JP2022543378A - Il-38特異的抗体 - Google Patents
Il-38特異的抗体 Download PDFInfo
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- JP2022543378A JP2022543378A JP2022506484A JP2022506484A JP2022543378A JP 2022543378 A JP2022543378 A JP 2022543378A JP 2022506484 A JP2022506484 A JP 2022506484A JP 2022506484 A JP2022506484 A JP 2022506484A JP 2022543378 A JP2022543378 A JP 2022543378A
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Abstract
Description
配列番号23、28、33、38、43、48、53、若しくは15のVH CDR1アミノ酸配列;
配列番号24、29、34、39、44、49、54、若しくは16のVH CDR2アミノ酸配列;
配列番号25、30、35、40、45、50、55、若しくは17のVH CDR3アミノ酸配列;
配列番号58、63、68、73、78、83、若しくは18のVL CDR1アミノ酸配列;
配列番号59、64、69、74、79、84、若しくは19のVL CDR2アミノ酸配列;及び/又は
配列番号60、65、70、75、80、85、若しくは20のVL CDR3アミノ酸配列
の少なくとも3つ、少なくとも4つ、少なくとも5つ、少なくとも6つ、少なくとも7つ、又は少なくとも8つの場合により隣接しているアミノ酸を含みえる。
無傷のヒトがん細胞の表面に結合する抗体を産生するヒトハイブリドーマの単離
PR087-29B5ハイブリドーマ細胞は、頭頚部がん患者のリンパ節から単離されたヒトB細胞とB56T融合パートナーの融合物から生成した。ヒトB細胞とB56Tの融合は、本質的にUSPTO#EP2242836「有用な抗体を発現するハイブリッド細胞を作製する方法(Method of making hybrid cells that express useful antibodies)」に記載されている電気融合により実行した。融合後、ハイブリドーマを蒔きおおよそ2週間増殖させられるようにした。次に、IgG/A陽性ハイブリドーマ由来の条件培地を収集し、がん細胞系の表面に結合する抗体の能力を求めてスクリーニングした。生きた無傷のがん細胞系のプールへのPR087-29B5産生Abの結合は、フルオロフォア標識抗ヒトIgG二次Ab及び96ウェルプレート用に構成されたLI-COR Odyssey(商標)Saイメージングシステムを使用して検出した。スクリーニングに先立って、がん細胞は等しい割合で混合し、プールを96ウェルプレート中にアリコートし24時間結合させられるようにした。ハイブリドーマ上澄みは細胞と一緒にインキュベートし、がん細胞系への結合は、抗ベイシジン、抗EGFR、及び抗ERBB2(BCH)抗体の混合物を等比で含む陽性対照と比べて評価した。BCH陽性対照は、それぞれの抗体66.6、22.2、及び7.4ng/mLで細胞と一緒にインキュベートした。抗インテグリン(ITGA3)抗体(20ng/mL)も陽性対照として使用した。二次抗体単体は陰性対照として使用した。対照の組合せは、細胞系プールとLI-COR機器の検出範囲の両方にわたり一定範囲の絶対シグナル強度を提供する。BCH(7.4ng/mL)陽性対照はバックグラウンドのシグナルのおおよそ160%のシグナルを示し、バックグラウンドは、二次単体対照の4ウェルで見出されるシグナルの平均として定義した。その4つのウェルにまたがるシグナルは、8.5%の標準偏差を有していた。PR087-29B5はバックグラウンドのレベルよりも上のシグナルを示さなかったが、むしろ、それに続くフォローアップのために選択された低レベル点状染色パターンとして提示された(図3)。
PR087-29B5ハイブリドーマはIGHV1/IGLV2可変ドメインを含むIgGを産生する。
PR087-29B5の可変重鎖(VH)及び可変軽鎖(VL)ドメインをコードするヌクレオチド配列は、PR087-29B5ハイブリドーマ系の細胞から単離されたRNAのRT-PCR増幅及び得られた抗体cDNAに配列決定反応を受けさせることにより得られた。配列番号1は、ハイブリドーマから単離されたPR087-29B5のVHのヌクレオチド配列に対応し、配列番号3はVLのヌクレオチド配列に対応する。配列番号2及び配列番号4は、ハイブリドーマから単離されたPR087-29B5のVH及びVLの対応するアミノ酸配列に対応する。IGHV1-18及びIGKV3-20遺伝子割当は公知の生殖系列遺伝子配列に対する相同性に基づいて予測し、VH及びVLの5’末端を生成するのに使用して、配列番号5及び配列番号8により表される完全長コード配列を創造し、これらの配列はそれぞれアミノ酸配列の配列番号7及び配列番号10をコードする。2つのプラスミド系を使用して、IgG1重鎖及びカッパ軽鎖定常ドメインと一緒にPR087-29B5の可変ドメインを含有する抗体の組換え発現を促進した。コドン最適化は配列番号5で実行し、配列番号7に対応するアミノ酸配列をコードする配列番号6に対応するヌクレオチド断片は、PR087-29B5のVHドメインを含む抗体の発現を促進するために合成した。コドン最適化は配列番号8でも実行し、配列番号9に対応するヌクレオチド断片は、配列番号10をコードするが、PR087-29B5のVLドメインを含む抗体の発現を促進するために合成した。PR087-29B5の重鎖又は軽鎖を発現するベクターは、VHとVLドメインを合成し、配列番号12及び配列番号14に対応するアミノ酸配列を含む完全長IgG1抗体をコードする2つのベクター系中にクローニングすることにより作製した。PR087-29B5VH及びVLドメインを含有する抗体は、標準条件を使用して、チャイニーズハムスター卵巣(CHO)及びヒト胎児性腎臓(HEK)などの哺乳動物細胞系中への一過性トラスフェクションにより組換え的に発現させた。組換え抗体は、IMM20130と呼ばれるが、当業者に周知である技法を使用して親和性クロマトグラフィーにより条件培地から精製した。
IMM20130 AbはIL-38上のエピトープに結合する。
IMM20130が結合した標的抗原を同定するため、標的タンパク質がその天然の立体構造で配置されたCDI HuProtアレイに対して抗体をスクリーニングした。さらに具体的には、IMM20130は天然のCDI HuProtアレイに対して4℃で一晩インキュベートした(1マイクログラム/mL)。スライドを洗浄し、IMM20130結合はAlexa-647コンジュゲート抗H+L二次抗体で検出した。二次抗体が結合した非特異的ヒットは任意の分析から排除した。標的タンパク質への選択的結合は、それぞれのスライド上での複製物への結合の再現性を判定するためのZ-スコア、と選択性対可能な標的の差を判定するためのS-スコアの組合せにより分析した。第1位と第2位のヒットの間のS-スコア>3は、第1位ヒットに高度に特異的であると見なされる。
IL-38は、炎症反応を阻害するプロ腫瘍形成性免疫抑制サイトカインである。
IMM20130を用いて種々のがん細胞系でのIL-38の発現を評価した後、TCGAデータベースを使用して、腫瘍微小環境に対するIL-38の効果を評価した。遺伝子発現分析は、上で明示される兆候由来のTCGA Firehouse Legacyデータセットを使用して実施した。それぞれのデータセットでの試料の数は、それぞれの分析についてのR-2乗値と一緒に示されている。RNA_Seq_v2_mRNA_median_Zスコアデータをデータ解析のために使用した。複数のがん型では、IL-38の発現は、T細胞及び骨髄細胞を含む、効果的な抗腫瘍応答に不可欠である免疫細胞型と関連する遺伝子の発現の減少と相関しており(図7)、IL-38が、腫瘍微小環境中への免疫細胞の浸潤を抑制するのに重要な役割を果たすことができることを示唆している。
IL-38機能をブロックする抗IL-38抗体の産生
図8で確立したインビトロ系を使用して、IL-38の機能をブロックするIMM20130の能力を試験した。THP-1単球は、100nMのPMAを用いて72時間マクロファージに分化させた。分化後、1μg/mLのIL-38(Adipogen、カタログ番号AG-40A-0191-C050)及び10μg/mLの指示された抗体を無添加のRPMIにおいて室温で1時間インキュベートした。マクロファージはPBSで洗浄し、指示されたIL-38/抗体含有培地を用いて24時間培養した。それに引き続き、細胞は10ng/mLのLPSで24時間刺激し、上澄みを収穫してIL-6産生はヒトIL-6DuoSet ELISAキット(R&D Systems)を使用して測定した。IL-38の阻害により、IL-38処置、LPS刺激THP-1細胞でのIL-6産生はLPS刺激細胞に匹敵するレベルにまで回復するはずである。しかし、IMM20130はこれらの細胞のIL-6産生を回復させることができなかった(図11)。対照として、IL-38タンパク質の異なる部分に対して産生された2つのポリクローナル抗体(Lifespan Biosciences、カタログ番号LS-C135753及びLS-C201139)もこの系でIL-6産生を回復するその能力について試験した。IL-38のC末端の一部に対して産生された1つのポリクローナル抗体は、IL-38処置、LPS刺激THP-1マクロファージのIL-6産生を首尾よく回復させ(図12)、IMM20130がIL-38機能をブロックしないIL-38のエピトープに結合することを示している。
インビボ腫瘍モデルでの抗IL-38抗体の効果を評価する
CD1-M3、CD1-M8、及びCD1-M26がIL-38に結合してその機能をインビトロでブロックすることが確かめられた後、これらの抗体は、薬物動態研究においてマウス血漿に存続するその能力について評価した。6~7週齢のC57BL/6マウスに0時間で10mg/kgをi.p.及びi.v.投与した(1群当たりn=9)。それぞれのマウスは2つの時点では眼窩後に出血させ、最終時点で末端に出血させた。血漿はK2 EDTAチューブを使用して単離し、直接IL-38 ELISAにより抗体についてアッセイした。PBS中IL-38の100μL(CD1-M3、M8では50ng/mL;CD1-M26では600ng/mL)を96ウェル高結合プレートのウェルごとに添加し、プレートは4℃で一晩インキュベートした。PBS 0.05%Tweenでの3回洗浄後、プレートはPBS 2%BSAを用いて室温で1時間ブロックした。3回洗浄後、PBS 2%BSAに希釈した100μLのマウス血漿をそれぞれのウェルに添加した。標準曲線を作成するため、CD1-M3、M8、M26抗体を、500ng/mLで開始してPBS2%BSAで希釈した未処置のマウス血漿中にスパイクした。プレートは室温で2時間インキュベートし、3回洗浄した。PBS2%BSAに1対2000で希釈したHRPコンジュゲート抗マウス抗体の100μLをウェルごとに添加し、室温で2時間インキュベートした。3回洗浄後、ホスホクエン酸/過ホウ酸ナトリウム緩衝液に希釈したOPD基質の100μLをウェルごとに添加し、5~30分間現像し、450nmで吸光度を測定した。10mg/kg投与後、すべての抗体は投与後すぐに100,000ng/mL血漿濃度に到達し、この濃度は時間をかけてゆっくり減少した(図17)。CD1-M3、CD1-M8、及びCD1-M26のi.v.及びi.p.投与は、1週間の試験期間中ずっと類似する血漿レベルの結果であった。
Claims (23)
- 単離されたインターロイキン-38(IL-38)結合抗体、又はその抗原結合断片であって、
配列番号22、配列番号27、配列番号32、配列番号37、配列番号42、配列番号47、配列番号52、配列番号2、若しくは配列番号7の可変重鎖(VH)アミノ酸配列;及び/又は配列番号57、配列番号62、配列番号67、配列番号72、配列番号77、配列番号82、配列番号4、若しくは配列番号9の可変軽鎖(VL)アミノ酸配列内に含まれる、少なくとも1つの相補性決定領域(CDR)の少なくとも3つ、少なくとも4つ、少なくとも5つ、少なくとも6つ、少なくとも7つ、若しくは少なくとも8つの場合により隣接するアミノ酸を含む、結合抗体、又はその抗原結合断片。 - 前記CDRがNorth法により又はKabat法により定義される、前記単離された抗体、又はその抗原結合断片。
- 配列番号23、28、33、38、43、48、53、若しくは15のアミノ酸配列から選択されるVH CDR1;
配列番号24、29、34、39、44、49、54、若しくは16のアミノ酸配列から選択されるVH CDR2;
配列番号25、30、35、40、45、50、55、若しくは17のアミノ酸配列から選択されるVH CDR3;
配列番号58、63、68、73、78、83、若しくは18のアミノ酸配列から選択されるVL CDR1;
配列番号59、64、69、74、79、84、若しくは19のアミノ酸配列から選択されるVL CDR2;及び
配列番号60、65、70、75、80、85、若しくは20のアミノ酸配列から選択されるVL CDR3
の少なくとも3つ、少なくとも4つ、少なくとも5つ、少なくとも6つ、少なくとも7つ、又は少なくとも8つのアミノ酸を含む、抗体、又はその抗原結合断片。 - 配列番号33のVH CDR1、配列番号34のVH CDR2、配列番号35のVH CDR3、配列番号63のVL CDR1、配列番号64のVL CDR2、及び配列番号65のVL CDR3から選択される少なくとも1つのCDRを含む、請求項3に記載の抗体、又はその抗原結合断片。
- 配列番号38のVH CDR1、配列番号39のVH CDR2、配列番号40のVH CDR3、配列番号68のVL CDR1、配列番号69のVL CDR2、及び配列番号70のVL CDR3から選択される少なくとも1つのCDRを含む、請求項3に記載の抗体、又はその抗原結合断片。
- 配列番号43のVH CDR1、配列番号44のVH CDR2、配列番号45のVH CDR3、配列番号73のVL CDR1、配列番号74のVL CDR2、及び配列番号75のVL CDR3から選択される少なくとも1つのCDRを含む、請求項3に記載の抗体、又はその抗原結合断片。
- 配列番号48のVH CDR1、配列番号49のVH CDR2、配列番号50のVH CDR3、配列番号78のVL CDR1、配列番号79のVL CDR2、及び配列番号80のVL CDR3から選択される少なくとも1つのCDRを含む、請求項3に記載の抗体、又はその抗原結合断片。
- 配列番号53のVH CDR1、配列番号54のVH CDR2、配列番号55のVH CDR3、配列番号83のVL CDR1、配列番号84のVL CDR2、及び配列番号85のVL CDR3から選択される少なくとも1つのCDRを含む、請求項3に記載の抗体、又はその抗原結合断片。
- 配列番号15のVH CDR1、配列番号16のVH CDR2、配列番号17のVH CDR3、配列番号18のVL CDR1、配列番号19のVL CDR2、及び配列番号20のVL CDR3から選択される少なくとも1つのCDRを含む、請求項3に記載の抗体、又はその抗原結合断片。
- 前記IL-38が多タンパク質複合体の構成要素である、請求項1から9までのいずれか一項に記載の抗体、又は抗原結合断片。
- 前記抗体、又は抗原結合断片がIL-38の生物活性を部分的に又は完全にブロックする、阻害する、又は中和する、請求項1から10までのいずれか一項に記載の抗体、又は抗原結合断片。
- 前記IL-38が体液中に存在する、請求項1から11までのいずれか一項に記載の抗体又は抗原結合断片。
- 前記体液が血液又は血液派生物である、請求項12に記載の抗体又は抗原結合断片。
- 前記血液派生物が血漿又は血清である、請求項13に記載の抗体又は抗原結合断片。
- 前記IL-38が細胞外マトリックス(「ECM」)、又はECMタンパク質に会合している、請求項1から14までのいずれか一項に記載の抗体又は抗原結合断片。
- 前記IL-38が腫瘍微小環境に存在している、請求項15に記載の抗体又は抗原結合断片。
- 前記抗原結合断片が、単離された可変重(VH)単一ドメインモノクローナル抗体である、請求項1から16までのいずれか一項に記載の抗原結合断片。
- 前記抗原結合断片が、一本鎖(sc)Fv-Fc断片である、請求項1から16までのいずれか一項に記載の抗原結合断片。
- 前記単離された抗原結合断片が、Fv、scFv、Fab、F(ab’)2、若しくはFab’断片、ダイアボディ、又はその半減期が増加されている可能性のある任意の断片を含む、請求項1から16までのいずれか一項に記載の抗原結合断片。
- 前記抗体又は抗原結合断片がCH3スキャフォールドを含み、免疫グロブリンFc領域由来の該CH3ドメインの野生型アミノ酸配列のうちの少なくとも1つの改変を含む、請求項1から19までのいずれか一項に記載の抗体又は抗原結合断片。
- 前記抗体又は抗原結合断片がモノクローナルである、請求項1から20までのいずれか一項に記載の抗体又は抗原結合断片。
- 前記抗体又は抗原結合断片がヒト、ヒト化、又は二重特異性である、請求項1から21までのいずれか一項に記載の抗体又は抗原結合断片。
- 対象において腫瘍増殖又は転移を阻害する方法であって、請求項1から22までのいずれか一項に記載の抗体又は抗原結合断片を含む組成物の治療有効量を該対象に投与するスッテプを含み、該抗体又は抗原結合断片が、IL-38の生物活性を部分的に又は完全にブロックする、阻害する、又は中和する方法。
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