JP5524441B2 - 短縮されたbaffレセプター - Google Patents
短縮されたbaffレセプター Download PDFInfo
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- JP5524441B2 JP5524441B2 JP2006507141A JP2006507141A JP5524441B2 JP 5524441 B2 JP5524441 B2 JP 5524441B2 JP 2006507141 A JP2006507141 A JP 2006507141A JP 2006507141 A JP2006507141 A JP 2006507141A JP 5524441 B2 JP5524441 B2 JP 5524441B2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
Description
本開示は、TNFファミリーのリガンドおよびレセプターならびにそれらのアンタゴニストおよびアゴニストならびに免疫応答の調節におけるそれらの使用に関する。
本発明は、TNFファミリーレセプタータンパク質のメンバーである、BAFFレセプター(「BAFF−R」、BR3およびZtnfe12としても公知)に関する。BAFF−Rは、国際特許出願公開公報WO02/24909に記載されている。
本発明は、部分的に、ヒトBAFF−Rおよびその改変体のグリコシル化パターンの発見および特徴付けを基礎としている。本発明は、部分的に、BAFF−R糖タンパク質の細胞外ドメイン(ECD)が、変化したグリコシル化パターンにもかかわらず、リガンド結合の実質的な損失なしで短縮され得るという上記発見および実証を、さらに基礎にしている。本開示は、変化したO結合型グリコシル化パターンを生じる上記ECDにおける欠失を有する、天然に存在しないBAFF−R糖タンパク質を提供する。BAFF−Rのそのような短縮された形態は、以降「ΔBAFF−R」または「ΔBAFF−Rポリペプチド」という。ΔBAFF−Rポリペプチドをコードする対応する核酸は、「ΔBAFF−R核酸」という。
添付の図面は、本明細書で援用され、本明細書の一部分を構成し、本発明のいくつかの実施形態を記載ととも説明し、本発明の趣旨を説明するのに役立つ。
本発明が、より容易に理解されるために、特定の用語について本明細書に定義されている。さらなる定義が詳細な説明の至る所で示されている。
用語「生物学的活性」は、生物系において分子により、インビボまたはインビトロで達成される機能もしくは一連の機能(または上記機能に起因する効果)をいう。生物学的活性は、例えば、リンパ球の増殖、生存率および機能(例えば、サイトカイン分泌)に対する効果、一群の分化マーカーの発現、転写、翻訳もしくは翻訳後レベルにおける遺伝子発現または自己抗体産生に対する効果などで評価され得る。
本明細書で用いられるように、用語「治療化合物」および「治療剤」は、障害の臨床症状を改善できるかまたは望ましい生物学的結果を生じさせることができる任意の化合物を言う。
本実施例は、野生型hBAFF−R:Fcのレセプタードメイン内での種々のペプチド欠失の生成と分析を記載する。これらの欠失変異体のhBAFF結合能を分析した。
本実施例では、短縮されたBAFF−Rストークドメインを含有するvBAFF−R(R3〜A72):Fc改変体の設計、構築および配列決定を記載する。上記融合タンパク質vBAFF−R(R3〜A49):Fcを、配列番号1の残基S50、S51、T56およびS63に位置する4つの潜在的O結合型グリコシル化部位を除去するために、作製した。
付着末端を有する2重鎖オリゴヌクレオチドカセットを用いて、BAFF−Rアミノ酸残基C33〜A72をコードするヌクレオチドを、vBAFF−R(R3〜A72):Fcコード配列の同じ部位への連結により、アミノ酸残基C33〜A49をコードするヌクレオチドで置換した。これらのオリゴヌクレオチドの配列(baf−911およびbaf−912)を、配列番号8および配列番号9に示す。このオリゴヌクレオチド置換は、vBAFF−R(R3〜A72):Fcの残基S50〜A72の除去を生じる。
本実施例は、BIAcoreTMによる液相結合分析による、完全長vBAFF−R:Fcおよび短縮されたvBAFF−R:Fcの両方の、BAFFに対する見掛けの結合親和性の決定を例示する。
遊離BAFFの量についての標準曲線を、種々の濃度のBAFFを含有する連続的な試料をチップ表面上を走らせることにより作成した。結合の初速度(Vi)を、BAFF濃度の関数としてプロットした。用いた条件下では、Viは、溶液中の遊離BAFF量と比例的である。
本実施例は、その表面(CHO:hBAFF)にヒトBAFFを安定に発現するCHO細胞株へのvBAFF−R(R3〜A49):Fcの結合能を例示する。
本実施例は、その表面にhBAFF−Rを発現するヒトB細胞株であるBJAB細胞へのhBAFFの結合を、vBAFF−R(R3〜A72):FcおよびvBAFF−R(R3〜A49):Fcが阻害する能力を例示する。
本実施例は、ヒトvBAFF−R(R3〜A72):FcおよびvBAFF−R(R3〜A49):Fcのグリコシル化パターンを実証する。マウスBAFF−R分子中のN結合型グリコシル化部位およびヒトBAFF−R分子中のO結合型グリコシル化部位を、図6Aおよび図6Bに示す。
本実施例は、vBAFF−R(R3〜A72)およびvBAFF−R(R3〜A49):Fcが、マウス脾臓B細胞におけるhBAFFのB細胞生存活性を阻害する能力を例示している。BAFF誘導細胞増殖アッセイを、マウス脾臓B細胞を用いて実施した。マウスB細胞を、B細胞回収カラム(Cedarlane Labs)を用いて2匹の1ヶ月齢C57/black6マウスの脾臓から単離した。B細胞を、平底96穴プレート(105細胞/穴 100μl 10%FBS加RPMI中)に、5μg/mlヤギ抗マウスμ鎖抗体(Jackson ImmunoReseach)、75ng/ml myc−hBAFF、およびvBAFF−R(R3〜A49):Fcの連続希釈液、vBAFF−R(R3〜A72):Fcの連続希釈液もしくはヒトIgGの連続希釈液の存在下で、72時間インキュベートした。細胞を、[3H]−チミジン(1μCi/穴)でさらに18時間パルスし、そして採取した。[3H]−チミジン取込みを、液体シンチレーション計数により、モニタリングした。図10は、インビトロでvBAFF−R(R3〜A49):FcおよびvBAFF−R(R3〜A72)が、hIgGとインキュベートした細胞と比較する場合、減少した[3H]−チミジン取込みにより示されるように、BAFF媒介のB細胞増殖を、同じようによく阻害することを示している。
本実施例は、インビボでvBAFF−R(R3〜A49):FcでのBAFF遮断が、B細胞生存を障害し、末梢B細胞の数を減少させ、B細胞表面マーカーであるCD21およびCD23の発現レベルの低下の原因となることを示している。
全部で37匹の雌性BALB/cマウスを、表5に示すように、8つの処置群に割当てた。全ての動物に、200μlのvBAFF−R(R3〜A49):FcまたはhIgGを腹腔内に(10ml/kg容量用量)投与した。投与後96時間で、マウスを安楽死させ、B細胞定量化のために脾臓を摘出した。
本実施例において、二つのELISA型式における、flag−huBAFFとvBAFF−R(R3〜A49):FcまたはvBAFF−R(R3〜A72):Fcとの結合を例示する。ELISAプレートを、pH9.6の50mM 重炭酸ナトリウム中で、50μl/穴、5μg/mlの捕獲抗体で、4℃一晩で、被覆した。捕獲抗体は、抗ヒトIgG Fc(Jackson ImmunoResearch)またはM2抗FLAG(Sigma)であった。プレートを室温(RT)30分間、3%BSA−PBSでブロックし、250μlのPBS+0.05%Tween20TMで3回洗浄した。その後のインキュベーションを、全て室温で3%BSA−PBSで希釈された試薬で行なった。
Claims (24)
- 配列番号1のアミノ酸14〜アミノ酸43のアミノ酸配列を有するポリペプチドを含み、免疫グロブリンの定常領域の少なくとも一部分および、必要に応じて、該ポリペプチドと免疫グロブリンの定常領域の該一部分とを結合するリンカーをさらに包含し、ここで該ポリペプチドおよび該リンカーは、配列番号1のアミノ酸50〜アミノ酸56を含有せず、変化したO結合型グリコシル化パターンを生じる細胞外ドメインの欠失を有するが、BAFFへの結合能力は保持している、BAFF−R糖タンパク質の細胞外ドメインを含む糖タンパク質。
- 少なくとも一つのO結合型グリカンを有する、請求項1に記載の糖タンパク質。
- 前記O結合型グリカンが、配列番号1の18位のスレオニンまたは41位のスレオニンに相当するアミノ酸に結合している、請求項1に記載の糖タンパク質。
- 前記O結合型グリカンが、配列番号1の18位のスレオニン、41位のスレオニンまたは8位のセリンに相当するアミノ酸に結合している、請求項1に記載の糖タンパク質。
- 前記欠失が、配列番号1のアミノ酸50〜アミノ酸63である、請求項1に記載の糖タンパク質。
- 前記欠失が、配列番号1のアミノ酸50〜アミノ酸72である、請求項1に記載の糖タンパク質。
- 以下のアミノ酸配列:
(a)配列番号1のアミノ酸13〜アミノ酸43;
(b)配列番号1のアミノ酸1〜アミノ酸49;
(c)配列番号1のアミノ酸8〜アミノ酸49;
(d)配列番号1のアミノ酸13〜アミノ酸49;
(e)配列番号1のアミノ酸14〜アミノ酸49;または、
(f)配列番号7のアミノ酸1〜アミノ酸49
を有するポリペプチドを含む、請求項1に記載の糖タンパク質。 - 配列番号1のアミノ酸1、2、3、4、5、6、7、8、9、10、11、12、13または14から、配列番号1のアミノ酸43、44、45、46、47、48または49までのアミノ酸配列を有するポリペプチドを含む、請求項7に記載の糖タンパク質。
- 配列番号1の21位のアミノ酸がバリンであり、配列番号1の28位のアミノ酸がロイシンである、請求項7に記載の糖タンパク質。
- 配列番号1の21位のアミノ酸が、アスパラギンであり、配列番号1の28位のアミノ酸がプロリンである、請求項7に記載の糖タンパク質。
- 免疫グロブリンの前記部分が、IgG1またはIgG4である、請求項1に記載の糖タンパク質。
- 前記免疫グロブリンの定常領域の前記部分が、配列番号4のアミノ酸3〜アミノ酸227を含む、請求項11に記載の糖タンパク質。
- 請求項1に記載の糖タンパク質をコードする核酸。
- 少なくとも以下をコードする核酸配列:
(a)配列番号1のアミノ酸13〜アミノ酸43;
(b)配列番号1のアミノ酸1〜アミノ酸49;
(c)配列番号1のアミノ酸8〜アミノ酸49;
(d)配列番号1のアミノ酸13〜アミノ酸49;
(e)配列番号1のアミノ酸14〜アミノ酸49;または、
(f)配列番号7のアミノ酸1〜アミノ酸49
含む、請求項13に記載の核酸。 - 配列番号2または3のヌクレオチド1〜ヌクレオチド216を含む、請求項13に記載の核酸。
- 請求項13〜15のいずれか一項に記載した核酸を含むベクター。
- 請求項13〜15のいずれかに記載の核酸を含む、宿主細胞。
- 糖タンパク質を産生する方法であって、該方法が、以下の工程:
(a)請求項16に記載の前記ベクターで、宿主細胞を形質転換する工程;
(b)該糖タンパク質の産生を可能にする条件下で、該宿主細胞を培養する工程;および
(c)前記宿主細胞から該糖タンパク質を単離する工程を含む、方法。 - 請求項1に記載の糖タンパク質を含む、薬学的組成物。
- 請求項13に記載の核酸を含む、薬学的組成物。
- 請求項19または20に記載されている治療有効量の前記薬学的組成物を含む、免疫学的障害を処置するための組成物。
- ナノモル濃度範囲でBAFFに対する見掛けの親和性を有する、請求項1に記載の糖タンパク質。
- 配列番号1のアミノ酸50、アミノ酸51およびアミノ酸56に変異を有する、配列番号1のアミノ酸14〜アミノ酸56を含む、BAFF−Rポリペプチドであって、ここでアミノ酸50が、セリンでもスレオニンでもなく、アミノ酸51が、セリンでもスレオニンでもなく、そしてアミノ酸56が、セリンでもなくスレオニンでもないBAFF−Rポリペプチド。
- 配列番号1のアミノ酸14〜アミノ酸63をさらに包含し、配列番号1のアミノ酸63に変異を有し、ここでアミノ酸63は、セリンでもスレオニンでもない、請求項23に記載のBAFF−Rポリペプチド。
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US8303958B2 (en) | 2012-11-06 |
AU2004233164B2 (en) | 2009-10-08 |
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JP2013236635A (ja) | 2013-11-28 |
WO2004094620A3 (en) | 2006-01-19 |
EP1608730B1 (en) | 2013-11-06 |
US20060234917A1 (en) | 2006-10-19 |
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US20100184951A1 (en) | 2010-07-22 |
WO2004094620A2 (en) | 2004-11-04 |
EP1608730A2 (en) | 2005-12-28 |
CA2520097A1 (en) | 2004-11-04 |
AU2004233164A1 (en) | 2004-11-04 |
US20110311530A1 (en) | 2011-12-22 |
CA2520097C (en) | 2014-10-07 |
US8022182B2 (en) | 2011-09-20 |
JP2010158254A (ja) | 2010-07-22 |
JP2006523098A (ja) | 2006-10-12 |
AU2010200092A1 (en) | 2010-01-28 |
NZ543174A (en) | 2008-09-26 |
US8821883B2 (en) | 2014-09-02 |
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