CNR, MEDICINA

Monoclonal antibody for Alzheimer’s Disease

The present invention refers to a monoclonal antibody which specifically binds and neutralizes a neurotoxic tau-derived peptide and its therapeutic application for the cure and treatment of Alzheimer’s Disease.

Patent status

SUBMITTED

Priority Number

IT-102018000004936

Priority Date

27/04/2018

License

INTERNATIONAL

Market

The major limitations of the use of antibodies against amyloid for the therapeutic treatment of AD include the development of encephalitis, lack of clinical improvement and the absence of an effect on the pathology of tau which is another important neuropathological feature of AD. Our antibody that selectively neutralizes a toxic form of tau and also has a powerful effect on amyloid production and memory deficits will allow us to optimize a better therapeutic strategy for treating AD. The SOM to which the humanized version of our anti-tau monoclonal antibody is directed is the bio-medical and health one. Considering that the incidence of dementigenic diseases, such as Alzheimer's Disease (AD) is increasing due to the progressive aging of the world population, forecasts in the following decades are for future growth of the market for the marketing of the product.

Problem

Due to the progressive aging of the worldwide population, neurodegenerative diseases, such as Alzheimer's Disease (AD), show heavy health and socio-economic burden on our society and pharmacological treatments aimed at slowing down or even stopping its irreversible clinical course are urgently needed. Pharmacological interventions currently available are really ineffective and only symptomatic. In this perspective, it is believed that the development of novel and best-targeted therapeutic approaches for the treatment of this devastating disorder represents the winning strategy.

Current Technology Limitations

The use of specific monoclonal antibodies binding and neutralizing the neurotoxic peptides (beta-amyloid and tau) causally involved in the onset and development of Alzheimer's disease represents a novel avenue of immunotherapeutic approaches for the treatment of this neurodegenerative illness. In this framework, the development of antibodies, that selectively remove these target toxic peptides from the brain -without interfering with the normal physiology of the neuronal proteins they are derived from- is crucial to ensure a cure that is both effective and avoid of harmful potential side-effects.

Killer Application

Engineering of the mouse antibody 12A12mAb in an its ‘’humanized’’ variant endowed with high affinity, high specificity and absence of immunogenicity followed by biochemical, biophysical and functional characterization.

Our Technology and solutions

Our research group has developed a monoclonal antibody (12A12mAb) which has been patented (PCT060934 "Antibody directed against a tau-derived neurotoxic peptide and uses thereof", 27.04.2018). Such antibody, which is unique in its ability of selectively recognizing a highly-neurotoxic peptide generated by abnormal cleavage of human tau without interfering with the important physiological function of the whole protein, when intravenously injected into two animal models of Alzheimer's disease (AD), markedly reduces the symptoms, both at a behavioral (spatial memory, orientation) and anatomo-pathological (senile plaques and neuro-fibrillar aggregates) levels. A "humanized" version of this antibody will allow patients a best targeted and safer therapeutic pathway for AD.

Advantages

The clinical use of a "humanized" version of the 12A12mAb antibody will allow patients to initiate a therapeutic approach to Alzheimer's disease that is more advantageous than traditional immunotherapies as it is: 1) best-targeted and, therefore, potentially more effective (selective for the toxic target in the absence of non-specific, "non-productive" and highly harmful interactions); 2) free from potential side-effects (possibility of long-term treatments which are essential for the clinical management of chronic age-associated diseases, use of a lower dosages with reduction of side effects); 3) non-invasive (intravenous) administration route (ease of therapeutic use on a large number of patients).

Roadmap

The production and characterization of the "humanized" variant of 12A12mAb is the essential step to be performed before starting in patients a future therapeutic avenue for AD. The following steps are required: dose-response studies in animal models, preclinical pharmacology and pharmacokinetic studies, analysis of biochemical and biophysical properties for optimal formulation, human clinical studies. It needs the support of a pharmaceutical industry which is interested in the production, development and optimization of pharmacologically active molecules (therapeutic monoclonal antibodies) with GMP technology.

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The team

Pietro Calissano

Full Professor in Neurophysiology, is Group Leader at EBRI and co-founder of the institute. After the degree in Medicine in 1964, he started working with the Rita Levi-Montalcini, Nobel prize for the discovery of NGF and founder of EBRI: this fruitful collaboration continued for the rest of her life. Since 2012 he is President of EBRI. His research interests are focused on the physiopathology of neurodeneration, in particular the molecular and cellular biology of tau, synucleins, amyloid beta precursor proteins (APPs) in Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS) and related neurodegenerative disorders of aging.

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Antonino Cattaneo

He undertook research in Neurobiology at Scuola Normale Superiore with Lamberto Maffei, working on the encoding of visual information by cells of the the visual cortex (1977-1980). He then worked at the CNR Institute of Cell Biology with Rita Levi Montalcini and Pietro Calissano on the molecular mechanisms of neuronal differentiation by Nerve Growth Factor (1981-1984). From 2004 he assisted Rita Levi-Montalcini in launching the European Brain Research Institute, for which he served as the Scientific Director, before joyning Scuola Normale Superiore in 2009. He is a member of the European Molecular Biology Organization (EMBO) and of the Accademia delle Scienze dei XL. His research led to i) the development of the intrabody protein silencing technology, ii) the discovery of proNGF/NGF imbalance as an unpstream driver mechanism for Alzheimer's neurodegeneration, iii) the development of innovative neurotrophic factor based therapies for neurodegenerative diseases. Two humanized recombinant antibodies developed in his laboratory are currently under clinical testing in man.

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Valentina Latina

PhD in Toxicology and graduated in Biological Sciences and actively participating in the research of our laboratory for years.

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Giuseppina Amadoro

Permanent researcher at CNR and for years she has been interested in the study of the molecular mechanisms of tau-mediate neurodegeneration;

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