Development and application of an in vitro assay to assess target-independent B-cell activation by targeted TLR7 immune agonists

Targeted immune agonist (TIA) comprising a TLR7 agonist conjugated to tumor-targeting antibodies have been shown to induce potent anti-tumor responses in various preclinical models. However, the clinical proof-of-concept of a TIA has been hampered by systemic dose-limiting immune-related toxicities,...

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Veröffentlicht in:Journal of immunological methods 2023-11, Vol.522, p.113553-113553, Article 113553
Hauptverfasser: Chen, Ying, Zhou, Siqun, Pradhan, Komal, Chernyak, Natalia, Kofman, Esther, Zhang, Fan, Kim, Sang Yeop, Seghezzi, Wolfgang, Willingham, Aarron, Seganish, W. Michael, Bhagwat, Bhagyashree, Han, Jin-Hwan
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Sprache:eng
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Zusammenfassung:Targeted immune agonist (TIA) comprising a TLR7 agonist conjugated to tumor-targeting antibodies have been shown to induce potent anti-tumor responses in various preclinical models. However, the clinical proof-of-concept of a TIA has been hampered by systemic dose-limiting immune-related toxicities, including rapid induction of anti-drug antibodies in patients. We have developed ELISPOT-based assay to measure activation of antibody-secreting cells (ASCs), intended to simulate the interaction between TIA and peripheral B cells as a tool to pre-clinically de-risk tumor target-independent peripheral B-cell activation by TIA. This method has proven to be robust and has fast turn-around time to evaluate the induction of spontaneous B-cell activation by TIA in a tumor target- and FcγR-independent manner. This novel ASC assay platform may serve as a preclinical tool to de-risk TIAs that can potentially induce immune-related adverse effects in the clinic.
ISSN:0022-1759
1872-7905
DOI:10.1016/j.jim.2023.113553