Drug-conjugates with a targeting molecule and two different drugs
View Patent ↗There is disclosed an improved ADC (antibody drug conjugate) type composition having at least two different drug payloads conjugated to a single targeting protein. More specifically, the present disclosure attaches a first drug conjugate to a dual Cysteine residue on a targeting protein and a second drug conjugate with a different drug to a Lys residue on the targeting protein.
1. A dual-drug conjugate comprising a structure of Formula I
or a pharmaceutically acceptable salt thereof,
wherein:
A comprises an antibody or antigen-binding antibody fragment;
D 1 is an active agent;
each L 1 is independently a linker comprising at least one N (nitrogen) atom;
the nitrogen between the antibody or antigen binding antibody fragment and the carbonyl of C(O)—L 1 -D 1 is the nitrogen of a Lys side chain of the antibody or antigen-binding antibody fragment;
D 2 an active agent, wherein D 1 and D 2 are different active agents;
each L 2 is independently a linker;
the E-component is selected from the group consisting of
L 3 is —(CH2)—;
L 4 is —(CH2)—;
m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and
n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
2. The dual-drug conjugate of claim 1 , wherein:
is:
3. The dual-drug conjugate of claim 1 , wherein L 1 comprises
where X 1 is N (nitrogen) or CH; Y 1 is N (nitrogen), or CH; and p is 0, 1, or 2.
4. The active agent-conjugate of claim 1 , wherein L 1
comprises
5. The dual-drug conjugate of claim 1 , wherein D 1 is selected from the group consisting of tubulin binders, DNA alkylators, DNA intercalator, enzyme inhibitors, immune modulators, peptides, and nucleotides.
6. The dual-drug conjugate of claim 1 , wherein D 2 is selected from the group consisting of tubulin binders, DNA alkylators, DNA intercalator, enzyme inhibitors, immune modulators, peptides, and nucleotides.
7. The dual-drug conjugate of claim 1 , wherein L 1 or L 2 comprises —(CH 2 ) n- where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
8. The dual-drug conjugate of claim 1 , wherein L 1 or L 2 includes —(CH 2 CH 2 O) n- where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
9. The dual-drug conjugate of claim 1 , wherein the
S-linked portion of
comprises a modified L-Alanine residue.
10. The dual-drug conjugate of claim 1 , wherein each
is:
wherein G is —NH—.
11. The dual-drug conjugate of claim 1 , wherein each
is:
12. A dual-drug conjugate selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
13. The dual-drug conjugate of claim 1 , wherein A comprises an antibody.
14. The dual-drug conjugate of claim 1 , wherein A comprises an antigen-binding antibody fragment.