Combination therapy with antibody-drug conjugates and hyaluronidases
Provided are combination dosing regimens comprising administering an antibody-drug conjugate and hyaluronidase. Combinations and compositions containing the antibody-drug conjugate and hyaluronidase are provided. The dosing regimens and combinations are for treating or preventing cancer.
1 . A combination dosing regimen, comprising:
(i) subcutaneously administering to a patient in need thereof a composition comprising (a) a soluble hyaluronidase comprising a sequence of amino acids that has at least 85% sequence identity to a sequence of amino acids that contains at least amino acids 36-464 of SEQ ID NO: 1 and retains hyaluronidase activity, and (b) an effective dose of an antibody-drug conjugate (ADC); or
(ii) (a) subcutaneously administering to a patient in need thereof a first composition comprising a soluble hyaluronidase comprising a sequence of amino acids that has at least 85% sequence identity to a sequence of amino acids that contains at least amino acids 36-464 of SEQ ID NO: 1 and retains hyaluronidase activity, and (b) subcutaneously administering to the patient in need thereof a second composition comprising the effective dose of the ADC,
wherein:
the subcutaneous administration of the combination dosing regimen is administered in an amount that yields an area under the curve (AUC) of the ADC that is equal or greater than an AUC of an intravenous administration of a dosing regimen comprising the effective dose of the ADC without the soluble hyaluronidase, and
the subcutaneous administration of the combination dosing regimen yields a maximum concentration (C max ) of the ADC that is lower than the C max of the ADC obtained from the intravenous administration of the dosing regimen without the soluble hyaluronidase.
2 . The combination dosing regimen of claim 1 , wherein the ADC comprises an antibody and a payload conjugated to the antibody via a cleavable linker, wherein free antibody and free payload are released upon cleavage of the cleavable linker, and wherein the subcutaneous administration of the combination dosing regimen yields an AUC of the free payload in blood that is about 50% to about 90% of an AUC of an intravenous administration of a dosing regimen comprising an equivalent dose of the ADC without the soluble hyaluronidase.
3 . The combination dosing regimen of claim 1 , wherein the ADC comprises an antibody and a payload conjugated to the antibody via a cleavable linker, wherein free antibody and free payload are released upon cleavage of the cleavable linker, and wherein the subcutaneous administration of the combination dosing regimen yields a C max of the free payload in blood that is about 30% to about 80% of a C max of an intravenous administration of a dosing regimen comprising an equivalent dose of the ADC without the soluble hyaluronidase.
4 . The combination dosing regimen of claim 1 , wherein the subcutaneous administration of the combination dosing regimen yields a C max of the ADC that is about 20% to about 55% of the C max of the ADC obtained from an intravenous administration of an equivalent dose of the dosing regimen without the soluble hyaluronidase.
5 . The combination dosing regimen of claim 1 , wherein:
(a) the soluble hyaluronidase has an amino acid sequence selected from amino acids 36-465 of SEQ ID NO: 1, 36-466 of SEQ ID NO: 1, 36-467 of SEQ ID NO: 1, 36-468 of SEQ ID NO: 1, 36-469 of SEQ ID NO: 1, 35-470 of SEQ ID NO: 1, 36-471 of SEQ ID NO: 1, 36-472 of SEQ ID NO: 1, 36-474 of SEQ ID NO: 1, 36-475 of SEQ ID NO: 1, 36-476 of SEQ ID NO: 1, 35-477 of SEQ ID NO: 1, 36-478 of SEQ ID NO: 1 (i.e., SEQ ID NO: 8), 36-479 of SEQ ID NO: 1 (i.e., SEQ ID NO: 7), 36-480 of SEQ ID NO: 1 (i.e., SEQ ID NO: 6), 36-481 of SEQ ID NO: 1 (i.e., SEQ ID NO: 5), 36-482 of SEQ ID NO: 1 (i.e., SEQ ID NO: 4), 36-483 of SEQ ID NO: 1 (i.e., SEQ ID NO: 46), 35-484 of SEQ ID NO: 1, 36-485 of SEQ ID NO: 1, 36-486 of SEQ ID NO: 1, 36-487 of SEQ ID NO: 1, 36-488 of SEQ ID NO: 1, 36-489 of SEQ ID NO: 1, 36-490 of SEQ ID NO: 1, 35-491 of SEQ ID NO: 1, 36-492 of SEQ ID NO: 1, 36-493 of SEQ ID NO: 1, 36-494 of SEQ ID NO: 1, 36-495 of SEQ ID NO: 1, 36-496 of SEQ ID NO: 1, 36-497 of SEQ ID NO: 1, 35-498 of SEQ ID NO: 1, 36-499 of SEQ ID NO: 1, and 36-500 of SEQ ID NO: 1; or
(b) the soluble hyaluronidase is a variant soluble hyaluronidase that has at least 91% sequence identity to a reference soluble hyaluronidase having the amino acid sequence of (a).
6 . The combination dosing regimen of claim 5 , wherein the soluble hyaluronidase comprises a modified PH20 hyaluronidase with amino acid substitution F204P, and has increased stability relative to an unmodified PH20 hyaluronidase that does not comprise F204P; and wherein the modified PH20 hyaluronidase comprises one or more further replacements selected from:
(a) T341S, L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D and I361T;
(b) L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D and I361T;
(c) M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D, I361T and N363G;
(d) T341G, L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D and I361T;
(e) T341A, L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D and I361T;
(f) T341C, L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D and I361T;
(g) T341D, L342W, S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D and I361T;
(h) I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D and I361T; and
(i) S343E, I344N, M345T, S347T, M348K, K349E, L352Q, L353A, L354I, D355K, N356E, E359D and I361T, and
wherein increased stability is measured as increased stability in a denaturing condition or at elevated temperatures.
7 . The combination dosing regimen of claim 5 , wherein:
the soluble hyaluronidase is a variant modified polypeptide or catalytically active portion thereof that comprises one or more amino acid substitutions selected from among T341A, T341C, T341D, T341G, T341S, L342W, S343E, I344N, M348K, and N363G, wherein amino acid numbering is with reference to SEQ ID NO:1; and
the variant modified polypeptide has an N-terminus at amino acid 36, 37, 38, 39, or 40 and a C-terminus at an amino acid corresponding to amino acids 465 to 500 with reference to SEQ ID NO: 1, optionally wherein the C-terminus of the variant modified polypeptide is at an amino acid corresponding to amino acid 467, 468, 469, 470, or 471 with reference to SEQ ID NO:1.
8 . The combination dosing regimen of claim 1 , wherein:
the soluble hyaluronidase is administered at a dose of 2,000 to 96,000 U; and
the ADC is administered at a dose of at least or at 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, or 100 mg/kg; optionally at a dose of 10 mg/kg.
9 . The combination dosing regimen of claim 1 , wherein the soluble hyaluronidase and the ADC are administered once per day on at least two days in a treatment cycle.
10 . The combination dosing regimen of claim 1 , wherein the soluble hyaluronidase and the ADC are administered once a day (Q1).
11 . The combination dosing regimen of claim 1 , wherein the ADC is selected from sacituzumab govitecan, patritumab deruxtecan, datopotamab deruxtecan, brentuximab vedotin, trastuzumab emtansine, trastuzumab deruxtecan, tisotumab vedotin, mirvetuximab soravtansine, and loncastuximab tesirine.
12 . The combination dosing regimen of claim 1 , wherein the AUC is a weekly average AUC.
13 . The combination dosing regimen of claim 1 , wherein the AUC is measured over a time interval selected from a group consisting of twenty-four (24) hours, forty-eight (48) hours, seventy-two (72) hours, ninety-six (96) hours, one-hundred-and-twenty (120) hours, one-hundred-and-forty-four (144) hours, and one-hundred-and-sixty-eight (168) hours.
14 . The combination dosing regimen of claim 1 , wherein the AUC is measured over a time interval selected from a group consisting of seven (7) days, fourteen (14) days, twenty-one (21) days, twenty-eight (28) days, eighty-four (84) days, and one-hundred-and-sixty-eight (168) days.
15 . The combination dosing regimen of claim 1 , wherein the sequence of amino acids of the soluble hyaluronidase has at least 86% sequence identity to the sequence of amino acids that contains at least amino acids 36-464 of SEQ ID NO:1.
16 . The combination dosing regimen of claim 15 , wherein the sequence of amino acids of the soluble hyaluronidase has at least 87% sequence identity to the sequence of amino acids that contains at least amino acids 36-464 of SEQ ID NO:1.
17 . The combination dosing regimen of claim 16 , wherein the sequence of amino acids of the soluble hyaluronidase has at least 88% sequence identity to the sequence of amino acids that contains at least amino acids 36-464 of SEQ ID NO:1.
18 . The combination dosing regimen of claim 17 , wherein the sequence of amino acids of the soluble hyaluronidase has at least 89% sequence identity to the sequence of amino acids that contains at least amino acids 36-464 of SEQ ID NO:1.
19 . The combination dosing regimen of claim 18 , wherein the sequence of amino acids of the soluble hyaluronidase has at least 90% sequence identity to the sequence of amino acids that contains at least amino acids 36-464 of SEQ ID NO:1.
20 . The combination dosing regimen of claim 19 , wherein the sequence of amino acids of the soluble hyaluronidase has at least 91% sequence identity to the sequence of amino acids that contains at least amino acids 36-464 of SEQ ID NO:1.
21 . The combination dosing regimen of claim 20 , wherein the sequence of amino acids of the soluble hyaluronidase has at least 92% sequence identity to the sequence of amino acids that contains at least amino acids 36-464 of SEQ ID NO:1.
22 . The combination dosing regimen of claim 21 , wherein the sequence of amino acids of the soluble hyaluronidase has at least 93% sequence identity to the sequence of amino acids that contains at least amino acids 36-464 of SEQ ID NO:1.
23 . The combination dosing regimen of claim 22 , wherein the sequence of amino acids of the soluble hyaluronidase has at least 94% sequence identity to the sequence of amino acids that contains at least amino acids 36-464 of SEQ ID NO:1.
24 . The combination dosing regimen of claim 23 , wherein the sequence of amino acids of the soluble hyaluronidase has at least 95% sequence identity to the sequence of amino acids that contains at least amino acids 36-464 of SEQ ID NO:1.
25 . The combination dosing regimen of claim 24 , wherein the sequence of amino acids of the soluble hyaluronidase has at least 96% sequence identity to the sequence of amino acids that contains at least amino acids 36-464 of SEQ ID NO:1.
26 . The combination dosing regimen of claim 25 , wherein the sequence of amino acids of the soluble hyaluronidase has at least 97% sequence identity to the sequence of amino acids that contains at least amino acids 36-464 of SEQ ID NO:1.
27 . The combination dosing regimen of claim 26 , wherein the sequence of amino acids of the soluble hyaluronidase has at least 98% sequence identity to the sequence of amino acids that contains at least amino acids 36-464 of SEQ ID NO:1.
28 . The combination dosing regimen of claim 27 , wherein the sequence of amino acids of the soluble hyaluronidase has at least 99% sequence identity to the sequence of amino acids that contains at least amino acids 36-464 of SEQ ID NO:1.
29 . The combination dosing regimen of claim 9 , wherein the soluble hyaluronidase and the ADC are administered on day one (1) and day eight (8) of a twenty-one (21) day treatment cycle for three (3) cycles.
30 . The combination dosing regimen of claim 9 , wherein the soluble hyaluronidase and the ADC are administered on day one (1) and day fifteen (15) of a twenty-one (21) day treatment cycle.
31 . The combination dosing regimen of claim 9 , wherein the soluble hyaluronidase and the ADC are administered on day one (1), day fifteen (15), and day twenty-nine (29) of a forty-two (42) day treatment cycle.
32 . The combination dosing regimen of claim 9 , wherein the soluble hyaluronidase and the ADC are administered on day one (1), day eight (8), and day fifteen (15) of a twenty-eight (28) day treatment cycle.
33 . The combination dosing regimen of claim 9 , wherein the soluble hyaluronidase and the ADC are administered on day one (1), day four (4), and day seven (7) of an induction cycle.
34 . The combination dosing regimen of claim 1 , wherein the soluble hyaluronidase and the ADC are administered twice a day (Q2).
35 . The combination dosing regimen of claim 1 , wherein the soluble hyaluronidase and the ADC are administered three times a day (Q3).
36 . The combination dosing regimen of claim 1 , wherein the soluble hyaluronidase and the ADC are administered four times a day (Q4).
37 . The combination dosing regimen of claim 1 , wherein the subcutaneous administration of the combination dosing regimen yields an AUC of the ADC in blood that is about 50% to about 90% of an AUC of an intravenous administration of a dosing regimen comprising an equivalent dose of the ADC without the soluble hyaluronidase.