JP6483766B2 - ヘモグロビン組成物 - Google Patents
ヘモグロビン組成物 Download PDFInfo
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- JP6483766B2 JP6483766B2 JP2017145738A JP2017145738A JP6483766B2 JP 6483766 B2 JP6483766 B2 JP 6483766B2 JP 2017145738 A JP2017145738 A JP 2017145738A JP 2017145738 A JP2017145738 A JP 2017145738A JP 6483766 B2 JP6483766 B2 JP 6483766B2
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Description
本願は、2010年6月9日に出願された米国仮特許出願第61/185,547号の優先権を主張し、これは、すべての目的について、その全体が参照により本明細書に組み込まれる。
疾患、傷害、および発作、例えば、血液喪失(例えば、急性出血から、もしくは外科手術の間のもの)から、貧血(例えば、悪性貧血もしくは鎌状赤血球性貧血)から生じ、またはショック(例えば、低血量性ショック(volume deficiency shock)、アナフィラキシーショック、敗血症ショック、もしくはアレルギー性ショック)から生じる低酸素症を治療または予防するための酸素移動剤の必要性が存在する。これらの立場における全血または血液画分の使用は、不利点を伴う。例えば、全血の使用は、肝炎を生じさせるウイルスおよびAIDSを生じさせるウイルスを含めた、任意の数のウイルスの伝播のリスクを伴うことが多く、これは、患者の回復を複雑にし、または患者の死に至る場合がある。さらに、全血の使用は、免疫血液学的問題およびドナー間不適合性を回避するために、血液型判定および交差マッチングを必要とする。
定義
「CO」は、一酸化炭素を指す。
実施形態
以下に示される考察は、以下に本明細書で示される実施形態、ならびに上記および添付の特許請求の範囲において示される実施形態と密接な関係がある。実施形態の要素は、どんなものであれ任意の様式で組み合わされることが意図されており、本明細書に提示される考察は、典型的な組合せの例示的なものであり、限定するものではない。
コンジュゲートの調製
ウイルス不活化されたヘモグロビンの調製
本発明のコンジュゲートを調製するのに使用する前駆体ヘモグロビンは、赤血球(RBC)から単離することができる。適当なRBC源として、ヒト血液、ウシ血液、ヒツジ血液、ブタ血液、他の対象に由来する血液、およびBIO/TECHNOLOGY,12:55−59(1994)に記載されているトランスジェニックHbなどの遺伝子導入で生成されたヘモグロビンが挙げられる。
コンジュゲートの合成
様々な実施形態では、本発明は、1つまたは複数の水溶性ポリマー部分とヘモグロビンポリペプチドとの間のコンジュゲートを提供する。例示的な実施形態では、前駆体ヘモグロビンは、水溶性の、機能的な、脱酸素化された天然ヘモグロビンを含むウイルス不活化されたヘモグロビン組成物である。この組成物は、脱酸素化されたヘモグロビンおよび安定化剤の溶液を、熱ウイルス不活化プロセスにかける工程を含む方法によって調製される。例示的な実施形態では、熱ウイルス不活化プロセスは、前記溶液中の本質的にすべてのウイルス活性を不活化するのに十分に上昇した温度に溶液を曝す工程を含み、熱は、溶液中の本質的にすべてのウイルス活性の不活化を達成するのに十分な時間上昇される。例示的な安定化剤は、溶液中の脱酸素化されたヘモグロビンよりも酸素と反応性である構造要素を含み、それによって脱酸素化されたヘモグロビンによる酸素結合を最小限にする。溶液は、熱ウイルス失活プロセスにおいて、約10%、8%、6%、4%、または2%を超えるメトヘモグロビンの形成を防止するのに十分な、ある量の安定化剤を含む。様々な実施形態では、安定化剤は、メトヘモグロビン濃度を約5%以下に維持するように選択され、この濃度以下に維持するのに十分な量で存在する。
(a)それだけに限らないが、N−ヒドロキシスクシンイミドエステル、N−ヒドロキシベンズトリアゾールエステル、酸ハロゲン化物、アシルイミダゾール、チオエステル、p−ニトロフェニルエステル、アルキル、アルケニル、アルキニル、および芳香族エステルを含めたカルボキシル基およびこれらの誘導体;
(b)例えば、エステル、エーテル、アルデヒドなどに変換することができるヒドロキシル基、
(c)ハライドを、求核基、例えば、アミン、カルボキシレート陰イオン、チオール陰イオン、カルボアニオン、またはアルコキシドイオンなどと後に置換することができ、それによって、ハロゲン原子の官能基において新しい基の共有結合をもたらすハロアルキル基;
(d)例えば、マレイミド基などのディールス−アルダー反応に関与することができるジエノフィル基;
(e)カルボニル誘導体、例えば、イミン、ヒドラゾン、セミカルバゾン、もしくはオキシムなどの形成を介して、またはグリニャール付加もしくはアルキルリチウム付加などのメカニズムを介して、引き続いて誘導体化が可能であるようなアルデヒド基またはケトン基;
(f)例えば、スルホンアミドを形成するために、引き続いてアミンと反応させるためのハロゲン化スルホニル基;
(g)例えば、ジスルフィドに変換し、またはハロゲン化アシルと反応し、または例えば、マレイミドとの反応によって、チオエーテルに変換することができるチオール基;
(h)例えば、アシル化、アルキル化、または酸化することができるアミン基またはスルフヒドリル基;
(i)例えば、環付加、アシル化、マイケル付加などを行うことができるアルケン;
(j)例えば、アミンおよびヒドロキシル化合物と反応することができるエポキシド;ならびに
(k)例えば、アミンおよびスルフヒドリルと反応することができるマレイミド
が挙げられる。
コンジュゲートの安定性
様々な実施形態では、本発明は、メトグロビン形成に対する耐性による測定で、高度に安定なPEG−ヘモグロビンコンジュゲートを提供する。1つの実施形態では、本発明は、45℃で、少なくとも約4日間、少なくとも約5日間、少なくとも約6日間、少なくとも約7日間、少なくとも約8日間、少なくとも約9日間、少なくとも約10日間、少なくとも約11日間、少なくとも約12日間、少なくとも約13日間、少なくとも約14日間または少なくとも約15日間貯蔵後、約10%、9%、8%、7%、6%、5%、4%または3%未満のメトヘモグロビンを含むコンジュゲートを提供する。
組合せ製剤
様々な例示的な実施形態では、本発明は、別の治療剤、または製剤中のPEG−Hbコンジュゲートの活性を助長、補完、または増強する作用剤と組み合わせて、本発明の1つまたは複数のPEG−Hbコンジュゲートまたは製剤を含む組合せ製剤を提供する。例示的な作用剤には、それだけに限らないが、血液凝固剤、または血液凝固剤の前駆体、抗酸化酵素、および虚血/再灌流傷害を予防し、もしくは治療する作用剤が含まれる。これらの例による例示的な化学種は、以下に示されている。
使用方法
血液喪失(例えば、急性出血から、もしくは外科手術の間のもの)から生じ、貧血(例えば、悪性貧血もしくは鎌状赤血球性貧血)から生じ、あるいはショック(例えば、低血量性ショック、アナフィラキシーショック、敗血症ショック、もしくはアレルギー性ショック)、心筋梗塞、脳卒中、または外傷性脳障害から生じる低酸素症を治療または予防するための酸素移動剤の必要性が存在する。さらに、放射線療法または化学療法の治療効果を改善するために、腫瘍を過剰酸素化する必要がある。本発明は、例えば、血液喪失、虚血、または低酸素症に関連するこれらの状態および他の状態を治療および予防するのに有用な、先に例示したような化合物および方法を提供する。
ヘモグロビンの精製
この第1の工程では、血漿を含まない血液細胞を洗浄する。ベンチスケールで、これは、洗浄、遠心分離、およびデカントを繰り返すことによって達成した。このプロセスは、垂直連続フロー遠心分離機(vertical continuous flow centrifuge)より効率的であると思われる。
ヘモグロビン生成の間のウイルス不活化/除去工程の展開
ウシヘモグロビンを、ヒト用製品中で使用可能とする前に、機能的に活性なタンパク質生物製剤を維持しながら、任意の潜在的なウイルス混入物を不活化するための手順が必要である。FDAは、動物の産物に由来するタンパク質のウイルス不活化を要求している。これは、ウイルス不活化が達成されるまで、この場合、4時間、60℃に曝すことによって達成される。次いで溶液を冷却し、0.45/0.2μで濾過して貯蔵タンク中に入れる。これは、精製ヘモグロビンである。生成物に、FPLC(1本のピーク)、可視スペクトル分析(540nmおよび577nmにおけるピーク)、SDSゲル電気泳動、%Hb、%HbO2、%MetHb、pH、質量オスモル濃度、エンドトキシン、脂質、および遊離鉄によるQC分析を行う。
希釈緩衝液(25mMのリン酸ナトリウム、120mMの炭酸水素ナトリウム、および4.5%のNaCl、pH8.0)を添加して、ヘモグロビン溶液を4〜5%の濃度にする。ヘモグロビンを、17:1のPEGとヘモグロビンのモル比を使用してペグ化する。反応は、pH7.6〜7.8に維持し、反応を1時間進行させる。この時点で、2つのプロセスのうちの1つを使用することができる。
プロセスA
15mMのシステインを添加することによって反応を停止する。その溶液を4℃で一晩貯蔵した後、50Kdのカットオフ膜を使用して、20体積の緩衝液(5.0mMの炭酸水素ナトリウム、1.0mMのリン酸ナトリウム、150mMの塩化ナトリウム、4.7mMの塩化カリウム、2.5mMの硫酸マグネシウム、0.5mMの塩化カルシウム、pH8.1)に対して溶液を透析する。次いでPEG−Hbを4%のHbまで希釈し、デキストロース(5mg/mL)およびシステイン(5mM)を添加し、%HbO2が10%未満になるまで、中空糸膜コンタクター中を循環させる。次いで、溶液を無菌濾過して血液バッグ中に入れる。生成物に、FPLC(1本のピーク)、可視スペクトル分析(540nmおよび577nmにおけるピーク)、SDSゲル電気泳動、%Hb、%HbO2、%MetHb、pH、質量オスモル濃度、エンドトキシン、脂質、および遊離鉄によるQC分析を行う。
プロセスB
15mMのシステインを添加することによって反応を停止する。4℃で一晩貯蔵した後、50Kdのカットオフ膜を使用して、20体積の緩衝液(5.0mMの炭酸水素ナトリウム、1.0mMのリン酸ナトリウム、150mMの塩化ナトリウム、4.7mMの塩化カリウム、2.5mMの硫酸マグネシウム、0.5mMの塩化カルシウム、pH8.1)に対して溶液を透析する。次いでPEG−Hbを4%のHbまで希釈し、デキストロース(5mg/mL)およびL−システイン(5mM)を添加し、溶液を置いて、%酸素が「0」未満になり、一酸化炭素(CO)が95%以上になるまで絶えず混合して、溶液に一酸化炭素をゆっくりバブリングすることによって、一酸化炭素形態にする。次いで、溶液を無菌濾過して血液バッグ中に入れる。生成物に、FPLC(1本のピーク)、可視スペクトル分析(540nmおよび577nmにおけるピーク)、SDSゲル電気泳動、%Hb、%HbO2、%MetHb、pH、質量オスモル濃度、エンドトキシン、脂質、および遊離鉄によるQC分析を行う。
PEG−Hbの一酸化炭素形態の開発
これらの試験の目的は、PEG−ヘモグロビンの一酸化炭素(CO)形態を開発することであった。この形態は、図1に示したように、%MET−Hb形成を低く維持することに関して特に安定であるように思われる。これは、機械的に脱酸素化された形態より安定である。
酸素負債を逆転する、PEG−Hb/HSの効力
] 組織への酸素供給における本発明者らのPEG−Hb/HSの活性を試験するための予備試験において、重度の外傷性ショックのブタモデルにおける、組織への酸素送達を増大させ、酸素負債を逆転するその能力を試験した。
(実施例2)
原理:大腿動脈結紮によって誘導された後肢虚血のマウスモデルにおいて、糖尿病を有するマウスは、非糖尿病動物と比較して、血流および血管新生応答の回復が著しく損なわれることを示す。この試験において、本発明者らは、Sanguinateの投与は、血流および血管新生の回復を促進するという仮説を試験した。
群#2 − 糖尿病のWTマウス+PBS(20mL/kg/日 IP)
エンドポイント
レーザードップラー血流イメージング(28日目)。左(傷害された)および右脚(シャム)において血流を検査し、次いで左/右の比として報告することに注意されたい。糖尿病/Sanguinateおよび糖尿病/PBSの値の平均値を報告する。
データ
エンドポイント#1:血管新生の定量的評価
28日目に、マウスを屠殺し、大腿動脈結紮の分布区域における後肢骨格筋を回収し、抗cD31 IgGを使用して免疫組織化学にかけた。連続画像を回収し、画像解析を実施することによって、血管新生に対するSanguinateの効果を判定した。
結紮した大腿動脈の肢/対側の(シャム)肢を比較する%血流回復を、レーザードップラーイメージングを使用して評価した。これらの試験において、基礎の血管機能不全を考慮するよう、傷害された脚とその対側のシャムの脚との間の比を報告する。データは以下の通りである。
大腿動脈結紮によって誘導された後肢の虚血を受けている糖尿病マウスにSanguinateを投与することにより、ビヒクルを使用した知見と比較した場合、血管新生の定量化において著しい改善がもたらされる。大腿動脈結紮によって誘導された後肢の虚血を受けている糖尿病マウスにSanguinateを投与することにより、ビヒクル(PBS)処置と比較した場合、レーザードップラーイメージングによって測定した場合の血流回復が著しく改善される。
(実施例3)
ペグ化CO−ヘモグロビン(PEG-COHb)の輸液の効果を、2時間の局所的な脳虚血および1日の再灌流にかけた、麻酔したラットにおいて評価した。PEG−Hbを、カルボキシ状態(PEG-COHb)で貯蔵することによって、CO源を提供し、自動酸化を低減し、有効期間を延ばした。虚血から20分における10ml/kgのPEG−COHbの輸液により、動脈圧は変化せず、虚血性コア内の赤血球フラックスは増大しなかった。血漿ヘモグロビンは、0.6g/dLまでしか増加しなかったが、梗塞体積は著しく減少し、神経障害は改善した。PEG−COHbの初期のトップロード(topload)輸液は、脳を虚血性脳卒中から保護する。
外科的準備
すべての手順は、Johns Hopkins University Animal Care and Use Committeeによって認可された。5%のイソフルランを用いてオスのウィスターラット(250〜350g)に麻酔を誘導し、鼻円錐部を介して約2%のイソフルランを用いて維持し、手術の間自発呼吸であった。イソフルラン濃度は、手術後に、約1.5%に減少させた。吸気されるO2は、約25〜30%であった。カテーテルを、輸液のために大腿静脈中に、および動脈圧を測定し、動脈血を試料採取するために大腿動脈中に挿入した。加熱灯を使用することによって、虚血および初期再灌流の間、直腸温度を維持した。頭皮に小さい切開を行い、外側の頭頂骨中に、ほんの希薄な量の骨が残るまで、小さい穿頭孔を作った。直径1mmの光ファイバープローブを、薄くなった骨に対して固定した。このプローブを、近赤外光を送受信し、赤血球フラックスの相対的な変化を計算するレーザー−ドップラー流量計に接続した。レーザー−ドップラーフラックスシグナルを使用することによって、虚血期間の間の血管閉塞の妥当性を評価した。
実験設計
PEG−アルブミンおよびPEG−COHbは、Prolong Pharmaceuticals(South Plainfield, New Jersey)で合成した。精製ウシHb上の表面リシン残基を、分子量5000のPEGとコンジュゲートした。PEG−Hb溶液をCOでバブリングすることによって、PEG−Hbの80%超をPEG−COHbに変換した後、貯蔵した。4〜6%のタンパク質を含有する溶液を、滅菌した血液バッグ中に、2〜10℃で貯蔵した。10匹のラットの3つの群を試験した:1)輸液なし、2)ウシPEG−アルブミン輸液、および3)ウシPEG−COHbの輸液。実験日に、溶液のアリコートを加温し、体重1kg当たり10mlに等価なトップロードとして輸液した。輸液は、MCAO20分において開始した。静脈内輸液の速度は0.5ml/分であり、約5〜7分かけて行った。平均動脈圧およびレーザー−ドップラー流量の変化率を、2時間のMCAOおよび30分の再灌流の間、15分間隔で記録した。麻酔から回復する動物が暖かい環境にあるように、1時間の再灌流を通じて直腸温度をモニターした。動脈血(約0.7ml)を、ベースライン、MCAO1時間、および再灌流30分で試料採取した。動脈血のpH、PCO2、PO2、および電解質を、Radiometer血液ガス分析装置(ABL80)で測定した。動脈のHb濃度、O2飽和度、MetHb、およびCOHbを、Radiometer Hemoximeter(OSM3)で測定した。試料からの血漿を、Hb濃度について分析した。再灌流1時間および24時間で、0〜4のスケール(0=欠損なし、1=置かれている間前肢を伸ばすことができない、2=旋回、3=片側性の脱力感、および4=自発的な運動活性なし)で、神経障害についてラットを評価した。24時間で、脳を回収して梗塞体積を測定した。脳を、7つの冠状切片(2mmの厚さ)に分割した。切片を、塩化トリフェニルテトラゾリウムの1%溶液を用いて染色した。これは、生存可能な領域を赤色に染色する。大脳皮質および線条体の弱い、生育不能な範囲は、各切片の前方および後方の表面上で測定した。各切片の梗塞体積は、切片の厚さと前方および後方の表面上の梗塞面積の平均との積から計算した。皮質および線条体についての総梗塞体積は、各切片からの体積を合計することによって得た。値は、全体の構造の百分率として表す。測定値は、0.05レベルの有意性で、ANOVAおよびNewman−Keuls多重範囲検定によって、3つの群の中で比較した。データを、平均±SEとして提示する。
結果
動脈のpH、PCO2、およびPO2は、ラットのすべての群において、MCAOおよび初期再灌流の間、安定で、生理学的範囲内のままであった(表1)。MCAO20分で輸液された群の中で有意な差異はまったくなかった。電解質濃度は、輸液後に群の間で同様のままであった(表2)。トップロードタンパク質輸液で予期されるように、ヘマトクリットのわずかな減少が起こった(表3)。
考察
一過性の局所的脳虚血の間のPEG−COHbトップロード輸液による組織救済の程度は、ラットにおいてαα−架橋Hb、またはマウスにおいてポリマーHbを用いて、循環血液量過多交換輸血で報告されたものより実質的に大きい。この知見は注目すべきであり、その理由は、10ml/kgのトップロードで達した血漿Hb濃度は、0.6g/dLであったためであり、これは、6g/dLのHbを含有する流体の30〜40%の交換輸血で一般に達する2〜2.5g/dLより相当に低い。さらに、輸血流体中のHbの濃度を増大させることにより、αα−架橋Hbの血漿濃度を10g/dLから20g/dLにさらに増大させることにより、梗塞体積がさらに低減する。これらの比較は、PEG−COHbは、脳卒中から脳を救済することにおいて、αα−架橋HbおよびポリマーHbと比較して、ヘム1モル当たりで優れている場合があることを示唆する。この結果は、脳を救済するのに、高い血漿濃度のペグ化COHbを必要としないことを示す。交換輸血の理論的な利点は、全血粘度を、ヘマトクリットを減少させることによって低減し、側副血流を促進することができることである。交換輸血に対するトップロードの利点は、このプロトコールは、臨床的な脳卒中において実施することがより容易であり、10ml/kgの体積が、顕著な循環血液量過多誘導性高血圧症を生じさせることなく、容易に許容されることである。有意な高血圧症は、本試験において観察されなかった。PEG−COHbによる救済は、1つの部位でのレーザー−ドップラー流量測定によって評価した場合、皮質の虚血コア内の血流の増大に関係しているように思われなかった。しかし、側副血流が、組織を救済するのに十分に、虚血境界領域において改善されたことがありうる。ペグ化Hb溶液の粘度は、架橋HbおよびポリマーHbの溶液と比較して全血の粘度により近く、したがって、内皮の剪断応力および関連するNO生成をより良好に維持することができ、これは、側副動脈の拡張を維持することに役立つことができる。
Claims (11)
- 機能的な天然ウシヘモグロビン分子と、ポリ(エチレングリコール)の少なくとも1つの分子との間の共有結合性コンジュゲートを含む組成物であって、
A.ウシヘモグロビン分子の群を含む水溶性ヘモグロビン画分であって、前記ヘモグロビンの少なくとも95%がカルボキシヘモグロビン(COHb)形態であり、前記ヘモグロビン分子の群の各メンバーが、
i.アミノ酸残基のアミン部分を通じて、前記ポリ(エチレングリコール)の少なくとも1つの分子に共有結合的にコンジュゲートされており、
ii.化学架橋剤を含まず、
iii.5%未満の架橋されたヘモグロビンを含み、かつ
iv.10mmHg〜14mmHgのP50を有する
水溶性ヘモグロビン画分と、
B.前記ヘモグロビン分子の群を酸化耐性にする水溶性安定剤画分と、
C.前記ヘモグロビン画分が可溶性である薬学的に許容される希釈剤を含む希釈剤画分と
を含み、ウイルス活性がなく、45℃で少なくとも4日間保存後、メトヘモグロビン含量が10%未満のままである、組成物。 - 前記ヘモグロビン分子の群の各メンバーが、5つ以上の前記アミノ酸残基の前記アミン部分を通じて、5つ以上の前記ポリ(エチレングリコール)部分に共有結合的にコンジュゲートされる、請求項1に記載の組成物。
- 前記アミノ酸残基の前記アミン部分が、リシン残基のε−アミン部分である、請求項1〜2のいずれか1項に記載の組成物。
- 前記ヘモグロビン分子が、酸素および一酸化炭素から選択されるメンバーに結合している、請求項1に記載の組成物。
- 前記ヘモグロビン分子が、前記結合した酸素および前記結合した一酸化炭素から選択されるメンバーを、組織に移動させることができる、請求項4に記載の組成物。
- 前記希釈剤が、高張性食塩水を含む、請求項1に記載の組成物。
- 前記高張性食塩水希釈剤が、3%〜7%の濃度でNaClを含む、請求項6に記載の組成物。
- 酸素または一酸化炭素を組織に送達するための輸血薬剤を製造するための、請求項1〜7のいずれか1項に記載の組成物の使用。
- それぞれの場合に側副動脈の拡張を維持する一方、外傷、出血性ショック、虚血、再灌流傷害または鎌状赤血球性貧血を治療するための輸血薬剤を製造するための、請求項1〜7のいずれか1項に記載の組成物の使用。
- 血管新生を誘導するためまたは組織への血流を増加させるための輸血薬剤を製造するための、請求項1〜7のいずれか1項に記載の組成物の使用。
- 血液減少、貧血、ショック、心筋梗塞、脳卒中または外傷性脳障害から生じる低酸素症を治療または予防するための輸血薬剤、あるいは放射線療法または化学療法の治療効果を改善するために腫瘍を過剰酸素化するための輸血薬剤を製造するための、請求項1〜7のいずれか1項に記載の組成物の使用。
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