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Frontiers of Medicine ; (4): 1170-1185, 2023.
Article in English | WPRIM | ID: wpr-1010819


OX40 is a costimulatory receptor that is expressed primarily on activated CD4+, CD8+, and regulatory T cells. The ligation of OX40 to its sole ligand OX40L potentiates T cell expansion, differentiation, and activation and also promotes dendritic cells to mature to enhance their cytokine production. Therefore, the use of agonistic anti-OX40 antibodies for cancer immunotherapy has gained great interest. However, most of the agonistic anti-OX40 antibodies in the clinic are OX40L-competitive and show limited efficacy. Here, we discovered that BGB-A445, a non-ligand-competitive agonistic anti-OX40 antibody currently under clinical investigation, induced optimal T cell activation without impairing dendritic cell function. In addition, BGB-A445 dose-dependently and significantly depleted regulatory T cells in vitro and in vivo via antibody-dependent cellular cytotoxicity. In the MC38 syngeneic model established in humanized OX40 knock-in mice, BGB-A445 demonstrated robust and dose-dependent antitumor efficacy, whereas the ligand-competitive anti-OX40 antibody showed antitumor efficacy characterized by a hook effect. Furthermore, BGB-A445 demonstrated a strong combination antitumor effect with an anti-PD-1 antibody. Taken together, our findings show that BGB-A445, which does not block OX40-OX40L interaction in contrast to clinical-stage anti-OX40 antibodies, shows superior immune-stimulating effects and antitumor efficacy and thus warrants further clinical investigation.

Mice , Animals , Receptors, Tumor Necrosis Factor/physiology , Receptors, OX40 , Membrane Glycoproteins , Ligands , Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/pharmacology
Article in Chinese | WPRIM | ID: wpr-475445


Objective To prepare a recombinant pneumococcal surface protein A clade 4 ( PspA4) and to analyze its immunogenicity.Methods The gene encoding PspA4 protein was synthesized and inserted into pET-20b to construct the recombinant expression plasmid.The transformed E.coli strains carrying expression plasmid were induced to express PspA4 protein.ELISA was performed to analyze the ti-ters of PspA4-specific IgG in a mouse model.Results The recombinant PspA4 protein of high purity ( 90%) was successfully prepared.The titers of PspA4-specific antibody in mice received PspA4 immuniza-tion were 106 times higher than those of the blank control group, suggesting that the expressed PspA4 protein had the advantage of high immunogenicity.Conclusion This study suggested that the PspA4 protein might be used as one of the candidate protein for the development of pneumovax and laid a foundation for further in-vestigation on pneumococcal protein based vaccine.