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Indi Molecular Inks PCC Development Deal with Sigma, But Main Focus Now on Therapeutics

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NEW YORK (GenomeWeb) – Indi Molecular this week announced a co-development deal with Sigma-Aldrich to explore use of its PCC (protein catalyzed capture) agent technology in Sigma-Aldrich's line of protein research reagents.

Despite the deal, though, Indi Molecular has shifted its focus from developing PCCs as research and diagnostic tools to therapeutics, CEO Albert Luderer told GenomeWeb.

A spinoff of proteomics firm Integrated Diagnostics, Indi Molecular launched as a separate entity in September 2013 with $1.8 million in seed funding from InterWest Partners and co-founders including Luderer; James Heath, a California Institute of Technology researcher and inventor of the PCC technology; Lee Hood; and Michael Phelps, a University of California, Los Angeles, professor and inventor of PET imaging.

Indi Molecular had initially planned to focus on PCCs' potential as therapeutics but, after funding difficulties delayed the company's launch by a year, it moved to establish their usefulness as reagents for biological research and in vitro diagnostics.

PCCs use click chemistry combined with pairs of random peptide libraries — one containing acetylene functionalities and the other containing azide groups — to create affinity reagents to given proteins. Target proteins are screened against these libraries to find peptides that bind them, and when these peptides bind, the protein epitope acts as a catalytic point for the acetylene- and azide-containing peptides, which then link together via click chemistry, forming multi-peptide, protein-binding constructs that can then be pulled down and identified.

According to the company, the reagents have several potential advantages over monoclonal antibodies, including better specificity and the ability to target regions of proteins inaccessible to monoclonals.

Additionally, recent alterations to the PCCs' structure have enabled binding affinities potentially better than those provided by monoclonal antibodies, Luderer said, noting that this was a significant development driving the company's shift back toward therapeutics.

"As we have talked to pharmaceutical companies, it has become very clear that their interest is in super-binding molecules that can target very low abundance therapeutic targets, things that are really hard to reach with a monoclonal," he said.

"We've been able to advance our chemistries to the point now where we're starting to move into in vitro models of drug activity using PCC in novel targets, and so our focus has moved strongly in that direction and our dialogue now with commercial companies is more focused towards the large pharmaceutical players," he added.

The advance in the PCC technology is based on a move from using a linear peptide backbone to a circular peptide backbone, which, Luderer said, have much higher binding affinities. Indi Molecular and its collaborators at the California Institute of Technology currently have a paper in press describing the new structure, he said.

PCCs based on the circular structure are also easier to introduce into cells, Luderer said, noting that this was an advantage compared to monoclonal antibodies. He said that in recent work with botulism toxin done in collaboration with the US Department of Defense, company researchers have been able to preload the toxin with PCCs that block its activity and then demonstrate that the toxin-PCC complex is taken up by neurons.

Luderer additionally cited recent work demonstrating the molecules high specificity, another of its potential advantages compared to antibodies. In work funded by the Bill and Melinda Gates Foundation, the company demonstrated that it could target with its PCCs a pathogenic form of an enzyme involved in oxidative metabolism that is carried by malarial mosquitoes.

"It's a slight difference between the pathogenic form in the malarial mosquito and the non-pathogenic form, and we can nail it," Luderer said, adding that this PCC was currently in field tests.

In terms of choosing areas of drug development to focus on, the company's strategy is to let its future pharma partners tell it what targets they need help with, Luderer said.

"Part of the dialogue with potential pharma partners is, 'What target or targets do you have that you believe are breakthrough from a therapeutic point of view that are very difficult or not possible for you to hit?'" he said. "Those are the ones that we want."

The company is still operating off its 2013 seed funding round, but, Luderer said, Indi Molecular anticipates raising additional funds once it has established a formal pharma partnership.

He said he hoped to lock in such a partnership early in the first quarter of 2015, after which the company, most likely in coordination with that pharma partner, plans to launch a Series A round targeting around $5 million to $10 million.

In light of these ambitions, the Sigma-Aldrich deal announced this week is no longer as central to Indi Molecular's PCC strategy as it once was.

"We actively sought to talk to Sigma because not only are they a tools company, but they are a major vendor of diagnostic reagents, so it fit with Indi Molecular's initial strategy to try to put a footprint into both of those spaces," Luderer said. "And in the interim, of course, we have made discoveries realizing that our efforts are probably best spent not loading up on tools or diagnostics but on pharmaceutical projects."

Nonetheless, he said, the Sigma-Aldrich deal will be beneficial in the sense of providing an opportunity to validate the PCC technology with an external commercial partner.

Such validation "is something that a company needs beyond their peer-reviewed publications to help transition to a commercial presence," he added. "So we wanted somebody to come in and take a look, so we're pleased to be able to work with [Sigma-Aldrich]."

The partnership is focused on one specific target, which Luderer declined to name, with Sigma-Aldrich having global rights to commercialize any reagent emerging from the work on that target.

Indi Molecular plans to explore using both the linear and circular PCC structures in the project and is aiming for a statement of commercial feasibility by summer of 2015, Luderer said.

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