Apogenix targets cancer with TNFSF therapeutics

November 2, 2015 ctheodoropulos

Apogenix was active in immuno-oncology before the term became fashionable. Focused on oncology, it is developing TNFSF (tumor necrosis factor superfamily) therapeutics to modulate the immune response, thereby, restoring the immune system’s anti-tumor capabilities.

“We are building molecules that either activate or inhibit the TNFSF members,” Jürgen Gamer, PhD, VP business development, elaborated. These innovative protein formats target TNFSF receptors that play critical roles in regulating the immune response.

Juergen Gamer, Jürgen Gamer, Ph.D., VP business development, Apogenix

Jürgen Gamer, PhD, VP Business Development, Apogenix

 

 

 

 

 

 

 

 

 

Why target TNF signaling

“The hallmark of TNF signaling is trimerization of the receptors on the cell surface. Activation is directly proportional to the amount of multimerization the more multimerization, the more signal induction.”

There are several ways to address TNF signal activation. Proteins structurally related to the respective endogenous ligands (natural ligands) and antibodies are the obvious approaches, but not necessarily the most effective. “Natural ligands are low molecular weight trimers that have a short half-life and disappear in the body quicklyusually within a couple of hours. As an alternative, antibodies have a longer half-life but, based on their bivalent binding mode, can only associate with two receptor chains. Therefore, they have low multimerization capacity,” Gamer said. This limited multimerization capacity in most cases only can be overcome by further cross-linking by, for example, anti Fc antibodies or Fcγ receptors.

When Apogenix decided to modulate TNFSF signaling pathways to target tumors, it was clear that something different was needed. As Gamer said, “We looked at the biology and asked how to design the most effective compounds, rather than using the obvious antibodies just because they’re industry standard.”

Instead, Apogenix built a technology to construct multimerized single chain agonists that are superior to standard approaches.

For a ligand approach to be successful, Apogenix had to optimize the structure of TNFSF receptor-binding domains. The resulting ligands consist of three binding domains encoded on one single polypeptide chain fused to an Fc portion. The Fc part the single chain trimer is dimerized, resulting in a hexavalent structure providing six binding sites.

“These ligands act as hexavalent molecules and have a strong multimerization capacity compared to antibodies and, thereby, a superior efficacy,” Gamer said. They have six binding sites to induce a higher signal, unlike antibodies, which have only two binding sites. And, he said, thanks to their single-chain structure, the Apogenix receptor agonists are more stable than the natural ligand.

TRAIL system induces apoptosis

That work developing Apogenix TNF receptor agonists led to the development of its TRAIL compounds, which induce apoptosis in tumor cells.

“We developed a technology platform for the construction of ligands that allow very effective multimerization,” Gamer said. “We started with TRAIL, using the ligand appearing most attractive to us.

“The preclinical work that has been performed so far makes us believe that APG880 might be the first TRAIL receptor agonist that will work in humans and provide benefit to the patient.” Based on these results, Apogenix closed a comprehensive licensing agreement for APG880 and the related compound, APG350 with AbbVie.

As TRAIL was being developed, Apogenix also was looking at the potential of other TNFSF members to be developed using systems and architecture similar to those developed for APG880.

“It’s all about helping the immune system fight cancer,” Gamer said. Apogenix targets various key checkpoints that control the immune system and help to re-establish immune surveillance. For example, “Many of the TNF family members provide co-stimulatory signals that activate T cells to attack cancer cells,” Gamer said. Our technology platform creates biologically-active CD27, HVEM, CD40 and OX40 agonists intended to activate immune cells to stimulate an anti-tumor response. Further candidates are in discovery.

Stopping the tumor counter-attack

One of the drugs developed from those multiple approaches, APG101, targets both solid and hematological tumors. APG101 works by blocking the CD95 pathway and thereby preventing T cells from being killed by CD95 ligand expressing tumor cells.

“Usually—during recovery from an infection, for example—the body down-regulates the immune response by killing activated T cells using the CD95 signaling pathway,” Gamer said. “A recent Nature publication describes that cancer cells use the CD95 ligand (a TNF family member) to kill activated T cells to prevent those T cells from attacking them.” Blocking the CD95 signal helps T cells survive, allowing them to attack the tumor cells.

A controlled Phase II study using APG101 to combat glioblastoma showed excellent results. In the CD95 ligand biomarker positive group, overall survival in the APG101/radiotherapy combination group was 16.1 months, compared to only 7.3 months in the radiotherapy-only group.

Apogenix is working with key opinion leaders to design the next phase of the trials. The company is seeking funding to support further development, but, he says, “we expect to begin the next clinical trials by mid-2016.”

APG101 also is in a Phase I trial against myelodysplastic syndromes (MDS). Interim results from this open label study indicated good safety and tolerability. Numbers of erythrocyte precursor cells increased and the need for transfusions decreased in patients who completed the treatment. Final results are expected within a few months.

Partnerships increasing

Since Apogenix was formed in 2005, it has raised more than EUR 70 million from investors, public grants and licensing payments.

It has a drug development agreement in place with AbbVie, and signed another during the summer with CANbridge Life Sciences. Apogenix also recently signed an agreement with R-Biopharm to develop a companion diagnostic to identify patients most likely to benefit from APG101.

Apogenix is continuing to seek additional partners to help it explore the TNF receptor agonist technology, Gamer said. “There is broad applicability for each of the members in the TNF family.”

Management expertise

Apogenix’s management team combines big pharma and biotech experience, resulting in a savvy, entrepreneurial approach to drug development.

CEO Thomas Hoeger, PhD, joined the company soon after its inception. His background includes five years as a stock analyst for DZ Bank in Frankfurt after heading central nervous system research at BASF AF and Knoll AG. He was a Fulbright Scholar at the Massachusetts Institute of Technology.

Before joining Apogenix in 2006, Chief Medical Officer Harald Fricke, MD, was responsible for global clinical development at Fresenius Biotech GmbH after heading the clinical oncology department at Baxter and multiple positions at SmithKlineBeecham and GlaxoSmithKline.

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