Advanced Cell Models for Drug Discovery and Translational Research

Leveraging ATMP development with advanced human cell models reconstructing disease microenvironments

Advanced Cell Models at iBET

In the last 15+ years, iBET has built solid competences developing and implementing 3D in vitro human models to tackle preclinical challenges in the imminent areas of cancer immunotherapies and gene therapies.

Our advanced cell models reproduce key features of cellular microenvironments and their deregulation in disease, representing valuable platforms to accelerate drug discovery and development in the pharma industry.

In this R&D area we focus on:

  • Platform Development
  • Innate immune microenvironments in therapeutic response
  • Preclinical & Translational Research

Platform Development

We develop immunocompetent 3D in vitro models to study the impact of the cell microenvironment on therapeutic responses in tissues such as the central nervous system, liver, and solid tumors.  Depending on the target tissue and available cell sources, the culture systems employed may include 3D co-cultures, primary cultures of patient-derived cells and differentiation of human induced-pluripotent stem cells (hiPSCs). A strong focus is on a comprehensive functional characterization of the models, assuring reproducible and scalable bioprocesses. 

Innate immune microenvironments in therapeutic response

We interrogate innate immunity mechanisms modulating the cell microenvironment in disease to better understand therapeutic responses (ex. to rAAV vectors and monoclonal antibodies). We focus on inflammation and immunosuppression as key biological events underlying the crosstalk between tissue-/tumor-resident macrophages and other resident cells.

We explore cell-extracellular matrix (ECM) crosstalk and protein-protein and protein-glycan interactions to address the pathological consequences of microenvironment remodeling in the context of cancer, neurodegeneration, aging and infection.

 

 

 

Allow the study of innate immune responses to gene therapy vectors (rAAV) by addressing the cellular crosstalk between tissue-resident cells, including immune cells.

Targets:

  • neuron-astrocyte-microglia (CNS)
  • hepatocyte-Kupffer cell-liver sinusoidal endothelial cell (liver)

Reproduce the build-up of immunosuppressive microenvironments allowing for in-depth evaluation of therapeutic responses to advanced therapies.

Targets:

  • astrocyte-microglia/macrophage crosstalk in pediatric gliomas
  • tumor glycan-macrophage lectin interactions shaping immunosuppressive macrophages

Preclinical & Translational Research

We evaluate the contribution of the innate immune microenvironment to therapeutic response/resistance, in collaboration with biopharma industry partners and clinicians. Ongoing applications include target identification and validation, pre-clinical assays, prediction of patient outcomes and predictive biomarker discovery.

Disease Targets & Research Topics

Our 3D human cell model portfolio covers the areas of the central nervous system, liver, and solid tumors.

 

Innate immune microenvironments in therapeutic response

Related Technologies

Cell Sources and Culture Approaches
Bioreactor Platforms
Molecular and Cell Biology Tools
Imaging
Metabolic Characterization
Multi-Omics Tools

Highlights

Accelerating Research & Development for Advanced Therapies
iBET’s role in the ARDAT project is to develop and employ 3D innate immune-competent in vitro models of the human CNS to study immune responses elicited by gene therapy vectors (rAAV).

iBET’s role in the ARDAT project is to develop and employ 3D innate immune-competent in vitro models of the human CNS to study immune responses elicited by gene therapy vectors (rAAV).

Quality control readouts include assessment of vector tropism, transduction efficiency, cytotoxicity, innate immune response and persistence of viral genomes.

ARDAT is an EU-funded consortium of 34 international partners from academia, industry, and small/medium enterprises whose aim is to develop and deliver knowledge, tools and standards required to accelerate the development of ATMPs for the treatment of rare diseases.

ARDAT
Towards human innate immune-competent 3D hepatic models to address early tissue response to therapeutic AAV vectors
In collaboration with Boehringer Ingelheim International, we are developing human 3D models to explore the role of liver cell compartments in the innate immune response to rAAVs.

In collaboration with Boehringer Ingelheim International, we are developing human 3D models to explore the role of liver cell compartments in the innate immune response to rAAVs.

In 2023, an important milestone was achieved, with the establishment of a Kupffer-like cell (KLC) differentiation protocol from human monocytes. Leveraging an in-house method for long-term culture of primary human hepatocytes (PHH) as a spheroid, we showed that the KLCs in PHH spheroids exhibited phenotypic and functional features of their in vivo counterparts. A proof-of-concept study for gene therapy applications demonstrated mild inflammatory responses, which varied depending on the rAAV serotype and cassette. This model is suitable to address the liver’s early response to rAAV and other ATMPs, serving as a preclinical tool.

Addressing immunosuppression in brain tumors
In this project funded by FCT, I.P. (Portugal) and iBETXplore Innovation Program, we are engineering a novel 3D model mimicking the microenvironment of high-grade gliomas, a highly fatal group of brain cancers.

In this project funded by FCT, I.P., Ref 2022.02117.PTDC (Portugal) and iBETXplore Innovation Program, we are engineering a novel 3D model mimicking the microenvironment of high-grade gliomas, a highly fatal group of brain cancers.

The goal is to provide a platform which incorporates tumor cells, neural lineages, and brain resident immune cells to recapitulate immunosuppressive clues. This project will ultimately leverage the identification of new potential targets of markers of response to immunotherapies.

FCT, IP (Portuguese Science Foundation)
Leveraging patient-derived cancer models for the R&D of immunotherapeutics
An ambitious collaboration project between iBET and Abbvie (North Chicago, USA) resulted in the development of patient-derived cancer ex vivo models and their application to the discovery and development of cancer immunotherapeutics.

An ambitious collaboration project between iBET and Abbvie (North Chicago, USA) resulted in the development of patient-derived cancer ex vivo models and their application to the discovery and development of cancer immunotherapeutics.

The program spanned the period 2017/2022 and sponsored a postdoctoral researcher, three PhD theses, and two MSc theses, resulting in eight collaborative papers. This program further leveraged strong interactions between iBET and clinicians at IPOLFG (Lisbon, Portugal), which expanded beyond the scope of Abbvie’s project. The models developed are available for translational and clinical research studies, including biomarker discovery.

Preclinical model of hepatic Plasmodium infection
In a long-term collaboration project with Merck Global Health (Geneva, Switzerland) and iMM (Lisbon, Portugal) we developed 3D models of hepatic infection by Plasmodium to leverage Malaria Drug Discovery.

In a long-term collaboration project with Merck Global Health (Geneva, Switzerland) and iMM (Lisbon, Portugal) we developed 3D models of hepatic infection by Plasmodium to leverage Malaria Drug Discovery.

The project, concluded in 2022, resulted in 5 collaborative manuscripts and one PhD thesis. The models developed have been incorporated in the anti-malarial drug development cascade at Merck. Moreover, the data obtained in dose-response studies using the 3D models contributed to determine the dose of a new anti-malarial drug candidate for a phase I clinical trial. This was aligned with the 3Rs Principle in the pharmaceutical industry, namely in the reduction of animal experimentation.

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Related Teams

Advanced Cell Models Lab
Catarina Brito
Catarina Brito

Lab Head, Advanced Cell Models Laboratory

Leveraging ATMP development with advanced human cell models

Translational Immunology Lab
Nádia Duarte

Senior Scientist, Translational Immunology Lab

Strengthening immunology expertise at iBET, with a focus on developing tools and strategies to test and potentiate the effectiveness of advanced cell immunotherapies

Cellular Bioprocesses Lab
Paula Alves

Chief Executive Officer and Head of Cell Bioprocesses Lab

Improving cellular bioprocess understanding using state-of-the-art bioanalytics and omics tools.

Biosystems & Data Science Team
Inês Isidro

Head of Biosystems and Data Science

Deploying advanced data analytics to elucidate complex biological systems.

Mass Spectrometry Unit Team
Patrícia Gomes-Alves

Head of the Sanofi Satellite Lab | Coordinator of Analytical Services Unit and Mass Spectrometry Unit

Mass Spectrometry-based R&D services to support our partners in bioprocess understanding & development and in-depth characterization of biologics.

Selected Publications

Advanced Cell Models for Drug Discovery and Translational Research
2024
Advanced Cell Models for Drug Discovery and Translational Research
2023
Advanced Cell Models for Drug Discovery and Translational Research
2023
Advanced Cell Models for Drug Discovery and Translational Research
2020
Advanced Cell Models for Drug Discovery and Translational Research
2019
Advanced Cell Models for Drug Discovery and Translational Research
2018