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.

Disclosed herein are therapeutic constructs including a delivery particle, at least one mitotic kinase inhibitor, and at least one immune checkpoint inhibitor. Also disclosed are therapeutic constructs including a mitotic kinase inhibitor, an immune checkpoint inhibitor, and a chemical linker. These therapeutic constructs cause cancer death by both therapeutic and immune effects and promote targeted delivery of more therapeutics to the surviving cancer cells in a positive feed-back loop. They enhance therapeutic index of free drugs and can be used intratumorally or systemically. This strategy can treat broad cancer types and is particular useful for cancer without obvious receptors for cancer-targeted delivery of otherwise toxic therapeutics.

An anti-MUC18 immunotoxin including an anti-MUC18 single-chain variable fragment (scFv) with a nucleotide sequence as set forth in SEQ ID No. 3, and a truncated Pseudomonas exotoxin A (PEA) with a nucleotide sequence as set forth in SEQ ID No. 5. The truncated PEA may be conjugated with the scFv through a connector.

Provided is a method of treating a tumor in an individual by neoadjuvant therapy, wherein the individual has not previously undergone a resection of the tumor, the method comprising administering an immunotoxin alone or an immune checkpoint inhibitor and an immunotoxin, such as D2C7-immunotoxin (D2C7-IT), followed by resection of the tumor. The method may further comprise administration of immune checkpoint inhibitor following resection.

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., for the selective delivery of cargos to target-expressing cells and as diagnostic and/or therapeutic molecules for the treatment of a variety of diseases, disorders, and conditions, which include genetic disorders, genetic predispositions, infections, cancers, tumors, growth abnormalities, and/or immune disorders.

The invention provides a Pseudomonas exotoxin A (PE) comprising an amino acid sequence having a substitution of one or more B-cell and/or T-cell epitopes. The invention further provides related chimeric molecules, as well as related nucleic acids, recombinant expression vectors, host cells, populations of cells, and pharmaceutical compositions. Methods of treating or preventing cancer in a mammal, methods of inhibiting the growth of a target cell, methods of producing the PE, and methods of producing the chimeric molecule are further provided by the invention.

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., for the selective delivery of cargos to target-expressing cells and as diagnostic and/or therapeutic molecules for the treatment of a variety of diseases, disorders, and conditions, which include genetic disorders, genetic predispositions, infections, cancers, tumors, growth abnormalities, and/or immune disorders.

Embodiments of near-infrared light-cleavable heptamethine cyanine-based conjugates, particularly targeting agent-drug conjugates, according to Formula I and conjugate precursors are disclosed. The disclosed targeting agent-drug conjugates are useful for targeted delivery and release of a drug. Methods of making and using the conjugates and precursors also are disclosed. ##STR00001##

The present invention relates to an antibody conjugating peptide including an amino acid having a photoreactive functional group, a physiologically active substance modified with the conjugating peptide, and an antibody conjugate having an antibody linked to the physiologically active substance. When the physiologically active substance modified with the conjugating peptide according to the present invention is linked to the antibody, the conjugation efficiency between the antibody and the physiologically active substance is remarkably improved as compared to that of the conventional art, and thus, the drug may be firmly bound without impairing the specificity of the antibody, thereby making it possible to accelerate commercialization of the antibody conjugate.

The present invention relates to conjugates, in particular antibody-drug conjugates and immunotoxins, having the formula I:
A-(L-D)p(I)
or a pharmaceutically acceptable salts or solvates thereof,
wherein:
A is an antibody that selectively binds FAP;
L is a linker;
D is a drug comprising a cytolysin or a Nigrin-b A-chain; and
p is 1 to 10, and to use of such conjugates in the therapeutic treatment of tumors. Methods of producing such conjugates and components for use in such methods are disclosed.