JP2017533207A - Slamf1アンタゴニスト及びその使用 - Google Patents
Slamf1アンタゴニスト及びその使用 Download PDFInfo
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- JP2017533207A JP2017533207A JP2017522170A JP2017522170A JP2017533207A JP 2017533207 A JP2017533207 A JP 2017533207A JP 2017522170 A JP2017522170 A JP 2017522170A JP 2017522170 A JP2017522170 A JP 2017522170A JP 2017533207 A JP2017533207 A JP 2017533207A
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Abstract
Description
本出願は2014年10月23日に出願の米国特許仮出願第62/067638号及び2015年5月1日に出願の米国特許仮出願第62/155810号の優先権の利益を主張し、これらのそれぞれはあらゆる目的で出典明示によりその全体が本明細書に援用される。
a)T細胞又はNK細胞で見出される免疫刺激分子などの、共刺激分子を含む免疫刺激分子のアゴニスト;
b)T細胞又はNK細胞で見出される免疫刺激分子などの、共阻害分子を含む免疫阻害分子のアンタゴニスト;
c)CTLA4、LAG−3、PD−1、PDL1、PDL2、ガレクチン1、ガレクチン9、CEACAM−1、BTLA、CD25、CD69、TIGIT、CD113、GPR56、VISTA、B7−H3、B7−H4、2B4、CD48、GARP、PD1H、LAIR1、TIM1、TIM3、TIM4、ILT4、IL−6、IL−10、TGFβ、VEGF、KIR、アデノシンA2A受容体、PI3Kデルタ又はIDOのアンタゴニスト;
d)B7−1、B7−2、CD28、4−1BB(CD137)、4−1BBL、ICOS、ICOS−L、OX40、OX40L、GITR、GITRL、CD27、CD40、CD40L、DR3、CD28H、IL−2、IL−7、IL−12、IL−15、IL−21、IFNα、STINGのアゴニスト、又はTLR2/4アゴニストなどのToll様受容体アゴニスト;
e)B7−1、B7−2、B7−H2(ICOS−L)、B7−H3、B7−H4、B7−H5(VISTA)及びB7−H6などの膜結合タンパク質のB7ファミリーのメンバーに結合する薬剤;
f)CD40、CD40L、OX40、OX40L、GITR、GITRL、CD70、CD27L、CD30、CD30L、4−1BBL、CD137(4−1BB)、TRAIL/Apo2−L、TRAILR1/DR4、TRAILR2/DR5、TRAILR3、TRAILR4、OPG、RANK、RANKL、TWEAKR/Fn14、TWEAK、BAFFR、EDAR、XEDAR、EDA1、EDA2、TACI、APRIL、BCMA、LTβR、LIGHT、DeR3、HVEM、VEGL/TL1A、TRAMP/DR3、TNFR1、TNFβ、TNFR2、TNFα、1β2、FAS、FASL、RELT、DR6、TROY又はNGFβなどの、TNF受容体ファミリーのメンバー又はTNF受容体ファミリーのメンバーに結合する共刺激若しくは共阻害分子に結合する薬剤;
g)IL−6、IL−10、TGFβ、VEGFなどの、T細胞活性化を阻害するサイトカインに拮抗するか又はそれを阻害する薬剤;
h)IL−2、IL−7、IL−12、IL−15、IL−21及びIFNαなどの、T細胞活性化を刺激するサイトカインのアゴニスト;並びに
i)CXCR2、CXCR4、CCR2又はCCR4などのケモカインのアンタゴニスト
の1つ又は複数に含まれる薬剤から選択される。
a)活性化T細胞を候補分子及びSLAMF1分子と接触させることであって、SLAMF1分子は、SLAMF1、SLAMF1 ECD又はSLAMF1 ECD融合分子を含む、接触させること;並びに
b)活性化T細胞の増殖を検出すること
を含み、候補分子の非存在下における活性化T細胞の増殖の抑制と比較したときの、候補分子の存在下における活性化T細胞の増殖の抑制の低減は、その候補分子がSLAMF1アンタゴニストであることを指し示す。一部の実施態様では、候補分子の存在下において、活性化T細胞の増殖の抑制は、少なくとも30%、少なくとも40%、少なくとも50%、少なくとも60%、少なくとも70%又は少なくとも80%低減される。一部の実施態様では、候補分子はSLAMF1に結合する。一部の実施態様では、候補分子は、SLAMF1に結合する抗体である。一部の実施態様では、候補分子は、小分子である。一部の実施態様では、候補分子は、小ペプチドである。一部の実施態様では、活性化T細胞は、活性化CD3+T細胞である。一部の実施態様では、活性化T細胞は、IL−2活性化CD3+T細胞である。
a)活性化T細胞をSLAMF1抗体及びSLAMF1分子と接触させることであって、SLAMF1分子は、SLAMF1、SLAMF1 ECD又はSLAMF1 ECD融合分子を含む、接触させること;並びに
b)活性化T細胞の増殖を検出すること
を含み、SLAMF1抗体の非存在下における活性化T細胞の増殖の抑制と比較したときの、SLAMF1抗体の存在下における活性化T細胞の増殖の抑制の低減は、そのSLAMF1抗体がSLAMF1アンタゴニストであることを指し示す。一部の実施態様では、SLAMF1抗体の存在下において、活性化T細胞の増殖の抑制は、少なくとも30%、少なくとも40%、少なくとも50%、少なくとも60%、少なくとも70%又は少なくとも80%低減される。一部の実施態様では、活性化T細胞は、活性化CD3+T細胞である。一部の実施態様では、活性化T細胞は、IL−2活性化CD3+T細胞である。
特記されない限り、本発明に関連して使用される科学的及び専門用語は、当業者によって一般的に理解される意味を有するものとする。さらに、文脈から特に必要とされない限り、単数形用語は複数形を含み、複数形用語は単数形を含むものとする。
疾患の治療方法
ヒト及び他の哺乳動物を治療する方法で使用するための、SLAMF1アンタゴニストが提供される。ヒト及び他の哺乳動物にSLAMF1アンタゴニストを投与することを含む、疾患を治療する方法が提供される。
一部の実施態様では、がんを治療又は予防する方法であって、そのような治療を必要とする対象にSLAMF1アンタゴニストの有効量を投与することを含む方法が提供される。
一部の実施態様では、活性化T細胞の抑制を阻害する方法であって、活性化T細胞を含む組織をSLAMF1アンタゴニストと接触させることを含む方法が提供される。一部のそのような実施態様では、活性化T細胞の抑制を阻害する方法であって、活性化T細胞がSLAMF1によって抑制される方法が提供される。
様々な実施態様では、SLAMF1アンタゴニストは、皮下又は静脈内に投与することができる。一部の実施態様では、SLAMF1アンタゴニストは、経口、動脈内、非経口、鼻腔内、筋肉内、心臓内、心室内、気管内、口内、直腸、腹腔内、吸入、皮内、局所、経皮及びクモ膜下、その他、例えば移植を限定されずに含む様々な経路によってインビボで投与することができる。対象組成物は、錠剤、カプセル剤、散剤、顆粒、軟膏、溶液、坐薬、浣腸、注射、吸入剤及びエアゾールを限定されずに含む、固体、半固体、液体又は気体の形態の調製物に製剤化することができる。一部の実施態様では、SLAMF1アンタゴニストは、遺伝子療法を使用して送達される。非限定例として、例えば、文献に記載されるように(例えば、Tang等、Nature 356:152-154 (1992)を参照)、SLAMF1アンタゴニストをコードする核酸分子は、金微粒子にコーティングして、微粒子銃デバイス又は「遺伝子銃」によって皮内に送達することができる。
その任意の機能的断片を含む本発明によるSLAMF1アンタゴニストは、他の生物学的に活性な物質又は疾患の治療のための他の治療手法と組み合わせて、それを必要とする対象に投与することができる。例えば、SLAMF1アンタゴニストは、単独で、又は他の様式の治療と一緒に投与することができる。それらは、放射線療法などの他の様式の治療の前、実質的に同時又は後に提供することができる。
一部の実施態様では、SLAMF1活性を阻害する抗体が提供される。一部の実施態様では、SLAMF1活性は、活性化T細胞のSLAMF1媒介抑制である。一部のそのような実施態様では、抗体はSLAMF1抗体である。一部の実施態様では、SLAMF1抗体は、SLAMF1細胞外ドメイン(ECD)に結合する。一部の実施態様では、SLAMF1抗体は、SLAMF1媒介シグナル伝達を阻害する。
一部の実施態様では、SLAMF1抗体は、ヒト化抗体である。ヒト化抗体は、抗体治療薬への免疫応答及び治療薬の有効性の減少をもたらすことができる非ヒト抗体へのヒト免疫応答(ヒト抗マウス抗体(HAMA)応答など)を低減又は排除するので、治療分子として有益である。
一部の実施態様では、SLAMF1抗体は、キメラ抗体である。一部の実施態様では、SLAMF1抗体は、少なくとも1つの非ヒト可変領域及び少なくとも1つのヒト定常領域を含む。一部のそのような実施態様では、SLAMF1抗体の可変領域の全ては非ヒト可変領域であり、SLAMF1抗体の定常領域の全てはヒト定常領域である。一部の実施態様では、キメラ抗体の1つ又は複数の可変領域は、マウス可変領域である。キメラ抗体のヒト定常領域は、あるならばそれが置き換える非ヒト定常領域と同じアイソタイプのものである必要はない。キメラ抗体は、例えば、米国特許第4816567号;及びMorrison等、Proc. Natl. Acad. Sci. USA 81: 6851−55(1984)で議論される。
一部の実施態様では、SLAMF1抗体は、ヒト抗体である。ヒト抗体は、任意の適する方法によって作製することができる。非限定的な例示的方法には、ヒト免疫グロブリン遺伝子座を含むトランスジェニックマウスでヒト抗体を作製することが含まれる。例えば、Jakobovits等、Proc. Natl. Acad. Sci. USA 90: 2551−55(1993);Jakobovits等、Nature 362: 255−8(1993);Lonberg等、Nature 368: 856−9(1994);並びに米国特許第5545807号;第6713610号;第6673986号;第6162963号;第5545807号;第6300129号;第6255458号;第5877397号;第5874299号;及び第5545806号を参照。
一部の実施態様では、本明細書に記載されるヒト化、キメラ又はヒト抗体は、1つ又は複数のヒト定常領域を含む。一部の実施態様では、ヒト重鎖定常領域は、IgA、IgG及びIgDから選択されるアイソタイプのものである。一部の実施態様では、ヒト軽鎖定常領域は、κ及びλから選択されるアイソタイプのものである。一部の実施態様では、本明細書に記載される抗体は、ヒトIgG定常領域、例えば、ヒトIgG1、IgG2、IgG3又はIgG4を含む。一部の実施態様では、抗体又はFc融合パートナーは、例えばIgG1定常領域にC237S突然変異を含む。例えば、配列番号6を参照。一部の実施態様では、本明細書に記載される抗体は、ヒトIgG2重鎖定常領域を含む。一部のそのような実施態様では、IgG2定常領域は、米国特許第6900292号に記載されるように、P331S突然変異を含む。一部の実施態様では、本明細書に記載される抗体は、ヒトIgG4重鎖定常領域を含む。一部のそのような実施態様では、本明細書に記載される抗体は、ヒトIgG4定常領域にS241P突然変異を含む。例えば、Angal等、Mol. Immunol. 30(1): 105−108(1993)を参照。一部の実施態様では、本明細書に記載される抗体は、ヒトIgG4定常領域及びヒトκ軽鎖を含む。
SLAMF1抗体の例示的性質
一部の実施態様では、SLAMF1抗体はSLAMF1に結合して、SLAMF1媒介シグナル伝達を阻害する。一部の実施態様では、SLAMF1抗体は、活性化T細胞のSLAMF1媒介抑制を阻害する。一部の実施態様では、SLAMF1抗体は、活性化CD3+T細胞のSLAMF1媒介抑制を阻害する。一部の実施態様では、SLAMF1抗体は、IL−2活性化CD3+T細胞のSLAMF1媒介抑制を阻害する。一部の実施態様では、SLAMF1抗体は、50nM未満、20nM未満、10nM未満又は1nM未満の結合親和性(KD)でSLAMF1に結合する。一部の実施態様では、例えばラジオイムノアッセイ(RIA)によって測定したとき、無関係な非SLAMF1タンパク質へのSLAMF1抗体の結合の程度は、SLAMF1への抗体の結合の約10%未満である。一部の実施態様では、SLAMF1抗体は、異なる種からのSLAMF1の間で保存されるSLAMF1のエピトープに結合する。一部の実施態様では、SLAMF1抗体は、ヒトSLAMF1に結合するヒトの又はヒト化SLAMF1抗体と同じエピトープに結合する。
一部の実施態様では、SLAMF1は標識にコンジュゲートされる。本明細書で用いるように、標識は、抗体の検出を促進する、及び/又は抗体が結合する分子の検出を促進する部分である。非限定的な例示的標識には、放射性同位体、蛍光性の基、酵素の基、化学発光性の基、ビオチン、エピトープタグ、金属結合性タグなどが限定されずに含まれる。当業者は、目的の適用に従って適する標識を選択することができる。
一部の分泌タンパク質が発現し、大量に分泌するためには、異種タンパク質からのシグナルペプチドが望ましいことがある。分泌の過程でERにおいてシグナルペプチドが除去されるので生じる成熟したポリペプチドが不変のままであることができるという点で、異種シグナルペプチドを用いることが有利かもしれない。一部のタンパク質を発現させ、分泌するために、異種シグナルペプチドの付加を必要とすることがある。
一部の実施態様では、SLAMF1などのポリペプチドは、翻訳の間か後に、例えばグリコシル化、シアリル化、アセチル化、リン酸化、アミド化、公知の保護/ブロック基による誘導体化、タンパク分解性開裂又は抗体分子若しくは他の細胞性リガンドへの連結によって差別的に修飾される。多数の化学修飾のいずれも、臭化シアン、トリプシン、キモトリプシン、パパイン、V8プロテアーゼによる特異的化学的開裂;NaBH4;アセチル化;ホルミル化;酸化;還元;及び/又はツニカマイシンの存在下での代謝合成を限定されずに含む公知の技術によって実行することができる。
SLAMF1などの、本明細書に記載される抗体の1つ又は複数の鎖をコードするポリヌクレオチドを含む核酸分子が、提供される。一部の実施態様では、核酸分子は、本明細書に記載される抗体の重鎖又は軽鎖をコードするポリヌクレオチドを含む。一部の実施態様では、核酸分子は、本明細書に記載される抗体の重鎖をコードするポリヌクレオチド及び軽鎖をコードするポリヌクレオチドの両方を含む。一部の実施態様では、第1の核酸分子は重鎖をコードする第1のポリヌクレオチドを含み、第2の核酸分子は軽鎖をコードする第2のポリヌクレオチドを含む。
ベクター
本明細書に記載される抗体の重鎖及び/又は軽鎖をコードするポリヌクレオチドを含むベクターが提供される。そのようなベクターには、DNAベクター、ファージベクター、ウイルスベクター、レトロウイルスベクターなどが限定されずに含まれる。一部の実施態様では、ベクターは、重鎖をコードする第1のポリヌクレオチド配列及び軽鎖をコードする第2のポリヌクレオチド配列を含む。一部の実施態様では、重鎖及び軽鎖は2つの別個のポリペプチドとしてベクターから発現される。一部の実施態様では、重鎖及び軽鎖は、例えば抗体がscFvであるとき、単一のポリペプチドの一部として発現される。
様々な実施態様では、本明細書に記載される抗体の重鎖及び/又は軽鎖は、細菌細胞などの原核細胞;又は真菌細胞(酵母など)、植物細胞、昆虫細胞及び哺乳動物細胞などの真核細胞で発現させることができる。そのような発現は、例えば当該技術分野で公知の手法によって実行することができる。ポリペプチドを発現させるために使用することができる例示的な真核細胞には、COS7細胞を含むCOS細胞;293−6E細胞を含む293細胞;CHO−S及びDG44細胞を含むCHO細胞;PER.C6(登録商標)細胞(Crucell);並びにNSO細胞が限定されずに含まれる。一部の実施態様では、本明細書に記載される抗体の重鎖及び/又は軽鎖は、酵母で発現させることができる。例えば、米国特許出願公開番号US2006/0270045 A1を参照。一部の実施態様では、SLAMF1抗体の重鎖及び/又は軽鎖に所望の翻訳後修飾を加えるその能力に基づいて、特定の真核宿主細胞が選択される。例えば、一部の実施態様では、CHO細胞は、293細胞で生成される同じポリペプチドより高いレベルのシアリル化を有するポリペプチドを生成する。
本明細書に記載される抗体は、任意の適する方法によって精製することができる。そのような方法には、親和性マトリックス又は疎水性相互作用クロマトグラフィーの使用が限定されずに含まれる。適する親和性リガンドには、抗体が結合する抗原及び/又はエピトープ並びに抗体定常領域に結合するリガンドが含まれる。定常領域に結合して抗体を精製するために、例えば、プロテインA、プロテインG、プロテインA/G又は抗体親和性カラムを使用することができる。
一部の実施態様では、本明細書に記載される抗体は、無細胞系で生成される。非限定的な例示的無細胞系は、例えば、Sitaraman等、Methods Mol. Biol. 498: 229−44(2009);Spirin、Trends Biotechnol. 22: 538−45(2004);Endo等、Biotechnol. Adv. 21: 695−713(2003)に記載される。
一部の実施態様では、SLAMF1アンタゴニストを同定する方法が提供される。一部の実施態様では、方法は、SLAMF1、SLAMF1 ECD又はSLAMF1 ECD融合分子(「SLAMF1分子」と総称される)と候補分子を接触させることを含む。一部の実施態様では、本方法は、候補分子/SLAMF1分子混合物とIL−2活性化CD3+T細胞を接触させて、T細胞活性化に対する影響を判定することをさらに含む。一部の実施態様では、本方法は、候補分子とIL−2活性化CD3+T細胞を接触させ、次に混合物をSLAMF1分子と接触させて、T細胞活性化に対する影響を判定することを含む。一部の実施態様では、アッセイは、実質的に本明細書の実施例3に記載される通りであるが、候補分子の存在下で実行される。一部の実施態様では、SLAMF1分子単独の存在下におけるT細胞活性化の抑制と比較して、候補分子の存在下におけるT細胞活性化の抑制が低減されるならば、候補分子はSLAMF1アンタゴニストである。一部の実施態様では、候補分子は、T細胞活性化の抑制を少なくとも20%、少なくとも30%、少なくとも40%、少なくとも50%、少なくとも60%、少なくとも70%、少なくとも80%又は少なくとも90%低減する。一部の実施態様では、候補分子は、抗SLAMF1抗体である。当業者は、成分がお互いと接触する順序は、アッセイ設計によって変えることができることを認めるであろう。
一部の実施態様では、バイオマーカー(例えば、SLAMF1)の検出又は上記の障害の治療、予防及び/若しくは診断のために有益な物質を含有する製造品又はキットが提供される。製造品は、容器、及び容器の上に又はそれに関連して表示又は添付文書を含む。適する容器には、例えば、ボトル、バイアル、シリンジなどが含まれる。容器はガラス又はプラスチックなどの様々な材料で形成することができる。一部の実施態様では、容器は、単独であるか、状態を治療、予防及び/又は診断するために有効な別の組成物と組み合わされた組成物を保持し、滅菌アクセスポートを有することができる(例えば、容器は、皮下注射針で穿刺可能なストッパを有する静脈内溶液バッグ又はバイアルであってもよい)。表示又は添付文書は、組成物が選択された状態を治療するために使用されることを示す。一部の実施態様では、製造品は、(a)本発明のSLAMF1アンタゴニストを含む組成物をその中に含有する第1の容器;及び(b)さらなる治療剤を含む組成物をその中に含有する第2の容器を含むことができる。製造品は、特定の状態を治療するために組成物を使用することができることを表示する添付文書をさらに含むことができる。あるいは、又はさらに、製造品は、薬学的に許容されるバッファー、例えば静菌性注射用水(BWFI)、リン酸緩衝食塩水、リンゲル液及びデキストロース溶液を含む第2の(又は第3の)容器をさらに含むことができる。それは、他のバッファー、希釈剤、フィルター、針及びシリンジを含む、商業的及びユーザーの見地から望ましい他の材料をさらに含むことができる。
材料及び方法
細胞/血液。全てのバフィーコートは、Stanford Blood Centerから得られた。
PD−L1は活性化/IL−2静止CD3+T細胞の増殖を抑制する
この固定化されているFcタンパク質アッセイフォーマットがT細胞の増殖を抑制することが可能なタンパク質を同定することができるかどうかについて探究するために、前に活性化され、IL−2で静止されたCD3+T細胞を、抗CD3、抗ヒトIgG並びにR&D SystemsからのhIgG1及びPD−L1又はFive Prime Therapeuticsにて生産されたPD−L1のいずれかでコーティングされたプレートに加えた。これらのFcタンパク質の存在下での活性化/IL−2静止T細胞の72時間の再刺激は、PD−L1の存在下でだけ増殖が抑制されることを実証した(図1)。用量依存的抑制がいずれのPD−L1タンパク質の存在下でも観察されたのに対して、hIgG1の存在下で用量依存的抑制は観察されなかった。試験したhIgG1の最も高い濃度(すなわち100μg/mL)で多少の抑制があり、≧100μg/mLの濃度が多少の非特異的抑制を生じ得ることを示唆する。このデータは、このアッセイ系がT細胞の増殖を抑制することが可能なFcタンパク質を同定することが可能なことを実証する。
SLAMF1−Fcは活性化/IL−2静止CD3+T細胞の増殖を抑制する
この精製T細胞アッセイフォーマットでSLAMF1 ECD−FcがT細胞の増殖を抑制するかどうかについて探究するために、前に活性化され、IL−2で静止されたCD3+T細胞を、抗CD3、抗ヒトIgG及びFive Prime Therapeuticsにて生産されたSLLAMF1−Fcでコーティングされたプレートに再び加えた。SLAMF1−Fcの存在下での活性化/IL−2静止T細胞の72時間の再刺激は、SLAMF1−Fcが増殖を用量依存的に抑制することを実証した(図2)。SLAMF1−Fcは試験した3ドナーで完全に近い阻害を、及び試験した3ドナーで部分的阻害を実証した。これらのデータは、SLAMF1−FcがT細胞の増殖を抑制することを示唆する。
ヒト組織におけるSLAMF1の発現
SLAMF1は、本来RT−PCRによってリンパ細胞で排他的に発現されると同定された。Cocks等、1995、Nature 376: 260−263を参照。RT−PCRはヒト組織RNA(Clontech)及びヒト免疫細胞RNA(AllCells、LLC)の群で実行され、それらは製造業者のプロトコール(Qiagen)に従ってcDNAに逆転写された。SLAMF1のための遺伝子特異的プライマー又はGUSB(Qiagen)及びSYBR Green試薬(Qiagen)を使用した定量的PCRのために、cDNAを希釈し、並行ウェルに分配した。95℃で15秒、55℃で30秒及び72℃で30秒の合計40サイクルの間、製造業者の推奨プロトコールに従ってqPCRを実行した。各組織の中の発現は、ΔΔCt方法を使用してGUSBの相対発現に正規化した。SLAMF1のmRNAは、胸腺で、並びにCD4+T細胞(ナイーブ及び記憶細胞の両方、記憶T細胞でより高い発現)、CD8+細胞傷害性T細胞、T調節細胞、B細胞及び単球由来の樹状細胞で発現されることが見出された。図3を参照。このRT−PCRデータは、公開されたタンパク質発現データと一致する。例えば、Aversa等、1997、J Immunol 158:4036−4044;Punnonen等、1997、J Exp Med 185: 993−1004;Bleharski等、2001、J Immunol 167: 3174−3181を参照。これらのデータは、SLAMF1の発現が活性化T細胞、B細胞及び樹状細胞で濃縮されることを示す−PD−1及びTIM3を含む他の免疫チェックポイントに一致するパターン。
SLAMF1はインビボで腫瘍増殖を増加させる
11週齢雌C57BL/6マウスをCharles River Laboratories(Hollister、CA)から購入し、試験開始前の9日間順応させた。SLAMF1 ECD Fcをコードする核酸の尾静脈トランスフェクションを用いて、SLAMF1 ECD Fcの構成的、全身性発現を誘導するために、マウスを処置した。遺伝子発現の誘導を模倣するために、コントロール動物を食塩水で処置した。次に、マウスの右側腹部に、マウスのT細胞リンパ腫細胞株E.G7−OVAを1×106細胞数/100μl/マウスで皮下に植え込んだ。E.G7−OVA細胞株は、ATCC(Manassas、VA;カタログ番号CRL−2113)から購入した。接種の前に、10%熱不活性化ウシ胎児血清(FBS)、2mM L−グルタミン、1.5g/L重炭酸ナトリウム、4.5g/Lグルコース、10mM HEPES、1.0mMピルビン酸ナトリウム、0.05mM 2−メルカプトエタノール、0.4mg/ml G418及び抗生−抗真菌性溶液を追加したRPMI 1640の培養液で細胞を3継代培養した。5%CO2の加湿雰囲気中の37℃で、細胞を増殖させた。80−85%の集密度に到達した後、細胞を収集し、1ミリリットルにつき1×107細胞数で、50%マトリゲルを含有する冷たいCa2+及びMg2+フリーのリン酸緩衝食塩水(PBS)に再懸濁させた。
抗SLAMF1抗体は、人工APCアッセイでT細胞阻害を軽減する
完全長マウスSLAMF1をコードするDNAを含有するレンチウイルス(Genecopoeia EX−Mm06571−Lv105)、又は空のベクターコントロールに、マウスA20細胞(ATCC TIB−208)を感染させた。A20細胞でのマウスSLAMF1の安定した発現が、フローサイトメトリーによって確認された(BioLegendクローンTC15−12F12.2)。
人工APCアッセイでのヒトSLAMF1によるT細胞阻害は、ブロッキング抗体によって軽減することができる
Gerdemann等、2012 Molecular Therapy 20: 1622−32から適合させたプロトコールを使用して、Cellular Technology LtdからのHLA−A*02陽性末梢血単核細胞(PBMC)からCMV反応性CD8+T細胞を増殖させた。簡潔には、10μg/mLのCMVpp65495−503(Anaspec28328)を37℃で2時間、PBMCに加え、その後、2ng/mLの組換えIL−2(Sigma−Aldrich)及び10ng/mLの組換えIL−7(R&D Systems)を加えたCTL培養液(10%熱不活性化ヒトAB血清(Sigma−Aldrich)、2mMのL−グルタミン、1×ペニシリン/ストレプトマイシン及び0.05mMの2−メルカプトエタノールを加えたRPMI 1640培養液)に平板培養した。11日後に、10μg/mLのCMVペプチドを加えた、自家マイトマイシンC処置PHA芽球で細胞を再刺激した(実施例6のように)。細胞をさらに10日間増殖させ、次に、CD8+T細胞をMiltenyiヒトCD8+T細胞分離キット(130−096−495)で分離し、低温保存した。
SLAMF1は、腫瘍浸潤性T細胞の上で発現される
BALB/cマウスをCharles River Laboratoriesから購入し、順化の後、マウス当たり1×106細胞数/200μlで右側腹部の皮下にマウス結腸癌細胞株CT26(ATCC CRL−2638)を接種した。接種の前に、10%ウシ胎児血清(FBS)を加えたRPMI 1640培養液で、細胞を3継代以下培養した。5%CO2の加湿雰囲気中の37℃で、細胞を増殖させた。80−85%の集密度に到達した後、細胞を収集し、1ミリリットルにつき5×106細胞数で、50%マトリゲルを含有する冷RPMI 1640に再懸濁させた。
表3:マウス腫瘍リンパ球抗体染色パネル
Claims (41)
- がんを治療する方法であって、がんを有する対象に少なくとも1つのSLAMF1アンタゴニストの有効量を投与することを含む方法。
- 対象における活性化T細胞の抑制を阻害する方法であって、対象に少なくとも1つのSLAMF1アンタゴニストを投与することを含む方法。
- 対象に化学療法剤、抗血管新生剤、増殖阻害剤及び抗腫瘍組成物から選択される治療剤の有効量を投与することをさらに含む、請求項1又は2に記載の方法。
- 抗腫瘍組成物が免疫刺激剤を含む、請求項3に記載の方法。
- 免疫刺激剤が以下のカテゴリー:
a)T細胞又はNK細胞で見出される免疫刺激分子などの、共刺激分子を含む免疫刺激分子のアゴニスト;
b)T細胞又はNK細胞で見出される免疫刺激分子などの、共阻害分子を含む免疫阻害分子のアンタゴニスト;
c)CTLA4、LAG−3、PD−1、PDL1、PDL2、ガレクチン1、ガレクチン9、CEACAM−1、BTLA、CD25、CD69、TIGIT、CD113、GPR56、VISTA、B7−H3、B7−H4、2B4、CD48、GARP、PD1H、LAIR1、TIM1、TIM3、TIM4、ILT4、IL−6、IL−10、TGFβ、VEGF、KIR、アデノシンA2A受容体、PI3Kデルタ又はIDOのアンタゴニスト;
d)B7−1、B7−2、CD28、4−1BB(CD137)、4−1BBL、ICOS、ICOS−L、OX40、OX40L、GITR、GITRL、CD27、CD40、CD40L、DR3、CD28H、IL−2、IL−7、IL−12、IL−15、IL−21、IFNα、STINGのアゴニスト、又はTLR2/4アゴニストなどのToll様受容体アゴニスト;
e)B7−1、B7−2、B7−H2(ICOS−L)、B7−H3、B7−H4、B7−H5(VISTA)及びB7−H6などの膜結合タンパク質のB7ファミリーのメンバーに結合する薬剤;
f)CD40、CD40L、OX40、OX40L、GITR、GITRL、CD70、CD27L、CD30、CD30L、4−1BBL、CD137(4−1BB)、TRAIL/Apo2−L、TRAILR1/DR4、TRAILR2/DR5、TRAILR3、TRAILR4、OPG、RANK、RANKL、TWEAKR/Fn14、TWEAK、BAFFR、EDAR、XEDAR、EDA1、EDA2、TACI、APRIL、BCMA、LTβR、LIGHT、DeR3、HVEM、VEGL/TL1A、TRAMP/DR3、TNFR1、TNFβ、TNFR2、TNFα、1β2、FAS、FASL、RELT、DR6、TROY又はNGFβなどの、TNF受容体ファミリーのメンバー又はTNF受容体ファミリーのメンバーに結合する共刺激若しくは共阻害分子に結合する薬剤;
g)IL−6、IL−10、TGFβ、VEGFなどの、T細胞活性化を阻害するサイトカインに拮抗するか又はそれを阻害する薬剤;
h)IL−2、IL−7、IL−12、IL−15、IL−21及びIFNαなどの、T細胞活性化を刺激するサイトカインのアゴニスト;並びに
i)CXCR2、CXCR4、CCR2又はCCR4などのケモカインのアンタゴニスト
の1つ又は複数に含まれる薬剤から選択される、請求項4に記載の方法。 - 活性化T細胞の抑制を阻害する方法であって、T細胞を少なくとも1つのSLAMF1アンタゴニストと接触させることを含む方法。
- T細胞がインビトロである、請求項6に記載の方法。
- 少なくとも1つのSLAMF1アンタゴニストが、活性化T細胞の増殖の抑制を少なくとも30%、少なくとも40%、少なくとも50%、少なくとも60%、少なくとも70%又は少なくとも80%低減する、請求項1から7のいずれか一項に記載の方法。
- 活性化T細胞がCD3+T細胞である、請求項8に記載の方法。
- 活性化T細胞がIL−2活性化CD3+T細胞である、請求項9に記載の方法。
- SLAMF1アンタゴニストがSLAMF1細胞外ドメイン(ECD)又はSLAMF1 ECD融合分子である、請求項1から10のいずれか一項に記載の方法。
- SLAMF1 ECD又はSLAMF1 ECD融合分子がモノマーである、請求項11に記載の方法。
- SLAMF1 ECD又はSLAMF1 ECD融合分子がダイマーである、請求項11に記載の方法。
- SLAMF1アンタゴニストがSLAMF1抗体である、請求項1から10のいずれか一項に記載の方法。
- 前記抗体が、キメラ抗体、ヒト化抗体及びヒト抗体から選択される、請求項14に記載の方法。
- 前記抗体が二重特異性抗体又は単鎖抗体である、請求項14に記載の方法。
- 前記抗体が抗体断片である、請求項14から16のいずれか一項に記載の方法。
- 前記抗体断片が、Fv、単鎖Fv(scFv)、Fab、Fab’及び(Fab’)2から選択される、請求項17に記載の方法。
- SLAMF1アンタゴニストが小分子又は小ペプチドである、請求項1から10のいずれか一項に記載の方法。
- SLAMF1アンタゴニストを同定する方法であって、
c)活性化T細胞を候補分子及びSLAMF1分子と接触させることであって、SLAMF1分子はSLAMF1、SLAMF1 ECD又はSLAMF1 ECD融合分子を含む、接触させること;並びに
d)活性化T細胞の増殖を検出すること
を含み、候補分子の非存在下における活性化T細胞の増殖の抑制と比較したときの、候補分子の存在下における活性化T細胞の増殖の抑制の低減は、その候補分子がSLAMF1アンタゴニストであることを指し示す方法。 - 候補分子の存在下において、活性化T細胞の増殖の抑制が、少なくとも30%、少なくとも40%、少なくとも50%、少なくとも60%、少なくとも70%又は少なくとも80%低減される、請求項20に記載の方法。
- 候補分子がSLAMF1に結合する、請求項20又は21に記載の方法。
- 候補分子がSLAMF1に結合する抗体である、請求項22に記載の方法。
- 候補分子が小分子である、請求項20から22のいずれか一項に記載の方法。
- 候補分子が小ペプチドである、請求項20から22のいずれか一項に記載の方法。
- 活性化T細胞が活性化CD3+T細胞である、請求項20から25のいずれか一項に記載の方法。
- 活性化T細胞がIL−2活性化CD3+T細胞である、請求項26に記載の方法。
- SLAMF1抗体がSLAMF1アンタゴニストであるかどうかを判定する方法であって、
c)活性化T細胞をSLAMF1抗体及びSLAMF1分子と接触させることであって、SLAMF1分子は、SLAMF1、SLAMF1 ECD又はSLAMF1 ECD融合分子を含む、接触させること;並びに
d)活性化T細胞の増殖を検出すること
を含み、SLAMF1抗体の非存在下における活性化T細胞の増殖の抑制と比較したときの、SLAMF1抗体の存在下における活性化T細胞の増殖の抑制の低減は、そのSLAMF1抗体がSLAMF1アンタゴニストであることを指し示す方法。 - SLAMF1抗体の存在下において、活性化T細胞の増殖の抑制が、少なくとも30%、少なくとも40%、少なくとも50%、少なくとも60%、少なくとも70%又は少なくとも80%低減される、請求項28に記載の方法。
- 活性化T細胞が活性化CD3+T細胞である、請求項28又は29に記載の方法。
- 活性化T細胞がIL−2活性化CD3+T細胞である、請求項30に記載の方法。
- 対象におけるがんを治療するためのSLAMF1アンタゴニストの使用。
- SLAMF1アンタゴニストがSLAMF1抗体である、請求項32に記載の使用。
- 抗体が、キメラ抗体、ヒト化抗体及びヒト抗体から選択される、請求項33に記載の使用。
- 抗体が抗体断片である、請求項33又は34に記載の使用。
- 抗体断片が、Fv、単鎖Fv(scFv)、Fab、Fab’及び(Fab’)2から選択される、請求項35に記載の使用。
- 抗体が二重特異性抗体又は単鎖抗体である、請求項33に記載の使用。
- SLAMF1アンタゴニストがSLAMF1細胞外ドメイン(ECD)又はSLAMF1 ECD融合分子である、請求項32に記載の使用。
- SLAMF1 ECD又はSLAMF1 ECD融合分子がモノマーである、請求項38に記載の使用。
- SLAMF1 ECD又はSLAMF1 ECD融合分子がダイマーである、請求項38に記載の使用。
- SLAMF1アンタゴニストが小分子又は小ペプチドである、請求項32に記載の使用。
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US201462067638P | 2014-10-23 | 2014-10-23 | |
US62/067,638 | 2014-10-23 | ||
US201562155810P | 2015-05-01 | 2015-05-01 | |
US62/155,810 | 2015-05-01 | ||
PCT/US2015/056714 WO2016065038A1 (en) | 2014-10-23 | 2015-10-21 | Slamf1 antagonists and uses thereof |
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JP2017533207A true JP2017533207A (ja) | 2017-11-09 |
JP2017533207A5 JP2017533207A5 (ja) | 2018-11-29 |
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US (1) | US20180016555A1 (ja) |
EP (1) | EP3209688A1 (ja) |
JP (1) | JP2017533207A (ja) |
CN (1) | CN108064166A (ja) |
WO (1) | WO2016065038A1 (ja) |
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BR112017019559B1 (pt) | 2015-03-13 | 2020-08-04 | Cytomx Therapeutics, Inc | Anticorpos anti-pdl1, anticorpos anti-pdl1 ativáveis, e métodos de uso destes |
US10513558B2 (en) | 2015-07-13 | 2019-12-24 | Cytomx Therapeutics, Inc. | Anti-PD1 antibodies, activatable anti-PD1 antibodies, and methods of use thereof |
SG11201909154SA (en) | 2017-04-05 | 2019-10-30 | Hoffmann La Roche | Bispecific antibodies specifically binding to pd1 and lag3 |
KR20200016899A (ko) | 2017-06-01 | 2020-02-17 | 싸이톰스 테라퓨틱스, 인크. | 활성화가능 항-pdl1 항체, 및 이의 이용 방법 |
CN110305210B (zh) * | 2018-03-27 | 2023-02-28 | 信达生物制药(苏州)有限公司 | 新型抗体分子、其制备方法及其用途 |
WO2019184909A1 (zh) * | 2018-03-27 | 2019-10-03 | 信达生物制药(苏州)有限公司 | 新型抗体分子、其制备方法及其用途 |
EP3994172A1 (en) * | 2019-07-03 | 2022-05-11 | Oxford BioTherapeutics Ltd | Antibodies and methods of use |
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US5576423A (en) * | 1994-12-02 | 1996-11-19 | Schering Corporation | Antibodies to the slam protein expressed on activated T cells |
AU2003291625B2 (en) * | 2002-09-16 | 2009-10-08 | Genentech, Inc. | Compositions and methods for the treatment of immune related diseases |
WO2012121429A1 (ko) * | 2011-03-07 | 2012-09-13 | 연세대학교 산학협력단 | 암 세포 바이오 마커를 동정하는 방법 및 상기 방법으로 동정한 nmd-무관 암 세포 바이오 마커 |
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2015
- 2015-10-21 JP JP2017522170A patent/JP2017533207A/ja active Pending
- 2015-10-21 US US15/520,998 patent/US20180016555A1/en not_active Abandoned
- 2015-10-21 CN CN201580070049.7A patent/CN108064166A/zh active Pending
- 2015-10-21 EP EP15790387.3A patent/EP3209688A1/en not_active Withdrawn
- 2015-10-21 WO PCT/US2015/056714 patent/WO2016065038A1/en active Application Filing
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EP3209688A1 (en) | 2017-08-30 |
CN108064166A (zh) | 2018-05-22 |
WO2016065038A1 (en) | 2016-04-28 |
US20180016555A1 (en) | 2018-01-18 |
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