ANTI-IL-13RALPHA2 CONJUGATES
This disclosure relates to antibody conjugates comprising antibodies that bind specifically to the Interleukin-13 receptor subunit alpha-2 (IL-13Rα2) protein, conjugated to cytotoxic warheads, and associated uses.
1 - 12 . (canceled)
13 . An antibody drug conjugate of formula (I):
wherein:
Ab is an antibody that binds to IL-13Ralpha2, which antibody comprises (i) an immunoglobulin heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 1; and (ii) an immunoglobulin light chain variable region having the amino acid sequence shown in SEQ ID NO: 2; and
L-D is of formula (II):
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;
(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
.
14 . The conjugate according to claim 13 , wherein the antibody is humanized or fully human.
15 . The conjugate according to claim 13 , wherein L-D 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.
16 . The conjugate according to claim 15 , wherein m = 0.
17 . The conjugate according to claim 13 , wherein R 10 and R 11 together form a double bond between the nitrogen and carbon atoms to which they are attached.
18 . The conjugate according to claim 13 , wherein R LL is of formula (IIa):
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 (connected to G LL ) 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.
19 . The conjugate according to claim 13 , wherein the linker is a cleavable linker, such as a linker comprising a cathepsin cleavable sequence e.g. Val-Ala or Val-Cit.
20 . The conjugate according to claim 18 , wherein c2 = 1 and b1 is from 2 to 8.
21 . The conjugate according to claim 13 , where the cytotoxin is conjugated to the antibody at an endogenous and/or engineered N-linked glycosylation site.
22 . The conjugate according to claim 13 , where L-D is:
.
23 . A method of treating an individual suffering from a proliferative disease, said method comprising administering to the individual a conjugate according to claim 13 .
24 . The conjugate according to claim 15 , wherein R 10 and R 11 together form a double bond between the nitrogen and carbon atoms to which they are attached.