DOSAGE REGIMES
The present disclosure relates to novel dosage regimes for the treatment of pathological conditions, such as cancer, with Antibody Drug Conjugates (ADCs). In particular, the present disclosure relates to novel dosage regimes for the administration of ADCs which bind to CD25 (CD25-ADCs).
1 - 71 . (canceled)
72 . A method of treating a proliferative disease in a subject, said method comprising administering to a subject a CD25-antibody drug conjugate (ADC), wherein the CD25−ADC comprises as the drug, a pyrrolobenzodiazepine (PBD) dimer, linked to an antibody that binds to CD25, the CD25−ADC having a drug to antibody ratio (DAR) of between 1 and 8, wherein the CD25−ADC is administered to the subject in a dosage regime comprising multiple treatment cycles and wherein the dose of CD25−ADC is reduced following the first or second treatment cycle by about 50% or more.
73 . The method of claim 72 , wherein the PBD dimer is of formula I:
wherein
(a) R L1′ is a linker for connection to the antibody;
(b) (i) R 20 and R 21 either together form a double bond between the nitrogen and carbon atoms to which they are bound; or (ii) R 20 is a capping group R C , and R 21 is OH;
(c) m is 0 or 1; and
(d) when there is a double bond between C2 and C3, R 2 is methyl;
when there is a single bond between C2 and C3, R 2 is either H or
when there is a double bond between C2′ and C3′, R 12 is methyl;
when there is a single bond between C2′ and C3′, R 12 is H or
74 . The method of claim 72 , wherein the antibody comprises a VH domain comprising a VH CDR1 with the amino acid sequence of SEQ ID NO:3, a VH CDR2 with the amino acid sequence of SEQ ID NO:4, and a VH CDR3 with the amino acid sequence of SEQ ID NO:5, and
a VL domain comprising a VL CDR1 with the amino acid sequence of SEQ ID NO:6, a VL CDR2 with the amino acid sequence of SEQ ID NO:7, and a VL CDR3 with the amino acid sequence of SEQ ID NO:8.
75 . The method of claim 74 , wherein Ab comprises a VH domain having the amino acid sequence of SEQ ID NO:1 and a VL domain having the amino acid sequence of SEQ ID NO:2.
76 . The method of claim 73 , wherein the PBD is:
wherein R L1′ is a linker for connection to the antibody.
77 . The method of claim 76 , wherein the CD25−ADC has the following structure:
wherein Ab is a CD25 antibody comprising:
a VH domain comprising a VH CDR1 with the amino acid sequence of SEQ ID NO:3, a VH CDR2 with the amino acid sequence of SEQ ID NO:4, and a VH CDR3 with the amino acid sequence of SEQ ID NO:5, and
a VL domain comprising a VL CDR1 with the amino acid sequence of SEQ ID NO:6, a VL CDR2 with the amino acid sequence of SEQ ID NO:7, and a VL CDR3 with the amino acid sequence of SEQ ID NO:8.
78 . The method of claim 77 , wherein Ab comprises a VH domain having the amino acid sequence of SEQ ID NO:1 and a VL domain having the amino acid sequence of SEQ ID NO:2.
79 . The method of claim 72 , wherein the starting dose of CD25−ADC is reduced no more than once during the dosage regime.
80 . The method of claim 72 , wherein the starting dose of CD25−ADC is from about 40 μg/kg to about 80 μg/kg.
81 . The method of claim 80 , wherein the starting dose of CD25−ADC is from about 40 μg/kg to about 50 μg/kg.
82 . The method of claim 72 , wherein each treatment cycle is about 3 weeks.
83 . The method of claim 72 , wherein the dose of CD25−ADC is reduced following the second treatment cycle.
84 . The method of claim 72 , wherein the CD25−ADC is administered in combination with a steroid.