Use of trifunctional bispecific and trispecific antibodies for the treatment of malignant ascites

Abstract

The invention describes the use of a pharmaceutical preparation containing a trifunctional bispecific and/or trispecific having the following properties: a) binding to a T cell; b) binding to at least an antigen on a tumor cell associated with malignant ascites and/or pleural effusion; c) binding, by its Fc portion (in the case of bispecific antibodies) or by a third specificity (in the case of trispecific antibodies), to Fc receptor-positive cells for the destruction of the tumor cells in the treatment of malignant ascites and/or pleural effusion.

1 . A method for inhibiting or reducing the formation of malignant ascites, pleural effusion, or a combination thereof in a subject, the method comprising administering to a subject having malignant ascites and/or pleural effusion one or more doses of a pharmaceutical preparation comprising a trifunctional bispecific and/or trispecific antibody, wherein the trifunctional bispecific and/or the trispecific antibody comprises:
 a) a first binding arm that binds to a T cell in the subject;   b) a second binding arm that binds to an antigen on a tumor cell associated with malignant ascites or pleural effusion in the subject; and;   c) an Fc portion that binds to an Fc receptor-positive cell in the subject,   
       thereby destroying the tumor cell and treating the malignant ascites, the pleural effusion, or the combination thereof in the subject. 
     
     
         2 . The method according to  claim 1 , wherein the pharmaceutical preparation is adapted for administration in the form of a first dose and of at least one further dose. 
     
     
         3 . The use method according to  claim 1 , wherein the administering step comprises administering at least three doses of the pharmaceutical preparation, a first dose for testing the subject for an allergic reaction against the trifunctional bispecific and/or trispecific antibody, a second dose for activating and proliferating immune cells in the subject, and a third dose, and optionally one or more subsequent doses, each of which is for destroying tumor cells associated with malignant ascites, pleural effusion, or the combination thereof in the subject. 
     
     
         4 . The use method according to  claim 1 , wherein said pharmaceutical preparation is adapted for administration in the form of a first dose to test for allergic reactions against the antibody administered. 
     
     
         5 . The method according to  claim 3 , wherein the first dose comprises 1 to 20 μg of the trifunctional bispecific and/or trispecific antibody, the second dose comprises 20 to 100 μg of the trifunctional bispecific and/or trispecific antibody, and the third dose, and each of the one or more subsequent doses if present, comprises 100 to 500 μg of the trifunctional bispecific and/or trispecific antibody. 
     
     
         6 . The method according to  claim 1 , wherein the administering step comprises administering 3 to 8 doses. 
     
     
         7 . The use method according to  claim 1 , wherein the pharmaceutical preparation further comprises inactivated autologous tumor cells, inactivated allogenic tumor cells, autologous immune cells, or combinations thereof. 
     
     
         8 . The method according to  claim 7 , wherein the autologous immune cells comprise apheresis cells obtained from the subject. 
     
     
         9 . The method according to  claim 1 , wherein the administering step comprises a primary immunization of the pharmaceutical preparation intraperitoneal administration, followed by one or more secondary immunizations by intradermal, subcutaneous, or intramuscular administration of the pharmaceutical preparation. 
     
     
         10 . The method according to  claim 7 , wherein for the one or more secondary immunizations, the pharmaceutical preparation comprises 1-10 μg trifunctional bispecific and/or trispecific antibodies and at least one of:
 a) 1-200×10 6  inactivated tumor cells, and 
 b) 10-500×10 6  immune cells. 
 
     
     
         11 . The method according to  claim 1 , wherein the trifunctional bispecific and/or trispecific antibody is an intact bispecific and/or trispecific antibody. 
     
     
         12 . The method according to  claim 1 , wherein the trifunctional bispecific and/or trispecific antibody binds to an Fc receptor-positive cell having an Fcγ receptor I or III. 
     
     
         13 . The method according to  claim 1 , wherein the trifunctional bispecific and/or trispecific antibody binds to an Fcγ receptor I- or III-positive cell selected from the group consisting of a monocyte, a macrophage, a dendritic cell, a “natural killer” cell (NK cell, and an activated neutrophil. 
     
     
         14 . The method according to  claim 1 , wherein the trifunctional bispecific and/or trispecific antibody induces tumor-reactive complement-binding antibodies and a humoral immune response in the subject. 
     
     
         15 . The method according to  claim 1 , wherein the first binding arm binds to a molecule selected from the group consisting of CD2, CD3, CD4, CD5, CD6, CD8, CD28, CD154, and CD44 that is present on the T cell. 
     
     
         16 . The method according to  claim 1 , wherein binding of the trifunctional bispecific and/or trispecific antibody to the Fc receptor-positive cell, induces or enhances Fc receptor-positive cell expression of at least one of CD40, CD80, CD86, ICAM-1, and LFA-3; secretion of a cytokine; or combinations thereof. 
     
     
         17 . The method according to  claim 16 , wherein the cytokine is selected from the group consisting of IL-1, IL-2, IL-4, IL-6, IL-8, IL-12, INF-γ, and TNF-α. 
     
     
         18 . The method according to  claim 15 , wherein the bispecific and/or trispecific antibody is selected from the group consisting of an anti-CD3 X anti-tumor-associated antigen bispecific and/or trispecific antibody; an anti-CD4 X anti-tumor-associated bispecific and/or trispecific antibodyl an anti-CD5 X anti-tumor-associated antigen bispecific and/or trispecific antibody; an anti-CD6 X anti-tumor-associated antigen bispecific and/or trispecific antibody; an anti-CD8 X anti-tumor-associated antigen bispecific and/or trispecific antibody; an anti-CD2 X anti-tumor-associated antigen bispecific and/or trispecific antibody; an anti-CD28 X anti-tumor-associated antigen bispecific and/or trispecific antibody; an anti-CD40L X anti-tumor-associated antigen bispecific and/or trispecific antibody; and an anti-CD44 X anti-tumor-associated antigen bispecific and/or trispecific antibody. 
     
     
         19 . The method according to  claim 1 , wherein the trifunctional bispecific and/or trispecific antibody is a heterologous trifunctional bispecific and/or trispecific antibody. 
     
     
         20 . The method according to  claim 1 , wherein said trispecific antibody has one T cell binding arm, one tumor cell binding arm, and a third specificity for binding to Fc receptor-positive cells. 
     
     
         21 . The method according to  claim 1 , wherein the trispecific antibody is selected from the group consisting of an anti-CD3 X anti-tumor-associated antigen antibody, an anti-CD4 X anti-tumor-associated antigen antibody, an anti-CD5 X anti-tumor-associated antigen antibody, an anti-CD6 X anti-tumor-associated antigen antibody, an anti-CD8 X anti-tumor-associated antigen antibody, an anti-CD2 X anti-tumor-associated antigen antibody, an anti-CD28 X anti-tumor-associated antigen antibody, an anti-CD40L X anti-tumor-associated antigen antibody, and an anti-CD44 X anti-tumor-associated antigen antibody. 
     
     
         22 . The method according to  claim 7 , wherein the inactivated autologous tumor cells or the inactivated allogenic tumor cells have been inactivated by exposing autologous tumor cells or allogenic tumor cells to irradiation. 
     
     
         23 . The method according to  claim 7 , further comprising heating the inactivated allogenic tumor cells or the inactivated allogenic tumor cells prior to administration to the subject, whereby immunogenicity of the heated inactivated autologous tumor cells or the heated inactivated allogenic tumor cells is enhanced in the subject. 
     
     
         24 . The method according to  claim 1 , wherein the inding of the trifunctional bispecific and/or trispecific antibody to an Fc receptor-positive cell induces or enhances expression of a cytokine, a co-stimulatory antigen, or combinations thereof in the Fc-receptor-positive cell.