SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Dec. 14, 2016, is named P155_US003_SL.txt and is 22,322 bytes in size.

FIELD

The present disclosure relates to pharmaceuticals. More specifically, this disclosure relates to formulations for antibody-drug conjugates and methods related to antibody-drug conjugate compositions.

BACKGROUND

In recent years, the treatment of cancer has become more targeted through the development of antibody-drug conjugates (herein referred to as “ADCs,” “conjugates,” or “immunoconjugates”). Researchers have identified and taken advantage of cell-surface receptors and antigens selectively expressed by cancer cells to develop drugs based on antibodies that bind tumor-specific or tumor-associated antigens. This specific binding allows for the delivery to the cancer cells of cytotoxic compounds linked to the antibody. The selectivity afforded by ADCs minimizes toxicity to normal cells, thereby enhancing tolerability of the drug in the patient.

Despite the tumor selectivity afforded by ADCs, the use of ADCs in a clinical context is limited by a number of factors. Among those factors is the ability of the ADCs to aggregate and reversibly self-associate. ADCs are able to aggregate to each other through various mechanisms, including covalent bonding and hydrophobic interactions. ADCs are also able to reversibly self-associate through weak interactions that create equilibrium between monomers and higher ordered species. In either case, aggregation and reversible self-association inhibit the ability of the ADC to bind to the target, thereby reducing the clinical efficacy of the ADC. Accordingly, researchers continue to work to discover ways to limit aggregation and reversible self-association of the ADCs and increase the efficacy of ADCs.

SUMMARY

This disclosure is directed to ADC compositions with reduced reversible self-association, methods of treating cancer using such compositions, methods of formulating such compositions, and methods of reducing reversible self-association. In one aspect, this disclosure provides a composition comprising (a) an ADC comprising at least one benzodiazepine; and (b) a small hydrophobic molecule selected from the group consisting of betaines and amino acids with hydrophobic side chains. In some embodiments, the composition has a pH between about 4.0 and about 4.5. In some embodiments, the benzodiazepine is an indolinobenzodiazepine. In some embodiments, 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), which are described below in Table 1. In certain embodiments, 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), which are described below in Table 2. In some embodiments, the composition is an aqueous solution.

In some embodiments, the antibody is selected from the group consisting of huMy9-6, huB4, huDS6, huMov19, and huCD37-3. In other embodiments, the antibody is a humanized CD123 antibody. In certain embodiments, the antibody is a humanized CD123 antibody described in U.S. Provisional application No. 62/186,161, U.S. Patent Application Publication No. US20170029514A1, and PCT Application publication no. WO2017004026, which are herein incorporated by reference in their entireties. As used herein, “AbX” refers to humanized CD123 antibodies described in U.S. Provisional Application No. 62/186,161, U.S. Patent Application Publication No. US20170029514A1, and PCT Application publication no. WO2017004026. All applications, patents, and other publications referenced herein are incorporated by reference. In some embodiments, the AbX antibody comprises the CDR sequences disclosed herein. In some embodiments, the AbX antibody comprises the heavy chain variable region domain sequences and light chain variable region domain sequences disclosed herein.

In further embodiments, the composition is a lyophilized composition. In still further embodiments, the composition is a reconstituted lyophilized composition. Although the small hydrophobic molecule can be added to compositions prior to lyophilization, the benefits of reduced or inhibited reduced reversible self-association are still realized in compositions that are reconstituted after lyophilization.

In some embodiments, the small hydrophobic molecule is trimethylglycine. In certain embodiments, the small hydrophobic molecule is proline. In other embodiments, the small hydrophobic molecule is leucine. In further embodiments, the small hydrophobic molecule is isoleucine. In still further embodiments, two or more small hydrophobic molecules are used in combination in the compositions.

The number of benzodiazepines per antibody in an ADC can vary. In some embodiments, the ADC comprises at least one benzodiazepine. In certain embodiments, the ADC comprises at least two benzodiazepines. In further embodiments, the ADC comprises at least three benzodiazepines. In still further embodiments, the ADC comprises at least four benzodiazepines. In other embodiments, the ADC comprises at least five benzodiazepines. In certain embodiments, the ADC comprises at least six benzodiazepines. In some embodiments, the ADC comprises about seven benzodiazepines. In compositions comprising more than one ADC, the average number of benzodiazepines per antibody can be measured. This number is referred to as the drug-to-antibody ratio, or “DAR.” In some embodiments, a composition comprising more than one ADC has a DAR between about 1 and about 4. In some embodiments, a composition comprising more than one ADC has a DAR between 0 and about 1. In other embodiments, a composition comprising more than one ADC has a DAR between about 1 and about 2. In still other embodiments, a composition comprising more than one ADC has a DAR between about 2 and about 3. In further embodiments, a composition comprising more than one ADC has a DAR of between about 3 and about 4. In still further embodiments, a composition comprising more than one ADC has a DAR between about 4 and about 5. In yet further embodiments, a composition comprising more than one ADC has a DAR between about 5 and about 6. In some embodiments the benzodiazepine is conjugated to the antibody in a site-specific manner, for example, through conjugation to an engineered cysteine or serine residue.

In some embodiments, the composition is an aqueous formulation comprising: (a) water; (b) huMy9-6-sSPDB-DGN462; (c) 10 mM sodium succinate; and (d) 280 mM betaine, wherein the formulation has a pH of about 4.2. In another embodiment, the composition is an aqueous formulation comprising: (a) water; (b) huMy9-6-sSPDB-DGN462; (c) 10 mM sodium succinate; and (d) 280 mM proline, wherein the formulation has a pH of about 4.2. In yet another embodiment, the composition is an aqueous formulation comprising: (a) water; (b) AbX-D2; (c) 10 mM sodium succinate; and (d) a small hydrophobic molecule selected from the group consisting of 280 mM proline and 280 mM betaine, wherein the formulation has a pH of about 4.2. In one embodiment, the composition is an aqueous formulation comprising: water; (a) huMov19-sSPDB-D1; (b) 10 mM sodium succinate; and (c) 125 mM leucine, wherein the formulation has a pH of about 4.2. In another embodiment, the composition is an aqueous formulation comprising: (a) water; (b) huMov19-sSPDB-D4; (c) 10 mM sodium succinate; and (a) 125 mM isoleucine, wherein the formulation has a pH of about 4.2. In some embodiments, the composition is a lyophilized composition of any of the aqueous compositions described herein.

In another aspect, the disclosure provides a method of treating cancer in a subject, comprising administering to a subject in need thereof an effective amount of a composition comprising (i) an ADC comprising a benzodiazepine; and (ii) a small hydrophobic molecule selected from the group consisting of betaines and amino acids with hydrophobic side chains, wherein the ADC is cytotoxic in one or more cells, thereby treating the cancer. In some embodiments, the composition is a lyophilized composition. In certain embodiments, the composition is a reconstituted lyophilized composition. In some embodiments of the method, 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). In certain embodiments, 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). In some embodiments, the antibody (Ab) is selected from the group consisting of huMy9-6, huB4, huDS6, huMov19, and huCD37-3. In other embodiments, the antibody is a humanized CD123 antibody. In certain embodiments, the antibody is AbX. In some embodiments, the AbX antibody comprises the CDR sequences disclosed herein. In some embodiments, the AbX antibody comprises the heavy chain variable region domain sequences and light chain variable region domain sequences disclosed herein.

In some embodiments of the method, the small hydrophobic molecule is trimethylglycine. In further embodiments of the method, the small hydrophobic molecule is proline. In some embodiments of the method, the small hydrophobic molecule is leucine. In certain embodiments of the method, the small hydrophobic molecule is isoleucine. In still further embodiments of the method, two or more small hydrophobic molecules are used in combination in the compositions.

In some embodiments of the method, the composition used in the methods is one of the specific aqueous formulations described above. In certain embodiments of the method, the composition is a reconstituted lyophilized composition derived from one of the aqueous formulations disclosed herein.

In yet another aspect, this disclosure provides a method of formulating a composition, comprising (a) providing an ADC comprising a benzodiazepine in an aqueous solution; and (b) adding to the aqueous solution a small hydrophobic molecule selected from the group consisting of betaines and amino acids with hydrophobic side chains. In some embodiments, the method further comprises adjusting the pH of the aqueous solution to between about 4.0 and about 4.5. In some embodiments of the method, 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). In certain embodiments of the method, 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). In some embodiments, the antibody is selected from the group consisting of huMy9-6, huB4, huDS6, huMov19, and huCD37-3. In other embodiments, the antibody is a humanized CD123 antibody. In certain embodiments, the antibody is AbX. In some embodiments, the AbX antibody comprises the CDR sequences disclosed herein. In some embodiments, the AbX antibody comprises the heavy chain variable region domain sequences and light chain variable region domain sequences disclosed herein.

In some embodiments of the method, the small hydrophobic molecule is trimethylglycine. In other embodiments of the method, the small hydrophobic molecule is leucine. In some embodiments of the method, the small hydrophobic molecule is isoleucine. In certain embodiments of the method, the small hydrophobic molecule is proline. In still other embodiments of the method, a combination of small hydrophobic molecules are added.

In further embodiments of the method, the addition of a small hydrophobic molecule reduces RSA in the aqueous solution by about 30% to about 40%. In some embodiments, the addition of a small hydrophobic molecule reduces RSA in the aqueous solution by about 40% to about 50%. In certain embodiments, the addition of a small hydrophobic molecule reduces RSA in the aqueous solution by about 50% to about 60%. In further embodiments, the addition of a small hydrophobic molecule reduces RSA in the aqueous solution by about 60% to about 70%. In still further embodiments, the addition of a small hydrophobic molecule reduces RSA in the aqueous solution by about 70% to about 80%. In yet further embodiments, the addition of a small hydrophobic molecule reduces RSA in the aqueous solution by about 80% to about 90%. In some embodiments, the addition of a small hydrophobic molecule reduces RSA in the aqueous solution by about 90% to 100%. In still further embodiments, the addition of a small hydrophobic molecule eliminates RSA in the aqueous solution. In some embodiments, the amount of RSA is measured by multiangle light scattering. In some further embodiments, the amount of RSA is measured by dynamic light scattering.

In some embodiments, the method further comprises lyophilizing the aqueous solution, thereby obtaining a lyophilized composition. In certain embodiments, the method further comprises reconstituting the lyophilized composition, thereby creating a reconstituted lyophilized composition. In further embodiments of the method, the addition of a small hydrophobic molecule reduces RSA in the reconstituted lyophilized composition by about 30% to about 40%. In some embodiments, the addition of a small hydrophobic molecule reduces RSA in the reconstituted lyophilized composition by about 40% to about 50%. In certain embodiments, the addition of a small hydrophobic molecule reduces RSA in the reconstituted lyophilized composition by about 50% to about 60%. In further embodiments, the addition of a small hydrophobic molecule reduces RSA in the reconstituted lyophilized composition by about 60% to about 70%. In still further embodiments, the addition of a small hydrophobic molecule reduces RSA in the reconstituted lyophilized composition by about 60% to about 70%. In yet further embodiments, the addition of a small hydrophobic molecule reduces RSA in the reconstituted lyophilized composition by about 70% to about 80%. In some embodiments, the addition of a small hydrophobic molecule reduces RSA in the reconstituted lyophilized composition by about 80% to about 90%. In certain embodiments, the addition of a small hydrophobic molecule reduces RSA in the reconstituted lyophilized composition by about 90% to 100%. In some embodiments, the addition of a small hydrophobic molecule eliminates RSA in the reconstituted lyophilized composition.

In still another aspect, this disclosure provides a method of reducing reversible self-association, the method comprising (a) providing an ADC comprising a benzodiazepine in an aqueous solution, wherein the ADC exhibits reversible self association; and (b) adding to the aqueous solution a small hydrophobic molecule selected from the group consisting of betaines and amino acids with hydrophobic side chains, wherein the small hydrophobic molecule reduces reversible self association. In some embodiments, the small hydrophobic molecule is trimethylglycine. In further embodiments, the small hydrophobic molecule is proline. In certain embodiments, the small hydrophobic molecule is leucine. In still further embodiments, the small hydrophobic molecule is isoleucine.

In certain embodiments, the method further comprises detecting reversible self-association. In further embodiments, the method further comprises adjusting the pH of the aqueous solution to between about 4.0 and about 4.5.

In some embodiments of the method, 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). In certain embodiments of the method, 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). In some embodiments, the antibody is selected from the group consisting of huMy9-6, huB4, huDS6, huMov19, and huCD37-3. In other embodiments, the antibody is a humanized CD123 antibody. In certain embodiments, the antibody is AbX and refers to humanized CD123 antibodies described in U.S. Provisional Application No. 62/186,161, U.S. Patent Application Publication No. US20170029514A1, and PCT Application publication no. WO2017004026. In some embodiments, the AbX antibody comprises the CDR sequences disclosed herein. In some embodiments, the AbX antibody comprises the heavy chain variable region domain sequences and light chain variable region domain sequences disclosed herein.

In some embodiments of the method, the reversible self-association is reduced by about 30% to about 40%. In further embodiments of the method, the reversible self-association is reduced by about 40% to about 50%. In still further embodiments of the method, the reversible self-association is reduced by about 50% to about 60%. In yet further embodiments of the method, the reversible self-association is reduced by about 60% to about 70%. In some embodiments of the method, the reversible self-association is reduced by about 70% to about 80%. In certain embodiments of the method, the reversible self-association is reduced by about 80% to about 90%. In further embodiments of the method, the reversible self-association is reduced by about 90% to 100%. In certain embodiments of the method, the reversible self-association is eliminated.

In some embodiments, the method further comprises lyophilizing the aqueous solution, thereby creating a lyophilized composition. In further embodiments, the method further comprises reconstituting the lyophilized composition.

It has been discovered that compositions comprising an ADC exhibit reduced reversible self-association when formulated with a buffer (e.g., succinate buffer) at a pH ranging from about 4.0 to about 4.5. Accordingly, yet another aspect of this disclosure is directed to compositions comprising an ADC comprising a benzodiazepine, wherein the ADC exhibits reversible self-association, and a buffer, wherein the composition has a pH ranging from about 4.0 to about 4.5. In some embodiments, 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). In certain embodiments, 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). In some embodiments, the antibody is selected from the group consisting of huMy9-6, huB4, huDS6, huMov19, and huCD37-3. In other embodiments, the antibody is a humanized CD123 antibody. In certain embodiments, the antibody is AbX and refers to humanized CD123 antibodies described in U.S. Provisional Application No. 62/186,161, U.S. Patent Application Publication No. US20170029514A1, and PCT Application publication no. WO2017004026. In some embodiments, the AbX antibody comprises the CDR sequences disclosed herein. In some embodiments, the AbX antibody comprises the heavy chain variable region domain sequences and light chain variable region domain sequences disclosed herein.

In some embodiments, the composition further comprises a sugar. In certain embodiments, the sugar is trehalose. In some embodiments, the trehalose is trehalose dihydrate. In other embodiments, the trehalose is trehalose anhydrous. In other embodiments, the sugar is sucrose. In some embodiments, the buffer is succinate. In some embodiments, the composition further comprises sodium bisulfite. In some embodiments, the composition is an aqueous formulation. In other embodiments, the composition is a lyophilized composition. In some embodiments, the composition further comprises a bulking agent. In certain embodiments, the bulking agent is glycine. In other embodiments, the bulking agent is mannitol.

In some embodiments, the aqueous formulation comprises (a) water; (b) huMy9-6-sSPDB DGN462; (c) 10 mM sodium succinate; and (d) 8% trehalose, wherein the formulation has a pH ranging from about 4.0 to about 4.5. In certain embodiments, the aqueous formulation comprises (a) water; (b) AbX D2 or AbX-D2(a); (c) 10 mM sodium succinate; and (d) 8% trehalose, wherein the formulation has a pH ranging from about 4.0 to about 4.5, and optionally includes 2-200 μM sodium bisulfite. In certain embodiments, the aqueous formulation comprises (a) water; (b) AbX-D5 or AbX-D5(a); (c) 10 mM sodium succinate; and (d) 8% trehalose, wherein the formulation has a pH ranging from about 4.0 to about 4.5 and optionally includes 2-200 μM sodium bisulfite. In some embodiments, the aqueous formulation comprises (a) water; (b) 2 mg/mL AbX-D5 or AbX-D5(a); (c) 10 mM sodium succinate; (d) 8% trehalose dihydrate; (e) 50 μM sodium bisulfite; and 0.01% (w/v) polysorbate 20, wherein the formulation has a pH of about 4.2. In some embodiments, the aqueous formulation comprises (a) water; (b) huMov19-sSPDB D1 or D1(a); (c) 10 mM sodium succinate; and (d) 8% trehalose, wherein the formulation has a pH ranging from about 4.0 to about 4.5. In another embodiment, the aqueous formulation comprises (a) water; (b) huMov19-sSPDB D2 or D2(a); (c) 10 mM sodium succinate; and (d) 8% trehalose. In further embodiments, the aqueous formulation comprises (a) water; (b) huMov19-sSPDB D4; (c) 10 mM sodium succinate; and (d) 8% trehalose, wherein the formulation has a pH ranging from about 4.0 to about 4.5. In some embodiments, the composition is a lyophilized composition of any of the aqueous compositions described herein. In some embodiments, the pH of any of the compositions described above is 4.2. In some embodiments, the AbX antibody comprises the CDR sequences disclosed herein. In some embodiments, the AbX antibody comprises the heavy chain variable region domain sequences and light chain variable region domain sequences disclosed herein.

In some embodiments, the composition further comprises a surfactant. In some embodiments, the surfactant is 0.01% polysorbate 20. In some embodiments, the composition further comprises sodium bisulfite. In some embodiments, the composition comprises 2-200 μM sodium bisulfite. In other embodiments, the composition further comprises 5-100 μM sodium bisulfite. In certain embodiments, the composition further comprises about 50 μM sodium bisulfite.

In some embodiments, the pH of the composition is about 4.2. In some embodiments, the aqueous formulation comprises (a) water; (b) 2 mg/mL AbX-D5 or AbX-D5(a); (c) 10 mM sodium succinate; (d) 8% trehalose dihydrate; (e) 50 μM sodium bisulfite; and 0.01% (w/v) polysorbate 20, wherein the formulation has a pH of about 4.2.

Another aspect of this disclosure is directed to a method of reducing reversible self association, comprising (a) providing an ADC comprising a benzodiazepine in an aqueous solution at a first pH, wherein the ADC exhibits reversible self association; and (b) adjusting the pH of the aqueous solution to a second pH ranging from about 4.0 to about 4.5, wherein the adjustment of the pH from the first pH to the second pH reduces reversible self association. In some embodiments, the second pH is about 4.2.

In some embodiments of the disclosed methods, 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). In some embodiments, 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).

In some embodiments, the reversible self association is reduced by about 70% to about 80%. In further embodiments, the reversible self association is reduced by about 80% to about 90%. In yet further embodiments, the reversible self association is reduced by about 90% to 100%.

In some embodiments, the method further comprises lyophilizing the aqueous solution, thereby creating a lyophilized composition. In still further embodiments, the method also comprises reconstituting the lyophilized composition.

In some embodiments, the ADC comprises an antibody selected from the group consisting of huMy9-6, huB4, huDS6, huMov19, and huCD37-3. In some embodiments, the ADC comprises a humanized CD123 antibody. In some embodiments, the humanized CD123 antibody is AbX. In some embodiments, the AbX antibody comprises the CDR sequences disclosed herein. In some embodiments, the AbX antibody comprises the heavy chain variable region domain sequences and light chain variable region domain sequences disclosed herein.

A further aspect of this disclosure is directed to a composition comprising (a) an ADC comprising a benzodiazepine and (b) trehalose, wherein the composition has a pH ranges from about 4.0 to about 4.5. In some embodiments, the composition further comprises sodium succinate. In some embodiments, the composition further comprises sodium bisulfate. In further embodiments, the composition further comprises a surfactant. In some embodiments, 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). In further embodiments, 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).

