JP2018523708A - マイコプラズマ・ボビス組成物 - Google Patents
マイコプラズマ・ボビス組成物 Download PDFInfo
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- JP2018523708A JP2018523708A JP2018527845A JP2018527845A JP2018523708A JP 2018523708 A JP2018523708 A JP 2018523708A JP 2018527845 A JP2018527845 A JP 2018527845A JP 2018527845 A JP2018527845 A JP 2018527845A JP 2018523708 A JP2018523708 A JP 2018523708A
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- Prior art keywords
- mycoplasma bovis
- strain
- immunogenic composition
- culture
- mycoplasma
- Prior art date
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Abstract
【選択図】図1
Description
別の実施形態は、上記実施形態のいずれかの免疫原性組成物であって、少なくとも1つの追加の抗原をさらに含む免疫原性組成物を提供する。
別の実施形態は、マイコプラズマ・ボビスのワクチンを提供する方法であって、前記ワクチンは、(A)PTA−122167として、ATCCで寄託されたマイコプラズマ・ボビスの培養物を得ることと、(B)少なくとも1回、マイコプラズマ・ボビスの前記培養物をさらに継代し、(C)前記継代した培養物からクローンを単離し、(D)担体または賦形剤、および任意にアジュバントとともに、前記クローンを処方することを含むステップにより生成される方法を提供する。
別の実施形態は、マイコプラズマ・ボビスの親株を突然変異誘発する方法であって、前記後代の株は、受け入れ番号PTA−122167でアメリカ合衆国培養細胞系統保存機関に寄託されている方法を提供する。
本明細書において他に定義されない限り、本実施形態に関連して使用される科学技術用語は、当業者によって一般に理解される意味を有するものとする。さらに、文脈によって特に要求されない限り、単数形の用語は複数形を含み、複数形の用語は単数形を含むものとする。
免疫グロブリンは、「定常」および「可変」領域を有する「軽」および「重」ポリペプチド鎖からなる血清タンパク質であり、定常領域の組成物(例えば、IgA、IgD、IgE、IgGおよびIgM)によりクラスに分類される。所与の抗原に対して「特異的」である抗体は、抗体の可変領域が特定の抗原のみを認識して結合することを示す。抗体は、ポリクローナル混合物またはモノクローナルであり得る。これらは、天然または組換え源由来のインタクトな免疫グロブリンであり得るか、またはインタクトな免疫グロブリンの免疫反応性部分であり得る。抗体は、Fv、Fab’、F(ab’)2、Fc、ならびに一本鎖を含む様々な形態で存在し得る。抗体は、限定されるものではないが、抗体断片を含む抗原結合タンパク質に変換することができる。本明細書中で使用される場合、交換可能に使用され得る用語「抗原結合タンパク質」、「抗体」などは、抗原結合部位を含むポリペプチド、またはその断片をいう。「抗原結合タンパク質」または「抗体」という用語は、好ましくは、特定のタンパク質およびその断片に結合することができるモノクローナル抗体およびそのフラグメント、ならびにその免疫学的結合等価物を指す。本明細書中で使用される場合、その用語はインタクトなポリクローナルまたはモノクローナル抗体だけでなく、そのフラグメントも包含する。本発明の目的のために、「抗体」および「抗原結合タンパク質」は、他に記載がない限り、抗体フラグメントも含む。例示的な抗体フラグメントには、Fab、Fab’、F(ab’)2、Fv、scFv、Fd、dAb、ダイアボディ、それらの抗原認識フラグメント、小型モジュラー免疫医薬品(SMIP)ナノボディなどが含まれ、全ては、抗原結合タンパク質または抗体断片、ならびに上述の断片およびそれらの化学的または遺伝子操作された対応物のいずれか、ならびに他の抗体断片およびその突然変異株、抗体部分を含む融合タンパク質、および抗原認識部位を含む免疫グロブリン分子の変更された他のいずれかの構成であることが当業者により認識される。抗体および抗原結合タンパク質は、例えば、従来のハイブリドーマ技術(Kohlerら、Nature 256:495−499(1975))、組換えDNA法(米国特許第4,816,567号)、または抗体ライブラリーを用いるファージディスプレイ技術(Clacksonら、Nature 352:624−628(1991);Marksら、J. Mol.Biol.222:581−597(1991))により作成することができる。様々な他の抗体産生技術については、Antibodies:A Laboratory Manual、eds. Harlowら、Cold Spring Harbor Laboratory、1988、並びに当業者に周知の他の技術を参照されたい。
本明細書で使用される「ウシ」という用語は、一般に蹄鉄を有する中〜大規模な有蹄動物の多様な群を意味し、少なくとも1つの性が真の角を有するものを意味する。ウシには、家畜、バイソン、アフリカの水牛、水牛、ヤク、4角型または螺旋状の角虫が含まれるが、これらに限定されない。
本明細書で使用される「突然変異体」という用語は、生物の核酸または染色体内の塩基対配列の変化である突然変異の実例から生じたまたは突然変異した結果の個体または生物であって、野生型の個体または生物には見られない新しい性質または形質の創造をもたらす個体または生物を意味する。
細菌;免疫原性組成物
本発明の特定の実施形態において、ウシ由来のマイコプラズマ・ボビス株は、弱毒化されただけでなく、特徴付けられている。当該マイコプラズマ・ボビス株の単離物は、2015年5月12日に米国バージニア州マナサスのアメリカ合衆国培養細胞系統保存機関(ATCC)で寄託され、受付番号、PTA−122167が付与された。
本発明の免疫原性組成物は、抗生物質を含むこともできる。そのような抗生物質には、アミノグリコシド、カルバペネム、セファロスポリン、グリコペプチド、マクロライド、ペニシリン、ポリペプチド、キノロン、スルホンアミドおよびテトラサイクリンのクラスのものが含まれるが、これらに限定されない。一実施形態では、本発明は、約1pg/ml〜約60pg/mlの抗生物質を含む免疫原性組成物が考慮される。別の実施形態において、免疫原性組成物は、約5pg/ml〜約55pg/mlの抗生物質、または約10pg/ml〜約50pg/mlの抗生物質、または約15pg/ml〜約45pg/mlの抗生物質、または約20pg/ml〜約40pg/mlの抗生物質、または約25pg/ml〜約35pg/mlの抗生物質を含む。さらに別の実施形態において、免疫原性組成物は、約30pg/ml未満の抗生物質を含む。
本発明の免疫原性組成物は、マイコプラズマ・ボビスに対して有効な免疫応答を誘導するために動物に投与することができる。したがって、本発明は、本明細書に記載の本発明の免疫原性組成物の治療有効量を動物に投与することにより、マイコプラズマ・ボビスに対する有効な免疫応答を刺激する方法を提供する。
免疫原性組成物を個々にまたは追加の化合物と組み合わせて、例えば特定の疾病または状態を治療する目的で投与することが望ましい場合があるため、本発明の範囲内で免疫原性組成物は、組成物の投与または共投与に適したキットの形態に含まれるか、または組み合わせられることが好都合である。本発明のキットは、少なくとも1つが本発明による免疫原性組成物である1種以上の別個の医薬品組成物、およびその組成物を別個に保持するための手段、例えば容器、分割されたボトル、または分割されたフォイルパケットを含むことができる。そのようなキットの例は、注射器および針などである。 本発明のキットは、異なる投薬形態、例えば、経口または非経口、異なる投薬間隔で別個の組成物を投与すること、または別個の組成物を互いに対して滴定することに特に適している。本発明の組成物の投与を補助するために、キットは典型的には投与のための指示を含む。
抗体は、モノクローナル、ポリクローナルまたは組換えのいずれかであり得る。抗体は、免疫原またはその一部に対して調製することができる。例えば、免疫原のアミノ酸配列に基づく合成ペプチド、またはクローニング技術によって組換えて調製された合成ペプチド、または天然の遺伝子産物および/またはその一部を単離して免疫原として使用することができる。免疫原は、Harlow and Lane,”Antibodies:A Laboratory Manual”,Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,(1988)、およびBorrebaeck,”Antibody Engineering − A Practical Guide”,W.H. Freeman and Co.(1992)に概説されているような、当業者に周知の標準抗体産生技術によって抗体を産生するために使用することができる。抗体フラグメントは、抗体から調製することもでき、Fab、F(ab’)2、およびFvを当業者に公知の方法によって調製されることとしてもよい。
本発明のさらに他の実施形態では、免疫原性組成物は組換えワクチンを含むことができる。そのような組換えワクチンは、概して、マイコプラズマ・ボビス抗原を含むベクターおよび異種インサートを含むであろう。適切なマイコプラズマ・ボビス抗原には、限定されないが、可変表面タンパク質(Vsps)、シタデシン、リポタンパク質、例えばP48およびP68、並びに、調査され、特徴づけられるままである潜在的な他の仮定タンパク質、を含む膜および膜関連タンパク質が含まれ得る。
実施例1.マイコプラズマ・ボビス突然変異株の生成と単離
ウシ(Millerran、Queensland、1999)の関節から単離したマイコプラズマ・ボビスを、マイコプラズマ・ボビス(「Bovis」)ブロス(PPLO;酵母エキス;フェノールレッド;熱で不活化されたγ−照射ブタ血清)で2回継代し、Bovis寒天培地上で4倍フィルタークローニングし、さらにブロスで継代培養した。菌株(10ml)の培養物を調製し、適切な温度で24時間インキュベートした。 その後、13,000gで10分間、4℃で遠心分離することにより培養物を採取した。得られたペレットを1mlのリン酸緩衝生理食塩水(PBS)で3回洗浄した。 最終ペレットを1mlのPBSに再懸濁し、2つの1.5mlのエッペンドルフチューブに分けた。菌株(3683と指定)は、化学物質である、メチルニトロニトロソグアニジン(NTG)を使用して突然変異誘発された。温度感受性のマイコプラズマ・ボビスの突然変異株は、もともとNonomura およびImada (Avian Dis. 26(4):763−775; 1982)に記載されたプロトコルに従って生成され選択された。突然変異誘発および表現型選択の後、ボビスブロス中のフィルタークローニングおよび継代を行った。
臨床的に健康な、初乳を摂取していない(CD)子ウシを試験に登録した。すべての子ウシは、ELISAによるマイコプラズマ・ボビス抗体について血清陰性であり(<1:1600力価)、0日目より前に採取した鼻スワブのマイコプラズマ・ボビスについてPCR陰性であった。
実施例3.温度感受性の突然変異株、3863 22/3/12、および非温度感受性突然変異株、N2805−1のゲノムの特徴化
3683#22/3/12で接種した子ウシから単離された、マイコプラズマ・ボビス温度感受性の突然変異株、3683#22/3/12および非温度感受性突然変異株、N2805−1間のゲノムの相違を特徴づけるための努力において、両方のゲノムがイルミナテクノロジーを用いてシーケンスされた。DNAライブラリーを調製し、バーコードされたサンプルを配列決定して、サンプルあたりの対の末端配列の平均60X被覆率を得た。すべての読み取りの品質管理が行われ、マッピングおよび一塩基多型(SNP)分析の前に、失敗および低品質の読み取りが除去された。シーケンス読み取りは、CLCゲノムワークベンチソフトウェア(Qiagen; Redwood City, CA)を用いて、リファレンスゲノム(Hubei−1;ジェンバンク受け入れ番号CP002513)に対してマッピングされた。CLCゲノムワークベンチの変異検出モジュールをSNP発見に使用した。SNPの同一性および位置を表14に示す。2つの突然変異株間で、56SNPが特定され、そのうち17がアミノ酸変化をもたらし(停止コドンの導入をもたらす2つを含む)、6がフレームシフト突然変異をもたらし、33が非コード領域で生じた。
Claims (18)
- 化学的に弱毒化されたマイコプラズマ・ボビス株を含む、有効な免疫原性組成物であって、前記株は、受け入れ番号PTA−122167で、アメリカ合衆国培養細胞系統保存機関に寄託されている、免疫原性組成物。
- 前記化学的に弱毒化されたマイコプラズマ・ボビス株は、親株と比較して、ニトロレダクターゼ、酸性ヒスチジンホスファターゼ、エキシヌクレアーゼABCサブユニットB、DNAポリメラーゼIIIサブユニットベータ、およびATPシンターゼF1サブユニットデルタの1つ以上において、1つ以上の突然変異を含む、請求項1に記載の免疫原性組成物。
- 化学的に弱毒化されたマイコプラズマ・ボビス株を含む有効な免疫原性組成物であって、前記株はPTA−122167であり、さらに、前記株は、マイコプラズマ・ボビス株、Hubei−1のリファレンスゲノムのヌクレオチドナンバリングによる、位置115273、194478、194484、194525、194724、204966、207629、262327、271487、271661、271666、272086、272133、309463、310075、310078、310086、310090、311988、334184、358013、365101、365188、397010、397901 、399129、410247、410253、410334、410514、410733、414666、453388、468457、502577、502678、502963、543859、560986、632309、632366、632612、633994、686074、687874、687915、696348、729874、730046、761587、761663、761810、761815、765176、765328、および765403でのマイコプラズマ・ボビス株、3683 #22/3/12におけるいずれかのオリジナルヌクレオチドの1つ以上を含むようにリバースエンジニアリングされている、免疫原性組成物。
- 前記マイコプラズマ・ボビス株は不活化されている、請求項1〜3のいずれかに記載の免疫原性組成物。
- 前記組成物は、追加的にアジュバントを含むことができる、請求項4に記載の免疫原性組成物。
- 少なくとも1つの追加の抗原をさらに含む、請求項4に記載の免疫原性組成物。
- 前記追加の抗原は、ウイルス、細菌、真菌類、および寄生生物からなる群から選択される、請求項6に記載の免疫原性組成物。
- 前記組成物は、筋肉内、皮下、鼻腔内、気管内、経口、およびエアゾールからなる群から選択される経路による投与のために処方される、請求項1〜7のいずれかに記載の免疫原性組成物。
- ウシ属の動物におけるマイコプラズマ・ボビスに起因する疾病を防止する方法であって、免疫化する量の請求項1〜5のいずれかに記載の免疫原性組成物を前記動物に投与することを含む方法。
- ウシ属の動物のマイコプラズマ・ボビスおよび他の感染病原体により引き起こされる疾病を防止する方法であって、免疫化する量の請求項6または7のいずれかに記載の免疫原性組成物を前記動物に投与することを含む、方法。
- ウシ属の動物におけるマイコプラズマ・ボビスにより引き起こされる疾病を防止するための薬物の製造における、請求項1〜5のいずれかに記載の免疫原性組成物の使用。
- マイコプラズマ・ボビスのワクチンであって、
A.PTA−122167として、ATCCで寄託されたマイコプラズマ・ボビスの培養物を得ることと、
B.少なくとも1回、マイコプラズマ・ボビスの前記培養物をさらに継代することと、
C.前記継代した培養物からクローンを単離すること、および、
D.担体または賦形剤で、任意にアジュバントとともに、前記クローンを処方すること、
とを含むステップにより生成される、マイコプラズマ・ボビスのワクチン。 - 前記継代された培養物から得られた前記クローンがPTA−122167よりもさらに弱毒化されている、請求項12に記載のワクチン。
- マイコプラズマ・ボビスのワクチンを提供する方法であって、前記ワクチンは、
A.PTA−122167として、ATCCで寄託されたマイコプラズマ・ボビスの培養物を得ることと、
B.少なくとも1回、マイコプラズマ・ボビスの前記培養物をさらに継代することと、
C.前記継代した培養物からクローンを単離すること、および、
D.担体または賦形剤、および任意にアジュバントとともに、前記クローンを処方すること、
とを含むステップにより生成される、方法。 - マイコプラズマ・ボビスの親株を突然変異誘発する方法であって、前記方法は、前記株を化学変異原に供することと、その後インビトロでの連続継代の後に、生存したままの後代の株を選択すること、とを含み、前記方法はさらに、受け入れ番号 PTA−122167でアメリカ合衆国培養細胞系統保存機関に寄託されている前記株を産生する、方法。
- 前記親株は、マイコプラズマ・ボビス株3683である、請求項15に記載の方法。
- 前記後代の株は、受け入れ番号 PTA−122167でアメリカ合衆国培養細胞系統保存機関に寄託されている、請求項15に記載の方法。
- 前記後代の株は、マイコプラズマ・ボビス株、Hubei−1のリファレンスゲノムのヌクレオチドナンバリングによる、位置115273、194478、194484、194525、194724、204966、207629、262327、271487、271661、271666、272086、272133、309463、310075、310078、310086、310090、311988、334184、358013、365101、365188、397010、397901、399129、410247、410253、410334、410514、410733、414666、453388、468457、502577、502678、502963、543859、560986、632309、632366、632612、633994、686074、687874、687915、696348、729874、730046、761587、761663、761810、761815、765176、765328、および765403におけるいずれかのオリジナルヌクレオチドの1つ以上を含む、請求項15に記載の方法。
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