The majority of patients with chronic kidney disease (CKD) receiving dialysis do not achieve target serum phosphorus concentrations, despite treatment with phosphate binders. Tenapanor is a nonbinder, sodium/hydrogen exchanger isoform 3 (NHE3) inhibitor that reduces paracellular intestinal phosphate absorption. This preclinical study evaluated the effect of tenapanor and varying doses of sevelamer carbonate on urinary phosphorus excretion, a direct reflection of intestinal phosphate absorption. We measured 24-h urinary phosphorus excretion in male rats assigned to groups dosed orally with vehicle or tenapanor (0.3 mg/kg/day) and provided a diet containing varying amounts of sevelamer [0–3% (wt/wt)]. We also evaluated the effect of the addition of tenapanor or vehicle on 24-h urinary phosphorus excretion to rats on a stable dose of sevelamer [1.5% (wt/wt)]. When administered together, tenapanor and sevelamer decreased urinary phosphorus excretion significantly more than either tenapanor or sevelamer alone across all sevelamer dose levels. The Bliss statistical model of independence indicated that the combination was synergistic. A stable sevelamer dose [1.5% (wt/wt)] reduced mean ± SE urinary phosphorus excretion by 42 ± 3% compared with vehicle; together, tenapanor and sevelamer reduced residual urinary phosphorus excretion by an additional 37 ± 6% ( P < 0.05). Although both tenapanor and sevelamer reduce intestinal phosphate absorption individually, administration of tenapanor and sevelamer together results in more pronounced reductions in intestinal phosphate absorption than if either agent is administered alone. Further evaluation of combination tenapanor plus phosphate binder treatment in patients receiving dialysis with hyperphosphatemia is warranted.
<p>Supplementary Figure1 shows MSC homing to tumor and other organs in vivo using a bioluminescent reporter. Supplementary Figure 2. Characterization of tumor immune infiltrate of syngeneic preclinical intraperitoneal tumor models CT26-ip and B16F10-ip using IHC and flow cytometry. Supplementary Figure 3. Kaplan Meier Survival in B16F10-ip model comparing multiple combinations of effector cytokines expressed by MSCs. Supplementary Figure 4. Shows data supporting the construct optimization for SENTI-101 including promoter, orientation and signal sequence changes. Supplementary Figure 5. IL-21 functional validation using UO2S IL-21 receptor dimerization reporter assay. Supplementary Table 1. Shows the DNA sequence of SB00880, the lentiviral construct used to engineer SENTI-101. Supplementary Figure 6. Shows the SENTI-101 manufacturing process overview. Supplementary Figure 7. Shows supporting data for the study of pharmacokinetics and pharmacodynamics of SENTI-101. Supplementary Figure 8. Shows individual tumor burden for each mouse measured by bioluminescence imaging (BLI) after treatment with SENTI-101 or controls. Supplementary Figure 9. Percent change in mouse body weight after treatment. Supplementary Figure 10. Shows the controls and supporting data for the selective depletion of immune cell types. Supplementary Figure 11. Characterization of tumor infiltrating lymphocytes (TILs) in the B16F10-ip tumor model after treatment with mSENTI-101. Supplementary Figure 12. Anti-tumor immune response induced by SENTI-101 in CT-26ip model. Supplementary Figure 13. Shows individual tumor burden for each mouse measured by BLI after treatment with SENTI-101 and in combination with checkpoint inhibitor anti-PD-1.</p>
<div>Abstract<p>Advanced peritoneal carcinomatosis including high-grade ovarian cancer has poor prognoses and a poor response rate to current checkpoint inhibitor immunotherapies; thus, there is an unmet need for effective therapeutics that would provide benefit to these patients. Here we present the preclinical development of SENTI-101, a cell preparation of bone marrow-derived mesenchymal stromal (also known as stem) cells (MSC), which are engineered to express two potent immune-modulatory cytokines, IL12 and IL21. Intraperitoneal administration of SENTI-101 results in selective tumor-homing and localized and sustained cytokine production in murine models of peritoneal cancer. SENTI-101 has extended half-life, reduced systemic distribution, and improved antitumor activity when compared with recombinant cytokines, suggesting that it is more effective and has lower risk of systemic immunotoxicities. Treatment of tumor-bearing immune-competent mice with a murine surrogate of SENTI-101 (mSENTI-101) results in a potent and localized immune response consistent with increased number and activation of antigen presenting cells, T cells and B cells, which leads to antitumor response and memory-induced long-term immunity. Consistent with this mechanism of action, co-administration of mSENTI-101 with checkpoint inhibitors leads to synergistic improvement in antitumor response. Collectively, these data warrant potential clinical development of SENTI-101 for patients with peritoneal carcinomatosis and high-grade ovarian cancer.</p><p>Graphical abstract: SENTI-101 schematic and mechanism of action</p><p>SENTI-101 is a novel cell-based immunotherapeutic consisting of bone marrow–derived mesenchymal stromal cells (BM-MSC) engineered to express IL12 and IL21 intended for the treatment of peritoneal carcinomatosis including high-grade serous ovarian cancer. Upon intraperitoneal administration, SENTI-101 homes to peritoneal solid tumors and secretes IL12 and IL21 in a localized and sustained fashion. The expression of these two potent cytokines drives tumor infiltration and engagement of multiple components of the immune system: antigen-presenting cells, T cells, and B cells, resulting in durable antitumor immunity in preclinical models of cancer.</p></div>
<div>Abstract<p>Advanced peritoneal carcinomatosis including high-grade ovarian cancer has poor prognoses and a poor response rate to current checkpoint inhibitor immunotherapies; thus, there is an unmet need for effective therapeutics that would provide benefit to these patients. Here we present the preclinical development of SENTI-101, a cell preparation of bone marrow-derived mesenchymal stromal (also known as stem) cells (MSC), which are engineered to express two potent immune-modulatory cytokines, IL12 and IL21. Intraperitoneal administration of SENTI-101 results in selective tumor-homing and localized and sustained cytokine production in murine models of peritoneal cancer. SENTI-101 has extended half-life, reduced systemic distribution, and improved antitumor activity when compared with recombinant cytokines, suggesting that it is more effective and has lower risk of systemic immunotoxicities. Treatment of tumor-bearing immune-competent mice with a murine surrogate of SENTI-101 (mSENTI-101) results in a potent and localized immune response consistent with increased number and activation of antigen presenting cells, T cells and B cells, which leads to antitumor response and memory-induced long-term immunity. Consistent with this mechanism of action, co-administration of mSENTI-101 with checkpoint inhibitors leads to synergistic improvement in antitumor response. Collectively, these data warrant potential clinical development of SENTI-101 for patients with peritoneal carcinomatosis and high-grade ovarian cancer.</p><p>Graphical abstract: SENTI-101 schematic and mechanism of action</p><p>SENTI-101 is a novel cell-based immunotherapeutic consisting of bone marrow–derived mesenchymal stromal cells (BM-MSC) engineered to express IL12 and IL21 intended for the treatment of peritoneal carcinomatosis including high-grade serous ovarian cancer. Upon intraperitoneal administration, SENTI-101 homes to peritoneal solid tumors and secretes IL12 and IL21 in a localized and sustained fashion. The expression of these two potent cytokines drives tumor infiltration and engagement of multiple components of the immune system: antigen-presenting cells, T cells, and B cells, resulting in durable antitumor immunity in preclinical models of cancer.</p></div>
Interleukin 2 (IL-2) is a pivotal immune agonist for tumor immunotherapy that has produced impressive clinical efficacy in a number of cancer types. Nevertheless, its pleiotropic effect has led to prohibitory side effects and immune restraint. In contrast, the PD-1 blockade-based cancer immunotherapy has a good safety profile by targeting and sustaining the activity of tumor-antigen specific T cells within cancer tissues. To take full advantage of complementary antitumor activity of PD-1 monoclonal antibody (mAb) and IL-2 as well as supreme intratumoral T-cell-targeting property of PD-1, a bifunctional fusion protein composed of PD-1 mAb and IL-2 mutein (αPD-1-IL-2c) is designed. IL-2c is a chimeric molecule that contains a fragment from IL-15 and does not bind to IL-2 receptor alpha (IL-2Rα). αPD-1-IL-2c stimulated greater pSTAT5 activation and proliferation in PD-1+ T cells than PD-1- T cells. αPD-1-IL-2c also induced a much stronger anti-tumor immune response compared to PD-1 mAb, IL-2c, or PD-1 mAb in combination with IL-2c in multiple syngeneic models such as B16F10, CT26, and MC38. In CT26 and MC38 models, αPD-1-IL-2c achieved complete response starting from 0.3 mg/kg dosing. In B16F10 model, αPD-1-IL-2c showed greater than 70% tumor growth inhibition (TGI). Global gene expression profiling studies showed that PD-1-IL-2c treatment significantly elevated expression levels of Cd3d, Cd3e, Cd8a, Il2rα, Cxcr3, Cxcr6, Zap70, Lck, and Pdcd1 in tumor tissues compared to treatment with PD-1 mAbs or IL-2c, indicating a specific expansion and activation of T cell in the tumor microenvironment (TME). The safety profile of αPD-1-IL-2c was assessed and compared to WT IL-2 and a leading “No-α” αPD-1-IL-2 fusion protein (αPD-1-IL-2x). WT IL-2 and αPD-1-IL-2x induced significant body weight loss and severe splenomegaly when dosed at 1.25 mg/kg. In contrast, αPD-1-IL-2c dosed at 10 mg/kg did not cause appreciable body weight loss and only led to minimal splenomegaly. In summary, we have developed a safe and highly potent αPD-1-IL-2 mutein that achieves full PD-1 blockade and TME-specific T cell activation and expansion without appreciable toxicity. Citation Format: Fan Ye, Jianing Huang, Zoey Huang, Sandra Chen, Eric Liao, Ella Li, Allison Quach, Jenny Jiang, Hanna Lin, Michael Hua, Savannah Yung, Lili Cheng, Ziyang Zhong. A safe and highly potent anti-PD-1-IL-2c fusion that decouples efficacy and toxicity of IL-2 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB218.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.