JP6890421B2 - Pd‐1及びlag‐3との免疫反応性を有する共有結合ダイアボディ並びにその使用方法 - Google Patents
Pd‐1及びlag‐3との免疫反応性を有する共有結合ダイアボディ並びにその使用方法 Download PDFInfo
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Description
本出願は、連邦規則法典第37巻第1.821節以下による1つ又は複数の配列表を含み、これらの配列表は、コンピュータ可読媒体(ファイル名:1301_0115PCT_Sequence_Listing_ST25.txt、2015年6月2日作成、サイズ:50,015バイト)において開示されており、上記ファイルは、参照によりその全体が本出願に援用される。
I.細胞仲介性免疫応答
ヒト及び他の哺乳類の免疫系は、感染及び疾患に対して保護を提供する役割を果たす。このような保護は、体液性免疫応答及び細胞仲介性免疫応答の両方によって提供される。体液性免疫応答により、異物標的(抗原)を認識して中和できる抗体及び他の生体分子の産生が得られる。対照的に、細胞仲介性免疫応答は、T細胞によるマクロファージ、ナチュラルキラー(NK)細胞及び抗原特異性細胞毒性Tリンパ球の活性化、並びに抗原の認識に応じた様々なサイトカインの放出を伴う(非特許文献1)。
プログラム死‐1(「PD‐1」)は、免疫応答を幅広く下方制御するT細胞制御因子の拡張CD28/CTLA4ファミリーの、およそ31kDのI型膜タンパク質メンバーである(非特許文献19、特許文献1〜9)。CTLA4に比べてPD‐1は多い。
リンパ球活性化遺伝子3(lymphocyte activation gene:LAG‐3、CD223)は、活性化されたCD4+及びCD8+T細胞並びにNK細胞が発現する細胞表面受容体タンパク質であり、形質細胞様樹状細胞によって恒常的に発現される。LAG‐3はB細胞、単球又は試験された他のいずれの細胞タイプによって発現されない(非特許文献36)。
(A)上記第1及び第2のポリペプチド鎖は互いに共有結合し、上記第1及び第3のポリペプチド鎖は互いに共有結合し、また上記第3及び第4のポリペプチド鎖は互いに共有結合し;
(B)上記ダイアボディの上記第1及び第3のポリペプチド鎖はそれぞれ、N末端からC末端への方向に、PD‐1又はLAG‐3に対して免疫特異的である抗体の軽鎖可変ドメイン、LAG‐3又はPD‐1に対して免疫特異的である抗体の重鎖可変ドメイン、ヘテロ二量体促進ドメイン及びCH2‐CH3ドメインを含み、上記軽鎖可変ドメイン及び重鎖可変ドメインは、PD‐1のエピトープ又はLAG‐3のエピトープに結合できるエピトープ結合部位を形成するために連結できず;
(C)上記ダイアボディの上記第2及び第4のポリペプチド鎖はそれぞれ、N末端からC末端の方向に、PD‐1又はLAG‐3に対して免疫特異的である抗体の軽鎖可変ドメイン、LAG‐3又はPD‐1に対して免疫特異的である抗体の重鎖可変ドメイン、及びヘテロ二量体促進ドメインを含み、上記軽鎖可変ドメイン及び重鎖可変ドメインは、PD‐1のエピトープ又はLAG‐3のエピトープに結合できるエピトープ結合部位を形成するために連結できず;
(I)(1)上記第1のポリペプチド鎖の軽鎖可変ドメイン及び上記第2のポリペプチド鎖の重鎖可変ドメインは、連結して第1のエピトープ結合部位を形成し、上記第1のポリペプチド鎖の重鎖可変ドメイン及び上記第2のポリペプチド鎖の軽鎖可変ドメインは、連結して第2のエピトープ結合部位を形成し;
(2)上記第3のポリペプチド鎖の軽鎖可変ドメイン及び上記第4のポリペプチド鎖の重鎖可変ドメインは、連結して第3のエピトープ結合部位を形成し、上記第3のポリペプチド鎖の重鎖可変ドメイン及び上記第4のポリペプチド鎖の軽鎖可変ドメインは、連結して第4のエピトープ結合部位を形成し;
形成された上記エピトープ結合部位のうちの2つは、PD‐1のエピトープに免疫特異的に結合でき、形成された上記エピトープ結合部位のうちの2つは、LAG‐3のエピトープに免疫特異的に結合でき;
(II)上記第1のポリペプチド鎖の上記ヘテロ二量体促進ドメインは上記第2のポリペプチド鎖の上記ヘテロ二量体促進ドメインと異なっており、配列番号16及び配列番号17からなる群から選択されるアミノ酸配列を有し;
(III)上記第1及び第3のポリペプチド鎖の上記CH2‐CH3ドメインは、連結してFcドメインを形成する。
本発明の実践は、そうでないことが示されていない限り、当該技術の範囲内の分子生物学(組み換え技術を含む)、微生物学、細胞生物学、生化学及び免疫学の従来技術を採用する。
このような技術は:MOLECULAR CLONING: A LABORATORY MANUAL, Third Edition (Sambrook et al. Eds., 2001) Cold Spring Harbor Press, Cold Spring Harbor, NY; OLIGONUCLEOTIDE SYNTHESIS: METHODS AND APPLICATIONS (Methods in Molecular Biology), Herdewijn, P., Ed., Humana Press, Totowa, NJ; OLIGONUCLEOTIDE SYNTHESIS (Gait, M.J., Ed., 1984); METHODS IN MOLECULAR BIOLOGY, Humana Press, Totowa, NJ; CELL BIOLOGY: A LABORATORY NOTEBOOK (Cellis, J.E., Ed., 1998) Academic Press, New York, NY; ANIMAL CELL CULTURE (Freshney, R.I., Ed., 1987); INTRODUCTION TO CELL AND TISSUE CULTURE (Mather, J.P. and Roberts, P.E., Eds., 1998) Plenum Press, New York, NY; CELL AND TISSUE CULTURE: LABORATORY PROCEDURES (Doyle, A. et al, Eds., 1993‐8) John Wiley and Sons, Hoboken, NJ; METHODS IN ENZYMOLOGY (Academic Press, Inc.) New York, NY; WEIR' S HANDBOOK OF EXPERIMENTAL IMMUNOLOGY (Herzenberg, L.A. et al. Eds. 1997) Wiley‐Blackwell Publishers, New York, NY; GENE TRANSFER VECTORS FOR MAMMALIAN CELLS (Miller, J.M. et al. Eds., 1987) Cold Spring Harbor Press, Cold Spring Harbor, NY; CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (Ausubel, F.M. et al, Eds., 1987) Greene Pub. Associates, New York, NY; PCR: THE POLYMERASE CHAIN REACTION, (Mullis, K. et al, Eds., 1994) Birkhauser, Boston MA; CURRENT PROTOCOLS IN IMMUNOLOGY (Coligan, J.E. et al, eds., 1991) John Wiley and Sons, Hoboken, NJ; SHORT PROTOCOLS IN MOLECULAR BIOLOGY (John Wiley and Sons, 1999) Hoboken, NJ; IMMUNOBIOLOGY 7 (Janeway, C.A. et al 2007) Garland Science, London, UK; Antibodies (P. Finch, 1997) Stride Publications, Devoran, UK; ANTIBODIES: A PRACTICAL APPROACH (D. Catty., ed., 1989) Oxford University Press, USA, New York NY); MONOCLONAL ANTIBODIES: A PRACTICAL APPROACH (Shepherd, P. et al Eds., 2000) Oxford University Press, USA, New York NY; USING ANTIBODIES: A LABORATORY MANUAL (Harlow, E. et al Eds., 1998) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; THE ANTIBODIES (Zanetti, M. et al Eds. 1995) Harwood Academic Publishers, London, UK); 及びDEVITA, HELLMAN, AND ROSENBERG'S CANCER: PRINCIPLES & PRACTICE OF ONCOLOGY, EIGHTH EDITION, DeVita, V. et al Eds. 2008, Lippincott Williams & Wilkins, Philadelphia, PA等の文献に十分に説明されている。
本発明は、PD‐1xLAG‐3二重特異性ダイアボディに関する。本発明の好ましいPD‐1xLAG‐3二重特異性ダイアボディは、抗体を2つの異なるエピトープ:PD‐1のエピトープ及びLAG‐3のエピトープに協調的に結合させることによって、このような分子の阻害活性を減衰させることができる、抗体のエピトープ結合断片を有する。本明細書において使用される場合、このような減衰は、検出可能なPD‐1及び/若しくはLAG‐3阻害活性の少なくとも20%の低下、少なくとも50%の低下、少なくとも80%の低下若しくは少なくとも90%の低下、又は検出可能なPD‐1及び/若しくはLAG‐3阻害活性の完全な排除を指す。
PD‐1に対して免疫特異的である抗体が公知である(例えば米国特許第8,008,449号、米国特許第8,552,154号、国際公開第2012/135408号、国際公開第2012/145549号、国際公開第2013/014668号を参照)。更なる望ましい抗体は、PD‐1又はそのペプチド断片を用いて誘発された抗体分泌性ハイブリドーマを単離することによって作製できる。(20個のアミノ酸残基シグナル配列(下線を付して示す)及び268個のアミノ酸残基成熟タンパク質を含む)ヒトPD‐1は、アミノ酸配列(配列番号1):
MQIPQAPWPV VWAVLQLGWRPGWFLDSPDR PWNPPTFSPA LLVVTEGDNA
TFTCSFSNTS ESFVLNWYRM SPSNQTDKLA AFPEDRSQPG QDCRFRVTQL
PNGRDFHMSV VRARRNDSGT YLCGAISLAP KAQIKESLRA ELRVTERRAE
VPTAHPSPSP RPAGQFQTLV VGVVGGLLGS LVLLVWVLAV ICSRAARGTI
GARRTGQPLK EDPSAVPVFS VDYGELDFQW REKTPEPPVP CVPEQTEYAT
IVFPSGMGTS SPARRGSADG PRSAQPLRPE DGHCSWPL
を有する。
QVQLVESGGG VVQPGRSLRL DCKASGITFS NSGMHWVRQA PGKGLEWVAV
IWYDGSKRYY ADSVKGRFTI SRDNSKNTLF LQMNSLRAED TAVYYCATND
DYWGQGTLVT VSS
を有する。
EIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKP GQAPRLLIYD
ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ SSNWPRTFGQ
GTKVEIK
を有する。
QVQLVQSGVE VKKPGASVKV SCKASGYTFT NYYMYWVRQA PGQGLEWMGG
INPSNGGTNF NEKFKNRVTL TTDSSTTTAY MELKSLQFDD TAVYYCARRD
YRFDMGFDYW GQGTTVTVSS
を有する。
EIVLTQSPAT LSLSPGERAT LSCRASKGVS TSGYSYLHWY QQKPGQAPRL
LIYLASYLESGVPARFSGSG SGTDFTLTIS SLEPEDFAVY YCQHSRDLPL
TFGGGTKVEIK
を有する。
QVQLQQSGAE LAKPGASVQM SCKASGYSFT SSWIHWVKQR PGQGLEWIGY
IYPSTGFTEY NQKFKDKATL TADKSSSTAY MQLSSLTSED SAVYYCARWR
DSSGYHAMDY WGQGTSVTVSS
を有する。
DIVLTQSPAS LTVSLGQRAT ISCRASQSVS TSGYSYMHWY QQKPGQPPKL
LIKFGSNLESGIPARFSGSG SGTDFTLNIH PVEEEDTATY YCQHSWEIPY
TFGGGTKLEI K
を有する。
QVQLVQSGSE LKKPGASVKI SCKASGYTFT NYGMNWVRQA PGQGLQWMGW
INTDSGESTY AEEFKGRFVF SLDTSVNTAY LQITSLTAED TGMYFCVRVG
YDALDYWGQG TLVTVSS
を有する。
EIVLTQSPSS LSASVGDRVT ITCSARSSVS YMHWFQQKPG KAPKLWIYRT
SNLASGVPSR FSGSGSGTSY CLTINSLQPE DFATYYCQQR SSFPLTFGGG
TKLEIK
を有する。
LAG‐3に対して免疫特異的である抗体が公知である(例えば国際公開第2014/008218号を参照)。更なる望ましい抗体は、LAG‐3又はそのペプチド断片を用いて誘発された抗体分泌性ハイブリドーマを単離することによって作製できる。(28個のアミノ酸残基シグナル配列(下線を付して示す)及び497個のアミノ酸残基成熟タンパク質を含む)ヒトLAG‐3は、アミノ酸配列(配列番号10):
MWEAQFLGLL FLQPLWVAPV KPLQPGAEVP VVWAQEGAPA QLPCSPTIPL
QDLSLLRRAG VTWQHQPDSG PPAAAPGHPL APGPHPAAPS SWGPRPRRYT
VLSVGPGGLR SGRLPLQPRV QLDERGRQRG DFSLWLRPAR RADAGEYRAA
VHLRDRALSC RLRLRLGQAS MTASPPGSLR ASDWVILNCS FSRPDRPASV
HWFRNRGQGR VPVRESPHHH LAESFLFLPQ VSPMDSGPWG CILTYRDGFN
VSIMYNLTVL GLEPPTPLTV YAGAGSRVGL PCRLPAGVGT RSFLTAKWTP
PGGGPDLLVT GDNGDFTLRL EDVSQAQAGT YTCHIHLQEQ QLNATVTLAI
ITVTPKSFGS PGSLGKLLCE VTPVSGQERF VWSSLDTPSQ RSFSGPWLEA
QEAQLLSQPW QCQLYQGERL LGAAVYFTEL SSPGAQRSGR APGALPAGHL
LLFLILGVLS LLLLVTGAFG FHLWRRQWRP RRFSALEQGI HPPQAQSKIE
ELEQEPEPEP EPEPEPEPEP EPEQL
を有する。
QVQLQQWGAG LLKPSETLSL TCAVYGGSFS DYYWNWIRQP PGKGLEWIGE
INHNGNTNSN PSLKSRVTLS LDTSKNQFSL KLRSVTAADT AVYYCAFGYS
DYEYNWFDPW GQGTLVTVSS
を有する。
EIVLTQSPAT LSLSPGERAT LSCRASQSIS SYLAWYQQKP GQAPRLLIYD
ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ RSNWPLTFGQ
GTNLEIK
を有する。
1.一般的考察
本発明の好ましいダイアボディは、合計4つのポリペプチド鎖からなる二重特異性4価Fc‐DART(登録商標)ダイアボディ(図3)である。上記4つのポリペプチド鎖は、一体として複合体化してFcドメインを形成する2つのCH2‐CH3含有ポリペプチド(即ち上記ダイアボディの「第1(first)」及び「第3(third)」のポリペプチド鎖)と、それぞれ上記ダイアボディのCH2‐CH3含有ポリペプチドと複合体化してPD‐1又はLAG‐3に対して免疫特異的であるエピトープ結合ドメインを形成する2つの同一の非CH3含有ポリペプチド(即ち上記ダイアボディの「第2(second)」及び「第4(fourth)」のポリペプチド鎖)とを備える。従って例えば、第1のポリペプチド鎖は抗PD‐1(又は抗LAG‐3)可変軽鎖(VL)ドメイン及び抗LAG‐3(又は抗PD‐1)可変重鎖(VH)ドメインを含有し、相補的な抗PD‐1(又は抗LAG‐3)VHドメイン及び相補的な抗LAG‐3(又は抗PD‐1)VLドメインを有する第2のポリペプチド鎖と複合体化して、PD‐1及びLAG‐3エピトープ結合ドメインの第1のペアを形成する。同様に、第3のポリペプチド鎖は抗PD‐1(又は抗LAG‐3)可変軽鎖(VL)ドメイン及び抗LAG‐3(又は抗PD‐1)可変重鎖(VH)ドメインを含有し、相補的な抗PD‐1(又は抗LAG‐3)VHドメイン及び相補的な抗LAG‐3(又は抗PD‐1)VLドメインを有する第4のポリペプチド鎖と複合体化して、PD‐1及びLAG‐3エピトープ結合ドメインの第2のペアを形成する。
|CH2 →
PAPELLGGPS VFLFPPKPKD TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT
230 240 250 260 270 280
←CH2│CH3→
KPREEQYNST YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA K GQPREPQVY
290 300 310 320 330 340
TLPPSREEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD SDGSFFLYSK
350 360 370 380 390 400
←CH3|
LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK
410 420 430 440
PAPEAAGGPS VFLFPPKPKD TLMISRTPEV TCVVVDVSHE DPEVKFNWYV
DGVEVHNAKT KPREEQYNST YRVVSVLTVL HQDWLNGKEY KCKVSNKALP
APIEKTISKA KGQPREPQVY TLPPSREEMT KNQVSLWCLV KGFYPSDIAV
EWESNGQPEN NYKTTPPVLD SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH
EALHNHYTQK SLSLSPGK
又はタンパク質A結合を無効化するためのH435R置換を有する「ホール担持(hole‐bearing)」配列(配列番号23):
PAPEAAGGPS VFLFPPKPKD TLMISRTPEV TCVVVDVSHE DPEVKFNWYV
DGVEVHNAKT KPREEQYNST YRVVSVLTVL HQDWLNGKEY KCKVSNKALP
APIEKTISKA KGQPREPQVY TLPPSREEMT KNQVSLSCAV KGFYPSDIAV
EWESNGQPEN NYKTTPPVLD SDGSFFLVSK LTVDKSRWQQ GNVFSCSVMH
EALHNRYTQK SLSLSPGK
を有する。
PAPEAAGGPS VFLFPPKPKD TLYITREPEV TCVVVDVSHE DPEVKFNWYV
DGVEVHNAKT KPREEQYNST YRVVSVLTVL HQDWLNGKEY KCKVSNKALP
APIEKTISKA KGQPREPQVY TLPPSREEMT KNQVSLTCLV KGFYPSDIAV
EWESNGQPEN NYKTTPPVLD SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH
EALHNHYTQK SLSLSPG
を有する修飾CH2‐CH3ドメインである。
本発明の第1の、特に好ましいPD‐1xLAG‐3二重特異性4価Fc‐DART(登録商標)ダイアボディは、同一の配列の第1及び第3のポリペプチド鎖を有する。このような第1/第3のポリペプチド鎖は、アミノ酸配列(配列番号25):
EIVLTQSPAT LSLSPGERAT LSCRASQSIS SYLAWYQQKP GQAPRLLIYD
ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ RSNWPLTFGQ
GTNLEIKGGG SGGGGQVQLV ESGGGVVQPG RSLRLDCKAS GITFSNSGMH
WVRQAPGKGL EWVAVIWYDG SKRYYADSVK GRFTISRDNS KNTLFLQMNS
LRAEDTAVYY CATNDDYWGQ GTLVTVSSGG CGGGEVAACE KEVAALEKEV
AALEKEVAAL EKLEPKSADK THTCPPCPAP EAAGGPSVFL FPPKPKDTLY
ITREPEVTCV VVDVSHEDPE VKFNWYVDGV EVHNAKTKPR EEQYNSTYRV
VSVLTVLHQD WLNGKEYKCK VSNKALPAPI EKTISKAKGQ PREPQVYTLP
PSREEMTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG
SFFLYSKLTV DKSRWQQGNV FSCSVMHEAL HNHYTQKSLS LSPG
を有し、ここでアミノ酸残基1‐107は、LAG‐3 mAb 1の軽鎖可変ドメイン(配列番号12)のアミノ酸残基であり、アミノ酸残基108‐115は、リンカーGGGSGGGG(配列番号13)のアミノ酸残基であり、アミノ酸残基116‐228は、PD‐1 mAb 1の重鎖可変ドメイン(配列番号2)のアミノ酸残基であり、アミノ酸残基229‐234は、システイン含有スペーサペプチドGGCGGG(配列番号18)のアミノ酸残基であり、アミノ酸残基235‐262は、修飾Eコイル(配列番号16)のアミノ酸残基であり、アミノ酸残基263‐277は、システイン含有リンカーペプチドLEPKSADKTHTCPPC(配列番号20)のアミノ酸残基であり、アミノ酸残基278‐494は、修飾CH2‐CH3ドメイン(配列番号24)のアミノ酸残基である。
gaaattgtcc tgacacagtc tcccgcaacc ctgagtttga gtcctgggga
gcgagcaact ctctcctgcc gagcctccca gagtatctcc tcctacctcg
cctggtacca acagaagcca gggcaggctc caaggctgct tatctatgac
gcctctaacc gcgcaactgg gattcccgca cgcttctccg gctctggttc
cggcacagac tttacactta ctatctctag cctggagcca gaagactttg
ccgtgtacta ttgtcagcaa cgttccaatt ggccccttac ctttgggcag
ggcactaact tggaaatcaa aggtggcgga tccggcggcg gaggccaggt
tcagctggtc gagagtggtg gcggcgttgt gcaacctggg cgttccctcc
gattggactg taaagcttcc ggcattactt tctcaaattc cggcatgcat
tgggtgaggc aagcccctgg aaaagggctc gaatgggtgg ctgtgatttg
gtacgatggc agcaaacggt actacgccga ttctgttaag ggccgcttta
ccatctcccg cgataactca aagaacacac tgtttctgca aatgaatagt
cttagagccg aggacaccgc cgtgtactac tgtgccacaa atgacgatta
ttgggggcag ggcacattgg tcacagtgtc ttccggagga tgtggcggtg
gagaagtggc cgcatgtgag aaagaggttg ctgctttgga gaaggaggtc
gctgcacttg aaaaggaggt cgcagccctg gagaaactgg agcccaaatc
tgctgacaaa actcacacat gcccaccgtg cccagcacct gaagccgcgg
ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctctat
atcacccggg agcctgaggt cacatgcgtg gtggtggacg tgagccacga
agaccctgag gtcaagttca actggtacgt ggacggcgtg gaggtgcata
atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg
gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta
caagtgcaag gtctccaaca aagccctccc agcccccatc gagaaaacca
tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc
ccatcccggg aggagatgac caagaaccag gtcagcctga cctgcctggt
caaaggcttc tatcccagcg acatcgccgt ggagtgggag agcaatgggc
agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc
tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca
ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg cacaaccact
acacgcagaa gagcctctcc ctgtctccgg gt
EIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKP GQAPRLLIYD
ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ SSNWPRTFGQ
GTKVEIKGGG SGGGGQVQLQ QWGAGLLKPS ETLSLTCAVY GGSFSDYYWN
WIRQPPGKGL EWIGEINHNG NTNSNPSLKS RVTLSLDTSK NQFSLKLRSV
TAADTAVYYC AFGYSDYEYN WFDPWGQGTL VTVSSGGCGG GKVAACKEKV
AALKEKVAAL KEKVAALKE
を有し、ここでアミノ酸残基1‐107は、PD‐1 mAb 1の軽鎖可変ドメイン(配列番号3)のアミノ酸残基であり、アミノ酸残基108‐115は、リンカーGGGSGGGG(配列番号13)のアミノ酸残基であり、アミノ酸残基116‐235は、LAG‐3 mAb 1の重鎖可変ドメイン(配列番号11)のアミノ酸残基であり、アミノ酸残基236‐241は、システイン含有スペーサペプチドGGCGGG(配列番号18)のアミノ酸残基であり、アミノ酸残基242‐269は、修飾Kコイル(配列番号17)のアミノ酸残基である。
gagatcgtac ttacccagtc tcccgccacc ctttccctga gtcctggtga
gcgggccact ctttcctgtc gcgcaagcca atcagtttct agctacctcg
catggtatca gcagaagcca gggcaggcac ccaggcttct catctatgac
gccagtaacc gcgcaaccgg gatacctgct agattttccg gcagtggatc
tgggaccgat ttcacactga caatttcatc cttggaacca gaagatttcg
cagtctacta ctgccagcaa tcttccaact ggccaagaac tttcggacag
gggaccaaag tggaaattaa aggtggcgga tccggcggcg gaggccaggt
ccagctccag caatggggag ccgggctgct gaaaccctct gaaacactga
gtctcacatg tgccgtttat ggaggttcct tctccgatta ttactggaac
tggattcgtc agcctcccgg caagggcctg gagtggatcg gtgagattaa
ccacaatggc aataccaata gcaatcctag tttgaaatct cgcgtcactc
tttccctcga tacaagcaaa aaccagtttt ctttgaaatt gcgatctgta
actgctgctg atactgccgt gtattactgc gcattcggct actccgacta
tgaatataat tggttcgatc cttggggaca gggaacattg gtaaccgtgt
catccggagg atgtggcggt ggaaaagtgg ccgcatgtaa ggagaaagtt
gctgctttga aagagaaggt cgccgcactt aaggaaaagg tcgcagccct
gaaagag
本発明の第2の、特に好ましいPD‐1xLAG‐3二重特異性4価Fc‐DART(登録商標)ダイアボディは、同一の配列の第1及び第3のポリペプチド鎖を有する。このような第1/第3のポリペプチド鎖は、アミノ酸配列(配列番号29):
EIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKP GQAPRLLIYD
ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ SSNWPRTFGQ
GTKVEIKGGG SGGGGQVQLQ QWGAGLLKPS ETLSLTCAVY GGSFSDYYWN
WIRQPPGKGL EWIGEINHNG NTNSNPSLKS RVTLSLDTSK NQFSLKLRSV
TAADTAVYYC AFGYSDYEYN WFDPWGQGTL VTVSSGGCGG GEVAACEKEV
AALEKEVAAL EKEVAALEKL EPKSADKTHT CPPCPAPEAA GGPSVFLFPP
KPKDTLYITR EPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ
YNSTYRVVSV LTVLHQDWLN GKEYKCKVSN KALPAPIEKT ISKAKGQPRE
PQVYTLPPSR EEMTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP
PVLDSDGSFF LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP
G
を有し、ここでアミノ酸残基1‐107は、PD‐1 mAb 1の軽鎖可変ドメイン(配列番号3)のアミノ酸残基であり、アミノ酸残基108‐115は、リンカーGGGSGGGG(配列番号13)のアミノ酸残基であり、アミノ酸残基116‐235は、LAG‐3 mAb 1の重鎖可変ドメイン(配列番号11)のアミノ酸残基であり、アミノ酸残基236‐241は、システイン含有スペーサペプチドGGCGGG(配列番号18)のアミノ酸残基であり、アミノ酸残基242‐269は、修飾Eコイル(配列番号16)のアミノ酸残基であり、アミノ酸残基270‐284は、システイン含有リンカーペプチドLEPKSADKTHTCPPC(配列番号20)のアミノ酸残基であり、アミノ酸残基285‐501は、修飾CH2‐CH3ドメイン(配列番号24)のアミノ酸残基である。
gagatcgtac ttacccagtc tcccgccacc ctttccctga gtcctggtga
gcgggccact ctttcctgtc gcgcaagcca atcagtttct agctacctcg
catggtatca gcagaagcca gggcaggcac ccaggcttct catctatgac
gccagtaacc gcgcaaccgg gatacctgct agattttccg gcagtggatc
tgggaccgat ttcacactga caatttcatc cttggaacca gaagatttcg
cagtctacta ctgccagcaa tcttccaact ggccaagaac tttcggacag
gggaccaaag tggaaattaa aggtggcgga tccggcggcg gaggccaggt
ccagctccag caatggggag ccgggctgct gaaaccctct gaaacactga
gtctcacatg tgccgtttat ggaggttcct tctccgatta ttactggaac
tggattcgtc agcctcccgg caagggcctg gagtggatcg gtgagattaa
ccacaatggc aataccaata gcaatcctag tttgaaatct cgcgtcactc
tttccctcga tacaagcaaa aaccagtttt ctttgaaatt gcgatctgta
actgctgctg atactgccgt gtattactgc gcattcggct actccgacta
tgaatataat tggttcgatc cttggggaca gggaacattg gtaaccgtgt
catccggagg atgtggcggt ggagaagtgg ccgcatgtga gaaagaggtt
gctgctttgg agaaggaggt cgctgcactt gaaaaggagg tcgcagccct
ggagaaactg gagcccaaat ctgctgacaa aactcacaca tgcccaccgt
gcccagcacc tgaagccgcg gggggaccgt cagtcttcct cttcccccca
aaacccaagg acaccctcta tatcacccgg gagcctgagg tcacatgcgt
ggtggtggac gtgagccacg aagaccctga ggtcaagttc aactggtacg
tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga
ctggctgaat ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc
cagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa
ccacaggtgt acaccctgcc cccatcccgg gaggagatga ccaagaacca
ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc gacatcgccg
tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt
ggacaagagc aggtggcagc aggggaacgt cttctcatgc tccgtgatgc
atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg
ggt
EIVLTQSPAT LSLSPGERAT LSCRASQSIS SYLAWYQQKP GQAPRLLIYD
ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ RSNWPLTFGQ
GTNLEIKGGG SGGGGQVQLV ESGGGVVQPG RSLRLDCKAS GITFSNSGMH
WVRQAPGKGL EWVAVIWYDG SKRYYADSVK GRFTISRDNS KNTLFLQMNS
LRAEDTAVYY CATNDDYWGQ GTLVTVSSGG CGGGKVAACK EKVAALKEKV
AALKEKVAAL KE
を有し、ここでアミノ酸残基1‐107は、LAG‐3 mAb 1の軽鎖可変ドメイン(配列番号12)のアミノ酸残基であり、アミノ酸残基108‐115は、リンカーGGGSGGGG(配列番号13)のアミノ酸残基であり、アミノ酸残基116‐228は、PD‐1 mAb 1の重鎖可変ドメイン(配列番号2)のアミノ酸残基であり、アミノ酸残基229‐234は、システイン含有スペーサペプチドGGCGGG(配列番号18)のアミノ酸残基であり、アミノ酸残基235‐262は、修飾Kコイル(配列番号17)のアミノ酸残基である。
gaaattgtcc tgacacagtc tcccgcaacc ctgagtttga gtcctgggga
gcgagcaact ctctcctgcc gagcctccca gagtatctcc tcctacctcg
cctggtacca acagaagcca gggcaggctc caaggctgct tatctatgac
gcctctaacc gcgcaactgg gattcccgca cgcttctccg gctctggttc
cggcacagac tttacactta ctatctctag cctggagcca gaagactttg
ccgtgtacta ttgtcagcaa cgttccaatt ggccccttac ctttgggcag
ggcactaact tggaaatcaa aggtggcgga tccggcggcg gaggccaggt
tcagctggtc gagagtggtg gcggcgttgt gcaacctggg cgttccctcc
gattggactg taaagcttcc ggcattactt tctcaaattc cggcatgcat
tgggtgaggc aagcccctgg aaaagggctc gaatgggtgg ctgtgatttg
gtacgatggc agcaaacggt actacgccga ttctgttaag ggccgcttta
ccatctcccg cgataactca aagaacacac tgtttctgca aatgaatagt
cttagagccg aggacaccgc cgtgtactac tgtgccacaa atgacgatta
ttgggggcag ggcacattgg tcacagtgtc ttccggagga tgtggcggtg
gaaaagtggc cgcatgtaag gagaaagttg ctgctttgaa agagaaggtc
gccgcactta aggaaaaggt cgcagccctg aaagag
本発明は、癌、又は病原体の存在に関連する疾患の治療のための医薬組成物を含む。このような組成物は、医薬組成物の製造に使用できるバルク薬剤組成物(例えば不純又は非滅菌組成物)、及び単位剤形の調製に使用できる医薬組成物(即ち被験体又は患者への投与に好適な組成物)を含む。上記組成物は、予防的又は治療的有効量の本発明の修飾PD‐1xLAG‐3二重特異性ダイアボディ(及び特に本発明のPD‐1xLAG‐3二重特異性4価Fc‐DART(登録商標)ダイアボディ)と、薬学的に許容可能なキャリアとを含む。好ましくは、本発明の組成物は、予防的又は治療的有効量の本発明の分子のうちの1つ又は複数と、薬学的に許容可能なキャリアとを含む。本発明はまた、このような修飾されたダイアボディ、及び特定の病原体関連抗原に対して特異的な第2の治療用抗体、並びに薬学的に許容可能なキャリアを含む、医薬組成物を包含する。
当該技術分野において公知であるように、最も好ましくは、本発明のPD‐1xLAG‐3二重特異性ダイアボディは、上述のようなポリペプチドをエンコードする核酸分子の組み換え発現によって産生される。
本発明は、本発明のPD‐1xLAG‐3二重特異性ダイアボディ、上記分子由来のポリペプチド、上記分子又は上記ポリペプチドをエンコードする配列を備えるポリヌクレオチド、及び本明細書に記載の他の作用材を含む、医薬組成物を含む組成物を包含する。
本発明の組成物は、有効量の本発明の医薬組成物を被験体に投与することによる、疾患、障害又は感染症に関連する1つ又は複数の症状の治療、予防及び改善のために提供できる。好ましい態様では、上記組成物は実質的に精製される(即ち上記組成物の効果を制限する、又は望ましくない副作用を生成する物質を実質的に含まない)。ある具体的実施形態では、被験体は動物、好ましくは非霊長類(例えばウシ属、ウマ科、ネコ科、イヌ科、齧歯類等)又は霊長類(例えばカニクイザル等のサル、ヒト等)といった哺乳類である。ある好ましい実施形態では、被験体はヒトである。
アロ‐MLRアッセイにおいて、T細胞を、HLAミスマッチ(Latchman, Y.E. et al. (2004) “PD‐L1‐Deficient Mice Show That PD‐L1 On T‐Cells, Antigen‐Presenting Cells, And Host Tissues Negatively Regulates T‐Cells.” Proc. Natl. Acad. Sci. (U.S.A.) 101(29):10691‐10696; Wang, W. et al. (2008) “PD‐L1/PD‐1 Signal Deficiency Promotes Allogeneic Immune Responses And Accelerates Heart Allograft Rejection,” Transplantation 86(6):836‐44)又は分裂促進/薬理学的刺激に応答して増殖するよう誘導する。共刺激分子を標的とするアゴニスト抗体は、T細胞シグナリングの再強化、及びT細胞エフェクタ機能を促進する転写因子の安定化によって、増殖応答を誘導することが知られている(Melero, I. et al. (2013) “Agonist Antibodies to TNFR Molecules That Costimulate T and NK Cells,” Clin. Cancer Res. 19(5):1044‐1053)。同様に、T細胞応答を下方調節する重要なチェックポイント分子を標的とするアンタゴニスト抗体は、T細胞シグナリング及びエフェクタ機能の維持、並びにそれによる抗腫瘍免疫の改善によって、増殖応答を誘導できる(Capece, D. et al. (2012) “Targeting Costimulatory Molecules to Improve Antitumor Immunity,” J. Biomed. Biotech. 2012:926321)。同種抗原に応答しての増殖における、共刺激又はチェックポイント標的に対するモノクローナル抗体の影響は、以下の3H‐チミジンの取り込みによる続く短期混合リンパ球(アロ‐MLR)反応において容易に測定できる。チェックポイント阻害剤に対して抗体が増殖を増強する能力を扱うために、ベンチマーク抗PD‐1又は抗LAG‐3 mAbを産生し、精製し、アロ‐MLRアッセイの開始時に、20、10、5、2.5及び1.25μg/mlの量で外因的に添加した(図5)。5〜6日目の終わりに、96ウェルプレートに3H‐チミジンを送り込み、18時間培養して増殖を測定した。ヒトPD‐1、LAG‐3及びCTLA‐4に対するいくつかのベンチマーク抗体を、アロ抗原刺激に応答してのT細胞増殖を増強する能力において評価した。図6に示すように、アロMLRアッセイの開始時におけるPD‐1 mAb 1(5C4;BMS‐936558)、PD‐1 mAb 2(MK‐3475;Merck、ランブロリズマブ)及びPD‐1 mAb 3(EH12.2H7;Dana Farber)の添加は、IgG1アイソタイプ対照抗体、又はレスポンダ及びスティミュレータを含有する対照ウェルに比べて強いT細胞増殖応答を誘起した。照射した刺激細胞のみを含有するウェルは、増殖を示さなかった。用量依存性増殖応答が観察されたものの、PD‐1 mAb 4(CT‐011;CureTech、BAT‐1)は、PD‐1 mAb 1(5C4;BMS‐936558)、PD‐1 mAb 2(MK‐3475;Merck、ランブロリズマブ)又はPD‐1 mAb 3(EH12.2H7;Dana Farber)に比べて最小の増殖を示した。LAG‐3 mAb 1(25F7;BMS‐986016、Medarex/BMS)についてもわずかな用量依存性増殖応答が観察され、これを同様にYervoy(登録商標)イピリムマブ、抗CTLA‐4 mAb(Bristol Myers‐Squib)と比較した。
配列番号1:シグナル配列を含むヒトPD‐1
配列番号2:抗PD‐1抗体 mAb 1の重鎖可変ドメイン
配列番号3:抗PD‐1抗体 mAb 1の軽鎖可変ドメイン
配列番号4:ヒト化抗PD‐1抗体 mAb 2の重鎖可変ドメイン
配列番号5:ヒト化抗PD‐1抗体 mAb 2の軽鎖可変ドメイン
配列番号7:抗PD‐1抗体 mAb 3の軽鎖可変ドメイン
配列番号8:ヒト化抗PD‐1抗体 mAb 4の重鎖可変ドメイン
配列番号9:ヒト化抗PD‐1抗体 mAb 4の軽鎖可変ドメイン
配列番号10:シグナル配列を含むヒトLAG‐3(CD223)タンパク質
配列番号11:抗LAG‐3抗体は mAb 1の重鎖可変ドメイン
配列番号12:抗LAG‐3抗体は mAb 1の軽鎖可変ドメイン
配列番号13:リンカー1
配列番号14:ヘテロ二量体促進Eコイルドメイン
配列番号15:ヘテロ二量体促進Kコイルドメイン
配列番号16:システイン含有ヘテロ二量体促進Eコイルドメイン
配列番号17:システイン含有ヘテロ二量体促進Kコイルドメイン
配列番号18:システイン含有スペーサペプチド
配列番号19:システイン含有リンカーペプチド
配列番号20:他のシステイン含有リンカーペプチド
配列番号21:IgG1 Fc領域
配列番号22:「ノブ担持」IgG1 CH2‐CH3ドメイン
配列番号23:「ホール担持」IgG1 CH2‐CH3ドメイン
配列番号24:L234A/L235A変異IgG1 Fc領域
配列番号25:例示的なPD‐1xLAG‐3Fc‐DART−1ダイアボディの第1及び第3のポリペプチド鎖
配列番号26:例示的なPD‐1xLAG‐3Fc‐DART−1ダイアボディの第1及び第3のポリペプチド鎖をエンコードするポリヌクレオチド
配列番号27:例示的なPD‐1xLAG‐3Fc‐DART−1ダイアボディの第2及び第4のポリペプチド鎖
配列番号28:例示的なPD‐1xLAG‐3Fc‐DART−1ダイアボディの第2及び第4のポリペプチド鎖をエンコードするポリヌクレオチド
配列番号29:例示的なPD‐1xLAG‐3Fc‐DART−2ダイアボディの第1及び第3のポリペプチド鎖
配列番号30:例示的なPD‐1xLAG‐3Fc‐DART−2ダイアボディの第1及び第3のポリペプチド鎖をエンコードするポリヌクレオチド
配列番号31:例示的なPD‐1xLAG‐3Fc‐DART−2ダイアボディの第2及び第4のポリペプチド鎖
配列番号32:例示的なPD‐1xLAG‐3Fc‐DART−2ダイアボディの第2及び第4のポリペプチド鎖をエンコードするポリヌクレオチド
Claims (15)
- PD‐1のエピトープ及びLAG‐3のエピトープに対して免疫特異的に結合できる二重特異性Fcダイアボディであって、
前記ダイアボディは、アミノ末端及びカルボキシ末端をそれぞれ有する4つの第1乃至第4のポリペプチド鎖を含み:
(A)前記第1のポリペプチド鎖及び前記第2のポリペプチド鎖は互いに共有結合し、前記第1のポリペプチド鎖及び前記第3のポリペプチド鎖は互いに共有結合し、また前記第3のポリペプチド鎖及び前記第4のポリペプチド鎖は互いに共有結合し;
(B)前記ダイアボディの前記第1のポリペプチド鎖及び前記第3のポリペプチド鎖はそれぞれ、N末端からC末端への方向に、PD‐1又はLAG‐3に対して免疫特異的である抗体の軽鎖可変ドメイン、LAG‐3又はPD‐1に対して免疫特異的である抗体の重鎖可変ドメイン、ヘテロ二量体促進ドメイン、及びCH2‐CH3ドメインを含み、前記軽鎖可変ドメイン及び前記重鎖可変ドメインは、前記PD‐1のエピトープ又は前記LAG‐3のエピトープに結合できるエピトープ結合部位を形成するために連結できず;
(C)前記ダイアボディの前記第2のポリペプチド鎖及び前記第4のポリペプチド鎖はそれぞれ、N末端からC末端の方向に、PD‐1又はLAG‐3に対して免疫特異的である抗体の軽鎖可変ドメイン、LAG‐3又はPD‐1に対して免疫特異的である抗体の重鎖可変ドメイン、及びヘテロ二量体促進ドメインを含み、前記軽鎖可変ドメイン及び前記重鎖可変ドメインは、前記PD‐1のエピトープ又は前記LAG‐3のエピトープに結合できるエピトープ結合部位を形成するために連結できず;
I.(1)前記第1のポリペプチド鎖の前記軽鎖可変ドメイン及び前記第2のポリペプチド鎖の前記重鎖可変ドメインは、連結して第1のエピトープ結合部位を形成し、前記第1のポリペプチド鎖の前記重鎖可変ドメイン及び前記第2のポリペプチド鎖の前記軽鎖可変ドメインは、連結して第2のエピトープ結合部位を形成し;且つ
(2)前記第3のポリペプチド鎖の前記軽鎖可変ドメイン及び前記第4のポリペプチド鎖の前記重鎖可変ドメインは、連結して第3のエピトープ結合部位を形成し、前記第3のポリペプチド鎖の前記重鎖可変ドメイン及び前記第4のポリペプチド鎖の前記軽鎖可変ドメインは、連結して第4のエピトープ結合部位を形成し;
形成された前記エピトープ結合部位のうちの2つは、前記PD‐1のエピトープに免疫特異的に結合でき、形成された前記エピトープ結合部位のうちの2つは、前記LAG‐3のエピトープに免疫特異的に結合でき;
II.(1)前記第1及び第3のポリペプチド鎖の前記ヘテロ二量体促進ドメインは配列番号14のアミノ酸配列を含み、前記第2及び第4のポリペプチド鎖の前記ヘテロ二量体促進ドメインは配列番号15のアミノ酸配列を含むか;
(2)前記第1及び第3のポリペプチド鎖の前記ヘテロ二量体促進ドメインは配列番号15のアミノ酸配列を含み、前記第2及び第4のポリペプチド鎖の前記ヘテロ二量体促進ドメインは配列番号14のアミノ酸配列を含むか;
(3)前記第1及び第3のポリペプチド鎖の前記ヘテロ二量体促進ドメインは配列番号16のアミノ酸配列を含み、前記第2及び第4のポリペプチド鎖の前記ヘテロ二量体促進ドメインは配列番号17のアミノ酸配列を含むか;又は
(4)前記第1及び第3のポリペプチド鎖の前記ヘテロ二量体促進ドメインは配列番号17のアミノ酸配列を含み、前記第2及び第4のポリペプチド鎖の前記ヘテロ二量体促進ドメインは配列番号16のアミノ酸配列を含み、
III.前記第1のポリペプチド鎖及び前記第3のポリペプチド鎖の前記CH2‐CH3ドメインは、連結してFcドメインを形成する、二重特異性Fcダイアボディ。 - 前記第1のポリペプチド鎖の前記ヘテロ二量体促進ドメインは配列番号14を含み、前記第2のポリペプチド鎖の前記ヘテロ二量体促進ドメインは配列番号15を含む、請求項1に記載の二重特異性Fcダイアボディ。
- 前記第1のポリペプチド鎖の前記ヘテロ二量体促進ドメインは配列番号16を含み、前記第2のポリペプチド鎖の前記ヘテロ二量体促進ドメインは配列番号17を含む、請求項1に記載の二重特異性Fcダイアボディ。
- 前記第1のポリペプチド鎖及び前記第3のポリペプチド鎖の前記CH2‐CH3ドメインはそれぞれ、配列番号24のアミノ酸配列を含む、請求項1〜3のいずれか1項に記載の二重特異性Fcダイアボディ。
- LAG‐3に対して免疫特異的である抗体の前記重鎖可変ドメインは、配列番号11のアミノ酸配列を含み、
LAG‐3に対して免疫特異的である抗体の前記軽鎖可変ドメインは、配列番号12のアミノ酸配列を含む、請求項1〜4のいずれか1項に記載の二重特異性Fcダイアボディ。 - PD‐1に対して免疫特異的である抗体の前記重鎖可変ドメインは、配列番号2のアミノ酸配列を含み、
PD‐1に対して免疫特異的である抗体の前記軽鎖可変ドメインは、配列番号3のアミノ酸配列を含む、請求項1〜5のいずれか1項に記載の二重特異性Fcダイアボディ。 - (A)前記第1のポリペプチド鎖及び前記第3のポリペプチド鎖はそれぞれ、PD‐1に対して免疫特異的である抗体の軽鎖可変ドメイン、及びLAG‐3に対して免疫特異的である抗体の重鎖可変ドメインを含み;
(B)前記第2のポリペプチド鎖及び前記第4のポリペプチド鎖はそれぞれ、LAG‐3に対して免疫特異的である抗体の軽鎖可変ドメイン、及びPD‐1に対して免疫特異的である抗体の重鎖可変ドメインを含む、請求項1〜6のいずれか1項に記載の二重特異性Fcダイアボディ。 - (A)前記第1のポリペプチド鎖及び前記第3のポリペプチド鎖はそれぞれ、LAG‐3に対して免疫特異的である抗体の軽鎖可変ドメイン、及びPD‐1に対して免疫特異的である抗体の重鎖可変ドメインを含み;
(B)前記第2のポリペプチド鎖及び前記第4のポリペプチド鎖はそれぞれ、PD‐1に対して免疫特異的である抗体の軽鎖可変ドメイン、及びLAG‐3に対して免疫特異的である抗体の重鎖可変ドメインを含む、請求項1〜6のいずれか1項に記載の二重特異性Fcダイアボディ。 - 有効量の請求項1〜8のいずれか1項に記載のFcダイアボディと、薬学的に許容可能なキャリアとを含む、医薬組成物。
- 前記二重特異性Fcダイアボディの前記有効量は、治療を必要とするレシピエント個体の癌を治療するために有効な量である、請求項9に記載の医薬組成物。
- 前記癌は:副腎癌;AIDS関連癌;胞巣状軟部肉腫;星細胞腫瘍;膀胱癌;骨癌;脳及び脊髄癌;転移性脳腫瘍;乳癌;頸動脈球腫瘍;子宮頸癌;軟骨肉腫;脊索腫;発色性腎細胞癌;明細胞癌;大腸癌;結腸直腸癌;線維形成性小円形細胞腫瘍;上衣腫;ユーイング腫瘍;骨外性粘液型軟骨肉腫;胆嚢若しくは胆管癌;消化器癌;妊娠性絨毛性疾患;胚細胞腫瘍;頭頸部癌;肝細胞癌;膵島細胞腫;カポジ肉腫;腎臓癌;白血病;脂肪肉腫/悪性リポソーム腫瘍;肝臓癌;リンパ腫;肺癌;髄芽腫;黒色腫;髄膜腫;多発性内分泌腫瘍;多発性骨髄腫;骨髄異形成症候群;神経芽細胞腫;神経内分泌腫瘍;卵巣癌;膵臓癌;乳頭状甲状腺癌;副甲状腺腫瘍;小児癌;末梢神経鞘腫瘍;褐色細胞腫;下垂体腫瘍;前立腺癌;後部ブドウ膜黒色腫;腎転移性癌;ラブドイド腫瘍;横紋筋肉腫;肉腫;皮膚癌;軟組織肉腫;扁平上皮細胞癌;胃癌;滑膜肉腫;精巣癌;胸腺癌;胸腺腫;甲状腺転移性癌;又は子宮癌である、請求項10に記載の医薬組成物。
- 前記二重特異性Fcダイアボディの前記有効量は、治療を必要とするレシピエント個体の、病原体の存在に関連する疾患を治療するために有効な量である、請求項9に記載の医薬組成物。
- 前記病原体は、細菌、真菌又はウイルスである、請求項12に記載の医薬組成物。
- 癌の治療のための薬剤の製造における、請求項1〜8のいずれか1項に記載の二重特異性Fcダイアボディ、又は請求項10又は11に記載の医薬組成物の使用。
- 病原体の存在に関連する疾患の治療のための薬剤の製造における、請求項1〜8のいずれか1項に記載の二重特異性Fcダイアボディ、又は請求項12又は13に記載の医薬組成物の使用。
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