Polyoxazoline antibody drug conjugates
In the present disclosure, polymer conjugates, including polymer-antibody-drug conjugates (polymer ADCs) are described, as well as the use of such conjugates to treat human disease. The polymer conjugates can contain a large number of polymer-bound agents, thus effectively increasing the drug antibody ration (DAR) of the antibody significantly beyond the currently available technology. This may be of particular importance when antibodies to low density antigens are used as target antibodies. The described polymer-ADCs have improved pharmacokinetics and solubility relative to traditional ADCs. The linker between agent and the polymer can be tailored to provide release of toxin at the desired site and under the desired conditions within the tumor. An additional feature of the polymer-ADCs of the current disclosure is that a purification moiety can be attached to the polymer backbone to provide ease of purification of the polymer-ADCs.
1. A polymer conjugate, the polymer conjugate comprising a polyoxazoline polymer, a recognition moiety linked to the polyoxazoline polymer, an optional biotin purification moiety and a plurality of auristatin molecules linked to the polyoxazoline polymer via a releasable linkage, wherein the recognition moiety and the polyoxazoline polymer are present in a 1:1 ratio, the polymer conjugate having the structure:
wherein
a is a random copolymer;
R 1 is H;
o is 5;
m is 3;
n is 20;
b is 4;
scAb is a single chain antibody;
Se is a selenocysteine residue;
and
the number of auristatin molecules and optional biotin purification moieties linked to the conjugate is less than or equal to the sum of o and m.
2. The polymer conjugate of claim 1 , wherein the selenocysteine residue is part of the single chain antibody and the selenocysteine residue is conjugated to the polyoxazoline polymer.
3. The polymer conjugate of claim 1 , wherein the conjugate has an auristatin molecule to antibody ratio of 1:1 to 5:1 (auristatin molecule to antibody).
4. The polymer conjugate of claim 1 , wherein the conjugate comprises at least two auristatin molecules and at least one biotin purification moiety.
5. The polymer conjugate of claim 1 , wherein conjugate has an auristatin molecule to antibody ratio of 5:1 (auristatin molecule to antibody).
6. The polymer conjugate of claim 1 , wherein conjugate has an auristatin molecule to antibody ratio of 4:1 (auristatin molecule to antibody).
7. The polymer conjugate of claim 1 , wherein conjugate has an auristatin molecule to antibody ratio of 3:1 (auristatin molecule to antibody).
8. The polymer conjugate of claim 1 , wherein conjugate has an auristatin molecule to antibody ratio of 2:1 (auristatin molecule to antibody).
9. The polymer conjugate of claim 1 , wherein the optional biotin purification moiety is absent.
10. The polymer conjugate of claim 1 , wherein the optional biotin purification moiety is present.
11. The polymer conjugate of claim 1 having the structure:
wherein
d is an integer from 1 to 30.
12. The polymer conjugate of claim 1 having the structure:
13. The polymer conjugate of claim 1 having the structure:
14. A polymer conjugate, the polymer conjugate comprising a polyoxazoline polymer, a recognition moiety linked to the polyoxazoline polymer, an optional purification moiety and a plurality of agents linked to the polyoxazoline polymer via a releasable linkage, wherein the recognition moiety and the polyoxazoline polymer are present in a 1:1 ratio, the polymer conjugate having the structure:
wherein
a is ran which is a random copolymer or block which is a block copolymer;
R 1 is H;
o is an integer from 0 to 50;
m is an integer from 0 to 50;
n is an integer from 0 to 1000;
b is an integer from 1 to 30;
scAb is a single chain antibody;
Se is a selenocysteine residue;
Agent represent a diagnostic agent or a therapeutic agent; and
the number of agents and optional purification moieties linked to the conjugate is less than or equal to the sum of o and m,
provided that both o and m are not each 0 and the total of n, o and m is at least 30.
15. The polymer conjugate of claim 14 , wherein the selenocysteine residue is part of the single chain antibody and the selenocysteine residue is conjugated to the polyoxazoline polymer.
16. The polymer conjugate of claim 14 , wherein m is 0, o is an integer from 5 to 20 and the total of o and n is from 30 to 100.
17. The polymer conjugate of claim 16 , wherein the conjugate has an agent to antibody ratio of 5:1 to 20:1 (agent to antibody).
18. The polymer conjugate of claim 14 , wherein m is 0, o is 5 and the total of o and n is from 30 to 100.
19. The polymer conjugate of claim 18 , wherein the conjugate has an agent to antibody ratio of 1:1 to 5:1 (agent to antibody).
20. The polymer conjugate of claim 14 , wherein m is 0, o is 10 and the total of o and n is from 30 to 100.
21. The polymer conjugate of claim 20 , wherein the conjugate has an agent to antibody ratio of 1:1 to 10:1 (agent to antibody).
22. The polymer conjugate of claim 14 , wherein the optional purification moiety is absent.
23. The polymer conjugate of claim 14 , wherein the optional purification moiety is present.
24. The polymer conjugate of claim 23 , wherein the purification moiety is biotin.