sensitive therapeutic enhances the intact, active molecule local-regional or targeted cell or tissue concentration, peak concentration and/or duration of the therapeutic exposure, thereby increasing its therapeutic efficacy. The protease inhibitors are particularly useful for tumor-targeted therapies and for vaccines.

Growing community of inventors

Woodland Hills, CA, United States of America

David Gordon Bermudes