JP7486566B2 - 改良lamp構築物 - Google Patents
改良lamp構築物 Download PDFInfo
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Description
好ましい一態様では、動物はヒトである。
その他の非ヒト脊椎動物には、ウサギ、ラマ、ラクダ、牛、モルモット、ハムスター、イヌ、ネコ、ウマ、非ヒト霊長類、真猿類(例えばサルまたは類人猿)、サル(例えば、マーモセット、ヒヒ、アカゲザル)、または類人猿(例えば、ゴリラ、チンパンジー、オランウータン、テナガザル)が含まれる。
以下の定義は、以下の記述で使用される特定の用語に対して提供される。
通常、安定した維持には、導入された改良LAMP構築物が、宿主細胞と互換性のある複製起点を含むか、染色体外レプリコン(プラスミドなど)または核またはミトコンドリア染色体などの宿主細胞のレプリコンに組み込まれることが必要である。
適切なハイブリダイゼーション条件を定義することは、当業者の技術の範囲内である。例えば、ストリンジェントな条件は、42°Cにおける5xSSCおよび50%ホルムアミドでのハイブリダイゼーション、60°Cのける0.1xSSCおよび0.1%ドデシル硫酸ナトリウムでの洗浄である。ストリンジェントなハイブリダイゼーション条件のさらなる例としては、以下が挙げられる:約25℃~約37℃のインキュベーション温度;約6xSSC~約10xSSCのハイブリダイゼーションバッファー濃度;約0%~約25%のホルムアミド濃度;約6xSSCの洗浄液。中程度のハイブリダイゼーション条件の例としては、以下が挙げられる:約40℃~約50℃のインキュベーション温度;約9xSSC~約2xSSCのバッファー濃度;約30%~約50%のホルムアミド濃度;約5xSSC~約2xSSCの洗浄溶液。高ストリンジェントな条件の例としては、以下が挙げられる:約55℃~約68℃のインキュベーション温度;約1xSSC~約0.1xSSCのバッファー濃度;約55%~約75%のホルムアミド濃度;約1xSSC、0.1xSSC、または脱イオン水の洗浄溶液。一般に、ハイブリダイゼーションのインキュベーション時間は5分~24時間で1、2回、またはそれ以上の洗浄工程があり、洗浄インキュベーション時間は約1、2、または15分である。SSCは0.15M NaClおよび15mMクエン酸バッファーである。他のバッファー系を使用するSSCの同等物を使用できることは理解されよう。類似性は配列決定により検証できるが、好ましくは、または代替として、問題の特定のドメインに適したアッセイを使用して、機能(例えば、エンドソーム区画への輸送能力など)により検証することもできる。
このようなアルゴリズムは、GCG配列アライメントソフトウェアパッケージの一部であるALIGNプログラム(バージョン2.0)に組み込まれている。アミノ酸配列を比較するためにALIGNプログラムを利用する場合、PAM120重み残基表(weight residue table)、12のギャップ長ペナルティ、および4のギャップペナルティを使用できる。
通常固形腫瘍として現れるタイプのがんに言及する場合、「臨床的に検出可能な」腫瘍は、例えば、CATスキャン、MRイメージング、X線、超音波または触診などの手順によって、腫瘍塊に基づいて検出可能なもの、および/または患者から得られるサンプル中の1または複数のがん特異的抗原の発現のために検出可能なものである。
「クローン」とは、有糸分裂による単一の細胞または共通の祖先に由来する細胞の集団である。「細胞株」は、多くの世代(例えば、少なくとも約10世代)にわたってin vitroで安定した増殖が可能な、初代細胞のクローンである。
したがって、抗体という用語は、全抗体分子だけでなく、抗体断片、ならびに抗体および抗体断片の変異体(融合タンパク質などの誘導体を含む)も包含する。本出願において「抗体」という用語によって説明される分子の例には、限定するものではないが、単鎖Fv(scFv)、Fab断片、Fab’断片、F(ab’)2、ジスルフィド結合Fv(sdFv)、Fv、およびVLまたはVHドメインのいずれかを含むか、またはそれらからなる断片が含まれる。本明細書で使用される「単鎖Fv」または「scFv」という用語は、抗体のVHドメインに連結された抗体のVLドメインを含むポリペプチドを指す。Carter(2006)Nature Rev.Immunol.6:243を参照されたい。
cDNAクローンから推定されるLAMP-1(Chen,et al.,J.Biol.Chem.263:8754,1988)は、約382アミノ酸のポリペプチドコアからなり、大きな(346残基)内腔アミノ末端ドメイン、それに続く24残基の疎水性膜貫通領域および短い(12残基)カルボキシル末端細胞質尾部を有する。図2Aおよび2Bを参照されたい。内腔ドメインは高度にグリコシル化され、約20個のアスパラギン連結複合型オリゴ糖で置換されており、プロリン/セリンリッチヒンジ領域によって分離された2つの約160残基の「相同ドメイン」からなる。これらの「相同ドメイン」はそれぞれ、4つの均一に間隔を空けたシステイン残基を含み、ジスルフィド結合して、内腔ドメインの両半分に対称的に配置された4つの36~38の残基ループを形成する(Arterburn,et al.,J.Biol.Chem.265:7419,1990;Chen,et al.,J.Biol.Chem.25:263(18):8754-8,1988も参照されたい)。図2Aは、LAMP-1、LAMP-2、LAMP-3、Endolyn、LIMBIC、LAMP5、またはマクロシアリン(Macrosailin)間の保存されたドメインを模式的に示している。
本明細書に記載の改良LAMP構築物は、先行技術に記載の完全LAMP構築物は含まない。
例えば、図3~10を参照されたい。図2Aおよび2Bで定義された同等のドメインを使用して、オルソロガス配列について図1に例示された改良LAMP構築物を作製することが明確に企図される。さらに、図3~10に示されているオルソロガス配列は、ドメインの生成に使用できる配列の代表である。他のオルソロガス配列および/またはアイソタイプを同定し、それらを図3~10に示されているアラインメントと比較することは、十分に当業者の技術の範囲内である。したがって、図3~10に示す配列を有するヒトLAMPタンパク質の図2Aおよび2Bで定義された同等の境界を同定することにより、図1に例示する改良LAMP構築物を生成することができる。
さらに、LAMP相同ドメイン、LAMP内腔ドメイン、LAMP膜貫通ドメイン、および/またはLAMPサイトゾル尾部ドメインは、同じLAMPタンパク質(例えば、ヒトLAMP-1)または異なるLAMPタンパク質(例えば、ヒトLAMP-1由来の内腔ドメイン、ヒトLAMP-2由来の膜貫通ドメイン、および/または同じ遺伝子ファミリー(例えばLAMP-1)または異なる遺伝子ファミリー(LAMP-1およびLAMP-2)のオルソロガスドメインの混合)が起源であってよい。
目的の抗原を含む改良LAMP構築物を構築する手順は、当技術分野で周知である(例えば、Williams,et al.,J.Cell Biol.111:955,1990を参照されたい)。所望のセグメントをコードするDNA配列は、American Type Culture Collection、12301 Parklawn Drive、Rockville、Md.20852,U.S.A.または所望のDNAを含むDNAライブラリーから入手可能なものなど、容易に入手可能な組換えDNA材料から得ることができる。
一態様では、改良LAMP構築物を含むワクチン組成物が細胞に導入される。細胞は、核酸を複製するため、または改良LAMP構築物を発現するための宿主細胞であり得る。
好ましくは、改良LAMP構築物を発現するための宿主細胞は抗原提示細胞である(以下でさらに説明する)。
改良LAMP構築物の細胞内送達を促進するように設計された送達ビヒクルは、非極性環境と極性環境との両方と(例えば、原形質膜、組織液、細胞内の区画などにおいて)相互作用する必要がある。したがって、好ましくは、送達ビヒクルは、極性および非極性ドメインの両方、または改良LAMP構築物を細胞に移行させるための移行配列を含むように設計されている。
循環半減期が延長されたリポソームは、通常、治療および診断用途に望ましい。薬物動態の一般的な考察については、例えば、emington’s,Chapters 37-39,Lee,et al.,In Pharmacokinetic Analysis:A Practical Approach(Technomic Publishing AG,Basel,Switzerland 1996)を参照されたい。
一態様では、改良LAMP構築物送達ビヒクルは、ウイルスまたはウイルス粒子を含む。この態様において、好ましくは、改良LAMP構築物はウイルスベクターを含む。レトロウイルス、アデノウイルス、アデノ随伴ウイルス、およびヘルペスウイルスなどのウイルスベクターは、多くの場合2つの成分、改変されたウイルスゲノムとそれを囲むコート構造とで構成されている(例えば、Smith et al.,1995,Ann.Rev.Microbiol.49:807-838を参照されたい)が、ウイルスベクターは裸の形で導入されたり、ウイルスタンパク質以外のタンパク質でコーティングされることがある。現在の大部分のベクターは、野生型ウイルスと類似のコート構造を有する。この構造は、ウイルス核酸をパッケージングして保護し、標的細胞に結合して進入する手段を提供する。
アデノウイルスゲノムは、ウイルス複製サイクルを完了するために必要な約30を超える遺伝子を運ぶ約36kbの線形二本鎖DNA分子で構成されている。初期遺伝子は4つの領域(E1~E4)に分けられ、抗ウイルス宿主免疫応答を調節すると考えられているE3領域は別として、これらはウイルス複製に不可欠である。E1領域(EIAおよびEIB)は、ウイルスゲノムの転写制御に関与するタンパク質をコードする。E2領域遺伝子(E2AおよびE2B)の発現は、ウイルス複製に必要なポリペプチドの合成をもたらす。E3領域によってコードされるタンパク質は、細胞傷害性T細胞および腫瘍壊死因子による細胞溶解を防ぐ(Wold and Gooding,1991,Virology 184:1-8)。E4領域によってコードされるタンパク質は、DNA複製、後期遺伝子発現およびスプライシング、ならびに宿主細胞の遮断に関与する(Halbert,et al.,1985,J.Virol.56:250-257)。後期遺伝子は一般に、ウイルスカプシドに寄与する構造タンパク質をコードする。さらに、アデノウイルスゲノムは、シス作用性5’および3’ITR(逆位末端配列)およびDNA複製に不可欠なパッケージング配列を保有している。ITRはDNA複製の起点を有し、アデノウイルスDNAの感染粒子へのパッケージングにはカプシド形成領域が必要である。
トランスフェクションと組換えの効率に応じて、最大80個のプラークが望ましい組換え体であり、残りは自発的TK変異体である。
自己複製RNAウイルスベクターは、本明細書に記載の改良LAMP構築物を使用して構築することもできる。例えば、アルファウイルス、フラビウイルス(flavivus)、麻疹ウイルス(measle virus)およびラブドウイルスを使用して、自己複製RNAウイルスワクチンを生成することができる。自己複製RNAウイルスの好ましい株には、限定するものではないが、狂犬病ウイルス(RABV)、水疱性口内炎ウイルス(vesicular stomatisitis virus)(VSV)、西ナイルウイルス、クンジンウイルス、セムリキ森林ウイルス(SFV)、シンドビスウイルス(SIN)および/またはベネズエラウマ脳炎ウイルス(VEE)が含まれる。
本発明による改良LAMP構築物は、この構築物を含む他の細胞(「送達細胞」)によって標的細胞に送達することができる。構築物を細胞に導入する方法は当技術分野で公知であり、細胞の核へのDNAのマイクロインジェクション(Capechi,et al.,1980,Cell 22:479-488);CaP04によるトランスフェクション(Chen and Okayama,1987,Mol.Cell Biol.7:2745 2752)、エレクトロポレーション(Chu,et al.,1987,Nucleic Acid Res.15:1311-1326);リポフェクション/リポソーム融合(Feigner,et al.,1987,Proc.Natl.Acad.Sci.USA 84:7413-7417)および粒子衝撃(Yang,et al.,1990,Proc.Natl.Acad.Sci.USA 87:9568-9572)が含まれる。適切な細胞には、自己細胞および非自己細胞が含まれ、異種細胞が含まれてもよい。送達細胞は、それらの死を誘導することにより(例えば、これらの細胞に誘導性自殺遺伝子を提供することにより)標的細胞にその内容物を送達するよう誘導することができる。
本発明による改良LAMP構築物を含む組成物は、細胞への改良LAMP構築物の導入を促進するため、および/または特定の治療効果の増強および/または抗体産生の増強のために、1または複数のアクセサリー分子を含むことができる。
本発明による改良LAMP構築物は、さまざまな宿主細胞、限定するものではないが、原核細胞(例えば、大腸菌(E.coli)、ブドウ球菌属(Staphylococcus sp.)、バチルス属(Bacillus sp.);酵母細胞(例えば、サッカロマイセス属(Saccharomyces sp.));昆虫細胞;線虫細胞;植物細胞;両生類細胞(アフリカツメガエルなど);鳥類細胞;および哺乳動物細胞(例えば、ヒト細胞、マウス細胞、哺乳動物細胞株、解剖組織などからの初代培養哺乳動物細胞)において発現され得る。
本発明の好ましい態様では、本明細書に記載の改良LAMP構築物は、天然または操作された抗原提示細胞に導入される。
改良LAMP構築物によってコードされるペプチドワクチンも本発明の範囲内である。
好ましくは、抗原は区画/オルガネラ(またはそれが送達される後続の区画/オルガネラ)内でプロセシングされ、MHCクラスII分子に結合した免疫応答を調節することができるエピトープを生成する。
ポリヌクレオチドとしての改良LAMP構築物、改良LAMP構築物のコードされたタンパク質、および/または細胞(本明細書に記載の改良LAMP構築物を発現する抗原提示細胞など)を使用して、当業者に周知の方法、例えば、当技術分野で説明されている方法などにより抗体を生成することができる。例えば、Sutcliffe et al.、上記;Wilson et al.、上記;Chow et al.,Proc.Natl.Acad.Sci.USA 82:910-914(1985);およびBittle et al.,J.Gen.Virol.66:2347-2354(1985)を参照されたい。in vivo免疫化が使用される場合、動物は、改良LAMP構築物によってコードされるタンパク質および/または本明細書に記載の抗原を含む改良LAMP構築物を含むポリヌクレオチドを用いて免疫化することができる。ポリヌクレオチドとしての改良LAMP構築物、改良LAMP構築物のコードタンパク質、および/または細胞(本明細書に記載の改良LAMP構築物を発現する抗原提示細胞など)を用いたプライミング、それに続く抗原を用いたブースティングは本発明の好ましい実施形態である。さらなる好ましい実施形態では、本明細書に記載の改良LAMP構築物を用いたプライミング、それに続く抗原を用いたブースティングが特に企図され、特に抗体レパートリーの多様性および力価の点から見て、さらに強固な免疫応答を生み出すために使用できる。
本発明によるワクチン材料は、本明細書に記載の免疫刺激性改良LAMP構築物を含んでも、または組換え微生物、または免疫刺激性改良LAMP構築物を発現する抗原提示細胞であってもよい。本発明によるワクチン材料を含む改良LAMP構築物の調製および個体の免疫化のためのそのような改良LAMP構築物の投与は、当業者に周知の免疫化の原理に従って達成される。
予防と治療の候補
がん免疫療法の候補者は、本明細書に記載の改良LAMP構築物のいずれかで治療される任意のがん患者である。例としては、エプスタイン-バーウイルス関連リンパ腫が記録されている患者、HPV関連子宮頸がん患者、慢性HCV患者、またはがん遺伝子もしくは腫瘍抑制遺伝子に明確な再配列または変異がある患者が挙げられる。
一実施形態では、改良LAMP構築物は、悪性腫瘍の経過中の任意の適切な時間に患者に注入することができる。例えば、改良LAMP構築物は、腫瘍の負荷が低い段階で注入される。改良LAMP構築物が個体の抗原提示細胞に導入される代替実施形態では、抗原提示細胞または成熟抗原提示細胞の前駆体は、静脈穿刺により個体の骨髄または末梢血のいずれかから採取される。これらの細胞は培養で確立され、改良LAMP構築物を形質導入される。形質導入が行われると、これらの抗原提示細胞が患者に注入され、戻される。
本発明はさらに、本明細書に記載の方法の実施を容易にするキットを含む。一態様では、キットは、本明細書に記載の改良LAMP構築物と、改良LAMP構築物を受け取るための細胞とを含む。キットは、細胞をプロフェッショナルAPCに操作するための1または複数の核酸をさらに含んでもよい。しかし、一態様にでは、細胞はプロフェッショナルAPCである。細胞は共刺激分子を発現しても、またはしなくてもよい。好ましい態様では、細胞が共刺激分子を発現しない場合、改良LAMP構築物によりコードされる抗原は自己抗原である。別の態様において、異なるMHC分子(例えば、ヒトで発現されることが知られている)を発現する細胞のパネルが提供される。さらなる態様において、キットは、改良LAMP構築物の細胞への進入を促進する試薬(例えば、脂質ベースの製剤、ウイルスパッケージング材料、細胞など)を含む。なおさらなる態様では、改良LAMP構築物によってコードされる抗原に特異的な1または複数のT細胞株が提供され、改良LAMP構築物の免疫応答を誘発、調節または増強する能力が検証される。
図1に示す改良LAMP構築物は、当業者に周知の標準的な分子生物学技術を使用して構築することができる。例えば、ポリヌクレオチドを含むプラスミドは、図1に示されるILC-1からILC-6の異なる構造を生成するように設計できる。図1に示したLAMPドメインは、図3~10に示したアミノ酸配列に由来する。好ましくは、LAMPドメインは、図3~10に示されるヒトLAMPタンパク質に由来する。ヒト配列と比較して同等のドメインを同定することにより、対応するドメインをオルソロガス配列からクローニングすることも想定される。目的の抗原(目的の1または複数の抗原を含む)は、個別にまたは組み合わせて、記載のLAMP構築物にクローニングできる。
実施例1に記載の改良LAMP構築物の能力を、免疫応答を調節する能力について試験することができる。例えば、メスBALB/cマウスを、0、14、28日目にナノパスを使用して、100μlPBS中50μgの改良LAMP構築物と5μgのGMCSFで免疫化することができる。実験は、最後の投与の4週間後に終了させた。
サバイビンは、アポトーシスの阻害と細胞周期の調節に関与する、タンパク質のアポトーシス阻害剤(IAP)ファミリーの最小メンバーである。これらの機能的属性により、サバイビンは、多様な機能、すなわち細胞増殖と細胞死の調節を示す独特なタンパク質となる。腫瘍におけるサバイビンの発現は、アポトーシスの阻害および細胞死の減少率と相関するだけでなく、化学療法および腫瘍の攻撃性に対する耐性とも相関する[1-6]。
したがって、サバイビンはがんワクチンおよび治療薬の重要な標的である[7-9]。サバイビンは、ヒトおよび胚性幹細胞の両方において優勢に発現されることがわかっており、多くの体性幹細胞型は、幹細胞の生成と維持における未だ未解明の役割を示している。
図13は、すべての被験LAMP構築物が適切なサイズのタンパク質を生成したことを示している。
1.Kami K,Doi R,Koizumi M,Toyoda E,Mori T,Ito D,et al.Survivin expression is a prognostic marker in pancreatic cancer patients.Surgery.2004;136(2):443-8.doi:10.1016/j.surg.2004.05.023.PubMed PMID:15300213.
2.Zhang SQ,Qiang SY,Yang WB,Jiang JT,Ji ZZ.[Expression of survivin in different stages of carcinogenesis and progression of breast cancer].Ai Zheng.2004;23(6):697-700.PubMed PMID:15191674.
3.Zhang X,Zhong L,Hu K,Li Q.[Expression of survivin and its correlation with apoptosis in non-small cell lung cancer].Zhongguo Fei Ai Za Zhi.2004;7(2):138-41.doi:10.3779/j.issn.1009-3419.2004.02.14.PubMed PMID:21215009.
4.Kishi H,Igawa M,Kikuno N,Yoshino T,Urakami S,Shiina H.Expression of the survivin gene in prostate cancer:correlation with clinicopathological characteristics,proliferative activity and apoptosis.J Urol.2004;171(5):1855-60.doi:10.1097/01.ju.0000120317.88372.03.PubMed PMID:15076293.
5.Asanuma K,Tsuji N,Endoh T,Yagihashi A,Watanabe N.Survivin enhances Fas ligand expression via up-regulation of specificity protein 1-mediated gene transcription in colon cancer cells.J Immunol.2004;172(6):3922-9.PubMed PMID:15004200.
6.Miyachi K,Sasaki K,Onodera S,Taguchi T,Nagamachi M,Kaneko H,et al.Correlation between survivin mRNA expression and lymph node metastasis in gastric cancer.Gastric Cancer.2003;6(4):217-24.doi:10.1007/s10120-003-0255-2.PubMed PMID:14716515.
7.Badana AK,Chintala M,Gavara MM,Naik S,Kumari S,Kappala VR,et al.Lipid rafts disruption induces apoptosis by attenuating expression of LRP6 and survivin in triple negative breast cancer.Biomed Pharmacother.2017;97:359-68.doi:10.1016/j.biopha.2017.10.045.PubMed PMID:29091885.
8.Cai JP,Wang YD,Zhang X,Xue HZ.[Expression of P16 and survivin in liver cancer and their clinical significance].Zhonghua Gan Zang Bing Za Zhi.2017;25(10):778-80.doi:10.3760/cma.j.issn.1007-3418.2017.10.013.PubMed PMID:29108210.
9.Cho HJ,Kim HR,Park YS,Kim YH,Kim DK,Park SI.Prognostic value of survivin expression in stage III non-small cell lung cancer patients treated with platinum-based therapy.Surg Oncol.2015;24(4):329-34.doi:10.1016/j.suronc.2015.09.001.PubMed PMID:26690822.
10.Godinho RM,Matassoli FL,Lucas CG,Rigato PO,Goncalves JL,Sato MN,et al.Regulation of HIV-Gag expression and targeting to the endolysosomal/secretory pathway by the luminal domain of lysosomal-associated membrane protein(LAMP-1)enhance Gag-specific immune response.PLoS One.2014;9(6):e99887.doi:10.1371/journal.pone.0099887.PubMed PMID:24932692;PubMed Central PMCID:PMCPMC4059647.
LAMP構築物による治療的処置
雌のBALB/cマウスに、同系の7000 4T1乳がん細胞を0日目に皮下接種することができる。腫瘍が触知可能になったら、ナノパスを使用して、100ul PBS中50ugのワクチンおよび5ugのGMCSFをi.d投与する。原発腫瘍はノギスで測定し、腫瘍体積は式p/6(長さx幅)3/2を使用して計算する。腫瘍接種後の日数の関数として平均腫瘍体積を測定することができる。Kaplan-Meierプロットを使用して、終了時点での全生存率を示すことができる。
腫瘍壊死因子受容体スーパーファミリーメンバー14(TNFRSF14)またはCD270としても知られるヘルペスウイルス侵入メディエーター(HVEM)は、TNF受容体スーパーファミリーのヒト細胞表面受容体である。近年、HVEMは、造血細胞、ならびに乳がん、黒色腫、結腸直腸がん、および卵巣がんの細胞などの実質細胞、ならびに腸上皮に高度に発現していることがわかっている。HVEMは、BTLAまたはLIGHT(TNFSF14)への結合を介して、T細胞の阻害または刺激のいずれかを行う双方向タンパク質である。
HVEMアミノ酸39-202(配列番号114)
LPSCKEDEYPVGSECCPKCSPGYRVKEACGELTGTVCEPCPPGTYIAHLNGLSKCLQCQMCDPAMGLRASRNCSRTENAVCGCSPGHFCIVQDGDHCAACRAYATSSPGQRVQKGGTESQDTLCQNCPPGTFSPNGTLEECQHQTKCSWLVTKAGAGTSSSHWV
以下のHVEM配列をコードするポリヌクレオチドを、本明細書に記載の改良LAMP構築物にクローンニングした:
ポリペプチドからの抗体作製
抗抗原抗体は、動物への注射を使用して抗体を産生させるさまざまな標準的な方法で調製することができる。(現在のプロトコル、第2章を参照されたい。)例えば、本明細書に記載の抗原を含む改良LAMP構築物を発現する細胞を非ヒト脊椎動物に投与して、ポリクローナル抗体を含む血清の産生を誘導する。好ましい方法では、LAMP/抗原タンパク質の調製物を調製および精製して、天然汚染物質を実質的に含まないようにする。次いで、そのような調製物を非ヒト脊椎動物に導入して、より高い特異的活性のポリクローナル抗血清を産生させる。
そのような細胞は、任意の適切な組織培養培地で培養することができるが、10%ウシ胎児血清(約56℃で不活性化)を添加し、約10g/lの非必須アミノ酸、約1,000U/mlのペニシリンおよび約100ug/mlのストレプトマイシンを添加したEarleの改変イーグル培地で細胞を培養することが好ましい。
ポリクローナル抗体およびモノクローナル抗体を作製するためのポリヌクレオチドの使用
動物にポリヌクレオチドを直接注入する方法は、当技術分野で十分に説明されている。
例えば、米国特許第5,676,954号;第6,875,748号;第5,661,133号を参照されたい。例えば、抗原を含む改良LAMP構築物をコードするポリヌクレオチドを、拘束された覚醒マウス(雌6~12週齢BALB/cまたはヌード、nu/nu(Harlan Sprague Dawley,Indianapolis,Ind.による))の四頭筋に注射することができる。一実施形態では、Hartikka,J.,et al.,Hum.Gene Ther.7:1205-1217(1996)に記載のように、50μl溶液中の50μgのポリヌクレオチドを、使い捨ての滅菌プラスチックインスリン注射器およびマイクロピペットチップからカットされたプラスチックカラーを備えた28G1/2針(Becton-Dickinson、Franklin Lakes、N.J.、カタログ番号329430)を使用して、マウスに注射することができる。
ハイブリドーマを限界希釈によって3回クローニングして、抗体を産生する。
抗原を含む改良LAMP構築物による免疫化
哺乳動物において抗体を産生させる方法は、当技術分野で周知である。一例において、抗原を含むLAMP構築物に対するポリクローナル抗血清は、抗原を含む改良LAMP構築物合計500μgを用いた病原体フリーウサギの2ヶ月間にわたる免疫化により産生される。例えば、抗原を含む改良LAMP構築物をPBSに溶解し、等量のフロイントアジュバントで乳化することができる。最終ブースターの後、ウサギの血清を分離して、ポリクローナル抗血清の力価を決定することができる。
また、本発明は以下の実施形態を含む。
[1]
以下を含む改良LAMP構築物:
a.LAMPタンパク質のシステイン保存断片、および
b.抗原性ドメイン。
[2]
a.前記抗原性ドメインが前記システイン保存断片のN末端に配置されている、
b.前記抗原性ドメインが単一のシステイン保存断片のC末端に配置されている、または
c.前記抗原性ドメインが2つのシステイン保存断片の間に配置されている、
[1]に記載の改良LAMP構築物。
[3]
図1のILC-1、ILC-2、ILC-3、ILC-4、ILC-5またはILC-6に示される構造を含む、[1]または[2]のいずれかに記載の改良LAMP構築物。
[4]
各抗原がリンカーによって分離されている、[3]に記載の改良LAMP構築物。
[5]
前記リンカーがアミノ酸配列GPGPGまたはPMGLPから選択される、[4]に記載のLAMP構築物。
[6]
複数のシステイン保存断片を含む、[1]~[5]のいずれかに記載の改良LAMP構築物。
[7]
前記システイン保存断片がLAMPタンパク質の相同ドメインを含む、[1]~[6]のいずれか一項に記載の改良LAMP構築物。
[8]
LAMPタンパク質の膜貫通ドメインをさらに含む、[1]~[7]のいずれか一項に記載の改良LAMP構築物。
[9]
シグナル配列をさらに含む、[1]~[8]のいずれかに記載の改良LAMP構築物。
[10]
前記シグナル配列がLAMPタンパク質に由来する、[9]に記載の改良LAMP構築物。
[11]
前記LAMPタンパク質が、LAMP-1、LAMP2、LAMP-3、LIMP2、マクロシアリン(Macrosailin)、Endolyn、LAMP5またはLIMBICから選択される、[1]~[10]のいずれか一項に記載の改良LAMP構築物。
[12]
前記LAMPタンパク質が配列番号1~113のいずれか1つから選択される、[11]に記載の改良LAMP構築物。
[13]
前記LAMPタンパク質が、配列番号1~113と少なくとも約70%、少なくとも約75%、少なくとも約80%、少なくとも約85%、少なくとも約90%、少なくとも約95%、96%、97%、98%または99%同一である、[12]に記載の改良LAMP構築物。
[14]
[1]~[13]のいずれか一項に記載の改良LAMP構築物をコードするポリヌクレオチド。
[15]
[14]に記載のポリヌクレオチドを含む宿主細胞。
[16]
[1]~[13]のいずれか一項に記載の改良LAMP構築物、[14]に記載のポリヌクレオチド、または[15]に記載の宿主細胞を含む組成物。
[17]
疾患または障害を有する対象を治療する方法であって、[1]~[13]のいずれか一項に記載の改良LAMP構築物、[14]に記載のポリヌクレオチド、[15]に記載の宿主細胞、または[16]に記載の組成物を、それを必要とする対象に前記疾患または障害を軽減または治療するための十分量で投与する工程を含む方法。
[18]
プライミング工程および少なくとも1回のブースティング工程を含む、[17]に記載の方法。
[19]
前記改良LAMP構築物が前記プライミング工程に使用される、[18]に記載の方法。
[20]
前記ブースティング工程が、抗原、改良LAMP構築物、改良LAMP構築物によりコードされるポリペプチド、または前記改良LAMP構築物を含む細胞の投与を含む、[18]または[19]に記載の方法。
[21]
プライムに使用される抗原がブーストに使用される抗原と同じである、[17]~[20]のいずれか一項に記載の方法。
[22]
プライムに使用される抗原がブーストに使用される第2の抗原と同じタンパク質に由来する、[17]~[21]のいずれか一項に記載の方法。
[23]
複数の抗原がプライムおよび/またはブーストに使用される、[17]~[22]のいずれか一項に記載の方法。
Claims (26)
- リソソーム関連膜タンパク質(LAMP)構築物をコードするポリヌクレオチドを含む樹状細胞であって、前記LAMP構築物がLAMPタンパク質の内腔ドメインの2つの相同ドメイン、前記LAMPタンパク質と異種の抗原性ドメイン、および、LAMPタンパク質の膜貫通ドメインを含み、
前記抗原性ドメインが前記2つの相同ドメインの間に配置され、
前記膜貫通ドメインが、前記2つの相同ドメインのうち第2の相同ドメインの後に配置され、
前記LAMPタンパク質がヒトのLAMP-1またはLAMP-2から選択される、樹状細胞。 - 前記LAMP構築物がシグナル配列をさらに含む、請求項1に記載の樹状細胞。
- 前記シグナル配列がLAMPタンパク質に由来する、請求項2に記載の樹状細胞。
- 前記LAMP構築物がヒトのLAMP-1またはLAMP-2タンパク質の細胞質尾部をさらに含む、請求項1~3のいずれか一項に記載の樹状細胞。
- 前記抗原性ドメインがリンカーによって1または両方の前記相同ドメインから分離されている、請求項1~4のいずれか一項に記載の樹状細胞。
- 前記リンカーがアミノ酸配列GPGPGまたはPMGLPから選択される、請求項5に記載の樹状細胞。
- 前記LAMPタンパク質が配列番号1および2のうちいずれか1つから選択されるアミノ酸配列を含む、請求項1~6のいずれか一項に記載の樹状細胞。
- 前記LAMPタンパク質が、配列番号1および2のうち少なくとも1つと、少なくとも90%、95%、96%、97%、98%または99%同一であるアミノ酸配列を含む、請求項1~6のいずれか一項に記載の樹状細胞。
- 前記LAMPタンパク質がヒトLAMP-1である、請求項1~6のいずれか一項に記載の樹状細胞。
- 前記2つの相同ドメインがヒトLAMP-1相同ドメイン1およびヒトLAMP-1相同ドメイン2を含む、請求項1~6のいずれか一項に記載の樹状細胞。
- 前記ヒトLAMP-1相同ドメイン1が、配列番号1の残基29~194のアミノ酸配列と少なくとも95%同一のアミノ酸配列を含む、請求項10に記載の樹状細胞。
- 前記ヒトLAMP-1相同ドメイン1が、配列番号1の残基29~194のアミノ酸配列と少なくとも97%同一のアミノ酸配列を含む、請求項10に記載の樹状細胞。
- 前記ヒトLAMP-1相同ドメイン1が、配列番号1の残基29~194のアミノ酸配列を含む、請求項10に記載の樹状細胞。
- 前記ヒトLAMP-1相同ドメイン2が、配列番号1の残基228~381のアミノ酸配列を含む、請求項10~13のいずれか一項に記載の樹状細胞。
- 前記膜貫通ドメインが配列番号1の残基383~405を含む、請求項1~14のいずれか一項に記載の樹状細胞。
- 前記細胞質尾部が配列番号1の残基406~417を含む、請求項4~15のいずれか一項に記載の樹状細胞。
- 前記抗原性ドメインがサバイビンまたはHVEMを含む、請求項1~16のいずれか一項に記載の樹状細胞。
- 前記LAMP構築物が配列番号119のアミノ酸配列を含む、請求項1に記載の樹状細胞。
- 請求項1~18のいずれか一項に記載の樹状細胞を含む、組成物。
- 疾患または障害を軽減または治療するための、請求項19に記載の組成物であって、それを必要とする対象に前記疾患または障害を軽減または治療するのに十分な量で投与される、組成物。
- プライミング工程および/または少なくとも1回のブースティング工程で使用される、請求項20に記載の組成物。
- 前記プライミング工程で使用される、請求項21に記載の組成物。
- 前記少なくとも1回のブースティング工程が、抗原、LAMP構築物、LAMP構築物のポリヌクレオチド配列によりコードされるポリペプチド、またはLAMP構築物を含む細胞の投与を含む、請求項21または22に記載の組成物。
- プライムに使用される抗原がブーストに使用される抗原と同じである、請求項21~23のいずれか一項に記載の組成物。
- プライムに使用される抗原がブーストに使用される第2の抗原と同じタンパク質に由来する、請求項21~24のいずれか一項に記載の組成物。
- 複数の抗原がプライムおよび/またはブーストに使用される、請求項21~25のいずれか一項に記載の組成物。
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WO2018204534A1 (en) * | 2017-05-02 | 2018-11-08 | Immunomic Therapeutics, Inc. | Lamp (lysosomal associated membrane protein) constructs comprising cancer antigens |
EP3793595A1 (en) * | 2018-05-15 | 2021-03-24 | Immunomic Therapeutics, Inc. | Improved lamp constructs comprising allergens |
CN114641306A (zh) * | 2019-10-18 | 2022-06-17 | 免疫治疗有限公司 | 包含癌抗原的改良lamp构建物 |
WO2022099695A1 (en) * | 2020-11-16 | 2022-05-19 | Jiangsu Cell Tech Medical Research Institute Co., Ltd. | Cd164 fusion and uses thereof |
WO2023201201A1 (en) | 2022-04-10 | 2023-10-19 | Immunomic Therapeutics, Inc. | Bicistronic lamp constructs comprising immune response enhancing genes and methods of use thereof |
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US11203629B2 (en) | 2021-12-21 |
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AU2018254776A1 (en) | 2019-10-31 |
US20200377570A1 (en) | 2020-12-03 |
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US20220153809A1 (en) | 2022-05-19 |
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