Selective activation of interleukin-2/interleukin-15 receptor signaling in tumor microenvironment using paired bispecific antibodies

Journal for ImmunoTherapy of Cancer, Journal Year: 2025, Volume and Issue: 13(3), P. e010650 - e010650

Published: March 1, 2025

Background Owing to their roles in promoting T cell and natural killer (NK) activation proliferation, interleukins-2 (IL-2) interleukins-15 (IL-15) have been pursued as promising pathways target cancer immunotherapy. Nonetheless, wider therapeutic application has hampered by severe dose-limiting toxicities including systemic cytokine release organ edema for IL-2, inconvenient intratumoral administration IL-15. To address these safety issues, we generated IL-2R/IL-15R×TAA (tumor-associated antigen) bispecific antibody (bsAb) pairs selectively activate IL-2R signaling the tumor microenvironment. Methods Each bsAb pair is composed of one targeting CD122 a TAA epitope, other CD132 same or different epitope. In vitro assays were performed characterize IL-2R/IL-15R agonistic activity pairs, well capacity enhance T-cell-mediated killing + malignant cells. Using syngeneic mouse model, vivo biological toxicity assessed comparison with IL-2. The antitumor was combination an anti-mouse programmed death protein 1 (mPD-1) monoclonal antibody. Results We demonstrated two TAAs (human epidermal growth factor receptor 2 (HER2) mesothelin (MSLN)) that CD122×TAA/CD132×TAA mediate effective immune cells exclusively presence hMSLN-MC38 tumor-bearing mice, CD122×MSLN-1/CD132×MSLN-2 promotes selective expansion NK central memory CD8 inside without inducing release, well-known manifestations IL-2 associated toxicity. checkpoint inhibitor anti-mPD-1, boosts accumulation effector cells, leading favorable CD4 regulatory ratio more robust inhibition growth. Conclusions Overall, findings suggest this innovative approach effectively leverages IL-15 while minimizing toxicities. This dual format holds potential broader immune-activating pathways.

Language: Английский

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CLEC12A-directed immunocytokine with target cell–restricted IL-15 activity for treatment of acute myeloid leukemia

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: March 27, 2025

Despite recent advancements, acute myeloid leukemia (AML) remains a therapeutic challenge. While monoclonal antibodies (mAbs) leveraging natural killer (NK) cells through antibody-dependent cellular cytotoxicity show great potential, none have gained clinical approval for AML. Immunocytokines emerged as promising strategy to overcome the limited efficacy of antibodies. IL-15 stimulates activation, proliferation cytotoxic activity NK cells, but its use is prevented by short half-life, poor accumulation in tumor, and toxicity due systemic off-target immune activation. Here we report on generation preclinical characterization modified immunocytokines consisting an Fc-optimized CLEC12A (CLL-1) antibody fused moiety with E46K mutation. The mutation abrogates binding IL-15Rα, thereby enabling substitution physiological trans-presentation target thus conditional IL-15Rβ/γ stimulation reduce toxicity. An optimal binder was selected from range murine mAbs, based analysis AML cell lines leukemic patients. This then used construct immunocytokine (MIC12) that subsequently characterized functionally. Analysis cytokine release, anti-leukemia reactivity demonstrated MIC12 induced superior killing expansion compared antibody, being dependent antigen binding. Our results novel are capable inducing potent responses against identify candidate treatment.

Language: Английский

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Reprogramming the breast tumor immune microenvironment: cold-to-hot transition for enhanced immunotherapy

Journal of Experimental & Clinical Cancer Research, Journal Year: 2025, Volume and Issue: 44(1)

Published: April 25, 2025

Abstract This review discusses reprogramming the breast tumor immune microenvironment from an immunosuppressive cold state to immunologically active hot state. A complex interplay is revealed, in which accumulation of metabolic byproducts—such as lactate, reactive oxygen species (ROS), and ammonia—is shown impair T-cell function promote escape. It demonstrated that (TME) dominated by cytokines, including interleukin-10 (IL-10), transforming growth factorβ (TGFβ), IL-35. Notably, IL-35 produced regulatory T cells cancer cells. The conversion conventional into IL-35-producing induced cells, along with inhibition pro-inflammatory cytokine secretion, contributes suppression anti-tumor immunity. further key checkpoint molecules—such PD-1, PDL1, CTLA-4, TIM-3, LAG-3, TIGIT—are upregulated within TME, leading Tcell exhaustion diminished responses. blockade these checkpoints restore functionality proposed a strategy convert tumors ones robust effector cell infiltration. therapeutic potential chimeric antigen receptor (CAR)T therapy also explored, targeting specific tumor-associated antigens, such glycoproteins tyrosine kinases, highlighted. suggested CART efficacy can be enhanced combining inhibitors other immunomodulatory agents, thereby overcoming barriers imposed TME. Moreover, role microbiome regulating estrogen metabolism systemic inflammation reviewed. Alterations gut microbiota are affect microbiome-based interventions additional means facilitate cold-to-hot transition. concluded immunological pathways underpin suppression—through combination strategies involving blockade, therapies, modulation—the TME achieved. anticipated enhance infiltration function, improving overall immunotherapies better clinical outcomes for patients.

Language: Английский

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Stimulating the Antitumor Immune Response Using Immunocytokines: A Preclinical and Clinical Overview

Pharmaceutics, Journal Year: 2024, Volume and Issue: 16(8), P. 974 - 974

Published: July 24, 2024

Cytokines are immune modulators which can enhance the response and have been proven to be an effective class of immunotherapy. Nevertheless, clinical use cytokines in cancer treatment has faced several challenges associated with poor pharmacokinetic properties occurrence adverse effects. Immunocytokines (ICKs) emerged as a promising approach overcome pharmacological limitations observed cytokines. ICKs fusion proteins designed deliver tumor microenvironment by taking advantage stability specificity immunoglobulin-based scaffolds. Several technological approaches developed. This review focuses on most impactful field: IL-2, TNFα, IL-10, IL-12, IL-15, IL-21, IFNγ, GM-CSF, IFNα. An overview effects naked tested for therapy is detailed. A particular emphasis given immunomodulatory their design. In conclusion, this highlights active ways development ICKs. Their already results trials likely improved advances targeting technologies such cytokine/linker engineering design multispecific antibodies immunostimulatory functional properties.

Language: Английский

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The dichotomic role of cytokines in aging

Biogerontology, Journal Year: 2024, Volume and Issue: 26(1)

Published: Dec. 2, 2024

Language: Английский

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Molecular Matchmakers: Bioconjugation Techniques Enhance Prodrug Potency for Immunotherapy

Molecular Pharmaceutics, Journal Year: 2024, Volume and Issue: 22(1), P. 58 - 80

Published: Nov. 21, 2024

Cancer patients suffer greatly from the severe off-target side effects of small molecule drugs, chemotherapy, and radiotherapy─therapies that offer little protection following remission. Engineered immunotherapies─including cytokines, immune checkpoint blockade, monoclonal antibodies, CAR-T cells─provide better targeting future tumor growth prevention. Still, issues such as ineffective activation, immunogenicity, remain primary concerns. "Prodrug" therapies─classified therapies administered inactive then selectively activated to control time area release─hold significant promise in overcoming these Bioconjugation techniques (e.g., natural linker conjugation, bioorthogonal reactions, noncanonical amino acid incorporation) enable rapid homogeneous synthesis prodrugs selective loading immunotherapeutic agents carrier molecules protecting groups prevent after administration. Several prodrug activation mechanisms have been highlighted for cancer therapeutics, including endogenous by hypoxic or acidic conditions common tumors, exogenous targeted cleavage, stimuli-responsive light dual-stimuli which adds specificity combining mechanisms. This review will explore modern conjugation options, focusing on how strategies can enhance immunotherapy responses improve patient outcomes. We also discuss implications computational methodology therapy design recommend procedures determine where conjugate systems "prodrug" onto therapeutic safety delivery platforms.

Language: Английский

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γc-Family Cytokines in Health and Disease

Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Language: Английский

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