Cell Networx, an early-stage drug-discovery firm from Cambridge, Mass., has won a $100,000 Phase I SBIR grant to validate and further develop its cellular pathway-based approach to angiogenesis-related drug discovery, CBA News has learned.
If successful, Cell Networx stands to garner a Phase II SBIR award for an as-yet undisclosed but “substantial” amount, which the company will use to support its internal efforts to develop drugs for age-related macular degeneration and diabetic retinopathies, Michelle Palmer, the company’s managing director and CSO, said this week.
Palmer founded Cell Networx in 2004 along with Georges von Degenfeld, the cardiovascular pharmacology group leader at Bayer Healthcare in Wuppertal, Germany; and Robert Bals, a lecturer in internal and pulmonary diseases at the University of Marburg’s Hospital of Philipps in Marburg, Germany.
Palmer and von Degenfeld collaborated at Stanford University, and Bals had been von Degenfeld’s research advisor at the University of Marburg, Palmer said. Together the group discovered a proprietary drug target: a small peptide called L37 that interacts with a receptor on endothelial cells during angiogenesis.
“This peptide has been shown by my partners, in cell-based and animal models, to mediate angiogenesis independently of [vascular endothelial growth factor],” Palmer said. “This is a new angiogenesis target, and it’s recently been more widely studied.
“It’s an anti-microbial peptide, but it’s now being shown to be a key in innate immunity, and it’s over-expressed under inflammatory conditions and hypoxia, which are key elements in angiogenesis,” she said.
In addition, Palmer and colleagues developed a method, dubbed the Pathway Assay Matrix (PAM), to interrogate the effects of small molecules on the cellular pathway surrounding the target.
Basically, PAM is a collection of cell-based assays performed simultaneously using various readout methods. Collectively, the assays represent various nodes within the pathways of particular diseases which, in Cell Networx’s case, are diseases in which angiogenesis plays a crucial role.
“[In] traditional drug discovery, it’s still very much [about] the single target: do the high-throughput screening; find a lead and optimize it based on that target; and then much later go and look at how this drug candidate is affecting the pathway,” Palmer said. “We want to move this much more upstream, and not just look at gene expression and protein expression, but look at function at these pathway nodes.
“We would focus on phenotypic screens rather than single-target screens to identify things that are affecting a phenotype that is a surrogate for these pathways; but then do the lead optimization and further refinement on the PAM,” Palmer added.
An additional proposed benefit of the approach, according to Cell Networx’s SBIR grant abstract, is that it would yield data that better predicts the performance of a small molecule in in vivo models.
“We go into animal models very early and look for those same pathway nodes in the animal model data, and then we may need to iterate and make some changes as we continue to optimize,” Palmer said. “It’s meant to be a very integrated and flexible system in that we can continually modify and refine that cell model to get better and better lead drug candidates out of the system.”
Such a multiplexed approach would seem amenable to the application of high-content imaging methods, but according to Palmer, this is only a small part of the PAM platform. Cell Networx uses an array of reagents and detection technologies as part of its approach, but in particular favors bulk chemiluminescence and fluorescence cell-based reporter assays – a result of time Palmer spent as a researcher with Applied Biosystems.
“[At] Applied Biosystems … we applied a lot of technologies that used a chemiluminescent readout,” Palmer said. “There is a lot of glamour and cachet around high-content imaging, and I think it’s very valuable, but some of the old tried and true methods are certainly working well for us, and I think they’re still the standard.”
Despite Palmer’s stint with ABI, Cell Networx has not incorporated that company’s line of reporter assays or chemiluminescence detection platforms in its research. Palmer said that Cell Networx has licensed β-galactosidase complementation protein-protein interaction assay technology for use in its drug-discovery programs.
One hurdle Cell Networx may need to overcome is the fact that its multiplexed approach to target identification and validation does not necessarily lend itself to high-throughput methods. This is one reason that many pharma companies still screen small molecule libraries for hits first using biochemical screens, and then later using more complex cell-based or animal models.
“I worked in the HT screening field for many years, and am certainly aware of the benefits,” Palmer said. “It is going to be a balance between getting the information we want, and our capacity and throughput.
“There is a lot of glamour and cachet around high-content imaging, and I think it’s very valuable, but some of the old tried and true methods are certainly working well for us, and I think they’re still the standard.”
“Automation can take you a long way in terms of capacity … and the libraries that we’re screening are more directed and focused libraries,” she added. “So we’ve decided to take more of a rational approach to selecting the compounds, but we could do a very large screen in a proliferation assay, or some kinds of phenotypic screens. Many of those are amenable to high-throughput standards.”
Further down the road, Cell Networx may have some interest in miniaturizing its approach, most likely through the application of microfludics.
“I think it’s an interesting way to look at it,” Palmer said. “We certainly don’t have plans to do that immediately. That would most likely be with a partner. We don’t plan to develop any microfluidics here. We’d like to leverage our expertise and do what we do well, and bring in partners where needed.”
Furthermore, Cell Networx believes that if its approach proves successful in validating targets and identifying suitable lead candidates for angiogenesis-based diseases such as AMD, then a move to cancer drug discovery would be a natural one, given the importance of angiogenesis in that disease.
“We focus on angiogenesis pathways, but it could easily translate to other pathways that could take advantage of this multi-target approach,” Palmer said. “We see partnering very early on for areas outside of our own focus.”
However, the company must first demonstrate the feasibility of PAM to trigger the next phase of SBIR founding. Prior to the Phase I award, Cell Networx had sustained itself on seed funding from friends and family.
“I prefer not to say at this point what the value of the grant is in Stage II,” Palmer said. “It’s actually a substantial amount of money, but even proceeding to Stage I is a nice validation of the technology and the approach and what we’re trying to accomplish.”