JP2016521258A - ポリアルキレンオキシド吉草酸ヘモグロビン接合体 - Google Patents
ポリアルキレンオキシド吉草酸ヘモグロビン接合体 Download PDFInfo
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- JP2016521258A JP2016521258A JP2016503422A JP2016503422A JP2016521258A JP 2016521258 A JP2016521258 A JP 2016521258A JP 2016503422 A JP2016503422 A JP 2016503422A JP 2016503422 A JP2016503422 A JP 2016503422A JP 2016521258 A JP2016521258 A JP 2016521258A
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Abstract
Description
この開示において「一つの」「不定冠詞(aまたはan)」の用語が用いられるとき、別途に指示しない限り、それらは「少なくとも一つ」または「1以上」を意味する。
本発明を詳細に説明するに当たり、添付の請求項で定義される、本発明の趣旨から逸脱することなく、変形および変更が可能であることが明らかであろう。
実施例1-SVA−PEG−Hbの調製
実施例2-SVA−PEG−Hbの安定性試験
Claims (94)
- 37℃且つpH7.4で測定したときに約2〜約30mmHgに亘るP50を有する、ポリアルキレン(PAO)ヘモグロビン接合体であって、該PAOは、ヘモグロビン分子上のアミノ酸側鎖のアミノ反応性部分を介して共有結合され、該アミノ反応性部分は、−C(O)−(CH2)p−によってPAOに連結され、ここでのpは1〜約20の整数であり、該ヘモグロビンは、任意に分子内架橋される前記ポリアルキレン(PAO)ヘモグロビン接合体。
- 請求項1〜3の何れか1項に記載のヘモグロビン接合体であって、前記P50は約2〜20mmHgである前記接合体。
- 請求項1〜4の何れか1項に記載のヘモグロビン接合体であって、前記アミノ反応性部分は、−C(O)−(CH2)p−によって前記PAOに連結され、ここでのpは1〜約12の整数である前記接合体。
- 請求項1〜4の何れか1項に記載のヘモグロビン接合体であって、前記アミノ反応性部分は、−C(O)−(CH2)p−によって前記PAOに連結され、ここでのpは1〜約8の整数である前記接合体。
- 請求項6に記載のヘモグロビン接合体であって、前記アミノ反応性部分は、−C(O)−(CH2)p−によって前記PAOに連結され、ここでのpは2〜6の整数である前記接合体。
- 請求項6に記載のヘモグロビン接合体であって、前記アミノ反応性部分は、−C(O)−(CH2)p−によって前記PAOに連結され、ここでのpは4である前記接合体。
- 請求項3に記載のヘモグロビン接合体であって、Rはスクシンイミジルまたはp−ニトロフェニルである前記接合体。
- 請求項9に記載のヘモグロビン接合体であって、Rはスクシンイミジルである前記接合体。
- 請求項2〜10の何れか1項に記載のヘモグロビン接合体であって、Xはヒドロキシ、アリーロキシ、またはC1〜C20アルコキシである前記接合体。
- 請求項2〜10の何れか1項に記載のヘモグロビン接合体であって、Xはメトキシである前記接合体。
- 請求項1〜12の何れか1項に記載のヘモグロビン接合体であって、mは四量体当たり平均約6〜約10のPAO分子である前記接合体。
- 請求項1〜12の何れか1項に記載のヘモグロビン接合体であって、mは四量体当たり平均約8〜約9のPAO分子である前記接合体。
- 請求項1〜14の何れか1項に記載のヘモグロビン接合体であって、前記ポリアルキレンオキシドは、前記アミン反応性部分を介して前記ヘモグロビン分子上の前記アミノ酸側鎖のアミノ基に共有結合されており、前記ヘモグロビンは酸素付加状態にある前記接合体。
- 請求項1〜14の何れか1項に記載のヘモグロビン接合体であって、前記ポリアルキレンオキシドは、アミン反応性部分を介して前記ヘモグロビン分子上のアミノ酸側鎖のアミノ基に共有結合されており、前記ヘモグロビンは脱酸素状態にある前記接合体。
- 請求項1〜16の何れか1項に記載のヘモグロビン接合体であって、前記ヘモグロビンはβ,β−分子内架橋されている前記接合体。
- 請求項17に記載のヘモグロビン接合体であって、前記ヘモグロビン分子の二つのβ82リジン残基において、フマル酸ビス(2,5−ジブロモサリチル)が架橋されている前記接合体。
- 請求項1〜18の何れか1項に記載のヘモグロビン接合体であって、前記P50が約2〜15mmHgである前記接合体。
- 請求項1〜18の何れか1項に記載のヘモグロビン接合体であって、前記P50が約2〜10mmHgである前記接合体。
- 請求項20に記載のヘモグロビン接合体であって、前記P50が約7mmHgである前記接合体。
- 請求項1〜16の何れか1項に記載のヘモグロビン接合体であって、前記ヘモグロビンがα,α−分子内架橋されている前記接合体。
- 請求項22に記載のヘモグロビン接合体であって、前記P50は約20〜30mmHgである前記接合体。
- 請求項1〜23の何れか1項に記載のヘモグロビン接合体であって、前記コロイド浸透圧は少なくとも50mmHgである前記接合体。
- 請求項1〜24の何れか1項に記載のヘモグロビン接合体であって、該ヘモグロビン接合体は酸素にリガンド結合される前記接合体。
- 請求項1〜25の何れか1項に記載のヘモグロビン接合体であって、該ヘモグロビン接合体は一酸化炭素にリガンド結合される前記接合体。
- 請求項1〜26の何れか1項に記載のヘモグロビン接合体であって、該ヘモグロビン接合体は一酸化窒素にリガンド結合される前記接合体。
- 請求項1〜24の何れか1項に記載のヘモグロビン接合体であって、該ヘモグロビン接合体は脱酸素化される前記接合体。
- 請求項1、4〜8及び13〜28の何れか1項に記載のヘモグロビン接合体であって、前記PAOはポリエチレングリコール(PEG)である前記接合体。
- 請求項29に記載のヘモグロビン接合体であって、前記PEGは約3,000〜約10,000ダルトンの平均分子量を有する前記接合体。
- 請求項29に記載のヘモグロビン接合体であって、前記PEGは約4,000〜約6,000ダルトンの平均分子量を有する前記接合体。
- 請求項29に記載のヘモグロビン接合体であって、前記PEGは約5,000ダルトンの平均分子量を有する前記接合体。
- 請求項29〜32の何れか1項に記載のヘモグロビン接合体であって、前記PEGはメトキシPEG−スクシンイミジル吉草酸(mPEG−SVA)である前記接合体
- 請求項29〜33の何れか1項に記載のヘモグロビン接合体であって、前記PEGのアミノ反応性部分は、前記ヘモグロビンのリジン残基のε−アミノ部分、前記ヘモグロビンの末端バリン残基のα−アミノ部分、またはこれらの組合せから選択される前記ヘモグロビンのアミノ部分に接合される前記接合体。
- 請求項34に記載のヘモグロビン接合体であって、前記PEGのアミノ反応性部分は、ヘモグロビンα−サブユニットまたはβ−サブユニットのリジン残基のε−アミノ部分に接合される前記接合体。
- 請求項34または35に記載のヘモグロビン接合体であって、前記PEGのアミノ反応性部分は、ヘモグロビンα−サブユニットまたはβ−サブユニットにおける末端バリン残基のα−アミノ部分に接合される前記接合体。
- 請求項35または36に記載のヘモグロビン接合体であって、前記リジン残基は、リジン−7、リジン−11、リジン−16、リジン−40、リジン−56、リジン−60、リジン−61、リジン−90、リジン−99、リジン−127、リジン−139及びこれらの組合せからなる群から選択されるヒトヘモグロビンα−サブユニットのリジン残基である前記接合体。
- 請求項35または36に記載のヘモグロビン接合体であって、前記リジン残基は、リジン−8、リジン−17、リジン−59、リジン−61、リジン−65、リジン−66、リジン−82、リジン−95、リジン−120、リジン−132、リジン−144及びこれらの組合せからなる群から選択されるヒトヘモグロビンβ−サブユニットのリジン残基である前記接合体。
- 請求項1〜38の何れか1項に記載のヘモグロビン接合体であって、N−エチルマレイミドが、前記ヘモグロビンのβ93システイン残基に接合される前記接合体。
- 請求項2〜40の何れか1項に記載のヘモグロビン接合体であって、Xがヒドロキシ、アリーロキシ、またはC1〜C20アルコキシである前記接合体。
- 請求項1〜41の何れか1項に記載のヘモグロビン接合体であって、前記ヘモグロビンが組換え体である前記接合体。
- 請求項1〜42の何れか1項に記載のヘモグロビン接合体及び医薬的に許容可能な担体を含有してなる医薬組成物。
- 請求項43に記載の医薬組成物であって、該組成物は血液と同張性(normo−oncotic)である前記医薬組成物。
- 請求項43に記載の医薬組成物であって、該組成物は、血液と比較して高張性(hyperoncotic)である前記医薬組成物。
- 請求項43〜45の何れか1項に記載の医薬組成物であって、急性肝不全、β地中海貧血症、火傷、慢性重症四肢虚血(chronic critical limb ischemia)、二酸化炭素またはシアン化物中毒、慢性閉塞性肺疾患(COPD)、鬱血性心不全、低酸素症、マラリア、臓器虚血、抹消血管疾患、ポルフィリン症、妊娠における子癇前症、敗血症、鎌形赤血球病、網膜症、眼内症状、精巣捻転症、外傷、ショック、外傷性脳障害、潰瘍、血管痙攣、またはこれらの組合せの治療において使用するための前記医薬組成物。
- 請求項46に記載の医薬組成物であって、前記臓器虚血が、急性腸管虚血(腸軸捻症)、急性腸管虚血(塞栓症)、心原性ショック、急性血管性臓器虚血、発作、心筋梗塞、または重篤な心臓虚血を含んでなる前記医薬組成物。
- 請求項43〜45の何れか1項に記載の医薬組成物であって、非外傷性出血性ショック、病院到着前の外傷、外傷性出血性ショック、急性肺損傷、成人呼吸困難症候群、外傷性脳損傷、発作、固形腫瘍癌、臓器退廃(ex−vivo)、臓器退廃(レシピエントにおいて)、重篤な敗血症、敗血症ショック、心筋梗塞、心虚血、心原性ショック、急性心不全、肺塞栓症、またはこれらの組合せの治療において使用するための前記医薬組成物。
- 請求項43〜45の何れか1項に記載の医薬組成物であって、血管形成術に対する補助療法として、形成外科のための補助療法として、または補助人工心臓を移植する際の補助療法として;血液代用剤、心保護剤、冷凍保存剤、血液透析補助剤、腫瘍治療剤、臓器保存剤、性能強化剤、手術補助剤、または創傷治癒剤として;撮像において;肺機能を改善するため;またはそれらの組合せにおいて使用するためのものである前記医薬組成物。
- 血液喪失の獣医学的治療のための請求項43〜45の何れか1項に記載の医薬組成物であって、前記血液喪失は、傷害、溶血性貧血、感染性貧血、細菌感染、第IV因子断片化、脾機能亢進及び脾腫大、家禽における出血性症候群、再生不良性貧血、形成不全性貧血、突発性免疫性溶血症状、鉄欠乏症、同種免疫溶血性貧血、微小血管性溶血性貧血、寄生、もしくは外科麻酔に誘導された脳損傷によるものである前記医薬組成物。
- 請求項1〜42の何れか1項に記載のヘモグロビン接合体または請求項43〜45の何れか1項に記載の医薬組成物を、それを必要としている被験者に投与することを含んでなる治療方法。
- 請求項51に記載の治療方法であって、前記被験者が動物である前記治療方法。
- 請求項51に記載の治療方法であって、前記被験者がヒトである前記治療方法。
- 請求項51〜53の何れか1項に記載の治療方法であって、該方法は、急性肝不全、β地中海貧血症、火傷、慢性重症四肢虚血(chronic critical limb ischemia)、二酸化炭素またはシアン化物中毒、慢性閉塞性肺疾患(COPD)、鬱血性心不全、低酸素症、マラリア、臓器虚血、抹消血管疾患、ポルフィリン症、妊娠における子癇前症、敗血症、鎌形赤血球病、網膜症、眼内症状、精巣捻転症、外傷、ショック、外傷性脳障害、潰瘍、血管痙攣、またはこれらの組合せの治療のためのものである前記治療方法。
- 請求項54に記載の治療方法であって、前記臓器虚血が、急性腸管虚血(腸軸捻症)、急性腸管虚血(塞栓症)、心原性ショック、急性血管性臓器虚血、発作、心筋梗塞、または重篤な心臓虚血を含んでなる、前記治療方法。
- 請求項51〜53の何れか1項に記載の治療方法であって、該方法は、非外傷性出血性ショック、病院到着前の外傷、外傷性週血性ショック、急性肺損傷、成人呼吸困難症候群、外傷性脳損傷、発作、固形腫瘍癌、臓器退廃(ex−vivo)、臓器退廃(レシピエントにおいて)、重篤な敗血症、敗血症ショック、心筋梗塞、心虚血、心原性ショック、急性心不全、肺塞栓症、またはこれらの組合せを治療するための方法である前記治療方法。
- 請求項51〜53の何れか1項に記載の治療方法であって、前記ヘモグロビン四量体または医薬組成物は、血管形成術に対する補助療法として、形成外科のための補助療法として、または補助人工心臓を移植する際の補助療法として;血液代用剤、心保護剤、冷凍保存剤、血液透析補助剤、腫瘍治療剤、臓器保存剤、性能強化剤、手術補助剤、または創傷治癒剤として;撮像において;肺機能を改善するため;またはそれらの組合せのために投与される前記治療方法。
- 請求項51〜53の何れか1項に記載の治療方法であって、前記ヘモグロビン四量体または医薬組成物は、血管形成術に対する補助療法として、胸部大動脈修復に対する補助療法として、心肺バイパス術に対する補助療法として、または心肺バイパスのためのプライミング溶液として投与される前記治療方法。
- 請求項51または52に記載の治療方法であって、前記被験者は非ヒト動物であり、また前記方法は、傷害、溶血性貧血、感染性貧血、細菌感染、第IV因子断片化、脾機能亢進及び脾腫大、家禽における出血性症候群、再生不良性貧血、形成不全性貧血、突発性免疫性溶血症状、鉄欠乏症、同種免疫溶血性貧血、微小血管性溶血性貧血、寄生、もしくは外科麻酔に誘導された脳損傷による血液喪失の獣医学的治療のための方法である前記治療方法。
- 酸素、一酸化窒素、一酸化炭素またはそれらの混合物を組織へと送達し、微小血管系中で亜硝酸塩を一酸化窒素(NO)へと還元する方法であって、該方法は、請求項1〜42の何れか1項のヘモグロビン接合体または請求項43〜50の何れか1項の医薬組成物を、それを必要としている被験者に投与することを含んでなり、ここでの投与後に、前記ヘモグロビンは脱リガンドされるに至り、前記微小血管系において亜硝酸塩を一酸化窒素に変換する前記方法。
- 請求項61に記載の方法であって、前記アミノ反応性部分は、−C(O)−(CH2)p−によって前記PAOに連結され、ここでのpは1〜12の整数である前記方法。
- 請求項61または62に記載の方法であって、前記アミノ反応性部分は、−C(O)−(CH2)p−によって前記PAOに連結され、ここでのpは1〜8の整数である前記方法。
- 請求項63に記載のヘモグロビン接合体であって、前記アミノ反応性部分は、−C(O)−(CH2)p−によって前記PAOに連結され、ここでのpは2〜6の整数である前記接合体。
- 請求項63に記載のヘモグロビン接合体であって、前記アミノ反応性部分は、−C(O)−(CH2)p−によって前記PAOに連結され、ここでのpは4である前記接合体。
- 請求項61に記載の方法であって、前記PAOポリマーは、前記ヘモグロビン濃度に対して約8〜20倍モル過剰の濃度で存在する前記方法。
- 請求項61に記載の方法であって、前記PAOポリマーは、前記ヘモグロビン濃度に対して約10倍モル過剰の濃度で存在する前記方法。
- 請求項61〜67の何れか1項に記載の方法であって、前記反応は、約6.5〜約8.5のpHにおいて、約5〜約15℃で約1〜2時間行われる前記方法。
- 請求項61〜68の何れか1項に記載の方法であって、前記アミノ反応性部分はスクシンイミジルまたはp−ニトロフェニルである前記方法。
- 請求項69に記載の方法であって、前記アミノ反応性部分はスクシンイミジルである前記方法。
- 請求項61〜70の何れか1項に記載の方法であって、Xはヒドロキシ、アリーロキシ、またはC1〜C20アルコキシである前記方法。
- 請求項71に記載の方法であって、前記Xはメトキシである前記方法。
- 請求項61〜72の何れか1項に記載の方法であって、前記ヘモグロビンは、四量体当たり平均で約6〜約10のPAO分子に接合される前記方法。
- 請求項61〜72の何れか1項に記載の方法であって、前記ヘモグロビンは、四量体当たり平均で約7〜約9のPAO分子に接合される前記方法。
- 請求項61〜74の何れか1項に記載の方法であって、前記ポリアルキレンオキシドは、前記ヘモグロビンが酸素付加された状態にある間に、前記アミノ反応性部分を介して前記ヘモグロビン分子上の前記アミノ酸側鎖におけるアミノ基に共有結合される前記方法。
- 請求項61〜74の何れか1項に記載の方法であって、前記ポリアルキレンオキシドは、前記ヘモグロビンが脱酸素化された状態にある間に、前記アミノ反応性部分を介して前記ヘモグロビン分子上の前記アミノ酸側鎖におけるアミノ基に共有結合される前記方法。
- 請求項61〜76の何れか1項に記載の方法であって、前記ヘモグロビンはβ,β−分子内架橋される前記方法。
- 請求項77に記載のヘモグロビン接合体であって、フマル酸ビス(2,5−ジブロモサリチル)が、前記ヘモグロビン分子の二つのβ82リジン残基において架橋した前記接合体。
- 請求項61〜77の何れか1項に記載のヘモグロビン接合体であって、前記ヘモグロビンはα,α−分子内架橋される前記接合体。
- 請求項61〜79の何れか1項に記載の方法であって、前記コロイド浸透圧は少なくとも50mmHgである前記方法。
- 請求項61〜80の何れか1項に記載の方法であって、前記P50は約2〜15mmHgである前記方法。
- 請求項61〜80の何れか1項に記載のヘモグロビン接合体であって、前記P50は約2〜10mmHgである前記接合体。
- 請求項82に記載の方法であって、前記P50は約7mmHgである前記方法。
- 請求項61〜83の何れか1項に記載の方法であって、更に、前記ヘモグロビン接合体を酸素に露出して酸素付加されたヘモグロビンを形成することを含んでなる前記方法。
- 請求項61〜83の何れか1項に記載の方法であって、更に、前記ヘモグロビン接合体を一酸化炭素に露出してCO−PEG−ヘモグロビン接合体を形成することを含んでなる前記方法。
- 請求項61〜85の何れか1項に記載の方法であって、更に、COヘモグロビンを一酸化窒素に露出してNO−PEG−ヘモグロビン接合体を形成することを含んでなる前記方法。
- 請求項61〜84の何れか1項に記載の方法であって、更に、前記ヘモグロビン接合体を脱酸素化することを含んでなる前記方法。
- 請求項61〜87の何れか1項に記載の方法であって、前記PAOはポリエチレングリコール(PEG)である前記方法。
- 請求項88に記載の方法であって、前記PEGは約3,000〜約10,000ダルトンの平均分子量を有する前記方法。
- 請求項89に記載の方法であって、前記PEGは約4,000〜約6,000ダルトンの平均分子量を有する前記方法。
- 請求項90に記載の方法であって、前記PEGは約5,000ダルトンの平均分子量を有する前記方法。
- 請求項61〜91の何れか1項に記載の方法であって、前記PEGはメトキシPEG−スクシンイミジル吉草酸(mPEG−SVA)である前記方法。
- 請求項61〜92の何れか1項に記載の方法であって、前記PEGのアミノ反応性部分が、前記ヘモグロビンのリジン残基のε−アミノ部分、前記ヘモグロビンの末端バリン残基のα−アミノ部分、またはそれらの組合せから選択されるヘモグロビンのアミノ部分に接合される前記方法。
- 請求項61〜93の何れか1項に記載の方法であって、更に、N−エチルマレイミドを前記ヘモグロビンのβ93システイン残基に接合することを含んでなる前記方法。
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CA2906878C (en) | 2021-09-21 |
CN105188761A (zh) | 2015-12-23 |
CA2906878A1 (en) | 2014-09-18 |
US20160022783A1 (en) | 2016-01-28 |
EP2968597A1 (en) | 2016-01-20 |
KR102238718B1 (ko) | 2021-04-12 |
JP6657070B2 (ja) | 2020-03-04 |
HK1219053A1 (zh) | 2017-03-24 |
MX2015013263A (es) | 2015-12-11 |
EP2968597A4 (en) | 2016-11-02 |
KR20150132235A (ko) | 2015-11-25 |
AU2014232540B2 (en) | 2018-09-20 |
AU2014232540A1 (en) | 2015-10-29 |
US10821158B2 (en) | 2020-11-03 |
BR112015023233A8 (pt) | 2019-12-03 |
EP2968597B1 (en) | 2021-08-18 |
WO2014145755A1 (en) | 2014-09-18 |
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