Dosage and administration for preventing cardiotoxicity in treatment with erbb2-targeted immunoliposomes comprising anthracycline chemotherapeutic agents

Abstract

Methods for determining dosage of HER2-targeted anthracycline-containing immunoliposomes are disclosed, as are methods of treating cancer patients with HER2-positive tumors using dosages so determined. Upon administration, the dosages share the low cardiotoxicity profile of standard dosages of non-immunoliposomal (untargeted), anthracycline-containing liposomes.

1 .- 20 . (canceled) 
     
     
         21 . An injectable pharmaceutical composition comprising an immunoliposome encapsulating about 1.8 to about 2.2 mg/mL of doxorubicin, the immunoliposome having a diameter of approximately 75-110 nm, wherein the immunoliposome comprises an antibody fragment that binds to HER2 and the immunoliposome is internalized into a cell having at least 200,000 HER2 receptors per cell to a greater degree than into a cell having less than 200,000 HER2 receptors per cell, wherein the degree of internalization is determined after treatment of the cell with 15 μg/ml of the immunoliposome for 180 minutes. 
     
     
         22 . The composition of  claim 21 , wherein the pharmaceutical composition is formulated for intravenous administration. 
     
     
         23 . The composition of  claim 21 , wherein the immunoliposome comprises hydrogenated soy phosphatidylcholine (HSPC), cholesterol and polyethylene glycol-disteroylphosphoethanolamine (PEG-DSPE) at a molar ratio of 3:2:0.3, the liposome having a. a total of about 10 mmol/L of lipid and a total of polyethyleneglycol-derivatized phosphatidylethanolamine in the amount of approximately one polyethyleneglycol (PEG) molecule for 200 phospholipid molecules, of which approximately one PEG molecule for each 1780 phospholipid molecules bears at its end an F5 single-chain Fv antibody fragment that binds to HER2 (DSPE-PEG-F5), wherein F5 is an anti-ErbB2 (anti-HER2) scFv antibody fragment (encoded by ATCC plasmid deposit designation PTA-7843);
 b. a HSPC lipid concentration of about 40 mmol/L;   c. a total of about 0.16 to about 0.30 mg/mL DSPE-PEG-F5   d. a total of about 130 to about 170 g doxorubicin/mol phospholipid; and   e. about 12 to about 22 g DSPE-PEG-F5/mol phospholipid.   
     
     
         24 . The composition of  claim 23 , comprising 10 mM/L histidine-HC1 as a buffer (pH 6.5), and 10% sucrose. 
     
     
         25 . A doxorubicin liposome formulation comprising doxorubicin encapsulated in a unilamellar lipid bilayer vesicle of approximately 75-110 nm in diameter composed of phosphatidylcholine, cholesterol, and a polyethyleneglycol-derivatized phosphatidylethanolamine in the amount of approximately one PEG molecule for 200 phospholipid molecules, of which approximately one PEG chain for each 1780 phospholipid molecules bears at its end an F5 single-chain Fv antibody fragment that binds to HER2, wherein F5 is an anti-ErbB2 (anti-HER2) scFv antibody fragment (encoded by ATCC plasmid deposit designation PTA-7843). 
     
     
         26 . The formulation of  claim 25 , wherein the unilamellar lipid bilayer comprises HSPC:cholesterol:PEG-DSPE at a molar ratio of 3:2:0.3. 
     
     
         27 . The formulation of  claim 26 , wherein the total HSPC lipid concentration of the liposome is about 40 mmol/L. 
     
     
         28 . The formulation of  claim 25 , comprising a total of about 10 mmol/L of lipid, and about 2 mg/mL of doxorubicin. 
     
     
         29 . The formulation of  claim 25 , comprising a total of about 1.8 to about 2.2 mg/mL of doxorubicin in liposomes that contain about 0.16 to about 0.30 mg/mL DSPE-PEG-F5. 
     
     
         30 . The formulation of  claim 25 , comprising about 130 to about 170 g doxorubicin/mol phospholipid and about 12 to about 22 g DSPE-PEG-F5/mol phospholipid. 
     
     
         31 . The formulation of  claim 25 , comprising 10 mM/L histidine-HC1 as a buffer (pH 6.5), and 10% sucrose to maintain isotonicity. 
     
     
         32 . The formulation of  claim 27 , formulated for intravenous injection. 
     
     
         33 . A pharmaceutical composition comprising an immunoliposome encapsulating about 1.8 to about 2.2 mg/mL of doxorubicin, the immunoliposome having a diameter of approximately 75-110 nm, and is composed of phosphatidylcholine, cholesterol, and a polyethyleneglycol-derivatized phosphatidylethanolamine in the amount of approximately one PEG molecule for 200 phosphatidylethanolamine phospholipid molecules, and wherein a plurality of the immunoliposomes bear on average about 45 F5 anti-ErbB2 (anti-HER2) scFv antibody fragments per immunoliposome, the scFv antibody fragments being encoded by ATCC plasmid deposit designation PTA-7843. 
     
     
         34 . The composition of  claim 33 , comprising 10 mM/L histidine-HCl as a buffer (pH 6.5), and 10% sucrose. 
     
     
         35 . The composition of  claim 33 , wherein the composition is formulated for intravenous administration.