JP6423351B2 - Fcγ受容体IIB変異体 - Google Patents
Fcγ受容体IIB変異体 Download PDFInfo
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- JP6423351B2 JP6423351B2 JP2015538506A JP2015538506A JP6423351B2 JP 6423351 B2 JP6423351 B2 JP 6423351B2 JP 2015538506 A JP2015538506 A JP 2015538506A JP 2015538506 A JP2015538506 A JP 2015538506A JP 6423351 B2 JP6423351 B2 JP 6423351B2
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Description
本発明は、SEQ ID NO:1のタンパク質をコードする核酸配列、前記核酸配列を含むベクター、および前記核酸配列または前記ベクターを含む宿主細胞に関する。本発明はまた、宿主細胞における前記核酸配列または前記ベクターの発現によって得られた、または得ることができるタンパク質に関する。さらに、本発明は、SEQ ID NO:6の核酸配列によってコードされるタンパク質に関する。さらに本発明に含まれるものは、薬学的組成物および薬学的組成物を製造する方法である。さらに、本発明は、SEQ ID NO:2および/または3のタンパク質を含む組成物に関する。前記組成物はSEQ ID NO:4 および/または5のタンパク質をさらに含んでもよい。
FcγRは、感染からヒト生物を防御するのに重要なFc受容体(FcR)ファミリーに属する。一般的に、FcγRの活性化とFcγRの阻害は区別されなければならない。ヒトにおける3つの主なFcγRのうち、FcγRIは単量体IgGに結合することができるのに対して、FcγRIIおよびFcγRIIIは、抗体および抗原からなる多価免疫複合体(IC)に結合する(Takai, T. Nature Reviews Immunology 2002: 580-592(非特許文献1))。FcγRによって誘発されるエフェクター機能には、発現されるFcRタイプおよび関連するタンパク質に応じて、エンドサイトーシスとその後の病原体中和および抗原提示、抗体依存性細胞傷害(ADCC)、メディエーターの分泌または抗体生成の調節が含まれる(Fridman et al. Immunol Rev. 1992125:49-76(非特許文献2), van de Winkel and Capel Immunol Today. 1993: 14(5):215-21(非特許文献3))。
本発明は、SEQ ID NO:1のタンパク質をコードする核酸配列に関する。本発明はまた、SEQ ID NO:2、3、4、5、または9に示したタンパク質をコードする核酸配列を提供する。SEQ ID NO:6に示した核酸配列はSEQ ID NO:1のタンパク質をコードする。
[本発明1001]
SEQ ID NO:1のタンパク質をコードする、核酸配列。
[本発明1002]
本発明1001の核酸配列を含む、ベクター。
[本発明1003]
宿主細胞における本発明1001の核酸配列または本発明1002のベクターの発現によって得られた、または得ることができる、タンパク質。
[本発明1004]
宿主細胞が原核生物宿主細胞である、本発明1003のタンパク質。
[本発明1005]
宿主細胞が大腸菌である、本発明1003または1004のタンパク質。
[本発明1006]
SEQ ID NO:6の核酸配列によってコードされる、タンパク質。
[本発明1007]
本発明1003または1004のタンパク質を含む、薬学的組成物。
[本発明1008]
SEQ ID NO:2および/または3のタンパク質を含む、組成物。
[本発明1009]
SEQ ID NO:4および/または5のタンパク質をさらに含む、組成物。
[本発明1010]
SEQ ID NO:2のタンパク質の量がSEQ ID NO:3のタンパク質の量より多い、本発明1008の組成物。
[本発明1011]
SEQ ID NO:2および3のタンパク質の量がSEQ ID NO:4および/または5のタンパク質の量より多い、本発明1008〜1010いずれかの組成物。
[本発明1012]
本発明1001の核酸配列または本発明1002のベクターを含む、宿主細胞。
[本発明1013]
原核生物宿主細胞または真核生物宿主細胞である、本発明1012の宿主細胞。
[本発明1014]
大腸菌である、本発明1012の原核生物宿主細胞。
[本発明1015]
大腸菌BL21である、本発明1014の原核生物宿主細胞。
[本発明1016]
コードされるタンパク質の発現を可能にする条件下で本発明1012〜1015いずれかの宿主細胞を培養する工程および得られた薬学的組成物を回収する工程を含む、薬学的組成物を製造する方法。
本明細書で使用する単数形「1つの(a)」、「1つの(an)」、および「その(the)」は、特に文脈によってはっきり示されていない限り複数の言及を含むことに留意しなければならない。従って、例えば、「1つの試薬」についての言及は、このような異なる試薬の1つまたは複数を含み、「その試薬」についての言及は、本明細書に記載の方法の代わりに改変または使用することができる、当業者に公知の等価な工程および方法についての言及を含む。
(i)第1のコドン(ATG)がSEQ ID NO:6から取り除かれると、SEQ ID NO:2のタンパク質が得られ、
(ii)第1のコドン(ATG)および第2のコドン(GCA)がSEQ ID NO:6から取り除かれると、SEQ ID NO:3のタンパク質が得られ、
(iii)第1のコドン(ATG)、第2のコドン(GCA)、および第3のコドン(CCG)がSEQ ID NO:6から取り除かれると、SEQ ID NO:4のタンパク質が得られ、
(iv)第1のコドン(ATG)、第2のコドン(GCA)、第3のコドン(CCG)、第4のコドン(CCG)、および第5のコドン(AAA)がSEQ ID NO:6から取り除かれると、SEQ ID NO:5のタンパク質が得られ、
(v)N末端からC末端にかけてアミノ酸TPAをコードするコドンが、SEQ ID NO:6の第1のコドン(ATG)と第2のコドン(GCA)コドンとの間に付加され、アミノ酸配列MGIをコードするコドンが、SEQ ID NO:6の最後から2番目のコドン(CCG)の3'側に付加されると、SEQ ID NO:9のタンパク質が得られる。
(a)SEQ ID NO:1のタンパク質をコードする核酸の発現によって得られた、もしくは得ることができる少なくとも1つのタンパク質を含む組成物;または
(b)SEQ ID NO:1、2、3、4、5、もしくは9のタンパク質をコードする核酸を含むベクター;または
(c)SEQ ID NO:6の核酸配列によってコードされるタンパク質;
(d)SEQ ID NO:1、2、3、4、5、もしくは9のタンパク質をコードする核酸配列
に関する。
FcR変異体の生成
250mLバッフル付コニカルフラスコに入っている50μg/mLカナマイシンを添加したLB 75mLにグリセロールストック5μLを接種し、37℃、170rpmで15時間、振盪した(Multitron Standard, Infors HT)。その後に、2Lバッフル付コニカルフラスコに入っているLB 1Lに一晩培養物10mLを接種し、37℃、170rpmで振盪した。OD6001.6になったら、1mM IPTGを添加することによって発現を誘導した。37℃、170rpmでさらに3時間、培養した後に、細胞を遠心分離(5,000gで10分、4℃)によって収集し、200mL氷冷PBSで1回、洗浄し、-20℃で保管した。
6〜8gの凍結大腸菌細胞を室温で解凍し、100μg/mLリゾチームを添加した溶解緩衝液(50mM Tris/HCl、25mM NaCl、2mM EDTA、pH8.0)30mLをテフロン・イン・ガラス(teflon-in-glass)ホモジナイザーを用いて再懸濁した。氷上で15分インキュベートした後に、細胞を超音波処理によって破壊し(出力設定6、デューティサイクル30%、30分、マイクロチップを備えたsonifier 250, Branson)、懸濁液を遠心分離(13,000gで45分、4℃)した。上清1mLをサンプリングし、残っている液体を捨てた。ペレット、すなわち、粗封入体を、0.5%(v/v) Polysorbate20を添加した溶解緩衝液35mLにテフロン・イン・ガラスホモジナイザーを用いて再懸濁し、遠心分離(13,000gで15分、4℃)した。界面活性剤を用いて、もう1回、洗浄工程を行った後、溶解緩衝液だけを用いて最終洗浄工程を行った。洗浄された封入体を使用するまで-20℃で保管した。
湿った封入体を、20mM Tris/HCl、6Mグアニジン、3mM EDTA、5mM DTT、pH8.0に溶解して200mg/mLで、密閉した遠心管に入れて一定に攪拌(400rpm)しながら20℃で2.5時間、可溶化した。遠心分離(20,000g、10分、20℃)後、上清をデカンテーションによって収集し、1:60に希釈した後に、FcR含有率をRP-HPLCによってKnauer Bioselect C4で求めた。分析結果に基づいて、可溶化封入体を、FcR含有率21mg/mLまで20mM Tris/HCl、6Mグアニジン、3mM EDTA、5mM DTT、pH8.0で希釈した。希釈されたFcR溶液の一部を、20部の攪拌(800rpm)されている再折り畳み用緩衝液(20mM Tris/HCl、2M尿素、0.5Mアルギニン、2mMシステアミン、2mMシスタミン、6℃でpH7.7)に滴下した。攪拌せずに密閉容器に入れて10℃で16時間インキュベートした後に、再折り畳み用溶液を室温まで温めた。一定に攪拌(400rpm)しながら、3.5M(NH4)2SO4、20mM NH4H2PO4、pH7.0を滴下することによって、温かい再折り畳み溶液を1.1M(NH4)2SO4に調整した。200rpmでもう1時間、攪拌した後、懸濁液を遠心分離(20,000g、20分、20℃)し、上清を濾過(0.2μm Durapore(登録商標), Millipore)し、濾液を、1.2M(NH4)2SO4、20mM NH4H2PO4、pH7.0で平衡化した35mL フェニルセファロースHPカラム(h=6.6cm、d=2.6cm、GE Healthcare)に、4mL/分、<4mgタンパク質/mL樹脂でロードした。カラムを1.2M(NH4)2SO4、20mM NH4H2PO4、pH7.0 100mLで洗浄した。結合タンパク質を、20mM NH4H2PO4、pH7.0に溶解した1.2M〜0M(NH4)2SO4の350mL直線勾配を用いて5mL/分で溶出した。溶出液を7.5mL画分に収集し、Phenomenex Jupiter C4によるRP-HPLC分析に供した。求められているFcR変異体に対して85%を超える純度を有する画分をプールし、約2倍に濃縮し、伝導率が約5mS/cmに低下するまでタンジェンシャルフロー・フィルトレーション(Vivaflow 50、5kDa MWCO、0.01m2、クロスフロー200mL/分、pIN=2bar; Sartorius)で20mM L-ヒスチジンpH6.5に対してダイアフィルター(diafilter)した。緩衝液交換の後、溶液を、20mM L-ヒスチジン、pH6.5で平衡化した9mL SP Sepharose HPカラム(h=4.5cm、d=1.6cm、GE Healthcare)に、2mL/分、<20mgタンパク質/mL樹脂でロードした。カラムを、20mM L-ヒスチジン、30mM NaCl、pH6.5 30mLで洗浄し、結合タンパク質を、20mM L-ヒスチジン、pH6.5に溶解した20mM〜400mM NaClの90mL直線勾配を用いて3mL/分で溶出した。主ピークを含む画分をプールし、20mM L-ヒスチジンpH6.5を用いて15.4mS/cmに調整し、限外濾過(4,000g、5kDa MWCO, Vivaspin 20, Sartorius)によって約20mg/mLに濃縮し、20mM L-ヒスチジン、150mM NaCl、pH6.5を用いて15mg/mLまで希釈した。希釈されたFcR溶液を濾過(0.45μm PES膜、Puradisc(商標)25mm, Whatman)し、分注し、液体窒素で瞬間凍結し、-80℃で保管した。
適量のddH2O、10Xヒスチジン/NaCl原液(200mMヒスチジン、1.5M NaCl)、および硫酸アンモニウム原液(ddH2Oに溶解して4M)を添加することによって、FcRを20mMヒスチジン、150mM NaCl、および0〜2.8M硫酸アンモニウムの存在下で0.7mg/mLに調整した。適切なpHの10Xヒスチジン/NaClおよび硫酸アンモニウムストックを使用することによって、pHを6、7、または8に設定した。各条件について2つ同じものを準備した。試料を25℃で1時間インキュベートし、遠心分離(20,000xg、10分)し、30μLの上清を384ウェルプレート(μclear, non-binding, black, Greiner Bio-one)に移した。280nmでの吸光度を測定し(Spectrofluor plus, Tecan)、タンパク質含有率をランバート・ベールの法則に従って1.5625mLxmg-1xcm-1の質量吸光係数および0.24cmの経路の長さ(path length)を用いて計算した。試料ウェルの吸光度をブランク緩衝液しか含まないウェルの吸光度で補正した。
後のジスルフィド交換を抑制するために、可溶化IBまたは再折り畳み用ブロス18μLを、H2Oに溶解した新たに調製された250mMヨードアセトアミド2μLと混合することによって、遊離チオールをヨードアセトアミドでアルキル化した。混合物を30℃、750rpmで45分間、暗所でインキュベートし、NuPAGE(登録商標)Novex(登録商標)マニュアル(Invitrogen)に従ってSDS-PAGE試料調製に直接使用した。タンパク質を、MESランニング緩衝液(NuPAGE(登録商標)Novex(登録商標), Invitrogen)の中に入れた4〜12%Bis-Trisゲルによって製造業者の説明書に従って分離した。ゲルをddH2Oで3回洗浄し、Simply Blue(商標) Safe Stain(Invitrogen)を用いて室温で少なくとも6時間、染色した。分子量マーカーとして、10μLのSeeBlue(登録商標)Plus2 pre-stained standard(Invitrogen)を適用した。
インタクトな発現タンパク質の分子量を、MPI of Biochemistry(Martinsried)と協力して質量分析法によって求めた。30%アセトニトリル、0.05%TFAで予め平衡化されたPhenomenex Aeris(商標)Widepore C4カラム(100mmx2.1mm、3.6μM粒径、300Å孔径)を備えたESI-TOF質量分析計(microTOF, Bruker)によって試料を分析した。FcR含有試料を0.25mL/分、20℃で注入し、結合タンパク質を、30%〜80%アセトニトリル、0.05%TFAの15分直線勾配によって溶出した。
必要に応じて、タンパク質溶液を、それぞれの緩衝液を用いて0.2〜0.8のOD280まで希釈した。400μLの溶液をUV-マイクロキュベット(UV-cuvette micro,Brand)に移した。280nmおよび320nMでの吸光度を記録し(TidasE, J&M Analytik)、タンパク質濃度、mg/mLを以下の式に従って計算した:
Cタンパク質=(OD280-OD320)x0.64mg/mL
再折り畳みに基づくプロセスによるFcRタンパク質の製造には、普通、硫安沈殿工程が必要である。コスモトロピック硫酸アンモニウムを添加することによって、折り畳まれていない種および誤って折り畳まれた種のような折り畳み副産物だけでなく、細胞壁成分およびタンパク質のような宿主細胞に由来する不純物も沈殿する。沈殿剤の濃度が増加するにつれて、沈殿効率は上昇し、従って、このような高い硫酸アンモニウム濃度での沈殿に対する耐性がFcR変異体にある限り、高度に精製されたFcR調製物が得られる。従って、1.5Mに等しいか、または1.5Mを上回る硫酸アンモニウム濃度で溶解度の高いFcR変異体を有することが望ましい。高い硫酸アンモニウム濃度は簡単な不純物沈殿に加えてHIC樹脂への効率的な結合を促進する。高い動的結合能は常にクロマトグラフィー捕獲工程の重要な開発目標であるので、高い硫酸アンモニウム濃度の存在下での可溶性は必須である。
Claims (11)
- SEQ ID NO:1からなるタンパク質をコードする、核酸分子。
- 請求項1記載の核酸分子を含む、ベクター。
- 宿主細胞における請求項1記載の核酸分子または請求項2記載のベクターの発現によって得られた、タンパク質。
- 宿主細胞が原核生物宿主細胞である、請求項3記載のタンパク質。
- 宿主細胞が大腸菌である、請求項3または4記載のタンパク質。
- SEQ ID NO:6からなる核酸配列によってコードされる、タンパク質。
- 請求項3または4記載のタンパク質を含む、薬学的組成物。
- 請求項1記載の核酸分子または請求項2記載のベクターを含む、宿主細胞。
- 原核生物宿主細胞または真核生物宿主細胞である、請求項8記載の宿主細胞。
- 大腸菌である、請求項9記載の原核生物宿主細胞。
- コードされるタンパク質の発現を可能にする条件下で請求項8〜10いずれか一項記載の宿主細胞を培養する工程および得られた薬学的組成物を回収する工程を含む、薬学的組成物を製造する方法。
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