Roche Advances FAP-CD40 Bispecific Antibody RO7300490 into Phase I Clinical Trial, Discontinues Selicrelumab Development

By | Shi Bei

Recently, Roche disclosed its latest pipeline in its semi-annual report. Its FAP-CD40-targeting bispecific antibody RG6189 (RO7300490) has entered Phase I clinical trials, while the non-selective CD40 agonist selicrelumab has been discontinued from the pipeline.

The CD40 receptor on antigen-presenting cells (APCs) plays a critical role in regulating immune responses and triggering adaptive immune responses. Owing to their ability to enhance dendritic cell (DC) activation and the subsequent priming of tumor-specific T cells, CD40 agonists have established this target as highly promising in cancer immunotherapy (CIT).

However, the widespread expression of CD40 leads to dose-limiting adverse events, such as cytokine release syndrome (CRS) and hepatotoxicity. Additionally, the extensive expression of CD40 receptors on hematopoietic and non-hematopoietic cells induces a sink effect, causing agonistic anti-CD40 molecules to exhibit a very short serum half-life, thereby limiting the therapeutic efficacy of CD40 antibodies. If CD40 agonism could be selectively targeted to tumor cells, these limitations could be overcome.

Therefore, researchers at Roche have developed RO7300490, a bispecific FAP-CD40 antibody that induces CD40 agonistic activity only in the presence of fibroblast activation protein α (FAP), a protease specifically expressed in the tumor stroma. The preclinical research data for this product have been published in the journal Clinical Cancer Research.

This bispecific antibody is a fully human IgG1 bispecific antibody containing two CD40 Fv domains.

In vitro studies demonstrated that RO7300490 triggered effective FAP-dependent APC activation and DC activation, leading to enhanced T cell priming.

Among 10 hud40tg mice bearing MC38-FAP tumors, 8 exhibited rapid tumor regression in the high-dose FAP-huCD40 bispecific antibody group (13.3 mg/kg), whereas selicrelumab at an equivalent dose demonstrated only mild tumor inhibition.

Furthermore, studies have demonstrated that the FAP-CD40 bispecific antibody induces tumor growth inhibition in pancreatic tumor models characterized by low infiltration and abundant stromal FAP expression.

In terms of safety, the high-dose FAP-CD40 bispecific antibody group was well tolerated in cynomolgus monkeys and did not induce CD40-related toxicity.