Of antigens and antitumor effects

As the company notes, HERA-CD40L—in contrast to antibodies—does not depend on Fcγ receptor-mediated crosslinking for activity, adding, “As the first pure CD40 receptor agonist with a well-defined mechanism of action, HERA-CD40L is not restrained by dose-limiting toxicities observed with anti-CD40 antibodies.”

According to Apogenix, the strong antitumor efficacy of HERA-CD40L was demonstrated in multiple in-vitro and in-vivo tumor models. In the case of the former, comprehensive in-vitro analysis of the mechanism of action revealed that HERA-CD40L induced the development of pro-inflammatory antigen-presenting cells, including B cells, macrophages and dendritic cells. Specifically, HERA-CD40L promoted a shift in the balance from tumor-promoting (M2-type) macrophages to antitumor (M1-type) macrophages.

As explained in the company news release about the published data, “The potent antigen-specific activation of T cells by HERA-CD40L-treated macrophages led to an immune response specifically directed against the tumor. This is an important advantage over numerous other immunotherapeutic approaches that often cause serious side effects due to non-specific activation of the immune system.”

The company maintains that HERA-CD40L “is perfectly suitable for standard large-scale production processes,” and says that its mechanism of action as a central mediator of T cell activation and co-stimulation “predestines” this molecule for combination therapies, such as adding it along with radiotherapy or checkpoint inhibitors.

“HERA-CD40L is a novel TNF [tumor necrosis factor] superfamily receptor agonist based on our proprietary HERA-ligand technology platform that has demonstrated a strong antitumor efficacy in preclinical tumor models,” said Dr. Harald Fricke, chief medical officer of Apogenix. “CD40 is a key target because it has a unique role in initiating an antigen-specific immune response against tumors. We will continue to apply our HERA-ligand technology to address other TNF superfamily receptors that play a critical role in the antitumor immune response and evaluate the synergistic potential of these development candidates in combination with traditional cancer therapies as well as other immuno-oncology therapeutics.”

The news of HERA-CD40L came a little more than a week on the heels of some other published preclinical efficacy data, this time with regard to HERA-CD27L. In that preclinical work, which appeared in Frontiers in Oncology, the company says that it has demonstrated the potent antitumor efficacy of HERA-CD27L in two different tumor models.

As with HERA-CD40L, Apogenix touts the distinction of HERA-CD27L compared to antibodies against cancer that are currently in development, saying that “HERA-CD27L is the first true CD27 receptor agonist with a well-defined mode of action that acts directly on immune cells, thereby enhancing their antitumor immunity.”

In the Frontiers of Oncology paper, data indicate that HERA-CD27L treatment boosted specific T cell activity while having no effect on regulatory T cell activity or survival, which Apogenix says “is a great advantage over other strategies in development, which have been shown to lead to serious immune-related adverse events due to their ill-defined mechanisms of action.”

The company also noted that HERA-CD27L has shown significantly enhanced activity compared to a clinical benchmark anti-CD27 antibody and that combining HERA-CD27L with an anti-PD-1 antibody revealed additive antitumor effects, highlighting the importance of both T cell co-stimulation and checkpoint inhibition in antitumor immunity.

Apogenix has developed a proprietary technology platform for the construction of novel hexavalent TNF superfamily receptor agonists (HERA-ligands). By stimulating different TNF signaling pathways, these HERA-ligands can increase the antitumor immune response. The specific molecular structure of Apogenix’s HERA-ligands induces a well-defined clustering of functional TNF receptors on the surface of target immune cells. In contrast to agonistic antibodies, Apogenix’s fusion proteins are pure agonists whose potent signaling capacity is independent of secondary Fcγ receptor-mediated cross-linking. In addition, HERA-ligands reportedly cause neither antibody-dependent cellular cytotoxicity nor complement-dependent cytotoxicity and exhibit a shorter half-life than antibodies. It is therefore expected that HERA-ligands will cause fewer side effects in clinical development.

The company has built what it calls “a promising pipeline” of immuno-oncology drug candidates that target TNF superfamily-dependent signaling pathways, thereby restoring the immune response against tumors. Checkpoint inhibitor asunercept, the company’s lead immuno-oncology candidate, is in late-stage clinical development. In 2017, asunercept received PRIME (PRIority MEdicines) designation by the European Medicines Agency for the treatment of glioblastoma. Based on its proprietary technology platform for HERA-ligands, Apogenix is developing CD40, CD27, GITR, HVEM, 4-1BB and OX40 receptor agonists for cancer immunotherapy.