JP2018533360A - ヒトcd40に特異的に結合するアゴニスト抗体及び使用方法 - Google Patents
ヒトcd40に特異的に結合するアゴニスト抗体及び使用方法 Download PDFInfo
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Abstract
Description
本発明は、抗原提示細胞(APC)及びB細胞を強力に活性化する、ヒトCD40に特異的に結合するアゴニスト抗体を提供する。抗体が示し得るアゴニスト活性は、架橋の非存在下では極めてわずかであるか又はないため、抗体は、がん適応のための臨床開発において他の抗CD40抗体と比較したときに、有効性を維持しながら改善された安全性プロファイルを有し得る。
0.01%のポリソルベート20(PS−20)及び100μg/mlのウシ血清アルブミンを含有するダルベッコリン酸緩衝生理食塩水中で25℃でProteOn XPR36システムを使用して解離定数(KD)が測定される場合に、約5×10-9M以下のKDで配列番号75のヒトCD40に結合すること、又は
B細胞及び樹状細胞(DC)に対するそのアゴニスト活性のために架橋を必要とし、CD23及びCD83表面発現がフローサイトメトリーを使用して測定される場合に、20μg/mlの架橋剤抗ヒトF(ab’)2の存在下で、B細胞に対するアゴニスト活性がB細胞CD23表面発現によって測定され、DCに対するアゴニスト活性がDC CD83表面発現によって測定されること。
0.01%のポリソルベート20(PS−20)及び100μg/mlのウシ血清アルブミンを含有するダルベッコリン酸緩衝生理食塩水中で25℃でProteOn XPR36システムを使用して解離定数(KD)が測定される場合に、約5×10-9M以下のKDで配列番号75のヒトCD40に結合すること、又は
B細胞及び樹状細胞(DC)に対するそのアゴニスト活性のために架橋を必要とし、CD23及びCD83表面発現がフローサイトメトリーを使用して測定される場合に、20μg/mlの架橋剤抗ヒトF(ab’)2の存在下で、B細胞に対するアゴニスト活性がB細胞CD23表面発現によって測定され、DCに対するアゴニスト活性がDC CD83表面発現によって測定されること、
のうちの少なくとも1つを有する、抗体又はその抗原結合フラグメントも提供する。
0.01%のポリソルベート20(PS−20)及び100μg/mlのウシ血清アルブミンを含有するダルベッコリン酸緩衝生理食塩水中で25℃でProteOn XPR36システムを使用して解離定数(KD)が測定される場合に、約5×10-9M以下のKDで配列番号75のヒトCD40に結合すること、又は
B細胞及び樹状細胞(DC)に対するそのアゴニスト活性のために架橋を必要し、CD23及びCD83表面発現がフローサイトメトリーを使用して測定される場合に、20μg/mlの架橋剤抗ヒトF(ab’)2の存在下で、B細胞に対するアゴニスト活性がB細胞CD23表面発現によって測定され、DCに対するアゴニスト活性がDC CD83表面発現によって測定されること、のうちの少なくとも1つを有する。
本発明はまた、本発明の抗体のVH、本発明の抗体のVL、本発明の抗体の重鎖又は本発明の抗体の軽鎖をコードする、単離されたポリヌクレオチドも提供する。
抗体のVHをコードしている第1のポリヌクレオチド及び抗体のVLをコードしている第2のポリヌクレオチドを発現ベクターに組み込むステップと、
宿主細胞を発現ベクターで形質転換させるステップと、
VL及びVHが発現し、抗体を生成する条件下で、培養培地中で宿主細胞を培養するステップと、
宿主細胞又は培養培地から抗体を回収するステップと、を含む方法である。
ヒトCD40に特異的に結合する本発明のアゴニスト抗体は、インビトロ及びインビボで、診断上の有用性、並びに治療及び予防上の有用性を有する。例えば、本発明の抗体を、培養中の細胞にインビトロ若しくはエクスビボで、又はがん及び感染性疾患などの様々な障害を処置、予防及び/若しくは診断する対象に、投与することができる。
ヒトCD40に特異的に結合する本発明のアゴニスト抗体は、抗体と薬学的に許容される担体とを含む好適な医薬組成物の状態で提供することができる。担体は、CD40に特異的に結合するアゴニスト抗体と一緒に投与される賦形剤、アジュバント、添加剤、又はビヒクルであり得る。そのようなビヒクルは、水、及び石油、動物、植物、又は合成物起源のものを含む油、例えば落花生油、大豆油、鉱物油、ゴマ油などの液体であってよい。例えば、0.4%生理食塩水及び0.3%グリシンを用いることができる。これらの溶液は滅菌されており、一般には粒子状物質を含まない。これらは、通常の周知の滅菌技術(例えば、濾過)によって滅菌することができる。組成物は、生理学的条件に近づけるために必要とされる薬学的に許容される補助物質、例えばpH調製剤及び緩衝剤、安定化剤、増粘剤、滑剤並びに着色剤などを含有し得る。そのような医薬製剤中の本発明の分子又は抗体の濃度は、幅広く異なっていてもよく、すなわち、約0.5重量%未満から、通常は少なくとも約1重量%まで、最大で15又は20重量%、25重量%、30重量%、35重量%、40重量%、45重量%、又は50重量%までであってよく、選択される特定の投与方法に従って、必要とされる用量、流体体積、粘度などに主に基づいて選択される。好適なビヒクル及び製剤(他のヒトタンパク質、例えばヒト血清アルブミンを含む)は、例えば、Remington:The Science and Practice of Pharmacy,21st Edition,Troy,D.B.ed.,Lipincott Williams and Wilkins,Philadelphia,PA 2006,Part 5,Pharmaceutical Manufacturing pp 691〜1092に記載されており、特にpp.958〜989を参照されたい。
本発明は、がんを有する対象を処置する方法であって、ヒトCD40に特異的に結合する治療有効量の本発明のアゴニスト抗体を、第2の治療剤と組み合わせて投与するステップを含む、方法を提供する。
QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSS
配列番号167
EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASY
LESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIK
配列番号168
QVQLVESGGGVWQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSS
配列番号169
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATG
IPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK
EVQLVESGGG LVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVAN IKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREG GWFGELAFDYWGQGTLVTVSS
配列番号171
EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQK PGQAPRLLIY
DASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFG
QGTKVEIK
配列番号172
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAW
ISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRH
WPGGFDYWGQGTLVTVSS
配列番号173
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYS
ASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQ
GTKVEIK
配列番号174
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSS
IYPSGGITFYADTVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIK
LGTVTTVDYWGQGTLVTVSS
配列番号175
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMI
YDVSNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRV
FGTGTKVTVL
本発明は、本発明の抗体に結合する抗イディオタイプ抗体を提供する。
「免疫複合体(immunoconjugate)」は、1つ以上の異種分子とコンジュゲートした本発明の抗体を指す。
本発明はまた、ヒトCD40に特異的に結合する本発明のアンタゴニスト抗体を含むキットも提供する。
本発明はまた、サンプル中のCD40を検出する方法であって、サンプルを入手するステップと、サンプルを本発明の抗体と接触させるステップと、サンプル中のCD40に結合している抗体を検出するステップと、を含む方法も提供する。
試験において使用される抗原の作製
抗原のクローニング、発現及び精製は、標準的な方法を使用して行った。使用したタンパク質のアミノ酸配列を以下に示す;
完全長ヒトCD40(huCD40);配列番号75
MVRLPLQCVLWGCLLTAVHPEPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTETECLPCGESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTICTCEEGWHCTSEACESCVLHRSCSPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKDLVVQQAGTNKTDVVCGPQDRLRALVVIPIIFGILFAILLVLVFIKKVAKKPTNKAPHPKQEPQEINFPDDLPGSNTAAPVQETLHGCQPVTQEDGKESRISVQERQ
ヒトCD40細胞外ドメイン(huCD40−ECD);配列番号76
EPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTETECLPCGESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTICTCEEGWHCTSEACESCVLHRSCSPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKDLVVQQAGTNKTDVVCGPQDRLR
カニクイザル(Macaca fascicularis)(カニクイザル(cynomolgous)、本明細書では以降カニクイザルと称する)CD40(cCD40);配列番号77
MVRLPLQCVLWGCLLTAVYPEPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTETECLPCSESEFLDTWNRETRCHQHKYCDPNLGLRVQQKGTSETDTICTCEEGLHCMSESCESCVPHRSCLPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCRPWTSCETKDLVVQQAGTNKTDVVCGPQDRQRALVVIPICLGILFVILLLVLVFIKKVAKKPNDKAPHPKQEPQEINFLDDLPGSNPAAPVQETLHGCQPVTQEDGKESRISVQERQ
カニクイザルCD40細胞外ドメイン(cCD40−ECD);配列番号78
EPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTETECL
PCSESEFLDTWNRETRCHQHKYCDPNLGLRVQQKGTSETDTICTCEEGLHCMSESCESCVPHRSCLPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCRPWTSCETKDLVVQQAGTNKTDVVCGPQDRQR
完全長ヒトCD154;配列番号83
MIETYNQTSPRSAATGLPISMKIFMYLLTVFLITQMIGSALFAVYLHRRLDKIEDERNLHEDFVFMKTIQRCNTGERSLSLLNCEEIKSQFEGFVKDIMLNKEETKKENSFEMQKGDQNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLL
可溶性ヒトCD154;配列番号88
MQKGDQNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL
可溶性カニクイザルCD154(配列番号45)
MQKGDQNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL
製造者(MACS Miltenyi)のプロトコールに従ってCD14ネガティブアイソレーションキットを使用して、凍結/新鮮PBMCのいずれかからヒト単球を単離した。製造者(MACS Miltenyi)のプロトコールに従ってCD14ポジティブアイソレーションキットを使用して、新鮮PBMCからカニクイザル単球を単離した。DCを作製するために、完全培地RPMI(Invitrogen)中で、100ng/mlのヒトGM−CSF及びヒトIL−4(Peprotech)の存在下で5日間、単球を培養し、培地を2日ごとに補充した。5日目に、100ng/mlのLPS(Sigma)で24時間、DCを刺激した。次に、試験したCD40抗体のそれぞれを用いて100μlの体積のフローサイトメトリー緩衝液(PBS+1%FBS;BD Bioscience)中で異なる濃度で氷上で30分間、細胞を染色し、その後、フローバッファーで2回洗浄した。次に、細胞を更に30分間氷上で、APCコンジュゲート抗ヒトIgG(Jackson ImmunoResearch)を推奨される1:100の希釈率で用いて染色し、フローバッファーで2回洗浄した。細胞の陽性パーセント及び平均蛍光強度(Mean Fluorescence Intensity、MFI)を分析して、Fortessa(BD Bioscience)を使用して抗体の結合を測定した。
Raji細胞はATCCから入手し、HEK CD40細胞株はInvivogenから入手した。会社の推奨に従って完全RMPI培地中で細胞を培養した。染色は、初代ヒト及びカニクイザルDCでの結合アッセイに関して上述したとおり行った。
ヒトDCは、上述したとおり作製した。ヒトB細胞は、製造者(MACS Miltenyi)のプロトコールに従ってB細胞ネガティブアイソレーションキットを使用して、新鮮な又は凍結したPBMCから単離した。各CD40抗体の力価測定(titration)は、96ウェルU底プレートにプレーティングして、細胞を添加し、混合物を室温で15分間インキュベートした。培地又は一定濃度20μg/mlの架橋剤抗ヒトF(ab’)2のいずれかを添加し、複合体を、DCアッセイでは24時間、B細胞アッセイでは48時間、37℃のインキュベーターでインキュベートした。終了時点で細胞を回収し、フローバッファーで2回洗浄し、ヒトFcブロック(Miltenyi)と一緒に室温で15分間インキュベートし、その後1回洗浄した。次に、細胞を、活性化マーカーCD80、CD83、CD86、HLA−DR及びCD23(BD Bioscience及びBioLegend)に関して30分間氷上で染色し、その後2回洗浄した。BD Fortessaを使用して細胞を分析した。
製造者(MACS Milteny)のプロトコールに従ってB細胞ポジティブアイソレーションキットを使用して、新鮮PBMCからカニクイザルB細胞を単離した。活性化アッセイは、ヒトDC及びB細胞に関して上述したとおりに準備した。
CD40を過剰発現するHEK−Blue(商標)CD40L細胞(Invivogen)を使用して、抗体がCD40〜CD154相互作用をブロックする能力又はCD40を活性化する能力のいずれかを評価した。HEK−Blue(商標)CD40L細胞株は、ヒトCD40及びNF−κB誘導性分泌型アルカリホスファターゼ(SEAP)を安定して発現する。HEK−Blue(商標)CD40L細胞においてCD40を活性化することにより、下流のシグナル伝達イベントが誘導され、NF−κBの活性化及びSEAPの分泌が引き起こされる。これを、製造者の指示に従ってQUANTI−Blue(商標)を使用して測定することができる。CD40活性化をブロック又は受容体活性化する能力のいずれかに関して、抗CD40抗体を評価した。
販売業者のプロトコールに従って取り扱い及び維持したHEK−Blue(商標)CD40L細胞株(Invivogen)を、96ウェル組織培養プレート中に、1ウェル当たり2.5×104個の細胞密度で100μlの体積で播種した。アッセイプレートに蓋をし、細胞を終夜回収した(37℃、5% CO2)。翌日、rhCD154−ECD−Hisの4×溶液(40ng/mlの最終濃度)及び適切な濃度(1〜25μg/mlの最終濃度)の4×抗CD40mAb又はFabを調製し、100μl/ウェルの得られる2×溶液を、HEK−Blue CD40L(商標)細胞を含有する96ウェルアッセイプレートに添加した(200μl/ウェルの最終体積)。16〜24時間のインキュベーション(37℃、5% CO2)時間の後、販売業者のプロトコールに従って調製した160μl/ウェルの予め加温したQUANTI−Blue(商標)(Invivogen)に40μl/ウェルの上清を添加することによって、96ウェルアッセイプレート中でホスファターゼ活性について上清を分析した。プレートを密封し、30〜60分間インキュベートした後、650nmでの吸光度を得た。
HEK−Blue(商標)CD40L細胞を前述のとおり播種し、終夜回収した。翌日、HEK−Blue(商標)CD40L細胞を含有する96ウェルプレートにCD40 mAbを2×溶液として添加し(200μlの最終体積/ウェル)添加し、プレートを終夜インキュベートした(37℃、5% CO2)。抗CD40 mAb単独のアゴニスト活性を測定するために、1〜25μg/mlの広範囲の最終アッセイ濃度を使用した。抗CD40 mAbのアゴニスト活性に対する架橋の影響を測定するために、抗体の4×溶液及び抗hIgG Fcフラグメントに対するF(ab’)2フラグメントの4×溶液(mAbに対して5〜10倍過剰)を、細胞添加の前にRTで1時間プレインキュベートし、1μg/mlの抗CD40 mAbで力価測定を開始して用量曲線を得た。16〜24hのインキュベーション(37℃、5% CO2)の後、販売業者のプロトコールに従って調製した160μl/ウェルの予め加温したQUANTI−Blue(商標)(Invivogen)に40μl/ウェルの上清を添加することによって、96ウェルアッセイプレート中でホスファターゼ活性について上清を分析した。プレートを密封し、30〜60分間インキュベートした後、650nmでの吸光度を得た。
ファージディスプレイライブラリーからの抗CD40抗体の単離
Shi et al.,J Mol Biol 397:385〜96,2010、国際公開第2009/085462号及び米国特許出願公開第2010/0021477号に記載されているように、デノボpIXファージディスプレイライブラリーからCD40結合Fabを選択した。簡潔に述べると、ヒト足場を多様化することによってライブラリーが作製され、生殖系列VH遺伝子IGHV1−69*01、IGHV3−23*01、及びIGHV5−51*01が、H3ループを介してヒトIGHJ−4ミニ遺伝子と組み換えられ、ヒト生殖系列VLκ遺伝子O12(IGKV1−39*01)、L6(IGKV3−11*01)、A27(IGKV3−20*01)、及びB3(IGKV4−1*01)がIGKJ−1ミニ遺伝子と組み換えられて、完全なVH及びVLドメインのアセンブリが行われた。多様化のために、タンパク質抗原及びペプチド抗原と高頻度に接していると特定された位置に相当する、H1、H2、L1、L2及びL3ループ周辺の重鎖及び軽鎖可変領域内の位置を選択した。選択した位置での配列多様性は、それぞれのIGHV又はIGLV遺伝子のIGHV又はIGLV生殖系列遺伝子ファミリーにおいてそれぞれの位置で見られる残基に制限した。H3ループにおける多様性は、7〜14アミノ酸長の単鎖〜中鎖の合成ループを使用して作製した。H3におけるアミノ酸分布は、ヒト抗体において観察されたアミノ酸変異を模倣するように設計された。ライブラリー設計の詳細は、Shi et al.,J Mol Biol 397:385〜96,2010に記載されている。ライブラリーを作製するために利用した足場は、これらの由来するヒトVH及びVL生殖系列遺伝子に従って命名した。3つの重鎖ライブラリーを、4つの生殖系列軽鎖と組み合わせるか、又は多様化した軽鎖ライブラリーと組み合わせて、12の特有のVH:VL組み合わせを作製した。3つのライブラリーは、その後、ライブラリーのバージョンに基づいて更に組み合わせて、CD40に対するパニング実験用の更なるライブラリーを作製した。
ヒト免疫グロブリンの遺伝子座を発現しているトランスジェニックラット、OmniRat(登録商標)(OMT,Inc)を使用して、抗CD40抗体を作製した。OmniRat(登録商標)の内因性イムノグロブリン遺伝子座は、ヒトIgκ及びIgλ遺伝子座と、ラットCH遺伝子座に結合したヒト起源のV、D及びJセグメントを有するヒト/ラットキメラIgH遺伝子座とで置き換えられている。IgH遺伝子座は、22個のヒトVHセグメント、全てのヒトDセグメント及びJHセグメントを、ラットCH遺伝子座に結合された天然の構成で含有する。OmniRat(登録商標)の作製及び特徴付けは、Osborn,et al.J Immunol 190:1481〜1490,2013、及び国際公開第14/093908号に記載されている。
CD40に対するCD154の結合をブロックした選択抗体を、CD40を発現する様々な細胞に対する結合について更に特徴付けた。
前述のアッセイを使用して、架橋剤抗ヒト(F(ab’)2の存在下又は非存在下で、初代ヒト樹状細胞及びB細胞を架橋依存的に活性化する能力について選択抗体を試験した。図1は、CD23表面発現誘導(図1A及び図1B)又はHLA−DR表面発現誘導(図1C及び図1D)によってB細胞活性化を評価した場合に、選択抗体が、架橋剤の存在下においてのみB細胞を活性化可能であったことを示す。図2は、CD83表面発現誘導(図2A及び図2B)又はHLA−DR表面発現誘導(図2C及び図2D)によってDC活性化を評価した場合に、選択抗体が、架橋剤の存在下においてのみDC細胞を活性化可能であったことを示す。アッセイにおいて使用した対照抗体は、架橋非依存的にB及びDC細胞活性化を誘導する(CP−870,893)。
抗体単離及びポリペプチド鎖のシーケンシングは、標準的な方法を使用して行った。選択抗CD40抗体のHCDR1アミノ酸配列を、表7に示す。
IGHV3−23*03(配列番号79)
>IGHV3−23*03
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSVIYSGGSSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK
IGHV1−69*01(配列番号80)
>IGHV1−69*01
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCAR
IGHV3−23*01(配列番号81)
>IGHV3−23*01
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK
IGHV3−23*04(配列番号82)
>IGHV3−23*04
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK
IGHV4−39*01(配列番号73)
>IGHV4−39*01
QLQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPGKGLEWIGSIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAR
IGKV3−20*01(配列番号74)
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSP
IGKV4−1*01(配列番号84)
>IGKV4−1*01
DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTP
IGKV1−39*01(配列番号85)
>IGKV1−39*01
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTP
IGLV3−1*01(配列番号86)
IGLV3−1*01
SYELTQPPSVSVSPGQTASITCSGDKLGDKYACWYQQKPGQSPVLVIYQDSKRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCQAWDSST
IGLV2−8*01(配列番号87)
>IGLV2−8*01
QSALTQPPSASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVSKRPSGVPDRFSGSKSGNTASLTVSGLQAEDEADYYCSSYAGSNNF
C40M9のVH(C40H43;配列番号60)は、IGHV4−39の最も近いヒト生殖系列配列の配列(配列番号73)とは異なる、フレームワーク領域中の3つのアミノ酸を有していた。IGHV4−39と比較したC40H43残基1〜98のアライメントを図3に示す。
QLQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPGKGLEWIGSIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAR
SYELTQPPSVSVSPGQTASITCSGDKLGDKYACWYQQKPGQSPVLVIYQDSKRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCQAWDSST
ProteOn XPR36システム(BioRad)を用いた表面プラズモン共鳴(SPR)を使用して、親和性測定を実施した。アミンカップリング化学反応についての製造者の使用説明書を用いて、抗ヒトIgG Fc(Jacksonカタログ番号109−005−098)を、GLCチップ(BioRad,カタログ番号176−5011)の加工アルギン酸ポリマー層表面にカップリングさせて、バイオセンサー表面を調製した。約5000RU(レスポンスユニット)のmAbを固定化した。速度論的実験は、ランニングバッファー(DPBS+0.01%P20+100μg/ml BSA)中で25℃で行った。速度論的実験を行うために、200RUのmAbを捕捉した後、分析物(ヒト又はカニクイザルCD40)を5つの濃度(4倍の段階希釈)で注入した。50μL/minで3分間、結合相をモニターした後、15分間バッファーを流した(解離相)。100μL/分で100mM H3PO4(Sigma、カタログ番号7961)を18秒間ずつ2回流してチップ表面を再生した。
C40M55 n=2回の反復試験、値は平均及び(範囲)で記載
2つのサンプル(C40M9、C40M55)は1:1結合モデルにうまく適合しなかった。
S267E変異をC40M121に導入して、mAb C40M126を作製した。C40M126は、樹状細胞におけるHLA−DR表面発現誘導によって評価した場合、架橋に非依存的に受容体活性化を強化することを示した(図6)。
方法
ヒトCD40のHisタグ付き細胞外ドメイン(ECD)を、バキュロウイルスに感染させたHi5昆虫細胞において発現させ、Genscript(Piscataway,NJ)でアフィニティ及びサイズ排除クロマトグラフィーによって精製した。mAb C40M126のHisタグ付きFabフラグメントを、HEK293 Expi細胞において発現させ、アフィニティ及びサイズ排除クロマトグラフィーによって精製した。1:1.2のモル比でFabを過剰にして成分を混合して抗体−抗原複合体を調製し、4℃で終夜インキュベートした。タンパク質を、20mM HEPES pH7.5、100mM NaCl中で12mg/mLまで濃縮し、1.6M硫酸アンモニウム、5% PEG 400、0.1M HEPESを含有するpH7.5の溶液から蒸気拡散法によって結晶化した。1つの結晶を、24%グリセロールを加えた母液に移し、液体窒素中で凍結させ、X線回折データ収集に使用した。構造を、3.0Åの解像度で決定した。
C40M126は、細胞表面から遠い位置でCD40に結合する(図5)。エピトープは立体構造であり、β−ヘアピンを形成するアミノ酸残基46〜64の連続的な区間及び隣接するループの更に2つの残基75〜76(残基番号付けは配列番号75に従う)を含む。CD40の結合に関与する抗体残基は、軽鎖の9残基及び重鎖の11残基を含む(図6)。6つ全てのCDRが結合に関与している。抗体−抗原境界面は、各分子上で900Å2に及び広がっている。
材料及び方法
終夜(又は少なくとも8時間)絶食したナイーブなカニクイザルに、0.1mg/kg、10mg/kg又は10mg/kgで、抗CD40抗体C40M9、C40M126又は対照抗体CP−870,893の単回ボーラス静脈内注射を行った。この試験の動物福祉は、米国農務省(USDA)の動物福祉法(Animal Welfare Act)(米国連邦規則集(CFR)第9巻1、2及び3条)を遵守した。
雄のカニクイザルに、C40M9、C40M126又は対照抗体CP−870,893の単回静脈内ボーラスを、0.1、1.0、又は10mg/kgの用量で投与した。概して、CP−870,893の投与で影響が生じやすく、又は影響が最も顕著であった。以下の所見が観察された:
・10mg/kgのC40M9並びに1.0及び10mg/kgのCP−870,893において、血液塗抹標本顕微鏡検査において網状赤血球数、赤血球分布幅(RDW)、多染性、及び/又は有核赤血球が増加したこと;赤血球量の減少は21日目及び/又は28日目までに回復傾向であったが再生応答は概して持続したことによって示されるように、適切な再生応答のエビデンスで以て、赤血球量の中程度の減少。
・0.1、1.0、及び10mg/kgのCP−870,893において、血小板数の一時的な軽微〜中程度の減少。
・10mg/kgのCP−870,893において、軽い炎症性刺激を示唆するアルブミンの一時的な中程度の減少、グロブリンの中程度の増加、及び/又は好中球細胞質変化。
・10mg/kgのCP−870,893において、14日目から28日目のフィブリノゲンの軽微な減少。
・10mg/kgのCP−870,893において、APTT及びプロトロンビン時間がわずかに長くなることによって示される、凝固の一時的な変化のエビデンス(変化幅は小さかったため生物学的に重要である可能性は低い)。
10mg/kgのC40M9並びに1.0及び10mg/kgのCP−870,893での雄における投与後72時間、7日目、及び/又は14日目の採取で、他の処置群における赤血球量の減少(最大−20%)よりも大きい赤血球量の中程度の減少(最大−29%;変化パーセントは試験前平均に対する群平均として表す)があった。他の処置群における赤血球量の減少幅は、概して、群間でほぼ同等であり、これらは主に手順に関連した(procedure-related)ものであり、薬物動態検査用血液採取の繰り返しに起因するものである可能性が最も高いと考えられるが、比較のための対照が存在しなかったため、決定的な比較は行うことができなかった。10mg/kgのC40M9並びに1.0及び10mg/kgのCP−870,893での赤血球量のより大幅な減少は、同時に存在する手順に関連する寄与要因とともに、被験物質に関連する可能性が最も高かった。赤血球量の減少は、21日目及び/又は28日目までに回復傾向であった。
10mg/kgのCP−870,893での雄における7日目及び14日目の採取では、試験前と比較して、APTT(最大+32%)及びプロトロンビン時間(最大+22%)がわずかに長くなった。これらの変化はCP−870,893に関連する、凝固の変化を示すものであったが、これらの変化幅は小さかったため、生物学的に重要である可能性は低かった。これらの変化はその後の採取で回復した。
10mg/kgのCP−870,893での雄における7日目、14日目、及び21日目の採取では、試験前と比較して、アルブミンの中程度の減少(最大−30%)及びグロブリンの増加(最大+33%)があった。これらの変化は、被験物質に関連するものと考えられ、2匹のうちの1匹の動物において見られた好中球細胞質変化(血液学的検査の節を参照)に関連していたことから、軽い炎症性刺激を示唆していた。これらの変化は、28日目の採取で回復傾向であった。アルブミンのわずか〜軽微な減少(最大−16%)は、他の処置群全体でも全ての採取において広く観察されたが、これらの減少は典型的には、21日目及び/又は28日目の採取時には試験前の値に戻る傾向があった。これらの減少は、赤血球量の減少(血液学的検査を参照)と関連していたことから、手順に関連する可能性が最も高いと考えられた。アルブミンは血中の主なカルシウム運搬体であるため、概してアルブミンの減少と同時にカルシウムが減少し、加えて、同時に全タンパク質及び/又はアルブミン対グロブリン比が減少した。これらの変化に関して、他の試験評価項目の中で相関関係のある所見はなかった。
Claims (65)
- 配列番号75のヒトCD40に特異的に結合する単離されたアゴニスト抗体又はその抗原結合フラグメントであって、配列番号5の重鎖可変領域(HCDR)1、配列番号10のHCDR2、配列番号18のHCDR3、配列番号32の軽鎖可変領域(LCDR)1、配列番号34のLCDR2、及び配列番号47のLCDR3を含む、抗体又はその抗原結合フラグメント。
- 前記抗体が、配列番号75のヒトCD40残基46〜64及び75〜76の範囲内で配列番号75のヒトCD40に結合する、請求項1に記載の抗体。
- 前記抗体が、以下の特性:
a)0.01%のポリソルベート20(PS−20)及び100μg/mlのウシ血清アルブミンを含有するダルベッコリン酸緩衝生理食塩水中で25℃でProteOn XPR36システムを使用して解離定数(KD)が測定される場合に、約5×10−9M以下のKDで配列番号75のヒトCD40に結合すること、又は
b)B細胞及び樹状細胞(DC)に対するそのアゴニスト活性のために架橋を必要とし、CD23及びCD83表面発現がフローサイトメトリーを使用して測定される場合に、20μg/mlの架橋剤抗ヒトF(ab’)2の存在下で、B細胞に対するアゴニスト活性がB細胞CD23表面発現によって測定され、DCに対するアゴニスト活性がDC CD83表面発現によって測定されること、
のうちの少なくとも1つを有する、請求項1又は2に記載の抗体。 - 配列番号62又は61の重鎖可変領域(VH)、及び配列番号69の軽鎖可変領域(VL)を含む、請求項3に記載の抗体。
- それぞれ配列番号62及び69のVH及びVLを含む、請求項3に記載の抗体。
- それぞれ配列番号61及び69のVH及びVLを含む、請求項3に記載の抗体。
- 前記抗体が、ヒトIGHV4−39*01(配列番号73)由来の重鎖フレームワーク、及びヒトIGLV2−8*01(配列番号87)由来の軽鎖フレームワークを含む、請求項3に記載の抗体。
- 前記抗体が、IgG1、IgG2、IgG3又はIgG4アイソタイプである、請求項1〜7のいずれかに記載の抗体。
- それぞれ配列番号129及び136の重鎖及び軽鎖を含む、請求項5に記載の抗体。
- それぞれ配列番号128及び136の重鎖及び軽鎖を含む、請求項5に記載の抗体。
- それぞれ配列番号127及び136の重鎖及び軽鎖を含む、請求項6に記載の抗体。
- Fc領域中に少なくとも1つの変異を更に含む、請求項1〜11のいずれかに記載の抗体。
- 前記Fc領域中の前記少なくとも1つの変異が、FcγRIIbに対する前記抗体の結合を強化する、請求項12に記載の抗体。
- 前記Fc領域中の前記少なくとも1つの変異が、S267E変異、S267E/I332E変異、S267E/L328F変異、G236D/S267E変異又はE233D/G237D/H268D/P271G/A330R/P238D変異であり、残基の番号付けはEU Indexに従う、請求項13に記載の抗体。
- 前記Fc領域中の前記少なくとも1つの変異が、S267E変異である、請求項13に記載の抗体。
- 前記抗体が多重特異性抗体である、請求項1〜15のいずれかに記載の抗体。
- 前記抗体が二重特異性抗体である、請求項16に記載の抗体。
- 細胞毒性剤又は造影剤に連結させた請求項1〜17のいずれかに記載の抗体を含む、免疫複合体。
- 請求項1〜17のいずれかに記載の抗体と、薬学的に許容される担体と、を含む医薬組成物。
- 請求項18に記載の免疫複合体と、薬学的に許容される担体と、を含む医薬組成物。
- 配列番号62若しくは61の抗体VH、配列番号69の抗体VL、又は配列番号62若しくは61の抗体VH及び配列番号69の抗体VLをコードするポリヌクレオチド。
- 配列番号129、128若しくは127の抗体重鎖、配列番号136の抗体軽鎖、又は配列番号129、128若しくは127の抗体重鎖及び配列番号136の抗体軽鎖をコードするポリヌクレオチド。
- 配列番号102、103、110、153、154、155又は162のポリヌクレオチド配列を含むポリヌクレオチド。
- 請求項21に記載のポリヌクレオチドを含むベクター。
- 請求項22に記載のポリヌクレオチドを含むベクター。
- 請求項23に記載のポリヌクレオチドを含むベクター。
- 請求項24に記載のベクターを含む宿主細胞。
- 請求項25に記載のベクターを含む宿主細胞。
- 請求項26に記載のベクターを含む宿主細胞。
- ヒトCD40に特異的に結合するアゴニスト抗体の製造方法であって、前記抗体が発現する条件で請求項27、28又は29に記載の宿主細胞を培養するステップと、前記宿主細胞によって産生された前記抗体を回収するステップと、を含む、方法。
- 対象においてがんを処置する方法であって、治療有効量の請求項1〜17のいずれかに記載の単離された抗体を、前記がんを処置するのに十分な時間にわたって、それを必要とする前記対象に投与するステップを含む、方法。
- 前記がんが、固形腫瘍又は血液学的悪性疾患である、請求項31に記載の方法。
- 前記固形腫瘍が、膀胱がん、腎がん、肺がん、非小細胞肺がん、膵がん、卵巣がん、乳がん又は頭頚部がんである、請求項32に記載の方法。
- 前記抗体が、第2の治療剤と組み合わせて投与される、請求項31〜33のいずれかに記載の方法。
- 前記第2の治療剤が、化学療法剤、固形腫瘍若しくは血液学的悪性疾患の処置のための標準治療薬、又は免疫チェックポイントモジュレーターである、請求項34に記載の方法。
- 前記第2の治療剤が、同時に、順次に、又は別々に投与される、請求項34又は35に記載の方法。
- 請求項4、5又は6に記載の抗体に結合する抗イディオタイプ抗体。
- 請求項4、5又は6に記載の抗体を含むキット。
- 前記抗体を検出するための試薬と、使用説明書と、を更に含む、請求項38に記載のキット。
- 治療に使用するための、請求項1〜17のいずれかに記載の抗体、又は請求項19若しくは20に記載の医薬組成物。
- 配列番号75のヒトCD40に特異的に結合する単離されたアゴニスト抗体又はその抗原結合フラグメントであって、前記抗体が、以下の特性:
a)0.01%のポリソルベート20(PS−20)及び100μg/mlのウシ血清アルブミンを含有するダルベッコリン酸緩衝生理食塩水中で25℃でProteOn XPR36システムを使用して解離定数(KD)が測定される場合に、約5×10−9M以下のKDで配列番号75のヒトCD40に結合すること、又は
b)B細胞及び樹状細胞(DC)に対するそのアゴニスト活性のために架橋を必要とし、CD23及びCD83表面発現がフローサイトメトリーを使用して測定される場合に、20μg/mlの架橋剤抗ヒトF(ab’)2の存在下で、B細胞に対するアゴニスト活性がB細胞CD23表面発現によって測定され、DCに対するアゴニスト活性がDC CD83表面発現によって測定されること、
のうちの少なくとも1つを有する、抗体又はその抗原結合フラグメント。 - a)それぞれ配列番号1、8、22、28、38及び42のHCDR1、HCDR2、HCDR3、LCDR1、LCDR2及びLCDR3、それぞれ配列番号48及び63のVH及びVL、並びに/又はそれぞれ配列番号114及び130の重鎖(HC)及び軽鎖(LC);
b)それぞれ配列番号2、7、25、26、39及び44のHCDR1、HCDR2、HCDR3、LCDR1、LCDR2及びLCDR3、それぞれ配列番号49及び64のVH及びVL、並びに/又はそれぞれ配列番号115及び131の重鎖(HC)及び軽鎖(LC);
c)それぞれ配列番号2、7、24、26、39及び44のHCDR1、HCDR2、HCDR3、LCDR1、LCDR2及びLCDR3、それぞれ配列番号50及び64のVH及びVL、並びに/又はそれぞれ配列番号116及び131の重鎖(HC)及び軽鎖(LC);
d)それぞれ配列番号2、7、23、26、39及び44のHCDR1、HCDR2、HCDR3、LCDR1、LCDR2及びLCDR3、それぞれ配列番号51及び64のVH及びVL;又はそれぞれ配列番号117及び131の重鎖(HC)及び軽鎖(LC);
e)それぞれ配列番号3、13、17、27、33及び43のHCDR1、HCDR2、HCDR3、LCDR1、LCDR2及びLCDR3;それぞれ配列番号52及び65のVH及びVL;又はそれぞれ配列番号118及び132の重鎖(HC)及び軽鎖(LC);
f)それぞれ配列番号4、6、19、27、33及び43のHCDR1、HCDR2、HCDR3、LCDR1、LCDR2及びLCDR3;それぞれ配列番号53及び65のVH及びVL;又はそれぞれ配列番号119及び132の重鎖(HC)及び軽鎖(LC);
g)それぞれ配列番号4、6、20、27、33及び43のHCDR1、HCDR2、HCDR3、LCDR1、LCDR2及びLCDR3;それぞれ配列番号54及び65のVH及びVL;又はそれぞれ配列番号120及び132の重鎖(HC)及び軽鎖(LC);
h)それぞれ配列番号2、7、14、27、33及び43のHCDR1、HCDR2、HCDR3、LCDR1、LCDR2及びLCDR3;それぞれ配列番号55及び65のVH及びVL;又はそれぞれ配列番号121及び132の重鎖(HC)及び軽鎖(LC);
i)それぞれ配列番号4、6、21、27、33及び43のHCDR1、HCDR2、HCDR3、LCDR1、LCDR2及びLCDR3;それぞれ配列番号56及び65のVH及びVL;又はそれぞれ配列番号122及び132の重鎖(HC)及び軽鎖(LC);
j)それぞれ配列番号4、9、15、30、36及び41のHCDR1、HCDR2、HCDR3、LCDR1、LCDR2及びLCDR3;それぞれ配列番号57及び66のVH及びVL;又はそれぞれ配列番号123及び133の重鎖(HC)及び軽鎖(LC);
k)それぞれ配列番号4、11、16、29、37及び40のHCDR1、HCDR2、HCDR3、LCDR1、LCDR2及びLCDR3;それぞれ配列番号58及び67のVH及びVL;又はそれぞれ配列番号124及び134の重鎖(HC)及び軽鎖(LC);
l)それぞれ配列番号4、12、15、30、35及び46のHCDR1、HCDR2、HCDR3、LCDR1、LCDR2及びLCDR3、それぞれ配列番号59及び68のVH及びVL、並びに/又はそれぞれ配列番号125及び135の重鎖(HC)及び軽鎖(LC);
m)それぞれ配列番号4、9、15、30、36及び41のHCDR1、HCDR2、HCDR3、LCDR1、LCDR2及びLCDR3、それぞれ配列番号57及び70のVH及びVL、並びに/又はそれぞれ配列番号123及び137の重鎖(HC)及び軽鎖(LC);
n)それぞれ配列番号4、9、15、31、36及び41のHCDR1、HCDR2、HCDR3、LCDR1、LCDR2及びLCDR3、それぞれ配列番号57及び71のVH及びVL、並びに/又はそれぞれ配列番号123及び138の重鎖(HC)及び軽鎖(LC);
o)それぞれ配列番号4、9、15、31、36及び41のHCDR1、HCDR2、HCDR3、LCDR1、LCDR2及びLCDR3、それぞれ配列番号57及び72のVH及びVL、並びに/又はそれぞれ配列番号123及び139の重鎖(HC)及び軽鎖(LC)
を含む、請求項41に記載の抗体。 - 前記抗体が、IgG1、IgG2、IgG3又はIgG4アイソタイプである、請求項41〜42のいずれかに記載の抗体。
- Fc領域中に少なくとも1つの変異を更に含む、請求項43に記載の抗体。
- 前記Fc領域中の前記少なくとも1つの変異が、FcγRIIbに対する前記抗体の結合を強化する、請求項44に記載の抗体。
- 前記Fc領域中の前記少なくとも1つの変異が、S267E変異、S267E/I332E変異、S267E/L328F変異、G236D/S267E変異又はE233D/G237D/H268D/P271G/A330R/P238D変異であり、残基の番号付けはEU Indexに従う、請求項45に記載の抗体。
- 前記抗体が多重特異性抗体である、請求項41〜46のいずれかに記載の抗体。
- 前記抗体が二重特異性抗体である、請求項47に記載の抗体。
- 細胞毒性剤又は造影剤に連結させた請求項41〜48のいずれかに記載の抗体を含む免疫複合体。
- 請求項41〜48のいずれかに記載の抗体と、薬学的に許容される担体と、を含む医薬組成物。
- 請求項49に記載の免疫複合体と、薬学的に許容される担体と、を含む医薬組成物。
- 配列番号48、49、50、51、52、53、54、55、56、57、58若しくは59の抗体VH、配列番号63、64、65、66、67、68、70、71若しくは72の抗体VL、又は配列番号48、49、50、51、52、53、54、55、56、57、58若しくは59の抗体VH及び配列番号63、64、65、66、67、68、70、71若しくは72の抗体VL、をコードするポリヌクレオチド。
- 請求項52に記載のポリヌクレオチドを含むベクター。
- 請求項53に記載のベクターを含む宿主細胞。
- ヒトCD40に特異的に結合するアゴニスト抗体の製造方法であって、前記抗体が発現する条件で請求項54に記載の宿主細胞を培養するステップと、前記宿主細胞によって産生された前記抗体を回収するステップと、を含む、方法。
- 対象においてがんを処置する方法であって、治療有効量の請求項41〜48のいずれかに記載の単離された抗体を、前記がんを処置するのに十分な時間にわたって、それを必要とする前記対象に投与するステップを含む、方法。
- 前記がんが、固形腫瘍又は血液学的悪性疾患である、請求項56に記載の方法。
- 前記固形腫瘍が、膀胱がん、腎がん、肺がん、非小細胞肺がん、膵がん、卵巣がん、乳がん又は頭頚部がんである、請求項57に記載の方法。
- 前記抗体が、第2の治療剤と組み合わせて投与される、請求項56〜58のいずれかに記載の方法。
- 前記第2の治療剤が、化学療法剤、固形腫瘍若しくは血液学的悪性疾患の処置のための標準治療薬、又は免疫チェックポイントモジュレーターである、請求項59に記載の方法。
- 前記第2の治療剤が、同時に、順次に、又は別々に投与される、請求項59又は60に記載の方法。
- 請求項42に記載の抗体に結合する抗イディオタイプ抗体。
- 請求項42に記載の抗体を含むキット。
- 前記抗体を検出するための試薬と、使用説明書と、を更に含む、請求項63に記載のキット。
- 治療に使用するための、請求項41〜48のいずれかに記載の抗体、又は請求項49若しくは50に記載の医薬組成物。
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