Synergistic effect of Abraxane that combines human IL15 fused with an albumin‐binding domain on murine models of pancreatic ductal adenocarcinoma

Hsu, Fei‐Ting; Tsai, Chang Liang; Chiang, I-Tsang; Lan, Keng-Hsueh; Yueh, Po-Fu; Liang, Wenyi; Lin, Chin-Hsiang; Chao, Yee; Lan, Keng‐Li

doi:10.1111/jcmm.17220

Cited by 6 publications

(5 citation statements)

References 59 publications

(141 reference statements)

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“…Our in vitro data suggest that SON-1210 should stimulate the expected mechanisms associated with the therapeutic efficacy of the molecule, particularly T-and NK-cell stimulation and IFNg production, which is important for local tumor surveillance (57). Such an effect has been previously reported using IL-15 attached to an albumin construct alone or in combination with a PD-L1 inhibitor (58,59). Based on our FACS data, we conclude that treatment with mIL12-F H AB-hIL15 transformed the "cold" B16F10 tumor into a "hot" tumor.…”

Section: Characterization Of the F H Ab And Son-1210supporting

confidence: 86%

SON-1210 - a novel bifunctional IL-12 / IL-15 fusion protein that improves cytokine half-life, targets tumors, and enhances therapeutic efficacy

Cini,

Dexter,

Rezac

et al. 2023

Front. Immunol.

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BackgroundThe potential synergy between interleukin-12 (IL-12) and IL-15 holds promise for more effective solid tumor immunotherapy. Nevertheless, previous clinical trials involving therapeutic cytokines have encountered obstacles such as short pharmacokinetics, limited tumor microenvironment (TME) targeting, and substantial systemic toxicity.MethodsTo address these challenges, we fused single-chain human IL-12 and native human IL-15 in cis onto a fully human albumin binding (FHAB) domain single-chain antibody fragment (scFv). This novel fusion protein, IL12-FHAB-IL15 (SON-1210), is anticipated to amplify the therapeutic impact of interleukins and combination immunotherapies in human TME. The molecule was studied in vitro and in animal models to assess its pharmacokinetics, potency, functional characteristics, safety, immune response, and efficacy.ResultsSON-1210 demonstrated robust binding affinity to albumin and exhibited the anticipated in vitro activity and tumor model efficacy that might be expected based on decades of research on native IL-12 and IL-15. Notably, in the B16F10 melanoma model (a non-immunogenic, relatively “cold” tumor), the murine counterpart of the construct, which had mouse (m) and human (h) cytokine sequences for the respective payloads (mIL12-FHAB-hIL15), outperformed equimolar doses of the co-administered native cytokines in a dose-dependent manner. A single dose caused a marked reduction in tumor growth that was concomitant with increased IFNγ levels; increased Th1, CTL, and activated NK cells; a shift in macrophages from the M2 to M1 phenotype; and a reduction in Treg cells. In addition, a repeat-dose non-human primate (NHP) toxicology study displayed excellent tolerability up to 62.5 µg/kg of SON-1210 administered three times, which was accompanied by the anticipated increases in IFNγ levels. Toxicokinetic analyses showed sustained serum levels of SON-1210, using a sandwich ELISA with anti-IL-15 for capture and biotinylated anti-IL-12 for detection, along with sustained IFNγ levels, indicating prolonged kinetics and biological activity.ConclusionCollectively, these findings support the suitability of SON-1210 for patient trials in terms of activity, efficacy, and safety, offering a promising opportunity for solid tumor immunotherapy. Linking cytokine payloads to a fully human albumin binding domain provides an indirect opportunity to target the TME using potent cytokines in cis that can redirect the immune response and control tumor growth.

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Section: Characterization Of the F H Ab And Son-1210supporting

confidence: 86%

SON-1210 - a novel bifunctional IL-12 / IL-15 fusion protein that improves cytokine half-life, targets tumors, and enhances therapeutic efficacy

Cini,

Dexter,

Rezac

et al. 2023

Front. Immunol.

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“…Abraxane in combination with hIL15-ABD causes CD8+ T cells to secrete increased IFN-γ and suppresses the production of immunosuppressive markers (FOXP3, VEGF, etc.) ( 124 ). The combination of CCKR blockade results in a significant decrease in tumor FOXP3+ Tregs and an increase in CD4+ and CD8+ lymphocytes ( 125 ).…”

Section: Factors Influencing Formation Of Tlssmentioning

confidence: 99%

Tertiary lymphoid structures in pancreatic cancer: a new target for immunotherapy

et al. 2023

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Pancreatic cancer (PC) is extremely malignant and shows limited response to available immunotherapies due to the hypoxic and immunosuppressive nature of its tumor microenvironment (TME). The aggregation of immune cells (B cells, T cells, dendritic cells, etc.), which is induced in various chronic inflammatory settings such as infection, inflammation, and tumors, is known as the tertiary lymphoid structure (TLS). Several studies have shown that TLSs can be found in both intra- and peritumor tissues of PC. The role of TLSs in peritumor tissues in tumors remains unclear, though intratumoral TLSs are known to play an active role in a variety of tumors, including PC. The formation of intratumoral TLSs in PC is associated with a good prognosis. In addition, TLSs can be used as an indicator to assess the effectiveness of treatment. Targeted induction of TLS formation may become a new avenue of immunotherapy for PC. This review summarizes the formation, characteristics, relevant clinical outcomes, and clinical applications of TLSs in the pancreatic TME. We aim to provide new ideas for future immunotherapy of PC.

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“…Intracellular markers, such as IFN-γ and IL-2, were stained after the cells were fixed and permeabilized using BD fixation and permeabilization solution (BD Biosciences, Franklin Lakes, NJ, USA) as per the manufacturer's protocol. The fluorescence intensity from each group was recorded using a NovoCyte flow cytometer and quantified using NovoExpress ® software (Agilent Technologies Inc., Santa Clara, CA, USA) (16,17). The markers used in the flow cytometry analysis are listed in Table I.…”

Section: Magnetic Resonance Imaging (Mri) Scanning Of Mouse Brainmentioning

confidence: 99%

Humanized PD-1 Knock-in Mice Reveal Nivolumab’s Inhibitory Effects on Glioblastoma Tumor ProgressionIn Vivo

CHIANG,

HUANG,

TSAI

et al. 2023

In Vivo

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Background/Aim: Immunotherapy has been considered a promising approach for brain tumor treatment since the discovery of the brain lymphatic system. Glioblastoma (GBM), the most aggressive type of brain tumor, is associated with poor prognosis and a lack of effective treatment options. Materials and Methods: To test the efficacy of human anti-PD-1, we used a humanized PD-1 knock-in mouse to establish an orthotopic GBM-bearing model. Results: Nivolumab, a human anti-PD-1, effectively inhibited tumor growth, increased the survival rate of mice, enhanced the accumulation and function of cytotoxic T cells, reduced the accumulation and function of immunosuppressive cells and their related factors, and did not induce tissue damage or biochemical changes. The treatment also induced the accumulation and activation of CD8 + cytotoxic T cells, while reducing the accumulation and activation of myeloid-derived suppressor cells, regulatory T cells, and tumor-associated macrophages in the immune microenvironment. Conclusion:Nivolumab has the potential to be a treatment for GBM.Glioblastoma (GBM) is a prevalent malignant tumor of the central nervous system that frequently occurs in both adults and children. Despite the benefits of resection, radiotherapy, and temozolomide chemotherapy in improving the prognosis, glioblastoma patients continue to face a significant mortality risk. The improvement of prognosis in glioblastoma is a critical area of research that necessitates the development of effective innovative approaches (1-3).Vascular endothelial growth factor (VEGF) is an angiogenic protein required for tumor progression. Glioblastoma employs the expression of VEGF to induce angiogenesis and increase blood-brain barrier (BBB) permeability. Consequently, this process results in the development of peritumoral edema (4, 5). Tumor-associated edema is frequently treated with corticosteroid therapy (6). Bevacizumab is a humanized anti-VEGF monoclonal antibody that was approved by the FDA in 2009 for the treatment of recurrent glioblastoma. By targeting the VEGF pathway, it does not only inhibit angiogenesis but also alleviates BBB permeability and peritumoral edema (4,7,8).The synergy between the innate and adaptive immune systems is crucial for achieving antitumor immunity, which involves the combined action of both immune responses to effectively suppress tumors (9). CD8 + T cells, also known as cytotoxic T lymphocytes (CTLs), play a vital role in the immune response against tumors by eliminating tumor cells 1991

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Synergistic effect of Abraxane that combines human IL15 fused with an albumin‐binding domain on murine models of pancreatic ductal adenocarcinoma

Cited by 6 publications

References 59 publications

SON-1210 - a novel bifunctional IL-12 / IL-15 fusion protein that improves cytokine half-life, targets tumors, and enhances therapeutic efficacy

SON-1210 - a novel bifunctional IL-12 / IL-15 fusion protein that improves cytokine half-life, targets tumors, and enhances therapeutic efficacy

Tertiary lymphoid structures in pancreatic cancer: a new target for immunotherapy

Humanized PD-1 Knock-in Mice Reveal Nivolumab’s Inhibitory Effects on Glioblastoma Tumor ProgressionIn Vivo

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