| Autor: |
Scholz, Alexander, DeFalco, Jeff, Yvonne Leung, Aydin, Iraz T., Czupalla, Cathrin J., Wei Cao, Santos, Daniel, Vad, Nikhil, Lippow, Shaun M., Baia, Gilson, Harbell, Michael, Sapugay, Judevin, Danhui Zhang, Dai-Chen Wu, Wechsler, Erin, Ye, Anne Z., Wu, Jenny W., Xiao Peng, Vivian, John, Kaplan, Hargita |
| Předmět: |
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| Zdroj: |
Proceedings of the National Academy of Sciences of the United States of America; 5/10/2022, Vol. 119 Issue 19, p1-19, 28p |
| Abstrakt: |
Immunotherapy approaches focusing on T cells have provided breakthroughs in treating solid tumors. However, there remains an opportunity to drive anticancer immune responses via other cell types, particularly myeloid cells. ATRC-101 was identified via a target-agnostic process evaluating antibodies produced by the plasmablast population of B cells in a patient with non-small cell lung cancer experiencing an antitumor immune response during treatment with checkpoint inhibitor therapy. Here, we describe the target, antitumor activity in preclinical models, and data supporting a mechanism of action of ATRC-101. Immunohistochemistry studies demonstrated tumor-selective binding of ATRC-101 to multiple nonautologous tumor tissues. In biochemical analyses, ATRC-101 appears to target an extracellular, tumor-specific ribonucleoprotein (RNP) complex. In syngeneic murine models, ATRC-101 demonstrated robust antitumor activity and evidence of immune memory following rechallenge of cured mice with fresh tumor cells. ATRC-101 increased the relative abundance of conventional dendritic cell (cDC) type 1 cells in the blood within 24 h of dosing, increased CD8+ T cells and natural killer cells in blood and tumor over time, decreased cDC type 2 cells in the blood, and decreased monocytic myeloid-derived suppressor cells in the tumor. Cellular stress, including that induced by chemotherapy, increased the amount of ATRC-101 target in tumor cells, and ATRC-101 combined with doxorubicin enhanced efficacy compared with either agent alone. Taken together, these data demonstrate that ATRC- 101 drives tumor destruction in preclinical models by targeting a tumor-specific RNP complex leading to activation of innate and adaptive immune responses. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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