Methods of therapy for cancers characterized by overexpression of the HER2 receptor protein

Abstract

Methods for treating a subject with a cancer that is characterized by overexpression of HER2 receptor protein using a combination of interleukin-2 (IL-2) or variant thereof and at least one anti-HER2 antibody or fragment thereof are provided. These anti-tumor agents are administered as two separate pharmaceutical compositions, one containing IL-2 (or variant thereof), the other containing at least one anti-HER2 antibody (or fragment thereof), according to a dosing regimen. Administering of these two agents together potentiates the effectiveness of the anti-HER2 antibody alone, resulting in a positive therapeutic response that is improved with respect to that observed with this anti-tumor agent.

1 . A method of treating a cancer characterized by overexpression of the HER2 receptor protein in a subject, said method comprising concurrent therapy with an anti-HER2 antibody or fragment thereof and interleukin-2 (IL-2) or variant thereof, wherein said concurrent therapy promotes a positive therapeutic response in a treated subject. 
     
     
         2 . The method of  claim 1 , wherein said positive therapeutic response is greater than a therapeutic response that would be observed with therapy using said anti-HER2 antibody or fragment thereof alone. 
     
     
         3 . The method of  claim 1 , wherein said concurrent therapy comprises administering to said subject at least one therapeutically effective dose of a pharmaceutical composition comprising said IL-2 or variant thereof in combination with a dosing regimen for said anti-HER2 antibody or fragment thereof. 
     
     
         4 . The method of  claim 3 , wherein said IL-2 or variant thereof is administered subcutaneously. 
     
     
         5 . The method of  claim 3 , wherein said anti-HER2 antibody comprises at least one human constant region. 
     
     
         6 . The method of  claim 3 , wherein said anti-HER2 antibody is selected from the group consisting of 4D5 and 520C9, or fragment thereof. 
     
     
         7 . The method of  claim 3 , wherein said pharmaceutical composition comprising IL-2 is selected from the group consisting of a stabilized monomeric IL-2 pharmaceutical composition, a multimeric IL-2 composition, a stabilized lyophilized IL-2 pharmaceutical composition, and a stabilized spray-dried IL-2 pharmaceutical composition. 
     
     
         8 . The method of  claim 7 , wherein said IL-2 is recombinantly produced IL-2 having an amino acid sequence for human IL-2 or variant thereof. 
     
     
         9 . The method of  claim 8 , wherein said variant thereof has an amino acid sequence having at least about 70% sequence identity to the amino acid sequence for said human IL-2. 
     
     
         10 . The method of  claim 9 , wherein said anti-HER2 antibody comprises at least one human constant region. 
     
     
         11 . The method of  claim 9 , wherein said anti-HER2 antibody is selected from the group consisting of 4D5 and 520C9, or fragment thereof. 
     
     
         12 . The method of  claim 3 , wherein said therapeutically effective dose of said anti-HER2 antibody or fragment thereof is in the range from about 1.0 mg/kg to about 10.0 mg/kg and wherein said therapeutically effective dose of IL-2 or variant thereof is in the range from about 0.5 mIU/m 2  to about 4.0 mIU/m 2 . 
     
     
         13 . The method of  claim 12 , wherein said therapeutically effective dose of said anti-HER2 antibody or fragment thereof is in the range from about 2.0 mg/kg to about 9.0 mg/kg and wherein said therapeutically effective dose of IL-2 or variant thereof is in the range from about 0.6 mIU/m 2  to about 3.0 mIU/m 2 . 
     
     
         14 . The method of  claim 13 , wherein said therapeutically effective dose of said anti-HER2 antibody is in the range from about 3.0 mg/kg to about 8.0 mg/kg and wherein said therapeutically effective dose of IL-2 or variant thereof is in the range from about 0.8 mIU/m 2  to about 1.5 mIU/m 2 . 
     
     
         15 . The method of  claim 14 , wherein said therapeutically effective dose of said anti-HER2 antibody is about 4.0 mg/m 2  and wherein said therapeutically effective dose of IL-2 or variant thereof is about 1.0 MIU/m 2 . 
     
     
         16 . The method of  claim 3 , wherein said concurrent therapy comprises a first administration of said IL-2 or variant thereof on day 1 of a treatment period followed by a first administration of said anti-HER2 antibody or fragment thereof within 6 days of said first administration of said anti-HER2 antibody or fragment thereof to said subject. 
     
     
         17 . The method of  claim 3 , wherein said concurrent therapy comprises multiple dosing of said anti-HER2 antibody or fragment thereof and said IL-2 or variant thereof. 
     
     
         18 . The method of  claim 17 , wherein said multiple dosing comprises administering said IL-2 or variant thereof and said anti-HER2 antibody or fragment thereof during an introductory cycle, wherein said introductory cycle comprises administering a daily dose of said IL-2 or variant thereof on day 1 of said introductory cycle through day 20 of said introductory cycle, and administering a single dose of said anti-HER2 antibody on day 7 of said introductory cycle. 
     
     
         19 . The method of  claim 18 , further comprising administering said IL-2 or variant thereof and said anti-HER2 antibody or fragment thereof during at least one subsequent cycle, wherein said subsequent cycle comprises administering a daily dose of IL-2 or variant thereof on day 1 of said subsequent cycle through day 14 of said subsequent cycle, and administering said anti-HER2 antibody on day 1 of said subsequent cycle. 
     
     
         20 . The method of  claim 18 , further comprising intermediate-dose IL-2 pulsing on days 8-10 of said introductory cycle, wherein said pulsing comprises administering in place of said therapeutically effective dose of said IL-2 or variant thereof an intermediate dose of a pharmaceutical composition comprising IL-2 or variant thereof, wherein said intermediate dose comprises about 12.0 mIU/m 2  IL-2 or variant thereof. 
     
     
         21 . The method of  claim 19 , further comprising intermediate-dose IL-2 pulsing on days 1-3 of said subsequent cycle, wherein said pulsing comprises administering in place of said therapeutically effective dose of said IL-2 or variant thereof an intermediate dose of a pharmaceutical composition comprising IL-2 or variant thereof, wherein said intermediate dose comprises about 12.0 MIU/m 2  IL-2 or variant thereof.