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Evaluation of the clinical molecule anti-human-PD-L1/IL-15 KD033 in the human-PD-1/PD-L1-expressing murine model demonstrates PD-L1 targeting of IL-15 in vivo.

ABSTRACT: KD033 is a clinical-stage immunocytokine composed of a high-affinity anti-human-PD-L1 antibody and the human IL-15/ IL-15 receptor sushi-domain complex. We have previously shown that KD033-surrogate, the anti-mouse-PD-L1/IL-15 immunocytokine, was efficacious in several syngeneic murine tumor models including those that were refractory to anti-PD-1/PD-L1 checkpoint blockers. KD033-surrogate showed better efficacy than the combination treatment of its component, anti-PD-L1 antibody with the non-targeting IL-15. KD033-surrogate was also efficacious in both low and high PD-L1-expressing tumors. In this study, we have utilized double knock-in mice expressing functional human PD-1/PD-L1 to show that the clinical molecule, KD033, reproduced the anti-tumor efficacy observed with KD033-surrogate in the syngeneic models. KD033 was equally efficacious in reducing the growth of human-PD-L1 positive (hPDL1+) and negative (hPDL1-) MC38 murine tumors. We observed similar peripheral pharmacodynamics changes in KD033-treated mice bearing either hPDL1+ or hPDL1- MC38 tumors. However, different transcriptomic profiles were observed between KD033-treated hPDL1+ and hPDL1- MC38 tumors with marked changes involving mostly downregulated genes in hPDL1- tumors in addition to the immune-related genes changes observed in both hPDL1+ and hPDL1- MC38 tumors. Cytotoxic and myeloid cell signatures were upregulated in both tumors with relatively greater increases observed in hPDL1- MC38 tumors. These effects of KD033 treatment in PD-L1 positive and negative tumors demonstrate the role of PD-L1 in targeting of IL-15 cytokine in vivo.

SUBMITTER: Martomo SA

PROVIDER: S-EPMC10198867 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Evaluation of the clinical molecule anti-human-PD-L1/IL-15 KD033 in the human-PD-1/PD-L1-expressing murine model demonstrates PD-L1 targeting of IL-15 in vivo.

Martomo Stella A SA Patel Jeegar J

Cancer immunology, immunotherapy : CII 20221201 6

KD033 is a clinical-stage immunocytokine composed of a high-affinity anti-human-PD-L1 antibody and the human IL-15/ IL-15 receptor sushi-domain complex. We have previously shown that KD033-surrogate, the anti-mouse-PD-L1/IL-15 immunocytokine, was efficacious in several syngeneic murine tumor models including those that were refractory to anti-PD-1/PD-L1 checkpoint blockers. KD033-surrogate showed better efficacy than the combination treatment of its component, anti-PD-L1 antibody with the non-ta ...[more]

PMID: 36454338

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Project description:BackgroundImmunotherapy targeting PD-1/PD-L1 fails to induce clinical responses in most patients with solid cancers. N-803, formerly ALT-803, is an IL-15 superagonist mutant and dimeric IL-15RαSushi-Fc fusion protein complex that enhances CD8+ T and NK cell expansion and function and exhibits anti-tumor efficacy in preclinical models. Previous in vitro studies have shown that IL-15 increases PD-L1 expression, a negative regulator of CD8+ T and NK cell function. Most reported preclinical studies administered N-803 intraperitoneally not subcutaneously, the current clinical route of administration. N-803 is now being evaluated clinically in combination with PD-1/PD-L1 inhibitors. However, the mechanism of action has not been fully elucidated. Here, we examined the anti-tumor efficacy and immunomodulatory effects of combining N-803 with an anti-PD-L1 antibody in preclinical models of solid carcinomas refractory to anti-PD-L1 or N-803.MethodsSubcutaneous N-803 and an anti-PD-L1 monoclonal antibody were administered as monotherapy or in combination to 4T1 triple negative breast and MC38-CEA colon tumor-bearing mice. Anti-tumor efficacy was evaluated, and a comprehensive analysis of the immune-mediated effects of each therapy was performed on the primary tumor, lung as a site of metastasis, and spleen.ResultsWe demonstrate that N-803 treatment increased PD-L1 expression on immune cells in vivo, supporting the combination of N-803 and anti-PD-L1. N-803 plus anti-PD-L1 was well-tolerated, reduced 4T1 lung metastasis and MC38-CEA tumor burden, and increased survival as compared to N-803 and anti-PD-L1 monotherapies. Efficacy of the combination therapy was dependent on both CD8+ T and NK cells and was associated with increased numbers of these activated immune cells in the lung and spleen. Most alterations to NK and CD8+ T cell phenotype and number were driven by N-803. However, the addition of anti-PD-L1 to N-803 significantly enhanced CD8+ T cell effector function versus N-803 and anti-PD-L1 monotherapies, as indicated by increased Granzyme B and IFNγ production, at the site of metastasis and in the periphery. Increased CD8+ T cell effector function correlated with higher serum IFNγ levels, without related toxicities, and enhanced anti-tumor efficacy of the N-803 plus anti-PD-L1 combination versus either monotherapy.ConclusionsWe provide novel insight into the mechanism of action of N-803 plus anti-PD-L1 combination and offer preclinical proof of concept supporting clinical use of N-803 in combination with checkpoint inhibitors, including for patients non- and/or minimally responsive to either monotherapy.

Project description:BACKGROUND:Anti(?)-programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) monotherapy fails to provide durable clinical benefit for most patients with carcinoma. Recent studies suggested that strategies to reduce immunosuppressive cells, promote systemic T-cell responses and lymphocyte trafficking to the tumor microenvironment (TME) may improve efficacy. N-809 is a first-in-class bifunctional agent comprising the interleukin (IL)-15 superagonist N-803 fused to two ?PD-L1 domains. Thus, N-809 can potentially stimulate effector immune cells through IL-15 and block immunosuppressive PD-L1. Here, we examined the antitumor efficacy and immunomodulatory effects of N-809 versus N-803+?PD-L1 combination. METHODS:The ability of N-809 to block PD-L1 and induce IL-15-dependent immune effects was examined in vitro and in vivo. Antitumor efficacy of N-809 or N-803+?PD-L1 was evaluated in two murine carcinoma models and an extensive analysis of immune correlates was performed in the tumor and tumor-draining lymph node (dLN). RESULTS:We demonstrate that N-809 blocks PD-L1 and induces IL-15-dependent immune effects. N-809 was well-tolerated and reduced 4T1 lung metastasis, decreased MC38 tumor burden and increased survival versus N-803+?PD-L1. Compared with N-803+?PD-L1, N-809 enhanced natural killer (NK) and CD8+ T-cell activation and function in the dLN and TME, relating to increased gene expression associated with interferon and cytokine signaling, lymphoid compartment, costimulation and cytotoxicity. The higher number of TME CD8+ T cells was attributed to enhanced infiltration, not in situ expansion. Increased TME NK and CD8+ T-cell numbers correlated with augmented chemokine ligands and receptors. Moreover, in contrast to N-803+?PD-L1, N-809 reduced immunosuppressive regulatory T cells (Treg), monocytic myeloid-derived suppressor cells (M-MDSC) and M2-like macrophages in the TME. CONCLUSIONS:Our results suggest that N-809 functions by a novel immune mechanism to promote antitumor efficacy. Foremost, N-809 enhances intratumoral lymphocyte numbers by increasing trafficking via altered chemokine levels in the TME and chemokine receptor expression on CD8+ T cells and NK cells. In addition, N-809 reduces immunosuppressive and pro-tumorigenic immune cells in the TME, including Treg, M2-like macrophages and M-MDSC. Overall, these novel effects of N-809 promote an inflamed TME, leading to lower tumor burden and increased survival. These results provide mechanistic insight and rationale supporting the potential clinical study of N-809 in patients with carcinoma.

Dataset Information

Evaluation of the clinical molecule anti-human-PD-L1/IL-15 KD033 in the human-PD-1/PD-L1-expressing murine model demonstrates PD-L1 targeting of IL-15 in vivo.

Publications

Evaluation of the clinical molecule anti-human-PD-L1/IL-15 KD033 in the human-PD-1/PD-L1-expressing murine model demonstrates PD-L1 targeting of IL-15 in vivo.

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