JP7536424B2 - 多重特異性分子 - Google Patents
多重特異性分子 Download PDFInfo
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- JP7536424B2 JP7536424B2 JP2018563747A JP2018563747A JP7536424B2 JP 7536424 B2 JP7536424 B2 JP 7536424B2 JP 2018563747 A JP2018563747 A JP 2018563747A JP 2018563747 A JP2018563747 A JP 2018563747A JP 7536424 B2 JP7536424 B2 JP 7536424B2
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Classifications
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Description
本明細書において引用または参照されている全資料、及び本明細書で引用した資料において引用または参照されている全資料は、本明細書または参照により本明細書に組み込まれるあらゆる文献で言及されるあらゆる製品についてのあらゆる製造者による説明書、記載事項、製品仕様書、及び製品シートと併せて、その全体が本明細書によって参照により本明細書に組み込まれる。
電子的に提出された配列表の全記載内容はあらゆる目的のために参照によりその全体が組み込まれる。
(i)第1の標的抗原または標的エピトープに結合する少なくとも1つの結合ドメイン分子(BDM)であり、かかるBDMは、内部に含有される3つの露出した結合ループ(BL)を有するV様ドメイン(VLD)足場を含むかまたは構成要素とし、ここで、かかる3つのBLのうち少なくとも2つは、異種の標的抗原または標的エピトープに選択的に結合するよう、足場内のそれらの対応天然配列に関して修飾または置換されていること、かつ
(ii)第2の標的抗原または標的エピトープに結合する、抗体もしくはその抗原結合断片または非抗体タンパク質もしくはペプチドである薬理的に活性なタンパク質またはペプチドを含み、
ここで、少なくとも1つのBDMは、その薬理的に活性なタンパク質またはペプチド内に存在するポリペプチドのC末端に結合されていることを含む。
(i)抗体軽鎖ポリペプチドのC末端、
(ii)各抗体軽鎖ポリペプチドのC末端、
(iii)抗体重鎖ポリペプチドのC末端、
(iv)各抗体重鎖ポリペプチドのC末端
に結合させる。
(i)少なくとも1つのBDMを抗体の重鎖ポリペプチドのCH3ドメインのC末端に結合させる、
(ii)少なくとも1つのBDMを軽鎖ポリペプチドのCH1ドメインのC末端に結合させる、
(iii)少なくとも1つのBDMを重鎖ポリペプチドのCH3ドメインのC末端及び軽鎖ポリペプチドのCH1ドメインのC末端に結合させる、
(iv)少なくとも1つのBDMを両方の重鎖ポリペプチドのCH3ドメインのC末端に結合させる、または
(v)少なくとも1つのBDMを両方軽鎖ポリペプチドのCH1ドメインのC末端に結合させる。
(i)少なくとも1つのBDMをFabの軽鎖ポリペプチドの定常領域のC末端に結合させる、
(ii)少なくとも1つのBDMをFabの重鎖ポリペプチドのCH1のC末端に結合させる、または
(iii)少なくとも1つのBDMをFabの軽鎖ポリペプチドの定常領域のC末端及び重鎖ポリペプチドのCH1のC末端に結合させる。
に記載の配列を含むかまたは構成要素とする。
を含むかまたは構成要素とし、
ここで、Xn1、Xn2及びXn3は任意のアミノ酸残基であり、nは5~15の数であり、数字の1、2及び3は結合ループ領域を指す。より詳細には、1、2及び3はそれぞれ、BDMのBL-1、BL-2及びBL-3に対応する。
を含むかまたは構成要素とし、
ここで、Xn1、Xn2及びXn3は任意のアミノ酸残基であり、nは5~15の数であり、数字の1、2、及び3は結合ループ領域を指す。より詳細には、1、2及び3はそれぞれ、BDMのBL-1、BL-2及びBL-3に対応する。
に記載のBDM VLD核酸配列を含むかまたは構成要素とし、ここで、N1は第1の結合ループをコードするヌクレオチドの長さ、N2は第2の結合ループをコードするヌクレオチドの長さ及びN3は第3の結合ループをコードするヌクレオチドの長さである。一例では、N1、N2及びN3は、15~45ヌクレオチドである。一例では、N1は15~24ヌクレオチドである。N2は15ヌクレオチドであり、N3は30~45ヌクレオチドである。Nは任意のヌクレオチド(A、C、T、G)である。
(i)BDM VLD配列をコードする核酸であり、ここで、VLDの3つのBLのうち少なくとも2つが異種配列で修飾または置き換られている核酸を提供すること、
(ii)薬理的に活性なタンパク質またはペプチドをコードする核酸を提供すること、及び
(iii)任意選択で、リンカー配列をコードする核酸を提供すること、
(iv)上述核酸配列を好適なベクターに発現させること、
(v)発現したタンパク質を回収すること
を含む。
(i)抗体軽鎖配列またはその一部をコードする核酸を提供すること、
(ii)抗体重鎖配列またはその一部をコードする核酸を提供すること、
(iii)BDM VLD配列をコードする核酸であり、ここで、VLDの3つのBLのうち少なくとも2つが異種配列で修飾または置き換られている核酸を提供すること、
(iv)上述核酸配列を好適なベクター(複数可)に発現させること、及び
(v)発現したタンパク質を回収すること
を含む。
本明細書全体を通して、特に具体的な断りがある、または文脈において特に指定がある場合を除いては、単一のステップ、組成物、ステップ群または組成物群への言及には、かかるステップ、組成物、ステップ群または組成物群を1つ及び複数(すなわち1つ以上)包含すると解釈されるべきである。
本明細書においてアミノ酸配列で使用される文字「x」は、特に明記しない限り、標準アミノ酸20個のうちいずれをこの位置に置いてもよいことを示すものとする。
本開示の結合ドメイン分子(BDM)は、好ましくは、3つの露出結合ループ(BL)を有するタンパク質足場を含有する。BLを改変して、すなわち、アミノ酸置換により置き換えまたは修飾を行って、BDMに所与の標的抗原に対する結合特異性を付与することができる。本開示のBDM足場は、免疫グロブリン様(Ig様)ドメイン含有スーパーファミリーメンバー、i-body、VNARまたはVHHからなる群から選択されてよい。
(i)タンパク質またはペプチドは、BDMが結合している第2の標的抗原と同一であるかまたは異なる第1の標的抗原に結合する、
(ii)抗体または免疫グロブリン抗原結合性断片は、BDMが結合している第2の標的抗原と同一である第1の標的抗原に結合する、
(iii)抗体または免疫グロブリン抗原結合性断片は、BDMが結合している第2の標的抗原とは異なる第1の標的抗原に結合する、
(iv)抗体または免疫グロブリン抗原結合性断片は第1の標的抗原に結合し、BDMは第1の標的抗原と同一の第2の標的抗原に結合し、さらなるBDMは第1及び第2の標的抗原とは異なる第3の標的抗原に結合する、
(v)抗体または免疫グロブリン抗原結合性断片は第1の標的抗原に結合し、BDMとさらなるBDMはそれぞれ第2及び第3の標的抗原に結合し、ここで、第2及び第3の標的抗原は同一であっても異なっていてもよいが、第2及び第3の標的抗原は第1の標的抗原とは異なる、
(vi)抗体または免疫グロブリン抗原結合性断片は第1の標的抗原に結合し、BDMは第2の標的抗原に結合し、さらなるBDMは第3の標的抗原に結合し、ここで、第1、第2、及び第3の標的抗原は異なる
ことが含まれる。
本明細書で示されるように、細菌の発現系を使用して、BDMドメイン(例えば、CTLA-4)の1つ以上の結合ループ構造をスクレロスチンまたはCD3の異種の結合ループ配列で置き換えると、可溶性の非グリコシル化単量体結合分子が生成された。したがって、V様ドメインにより、結合ループ構造を修飾して分子の結合特異性を工学的に操作できる、可溶性単一ドメイン分子構築用の基本的フレームワークが提供される。
一例では、分子のBDM部分はBDM単量体の二量体である。二量体形成は、天然に生じても、またはリンカーを使用して促進してもよい。例えば、BDMがCTLA-4 VLDである場合、二量体化は、2つの茎の配列が保持されている場合、それらのシステイン残基(Cys120)同士のジスルフィド結合を介して生じてよい。
ヒトCTLA-4分子の細胞外ドメインもV様ドメイン(VLD)も、細菌細胞で可溶性単量体としての発現に成功しておらず、これは恐らく発現タンパク質の凝集によるものと思われる(Linsley PS et al,(1995)J.Biol.Chem 270:15417-24)。E.coliで細胞外N末端ドメイン(Met1~Asp124、Cys120を含む)を発現させると、分子量28kDaの二量体タンパク質が精製され、2つのCTLA-4 V様ドメインがCys120にてジスルフィド結合により繋がれている。Val114で切断するとこれらのシステインは除去されるが、この切断は、14kDaのVLDを可溶性の単量体形態で発現させることを意図したものであった。しかしながら、生成物は凝集し、これは、通常グリコシル化によって隠れている疎水性部位が露出したため、凝集が引き起こされたと結論づけられた(Linsley PS et al,(1995)J.Biol.Chem 270:15417-24)。
B7タンパク質は、活性化抗原提示細胞(APC)に見られる表在性膜タンパク質であり、T細胞の表面タンパク質CD28またはCD152(CTLA-4)のいずれかと対になると、それぞれ、共刺激シグナルまたは共抑制性シグナルを発してAPCとT細胞間のMHC-TCRシグナルの活性の増強または低下を行うことができる。B7は、活性化APC上に存在するほか、T細胞上にも見られる。
スクレロスチンは、C末端にシステインノット様ドメイン、及び骨形成タンパク質(BMP)アンタゴニストのDAN(ディファレンシャルスクリーニング法で選択した神経芽腫における異常遺伝子)ファミリーに対する配列類似性を有する分泌糖タンパク質である。スクレロスチンは骨細胞により産生され、骨形成の抗同化作用を有する。ヒト配列のUniprot参照番号はQ9BQB4である。
本開示の完全なタンパク質種は薬理学的に活性である。そのようなタンパク質には、抗体(例えば、完全長抗体)もしくは免疫グロブリン抗原結合性断片または本明細書に記載する非抗体タンパク質が含まれる。
特定の例では、多重特異性分子は完全長抗体を含む。一例では、抗体はヒト化抗体である。別の例では、抗体はヒト抗体である。別の例では、抗体はキメラ抗体である。
抗体断片は、無傷抗体の部分を含み、それには、無傷抗体の抗原結合領域または可変領域が含まれ得る。本開示での使用に好適な抗体断片の例としては、Fab、F(ab’)2、Fab’、scFv、di-scFv、または化学的に結合しているF(ab’)2が挙げられる。特定の例では、抗体断片はFabである。
本開示は、本開示の多重特異性分子を作成するための方法も提供する。
(i)タンパク質(例えば、抗体)及びBDMをコードするポリヌクレオチドを含むベクター(複数可)を提供し、
(ii)かかるベクターを用いて哺乳類宿主細胞(例えば、CHO)を形質転換し、
(iii)ステップ(ii)の宿主細胞を、宿主細胞から培地中へのタンパク質分泌を促す条件下で培養し、かつ
(iv)ステップ(iii)の分泌タンパク質を回収する
というステッップを含む。
(i)多重特異性分子の重鎖をコードする第1のベクターを提供すること、
(ii)多重特異性分子の軽鎖をコードする第2のベクターを提供すること、及び
(iii)前記第1及び第2のベクターを用いて哺乳類宿主細胞(例えば、CHO)を形質転換すること
を含む。
本開示のポリペプチドをコードする核酸は、クローニングによることに加えて、またはクローニングによってではなく、合成によって調製することができる。核酸は、ポリペプチド部分(例えば、免疫グロブリン及びBDM)のための適切なコドンを用いて設計することができる。一般に、配列を発現に使用するのであれば、ある意図する宿主に好ましいコドンが選択されるであろう。一般に、配列を発現に使用するのであれば、その意図する宿主に好ましいコドンが選択されるであろう。完全ポリヌクレオチドは、標準的方法で調製され、完全なコード配列に構築されている重複オリゴヌクレオチドから組み立てることができる。例えば、Edge,Nature,292:756(1981);Nambair et al.,Science,223:1299(1984);Jay et al.,J.Biol.Chem.,259:6311(1984)を参照のこと。
ポリペプチドを単離する方法は、当該技術分野で公知であり、及び/または本明細書に記載されている。
薬理的に活性なタンパク質またはペプチドと、少なくとも本開示によるBDMとの結合は、化学的結合(Brennan et al(1985)Science 229:81)または化学的カップリング(Shalaby et al(1992)J Exp Med 175:217-225)または遺伝子融合を使用して調製することができる。
公知の方法に従ったさまざまな手段によって本開示のタンパク質(またはペプチド)及びBDM部分を評価することができる。そのような評価法には、機能解析、例えば、殺細胞アッセイ(cell killing assay)、cAMPもしくはカルシウムフラックスアッセイまたは結合アッセイ、例えば、ELISAまたは競合アッセイが含まれ得る。
エピトープの結合は、ELISAのような従来の抗原結合アッセイ、FRETなど蛍光を利用する技術、または分子の質量を測定するする表面プラズモン共鳴のような技術によって測定することができる。抗原結合タンパク質(例えば、BDM)の抗原またはエピトープに対する特異的結合は、例えば、スキャッチャード解析及び/またはラジオイムノアッセイ(RIA)、ELISA及びサンドイッチ競合アッセイのような酵素免疫測定法といった競合結合アッセイを含む、好適なアッセイによって決定することができる。
本開示による標的は好ましくは抗原である。抗原は、タンパク質、グリカン、脂質、リポタンパク質または核酸から選択されてよい。タンパク質は、ヒトタンパク質、非ヒトタンパク質(例えば、霊長類、イヌ科、ネコ科など)、ウイルスタンパク質、酵母タンパク質、細菌タンパク質、藻類タンパク質、植物タンパク質または原生動物タンパク質であってよい。タンパク質は、可溶性タンパク質または膜結合型タンパク質であってよい。可溶性タンパク質の例には、転写因子、抗体、増殖因子、血液タンパク質(例えば、アルブミン)、または薬物(例えば、ステロイド、医薬品など)が挙げられるが、これに限定されるものではない。膜結合型タンパク質の種類には、増殖因子受容体、腫瘍マーカー、もしくは細胞内への輸送を媒介するマーカー(例えば、トランスフェリン)、またはFc受容体が含まれる。
抗原は細菌に由来し得、それらとしてはHelicobacter pylori、Chlamydia pneumoniae、Chlamydia trachomatis、Ureaplasma urealyticum、Mycoplasma pneumoniae、Staphylococcus spp.、Staphylococcus aureus、Streptococcus spp.、Streptococcus pyogenes、Streptococcus pneumoniae、Streptococcus viridans、Enterococcus faecalis、Neisseria meningitidis、Neisseria gonorrhoeae、Bacillus anthracis、Salmonella spp.、Salmonella typhi、Vibrio cholera、Pasteurella pestis、Pseudomonas aeruginosa、Campylobacter spp.、Campylobacter jejuni、Clostridium spp.、Clostridium difficile、Mycobacterium spp.、Mycobacterium tuberculosis、Treponema spp.、Borrelia spp.、Borrelia burgdorferi、Leptospira spp.、Hemophilus ducreyi、Corynebacterium diphtheria、Bordetella pertussis、Bordetella parapertussis、Bordetella bronchiseptica、hemophilus influenza、Escherichia coli、Shigella spp.、Erlichia spp.、及びRickettsia sppが挙げられるが、これに限定されるものではない。
抗原はウイルスに由来し得、それらとしてはインフルエンザウイルス、パラインフルエンザウイルス、ムンプスウイルス、アデノウイルス、呼吸器多核体ウイルス、エプスタイン-バーウイスル、ライノウイルス、ポリオウイルス、コクサッキーウイルス、エコーウイルス、麻疹ウイルス、風疹ウイルス、水痘・帯状疱疹ウイルス、ヘルペスウイルス(ヒト及び動物)、単純ヘルペスウイルス、パルボウイルス(ヒト及び動物)、サイトメガロウイルス、肝炎ウイルス、ヒトパピローマウイルス、アルファウイルス、フラビウイルス、ブニヤウイルス、狂犬病ウイルス、アレナウイルス、フィロウイルス、HIV1、HIV2、HTLV-1、HTLV-II、FeLV、ウシLV、FeIV、イヌジステンパーウイルス、イヌ伝染性肝炎ウイルス、ネコカリシウイルス、ネコ鼻気管炎ウイルス、TGEウイルス(ブタ)、及び口蹄疫が挙げられるが、これに限定されるものではない。
標的抗原は腫瘍関連抗原であってよい。そのような腫瘍関連抗原としては、MUC-1及びそのペプチド断片、タンパク質MZ2-E、多形性上皮ムチン、葉酸結合タンパク質LK26、MAGE-1またはMAGE-3及びそのペプチド断片、ヒト絨毛性ゴナドトロピン(HCG)及びそのペプチド断片、癌胎児性抗原(CEA)及びそのペプチド断片、アルファフェトプロテイン(AFP)及びそのペプチド断片、膵癌胎児抗原及びそのペプチド断片、CA125、CA15-3、CA19-9、CA549、CA195及びそのペプチド断片、前立腺特異抗原(PSA)及びそのペプチド断片、前立腺特異的膜抗原(PSMA)及びそのペプチド断片、扁平上皮癌抗原(SCCA)及びそのペプチド断片、卵巣癌抗原(OCA)及びそのペプチド断片、膵癌関連抗原(PaA)及びそのペプチド断片、Her1/neu及びそのペプチド断片、gp-100及びそのペプチド断片、変異K-rasタンパク質及びそのペプチド断片、変異p53及びそのペプチド断片、非変異p53及びそのペプチド断片、切断型上皮増殖因子受容体(EGFR)、キメラタンパク質p210BCR-ABL、テロメラーゼ及びそのペプチド断片、サバイビン及びそのペプチド断片、Melan-A/MART-1タンパク質及びそのペプチド断片、WT1タンパク質及びペプチド断片、LMP2タンパク質及びペプチド断片、HPV E6 E7タンパク質及びペプチド断片、イディオタイプタンパク質及びペプチド断片、NY-ESO-1タンパク質及びペプチド断片、PAPタンパク質及びペプチド断片、癌・精巣タンパク質及びペプチド断片、及び5T4タンパク質及びペプチド断片が挙げられるが、これに限定されるものではない。
標的抗原は、心臓、血液系、肺、腸、胃、直腸、前立腺、甲状腺、肝臓または食道内に位置する細胞上に存在する抗原またはエピトープであってよい。標的抗原は、分泌タンパク質上に存在する抗原またはエピトープであってよい。分泌タンパク質の例には、ホルモン、酵素、毒素及び抗菌物質、ペプチドが挙げられるが、これに限定されるものではない。別法として、抗原またはエピトープは非膜結合型タンパク質上に存在する。
一例では、分子は、多重特異性分子の異なる標的抗原のうち1つしか発現しない細胞よりも、その標的抗原の2つ以上を発現する細胞に選択的に結合することができる。
本開示の多重特異性分子は、薬理学的に許容される担体または添加物と組み合わせた場合に組成物として使用することができる。そのような医薬組成物は、対象の生体内投与にとって有用である。
本開示は、薬剤で標識した本明細書に記載の分子を提供する。一例では、薬剤は造影用/検出用部分である。別の例では、薬剤は治療用部分である。ポリペプチドを標識する方法は当業者に馴染みがあるであろう。
一例では、アフィニティ精製または、タンパク質(またはペプチド)及び/またはBDMが結合するエピトープを担持している所望抗原の検出に本開示の分子を使用することができる。
非抗体タンパク質に関しては、そのようなタンパク質にBDMを付加することにより、タンパク質の安定性、循環時間及び/または生物学的活性の増加が促され得る。例えば、第VIII因子タンパク質を、ヒト血清アルブミンに結合するVLDと結合させて、かかるタンパク質の半減期を延長させることができる。これは、血友病に罹患した対象にとって、投与頻度の減少という点で明らかに利点となる。
本開示は、本明細書に記載する多重特異性分子を、使用説明書と共に含むキットも提供する。組成物が凍結乾燥されている場合、キットには、調製物を再構成するさらなる溶液調製物が含有され得る。指示書きは、「印刷物」、例えば、キット内に入っているかまたはキットに添付の紙もしくは厚紙に記されている、またはキットもしくは包装材料に貼付のラベルに記されている、またはキットの構成成分を含有するバイアルもしくは管に貼付されていてよい。
i)ベクター作製
CTLA-4 BDMの遺伝子構築とクローニングは標準的で、十分な記載のある技術、さらには先に記載されているUS7,166,697に従った。CTLA-4 BDMはライブラリー(Geneart)から得た。結合ループ領域に相当するDNA配列中に異なる置換を含有させる目的で、縮重オリゴヌクレオチド合成を使用して遺伝子ライブラリー1696327を構築した。
これらの構成体の配列を下記に示す。抗原結合性ループは該当箇所に下線が引かれている:
B7-1結合V様ドメイン(VLD)の配列(配列番号13)
リンカー配列(配列番号16)
抗リゾチームIgGカッパ軽鎖(配列番号20)
21アミノ酸Gly-Serリンカーを有するB7.1結合VLDと結合させた抗リゾチームFabカッパ軽鎖(D1.3 Fab-VLD×1(LC)と表す(配列番号22)
21アミノ酸Gly-Serリンカーを有するB7.1結合VLDと結合させた抗リゾチームFab重鎖(D1.3 Fab-VLD×1(HC)と表す(配列番号23)
抗リゾチームFab重鎖(C末端にHis6タグとmycタグを有する)(配列番号24)
抗体-VLD配列またはFab-VLD配列をコードする個々の重鎖及び軽鎖を発現ベクターpcDNA3.4(Thermo Fisher)にクローニングした。E.coli細胞(Agilent Technologies製Electro Ten Blue)にベクターの作製/増幅を行った。
Expi293 Expression System(ThermoFisher Scientific)を使用して、約2×106Expi293細胞/mLのトランスフェクション(哺乳類細胞生存率95%超)を実施した。二重特異性または三重特異性のDNAベクターをHC DNA:LC DNA比1:3で調製した。DNAを65℃まで5分間加熱し、室温まで降温させてからOpti-MEM I(Life Technologiesカタログ番号31985070)及びExpiFectamine293試薬(ThermoFisherカタログ番号A14525)を加え、室温で30分間インキュベートした。トランスフェクション複合体を細胞に加え、37℃、5%CO2、120rpmでインキュベートした。約4~5日後、タンパク質を含有している上清を採取した。
表1 二重特異性及び三重特異性の抗体-VLD変異型におけるタンパク質発現レベル
二重特異性分子及び三重特異性分子の精製にはProsepA精製を使用した。カラム容量の5倍のPBS/Tris(2mM Tris、pH8)を用いてProsepAカラムの平衡化を行った。二重特異性分子をpH8で含有しているトランスフェクトされた細胞の上清をカラムに担持させ、PBS、2mM Tris、pH8をカラム容量の10倍用いてカラムを洗浄した。0.1Mグリシン(pH3)でタンパク質を溶出させた。溶出したタンパク質画分を1M Tris、pH8で約pH7に中和し、標準的方法に従って透析を行った。
親D1.3 Fab、及び最適化していない標準Expi293発現系で発現させた親D1.3 Fabの二重特異性変異型と三重特異性変異型の発現を、非還元条件下及び還元条件下でSDS PAGEによって分析した。アフィニティクロマトグラフィーにより精製した30mlの発現培養物から各値を得た。親FabはD1.3 Fabであり、二重特異性型はD1.3 Fabと、D1.3 FabのCH配列の末端に融合させたVLDとを合わせたD1.3 Fab-VLD×1(HC)、及びD1.3 Fabと、D1.3 FabのCL配列の末端に融合させたVLDとを合わせたD1.3 Fab-VLD×1(CL)である。三重特異性分子は、D1.3 Fabと、D1.3 FabのCH配列及びCL配列の両方の末端に融合させた各VLDとを合わせたD1.3 Fab-VLD×2(HC+LC)である。非還元条件下の結果を図8に示す。還元条件下の結果を図9に示す。解析から、適切な重鎖と軽鎖の融合体は予測した大きさの範囲であったことが指された。
標準の化学と試薬を使用し、ForteBio Blitzバイオセンサーを使用して、精製した二重特異性分子及び三重特異性分子の結合特性の特徴付けを行った。
本項での結合分析は、標準の化学と試薬を使用してBiacore X100SPR装置(GE)で実施した。濃度系列トレースは、重ね合わせて表示し、全データとも、リゾチームを含有していなかった参照用表面からの応答を差し引いた後の応答ユニット(RU)として提示されている。
二重特異性分子の注入:これは、センサー表面にIgG VLD×2(HC)を加えるポイントである。トレースは、バイオセンサー表面に固定化したリゾチームに対するIgG VLD×2(HC)の結合を示す。
バッファーの注入1:IgG VLD×2(HC)の注入を中止し、バッファー注入で置き換えるポイントである。トレースは、バイオセンサー表面に固定化したリゾチームからのIgG VLD×2(HC)の解離を示す。
B7-1-Fcの注入:第2の分析対象物B7-1-Fcを特定の濃度(50、25、12.5、6.25、3.125、1.56及び0uμg/ml)で加えるポイント。トレースは、バイオセンサー表面に固定化したリゾチームにまだ結合したままのIgG VLD×2(HC)に対するB7-1-Fcの結合を示す。
バッファーの注入2:B7-1-Fcの注入を中止し、バッファー注入で置き換えるポイント。トレースは、バイオセンサー表面に固定化したリゾチームとまだ結合したままのIgG VLD×2(HC)からのB7-1-Fcの解離を示す。
二重特異性分子の注入:センサー表面にIgG VLD×2(LC)を加えるポイントである。トレースは、バイオセンサー表面に固定化したリゾチームに対するIgG VLD×2(LC)の結合を示す。
バッファーの注入1:IgG VLD×2(LC)の注入を中止し、バッファー注入で置き換えるポイント。トレースは、バイオセンサー表面に固定化したリゾチームからのIgG VLD×2(LC)の解離を示す。
B7-1-Fcの注入:第2の分析対象物B7-1-Fcを特定の濃度(50、25、12.5、6.25、3.125、1.56及び0μg/ml)で加えるポイント。トレースは、バイオセンサー表面に固定化したリゾチームにまだ結合したままのIgG VLD×2(LC)に対するB7-1-Fcの結合を示す。
バッファーの注入2:B7-1-Fcの注入を中止し、バッファー注入で置き換えるポイント。トレースは、バイオセンサー表面に固定化したリゾチームとまだ結合したままのIgG VLD×2(LC)からのB7-1-Fcの解離を示す。
三重特異性分子の注入:センサー表面にIgG VLD×4(HC+LC)を加えるポイント。トレースは、バイオセンサー表面に固定化したリゾチームに対するIgG Im×4(HCLC)の結合を示す。
バッファーの注入1:IgG VLD×4(HC+LC)の注入を中止し、バッファー注入で置き換えるポイント。トレースは、バイオセンサー表面に固定化したリゾチームからのIgG VLD×4(HC+LC)の解離を示す。
B7-1-Fcの注入:第2の分析対象物B7-1-Fcを特定の濃度(25、12.5、6.25、3.125、1.56及び0μg/ml)で加えるポイント。トレースは、バイオセンサー表面に固定化したリゾチームにまだ結合したままのIgG VLD×4(HC+LC)に対するB7-1-Fcの結合を示す。
バッファーの注入2:B7-1-Fcの注入を中止し、バッファー注入で置き換えるポイント。トレースは、バイオセンサー表面に固定化したリゾチームとまだ結合したままのIgG VLD×4(HC+LC)からのB7-1-Fcの解離を示す。
二重特異性分子の注入:センサー表面にFab-VLD×1(HC)を加えるポイント。トレースは、バイオセンサー表面に固定化したリゾチームに対するFab-VLD×1(HC)の結合を示す。
バッファーの注入1:Fab-VLD×1(HC)の注入を中止し、バッファー注入で置き換えるポイント。トレースは、バイオセンサー表面に固定化したリゾチームからのFab-VLD×1(HC)の解離を示す。
B7-1-Fcの注入:第2の分析対象物B7-1-Fcを特定の濃度(25、12.5、6.25、3.125、1.56及び0ug/ml)で加えるポイント。トレースは、バイオセンサー表面に固定化したリゾチームにまだ結合したままのFab-VLD×1(HC)に対するB7-1-Fcの結合を示す。
バッファーの注入2:B7-1-Fcの注入を中止し、バッファー注入で置き換えるポイント。トレースは、バイオセンサー表面に固定化したリゾチームとまだ結合したままのFab-VLD×1(HC)からのB7-1-Fcの解離を示す。
二重特異性分子の注入:センサー表面にFab-VLD×1(LC)を加えるポイント。トレースは、バイオセンサー表面に固定化したリゾチームに対するFab-VLD×1(LC)の結合を示す。
バッファーの注入1:Fab-VLD×1(LC)の注入を中止し、バッファー注入で置き換えるポイント。トレースは、バイオセンサー表面に固定化したリゾチームからのFab-VLD×1(LC)の解離を示す。
B7-1-Fcの注入:第2の分析対象物B7-1-Fcを特定の濃度(25、12.5、6.25、3.125、1.56及び0ug/ml)で加えるポイント。トレースは、バイオセンサー表面に固定化したリゾチームにまだ結合したままのFab-VLD×1(LC)に対するB7-1-Fcの結合を示す。
バッファーの注入2:B7-1-Fcの注入を中止し、バッファー注入で置き換えるポイント。トレースは、バイオセンサー表面に固定化したリゾチームとまだ結合したままのFab-VLD×1(LC)からのB7-1-Fcの解離を示す。
三重特異性分子の注入:センサー表面にFab-VLD×2(HC+LC)を加えるポイント。トレースは、バイオセンサー表面に固定化したリゾチームに対するFab-VLD×2(HC+LC)の結合を示す。
バッファーの注入1:Fab-VLD×2(HC+LC)の注入を中止し、バッファー注入で置き換えるポイント。トレースは、バイオセンサー表面に固定化したリゾチームからのFab-VLD×2(HC+LC)の解離を示す。
B7-1-Fcの注入:第2の分析対象物B7-1-Fcを特定の濃度(25、12.5、6.25、3.125、1.56及び0μg/ml)で加えるポイント。トレースは、バイオセンサー表面に固定化したリゾチームにまだ結合したままのFab-VLD×2(HC+LC)に対するB7-1-Fcの結合を示す。
バッファーの注入2:B7-1-Fcの注入を中止し、バッファー注入で置き換えるポイント。トレースは、バイオセンサー表面に固定化したリゾチームとまだ結合したままのFab-VLD×2(HC+LC)からのB7-1-Fcの解離を示す。
B7-1-Fcに対する二重特異性分子[IgG VLD×2(HC)]及び三重特異性分子[IgG Im×4(HC+LC)]の結合化学量論もSPRにより決定した(図20)。ビオチン-リゾチーム表面で捕捉し、分析対象物として一連の濃度のB7-1-Fc(50、25、12.5、6.25、3.125、1.56及び0μg/ml)を用いて、IgG-VLD×2(HC)、IgG-VLD×2(LC)及びIgG-VLD×4(HCLC)の速度論的解析を実施した。分析対象物及びリガンドの分子量を考慮し、捕捉したIgG-VLDタンパク質量に基づいて、分析対象物の理論的最大結合シグナル(Rmax)を計算した。
抗体-VLDの二重特異性分子と三重特異性分子及びFab-VLDの二重特異性分子と三重特異性分子の結合速度論を表面プラズモン共鳴により決定した。会合定数(Ka)、解離定数(Kd)及び平衡解離定数/結合定数KDをそれぞれ表3及び表4に示す。
表3 B7.1-Fcに対する抗体-VLD分子の親和性
表4 B7.1-Fcに対するFab-VLD分子の親和性
IgG VLD×4(HCLC)構成体の修飾を行い、ここでは、スクレロスチン(Scl)結合VLDを抗リゾチーム抗体D1.3の重鎖のC末端と結合させ、B7-1結合VLDを抗リゾチーム抗体の抗体軽鎖定常領域(CL)と結合させた。この三重特異性分子を[IgG VLD×4(Scl-HC)(B7-LC)]とした。抗スクレロスチンVLD「1E1」と融合させた抗リゾチームIgG1重鎖の配列を下記に示す(配列番号25):
配列番号25及び配列番号14のVLD結合ループには下線が引かれている。
図22は、三重特異性[IgG VLD×4(Scl-HC)(B7-LC)]が、ストレプトアビジンで捕捉したビオチン標識化リゾチームに最初に結合し、続いてB7-1-Fc及びスクレロスチンに対し同時結合することを示す、一連のSPRによる結合のセンサーグラムを重ね合わせたものを示す。三重特異性分子は、D1.3抗体[D1.3 IgG]の重鎖と融合させたスクレロスチン結合VLD及び軽鎖と融合させたB7-1結合VLDを有する。
Fab VLD×2(HC+LC)構成体の修飾を行い、ここでは、B7-1結合VLDを抗リゾチームFab D3.1の重鎖のC末端と結合させ、スクレロスチン(Scl)結合VLDを抗リゾチームFabのFab軽鎖定常領域(CL)と結合させた。この三重特異性分子を[Fab VLD×2(B7-1-HC)(Scl-LC)]とした。第2の構成体の作製を行い、ここでは、スクレロスチン結合VLDを抗リゾチームFab D3.1の重鎖のC末端と結合させ、B7-1結合VLDを抗リゾチームFabのFab軽鎖定常領域(CL)と結合させた。この三重特異性分子を、[Fab VLD×2(Scl-HC)(B7-1-LC)]とした。
方法
図25は、本開示の一例に従ったVLDと結合させたタンパク質の概略図を示す。二重特異性分子は、標的Aと標的Bの両方に個々別々または同時に結合することができる。
1つまたは2つのVLDと融合させたヒト血清アルブミン(HSA)をコードする配列を作製し、これには、16アミノ酸のリンカー配列(SGGGGSGGGGSGGGGS)(強調表示)及びC末端ヒスチジンタグが含まれる。配列を哺乳類の発現ベクターにクローニングした。使用したベクターpcDNA3.4ベクター(Thermo Fisher)であった。タンパク質が分泌されるようシグナルペプチドを用いて配列をクローニングした。ペプチドの配列はMAWMMLLLGLLAYGSG(配列番号8)である。
Expi293 Expression System(ThermoFisher Scientificカタログ番号A14635)を使用して、密度3×106~5×106細胞/mL、生存率>95%のExpi293哺乳類細胞のトランスフェクションを実施した。Opti-MEM I Reduced Serum Medium(Life Technologiesカタログ番号31985070)及びExpiFectamine293試薬(ThermoFisherカタログ番号A14525)にDNAベクターを加え、室温で20分間インキュベートした。トランスフェクション複合体を細胞に加え、37℃、5%CO2、120rpmでインキュベートした。20時間後、細胞にExpifectamine 293 Transfection Enhancer 1及び2(ThermoFisherカタログ番号A14525)を加えた。約4~5日後、タンパク質を含有している上清を採取した。
Nickel Sepharose Excel(GE、カタログ番号17-3712-01)を使用してアフィニティクロマトグラフィーによりタンパク質を精製した。20mMリン酸ナトリウム、0.5M NaCl、ph7.4をカラム容量の5倍用いてNickel Sepharoseカラムの平衡化を行った。Hisタグの付いたHSA-VLDタンパク質を含有している、トランスフェクトした細胞培養上清をカラムに担持させ、20mMリン酸ナトリウム、0.5M NaCl、5mMイミダゾール、ph7.4をカラム容量の10倍用いてカラムを洗浄した。20mMリン酸ナトリウム、0.5M NaCl、500mMイミダゾールph7.4を用いてタンパク質を溶出させた。溶出させた画分をプールし、標準的な方法に従ってPBSで透析を行った。
標準の化学と試薬を使用し、ForteBio Blitzバイオセンサーを使用して、精製した分子の結合特性の特徴付けを行った。
結果
(i)HSAのC末端、N末端またはC末端とN末端の両方のいずれかでヒト血清アルブミンと融合させたCTLA4 VLD。
配列を下記に示す:
HSAのC末端と融合させたB7-2結合VLD(配列番号26):
配列は下記に示す:
HSAのC末端と融合させたCD3結合VLD「AF3」(配列番号29):
Claims (11)
- 2つ以上の異なる標的抗原または標的エピトープに結合することができる多重特異性分子であって、
(i)配列番号5:
(ii)第2の標的抗原または標的エピトープに結合する、完全長抗体もしくはその抗原結合断片である薬理的に活性なタンパク質と
を含み、
ここで、前記少なくとも1つのBDMは、そのN末端を介して、前記抗体又はその抗原結合断片の各重鎖及び/もしくは軽鎖のC末端にペプチドリンカーにより結合されている、前記分子。 - 少なくとも1つのBDMがすべての抗体重鎖及び抗体軽鎖のC末端に結合されている、請求項1に記載の分子。
- 抗体鎖とBDMの比は4:2nであり、ここで、nは1~5の数である、請求項1または2に記載の分子。
- 抗原結合性断片鎖とBDMの比が2:2nであり、ここで、nは0~5の数である、請求項3に記載の分子。
- 少なくとも1つのBDMが前記重鎖のCH1ドメイン、CH2ドメインまたはCH3ドメインのC末端に結合されている、請求項1~3のいずれか1項に記載の分子。
- (i)前記第1の標的抗原及び前記第2の標的抗原は異なる、または、
(ii)前記第1の標的エピトープ及び前記第2の標的エピトープは、同一抗原または異なる抗原上にある、請求項1から5のいずれか1項に記載の分子。 - 前記分子は、抗体またはその抗原結合断片及び1対または2対のBDM(ここで、前記対の前記BDMは同一である)を含む、請求項1に記載の分子。
- 前記第一の結合ループ(Xn1)は5~8アミノ酸であり、
前記第二の結合ループ(Xn2)は5~8アミノ酸であり、
前記第三の結合ループ(Xn3)は10~15アミノ酸である、
請求項1から7のいずれか1項に記載の分子。 - 前記第一の結合ループ(Xn1)は8アミノ酸であり、
前記第二の結合ループ(Xn2)は5アミノ酸であり、
前記第三の結合ループ(Xn3)は10~15アミノ酸である、
請求項8に記載の分子。 - 配列番号19、21、22、23または25からなる群から選択されるアミノ酸配列を有する、多重特異性分子。
- 請求項1~10のいずれか1項に記載の分子を、薬理学的に許容される担体及び/または添加物と共に含む、医薬組成物。
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