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: 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.

Core Innovation

The invention relates to treating cancer by administering a conjugate in which a Toll-like Receptor (TLR) 7/8 agonist is 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. The polymer includes a specified linkage structure and substituent definitions, with each m independently an integer from 1 to 5 and each n independently an integer from 40 to 350, and the conjugate is provided as a pharmaceutically acceptable salt or stereoisomer thereof.

The invention also encompasses a method of administration that combines a TLR 7/8 activating amount of the TLR7/8 agonist conjugate with an IL-2Rβ-activating amount of a long acting interleukin-2 receptor beta (IL-2Rβ)-biased agonist. The combined administration is directed to a subject having cancer and provides innate immunity activation from the TLR7/8 conjugate together with IL-2Rβ activation from the long acting IL-2Rβ-biased agonist.

The document further describes preferred TLR7/8 agonist–multi-arm PEG polymer conjugates, including 4-arm-PEG-CM-N-R848 and related variants such as 4-arm-PEG20k-CM-Gly-N-R848 (Compound 6) and Compound 11. It also describes intratumoral administration and example summary content comparing PEGylated TLR7/8 agonist conjugates with free R848, including cytokine induction and pharmacokinetic assessments in plasma and tumor in CT26 and EMT6 tumor models.

Claims Coverage

The independent claims cover three core aspects: administering a TLR7/8 agonist conjugate to treat cancer, administering the conjugate together with a long acting IL-2Rβ-biased agonist, and providing a combination for use with instructions for treating cancer. Across the independent claims, the coverage centers on the conjugate structure defined by Formula III and on pairing with a long acting IL-2Rβ-biased agonist in the cancer-treatment context.

Overall, the independent claims are directed to cancer treatment using a specified TLR7/8 agonist-polymer conjugate defined by Formula III, and in combination formulations, pairing that conjugate with a long acting IL-2Rβ-biased agonist to provide both IL-2Rβ activation and innate immunity activation, with instructions for use included in one claim.

Stated Advantages

Documented Applications