Modeling Science for
Cancer Therapy

MIMO Biosciences is a spin-off company emerging from research outcomes obtained at CIMA Universidad de Navarra during the last twelve years . MIMO’s mission is to provide preclinical research services based on unique animal models that recapitulate a wide array of genetic alterations of different hematological malignancies including multiple myeloma and lymphomas. These models, which can be customised to the needs of each client, have been generated through thoughtful scientific and clinical collaboration by Dr. Jose Angel Martinez-Climent and his research team.

Our group at the University of Navarra has generated a collection of pre-clinical mouse models that accurately recapitulate the principal features of human multiple myeloma (MM) and B-cell lymphomas. Using these models in the Martinez-Climent lab, we are starting to unravel the sequential interplay between the tumor cell and the immune and non-immune microenvironment at unprecedented levels. In this context, we have set up preclinical therapy trials in genetically and immunologically diverse MM models to evaluate immunotherapy combinations, defining biomarkers of therapy response that were validated in two clinical series of MM (1). We have also established models for clinical indolent and aggressive B-cell lymphoma subtypes, which have been used to decipher how particular lymphoma microenvironment subtypes condition responses to chemo-immunotherapy in mouse models and clinical series (2). A second step has been to make our models closer to humans, by selective replacement of endogenous mouse genes coding for therapeutic target proteins by human ortholog gene sequences. As proof-of-concept we have developed mouse models with human CRBN, BCMA and GPRC5D expression in the tumor cells and CRBN and CD3 in the T-cell compartment, which allow testing clinical immunotherapy such as IMiDs/CELMoDs, CAR T cells and TCEs that otherwise cannot be tested in mouse systems. Critically, studies in mice are integrated with data from MM patients in collaboration with our clinical colleagues at the University of Navarra, aiming to provide scientific information with immediate clinical impact (3-5). Using our models, we have established collaborations with research groups from European and American top universities focused on MM and lymphoma. In addition, we have signed and executed 15 research agreements with major pharmaceutical companies in the last 3 years, with the goal of investigating preclinical and clinical agents for hematologic malignancies. We think our models constitute the next level of preclinical research that may translate scientific knowledge to clinical trials.

Mimo Biosciences, a spin-off of the university of navarra

In February 2024 we founded MIMO Biosciences, a start-up of the University of Navarra directed by Ricardo Perez-Merino, MBA (CEO), with Dr. Marta Larrayoz as R&D Director and Prof. Martinez-Climent as CSO. Knowhow, technology, models and IP rights have been licensed from M-Climent´s lab to MIMO, which has the mission of providing research services to academic and pharmaceutical partners in MM, lymphoma, and related fields. With a highly qualified scientific and management team of 7 employees, and with three research contracts with two pharmas already in place, MIMO has launched an ambitious program to develop newly designed, proprietary models of genetically diverse MM with multiple humanized targets.

These new models recreate clinical situations that require more effective therapies, such as high-risk MM with TP53 loss, genetic instability, or t(4;14), VRD and BCMA-targeted refractory states, extramedullary disease, and light-chain amyloidosis. In parallel, MIMO is generating patient-derived xenograft (PDX) models from MM patient samples engrafted into IL6-secreting immunodeficient mice reconstituted with a human immune system. The goal of the humanized PDX is to directly study clinical immunotherapy agents that cannot be tested in other experimental systems. These new models will be available by Q1-Q2 2025. Additionally, MIMO is expanding the generation of humanized mouse and PDX models for the principal B-cell lymphoma subtypes (DLBCL, FCL, LPL/WM, MZL/MALT lymphoma), as well as for acute myeloid leukemia (AML), which will be sequentially available by Q2-Q3 2025. As proof-of-principle, DLBCL of ABC and GCB subtypes with humanized CD19 or CD20 and CD3ε are being used to evaluate TCE and CAR T-cell therapies, while AML PDXs are serving to test targeted agents and immunotherapy combinations. Our expectation at MIMO is that such optimized, complementary mouse and human platforms will broaden and strengthen research collaborations with pharmaceutical companies for addressing virtually all scientific and clinical issues in hematology/oncology. Now located at the University of Navarra CIMA building, in Q1 2025 MIMO will move to its own state-of-the art research facilities currently under construction within the University of Navarra campus. Close to the Schools of Medicine, Science and Pharmacy, the Clinica University of Navarra hospital and CIMA buildings, MIMO and the University of Navarra have signed a collaboration agreement for the interchange and use of a wide range of services, including multiparametric flow cytometry, cell sorting, high-throughput and single-cell genomics, micro-CT and micro-PET imaging for rodents, surgery, histopathology, toxicology, human tissue bank, and computational data resources. MIMO counts on an international advisory network with key opinion leaders in hematology, oncology and immunology. Our final goal at MIMO is to become the preferred partner of pharmaceutical companies for preclinical research in cancer.

REFERENCES

1. Larrayoz M, Garcia-Barchino MJ, Celay J, Etxebeste A, Jimenez M, Perez C, Ordoñez R, Cobaleda C, Botta C, Fresquet V, Roa S, Goicoechea I, Maia C, Lasaga M, Chesi M, Bergsagel PL, Larrayoz MJ, Calasanz MJ, Campos-Sanchez E, Martinez-Cano J, Panizo C, Rodriguez-Otero P, Vicent S, Roncador G, Gonzalez P, Takahashi S, Katz SG, Walensky LD, Ruppert SM, Lasater EA, Amann M, Lozano T, Llopiz D, Sarobe P, Lasarte JJ, Planell N, Gomez-Cabrero D, Kudryashova O, Kurilovich A, Revuelta MV, Cerchietti L, Agirre X, San Miguel J, Paiva B, Prosper F, Martinez-Climent JA.
Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma.
Nature Med. 2023 Mar;29(3):632-645

2. Celay J, Recalde M, Revuelta MV, Larrayoz M, Rodriguez S, Garcia-Barchino MJ, Chapman-Fredricks JR, Lozano T, Lasarte JJ, Du MQ, Lossos IS, Roa S, Roccaro A, Canales M, Prosper F, Paiva B, Cerchietti L*, Martinez-Climent, JA*.
Remodeling of the Immune Microenvironment By Oncogenic MYD88 Dictates Immunotherapy Responses across Indolent and Aggressive B-Cell Lymphomas
Blood vol. 142; Supplement 1; DOI10.1182/blood-2023-173394; Nov 2, 2023

3. Rodriguez S, Celay J, Goicoechea I, Jimenez C, Botta C, Garcia-Barchino MJ, Garces JJ, Larrayoz M, Santos S, Alignani D, Vilas-Zornoza A, Perez C, Garate S, Sarvide S, Lopez A, Reinhardt HC, Carrasco YR, Sanchez-Garcia I, Larrayoz MJ, Calasanz MJ, Panizo C, Prosper F, Lamo-Espinosa JM, Motta M, Tucci A, Sacco A, Gentile M, Vitoria H, Geraldes C, Paiva A, Puig N, Garcia-Sanz R, Roccaro AM, Fuerte G, San Miguel JF, Martinez-Climent JA*, Paiva B*.
Preneoplastic somatic mutations including MYD88L265P in lymphoplasmacytic lymphoma.
Science Adv. 2022 Jan 21;8(3):eabl4644.

4. Botta C, Perez C, Larrayoz M, Puig N, Cedena MT, Termini R, Goicoechea I, Rodriguez S, Zabaleta A, Lopez A, Sarvide S, Blanco L, Papetti DM, Nobile MS, Besozzi D, Gentile M, Correale P, Siragusa S, Oriol A, González-Garcia ME, Sureda A, de Arriba F, Rios Tamayo R, Moraleda JM, Gironella M, Hernandez MT, Bargay J, Palomera L, Pérez-Montaña A, Goldschmidt H, Avet-Loiseau H, Roccaro A, Orfao A, Martinez-Lopez J, Rosiñol L, Lahuerta JJ, Blade J, Mateos MV, San-Miguel JF, Martinez Climent JA, Paiva B.
Large T cell clones expressing immune checkpoints increase during multiple myeloma evolution and predict treatment resistance.
Nature Commun. 2023 Sep 20;14(1):5825.

5. Itziar Cenzano, Miguel Cócera, Azari Bantan, Marta Larrayoz, Amaia Vilas-Zornoza, Patxi San-Martin, Paula Aguirre-Ruiz, Diego Alignani, Aitziber Lopez, Marta Miñana Barrios, Delia Quilez Agreda, Ignacio Sancho González, Javier Ruiz, Vincenzo Lagani, Jesper Tegner, Ignacio Martín-Subero, Xabier Agirre, Bruno Paiva, Paula Rodriguez-Otero, Luis-Esteban Tamariz-Amador, Jesús San-Miguel, Jose A. Martinez-Climent, Borja Saez, Mikel Hernáez, Isabel A. Calvo, David Gomez-Cabrero, Felipe Prosper. Transcriptional Remodeling of the Stromal and Endothelial Microenvironment in MGUS to Multiple Myeloma Progression. BioRxiv. 2024 May 7; doi: https://doi.org/10.1101/2024.04.24.589777

Modeling Science for
Cancer Therapy

Mimo Biosciences, a spin-off of the university of navarra

REFERENCES

Modeling Science for Cancer Therapy

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