Therapy involving antibodies against claudin 18.2 for treatment of cancer

Abstract

The present invention generally provides a therapy for effectively treating and/or preventing diseases associated with cells expressing CLDN18.2, in particular cancer diseases such as gastroesophageal cancer. Data are presented demonstrating that administration of an anti-CLDN18.2 antibody to human patients with gastroesophageal cancer is safe and well-tolerated up to a dose of at least 1000 mg/m2. Furthermore, data are presented demonstrating that the antibody is fully functional in these patients to execute anti-tumor cell effects and evidence for antitumoral activity was obtained.

1 . A method of treating or preventing a cancer disease comprising administering to a patient an antibody having the ability of binding to CLDN18.2, wherein the antibody is administered so as to provide a serum level of at least 40 μg/ml. 
     
     
         2 . The method of  claim 1  wherein the serum level provided is between 40 μg/ml and 700 μg/ml. 
     
     
         3 . The method of  claim 1  or  2  wherein the serum level is provided for at least 7 days. 
     
     
         4 . The method of any one of  claims 1  to  3  wherein the method comprises administering a dose of the antibody of at least 300 mg/m 2 . 
     
     
         5 . A method of treating or preventing a cancer disease comprising administering to a patient an antibody having the ability of binding to CLDN18.2, wherein the antibody is administered at a dose of at least 300 mg/m 2 . 
     
     
         6 . A method of treating or preventing a cancer disease comprising administering to a patient an antibody having the ability of binding to CLDN18.2, wherein at least 50% of the cancer cells of the patient are CLDN18.2 positive and/or at least 40% of the cancer cells of the patient are positive for surface expression of CLDN18.2. 
     
     
         7 . The method of any one of  claims 1  to  6  wherein treatment of the cancer disease results in achieving stable disease. 
     
     
         8 . A method of achieving stable disease in a cancer patient comprising administering to the patient an antibody having the ability of binding to CLDN18.2. 
     
     
         9 . The method of  claim 7  or  8  wherein stable disease is achieved for at least 2 months. 
     
     
         10 . The method of any one of  claims 1  to  9  wherein the antibody is administered in a single dose or in multiple doses. 
     
     
         11 . A method of treating or preventing a cancer disease comprising administering to a patient an antibody having the ability of binding to CLDN18.2, wherein the antibody is administered in multiple doses. 
     
     
         12 . The method of  claim 10  or  11  wherein the antibody is administered in at least 3 doses. 
     
     
         13 . The method of any one of  claims 10  to  12  wherein the doses of the antibody are administered in time intervals of at least 7 days. 
     
     
         14 . The method of any one of  claims 1  to  13  further comprising administering one or more selected from the group consisting of antiemetics, antispasmodics, parasympatholytics and agents which protect gastric mucosa. 
     
     
         15 . A method of treating or preventing a cancer disease comprising administering to a patient an antibody having the ability of binding to CLDN18.2 and one or more selected from the group consisting of antiemetics, antispasmodics, parasympatholytics and agents which protect gastric mucosa. 
     
     
         16 . The method of  claim 14  or  15  wherein the method comprises administering to the patient a neurokinin 1 (NK1) receptor antagonist such as Aprepitant (e.g. Emend), a 5-HT3 receptor antagonist such as Ondansetron (e.g. Zofran), Granisetron (e.g. Kytril, Sancuso) or Palonosetron (e.g. Aloxi), or a combination of two or more thereof, an antispasmodic such as butylscopolamine (e.g. Buscopan) and a proton pump inhibitor such as Pantoprazole (e.g. Pantozol). 
     
     
         17 . The method of any one of  claims 1  to  16  wherein the antibody is administered by i.v. infusion. 
     
     
         18 . The method of  claim 17  wherein the i.v. infusion is over a time period of between 1 and 4 hours. 
     
     
         19 . A method of determining the responsiveness of a cancer patient to treatment or prevention of a cancer disease comprising administering an antibody having the ability of binding to CLDN18.2, said method comprising the step of determining the blood level of one or more markers in the patient, wherein the one or more markers are selected from the group consisting of CA 125, CA 15-3, CA 19-9, CEA, IL-2, IL-15, IL-6, IFNγ, and TNFα. 
     
     
         20 . The method of  claim 19  wherein the level is determined in blood, plasma or serum. 
     
     
         21 . The method of  claim 19  or  20  wherein the one or more markers are selected from the group consisting of CA 125, CA 15-3, CA 19-9, CEA, IL-2, IL-15, IFNγ, and TNFα and a decrease in the level of at least one of the markers following administration of the antibody indicates that the patient is responsive to treatment or prevention of a cancer disease. 
     
     
         22 . The method of  claim 19  or  20  wherein the marker is IL-6 and an increase in the level of the marker following administration of the antibody indicates that the patient is responsive to treatment or prevention of a cancer disease. 
     
     
         23 . A method of determining whether a cancer patient is amenable to treatment or prevention of a cancer disease comprising administering an antibody having the ability of binding to CLDN18.2, said method comprising the step of determining the percentage of CLDN18.2 positive cancer cells. 
     
     
         24 . The method of  claim 23  wherein a level of at least 50% CLDN18.2 positive cancer cells indicates that the patient is amenable to treatment or prevention of a cancer disease. 
     
     
         25 . The method of  claim 23  or  24  wherein a level of at least 50% cancer cells which are positive for surface expression of CLDN18.2 indicates that the patient is amenable to treatment or prevention of a cancer disease. 
     
     
         26 . The method of any one of  claims 1  to  25 , wherein the antibody mediates cell killing by one or more of complement dependent cytotoxicity (CDC) mediated lysis, antibody dependent cellular cytotoxicity (ADCC) mediated lysis, induction of apoptosis and inhibition of proliferation. 
     
     
         27 . The method of any one of  claims 1  to  26 , wherein the antibody is an antibody selected from the group consisting of (i) an antibody produced by and/or obtainable from a clone deposited under the accession no. DSM ACC2737, DSM ACC2738, DSM ACC2739, DSM ACC2740, DSM ACC2741, DSM ACC2742, DSM ACC2743, DSM ACC2745, DSM ACC2746, DSM ACC2747, DSM ACC2748, DSM ACC2808, DSM ACC2809, or DSM ACC2810, (ii) an antibody which is a chimerized or humanized form of the antibody under (i), (iii) an antibody having the specificity of the antibody under (i), and (iv) an antibody comprising the antigen binding portion or antigen binding site, in particular the variable region, of the antibody under (i) and preferably having the specificity of the antibody under (i). 
     
     
         28 . The method of any one of  claims 1  to  27  wherein the cancer is gastroesophageal cancer. 
     
     
         29 . The method of any one of  claims 1  to  28  wherein the cancer is metastatic, refractory or recurrent advanced gastroesophageal cancer. 
     
     
         30 . The method of any one of  claims 1  to  29  wherein the patient had prior therapy with at least one drug selected from the group consisting of pyrimidine analogs, platinum compounds, epirubicine, docetaxel and detoxifying agents for antineoplastic treatment. 
     
     
         31 . The method of any one of  claims 1  to  30  wherein the patient has an ECOG performance status of between 0 and 1 and/or a Karnofsky Index of between 70 and 100%. 
     
     
         32 . The method of any one of  claims 1  to  31  wherein the patient is a human patient. 
     
     
         33 . The method of any one of  claims 1  to  32  wherein CLDN18.2 has the amino acid sequence according to SEQ ID NO: 1