What is the key to treatment of brain diseases?
While there are many companies working on therapeutics for brain diseases, successful treatments have not been developed yet. We believe that no single method is enough to tackle the current obstacles of treating brain diseases, and that it’s important to combine the different approaches to crack the code. AIMEDBIO’s biggest strength lies in the fact that it is positioned in an environment where these different approaches are available. We call the coalescence of these approaches a “brain-oriented multi-disciplinary platform”.
With our CEO and many clinical advisory board members who are actively engaged in patient care, AIMEDBIO is in a good position to identify clinical unmet needs. Based on this understanding of the patients’ needs, AIMEDBIO uses its brain-oriented multi-disciplinary platform, consisting of largely five parts - big data, antibody-drug conjugate, blood-brain barrier penetration, brain immune modulation and patient-derived model (PDC/PDX), along the development process of therapeutics for brain diseases.
Our primary objective is to bring innovative therapeutics for brain diseases from bench to bedside.
The Blood brain barrier (BBB) is composed of tight junctions formed around the blood vessels in the brain with endothelial cells, pericytes and astrocytes. The BBB possesses highly selective permeability, only allowing the necessary molecules (water, carbon dioxide, and oxygen), fat-soluble substances (anesthetics and alcohols), and very small molecules with molecular weight less than 500Da to penetrate through from the blood vessel to the brain’s extracellular space.
Generally, therapeutic antibodies, which have molecular weight of 150kDa, have negligible BBB penetration rates below 0.1%. Large molecules like antibodies require a pathway called the receptor-mediated transcytosis (RMT) to pass through the BBB. A BBB-crossing platform would work like a ‘Trojan horse’, binding to one of the receptors expressed on brain endothelial cells, and carrying therapeutics across the BBB, into the brain.
AIMEDBIO’s BBB crossing platform improves BBB penetration of therapeutic antibodies by 20-times when tested in our proprietary 3D BBB model.
AIMEDBIO’s proprietary 3D BBB model largely enhanced the low physiological relevance of conventional 2D culture models to the BBB. By co-culturing endothelial cells and astrocytes, the 3D BBB model creates tight junctions resembling those of the BBB. AIMEDBIO’s BBB crossing platform was confirmed with the 3D BBB model to have good BBB penetration while maintaining therapeutic efficacy of its base therapeutic antibody.
Brain immune system plays crucial roles in the pathogenesis of neurodegenerative diseases and brain tumors. However, our understanding of the brain and its mechanism of immune homeostasis has been relatively poor compared with other organs. This has been a major hurdle for development of treatments for neurological diseases.
Recent advances in neuroimmunology research has shed light on how imbalances of brain immune homeostasis can lead to neurodegenerative diseases and brain tumors. By targeting key factors causing these imbalance, we aim to restore brain immune homeostasis, thereby reversing from disease state to healthy state.
A novel potent therapeutic targets are selected through bioinformatic analyses of patients’ brain immune system.
Patient-derived immune cells are utilized in high throughput immunological assays to validate our immune modulators, to maximize the relevancy of assay results.
To verify the efficacy of new treatments, behavioral screening platforms are differentiated by identifying specific symptoms in neurodegenerative animal models and humanized mouse models.
Conventional chemotherapy for cancer is a powerful treatment but there are many unwanted adverse effects as chemotherapy agents cannot differentiate cancer cells from healthy cells. Antibody, on the other hand, can be delivered specifically to its target, but have limited potency. Combining only the advantages of these two therapeutics, ADCs are designed to specifically bind to their target cells and deliver toxin payload directly into these cells, minimizing off-target killing of healthy cells and unwanted side-effects.
PRO: powerful treatment
CON: unwanted adverse effect by
also killing healthy cells
PRO: delivery to specific targets
CON: treatment effect not as
potent as chemotherapy
specifically bind to target cells
to directly deliver
powerful toxin payload
ADCs are composed of 1) monoclonal antibody (mAb) that binds a specific antigen on the surface of target cells, 2) linker molecule which functions as a stable bridge between the mAb and the payload, and 3) a potent toxin payload which induces cell killing.
Targets are selected based on big data analysis and validation through patient-derived cell and xenograft (PDC/PDX) system.
AIMEDBIO’s proprietary linker-payloads, AIMEDuoca™ and AIMEDecan™, confirmed to have higher sensitivity to brain tumors and brain metastasis tumors compared with other commonly used payloads.
valuation of the best combination of antibody-linker-payload through:
1) in vitro high-throughput screening system using 3D-organoid
2) in vivo orthotopic PDX models which represent the genomics of tumor models
Multi-omics platform helps us gain insights required for neuro-oncology and neurodegenerative disease treatment and enables us to select most relevant indications to our targets with higher speed and accuracy.
Targets related to drug responses of patient-derived cells (PDCs) are discovered through multi-omics (genomics, transcriptome, etc.) data analysis.
AIMEDBIO leverages big data to identify new drug indications and biomarkers. Through multi-omics data analysis, clinical studies will proceed in a specific subset of diseases where AIMEDBIO’s drugs are expected to be most effective.
AIMEDBIO is establishing an in-silico environment based on Machine Learning(ML) and Artificial Intelligence(AI). Our algorithm will analyze the association and significance of patients' genetic variations and drug responses to realize precision medicine
For development of tumor-targeting drugs, immortalized tumor cell lines, are widely used. However, cell lines lack the genetic complexity found in patients, and thus may not adequately recapitulate patient tumor biology, causing difficulties in prediction of clinical outcome.
Patient-derived cells (PDCs) are cells directly generated from patients’ tumor specimens, and patient-derived xenografts (PDXs) are cancer models which are made by implanting patients' tumor tissue or cells into mice. PDCs/PDXs allow for a more relevant drug efficacy assessment by representing each patient’s heterogeneous characteristics compared with cell lines. The reason cell lines are mostly used is because PDCs can be challenging to obtain and culture.
AIMEDBIO’s researchers have more than 10 years of experience in culturing PDCs and generating PDXs of various cancer types. We have PDCs/PDXs of over 12 types of cancer, including more than 152 models of brain tumor PDXs. AIMEDBIO has the ability to generate not only subcutaneous models frequently used in efficacy tests, but also orthotopic models which enables us to assess tumor characteristics (e.g. tumor invasion, metastasis) and specific drug effect on target organ.
We are actively collaborating with the major hospitals in Korea to receive patient tumor samples straight from the operating room.
For accurate clinical outcome prediction, PDCs are used from target/indication selection to efficacy evaluation.
To overcome possible hurdles caused by low homology of brain among different species, AIMEDBIO has developed patient-derived 3D tumor organoid assay platforms which allows more precise and accurate clinical outcome prediction.