JP2015506931A - 成長因子、サイトカイン、抗菌/抗ウイルス因子、幹細胞刺激因子、補体タンパク質c3a/c4a、および走化性因子の組合せ - Google Patents
成長因子、サイトカイン、抗菌/抗ウイルス因子、幹細胞刺激因子、補体タンパク質c3a/c4a、および走化性因子の組合せ Download PDFInfo
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Abstract
Description
サイトカイン:約50から約500pg/mg、好ましくは71.46から340.76、
成長因子:約1000から約7000pg/mg、好ましくは1321.80から6494.40、
走化性因子:約5から50pg/mg、好ましくは6から24、
幹細胞刺激因子:約100から1500pg/mg、好ましくは191から1105、
抗菌/抗ウイルス因子:約15から80μg/mg、好ましくは18から75、
補体C3a/C4aタンパク質:約1から5pg/mg、好ましくは1.10から2.70。
TGF−β1−形質転換成長因子:粘膜における免疫防御に関与している、クラスA免疫グロブリンの産生を刺激する。細胞増殖を調節し、細胞外基質の沈着を刺激する。
EGF−上皮細胞成長因子:粘膜の発達を制御する。上皮細胞の形成を促進する。
IGF1−インスリン様成長因子:細胞増殖、付着および遊走を調節し、粘膜の成熟を誘導する。
VEGF−血管内皮細胞成長因子:血管産生を刺激する。細胞分裂活性および血管透過性の活性化を提示する。
FGF−b−線維芽細胞成長因子基礎:線維芽細胞、内皮細胞、星状膠細胞およびケラチノサイトなどの、間葉細胞起源の細胞の増殖を刺激する。それはまた、走化性因子としても作用する。
GH−成長ホルモン:全ての組織の全体的な成長因子。
GHRF−成長ホルモン放出因子:正常な生後の成長、骨成長、タンパク質、炭水化物および脂質代謝に対する調節作用に必要とされるGHの放出を刺激する。
NGF−神経成長因子:活性を刺激し、交換神経系の成長および分化を制御する。
PDGF−血小板由来成長因子:中胚葉起源の細胞の分化の成長。
BMP−2−骨形成タンパク質2:骨および軟骨の発達、心臓細胞分化。
エオタキシン:炎症組織に対して好酸球を動員するためにケモカイン受容体に結合する。
MCP−1 単球走化性因子−1:炎症組織に対して単球の凝集を促進する。
IL−1Raは、インターロイキン1アルファおよびインターロイキン1−ベータの活性を阻害し、種々のIL1関連免疫および炎症反応を調節する。
IL−2はTリンパ球の増殖を誘導する。
IL−4は抗炎症活性を保有する。
IL−6は先天性および適応免疫を刺激する。
IL−9は造血細胞の調節因子であり、細胞増殖を刺激し、アポトーシスを防ぐ。
IL−17はNF−KBの活性を制御し、一酸化窒素(NO)産生を増加させる。
IL−10は免疫制御および炎症において多面発現効果を有する。B細胞生存、およびそれによる抗体産生を改善する。ノックアウトマウスで行われた研究により、このタンパク質は粘膜の免疫制御において必須であることが実証されている。IL−12はTおよびナチュラルキラー細胞を刺激する。
IL−15はTおよびナチュラルキラー細胞活性化および増殖を制御する。
インターフェロン−ガンマは、既知の抗ウイルス、抗腫瘍および免疫調節性活性を有する。それは強力なマクロファージ活性化因子であり、細菌およびウイルスに対して細胞媒介性活性を活性化する。
TNF−α−腫瘍壊死因子は感染部位への好中球および単球の遊走を刺激する。
GM−CSF−顆粒球コロニー刺激因子:骨髄由来の免疫前駆体の刺激および末梢部のディスミッション(peripheral dismission)に関与する。
LIF−白血病抑制因子:例えば、正常および骨髄性白血病細胞における造血分化の誘導、神経細胞分化の誘導、腎臓発達の間の上皮変換に対する間葉細胞の調節因子に関与するいくつかの異なる系において役割を有する多面的サイトカイン。
SCF−幹細胞因子:胚細胞および神経系細胞発達および造血において子宮内で作用する。
SDF−1−ストロマ細胞由来因子−1:CXCR4リガンドを発現する幹前駆体細胞の走化性因子として作用する。
トランスフェリン:鉄を赤血球に送達し、細菌およびウイルスが鉄に結合することを防ぐ。
ラクトフェリン:細菌およびウイルスの成長に必要とされる鉄をそれらから奪う。
リゾチーム:その酵素活性を考慮して、ならびにそのカチオン性および疎水性特性の結果として抗菌作用を有する。
ラクトペルオキシダーゼ:必須タンパク質SH基の酸化により細菌代謝を阻害する。
妊娠したメスの哺乳動物の血清は、分娩または出産前の最後の数日、通常、最後の5〜15日において、本発明の組合せについて成分の最も高いピークを有する。
哺乳動物血液から凝固および遠心分離により得た血清試料(−20℃で凍結した)を室温にて解凍し、2体積の脱塩水で希釈した。得られた溶液を、4℃にて冷却した部屋において0.5から1バールのPiにてポリエーテルスルホン中でMillipore Biomax Pellicon300,000Da平面接線フロー膜を通して限外濾過する。
残存している透過物を、5000Da膜を通して限外濾過する。300,000Da限外濾過からの透過物を、4℃にて冷却した部屋において0.5から1バールのPiにてポリエーテルスルホン中で5000Da平面接線フロー膜Millipore Biomax Pellicon上で濃縮する。
ウシ、ウマまたはブタの胎盤が好ましくは使用される。
胎盤(−20℃で凍結した)を室温にて解凍し、小切片に切断し、多量の冷却した(4℃)生理食塩水(NaCl0.9%)で洗浄し、pH7.4にて以下の成分:Tris/HCl 50mM、EDTA 25mM、トリトンX−100 0.001%を有する溶解緩衝液中でSirammカッターを使用して均質化する。0.9%の濃度でNaClを得られた懸濁液に加える。上清を2時間、(マグネチックスターラーで)撹拌し、4℃にて冷却した部屋で終夜静置した。
45分間4℃にて、Sorvall RC6およびローターSLA15000を用いて上清を13,000rpmにて遠心分離した。遠心分離からの上清を回収し、0.45μmから0.22μmのDicaliteおよび再生セルロールフィルター上で、真空前濾過する。
産物を、4℃にて冷却した部屋において、0.5から1バールのPiにて300.000Da Millipore Biomax Pellicon平面接線フロー膜を通して濾過および限外濾過する。
300,000Da限外濾過からの透過物を、4℃にて冷却した部屋において、0.5から1バールのPiにてポリエーテルスルホン中の5000Da Millipore Biomax Pellicon平面接線フロー膜上で濃縮する。残余分を再生セルロース中でSpectrum SpectraPor製の1,000Da析管に移し、脱塩水に対して透析し、次いですぐに凍結乾燥する。
特にホルスタイン(フリージアン)およびガーンジーウシからのウシ初乳が好ましい。これらのウシは、最も高い濃度の成長因子、免疫調節因子、走化性因子および抗菌/抗ウイルス因子を有する初乳を産生することが実証されている。ウシは好ましくは2回または3回分娩している。初乳は好ましくは分娩後5〜6時間以内に採取され、好ましくは初乳は分娩後1時間で採取される。なぜなら、最も高い濃度の活性物質がこの時間の間に見られるのに対して、6時間から先へ進むと、活性因子は急速に減少するからである(20%のみが分娩後24時間で存在する)。
免疫グロブリンIgG、IgAおよびIgMは、以下の工程からなる方法によって、以前に開示された抽出物により得られた画分から定量的に喪失させる:1)アフィニティクロマトグラフィーによるIgG枯渇、2)接線フロー濾過による、および100kDaのカットオフを有する膜を使用するIgAおよびIgM枯渇、3)3kDaのカットオフを有する膜を使用する透析濾過による脱塩および濃縮、4)凍結乾燥。
今までのところ、抗体精製に採用されている最も一般的な技術は、黄色ブドウ球菌(Staphylococcus aureus)由来のプロテインAおよび連鎖球菌(Streptococci)由来のプロテインGなどの細菌表面から単離された非常に特異的な免疫グロブリン結合タンパク質(IBP)を使用するアフィニティクロマトグラフィーに基づく。このようなタンパク質は、通常、分取クロマトグラフィーカラムにおいて固定され、高い程度の純度で免疫グロブリンを捕捉し、1工程のみで回収する。IgGに対する最も高い親和性により特徴付けられる、最も好適なウシIBPが選択され、セファロース上で固定された5mlのプロテインAまたはGを含有するHiTrapカラムを試験した。電気泳動およびELISAの両方によりIgG喪失を測定することによって、本発明者らは、プロテインGが、ウシIgGについての最も好適なIBPであり、95%より高い喪失に至ることを発見した。ほぼ1gの全量に対して23mgのIgG/mlを結合できる臭化シアン(CNBr)によりセファロース上で固定された組換えプロテインGからなる400mlのプロテインGセファロース4高速流(GE Healthcare)を含有する、HiScale(商標)50カラムIの使用が好ましい。移動相はFPLCシステム(AKT Aprime plus、GE Health care)により溶出され、280nmにてUV検出器、導電率計(0.001〜999.9mS/cm)およびpHメータによりモニターされる。アフィニティクロマトグラフィー法は以下の工程からなる:1)結合、2)溶出、3)カラム再生。結合工程は、20ml/分の流速にて、0.1MPaの背圧を超えずに、5体積の結合緩衝液(リン酸緩衝液、20mM pH7)でカラムを平衡化することからなる。次いで抽出物の試料をカラム上に負荷し、次いで結合緩衝液で溶出する。この段階の間、免疫グロブリンは固定相に結合するのに対して、他のタンパク質はカラムから溶出される。IgGから喪失させた溶出タンパク質の回収は溶出液のUVをモニターすることにより自動的に誘導される。次の工程は、20ml/分の流速に設定したpH2.5にて酸性移動相(グリシン−HCl)を使用することにより免疫グロブリンを溶出することからなる。溶出工程の後、その正確な再生および保存のためにエタノール(20%)をカラム内にフラッシュすることが必要である。
5000Daからの限外濾過残余分を、0.2μmから再生されたセルロースから作製されたMilliporeフィルタ上で、真空下で濾過し、−20℃にて凍結し、凍結乾燥する。
緒にプールされてもよい。産物はいかなる場合も表1〜6に指定した定量的範囲を満たす。
インビトロ試験
最初の(Ex novo)骨形成
骨形成に対するP.M.F.の効果を、ヒトおよびマウスの骨形成間葉系幹細胞、および骨の前駆体の増殖および分化アッセイによりインビトロにおいて評価した。インビボで、PMFの骨形成活性を、PMFおよびヒドロキシアパタイトを含有するマトリゲル、無定形基質の皮下注射のモデルにおいて評価した。
骨芽前駆体(ヒト脂肪組織由来の幹細胞、hASC)のモデルとして、ヒト骨芽(Saos−2およびMG−63)細胞およびヒト間葉系幹細胞を使用して、細胞増殖に対するP.M.F.の効果を評価した。
間葉前駆体(ASC)およびヒト骨芽細胞(MG−63およびSAOS)を動員するPMFの能力を、細胞運動性を誘導する能力を研究するための重要な試験として認識されている、創傷治癒アッセイにより評価した。示した濃度(5mg/ml)におけるPMFは、ASCおよびMG−63について陽性対照(10%FBS)の条件と匹敵するように、ならびにSaosについて常に統計的に有意であるが、より少ない程度で細胞運動性を促進する。
歯科インプラントの表面をインビトロで試験するために一般に使用されている、平滑なチタンのシリンダを、PMFの機能化を可能にするためにポリアクリレート薄膜で被覆した。表面上のカルボキシル基の導入により、実際に、PMFに含まれる成長因子のアミノ酸残基に存在するアミノ基との共有結合の形成が可能となる。Saos−2ヒト骨芽細胞を試料上に播種し、3および6時間後に固定し、免疫細胞化学的分析のために調製した。ちょうど3時間後、処理していない表面と比べて、処理した表面上の細胞のより広い拡散に気づくことができ、一方、播種の6時間後において、拡散は2つの条件において同様であるが、細胞の数は機能化した表面について著しく多い。
マトリゲルにおける骨形成のインビボモデル
PMFの骨形成活性を、100マイクログラム/mlのPMFの存在または非存在下でBalb−C内にマトリゲルを皮下に接種することによって評価した。PMFを含有する基質の検査は、接種の10〜15日後、炎症細胞の動員を示した。
癒着不能または遷延治癒の高いリスクがある長い骨を骨折している5匹のイヌにおいて、3から15gのPMFを含有する骨格を骨折とプラークとの間に置いた。
インビボでの歯髄損傷
10匹のSprague−Dawleyラット、3ヶ月齢を、歯冠に対する傷害のモデルのために使用し、続いて、非特許文献6のプロトコルに従って充填した。ゼロ日目に、穴を臼歯の右近心面上に開け、水酸化カルシウムまたは200マイクログラムのPMFによる充填を空洞内に適用した。2つの歯は髄質炎症の陽性対照として開けたままにした。
陽性対照は顕著な炎症性浸潤を示した(図1A)のに対して、水酸化カルシウムで処理した歯は充血および浮腫を有する歯髄炎を示した(図1B)。PMFを含有する充填は正常な歯髄の特徴を維持した(図1C)。
インビトロ試験
PMFは、対照(10%FBS)と比較してヒト脂肪組織(hASC)に由来する間葉系幹細胞の増殖能力をかなり増加させた(>100%)。培養培地中で、2つの異なる濃度(5mg/mlおよび1mg/ml)で使用したPMFは、用量およびインキュベーション時間に依存した効果を有した。
PMF(100γ)を、1mlの架橋していないヒアルロン酸と混合した。ヒアルロン酸またはマトリゲルなどの他の媒体は、長期の真皮およびコラーゲンの再生を可能にするように15〜20日の期間でPMFを放出するように設計する。
PMF、マトリゲルまたはヒアルロン酸の混合物をマウスに皮下に注射する。7日後、支持体非晶質の周囲において血管細胞増殖が観察される。20日後、非晶質支持体には、細胞が完全にコロニー形成している。さらに30日後、コラーゲンの著しい形成が観察される。
ブタの尾の結紮は尾の下流の壊死を生じる。実験モデルは、1)生理的、2)生理食塩水+PMF、3)ヒアルロン酸+PMFの上流の注射を含む。
注射針による心筋の障害は、針自体からマトリゲル+100マイクログラムのPMFを放出することにより防がれた。筋細胞による病変のコロニー形成が最初に起こり、続いて完全な修復が起こる。
Claims (12)
- サイトカイン:約50から約500pg/mg、好ましくは71.46から340.76pg/mg、
成長因子:約1000から約7000pg/mg、好ましくは1321.80から6494.40pg/mg、
走化性因子:約5から50pg/mg、好ましくは6から24pg/mg、
幹細胞刺激因子:約100から1500pg/mg、好ましくは191から1105pg/mg、
抗菌/抗ウイルス因子:約15から80μg/mg、好ましくは18から75μg/mg、
補体C3a/C4aタンパク質:約1から5pg/mg、好ましくは1.10から2.70pg/mg、
の組合せ。 - 初乳の抽出により得られることを特徴とする請求項1に記載の組合せ。
- 胎盤の抽出により得られることを特徴とする請求項1に記載の組合せ。
- 分娩前血清から血清の抽出により得られることを特徴とする請求項1に記載の組合せ。
- 組織修復および再生を必要とする状態の処置に使用するためおよび幹細胞治療の代替のための請求項1〜4のいずれか一項に記載の組合せ。
- 前記状態は、骨外傷および変性病状、転移性骨病変、下顎または上顎歯槽突起の萎縮、骨折、小窩齲食および髄質炎症から選択されることを特徴とする請求項5に記載の組合せ。
- 場合により生体材料と組合せて、皮膚科および形成外科ならびに美容外科において充填剤として使用するための請求項1〜4のいずれか一項に記載の組合せ。
- 前記生体材料は、コラーゲン、ヒアルロン酸、マトリゲル、親水コロイド、ポリラクチド、ポリグリコリド、ポリカプロラクトンなどから選択されることを特徴とする、請求項7に記載の組合せ。
- 好適な担体および/または添加剤と混合して、活性成分として請求項1〜4のいずれか一項に記載の組合せを含むことを特徴とする医薬組成物。
- 非経口投与のための請求項9に記載の医薬組成物。
- 局所投与のための請求項9に記載の医薬組成物。
- 骨格、セメント、支持体、再吸収可能または再吸収不可能なインプラントの形態で請求項1に記載の組合せを含むことを特徴とする埋め込み可能な材料。
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ITMI2011A002438 | 2011-12-30 | ||
ITMI2011A002444 | 2011-12-30 | ||
ITMI2011A002437 | 2011-12-30 | ||
IT002438A ITMI20112438A1 (it) | 2011-12-30 | 2011-12-30 | Formulazioni iniettabili di citochine, fattori di crescita, fattori chemiotattici, fattori di stimolazione staminale e rna per la rigenerazione del derma |
IT002442A ITMI20112442A1 (it) | 2011-12-30 | 2011-12-30 | Composizioni per la terapia locale delle patologie ossee, traumatiche e degenerative comprendenti fattori di crescita e citochine |
IT002444A ITMI20112444A1 (it) | 2011-12-30 | 2011-12-30 | Composizioni per la riparazione tissutale comprendenti citochine, fattori di crescita e rna |
IT002437A ITMI20112437A1 (it) | 2011-12-30 | 2011-12-30 | Uso di citochine, fattori di crescita e fattori antibatterici come materiale di sottofondo di cavita' per la terapia della carie penetrante dei denti e dell'infiammazione pulpare |
ITMI2011A002442 | 2011-12-30 | ||
PCT/EP2012/076960 WO2013098331A1 (en) | 2011-12-30 | 2012-12-27 | Combination of growth factors, cytokines, antibacterial/antiviral factors, stem cell stimulating factors, complement proteins c3a/c4a, and chemotactic factors |
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EP3853356A4 (en) * | 2018-09-20 | 2022-09-14 | Mystem Biotechnologies Inc. | COLOSTRUM-DERIVED STEM CELLS, NEURAL DIFFERENTIATION, COMPOSITIONS AND SUPPLEMENTS TO IMPROVE MAMMAL HEALTH |
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JP6139562B2 (ja) | 2011-12-30 | 2017-05-31 | イノメッド ソシエテ アノニム | 成長因子、サイトカイン、抗菌/抗ウイルス因子、幹細胞刺激因子、補体タンパク質c3a/c4a、免疫グロブリンおよび走化性因子の組合せ |
WO2017059321A1 (en) * | 2015-10-02 | 2017-04-06 | Robert Diluccio | Composition for soft tissue augmentation providing protection from infection |
MX2022001441A (es) * | 2019-08-01 | 2022-02-22 | Septodont Ou Septodont Sas Ou Specialites Septodont | Biomaterial tridimensional cargado con fragmentos activos del complemento para la regeneracion dental y/o de otros tejidos. |
CN113230277A (zh) * | 2021-05-08 | 2021-08-10 | 陕西鸿瑞康生物科技有限公司 | 一种干细胞复合制剂及其制备方法 |
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