JP7487938B2 - 抗cd5l抗体及びその使用 - Google Patents
抗cd5l抗体及びその使用 Download PDFInfo
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- JP7487938B2 JP7487938B2 JP2020524126A JP2020524126A JP7487938B2 JP 7487938 B2 JP7487938 B2 JP 7487938B2 JP 2020524126 A JP2020524126 A JP 2020524126A JP 2020524126 A JP2020524126 A JP 2020524126A JP 7487938 B2 JP7487938 B2 JP 7487938B2
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Description
本願は、2017年10月30日付けで出願された欧州特許出願第17382725.4号の利益を主張する。
(a)医療レジメンの適用前に、被験体の単離された生体サンプル中のマクロファージ内のCD5Lの量をin vitroで測定する工程と、
(b)医療レジメンの適用を開始した後に、被験体の単離された生体サンプル中のマクロファージ内のCD5Lの量をin vitroで測定する工程と、
(c)工程(b)で測定されたマクロファージ内のCD5Lの量が工程(a)で測定されたマクロファージ内のCD5Lの量よりも少ない場合、その医療レジメンが癌の治療に有効であることを示すような方法で、工程(a)及び工程(b)で測定されたレベルを比較する工程と、
を含むか、又は、代替的には、上記方法は、
(i)医療レジメンの適用を開始した後に、被験体の単離された生体サンプル中のマクロファージ内のCD5Lの量をin vitroで測定する工程と、
(ii)工程(i)で測定されたレベルをマクロファージ内のCD5Lの基準対照レベルと比較する工程と、
を含み、
ここで、工程(i)で測定されたマクロファージ内のCD5Lの量が基準対照レベルより高くない場合、その医療レジメンが癌の治療に有効であることを示す。
VH配列は、配列番号7と85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%又は100%の配列同一性を有する、又は、代替的には、
VL配列は、配列番号8と85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%又は100%の配列同一性を有する、又は、代替的には、
VH配列は、配列番号7と85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%又は100%の配列同一性を有し、VLドメインは、配列番号8と85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、又は100%の配列同一性を有する配列からなる。
配列番号7の配列であるVH、又は、代替的には、
配列番号8の配列であるVL、又は、代替的には、
配列番号7の配列であるVH、及び配列番号8の配列であるVL、
を含む。
材料及び方法
組み換えヒトCD5L(rhCD5L)の生産
ヒトCD5LのcDNAは、NCBI参照配列NP_005885(バージョンNP_005885.1)に従って遺伝子合成(米国ニュージャージー州ピスカタウェイのGenScript)によって取得され、免疫グロブリンg鎖シグナルペプチドがhCD5Lのペプチドに置き換わった修飾を有する。cDNAをp.eviベクターにクローニングし、eviFectシステム(スイス国のEvitria AG)を使用してCHO K1細胞に一過性にトランスフェクトした。細胞を、化学的に定義された血清不含の動物性成分を含まない培地であるeviMake(商標)で成長させた。細胞培養上清をトランスフェクション後8日目に採取し、20mM Na2HPO4、pH7.4で透析し、MonoQクロマトグラフィーに供した。組み換えhCD5L(rhCD5L)を塩化ナトリウム勾配で溶出し、SDS-PAGEで精製をモニターした。精製されたタンパク質をPBSに透析し、Amicon ultra(Millipore、UFC901024)での遠心分離により濃縮し、可能性のあるエンドトキシン汚染をEndotrapカラム(Hyglos GmbH、321063)により、製造業者のプロトコルに従って除去した。精製したrhCD5Lを予備実験で試験したところ、マクロファージ(MФ)TNFα分泌に関するその活性と並んで、シクロヘキシミド処理によって誘導されるアポトーシスの阻害は、商業的に入手可能なrhCD5L(R&D Systems)のものに匹敵した(データは示していない)。
動物の維持管理は欧州連合に従い、動物実験及び治療プロトコルに関する国のガイドラインは、CNB/CSIC動物研究倫理委員会によって承認された。研究は、共同研究に関するCNB/CBMSO/CSIC倫理委員会、及びバルセロナサイエンスパーク(Parc Cientific de Barcelona)及びバルセロナ大学の倫理委員会によって承認された。
ヒトCD5Lに対するマウスmAbを、25μgのKLH結合rCD5Lを用いたBALB/cマウスの皮下免疫によって産生させた。SIGMA(マレイミド活性化BSA、KLHコンジュゲーションキット、米国ミズーリ州)において推奨されている標準手順に従って、マレイミド活性化KLHを使用して、KLHへの結合を行って免疫原性を高めた。0.15mLの滅菌PBSに結合させた25μgのKLHを、同量のフロイント完全アジュバント(Difco)で乳化した。28日目及び56日目にフロイントの不完全アジュバントに含まれる同量のタンパク質でマウスを皮下追加免疫した。
抗CD5Lモノクローナル抗体を、RNeasyミニキット(ドイツ国、Qiagen)を使用し、4D7産生ハイブリドーマ細胞株から抽出されたmRNAから製造業者の指示に従って配列決定した。次いで、製造業者の指示に従い、RNA to cDNAエコドライキット(日本国、タカラバイオ株式会社)を用いてmRNAをcDNAに逆転写した。該cDNAを使用して、表2に収載されているプライマーを使用してPCR増幅を行った。増幅されたcDNAをアガロースゲルで分解し、ゲルから切り出し、Qiaquick PCR精製キット(Qiagen)を使用して精製し、BigDye(商標)Terminator v3.1サイクルシーケンシングキット(米国ミシシッピ州のThermofisher)及びIGTP Genomicsプラットフォームサービスを使用して、SANGERシーケンシングにより同じプライマーで配列決定した。RT-PCR及び配列決定に使用したプライマーを表2に示す。
Blood and Tissue Bank(スペイン国バルセロナ)によって提供されるバフィーコートは、献血及び加工に関する機関の標準業務手続に従って、健康な献血者から入手した。
HepG2細胞、Huh7細胞及びSNU398細胞をATCC(The American Type Culture Collection)から購入し、2mMグルタミン(スイス国バーゼルのLonza)、100U/mLのペニシリン及びストレプトマイシン(Sigma-Aldrich)、並びに10%熱不活化ウシ胎児血清(FBS)(Lonza)で補完したEMEM(HepG2)、DMEM(Huh7)、又はRPMI(SNU398)で培養した。
培養培地にINF(インターフェロン)/LPS(リポ多糖)、IL4(インターロイキン4)、IL10(インターロイキン10)、DXM(デキサメタゾン)又は肝癌細胞CM(馴化培地)を次の通り添加することでPB単球を分極化させた:
INF/LPS:50ng/mLのIFNγ(米国ニュージャージー州ロッキーヒルのPreprotech、300-02-A)に加えて100ng/mLのE.コリO111:B4に由来するLPS(Sigma-Aldrich、l4391);
IL4、40ng/mlのIL-4(Preprotech;200-04-A);
IL10、50ng/mlのIL-10(Preprotech;200-10-A);
DXM、40ng/mlのデキサメタゾン(スペイン国テラサのKern pharma、672066.0);
CM、Huh7細胞、HepG2細胞、又はSNU-398細胞から収集した馴化培地のプール(上記を参照されたい)。
50.000不活性化又はIL10活性化されたPBマクロファージを10ng/mlのLPS(E.コリO111:B4、米国カリフォルニア州サンディエゴのInvivogen)で4時間刺激した。次いで、上清中のサイトカインを、製造業者の指示に従って、OptEIA ELISA(BD Biosciences)を用いるELISAによって測定した。3,3’,5,5’-テトラメチルベンジジン液体基質(Sigma-Aldrich、T8665)を添加することによって発色させ、光学密度をVarioskan Flashマイクロプレートリーダー(Thermo Fisher Scientific Inc.)により450nmで読み取った。
分極化マクロファージをAccutase(Sigma-Aldrich)で剥離させ、PBSで2回洗浄し、10%ヒトAB血清、2%FBS、及び0.02%NaN3(ブロッキングバッファー)を含むPBS 50μlと共に氷上で30分間インキュベートした。
PB単球(1×106細胞/ウェル)を、5%FCS及び上記の分極化刺激又はLXRアゴニストT1317(英国ブリストルのTocris Bioscience)に加えてCD5L mRNA誘導の陽性対照として使用される9-cis-レチノイン酸(9cRa)(Sigma-Aldrich)(T13+9CR)、1μMを含むRPMI培地中で24時間インキュベートした。
上記の培養培地中の2×105個のPB単球、又は図面に示す刺激で72時間分極化したものをアキュターゼ(Sigma-Aldrich、A6964)で剥離させ、氷冷PBSで2回洗浄し、100μlのブロッキングバッファー、10%FCS(Lonza)及び10%ヒトAB血清(Sigma-Aldrich、H4522)を含むPBSと共に氷上で30分間インキュベートした。
ヒトに関する研究はいずれも、ヘルシンキ宣言の原則及び個人データの機密性に関する現在の法律に従って行われ、Germans Trias i Pujol大学病院のヒト倫理委員会によって承認された。HCC患者からのレトロスペクティブサンプルを様々なスペインの病院:Josep Trueta、HuGTiP、Mar、Universitario Central de Asturias、及びParc Tauli Consortiumから得た。徹底的な病理検査の後、腫瘍又は隣接する組織の最も代表的な領域を、組織マイクロアレイ(TMA)を構築するために選択した。
野生型C57BL/6の脇腹に3×106個の3LLR細胞を皮下注射した。腫瘍を7日間成長させた後、PBS中150μgのCD5L moAb D7又は対照として同量のPBS(n=5マウス/群)を3日毎に7日間、腹腔内(i.p.)に与えた。腫瘍のサイズは、7日目から毎日カリパスを用いて手作業で測定し、腫瘍体積を(v=π×[w^2×l]/6)(幅、w、及び長さ、l)により計算した。15日目にマウスを屠殺し、更なる分析のため腫瘍及び脾臓を収集した。
CD3+T細胞をCellTrace Violet細胞増殖キット(Invitrogen)で製造業者の指示に従って染色した。細胞を一晩静置した後、1μg/mlのrhCD5Lの存在下/不在下で37℃、5%CO2にて5日間T細胞活性化/拡張キット(Miltenyi Biotech)を使用して、1:10の比率(ビーズ/T細胞)でCD2/3/28被覆ビーズにより刺激した。5日後にLSR Fortessa Analyzer(BD Biosciences)でT細胞の増殖を測定し、FlowJo V9.8.2の増殖モジュールを使用してFSC/SSCによってゲートされた生細胞のうちFSChighVioletlow細胞のパーセンテージとして表した。
統計分析をGraphPad Prism V.5ソフトウェア(米国カリフォルニア州ラホール)を使用して行った。特定の統計的検定は、各図の凡例に示されている。生存分析のために、カプラン-マイヤー法及びログランク検定を実施して、曲線間の違いを比較した。*p≦0.05の値を有意であると見なした。
M2活性化マクロファージはCD5Lを発現する
本発明者らは、マクロファージのin viroでのM2分極化がCD5L発現に何らかの変化を誘導するかどうかを試験した。
CD5Lの高発現がM2マクロファージで観察されたことを考慮して、本発明者らは次に、CD5L自体がこの細胞表現型を誘導することができたかどうかを試験した。図2で観察されるように、初代細胞培養物(すなわちPB単球)に組換えヒトCD5L(rhCD5L)を添加すると、未処理(M)又はアルブミン(hSA)で処理した細胞と比較して、これらの細胞でCD163の発現の増加を促進した。したがって、CD5LはM2様分子及び機能的表現型の獲得における活発な分子プレーヤーである。
CD5LがM2分極化を誘導し、IL-10と同様に肝癌CMの分極化マクロファージで過剰発現することを考慮して、本発明者らは次に、抗体によるCD5Lの阻害がIL10(M2)分極化に影響するかどうかを試験した。
抗CD5L抗体がM2活性化を阻害することができたことを考慮して、本発明者らは次に、上記抗体がM2活性化マクロファージの炎症反応を回復できるかどうかを試験した。
HCCにおけるCD5Lの肝臓マクロファージ発現を評価するために、n=60のHCC腫瘍(T)/44の隣接する肝臓(NT)を含むTMAでIF染色を行った。
本発明者らは次に、CD5Lを免疫療法の標的として使用できるかどうかを評価した。n=5マウスの野生型マウスの脇腹にルイス肺癌(LLC)細胞を皮下注射し、3日毎に腹腔内(i.p.)にCD5L特異的moAb D7を与え、続いて腫瘍の成長をモニタリングした。対照動物には同量のPBSを与えた。本発明者らは、抗CD5L moAb D7で処理したLLC担腫瘍マウスは、PBS注射マウスと比較して、腫瘍体積として測定された腫瘍がより小さいことを見出した(図5を参照されたい)。
rhCD5LがT細胞生物学に影響を与えるかどうかを評価するため、本発明者らは、rhCD5Lの添加がポリクローナル刺激に応答してT細胞の増殖を変更し得るかどうかを判断した。このため、T細胞をrhCD5Lの存在下又は不在下でCD2/3/28ビーズを用いて刺激した。図6で観察されるように、rhCD5Lの存在は生存率(B)に影響を与えることなく、T細胞の増殖(A)を低下させた。
WO9839443
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Claims (7)
- マクロファージにおいて免疫抑制性M2表現型を阻害するための医薬組成物であって、治療有効量のCD5L結合剤を、1つ以上の薬学的に許容可能な担体又は添加剤と共に含み、
前記CD5L結合剤が、マクロファージにおける免疫抑制性M2表現型を阻害することができる抗CD5Lモノクローナル抗体であり、
前記抗CD5Lモノクローナル抗体が、
a.配列番号3からなる配列のCDR1、配列番号4からなる配列のCDR2、及び配列番号1からなる配列のCDR3を、前記順序で含むVH配列;及び、
b.配列番号5からなる配列のCDR1、配列番号6からなる配列のCDR2、及び配列番号2からなる配列のCDR3を、前記順序で含むVL配列
を含む、医薬組成物。 - マクロファージにおいて免疫抑制性M2表現型を阻害するための医薬組成物であって、治療有効量のCD5L結合剤を、1つ以上の薬学的に許容可能な担体又は添加剤と共に含み、
前記CD5L結合剤が、マクロファージにおける免疫抑制性M2表現型を阻害することができる抗CD5Lモノクローナル抗体であり、
前記抗CD5Lモノクローナル抗体が、
a.配列番号9からなる重鎖;及び、
b.配列番号10からなる軽鎖
を含む、医薬組成物。 - 治療方法において炎症促進性応答の支持のために用いられる、請求項1又は2に記載の医薬組成物。
- 癌免疫療法のために用いられる、請求項1又は2に記載の医薬組成物。
- 前記癌が、乳頭腫、腺腫、脂肪腫、骨腫、筋腫、血管腫、母斑、成熟奇形腫、癌腫、肉腫、未熟奇形腫、黒色腫、骨髄腫、白血病、ホジキンリンパ腫、基底細胞腫、脊髄腫、乳癌、卵巣癌、子宮癌、肺癌、気管支癌、前立腺癌、結腸癌、膵臓癌、腎臓癌、食道癌、肝細胞癌(HCC)、及び頭頸部癌からなる一覧から選択される、請求項4に記載の医薬組成物。
- a.(a)請求項1又は2で定義されるCD5L結合剤と、
b.(b)前記CD5L結合剤を被験体に投与して、該被験体において炎症促進性応答を誘導し、M2活性化を阻害するための説明書と、
を備え、
被験体において炎症促進性応答を誘導し、M2活性化を阻害する方法において使用するためのキット。 - 前記使用が癌免疫療法のための使用である、請求項6に記載のキット。
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