Combination therapies involving claudin 18.2 antagonists for treatment of cancer

A method of identifying and treating a subject having a Claudin 18.2 (CLDN18.2)-expressing cancer who may benefit from a treatment comprising a CLDN18.2 antagonist in combination with chemotherapy, the method comprising:

• (a) determining the level of CLDN18.2 protein in a cancer sample (e.g., in a tumor tissue sample), and
• (b) selecting a subject having a medium-to-high level, or a low level of the CLDN18.2 protein for the treatment.

The method of any one of the preceding claims, wherein the level of CLDN18.2 protein or the level of CLDN18.2 expression is quantified by membrane staining intensity measured by IHC using an anti-CLDN18.2 diagnostic reagent (e.g., anti-CLDN18.2 diagnostic antibody).

The method of any one of the preceding claims, wherein the level of CLDN18.2 protein or the level of CLDN18.2 expression is quantified by percentage of cancer cells having a predetermined threshold of the membrane staining intensity measured by IHC using an anti-CLDN18.2 diagnostic reagent (e.g., anti-CLDN18.2 diagnostic antibody).

The method of any one of the preceding claims, wherein:

• a) the medium-to-high level of CLDN18.2 protein or CLDN18.2 expression corresponds to at least 40% of the cancer cells in the cancer sample (e.g., tumor tissue sample) having an expression level of CLDN18.2 characterized by membrane staining intensity of at least 2+ (e.g. 2+ or 3+), as measured using an anti-CLDN18.2 diagnostic antibody optionally on Leica Bond III LDT platform, or corresponds to an equivalent readout as measured on another test platform, and/or
• b) the low level of CLDN18.2 protein or CLDN18.2 expression corresponds to at least 1% (e.g., at least 2%, at least 5% or at least 10%) of the cancer cells in the cancer sample (e.g., tumor tissue sample) having an expression level of CLDN18.2 characterized by membrane staining intensity of at least 1+, and less than 40% of the cancer cells in the cancer sample (e.g., tumor tissue sample) having an expression level of CLDN18.2 characterized by membrane staining intensity of at least 2+ or 3+ as measured using an anti-CLDN18.2 diagnostic antibody optionally on Leica Bond III LDT platform, or corresponds to an equivalent readout as measured on another test platform.

The method of any one of the preceding claims, wherein the anti-CLDN18.2 diagnostic antibody has a concentration of about 0.05-20 pg/mL (e.g., about 0.05-20 ug/ml, about 0.1-15 ug/ml, about 0.15-10 ug/ml, about 0.15-5 ug/ml, about 0.2-10 ug/ml, about 0.3-10 ug/ml, about 0.4-10 ug/ml, about 0.5-10 ug/ml, about 0.6-10 ug/ml, about 0.7-10 ug/ml, about 0.8-10 ug/ml, about 0.9-10 ug/ml, about 1-10 ug/ml or about 0.15-5 ug/ml).

The method of any one of the preceding claims, wherein the anti-CLDN18.2 diagnostic antibody is diluted in a dilution buffer for about 10-60 min (e.g., about 10-60 min, about 15-50 min, about 15-40 min, about 15-35 min, about 15-30 min, about 16-32 min or about 20-30 min).

The method of any one of the preceding claims, wherein the IHC assay comprises antigen retrieval for about 15-120 min (e.g., about 15-120 min, about 25-100 min, about 35-90 min, about 45-80 min, about 55-90 min, about 65-80 min, about 70 min, about 15-30 min, about 20-30 min, or about 64-104 min).

The method of any one of the preceding claims, wherein the chemotherapy comprises a chemotherapeutic agents selected from the group consisting of:

• erlotinib, afatinib, docetaxel, adriamycin, 5-fluorouracil (5-FU), panobinostat, gemcitabine, cisplatin, pemetrexed, carboplatin, paclitaxel, bevacizumab, trastuzumab, pertuzumab, metformin, temozolomide, tamoxifen, oteracil, doxorubicin, rapamycin, lapatinib, hydroxycamptothecin, trametinib, tegafur, gimeracil, leucovorin calcium (folinic acid) (LV), irinotecan hydrochloride (CPT-11), platinum (e.g., cisplatin), epirubicin, oxaliplatin, capecitabine.

The method of any one of the preceding claims, wherein the chemotherapy comprises a combination of chemotherapeutic agents.

The method of any one of the preceding claims, wherein the treatment further comprises an immunotherapy, or wherein the method further comprises administering to the subject a therapeutically effective amount of an immunotherapy.

The method of any one of the preceding claims, wherein the immunotherapy comprises an immunotherapeutic agent, such as a PD-1/PD-L1 axis inhibitor.

The method of any one of preceding claims, wherein the subject is determined to have in a cancer sample (e.g., in a tumor tissue sample):

• a) a high level of PD-L1 expression;
• or b) a low level of PD-L1 expression.

A method for treating a CLDN18.2-expressing cancer in a human subject in need thereof, comprising:

• administering to the subject a therapeutically effective amount of a CLDN18.2 antagonist in combination with chemotherapy and a PD-1/PD-L1 axis inhibitor,
• wherein the subject is determined to have low level of PD-L1 expression in a cancer sample (e.g., in a tumor tissue sample).

The method of any one of the preceding claims, wherein the CLDN18.2 antagonist comprises an anti-CLDN18.2 antibody, such as a monoclonal anti-CLDN18.2 antibody, a bi-specific antibody targeting CLDN18.2 and a second antigen comprising an anti-CLDN18.2 antigen binding domain.

The method of any one of the preceding claims, wherein the anti-CLDN18.2 antagonist further comprises an immunoglobulin constant region, optionally a constant region of human Ig, or optionally a constant region of human IgG.

The method of any one of the preceding claims, wherein the CLDN18.2 antagonist is a humanized anti-CLDN18.2 antibody.

The method of any one of the preceding claims, wherein the CLDN18.2 antagonist is further linked to one or more conjugate moieties.

The method of any one of the preceding claims, wherein the subject is human.

The method of any one of the preceding claims, wherein the administration is via oral, nasal, intravenous, subcutaneous, sublingual, or intramuscular administration.

The method of any one of the preceding claims, wherein the CLDN18.2 antagonist is administered at a dosage of about 1 mg/kg to about 30 mg/kg (e.g., 2 mg/kg, 4 mg/kg, 6 mg/kg, 8 mg/kg, 10 mg/kg, 12 mg/kg, 14 mg/kg, 16 mg/kg, 18 mg/kg, 20 mg/kg, 22 mg/kg, 24 mg/kg, 26 mg/kg, 28 mg/kg or 30 mg/kg).

The method of any one of the preceding claims, wherein the CLDN18.2 antagonist is administered at a dosage of about 4 mg/kg or 6 mg/kg.

The method of any one of the preceding claims, wherein the CLDN18.2 antagonist is administered at a dosing interval of once a week to once every 12-weeks (Q1W, Q2W, Q3W, Q4W, Q5W, Q6W, Q7W, Q8W, Q9W, Q10W, Q11W or Q12W), or once a month to once every 3 months (Q1M, Q2M or Q3M), or once quarterly.

The method of any one of the preceding claims, wherein the CLDN18.2 antagonist is administered at a dosing interval of once every 2-weeks (Q2W) or once every 3-weeks (Q3W).

The method of any one of the preceding claims, wherein the CLDN18.2 antagonist is administered at a dosing of 4 mg/kg with interval of once every 2-weeks (Q2W) or administered at a dosing of 6 mg/kg with interval of once every 3-weeks (Q3W).

The method of any one of the preceding claims, wherein the administration of the CLDN18.2 antagonist is prior to, simultaneously with, or after the administration of the chemotherapy.

The method of any one of the preceding claims, wherein the CLDN18.2-expressing cancer is selected from the group consisting of gastric cancer, esophageal adenocarcinoma, gastric/gastro-esophageal junction (G/GEJ) cancer, lung cancer, bronchial cancer, bone cancer, liver and bile duct cancer, pancreatic cancer, breast cancer, liver cancer, ovarian cancer, testicle cancer, kidney cancer, bladder cancer, cholangiocarcinoma (biliary tract carcinoma), head and neck cancer, spine cancer, brain cancer, cervix cancer, uterine cancer, endometrial cancer, colon cancer, colorectal cancer, rectal cancer, anal cancer, esophageal cancer, gastrointestinal cancer, skin cancer, prostate cancer, pituitary cancer, stomach cancer, vagina cancer, thyroid cancer, glioblastoma, astrocytoma, melanoma, myelodysplastic syndrome, sarcoma, teratoma, and adenocarcinoma.

The method of any one of the preceding claims, wherein the CLDN18.2-expressing cancer is HER2 negative.

The method of any one of the preceding claims, wherein the CLDN18.2-expressing cancer is locally advanced.

The method of any one of the preceding claims, wherein the CLDN18.2-expressing cancer is metastatic.

The method of any one of the preceding claims, wherein the subject is treatment naïve.

The method of any one of the preceding claims, wherein the subject has not shown any resistance to a CLDN18.2 antagonist, a chemotherapy or a PD-1/PD-L1 axis inhibitor.

The method of any one of the preceding claims, wherein the subject has a survival of a longer period as compared to a subject who has been treated with a reference antibody (e.g., Nivolumab or Zolbetuximab) in combination with chemotherapy.

Use of a CLDN18.2 antagonist in the manufacture of a medicament for treating a CLDN18.2-expressing cancer in a subject in need thereof, wherein the treatment comprises administering to the subject the medicament in combination with chemotherapy, wherein the subject is determined to have medium-to-high, or low level of CLDN18.2 expression in a cancer sample (e.g., in a tumor tissue sample).

Use of a CLDN18.2 antagonist in the manufacture of a medicament for treating a CLDN18.2-expressing cancer in a subject in need thereof, wherein the medicament further comprises chemotherapy, wherein the subject is determined to have medium-to-high, or low level of CLDN18.2 expression in a cancer sample (e.g., in a tumor tissue sample).

A kit for use in identifying and treating a subject having a CLDN18.2-expressing cancer who may benefit from a treatment comprising a CLDN18.2 antagonist in combination with chemotherapy, comprising an anti-CLDN18.2 diagnostic reagent (e.g., anti-CLDN18.2 diagnostic antibody) and a package insert comprising instructions for using the treatment in a subject having medium-to-high, or low level of the CLDN18.2 expression.