JP7127876B2 - 免疫療法のためのナノ粒子組成物及び方法 - Google Patents
免疫療法のためのナノ粒子組成物及び方法 Download PDFInfo
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Description
本出願は、2014年12月24日出願の米国仮特許出願第62/096,725号に対する優先権を主張するものであり、その全体が参照により本明細書に組み込まれる。
)約150個未満のリガンドまたは約100個未満のリガンドがその表面にコンジュゲートされていて、それによって活性及び/または力価の損失を伴わずに、表面の多量のリガンドによる立体的制約を回避する。
親水性の外装を形成する。粒子は、循環特性、体内分布及び分解速度論を含む薬力学的利点、ならびに抗原特異的T細胞を活性化する高い力価をもたらすように設計される。物理的パラメーターとしては、主にサイズ、表面電荷、ポリマー組成、リガンドコンジュゲートケミストリー、リガンド密度が挙げられる。例えば、いくつかの実施形態では、粒子はPLGAまたはPLAポリマーのコア、及びコポリマーのPEG部分によって形成される親水性シェルを有し、ポリマーの一部はポリペプチドリガンドの末端と結合する。親水性シェルは、リガンドコンジュゲートの官能基に対して不活性である、いくつかのPEG鎖、例えばPLGA-PEG-MeOHまたはPLA-PEG-MeOHポリマーを含む。これらの実施形態では、粒子の化学物質により、リガンド密度の良好な調整が可能である。
LA-ヒト白血球抗原、MHC-主要組織適合遺伝子複合体、VH-可変重鎖、Vκ-可変カッパ軽鎖、及びV領域-抗体の可変領域、VHまたはVκのいずれか。
ように修飾されていてもよい。
mAbのVH鎖及びVL鎖によって形成される抗原結合ループからなる、または本質的にそれからなる一本鎖可変断片(scFv)である。scFv抗体構築物は、短いペプチドリンカーによって頭部-頭部または頭部-尾部の構成で共に結合された、1つまたは複数(2、3、4または5)のVH及びVL超可変領域鎖(3D抗原エピトープ結合ポケットを一緒に形成する各鎖の部分)を含んでいてよい。このような構築物はサイズが小さいため、完全に合成経路によって利便に生成することができる。更に、scFvは免疫原性の可能性を低下させることができる。
いる、合成または組換えのHLAモノマー(例えば、β2ミクログロブリンを有するクラスIアルファ鎖)である。更に、共刺激シグナル(または、他の抗体系のリガンド)は、FabであってもscFvであってもよい。このような実施形態では、2つのシグナルを、目的受容体と結合する抗原結合抗体断片(例えば、scFv)に係留されたHLA分子を含む単一の多機能構築物に組み込むことができる。
面に10~約80個のコンジュゲートされたリガンド、すなわち粒子当たり10~約70個、または約10~約50個のコンジュゲートされたリガンドを含む。
築される。いくつかの実施形態では、捕捉された化合物は、粒子マトリックスの分解により放出される。このようなaAPCによって、オフターゲットの相互作用による不必要な活性を制限することにより、併用療法の許容性と有効性を高めることができ得る。いくつかの実施形態では、ナノ粒子aAPCには、薬物化合物、例えばサイトカイン及び小分子薬が封入されない。
などの、本明細書に記載のHLA抗原提示複合体によって提示されるMART-1、gp100、NY-ESO-1及びMAGE-A3を含む。
を模倣するaAPCの作成が試みられてきたが、本ナノスケールのaAPCは、種々の実施形態において、設計された粒度及び化学物質、T細胞リガンド、リガンド配向、リガンド密度及びリガンド比を有するナノサイズ粒子によって生体系を模倣する。
、または約40nm~約110nmの範囲内である粒子は、好ましくは上記の平均粒子サイズで、サイズが均一であっても、またはサイズが変化してもよい。いくつかの実施形態では、粒子は、「EPR効果」(Enhanced permeability and
retention effect:血管透過性・滞留性亢進効果)を利用するのに十分に小さい。
は、1~約100μg、または約1~約50μg、または粒子1mg当たり1~約10μg、またはいくつかの実施形態では、粒子1mg当たり2~6μgであり得る。いくつかの実施形態では、粒子のリガンド密度は、約103~約105リガンド/μm2または約104リガンド/μm2である。例えば、サイズが20~200nmの範囲のナノ粒子の場合、ナノ粒子は、平均して粒子当たり約5~約1500個のリガンド、例えば、粒子当たり約10~約1500個のリガンド、または粒子当たり約10~約1200個のリガンド、または粒子当たり約10~約1000個のリガンド、または粒子当たり約10~約800個のリガンドを有する。いくつかの実施形態では、粒子は、粒子当たり少なくとも約500個のリガンド、または粒子当たり少なくとも約400個のリガンド、または粒子当たり少なくとも約300個のリガンド、または粒子当たり少なくとも約100個のリガンド、または粒子当たり少なくとも約90個のリガンド、または粒子当たり少なくとも約80個のリガンド、または粒子当たり少なくとも約70個のリガンド、または粒子当たり少なくとも約60個のリガンド、または粒子当たり少なくとも約50個のリガンド、または粒子当たり少なくとも約40個のリガンド、または粒子当たり少なくとも約30個のリガンド、または粒子当たり少なくとも約20個のリガンド、または粒子当たり少なくとも約10個のリガンド、いくつかの実施形態では最小でも粒子当たり約5個のリガンドを含む。
、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)、PLA-PEG-マレイミド、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-コ-D,L-ラクチド)、ポリアルキル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(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(例えばポリエチレン及びポリプロピレン)、ポリ(エチレングリコール)(PEG)などのポリアルキレングリコール、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)のようなポリアルキ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)などのポリビニルハライド、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、アクリル酸のポリマー、例えばポリメチルメタクリレート)(P MA)、
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(ヘキシル(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)、及びそれらのコポリマー及び混合物、ポリジオキサノンとそのコポリマー、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、そのデンドリマー及び誘導体、ならびに2つ以上のこのようなポリマーの混合物及び/またはブロックコポリマーのうち1つ以上を含む。
る。例示的な粒子は、0.3以下の多分散指数(PDI)を有する。いくつかの実施形態では、タンパク質リガンドはそれぞれ、スルフヒドリル-マレイミドの化学作用により粒子と結合される。リガンドは、抗CD28抗体リガンドの集団及びHLAリガンドの集団、ならびにT細胞に提示される1種以上の抗原ペプチドを含む。組成物は、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許容される担体を含む。いくつかの実施形態では、組成物は皮下投与用に製剤化される。
例えばニボルマブ、ペムブロリズマブ及びイピリムマブとともに与えられる。いくつかの実施形態では、付加的療法は、抗CTLA4もしくは抗PD1、または抗PD-L1である。付加的療法またはチェックポイント阻害剤は、その従来的なレジメンに沿って個別に投与しても、または本明細書に記載するナノ粒子への、もしくは別のナノ粒子集団に結合された、追加のリガンドとして投与してもよい。いくつかの実施形態では、初期療法として1種以上の免疫チェックポイント阻害剤を与え、その後、例えば、チェックポイント阻害剤療法の約1~約8週間後、またはチェックポイント阻害剤療法の約2~約4週間後に、本明細書に記載するaAPCによる療法を開始する。いくつかの実施形態では、1種以上のチェックポイント阻害剤をナノ粒子療法と同時に与え、例えば、療法の開始時と約2週間毎に、または療法の開始時と1種以上のチェックポイント阻害剤については約2週間毎に、及びナノ粒子療法については約4週間毎に与える。いくつかの実施形態では、患者は、チェックポイント阻害剤療法に対して耐性であるか、または部分的応答もしくは一過性応答のみを示し、本明細書に記載するaAPCは、このような患者における腫瘍退縮を増強する。更に他の実施形態では、通常はチェックポイント阻害剤療法に耐性のある癌に対して、本明細書に記載する組成物は、このような癌へのチェックポイント阻害剤使用の奏功性を高める。
本実施例では、特に、マウス抗CD28抗体のテンプレート由来の生殖細胞系列ヒト化(CDR移植)抗体の配列設計;S241P(Kabat番号付け)ヒンジ安定化突然変異、残存するFcガンマ受容体結合を除去するためのL248E(Kabat番号付け)
突然変異、及び抗体の結合に適したCys残基(S473C、Kabat番号付け)を含有するヒトIgG4を含むヒト定常領域配列の設計;CD28と結合する可能性がない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末端にHLA-A*02:01を融合するためのリンカー配列の設計について示す。
2002 169:1119-1125によって選択されたIGHV3/OR16-10よりむしろ)ヒトIGHV4-59生殖細胞系列FWを選択した。軽鎖のテンプレートとしてIGKV4-01生殖細胞系列FWを選択した。このFWはいずれも、それぞれのマウスVH及びVκ配列と62%の相同性を有する。マウスCDRをこれらのFWに移植し、また様々な数のマウスFW残基を加え、3種のヒト化VH変異体及び3種のヒト化Vκ変異体を作製した(図1~6)。
ヒト化抗CD28抗体のN末端にHLA-A*02:01(IMGTアクセッション番号HLA00005)を融合するリンカーを構築し、潜在的な免疫原性を排除するためにiTope(商標)及びTCED(商標)による分析を取り入れた。
対立遺伝子各々に対して試験したリンカー配列にわたって重複する9量体を用いて実施した。各9量体を、MHCクラスII分子との潜在的な「適合性」及び相互作用に基づいてスコア付けした。ソフトウェアによって算出されるペプチドのスコアは0から1の間である。高い平均結合スコア(iTope(商標)のスコア関数で0.55超)を得た非生殖細胞系列ペプチドが強調表示され、50%以上のMHCクラスII結合ペプチド(すなわち、34個の対立遺伝子のうち17個)が高い結合親和性(スコア0.6超)を有する場合、このようなペプチドを「無差別な高親和性」MHCクラスII結合ペプチドと定義した(これは、CD4+T細胞エピトープを含むため高リスクであると考えられる)。50%以上のMHCクラスII結合ペプチドがスコア0.55超を有する(ただし、0.6超が過半数ではない)ペプチドは、「無差別な中親和性」MHCクラスII結合ペプチドと定義した。配列の更なる分析はTCED(商標)を使用して実施した。先のEpiScreen(商標)試験でT細胞応答を刺激した無関係なタンパク質から、ペプチド(T細胞エピトープ)間の高配列相同性を同定するため、この配列を使用して、BLAST検索によりTCED(商標)を調べた。
GeneOptimizer(登録商標)を使用してコドンを最適化し、最適化した配列を以下に示すようにクローニングして発現させた。
Biacore親和性データ及びその他の考察に基づいて、HC1::LC3及びHC2::LC3の重鎖と軽鎖の組み合わせを、それぞれ第1及び第2のmAb候補として選抜し、StableFast-NS0細胞株を作製した。
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した。図17に示すように、ヒト化抗CD28は親と近似した機能を果たしており、スーパーアゴニストではない。
LA mAbを使用して、ペプチドが負荷されたタンパク質を捕捉し、ELISA法により抗原ペプチド負荷効率を確認する。非特異的ペプチドでは0%(すなわちMHCミスマッチ)であるのに対して、特異的ペプチドでは約90%の再現可能な負荷効率(すなわち正確なMHC制限)が予測される。
以下の実施例は、分子量35KであるPLGA(LA:GA=1:1)から形成されたコアを有するナノ粒子の合成を示す。粒子のコロナは、PLGA-PEG-COOHまたはPLGA-PEG-マレイミドと、PLGA-mPEG(メトキシPEG)の混合物からのPEGコポリマーによって形成する。COOH及びマレイミドの末端官能基により、ポリペプチドのコンジュゲートが可能である。メトキシPEGは、PEG鎖上の末端官能基に対して不活性である。PLGA部分は10~30K(例えば、約20K)の分子量を有し、PEG部分の分子量は3K及び5Kである。この実施例では、ナノ粒子は、50%のコアPLGA(35K)、及び25%のPLGA-PEG-COOHと25%のPLGA-mPEGとの混合物により形成される。PLGA-PEG-COOH(またはマレイミド)とPLGA-mPEGとの比率によって、粒子表面のリガンド密度の微調整が可能である。例えば類似した分子量及び官能基密度を有する、PLA及びPLA-PEGなどの他のポリマーを使用して類似した粒子を調製することができる。
(例えば、いくつかの実施形態では0.3以下)であり、ゼータ電位(表面電荷)は-15mV~0mVである。この組成、サイズ及び電荷を有するナノ粒子は、in vivoでのPK/ADMEに有益な特性を有することが予測される。具体的には、腫瘍微小環境を含む標的組織への輸送、ならびに血液とリンパ間の移動が十分可能である程度に小さい(200nm未満)。また、その親水性PEG層及びわずかな負電荷により、血清タンパク質の結合、及び標的組織に分布する前にMPS細胞によって循環から排除される恐れのあるナノ粒子のオプソニン化を遅延させるのに役立つ。このポリマー混合物は、日数で測定される微生物分解速度が2週間程度になるはずである。またタンパク質リガンドが外側に配向されることで、同族のTCR及び共刺激受容体(例えばCD28、4-1BB)とのT細胞の結合と比較して、必然的に最大限の生物学的活性をもたらす。更に、いくつかの実施形態では、製剤化する際、ナノ粒子の疎水性コアに可溶性のペイロード(例えばIL-2、抗TGF-b、IL-21または小分子薬)を充填することができる。
PLGA 35KDa 50% w/w
PLGA-PEG官能基 20KDa~5KDa 25% w/w
PLGA-PEG-MeOH 20KDa~5KDa 25% w/w
抗原提示複合体(例えばH2-KbまたはHLA-2)をIgヒンジ領域と直接融合させることによって、二量体の抗原提示リガンドを設計した。H2-KbのFcヒンジタンパク質は、マウスIgG1のヒンジ-CH2-CH3部分に融合されたマウスクラスI Kb細胞外ドメインを含み、不対システイン残基が重鎖231位のセリン残基を置換するように遺伝子操作されている。この設計を図19に示す。
利用可能な一級アミンを介してコンジュゲートされるリガンドとともに、PLGA及びPLGA-PEG-COOHのナノaAPCを調製した。PLGA 40(200nm)を基とするPLGA粒子は、有意な安定性を示さなかった。PLGA-PEG-COOH(40K/3K):PLGA-mPEG(17K/3K)を基とし、1:4のPEG:mPEG比を有する粒子は、良好な安定性及び活性を示した。図20。
粒子をナノ析出法によって調製する。例えば、PLGA-mPEGとPLGA-PEG-マレイミドの混合物(PLGA-PEG-マレイミドの%w/wは1~55%の間で変化する)をアセトニトリルに溶解して、最終濃度50mg/mLにする。この溶液を、シリンジポンプを使用して5mL/分でPVA溶液(MnPVA=9kDa、0.5%w/v)に撹拌しながら注入する。有機溶媒と水性溶媒の混合比は1:1~1:20の間で急変させた。マイクロ流体装置、拘束衝突噴流装置及び多重注入口ボルテックスミキサー装置を使用して、優れた均一性と狭い粒度分布を確保した粒子を調製することができる。粒子は、タンジェンシャルフローフィルトレーション(TFF)またはAmicon遠心フィルターを使用して精製する。次に粒子をコンジュゲート緩衝液(HEPES 50mM、EDTA 10mM、pH=6.7)に再懸濁した。最後に、抗CD28及びKbSIY/HLAリガンドの混合物を粒子にコンジュゲートすることにより、ナノaAPCを調製する。リガンドの粒子とのコンジュゲートは、室温で一晩続行する。リガンド:粒子の質量比は、1~500μg/mg粒子の範囲である。抗CD28:Kb/HLAの比は、0~1の間で変化する。結合されなかったリガンドはSECまたはTFFを使用して除去する。90nmの平均粒径及び50~120nmの粒度分布を有する粒子を調製した。図32。
本明細書で言及される特許及び刊行物は全て、その全体が参照により本明細書に組み込まれる。
Claims (13)
- 抗原特異的T細胞活性化のためのポリペプチドリガンドを結合させたポリマーナノ粒子を含む人工抗原提示細胞(aAPC)であって、
該ナノ粒子が20~200nmの範囲のサイズを有し、
ポリ(乳酸-コ-グリコール酸)(PLGA)ポリマーコアまたはポリ乳酸(PLA)ポリマーコア(PLGA/PLA)と、
ポリエチレングリコール(PEG)で形成される親水性シェルとを含み、
前記ポリマーナノ粒子は、10kDa~30kDaの分子量を有するPLGA/PLA部分と2kDa~10kDaの分子量(複数可)を有するPEG部分とを含有するPLGA/PLA-PEGおよびPLGA/PLA-メトキシPEG(mPEG)ブロックコポリマーを含み、前記PEG部分は親水性シェルを形成し、
前記PLGA/PLA-PEGおよびPLGA/PLA-mPEGブロックコポリマーは、1:10~2:1の質量比で存在し、前記PLGA/PLA-PEGポリマーの一部はポリペプチドリガンドの末端と結合し、
前記ポリペプチドリガンドは、ペプチド-HLAリガンドと、抗CD28および抗4-1BBリガンドの1つ以上とを含む、前記aAPC。 - 前記ポリマーコアが、20:1~1:20の乳酸:グリコール酸比を有する、請求項1に記載のaAPC。
- 前記親水性シェルが、異なる分子量を有するPEG鎖の混合物を含む、請求項1または2に記載のaAPC。
- 前記ポリペプチドリガンドが、前記ポリペプチドリガンド上の一級アミンによって、または不対システイン側鎖によってPEGと結合される、請求項3に記載のaAPC。
- 0~-20mVまたは-5~-10mVの表面電荷を有する、請求項1~4のいずれか1項に記載のaAPC。
- 粒子当たり200個未満のリガンドを有する、請求項1~5のいずれか1項に記載のaAPC。
- 前記HLAリガンドが二量体である、請求項1~6のいずれか1項に記載のaAPC。
- 前記HLAリガンドが免疫グロブリン配列との融合体を含む、請求項7に記載のaAPC。
- 前記HLAリガンドが、免疫グロブリン可変ドメイン配列なしで、免疫グロブリンヒンジ領域に融合されるHLAの細胞外ドメインを含む、請求項8に記載のaAPC。
- 患者において抗原特異的な細胞傷害性T細胞の形成を誘導するための組成物であって、請求項1~9のいずれか1項に記載のaAPCを含む、組成物。
- 静脈内投与、動脈内投与、皮下投与、皮内投与、リンパ内投与、または腫瘍内投与のために製剤化されている、請求項10に記載の組成物。
- 前記患者が癌患者である、請求項10に記載の組成物。
- 前記患者が、1種以上のチェックポイント阻害剤による療法を受けている、もしくは受けた経験がある、および/またはT細胞養子免疫療法を受けている、請求項12に記載の組成物。
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