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Indi Molecular Applying High-Throughput PCC Platform to Imaging, Therapeutic Compounds

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NEW YORK (GenomeWeb) – Indi Molecular has developed a barcoding-based screening system that it said lowers the time required to generate one of its protein catalyzed capture agents from 75 to 80 days to around 15 days.

According to Albert Luderer, the company's cofounder and CEO, the system allows for "truly high-throughput PCC creation," enabling rapid creation of the PCC affinity agents, which Indi is positioning for use in therapeutic, imaging, and diagnostic applications.

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 targets. Targets are screened against these libraries to find peptides that bind them, and when these peptides bind, the target acts as a catalytic point for the acetylene- and azide-containing peptides, which then link together via click chemistry, forming multi-peptide, target-binding constructs that can then be pulled down and identified.

Indi Molecular cites several advantages of PCCs over conventional antibodies. For one, their synthetic nature allows for potentially easier tuning of their binding properties. Additionally, their small size allows them to target regions of proteins or other targets that may not be accessible to antibodies. It also allows them to penetrate cells to target proteins within. The 15-day production time cited by the company is also significantly shorter than what it required to produce a high-quality antibody.

Indi Molecular is a spinoff from proteomics firm Integrated Diagnostics, which recently shut down after selling its lead product, XL2, a protein-based test for evaluating indeterminate lung nodules detected during CT scans, to Biodesix.

Indi Molecular launched in September 2013 with an initial focus on developing its PCCs as therapeutics. In then shifted to a focus on developing them as reagents for biological research and in vitro diagnostics. More recently, the company has moved to focus on using the molecules for PET imaging and therapeutic applications, though it also maintains several projects in the IVD space, including a partnership with the US Department of Defense to investigate markers of brain trauma and a project funded by the Bill and Melinda Gates Foundation that aims to use PCCs as part of a point-of-care HIV test.

The company last year closed an $11.5 million Series A funding round led by Merck's venture arm, Legend Capital, and Sabey.

The new barcode-based screening platform was detailed in a paper published last month in Analytical Chemistry. James Heath, an Indi Molecular cofounder and board member who developed the PCC technology in his lab at the California Institute of Technology, was senior author on the study.

Typically, an initial PCC screen will generate around five to 10 lead compounds to a target, which are then tested for binding to that target (typically a protein) in a variety of different backgrounds and under a variety of different conditions. The company has been using ELISAs in 96-well formats for this work, but these assays are laborious and required significant amounts of reagents.

To make the process more efficient, Heath and his colleagues developed what they have termed a barcoded rapid assay platform (B-RAP), which combines a microfluidic format and DNA-barcoding to allow simultaneous evaluation of a full set of PCC leads across a range of conditions.

The systems uses a slide divided into microliter wells each patterned with copies of a barcode of orthogonal single-strand DNA oligomers. The PCC candidates are then linked via biotin labeling to a streptavidin scaffold containing a set of complementary ssDNA oligomers. These complementary ssDNA oligomers bind the different candidate PCCs to different portions of the larger barcode and the different wells can be used for assessing binding under different conditions, allowing researchers to test all the candidate PCCs in one pass.

"The real benefit of the B-RAP platform is the major time savings it yields in testing the PCC agent candidates, and the fact that the actual assays themselves are quite a bit cleaner than standard ELISAs," Heath said, noting that the system will be part of the high-throughput PCC production line Indi Molecular is establishing.

Luderer said the company has also placed the technology with outside partners who have likewise been able to generate PCCs in a high-throughput manner, which he suggested speaks to its broad applicability and transferability.

Indi Molecular's current focus is developing PCCs for imaging and therapeutic purposes. In the case of the former, the company envisions the compounds as reagents for use in PET-CT studies. Michael Phelps, a professor at the University of California, Los Angeles, and the inventor of PET imaging, is an advisor to Indi Molecular.

The company is currently working with a pharma partner that Luderer declined to name to develop a PCC for PET-CT imaging in immune-oncology. Luderer said the company plans to use its imaging program to gather data on the behavior of the PCCs in humans before moving on to therapeutic development.

Indi Molecular is also pursuing broader efforts in immune-oncology, Luderer said.

"We're very interested if it is possible or use to look at three or four or five very unique targets simultaneously and create essentially a diagnostic tool kit to help evaluate, stage, and follow patients," he said. "That's probably our next major program. We're actually in discussions with a partner about it right now."

On the drug development side, Luderer said the company recently demonstrated that its compounds are able to penetrate a cell and maintain their therapeutic activity. Another reason it believes PCCs could prove successful as therapeutics is their ability to target molecules like the protein KRas, which has been largely undruggable thus far despite its major role in a variety of cancers.

In the Analytical Chemistry paper, the researchers used the B-RAP platform to develop a PCC that inhibited the GTPase activity of KRas, a result that Heath highlighted as among the most notable findings of the study despite its emphasis on the platform development.

"The fact that we made an inhibitor against KRAS in a single-generation screen is a pretty big deal part of the paper," he said, noting how difficult the protein has been to target.

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