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 for administration of such therapeutic compositions within a narrow intended range.
1. A method of reducing potency variability in a composition comprising a huMy9-6-sulfo-SPDB-DGN462 antibody benzodiazepine conjugate, the method comprising:
(a) measuring the drug-to-antibody ratio (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 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.
2. The method of claim 1 , wherein the method narrows the range of the upper and lower specification limits for the drug and the antibody to about ±3-5%.
3. The method of claim 1 , wherein the method narrows the range of the upper and lower specification limits to about ±4%.
4. The method of claim 1 , wherein the maximum variation allowed by the specification in step (b) is about ±15%.
5. The method of claim 1 , wherein the maximum variation allowed by the specification in step (b) is less than about ±10, 11, 12, 13, or 14%.
6. The method of claim 1 , wherein the maximum variation allowed by the specification in step (c) is about ±15%.
7. The method of claim 1 , wherein the maximum variation allowed by the specification in step (c) is less than about ±10, 11, 12, 13, or 14%.