دورية أكاديمية
Therapeutically targeting type I interferon directly to XCR1+ dendritic cells reveals the role of cDC1s in anti-drug antibodies.
العنوان: | Therapeutically targeting type I interferon directly to XCR1+ dendritic cells reveals the role of cDC1s in anti-drug antibodies. |
---|---|
المؤلفون: | Noe, Paul, Wang, Joy H., Kyu Chung, Zhiyong Cheng, Field, Jessica J., Xiaomeng Shen, Casey, Stephanie C., Cortesio, Christa L., Pastuskovas, Cinthia V., Hyewon Phee, Tarbell, Kristin V., Egen, Jackson G., Casbon, Amy-Jo |
المصدر: | Frontiers in Immunology; 2024, p1-16, 16p |
مصطلحات موضوعية: | TYPE I interferons, DENDRITIC cells, IMMUNOGLOBULINS, CHIMERIC proteins, ANTINEOPLASTIC agents, GENE targeting |
مستخلص: | Conventional type 1 dendritic cells (cDC1s) are superior in antigen crosspresentation and priming CD8+ T cell anti-tumor immunity and thus, are a target of high interest for cancer immunotherapy. Type I interferon (IFN) is a potent inducer of antigen cross-presentation, but, unfortunately, shows only modest results in the clinic given the short half-life and high toxicity of current type I IFN therapies, which limit IFN exposure in the tumor. CD8+ T cell immunity is dependent on IFN signaling in cDC1s and preclinical studies suggest targeting IFN directly to cDC1s may be sufficient to drive anti-tumor immunity. Here, we engineered an anti-XCR1 antibody (Ab) and IFN mutein (IFNmut) fusion protein (XCR1Ab-IFNmut) to determine whether systemic delivery could drive selective and sustained type I IFN signaling in cDC1s leading to anti-tumor activity and, in parallel, reduced systemic toxicity. We found that the XCR1Ab-IFNmut fusion specifically enhanced cDC1 activation in the tumor and spleen compared to an untargeted control IFN. However, multiple treatments with the XCR1Ab-IFNmut fusion resulted in robust anti-drug antibodies (ADA) and loss of drug exposure. Using other cDC1-targeting Ab-IFNmut fusions, we found that localizing IFN directly to cDC1s activates their ability to promote ADA responses, regardless of the cDC1 targeting antigen. The development of ADA remains a major hurdle in immunotherapy drug development and the cellular and molecular mechanisms governing the development of ADA responses in humans is not well understood. Our results reveal a role of cDC1s in ADA generation and highlight the potential ADA challenges with targeting immunostimulatory agents to this cellular compartment. [ABSTRACT FROM AUTHOR] |
Copyright of Frontiers in Immunology is the property of Frontiers Media S.A. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
قاعدة البيانات: | Complementary Index |
كن أول من يترك تعليقا!