JP6353500B2 - Dkk1抗体およびその使用方法 - Google Patents
Dkk1抗体およびその使用方法 Download PDFInfo
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- JP6353500B2 JP6353500B2 JP2016175266A JP2016175266A JP6353500B2 JP 6353500 B2 JP6353500 B2 JP 6353500B2 JP 2016175266 A JP2016175266 A JP 2016175266A JP 2016175266 A JP2016175266 A JP 2016175266A JP 6353500 B2 JP6353500 B2 JP 6353500B2
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Description
アルゴリズム:Needleman et al.,1970,J.Mol.Biol.48:443−453、
比較マトリックス:BLOSUM 62 from Henikoff et al.,1992,上記参照、
ギャップペナルティ:12(但し、末端ギャップにはペナルティを用いない)
ギャップ長ペナルティ:4
類似度の閾値:0
本発明の方法は、骨関連障害、例えば、異常な骨芽細胞または破骨細胞活性と関連する骨関連障害の治療または予防に有用である。実際、本発明の治療剤は、軟骨形成不全、鎖骨頭蓋異骨症、内軟骨腫症、繊維性骨異形成症、ゴーシェ病、低リン血症、X連鎖低リン血症性くる病、マルファン症候群、多発性遺伝性外骨腫(multiple hereditary exotoses)、神経線維腫症、骨形成不全症、大理石骨病、骨斑紋症、硬化性病変、偽関節、化膿性骨髄炎、歯周病、抗てんかん薬誘発性骨量減少、原発性および続発性副甲状腺機能亢進症、家族性副甲状腺機能亢進症候群、無重力誘発性骨量減少、男性の骨粗鬆症、閉経後骨量減少、脊椎固定術、骨関節炎、腎性骨ジストロフィー、骨の浸潤性障害、口腔骨量減少、顎の骨壊死、若年性パジェット病、メロレオストーシス、代謝性骨疾患、肥満細胞症、鎌状細胞貧血/疾患、臓器移植関連骨量減少、腎臓移植関連骨量減少、全身性エリテマトーデス、強直性脊椎炎、てんかん、若年性関節炎症、地中海貧血症、ムコ多糖症、ファブリー病、ターナー症候群、ダウン症候群、クラインフェルター症候群、ハンセン病、ペルテス病(Perthe’s Disease)、青年期特発性脊柱側弯症、乳児性発症多系統炎症性疾患(infantile onset multi−system inflammatory disease)、ウィンチェスター症候群、メンケス病、ウィルソン病、虚血性骨疾患(例えばレッグ・カルベ・ペルテス病および局所遊走性骨粗鬆症)、貧血状態、ステロイドに起因する症状、糖質コルチコイド誘発性骨量減少、ヘパリン誘発性骨量減少、骨髄障害、壊血病、栄養不良、カルシウム欠乏症、骨粗鬆症、骨減少症、アルコール依存症、慢性肝疾患、閉経後状態、慢性炎症性症状、リウマチ性関節炎、炎症性腸疾患、潰瘍性大腸炎、炎症性大腸炎、クローン病、希発月経、無月経、妊娠、真性糖尿病、甲状腺機能亢進症、甲状腺障害、副甲状腺障害、クッシング病、末端肥大症、性腺機能低下症、運動不足または廃用、反射***感神経性ジストロフィー症候群、局所骨粗鬆症、骨軟化症、関節置換に関連する骨量減少、HIV関連骨量減少、成長ホルモンの損失に関連する骨量減少、嚢胞性線維症に関連する骨量減少、化学療法関連骨量減少、腫瘍誘発性骨量減少、癌関連骨量減少、ホルモン切除の骨量減少(hormone ablative bone loss)、多発性骨髄腫、薬物誘発性骨量減少、神経性無食欲症、疾患関連顔面骨量減少、疾患関連頭蓋(cranial)骨量減少、顎の疾患関連骨量減少、頭蓋(skull)の疾患関連骨量減少、加齢に伴う骨量減少、加齢に伴う顔面骨量減少、加齢に伴う頭蓋(cranial)骨量減少、加齢に伴う顎骨量減少、加齢に伴う頭蓋(skull)骨量減少、および宇宙旅行に関連する骨量減少からなる群から選択される骨関連障害に罹患しているヒトに投与することができる。
ヒトDKK1(huDKK1)免疫原の調製
ヒトDKK1のクローニングは、以下の修飾を用い、米国特許第6,344,541号に記載される通りに行った。ヒトDKK1の2つの異なるエピトープ標識された変形が、免疫原として使用され、1つはFLAGエピトープを含み、他方は、fc−融合分子であった。両方のエピトープタグは、当業者には明らかである標準の分子生物学技術を用いてヒトDKK1のカルボキシ末端に付加された。
免疫化および力価決定
組換えFLAG標識したヒトDKK1(FLAG−DKK1)および組換えFc標識したヒトDKK1(DKK1−fc)を、抗原として使用した。DKK1に対するモノクローナル抗体は、XenoMouse(登録商標)マウス(Abgenix,Inc.Fremont,CA)を連続的に免疫化することによって開発した(例えば米国特許第7,435,871号およびその中の説明を参照)。XenoMouse動物は、全ての注射について足蹠経路によって免疫を行った。免疫化XenoMouseマウスからの血清中の抗DKK抗体力価はELISAにより決定した。
リンパ球回収、B細胞単離、融合、およびハイブリドーマの生成
リンパ節を採取し、それぞれのコホートからプールした。総流出物をCD90陰性分画(これらの細胞の大部分は、B細胞であることが期待された)として収集した。上記の洗浄された濃縮B細胞と、ATCC、カタログ番号CRL1580から購入した非分泌性骨髄腫P3X63Ag8.653細胞(Kearney et al,J.Immunol.123,1979,1548−1550)とを1:1に比率で混合することによって融合を行った。電気細胞融合(ECF)は、融合発生器、モデルECM2001,Genetronic,Inc.,San Diego,CAを用いて実施した。使用された融合チャンバの大きさは2.0mLであった。
十分に培養した後、ハイブリドーマの上清をDKK1に特異的なモノクローナル抗体についてスクリーニングした。一次スクリーニングにおいて、ELISAプレートを、50μL/ウェルのFlag標識したrhDKK1(2μg/mL)で被覆し、次いで、4℃で一晩インキュベートした。インキュベーション後、プレートを洗浄緩衝液で3回洗浄し、次いで、200μL/ウェルのブロッキング緩衝液を添加し、プレートを室温でインキュベートした。インキュベーション後、プレートを洗浄緩衝液で3回洗浄した。ハイブリドーマの上清および陽性と陰性の対照のアリコート(50μL/ウェル)を添加し、プレートを室温で2時間インキュベートした。
生物活性によるヒトDKK1への中和抗体を生成するハイブリドーマの選択
実施例2に記載されるように得られたハイブリドーマを、ルシフェラーゼ発現が標準Wnt経路の制御下にあるTCF/lefルシフェラーゼレポーター構築体を利用して試験した。この構築体により形質移入された細胞が、生物学的に活性なWntに曝露された場合、ルシフェラーゼ活性が誘導される。Wnt誘導ルシフェラーゼ活性は、この構築体を含有する細胞に組換えDKK1タンパク質を添加することによって抑制することができる。本実験に関して、Wnt3aおよびDKK1の両方を最初に、Wnt依存ルシフェラーゼ発現の約80%を抑制する最適化量で細胞に添加した。中和活性のある抗DKK1抗体のこれらの同じ細胞へのさらなる添加は、Wnt活性を再生させ、したがって、ルシフェラーゼ発現を増加させることが予想される。Wnt/ルシフェラーゼ構築体でトランスフェクトされた細胞中のルシフェラーゼ発現を再生することが可能であるかどうかを判定するために、ハイブリドーマの上清を試験した。ルシフェラーゼ活性は、下記のように定量化した。
抗体のクローニングおよび配列分析
総RNAは、抗DKK1ハイブリドーマ細胞株から調製された。DNA配列は、Abgenixによって提供されたか、またはクローン化したRACE(cDNA末端の迅速増幅)PCR(ポリメラーゼ鎖反応)産物の配列決定によって得られた。
CHO細胞中のヒト抗huDKK1抗体の発現および精製
抗DKK1細胞株を、標準的な電気穿孔法の手順を用いて、発現プラスミドpDC323−抗DKK1カッパ、ならびに2.40.3、6.35.5、6.116.6のHC−IgG2およびLC−カッパのpDC324[抗DKK1−IgG2]と共にCHO宿主細胞をトランスフェクトすることによって創出した。発現プラスミドと共に宿主細胞株をトランスフェクトした後、プラスミドの選択および細胞の回収を可能するために、細胞を、4% 透析したウシ胎仔血清(dsまたはdfFBS)を含有する−GHT選択培地中で2〜3週間生育させた。次いで、血清を培地から除去し、細胞をGHT選択培地中で、>85%生存率に達するまで生育させた。次いで、このトランスフェクトされた細胞プールを、高度発現細胞に対して選択するために、[150−300]nM MTXを含有する培地中で培養し、続いて、500−1000nM MTXを含有する培地中で培養した。
ELISAベースの交差遮断アッセイ
本実施例において使用される液体体積は、96ウェルプレート ELISA(例えば、50〜200uL/ウェル)において一般的に使用されるものであった。本実施例では、Ab−XおよびAb−Yは、約145Kdの分子量を有し、1抗体分子当たり2つのDKK1結合部位を有することが想定された。抗DKK1抗体(Ab−X)を、96ウェルELISAプレート上に少なくとも1時間被覆した(例えば、50uLの1ug/mL)。このコーティングステップ後、抗体溶液を除去し、プレートを洗浄溶液で洗浄し、次いで、当該技術分野で公知の適切なブロッキング溶液および手順を用いて遮断した。ブロッキング溶液をELISAプレートから除去し、被覆抗体を交差遮断する能力について試験した第2の抗DKK1抗体(Ab−Y)を、ELISAプレートの適切なウェルにブロッキング溶液中で過剰に添加した(例えば、50uLの10ug/mL)。
5.25.1抗体に結合するヒトDKK1エピトープの特徴付け
ヒトDKK1は、N末端近傍およびC末端の端部に位置する2つのジスルフィドリッチドメインを含有し、本明細書では、N末端およびC末端ジスルフィドドメインと称される。N末端ジスルフィドドメイン(以後、「ジスルフィドドメイン1」または「D1」)は、55のアミノ酸残基(配列番号2のアミノ酸85〜139)を含有し、10個のシステインを有して、5つの分子内ジスルフィド結合を形成する。C末端ジスルフィドドメイン(以後、「ジスルフィドドメイン2」または「D2」)は、75のアミノ酸(配列番号2のアミノ酸189〜263)を含有し、10個のシステインを含有して、5つの分子内ジスルフィド結合も形成する。これらの2つのジスルフィドドメインは、約50のアミノ酸の伸長によって分離される。DKK1のジスルフィドドメイン2(D2)は、カノニカル補リパーゼ折り畳み体と同様の分子構造を有することが提案されており、その結晶構造は、ブタ補リパーゼを用いて決定されている(Aravind,A.and Koonin,E.V.,Current Biology 8:R477−479(1998))。DKK分子のN末端D1ドメイン中の10個のシステイン残基間で分子内ジスルフィド結合は、最近、決定されている。
hDKK1のCNBr開裂により、2つの大型断片が生成した。これらは、CNBr1およびCNBr2であり、これらはそれぞれ、D2およびD1ジスルフィドドメインを表した。CNBr1は、5つのジスルフィド結合により一緒に保持された2つのペプチド(配列番号2のアミノ酸179〜206および配列番号2のアミノ酸207〜266[または274(さらなるC末端flagペプチドを含む場合)])からなった。同様に、CNBr2は、2つのペプチド(配列番号2のアミノ酸32〜122および配列番号2のアミノ酸127〜178)からなり、5つのジスルフィド結合により一緒に保持された(表4)。BiaCore分析の結果は、5.25.1がCNBr2には有意に結合することができたが、CNBr1には全く結合しないことが示された。したがって、5.25.1は、HuDKK1のD1ジスルフィドドメインに位置したエピトープ領域に結合することが結論付けられた。
次に、ヒトDKK1を、ARGおよびLYS残基の後で開裂するトリプシンで消化した。0.5〜1.0mg/mLで約200μgのDKK1を、8μgのこれらのプロテアーゼの1つまたは他のものと共に37℃で20時間PBS(pH7.2)中でインキュベートし、DKK1の完全消化を達成した。
5.25.1結合エピトープをさらに描写するために、HuDKK1は、プロテアーゼAspNで消化し、得られた断片を上述のように分析した。AspN消化により生成した主要なHPLCピークのうち、抗体5.25.1に結合したピークは、AspN1、AspN2、およびAspN3であった。配列分析により、AspN1およびAspN2がジスルフィドドメインD1に由来することが示された。AspN1およびAspN2は、アミノ酸配列が同一であり、それらのそれぞれが、ジスルフィドドメインD1における5つのジスルフィド結合によって一緒に保持される2つのペプチドからなった。これらの2つのペプチドは、配列番号2のアミノ酸78〜104および105〜141からなった(表4を参照)。AspN3は、配列がドメインD1およびD2配列の両方を含有する部分的消化産物である。2つの他のピーク、AspN4およびAspN5はまた、単離され、ドメインD2においてジスルフィド結合したペプチドであることが確認され、AspN4またはAspN5は、5.25.1結合のためにはDKK1と競合しない。
上記の結果により、5.25.1は、ジスルフィドドメインD1に位置しているヒトDKK1の非線形エピトープに結合することを示す。図1に示されるように、エピトープ領域は、以下に記載される観察により推定される。
DKK1に対するモノクローナル抗体の結合親和性
BiaCore2000(BIACORE,Uppsala,Sweden)を用いてヒト抗huDKK1抗体のDKK1への結合を試験するために分析が実施された。BiaCoreにより、選択した抗体のkdの測定が可能であった。より低いkdを有する抗体は、より高いkdを有するものよりも長くhDKK1と結合するためより望ましく、したがって、より大きな応答を生じさせる可能性が高い。結合のセンサーグラムを分析し、データを以下に要約する。
11H10ビン抗体のみが、huDKK1のLRP6およびKremin2への結合を遮断する
DKK1のWnt共受容体LRP6またはKremin2への結合を遮断するための11H10ビンおよび5.25.1ビン抗体の能力を、共免疫沈降法を用いて調べた。組換えマウスLRP6−HisおよびrhDKK1−Flagまたは組換えヒトクレメン2−hisおよびhDKK1−flagは、一晩振とうしながら、ハンクス平衡塩類溶液中の抗DKK1抗体を用いて、または用いないで予めインキュベートし、複合体形成を可能にした。
選択した抗体のインビボ活性
マウス動物モデルにおけるDKK1の中和が、骨塩密度(BMD)および骨形成マーカー血清オステオカルシンの増加をもたらすかどうかを判定するために、実験を行った。試験した抗体は、2.40.2、5.32.5、5.80、6.37.5、6.116.6であり、上述のように精製した。
ヒトおよび動物モデルの血清および組織試料中のDKK1の検出
本明細書に記載される抗体を用いて、血清が含まれるが、これに限定されないヒト試料中のDKK1レベルを検出する。このタイプのアッセイを開発するために、本明細書に記載される2つの異なるエピトープ等の同じエピトープを認識しなかった2つの抗体を選択することは重要であった。ヒト血清または他の組織中のDKK1に対してアッセイするために、標準曲線が、最初に、組換えhuDKK1を用いて構築された。この標準曲線は、huDKK1を欠いている、または低レベルのhuDKK1を含むヒト血清中で構築されることが好ましかった。一般には、血清のために使用される標準曲線の範囲は、この範囲が分析される試料中に得られるhuDKK1の最小値および最大値に応じて調整する必要があり得るが、25pg/mL〜10ng/mLのhuDKK1である。使用したプロトコルの一例は、以下の通りであるが、当業者には明らかである修正は、利用される特定の抗体および試料に応じて行われ得る。
スクレロスチンおよびDKK1は、骨形成の負の調節因子である。スクレロスチンモノクローナル抗体(Scl−Ab)による全身療法によるスクレロスチンの阻害は、骨粗鬆症の動物モデルにおいて骨形成、骨量、および骨強度を有意に増加させた(Li XD,et al.J Bone Miner Res 2009;24:578)。さらに、Scl−Abによる処置が、骨修復の動物モデルにおいて骨折治癒を強化した(Ke HZ,et al.Trans ORS 2009;34:22、Ominsky M,et al.ASBMR abstract Sept 2009;Denver,CO)。同様に、モノクローナル抗体r11H10(DKK1−Ab)の全身投与によるDKK1の中和化は、マウス(Komatsu DE,et al.J Orthop Res 2010、DOI 10.1002/JOR.21078)およびラット骨折モデルの骨折部位での骨塩密度(BMD)および強度を増加した。Scl−AbおよびDKK1−Abの組み合わせが、成熟ラットモデルにおいて、骨形成を刺激し、骨折したおよび骨折していない骨における骨強度を増加させる上で相乗効果を有し得ると仮説を立てた。
Claims (15)
- 配列番号223〜228のアミノ酸配列を、それぞれ、軽鎖CDR1〜3および重鎖CDR1〜3として含み、ヒトDKK1に結合し、ヒトDKK1活性を阻害する、抗体またはその抗原結合断片。
- 配列番号94および96に示されるアミノ酸配列をそれぞれ軽鎖可変部および重鎖可変部として含み、ヒトDKK1に結合する、請求項1に記載の単離された抗体またはその抗原結合断片。
- 配列番号2のアミノ酸221〜236および/または246〜262の不連続エピトープに特異的に結合する、請求項1または2に記載の単離された抗体またはその抗原結合断片。
- エピトープが高次構造的である、請求項3に記載の抗体またはその抗原結合断片。
- Kremin2のヒトDKK1への結合を遮断する、請求項1〜4のいずれか1項に記載の抗体またはその抗原結合断片。
- 2.510E−04(1/s)以下のKdでヒトDKK1と結合する、請求項5に記載の抗体またはその抗原結合断片。
- 患者において骨塩密度を増加させる、請求項1〜6のいずれか1項に記載の抗体またはその抗原結合断片。
- 1×10−7M未満の親和性を有し、DKK1活性を阻害する、請求項1〜7のいずれか1項に記載の抗体を含む、骨障害を治療するための薬学的組成物。
- 骨障害が、骨折である、請求項8に記載の薬学的組成物。
- 請求項1〜7のいずれか1項に記載の抗体またはその抗原結合断片を含む、薬学的組成物。
- 薬学的に許容される賦形剤、希釈剤、または担体のうちの1つ以上と組み合わされる、請求項1〜7のいずれか1項に記載の抗体またはその抗原結合断片。
- 骨折修復を加速させるための薬学的組成物であって、請求項1〜7のいずれか1項に記載のDKK1抗体またはその抗原結合断片およびスクレロスチン抗体またはその抗原結合断片の組み合わせを含む、薬学的組成物。
- 前記DKK1抗体またはその抗原結合断片及びスクレロスチン抗体またはその抗原結合断片が、同時に投与される、請求項12に記載の薬学的組成物。
- 前記DKK1抗体またはその抗原結合断片及びスクレロスチン抗体またはその抗原結合断片が、骨折から1日以内に投与される、請求項13に記載の薬学的組成物。
- 前記DKK1抗体またはその抗原結合断片及びスクレロスチン抗体またはその抗原結合断片が、二重特異性または多特異性の成分である、請求項12に記載の薬学的組成物。
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