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2. Bifunctional TGF-β trap/IL-15 protein complex elicits potent NK cell and CD8+ T cell immunity against solid tumors

Author

Liu, Bai, Zhu, Xiaoyun, Kong, Lin, Wang, Meng, Spanoudis, Catherine, Chaturvedi, Pallavi, George, Varghese, Jiao, Jin-an, You, Lijing, Egan, Jack O., Echeverri, Christian, Gallo, Victor L., Xing, Jilan, Ravelo, Kristine, Prendes, Caitlin, Antolinez, Julian, Denissova, Julia, Muniz, Gabriela J., Jeng, Emily K., Rhode, Peter R., and Wong, Hing C.

Published
2021
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4. Supplementary Table 5 from A Fusion Protein Complex that Combines IL-12, IL-15, and IL-18 Signaling to Induce Memory-Like NK Cells for Cancer Immunotherapy

Author

Becker-Hapak, Michelle K., primary, Shrestha, Niraj, primary, McClain, Ethan, primary, Dee, Michael J., primary, Chaturvedi, Pallavi, primary, Leclerc, Gilles M., primary, Marsala, Lynne I., primary, Foster, Mark, primary, Schappe, Timothy, primary, Tran, Jennifer, primary, Desai, Sweta, primary, Neal, Carly C., primary, Pence, Patrick, primary, Wong, Pamela, primary, Wagner, Julia A., primary, Russler-Germain, David A., primary, Zhu, Xiaoyun, primary, Spanoudis, Catherine M., primary, Gallo, Victor L., primary, Echeverri, Christian A., primary, Ramirez, Laritza L., primary, You, Lijing, primary, Egan, Jack O., primary, Rhode, Peter R., primary, Jiao, Jin-an, primary, Muniz, Gabriela J., primary, Jeng, Emily K., primary, Prendes, Caitlin A., primary, Sullivan, Ryan P., primary, Berrien-Elliott, Melissa M., primary, Wong, Hing C., primary, and Fehniger, Todd A., primary

Published
2023
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5. Data from A Fusion Protein Complex that Combines IL-12, IL-15, and IL-18 Signaling to Induce Memory-Like NK Cells for Cancer Immunotherapy

Author

Becker-Hapak, Michelle K., primary, Shrestha, Niraj, primary, McClain, Ethan, primary, Dee, Michael J., primary, Chaturvedi, Pallavi, primary, Leclerc, Gilles M., primary, Marsala, Lynne I., primary, Foster, Mark, primary, Schappe, Timothy, primary, Tran, Jennifer, primary, Desai, Sweta, primary, Neal, Carly C., primary, Pence, Patrick, primary, Wong, Pamela, primary, Wagner, Julia A., primary, Russler-Germain, David A., primary, Zhu, Xiaoyun, primary, Spanoudis, Catherine M., primary, Gallo, Victor L., primary, Echeverri, Christian A., primary, Ramirez, Laritza L., primary, You, Lijing, primary, Egan, Jack O., primary, Rhode, Peter R., primary, Jiao, Jin-an, primary, Muniz, Gabriela J., primary, Jeng, Emily K., primary, Prendes, Caitlin A., primary, Sullivan, Ryan P., primary, Berrien-Elliott, Melissa M., primary, Wong, Hing C., primary, and Fehniger, Todd A., primary

Published
2023
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6. Supplementary Figure Legends from A Fusion Protein Complex that Combines IL-12, IL-15, and IL-18 Signaling to Induce Memory-Like NK Cells for Cancer Immunotherapy

Author

Becker-Hapak, Michelle K., primary, Shrestha, Niraj, primary, McClain, Ethan, primary, Dee, Michael J., primary, Chaturvedi, Pallavi, primary, Leclerc, Gilles M., primary, Marsala, Lynne I., primary, Foster, Mark, primary, Schappe, Timothy, primary, Tran, Jennifer, primary, Desai, Sweta, primary, Neal, Carly C., primary, Pence, Patrick, primary, Wong, Pamela, primary, Wagner, Julia A., primary, Russler-Germain, David A., primary, Zhu, Xiaoyun, primary, Spanoudis, Catherine M., primary, Gallo, Victor L., primary, Echeverri, Christian A., primary, Ramirez, Laritza L., primary, You, Lijing, primary, Egan, Jack O., primary, Rhode, Peter R., primary, Jiao, Jin-an, primary, Muniz, Gabriela J., primary, Jeng, Emily K., primary, Prendes, Caitlin A., primary, Sullivan, Ryan P., primary, Berrien-Elliott, Melissa M., primary, Wong, Hing C., primary, and Fehniger, Todd A., primary

Published
2023
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7. Supplementary Table 4 from A Fusion Protein Complex that Combines IL-12, IL-15, and IL-18 Signaling to Induce Memory-Like NK Cells for Cancer Immunotherapy

Author

Becker-Hapak, Michelle K., primary, Shrestha, Niraj, primary, McClain, Ethan, primary, Dee, Michael J., primary, Chaturvedi, Pallavi, primary, Leclerc, Gilles M., primary, Marsala, Lynne I., primary, Foster, Mark, primary, Schappe, Timothy, primary, Tran, Jennifer, primary, Desai, Sweta, primary, Neal, Carly C., primary, Pence, Patrick, primary, Wong, Pamela, primary, Wagner, Julia A., primary, Russler-Germain, David A., primary, Zhu, Xiaoyun, primary, Spanoudis, Catherine M., primary, Gallo, Victor L., primary, Echeverri, Christian A., primary, Ramirez, Laritza L., primary, You, Lijing, primary, Egan, Jack O., primary, Rhode, Peter R., primary, Jiao, Jin-an, primary, Muniz, Gabriela J., primary, Jeng, Emily K., primary, Prendes, Caitlin A., primary, Sullivan, Ryan P., primary, Berrien-Elliott, Melissa M., primary, Wong, Hing C., primary, and Fehniger, Todd A., primary

Published
2023
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8. Supplementary Figures 1-8 and Tables 1-3 from A Fusion Protein Complex that Combines IL-12, IL-15, and IL-18 Signaling to Induce Memory-Like NK Cells for Cancer Immunotherapy

Author

Becker-Hapak, Michelle K., primary, Shrestha, Niraj, primary, McClain, Ethan, primary, Dee, Michael J., primary, Chaturvedi, Pallavi, primary, Leclerc, Gilles M., primary, Marsala, Lynne I., primary, Foster, Mark, primary, Schappe, Timothy, primary, Tran, Jennifer, primary, Desai, Sweta, primary, Neal, Carly C., primary, Pence, Patrick, primary, Wong, Pamela, primary, Wagner, Julia A., primary, Russler-Germain, David A., primary, Zhu, Xiaoyun, primary, Spanoudis, Catherine M., primary, Gallo, Victor L., primary, Echeverri, Christian A., primary, Ramirez, Laritza L., primary, You, Lijing, primary, Egan, Jack O., primary, Rhode, Peter R., primary, Jiao, Jin-an, primary, Muniz, Gabriela J., primary, Jeng, Emily K., primary, Prendes, Caitlin A., primary, Sullivan, Ryan P., primary, Berrien-Elliott, Melissa M., primary, Wong, Hing C., primary, and Fehniger, Todd A., primary

Published
2023
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9. A novel interleukin-2-based fusion molecule, HCW9302, differentially promotes regulatory T cell expansion to treat atherosclerosis in mice

Author

Zhu, Xiaoyun, primary, Li, Qiongzhen, additional, George, Varghese, additional, Spanoudis, Catherine, additional, Gilkes, Crystal, additional, Shrestha, Niraj, additional, Liu, Bai, additional, Kong, Lin, additional, You, Lijing, additional, Echeverri, Christian, additional, Li, Liying, additional, Wang, Zheng, additional, Chaturvedi, Pallavi, additional, Muniz, Gabriela J., additional, Egan, Jack O., additional, Rhode, Peter R., additional, and Wong, Hing C., additional

Published
2023
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10. Immunotherapeutic approach to reduce senescent cells and alleviate senescence‐associated secretory phenotype in mice.

Author

Shrestha, Niraj, Chaturvedi, Pallavi, Zhu, Xiaoyun, Dee, Michael J., George, Varghese, Janney, Christopher, Egan, Jack O., Liu, Bai, Foster, Mark, Marsala, Lynne, Wong, Pamela, Cubitt, Celia C., Foltz, Jennifer A., Tran, Jennifer, Schappe, Timothy, Hsiao, Karin, Leclerc, Gilles M., You, Lijing, Echeverri, Christian, and Spanoudis, Catherine

Subjects
MOLECULAR clock, HEPATIC fibrosis, CLOCK genes, REGULATOR genes, MICE, PHENOTYPES, PHYSICAL mobility
Abstract

Accumulation of senescent cells (SNCs) with a senescence‐associated secretory phenotype (SASP) has been implicated as a major source of chronic sterile inflammation leading to many age‐related pathologies. Herein, we provide evidence that a bifunctional immunotherapeutic, HCW9218, with capabilities of neutralizing TGF‐β and stimulating immune cells, can be safely administered systemically to reduce SNCs and alleviate SASP in mice. In the diabetic db/db mouse model, subcutaneous administration of HCW9218 reduced senescent islet β cells and SASP resulting in improved glucose tolerance, insulin resistance, and aging index. In naturally aged mice, subcutaneous administration of HCW9218 durably reduced the level of SNCs and SASP, leading to lower expression of pro‐inflammatory genes in peripheral organs. HCW9218 treatment also reverted the pattern of key regulatory circadian gene expression in aged mice to levels observed in young mice and impacted genes associated with metabolism and fibrosis in the liver. Single‐nucleus RNA Sequencing analysis further revealed that HCW9218 treatment differentially changed the transcriptomic landscape of hepatocyte subtypes involving metabolic, signaling, cell‐cycle, and senescence‐associated pathways in naturally aged mice. Long‐term survival studies also showed that HCW9218 treatment improved physical performance without compromising the health span of naturally aged mice. Thus, HCW9218 represents a novel immunotherapeutic approach and a clinically promising new class of senotherapeutic agents targeting cellular senescence‐associated diseases. [ABSTRACT FROM AUTHOR]

Published
2023
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12. Abstract 1299: Immunotherapeutic hcw9218 enhances anti-tumor activity of chemotherapy by facilitating immune-mediated elimination of therapy induced senescent cells

Author

Chaturvedi, Pallavi, primary, George, Varghese, additional, Liu, Bai, additional, Shrestha, Niraj, additional, Wang, Meng, additional, Dee, Micheal, additional, Zhu, Xiaoyun, additional, Egan, Jack, additional, Jiao, Jin-an, additional, Spanoudis, Catherine, additional, Xing, Jilan, additional, Gallo, Victor, additional, Echeverri, Christian, additional, You, Lijing, additional, Kong, Lin, additional, Muniz, Gabriela, additional, Rhode, Peter, additional, and Wong, Hing, additional

Published
2022
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13. A novel interleukin-2-based fusion molecule, HCW9302, differentially promotes regulatory T cell expansion to treat atherosclerosis in mice.

Author

Xiaoyun Zhu, Qiongzhen Li, George, Varghese, Spanoudis, Catherine, Gilkes, Crystal, Shrestha, Niraj, Bai Liu, Lin Kong, Lijing You, Echeverri, Christian, Liying Li, Zheng Wang, Chaturvedi, Pallavi, Muniz, Gabriela J., Egan, Jack O., Rhode, Peter R., and Wong, Hing C.

Abstract

Atherosclerosis is a chronic inflammatory disease caused by deposition of oxidative low-density lipoprotein (LDL) in the arterial intima which triggers the innate immune response through myeloid cells such as macrophages. Regulatory T cells (Tregs) play an important role in controlling the progression or regression of atherosclerosis by resolving macrophage-mediated inflammatory functions. Interleukin-2 (IL-2) signaling is essential for homeostasis of Tregs. Since recombinant IL-2 has an unfavorable pharmacokinetic profile limiting its therapeutic use, we constructed a fusion protein, designated HCW9302, containing two IL-2 domains linked by an extracellular tissue factor domain. We found that HCW9302 exhibited a longer serum half-life with an approximately 1000-fold higher affinity for the IL-2Rα than IL-2. HCW9302 could be administered to mice at a dosing range that expanded and activated Tregs but not CD4+ effector T cells. In an ApoE-/- mouse model, HCW9302 treatment curtailed the progression of atherosclerosis through Treg activation and expansion, M2 macrophage polarization and myeloid-derived suppressor cell induction. HCW9302 treatment also lessened inflammatory responses in the aorta. Thus, HCW9302 is a potential therapeutic agent to expand and activate Tregs for treatment of inflammatory and autoimmune diseases. [ABSTRACT FROM AUTHOR]

Published
2023
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15. A Fusion Protein Complex that Combines IL-12, IL-15, and IL-18 Signaling to Induce Memory-Like NK Cells for Cancer Immunotherapy

Author

Becker-Hapak, Michelle K., primary, Shrestha, Niraj, additional, McClain, Ethan, additional, Dee, Michael J., additional, Chaturvedi, Pallavi, additional, Leclerc, Gilles M., additional, Marsala, Lynne I., additional, Foster, Mark, additional, Schappe, Timothy, additional, Tran, Jennifer, additional, Desai, Sweta, additional, Neal, Carly C., additional, Pence, Patrick, additional, Wong, Pamela, additional, Wagner, Julia A., additional, Russler-Germain, David A., additional, Zhu, Xiaoyun, additional, Spanoudis, Catherine M., additional, Gallo, Victor L., additional, Echeverri, Christian A., additional, Ramirez, Laritza L., additional, You, Lijing, additional, Egan, Jack O., additional, Rhode, Peter R., additional, Jiao, Jin-an, additional, Muniz, Gabriela J., additional, Jeng, Emily K., additional, Prendes, Caitlin A., additional, Sullivan, Ryan P., additional, Berrien-Elliott, Melissa M., additional, Wong, Hing C., additional, and Fehniger, Todd A., additional

Published
2021
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18. A Novel Bifunctional Fusion Protein Comprising of TGF-βRII trap and IL15/IL-15Rα as an Immunotherapeutic against Cancer

Author

Liu, Bai, primary, Chaturvedi, Pallavi, additional, Wang, Meng, additional, Zhu, Xiaoyun, additional, George, Varghese, additional, Revelo, Kristine, additional, Spanoudis, Catherine, additional, Kong, Lin, additional, Xing, Jilan, additional, Prendes, Caitlin, additional, You, Lijing, additional, Rhode, Peter, additional, and Wong, Hing C, additional

Published
2020
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20. Author response: An essential Staphylococcus aureus cell division protein directly regulates FtsZ dynamics

Author

Eswara, Prahathees J, primary, Brzozowski, Robert S, additional, Viola, Marissa G, additional, Graham, Gianni, additional, Spanoudis, Catherine, additional, Trebino, Catherine, additional, Jha, Jyoti, additional, Aubee, Joseph I, additional, Thompson, Karl M, additional, Camberg, Jodi L, additional, and Ramamurthi, Kumaran S, additional

Published
2018
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21. Bifunctional TGF-β trap/IL-15 protein complex elicits potent NK cell and CD8+T cell immunity against solid tumors

Author

Liu, Bai, Zhu, Xiaoyun, Kong, Lin, Wang, Meng, Spanoudis, Catherine, Chaturvedi, Pallavi, George, Varghese, Jiao, Jin-an, You, Lijing, Egan, Jack O., Echeverri, Christian, Gallo, Victor L., Xing, Jilan, Ravelo, Kristine, Prendes, Caitlin, Antolinez, Julian, Denissova, Julia, Muniz, Gabriela J., Jeng, Emily K., Rhode, Peter R., and Wong, Hing C.

Abstract

Advances in immunostimulatory and anti-immunosuppressive therapeutics have revolutionized cancer treatment. However, novel immunotherapeutics with these dual functions are not frequently reported. Here we describe the creation of a heterodimeric bifunctional fusion molecule, HCW9218, constructed using our soluble tissue factor (TF)-based scaffold technology. This complex comprises extracellular domains of the human transforming growth factor-β (TGF-β) receptor II and a human interleukin-15 (IL-15)/IL-15 receptor α complex. HCW9218 can be readily expressed in CHO cells and purified using antibody-based affinity chromatography in a large-scale manufacturing setting. HCW9218 potently activates mouse natural killer (NK) cells and CD8+T cells in vitroand in vivoto enhance cell proliferation, metabolism, and antitumor cytotoxic activities. Similarly, human immune cells become activated with increased cytotoxicity following incubation with HCW9218. This fusion complex also exhibits TGF-β neutralizing activity in vitroand sequesters plasma TGF-β in vivo. In a syngeneic B16F10 melanoma model, HCW9218 displayed strong antitumor activity mediated by NK cells and CD8+T cells and increased their infiltration into tumors. Repeat-dose subcutaneous administration of HCW9218 was well tolerated by mice, with a half-life sufficient to provide long-lasting biological activity. Thus, HCW9218 may serve as a novel therapeutic to simultaneously provide immunostimulation and lessen immunosuppression associated with tumors.

Published
2021
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