Antibody conjugates for targeted delivery of Toll-like receptor 9 agonist to the tumor tissue.

Autor: Corogeanu D; National Institute for Biological Standards and Control (NIBSC), Biotherapeutics Division, Medicines and Healthcare products Regulatory Agency, Potters Bar, United Kingdom., Zaki K; National Institute for Biological Standards and Control (NIBSC), Advanced Therapies Division, Medicines and Healthcare products Regulatory Agency, Potters Bar, United Kingdom., Beavil AJ; King's College London, School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy's Hospital, London, United Kingdom., Arnold JN; King's College London, School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, Guy's Hospital, London, United Kingdom., Diebold SS; National Institute for Biological Standards and Control (NIBSC), Biotherapeutics Division, Medicines and Healthcare products Regulatory Agency, Potters Bar, United Kingdom.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2023 Mar 13; Vol. 18 (3), pp. e0282831. Date of Electronic Publication: 2023 Mar 13 (Print Publication: 2023).
DOI: 10.1371/journal.pone.0282831
Abstrakt: Imiquimod, a Toll-like receptor 7 (TLR7) agonist is routinely used for topical administration in basal cell carcinoma and stage zero melanoma. Similarly, the TLR agonist Bacillus Calmette-Guérin is used for the local treatment of bladder cancer and clinical trials showed treatment efficacy of intratumoral injections with TLR9 agonists. However, when administered systemically, endosomal TLR agonists cause adverse responses due to broad immune activation. Hence, strategies for targeted delivery of TLR agonists to the tumor tissue are needed to enable the widespread use of endosomal TLR agonists in the context of tumor immunotherapy. One strategy for targeted delivery of TLR agonist is their conjugation to tumor antigen-specific therapeutic antibodies. Such antibody-TLR agonist conjugates act synergistically by inducing local TLR-mediated innate immune activation which complements the anti-tumor immune mechanisms induced by the therapeutic antibody. In this study, we explored different conjugation strategies for TLR9 agonists to immunoglobulin G (IgG). We evaluated biochemical conjugation of immunostimulatory CpG oligodesoxyribonucleotides (ODN) to the HER2-specific therapeutic antibody Trastuzumab with different cross-linkers comparing stochastic with site-specific conjugation. The physiochemical make-up and biological activities of the generated Trastuzumab-ODN conjugates were characterized in vitro and demonstrated that site-specific conjugation of CpG ODN is crucial for maintaining the antigen-binding capabilities of Trastuzumab. Furthermore, site-specific conjugate was effective in promoting anti-tumor immune responses in vivo in a pseudo-metastasis mouse model with engineered human HER2-transgenic tumor cells. In this in vivo model, co-delivery of Trastuzumab and CpG ODN in form of site-specific conjugates was superior to co-injection of unconjugated Trastuzumab, CpG ODN or stochastic conjugate in promoting T cell activation and expansion. Thereby, this study highlights that site-specific conjugation of CpG ODN to therapeutic antibodies targeting tumor markers is a feasible and more reliable approach for generation of conjugates which retain and combine the functional properties of the adjuvant and the antibody.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2023 Corogeanu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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