JP6556742B2 - 抗ccl17抗体 - Google Patents
抗ccl17抗体 Download PDFInfo
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- JP6556742B2 JP6556742B2 JP2016552480A JP2016552480A JP6556742B2 JP 6556742 B2 JP6556742 B2 JP 6556742B2 JP 2016552480 A JP2016552480 A JP 2016552480A JP 2016552480 A JP2016552480 A JP 2016552480A JP 6556742 B2 JP6556742 B2 JP 6556742B2
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Description
本願は、2013年11月6日出願の米国仮特許出願第61/900,596号の利益を主張するものであり、その全容が参照により本明細書に組み込まれる。
本発明は、CCL17に特異的に結合する抗体、該抗体又は断片をコードするポリヌクレオチド、並びに前述のものを作製及び使用する方法に関する。
本発明は、ヒトCCL17に特異的に結合するモノクローナル抗体を提供する。本発明の抗体は、細胞におけるCCL17の生物活性を阻害し、かつ任意に、cyno CCL17と交差反応し得る。本発明は、抗体及びその断片をコードする合成ポリヌクレオチド、ベクター及び宿主細胞、並びに本発明の抗体を作製及び使用する方法を提供する。
VGPADVWDX1FDY(配列番号71)
式中、
X1は、S、A、又はTである。
KSSQSVLX1SX2X3NX4NX5LA(配列番号72)
式中、
X1は、L、Y、S、又はNであり、
X2は、F、P、H、又はIであり、
X3は、D、Y、W、T、又はVであり、
X4は、I、F、S、T、Y、N、K、又はVであり、かつ
X5は、K、A、Q、T、又はDである。
X1ASTRE(配列番号73)
式中、
X1は、N、H、G、E、T、又はDである。
QQX1X2X3X4PX5T(配列番号74)
式中、
X1は、F、Y、T、又はHであり、
X2は、Y、L、N、又はWであり、
X3は、S、A、L、I、T、Q、又はHであり、
X4は、V、T、I、Y、L、又はDであり、かつ
X5は、S、F、A、又はLである。
EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIDPSDSDTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARVGPADVWDX1FDYWGQGTLVTVSS
式中、
X1は、S、A、又はTである。
DIVMTQSPDSLAVSLGERATINCKSSQSVLX1SX2X3NX4NX5LAWYQQKPGQPPKLLIYX6ASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQX7X8X9X10PX11TFGQGTKVEIK;式中、
X1は、L、Y、S、又はNであり、
X2は、F、P、H、又はIであり、
X3は、D、Y、W、T、又はVであり、
X4は、I、F、S、T、Y、N、K、又はVであり、
X5は、K、A、Q、T、又はDであり、
X6は、N、H、G、E、T、又はDであり、
X7は、F、Y、T、又はHであり、
X8は、Y、L、N、又はWであり、
X9は、S、A、L、I、T、Q、又はHであり、
X10は、V、T、I、Y、L、又はDであり、かつ
X11は、S、F、A、又はLである。
それぞれ、配列番号4、5、6、7、19、及び27、
それぞれ、配列番号4、5、6、8、20、及び28、
それぞれ、配列番号4、5、6、9、21、及び29、
それぞれ、配列番号4、5、6、10、22、及び30、
それぞれ、配列番号4、5、6、11、23、及び31、
それぞれ、配列番号4、5、6、12、24、及び32、
それぞれ、配列番号4、5、6、13、21、及び33、
それぞれ、配列番号4、5、6、14、20、及び34、
それぞれ、配列番号4、5、6、15、25、及び35、
それぞれ、配列番号4、5、6、16、21、及び36、
それぞれ、配列番号4、5、6、17、25、及び37、
それぞれ、配列番号4、5、6、18、26、及び38、
それぞれ、配列番号4、5、6、8、39、及び28、
それぞれ、配列番号4、5、6、8、24、及び28、
それぞれ、配列番号4、5、6、8、22、及び28、
それぞれ、配列番号4、5、6、8、40、及び28、
それぞれ、配列番号4、5、6、8、26、及び28、
それぞれ、配列番号4、5、6、8、41、及び28、
それぞれ、配列番号4、5、42、8、24、及び28、
それぞれ、配列番号4、5、43、8、24、及び28、又は
それぞれ配列番号4、5、44、8、24、及び28のHCDR1、HCDR2、HCDR3、LCDR1、LCDR2、及びLCDR3配列を含む。
配列番号45のVH、及び配列番号49、50、51、52、53、54、55、56、57、58、58、59、60、61、62、63、64、65、又は66のVL、
それぞれ、配列番号46及び62のVH及びVL、
それぞれ、配列番号47及び62のVH及びVL、又は
それぞれ、配列番号48及び62のVH及びVLを含む。
配列番号45のVH、及び配列番号50、51、52、55、56、57、59、又は60のVL、
それぞれ、配列番号46及び62のVH及びVL、又は
それぞれ、配列番号47及び62のVH及びVLを含む。
ヒトCCL17に特異的に結合する抗体は、CCL17媒介状態のスペクトルを治療又は阻止するのに好適であり得る。
本発明は、本発明の本発明のCCL17に特異的に結合する抗体及び医薬的に許容される担体を含む医薬組成物を提供する。治療使用としての本発明のCCL17に特異的に結合する抗体は、医薬的に許容される担体内の活性成分として、有効量のドメイン、分子、又は抗体を含有する医薬組成物として調製することができる。用語「担体」は、活性化合物と共に投与される希釈剤、補助剤、賦形剤、又はビヒクルを指す。そのようなビヒクルは、落花生油、大豆油、鉱物油、ゴマ油等の、石油、動物、植物、又は合成物起源のものを含む、水及び油等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、一般には粒子状物質を含まないものである。これらは、従来周知の滅菌技術(例えば、濾過)によって滅菌することができる。この組成物は、生理学的条件に近づけるために必要とされる医薬的に許容される補助物質、例えばpH調整剤及び緩衝剤、安定化剤、増粘剤、潤滑剤及び着色剤等を含むことができる。そのような医薬製剤中の本明細書に記載される本発明の分子又は抗体の濃度は幅広く変化してよく、即ち約0.5重量%未満、通常は約1重量%又は少なくとも約1重量%か、最大で15又は20重量%までであってよく、また、選択される特定の投与方法に従って、主として必要とされる用量、液体の体積、粘度等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、特にpp.958〜989を参照されたい。
ヒトCCL17結合Fabを、Shi et al.,J.Mol.Biol.397:385〜396,2010、国際特許公開第WO2009/085462号、米国特許公開第US2010/0021477号、米国特許公開第US2012/0108795号に記載される新規pIXファージ提示ライブラリから選択した。簡潔に言えば、ライブラリは、ヒト足場を多様化することによって生成されたものであり、生殖系列VH遺伝子であるIGHV1−69*01、IGHV3−23*01、及びIGHV5−51*01を、H3ループを介してヒトIGHJ−4ミニ遺伝子で組換え、そしてヒト生殖系列VLカッパ遺伝子であるO12(IGKV1−39*01)、L6(IGKV3−11*01)、A27(IGKV3−20*01)及びB3(IGKV4−1*01)をIGKJ−1ミニ遺伝子で組換えて、完全なVH及びVLドメインが構築された。多様化に際し、重鎖及び軽鎖可変領域内の、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確認された位置に相当するH1、H2、L1、L2及びL3ループ周辺の位置を選択した。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それぞれの位置で見られる残基に制限した。長さがアミノ酸7〜14個分の単鎖〜中鎖型の合成ループを用いることで、H3ループにおいて多様性が発生した。H3でのアミノ酸分布は、ヒト抗体において観察されるアミノ酸の変動を模倣するよう設計された。ライブラリ設計の詳細は、Shi et al.、J.Mol.Biol.397、385〜96、2010年に記載されている。ライブラリを生成するために利用した足場は、これらのヒトVH及びVL生殖系列遺伝子起源に準じて命名した。スクリーニングにあたって、3つの重鎖ライブラリを、4個の生殖系列軽鎖又は生殖系列軽鎖ライブラリと組み合わせることで24個の固有VH:VLの組み合わせを生成した。ヒトCCL17に対するファージパニンク実験では、24個全てのVH:VLライブラリの組み合わせを利用した。
これらの初期特徴付けプロファイルに基づき5つのFabを親和性成熟用に選択した。Shiら(Shi et al.,J Mol Biol 397:385〜396,2010)に記載されるインライン成熟技術を用いて軽鎖を多様化し、重鎖を不変に保つことによりFabを親和性成熟させた。Fabの重鎖はVH3−23又はVH5−51のいずれかであった。生成されたF24親和性成熟ライブラリはCCL17結合剤を改善した。
溶液平衡親和性(SEA)を用いて抗体を、ヒトCCL17及びcyno CCL17へのそれらの結合について評価した。これらの実験の手順は、Haenelら(Haenel et al.,Anal Biochem 339:182〜184,2005)が用いたものに類似した。抗原−抗体複合体を調製するために、ヒトCCL17又はcyno CCL17を、96ディープウェルポリプロピレンプレートで2,000,000pMの濃度から開始する、0.05%のTween−20、TBST(Thermo Scientific)を含有するトリス系生理食塩水緩衝液に1:6の割合で系列希釈した。40pM又は200pMの等体積の抗hCCL17 mAbを各ケモカイン希釈物に添加して、1μMの最終濃度から開始するケモカインの系列希釈物と一定濃度(20pM又は100pM)の抗CCL17抗体とを含む混合物を得た。混合物を2組調製し、平衡に達するように4℃で48時間インキュベートした。SECTOR Imager 6000(Meso Scale Discovery)機器を用いて遊離抗体を検出した。得られた結合曲線を、データの非線形最小二乗法の回帰分析を行うために1:1結合モデルを使用するGraphPad Prismソフトウェア(v 5.01)を用いて適合し、解離平衡定数(KD)を得た。表5は、ヒト及びcyno CCL17に対する抗体の親和性を示す。ヒトCCL17の親和性は、約2pM〜約700pMの範囲であり、cyno CCL17の親和性は、約200pM〜約9500pMの範囲であった。生成された抗体は、cyno CCL17への結合と比較して、ヒトCCL17に約2−〜約150倍高い親和性で結合した。
C17B234及びC17B240の抗CCL17抗体は、LCDR2の最初に潜在的なN連結グリコシル化部位(「NAS」)を含んだ。C17B234の残基位置50(Kabat番号付け)のアスパラギン残基(N)は、6つの異なるアミノ酸(A、D、G、S、T、及びI)に変異した。
選択抗体は、標準的な方法を用いて、以下の置換:IgG4 S228P/L234A/L235A又はIgG2 V234A/G237A/P238S/H268A/V309L/A330S/P331SによりIgG2又はIgG4としてクローン化された。表10は、得られた抗体を示す。
CB302 HC(配列番号67)
EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIDPSDSDTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARVGPADVWDAFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVTSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPAAASSVFLFPPKPKDTLMISRTPEVTCVVVDVSAEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
DIVMTQSPDSLAVSLGERATINCKSSQSVLLSFDNINKLAWYQQKPGQPPKLLIYDASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQFYSVPSTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIDPSDSDTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARVGPADVWDTFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVTSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPAAASSVFLFPPKPKDTLMISRTPEVTCVVVDVSAEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
DIVMTQSPDSLAVSLGERATINCKSSQSVLLSFDNINKLAWYQQKPGQPPKLLIYDASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQFYSVPSTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
選択抗CCL17抗体は、それらのCCL17生物活性の阻害能力を評価するために、カルシウム流入、β−アレスチンレポーターアッセイ、及び走化性アッセイにおいて特徴付けされた。
抗体C17B236(VH:配列番号45、VL:配列番号52)結合エピトープは、X線結晶解析によって決定された。
本発明は、以下の態様を包含し得る。
[1]
重鎖可変領域(VH)及び軽鎖可変領域(VL)を含む、ヒトCCL17に特異的に結合する単離された抗体であって、前記抗体は、配列番号45のVH及び配列番号52のVLを含む抗体と、ヒトCCL17への結合を競合する、抗体。
[2]
前記抗体が、配列番号1の少なくともCCL17のアミノ酸残基21〜23、44〜45、及び60〜68内でヒトCCL17と結合する、上記[1]に記載の抗体。
[3]
前記抗体が、配列番号1の少なくとも残基R22及びK23においてヒトCCL17に結合する、上記[2]に記載の抗体。
[4]
前記抗体が、CCL17/CCR4相互作用を阻止する、上記[1]に記載の抗体。
[5]
前記抗体が、約1×10 -10 M以下の親和性定数(K D )でヒトCCL17に結合し、このとき、前記K D が、前記抗体及びヒトCCL17を4℃で48時間同時にインキュベートした後、0.05%のTween−20を含有するトリス系生理食塩水緩衝液中の溶液平衡親和性を使用して測定される、上記[4]に記載の抗体。
[6]
前記抗体が、約5×10 -12 M以下のK D でヒトCCL17に結合する、上記[1]〜[5]に記載の抗体。
[7]
前記抗体が、約1×10 -8 M以下のK D でカニクイザル(cyno)CCL17に結合し、このとき、前記K D が、前記抗体及びcyno CCL17を4℃で48時間同時にインキュベートした後、0.05%のTween−20を含有するトリス系生理食塩水緩衝液中の溶液平衡親和性を使用して測定される、上記[1]〜[6]に記載の抗体。
[8]
前記抗体が、約1×10 -9 M以下のIC 50 値で、Fluo−8 NWを使用して測定される、10ng/mlのヒトCCL17によって誘導されるCCRF−CEM細胞中のカルシウム動員を阻害する、上記[1]〜[7]に記載の抗体。
[9]
重鎖相補性決定領域(HCDR)の1(HCDR1)、2(HCDR2)、及び3(HCDR3)と、軽鎖相補性決定領域(LCDR)の1(LCDR1)、2(LCDR2)、及び3(LCDR3)と、を含み、前記HCDR1、前記HCDR2、前記HCDR3、前記LCDR1、前記LCDR2、及び前記LCDR3が、それぞれ、配列番号4、5、42、8、24、及び28のアミノ酸配列、又はそれぞれ、配列番号46及び62のVH及びVLを含む、上記[5]に記載の抗体。
[10]
重鎖相補性決定領域(HCDR)の1(HCDR1)、2(HCDR2)、及び3(HCDR3)と、軽鎖相補性決定領域(LCDR)の1(LCDR1)、2(LCDR2)、及び3(LCDR3)と、を含み、前記HCDR1、前記HCDR2、前記HCDR3、前記LCDR1、前記LCDR2、及び前記LCDR3が、それぞれ、配列番号4、5、71、72、73、及び74のアミノ酸配列を含む、上記[1]〜[8]に記載の抗体。
[11]
前記HCDR1が、配列番号4のアミノ酸配列を含み、前記HCDR2が、配列番号5のアミノ酸配列を含み、前記HCDR3が、配列番号6、42、又は43のアミノ酸配列を含む、上記[10]に記載の抗体。
[12]
前記LCDR1が、配列番号8、9、10、13、14、15、17、又は18のアミノ酸配列を含み、前記LCDR2が、配列番号20、21、22、24、25、及び26のアミノ酸配列を含み、前記LCDR3が、配列番号28、29、30、33、34、35、37、又は38のアミノ酸配列を含む、上記[11]に記載の抗体。
[13]
a)それぞれ、配列番号4、5、6、8、20、及び28、
b)それぞれ、配列番号4、5、6、9、21、及び29、
c)それぞれ、配列番号4、5、6、10、22、及び30、
d)それぞれ、配列番号4、5、6、13、21、及び33、
e)それぞれ、配列番号4、5、6、14、20、及び34、
f)それぞれ、配列番号4、5、6、15、25、及び35、
g)それぞれ、配列番号4、5、6、17、25、及び37、
h)それぞれ、配列番号4、5、6、18、26、及び38、
i)それぞれ、配列番号4、5、42、8、24、及び28、又は
j)それぞれ、配列番号4、5、43、8、24、及び28の前記HCDR1、HCDR2、HCDR3、LCDR1、LCDR2、及びLCDR3の配列を含む、上記[12]に記載の抗体。
[14]
前記抗体が、配列番号75のVH、及び配列番号76のVLを含む、上記[10]に記載の抗体。
[15]
前記VHが、配列番号45、46、又は47のアミノ酸配列を含む、上記[14]に記載の抗体。
[16]
前記VLが、配列番号50、51、52、55、56、57、59、60、又は62のアミノ酸配列を含む、上記[15]に記載の抗体。
[17]
前記抗体が、
a)配列番号45のVH、及び配列番号50、51、52、55、56、57、59、若しくは60のVL、
b)それぞれ、配列番号46及び62のVH及びVL、又は
c)それぞれ、配列番号47及び62のVH及びVLを含む、上記[16]に記載の抗体。
[18]
前記抗体が、配列番号46のVHと少なくとも90%、91%、92%、93%、94%、95%、96%、97%、98%、又は99%同一であるアミノ酸配列を含むVHと、配列番号62のVLと少なくとも90%、91%、92%、93%、94%、95%、96%、97%、98%、又は99%同一であるアミノ酸配列を含むVLと、を含む、上記[5]に記載の抗体。
[19]
前記抗体が、ヒト又はヒト化されている、上記[1]〜[18]に記載の抗体。
[20]
前記抗体が、IgG1、IgG2、IgG3、又はIgG4のアイソタイプのものである、上記[19]に記載の抗体。
[21]
前記抗体が、Fc領域内に置換を含む、上記[20]に記載の抗体。
[22]
前記置換が、IgG2上のV234A、G237A、P238S、H268A、V309L、A330S、若しくはP331S置換、又はIgG4上のS228P、L234A、若しくはL235A置換を含み、残基の番号付けがEUインデックスに準ずる、上記[21]に記載の抗体。
[23]
前記置換が、IgG2上のV234A/G237A/P238S/H268A/V309L/A330S/P331S置換、又はIgG4上のS228P/L234A/L235A置換を含み、残基の番号付けがEUインデックスに準ずる、上記[22]に記載の抗体。
[24]
上記[1]〜[23]に記載の抗体と、医薬的に許容される担体と、を含む、医薬組成物。
[25]
上記[9]〜[24]のいずれかに記載の抗体の前記VH又は前記VLをコードする、単離されたポリヌクレオチド。
[26]
上記[25]に記載のポリヌクレオチドを含む、ベクター。
[27]
上記[26]に記載のベクターを含む、宿主細胞。
[28]
上記[9]〜[24]に記載の抗体を生成する方法であって、
前記抗体が生成される条件下で、上記[27]に記載の宿主細胞を培養する工程を含む、方法。
[29]
CCL17媒介疾患を治療する方法であって、
それを必要とする対象に、前記CCL17媒介疾患を治療するのに十分な時間の間、上記[1]〜[24]に記載の抗体を投与する工程を含む、方法。
[30]
前記CCL17媒介疾患が、炎症性疾患である、上記[29]に記載の方法。
[31]
前記炎症性疾患が、喘息、潰瘍性大腸炎(UC)、アトピー性皮膚炎(AD)、又は特発性肺線維症(IPF)である、上記[30]に記載の方法。
[32]
喘息又は気道過敏性を治療する方法であって、
喘息を治療するのに十分な時間の間、上記[1]〜[24]に記載の抗体を対象に投与する工程を含む、方法。
[33]
療法のための上記[1]〜[24]に記載の抗体の使用。
[34]
療法において使用するための、上記[1]〜[24]に記載の抗体。
[35]
CCL17媒介疾患を有する対象の治療において使用するための、上記[1]〜[24]に記載の抗体。
[36]
前記CCL17媒介疾患が、炎症性疾患、喘息、潰瘍性大腸炎(UC)、アトピー性皮膚炎(AD)、又は特発性肺線維症(IPF)である、上記[35]に記載の使用のための抗体。
[37]
前記CCL17媒介疾患が、喘息である、上記[36]に記載の使用のための抗体。
Claims (25)
- ヒトCCL17に特異的に結合する単離された抗体であって、
重鎖相補性決定領域(HCDR)の1(HCDR1)、2(HCDR2)、及び3(HCDR3)と、軽鎖相補性決定領域(LCDR)の1(LCDR1)、2(LCDR2)、及び3(LCDR3)と、を含み、前記HCDR1、前記HCDR2、前記HCDR3、前記LCDR1、前記LCDR2、及び前記LCDR3が、それぞれ、配列番号4、5、42、8、24、及び28のアミノ酸配列を含む、抗体。 - 前記抗体が、重鎖可変領域(VH)および軽鎖可変領域(VL)を含み、前記VHおよびVLは、それぞれ、配列番号46および62を含む、請求項1に記載の抗体。
- 前記抗体が、ヒト又はヒト化されている、請求項1又は2に記載の抗体。
- 前記抗体が、IgG1、IgG2、IgG3、又はIgG4のアイソタイプのものである、請求項3に記載の抗体。
- 前記抗体が、Fc領域内に置換を含む、請求項4に記載の抗体。
- 前記置換が、IgG2上のV234A、G237A、P238S、H268A、V309L、A330S、若しくはP331S置換、又はIgG4上のS228P、L234A、若しくはL235A置換を含み、残基の番号付けがEUインデックスに準ずる、請求項5に記載の抗体。
- 前記置換が、IgG2上のV234A/G237A/P238S/H268A/V309L/A330S/P331S置換、又はIgG4上のS228P/L234A/L235A置換を含み、残基の番号付けがEUインデックスに準ずる、請求項6に記載の抗体。
- 前記抗体が、CCL17/CCR4相互作用を阻止する、請求項1〜7のいずれか一項に記載の抗体。
- 前記抗体が、約1×10-10M以下の親和性定数(KD)でヒトCCL17に結合し、このとき、前記KDが、前記抗体及びヒトCCL17を4℃で48時間同時にインキュベートした後、0.05%のTween−20を含有するトリス系生理食塩水緩衝液中の溶液平衡親和性を使用して測定される、請求項1〜8のいずれか一項に記載の抗体。
- 前記抗体が、約5×10-12M以下のKDでヒトCCL17に結合する、請求項9に記載の抗体。
- 前記抗体が、約1×10-8M以下のKDでカニクイザル(cyno)CCL17に結合し、このとき、前記KDが、前記抗体及びcyno CCL17を4℃で48時間同時にインキュベートした後、0.05%のTween−20を含有するトリス系生理食塩水緩衝液中の溶液平衡親和性を使用して測定される、請求項1〜10のいずれか一項に記載の抗体。
- 前記抗体が、約1×10-9M以下のIC50値で、Fluo−8 NWを使用して測定される、10ng/mlのヒトCCL17によって誘導されるCCRF−CEM細胞中のカルシウム動員を阻害する、請求項1〜11のいずれか一項に記載の抗体。
- 請求項1〜12のいずれか一項に記載の抗体と、医薬的に許容される担体と、を含む、医薬組成物。
- 請求項1〜12のいずれか一項に記載の抗体の前記VH又は前記VLをコードする、単離されたポリヌクレオチド。
- 請求項14に記載のポリヌクレオチドを含む、ベクター。
- 請求項15に記載のベクターを含む、宿主細胞。
- 抗体を生成する方法であって、
前記抗体が生成される条件下で、請求項16に記載の宿主細胞を培養する工程を含む、方法。 - 薬剤を調製するための、請求項1〜12のいずれか一項に記載の抗体の使用。
- CCL17媒介疾患を有する対象を治療するため薬剤を調製するための、請求項1〜12のいずれか一項に記載の抗体の使用。
- 前記CCL17媒介疾患が、炎症性疾患、喘息、潰瘍性大腸炎(UC)、アトピー性皮膚炎(AD)、又は特発性肺線維症(IPF)である、請求項19に記載の使用。
- 前記CCL17媒介疾患が、喘息である、請求項20に記載の使用。
- 療法において使用するための、請求項13に記載の医薬組成物。
- CCL17媒介疾患を有する対象を治療するための、請求項13に記載の医薬組成物。
- 前記CCL17媒介疾患が、炎症性疾患、喘息、潰瘍性大腸炎(UC)、アトピー性皮膚炎(AD)、又は特発性肺線維症(IPF)である、請求項23に記載の医薬組成物。
- 前記CCL17媒介疾患が、喘息である、請求項24に記載の医薬組成物。
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