Protein-Catalyzed Capture Agents (PCCs) Designed Using “Click Chemistry” Show Promise for Broad Use in Diagnostics and Therapeutics
Data Demonstrating Synthetic Class of Site-Specific Binding Molecules is Published in the Journal of the American Chemical Society
SEATTLE – Integrated Diagnostics, an emerging leader in molecular diagnostics, today announced that it has created a synthetic class of diagnostic and therapeutic agents with antibody-like properties: protein-catalyzed capture agents. PCCs were created in collaboration with the California Institute of Technology (Caltech) using “click chemistry,” a synthetic process that allows scientists to permanently join (“click”) together molecular components with unusual precision and stability. PCCs offer the promise of superior stability, lower cost and faster creation compared to monoclonal antibodies, the current standard for identifying biomarkers in most diagnostics platforms – and in many therapeutic uses. Data demonstrating the design and use of this synthetic class of site-specific binding molecules was recently published in the Journal of the American Chemical Society (JACS). In a separate release, Integrated Diagnostics also announced that it has licensed click chemistry from The Scripps Research Institute and appointed K. Barry Sharpless, Ph.D., the inventor of the process, as an advisor.
“For two decades scientists have sought to create small molecule versions of antibodies and other binding molecules using a scalable, synthetic process,” said Jim Heath, Ph.D., co-founder and Board member, Integrated Diagnostics; Gilloon Professor, Caltech; and co-author of the JACS article. “Integrated Diagnostics and Caltech researchers successfully used click chemistry to design a peptide-based drop-in replacement for monoclonal antibodies. Another way to describe it: we’ve taken a complex piece of biology and turned it into a much simpler piece of chemistry.”
The JACS paper builds on a growing body of published literature by Integrated Diagnostics and Caltech focused on crafting site-specific binding molecules. With click chemistry, the process is “directed” by the actual site targeted – allowing for a precise fit that results in a molecule that is highly stable both on the shelf and in vivo. The small size of the resulting molecule – approximately one-fortieth the molecular weight of an equivalent monoclonal antibody – suggests a new class of diagnostic and therapeutic agents that resembles a peptide therapeutic with antibody-like binding properties that can be utilized therapeutically and for in vivo molecular targeting.
“Integrated Diagnostics’ ongoing, close collaboration with Caltech researchers, including our co-founder Jim Heath, has produced a new therapeutic agent – PCCs – that we believe have the potential to be an excellent replacement for monoclonal antibodies,” said Albert “Al” A. Luderer, Ph.D., CEO of Integrated Diagnostics. “The emergence of the next generation of diagnostics has been hampered until now by dependence on antibodies to recognize disease biomarkers. Antibodies are expensive, relatively unstable, slow to design, and less specific than is commonly believed. In contrast, our data suggests that PCCs, which are produced synthetically, will be inexpensive, stable, quick to design and produce, and highly specific. We believe the introduction of PCCs will allow for a diagnostics renaissance – a shift from the era of tests that monitor only one or two biomarkers, to large-scale diagnostics that monitor dozens or hundreds of biomarkers to detect cancer and other serious diseases earlier than previously possible.”
“The paper establishes the technology used to create PCCs as a useful tool for creating a full range of peptide-based diagnostic and therapeutic agents,” said Steve Millward, Ph.D., the lead author of The JACS paper and a postdoctoral scholar at Caltech. “The novel inhibitory properties of the molecule also present an exciting route to designing therapeutic compounds that target aberrant kinase activity.”
The paper is titled “Iterative in Situ Click Chemistry Assembles a Branched Capture Agent and Allosteric Inhibitor for Akt1.” Dr. Millward, Dr. Heath and their co-authors describe the process of using click chemistry to design one PCC: an Akt-specific branched peptide triligand. Akt is a protein kinase that is believed to play a critical role in the growth of many types of cancer cells. The Akt PCC displays allosteric-like inhibition, which means that it inhibits the activity of the kinase without binding to the highly conserved active site. This is in contrast to many experimental and commercial kinase inhibitors that directly interfere with substrate binding and often suffer from poor specificity and therapeutic efficacy.
The Akt PCC functions as both a capture agent and a detection agent in standard diagnostic assays; it efficiently immunoprecipitates Akt from cell lysates; and it labels Akt in fixed cancer line cells.
About the Akt PCC (branched peptide triligand)
In the JACS article, Dr. Heath and his co-authors describe the use of iterative in situ click chemistry to design an Akt-specific branched peptide triligand that serves as a drop-in replacement for monoclonal antibodies in multiple biochemical assays. Each peptide module in the branched structure makes unique contributions to affinity and/or specificity resulting in a 200 nM affinity ligand that efficiently immunoprecipitates Akt from cancer-cell lysates and labels Akt in fixed cells. The collaborators’ use of a small molecule to pre-inhibit Akt prior to screening may have contributed to low micromolar inhibitory potency and an allosteric mode of inhibition, which is demonstrated through a series of competitive enzyme-kinetic assays. To demonstrate the efficiency and selectivity of the protein-templated in situ click reaction, the researchers developed a novel QPCR-based methodology that enabled a quantitative assessment of its yield. These results demonstrate the potential for iterative in situ click chemistry to generate potent, synthetically accessible antibody replacements with novel inhibitory properties.
About Integrated Diagnostics
Integrated Diagnostics is developing large-scale, blood-based molecular diagnostics that detect important diseases like lung cancer and Alzheimer’s at their earliest stages by simultaneously monitoring tens to hundreds of disease markers. The company, founded in October 2009 by systems biology pioneer Dr. Lee Hood, creating a new generation of personalized medical solutions using sophisticated informatics for biomarker selection and a novel class of synthetically created diagnostic and therapeutic agents with antibody-like properties: protein-catalyzed capture agents (PCCs). Integrated Diagnostics’ mission is to build a new generation of low-cost, large-scale diagnostic assays for early detection of serious diseases. The company is conceptually based on a systems view of disease where pathophysiology arises from disease-perturbed networks of proteins, genes, and other molecules. Investors include InterWest Partners, The Wellcome Trust, and BioTechCube Luxembourg. Foundational intellectual property is exclusively licensed from the Institute of Systems Biology and Caltech. Learn more at www.integrated-diagnostics.com
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