Erenumab compositions and uses thereof

Abstract

The present invention relates to compositions comprising erenumab and one or more erenumab variants, including isomerization variants, deamidation variants, acidic variants, and HMW species. Pharmaceutical formulations comprising the erenumab compositions and methods of using and characterizing the compositions are also described.

What is claimed: 
     
         1 . A method for assessing the quality of an erenumab composition, comprising:
 obtaining an erenumab composition that contains erenumab and one or more erenumab variants, wherein erenumab comprises two heavy chain and two light chains, each said heavy chain having a sequence of SEQ ID NO: 1 or SEQ ID NO: 3 and each said light chain having a sequence of SEQ ID NO: 2 or SEQ ID NO: 4;   measuring the amount of one or more erenumab variants in the composition, wherein the erenumab variants comprise isomerization variants, deamidation variants, acidic variants, HMW species, or combinations thereof;   comparing the measured amount of the one or more erenumab variants to a pre-determined reference criterion: and   preparing a pharmaceutical formulation or pharmaceutical product of the erenumab composition if the comparison indicates that the pre-determined reference criterion is met.   
     
     
         2 . The method of  claim 1 , wherein the method comprises measuring the amount of isomerization and deamidation variants in the composition and the pre-determined reference criterion is about 15% or less, and wherein the isomerization variant has an isoaspartic acid residue or succinimide at position 105 in either or both heavy chains of erenumab and the deamidation variant has an aspartic acid residue, a succinimide, or an isoaspartic acid residue at amino acid position 102 in either or both heavy chains of erenumab. 
     
     
         3 . The method of  claim 2 , wherein the pre-determined reference criterion is a range from about 1% to about 10%. 
     
     
         4 . The method of  claim 2 , wherein the amount of isomerization and deamidation variants in the composition is measured by hydrophobic interaction chromatography high performance liquid chromatography (HIC-HPLC). 
     
     
         5 . The method of  claim 1 , wherein the method comprises measuring the amount of acidic variants in the composition and the pre-determined reference criterion is about 38% or less. 
     
     
         6 . The method of  claim 5 , wherein the pre-determined reference criterion is a range from about 25% to about 38%. 
     
     
         7 . The method of  claim 5 , wherein the amount of acidic variants in the composition is measured by cation exchange high performance liquid chromatography (CEX-HPLC). 
     
     
         8 . The method of  claim 1 , wherein the method comprises measuring the amount of HMW species in the composition and the pre-determined reference criterion is about 2.5% or less. 
     
     
         9 . The method of  claim 8 , wherein the pre-determined reference criterion is a range from about 0.3% to about 2.4%. 
     
     
         10 . The method of  claim 8 , wherein the amount of HMV species in the composition is measured by size exclusion ultra-high performance liquid chromatography (SE-UHPLC). 
     
     
         11 . The method of  claim 1 , wherein the erenumab composition is a cell culture harvest from a Chinese Hamster Ovary (CHO) cell line that recombinantly expresses a nucleic acid encoding a heavy chain of SEQ ID NO: 1 and a nucleic acid encoding a light chain of SEQ ID NO: 2. 
     
     
         12 . The method of  claim 1 , wherein the erenumab composition is an erenumab drug substance. 
     
     
         13 . The method of  claim 1 , wherein the erenumab composition is an erenumab drug product. 
     
     
         14 . A method for assessing the quality of an erenumab composition, comprising:
 (a) obtaining an erenumab composition that contains erenumab and one or more erenumab variants, wherein erenumab comprises two heavy chain and two light chains, each said heavy chain having a sequence of SEQ ID NO: 1 or SEQ ID NO: 3 and each said light chain having a sequence of SEQ ID NO: 2 or SEQ ID NO: 4 and wherein the erenumab variants comprise isomerization variants, deamidation variants, acidic variants, HAM species or combinations thereof;   (b) evaluating the erenumab composition by performing one, two, or all three of following:
 (i) measuring the amount of isomerization and deamidation variants in the composition by the pre-peaks in HIC-HPLC and comparing the measured amount to a pre-determined reference criterion of about 10% or less; 
 (ii) measuring the amount of acidic variants in the composition by the acidic peaks in CEX-HPLC and comparing the measured amount to a pre-determined reference criterion of about 25% to about 38%; and/or 
 (iii) measuring the amount of HMW species in the composition by the pre-peaks in SE-UHPLC and comparing the measured about to a pre-determined reference criterion of about 2.5% or less; and 
   (c) preparing a pharmaceutical formulation or pharmaceutical product of the erenumab composition if the comparison or comparisons in step (b) indicate that the pre-determined reference criteria are met.   
     
     
         15 . The method of  claim 14 , wherein all three steps (b)(i), (b)(ii), and (b)(iii) are performed. 
     
     
         16 . The method of  claim 14 , wherein the isomerization variant has an isoaspartic acid residue or succinimide at position 105 in either or both heavy chains of erenumab and the deamidation variant has an aspartic acid residue, a succinimide, or an isoaspartic acid residue at amino acid position 102 in either or both heavy chains of erenumab. 
     
     
         17 . The method of  claim 14 , wherein the erenumab composition is an erenumab drug substance. 
     
     
         18 . The method of  claim 14 , wherein the erenumab composition is an erenumab drug product. 
     
     
         19 . A method for treating, preventing, or reducing the occurrence of headache in a patient in need thereof comprising administering to the patient a pharmaceutical formulation comprising an erenumab composition and one or more pharmaceutically acceptable excipients, wherein the erenumab composition comprises erenumab and one or more erenumab variants, wherein the erenumab variants comprise isomerization variants, deamidation variants, acidic variants, HMW species, or combinations thereof, and wherein the composition has one or more of the following characteristics:
 (a) the amount of acidic variants in the composition is from about 25% to about 38% as measured by CEX-HPLC;   (b) the amount of HMW species in the composition is about 2.1% or less as measured by SE-UHPLC; and   (c) the amount of isomerization variants and deamidation variants in the composition is about 8% or less as measured by the pre-peaks in HIC-HPLC.   
     
     
         20 . The method of  claim 19 , wherein the headache is migraine.