JP7270379B2 - Siglec中和抗体 - Google Patents
Siglec中和抗体 Download PDFInfo
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- JP7270379B2 JP7270379B2 JP2018546850A JP2018546850A JP7270379B2 JP 7270379 B2 JP7270379 B2 JP 7270379B2 JP 2018546850 A JP2018546850 A JP 2018546850A JP 2018546850 A JP2018546850 A JP 2018546850A JP 7270379 B2 JP7270379 B2 JP 7270379B2
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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
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- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
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Description
本願は、任意の図面および配列表を含む、その全体において参照により本明細書中に組み込まれる2016年3月8日提出の米国仮特許出願第62/304,957号明細書の利益を主張する。
本願は、電子方式の配列リストと共に提出されている。本配列リストは、2017年2月22日作成の「Sig792PCT_ST25txt」という名称で提供されており、サイズは124kBである。本配列リストの電子方式の情報は、その全体において参照により本明細書中に組み込まれる。
(a)(i)配列番号3の重鎖可変領域のCDR1、2および3を含む重鎖と、(ii)配列番号4の軽鎖可変領域のCDR1、2および3を含む軽鎖とを含むモノクローナル抗体、
(b)(i)配列番号5の重鎖可変領域のCDR1、2および3を含む重鎖と、(ii)配列番号6の軽鎖可変領域のCDR1、2および3を含む軽鎖とを含むモノクローナル抗体、
(c)(i)配列番号7の重鎖可変領域のCDR1、2および3を含む重鎖と、(ii)配列番号8の軽鎖可変領域のCDR1、2および3を含む軽鎖とを含むモノクローナル抗体、
(d)(i)配列番号9の重鎖可変領域のCDR1、2および3を含む重鎖と、(ii)配列番号10の軽鎖可変領域のCDR1、2および3を含む軽鎖とを含むモノクローナル抗体、
(e)(i)配列番号11の重鎖可変領域のCDR1、2および3を含む重鎖と、(ii)配列番号12の軽鎖可変領域のCDR1、2および3を含む軽鎖とを含むモノクローナル抗体、および
(f)(i)配列番号13の重鎖可変領域のCDR1、2および3を含む重鎖と、(ii)配列番号14の軽鎖可変領域のCDR1、2および3を含む軽鎖とを含むモノクローナル抗体、
(g)(i)配列番号15の重鎖可変領域のCDR1、2および3を含む重鎖と、(ii)配列番号16の軽鎖可変領域のCDR1、2および3を含む軽鎖とを含むモノクローナル抗体、
(h)(i)配列番号17の重鎖可変領域のCDR1、2および3を含む重鎖と、(ii)配列番号18の軽鎖可変領域のCDR1、2および3を含む軽鎖とを含むモノクローナル抗体、
(i)(i)配列番号19の重鎖可変領域のCDR1、2および3を含む重鎖と、(ii)配列番号20の軽鎖可変領域のCDR1、2および3を含む軽鎖とを含むモノクローナル抗体、
(j)(i)配列番号21の重鎖可変領域のCDR1、2および3を含む重鎖と、(ii)配列番号22の軽鎖可変領域のCDR1、2および3を含む軽鎖とを含むモノクローナル抗体、
(k)(i)配列番号23の重鎖可変領域のCDR1、2および3を含む重鎖と、(ii)配列番号24の軽鎖可変領域のCDR1、2および3を含む軽鎖とを含むモノクローナル抗体、および
(l)(i)配列番号25の重鎖可変領域のCDR1、2および3を含む重鎖と、(ii)配列番号26の軽鎖可変領域のCDR1、2および3を含む軽鎖とを含むモノクローナル抗体
からなる群から選択される抗体の重鎖および軽鎖CDR1、2および3を含むか、あるいはその抗体と同じエピトープに結合し、かつ/またはSiglec-7および/もしくはSiglec-9ポリペプチドへの結合についてその抗体と競合する抗原結合化合物が提供される。
(a)Siglec-9ポリペプチドに結合する複数の抗体を提供するステップと、
(b)(任意選択により、初代ヒトNK細胞、例えばCD56dimNK細胞における)Siglec-9ポリペプチドの阻害活性を中和する抗体(例えば、ステップ(a)のもの)を選択するステップと、
(c)Siglec-9ポリペプチドとそのシアル酸リガンドとの間の相互作用を実質的に阻止しない抗体(例えば、ステップ(b)のもの)を選択するステップと
を含む方法が提供される。ある実施形態において、Siglec-9ポリペプチドは、細胞、例えばCHO細胞、リンパ球、NK細胞の表面で発現される。
(a)Siglec-9ポリペプチドに結合する複数の抗体を提供するステップと、
(b)(任意選択により、初代ヒトNK細胞、例えばCD56dimNK細胞における)Siglec-9ポリペプチドの阻害活性を中和する抗体(例えば、ステップ(a)のもの)を選択するステップと、
(c)Siglec-9ポリペプチドとそのシアル酸リガンドとの間の相互作用を実質的に阻止する抗体(例えば、ステップ(b)のもの)を選択し、任意選択により、Neu5Aca2-3Galb1-4GlcNAcbおよびSiglec-9の6’-シアリルラクトースシアル酸リガンドの両方を阻止する抗体を選択するステップと
を含む方法が提供される。
(a)Siglec-7ポリペプチドに結合する複数の抗体を提供するステップと、
(b)Siglec-7ポリペプチドの阻害活性を中和する抗体(例えば、ステップ(a)のもの)を選択するステップと、
(c)Siglec-7ポリペプチドとそのシアル酸リガンドとの間の相互作用を実質的に阻止しない抗体(例えば、ステップ(b)のもの)を選択するステップと
を含む方法が提供される。ある実施形態において、Siglec-7ポリペプチドは、細胞、例えばCHO細胞、リンパ球、NK細胞の表面で発現される。
(a)Siglec-9およびSiglec-7ポリペプチドに結合する複数の抗体を提供するステップと、
(b)(任意選択により、初代ヒトNK細胞、例えばCD56brightおよびCD56dimNK細胞における)Siglec-9ポリペプチドおよびSiglec-7ポリペプチドの阻害活性を中和する抗体(例えば、ステップ(a)のもの)を選択するステップと
を含む方法が提供される。
本明細書で使用される場合、「1つの(a)」または「1つの(an)」は1つ以上を意味し得る。請求項で使用される場合、「含む」という語と組み合わせて使用されるとき、「1つの(a)」または「1つの(an)」という語は、1つまたは2つ以上を意味し得る。本明細書中で使用される場合、「別の」は、少なくとも第2またはそれを超えるものを意味し得る。
疾患(例えば、癌、感染性疾患)の治療に有用な抗Siglec剤は、ヒトSiglec-9タンパク質の細胞外部分に結合し(および任意選択により、さらなるSiglec-12結合を伴うまたは伴わないヒトSiglec-7タンパク質にさらに結合する)、Siglec陽性免疫細胞の表面上に発現されたヒトSiglecの阻害活性を低下させる。ある実施形態において、本剤は、好中球、樹状細胞、マクロファージ、M2マクロファージ、NK細胞および/またはCD8+T細胞において、シアル酸分子がSiglecによる阻害シグナル伝達を引き起こす能力を阻害する。
抗体mAb1、-2、-3、-4、-5、-6、-A、-B、-C、-D、-Eおよび-Fの重鎖および軽鎖可変領域のアミノ酸配列を示す。具体的な実施形態において、モノクローナル抗体mAb1、-2、-3、-4、-5、-6、-A、-B、-C、-D、-Eまたは-Fと同じエピトープまたは決定基と基本的に結合する抗体を提供し、任意選択により、本抗体は、抗体mAb1、-2、-3、-4、-5、-6、-A、-B、-C、-D、-Eまたは-Fの超可変領域を含む。本明細書中の実施形態の何れかにおいて、抗体mAb1、-2、-3、-4、-5、-6、-A、-B、-C、-D、-Eまたは-Fは、アミノ酸配列および/またはそれをコードする核酸配列によって特徴付けられ得る。ある実施形態において、モノクローナル抗体は、mAb1、-2、-3、-4、-5、-6、-A、-B、-C、-D、-Eまたは-FのVHおよび/もしくはVL、またはFabもしくはF(ab’)2部分を含む。mAb1の重鎖可変領域を含むモノクローナル抗体も提供される。ある実施形態によれば、本モノクローナル抗体は、mAb1、-2、-3、-4、-5、-6、-A、-B、-C、-D、-Eまたは-Fの重鎖可変領域の3つのCDRを含む。mAb1、-2、-3、-4、-5、-6、-A、-B、-C、-D、-Eまたは-Fの可変軽鎖可変領域またはmAb1、-2、-3、-4、-5、-6、-A、-B、-C、-D、-Eまたは-Fの軽鎖可変領域のCDRの1、2または3つをさらに含むモノクローナル抗体も提供される。任意選択により、前記軽鎖または重鎖CDRの何れか1つ以上は、1、2、3、4もしくは5つまたはそれを超えるアミノ酸修飾(例えば、置換、挿入または欠失)を含有し得る。任意選択により、抗体mAb1の抗原結合領域の一部または全てを含む軽鎖および/または重鎖可変領域の何れかが、ヒトIgG型の免疫グロブリン定常領域、任意選択により、ヒト定常領域、任意選択により、ヒトIgG1、IgG2、IgG3またはIgG4アイソタイプと融合され、任意選択により、エフェクター機能(ヒトFcγ受容体への結合)を低下させるためにアミノ酸置換をさらに含む抗体が提供される。
1mg/mL~500mg/mLの濃度で含む医薬処方物中に抗Siglec抗体が組み込まれ得、前記処方物のpHは2.0~10.0である。本処方物は、緩衝液系、保存剤、等張化剤、キレート剤、安定化剤および界面活性剤をさらに含み得る。ある実施形態において、医薬処方物は、水性処方物、すなわち水を含む処方物である。このような処方物は、一般に溶液または懸濁液である。さらなる実施形態において、本医薬処方物は水性溶液である。「水性処方物」という用語は、少なくとも50%w/wの水を含む処方物として定義される。同様に「水溶液」という用語は、少なくとも50%w/wの水を含む溶液として定義され、「水性懸濁液」という用語は、少なくとも50%w/wの水を含む懸濁液として定義される。
本明細書中に記載のような抗Siglec抗体を使用して、個体、とりわけヒト患者を処置する方法も提供される。ある実施形態において、本発明は、ヒト患者への投与のための医薬組成物の調製における本明細書中で記載のような抗体の使用を提供する。一般的には、患者は、癌または感染性疾患、例えば細菌性またはウイルス性疾患に罹患しているか、またはそのリスクがある。
a)癌を有する個体内の悪性細胞(例えば、腫瘍細胞)がSiglec-7のリガンドおよび/またはSiglec-9のリガンドを発現するか否かを決定することと、
b)悪性細胞(例えば、腫瘍細胞)(の例えば表面上)によりSiglec-7のリガンドおよび/またはSiglec-9のリガンドが顕著に発現されると判定されたら、それぞれの抗Siglec7および/または-9抗体、例えば本開示の何れかの態様に従う抗体をその個体に投与することと
を含む。
CD33関連Siglecの中でも、Siglec-7(CD328)およびSiglec-9(CD329)は、癌細胞により過剰発現されるグリカンを含め、シアル酸に対する結合の特性を共有し、それらが発現される免疫細胞において阻害受容体として機能すると考えられる。リンパ球上でのSiglecの発現を調べるために、ヒトNK細胞上でのSiglec-7およびSiglec-9の分布を調べた。
抗ヒトSiglec-7およびSiglec-9抗体を得るために、ヒトSiglec-7 FcおよびヒトSiglec-9 Fc細胞外ドメイン組み換えタンパク質を用いてBalb/cマウスに免疫付与を行った。2つの異なる免疫化を行った。
Siglec-7および-9と配列類似性を共有するCD33関連Siglecは、一般に、2つの群、Siglec-1、-2、-4および-15から構成される第1のサブセットと、Siglec-3、-5、-6、-7、-8、-9、-10、-11、-12、-14および-16を含むSiglecのCD33関連群とに分けられる。他のCD33関連Siglecは異なる生物学的機能を有し、および/または腫瘍監視に関与しないと考えられるため、他のCD33関連Siglecに結合しない交差反応性Siglec-7/9抗体を得ることが可能か否かを評価するために抗体をさらにスクリーニングした。
ヒトSiglec-7、ヒトSiglec-9およびカニクイザルSiglec-9における抗体の結合を、ヒトSiglec-7およびヒトSiglec-9およびカニクイザルSiglec-9で遺伝子移入したCHO細胞でのフローサイトメトリーによる滴定実験によって試験した。細胞を、一次抗体を20μg/mlとし、かつ一連の希釈率1:5において染色緩衝液(SB)中で1時間温置した。それらをSBで3回洗浄し、次いでヤギF(ab’)2抗ヒトIgG(Fc)PE(Beckman Coulter#IM05510)で30分間温置し、SBで2回洗浄した。HTFC Intellicytサイトメーターで蛍光を明らかにした。
Biacore(商標)T100の一般手順および試薬
SPR測定は、Biacore(商標)T200装置(Biacore(商標)GE Healthcare)で25℃において行った。全てのBiacore(商標)実験において、HBS-EP+(Biacore(商標)GE Healthcare)およびNaOH 10mMは、ランニング緩衝液および再生緩衝液としてそれぞれ機能した。センサーグラムは、Biacore(商標)T200評価ソフトウェアを用いて分析した。ヒトSiglec-9および-7多量体タンパク質をInnate Pharmaでクローニングし、産生させ、精製した。
タンパク質をSensor Chip CM5上のデキストラン層のカルボキシル基に共有結合的に固定化した。チップ表面をEDC/NHS(N-エチル-N’-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩およびN-ヒドロキシスクシンイミド(Biacore(商標)、GE Healthcare)で活性化した。タンパク質を結合緩衝液(10mM酢酸塩、pH4.2および5.0)中で10μg/mlに希釈し、適切な固定化レベルに達するまで(すなわち600~2000RU)注入した。残りの活性化された基の失活は、100mMエタノールアミンpH8(Biacore(商標)、GE Healthcare)を用いて行った。
親和性研究は、製造業者(Biacore(商標)GE Healthcare kinetic wizard)によって推奨される標準的なKineticプロトコールに従って実施した。600nM~0.975nMの範囲の抗Siglec-9および-7/9抗体Fab断片の連続的希釈物を固定化Siglec-9FcおよびSiglec-7Fcタンパク質上に順次注入し、再分化前に10分間分離させた。センサーグラムセット全体を、1:1動態結合モデルを用いてフィッティングした。一価の親和性および動態学的会合および解離速度定数を以下の表2に示す。
単球由来樹状細胞(moDC)の生成:
単球由来の樹状細胞は、末梢血単核球から生成した。健常ドナーから得られた軟膜からPBMCを単離した。単球をキットMonocyte Isolation Kit II(Miltenyi Biotec)を用いて精製し、10%不活性化FBS(GIBCO)、グルタミン(GIBCO)、MEM NEAA(GIBCO)、ピルビン酸ナトリウム(GIBCO)、IL-4(20ng/ml)(Peprotech)およびGM-CSF(400ng/ml)(Miltenyi Biotec)を添加したRPMI培地(GIBCO)中で合計6日間にわたりmoDC中で分化させた。細胞を37℃の加湿CO2恒温器で培養し、サイトカインを4日目に更新した。
moDCおよびノイラミニダーゼで処理したmoDCに対する結合をフローサイトメトリーによる滴定実験で試験した。細胞を、一次抗体を10μg/mlとし、かつおよび一連の希釈率1:10で染色緩衝液(SB)中において1時間温置した。それらをSBで2回洗浄し、次いでヤギF(ab’)2抗ヒトIgG(Fc)PE(Jackson Immunoresearch)で30分間温置し、SBで2回洗浄した。蛍光をHTFC Intellicytサイトメーターで明らかにした。
EC50はノイラミニダーゼ処理後に高度に増強され(10倍)、これは、moDC上に発現したSiglec-9がノイラミニダーゼ処理前のシアル酸リガンドとのシス相互作用に関与していることを示唆する。しかし、プラトー相レベルは改変されておらず、高親和性抗体は細胞表面上の全てのSiglec-9(結合および非結合)立体構造に結合することができ、monoDCならびに他の細胞型(例えば、NK細胞、CD8 T細胞、単球ならびにマクロファージM1およびM2)におけるシス相互作用およびシグナル伝達を阻害することを示唆する。結果は、moDC(左側パネル)およびノイラミダーゼ処理moDC(右側パネル)における代表的な抗体mAbA、mAbCおよびmAbDについて、それぞれEC50値を伴って図3に示す。
初代NK細胞(ヒトドナーから精製され、使用前に37℃で一晩温置した新鮮なNK細胞)を用いたNK細胞活性化アッセイにおいて、Siglec活性の阻止について、第1および第2の免疫付与において試験した抗Siglec-7/9抗体を試験した。24時間でのCD137発現上昇は、NK細胞を含む一部のリンパ球の活性化と相関する(Kohrt et al.(2011)Blood 117(8):2423-2432)。フローサイトメトリーによるNK細胞上でのCD137発現の分析により、NK細胞活性化における抗Siglec-7/9抗体の効果および標的細胞の脱シアル化を判定した。抗Siglec-7/9mAb mAb1、mAb2、mAb3、mAb4、mAb5およびmAb6は、それぞれ24時間でCD137発現の増加を誘導した。
本発明者らは、以前の抗体がNK細胞においてSiglec-9を中和し得ないことが、例えば、その表面においてSiglec-9をより高いレベルで発現する好中球および他の細胞と比較した、初代NK細胞におけるSiglec-9発現の差異および異なるNK細胞サブセットで発現されるSiglec-7に関連し得る可能性を考慮した。NK細胞においてSiglec-9を中和する抗体を得ることができるかどうかを調べるために、本発明者らは、フローサイトメトリーによってSiglec-9上でゲートされた多数のヒトドナー由来の初代NK細胞において抗体を研究および選択した。抗Siglec-9抗体の効果を、古典的51Cr放出アッセイにおいて腫瘍細胞溶解を評価することにより、およびNK細胞上のCD137表面発現を評価することによる活性化アッセイにより、細胞傷害性によって研究した。それぞれの場合において、エフェクター細胞として初代NK細胞(ドナーから精製された新鮮なNK細胞として)を使用し、HT29結腸直腸癌細胞株を標的として使用した。
細胞傷害性アッセイは、51Cr負荷標的細胞の溶解を直接定量することによってNK細胞の細胞傷害性を測定した。簡潔に述べると、標的細胞をまず放射性51Cr同位体で標識し、次にエフェクター細胞と共に37℃で4時間共温置した。この間に、NK細胞に感受性である標的細胞を溶解し、51Crを培地に放出させた。回収された上清中の51Crは、液体シンチレーション測定によって測定した。得られた結果は、NK細胞による標的細胞の溶解パーセントの評価を可能にする。完全RPMI中、200μL最終/ウェル、E:T比8/1において96Uウェルプレートでアッセイを行った。抗Siglec-9抗体およびアイソタイプ対照を10μg/mlで添加した。
フローサイトメトリーによるSiglec-9陽性NK細胞上のCD137発現の分析により、抗Siglec-7/9および抗Siglec-9抗体のNK細胞活性化における効果を決定した。エフェクター細胞は初代NK細胞(ドナーから精製された新鮮なNK細胞、使用前に37℃で一晩温置)であり、標的細胞(HT29細胞株)は1:1の比率で混合した。完全RPMI中、200μL最終/ウェルにおいて96UウェルプレートでCD137アッセイを行った。抗体をエフェクター細胞と共に37℃で30分間予備温置し、次いで標的細胞を37℃で一晩共温置した。ステップは以下の通りである:500gで3分間スピン;染色緩衝液(SB)で2回洗浄;50μLの染色Ab混合液(抗CD3 パシフィックブルー-BD Pharmingen;抗CD56-PE-Vio770(Miltenyi);抗CD137-APC(Miltenyi)、抗Siglec-9 K8-PE(Biolegend))の添加;4℃で30分間の温置;SBで2回洗浄;SBでペレットを再懸濁;およびCanto II(HTS)で明らかにした蛍光。
1つの抗Siglec-9(mAb.A)および1つの抗Siglec-7/9(mAb1)を用いて、6人のドナーで実験を再現した。抗体の非存在下において(「中」設定)、NK発現CD137の%は、ドナー間で6%~27%で変動した((図7、左側パネル)を参照されたい)。データは、各実験からの対照中央値と比較して相対的な変化であるように標準化された:((X-X中央値))/X中央値(%)。図7に示すように、mAbAおよびmAb1は、Siglec-9+ CD137+NK%の増加を誘導し(図7、中央パネル)、Siglec-9-CD137+NK%の増加を誘導しなかった(図7、右側パネル)。
新鮮な精製ヒトNK細胞に対する抗体の結合をフローサイトメトリーによる滴定実験によって試験した。細胞を、一次抗体を10μg/mlとし、かつ一連の希釈率1:10において染色緩衝液(SB)中で1時間温置した。それらをSBで3回洗浄し、次いでヤギF(ab’)2抗ヒトIgG(Fc)PE(Jackson ImmunoResearch)で30分間温置した。染色はBD FACS CantoIIで行い、FlowJoソフトウェアを用いて分析した。以下の表にEC50値をμg/mlで示す(4パラメーターロジスティックフィットを用いて計算した)。
パートA:フローサイトメトリーによるシアル酸発現腫瘍細胞へのSiglec-9結合の阻止
用量範囲の抗ヒトSiglec-9 Fabを室温で30分にわたりヒトSiglec-9Fc融合組み換えタンパク質と固定用量で共温置し、次いで様々なシアル酸発現細胞株K562 E6(ヒトHLA-Eで遺伝子移入したK562細胞株)およびRamosを1時間にわたり添加した。染色緩衝液で細胞を2回洗浄した後、染色緩衝液で希釈したPE結合ヤギ抗マウスIgGFcフラグメント二次抗体(Jackson Immunoresearch)を細胞に添加し、プレートを4℃でさらに30分間温置した。細胞を2回洗浄し、HTFCプレートリーダーを備えたAccury C6フローサイトメーターで分析した。蛍光強度の平均対FabとSiglec-9Fc融合組み換えタンパク質の比をグラフにプロットした。
シアル酸は、グリコシル化タンパク質および形成脂質上の9炭素カルボキシル化単糖である。シアリルトランスフェラーゼ(それらの生合成を触媒する)およびノイラミニダーゼとも呼ばれるシアリダーゼ(それらの切断を触媒する)を含むいくつかの酵素は、哺乳動物系におけるそれらの発生を調整する。癌において、改変されたシアル酸プロファイルは、腫瘍成長、転移および免疫監視回避を増強し、癌細胞の生存につながる支配的な役割を果たす(Bork et al.,J Pharm Sci.2009 Oct;98(10):3499-508)。増加したシアル酸付加は、シアル酸付加を制御する改変された酵素プロファイルと共にいくつかの癌において報告されている。ST3GAL6酵素は、多発性骨髄腫細胞株および患者において過剰発現され、多発性骨髄腫細胞の表面上のα-2,3結合シアル酸の発現とインビトロで関連する。インビボでは、ST3GAL6ノックダウンは、腫瘍負荷の減少および生存期間の延長に加えて、骨髄微小環境への多発性骨髄腫細胞のホーミングおよび生着の減少に関連する(Glavey et al.,Blood.2014 Sep 11;124(11):1765-76)。グリオーマにおける高いST3GAL1酵素発現は、間葉系分子分類のより高い腫瘍等級と関連している(Chong et al.,Natl Cancer Inst.2015 Nov 7;108(2)。プロモーターのメチル化異常は、癌におけるいくつかのシアリルトランスフェラーゼ発現の調整において役割を果たす(Vojta et al.,Biochim Biophys Acta.2016 Jan 12)。膀胱癌では、ST6GAL1プロモーターのメチル化異常がST6Gal1の発現低下を誘導する(Antony et al.,BMC Cancer.2014 Dec 2;14:901)。
抗Siglec-9抗体のエピトープを定義するために、本発明者らは、まずHEK293T細胞中のタグV5を用いて各単一Siglec-9ドメイン(V-セットIg様ドメイン、Ig様C2型ドメイン1、およびIg様C2型ドメイン2)を発現させ、抗体の各タンパク質への結合を試験することによって本抗体の結合ドメインを同定した。
Siglec-9突然変異体をPCRにより生成した。増幅した配列をアガロースゲル上に流し、Macherey Nagel PCR Clean-Up Gel Extractionキットを用いて精製した。各突然変異体について生成した精製PCR産物を、ClonTech InFusion(商標)システムを用いて発現ベクターに連結した。突然変異した配列を含むベクターをMiniprepとして調製し、配列決定した。配列決定後、突然変異した配列を含むベクターを、Promega PureYield(商標)Plasmid Midiprep Systemを用いてMidiprep(商標)として調製した。HEK293T細胞をDMEM培地(Invitrogen)中で増殖させ、InvitrogenのLipofectamine(商標)2000を用いてベクターで遺伝子移入し、導入遺伝子の発現を試験する前にCO2恒温器中において37℃で24時間または48時間温置した。
抗体mAb4、mAb5およびmAb6はIg様C2型ドメイン1に結合し、mAb、mAbB、mAbD、mAbE mAbF、mAb1、mAb2およびmAb3はN末端V-セットIg様ドメインに結合した。V-セットIg様ドメイン結合抗体をフローサイトメトリーによって突然変異体1~16のそれぞれへのそれらの結合について試験した。1つの濃度で1つまたは複数の突然変異体への結合を失う抗体を決定するために第1の実験を行った。結合の喪失を確認するために、結合がSiglec-9突然変異によって影響を受けていると思われる抗体について抗体の滴定を行った。結果を以下の表4に示す。
Claims (17)
- ヒトSiglec-9ポリペプチドに結合し、かつヒトNK細胞によって発現されるSiglec-9ポリペプチドの阻害活性を中和することができる単離抗体であって、
前記抗体が、
(a)(i)配列番号15のアミノ酸配列を有する重鎖可変領域と(ii)配列番号16のアミノ酸配列を有する軽鎖可変領域とを含む抗体、
(b)(i)配列番号17のアミノ酸配列を有する重鎖可変領域と(ii)配列番号18のアミノ酸配列を有する軽鎖可変領域とを含む抗体、
(c)(i)配列番号19のアミノ酸配列を有する重鎖可変領域と(ii)配列番号20のアミノ酸配列を有する軽鎖可変領域とを含む抗体、および
(d)(i)配列番号21のアミノ酸配列を有する重鎖可変領域と(ii)配列番号22のアミノ酸配列を有する軽鎖可変領域とを含む抗体、
からなる群から選択される、
単離抗体。 - Siglec-9を発現するNK細胞がヒトドナーから精製され、かつSiglec-9のシアル酸リガンドを発現する標的細胞と温置される標準的な4時間のインビトロ51Cr放出細胞傷害性アッセイにおいて、NK細胞の細胞傷害性を増強および/または回復させる、請求項1に記載の抗体。
- ヒトmoDCであって、シアル酸とのシス相互作用に関与するSiglec-9ポリペプチドをその表面に保有するヒトmoDCによって発現されるSiglec-9ポリペプチドの阻害活性を中和することができる、請求項1~2の何れか一項に記載の抗体。
- CD16ヒトFcγ受容体に結合する能力を欠く、請求項1~3の何れか一項に記載の抗体。
- ヒトCD16A、CD16B、CD32A、CD32BおよびCD64に結合する能力を欠く、請求項1~4の何れか一項に記載の抗体。
- ヒトSiglec-9ポリペプチドとそのシアル酸リガンドとの間の相互作用を実質的に阻止する、請求項1~5の何れか一項に記載の抗体。
- (a)ヒトSiglec-9ポリペプチドとNeu5Aca2-3Galb1-4GlcNAcbとの間の相互作用を実質的に阻止し、かつ(b)ヒトSiglec-9ポリペプチドと6’-シアリルラクトースとの間の相互作用を実質的に阻止する、請求項6に記載の抗体。
- 配列番号2のアミノ酸配列を含むSiglec-9ポリペプチドおよび配列番号160のアミノ酸配列を含むSiglec-9ポリペプチドに結合する、請求項1~7の何れか一項に記載の抗体。
- ヒトドナーから精製されたSiglec発現NK細胞において、前記NK細胞が、標的ヒト細胞であって、標的細胞表面上に前記Siglecのリガンドを保有する標的ヒト細胞と接触されると、細胞傷害性および/または細胞傷害性に関連するマーカーの上昇を引き起こす、請求項1~8の何れか一項に記載の抗体。
- 配列番号2の野生型Siglec-9ポリペプチドへの結合と比較して、
- 残基N78、P79、A80、R81、A82および/もしくはV83における突然変異;残基N77、D96、H98および/もしくはT99における突然変異、ならびに/または残基W84、E85、E86および/もしくはR88における突然変異を有するSiglec-9ポリペプチド、
- 残基S47、H48、G49、W50、I51、Y52、P53および/またはG54における突然変異を有するSiglec-9ポリペプチド、
- 残基P55、H58、E122、G124、S125および/またはK127における突然変異を有するSiglec-9ポリペプチド、
- 残基K131および/またはH132における突然変異を有するSiglec-9ポリペプチド、および/または
- 残基R63、A66、N67、T68、D69、Q70および/またはD71における突然変異を有するSiglec-9ポリペプチド
への減少した結合によって特徴付けられ、アミノ酸残基は、配列番号2の前記Siglec-9ポリペプチドに関して示される、請求項1~9の何れか一項に記載の抗体。 - Fcドメインであって、前記FcドメインとFcγ受容体との間の結合を減少させるために修飾されているFcドメインを有する抗体である、請求項1~10の何れか一項に記載の抗体。
- ヒトSiglec-9ポリペプチドに結合し、かつヒトNK細胞によって発現されるSiglec-9ポリペプチドの阻害活性を中和することができる、請求項1~11の何れか一項に記載の抗体の断片。
- 請求項1~12の何れか一項に記載の抗体または断片と、薬学的に許容可能な担体とを含む医薬組成物。
- 請求項1~12の何れか一項に記載の抗体または断片の重鎖および/または軽鎖をコードする核酸。
- 請求項1~12の何れか一項に記載の抗体または断片を産生する組み換え宿主細胞。
- 患者において癌の処置に使用するための医薬組成物であって、有効量の請求項1~12の何れか一項に記載の抗体または断片または請求項13に記載の組成物を含む、医薬組成物。
- 前記癌は、ST3GAL1および/またはST3GAL6酵素の発現によって特徴付けられる癌である、請求項16に記載の医薬組成物。
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