JP5984810B2 - 抗ox40抗体およびそれを使用する方法 - Google Patents
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Description
本発明は、一般的にはOX40受容体活性化の調節に関し、より詳細には、OX40受容体を調節して、インターロイキン10(IL-10)産生CD4+ 1型調節性T細胞(「Tr1細胞」)およびFoxp3+発現調節性T細胞(場合によっては、本明細書において「Foxp3+ T-reg」細胞とも称される)の免疫抑制機能、ならびにCD4+細胞またはナイーブ細胞からのTr1細胞の生成、ならびにIL-10産生を阻害することに関する。
本出願は、2010年8月23日に出願された米国特許出願第61/375,999号、および2010年9月8日に出願された米国特許出願第61/380,827号の恩典および優先権を主張する。いずれの出願も、参照により本明細書に組み入れられる。
本発明は、米国立衛生研究所により付与されたR01 AI061645-01、R01 AI062888-01、およびU19 AI071130-01の下で、政府の支援を受けてなされたものである。政府は、本発明において一定の権利を有する。
該当なし。
本開示は、2011年8月23日に作成された、13,836バイトのサイズのsequence listing.txtという名称のテキストファイルとして、37 C.F.R. § 1.52(e)(v)に従って提出された配列表を含み、これは参照により本明細書に組み入れられる。添付の配列の記述および配列表は、37 C.F.R. §§ 1.821〜1.825に記載される、特許出願におけるヌクレオチドおよび/またはアミノ酸配列の開示に適用される規則に従う。配列表は、Nucleic Acids Res. 13:3021-3030 (1985)およびBiochemical J. 219 (No. 2):345-373 (1984)に記述されるIUPAC-IUBMB基準に従って定義されるような、ヌクレオチド配列文字についての1文字記号およびアミノ酸についての3文字記号を含む。ヌクレオチドおよびアミノ酸配列データのために使用される記号および型式は、37 C.F.R. §1.822に記載される規則に従う。
Tr1細胞は、末梢性寛容において重要な役割を有する。Tr1細胞は、炎症性免疫応答中に宿主に対する組織損傷を制限する上で特に重要である。Tr1細胞の生成は、インビボおよびインビトロにおいてTH1およびTH2免疫応答の両方を伴う。
OX40受容体の活性化は、ナイーブまたはメモリーCD4+ T細胞からのTr1生成、ならびにTr1細胞からのIL-10産生、およびTr1細胞の免疫抑制機能を阻止する。OX40受容体の活性化はまた、Foxp3+ T-reg細胞によるIL-10産生、および免疫抑制機能を阻止する。したがって、OX40受容体に結合するアゴニスト抗体を本明細書において提示するが、該アゴニストは、OX40受容体の活性化を調節して、IL-10サイトカイン分泌、ならびに/またはTr1細胞およびFoxp3+ T-reg細胞の全体的な免疫抑制機能を阻止する。本質的に、この抗体はOX40リガンドを模倣し、Tr1細胞、および/または「Foxp3+ T-reg」とも称される天然T調節性細胞(「nTreg」)上のOX40受容体を誘発し得る。
[本発明1001]
OX40に結合し、(a) SEQ ID NO: 1のアミノ酸配列を含む重鎖可変領域CDR1と;(b) SEQ ID NO: 2のアミノ酸配列を含む重鎖可変領域CDR2と;(c) SEQ ID NO: 3のアミノ酸配列を含む重鎖可変領域CDR3と;(d) SEQ ID NO: 7のアミノ酸配列を含む軽鎖可変領域CDR1と;(e) SEQ ID NO: 8のアミノ酸配列を含む軽鎖可変領域CDR2と; (f) SEQ ID NO: 9のアミノ酸配列を含む軽鎖可変領域CDR3とを含む、単離された抗体。
[本発明1002]
OX40に結合し、(a) SEQ ID NO: 13のアミノ酸配列を含む重鎖可変領域CDR1と;(b) SEQ ID NO: 14のアミノ酸配列を含む重鎖可変領域CDR2と;(c) SEQ ID NO: 15のアミノ酸配列を含む重鎖可変領域CDR3と;(d) SEQ ID NO: 19のアミノ酸配列を含む軽鎖可変領域CDR1と;(e) SEQ ID NO: 20のアミノ酸配列を含む軽鎖可変領域CDR2と; (f) SEQ ID NO: 21のアミノ酸配列を含む軽鎖可変領域CDR3とを含む、単離された抗体。
[本発明1003]
OX40と結合し、SEQ ID NO: 7もしくは19のアミノ酸配列を含む、単離された抗体、または、SEQ ID NO: 7もしくは19のアミノ酸配列と90パーセントの相同性を有するアミノ酸配列を含む、抗体。
[本発明1004]
OX40と結合し、SEQ ID NO: 8もしくは20のアミノ酸配列を含む、単離された抗体、または、SEQ ID NO: 8もしくは20のアミノ酸配列と90パーセントの相同性を有するアミノ酸配列を含む、抗体。
[本発明1005]
OX40と結合し、SEQ ID NO: 9もしくは21のアミノ酸配列を含む、単離された抗体、または、SEQ ID NO: 9もしくは21のアミノ酸配列と90パーセントの相同性を有するアミノ酸配列を含む、抗体。
[本発明1006]
OX40と結合し、SEQ ID NO: 1もしくは13のアミノ酸配列を含む、単離された抗体、または、SEQ ID NO: 1もしくは13のアミノ酸配列と90パーセントの相同性を有するアミノ酸配列を含む、抗体。
[本発明1007]
OX40と結合し、SEQ ID NO: 2もしくは14のアミノ酸配列を含む、単離された抗体、または、SEQ ID NO: 2もしくは14のアミノ酸配列と90パーセントの相同性を有するアミノ酸配列を含む、抗体。
[本発明1008]
OX40と結合し、SEQ ID NO: 3もしくは15のアミノ酸配列を含む、単離された抗体、または、SEQ ID NO: 3もしくは15のアミノ酸配列と90パーセントの相同性を有するアミノ酸配列を含む、抗体。
[本発明1009]
SEQ ID NO: 5もしくは17のアミノ酸配列を含む重鎖可変領域と、SEQ ID NO: 11もしくは23のアミノ酸配列を含む軽鎖可変領域とを有する抗体によって、またはそれらと少なくとも90パーセントの相同性を有するアミノ酸配列を有する抗体によって認識されるOX40上のエピトープに結合する、単離された抗体。
[本発明1010]
OX40と結合し、軽鎖可変領域を含み、該軽鎖可変領域が、SEQ ID NO: 7もしくは19、SEQ ID NO: 8もしくは20、SEQ ID NO: 9もしくは21のアミノ酸配列を含むCDRを有する、単離された抗体、または、それらと少なくとも90パーセントの相同性を有するアミノ酸配列を有する、抗体。
[本発明1011]
OX40と結合し、重鎖可変領域を含み、該重鎖可変領域が、SEQ ID NO: 1もしくは13、SEQ ID NO: 2もしくは14、SEQ ID NO: 3もしくは15のアミノ酸配列を含むCDRを有する、単離された抗体、または、それらと少なくとも90パーセントの相同性を有するアミノ酸配列を有する、抗体。
[本発明1012]
本発明1001〜1011のいずれかの抗体をコードする、単離された核酸。
[本発明1013]
本発明1001〜1011のいずれかの抗体をコードする核酸を含む、宿主細胞。
[本発明1014]
本発明1013の宿主細胞を培養する段階を含む、抗体を作製する方法。
[本発明1015]
前記宿主細胞から前記抗体を回収する段階をさらに含む、本発明1014の方法。
[本発明1016]
医薬として使用するための、本発明1001〜1011のいずれかの抗体。
[本発明1017]
自己免疫疾患の治療に使用するための、本発明1001〜1011のいずれかの抗体。
[本発明1018]
癌の治療に使用するための、本発明1001〜1011のいずれかの抗体。
[本発明1019]
癌または自己免疫疾患を治療するための医薬の製造における、本発明1001〜1011のいずれかの抗体の使用。
「抗体」という用語は、4本のポリペプチド鎖、すなわちジスルフィド結合によって相互接続された2本の重(H)鎖および2本の軽(L)鎖からなる免疫グロブリン分子を含む。各重鎖は、重鎖可変領域(本明細書ではHCVRまたはVHと省略される)および重鎖定常領域からなる。重鎖定常領域は、3つのドメイン、CH1、CH2、およびCH3からなる。各軽鎖は、軽鎖可変領域(本明細書ではLCVRまたはVLと省略される)およ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。VH領域およびVL領域は、フレームワーク領域(FR)と称されるより保存された領域が散在する、相補性決定領域(CDR)と称される超可変性の領域にさらに細分され得る。各VHおよびVLは、アミノ末端からカルボキシ末端へ以下の順序:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4で配置された3つのCDRおよび4つのFRから構成される。
性ヘモグロビン尿症、性腺機能低下症、限局性回腸炎、白血球減少症、伝染性単核球症、横断性脊髄炎、原発性特発性粘液水腫、ネフローゼ、交感性眼炎、肉芽腫性精巣炎、膵炎、急性多発性神経根炎、壊疽性膿皮症、ケルバン甲状腺炎、後天性脾臓萎縮、非悪性胸腺腫、白斑症、毒素性ショック症候群、食中毒、T細胞の浸潤を伴う状態、白血球接着不全症、サイトカインおよびTリンパ球によって媒介される急性および遅発型過敏症と関連する免疫応答、白血球漏出を伴う疾患、多臓器損傷症候群、抗原抗体複合体媒介性疾患、抗糸球体基底膜疾患、アレルギー性神経炎、自己免疫性多腺性内分泌障害、卵巣炎、原発性粘液水腫、自己免疫性萎縮性胃炎、交感性眼炎(sympathetic ophthalmia)、リウマチ性疾患、混合性結合組織病、ネフローゼ症候群、膵島炎、多内分泌不全、多腺性自己免疫症候群I型、成人発症型特発性副甲状腺機能低下症 (AOIH)、心筋症、例えば、拡張型心筋症、後天性表皮水疱症 (EBA)、ヘモクロマトーシス、心筋炎、ネフローゼ症候群、原発性硬化性胆管炎、化膿性または非化膿性副鼻腔炎、急性または慢性副鼻腔炎、篩骨洞炎、前頭洞炎、上顎洞炎、または蝶形骨洞炎、好酸球関連障害、例えば、好酸球増加症、肺浸潤好酸球増加症、好酸球増多筋痛症候群、レフラー症候群、慢性好酸球性肺炎、熱帯性肺好酸球増多症、気管支肺炎アスペルギルス症、アスペルギルス腫、または好酸球を含む肉芽腫、アナフィラキシー、血清陰性脊椎関節炎、多内分泌性自己免疫疾患、硬化性胆管炎、強膜、上強膜、慢性粘膜皮膚カンジダ症、ブルートン症候群、乳児一過性低γグロブリン血症、ウィスコット・アルドリッチ症候群、毛細血管拡張性運動失調症候群、血管拡張症、膠原病と関連する自己免疫障害、リウマチ、神経系疾患、リンパ節炎、血圧反応の低下、血管機能不全、組織損傷、心血管虚血、痛覚過敏、腎虚血、脳虚血、および血管新生を伴う疾患、アレルギー性過敏性障害、糸球体腎炎、再灌流障害、虚血性再灌流障害、心筋または他の組織の再灌流障害、リンパ腫性気管気管支炎、炎症性皮膚病、急性炎症性成分を有する皮膚病、多臓器不全、水疱性疾患、腎皮質壊死、急性化膿性髄膜炎またはその他の中枢神経系炎症性障害、眼球および眼窩の炎症性障害、顆粒球輸血関連症候群、サイトカイン誘発毒性、ナルコレプシー、急性の重篤な炎症、慢性難治性炎症、腎盂炎、動脈内過形成、消化性潰瘍、弁膜炎、ならびに子宮内膜症。
本発明者らは、ヒトOX40に対する複数のアゴニストマウスモノクローナル抗体を作製した。抗体の抗原結合特異性は、フローサイトメトリーによって確認した(図10〜12)。抗体のアゴニスト活性は、機能アッセイ法により検証した。本発明者らは、20種のOX40特異的抗体のうちの9種が、ビタミンD3/デキサメタゾンによって媒介されるCD4+ T細胞からのTr1細胞の生成を阻止し(図13)、CD4+ T細胞増殖を増強し(図14)、およびICOS+CD4+CD25highFOXP3+ Treg IL-10産生を抑制し得る(図16)ことを見出した。本発明者らは抗体を力価測定し、5種が、4 ng/ml程の低い濃度で、Tr1細胞生成を抑制する上で強力な活性を有することを見出した(図15)。
OX40モノクローナル抗体のうちのいくつかは、FOXP3+ Tregの抑制機能を阻害する(図17)。Tr1細胞およびCD4+CD25highCD127-FOXP3+ TregからのIL-10産生を強く阻害する5種の抗体(119-8B、119-43、119-122、119-173B、および106-222)のうち、3種(119-43、119-122、および106-222)が、CD4+CD25highCD127-FOXP3+ Treg機能を阻止するのに強力であった(図17)。しかしながら、IL-10産生に対して活性を有さない11種の抗体のうち2種(119-33および120-140A)は、しかしCD4+CD25highFOXP3+ Treg機能を阻止する(図18)。
抗ヒトOX40モノクローナル抗体の作製は、例えば、確立されたプロトコールに従って、6〜8週齢のBALB/cマウスに、ヒトOX40がトランスフェクトされたマウス細胞株を免疫することによって行った。OX40+細胞を特異的に染色するモノクローナル抗体を分泌するハイブリドーマクローンを樹立し、これらをさらに解析した。
1. CD4+ T細胞からのTr1細胞生成(誘導性Treg)を阻害する。
2. FOXP3+ nTreg細胞の抑制機能を逆戻りさせる。
3. Tr1細胞停止およびFOXP3+ Treg機能の逆転の用量依存的阻害を示す。
ヒト化(再形成またはCDR移植とも称される)は、異種供給源(齧歯類を含むがこれに限定されない)からのモノクローナル抗体の免疫原性を減少させるため、およびヒト免疫系のそれらの活性化を改善するための確立された技法である。分子生物学の技法を用いて、操作されたモノクローナル抗体を作製する方法は公知であるが、ヒトフレームワークへの齧歯類相補性決定領域(CDR)の単純な移植は、元のモノクローナル抗体の結合親和性および特異性を常に再構成するわけではない。
本発明の抗体または抗体部分は、免疫グロブリン軽鎖および重鎖遺伝子の宿主細胞における組換え発現によって調製することができる。抗体を組換えにより発現させるために、宿主細胞に、抗体の免疫グロブリン軽鎖および重鎖をコードするDNA断片を保有する1つまたは複数の組換え発現ベクターをトランスフェクトし、該軽鎖および該重鎖を宿主細胞内で発現させ、好ましくは宿主細胞を培養する培地中に分泌させ、その培地から抗体を回収できるようにする。抗体重鎖および軽鎖遺伝子を得て、これらの遺伝子を組換え発現ベクター中に組み込み、該ベクターを宿主細胞に導入するためには、Sambrook, Fritsch and Maniatis (eds), Molecular Cloning; A Laboratory Manual, Second Edition, Cold Spring Harbor, N.Y., (1989)、Ausubel, F. M. et al. (eds.) Current Protocols in Molecular Biology, Greene Publishing Associates, (1989)、およびBoss et alによる米国特許第4,816,397号に記載されているような、標準的な組換えDNA方法論が用いられる。
本発明の抗体および抗体部分は、対象への投与に適した薬学的組成物中に組み入れることができる。典型的に、薬学的組成物は、本発明の抗体または抗体部分、および薬学的に許容される担体を含む。本明細書で用いられる「薬学的に許容される担体」には、生理的に適合性のあるありとあらゆる溶媒、分散媒、コーティング、抗菌剤および抗真菌剤、等張吸収遅延剤等が含まれる。薬学的に許容される担体の例には、水、生理食塩水、リン酸緩衝生理食塩水、ブドウ糖、グリセロール、エタノール等のうちの1つまたは複数、およびそれらの組み合わせが含まれる。多くの場合、等張剤、例えば、糖、多価アルコール、例えば、マンニトール、ソルビトール、または塩化ナトリウムを組成物中に含めることが好ましい。薬学的に許容される担体は、抗体または抗体部分の有効期間または有効性を増強する、湿潤剤もしくは乳化剤、保存剤、または緩衝液などの少量の補助物質をさらに含み得る。
キメラおよびヒト化106-222 IgG1/κモノクローナル抗体(それぞれ、Ch222およびHu222)は、添付物AおよびBに記載されているとおりに、プロテインAカラムを用いて、対応するNS0トランスフェクタントの培養上清から精製した。Hu222は、2つの異なる方法によってカラムから溶出させた。簡潔に説明すると、Hu222ロットIは低pH緩衝液で溶出させ、ロットIIはPierceのGentle Ag/Ab溶出緩衝液で溶出させた。Hu222の収率は、溶出に低pH緩衝液を使用した場合に、より良かった。Ch222は、Gentle Ag/Ab溶出緩衝液でカラムから溶出させた。
マウス106-222、Ch106-222、およびHu106-222抗体のOX40への結合は、本質的にはDr. Laura Boverによって提供されるプロトコールに従って、L/hOX40細胞を用いてFACS結合アッセイ法で調べた。L/hOX40細胞に結合した抗体は、PE標識ヤギ抗マウスIgG抗体(マウス106-222について)、またはPE標識ヤギ抗ヒトIgG抗体(Ch106およびHu106について)で検出した。
NS0安定トランスフェクタントC8を、ローラーボトル中のInvitrogenのハイブリドーマSFM培地500 ml中で消耗するまで増殖させた。培養物を、Beckman CoulterのAllegra X-12R遠心機において、Corningの250 ml遠心管(カタログ番号 430776)中で遠心沈殿させた(2000 RPMで15分間)。Pharmacia P1ポンプを用いて、培養上清を1 ml GE Healthcare HiTrap MabSelect SuReカラム(カタログ番号 11-034-95)上に負荷した。カラムをTris緩衝生理食塩水(Pierce、カタログ番号 28379)で洗浄し、PierceのGentle Ag/Ab溶出緩衝液(Cat # 21027)で溶出した。画分(約1 ml)を回収し、それらの280 nmでのODを読み取った。
NS0安定トランスフェクタント1-C6を、ローラーボトル中のInvitrogenのハイブリドーマSFM培地500 ml中で消耗するまで増殖させた。培養物を、Beckman CoulterのAllegra X-12R遠心機において、Corningの250 ml遠心管(カタログ番号 430776)中で遠心沈殿させた(2000 RPMで15分間)。
Pharmacia P1ポンプを用いて、培養上清150 mlを1 ml GE Healthcare HiTrap MabSelect SuReカラム(カタログ番号 11-034-95)上に負荷した。カラムをPBSで洗浄し、結合している抗体を0.1Mグリシン-HCl、0.1 M NaCl (pH 3.0)で溶出させた。溶出された画分(各1 ml)を、50μl 1M Tris-HCl (pH 8.0)を含むチューブ中に回収した。
Pharmacia P1ポンプを用いて、残りの培養上清(350 ml)を1 ml GE Healthcare HiTrap MabSelect SuReカラム上に負荷した。カラムをTris緩衝生理食塩水で洗浄し、Gentle Ag/Ab溶出緩衝液で溶出した。画分(約1 ml)を回収し、それらのODを280 nmで読み取った。
Ch119-122抗体およびHu119-122抗体の精製
キメラ119-122 IgG1/κモノクローナル抗体(Ch119)は、プロテインAカラムを用いて、ハイブリドーマSFM培地(Invitrogen)中で増殖させた対応するNS0安定トランスフェクタント(クローンG11)の培養上清から精製した。PierceのGentle Ag/Ab溶出緩衝液での溶出後、ゲル濾過およびその後の透析によって、Ch119の緩衝液をPBSに交換した。Ch119の濃度は0.21 mg/mlであった。
マウス119-122、Ch119-122、およびHu119-122抗体のOX40への結合は、本質的にはDr. Laura Boverによって提供されるプロトコールに従って、L/OX40細胞を用いてFACS結合アッセイ法で調べた。L/OX40細胞に結合した抗体は、PE標識ヤギ抗マウスIgG抗体(マウス119-122について)、またはPE標識ヤギ抗ヒトIgG抗体(Ch119-122およびHu119-122について)で検出した。
本発明者らのヒト化抗ヒトOX40抗体がT細胞増殖を増強する能力を評価するため、本発明者らは、抗CD3コーティングされたCD32-L細胞および新たに選別されたナイーブCD4+ T細胞を用いて増殖アッセイ法を行った。図27は、ヒト化抗ヒトOX40 mAbクローン119-122(Hu122)およびそのFcR結合変異型抗体(Hu122-AA)が、ナイーブCD4+ T細胞増殖を増強したことを示す。Hu122は、親のマウス抗ヒトOX40 mAb(マウス122)と比較してより良好なT細胞刺激活性をもたらした。(図27)
抗体は、静脈内注射により患者に投与された場合、全末梢血単核細胞(PBMC)に遭遇するため、本発明者らは、本発明者らの増殖アッセイ法において抗原提示細胞(APC)としてPBMCを用いて、本発明者らの抗ヒトOX40抗体がT細胞増殖を刺激する能力を試験した。しかしながら、APCとしてPBMCを用いた場合、本発明者らのマウス抗ヒトOX40 mAbにより、APCとして単球を用いた場合には見られない非常にばらつきがあるデータが得られ、本発明者らの抗体が、活性にある種の架橋を必要とすることが示唆された。この可能性を試験するため、プレートを本発明者らの抗ヒトOX40 mAbおよび抗CD3でコーティングし、洗浄し、補助細胞の非存在下でCD4+またはCD8+ T細胞増殖を刺激するのに使用した。図30は、抗ヒトOX40抗体がCD4+およびCD8+ T細胞増殖を増強するという結果を示す。
捕捉の予備的なインビボデータから、抗ヒトOX40抗体がマウスにおいて機能し、マウスにおけるT細胞増殖および腫瘍拒絶を増強することが示された。抗ヒトOX40 mAbが、ヒトOX40が形質導入されたマウスCD8+ T細胞におけるNF-κBカスケードを特異的に活性化し得ることが以前に示された。インビボにおいて、抗hOX40 mAbが、エフェクターCD8+ T細胞の生存およびクローン増殖を促進することにより腫瘍拒絶を増強し得るのかどうかを判定するため、ルシフェラーゼ遺伝子およびhOX40が形質導入されたトランスジェニックPmel CD8+ T細胞を、非色素性MC38腫瘍を有するC57BL/6アルビノマウスに養子移入した。形質導入されたT細胞の養子移入の後、マウスをAbで処置した。IgG1対照抗体で処置したマウスと比較して、抗hOX40 mAbで処置したマウスでは、4日目に、有意により多くのヒトOX40+ルシフェラーゼ+ Pmel T細胞が肺に遊走したことが見出され(図35B)、マウスにおけるhOX40の誘発がCD8+ T細胞増殖を促進したことが示された。処置後の8日目(データは表示せず)および12日目に、IgG1で処置した対照マウス群と比較して、抗hOX40 mAbで処置した同じマウス群が、腫瘍部位において有意により多くのルシフェラーゼ+ Pmel T細胞を保持したことが見出され(図35B)、マウスにおけるhOX40の誘発がCD8+ T細胞の生存を促進したことが再度示された。最後に、hOX40+ Pmel CD8+ T細胞を投与し、続いて抗hOX40 mAbで処置したマウスの腫瘍サイズは、形質導入されていないPmel T細胞を投与し、抗hOX40 mAbで処置したマウス、またはhOX40+ Pmel T細胞を投与した後に、対照マウスIgG1一致抗体で処置したマウスの腫瘍サイズと比較して、有意により小さかった。これらの結果から、マウスにおけるヒトOX40の誘発が、マウスOX40の生物学的効果(Gough MJ et, 2008)と同様の生物学的効果をもたらすことが示される。したがって、このデータから、インビボにおいてCD+ T細胞の増殖および生存を促進し、腫瘍拒絶を増強する抗ヒトOX40 mAbの能力が実証される。
本発明者らの治療的ワクチン接種レジメンを図35Aに示す。5匹ずつの群のC57BL/6アルビノマウスの皮下に(S.C)、5×105個の非色素性MC38/gp100腫瘍細胞を移植した(0日目)。6日目に、350 cGy線量の照射を施すことによりリンパ球減少を誘導した。7日目に、ヒトOX40発現を有するかまたは有さないルシフェラーゼ形質導入Pmel-1 T細胞1×106個を腫瘍保有マウスに養子移入し(n=5/群)、その後Gp100ペプチドをパルスしたDC 5×105個を静脈内注射した。T細胞移入後の3日間、組換えヒトIL-2を腹腔内投与した。7日目、9日目、および11日目に、抗体をそれぞれ100μg、50μg、および50μg/注射/マウスで投与した(図35B)。インビボ生物発光像から、4日目および12日目の肺および腫瘍部位におけるルシフェラーゼ発現CD8+ pmel-1 T細胞の蓄積が示された。4日目および12日目の、群当たり5匹のマウスのうちの2匹を示す(図35C)。腫瘍は、抗hOX40 mAbを用いた処置に反応した。3日ごとに腫瘍サイズを測定した。Pmel-1およびPmel-1+マウスIgG1を対照とした。
Claims (18)
- ヒトOX40に結合し、(a) SEQ ID NO: 1のアミノ酸配列を含む重鎖可変領域CDR1と;(b) SEQ ID NO: 2のアミノ酸配列を含む重鎖可変領域CDR2と;(c) SEQ ID NO: 3のアミノ酸配列を含む重鎖可変領域CDR3と;(d) SEQ ID NO: 7のアミノ酸配列を含む軽鎖可変領域CDR1と;(e) SEQ ID NO: 8のアミノ酸配列を含む軽鎖可変領域CDR2と; (f) SEQ ID NO: 9のアミノ酸配列を含む軽鎖可変領域CDR3とを含む、単離された抗体。
- ヒトOX40に結合し、(a) SEQ ID NO: 13のアミノ酸配列を含む重鎖可変領域CDR1と;(b) SEQ ID NO: 14のアミノ酸配列を含む重鎖可変領域CDR2と;(c) SEQ ID NO: 15のアミノ酸配列を含む重鎖可変領域CDR3と;(d) SEQ ID NO: 19のアミノ酸配列を含む軽鎖可変領域CDR1と;(e) SEQ ID NO: 20のアミノ酸配列を含む軽鎖可変領域CDR2と; (f) SEQ ID NO: 21のアミノ酸配列を含む軽鎖可変領域CDR3とを含む、単離された抗体。
- SEQ ID NO: 10のアミノ酸配列と少なくとも90パーセントの同一性を有する配列を有する軽鎖可変領域およびSEQ ID NO: 4のアミノ酸配列と少なくとも90パーセントの同一性を有する配列を有する重鎖可変領域を含む、請求項1記載の単離された抗体。
- SEQ ID NO: 22のアミノ酸配列と少なくとも90パーセントの同一性を有する配列を有する軽鎖可変領域およびSEQ ID NO: 16のアミノ酸配列と少なくとも90パーセントの同一性を有する配列を有する重鎖可変領域を含む、請求項2記載の単離された抗体。
- モノクローナル抗体である、請求項1〜4のいずれか一項記載の単離された抗体。
- ヒト化抗体である、請求項1〜5のいずれか一項記載の単離された抗体。
- SEQ ID NO: 11のアミノ酸配列と少なくとも90パーセントの同一性を有する配列を有する軽鎖可変領域およびSEQ ID NO: 5のアミノ酸配列と少なくとも90パーセントの同一性を有する配列を有する重鎖可変領域を含む、請求項6記載の単離された抗体。
- SEQ ID NO: 23のアミノ酸配列と少なくとも90パーセントの同一性を有する配列を有する軽鎖可変領域およびSEQ ID NO: 17のアミノ酸配列と少なくとも90パーセントの同一性を有する配列を有する重鎖可変領域を含む、請求項6記載の単離された抗体。
- ヒトOX40に特異的に結合し、かつヒトOX40を刺激する能力を保持している、請求項1〜8のいずれか一項記載の抗体の抗原結合部分。
- SEQ ID NO: 11のアミノ酸配列と同一の配列を有する軽鎖可変領域およびSEQ ID NO: 5のアミノ酸配列と同一の配列を有する重鎖可変領域を含む、単離された抗体。
- SEQ ID NO: 23のアミノ酸配列と同一の配列を有する軽鎖可変領域およびSEQ ID NO: 17のアミノ酸配列と同一の配列を有する重鎖可変領域を含む、単離された抗体。
- 請求項1〜11のいずれか一項記載の抗体またはその抗原結合部分をコードする、単離された核酸。
- 請求項1〜11のいずれか一項記載の抗体またはその抗原結合部分をコードする核酸を含む、宿主細胞。
- 請求項13記載の宿主細胞を培養する段階を含む、抗体またはその抗原結合部分を作製する方法。
- 前記宿主細胞から前記抗体またはその抗原結合部分を回収する段階をさらに含む、請求項14記載の方法。
- 医薬として使用するための、請求項1〜11のいずれか一項記載の抗体またはその抗原結合部分。
- 癌の治療に使用するための、請求項1〜11のいずれか一項記載の抗体またはその抗原結合部分。
- 癌を治療するための医薬の製造における、請求項1〜11のいずれか一項記載の抗体またはその抗原結合部分の使用。
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