Tokyo Medical and Dental University

Institute of Science Tokyo

Hitoshi Okazawa

Masunori Kajikawa

It is an object of the present invention to provide a human monoclonal antibody that has a high inhibitory activity on phosphorylation of Ser46 of human MARCKS and binds specifically to human HMGB1, and a pharmaceutical composition or the like for treating or preventing Alzheimer's disease, containing the antibody as an active component. A human monoclonal antibody that binds specifically to human HMGB1 and contains a heavy-chain CDR1, a heavy-chain CDR2, and a heavy-chain CDR3 consisting of specific amino acid sequences and a light-chain CDR1, a light-chain CDR2, and a light-chain CDR3 consisting of specific amino acid sequences is used. The human monoclonal antibody can also be used as a pharmaceutical composition for treating or preventing Alzheimer's disease.

Human monoclonal antibody binding specifically to human HMGB1, and pharmaceutical composition for treating or preventing Alzheimer's disease containing said human monoclonal antibody

It has been revealed that, from a pre-onset stage of Alzheimer's disease, enhancement of phosphorylations of MARCKS and the like causes abnormal spine formation or the like, consequently developing the disease. Moreover, it has also been revealed that the phosphorylations of MARCKS and the like are caused by PKC and the like, and further that b-raf is involved in the phosphorylation of a tau protein important for the progression of Alzheimer's disease. Thus, these proteins have been found to be target molecules useful in the diagnosis and treatment of Alzheimer's disease. In addition, it has also been revealed that, pre-onset in a stage of frontotemporal lobar degeneration also, b-RAF phosphorylation enhancement causes a decrease in the number of spines and the like, consequently developing the disease. Thus, b-RAF has been found to be a target molecule useful in the diagnosis and treatment of frontotemporal lobar degeneration.

Diagnosis methods, diagnostic agents, and therapeutic agents against alzheimer's disease and frontotemporal lobar degeneration, and screening methods for these agents

To provide a compound which enables treatment or prevention of spinocerebellar ataxia, analyses were carried out based on a screening using a spinocerebellar ataxia type 1 (SCA1) fly model and on the like. As a result, the following proteins ameliorating the pathology of spinocerebellar ataxia were identified: RPA1, PNKP, XRCC3, XRCC4, CCNH, POLE, POLH, and PER1. On the other hand, the following proteins aggravating the pathology were identified: CHK1, LIG3, FEN1, LIG1, ERCC5, XAB2, ERCC2, DMC1, RECQL5, MUS81, EME1, SPO11, and BLM. In addition, it has been revealed that ATXN1, which is a cause of SCA1, binds to RPA1, BRCA1, and BRCA2, and suppresses the activities of these proteins, so that the above-described pathology is caused.

Methods for treating spinocerebellar ataxia type I using RPA1

An anti-HMGB1 antibody comprising a light chain variable region comprising complementarity-determining regions or the like including amino acid sequences of SEQ ID NOs: 4 to 6, and a heavy chain variable region comprising complementarity-determining regions or the like including amino acid sequences of SEQ ID NOs: 10 to 12, or an anti-HMGB1 antibody comprising a light chain variable region or the like comprising an amino acid sequence of SEQ ID NO: 3, and a heavy chain variable region comprising an amino acid sequence or the like of SEQ ID NO: 9, and a composition for treating or preventing Alzheimer's disease, comprising the same as an active ingredient.

Antibodies against HMB1, and composition comprising same for treating or preventing alzheimer's disease

To provide a novel protein that can be a preventive/remedy in neurodegenerative diseases such as polyglutamine diseases based on the finding obtained by revealing the relationship between transcriptional dysfunction and neuronal death. Disclosed is a protein that is one of the following proteins (a) and (b).

Gene encoding a protein and preventive/remedy for neurodegenerative diseases such as polyglutamine diseases by utilizing the same

To provide a prophylactic/therapeutic agent for neurodegenerative diseases (such as polyglutamine diseases), the agent containing an HMGB family protein or a derivative thereof, such as a protein according any one of (a) and (b) below:

Growing community of inventors

Tokyo, Japan

Hitoshi Okazawa