JP6282232B2 - 抗体及びそのFcフラグメントの酵素化学的糖鎖改変 - Google Patents
抗体及びそのFcフラグメントの酵素化学的糖鎖改変 Download PDFInfo
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- JP6282232B2 JP6282232B2 JP2014556776A JP2014556776A JP6282232B2 JP 6282232 B2 JP6282232 B2 JP 6282232B2 JP 2014556776 A JP2014556776 A JP 2014556776A JP 2014556776 A JP2014556776 A JP 2014556776A JP 6282232 B2 JP6282232 B2 JP 6282232B2
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Description
[001] 本発明は、国立衛生研究所から授与された助成金番号GM080374及びGM096973による政府の支援を受けてなされた。政府は本発明に一定の権利を有する。
[002] 本出願は、2012年2月10日出願の米国仮出願第61/597,468号に対する優先権を主張し、その内容はあらゆる意味で参照により本明細書に組み込まれる。
[004] 本発明は、糖タンパク質合成に関し、特にグリコシル転移活性及び限られた加水分解活性を保有する化膿性連鎖球菌からの組換え型及び突然変異エンドS、すなわち、エンド−β−N−アセチルグルコサミニダーゼの使用、及びそれにより、抗体−Fcドメインの効率的なグリコシル化リモデリングを提供することに関する。
a.コアフコシル化GlcNAc−IgG、非フコシル化GlcNAc−IgG又は対応するIgG−Fcフラグメントからなる群から選択されるアクセプタを提供するステップと、
b.活性化したオリゴ糖部分を前記アクセプタに転移し、均一なフコシル化又は非フコシル化糖タンパク質を生成するために、化膿性連鎖球菌エンド−S Asp−233突然変異体の存在下で、前記アクセプタを活性化オリゴ糖部分を含む供与体基質と反応させるステップと、を含む。
a.アスパラギン結合コアフコシル化N−アセチルグルコサミン(GlcNAc)残基を含むコアフコシル化IgGアクセプタを提供するステップと、
b.エンドグリコシダーゼ−S D233Q(配列番号:2)及びD233A(配列番号:3)突然変異体の存在下で前記コアフコシル化IgGアクセプタを活性オリゴ糖供与体と酵素的に反応させるステップであって、活性オリゴ糖供与体は、所定の数及びタイプの糖残基を含むオリゴ糖部分を保有し、該オリゴ糖部分は前記コアフコシル化IgGアクセプタと共有結合し、それにより所定のオリゴ糖部分を有するコアフコシル化IgG又はIgG−Fcフラグメントを調製するステップと、を含む。
コアフコシル化又は非フコシル化GlcNAc−抗体又はそのFcフラグメントから選択されたアクセプタを提供するステップと、
化膿性連鎖球菌エンド−S Asp−233突然変異体の存在下で、前記アクセプタを供与体基質と反応させるステップであって、該供与体基質は、規定された数及びタイプの糖残基並びに特異的結合タイプを有する所定のオリゴ糖成分を含み、それにより均一なフコシル化又は非フコシル化単量体抗体又はそのFcフラグメントを提供するステップとを含む。一実施形態では、フコシル化GlcNAc含有タンパク質はアルファ−1−6−フコシル−GlcNAc−タンパク質である。
a.Fc N−グリカンを含むコアフコシル化抗体又はそのFcフラグメントを提供するステップと、
b.Asn結合GlcNAc部分を生成するために、前記コアフコシル化抗体又はFcフラグメントを加水分解エンド酵素で処理するステップと、
c.配列番号:2及び配列番号:3からなる群から選択されるアミノ酸配列を有するエンド−S突然変異体の存在下で、オリゴ糖をAsn−結合GlcNAc部分に結合させ、それにより所定のオリゴ糖成分を付加させるステップと、を含む。
a.均一なN−グリカンを保有する天然又は組換え型原料から得たコアフコシル化又は非フコシル化IgG又はIgG−Fcフラグメントを提供するステップと、
b.ペプチドドメインに最も近く位置する2つのGlcNAc残基間の結合を加水分解するために、前記天然又は組換え型IgG又はIgG−Fcフラグメントをエンド−酵素(効率的な加水分解活性がある野生型エンドグリコシダーゼ又は組換え型エンドグリコシダーゼ)で処理し、それによってコアフコシル化又は非フコシル化GlcNAc−アクセプタを保有する脱グリコシル化タンパク質を形成するステップと、
c.化膿性連鎖球菌エンド−S Asp−233突然変異体でのグリコシル転移を通して天然ベータ−1,4−グリコシド結合を再構成するために、所定のオリゴ糖成分を前記GlcNAc−アクセプタに結合させ、それにより前記所定のオリゴ糖成分を付加して、コアフコシル化又は非フコシル化IgG又はIgG−Fcフラグメントをリモデリングするステップと、を含む。
a.前駆物質としてFc N−グリカンを保有する天然に存在するIgG抗体、組換え型抗体又はFcドメインを提供するステップと、
b.Fcドメインを脱グリコシル化してGlcNAc−アクセプタを形成するために、野生型エンド−Sなどのエンドグリコシダーゼを使用してFc脱グリコシル化するステップであって、該GlcNAc−アクセプタは前記抗体のFc領域に位置し、GlcNAc−アクセプタはコアフコシル化又は非フコシル化されるステップと、
c.所定の数の糖残基を有する修飾抗体を形成するために、配列番号:2及び配列番号:3を含むエンド−S突然変異体からなる群から選択される酵素の触媒で、所定の数の糖残基を有するオリゴ糖オキサゾリン又はシアログリカンオキサゾリンで前記天然に存在するIgG抗体、組換え型抗体又はFcドメインのGlcNAc−アクセプタをグリコシル転移するステップと、を含む。
a.Fc N−グリカンを保有するIVIGを提供するステップと、
b.GlcNAc−アクセプタを形成するために野生型エンド−Sを含むエンドグリコシダーゼを使用して前記Fc N−グリカンをFc脱グリコシル化するステップであって、該GlcNAc−アクセプタは前記IVIGのFc領域に位置し、GlcNAc−アクセプタはフコシル化又は非フコシル化されるステップと、
c.シアル酸付加IVIGを形成するために、配列番号:2及び配列番号:3を含むエンド−S突然変異体からなる群から選択される酵素の触媒で、所定の数の糖残基を有するシアログリカンオキサゾリンで前記GlcNAc−アクセプタをグリコシル転移するステップと、を含む。
a.天然又は組換え型IgG抗体又はIgG−Fcフラグメントを提供するステップであって、該組換え型IgG又はIgG−Fcは酵母、昆虫、植物、及び任意の哺乳類発現系を含むが、これらに限定されない典型的なタンパク質発現系から産生されるステップと、
b.コアフコシル化又は非フコシル化GlcNAc−含有タンパク質を形成するために、エンド−H、エンド−A、エンド−S及び/又はエンド−F3からなる群から選択される酵素によってN−グリカンを除去するステップと、
c.鎖中に規定された数及びタイプの糖残基を含む所望のオリゴ糖成分を有する、糖オキサゾリン又はシアログリカンオキサゾリンを提供するステップと、
d.所望の数の糖残基を有する糖オキサゾリン又は所望の数の糖及びシアル酸残基を有するシアログリカンオキサゾリンで前記フコシル化又は非フコシル化GlcNAc−含有タンパク質を、化膿性連鎖球菌エンド−S Asp−233突然変異体からなる群から選択されるエンドグリコシダーゼで酵素グリコシル転移し、それにより所望の数の糖残基及び/又はシアル酸の伸長部を有する均一なコアフコシル化又は非フコシル化IgG抗体又はIgG−Fcフラグメントを形成するステップと、を含む。
a.元のグリコシル化部位に結合した単フコシル化又は非フコシル化GlcNAc部分を残すために、エンドグリコシダーゼで抗体から不均一な糖鎖を除去するステップと、
b.タグ付き抗体を生成するために、エンドグリコシダーゼ触媒グリコシル転移により、少なくとも1つのタグがあるコアオリゴ糖又はシアログリカンオキサゾリンをフコシル化又は非フコシル化GlcNAc部分に転移するステップであって、前記エンドグリコシダーゼは配列番号:2及び配列番号:3を含むエンド−S突然変異体からなる群から選択されるステップと、を含む。
[0059] 本明細書で使用する「a」又は「an」は、1つ又は複数を意味することがある。特許請求の範囲で使用する「a」又は「an」という言葉は、「含む」という言葉と組み合わせて使用した場合、1つ又は複数を意味することがある。本明細書で使用する「別の」は、少なくとも2つ目以上を意味することがある。
[0087] SCH−C、SCH−D、PRO140、TAK779、TAK−220、RANTES類似体、AK602、UK−427、857、モノクローナル抗体などのCCR5阻害剤/拮抗薬;及びフゼオン(T−20)(エンフビルチド)、NB−2、NB−64、T−649、T−1249、SCH−C、SCH−D、PRO140、TAK779、TAK−220、RANTES類似体、AK602、UK−427、857などのウイルス侵入阻害剤;及びその機能的類似体又は等価物でよい。
[0094] グリコシンターゼは以前は、加水分解中にオキサゾリニウムイオンの中間形成を促進する役割を果たす重要なアスパラギン(Asn)残基の部位特異的突然変異によって、エンドA、エンドM及びエンドDなどの幾つかのGH85エンドグリコシダーゼ(ENGase)から作成されていた(36〜39、43)。エンドSはグリコシドヒドロラーゼ科18(GH18)に属するエンドグリコシダーゼであり(40,41)、これはエンドF1、エンドF2及びエンドF3と同じGH科であり、最近、グリコシル転移活性を有することが示された(44)。エンドF3などの他のGH18エンドグリコシダーゼで実証されたように、エンドS触媒の加水分解も、オキサゾリニウムイオン中間体の形成に関与する基質補助メカニズムによって進行するという仮説(45)に基づき、オキサゾリニウムイオン形成を促進する役割を果たす残基の同定及び突然変異によって、エンドSから潜在的グリコシダーゼが作り出された。以前のエンドF3に関する構造及び突然変異誘発研究は、GH85科酵素の場合のようにアスパラギン残基ではなく、位置165にあるアスパラギン酸残基(D165)が、オキサゾリン形成を促進する役割を果たし、E167残基が触媒加水分解の一般酸/塩基であることを示している(45)。エンドSとエンドF3との配列アラインメント(図2)により、触媒作用のためのエンドSの2つの重要な残基、すなわち、図2に示すように、オキサゾリニウムイオン形成を促進する役割を果たすD233残基(エンドF3のD165に対応する)、及びグリカン加水分解における一般酸/塩基残基としてのE235残基(エンドF3のE167の等価物)が同定された。機能的には、D233残基が、GH85エンドグリコシダーゼであるエンドA、エンドM及びエンドDそれぞれのN171、N175、及びN322とも同等であるはずである。このように、オキサゾリニウムイオン中間体を介して基質補助メカニズムで進行するエンドA、エンドM及びエンドDからグリコシンターゼを生成する方法(36〜39)に従い、図17に示すように、2つの特異的突然変異体D233A(配列番号:2)及びD233Q(配列番号:3)を、エンドS(配列番号:1)の部位特異的突然変異によって生成した。これらの突然変異体も野生型エンドSも、GST融合タンパク質として高い収率(30〜40mg/L)で大腸菌中に発現し、グルタチオン親和クロマトグラフィで精製した。
[00101] 抗がん療法には非フコシル化IgGグリコフォームが望ましい。何故なら、Fc N−グリカンのフコース含有率が低いmAbはin vitroでADCC活性の向上を、in vivoで抗がん有効性の向上を示し、FcγIIIa受容体の親和性が低いF158対立遺伝子を保有する患者では特にそうであることが以前に実証されている(16〜19、52)からである。既存のフコシル化mAb(哺乳類の細胞で産生される組換え型mAbの主要グリコフォーム)を非フコシル化mAbに効率的に変換する効率的な方法はなかった。この問題に対応するために、一連の市販のα−フコシダーゼを試験したが、インタクトなリツキシマブ中でα1,6−フコースを除去できるものはなかった。図5A及び図5Bの概略図を参照されたい。これらの結果は、α−1,6−フコース部分がFcドメイン及び/又は複合N−グリカンによって遮蔽され、α−フコシダーゼへのアクセスを不可能にしているかもしれないことを意味する。脱グリコシル化の後、得られたリツキシマブのFuc(α1,6)GlcNAcグリコフォームが、α−フコシダーゼへよりアクセス可能になるかもしれないとの理論を立てた。したがって、Fuc(α1,6)GlcNAc部分のみを保持する脱グリコシル化リツキシマブ(1)で、幾つかの市販のα−フコシダーゼの活性を試験した。ウシ腎臓からの非特異的α−フコシダーゼは実際に穏やかな活性を有し、脱グリコシル化リツキシマブ(1)からフコース残基を除去し、GlcNAc−含有リツキシマブ(8)を与えられることが判明した(図15A及び図15B参照)。α−フコシダーゼの穏やかな活性により、エンドS−脱グリコシル化リツキシマブの完全な脱フコシル化を達成するために比較的大量のα−フコシダーゼ及び長い反応時間が必要であったが、このα−フコシダーゼの活性の発見は、更なる糖鎖改変のために脱フコシル化リツキシマブ前駆物質(8)を得る代替法を提供する。
[00104] リツキシマブのグリコシル化リモデリングが成功したことにより、抗炎症活性を向上させることを目的としたIVIGの糖鎖改変のための酵素化学的方法の考察が促進された。IVIGは、数千人の健康なドナーの血漿から精製されてプールされたIgG画分である。最近の研究は、微小なα2,6−シアル酸付加Fcグリコフォームは、関節リウマチのマウスモデルで実証された(21,22,53、54)ように、抗炎症活性を与えるIVIG中の活性種であることを示唆している。シアル酸付加FcグリコフォームはIVIGのマイナーな構成部分であるので(55)、末端Fcシアル酸付加に対するIVIGの抗炎症活性の依存性により、防御を与えるためにIVIGの高用量(1〜2g/kg)の注入が必要である理由が部分的に説明される。ヒトα−1,6−シアリル転移酵素(ST6Gal−I)を使用してFc及びIVIGの直接的なシアル酸付加を試みたが、効率は低く、大抵の場合、主要産物としてモノシアル酸付加グリコフォームしか得られなかった(22,56)。さらに、FABグリカンにシアル酸付加した場合、IVIGのFABドメインの約30%がN−グリコシル化され、IVIGのFcシアル酸付加グリコフォームのレクチン強化の効率が低下することになる(2,57)。したがって、FABグリコシル化を変化させずに、シアル酸付加N−グリカンでFc特異的糖鎖改変が達成できれば非常に望ましい。
[00107] 表面プラズモン共鳴(SPR)分析で、個々のFcγ受容体(FcγRIIIa−F158、FcγRIIIa−V158及びFcγRIIb)に対するリツキシマブのリモデリングしたグリコフォームの親和性を試験した。本発明者の最近報告した手順(35)に従い、リツキシマブグリコフォームをタンパク質Aチップ上で部位特異的に固定化し、様々な濃度のFcγ受容体を検体として注入した。予測通りに、非フコシル化G2グリコフォームは、市販のリツキシマブと比較した場合、図9に示すように低親和性及び高親和性の両方のFcγIIIa受容体、FcγRIIIa−F158及びFcγRIII−V158に対して大幅に向上した親和性を示した。FcγRIIIa−F158及びFcγRIIIa−V158に対するG2グリコフォーム(10)の結合のKD値は、それぞれ123±11及び12±2nMであり、それはBIAcore T100評価ソフトウェアを使用して、結合データを1:1定常状態モデルに当てはめることによって取得した。他方で、FcγRIIIa−F158及びFcγRIIIa−V158に対する市販のリツキシマブの結合のKD値は、それぞれ1042±155及び252±18nMと推定された。したがって、低親和性及び高親和性Fcγ受容体(FcγRIIIa−F158及びFcγRIIIa−V158)に対する糖鎖改変G2グリコフォームの親和性は、それぞれ市販のリツキシマブより約9倍及び20倍高かった。他方で、G2グリコフォーム及び市販のリツキシマブは、抑制性Fcγ受容体FcγRIIbに対して同等の親和性を実際に示し、Kd値はそれぞれ2.3±0.5及び2.0±0.7μMであった。これらの結果は、糖鎖改変したリツキシマブで有利な機能の明白な増加を明らかにする。高親和性FcγRIIIa−結合グリコフォームの効率的な製剤は、一般的MAbでの治療に対する反応が低い又は反応しないがん患者で見られるFcγ受容体多形の問題に対応するために、臨床的に重大であることを指摘しておかねばならない。これらの患者では、そのFcγRIIIa−F158対立遺伝子は、高親和性受容体FcγRIIIa−V158対立遺伝子と比較して、リツキシマブなどの治療用mAbに対して親和性が低い(52,60,61)。Fcγ受容体媒介のエフェクター機能は、HIV−中和抗体に対する防御免疫を達成するために重要なメカニズムであることも示唆された(62)。したがって、本明細書で述べる糖鎖改変方法は、機能研究、さらに生物医学的用途にとって貴重なモノクローナル抗体の様々な規定されたグリコフォームを産生する上で広い用途を見出すことができる。
[00109] Premium Health Services Inc.(メリーランド州コロンビア)を通してモノクローナル抗体リツキシマブ(リツキサン、Genentech Inc.、カリフォルニア州サウスサンフランシスコ)及びIVIGを購入した。以前に報告された手順(38,46)に従って、シアログリカンオキサゾリン(2)及びアシアロ複合型グリカンオキサゾリン(5)を合成した。ウシ腎臓α−1−フコシダーゼをSigma(ミズーリ州セントルイス)及びProzyme(カリフォルニア州ヘイワード)から購入し、Arthrobacter protophormiaeからのエンド−β−N−アセチルグルコサミニダーゼ(エンドA)及びMucor hiemalisからのエンド−β−N−アセチルグルコサミニダーゼ(エンドM)及びその突然変異体を、報告された手順(38)に従って大腸菌から過剰産生した。PNGaseFをNew England Biolabs(マサチューセッツ州イプスウィッチ)から購入した。
[00111] Hypersil GOLDカラム(1.9μm、50×2.1mm)を有するLXQシステム(Thermo Scientific)でLC−MSを実施した。IgGサンプルを0.5%のβ−メルカプトエタノールで処理し、60℃で15分間加熱してから、LC−MS測定にかけた。分析は、0.1%の蟻酸を含有する10〜40%のMeCNの線形勾配で溶出させ、60℃で10分以内、0.25mL/分の流量で実施した。
[00113] ESI−MSスペクトルを、Waters Micromass ZQ-4000単四重極質量分析計で測定した。MALDI−TOF MSは、Autoflex II NIALD-TOF質量分析計(Bruker Daltonics、マサチューセッツ州ダルトニックス)で実施した。計器は、ProteoMass Peptide MALDI-MS較正キット(MSCAL2、Sigma/Aldirich)を使用して較正した。中性のグリカンには2,5−ジヒドロキシ安息香酸(DHB)のマトリクスを使用し、産生グリカンには2’,4’,6’−トリヒドロキシアセトフェノン(THAP)を使用した。
[00115] 野生型エンドSを、以前に報告された手順(40,63)に従い、M. Collin博士(スウェーデン、ルンド大学)が親切にも提供してくれたプラスミドpGEX−エンドSを使用して大腸菌で過剰産生し、精製した。製造業者の指示に従ってGENEART部位特異的突然変異キット(Invitrogen)を使用して、2つのエンドS突然変異体、D233A及びD233Qを生成した。pGEX−エンドSプラスミドをテンプレートとして使用し、LA Taqポリメラーゼ(日本、タカラ)をPCRに使用した。突然変異をDNA配列で確認し、BL21(DE3)に形質転換した。形質転換体を、100mg/Lのカルベニシリンを含有するLuria-Bertani媒質中で培養し、0.1mMのイソプロピル−β−d−チオガラクトピラノシドで16時間、25℃で誘導した。1700gで15分間、4℃で遠心分離し、細胞を採取した。細胞ペレットを、リゾチーム及びPMSFを含むリン酸緩衝食塩水(pH7.4)中に懸濁させた。溶解混合物を16000gで20分間、4℃で遠心分離した。遠心分離後、細胞溶解からの上澄みを3mLの50%グルタチオン−セファロース4B樹脂(Ge Healthcare)に塗布した。サンプルを、穏やかに揺動し、25℃で60分間インキュベートした。樹脂を100mLのカラム(PD-10、GE Healthcare)に適用し、PBSで5回洗浄した。500μLのグルタチオン溶出緩衝液(50mMのトリス−HCl、10mMのグルタチオン、pH8.0)をカラムに添加し、室温で5分間インキュベートし、採取して、次に3回繰り返した。溶出したフラクションをプールし、リン酸ナトリウム緩衝液(50mM、pH7.0)に対して一晩、4℃で透析分離した。次に、Amicon超遠心分離フィルタ10kDa(ミリポア)を使用してタンパク質サンプルを濃縮した。濃縮したタンパク質サンプルをSDS−PAGEで分析し、Nano-Drop 2000c分光測光器を使用してタンパク質濃縮物を数量化した。野生型エンドSの過剰産生の収率は約40mg/Lであり、突然変異体の収率は約30mg/Lであった。
[00117] トリス−Cl緩衝液(50mM、pH8.0、2mL)中に市販のリツキシマブ(20mg)をエンドS(30μg)で1時間、37℃でインキュベートした。LC−MS及びSDS−PAGE分析は、重鎖上のN−グリカンが完全に切断していることを示した。反応混合物を、トリス−Cl緩衝液(20mM、pH8.0)で事前平衡化したタンパク質A−アガロース樹脂(5mL)のカラム上で親和クロマトグラフィにかけた。カラムをトリス−Cl(20mM、pH8.0、25mL)及びグリシン−HCl(20mM、pH5.0、20mL)で続けて洗浄した。結合IgGをグリシン−HCl(100mM、pH2.5、20mL)で放出させ、溶出フラクションを即座にトリス−Cl緩衝液(1.0M、pH8.8)で中和した。Fcフラグメントを含有するフラクションを化合させ、遠心濾過(Amicon Ultra遠心フィルタ、Millipore、マサチューセッツ州ビルリカ)で濃縮し、(Fucα1,6)GlcNAc−リツキシマブ(1)(18mg)を得た。LC−MS:(Fucα1,6)GlcNAc−リツキシマブ(1)の重鎖に対し計算、M=49420Da(47)、(m/z)49420であると判明(逆畳込み解析データ)。
[00119] トリス緩衝液(50mM、pH7.4、2mL)中に(Fucα1,6)GlcNAc−リツキシマブ(1)(10mg)及びシアログリカン−オキサゾリン(2)(10mg)を入れた溶液を、エンドS突然変異体D233A又はD233Q(200μg)で30℃でインキュベートした。間隔をあけてアリコートを採取し、LC−MSで分析した。2〜3時間後、LC−MSのモニタリングで(Fucα1,6)GlcNAc−リツキシマブ(1)が完全に反応し、完全にシアル酸付加したN−グリカンを保有するグリコシル転移産物(3)が得られたことが示された。反応混合物を、上述した手順に従ってタンパク質A−アガロースカラム上で親和クロマトグラフィにかけた。産物を含有するフラクションを化合させ、超遠心分離で濃縮して、シアル酸付加リツキシマブ(3)(11mg、定量)が得られた。LC−MS:完全シアル酸付加N−グリカンを保有する(3)の重鎖に対し計算、M=51421Da、(m/z)51426であると判明(逆畳込み解析データ)。
[00121] (3)を調製して対応する産物を与えるために、上述したようにグリコシル転移を実施した。糖鎖改変したリツキシマブ(5及び7)のLC−MS分析:フコシル化Man3GlcNAc2 N−グリカンを保持する(5)の重鎖に対し計算、M=50109Da、(m/z)50112であると判明(逆畳込み解析データ);フコシル化アジド−Man3GlcNAc2 N−グリカンを保有する(7)の重鎖に対し計算、M=50134Da、(m/z)50143であると判明(逆畳込み解析データ)。
[00123] 0.05のアジ化ナトリウムを含有するリン酸緩衝液(500mM、pH5.5、200μL)に(Fucα1,6)GlcNAc−リツキシマブ(1)(2mg)を入れた溶液を、ウシ腎臓からのフコシダーゼ(Prozyme、5U)で37℃でインキュベートした。間隔をあけてアリコートを採取し、LC−MSで分析した。20日後、LC−MSのモニタリングで、(Fucα1,6)GlcNAc−リツキシマブ(1)が完全に脱フコシル化し、産物のGlcNAc−リツキシマブ(2)が得られたことが示された。反応混合物を、上述した手順に従ってタンパク質Aのカラム上で親和クロマトグラフィにかけた。産物を含有するフラクションを化合させ、超遠心分離で濃縮してGlcNAc−リツキシマブ(2)(2mg、定量)が得られた。LC−MS:GlcNAc部分を保有するGlcNAc−リツキシマブ(2)の重鎖に対し計算、M=49274Da、(m/z)49274であることが判明(逆畳込み解析データ)。
[00125] トリス緩衝液(50mM、pH7.4、0.5mL)にGlcNAc−リツキシマブ(4)(2mg)及びオキサゾリン(5)(5mg)を入れた溶液を、エンドS−D233Q(200μg)で37℃でインキュベートした。間隔をあけてアリコートを採取し、LC−MSで分析した。2時間後、LC−MSのモニタリングで、4が完全に反応し、対応するグリコシル転移産物(6)が得られたことが示された。反応混合物をタンパク質Aのカラム上で親和クロマトグラフィにかけた。産物を含有するフラクションを化合させ、超遠心分離で濃縮して、非フコシル化リツキシマブグリコフォーム(6)(2mg、定量)が得られた。LC−MS:非フコシル化N−グリカンを保有する(6)の重鎖に対し計算、M=50693Da、(m/z)50695であると判明(逆畳込み解析データ)。
[00127] トリス−Cl緩衝液(50mM、pH8.0、2mL)中に市販のIVIG(20mg)をエンドS(配列番号:1)(30μg)で1時間、37℃でインキュベートした。残基をタンパク質Aのカラム上で親和クロマトグラフィにかけ、(Fucα1,6)GlcNAc−IVIG(20mg、定量)が得られ、このFc N−グリカンを除去して、N297部位にα1,6−フコシル化GlcNAcを残した。
[00129] トリス緩衝液(50mM、pH7.4、2mL)中に(Fucα1,6)GlcNAc−IVIG(3mg)及びシアログリカン−オキサゾリン(2)(3mg)を入れた溶液をD233Q突然変異体(配列番号:2)(60μg)で30℃でインキュベートした。2時間後、SDS−PAGE分析で、(Fucα1,6)GlcNAc−IVIGが完全に反応し、グリコシル転移産物が得られたことが示された。反応混合物をタンパク質Aのカラム上で親和クロマトグラフィにかけ、グリコ−リモデリングしたIVIG(3mg、定量)が提供され、そのFc N−グリカンをリモデリングして、完全にシアル酸付加した複合型N−グリカンにした。
[00131] Biacore T100計器(GE Healthcare、米国)を使用し、表面プラズモン共鳴(SPR)でIgG及びFcγ受容体の様々なグリコフォーム間の結合を測定した。標準的な第一アミンカップリング化学を用いてpH4.5でCM5バイオセンサチップ(Ge Healthcare)上に5000RUのタンパク質Aを固定化し、IgGの様々なグリコフォームを捕捉した。タンパク質Aを注入せずに、基準のフローセルを同様に調製した。HBS−P緩衝液(10mMのHEPES、pH7.4、0.15MのNaCl、0.05%v/v界面活性剤P20)にIgGの個々の各グリコフォームを入れて10μL/分でタンパク質Aの表面上に注入し、150RUの捕捉レベルに達した。FcγIIIa及びFcγIIb受容体の連続希釈を10μL/分で注入した。各サイクルの後、10mMのHClを10μL/分で30秒注入することにより、表面を再生した。BIAcore T100評価ソフトウェアを使用してデータを1:1 Langmuir結合モデルに当てはめ、平衡定数(KD)データを取得した。
[00134] 本明細書で引用された全ての参照文献の内容は、全ての目的のために参照により本明細書に組み込まれる。
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Claims (15)
- 所定のオリゴ糖部分を有するコアフコシル化若しくは非フコシル化抗体又はそのFcフラグメントを調製する方法であって、
コアフコシル化若しくは非フコシル化GlcNAc−アクセプタを含む抗体又はFcフラグメントを提供するステップと、
化膿性連鎖球菌(Streptococcus pyogenes)エンドグリコシダーゼ−S Asp233突然変異体を使用して、前記コアフコシル化又は非フコシル化GlcNAc−アクセプタを活性オリゴ糖供与体と酵素的に反応させるステップであって、前記活性オリゴ糖供与体が、所定の数及びタイプの糖残基を含むオリゴ糖部分を保持し、酵素反応を介して、前記活性オリゴ糖供与体が前記コアフコシル化又は非フコシル化GlcNAc−アクセプタと共有結合し、それによって前記所定のオリゴ糖部分を有する前記フコシル化若しくは非フコシル化抗体又はFcフラグメントを調製するステップと、
を含み、
前記突然変異体が、D233Q(配列番号:2)部位特異的突然変異又はD233A(配列番号:3)部位特異的突然変異を含む突然変異体から選択される、方法。 - 前記活性オリゴ糖供与体が、合成オリゴ糖オキサゾリン又はシアル酸付加オキサゾリンである、請求項1に記載の方法。
- 前記合成オリゴ糖オキサゾリンが、二糖、三糖、四糖、五糖、六糖、七糖、八糖、九糖、十糖、又は十一糖オキサゾリンである、請求項2に記載の方法。
- 前記活性オリゴ糖供与体が、付加的な生物活性治療剤又はタグをさらに含む、請求項1〜3のいずれか1項に記載の方法。
- 前記付加的な生物活性治療剤又はタグが、薬物、毒素、蛍光プローブ、ビオチン、PEG、脂質、又はポリペプチドである、請求項4に記載の方法。
- 前記コアフコシル化GlcNAc−アクセプタが、アルファ−1−6−フコシル−GlcNAc含有抗体又はFcフラグメントである、請求項1〜5のいずれか1項に記載の方法。
- 前記コアフコシル化又は非フコシル化抗体が、17b、48d、A32、C11、2Gl2、F240、IgGlb12、19e、X5、TNX−355、セツキシマブ、リツキシマブ、ムロモナブ−CD3、アブシキマブ、ダクリズマブ、バシリキシマブ、パリビズマブ、インフリキシマブ、トラスツズマブ、ゲムツズマブ・オゾガミシン、アレムツズマブ、イブリツモマブ・チウキセタン、アダリムマブ、オマリズマブ、トシツモマブ、I−131トシツモマブ、エファリズマブ、ベバシズマブ、パニツムマブ、ペルツズマブ、ナタリズマブ、エタネルセプト、IGN101、ボロシキマブ、抗CD80mAb、抗CD23mAb、CAT−3888、CDP−791、エラプツズマブ、MDX−010、MDX−060、MDX−070、マツズマブ、CP−675,206、CAL、SGN−30、ザノリムマブ、アデカツムマブ、オレゴボマブ、ニモツズマブ、ABT−874、デノスマブ、AM108、AMG714、フォントリズマブ、ダクリズマブ、ゴリムマブ、CNTO 1275、オクレンズマブ、HuMax−CD20、ベリムマブ、エプラツズマブ、MLN1202、ビジリズマブ、トシリズマブ、オクレリズマブ、セルトリズマブペゴル、エクリズマブ、パキセリズマブ、アブシキシマブ、ラニビジムマブ、メポリズマブ及びMYO−029からなる群から選択されるモノクローナル抗体である、請求項1〜6のいずれか1項に記載の方法。
- 前記抗体が、がんを治療する治療剤、HIVの治療剤、毒素、別の受容体に反応する前記修飾抗体とは異なる抗体、抗原、ケモカイン及びサイトカインからなる群から選択される付加部分をさらに含む、請求項1に記載の方法。
- 均一なコアフコシル化若しくは非フコシル化IgG糖タンパク質又はIgG−Fcフラグメントを合成する方法であって、
(a)不均一な又は望ましくないN−グリカンを含むコアフコシル化若しくは非フコシル化IgG糖タンパク質又はIgG−Fcフラグメントを提供するステップと、
(b)コア均一なフコシル化又は非フコシル化GlcNAc−IgGアクセプタを形成するために、エンド−H、エンド−F3、エンドS及びエンド−Aからなる群から選択された酵素を用いて前記不均一な又は望ましくないN−グリカンを除去するステップと、
(c)規定された数及びタイプの糖残基を有するN−グリカンを含む所望のオリゴ糖成分を有する、オリゴ糖含有オキサゾリンを提供するステップと、
(d)化膿性連鎖球菌エンド−S Asp233突然変異体を使用して、前記オリゴ糖含有オキサゾリンで前記コアフコシル化又は非フコシル化GlcNAc−IgGアクセプタを酵素的にグリコシル転移し、それによって前記規定された数及びタイプの糖残基を有する均一なコアフコシル化若しくは非フコシル化IgG糖タンパク質又はIgG−Fcフラグメントを形成するステップと、
を含み、
前記突然変異体が、D233Q(配列番号:2)部位特異的突然変異又はD233A(配列番号:3)部位特異的突然変異を含む突然変異体から選択される、方法。 - 前記オリゴ糖含有オキサゾリンが、二糖、三糖、四糖、五糖、六糖、七糖、八糖、九糖、十糖、又は十一糖オキサゾリンである、請求項9に記載の方法。
- 前記コア−フコシル化GlcNAcアクセプタが、アルファ−1−6−フコシル−GlcNAc含有抗体又はFcフラグメントである、請求項9又は10に記載の方法。
- 修飾抗体又はそのFc−フラグメントを合成する方法であって、
GlcNAc−タンパク質アクセプタを形成するために、フコシル化若しくは非フコシル化N−アセチルグルコサミン(GlcNAc)部分を含む抗体又はFcフラグメントを提供するステップであって、前記フコシル化又は非フコシル化N−アセチルグルコサミン(GlcNAc)部分が前記抗体の前記Fc領域に位置するステップと、
所定の数の糖を有する前記修飾抗体又はそのFcフラグメントを形成するために、化膿性連鎖球菌エンド−S Asp233突然変異体酵素の触媒で、前記所定の数の糖を有するオリゴ糖オキサゾリンと前記GlcNAc−タンパク質アクセプタをグリコシル転移するステップと、
を含み、
前記突然変異体酵素が、D233Q(配列番号:2)部位特異的突然変異又はD233A(配列番号:3)部位特異的突然変異を含む突然変異体から選択される、方法。 - 前記修飾抗体が、がんを治療する治療剤、HIVの治療剤、毒素、別の受容体に反応する前記修飾抗体とは異なる抗体、抗原、治療用ポリペプチド、前記オリゴ糖オキサゾリンに結合したケモカイン及び/又はサイトカインを含む付加部分をさらに含む、請求項12に記載の方法。
- Fc−シアル酸付加グリコフォームを示す静脈内免疫グロブリン(IVIG)製剤を合成する方法であって、
Fc N−グリカンを保有するIVIGを提供するステップと、
GlcNAc−アクセプタを形成するためにエンド−H、エンド−F3、エンドS及びエンド−Aからなる群から選択されるエンドグリコシダーゼを使用して前記Fc N−グリカンを脱グリコシル化するステップであって、前記GlcNAc−アクセプタが前記IVIGの前記Fc領域に位置し、前記GlcNAc−アクセプタがコアフコシル化又は非フコシル化されるステップと、
シアル酸付加IVIGを形成するために、配列番号:2及び配列番号:3を含むエンド−S突然変異体からなる群から選択される酵素の触媒で、所定の数の糖残基を有するシアログリカンオキサゾリンで前記IVIG上の前記GlcNAc−アクセプタをグリコシル転移するステップと、
を含む方法。 - D233Q(配列番号:2)及びD233A(配列番号:3)からなる群から選択される少なくとも1つの化膿性連鎖球菌エンド−S Asp−233突然変異体を含む組成物。
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