RG-6333 is a bispecific agonist targeting CD19 and CD28. It specifically identifies and binds to the CD19 antigen present on the surface of malignant B cells, effectively targeting tumor cells. By engaging with CD28, RG-6333 activates T cells, overcoming activation barriers and boosting antitumor immunity. RG-6333 is applicable for research in relapsed/refractory non-Hodgkin lymphoma.

RG-6333 (RO 7443904) exhibits a low affinity for CD28 in CHO cells (K d : 36 nM), resulting in weak binding that is nonetheless sufficient to deliver a costimulatory signal. In human peripheral blood mononuclear cells (PBMC), RG-6333 is inactive on its own and only activates T cells when the T cell receptor (TCR) is engaged.

RG-6333 at a dose of 1.10 mg/kg, administered intravenously as a single dose, selectively activates T cells in humanized NSG mice only when T cell receptor (TCR) signaling is present, without inducing a cytokine storm. When administered at 1 mg/kg intravenously once, RG-6333, in combination with Glofitamab (0.15 mg/kg), significantly inhibits tumor growth and increases tumor-infiltrating CD8+ T cells in humanized NSG mice carrying subcutaneous NALM-6 lymphomas. In a model of aggressive diffuse large B-cell lymphoma (DLBCL WSU-DLCL2-Fluc) in humanized mice, administering RG-6333 at 1 mg/kg intravenously three times alongside Glofitamab (0.15 mg/kg) leads to complete tumor regression, with initial transient weight loss due to T cell activation, which subsequently recovers. Additionally, in humanized NSG mice bearing subcutaneous OCI-Ly18 tumors, a treatment regimen of RG-6333 (1 mg/kg, i.v. three times) with Glofitamab (0.15 mg/kg) enhances pro-inflammatory T cell characteristics within the tumor and facilitates transendothelial migration. Moreover, the inclusion of CD19–4-1BBL in a triple combination therapy intensifies and prolongs the in vivo antitumor response.