Provided herein are compounds, compositions, and methods for the treatment of diseases and disorders associated with cancer, including tubulysins and protein (e.g., antibody) drug conjugates thereof.

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 disclosure provides various linker units and molecular constructs, each of which has a targeting element and an effector element linked therewith. Methods for treating various diseases using such linker units and molecular constructs are also disclosed.

Antibody drug conjugates (ADC's) that bind to 191P4D12 protein and variants thereof are described herein. 191P4D12 exhibits tissue specific expression in normal adult tissue, and is aberrantly expressed in the cancers listed in Table I. Consequently, the ADC's of the invention provide a therapeutic composition for the treatment of cancer.

Antibody drug conjugates (ADC's) that bind to 191P4D12 protein and variants thereof are described herein. 191P4D12 exhibits tissue specific expression in normal adult tissue, and is aberrantly expressed in the cancers listed in Table I. Consequently, the ADC's of the invention provide a therapeutic composition for the treatment of cancer.

Provided is a broad-spectrum, efficient and anti-tumor anti-TRAILR2 antibody-toxin-conjugate (ADC, named Zapadcine-1(a, b, c, d) and Zapadcine-3(a, b, c, d, e)). Toxin with cytotoxic effect is linked to an anti-TRAILR2 humanized monoclonal antibody by means of a covalent bond by using disulfide bond bridging or conventional coupling technology and chemical linkers, so as to form an anti-TRAILR2 humanized antibody-toxin-conjugate. The ADC has the specificity of TRAILR2 positive tumors, and after conjugated to TRAILR2, the positive tumors can be endocytosed into lysosomes of tumor cells, and is degraded by means of proteases inside the lysosomes to release free micromolecule urotoxins, so that different TRAILR2 positive tumor cells are killed specifically, the tumor growth is suppressed, the tumor cells are even completely eliminated, and the tumor is cured.

The present invention provides antibodies useful as therapeutics for treating and/or preventing diseases associated with cells expressing CLD18, including tumor-related diseases such as gastric cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, colon cancer, hepatic cancer, head-neck cancer, and cancer of the gallbladder.

As an antitumor drug which is excellent in terms of antitumor effect and safety and has an excellent therapeutic effect, there is provided an antibody-drug conjugate in which an antitumor compound represented by the following formula is conjugated to an anti-HER2 antibody via a linker having a structure represented by the following formula: -L.sup.1-L.sup.2-L.sup.P-NH(CH.sub.2)n.sup.1-L.sup.a-(CH.sub.2)n.sup.2-C(O) wherein the anti-HER2 antibody is connected to the terminal L.sup.1, and the antitumor compound is connected to the carbonyl group of the (CH.sub.2)n.sup.2-C(O) moiety with the nitrogen atom of the amino group at position 1 as the connecting position.

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The present invention relates to therapeutic immunoconjugates comprising SN-38 attached to an antibody or antigen-binding antibody fragment. The antibody may bind to Trop-2 or CEACAM5 and the immunoconjugate may be administered at a dosage of between 4 mg/kg and 16 mg/kg, preferably 4, 6, 8, 9, 10, 12, or 16 mg/kg. When administered at specified dosages and schedules, the immunoconjugate can reduce solid tumors in size, reduce or eliminate metastases and is effective to treat cancers resistant to standard therapies, such as radiation therapy, chemotherapy or immunotherapy. Surprisingly, the immunoconjugate is effective to treat cancers that are refractory to or relapsed from irinotecan.

In various embodiments the invention provides anti-mucin-like protein (MLP) monoclonal antibodies, compositions and methods for detecting MLP as a biomarker for mucin-secreting type of cancer such as ovarian or pancreatic cancer.