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ANTIBODY FRAGMENT AND BISPECIFIC ANTIBODY COMPRISING SAID ANTIBODY FRAGMENT

Foreign code F200010005
File No. (S2018-0495-N0)
Posted date Jan 29, 2020
Country WIPO
International application number 2019JP015528
International publication number WO 2019198731
Date of international filing Apr 9, 2019
Date of international publication Oct 17, 2019
Priority data
  • P2018-075339 (Apr 10, 2018) JP
Title ANTIBODY FRAGMENT AND BISPECIFIC ANTIBODY COMPRISING SAID ANTIBODY FRAGMENT
Abstract In the present invention, an antibody fragment that binds specifically to human HER2 comprises the amino acid sequence of a single polypeptide chain having the structure in formula (1). Formula (1): FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 (In the formula, FR1, FR2, FR3, and FR4 are framework regions, and CDR1, CDR2, and CDR3 are complementarity determining regions and satisfy at least one of conditions (I) to (III): (I) CDR1 comprises an amino acid sequence represented by any of SEQ ID NOs: 5–11, 53–55, and 59–64, comprises an amino acid sequence containing one or more deletions, substitutions, or additions in an amino acid sequence represented by any of SEQ ID NOs: 5–11, 53–55, and 59–64, or comprises an amino acid sequence having at least 80% identity with an amino acid sequence represented by any of SEQ ID NOs: 5–11, 53–55, and 59–64; (II) CDR2 comprises an amino acid sequence represented by any of SEQ ID NOs: 12–18, comprises an amino acid sequence containing one or more deletions, substitutions, or additions in an amino acid sequence represented by any of SEQ ID NOs: 12–18, or comprises an amino acid sequence having at least 80% identity with an amino acid sequence represented by any of SEQ ID NOs: 12–18; and (III) CDR3 comprises an amino acid sequence represented by any of SEQ ID NOs: 19–25, 56–58, and 65–84, comprises an amino acid sequence containing one or more deletions, substitutions, or additions in an amino acid sequence represented by any of SEQ ID NOs: 19–25, 56–58, and 65–84, or comprises an amino acid sequence having at least 80% identity with an amino acid sequence represented by any of SEQ ID NOs: 19–25, 56–58, and 65–84.)
Outline of related art and contending technology BACKGROUND ART
Cancer (malignant tumor) as the safety with respect to the therapeutic agent, immunotherapy is used. Immunotherapy for cancer, cancer-specific cytotoxic activity of the antibody are used.
Human epidermal growth factor Receptor 2 (HER2) is present on the cell surface glycoprotein receptor tyrosine kinase (molecular weight of about 185kDa) and, EGFR2, ErbB2, CD340, or also referred to as the NEU. HER2 Is deficient or a variant thereof including breast cancer including a plurality of over-expressed in cancer, has attracted attention as a therapeutic target. HER2 Antibody is targeted, targeting the expected therapeutic effect of the cancer cell surface antigens one.
Has a basic structure of the antibody, the heavy and light chain subunit by a disulfide bond is formed by, such as the type of polymer since the amount of the IgG, is not able to penetrate the deep portion of the tumor. Therefore, the variable region of the low molecular weight fragments of the antibody is currently under development.
In recent years, Hamers-Casterman et al. in an animal such as a family or a dromedary germlining germlining, only the heavy chain CH1 domain does not include the presence of antibody was reported (Non-Patent Document 1). Camel (single Variable domain of the Heavy chain of a Heavy-chain camel antibody variable region fragment of an antibody derived from: VHH) is, in spite of a single domain, a high affinity, has a high specificity. Thus, obtained by immunization of animals and plants llama antibody phage display library group such as in vitro selection operation is performed that specifically binds to a variety of targets are VHH is obtained (non-patent document 2, 3).
On the other hand, in order to improve the affinity for the antigen, the antibody or a multivalent multimerisation also known technology. Harwood et al. for a three-dimer domain are known as anti-CD3 scFv1 antibody collagen XVIIItrimerization domain 3 and the anti-EGFR VHH molecule can be a fusion molecule, EGFR trivalent to design a recombinant antibody, a recombinant antibody according to the same domain is composed of a single one value higher than the recombinant antibodies of exerting damage reported (Non-Patent Document 4).
IgG type antibodies in a conventional, natural killer cells than the high activity of the T cells cannot be used, the T cells can be used a low molecular weight antibodies are developed, a low molecule, and bind to cells having a valence of 1, a low affinity for antigen binding.
To increase the binding affinity of the antibody and antigen antibody designed to provide enhanced active injury by a multi-value, is considered to be an effective approach, the heavy and light chain of the linker between the shortening of the sequence, removing a multi-value multi-value design is effective to some extent the formation of the association of the (non-patent document 5, 6), only a single multi-value association is formed has not been a design.
Scope of claims (In Japanese)[請求項1]
 ヒトHER2に特異的に結合する抗体断片であって、下記式(1)の構造を有する単一ポリペプチド鎖のアミノ酸配列を有する抗体断片。
 FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 … (1)
(式中、
 FR1、FR2、FR3、及びFR4はフレームワーク領域であり、
 CDR1、CDR2、及びCDR3は相補性決定領域であり、以下の(I)~(III)の少なくとも一つを満たす:
 (I)CDR1は、配列番号5~11、53~55、及び59~64のいずれかで表されるアミノ酸配列を有するか、配列番号5~11、53~55、及び59~64のいずれかで表されるアミノ酸配列において1から数個の欠失、置換若しくは付加を含むアミノ酸配列を有するか、又は配列番号5~11、53~55、及び59~64のいずれかで表されるアミノ酸配列と80%以上の同一性を有するアミノ酸配列を有する
 (II)CDR2は配列番号12~18のいずれかで表されるアミノ酸配列を有するか、配列番号12~18のいずれかで表されるアミノ酸配列において1から数個の欠失、置換若しくは付加を含むアミノ酸配列を有するか、又は配列番号12~18のいずれかで表されるアミノ酸配列と80%以上の同一性を有するアミノ酸配列を有する
 (III)CDR3は配列番号19~25、56~58、及び65~84のいずれかで表されるアミノ酸配列を有するか、配列番号19~25、56~58、及び65~84のいずれかで表されるアミノ酸配列において1から数個の欠失、置換若しくは付加を含むアミノ酸配列を有するか、又は配列番号19~25、56~58、及び65~84のいずれかで表されるアミノ酸配列と80%以上の同一性を有するアミノ酸配列を有する。)

[請求項2]
 前記CDR1は配列番号5~11、53~55、及び59~64のいずれかで表されるアミノ酸配列を有し、前記CDR2は配列番号12~18のいずれかで表されるアミノ酸配列を有し、前記CDR3は配列番号19~25、56~58、及び65~84のいずれかで表されるアミノ酸配列を有する請求項1に記載の抗体断片。

[請求項3]
 下記(i)~(xii)のCDR1、CDR2及び/又はCDR3を有する請求項1又は2に記載の抗体断片。
(i) CDR1:配列番号5、CDR2:配列番号12、及びCDR3:配列番号19
(ii) CDR1:配列番号6、CDR2:配列番号13、及びCDR3:配列番号20
(iii) CDR1:配列番号7、CDR2:配列番号14、及びCDR3:配列番号21
(iv) CDR1:配列番号8、CDR2:配列番号15、及びCDR3:配列番号22
(v) CDR1:配列番号9、CDR2:配列番号16、及びCDR3:配列番号23
(vi) CDR1:配列番号10、CDR2:配列番号17、及びCDR3:配列番号24
(vii) CDR1:配列番号11、CDR2:配列番号18、及びCDR3:配列番号25
(viii) CDR1:配列番号53
(ix) CDR1:配列番号53、及びCDR3:配列番号57
(x) CDR1:配列番号54
(xi) CDR1:配列番号55
(xii) CDR3:配列番号58

[請求項4]
 FR1、FR2、FR3、及びFR4は配列番号1~4で表されるアミノ酸配列を有するか、配列番号1~4で表されるアミノ酸配列において1から数個の欠失、置換若しくは付加を含むアミノ酸配列を有するか、又は配列番号1~4で表されるアミノ酸配列と80%以上の同一性を有するアミノ酸配列を有する請求項1~3のいずれか一項に記載の抗体断片。

[請求項5]
 配列番号26~32のいずれかで表されるアミノ酸配列を有する請求項1~4のいずれか一項に記載の抗体断片。

[請求項6]
 請求項1~5のいずれか一項に記載の抗体断片からなる第1の可変領域と、HER2とは異なる抗原に特異的に結合する第2の可変領域とを備え、前記第1の可変領域と前記第2の可変領域が単一のポリペプチド鎖上に含まれる、二重特異性抗体。

[請求項7]
 前記第2の可変領域が、T細胞上の抗原に特異的に結合する、請求項6に記載の二重特異性抗体。

[請求項8]
 前記第2の可変領域が、抗CD3抗体の重鎖の可変領域と、抗CD3抗体の軽鎖の可変領域とを含む請求項7に記載の二重特異性抗体。

[請求項9]
 単量体、二量体、三量体、四量体、五量体又はそれらのFc領域融合体である請求項6~8のいずれか一項に記載の二重特異性抗体。

[請求項10]
 請求項1~5のいずれか一項に記載の抗体断片又は請求項6~9のいずれか一項に記載の二重特異性抗体と、蛍光物質、発光物質、低分子化合物、核酸、放射性物質、薬剤、毒素、サイトカイン、アルブミン、酵素、及び非ペプチド性ポリマーからなる群の少なくとも1種の化合物とが結合されたコンジュゲート抗体。

[請求項11]
請求項1~5のいずれか一項に記載の抗体断片又は請求項6~9のいずれか一項に記載の二重特異性抗体をコードする塩基配列を含む核酸分子。

[請求項12]
請求項11に記載の核酸分子を含む発現ベクター。

[請求項13]
請求項12に記載の発現ベクターにより形質転換した宿主細胞。

[請求項14]
請求項1~5のいずれか一項に記載の抗体断片又は請求項6~9のいずれか一項に記載の二重特異性抗体を含有する医薬組成物。

[請求項15]
請求項1~5のいずれか一項に記載の抗体断片又は請求項6~9のいずれか一項に記載の二重特異性抗体を備えたキット。
  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • TOHOKU UNIVERSITY
  • UNIVERSITY OF THE RYUKYUS
  • Inventor
  • UMETSU, Mitsuo
  • SUGIYAMA, Aruto
  • NAKAZAWA, Hikaru
  • NIIDE, Teppei
  • KISHIMOTO, Hidehiro
  • MURAKAMI, Akikazu
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DJ DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IR IS JO JP KE KG KH KN KP KR KW KZ LA LC LK LR LS LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SA 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 RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ 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 KM ML MR NE SN ST TD TG
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