US20170189548A1 - Pharmaceutical formulations and methods of use thereof - Google Patents
Pharmaceutical formulations and methods of use thereof Download PDFInfo
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- US20170189548A1 US20170189548A1 US15/360,689 US201615360689A US2017189548A1 US 20170189548 A1 US20170189548 A1 US 20170189548A1 US 201615360689 A US201615360689 A US 201615360689A US 2017189548 A1 US2017189548 A1 US 2017189548A1
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Definitions
- 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.
- ADCs antibody-drug conjugates
- conjugates include 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.
- 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.
- 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.
- 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.
- the composition has a pH between about 4.0 and about 4.5.
- the benzodiazepine is an indolinobenzodiazepine.
- 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.
- 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.
- the composition is an aqueous solution.
- the antibody is selected from the group consisting of huMy9-6, huB4, huDS6, huMov19, and huCD37-3.
- the antibody is a humanized CD123 antibody.
- the antibody is a humanized CD123 antibody described in U.S. Provisional application No. 62/186,161, U.S. Patent Application Publication No. 20170029514A1, and PCT Application publication no. WO2017004026, which are herein incorporated by reference in their entireties.
- “AbX” refers to humanized CD123 antibodies described in U.S. Provisional Application No. 62/186,161, U.S. Patent Application Publication No.
- 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.
- the composition is a lyophilized composition. In still further embodiments, the composition is a reconstituted lyophilized composition.
- 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.
- 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.
- the ADC comprises at least one benzodiazepine.
- the ADC comprises at least two benzodiazepines.
- the ADC comprises at least three benzodiazepines.
- the ADC comprises at least four benzodiazepines.
- the ADC comprises at least five benzodiazepines.
- the ADC comprises at least six benzodiazepines.
- the ADC comprises about seven benzodiazepines. In compositions comprising more than one ADC, the average number of benzodiazepines per antibody can be measured.
- 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.
- composition comprising more than one ADC has a DAR between about 5 and about 6.
- the benzodiazepine is conjugated to the antibody in a site-specific manner, for example, through conjugation to an engineered cysteine or serine residue.
- 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.
- 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.
- 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.
- 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.
- 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.
- the composition is a lyophilized composition of any of the aqueous compositions described herein.
- 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.
- the composition is a lyophilized composition.
- the composition is a reconstituted lyophilized composition.
- 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).
- 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).
- 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.
- 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.
- 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.
- 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.
- the method further comprises adjusting the pH of the aqueous solution to between about 4.0 and about 4.5.
- the benzodiazepine is selected from the group consisting of
- 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),
- 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.
- 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.
- 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%.
- 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.
- 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%.
- 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.
- 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.
- the small hydrophobic molecule is trimethylglycine.
- the small hydrophobic molecule is proline.
- the small hydrophobic molecule is leucine.
- the small hydrophobic molecule is isoleucine.
- 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.
- 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).
- 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).
- the antibody is selected from the group consisting of huMy9-6, huB4, huDS6, huMov19, and huCD37-3.
- the antibody is a humanized CD123 antibody.
- 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. 20170029514A1, and PCT Application publication no. WO2017004026.
- the AbX antibody comprises the CDR sequences disclosed herein.
- the AbX antibody comprises the heavy chain variable region domain sequences and light chain variable region domain sequences disclosed herein.
- 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.
- the method further comprises lyophilizing the aqueous solution, thereby creating a lyophilized composition. In further embodiments, the method further comprises reconstituting the lyophilized composition.
- 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.
- a buffer e.g., succinate buffer
- 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.
- 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).
- 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).
- the antibody is selected from the group consisting of huMy9-6, huB4, huDS6, huMov19, and huCD37-3.
- the antibody is a humanized CD123 antibody.
- 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.
- the AbX antibody comprises the CDR sequences disclosed herein.
- the AbX antibody comprises the heavy chain variable region domain sequences and light chain variable region domain sequences disclosed herein.
- the composition further comprises a sugar.
- the sugar is trehalose.
- the trehalose is trehalose dihydrate.
- the trehalose is trehalose anhydrous.
- the sugar is sucrose.
- the buffer is succinate.
- the composition further comprises sodium bisulfite.
- the composition is an aqueous formulation.
- the composition is a lyophilized composition.
- the composition further comprises a bulking agent.
- the bulking agent is glycine.
- the bulking agent is mannitol.
- 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.
- 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 ⁇ M sodium bisulfite.
- 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 ⁇ M sodium bisulfite.
- 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 ⁇ M sodium bisulfite; and 0.01% (w/v) polysorbate 20, wherein the formulation has a pH of about 4.2.
- 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.
- the aqueous formulation comprises (a) water; (b) huMov19-sSPDB D2 or D2(a); (c) 10 mM sodium succinate; and (d) 8% trehalose.
- 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.
- the composition is a lyophilized composition of any of the aqueous compositions described herein.
- the pH of any of the compositions described above is 4.2.
- the AbX antibody comprises the CDR sequences disclosed herein.
- the AbX antibody comprises the heavy chain variable region domain sequences and light chain variable region domain sequences disclosed herein.
- 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 ⁇ M sodium bisulfite. In other embodiments, the composition further comprises 5-100 ⁇ M sodium bisulfite. In certain embodiments, the composition further comprises about 50 ⁇ M sodium bisulfite.
- the pH of the composition is about 4.2.
- 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 ⁇ M 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.
- the second pH is about 4.2.
- 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).
- 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).
- 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%.
- 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.
- the ADC comprises an antibody selected from the group consisting of huMy9-6, huB4, huDS6, huMov19, and huCD37-3.
- the ADC comprises a humanized CD123 antibody.
- the humanized CD123 antibody is AbX.
- the AbX antibody comprises the CDR sequences disclosed herein.
- 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
- 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.
- the composition further comprises sodium succinate.
- the composition further comprises sodium bisulfate.
- the composition further comprises a surfactant.
- 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).
- 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).
- FIG. 1 shows the dynamic light scattering plot of a reversible self-associating system using huM9-6-sSPDB-DGN462 as an example.
- FIGS. 2A and 2B show the SV-AUC distribution of a reversibly self-associating system using huM9-6-sSPDB-DGN462 as an example.
- FIG. 3 shows the changes in hydrodynamic diameter in relation to drug-to-antibody ratio as measured by dynamic light scattering.
- FIG. 4 shows the dynamic light scattering plot of different ADC compositions.
- FIG. 5 shows the SV-AUC distribution of different ADC compositions.
- FIG. 6 shows the mass spectrometry data for deglycosylated huMOV19-90 conjugate.
- FIG. 7 shows the mass spectrometry data for deglycosylated huMov19-sSPDB-107 conjugate.
- FIG. 8 shows the dynamic light scattering plot of different ADC compositions.
- FIG. 9 shows the dynamic light scattering plot of different ADC compositions.
- FIG. 10 shows data obtained from an assessment of RSA for a succinate-trehalose formulation over a range of pH.
- FIG. 11 shows RSA of ADC in 10 mM Sodium succinate, 8% trehalose, 0.01% Polysorbate-20, pH 4.0
- the term “subject” means a human or an animal.
- exemplary animals include, but are not limited to, mammals such as mouse, rat, guinea pig, dog, cat, horse, cow, pig, monkey, chimpanzee, baboon, or rhesus monkey.
- the term “pharmaceutical formulation” refers to a preparation in a form that may be administered to a subject while allowing the biological activity of the active ingredient to be effective.
- terapéuticaally effective amount refers to an amount of a drug that is effective to treat a disease or disorder.
- treat refers to the reduction, amelioration, or improvement of a disease or disorder, or the reduction, amelioration, or improvement of at least one symptom of a disease or disorder.
- the term “irreversible aggregate” refers to non-covalent aggregation typically resulting from a hydrophobic interaction due to partial unfolding.
- chimeric antibody refers to an antibody wherein the amino acid sequence of the immunoglobulin molecule is derived from two or more species.
- the variable region of both light and heavy chains corresponds to the variable region of antibodies derived from one species of mammals (e.g., mouse, rat, rabbit, etc.) with the desired specificity, affinity, and capability while the constant regions are homologous to the sequences in antibodies derived from another (usually human) to avoid or reduce the chance of eliciting an immune response in that species (e.g., human).
- a chimeric antibody may include an antibody or antigen-binding fragment thereof comprising at least one human heavy and/or light chain polypeptide, such as, for example, an antibody comprising murine light chain and human heavy chain polypeptides.
- antigen-binding fragment of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen.
- polyclonal antibodies refer to heterogeneous populations of antibody, typically contained in the sera of immunized animals.
- monoclonal antibodies refer to homogenous populations of antibody molecules that are specific to a particular antigen.
- linker refers to a moiety that connects two groups, such as an antibody and a cytotoxic compound, together.
- cancer and “cancerous” refer to or describe the physiological condition in mammals in which a population of cells are characterized by unregulated cell growth. Cancer can include a hematological cancer or a solid tumor.
- ADC compositions development of commercially viable and clinically useful ADC compositions is complicated by the unpredictable behaviors of different antibodies and ADCs during formulation.
- the ability of antibodies and ADCs to aggregate and reversibly self-associate can lead to many undesirable effects commercially and clinically. Aggregation and reversible self-association can lead to reduced potency, decreased stability, increased toxicity, increased viscosity, discoloration of solution, and other undesirable effects. In some circumstances, aggregates can trigger an immune system response, a potential safety concern in patients.
- Covalent aggregates occur through the formation of a chemical bond between at least two monomers.
- covalent aggregates can result from disulfide bonds formed between unpaired cysteines on a monomer, or as a result of intermolecular disulfide scrambling, or through thioether linking.
- aggregation is irreversible.
- the irreversible aggregation of immunoglobulins leads to decreased activity or functionality of the immunoglobulins in formulations.
- Irreversible aggregates can be inhibited by agents such as urea, guanidine, or sodium dodecyl sulfate (“SDS”), but not through reducing the concentration of the antibody.
- Reversible self-association occurs as a result of an ADC's ability to form oligomeric species through weak, non-covalent intermolecular interactions.
- the amount of these interactions for any given ADC in solution depends on a variety of factors, including the antibody itself (e.g., primary and secondary structures) and solution characteristics such as pH, as well as ADC concentration.
- the amount and extent of the self-association varies by ADC depending on the characteristics of the cytotoxic compound and the antibody. Cytotoxic compounds that are hydrophobic, insoluble, and/or comprise multiple aromatic rings can increase RSA. Therefore, more hydrophobic ADCs have an increased tendency to reversibly self-associate in solution.
- the ADCs self-associate and attain equilibrium in solution between monomers and in higher ordered oligomeric species.
- ADC reversible self-association has numerous detrimental effects in formulations.
- RSA can create problems for manufacturing, stability, delivery, and safety of the ADC in a therapeutic context. From a delivery perspective, RSA can increase the viscosity of a solution, which can impede the plunger of a pre-filled syringe. From a stability and safety perspective, RSA can reduce potency (because the oligomeric species do not function therapeutically) and increase the possibility of triggering an immune response.
- the amount of ADC monomer in solution can be measured by size exclusion chromatography (both SEC and SEC-MS) and sedimentation velocity (SV).
- SEC size exclusion chromatography
- SV sedimentation velocity
- SV analyzes the behavior of the ADC in solution by applying angular acceleration to the solution (generally through centrifugation) to cause the ADCs to sediment.
- angular acceleration generally through centrifugation
- larger particles e.g., ADC aggregates or reversibly self-associated oligomers, sediment more quickly. Therefore, SV can be used to assess the amount of ADC monomer in solution because the aggregates and oligomers sediment more quickly than the monomers.
- SEC or SEC-MS and SV may give different monomer percentages for the same antibody. Such discrepancies can indicate the presence of reversibly self-associating monomers. Moreover, changes in concentration and solution characteristics typically reduce RSA, but may not affect the amount of either covalent or irreversible aggregates present.
- Multiangle Light Scattering can be used to determine the amount of reversibly associated oligomers in a given solution based on how the monomers and the oligomers of different order scatter light. As the concentration of an antibody in solution increases, MALS typically detects the increase of a species of higher molecular weight, e.g., an oligomer, than the monomer. This increase indicates an increase in RSA.
- DLS Dynamic Light Scattering
- DLS-measuring instruments can also be used to determine the existence and extent of RSA in a solution.
- DLS involves measuring the time-dependent change in intensity of light scattered by a species in solution.
- DLS-measuring instruments yield the hydrodynamic diameter of a particle.
- a DLS-measuring instrument will detect an increased presence of species having greater hydrodynamic diameters, e.g., oligomers. This increase indicates an increase in RSA.
- DLS-measuring instruments can also be used to determine the diffusion coefficients of the species in solution. Diffusion coefficients decrease with increased antibody concentration, indicating the existence of RSA.
- ADCs comprise an antibody, or an antibody fragment, conjugated to a cytotoxic compound.
- the cytotoxic compound is conjugated to an antibody via a linker.
- the cytotoxic compound is linked directly to the antibody.
- compositions that comprise antibodies and antigen-binding fragments thereof.
- Antibodies are large glycoproteins that can exist as soluble and membrane-bound forms and comprise five natural isotypes—IgA, IgD, IgE, IgG, and IgM, based on the identity of their heavy-chain constant domains referred to as alpha, delta, epsilon, gamma, and mu, respectively.
- the different classes of immunoglobulins have different and well-known subunit structures and three-dimensional configurations.
- the disclosed compositions can comprise polyclonal antibodies and monoclonal antibodies.
- the antibodies comprise antibodies such as multispecific antibodies such as bispecific antibodies, chimeric antibodies, humanized antibodies, and human antibodies.
- the compositions can also comprise antibodies that have one or more conservative or non-conservative amino acid substitutions.
- the compositions can comprise modified glycosylation at one or more amino acid residues. Such modified antibodies or binding fragments fall within the scope of the compositions disclosed herein so long as the modified antibodies exhibit the desired biological activity.
- a “humanized” antibody is one in which the complementarity-determining regions (CDRs) of a mouse monoclonal antibody, which form the antigen binding loops of the antibody, are grafted onto the framework of a human antibody molecule or where the variable domains of the framework of a murine antibody have been resurfaced (i.e., the exposed residues are replaced with the residues that are present in the corresponding positions of human antibodies).
- CDRs complementarity-determining regions
- Exemplary antibodies include humanized monoclonal antibodies, examples of which include, huMy9-6, huB4, huDS6, huMov19, and huCD37-3. Exemplary antibodies also include humanized CD123 antibodies, exemplary sequences of which are described in U.S. application publication no. US20170029514A1 and PCT application publication no. WO2017004026 and are referred to herein as “AbX”.
- Humanized CD123 antibodies that include the following heavy chain variable region CDR amino acid sequences:
- V H CDR1 SSIMH (SEQ ID NO: 2)
- V H CDR2 YIKPYNDGTKYNEKFKG (SEQ ID NO: 3)
- V H CDR3 EGGNDYYDTMDY
- Humanized CD123 antibodies that include the following light chain variable region CDR amino acid sequences:
- V L CDR1 RASQDINSYLS (SEQ ID NO: 5)
- V L CDR2 RVNRLVD (SEQ ID NO: 6)
- V L CDR3 LQYDAFPYT
- Humanized anti-CD123 antibodies that include the following heavy chain variable region amino acid sequences:
- AbX 1 (SEQ ID NO: 7) Q(FN)QLVQSGAEVKKPGASVKVSCKASGYIFTSSIMHWVRQAPGQGLEW IGYIKPYNDGTKYNEKFKGRATLTSDRSTSTAYMELSSLRSEDTAVYYCA REGGNDYYDTMDYWGQGTLVTVSS
- AbX 2 (SEQ ID NO: 8) QVQLVQSGAEVKKPGASVKVSCKASGYGFTSSIMHWVRQAPGQGLEWMGY IKPYNDGTKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAREG GNDYYDTMDYWGQGTLVTVSS
- Humanized anti-CD123 antibodies that include the following light chain variable region amino acid sequences:
- AbX 1 (SEQ ID NO: 9) DIQMTQSPSSLSASVGDRVTITCRASQDINSYLSWFQQKPGKAPKTLIYR VNRLVDGVPSRFSGSGSGNDYTLTISSLQPEDFATYYCLQYDAFPYTFGQ GTKVEIKR
- AbX 2 (SEQ ID NO: 10) DIQMTQSPSSLSASVGDRVTITCRASQDINSYLAWFQQKPGKAPKSLIYR VNRLVSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYDAFPYTFGQ GTKVEIKR
- the anti-CD123 antibody or antigen-binding fragment thereof comprises an engineered Cys residue (e.g., C442); an immunoglobulin heavy chain variable domain at least about 90%, 95%, 99% or 100% identical to QXQLVQSGAEVKKPGASVKVSCKASGYIFTSSIMHWVRQAPGQGLEWIGYIKPYNDGT KYNEKFKGRATLTSDRSTSTAYMELSSLRSEDTAVYYCAREGGNDYYDTMDYWGQGT LVTVSS (SEQ ID NO: 7); and an immunoglobulin light chain variable region having the amino acid sequence at least about 90%, 95%, 99% or 100% identical to DIQMTQSPSSLSASVGDRVTITCRASQDINSYLSWFQQKPGKAPKTLIYRVNRLVDGVPS RFSGSGNDYTLTISSLQPEDFATYYCLQYDAFPYTFGQGTKVEIKR (SEQ ID NO: 9).
- Xa an engineered Cys residue
- the anti-CD123 antibody or antigen-binding fragment thereof comprises an engineered Cys residue (e.g., C442); an immunoglobulin heavy chain variable domain at least about 90%, 95%, 99% or 100% identical to QVQLVQSGAEVKKPGASVKVSCKASGYGFTSSIMHWVRQAPGQGLEWMGYIKPYNDG TKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAREGGNDYYDTMDYWGQ GTLVTVSS (SEQ ID NO: 8); and an immunoglobulin light chain variable region having the amino acid sequence at least about 90%, 95%, 99% or 100% identical to DIQMTQSPSSLSASVGDRVTITCRASQDINSYLAWFQQKPGKAPKSLIYRVNRLVSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCLQYDAFPYTFGQGTKVEIKR (SEQ ID NO: 10).
- an engineered Cys residue e.
- Humanized anti-CD123 antibodies that include the following heavy chain amino acid sequences:
- Humanized anti-CD123 antibodies that include the following light chain amino acid sequences:
- AbX 1 (SEQ ID NO: 14) DIQMTQSPSSLSASVGDRVTITCRASQDINSYLSWFQQKPGKAPKTLIYR VNRLVDGVPSRFSGSGSGNDYTLTISSLQPEDFATYYCLQYDAFPYTFGQ GTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG LSSPVTKSFNRGEC
- AbX 2 (SEQ ID NO: 15) DIQMTQSPSSLSASVGDRVTITCRASQDINSYLAWFQQKPGKAPKSLIYR VNRLVSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQYDAFPYTFGQ GTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV DNALQSGNSQESVTEQDS
- the anti-CD123 antibody or antigen-binding fragment thereof comprises an engineered Lys residue; an immunoglobulin heavy chain variable domain at least about 90%, 95%, 99% or 100% identical to Q(F/V)QLVQSGAEVKKPGASVKVSCKASGYIFTSSIMHWVRQAPGQGLEWIGYIKPYND GTKYNEKFKGRATLTSDRSTSTAYMELSSLRSEDTAVYYCAREGGNDYYDTMDYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE
- the anti-CD123 antibody or antigen-binding fragment thereof comprises an immunoglobulin heavy chain variable domain at least about 90%, 95%, 99% or 100% identical to Q(F/V)QLVQSGAEVKKPGASVKVSCKASGYIFTSSIMHWVRQAPGQGLEWIGYIKPYND GTKYNEKFKGRATLTSDRSTSTAYMELSSLRSEDTAVYYCAREGGNDYYDTMDYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREP
- the anti-CD123 antibody or antigen-binding fragment thereof comprises an immunoglobulin heavy chain variable domain at least about 90%, 95%, 99% or 100% identical to QVQLVQSGAEVKKPGASVKVSCKASGYGFTSSIMHWVRQAPGQGLEWMGYIKPYNDG TKYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAREGGNDYYDTMDYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ V
- Exemplary sequences for huDS6 are described in U.S. Pat. No. 7,834,155 and International Pat. Appl. Publication Nos.: WO2005/009369 and WO2007/024222, which are incorporated herein by reference in their entireties.
- Detailed sequences for huMov19 are described in U.S. Pat. Nos. 8,557,966 and 8,709,432 and International Pat. Appl. Publication Nos.: WO2011/106528, which are incorporated herein by reference in their entireties.
- Exemplary sequences for the huMy9-6 heavy chain variable region portion are described in U.S. Patent Publication No. 20060177455, which is incorporated herein by reference in its entirety.
- Exemplary sequences for the huMy9-6 light chain variable region portion are known in the art and described in U.S. Pat. Nos. 7,557,189, 7,342,110, 8,119,787 and 8,337,855, which are incorporated herein by reference in their entireties.
- Exemplary sequences for huCD37-3 are described in U.S. Pat. No. 8,765,917 and International Pat. Appl. Publication No. WO2011/112978, which are incorporated herein by reference in their entireties.
- Exemplary sequences for huB4 is described in International Pat. Appl. Publication No. WO2012/156455, which is incorporated herein by reference in its entirety.
- Additional exemplary antibodies include antibodies that target specific antigens. Examples include antibodies that target CD33, CD19, CD37, CA6, or FOLR1. Further, antibodies that target CD123 are also included herein.
- humanized antibody refers to forms of non-human (e.g., murine) antibodies that are specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof that contain minimal non-human (e.g., murine) sequences.
- humanized antibodies are human immunoglobulins in which residues from the complementary determining region (CDR) are replaced by residues from the CDR of a non-human species (e.g., mouse, rat, rabbit, hamster) that have the desired specificity, affinity, and capability (Jones et al, Nature 321:522-525, 1986; Riechmann et al, Nature 332:323-327, 1988; Verhoeyen et al, Science 239:1534-1536, 1988).
- CDR complementary determining region
- Antibodies can be humanized using a variety of other techniques including CDR-grafting (EP 0 239 400; WO 91/09967; U.S. Pat. Nos. 5,530,101; and 5,585,089), veneering or resurfacing (EP 0 592 106; EP 0 519 596; Padlan E. A., 1991, Molecular Immunology 28(4/5):489-498; Studnicka G. M. et al., 1994, Protein Engineering 7(6):805-814; Roguska M. A. et al., 1994, PNAS 91:969-973), and chain shuffling (U.S. Pat. No. 5,565,332).
- Human antibodies can be made by a variety of methods known in the art including phage display methods. See also U.S. Pat. Nos. 4,444,887, 4,716,111, 5,545,806, and 5,814,318; and International Pat. Appl. Publication Nos.: WO 98/46645, WO 98/50433, WO 98/24893, WO 98/16654, WO 96/34096, WO 96/33735, and WO 91/10741 (said references incorporated by reference in their entireties).
- the F v framework region (FR) residues of a human immunoglobulin are replaced with the corresponding residues in an antibody from a non-human species that has the desired specificity, affinity, and capability.
- the humanized antibody can be further modified by the substitution of additional residues either in the F v framework region and/or within the replaced non-human residues to refine and optimize antibody specificity, affinity, and/or capability.
- the humanized antibody will comprise substantially all of at least one, and typically two or three, variable domains containing all or substantially all of the CDR regions that correspond to the non-human immunoglobulin whereas all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence.
- the humanized antibody can also comprise at least a portion of an immunoglobulin constant region or domain (F c ), typically that of a human immunoglobulin.
- F c immunoglobulin constant region or domain
- Examples of methods used to generate humanized antibodies are described in U.S. Pat. Nos. 5,225,539 and 5,639,641, Roguska et al, Proc. Natl. Acad. Sci. USA 91(3):969-973, 1994; and Roguska et al, Protein Eng. 9(10):895-904, 1996 (all incorporated herein by reference).
- a “humanized antibody” is a resurfaced antibody.
- a “humanized antibody” is a CDR-grafted antibody.
- the antibody can be a chimeric antibody.
- compositions can comprise antigen-binding fragments such as antibody fragments (such as Fab, Fab′, F(ab)2, and Fv fragments) or single chain Fv (scFv) mutants.
- the binding fragments are attached to a separate protein, peptide, or oligopeptide to form a fusion protein.
- the fusion protein comprises an antigen-determination portion of an antibody fused to a one or more peptides, oligopeptides, or polypeptides.
- an appropriate antibody will depend upon the cell population to be targeted.
- the type and number of cell surface molecules (i.e., antigens) that are selectively expressed in a particular cell population will inform the selection of an appropriate antibody for use in the disclosed compositions.
- Cell surface expression profiles are known for a wide variety of cell types, including tumor cell types, or, if unknown, can be determined using routine molecular biology and histochemistry techniques.
- the antibodies can be polyclonal or monoclonal.
- Monoclonal antibodies are typically produced by a single clone of B lymphocytes (“B cells”).
- B cells B lymphocytes
- Monoclonal antibodies may be obtained using a variety of techniques known to those skilled in the art, including standard hybridoma technology (see, e.g., Köhler and Milstein, Eur. J. Immunol., 5, 511-519 (1976), Harlow and Lane (eds.), Antibodies: A Laboratory Manual, CSH Press (1988), and C. A. Janeway et al. (eds.), Immunobiology, 5th Ed., Garland Publishing, New York, N.Y. (2001)).
- the hybridoma method of producing monoclonal antibodies typically involves injecting any suitable animal, typically a mouse, with an antigen (i.e., an “immunogen”). The animal is subsequently sacrificed, and B cells isolated from its spleen are fused with human myeloma cells. A hybrid cell is produced (i.e., a “hybridoma”), which proliferates indefinitely and continuously secretes high titers of an antibody with the desired specificity in vitro. Any appropriate method known in the art can be used to identify hybridoma cells that produce an antibody with the desired specificity. Such methods include, for example, enzyme-linked immunosorbent assay (ELISA), Western blot analysis, and radioimmunoassay.
- ELISA enzyme-linked immunosorbent assay
- Western blot analysis Western blot analysis
- radioimmunoassay radioimmunoassay.
- hybridomas The population of hybridomas is screened to isolate individual clones, each of which secretes a single antibody species to the antigen. Because each hybridoma is a clone derived from fusion with a single B cell, all the antibody molecules it produces are identical in structure, including their antigen binding site and isotype. Monoclonal antibodies also may be generated using other suitable techniques including EBV-hybridoma technology (see, e.g., Haskard and Archer, J. Immunol.
- the monoclonal antibody can be isolated from or produced in any suitable animal.
- the antibody is produced in a mammal.
- the mammal is a mouse.
- the mammal is a human.
- Methods for producing an antibody in mice are well known to those skilled in the art and are described herein.
- human antibodies one of ordinary skill in the art will appreciate that polyclonal antibodies can be isolated from the sera of human subjects vaccinated or immunized with an appropriate antigen.
- human antibodies can be generated by adapting known techniques for producing human antibodies in non-human animals such as mice (see, e.g., U.S. Pat. Nos. 5,545,806, 5,569,825, and 5,714,352, and U.S. Patent Application Publication No. 2002/0197266 A1).
- a monoclonal antibody typically is not recognized as “foreign” by the human immune system.
- phage display can be used to generate the antibody.
- phage libraries encoding antigen-binding variable (V) domains of antibodies can be generated using standard molecular biology and recombinant DNA techniques (see, e.g., Sambrook et al. (eds.), Molecular Cloning, A Laboratory Manual, 3rd Edition, Cold Spring
- Phage encoding a variable region with the desired specificity are selected for specific binding to the desired antigen, and a complete human antibody is reconstituted comprising the selected variable domain.
- Nucleic acid sequences encoding the reconstituted antibody are introduced into a suitable cell line, such as a myeloma cell used for hybridoma production, such that human antibodies having the characteristics of monoclonal antibodies are secreted by the cell (see, e.g., Janeway et al., supra, Huse et al., supra, and U.S. Pat. No. 6,265,150).
- monoclonal antibodies can be generated from mice that are transgenic for specific human heavy and light chain immunoglobulin genes.
- the antibody is a humanized antibody.
- this approach produces a monoclonal antibody that is antigenically identical to a human antibody but binds the same antigen as the mouse monoclonal antibody from which the CDR sequences were derived.
- Methods for generating humanized antibodies are known in the art and are described in detail in, for example, Janeway et al., supra, U.S. Pat. Nos.
- Humanized antibodies can also be generated using the antibody resurfacing technology described in U.S. Pat. No. 5,639,641, Pedersen et al., J. Mol. Biol., 235, 959-973 (1994), Roguska et al., Proc. Natl. Acad. Sci. USA 91(3):969-973, 1994; and Roguska et al, Protein Eng. 9(10):895-904, 1996.
- Antibody fragments that have at least one antigen-binding site, and thus recognize and bind to at least one antigen or receptor present on the surface of a target cell also are within the scope of this disclosure.
- proteolytic cleavage of an intact antibody molecule can produce a variety of antibody fragments that retain the ability to recognize and bind antigens.
- limited digestion of an antibody molecule with the protease papain typically produces three fragments, two of which are identical and are referred to as the Fab fragments, as they retain the antigen binding activity of the parent antibody molecule.
- a single-chain variable region fragment (sFv) antibody fragment which consists of a truncated Fab fragment comprising the variable (V) domain of an antibody heavy chain linked to a V domain of a light antibody chain via a synthetic peptide, can be generated using routine recombinant DNA technology techniques (see, e.g., Janeway et al., supra).
- disulfide-stabilized variable region fragments can be prepared by recombinant DNA technology (see, e.g., Reiter et al., Protein Engineering, 7, 697-704 (1994)).
- Antibody fragments of the present disclosure are not limited to these exemplary types of antibody fragments. Any suitable antibody fragment that recognizes and binds to a desired cell surface receptor or antigen can be employed.
- Antibody-antigen binding can be assayed using any suitable method known in the art, such as, for example, radioimmunoassay (RIA), ELISA, Western blot, immunoprecipitation, and competitive inhibition assays (see, e.g., Janeway et al., supra, and U.S. Patent Application Publication No. 2002/0197266 A1).
- RIA radioimmunoassay
- ELISA ELISA
- Western blot Western blot
- immunoprecipitation immunoprecipitation
- competitive inhibition assays see, e.g., Janeway et al., supra, and U.S. Patent Application Publication No. 2002/0197266 A1.
- compositions disclosed herein comprise antibodies and antigen-binding fragments thereof attached to a linker.
- Any suitable linker can be used with the ADCs of the present disclosure as long as the linker does not prevent the antibody from binding to its target or eliminate a cytotoxic compound's cytotoxicity.
- a linker is substantially inert under conditions for linking two groups.
- a linker moiety comprises two reactive groups, such that one reactive group can be first reacted with the cytotoxic compound to provide a compound bearing the linker moiety and a second reactive group, which can then react with an antibody.
- one reactive group of the linker moiety can be first reacted with an antibody to provide an antibody and a linker moiety and a second reactive group, which can then react with a cytotoxic compound.
- linkers include, but are not limited to, disulfide linkers, thioether linkers, amide bonded linkers, peptidase-labile linkers, acid-labile linkers, and esterase-labile linkers.
- the linker is cleavable.
- cleavable linkers include, but are not limited to, N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP), N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB), N-succinimidyl 4-(2-pyridyldithio)2-sulfobutanoate (sulfo-SPDB), N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP), or N-succinimidyl 4-methyl-4-[2-(5-nitro-pyridyl)-dithio]pentanoate (SMNP).
- the linker is non-cleavable.
- non-cleavable linkers include, but are not limited to, 2-iminothiolane, acetylsuccinic anhydride, and succinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (SMCC).
- exemplary linkers such as CX1-1 (as described in U.S. Pat. Publication No. US20120253021, which is incorporated herein by reference) and acetylsuccinic anhydride, can be used as cleavable or non-cleavable linkers.
- the linking moiety contains a chemical bond that allows for the release of the cytotoxic compound at a particular site.
- Suitable chemical bonds are well known in the art and include disulfide bonds, thioether bonds, acid labile bonds, photolabile bonds, peptidase labile bonds and esterase labile bonds (see for example US Pat. Nos. 5,208,020; 5,475,092; 6,441,163; 6,716,821; 6,913,748; 7,276,497; 7,276,499; 7,368,565; 7,388,026 and 7,414,073).
- Other suitable linkers include non-cleavable linkers, such as those described in are described in detail in U.S. publication number 20050169933, or charged linkers or hydrophilic linkers and are described in US 2009/0274713, US 2010/01293140 and WO 2009/134976, each of which is expressly incorporated herein by reference.
- aspects of this disclosure are directed to several cytotoxic compounds. These cytotoxic compounds can induce cytotoxicity in cells. When coupled to any of the above-described antibodies to form the ADCs of this disclosure, these cytotoxic compounds can be delivered directly to targeted cells. As a result of normal pharmacologic clearance mechanisms, an antibody employed in an ADC contacts and binds to target cells only in limited amounts. Therefore, the cytotoxic agent employed in the conjugate must be highly cytotoxic such that cell killing sufficient to elicit a therapeutic effect occurs.
- the cytotoxic compounds of this disclosure comprise benzodiazepines.
- the cytotoxic compound is a pyrrolobenzodiazepine.
- the cytotoxic compound is a indolinobenzodiazepine.
- the cytotoxic compound is a compound in Table 1.
- DGN462 is described, for example, in U.S. Pat. No. 8,765,740, which is incorporated herein by reference in its entirety.
- Compound D3 is described, for example, in U.S. Pat. Nos. 8,426,402, 8,809,320 and 8,802,667, which are incorporated herein by reference in their entirety.
- Compounds D1, D2, and D4 are described, for example, in U.S.
- the benzodiazepines including the compounds in Table 1, are linked to antibodies and antigen-binding fragments thereof with the linkers described herein.
- the benzodiazepines may be Cys-linked. In other embodiments, the benzodiazepines may be Ser-linked.
- This disclosure is also directed to variations of the compounds in Table 1, such as modification of a compound in Table 1 by sulfonation.
- Other variations of the compounds in Table 1 are readily apparent to those of ordinary skill in the art. Such variations are encompassed by this disclosure.
- ADCs comprising benzodiazepines are shown herein to exhibit increased RSA. It is believed that the increased RSA results from the increased hydrophobic interactions from the benzodiazepines resulting in additional reversible intermolecular interactions. As demonstrated below in the Examples, an increase in the drug load (the “DAR” or drug-to-antibody ratio) results in increased RSA. Compositions with higher DARs have higher amounts of benzodiazepines per antibody. The benzodiazepines are hydrophobic and insoluble and comprise multiple aromatic rings. Thus, it is believed, the benzodiazepines interact with other components in an ADC. These additional reversible intermolecular interactions result in increased RSA for the ADCs disclosed herein.
- small hydrophobic molecules inhibit or reduce RSA in compositions comprising the ADCs of this disclosure.
- These small molecules fall into two classes: (1) amino acids with hydrophobic side chains, including proline, alanine, leucine, isoleucine, methionine, phenylalanine, tryptophan, tyrosine, and valine; and (2) betaines, small neutral molecules with a positively charged cationic functional group and a negatively charged functional group.
- the cationic functional group and negatively charged functional group need not be adjacent.
- the cationic functional groups include onium ions such as quaternary ammonium and quaternary phosphonium.
- the negatively charged functional groups include carboxylate, sulfite, and phosphite.
- betaine is trimethylglycine. Historically, the term betaine referred to trimethlyglycine. Therefore, depending on the context as used herein, the term “betaine” can refer to betaines generally or to trimethlyglycine specifically.
- One aspect of this disclosure is directed to a composition
- a composition comprising: (a) an ADC comprising a benzodiazepine; and (b) a small hydrophobic molecule selected from the group consisting of betaines and or amino acids with hydrophobic side chains.
- the small hydrophobic molecule is an amino acid with a hydrophobic side chain.
- the small hydrophobic molecule is a betaine.
- the small hydrophobic molecule is trimethlyglycine.
- 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.
- the antibody is AbX.
- the benzodiazepine is an indolinobenzodiazepine.
- the benzodiazepine is a compound in Table 1.
- the ADC is an ADC in Table 2.
- r is an integer from 1 to 10;
- Ab-NH is an antibody covalently linked to the compound through a lysine;
- Ser indicates an antibody linked to the compound through an N-terminal serine;
- Cys indicates an antibody linked to the compound through a cysteine; and
- M is H + , Na + , K + , or any pharmaceutically acceptable cation.
- This disclosure is also directed to other variations in the linker of the ADCs in Table 2, that are readily apparent to those of ordinary skill in the art.
- the SO 3 M group shown on the linker can be substituted with ‘H’ to obtain an ADC wherein the antibody Ab is linked via SPDB linker to the cytotoxic compounds D1, D1(a), D2, D2(a), DGN462, DGN462(a), D3, D3(a), D4, D4(a), D5, D5(a), D6, and D6(a), respectively.
- Such variations and similar variations are encompassed by this disclosure.
- RSA is eliminated in the disclosed compositions. In some embodiments, RSA is decreased by about 90% to 100% in the disclosed compositions. In certain embodiments, RSA is decreased by about 80% to about 90% in the disclosed compositions. In some embodiments, RSA is decreased by about 70% to about 80% in the disclosed compositions. In further embodiments, RSA is decreased by about 60% to about 70% in the disclosed compositions. In still further embodiments, the RSA is decreased by about 50% to about 60% in the disclosed compositions. In yet further embodiments, RSA is decreased by about 40% to about 50% in the disclosed compositions. In some embodiments, RSA is decreased by about 30% to about 40% in the disclosed compositions.
- compositions comprising ADCs comprising a benzodiazepine, wherein the composition has a low pH. It is believed that a lower pH allows for a higher amount of H + ions that can interact non-covalently with the antibodies in solution and inhibit the antibodies' ability to form oligomeric species through intermolecular interactions, thereby reducing RSA.
- the composition has a pH between about 4.0 to about 4.5.
- One aspect of this disclosure is directed to a composition having a pH between about 4.0 and about 4.5 and comprising a betaine and an ADC comprising a benzodiazepine.
- the betaine is trimethlyglycine.
- Another aspect of this disclosure is directed to a composition having a pH between 4.0 and 4.5 and comprising an amino acid with a hydrophobic side chain and an ADC comprising a benzodiazepine.
- the benzodiazepine is a compound in Table 1.
- the ADC is an ADC in Table 2.
- compositions of this disclosure are formulated to be acceptable for pharmaceutical use, such as, for example, administration to a human in need thereof.
- the ADC is formulated into a composition comprising a physiologically acceptable carrier (e.g., excipient or diluent).
- physiologically acceptable carriers are well known and are readily available, and include buffering agents, anti-oxidants, bacteriostats, salts, and solutes that render the composition isotonic with the blood or other bodily fluid of the human patient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers (e.g., surfactants), and preservatives.
- the choice of carrier will be determined, at least in part, by the location of the target tissue and/or cells, and the particular method used to administer the composition.
- suitable carriers and excipients for use in ADC pharmaceutical formulations are disclosed in, for example, International (PCT) Patent Application Nos. WO 00/02587, WO 02/060955, and WO 02/092127, and Ghetie et al., J. Immunol. Methods, 112, 267-277 (1988).
- buffering agents may be used in connection with the disclosed compositions.
- succinate may be used as a buffering agent in connection with the disclosed compositions.
- citrate may be used as a buffering agent in connection with the disclosed compositions.
- sodium bisulfate may be used in addition to succinate or citrate.
- Other exemplary buffering agents that may be used with the disclosed compositions include acetate and phosphate.
- the buffering agent may be present in the compositions of this disclosure in any suitable concentration, so long as sufficient stability of the composition is achieved under the desired conditions.
- the concentration of the buffering agent in the composition is about 2 mM to about 50 mM (e.g., about 2-10 mM, about 10-20 mM, about 20-30 mM, about 30-40 mM, or about 40-50 mM). In some embodiments, the concentration of the buffering agent in the composition is about 5-15 mM (e.g., about 10 mM). In some embodiments, the buffering agent is sodium succinate or sodium acetate. In some embodiments, the buffering agent is sodium citrate. The buffering agent typically is present in the disclosed compositions such that the pH is maintained within a desired range.
- compositions of this disclosure also optionally contain a surfactant.
- a surfactant Any suitable surfactant can be used. Suitable surfactants are well known to those skilled in the art.
- the surfactant is a polysorbate.
- the surfactant is polysorbate 20 or polysorbate 80.
- the surfactant may be present in the compositions of this disclosure in any suitable concentration, so long as sufficient stability of the composition is achieved under the desired conditions.
- the concentration of the surfactant in the composition is about 0.002% to about 0.1% wt./vol. (e.g., about 0.002-0.01%, about 0.005-0.02%, or about 0.01-0.1% wt./vol.) of the total volume of the composition.
- the concentration of the surfactant in the composition is about 0.005-0.02% wt./vol. (e.g., about 0.01% wt./vol.) of the total volume of the composition.
- composition of this disclosure can further be stabilized by the addition of sugar.
- the sugar is sucrose or trehalose.
- the concentration of sucrose or trehalose in the composition is about 0.1% to about 10% wt./vol. (e.g., about 0.1-1%, about 2-5%, or about 7-10% wt./vol.) of the total volume of the composition.
- the composition can also further comprise bulking agents.
- the bulking agent is mannitol. In other embodiments, the bulking agent is glycine.
- compositions of this disclosure can be lyophilized. Lyophilization refers to freeze drying under a vacuum. Lyophilization typically is accomplished by freezing a particular formulation such that the solutes are separated from the solvent(s). The solvent is then removed by sublimation (i.e., primary drying) and next by desorption (i.e., secondary drying). When the compositions of this disclosure are lyophilized and then reconstituted, RSA is still reduced or inhibited. Thus, although the small hydrophobic molecule can be added to compositions prior to lyophilization, the benefits of reduced or inhibited RSA are still realized in the compositions that are reconstituted after lyophilization.
- the lyophilized composition optionally further comprises a cryoprotectant.
- the cryoprotectant is an amorphous cryoprotectant.
- cryoprotectant refers to an excipient that protects unstable molecules during freezing.
- Suitable cryoprotectants for use in the compositions of this disclosure are known to those skilled in the art, and include, for example, glycerol, dimethyl sulfoxide (DMSO), polyethylene glycol (PEG), dextran, glucose, trehalose, and sucrose.
- DMSO dimethyl sulfoxide
- PEG polyethylene glycol
- dextran glucose
- trehalose trehalose
- sucrose sucrose.
- the cryoprotectant may be present in the lyophilized composition in any suitable amount.
- the lyophilized composition comprises about 0.5 mg to about 5 mg (e.g., about 0.5 mg to about 2 mg) of the cryoprotectant per mg of the conjugate (e.g., about 0.8 mg cryoprotectant per mg of the conjugate. In some embodiments, the lyophilized composition comprises about 2 mg cryoprotectant per mg of the conjugate. In some embodiments, the lyophilized composition comprises about 4 mg cryoprotectant per mg of the conjugate. In some embodiments, the cryoprotectant is sucrose and the lyophilized composition comprises about 0.5 mg to about 2 mg (e.g., about 1 mg) sucrose per mg of the conjugate
- the lyophilized compositions of this disclosure can be produced using a lyophilization cycle comprising the following steps: (1) pre-cooling at a shelf temperature of 4° C. and ambient chamber pressure for 2.5 hours, (2) freezing at a shelf temperature of ⁇ 50° C. and ambient chamber pressure for 14 hours, (3) glycine recrystallization at a shelf temperature of ⁇ 20° C. and ambient chamber pressure for 6 hours, (4) re-freezing at a shelf temperature of ⁇ 50° C. and ambient chamber pressure for 16 hours, (5) primary drying at a shelf temperature of ⁇ 13 ° C.
- lyophilized compositions of this disclosure are not limited to compositions produced by the above-described method. Indeed, any suitable lyophilization method can be used to produce the lyophilized compositions of this disclosure, and it will be apparent to those skilled in the art that the chosen lyophilization parameters (e.g., drying times) will vary depending on a variety of factors, including the volume of the solution to be lyophilized.
- compositions of this disclosure are advantageous over the prior art formulations for many reasons.
- the increase in the amount of monomer results in compositions of increased potency.
- Efficacy is increased because each composition delivers greater therapeutic effect per dose. This is advantageous because it reduces the number of doses that subjects need.
- compositions of this disclosure also decrease toxicity, hence improving patient safety.
- the compositions of this disclosure deliver more of the cytotoxic compounds to the targeted sites by virtue of the reduced RSA, thereby reducing the amount of cytotoxic compounds that can interact with non-targeted sites.
- the reduced RSA decreases the viscosity of a solution, thereby improving the efficacy of some modes of administration because the disclosed compositions are less likely to clog or impede the plunger of a syringe.
- This disclosure is also directed to methods of treating cancer in a subject comprising administering to the subject a composition comprising (a) an effective amount of an ADC comprising a benzodiazepine and (b) 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.
- the composition has a pH of about 4.0 to about 4.5.
- excipients e.g., buffering agents, surfactants, sugars, etc.
- the disclosed compositions are administered to a human via injection.
- the disclosed compositions are administered to a human via infusion.
- injection refers to the forceful introduction of the disclosed compositions into a target tissue of the human.
- infusion refers to the introduction of the disclosed compositions into a tissue, e.g., a vein, of the human.
- the composition can be administered to the human by any suitable route.
- the compositions are administered to the human intravenously or intraperitoneally. In some embodiments, administration is intratumoral.
- any suitable injection device can be used to administer the composition.
- the common medical syringe can be used to directly inject the composition into a subcutaneous tumor.
- the composition can be topically applied to the tumor by bathing the tumor in the disclosed liquid composition.
- the tumor can be perfused with the disclosed composition over a period of time using any suitable delivery device, e.g., a catheter.
- Other routes of administration can be used to deliver the composition to the human. Some routes can provide a more immediate and more effective reaction than other routes.
- the composition is administered to a surface of the subject selected from the group of dermal and mucosal surfaces and combinations thereof.
- the disclosed compositions can be applied or instilled into body cavities, absorbed through the skin, inhaled, or administered parenterally via, for instance, intramuscular or intraarterial administration.
- the disclosed compositions parenterally administered to a human are specifically targeted to particular cells, e.g., cancer cells.
- This disclosure is also directed to methods of formulating, comprising providing an ADC comprising a benzodiazepine in an aqueous solution, adding to the aqueous solution comprising the ADC a small hydrophobic molecule selected from the group consisting of betaines and amino acids with hydrophobic side chains.
- the method further comprises adjusting the pH of the aqueous solution to between about 4.0 and about 4.5.
- the method further comprises lyophilizing the solution.
- the method further comprises reconstituting the lyophilized composition.
- 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%.
- 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.
- 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%.
- 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.
- ADCs comprising a benzodiazepine, the small hydrophobic molecules, excipients (e.g., buffering agents, surfactants, sugars, etc.), and other components described herein are also applicable to the compositions that are used in the methods of treating.
- excipients e.g., buffering agents, surfactants, sugars, etc.
- This disclosure is also directed to methods of reducing RSA in ADCs comprising benzodiazepines.
- One aspect is directed to methods of reducing RSA in an ADC comprising a benzodiazepine, the method comprising providing an ADC comprising a benzodiazepine in an aqueous solution, wherein the ADC exhibits RSA, 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 or inhibits RSA.
- the method further comprises detecting reversible self-association.
- the method further comprises lyophilizing the aqueous solution.
- the method further comprises reconstituting a lyophilized composition.
- RSA is eliminated in the disclosed compositions. In some embodiments, RSA is decreased by about 90% to 100% in the disclosed compositions. In certain embodiments, RSA is decreased by about 80% to about 90% in the disclosed compositions. In some embodiments, RSA is decreased by about 70% to about 80% in the disclosed compositions. In further embodiments, RSA is decreased by about 60% to about 70% in the disclosed compositions. In still further embodiments, the RSA is decreased by about 50% to about 60% in the disclosed compositions. In yet further embodiments, RSA is decreased by about 40% to about 50% in the disclosed compositions. In some embodiments, RSA is decreased by about 30% to about 40% in the disclosed compositions. In some embodiments, the method further comprises adjusting the pH of the solution to between about 4.0 to about 4.5.
- ADCs comprising benzodiazepine, the small hydrophobic molecules, excipients (e.g., buffering agents, surfactants, sugars, etc.), and other components described herein are also applicable to the compositions that are used in the methods of reducing RSA.
- excipients e.g., buffering agents, surfactants, sugars, etc.
- This example demonstrates the use of dynamic light scattering and sedimentation velocity analytical ultracentrifugation as techniques for evaluating the extent of reversible self-association in an indolinobenzodiazepine ADC, huMy9-6-DGN462.
- Dynamic Light Scattering measures the time-dependent fluctuation in the intensity of light scattered from the proteins or antibodies in solution at a fixed scattering angle. As the protein or antibody or ADC molecules undergo Brownian motion, their relative positions change with time. Small molecules, which diffuse quickly, generate signals that fluctuate rapidly, while larger proteins and antibodies generate slower signal fluctuations.
- the translational diffusion coefficient, D t is related to the intensity autocorrelation function of the time-dependent fluctuation in intensity.
- DLS can be used to measure a unique diffusion coefficient for a given concentration.
- a plot of translational diffusion coefficient against protein or antibody concentration yields a best fit line with slope m and a y-intercept, b.
- a line where the slope m, is positive indicates a net repulsive interaction of the proteins or antibodies, while a negative slope is indicative of a net attractive interaction. This can be seen in FIG. 1 .
- Sedimentation velocity analytical ultracentrifugation measures the rate at which molecules in solution move in response to centrifugal force generated in a centrifuge.
- SV-AUC Sedimentation velocity analytical ultracentrifugation
- UV absorbance optics The high centrifugal force rapidly depletes the protein or antibody from the center of the rotor and forms a boundary that moves towards the outside of the rotor over time.
- the rate at which the boundary moves is also dependent on the diffusion and frictional forces that act in the opposite direction of sedimentation of the molecule.
- the minimum width of the sedimentation boundary is related to the diffusion coefficient. The presence of several species with similar sedimentation coefficients will cause the boundary to be broader than expected.
- the sedimentation boundary is broader than expected due to the presence of higher ordered oligomers that are stable over the time scale of sedimentation. This manifests as diffusion that is much faster than would be expected for molecules of the measured sedimentation coefficients.
- the shape of the molecule which is inferred from the frictional ratio f/f 0 , where f is the frictional coefficient for the protein or antibody and f 0 is the frictional coefficient for a hard solid sphere of radius r, is calculated to be more spherical.
- the frictional ratio is considerably smaller ( ⁇ 1) than for non-associating antibodies ( ⁇ 1.5).
- DAR drug load
- Conjugates comprising the huMy-9-6 monoclonal antibody chemically coupled to the indolinobenzodiazepine DGN462 via a 4-(2-pyridinyldithio)-2-sulfo-,1-(2,5-dioxo-1-pyrrolidinyl) butanoic acid ester (sSPDB) linker (the ADC is referred to as “huMy9-6-sSPDB-DGN462”) were prepared using methods described herein and known in the art (see, e.g., U.S. Pat. No. 8,889,669, which is herein incorporated by reference) to yield drug to antibody ratios (DAR) of 1.8, 2.4, and 2.8.
- DAR drug to antibody ratios
- compositions with a lower drug load had smaller hydrodynamic diameters than those with higher drug loads suggesting that the intermolecular interactions are between the indolinobenzodiazepine moieties attached to each antibody.
- compositions that reduces or inhibits reversible self-association comprising an ADC comprising an antibody chemically coupled to an indolinobenzodiazepine (DGN462), buffering agent, surfactant, hydrophobic amino acid, sugar, and water.
- DGN462 indolinobenzodiazepine
- a conjugate comprising the huMy-9-6 monoclonal antibody chemically coupled to the indolinobenzodiazepine DGN462 via a 4-(2-pyridinyldithio)-2-sulfo-,1-(2,5-dioxo-1-pyrrolidinyl) butanoic acid ester (sSPDB) linker (the ADC is referred to as “huMy9-6-sSPDB-DGN462”) was prepared using methods described herein and known in the art (see, e.g., U.S. Pat. No. 8,889,669).
- huMy9-6-sSPDB-DGN462 conjugates were formulated as follows: (a) 0.2 mg/mL ADC, 20 mM histidine, 8% trehalose, 0.02% polysorbate 20, pH 6.1; (b) 0.2 mg/mL ADC, 10 mM succinate, 8% trehalose, pH 4.2; (c) 0.5 mg/mL ADC, 10 mM sodium succinate, 280 mM betaine, pH 4.2; and (d) 0.5 mg/mL ADC, 10 mM sodium succinate, 280 mM proline, pH 4.2.
- the results of analysis of dynamic light scattering demonstrating the effects of the formulation pH and excipients on reversible self-association are set forth in FIG.
- the formulations with proline and betaine have the least negative slope, indicating a lower amount of net attractive interaction when compared to the other formulations.
- the results of SV-AUC for the 10 mM succinate, 280 mM proline formulation and the 10 mM succinate, 280 mM betaine formulation are set forth in FIG. 5 .
- the results show that succinate/proline or succinate/betaine formulations are superior to trehalose/histidine pH 6.1 formulations for reducing RSA.
- compositions for reducing or inhibiting reversible self-association comprising a conjugate comprising an antibody chemically coupled to an indolinobenzodiazepine D2, buffering agent, surfactant, hydrophobic amino acid, sugar, and water.
- a conjugate comprising a monoclonal antibody AbX chemically coupled to the indolinobenzodiazepine D2 (herein referred to as “AbX-D2”) is prepared using methods described herein and in U.S. Application Publication No. US20160082114A1, which is herein incorporated by reference in its entirety.
- compositions comprising the AbX-D2 conjugate are formulated as follows: (a) 20 mM histidine, 8% trehalose, 0.02% polysorbate 20, pH 6.1; (b) 10 mM acetate, 8% trehalose, pH 4.2; (c) 10 mM sodium succinate, 280 mM proline or 280 mM Betaine, pH 4.2; and (d) 10 mM sodium succinate, 8% trehalose, and optionally 0.02% polysorbate, pH4.2.
- 2-200 ⁇ M bisulfate may also be included.
- compositions for reducing or inhibiting reversible self-association comprising a conjugate comprising an antibody chemically coupled to an indolinobenzodiazepine D3, buffering agent, surfactant, hydrophobic amino acid, sugar, and water.
- a conjugate comprising the huMov19 monoclonal antibody chemically coupled to the indolinobenzodiazepine D1 (herein referred to as “huMov19-sSPDB-D1”) is prepared using methods described herein (see, e.g., U.S. Application Publication No. US20160106863).
- compositions comprising the huMov19-sSPDB-D1 conjugate are formulated as follows: (a) 20 mM histidine, 8% trehalose, 0.02% polysorbate 20, pH 6.1; (b) 10 mM acetate, 8% trehalose, pH 4.2; (c) 10 mM sodium succinate, 125 mM leucine, pH 4.2; and (d) 10 mM sodium succinate, 8% trehalose, and optionally 0.02% polysorbate, pH4.2.
- compositions for reducing or eliminating reversible self-association comprising a conjugate comprising an antibody chemically coupled to an indolinobenzodiazepine D4, buffering agent, surfactant, hydrophobic amino acid, sugar, and water.
- a conjugate comprising the huMov19 monoclonal antibody chemically coupled to the indolinobenzodiazepine D4 (herein referred to as “huMov19-sSPDB-D4”) is prepared using methods described herein (see, e.g., U.S. Application Publication No: US20160082114A1).
- compositions comprising the huMov19-sSPDB -D4 conjugate are formulated as follows: (a) 20 mM histidine, 8% trehalose, 0.02% polysorbate 20, pH 6.1; (b) 10 mM acetate, 8% trehalose, pH 4.2; (c) 10 mM sodium succinate, 125 mM isoleucine, pH 4.2; and (d) 10 mM sodium succinate, 8% trehalose, and optionally 0.02% polysorbate, pH4.2.
- the in situ mixture was prepared by reacting 1.5 mM sulfo-SPDB linker with 1.95 mM of compound 1d in 100% DMA for 4 hours in the presence of 10 mM N,N-Diisopropylethyl amine (DIPEA). Free thiol was then capped by adding a 3-fold excess of maleimido-propionic acid.
- DIPEA N,N-Diisopropylethyl amine
- the conjugate was purified and buffer exchanged into 100 mM Arginine, 20 mM Histidine, 2% sucrose, 0.01% Tween-20, 50 ⁇ M sodium bisulfite formulation buffer pH 6.1 using NAP desalting columns (Illustra Sephadex G-25 DNA Grade, GE Healthcare). Dialysis was performed in the same buffer for 20 hours at 4° C. utilizing Slide-a-Lyzer dialysis cassettes (ThermoScientific 20,000 MWCO).
- the conjugated antibody was found to be >80% intact by gel chip analysis.
- Step 1 (S)-2-(((benzyloxy)carbonyl)amino)propanoic acid (5 g, 22.40 mmol) and (S)-tert-butyl 2-aminopropanoate hydrochloride (4.48 g, 24.64 mmol) were dissolved in anhydrous DMF (44.8 mL). EDC ⁇ HCl (4.72 g, 24.64 mmol), HOBt (3.43 g, 22.40 mmol), and DIPEA (9.75 mL, 56.0 mmol) were added. The reaction stirred under argon, at room temperature, overnight.
- Step 2 Compound 81 (6.7 g, 19.12 mmol) was dissolved in methanol (60.7 mL) and water (3.03 mL). The solution was purged with argon for five minutes. Palladium on carbon (wet, 10%) (1.017 g, 0.956 mmol) was added slowly. The reaction was stirred overnight under an atmosphere of hydrogen. The solution was filtered through Celite, rinsed with methanol and concentrated. It was azeotroped with methanol and acetonitrile and the resulting oil was placed directly on the high vacuum to give compound 82 (4.02 g, 97% yield) which was used directly in the next step.
- Step 3 Compound 82 (4.02 g, 18.59 mmol) and mono methyladipate (3.03 mL, 20.45 mmol) were dissolved in anhydrous DMF (62.0 mL). EDC ⁇ HCl (3.92 g, 20.45 mmol), HOBt (2.85 g, 18.59 mmol) and DIPEA (6.49 mL, 37.2 mmol) were added. The mixture was stirred overnight at room temperature. The reaction was diluted with dichloromethane/methanol (150 mL, 5:1) and washed with saturated ammonium chloride, saturated sodium bicarbonate, and brine. It was dried over sodium sulfate, filtered and stripped.
- Step 4 Compound 83 (5.91 g, 16.5 mmol) was stirred in TFA (28.6 mL, 372 mmol) and deionized water (1.5 mL) at room temperature for three hours. The reaction mixture was concentrated with acetonitrile and placed on high vacuum to give crude compound 84 as a sticky solid (5.88 g, 100% yield).
- Step 5 Compound 84 (5.6 g, 18.52 mmol) was dissolved in anhydrous dichloromethane (118 mL) and anhydrous methanol (58.8 mL). (5-amino-1,3-phenylene)dimethanol (2.70 g, 17.64 mmol) and EEDQ (8.72 g, 35.3 mmol) were added and the reaction was stirred at room temperature, overnight. The solvent was stripped and ethyl acetate was added. The resulting slurry was filtered, washed with ethyl acetate and dried under vacuum/N 2 to give compound 85 (2.79 g, 36% yield).
- Step 6 Compound 85 (0.52 g, 1.189 mmol) and carbon tetrabromide (1.183 g, 3.57 mmol) were dissolved in anhydrous DMF (11.89 mL). Triphenylphosphine (PPH3) (0.935 g, 3.57 mmol) was added and the reaction stirred under argon for four hours. The reaction mixture was diluted with DCM/MeOH (10:1) and washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (DCM/MeOH) to give compound 86 (262 mg, 39% yield).
- DCM/MeOH silica gel chromatography
- Step 10 EDC ⁇ HCl was added to a stirred solution of acid compound 89 and N-hydroxysuccinamide in CH 2 Cl 2 at rt. The reaction mixture was stirred for 2 h. The reaction mixture was diluted with CH 2 Cl 2 and was washed with water and brine. The organic layer was dried over Na 2 SO 4 , filtered and concentrated.
- reaction containing 2.0 mg/mL huMOV19 antibody and 3.9 molar equivalents of compound 90 pretreated with 5-fold excess of sodium bisulfite in 95:5 DMA:50 mM succinate pH 5.5 for 4 hours at 25° C.
- 15 mM HEPES (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid) pH 8.5 buffer and 15% v/v DMA (N,N-Dimethylacetamide) cosolvent was incubated for 4 hours at 25° C.
- the conjugate was purified and buffer exchanged into 10 mM succinate, 50 mM sodium chloride, 8.5% w/v sucrose, 0.01% Tween-20, 50 ⁇ M sodium bisulfite pH 6.2 formulation buffer using NAP desalting columns (Illustra Sephadex G-25 DNA Grade, GE Healthcare). Dialysis was performed in the same buffer for 4 hours at room temperature and then overnight at 4° C. utilizing Slide-a-Lyzer dialysis cassettes (ThermoScientific 30,000 MWCO).
- the MS spectrometry data is shown in FIG. 6 .
- DAR0 represents an unconjugated antibody, i.e., an antibody that has no benzodiazepines conjugated to it.
- DAR6 represents an antibody with six benzodiazepines linked to it. The peaks in the middle correspond, from left to right, DAR1, DAR2, DAR3, DAR4, and DAR5.
- Step 1 Compound 82 (500 mg, 2.31 mmol), 4-methyl-4-(methyldisulfanyl)pentanoic acid (449mg, 2.31mmol), EDC ⁇ HCl (465 mg, 2.43 mmol), HOBt (354 mg, 2.31 mmol), and DIPEA (0.81 mL, 4.62 mmol) were dissolved in DMF (7.7 mL) and stirred overnight until the reaction was complete. The reaction was diluted with ethyl acetate and washed with saturated sodium bicarbonate, saturated ammonium chloride, and twice with water. The organic was dried and concentrated in vacuo to give compound 100 (875 mg, 96% yield) which was used directly in the next step.
- Step 7 Compound 106 was dissolved in THF (0.5 mL) and ACN (0.23 mL) at room temperature. It was then prepared similarly to compound 98 in Example 9. The mixture was stirred until completion and then diluted with DCM and DI water. The organic layer was washed with brine, dried and filtered. The filtrate was concentrated to give the crude thiol, compound 106 (21 mg, 100% yield) which was used directly in the next reaction.
- LCMS 5.67 min (8 min method). MS (m/z): 980.4 (M+1) + .
- the conjugate was purified and buffer exchanged into 10 mM Tris, 80 mM NaCl, 50 uM Bisulfite, 3.5% Sucrose, 0.01% Tween-20 formulation buffer pH 7.6 using NAP desalting columns (Illustra Sephadex G-25 DNA Grade, GE Healthcare). Dialysis was performed in the same buffer over night at 4° C. utilizing Slide-a-Lyzer dialysis cassettes (ThermoScientific 10,000 MWCO).
- the MS spectrometry data is shown in FIG. 7 .
- DAR0 represents an unconjugated antibody, i.e., an antibody that has no benzodiazepines conjugated to it.
- DAR5 represents an antibody with five benzodiazepines linked to it. The peaks in the middle correspond, from left to right, DAR1, DAR2, DAR3, and DAR4.
- compositions that reduce, inhibit, or eliminate reversible self-association
- the compositions include a conjugate comprising an antibody with an engineered cysteine (e.g., a non-naturally occurring cysteine introduced into the antibody heavy chain or light chain in place of another non-cysteine amino acid) chemically coupled to an indolinobenzodiazepine, buffering agent, surfactant, sugar, and water.
- an engineered cysteine e.g., a non-naturally occurring cysteine introduced into the antibody heavy chain or light chain in place of another non-cysteine amino acid
- Conjugates comprising the AbX monoclonal antibody chemically coupled to the indolinobenzodiazepine D2(a) through engineered cysteines were produced.
- the conjugates were formulated as (a) 10 mM histidine, 8% trehalose, 0.01% polysorbate 20, pH 5.5; or (b) 10 mM sodium succinate, 8% trehalose, 0.01% polysorbate 20, pH 4.2.
- the succinate and trehalose combination at pH 4.2 showed a greater reduction in reversible self-association as measured by DLS when compared to the histidine trehalose combination (formula (a)).
- compositions disclosed herein demonstrate the ability of compositions disclosed herein to reduce, inhibit, or eliminate reversible self-association at lower pH ranges such as pH 4.2.
- compositions that reduce, inhibit, or eliminate reversible self-association comprising a conjugate comprising an antibody chemically coupled to an indolinobenzodiazepine, succinate-based buffering agent, surfactant, sugar, and water.
- Conjugates comprising the huMy-9-6 monoclonal antibody chemically coupled to the indolinobenzodiazepine DGN462 via a 4-(2-pyridinyldithio)-2-sulfo-,1-(2,5-dioxo-1-pyrrolidinyl) butanoic acid ester (sSPDB) linker (“huMy-9-6-sSPDB-DGN462”) were prepared using methods described herein and known in the art (see, e.g., U.S. Pat. No. 6,441,163).
- the huMy-9-6-sSPDB-DGN462 conjugate was formulated as follows: (a) 20 mM histidine, 8% trehalose, 0.02% polysorbate 20, pH 6.1; (b) 10 mM acetate, 8% trehalose, pH 4.2; and (c) 10 mM sodium succinate, 8% trehalose, pH 4.2.
- the succinate trehalose combination (formula (c)) is more effective than the acetate trehalose combination (formula (b)) at reducing reversible self-association at pH 4.2.
- compositions that reduce, inhibit, or eliminate reversible self-association
- the compositions include a conjugate comprising an antibody with an engineered cysteine (e.g., a non-naturally occurring cysteine introduced into the antibody heavy chain or light chain in place of another non-cysteine amino acid) chemically coupled to an indolinobenzodiazepine, buffering agent, surfactant, sugar, and water.
- an engineered cysteine e.g., a non-naturally occurring cysteine introduced into the antibody heavy chain or light chain in place of another non-cysteine amino acid
- Conjugates comprising the AbX monoclonal antibody chemically coupled to the indolinobenzodiazepine D2(a) through engineered cysteines were produced.
- the conjugate was formulated as 10 mM sodium succinate, 8% trehalose, 0.01% polysorbate 20, pH 4.0.
- the succinate and trehalose combination at pH 4.0 showed an equivalent or greater reduction in reversible self-association as measured by DLS when compared to the succinate/trehalose formulation at pH 4.2.
- this example shows the reduction of RSA even in a conjugate with a lower DAR.
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20180079819A1 (en) * | 2015-06-29 | 2018-03-22 | Immunogen, Inc. | Anti-cd123 antibodies and conjugates and derivatives thereof |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108026103B (zh) * | 2015-07-21 | 2021-04-16 | 伊缪诺金公司 | 制备细胞毒性苯并二氮杂䓬衍生物的方法 |
CN117065043A (zh) * | 2017-09-22 | 2023-11-17 | 伊缪诺金公司 | 防止免疫结合物中的甲硫氨酸氧化的方法 |
WO2020102053A1 (en) * | 2018-11-12 | 2020-05-22 | Immunogen, Inc. | Methods of preparing cytotoxic benzodiazepine derivatives |
US10851117B2 (en) * | 2018-11-12 | 2020-12-01 | Immunogen, Inc. | Methods of preparing cytotoxic benzodiazepine derivatives |
WO2020223351A1 (en) | 2019-04-29 | 2020-11-05 | Immunogen, Inc. | Therapeutic combinations comprising anti-cd123 immunoconjugates |
AU2020331036A1 (en) * | 2019-08-15 | 2022-03-03 | Silverback Therapeutics, Inc. | Formulations of benzazepine conjugates and uses thereof |
WO2021168274A1 (en) | 2020-02-21 | 2021-08-26 | Silverback Therapeutics, Inc. | Nectin-4 antibody conjugates and uses thereof |
JP2023532304A (ja) | 2020-07-01 | 2023-07-27 | エーアールエス ファーマシューティカルズ オペレーションズ,インク. | 抗asgr1抗体コンジュゲートおよびその使用 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060246004A1 (en) * | 2005-02-07 | 2006-11-02 | Genentech, Inc. | Antibody variants and uses thereof |
US20120238731A1 (en) * | 2011-02-15 | 2012-09-20 | Immunogen, Inc. | Methods of preparation of conjugates |
US20140314781A1 (en) * | 2002-08-16 | 2014-10-23 | Abbvie Biotechnology Ltd | Formulation of human antibodies for treating tnf-alpha associated disorders |
WO2017004025A1 (en) * | 2015-06-29 | 2017-01-05 | Immunogen, Inc. | Conjugates of cysteine engineered antibodies |
WO2017004026A1 (en) * | 2015-06-29 | 2017-01-05 | Immunogen, Inc. | Anti-cd 123 antibodies and conjugates and derivatives thereof |
Family Cites Families (61)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4444887A (en) | 1979-12-10 | 1984-04-24 | Sloan-Kettering Institute | Process for making human antibody producing B-lymphocytes |
US4716111A (en) | 1982-08-11 | 1987-12-29 | Trustees Of Boston University | Process for producing human antibodies |
GB8607679D0 (en) | 1986-03-27 | 1986-04-30 | Winter G P | Recombinant dna product |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5208020A (en) | 1989-10-25 | 1993-05-04 | Immunogen Inc. | Cytotoxic agents comprising maytansinoids and their therapeutic use |
GB8928874D0 (en) | 1989-12-21 | 1990-02-28 | Celltech Ltd | Humanised antibodies |
AU633698B2 (en) | 1990-01-12 | 1993-02-04 | Amgen Fremont Inc. | Generation of xenogeneic antibodies |
US5545806A (en) | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
US5814318A (en) | 1990-08-29 | 1998-09-29 | Genpharm International Inc. | Transgenic non-human animals for producing heterologous antibodies |
WO1992003918A1 (en) | 1990-08-29 | 1992-03-19 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
EP0519596B1 (en) | 1991-05-17 | 2005-02-23 | Merck & Co. Inc. | A method for reducing the immunogenicity of antibody variable domains |
US5565332A (en) | 1991-09-23 | 1996-10-15 | Medical Research Council | Production of chimeric antibodies - a combinatorial approach |
CA2076465C (en) | 1992-03-25 | 2002-11-26 | Ravi V. J. Chari | Cell binding agent conjugates of analogues and derivatives of cc-1065 |
US5639641A (en) | 1992-09-09 | 1997-06-17 | Immunogen Inc. | Resurfacing of rodent antibodies |
EP1978033A3 (en) | 1995-04-27 | 2008-12-24 | Amgen Fremont Inc. | Human antibodies derived from immunized xenomice |
CA2219486A1 (en) | 1995-04-28 | 1996-10-31 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
US6265150B1 (en) | 1995-06-07 | 2001-07-24 | Becton Dickinson & Company | Phage antibodies |
US5714352A (en) | 1996-03-20 | 1998-02-03 | Xenotech Incorporated | Directed switch-mediated DNA recombination |
US5916771A (en) | 1996-10-11 | 1999-06-29 | Abgenix, Inc. | Production of a multimeric protein by cell fusion method |
CA2616914C (en) | 1996-12-03 | 2012-05-29 | Abgenix, Inc. | Egfr-binding antibody |
CZ294425B6 (cs) | 1997-04-14 | 2005-01-12 | Micromet Ag | Způsob výroby anti-humánního antigenového receptoru, anti-humánní antigenový receptor, řetězec VH a VL, souprava pro selekci anti-humánních antigenových receptorů a farmaceutická kompozice, obsahující uvedený receptor |
US6235883B1 (en) | 1997-05-05 | 2001-05-22 | Abgenix, Inc. | Human monoclonal antibodies to epidermal growth factor receptor |
JP2002520297A (ja) | 1998-07-13 | 2002-07-09 | ボード オブ リージェンツ, ザ ユニバーシティ オブ テキサス システム | アミノリン脂質に結合する治療結合体を用いる癌処置方法 |
DE60032633T2 (de) | 1999-11-24 | 2007-10-04 | Immunogen Inc., Cambridge | Zytotoxische mittel, die taxane enthalten und ihre therapeutische anwendung |
CA2398136A1 (en) | 2000-02-08 | 2001-08-16 | The Penn State Research Foundation | Immunotherapy using interleukin 13 receptor subunit alpha 2 |
BR0206985A (pt) | 2001-01-29 | 2005-04-19 | Idec Pharma Corp | Anticorpos modificados e métodos de uso |
AU2002308637B2 (en) | 2001-05-11 | 2007-05-17 | Board Of Regents, The University Of Texas System | Anti-cd26 monoclonal antibodies as therapy for diseases associated with cells expressing cd26 |
US6441163B1 (en) | 2001-05-31 | 2002-08-27 | Immunogen, Inc. | Methods for preparation of cytotoxic conjugates of maytansinoids and cell binding agents |
US20040161776A1 (en) * | 2001-10-23 | 2004-08-19 | Maddon Paul J. | PSMA formulations and uses thereof |
US6716821B2 (en) | 2001-12-21 | 2004-04-06 | Immunogen Inc. | Cytotoxic agents bearing a reactive polyethylene glycol moiety, cytotoxic conjugates comprising polyethylene glycol linking groups, and methods of making and using the same |
US6756397B2 (en) | 2002-04-05 | 2004-06-29 | Immunogen, Inc. | Prodrugs of CC-1065 analogs |
KR20050032110A (ko) | 2002-08-02 | 2005-04-06 | 이뮤노젠 아이엔씨 | 신규의 효능을 갖는 탁산을 포함하는 세포독성제 및 그치료용도 |
US6913748B2 (en) | 2002-08-16 | 2005-07-05 | Immunogen, Inc. | Cross-linkers with high reactivity and solubility and their use in the preparation of conjugates for targeted delivery of small molecule drugs |
EA010570B1 (ru) | 2002-11-07 | 2008-10-30 | Иммьюноджен, Инк. | Антитело к cd33 и способы его применения |
US8088387B2 (en) | 2003-10-10 | 2012-01-03 | Immunogen Inc. | Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates |
US7276497B2 (en) | 2003-05-20 | 2007-10-02 | Immunogen Inc. | Cytotoxic agents comprising new maytansinoids |
JP2007503202A (ja) | 2003-07-21 | 2007-02-22 | イミュノジェン・インコーポレーテッド | Ca6抗原特異的な細胞毒性コンジュゲートおよびその使用方法 |
US7834155B2 (en) | 2003-07-21 | 2010-11-16 | Immunogen Inc. | CA6 antigen-specific cytotoxic conjugate and methods of using the same |
AR048098A1 (es) * | 2004-03-15 | 2006-03-29 | Wyeth Corp | Conjugados de caliqueamicina |
AU2006278573A1 (en) * | 2005-08-03 | 2007-02-15 | Immunogen, Inc. | Immunoconjugate formulations |
EP1917034A4 (en) | 2005-08-22 | 2009-04-29 | Immunogen Inc | CA6 ANTIGEN-SPECIFIC CYTOTOXIC CONJUGATE AND METHOD OF ITS APPLICATION |
ES2748526T3 (es) | 2006-12-21 | 2020-03-17 | Amgen Inc | Formulaciones tamponadas estables que contienen polipéptidos |
EP2170268A2 (en) * | 2007-06-25 | 2010-04-07 | Amgen, Inc. | Compositions of specific binding agents to hepatocyte growth factor |
SI2281006T1 (sl) | 2008-04-30 | 2017-12-29 | Immunogen, Inc. | Premreževalci in njihova uporaba |
BRPI0911442A2 (pt) | 2008-04-30 | 2019-03-12 | Immunogen, Inc. | conjugados potentes e ligantes hidrofílicos |
EP3100745B1 (en) | 2009-02-05 | 2018-04-18 | Immunogen, Inc. | Novel benzodiazepine derivatives |
EP4134095A1 (en) * | 2009-09-15 | 2023-02-15 | The Board of Trustees of the Leland Stanford Junior University | Synergistic anti-cd47 therapy for hematologic cancers |
KR20220017432A (ko) | 2010-02-24 | 2022-02-11 | 이뮤노젠 아이엔씨 | 엽산염 수용체 1 항체와 면역접합체 및 이들의 용도 |
LT2544719T (lt) | 2010-03-12 | 2019-10-25 | Debiopharm Int Sa | Cd37 surišančios molekulės, ir jų imunokonjugatai |
BR112012026213B1 (pt) | 2010-04-15 | 2021-12-28 | Medimmune Limited | Compostos de pirrolobenzodiazepinas, conjugado das mesmas, composição farmacêutica compreendendo o conjugado e uso do mesmo para o tratamento de uma doença proliferativa |
CN103108658B (zh) * | 2010-07-02 | 2015-08-19 | 米迪缪尼有限公司 | 抗体制剂 |
US8795673B2 (en) | 2011-03-29 | 2014-08-05 | Immunogen, Inc. | Preparation of maytansinoid antibody conjugates by a one-step process |
MX346555B (es) | 2011-04-01 | 2017-03-24 | Immunogen Inc | Metodos para aumentar la eficacia de la terapia contra el cancer con receptor 1 de folato (folr1). |
EP2524929A1 (en) | 2011-05-17 | 2012-11-21 | Sanofi | Use of anti-CD19 maytansinoid immunoconjugate antibody for the treatment of CD19+ B-cell malignancies syptoms |
GB2516808A (en) * | 2013-05-31 | 2015-02-11 | Innova Biosciences Ltd | Antibody composition and buffer system therefor |
FR3008463B1 (fr) | 2013-07-10 | 2015-08-07 | Hispano Suiza Sa | Structure compacte de boitier d'entrainement pour turbomachine d'aeronef |
EP3071237B1 (en) | 2013-11-21 | 2024-06-26 | Genmab A/S | Antibody-drug conjugate lyophilised formulation |
EP3069735B1 (en) * | 2014-01-10 | 2018-03-14 | Synthon Biopharmaceuticals B.V. | Duocarmycin adcs for use in the treatment of bladder cancer |
TW201613930A (en) | 2014-09-03 | 2016-04-16 | Immunogen Inc | Cytotoxic benzodiazepine derivatives |
EA034138B1 (ru) | 2014-09-03 | 2020-01-09 | Иммуноджен, Инк. | Цитотоксические бензодиазепиновые производные |
-
2016
- 2016-11-23 US US15/360,689 patent/US20170189548A1/en not_active Abandoned
- 2016-11-23 EP EP16869289.5A patent/EP3380525B1/en active Active
- 2016-11-23 WO PCT/US2016/063624 patent/WO2017091745A1/en active Application Filing
- 2016-11-23 RS RS20240036A patent/RS65120B1/sr unknown
- 2016-11-23 JP JP2018527232A patent/JP2019501139A/ja active Pending
- 2016-11-23 ES ES16869289T patent/ES2970186T3/es active Active
- 2016-11-23 EP EP23200032.3A patent/EP4335851A3/en active Pending
- 2016-11-23 FI FIEP16869289.5T patent/FI3380525T3/fi active
- 2016-11-23 DK DK16869289.5T patent/DK3380525T3/da active
- 2016-11-23 PT PT168692895T patent/PT3380525T/pt unknown
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2017
- 2017-08-16 US US15/678,421 patent/US20170348427A1/en not_active Abandoned
-
2019
- 2019-11-12 US US16/680,930 patent/US11278628B2/en active Active
-
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- 2021-04-28 JP JP2021075689A patent/JP7157204B2/ja active Active
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20140314781A1 (en) * | 2002-08-16 | 2014-10-23 | Abbvie Biotechnology Ltd | Formulation of human antibodies for treating tnf-alpha associated disorders |
US20060246004A1 (en) * | 2005-02-07 | 2006-11-02 | Genentech, Inc. | Antibody variants and uses thereof |
US20120238731A1 (en) * | 2011-02-15 | 2012-09-20 | Immunogen, Inc. | Methods of preparation of conjugates |
WO2017004025A1 (en) * | 2015-06-29 | 2017-01-05 | Immunogen, Inc. | Conjugates of cysteine engineered antibodies |
WO2017004026A1 (en) * | 2015-06-29 | 2017-01-05 | Immunogen, Inc. | Anti-cd 123 antibodies and conjugates and derivatives thereof |
US20170014522A1 (en) * | 2015-06-29 | 2017-01-19 | Immunogen, Inc. | Conjugates of cysteine engineered antibodies |
US20170029514A1 (en) * | 2015-06-29 | 2017-02-02 | Immunogen, Inc. | Anti-cd123 antibodies and conjugates and derivatives thereof |
Non-Patent Citations (5)
Title |
---|
Bendig, Methods: A Companion to Methods in Enzymology, 1995; 8:83-93. * |
Colman, Research in Immunology, 145:33-36, 1994. * |
Khantasup et al., Monoclonal Antibodies in Immunodiagnosis and Immunotherapy, 2015, 34(6): 404-417. * |
Paul, Fundamental Immunology, 3rd Edition, 1993, pp. 292-295, under the heading "Fv Structure and Diversity in Three Dimensions". * |
Rudikoff et al., Proc. Natl. Acad. Sci. USA, 79(6):1979-1983, March 1982 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20180079819A1 (en) * | 2015-06-29 | 2018-03-22 | Immunogen, Inc. | Anti-cd123 antibodies and conjugates and derivatives thereof |
US10442865B2 (en) | 2015-06-29 | 2019-10-15 | Immunogen, Inc. | Methods of use of anti-CD123 antibodies and antigen-binding fragments thereof |
US10875925B2 (en) | 2015-06-29 | 2020-12-29 | Immunogen, Inc. | Anti-CD123 antibodies and conjugates and derivatives thereof |
US10919969B2 (en) * | 2015-06-29 | 2021-02-16 | Immunogen, Inc. | Anti-CD123 antibodies and conjugates and derivatives thereof |
US11332535B2 (en) | 2015-06-29 | 2022-05-17 | Immunogen, Inc. | Anti-CD123 antibodies and conjugates and derivatives thereof |
US11897961B2 (en) | 2015-06-29 | 2024-02-13 | Immunogen, Inc. | Anti-CD123 antibodies and conjugates and derivatives thereof |
Also Published As
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FI3380525T3 (fi) | 2024-01-30 |
EP3380525A4 (en) | 2019-11-13 |
EP3380525B1 (en) | 2023-11-08 |
DK3380525T3 (da) | 2024-01-29 |
EP4335851A3 (en) | 2024-06-05 |
EP4335851A2 (en) | 2024-03-13 |
US20200222552A1 (en) | 2020-07-16 |
RS65120B1 (sr) | 2024-02-29 |
US11278628B2 (en) | 2022-03-22 |
JP2021119171A (ja) | 2021-08-12 |
EP3380525A1 (en) | 2018-10-03 |
PT3380525T (pt) | 2024-02-05 |
ES2970186T3 (es) | 2024-05-27 |
JP7157204B2 (ja) | 2022-10-19 |
US20170348427A1 (en) | 2017-12-07 |
JP2019501139A (ja) | 2019-01-17 |
WO2017091745A1 (en) | 2017-06-01 |
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