JP6794255B2 - 組合せ医薬組成物 - Google Patents
組合せ医薬組成物 Download PDFInfo
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- JP6794255B2 JP6794255B2 JP2016532266A JP2016532266A JP6794255B2 JP 6794255 B2 JP6794255 B2 JP 6794255B2 JP 2016532266 A JP2016532266 A JP 2016532266A JP 2016532266 A JP2016532266 A JP 2016532266A JP 6794255 B2 JP6794255 B2 JP 6794255B2
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Description
本発明は、新規な「組合せ医薬組成物」、より具体的には癌を処置するための、特異的IL−15スーパーアゴニストと、T細胞活性化の阻害に関係づけられている免疫経路に拮抗する抗体との組合せに関する。
適応免疫応答は、T細胞及びB細胞と呼ばれる2つの主要クラスのリンパ球の活性化、選択、及びクローン増殖を伴う。抗原と遭遇後に、T細胞が増殖し、抗原特異的エフェクター細胞に分化する一方で、B細胞は増殖し、抗体分泌細胞に分化する。
さて、本発明者らは、RLIという名の本発明者らの特異的化合物と、T細胞活性化の阻害に関係づけられている免疫経路に拮抗する抗体との組合せが、非常に高い率の腫瘍寛解を招く一方で、そのような寛解は、RLI又は免疫抑制受容体アンタゴニスト単独で得られる腫瘍寛解を考慮すると構想できないことを示す。
1)(i)インターロイキン15又はその誘導体のアミノ酸配列を含むポリペプチド、及びii)IL−15Rαのスシドメイン若しくはその誘導体のアミノ酸配列を含むポリペプチド、を含むコンジュゲート;それをコードするポリヌクレオチド、又はそのようなポリヌクレオチドを含むベクター;並びに
2)T細胞活性化の阻害に関係づけられている免疫経路に拮抗する抗体若しくはそのフラグメント、それをコードするポリヌクレオチド、又はそのようなポリヌクレオチドを含むベクター
を、対象における癌を処置するための同時使用、分離使用、又は順次使用用の組合せ調製物として含む組合せ医薬組成物に関する。
1)上記コンジュゲート、それをコードする核酸配列、又はそのようなポリヌクレオチドを含むベクター、及び
2)T細胞活性化の阻害に関係づけられている免疫経路に拮抗する抗体若しくはそのフラグメント、それをコードする核酸配列、又はそのようなポリヌクレオチドを含むベクター
を同時に、別々に、又は順次に投与する段階を含む方法に関する。
コンジュゲート
用語「インターロイキン15」は、当技術分野においてその一般的な意味でIL−2と構造的類似性を有するサイトカインを表す(GRABSTEIN et al., Science, vol.264(5161), p:965-968, 1994)。このサイトカインは、IL−15、IL15又はMGC9721としても公知である。このサイトカイン及びIL−2は、多くの生物学的活性を共有し、共通のヘマトポイエチン受容体サブユニットに結合することが見出された。したがって、それらは、相互の活性をマイナスに調節しながら同じ受容体をかけて競合し得る。IL−15がT細胞及びナチュラルキラー細胞の活性化及び増殖を調節すること、並びにCD8+メモリー細胞数がこのサイトカインとIL2とのバランスによって制御されると示されることが立証されている。実施例に開示されているように、IL−15の活性は、kit225細胞系を用いてその増殖誘導を決定することによって測定することができる(HORI et al., Blood, vol.70(4), p:1069-72, 1987)。
用語「抗体」は、ジスルフィド結合によって相互に繋がった4つのポリペプチド鎖、すなわち2つの同一の重(H)鎖(全長の場合約50〜70kDa)及び2つの同一の軽(L)鎖(全長の場合約25kDa)を含む四量体に対応する免疫グロブリン分子を表す。軽鎖は、カッパ及びラムダとして分類される。重鎖は、ガンマ、ミュウ、アルファ、デルタ、又はイプシロンとして分類され、抗体のアイソタイプをそれぞれIgG、IgM、IgA、IgD、及びIgEとして定義する。各重鎖は、N末端重鎖可変領域(本明細書においてHCVRと略記)及び重鎖定常領域からなる。重鎖定常領域は、IgG、IgD、及びIgAについて3つのドメイン(CH1、CH2、及びCH3);並びにIgM及びIgEについて4つのドメイン(CH1、CH2、CH3、及びCH4)からなる。各軽鎖は、N末端軽鎖可変領域(本明細書においてLCVRと略記)及び軽鎖定常領域からなる。軽鎖定常領域は、1つのドメインCLからなる。HCVR及びLCVR領域は、さらに、フレームワーク領域(FR)と呼ばれるより保存された領域によって分散された、相補性決定領域(CDR)と呼ばれる超可変性領域に細分することができる。各HCVR及びLCVRは、アミノ末端からカルボキシ末端にかけて以下の順序:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4で配列された3つのCDR及び4つのFRから構成される。各ドメインへのアミノ酸の割り当ては、周知の慣例に従う。抗体が特定の抗原に結合する機能的能力は、各軽/重鎖対の可変領域に依存し、主としてCDRによって決定される。
本明細書に使用される用語「ポリヌクレオチド」は、RNA又はDNA、好ましくはDNAを表す。
本明細書に使用される用語「対象」は、齧歯類、ネコ、イヌ又は霊長類などの哺乳類、最も好ましくはヒトを意味する。
1)PD1/PD−L1癌モデル
BALB/Cマウスの右脇腹にCT26腫瘍細胞を皮下注射した(2.105/匹)。9日目に腫瘍が20〜30mm2に達したとき、マウスを250μg/匹の抗PD1(BIOXCELL、クローンRPM1−14、#BE0146)単独又はアイソタイプ対照(ラットIgG2a;BIOXCELL、クローン2A3、#BE0089)で処置した。抗PD1(α−PD1)又はアイソタイプ対照(2A3)を9、12及び15日目に注射した。13日から37日にかけて、マウスを週に2回、RLI CHO(1004−14p) 2μgで、又は対照群ではPBSで処置した。腫瘍を週に3回ノギスで測定し、以下のように腫瘍面積を計算した:長さ×幅。腫瘍サイズが300mm2に達したとき又は潰瘍化したときにマウスを屠殺した。
0日目にC57BL/6マウスの脇腹にB16F10細胞3×104個をi.d.注射することによってB16F10腫瘍を移植した。7〜25日目にRLI CHO 2μgを1週間に2回i.p.注射したRLI CHO(2μg/匹)と組み合わせて又は組み合わせずに、マウスを抗CTLA−4(クローン:UC10−4F10−11 100又はクローン:9D9)又は抗PD−1(クローンRPM1−14、#BE0146)又は抗PD−L1 mAb(クローン:10F.9G2)でi.p.処置した。注射1回あたりの抗CTLA−4又は抗PD−1又は抗PD−L1抗体の用量は、3日目に200μgに加えて6及び9日目に100μgである。対照群は、対応する用量の抗体アイソタイプの投与を受けた。腫瘍サイズ及び発生率を身体検査により経時的にモニターした。
3)進行肺癌
腫瘍細胞系TC−1は、C57BL/6マウスの初代肺上皮細胞から得られ、ヒトパピローマウイルス16(HPV−16)E6/E7及びc−Ha−Rasを共トランスフォーメーションされている。TC−1肺癌細胞105個をC57BL/6マウスの背中の真皮上層中にs.c.注射する。腫瘍がサイズ≒15〜20mm2で明らかに目に見え、触知可能になったときに対応する、腫瘍接種後10日目に処置を開始する。抗CTLA−4 mAb(100μg/匹、クローン:UC10−4F10−11 100若しくはクローン:9D9)又は抗PD−1(250μg/匹、クローンRPM1−14、#BE0146)又は抗PD−L1 mAb(100μg/匹、クローン:10F.9G2)を3つの単一時点で(10、14、17日目)与え、RLI(2μg/匹)を10、13及び18日目に与える。エンドポイントとして1週間に2回測定した腫瘍成長を用いて、単一薬剤に対して各抗体とRLIとの対組合せを用いた処置を比較する。対応する用量の抗体アイソタイプの投与を対照群に受けさせた。
MB49腫瘍細胞系は、C57BL/6雄性マウスからの膀胱上皮起源の発癌物質誘導腫瘍を起源とする。MB49膀胱ガン細胞106個をC57BL/6マウスの背中の真皮上層中にs.c.注射する。腫瘍がサイズ≒15mm2で明らかに目に見え、触知可能になったときに対応する、腫瘍接種後6日目に処置を開始する。抗CTLA−4 mAb(100μg/匹、クローン:UC10−4F10−11 100若しくはクローン:9D9)又は抗PD−1(100μg/匹、クローンRPM1−14、#BE0146)又は抗PD−L1 mAb(100μg/匹、クローン:10F.9G2)を4つの単一時点で(6、9、12日目)与え、RLI(2μg/匹)を7、8、10、11、13、14、及び16、17日目に与える。単一薬剤に対して各抗体とRLIとの対組合せを用いた処置を比較する。対応する用量の抗体アイソタイプの投与を対照群に受けさせた。腫瘍を1週間に3回ノギスで測定し、以下のように腫瘍面積を計算した:長さ×幅。腫瘍サイズが300mm2に達したとき又は潰瘍化したときにマウスを屠殺した。
0日目にBALB/cマウスの乳腺に4T1乳癌細胞5×104個を接種する。腫瘍がサイズ≒15〜20mm2で明らかに目に見え、触知可能になったときに対応する、腫瘍接種後10日目に処置を開始する。抗CTLA−4 mAb(100μg/匹、クローン:UC10−4F10−11 100若しくはクローン:9D9)又は抗PD−1(250μg/匹、クローンRPM1−14、#BE0146)又は抗PD−L1 mAb(200μg/匹、クローン:10F.9G2)を4つの単一時点で(10、13、16日目)与え、RLI(2μg/匹)を10、11、13、14、16、17、及び19、20日目に与える。単一薬剤に対して各抗体とRLIとの対組合せを用いた処置を比較する。対応する用量の抗体アイソタイプの投与を対照群に受けさせた。腫瘍を1週間に3回ノギスで測定し、以下のように腫瘍面積を計算する:長さ×幅。マウスを27日目に屠殺する。肺転移結節を双眼顕微鏡で計数する。
6)卵巣癌
ID8−VEGF卵巣癌細胞系は、マウス卵巣上皮乳頭漿液性腺癌細胞系から以前に開発された。C57BL/6マウスの右脇腹にいずれかのID8腫瘍細胞5×106個を皮下移植する。腫瘍がサイズ≒15〜20mm2で明らかに目に見え、触知可能になったときに対応する、腫瘍接種後10日目に処置を開始する。抗CTLA−4 mAb(100μg/匹、クローン:UC10−4F10−11 100若しくはクローン:9D9)又は抗PD−1(250μg/匹、クローンRPM1−14、#BE0146)又は抗PD−L1 mAb(200μg/匹、クローン:10F.9G2)を4つの単一時点で(10、13、16日目)与え、RLI(2μg/匹)を10、11、13、14、16、17、及び19、20日目に与える。エンドポイントとして1週間に2回測定した腫瘍成長を用いて、単一薬剤に対して各抗体とRLIとの対組合せを用いた処置を比較する。対応する用量の抗体アイソタイプの投与を対照群に受けさせた。腫瘍を1週間に3回ノギスで測定し、以下のように腫瘍面積を計算する:長さ×幅。腫瘍サイズが300mm2に達したとき又は潰瘍化したときにマウスを屠殺する。
C57BL/6雌性マウスにRM−1マウス前立腺癌細胞2×105個をs.c.接種する。腫瘍がサイズ≒15〜20mm2で明らかに目に見え、触知可能になったときに対応する、腫瘍接種後3日目に処置を開始する。抗CTLA−4 mAb(100μg/匹、クローン:UC10−4F10−11 100若しくはクローン:9D9)又は抗PD−1(250μg/匹、クローンRPM1−14、#BE0146)又は抗PD−L1 mAb(200μg/匹、クローン:10F.9G2)を3つの単一時点で(3、6、9日目)与え、RLI(2μg/匹)を6、7、9、10、12、13、15、16及び18、19日目に与える。エンドポイントとして1週間に2回測定した腫瘍成長を用いて、単一薬剤に対して各抗体とRLIとの対組合せを用いた処置を比較する。対応する用量の抗体アイソタイプの投与を対照群に受けさせた。腫瘍を1週間に3回ノギスで測定し、以下のように腫瘍面積を計算する:長さ×幅。腫瘍サイズが300mm2に達したとき又は潰瘍化したときにマウスを屠殺した。
Claims (6)
- 癌を処置するための組合せ医薬組成物であって:
a)(i)配列番号16又は配列番号17のアミノ酸配列を含むコンジュゲート;それをコードするポリヌクレオチド、又はそのようなポリヌクレオチドを含むベクター、;並びに
b)T細胞活性化の阻害に関係づけられている免疫経路に拮抗する抗体、それをコードするポリヌクレオチド、又はそのようなポリヌクレオチドを含むベクター
を含み、
ここで、抗体は、PD−1/PD−L1アンタゴニスト及びPD−1/PD−L2アンタゴニストから選択され、
前記コンジュゲート及び抗体は連結されていない、
組合せ医薬組成物。 - 配列番号16又は配列番号17のアミノ酸配列を含むコンジュゲート;それをコードするポリヌクレオチド、又はそのようなポリヌクレオチドを含むベクターを含む、対象における癌を処置する用途のための医薬組成物であって、
該用途は、(a)前記医薬組成物と、(b)T細胞活性化の阻害に関係づけられている免疫経路に拮抗する抗体、それをコードするポリヌクレオチド、又はそのようなポリヌクレオチドを含むベクターとを同時投与、分離投与、又は順次投与することを含み、
ここで、抗体は、PD−1/PD−L1アンタゴニスト及びPD−1/PD−L2アンタゴニストから選択される、
医薬組成物。 - T細胞活性化の阻害に関係づけられている免疫経路に拮抗する抗体、それをコードするポリヌクレオチド、又はそのようなポリヌクレオチドを含むベクターを含む、対象における癌を処置する用途のための医薬組成物であって、
ここで、抗体は、PD−1/PD−L1アンタゴニスト及びPD−1/PD−L2アンタゴニストから選択され、
該用途は、(a)前記医薬組成物と、(b)アミノ酸配列16又はアミノ酸配列17を含むコンジュゲート;それをコードするポリヌクレオチド、又はそのようなポリヌクレオチドを含むベクターとを同時投与、分離投与、又は順次投与することを含む、
医薬組成物。 - 請求項1に記載の組合せ医薬組成物、又は請求項2又は3に記載の癌を処置する用途のための医薬組成物であって、対象における癌を処置する用途のための同時投与、分離投与、又は順次投与用に適合させた、組合せ医薬組成物、又は医薬組成物。
- a)コンジュゲートが、注射によって用量60μg/kg以下で投与され;
b)T細胞活性化の阻害に関係づけられている免疫経路に拮抗する抗体が、用量500μg/kg以下の注射によって投与される、
請求項1ないし4のいずれか一項記載の、組合せ医薬組成物、又は癌を処置する用途のための医薬組成物。 - 抗体が、ニボルマブ、Merck3745、CT−011、ランブロリズマブ(lambrolizumab)、AMP514、MDX−1105又はYW243.55.S70より選択される、請求項1〜5のいずれか一項記載の、組合せ医薬組成物、又は癌を処置する用途のための医薬組成物。
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CY1122465T1 (el) | 2021-01-27 |
JP2019189638A (ja) | 2019-10-31 |
HUE046964T2 (hu) | 2020-04-28 |
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CA2920539C (en) | 2024-01-02 |
PT3030262T (pt) | 2019-12-11 |
HRP20192174T1 (hr) | 2020-03-06 |
EP3030262B1 (en) | 2019-10-09 |
RS59756B1 (sr) | 2020-02-28 |
CN105579062A (zh) | 2016-05-11 |
SI3030262T1 (sl) | 2020-03-31 |
JP2016527286A (ja) | 2016-09-08 |
ES2760249T3 (es) | 2020-05-13 |
WO2015018529A1 (en) | 2015-02-12 |
PL3030262T3 (pl) | 2020-07-27 |
JP2022091985A (ja) | 2022-06-21 |
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