Pharmaceutical formulations and methods of use thereof

Abstract

This disclosure is directed to antibody-drug conjugates. More specifically, this disclosure is directed to compositions comprising (i) antibody-drug conjugates comprising benzodiazepines, and (ii) a small hydrophobic molecule, methods of treatment using the compositions, and methods of formulating the compositions. Furthermore, this disclosure is directed to methods of reducing reversible self-association in antibodies and in antibody-drug conjugates.

1 - 71 . (canceled). 
     
     
         72 . An aqueous formulation comprising:
 (a) water;   (b) 2 mg/mL AbX 1 -Cys-D5 or AbX 1 -Cys-D5(a);   (c) 10 mM sodium succinate; and   (d) 8% trehalose dihydrate;   wherein the formulation has a pH ranging from about 4.0 to about 4.5.   
     
     
         73 . The aqueous formulation of  claim 72 , wherein ABX 1  comprises the heavy chain variable region CDR sequences SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 and the light chain variable region CDR sequences SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6. 
     
     
         74 . The aqueous formulation of  claim 72 , wherein AbX 1  comprises a heavy chain variable region domain at least about 90% identical to SEQ ID NO: 7 and a light chain variable region at least about 90% identical to SEQ ID NO: 9. 
     
     
         75 . The aqueous formulation of  claim 72 , wherein AbX 1  comprises a heavy chain variable region domain at least about 90% identical to SEQ ID NO: 11 and a light chain variable region at least about 90% identical to SEQ ID NO: 14. 
     
     
         76 . The aqueous formulation of  claim 72 , wherein AbX 1  comprises a heavy chain variable region domain at least about 90% identical to SEQ ID NO: 12 and a light chain variable region at least about 90% identical to SEQ ID NO: 14. 
     
     
         77 . The formulation of  claim 76 , further comprising 01% polysorbate 20. 
     
     
         78 . The formulation of  claim 77 , wherein the pH is about 4.2. 
     
     
         79 . The formulation of  claim 78 , further comprising sodium bisulfite. 
     
     
         80 . The formulation of  claim 79 , wherein the sodium bisulfite has a concentration of 50 μM. 
     
     
         81 . A method of formulating an ADC, comprising
 (a) reducing reversible self-association in a formulation by
 (i) providing an ADC comprising a benzodiazepine in an aqueous solution at a first pH, wherein the ADC exhibits reversible self-association; 
 (ii) adjusting the pH of the aqueous solution to a second pH, wherein the second pH ranges from about 4.0 to about 4.5, and 
 wherein the adjustment of the pH from the first pH to the second pH reduces reversible self-association. 
   
     
     
         82 . The method of  claim 81 , wherein the second pH is about 4.2. 
     
     
         83 . The method of  claim 81 , wherein the benzodiazepine is selected from the group consisting of D1, D1(a), D2, D2(a), DGN462, DGN462(a), D3, D3(a), D4, D4(a), D5, D5(a), D6, and D6(a). 
     
     
         84 . The method of  claim 81 , wherein the ADC is selected from the group consisting of Ab-sSPDB-D1, Ab-sSPDB-D1(a), Ab-D2, Ab-D2(a), Ab-sSPDB-DGN462, Ab-sSPDB-DGN462(a), Ab-D3, Ab-D3(a), Ab-sSPDB-D4, Ab-sSPDB-D4(a), Ab-Cys-D1, Ab-Cys-D1(a), Ab-Ser-D1, Ab-Ser-D1(a), Ab-Cys-DGN462, Ab-Cys-DGN462(a), Ab-Ser-DGN462, Ab-Ser-DGN462(a), Ab-Cys-D5, Ab-Cys-D5(a), Ab-Ser-D6, and Ab-Ser-D6(a). 
     
     
         85 . The method of  claim 81 , wherein the reversible self-association is reduced by about 70% to about 80%. 
     
     
         86 . The method of  claim 81 , wherein the reversible self-association is reduced by about 80% to about 90%. 
     
     
         87 . The method of  claim 81 , wherein the reversible self-association is reduced by about 90% to 100%. 
     
     
         88 . The method of  claim 81 , further comprising lyophilizing the aqueous solution, thereby creating a lyophilized composition. 
     
     
         89 . The method of  claim 88 , further comprising reconstituting the lyophilized composition. 
     
     
         90 . The method of  claim 81 , wherein the ADC comprises an antibody selected from the group consisting of huMy9-6, huB4, huDS6, huMov19, and huCD37-3. 
     
     
         91 . The method of  claim 81 , wherein the ADC comprises a humanized CD123 antibody. 
     
     
         92 . The method of  claim 91 , wherein the humanized CD123 antibody is AbX. 
     
     
         93 . The method of  claim 92 , wherein the CD123 antibody is AbX 1 . 
     
     
         94 . The method of  claim 93 , wherein AbX 1  comprises the heavy chain variable region CDR sequences SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 and the light chain variable region CDR sequences SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6. 
     
     
         95 . The method of  claim 93 , wherein AbX 1  comprises a heavy chain variable region domain at least about 90% identical to SEQ ID NO: 7 and a light chain variable region at least about 90% identical to SEQ ID NO: 9. 
     
     
         96 . The method of  claim 93 , wherein AbX 1  comprises a heavy chain variable region domain at least about 90% identical to SEQ ID NO: 11 and a light chain variable region at least about 90% identical to SEQ ID NO: 14. 
     
     
         97 . The method of  claim 93 , wherein AbX1 comprises a heavy chain variable region domain at least about 90% identical to SEQ ID NO: 12 and a light chain variable region at least about 90% identical to SEQ ID NO: 14. 
     
     
         98 . The method of  claim 92 , wherein the CD123 antibody is AbX 2 . 
     
     
         99 . The method of  claim 98 , wherein AbX 2  comprises a heavy chain variable region domain at least about 90% identical to SEQ ID NO: 8 and a light chain variable region at least about 90% identical to SEQ ID NO: 10. 
     
     
         100 . The method of  claim 98 , wherein AbX2 comprises a heavy chain variable region domain at least about 90% identical to SEQ ID NO: 13 and a light chain variable region at least about 90% identical to SEQ ID NO: 15. 
     
     
         101 . The method of  claim 91 , wherein the benzodiazepine is D5 or D5(a). 
     
     
         102 - 118 . (canceled). 
     
     
         119 . The method of  claim 81 , further comprising adding trehalose dehydrate to the formulation.