Heralding HERA-CD27L

 

“Many key immune stimulatory proteins belong to the tumor necrosis factor superfamily (TNFSF) and their cognate receptors, the TNF receptor superfamily (TNFRSF). These important target receptors include CD27, GITR, OX40, 4-1BB, CD40, and HVEM,” notes Dr. David Richards, head of immunology at Apogenix. “Although many companies have been trying (and failing) to stimulate these receptors for over a decade, the field is only recently beginning to accept that antibodies are not the correct tool to stimulate the TNFRSF. Due to the dependency on a stabilized trimeric receptor complex for signaling, it is clear that flexible bivalent antibodies are not able to act as TNFRSF agonists.”

 

“Recently, multiple companies have started to explore the HERA ligand-based drug design pioneered by Apogenix,” he continues. “This shift shows promise and suggests that we might finally bring a stimulatory immunotherapy drug to the market to join the checkpoint inhibitors. HERA-CD27L is a promising development candidate that has been generated using our HERA-ligand technology platform.”

 

HERA-CD27L was generated using the Apogenix single-chain TNFSF technology, which is designed in a way that resembles the natural TNFSF receptor-binding domain, the company says. HERA-CD27L has a double trivalent, or hexavalent, structure composed of two single-chain receptor-binding-domain modules linked together with an IgG1-Fc domain, which has been silenced to prevent Fc-receptor binding, and according to Richards: “This double trivalent, or hexavalent, structure has been shown to cluster a sufficient number of TNFRSF molecules in the correctly stabilized conformation to produce biological activity.”

 

He adds that HERA-CD27L is a true TNFRSF agonist that provides a co-stimulatory signal in combination with a T cell receptor (TCR)-specific signal—together with the TCR signal, HERA-CD27L acts to boost specific T cell activation, proliferation and differentiation.

 

The strong antitumor efficacy of HERA-CD27L was demonstrated in two different tumor models—MC38-CEA and CT26wt—as noted by the Frontiers in Oncology paper. HERA-CD27L treatment boosted specific T cell activity, while having no effect on regulatory T cell activity or survival. This could be an advantage over other strategies in development, which have reportedly been shown to lead to serious immune-related adverse events due to their ill-defined mechanisms of action.

 

HERA-CD27L has also shown significantly enhanced activity compared to a clinical benchmark anti-CD27 antibody. When asked how how HERA-CD27L differs from other antibodies that also target immune cells, Richards says, “Although HERA-CD27L is roughly the same size as an antibody and contains a mutated human IgG1 domain as a scaffold, it is a fusion protein containing two sets of three CD27-binding domains. The most important difference is that antibodies have only two receptor-binding sites per molecule while HERA-CD27L has six.”

 

“Anti-CD27 antibodies in development are not CD27 agonists. In the manuscript, we compare treatment with HERA-CD27L to a clinical benchmark antibody. Treatment with the bivalent clinical benchmark antibody significantly reduced the proliferation of stimulated T cells. In addition, this benchmark antibody failed to induce CD27-mediated signaling activity at a wide range of concentrations,” he continues.

 

“Finally, antibodies have a functional Fc-receptor binding domain, while the IgG1 scaffold domain in HERA-CD27L has been mutated to prevent Fc-receptor binding. Fc receptor binding leads to depletion of target cells and other immune-related adverse events seen with antibody-based therapies.”

 

The combination of HERA-CD27L with an anti-PD-1 antibody revealed additive anti-tumor effects, highlighting the importance of both T cell co-stimulation and checkpoint inhibition in anti-tumor immunity.

 

“HERA-CD27L treatment stimulates T cell responses. Therefore, combination with checkpoint inhibitors and strategies that provide additional antigen-specific T cell populations (such as radiation therapy, chemotherapy, vaccination or CAR T cells) would make sense. In fact, we show in the manuscript an additive benefit of using HERA-CD27L together with PD-1 inhibition in a preclinical tumor model,” Richards adds.

 

“Strategies to enhance the antitumor immune response have tremendous potential and are considered the future of cancer therapy,” according to Dr. Harald Fricke, chief medical officer of Apogenix. “Apogenix has developed the proprietary HERA-ligand technology platform to generate potent tumor necrosis factor superfamily (TNFSF) receptor agonists that play a crucial role in the regulation of the immune response. These agonists overcome the significant limitations of antibody-based approaches by inducing optimal assembly of the TNFSF receptors.”

 

“We have recently completed the generation of a research cell bank for our lead candidate. We are now ready for GMP process development,” mentions Richards. “The development of a robust CMC process together with the respective preclinical IND-enabling studies will be the next essential developmental steps towards clinical trials.”

 

“CD27 is an important target due to its unique role in both initiating as well as maintaining T cell responses,” Fricke added. “We are in the process of evaluating the antitumor efficacy of additional HERA-ligands in a variety of preclinical studies and look forward to advancing them to the next stage.”