JP2016530224A - 免疫療法のための組成物及び方法 - Google Patents
免疫療法のための組成物及び方法 Download PDFInfo
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Abstract
Description
本出願は、2013年6月24日に出願された米国仮出願第61/838,547号、及び2014年3月6日に出願された米国仮出願第61/948,916号の利益と優先権を主張するものであり、これらは、それらの全体が参照により本明細書に組込まれる。
本発明は、遺伝子療法に有用な、医薬組成物を含む組成物、及び方法に関する。
抗原特異的な免疫療法を含む、免疫療法のために有効な(貯蔵安定な医薬組成物を含む)組成物及び方法の必要性が、依然として存在する。
本実施例は、特に、マウス抗CD28抗体のテンプレートからの生殖系列ヒト化(CDR移植)抗体の設計;S241P(Kabat番号)ヒンジ安定化変異、抗体を結合するのに適した、残存Fcガンマ受容体結合及びCys残基(S473C、Kabat番号)を除去するためのL248E(Kabat番号)変異を含有するヒトIgG4の設計;CD28に潜在的非結合の変異体生殖細胞系列ヒト化抗体のVドメインの設計;潜在的なT細胞エピトープを含まない生殖細胞系列ヒト化抗体のN末端へのHLA−A*02:01の融合のためのリンカー配列の設計、を示す。
ヒト化抗CD28抗体のN末端へのHLA−A*02:01(IMGT Accession No.HLA00005)の融合のためのリンカーが構築され、潜在的な免疫原性を除去するためにiTope(商標)とTCED(商標)による分析が導入された。
コドンはGeneOptimizer(登録商標)を使用して最適化され、最適化された配列は、以下に示すように、発現のためにクローニングされた。
Biacore親和性データと他の考察に基いて、HC1::LC3およびHC2::LC3の重鎖と軽鎖の組合せが、StableFast−NS0細胞株開発のために、第1及び第2mAb候補として、それぞれ、選択された。
CD28に対するヒト化モノクローナル抗体が、mAbをコーティングしたプレート上で新たに単離したPBMCの増殖を誘導する能力について試験された。図17に示されるように、ヒト化抗CD28はスーパーアゴニストではない。
本明細書で参照されるすべての特許および刊行物は、本明細書にその全体が参照により組込まれる。
Claims (69)
- 約100〜200nmの範囲内のサイズを有するポリマーPLGA−PEG粒子,約0〜20mVの表面電荷,及び粒子あたり約100〜1500個の、スルフヒドリル−マレイミド化学を介して選択的に結合されているタンパク質リガンド;
抗CD28抗体リガンドの集団;
HLAリガンドの集団;
T細胞への提示のための1つまたは複数の抗原性ペプチド;及び
静脈内,動脈内,皮下,皮内,リンパ内,または腫瘍内投与のための薬学的に受容可能な担体、
を含む医薬組成物。 - 前記粒子は実質的に球状又は概ね球状である、請求項1に記載の医薬組成物。
- 前記PLGAは、約50%の乳酸(LA)及び50%のグリコール酸(GA)からなるポリマーである、請求項1または2に記載の医薬組成物。
- 前記PLGAは約25Kから約35Kの分子量を有し、前記PEGは約3Kから約10Kの分子量を有する、請求項1〜3のいずれか1項に記載の医薬組成物。
- 粒子あたり400〜1000個のリガンドを有する、請求項1〜4のいずれか1項に記載の医薬組成物。
- 前記抗CD28抗体リガンドは、任意選択で5〜15個のマウスフレームワーク残基を有するヒトIGHV4−59生殖系列フレームワーク、及び任意選択で3〜15個のマウスフレームワーク残基を有するIGKV4−01生殖系列フレームワークを含む、請求項1〜5のいずれか1項に記載の医薬組成物。
- 前記抗CD28リガンドは抗原結合抗体フラグメントである、請求項1〜5のいずれか1項に記載の医薬組成物。
- 前記抗CD28リガンドはscFvを含む、請求項1〜7のいずれか1項に記載の医薬組成物。
- 前記HLAリガンドは二量体である、請求項1〜8のいずれか1項に記載の医薬組成物。
- 前記HLAはHLA−A*02:01である、請求項9に記載の医薬組成物。
- 前記HLAは免疫グロブリン融合体を含む、請求項9または10に記載の医薬組成物。
- 前記抗CD28抗体リガンドと前記HLA−A*02:01免疫グロブリン融合体は、S241及びL248に変異を有し、コドン473にシステインを有するIgG4定常領域を有する、請求項11に記載の医薬組成物。
- 前記抗CD28抗体リガンドは、免疫グロブリン重鎖のコドン473のシステインを介して前記粒子にコンジュゲートされている、請求項12に記載の医薬組成物。
- 前記HLAリガンドは、免疫グロブリン重鎖のコドン473のシステインを介して前記粒子にコンジュゲートされている、請求項12または13に記載の医薬組成物。
- 前記HLAリガンドは、HLAの細胞外ドメインを含み、前記HLA細胞外ドメインのC末端に結合したペプチドまたは化学リンカーを介して前記粒子に連結されたHLAモノマーであり、前記HLAは任意選択的でHLA−A2である、請求項1に記載の医薬組成物。
- 前記HLAリガンドは、HLAの細胞外ドメインを含み、前記HLA細胞外ドメインのC末端に結合したペプチドまたは化学リンカーを介して抗CD28リガンドのscFvと前記粒子の両方に連結されたHLAモノマーであり、前記HLAは任意選択でHLA−A2である、請求項1に記載の医薬組成物。
- 前記組成物は凍結乾燥される、請求項1〜16のいずれか1項に記載の医薬組成物。
- 任意選択で1〜15個のアミノ酸修飾を有するヒトIGHV4重鎖アミノ酸配列を含み、少なくとも1つの相補性決定領域(CDR)は、マウス抗体のアミノ酸配列に基く、抗CD28抗体またはその一部。
- 前記CDRは、マウス9.3mAbに基く、請求項18に記載の抗体。
- 前記重鎖はヒトIGHV4−59生殖系列フレームワーク(FW)の変異体である、請求項18または19に記載の抗体。
- 前記抗体は軽鎖を含み、前記軽鎖はヒトIGKV4−01FWの変異体を含む、請求項18〜20のいずれか1項に記載の抗体。
- 前記重鎖は、1,3,6,37,48,67,71,73,76,78,82,82a,及び82cから選択される位置に1つまたは複数のマウスFW残基を含む、請求項18〜21のいずれか1項に記載の抗体。
- 前記軽鎖は、3,4,49,70,85,87,及び80から選択される位置に1つまたは複数のマウスFW残基を含む、請求項22に記載の抗体。
- 前記抗体はその定常領域またはその一部を含み、前記定常領域は、任意選択でヒトIgG4の変異体である、請求項18〜23のいずれか1項に記載の抗体。
- 前記定常領域は、1つまたは複数のヒンジ安定化変異を含む、請求項24に記載の抗体。
- 前記ヒンジ安定化変異はCH鎖に導入された1つまたは複数の変異を含む、請求項25に記載の抗体。
- 前記CH鎖に導入された前記1つまたは複数の変異はS241Pを含む、請求項26に記載の抗体。
- 前記抗体は定常領域を含み、前記定常領域は前記抗体を固体支持体に化学結合させるのに適した1つまたは複数の変異を含む、請求項18〜27のいずれか1項に記載の抗体。
- 結合に適した前記1つまたは複数の変異は不対システインを作成する、請求項28に記載の抗体。
- 前記不対システインはS473Cである、請求項29に記載の抗体。
- 前記不対システインは、固体支持体への共有結合を提供する、請求項29または30に記載の抗体。
- 前記固体支持体は、任意選択で共有結合に利用可能なエステル、カルボン酸、マレイミド、アルコールである官能基を任意選択で有する、ビーズまたは粒子である、請求項18〜31のいずれか1項に記載の抗体。
- 前記ビーズまたは粒子は、シクロデキストリン含有ポリマー,カチオン性シクロデキストリン含有ポチマー,ポリ(D,L−乳酸−コ−グリコール酸)(PLGA),ポリ(カプロラクトン)(PCL),エチレン酢酸ビニルポリマー(EVA),ポリ(乳酸)(PLA),ポリ(L−乳酸)(PLLA),ポリ(グリコール酸)(PGA),ポリ(L−乳酸−コ−グリコール酸)(PLLGA),ポリ(D,L−ラクチド)(PDLA),ポリ(L−ラクチド)(PLLA),PLGA−b−ポリ(エチレングリコール)−PLGA(PLGA−BPEG−PLGA),PLLA−BPEG−PLLA,PLGA−PEGマレイミド(PLGA−PEG−MAL),ポリ(D、L−ラクチド−コ−カプロラクトン),ポリ(D,L−ラクチド−コ−カプロラクトン−コ−グリコリド),ポリ(D,L−ラクチド−コ−PEO−コ−D,L−ラクチド),ポリ(D,L−ラクチド−コ−PPO−CO−D,L−ラクチド),ポリシアノアクラレート(cyanoacralate),ポリウレタン,ポリ−L−リジン(PLL),ヒドロキシプロピルメタクリレート(HPMA),ポリエチレングリコール,ポリ−L−グルタミン酸,ポリエチレン,ポリプロピレン,ポリ(ヒドロキシ酸),ポリ無水物,ポリオルトエステル,ポリ(エステルアミド),ポリアミド,ポリ(エステルエーテル),ポリカーボネート,ポリアルキレン,ポリ(エチレングリコール)などのポリアルキレングリコール(PEG),ポリアルキレンオキシド(PEO),ポリ(エチレンテレフタレート),ポリビニルアルコール(PVA),ポリビニルエーテル,ポリ(酢酸ビニル)などのポリビニルエステル,ポリ(塩化ビニル)(PVC),ポリビニルピロリドン,ポリシロキサン,ポリスチレン(PS),ポリウレタン,アルキルセルロースなどの誘導体化セルロース,ヒドロキシアルキルセルロース,セルロースエーテル,セルロースエステル,ニトロセルロース,ヒドロキシプロピルセルロース,カルボキシメチルセルロース,ポリ(メチル(メタ)アクリレート)(PMMA),ポリ(エチル(メタ)アクリレート),ポリ(ブチル(メタ)アクリレート),ポリ(イソブチル(メタ)アクリレート),ポリカルボン酸,(ヘキシルのポリマー(メタ)アクリレート),ポリ(イソデシル(メタ)アクリレート),ポリ(ラウリル(メタ)アクリレート),ポリ(フェニル(メタ)アクリレート),ポリ(メチルアクリレート),ポリ(イソプロピルアクリレート),ポリ(イソブチルアクリレート),ポリ(オクタデシルアクリレート)(ポリアクリル酸),並びにそれらのコポリマー及び混合物などの,アクリル酸のポリマー,ポリジオキサノン及びそのコポリマー,ポリヒドロキシアルカノエート,ポリプロピレンフマレート),ポリオキシメチレン,ポロキサマー,ポリ(オルト)エステル,ポリ(酪酸),ポリ(吉草酸),ポリ(ラクチド−コ−カプロラクトン),トリメチレンカーボネート,ポリビニルピロリドン,ポリオルトエステル,ポリホスファゼン,及びポリホスホエステル,並びに2つ以上のそのようなポリマーの混合物及び/またはブロック共重合体、の1つまたは複数から選択されたポリマーを含む、請求項32に記載の抗体。
- 定常領域を含み、前記定常領域は、Fcガンマ受容体結合を低減するために、1つまたは複数の変異を含む、請求項18〜33のいずれか1項に記載の抗体。
- Fcガンマ受容体結合を低減するための前記1つまたは複数の変異は、CH鎖に導入された1つまたは複数の変異を含む、請求項34に記載の抗体。
- 前記CH鎖に導入された前記1つまたは複数の変異はL248Eを含む、請求項35に記載の抗体。
- 前記抗体は、T細胞による認識のために抗原を提示する分子複合体を有する固体支持体にコンジュゲートされている、請求項18〜36のいずれか1項に記載の抗体。
- 抗原提示複合体であって、HLAのアミノ酸配列に融合したヒト化免疫グロブリン重鎖配列を含み、前記複合体は、任意選択で免疫グロブリン軽鎖配列を含まない、抗原提示複合体。
- 前記HLA−Ig融合は二量体である、請求項36に記載の抗原提示複合体。
- 前記免疫グロブリン配列はIGV4配列を含む、請求項38または39に記載の抗原提示複合体。
- 前記HLAアミノ酸配列はHLA−A*02:01(IMGT Accession No.HLA00005)またはその誘導体である、請求項38〜40のいずれか1項に記載の抗原提示複合体。
- さらに、前記HLAと免疫グロブリン配列の間にリンカーを含む、請求項38〜41のいずれか1項に記載の抗原提示複合体。
- さらに、T細胞への提示のために前記HLAに結合した抗原性ペプチドを含む、請求項38〜42のいずれか1項に記載の抗原提示複合体。
- 前記抗原性ペプチドは、チロシナーゼ,MAGE−A1,MAGE−A3,gp100,Melan A/MART−1,gp75/ブラウン,BAGE,NY−ESO−1,及びS−100、のうちの1つまたは複数である、請求項43に記載の抗原提示複合体。
- 前記ポリペプチドは、任意選択でビーズまたは粒子である固体支持体に結合している、請求項38〜44のいずれか1項に記載の抗原提示複合体。
- 前記ビーズまたは粒子は、シクロデキストリン含有ポリマー,カチオン性シクロデキストリン含有ポリマー,ポリ(D,L−乳酸−コ−グリコール酸)(PLGA),ポリ(カプロラクトン)(PCL),エチレン酢酸ビニルポリマー(EVA),ポリ(乳酸)(PLA),ポリ(L−乳酸)(PLLA),PLGA−b−ポリ(エチレングリコール)−PLGA(PLGA−BPEG−PLGA),PLLA−BPEG−PLLA,PLGA−PEGマレイミド(PLGA−PEG−MAL),ポリ(グリコール酸)(PGA),ポリ(L−乳酸−コ−グリコール酸)(PLLGA),ポリ(D,L−ラクチド)(PDLA),ポリ(L−ラクチド)(PLLA),ポリ(D、L−ラクチド−コ−カプロラクトン),ポリ(D,L−ラクチド−コ−カプロラクトン−コ−グリコリド),ポリ(D,L−ラクチド−コ−PEO−コ−D,L−ラクチド),ポリ(D,L−ラクチド−コ−PPO−CO−D,L−ラクチド),ポリシアノアクラレート(cyanoacralate),ポリウレタン,ポリ−L−リジン(PLL),ヒドロキシプロピルメタクリレート(HPMA),ポリエチレングリコール,ポリ−L−グルタミン酸,ポリエチレン,ポリプロピレン,ポリ(ヒドロキシ酸),ポリ無水物,ポリオルトエステル,ポリ(エステルアミド),ポリアミド,ポリ(エステルエーテル),ポリカーボネート,ポリアルキレン,ポリ(エチレングリコール)などのポリアルキレングリコール(PEG),ポリアルキレンオキシド(PEO),ポリ(エチレンテレフタレート),ポリビニルアルコール(PVA),ポリビニルエーテル,ポリ(酢酸ビニル)などのポリビニルエステル,ポリ(塩化ビニル)(PVC),ポリビニルピロリドン,ポリシロキサン,ポリスチレン(PS),ポリウレタン,アルキルセルロースなどの誘導体化セルロース,ヒドロキシアルキルセルロース,セルロースエーテル,セルロースエステル,ニトロセルロース,ヒドロキシプロピルセルロース,カルボキシメチルセルロース,ポリ(メチル(メタ)アクリレート)(PMMA),ポリ(エチル(メタ)アクリレート),ポリ(ブチル(メタ)アクリレート),ポリ(イソブチル(メタ)アクリレート),ポリカルボン酸,(ヘキシルのポリマー(メタ)アクリレート),ポリ(イソデシル(メタ)アクリレート),ポリ(ラウリル(メタ)アクリレート),ポリ(フェニル(メタ)アクリレート),ポリ(メチルアクリレート),ポリ(イソプロピルアクリレート),ポリ(イソブチルアクリレート),ポリ(オクタデシルアクリレート)(ポリアクリル酸),並びにそれらのコポリマー及び混合物などの,アクリル酸のポリマー,ポリジオキサノン及びそのコポリマー,ポリヒドロキシアルカノエート,ポリプロピレンフマレート),ポリオキシメチレン,ポロキサマー,ポリ(オルト)エステル,ポリ(酪酸),ポリ(吉草酸),ポリ(ラクチド−コ−カプロラクトン),トリメチレンカーボネート,ポリビニルピロリドン,ポリオルトエステル,ポリホスファゼン,及びポリホスホエステル,並びに2つ以上のそのようなポリマーの混合物及び/またはブロック共重合体、の1つまたは複数から選択されたポリマーを含む、請求項45に記載の抗原提示複合体。
- ポリマービーズまたは粒子、請求項18〜37のいずれか1項に記載の抗体、及び/または請求項38〜46のいずれか1項に記載の抗原提示複合体を含む医薬組成物。
- 約100〜200nmの範囲のサイズを有する、任意選択でPLGA−PEGマレイミド粒子である、ポリマーPLGA−PEG粒子を含む、請求項47に記載の医薬組成物。
- 前記粒子は、約−0〜−15mVの表面電荷、及び、任意選択で約−5〜−15mVの表面電荷を有する、請求項47または48に記載の医薬組成物。
- スルフヒドリル−マレイミド化学を介して選択的に結合されている、粒子あたり約100〜1500個のタンパク質リガンドを含む、請求項47〜49のいずれか1項に記載の医薬組成物。
- 静脈内,動脈内,皮下,皮内,リンパ内,または腫瘍内投与のための薬学的に受容可能な担体を含む、請求項47〜50のいずれか1項に記載の医薬組成物。
- 前記粒子は実質的に球状又は概ね球状である、請求項47〜51のいずれか1項に記載の医薬組成物。
- 前記PLGAは、約50%の乳酸(LA)及び50%のグリコール酸(GA)からなるポリマーである、請求項47〜52のいずれか1項に記載の医薬組成物。
- 前記PLGAは約25Kから約35Kの分子量を有し、前記PEGは約3Kから約10Kの分子量を有する、請求項47〜53のいずれか1項に記載の医薬組成物。
- 粒子あたり400〜1000個のリガンドを有する、請求項47〜54のいずれか1項に記載の医薬組成物。
- 前記抗CD28リガンドは抗原結合抗体フラグメントである、請求項47〜55のいずれか1項に記載の医薬組成物。
- 前記抗CD28リガンドはscFvを含む、請求項47〜56のいずれか1項に記載の医薬組成物。
- 前記HLAリガンドは二量体である、請求項47〜57のいずれか1項に記載の医薬組成物。
- 前記HLAはHLA−A*02:01である、請求項58に記載の医薬組成物。
- 前記HLAは、免疫グロブリン重鎖融合体を含み、任意選択で免疫グロブリン軽鎖配列を含まない、請求項58または59に記載の医薬組成物
- さらに、T細胞への提示のための抗原性ペプチドを含む、請求項47〜60のいずれか1項に記載の医薬組成物。
- 前記医薬組成物は、T細胞への提示のための抗原性ペプチドと共製剤化される、請求項61に記載の医薬組成物。
- 前記抗原性ペプチドは、チロシナーゼ,MAGE−A1,MAGE−A3,gp100,Melan A/MART−1,gp75/ブラウン,BAGE,NY−ESO−1,及びS−100、のうちの1つまたは複数である、請求項61または62に記載の医薬組成物。
- 前記医薬組成物は貯蔵安定性である、請求項47〜63のいずれか1項に記載の医薬組成物。
- 前記医薬組成物は凍結乾燥される、請求項64に記載の医薬組成物。
- 前記組成物は非経口送達のために製剤化される、請求項47〜65のいずれか1項に記載の医薬組成物。
- 患者へ請求項47から66のいずれか1項に記載の組成物を投与することを含む、抗原特異的細胞毒性T細胞の形成を誘導するための方法。
- 前記患者は癌患者である、請求項67に記載の方法。
- 前記患者は、1つまたは複数のチェックポイント阻害剤で治療を受けている、または受けたことがある、請求項67または68に記載の方法。
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JP6566938B2 (ja) | 2019-08-28 |
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WO2014209868A1 (en) | 2014-12-31 |
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AU2014302784B2 (en) | 2020-01-23 |
SG10201710737VA (en) | 2018-01-30 |
CN113797332A (zh) | 2021-12-17 |
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AU2014302784A1 (en) | 2016-01-21 |
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BR112015032277B1 (pt) | 2020-12-01 |
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CA2916465A1 (en) | 2014-12-31 |
IL243235A0 (en) | 2016-03-31 |
EP3013361A1 (en) | 2016-05-04 |
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