JP2017214388A - 黄色ブドウ球菌(staphylococcus aureus)感染症を治療および予防するための組成物および方法 - Google Patents
黄色ブドウ球菌(staphylococcus aureus)感染症を治療および予防するための組成物および方法 Download PDFInfo
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- JP2017214388A JP2017214388A JP2017120971A JP2017120971A JP2017214388A JP 2017214388 A JP2017214388 A JP 2017214388A JP 2017120971 A JP2017120971 A JP 2017120971A JP 2017120971 A JP2017120971 A JP 2017120971A JP 2017214388 A JP2017214388 A JP 2017214388A
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Abstract
【解決手段】黄色ブドウ球菌タンパク質Aに特異的に結合するFab領域を有する抗体。
【効果】前記抗体は、抗体中和タンパク質Aの発現にもかかわらず黄色ブドウ球菌菌血症のオプシニゼーションを媒介することができ、前記抗体及びその抗原結合フラグメントは、黄色ブドウ球菌感染症を治療及び/又は予防する方法において使用することができる。
【選択図】なし
Description
本出願は、2014年6月3日に出願された米国仮特許出願第62/007,242号明細書、2014年8月25日に出願された同第62/041,423号明細書および2015年2月13日に出願された同第62/115,665号明細書からの優先権を主張するものである。
本出願は、ASCIIフォーマットで電子的に提出されており、参照により全体として本明細書に組み込まれる配列表を含有する。2015年5月28日に作成された上記のASCIIコピーは、5407−0234_SL.txtと指名されており、サイズは83,036バイトである。
本明細書では、SpAに結合し、SAの抗体(Ab)中和SpAの発現にもかかわらずSA細菌のオプシニゼーションを媒介することができる、精製または単離(例えば、重量で少なくとも90%、92%、94%、95%、96%、97%、98%または99%純粋な)Ab(例えば、好ましくは完全ヒト、ヒトまたはヒト化IgG3)について記載する。好ましいそのようなAbは、配列番号1のペプチドに、それらのFc領域を介してSpAに結合したヒトIgG免疫グロブリン(例えば、IgG1、IgG2およびIgG4のうちの1つ以上)を置換するために十分な結合親和性で結合する。好ましいAbは、それらのFab領域パラトープを介して1×10−10M未満(例えば、1×10−11M未満、1×10−12M未満、0.5×10−12M未満または1×10−13M未満)のKDで、生理的条件(例えば、リン酸緩衝食塩液)下において(例えば、表面プラズモン共鳴または組換えSpAを使用するバイオレイヤー干渉分光法(Bio−Layer Interferometry)を使用して決定されるように)SpAに結合できる。例えば、本明細書で記載したそれらのFab領域を介してSpAに(例えば、生理的条件下、例えばリン酸緩衝食塩液中で、例えば組換えSpAを使用する表面プラズモン共鳴を使用して測定して)1×10−10M〜0.5×10−12M、1×10−11M〜0.5×10−12M、1×10−11M〜0.2×10−12MのKDで結合するAbが好ましい。本明細書に記載したそれらのAbまたは抗原結合フラグメントは、好ましくはそれらのFc領域を介してSA細菌の細胞壁内のSpAに結合したヒトAb(例えば、IgG1、IgG2およびIgG4のうちの1つ以上)を置換することができる。さらに本明細書では、それらのFab領域パラトープを介して黄色ブドウ球菌(Staphylococcus aureus)タンパク質A(SpA)に1×10−10M未満のKDで特異的に結合する精製または単離(例えば、重量で少なくとも90%、92%、94%、95%、96%、97%、98%または99%純粋の)mAb(例えば、好ましくは完全ヒト、ヒトまたはヒト化IgG3)が提供されるが、このときmAbは、それらのFc領域を介してSpAに結合する少なくとも1mg/mL(例えば、少なくとも1、2、3、4、5、10、25、50または100mg/mLまたはヒト血清中に通常含有される量)のIgG免疫グロブリンの存在下で、SpA発現性黄色ブドウ球菌(Staphylococcus aureus)細菌のオプシニゼーションを媒介することができる。
(i)それぞれ配列番号2、3および4のCDR1、CDR2およびCDR3を含む重鎖、ならびに/またはそれぞれ配列番号7、8および9のCDR1、CDR2およびCDR3を含む軽鎖;
(ii)それぞれ配列番号12、13および14のCDR1、CDR2およびCDR3を含む重鎖、ならびに/またはそれぞれ配列番号17、18および19のCDR1、CDR2およびCDR3を含む軽鎖;
(iii)それぞれ配列番号22、23および24のCDR1、CDR2およびCDR3を含む重鎖、ならびに/またはそれぞれ配列番号27、28および29のCDR1、CDR2およびCDR3を含む軽鎖;
(iv)それぞれ配列番号32、33および34のCDR1、CDR2およびCDR3を含む重鎖、ならびに/またはそれぞれ配列番号37、38および39のCDR1、CDR2およびCDR3を含む軽鎖;
(v)それぞれ配列番号42、43および44のCDR1、CDR2およびCDR3を含む重鎖、ならびに/またはそれぞれ配列番号47、48および49のCDR1、CDR2およびCDR3を含む軽鎖;
(vi)それぞれ配列番号52、53および54のCDR1、CDR2およびCDR3を含む重鎖、ならびに/またはそれぞれ配列番号57、58および59のCDR1、CDR2およびCDR3を含む軽鎖;
(vii)それぞれ配列番号62、63および64のCDR1、CDR2およびCDR3を含む重鎖、ならびに/またはそれぞれ配列番号67、68および69のCDR1、CDR2およびCDR3を含む軽鎖;または
(viii)それぞれ配列番号72、73および74のCDR1、CDR2およびCDR3を含む重鎖、ならびに/またはそれぞれ配列番号77、78および79のCDR1、CDR2およびCDR3を含む軽鎖を含むことができる。
(i)配列番号2、3、4、7、8および9;
(ii)配列番号12、13、14、17、18および19;
(iii)配列番号22、23、24、27、28および29;
(iv)配列番号32、33、34、37、38および39;
(v)配列番号42、43、44、47、48および49;
(vi)配列番号52、53、54、57、58および59;
(vii)配列番号62、63、64、67、68および69;または
(viii)配列番号72、73、74、77、78および79
からなる群から選択される6つのCDRのセット(セット全体)内に1個、2個、3個、4個、5個または6個以下の全アミノ酸置換(例えば、保存アミノ酸置換)を有する、6つCDRのセットを有する。
(i)配列番号2、3、4、7、8および9の6つのCDRのセット;
(ii)配列番号12、13、14、17、18および19の6つのCDRのセット;
(iii)配列番号22、23、24、27、28および29の6つのCDRのセット;
(iv)配列番号32、33、34、37、38および39の6つのCDRのセット;
(v)配列番号42、43、44、47、48および49の6つのCDRのセット;
(vi)配列番号52、53、54、57、58および59の6つのCDRのセット;
(vii)配列番号62、63、64、67、68および69の6つのCDRのセット;または
(viii)配列番号72、73、74、77、78および79の6つのCDRのセット
を含むか、またはそれらからなる可能性がある。
本明細書では、少なくとも1つの医薬上許容される担体(例えば、非天然の医薬上許容される担体)および少なくとも1つ(例えば、2つ、3つまたは4つ)の本明細書に提供したAbまたはその抗原結合フラグメントの何れかを含有する医薬組成物が提供される。医薬上許容される担体の非限定的な例には、滅菌水、生理的食塩水、安定剤、賦形剤、酸化防止剤(例えば、アスコルビン酸)、バッファー(例えば、リン酸塩、クエン酸塩、ヒスチジンおよび他の有機酸)、防腐剤、界面活性剤(例えば、PEGおよびTween)、キレート剤(例えば、EDTAまたはEGTA)ならびに結合剤が含まれる。医薬上許容される担体の追加の例には、さらにまた低分子量ポリペプチド、タンパク質(例えば、血清アルブミンおよびゼラチン)、アミノ酸(例えば、グリシン、グルタミン、アスパラギン、グルタミン酸、アスパラギン酸、メチオニン、アルギニンおよびリシン)、糖および炭水化物(例えば、多糖類および単糖類)ならびに糖アルコール(例えば、マンニトールおよびソルビトール)も含まれる。注射用水溶液を調製する場合は、グルコースおよび他のアジュバント、例えばD−ソルビトール、D−マンノース、D−マンニトールおよび塩化ナトリウムを含む生理的食塩水および等張性溶液を、および必要であれば、適切な可溶化剤、例えばアルコール(例えば、エタノール)、ポリアルコール(例えば、プロピレングリコールおよびPEG)、および非イオン性界面活性剤(例えば、ポリソルベート80、ポリソルベート20、ポロキサマー188およびHCO−50)と組み合わせて使用することができる。調製物中にヒアルロニダーゼを混合することによって、より多量の流体量を皮下投与することができる(例えば、Expert.Opin.Drug.Deliv.4(4):427−440,2007を参照されたい)。
さらに、SA感染症(MRSA感染症、SA菌血症、SA皮膚感染症、SA乳腺炎、SA蜂巣炎もしくは毛包炎、またはSA関連性創感染症、膿瘍、骨髄炎、心内膜炎、肺炎、敗血症性ショック、食中毒、毒性ショック症候群)を有する対象を治療する方法において、それを必要とする対象(例えば、人間または他の哺乳動物、例えばウシ、ヒツジ、イヌ、ネコ、ウマ、ヤギ、ウサギ、ブタまたは鳥類)に治療有効量の本明細書に提供した医薬組成物の何れかの少なくとも1つまたは本明細書に提供したAbまたはその抗原結合フラグメントの何れかの少なくとも1つを投与するステップを含む方法が提供される。一部の例では、対象は、SA感染症(例えば、MRSA感染症)を有すると診断または同定されている。一部の実施形態は、さらに(投与するステップの前に)SA感染症(例えば、MRSAまたはVRSA感染症)を有する対象を診断、同定もしくは選択する、または対象がSA感染症(例えば、MRSAまたはVRSA感染症)を有すると診断、同定または選択するステップを含むことができる。一部の例では、SA感染症は、院内感染症である。一部の例では、対象は、以前に抗菌治療を用いて治療されており、以前の治療は不成功であった。
本明細書では、さらに本明細書に提供したAbまたは抗原結合フラグメントの何れかの少なくとも1つ(例えば、2つ、3つ、4つまたは5つ)を含有するキットが提供される。一部の例では、キットは、配列番号1を含むか、または配列番号1からなる組換えSpAまたはペプチドまたは配列番号1の抗原フラグメント(例えば、配列番号1の少なくとも7個の(例えば、配列番号1のアミノ酸1、2、3、4、5、6、7、8、9、10、11、12または13位から始まる)隣接アミノ酸))を含有することができる。一部の例では、少なくとも1つのAbまたは抗原結合フラグメントは、1つの固体基質(例えば、ウエル、チップ、フィルム、ビーズまたはクロマトグラフィ樹脂)に付着させられている。そのようなキットは、商業包装および/またはAbおよびそれらの使用方法についての印刷された情報を含むことができる。
SpAエピトープに結合するヒトIgG3 Abを下記に記載するように生成した。SpA内のIgG結合配列およびXr反復配列にわたる5つの合成ペプチドを使用して311人の健常成人志願者の血液中の抗ペプチドAbをスクリーニングした。スクリーニングのために使用したSpA由来の5つの合成ペプチドは、配列番号82、83、84、85および1(各々、ペプチド1、2、3、4および5)と指定した配列を有していた。健常対象の約4%は、酵素結合免疫吸着検定法(ELISA)を使用して決定したバックグラウンドに比して、10倍を超えるレベルの抗ペプチドAb(抗SpA)を有していた(以下では、「陽性ドナー」と呼ぶ)。これらの陽性ドナー由来の血漿を入手し、これを使用して米国特許出願公開第2013/0018173号明細書に記載された方法を使用してSpAのIgG結合配列およびXr反復配列にわたるペプチドに特異的に結合する完全ヒトAbを単離した。要約すると、抗原アフィニティクロマトグラフィを使用して関心のあるAbを単離し、さらに質量分析法を使用してde novoシーケンシングした。同時に、ヒトアイソタイピングキットを使用してAbをアイソタイピングした。
PA8−G3 Ab
配列番号5の重鎖可変ドメイン。
それぞれ配列番号2、3および4の重鎖CDR1、2および3。
配列番号6の重鎖。
配列番号10の軽鎖可変ドメイン。
それぞれ配列番号7、8および9の軽鎖CDR1、2および3。
配列番号11の軽鎖。
PA4−G3 Ab
配列番号15の重鎖可変ドメイン。
それぞれ配列番号12、13および14の重鎖CDR1、2および3。
配列番号16の重鎖。
配列番号20の軽鎖可変ドメイン。
それぞれ配列番号17、18および19の軽鎖CDR1、2および3。
配列番号21の軽鎖。
PA7.2−G3 Ab
配列番号25の重鎖可変ドメイン。
それぞれ配列番号22、23および24の重鎖CDR1、2および3。
配列番号26の重鎖。
配列番号30の軽鎖可変ドメイン。
それぞれ配列番号27、28および29の軽鎖CDR1、2および3。
配列番号31の軽鎖。
PA15−G3 Ab
配列番号35の重鎖可変ドメイン。
それぞれ配列番号32、33および34の重鎖CDR1、2および3。
配列番号36の重鎖。
配列番号40の軽鎖可変ドメイン。
それぞれ配列番号37、38および39の軽鎖CDR1、2および3。
配列番号41の軽鎖。
PA21−G3 Ab
配列番号45の重鎖可変ドメイン。
それぞれ配列番号42、43および44の重鎖CDR1、2および3。
配列番号46の重鎖。
配列番号50の軽鎖可変ドメイン。
それぞれ配列番号47、48および49の軽鎖CDR1、2および3。
配列番号51の軽鎖。
PA27−G3 Ab
配列番号55の重鎖可変ドメイン。
それぞれ配列番号52、53および54の重鎖CDR1、2および3。
配列番号56の重鎖。
配列番号60の軽鎖可変ドメイン。
それぞれ配列番号57、58および59の軽鎖CDR1、2および3。
配列番号61の軽鎖。
PA32−G3 Ab
配列番号65の重鎖可変ドメイン。
それぞれ配列番号62、63および64の重鎖CDR1、2および3。
配列番号66の重鎖。
配列番号70の軽鎖可変ドメイン。
それぞれ配列番号67、68および69の軽鎖CDR1、2および3。
配列番号71の軽鎖。
PA37−G3 Ab
配列番号75の重鎖可変ドメイン。
それぞれ配列番号72、73および74の重鎖CDR1、2および3。
配列番号76の重鎖。
配列番号80の軽鎖可変ドメイン。
それぞれ配列番号77、78および79の軽鎖CDR1、2および3。
配列番号81の軽鎖。
本発明をその詳細な説明と併せて記載してきたが、上記の説明は具体的に説明するためのものであり、添付の特許請求の範囲によって規定される本発明の範囲を限定することは意図していない。他の態様、利点および修飾形態は、以下の特許請求の範囲に含まれる。
Claims (8)
- 対象における黄色ブドウ球菌(Staphylococcus aureus)感染症を治療する、または黄色ブドウ球菌(Staphylococcus aureus)感染症を発現するリスクを減少させるための医薬組成物であって、前記医薬組成物が、
医薬上許容される担体と、Fab領域パラトープを介して1×10−10M未満のKDで黄色ブドウ球菌(Staphylococcus aureus)タンパク質A(SpA)に特異的に結合する精製モノクローナル抗体とを含み、
前記モノクローナル抗体が、黄色ブドウ球菌(Staphylococcus aureus)細菌上のSpAにそれらのFc領域を介して結合したヒトIgG免疫グロブリンを置換することができることを特徴とする、医薬組成物。 - 請求項1に記載の医薬組成物において、前記モノクローナル抗体が、ヒトまたはヒト化IgG3モノクローナル抗体であることを特徴とする、医薬組成物。
- 請求項1に記載の医薬組成物において、前記モノクローナル抗体が、配列番号1のアミノ酸配列に特異的に結合することを特徴とする、医薬組成物。
- 請求項1に記載の医薬組成物において、前記モノクローナル抗体が、それらのFc領域を介してSpAに結合する少なくとも1mg/mLのIgG免疫グロブリンの存在下でSpA発現性黄色ブドウ球菌(Staphylococcus aureus)細菌のオプシニゼーションを媒介することができることを特徴とする、医薬組成物。
- 請求項1に記載の医薬組成物において、前記黄色ブドウ球菌(Staphylococcus aureus)感染症が、菌血症であることを特徴とする、医薬組成物。
- 請求項1に記載の医薬組成物において、前記黄色ブドウ球菌(Staphylococcus aureus)感染症が、メチシリン耐性黄色ブドウ球菌によって引き起こされることを特徴とする、医薬組成物。
- 請求項1に記載の医薬組成物において、前記モノクローナル抗体が、対象に静脈投与されるものであることを特徴とする、医薬組成物。
- 請求項1に記載の医薬組成物において、バンコマイシンが、対象に前記モノクローナル抗体と共に投与されるものであることを特徴とする、医薬組成物。
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