JP6807890B2 - 抗cd40抗体および使用方法 - Google Patents
抗cd40抗体および使用方法 Download PDFInfo
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- FKBHRUQOROFRGD-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2[C]3C=CC=CC3=NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC FKBHRUQOROFRGD-IELIFDKJSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 229940087652 vioxx Drugs 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940053867 xeloda Drugs 0.000 description 1
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Description
本願は、2012年4月10日に出願された米国仮出願第61/622,435号および2011年4月29日に出願された米国仮出願第61/480,863号に対する優先権を主張する。これらの出願は、その全体が本明細書中に参考として援用される。
本願に関連した配列表をハードコピーの代わりにテキスト形式で提供し、参照により本明細書に援用する。配列表を含むテキストファイル名は、APEX−013_02US_ST25.txtである。該テキストファイルは、86KBであり、2012年4月27日に作成したものであり、それをEFS−Web経由で電子提出している。
技術分野
本発明は、一般に、抗CD40抗体、組成物、およびそれらの使用方法に関する。かかる抗体は、例えば、様々な腫瘍学的疾患の処置方法に有用である。
白血病およびリンパ腫の大部分は、B系列細胞の悪性形質転換から生ずる。CD20などの細胞表面B系列拘束性抗原の発現は、それを抗体療法の魅力的な標的にする。抗体療法は、非ホジキンリンパ腫(NHL)および慢性リンパ球性白血病(CLL)を有する患者への対応を劇的に変えた。リツキシマブの認可以来、単独でのまたは化学療法と併用での該抗体は、奏効率、長期成績および生活の質を著しく向上させてきた(非特許文献1(Chinn P、Braslawsky G、White Cら、Antibody therapy of non−Hodgkin’s B−cell lymphoma、Cancer Immunol Immunother 2003;52:257−280);非特許文献2(Rastetter W、Molina A、White CA、Rituximab:Expanding role in therapy for lymphomas and autoimmune diseases、Annu Rev Med 2004;55:477−503))。しかし、相当な数の患者がリツキシマブに対する初期耐性または獲得耐性のいずれかを呈示し、これは、CD20を標的にする現行アプローチには臨床成績の限界があること、ならびに抗CD40 mAb、APX005などの、異なる作用機序を有するB細胞リンパ腫および白血病のための新規免疫療法を開発することにより向上させる必要があること(非特許文献3(Stolz C、Schuler M、Molecular mechanisms of resistance to Rituximab and pharmacologic strategies for its circumvention、Leukemia and lymphoma、2009;50(6):873−885);非特許文献4(Bello C、Sotomayor EM、Monoclonal antibodies for B−cell lymphomas:Rituximab and beyond、Hematology Am Soc Hematol Educ Program 2007;233−242);非特許文献5(Dupire S、Coiffier B、Targeted treatment and new agents in diffuse large B cell lymphoma、Int J Hematol 2010;6月18日(オンライン)))を示唆している。
T細胞の完全活性化は、2つの別個のしかし相乗的なシグナルを必要とする。T細胞抗原受容体によって送達される第一のシグナルは、APC上の抗原およびMHC複合体によって提供され、免疫応答の特異性を担う。第二の、すなわち共刺激シグナルは、CD28とB7−1(CD80)/B7−2(CD86)の相互作用およびCD40とCD40Lの相互作用によるものであり、これらの相互作用は、フルスケールT細胞応答を開始するために必要とされる。共刺激シグナル不在下では、T細胞は、抗原刺激に対して無応答性(アネルギー)になることがあり、または抗原刺激によりプログラム細胞死(アポトーシス)を被ることがある。
CD40は、正常免疫細胞によって発現されるばかりでなく、多くの悪性細胞によっても発現される。詳細には、CD40は、B系列NHL、慢性リンパ球性白血病(CLL)、有毛細胞白血病(HCL)、ホジキン病(非特許文献12(Uckun FM、Gajl−Peczalska K、Myers DEら、Blood 1990;76:2449−2456);非特許文献13(O’Grady JT、Stewart S、Lowrey Jら、Am J Pathol 1994;144:21−26))、多発性骨髄腫(非特許文献14(Pellat−Deceunynck C、Bataille R、Robillard N、Harousseau JL、Rapp MJ、Juge−Morineau N、Wijdenes J、Amiot M、Blood、1994;84(8):2597−603))において、ならびに膀胱、腎臓、卵巣、子宮頚部、乳房、肺、上咽頭の癌腫および悪性黒色腫(非特許文献15(Young LS、Eliopoulos AG、Gallagher NJら、Immunol Today 1998;19:502−6);非特許文献16(Ziebold JL、Hixon J、Boyd Aら、Arch Immunol Ther Exp(Warsz)2000;48:225−33);非特許文献17(Gladue R、Cole S、Donovan Cら、J Clin Oncol 2006;24(18S):103s))において過発現される。
AG、Davies C, Knox PGら、Mol Cell Biol 2000;20(15):5503−15);非特許文献28(Tong AW、Papayoti MH、Netto Gら、Clin Cancer Res 2001;7(3):691−703))。
CD40は、広範な悪性細胞上で過発現される。腫瘍阻害および免疫系の刺激に関するCD40の役割がCD40を抗体による免疫療法の魅力的な標的にする(非特許文献29(van Mierlo GJ、den Boer AT、Medema JPら、Proc Natl Acad Sci U S A、2002;99(8):5561−5566);非特許文献30(French RR、Chan HT、Tutt AL、Glennie MJ、Nat Med、1999;5(5):548−553))。抗CD40抗体は、多数の機序によって癌細胞に対して作用し得る:(i)抗体エフェクター機能、例えばADCC、(ii)腫瘍細胞に対する直接細胞傷害効果、および(iii)抗腫瘍免疫応答の活性化。
幾つかの抗CD40抗体が抗腫瘍療法薬としての可能性を有すると報告されている。CP−870,893は、Pfizerによって開発された完全ヒトIgG2CD40アゴニスト抗体である。これは、3.48×10−10MのKDでCD40を結合するが、CD40Lの結合を遮断しない(例えば、特許文献1(米国特許第7,338,660号明細書)参照)。CP−870893は、ADCC効果を証明しており、これは、ことによるとそのIgG2アイソタイプに起因する。したがって、この抗体は、CD40アゴニストとして作用し(すなわち、CD40L結合に影響を及ぼさず)、アポトーシス促進性シグナリングを誘導し、ならびにDCおよび免疫監視機構(immune surveilance)を活性化する。しかし、この抗体は、ADCCを媒介しない。
本開示の1つの態様は、(i)配列番号3に示すVHCDR1領域、配列番号4に示すVHCDR2領域および配列番号5に示すVHCDR3領域を含む重鎖可変領域と、(ii)配列番号6に示すVLCDR1領域、配列番号7に示すVLCDR2領域および配列番号8に示すVLCDR3領域を含む軽鎖可変領域とを含む、ヒトCD40に結合する単離された抗体、もしくはその抗原結合断片;または前記CDR領域における8以下のアミノ酸置換を除き、(i)および(ii)の重鎖可変領域および軽鎖可変領域と同一である重鎖可変領域および軽鎖可変領域を含む前記抗体のバリアント、もしくはその抗原結合断片を提供する。本明細書に開示する抗体の1つの実施形態において、前記重鎖可変領域は、配列番号1に示すアミノ酸配列を含む。さらなる実施形態において、前記軽鎖可変領域は、配列番号2に示すアミノ酸配列を含む。
特定の実施形態では、例えば以下が提供される:
(項目1)
(i)配列番号3に示すVHCDR1領域、配列番号4に示すVHCDR2領域および配列番号5に示すVHCDR3領域を含む重鎖可変領域と、(ii)配列番号6に示すVLCDR1領域、配列番号7に示すVLCDR2領域および配列番号8に示すVLCDR3領域を含む軽鎖可変領域とを含み、CD40に結合する、単離された抗体、もしくはその抗原結合断片;または
該CDR領域における8以下のアミノ酸置換を除き、(i)および(ii)の重鎖可変領域および軽鎖可変領域と同一である重鎖可変領域および軽鎖可変領域を含む、該抗体のバリアント、もしくはその抗原結合断片。
(項目2)
前記重鎖可変領域が、配列番号1に示すアミノ酸配列を含む、項目1に記載の単離された抗体、またはその抗原結合断片。
(項目3)
前記軽鎖可変領域が、配列番号2に示すアミノ酸配列を含む、項目1に記載の単離された抗体、またはその抗原結合断片。
(項目4)
配列番号1に示すアミノ酸配列を含む重鎖可変領域を含み、CD40に結合する、単離された抗体、またはその抗原結合断片。
(項目5)
配列番号2に示すアミノ酸配列と少なくとも90%の同一性を有するアミノ酸配列を含む軽鎖可変領域を含む、項目4に記載の単離された抗体、またはその抗原結合断片。
(項目6)
配列番号2に示すアミノ酸配列を含む軽鎖可変領域を含む、項目4に記載の単離された抗体、またはその抗原結合断片。
(項目7)
配列番号2に示すアミノ酸配列を含む軽鎖可変領域を含み、CD40に結合する、単離された抗体、またはその抗原結合断片。
(項目8)
配列番号1に示すアミノ酸配列と少なくとも90%の同一性を有するアミノ酸配列を含む重鎖可変領域を含む、項目7に記載の単離された抗体、またはその抗原結合断片。
(項目9)
ヒト化されている、項目1に記載の単離された抗体。
(項目10)
前記VH領域が、配列番号9に示すアミノ酸配列を含み;および前記VL領域が、配列番号10に示すアミノ酸配列を含む、項目9に記載の単離された抗体。
(項目11)
単鎖抗体、ScFv、ヒンジ領域を欠く一価抗体、およびミニボディから成る群より選択される、項目1に記載の抗体。
(項目12)
FabまたはFab’断片である、項目1に記載の単離された抗体。
(項目13)
F(ab’)2断片である、項目1に記載の単離された抗体。
(項目14)
抗体全体である、項目1に記載の単離された抗体。
(項目15)
ヒトIgG定常ドメインを含む、項目1に記載の単離された抗体。
(項目16)
前記IgG定常ドメインが、IgG1 CH1ドメインを含む、項目15に記載の単離された抗体。
(項目17)
前記IgG定常ドメインが、IgG1 Fc領域を含む、項目15に記載の単離された抗体。
(項目18)
項目1に記載の抗体とCD40への結合について競合する、単離された抗体、またはその抗原結合断片。
(項目19)
0.96nM以下のKDでCD40に結合する、単離された抗体またはその抗原結合断片。
(項目20)
a.CD40のCD40Lへの結合を遮断する;
b.CD40アゴニストである;
c.抗原提示細胞を活性化する;
d.抗原提示細胞からのサイトカイン放出を刺激する;
e.腫瘍細胞アポトーシスを誘導する;
f.腫瘍細胞増殖を阻害する;
g.抗体依存性細胞傷害、補体依存性細胞傷害および抗体依存性細胞食作用から成る群より選択されるエフェクター機能の誘導により腫瘍細胞を死なせる;
h.抗腫瘍T細胞応答を刺激する;
i.定着腫瘍を低減させる;
j.リツキシマブ耐性腫瘍を阻害する;または
k.a.〜j.のいずれか1つ以上の組み合わせである、
項目1〜19のいずれか一項に記載の単離された抗体またはその抗原結合断片。
(項目21)
a.CD40のCD40Lへの結合を遮断する;
b.CD40アゴニストである;
c.抗原提示細胞を活性化する;
d.抗原提示細胞からのサイトカイン放出を刺激する;
e.腫瘍細胞アポトーシスを誘導する;
f.腫瘍細胞増殖を阻害する;
g.抗体依存性細胞傷害、補体依存性細胞傷害および抗体依存性細胞食作用から成る群より選択されるエフェクター機能の誘導により腫瘍細胞を死なせる;
h.抗腫瘍T細胞応答を刺激する;
i.定着腫瘍を低減させる;
j.リツキシマブ耐性腫瘍を阻害する;または
k.a.〜j.のいずれか1つ以上の組み合わせである、
単離された抗体またはその抗原結合断片。
(項目22)
項目1、10、18、19および21のいずれか一項に記載の単離された抗体またはその抗原結合断片をコードする単離されたポリヌクレオチド。
(項目23)
項目22に記載の単離されたポリヌクレオチドを含む発現ベクター。
(項目24)
項目23に記載のベクターを含む単離された宿主細胞。
(項目25)
生理的に許容され得る担体と治療有効量の項目1、10、18、19および21のいずれか一項に記載の単離された抗体またはその抗原結合断片とを含む組成物。
(項目26)
癌を有する患者における症状を処置または改善するための方法であって、項目25に記載の組成物を該患者に投与し、それによって該癌を有する該患者における該症状を処置または改善することを含む方法。
(項目27)
前記癌が、非ホジキンリンパ腫、ホジキンリンパ腫、慢性リンパ球性白血病、有毛細胞白血病、急性リンパ芽球性白血病、多発性骨髄腫、膀胱の癌腫、腎臓の癌腫、卵巣の癌腫、子宮頚の癌腫、乳房の癌腫、肺の癌腫、上咽頭の癌腫、悪性黒色腫ならびにリツキシマブ耐性NHLおよび白血病から成る群より選択される、項目26に記載の方法。
(項目28)
自己免疫疾患を有する患者における症状を改善するための方法であって、項目25に記載の組成物を該患者に投与し、それによって該自己免疫疾患を有する該患者における症状を改善することを含む方法。
(項目29)
炎症性疾患を有する患者における症状を改善するための方法であって、項目25に記載の組成物を該患者に投与し、それによって該炎症性疾患を有する該患者における症状を改善することを含む方法。
(項目30)
(i)図16に示すVH領域のいずれか1つのVHCDR1、VHCDR2およびVHCDR3を含む重鎖可変領域と(ii)図16に示す抗体のいずれか1つの対応するVL領域のVLCDR1、VLCDR2およびVLCDR3領域を含む軽鎖可変領域とを含み、CD40に結合する、単離された抗体もしくはその抗原結合断片、または
該CDR領域における8以下のアミノ酸置換を除き、(i)および(ii)の重鎖可変領域および軽鎖可変領域と同一である重鎖可変領域および軽鎖可変領域を含む、該抗体のバリアントもしくはその抗原結合断片。
(項目31)
図16に示すVH領域のいずれか1つを含む重鎖可変領域を含み、CD40に結合する、単離された抗体もしくはその抗原結合断片。
(項目32)
図16に示す通りの対応するVL領域と少なくとも90%の同一性を有するアミノ酸配列を含む軽鎖可変領域をさらに含む、項目31に記載の単離された抗体、またはその抗原結合断片。
(項目33)
図16に示す通りの対応する軽鎖可変領域をさらに含む、項目31に記載の単離された抗体またはその抗原結合断片。
(項目34)
図16に示すVL領域のいずれか1つを含む軽鎖可変領域を含み、CD40に結合する、単離された抗体、またはその抗原結合断片。
(項目35)
図16に示す通りの対応するVH領域と少なくとも90%の同一性を有するアミノ酸配列を含む重鎖可変領域をさらに含む、項目34に記載の単離された抗体またはその抗原結合断片。
(項目36)
図16に示す通りの対応する重鎖可変領域をさらに含む、項目34に記載の単離された抗体またはその抗原結合断片。
配列番号1は、R−8ウサギ抗CD40抗体のVH領域のアミノ酸配列である。
本開示は、CD40に特異的に結合する抗体およびそれらの抗原結合断片、詳細には、特異的エピトープ特異性および機能特性を有する抗体に関する。本発明の1つの実施形態は、CD40への結合が可能であり、ならびにCD40媒介下流細胞シグナリングおよび生物学的効果を誘導/強化することによりCD40アゴニストとして機能する、特異的ヒト化抗体およびそれらの断片を包含する。本発明のより特異的な実施形態において、本明細書に記載する抗体は、非常に高い親和性、例えば、少なくとも、980ピコモルと950ピコモルの間、少なくとも、970ピコモルと950ピコモルの間の親和性で、および一定の実施形態では960ピコモルの親和性でCD40に特異的に結合する。本明細書に記載する抗体は、数ある特質の中でも、腫瘍細胞においてCD40シグナリングを誘導し;樹状細胞および免疫監視機構を活性化し;腫瘍細胞に対する抗体依存性細胞傷害(ADCC)を活性化し;CD40LへのCD40の結合を遮断し;CD40アゴニスト活性を有し;抗原提示細胞を活性化し;抗原提示細胞からのサイトカイン放出を刺激し;腫瘍細胞アポトーシスを誘導し;腫瘍細胞増殖を阻害し;ADCC、CDCおよびADCPをはじめとする(しかしこれらに限定されない)エフェクター機能の誘導により腫瘍細胞を死なせ;抗腫瘍T細胞応答を刺激し;定着腫瘍を低減させ;ならびにリツキシマブ耐性腫瘍を阻害する。本明細書に記載する抗体は、これらの特質または活性のいずれか1つ以上の組み合わせを有するまたは誘導することができる。
マブ耐性NHLおよび白血病が挙げられるが、これらに限定されない)、自己免疫疾患および炎症性疾患の処置または予防において使用される。
USA 86:4220−4224;Queen et alら、PNAS(1988)86:10029−10033;Riechmannら、Nature(1988)332:323−327)。本明細書に開示する抗CD40抗体の例証的ヒト化方法は、米国特許第7,462,697号明細書に記載されている方法を含む。本発明の一定の実施形態による例証的ヒト化抗体は、配列番号9および10に提供するヒト化配列を含む。
ントを得ることができる。これらの方法およびプロトコルに関する具体的な詳細は、Maloyら、1994;Segal、1976;Prokop and Bajpai、1991;Kuby、1994;およびManiatisら、1982の教示の中で見出され、その目的のために、前記各教示は参照により本明細書に援用されている。
している、または(7)自然界に存在しないことを意味する。かかる単離されたタンパク質は、ゲノムDNA、cDNA、mRNAもしくは他のRNAによってコードされている場合があり、合成起源のものであることがあり、またはそれらの任意の組み合わせであることがある。一定の実施形態において、前記単離されたタンパク質には、その用途(治療、診断、予防、研究または別様の用途)に干渉することとなるその天然の環境において見つけられるタンパク質またはポリペプチドまたは他の混入物が実質的にない。
具体的に示す抗体配列ばかりでなく、かかるバリアント抗体もしくはそれらの抗原結合断片、またはそれらのCDRは、本明細書に示す抗体より大きい親和性でCD40に結合する、例えば、定量的に少なくとも約105%、106%、107%、108%、109%または110%結合する。
本開示は、CD40特異的抗体、それらの抗原結合断片、を含む組成物、様々な治療設定でのかかる組成物の投与を提供する。
できる。さらに、検出可能標識を第二および/または第三および/または第四および/または第五の結合剤または抗体などにもコンジュゲートさせることができることは、当業者には理解されるであろう。さらに、対象となる生物学的マーカーの特性付けに使用する各追加の結合剤または抗体が、シグナル増幅段階としての役割を果たし得ることは、当業者には理解されるであろう。検出可能物質が、例えば色素、コロイド状金粒子、発光性試薬である場合、例えば、光学顕微鏡法、蛍光顕微鏡法、電子顕微鏡法を使用して、前記生物学的マーカーを視覚的に検出することができる。生物学的マーカーに結合している視覚的検出可能物質を、分光光度計を使用して検出することもできる。検出可能物質が、放射活性同位元素である場合、検出は、オートラジオグラフィーによる視覚的検出である場合もあり、シンチレーションカウンターを使用する非視覚的検出である場合もある。例えば、Larsson、1988、Immunocytochemistry:Theory and Practice(CRC Press、Boca Raton、Fla.);Methods in Molecular Biology、第80巻、1998、John D.Pound(編集)(Humana Press、Totowa、N.J.)を参照されたし。
4羽のニュージーランドホワイトウサギを、組換えウサギFc−hCD40で免疫した。ヒトCD40への特異的結合の最高血清力価を有するウサギを細胞融合に選択した。合計172のハイブリドーマを可溶性Fc−hCD40への陽性結合剤として同定し、そのうち44のクローンは、細胞表面CD40への陽性結合剤であることが判明した。エピトープ・クラスタリング・アッセイの後、24の代表ハイブリドーマを組換え発現のために選択し、さらに特性付けした。下でさらに説明するとおりのおよび次のことを含む、第二の機能性スクリーニングを行った:1)CD80、CD83、CD86アップレギュレーション(アゴニスト活性)によって測定されるようなDC成熟の誘導;直接腫瘍成長阻害(アゴニスト活性)の誘導;および3)ADCC抗体エフェクター機能。次の2つのアームを含む二重機能性スクリーニングに基づき候補を選択した:1)結合親和性、抗体内在化、抗体依存性細胞傷害(ADCC)、補体依存性細胞傷害(CDC)および抗体依存性細胞食作用(ADCP);および2)アゴニストDC活性化/成熟機能、受容体−リガンド相互作用、混合リンパ球反応(MLR)、細胞増殖およびアポトーシス。
抗CD40抗体の初期パネルのアゴニストまたはアンタゴニスト効果をさらに明らかにするために、機能性抗体についてのスクリーニングの指標としてDC成熟アッセイを用いた。抗CD40または対照抗体をヒト単球由来DC培養溶液に2日間にわたって添加した。ヒト樹状細胞の最も知られている成熟マーカーの1つであるCD83のアップレギュレーションを測定して、アゴニスト抗体についてスクリーニングした。樹状細胞成熟を誘導するマウスモノクローナル抗体である5C11を陽性対照として使用した。抗体R−3、R−6、R−8、R−9、R−16、R−18、R−24、R−33、R−36、19−21、19−45および19−59は、CD83発現の50%より多くをIg対照と比較して増加させた(図1A)。共刺激分子CD80およびCD86の抗体誘導アップレギュレーションを選択された抗体について測定することにより、DC成熟をさらに判定した。図1Bおよび図1Cに示すように、抗体R−3、R−8、R−9、R−33および19−21は、CD80とCD86の両方をアップレギュレートしたが、他の抗体は、ほんのわずかな効果しかなかった。これらの結果は、これらの抗体のCD83変調効果と一致した。興味深いことに、DC成熟の誘導が可能な抗体の中で、クローン19−21のみが、混合リンパ球反応においてT細胞増殖を増進させる強い活性を示した(図1D)。
アゴニスト抗CD40抗体のパネルを、CD40発現腫瘍細胞の腫瘍成長阻害を誘導する能力についてさらに評定した。試験したすべての抗CD40抗体が腫瘍細胞増殖を阻害した。抗体19−21は、最高力価を明示した。(図2)。
APC活性化および腫瘍成長阻害の誘導に加えて、抗体エフェクター機能、ADCC、を抗体候補のスクリーニングおよびランク付けのための重要な基準として用いた。ヒトPBMCを使用するADCCアッセイを行うために、選択抗体すべてを、ウサギFabおよびヒトIgG1でウサギmAbからキメラmAbに変換した。図3に示すように、選択候補すべてがIgG1対照と比較して有意なADCC活性を示した。最大ADCC活性に基づき、リードmAbをcR−8>cR−3>cR−33>c19−21>cR−9>c19−59とランク付けした。
最上位4候補が異なるin vitroアッセイにおいて異なる効力を示したので、本発明者らは、リード選択のために、それらの抗腫瘍活性を評価および比較するためのin
vivo研究を行った。Ramos腫瘍異種移植モデルを使用した。腫瘍保有マウスを5mg/kgで週3回、合計9用量のキメラ抗体cR−3、cR−8、cR−33またはc19−21で、腹腔内処置した(1群あたり8匹のマウス)。同じレジメンでのリツキシマブの抗腫瘍活性を基準として用いた。図4Aに示すように、cR−8およびcR−3は、最強の抗腫瘍効果を示した。対照的に、19−21は、より低い抗腫瘍活性を呈示し、投薬停止後により速やかに腫瘍がリバウンドした。cR−33の抗腫瘍効果は、間であったが、リツキシマブより良好なin vivo効力を依然として呈示した。抗体cR−3およびcR−8のin vivo効力を用量応答研究でさらに評価した。図4Bに示すように、cR−8は、cR−3より強力な抗腫瘍効力を示し、したがって、リード抗CD40抗体と同定した。
非常に多くのin vitro実験を行って、APX005ヒト化抗体をさらに特性付けした。
APX005の結合選択性をTNFRファミリータンパク質のパネルに対する直接ELISAによって評定した。ウサギFcおよびCD40、RANK TweakR、OX40、DR5および4−1BBの合計1μg/mLの融合タンパク質をELISAプレートにコーティングした。ヤギ抗ヒトHRPコンジュゲートIgGを使用して結合APX005を検出した。図5に示すように、APX005は、ヒトCD40に選択的に結合するが、試験した他のTNFRファミリータンパク質にはしなかった。
ELISAを行って、CD40へのCD40Lの結合に対するAPX005の効果を評定した。詳細には、CD40L(4μg/mLの最終濃度)を使用して、ELISAプレート上の固定化ヒトCD40を結合し、固定化CD40をAPX005と共にプレインキュベートした後、CD40へのCD40Lの結合量の変化を測定した。固定化CD40へのCD40Lの結合は、マウス抗CD40Lモノクローナル抗体によって検出した。図6に示すように、APX005は、CD40へのCD40Lの結合を遮断する。対照的に、SGN−40はその結合を増加させる。
ADCC活性に対するその影響を評価するためにAPX005の標的媒介内在化を評定するために、Ramos細胞をAPX005と共に4時間、37℃(内在化が許容される温度)で、または30分間4℃(内在化が最小にされる温度)でインキュベートした。細胞を染色用緩衝液で洗浄し、その後、Alexa 488標識ヤギ抗ヒトIgGと共にさらに30分間、4℃でインキュベートした。FACS分析を行って、細胞表面のAPX005レベルを検査した。図7に示すように、37℃でのインキュベーション後、細胞表面のAPX005レベルの低減はなかった(わずかに増加)。このデータは、CD40に結合すると、APX005/CD40複合体は腫瘍細胞によって内在化されず、それ故、ADCCへのエフェクター細胞の動員に最適な条件がもたらされたことを示唆している。
CD40を発現する腫瘍細胞に対するAPX005のADCC活性を評定するために、CD40発現性RamosおよびDaujiを標的細胞として使用し、新鮮なヒト末梢血単核細胞(PBMC)をエフェクター細胞として使用した。カルセイン−AM放出アッセイによりADCCを測定した。標的細胞をカルセイン−AM(15uM/106細胞)で標識し、洗浄し、丸底96ウェルプレートに1ウェルあたり5×103で、三つ組みでプレーティングした。漸増濃度(0.0001〜10μg/mL)のAPX005または対照抗体いずれかを4℃で30分間プレインキュベートし、その後、健常ヒトドナーからのPBMCエフェクター細胞を、1ウェルあたり200μLの最終体積中、40:1の最終エフェクター:標的細胞比で添加した。少なくとも3人の異なるドナーからのPBMCを使用して実験を行った。4時間のインキュベーションの後、100μLの培養上清をBlack View Plate−96プレートに移し、任意蛍光単位(AFU)をVictor IIプレートリーダー(485nm励起/535nm放射)で読み取った。特異的溶解パーセント=(AFU平均実験放出−AFU平均自然放出)/(AFU平均最大放出−AFU平均自然放出)。図8に示すように、APX005は、用量依存式にADCCを誘導した。同様の効果がSGN−40について観察された。RamosおよびDaudi細胞のADCCに対する異なる感度は、異なるCD40発現レベルに起因し得る(Cancer Res 2005;65:8331−8338)。
腫瘍細胞増殖を阻害するAPX005の能力を評定するために、96ウェル平底プレート内の、様々な濃度のAPX005、SGN−40または対照ヒトIgGを含有する、10%FBSを補足した200μLのRPMI 1640に、50,000細胞/ウェルでRamos細胞を播種した。架橋のために、APX005、SGN−40または対照IgGをヤギ抗ヒトIgG Fc断片特異的抗体のF(ab’)2断片と共に前記培地中で30分間、室温でプレインキュベートし、その後、前記細胞に添加した。細胞を合計72時間処置した。その後、10%AlamarBlue(登録商標)(Serotec、英国オックスフォード)を各ウェルに添加し、さらに24時間インキュベートした。細胞生存率をCytoFluor蛍光リーダーにより530nmの励起波長および590nmの放射波長で測定した。すべての研究を2回、および各試料濃度について三重反復で行った。図9に示すように、モノマーAPX005は、Ramos細胞の増殖を阻害した(図9A)。APX005を二次抗体によって架橋させたとき、それは、増加したおよび用量依存性の増殖阻害効果をもたらした(図9B)。APX005の架橋は、Fc受容体発現細胞によってin vivoで達成することができる。
DC細胞の成熟を刺激するAPX005の能力を評定するために、リンパ球単離溶液を使用して密度勾配遠心法によりPBMCを調製した。2時間、37℃でインキュベートした後、付着単球を回収した。単離された単球を、24ウェルプレートにおいて10%FCSを補足したRPMI1640培地中の100ng/mLの組換えヒトGM−CSFおよび100ng/mLの組換えヒトIL−4と共に培養した。培地の半分を3日後に交換した。培養第5日に、1.3nMの抗CD40抗体、CD40Lまたは対照抗体をそれらのDC細胞に添加し、さらに48時間、24ウェルプレートにおいて培養した。DC活性化マーカー染色のために、PEコンジュゲート抗CD83、抗CD86抗体および抗CD80抗体を使用した。FACSを用いて分析を行った。データは、1つの代表研究からのものである。図10に示すように、APX005は、著しいDC成熟を誘導した。その効果は、SGN−40およびCD40Lより強力に見える。DCの活性化増加は、より強力な抗腫瘍T細胞応答をもたらすことができる。
交差反応性を直接ELISAによって評定した。合計1μg/mLのヒトCD40、サルCD40またはマウスCD40をELISAプレートにコーティングし、その後、1μg/mLのAPX005または対照IgG1と共にインキュベートした。CD40に結合した抗体を、HRPとコンジュゲートしているヤギ抗ヒトIgGを使用して検出した。APX005は、サルCD40と明確に交差反応するが、マウスCD40とはしない。(図11A)。
Biotech CAT#2040−09)をPBS中、1:200希釈で試料に添加し、インキュベートした。PEとコンジュゲートしているラット抗マウスCD40抗体を陽性対照として使用した。試料を0.5mL PBSで再び懸濁させ、FACSによって分析した。FACSデータは、APX005がマウスCD40と交差反応しないことを示した(図11B)。
非常に多くのin vivo実験を行って、APX005ヒト化抗体をさらに特性付けした。
ヒトB細胞リンパ腫の異種移植モデルに対するAPX005の効果を評価するために、雌BALB/c nu/nuマウス6〜8週齢を腫瘍細胞接種(innoculation)に使用した。1×107腫瘍細胞/マウスの背側・側腹部への皮下接種によって異種移植片を定着させた。腫瘍が約100mm3(50〜200mm3)の平均体積に達したら、マウスを無作為に群に割り当てた。第13日に開始して3mg/kgの抗体を腹腔内投与した(図12参照)。週3回、合計9用量の投薬を施した(1群あたり8匹のマウス)。Vernierスケールキャリパーを使用して、腫瘍の垂直寸法を測定した。次の式を用いて腫瘍体積を計算した:体積=(長さ×幅2)/2。図12Aに示すように、APX005は、強力な持続性の抗腫瘍活性を明示した。ヒトIgG濃度を測定することによりin vivo薬物レベルを判定するために、最終投薬の2日後の第34日に血清を採取した(図12B参照)。APX005によって媒介される抗腫瘍効力は、SGN−40のものより大きく、投薬期間後、長く持続された。1点PK分析は、APX005の優れた抗腫瘍活性がPKの差に起因しないことを示した。
この実験の目的は、リツキシマブで前処置したリツキシマブ耐性B細胞リンパ腫に対するAPX005の効果を評価することであった。定着したRamos腫瘍を保有するヌードマウスを、先ず、3mg/kgのリツキシマブで5用量にわたって処置した。腫瘍成長は、部分的にリツキシマブによって阻害された(図13A)。これらの腫瘍が約700mm3のサイズに達したら、それらマウスを無作為に4群に割り当て(1群あたり7匹のマウス)、APX005、リツキシマブ、SGN40アナログ 3mg/kgまたは食塩水対照を用いて3週間、腹腔内経路で再処置した(図13B)。図13に示すように、リツキシマブ前処置腫瘍は、リツキシマブ再処置に応答することができなかった。これは、これらの腫瘍がリツキシマブ耐性であることを示唆している(図13B)。APX005は、リツキシマブ耐性腫瘍の成長を阻害する能力を呈示した。
この実験の目的は、in vivoでのAPX005の用量と効力の関係を判定することであった。定着したCD40陽性Raji腫瘍を保有するヌードマウスを、第15日に開始してAPX005で処置した。0.1mg/kg〜10mg/kgにわたるAPX005の用量を3回/週で2週間、腹腔内投与した(1群あたり8匹のマウス)(図14参照)。食塩水を対照処置として使用した。各投薬日に腫瘍体積を測定した。最終投薬の3日後に各群におけるAPX005の血清レベルも測定して、そのin vivo効力と循環におけるAPX005のレベルとの相関関係を判定した。明確な用量依存性抗腫瘍活性が観察された(図14参照)。第29から33日における対照群と用量レベル≧1mg/kgでの抗体処置群の間の腫瘍体積の差は有意であった(P≦0.05)。最小有効用量は、1mg/kgと判定され、これは、第36日における0.49μg/mLの中央値血清濃度に対応した。3、5および10mg/kg用量群間の腫瘍体積の差は、統計学的に有意でなかった。したがって、最大抗腫瘍活性は、中央値血清濃度≧1.6μg/mLでの用量≧3mg/kgで達成された。
ヒト多発性骨髄腫モデルにおけるAPX005の抗腫瘍活性を評価するために、定着したCD40陽性多発性骨髄腫IM−9腫瘍を保有するヌードマウスを、第15日で開始してAPX005またはSGN40で腹腔内処置した。APX005を3mg/kg、3回/週で3週間にわたって与えた(1群あたり5匹のマウス)。各投薬日に腫瘍体積を測定した。
この実験の目的は、ヒトB細胞リンパ腫Ramos異種移植モデルにおけるAPX005、リツキシマブおよびSGN−40の抗腫瘍活性を比較することであった。雌SCID
C.B −17マウスの背側・側腹部へのRamos細胞の皮下接種により、異種移植片を定着させた。腫瘍が約200〜300mm3の平均体積に達したら、マウスを無作為に6群に割り当てた。図17に示した通りの用量で抗体を腹腔内投与した。週3回、合計9用量の投薬を施した(1群あたり10匹のマウス)。Vernierスケールキャリパーを使用して、腫瘍の垂直寸法を測定した。次の式を用いて腫瘍体積を計算した:体積=(長さ×幅2)/2。マウスの生存期間も判定し、記録した。
この実験の目的は、リツキシマブ耐性ヒトNamalwaリンパ腫モデルにおけるAPX005、リツキシマブおよびSGN−40の抗腫瘍活性を比較することであった。雌SCID C.B −17マウスの背側・側腹部へのNamalwa細胞の皮下接種により、異種移植片を定着させた。腫瘍が約200〜300mm3の平均体積に達したら、マウスを無作為に6群に割り当てた。図18に示した通りの用量で抗体を腹腔内投与した。週3回、合計9用量の投薬を施した(1群あたり10匹のマウス)。Vernierスケールキャリパーを使用して、腫瘍の垂直寸法を測定した。次の式を用いて腫瘍体積を計算した:体積=(長さ×幅2)/2。マウスの生存期間も判定し、記録した。
Claims (20)
- CD40に結合し、かつCD40アゴニストである、単離された抗体、またはその抗原結合断片であって、
(A)(i)配列番号9に示すアミノ酸配列を含む重鎖可変領域と、(ii)配列番号6に示すVLCDR1領域、配列番号7に示すVLCDR2領域、および配列番号8に示すVLCDR3領域を含む軽鎖可変領域とを含むか、あるいは
(B)(A)における(i)および(ii)の重鎖可変領域および軽鎖可変領域と同一の重鎖可変領域および軽鎖可変領域を含み、ここで該単離された抗体、またはその抗原結合断片が、1アミノ酸置換を含み、該1アミノ酸置換は、該CDR領域におけるものである、
単離された抗体、またはその抗原結合断片。 - (a)前記抗体がヒト化されている;
(b)前記抗体が単鎖抗体、ScFv、ヒンジ領域を欠く一価抗体、およびミニボディから成る群より選択される;
(c)前記抗体がFabまたはFab’断片である;
(d)前記抗体がF(ab’)2断片である;
(e)前記抗体が抗体全体である;または
(f)前記抗体がヒトIgG定常ドメインを含み、ここで、必要に応じて、該IgG定常ドメインが、IgG1 CH1ドメインもしくはIgG1 Fc領域を含む、
請求項1に記載の単離された抗体、またはその抗原結合断片。 - 0.96nm以下のKDでCD40に結合する、請求項2(a)に記載の単離された抗体、またはその抗原結合断片。
- a.CD40のCD40Lへの結合を遮断する;
b.抗原提示細胞を活性化する;
c.抗原提示細胞からのサイトカイン放出を刺激する;
d.腫瘍細胞アポトーシスを誘導する;
e.腫瘍細胞増殖を阻害する;
f.抗体依存性細胞傷害、補体依存性細胞傷害および抗体依存性細胞食作用から成る群より選択されるエフェクター機能の誘導により腫瘍細胞を死なせる;
g.抗腫瘍T細胞応答を刺激する;
h.定着腫瘍を低減させる;
i.リツキシマブ耐性腫瘍を阻害する;または
j.a.〜i.のいずれか1つ以上の組み合わせである、
請求項1〜3のいずれか一項に記載の単離された抗体またはその抗原結合断片。 - 請求項1〜4のいずれか一項に記載の単離された抗体またはその抗原結合断片をコードする単離されたポリヌクレオチド。
- 請求項5に記載の単離されたポリヌクレオチドを含む発現ベクター。
- 請求項6に記載のベクターを含む単離された宿主細胞。
- 生理的に許容され得る担体と、治療有効量の請求項1〜4のいずれか一項に記載の単離された抗体またはその抗原結合断片とを含む組成物。
- 癌を処置または改善するための、請求項8に記載の組成物。
- 前記癌が、非ホジキンリンパ腫、ホジキンリンパ腫、慢性リンパ球性白血病、有毛細胞白血病、急性リンパ芽球性白血病、多発性骨髄腫、膀胱の癌腫、腎臓の癌腫、卵巣の癌腫、子宮頚の癌腫、乳房の癌腫、肺の癌腫、上咽頭の癌腫、悪性黒色腫ならびにリツキシマブ耐性NHLおよび白血病から成る群より選択される、請求項9に記載の組成物。
- 自己免疫疾患を処置するための、請求項8に記載の組成物。
- 前記自己免疫疾患が、関節炎(関節リウマチ、反応性関節炎を含む)、全身性エリテマトーデス(SLE)、乾癬および炎症性腸疾患(IBD)、脳脊髄炎、ブドウ膜炎、重症筋無力症、多発性硬化症、インスリン依存型糖尿病、アジソン病、セリアック病、慢性疲労症候群、自己免疫性肝炎、自己免疫性脱毛症、強直性脊椎炎、潰瘍性大腸炎、クローン病、線維筋痛症、尋常性天疱瘡、シェーグレン症候群、川崎病、甲状腺機能亢進/ブレーブス病、甲状腺機能低下/橋本病、子宮内膜症、強皮症、悪性貧血、グッドパスチャー症候群、ギラン・バレー症候群、ウェーグナー病、糸球体腎炎、再生不良性貧血(頻回輸血再生不良性貧血患者を含む)、発作性夜間ヘモグロビン尿症、骨髄異形成症候群、特発性血小板減少性紫斑病、自己免疫性溶血性貧血、エバンス症候群、第VIII因子阻害物質症候群、全身性血管炎、皮膚筋炎、多発性筋炎およびリウマチ熱、自己免疫性リンパ増殖症候群(ALPS)、自己免疫性水疱性類天疱瘡、パーキンソン病、サルコイドーシス、白斑、原発性胆汁性肝硬変、ならびに自己免疫性心筋炎から成る群より選択される、請求項11に記載の組成物。
- 炎症性疾患を処置するための、請求項8に記載の組成物。
- 前記炎症性疾患が、クローン病、大腸炎、皮膚炎、乾癬、憩室炎、肝炎、過敏性腸症候群(IBS)、エリテマトーデス、腎炎、パーキンソン病、潰瘍性大腸炎、多発性硬化症(MS)、アルツハイマー病、関節炎、関節リウマチ、喘息、アテローム性動脈硬化症および血管炎などの心血管疾患、糖尿病、痛風、クリオピリン関連周期性症候群、および慢性閉塞性肺疾患から成る群より選択される、請求項13に記載の組成物。
- 癌を処置または改善するための医薬の製造における、請求項8に記載の組成物の使用。
- 前記癌が、非ホジキンリンパ腫、ホジキンリンパ腫、慢性リンパ球性白血病、有毛細胞白血病、急性リンパ芽球性白血病、多発性骨髄腫、膀胱の癌腫、腎臓の癌腫、卵巣の癌腫、子宮頚の癌腫、乳房の癌腫、肺の癌腫、上咽頭の癌腫、悪性黒色腫ならびにリツキシマブ耐性NHLおよび白血病から成る群より選択される、請求項15に記載の使用。
- 自己免疫疾患を処置するための医薬の製造における、請求項8に記載の組成物の使用。
- 前記自己免疫疾患が、関節炎(関節リウマチ、反応性関節炎を含む)、全身性エリテマトーデス(SLE)、乾癬および炎症性腸疾患(IBD)、脳脊髄炎、ブドウ膜炎、重症筋無力症、多発性硬化症、インスリン依存型糖尿病、アジソン病、セリアック病、慢性疲労症候群、自己免疫性肝炎、自己免疫性脱毛症、強直性脊椎炎、潰瘍性大腸炎、クローン病、線維筋痛症、尋常性天疱瘡、シェーグレン症候群、川崎病、甲状腺機能亢進/ブレーブス病、甲状腺機能低下/橋本病、子宮内膜症、強皮症、悪性貧血、グッドパスチャー症候群、ギラン・バレー症候群、ウェーグナー病、糸球体腎炎、再生不良性貧血(頻回輸血再生不良性貧血患者を含む)、発作性夜間ヘモグロビン尿症、骨髄異形成症候群、特発性血小板減少性紫斑病、自己免疫性溶血性貧血、エバンス症候群、第VIII因子阻害物質症候群、全身性血管炎、皮膚筋炎、多発性筋炎およびリウマチ熱、自己免疫性リンパ増殖症候群(ALPS)、自己免疫性水疱性類天疱瘡、パーキンソン病、サルコイドーシス、白斑、原発性胆汁性肝硬変、ならびに自己免疫性心筋炎から成る群より選択される、請求項17に記載の使用。
- 炎症性疾患を処置するための医薬の製造における、請求項8に記載の組成物の使用。
- 前記炎症性疾患が、クローン病、大腸炎、皮膚炎、乾癬、憩室炎、肝炎、過敏性腸症候群(IBS)、エリテマトーデス、腎炎、パーキンソン病、潰瘍性大腸炎、多発性硬化症(MS)、アルツハイマー病、関節炎、関節リウマチ、喘息、アテローム性動脈硬化症および血管炎などの心血管疾患、糖尿病、痛風、クリオピリン関連周期性症候群、および慢性閉塞性肺疾患から成る群より選択される、請求項19に記載の使用。
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