Stability-modulating linkers for use with antibody drug conjugates
The present invention provides stability-modulated antibody-drug conjugates, stability-modulating linker components used to make these stability-modulated antibody-drug conjugates, therapeutic methods using stability-modulated antibody-drug conjugates, and methods of making stability modulating linkers and stability-modulated antibody-drug conjugates.
1. A compound of Formula (III):
or a pharmaceutically acceptable salt or solvate thereof;
wherein:
M is a stability modulator -M 1 -M 2 , where M 1 is —NR 1 —C(O)—, —NR 1 —S(O) 2 —, or is absent, and
M 2 is selected from the group consisting of:
each E is independently selected from the group consisting of: 1) —C(R 1 ) 2 —, 2) —O—C(R 1 ) 2 —C(R 1 ) 2 —, and 3) —C(R 1 ) 2 —C(R 1 ) 2 —O, wherein when E is —O—C(R 1 ) 2 —C(R 1 ) 2 , r is 2, and wherein when E is —C(R 1 ) 2 —C(R 1 ) 2 —O—, s is at least 1;
each R 1 is independently selected from the group consisting of: H, and C 1 -C 6 straight or branched alkyl;
wherein —X m —Y n — is -X-Y- and where X-Y is selected from the group consisting of Gly, β-Ala, Val-Cit, Phe-Lys, Val-Lys, Phe-Phe-Lys, Ala-Lys, Phe-Cit, Leu-Cit, Ala-Cit, Trp-Cit, Phe-Ala, Gly-Phe-Leu-Gly (SEQ ID NO: 38), Ala-Leu-Ala-Leu (SEQ ID NO: 39), Phe-N9-tosyl-Arg, Phe-N9-Nitro-Arg, Val-Ala, and Ala-Ala-Asn;
each Z is PABC (p-aminobenzyl-carbamoyl);
p is 0-2, q is 0-10, r is 0-2, and s is 0-2, where q+r+s=2 or more; and
D is a cytotoxic agent.
2. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt or solvate thereof.