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HIGHLY-FUNCTIONAL MUTANT OF HUMANIZED ANTI-EGFR ANTIBODY VARIABLE REGION UPDATE

外国特許コード F120006673
整理番号 S2010-0177
掲載日 2012年5月24日
出願国 世界知的所有権機関(WIPO)
国際出願番号 2010JP070127
国際公開番号 WO 2011062112
国際出願日 平成22年11月11日(2010.11.11)
国際公開日 平成23年5月26日(2011.5.26)
優先権データ
  • 特願2009-263147 (2009.11.18) JP
発明の名称 (英語) HIGHLY-FUNCTIONAL MUTANT OF HUMANIZED ANTI-EGFR ANTIBODY VARIABLE REGION UPDATE
発明の概要(英語) Disclosed is an antibody that exhibits excellent cytotoxicity and cell growth inhibition and that is based on an anti-human epithelial cell growth factor receptor (1) (Her1) antibody (528). Further disclosed is a method for producing same, and the like. The mutant of an H chain humanized variable region (5H) or an L chain humanized variable region (5L) of the anti-human epithelial cell growth factor receptor (1) (Her1) antibody (528) is the aforementioned antibody characterized by having one to a plurality (for example: 1 to 5, or 1 to 3) of amino acid mutations within CDR2. Further disclosed are antibody molecules containing said region, a nucleic acid molecule coding for these polypeptides, a method for producing said antibody molecules, and the like.
従来技術、競合技術の概要(英語) BACKGROUND ART
Rheumatoid arthritis and cancer (malignant tumor) security against therapy, in recent years, immunotherapy has been used. Immunotherapy for cancer, cancer cytotoxic activity specific for the antibodies are used. Such antibodies from the antibody medicament is, with fewer side effects, with the manufacturing of high therapeutic effect can be seen that on the other hand, an established animal cell is used to generate high costs for manufacture must be in question.
For this reason, of an antibody VH and VL domains of a single polypeptide chain in the single-chain antibody (scFv) antibody of the fabrication of a low molecule is a worldwide trend. The small molecule antibodies may also be produced in E. coli is inexpensive, by lowering of the molecular weight is reduced in vivo half-life, efficacy duration is reduced there is a concern. In addition, is an intact antibody such as IgG, against an antigen in a multivalent target binding on the other hand, typically, a monovalent low-molecular-weight antibody valency and therefore, the decrease of the affinity in question. Further, the main mechanism of action of antibody pharmaceuticals Fc mediated antibody dependent cell-mediated cytoxicity (ADCC) since the lit, do not have scFv Fc is a concern that the effect is low. It should be noted that, for the scFv, the non-patent document 1 can be referred to.
For this reason, specific immune cells and the cancer cells with the small molecule bridge the bispecific antibody and the like have been developed, referred to as BiTE, one portion of the first scFv and 2 tandem scFv type low-molecular bispecific antibody (Science. 2008 Aug 15 advanced in clinical trials is the only; 321 (5891): 974-7.). However this BiTE is, since the prepared using animal cells, the problems inherent to the yield and the manufacturing cost. Such as BiTE tandem scFv type low-molecular double-specific antibody may be, of the soluble low molecular weight prepared from E. coli but is difficult and also reports (J Mol Biol. 2003 330 (1): 99-111.), using the fact that animal cells BiTE is prepared.
One of the multispecific antibody is bispecific antibody (Bispecific Antibody: BsAb) two different 2 is capable of binding to a specifically to an antigen and therefore, this making the specific anti-tumor having an effect as a therapeutic as enabling a utilization method, which has been actively carried out thereof. (Diabody: Db) diabody such bispecific antibody is a minimum unit, derived from the same parent antibody variable region of the heavy chain (H chain) (V region) and light chain ('VH' by each other) the variable region of (L chain) ('VL' by each) (V region) non-covalently to each other to form a heterodimer is devised utilizing a property that the (non-patent document 2) in.
Such a diabody-type bispecific antibody is characterized by a high, low-molecular-weight (molecular weight of about 60,000) and low immunogenic attributed to the fact that high-permeability to tumor tissue, and further, for example, using microorganisms such as Escherichia coli can be prepared by an inexpensive mass, also, the functions using the genetic engineering can be readily changed can be exemplified.
The present inventors have, thus far, anti-human epidermal growth factor receptor antibody 528 and anti-CD3 antibody 1 OKT3 (Her1) that is produced using a diabody-type bispecific antibodies and humanized antibody (Ex3) and the diabody-type bispecific antibody is extremely potent anti-tumor effect (hExh3) has a finding (Patent Document 1). Further, other antibody that is produced using a diabody-type bispecific antibody by comparison, the above diabody-type bispecific antibody exhibits a superior effect in order to, humanized 528 antibody and humanized OKT3 variable region of the humanized antibody of the structural stability of itself, and combinations thereof is very important to be estimated.
Further, the present inventors have humanized diabody-type bispecific antibodies is based on the control of diverse structure and are highly functional bispecific antibody (Patent Document 2) have developed.
It should be noted that, other than the diabody-type bispecific antibody in the preparation of a bispecific antibody and the like, and non-patent document Non-patent Documents 3 to 4 described.
1 Anti-human epidermal growth factor receptor antibody 528 (Her1) cancer cell growth inhibiting effect. However, as already described, in the case of binding to a monovalent divalent EGFR, a low affinity for the antigen, the effect is hardly known. Actually humanized 528 (scFv) is a single chain antibody of cancer cell growth inhibiting effect was observed. A scFv in order to overcome such a drawback, by modification of the linker scFv already has been tried is the multimerization of (non-patent document 5). In recent years, inducing apoptosis in lymphoma scFv dimer and the like have been reported (non-patent document 6). However, with respect to solid cancer and carcinoma positive EGFR, exhibit growth inhibitory effects of the multimeric scFv not reports.
  • 出願人(英語)
  • ※2012年7月以前掲載分については米国以外のすべての指定国
  • TOHOKU UNIVERSITY
  • 発明者(英語)
  • KUMAGAI Izumi
  • NAKANISHI Takeshi
  • ASANO Ryutaro
  • UMETSU Mitsuo
国際特許分類(IPC)
指定国 National States: AE AG AL AM AO AT AU AZ BA BB BG BH BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LA LC LK LR LS LT LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PE PG PH PL PT RO RS RU SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ MD RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG
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