Cyclodextrin and antibody-drug conjugate formulations

1. A liquid pharmaceutical formulation, wherein the formulation is an aqueous solution comprising:

a benzodiazepine ADC at a concentration of from about 1 mg/mL to about 3 mg/mL;

a cyclodextrin, wherein the cyclodextrin is hydroxypropyl beta cyclodextrin or sulfobutylether beta cyclodextrin at a concentration of from about 6% w/v to about 10% w/v;

a lyoprotectant, wherein the lyoprotectant is a sugar at a concentration of about 4% to about 8%;

a buffer, wherein the buffer is TRIS at a concentration of about 50 mM; and

wherein the pH of the aqueous solution is from about 7 to about 7.5.

2. The liquid pharmaceutical formulation of claim 1 , wherein the concentration of the benzodiazepine ADC within the aqueous solution is about 1 mg/mL.

3. The liquid pharmaceutical formulation of claim 1 , wherein the lyoprotectant is sucrose, wherein the concentration of sucrose within the aquesous solution is about 6% w/v.

4. The liquid pharmaceutical formulation of claim 1 , wherein, wherein the cyclodextrin is hydroxypropyl beta cyclodextrin, wherein the concentration of hydroxypropyl beta cyclodextrin within the aqueous solution is about 6% w/v.

5. The liquid pharmaceutical formulation of claim 1 wherein the aqueous solution has no more than 0.1 μM benzodiazepine drug-related impurites.

6. The liquid pharmaceutical formulation of claim 1 , wherein the aqueous solution comprises:

benzodiazepine ADC at a concentration of about 1 mg/mL or about 3 mg/mL;

hydroxypropyl beta cyclodextrin at a concentration of about 6% w/v;

sucrose as the lyoprotectant at a concentration of about 6% w/v; and

TRIS buffer at a concentration of about 50 mM;

wherein the pH of the aqueous solution is about 7.3; and

wherein the aqueous solution has no more than 0.1 μM benzodiazepine drug-related impurites.

7. The liquid pharmaceutical formulation of claim 6 wherein the benzodiazepine ADC is a monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer, an indolinobenzodiazepine dimer or an oxazolidinobenzodiazepine.

8. The liquid pharmaceutical formulation of claim 7 wherein the benzodiazepine ADC is a monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer and the benzodiazepine ADC is as follows:

or a pharmaceutically acceptable salt thereof; wherein Ab is the monoclonal antibody and p represents the average number of drug-linker molecules in parentheses per antibody in the formulation and is about 2.

9. The liquid pharmaceutical formulation of claim 8 wherein the monoclonal antibody component of the benzodiazepine ADC is a monoclonal antibody that is capable of specifically binding to an extracellular domain of a cancer cell antigen that is expressed on the surface of a cancer cell.

10. A lyophilized pharmaceutical formulation wherein the lyophilized pharmaceutical formulation is from lyophilization of the aqueous solution of claim 6 .

11. A method of preparing a pharmaceutical formulation comprising the steps of:

diafiltration of an aqueous solution comprising benzodizepine ADCs and benzodiazepine drug-related impurities,

wherein diafiltration is through eluting of the aqueous solution through an ultrafiltration membrane of suitable pore size in a tagentail flow filtration device,

wherein the aqueous solution is further comprised of:

from about 1 mg/mL to about 3 mg/mL benzodiazepine ADC;

about 1 μM benzodiazepine drug-related impurities;

from about 6% w/v to about 10% w/v hydroxypropyl beta cyclodextrin;

about 6% w/v of a lyoprotectant; and

from about 20 mM to about 50 mM TRIS buffer,

wherein the aqueous solution is buffered at pH from about 7 to about 7.5,

wherein benzodizepine drug-related impurities are reduced to a level of no more than 0.1 μM.

12. The method of claim 11 wherein the benzodiazepine drug-related impurities have a hydrophobic SlogP value of no more than 7.50 or no more than 6.5.

13. The method of preparing a pharmaceutical formulation of claim 11 further comprising the step of lyophilization of the aqueous formulation obtained subsequent to diafiltration, wherein the formulation so prepared is a pharmaceutical lyophilized formulation.

14. The method of preparing a pharmaceutical formulation of claim 13 further comprising the step of contacting the pharmaceutical lyophilized formulation with a pharmaceutically acceptable diluent so as to reconstitute an aqueous formulation having a benzodiazepine ADC concentration from about 0.6 mg/mL to about 3 mg/mL.