JP7452932B2 - ヘテロ二量体タンパク質及びその使用 - Google Patents
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Classifications
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- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
- C07K14/7155—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for interleukins [IL]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- C—CHEMISTRY; METALLURGY
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- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
- C07K14/5434—IL-12
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- C07K2319/00—Fusion polypeptide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Description
本出願は、2018年6月21日に出願された米国仮出願第62/688,167号及び2018年7月25日に出願された米国仮出願第62/703,248号の利益を主張する。各出願の内容は、それぞれその内容全体が参照により本明細書に取り込まれる。
本明細書と共に電子的に提出されたテキストファイルである配列表のコンピュータ可読形式のコピー(ファイル名:SHK-004PC-Sequence_Listing_ST25、作成日:2019年6月21日、ファイルサイズ:112KB)の内容は、参照によりその全体が本明細書に取り込まれる。
ある態様では、本発明は、ヘテロ二量体タンパク質に関する。様々な実施形態では、本発明のヘテロ二量体タンパク質は、2種類のポリペプチド鎖を含む。第1のポリペプチド鎖は、アミノ末端において第1のタンパク質の第1のサブユニットを含み、前記第1のタンパク質の第1のサブユニットは、第1の電荷分極コアドメインによって、カルボキシ末端における第2のタンパク質の第1のサブユニットに連結されている。第2のポリペプチド鎖は、アミノ末端の前記第1のタンパク質の第2のサブユニットを含み、前記第1のタンパク質の第2のサブユニットは、第2の電荷分極コアドメインによって、カルボキシ末端における前記第2のタンパク質の第2のサブユニットに連結されている。様々な実施形態では、第1のポリペプチド鎖及び第2のポリペプチド鎖は、第1の電荷分極コアドメイン及び第2の電荷分極コアドメイン上の正に帯電したアミノ酸残基と負に帯電したアミノ酸残基との間の静電相互作用を介してヘテロ二量体を形成する。
GSGSRKGGKRGSKYGPPCPPCPAPEFLGGPSVFLFPPKPKDQLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLSGKEYKCKVSSKGLPSSIEKTISNATGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHNHYTQKSLSLSLGKDEGGEDGSGS(配列番号16)。
GSGSDEGGEDGSKYGPPCPPCPAPEFLGGPSVFLFPPKPKDQLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLSGKEYKCKVSSKGLPSSIEKTISNATGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHNHYTQKSLSLSLGKRKGGKRGSGS(配列番号17)。
SKYGPPCPPCPAPEFLGGPSVFLFPPKPKDQLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLSGKEYKCKVSSKGLPSSIEKTISNATGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHNHYTQKSLSLSLGKIEGRMD(配列番号15)。
EPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLYCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号24)。
EPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLTSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号25)
様々な実施形態では、本発明のヘテロ二量体タンパク質は、2種類のポリペプチド鎖を含む。様々な実施形態では、各ポリペプチド鎖は、電荷分極コアドメインによって第2のタンパク質のサブユニットに連結された第1のタンパク質のサブユニットを含む。電荷分極コアドメイン間の静電相互作用により、前記サブユニットはヘテロ二量体化されて、機能的な二量体の第1のタンパク質及び機能的な二量体の第2のタンパク質を形成する。いくつかの実施形態では、前記ポリペプチド鎖は、電荷分極コアドメインを介して連結された機能的な両側ヘテロ二量体タンパク質を形成し、これは、任意に、Fc領域などのリンカー(例えば、安定化ドメイン)を含む。
本発明の組成物及び方法に組み込むことができる例示的なタンパク質としては、以下が挙げられる(本明細書で使用される場合、「エントリー」は、Uniprotデータベースのタンパク質エントリーを指し、「エントリー名」は、Uniprotデータベースのタンパク質エントリーを指す)。
ELLDPCGYISPESPVVQLHSNFTAVCVLKEKCMDYFHVNANYIVWKTNHFTIPKEQYTIINRTASSVTFTDIASLNIQLTCNILTFGQLEQNVYGITIISGLPPEKPKNLSCIVNEGKKMRCEWDGGRETHLETNFTLKSEWATHKFADCKAKRDTPTSCTVDYSTVYFVNIEVWVEAENALGKVTSDHINFDPVYKVKPNPPHNLSVINSEELSSILKLTWTNPSIKSVIILKYNIQYRTKDASTWSQIPPEDTASTRSSFTVQDLKPFTEYVFRIRCMKEDGKGYWSDWSEEASGITYEDRPSKAPSFWYKIDPSHTQGYRTVQLVWKTLPPFEANGKILDYEVTLTRWKSHLQNYTVNATKLTVNLTNDRYLATLTVRNLVGKSDAAVLTIPACDFQATHPVMDLKAFPKDNMLWVEWTTPRESVKKYILEWCVLSDKAPCITDWQQEDGTVHRTYLRGNLAESKCYLITVTPVYADGPGSPESIKAYLKQAPPSKGPTVRTKKVGKNEAVLEWDQLPVDVQNGFIRNYTIFYRTIIGNETAVNVDSSHTEYTLSSLTSDTLYMVRMAAYTDEGGKDGPEFTFTTPKFAQGEIE(配列番号18)。
LAPRRCPAQEVARGVLTSLPGDSVTLTCPGVEPEDNATVHWVLRKPAAGSHPSRWAGMGRRLLLRSVQLHDSGNYSCYRAGRPAGTVHLLVDVPPEEPQLSCFRKSPLSNVVCEWGPRSTPSLTTKAVLLVRKFQNSPAEDFQEPCQYSQESQKFSCQLAVPEGDSSFYIVSMCVASSVGSKFSKTQTFQGCGILQPDPPANITVTAVARNPRWLSVTWQDPHSWNSSFYRLRFELRYRAERSKTFTTWMVKDLQHHCVIHDAWSGLRHVVQLRAQEEFGQGEWSEWSPEAMGTPWTESRSPPAENEVSTPMQALTTNKDDDNILFRDSANATSLPVQDSSSVPLP(配列番号19)。
RNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS(配列番号20)。
RKGPPAALTLPRVQCRASRYPIAVDCSWTLPPAPNSTSPVSFIATYRLGMAARGHSWPCLQQTPTSTSCTITDVQLFSMAPYVLNVTAVHPWGSSSSFVPFITEHIIKPDPPEGVRLSPLAERQLQVQWEPPGSWPFPEIFSLKYWIRYKRQGAARFHRVGPIEATSFILRAVRPRARYYVQVAAQDLTDYGELSDWSLPATATMSLGK(配列番号21)。
ELLDPCGYISPESPVVQLHSNFTAVCVLKEKCMDYFHVNANYIVWKTNHFTIPKEQYTIINRTASSVTFTDIASLNIQLTCNILTFGQLEQNVYGITIISGLPPEKPKNLSCIVNEGKKMRCEWDGGRETHLETNFTLKSEWATHKFADCKAKRDTPTSCTVDYSTVYFVNIEVWVEAENALGKVTSDHINFDPVYKVKPNPPHNLSVINSEELSSILKLTWTNPSIKSVIILKYNIQYRTKDASTWSQIPPEDTASTRSSFTVQDLKPFTEYVFRIRCMKEDGKGYWSDWSEEASGITYEDRPSKAPSFWYKIDPSHTQGYRTVQLVWKTLPPFEANGKILDYEVTLTRWKSHLQNYTVNATKLTVNLTNDRYLATLTVRNLVGKSDAAVLTIPACDFQATHPVMDLKAFPKDNMLWVEWTTPRESVKKYILEWCVLSDKAPCITDWQQEDGTVHRTYLRGNLAESKCYLITVTPVYADGPGSPESIKAYLKQAPPSKGPTVRTKKVGKNEAVLEWDQLPVDVQNGFIRNYTIFYRTIIGNETAVNVDSSHTEYTLSSLTSDTLYMVRMAAYTDEGGKDGPEFTFTTPKFAQGEIEGSGSRKGGKRGSKYGPPCPPCPAPEFLGGPSVFLFPPKPKDQLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLSGKEYKCKVSSKGLPSSIEKTISNATGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHNHYTQKSLSLSLGKDEGGEDGSGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS*(配列番号22)。
LAPRRCPAQEVARGVLTSLPGDSVTLTCPGVEPEDNATVHWVLRKPAAGSHPSRWAGMGRRLLLRSVQLHDSGNYSCYRAGRPAGTVHLLVDVPPEEPQLSCFRKSPLSNVVCEWGPRSTPSLTTKAVLLVRKFQNSPAEDFQEPCQYSQESQKFSCQLAVPEGDSSFYIVSMCVASSVGSKFSKTQTFQGCGILQPDPPANITVTAVARNPRWLSVTWQDPHSWNSSFYRLRFELRYRAERSKTFTTWMVKDLQHHCVIHDAWSGLRHVVQLRAQEEFGQGEWSEWSPEAMGTPWTESRSPPAENEVSTPMQALTTNKDDDNILFRDSANATSLPVQDSSSVPLPGSGSDEGGEDGSKYGPPCPPCPAPEFLGGPSVFLFPPKPKDQLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLSGKEYKCKVSSKGLPSSIEKTISNATGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHNHYTQKSLSLSLGKRKGGKRGSGSRKGPPAALTLPRVQCRASRYPIAVDCSWTLPPAPNSTSPVSFIATYRLGMAARGHSWPCLQQTPTSTSCTITDVQLFSMAPYVLNVTAVHPWGSSSSFVPFITEHIIKPDPPEGVRLSPLAERQLQVQWEPPGSWPFPEIFSLKYWIRYKRQGAARFHRVGPIEATSFILRAVRPRARYYVQVAAQDLTDYGELSDWSLPATATMSLGK*(配列番号23)。
CPDLVCYTDYLQTVICILEMWNLHPSTLTLTWQDQYEELKDEATSCSLHRSAHNATHATYTCHMDVFHFMADDIFSVNITDQSGNYSQECGSFLLAESIKPAPPFNVTVTFSGQYNISWRSDYEDPAFYMLKGKLQYELQYRNRGDPWAVSPRRKLISVDSRSVSLLPLEFRKDSSYELQVRAGPMPGSSYQGTWSEWSDPVIFQTQSEELKE(配列番号26)。
LNTTILTPNGNEDTTADFFLTTMPTDSLSVSTLPLPEVQCFVFNVEYMNCTWNSSSEPQPTNLTLHYWYKNSDNDKVQKCSHYLFSEEITSGCQLQKKEIHLYQTFVVQLQDPREPRRQATQMLKLQNLVIPWAPENLTLHKLSESQLELNWNNRFLNHCLEHLVQYRTDWDHSWTEQSVDYRHKFSLPSVDGQKRYTFRVRSRFNPLCGSAQHWSEWSHPIHWGSNTSKENPFLFALEA(配列番号27)。
CPDLVCYTDYLQTVICILEMWNLHPSTLTLTWQDQYEELKDEATSCSLHRSAHNATHATYTCHMDVFHFMADDIFSVNITDQSGNYSQECGSFLLAESIKPAPPFNVTVTFSGQYNISWRSDYEDPAFYMLKGKLQYELQYRNRGDPWAVSPRRKLISVDSRSVSLLPLEFRKDSSYELQVRAGPMPGSSYQGTWSEWSDPVIFQTQSEELKEGSGSRKGGKRGSKYGPPCPPCPAPEFLGGPSVFLFPPKPKDQLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLSGKEYKCKVSSKGLPSSIEKTISNATGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHNHYTQKSLSLSLGKDEGGEDGSGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS(配列番号28)。
LNTTILTPNGNEDTTADFFLTTMPTDSLSVSTLPLPEVQCFVFNVEYMNCTWNSSSEPQPTNLTLHYWYKNSDNDKVQKCSHYLFSEEITSGCQLQKKEIHLYQTFVVQLQDPREPRRQATQMLKLQNLVIPWAPENLTLHKLSESQLELNWNNRFLNHCLEHLVQYRTDWDHSWTEQSVDYRHKFSLPSVDGQKRYTFRVRSRFNPLCGSAQHWSEWSHPIHWGSNTSKENPFLFALEAGSGSDEGGEDGSKYGPPCPPCPAPEFLGGPSVFLFPPKPKDQLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLSGKEYKCKVSSKGLPSSIEKTISNATGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHNHYTQKSLSLSLGKRKGGKRGSGSRKGPPAALTLPRVQCRASRYPIAVDCSWTLPPAPNSTSPVSFIATYRLGMAARGHSWPCLQQTPTSTSCTITDVQLFSMAPYVLNVTAVHPWGSSSSFVPFITEHIIKPDPPEGVRLSPLAERQLQVQWEPPGSWPFPEIFSLKYWIRYKRQGAARFHRVGPIEATSFILRAVRPRARYYVQVAAQDLTDYGELSDWSLPATATMSLGK(配列番号29)。
CPDLVCYTDYLQTVICILEMWNLHPSTLTLTWQDQYEELKDEATSCSLHRSAHNATHATYTCHMDVFHFMADDIFSVNITDQSGNYSQECGSFLLAESIKPAPPFNVTVTFSGQYNISWRSDYEDPAFYMLKGKLQYELQYRNRGDPWAVSPRRKLISVDSRSVSLLPLEFRKDSSYELQVRAGPMPGSSYQGTWSEWSDPVIFQTQSEELKEGSGSDEGGEDGSKYGPPCPPCPAPEFLGGPSVFLFPPKPKDQLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLSGKEYKCKVSSKGLPSSIEKTISNATGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHNHYTQKSLSLSLGKRKGGKRGSGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS(配列番号37)。
LNTTILTPNGNEDTTADFFLTTMPTDSLSVSTLPLPEVQCFVFNVEYMNCTWNSSSEPQPTNLTLHYWYKNSDNDKVQKCSHYLFSEEITSGCQLQKKEIHLYQTFVVQLQDPREPRRQATQMLKLQNLVIPWAPENLTLHKLSESQLELNWNNRFLNHCLEHLVQYRTDWDHSWTEQSVDYRHKFSLPSVDGQKRYTFRVRSRFNPLCGSAQHWSEWSHPIHWGSNTSKENPFLFALEAGSGSRKGGKRGSKYGPPCPPCPAPEFLGGPSVFLFPPKPKDQLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLSGKEYKCKVSSKGLPSSIEKTISNATGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHNHYTQKSLSLSLGKDEGGEDGSGSRKGPPAALTLPRVQCRASRYPIAVDCSWTLPPAPNSTSPVSFIATYRLGMAARGHSWPCLQQTPTSTSCTITDVQLFSMAPYVLNVTAVHPWGSSSSFVPFITEHIIKPDPPEGVRLSPLAERQLQVQWEPPGSWPFPEIFSLKYWIRYKRQGAARFHRVGPIEATSFILRAVRPRARYYVQVAAQDLTDYGELSDWSLPATATMSLGK(配列番号36)。
EMGTADLGPSSVPTPTNVTIESYNMNPIVYWEYQIMPQVPVFTVEVKNYGVKNSEWIDACINISHHYCNISDHVGDPSNSLWVRVKARVGQKESAYAKSEEFAVCRDGKIGPPKLDIRKEEKQIMIDIFHPSVFVNGDEQEVDYDPETTCYIRVYNVYVRMNGSEIQYKILTQKEDDCDEIQCQLAIPVSSLNSQYCVSAEGVLHVWGVTTEKSKEVCITIFNSSIKG(配列番号30)。
SQLPAPQHPKIRLYNAEQVLSWEPVALSNSTRPVVYQVQFKYTDSKWFTADIMSIGVNCTQITATECDFTAASPSAGFPMDFNVTLRLRAELGALHSAWVTMPWFQHYRNVTVGPPENIEVTPGEGSLIIRFSSPFDIADTSTAFFCYYVHYWEKGGIQQVKGPFRSNSISLDNLKPSRVYCLQVQAQLLWNKSNIFRVGHLSNISCYETMADASTELQQ(配列番号31)。
EMGTADLGPSSVPTPTNVTIESYNMNPIVYWEYQIMPQVPVFTVEVKNYGVKNSEWIDACINISHHYCNISDHVGDPSNSLWVRVKARVGQKESAYAKSEEFAVCRDGKIGPPKLDIRKEEKQIMIDIFHPSVFVNGDEQEVDYDPETTCYIRVYNVYVRMNGSEIQYKILTQKEDDCDEIQCQLAIPVSSLNSQYCVSAEGVLHVWGVTTEKSKEVCITIFNSSIKGGSGSRKGGKRGSKYGPPCPPCPAPEFLGGPSVFLFPPKPKDQLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLSGKEYKCKVSSKGLPSSIEKTISNATGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHNHYTQKSLSLSLGKDEGGEDGSGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS(配列番号32)。
SQLPAPQHPKIRLYNAEQVLSWEPVALSNSTRPVVYQVQFKYTDSKWFTADIMSIGVNCTQITATECDFTAASPSAGFPMDFNVTLRLRAELGALHSAWVTMPWFQHYRNVTVGPPENIEVTPGEGSLIIRFSSPFDIADTSTAFFCYYVHYWEKGGIQQVKGPFRSNSISLDNLKPSRVYCLQVQAQLLWNKSNIFRVGHLSNISCYETMADASTELQQGSGSDEGGEDGSKYGPPCPPCPAPEFLGGPSVFLFPPKPKDQLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLSGKEYKCKVSSKGLPSSIEKTISNATGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHNHYTQKSLSLSLGKRKGGKRGSGSRKGPPAALTLPRVQCRASRYPIAVDCSWTLPPAPNSTSPVSFIATYRLGMAARGHSWPCLQQTPTSTSCTITDVQLFSMAPYVLNVTAVHPWGSSSSFVPFITEHIIKPDPPEGVRLSPLAERQLQVQWEPPGSWPFPEIFSLKYWIRYKRQGAARFHRVGPIEATSFILRAVRPRARYYVQVAAQDLTDYGELSDWSLPATATMSLGK(配列番号33)。
EMGTADLGPSSVPTPTNVTIESYNMNPIVYWEYQIMPQVPVFTVEVKNYGVKNSEWIDACINISHHYCNISDHVGDPSNSLWVRVKARVGQKESAYAKSEEFAVCRDGKIGPPKLDIRKEEKQIMIDIFHPSVFVNGDEQEVDYDPETTCYIRVYNVYVRMNGSEIQYKILTQKEDDCDEIQCQLAIPVSSLNSQYCVSAEGVLHVWGVTTEKSKEVCITIFNSSIKGGSGSDEGGEDGSKYGPPCPPCPAPEFLGGPSVFLFPPKPKDQLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLSGKEYKCKVSSKGLPSSIEKTISNATGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHNHYTQKSLSLSLGKRKGGKRGSGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS(配列番号38)。
SQLPAPQHPKIRLYNAEQVLSWEPVALSNSTRPVVYQVQFKYTDSKWFTADIMSIGVNCTQITATECDFTAASPSAGFPMDFNVTLRLRAELGALHSAWVTMPWFQHYRNVTVGPPENIEVTPGEGSLIIRFSSPFDIADTSTAFFCYYVHYWEKGGIQQVKGPFRSNSISLDNLKPSRVYCLQVQAQLLWNKSNIFRVGHLSNISCYETMADASTELQQGSGSRKGGKRGSKYGPPCPPCPAPEFLGGPSVFLFPPKPKDQLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLSGKEYKCKVSSKGLPSSIEKTISNATGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHNHYTQKSLSLSLGKDEGGEDGSGSRKGPPAALTLPRVQCRASRYPIAVDCSWTLPPAPNSTSPVSFIATYRLGMAARGHSWPCLQQTPTSTSCTITDVQLFSMAPYVLNVTAVHPWGSSSSFVPFITEHIIKPDPPEGVRLSPLAERQLQVQWEPPGSWPFPEIFSLKYWIRYKRQGAARFHRVGPIEATSFILRAVRPRARYYVQVAAQDLTDYGELSDWSLPATATMSLGK(配列番号39)。
LAPRRCPAQEVARGVLTSLPGDSVTLTCPGVEPEDNATVHWVLRKPAAGSHPSRWAGMGRRLLLRSVQLHDSGNYSCYRAGRPAGTVHLLVDVPPEEPQLSCFRKSPLSNVVCEWGPRSTPSLTTKAVLLVRKFQNSPAEDFQEPCQYSQESQKFSCQLAVPEGDSSFYIVSMCVASSVGSKFSKTQTFQGCGILQPDPPANITVTAVARNPRWLSVTWQDPHSWNSSFYRLRFELRYRAERSKTFTTWMVKDLQHHCVIHDAWSGLRHVVQLRAQEEFGQGEWSEWSPEAMGTPWTESRSPPAENEVSTPMQALTTNKDDDNILFRDSANATSLPVQDSSSVPLPGSGSRKGGKRGSKYGPPCPPCPAPEFLGGPSVFLFPPKPKDQLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLSGKEYKCKVSSKGLPSSIEKTISNATGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHNHYTQKSLSLSLGKDEGGEDGSGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS(配列番号34)。
ELLDPCGYISPESPVVQLHSNFTAVCVLKEKCMDYFHVNANYIVWKTNHFTIPKEQYTIINRTASSVTFTDIASLNIQLTCNILTFGQLEQNVYGITIISGLPPEKPKNLSCIVNEGKKMRCEWDGGRETHLETNFTLKSEWATHKFADCKAKRDTPTSCTVDYSTVYFVNIEVWVEAENALGKVTSDHINFDPVYKVKPNPPHNLSVINSEELSSILKLTWTNPSIKSVIILKYNIQYRTKDASTWSQIPPEDTASTRSSFTVQDLKPFTEYVFRIRCMKEDGKGYWSDWSEEASGITYEDRPSKAPSFWYKIDPSHTQGYRTVQLVWKTLPPFEANGKILDYEVTLTRWKSHLQNYTVNATKLTVNLTNDRYLATLTVRNLVGKSDAAVLTIPACDFQATHPVMDLKAFPKDNMLWVEWTTPRESVKKYILEWCVLSDKAPCITDWQQEDGTVHRTYLRGNLAESKCYLITVTPVYADGPGSPESIKAYLKQAPPSKGPTVRTKKVGKNEAVLEWDQLPVDVQNGFIRNYTIFYRTIIGNETAVNVDSSHTEYTLSSLTSDTLYMVRMAAYTDEGGKDGPEFTFTTPKFAQGEIE(配列番号35)。
様々な実施形態では、本発明は、1又は複数の自己免疫疾患又は自己免疫障害の治療のためのヘテロ二量体タンパク質の使用に関する。様々な実施形態では、自己免疫疾患又は自己免疫障害の治療は、免疫刺激よりも免疫阻害に有利になるように、本発明のヘテロ二量体タンパク質を用いて免疫系を調節することを含み得る。本発明のヘテロ二量体タンパク質で治療可能な例示的な自己免疫疾患又は自己免疫障害には、体自身の抗原が免疫応答の標的となるものが含まれ、例えば、関節リウマチ、全身性エリテマトーデス、糖尿病、強直性脊椎炎、シェーグレン症候群、炎症性腸疾患(例えば、潰瘍性大腸炎、クローン病)、多発性硬化症、サルコイドーシス、乾癬、グレーブス病、橋本病、乾癬、過敏反応(例えば、アレルギー、花粉症、喘息、及び急性浮腫を引き起こすI型過敏反応)、及び血管炎が挙げられる。
いくつかの実施形態では、本発明は、ヘテロ二量体タンパク質及び対象に追加の薬剤を投与することをさらに含む方法を提供する。いくつかの実施形態では、本発明は、同時投与及び/又は同時処方に関する。本明細書に記載の組成物のいずれも、同時処方及び/又は同時投与してもよい。
抗生物質、例えば、エンジイン抗生物質(例えば、カリケアマイシン、特に、カリケアマイシンガンマII及びカリケアマイシンオメガII(例えば、Agnew,Chem.Intl.Ed.Engl.,33:183-186(1994)を参照);ダイネマイシン(dynemicin)Aを含むダイネマイシン;クロドロネートなどのビスホスホネート;エスペラミシン;並びにネオカルジノスタチンクロモフォア及び関連する色素タンパク質エンジイン抗生物質クロモフォア)など、アクラシノマイシン、アクチノマイシン、オースラマイシン(authramycin)、アザセリン、ブレオマイシン、カクチノマイシン、カラビシン(carabicin)、カミノマイシン、カルジノフィリン、クロモマイシニス(chromomycinis)、ダクチノマイシン、ダウノルビシン、デトルビシン、6-ジアゾ-5-オキソ-L-ノルロイシン、ADRIAMYCINドキソルビシン(モルホリノドキソルビシン、シアノモルホリノドキソルビシン、2-ピロリノドキソルビシン、及びデオキシドキソルビシンを含む)、エピルビシン、エソルビシン、イダルビシン、マルセロマイシン、マイトマイシンCなどのマイトマイシン、ミコフェノール酸、ノガラマイシン、オリボマイシン、ペプロマイシン、ポトフィロマイシン(potfiromycin)、ピューロマイシン、ケラマイシン(quelamycin)、ロドルビシン(rodorubicin)、ストレプトニグリン、ストレプトゾシン、ツベルシジン、ウベニメクス、ジノスタチン、ゾルビシンなど;
代謝拮抗物質、例えば、メトトレキサート及び5-フルオロウラシル(5-FU)など;葉酸類似体、例えば、デノプテリン、メトトレキサート、プテロプテリン、トリメトレキサートなど;プリン類似体、例えば、フルダラビン、6-メルカプトプリン、チアミプリン(thiamiprine)、チオグアニンなど;ピリミジン類似体、例えば、アンシタビン、アザシチジン、6-アザウリジン、カルモフール、シタラビン、ジデオキシウリジン、ドキシフルリジン、エノシタビン、フロクスウリジンなど;アンドロゲン、例えば、カルステロン、プロピオン酸ドロモスタノロン、エピチオスタノール、メピチオスタン、テストラクトンなど;抗副腎剤、例えば、アミノグルテチミド、ミトタン、トリロスタンなど;葉酸補充剤、例えば、フロリン酸(frolinic acid)など;アセグラトン;アルドホスファミドグリコシド;アミノレブリン酸;エニルウラシル;アムサクリン;ベストラブシル;ビサントレン;エダトレキサート(edatraxate);デメコルチン;ジアジクオン;エルフォルミチン(elformithine);酢酸エリプチニウム;エポシロン;エトグルシド;硝酸ガリウム;ヒドロキシウレア;レンチナン;ロニダミン;マイタンシノイド、例えば、マイタンシン及びアンサミトシン(ansamitocin)など;ミトグアゾン;ミトキサントロン;モピダンモール;ニトラクリン;ペントスタチン;フェナメット;ピラルビシン;ロソキサントロン(losoxantrone);ポドフィリン酸;2-エチルヒドラジド;プロカルバジン;;PSK多糖複合体(JHS Natural Products社、オレゴン州ユージーン);ラゾキサン;リゾキシン(rhizoxin);シゾフィラン;スピロゲルマニウム;テヌアゾン酸;トリアジコン;2,2’,2”-トリクロロトリエチルアミン;トリコテセン(例えば、T-2トキシン、ベラキュリン(verracurin)A、ロリジン(roridin)A、及びアングイジン(anguidine));ウレタン;ビンデシン;ダカルバジン;マンノムスチン;ミトブロニトール;ミトラクトール;ピポブロマン;ガシトシン(gacytosine);アラビノシド(「Ara-C」);シクロホスファミド;チオテパ;タキソイド、例えば、TAXOLパクリタキセル(Bristol-Myers Squibb Oncology社、ニュージャージー州プリンストン)、ABRAXANE Cremophorフリー、パクリタキセルのアルブミン操作ナノ粒子製剤(American Pharmaceutical Partners社、イリノイ州シャンバーグ)、及びTAXOTERE ドキセタキセル(Rhone-Poulenc Rorer社、アントニー、フランス);クロラムブシル;GEMZAR ゲムシタビン;6-チオグアニン;メルカプトプリン;メトトレキセート;白金類似体、例えば、シスプラチン、オキサリプラチン、及びカルボプラチンなど;ビンブラスチン;白金;エトポシド(VP-16);イホスファミド;ミトキサントロン;ビンクリスチン;NAVELBINE ビノレルビン;ノバントロン;テニポシド;エダトレキサート;ダウノマイシン;アミノプテリン;ゼローダ;イバンドロン酸;イリノテカン(Camptosar、CPT-11)(イリノテカンと5-FU及びロイコボリンの処置レジメンを含む);トポイソメラーゼ阻害剤RFS2000;ジフルオロメチルオルニチン(DMFO);レチノイン酸などのレチノイド;カペシタビン;コンブレタスタチン;ロイコボリン(LV);オキサリプラチン処置レジメン(FOLFOX)を含む、オキサリプラチン;ラパチニブ(TYKERB);細胞増殖を低減させる、PKC-α、Raf、H-Ras、EGFRの阻害剤(例えば、エルロチニブ(Tarceva)及びVEGF-A、並びに上記のいずれかの薬学的に許容される塩、酸、又は誘導体が挙げられる。さらに、前記治療方法は、放射線の使用をさらに含み得る。さらに、前記治療方法は、光線力学療法の使用をさらに含み得る。
本明細書に記載のヘテロ二量体タンパク質(及び/又は追加の薬剤)は、無機酸又は有機酸と反応することができる充分に塩基性の官能基、あるいは無機塩基又は有機塩基と反応して薬学的に許容される塩を形成することができるカルボキシル基を有することができる。当技術分野で周知のように、薬学的に許容される酸付加塩は、薬学的に許容される酸から形成される。そのような塩としては、例えば、その全体が参照により本明細書に取り込まれるJournal of Pharmaceutical Science,66,2-19(1977)及びThe Handbook of Pharmaceutical Salts;Properties,Selection,and Use.P.H.Stahl and C.G.Wermuth(eds.),Verlag,Zurich(Switzerland)2002に記載される薬学的に許容される塩が挙げられる。
本発明は、様々な製剤中の本明細書に記載のヘテロ二量体タンパク質(及び/又は追加の薬剤)を含む。本明細書に記載の任意のヘテロ二量体タンパク質(及び/又は追加の薬剤)は、溶液、懸濁液、乳濁液、液滴、錠剤、丸薬、ペレット、カプセル、液体含有カプセル、粉末、徐放性製剤、坐剤、乳濁液、エアロゾル、スプレー、懸濁液、又は使用に適したその他の形態であり得る。タンパク質配列をコードするDNAコンストラクト又はRNAコンストラクトを使用してもよい。ある実施形態では、前記組成物はカプセルの形態である(例えば、米国特許第5,698,155号を参照)。適切な医薬品添加剤の他の例は、参照により本明細書に取り込まれるRemington’s Pharmaceutical Sciences 1447-1676(Alfonso R.Gennaro eds.,19th ed.1995)に記載されている。
様々な実施形態では、本発明は、本明細書に記載のヘテロ二量体タンパク質(第1のポリペプチド鎖及び第2のポリペプチド鎖を含むヘテロ二量体タンパク質)をコードする核酸を含む発現ベクターを提供する。様々な実施形態では、前記発現ベクターはDNA又はRNAを含む。様々な実施形態では、発現ベクターは哺乳動物発現ベクターである。
いくつかの実施形態では、対象及び/又は動物は、哺乳動物、例えば、ヒト、マウス、ラット、モルモット、イヌ、ネコ、ウマ、ウシ、ブタ、ウサギ、ヒツジ、又はサル、チンパンジー、若しくはヒヒなどの非ヒト霊長類である。他の実施形態では、対象及び/又は動物は、例えばゼブラフィッシュなどの非哺乳動物である。いくつかの実施形態では、対象及び/又は動物は、蛍光標識された(例えば、GFPを有する)細胞を含み得る。いくつかの実施形態では、対象及び/又は動物は、蛍光細胞を含むトランスジェニック動物である。
本発明は、本明細書に記載の任意の薬剤の投与を単純化することができるキットを提供する。本発明の例示的なキットは、単位剤形で本明細書に記載される任意の組成物を含む。ある実施形態では、単位剤形は、本明細書に記載の任意の薬剤及び薬学的に許容される担体、希釈剤、非薬効成分、又はビヒクルを含む、無菌であり得る予め充填されるシリンジなどの容器である。キットは、本明細書に記載の任意の薬剤の使用を指示するラベル又は印刷された説明書をさらに含むことができる。キットには、開瞼器、局所麻酔薬、及び投与部位洗浄剤も含まれる場合がある。キットはまた、本明細書に記載の1種類又は複数種類の追加の薬剤をさらに含んでいてもよい。ある実施形態では、キットは、有効量の本発明の組成物及び有効量の別の組成物(本明細書に記載されるものなど)を含む容器を含む。
本明細書及び添付の特許請求の範囲で使用されるように、単数形の「a」、「an」、及び「the」は、文脈が明らかに他のことを指示しない限り、複数の指示対象を含む。
電荷分極コアドメインによってIL-35に連結されたIL6受容体(IL6R)を含むヘテロ二量体タンパク質を構築した(例えば、図1を参照)。具体的には、ヘテロ二量体タンパク質は、2種類のポリペプチド鎖を含む。第1のポリペプチド鎖は、電荷分極コアドメインによってIL-35サブユニットIL12αに連結されたIL6RサブユニットGp130を含む。第2のポリペプチド鎖は、電荷分極コアドメインによってIL-35サブユニットIL27βに連結されたIL6RサブユニットIL6Rαを含む。IL-6R-Fc-IL-35ヘテロ二量体タンパク質は、IL6RA-β-IL27βコンストラクト及びgp130-α-IL12αコンストラクトの両方を用いた二重一過性トランスフェクションによって哺乳動物細胞で発現された。クーマシー染色は、発現されたタンパク質の存在を示し、これは、抗ヒトIgGウエスタンブロットを用いて、αコンストラクト及びβコンストラクトのおおよその分子量に対応するタンパク質を含むことが確認された(例えば、図2を参照)。
IL-6R-Fc-IL-35ヘテロ二量体タンパク質を用いてサイズ排除クロマトグラフィー(SEC)を実施した。SECによる吸光度波長210nmでの単一のピークの出現は、2種類のコンストラクトにおける電荷分極リンカードメイン(Fc-α及びFc-β)を使用することから意図された、単一種類のタンパク質のみが存在する可能性が高いことを示した(図16A)。興味深いことに、280nmの吸光度波長でのSECは、2番目の低分子量バンドを示した(図16B)。
IL21r-α-IL12a鎖及びIL2rg-β-IL27B鎖をコードするコンストラクトをCHO細胞に二重ルトランスフェクトした後、プロテインAを用いて分泌タンパク質を精製した。IL21r-α-IL12a鎖及びIL2rg-β-IL27B鎖が(細胞内又はインビトロで)組み合わされると、それらは本明細書でIL-21R-Fc-IL-35と称されるヘテロ二量体タンパク質を形成する(図19A)。
IFNgR-α-IL12a鎖及びIFNGR2-β-IL27B鎖をコードするコンストラクトをCHO細胞に二重トランスフェクトした後、プロテインAを用いて分泌タンパク質を精製した。IFNgR-α-IL12a鎖及びIFNGR2-β-IL27B鎖が(細胞内又はインビトロで)組み合わされると、それらは本明細書でIFNγR-Fc-IL-35と称されるヘテロ二量体タンパク質を形成する。
本発明は、その特定の実施形態に関連して説明されてきたが、本発明はさらに変更可能であり、以下の発明(通常は本発明の原理)の変形、使用、又は適合を含むことを目的とし、本発明が関係する当技術分野内の公知又は慣習的な実践の範囲内にあり、前述及び添付の特許請求の範囲において以下のように説明される本質的な特徴に適用され得る、本開示からの逸脱が含まれることが理解されよう。
本明細書で参照される全ての特許及び刊行物は、それらの全体が参照により本明細書に取り込まれる。
本発明の態様は以下を含む。
<1>
第1のポリペプチド鎖及び第2のポリペプチド鎖を含むヘテロ二量体タンパク質であって、
前記第1のポリペプチド鎖は、アミノ末端において第1のタンパク質の第1のサブユニットを含み、前記第1のタンパク質の第1のサブユニットは、第1の電荷分極コアドメインによって、カルボキシ末端における第2のタンパク質の第1のサブユニットに連結されており、
前記第2のポリペプチド鎖は、アミノ末端において前記第1のタンパク質の第2のサブユニットを含み、前記第1のタンパク質の第2のサブユニットは、第2の電荷分極コアドメインによって、カルボキシ末端における前記第2のタンパク質の第2のサブユニットに連結されており、
前記第1のポリペプチド鎖及び前記第2のポリペプチド鎖は、前記第1の電荷分極コアドメイン及び前記第2の電荷分極コアドメイン上の正に帯電したアミノ酸残基と負に帯電したアミノ酸残基との間の静電相互作用を介してヘテロ二量体を形成する、
前記ヘテロ二量体タンパク質。
<2>
前記第1の電荷分極コアドメイン及び/又は前記第2の電荷分極コアドメインが、可動性アミノ酸配列、IgGヒンジ領域、又は抗体配列から所望により選択されるポリペプチドリンカーを含む、<1>に記載のヘテロ二量体タンパク質。
<3>
前記リンカーが合成リンカー、所望によりPEGである、<2>に記載のヘテロ二量体タンパク質。
<4>
前記リンカーが、IgG1、所望によりヒトIgG1に由来する、ヒンジ-CH2-CH3 Fcドメインを含む、<2>に記載のヘテロ二量体タンパク質。
<5>
前記リンカーが、IgG4、所望によりヒトIgG4に由来する、ヒンジ-CH2-CH3 Fcドメインを含む、<2>に記載のヘテロ二量体タンパク質。
<6>
前記第1の電荷分極コアドメイン及び/又は前記第2の電荷分極コアドメインが、前記電荷分極コアドメインのアミノ末端及びカルボキシ末端に正に帯電したアミノ酸残基及び/又は負に帯電したアミノ酸残基を含むペプチドをさらに含む、<1>~<5>のいずれか一項に記載のヘテロ二量体タンパク質。
<7>
前記正に帯電したアミノ酸残基を含むペプチドが、ヒスチジン(His)、リシン(Lys)、及びアルギニン(Arg)から選択される1又は複数のアミノ酸を含み得る、<6>に記載のヘテロ二量体タンパク質。
<8>
前記正に帯電したアミノ酸残基を含むペプチドが、Y n X n Y n X n Y n (式中、Xはアルギニン、ヒスチジン、又はリシンなどの正に帯電したアミノ酸であり、Yはセリン又はグリシンなどのスペーサーアミノ酸である)(配列番号1)、YY n XX n YY n XX n YY n (式中、Xはアルギニン、ヒスチジン、又はリシンなどの正に帯電したアミノ酸であり、Yはセリン又はグリシンなどのスペーサーアミノ酸である)(配列番号3)、及びY n X n CY n X n Y n (式中、Xはアルギニン、ヒスチジン、又はリシンなどの正に帯電したアミノ酸であり、Yはセリン又はグリシンなどのスペーサーアミノ酸である)(配列番号5)から選択される配列を含む、<7>に記載のヘテロ二量体タンパク質。
<9>
前記正に帯電したアミノ酸残基を含むペプチドが、配列RKGGKR(配列番号11)又はGSGSRKGGKRGS(配列番号12)を含む、<8>に記載のヘテロ二量体タンパク質。
<10>
前記負に帯電したアミノ酸残基を含むペプチドが、アスパラギン酸(Asp)及びグルタミン酸(Glu)から選択される1又は複数のアミノ酸を含み得る、<6>記載のヘテロ二量体タンパク質。
<11>
前記負に帯電したアミノ酸残基を含むペプチドが、Y n Z n Y n Z n Y n (式中、Zはアスパラギン酸又はグルタミン酸などの負に帯電したアミノ酸であり、Yはセリン又はグリシンなどのスペーサーアミノ酸である)(配列番号2)、YY n ZZ n YY n ZZ n YY n (式中、Zはアスパラギン酸又はグルタミン酸などの負に帯電したアミノ酸であり、Yはセリン又はグリシンなどのスペーサーアミノ酸である)(配列番号4)、及びY n Z n CY n Z n Y n (式中、Zはアスパラギン酸又はグルタミン酸などの負に帯電したアミノ酸であり、Yはセリン又はグリシンなどのスペーサーアミノ酸である)(配列番号6)から選択される配列を含む、<9>に記載のヘテロ二量体タンパク質。
<12>
前記正に帯電したアミノ酸残基を含むペプチドが、配列DEGGED(配列番号13)又はGSGSDEGGEDGS(配列番号14)を含む、<8>に記載のヘテロ二量体タンパク質。
<13>
前記第1の電荷分極コアドメイン及び/又は前記第2の電荷分極コアドメインが、水素結合及び/又はファンデルワールス力の増大によってヘテロ二量体化を促進するための1又は複数のアミノ酸変化を含む、<1>~<12>のいずれか一項に記載のヘテロ二量体タンパク質。
<14>
前記1又は複数のアミノ酸変化が、ノブ・イン・ホール(knob-in-hole)モチーフを作成する、<13>に記載のヘテロ二量体タンパク質。
<15>
前記ノブ・イン・ホールモチーフは、前記第1の電荷分極コアドメインにおいて1又は複数のチロシン(Y)残基を1又は複数のスレオニン(T)残基で置換する1又は複数のアミノ酸変化によって形成される、及び/又は前記第2の電荷分極コアドメインにおいて1又は複数のスレオニン(T)残基を1又は複数のチロシン(Y)残基で置換する1又は複数のアミノ酸変化によって形成される、<14>に記載のヘテロ二量体タンパク質。
<16>
前記ノブ・イン・ホールモチーフは、前記第2の電荷分極コアドメインにおいて1又は複数のチロシン(Y)残基を1又は複数のスレオニン(T)残基で置換する1又は複数のアミノ酸変化によって形成される、及び/又は前記第1の電荷分極コアドメインにおいて1又は複数のスレオニン(T)残基を1又は複数のチロシン(Y)残基で置換する1又は複数のアミノ酸変化によって形成される、<14>又は<15>に記載のヘテロ二量体タンパク質。
<17>
前記電荷分極コアドメインの一方又は両方は、L234A及びL235A(LALA)、並びに所望によりP329Gから選択される1又は複数のエフェクター及び補体サイレンシング置換(effector and complement silencing substitution)を含む、<13>~<16>のいずれか一項に記載のヘテロ二量体タンパク質。
<18>
前記電荷分極コアドメインの一方又は両方は、M252Y、S254T、及びT256Eから選択される1又は複数の半減期延長変異を含む、<13>~<17>のいずれか一項に記載のヘテロ二量体タンパク質。
<19>
前記第1のタンパク質が表1から選択される、<1>~<18>のいずれか一項に記載のヘテロ二量体タンパク質。
<20>
前記第2のタンパク質が表1から選択される、<1>~<19>のいずれか一項に記載のヘテロ二量体タンパク質。
<21>
前記第1のタンパク質及び/又は前記第2のタンパク質が、サイトカイン、増殖因子、及び/又はホルモンから選択される、<1>~<20>のいずれか一項に記載のヘテロ二量体タンパク質。
<22>
前記第1のタンパク質及び/又は前記第2のタンパク質が、インターロイキンである、<21>に記載のヘテロ二量体タンパク質。
<23>
前記第1のタンパク質及び/又は前記第2のタンパク質が、IL12αサブユニット及びIL27βサブユニットを含むIL-35である、<22>に記載のヘテロ二量体タンパク質。
<24>
前記第1のタンパク質及び/又は前記第2のタンパク質が、サイトカインの受容体、増殖因子の受容体、及び/又はホルモンの受容体から選択される、<1>~<23>のいずれか一項に記載のヘテロ二量体タンパク質。
<25>
前記第1のタンパク質及び/又は前記第2のタンパク質が、インターロイキンの受容体である、<24>に記載のヘテロ二量体タンパク質。
<26>
前記第1のタンパク質及び/又は前記第2のタンパク質が、IL6Rαサブユニット及びgp130サブユニットを含むIL6受容体である、<25>に記載のヘテロ二量体タンパク質。
<27>
前記第1のタンパク質及び/又は前記第2のタンパク質が、IL21rサブユニット及びIL2rgサブユニットを含むIL21受容体である、<25>に記載のヘテロ二量体タンパク質。
<28>
前記第1のタンパク質及び/又は前記第2のタンパク質が、IFNgRサブユニット及びIFNGR2サブユニットを含むIL21受容体である、<25>に記載のヘテロ二量体タンパク質。
<29>
前記ヘテロ二量体タンパク質が、(i)免疫阻害シグナルを低減又は排除すること、及び(ii)免疫刺激シグナルを増加又は活性化することの両方が可能である、<1>~<28>のいずれか一項に記載のヘテロ二量体タンパク質。
<30>
前記ヘテロ二量体タンパク質が、制御性T細胞に対するエフェクターT細胞の比率を増加させることができる、<1>~<29>のいずれか一項に記載のヘテロ二量体タンパク質。
<31>
前記ヘテロ二量体タンパク質は、細胞傷害性T細胞の亜集団、エフェクターメモリーT細胞の亜集団、セントラルメモリーT細胞の亜集団、CD8 + 幹細胞メモリーエフェクター細胞の亜集団、TH1エフェクターT細胞の亜集団、TH2エフェクターT細胞の亜集団、TH9エフェクターT細胞の亜集団、TH17エフェクターT細胞の亜集団、及び/又はIL-2、IL-4、及び/又はIFN-γを分泌するエフェクターT細胞の亜集団を増加させることができる、及び/又は減少を防止することができる、<1>~<30>のいずれか一項に記載のヘテロ二量体タンパク質。
<32>
<1>~<31>のいずれか一項に記載のヘテロ二量体タンパク質を含む、医薬組成物。
<33>
<1>~<32>のいずれか一項に記載のヘテロ二量体タンパク質の前記第1のポリペプチド鎖及び/又は前記第2のポリペプチド鎖をコードする核酸を含む、発現ベクター。
<34>
前記発現ベクターが、哺乳動物発現ベクターである、<33>に記載の発現ベクター。
<35>
前記発現ベクターが、DNA又はRNAを含む、<34>に記載の発現ベクター。
<36>
<33>~<35>のいずれか一項に記載の発現ベクターを含む、宿主細胞。
<37>
<32>に記載の医薬組成物の有効量を、投与を必要とする対象に投与することを含む、がんを治療する方法。
<38>
<32>に記載の医薬組成物の有効量を、投与を必要とする対象に投与することを含む、自己免疫疾患又は自己免疫障害を治療する方法。
<39>
<32>に記載の医薬組成物の有効量を、投与を必要とする対象に投与することを含む、患者の免疫応答を調節する方法。
<40>
前記患者のT細胞が、免疫刺激シグナルを有する細胞外ドメインによって活性化されている、<37>~<39>のいずれか一項に記載の方法。
<41>
前記患者が腫瘍を有し、1又は複数の腫瘍細胞による、免疫阻害シグナルを有する細胞外ドメインにより活性化される免疫抑制シグナルの伝達が防止されている、<37>~<39>のいずれか一項に記載の方法。
<42>
前記自己免疫疾患又は前記自己免疫障害が、関節リウマチ、全身性エリテマトーデス、糖尿病、強直性脊椎炎、シェーグレン症候群、炎症性腸疾患(例えば、潰瘍性大腸炎、クローン病)、多発性硬化症、サルコイドーシス、乾癬、グレーブス病、橋本病、乾癬、過敏反応(例えば、アレルギー、花粉症、喘息、及び急性浮腫を引き起こすI型過敏反応)、及び血管炎から選択される、<38>に記載の方法。
Claims (15)
- 第1のポリペプチド鎖及び第2のポリペプチド鎖を含む2種類のポリペプチド鎖を含むヘテロ二量体タンパク質であって、
前記第1のポリペプチド鎖は、第1の電荷分極コアドメインによってカルボキシ末端のIL-35サブユニットIL12αに連結されている、アミノ末端のIL6Rサブユニットgp130を含み、
前記第2のポリペプチド鎖は、第2の電荷分極コアドメインによってカルボキシ末端のIL-35サブユニットIL27βに連結されている、アミノ末端のIL6RサブユニットIL6Rαを含み、
前記第1の電荷分極コアドメイン及び前記第2の電荷分極コアドメインは、それぞれ独立に、
ヒスチジン、リシン、及びアルギニンから選択される正に帯電したアミノ酸残基を含むペプチド、又は
アスパラギン酸及びグルタミン酸から選択される負に帯電したアミノ酸残基を含むペプチド
のいずれかを含み、
前記第1のポリペプチド鎖及び前記第2のポリペプチド鎖は、前記正に帯電したアミノ酸残基を含むペプチドと前記負に帯電したアミノ酸残基を含むペプチドとの間の静電相互作用を介して結合してIL-35とIL-6受容体の機能的なヘテロ二量体を形成する、
前記ヘテロ二量体タンパク質。 - 前記第1の電荷分極コアドメイン及び/又は前記第2の電荷分極コアドメインが、可動性アミノ酸配列、IgGヒンジ領域、又は抗体配列から選択されるポリペプチドリンカーを含む、請求項1に記載のヘテロ二量体タンパク質。
- 前記第1の電荷分極コアドメイン及び/又は前記第2の電荷分極コアドメインが、ポリエチレングリコール(PEG)分子を含む合成リンカーを含む、請求項1に記載のヘテロ二量体タンパク質。
- 前記ポリペプチドリンカーが、IgG1又はIgG4に由来する、ヒンジ-CH2-CH3 Fcドメインを含む、請求項2に記載のヘテロ二量体タンパク質。
- 前記正に帯電したアミノ酸残基を含むペプチドが、
YnXnYnXnYn(式中、Xはアルギニン、ヒスチジン、及びリシンから選択され、Yはセリン及びグリシンから選択される)(配列番号1)、
YYnXXnYYnXXnYYn(式中、Xはアルギニン、ヒスチジン、及びリシンから選択され、Yはセリン及びグリシンから選択される)(配列番号3)、及び
YnXnCYnXnYn(式中、Xはアルギニン、ヒスチジン、及びリシンから選択され、Yはセリン及びグリシンから選択される)(配列番号5)
から選択される配列を含む、請求項1に記載のヘテロ二量体タンパク質。 - 前記正に帯電したアミノ酸残基を含むペプチドが、配列RKGGKR(配列番号11)又はGSGSRKGGKRGS(配列番号12)を含む、請求項1に記載のヘテロ二量体タンパク質。
- 前記負に帯電したアミノ酸残基を含むペプチドが、
YnZnYnZnYn(式中、Zはアスパラギン酸及びグルタミン酸から選択され、Yはセリン及びグリシンから選択される)(配列番号2)、
YYnZZnYYnZZnYYn(式中、Zはアスパラギン酸及びグルタミン酸から選択され、Yはセリン及びグリシンから選択される)(配列番号4)、及び
YnZnCYnZnYn(式中、Zはアスパラギン酸及びグルタミン酸から選択され、Yはセリン及びグリシンから選択される)(配列番号6)
から選択される配列を含む、請求項1に記載のヘテロ二量体タンパク質。 - 前記負に帯電したアミノ酸残基を含むペプチドが、配列DEGGED(配列番号13)又はGSGSDEGGEDGS(配列番号14)を含む、請求項1に記載のヘテロ二量体タンパク質。
- 前記第1の電荷分極コアドメイン及び/又は前記第2の電荷分極コアドメインが、水素結合及び/又はファンデルワールス力の増大によってヘテロ二量体化を促進するための1又は複数のアミノ酸変化を含むヒンジ-CH2-CH3 Fcドメインを含む、請求項4に記載のヘテロ二量体タンパク質。
- 前記1又は複数のアミノ酸変化が、ノブ・イン・ホール(knob-in-hole)モチーフを作成する、請求項9に記載のヘテロ二量体タンパク質。
- 前記ノブ・イン・ホールモチーフは、前記第1の電荷分極コアドメインにおいて1又は複数のチロシン(Y)残基を1又は複数のスレオニン(T)残基で置換する1又は複数のアミノ酸変化によって形成される、及び/又は前記第2の電荷分極コアドメインにおいて1又は複数のスレオニン(T)残基を1又は複数のチロシン(Y)残基で置換する1又は複数のアミノ酸変化によって形成される、又は
前記ノブ・イン・ホールモチーフは、前記第2の電荷分極コアドメインにおいて1又は複数のチロシン(Y)残基を1又は複数のスレオニン(T)残基で置換する1又は複数のアミノ酸変化によって形成される、及び/又は前記第1の電荷分極コアドメインにおいて1又は複数のスレオニン(T)残基を1又は複数のチロシン(Y)残基で置換する1又は複数のアミノ酸変化によって形成される、
請求項10に記載のヘテロ二量体タンパク質。 - 前記電荷分極コアドメインの一方又は両方は、L234A、L235A(LALA)、及びP329Gから選択される1又は複数のエフェクター及び補体サイレンシング置換(effector and complement silencing substitution)を含むか、又は
前記電荷分極コアドメインの一方又は両方は、M252Y、S254T、及びT256Eから選択される1又は複数の半減期延長変異を含む、
請求項9に記載のヘテロ二量体タンパク質。 - 前記電荷分極コアドメインの一方又は両方は、L234A及びL235A(LALA)から選択される1又は複数のエフェクター及び補体サイレンシング置換を含む、
請求項12に記載のヘテロ二量体タンパク質。 - 前記ヘテロ二量体タンパク質が、(i)免疫阻害シグナルを低減又は排除すること、及び(ii)免疫刺激シグナルを増加又は活性化することの両方が可能である、請求項1に記載のヘテロ二量体タンパク質。
- 前記ヘテロ二量体タンパク質が、制御性T細胞に対するエフェクターT細胞の比率を増加させることができる、請求項1に記載のヘテロ二量体タンパク質。
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AU2019290192A1 (en) | 2021-01-07 |
CA3103975A1 (en) | 2019-12-26 |
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