Multi-arm polymer conjugates of TLR agonist compounds and related immunotherapeutic treatment methods
Provided are multi-arm polymer conjugates of Toll-Like Receptor (“TLR”) agonists such as TLR 7/8 agonists, as well as related compositions, and methods of making and using such conjugates. Exemplary conjugates are encompassed by Formula I: (I) or a pharmaceutically acceptable salt form thereof, where R, taken together with each Q, is a residue of a polyol, polythiol, or polyamine bearing from 3 to about 50 hydroxyl, thiol, or amino groups; each Q is a linker selected from oxygen, sulfur and —NH; each POLY is independently a water-soluble, non-peptidic polymer; each Xr is independently a linkage-containing spacer moiety; q is a positive integer from 3 to about 50; and each TLR 7/8 AG is a Toll-like receptor 7/8 agonist. Also provided is a method of administering to a patient having cancer (a) an IL-2Rβ-activating amount of a long-acting, IL-2Rβ-selective agonist; and (b) a Toll-like receptor agonist such as a conjugate as described above, as well as related compositions, kits and methods. R Q-POLY-Xr-TLR7/8 AG) q (I)
1. A conjugate comprising a Toll-like receptor 7/8 (TLR 7/8) agonist covalently attached, via a linkage-containing spacer moiety, to a multi-arm, water-soluble, non-peptidic polymer having a formula in accordance with Formula III:
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
L is —(CH 2 ) m —, —(CH 2 ) m —NH—C(O)—(CH 2 ) m —, —CHF—(CH 2 ) m —NH—C(O)—(CH 2 ) m —, —CH(CH 3 )—NH—C(O)—(CH 2 ) m —, —CH(CH(CH 3 ) 2 )—NH—C(O)—(CH 2 ) m —, —CH(CH 2 CH(CH 3 ) 2 )—NH—C(O)—(CH 2 ) m —, —C(CH 3 ) 2 —NH—C(O)—(CH 2 ) m —, a single bond, or —NH—(CH 2 ) m —,
each m is independently an integer from 1 to 5, inclusive;
each n is independently an integer from 40 to 350, inclusive;
R 1 is hydrogen or —CH 2 —O—CH 2 —CH 3 ; and
R 2 is hydrogen or hydroxyl.
2. The conjugate of claim 1 , wherein L is —CH 2 —, —CH 2 —CH 2 —NH—C(O)—CH 2 —, —CH 2 —CH 2 —CH 2 —, —CHF—CH 2 —NH—C(O)—CH 2 —, —CH 2 —NH—C(O)—CH 2 —, —CH(CH 3 )—NH—C(O)—CH 2 —, —CH(CH(CH 3 ) 2 )—NH—C(O)—CH 2 —, —CH(CH 2 CH(CH 3 ) 2 )—NH—C(O)—CH 2 —, —C(CH 3 ) 2 —NH—C(O)—CH 2 —, a single bond, or —NH—CH 2 —CH 2 —.
3. The conjugate of claim 1 , wherein each n is independently an integer from 100 to 250, inclusive.
4. The conjugate of claim 1 , wherein R 1 is hydrogen and R 2 is hydrogen.
5. The conjugate of claim 1 , wherein R 1 is —CH 2 —O—CH 2 —CH 3 and R 2 is hydroxyl.
6. A conjugate selected from the group consisting of Compounds 1-10 and 12-15:
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each n is independently an integer from 40 to 350.
7. A composition comprising the conjugate of claim 1 and a pharmaceutically acceptable excipient.
8. The conjugate of claim 1 , wherein n has a value corresponding to a weight average molecular weight of the poly(ethylene glycol) polymer selected from about 2,000 Daltons to about 150,000 Daltons, about 5,000 Daltons to about 40,000 Daltons, or about 5,000 Daltons to about 25,000 Daltons.