JP2017515470A - Cd269(bcma)に対するヒト化抗体 - Google Patents
Cd269(bcma)に対するヒト化抗体 Download PDFInfo
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- JP2017515470A JP2017515470A JP2016565168A JP2016565168A JP2017515470A JP 2017515470 A JP2017515470 A JP 2017515470A JP 2016565168 A JP2016565168 A JP 2016565168A JP 2016565168 A JP2016565168 A JP 2016565168A JP 2017515470 A JP2017515470 A JP 2017515470A
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Abstract
Description
EINPX2X3STINYAPSLKDK(H-CDR2;配列番号16)(ここで、X2X3:SS、NS、TS、GS、KS、RS、SD、SN、DEである)、及び/又は、
SLYX4DYGDAX5DYW(H-CDR3;配列番号17)(ここで、X4:Y、L、A、V、F、I、W及び/又はX5:Y、L、F、I、V、A、Cである)、
のCDR配列を含むVHドメインを含む抗体又は抗体フラグメントであって、該抗体又はそのフラグメントがCD269(BCMA)の細胞外ドメインのエピトープに特異的に結合する、抗体又は抗体フラグメントに関する。
SASLRFS(L-CDR2;配列番号24)、及び/又は、
QQYNNYPLTFG(L-CDR3;配列番号25)、
のCDR配列を含むVLドメインを含む抗体又は抗体フラグメントであって、該抗体又はそのフラグメントがCD269(BCMA)の細胞外ドメインのエピトープに特異的に結合する、抗体又は抗体フラグメントに関する。
本明細書で詳細に開示されるように、J22.9-xiによる本発明の好ましい実施の形態の配列は、ヒト被験体への投与により適合する試薬を提供するためにヒト化されている。J22.9-xiの様々なヒト化配列変異体を生成し、ヒト及びカニクイザルCD269(BCMA)の両方に対するそれらの結合親和性及び特異性について試験した。結合アッセイによる結果から、ヒト化配列がキメラ試薬J22.9-xiの所望の結合特性を維持することが実証される。下記配列において、下線の領域はCDR又は推定CDRを表す。
本発明のヒト化抗体配列に関する付加的な情報を下記に提示する。
HCマウス(配列番号1):
QVQLQQSGGGLVQPGGSLKLSCAASGIDFSRYWMSWVRRAPGKGLEWIGEINPDSSTINYAPSLKDKFIISRDNAKNTLYLQMSKVRSEDTALYYCASLYYDYGDAMDYWGQGTSVTVSS
HC部分ヒト化(配列番号2):
EVQLVESGGGLVQPGGSLRLSCAASGFTFDDYWMSWVRQAPGKGLEWVGEINPDSSTINYAPSLKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCASLYYDYGDAMDYWGQGTLVTVSS
hHC01(配列番号3):
EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLVWVGEINPDSSTINYAPSLKDKFTISRDNAKNTLYLQMNSLRAEDTAVYYCASLYYDYGDAMDYWGQGTLVTVSS
hHC02(配列番号4):
EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWX1SWVRQAPGKGLVWVGEINPX2X3STINYAPSLKDKFTISRDNAKNTLYLQMNSLRAEDTAVYYCASLYX4DYGDAX5DYWGQGTLVTVSS
ここで、
X1:I、F、L、V、Y、C、G、A、S、T、好ましくはI又はF;
X2X3:SS、NS、TS、GS、KS、RS、SD、SN、DE、好ましくはSS;
X4:Y、L、A、V、F、I、W、好ましくはY;及び/又は、
X5:Y、L、F、I、V、A、C、好ましくはYである。
HC(VH)配列のアミノ酸M34が任意のアミノ酸、好ましくはI、L、F、V、Y、C、G、A、S、Tで置換される;
HC(VH)配列のアミノ酸E46がVで置換される;
HC(VH)配列のアミノ酸D54及びS55が任意のアミノ酸の組合せ、好ましくはSS、TS、GS、KS、RS、SD、SN、DEで置換される;
HC(VH)配列のアミノ酸Y101が任意のアミノ酸、好ましくはL、A、V、F、I、Wで置換される;及び/又は、
HC(VH)配列のアミノ酸M107が任意のアミノ酸、好ましくはL、Y、F、I、V、A、Cで置換される。
hHC03 − BCMAとの相互作用に関与する修飾アミノ酸(配列番号5):
EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYX1MX2WVRQAPGKGLVX3VGX4INPDSSTINYAPSLKDKFTISRDNAKNTLYLQMNSLRAEDTAVYYCASX5X6X7DYGDX8MDYWGQGTLVTVSS
ここで好ましいアミノ酸は、
X1:W、F、Y、好ましくはW;
X2:S、T、N、Q、D、E、好ましくはS;
X3:W、F、Y、好ましくはW;
X4:E、Q、好ましくはE;
X5:L、I、V、G、A、好ましくはL;
X6:Y、X、好ましくはY;
X7:Y、F、L、I、V、M、好ましくはY;及び/又は、
X8:A、G、V、好ましくはAである。
HC(VH)配列のアミノ酸W33がW、F、Yである;
HC(VH)配列のアミノ酸S35がS、T、N、Q、D、Eである;
HC(VH)配列のアミノ酸W47がW、F、Yである;
HC(VH)配列のアミノ酸E50がE、Qである;
HC(VH)配列のアミノ酸L99がL、I、V、G、Aである;
HC(VH)配列のアミノ酸Y100がY、Xである;
HC(VH)配列のアミノ酸Y101がY、F、L、I、V、Mである;及び/又は、
HC(VH)配列のアミノ酸A106がA、G、Vである。
hHC04(配列番号6):
EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWISWVRQAPGKGLVWVGEINPNSSTINYAPSLKDKFTISRDNAKNTLYLQMNSLRAEDTAVYYCASLYYDYGDAYDYWGQGTLVTVSS
hHC05(配列番号7):
EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWFSWVRQAPGKGLVWVGEINPNSSTINYAPSLKDKFTISRDNAKNTLYLQMNSLRAEDTAVYYCASLYYDYGDAYDYWGQGTLVTVSS
hHC06(配列番号8):
EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWISWVRQAPGKGLVWVGEINPSSSTINYAPSLKDKFTISRDNAKNTLYLQMNSLRAEDTAVYYCASLYYDYGDAYDYWGQGTLVTVSS
hHC07(配列番号9):
EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWFSWVRQAPGKGLVWVGEINPSSSTINYAPSLKDKFTISRDNAKNTLYLQMNSLRAEDTAVYYCASLYYDYGDAYDYWGQGTLVTVSS
HC配列内の様々な置換位置のCLUSTAL W(1.83)多重配列アラインメントから、図8の適切な配列比較が得られる。「一般配列」はHC配列を表し、各々のXは任意の所与のアミノ酸に対する潜在的アミノ酸変化を表す。好ましいアミノ酸置換は潜在的突然変異位置の各々について上に記載されるものである。
キメラ配列:
LCマウス(配列番号43):
DIVMTQSQRFMTTSVGDRVSVTCKASQSVDSNVAWYQQKPRQSPKALIFSASLRFSGVPARFTGSGSGTDFTLTISNLQSEDLAEYFCQQYNNYPLTFGAGTKLELKR
LC部分ヒト化(配列番号10):
DIVMTQSPATLSVSVGDEVTLTCKASQSVDSNVAWYQQKPGQAPKLLIYSDDLRFSGVPARFSGSGSGTDFTLTISSLQSEDFAVYYCQQYNNYPLTFGAGTKLELKR
hLC01(配列番号11):
EIVMTQSPATLSVSPGERATLSCKASQSVDSNVAWYQQKPGQAPRALIYSASLRFSGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNYPLTFGAGTKLELKR
hLC02(配列番号12):
EIVMTQSPATLSVSPGERATLSCKASQSVX1X2NVAWYQQKPGQAPRALIYSASLRFSGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNYPLTFGAGTKLELKR
ここで、
X1X2:ES、SS、TS、QS、HS、DH、好ましくはESである。
LC(VL)配列のアミノ酸D1がEで置換される;
LC(VL)配列のアミノ酸V15がPで置換される;
LC(VL)配列のアミノ酸D17がEで置換される;
LC(VL)配列のアミノ酸V19がAで置換される;
LC(VL)配列のアミノ酸T22がSで置換される;
LC(VL)配列のアミノ酸D30及びS31が任意のアミノ酸の組合せ、好ましくはES、SS、TS、QS、HS、DHで置換される;
LC(VL)配列のアミノ酸V58がIで置換される;及び/又は、
LC(VL)配列のアミノ酸D70がEで置換される。
hLC03 − BCMAとの相互作用に関与する修飾アミノ酸(配列番号13):
EIVMTQSPATLSVSPGERATLSCKASQSVDX1X2VX3WX4QQKPGQAPRALIX5X6AX7X8RX9SGIPARFSGSX10X11GTEFTLTISSLQSEDFAVYYCX12QX13NNX14PX15TFGAGTKLELKR
ここで好ましいアミノ酸は、
X1:S、H、T、N、D、Q;
X2:N、E、Q;
X3:A、G、V、S、T、L、I;
X4:Y、F、L、I、V、A、G;
X5:Y、F、L;
X6:S、T;
X7:S、T、D、N、H、E、Q;
X8:L、V、I、M;
X9:F、L、I、V、Y、M;
X10:G、X;
X11:S、X;
X12:Q、V、L、I、M;
X13:Y、F、L、I、Q;
X14:Y、F、R、Q、K;及び/又は、
X15:L、I、V、Fである。
LC(VL)配列のアミノ酸S31がS、H、T、N、D、Qである;
LC(VL)配列のアミノ酸N32がN、E、Qである;
LC(VL)配列のアミノ酸A34がA、G、V、S、T、L、Iである;
LC(VL)配列のアミノ酸Y36がY、F、L、I、V、A、Gである;
LC(VL)配列のアミノ酸Y49がY、F、Lである;
LC(VL)配列のアミノ酸S50がS、Tである;
LC(VL)配列のアミノ酸S52がS、T、D、N、H、E、Qである;
LC(VL)配列のアミノ酸L53がL、V、I、Mである;
LC(VL)配列のアミノ酸F55がF、L、I、V、Y、Mである;
LC(VL)配列のアミノ酸G66がG、Xである;
LC(VL)配列のアミノ酸S67がS、Xである;
LC(VL)配列のアミノ酸Q89がQ、V、L、I、Mである;
LC(VL)配列のアミノ酸Y91がY、F、L、I、Qである;
LC(VL)配列のアミノ酸Y94がY、F、R、Q、Kである;及び/又は、
LC(VL)配列のアミノ酸L96がL、I、V、Fである。
hLC04(配列番号14):
EIVMTQSPATLSVSPGERATLSCKASQSVESNVAWYQQKPGQAPRALIYSASLRFSGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNYPLTFGAGTKLELKR
LC配列内の様々な潜在的修正部位のCLUSTAL W(1.83)多重配列アラインメントから、図9の適切な配列比較が得られる。「一般配列」はLC配列を表し、各々のXは潜在的アミノ酸変化を表す。好ましいアミノ酸置換は潜在的突然変異位置の各々について上に記載されるものである。
本発明はしたがって、CD269(BCMA)に結合する単離抗体又は抗体フラグメントであって、該抗体がCD269(BCMA)の残基13〜32の1つ又は複数のアミノ酸を含むエピトープに結合する、単離抗体又は抗体フラグメントに関する。
一実施の形態では、本発明はCD269標的と直接相互作用するアミノ酸の1つ若しくは複数、及び/又は水相互作用によって相互作用する1つ若しくは複数のアミノ酸によって規定されるアミノ酸配列を含む抗体又は抗体フラグメントに関する(表1〜表6を参照されたい)。エピトープへの本明細書に記載される抗体の結合に関与する多数の水相互作用は結合の独特な驚くべき態様である。特に、抗体とエピトープとの間の結合表面に関与する多数の水相互作用と組み合わせた本明細書に記載される特定のエピトープに対する抗体の高い親和性は、本発明の驚くべき予期せぬ態様である。
本発明の抗体は本明細書に記載されるエピトープに結合し、このエピトープの天然リガンドの相互作用を遮断し、CDC及びADCCを誘導することが可能である。
a)上述の請求項のいずれか一項に記載の単離抗体又は抗体フラグメントをコードし、
配列番号1〜31並びに41及び42による配列からなる群から選択されるアミノ酸配列をコードし、
配列番号32〜36の配列又は配列フラグメントを含む、
ヌクレオチド配列を含む核酸分子、
b)a)によるヌクレオチド配列に相補的な核酸分子、
c)a)又はb)によるヌクレオチド配列と機能的に類似/同等であるのに十分な配列同一性、好ましくはa)又はb)によるヌクレオチド配列と少なくとも80 %、好ましくは90 %、より好ましくは95 %の配列同一性を有するヌクレオチド配列を含む核酸分子、
d)遺伝コードのためにa)〜c)によるヌクレオチド配列へと縮重した核酸分子、並びに、
e)a)〜d)によるヌクレオチド配列と機能的に類似/同等である、欠失、付加、置換、転座、逆位及び/又は挿入により修飾されたa)〜d)のヌクレオチド配列による核酸分子、
からなる群から選択される単離核酸分子に関する。
本明細書で使用される場合、「抗体」は概して、免疫グロブリン遺伝子又は免疫グロブリン遺伝子のフラグメントによって実質的にコードされる1つ又は複数のポリペプチドからなるタンパク質を指す。「抗体」という用語が使用される場合、「抗体フラグメント」という用語への言及とみなすこともできる。認識される免疫グロブリン遺伝子としては、κ、λ、α、γ、δ、ε及びμ定常領域遺伝子、並びに無数の免疫グロブリン可変領域遺伝子が挙げられる。軽鎖はκ又はλとして分類される。重鎖はγ、μ、α、δ又はεとして分類され、これらは免疫グロブリンクラスIgG、IgM、IgA、IgD及びIgEをそれぞれ規定する。基本免疫グロブリン(抗体)構造単位は四量体又は二量体を含むことが知られている。各々の四量体は2つの同一のポリペプチド鎖対から構成され、各々の対は1つの「軽」(L)鎖(約25 kD)及び1つの「重」(H)鎖(約50 kD〜70 kD)を有する。各鎖のN末端は約100〜110以上のアミノ酸の可変領域を規定し、主に抗原認識に関与する。「可変軽鎖」及び「可変重鎖」という用語は、軽鎖及び重鎖のそれぞれのこれらの可変領域を指す。任意に、抗体又は抗体の免疫部分を他のタンパク質との融合タンパク質として化学的に複合するか又は発現することができる。
新規のキメラ抗体(J22.9-xi)はヒトCD269(BCMA、TNFRSF17)の細胞外ドメインに結合する。これを初めにヒト多発性骨髄腫細胞株MM.1Sに対するELISA及びフローサイトメトリーによって確認した(図1a、b)。BCMAに対するJ22.9-xiの親和性は表面プラズモン共鳴(SPR)を用いて決定した。平均Kdは図1cに示されるように54 pMである。
J22.9-xiから調製したFabフラグメントを、精製46アミノ酸残基BCMA細胞外ドメインと複合して結晶化し、複合体構造を1.9Åの分解能まで解明した。高品質電子密度がBCMAの残基6〜41について観察可能であり、J22.9-xi、主に抗体の軽鎖との広範な相互作用が示される(図2B)。740.4平方Åを覆い、BCMA残基の3分の1を含むこの界面は、APRIL及びsTALL1(BAFFとしても知られる)とのBMCA複合体の結合構造に観察される、保存DxLモチーフを含む同一のエピトープの12〜16残基をカバーし(Gordon N C, et al. (2003), BAFF/BlysS receptor 3comprises a minimal TNF receptor-like module that encodes a highly focusedligand-binding site. Biochemistry 42(20): 5977-83、及びPatelD R, et al. (2004), Engineeringan APRIL-specific B Cell Maturation Antigen. JBC 279(16): 16727-35)、BAFFを用いたin vitroアッセイにおいて見られる遮断効果の明らかな合理化をもたらす(図2A)。J22.9-xiとの相互作用は付加的にBCMA中のAla20及びPro23との直接側鎖接触、BAFF及びAPRILによってカバーされる結合エピトープの一部でない残基、並びに幾つかの水媒介性水素結合を含む。3つ全ての構造におけるBCMAの全体立体構造は、J22.9-xi及びAPRIL複合体間で1.4Å、J22.9-xi及びsTALL1複合体間で1.5ÅのC-α rmsdと極めて類似しており、J22.9-xi BCMA結合エピトープ(残基13〜30)のそれぞれのC-α rmsdは0.98Å及び0.88Åである。そのコアにDxLモチーフを有する同じBCMAエピトープを認識するにもかかわらず、J22.9-xiの結合部位は界面を含む相互作用群と同様、sTALL1及びAPRILとは極めて異なる。
重鎖
軽鎖
(sc=側鎖H結合、mc=主鎖H結合)
ルシフェラーゼベースの細胞傷害性アッセイを、ルシフェラーゼ形質導入MM.1S-Luc細胞株を用いて確立した。このアッセイでは、死細胞により放出されるルシフェラーゼが培地中にATPを欠くために機能することができないことから、生物発光は生細胞のみから検出される。健常ドナーに由来するPBMCを単離し、MM.1S-Luc細胞と20対1の比率で混合した。4時間後に生物発光を測定した。
機能B、T及びNK細胞集団を欠くNOD scid共通γ鎖ノックアウト(NSG)マウスを使用した。1×107のMM.1S-Luc細胞を静脈注射したマウスは、6週間以内に後肢麻痺を発症する(図4d-1)。初期症状が現れた日を屠殺日と規定する。
治療的投与を、抗体治療の開始を腫瘍細胞注射の5日後まで遅らせることによって模倣した。異種移植マウスを2つの群(n=6)に分けた。動物に200 μg/注射のアイソタイプ対照又はJ22.9-xi抗体のいずれかを週2回与えた。最初の測定は細胞注射後8日目に行った。J22.9-xiを与えた群(n=5)では35日目までに測定可能な腫瘍由来の生物発光は見られないが、腫瘍細胞量の着実な増大がアイソタイプ対照抗体を与えた群(n=6)で見られた(図5a、b)。アイソタイプ対照群のマウスは細胞注射後に平均56日間生存したが、J22.9-xiを与えた全てのマウスは77日目でも依然として生きている(図5c)。実験タイムラインの概要を図5dに提示する。
腫瘍成長に対する治療時期の影響を更に評価するために、種々の抗体を腫瘍細胞注射日から開始して5日連続で投与した。i.v.細胞注射後に動物を無作為に5つの群に分けた。群1(n=5)は200 μg/注射(i.p.)のアイソタイプ対照抗体で治療し、群2(n=6)には200 μg/注射のJ22.9-xi-N-グリカン抗体を与えた。群3(n=4)、群4(n=5)及び群5(n=5)のマウスにはそれぞれ200 μg/注射、20 μg/注射及び2 μg/注射のJ22.9-xi抗体を与えた。生物発光測定は細胞注射後9日目に開始した。44日目までに、腫瘍に由来しない生物発光が無傷J22.9-xi抗体を与えた群のいずれにも見られた。J22.9-xi-N-グリカンで治療した動物における腫瘍成長は減速するが、全腫瘍細胞量はアイソタイプ対照抗体を与えた動物とは有意に異ならない(図6a、b)。J22.9-xi-N-グリカン(脱グリコシル化)で治療した動物の全腫瘍細胞量は有意に異ならなかったが(図6b)、これらのマウスの寿命はisoAb治療群と比較して実質的に増大した(図6c)。J22.9-xi-N-グリカンはADCC又はCDCを誘導し得ないことが示されているため、この結果からBCMAへのJ22.9-xiの結合のみが腫瘍成長を妨げることが示唆される。これは受容体とそのネイティブリガンド(APRIL及びBAFF)との間の相互作用の遮断によるものであると合理的に考えることができる。実験タイムラインの概要を図6dに提示する。
J22.9-xi抗体を配列アラインメントに基づいてヒト化し、結晶構造からデータを得た。可変領域の配列を、それらのそれぞれのヒト相同体に対してIgBLAST(NCBI)又はClustal(EBI)を用いてアラインメントした。各々の提案される突然変異を改変前の構造の目視検査によって評価した。
BCMAへの突然変異体の結合をフローサイトメトリー、ELISA及びSPRを用いて試験した。ヒト化抗体の親和性は表面プラズモン共鳴(ProteOn(商標) XPR36、Bio-Rad)を用いて測定した。結合データは、J22.9-xi結合について試験したものと同じエピトープに対するヒト化抗体変異体の特異性及び親和性に関して驚くべき結果を示す。下記表に示されるように、本明細書に記載されるヒト化抗体は実に驚くべきことに元のキメラ抗体と同等の結合特徴を示した。SPRデータから、ヒト化変異体の親和性がキメラの親和性と同様であり、本明細書に提示される元のキメラ抗体のデータに照らしてそれらの臨床的関連を想定するのに十分であることが明らかになる。キメラのヒト化におけるCDRの修飾により結合特徴がかかる程度まで維持されることは当業者には予期せぬものであっただろう。
ヒト化J22.9中の潜在的翻訳後修飾部位を除去するために重鎖CDR2の残基D54をアスパラギン(N)へと突然変異させることで、N-結合型グリコシル化の新たな潜在的修飾部位が意図せず作製された。N54を含有する突然変異重鎖はSDSゲル上をより遅く移動し(図13)、より大きなサイズ及びCDRのグリコシル化が示される。
細胞株及び培養
ヒト多発性骨髄腫細胞株MM.1S(Greenstein et al. (2003) Exp Hematol31:271-282)をB. Doerken教授(MDC,Berlin,Germany)から入手した。腫瘍細胞成長のin vivoモニタリングのために、ルシフェラーゼ及びGFPをレンチウイルスベクター系ViraPower(Invitrogen)のpFUベクターにクローニングした。形質導入細胞のGFP発現により、モノクローナル細胞株を、蛍光活性化単一細胞選別を用いて単離した。細胞株を、フェノールレッドを含まず、10 %ウシ胎児血清、100単位/mlのペニシリン及び100 μg/mlのストレプトマイシン(全てPAA製)を含有するRPMI-1640培地中で培養した。
BCMA結合抗体を得るために標準ハイブリドーマ法を用いた。4匹のBL/6野生型マウスを不完全フロイントアジュバント及びグルタチオンS-トランスフェラーゼ(GST)にC末端融合させたヒトBCMAの細胞外ドメイン30 μgで6回免疫化した。細胞融合に続くスクリーニング期間の後、J22.9ハイブリドーマが抗BCMA抗体を分泌することが示された。
マイクロタイタープレートを10 μg/mlのヒトBCMAの細胞外ドメインでコーティングした。コーティングされたBCMAを、1 ng〜1000 ngの範囲のJ22.9-xi及びアイソタイプ対照の段階希釈物を用いて検出した。コーティングされたBCMAへのJ22.9-xi又はアイソタイプ対照抗体の結合を、ホースラディッシュペルオキシダーゼ(HRP)複合ヤギ抗ヒト二次抗体(Jackson ImmunoResearch,109-035-098、5000倍希釈)を用いて検出した。
細胞表面抗原検出実験のために、自製抗体(J22.9-xi、J22.9-H、J22.9-ISY、J22.9-FSY及びアイソタイプ対照)及び市販のマウス抗Hisタグ(AbD Serotec,AD1.1.10、100倍希釈、Alexa Fluor 488複合)及びヤギ抗ヒトIgG1(Jackson ImmunoResearch,109-116-098、400倍希釈、PE複合)抗体及びHisタグ(Biomol)に融合したヒト組み換えBAFFを使用した。実験はFACSCalibur又はFACSCanto IIフローサイトメーター(BD Bioscience)で行った。データはFlowjoソフトウェアバージョン7.6(TreeStar Inc.)を用いて分析した。
(Fab)2フラグメントを完全長J22.9-xi IgGからペプシンとのインキュベーションによって生成した。J22.9-xiをPD-10バッファー交換カラムから50 mM酢酸ナトリウム(pH 3.5)に通し、1 mgのJ22.9-xiにつき30 μgのペプシンを添加した。37℃で2.5時間のインキュベーションはフラグメント結晶化可能(Fc)領域を完全に消化するのに十分であり、ペプシンをPD-10カラムからPBS(pH 7.2)への交換によって不活性化した。(Fab)2フラグメントの個々のFabへの還元は、5 mMエチレンジアミン四酢酸(EDTA)の存在下での2-メルカプトエチルアミン(50 mM)の添加によりPBS中で達成された。37℃で90分間のインキュベーション後に、還元システインを500 μMヨードアセトアミドによる30分間のアルキル化に続くバッファーの新鮮PBSへの交換によって遮断した。Fabフラグメントを1.5モル当量の精製BCMAと合わせ、複合体をSuperdex 75 16/60カラムでのサイズ排除クロマトグラフィーによって単離した。画分を4 %〜12 % SDSポリアクリルアミドゲルで分析し、Fab及びBCMAの両方を含有する画分をプールし、結晶化試験のために濃縮した。
濃縮された複合体に飽和を確実にするために0.5モル当量の純粋BCMAを添加し、結晶化スクリーニングに供した。初期Fab:BCMA結晶化条件を、Gryphonピペッティングロボット(200 nlの液滴)を用いた96ウェルシッティングドロップフォーマットプレートでの市販のスクリーン(Qiagen)により特定し、24ウェルハンギングドロッププレート(2 ul〜3 ul)で最適化した。複合体を8 mg/mlまで濃縮し、21 % PEG 3350、0.1 M BisTris(pH 6.5)及び5 mM CuCl2中20℃で結晶化した。結晶は3日後に薄板のクラスターとして現れ、およそ7日以内にそれらの最終サイズ(0.2 mm〜0.3 mm)に達した。クラスターを分離し、個々のプレートを20 %グリセロールを抗凍結剤として含む母液中にて液体窒素で急速冷凍した。完全な回折データをヘルムホルツセンターベルリン研究所(Helmohltz Zentrum Berlin)のBESSYシンクロトロンで単一結晶から収集した。構造を、探索モデルとしてのエファリズマブ(3EO9)の構造から実験相を用いた分子置換によって1.9Åの分解能まで解明した。データ処理はccp4プログラムスイートを用いて行い、構造精緻化はPhenix(Adams P D, et al.(2010), Acta Cryst. D66: 213-221)並びにCootを用いるモデル構築及び評価を用いて行った(Emsley et al, Acta Crystallographica Section D - BiologicalCrystallography, 2010, 66:486-501)。画像はPyMOL(The PyMOL Molecular Graphics System、バージョン1.5.0.4Schroedinger,LLC)を用いて生成した。
このアッセイでは、J22.9-xiの細胞傷害効果を残存生細胞の発光を生物発光リーダーで測定することによって決定した。要するに、新たに得られたヒトフィルターバフィーコート(filter buffy coats;FBC)を、160 mlの溶出バッファー(5 mM Na2-EDTA及び2.5 [w/v]スクロースを含有するPBS(pH 7.4))を用いて重力によりバックフラッシュした。単核細胞を溶出細胞からフィコール勾配遠心分離によって単離した。単核細胞を中間相から取り出し、溶出バッファーで2回洗浄した。赤血球溶解の後、PBMCを再び洗浄し、計数し、フェノールレッドを含まないRPMI/10 % FCSでの希釈により1×107細胞/mlに調整した。50 μlのRPMI中5×104のMM.1S-Luc細胞をマイクロタイタープレートにプレーティングした。100 μlのPBMCを添加する10分前に、MM.1S-Luc細胞をJ22.9-xi又はアイソタイプ対照抗体の段階希釈物と200 μlのサンプル容量でインキュベートした。標的細胞、抗体及びエフェクター細胞の添加後に、マイクロタイタープレートを室温(RT)で2分間遠心分離し(300×g)、37℃、5 % CO2で保管した。対照ウェルは完全な溶解のために抗体の代わりに1 % Triton Xで処理した。4時間のインキュベーションの後、ルシフェリン(250 ng/ml)を含む25 μlのPBSを各ウェルに適用し、生細胞の生物発光を生物発光リーダー(Tecan)で測定した。特異的細胞傷害性を以下の式に従って算出した:
100−[値(J22.9-xi)−値(完全溶解)]/[値(アイソタイプ対照)−値(完全溶解)]×100。
The Jackson LaboratoryからのNOD.Cg-Prkdcscid Il2rgtm1WjlTg(CSF2)2Ygy Tg(IL3)1Ygy Tg(KITLG)3YgyJGckRolyJマウス(NSG)及びCharles River Deutschland(Sulzfeld,Germany)からのCB17.Cg-Prkdcscid Lystbg/Crlマウスを使用した。実験は8週齢〜14週齢のマウスを用いて行った。全ての動物研究は特定病原体を含まない条件下で施設及び州のガイドラインに従って行った。定着腫瘍の治療及び疾患の初期段階における腫瘍治療に関する実験例では、CB17.Cg-Prkdcscid Lystbg/Crlマウスを使用した。本明細書で言及される2つのマウス株の表現型は非常に類似している。動物は機能B、T及びNK細胞を有しない。僅かに遅い腫瘍成長がCB17.Cgマウスにおいて観察され、本発明の治療抗体の更に有望な効果が示唆される。
重鎖及び軽鎖可変領域配列(マウス)を対応する重鎖及び軽鎖サブタイプヒト配列とアラインメントして、どの残基変化が完全ヒト化配列変異体の産生に必要とされるかを決定した。J22.9-xi:hBCMA複合体の結晶構造を用いて、各々の修飾を初めにコンピューターにより評価して、BCMAへの抗体の結合を潜在的に破壊し得る突然変異を特定した。各鎖について、遺伝子を各々3つのカセットに分けるために2つの制限酵素部位が付加された1つは元のマウス配列を有し、1つは完全ヒト化配列を有する(すなわち必要なヒト化突然変異を全て含有する)2つの完全J22.9可変領域遺伝子を合成した。潜在的に問題となる突然変異をフラッギングした(flagging)後、元のマウス及び完全ヒト化遺伝子カセットの様々な組合せを作製し、それらの対応するIgGを発現させ、精製し、BCMA陽性細胞を用いたFACS分析に供して結合を評価した。フラッギングした問題残基を個別にPCRを用いて突然変異させ、BCMAに対する親和性へのそれらの影響を検証し、最終最適化構築物を続いてヒト及びカニクイザルBCMAの両方への結合についてSPRにより定量的に評価した。
SPRは0.005 % Tween-20を添加したリン酸緩衝食塩水(PBST)を用いてProteonXPR36で行った。濃度15 ug/mlの全IgGを、標準アミン化学を用いて製造業者の取扱説明書に従ってProteon GLHセンサーチップに固定化した。結合実験のために、PBST中のヒト又はカニクイザルBCMAを移動相として使用した。結合親和性(Kd)を、複数の濃度のBCMA(hBCMAについては0.4nM〜800 nM、cynoBCMAについては2.7 nM〜1 μMの範囲)で並行して決定された結合定数(kon)及び解離定数(koff)から算出し、単一部位結合モデルを想定した。
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図1
DeltaOD ΔOD
antibody 抗体
Isotype アイソタイプ
Counts カウント数
Response 応答
図2
Heavychain 重鎖
Lightchain 軽鎖
図3
Cytotoxicity 細胞傷害性
donor ドナー
J22.9-xiw/o N-glycan N-グリカンを有しないJ22.9-xi
Counts カウント数
Isotype アイソタイプ
storedat 4℃ 4℃での保管
storedat -80℃ -80℃での保管
図4
TotalFlux 全光束
time(d) 時間(日数)
Isotype アイソタイプ
noantibody 抗体なし
Areaunder the curve 曲線下面積
noAb 抗体なし
Survival 生存
control 対照
cells 細胞
ventralview 腹面図
dorsalview 背面図
Day7 7日目
Day14 14日目
Day21 21日目
Day 日数
isotypecontrol アイソタイプ対照
Radiance 放射輝度
Experimentaltime line 実験タイムライン
tumorcell injection 腫瘍細胞注射
cells/mouse 細胞/マウス
weeklytumor monitoring 毎週の腫瘍モニタリング
antibodyinjection 抗体注射
200μg J22.9-xi or isotype control 200 μgのJ22.9-xi又はアイソタイプ対照
図5
TotalFlux 全光束
days 日数
control 対照
Isotype アイソタイプ
Areaunder the curve 曲線下面積
Survival 生存
Experimentaltime line 実験タイムライン
tumorcell injection 腫瘍細胞注射
cells/mouse 細胞/マウス
weeklytumor monitoring 毎週の腫瘍モニタリング
antibodyinjection 抗体注射
200μg J22.9-xi or isotype control 200 μgのJ22.9-xi又はアイソタイプ対照
図6
TotalFlux 全光束
days 日数
control 対照
isotype アイソタイプ
deglycosylated 脱グリコシル化
noglycan グリカンなし
Survival 生存
Time(d) 時間(日数)
-N-glycan -N-グリカン
Experimentaltime line 実験タイムライン
tumorcell injection 腫瘍細胞注射
cells/mouse 細胞/マウス
tumormonitoring (IVIS) every week 毎週の腫瘍モニタリング(IVIS)
antibodyinjection 抗体注射
2 μg, 20 μg or 200 μgJ22.9-xi, J22.9-xi w/o N-glycan or isotype control 2 μg、20 μg若しくは200 μgのJ22.9-xi、N-グリカンを有しないJ22.9-xi又はアイソタイプ対照
図7
Time(d) 時間(日数)
図8
Variable amino acid according to humanized sequences ヒト化配列による可変アミノ酸
General heavy chain variable sequence 一般重鎖可変配列
mouse heavy chain variable sequence マウス重鎖可変配列
partially humanized heavy chain variable sequence 部分ヒト化重鎖可変配列
CDRs are underlined in general and mouse sequences. 一般配列及びマウス配列におけるCDRに下線を付ける。
図9
Variable amino acid according to either mouse orhumanized sequences マウス配列又はヒト化配列のいずれかによる可変アミノ酸
General heavy chain variable sequence 一般重鎖可変配列
mouse heavy chain variable sequence マウス重鎖可変配列
partially humanized heavy chain variable sequence 部分ヒト化重鎖可変配列
CDRs are underlined in general and mouse sequences. 一般配列及びマウス配列におけるCDRに下線を付ける。
図10
Bindingto hBCMA hBCMAへの結合
%of max 最大に対する%
Bindingto cyBCMA cyBCMAへの結合
図11
%of max 最大に対する%
図12
Response 応答
time(s) 時間(秒)
Claims (25)
- RYWX1S(H-CDR1;配列番号15)(ここで、X1:I、F、L、V、Y、C、G、A、S、Tである)、
EINPX2X3STINYAPSLKDK(H-CDR2;配列番号16)(ここで、X2X3:SS、NS、TS、GS、KS、RS、SD、SN、DEである)、及び、
SLYX4DYGDAX5DYW(H-CDR3;配列番号17)(ここで、X4:Y、L、A、V、F、I、W及び/又はX5:Y、L、F、I、V、A、Cである)、
のCDR配列を含むVHドメインを含む抗体又は抗体フラグメントであって、該抗体又はそのフラグメントがCD269(BCMA)の細胞外ドメインのエピトープに特異的に結合する、抗体又は抗体フラグメント。 - 前記VHドメインがCDR配列RYWIS(配列番号18)又はRYWFS(配列番号19)を含む、請求項1に記載の抗体又は抗体フラグメント。
- 前記VHドメインがCDR配列EINPNSSTINYAPSLKDK(配列番号20)又はEINPSSSTINYAPSLKDK(配列番号21)を含む、請求項1又は2に記載の抗体又は抗体フラグメント。
- 前記VHドメインがCDR配列SLYYDYGDAYDYW(配列番号22)を含む、請求項1〜3のいずれか一項に記載の抗体又は抗体フラグメント。
- KASQSVX1X2NVA(L-CDR1;配列番号23)(ここで、X1X2:ES、SS、TS、QS、HS、DHである)、
SASLRFS(L-CDR2;配列番号24)、及び、
QQYNNYPLTFG(L-CDR3;配列番号25)、
のCDR配列を含むVLドメインを含む抗体又は抗体フラグメントであって、該抗体又はそのフラグメントがCD269(BCMA)の細胞外ドメインのエピトープに特異的に結合する、抗体又は抗体フラグメント。 - 前記VLドメインがCDR配列KASQSVDSNVA(配列番号26)を含む、請求項1〜5のいずれか一項に記載の抗体又は抗体フラグメント。
- 配列EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWX1SWVRQAPGKGLVWVGEINPX2X3STINYAPSLKDKFTISRDNAKNTLYLQMNSLRAEDTAVYYCASLYX4DYGDAX5DYWGQGTLVTVSS(配列番号4)(ここで、X1:I、F、L、V、Y、C、G、A、S、T;X2X3:SS、NS、TS、GS、KS、RS、SD、SN、DE、又はSS;X4:Y、L、A、V、F、I、W;及びX5:Y、L、F、I、V、A、Cである)を含むVHドメインを含む、請求項1〜6のいずれか一項に記載の抗体又は抗体フラグメント。
- 配列番号6、配列番号7、配列番号8又は配列番号9による配列を含むVHドメインを含む、請求項1〜7のいずれか一項に記載の抗体又は抗体フラグメント。
- 配列EIVMTQSPATLSVSPGERATLSCKASQSVX1X2NVAWYQQKPGQAPRALIYSASLRFSGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNYPLTFGAGTKLELKR(配列番号12)(ここで、X1X2:ES、SS、TS、QS、HS、DHである)を含むVLドメインを含む、請求項1〜8のいずれか一項に記載の抗体又は抗体フラグメント。
- 配列番号14による配列を含むVLドメインを含む、請求項1〜9のいずれか一項に記載の抗体又は抗体フラグメント。
- 配列番号6、配列番号7、配列番号8又は配列番号9による配列を含むVHドメインと、配列番号14による配列を含むVLドメインとを含む、請求項1〜10のいずれか一項に記載の抗体又は抗体フラグメント。
- VHドメインを含み、該VHドメインがX1VQLX2X3SGGGLVQPGGSLX4LSCAASGX5X6FX7X8YWZ1SWVRX9APGKGLEWX10GEINPZ2SSTINYAPSLKX11X12FX13ISRDNAKNTLYLQMX14X15X16RX17EDTAX18YYCASLYYDYGDAZ3DYWGQGTX19VTVSS(配列番号41)(ここで、X1:Q、E;X2:Q、V;X3:Q、E;X4:K、R;X5:I、F;X6:D、T;X7:S、D;X8:R、D;X9:R、Q;X10:I、V;X11:D、G;X12:K、R;X13:I、T;X14:S、N;X15:K、S;X16:V、L;X17:S、A;X18:L、V;X19:S、Lであり、Z1:I又はF;Z2:S及び/又はZ3:Yの少なくとも1つである)による配列を含み、前記抗体又はそのフラグメントがCD269(BCMA)の細胞外ドメインのエピトープに特異的に結合する、請求項1〜11のいずれか一項に記載の抗体又は抗体フラグメント。
- VLドメインを含み、該VLドメインがDIVMTQSX1X2X3X4X5X6SVGDX7VX8X9TCKASQSVESNVAWYQQKPX10QX11PKX12LIX13SX14X15LRFSGVPARFX16GSGSGTDFTLTISX17LQSEDX18AX19YX20CQQYNNYPLTFGAGTKLELKR(配列番号42)(ここで、X1:Q、P;X2:R、A;X3:F、T;X4:M、L;X5:T、S;X6:T、V;X7:R、E;X8:S、T;X9:V、L;X10:R、G;X11:S、A;X12:A、L;X13:F、Y;X14:A、D;X15:S、D;X16:T、S;X17:N、S;X18:L、F;X19:E、V;X20:F、Yである)による配列を含み、前記抗体又はそのフラグメントがCD269(BCMA)の細胞外ドメインのエピトープに特異的に結合する、請求項1〜12のいずれか一項に記載の単離抗体又は抗体フラグメント。
- 前記抗体がCD269のアミノ酸13、15、16、17、18、19、20、22、23、26、27又は32からなるエピトープに結合する、請求項1〜13のいずれか一項に記載の単離抗体又は抗体フラグメント。
- CD269(BCMA)に結合する前記抗体がBAFF-CD269及び/又はAPRIL-CD269相互作用を破壊する、請求項1〜14のいずれか一項に記載の単離抗体又は抗体フラグメント。
- 前記抗体がグリコシル化されている、請求項1〜15のいずれか一項に記載の単離抗体又は抗体フラグメント。
- グリカンが重鎖のAsn297でのN-結合型オリゴ糖鎖である、請求項1〜16のいずれか一項に記載の単離抗体又は抗体フラグメント。
- 病原性B細胞の存在と関連する医学的障害の治療において薬剤として使用される、請求項1〜17のいずれか一項に記載の単離抗体又は抗体フラグメント。
- 病原性B細胞と関連する前記医学的障害が形質細胞及び/又は記憶B細胞の疾患である、請求項1〜18のいずれか一項に記載の単離抗体又は抗体フラグメント。
- 病原性B細胞と関連する前記医学的障害が形質細胞の癌、例えば多発性骨髄腫、形質細胞腫、ワルデンストレームマクログロブリン血症若しくは形質細胞白血病、又はホジキン病等のBリンパ球の癌である、請求項1〜19のいずれか一項に記載の単離抗体又は抗体フラグメント。
- 病原性B細胞と関連する前記医学的障害が、炎症性自己免疫疾患、例えば全身性エリテマトーデス(SLE)又はリウマチ性関節炎等の自己反応性形質細胞及び/又は自己反応性記憶B細胞と関連する自己免疫疾患である、請求項1〜20のいずれか一項に記載の単離抗体又は抗体フラグメント。
- 治療剤と複合した請求項1〜21のいずれか一項に記載の抗体又は抗体フラグメントを含む抗体薬物複合体(ADC)。
- a)請求項1〜21のいずれか一項に記載の単離抗体又は抗体フラグメントをコードし、
配列番号1〜31並びに41及び42による配列からなる群から選択されるアミノ酸配列をコードし、
配列番号32〜36の配列又は配列フラグメントを含む、
ヌクレオチド配列を含む核酸分子、
b)a)によるヌクレオチド配列に相補的な核酸分子、
c)a)又はb)によるヌクレオチド配列と機能的に類似/同等であるのに十分な配列同一性、又はa)又はb)によるヌクレオチド配列と少なくとも80 %、若しくは90 %、若しくは95 %の配列同一性を有するヌクレオチド配列を含む核酸分子、
d)遺伝コードのためにa)〜c)によるヌクレオチド配列へと縮重した核酸分子、並びに、
e)a)〜d)によるヌクレオチド配列と機能的に類似/同等である、欠失、付加、置換、転座、逆位及び/又は挿入により修飾されたa)〜d)のヌクレオチド配列による核酸分子、
を含む群から選択される核酸分子。 - 請求項1〜21のいずれか一項に記載の抗体又は抗体フラグメントを産生することが可能であり、及び/又は請求項23に記載の核酸分子を含む細菌細胞又は哺乳動物細胞、又はハイブリドーマ細胞若しくは細胞株である宿主細胞。
- 薬学的に許容可能な担体とともに請求項1〜21のいずれか一項に記載の単離抗体又は抗体フラグメント、請求項23に記載の核酸分子、請求項22に記載のADC又は請求項24に記載の宿主細胞を含む医薬組成物。
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