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News Article | June 29, 2017
Site: www.marketwired.com

CULVER CITY, CA--(Marketwired - Jun 29, 2017) - Indi Molecular, an emerging life sciences company that is developing a novel, synthetic class of binders with antibody-like properties called protein catalyzed capture agents (PCCs), announced today that it has raised a $11.5 million Series-A financing led by M Ventures (Merck Ventures BV, Amsterdam, the Netherlands, a subsidiary of Merck KGaA, Darmstadt Germany known as M Ventures in the United States and Canada), the strategic corporate venture capital arm of Merck KGaA Darmstadt, Germany; Legend Capital, a venture capital/private equity fund based in Beijing; Sabey Corporation; and existing investors including Asset Management Ventures. As part of the financing, Dr. Andreas Jurgeit from Merck Ventures and Dr. Darren Cai from Legend Capital will join Indi Molecular's board. The Series-A proceeds will be used to establish a high throughput PCC discovery platform and to advance existing leads in PET immuno-oncology imaging to clinical stage. Indi Molecular was founded in 2013 by Leroy Hood (Institute of Systems Biology, Seattle), James Heath (Caltech) and Al Luderer to commercialize a unique discovery platform, which leverages the PCC technology developed at James Heath's lab at Caltech. PCCs are highly specific, low molecular-weight binders with unprecedented specificity. The fully synthetic process allows for the creation of binders against difficult targets in a short time. PCCs combine the benefits of antibody-like binding with the flexibility and chemical properties of small molecules. As such, they represent a novel modality with broad potential impact across research, imaging and therapeutic use. Since its inception, Indi Molecular has shown the utility of PCC binders across a wide range of applications, ranging from research tools and diagnostic agents to PET imaging. The company has collaborated with partners including the Bill and Melinda Gates Foundation, the US Department of Defense and leading healthcare companies. With this round of funding, Indi Molecular will establish an automated high throughput PCC discovery process. Additionally, Indi Molecular's most advanced PCC candidate, a highly specific PET tracer that allows for noninvasive efficacy monitoring of immuno-oncology interventions, will be advanced to clinical stage. Al Luderer, Indi Molecular's CEO and co-founder, said: "The company is pleased with the confidence our new investors have in the demonstrated maturity of our PCC platform and its potential to transform biological measurements across many medical applications." Andreas Jurgeit, investment director of the Life science fund at M Ventures, said: "Indi Molecular's PCC technology promises significant impact across a wide range of applications from research tools to patients as a novel modality used in PET imaging. We are very excited to build a company based on this highly promising technology with an experienced team of founders and co-investors. M Ventures' Life Science team focuses on investments outside of the realm of drug development -- anything that is not a drug or not yet a drug -- ranging from process solutions to novel modalities." Darren Cai, Managing Director of Legend Capital, said: "We are impressed by the potential of Indi Molecular's technology in both the diagnostic and the therapeutic fields and believe their strong management team is poised to create a game-changing company. Legend Capital works with high quality entrepreneurs and investors globally to advance new technologies and business transformations." Indi Molecular is an emerging life sciences company that is developing 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 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. The company launched as a spinout from its parent company Integrated Diagnostics (Indi) in 2013 with a $1.8 million seed round led by InterWest Partners together with Asset Management Ventures and several angel investors. The company has received grants from the Department of Defense and the Bill & Melinda Gates Foundation. For more information visit www.IndiMolecular.com Merck Ventures BV, Amsterdam, The Netherlands, is a subsidiary of Merck KGaA, Darmstadt, Germany (known as M Ventures in the United States and Canada). Based in Amsterdam, The Netherlands, and a subsidiary of Merck KGaA, Darmstadt, Germany, Merck Ventures is the strategic, corporate venture capital arm of Merck KGaA, Darmstadt, Germany. Its mandate is to invest in innovative technologies and products with the potential to significantly impact Merck KGaA, Darmstadt, Germany's core business areas. From our headquarters in Amsterdam and offices in the US and Israel we invest globally in transformational ideas driven by great entrepreneurs. M Ventures takes an active role in its portfolio companies and teams up with entrepreneurs and co-investors to translate innovation towards commercial success. For more information visit www.m-ventures.com Legend Capital is an early-stage Venture Capital and expansion-stage Growth Capital investment fund based in Beijing, China. It is currently managing several USD funds and RMB funds, as well as dedicated Healthcare funds. The focus of Legend Capital is on innovation and growth enterprises with operations in China or related to China.


Deyle K.M.,California Institute of Technology | Farrow B.,California Institute of Technology | Qiao Hee Y.,California Institute of Technology | Work J.,California Institute of Technology | And 7 more authors.
Nature Chemistry | Year: 2015

Ligands that can bind selectively to proteins with single amino-acid point mutations offer the potential to detect or treat an abnormal protein in the presence of the wild type (WT). However, it is difficult to develop a selective ligand if the point mutation is not associated with an addressable location, such as a binding pocket. Here we report an all-chemical synthetic epitope-targeting strategy that we used to discover a 5-mer peptide with selectivity for the E17K-transforming point mutation in the pleckstrin homology domain of the Akt1 oncoprotein. A fragment of Akt1 that contained the E17K mutation and an I19[propargylglycine] substitution was synthesized to form an addressable synthetic epitope. Azide-presenting peptides that clicked covalently onto this alkyne-presenting epitope were selected from a library using in situ screening. One peptide exhibits a 10:1 in vitro selectivity for the oncoprotein relative to the WT, with a similar selectivity in cells. This 5-mer peptide was expanded into a larger ligand that selectively blocks the E17K Akt1 interaction with its PIP3 (phosphatidylinositol (3,4,5)-trisphosphate) substrate. © 2015 Macmillan Publishers Limited. All rights reserved.


Pfeilsticker J.A.,California Institute of Technology | Umeda A.,California Institute of Technology | Farrow B.,California Institute of Technology | Hsueh C.L.,California Institute of Technology | And 4 more authors.
PLoS ONE | Year: 2013

We report on a method to improve in vitro diagnostic assays that detect immune response, with specific application to HIV-1. The inherent polyclonal diversity of the humoral immune response was addressed by using sequential in situ click chemistry to develop a cocktail of peptide-based capture agents, the components of which were raised against different, representative anti-HIV antibodies that bind to a conserved epitope of the HIV-1 envelope protein gp41. The cocktail was used to detect anti-HIV-1 antibodies from a panel of sera collected from HIV-positive patients, with improved signal-to-noise ratio relative to the gold standard commercial recombinant protein antigen. The capture agents were stable when stored as a powder for two months at temperatures close to 60oC. © 2013 Pfeilsticker et al.


Farrow B.,California Institute of Technology | Hong S.A.,Gwangju Institute of Science and Technology | Romero E.C.,California Institute of Technology | Lai B.,Indi Molecular | And 7 more authors.
ACS Nano | Year: 2013

We report on a robust and sensitive approach for detecting protective antigen (PA) exotoxin from Bacillus anthracis in complex media. A peptide-based capture agent against PA was developed by improving a bacteria display-developed peptide into a highly selective biligand through in situ click screening against a large, chemically synthesized peptide library. This biligand was coupled with an electrochemical enzyme-linked immunosorbent assay utilizing nanostructured gold electrodes. The resultant assay yielded a limit of detection of PA of 170 pg/mL (2.1 pM) in buffer, with minimal sensitivity reduction in 1% serum. The powdered capture agent could be stably stored for several days at 65 C, and the full electrochemical biosensor showed no loss of performance after extended storage at 40 C. The engineered stability and specificity of this assay should be extendable to other cases in which biomolecular detection in demanding environments is required. © 2013 American Chemical Society.


Farrow B.,California Institute of Technology | Wong M.,California Institute of Technology | Malette J.,Indi Molecular | Lai B.,Indi Molecular | And 5 more authors.
Angewandte Chemie - International Edition | Year: 2015

Abstract: Botulinum neurotoxin (BoNT) serotype A is the most lethal known toxin and has an occluded structure, which prevents direct inhibition of its active site before it enters the cytosol. Target-guided synthesis by in situ click chemistry is combined with synthetic epitope targeting to exploit the tertiary structure of the BoNT protein as a landscape for assembling a competitive inhibitor. A substrate-mimicking peptide macrocycle is used as a direct inhibitor of BoNT. An epitope-targeting in situ click screen is utilized to identify a second peptide macrocycle ligand that binds to an epitope that, in the folded BoNT structure, is active-site-adjacent. A second in situ click screen identifies a molecular bridge between the two macrocycles. The resulting divalent inhibitor exhibits an in vitro inhibition constant of 165 pM against the BoNT/A catalytic chain. The inhibitor is carried into cells by the intact holotoxin, and demonstrates protection and rescue of BoNT intoxication in a human neuron model. Let the toxins pick their poison: The target-guided synthesis of a divalent peptide ligand that is a potent inhibitor of botulinum neurotoxin both in vitro and in cells was achieved. An active-site-binding substrate mimic was combined with epitope targeting of a nearby site in the folded structure of the toxin to obtain the peripheral binder. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Farrow B.,California Institute of Technology | Wong M.,California Institute of Technology | Malette J.,Indi Molecular | Lai B.,Indi Molecular | And 5 more authors.
Angewandte Chemie - International Edition | Year: 2015

Botulinum neurotoxin (BoNT) serotype A is the most lethal known toxin and has an occluded structure, which prevents direct inhibition of its active site before it enters the cytosol. Target-guided synthesis by in situ click chemistry is combined with synthetic epitope targeting to exploit the tertiary structure of the BoNT protein as a landscape for assembling a competitive inhibitor. A substrate-mimicking peptide macrocycle is used as a direct inhibitor of BoNT. An epitope-targeting in situ click screen is utilized to identify a second peptide macrocycle ligand that binds to an epitope that, in the folded BoNT structure, is active-site-adjacent. A second in situ click screen identifies a molecular bridge between the two macrocycles. The resulting divalent inhibitor exhibits an in vitro inhibition constant of 165 pM against the BoNT/A catalytic chain. The inhibitor is carried into cells by the intact holotoxin, and demonstrates protection and rescue of BoNT intoxication in a human neuron model. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Coppock M.B.,U.S. Army | Farrow B.,California Institute of Technology | Warner C.,Edgewood Chemical Biological Center | Finch A.S.,U.S. Army | And 4 more authors.
Proceedings of SPIE - The International Society for Optical Engineering | Year: 2014

Current biodetection assays that employ monoclonal antibodies as primary capture agents exhibit limited fieldability, shelf life, and performance due to batch-to-batch production variability and restricted thermal stability. In order to improve upon the detection of biological threats in fieldable assays and systems for the Army, we are investigating protein catalyzed capture (PCC) agents as drop-in replacements for the existing antibody technology through iterative in situ click chemistry. The PCC agent oligopeptides are developed against known protein epitopes and can be mass produced using robotic methods. In this work, a PCC agent under development will be discussed. The performance, including affinity, selectivity, and stability of the capture agent technology, is analyzed by immunoprecipitation, western blotting, and ELISA experiments. The oligopeptide demonstrates superb selectivity coupled with high affinity through multi-ligand design, and improved thermal, chemical, and biochemical stability due to non-natural amino acid PCC agent design. © 2014 SPIE.


PubMed | U.S. Army, Indi Molecular and California Institute of Technology
Type: Journal Article | Journal: Angewandte Chemie (International ed. in English) | Year: 2015

We describe a general synthetic strategy for developing high-affinity peptide binders against specific epitopes of challenging protein biomarkers. The epitope of interest is synthesized as a polypeptide, with a detection biotin tag and a strategically placed azide (or alkyne) presenting amino acid. This synthetic epitope (SynEp) is incubated with a library of complementary alkyne or azide presenting peptides. Library elements that bind the SynEp in the correct orientation undergo the Huisgen cycloaddition, and are covalently linked to the SynEp. Hit peptides are tested against the full-length protein to identify the best binder. We describe development of epitope-targeted linear or macrocycle peptide ligands against 12 different diagnostic or therapeutic analytes. The general epitope targeting capability for these low molecular weight synthetic ligands enables a range of therapeutic and diagnostic applications, similar to those of monoclonal antibodies.


PubMed | University of Houston, Indi Molecular and California Institute of Technology
Type: Journal Article | Journal: Nature chemistry | Year: 2015

Ligands that can bind selectively to proteins with single amino-acid point mutations offer the potential to detect or treat an abnormal protein in the presence of the wild type (WT). However, it is difficult to develop a selective ligand if the point mutation is not associated with an addressable location, such as a binding pocket. Here we report an all-chemical synthetic epitope-targeting strategy that we used to discover a 5-mer peptide with selectivity for the E17K-transforming point mutation in the pleckstrin homology domain of the Akt1 oncoprotein. A fragment of Akt1 that contained the E17K mutation and an I19[propargylglycine] substitution was synthesized to form an addressable synthetic epitope. Azide-presenting peptides that clicked covalently onto this alkyne-presenting epitope were selected from a library using in situ screening. One peptide exhibits a 10:1 in vitro selectivity for the oncoprotein relative to the WT, with a similar selectivity in cells. This 5-mer peptide was expanded into a larger ligand that selectively blocks the E17K Akt1 interaction with its PIP3 (phosphatidylinositol (3,4,5)-trisphosphate) substrate.


PubMed | Indi Molecular and California Institute of Technology
Type: Journal Article | Journal: Angewandte Chemie (International ed. in English) | Year: 2015

Botulinum neurotoxin (BoNT) serotypeA is the most lethal known toxin and has an occluded structure, which prevents direct inhibition of its active site before it enters the cytosol. Target-guided synthesis by insitu click chemistry is combined with synthetic epitope targeting to exploit the tertiary structure of the BoNT protein as a landscape for assembling a competitive inhibitor. A substrate-mimicking peptide macrocycle is used as a direct inhibitor of BoNT. An epitope-targeting insitu click screen is utilized to identify a second peptide macrocycle ligand that binds to an epitope that, in the folded BoNT structure, is active-site-adjacent. A second insitu click screen identifies a molecular bridge between the two macrocycles. The resulting divalent inhibitor exhibits an invitro inhibition constant of 165pM against the BoNT/A catalytic chain. The inhibitor is carried into cells by the intact holotoxin, and demonstrates protection and rescue of BoNT intoxication in a human neuron model.

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