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1. Mechanistic insights into a heterobifunctional degrader-induced PTPN2/N1 complex

Author

Hao, Qi, Rathinaswamy, Manoj K., Klinge, Kelly L., Bratkowski, Matthew, Mafi, Amirhossein, Baumgartner, Christina K., Hamel, Keith M., Veits, Gesine K., Jain, Rinku, Catalano, Claudio, Fitzgerald, Mark, Hird, Alexander W., Park, Eunice, Vora, Harit U., Henderson, James A., Longenecker, Kenton, Hutchins, Charles W., Qiu, Wei, Scapin, Giovanna, Sun, Qi, Stoll, Vincent S., Sun, Chaohong, Li, Ping, Eaton, Dan, Stokoe, David, Fisher, Stewart L., Nasveschuk, Christopher G., Paddock, Marcia, and Kort, Michael E.

Published
2024
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2. The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity

Author

Baumgartner, Christina K., Ebrahimi-Nik, Hakimeh, Iracheta-Vellve, Arvin, Hamel, Keith M., Olander, Kira E., Davis, Thomas G. R., McGuire, Kathleen A., Halvorsen, Geoff T., Avila, Omar I., Patel, Chirag H., Kim, Sarah Y., Kammula, Ashwin V., Muscato, Audrey J., Halliwill, Kyle, Geda, Prasanthi, Klinge, Kelly L., Xiong, Zhaoming, Duggan, Ryan, Mu, Liang, Yeary, Mitchell D., Patti, James C., Balon, Tyler M., Mathew, Rebecca, Backus, Carey, Kennedy, Domenick E., Chen, Angeline, Longenecker, Kenton, Klahn, Joseph T., Hrusch, Cara L., Krishnan, Navasona, Hutchins, Charles W., Dunning, Jax P., Bulic, Marinka, Tiwari, Payal, Colvin, Kayla J., Chuong, Cun Lan, Kohnle, Ian C., Rees, Matthew G., Boghossian, Andrew, Ronan, Melissa, Roth, Jennifer A., Wu, Meng-Ju, Suermondt, Juliette S. M. T., Knudsen, Nelson H., Cheruiyot, Collins K., Sen, Debattama R., Griffin, Gabriel K., Golub, Todd R., El-Bardeesy, Nabeel, Decker, Joshua H., Yang, Yi, Guffroy, Magali, Fossey, Stacey, Trusk, Patricia, Sun, Im-Meng, Liu, Yue, Qiu, Wei, Sun, Qi, Paddock, Marcia N., Farney, Elliot P., Matulenko, Mark A., Beauregard, Clay, Frost, Jennifer M., Yates, Kathleen B., Kym, Philip R., and Manguso, Robert T.

Published
2023
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3. 999 The PTPN2/N1 small molecule inhibitor ABBV-CLS-484 promotes NK cell activity driving primary tumor regression and preventing metastasis

Author

Patel, Chirag, primary, McGuire, Kathleen A, additional, Ebrahimi-Nik, Hakimeh, additional, Sun, Meng, additional, Liu, Yue, additional, Klinge, Kelly, additional, Aguado, Jacqueline, additional, Muscato, Audrey J, additional, Tiwari, Payal, additional, Avila-Monge, Omar, additional, Colvin, Kayla J, additional, Olander, Kira, additional, Halliwill, Kyle, additional, Klahn, Joseph, additional, Schutte, Alexander, additional, Paddock, Marcia N, additional, Powell, Jonathan, additional, Hamel, Keith M, additional, Frost, Jennifer M, additional, Yates, Kathleen B, additional, Kym, Philip R, additional, Manguso, Robert T, additional, and Baumgartner, Christina K, additional

Published
2023
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4. 1403-A PTPN2/N1 inhibitor ABBV-CLS-484 unleashes potent anti-tumor immunity

Author

Ebrahimi-Nik, Hakimeh, primary, Baumgartner, Christina K, additional, Iracheta-Vellve, Arvin, additional, Hamel, Keith M, additional, Olander, Kira, additional, Davis, Thomas GR, additional, McGuire, Kathleen A, additional, Halvorsen, Geoff T, additional, Avila, Omar I, additional, Patel, Chirag, additional, Kim, Sarah, additional, Kammula, Ashwin V, additional, Muscato, Audrey J, additional, Halliwill, Kyle, additional, Geda, Prasanthi, additional, Klinge, Kelly, additional, Xiong, Zhaoming, additional, Duggan, Ryan, additional, Mu, Liang, additional, Yeary, Mitchell D, additional, Patti, James C, additional, Balon, Tyler M, additional, Mathew, Rebecca, additional, Backus, Carey, additional, Kennedy, Domenick, additional, Chen, Angeline, additional, Longenecker, Kenton, additional, Klahn, Joseph, additional, Hrusch, Cara, additional, Krishnan, Navasona, additional, Hutchins, Charles W, additional, Aguado, Jacqueline, additional, Bulic, Marinka, additional, Tiwari, Payal, additional, Colvin, Kayla J, additional, Chuong, Cun Lan, additional, Kohnle, Ian C, additional, Rees, Matthew G, additional, Boghossian, Andrew, additional, Ronan, Melissa, additional, Roth, Jennifer A, additional, Wu, Meng-Ju, additional, Sen, Debattama R, additional, Griffin, Gabriel K, additional, El-Bardeesy, Nabeel, additional, Trusk, Patricia, additional, Sun, Meng, additional, Liu, Yue, additional, Decker, Joshua H, additional, Yang, Yi, additional, Fossey, Stacey, additional, Qiu, Wei, additional, Sun, Qi, additional, Paddock, Marcia N, additional, Farney, Elliot P, additional, Beauregard, Clay, additional, Frost, Jennifer M, additional, Yates, Kathleen B, additional, Kym, Philip R, additional, and Manguso, Robert T, additional

Published
2023
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5. Data from Venetoclax Increases Intratumoral Effector T Cells and Antitumor Efficacy in Combination with Immune Checkpoint Blockade

Author

Kohlhapp, Frederick J., primary, Haribhai, Dipica, primary, Mathew, Rebecca, primary, Duggan, Ryan, primary, Ellis, Paul A., primary, Wang, Rui, primary, Lasater, Elisabeth A., primary, Shi, Yan, primary, Dave, Nimita, primary, Riehm, Jacob J., primary, Robinson, Valerie A., primary, Do, An D., primary, Li, Yijin, primary, Orr, Christine J., primary, Sampath, Deepak, primary, Raval, Aparna, primary, Merchant, Mark, primary, Bhathena, Anahita, primary, Salem, Ahmed Hamed, primary, Hamel, Keith M., primary, Leverson, Joel D., primary, Donawho, Cherrie, primary, Pappano, William N., primary, and Uziel, Tamar, primary

Published
2023
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6. Supplementary Figures from Venetoclax Increases Intratumoral Effector T Cells and Antitumor Efficacy in Combination with Immune Checkpoint Blockade

Author

Kohlhapp, Frederick J., primary, Haribhai, Dipica, primary, Mathew, Rebecca, primary, Duggan, Ryan, primary, Ellis, Paul A., primary, Wang, Rui, primary, Lasater, Elisabeth A., primary, Shi, Yan, primary, Dave, Nimita, primary, Riehm, Jacob J., primary, Robinson, Valerie A., primary, Do, An D., primary, Li, Yijin, primary, Orr, Christine J., primary, Sampath, Deepak, primary, Raval, Aparna, primary, Merchant, Mark, primary, Bhathena, Anahita, primary, Salem, Ahmed Hamed, primary, Hamel, Keith M., primary, Leverson, Joel D., primary, Donawho, Cherrie, primary, Pappano, William N., primary, and Uziel, Tamar, primary

Published
2023
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7. Supplementary Data from Venetoclax Increases Intratumoral Effector T Cells and Antitumor Efficacy in Combination with Immune Checkpoint Blockade

Author

Kohlhapp, Frederick J., primary, Haribhai, Dipica, primary, Mathew, Rebecca, primary, Duggan, Ryan, primary, Ellis, Paul A., primary, Wang, Rui, primary, Lasater, Elisabeth A., primary, Shi, Yan, primary, Dave, Nimita, primary, Riehm, Jacob J., primary, Robinson, Valerie A., primary, Do, An D., primary, Li, Yijin, primary, Orr, Christine J., primary, Sampath, Deepak, primary, Raval, Aparna, primary, Merchant, Mark, primary, Bhathena, Anahita, primary, Salem, Ahmed Hamed, primary, Hamel, Keith M., primary, Leverson, Joel D., primary, Donawho, Cherrie, primary, Pappano, William N., primary, and Uziel, Tamar, primary

Published
2023
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8. Abstract A41: Small molecule inhibition of PTPN2/1 inflames the tumour microenvironment and unleashes potent CD8+ T cell immunity

Author

Ebrahimi-Nik, Hakimeh, primary, Iracheta-Vellve, Arvin, additional, Olander, Kira E., additional, Davis, Thomas R.G., additional, Kim, Sarah Y., additional, Yeary, Mitchell D., additional, Patti, James C., additional, Balon, Tyler M., additional, Avila, Omar Ismail, additional, Chuong, Cun Lan, additional, Wu, Meng-Ju, additional, Baumgartner, Christina K., additional, Hamel, Keith M., additional, McGuire, Kathleen A., additional, Mathew, Rebecca, additional, Backus, Carey, additional, Kohnle, Ian C., additional, Xiong, Zhaoming, additional, Farney, Elliot P., additional, Frost, Jennifer M., additional, Halvorsen, Geoff T., additional, Rees, Matthew, additional, Boghossian, Andrew, additional, Ronan, Melissa, additional, Roth, Jennifer A., additional, Golub, Todd R., additional, Griffin, Gabriel K., additional, El-Bardeesy, Nabeel, additional, Beauregard, Clay C., additional, Kym, Philip R., additional, Yates, Kathleen B., additional, and Manguso, Robert T., additional

Published
2022
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9. Abstract 606: Targeting the immune checkpoint PTPN2 with ABBV-CLS-484 inflames the tumor microenvironment and unleashes potent CD8+ T cell immunity

Author

Iracheta-Vellve, Arvin, primary, Ebrahimi-Nik, Hakimeh, additional, Davis, Thomas R., additional, Olander, Kira E., additional, Kim, Sarah Y., additional, Yeary, Mitchell D., additional, Patti, James C., additional, Kohnle, Ian C., additional, Baumgartner, Christina K., additional, Hamel, Keith M., additional, McGuire, Kathleen A., additional, Chuong, Cun Lan, additional, Xiong, Zhaoming, additional, Farney, Elliot P., additional, Frost, Jennifer M., additional, Rees, Matthew, additional, Boghossian, Andrew, additional, Ronan, Melissa, additional, Roth, Jennifer A., additional, Golub, Todd R., additional, Griffin, Gabriel K., additional, Beauregard, Clay, additional, Kym, Philip R., additional, Yates, Kathleen B., additional, and Manguso, Robert T., additional

Published
2022
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10. Abstract ND06: ABBV-CLS-484: An active site PTPN2/N1 inhibitor that augments the immune response and sensitizes tumors to immune-mediated killing

Author

Baumgartner, Christina K., primary, Paddock, Marcia N., additional, Frost, Jennifer M., additional, Hamel, Keith M., additional, McGuire, Kathleen A., additional, Halliwill, Kyle, additional, Xiong, Zhaoming, additional, Mu, Liang, additional, Klinge, Kelly, additional, Geda, Prasanthi, additional, Aguado, Jaqueline, additional, Bulic, Marinka, additional, Farney, Elliot P., additional, Yates, Kathleen B., additional, Manguso, Robert T., additional, Beauregard, Clay, additional, and Kym, Philip R., additional

Published
2022
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12. Venetoclax Increases Intratumoral Effector T Cells and Antitumor Efficacy in Combination with Immune Checkpoint Blockade

Author

Kohlhapp, Frederick J., primary, Haribhai, Dipica, additional, Mathew, Rebecca, additional, Duggan, Ryan, additional, Ellis, Paul A., additional, Wang, Rui, additional, Lasater, Elisabeth A., additional, Shi, Yan, additional, Dave, Nimita, additional, Riehm, Jacob J., additional, Robinson, Valerie A., additional, Do, An D., additional, Li, Yijin, additional, Orr, Christine J., additional, Sampath, Deepak, additional, Raval, Aparna, additional, Merchant, Mark, additional, Bhathena, Anahita, additional, Salem, Ahmed Hamed, additional, Hamel, Keith M., additional, Leverson, Joel D., additional, Donawho, Cherrie, additional, Pappano, William N., additional, and Uziel, Tamar, additional

Published
2021
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14. B7-H1 Promotes Germinal Center B cell Survival and Inhibits T cell Activation

Author

Hamel, Keith M., Cao, Yanxia, Wang, Yumei, Rodeghero, Rachel, Kobezda, Tamas, Chen, Lieping, and Finnegan, Alison

Subjects
Mice, Knockout, Mice, Inbred BALB C, Membrane Glycoproteins, Cell Survival, Interleukins, Plasma Cells, Programmed Cell Death 1 Receptor, Mice, SCID, Th1 Cells, Lymphocyte Activation, Antigens, Differentiation, Arthritis, Experimental, Article, B7-H1 Antigen, Arthritis, Rheumatoid, DNA-Binding Proteins, Mice, Gene Expression Regulation, Antibody Formation, B7-1 Antigen, Proto-Oncogene Proteins c-bcl-6, Animals, Peptides, Signal Transduction
Abstract

The immune system has developed several regulatory mechanisms to maintain homeostasis of adaptive immune responses. T-cell programmed death (PD)-1 recognition of B7-H1 (PD-L1) expressed on APC and non-lymphoid tissue regulates T-cell activation. We show that B7-H1(-/-) mice exhibit exacerbated proteoglycan (PG)-induced arthritis and increased Th-1 CD4(+) T-cell responses. Unexpectedly, the PG-specific antibody response in B7-H1(-/-) mice was diminished. A reduction in the number of peanut agglutinin(+) GC coincided with a decrease in CD19(+) GL-7(+) CD95(+) GC B cells that was a result of increased caspase-induced apoptosis. The percent of CD38(+) CD138(+) emerging plasma cells was decreased. B7-H1(-/-) mice exhibited an increased frequency of CD4(+) PD-1(hi) CXCR5(hi) ICOS(hi) CD62L(lo) T follicular helper cells that displayed a hyperactive phenotype with increased expression of mRNA transcripts for Bcl6, IL-21, and the apoptosis-inducer molecule FasL. In cell transfer of B7-H1(-/-) cells into SCID mice, non-B and non-T cells were sufficient to normalize the antibody response, T-cell hyperactivity, and the development of PG-induced arthritis. These findings indicate that B7-H1 on non-B and non-T cells signals through PD-1 on T effector cells to prevent excessive activation and reduce autoimmune arthritis. Furthermore, these findings demonstrate a novel role for B7-H1 expression in promoting B-cell survival by regulating the activation of T follicular helper cell.

Published
2010

23. Cover Picture: Eur. J. Immunol. 11/10

Author

Hamel, Keith M., primary, Cao, Yanxia, additional, Wang, Yumei, additional, Rodeghero, Rachel, additional, Kobezda, Tamas, additional, Chen, Lieping, additional, and Finnegan, Alison, additional

Published
2010
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29. IFN-gamma regulates the requirement for IL-17 in proteoglycan-induced arthritis.

Author

Doodes PD, Cao Y, Hamel KM, Wang Y, Rodeghero RL, Mikecz K, Glant TT, Iwakura Y, and Finnegan A

Subjects
Animals, Arthritis, Experimental pathology, Arthritis, Experimental prevention & control, Arthritis, Rheumatoid immunology, Arthritis, Rheumatoid pathology, Arthritis, Rheumatoid prevention & control, Cells, Cultured, Female, Humans, Inflammation Mediators antagonists & inhibitors, Inflammation Mediators metabolism, Interferon-gamma antagonists & inhibitors, Interferon-gamma deficiency, Interleukin-17 biosynthesis, Interleukin-17 deficiency, Mice, Mice, Inbred BALB C, Mice, Knockout, Proteoglycans administration & dosage, T-Lymphocytes, Helper-Inducer immunology, T-Lymphocytes, Helper-Inducer metabolism, Arthritis, Experimental immunology, Inflammation Mediators physiology, Interferon-gamma physiology, Interleukin-17 physiology, Proteoglycans immunology
Abstract

The contribution of the proinflammatory cytokines IFN-gamma and IL-17 to the pathogenesis of experimental arthritis is controversial. In proteoglycan (PG)-induced arthritis (PGIA), severe arthritis is dependent on the production of IFN-gamma, whereas IL-17 is dispensable. In collagen-induced arthritis and Ag-induced arthritis, although high levels of IFN-gamma are secreted, disease is exacerbated in IFN-gamma or IFN-gamma receptor-deficient mice due to the ability of IFN-gamma to suppress IL-17 expression. In the current study, we investigated the effect of IFN-gamma on the IL-17 response and its consequences in PGIA. In PG-immunized IFN-gamma(-/-) mice, despite reduction in arthritis, the PG-specific CD4(+) T cell IL-17 response was significantly increased. Elevated IL-17 contributed to development of arthritis, as disease in IFN-gamma/IL-17(-/-) was significantly reduced in comparison with either IFN-gamma(-/-) or IL-17(-/-) mice. A contribution of IFN-gamma and IL-17 to the development of arthritis was also identified in T-bet(-/-) mice. PG-specific CD4(+) T cells from T-bet(-/-) mice produced reduced IFN-gamma and elevated concentrations of IL-17. Both IFN-gamma and IL-17 contribute to arthritis, as T-bet(-/-) mice lacking IL-17 (T-bet/IL-17(-/-)) were resistant, whereas wild-type, T-bet(-/-), and IL-17(-/-) mice were susceptible to PGIA. T cell proliferation and autoantibody production did not correlate with development of disease; however, expression of cytokines and chemokines in joint tissues demonstrate that IFN-gamma and IL-17 cooperatively contribute to inflammation. These results demonstrate that both IFN-gamma and IL-17 have the potential to induce PGIA, but it is the strength of the IFN-gamma response that regulates the contribution of each of these Th effector cytokines to disease.

Published
2010
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30. Expression of CD80/86 on B cells is essential for autoreactive T cell activation and the development of arthritis.

Author

O'Neill SK, Cao Y, Hamel KM, Doodes PD, Hutas G, and Finnegan A

Subjects
Animals, Arthritis, Rheumatoid genetics, Autoantibodies biosynthesis, B7-1 Antigen genetics, B7-1 Antigen physiology, B7-2 Antigen genetics, B7-2 Antigen physiology, Female, Immunity, Innate genetics, Lymphocyte Activation genetics, Mice, Mice, Inbred BALB C, Mice, Knockout, Mice, SCID, Proteoglycans administration & dosage, Proteoglycans immunology, Radiation Chimera, T-Lymphocyte Subsets metabolism, T-Lymphocyte Subsets transplantation, Arthritis, Rheumatoid immunology, Autoantigens immunology, B-Lymphocyte Subsets immunology, B-Lymphocyte Subsets metabolism, B7-1 Antigen biosynthesis, B7-2 Antigen biosynthesis, Lymphocyte Activation immunology, T-Lymphocyte Subsets immunology
Abstract

Depletion of B cells in rheumatoid arthritis is therapeutically efficacious. Yet, the mechanism by which B cells participate in the inflammatory process is unclear. We previously demonstrated that Ag-specific B cells have two important functions in the development of arthritis in a murine model of rheumatoid arthritis, proteoglycan (PG)-induced arthritis (PGIA). PG-specific B cells function as autoantibody-producing cells and as APCs that activate PG-specific T cells. Moreover, the costimulatory molecule CD86 is up-regulated on PG-specific B cells in response to stimulation with PG. To address the requirement for CD80/CD86 expression on B cells in the development of PGIA, we generated mixed bone marrow chimeras in which CD80/CD86 is specifically deleted on B cells and not on other APC populations. Chimeras with a specific deficiency in CD80/CD86 expression on B cells are resistant to the induction of PGIA. The concentration of PG-specific autoantibody is similar in mice sufficient or deficient for CD80/86-expressing B cells, which indicates that resistance to PGIA is not due to the suppression of PG-specific autoantibody production. CD80/86-deficient B cells failed to effectively activate PG-specific autoreactive T cells as indicated by the failure of T cells from PG-immunized CD80/86-deficient B cell chimeras to transfer arthritis into SCID mice. In vitro secondary recall responses to PG are also dependent on CD80/86-expressing B cells. These results demonstrate that a CD80/86:CD28 costimulatory interaction between B cells and T cells is required for autoreactive T cell activation and the induction of arthritis but not for B cell autoantibody production.

Published
2007
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