ADCC活性又はCDC活性を有する抗Prominin-1抗体

Anticorps anti-prominine-1 à activité adcc ou activité cdc

Anti-prominin-1 antibody having adcc activity or cdc activity

Abstract

Disclosed is an antibody capable of binding to Prominin-1 and having an ADCC activity and/or a CDC activity. Also disclosed is a pharmaceutical composition comprising the antibody as an active ingredient. A nucleotide sequence of a variable region of an AC133 antibody is cloned to produce a recombinant antibody, and it is found that the recombinant antibody is imparted with an ADCC/CDC-inducing activity which is not found in the original AC133 antibody. It is also found that a chimeric antibody in which the sequence of a constant region is changed to human IgGl/k can induce potent ADCC when used in combination with a human effector cell. A humanized antibody having a CDR of an AC133 antibody grafted into a human antibody sequence therein is produced. The substitution of an amino acid residue is introduced into a humanized L-chain sequence in the humanized antibody to produce a humanized antibody having the same level of binding activity as that of the chimeric antibody. Thus, it becomes possible to provide an unlabeled AC133 human chimeric antibody having an anti-tumor activity and a humanized antibody.
本発明は、Prominin-1に結合し、ADCC活性及び/又はCDC活性を有する抗体、並びに該抗体を有効成分とする医薬組成物を提供することを目的とする。  本発明者らは、上記の課題を解決するために、AC133の抗体可変領域塩基配列をクローニングし、組換え抗体を作製することで、もともとのAC133抗体には存在しないADCC/CDC誘導作用が組換え抗体に付与されていることを見出し、本発明を完成させた。定常領域配列をヒトIgG1/kに変換したキメラ抗体は、ヒトキメラ抗体・ヒトエフェクター細胞との組み合わせにおいて強いADCCが誘導されることを見出した。また、本発明者らはAC133抗体のCDRをヒト抗体配列に移植したヒト化抗体を作製し、さらにヒト化L鎖配列にアミノ酸置換を導入することでキメラ抗体と同等の結合活性を有するヒト化抗体を作製した。本発明により抗腫瘍作用を有する非標識のAC133ヒトキメラ抗体、そしてヒト化抗体が提供される。
L'invention concerne un anticorps pouvant se lier à la prominine-1 et présentant une activité ADCC et/ou une activité CDC. Une composition pharmaceutique qui comprend l'anticorps en tant qu'ingrédient actif est également décrite. Une séquence nucléotidique d'une région variable d'un anticorps AC133 est clonée pour produire un anticorps recombiné ; il a été constaté que l'anticorps recombiné est transmis avec une activité induisant ADCC/CDC absente de l'anticorps AC133 original. Il a également été constaté qu'un anticorps chimérique dans lequel la séquence d'une région constante est changée en IgGl/k humain peut induire une ADCC efficace utilisée en combinaison avec une cellule effectrice humaine. Un anticorps humanisé pourvu d'un CDR d'un anticorps AC133 greffé dans une séquence d'anticorps humain à l'intérieur est ainsi produit. La substitution d'un résidu d'acide aminé est introduit dans une séquence à chaîne L humanisé dans l'anticorps humanisé pour produire un anticorps humanisé dont le niveau d'activité de liaison est le même que celui de l'anticorps chimérique. Ainsi, il devient possible de fournir un anticorps AC133 chimérique humain non étiqueté à activité antitumorale et anticorps humanisé.

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