JP7125249B2 - タンパク質及びペプチドの免疫原性を減少させる方法 - Google Patents
タンパク質及びペプチドの免疫原性を減少させる方法 Download PDFInfo
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- JP7125249B2 JP7125249B2 JP2016570961A JP2016570961A JP7125249B2 JP 7125249 B2 JP7125249 B2 JP 7125249B2 JP 2016570961 A JP2016570961 A JP 2016570961A JP 2016570961 A JP2016570961 A JP 2016570961A JP 7125249 B2 JP7125249 B2 JP 7125249B2
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- 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
Description
本発明の他の目的は、生理活性タンパク質またはペプチドの非末端内部残基に 非ペプチジルリンカーを介してキャリアが結合した生理活性タンパク質またはペプチド結合体を含む組成物を提供することにある。本発明の他の目的は、キャリアが生理活性タンパク質またはペプチドの非末端内部残基に結合した生理活性タンパク質またはペプチド結合体の製造方法を提供することにある。
(1)両末端にアルデヒド、マレイミド、またはスクシンイミド反応基を有する非ペプチジルポリマーを生理活性タンパク質またはペプチドのアミンまたはチオール基に共有結合させる工程;
(2)生理活性タンパク質またはペプチドのN-末端以外の位置を介して非ペプチジルポリマーに共有結合した生理活性タンパク質またはペプチドペプチドを前記(1)の反応混合物から分離する工程;及び
(3)生理活性タンパク質またはペプチドに共有結合した非ペプチジルポリマーの他の末端に免疫グロブリンFc領域を共有結合させて、非ペプチジルポリマーの両末端がそれぞれ免疫グロブリンFc領域および生理活性タンパク質またはペプチドと結合した工程を含む、生理活性タンパク質またはペプチド結合体を製造する方法を提供する。
(1)両末端にアルデヒド反応基を有する非ペプチジルポリマーを生理活性タンパク質またはペプチドのリジン残基に共有結合させる工程;
(2)生理活性タンパク質またはペプチドのりジン残基を介して非ペプチジルポリマーに共有結合した生理活性タンパク質またはペプチドペプチドを前記(1)の反応混合物から分離する工程;及び(3) 生理活性タンパク質またはペプチドに共有結合した非ペプチジルポリマーの他の末端に免疫グロブリンFc領域を共有結合させて、非ペプチジルポリマーの両末端がそれぞれ免疫グロブリンFc領域および生理活性タンパク質またはペプチドと結合した工程を含む、生理活性タンパク質またはペプチド結合体を製造する方法を提供する。より具体的には、(1)工程の非ペプチジルポリマー及び生理活性タンパク質またはペプチドであるインスリン分泌ペプチドのリジン残基は、pH 7.5以上で結合することができる。
3.4K PropionALD(2)PEG(プロピオンアルデヒド基を2個有している分子量3.4kDaのPEG、IDB Inc.、韓国)を天然型エキセンディン-4(米国のAmerican Peptides)のN-末端にペグ化させるため、3mg/ml濃度のペプチドとPEGとのモル比を1:15にして4℃で90分間反応させた。この時の反応は、100mM濃度のNaOAc緩衝液(pH4.0)内で行われ、還元剤である20mM SCB(NaCNBH3)を添加して反応された。
流速:2.0ml/分
勾配:A 0→40%80分B(A:20mMトリスpH8.5、B:A + 0.5M NaCl)
流速:2.0ml/分
勾配:A 0→100%50分B(A:20mMクエン酸pH3.0、B:A + 0.5M KCl)
3.4K PropionALD(2)PEGをCAエキセンディン-4(米国のAmerican Peptides)のリジン(Lys)残基にペグ化させるため、3mg/ml濃度のCAエキセンディン-4とPEGとのモル比を1:30にして、4℃で3時間反応させた。CAエキセンディン-4は、天然型エキセンディンのN-末端ヒスチジン残基でアルファ炭素が削除され、側鎖のβ-炭素が直接カルボキシル炭素に結合したN-末端変形エキセンディン-4である。この時の反応は、100mM濃度のNa-Phosphate緩衝液(pH9.0)内で行われ、還元剤である20mM SCBを添加して反応させた。前記反応液は、SOURCE Q(XK 16ml、アマシャムバイオサイエンス)を通じて一次的にモノ-ペグ化された(Mono-pegylated)ペプチドを精製し、SOURCES(XK 16ml、アマシャムバイオサイエンス)を通じて異性体を分離した。
流速:2.0ml/分
勾配:A 0→40%80分B(A:20mMトリスpH8.5、B:A + 0.5M NaCl)
流速:2.0ml/分
勾配:A 0→100%50分B(A:20mMクエン酸pH3.0、B:A + 0.5M KCl)
イミダゾ-アセチルエキセンディン-4(CAエキセンディン-4、AP、米国)を用いて実施例2と同様の方法で3.4K PropionALD(2)PEGをCAエキセンディン-4のLysと反応させた。その後、二つのLys異性体ピークのうち、主な反応性が示され、かつ、N-末端異性体と明確に区分されている最も後方の異性体ピーク(Lys27位置異性体)を用いてカップリング反応を行った。前記ペプチドと前記免疫グロブリンFcのモル比を1:8、全体タンパク質濃度を60mg/mlとし、4℃で20時間反応させた。反応は100mM K-P(pH6.0)及び還元剤である20mM SCBを添加した溶液で行った。前記カップリング反応の後、SOURCE Q 16ml及びSOURCE ISO 16mlを用いた2工程の精製は実施例2と同様で行った。HPLC逆相分析の結果、純度95.8%を示した。
ヒト末梢血単核細胞(peripheral blood mononuclear cells、PBMC)は、健康なドナーから採取した血液から24時間以内に分離した。供与血液はUK National Blood Transfusion Service(Addenbrooke◎Hospital、Cambridge、UK)から提供された。末梢血単核細胞は、 LymphoprepTM(Axis-shield、Dundee、Scotland)を用いた密度勾配遠心分離法により得られた白血球層(buffy coat)から分離した。このうち、CD8+T細胞は、CD8+RosetteSepTM(StemCell Technologies Inc、London、UK)を用いて除去された。各ドナーの末梢血単核細胞は、使用前まで液体窒素中に保管した。ドナーの細胞は、HLA SSP-PCR based tissue-typing kit(Biotest、Solihull、UK)を用いてHLA-DR半数体遺伝子型(haplotype)を鑑別した。T細胞の反応性は、インフルエンザA及びエプスタイン・バール・ウイルス(Epstein Barr virus)由来の抗原ペプチドであるKLH(Keyhole Limpet Haemocyanin、Pierce(Perbio)、Northumberland、UK)を用いて試験した。世界人口のHLA-DRタイプの頻度を代表する50人のドナーを選別して1つのコホート(cohort)で構成した。コホートを構成する各ドナーのMHC class II半数体遺伝子型とT細胞の反応性を表1に示し、ドナーの遺伝子型の頻度を世界の人口の頻度との比較結果を図1に示した。下記表1は、ドナー別のHLA-DR遺伝子型及び抗原ペプチドKLHに対するT細胞の反応性を示したものである。
代表的な生理活性タンパク質またはペプチドであるインスリン分泌ペプチドのペグ化位置に応じた免疫原性抑制メカニズムを確認するために、非結合天然型エキセンディン-4、非結合CAエキセンディン-4、CAエキセンディン-4のリジン残基にペグ化された連結体ペプチド(CAエキセンディン-4-PEG(inter))及び天然型エキセンディン-4のN-末端にペグ化された連結体ペプチド(エキセンディン-4-PEG(N-term))のT細胞増殖能を比較した。この時、CAエキセンディン-4はペグ化することができるN-末端残基を有していないため、CAエキセンディン-4に対してはN-末端ペグ化連結体を製造していなかった。
代表的な生理活性タンパク質またはペプチドであるインスリン分泌ペプチドのペグ化位置に応じた免疫原性抑制メカニズムを確認するために、EpiScreenTM T細胞の増殖アッセイでの同じ試料及びドナー細胞を用いて、実施例5のペグ化されたエキセンディン-4及び非結合エキセンディン-4に対してインターロイキン-2分泌能を比較測定した。抗インターロイキン-2抗体(R&D Systems、Abingdon、UK)はELISpotプレート(Millipore、Herts、UK)に結合させた。前記プレートをPBS(phosphate-buffered saline)で3回洗浄した後、1%の牛血清アルブミンが補充されたPBSを添加して反応させた。AIM-V培養培地で洗浄した後、AIM-V培養培地で希釈(4-6x106細胞/ml)したドナー細胞を100μl/ウェルずつ分注した。最終濃度が50μg/mlになるように試験試料を50μlずつ添加した(n=6)。8日間培養した後、ELISpotプレートにビオチン標識されたインターロイキン-2検出抗体とストレプトアビジン-AP(R&D Systems、Abingdon、UK)を順次的に結合させた後、スポットを表現するためにBCIP/NBT((R&D Systems、Abingdon、UK)をプレートに添加した。蒸留水で洗浄して前記反応を終了させた後、プレートを乾燥させた。Immunoscan Analyserを使用し、ウェル当り生成されたスポット(spw、spots per well)をスキャンして分析した。前記エクス・ビボ(ex vivo)T細胞活性度の測定試験の結果は、刺激指標(SI、stimulation index)の実験的閾値に基づいて、2以上(SI≧2、p<0.05)の場合を陽性(E)と判定した。SI≧1.9に該当する境界値を含む場合には、別途表示(E*)した。その結果、CAエキセンディン-4及びエキセンディン-4に対してそれぞれ12%及び16%のドナーからの陽性反応が確認された。しかし、ペプチド内部残基にペグ化されたCAエキセンディン-4は、ドナーから2%のみであった。一方、N-末端にペグ化されたエキセンディン-4は、6%のドナーで陽性を示した。即ち、N-末端よりペプチドの内部リジン残基にペグ化された場合、前記ペプチドの免疫原性は顕著に阻害された(表2~4)。表4は、T細胞のインターロイキン-2の分泌反応の強度及び頻度(SI≧1.9境界値を含む)を示す。
実施例3で製造したCAエキセンディン-4をPEGを介して免疫グロブリンFc断片に連結させた結合体を、正常のSprague Dawleyラットに週1回、26週間皮下投与し、その後、4週間を回復期間にした(n=40~60/群)。投与前と、投与中の13、19、26週目、回復期間終了時点でそれぞれ採血して血清を分離し、そこからインスリン分泌ペプチドに対する抗体の生成有無を測定した。
実施例3で製造したPEGを介してCAエキセンディン-4を免疫グロブリンFc断片に結合させた結合体を、カニクイザル(Cynomolgus monkey)に週1回、26週間皮下投与し、その後4週間回復期間にした(n=8~12/群)。投与前と、投与中の12、19、26週目及び回復期間終了時点でそれぞれ採血して血清を分離し、そこからインスリン分泌ペプチドに対する抗体の生成有無を測定した。その結果、すべての個体で抗体の生成は観察されなかった(表6)。表6は、カニクイザル(Cynomolgus monkey)における26週間投与による抗体の生成を示す。
実施例3の結合体がラットまたはカニクイザルの体内で抗薬物抗体(anti-drug antibody、ADA)を生成したかを検出するために、bridging ELISA法で調査した。ストレプトアビジン(streptavidin)が底部に結合された96ウェルマイクロプレートにビオチン化した実施例3の結合体を結合させた後、水で洗浄した。ジゴキシゲニン(digoxigenin、dig)-標識された実施例3の結合体(以下、HM11260C)をラットまたはサルの血清試料と共に添加して反応させた後、水で洗浄した。その後、ホースラディッシュペルオキシダーゼが結合された抗dig抗体(anti-DIG-POD antibody)を添加してTMB基質(3,3'、5,5'-Tetramethylbenzidine substrate)により発色した。ラット血清における測定感度は、3.1ng/ml、サル血清における測定感度は12.5ng/mlであった。検出された抗HM11260C抗体のHM11260Cに対する中和能を評価するために、ヒトGLP-1受容体を過発現させた細胞株(GLP-1R/CHO)に血清試料とHM11260Cを共に添加し、cAMP誘導能に対する抑制率を測定した。抗体は160匹のうちただ二匹で生成され、中和能がないことが確認した。
Claims (7)
- 生理活性タンパク質またはペプチドの非末端内部残基に免疫グロブリンFc領域を結合させる工程を含み、
前記生理活性タンパク質またはペプチド及び免疫グロブリンFc領域は、その間に介在する非ペプチド性リンカーを通じて結合され、
生理活性タンパク質またはペプチドと非ペプチド性リンカーとがpH7.5-9.0の条件下で結合され、
前記生理活性タンパク質またはペプチドがエキセンディン-4またはエキセンディン-4の誘導体である、
免疫グロブリンFc領域が生理活性タンパク質またはペプチドの末端残基に結合された生理活性タンパク質またはペプチドに比べて生理活性タンパク質またはペプチドの抗体産生反応を抑制する、方法。 - 前記非ペプチド性リンカーは、ポリエチレングリコール、ポリプロピレングリコール、エチレングリコール-プロピレングリコールコポリマー、ポリオキシエチル化ポリオール、ポリビニルアルコール、多糖類、デキストラン、ポリビニルエチルエーテル、生分解性ポリマー、脂質ポリマー、キチン、ヒアルロン酸及びこれらの組み合わせからなる群から選択される、請求項1に記載の方法。
- 前記生理活性タンパク質またはペプチドが、免疫グロブリンFc領域と、ポリエチレングリコール、ポリプロピレングリコール、エチレングリコール-プロピレングリコールコポリマー、ポリオキシエチル化ポリオール、ポリビニルアルコール、多糖類、デキストラン、ポリビニルエチルエーテル、生分解性ポリマー、脂質ポリマー、キチン、ヒアルロン酸及びこれらの組み合わせからなる群から選択される非ペプチド性リンカーを通じて連結される、請求項1に記載の方法。
- 前記エキセンディン-4の誘導体は、エキセンディン-4のN-末端アミン基が除去された、エキセンディン-4誘導体;エキセンディン-4のN-末端アミン基がヒドロキシル基で置換されたエキセンディン-4誘導体;エキセンディン-4のN-末端アミン基がカルボキシル基で置換された、エキセンディン-4誘導体;エキセンディン-4のN-末端アミン基がジメチル基で修飾された、エキセンディン-4誘導体;エキセンディン-4のN-末端ヒスチジン残基のアルファ炭素が除去された、エキセンディン-4誘導体からなる群から選択される、エキセンディン-4のN-末端電荷が修飾されたエキセンディン-4誘導体である、請求項1に記載の方法。
- 前記内部残基は、エキセンディン-4のN-末端電荷が修飾されたエキセンディン-4誘導体の12番目または27番目のリジン残基である、請求項4に記載の方法。
- 前記内部残基は、エキセンディン-4のN-末端電荷が修飾されたエキセンディン-4誘導体の27番目のリジン残基である、請求項5に記載の方法。
- 前記エキセンディン-4のN-末端電荷が修飾されたエキセンディン-4誘導体は、エキセンディン-4のN-末端ヒスチジン残基のアルファ炭素が除去された、エキセンディン-4誘導体である、請求項5に記載の方法。
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SG10202107752PA (en) * | 2014-03-31 | 2021-09-29 | Hanmi Pharmaceutical Co Ltd | Method for improving solubility of protein and peptide by using immunoglobulin fc fragment linkage |
KR20150140177A (ko) * | 2014-06-05 | 2015-12-15 | 한미약품 주식회사 | 단백질 및 펩타이드의 면역원성을 감소시키는 방법 |
JP2019532019A (ja) * | 2016-07-22 | 2019-11-07 | ネクター セラピューティクス | オキシム含有リンケージを有する第viii因子部分のコンジュゲート |
WO2018105988A1 (ko) * | 2016-12-05 | 2018-06-14 | 한미약품 주식회사 | 면역반응이 약화된 결합체 |
BR112019016077A2 (pt) * | 2017-02-03 | 2020-03-31 | Hanmi Pharm. Co., Ltd. | Conjugado da fórmula 1, método para preparar o conjugado, preparação de atuação longa, preparação para prevenir ou tratar diabetes e método para tratar diabetes |
WO2019036631A1 (en) * | 2017-08-18 | 2019-02-21 | The Johns Hopkins University | SUPRAMOLECULAR FILAMENT ASSEMBLIES FOR THE PURIFICATION OF PROTEINS |
MX2020002070A (es) | 2017-08-22 | 2020-03-24 | Sanabio Llc | Receptores solubles de interferon y usos de los mismos. |
CN111406073A (zh) * | 2017-09-29 | 2020-07-10 | 韩美药品株式会社 | 具有提高功效的持久性蛋白质缀合物 |
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JP2017521381A (ja) | 2017-08-03 |
EP3152236A1 (en) | 2017-04-12 |
PH12016502430A1 (en) | 2017-03-06 |
US20170100488A1 (en) | 2017-04-13 |
UA124183C2 (uk) | 2021-08-04 |
MX2021006021A (es) | 2021-07-06 |
CN106661118A (zh) | 2017-05-10 |
MX2016015668A (es) | 2017-02-27 |
WO2015186988A1 (en) | 2015-12-10 |
BR112016028227A2 (pt) | 2017-10-24 |
IL249131A0 (en) | 2017-01-31 |
KR20150140177A (ko) | 2015-12-15 |
SG11201610098YA (en) | 2016-12-29 |
AU2015269039B2 (en) | 2020-12-10 |
AU2015269039A1 (en) | 2016-12-08 |
EP4219565A1 (en) | 2023-08-02 |
US20220118103A1 (en) | 2022-04-21 |
CA2950576A1 (en) | 2015-12-10 |
MY193519A (en) | 2022-10-17 |
EA035964B1 (ru) | 2020-09-07 |
JP2021028329A (ja) | 2021-02-25 |
SG10202104313PA (en) | 2021-06-29 |
AR100768A1 (es) | 2016-11-02 |
KR20210111190A (ko) | 2021-09-10 |
KR20230023691A (ko) | 2023-02-17 |
EA201692279A1 (ru) | 2017-05-31 |
HUP1700024A2 (en) | 2017-05-29 |
EP3152236A4 (en) | 2018-07-04 |
NO20161980A1 (en) | 2016-12-14 |
TW201625314A (zh) | 2016-07-16 |
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