A consortium of five European partners, among which Tagworks Pharmaceuticals, has secured a €6 million grant from the EU Horizon2020 program for their research action entitled In Vivo Click PET Imaging Agents: Improving clinical companion diagnostics – Click-It. Coordinator of the Click-It consortium is the University of Copenhagen and next to Tagworks, the other partners are the Technical University of Vienna, the Austrian Institute of Technology and the Johannes Gutenberg University in Mainz (Germany).
Companion diagnostics are crucial for drug development and disease management with regard to patient selection, therapy planning and monitoring. Antibodies have been proven to be optimal disease-targeting and -modulating agents. However, to date, nuclear imaging of antibodies has been limited to the use of long-lived isotopes to be compatible with their slow pharmacokinetics. Major drawbacks include high radiation doses, precluding routine and repeated companion imaging procedures.
The Click-It consortium aims to circumvent this issue by using a pretargeting approach, which centers on the administration and target binding of a tagged antibody followed by administration and binding of a small, fast-clearing, short-lived radiolabeled probe to the tag of the antibody. This results in lower absorbed radiation doses and in a boost in target-blood ratios, which in turn leads to a superior imaging contrast. PET scan snapshots at multiple time-points provide long-term imaging information by applying short-lived nuclides. So far, only the fastest click reaction, the tetrazine ligation, has demonstrated potential in clinically relevant conditions. Tagworks has shown in SPECT imaging studies that this click reaction can be applied for the imaging of non-internalizing antibodies in vivo. This project aims at expanding the scope of click-pretargeted imaging to 18F-labeled tetrazines for PET imaging and to internalizing antibodies.
In a recent paper in the Journal of Nuclear Medicine, Tagworks, in collaboration with Austrialian biotech company Avipep, describes an alternative radioimmunotherapy strategy based on separate administration of the tumor-homing agent and a fast clearing radioactive probe. This way, the unwanted high renal retention of low-molecular weight radiometal tumor-homing agents can be overcome.
The Tagworks and Avipep researchers show that a pretargeting strategy with a small protein may be an attractive approach in radioimmunotherapy to reduce kidney uptake while maintaining high tumor targeting. An effective tumor-targeting agent, a TAG72 diabody that had a high kidney uptake as a directly radiometal-labeled analog, showed complete retention of its properties upon TCO-modification. Administration of a radiometal-labeled tetrazine in a second step, showed efficient tumor uptake and most importantly low kidney uptake. This pretargeting strategy could be an important alternative platform, superseding the use of peptides and small proteins as metal-chelate conjugates for imaging and therapy.
Read the full paper: doi:10.2967/jnumed.115.159145
Tagworks Pharmaceuticals has received two valorization grants, €180,000 total, from NanoNextNL, the Dutch research and innovation program on nanotechnology. The grants will be used to take two of the company’s core programs to the next level.
One grant concerns Tagworks’ antibody drug conjugate (ADC) technology and will be applied to further demonstrate the benefits of the use of click chemistry to activate ADCs on the tumor. The other grant will be dedicated to further development of a novel liver-targeted clearing agent. Through a chemical reaction, this agent enables instantaneous clearance of tagged nanomedicine from the blood at any desired time. Such an agent offers promising perspectives for boosting the therapeutic window of ADCs or drug containing liposomes by controlling and minimizing off-target toxicity. Furthermore, when used in combination with directly labelled antibodies in companion diagnostic applications, use of this agent will improve the target/blood ratio and thus enhance image quality.
For their proposal “Click chemistry-triggered activation of Antibody-Drug Conjugates”, Tagworks Pharmaceuticals and the research group of professor Paul Yazaki at the Department of Immunology, City of Hope Beckman Research Institute in Duarte, CA, were awarded a US$465,000 Breakthrough Award through the Breast Cancer Research Program (BCRP) of the US Department of Defense. The competition for a BCRP grant was extremely tight with less than 6% of the proposals being recommended for funding. The running time of the project is two years.
The latest edition of Medicines, a Dutch journal on drug development, features Tagworks Pharmaceuticals in the start-up sections. The article by Rik Nijland appeared in Medicines 1, February 2015 (in Dutch) 24_25_med1_startup
Developing an antibody tag with improved pharmacokinetics and stability allowed Tagworks to achieve increased tumor uptake of a radiolabeled pretargeting probe. Even though this adapted tag exhibited a slight loss in reactivity, its use in a antibody (CC49-TCO) conjugate demonstrated a longer clearance half-life, improved tumor accumulation and increased in vivo stability. The overall result was a 50% increase in tumor uptake as well as increased tumor/non-tumor ratios of the radiolabeled tetrazine probe. Read the Tagworks paper “Trans-cyclooctene tag with improved properties for tumor pretargeting with the Diels-Alder reaction” in Mol. Pharmaceutics 2014, 11(9). doi:10.1021/mp500725a
Approaches that use in vivo chemistry to enable non-invasive molecular imaging and therapy are much sought after. Taking the recent achievements in pretargeted radioimmuno-imaging and -therapy in mice as a starting point, the Tagworks team discuss how the application scope of this approach can eventually be extended towards humans. Read “Pretargeted imaging using bioorthogonal chemistry in mice” in Current Opinion in Chemical Biology 2014, 21:161-169. doi:10.1016/j.cbpa.2014.07.023
Marc Robillard, CEO of Tagworks Pharmaceuticals has been invited to speak during the Gordon Research Conference on Organic Reactions and Processes, held from 13-18 July 2014 at Bryant University, Smithfield, RI. In his lecture entitled “In vivo Chemistry for Cancer Imaging and Therapy” Marc Robillard will present the company’s R&D progress to a select audience of academic and industrial scientists active in the broad field of synthetic organic chemistry with particular focus on modern chemical transformations. More on the conference
Together with prof. Tom Quinn of the University of Missouri-Columbia, Tagworks succeeded in securing an Exploratory/Development grant from the US National Institutes of Health (NIH) Innovative Molecular Analysis Technologies (IMAT) program for the project “In vivo metal-free cycloaddition chemistry driven pretargeted cancer radiotherapy”. The proposal was ranked in the top 9% of all applications.
The project will focus on developing new pretargeting strategies for use in alpha-emitter-based radiotherapy of cancer. Prof. Tom Quinn is a world-leading expert on alpha-emitters for therapeutic applications. Combining his expertise with Tagworks’ in vivo pretargeting chemistry approaches offers exciting opportunities for broadening the scope of therapeutically feasible alpha-emitters and enhancing the effectiveness of alpha-emitter radioimmunotherapy by increasing tumor-to-blood ratios.
The grant will be shared between the group of prof. Quinn and Tagworks and has a running time of three years.
By modifying the fastest and highly selective click reaction, the inverse-electron-demand-Diels-Alder reaction, Tagworks has achieved selective bioorthogonal release. This holds promise for the chemically triggered release, and thus activation, of drugs from tumor-bound Antibody-Drug Conjugates (ADCs), which would greatly enhance the scope of suitable ADC targets. Published in: Angewandte Chemie online 26 Nov 2013 – doi:10.1002/anie.201305969