METHODS FOR FORMULATING ANTIBODY DRUG CONJUGATE COMPOSITIONS
The present invention provides improved methods for formulating therapeutic compositions comprising an antibody drug conjugate (“ADC”) that reduce potency variability between batches of ADC and provide administration of such therapeutic compositions within a narrow intended range.
1 . A method of reducing potency variability in an antibody drug conjugate composition, the method comprising:
(a) determining target drug concentration at a fixed antibody concentration and fixed drug antibody ratio (DAR); and
(b) formulating the antibody drug conjugate composition to achieve the target drug concentration, thereby reducing potency variability in the composition.
2 . A method of reducing potency variability in a composition comprising an antibody drug conjugate, the method comprising:
(a) determining drug concentration at a target antibody concentration and a fixed drug antibody ratio (DAR);
(b) targeting a variable drug concentration which identifies the midpoint of the range where the antibody concentration specification range and the drug concentration specification range overlap;
(c) formulating the antibody drug conjugate composition to the targeted variable drug concentration, thereby reducing potency variability in the composition.
3 . The method of claim 1 , wherein the variability in the drug concentration is about ±10%.
4 . The method of claim 2 , wherein the variability in the antibody concentration is about ±10%.
5 . (canceled)
6 . A method of reducing potency variability in a composition comprising an antibody drug conjugate, the method comprising:
(a) measuring the DAR for the antibody drug conjugate composition;
(b) determining the upper antibody specification limit and the lower antibody specification limit, wherein the upper antibody specification limit is the target antibody concentration plus the maximum variation allowed by the specification and the lower antibody specification limit is the target antibody concentration minus the maximum variation allowed by the specification;
(c) determining the defined upper drug specification limit and the defined lower drug specification limit, wherein the defined upper drug specification limit is the target drug concentration plus the maximum variation allowed by the specification and the defined lower drug specification limit is the target drug concentration minus the maximum variation allowed by the specification;
(d) determining the calculated upper drug specification limit (USL (drug)) as follows:
USL
(
drug
)
µg
/
mL
=
Upper
Antibody
Concentration
Specification
Limit
×
DAR
×
Drug
Mol
.
Wt
.
Antibody
Mol
.
Wt
.
×
1000
(e) determining the calculated lower drug specification limit (LSL (drug)) as follows:
LSL
(
drug
)
µg
/
mL
=
Lower
Antibody
Concentration
Specification
Limit
×
DAR
×
Drug
Mol
.
Wt
.
Antibody
Mol
.
Wt
.
×
1000
(f) comparing the calculated USL (drug) of step (d) to the defined upper drug specification limit of step (c), and selecting the lower of the two values as the effective upper drug specification limit;
(g) comparing the calculated LSL (drug) of step (e) to the defined lower drug specification limit of step (c), and selecting the higher of the two values as the effective lower drug specification limit; and
(h) formulating the antibody drug conjugate composition to a target drug concentration that is the midpoint between the effective upper drug specification limit and the effective lower drug specification limit, thereby reducing potency variability in said composition.
7 . The method of claim 6 , wherein the method narrows the range of the upper and lower specification limits for the drug and the antibody to about ±3-9%.
8 - 12 . (canceled)
13 . The method of claim 1 , wherein the antibody is a functional or a non-functional antibody.
14 . The method of claim 1 , wherein the drug concentration varies within the antibody specification concentration.
15 . The method of claim 2 , wherein the antibody concentration and the drug concentrations are allowed to vary.
16 . A method of formulating an antibody drug conjugate composition, the method comprising:
(a) determining target drug concentration at a fixed antibody concentration and fixed drug antibody ratio; and
(b) formulating the antibody drug conjugate composition to achieve the target drug concentration of step (a).
17 . The method of claim 1 , wherein the drug is a tubulin inhibitor, DNA damaging agent, DNA cross linker, DNA alkylating agent, or cell cycle disrupter.
18 . The method of claim 1 , wherein the drug is a maytansinoid, benzodiazepine compound, or auristatin.
19 . (canceled)
20 . The method of claim 18 , wherein the benzodiazepine compound is pyrrolobenzodiazepine or indolinobenzodiazepine.
21 . (canceled)
22 . (canceled)
23 . The method of claim 1 , wherein the drug is a benzodiazepine compound and the antibody is a non-functional antibody.
24 . The method of claim 1 , wherein the drug is a maytansinoid and the antibody is a non-functional antibody.
25 . (canceled)
26 . A method of reducing potency variability in a composition comprising an antibody maytansinoid conjugate, the method comprising:
(a) determining target maytansinoid concentration at a fixed antibody concentration and fixed maytansinoid-to-antibody ratio; and
(b) formulating the antibody maytansinoid conjugate composition to achieve the target maytansinoid concentration, thereby reducing potency variability in the composition.
27 . The method of claim 1 , wherein the method reduces batch-to-batch potency variability in producing the antibody drug conjugate.
28 . (canceled)
29 . A method of formulating an antibody maytansinoid conjugate composition, the method comprising:
(a) determining target maytansinoid concentration at a fixed antibody concentration and fixed maytansinoid-to-antibody ratio; and
(b) formulating the antibody maytansinoid conjugate composition to achieve the target maytansinoid concentration.
30 . A method of reducing potency variability in a composition comprising an antibody benzodiazepine conjugate, the method comprising:
(a) measuring the DAR for the antibody benzodiazepine conjugate composition;
(b) determining the upper antibody specification limit and the lower antibody specification limit, wherein the upper antibody specification limit is the target antibody concentration plus the maximum variation allowed by the specification and the lower antibody specification limit is the target antibody concentration minus the maximum variation allowed by the specification;
(c) determining the defined upper benzodiazepine specification limit and the defined lower benzodiazepine specification limit, wherein the defined upper benzodiazepine specification limit is the target benzodiazepine concentration plus the maximum variation allowed by the specification and the defined lower benzodiazepine specification limit is the target benzodiazepine concentration minus the maximum variation allowed by the specification;
(d) determining the calculated upper benzodiazepine specification limit (USL (drug)) as follows:
USL
(
drug
)
µg
/
mL
=
Upper
Antibody
Concentration
Specification
Limit
×
DAR
×
Drug
Mol
.
Wt
.
Antibody
Mol
.
Wt
.
×
1000
(e) determining the calculated lower benzodiazepine specification limit (LSL (drug)) as follows:
LSL
(
drug
)
µg
/
mL
=
Lower
Antibody
Concentration
Specification
Limit
×
DAR
×
Drug
Mol
.
Wt
.
Antibody
Mol
.
Wt
.
×
1000
(f) comparing the calculated USL (drug) of step (d) to the defined upper benzodiazepine specification limit of step (c), and selecting the lower of the two values as the effective upper benzodiazepine specification limit;
(g) comparing the calculated LSL (drug) of step (e) to the defined lower benzodiazepine specification limit of step (c), and selecting the higher of the two values as the effective lower benzodiazepine specification limit; and
(h) formulating the antibody benzodiazepine conjugate composition to a target benzodiazepine concentration that is the midpoint between the effective upper benzodiazepine specification limit and the effective lower benzodiazepine specification limit, thereby reducing potency variability in said composition.
31 - 37 . (canceled)
38 . The method of claim 6 , wherein the DAR is at the lower limit of DAR specification or at the upper limit of DAR specification.
39 - 49 . (canceled)
50 . The method of claim 18 , wherein the maytansinoid is DM1, DM3, or DM4.
51 - 55 . (canceled)
56 . The method of claim 6 , wherein the drug is a benzodiazepine compound and the antibody is a non-functional antibody.
57 . The method of claim 1 , wherein the antibody drug conjugate comprises a cleavable linker or non-cleavable linker.
58 . The method of claim 57 , wherein the cleavable linker is N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP), N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB), N-succinimidyl 4-(2-pyridyldithio)2-sulfobutanoate (sulfo-SPDB), or disulfide N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP).
59 . The method of claim 57 , wherein the non-cleavable linker is 2-iminothiolane, acetylsuccinic anhydride, or succinimidyl 4-[N-maleimidomethyl]cyclohexane-1-carboxylate (SMCC).
60 . The method of claim 1 , wherein the antibody drug conjugate is huMov19-sulfo-SPDB-DM4, huMov19-sulfo-SPDB-D1, huMov19-D2, huMov19-sulfo-SPDB-D10, huMov19-sulfo-SPDB-DGN462, huMy9-6-sulfo-SPDB-D1, huMy9-6-D2, huMy9-6-sulfo-SPDB-D10, huMy9-6-sulfo-SPDB-DGN462, huAnti-CD123-sulfo-SPDB-D1, huAnti-CD123-D2, huAnti-CD123-sulfo-SPDB-D10, huAnti-CD123-sulfo-SPDB-DGN462, huB4-SPDB-DM4, huDS6-SPDB-DM4, huCD37-3-SMCC-DM1, huCD37-50-SMCC-DM1, or huEGFR-7R-SMCC-DM1.
61 . A method for dosing a subject within a narrow intended range, the method comprising administering an antibody drug conjugate composition formulated according to the method of claim 1 to the subject.
62 . A pharmaceutical composition comprising an huMov19-sulfo-SPDB-DM4 antibody drug conjugate formulated according to the method of claim 1 , wherein a nominal maytansinoid concentration is provided on the label.
63 . A pharmaceutical composition comprising an huMy9-6-sulfo-SPDB-DGN462antibody drug conjugate formulated according to the method of claim 6 , wherein a nominal DGN462 concentration is provided on the label.