Abstract: The instant invention provides binding proteins (“CD38-binding proteins”) which each comprise (1) a CD38-binding region for cell-targeting and (2) a Shiga toxin A Subunit effector polypeptide (“Shiga toxin effector polypeptide”). The Shiga toxin effector polypeptide components of the CD38-binding proteins may comprise a combination of mutations relative to a wild-type Shiga toxin sequence providing (1) de-immunization and/or (2) a reduction in protease sensitivity; wherein each Shiga toxin effector polypeptide retains one or more Shiga toxin function, such as, e.g., stimulating cellular internalization, directing intracellular routing, catalytic activity, and/or potent cytotoxicity. The CD38-binding proteins may have one or multiple uses, e.g., the selective killing of a specific CD38-expressing cell-type; and more generally, for the diagnosis and treatment of cancers and disorders involving CD38-expressing cells, e.g., in CD38-positive hematopoietic cancers such as multiple myeloma.

Abstract: The present invention provides Shiga toxin A Subunit derived polypeptides, scaffolds, and cell-targeting molecules comprising amino acid substitutions which equip the molecules with site-specific positions (and often unique amino acid residues in the molecule) for linking other molecules while retaining Shiga toxin function(s), such as, e.g., efficient intracellular routing and/or potent cytotoxicity. The present invention also provides cell-targeting molecules, and/or components thereof, which comprise site-specific positions for linking other molecules, such as, e.g., agents that alters a property of the cell-targeting molecule or a cargo for delivery. Certain molecules comprising a polypeptide of the present invention exhibit reduced immunogenicity and/or are well-tolerated by mammals. The cell-targeting molecules of the present invention, and compositions thereof, have uses, e.g.

Abstract: Provided herein are PD-L1 binding molecules comprising or conjugated to a toxin, e.g. a Shiga toxin A Subunit derived polypeptide. In some embodiments, the PD-L1 binding molecules are cytotoxic. In some embodiments, the PD-L1 binding molecules are capable of delivering a CD8+ T-cell epitope to an MHC class molecule inside a PD-L1 positive cell. The PD-L1 binding molecules described herein have uses for selectively killing specific cells (e.g., PD-L1 positive tumor cells and/or immune cells); for selectively delivering cargos to specific cells (e.g., PD-L1 positive tumor cells or immune cells), and as therapeutic and/or diagnostic molecules for treating and diagnosing a variety of conditions, including cancers and tumors involving PD-L1 expressing cells (e.g., PD-L1 positive tumor cells or immune cells).

Abstract: The present invention provides Shiga toxin A Subunit derived polypeptides, scaffolds, and cell-targeting molecules comprising amino acid substitutions which equip the molecules with site-specific positions (and often unique amino acid residues in the molecule) for linking other molecules while retaining Shiga toxin function(s), such as, e.g., efficient intracellular routing and/or potent cytotoxicity. The present invention also provides cell-targeting molecules, and/or components thereof, which comprise site-specific positions for linking other molecules, such as, e.g., agents that alters a property of the cell-targeting molecule or a cargo for delivery. Certain molecules comprising a polypeptide of the present invention exhibit reduced immunogenicity and/or are well-tolerated by mammals. The cell-targeting molecules of the present invention, and compositions thereof, have uses, e.g.

Abstract: Provided herein are binding molecules that each comprise (1) a Shiga toxin A subunit effector polypeptide and (2) a binding region capable of specifically binding CTLA-4 on the surface of cell, such as a tumor cell or an immunosuppressive immune cell. Further provided are methods of using such binding molecules to treat diseases and disorders, such as cancer.

Abstract: Provided herein are HER2-targeting molecules comprising Shiga toxin A Subunit derived polypeptides having 1) de-immunization and 2) reduced, protease-cleavage sensitivity while retaining Shiga toxin function(s), such as, e.g., potent cytotoxicity via ribosome inhibition. Certain HER2-targeting molecules of the present invention exhibit reduced immunogenic potential in mammals and are well-tolerated by mammals while retaining aforementioned features. The HER2-targeting molecules of the present invention have uses for selectively killing specific cells (e.g., HER positive tumor cells); for selectively delivering cargos to specific cells (e.g., HER positive tumor cells), and as therapeutic and/or diagnostic molecules for treating and diagnosing a variety of conditions, including cancers and tumors involving the expression or over-expression of cell-surface HER2.

Abstract: The instant invention provides binding proteins (“CD38-binding proteins”) which each comprise (1) a CD38-binding region for cell-targeting and (2) a Shiga toxin A Subunit effector polypeptide (“Shiga toxin effector polypeptide”). The Shiga toxin effector polypeptide components of the CD38-binding proteins may comprise a combination of mutations relative to a wild-type Shiga toxin sequence providing (1) de-immunization and/or (2) a reduction in protease sensitivity; wherein each Shiga toxin effector polypeptide retains one or more Shiga toxin function, such as, e.g., stimulating cellular internalization, directing intracellular routing, catalytic activity, and/or potent cytotoxicity. The CD38-binding proteins may have one or multiple uses, e.g., the selective killing of a specific CD38-expressing cell-type; and more generally, for the diagnosis and treatment of cancers and disorders involving CD38-expressing cells, e.g., in CD38-positive hematopoietic cancers such as multiple myeloma.

Abstract: Provided in this disclosure are anti-CD38 binding domains, a composition comprising the anti-CD38 binding domains, nucleic acids encoding the anti-CD38 binding domains, and a method of using the anti-CD38 binding domains or the composition for treating multiple myeloma.

Abstract: The present invention provides cell-targeting molecules which can deliver a CD8+ T-cell epitope cargo to the MHC class I presentation pathway of the cell. The cell-targeting molecules of the invention can be used to deliver virtually any CD8+ T-cell epitope from an extracellular space to the MHC class I pathway of a target cell, which may be a malignant cell and/or non-immune cell. The target cell can then display on a cell-surface the delivered CD8+ T-cell epitope complexed with MHC I molecule. The cell-targeting molecules of the invention have uses which include the targeted labeling and/or killing of specific cell-types within a mixture of cell-types, including within a chordate, as well as the stimulation of beneficial immune responses. The cell-targeting molecules of the invention have uses, e.g., in the treatment of a variety of diseases, disorders, and conditions, including cancers, tumors, growth abnormalities, immune disorders, and microbial infections.

Abstract: The present invention provides cell-targeting molecules which can deliver a CD8+ T-cell epitope cargo to the MHC class I presentation pathway of a target cell. The cell-targeting molecules of the invention can be used to deliver virtually any CD8+ T-cell epitope from an extracellular space to the MHC class I pathway of a target cell, which may be a malignant cell and/or non-immune cell. The target cell can then display on a cell-surface the delivered CD8+ T-cell epitope complexed with MHC I molecule. The cell-targeting molecules of the invention have uses which include the targeted labeling and/or killing of specific cell-types within a mixture of cell-types, including within a chordate, as well as the stimulation of beneficial immune responses. The cell-targeting molecules of the invention have uses, e.g., in the treatment of a variety of diseases, disorders, and conditions, including cancers, tumors, growth abnormalities, immune disorders, and microbial infections.

Abstract: Provided herein are PD-L1 binding molecules comprising a toxin, e.g. a Shiga toxin A Subunit derived polypeptide. In some embodiments, the PD-L1 binding molecules are cytotoxic. In some embodiments, the PD-L1 binding molecules are capable of delivering a CD8+ T-cell epitope to an MHC class molecule inside a PD-L1 positive cell. The PD-L1 binding molecules described herein have uses for selectively killing specific cells (e.g., PD-L1 positive tumor cells and/or immune cells); for selectively delivering cargos to specific cells (e.g., PD-L1 positive tumor cells or immune cells), and as therapeutic and/or diagnostic molecules for treating and diagnosing a variety of conditions, including cancers and tumors involving PD-L1 expressing cells (e.g., PD-L1 positive tumor cells or immune cells).

Abstract: The present invention is directed to T-cell epitope delivering polypeptides which deliver one or more CD8+ T-cell epitopes to the MHC class I presentation pathway of a cell, including toxin-derived polypeptides which comprise embedded T-cell epitopes and are de-immunized. The present invention provides cell-targeted, CD8+ T-cell epitope delivering molecules for the targeted delivery of cytotoxicity to certain cells, e.g., infected or malignant cells, for the targeted killing of specific cell types, and the treatment of a variety of diseases, disorders, and conditions, including cancers, immune disorders, and microbial infections. The present invention also provides methods of generating polypeptides capable of delivering one or more heterologous T-cell epitopes to the MHC class I presentation pathway, including polypeptides which are 1) B-cell and/or CD4+ T-cell de-immunized, 2) comprise embedded T-cell epitopes, and/or 3) comprises toxin effectors which retain toxin functions.

Abstract: The present invention relates to Shiga toxin A Subunit derived polypeptides and cell-targeting molecules comprising amino acid substitutions which equip the polypeptides with 1) de-immunization; 2) reduced, protease-cleavage sensitivity; and/or 3) a heterologous epitope cargo(s) while retaining Shiga toxin function(s), such as, e.g., potent cytotoxicity. Certain polypeptides of the invention exhibit reduced immunogenic potential in mammals and/or are capable of delivering an epitope to an MHC class molecule of a cell in which the polypeptide is present. Certain molecules comprising a polypeptide of the invention are well-tolerated by mammals while retaining one or more of the features mentioned above.

Abstract: The present invention relates to Shiga toxin effector polypeptides with reduced antigenic and/or immunogenic potential. Immunogenicity can be a limitation for the repeated administration to mammals of proteins and polypeptides derived from Shiga toxins. The Shiga toxin effector polypeptides of the present invention have uses as components of therapeutics, diagnostics, and immunization materials. The cytotoxic proteins of the present invention have uses for selective killing of specific cell types and as therapeutics for the treatment of a variety of diseases, including cancers, immune disorders, and microbial infections. The proteins of the present invention also have uses for detecting specific cell types, collecting diagnostic information, and monitoring the treatment of a variety of diseases, such as, e.g., cancers, immune disorders, and microbial infections.

Abstract: The present invention provides proteins comprising binding regions for cell-type specific targeting, Shiga toxin effector regions derived from A Subunits of members of the Shiga toxin family for providing Shiga toxin effector functions (e.g. cellular internalization and cytotoxicity), and carboxy-terminal endoplasmic reticulum localization signal motifs. The presently disclosed proteins can comprise additional exogenous materials, such as, e.g., antigens, cytotoxic agents, and detection-promoting agents, and are capable of targeted delivery of these additional exogenous materials into the interiors of target cells. The proteins of the present invention have uses in methods such as, e.g., methods involving targeted killing of target cells, delivering exogenous materials into target cells, labeling subcellular compartments of target cells, and diagnosing and/or treating a variety of conditions including cancers, tumors, other growth abnormalities, immune disorders, and microbial infections.

Abstract: Provided in this disclosure are anti-CD38 binding domains, a composition comprising the anti-CD38 binding domains, nucleic acids encoding the anti-CD38 binding domains, and a method of using the anti-CD38 binding domains or the composition for treating multiple myeloma.

Abstract: The present invention provides cell-targeting molecules which can deliver a CD8+ T-cell epitope cargo to the MHC class I presentation pathway of a target cell. The cell-targeting molecules of the invention can be used to deliver virtually any CD8+ T-cell epitope from an extracellular space to the MHC class I pathway of a target cell, which may be a malignant cell and/or non-immune cell. The target cell can then display on a cell-surface the delivered CD8+ T-cell epitope complexed with MHC I molecule. The cell-targeting molecules of the invention have uses which include the targeted labeling and/or killing of specific cell-types within a mixture of cell-types, including within a chordate, as well as the stimulation of beneficial immune responses. The cell-targeting molecules of the invention have uses, e.g., in the treatment of a variety of diseases, disorders, and conditions, including cancers, tumors, growth abnormalities, immune disorders, and microbial infections.

Abstract: The present invention provides Shiga toxin A Subunit derived polypeptides, scaffolds, and cell-targeting molecules comprising amino acid substitutions which equip the molecules with site-specific positions (and often unique amino acid residues in the molecule) for linking other molecules while retaining Shiga toxin function(s), such as, e.g., efficient intracellular routing and/or potent cytotoxicity. The present invention also provides cell-targeting molecules, and/or components thereof, which comprise site-specific positions for linking other molecules, such as, e.g., agents that alters a property of the cell-targeting molecule or a cargo for delivery. Certain molecules comprising a polypeptide of the present invention exhibit reduced immunogenicity and/or are well-tolerated by mammals. The cell-targeting molecules of the present invention, and compositions thereof, have uses, e.g.

Abstract: The present disclosure relates to PD-L1-binding molecules comprising a Shiga toxin effector region, a PD-L1-binding region, and a T cell epitope, and pharmaceutical compositions thereof. The PD-L1 binding molecules and pharmaceutical compositions thereof have uses for selectively killing specific cells (e.g., PD-L1 positive tumor cells and/or immune cells), for selectively delivering cargos to specific cells (e.g., PD-L1 positive tumor cells or immune cells), and as therapeutics for treating or slowing the progression of cancer (e.g., non-small cell lung cancer or squamous cell carcinoma of the head and neck). The present disclosure also relates to clinical methods for use of the disclosed PD-L1 binding molecules for treating a subject in need thereof.

Abstract: The present invention relates to Shiga toxin A Subunit derived polypeptides and cell-targeting molecules comprising amino acid substitutions which equip the polypeptides with 1) de-immunization; 2) reduced, protease-cleavage sensitivity; and/or 3) a heterologous epitope cargo(s) while retaining Shiga toxin function(s), such as, e.g., potent cytotoxicity. Certain polypeptides of the invention exhibit reduced immunogenic potential in mammals and/or are capable of delivering an epitope to an MHC class molecule of a cell in which the polypeptide is present. Certain molecules comprising a polypeptide of the invention are well-tolerated by mammals while retaining one or more of the features mentioned above.