JP7473244B2 - C-kitに対する抗体及びその用途 - Google Patents
C-kitに対する抗体及びその用途 Download PDFInfo
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- JP7473244B2 JP7473244B2 JP2022530773A JP2022530773A JP7473244B2 JP 7473244 B2 JP7473244 B2 JP 7473244B2 JP 2022530773 A JP2022530773 A JP 2022530773A JP 2022530773 A JP2022530773 A JP 2022530773A JP 7473244 B2 JP7473244 B2 JP 7473244B2
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Description
本発明は、c-kitに対する抗体又はその抗原結合断片、これをコーディングする核酸、前記核酸を含むベクター、前記ベクターで形質転換された細胞、前記抗体又はその抗原結合断片の製造方法、これを含む血管新生疾患の予防又は治療用組成物、及び癌の予防又は治療用組成物に関する。
血管の生成及び血管透過性の調節は、低酸素症(hypoxia)と密接な連関性を有する。特に、胚発生段階や、細胞増殖が活発な癌組織、或いは血管が損傷した組織で表れる低酸素症状態は、既存の血管と内皮細胞との間の結合が切れ、透過性が増加する不安定な状態になり、このような状況で血管内皮細胞の増殖及び移動が促進されることによって新たな血管が形成される。このような血管不安定化及び血管新生過程を調節するメカニズムには、低酸素状態でHIF-1(hypoxia inducible factor-1)などの転写因子を通じて差次的に発現される多様な遺伝子が関与すると知られており、これらの遺伝子の相当数は、成長因子/サイトカインで血管内皮細胞の細胞間の結合を減少させ、血管の透過性を高めたり、血管内皮細胞の成長/移動能を促進することによって新生血管を形成する。
〔発明が解決しようとする課題〕
本発明の目的は、c-kitに対する新規抗体又はその抗原結合断片を提供することにある。
前記目的を達成するために、本発明は、配列番号1の配列を含む重鎖CDR1、配列番号2の配列を含む重鎖CDR2、配列番号3の配列を含む重鎖CDR3、配列番号4の配列を含む軽鎖CDR1、配列番号5の配列を含む軽鎖CDR2、配列番号6の配列を含む軽鎖CDR3を含む、c-kitに結合する抗体又はその抗原結合断片を提供する。
〔図1〕HUVECにおいてSCFによる細胞増殖をc-kit抗体が濃度依存的に抑制することを示す結果を示した図である。
別の方式で定義されない限り、本明細書で使用された全ての技術的及び科学的用語は、本発明の属する技術分野で熟練した専門家によって通常的に理解されるものと同一の意味を有する。一般に、本明細書で使用された命名法は、本技術分野でよく知られており、通常的に使用されるものである。
以下、実施例を通じて本発明をさらに詳細に説明する。これらの実施例は、本発明を例示するためのものに過ぎなく、本発明の範囲がこれらの実施例によって制限されると解釈されないことは、当業界で通常の知識を有する者にとって自明であろう。
1.抗原免疫
Elabscienceから購買した組換えc-kitタンパク質(cat#PKSH030939)50μg/マウスを同一の体積の完全フロイントアジュバント(Frend's Adjuvant)(sigma、USA)と混合し、エマルジョンを製造した。エマルジョンを7週齢雌ヒト(human)CD34+細胞注射で製作されたヒト化NSGマウス6匹の腹腔内に注入した。抗原50μgを総体積500μlでそれぞれのマウスに注入した。1週及び2週後、それぞれ不完全フロイントアジュバント(Sigma、USA)と抗原とを混合したエマルジョンをマウスの腹腔内に注入した。酵素免疫測定法を実施し、抗体生成を確認した後、細胞融合3日前に再度不完全フロイントアジュバント(Sigma、USA)と抗原とを混合したエマルジョンをマウスの腹腔内に注入した。
前記記載した方法によって免疫化されたマウスの眼球から血液を採取し、これを1.5mlの微細遠心分離チューブに入れ、13,000rpmで10分間遠心分離した。血清を分離し、抗体生成を確認する実験を実施するまで-20℃で保管した。抗原タンパク質を用いて酵素免疫測定法を実施し、抗体生成を確認した後、抗体-生成マウスの脾臓細胞の融合を実施した。
抗体生成を確認した後、マウスを犠牲させ、脾臓細胞を分離して骨髓種細胞P3X63Ag8.653(ATCC CRL-1580)と融合させた。10%ウシ胎児血清を補充したRPMI1640培地を用いて、培養プレート内でマウスのP3X63Ag8.653細胞を培養した。細胞融合を実施するために、P3X63Ag8.653細胞を無血清RPMI1640培地(Hyclone、USA)で2回洗浄し、1X107細胞濃度になるように調整した。マウスを頚椎脱臼によって犠牲させ、脾臓を採取した後、メッシュ容器(Sigma、USA)に入れて細胞を分離した。脾臓細胞の懸濁液を製造した後、懸濁液を遠心分離を用いて洗浄した。脾臓細胞溶液をトリス-NH4Cl(トリス20.6g/L、NH4Cl 8.3g/L)に露出させ、赤血球細胞を溶解した。完全に分離された抗体-生成細胞を400gで5分間遠心分離した後、これらは、無血清培地で2回洗浄し、10ml培地で再懸濁した。リンパ細胞を血球計を用いて計数し、リンパ球1x108を無血清培地内でP3X63Ag8.653細胞1x107(10:1)と混合した。遠心分離は、400xgで5分間実施した。
上で融合された細胞培養液の上澄み液を収集し、酵素免疫測定法を実施し、前記製造された抗原に特異的な抗体の製造を確認した。陰性対照群に比べて4倍以上の適正な濃度を示した融合細胞の培養液を選択し、これを24ウェル培養プレートに移して培養した。さらに、96ウェルプレートに1ウェル当たり1個の細胞が入るように希釈して(limiting dilution)培養した後、培養液を回収し、96ウェルプレートに抗原として使用したc-kitタンパク質を1ウェル当たり0.1μgコーティングした後、酵素免疫測定法を実施し、単クローン抗体を生産する融合細胞を選択した。
1.抗体配列
抗体をコーディングするCDR遺伝子をGenescriptで表1のように確認した。
上で得られた抗c-kit抗体の可変領域をヒトFcアミノ酸配列に移植(grafting)し、pCHOベクター(lifetechnology)内にクローニングした。
上で得られたプラスミドDNAをCHO-S細胞内に形質感染させた。形質感染する1週間前にCHO-S(Invitrogen、10743-029)をDMEM補充血清内の単層培養物内に移した。形質感染する1日前に、細胞を分注した後、形質感染試料に対してDNA-リポフェクタミン複合体を準備し、一晩中インキュベーターで5%CO2、37℃で細胞をインキュベートし、培地を2日~3日に1回ずつ添加しながら一週間にわたって培養した後、培養液を回収し、プロテインA/Gアガロース(invitrogen)に結合した後、PBSで洗浄し、0.1Mのグリシン(pH2.8)で溶出した後、1Mのトリス-HCl(pH8.0)で中和させ、再度PBSで透析した後、-70℃で保管した。分離・精製された4C9抗体を6%のSDS-PAGEに非還元及び還元条件で流し、抗体の純度及びサイズを確認した。
抗c-kit抗体がc-kitに結合する能力を確認するためにSPRを実施した。SR7500DC(Reichert、USA)を用いて、抗体製作のために使用されたヒトc-kit(elabscience、PKSH030939)20μgをPEG(Reichert、USA)チップに固定し、抗体を濃度別に流した後、KD値をScrubber2プログラムを用いて分析した。その結果を図3に示した。
ヒトc-kit遺伝子(NM_000222)の欠失変異体(deletion mutant)(Q26-P520、D113-P520DドメインI、A207-P520DドメインI-II、K310-P520DドメインI-III、T411-P520DドメインI-IV)を、c-末端へのFLAGタグによってHEK293に形質感染した後、培養液で分泌させ、FLAG抗体ビード(antibody bead)(Sigma-Aldrich)を用いて精製した後、ELISAを実施した。その結果を図4に示した。図4によると、抗体は、ドメインIが欠失したとき、c-kitを認知できないことが示され、抗体のc-kitに対する結合部位はドメインIであることが示された。
ヒトc-kit遺伝子(NM_000222、配列番号11)の欠失変異体(Q26-P520、R49-P520、I70-P520、K100-P520、K116-P520、N130-P520、S187-P520)を、c-末端へのFLAGタグによってHEK293に形質感染した後、培養液で分泌させ、FLAG抗体ビード(Sigma-Aldrich)を用いて精製した後、ELISAを実施した。
マウスのOIR(oxygen-induced retinopathy)モデルは、 増殖性糖尿病性網膜症と未熟児網膜症の動物モデルに広く用いられている。C57BL/6マウスを出生後7日から5日間75%の高酸素環境に露出させた後、再度正常酸素濃度に露出させると非正常的血管が形成されるようになるが、本発明に係るc-kit抗体(2μg/eye)がEYLEA(aflibercept)(2μg/eye)より優れた水準で非正常的血管形成を抑制することが示された(図7)。
SCF/c-kitシグナリングは、基本的にAktのERKリン酸化を誘導すると知られている。白血病細胞株であるTF-1にSCFを処理したとき、受容体であるc-kitのリン酸化及びAkt/ERKのリン酸化が増加し、本発明に係る抗体によってc-kitのリン酸化及びAktとERKのリン酸化が抑制されることを確認した。特に、前記抗体が濃度依存的にc-kitのタンパク質を減少させる結果を示した(図9)。
TF-1とHUVECに抗体を濃度別に30分間前処理し、50ng/mlのSCFを処理した後、72時間後にそれぞれの細胞増殖に対する細胞数のカウント(cell counting)を通じて細胞増殖率を比較した。
本発明に係るc-kitに結合する抗体又はその抗原結合断片は、c-kit、特にドメインI及び/又はドメインIIに高い親和力で結合しながらも、優れた水準で非正常的血管形成を抑制することができる。これを通じて、本発明に係るc-kitに結合する抗体又はその抗原結合断片は、目的とする血管新生疾患の予防又は治療に有用に使用可能である。
電子ファイルを添付した。
Claims (11)
- 配列番号1の配列を含む重鎖CDR1、
配列番号2の配列を含む重鎖CDR2、
配列番号3の配列を含む重鎖CDR3、
配列番号4の配列を含む軽鎖CDR1、
配列番号5の配列を含む軽鎖CDR2、及び
配列番号6の配列を含む軽鎖CDR3を含む、c-kitに結合する抗体又はその抗原結合断片であって、
前記抗体又はその抗原結合断片は、配列番号11のc-kitのドメインI及びIIに特異的に結合する、
抗体又はその抗原結合断片。 - 前記抗体は、配列番号11のc-kitのうちドメインIのR49からドメインIIのC186の部位に特異的に結合することを特徴とする、請求項1に記載の抗体又はその抗原結合断片。
- 前記抗体は、配列番号7の配列と90%以上の配列同一性を有する配列を含む重鎖可変領域を含む、請求項1に記載の抗体又はその抗原結合断片。
- 前記抗体は、配列番号8の配列と90%以上の配列同一性を有する配列を含む軽鎖可変領域を含む、請求項1に記載の抗体又はその抗原結合断片。
- 請求項1乃至請求項4のいずれか1項の抗体又はその抗原結合断片をコーディングする核酸。
- 配列番号9又は配列番号10の配列を含む、請求項5に記載の核酸。
- 請求項5の核酸を含む発現ベクター。
- 請求項7の発現ベクターで形質転換された細胞。
- 次の段階を含むc-kitに結合する抗体又はその抗原結合断片の製造方法:
(a)請求項8の細胞を培養する段階;及び
(b)前記培養された細胞から抗体又はその抗原結合断片を回収する段階。 - 請求項1乃至請求項4のいずれか1項の抗体若しくはその抗原結合断片、当該抗体若しくはその抗原結合断片をコーディングする核酸、又は当該核酸を含むベクターを含む血管新生疾患の予防又は治療用組成物。
- 請求項1乃至請求項4のいずれか1項の抗体若しくはその抗原結合断片、当該抗体若しくはその抗原結合断片をコーディングする核酸、又は当該核酸を含むベクターを含む癌の予防又は治療用組成物。
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KR10-2019-0152304 | 2019-11-25 | ||
PCT/KR2020/016704 WO2021107566A1 (ko) | 2019-11-25 | 2020-11-24 | C-kit에 대한 항체 및 이의 용도 |
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JP2004530730A (ja) | 2001-06-29 | 2004-10-07 | アブ サイエンス | 腫瘍の血管新生を治療するための強力で選択的かつ非毒性のc−kit阻害剤の使用法 |
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TWI395754B (zh) * | 2006-04-24 | 2013-05-11 | Amgen Inc | 人類化之c-kit抗體 |
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