1. Mobilization of innate and adaptive antitumor immune responses by the RNP-targeting antibody ATRC-101
- Author
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Alexander Scholz, Jeff DeFalco, Yvonne Leung, Iraz T. Aydin, Cathrin J. Czupalla, Wei Cao, Daniel Santos, Nikhil Vad, Shaun M. Lippow, Gilson Baia, Michael Harbell, Judevin Sapugay, Danhui Zhang, Dai-Chen Wu, Erin Wechsler, Anne Z. Ye, Jenny W. Wu, Xiao Peng, John Vivian, Hargita Kaplan, Rodney Collins, Ngan Nguyen, Mark Whidden, Dongkyoon Kim, Carl Millward, Jonathan Benjamin, Norman M. Greenberg, Tito A. Serafini, Daniel E. Emerling, Lawrence Steinman, William H. Robinson, and Amy Manning-Bog more...
- Subjects
Mice ,Lung Neoplasms ,Multidisciplinary ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Neoplasms ,Animals ,Humans ,Antineoplastic Agents ,Adaptive Immunity ,Immunity, Innate - Abstract
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. more...
- Published
- 2022
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