JP7475054B2 - 二重特異性抗体の組成物及びその使用方法 - Google Patents
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Description
本願は35 U.S.C. 119(e)に基づき2018年5月16日に出願された米国仮出願第62/672,325号の出願日の利益を主張し、その開示の全体は参照により本明細書に組み込まれる。
本明細書の開示は、典型的には、がん免疫療法の技術分野に関し、より詳細には、がん治療のためのカドヘリン-17(CDH17)特異的抗体及び細胞傷害性細胞に関する。
CDH17xCD3二重特異性抗体を生成し、それらの構造形態に基づいてグループ化した(図1及び表1に記載のscFv4-Ig又はtB(テトラB)、IgG-scFv又はfL(全長)、及びtaFv-Fc又はFc(バイト-Fc))。3種類のデザインすべてが、CD3への結合特異性を有すヒト化UCHT-1のscFvであるU1を含んでいる。fL(全長)はヒト化抗CDH17抗体のグループであり、一方、tB(テトラB)及びFc(バイト-Fc)は、抗CDH17 scFv及びヒト化UCHT-1のscFvをそれぞれ含む。図2に示すように、CDH17マウス抗体m5F6、m9B5、m9C6、及びm10C12、並びにTROP2マウス抗体m8B5の可変ドメインを、相同なヒト生殖細胞系列配列及びヒト化VH及びVL配列、h5F6、h9B5、h9C6、h10C12、及びh8B5とアラインメントした。ヒト化配列は、任意の位置「X」にマウス又はヒト生殖細胞列配残基を有していてもよい変異を含む。変異は、1つ以上の位置に置換を有していてもよい。抗CD3抗体UCHT-1の可変ドメイン、即ち、配列番号11及び12は、1992年に最初にヒト化された(Beverley 1981 and Shalaby 1992)。「X」で指定された部位のアミノ酸は、CD3エプシロンと水素結合を形成する(Arnett 2004)。これらの残基の特定の置換は、CD3に対する親和性の低下をもたらす可能性がある。
表1に記載された全てのCDH17xCD3二重特異性抗体のうち、h10G4fLはARB202と命名され、ARB202の一重特異性バージョンはARB102と命名された。ARB201はh3G1Fcと同じものであり、ヒト化可変ドメインh3又はLic3の配列がWO2017/120557A1に開示されているため、表1には記載されていない。しかしながら、ARB201は、フローサイトメトリー解析(図3)において、DLD-1(結腸がん)及びAGS(胃がん)の腫瘍細胞株においてCDH17が発現していることを示すために使用された。
CDH17xCD3二重特異性抗体h5G1fL及びh5G4fLを用いて、h5/fLグループ抗体の特性評価を行った。結合特異性を決定するために、CHO細胞を用いて、それぞれh5G1fL及びh5G4fLの発現及び生産を行った。異なるクローンを、組換えCDH17又は抗ヒトIgGでコーティングしたマイクロタイターウエル中の条件培地でインキュベートした。ELISAを使用した。CDH17又は抗ヒトIgG(生産を決定するため)のいずれかへのh5G1fL及びh5G4fLの結合を、ELISA中の抗ヒトFc-HRPコンジュゲートを用いて検出した。図8に示すように、相対的な結合活性を測定し、比較できる。その結果、h5/fLグループの抗体は、対照の抗CDH17抗体と同等のCDH17に対する結合特異性を有していることが示された。
CDH17xCD3二重特異性抗体h10G1fL及びh10G4fLを用いて、h10/fLグループ抗体の特性評価を行った。結合特異性を決定するために、CHO細胞を用いて、それぞれh10G1fL及びh10G4fLの発現及び生産を行った。異なるクローンを、組換えCDH17又は抗ヒトIgGでコーティングしたマイクロタイターウエル中の条件培地でインキュベートした。ELISAを使用した。CDH17又は抗ヒトIgG(生産を決定するため)のいずれかへのh10G1fL及びh10G4fLの結合を、ELISA中の抗ヒトFc-HRPコンジュゲートを用いて検出した。図10に示すように、相対的な結合活性を測定し、比較できる。その結果、h10/fLグループの抗体は、対照の抗CDH17抗体と同等のCDH17に対する結合特異性を有していることが示された。
CDH17xCD3二重特異性抗体h10G1tB及びh10G4tBを用いて、h10/tBグループ抗体の特性評価を行った。結合特異性を決定するために、CHO細胞を用いて、それぞれh10G1tB及びh10G4tBの発現及び生産を行った。異なるクローンを、組換えCDH17又は抗ヒトIgGでコーティングしたマイクロタイターウエル中の条件培地でインキュベートした。ELISAを使用した。CDH17又は抗ヒトIgG(生産を決定するため)のいずれかへのh10G1tB及びh10G4tBの結合を、ELISA中の抗ヒトFc-HRPコンジュゲートを用いて検出した。図12に示すように、相対的な結合活性を測定し、比較できる。その結果、h10/tBグループの抗体は、対照の抗CDH17抗体と同等のCDH17に対する結合特異性を有していることが示された。
CDH17xCD3二重特異性抗体h10G1fL、h10G4fL、h10G4tB、及びh3G4tBを本分析に使用した。新鮮なPBMCを、0~4ug/mlの濃度範囲の4つのCDH17xCD3二重特異性抗体のそれぞれとマイクロタイターウエル中で37℃で24時間インキュベートした。T細胞活性化及び細胞傷害性反応を、フローサイトフルオリメトリーで抗CD107a抗体及び抗mIgG蛍光コンジュゲートで細胞を染色することによって決定した。細胞傷害性T細胞活性化を示すCD107a陽性細胞の割合を抗体濃度に対してプロットした。
CDH17xCD3二重特異性抗体による腫瘍細胞依存性T細胞活性化の特性評価のために、PBMC及びh10G4fLを腫瘍細胞株AsPC1の有り又は無しで、5:1の比率で16時間インキュベートした。T細胞活性化は、定量的ELISAキットを用いてIL2生産を測定することにより決定した。図15に示すように、AsPC1の存在下では、IL2はEC50=30pM(A)でh10G4fL濃度依存的に誘導され、AsPC1の非存在下では、IL2はEC50>18,720pMで誘導された(B)。このように、CDH17xCD3二重特異性抗体h10G4fLは、600倍超の潜在的治療インデックスを示した。
h10G4fLの機能をさらに特性評価するために、CDH17陽性及び陰性腫瘍細胞の両方を使用して、T細胞細胞傷害性をリダイレクトする能力を評価した。ヒトPBMC由来活性化T細胞及びh10G4fL(又は抗体なし)を標識腫瘍細胞と5:1の比率で16時間、共培養した。培養終了時に、各混合物を洗浄し、基質を添加して、残存する生細胞を定量し、殺傷率を計算した。T細胞活性化は、定量的ELISAキットを用いてIL2生産を測定することにより決定した。図16に示すように、結果は、h10G4fLが、CDH17陽性ルシフェラーゼ標識膵臓細胞株及び結腸細胞株(図16A及び16B)に対しては濃度依存的な細胞傷害性を示したが(図16A及び16B)、CDH17陰性結腸腫瘍細胞株SW40(図16D)に対しては示さなかったことを示している。但し、SW40におけるCDH17のエクトピック発現は、h10G4fL依存性殺傷に対する感受性を付与し(図16C)、標的腫瘍細胞に対する特異性を実証した。
h10G4fLの薬物動態を決定するために、マウス及び非ヒト霊長類を小動物及び大動物モデルとして使用した。図17は、マウス(図17A)及び非ヒト霊長類(NHP)モデル(図17B)への3mg/kgの静脈内注射後のh10G4fL/ARB202の血清濃度の経時的変化を示す。h10G4fL/ARB202のアイソタイプバリアントであるh10G1/ARB102を、マウス(図17A)では1mg/kg、NHP(図17B)では10mg/kgで比較のために使用した。
CDH17陽性腫瘍のインビボ治療に対するARB202の有効性を決定するために、マウスの異種移植モデルを使用した。膵臓腫瘍モデルをAsPC-1膵臓腫瘍細胞の皮下注射を介してNSBマウスで樹立した。次に、マウスを図19に示されるように各時点でビヒクル(RPMI)、T細胞、T細胞プラス0.05mg/kg ARB202又はT細胞プラス0.5mg/kg ARB202の腫瘍内投与を介して処置した。腫瘍体積を4週間にわたって決定した。結果は、低用量及び高用量のARB202のみが、ビヒクルと比較して有意な腫瘍成長の減少をもたらしたことを示している(RPMI注入と比較して、P<0.05)。T細胞単独で観察された腫瘍成長の統計的に有意でない減少は、エクスパンドT細胞集団における高いNK活性とAsPC-1のNK感受性によるものと考えられる。この過程におけるT細胞の活性化をさらにバリデーションするために、血清IL-2を分析した。その結果、ARB202での処置のみが、血漿中のヒトIL-2のレベルの増加をもたらしたことが示された。このように、ARB202は、CDH17xCD3二重特異性抗体がCDh17陽性腫瘍の治療に使用できるというコンセプトの証明を提供する。
用語「有効量」は、所望の効果を達成するのに有効な薬剤の量、例えば、対象の疾患を改善するのに有効な量を指す。疾患ががんである場合、薬剤の有効量は、限定されないが、がん細胞増殖、がん細胞分裂、がん細胞運動性、がん細胞の末梢器官への浸潤、腫瘍転移、及び腫瘍増殖の1つ異常の特性を阻害する(例えば、ある程度遅くする、阻害する、又は停止する)ことができる。疾患ががんである場合、薬剤の有効量は、対象に投与されたときに、代替的に、腫瘍増殖を遅らせる又は停止させる、腫瘍の大きさ(例えば、ボリューム又はマス)を減少させる、がんに関連する症状の1つ又は複数をある程度緩和させる、無増悪生存期間を延長させる、客観的奏効(例えば、部分奏効又は完全奏効を含む)をもたらす、及び全生存期間を延長させるの1つ以上のことを行うことができる。薬物が増殖を阻止し、及び/又は既存のがん細胞を死滅させることができる範囲で、それは細胞増殖抑制性及び/又は細胞傷害性を有する。
Claims (19)
- N末端とC末端を有する抗体であって、重鎖と軽鎖を含み、
前記重鎖は、N末端からC末端へタンデムに、重鎖scFvドメインを含む可変要素、重鎖リンカー、CH1、ヒンジ、CH2及びCH3ドメインを含み、
前記軽鎖は、N末端からC末端へタンデムに、軽鎖scFvドメインを含む可変要素、軽鎖リンカー、CLドメインを含み、
前記重鎖scFvは、CD3に対する特異性を有し、
前記軽鎖scFvは、CDH17に対する特異性を有し、
前記重鎖scFvは、VH-CDR1:AASGYSFTGY、VH-CDR2:LINPYKGVSTYNQKFK、VH-CDR3:SGYYGDSD、VL-CDR1:RASQDIRNYLN、VL-CDR2:PKLLIYYTSRLE、VL-CDR3:GNTLPWを含み、
前記軽鎖scFvは、VH-CDR1:SSYAMS、VH-CDR2:VIDSNGGSTYYPDTVK、VH-CDR3:SYTNLGAY、VL-CDR1:RASQDISGYLN、VL-CDR2:TTSTLDS、VL-CDR3:LQYASSPFTを含み、
前記VH-CDRは、重鎖可変領域の相補性決定領域を示し、前記VL-CDRは、軽鎖可変領域の相補性決定領域を示す、抗体。 - CDH17がCDH17エクトドメインD1、D2、D3、D4、D5、D6及びD7を含む、請求項1に記載の抗体。
- 配列番号26に示されるアミノ酸配列及び配列番号30に示されるアミノ酸配列を含む、請求項1又は2に記載の抗体。
- 配列番号26に示されるアミノ酸配列及び配列番号15に示されるアミノ酸配列を含む、請求項1又は2に記載の抗体。
- コンジュゲート細胞傷害性部位をさらに含む、請求項1~4のいずれか1項に記載の抗体。
- 前記コンジュゲート細胞傷害性部位がイリノテカン、オーリスタチン類、PBD類、メイタンシン類、アマンチン類、スプライソソーム阻害剤、又はそれらの組み合わせを含む、請求項5に記載の抗体。
- 前記コンジュゲート細胞傷害性部位が化学療法剤を含む、請求項5に記載の抗体。
- 細胞傷害性T細胞又はNK細胞の細胞受容体、又は免疫チェックポイント阻害剤に対する特異性を有する、請求項7に記載の抗体。
- 前記免疫チェックポイント阻害剤がPD-1、TIM-3、LAG-3、TIGIT、CTLA-4、PD-L1、BTLA、VISTA、又はそれらの組み合わせを含む、請求項8に記載の抗体。
- 血管新生因子に対する特異性を有する、請求項9に記載の抗体。
- 前記血管新生因子がVEGFを含む、請求項10に記載の抗体。
- 請求項1~11のいずれか1項に記載の抗体をコードする単離核酸を含む、発現ベクター。
- 前記ベクターが細胞内で発現可能である、請求項12に記載の発現ベクター。
- 請求項1~11のいずれか1項に記載の抗体をコードする核酸を含む、宿主細胞。
- 請求項13に記載の発現ベクターを含む、宿主細胞。
- 前記宿主細胞が原核細胞又は真核細胞である、請求項15に記載の宿主細胞。
- 請求項1~11のいずれか1項に記載の抗体及び細胞傷害剤を含有する、医薬組成物。
- 前記細胞傷害剤がシスプラチン、ゲムシタビン、イリノテカン、又は抗腫瘍抗体を含む、請求項17に記載の医薬組成物。
- 請求項1~11のいずれか1項に記載の抗体及び薬学的に許容される担体を含む、医薬組成物。
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