Multi-arm polymer conjugates of TLR agonist compounds and related immunotherapeutic treatment methods

Inventors

Ren, Zhongxu • Anand, Neel K. • Cai, Haiying • Deng, Bo-Liang • Joshi, Bhalchandra V. • Zalevsky, Jonathan • Miyazaki, Takahiro • Kivimae, Saul

Assignees

Nektar Therapeutics

Abstract

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. RQ-POLY-Xr-TLR7/8 AG)q  (I)

Core Innovation

The invention relates to a conjugate comprising a Toll-like receptor 7/8 (TLR 7/8) agonist covalently attached to a multi-arm, water-soluble, non-peptidic polymer through a linkage-containing spacer moiety. The polymer is defined by Formula III, with defined ranges for the parameters m and n, and defined substituent options R1 and R2. The conjugate includes pharmaceutically acceptable salts or stereoisomers thereof.

The linkage-containing spacer moiety L provides the covalent connection between the TLR 7/8 agonist and the polymer and is described as stable or releasable. Representative linkage types and spacer examples include amide, thioether, carbamate, ester, carbonate, urea, enzyme-cleavable peptidic linkages, and carboxymethyl amino acid spacer examples, with linkage types and functional attachment options including O/S/N attachment groups.

The invention also encompasses representative TLR7/8 agonists as conjugate components, including imidazoquinolines such as resiquimod (R-848) and imiquimod. Representative conjugate structures are provided, including embodiments corresponding to Formula III and multiple named compounds, including Compounds 1-16 and specific examples such as PEG5k with y≥113.

The disclosure also includes pharmaceutical composition aspects and cancer immunotherapy concepts involving administration of a TLR agonist conjugate, including local intratumoral administration and combination with a long-acting IL-2Rβ-biased agonist to promote synergy and systemic immune effects, including an abscopal effect.

Claims Coverage

The independent claims cover a conjugate architecture pairing a TLR7/8 agonist with a multi-arm, water-soluble, non-peptidic polymer via a linkage-containing spacer, and a selection of specific conjugates with a defined polymer parameter n range. The claim set emphasizes Formula III structure, spacer-linker L, and substituent definitions for R1 and R2.

Overall, the independent claims define conjugates where a TLR7/8 agonist is covalently attached to a multi-arm water-soluble non-peptidic polymer through a linkage-containing spacer moiety and where polymer parameters, notably n, fall within 40–350, with one independent claim also specifying the Formula III structure and substituent definitions.

Stated Advantages

Documented Applications