The Imathera Platform

VECTORIZED INTERNAL RADIOTHERAPY – The COMETE project

The COMETE project (moleCular radiotherapy for METastatic Colorectal and gastric cancErs) responds to the FEDER-FSE+ regional call for projects. It focuses on the development of a portfolio of vectorized internal radiotherapy (RIV) molecules for the diagnosis and treatment of advanced digestive cancers. The project aims to develop two RIV candidates up to preclinical dosimetry studies, just before moving on to clinical evaluation. The COMETE project is led by a consortium consisting of the company Oncodesign Precision Medicine (OPM), the Institute of Molecular Chemistry of the University of Burgundy (ICMUB, UMR CNRS 6302) and the CGFL, all based in Dijon.

Internally Directed Radiotherapy (IDR) is a breakthrough therapeutic innovation for the treatment of certain metastatic cancers. It involves administering small molecules carrying a radioactive atom to patients, which will recognize and bind to a “target” expressed or overexpressed by tumor cells. The radioactivity delivered directly to the tumor cells will cause damage to their DNA and thus stop the progression of the disease. These treatments are administered under the responsibility of nuclear medicine physicians, in close collaboration with medical oncologists.

THE VIR IN 4 ACTS :

The other major advantage of IVR is the possibility of combining these treatments with “companion” diagnostic tools: the same molecule that targets the tumor can be used to obtain Positron Emission Tomography (PET) images, making it possible to verify that the target is indeed expressed by the tumors. This is called a “theranostic” approach (“thera” being the contraction of therapy and “nostic” the contraction of diagnostic). These images taken before IVR will make it possible to predict the effectiveness of the treatment, and therefore to only offer it to patients likely to benefit from it. This theranostic strategy, which also allows the monitoring of the effectiveness of IVR treatments, is therefore part of a personalized medicine approach.

Digestive cancers represent more than 20% of cancers in France, among which colorectal, gastric and pancreatic cancers correspond to 61%, 12% and 8% respectively. Colorectal cancer is the 2nd most diagnosed cancer in women and the 3rd in men. Surgery is the mainstay of treatment for local and loco-regional pathologies. However, nearly 50% of patients with colorectal cancer will develop metastases, which contributes to a high mortality rate in the face of the failure of current therapies. The rise of new therapeutic strategies for colorectal cancer, combining surgery, radiotherapy and chemotherapy, has not led to a significant improvement in the 5-year survival of metastatic patients, which remains below 10%.

Gastric cancer is the 5th most commonly diagnosed cancer and the 3rd leading cause of death worldwide. The prognosis of gastric cancer is linked to the stage of the disease at the time of diagnosis. The therapeutic offer for advanced gastric cancer, characterized by the appearance of metastases, is very limited. In particular, the presence of cerebral metastases worsens the prognosis and the average median survival is between 1.3 and 2.4 months.

Pancreatic cancer is the 6th most commonly diagnosed cancer in France and the 4th leading cause of death in women and the 5th leading cause of death in men. The 5-year survival rate for patients with pancreatic cancer is less than 4%, making it a cancer with a very poor prognosis.

In this project, we propose to develop treatments by vectorized internal radiotherapy (RIV), making it possible to meet this unmet clinical need and to increase the survival of patients with metastatic digestive cancers.

The COMETE project is structured around 4 main scientific objectives:

1. The identification and validation of tumor targets in metastatic digestive cancers, via artificial intelligence approaches and innovative technological platforms for the production of highly specific biological vectors.
2. The development of new RIV molecules to treat metastatic digestive cancers, from their design and optimization to the selection of the best molecule for early-phase human development.
3. Evaluation of the anti-tumor efficacy and toxicity of RIV molecules on preclinical models of metastatic colorectal and gastric cancers.
4. The development of “companion” imaging agents for IVR, to enable the personalization of therapeutic management (selection of responding patients, dose optimization, monitoring of efficacy).

Solid Tumor – TRIPLE Negative Breast Cancer

Among the different types of breast cancer, triple-negative breast cancer consists of tumor cells that do not express the receptors targeted by most of the innovative therapies currently available for other types of breast cancer. This cancer is particularly aggressive and associated with high mortality with a 5-year survival rate of less than 25%. Its treatment remains a real challenge today because no targeted therapy can be offered. Triple-negative breast cancer is characterized by an infiltration of immunosuppressive cells which, by suppressing anti-tumor immune responses, promote tumor progression and the development of metastases. Our project therefore aims, on the one hand, to develop new drugs targeting these immunosuppressive cells and, on the other hand, to validate markers for therapeutic monitoring of such treatments.

Our team is currently working in collaboration with the INSERM HSP-pathies team led by Dr. Carmen Garrido on a stress protein: Gp96, whose increased presence in certain tumors is associated with a poor prognosis. We have shown that Gp96 is present on the membrane of a type of immunosuppressive macrophage: M2 macrophages, whose expression is correlated with a poor prognosis. We were able to image these immunosuppressive macrophages in vivo using SPECT imaging in our triple-negative breast cancer models and monitor their reduction when using a Gp96 inhibitor. Thus, imaging these immunosuppressive macrophages could be an innovative tool as a potential marker for prognosis, therapeutic prediction, and/or monitoring in triple-negative breast cancer.

Related publications:

• Bouchard A, Sikner H, Baverel V, Garnier AR, Monterrat M, Moreau M, Limagne E, Garrido C, Kohli E, Collin B, Bellaye PS. The GRP94 Inhibitor PU-WS13 Decreases M2-like Macrophages in Murine TNBC Tumors: A Pharmaco-Imaging Study with ^99mTc-Tilmanocept SPECT. Cells. 2021 Dec 2;10(12):3393
• Chaumonnot, S. Masson, H. Sikner, A. Bouchard, V. Baverel, P. S. Bellaye, B. Collin, C. Garrido, E. Kohli, The HSP GRP94 interacts with macrophage intracellular complement C3 and impacts M2 profile during ER stress. Cell Death Dis 12, 114 (2021).
• 99mTc-Timanocept Spect Imaging As A Potential Non-Invasive Method To Quantify CD206+ Tumor-Associated M2-like Macrophages, EMIM 2021 (poster)

Solid Tumor – Low-HER2 Breast Cancer

Breast cancer is the most common cancer worldwide. In fact, breast tumors in women alone account for approximately 11.7% of new cancer cases each year, with more than two million women diagnosed in 2020, making this disease a major public health issue. At the molecular level, this malignant tumor is highly heterogeneous and can be divided into five groups (Luminal A, Luminal B HER2-negative, Luminal B HER2-positive, HER2-enriched, triple-negative) based on the immunohistochemical expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER2). Approximately 20% of newly diagnosed breast cancer cases are HER2-positive, and the prognosis for this group has improved with anti-HER2 targeted therapy based on monoclonal antibodies. Despite this progress, a high percentage of patients (40-50%) have low HER2 expression (HER2-low), in whom anti-HER2 therapies are not very effective. However, recent studies have shown that HER2-low patients may benefit from new HER2-targeted therapies based on “armed” antibodies (antibody drug conjugates, ADCs). However, resistance to these new therapies has been observed. In addition, accurate determination of HER2 expression is essential to identify patients who may benefit from

Our preliminary results showed that nuclear imaging, using a HER2-specific probe, could detect the level of HER2 expression in various preclinical breast cancer models. These results enabled our platform to obtain ANR funding (EITHER2BC) of €324,000 over 3 years (2023-2026) to develop these probes for the diagnosis and therapy of HER2-low breast cancers.

Solid Tumor – Fluorescence-Guided Surgery

Despite the emergence of targeted therapies, surgery still plays a vital role in the treatment of colorectal and pancreatic cancers. A major challenge is the difficulty of detecting and visualizing tumor margins. Fluorescence-guided surgery (FGS) allows surgeons to better visualize anatomical structures in real time. Additionally, FGS can be enhanced by combining preoperative imaging to accurately localize tumors. In this project, we propose to design and evaluate bimodal imaging conjugates (nuclear/fluorescence imaging) in order to improve pre-operative staging (SPECT), intra-operative detection of tumors and their resection (FGS) but also to improve post-operative monitoring (SPECT). Our probes will be tested for FGS in different preclinical models mimicking human pathology, such as orthotopic models of colon and pancreatic cancer, but also models mimicking the formation of liver metastases or peritoneal carcinomatosis. The expected results of this project are, a fine visualization of tumors before surgery (SPECT imaging) and a more precise detection by fluorescence to minimize the extent of resection. Finally, the absence of recurrence can be detected using this compound a few weeks after surgery (SPECT).

This project allowed our platform to contribute to a project funded by INCA (PLBIO23-023) to the tune of 593,460 euros over 3 years (2023-2026) led by Dr. Catherine Paul (École Pratique des Hautes Études – Université PSL) and in collaboration with ICMUB (Dr. Goze Christine) and the CHU of Besançon (Dr. Doussot Alexandre).

Related publications:

• M. Privat , A. Massot , F. Hermetet, H. Al Sabea, C. Racoeur, N. Mabrouk , M. Cordonnier, M. Moreau, B. Collin, A. Bettaieb, F. Denat, E. Bodio, PS Bellaye, C. Goze, C. Paul. Development of an Immuno-SPECT/Fluorescent Bimodal Tracer Targeting Human or Murine PD-L1 on Preclinical Models. J Med Chem 2024.
• Privat M, Bellaye PS, Chazeau E, Racoeur C, Adumeau P, Vivier D, Bernhard C, Moreau M, Collin B, Bettaieb A, Denat F, Bodio E, Paul C, Goze C. First Comparison Study of the In Vitro and In Vivo Properties of a Randomly and Site-Specifically Conjugated SPECT/NIRF Monomolecular Multimodal Imaging Probe (MOMIP) Based on an aza-BODIPY Fluorophore. Bioconjug Chem 2023.
• M. Privat, P. S. Bellaye, R. Lescure, A. Massot, O. Baffroy, M. Moreau, C. Racoeur, G. Marcion, F. Denat, A. Bettaieb, B. Collin, E. Bodio, C. Paul, C. Goze, Development of an Easily Bioconjugatable Water-Soluble Single-Photon Emission-Computed Tomography/Optical Imaging Bimodal Imaging Probe Based on the aza-BODIPY Fluorophore. J Med Chem, (2021).

Hematology – lymphoma / myeloma

Our hematology projects aim to develop new imaging agents to better detect these cancers and offer solutions that facilitate patient monitoring and therapeutic decisions. Our research focuses on two main targets: the IL-1RAP protein, involved in inflammation and tumor development, is found overexpressed in several cancers, including acute and chronic myeloid leukemias. And the CD38 receptor, currently used clinically in the treatment of myeloma, anti-CD38 antibodies (e.g., Daratumumab) could also prove effective in certain forms of lymphoma, such as Burkitt lymphoma, which mainly affects children and young adults.

Hematological cancers or “blood cancers” affect approximately 35,000 people each year in France and mainly concern children, young adults and the elderly. Leukemia, lymphoma, and myeloma are the most common. Hematological cancers occur when the maturation of blood cells—white blood cells, red blood cells, and platelets—is impaired, which promotes their abnormal proliferation. Blood cells first develop in the bone marrow, deep within the bones, before being released into the blood. The accumulation of altered blood cells hinders the normal functioning of other cells (fighting infections, preventing bleeding, etc.). The earlier the alterations appear in the maturation process, the more aggressive the cancer is likely to be. The discovery of new early biomarkers of progression and treatment efficacy in this type of pathology is crucial for improving patient care.

In this context, we are working in collaboration with Dr. Christophe Ferrand ( CanCell Therapeutics , Besançon) to develop a companion imaging biomarker for a new CAR-T cell therapy targeting IL-1RAP. This innovative therapy is currently in clinical trials (Besançon University Hospital, CanCell Therapeutics), and a companion imaging biomarker targeting IL-1RAP could help better select patients with overexpression of this target and for whom this therapy is most likely to work. Our goal is therefore to develop a diagnostic companion based on an antibody targeting IL-1RAP modified to visualize it using medical imaging by incorporating a radioactive isotope visible on PET/CT, SPECT/CT, and/or PET/MRI imaging. Using this technology, it is also possible to replace the radioactive imaging isotope with another, more irradiating isotope, thus making it possible to obtain a therapeutic agent using the vectorized internal radiotherapy technique in order to specifically eliminate tumor cells.

To demonstrate the usefulness of targeting the CD38 receptor in lymphomas, we are currently testing anti-CD38 antibodies in different lymphoma models in collaboration with the hematology department of the Dijon University Hospital. To do this, we are slightly modifying these antibodies so that they can be observed using medical imaging techniques (PET/CT, SPECT/CT, PET/MRI). In this context, it is also possible to replace the radioactive imaging isotope with another, more irradiating isotope, thus making it possible to obtain a therapeutic agent via the vectorized internal radiotherapy technique in order to specifically eliminate tumor cells.

Imaging of cell therapies (e.g. CAR-T cells)

Cell therapies are innovative therapies in several pathologies including cancers, heart disease and autoimmune diseases. Cell therapy consists of either producing cells from a healthy donor in a laboratory or taking cells from a patient, then possibly modifying them to assign them a specific function, to reimplant them in the patient. These therapies often show strong efficacy in certain patients but are sometimes accompanied by adverse effects that can be serious. It is in this context that our research projects aim to give these therapeutic cells imaging capabilities in order to be able to monitor them in real time once reinjected into the patient. To this end, we propose modifying the cells so that they express on their surface proteins capable of trapping radioactive molecules for nuclear imaging. In this way, we will be able to monitor the accumulation of cells in tumors to evaluate their effectiveness and, at the same time, monitor the accumulation of cells in other organs to evaluate potential side effects. In this context we work in collaboration with Dr Alvaro BAEZA GARCIA (INSERM U1231, HSP-pathies team, Dr Carmen Garrido).

Idiopathic pulmonary fibrosis (IPF) is a rare, irreversible disease of unknown causes. It is a chronic condition characterized by progressive scarring of the lungs, leading to an accumulation of collagen-producing cells responsible for stiffening the lungs. As a result, the passage of oxygen and the release of carbon dioxide are no longer ensured, and patients primarily suffer from significant breathing difficulties such as progressive shortness of breath, both during exercise and at rest, a chronic dry cough, and severe fatigue. IPF generally begins after the age of 50 and has a rather poor prognosis, with a median survival of approximately 5 years after diagnosis. France is estimated to have at least 12,000 people affected and at least 4,400 new cases each year. Treatments remain very limited, with two compounds, pirfenidone and nintedanib, which have proven effective in reducing disease progression without completely halting it. Diagnostic difficulties and the lack of tools for monitoring disease progression and/or treatment effectiveness are significant clinical issues. Our goal is to find nuclear imaging tools that facilitate early diagnosis and patient monitoring in order to improve their care and survival.

Our platform has obtained €240,000 in ANR (HYMAGE-IPF) funding over three years (2020-2023) to develop, in collaboration with the INSERM HSP-pathies team led by Dr. Carmen Garrido and the Dijon University Hospital’s Rare Lung Diseases Reference Center led by Professor Philippe Bonniaud, imaging tracers for IPF targeting:

Hypoxia

Due to the destruction of lung structure by excess scar tissue that disrupts gas exchange, hypoxia (lack of oxygen) is a significant characteristic of the lungs of patients with IPF. Using a radiotracer specific to hypoxic regions, 18F-FMISO (a radioactive molecule that specifically accumulates in cells under oxygen deficiency), we were able to show that areas of hypoxia were more prominent in lungs with fibrosis, correlating with disease severity. Furthermore, the level of pulmonary hypoxia measured by imaging with 18F-FMISO is a good predictive marker of disease progression and response to the anti-fibrosis treatments nintedanib and pirfenidone in our preclinical models (for more details, see the associated publication).

Related publication:

• Tanguy, F. Goirand, A. Bouchard, J. Frenay, M. Moreau, C. Mothes, A. Oudot, A. Helbling, M. Guillemin, P. Bonniaud, A. Cochet, B. Collin, P. S. Bellaye, [18F]FMISO PET/CT imaging of hypoxia as a non-invasive biomarker of disease progression and therapy efficacy in a preclinical model of pulmonary fibrosis: comparison with the [18F]FDG PET/CT approach. Eur J Nucl Med Mol Imaging, (2021).
• Bellaye PS, Beltramo G, Burgy O, Collin B, Cochet A, Bonniaud P. Measurement of hypoxia in the lung in idiopathic pulmonary fibrosis: a matter of control. Eur Respir J. 2022 Jan 27:2102711. doi: 10.1183/13993003.02711-2021.

Macrophages

Macrophages are circulating and/or resident immune cells in various organs, including the lungs, where they provide part of the defenses against infections. In a context of fibrosis, these macrophages take on a particular phenotype, called M2 macrophage, and secrete growth factors, notably TGF-β, which promote the production of scar tissue including collagen. Thanks to the use of a radiotracer specific to M2 macrophages, 99mTc-tilmanocept (a radioactive molecule that binds specifically to M2 macrophages), we were able to show that M2 macrophages were more present in the lungs in conditions of fibrosis. In addition, the rate of pulmonary M2 macrophages measured by imaging with 99mTc-tilmanocept makes it possible to precisely monitor the progression of the disease and the response to the anti-fibrosis treatment nintedanib. Finally, the inhibition of these aggressive pro-fibrosis macrophages makes it possible to reduce the progression of pulmonary fibrosis in our preclinical models.

Related publication:

• Pommerolle, G. Beltramo, L. Biziorek, M. Truchi, A MM Dias, L. Dondaine, J. Tanguy, N. Pernet, V. Goncalves, A. Bouchard, M. Monterrat, G. Savary, N. Pottier, K. Ask, M. RJ Kolb, B. Mari, C. Garrido, B. Collin, P. Bonniaud, O. Burgy, F. Goirand, PS. Bellaye. CD206+ macrophages are relevant non-invasive imaging biomarkers and therapeutic targets in experimental lung fibrosis. Thorax 2024.

Heat shock proteins

Heat shock proteins (or stress proteins, HSPs) are proteins that are overexpressed under stress conditions to ensure cell survival. In certain conditions, including pulmonary fibrosis, these proteins promote disease progression. Our team has already shown that HSPs are involved in the overproduction of scar tissue under fibrosis conditions and that their inhibition is a promising strategy to combat this disease. Thus, they are interesting targets for developing imaging agents to visualize the progression of fibrosis and the response to treatments. Our team focuses on HSP90 and Gp96 proteins, which are overexpressed and/or secreted in high quantities in patients with IPF and in preclinical models. Specific radioactive probes for imaging HSP90 and Gp96 in fibrosis are currently being developed at IMATHERA.

Related post:

• J Tanguy , PM Boutanquoi, O Burgy, L Dondaine, G Beltramo, B Uyanik, C Garrido, P Bonniaud, PS Bellaye, F Goirand. HSPB5 Inhibition by NCI-41356 Reduces Experimental Lung Fibrosis by Blocking TGF-β1 Signaling. Pharmaceuticals (Basel). 2023.
• P. S. Bellaye, O. Burgy, P. Bonniaud, M. Kolb, HSP47: a potential target for fibrotic diseases and implications for therapy. Expert Opin Ther Targets 25, 49-62 (2021).

Early detection of cardiac effects of anticancer drugs

Over the past 20 years, the prognosis for cancer patients has steadily improved. However, the potential long-term complications of certain treatments, particularly cardiac complications, are now a major concern.

Indeed, cardiac complications of cancer treatments, although rare, are currently treated late when the heart muscle becomes less efficient. The objective of the work carried out in the laboratory is to develop imaging tracers (molecules injected into patients and then detected by non-invasive imaging) to detect the cardiac impact of treatments before it affects the heart pump.

Related publications:

• Oudot A, Courteau A, Guillemin M, Vrigneaud JM, Walker PM, Brunotte F, Cochet A, Collin B. [¹²³I]MIBG is a better early marker of anthracycline cardiotoxicity than [¹⁸F]FDG: a preclinical SPECT/CT and simultaneous PET/MR study. EJNMMI Res. 2021 Sep 20;11(1):92.