JP2009500298A - Her−2ペプチド - Google Patents
Her−2ペプチド Download PDFInfo
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- JP2009500298A JP2009500298A JP2008517193A JP2008517193A JP2009500298A JP 2009500298 A JP2009500298 A JP 2009500298A JP 2008517193 A JP2008517193 A JP 2008517193A JP 2008517193 A JP2008517193 A JP 2008517193A JP 2009500298 A JP2009500298 A JP 2009500298A
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Abstract
Description
本出願は、2005年6月15日に出願され、表題「HER-2 Peptides」の米国仮出願第60/690,574号(この全体が、本明細書に参考として援用される)への優先権およびあらゆるほかの利益を主張する。
本出願に記載する研究は、少なくとも一部は、米国国立衛生研究所(the National Institute of Health)からの援助 NIH 5ROI CA 84356による支援を受けている。米国連邦政府は、本発明に関して一定の権利を有する。
現在、乳癌治療の最も一般的なアプローチは、手術、化学的介入および/または放射線療法を含む。癌が被定義領域に限定されなければ、手術のみで癌を除去することはできない。それ故、手術部位付近にあり、手術を免れた癌細胞を破壊するために、手術後、放射線治療を施すことが多い。こうした治療の副作用としては、皮膚の過敏性または痒み、免疫系への干渉、時として、吐き気、および希に、肺の患部が繊維性になる放射線肺線維症が挙げられる。化学療法が手術後に用いられることもある。化学療法には、癌細胞に対して傷害性である薬物が用いられる。これは、完全に選択的なシステムではないので、正常な細胞にも影響を及ぼす。負の副作用としては、悪心、疲労、脱毛、食欲不振および下痢が挙げられる。
Hudziak,R.M.ら、Mol.Cell.Biol.,1989,9:11−65−72 Tagliabue,E.ら、Int.J.Cancer,1991,47:933−7 Drebin,J.A.ら、Proc.Natil.Acad.Scie.USA,1986,83:9129−33 Drebin,J.A.ら、Oncogene,1988,2:273−7 Katsumata,M.ら、Nat.Med.,1995,1:644−8. Baselga,J.ら、J.Clin.Oncol.,1996,14:737−44 Pegram,M.D.ら、J.Clin.Oncol.,1988,16:2659−71 Bernards,R.ら、Proc.Natl.Acad.Sci.USA,1987,84:6854−8 Gu,X.G.ら、Cancer Res.,1998,58:3385−90 Esserman,L.J.,Cancer Immunol.Immunother.,1999,47:337−42 Cefai.D.ら、Int.J.Cancer,1999,83:393−400
実施形態に従って、HER−2 Bエピトープを提供する。該エピトープは、
さて、本発明の特定の実施形態を随時参照しながら本発明を説明する。しかし、本発明は、種々の形態で具体化することができ、本明細書に記載する実施形態に限定されると解釈すべきではない。むしろ、これらの実施形態は、本開示が、詳細、且つ、完全になるように、ならびに当業者に本発明の範囲を十分に知らせるために提供するものである。
免疫化および動物。雌ニュージーランド白ウサギを、Mochican Valley Rabbitry(オハイオ州、Loudenville)から入手した。ウサギを、CFA中で乳化させた合計1gのペプチドで、多数の部位に皮下免疫した。初回免疫の3および6週間後、続いてブースター注射(PBS中、1mgおよび500μg)を施した。血清を採取し、30分間、56℃に加熱することにより補体を不活性化した。血清アリコートを−5から−15℃で保管した。抗体を硫酸アンモニウム沈殿法によって精製した:硫酸アンモニウム飽和溶液(SAS)の保存溶液を調製し、オートクレーブで処理し、4℃に冷却した。冷室内で攪拌しながら35% v/vまでSASをゆっくりと添加することにより、抗体を沈殿させた。サンプルを14,000×gで20分間、遠心分離し、上清を−20℃で保存した。1/2原体積のペレットを0.1M PBSで溶解した。その後、画分をSlide−a−lyzerカセット(Pierce)内に配置し、>200体積のpH8の0.15M NaClの頻繁な交換により透析した。数滴の0.1M NaOHでその食塩水をpH8にした。IgG濃度を、放射免疫拡散(RID)(英国、The Binding Site)により決定した。モノクローナル抗体は、Oncogene Scienceから購入した。
2つの天然ジスルフィド結合が組み込まれている配座HER−2細胞エピトープは、強化された腫瘍細胞結合を示す。
新規HER−2 B細胞エピトープの設計および合成
表1に示すような4つの新規構築物を合成のために選択した。4つすべての構築物が、トラスツズマブと接触する3つの領域のうちの少なくとも1つの領域を含有する。HER−2 Bエピトープを、MVFプロミスカスThエピトープと共直線的に合成した。ペプチド合成は、Fmoc/t−But化学を用いて行った。エピトープ563−598についての3つのジスルフィド結合の形成は、図2に示す差次的保護システイン残基を使用して達成した。第一のジスルフィド結合は、ヨウ素酸化を用いて形成する。水の添加により、Acm除去、およびC567とC584の間のジスルフィド結合の付随的形成を増進する。C563とC576の間の最後のジスルフィド結合は、シリルクロライド−スルホキシド法を用いて形成する。
HER−2ペプチドの免疫原性
表1に記載した4つの構築物の免疫原性は、ジスルフィド結合構築物と線状構築物の両方を使用し、FBV/nマウス(n=4〜9)週齢6〜8週の群に免疫することにより判定した。563−598環化および非環化構築物の両方が、高度に免疫原性であった(図3A)。第三回免疫の3週後には、すべてのマウスが、120,000より高い力価を有し、環化構築物(MVF563SS)での2匹のマウスは、250,000より高い力価を有した。585−598構築物は、最小の免疫原性であることが判明し(図3B)、第三回免疫の3週間後、環化(SS)群と線状(NC)群の両方からの1匹のマウスだけが、120,000より高い力価を有し、平均力価は、約58,000であった。597−626ペプチド構築物と613−626ペプチド構築物の両方が、高度に免疫原性であった(図3C、D)。環化形の597−626を受けた3匹のマウスは、120,000より高い力価を有したが、線状形を受けたいずれのマウスも、120,000より高い力価を有さなかった。
ヘルセプチン結合ペプチドとヘルセプチン(トラスツズマブ)の交差反応性
ELISAにより、トラスツズマブ結合部位からの配座ペプチドがヘルセプチンを認識できるかどうかを試験した。図4に示すように、563−626の結合領域内の様々なペプチドが、トラスツズマブと結合した。最大の結合は、3つのジスルフィド対合を有する環化エピトープ563−598で発生した。この結果は、グリコシル化に起因するHER−2への抗体のFACS結合とは対照的である。
ペプチド抗体とHER−2タンパク質の交差反応性
ヘルセプチン−ペプチドエピトープにより惹起された抗体が、HER−2受容体を認識するそれらの能力に差を示すかどうかを判定するために、HER−2過剰発現ヒト乳癌細胞系統BT474へのFBV/n精製抗体の結合を試験した。図5C、Dは、597−626構築物と613−626構築物の両方が、正常マウス抗体に比べてシフトしていることを示している。しかし、563−598および585−598構築物は、正常マウス抗体と比較して殆どシフトを示さなかった(図5A、B)。563−598は、HER−2がトラスツズマブと共に作る3つの構築物のうちの2つを含有する。トラスツズマブとの最後の接点を含む597−626エピトープは、天然タンパク質を認識する11のアミノ酸から成る(図5C)。この配列613−626のさらに短いバージョンも、同様に天然タンパク質を認識する(図5D)。エピトープ563−598および585−598の認識の欠如についての尤もらしい説明は、残基571−573に潜在的グリコシル化部位(NGS)があり、その大きな嵩高い糖部分が立体的に干渉し、そのエピトープの結合を妨げるということである。
腫瘍攻撃
B細胞エピトープワクチンへの配座拘束の導入に随伴する潜在的な臨床的利点をさらに良好に理解するために、FVB/nマウスとneu−Nトランスジェニックマウスの両方を、neu−Nトランスジェニックマウスから単離した自然発生***腫瘍から採取した腫瘍細胞系統NT2.5で攻撃した。neu過剰発現の結果として、これらのマウスは、ヒト乳癌患者において観察されるものと同様の様式で自然発生乳腺癌を発症し、従って、ヒト乳癌研究の適するモデルである。FVB/nマウスの群を、最終免疫の2週間後に5×106のNT2.5細胞で皮下攻撃した(下腹部)。第55日まで週に2度、腫瘍測定を行った。腫瘍体積は、(長いほうの測定値×短いほうの測定値2)/2の式によって計算した。第30日の後、FBV/nマウスの腫瘍は退縮し始める(これは、腫瘍の拒絶を示す)ことに留意すること。FBV/nマウスを使用するその後の腫瘍研究に関しては、第30日まで腫瘍を測定した。563−598NCおよびSS構築物で免疫したマウスは、第30日に、それぞれ、166.517および173.7292mm3の平均腫瘍体積を有し、一方、免疫しなかったマウスは、346.6563mm3の平均腫瘍体積を有した(データは示さない)。第33日には、613−626および585−598CYCで免疫したマウスは、免疫しなかったマウスとMVFで免疫したマウスの両方と比較して、腫瘍体積の低減を示した。トラスツズマブB細胞エピトープで免疫したマウスの腫瘍負荷の低減の点で何らかの適度な成功があるように見えるが、ほぼすべてのマウスが腫瘍を発症した。
新規ペルツズマブ結合配座B細胞エピトープの設計および評価
表2に記載する3つのペプチド配列は、ペルツズマブ結合部位に類似した抗体を惹起する最小配列をさらに描写するために設計した。これらの複合配座ペプチドエピトープを合成し、首尾よく精製し、適正なジスルフィド対合で環化した。エピトープ266−296(Cys268−Cys295間のSH結合)、エピトープ298−333(Cys299−Cys311間のSH結合)およびエピトープ315−333(Cys315−Cys331間のSH結合)により、最小ペルツズマブ結合エピトープを描写することができよう。
Claims (36)
- 線状である、請求項1に記載の単離されたポリペプチド。
- 環化された、請求項1に記載の単離されたポリペプチド。
- レトロ−インベルソ形である、請求項1に記載の単離されたポリペプチド。
- グリコシル化されている、請求項1に記載の単離されたポリペプチド。
- 2つまたはそれ以上の前記キメラペプチドの混合物をさらに含む組成物であって、該2つまたはそれ以上のキメラペプチドの各々のHER−2 Bエピトープが異なる、請求項13に記載の組成物。
- 前記HER−2 Bエピトープのうちの少なくとも1つ、前記Thエピトープまたは前記リンカーが、レトロ−インベルソ形である、請求項13に記載の組成物。
- 前記リンカーが、2から15個のアミノ酸を含む、請求項13に記載の組成物。
- HER−2タンパク質の免疫応答を刺激するための組成物であって、該組成物は、多価ペプチドであり、2つまたはそれ以上のHER−2 BエピトープとTh細胞エピトープとテンプレートとを含み、
該2つまたはそれ以上のHER−2 Bエピトープの各々が、互いに異なり、
該2つまたはそれ以上のHER−2 Bエピトープの各々の配列が、
該Thエピトープが、
該HER−2 Bエピトープおよび該Th細胞エピトープが、該テンプレートに結合しており;ならびに
該テンプレートが、1〜15アミノ酸のリンカーによって連結された交互のロイシンおよびリシン残基の2本の鎖を含む、
組成物。 - 多価ペプチドを被験者に投与することを含む、該被験者における免疫応答を刺激する方法であって、
該多価ペプチドが、2つまたはそれ以上のHER−2 Bエピトープ、Th細胞エピトープおよびテンプレートを含み、
該2つまたはそれ以上のHER−2 Bエピトープの各々が、互いに異なり、
該2つまたはそれ以上のHER−2 Bエピトープの各々の配列が、
該Thエピトープが、
該HER−2タンパク質の免疫原性エピトープおよび該Th細胞エピトープが、該テンプレートに結合しており;ならびに
該テンプレートが、1〜15アミノ酸のリンカーによって連結された交互のロイシンおよびリシン残基の2本の鎖を含む、方法。 - 前記被験者が、ヒトであり、かつ乳癌、卵巣癌、肺癌、前立腺癌および大腸癌のうちの1つを有する、または乳癌、卵巣癌、肺癌、前立腺癌および大腸癌のうちの1つについての素因を有する、請求項31に記載の方法。
- 前記癌が、乳癌である、請求項32に記載の方法。
- 前記医薬組成物が、キメラペプチドの混合物をさらに含み;
該混合物が、2つまたはそれ以上のキメラペプチドを含み;および
該2つまたはそれ以上のキメラペプチドの各々が、前記HER−2 Bエピトープと、前記Tヘルパー(Th)エピトープと、該HER−2 Bエピトープを該Thエピトープに連結する前記リンカーとを含み、該2つまたはそれ以上のキメラペプチドの各々のHER−2 Bエピトープが、互いに異なる、
請求項31に記載の方法。 - 少なくとも1つの追加のHER−2 Bエピトープと、Tヘルパー(Th)エピトープと、該追加のHER−2 Bエピトープを該Thエピトープに連結するリンカーとをさらに含み、該少なくとも1つの追加のHER−2 Bエピトープが、前記HER−2 Bエピトープとは異なる、請求項35に記載のワクチン。
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KR20190137826A (ko) * | 2017-03-28 | 2019-12-11 | 오하이오 스테이트 이노베이션 파운데이션 | 인간 pd1 펩티드 백신 및 이의 용도 |
JP2020512375A (ja) * | 2017-03-28 | 2020-04-23 | オハイオ・ステイト・イノベーション・ファウンデーション | ヒトpd−1ペプチドワクチン及びその使用法 |
JP7346302B2 (ja) | 2017-03-28 | 2023-09-19 | オハイオ・ステイト・イノベーション・ファウンデーション | ヒトpd-1ペプチドワクチン及びその使用法 |
KR102653567B1 (ko) * | 2017-03-28 | 2024-04-02 | 오하이오 스테이트 이노베이션 파운데이션 | 인간 pd1 펩티드 백신 및 이의 용도 |
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US9452204B2 (en) | 2016-09-27 |
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EP1912680A4 (en) | 2010-09-22 |
ES2531483T3 (es) | 2015-03-16 |
WO2006138675A2 (en) | 2006-12-28 |
WO2006138675A9 (en) | 2010-01-28 |
US8470333B2 (en) | 2013-06-25 |
EP1912680B1 (en) | 2014-11-26 |
US20070060516A1 (en) | 2007-03-15 |
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CA2612394C (en) | 2017-02-21 |
AU2006261342A1 (en) | 2006-12-28 |
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US7691396B2 (en) | 2010-04-06 |
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JP5222134B2 (ja) | 2013-06-26 |
EP1912680A2 (en) | 2008-04-23 |
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