DOSAGE REGIMEN
This disclosure relates to dosage regimens for the treatment of proliferative disorders with antibody drug conjugates (ADCs), particularly methods of treatment comprising administration of an ADC using a flat dosing regimen.
1 . A method of treating a proliferative disorder in a subject which method comprises administering to the subject an antibody drug conjugate (ADC), wherein the drug is a pyrrolobenzodiazepine (PBD) dimer, and wherein the ADC is administered to the subject using a flat dosing regimen for one or more cycles.
2 . A method according to claim 1 where the dose of ADC administered per cycle is from 2 to 20 mg.
3 . A method according to claim 1 where the dose of ADC administered per cycle is from 2 to 5 mg, 6 to 10 mg, 11 to 15 mg, or 16 to 20 mg.
4 . A method according to claim 1 where the dose of ADC administered per cycle is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg.
5 . A method according to claim 1 or claim 2 wherein the antibody binds specifically to a tumour antigen.
6 . A method according to claim 3 wherein the tumour antigen is CD19, CD22, CD25, AXL, DLK-1 or KAAG1.
7 . A method according to any one of the preceding claims wherein the PBD dimer is of formula I:
wherein:
(a) R LL is a linker for connection to Ab;
(b) (i) R 10 and R 11 together form a double bond between the nitrogen and carbon atoms to which they are attached; or (ii) R 10 is R LLA which is a linker for connection to Ab, and R 11 is OH, where R LL and R LLA may be the same or different; or (iii) R 10 is a capping group R C and R 11 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
8 . A method according to any one of the preceding claims wherein the PBD dimer is of formula (III):
wherein:
(a) R LL is a linker for connection to Ab;
(b) (i) R 10 and R 11 together form a double bond between the nitrogen and carbon atoms to which they are attached; or (ii) R 10 is R LLA which is a linker for connection to Ab, and R 11 is OH; or (iii) R 10 is a capping group R C , and R 11 is OH; and
(c) m is 0 or 1.
9 . A method according to claim 7 or 8 wherein R LL is of formula (Ia):
wherein:
Q is:
where Q X is such that Q is an amino-acid residue, a dipeptide residue, a tripeptide residue or a tetrapeptide residue;
X is:
where a=0 to 5, b1=0 to 16, b2=0 to 16, c1=0 or 1, c2=0 or 1, d=0 to 5, wherein at least b1 or b2=0 and at least c1 or c2=0; and
G LL is a linker group connected to the antibody.
10 . A method according to any one of claims 7 to 9 , wherein the linker is a cleavable linker, such as a linker comprising a cathepsin cleavable sequence e.g. Val-Ala or Val-Cit.
11 . A method according to any one of the preceding claims wherein the PBD dimer is conjugated to the antibody at an endogenous and/or engineered N-linked glycosylation site.
12 . A method according to any one of the preceding claims where the dosing is Q3W.
13 . A method according to any one of the preceding claims where the flat dosing is for two or more cycles.
14 . A method according to any one of the preceding claims where all doses are administered to the patient as a flat dose regimen.
15 . A method according to any one of the preceding claims where the ADC is selected from ADCT-301, ADCT-402, ADCT-601, ADCT-602, ADCT-701, or ADCT-901.