US2023364252A1PendingUtilityA1
Methods for formulating antibody drug conjugate compositions
Est. expirySep 2, 2034(~8.1 yrs left)· nominal 20-yr term from priority
A61K 47/68035A61K 47/68033C07K 16/28A61K 2039/545A61K 2039/505A61K 47/6849A61K 47/6851A61K 47/6803A61K 31/5513C07K 16/2803C07K 16/2863C07K 16/30C07K 2317/92C07K 2317/24C07K 2317/73C07K 2317/94A61P 35/00A61K 47/68
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Claims
Abstract
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 for administration of such therapeutic compositions within a narrow intended range.
Claims
exact text as granted — not AI-modified1 . 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 16 , wherein the composition comprising an antibody drug conjugate is formulated to achieve a pharmaceutical composition with a drug concentration falling within ±5% of the targeted drug concentration.
4 - 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:
U
S
L
(
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:
L
S
L
(
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 - 12 . (canceled)
13 . The method of claim 16 , wherein the antibody is a non-functional antibody.
14 - 15 . (canceled)
16 . A method of preparing a pharmaceutical composition comprising:
(a) measuring a drug concentration in a composition comprising an antibody drug conjugate; and (b) formulating the composition comprising the antibody drug conjugate to achieve a pharmaceutical composition with a drug concentration falling within ±10% of a targeted drug concentration; wherein said formulating step (b) does not include formulating said composition comprising the antibody drug conjugate to achieve a targeted antibody concentration.
17 . The method of claim 16 , 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 16 , 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 - 22 . (canceled)
23 . The method of claim 16 , wherein the drug is a benzodiazepine compound and the antibody is a non-functional antibody.
24 . The method of claim 16 , wherein the drug is a maytansinoid and the antibody is a non-functional antibody.
25 - 26 . (canceled)
27 . The method of claim 16 , wherein the method reduces batch-to-batch potency variability in producing the pharmaceutical composition.
28 - 49 . (canceled)
50 . The method of claim 18 , wherein the maytansinoid is DM1, DM3, or DM4.
51 - 56 . (canceled)
57 . The method of claim 16 , wherein the antibody drug conjugate comprises a 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 68 , wherein the non-cleavable linker is 2-iminothiolane, acetylsuccinic anhydride, or succinimidyl 4-[N-maleimidomethyl]cyclohexane-1-carboxylate (SMCC).
60 . The method of claim 16 , wherein the antibody drug conjugate is huMov19-sulfo-SPDB-DM4, huMov19-sulfo-SPDB-D1, huMov19-D2, huMov19-sulfo-SPDB-D10, huMov19-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-DGN462 antibody drug conjugate formulated according to the method of claim 6 , wherein a nominal DGN462 concentration is provided on the label.
64 . The method of claim 16 , wherein the drug is a maytansinoid.
65 . The method of claim 64 , wherein the maytansinoid is DM4.
66 . The method of claim 58 , wherein the cleavable linker is N-succinimidyl 4-(2-pyridyldithio)2-sulfobutanoate (sulfo-SPDB).
67 . The method of claim 16 , wherein the antibody drug conjugate comprises an antibody comprising light chain CDR sequences comprising the amino acid sequences set forth in amino acids 24-38 of SEQ ID NO:4, amino acids 54-60 of SEQ ID NO:4, and amino acids 93-101 of SEQ ID NO:4 and heavy chain CDR sequences comprising the amino acid sequences set forth in amino acids 31-35 of SEQ ID NO:5, amino acids 50-66 of SEQ ID NO:5, and amino acids 99-107 of SEQ ID NO:5.
68 . The method of claim 16 wherein the antibody drug conjugate comprises a non-cleavable cleavable linker.
69 . The method of claim 16 , further comprising measuring the antibody concentration to determine the drug antibody ratio (DAR) of the pharmaceutical composition.
70 . The method of claim 67 , wherein the antibody is conjugated to DM4 via a sulfo-SPDB linker.
71 . The method of claim 16 , wherein the antibody drug conjugate comprises an antibody comprising a light chain comprising the amino acid sequence set forth in SEQ ID NO:4 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:5.
72 . The method of claim 71 , wherein the antibody is conjugated to DM4.
73 . The method of claim 72 , wherein the antibody is conjugated to the DM4 via a sulfo-SPDB linker.
74 . 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 16 to the subject.
75 . A pharmaceutical composition comprising an huMov19-sulfo-SPDB-DM4 antibody drug conjugate formulated according to the method of claim 16 .Join the waitlist — get patent alerts
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