A scoring method for an Anti-trop2 antibody drug conjugate therapy

Abstract

A method for predicting how a cancer patient will respond to an antibody drug conjugate (ADC) therapy involves computing a predictive response score by performing statistical operations on the staining of each cancer cell in a tissue sample. The ADC includes an ADC payload and an ADC antibody that targets the trophoblast antigen 2 (TROP2) protein in the cancer cells. The tissue sample is stained using a dye linked to a diagnostic antibody that binds to the protein. Cancer cells in digital images of tissue are detected. The statistical operations are performed for each cancer cell based on the staining intensities of the dye in the membrane and / or cytoplasm of each cancer cell and / or in the membranes of neighboring cancer cells. The response of the cancer patient to the ADC therapy is predicted based on whether the results of the statistical operations exceed various clinically derived thresholds.

Description

[0001] TROP2-403-PCT01-NP

[0002] A SCORING METHOD FOR AN ANTI-TROP2 ANTIBODY-DRUG CONJUGATE THERAPY

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004]

[0001] The present application claims the benefit of priority to U.S. Provisional Application No. 63 / 691,362, filed 06 September 2024; and 63 / 776,821, filed 24 March 2025, the content of which are hereby incorporated by references in its entirety for all purpose.

[0005] TECHNICAL FIELD

[0006]

[0002] The present disclosure relates to a method for computing a score indicative of how a cancer patient will respond to a therapy that uses an antibody-drug conjugate having a drug conjugated to an anti-TROP2 antibody via a linker structure.

[0007] BACKGROUND

[0008]

[0003] Assessing a cancer patient’s response probability to a given treatment is an essential step in determining a cancer patient’s treatment regimen. Such an assessment is often based on histological analysis of tissue samples from a cancer patient and involves identifying and classifying cancers using standard grading schemes by trained pathologists. Immunohistochemical (IHC) staining can be used to distinguish markerpositive cells that express a particular protein from marker-negative cells that do not express the protein. IHC staining typically involves multiple dyes, which includes one or more dyes connected to protein-specific antibodies and another dye that is a counterstain. A common counterstain is hematoxylin, which labels DNA and thus stains nuclei.

[0009]

[0004] A protein specific stain or biomarker can be used to identify the regions of the tissue of the cancer patient that are likely to exhibit a response to a predetermined therapy. For example, a biomarker that stains epithelial cells can help to identify the suspected tumor regions. Then other protein specific biomarkers are used to characterize the cells within the cancerous tissue. The cells stained by a specific biomarker can be identified and quantified, and subsequently a score indicating the number of positively stained cells and negatively stained cells can be visually estimated by pathologists. This score can then be compared to scores of other cancer TROP2-403-PCT01-NP patients that have been calculated in the same way. If the response of these other patients to a given cancer treatment is known, the pathologist can predict, based on a comparison of the score calculated for the cancer patient with the scores of the other patients, how likely the cancer patient is to respond to a given treatment. However, visual assessment by pathologists is prone to variability and subjectivity.

[0010]

[0005] One promising cancer treatment involves an antibody-drug conjugate (ADC) having a drug with cytotoxicity conjugated to an antibody, whose antigen is expressed on the surface of cancer cells. The ADC binds to the antigen and undergoes cellular internalization so as to deliver the drug selectively to cancer cells and to accumulate the drug within those cancer cells and kill them. Certain cytotoxic drug, such as deruxtecan (DXd) in datopotamab deruxtecan (Dato-DXd, also known as DS-1062), is known to have high membrane permeability, which is a favorable feature as a payload of ADC to be delivered not only to antibody target positive tumor cells, but also to target negative tumor cells nearby target positive tumor cells by passive diffusion, resulting in potential antitumor efficacy across tumors regardless of antigen expression and heterogeneity, an effect called the bystander antitumor effect. A computer-based method is sought for generating a repeatable and objective score indicating a cancer patient’s response to a treatment involving a therapeutic TROP2 antibody-drug conjugate.

[0011] SUMMARY

[0012]

[0006] According to an aspect of the present disclosure, a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) is described that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each TROP2-403-PCT01-NP cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0013]

[0007] According to a further aspect of the present disclosure, a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) is described that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0014]

[0008] According to a further aspect of the present disclosure, a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) is described that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a TROP2-403-PCT01-NP normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0015]

[0009] According to a further aspect of the present disclosure, a method of treating cancer is described comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and administering a therapy comprising the ADC to the cancer patient if the tissue sample is nmOD positive.

[0016]

[0010] According to a further aspect of the present disclosure, a method of treating cancer is described comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean TROP2-403-PCT01-NP optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and administering a therapy comprising the ADC to the cancer patient if the tissue sample is nmOD positive.

[0017]

[0011] According to a further aspect of the present disclosure, a method of treating cancer is described comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and administering a therapy comprising the ADC to the cancer patient if the tissue sample is nmOD positive.

[0018]

[0012] According to a further aspect of the present disclosure, a method of treating cancer is described comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, TROP2-403-PCT01-NP wherein the tissue sample was stained using a diagnostic antibody that binds to the protein in membranes and cytoplasm of cancer cells in the tissue sample, wherein for each cancer cell in a digital image of the tissue sample a mean optical density of membrane staining and a mean optical density of cytoplasm staining were determined, wherein for each cancer cell in the digital image a normalized membrane optical density (nmOD) was computed, and wherein the tissue sample was identified as nmOD positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold.

[0019]

[0013] According to a further aspect of the present disclosure, a method of treating cancer is described comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was stained using a diagnostic antibody that binds to the protein in membranes and cytoplasm of cancer cells in the tissue sample, wherein for each cancer cell in a digital image of the tissue sample a mean optical density of membrane staining and a mean optical density of cytoplasm staining were determined, wherein for each cancer cell in the digital image a normalized membrane optical density (nmOD) was computed, and wherein the tissue sample was identified as nmOD positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0020]

[0014] According to a further aspect of the present disclosure, a method of treating cancer is described comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was stained using a diagnostic antibody that binds to the TROP2-403-PCT01-NP protein in membranes and cytoplasm of cancer cells in the tissue sample, wherein for each cancer cell in a digital image of the tissue sample a mean optical density of membrane staining and a mean optical density of cytoplasm staining were determined, wherein for each cancer cell in the digital image a normalized membrane optical density (nmOD) was computed, and wherein the tissue sample was identified as nmOD positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0021]

[0015] According to a further aspect of the present disclosure, a method of treating cancer is described comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient is normalized membrane optical density (nmOD) positive.

[0022]

[0016] According to a further aspect of the present disclosure, a method of treating cancer is described comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient is normalized membrane optical density (nmOD) positive, wherein the tissue sample is normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample has nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60.

[0023]

[0017] According to a further aspect of the present disclosure, a method of treating cancer is described comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient is TROP2-403-PCT01-NP normalized membrane optical density (nmOD) positive, wherein the tissue sample is normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample has nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60.

[0018] According to a further aspect of the present disclosure, a method of treating cancer is described comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive.

[0019] According to a further aspect of the present disclosure, a method of treating cancer is described comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was determined to be normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0024]

[0020] According to a further aspect of the present disclosure, a method of treating cancer is described comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was determined to be normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample had TROP2-403-PCT01-NP nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0025]

[0021] According to a further aspect of the present disclosure, one or more non- transitory computer-readable storage media are described, storing instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0026]

[0022] According to a further aspect of the present disclosure, one or more non- transitory computer-readable storage media are described, storing instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining TROP2-403-PCT01-NP for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0027]

[0023] According to a further aspect of the present disclosure, one or more non- transitory computer-readable storage media are described, storing instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0028]

[0024] According to a further aspect of the present disclosure, a computer system is described comprising: one or more processors; and one or more non-transitory computer-readable media storing instructions which, when executed on the one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the TROP2-403-PCT01-NP protein is calcium signal transducer trophoblast antigen 2 (TR0P2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0029]

[0025] According to a further aspect of the present disclosure, a computer system is described comprising: one or more processors; and one or more non-transitory computer-readable media storing instructions which, when executed on the one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying TROP2-403-PCT01-NP the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0030]

[0026] According to a further aspect of the present disclosure, a computer system comprising: one or more processors; and one or more non-transitory computer- readable media storing instructions which, when executed on the one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0031]

[0027] According to a further aspect of the present disclosure, a computer program product is described comprising instructions which, when the program is executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound TROP2-403-PCT01-NP to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0032]

[0028] According to a further aspect of the present disclosure, a computer program product comprising instructions which, when the program is executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0033]

[0029] According to a further aspect of the present disclosure, a computer program product is described comprising instructions which, when the program is executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on TROP2-403-PCT01-NP cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0034]

[0030] According to a further aspect of the present disclosure, a computer- readable data carrier is described having stored thereon a computer program product as described herein.

[0035]

[0031] According to a further aspect of the present disclosure, a data carrier signal is described carrying a computer program product as described herein.

[0036]

[0032] Other embodiments and advantages are described in the detailed description below.

[0037] BRIEF DESCRIPTION OF THE DRAWINGS

[0038]

[0033] The accompanying drawings, where like numerals indicate like components, illustrate embodiments of the present disclosure.

[0039]

[0034] FIG. 1 shows: (A) determination of normalized membrane optical densities (nmOD) for individual cancer cells; (B) distribution plots of nmOD values for individual cancer cells in a tissue sample and selection of a percentage quantile (Q75); (C) a plot for determining whether tissue samples are biomarker positive (BM+) or biomarker negative (BM-) based on a nmOD threshold (cut-off).

[0040]

[0035] FIG. 2 shows a plot for the selection of different nmOD thresholds depending on the percentage quantile used. TROP2-403-PCT01-NP

[0041]

[0036] FIG. 3 shows a plot for p-values using various percentage quantiles.

[0037] FIG. 4 shows: (A) a plot for progression-free survival (PFS) in an intention-to-treat (ITT) patient population (N=604) and biomarker evaluable population (BEP) (N=352), treated with datopotamab deruxtecan (Dato-DXd) and docetaxel, in a full analysis set for patients with non-small cell lung cancer (NSCLC); (B) a plot for overall survival (OS) in an intention-to-treat (ITT) patient population (N=604) and biomarker evaluable population (BEP) (N=352), treated with datopotamab deruxtecan (Dato-DXd) and docetaxel, in a full analysis set for patients with NSCLC.

[0042]

[0038] FIG. 5 shows: (A) a plot for PFS in the full BEP cohort (N=352) of FIG. 4A treated with Dato-DXd and docetaxel, stratified into BM+ / BM-; (B) a plot for OS in the full BEP cohort (N=352) of FIG. 4B treated with Dato-DXd and docetaxel, stratified into BM+ / BM-.

[0043]

[0039] FIG. 6 shows: (A) a plot for PFS in an ITT patient population (N=370) and BEP (N=221), treated with datopotamab deruxtecan (Dato-DXd) and docetaxel, in a non-squamous (NSQ) without actionable genomic alterations (non- AGA) set for patients with NSCLC; (B) a plot for OS in an ITT patient population (N=370) and BEP (N=221), treated with datopotamab deruxtecan (Dato-DXd) and docetaxel, in a NSQ non-AGA set for patients with NSCLC.

[0044]

[0040] FIG. 7 shows: (A) a plot for PFS in the NSQ non-AGA BEP cohort (N=221) of FIG. 6 A treated with Dato-DXd and docetaxel, stratified into BM+ / BM-; (B) a plot for OS in the NSQ non-AGA BEP cohort (N=221) of FIG. 6B treated with Dato-DXd and docetaxel, stratified into BM+ / BM-.

[0045]

[0041] FIG. 8 shows: (A) a plot for PFS in an ITT patient population (N=98) and BEP (N=51), treated with datopotamab deruxtecan (Dato-DXd) and docetaxel, in a NSQ with actionable genomic alterations (AGA) set for patients with NSCLC; (B) a plot for OS in an ITT patient population (N=98) and BEP (N=51), treated with datopotamab deruxtecan (Dato-DXd) and docetaxel, in a NSQ AGA set for patients with NSCLC.

[0046]

[0042] FIG. 9 shows: (A) a plot for PFS in the NSQ AGA BEP cohort (N=51) of FIG. 8A treated with Dato-DXd and docetaxel, stratified into BM+ / BM-; (B) a plot for OS in the NSQ AGA BEP cohort (N=51) of FIG. 8B treated with Dato-DXd and docetaxel, stratified into BM+ / BM-. TROP2-403-PCT01-NP

[0047]

[0043] FIG. 10 shows: (A) a plot for PFS in an ITT patient population (N=136) and BEP (N=80), treated with datopotamab deruxtecan (Dato-DXd) and docetaxel, in a squamous (SQ) set for patients with NSCLC; (B) a plot for OS in an ITT patient population (N=136) and BEP (N=80), treated with datopotamab deruxtecan (Dato- DXd) and docetaxel, in a SQ set for patients with NSCLC.

[0048]

[0044] FIG. 11 shows: (A) a plot for PFS in the SQ BEP cohort (N=80) of FIG. 10A treated with Dato-DXd and docetaxel, stratified into BM+ / BM-; (B) a plot for OS in the SQ BEP cohort (N=80) of FIG. 10B treated with Dato-DXd and docetaxel, stratified into BM+ / BM-.

[0049]

[0045] FIG. 12 illustrates the anti-TROP2 antibody-drug conjugate datopotamab deruxtecan with four drug-linker units.

[0050]

[0046] FIG. 13 is a flowchart of steps by which an analysis system analyzes digital images of tissue from a cancer patient and predicts how the cancer patient will likely respond to a therapy using an anti-TROP2 antibody-drug conjugate; in particular, for predicting the response of a cancer patient to an ADC based on the normalized membrane optical density of each cancer cell.

[0051]

[0047] FIG. 14 is a schematic illustration of an exemplary computing system on which aspects described herein may be implemented.

[0052]

[0048] FIG. 15 shows a plot for PFS in a general BEP cohort (N=38) treated with Dato-DXd for patients with NSCLC.

[0053] DETAILED DESCRIPTION

[0054]

[0049] I. Definitions.

[0055]

[0050] To facilitate an understanding of the present disclosure, a number of terms and phrases are defined below. The term "cancer" is used to have the same meaning as that of the term "tumor". In the present disclosure, "TROP2" is synonymous with the calcium signal transducer trophoblast antigen 2 transmembrane protein. In the present disclosure, the term "TROP2 protein" is used in the same meaning as TROP2. The expression of the TROP2 protein can be detected using a method well known to those skilled in the art, such as immunohistochemistry (H4C) or immunofluorescence (IF).

[0056]

[0051] In the present disclosure, "anti-TROP2 antibody" means an antibody that specifically binds to TROP2. The anti-TROP2 antibody has an activity of binding to TROP2-403-PCT01-NP

[0057] TR0P2 and is thereby internalized into TROP2-expressing cells, such that after exhibiting the activity of binding to TR0P2, the antibody moves into the TR0P2 expressing cells. The anti-TROP2 antibody targets tumor cells, binds to the tumor cells, internalizes into the tumor cells, exhibits cytocidal activity against the tumor cells, and can be conjugated with a drug having antitumor activity via a linker to form an antibody-drug conjugate.

[0058]

[0052] An amino acid sequence of a heavy chain of an exemplary anti-TROP2 antibody may be represented by SEQ ID NO. 1. The heavy chain has the signal sequence (1-19), the variable region (20-140), and the constant region (141-470).

[0059]

[0053] An amino acid sequence of a light chain of an exemplary anti-TROP2 antibody may be presented by SEQ ID NO. 2. The light chain has the signal sequence (1-20), the variable region (21-129), and the constant region (130-234).

[0060]

[0054] An amino acid sequence of CDRH1 of an exemplary anti-TROP2 antibody may be represented by SEQ ID NO. 3, an amino acid sequence of CDRH2 of an exemplary anti-TROP2 antibody may be represented by SEQ ID NO. 4, and an amino acid sequence of CDRH3 of an exemplary anti-TROP2 antibody may be represented by SEQ ID NO. 5.

[0061]

[0055] An amino acid sequence of CDRL1 of an exemplary anti-TROP2 antibody may be represented by SEQ ID NO. 6, an amino acid sequence of CDRL2 (SAS) of an exemplary anti-TROP2 antibody may be represented by SEQ ID NO. 7, and an amino acid sequence of CDRL3 of an exemplary anti-TROP2 antibody may be represented by SEQ ID NO. 8.

[0062]

[0056] An amino acid sequence of a heavy chain variable region of an exemplary anti-TROP2 antibody may be represented by SEQ ID NO: 9, and an amino acid sequence of a light chain variable region of an exemplary anti-TROP2 antibody may be represented by SEQ ID NO. 10. An amino acid sequence of another heavy chain of an exemplary anti-TROP2 antibody may be represented by SEQ ID NO. 11.

[0063]

[0057] In one embodiment, an anti-TROP2 antibody of the anti-TROP2 antibodydrug conjugate used in the present disclosure is an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence represented by SEQ ID NO. 3 (an amino acid sequence consisting of amino acid residues 50 through 54 of SEQ ID NO. 1), CDRH2 consisting of an amino acid sequence represented by SEQ ID NO. 4 (an amino acid sequence consisting of amino acid residues 69 through 85 of TROP2-403-PCT01-NP

[0064] SEQ ID NO. 1) and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO. 5 (an amino acid sequence consisting of amino acid residues 118 through 129 of SEQ ID NO. 1), and a light chain comprising CDRL1 consisting of an amino acid sequence represented by SEQ ID NO. 6 (an amino acid sequence consisting of amino acid residues 44 through 54 of SEQ ID NO. 2), CDRL2 consisting of an amino acid sequence represented by SEQ ID NO. 7 (an amino acid sequence consisting of amino acid residues 70 to 76 of SEQ ID NO. 2) and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO. 8 (an amino acid sequence consisting of amino acid residues 109 through 117 of SEQ ID NO. 2), and in a specific embodiment, an antibody comprising a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO. 9 (an amino acid sequence consisting of amino acid residues 20 through 140 of SEQ ID NO. 1) and a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO. 10 (an amino acid sequence consisting of amino acid residues 21 through 129 of SEQ ID NO. 2). In other specific embodiments, the antibody comprises a heavy chain consisting of an amino acid sequence represented by SEQ ID NO. 11 (an amino acid sequence consisting of amino acid residues 20 through 469 of SEQ ID NO. 1) and a light chain consisting of an amino acid sequence represented by amino acid residues 21-234 of SEQ ID NO. 2. In other embodiments, the antibody comprises a heavy chain consisting of an amino acid sequence represented by amino acid residues 20-470 of SEQ ID NO. 1 and a light chain consisting of an amino acid sequence represented by amino acid residues 21-234 of SEQ ID NO. 2.

[0065]

[0058] In the present disclosure, the term "QCS Positive" (QCS+) refers to cancer that is likely to show a response to an anti-TROP2 ADC therapy. The term "QCS Negative" (QCS-) refers to cancer that is unlikely to show a response to an anti- TROP2 ADC therapy. The acronym QCS stands for Quantitative Continuous Score. The result of the novel predictive method of the present disclosure is generally referred to as a Quantitative Continuous Score and may be a response score, a treatment score or an indication of predicted survival time. The QCS score is obtained by performing statistical operations on all of the single-cell ADC scores obtained for a patient. Applying a predetermined threshold to the QCS scores discriminates between “QCS Positive” and “QCS Negative” patients. Stratifying the cancer patients into the QCS Positive and QCS Negative groups enables the TROP2-403-PCT01-NP identification of those QCS+ patients who likely benefit from the therapy which involves the ADC.

[0066]

[0059] II. The anti- TROP2 antibody-drug conjugate.

[0067]

[0060] An exemplary antibody-drug conjugate used in the present disclosure is an antibody-drug conjugate in which a drug-linker represented by the following formula:

[0061] [Formula 1]

[0068]

[0062] wherein A represents the connecting position to an antibody and is conjugated to an anti-TROP2 antibody via a thioether bond.

[0069]

[0063] In the present disclosure, the partial structure consisting of a linker and a drug in the antibody-drug conjugate is referred to as a "drug-linker". The drug-linker is connected to a thiol group (in other words, the sulfur atom of a cysteine residue) formed at an interchain disulfide bond site (two sites between heavy chains, and two sites between a heavy chain and a light chain) in the antibody.

[0070]

[0064] The drug-linker of the present disclosure may include exatecan (IUPAC name: (lS,9S)-l-amino-9-ethyl-5-fluoro-l,2,3,9,12,15-hexahydro-9-hydroxy-4- methyl-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-10,13-dione, (also expressed as chemical name: (lS,9S)-l-amino-9-ethyl-5-fluoro-2,3-dihydro-9- hydroxy-4-methyl-lH,12H-benzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin- 10,13(9H,15H)-dione)), which is a topoisomerase I inhibitor, as a component. Exatecan is a camptothecin derivative having an antitumor effect, represented by the following formula:

[0071]

[0065] [Formula 2] TROP2-403-PCT01-NP

[0072]

[0066] An exemplary anti-TROP2 antibody-drug conjugate used in the present disclosure can be also represented by the following formula:

[0073]

[0067] [Formula 3]

[0074]

[0068] Here, the drug-linker is conjugated to an anti-TROP2 antibody (‘Antibody- ’) via a thioether bond. The meaning of n is the same as that of what is called the average number of conjugated drug molecules (DAR; Drug-to- Antibody Ratio), and indicates the average number of units of the drug-linker conjugated per antibody molecule.

[0075]

[0069] FIG. 12 illustrates a particular anti-TROP2 antibody-drug conjugate datopotamab deruxtecan (DS-1062), with four drug-linker units designated as “DL”. The datopotamab portion of datopotamab deruxtecan shown in FIG. 12 is humanized anti-TROP2 IgGl mAb, wherein IgGl indicates the isotype of the anti-TROP2 antibody.

[0076]

[0070] After migrating into cancer cells, the particular anti-TROP2 antibody-drug conjugate used in the present disclosure is cleaved at the linker portion to release a compound represented by the following formula:

[0071] [Formula 4] TROP2-403-PCT01-NP

[0077]

[0072] The compound shown above is the primary source of antitumor activity of the particular anti-TROP2 antibody-drug conjugate used in the present disclosure, and has a topoisomerase I inhibitory effect.

[0078]

[0073] The particular anti-TROP2 antibody-drug conjugate used in the present disclosure also has a bystander effect in which the anti-TROP2 antibody-drug conjugate is internalized into cancer cells that express the target protein TROP2, and the compound shown above then also exerts an antitumor effect on neighboring cancer cells that do not express the target protein TROP2.

[0079]

[0074] III. The anti-TROP2 antibody in the antibody-drug conjugate.

[0080]

[0075] The anti-TROP2 antibody in the antibody-drug conjugate used in the present disclosure may be derived from any species and is, in a specific embodiment, an antibody derived from a human, a rat, a mouse, or a rabbit. In one specific embodiment, in cases when the antibody is derived from species other than human species, it is chimerized or humanized using a well known technique. The antibody of the present disclosure may be a polyclonal antibody or a monoclonal antibody and, in a particular embodiment, is a monoclonal antibody.

[0081]

[0076] In a specific embodiment, the antibody in the antibody-drug conjugate used in the present disclosure is an antibody having the characteristic of being able to target cancer cells, and is, in one specific embodiment, an antibody possessing, for example, the property of being able to recognize a cancer cell, the property of being able to bind to a cancer cell, the property of being internalized in a cancer cell, and / or cytocidal activity against cancer cells.

[0082]

[0077] The binding activity of the antibody against cancer cells can be confirmed using flow cytometry. The internalization of the antibody into tumor cells can be confirmed using (1) an assay of visualizing an antibody incorporated in cells under a TROP2-403-PCT01-NP fluorescence microscope using a secondary antibody (fluorescently labeled) binding to the therapeutic antibody (Cell Death and Differentiation (2008) 15, 751-761), (2) an assay of measuring a fluorescence intensity incorporated in cells using a secondary antibody (fluorescently labeled) binding to the therapeutic antibody (Molecular Biology of the Cell, Vol. 15, 5268-5282, December 2004), or (3) a Mab-ZAP assay using an immunotoxin binding to the therapeutic antibody wherein the toxin is released upon incorporation into cells to inhibit cell growth (Bio Techniques 28: 162- 165, January 2000). As the immunotoxin, a recombinant complex protein of a diphtheria toxin catalytic domain and protein G may be used.

[0083]

[0078] The antitumor activity of the antibody can be confirmed in vitro by determining inhibitory activity against cell growth. For example, a cancer cell line overexpressing a target protein for the antibody is cultured, and the antibody is added at varying concentrations into the culture system to determine inhibitory activity against focus formation, colony formation, and spheroid growth. The antitumor activity can be confirmed in vivo, for example, by administering the antibody to a nude mouse with a transplanted cancer cell line highly expressing the target protein, and determining changes in the cancer cells.

[0084]

[0079] Since the compound conjugated in the antibody-drug conjugate exerts an antitumor effect, in one embodiment, the antibody itself should have an antitumor effect. For the purpose of specifically and selectively exerting the cytotoxic activity of the antitumor compound against cancer cells, in one specific embodiment, the antibody should have the property of being internalized to migrate into cancer cells.

[0080] The antibody in the antibody-drug conjugate used in the present disclosure can be obtained by a procedure known in the art. For example, the antibody of the present disclosure can be obtained using a method usually carried out in the art, which involves immunizing animals with an antigenic polypeptide and collecting and purifying antibodies produced in vivo. The origin of the antigen is not limited to humans, and the animals may be immunized with an antigen derived from a nonhuman animal such as a mouse, a rat and the like. In this case, the cross-reactivity of antibodies binding to the obtained heterologous antigen with human antigens can be tested to screen for an antibody applicable to a human disease.

[0085]

[0081] Alternatively, antibody -producing cells which produce antibodies against the antigen can be fused with myeloma cells according to a method known in the art TROP2-403-PCT01-NP

[0086] (for example, Kohler and Milstein, Nature (1975) 256, p.495-497; Kennet, R. ed., Monoclonal Antibodies, p.365-367, Plenum Press, N.Y. (1980)), to establish hybridomas, from which monoclonal antibodies can in turn be obtained.

[0087]

[0082] The antigen can be obtained by genetically engineering host cells to produce a gene encoding the antigenic protein. Specifically, vectors that permit expression of the antigen gene are prepared and transferred to host cells so that the gene is expressed. The antigen thus expressed can be purified. The antibody can also be obtained by a method of immunizing animals with the above-described genetically engineered antigen-expressing cells or a cell line expressing the antigen.

[0088]

[0083] In one specific embodiment, the antibody in the antibody-drug conjugate used in the present disclosure is a recombinant antibody obtained by artificial modification for the purpose of decreasing heterologous antigenicity to humans such as a chimeric antibody or a humanized antibody, or is an antibody having only the gene sequence of an antibody derived from a human, that is, a human antibody.

[0089] These antibodies can be produced using a known method.

[0090]

[0084] As the chimeric antibody, an antibody in which antibody variable and constant regions are derived from different species, for example, a chimeric antibody in which a mouse- or rat-derived antibody variable region is connected to a human- derived antibody constant region can be exemplified (Proc. Natl. Acad. Sci. USA, 81, 6851-6855, (1984)).

[0091]

[0085] As the humanized antibody, an antibody obtained by integrating only the complementarity determining region (CDR) of a heterologous antibody into a human- derived antibody (Nature (1986) 321, pp. 522-525), an antibody obtained by grafting a part of the amino acid residues of the framework of a heterologous antibody as well as the CDR sequence of the heterologous antibody to a human antibody by a CDR- grafting method (WO 90 / 07861), and an antibody humanized using a gene conversion mutagenesis strategy (U.S. Patent No. 5821337) can be exemplified.

[0092]

[0086] As the human antibody, an antibody generated by using a human antibodyproducing mouse having a human chromosome fragment including genes of a heavy chain and light chain of a human antibody (see Tomizuka, K. et al., Nature Genetics (1997) 16, p.133-143; Kuroiwa, Y. et. al., Nucl. Acids Res. (1998) 26, p.3447-3448; Yoshida, H. et. al., Animal Cell Technology: Basic and Applied Aspects vol.10, p.69- 73 (Kitagawa, Y., Matsuda, T. and lijima, S. eds.), Kluwer Academic Publishers, TROP2-403-PCT01-NP

[0093] 1999; Tomizuka, K. et. al., Proc. Natl. Acad. Sci. USA (2000) 97, p.722-727, etc.) can be exemplified. As an alternative, an antibody obtained by phage display, the antibody being selected from a human antibody library (see Wormstone, I. M. et. al, Investigative Ophthalmology & Visual Science. (2002) 43 (7), p.2301-2308; Carmen, S. et. al., Briefings in Functional Genomics and Proteomics (2002), 1 (2), p.189-203; Siriwardena, D. et. al., Ophthalmology (2002) 109 (3), p.427-431, etc.) can be exemplified.

[0094]

[0087] In the antibody in the antibody-drug conjugate used in present disclosure, modified variants of the antibody are also included. The modified variant refers to a variant obtained by subjecting the antibody according to the present disclosure to chemical or biological modification. Examples of the chemically modified variant include variants including a linkage of a chemical moiety to an amino acid skeleton, variants including a linkage of a chemical moiety to an N-linked or O-linked carbohydrate chain, etc. Examples of the biologically modified variant include variants obtained by post-translational modification (such as N-linked or O-linked glycosylation, N- or C-terminal processing, deamidation, isomerization of aspartic acid, or oxidation of methionine), and variants in which a methionine residue has been added to the N terminus by being expressed in a prokaryotic host cell. Further, an antibody labeled so as to enable the detection or isolation of the antibody or an antigen according to the present disclosure, for example, an enzyme-labeled antibody, a fluorescence-labeled antibody, and an affinity-labeled antibody are also included in the meaning of the modified variant. Such a modified variant of the antibody according to the present disclosure is useful for improving the stability and blood retention of the antibody, reducing the antigenicity thereof, detecting or isolating an antibody or an antigen, and so on.

[0095]

[0088] Further, by regulating the modification of a glycan which is linked to the antibody according to the present disclosure (glycosylation, defucosylation, etc.), it is possible to enhance antibody-dependent cellular cytotoxic activity. As the technique for regulating the modification of a glycan of antibodies, International Publication No. WO 99 / 54342, International Publication No. WO 00 / 61739, International Publication No. WO 02 / 31140, International Publication No. WO 2007 / 133855, International Publication No. WO 2013 / 120066, etc. are known. However, the technique is not limited thereto. In the antibody according to the present disclosure, antibodies in TROP2-403-PCT01-NP which the modification of a glycan is regulated are also included.

[0096]

[0089] It is known that a lysine residue at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell is deleted (Journal of Chromatography A, 705: 129-134 (1995)), and it is also known that two amino acid residues (glycine and lysine) at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell are deleted and a proline residue newly located at the carboxyl terminus is amidated (Analytical Biochemistry, 360: 75- 83 (2007)). However, such deletion and modification of the heavy chain sequence do not affect the antigen-binding affinity and the effector function (complement activation, antibody-dependent cellular cytotoxicity, etc.) of the antibody. Therefore, in the antibody according to the present disclosure, antibodies subjected to such modification and functional fragments of the antibody are also included, and deletion variants in which one or two amino acids have been deleted at the carboxyl terminus of the heavy chain, variants obtained by amidation of the deletion variants (for example, a heavy chain in which the carboxyl terminal proline residue has been amidated) and the like are also included. The type of deletion variant having a deletion at the carboxyl terminus of the heavy chain of the antibody according to the present disclosure is not limited to the above variants as long as the antigen-binding affinity and the effector function are conserved. The two heavy chains constituting the antibody according to the present disclosure may be of one type selected from the group consisting of a full-length heavy chain and the above-described deletion variant, or may be of two types in combination selected therefrom. The ratio of the amount of each deletion variant can be affected by the type of cultured mammalian cells that produce the antibody according to the present disclosure and the culture conditions; however, in a specific embodiment, an antibody in which one amino acid residue at the carboxyl terminus has been deleted in both of the two heavy chains in the antibody according to the present disclosure can be exemplified.

[0097]

[0090] As isotypes of the antibody according to the present disclosure, for example, IgG (IgGl, IgG2, IgG3, IgG4) can be exemplified. In one specific embodiment, IgGl or IgG2 can be exemplified.

[0098]

[0091] In the present disclosure, the term "anti-TROP2 antibody" refers to an antibody which binds specifically to TROP2 (TACSTD2: Tumor-associated calcium signal transducer 2; EGP-1), and has an activity of internalization in TROP2- TROP2-403-PCT01-NP expressing cells by binding to TR0P2 in one specific embodiment.

[0099]

[0092] Examples of the anti-TROP2 antibody include hTINAl-HILl (WO 2015 / 098099).

[0100]

[0093] IV. Producing the anti-TROP2 antibody-drug conjugate.

[0101]

[0094] A drug-linker intermediate for use in the production of the antibody-drug conjugate according to the present disclosure is represented by the following formula.

[0102]

[0095] [Formula s]

[0103]

[0096] The drug-linker intermediate can be expressed as the chemical name N-[6- (2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)hexanoyl]glycylglycyl-L-phenylalanyl-N-[(2- {[(lS,9S)-9-ethyl-5-fhioro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15- hexahydro-lH,12H-benzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-l-yl]amino}- 2-oxoethoxy)methyl]glycinamide, and can be produced with reference to descriptions in WO 2014 / 057687, WO 2015 / 098099, WO 2015 / 115091, WO 2015 / 155998, WO 2019 / 044947, and so on.

[0104]

[0097] The antibody-drug conjugate used in the present disclosure can be produced by reacting the above-described drug-linker intermediate and an anti- TROP2 antibody having a thiol group (alternatively referred to as a sulfhydryl group).

[0098] The anti-TROP2 antibody having a sulfhydryl group can be obtained by a method well known in the art (Hermanson, G. T, Bioconjugate Techniques, pp. 56- 136, pp. 456-493, Academic Press (1996)). For example, by using 0.3 to 3 molar equivalents of a reducing agent such as tris(2-carboxyethyl)phosphine hydrochloride (TCEP) per interchain disulfide within the antibody and reacting with the antibody in a buffer solution containing a chelating agent such as ethylenediamine tetraacetic acid TROP2-403-PCT01-NP

[0105] (EDTA), an antibody having a sulfhydryl group with partially or completely reduced interchain disulfides within the antibody can be obtained.

[0106]

[0099] Further, by using 2 to 20 molar equivalents of the drug-linker intermediate per the antibody having a sulfhydryl group, an antibody-drug conjugate in which 2 to 8 drug molecules are conjugated per antibody molecule can be produced.

[0107]

[0100] The average number of conjugated drug molecules per antibody molecule of the antibody-drug conjugate produced can be determined, for example, by a method of calculation based on measurement of UV absorbance for the antibodydrug conjugate and the conjugation precursor thereof at two wavelengths of 280 nm and 370 nm (UV method), or a method of calculation based on quantification through HPLC measurement for fragments obtained by treating the antibody-drug conjugate with a reducing agent (HPLC method).

[0108]

[0101] Conjugation between the antibody and the drug-linker intermediate and calculation of the average number of conjugated drug molecules per antibody molecule of the antibody-drug conjugate can be performed with reference to descriptions in WO 2015 / 098099 and WO 2017 / 002776, for example.

[0109]

[0102] In the present disclosure, the term "anti-TROP2 antibody-drug conjugate" refers to an antibody-drug conjugate such that the antibody in the antibody-drug conjugate according to the disclosure is an anti-TROP2 antibody.

[0110]

[0103] In one specific embodiment, the anti-TROP2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 3 [= an amino acid sequence consisting of amino acid residues 50 to 54 of SEQ ID NO: 1], CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 4 [= an amino acid sequence consisting of amino acid residues 69 to 85 of SEQ ID NO: 1], and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 5 [= an amino acid sequence consisting of amino acid residues 118 to 129 of SEQ ID NO: 1], and a light chain comprising CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 6 [= an amino acid sequence consisting of amino acid residues 44 to 54 of SEQ ID NO: 2], CDRL2 consisting of an amino acid sequence represented by SEQ ID NO: 7 [= an amino acid sequence consisting of amino acid residues 70 to 76 of SEQ ID NO: 2], and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 8 [= an amino acid sequence consisting of amino acid residues 109 to 117 of SEQ ID NO: TROP2-403-PCT01-NP

[0111] 2]; in a further specific embodiment, an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 9 [= an amino acid sequence consisting of amino acid residues 20 to 140 of SEQ ID NO: 1], and a light chain comprising a light chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 10 [= an amino acid sequence consisting of amino acid residues 21 to 129 of SEQ ID NO: 2]; and in an even further specific embodiment, an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 12 [= an amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 1] and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 13 [= amino acid residues 21 to 234 of SEQ ID NO: 2], or an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 11 [= an amino acid sequence consisting of amino acid residues 20 to 469 of SEQ ID NO: 1] and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 13 [= amino acid residues 21 to 234 of SEQ ID NO: 2],

[0112]

[0104] In one specific embodiment, the average number of units of the druglinker conjugated per antibody molecule in the anti-TROP2 antibody-drug conjugate is 2 to 8; in a further specific embodiment, 3 to 5; in an even further specific embodiment, 3.5 to 4.5; and in an even further specific embodiment, about 4.

[0113]

[0105] The anti-TROP2 antibody-drug conjugate can be produced with reference to descriptions in WO 2015 / 098099 and WO 2017 / 002776.

[0114]

[0106] In specific embodiments, the anti-TROP2 antibody-drug conjugate is selected from the group consisting of: sacituzumab govitecan (Trodelvy®), sacituzumab tirumotecan (SKB264 / MK-2870) and datopotamab deruxtecan (DS- 1062); optionally wherein the ADC is datopotamab deruxtecan (DS-1062).

[0115]

[0107] V. Therapeutic use of the anti-TROP2 ADC.

[0116]

[0108] The antibody-drug conjugate of the present disclosure can be used for treating cancer. In one embodiment, the cancer is selected from group consisting of: lung cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, bladder cancer, and uterine cancer. In a specific embodiment, the cancer is lung cancer. In a further specific embodiment, the cancer is non-small cell lung cancer (e.g. non-squamous TROP2-403-PCT01-NP non-small cell lung cancer or squamous non-small cell lung cancer), including nonsmall cell lung cancer with actionable genomic alterations and non-small cell lung cancer without actionable genomic alterations, wherein the actionable genomic alterations include EGFR, ALK, ROS1, NTRK, BRAF, RET, and MET exon 14 skipping (i.e. non-small cell lung cancer without actionable genomic alterations may exclude EGFR, ALK, ROS1, NTRK, BRAF, RET, and MET exon 14 skipping). In one embodiment, the antibody-drug conjugate can be used for treating non-squamous non-small cell lung cancer without actionable genomic alterations (e.g. excluding EGFR, ALK, ROS1, NTRK, BRAF, RET, and MET exon 14 skipping). In another embodiment, the antibody-drug conjugate can be used for treating non-squamous non- small cell lung cancer with actionable genomic alterations (e.g. wherein the actionable genomic alteration is selected from EGFR, ALK, ROS1, NTRK, BRAF, RET, and MET exon 14 skipping). Furthermore, in one specific embodiment, the antibody-drug conjugate of the present disclosure can be used for treating cancer that is deficient in Homologous Recombination (HR) dependent DNA DSB repair activity, or cancer that is not deficient in Homologous Recombination (HR) dependent DNA DSB repair activity.

[0117]

[0109] In one specific embodiment, the antibody-drug conjugate of the present disclosure can be used for mammals; and in a further specific embodiment, can be used for humans.

[0118]

[0110] The antitumor effect of the antibody-drug conjugate of the present disclosure can be confirmed by, for example, generating a model in which cancer cells are transplanted to a test animal, and measuring reduction in tumor volume, lifeprolonging effects due to applying the antibody-drug conjugate of the present disclosure.

[0119]

[0111] In addition, the antitumor effect of the antibody-drug conjugate of the present disclosure can be confirmed, in a clinical study, with the Response Evaluation Criteria in Solid Tumors (RECIST) evaluation method, WHO's evaluation method, Macdonald's evaluation method, measurement of body weight, and other methods; and can be determined by indicators such as Complete response (CR), Partial response (PR), Progressive disease (PD), Objective response rate (ORR), Duration of response (DoR), Progression-free survival (PFS), and Overall survival (OS).

[0120]

[0112] The antibody-drug conjugate of the present disclosure can retard TROP2-403-PCT01-NP growth of cancer cells, suppress their proliferation, and further can kill cancer cells. These effects can allow cancer patients to be free from symptoms caused by cancer or can achieve an improvement in the QOL of cancer patients and attain a therapeutic effect by sustaining the lives of the cancer patients. Even if the antibody-drug conjugate does not accomplish the killing of cancer cells, it can achieve higher quality of life (QOL) of cancer patients while achieving longer-term survival, by inhibiting or controlling the growth of cancer cells.

[0121]

[0113] The antibody-drug conjugate of the present disclosure can be expected to exert a therapeutic effect by application as systemic therapy to patients, and additionally, by local application to cancer tissues.

[0122]

[0114] The antibody-drug conjugate of the present disclosure, in another aspect, provides for use as an adjunct in cancer therapy with ionizing radiation or at least one additional therapeutic agent, such as immune checkpoint inhibitors or other chemotherapeutic agents. For example, in the treatment of cancer, the treatment may comprise administering to a subject in need of treatment a therapeutically-effective amount of the antibody-drug conjugate, simultaneously or sequentially with the ionizing radiation or at least one additional therapeutic agent, such as immune checkpoint inhibitors or other chemotherapeutic agents.

[0123]

[0115] Suitable immune checkpoint inhibitors may block the activity of PD-1 or PD-L1. Non-limiting examples of immune checkpoint inhibitors include pembrolizumab, durvalumab, nivolumab, or combinations thereof. In particular, the immune checkpoint inhibitor may be durvalumab.

[0124]

[0116] Suitable chemotherapeutic agents include platinum-based chemotherapeutic agents. Non-limiting examples of platinum-based chemotherapeutic agents include cisplatin, carboplatin, oxaliplatin, nedaplatin, or combinations thereof. In particular, the platinum-based chemotherapeutic agent may be carboplatin.

[0125]

[0117] Where at least one additional therapeutic agent is used, in some embodiments, the antibody-drug conjugate and the at least one additional therapeutic agent may form part of the same medicament. In other embodiments, the antibodydrug conjugate and the at least one additional therapeutic agent may be provided as separate medicaments. The separate medicaments may be for administration in combination, or may be for administration sequentially. TROP2-403-PCT01-NP

[0126]

[0118] The antibody-drug conjugate of the present disclosure can be used as adjuvant chemotherapy combined with surgery operation. The antibody-drug conjugate of the present disclosure may be administered for the purpose of reducing tumor size before surgical operation (referred to as preoperative adjuvant chemotherapy or neoadjuvant therapy), or may be administered for the purpose of preventing recurrence of tumor after surgical operation (referred to as postoperative adjuvant chemotherapy or adjuvant therapy).

[0127]

[0119] In further aspects, the antibody-drug conjugate of the present disclosure may be used for the treatment of cancer which is deficient in Homologous Recombination (HR) dependent DNA DSB repair activity. The HR dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA via homologous mechanisms to reform a continuous DNA helix (K.K. Khanna and S.P. Jackson, Nat. Genet. 27(3): 247-254 (2001)). The components of the HR dependent DNA DSB repair pathway include, but are not limited to, ATM (NM_000051), RAD51 (NM_002875), RAD51L1 (NM_002877), RAD51C (NM_002876), RAD51L3 (NM_002878), DMC1 (NM_007068), XRCC2 (NM_005431), XRCC3 (NM_005432), RAD52 (NM_002879), RAD54L (NM_003579), RAD54B (NM_012415), BRCA1 (NM_007295), BRCA2 (NM_000059), RAD50 (NM_005732), MRE11 A (NM_005590) and NBS1 (NM_002485). Other proteins involved in the HR dependent DNA DSB repair pathway include regulatory factors such as EMSY (Hughes-Davies, et al., Cell, 115, pp523-535). HR components are also described in Wood, et al, Science, 291, 1284-1289 (2001). A cancer that is deficient in HR dependent DNA DSB repair may comprise or consist of one or more cancer cells which have a reduced or abrogated ability to repair DNA DSBs through that pathway, relative to normal cells, i.e., the activity of the HR dependent DNA DSB repair pathway may be reduced or abolished in the one or more cancer cells. The activity of one or more components of the HR dependent DNA DSB repair pathway may be abolished in the one or more cancer cells of an individual having a cancer which is deficient in HR dependent DNA DSB repair. Components of the HR dependent DNA DSB repair pathway are well characterised in the art (see for example, Wood, et al, Science, 291, 1284-1289 (2001)) and include the components listed above.

[0128]

[0120] In some embodiments, the cancer cells may have a BRCA1 and / or a TROP2-403-PCT01-NP

[0129] BRCA2 deficient phenotype, i.e., BRCA1 and / or BRCA2 activity is reduced or abolished in the cancer cells. Cancer cells with this phenotype may be deficient in BRCA1 and / or BRCA2, i.e., expression and / or activity of BRCA1 and / or BRCA2 may be reduced or abolished in the cancer cells, for example by means of mutation or polymorphism in the encoding nucleic acid, or by means of amplification, mutation or polymorphism in a gene encoding a regulatory factor, for example the EMSY gene which encodes a BRCA2 regulatory factor (Hughes-Davies, et al., Cell, 115, 523- 535). BRCA1 and BRCA2 are known tumor suppressors whose wild-type alleles are frequently lost in tumors of heterozygous carriers (Jasin M., Oncogene, 21(58), 8981- 93 (2002); Tutt, et al., Trends Mol Med., 8 (12), 571-6, (2002)). The association of BRCA1 and / or BRCA2 mutations with breast cancer is well-characterised in the art (Radice, P.J., Exp Clin Cancer Res., 21(3 Suppl), 9-12 (2002)). Amplification of the EMSY gene, which encodes a BRCA2 binding factor, is also known to be associated with breast and ovarian cancer. Carriers of mutations in BRCA1 and / or BRCA2 are also at elevated risk of certain cancers, including breast, ovary, pancreas, prostate, hematological, gastrointestinal and lung cancer. In some embodiments, the individual is heterozygous for one or more variations, such as mutations and polymorphisms, in BRCA1 and / or BRCA2 or a regulator thereof. The detection of variation in BRCA1 and BRCA2 is well-known in the art and is described, for example in EP 699 754, EP 705 903, Neuhausen, S.L. and Ostrander, E.A., Genet. Test, 1, 75-83 (1992);

[0130] Chappnis, P.O. and Foulkes, W.O., Cancer Treat Res, 107, 29-59 (2002); Janatova M., et al., Neoplasma, 50(4), 246-505 (2003); Jancarkova, N., Ceska GynekoL, 68{ 1), 11-6 (2003)). Determination of amplification of the BRCA2 binding factor EMSY is described in Hughes-Davies, et / ., Cell, 115, 523-535).

[0131]

[0121] Mutations and polymorphisms associated with cancer may be detected at the nucleic acid level by detecting the presence of a variant nucleic acid sequence or at the protein level by detecting the presence of a variant (i.e. a mutant or allelic variant) polypeptide.

[0132]

[0122] The antibody-drug conjugate of the present disclosure may be administered as a pharmaceutical composition containing at least one pharmaceutically suitable ingredient. The pharmaceutically suitable ingredient can be suitably selected and applied from formulation additives or the like that are generally used in the art, in accordance with the dosage, administration concentration or the like TROP2-403-PCT01-NP of the antibody-drug conjugate used in the present disclosure. For example, the antibody-drug conjugate used in the present disclosure can be administered as a pharmaceutical composition containing a buffer such as a histidine buffer, an excipient such as sucrose or trehalose, and a surfactant such as Polysorbate 80 or 20. In one specific embodiment, the pharmaceutical product containing the antibody-drug conjugate used in the present disclosure can be used as an injection; in a further specific embodiment, can be used as an aqueous injection or a lyophilized injection; and in an even further specific embodiment, can be used as a lyophilized injection.

[0123] In a specific embodiment, in the case that the pharmaceutical product containing the anti-TROP2 antibody-drug conjugate used in the present disclosure is an aqueous injection, it can be diluted with a suitable diluent and then given as an intravenous infusion. For the diluent, a dextrose solution, physiological saline, and the like, can be exemplified, and a dextrose solution can be exemplified in a specific embodiment, and a 5% dextrose solution can be exemplified in a further specific embodiment. In the case that the pharmaceutical product of the present disclosure is a lyophilized injection, it can be dissolved in water for injection in a specific embodiment, subsequently a required amount can be diluted with a suitable diluent and then given as an intravenous infusion. For the diluent, a dextrose solution, physiological saline, and the like, can be exemplified, and a dextrose solution can be exemplified in a specific embodiment, and a 5% dextrose solution can be exemplified in a further specific embodiment.

[0133]

[0124] Examples of the administration route which may be used to administer the pharmaceutical product of the present disclosure include intravenous, intradermal, subcutaneous, intramuscular, and intraperitoneal routes; and in a specific embodiment, include an intravenous route.

[0134]

[0125] The anti-TROP2 antibody-drug conjugate used in the present disclosure can be administered to a human once at intervals of 1 to 180 days; and, in a specific embodiment, can be administered once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks; and, in a further specific embodiment, can be administered once every 3 weeks. Also, the antibody-drug conjugate used in the present disclosure can be administered at a dose of about 0.001 to 100 mg / kg; and, in a specific embodiment, can be administered at a dose of 0.8 to 12.4 mg / kg. For example, the anti-TROP2 antibody-drug conjugate can be administered once every 3 TROP2-403-PCT01-NP weeks at a dose of 0.27 mg / kg, 0.5 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 4.0 mg / kg, 6.0 mg / kg, or 8.0 mg / kg; and, in a specific embodiment, can be administered once every 3 weeks at a dose of 6.0 mg / kg. Additional embodiments of anti-TROP2 antibody drug conjugates and the therapeutic use thereof are described in the international patent application PCT / JP2014 / 006421 (published as WO 2015 / 098099), the content of which is hereby incorporated by reference in its entirety for all purposes.

[0135]

[0126] VI. Method of predicting a patient response to an anti- TROP2 antibody-drug conjugate.

[0136]

[0127] FIG. 1 is an overview of how patient responses to an anti-TROP2 antibody-drug conjugate can be predicted. The normalized membrane optical densities are calculated by taking the mean optical density of staining of the membrane and dividing by the sum of the mean optical density of staining of the membrane plus the mean optical density of staining of the cytoplasm, as shown in FIG. 1 A. An appropriate percentage quantile value can be determined from the distribution of normalized membrane optical density values; illustrative right-skewed and left-skewed distributions with Q75 percentage quantiles are shown in FIG. IB. After choosing an appropriate percentage quantile value, a normalized membrane optical density threshold (cut-off) can be used to determine whether a tissue sample is biomarker positive (BM+) or biomarker negative (BM-); illustrative cut-off of <0.5585 with Q75 percentage quantiles is shown in FIG. 1C, with Cases A and B being determined to be BM+ and Cases C and D being determined to be BM-.

[0128] FIG. 13 is a flowchart of steps 11-17 of a method 10 by which an analysis system analyzes a digital image of tissue from a cancer patient and predicts how the cancer patient will likely respond to a therapy involving an anti-TROP2 antibody-drug conjugate (ADC). The method predicts the response to an ADC of a patient having lung cancer, in particular non-small cell lung cancer (e.g. non- squamous non-small cell lung cancer). In one embodiment, the ADC is datopotamab deruxtecan (DS-1062).

[0137]

[0129] In step 11, a digital image is acquired of a tissue slice from the cancer patient that has been stained via an immunohistochemistry (IHC) staining method, e.g., using a dye linked to a diagnostic antibody that targets the same protein as that targeted by the ADC therapy, in this case the TROP2 protein. To predict the efficacy of the ADC therapy, a diagnostic antibody (e.g., a diagnostic biomarker) with an TROP2-403-PCT01-NP attached dye is used that targets the same protein as that targeted by the ADC therapy. In one embodiment, the anti-TROP2 ADC therapy to which the scoring is directed is an anti-TROP2 antibody conjugated to a drug-linker via a thioether bond, wherein the drug-linker is represented by the formula:

[0138]

[0131] wherein “Antibody-” represents the position at which the anti-TROP2 antibody is connected. In one embodiment, the anti-TROP2 ADC to which the scoring is directed is datopotamab deruxtecan (DS-1062). Thus, in various embodiments, the diagnostic biomarker also targets the TROP2 protein.

[0139]

[0132] In step 12, image analysis is performed on the digital image to generate image objects of cancer cells, cell membranes and cytoplasm objects. A pretrained convolutional neural network processes a digital image of tissue of the cancer patient that has been stained with the diagnostic antibody linked to the dye, such as 3,3’- Diaminobenzidine (DAB). The staining intensity of the dye in the membrane of a cancer cell is determined based on the mean staining intensity of the dye of all pixels associated with the corresponding segmented membrane object. Moreover, the staining intensity of the dye in a single pixel is computed based on the red, green and blue color components of the pixel. The result of the image analysis processing provides, for each pixel in the digital image, the probability that the pixel belongs to a cell membrane and the probability that the pixel belongs to a cell cytoplasm. Suitable methods for generating these image objects are described in more detail in WO 2023 / 175483 Al.

[0140]

[0133] In step 13, the mean optical density (OD) of staining of the dye in the cell membrane is determined for each cancer cell.

[0141]

[0134] In step 14, the mean optical density (OD) of staining of the dye in the TROP2-403-PCT01-NP cytoplasm is determined for each cancer cell.

[0142]

[0135] In steps 13 and 14, where DAB is used as the dye, the amount of DAB can be determined by the staining intensity based on the mean (average) optical density of the brown diaminobenzidine (DAB) signal in all of the pixels of the membrane, or in all of the pixels of the cytoplasm, respectively.

[0143]

[0136] In step 15, the normalized membrane optical density for each cancer cell in the digital image is computed. The normalized membrane optical density equals the mean optical density of staining of the membrane divided by the sum of the mean optical density of staining of the membrane plus the mean optical density of staining of the cytoplasm.

[0144]

[0137] In step 16, a predicted response score is generated for the tissue sample based on a percentage quartile of cancer cells in the digital image that have normalized membrane optical density values equal to or less than a normalized membrane optical density threshold, or greater than the normalized membrane optical density threshold. The predicted response score is positive (in other words, the tissue sample is normalized membrane positive) if the percentage quartile of cancer cells in the tissue sample that are normalized membrane positive is equal to or less than the normalized membrane optical density threshold. The predicted response score is negative (in other words, the tissue sample is normalized membrane negative) if the percentage quartile of cancer cells in the tissue sample that are normalized membrane positive is greater than the normalized membrane optical density threshold.

[0145]

[0138] In step 17, the cancer patient is identified as one who will likely benefit from administration of the anti-TROP2 ADC if the predicted response score is positive (in other words, if the tissue sample is normalized membrane positive).

[0146]

[0139] VII. Methods of identifying cancer patients, methods of treating cancer and computer programs.

[0147]

[0140] The methods of predicting a patient response to an anti-TROP2 antibody-drug conjugate as described herein may be used in methods of identifying cancer patients and methods of treating cancer (or antibody drug conjugates for use in treating cancer, or uses of antibody drug conjugates in the manufacture of a medicament for treating cancer).

[0148]

[0141] Thus, in one embodiment, a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) is described that includes an ADC TROP2-403-PCT01-NP payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), and wherein the cancer patient has non-squamous non-small cell lung cancer, comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0142] In another embodiment, a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) is described that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0149]

[0143] In another embodiment, a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) is described that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the TROP2-403-PCT01-NP protein is calcium signal transducer trophoblast antigen 2 (TR0P2), and wherein the cancer patient has non-squamous non-small cell lung cancer, comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0150]

[0144] In some cases, a stained tissue sample from the cancer patient and analysis of the stained tissue sample has not yet been conducted.

[0151]

[0145] Thus, in one embodiment, a method of treating cancer is described comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and administering a therapy comprising the ADC to the cancer patient if the tissue sample is nmOD positive.

[0146] In another embodiment, a method of treating cancer is described TROP2-403-PCT01-NP comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), the method comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and administering a therapy comprising the ADC to the cancer patient if the tissue sample is nmOD positive.

[0152]

[0147] In another embodiment, a method of treating cancer is described comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and administering a therapy comprising the ADC to the cancer patient if the tissue sample is nmOD positive. TROP2-403-PCT01-NP

[0153]

[0148] In another embodiment, an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell for use in a method of treating non-squamous non-small cell lung cancer comprising administering to a cancer patient the antibody drug conjugate (ADC) is described, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and administering a therapy comprising the ADC to the cancer patient if the tissue sample is nmOD positive.

[0154]

[0149] In another embodiment, an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell for use in a method of treating cancer comprising administering to a cancer patient the antibody drug conjugate (ADC) is described, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and administering a therapy comprising the ADC to the cancer patient TROP2-403-PCT01-NP if the tissue sample is nmOD positive.

[0155]

[0150] In another embodiment, an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell for use in a method of treating non-squamous non-small cell lung cancer comprising administering to a cancer patient the antibody drug conjugate (ADC) is described, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and administering a therapy comprising the ADC to the cancer patient if the tissue sample is nmOD positive.

[0156]

[0151] In another embodiment, a use of an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell in the manufacture of a medicament for the treatment of non-squamous non-small cell lung cancer is described, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), wherein a tissue sample obtained from the cancer patient is determined to be normalized membrane optical density (nmOD) positive using a method comprising: staining the tissue sample immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density

[0157] (nmOD) for each cancer cell in the digital image; and identifying the tissue sample as TROP2-403-PCT01-NP nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold.

[0158]

[0152] In another embodiment, a use of an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell in the manufacture of a medicament for the treatment of cancer is described, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), wherein a tissue sample obtained from the cancer patient is determined to be normalized membrane optical density (nmOD) positive using a method comprising: staining the tissue sample immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; and identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60.

[0159]

[0153] In another embodiment, a use of an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell in the manufacture of a medicament for the treatment of non-squamous non-small cell lung cancer is described, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), wherein a tissue sample obtained from the cancer patient is determined to be normalized membrane optical density (nmOD) positive using a method comprising: staining the tissue sample immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density

[0160] (nmOD) for each cancer cell in the digital image; and identifying the tissue sample as TROP2-403-PCT01-NP nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60.

[0161]

[0154] In another embodiment, a method of treating cancer is described comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient is normalized membrane optical density (nmOD) positive.

[0162]

[0155] In another embodiment, a method of treating cancer is described comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient is normalized membrane optical density (nmOD) positive, wherein the tissue sample is normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample has nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60.

[0163]

[0156] In another embodiment, a method of treating cancer is described comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient is normalized membrane optical density (nmOD) positive, wherein the tissue sample is normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample has nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60.

[0164]

[0157] In another embodiment, an antibody drug conjugate (ADC) that TROP2-403-PCT01-NP includes an ADC payload and an ADC antibody that targets a protein on a cancer cell for use in a method of treating non-squamous non-small cell lung cancer comprising administering to a cancer patient the antibody drug conjugate (ADC) is described, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient is normalized membrane optical density (nmOD) positive.

[0165]

[0158] In another embodiment, an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell for use in a method of treating cancer comprising administering to a cancer patient the antibody drug conjugate (ADC) is described, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient is normalized membrane optical density (nmOD) positive, wherein the tissue sample is normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample has nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60.

[0166]

[0159] In another embodiment, an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell for use in a method of treating non-squamous non-small cell lung cancer comprising administering to a cancer patient the antibody drug conjugate (ADC) is described, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient is normalized membrane optical density (nmOD) positive, wherein the tissue sample is normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample has nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60.

[0167]

[0160] In another embodiment, a use of an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell in the manufacture of a medicament for the treatment of non-squamous non-small cell lung cancer is described, wherein the protein is calcium signal transducer TROP2-403-PCT01-NP trophoblast antigen 2 (TR0P2), and wherein a tissue sample obtained from the cancer patient is determined to be normalized membrane optical density (nmOD) positive.

[0161] In another embodiment, a use of an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell in the manufacture of a medicament for the treatment of cancer is described, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein a tissue sample obtained from the cancer patient is determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample is normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample has nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60.

[0162] In another embodiment, a use of an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell in the manufacture of a medicament for the treatment of non-squamous non-small cell lung cancer is described, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein a tissue sample obtained from the cancer patient is determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample is normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample has nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60.

[0168]

[0163] In other cases, a stained tissue sample from the cancer patient and analysis of the stained tissue sample has already been conducted.

[0169]

[0164] Thus, in one embodiment, a method of treating cancer is described comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was stained using a diagnostic antibody that binds to the protein in membranes and cytoplasm of cancer cells in the tissue sample, wherein for each cancer cell in a digital image of the tissue TROP2-403-PCT01-NP sample a mean optical density of membrane staining and a mean optical density of cytoplasm staining were determined, wherein for each cancer cell in the digital image a normalized membrane optical density (nmOD) was computed, and wherein the tissue sample was identified as nmOD positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold.

[0170]

[0165] In another embodiment, a method of treating cancer is described comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was stained using a diagnostic antibody that binds to the protein in membranes and cytoplasm of cancer cells in the tissue sample, wherein for each cancer cell in a digital image of the tissue sample a mean optical density of membrane staining and a mean optical density of cytoplasm staining were determined, wherein for each cancer cell in the digital image a normalized membrane optical density (nmOD) was computed, and wherein the tissue sample was identified as nmOD positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0171]

[0166] In another embodiment, a method of treating cancer is described comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was stained using a diagnostic antibody that binds to the protein in membranes and cytoplasm of cancer cells in the tissue sample, wherein for each cancer cell in a digital image of the tissue sample a mean optical density of membrane staining and a mean optical density of cytoplasm staining were determined, wherein for each cancer cell in the digital image a normalized membrane optical density (nmOD) was computed, and wherein the TROP2-403-PCT01-NP tissue sample was identified as nmOD positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0172]

[0167] In another embodiment, an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell for use in a method of treating non-squamous non-small cell lung cancer comprising administering to a cancer patient the antibody drug conjugate (ADC) is described, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was stained using a diagnostic antibody that binds to the protein in membranes and cytoplasm of cancer cells in the tissue sample, wherein for each cancer cell in a digital image of the tissue sample a mean optical density of membrane staining and a mean optical density of cytoplasm staining were determined, wherein for each cancer cell in the digital image a normalized membrane optical density (nmOD) was computed, and wherein the tissue sample was identified as nmOD positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold.

[0168] In another embodiment, an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell for use in a method of treating cancer comprising administering to a cancer patient the antibody drug conjugate (ADC) is described, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was stained using a diagnostic antibody that binds to the protein in membranes and cytoplasm of cancer cells in the tissue sample, wherein for each cancer cell in a digital image of the tissue sample a mean optical density of membrane staining and a mean optical density of cytoplasm staining were determined, wherein for each cancer cell in the digital image a normalized membrane optical density (nmOD) was computed, and wherein the tissue sample was identified as nmOD positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a TROP2-403-PCT01-NP range of about 0.50 to about 0.60.

[0173]

[0169] In another embodiment, an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell for use in a method of treating non-squamous non-small cell lung cancer comprising administering to a cancer patient the antibody drug conjugate (ADC) is described, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was stained using a diagnostic antibody that binds to the protein in membranes and cytoplasm of cancer cells in the tissue sample, wherein for each cancer cell in a digital image of the tissue sample a mean optical density of membrane staining and a mean optical density of cytoplasm staining were determined, wherein for each cancer cell in the digital image a normalized membrane optical density (nmOD) was computed, and wherein the tissue sample was identified as nmOD positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0174]

[0170] In another embodiment, a use of an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell in the manufacture of a medicament for the treatment of non-squamous non-small cell lung cancer is described, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), wherein a tissue sample obtained from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was stained using a diagnostic antibody that binds to the protein in membranes and cytoplasm of cancer cells in the tissue sample, wherein for each cancer cell in a digital image of the tissue sample a mean optical density of membrane staining and a mean optical density of cytoplasm staining were determined, wherein for each cancer cell in the digital image a normalized membrane optical density (nmOD) was computed, and wherein the tissue sample was identified as nmOD positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold.

[0175]

[0171] In another embodiment, a use of an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer TROP2-403-PCT01-NP cell in the manufacture of a medicament for the treatment of cancer is described, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), wherein a tissue sample obtained from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was stained using a diagnostic antibody that binds to the protein in membranes and cytoplasm of cancer cells in the tissue sample, wherein for each cancer cell in a digital image of the tissue sample a mean optical density of membrane staining and a mean optical density of cytoplasm staining were determined, wherein for each cancer cell in the digital image a normalized membrane optical density (nmOD) was computed, and wherein the tissue sample was identified as nmOD positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0172] In another embodiment, a use of an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell in the manufacture of a medicament for the treatment of non-squamous non-small cell lung cancer is described, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), wherein a tissue sample obtained from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was stained using a diagnostic antibody that binds to the protein in membranes and cytoplasm of cancer cells in the tissue sample, wherein for each cancer cell in a digital image of the tissue sample a mean optical density of membrane staining and a mean optical density of cytoplasm staining were determined, wherein for each cancer cell in the digital image a normalized membrane optical density (nmOD) was computed, and wherein the tissue sample was identified as nmOD positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0176]

[0173] In another embodiment, a method of treating cancer is described comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: administering a therapy comprising the ADC to the cancer patient if a TROP2-403-PCT01-NP tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive.

[0177]

[0174] In another embodiment, a method of treating cancer is described comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was determined to be normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0178]

[0175] In another embodiment, a method of treating cancer is described comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was determined to be normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0176] In another embodiment, an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell for use in a method of treating non-squamous non-small cell lung cancer comprising administering to a cancer patient the antibody drug conjugate (ADC) is described, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive.

[0179]

[0177] In another embodiment, an antibody drug conjugate (ADC) that TROP2-403-PCT01-NP includes an ADC payload and an ADC antibody that targets a protein on a cancer cell for use in a method of treating cancer comprising administering to a cancer patient the antibody drug conjugate (ADC) is described, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was determined to be normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0180]

[0178] In another embodiment, an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell for use in a method of treating non-squamous non-small cell lung cancer comprising administering to a cancer patient the antibody drug conjugate (ADC) is described, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was determined to be normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0181]

[0179] In another embodiment, a use of an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell in the manufacture of a medicament for the treatment of non-squamous non-small cell lung cancer is described, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein a tissue sample obtained from the cancer patient was determined to be normalized membrane optical density (nmOD) positive.

[0180] In another embodiment, a use of an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell in the manufacture of a medicament for the treatment of cancer is described, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein a tissue sample obtained from the cancer patient was determined to be TROP2-403-PCT01-NP normalized membrane optical density (nmOD) positive, wherein the tissue sample was determined to be normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0182]

[0181] In another embodiment, a use of an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell in the manufacture of a medicament for the treatment of non-squamous non-small cell lung cancer is described, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein a tissue sample obtained from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was determined to be normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0183]

[0182] The normalized membrane optical density equals the mean optical density of staining by the dye in the membrane of the cancer cell divided by the sum of the mean optical density of staining by the dye in the membrane of the cancer cell plus the mean optical density of staining by the dye in the cytoplasm of the cancer cell.

[0184]

[0183] For a tissue sample that is normalized membrane optical density positive, the percentage quartile of cancer cells that have (or had) nmOD values equal to or less than a nmOD threshold is typically in a range of about 50% to about 95%, about 65% to about 90%, or about 70% to about 80%. Statistically reliable results are typically achieved using percentage quartiles that are about 70% (Q70), about 75% (Q75), or about 80% (Q80); in particular, about 75% (Q75).

[0185]

[0184] For a tissue sample that is normalized membrane optical density positive, the normalized membrane optical density threshold is typically in a range of about 0.50 to about 0.60, about 0.51 to about 0.60, about 0.53 to about 0.59, about 0.55 to about 0.57, or about 0.558 to about 0.559. Statistically reliable results are typically achieved using normalized membrane optical density thresholds of about 0.558 or about 0.559; although other normalized membrane optical density thresholds of about 0.550 to about 0.552, about 0.552 to about 0.554, about 0.554 to about 0.556, TROP2-403-PCT01-NP about 0.556 to about 0.558, about 0.559 to about 0.561, about 0.561 to about 0.563, about 0.563 to about 0.565, about 0.565 to about 0.567, or about 0.567 to about 0.569 may also be used.

[0186]

[0185] In some embodiments, the percentage quartile of cancer cells may be in a range of about 50% to about 95%, and the normalized membrane optical density threshold may be in a range of about 0.50 to about 0.60, about 0.51 to about 0.60, about 0.53 to about 0.59, or about 0.55 to about 0.57 (e.g. about 0.550 to about 0.552, about 0.552 to about 0.554, about 0.554 to about 0.556, about 0.556 to about 0.558, about 0.558 to about 0.559, about 0.559 to about 0.561, about 0.561 to about 0.563, about 0.563 to about 0.565, about 0.565 to about 0.567, or about 0.567 to about

[0187] 0.569); typically about 0.558 or 0.559.

[0188]

[0186] In some embodiments, the percentage quartile of cancer cells may be in a range of about 65% to about 90%, and the normalized membrane optical density threshold may be in a range of about 0.50 to about 0.60, about 0.51 to about 0.60, about 0.53 to about 0.59, or about 0.55 to about 0.57 (e.g. about 0.550 to about 0.552, about 0.552 to about 0.554, about 0.554 to about 0.556, about 0.556 to about 0.558, about 0.558 to about 0.559, about 0.559 to about 0.561, about 0.561 to about 0.563, about 0.563 to about 0.565, about 0.565 to about 0.567, or about 0.567 to about

[0189] 0.569); typically about 0.558 or 0.559.

[0190]

[0187] In some embodiments, the percentage quartile of cancer cells may be in a range of about 70% to about 80%, and the normalized membrane optical density threshold may be in a range of about 0.50 to about 0.60, about 0.51 to about 0.60, about 0.53 to about 0.59, or about 0.55 to about 0.57 (e.g. about 0.550 to about 0.552, about 0.552 to about 0.554, about 0.554 to about 0.556, about 0.556 to about 0.558, about 0.558 to about 0.559, about 0.559 to about 0.561, about 0.561 to about 0.563, about 0.563 to about 0.565, about 0.565 to about 0.567, or about 0.567 to about

[0191] 0.569); typically about 0.558 or 0.559.

[0192]

[0188] In some embodiments, the percentage quartile of cancer cells may be about 70%, and the normalized membrane optical density threshold may be in a range of about 0.50 to about 0.60, about 0.51 to about 0.60, about 0.53 to about 0.59, or about 0.55 to about 0.57 (e.g. about 0.550 to about 0.552, about 0.552 to about 0.554, about 0.554 to about 0.556, about 0.556 to about 0.558, about 0.558 to about 0.559, about 0.559 to about 0.561, about 0.561 to about 0.563, about 0.563 to about 0.565, TROP2-403-PCT01-NP about 0.565 to about 0.567, or about 0.567 to about 0.569); typically about 0.558 or 0.559.

[0193]

[0189] In some embodiments, the percentage quartile of cancer cells may be about 75%, and the normalized membrane optical density threshold may be in a range of about 0.50 to about 0.60, about 0.51 to about 0.60, about 0.53 to about 0.59, or about 0.55 to about 0.57 (e.g. about 0.550 to about 0.552, about 0.552 to about 0.554, about 0.554 to about 0.556, about 0.556 to about 0.558, about 0.558 to about 0.559, about 0.559 to about 0.561, about 0.561 to about 0.563, about 0.563 to about 0.565, about 0.565 to about 0.567, or about 0.567 to about 0.569); typically about 0.558 or 0.559.

[0194]

[0190] In some embodiments, the percentage quartile of cancer cells may be about 80%, and the normalized membrane optical density threshold may be in a range of about 0.50 to about 0.60, about 0.51 to about 0.60, about 0.53 to about 0.59, or about 0.55 to about 0.57 (e.g. about 0.550 to about 0.552, about 0.552 to about 0.554, about 0.554 to about 0.556, about 0.556 to about 0.558, about 0.558 to about 0.559, about 0.559 to about 0.561, about 0.561 to about 0.563, about 0.563 to about 0.565, about 0.565 to about 0.567, or about 0.567 to about 0.569); typically about 0.558 or 0.559.

[0195]

[0191] Aspects described herein may be implemented by computer programs (e.g., carried on tangible carrier media such as disks or intangible carrier media such as communication signals). Aspects may also be implemented using suitable apparatus, which may take the form of programmable computers running computer programs arranged to implement the methods of identifying a cancer patient as described herein.

[0196]

[0192] Thus, in one embodiment, a computing system is described that is configured to perform the method 10 illustrated in FIG. 13. In one embodiment, a computing system is described that is configured to perform the method 10 illustrated in FIG. 13, wherein the tissue sample has been obtained from the cancer patient (prior to the staining) and the image of the tissue sample obtained from the cancer patient has been generated prior to the method 10 as performed by the computer system, and the computer system is configured to acquire the digital image (in step 11) by receiving the generated digital image (e.g., from another computing device). TROP2-403-PCT01-NP

[0197]

[0193] FIG. 14 schematically illustrates an exemplary arrangement of components which may provide a computing system 140 used to implement all or part of the methods of identifying a cancer patient and systems described herein, such as the method 10 illustrated in FIG. 13 and the corresponding analysis system.

[0198]

[0194] A processor, in this case in the form of a CPU 140a, is configured to read and execute instructions stored in a volatile memory 140b which takes the form of a random access memory. It will be appreciated that the processor may take other forms, such as, for example, a GPU. The volatile memory 140b stores instructions for execution by the CPU 140a and data used by those instructions.

[0199]

[0195] The computing system 140 comprises a storage device 150. It will be appreciated that the storage device 150 may be implemented in any way, such as for example, a hard disk drive, a solid state drive, etc. The storage device 150 may provide the means for storing data and / or instructions as described herein.

[0200]

[0196] The computing system 140 further comprises an I / O interface 140d to which are connected peripheral devices used in connection with the computing system. For example, a display 140e is configured so as to display output. The display 140e may be configured to display an output to a user that identifies the cancer patient as one who will likely benefit from administration of the anti-TROP2 ADC if the predicted response score is positive (in other words, if the tissue sample is normalized membrane positive), as determined in step 17 of the method 10. Input devices are also connected to the I / O interface 140d. Such input devices may include a keyboard 140f and a mouse 140g, which allow user interaction with the computing system 140. The computing system 140 may be configured to acquire the digital image of the tissue sample, as referred to in step 11 of FIG. 13, by receiving the image from an input device connected to the I / O interface 140d (e.g. from an imaging device (not shown)), that has captured the digital image of the tissue sample obtained from the cancer patient).

[0201]

[0197] A network interface 140h allows the computing system 140 to be connected to appropriate computer networks, such as the Internet, and so as to be able to send and receive from and to other computing devices. The computing system 140 may be configured to acquire the digital image of the tissue sample, as referred to in step 11 of FIG. 13, by receiving the image from one or more other computing devices via the network interface 140h. TROP2-403-PCT01-NP

[0202]

[0198] The CPU 140a, volatile memory 140b, the storage device 150, I / O interface 140d, and network interface 140h, are connected together by a bus 140i .

[0199] The methods of identifying a cancer patient described herein (e.g., the method 10 illustrated in FIG. 13) may be implemented in hardware, firmware, software, or any combination thereof. The methods of identifying a cancer patient may also be implemented as instructions stored on a machine-readable medium, which may be read and executed by one or more processors. A machine-readable medium may include any mechanism for storing or transmitting information in a form readable by a machine (e.g., a computing device). For example, a machine-readable medium may include read only memory (ROM); random access memory (RAM); magnetic storage media; optical storage media; flash memory devices; electrical, optical, acoustical or other forms of propagated signals (e.g., carrier waves, infrared signals, digital signals, etc.), and others. Further, firmware, software, routines, or instructions may be described herein as performing certain actions. However, it should be appreciated that such descriptions are merely for convenience and that such actions in fact result from computing devices, processors, controllers, or other devices executing the firmware, software, routines, instructions, etc. and in doing so may cause devices to interact with the physical world.

[0203]

[0200] Thus, in one embodiment, a computer-implemented method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) is described that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD TROP2-403-PCT01-NP threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. In embodiments, the tissue sample has been obtained from the cancer patient. In embodiments, acquiring the digital image of the tissue sample (e.g., the tissue sample obtained from the cancer patient) comprises receiving the digital image (e.g., from another computing device).

[0204]

[0201] In another embodiment, a computer-implemented method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) is described that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. In embodiments, the tissue sample has been obtained from the cancer patient. In embodiments, acquiring the digital image of the tissue sample (e.g., the tissue sample obtained from the cancer patient) comprises receiving the digital image (e.g., from another computing device).

[0205]

[0202] In another embodiment, a computer-implemented method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) is described that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically TROP2-403-PCT01-NP using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. In embodiments, the tissue sample has been obtained from the cancer patient. In embodiments, acquiring the digital image of the tissue sample (e.g., the tissue sample obtained from the cancer patient) comprises receiving the digital image (e.g., from another computing device).

[0206]

[0203] In another embodiment, a computer-implemented method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) is described that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. In embodiments, the tissue sample has been obtained from the cancer patient. In embodiments, acquiring the digital image of the tissue sample (e.g., the tissue sample obtained from TROP2-403-PCT01-NP the cancer patient) comprises receiving the digital image (e.g., from another computing device). In embodiments, the dye may be linked to a diagnostic antibody, and the diagnostic antibody may be bound to (or may bind to) the protein on the cancer cells in the tissue sample. In embodiments, the tissue sample may have been immunohistochemically stained using the dye (e.g., wherein the dye is linked to a diagnostic antibody, and the diagnostic antibody is bound to (or binds to) the protein on the cancer cells in the tissue sample).

[0207]

[0204] In another embodiment, a computer-implemented method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) is described that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. In embodiments, the tissue sample has been obtained from the cancer patient. In embodiments, acquiring the digital image of the tissue sample (e.g., the tissue sample obtained from the cancer patient) comprises receiving the digital image (e.g., from another computing device). In embodiments, the dye may be linked to a diagnostic antibody, and the diagnostic antibody may be bound to (or may bind to) the protein on the cancer cells in the tissue sample. In embodiments, the tissue sample may have been immunohistochemically stained using the dye (e.g., wherein the dye is linked to a diagnostic antibody, and the diagnostic antibody is bound to (or binds to) the protein on the cancer cells in the tissue sample). TROP2-403-PCT01-NP

[0208]

[0205] In another embodiment, a computer-implemented method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) is described that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. In embodiments, the tissue sample has been obtained from the cancer patient. In embodiments, acquiring the digital image of the tissue sample (e.g., the tissue sample obtained from the cancer patient) comprises receiving the digital image (e.g., from another computing device). In embodiments, the dye may be linked to a diagnostic antibody, and the diagnostic antibody may be bound to (or may bind to) the protein on the cancer cells in the tissue sample. In embodiments, the tissue sample may have been immunohistochemically stained using the dye (e.g., wherein the dye is linked to a diagnostic antibody, and the diagnostic antibody is bound to (or binds to) the protein on the cancer cells in the tissue sample).

[0209]

[0206] In another embodiment, one or more non-transitory computer-readable storage media are described, storing instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the TROP2-403-PCT01-NP cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to (or binds to) the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. In embodiments, the tissue sample has been obtained from the cancer patient. In embodiments, acquiring the digital image of the tissue sample (e.g., the tissue sample obtained from the cancer patient) comprises receiving the digital image (e.g., from another computing device).

[0210]

[0207] In another embodiment, one or more non-transitory computer-readable storage media are described, storing instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to (or binds to) the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and TROP2-403-PCT01-NP identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. In embodiments, the tissue sample has been obtained from the cancer patient. In embodiments, acquiring the digital image of the tissue sample (e.g., the tissue sample obtained from the cancer patient) comprises receiving the digital image (e.g., from another computing device).

[0211]

[0208] In another embodiment, one or more non-transitory computer-readable storage media are described, storing instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to (or binds to) the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. In embodiments, the tissue sample has been obtained from the cancer patient. In embodiments, acquiring the digital image of the tissue sample (e.g., the tissue sample obtained from the cancer patient) comprises receiving the digital image (e.g., from another computing device).

[0212]

[0209] In another embodiment, one or more non-transitory computer-readable storage media are described, storing instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the TROP2-403-PCT01-NP protein is calcium signal transducer trophoblast antigen 2 (TR0P2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by a dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. In embodiments, the tissue sample has been obtained from the cancer patient. In embodiments, acquiring the digital image of the tissue sample (e.g., the tissue sample obtained from the cancer patient) comprises receiving the digital image (e.g., from another computing device). In embodiments, the dye may be linked to a diagnostic antibody, and the diagnostic antibody may be bound to (or may bind to) the protein on the cancer cells in the tissue sample. In embodiments, the tissue sample may have been immunohistochemically stained using the dye (e.g., wherein the dye is linked to a diagnostic antibody, and the diagnostic antibody is bound to (or binds to) the protein on the cancer cells in the tissue sample).

[0213]

[0210] In another embodiment, one or more non-transitory computer-readable storage media are described, storing instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: acquiring a digital image of a tissue sample from the cancer patient; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by a dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or TROP2-403-PCT01-NP less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. In embodiments, the tissue sample has been obtained from the cancer patient. In embodiments, acquiring the digital image of the tissue sample (e.g., the tissue sample obtained from the cancer patient) comprises receiving the digital image (e.g., from another computing device). In embodiments, the dye may be linked to a diagnostic antibody, and the diagnostic antibody may be bound to (or may bind to) the protein on the cancer cells in the tissue sample. In embodiments, the tissue sample may have been immunohistochemically stained using the dye (e.g., wherein the dye is linked to a diagnostic antibody, and the diagnostic antibody is bound to (or binds to) the protein on the cancer cells in the tissue sample).

[0214]

[0211] In another embodiment, one or more non-transitory computer-readable storage media are described, storing instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by a dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. In embodiments, the tissue sample has been obtained from the cancer patient. In embodiments, acquiring the digital image of the tissue sample (e.g., the tissue sample obtained from the cancer patient) comprises receiving the digital image (e.g., from another computing device). In embodiments, the dye may be linked to a diagnostic antibody, and the diagnostic TROP2-403-PCT01-NP antibody may be bound to (or may bind to) the protein on the cancer cells in the tissue sample. In embodiments, the tissue sample may have been immunohistochemically stained using the dye (e.g., wherein the dye is linked to a diagnostic antibody, and the diagnostic antibody is bound to (or binds to) the protein on the cancer cells in the tissue sample).

[0215]

[0212] In another embodiment, one or more non-transitory computer-readable storage media are described storing instructions which, when executed by one or more processors, cause the one or more processors to perform the computer-implemented methods as described herein.

[0216]

[0213] In another embodiment, a computer system is described comprising one or more processors and one or more non-transitory computer-readable media storing instructions which, when executed on the one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to (or binds to) the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. In embodiments, the tissue sample has been obtained from the cancer patient. In embodiments, acquiring the digital image of the tissue sample (e.g., the tissue sample obtained from the cancer patient) comprises receiving the digital image (e.g., from another computing device).

[0217]

[0214] In another embodiment, a computer system is described comprising TROP2-403-PCT01-NP one or more processors and one or more non-transitory computer-readable media storing instructions which, when executed on the one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to (or binds to) the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. In embodiments, the tissue sample has been obtained from the cancer patient. In embodiments, acquiring the digital image of the tissue sample (e.g., the tissue sample obtained from the cancer patient) comprises receiving the digital image (e.g., from another computing device).

[0218]

[0215] In another embodiment, a computer system is described comprising one or more processors and one or more non-transitory computer-readable media storing instructions which, when executed on the one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to (or binds to) the protein on the cancer cells in the TROP2-403-PCT01-NP tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. In embodiments, the tissue sample has been obtained from the cancer patient. In embodiments, acquiring the digital image of the tissue sample (e.g., the tissue sample obtained from the cancer patient) comprises receiving the digital image (e.g., from another computing device).

[0219]

[0216] In another embodiment, a computer system is described comprising one or more processors and one or more non-transitory computer-readable media storing instructions which, when executed on the one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by a dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. In embodiments, the tissue sample has been obtained from the cancer patient. In embodiments, acquiring the digital image of the tissue sample (e.g., the tissue sample obtained from the cancer patient) comprises receiving the digital image (e.g., from another TROP2-403-PCT01-NP computing device). In embodiments, the dye may be linked to a diagnostic antibody, and the diagnostic antibody may be bound to (or binds to) the protein on the cancer cells in the tissue sample. In embodiments, the tissue sample may have been immunohistochemically stained using the dye (e.g., wherein the dye is linked to a diagnostic antibody, and the diagnostic antibody is bound to (or binds to) the protein on the cancer cells in the tissue sample).

[0220]

[0217] In another embodiment, a computer system is described comprising one or more processors and one or more non-transitory computer-readable media storing instructions which, when executed on the one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: acquiring a digital image of a tissue sample from the cancer patient; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by a dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. In embodiments, the tissue sample has been obtained from the cancer patient. In embodiments, acquiring the digital image of the tissue sample (e.g., the tissue sample obtained from the cancer patient) comprises receiving the digital image (e.g., from another computing device). In embodiments, the dye may be linked to a diagnostic antibody, and the diagnostic antibody may be bound to (or binds to) the protein on the cancer cells in the tissue sample. In embodiments, the tissue sample may have been immunohistochemically stained using the dye (e.g., wherein the dye is linked to a diagnostic antibody, and the diagnostic antibody is bound to (or binds to) the protein on the cancer cells in the tissue sample).

[0221]

[0218] In another embodiment, a computer system is described comprising TROP2-403-PCT01-NP one or more processors and one or more non-transitory computer-readable media storing instructions which, when executed on the one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by a dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. In embodiments, the tissue sample has been obtained from the cancer patient. In embodiments, acquiring the digital image of the tissue sample (e.g., the tissue sample obtained from the cancer patient) comprises receiving the digital image (e.g., from another computing device). In embodiments, the dye may be linked to a diagnostic antibody, and the diagnostic antibody may be bound to (or binds to) the protein on the cancer cells in the tissue sample. In embodiments, the tissue sample may have been immunohistochemically stained using the dye (e.g., wherein the dye is linked to a diagnostic antibody, and the diagnostic antibody is bound to (or binds to) the protein on the cancer cells in the tissue sample).

[0222]

[0219] In another embodiment, a computer system is described comprising one or more processors; and one or more non-transitory computer-readable storage media storing instructions which, when executed by the one or more processors, cause the one or more processors to perform the computer-implemented methods as described herein.

[0223]

[0220] In another embodiment, a computer program product is described comprising instructions which, when executed by one or more processors, cause the TROP2-403-PCT01-NP one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. In embodiments, the tissue sample has been obtained from the cancer patient. In embodiments, acquiring the digital image of the tissue sample (e.g., the tissue sample obtained from the cancer patient) comprises receiving the digital image (e.g., from another computing device).

[0224]

[0221] In another embodiment, a computer program product is described comprising instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density TROP2-403-PCT01-NP

[0225] (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. In embodiments, the tissue sample has been obtained from the cancer patient. In embodiments, acquiring the digital image of the tissue sample (e.g., the tissue sample obtained from the cancer patient) comprises receiving the digital image (e.g., from another computing device).

[0226]

[0222] In another embodiment, a computer program product is described comprising instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. In embodiments, the tissue sample has been obtained from the cancer patient. In embodiments, acquiring the digital image of the tissue sample (e.g., the tissue sample obtained from the cancer patient) comprises receiving the digital image (e.g., from another computing device).

[0227]

[0223] In another embodiment, a computer program product is described TROP2-403-PCT01-NP comprising instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by a dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. In embodiments, the tissue sample has been obtained from the cancer patient. In embodiments, acquiring the digital image of the tissue sample (e.g., the tissue sample obtained from the cancer patient) comprises receiving the digital image (e.g., from another computing device). In embodiments, the dye may be linked to a diagnostic antibody, and the diagnostic antibody may be bound to (or binds to) the protein on the cancer cells in the tissue sample. In embodiments, the tissue sample may have been immunohistochemically stained using the dye (e.g., wherein the dye is linked to a diagnostic antibody, and the diagnostic antibody is bound to (or binds to) the protein on the cancer cells in the tissue sample).

[0228]

[0224] In another embodiment, a computer program product is described comprising instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: acquiring a digital image of a tissue sample from the cancer patient; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by a dye in the membrane of the cancer cell; determining for each cancer cell a mean TROP2-403-PCT01-NP optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. In embodiments, the tissue sample has been obtained from the cancer patient. In embodiments, acquiring the digital image of the tissue sample (e.g., the tissue sample obtained from the cancer patient) comprises receiving the digital image (e.g., from another computing device). In embodiments, the dye may be linked to a diagnostic antibody, and the diagnostic antibody may be bound to (or binds to) the protein on the cancer cells in the tissue sample. In embodiments, the tissue sample may have been immunohistochemically stained using the dye (e.g., wherein the dye is linked to a diagnostic antibody, and the diagnostic antibody is bound to (or binds to) the protein on the cancer cells in the tissue sample).

[0229]

[0225] In another embodiment, a computer program product is described comprising instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by a dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. In embodiments, the tissue sample has TROP2-403-PCT01-NP been obtained from the cancer patient. In embodiments, acquiring the digital image of the tissue sample (e.g., the tissue sample obtained from the cancer patient) comprises receiving the digital image (e.g., from another computing device). In embodiments, the dye may be linked to a diagnostic antibody, and the diagnostic antibody may be bound to (or binds to) the protein on the cancer cells in the tissue sample. In embodiments, the tissue sample may have been immunohistochemically stained using the dye (e.g., wherein the dye is linked to a diagnostic antibody, and the diagnostic antibody is bound to (or binds to) the protein on the cancer cells in the tissue sample).

[0230]

[0226] In another embodiment, a computer program product is described comprising instructions which, when executed by one or more processors, cause the one or more processors to perform the computer-implemented methods as described herein.

[0231]

[0227] In another embodiment, a computer-readable data carrier is described having stored thereon a computer program product as described herein.

[0232]

[0228] In another embodiment, a data carrier signal is described carrying a computer program product as described herein.

[0233]

[0229] VIII. Examples of prediction and scoring method.

[0234]

[0230] Example 1

[0235]

[0231] A biomarker evaluable population (BEP) of 352 patients (i.e. those with available tissue samples for QCS determination) with non-small cell lung cancer were studied. The baseline characteristics of these patients are provided in the table below, where there were no significant differences in baseline characteristics between the randomized and biomarker-evaluable populations: TROP2-403-PCT01-NP

[0236] (NMR = normalized membrane ratio; ECOG PS = Eastern Cooperative Oncology Group Performance Status; NSQ = non-squamous; SQ = squamous; AGA = actionable genomic alterations; non-AGA = non-actionable genomic alterations;apatients who are no longer symptomatic and who require no treatment with corticosteroids and anticonvulsants and have recovered from acute toxic effects of radiation)

[0237]

[0232] In addition, the safety characteristics of treatment-related adverse events are provided in the table below, where overall / Grade 3+ adverse event rates were similar regardless of TROP2 QCS-NMR status:

[0238] (AESI = adverse event of special interest; ILD = interstitial lung disease; * Biomarker-evaluable population in safety analysis excludes patients who were randomized but did not receive treatment;bincludes events that were adjudicated as ILD and related to use of Dato-DXd or docetaxel (includes cases of potential ILD / pneumonitis based on MedDRA v26.0 for the narrow ILD SMQ, selected terms from the broad ILD SMQ, and PTs of respiratory failure and acute respiratory failure) TROP2-403-PCT01-NP

[0239]

[0233] Analysis of these treatment data is shown in FIGs 4-11.

[0240]

[0234] In FIG. 4, the Kaplan-Meier curves for progression-free survival and overall survival were plotted for the full intention-to-treat cohort (N=604) for nonsmall cell lung cancer, which includes patients who are biomarker evaluable (i.e. have available tissue samples for QCS determination) (N=352) and the remaining patients who are not biomarker evaluable (N=252). These data are further stratified to the type of treatment provided: either datopotamab deruxtecan (Dato-DXd) or docetaxel. Irrespective of whichever treatment was provided, the Kaplan-Meier curves for the respective BEP and ITT groups are similar to each other, indicating that the BEP cohort is a representative sample of the full ITT cohort.

[0241]

[0235] In FIG. 5, the BEP cohort was analyzed and the Kaplan-Meier curves for progression-free survival and overall survival were plotted. The data indicates that for the biomarker positive arm (BM+) treated with Dato-DXd, there is a significant increase in progression-free survival and overall survival as compared to the biomarker negative arm (BM-), where the biomarker measured is normalized membrane optical density (nmOD) at a percentage quantile of Q75 with an nmOD threshold of <0.5585. In contrast, when the same analysis is conducted on the patients treated with docetaxel, there is no statistically significant difference between the BM+ arm compared to the BM- arm. These data therefore indicate that ADC treatment outcomes of non-small cell lung cancer can be greatly improved by checking for the presence of this biomarker.

[0242]

[0236] In FIG. 6, the Kaplan-Meier curves for progression-free survival and overall survival were plotted for the cohort with non-squamous non-small lung cancer without actionable genomic alterations (N=370), which includes patients who are biomarker evaluable (i.e. have available tissue samples for QCS determination) (N=221) and the remaining patients who are not biomarker evaluable (N=149). Again, these data are further stratified to the type of treatment provided: either datopotamab deruxtecan (Dato-DXd) or docetaxel. Similar to FIG. 4, irrespective of whichever treatment was provided, the Kaplan-Meier curves for the respective BEP and ITT groups are similar to each other, indicating that the BEP cohort is a representative sample of the full ITT cohort. TROP2-403-PCT01-NP

[0243]

[0237] In FIG. 7, the BEP cohort for non-squamous non-small lung cancer without actionable genomic alterations was analyzed and the Kaplan-Meier curves for progression-free survival and overall survival were plotted. Similar to FIG. 5, the data indicates that for the BM+ arm treated with Dato-DXd, there is a significant increase in progression-free survival and overall survival as compared to the BM- arm. These data therefore indicate that ADC treatment outcomes of non-small cell lung cancer, in particular non-squamous non-small cell lung cancer without actionable genomic alterations, can be greatly improved by checking for the presence of this biomarker.

[0244]

[0238] In FIG. 8, the Kaplan-Meier curves for progression-free survival and overall survival were plotted for the cohort with non-squamous non-small lung cancer with actionable genomic alterations (N=98), which includes patients who are biomarker evaluable (i.e. have available tissue samples for QCS determination) (N=51) and the remaining patients who are not biomarker evaluable (N=47).

[0245]

[0239] In FIG. 9, the BEP cohort for non-squamous non-small lung cancer with actionable genomic alterations was analyzed and the Kaplan-Meier curves for progression-free survival and overall survival were plotted. These data seem to indicate a potential benefit in this patient population when comparing the BM+ arm treated with Dato-DXd with the BM- arm, particularly in the progression-free survival curve.

[0246]

[0240] In FIG. 10, the Kaplan-Meier curves for progression-free survival and overall survival were plotted for the cohort with squamous non-small lung cancer (N=136), which includes patients who are biomarker evaluable (i.e. have available tissue samples for QCS determination) (N=80) and the remaining patients who are not biomarker evaluable (N=56).

[0247]

[0241] In FIG. 11, the BEP cohort for squamous non-small lung cancer was analyzed and the Kaplan-Meier curves for progression-free survival and overall survival were plotted. These data seem to indicate a potential benefit in this patient population when comparing the BM+ arm treated with Dato-DXd with the BM- arm, particularly in the progression-free survival curve.

[0248]

[0242] An analysis of potentially using different percentage quantiles and different nmOD thresholds was also conducted. These data are presented in FIGs. 2 and 3. TROP2-403-PCT01-NP

[0249]

[0243] In FIG. 2, different nmOD values can be used for different percentage quantiles. For percentage quantiles of about 50% (Q50) to about 95% (Q95), typical values for the nmOD threshold can be in a range of about 0.53 to about 0.59. As shown in FIG. 2, when the percentage quantile is about 70% (Q70) to about 80% (Q80), suitable values for the nmOD threshold can be in a range of about 0.55 to about 0.57.

[0250]

[0244] In FIG. 3, different percentage quantiles can be used. Percentage quantiles of about 50% (Q50) to about 95% (Q95) generate statistically significant results where the p-value is typically <0.01 in nmOD thresholds of interest. More statistically significant results can be obtained as the percentage quantile is narrowed closer to about 75% (Q75), such as about 65% (Q65) to about 90% (Q90), or about 70% (Q70) to about 80% (Q80). In particular, percentage quantiles of about 70% (Q70) to about 80% (Q80) generate statistically significant results where the p-value is typically <0.001 in nmOD thresholds of interest.

[0251]

[0245] Example 2

[0252]

[0246] A further biomarker evaluable population (BEP) of 38 patients (i.e. those with available tissue samples for QCS determination) with non-small cell lung cancer were studied. The demographic and baseline characteristics of these patients are provided in the table below, where these were broadly comparable to those of the total patient population: TROP2-403-PCT01-NP

[0253] (AJCC, American Joint Committee on Cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; NMR, normalized membrane ratio; TROP2, trophoblast cell surface antigen 2; QCS, quantitative continuous scoring)

[0254]

[0247] In total, 52.6% (N=20 / 38) were TROP2 QCS-NMR positive. Of the 38 patients for whom QCS was evaluable, 21 were non-squamous and 17 were squamous. TROP2 QCS-NMR-positive tumors were numerically higher in patients with non-squamous (76.2%) vs. squamous histology (23.5%), as shown in the table below:

[0255] (NMR, normalized membrane ratio; QCS, quantitative continuous scoring; TROP2, trophoblast cell surface antigen 2)

[0256]

[0248] In addition, the safety characteristics of treatment-related adverse events are provided in the table below, where the safety profile by TROP2 QCS-NMR status was generally comparable:

[0257] (AESI, adverse event of special interest; ILD, interstitial lung disease; NMR, normalized membrane ratio; QCS, quantitative continuous scoring; TRAE, treatment-related adverse event; TROP2, trophoblast cell surface antigen 2; *AESIs are grouped terms using preferred terms selected from relevant standardized MedDRA query, MedDRA V26.0; Adjudicated ILD, CTCAE grade and relationship with study drug were assessed by the adjudication committee.) TROP2-403-PCT01-NP

[0258]

[0249] The response rate by TROP2 QCS-NMR status is provided in the table below, where ORR was numerically higher for patients with TROP2 QCS-NMR- positive tumors vs. TROP2 QCS-NMR-negative tumors:

[0259] (NMR, normalized membrane ratio; ORR, objective response rate; QCS, quantitative continuous score;

[0260] TROP2, trophoblast cell surface antigen 2)

[0261]

[0250] Analysis of the treatment data is also shown in FIG. 15.

[0262]

[0251] In FIG. 15, median progression-free survival was longer for patients with TROP2 QCS-NMR-positive tumors than patients with TROP2 QCS-NMR- negative tumors. These data reinforce the conclusion that ADC treatment outcomes of non-small cell lung cancer can be greatly improved by checking for the presence of this biomarker.

[0263]

[0252] Although the present disclosure has been described in connection with certain specific embodiments for instructional purposes, the present disclosure is not limited thereto. Various modifications, adaptations, and combinations of various features of the described embodiments can be practiced without departing from the scope of the disclosure as set forth in the claims.

[0264]

[0253] Embodiments are set out in the following clauses:

[0265] (1) A method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; TROP2-403-PCT01-NP acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0266] (2) A method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a TROP2-403-PCT01-NP nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0267] (3) A method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0268] (4) A method of treating cancer comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium TROP2-403-PCT01-NP signal transducer trophoblast antigen 2 (TR0P2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and administering a therapy comprising the ADC to the cancer patient if the tissue sample is nmOD positive.

[0269] (5) A method of treating cancer comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; TROP2-403-PCT01-NP determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and administering a therapy comprising the ADC to the cancer patient if the tissue sample is nmOD positive.

[0270] (6) A method of treating cancer comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and TROP2-403-PCT01-NP administering a therapy comprising the ADC to the cancer patient if the tissue sample is nmOD positive.

[0271] (7) An antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell for use in a method of treating non-squamous non-small cell lung cancer comprising administering to a cancer patient the antibody drug conjugate (ADC), wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), the method comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and administering a therapy comprising the ADC to the cancer patient if the tissue sample is nmOD positive.

[0272] (8) An antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell for use in a method of treating cancer comprising administering to a cancer patient the antibody drug conjugate (ADC), wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), the method comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein TROP2-403-PCT01-NP the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and administering a therapy comprising the ADC to the cancer patient if the tissue sample is nmOD positive.

[0273] (9) An antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell for use in a method of treating non-squamous non-small cell lung cancer comprising administering to a cancer patient the antibody drug conjugate (ADC), wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; TROP2-403-PCT01-NP identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and administering a therapy comprising the ADC to the cancer patient if the tissue sample is nmOD positive.

[0274] (10) Use of an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell in the manufacture of a medicament for the treatment of non-squamous non-small cell lung cancer, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), wherein a tissue sample obtained from the cancer patient is determined to be normalized membrane optical density (nmOD) positive using a method comprising: staining the tissue sample immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; and identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold.

[0275] (11) Use of an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell in the manufacture of a medicament for the treatment of cancer, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), wherein a tissue sample obtained TROP2-403-PCT01-NP from the cancer patient is determined to be normalized membrane optical density (nmOD) positive using a method comprising: staining the tissue sample immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; and identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60.

[0276] (12) Use of an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell in the manufacture of a medicament for the treatment of non-squamous non-small cell lung cancer, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), wherein a tissue sample obtained from the cancer patient is determined to be normalized membrane optical density (nmOD) positive using a method comprising: staining the tissue sample immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; TROP2-403-PCT01-NP determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; and identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60.

[0277] (13) A method of treating cancer comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was stained using a diagnostic antibody that binds to the protein in membranes and cytoplasm of cancer cells in the tissue sample, wherein for each cancer cell in a digital image of the tissue sample a mean optical density of membrane staining and a mean optical density of cytoplasm staining were determined, wherein for each cancer cell in the digital image a normalized membrane optical density (nmOD) was computed, and wherein the tissue sample was identified as nmOD positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold.

[0278] (14) A method of treating cancer comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was TROP2-403-PCT01-NP stained using a diagnostic antibody that binds to the protein in membranes and cytoplasm of cancer cells in the tissue sample, wherein for each cancer cell in a digital image of the tissue sample a mean optical density of membrane staining and a mean optical density of cytoplasm staining were determined, wherein for each cancer cell in the digital image a normalized membrane optical density (nmOD) was computed, and wherein the tissue sample was identified as nmOD positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0279] (15) A method of treating cancer comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was stained using a diagnostic antibody that binds to the protein in membranes and cytoplasm of cancer cells in the tissue sample, wherein for each cancer cell in a digital image of the tissue sample a mean optical density of membrane staining and a mean optical density of cytoplasm staining were determined, wherein for each cancer cell in the digital image a normalized membrane optical density (nmOD) was computed, and wherein the tissue sample was identified as nmOD positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0280] (16) An antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell for use in a method of treating non-squamous non-small cell lung cancer comprising administering to a cancer patient the antibody drug conjugate (ADC), wherein the protein is TROP2-403-PCT01-NP calcium signal transducer trophoblast antigen 2 (TR0P2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was stained using a diagnostic antibody that binds to the protein in membranes and cytoplasm of cancer cells in the tissue sample, wherein for each cancer cell in a digital image of the tissue sample a mean optical density of membrane staining and a mean optical density of cytoplasm staining were determined, wherein for each cancer cell in the digital image a normalized membrane optical density (nmOD) was computed, and wherein the tissue sample was identified as nmOD positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold.

[0281] (17) An antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell for use in a method of treating cancer comprising administering to a cancer patient the antibody drug conjugate (ADC), wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was stained using a diagnostic antibody that binds to the protein in membranes and cytoplasm of cancer cells in the tissue sample, wherein for each cancer cell in a digital image of the tissue sample a mean optical density of membrane staining and a mean optical density of cytoplasm staining were determined, wherein for each cancer cell in the digital image a normalized membrane optical density (nmOD) was computed, and wherein the tissue sample was identified as nmOD positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60. TROP2-403-PCT01-NP

[0282] (18) An antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell for use in a method of treating non-squamous non-small cell lung cancer comprising administering to a cancer patient the antibody drug conjugate (ADC), wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was stained using a diagnostic antibody that binds to the protein in membranes and cytoplasm of cancer cells in the tissue sample, wherein for each cancer cell in a digital image of the tissue sample a mean optical density of membrane staining and a mean optical density of cytoplasm staining were determined, wherein for each cancer cell in the digital image a normalized membrane optical density (nmOD) was computed, and wherein the tissue sample was identified as nmOD positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0283] (19) Use of an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell in the manufacture of a medicament for the treatment of non-squamous non-small cell lung cancer, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), wherein a tissue sample obtained from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was stained using a diagnostic antibody that binds to the protein in membranes and cytoplasm of cancer cells in the tissue sample, wherein for each cancer cell in a digital image of the tissue sample a mean optical density of membrane staining and a mean optical density of cytoplasm staining were determined, wherein for each cancer cell in the digital image a normalized membrane optical density (nmOD) was computed, and wherein the tissue sample was identified as nmOD positive if a percentage quantile of TROP2-403-PCT01-NP cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold.

[0284] (20) Use of an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell in the manufacture of a medicament for the treatment of cancer, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), wherein a tissue sample obtained from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was stained using a diagnostic antibody that binds to the protein in membranes and cytoplasm of cancer cells in the tissue sample, wherein for each cancer cell in a digital image of the tissue sample a mean optical density of membrane staining and a mean optical density of cytoplasm staining were determined, wherein for each cancer cell in the digital image a normalized membrane optical density (nmOD) was computed, and wherein the tissue sample was identified as nmOD positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0285] (21) Use of an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell in the manufacture of a medicament for the treatment of non-squamous non-small cell lung cancer, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), wherein a tissue sample obtained from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was stained using a diagnostic antibody that binds to the protein in membranes and cytoplasm of cancer cells in the tissue sample, wherein for each cancer cell in a digital image of the tissue sample a mean optical density of membrane staining and a mean optical density of cytoplasm staining were determined, wherein for each cancer cell in the digital image a normalized membrane optical density (nmOD) was computed, and wherein the TROP2-403-PCT01-NP tissue sample was identified as nmOD positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0286] (22) The method of any one of clauses (1) to (6); the antibody drug conjugate for use of any one of clauses (7) to (9); or the use of any one of clauses (10) to (12); wherein the detecting of cancer cells comprises (or comprised) detecting for each cancer cell the pixels that belong to the membrane and the pixels that belong to the cytoplasm.

[0287] (23) The method of any one of clauses (1) to (3), or clause (22) as dependent on any one of clauses (1) to (3), further comprising: recommending a therapy comprising the ADC to the cancer patient when the tissue sample is nmOD positive.

[0288] (24) The method of any one of clauses (1) to (6), (13) to (15), (22) and (23); the antibody drug conjugate for use of any one of clauses (7) to (9), (16) to (18), (22) and (23); or the use of any one of clauses (10) to (12) and (19) to (23); wherein the normalized membrane threshold is (or was) in a range of about 0.51 to about 0.60, about 0.53 to about 0.59, about 0.55 to about 0.57, or about 0.558 to about 0.559.

[0289] (25) The method of any one of clauses (1) to (6), (13) to (15), (22) and (23); the antibody drug conjugate for use of any one of clauses (7) to (9), (16) to (18), (22) and (23); or the use of any one of clauses (10) to (12) and (19) to (23); wherein the normalized membrane threshold is (or was) about 0.558 or about 0.559.

[0290] (26) The method of any one of clauses (1) to (6), (13) to (15) and (22) to (25); the antibody drug conjugate for use of any one of clauses (7) to (9), (16) to (18) and (22) to (25); or the use of any one of clauses (10) to (12) and (19) to (25); TROP2-403-PCT01-NP wherein the percentage quantile of cancer cells is (or was) in a range of about 50% to about 95%, about 65% to about 90%, or about 70% to about 80%.

[0291] (27) The method of any one of clauses (1) to (6), (13) to (15) and (22) to (25); the antibody drug conjugate for use of any one of clauses (7) to (9), (16) to (18) and (22) to (25); or the use of any one of clauses (10) to (12) and (19) to (25); wherein the percentage quantile of cancer cells is (or was) about 75%.

[0292] (28) The method of any one of clauses (1) to (6), (13) to (15) and (22) to (27); the antibody drug conjugate for use of any one of clauses (7) to (9), (16) to (18) and (22) to (27); or the use of any one of clauses (10) to (12) and (19) to (27);wherein the detecting of cancer cells comprises (or comprised) detecting for each cancer cell the pixels that belong to the membrane using a cell center determined for each cancer cell.

[0293] (29) The method of any one of clauses (1) to (6), (13) to (15) and (22) to (28); the antibody drug conjugate for use of any one of clauses (7) to (9), (16) to (18) and (22) to (28); or the use of any one of clauses (10) to (12) and (19) to (28); wherein the staining intensity of each membrane is (or was) computed based on an average optical density of a brown diaminobenzidine (DAB) signal in pixels of the membrane, and wherein the staining intensity of each cytoplasm is computed based on the average optical density of the brown DAB signal in pixels of the cytoplasm.

[0294] (30) The method of any one of clauses (1) to (6), (13) to (15) and (22) to (29); the antibody drug conjugate for use of any one of clauses (7) to (9), (16) to (18) and (22) to (29); or the use of any one of clauses (10) to (12) and (19) to (29); wherein the dye is 3,3'-Diaminobenzidine (DAB).

[0295] (31) The method of any one of clauses (1) to (6), (13) to (15) and (22) to (30); the antibody drug conjugate for use of any one of clauses (7) to (9), (16) to (18) and (22) to (30); or the use of any one of clauses (10) to (12) and (19) to (30); wherein the ADC is selected from the group consisting of: sacituzumab TROP2-403-PCT01-NP govitecan (Trodelvy®), sacituzumab tirumotecan (SKB264 / MK-2870) and datopotamab deruxtecan (DS-1062); optionally wherein the ADC is datopotamab deruxtecan (DS-1062).

[0296] (32) The method of any one of clauses (1) to (6), (13) to (15) and (22) to (30); the antibody drug conjugate for use of any one of clauses (7) to (9), (16) to (18) and (22) to (30); or the use of any one of clauses (10) to (12) and (19) to (30); wherein the ADC antibody is hTINAl-HILl.

[0297] (33) The method of any one of clauses (1) to (6), (13) to (15) and (22) to (30); the antibody drug conjugate for use of any one of clauses (7) to (9), (16) to (18) and (22) to (30); or the use of any one of clauses (10) to (12) and (19) to (30); wherein the ADC antibody is a humanized IgGl monoclonal antibody.

[0298] (34) The method of any one of clauses (1) to (6), (13) to (15) and (22) to (30); the antibody drug conjugate for use of any one of clauses (7) to (9), (16) to (18) and (22) to (30); or the use of any one of clauses (10) to (12) and (19) to (30); wherein the ADC payload is a topoisomerase I inhibitor.

[0299] (35) The method of clause (34); the antibody drug conjugate for use of clause (34); or the use of clause (34); wherein the topoisomerase I inhibitor is represented by the following formula:

[0300] (36) The method of any one of clauses (1) to (6), (13) to (15) and (22) to (35); the antibody drug conjugate for use of any one of clauses (7) to (9), (16) to (18) and (22) to (35); or the use of any one of clauses (10) to (12) and (19) to (35); wherein the diagnostic antibody is Abeam EPR 20043. TROP2-403-PCT01-NP

[0301] (37) The method of any one of clauses (1) to (6), (13) to (15), (22) to (30) and (36); the antibody drug conjugate for use of any one of clauses (7) to (9), (16) to (18), (22) to (30) and (36); or the use of any one of clauses (10) to (12), (19) to (30) and (36); wherein the ADC is an anti-TROP2 antibody conjugated to a drug-linker via a thioether bond, wherein the drug-linker is represented by the following formula: and wherein A represents a connecting position to the anti-TROP2 antibody.

[0302] (38) The method of any one of clauses (1) to (6), (13) to (15), (22) to (30) and (34) to (37); the antibody drug conjugate for use of any one of clauses (7) to (9), (16) to (18), (22) to (30) and (34) to (37); or the use of any one of clauses (10) to (12), (19) to (30) and (34) to (37); wherein the ADC includes an anti- TROP2 antibody comprising: a heavy chain comprising CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 4, and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 5; and a light chain comprising CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of an amino acid sequence represented by SEQ ID NO: 7, and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 8.

[0303] (39) The method of any one of clauses (1) to (6), (13) to (15), (22) to (30) and (34) to (37); the antibody drug conjugate for use of any one of clauses (7) to (9), TROP2-403-PCT01-NP

[0304] (16) to (18), (22) to (30) and (34) to (37); or the use of any one of clauses (10) to (12), (19) to (30) and (34) to (37); wherein the ADC includes an anti- TROP2 antibody comprising: a heavy chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 9; and a light chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 10.

[0305] (40) The method of any one of clauses (1) to (6), (13) to (15), (22) to (30) and (34) to (37); the antibody drug conjugate for use of any one of clauses (7) to (9), (16) to (18), (22) to (30) and (34) to (37); or the use of any one of clauses (10) to (12), (19) to (30) and (34) to (37); wherein the ADC includes an anti- TROP2 antibody comprising: a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 11; and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 13.

[0306] (41) The method of any one of clauses (1) to (6), (13) to (15), (22) to (30) and (34) to (37); the antibody drug conjugate for use of any one of clauses (7) to (9), (16) to (18), (22) to (30) and (34) to (37); or the use of any one of clauses (10) to (12), (19) to (30) and (34) to (37); wherein the ADC includes an anti- TROP2 antibody comprising: a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 12; and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 13.

[0307] (42) The method of any one of clauses (1) to (6), (13) to (15) and (22) to (41); the antibody drug conjugate for use of any one of clauses (7) to (9), (16) to (18) and (22) to (41); or the use of any one of clauses (10) to (12) and (19) to (41); wherein the cancer patient has non-squamous non-small cell lung cancer without actionable genomic alterations. TROP2-403-PCT01-NP

[0308] (43) The method of any one of clauses (1) to (6), (13) to (15) and (22) to (41); the antibody drug conjugate for use of any one of clauses (7) to (9), (16) to (18) and (22) to (41); or the use of any one of clauses (10) to (12) and (19) to (41); wherein the cancer patient has non-squamous non-small cell lung cancer with actionable genomic alterations.

[0309] (44) The method of any one of clauses (1) to (6), (13) to (15) and (22) to (43); the antibody drug conjugate for use of any one of clauses (7) to (9), (16) to (18) and (22) to (43); or the use of any one of clauses (10) to (12) and (19) to (43); further comprising treatment with at least one additional therapeutic agent.

[0310] (45) The method of clause (44); the antibody drug conjugate for use of clause (44); or the use of clause (44); wherein the at least one additional therapeutic agent comprises an immune checkpoint inhibitor.

[0311] (46) The method of clause (45); the antibody drug conjugate for use of clause (45); or the use of clause (45); wherein the immune checkpoint inhibitor blocks the activity ofPD-1 or PD-L1.

[0312] (47) The method of clause (45); the antibody drug conjugate for use of clause (45); or the use of clause (45); wherein the immune checkpoint inhibitor is selected from pembrolizumab, durvalumab, nivolumab, and combinations thereof.

[0313] (48) The method of clause (45); the antibody drug conjugate for use of clause (45); or the use of clause (45); wherein the immune checkpoint inhibitor is durvalumab.

[0314] (49) The method of any one of clauses (44) to (48); the antibody drug conjugate for use of any one of clauses (44) to (48); or the use of any one of clauses (44) to (48); wherein the at least one additional therapeutic agent comprises a chemotherapeutic agent. TROP2-403-PCT01-NP

[0315] (50) The method of clause (49); the antibody drug conjugate for use of clause (49); or the use of clause (49); wherein the chemotherapeutic agent is a platinumbased chemotherapeutic agent.

[0316] (51) The method of clause (50); the antibody drug conjugate for use of clause (50); or the use of clause (50); wherein the platinum-based chemotherapeutic agent is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, and combinations thereof.

[0317] (52) The method of clause (50); the antibody drug conjugate for use of clause (50); or the use of clause (50); wherein the platinum-based chemotherapeutic agent is carboplatin.

[0318] (53) The method of any one of clauses (44) to (52); the antibody drug conjugate for use of any one of clauses (44) to (52); or the use of any one of clauses (44) to (52); wherein the ADC and the at least one additional therapeutic agent form part of the same medicament.

[0319] (54) The method of any one of clauses (44) to (52); the antibody drug conjugate for use of any one of clauses (44) to (52); or the use of any one of clauses (44) to (52); wherein the ADC and the at least one therapeutic agent are provided as separate medicaments for administration in combination or sequentially.

[0320] (55) A method of treating cancer comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient is normalized membrane optical density (nmOD) positive. TROP2-403-PCT01-NP

[0321] (56) A method of treating cancer comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient is normalized membrane optical density (nmOD) positive, wherein the tissue sample is normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample has nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60.

[0322] (57) A method of treating cancer comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient is normalized membrane optical density (nmOD) positive, wherein the tissue sample is normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample has nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60.

[0323] (58) An antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell for use in a method of treating non-squamous non-small cell lung cancer comprising administering to a cancer patient the antibody drug conjugate (ADC), wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient is normalized membrane optical density (nmOD) positive. TROP2-403-PCT01-NP

[0324] (59) An antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell for use in a method of treating cancer comprising administering to a cancer patient the antibody drug conjugate (ADC), wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient is normalized membrane optical density (nmOD) positive, wherein the tissue sample is normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample has nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60.

[0325] (60) An antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell for use in a method of treating non-squamous non-small cell lung cancer comprising administering to a cancer patient the antibody drug conjugate (ADC), wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient is normalized membrane optical density (nmOD) positive, wherein the tissue sample is normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample has nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60.

[0326] (61) Use of an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell in the manufacture of a medicament for the treatment of non-squamous non-small cell lung cancer, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein a tissue sample obtained from the cancer patient is determined to be normalized membrane optical density (nmOD) positive. TROP2-403-PCT01-NP

[0327] (62) Use of an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell in the manufacture of a medicament for the treatment of cancer, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), and wherein a tissue sample obtained from the cancer patient is determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample is normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample has nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60.

[0328] (63) Use of an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell in the manufacture of a medicament for the treatment of non-squamous non-small cell lung cancer, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein a tissue sample obtained from the cancer patient is determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample is normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample has nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60.

[0329] (64) A method of treating cancer comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive. TROP2-403-PCT01-NP

[0330] (65) A method of treating cancer comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was determined to be normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0331] (66) A method of treating cancer comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was determined to be normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0332] (67) An antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell for use in a method of treating non-squamous non-small cell lung cancer comprising administering to a cancer patient the antibody drug conjugate (ADC), wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: TROP2-403-PCT01-NP administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive.

[0333] (68) An antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell for use in a method of treating cancer comprising administering to a cancer patient the antibody drug conjugate (ADC), wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was determined to be normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0334] (69) An antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell for use in a method of treating non-squamous non-small cell lung cancer comprising administering to a cancer patient the antibody drug conjugate (ADC), wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was determined to be normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0335] (70) Use of an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell in the manufacture of a TROP2-403-PCT01-NP medicament for the treatment of non-squamous non-small cell lung cancer, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), and wherein a tissue sample obtained from the cancer patient was determined to be normalized membrane optical density (nmOD) positive.

[0336] (71) Use of an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell in the manufacture of a medicament for the treatment of cancer, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), and wherein a tissue sample obtained from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was determined to be normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0337] (72) Use of an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell in the manufacture of a medicament for the treatment of non-squamous non-small cell lung cancer, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein a tissue sample obtained from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was determined to be normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

[0338] (73) A computer-implemented method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the TROP2-403-PCT01-NP cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0339] (74) A computer-implemented method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; TROP2-403-PCT01-NP computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0340] (75) A computer-implemented method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. TROP2-403-PCT01-NP

[0341] (76) A computer-implemented method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by a dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0342] (77) A computer-implemented method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: acquiring a digital image of a tissue sample from the cancer patient; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by a dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; TROP2-403-PCT01-NP identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0343] (78) A computer-implemented method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by a dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0344] (79) One or more non-transitory computer-readable storage media storing instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein TROP2-403-PCT01-NP the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0345] (80) One or more non-transitory computer-readable storage media storing instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; TROP2-403-PCT01-NP determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0346] (81) One or more non-transitory computer-readable storage media storing instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; TROP2-403-PCT01-NP identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0347] (82) One or more non-transitory computer-readable storage media storing instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by a dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0348] (83) One or more non-transitory computer-readable storage media storing instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC TROP2-403-PCT01-NP payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), the method comprising: acquiring a digital image of a tissue sample from the cancer patient; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by a dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0349] (84) One or more non-transitory computer-readable storage media storing instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by a dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; TROP2-403-PCT01-NP computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0350] (85) A computer system comprising: one or more processors; and one or more non-transitory computer-readable media storing instructions which, when executed on the one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; TROP2-403-PCT01-NP identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0351] (86) A computer system comprising: one or more processors; and one or more non-transitory computer-readable media storing instructions which, when executed on the one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. TROP2-403-PCT01-NP

[0352] (87) A computer system comprising: one or more processors; and one or more non-transitory computer-readable media storing instructions which, when executed on the one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0353] (88) A computer system comprising: one or more processors; and TROP2-403-PCT01-NP one or more non-transitory computer-readable media storing instructions which, when executed by the one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by a dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0354] (89) A computer system comprising: one or more processors; and one or more non-transitory computer-readable media storing instructions which, when executed by the one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: TROP2-403-PCT01-NP acquiring a digital image of a tissue sample from the cancer patient; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by a dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0355] (90) A computer system comprising: one or more processors; and one or more non-transitory computer-readable media storing instructions which, when executed by the one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by a dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; TROP2-403-PCT01-NP computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0356] (91) A computer program product comprising instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive. TROP2-403-PCT01-NP

[0357] (92) A computer program product comprising instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0358] (93) A computer program product comprising instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: TROP2-403-PCT01-NP acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0359] (94) A computer program product comprising instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by a dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; TROP2-403-PCT01-NP computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0360] (95) A computer program product comprising instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: acquiring a digital image of a tissue sample from the cancer patient; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by a dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0361] (96) A computer program product comprising instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug TROP2-403-PCT01-NP conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by a dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

[0362] (97) The computer-implemented method of any one of clauses (76) to (78); the one or more non-transitory computer-readable storage media of any one of clauses (82) to (84); the computer system of any one of clauses (88) to (90); or the computer program product of any one of clauses (94) to (96); wherein the dye is linked to a diagnostic antibody, and wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample.

[0363] (98) The computer-implemented method of any one of clauses (76) to (78) and (97); the one or more non-transitory computer-readable storage media of any one of clauses (82) to (84) and (97); the computer system of any one of clauses (88) to (90) and (97); or the computer program product of any one of clauses (94) to (96) and (97); wherein the tissue sample has been immunohistochemically stained using the dye. TROP2-403-PCT01-NP

[0364] (99) The computer-implemented method of any one of clauses (73) to (78), (97) and (98); the one or more non-transitory computer-readable storage media of any one of clauses (79) to (84), (97) and (98); the computer system of any one of clauses (85) to (90), (97) and (98); or the computer program product of any one of clauses (91) to (96), (97) and (98); wherein the detecting of cancer cells comprises detecting for each cancer cell the pixels that belong to the membrane and the pixels that belong to the cytoplasm.

[0365] (100) The computer-implemented method of any one of clauses (73) to (78) and (97) to (99); the one or more non-transitory computer-readable storage media of any one of clauses (79) to (84) and (97) to (99); the computer system of any one of clauses (85) to (90) and (97) to (99); or the computer program product of any one of clauses (91) to (99); further comprising: recommending a therapy comprising the ADC to the cancer patient when the tissue sample is nmOD positive.

[0366] (101) The computer-implemented method of any one of clauses (73) to (78) and (97) to (100); the one or more non-transitory computer-readable storage media of any one of clauses (79) to (84) and (97) to (100); the computer system of any one of clauses (85) to (90) and (97) to (100); or the computer program product of any one of clauses (91) to (100); wherein the normalized membrane threshold is in a range of about 0.51 to about 0.60, about 0.53 to about 0.59, about 0.55 to about 0.57, or about 0.558 to about 0.559.

[0367] (102) The computer-implemented method of any one of clauses (73) to (78) and (97) to (100); the one or more non-transitory computer-readable storage media of any one of clauses (79) to (84) and (97) to (100); the computer system of any one of clauses (85) to (90) and (97) to (100); or the computer program product of any one of clauses (91) to (100); wherein the normalized membrane threshold is (or was) about 0.558 or about 0.559. TROP2-403-PCT01-NP

[0368] (103) The computer-implemented method of any one of clauses (73) to (78) and (97) to (102); the one or more non-transitory computer-readable storage media of any one of clauses (79) to (84) and (97) to (102); the computer system of any one of clauses (85) to (90) and (97) to (102); or the computer program product of any one of clauses (91) to (102); wherein the percentage quantile of cancer cells is in a range of about 50% to about 95%, about 65% to about 90%, or about 70% to about 80%.

[0369] (104) The computer-implemented method of any one of clauses (73) to (78) and (97) to (102); the one or more non-transitory computer-readable storage media of any one of clauses (79) to (84) and (97) to (102); the computer system of any one of clauses (85) to (90) and (97) to (102); or the computer program product of any one of clauses (91) to (102); wherein the percentage quantile of cancer cells is (or was) about 75%.

[0370] (105) The computer-implemented method of any one of clauses (73) to (78) and (97) to (104); the one or more non-transitory computer-readable storage media of any one of clauses (79) to (84) and (97) to (104); the computer system of any one of clauses (85) to (90) and (97) to (104); or the computer program product of any one of clauses (91) to (104); wherein the detecting of cancer cells comprises detecting for each cancer cell the pixels that belong to the membrane using a cell center determined for each cancer cell.

[0371] (106) The computer-implemented method of any one of clauses (73) to (78) and (97) to (105); the one or more non-transitory computer-readable storage media of any one of clauses (79) to (84) and (97) to (105); the computer system of any one of clauses (85) to (90) and (97) to (105); or the computer program product of any one of clauses (91) to (105); wherein the staining intensity of each membrane is (or was) computed based on an average optical density of a brown diaminobenzidine (DAB) signal in pixels of the membrane, and wherein the staining intensity of each cytoplasm is computed based on the average optical density of the brown DAB signal in pixels of the cytoplasm. TROP2-403-PCT01-NP

[0372] (107) The computer-implemented method of any one of clauses (73) to (78) and (97) to (106); the one or more non-transitory computer-readable storage media of any one of clauses (79) to (84) and (97) to (106); the computer system of any one of clauses (85) to (90) and (97) to (106); or the computer program product of any one of clauses (91) to (106); wherein the dye is 3, 3 '-Diaminobenzidine (DAB).

[0373] (108) The computer-implemented method of any one of clauses (73) to (78) and (97) to (107); the one or more non-transitory computer-readable storage media of any one of clauses (79) to (84) and (97) to (107); the computer system of any one of clauses (85) to (90) and (97) to (107); or the computer program product of any one of clauses (91) to (107); wherein the ADC is selected from the group consisting of: sacituzumab govitecan (Trodelvy®), sacituzumab tirumotecan (SKB264 / MK-2870) and datopotamab deruxtecan (DS-1062); optionally wherein the ADC is datopotamab deruxtecan (DS-1062).

[0374] (109) The computer-implemented method of any one of clauses (73) to (78) and (97) to (107); the one or more non-transitory computer-readable storage media of any one of clauses (79) to (84) and (97) to (107); the computer system of any one of clauses (85) to (90) and (97) to (107); or the computer program product of any one of clauses (91) to (107); wherein the ADC antibody is hTINAl- H1L1.

[0375] (110) The computer-implemented method of any one of clauses (73) to (78) and (97) to (107); the one or more non-transitory computer-readable storage media of any one of clauses (79) to (84) and (97) to (107); the computer system of any one of clauses (85) to (90) and (97) to (107); or the computer program product of any one of clauses (91) to (107); wherein the ADC antibody is a humanized IgGl monoclonal antibody.

[0376] (111) The computer-implemented method of any one of clauses (73) to (78) and (97) to (107); the one or more non-transitory computer-readable storage media of any one of clauses (79) to (84) and (97) to (107); the computer system of any TROP2-403-PCT01-NP one of clauses (85) to (90) and (97) to (107); or the computer program product of any one of clauses (91) to (107); wherein the ADC payload is a topoisomerase I inhibitor.

[0377] (112) The computer-implemented method of clause (111); the one or more non- transitory computer-readable storage media of clause (111); the computer system of clause (111); or the computer program product of clause (111); wherein the topoisomerase I inhibitor is represented by the following formula:

[0378] (113) The computer-implemented method of any one of clauses (73) to (78) and (97) to (112); the one or more non-transitory computer-readable storage media of any one of clauses (79) to (84) and (97) to (112); the computer system of any one of clauses (85) to (90) and (97) to (112); or the computer program product of any one of clauses (91) to (112); wherein the diagnostic antibody is Abeam EPR 20043.

[0379] (114) The computer-implemented method of any one of clauses (73) to (78), (97) to (107) and (113); the one or more non-transitory computer-readable storage media of any one of clauses (79) to (84), (97) to (107) and (113); the computer system of any one of clauses (85) to (90), (97) to (107) and (113); or the computer program product of any one of clauses (91) to (107) and (113); wherein the ADC is an anti-TROP2 antibody conjugated to a drug-linker via a thioether bond, wherein the drug-linker is represented by the following formula: TROP2-403-PCT01-NP and wherein A represents a connecting position to the anti-TROP2 antibody.

[0380] (115) The computer-implemented method of any one of clauses (73) to (78), (97) to (107) and (111) to (114); the one or more non-transitory computer-readable storage media of any one of clauses (79) to (84), (97) to (107) and (111) to

[0381] (114); the computer system of any one of clauses (85) to (90), (97) to (107) and (111) to (114); or the computer program product of any one of clauses (91) to (107) and (111) to (114); wherein the ADC includes an anti-TROP2 antibody comprising: a heavy chain comprising CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 4, and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 5; and a light chain comprising CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of an amino acid sequence represented by SEQ ID NO: 7, and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 8.

[0382] (116) The computer-implemented method of any one of clauses (73) to (78), (97) to (107) and (111) to (114); the one or more non-transitory computer-readable storage media of any one of clauses (79) to (84), (97) to (107) and (111) to

[0383] (114); the computer system of any one of clauses (85) to (90), (97) to (107) and (111) to (114); or the computer program product of any one of clauses (91) to (107) and (111) to (114); wherein the ADC includes an anti-TROP2 antibody comprising: TROP2-403-PCT01-NP a heavy chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 9; and a light chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 10.

[0384] (117) The computer-implemented method of any one of clauses (73) to (78), (97) to (107) and (111) to (114); the one or more non-transitory computer-readable storage media of any one of clauses (79) to (84), (97) to (107) and (111) to

[0385] (114); the computer system of any one of clauses (85) to (90), (97) to (107) and (111) to (114); or the computer program product of any one of clauses (91) to (107) and (111) to (114); wherein the ADC includes an anti-TROP2 antibody comprising: a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 11; and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 13.

[0386] (118) The computer-implemented method of any one of clauses (73) to (78), (97) to (107) and (111) to (114); the one or more non-transitory computer-readable storage media of any one of clauses (79) to (84), (97) to (107) and (111) to

[0387] (114); the computer system of any one of clauses (85) to (90), (97) to (107) and (111) to (114); or the computer program product of any one of clauses (91) to (107) and (111) to (114); wherein the ADC includes an anti-TROP2 antibody comprising: a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 12; and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 13.

[0388] (119) The computer-implemented method of any one of clauses (73) to (78) and (97) to (118); the one or more non-transitory computer-readable storage media of any one of clauses (79) to (84) and (97) to (118); the computer system of any one of clauses (85) to (90) and (97) to (118); or the computer program product TROP2-403-PCT01-NP of any one of clauses (91) to (118); wherein the cancer patient has non- squamous non-small cell lung cancer without actionable genomic alterations.

[0389] (120) The computer-implemented method of any one of clauses (73) to (78) and (97) to (118); the one or more non-transitory computer-readable storage media of any one of clauses (79) to (84) and (97) to (118); the computer system of any one of clauses (85) to (90) and (97) to (118); or the computer program product of any one of clauses (91) to (118); wherein the cancer patient has non- squamous non-small cell lung cancer with actionable genomic alterations.

[0390] (121) One or more non-transitory computer-readable storage media storing instructions which, when executed by one or more processors, cause the one or more processors to perform the computer-implemented method of any one of clauses (73) to (78) and (97) to (120).

[0391] (122) A computer system comprising: one or more processors; and one or more non-transitory computer-readable storage media storing instructions which, when executed by the one or more processors, cause the one or more processors to perform the computer-implemented method of any one of clauses (73) to (78) and (97) to (120).

[0392] (123) A computer program product comprising instructions which, when executed by one or more processors, cause the one or more processors to perform the computer-implemented method of any one of clauses (73) to (78) and (97) to (120).

[0393] (124) The method of clause (2), or any one of clauses (22) to (54) as dependent on clause (2); the method of clause (5), or any one of clauses (22) and (24) to (54) as dependent on clause (5); the antibody drug conjugate for use of clause (8), or any one of clauses (22) and (24) to (54) as dependent on clause (8); the use of clause (11), or any one of clauses (22) and (24) to (54) as dependent on clause (11); the method of clause (14), or any one of clauses (24) to (54) as TROP2-403-PCT01-NP dependent on clause (14); the antibody drug conjugate for use of clause (17), or any one of clauses (24) to (54) as dependent on clause (17); the use of clause (20), or any one of clauses (24) to (54) as dependent on clause (20); the method of clause (56); the antibody drug conjugate for use of clause (59); the use of clause (62); the method of clause (65); the antibody drug conjugate for use of clause (68); the use of clause (71); the computer-implemented method of clause (74), or any one of clauses (99) to (120) as dependent on clause (74); the computer-implemented method of clause (77), or any one of clauses (97) to (120) as dependent on clause (77); the one or more non-transitory computer-readable storage media of clause (80), or any one of clauses (99) to (120) as dependent on clause (80); the one or more non-transitory computer- readable storage media of clause (83), or any one of clauses (97) to (120) as dependent on clause (83); the computer system of clause (86), or any one of clauses (99) to (120) as dependent on clause (86); the computer system of clause (89), or any one of clauses (97) to (120) as dependent on clause (89); the computer program product of clause (92), or any one of clauses (99) to (120) as dependent on clause (92); the computer program product of clause (95), or any one of clauses (97) to (120) as dependent on clause (95); wherein the cancer patient has a cancer selected from the group consisting of: lung cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, bladder cancer, and uterine cancer.

[0394] (125) The method of clause (2), or any one of clauses (22) to (54) as dependent on clause (2); the method of clause (5), or any one of clauses (22) and (24) to (54) as dependent on clause (5); the antibody drug conjugate for use of clause (8), or any one of clauses (22) and (24) to (54) as dependent on clause (8); the use of clause (11), or any one of clauses (22) and (24) to (54) as dependent on clause (11); the method of clause (14), or any one of clauses (24) to (54) as dependent on clause (14); the antibody drug conjugate for use of clause (17), or any one of clauses (24) to (54) as dependent on clause (17); the use of clause (20), or any one of clauses (24) to (54) as dependent on clause (20); the method of clause (56); the antibody drug conjugate for use of clause (59); the TROP2-403-PCT01-NP use of clause (62); the method of clause (65); the antibody drug conjugate for use of clause (68); the use of clause (71); the computer-implemented method of clause (74), or any one of clauses (99) to (120) as dependent on clause (74); the computer-implemented method of clause (77), or any one of clauses (97) to (120) as dependent on clause (77); the one or more non-transitory computer-readable storage media of clause (80), or any one of clauses (99) to (120) as dependent on clause (80); the one or more non-transitory computer- readable storage media of clause (83), or any one of clauses (97) to (120) as dependent on clause (83); the computer system of clause (86), or any one of clauses (99) to (120) as dependent on clause (86); the computer system of clause (89), or any one of clauses (97) to (120) as dependent on clause (89); the computer program product of clause (92), or any one of clauses (99) to (120) as dependent on clause (92); the computer program product of clause (95), or any one of clauses (97) to (120) as dependent on clause (95); wherein the cancer patient has lung cancer.

[0395] (126) A computer-readable data carrier having stored thereon a computer program product according to any one of clauses (91) to (120) and (123) to (125).

[0396] (127) A data carrier signal carrying a computer program product according to any one of clauses (91) to (120) and (123) to (125).

[0397] TROP2-403-PCT01-NP

[0398] SEQUENCE LISTING

[0399] SEQ ID NO. 1 : Amino acid sequence of a heavy chain of the anti-TROP2 antibody

[0400] MKHLWFFLLLVAAPRWVLSQVQLVQSGAEVKKPGASVKVSCKASGYTFTTAGMQWVR QAPGQGLEWMGWINTHSGVPKYAEDFKGRVTISADTSTSTAYLQLSSLKSEDTAVYY CARSGFGSSYWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHK PSNTKVDKRVEPKSCDKT...

Claims

1. TROP2-403-PCT01-NPCLAIMSWhat is claimed is:

1. A method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), and wherein the cancer patient has non-squamous non-small cell lung cancer, comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

2. A method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample;TROP2-403-PCT01-NP detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

3. A method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; andTROP2-403-PCT01-NP identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

4. A method of treating cancer comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and administering a therapy comprising the ADC to the cancer patient if the tissue sample is nmOD positive.

5. A method of treating cancer comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample;TROP2-403-PCT01-NP detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and administering a therapy comprising the ADC to the cancer patient if the tissue sample is nmOD positive.

6. A method of treating cancer comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: staining a tissue sample from the cancer patient immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody binds to the protein on the cancer cells in the tissue sample; acquiring a digital image of the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; andTROP2-403-PCT01-NP administering a therapy comprising the ADC to the cancer patient if the tissue sample is nmOD positive.

7. A method of treating cancer comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was stained using a diagnostic antibody that binds to the protein in membranes and cytoplasm of cancer cells in the tissue sample, wherein for each cancer cell in a digital image of the tissue sample a mean optical density of membrane staining and a mean optical density of cytoplasm staining were determined, wherein for each cancer cell in the digital image a normalized membrane optical density (nmOD) was computed, and wherein the tissue sample was identified as nmOD positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold.

8. A method of treating cancer comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was stained using a diagnostic antibody that binds to the protein in membranes and cytoplasm of cancer cells in the tissue sample, wherein for each cancer cell in a digital image of the tissue sample a mean optical density of membrane staining and a mean optical density of cytoplasm staining were determined, wherein for each cancer cell in the digital image a normalized membrane optical density (nmOD) was computed, and wherein the tissue sample was identified as nmOD positive if a percentage quantile of cancer cells in theTROP2-403-PCT01-NP tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

9. A method of treating cancer comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was stained using a diagnostic antibody that binds to the protein in membranes and cytoplasm of cancer cells in the tissue sample, wherein for each cancer cell in a digital image of the tissue sample a mean optical density of membrane staining and a mean optical density of cytoplasm staining were determined, wherein for each cancer cell in the digital image a normalized membrane optical density (nmOD) was computed, and wherein the tissue sample was identified as nmOD positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

10. The method of any one of claims 1-6, wherein the detecting of cancer cells comprises (or comprised) detecting for each cancer cell the pixels that belong to the membrane and the pixels that belong to the cytoplasm.

11. The method of any one of claims 1 to 3, or claim 10 as dependent on any one of claims 1 to 3, further comprising: recommending a therapy comprising the ADC to the cancer patient when the tissue sample is nmOD positive.

12. The method of any one of claims 1-11, wherein the normalized membrane threshold is (or was) in a range of about 0.51 to about 0.60, about 0.53 to about 0.59, about 0.55 to about 0.57, or about 0.558 to about 0.559.TROP2-403-PCT01-NP13. The method of any one of claims 1-11, wherein the normalized membrane threshold is (or was) about 0.558 or about 0.559.

14. The method of any one of claims 1-13, wherein the percentage quantile of cancer cells is (or was) in a range of about 50% to about 95%, about 65% to about 90%, or about 70% to about 80%.

15. The method of any one of claims 1-13, wherein the percentage quantile of cancer cells is (or was) about 75%.

16. The method of any one of claims 1-15, wherein the detecting of cancer cells comprises (or comprised) detecting for each cancer cell the pixels that belong to the membrane using a cell center determined for each cancer cell.

17. The method of any one of claims 1-16, wherein the staining intensity of each membrane is (or was) computed based on an average optical density of a brown diaminobenzidine (DAB) signal in pixels of the membrane, and wherein the staining intensity of each cytoplasm is computed based on the average optical density of the brown DAB signal in pixels of the cytoplasm.

18. The method of any one of claims 1-17, wherein the dye is 3, 3 '-Diaminobenzidine (DAB).

19. The method of any one of claims 1-18, wherein the ADC is selected from the group consisting of: sacituzumab govitecan (Trodelvy®), sacituzumab tirumotecan (SKB264 / MK-2870) and datopotamab deruxtecan (DS-1062); optionally wherein the ADC is datopotamab deruxtecan (DS-1062).

20. The method of any one of claims 1-18, wherein the ADC antibody is hTINAl- H1L1.

21. The method of any one of claims 1-18, wherein the ADC antibody is a humanized IgGl monoclonal antibody.142TROP2-403-PCT01-NP22. The method of any one of claims 1-18, wherein the ADC payload is a topoisomerase I inhibitor.

23. The method of claim 22, wherein the topoisomerase I inhibitor is represented by the following formula:

24. The method of any one of claims 1-23, wherein the diagnostic antibody is Abeam EPR 20043.

25. The method of any one of claims 1-18 and 24, wherein the ADC is an anti- TROP2 antibody conjugated to a drug-linker via a thioether bond, wherein the druglinker is represented by the following formula:and wherein A represents a connecting position to the anti-TROP2 antibody.

26. The method of any one of claims 1-18 and 22-25, wherein the ADC includes an anti-TROP2 antibody comprising:143TROP2-403-PCT01-NP a heavy chain comprising CDRH1 consisting of an amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of an amino acid sequence represented by SEQ ID NO: 4, and CDRH3 consisting of an amino acid sequence represented by SEQ ID NO: 5; and a light chain comprising CDRL1 consisting of an amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of an amino acid sequence represented by SEQ ID NO: 7, and CDRL3 consisting of an amino acid sequence represented by SEQ ID NO: 8.

27. The method of any one of claims 1-18 and 22-25, wherein the ADC includes an anti-TROP2 antibody comprising: a heavy chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 9; and a light chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 10.

28. The method of any one of claims 1-18 and 22-25, wherein the ADC includes an anti-TROP2 antibody comprising: a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 11; and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 13.

29. The method of any one of claims 1-18 and 22-25, wherein the ADC includes an anti-TROP2 antibody comprising: a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 12; and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 13.

30. The method of any one of claims 1-29, wherein the cancer patient has non- squamous non-small cell lung cancer without actionable genomic alterations.TROP2-403-PCT01-NP31. The method of any one of claims 1-30, further comprising treatment with at least one additional therapeutic agent.

32. The method of claim 31, wherein the at least one additional therapeutic agent comprises an immune checkpoint inhibitor.

33. The method of claim 32, wherein the immune checkpoint inhibitor blocks the activity ofPD-1 or PD-Ll.

34. The method of claim 32, wherein the immune checkpoint inhibitor is selected from pembrolizumab, durvalumab, nivolumab, and combinations thereof.

35. The method of claim 32, wherein the immune checkpoint inhibitor is durvalumab.

36. The method of any one of claims 31-35, wherein the at least one additional therapeutic agent comprises a chemotherapeutic agent.

37. The method of claim 36, wherein the chemotherapeutic agent is a platinum-based chemotherapeutic agent.

38. The method of claim 37, wherein the platinum-based chemotherapeutic agent is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, and combinations thereof.

39. The method of claim 37, wherein the platinum-based chemotherapeutic agent is carboplatin.

40. The method of any one of claims 31-39, wherein the ADC and the at least one additional therapeutic agent form part of the same medicament.

41. The method of any one of claims 31-39, wherein the ADC and the at least one therapeutic agent are provided as separate medicaments for administration in combination or sequentially.145TROP2-403-PCT01-NP42. A method of treating cancer comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient is normalized membrane optical density (nmOD) positive.

43. A method of treating cancer comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient is normalized membrane optical density (nmOD) positive, wherein the tissue sample is normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample has nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60.

44. A method of treating cancer comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient is normalized membrane optical density (nmOD) positive, wherein the tissue sample is normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample has nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60.146TROP2-403-PCT01-NP45. A method of treating cancer comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive.

46. A method of treating cancer comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was determined to be normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.

47. A method of treating cancer comprising administering to a cancer patient an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on a cancer cell, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: administering a therapy comprising the ADC to the cancer patient if a tissue sample from the cancer patient was determined to be normalized membrane optical density (nmOD) positive, wherein the tissue sample was determined to be normalized membrane optical density (nmOD) positive if a percentage quantile of cancer cells in the tissue sample had nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold was in a range of about 0.50 to about 0.60.147TROP2-403-PCT01-NP48. One or more non-transitory computer-readable storage media storing instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

49. One or more non-transitory computer-readable storage media storing instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a148TROP2-403-PCT01-NP diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

50. One or more non-transitory computer-readable storage media storing instructions which, when executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image;TROP2-403-PCT01-NP identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

51. A computer system comprising: one or more processors; and one or more non-transitory computer-readable media storing instructions which, when executed on the one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

52. A computer system comprising:TROP2-403-PCT01-NP one or more processors; and one or more non-transitory computer-readable media storing instructions which, when executed on the one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

53. A computer system comprising: one or more processors; and one or more non-transitory computer-readable media storing instructions which, when executed on the one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising:TROP2-403-PCT01-NP acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

54. A computer program product comprising instructions which, when the program is executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell;152TROP2-403-PCT01-NP computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

55. A computer program product comprising instructions which, when the program is executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TROP2), the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.TROP2-403-PCT01-NP56. A computer program product comprising instructions which, when the program is executed by one or more processors, cause the one or more processors to perform a method of identifying a cancer patient for treatment with an antibody drug conjugate (ADC) that includes an ADC payload and an ADC antibody that targets a protein on cancer cells, wherein the protein is calcium signal transducer trophoblast antigen 2 (TR0P2), and wherein the cancer patient has non-squamous non-small cell lung cancer, the method comprising: acquiring a digital image of a tissue sample from the cancer patient, wherein the tissue sample has been stained immunohistochemically using a dye linked to a diagnostic antibody, wherein the diagnostic antibody is bound to the protein on the cancer cells in the tissue sample; detecting cancer cells in the digital image; determining for each cancer cell a mean optical density of staining by the dye in the membrane of the cancer cell; determining for each cancer cell a mean optical density of staining by the dye in the cytoplasm of the cancer cell; computing a normalized membrane optical density (nmOD) for each cancer cell in the digital image; identifying the tissue sample as nmOD positive if a percentage quantile of cancer cells in the tissue sample have nmOD values equal to or less than a nmOD threshold, wherein the nmOD threshold is in a range of about 0.50 to about 0.60; and identifying the cancer patient as one who will likely benefit from administration of the ADC if the tissue sample is nmOD positive.

57. The method of claim 2, or any one of claims 10-41 as dependent on claim 2; the method of claim 5, or any one of claims 10 and 12-41 as dependent on claim 5; the method of claim 8, or any one of claims 12-41 as dependent on claim 8; the method of claim 43; the method of claim 46; the one or more non-transitory computer-readable storage media according to claim 49; the computer system according to claim 52; or the computer program product according to claim 55; wherein the cancer patient has a cancer selected from the group consisting of: lung cancer, breast cancer, colorectal cancer, esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, bladder cancer, and uterine cancer.154TROP2-403-PCT01-NP58. The method of claim 2, or any one of claims 10-41 as dependent on claim 2; the method of claim 5, or any one of claims 10 and 12-41 as dependent on claim 5; the method of claim 8, or any one of claims 12-41 as dependent on claim 8; the method of claim 43; the method of claim 46; the one or more non-transitory computer-readable storage media according to claim 49; the computer system according to claim 52; or the computer program product according to claim 55; wherein the cancer patient has lung cancer.

59. A computer-readable data carrier having stored thereon a computer program product of any one of claims 54-58.

60. A data carrier signal carrying a computer program product of any one of claims 54-58.155

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