JP6923658B2 - 抗cd47抗体およびその使用 - Google Patents
抗cd47抗体およびその使用 Download PDFInfo
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- JP6923658B2 JP6923658B2 JP2019541431A JP2019541431A JP6923658B2 JP 6923658 B2 JP6923658 B2 JP 6923658B2 JP 2019541431 A JP2019541431 A JP 2019541431A JP 2019541431 A JP2019541431 A JP 2019541431A JP 6923658 B2 JP6923658 B2 JP 6923658B2
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- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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Description
から成る群より選択された1〜3つのHCDRs;およびB)下記の軽鎖相補性決定領域(LCDRs)の群:(i) 配列番号23および24のアミノ酸配列を含むLCDR1、(ii) 配列番号25と26のアミノ酸配列を含むLCDR2、(iii) 配列番号27, 28, 29および30のアミノ酸配列を含むLCDR3、および(iv) 少なくとも1アミノ酸でかつ多くても5アミノ酸のアミノ酸置換(例えば保存的置換)、欠失もしくは挿入を含む、前記(i), (ii)および(iii)に記載のLCDRsから成る群より選択された1〜3つのLCDRsを含むまたはから成り、ここで改変されたCDRsを含む前記抗CD47抗体は、CD47に結合する能力をまだ保有している。
幾つかの実施形態では、本発明により提供される抗CD47抗体またはその抗原結合性断片は、驚くべきことに、対照抗体と比較して腫瘍の増殖を効果的に阻害することができる。
1.1 定義
VL中の第24〜34位(LCDR1)、第50〜56位(LCDR2)、および第89〜97位(LCDR3)、並びにVH中の第27〜35位(HCDR1)、第50〜65位(HCDR2)、および第93〜102位(HCDR3)。
1.2 本発明の抗CD47抗体
一態様では、本発明は、上述した抗CD47抗体またはその断片のいずれかをコードする核酸を提供する。該核酸は、抗体の軽鎖および/または重鎖可変領域を含むアミノ酸配列、または抗体の軽鎖および/または重鎖を含むアミノ酸配列をコードする。
本発明は更に、CD47に結合する1以上のモノクローナル抗体またはそれの免疫学的活性断片を含む医薬組成物を提供する。本発明で提供される抗CD47抗体または医薬組成物は、担体、賦形剤、および同時投与用製剤に適する他の剤の中に製剤化することができ、それにより輸送、伝達、寛容性などの改善をもたらすことができる。
一態様では、本発明は、対象におけるSIRPαへのCD47の結合を阻害するおよび/または拮抗する方法であって、本明細書に記載の抗CD47抗体またはその断片のいずれかの有効量を該対象に投与することを含む方法に向けられる。別の態様では、本発明は、本明細書に記載の抗CD47抗体またはその断片のいずれかの有効量を該対象に投与することを含む、対象における食細胞の貪食を促進する方法に向けられる。一態様では、本発明は、治療標的であるCD47関連疾患を治療する方法であって、対象に本開示の抗CD47抗体またはその断片のいずれかの有効量を投与することを含む方法に向けられる。一態様では、本発明は、SIRPαへのCD47の結合を排除、阻害または減少させることにより任意の疾患または障害を抑制、遅延、阻害または予防することができる方法に向けられる。別の態様では、本発明は、必要とする対象において癌または腫瘍を治療する方法であって、本発明の抗CD47抗体またはその断片を該対象に投与することを通して、該対象の癌または腫瘍の症状を軽減するため、および該対象において癌または腫瘍の再発を回避するための方法を提供する。
投与は適当な経路を介することができ、投与の短期または長期性質にある程度依存するが、注射、例えば静脈注射または皮下注射によることができる。限定されないが、様々な時点に渡る単回または多数回投与、ボーラス投与およびパルス注入をはじめとする様々な投薬スケジュールが本発明で意図される。
貪食作用を促進するSIPRαとのCD47の相互作用を遮断する当該技術分野で開示されているほとんどの抗体が明白な細胞凝集を生じるとすると、マクロファージ貪食を効果的に促進することができないだけでなく、細胞の凝集にも至らない新規な抗CD47抗体の大きな必要がなおある。この点での要望は、本出願明細書中に開示される抗CD47抗体により満たされ、貪食を促進するのに効果的であり、抗腫瘍成長および腫瘍の除去という優れた効果を発揮するだけでなく、治療効果を発揮しながら明白な細胞凝集を引き起こさず、それにより有意に減少した副作用を有する。
1.6 診断および検出のための方法と組成物
1.7 本発明の典型的抗CD47抗体の配列
ADI26624−IgG4
HCのアミノ酸配列(配列番号74):
HCのアミノ酸配列(配列番号76)
ADI29340−IgG4
HCのアミノ酸配列(配列番号77)
ADI26630−IgG4
HCのアミノ酸配列(配列番号78)
HCのアミノ酸配列(配列番号80)
ADI29349−IgG4
HCのアミノ酸配列(配列番号81)
ADI26591−IgG4
HCのアミノ酸配列(配列番号82)
HCのアミノ酸配列(配列番号84)
ADI30793−IgG4
HCのアミノ酸配列(配列番号85)
HCのアミノ酸配列(配列番号87)
ADI26624−IgG1
HCのアミノ酸配列(配列番号88)
ADI29336−IgG1
HCのアミノ酸配列(配列番号89)
ADI29340−IgG1
HCのアミノ酸配列(配列番号90)
ADI26630−IgG1
HCのアミノ酸配列(配列番号91)
ADI29341−IgG1
HCのアミノ酸配列(配列番号92)
ADI29349−IgG1
HCのアミノ酸配列(配列番号93)
ADI26591−IgG1
HCのアミノ酸配列(配列番号94)
ADI29371−IgG1
HCのアミノ酸配列(配列番号95)
ADI30793−IgG1
HCのアミノ酸配列(配列番号96)
ADI30794−IgG1
HCのアミノ酸配列(配列番号97)
CD47タンパク質のアミノ酸配列(配列番号56)
本願の「配列表」の項目に、本発明に代表される10種の抗体(ADI-26624, ADI-29336, ADI-29340, ADI-26630, ADI-29341, ADI-29349, ADI-26591, ADI-29371, ADI-30793, ADI-30794)のCDR領域、軽鎖および重鎖可変領域、並びに軽鎖および重鎖のアミノ酸配列と、対応するヌクレオチド配列が列挙される。更に、本発明において上述した典型的抗体の軽鎖、重鎖、軽鎖および重鎖可変領域についての配列番号付けが第1表に示される。
本発明の抗体は酵母細胞中とCHO-S細胞中で発現させ、次いで精製した。
現行手順(WO 2009036379;WO 2010105256; WO 2012009568)に従って、酵母ベースの抗体提示ライブラリー(Adimab)を、各ライブラリーが1×109の多様性になるように増幅させた。簡単に言えば、Miltenyi ComanyからのMACSシステムを使って、最初の2ラウンドのスクリーニングにより磁気活性化細胞選別を行った。1ラウンド目は、該ライブラリーの酵母細胞(〜1×1010細胞/ライブラリー)を別々に、100 nMビオチン標識CD47抗原(Acro Biosystems, カタログ番号CD7-H5227-1 mg)を含有するFACS洗浄緩衝液(0.1%ウシ血清タンパク質を含むリン酸塩緩衝液)中で室温にて15分間インキュベートした。細胞を50 mLの予冷したFACS洗浄緩衝液で洗浄し、次いで40 mLの同洗浄緩衝液中に再懸濁し、そして500μLのストレプトマイシンマイクロビーズ(Miltenyi LS)の添加後、4℃にて15分間インキュベートした。1000 rpmでの5分間の遠心分離により上清を捨て、細胞ペレットを5 mLのFACS洗浄緩衝液中に再懸濁し、その細胞懸濁液をMiltenyi LSカラムに投入した。添加が終了した後、カラムを各洗浄3 mLのFACS洗浄緩衝液で3回洗浄した。Miltenyi LSカラムを磁気領域から取り外し、次いで5 mLの培養培地を用いて溶出させた。溶出した酵母細胞を収集し、37℃で一晩増殖させた。
当該抗体を発現するCHO-S細胞系は、Freedom(登録商標)CHO-S(登録商標)キット(Invitrogen)を使って製造元の指示書に従って確立した。まず、抗体分子の重鎖と軽鎖のDNA配列を同じpCHO1.0プラスミド中に、重鎖が軽鎖の上流にくるように挿入した。作製されたpCHO1.0プラスミドを次いで化学的トランスフェクションとエレクトロポレーションによりCHO細胞系中に導入した。トランスフェクションの48時間後に、ForteBioを使って抗体の収量を検出してトランスフェクション効率を測定した。トランスフェクト細胞を2ラウンドの選択的スクリーニングにかけた後、高い抗体発現率を有する細胞プールを得た。次いで細胞プールを増殖させて抗体を高度に発現させ、細胞上清を収集し、プロテインAカラム上で>95%の抗体純度に精製した。
本発明の上述した10種の典型的抗体の平衡解離定数(KD)を、生物光学干渉法(bio-light interferometry)(ForteBio)アッセイを用いて決定した。
本発明の上記10種の抗体の全てが、当業界で認められている既知の抗CD47抗体であるHu5F9の親和性に匹敵する、非常に高い親和性を呈することが分かる。
フローサイトメトリーに基づいたアッセイにおいて、ヒトCD47への前記10種の典型的な本発明抗体の結合を測定した。
SIRPαへのヒトCD47の結合を遮断する10種の典型的抗体の能力を、フローサイトメトリーにより測定した。
フローサイトメトリーに基づくアッセイにおいて、本発明の抗体(ADI-26624、ADI-29336、ADI-29340、ADI-26630、ADI-29341、ADI-29349、ADI-29371、ADI-30793およびADI-30794)の、マクロファージによる腫瘍細胞の貪食を促進する能力を測定した。
本発明の抗CD47抗体(ADI-26624、ADI-26630、ADI-29340およびADI-29341)の抗腫瘍効果を、NOD/SCIDマウスモデルにおいて試験した。
手順は以下の通りである:
ヒトバーキットリンパ腫Raji細胞(ATCC# CCL-86)はATCCから購入し、その後のインビボ実験のためATCCの必須要件に厳密に従って、規定通りに継代培養した。細胞を遠心分離により採取し、滅菌PBS中に再懸濁し、そして107細胞/mLの細胞密度になるよう調整した。0.1 mLの細胞懸濁液を取り、Matrigelと1:1で混合し、NOD/SCIDマウス(Beijing Vital River Laboratory Animal Technology Co., Ltd.)の右脇腹に皮下接種した。試験期間中週2回、腫瘍と体重を測定した。腫瘍エンドポイントを満たした時またはマウスが>20%の体重減少を示した時、マウスを安楽死させた。接種10日後、実験に適格なマウスを1群あたり8匹の動物で無作為化した。マウスにおける腫瘍体積は、各群において以下の式:(幅)2×長さ/2を用いてキャリパーにより測定され、マウスの各群の最大腫瘍体積は110 mm3であった。
上述の方法により得られたマウスを無作為化し、異なる処置を施した:連続2週間に渡り隔日に1回の投与頻度で、1 mg/kgまたは5 mg/kgのPBS、対照IgG抗体(IgG4)、ベンチマーク(Hu5F9)、並びに本発明の抗体ADI-26624およびADI-26630の腹腔内注射。詳細な分類と投与方法は第3表に示される。
従って、本発明の抗体は腫瘍に対する非常に良好な治療効果を示し、これは対照抗体Hu5F9の治療効果よりも優れていることが分かる。
上記方法により得られたマウスを無作為化し、異なる処置を施した。すなわち、0.5 mg/kgまたは5 mg/kgのPBS、対照IgG抗体(IgG4)並びに本発明の抗体ADI-26630、ADI-29340およびADI-29341の腹腔内注射を連続2週間に渡り2日に1回行った。詳細な分類と投与方法は下の第5表に示される。
大部分の抗CD47抗体は、RBC凝集を促進する副作用を有し、それによりそれらの抗体の治療用途を制限することが従来知られている。従って、本発明者らは更に、本明細書に開示される抗体のRBC凝集を検討した。
新鮮なヒト血液を採取し、PBSで3回洗浄し、10%ヒトRBC懸濁液を調製した。ヒトRBCを96ウェルの丸底プレート中で試験抗体(最大濃度60μg/mL、3倍希釈系列、合計11種の濃度)と共に37℃で2〜6時間インキュベートした。反応終了後、写真撮影し、結果を判断した。結果の判定基準は、赤血球がウェルの底に沈み網目状に広がり、霞のように見える場合にRBC凝集反応が起こったと判定し(図12のHu5F9の結果を参照のこと)そしてRBCがウェルの底に断続的な赤い斑点として沈降するような場合にはRBC凝集反応が起こらないと判定するものである(図12の対照を参照のこと)。
Claims (22)
- 単離された抗CD47モノクローナル抗体またはそれの抗原結合性断片であって、重鎖可変領域の3つの相補性決定領域HCDR1、HCDR2およびHCDR3と軽鎖可変領域の3つの相補性決定領域LCDR1、LCDR2およびLCDR3とを含み、ここで
(i) HCDR1が配列番号1に示されるとおりであり、HCDR2が配列番号9に示されるとおりであり、HCDR3が配列番号17に示されるとおりであり、LCDR1が配列番号23に示されるとおりであり、LCDR2が配列番号25に示されるとおりであり、そしてLCDR3が配列番号27に示されるとおりであり;
(ii) HCDR1が配列番号2に示されるとおりであり、HCDR2が配列番号10に示されるとおりであり、HCDR3が配列番号18に示されるとおりであり、LCDR1が配列番号23に示されるとおりであり、LCDR2が配列番号25に示されるとおりであり、そしてLCDR3が配列番号27に示されるとおりであり;
(iii) HCDR1が配列番号3に示されるとおりであり、HCDR2が配列番号11に示されるとおりであり、HCDR3が配列番号17に示されるとおりであり、LCDR1が配列番号23に示されるとおりであり、LCDR2が配列番号25に示されるとおりであり、そしてLCDR3が配列番号27に示されるとおりであり;
(iv) HCDR1が配列番号1に示されるとおりであり、HCDR2が配列番号9に示されるとおりであり、HCDR3が配列番号19に示されるとおりであり、LCDR1が配列番号23に示されるとおりであり、LCDR2が配列番号25に示されるとおりであり、そしてLCDR3が配列番号28に示されるとおりであり;
(v) HCDR1が配列番号4に示されるとおりであり、HCDR2が配列番号9に示されるとおりであり、HCDR3が配列番号19に示されるとおりであり、LCDR1が配列番号23に示されるとおりであり、LCDR2が配列番号25に示されるとおりであり、そしてLCDR3が配列番号28に示されるとおりであり;または
(vi) HCDR1が配列番号5に示されるとおりであり、HCDR2が配列番号12に示されるとおりであり、HCDR3が配列番号19に示されるとおりであり、LCDR1が配列番号23に示されるとおりであり、LCDR2が配列番号25に示されるとおりであり、そしてLCDR3が配列番号28に示されるとおりである、
前記抗体またはそれの抗原結合性断片。 - (i) 重鎖可変領域が配列番号44に示されるとおりであり、そして軽鎖可変領域が配列番号54に示されるとおりであり;
(ii) 重鎖可変領域が配列番号45に示されるとおりであり、そして軽鎖可変領域が配列番号54に示されるとおりであり;
(iii) 重鎖可変領域が配列番号46に示されるとおりであり、そして軽鎖可変領域が配列番号54に示されるとおりであり;
(iv) 重鎖可変領域が配列番号47に示されるとおりであり、そして軽鎖可変領域が配列番号55に示されるとおりであり;
(v) 重鎖可変領域が配列番号48に示されるとおりであり、そして軽鎖可変領域が配列番号55に示されるとおりであり;または
(vi) 重鎖可変領域が配列番号49に示されるとおりであり、そして軽鎖可変領域が配列番号55に示されるとおりである、
請求項1に記載の単離されたモノクローナル抗体またはそれの抗原結合性断片。 - (i) 重鎖が配列番号74または88に示されるとおりであり、そして軽鎖が配列番号75に示されるとおりであり;
(ii) 重鎖が配列番号76または89に示されるとおりであり、そして軽鎖が配列番号75に示されるとおりであり;
(iii) 重鎖が配列番号77または90に示されるとおりであり、そして軽鎖が配列番号75に示されるとおりであり;
(iv) 重鎖が配列番号78または91に示されるとおりであり、そして軽鎖が配列番号79に示されるとおりであり;
(v) 重鎖が配列番号80または92に示されるとおりであり、そして軽鎖が配列番号79に示されるとおりであり;または
(vi) 重鎖が配列番号81または93に示されるとおりであり、そして軽鎖が配列番号79に示されるとおりである、
請求項1または2に記載の単離されたモノクローナル抗体またはそれの抗原結合性断片。 - 前記抗体がヒト化抗体である、請求項1〜3のいずれか一項に記載の単離されたモノクローナル抗体またはそれの抗原結合性断片。
- 前記抗原結合性断片がFab、Fab’-SH、Fv、scFv、または(Fab’)2断片からなる群より選択される、請求項1〜4のいずれか一項に記載の単離されたモノクローナル抗体またはそれの抗原結合性断片。
- フレームワーク配列を含む、請求項1〜5のいずれか一項に記載の単離されたモノクローナル抗体またはそれの抗原結合性断片。
- 前記フレームワーク配列の少なくとも一部分がヒトコンセンサスフレームワーク配列である、請求項6に記載の単離されたモノクローナル抗体またはそれの抗原結合性断片。
- 請求項1〜7のいずれか一項に記載の単離された抗CD47モノクローナル抗体またはそれの抗原結合性断片をコードする、単離された核酸。
- 請求項8に記載の核酸を含むベクター。
- 前記ベクターが発現ベクターである、請求項9に記載のベクター。
- 請求項9または10に記載のベクターを含む宿主細胞。
- 前記宿主細胞が酵母細胞、哺乳類細胞、または前記抗体もしくはそれの抗原結合性断片を調製するのに適当である他の細胞である、請求項11に記載の宿主細胞。
- 請求項1〜7のいずれか一項に記載の抗CD47モノクローナル抗体またはそれの抗原結合性断片をコードする核酸を発現させるのに適当である条件下で、請求項11または12に記載の宿主細胞を培養することを含む、前記抗CD47モノクローナル抗体またはそれの抗原結合性断片の調製方法。
- 請求項13に記載の方法により調製された抗CD47モノクローナル抗体またはそれの抗原結合性断片。
- 請求項1〜7および14のいずれか一項に記載の抗CD47抗体またはそれの抗原結合性断片を含む、医薬組成物。
- 対象において癌もしくは腫瘍を治療するための、または癌もしくは腫瘍の症状を緩和するための医薬の製造における、請求項1〜7および14のいずれか一項に記載の抗CD47抗体もしくはそれの抗原結合性断片または請求項15に記載の医薬組成物の使用。
- 前記対象がヒトである、請求項16に記載の使用。
- 前記癌または腫瘍が、急性骨髄性白血病(AML)、慢性骨髄性白血病(CML)、急性リンパ球性白血病(ALL)、慢性リンパ球性白血病(CLL)、非ホジキンリンパ腫(NHL)、多発性骨髄腫(MM)、リンパ腫、乳癌、頭頸部癌、胃癌、肺癌、食道癌、腸癌、卵巣癌、頸癌、肝癌、腎臓癌、膵臓癌、膀胱癌、結腸直腸癌、神経膠腫、黒色腫および他の固形腫瘍からなる群より選択される血液学的腫瘍および固形腫瘍である、請求項16または17に記載の使用。
- 1以上の他の医薬と組み合わせて投与する医薬の製造における、請求項16〜18のいずれか一項に記載の使用。
- 前記他の医薬が、T細胞による認識を通して腫瘍細胞を攻撃する様々なモノクローナル抗体医薬である、請求項19に記載の使用。
- 試料中のCD47タンパク質の存在を検出する方法であって、
(a) 該試料を請求項1〜7および14のいずれか一項に記載の抗体またはそれの抗原結合性断片と接触させ;そして
(b) 前記抗体またはそれの抗原結合性断片とCD47タンパク質との間の複合体の形成を検出する
ことを含む、前記方法。 - 請求項1〜7および14のいずれか一項に記載の抗CD47抗体またはそれの抗原結合性断片を含み、そして腫瘍療法の効果を測定するために使用されるキットであって、該療法の前後に対象からの試料中のCD47発現癌細胞の数を決定するために使用される試薬を含み、ここで該療法後のCD47発現癌細胞の数の減少が該療法が効果的であることを示す、キット。
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