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 single chain antibody 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 single chain antibody and the polyoxazoline polymer are present in a 1:1 ratio, the polymer conjugate having the structure:
wherein
a is ran which indicates a random copolymer or block which indicates 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 is selected from the group consisting of monomethyl auristatin E, monomethyl auristatin F, desmethyl-auristatin F, daunorubicine, doxorubicin, epirubicin, idarubicin, valrubicin, mitoxantrone, calicheamicin, N-acetyl-γ calicheamicin 1,2-dimethyl hydrazine dichloride, DM1, DM4, ansomitocin, abbeymycin, chicamycin, DC-81, mazethramycin, neothramycins A and B, porothramycin prothracarcin, sibanomicin, sibiromycin, tomamycin, SJG-136, SG 2285, DRG-16, ELB-21, colchicine, deacetylcholchicine, dolstatin 10, dolstatin 15, dolstatin 16, tubulysin A, tubulysin B, tubulysin D, tubulysin M, maytansinol, duocarmycin A, duocarmycin B1, duocarmycin B2, duocarmycin C1, duocarmycin C2, duocarmycin D, duocarmycin SA, CC-1065, adozelesin, bizelesin, carzelesin, nemorubicin, cryptophycin 1, cryptophycin 8, cryptophycin 24, cryptophycin 52, cryptophycin 55, cryptophycin 296, cryptophycin 309, epithilone A, epithilone B, epithilone C, epithilone D, epithilone E, epithilone F, BMS 247550, BMS 310705, safracin A and safracin B; 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.
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 m is 0, o is an integer from 5 to 20 and the total of o and n is from 30 to 100.
4. The polymer conjugate of claim 3 , wherein the conjugate has an agent to antibody ratio of 5:1 (agent to antibody).
5. The polymer conjugate of claim 1 , wherein m is 0, o is 5 and the total of o and n is from 30 to 100.
6. The polymer conjugate of claim 1 , wherein m is 0, o is 10 and the total of o and n is from 30 to 100.
7. The polymer conjugate of claim 6 , wherein the conjugate has an agent to antibody ratio of 10:1 (agent to antibody).
8. The polymer conjugate of claim 1 , wherein the optional purification moiety is absent.
9. The polymer conjugate of claim 1 , wherein the optional purification moiety is present.
10. The polymer conjugate of claim 1 , wherein the purification moiety is biotin.