Article ; Online: Bispecific antibodies targeting CD40 and tumor-associated antigens promote cross-priming of T cells resulting in an antitumor response superior to monospecific antibodies.
Journal for immunotherapy of cancer
2022 Volume 10, Issue 11
Abstract: Background: Indications with poor T-cell infiltration or deficiencies in T-cell priming and associated unresponsiveness to established immunotherapies represent an unmet medical need in oncology. CD40-targeting therapies designed to enhance antigen ... ...
| Abstract | Background: Indications with poor T-cell infiltration or deficiencies in T-cell priming and associated unresponsiveness to established immunotherapies represent an unmet medical need in oncology. CD40-targeting therapies designed to enhance antigen presentation, generate new tumor-specific T cells, and activate tumor-infiltrating myeloid cells to remodel the tumor microenvironment, represent a promising opportunity to meet this need. In this study, we present the first in vivo data supporting a role for tumor-associated antigen (TAA)-mediated uptake and cross-presentation of tumor antigens to enhance tumor-specific T-cell priming using CD40×TAA bispecific antibodies, a concept we named Neo-X-Prime. Methods: Bispecific antibodies targeting CD40 and either of two cell-surface expressed TAA, carcinoembryonic antigen-related cell adhesion molecule 5 (CEA) or epithelial cell adhesion molecule (EpCAM), were developed in a tetravalent format. TAA-conditional CD40 agonism, activation of tumor-infiltrating immune cells, antitumor efficacy and the role of delivery of tumor-derived material such as extracellular vesicles, tumor debris and exosomes by the CD40×TAA bispecific antibodies were demonstrated in vitro using primary human and murine cells and in vivo using human CD40 transgenic mice with different tumor models. Results: The results showed that the CD40×TAA bispecific antibodies induced TAA-conditional CD40 activation both in vitro and in vivo. Further, it was demonstrated in vitro that they induced clustering of tumor debris and CD40-expressing cells in a dose-dependent manner and superior T-cell priming when added to dendritic cells (DC), ovalbumin (OVA)-specific T cells and OVA-containing tumor debris or exosomes. The antitumor activity of the Neo-X-Prime bispecific antibodies was demonstrated to be significantly superior to the monospecific CD40 antibody, and the resulting T-cell dependent antitumor immunity was directed to tumor antigens other than the TAA used for targeting (EpCAM). Conclusions: The data presented herein support the hypothesis that CD40×TAA bispecific antibodies can engage tumor-derived vesicles containing tumor neoantigens to myeloid cells such as DCs resulting in an improved DC-mediated cross-priming of tumor-specific CD8 |
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| MeSH term(s) | Humans ; Mice ; Animals ; Cross-Priming ; Antibodies, Bispecific/pharmacology ; Antibodies, Bispecific/therapeutic use ; CD8-Positive T-Lymphocytes ; Epithelial Cell Adhesion Molecule/metabolism ; Dendritic Cells ; CD40 Antigens/metabolism ; Antigens, Neoplasm |
| Chemical Substances | Antibodies, Bispecific ; Epithelial Cell Adhesion Molecule ; CD40 Antigens ; Antigens, Neoplasm |
| Language | English |
| Publishing date | 2022-11-02 |
| Publishing country | England |
| Document type | Journal Article |
| ZDB-ID | 2719863-7 |
| ISSN | 2051-1426 ; 2051-1426 |
| ISSN (online) | 2051-1426 |
| ISSN | 2051-1426 |
| DOI | 10.1136/jitc-2022-005018 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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