JP2015227386A - 天然の免疫グロブリン形式を有する容易に単離される二重特異性抗体 - Google Patents
天然の免疫グロブリン形式を有する容易に単離される二重特異性抗体 Download PDFInfo
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
【解決手段】単離が容易である二重特異性抗体の形式が提供され、その形式は、CH3ドメイン内を識別的に改変されている免疫グロブリン重鎖可変ドメインを含み、ここで、その識別的改変は、そのCH3改変に関して免疫原性でないかまたは実質的に免疫原性でなく、それらの改変の少なくとも1つは、プロテインAなどの親和性試薬に対する二重特異性抗体の親和性に違いをもたらし、その二重特異性抗体は、プロテインAに対するその親和性に基づいて、破壊された細胞、培地、または抗体の混合物から単離可能である。
【選択図】なし
Description
本発明は、重鎖のヘテロ二量体を有する、抗原結合タンパク質または抗体、すなわち、親和性試薬に対する免疫グロブリン重鎖の親和性と改変免疫グロブリン重鎖または変異免疫グロブリン重鎖の親和性との違いに基づいて抗原結合タンパク質の単離を可能にする、少なくとも1つのアミノ酸が異なる2つの免疫グロブリン重鎖を有する、抗原結合タンパク質または抗体に関する。本発明はまた、プロテインAに対するIgG領域の結合性の違いによる迅速な単離を可能にする、プロテインAに対して異なる親和性を有するIgG CH2およびCH3領域を有する抗原結合タンパク質(二重特異性抗体を含む)にも関する。
抗体は、標的抗原に対する独特の結合特異性ならびに抗原とは無関係な機序を介して免疫系と相互作用する能力を保有する多機能性分子である。癌に対して現在使用されている多くの生物学的治療薬は、標的にされている癌細胞上で代表的に過剰発現されている抗原に対するモノクローナル抗体である。そのような抗体は、腫瘍細胞に結合すると、抗体依存性細胞傷害(ADCC)または補体依存性細胞傷害(CDC)の引き金を引くことがある。残念なことに、癌性細胞は、これらの正常な免疫応答を抑制する機序を発達させることが多い。
本発明は、二重特異性抗原結合タンパク質において少なくとも1つのアミノ酸が異なる2つの免疫グロブリンCH3重鎖定常ドメイン配列を使用することに少なくとも部分的に基づく。少なくとも1つのアミノ酸が異なることにより、CH3ドメイン配列が親和性物質に結合する能力に違いがもたらされるので、そのタンパク質を単離する能力が改善される。
特定の実施形態では、例えば以下が提供される:
(項目1)
a.N末端からC末端に向かって、第1のエピトープに選択的に結合する第1のエピトープ結合領域、IgG1、IgG2およびIgG4から選択されるヒトIgGの第1のCH3領域を含む免疫グロブリン定常領域を含む、第1のポリペプチド;ならびに
b.N末端からC末端に向かって、第2のエピトープに選択的に結合する第2のエピトープ結合領域、IgG1、IgG2およびIgG4から選択されるヒトIgGの第2のCH3領域を含む免疫グロブリン定常領域を含む、第2のポリペプチド;
を含むヘテロ二量体の二重特異性抗原結合タンパク質であって、ここで、前記第2のCH3領域は、プロテインAへの該第2のCH3ドメインの結合を減少させるかまたは排除する改変を含む、ヘテロ二量体の二重特異性抗原結合タンパク質。
(項目2)
前記第1のポリペプチドおよび前記第2のポリペプチドが、ヒトIgG重鎖である、項目1に記載の二重特異性タンパク質。
(項目3)
免疫グロブリン軽鎖をさらに含む、項目1に記載の二重特異性タンパク質。
(項目4)
前記免疫グロブリン軽鎖が、ヒト免疫グロブリン軽鎖である、項目3に記載の二重特異性タンパク質。
(項目5)
前記第1のポリペプチドおよび前記第2のポリペプチドが各々、ヒトIgG1重鎖である、項目1に記載の二重特異性タンパク質。
(項目6)
前記改変が、IMGTエキソンナンバリングシステムにおける(a)95Rならびに(b)95Rおよび96F、またはEUナンバリングシステムにおける(a’)435Rならびに(b’)435Rおよび436Fからなる群から選択される、項目1に記載の二重特異性タンパク質。
(項目7)
IMGTエキソンナンバリングシステムにおける16E、18M、44S、52N、57Mおよび82I、またはEUナンバリングシステムにおける356E、358M、384S、392N、397Mおよび422Iからなる群から選択される1から5つの改変をさらに含む、項目6に記載の二重特異性タンパク質。
(項目8)
前記二重特異性抗体のCH3ドメインが、ヒトにおいて免疫原性でないかまたは実質的に免疫原性でない、項目6に記載の二重特異性タンパク質。
(項目9)
前記二重特異性抗体のCH3ドメインが、ヒトにおいて免疫原性でないかまたは実質的に免疫原性でない、項目7に記載の二重特異性タンパク質。
(項目10)
二重特異性抗体を作製するための方法であって、前記方法は:
a.第1のエピトープを認識する第1の可変ドメインを含む第1の免疫グロブリン重鎖をコードする核酸配列を得る工程であって、ここで、該第1の免疫グロブリン重鎖は、IgG1、IgG2またはIgG4のアイソタイプ定常ドメインを含む、工程;
b.第2のエピトープを認識する第2の可変ドメインを含む第2の免疫グロブリン重鎖をコードする第2の核酸配列を得る工程であって、ここで、該第2の免疫グロブリン重鎖は、プロテインAへの結合を無くすかまたは減少させる改変をそのCH3ドメインに含むIgG1、IgG2またはIgG4のアイソタイプ定常ドメインを含む、工程;
c.該第1の免疫グロブリン重鎖および該第2の免疫グロブリン重鎖と対形成する免疫グロブリン軽鎖をコードする第3の核酸配列を得る工程;
d.該第1の核酸配列、該第2の核酸配列および該第3の核酸配列を哺乳動物細胞に導入する工程;
e.該細胞が二重特異性抗体を発現するのを可能にする工程;ならびに
f.該二重特異性抗体がプロテインAに結合する能力に基づいて該二重特異性抗体を単離する工程
を包含する、方法。
(項目11)
前記改変が、IMGTエキソンナンバリングシステムにおける(a)95Rならびに(b)95Rおよび96F、またはEUナンバリングシステムにおける(a’)435Rならびに(b’)435Rおよび436Fからなる群から選択される、項目10に記載の方法。
(項目12)
IMGTエキソンナンバリングシステムにおける16E、18M、44S、52N、57Mおよび82I、またはEUナンバリングシステムにおける356E、358M、384S、392N、397Mおよび422Iからなる群から選択される1から5つの改変をさらに含む、項目11に記載の方法。
(項目13)
前記二重特異性抗体の前記CH3ドメインが、ヒトにおいて免疫原性でないかまたは実質的に免疫原性でない、項目11に記載の方法。
(項目14)
前記二重特異性抗体の前記CH3ドメインが、ヒトにおいて免疫原性でないかまたは実質的に免疫原性でない、項目12に記載の方法。
(項目15)
前記二重特異性抗体が、プロテインAを備える固体支持体で単離される、項目10に記載の方法。
(項目16)
前記固体支持体が、プロテインAアフィニティーカラムを含み、前記二重特異性抗体が、pH勾配を使用して単離される、項目15に記載の方法。
(項目17)
前記pH勾配が、pH3とpH5との間の1またはそれより多いpH段階を含む段階勾配である、項目16に記載の方法。
(項目18)
二重特異性抗体を単離するための方法であって、
破壊された細胞または抗体の混合物から、識別的に改変されたIgG1、IgG2またはIgG4のCH3ドメインを有する二重特異性抗体を単離する工程を包含し、ここで、該識別的に改変されたCH3ドメインは、ヒトにおいて免疫原性でないかまたは実質的に免疫原性でなく、該改変は、プロテインAに対するモノマーの親和性が互いに異なるヘテロ二量体の重鎖定常領域を有する二重特異性抗体をもたらし、該二重特異性抗体は、プロテインAに対するその親和性に基づいて、該破壊された細胞または該混合物から単離される、方法。
(項目19)
前記ヘテロ二量体の重鎖定常領域の一方のモノマーが、ヒトIgG1であり、該ヘテロ二量体の重鎖定常領域の他方のモノマーが、IMGTエキソンナンバリングシステムにおける(a)H95Rならびに(b)H95RおよびY96F、またはEUナンバリングシステムにおける(a’)H435Rならびに(b’)H435RおよびY436Fからなる群から選択される改変を含む改変されたヒトIgG1である、項目18に記載の方法。(項目20)
前記改変されたヒトIgG1が、IMGTエキソンナンバリングシステムにおけるD16E、L18M、N44S、K52N、V57MおよびV82I、またはEUナンバリングシステムにおけるD356E、L358M、N384S、K392N、V397MおよびV422Iからなる群から選択される改変をさらに含む、項目19に記載の方法。
特定の方法および記載される実験条件は変動し得るので、本発明は、そのような方法および条件に限定されない。本発明の範囲は、請求項によって定義されるので、本明細書中で使用される用語は、特定の実施形態だけを記載する目的であって、限定する意図はないことも理解される。
本発明者らは、通常の軽鎖ストラテジーを、ヒト抗体の構成要素とともに使用され得る選択的なプロテインA精製スキームの実行と組み合わせる新規形式を開発した。
本発明者らは、CH3ドメインにおける1つ以上のアミノ酸に関してヘテロ二量体である免疫グロブリン重鎖(またはその機能的なCH2およびCH3含有フラグメント)を含む結合タンパク質を容易に単離するための方法を考案した。マウスIgG CHドメインの改変を慎重に選択し、特定の分離技術を適用することにより、それらの改変を含まないホモ二量体およびヘテロ二量体から2つの識別的に改変されたマウスCH領域を含む結合タンパク質を容易に単離することができるようになる。
本発明の多くの実施形態の利点の1つは、プロテインAに対する結合性の違いに基づいて容易に単離可能であり、かつヒトにおいて免疫原性でないかまたは実質的に免疫原性でない、二重特異性抗体をもたらす改変を使用することができることである。この特性のおかげで、そのような実施形態は、ヒトへの治療に使用するための二重特異性抗体を作製する際、および例えば、免疫原性でないかまたは実質的に免疫原性でないイムノアドヘシンを作製する際(ヒト結合部分、すなわち、ヒトレセプター構成要素および/またはヒトリガンドを使用するとき)に、特に有用になる。この特性は、IgG1、IgG2およびIgG3のH95R/Y96F(IMGTナンバリング)改変を伴うCH3ドメイン、ならびに異なるIgGアイソタイプの野生型配列を反映して改変された位置をもたらすさらなる改変を含むCH3ドメインを有する二重特異性抗体に関連する。よって、特定のIgGアイソタイプに関連する改変は、天然には見られないが、改変された配列は、異なるIgGアイソタイプの野生型配列と局所的に同一であり、その改変は、免疫原性であるかまたは実質的に免疫原性であると予想されない。配列が、任意の天然の配列と局所的に同一でなかったとしても、その改変は、免疫原性でない可能性もあり;そのような改変は、等しく有用であり得る。ゆえに、最小の点変異H95R(IMGTナンバリング)は、免疫原性でない場合、本発明の適当な実施形態であり得る。
プロテインAに対する結合部位は、免疫グロブリンに長い血清半減期を与えるのに関与すると考えられている新生児FcレセプターFcRNに対する結合部位と重複する。ゆえに、ヒトIgG3が、他のIgGサブクラス(約21日)よりも短い血清半減期を有する(約7日)ことを考えると、プロテインA結合部位の近傍の改変は、ここで提案される形式がIgG1、2および4よりも短い血清半減期を有し得る可能性を高める。His435に影響するいくつかのFc変異体は、FcRNに結合しないことおよびマウスにおいてより短い半減期を有することが示されている。しかしながら、薬物動態学的解析から、IgG1ΔA/IgG1ヘテロ二量体の血清半減期が、IgG1ホモ二量体の血清半減期と大きく異ならないことが示されている(実施例2を参照のこと)。よって、IgG1ΔAdp変異は、IgG1の長い半減期をなおも保ちつつ、プロテインA結合性をなくすという利点を有する。
所望の特徴(例えば、所望の特異性、所望の親和性、所望の機能性、例えば、遮断、非遮断、阻害、活性化など)を備えた二重特異性抗体を作製するために使用することができる免疫グロブリン重鎖可変領域は、当該分野で公知の任意の方法を用いて作製され得る。次いで、所望の重鎖は、本明細書中に記載される所望の重鎖定常領域を有する構築物内に可変領域を含む核酸配列をクローニングすることによって構築され得る。
2つの異なるエピトープ(または2つの異なる抗原)を認識する2つの重鎖を含む二重特異性抗体は、同じ軽鎖(すなわち、同一の可変ドメインおよび定常ドメインを有する軽鎖)と対形成し得る場合、より容易に単離される。重鎖可変ドメインの選択性および/またはその標的抗原との親和性を干渉せずにまたは実質的に干渉せずに、特異性が異なる2つの重鎖と対形成し得る軽鎖を作製するための種々の方法が当該分野で公知である。
上記組成物および方法は、ヒト二重特異性抗体、すなわち、ヒト定常ドメインおよびヒト可変ドメインを含む二重特異性抗体を作製する際に特に有用である。いくつかの実施形態において、ヒト抗体には、ヒト生殖細胞系列の免疫グロブリン配列に由来する重鎖可変ドメインおよび重鎖定常ドメイン、いくつかの実施形態では、体細胞変異したヒト免疫グロブリン配列(例えば、ヒト免疫グロブリン遺伝子配列を含む動物において産生されるヒト免疫グロブリン配列)に由来する重鎖可変ドメインおよび重鎖定常ドメインを有する抗体が含まれる。いくつかの実施形態において、ヒト可変領域および/またはヒト定常領域は、ヒト生殖細胞系列の免疫グロブリン配列によってコードされないアミノ酸残基、または例えばCDR、特にCDR3における、組換えおよび/もしくはスプライシングの結果としてコードされるアミノ酸残基を含み得る。ヒト抗体は、マウスなどの別の哺乳動物種の生殖細胞系列に由来するCDR配列がヒトフレームワーク配列に移植された抗体を含むと意図されない。それらの抗体は、ヒト化抗体またはキメラ抗体と呼ばれる。ヒト抗体には、例えば、ランダム突然変異誘発または部位特異的突然変異誘発によってインビトロにおいて導入された変異を含む抗体が含まれるが、その変異は、好ましくは、ヒトにおいて免疫原性でない。
モノクローナル抗体をコードする核酸配列は、当該分野で公知の任意の適当な方法によって得ることができる。モノクローナル抗体(およびそれらの核酸配列)を得るための適当な方法の例としては、例えば、ハイブリドーマ法(例えば、Kohlerら(1975)Nature 256:495−497を参照のこと)またはファージ抗体ライブラリー(例えば、Clacksonら(1991)Nature 352:624−628を参照のこと)による方法が挙げられる。
適当な改変のセットが、本明細書中の情報に基づいて選択されたら、当該分野で公知の方法を用いて二重特異性抗原結合タンパク質を単離する試みを行った。公開された方法を単に適用することによって、すべての場合において満足な分離が提供されるわけではなかった。
ヒトIgG1アイソタイプの2つの公知抗体(1つは、IL−4Raに対する抗体で、1つは、IL−6Raに対する抗体)が、4つのアミノ酸だけが異なる軽鎖を有することが見出された。共発現実験から、抗IL−4Ra抗体の軽鎖が、IL−6Ra由来の軽鎖で置き換えられ得、IL−4Raに対する高親和性結合をなおも維持し、ゆえに抗IL−4Ra重鎖および抗IL−6Ra重鎖ならびに同じ軽鎖を用いて二重特異性抗体を作製することが可能になることが明らかになった。したがって、IL−6Ra抗体の重鎖をFcΔAdp型に改変した(すなわち、IMGTエキソンナンバリングではH95R/Y96FのCH3ジペプチド改変)。
FcΔAdp改変が、ヘテロ二量体のFc/FcΔAdpを含む分子の薬物動態に影響したか否かを試験するために、上に記載された抗IL−4Ra/抗IL−6Raの精製されたヘテロ二量体種をマウスに注射し、28日間にわたって血清中のヒト免疫グロブリン濃度を測定した(図6;表1)。そのヘテロ二量体の血清半減期は、約10日であり、これは、野生型の血清半減期と同様だった。このことから、FcΔAdp改変は、血清半減期に検出可能な影響を及ぼさないことが立証された。
実施例3:二重特異性CD20/CD3抗原結合タンパク質
公知の抗ヒトCD20抗体の重鎖は、公知の(活性化する)抗ヒトCD3抗体の軽鎖と共発現したときも、依然としてCD20に結合することができることが見出された。次いで、その抗CD3軽鎖を抗CD20/Fc重鎖、抗CD3/FcΔAdp重鎖または両方の重鎖と共発現させた。次いで、得られたホモ二量体およびヘテロ二量体の混合集団をバイオアッセイに使用して、CD20を発現している標的細胞を殺滅する能力を測定した(図7)。簡潔には、2×107個のヒトPBMC細胞を、6×107個のCD3×CD28ビーズ(Invitrogen)で72時間活性化した。次いで、30単位のIL−2(R&D Systems)を加え、その細胞をさらに24時間インキュベートした。次いで、その細胞を0.5×106/mLの濃度に分け、さらに30UのIL−2を加えた。次いで、その細胞をさらに48時間インキュベートし、バイオアッセイに使用した。バイオアッセイの当日、CD20を発現している2×106個/mLの標的細胞(Raji)を、8μMのカルセイン−AM(Invitrogen)で30分間標識した。洗浄した標的細胞を、活性化されたhPBMC細胞に、示されている量の抗体含有上清を含む総体積200マイクロリットルにおいて標的:エフェクター細胞(1ウェルあたり合計220,000個の細胞)1:10の比で加えた。細胞を2時間インキュベートし、上清を回収し、蛍光を定量化した。特異的な蛍光と最大蛍光との比を計算することによって、細胞傷害性を測定した。CD20抗体単独(抗CD3軽鎖を用いた)と抗CD3抗体の両方が、標的細胞の殺滅を誘発できなかった;それら2つの試薬を混合したときでさえ、効果がなかった。しかしながら、3つすべての構成要素を共発現させると、有意な殺滅が観察されたことから、その効果はヘテロ二量体の二重特異性種に起因したことが示唆される。一過性にトランスフェクトされたCHO細胞の上清中の二重特異性抗体の推定量に基づいて、この効果に対するEC50が、約15pMであると推定された。
実施例3に記載されたようなトランスフェクションからのCHO細胞上清を、溶出のために段階勾配を利用するプロテインAアフィニティークロマトグラフィに供した。その段階勾配は、それぞれpH5.2、pH4.2およびpH2.8で3相となるように2つの緩衝液(A:20mMクエン酸Na、1M NaCl,pH5.2;B:20mMクエン酸Na、1M NaCl,pH2.7)の組み合わせを変化させることによって作製された。次いで、pH4.2で溶出するピークからのタンパク質を、実施例3に記載されたような細胞死滅アッセイにおいて使用した。3pMというEC50で標的細胞の殺滅が観察された(図8)。観察された殺滅の標的特異性を調べる追加の細胞傷害性アッセイを行った。この実験では、CD20を発現する標識された標的細胞(Raji)またはCD20を有しない標識された標的細胞(293)を、活性化されたヒトPBMCとともにインキュベートした。各標的細胞型をそのアッセイに単独でまたは他のタイプの未標識の標的細胞と組み合わせて加えた。すべての場合において、CD20を発現している標的細胞は、3pMというEC50で特異的に殺滅されたが、CD20陰性細胞株は、殺滅されなかった。
識別的に改変されたヘテロ二量体のヒトIgG2 Fc/ΔAdpFcおよび改変されていないヒトホモ二量体のIgG2 Fc/Fcを、まず、プロテインAカラム(rProteinA FF,GE)に通す結合・洗浄(bind−and−wash)プロセスによって濃縮した。hIgG2 Fc/FcからhIgG2 Fc/ΔAdpFcをさらに分離するために、以下のとおり、SMART(商標)システム(GE)を使用して段階勾配溶出を行った。この溶媒系は、溶媒A(PBS,1×)、溶媒B(20mMクエン酸ナトリウムおよび1M NaCl,pH5.5)および溶媒C(20mMクエン酸ナトリウムおよび1M NaCl,pH2.5)からなるものだった。溶出を、最初の20分間の100%Aによるアイソクラティック溶出から開始し、続いて、20分後に素早く100%Bに切り換えた。次いで、次の10分間にわたって、33.5%Cおよび66.5%Bに向かって直線勾配を開始した;第1のピーク(Fc/ΔAdpFc)が完全に溶出するまで、Cの濃度を20分間33.5%に維持した。続いて、33.5%Cから100%Cへの直線勾配を30分間行った。流速を250マイクロリットル/分に維持し、UV検出器によって280nmでクロマトグラムを検出した。hIgG2 Fc/ΔAdpFcは、pH4.5で溶出し、一方、hIgG2は、pH3.5で溶出した。
識別的に改変されたヘテロ二量体のヒトIgG4(Fc/ΔAdpFc)および改変されていないホモ二量体のIgG4(Fc/Fc)をまず、プロテインAカラム(rProteinA FF,GE)に通す結合・洗浄プロセスによって濃縮した。hIgG4 Fc/FcからhIgG4 Fc/ΔAdpFcをさらに分離するために、以下のとおり、SMART(商標)システム(GE)を使用して段階勾配溶出を行った。この溶媒系は、溶媒A(PBS,1×)、溶媒B(20mMクエン酸ナトリウムおよび1M NaCl,pH5.1)および溶媒C(20mMクエン酸ナトリウムおよび1M NaCl,pH2.8)からなるものだった。溶出を、最初の20分間の100%Aによるアイソクラティック溶出から開始し、続いて、20分後に素早く100%Bに切り換えた。次いで、次の10分間にわたって、50%Cおよび50%Bに向かって直線勾配を開始した;第1のピーク(Fc/ΔAdpFc)が完全に溶出するまで、Cの濃度を20分間50%に維持した。続いて、50%Cから100%Cへの直線勾配を30分間行った。流速を250マイクロリットル/分に維持し、UV検出器によって280nmでクロマトグラムを検出した。hIgG4 Fc/ΔdpFcは、pH約4で溶出し、一方、ホモ二量体は、pH約4からpH2.8までの勾配中に溶出した。
識別的に改変されたヘテロ二量体の抗hCD3×CD20 IgG1(Fc/ΔAdpFc)および改変されていないホモ二量体の抗hCD20を、以下のとおり、1mLのrProtein AFF(GE Biosciences)カラムにおいて分離した。この溶媒系は、緩衝液A1(PBS 1×)、緩衝液A2(20mMクエン酸ナトリウムおよび1M NaCl pH5.1)、緩衝液B(20mMクエン酸ナトリウムおよび1M NaCl pH2.8)だった。混合サンプルを結合させ、PBSおよび緩衝液A2で洗浄した。段階を用いてpH4.2に達したところ、それにより、二重特異性CD3*×CD20 IgG1(Fc/ΔAdpFc)が溶出し、次いで、pH4.2からpH2.8までの直線勾配により、ホモ二量体の抗hCD20 IgG1が溶出した。
ΔAdp改変(H435RおよびY436F,EUナンバリング)を有するヒトIgG1アイソタイプ二重特異性抗体の種々のヒトFcレセプターに対する結合親和性を、Biacore(商標)定常状態平衡結合アッセイにおいて試験した。
実施例9:hFcRnマウスにおける二重特異性hIgG1ΔAdpの薬物動態
二重特異性抗hCD3/hCD20 IgG1ΔAdp抗体およびその抗体に関するコントロール(抗hCD3 IgGおよび抗hCD3 IgGΔAdpホモ二量体)の薬物動態学的クリアランス速度を、野生型(WT)マウスおよびhFcRn遺伝子によるマウスFcRnの置き換えについてホモ接合性のマウス(hFcRnマウス)において測定した。野生型マウスおよびhFcRnマウスは、C57BL6(75%)および129Sv(25%)を含むバックグラウンドの交雑系統由来のものだった。IgG1アイソタイプマッチコントロール抗体を投与されるWTマウスの1つのコホートの場合(このコホートは3匹のマウスを含んだ)を除いて、コホートは、WTマウスまたはhFcRnマウスの各々を4匹含んだ。1mg/kgのアイソタイプマッチ(hIgG1)コントロール、抗hCD3×CD20IgG1ΔAdp二重特異性、抗hCD3IgG1または抗hCD3IgG1ΔAdpホモ二量体をマウスに投与した。すべての被験物質を皮下に投与した。血液(Bleeds)を0時間、6時間、1日、2日、3日、4日、7日、10日、14日、21日および30日の時点で回収した。
実施例10:低塩緩衝液における大量単離
二重特異性CD3×CD20ΔAdp抗体を、本発明に従って大量培養物から単離した。簡潔には、二重特異性抗hCD3×CD20ΔAdp(CD3重鎖に改変)抗体を発現しているCHO−K1細胞株を11リットルのバイオリアクターにおいて培養した。二重特異性抗体を産出する細胞は、約8.25×106細胞/mLの密度まで成長し、約250〜350mg抗体/Lが得られた。対照的に、コントロール抗hCD3抗体は、約100〜150mg/Lで得られた。
野生型または変異体(TTTKまたはPTTK)mIgG2a Fcと融合された、ヒトIFNAR1(hIFNAR1)およびヒトIFNAR2(hIFNAR2)細胞外ドメインに対する発現構築物でCHO−K1細胞を一過性にトランスフェクトした。等量の2つの発現プラスミドで細胞をトランスフェクトすることによって、hIFNAR1−mFcとhIFNAR2−mFcとの比を1:1に保った。トランスフェクションの4日後に培養液を回収し、それを、0.2mLのNAb Protein A Plus(商標)スピンカラム(Thermo Scientific/Pierce)を使用するプロテインA精製に供した。簡潔には、カラムを1×PBS,pH7.2で平衡化した。1mlのCHO−K1培養液を、室温で10分間、プロテインA樹脂とともにインキュベートした。次いで、そのカラムを1×PBS,pH7.2で3回洗浄した。結合したタンパク質を、1M NaClを含む20mMクエン酸ナトリウム緩衝液を用いて溶出した。pHを下げながら0.4mLの溶出緩衝液を使用して、溶出を3回行った。異なる画分中のタンパク質を、ウエスタンブロット解析によって検出した。
C末端のマウスFc(mIgG2aまたはmIgG1)を有するヒトI型インターフェロンレセプター(hIFNAR1およびhIFNAR2)の細胞外ドメインの哺乳動物発現用のDNAプラスミドを構築した。部位特異的突然変異誘発を用いて、mIgG2a配列内に変異を導入した。これらの変異体は、TTT=M252T、S254T、S256T;TTTK=M252T、S254T、S256T、I258K;PTTTK=I247P、M252T、S254T、S256T、I258K;RF=H435R、H436Fである。CHO−K1細胞を、上記発現構築物で一過性にトランスフェクトした。hIFNAR2−mFc(mIgG1または変異体mIgG2a)よりも4倍多いhIFNAR1−mFc発現プラスミド(hIFNAR1−mIgG2a)で細胞をトランスフェクトすることによって、IFNAR1−mFcとIFNAR2−mFcとの比を4:1に保った。トランスフェクションの4日後に培養液を回収し、mFcタンパク質をウエスタンブロット解析によって検出した。
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