Therapeutic compositions and methods for antibody and Fc-containing targeting molecule-based targeted delivery of bioactive molecules by bacterial minicells
Inventors
Giacalone, Matthew J. • Newman, Michael J.
Assignees
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Publication Number
US-10005820-B2
Publication Date
2018-06-26
Expiration Date
Abstract
The present application relates to the use of bacterial minicells as targeted delivery agents in vivo and in vitro. Described herein are genetically engineered eubacterial minicells designed to preferentially target and deliver therapeutically relevant agents using a minicell surface coupling molecule capable of binding and displaying antibodies or other Fc-containing targeting moiety fusions and conjugates.
Core Innovation
The invention provides genetically engineered eubacterial minicells for targeted delivery, diagnostic, and theranostic use for engaging eukaryotic antigens. The minicells include a surface-displayed Fc-binding fusion protein comprising an outer membrane anchoring domain and an Fc-binding portion of Protein A, or Protein G, so that bound Fc-containing targeting molecules recognize a eukaryotic antigen.
The Protein A Fc-binding portion is described as lacking F(ab')2 binding capability and as comprising no cleavage sites by OmpT protease, supporting oriented Fc-associated binding and Fc region masking/concealment. The minicells are described as targeting-competent toward eukaryotic antigens, including tumor cell surface molecule targets, endothelial cell surface molecule targets, and professional antigen-presenting cells such as dendritic cells and macrophages.
The minicells carry one or more bioactive molecules, including protein toxins, therapeutic small molecule drugs, therapeutic nucleic acids, radionuclides, and imaging agents, alone or in combination. Optional components described include endosomal escape agents and immunomodulatory adjuvants, and diagnostic use is also described, including minicell detection reagents in connection with lateral flow immunoassays.
Claims Coverage
The consolidated claim coverage centers on one independent minicell claim, with two core inventive features and related refinements. The claims define a bacterial minicell architecture with a surface-displayed Fc-binding fusion protein, bioactive molecules, and Fc-containing targeting molecules that recognize a eukaryotic antigen.
Surface-displayed Fc-binding fusion for oriented Fc-associated targeting
A bacterial minicell comprising an Fc-binding fusion protein displayed on the surface of the minicell, wherein the Fc-binding fusion protein comprises an outer membrane anchoring domain and an Fc binding portion of Protein A, with the Protein A Fc-binding portion having no F(ab')2 binding capability and comprising no cleavage sites by OmpT protease.
Bioactive payload plus eukaryotic antigen-recognizing Fc-containing targeting molecules
A bacterial minicell comprising one or more bioactive molecules and one or more Fc-containing targeting molecules bound to the Fc binding portion, wherein the one or more Fc-containing targeting molecules recognize a eukaryotic antigen.
Optional endosomal escape agent component
The minicell further includes an endosomal escape agent.
Immune cell class-specific Fc-targeting molecules
The minicell includes at least one Fc-containing targeting molecule that is specific for a specified eukaryotic immune cell type.
The inventive scope is defined by a surface-displayed Protein A Fc-binding fusion on a minicell, with no F(ab')2 binding capability and no OmpT cleavage sites, combined with bioactive molecules and Fc-containing targeting molecules that recognize a eukaryotic antigen. The additional refinements include an endosomal escape agent and specificity of Fc-targeting molecules for particular eukaryotic immune cell types.
Stated Advantages
Oriented antigen-binding exposure via Fc-associated binding while maintaining Fc region masking/concealment.
Targeting-competent behavior toward eukaryotic antigens, including tumor and endothelial and professional antigen-presenting cells.
Compatibility with multiple payload classes including protein toxins, therapeutic small molecules, therapeutic nucleic acids, and radionuclides/imaging agents.
Diagnostic use is described, including minicell detection in lateral flow immunoassays.
Documented Applications
Diagnostic use using minicell detection reagents in connection with lateral flow immunoassays.
Targeted delivery and theranostic/therapeutic use toward eukaryotic antigens including tumor cell surface molecule targets and endothelial cell surface molecule targets and toward professional antigen-presenting cells such as dendritic cells and macrophages.
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