JP2022068294A - 抗cd40抗体とその使用 - Google Patents
抗cd40抗体とその使用 Download PDFInfo
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Abstract
Description
本願は35 U.S.C.§119(e)に基づき、2016年5月27日付け米国仮出願第62/342,417号の優先権を主張し、その開示内容全体を本願に援用する。
本願はASCIIフォーマットの電子形式で提出された配列表を含み、その全体を本願に援用する。前記ASCIIコピーは2017年5月17日に作成され、ファイル名381493-285WO_SL.txt、サイズ108,670バイトである。
本願は特に、新規抗CD40抗体、前記新規抗体を含有する組成物、前記抗体をコードする核酸、及びそれらの製造方法と使用方法に関する。
がん治療法には外科手術、放射線療法及び化学療法をはじめとする広範な治療アプローチがある。これらの種々のアプローチにより、医師はがんを治療するために幅広い治療選択肢があるが、既存の治療法は、正常・健常細胞に優先してがん細胞を標的とする選択性を欠いていたり、がんが治療耐性を獲得する等の多数の欠点がある。
ヒトCD40(配列番号40)はB細胞、樹状細胞(DC)及び単球等の抗原提示細胞と、ある種の腫瘍細胞を含む非免疫細胞で発現される腫瘍壊死因子(TNF)受容体スーパーファミリーメンバー(TNFスーパーファミリーメンバー5)である。ヒトCD40リガンド(配列番号41)により活性化されると、ヒトCD40は抗原提示細胞を活性化させ、自然免疫系と適応免疫系の双方から応答を誘導する。免疫系に腫瘍細胞の増殖を防止させ、及び/又は腫瘍細胞を死滅させ、その結果として固形腫瘍の有効な治療を提供するために、アゴニストCD40剤を使用することができる。
本開示は、ヒトCD40(配列番号40)と特異的に結合する抗体及び断片、前記抗体を含有する組成物、抗CD40抗体をコードするポリヌクレオチド、前記抗体を産生することが可能な宿主細胞、前記抗体及び結合断片の作製に有用な方法及び組成物、並びにこれらの種々の使用方法に関する。
本願に記載する抗体、結合断片、ADC及びポリヌクレオチドは、多くの実施形態では夫々のポリペプチド又はポリヌクレオチド配列により説明する。特に指定しない限り、ポリペプチド配列はN→C方向に記載し、ポリヌクレオチド配列は5’→3’方向に記載する。ポリペプチド配列については、下表1に記載するように、遺伝子にコードされるアミノ酸の従来の3文字又は1文字略号を使用する場合もある。
本願で特に定義しない限り、本開示に関連して使用する科学技術用語は、当分野における通常の知識をもつ者に広く理解されている意味とする。
1態様において、本開示は、ヒトCD40受容体(別称、腫瘍壊死因子受容体スーパーファミリーメンバー5、TNFRSF5、Bp50及びCD40L受容体)と特異的に結合する抗体及び/又はその結合断片に関する。
Ki=IC50/(1+[参照Ab濃度]/Kd)
として表すことができ、式中、IC50は参照抗体の結合を50%低減させる試験抗体の濃度であり、Kdは参照抗体の解離定数であり、ヒトCD40に対するその親和性の尺度である。本願に開示する抗CD40抗体と競合する抗体は、本願に記載するアッセイ条件下で10pM~1000nMのKiをもつことができる。
本開示は、抗CD40抗体の免疫グロブリン軽鎖及び重鎖遺伝子をコードする核酸分子、このような核酸を含むベクター、並びに本開示の抗CD40抗体を産生することが可能な宿主細胞を包含する。
本願に記載する抗CD40抗体は、前記抗体と1種以上の担体、賦形剤及び/又は希釈剤を含有する組成物の形態とすることができる。前記組成物は、獣医学用やヒト医薬用等の特定の用途に合わせて製剤化することができる。組成物の形態(例えば乾燥粉末、液体製剤等)と、賦形剤、希釈剤及び/又は担体は、目的とする抗体の用途と、治療用の場合には投与方式により異なる。
7.6.1.治療効果
本願に提供するデータから明らかなように、腫瘍細胞の存在下でCD40を作動させる本願に記載する抗CD40抗体は、これらの固形腫瘍に対してインビボで強力な抗腫瘍作用を発揮する。したがって、前記抗CD40抗体、結合断片及び/又は前記抗CD40抗体を含有する医薬組成物は、固形腫瘍を治療するために治療用として使用することができる。
抗がん性をもつ他の薬剤又は治療の補助療法として、抗CD40抗体を使用してもよい。補助療法として使用する場合には、抗CD40抗体と他の薬剤とを単一の併用医薬製剤として製剤化してもよいし、単一の調整された投与レジメン又は異なる投与レジメンで別々に製剤化・投与してもよい。抗CD40抗体の補助薬として投与される薬剤は、抗CD40抗体と他の薬剤とが相互に悪影響を与えないように、一般的に前記抗体に相補的な作用をもつ。
抗CD40抗体の投与量は、種々の因子に依存し、限定されないが、治療する固形腫瘍の個々の種類、治療する固形腫瘍のステージ、投与方式、投与頻度、所望の治療効果に加え、患者の年齢、体重及び他の特徴等の他のパラメーター等が挙げられる。特定の投与方式及び投与頻度で治療効果を提供するために有効な投与量を決定することは、当業者がなし得る範囲内である。
以下の実施例では、本願に記載する抗CD40抗体の代表的な実施形態の所定の特徴と特性について具体的に説明するが、これらの実施例は例証を目的とし、制限を目的とするものではない。
ヒトCD40を過剰発現するマウス3T12細胞をBalb/Cマウス又はSJLマウスに腹腔内免疫することにより、モノクローナル抗体を作製した。脾臓を摘出し、脾細胞を多発性骨髄腫細胞株NS0と融合させた。アミノプテリンを使用して、ハイブリドーマを選択した。選択したハイブリドーマのうちでアゴニスト活性をもつ抗CD40抗体を発現するものをスクリーニングしてサブクローニングし、個々のクローンを単離した。
DMEM+10%熱不活化ウシ胎仔血清(FBS)にブラスチシジン30μg/mLとゼオシン100μg/mLとを添加し、ヒトCD40とNFκBレポーター遺伝子を安定発現するHEK293 blue CD40細胞株(InVivogen)を保持した。HEK293 blue CD40細胞の表面のCD40を活性化させてシグナル伝達カスケードを開始させ、NFκBを活性化させることにより、胎盤由来アルカリホスファターゼ(SEAP)を分泌させた。アゴニスト抗CD40を含むハイブリドーマ上清を、HEK293 blue CD40細胞2.5×105個/mLと共にインキュベートしてSEAPの産生を刺激し、酵素比色アッセイにより測定した。したがって、SEAP濃度は、ハイブリドーマ上清中の抗CD40の活性に対応した。
単球系細胞株THP1-XBlue細胞(InVivogen)を使用して、単球活性アッセイを実施した。この細胞株は、NFκBとAP-1により誘導されるSEAPレポーター遺伝子を安定発現するものであり、10%熱不活化FBSとゼオシン200μg/mLとを添加したRPMI 1640にこの細胞株を保持した。このアッセイでは、先ずTHP1-XBlue細胞5×105個/mLをIFNγ 40ng/mLで24時間プライミングした後、被験試料と共に更に24時間インキュベートした。アゴニスト抗CD40により誘導されるSEAP活性を酵素アッセイによりモニターした。
単球由来樹状細胞(moDC)を活性化させる能力についても抗CD40クローンをスクリーニングした。IL-12p70産生により活性化をモニターした。先ず、ヒト末梢血単核細胞(PBMC)をFicoll密度勾配で分離した。要約すると、健康なヒトドナーに由来する全血を等容量のPBSで希釈し、Ficoll-Paque Plusをフリットの下(15mL)まで入れたLeucosep(Greiner Bio One)チューブに加えた。次に、ブレーキをオフにして血液を1,000gで15分間遠心した。PBMCを採取し、PBSで1回洗浄し、室温にて1,300rpmで5分間遠心し、RPMI 1640で1回洗浄した。細胞を培地(RPMI 1640+10%熱不活化FBS)に再懸濁した。次に、StemCell社製エンリッチメントキットを使用してPBMCから単球を分離し、10ng/mLのGM-CSFと20ng/mLのIL-4を添加したStemSep無血清培地で37℃、5%CO2にて6日間培養した。DC分化を維持し易くするために3日目に新鮮なGM-CSFとIL-4を培養液に加えた。6日間培養後に、単球由来未成熟DCをFACS解析し、未成熟DC表現型であるLin-、CD80/CD86+、HLA-DR+又はCD11c+を確かめた。未成熟moDCをIFNγでプライミングし、GM-CSFとIL-4を添加したStemSep無血清培地中で抗CD40抗体を含む試料により48時間刺激した。培養上清を回収し、市販のELISAキットによりIL-12p70産生についてアッセイした。スクリーニング結果と代表的な活性を表1-1にまとめる。
BIAcore解析とELISA法を使用し、CD40との結合に関して相互間で又はCD40リガンド(CD40L)と競合する能力に基づいて、マウス抗ヒトCD40アゴニスト抗体を分類した。
Queen,C.et al.(Proc.Natl.Acad.Sci.USA,1989;86:10029-10033)に概説されているように、抗体V領域のヒト化を実施した。Huangら(Methods,2005;36:35-42)に従って、CDRのカノニカル構造を決定した。同一又はほぼ同様のCDRカノニカル構造をもつヒト生殖細胞系列可変領域配列を同定し、抗CD40可変領域のフレームワークを提供するために適切なヒトVH、VL及びJセグメント配列を選択した。コンピューターモデルによりCDRとの有位接触が示唆されたフレームワーク位置で、元のヒトフレームワークアミノ酸をマウス抗CD40V領域に由来するアミノ酸に置換した(復帰突然変異)。特に指定しない限り、天然変異D356E及びL358Mを含む重鎖とκ軽鎖とをもつヒトIgG1の定常領域を使用した。ヒト化抗体のVH領域とVL領域との全長アミノ酸配列を、図2D~2Gに示す。
ヒト化抗CD40抗体が親マウス抗体のアゴニスト特性及び他の望ましい特性を維持していることを検証するために、一連の特性決定アッセイを実施し、本開示のヒト化抗体のNFκB活性化、CD40結合キネティクス、種間交差反応性及びエピトープ分類を判定した。
本発明のヒト化抗CD40抗体によるNFκB活性化をHEK293 blue CD40 NFκBレポーター細胞において評価した。OD655で測定したSEAP(胎盤由来分泌型アルカリホスファターゼ)レポーター遺伝子活性として活性化を表した。最大OD655測定値と、最大活性化の50%(EC50)の濃度を表4-1にまとめる。
本願に開示するヒト化抗CD40抗体の結合親和性を、BIAcore及びフローサイトメトリー解析により解析した。
フローサイトメトリー解析及びELISA法を使用し、CD40との結合に関して相互間で又はCD40リガンド(CD40L)と競合する能力に基づいてヒト化アゴニスト抗CD40抗体を分類した。
FcγRIIB結合を強化するようにFc領域を改変することにより、CD40のアゴニスト活性を増大させることができる(Li and Ravetch,Science,2011;333:1030-1034;及びWhite,et al.,J.Immunol,2011;187:1754-1763)。ヒトIgG1定常領域の273位の2種類の突然変異V273E及びV273Yをヒト化抗CD40抗体huAb6-1、huAb8-1、huAb9-5及びhuAb9A2Iに導入した。Fcγ受容体との結合に及ぼすFc突然変異の影響をFACS解析と抗体依存性細胞傷害活性(ADCC)によりモニターした。Fcを改変したヒト化抗CD40のアゴニスト活性をNF-kBレポーター、B細胞、単球由来DC及びT細胞の活性化によりモニターした。
抗CD40ヒトIgG1抗体及びそれらのFc変異体の量を増加させながら、F又はV多形をもつFcγRI(CD64)、FcγRIIA(CD32a)、FcγRIIB(CD32b)及びFcγRIIIA(CD16)を含む種々のヒトFcγ受容体を安定発現するCHO細胞と共にインキュベートした。蛍光標識した抗ヒトF(ab’)2特異的二次抗体(Jackson ImmunoResearch)により結合を検出した。突然変異V273E又はV273Yは、FcγRI(CD64)との結合を維持すると共にFcγRIIA(CD32a)又はFcγRIIB(CD32b)との結合を強化しながら、FcγRIIIA(CD16F又はV)との結合を低減させた(図6A~6B)。
抗CD40のアゴニスト活性に及ぼすFcγ受容体結合の影響を評価するために、huIgG1V273E突然変異を加えたhuAb9A2Iを使用し、種々のヒトFcγ受容体を安定発現するCHO細胞と共培養したHEK293 blue CD40 NFκBレポーター細胞を処理し、NFκB活性をモニターした。表5-1に示すように、NFκB活性化の刺激におけるCP-870,893のアゴニスト活性は、Fcγ受容体結合に依存しなかったが、huAb9A2Iのアゴニスト活性は、Fcγ受容体結合に依存性であることが分かった。レポーター細胞を、CD32a、CD32b又はCD64を発現するCHO細胞と共培養すると、Fcγ受容体を発現しないか又はCD16VもしくはCD16Fを発現するCHO細胞と共培養した場合に比較して、NFκB活性の刺激におけるhuAb9A2Iの効力は10倍であった。
抗CD40のアゴニスト活性に及ぼすFcV273E又はV273Y突然変異の影響もB細胞増殖アッセイにより評価した。このアッセイでは、B細胞エンリッチメントキット(StemCell Technologies)を使用してネガティブセレクションによりヒトB細胞を集積させた。96ウェルプレートにAIM-V無血清培地(GIBCO)を注ぎ、精製したB細胞をウェル当たり200μLとなるように5×105個/mlの密度で播種した。系列希釈した抗CD40抗体を加え、B細胞と共に6日間培養した。最後の16時間の培養では、H3TdR 1μCiを培養液の各ウェルに加え、H3TdR取り込みによりB細胞増殖を判定した。H3TdR取り込みに伴う放射能をシンチレーションカウンターにより毎分カウント(CPM)として記録した。対応するヒトIgG1野生型抗体に比較して、抗CD40(huAb6-1、huAb8-1及びhuAb9-5)ヒトIgG1Fc変異体V273E及びV273Yは、B細胞活性化の亢進を示した(図8)。一方、CP-870,893に比較した場合、huAb9A2I(ヒトIgG1V273E)は、B細胞増殖の刺激において約10分の1の効力を示した(右下グラフ)。
IL-12p70を読取り値として使用して、抗CD40のアゴニスト活性に及ぼすFcV273E又はV273Y突然変異の影響を、DC活性化アッセイにより更に評価した。このアッセイでは、先ずヒトPBMCから精製した単球から未成熟DCを誘導し、IL4とGM-CSFで処理した。IFNγでプライミング後にDC成熟とIL-12p70産生とを、抗CD40により誘導した。V273E又はV273Y Fc突然変異体は、IL-12p70産生を亢進させることによりDC活性化の効力を増加した。図9に示すように、huIgG1Fc変異体V273E又はV273Yを含むhuAb6-1(左上)、huAb8-1(右上)及びhuAb9-5(左下)は、野生型huIgG1を示すそれらの対応する抗体に比較してIL-12p70産生の増加を示した。huAb6-1及びhuAb8-1では、huIgG1V273Y突然変異を含む変異体は、V273E突然変異を含む変異体よりもインビトロIL-12p70産生を増加させるのに有効であった。huAb9-5では、huIgG1V273E又はV273Yを含む変異体は、同等の効力を示した。huAb9A2I(右下グラフ)の場合には、huIgG1V273E突然変異を含む変異体はDCを刺激してIL-12p70を産生させるのにCP-870,893と同等の効力を示した。
抗CD40がDC等の抗原提示細胞を刺激することによりT細胞活性化を駆動できることを実証するために、抗CD40 Fc変異体を同種DC及びT細胞共培養で試験した。このアッセイでは、先ず上記方法を使用して樹状細胞(5×103個)を単球から誘導した後、別のドナーから精製したT細胞1×105個と混合した。野生型ヒトIgG1定常領域又はそのFc変異体V273Yを含む抗CD40抗体huAb6-1、huAb8-1又はhuAb9-5を種々の量でDCとT細胞の共培養物に加えた。4日間インキュベーション後に、上清を採取し、IFN-γをELISAにより測定した。
野生型ヒトIgG1又はFc変異体を含むヒト化抗CD40抗体huAb6-1、huAb9-5及びhuAb9A2Iが前立腺PC3腫瘍をもつNSGマウスにおいてヒト免疫細胞の存在下で腫瘍成長を抑制する能力について評価した。
本開示の代表的な抗CD40抗体はマウスCD40と結合しないため、マウスCD40アゴニスト抗体1C10muIgG1を使用してマウスにおける薬理効果の評価を行った。上記huIgG1FcV273E突然変異と同様に、マウスIgG1(muIgG1)Fcを含む1C10は、muFcγRIIBと強い結合を示し、ヒトFcγRIIIとの機能的等価物であるmuFcγRI及びmuFcγRIVとは最低の結合を示した。本開示の抗CD40抗体と同様に、1C10muIgG1は、マウス脾臓B細胞活性化をインビトロ及びインビボで刺激するのに効力を示した。そこで、マウスIgG1定常領域をもつ抗マウスCD40抗体1C10を概念実証分子として使用し、腫瘍内送達又は抗PD-1抗体の同時投与による併用療法の使用を含む潜在的臨床開発の糸口を探った。
マウスに両側皮下腫瘍を作製したCT26同系モデルを使用し、腫瘍内投与について検討した。0日目に雌性Balb/cマウスの左右後部脇腹に1匹当たり生存細胞(1×105個)を皮下接種した。12日目に各群10匹ずつランダムに分けた。投与開始時の右脇腹の平均腫瘍体積は、約85mm3であった。最初の投与から24時間後に、血清中ALT値を評価するために各群3匹を屠殺した。残りの動物を両側の腫瘍の成長についてモニターした。週2回腫瘍体積を測定した。電子キャリパーにより腫瘍の長さ(L)、幅(W)及び高さ(H)を測定し、次式:L×W×H/2に従って体積を計算した。抗体投与はランダム化の直後に開始した。
0日目に雌性BALB/cマウスの右脇腹に1匹当たり生存細胞1×105個を皮下接種することによりCT26腫瘍を作製した。15日目に動物をランダムにグループ分けした。抗CD40抗体1C10(0.6mg/kg)を商業製品である抗PD1 muIgG2a抗体(10mg/kg)と併用してCT26同系マウスモデルに週2回IP投与した。併用投与レジメンは、有意な抗腫瘍活性を示し(10匹中の7匹が腫瘍退縮を示したが、対照では0匹、抗PD1又は抗CD40投与群では各々10匹中1匹)、この併用の成果を裏付けた(図13)。
Claims (23)
- 配列番号8、18、35、58、68及び88の配列を有するCDRを含む、請求項1に記載の抗CD40抗体又は結合断片。
- ヒト型又はヒト化型である、請求項1に記載の抗CD40抗体又は結合断片。
- 配列番号110、111、112、113、114、115、116、117、118、119、120、121、122又は123のいずれか1種に対応する配列のVH鎖と、配列番号161、162、163、164、165、166、167、168、169、170又は171のいずれか1種に対応する配列のVL鎖を含む、請求項1に記載の抗CD40抗体又は結合断片。
- 配列番号117の配列に対応するVH鎖と、配列番号170の配列に対応するVL鎖を含む、請求項1~4のいずれか一項に記載の抗CD40抗体又は結合断片。
- IgGであり、任意にIgG1である、請求項1~5のいずれか一項に記載の抗CD40抗体又は結合断片。
- IgG1であり、アミノ酸置換V273E又はV273Yを含む変異型CH2領域を含む、請求項6に記載の抗CD40抗体。
- IgG1であり、アミノ酸置換D356E及びL358Mを含む変異型Fc領域を含む、請求項6又は7に記載の抗CD40抗体。
- κ軽鎖定常領域を含む、請求項6~8のいずれか一項に記載の抗CD40抗体。
- 配列番号130~135のいずれか1種の重鎖配列と、配列番号140~142のいずれか1種の軽鎖配列を有する、請求項1~9のいずれか一項に記載の抗CD40抗体。
- 配列番号130又は131の重鎖配列と、配列番号140の軽鎖配列を有する、請求項10に記載の抗CD40抗体。
- 配列番号132又は133の重鎖配列と、配列番号141の軽鎖配列を有する、請求項10に記載の抗CD40抗体。
- 配列番号132又は133の重鎖配列と、配列番号142の軽鎖配列を有する、請求項10に記載の抗CD40抗体。
- 請求項1~13のいずれか一項に記載の抗CD40抗体又は結合断片と、薬学的に許容される担体を含有する医薬組成物。
- がんの治療方法であって、がんの治療を必要とする患者に請求項1~13のいずれか一項に記載の抗CD40抗体もしくは結合断片又は請求項14に記載の医薬組成物を投与することを含む前記方法。
- 請求項1~13のいずれか一項に記載の抗CD40抗体又は結合断片をコードするヌクレオチド配列を含む核酸。
- 請求項16に記載の核酸を含むベクター。
- 請求項17に記載のベクターで形質転換された原核宿主細胞。
- 請求項17に記載のベクターで形質転換された真核宿主細胞。
- 請求項16に記載の核酸を発現するように操作された真核宿主細胞。
- 哺乳動物宿主細胞である、請求項20に記載の真核宿主細胞。
- 抗CD40抗体又はその結合断片の作製方法であって、(a)請求項19又は20に記載の宿主細胞を培養する工程と、(b)前記抗体又は結合断片を回収する工程を含む前記方法。
- 免疫系の活性化方法であって、免疫系の活性化を必要とする患者に、請求項1~13のいずれか一項に記載の抗CD40抗体もしくは結合断片又は請求項14に記載の医薬組成物を投与することを含む前記方法。
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