Switchable immune modulator for tumor-specific activation of anticancer immunity

Abstract

Immune stimulatory antibodies and cytokines elicit potent antitumor immunity. However, the dose-limiting systemic toxicity greatly hinders their clinical applications. Here, we demonstrate a chemical approach, termed "switchable" immune modulator (Sw-IM), to limit the systemic exposure and therefore ameliorate their toxicities. Sw-IM is a biomacromolecular therapeutic reversibly masked by biocompatible polymers through chemical linkers that are responsive to tumor-specific stimuli, such as high reducing potential and acidic pH. Sw-IMs stay inert (switch off) in the circulation and healthy tissues but get reactivated (switch on) selectively in tumor via responsive removal of the polymer masks, thus focusing the immune boosting activities in the tumor microenvironment. Sw-IMs applied to anti-4-1BB agonistic antibody and IL-15 cytokine led to equivalent antitumor efficacy to the parental IMs with markedly reduced toxicities. Sw-IM provides a highly modular and generic approach to improve the therapeutic window and clinical applicability of potent IMs in mono-and combinational immunotherapies.

Platelet Pharmacytes for the Hierarchical Amplification of Antitumor Immunity in Response to Self‐Generated Immune Signals

“…Pronounced splenomegaly was noted for mice treated with siRab@aPDL1/PLTs, probably due to the massive expansion of CD8 + T cells that indicated marked immune response (Figures S22 and S23, Supporting Information). [ 21 ] Nonetheless, the spleens from mice treated with siRab@aPDL1/PLTs recovered to the normal size and weight of those from healthy mice on day 35 (tumors being surgically removed on day 7, Figure S23, Supporting Information). It thus demonstrated that the splenomegaly was transient and nonpathologic, and could be recovered.…”

Bioengineered nanogels for cancer immunotherapy

“…305 For instance, Irvine's group took advantage of the specific physiological environment in the TME to transform hydrophilic polymers such as PEG into immunomodulatory proteins (such as anti-4-1BB agonistic antibody, and IL-15 cytokine) using responsive covalent linkers such as disulfide bonds and maleimides, to block biological activity and avoid toxicity to normal tissues by using switchable immune modulator (Sw-IM); the therapeutic effect on solid tumours was enhanced by adoptive T cell transfer (ACT). 306 The results showed that the use of “switch” IL-15 cytokine super agonist (Sw redox IL15) combined with ACT not only achieved a normal IL-15 anti-tumour effect of super agonists but also effectively avoided the activation and expansion of CD8 + T cells and NK cells in healthy tissues and irAEs. In B16F10 tumour-bearing-mice, the cytokine IL-15 is specifically stimulated and released.…”

Strategies to mitigate the on- and off-target toxicities of recombinant immunotoxins: an antibody engineering perspective

“…In the Pro-XTEN concept, the low immunogenic XTEN masks reduce systemic exposure by serving as spatial shields that can be removed by the intrinsically high protease activity in the tumor [ 51 ]. Beyond such a genetic engineering approach, biocompatible polymers were also used to enlarge the therapeutic window by limiting the systemic exposure of therapeutic candidates [ 95 ]. In the concept of switchable immune modulators (Sw-IM), biologics were reversibly blocked by biocompatible polymers via a tumor microenvironment responsive covalent chemical linker.…”

“…In the concept of switchable immune modulators (Sw-IM), biologics were reversibly blocked by biocompatible polymers via a tumor microenvironment responsive covalent chemical linker. The redox-responsive and/or pH-responsive stimuli in the tumor microenvironment degrade the chemical linker to achieve selective activation [ 95 ]. Such a concept was validated with several immune-modulating antibodies against immune checkpoints like 4-1BB, PD-1 and CTLA-4 [ 95 ].…”

“…The redox-responsive and/or pH-responsive stimuli in the tumor microenvironment degrade the chemical linker to achieve selective activation [ 95 ]. Such a concept was validated with several immune-modulating antibodies against immune checkpoints like 4-1BB, PD-1 and CTLA-4 [ 95 ].…”