JP2014528913A - Wapドメイン融合ポリペプチド及びその使用方法 - Google Patents
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Abstract
Description
本出願は、2011年6月28日に出願された米国特許仮出願第61/502052号;2011年12月1日に出願された米国特許仮出願第61/565625号;及び2012年4月25日に出願された米国特許仮出願第61/638168号;並びに2012年4月26日に出願された米国特許仮出願第61/638516号の利益を主張する。これらの出願それぞれの内容全体を参照により本明細書中に援用する。
本発明の分野
ポリペプチド1(a)−ヒンジm−ポリペプチド2(b)
ポリペプチド1(a)−リンカーn−ポリペプチド2(b)
ポリペプチド1(a)−リンカーn−ヒンジm−ポリペプチド2(b)
ポリペプチド1(a)−ヒンジm−リンカーn−ポリペプチド2(b)
ポリペプチド1(a)−ポリペプチド2(b)−ポリペプチド3(c)
ポリペプチド1(a)−ヒンジm−ポリペプチド2(b)−ヒンジm−ポリペプチド3(c)
ポリペプチド1(a)−リンカーn−ポリペプチド2(b)−リンカーn−ポリペプチド3(c)
ポリペプチド1(a)−ヒンジm−リンカーn−ポリペプチド2(b)−ヒンジm−リンカーn−ポリペプチド3(c)
ポリペプチド1(a)−リンカーn−ヒンジm−ポリペプチド2(b)−リンカーn−ヒンジm−ポリペプチド3(c)
式中、nは0〜20の整数であり、mは1〜62までの整数であり、そして、a、b、及びcは少なくとも1の整数である。これらの実施形態には、上記の式、及びその変形又は組み合わせのいずれもが含まれる。例えば、前記式のポリペプチドの順序には、ポリペプチド3(c)−ポリペプチド1(a)−ポリペプチド2(b)、ポリペプチド2(b)−ポリペプチド3(c)−ポリペプチド1(a)、又はその変形や組み合わせもまた含まれる。
例えば、WAP(a’)−Fc融合タンパク質のWAPドメイン含有ポリペプチドは、SLPI又はElafinポリペプチドに由来し得るが、その両方に由来することはない(例えば、Elafin−Fc−Elafin又はSLPI−Fc−SLPI)。他の実施形態において、WAP(a’)−Fc融合タンパク質のWAPドメイン含有ポリペプチドは、異なったアミノ酸配列を含み得る。例えば、融合タンパク質は、SLPI及びElafmの両方に由来するアミノ酸配列を組み込むことができる(例えば、SLPI−Fc−Elafm又はElafm−Fc−SLPI)。
融合タンパク質のFcポリペプチドは、配列番号8のアミノ酸配列と少なくとも50%、60%、65%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%又は99%同一であるヒトIgG2 Fcポリペプチド配列を含んでいる。
好ましい実施形態において、サイトカイン標的ポリペプチド又は抗体若しくは抗体断片に由来するアミノ酸配列は、キメラ抗体配列、ヒト化抗体配列、又は完全なヒト抗体配列に由来する。他の実施形態において、サイトカイン標的ポリペプチドは、サイトカイン受容体に結合し、サイトカインの受容体への結合を妨げる。
本発明の融合タンパク質がセルピンポリペプチドを含んでいるいくつかの実施形態において、融合タンパク質のセルピンポリペプチドは、AATタンパク質の反応部位ループ部分の修飾された変異型を含んでいるか、又は少なくとも以下のアミノ酸配列を含んでいる:
医薬組成物
代表的ではあるが、制限されることのない本発明によるAAT−Fc融合タンパク質の例には以下の配列が含まれるが、そこで、融合タンパク質のSLPI又はElafinポリペプチド部分を太字で示し、WAPドメインに下線を引き、融合タンパク質のIgG−Fcポリペプチド部分をイタリック体にし、SLPI内のMet98Leu(ML)突然変異を四角で囲み、FcRn結合を増強するFc突然変異Met252Tyr、Ser254Thr、Thr256Glu(YTE)又はMet428Leu、Asn434Ser(LS)を太字にして、四角で囲み、灰色で陰影をつけた。これらの例はヒンジ配列及び/又はリンカー配列を含んでいるが、本発明の融合タンパク質は、長さ及び/又は柔軟性の点で好適な任意のヒンジ配列及び/又はリンカー配列を使用して作製できる。あるいは、融合タンパク質は、ヒンジ及び/又はリンカー配列を使用せずに作製できる。例えば、ポリペプチド成分を直接結合することができる。
SLPI−hFc1(ヒトIgG1 Fc、長ヒンジ)(配列番号16)
SLPI−hFc2(ヒトIgG2 Fc、長ヒンジ)(配列番号17)
SLPI−ML−hFc1(ヒトIgG1 Fc、Met98Leu)(配列番号18)
以下に示すように、融合タンパク質のSLPIポリペプチド部分を太字で示し(配列番号39)、WAPドメインに下線を引き、融合タンパク質のIgG−Fcポリペプチド部分をイタリック体にし(配列番号40)、そして、Fc突然変異群Met252Tyr、Ser254Thr、Thr256Glu(YTE)を四角で囲み、太字にし、灰色で陰影をつけた。
SLPI−hFc1−YTE、(ヒトIgG1 Fc、Met252Tyr、Ser254Thr、Thr256Glu)(配列番号19)
SLPI−hFc1−LS(ヒトIgG1 Fc、Met428Leu、Asn434Ser)
Elafin−hFc1(ヒトIgG1)
SLPI−hFc1−SLPI(ヒトIgG1)
エラフィン−hFc1−Elafin(ヒトIgG1)
エラフィン−hFc1−SLPI(ヒトIgG1)
SLPI−hFc1−Elafin(ヒトIgG1)
実施例2:SLPI−TNFα標的分子融合タンパク質
D2E7−軽鎖−SLPI(G3S)2リンカー
D2E7−軽鎖−SLPI ASTGSリンカー
D2E7−重鎖−SLPI(G3S)2リンカー
D2E7−重鎖−SLPI ASTGSリンカー
TNFR2−ECD−Fc1−SLPI(G3S)2リンカー
TNFR2−ECD−Fc1−SLPI ASTGSリンカー
実施例3:AAT−Fc−SLPI及びAAT−Fc−Elafin
AAT−hFc1−SLPI(ヒトIgG1 Fc)
AAT−hFc1−エラフィン(ヒトIgG1 Fc)
実施例4:SLPI−アルブミン及びエラフィン−アルブミン
SLPI−HSAドメイン3
SLPI−HSA
エラフィン−HSAドメイン3
他の実施形態
Claims (44)
- 次の:
免疫グロブリンFcポリペプチド又は免疫グロブリンFcポリペプチドに由来するアミノ酸配列;
サイトカイン標的ポリペプチド又はサイトカイン標的ポリペプチドに由来する配列;
セルピンポリペプチド又はセルピンポリペプチドに由来する配列;又は
アルブミンポリペプチド又は血清アルブミンポリペプチドに由来するアミノ酸配列、
のうちの少なくとも1つから成る第二のポリペプチドに作動できるように連結された、少なくとも1つのヒトヒト乳清酸性タンパク質(WAP)ドメイン含有ポリペプチドを含んでいる単離された融合タンパク質。 - 次の:
免疫グロブリンFcポリペプチド;
サイトカイン標的ポリペプチド;
α1アンチトリプシン(AAT)ポリペプチド;
α1アンチトリプシン(AAT)ポリペプチド及び免疫グロブリンFcポリペプチド;並びに
ヒトアルブミン(HSA)ポリペプチド、
のうちの少なくとも1つから成る第二のポリペプチドに作動できるように連結された、少なくとも1つのヒト分泌白血球プロテイナーゼインヒビタ(SLPI)ポリペプチドを含んでいる単離された融合タンパク質。 - 次の:
免疫グロブリンFcポリペプチド;
サイトカイン標的ペプチド;
α1アンチトリプシン(AAT)ポリペプチド;
α1アンチトリプシン(AAT)ポリペプチド及び免疫グロブリンFcポリペプチド;並びに
ヒトアルブミン(HSA)ポリペプチド、
のうちの少なくとも1つから成る第二のポリペプチドに作動できるように連結された、少なくとも1つのヒトElafinポリペプチドを含んでいる単離された融合タンパク質。 - 前記ヒトSLPIポリペプチドが、完全長のSLPIポリペプチドであるか、又はヒトSLPIポリペプチドに由来する、請求項2に記載の単離された融合タンパク質。
- 前記SLPIポリペプチドが、配列番号1、2、及び3から成る群から選択されるアミノ酸配列を含む、請求項2〜4のいずれか1項に記載の単離された融合タンパク質。
- 前記ヒトElafinポリペプチドが、完全長のElafinポリペプチドであるか、又はヒトElafrnポリペプチドに由来する、請求項3に記載の単離された融合タンパク質。
- 前記Elafinポリペプチドが、ところでは配列番号4、5、及び6から成る群から選択されるアミノ酸配列を含む、請求項3又は6に記載の単離された融合タンパク質。
- 前記免疫グロブリンFcポリペプチドが、ヒトFcポリペプチドである、請求項1〜6のいずれか1項に記載の単離された融合タンパク質。
- 前記ヒトのFcポリペプチドが、ヒトIgMポリペプチド又はヒトIgGポリペプチドである、請求項8に記載の単離された融合タンパク質。
- 前記ヒトIgG Fcポリペプチドが、ヒトIgG1 Fcポリペプチド、ヒトIgG2 Fcポリペプチド、ヒトIgG3 Fcポリペプチド、又はヒトIgG4 Fcポリペプチドである、請求項9に記載の単離された融合タンパク質。
- 前記免疫グロブリンFcポリペプチドが、配列番号7、8、9、10、及び11から成る群から選択されるアミノ酸配列を含む、請求項1〜3のいずれか1項に記載の単離された融合タンパク質。
- 前記WAPドメイン含有ポリペプチドと免疫グロブリンFcポリペプチドが、ヒンジ領域、リンカー領域、又はヒンジ領域とリンカー領域の両方を介して作動できるように連結される、請求項1に記載の単離された融合タンパク質。
- 前記SLPIポリペプチドと免疫グロブリンFcポリペプチドが、ヒンジ領域、リンカー領域、又はヒンジ領域とリンカー領域の両方を介して作動できるように連結される、請求項2〜4のいずれか1項に記載の単離された融合タンパク質。
- 前記Elafrnポリペプチドと免疫グロブリンFcポリペプチドが、ヒンジ領域、リンカー領域、又はヒンジ領域とリンカー領域の両方を介して作動できるように連結される、請求項3又は6に記載の単離された融合タンパク質。
- 前記ヒンジ領域、リンカー領域、又はヒンジ領域とリンカー領域の両方が、ペプチド配列を含む、請求項12〜14のいずれか1項に記載の単離された融合タンパク質。
- 前記アルブミンポリペプチドが、ヒト血清アルブミン(HSA)ポリペプチドであるか、又はHSAポリペプチドに由来する、請求項1に記載の単離された融合タンパク質。
- 前記HSAポリペプチドが、配列番号14のアミノ酸配列又は配列番号15のアミノ酸配列を含む、請求項2、3又は16のいずれか1項に記載の単離された融合タンパク質。
- 前記HSAポリペプチドが、HSAのドメイン3を含む、請求項2、3又は16のいずれか1項に記載の単離された融合タンパク質。
- 前記WAPドメイン含有ポリペプチドが、アルブミン結合ポリペプチドを介してHSAに作動できるように連結される、請求項1に記載の単離された融合タンパク質。
- 前記アルブミン結合ポリペプチドが、抗体若しくは抗体断片であるか、又は抗体若しくは抗体断片に由来する、請求項19に記載の単離された融合タンパク質。
- 前記抗体又は抗体断片が、キメラ抗体又は抗体断片、ヒト化抗体又は抗体断片、或いは完全なヒト抗体又は抗体断片である、請求項20に記載の単離された融合タンパク質。
- 前記アルブミン結合ポリペプチドがペプチドである、請求項19に記載の単離された融合タンパク質。
- 前記アルブミン結合ポリペプチドが、連鎖球菌Gタンパク質のドメイン3又は連鎖球菌Gタンパク質のドメイン3に由来する配列である、請求項19に記載の単離された融合タンパク質。
- 前記WAPドメイン含有ポリペプチドが、HSAポリペプチドに共有結合により連結される、請求項1に記載の単離された融合タンパク質。
- 前記WAPドメイン含有ポリペプチドが、HSAポリペプチドに非共有結合により連結される、請求項1に記載の単離された融合タンパク質。
- 前記サイトカイン標的ポリペプチドが、サイトカイン受容体ポリペプチド又はサイトカイン受容体ポリペプチドの誘導体、サイトカイン受容体に結合するサイトカイン標的ポリペプチド、又はヒトサイトカインに結合するサイトカイン標的ポリペプチドである、請求項1、2、又は3のいずれか1項に記載の単離された融合タンパク質。
- 前記サイトカイン受容体が、ヒトサイトカイン受容体ポリペプチドである、請求項26に記載の単離された融合タンパク質。
- 前記ヒトサイトカイン受容体ポリペプチドが、複数のサブユニットを含む、請求項27に記載の単離された融合タンパク質。
- 前記ヒトサイトカイン受容体が、TNFα、IgE、IL−12、IL−23、IL−6、IL−1α、IL−1β、IL−17、IL−13、IL−12及びIL−23のp40サブユニット、IL−4、IL−10、IL−2、IL−18、IL−27、又はIL−32の受容体である、請求項27に記載の単離された融合タンパク質。
- 前記サイトカイン標的ポリペプチドが、抗体又は抗体断片である、請求項26に記載の単離された融合タンパク質。
- 前記抗体が、キメラ抗体、ヒト化抗体、又は完全なヒト抗体である、請求項30に記載の単離された融合タンパク質。
- 前記ヒトサイトカインが、TNFα、IgE、IL−12、IL−23、IL−6、IL−1α、IL−1β、IL−17、IL−13、IL−12及びIL−23のp40サブユニット、IL−4、IL−10、IL−2、IL−18、IL−27、又はIL−32である、請求項26に記載の単離された融合タンパク質。
- 前記サイトカインが、ヒトTNFαである、請求項32に記載の単離された融合タンパク質。
- 前記AATポリペプチドが、配列番号13又は配列番号38のアミノ酸配列を含む、請求項2又は項3に記載の単離された融合タンパク質。
- 前記融合タンパク質が、セルピン、WAPドメイン含有ポリペプチド、及び免疫グロブリンFcポリペプチドを、該セルピン、WAPドメイン含有ポリペプチド、及び免疫グロブリンFcポリペプチドのうちの少なくとも2つが、ヒンジ領域、リンカー領域、又はヒンジ領域とリンカー領域の両方を介して作動できるように連結されるように含んでいる、請求項1に記載の単離された融合タンパク質。
- 前記融合タンパク質が、AATポリペプチド、SLPIポリペプチド、及び免疫グロブリンFcポリペプチドを、該AATポリペプチド、SLPIポリペプチド、及び免疫グロブリンFcポリペプチドのうちの少なくとも2つが、ヒンジ領域、リンカー領域、又はヒンジ領域とリンカー領域の両方を介して作動できるように連結されるように含んでいる、請求項2に記載の単離された融合タンパク質。
- 前記ヒンジ領域、リンカー領域、又はヒンジ領域とリンカー領域の両方が、ペプチド配列を含む、請求項35又は36に記載の単離された融合タンパク質。
- 前記Fcポリペプチドは、FcRn結合を増強するために修飾される、請求項1、2又は3のいずれか1項に記載の単離された融合タンパク質。
- 前記免疫グロブリンFcポリペプチドが、次の突然変異:Met252Tyr、Ser254Thr、Thr256Glu又はMet428Leu、及びAsn434Ser、のうちの少なくとも1つを含む、請求項1〜3のいずれか1項に記載の単離された融合タンパク質。
- 前記融合タンパク質が、配列番号16、配列番号17、配列番号18、配列番号19、配列番号20、配列番号21、配列番号22、配列番号23、配列番号24、配列番号25、配列番号26、配列番号27、配列番号28、配列番号29、配列番号30、配列番号31、配列番号32、配列番号33、配列番号34、配列番号35、配列番号36、及び配列番号37から選択されるアミノ酸配列を含む、請求項1〜3のいずれか1項に記載の単離された融合タンパク質。
- 請求項1〜40のいずれか1項に記載の融合タンパク質を投与することを含む、それを必要としている対象における異常なセリンプロテアーゼ発現又は活性に関連する疾患又は障害の症状を処置又は緩和する方法。
- 請求項1〜41のいずれか1項に記載の融合タンパク質を投与することを含む、それを必要としている対象における炎症性疾患又は障害の症状を処置又は緩和する方法。
- 請求項1〜42のいずれか1項に記載の融合タンパク質を投与することを含む、それを必要としている対象における感染性疾患又は障害の症状を処置又は緩和する方法。
- 前記対象がヒトである、請求項41〜43のいずれか1項に記載の方法。
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- 2012-06-28 IN IN2442MUN2013 patent/IN2013MN02442A/en unknown
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RU2014102585A (ru) | 2015-08-10 |
US20130011399A1 (en) | 2013-01-10 |
WO2013003649A3 (en) | 2013-03-21 |
AU2012275295B2 (en) | 2016-11-10 |
IN2013MN02442A (ja) | 2015-06-12 |
RU2639526C2 (ru) | 2017-12-21 |
BR112013033801A2 (pt) | 2017-12-19 |
WO2013003649A2 (en) | 2013-01-03 |
MX2013015324A (es) | 2014-05-01 |
EP2726093A4 (en) | 2015-08-19 |
AU2012275295A1 (en) | 2014-01-16 |
US8986688B2 (en) | 2015-03-24 |
US9914765B2 (en) | 2018-03-13 |
KR20140068861A (ko) | 2014-06-09 |
US20150147324A1 (en) | 2015-05-28 |
CN103946388A (zh) | 2014-07-23 |
NZ619035A (en) | 2015-07-31 |
AU2017200928A1 (en) | 2017-03-02 |
EP2726093A2 (en) | 2014-05-07 |
CA2839622A1 (en) | 2013-01-03 |
MX356433B (es) | 2018-05-29 |
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