JP2021517169A - 関節炎の持続性関節内治療用多価ペプチドコンジュゲート - Google Patents
関節炎の持続性関節内治療用多価ペプチドコンジュゲート Download PDFInfo
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Abstract
Description
本願は、あらゆる目的についてその全体が本明細書に組み込まれる、2018年3月9日に出願された米国仮出願第62/640,749号の優先権を主張する。
配列表に関する記載
本発明は、高分子ポリマーと複数のペプチドとのコンジュゲートを提供し、これは、非コンジュゲートペプチドよりも高い効力と、増大した半減期とを有するため、コンジュゲートが特に関節内疾患及び障害を治療するのが可能になる。
特に別段の指定がない限り、本明細書中で使用されるすべての科学技術用語は、本発明が属する分野の当業者によって通常理解されるのと同じ意味を有する。加えて、本明細書中で記載する方法及び材料と類似又は同等の任意の方法又は材料を本発明の実施で使用することができる。本発明の目的のために、以下の用語を定義する。
本発明は、高分子ポリマーと複数のペプチドとのコンジュゲートを提供し、これは、非コンジュゲート化ペプチドの同様の濃度よりも高い効力を有する。いくつかの実施形態では、本発明は、約0.1MDa〜約3MDaの分子量を有する生体適合性ポリマーと、複数のペプチドとのコンジュゲートを提供し、ペプチドは、約5kDa〜約150kDaの分子量を有し;各ペプチドはポリマーと共有結合し、コンジュゲートにおけるペプチドのポリマーに対するモル比は少なくとも約5:1である。
本発明のコンジュゲートにおいて有用なポリマーには、任意の好適な生体適合性ポリマーが含まれる。生体適合性ポリマーは、親水性ポリマーであって、概して免疫応答を引き起こさないものである。好適な生体適合性ポリマーには、限定されるものではないが、ポリサッカリド、グリコサミノグリカン、ヒアルロン酸及びその誘導体,セルロース、カルボキシメチルセルロース及びその誘導体、ヘパリン及びその誘導体、ダーマチン、デンプン及び加工デンプン、コンドロイチン、キトサン、カルボキシメチルキトサンなどが挙げられる。生体適合性ポリマーはまた、ポリ塩化ビニル、ポリテトラフルオロエチレン、ポリエーテルスルホン、ポリエチレン、ポリエーテルエーテルケトン、ポリスルホン、ポリプロピレン、ポリ(エチレングリコール)、ポリ(プロピレングリコール)、ポリウレタン、エチレン酢酸ビニルコポリマー、コラーゲン、ポリイソブチレン、エチレンビニルアルコールコポリマー、ポリエチレンポリカーボネート、ポリカプロラクトン、ポリラクチド、ポリグリコリド、カーボマー、ポリエステル、ポリエーテル、ポリ無水物、ポリアクリレート、ポリ酢酸ビニル、ポリビニルピロリドン、ポリサッカリド(例えば、ヒアルロン酸、ヒドロキシアルキルセルロース、カルボキシアルキルセルロース、又はその誘導体)、ポリエーテル、その誘導体及びそれらの組み合わせが含まれ得る。生体適合性ポリマーは、例えば硫酸化、スルホン化、重水素化などの方法によってさらに修飾することができる。
本発明において好適なペプチドは、少なくとも約2kDaの分子量を有するものであり、三次構造を示す。代表的なペプチドとしては、限定されるものではないが、ポリペプチド、一つ以上のアプタマー、ヒトAドメインスカフォールドに基づくアビマー(avimer)スカフォールド、ダイアボディ、ラクダ科、サメIgNAR抗体、特異性が修飾されたフィブロネクチンIII型スカフォールド、抗体、抗体フラグメント、タンパク質、ペプチド、ポリペプチドが挙げられる。
本発明のコンジュゲートは、式I:
(X−Y)n−Z (I)
の化合物として記述することができ、式中、Xは上述したペプチドであり、Zは上述の生体適合性ポリマーであり、Yは任意のリンカーであり、下付き文字nは5〜500である。
いくつかの実施形態では、本発明は、本発明のコンジュゲートと薬剤的に許容される賦形剤とを含む医薬組成物を提供する。
本発明のコンジュゲートから医薬組成物を調製するために、薬剤的に許容される担体は固体又は液体のいずれかであり得る。固体形態製剤としては、散剤、カシェー、及び分散性顆粒が挙げられる。固体担体は、希釈剤、バインダー、防腐剤、崩壊剤、又は封入材料としても作用し得る一つ以上の物質であり得る。処方及び投与の技術に関する詳細は、科学及び特許文献で充分に記載されており、例えばRemington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA ("Remington's")の最新版を参照のこと。
本発明のコンジュゲート及び組成物は、経口、非経口及び局所的方法をはじめとする任意の好適な手段で送達することができる。いくつかの実施形態では、送達方法は関節内である。
本発明は、本発明のペプチド−ポリマーコンジュゲートを使用して関節結合部における疾患又は障害を治療する方法を提供する。いくつかの実施形態では、本発明は、関節結合部における疾患又は障害を治療する方法であって、関節結合部に、約0.1MDa〜約3MDaの分子量を有する生体適合性ポリマーと、複数のペプチドとを含む、有効量のコンジュゲートを注射することを含む方法を提供し、ペプチドは、約5kDa〜約150kDaの分子量を有し;各ペプチドはポリマーと共有結合し、コンジュゲートにおけるペプチドのポリマーに対するモル比は少なくとも約5:1である。いくつかの実施形態では、本発明は、関節結合部における疾患又は障害を治療する方法であって、関節結合部に、約0.1MDa〜約2MDaの分子量を有する生体適合性ポリマーと、複数のペプチドとを含む有効量のコンジュゲートを注射することを含む方法を提供し、ペプチドは約5kDa〜約100kDaの分子量を有し;各ペプチドはポリマーと共有結合し、ポリマーの分子量はペプチドあたり約5kDa〜約50kDaであり、コンジュゲートにおけるペプチドのポリマーに対するモル比は少なくとも約5:1である。
2015年に、推定775万人の米国人が公知関節損傷に関連し得る変形性関節症(OA)の症状を経験した。外傷後OA(PTOA)は全てのOA例の少なくとも15%を占めるが、多くの他のOA診断はまた、事前の関節外傷に関連する可能性があると推測される。疾患修飾性療法がないために、関節置換手術は、多くの場合、伴う不快感を取り除き可動性を回復するための治療法の選択肢に過ぎない。しかしながら、PTOAは、若年の患者で診断されることが多く、かかる患者への関節置換は実効可能な選択肢ではない。全体として、これらのPTOA患者の治療コストは、毎年40億ドルを越える。
関節の関節表面間で生じる摩耗は、ミクロン規模の粒子を生じる可能性があり、これは関節炎及び骨溶解を推進する。摩耗粒子は、骨化軟骨損傷、骨増殖体(骨棘)、又は露出軟骨下骨損傷などの内因性表面間の摩滅のために生じる可能性がある。このタイプの摩耗粒子生成は、OAの後期で頻繁に起こり、結果として重度の関節の痛み及び不動性が起こる。このさらなる炎症応答はOAにおける関節組織変性の速度を加速する。
DHSGYTYTIG(配列番号3)、
ARIYWSSGNTYYADSVKG(配列番号4)、及び
RDGIPT(配列番号5)。
QVQLQESGGGLVQPGGSLRLSCAASGRTFSDHSGYTYTIGWFRQAPGKEREFVARIYWSSGNTYYADSVKGRFAISRDIAKNTVDLTMNNLEPEDTAVYYCAARDGIPTSRSVESYNYWGQGTQVTVSS(配列番号1)。
SNAQVQLQESGGGLVQPGGSLRLSCAASGRTFSDHSGYTYTIGWFRQAPGKEREFVARIYWSSGNTYYADSVKGRFAISRDIAKNTVDLTMNNLEPEDTAVYYCAARDGIPTSRSVESYNYWGQGTQVTVSSSPSTPPTPSPSTPPGGC(配列番号2)。
実施例1 コンジュゲートの調製
一般法。抗炎症バイオコンジュゲートを以前に記載された方法に従って調製した(PMID:28679037)。ここでは製造業者によって特定されるそれらの重量平均MWに基づいて言及される、150kDa〜2.0MDaのMWの範囲にわたるポリマーを得た。pHを5.5〜8.5の範囲に維持するために適切な0.1〜1Mの緩衝液、例えばMES、リン酸塩緩衝液、His緩衝液、MOPS、グルクロン酸、シトレート、アセテートHEPESを含む水溶液を使用した溶液にポリマーを入れた。
様々な方法を使用して、炎症性関節疾患又は障害に罹っている個人の開示された治療方法に適した組成物を評価した。コンジュゲーション反応におけるペプチド内容物の濃度は、タンパク質濃度についての標準的方法、例えば、BCA、Bradford、及び/又はA280でのUV吸収を使用して測定した。コンジュゲーション反応におけるポリマー内容物の濃度は、A204でのUV吸収を用いて測定した。ポリマー内容物の濃度はまた、硫酸で消化し、続いてフェノールとともにインキュベーションすることによって測定して、比色分析によって分析することができ、また標準曲線に対して比較することができる生成物を誘導することもできる。ペプチド及びポリマーの濃度はまた、酵素又は酸消化のいずれかによってポリマー成分の完全解重合後の質量分析によって分析することもできる。濃度測定から決定される、ポリマーのペプチドに対するモル比を使用して、各コンジュゲートの価数を推定した。
一つ以上の以下の方法を使用して、タンパク質−ポリマーコンジュゲートの生物活性を測定した。一例として、BLI; ForteBio Octet Red)を使用して、各ペプチド及びペプチド−ポリマーコンジュゲートのそれらの標的に対する結合アフィニティを測定した。このアッセイのために、ペプチド標的をガラスBLIプローブ上に吸着させる。ビオチンとコンジュゲート化又はビオチンを含有する融合ペプチドとして発現された最も一般的な標的を使用して、それらを、共有結合したストレプトアビジン表面層で前処理されたBLIプローブに吸着させる。標的で吸着されたプローブを次に既知濃度のペプチド又はペプチド−ポリマーコンジュゲートのいずれかの溶液中に入れる。レーザー光を次にBLIプローブの長さを下降させ、プローブ先端でその標的と結合するペプチド又はコンジュゲートによって生じるレーザー光干渉を、結合したペプチド又はコンジュゲートの質量と直接関連づけることができる。長時間にわたる干渉データを使用して、k−オン結合キネティクスを算出することができる。次にペプチド又はコンジュゲートのいずれも含まない溶液中にプローブを入れることによって、レーザー光干渉は逆転し、そのキネティクスを使用して、k−オフを決定することができる。したがって、このBLI法は、各ペプチド及びコンジュゲートのその標的に対する結合アフィニティ(kD)を測定することができる。
多価コンジュゲートはより低速の有窓膜を越える拡散速度を示す。滑液は、グリコサミノグリカン分子の膜により関節腔内に保持される高分子量巨大分子を含む。この膜は、小分子及びタンパク質の関節腔からの脱出を可能にする有窓を含むが、巨大分子を保持する。
周知のラットモデルを、関節からのタンパク質のクリアランス率を評価するために使用して、mvAntiTNFのIA半減期を測定した(Arthritis Rheum. 1999;42(10):2094)。このアッセイのために、ラットを麻酔し、それらの後肢の膝を滅菌注射のために準備した。30G針を使用して、各膝関節の滑膜を通して注射し、滑液に40μLの滅菌緩衝液を注射した。各々の右膝で、注射はまた、抗炎症ペプチド、又は抗炎症ペプチドのいずれかを総ペプチドの等濃度で含んでいた。概して、この実験に使用したペプチドを、近赤外線フルオロフォア(例えば、Alexa Fluor 750)で、所定のペプチドタグ付け法を用いてタグ付けした。注射後10日までの様々な時点で、ラットを、インビボイメージングシステム(例えば、Perkin Elmer IVIS Spectrum)を使用して撮像して、膝での蛍光シグナル(例えば、平均放射効率)の強度を測定した。各々の左膝を対側イメージング対照として使用した。近赤外線レポータは、関節中のタンパク質のピコグラム量までの検出を可能にするインビボイメージングシステムを使用して高感度でラット膝において検出することができる。各治療の半減期をIA注射後に、光学インビボイメージングの確立された指数関数的減衰計算を使用して決定した(Pharmaceutical research. 2013;30(1):257)。したがって、ペプチド濃度を使用して、投与後の関節内の各ペプチド又はコンジュゲートの関節内半減期を推定した。滑液を、質量分析によるプロテオーム解析の実験の最後に集めて、膝関節におけるペプチドの最終濃度を測定することができる。投与前に、ペプチドを、Alexa Fluor 750近赤外線プローブ(ThermoFisher)で、製造業者のプロトコルに従ってタグ付けした。簡単に言うと、ペプチドを、スルホ−Cy7−NHSエステルと2:1のプローブ:ペプチド比で混合した。プローブをペプチドと1時間、室温にて反応させ、次いで1部の1.5MのTrisを各々10部の反応溶液に添加することによってクエンチした。ペプチドを、NAP−10脱塩カラムを使用し、PBS、pH7.0で溶出して、精製した。
有効治療用量を維持するために必要な抗炎症ペプチドの必要な再投薬頻度を予想するためのモデルを開発した。モデルは、異なる局所組織半減期の観点から一連の標的結合アフィニティにわたって必要な抗VEGF薬を予想するために本来開発されたモデルに基づく。このモデルにおいて立てられた重要な仮説は、単相指数関数的減衰後の標的組織から排出させるということであり、これは、関節内投与後の本発明の抗炎症ポリマー−ペプチドコンジュゲートについて証明されている(実施例3を参照)。再投薬頻度は、抗炎症ペプチドについて、臨床研究の結果(PMID:20642840、17216015、18415775)を用いて、ヒト関節において有効な応答を提供するように確立された(1〜2週ごとに注射)。
本開示の方法での治療に適した対象には、炎症性関節疾患又は障害、例えば、前記の関節疾患又は障害のいずれかに罹っていると診断された個人が含まれる。
変形性関節症により誘導された軟骨異化を防止するための本開示の方法に基づく治療の有効性は、以前に記載された非臨床アッセイを用いて評価することができる。この研究で、軟骨異化バイオマーカー、軟骨オリゴマーマトリックスタンパク質(COMP)及びII型コラーゲンのC−テロペプチド(CTX−II)の正確な長期的測定を可能にするためには、成体(>5月齢)のラットが必要である。麻酔下で、ラットを、二つのローディングプラテンからなる脛骨圧縮システムにロードする:ボトムプラテンは曲がった膝を保持し、トッププラテンは足首を30°曲げて足を保持する。軸力試験機(Bose ElectroForce 3200)は1mm/sの割合で単一の12−N圧縮荷重を加える。このローディング法は、大腿遠位に対して脛骨の一時的前部亜脱臼によりマウスにおいて一貫性のある圧縮損傷を生じさせるために充分であった。25ラットを次に体重によりランダム化された山群に分割し、各群に以下の治療のうちの一つを施す:抗炎症バイオコンジュゲート、非コンジュゲート抗炎症ペプチド、又はビヒクル生理食塩水。
配列
配列番号1(抗TNFaシングルドメイン重鎖(VHH)抗体)
QVQLQESGGGLVQPGGSLRLSCAASGRTFSDHSGYTYTIGWFRQAPGKER
EFVARIYWSSGNTYYADSVKGRFAISRDIAKNTVDLTMNNLEPEDTAVYY
CAARDGIPTSRSVESYNYWGQGTQVTVSS
配列番号2(抗TNFaシングルドメイン重鎖(VHH)抗体)
SNAQVQLQESGGGLVQPGGSLRLSCAASGRTFSDHSGYTYTIGWFRQAPGKER
EFVARIYWSSGNTYYADSVKGRFAISRDIAKNTVDLTMNNLEPEDTAVYY
CAARDGIPTSRSVESYNYWGQGTQVTVSSSPSTPPTPSPSTPPGGC
配列番号3
DHSGYTYTIG,
配列番号4
ARIYWSSGNTYYADSVKG
配列番号5
RDGIPT
配列番号6(抗TNFaアフィボディ)
SNACGGGVDN KFNKEVGWAF GEIGALPNLN ALQFRAFIIS LWDDPSQSAN 50
LLAEAKKLND AQAPK 65
配列番号7(抗TNFaシングルドメイン重鎖(VHH)抗体)
SNAQVQLQES GGGLVQPGGS LRLSCAASGR TFSDHSGYTY TIGWFRQAPG 50
KEREFVARIY WSSGNTYYAD SVKGRFAISR DIAKNTVDLT MNNLEPEDTA 100
VYYCAARDGI PTSRSVESYN YWGQGTQVTV SSSPSTPPTP SPSTPPGGCD 150
DDDKHHHHHH DYKDDDDK 168
配列番号8(抗TNFa設計アンキリンリピートタンパク質(DARPin))
SNADLGKKLL EVARAGQDDE VRILMANGAD VNAADHQSFT PLHLYAIFGH 50
LEIVEVLLKN GADVNASDWH GNTPLHLAAW IGHLEIVEVL LKYGADVNAT 100
DHSGSTPLHL AATLGHLEIV EVLLKYGADV NAQDKFGKTA FDISIDNGNE 150
DLAEILQKAA GGGSGGGSC 169
配列番号9 (抗IL−1B単鎖(scFv)抗体)
SNAEIVMTQS PSTLSASVGD RVIITCQASQ SIDNWLSWYQ QKPGKAPKLL 50
IYRASTLASG VPSRFSGSGS GAEFTLTISS LQPDDFATYY CQNTGGGVSI 100
AFGQGTKLTV LGGGGGSGGG GSGGGGSGGG GSEVQLVESG GGLVQPGGSL 150
RLSCTASGFS LSSAAMAWVR QAPGKGLEWV GIIYDSASTY YASWAKGRFT 200
ISRDTSKNTV YLQMNSLRAE DTAVYYCARE RAIFSGDFVL WGQGTLVTVS 250
SSPSTPPTPS PSTPPGGC 268
配列番号10(可溶性インターロイキン受容体2(sILR2))
HTGAARSCRF RGRHYKREFR LEGEPVALRC PQVPYWLWAS VSPRINLTWH 50
KNDSARTVPG EEETRMWAQD GALWLLPALQ EDSGTYVCTT RNASYCDKMS 100
IELRVFENTD AFLPFISYPQ ILTLSTSGVL VCPDLSEFTR DKTDVKIQWY 150
KDSLLLDKDN EKFLSVRGTT HLLVHDVALE DAGYYRCVLT FAHEGQQYNI 200
TRSIELRIKK KKEETIPVII SPLKTISASL GSRLTIPCKV FLGTGTPLTT 250
MLWWTANDTH IESAYPGGRV TEGPRQEYSE NNENYIEVPL IFDPVTREDL 300
HMDFKCVVHN TLSFQTLRTT VKESPSTPPT PSPSTPPGGC 340
配列番号11 抗(マウス)TNFaシングルドメイン重鎖(VHH)抗体
SNAQVQLQDS GGGLVQAGGS LRLSCAASGG TFSSIIMAWF RQAPGKEREF 50
VGAVSWSGGT TVYADSVLGR FEISRDSARK SVYLQMNSLK PEDTAVYYCA 100
ARPYQKYNWA SASYNVWGQG TQVTVSSSPS TPPTPSPSTP PGGCDDDDKH 150
HHHHH 155
Claims (57)
- 関節結合部における疾患又は障害を治療する方法であって、前記関節結合部に、約0.1MDa〜約3MDaの分子量を有する生体適合性ポリマーと複数のペプチドとを含む、有効量のコンジュゲートを注射することを含み、前記ペプチドが約5kDa〜約150kDaの分子量を有し;
各ペプチドが前記ポリマーと共有結合し、
前記コンジュゲートにおける前記ペプチドの前記ポリマーに対するモル比が少なくとも約5:1である、方法。 - 前記生体適合性ポリマーが約0.1MDa〜約2MDaの分子量;及び複数のペプチドを有し、前記ペプチドが約5kDa〜約100kDaの分子量を有し;
各ペプチドが前記ポリマーと共有結合し;
前記ポリマーの前記分子量がペプチドあたり約5kDa〜約50kDaであり、
前記コンジュゲートにおける前記ペプチドの前記ポリマーに対する前記モル比が少なくとも約5:1である、請求項1に記載の方法。 - 前記生体適合性ポリマーがポリサッカリドである、請求項1に記載の方法。
- 前記生体適合性ポリマーがグリコサミノグリカンである、請求項1〜3のいずれか一項に記載の方法。
- 前記生体適合性ポリマーがヒアルロン酸である、請求項1〜4のいずれか一項に記載の方法。
- 前記生体適合性ポリマーが約0.2MDa〜約1.5MDaの分子量を有する、請求項1〜5のいずれか一項に記載の方法。
- 前記生体適合性ポリマーが約0.9MDaの分子量を有する、請求項1〜6のいずれか一項に記載の方法。
- 前記生体適合性ポリマーが約0.8MDa〜約3MDaの分子量を有する、請求項1〜5のいずれか一項に記載の方法。
- 前記生体適合性ポリマーが約2MDaの分子量を有する、請求項1〜5のいずれか一項に記載の方法。
- 前記ペプチドが免疫細胞機能の活性を調整する、請求項1〜7のいずれか一項に記載の方法。
- 前記ペプチドが、腫瘍壊死因子α、インターロイキン1β、インターロイキン6、又はインターフェロンγを阻害する、請求項1〜10のいずれか一項に記載の方法。
- 前記ペプチドが腫瘍壊死因子αを阻害する、請求項1〜11のいずれか一項に記載の方法。
- 前記ペプチドが、モノクローナルIgG抗体、IgG抗体フラグメント、単鎖可変領域抗体、シングルドメイン重鎖抗体、アドネクチン、アフィボディ、アンチカリン、DARPin、Kunitz型阻害剤、又は受容体デコイである、請求項1〜12のいずれか一項に記載の方法。
- 前記ペプチドが約5kDa〜約30kDaの分子量を有する、請求項1〜13のいずれか一項に記載の方法。
- 前記ペプチドが約10kDa〜約20kDaの分子量を有する、請求項1〜14のいずれか一項に記載の方法。
- 前記ペプチドが、配列番号1、配列番号2、配列番号6、配列番号7、配列番号8、配列番号9、配列番号10及び配列番号11からなる群から選択されるアミノ酸配列を有する、請求項1〜15のいずれか一項に記載の方法。
- 前記ペプチドが配列番号1のアミノ酸配列を有する、請求項1〜16のいずれか一項に記載の方法:
QVQLQESGGGLVQPGGSLRLSCAASGRTFSDHSGYTYTIGWFRQAPGKEREFVARIYWSSGNTYYADSVKGRFAISRDIAKNTVDLTMNNLEPEDTAVYYCAARDGIPTSRSVESYNYWGQGTQVTVSS(配列番号1)。 - 前記ペプチドの前記ポリマーに対する前記モル比が約5:1〜約400:1である、請求項1〜17のいずれか一項に記載の方法。
- 前記ペプチドの前記ポリマーに対する前記モル比が約10:1〜約100:1である、請求項1〜18のいずれか一項に記載の方法。
- 前記ペプチドの前記ポリマーに対する前記モル比が約30:1〜約50:1である、請求項1〜19のいずれか一項に記載の方法。
- 前記ペプチドが、スルフィド結合と約100Da〜約500Daの分子量を有するリンカーとを介して前記ポリマーと共有結合している、請求項1〜20のいずれか一項に記載の方法。
- 前記リンカーが約100Da〜約300Daの分子量を有する、請求項21に記載の方法。
- 前記リンカーがスクシンイミドを含む、請求項21〜22のいずれか一項に記載の方法。
- 前記コンジュゲートの拡散半減期が前記ペプチドよりも少なくとも2倍長い、請求項1〜23のいずれか一項に記載の方法。
- 前記コンジュゲートの前記拡散半減期が前記ペプチドよりも約2〜約100倍長い、請求項1〜24のいずれか一項に記載の方法。
- 前記コンジュゲートの関節内半減期が前記ペプチドよりも少なくとも約20%長い、請求項1〜25のいずれか一項に記載の方法。
- 前記コンジュゲートの前記関節内半減期が前記ペプチドよりも約20%〜約1000%長い、請求項1〜26のいずれか一項に記載の方法。
- 前記疾患又は障害が、関節リウマチ、摩耗関連変形性関節症、加齢関連変形性関節症、外傷後変形性関節症、乾癬性関節炎、及び無腐性のインプラントの緩み、関節滲出液、強直性脊椎炎、滑液包炎、痛風、反応性関節炎、滑膜炎、又は虚血壊死である、請求項1〜27のいずれか一項に記載の方法。
- 前記コンジュゲートを前記関節結合部におよそ一カ月に一度以下注射する、請求項1〜28のいずれか一項に記載の方法。
- 前記コンジュゲートを前記関節結合部におよそ一月に一度から六カ月に一度注射する、請求項1〜29のいずれか一項に記載の方法。
- 前記コンジュゲートを前記関節結合部に二カ月に一度又は三カ月に一度注射する、請求項1〜30のいずれか一項に記載の方法。
- 約0.1MDa〜約3MDaの分子量を有する生体適合性ポリマーと複数のペプチドとを含むコンジュゲートであって、前記ペプチドが約5kDa〜約150kDaの分子量を有し;
各ペプチドが前記ポリマーと共有結合し、
前記コンジュゲートにおける前記ペプチドの前記ポリマーに対する前記モル比が少なくとも約5:1である、コンジュゲート。 - 前記生体適合性ポリマーが約0.1MDa〜約2MDaの分子量と複数のペプチドとを有し、前記ペプチドが約5kDa〜約100kDaの分子量を有し;
各ペプチドが前記ポリマーと共有結合し;
前記ポリマーの前記分子量がペプチドあたり約5kDa〜約50kDaであり、
前記コンジュゲートにおける前記ペプチドの前記ポリマーに対する前記モル比が少なくとも約5:1である、請求項32に記載のコンジュゲート。 - 前記生体適合性ポリマーがポリサッカリドである、請求項32に記載のコンジュゲート。
- 前記生体適合性ポリマーがグリコサミノグリカンである、請求項32〜34のいずれか一項に記載のコンジュゲート。
- 前記生体適合性ポリマーがヒアルロン酸である、請求項32〜35のいずれか一項に記載のコンジュゲート。
- 前記生体適合性ポリマーが約0.2MDa〜約1.5MDaの分子量を有する、請求項32〜36のいずれか一項に記載のコンジュゲート。
- 前記生体適合性ポリマーが約0.9MDaの分子量を有する、請求項32〜37のいずれか一項に記載のコンジュゲート。
- 前記生体適合性ポリマーが約0.8MDa〜約3MDaの分子量を有する、請求項32〜36のいずれか一項に記載のコンジュゲート。
- 前記生体適合性ポリマーが約2MDaの分子量を有する、請求項32〜36のいずれか一項に記載のコンジュゲート。
- 前記ペプチドが免疫細胞機能の前記活性を調整する、請求項32〜38のいずれか一項に記載のコンジュゲート。
- 前記ペプチドが、腫瘍壊死因子α、インターロイキン1β、インターロイキン6、又はインターフェロンγを阻害する、請求項32〜41のいずれか一項に記載のコンジュゲート。
- 前記ペプチドが腫瘍壊死因子αを阻害する、請求項32〜42のいずれか一項に記載のコンジュゲート。
- 前記ペプチドが、モノクローナルIgG抗体、IgG抗体フラグメント、単鎖可変領域抗体、シングルドメイン重鎖抗体、アドネクチン、アフィボディ、アンチカリン、DARPin、Kunitz型阻害剤、又は受容体デコイである、請求項32〜43のいずれか一項に記載のコンジュゲート。
- 前記ペプチドが約5kDa〜約30kDaの分子量を有する、請求項32〜44のいずれか一項に記載のコンジュゲート。
- 前記ペプチドが約10kDa〜約20kDaの分子量を有する、請求項32〜45のいずれか一項に記載のコンジュゲート。
- 前記ペプチドが、配列番号1、配列番号2、配列番号6、配列番号7、配列番号8、配列番号9、及び配列番号10からなる群から選択されるアミノ酸配列を有する、請求項32〜46のいずれか一項に記載のコンジュゲート。
- 前記ペプチドが、配列:
QVQLQESGGGLVQPGGSLRLSCAASGRTFSDHSGYTYTIGWFRQAPGKEREFVARIYWSSGNTYYADSVKGRFAISRDIAKNTVDLTMNNLEPEDTAVYYCAARDGIPTSRSVESYNYWGQGTQVTVSS(配列番号1)を有する、請求項32〜47のいずれか一項に記載のコンジュゲート。 - 前記ペプチドの前記ポリマーに対する前記モル比が約5:1〜約400:1である、請求項32〜46のいずれか一項に記載のコンジュゲート。
- 前記ペプチドの前記ポリマーに対する前記モル比が約10:1〜約100:1である、請求項32〜49のいずれか一項に記載のコンジュゲート。
- 前記ペプチドの前記ポリマーに対する前記モル比が約30:1〜約50:1である、請求項32〜50のいずれか一項に記載のコンジュゲート。
- 前記ペプチドが、スルフィド結合と約100Da〜約500Daの分子量を有するリンカーとを介して前記ポリマーと共有結合している、請求項32〜51のいずれか一項に記載のコンジュゲート。
- 前記リンカーが約100Da〜約300Daの分子量を有する、請求項52に記載のコンジュゲート。
- 前記リンカーがスクシンイミドを含む、請求項52〜53のいずれか一項に記載のコンジュゲート。
- 前記コンジュゲートの前記拡散半減期が前記ペプチドよりも少なくとも2倍長い、請求項32〜54のいずれか一項に記載のコンジュゲート。
- 前記コンジュゲートの前記拡散半減期が前記ペプチドよりも約2〜約100倍長い、請求項32〜55のいずれか一項に記載のコンジュゲート。
- 請求項32〜56のいずれか一項に記載のコンジュゲートと、薬剤的に許容される担体とを含む医薬組成物。
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