JP2017519744A - 三重特異性結合分子及びその使用方法 - Google Patents
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Abstract
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_0114PCT_Sequence_Listing_ST25.txt、2015年5月18日作成、サイズ:244,021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。
哺乳類免疫系は、例えば創傷、感染及び新生物を含む多様な状態に対する防御として機能する。ヒト及び他の哺乳類が病原体、外来物質及び癌抗原に対する免疫応答を発現する効率は、2つの特徴:抗原認識に対する免疫応答の優れた特異性、及び同一の抗原による再活性化に対するより迅速かつより活発な応答を可能とする免疫記憶に基づくものである(非特許文献1、2)。
A.抗体
「抗体」は、当該免疫グロブリン分子の可変ドメインに位置する少なくとも1つの抗原認識部位によって、炭水化物、ポリヌクレオチド、脂質、ポリペプチド等の標的に特異的に結合できる、免疫グロブリン分子である。本明細書において使用される場合、この用語は、完全なポリクローナル又はモノクローナル抗体だけでなく、その突然変異体、自然に発生する変異体、必要な特異性の抗原認識部位を有する抗体部分を備える融合タンパク質、ヒト化抗体及びキメラ抗体、並びに必要な特異性の抗原認識部位を備える免疫グロブリン分子の他のいずれの修飾構成を包含する。本出願全体を通して、抗体の軽鎖及び重鎖のアミノ酸残基の番号付与は、非特許文献18中のもののようなEUインデックスに従ったものである。本明細書において使用される場合、「抗体の抗原結合性断片」は、少なくとも1つの抗原認識部位を有する抗体の一部分である。本明細書において使用される場合、この用語は、断片(例えばFab、Fab’、F(ab’)2Fv)及び単鎖分子(例えばscFv)を包含する。
天然の抗体は、1つのエピトープ種のみと結合できる(即ち「単一特異性」である)が、これらは当該種の複数の複製にも結合できる(即ち2価性又は多価性を呈することができる)。幅広い組み換え二重特異性抗体フォーマットが開発されており(例えば特許文献5、6、7、8、9、10、11参照)、その殆どは、抗体コア(IgA、IgD、IgE、IgG若しくはIgM)を当該抗体コアに対する若しくは当該抗体コア内の更なる結合タンパク質(例えばscFv、VLVH等)に融合させるため、又は複数の抗体部分を、若しくは(例えば2つのFab断片若しくはscFv)を、CH2‐CH3ドメイン若しくは代替となるポリペプチド等のヘテロ二量体化促進ドメインに融合させるために、リンカーペプチドを使用する(特許文献12、13、14、15)。典型的には、このようなアプローチは妥協及びトレードオフを伴う。例えば特許文献16、17、18は、リンカーの使用によって、治療的設定に問題が生じる場合があることを開示しており、2つ以上の抗原に結合できるように、CL及びCH1ドメインがそれぞれの自然位置から切り替わり、かつVL及びVHドメインが多様化されている、三重特異性抗体を教示している(特許文献19、20)。従って、これらの文書に開示されている分子は、結合特異性を、追加の抗原種に結合できる能力と交換している。特許文献21、22は、CH2ドメインを修飾して、結合ドメインを備える融合タンパク付加物を含有させるステップを開示している。この文書は、CH2が、エフェクタ機能の仲介において最低限の役割しか果たさないらしいことを記載している。特許文献23、24、25は、Fcドメインが追加のVL及びVHドメインで置換されて、3価結合分子を形成している、組み換え抗体を開示している。特許文献26、27は、個々の鎖がscFvドメインを含有する組み換えダイアボディを開示している。特許文献28は、単一のポリペプチド鎖として合成された後、タンパク質分解に供されることによってヘテロ二量体構造が得られる、多価fab分子を開示している。従って、これらの文書に開示されている分子は、エフェクタ機能を仲介する能力の全て又はある程度を、追加の抗原種に結合できる能力と交換している。特許文献29、30、31、32、33、34、35、36、37は、追加の結合ドメイン又は官能基を抗体又は抗体部分に付加するステップ(例えば抗体の軽鎖にダイアボディを付加するステップ、又は抗体の軽鎖及び重鎖に追加のVL及びVHドメインを付加するステップ、又は異種融合タンパク質を互いに対して付加するステップ若しくは複数のFabドメインを互いに対して連鎖させるステップ)を開示している。従って、これらの文書に開示されている分子は、ナイーブ抗体構造を、追加の抗原種に結合できる能力と交換している。
上述のように、CD8、MHCI及びT細胞受容体の間の相互作用は、細胞毒性T細胞、及び近隣の細胞を殺滅する上記細胞毒性T細胞の能力の活性化につながる。CD3及び腫瘍抗原に結合する二重特異性ダイアボディを用いて、腫瘍細胞に対して細胞毒性CD8+T細胞を共局在化し、このような細胞の「標的転換殺滅」を達成できる(特許文献46、47、48、66、65)。
(I)第1の抗原上に存在するエピトープIに免疫特異的に結合できる抗原‐結合ドメインI、及び第2の抗原上に存在するエピトープIIに免疫特異的に結合できる抗原‐結合ドメインII(ここで抗原‐結合ドメインI及び抗原‐結合ドメインIIはいずれもダイアボディタイプ結合ドメインである);
(II)第3の抗原上に存在するエピトープIIIに免疫特異的に結合できる、非ダイアボディタイプ抗原‐結合ドメインIII;並びに
(III)2つのCH2‐CH3ドメインが互いに連結することによって形成される、Fcドメイン
を備え、ここで第1、第2及び第3の抗原は同一の抗原であるか、又は独立して、これらの抗原のうちの別のものと同一の若しくは異なるものである。
(A)第1のポリペプチド鎖であって:
(I)N末端からC末端への方向に:
(1)3つのエピトープのうちの第1のものに結合できる免疫グロブリンの軽鎖可変ドメイン(VLI);
(2)3つのエピトープのうちの第2のものに結合できる免疫グロブリンの重鎖可変ドメイン(VHII);
(3)(a)第1のシステイン含有ドメイン;及びヘテロ二量体促進ドメイン;若しくは
(b)システイン含有ヘテロ二量体促進ドメイン;
(4)第2のシステイン含有ドメイン;並びに
(5)IgGのCH2及びCH3ドメイン
を備えるか、又は
(II)N末端からC末端への方向に:
(1)第1のシステイン含有ドメイン;
(2)IgGのCH2及びCH3ドメイン;
(3)3つのエピトープのうちの第1のものに結合できる免疫グロブリンの軽鎖可変ドメイン(VLI);
(4)3つのエピトープのうちの第2のものに結合できる免疫グロブリンの重鎖可変ドメイン(VHII);並びに
(5)(a)第2のシステイン含有ドメイン;及びヘテロ二量体促進ドメイン;若しくは
(b)システイン含有ヘテロ二量体促進ドメイン
を備える、第1のポリペプチド鎖;
(B)第2のポリペプチド鎖であって、N末端からC末端への方向に:
(1)3つのエピトープのうちの第2のものに結合できる免疫グロブリンの軽鎖可変ドメイン(VLII);
(2)3つのエピトープのうちの第1のものに結合できる免疫グロブリンの重鎖可変ドメイン重鎖可変ドメイン(VHI);並びに
(3)(a)第1のシステイン含有ドメイン;及びヘテロ二量体促進ドメイン;若しくは
(b)システイン含有ヘテロ二量体促進ドメイン;
を備え、上記第2のポリペプチド鎖のヘテロ二量体促進ドメインは、上記第1のポリペプチド鎖ヘテロ二量体促進ドメインに対して相補的である、第2のポリペプチド鎖;
(C)第3のポリペプチド鎖であって、N末端からC末端への方向に:
(1)3つのエピトープのうちの第3のものに結合できる免疫グロブリンの重鎖可変ドメイン(VHIII);並びに
(2)IgGのCH1ドメイン、システイン含有ヒンジドメイン、及びCH2‐CH3ドメイン
を備える、第3のポリペプチド鎖;並びに
(D)第4のポリペプチド鎖であって、N末端からC末端への方向に:
(1)3つのエピトープのうちの第3のものに結合できる免疫グロブリンの軽鎖可変ドメイン(VLIII);及び
(2)システイン含有軽鎖定常ドメイン(CL);
を備える、第4のポリペプチド鎖
を備え、
(i)VLI及びVHIドメインは連結して、エピトープIに結合できるドメインを形成し;
(ii)VLII及びVHIIドメインは連結して、エピトープIIに結合できるドメインを形成し;
(iii)VLIII及びVHIIIドメインは連結して、エピトープIIIに結合できるドメインを形成し;
(iv)第1のポリペプチド鎖のCH2‐CH3ドメイン及び第3のポリペプチド鎖のCH2‐CH3ドメインは連結して、Fcドメインを形成し;
(v)第1及び第2のポリペプチド鎖は、互いに対して共有結合し;
(vi)第1及び第3のポリペプチド鎖は、互いに対して共有結合し;
(vii)第3及び第4のポリペプチド鎖は、互いに対して共有結合する、上述の三重特異性結合分子の実施形態に関する。
(A)上記ヘテロ二量体促進ドメインがEコイルであり、上記相補的なヘテロ二量体促進ドメインがKコイルである;又は
(B)上記ヘテロ二量体促進ドメインがKコイルであり、上記相補的なヘテロ二量体促進ドメインがEコイルである、上述の三重特異性結合分子の実施形態に関する。
(A)第1及び第3のポリペプチド鎖のCH2‐CH3ドメインがそれぞれ、これらの連結によって形成されるFcドメインが正常なFcγR仲介性エフェクタ機能を呈するように、配列番号6の配列を有し;又は
(B)第1及び第3のポリペプチド鎖のCH2‐CH3ドメインがそれぞれ、これらの連結によって形成されるFcドメインが変化したFcγR仲介性エフェクタ機能を呈するように、配列番号6の配列に対して少なくとも1つのアミノ酸置換を有する、上述の三重特異性結合分子の実施形態に関する。
(A)エピトープI、エピトープII及びエピトープIIIはそれぞれ、CD3のエピトープ、CD8のエピトープ及び疾患関連抗原のエピトープであり;
(B)エピトープI、エピトープII及びエピトープIIIはそれぞれ、CD3のエピトープ、疾患関連抗原のエピトープ及びCD8のエピトープであり;
(C)エピトープI、エピトープII及びエピトープIIIはそれぞれ、CD8のエピトープ、CD3のエピトープ及び疾患関連抗原のエピトープであり;
(D)エピトープI、エピトープII及びエピトープIIIはそれぞれ、CD8のエピトープ、疾患関連抗原のエピトープ及びCD3のエピトープであり;
(E)エピトープI、エピトープII及びエピトープIIIはそれぞれ、疾患関連抗原のエピトープ、CD3のエピトープ及びCD8のエピトープであり;又は
(F)エピトープI、エピトープII及びエピトープIIIはそれぞれ、疾患関連抗原のエピトープ、CD8のエピトープ及びCD3のエピトープである、上述のような三重特異性結合分子の実施形態に関する。
(A)CD3のエピトープは、抗体OKT3、M291、YTH12.5、CD3mAb1若しくはCD3mAb2によって認識されるCD3エピトープであり;又は
(B)CD8のエピトープは、抗体TRX2若しくはOKT8によって認識されるCD8エピトープである、上述の三重特異性結合分子の実施形態に関する。
(A)配列番号117の配列を有するCDRL1、配列番号118の配列を有するCDRL2、及び配列番号119の配列を有するCDRL3を備える、軽鎖可変ドメイン;並びに
(B)配列番号120の配列を有するCDRH1、配列番号121の配列を有するCDRH2、及び配列番号122の配列を有するCDRH3を備える、重鎖可変ドメイン
を備える。
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。
A.結合能力
本発明の好ましい三重特異性結合分子は、3つの異なるエピトープに協調的かつ同時に結合できる。このような本発明の好ましい三重特異性結合分子は:
(I)第1の抗原上に存在する「エピトープI」に免疫特異的に結合できる「結合ドメインI」及び第2の抗原上に存在する「エピトープII」に免疫特異的に結合できる「結合ドメインII」。ここで上記結合ドメインI及び上記結合ドメインIIは共に「ダイアボディタイプ結合ドメイン」である;
(II)第3の抗原上に存在する「エピトープIII」に免疫特異的に結合できる「非ダイアボディタイプ」「結合ドメインIII」;並びに
(III)2つのCH2‐CH3ドメインを互いに複合体化することによって形成される、Fcドメイン
を備える。
M. (1984) "A Study On Clinical Significance Of Oncofetal Antigen-1 In Gynecologic Tumors," Nihon Sanka Fujinka Gakkai Zasshi. 36(12):2613-2618);オンコスタチンM(オンコスタチン受容体ベータ)(米国特許第7,572,896号;国際公開第06/084092号);pl5(Gil, J. et al. 2006 Nat Rev Mol Cell Biol. 7(9):667-77);PSA(前立腺特異性抗原;Cracco, CM. et al. 2005 Minerva Urol Nefrol. 57(4):301-11);PSMA(Ragupathi, G. 2005 Cancer Treat Res. 123: 157-80);PEMA(多型性上皮ムチン抗原)(Chu, N.J. et al. (2015) "Nonviral Oncogenic Antigens and the Inflammatory Signals Driving Early Cancer Development as Targets for Cancer Immunoprevention," Clin. Cancer Res. 21(7): 1549-1557);PIPA(米国特許第7,405,061号;国際公開第04/043239号);前立腺酸性ホスファターゼ(Tailor et al. (1990) "Nucleotide Sequence Of Human Prostatic Acid Phosphatase Determined From A Full-Length cDNA Clone, " Nucl. Acids Res. 18(16):4928);R24(Zhou, M. et al. (2008) "Constitutive Overexpression Of A Novel 21 Kda Protein By Hodgkin Lymphoma And Aggressive Non-Hodgkin Lymphomas " Mol. Cancer 7: 12);ROR1(米国特許第5,843,749号;Rabbani, H. et al. (2010) "Expression Of ROR1 In Patients With Renal Cancer- A Potential Diagnostic Marker " Iran Biomed. J. 14(3):77-82);スフィンゴ脂質(Hakomori, S. (1998) "Cancer-Associated Glycosphingolipid Antigens: Their Structure, Organization, And Function " Acta Anat. (Basel) 161(l-4):79-90);SSEA‐1、SSEA‐3及びSSEA‐4(Muramatsu, T. et al. (2004) "Carbohydrate Antigens Expressed On Stem Cells And Early Embryonic Cells " Glycoconj. J. 21(l-2):41-45);sTn(Holmberg, L.A. 2001 Expert Opin Biol Ther. 1(5):881-91);T細胞受容体由来ペプチド(Edelson (1998) "Cutaneous T-Cell Lymphoma: A Model For Selective Immunotherapy, " Cancer J Sci Am. 4:62-71);T5A7(Hogg, R.J. et al. (1991) "A monoclonal antibody exhibiting reactivity with both X-hapten- and lactose-bearing glycolipids," Tissue Antigens 37(l):33-38);TAG‐72(Yokota et al. (1992) "Rapid Tumor Penetration Of A Single-Chain Fv And Comparison With Other Immunoglobulin Forms, " Cancer Res. 52:3402-3408);TL5(血液型A)(Gooi, H.C. et al. (1983) "Monoclonal antibody reactive with the human epidermal-growth-factor receptor recognizes the blood-group-A antigen," Biosci. Rep. 3(11): 1045-1052);TNF受容体(TNF‐α受容体、TNF‐β受容体;又はTNF‐γ受容体)(van Horssen, R. et al. 2006 Oncologist. 11(4):397-408;Gardnerova, M. et al. 2000 Curr Drug Targets. l(4):327-64);TRA‐1‐85(血液型H)(Williams, B.P. et al. (1988) "Biochemical and genetic analysis of the OKa blood group antigen," Immunogenetics 27(5):322-329);トランスフェリン受容体(米国特許第7,572,895号;国際公開第05/121179号);TSTA腫瘍特異性移植抗原(Hellstrom et al. (1985) "Monoclonal Antibodies To Cell Surface Antigens Shared By Chemically Induced Mouse Bladder Carcinomas, " Cancer. Res. 45 :2210-2188);VEGF‐R(O’Dwyer. P.J. 2006 Oncologist. 11(9):992-8);並びにYヘプタン、Ley(Durrant, L.G. et al. (1989) "Development Of An ELISA To Detect Early Local Relapse Of Colorectal Cancer " Br. J. Cancer 60(4):533-537)が挙げられる。
典型的には、本発明の三重特異性結合分子は4つの異なるポリペプチド鎖を備えることになり、これらはそれぞれ、アミノ末端及びカルボキシ末端を有する(図4A〜4D参照)が、上記分子は、このようなポリペプチド鎖を(例えばペプチド結合を介して)互いに融合することによって、又はこのようなポリペプチド鎖を分割して更なるポリペプチド鎖を形成することによって、より少数又はより多数のポリペプチド鎖を備えてよい。図4E〜4Jは、3つのポリペプチド鎖を有するこのような分子を概略的に示すことにより、本発明のこの態様を例示している。図4K〜4Lは、5つのポリペプチド鎖を有する分子を概略的に示すことにより、本発明のこの態様を例示している。
本発明の好ましい三重特異性結合分子の第1のポリペプチド鎖は、エピトープIに結合できる可変軽鎖ドメイン(VLI)、エピトープIIに結合できる可変重鎖ドメイン(VHII)、システイン残基又はシステイン含有ドメイン及びヘテロ二量体促進ドメイン並びにCH2‐CH3ドメインを備える。
|CH2 →
APELLGGPS VFLFPPKPKD TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT
231 240 250 260 270 280
←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
APEAAGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD
GVEVHNAKTK PREEQYNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPA
PIEKTISKAK GQPREPQVYT LPPSREEMTK NQVSLWCLVK GFYPSDIAVE
WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE
ALHNHYTQKS LSLSPGK
又はタンパク質A結合を抑制するためのH435R置換を有する「ホール担持(hole‐bearing)」配列(配列番号8):
APEAAGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD
GVEVHNAKTK PREEQYNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPA
PIEKTISKAK GQPREPQVYT LPPSREEMTK NQVSLSCAVK GFYPSDIAVE
WESNGQPENN YKTTPPVLDS DGSFFLVSKL TVDKSRWQQG NVFSCSVMHE
ALHNRYTQKS LSLSPGK
を有する。
上述のような好ましい三重特異性結合分子の第2のポリペプチド鎖は、N末端からC末端への方向に、エピトープIIに結合できる可変軽鎖ドメイン(VLII)、エピトープIに結合できる可変重鎖ドメイン(VHI)、システイン残基又はシステイン含有ドメイン、及びヘテロ二量体促進ドメインを備える。
本発明の好ましい三重特異性結合分子の第3のポリペプチド鎖は、N末端からC末端への方向に、結合ドメイン、CH1‐ヒンジドメインを任意に備えるシステイン含有ドメイン、及びCH2‐CH3ドメインを備えるポリペプチドである。本発明の好ましい三重特異性結合分子の第3のポリペプチド鎖の結合ドメインは、エピトープIIIに結合できる可変重鎖ドメイン(VHIII)であってよく、この場合、(以下において議論される)本発明の好ましい三重特異性結合分子の第4のポリペプチド鎖は、エピトープIIIに結合できる可変軽鎖ドメイン(VLIII)を備えるポリペプチドであり、これにより上記結合ドメインが、エピトープIIIを有する抗原に免疫特異的に結合できる。あるいは、本発明の好ましい三重特異性結合分子の第3のポリペプチド鎖の結合ドメインは、T細胞受容体タイプ結合ドメインを備えてよく、この場合、(以下において議論される)本発明の好ましい三重特異性結合分子の第4のポリペプチド鎖は、相補的なT細胞受容体タイプ結合ドメインを備えるポリペプチドであり、これにより、2つのポリペプチド鎖の相互作用が、細胞の表面上に配列されたMHC複合体中に発現される抗原分子に生理学的に特異的に結合できる結合ドメインを形成する。第3のポリペプチド鎖は、自然に発生する抗体から単離できる。あるいは第3のポリペプチド鎖は、組み換えによって構成してよい。例示的なCH1ドメインは、アミノ酸配列(配列番号9):
ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV
HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKV
を有するヒトIgG1 CH1ドメインである。
本発明の好ましい三重特異性結合分子の第4のポリペプチド鎖は、受容体タイプ結合ドメインのポリペプチド(ここで第3及び第4のポリペプチド鎖は受容体タイプ結合ドメインを形成する)、又はより好ましくは、エピトープIIIに免疫特異的に結合する、及び/若しくは及び/又は第3のポリペプチド鎖の結合ドメインに対して相補的な、上述の抗体の軽鎖のポリペプチド部分である。
RTVAAPSVFI FPPSDEQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSG
NSQESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK
SFNRGEC
を有するヒトIgG1 CLカッパドメインである。
QPKAAPSVTL FPPSSEELQA NKATLVCLIS DFYPGAVTVA WKADSSPVKA
GVETTPSKQS NNKYAASSYL SLTPEQWKSH RSYSCQVTHE GSTVEKTVAP
TECS
を有するヒトIgG1 CLラムダ2ドメインである。
一実施形態では、上述のドメインの配向は、N末端からC末端への方向である。しかしながら本発明はその変形例も考察し、ここでは第1のポリペプチド鎖のドメインの配向は:NH2‐(ノブ担持CH3‐CH2ドメイン)‐(VLIドメイン)‐(リンカー1)‐(VHIIドメイン)‐(システイン含有ドメインリンカー2)‐(Eコイルヘテロ二量体促進ドメイン)となる。好ましくは、上記CH2‐CH3ドメインへのN末端にシステイン含有ドメインが存在する。例示的なペプチドの配列は(配列番号5):DKTHTCPPCPであるが、代替的なリンカー、例えばEPKSCDKTHTCPPCP(配列番号129)又はLEPKSSDKTHTCPPCP;配列番号130)を採用してよい。この実施形態において好ましくは、CH3ドメインは、アミノ酸配列(配列番号15):APSSS、及びより好ましくはアミノ酸配列(配列番号16)APSSSPMEを有するもの等の介在ペプチドリンカーによって、VLIドメインから分離されているが、代替的なリンカー、例えばASTKG(配列番号131)、LEPKSS(配列番号132)、GGC又はGGGを採用してよい。
特許文献47に開示されているように、ダイアボディのインビボ薬学動態学的特性を改善するために、ダイアボディを、上記ダイアボディの末端のうちの1つ又は複数において血清結合性タンパク質のポリペプチド部分を含有するように、修飾してよい。このような考察は、本発明の三重特異性結合分子にも適用可能である。最も好ましくは、血清結合性タンパク質のポリペプチド部分を本発明の三重特異性結合分子に組み込むことが望まれる場合に、このようなポリペプチド部分を、上記三重特異性結合分子のポリペプチド鎖のうちの1つのC末端に配置する。
一実施形態では、第1のポリペプチド鎖のCH2‐CH3ドメイン及び第3のポリペプチドのCH2‐CH3ドメインは、複合体化して、Fc受容体に実質的に結合できない(即ち野生型Fcドメインの範囲の10%未満に結合する)Fcドメインを形成する。あるいは、このような分子のFcドメインは、生理学的条件下でFc受容体に結合でき、これにより上記三重特異性結合分子は四重特異性となり、4つの分子(エピトープI、エピトープII及びエピトープIII、並びにFc受容体)への協調的結合を仲介できる。最も好ましくは、Fc受容体に結合できるこのような分子は更に、Fc受容体依存性エフェクタ機能を仲介する。
上述のように、本発明は特に、3つのエピトープが、このようなエピトープのうちの1つ又は2つが免疫系細胞、特に細胞毒性リンパ球免疫系細胞(CTL)の1つ又は複数のエピトープとなり、残りの1つ又は複数のエピトープが疾患関連抗原の1つ又は複数のエピトープとなるように選択された、三重特異性結合分子の実施形態に関する。このような三重特異性結合分子の特に好ましい実施形態では、このような分子の結合ドメインは、エピトープI、エピトープII又はエピトープIIIがCD3のエピトープとなり、エピトープI、エピトープII又はエピトープIIIのうちの第2のものがCD8のエピトープとなり、エピトープI、エピトープII又はエピトープIIIが疾患関連抗原のエピトープとなり、ここで上記三重特異性結合分子の結合ドメインI、II及びIIIが、細胞毒性T細胞及び疾患関連抗原を発現する細胞の協調的結合を仲介するように、選択される。このような三重特異性結合分子は、細胞毒性リンパ球細胞を、疾患関連抗原を発現する細胞に対して局在化でき、またこれによって、疾患関連抗原を発現する細胞の殺滅を促進できる。上記疾患関連抗原は、癌抗原であってよく、又は病原体(例えば細菌、真菌、ウイルス若しくは原生動物)感染の特徴である抗原であってよい。より詳細には、本発明は:(1)CD3のエピトープ;(2)CD8のエピトープ;及び(3)疾患関連抗原のエピトープに対する協調的結合を仲介できる、上述のような三重特異性結合分子に関する。CD3及びCD8に対して、並びに疾患関連抗原に対して結合することにより、このような分子は、上記疾患関連抗原を提示する細胞に対して細胞毒性T細胞を共局在化でき、これは、このようなT細胞の活性化、及び上記疾患関連抗原を発現する細胞に対する細胞毒性応答の開始につながる。
本発明の三重特異性結合分子のCD3又はCD8結合ドメインを作製するために、以下に提供する抗CD3又は抗CD8抗体のいずれを採用してよい。
OKT3軽鎖可変ドメイン(配列番号17)(CDRは下線を付して示す):
QIVLTQSPAI MSASPGEKVT MTCSASSSVSYMNWYQQKSG TSPKRWIYDT
SKLASGVPAH FRGSGSGTSY SLTISGMEAE DAATYYCQQW SSNPFTFGSG
TKLEINR
QVQLQQSGAE LARPGASVKM SCKASGYTFT RYTMHWVKQR PGQGLEWIGY
INPSRGYTNY NQKFKDKATL TTDKSSSTAY MQLSSLTSED SAVYYCARYY
DDHYCLDYWG QGTTLTVSSA KTTAPSVYPL APVCGDTTGS SVTLGCLVKG
YFPEPVTLTW NSGSLSSGVH TFPAVLQSDL YTLSSSVTVT SS
M291軽鎖可変ドメイン(配列番号19)(CDRは下線を付して示す):
DIVLTQSPAI MSASPGEKVT MTCSASSSVS YMNWYQQKSG TSPKRWTYDT
SKLASGVPAR FSGSGSGTSY SLTISSMEAE DADTYYCQQW SSNPPTFGSG
TKLEIK
QVQLQQSGAE LARPGASVKM SCKASGYTFI SYTMHWVKQR PGQGLEWIGY
INPRSGYTHY NQKLKDKATL TADKSSSSAY MQLSSLTSED SAVYYCARSA
YYDYDGFAYW GQGTLVTVSA
YTH12.5軽鎖可変ドメイン(配列番号21)(CDRは下線を付して示す):
MGWSCIILFL VATATGVHSD IQLTQPNSVS TSLGSTVKLS CTLSSGNIEN
NYVHWYQLYE GRSPTTMIYDDDKRPDGVPD RFSGSIDRSS NSAFLTIHNV
AIEDEAIYFC HSYVSSFNVF GGGTKLTVLR
MGWSCIILFL VATATGVHSE VQLLESGGGL VQPGGSLRLS CAASGFTFSS
FPMAWVRQAP GKGLEWVSTISTSGGRTYYR DSVKGRFTIS RDNSKNTLYL
QMNSLRAEDT AVYYCAKFRQ YSGGFDYWGQ GTLVTVSS
CD3 mAb 1軽鎖可変ドメイン(配列番号23)変異体1(CDRは下線を付して示す):
DIQMTQSPSS LSASVGDRVT ITCSASSSVS YMNWYQQKPG KAPKRLIYDS
SKLASGVPSR FSGSGSGTEF TLTISSLQPE DFATYYCQQW SRNPPTFGGG
TKVEIK
DVVMTQSPAI MSAFPGEKVT ITCSASSSVS YMNWYQQKPG KAPKRWIYDS
SKLASGVPSR FSGSGSGTEF TLTISSLQPE DFATYYCQQW SRNPPTFGGG
TKVEIK
QVQLVQSGAE VKKPGASVKV SCKASGYTFT RSTMHWVRQA PGQGLEWIGY
INPSSAYTNY NQKFKDRVTI TADKSTSTAY MELSSLRSED TAVYYCASPQ
VHYDYNGFPY WGQGTLVTVS S
CD3 mAb 2軽鎖可変ドメイン(配列番号26)(CDRは下線を付して示す):
QAVVTQEPSL TVSPGGTVTL TCRSSTGAVT TSNYANWVQQ KPGQAPRGLI
GGTNKRAPWT PARFSGSLLG GKAALTITGA QAEDEADYYC ALWYSNLWVF
GGGTKLTVLG
EVQLVESGGG LVQPGGSLRL SCAASGFTFS TYAMNWVRQA PGKGLEWVGR
IRSKYNNYAT YYADSVKDRF TISRDDSKNS LYLQMNSLKT EDTAVYYCVR
HGNFGNSYVS WFAYWGQGTL VTVSS
EVQLVESGGG LVQPGGSLRL SCAASGFTFS TYAMNWVRQA PGKGLEWVGR
IRSKYNNYAT YYADSVKGRF TISRDDSKNS LYLQMNSLKT EDTAVYYCVR
HGNFGNSYVS WFAYWGQGTL VTVSS
OKT8(「CD8 mAb 1」)
OKT8軽鎖可変ドメイン(配列番号29)(CDRは下線を付して示す):
DIVMTQSPAS LAVSLGQRAT ISCRASESVD SYDNSLMHWY QQKPGQPPKV
LIYLASNLES GVPARFSGSG SRTDFTLTID PVEADDAATY YCQQNNEDPY
TFGGGTKLEI KR
QVQLLESGPE LLKPGASVKM SCKASGYTFT DYNMHWVKQS HGKSLEWIGY
IYPYTGGTGY NQKFKNKATL TVDSSSSTAY MELRSLTSED SAVYYCARNF
RYTYWYFDVW GQGTTVTVSS
TRX2軽鎖可変ドメイン(配列番号31)(CDRは下線を付して示す):
DIQMTQSPSS LSASVGDRVT ITCKGSQDIN NYLAWYQQKP GKAPKLLIYN
TDILHTGVPS RFSGSGSGTD FTFTISSLQP EDIATYYCYQ YNNGYTFGQG
TKVEIK
QVQLVESGGG VVQPGRSLRL SCAASGFTFS DFGMNWVRQA PGKGLEWVAL
IYYDGSNKFY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAKPH
YDGYYHFFDS WGQGTLVTVS S
(a)HIV gp41
例示的な疾患関連抗原は、HIV gp41である。例示的なgp41抗体は、7B2(「HIV mAb 1」)である。
DIVMTQSPDS LAVSPGERAT IHCKSSQTLL YSSNNRHSIA WYQQRPGQPP
KLLLYWASMR LSGVPDRFSG SGSGTDFTLT INNLQAEDVA IYYCHQYSSH
PPTFGHGTRV EIK
QVQLVQSGGG VFKPGGSLRL SCEASGFTFT EYYMTWVRQA PGKGLEWLAY
ISKNGEYSKY SPSSNGRFTI SRDNAKNSVF LQLDRLSADD TAVYYCARAD
GLTYFSELLQ YIFDLWGQGA RVTVSS
第2の例示的な疾患関連抗原は、HIV gp120である。例示的なgp120抗体は、A32(「HIV mAb 2」)である。
QSALTQPPSA SGSPGQSVTI SCTGTSSDVG GYNYVSWYQH HPGKAPKLII SEVNNRPSGV PDRFSGSKSG NTASLTVSGL QAEDEAEYYC SSYTDIHNFV FGGGTKLTVL
QVQLQESGPG LVKPSQTLSL SCTVSGGSSS SGAHYWSWIR QYPGKGLEWI
GYIHYSGNTY YNPSLKSRIT ISQHTSENQF SLKLNSVTVA DTAVYYCARG
TRLRTLRNAF DIWGQGTMVT
VSS
更なる例示的な疾患関連抗原は、RSV糖タンパク質Fである。例示的な抗RSV糖タンパク質F抗体は、パリビズマブ(「RSV mAb 1」)である。
DIQMTQSPST LSASVGDRVT ITCRASQSVG YMHWYQQKPG KAPKLLIYDT
SKLASGVPSR FSGSGSGTEF TLTISSLQPD DFATYYCFQG SGYPFTFGGG
TKLEIK
QVTLRESGPA LVKPTQTLTL TCTFSGFSLS TSGMSVGWIR QPPGKALEWL
ADIWWDDKKD YNPSLKSRLT ISKDTSKNQV VLKVTNMDPA DTATYYCARS
MITNWYFDVW GAGTTVTVSS
特に好ましい例示的な疾患関連抗原はB7‐H3であり、これは、様々な癌細胞(例えば神経芽腫、胃、卵巣及び非小細胞肺癌等)上に発現する。B7‐H3タンパク質発現は、腫瘍細胞株において免疫組織学的に検出されている(Chapoval, A. et al. (2001) “B7-H3: A Costimulatory Molecule For T Cell Activation and IFN-y Production”Nature Immunol. 2:269-274; Saatian, B. et al. (2004) “Expression Of Genes For B7-H3 And Other T Cell Ligands By Nasal Epithelial Cells During Differentiation And Activation,” Amer. J. Physiol. Lung Cell. Mol. Physiol. 287:L217-L225; Castriconi et al. (2004) “Identification Of 4Ig-B7-H3 As A Neuroblastoma-Associated Molecule That Exerts A Protective Role From An NK Cell-Mediated Lysis,” Proc. Natl. Acad. Sci. (U.S.A.) 101(34): 12640-12645);Sun, M. et al. (2002) “Characterization of Mouse and Human B7-H3 Genes,” J. Immunol. 168:6294-6297)。mRNA発現は、心臓、腎臓、精巣、肺、肝臓、膵臓、前立腺、結腸及び骨芽細胞に見られる(Collins, M. et al. (2005) “The B7 Family Of Immune-Regulatory Ligands,” Genome Biol. 6:223.1-223.7)。タンパク質レベルでは、B7‐H3はヒト肝臓、肺、膀胱、精巣、前立腺、乳房、胎盤及びリンパ器官に見られる(Hofmeyer, K. et al. (2008) “The Contrasting Role Of B7-H3,” Proc. Natl. Acad. Sci. (U.S.A.) 105(30):10277-10278)。B7‐H3に結合する例示的な抗体としては、ヒト化「BRCA84D」、「BRCA69D」及び「PRCA157」が挙げられる(国際公開第2011/109400号)。例示的な可変軽鎖及び重鎖は、以下の配列を有する(CDRは下線を付して示す):
DIQLTQSPSF LSASVGDRVT ITCKASQNVD TNVAWYQQKP GQAPKALIYS
ASYRYSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YNNYPFTFGQ
GTKLEIK
EVQLVESGGG LVQPGGSLRL SCAASGFTFS SFGMHWVRQA PGKGLEWVAY
ISSDSSAIYY ADTVKGRFTI SRDNAKNSLY LQMNSLRDED TAVYYCGRGR
ENIYYGSRLD YWGQGTTVTV SS
DIQMTQSPSS LSASVGDRVT ITCRASQDIS NYLNWYQQKP GKAPKLLIYY
TSRLHSGVPS RFSGSGSGTD FTLTISSLQP EDIATYYCQQ GNTLPPTFGG
GTKLEIK
QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYWMQWVRQA PGQGLEWMGT
IYPGDGDTRY TQKFKGRVTI TADKSTSTAY MELSSLRSED TAVYYCARRG
IPRLWYFDVW GQGTTVTVSS
DIQMTQSPAS LSVSVGETVT ITCRASESIY SYLAWYQQKQ GKSPQLLVYN
TKTLPEGVPS RFSGSGSGTQ FSLKINSLQP EDFGRYYCQH HYGTPPWTFG
GGTNLEIK
EVQQVESGGD LVKPGGSLKL SCAASGFTFS SYGMSWVRQT PDKRLEWVAT
INSGGSNTYY PDSLKGRFTI SRDNAKNTLY LQMRSLKSED TAMYYCARHD
GGAMDYWGQG TSVTVSS
A33腫瘍抗原は、別の例示的な疾患関連抗原である。例示的なヒト化抗A33抗体(「gpA33 mAb 1」)の軽鎖可変ドメインのアミノ酸配列は(配列番号45):
QIVLTQSPAI MSASPGERVT MTCSARSSIS FMYWYQQKPG SSPRLLIYDT
SNLASGVPVR FSGSGSGTSY SLTISRMEAE DAATYYCQQW SSYPLTFGSG
TKLELKR
である。
QVQLQQSGPE LVKPGASVKI SCKASGYTFS GSWMNWVKQR PGQGLEWIGR
IYPGDGETNY NGKFKDKATL TADKSSTTAY MELSSLTSVD SAVYFCARIY
GNNVYFDVWG AGTTVTVSS
である。
5T4腫瘍抗原は、別の例示的な疾患関連抗原である。例示的なヒト化抗5T4抗体(「5T4 mAb 1」)の軽鎖可変ドメインのアミノ酸配列は(配列番号47):
DIQMTQSPSS LSASVGDRVT ITCRASQGIS NYLAWFQQKP GKAPKSLIYR
ANRLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCLQ YDDFPWTFGQ
GTKLEIK
である。
QVQLVQSGAE VKKPGASVKV SCKASGYTFT SFWMHWVRQA PGQGLEWMGR
IDPNRGGTEY NEKAKSRVTM TADKSTSTAY MELSSLRSED TAVYYCAGGN
PYYPMDYWGQ GTTVTVSS
である。
DVLMTQTPLS LPVSLGDQAS ISCRSSQSIV YSNGNTYLEW YLQKPGQSPK
LLIYKVSNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDLGV YYCFQGSHVP
FTFGSGTKLE IK
である。
QVQLQQPGAE LVKPGASVKM SCKASGYTFT SYWITWVKQR PGQGLEWIGD
IYPGSGRANY NEKFKSKATL TVDTSSSTAY MQLSSLTSED SAVYNCARYG
PLFTTVVDPN SYAMDYWGQG TSVTVSS
である。
ROR1腫瘍抗原は、別の例示的な疾患関連抗原である。例示的な抗ROR1抗体としては、抗体2A2(国際公開第2010/124188号)、R11(国際公開第2012/075158号)及びR12(国際公開第2012/075158号)が挙げられる。
DIVMTQSQKI MSTTVGDRVS ITCKASQNVD AAVAWYQQKP GQSPKLLIYS
ASNRYTGVPD RFTGSGSGTD FTLTISNMQS EDLADYFCQQ YDIYPYTFGG
GTKLEIK
である。
QVQLQQSGAE LVRPGASVTL SCKASGYTFS DYEMHWVIQT PVHGLEWIGA
IDPETGGTAY NQKFKGKAIL TADKSSSTAY MELRSLTSED SAVYYCTGYY
DYDSFTYWGQ GTLVTVSA
である。
ELVMTQTPSS TSGAVGGTVT INCQASQSID SNLAWFQQKP GQPPTLLIYR
ASNLASGVPS RFSGSRSGTE YTLTISGVQR EDAATYYCLG GVGNVSYRTS
FGGGTEVVVK
である。
QSVKESEGDL VTPAGNLTLT CTASGSDIND YPISWVRQAP GKGLEWIGFI
NSGGSTWYAS WVKGRFTISR TSTTVDLKMT SLTTDDTATY FCARGYSTYY
GDFNIWGPGT LVTISS
である。
ELVLTQSPSV SAALGSPAKI TCTLSSAHKT DTIDWYQQLQ GEAPRYLMQV
QSDGSYTKRP GVPDRFSGSS SGADRYLIIP SVQADDEADY YCGADYIGGY
VFGGGTQLTV TG
である。
QEQLVESGGR LVTPGGSLTL SCKASGFDFS AYYMSWVRQA PGKGLEWIAT
IYPSSGKTYY ATWVNGRFTI SSDNAQNTVD LQMNSLTAAD RATYFCARDS
YADDGALFNI WGPGTLVTIS S
である。
QLVLTQSPSA SASLGSSVKL TCTLSSGHKT DTIDWYQQQP GKAPRYLMKL
EGSGSYNKGS GVPDRFGSGS SSGADRYLTI SSLQSEDEAD YYCGTDYPGN
YLFGGGTQLT VL
を有する軽鎖可変ドメインを有する。
QEQLVESGGG LVQPGGSLRL SCAASGFTFS DYYMSWVRQA PGKGLEWVAT
IYPSSGKTYY ADSVKGRFTI SSDNAKNSLY LQMNSLRAED TAVYYCARDS
YADDAALFDI WGQGTTVTVS S
である。
上述のように、本発明の好ましい三重特異性結合分子は少なくとも三重特異性であり、結合ドメインIIIから最も離れて位置している「外部」ダイアボディタイプ結合ドメイン(部位A)、結合ドメインIIIに最も近接して位置している「内部」ダイアボディタイプ結合ドメイン(部位B)、及び結合ドメインIII自体(部位C)を有する。本明細書において使用される場合、「X/Y/Z」のような三重特異性結合分子の記載は、X結合ドメインが部位Aにあり、Y結合ドメインが部位Bにあり、Z結合ドメインが部位Cにあることを示している。例えば三重特異性結合分子の呼称「B7‐H3 mAb 1/CD3 mAb 2/CD8 mAb 1」は、B7‐H3 mAb 1可変ドメインが上記三重特異性結合分子の部位Aを占有しており、CD3 mAb 2可変ドメインが上記三重特異性結合分子の部位Bを占有しており、CD8 mAb 1可変ドメインが上記三重特異性結合分子の部位Cを占有していることを示している。
上述のように、本出願の一態様は、その軽鎖可変ドメインがアミノ酸配列(配列番号51):
QLVLTQSPSA SASLGSSVKL TCTLSSGHKT DTIDWYQQQP GKAPRYLMKL
EGSGSYNKGS GVPDRFGSGS SSGADRYLTI SSLQSEDEAD YYCGTDYPGN
YLFGGGTQLT VL
を有し、またその重鎖可変ドメインがアミノ酸配列(配列番号52):
QEQLVESGGG LVQPGGSLRL SCAASGFTFS DYYMSWVRQA PGKGLEWVAT
IYPSSGKTYY ADSVKGRFTI SSDNAKNSLY LQMNSLRAED TAVYYCARDS
YADDAALFDI WGQGTTVTVS S
を有する、極めて好ましいヒト化抗ROR1抗体(「ROR1 mAb 1」)の提案である。
軽鎖可変ドメインCDRL1(配列番号117):TLSSGHKTDTID
軽鎖可変ドメインCDRL2(配列番号118):LEGSGSY
軽鎖可変ドメインCDRL3(配列番号119):GTDYPGNYL
である。
重鎖可変ドメインCDRH1(配列番号120):GFTFSDYYMS
重鎖可変ドメインCDRH2(配列番号121):TIYPSSGKTYYADSVKG
重鎖可変ドメインCDRH3(配列番号122):DSYADDAALFDI
である。
(A)F243L、R292P、Y300L、V305I、及びP396Lからなる群から選択される、少なくとも1つの置換;
(B)(1)F243L及びP396L;
(2)F243L及びR292P;並びに
(3)R292P及びV305I;
からなる群から選択される、少なくとも2つの置換;
(C)(1)F243L、R292P及びY300L;
(2)F243L、R292P及びV305I;
(3)F243L、R292P及びP396L;並びに
(4)R292P、V305I及びP396L;
からなる群から選択される、少なくとも3つの置換;
(D)(1)F243L、R292P、Y300L及びP396L;並びに
(2)F243L、R292P、V305I及びP396L;
からなる群から選択される、少なくとも4つの置換;又は
(E)(1)F243L、R292P、Y300L、V305I及びP396L;並びに
(2)L235V、F243L、R292P、Y300L及びP396L
からなる群から選択される、少なくとも5つの置換。
(A)F243L、R292P、及びY300L;
(B)L235V、F243L、R292P、Y300L、及びP396L;又は
(C)F243L、R292P、Y300L、V305I、及びP396L。
一実施形態では、本発明は、疾患関連抗原の存在を特徴とする癌又は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。これらの組成物は、予防的又は治療的有効量の本発明の修飾されたダイアボディ、又はこのような作用剤と薬学的に許容可能なキャリアとの組み合わせを含む。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、及び特定の疾患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、本発明の三重特異性結合分子は、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、本発明の三重特異性結合分子、このような分子に由来するポリペプチド、このような分子又は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剤を備える、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。
CD8+T細胞に対するより高い特異性、及びより強力な標的転換殺滅を呈する治療用分子を開発するために、CD3、CD8及び疾患関連抗原に対して協調的に結合する能力を有する三重特異性結合分子を構成した。産生された三重特異性結合分子は更に、上記三重特異性結合分子のインビボ半減期を増強するために、Fcドメインを有していた。三重特異性結合分子の一般的構造を、図4A〜4Dに示す。疾患関連抗原B7‐H3に対して特異的な例示的三重特異性結合分子を構成した。上記三重特異性結合分子内の結合ドメインの相対的位置を示すために、上記三重特異性結合分子をB7‐H3 mAb 1/CD3 mAb 2/CD8 mAb 1と呼ぶ。B7‐H3結合ドメインは部位Aの位置を占有し、CD3結合ドメインは部位Bの位置を占有し、CD8結合ドメインは部位Cの位置を占有する(図4A)。B7‐H3 mAb 1/CD3 mAb 2/CD8 mAb 1三重特異性結合分子は、4つの異なるポリペプチド鎖で構成された(表5)。
DIQMTQSPSS LSASVGDRVT ITCRASQDIS NYLNWYQQKP GKAPKLLIYY
TSRLHSGVPS RFSGSGSGTD FTLTISSLQP EDIATYYCQQ GNTLPPTFGG
GTKLEIKGGG SGGGGEVQLV ESGGGLVQPG GSLRLSCAAS GFTFSTYAMN
WVRQAPGKGL EWVGRIRSKY NNYATYYADS VKDRFTISRD DSKNSLYLQM
NSLKTEDTAV YYCVRHGNFG NSYVSWFAYW GQGTLVTVSS GGCGGGEVAA
LEKEVAALEK EVAALEKEVA ALEKGGGDKT HTCPPCPAPE AAGGPSVFLF
PPKPKDTLMI SRTPEVTCVV VDVSHEDPEV KFNWYVDGVE VHNAKTKPRE
EQYNSTYRVV SVLTVLHQDW LNGKEYKCKV SNKALPAPIE KTISKAKGQP
REPQVYTLPP SREEMTKNQV SLWCLVKGFY PSDIAVEWES NGQPENNYKT
TPPVLDSDGS FFLYSKLTVD KSRWQQGNVF SCSVMHEALH NHYTQKSLSL
SPGK
QAVVTQEPSL TVSPGGTVTL TCRSSTGAVT TSNYANWVQQ KPGQAPRGLI
GGTNKRAPWT PARFSGSLLG GKAALTITGA QAEDEADYYC ALWYSNLWVF
GGGTKLTVLG GGGSGGGGQV QLVQSGAEVK KPGASVKVSC KASGYTFTSY
WMQWVRQAPG QGLEWMGTIY PGDGDTRYTQ KFKGRVTITA DKSTSTAYME
LSSLRSEDTA VYYCARRGIP RLWYFDVWGQ GTTVTVSSGG CGGGKVAALK
EKVAALKEKV AALKEKVAAL KE
IDPANDNTLY ASKFQGKATI TADTSSNTAY MHLCSLTSGD TAVYYCGRGY
GYYVFDHWGQ GTTLTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY
FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI
CNVNHKPSNT KVDKRVEPKS CDKTHTCPPC PAPEAAGGPS VFLFPPKPKD
TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST
YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY
TLPPSREEMT KNQVSLSCAV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD
SDGSFFLVSK LTVDKSRWQQ GNVFSCSVMH EALHNRYTQK SLSLSPGK
DVQINQSPSF LAASPGETIT INCRTSRSIS QYLAWYQEKP GKTNKLLIYS
GSTLQSGIPS RFSGSGSGTD FTLTISGLEP EDFAMYYCQQ HNENPLTFGA
GTKLELRRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV
DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG
LSSPVTKSFN RGEC
CD8特異性の影響を評価するために、疾患関連抗原B7‐H3に対して特異的な第2の三重特異性結合分子を、異なるCD8抗体可変ドメイン配列を利用して構成した。B7‐H3可変ドメイン特異性及びCD3可変ドメイン特異性は、B7‐H3 mAb 1/CD3 mAb 2/CD8 mAb 1三重特異性結合分子を構成するために使用したものと同一であった。この三重特異性結合分子はB7‐H3 mAb 1/CD3 mAb 2/CD8 mAb 2と呼ばれ、4つの異なるポリペプチド鎖で構成された(表8)。
DIQMTQSPSS LSASVGDRVT ITCRASQDIS NYLNWYQQKP GKAPKLLIYY
TSRLHSGVPS RFSGSGSGTD FTLTISSLQP EDIATYYCQQ GNTLPPTFGG
GTKLEIKGGG SGGGGEVQLV ESGGGLVQPG GSLRLSCAAS GFTFSTYAMN
WVRQAPGKGL EWVGRIRSKY NNYATYYADS VKDRFTISRD DSKNSLYLQM
NSLKTEDTAV YYCVRHGNFG NSYVSWFAYW GQGTLVTVSS GGCGGGEVAA
LEKEVAALEK EVAALEKEVA ALEKGGGDKT HTCPPCPAPE AAGGPSVFLF
PPKPKDTLMI SRTPEVTCVV VDVSHEDPEV KFNWYVDGVE VHNAKTKPRE
EQYNSTYRVV SVLTVLHQDW LNGKEYKCKV SNKALPAPIE KTISKAKGQP
REPQVYTLPP SREEMTKNQV SLWCLVKGFY PSDIAVEWES NGQPENNYKT
TPPVLDSDGS FFLYSKLTVD KSRWQQGNVF SCSVMHEALH NHYTQKSLSL
SPGK
QAVVTQEPSL TVSPGGTVTL TCRSSTGAVT TSNYANWVQQ KPGQAPRGLI
GGTNKRAPWT PARFSGSLLG GKAALTITGA QAEDEADYYC ALWYSNLWVF
GGGTKLTVLG GGGSGGGGQV QLVQSGAEVK KPGASVKVSC KASGYTFTSY
WMQWVRQAPG QGLEWMGTIY PGDGDTRYTQ KFKGRVTITA DKSTSTAYME
LSSLRSEDTA VYYCARRGIP RLWYFDVWGQ GTTVTVSSGG CGGGKVAALK
EKVAALKEKV AALKEKVAAL KE
QVQLVESGGG VVQPGRSLRL SCAASGFTFS DFGMNWVRQA PGKGLEWVAL
IYYDGSNKFY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAKPH
YDGYYHFFDS WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV
KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ
TYICNVNHKP SNTKVDKRVE PKSCDKTHTC PPCPAPEAAG GPSVFLFPPK
PKDTLMISRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY
NSTYRVVSVL TVLHQDWLNG KEYKCKVSNK ALPAPIEKTI SKAKGQPREP
QVYTLPPSRE EMTKNQVSLS CAVKGFYPSD IAVEWESNGQ PENNYKTTPP
VLDSDGSFFL VSKLTVDKSR WQQGNVFSCS VMHEALHNRY TQKSLSLSPG
K
DIQMTQSPSS LSASVGDRVT ITCKGSQDIN NYLAWYQQKP
GKAPKLLIYN TDILHTGVPS RFSGSGSGTD FTFTISSLQP
EDIATYYCYQ YNNGYTFGQG TKVEIKRTVA APSVFIFPPS
DEQLKSGTAS VVCLLNNFYP REAKVQWKVD NALQSGNSQE
SVTEQDSKDS TYSLSSTLTL SKADYEKHKV YACEVTHQGL
SSPVTKSFNR GEC
三重特異性結合分子内での所与の結合ドメイン(CD3、CD8及び疾患関連抗原)に関する位置(部位A、部位B及び部位C)の影響を評価するために、複数の追加の三重特異性結合分子を構成した。表9は、これら三重特異性結合分子と、様々な結合ドメイン(CD3、CD8及び疾患関連抗原)の位置(部位A、部位B及び部位C)とを示す。
DVQINQSPSF LAASPGETIT INCRTSRSIS QYLAWYQEKP GKTNKLLIYS
GSTLQSGIPS RFSGSGSGTD FTLTISGLEP EDFAMYYCQQ HNENPLTFGA
GTKLELRGGG SGGGGEVQLV ESGGGLVQPG GSLRLSCAAS GFTFSTYAMN
WVRQAPGKGL EWVGRIRSKY NNYATYYADS VKGRFTISRD DSKNSLYLQM
NSLKTEDTAV YYCVRHGNFG NSYVSWFAYW GQGTLVTVSS GGCGGGEVAA
LEKEVAALEK EVAALEKEVA ALEKGGGDKT HTCPPCPAPE AAGGPSVFLF
PPKPKDTLMI SRTPEVTCVV VDVSHEDPEV KFNWYVDGVE VHNAKTKPRE
EQYNSTYRVV SVLTVLHQDW LNGKEYKCKV SNKALPAPIE KTISKAKGQP
REPQVYTLPP SREEMTKNQV SLWCLVKGFY PSDIAVEWES NGQPENNYKT
TPPVLDSDGS FFLYSKLTVD KSRWQQGNVF SCSVMHEALH NHYTQKSLSL
SPGK
QAVVTQEPSL TVSPGGTVTL TCRSSTGAVT TSNYANWVQQ KPGQAPRGLI
GGTNKRAPWT PARFSGSLLG GKAALTITGA QAEDEADYYC ALWYSNLWVF
GGGTKLTVLG GGGSGGGGEV QLQQSGAELV KPGASVKLSC TASGFNIKDT
YIHFVRQRPE QGLEWIGRID PANDNTLYAS KFQGKATITA DTSSNTAYMH
LCSLTSGDTA VYYCGRGYGY YVFDHWGQGT TLTVSSGGCG GGKVAALKEK
VAALKEKVAA LKEKVAALKE
QVQLVQSGAE VKKPGASVKV SCKASGYTFT SYWMQWVRQA PGQGLEWMGT
IYPGDGDTRY TQKFKGRVTI TADKSTSTAY MELSSLRSED TAVYYCARRG
IPRLWYFDVW GQGTTVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK
DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT
YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPEAAGG PSVFLFPPKP
KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN
STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ
VYTLPPSREE MTKNQVSLSC AVKGFYPSDI AVEWESNGQP ENNYKTTPPV
LDSDGSFFLV SKLTVDKSRW QQGNVFSCSV MHEALHNRYT QKSLSLSPGK
DIQMTQSPSS LSASVGDRVT ITCRASQDIS NYLNWYQQKP GKAPKLLIYY
TSRLHSGVPS RFSGSGSGTD FTLTISSLQP EDIATYYCQQ GNTLPPTFGG
GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV
DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG
LSSPVTKSFN RGEC
DVQINQSPSF LAASPGETIT INCRTSRSIS QYLAWYQEKP GKTNKLLIYS
GSTLQSGIPS RFSGSGSGTD FTLTISGLEP EDFAMYYCQQ HNENPLTFGA
GTKLELRGGG SGGGGQVQLV QSGAEVKKPG ASVKVSCKAS GYTFTSYWMQ
WVRQAPGQGL EWMGTIYPGD GDTRYTQKFK GRVTITADKS TSTAYMELSS
LRSEDTAVYY CARRGIPRLW YFDVWGQGTT VTVSSGGCGG GEVAALEKEV
AALEKEVAAL EKEVAALEKG GGDKTHTCPP CPAPEAAGGP SVFLFPPKPK
DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS
TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV
YTLPPSREEM TKNQVSLWCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL
DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK
DIQMTQSPSS LSASVGDRVT ITCRASQDIS NYLNWYQQKP GKAPKLLIYY
TSRLHSGVPS RFSGSGSGTD FTLTISSLQP EDIATYYCQQ GNTLPPTFGG
GTKLEIKGGG SGGGGEVQLQ QSGAELVKPG ASVKLSCTAS GFNIKDTYIH
FVRQRPEQGL EWIGRIDPAN DNTLYASKFQ GKATITADTS SNTAYMHLCS
LTSGDTAVYY CGRGYGYYVF DHWGQGTTLT VSSGGCGGGK VAALKEKVAA
LKEKVAALKE KVAALKE
EVQLVESGGG LVQPGGSLRL SCAASGFTFS TYAMNWVRQA PGKGLEWVGR
IRSKYNNYAT YYADSVKDRF TISRDDSKNS LYLQMNSLKT EDTAVYYCVR
HGNFGNSYVS WFAYWGQGTL VTVSSASTKG PSVFPLAPSS KSTSGGTAAL
GCLVKDYFPE PVTVSWNSGA LTSGVHTFPA VLQSSGLYSL SSVVTVPSSS
LGTQTYICNV NHKPSNTKVD KRVEPKSCDK THTCPPCPAP EAAGGPSVFL
FPPKPKDTLM ISRTPEVTCV VVDVSHEDPE VKFNWYVDGV EVHNAKTKPR
EEQYNSTYRV VSVLTVLHQD WLNGKEYKCK VSNKALPAPI EKTISKAKGQ
PREPQVYTLP PSREEMTKNQ VSLSCAVKGF YPSDIAVEWE SNGQPENNYK
TTPPVLDSDG SFFLVSKLTV DKSRWQQGNV FSCSVMHEAL HNRYTQKSLS
LSPGK
QAVVTQEPSL TVSPGGTVTL TCRSSTGAVT TSNYANWVQQ KPGQAPRGLI
GGTNKRAPWT PARFSGSLLG GKAALTITGA QAEDEADYYC ALWYSNLWVF
GGGTKLTVLG RTVAAPSVFI FPPSDEQLKS GTASVVCLLN NFYPREAKVQ
WKVDNALQSG NSQESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT
HQGLSSPVTK SFNRGEC
疾患関連抗原5T4に対して特異的な、更なる例示的な三重特異性結合分子を構成した。5T4 mAb 2/CD3 mAb 2/CD8 mAb 1三重特異性結合分子は、4つの異なるポリペプチド鎖で構成された(表12)。
DVLMTQTPLS LPVSLGDQAS ISCRSSQSIV YSNGNTYLEW YLQKPGQSPK LLIYKVSNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDLGV YYCFQGSHVP FTFGSGTKLE IKGGGSGGGG EVQLVESGGG LVQPGGSLRL SCAASGFTFS TYAMNWVRQA PGKGLEWVGR IRSKYNNYAT YYADSVKGRF TISRDDSKNS LYLQMNSLKT EDTAVYYCVR HGNFGNSYVS WFAYWGQGTL VTVSSGGCGG GEVAALEKEV AALEKEVAAL EKEVAALEKG GGDKTHTCPP CPAPEAAGGP SVFLFPPKPK DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV YTLPPSREEM TKNQVSLWCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK
QAVVTQEPSL TVSPGGTVTL TCRSSTGAVT TSNYANWVQQ KPGQAPRGLI
GGTNKRAPWT PARFSGSLLG GKAALTITGA QAEDEADYYC ALWYSNLWVF
GGGTKLTVLG GGGSGGGGQV QLQQPGAELV KPGASVKMSC KASGYTFTSY
WITWVKQRPG QGLEWIGDIY PGSGRANYNE KFKSKATLTV DTSSSTAYMQ
LSSLTSEDSA VYNCARYGPL FTTVVDPNSY AMDYWGQGTS VTVSSGGCGG
GKVAALKEKV AALKEKVAAL KEKVAALKE
EVQLQQSGAE LVKPGASVKL SCTASGFNIK DTYIHFVRQR PEQGLEWIGR
IDPANDNTLY ASKFQGKATI TADTSSNTAY MHLCSLTSGD TAVYYCGRGY
GYYVFDHWGQ GTTLTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY
FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI
CNVNHKPSNT KVDKRVEPKS CDKTHTCPPC PAPEAAGGPS VFLFPPKPKD
TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST
YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY
TLPPSREEMT KNQVSLSCAV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD
SDGSFFLVSK LTVDKSRWQQ GNVFSCSVMH EALHNRYTQK SLSLSPGK
DVQINQSPSF LAASPGETIT INCRTSRSIS QYLAWYQEKP GKTNKLLIYS
GSTLQSGIPS RFSGSGSGTD FTLTISGLEP EDFAMYYCQQ HNENPLTFGA
GTKLELRRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV
DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG
LSSPVTKSFN RGEC
DVLMTQTPLS LPVSLGDQAS ISCRSSQSIV YSNGNTYLEW YLQKPGQSPK
LLIYKVSNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDLGV YYCFQGSHVP
FTFGSGTKLE IKGGGSGGGG EVQLVESGGG LVQPGGSLRL SCAASGFTFS
TYAMNWVRQA PGKGLEWVGR IRSKYNNYAT YYADSVKGRF TISRDDSKNS
LYLQMNSLKT EDTAVYYCVR HGNFGNSYVS WFAYWGQGTL VTVSSGGCGG
GEVAALEKEV AALEKEVAAL EKEVAALEKG GGDKTHTCPP CPAPEAAGGP
SVFLFPPKPK DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK
TKPREEQYNS TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK
AKGQPREPQV YTLPPSREEM TKNQVSLWCL VKGFYPSDIA VEWESNGQPE
NNYKTTPPVL DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ
KSLSLSPGK
QAVVTQEPSL TVSPGGTVTL TCRSSTGAVT TSNYANWVQQ KPGQAPRGLI
GGTNKRAPWT PARFSGSLLG GKAALTITGA QAEDEADYYC ALWYSNLWVF
GGGTKLTVLG GGGSGGGGQV QLQQPGAELV KPGASVKMSC KASGYTFTSY
WITWVKQRPG QGLEWIGDIY PGSGRANYNE KFKSKATLTV DTSSSTAYMQ
LSSLTSEDSA VYNCARYGPL FTTVVDPNSY AMDYWGQGTS VTVSSGGCGG
GKVAALKEKV AALKEKVAAL KEKVAALKE
QVQLVESGGG VVQPGRSLRL SCAASGFTFS DFGMNWVRQA PGKGLEWVAL
IYYDGSNKFY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAKPH
YDGYYHFFDS WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV
KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ
TYICNVNHKP SNTKVDKRVE PKSCDKTHTC PPCPAPEAAG GPSVFLFPPK
PKDTLMISRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY
NSTYRVVSVL TVLHQDWLNG KEYKCKVSNK ALPAPIEKTI SKAKGQPREP
QVYTLPPSRE EMTKNQVSLS CAVKGFYPSD IAVEWESNGQ PENNYKTTPP
VLDSDGSFFL VSKLTVDKSR WQQGNVFSCS VMHEALHNRY TQKSLSLSPG
K
DIQMTQSPSS LSASVGDRVT ITCKGSQDIN NYLAWYQQKP GKAPKLLIYN
TDILHTGVPS RFSGSGSGTD FTFTISSLQP EDIATYYCYQ YNNGYTFGQG
TKVEIKRTVA APSVFIFPPS DEQLKSGTAS VVCLLNNFYP REAKVQWKVD
NALQSGNSQE SVTEQDSKDS TYSLSSTLTL SKADYEKHKV YACEVTHQGL
SSPVTKSFNR GEC
疾患関連抗原ROR1に対して特異的な、更なる例示的な三重特異性結合分子を構成した。 ROR1 mAb 1/CD3 mAb 2/CD8 mAb 1三重特異性結合分子は、4つの異なるポリペプチド鎖で構成された(表14)。
QLVLTQSPSA SASLGSSVKL TCTLSSGHKT DTIDWYQQQP GKAPRYLMKL
EGSGSYNKGS GVPDRFGSGS SSGADRYLTI SSLQSEDEAD YYCGTDYPGN
YLFGGGTQLT VLGGGGSGGG GEVQLVESGG GLVQPGGSLR LSCAASGFTF
STYAMNWVRQ APGKGLEWVG RIRSKYNNYA TYYADSVKGR FTISRDDSKN
SLYLQMNSLK TEDTAVYYCV RHGNFGNSYV SWFAYWGQGT LVTVSSGGCG
GGEVAALEKE VAALEKEVAA LEKEVAALEK GGGDKTHTCP PCPAPEAAGG
PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA
KTKPREEQYN STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS
KAKGQPREPQ VYTLPPSREE MTKNQVSLWC LVKGFYPSDI AVEWESNGQP
ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT
QKSLSLSPGK
QAVVTQEPSL TVSPGGTVTL TCRSSTGAVT TSNYANWVQQ KPGQAPRGLI
GGTNKRAPWT PARFSGSLLG GKAALTITGA QAEDEADYYC ALWYSNLWVF
GGGTKLTVLG GGGSGGGGQE QLVESGGGLV QPGGSLRLSC AASGFTFSDY
YMSWVRQAPG KGLEWVATIY PSSGKTYYAD SVKGRFTISS DNAKNSLYLQ
MNSLRAEDTA VYYCARDSYA DDAALFDIWG QGTTVTVSSG GCGGGKVAAL
KEKVAALKEK VAALKEKVAA LKE
EVQLQQSGAE LVKPGASVKL SCTASGFNIK DTYIHFVRQR PEQGLEWIGR
IDPANDNTLY ASKFQGKATI TADTSSNTAY MHLCSLTSGD TAVYYCGRGY
GYYVFDHWGQ GTTLTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY
FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI
CNVNHKPSNT KVDKRVEPKS CDKTHTCPPC PAPEAAGGPS VFLFPPKPKD
TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST
YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY
TLPPSREEMT KNQVSLSCAV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD
SDGSFFLVSK LTVDKSRWQQ GNVFSCSVMH EALHNRYTQK SLSLSPG
DVQINQSPSF LAASPGETIT INCRTSRSIS QYLAWYQEKP GKTNKLLIYS
GSTLQSGIPS RFSGSGSGTD FTLTISGLEP EDFAMYYCQQ HNENPLTFGA
GTKLELRRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV
DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG
LSSPVTKSFN RGEC
QLVLTQSPSA SASLGSSVKL TCTLSSGHKT DTIDWYQQQP GKAPRYLMKL
EGSGSYNKGS GVPDRFGSGS SSGADRYLTI SSLQSEDEAD YYCGTDYPGN
YLFGGGTQLT VLGGGGSGGG GEVQLVESGG GLVQPGGSLR LSCAASGFTF
STYAMNWVRQ APGKGLEWVG RIRSKYNNYA TYYADSVKGR FTISRDDSKN
SLYLQMNSLK TEDTAVYYCV RHGNFGNSYV SWFAYWGQGT LVTVSSGGCG
GGEVAALEKE VAALEKEVAA LEKEVAALEK GGGDKTHTCP PCPAPEAAGG
PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA
KTKPREEQYN STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS
KAKGQPREPQ VYTLPPSREE MTKNQVSLWC LVKGFYPSDI AVEWESNGQP
ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT
QKSLSLSPGK
QAVVTQEPSL TVSPGGTVTL TCRSSTGAVT TSNYANWVQQ KPGQAPRGLI
GGTNKRAPWT PARFSGSLLG GKAALTITGA QAEDEADYYC ALWYSNLWVF
GGGTKLTVLG GGGSGGGGQE QLVESGGGLV QPGGSLRLSC AASGFTFSDY
YMSWVRQAPG KGLEWVATIY PSSGKTYYAD SVKGRFTISS DNAKNSLYLQ
MNSLRAEDTA VYYCARDSYA DDAALFDIWG QGTTVTVSSG GCGGGKVAAL
KEKVAALKEK VAALKEKVAA LKE
QVQLVESGGG VVQPGRSLRL SCAASGFTFS DFGMNWVRQA PGKGLEWVAL
IYYDGSNKFY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAKPH
YDGYYHFFDS WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV
KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ
TYICNVNHKP SNTKVDKRVE PKSCDKTHTC PPCPAPEAAG GPSVFLFPPK
PKDTLMISRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY
NSTYRVVSVL TVLHQDWLNG KEYKCKVSNK ALPAPIEKTI SKAKGQPREP
QVYTLPPSRE EMTKNQVSLS CAVKGFYPSD IAVEWESNGQ PENNYKTTPP
VLDSDGSFFL VSKLTVDKSR WQQGNVFSCS VMHEALHNRY TQKSLSLSPG
K
DIQMTQSPSS LSASVGDRVT ITCKGSQDIN NYLAWYQQKP GKAPKLLIYN
TDILHTGVPS RFSGSGSGTD FTFTISSLQP EDIATYYCYQ YNNGYTFGQG
TKVEIKRTVA APSVFIFPPS DEQLKSGTAS VVCLLNNFYP REAKVQWKVD
NALQSGNSQE SVTEQDSKDS TYSLSSTLTL SKADYEKHKV YACEVTHQGL
SSPVTKSFNR GEC
疾患関連抗原HIV(gp140抗原)に対して特異的な、更なる例示的な三重特異性結合分子を構成した。HIV mAb 1/CD3 mAb 2/CD8 mAb 1三重特異性結合分子は、4つの異なるポリペプチド鎖で構成された(表17)。
DIVMTQSPDS LAVSPGERAT IHCKSSQTLL YSSNNRHSIA WYQQRPGQPP
KLLLYWASMR LSGVPDRFSG SGSGTDFTLT INNLQAEDVA IYYCHQYSSH
PPTFGHGTRV EIKGGGSGGG GEVQLVESGG GLVQPGGSLR LSCAASGFTF
STYAMNWVRQ APGKGLEWVG RIRSKYNNYA TYYADSVKGR FTISRDDSKN
SLYLQMNSLK TEDTAVYYCV RHGNFGNSYV SWFAYWGQGT LVTVSSASTK
GEVAACEKEV AALEKEVAAL EKEVAALEKG GGDKTHTCPP CPAPEAAGGP
SVFLFPPKPK DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK
TKPREEQYNS TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK
AKGQPREPQV YTLPPSREEM TKNQVSLWCL VKGFYPSDIA VEWESNGQPE
NNYKTTPPVL DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ
KSLSLSPGK
QAVVTQEPSL TVSPGGTVTL TCRSSTGAVT TSNYANWVQQ KPGQAPRGLI
GGTNKRAPWT PARFSGSLLG GKAALTITGA QAEDEADYYC ALWYSNLWVF
GGGTKLTVLG GGGSGGGGQV QLVQSGGGVF KPGGSLRLSC EASGFTFTEY
YMTWVRQAPG KGLEWLAYIS KNGEYSKYSP SSNGRFTISR DNAKNSVFLQ
LDRLSADDTA VYYCARADGL TYFSELLQYI FDLWGQGARV TVSSASTKGK
VAACKEKVAA LKEKVAALKE KVAALKE
EVQLQQSGAE LVKPGASVKL SCTASGFNIK DTYIHFVRQR PEQGLEWIGR
IDPANDNTLY ASKFQGKATI TADTSSNTAY MHLCSLTSGD TAVYYCGRGY
GYYVFDHWGQ GTTLTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY
FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI
CNVNHKPSNT KVDKRVEPKS CDKTHTCPPC PAPEAAGGPS VFLFPPKPKD
TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST
YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY
TLPPSREEMT KNQVSLSCAV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD
SDGSFFLVSK LTVDKSRWQQ GNVFSCSVMH EALHNRYTQK SLSLSPG
DVQINQSPSF LAASPGETIT INCRTSRSIS QYLAWYQEKP GKTNKLLIYS GSTLQSGIPS RFSGSGSGTD FTLTISGLEP EDFAMYYCQQ HNENPLTFGA GTKLELRRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
QSALTQPPSA SGSPGQSVTI SCTGTSSDVG GYNYVSWYQH HPGKAPKLII
SEVNNRPSGV PDRFSGSKSG NTASLTVSGL QAEDEAEYYC SSYTDIHNFV
FGGGTKLTVL GGGSGGGGEV QLVESGGGLV QPGGSLRLSC AASGFTFSTY
AMNWVRQAPG KGLEWVGRIR SKYNNYATYY ADSVKGRFTI SRDDSKNSLY
LQMNSLKTED TAVYYCVRHG NFGNSYVSWF AYWGQGTLVT VSSASTKGEV
AACEKEVAAL EKEVAALEKE VAALEKGGGD KTHTCPPCPA PEAAGGPSVF
LFPPKPKDTL MISRTPEVTC VVVDVSHEDP EVKFNWYVDG VEVHNAKTKP
REEQYNSTYR VVSVLTVLHQ DWLNGKEYKC KVSNKALPAP IEKTISKAKG
QPREPQVYTL PPSREEMTKN QVSLWCLVKG FYPSDIAVEW ESNGQPENNY
KTTPPVLDSD GSFFLYSKLT VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL
SLSPGK
QAVVTQEPSL TVSPGGTVTL TCRSSTGAVT TSNYANWVQQ KPGQAPRGLI
GGTNKRAPWT PARFSGSLLG GKAALTITGA QAEDEADYYC ALWYSNLWVF
GGGTKLTVLG GGGSGGGGQV QLQESGPGLV KPSQTLSLSC TVSGGSSSSG
AHYWSWIRQY PGKGLEWIGY IHYSGNTYYN PSLKSRITIS QHTSENQFSL
KLNSVTVADT AVYYCARGTR LRTLRNAFDI WGQGTLVTVS SASTKGKVAA
CKEKVAALKE KVAALKEKVA ALKE
EVQLQQSGAE LVKPGASVKL SCTASGFNIK DTYIHFVRQR PEQGLEWIGR
IDPANDNTLY ASKFQGKATI TADTSSNTAY MHLCSLTSGD TAVYYCGRGY
GYYVFDHWGQ GTTLTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY
FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI
CNVNHKPSNT KVDKRVEPKS CDKTHTCPPC PAPEAAGGPS VFLFPPKPKD
TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST
YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY
TLPPSREEMT KNQVSLSCAV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD
SDGSFFLVSK LTVDKSRWQQ GNVFSCSVMH EALHNRYTQK SLSLSPG
DVQINQSPSF LAASPGETIT INCRTSRSIS QYLAWYQEKP GKTNKLLIYS
GSTLQSGIPS RFSGSGSGTD FTLTISGLEP EDFAMYYCQQ HNENPLTFGA
GTKLELRRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV
DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG
LSSPVTKSFN RGEC
上述のように、本発明の三重特異性結合分子のCD3、CD8又は疾患関連抗原結合ドメインは、より望ましい結合特性を有するようにするために突然変異させることができる。CD3 mAb 2結合ドメインをこのような突然変異誘発に供し、2つの親和性変異体(CD3 mAb 2 Low及びCD3 mAb 2 Fast)を単離した。
QAVVTQEPSL TVSPGGTVTL TCRSSTGAVTTSNYANWVQQ KPGQAPRGLI
GGTNKRAPWT PARFSGSLLG GKAALTITGA QAEDEADYYC ALWYSNLWVF
GGGTKLTVLG
EVQLVESGGG LVQPGGSLRL SCAASGFTFS TYAMNWVRQA PGKGLEWVGR
IRSKYNNYAT YYADSVKGRF TISRDDSKNS LYLQMNSLKT EDTAVYYCVR
HGNFGNSYVT WFAYWGQGTL VTVSS
QAVVTQEPSL TVSPGGTVTL TCRSSTGAVT TSNYANWVQQ KPGQAPRGLI
GGTNKRAPWT PARFSGSLLG GKAALTITGA QAEDEADYYC ALWYSNLWVF
GGGTKLTVLG
EVQLVESGGG LVQPGGSLRL SCAASGFTFS TYAMNWVRQA PGKGLEWVGR
IRSKYNNYAT YYADSVKGRF TISRDDSKNS LYLQMNSLKT EDTAVYYCVR
HKNFGNSYVT WFAYWGQGTL VTVSS
DIQMTQSPSS LSASVGDRVT ITCRASQGIS NYLAWFQQKP GKAPKSLIYR
ANRLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCLQ YDDFPWTFGQ
GTKLEIKGGG SGGGGEVQLV ESGGGLVQPG GSLRLSCAAS GFTFSTYAMN
WVRQAPGKGL EWVGRIRSKY NNYATYYADS VKGRFTISRD DSKNSLYLQM
NSLKTEDTAV YYCVRHGNFG NSYVSWFAYW GQGTLVTVSS GGCGGGEVAA
LEKEVAALEK EVAALEKEVA ALEKGGGDKT HTCPPCPAPE AAGGPSVFLF
PPKPKDTLMI SRTPEVTCVV VDVSHEDPEV KFNWYVDGVE VHNAKTKPRE
EQYNSTYRVV SVLTVLHQDW LNGKEYKCKV SNKALPAPIE KTISKAKGQP
REPQVYTLPP SREEMTKNQV SLWCLVKGFY PSDIAVEWES NGQPENNYKT
TPPVLDSDGS FFLYSKLTVD KSRWQQGNVF SCSVMHEALH NHYTQKSLSL
SPGK
QAVVTQEPSL TVSPGGTVTL TCRSSTGAVT TSNYANWVQQ KPGQAPRGLI
GGTNKRAPWT PARFSGSLLG GKAALTITGA QAEDEADYYC ALWYSNLWVF
GGGTKLTVLG GGGSGGGGQV QLVQSGAEVK KPGASVKVSC KASGYTFTSF
WMHWVRQAPG QGLEWMGRID PNRGGTEYNE KAKSRVTMTA DKSTSTAYME
LSSLRSEDTA VYYCAGGNPY YPMDYWGQGT TVTVSSGGCG GGKVAALKEK
VAALKEKVAA LKEKVAALKE
EVQLQQSGAE LVKPGASVKL SCTASGFNIK DTYIHFVRQR PEQGLEWIGR
IDPANDNTLY ASKFQGKATI TADTSSNTAY MHLCSLTSGD TAVYYCGRGY
GYYVFDHWGQ GTTLTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY
FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI
CNVNHKPSNT KVDKRVEPKS CDKTHTCPPC PAPEAAGGPS VFLFPPKPKD
TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST
YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY
TLPPSREEMT KNQVSLSCAV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD
SDGSFFLVSK LTVDKSRWQQ GNVFSCSVMH EALHNRYTQK SLSLSPGK
DVQINQSPSF LAASPGETIT INCRTSRSIS QYLAWYQEKP GKTNKLLIYS
GSTLQSGIPS RFSGSGSGTD FTLTISGLEP EDFAMYYCQQ HNENPLTFGA
GTKLELRRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV
DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG
LSSPVTKSFN RGEC
DIQMTQSPSS LSASVGDRVT ITCRASQGIS NYLAWFQQKP GKAPKSLIYR ANRLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCLQ YDDFPWTFGQ GTKLEIKGGG SGGGGEVQLV ESGGGLVQPG GSLRLSCAAS GFTFSTYAMN WVRQAPGKGL EWVGRIRSKY NNYATYYADS VKGRFTISRD DSKNSLYLQM NSLKTEDTAV YYCVRHGNFG NSYVTWFAYW GQGTLVTVSS ASTKGEVAAC EKEVAALEKE VAALEKEVAA LEKGGGDKTH TCPPCPAPEA AGGPSVFLFP PKPKDTLMIS RTPEVTCVVV DVSHEDPEVK FNWYVDGVEV HNAKTKPREE QYNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKALPAPIEK TISKAKGQPR EPQVYTLPPS REEMTKNQVS LWCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF FLYSKLTVDK SRWQQGNVFS CSVMHEALHN HYTQKSLSLS PGK
QAVVTQEPSL TVSPGGTVTL TCRSSTGAVT TSNYANWVQQ KPGQAPRGLI
GGTNKRAPWT PARFSGSLLG GKAALTITGA QAEDEADYYC ALWYSNLWVF
GGGTKLTVLG GGGSGGGGQV QLVQSGAEVK KPGASVKVSC KASGYTFTSF
WMHWVRQAPG QGLEWMGRID PNRGGTEYNE KAKSRVTMTA DKSTSTAYME
LSSLRSEDTA VYYCAGGNPY YPMDYWGQGT TVTVSSASTK GKVAACKEKV
AALKEKVAAL KEKVAALKE
EVQLQQSGAE LVKPGASVKL SCTASGFNIK DTYIHFVRQR PEQGLEWIGR
IDPANDNTLY ASKFQGKATI TADTSSNTAY MHLCSLTSGD TAVYYCGRGY
GYYVFDHWGQ GTTLTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY
FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI
CNVNHKPSNT KVDKRVEPKS CDKTHTCPPC PAPEAAGGPS VFLFPPKPKD
TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST
YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY
TLPPSREEMT KNQVSLSCAV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD
SDGSFFLVSK LTVDKSRWQQ GNVFSCSVMH EALHNRYTQK SLSLSPGK
DVQINQSPSF LAASPGETIT INCRTSRSIS QYLAWYQEKP GKTNKLLIYS
GSTLQSGIPS RFSGSGSGTD FTLTISGLEP EDFAMYYCQQ HNENPLTFGA
GTKLELRRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV
DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG
LSSPVTKSFN RGEC
DIQMTQSPSS LSASVGDRVT ITCRASQGIS NYLAWFQQKP GKAPKSLIYR
ANRLQSGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCLQ YDDFPWTFGQ
GTKLEIKGGG SGGGGEVQLV ESGGGLVQPG GSLRLSCAAS GFTFSTYAMN
WVRQAPGKGL EWVGRIRSKY NNYATYYADS VKGRFTISRD DSKNSLYLQM
NSLKTEDTAV YYCVRHKNFG NSYVTWFAYW GQGTLVTVSS ASTKGEVAAC
EKEVAALEKE VAALEKEVAA LEKGGGDKTH TCPPCPAPEA AGGPSVFLFP
PKPKDTLMIS RTPEVTCVVV DVSHEDPEVK FNWYVDGVEV HNAKTKPREE
QYNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKALPAPIEK TISKAKGQPR
EPQVYTLPPS REEMTKNQVS LWCLVKGFYP SDIAVEWESN GQPENNYKTT
PPVLDSDGSF FLYSKLTVDK SRWQQGNVFS CSVMHEALHN HYTQKSLSLS
PGK
QAVVTQEPSL TVSPGGTVTL TCRSSTGAVT TSNYANWVQQ KPGQAPRGLI
GGTNKRAPWT PARFSGSLLG GKAALTITGA QAEDEADYYC ALWYSNLWVF
GGGTKLTVLG GGGSGGGGQV QLVQSGAEVK KPGASVKVSC KASGYTFTSF
WMHWVRQAPG QGLEWMGRID PNRGGTEYNE KAKSRVTMTA DKSTSTAYME
LSSLRSEDTA VYYCAGGNPY YPMDYWGQGT TVTVSSASTK GKVAACKEKV
AALKEKVAAL KEKVAALKE
EVQLQQSGAE LVKPGASVKL SCTASGFNIK DTYIHFVRQR PEQGLEWIGR
IDPANDNTLY ASKFQGKATI TADTSSNTAY MHLCSLTSGD TAVYYCGRGY
GYYVFDHWGQ GTTLTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY
FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI
CNVNHKPSNT KVDKRVEPKS CDKTHTCPPC PAPEAAGGPS VFLFPPKPKD
TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST
YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY
TLPPSREEMT KNQVSLSCAV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD
SDGSFFLVSK LTVDKSRWQQ GNVFSCSVMH EALHNRYTQK SLSLSPGK
DVQINQSPSF LAASPGETIT INCRTSRSIS QYLAWYQEKP GKTNKLLIYS
GSTLQSGIPS RFSGSGSGTD FTLTISGLEP EDFAMYYCQQ HNENPLTFGA
GTKLELRRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV
DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG
LSSPVTKSFN RGEC
要約すると、それぞれ2つのダイアボディタイプ結合ドメイン(部位A及び部位B)並びにFabタイプ結合ドメイン(部位C)を有する、一連の14個の三重特異性結合分子が構成された(表25)。
配列番号1:リンカー1
配列番号2:システイン含有ドメイン(「リンカー2」)
配列番号3:Eコイルヘテロ二量体促進ドメイン
配列番号4:Kコイルヘテロ二量体促進ドメイン
配列番号5:システイン含有リンカーペプチド(「リンカー3」)
配列番号6:ヒト野生型IgG CH2‐CH3ドメイン
配列番号7:「ノブ担持」CH2‐CH3ドメイン
配列番号8:「ホール担持」IgG CH2‐CH3ドメイン
配列番号9:ヒトIgG1 CH1ドメイン
配列番号10:ヒトIgG1ヒンジドメイン
配列番号11:ヒトCLドメインのシステイン含有部分
配列番号12:ヒトIgGヒンジドメインのシステイン含有部分
配列番号13:ヒトIgG1 CLカッパドメイン
配列番号14:ヒトIgG1 CLラムダ2ドメイン
配列番号15:ペプチドリンカー
配列番号16:ペプチドリンカー
配列番号17:OKT3抗CD3抗体の軽鎖可変ドメイン
配列番号18:OKT3抗CD3抗体の重鎖可変ドメイン
配列番号19:M291抗CD3抗体の軽鎖可変ドメイン
配列番号20:M291抗CD3抗体の重鎖可変ドメイン
配列番号21:YTH12.5抗CD3抗体の軽鎖可変ドメイン
配列番号22:YTH12.5抗CD3抗体の重鎖可変ドメイン
配列番号23:ヒト化抗CD3「mAb 1」の軽鎖可変ドメイン変異体1
配列番号24:ヒト化抗CD3「mAb 1」の軽鎖可変ドメイン変異体2
配列番号25:ヒト化抗CD3「mAb 1」の重鎖可変ドメイン
配列番号26:ヒト化抗CD3「mAb 2」の軽鎖可変ドメイン
配列番号27:ヒト化抗CD3「mAb 2」の重鎖可変ドメイン
配列番号28:ヒト化抗CD3「mAb 2」の重鎖可変ドメインD65G変異体
配列番号29:OKT8抗CD8抗体の軽鎖可変ドメイン
配列番号30:OKT8抗CD8抗体の重鎖可変ドメイン
配列番号31:TRX2抗CD8抗体の軽鎖可変ドメイン
配列番号32:TRX2抗CD8抗体の重鎖可変ドメイン
配列番号33:A32抗HIV gp120抗体の軽鎖可変ドメイン
配列番号34:A32抗HIV gp120抗体の重鎖可変ドメイン
配列番号35:7B2抗HIV gp41抗体の軽鎖可変ドメイン
配列番号36:7B2抗HIV gp41抗体の重鎖可変ドメイン
配列番号37:パリビズマブ抗RSV糖タンパク質F抗体の軽鎖可変ドメイン
配列番号38:パリビズマブ抗RSV糖タンパク質F抗体の重鎖可変ドメイン
配列番号39:「BRCA84D‐5VL」ヒト化抗B7‐H3抗体の軽鎖可変ドメイン
配列番号40:「BRCA84D‐2VH」ヒト化抗B7‐H3抗体の重鎖可変ドメイン
配列番号41:「BRCA69D」ヒト化抗B7‐H3抗体の軽鎖可変ドメイン
配列番号42:「BRCA69D」ヒト化抗B7‐H3抗体の重鎖可変ドメイン
配列番号43:「PRCA157」ヒト化抗B7‐H3抗体の軽鎖可変ドメイン
配列番号44:「PRCA157」ヒト化抗B7‐H3抗体の重鎖可変ドメイン
配列番号45:ヒト化抗A33抗体の軽鎖可変ドメイン
配列番号46:ヒト化抗A33抗体の重鎖可変ドメイン
配列番号47:ヒト化抗5T4抗体「mAb 1」の軽鎖可変ドメイン
配列番号48:ヒト化抗5T4抗体「mAb 1」の重鎖可変ドメイン
配列番号49:ヒト化抗5T4抗体「mAb 2」の軽鎖可変ドメイン
配列番号50:ヒト化抗5T4抗体「mAb 2」の重鎖可変ドメイン
配列番号51:ヒト化抗ROR1 mAb 1抗体の軽鎖可変ドメイン
配列番号52:ヒト化抗ROR1 mAb 1抗体の重鎖可変ドメイン
配列番号53:2A2抗ROR1抗体の軽鎖可変ドメイン
配列番号54:2A2抗ROR1抗体の重鎖可変ドメイン
配列番号55:R11抗ROR1抗体の軽鎖可変ドメイン
配列番号56:R11抗ROR1抗体の重鎖可変ドメイン
配列番号57:R12抗ROR1抗体の軽鎖可変ドメイン
配列番号58:R12抗ROR1抗体の重鎖可変ドメイン
配列番号59:例示的なB7‐H3 mAb 1/CD3 mAb 2/CD8 mAb 1三重特異性結合分子の第1のポリペプチド鎖(VL(B7‐H3 mAb 1)‐VH(CD3 mAb 2)‐Eコイル‐(CH2‐CH3))
配列番号60:例示的なB7‐H3 mAb 1/CD3 mAb 2/CD8 mAb 1三重特異性結合分子の第2のポリペプチド鎖(VL(CD3 mAb 2)‐VH(B7‐H3 mAb 1)‐Kコイル)
配列番号61:例示的なB7‐H3 mAb 1/CD3 mAb 2/CD8 mAb 1三重特異性結合分子の第3のポリペプチド鎖(CD8 mAb 1重鎖)
配列番号62:例示的なB7‐H3 mAb 1/CD3 mAb 2/CD8 mAb 1三重特異性結合分子の第4のポリペプチド鎖(CD8 mAb 1軽鎖)
配列番号63:例示的なB7‐H3 mAb 1/CD3 mAb 2/CD8 mAb 2三重特異性結合分子の第1のポリペプチド鎖(VL(B7‐H3 mAb 1)‐VH(CD3 mAb 2)‐Eコイル‐(CH2‐CH3))
配列番号64:例示的なB7‐H3 mAb 1/CD3 mAb 2/CD8 mAb 2三重特異性結合分子の第2のポリペプチド鎖(VL(CD3 mAb 2)‐VH(B7‐H3 mAb 1)‐Kコイル)
配列番号65:例示的なB7‐H3 mAb 1/CD3 mAb 2/CD8 mAb 2三重特異性結合分子の第3のポリペプチド鎖(CD8 mAb 2重鎖)
配列番号66:例示的なB7‐H3 mAb 1/CD3 mAb 2/CD8 mAb 2三重特異性結合分子の第4のポリペプチド鎖(CD8 mAb 2軽鎖)
配列番号67:例示的なCD3 mAb 2/CD8 mAb 1/B7‐H3 mAb 1三重特異性結合分子の第1のポリペプチド鎖(VL(CD3 mAb 2)‐VH(CD8 mAb 1)‐Eコイル‐(CH2‐CH3))
配列番号68:例示的なCD3 mAb 2/CD8 mAb 1/B7‐H3 mAb 1三重特異性結合分子の第2のポリペプチド鎖(VL(CD8 mAb 1)‐VH(CD3 mAb 1)‐Kコイル)
配列番号69:例示的なCD3 mAb 2/CD8 mAb 1/B7‐H3 mAb 1三重特異性結合分子の第3のポリペプチド鎖(B7‐H3 mAb 1重鎖)
配列番号70:例示的なCD3 mAb 2/CD8 mAb 1/B7‐H3 mAb 1三重特異性結合分子の第3のポリペプチド鎖(B7‐H3 mAb 1軽鎖)
配列番号71:例示的なB7‐H3 mAb 1/CD8 mAb 1/CD3 mAb 2三重特異性結合分子の第1のポリペプチド鎖(VL(B7‐H3 mAb 1)‐VH(CD8 mAb 1)‐Eコイル‐(CH2‐CH3))
配列番号72:例示的なB7‐H3 mAb 1/CD8 mAb 1/CD3 mAb 2三重特異性結合分子の第2のポリペプチド鎖(VL(CD8 mAb 1)‐VH(B7‐H3 mAb 1)‐Kコイル)
配列番号73:例示的なB7‐H3 mAb 1/CD8 mAb 1/CD3 mAb 2三重特異性結合分子の第3のポリペプチド鎖(CD3 mAb 2重鎖)
配列番号74:例示的なB7‐H3 mAb 1/CD8 mAb 1/CD3 mAb 2三重特異性結合分子の第4のポリペプチド鎖(CD3 mAb 2軽鎖)
配列番号75:例示的な5T4 mAb 2/CD3 mAb 2/CD8 mAb 1三重特異性結合分子の第1のポリペプチド鎖(VL(5T4 mAb 2)‐VH(CD3 mAb 2)‐Eコイル‐(CH2‐CH3))
配列番号76:例示的な5T4 mAb 2/CD3 mAb 2/CD8 mAb 1三重特異性結合分子の第2のポリペプチド鎖(VL(CD3 mAb 2)‐VH(5T4 mAb 2)‐Kコイル)
配列番号77:例示的な5T4 mAb 2/CD3 mAb 2/CD8 mAb 1三重特異性結合分子の第3のポリペプチド鎖(CD8 mAb 1重鎖)
配列番号78:例示的な5T4 mAb 2/CD3 mAb 2/CD8 mAb 1三重特異性結合分子の第4のポリペプチド鎖(CD8 mAb 1軽鎖)
配列番号79:例示的な5T4 mAb 2/CD3 mAb 2/CD8 mAb 2三重特異性結合分子の第1のポリペプチド鎖(VL(5T4 mAb 2)‐VH(CD3 mAb 2)‐Eコイル‐(CH2‐CH3))
配列番号80:例示的な5T4 mAb 2/CD3 mAb 2/CD8 mAb 2三重特異性結合分子の第2のポリペプチド鎖(VL(CD3 mAb 2)‐VH(5T4 mAb 2)‐Kコイル)
配列番号81:例示的な5T4 mAb 2/CD3 mAb 2/CD8 mAb 2三重特異性結合分子の第3のポリペプチド鎖(CD8 mAb 2重鎖)
配列番号82:例示的な5T4 mAb 2/CD3 mAb 2/CD8 mAb 2三重特異性結合分子の第4のポリペプチド鎖(CD8 mAb 2軽鎖)
配列番号83:例示的なROR1 mAb 1/CD3 mAb 2/CD8 mAb 1三重特異性結合分子の第1のポリペプチド鎖(VL(ROR1 mAb 1)‐VH(CD3 mAb 2)‐Eコイル‐(CH2‐CH3))
配列番号84:例示的なROR1 mAb 1/CD3 mAb 2/CD8 mAb 1三重特異性結合分子の第2のポリペプチド鎖(VL(CD3 mAb 2)‐VH(ROR1 mAb 1)‐Kコイル)
配列番号85:例示的なROR1 mAb 1/CD3 mAb 2/CD8 mAb 1三重特異性結合分子の第3のポリペプチド鎖(CD8 mAb 1重鎖)
配列番号86:例示的なROR1 mAb 1/CD3 mAb 2/CD8 mAb 1三重特異性結合分子の第4のポリペプチド鎖(CD8 mAb 1軽鎖)
配列番号87:例示的なROR1 mAb 1/CD3 mAb 2/CD8 mAb 2三重特異性結合分子の第1のポリペプチド鎖(VL(ROR1 mAb 1)‐VH(CD3 mAb 2)‐Eコイル‐(CH2‐CH3))
配列番号88:例示的なROR1 mAb 1/CD3 mAb 2/CD8 mAb 2三重特異性結合分子の第2のポリペプチド鎖(VL(CD3 mAb 2)‐VH(ROR1 mAb 1)‐Kコイル)
配列番号89:例示的なROR1 mAb 1/CD3 mAb 2/CD8 mAb 2三重特異性結合分子の第3のポリペプチド鎖(CD8 mAb 2重鎖)
配列番号90:例示的なROR1 mAb 1/CD3 mAb 2/CD8 mAb 2三重特異性結合分子の第4のポリペプチド鎖(CD8 mAb 2軽鎖)
配列番号91:例示的なHIV mAb 1/CD3 mAb 2/CD8 mAb 1三重特異性結合分子の第1のポリペプチド鎖(VL(HIV mAb 1)‐VH(CD3 mAb 2)‐Eコイル‐(CH2‐CH3))
配列番号92:例示的なHIV mAb 1/CD3 mAb 2/CD8 mAb 1三重特異性結合分子の第2のポリペプチド鎖(VL(CD3 mAb 2)‐VH(HIV mAb 1)‐Kコイル)
配列番号93:例示的なHIV mAb 1/CD3 mAb 2/CD8 mAb 1三重特異性結合分子の第3のポリペプチド鎖(CD8 mAb 1重鎖)
配列番号94:例示的なHIV mAb 1/CD3 mAb 2/CD8 mAb 1三重特異性結合分子の第4のポリペプチド鎖(CD8 mAb 1軽鎖)
配列番号95:例示的なHIV mAb 2/CD3 mAb 2/CD8 mAb 1三重特異性結合分子の第1のポリペプチド鎖(VL(HIV mAb 2)‐VH(CD3 mAb 2)‐Eコイル‐(CH2‐CH3))
配列番号96:例示的なHIV mAb 2/CD3 mAb 2/CD8 mAb 1三重特異性結合分子の第2のポリペプチド鎖(VL(CD3 mAb 2)‐VH(HIV mAb 2)‐Kコイル)
配列番号97:例示的なHIV mAb 2/CD3 mAb 2/CD8 mAb 1三重特異性結合分子の第3のポリペプチド鎖(CD8 mAb 1重鎖)
配列番号98:例示的なHIV mAb 2/CD3 mAb 2/CD8 mAb 1三重特異性結合分子の第4のポリペプチド鎖(CD8 mAb 1軽鎖)
配列番号99:抗ヒトCD3 mAb 2 Lowの可変軽鎖ドメイン
配列番号100:抗ヒトCD3 mAb 2 Lowの可変重鎖ドメイン
配列番号101:抗ヒトCD3 mAb 2 Fastの可変軽鎖ドメイン
配列番号102:抗ヒトCD3 mAb 2 Fastの可変重鎖ドメイン
配列番号103:例示的な5T4 mAb 1/CD3 mAb 2/CD8 mAb 1三重特異性結合分子の第1のポリペプチド鎖(VL(5T4 mAb 1)‐VH(CD3 mAb 2)‐Eコイル‐(CH2‐CH3))
配列番号104:例示的な5T4 mAb 1/CD3 mAb 2/CD8 mAb 1三重特異性結合分子の第2のポリペプチド鎖(VL(CD3 mAb 2)‐VH(5T4 mAb 1)‐Kコイル)
配列番号105:例示的な5T4 mAb 1/CD3 mAb 2/CD8 mAb 1三重特異性結合分子の第3のポリペプチド鎖(CD8 mAb 1重鎖)
配列番号106:例示的な5T4 mAb 1/CD3 mAb 2/CD8 mAb 1三重特異性結合分子の第4のポリペプチド鎖(CD8 mAb 1軽鎖)
配列番号107:例示的な5T4 mAb 1/CD3 mAb 2 Low/CD8 mAb 1三重特異性結合分子の第1のポリペプチド鎖(VL(5T4 mAb 1)‐VH(CD3 mAb 2 Low)‐Eコイル‐(CH2‐CH3))
配列番号108:例示的な5T4 mAb 1/CD3 mAb 2 Low/CD8 mAb 1三重特異性結合分子の第2のポリペプチド鎖(VL(CD3 mAb 2 Low)‐VH(5T4 mAb 1)‐Kコイル)
配列番号109:例示的な5T4 mAb 1/CD3 mAb 2 Low/CD8 mAb 1三重特異性結合分子の第3のポリペプチド鎖(CD8 mAb 1重鎖)
配列番号110:例示的な5T4 mAb 1/CD3 mAb 2 Low/CD8 mAb 1三重特異性結合分子の第4のポリペプチド鎖(CD8 mAb 1軽鎖)
配列番号111:例示的な5T4 mAb 1/CD3 mAb 2 Fast/CD8 mAb 1三重特異性結合分子の第1のポリペプチド鎖(VL(5T4 mAb 1)‐VH(CD3 mAb 2 Fast)‐Eコイル‐(CH2‐CH3))
配列番号112:例示的な5T4 mAb 1/CD3 mAb 2 Fast/CD8 mAb 1三重特異性結合分子の第2のポリペプチド鎖(VL(CD3 mAb 2 Fast)‐VH(5T4 mAb 1)‐Kコイル)
配列番号113:例示的な5T4 mAb 1/CD3 mAb 2 Fast/CD8 mAb 1三重特異性結合分子の第3のポリペプチド鎖(CD8 mAb 1重鎖)
配列番号114:例示的な5T4 mAb 1/CD3 mAb 2 Fast/CD8 mAb 1三重特異性結合分子の第4のポリペプチド鎖(CD8 mAb 1軽鎖)
配列番号115:システイン含有Eコイルヘテロ二量体促進ドメイン
配列番号116:システイン含有Kコイルヘテロ二量体促進ドメイン
配列番号117:抗ROR1 mAb 1の軽鎖可変ドメインのCDRL1
配列番号118:抗ROR1 mAb 1の軽鎖可変ドメインのCDRL2
配列番号119:抗ROR1 mAb 1の軽鎖可変ドメインのCDRL3
配列番号120:抗ROR1 mAb 1の重鎖可変ドメインのCDRH1
配列番号121:抗ROR1 mAb 1の重鎖可変ドメインのCDRH2
配列番号122:抗ROR1 mAb 1の重鎖可変ドメインのCDRH3
配列番号123:連鎖球菌株G148のタンパク質Gのアルブミン結合ドメイン3(ABD3)
配列番号124:連鎖球菌株G148のタンパク質Gのアルブミン結合ドメイン3(ABD3)の脱免疫化変異体
配列番号125:連鎖球菌株G148のタンパク質Gのアルブミン結合ドメイン3(ABD3)の脱免疫化変異体
配列番号126:ペプチドリンカー
配列番号127:システイン含有ドメイン
配列番号128:ヒトCLドメインのシステイン含有変異体部分
配列番号129:代替的なシステイン含有リンカーペプチド(「リンカー3」)
配列番号130:代替的なシステイン含有リンカーペプチド(「リンカー3」)
配列番号131:ペプチドリンカー
配列番号132:ペプチドリンカー
配列番号133:ヒトIgGヒンジドメインのシステイン含有部分の変異体
Claims (23)
- 3つの異なるエピトープに免疫特異的に結合できる三重特異性結合分子であって、
前記結合分子は、一体として共有結合的に複合体化した4つの異なるポリペプチド鎖を備え、また:
(I)第1の抗原上に存在するエピトープIに免疫特異的に結合できる抗原‐結合ドメインI、及び第2の抗原上に存在するエピトープIIに免疫特異的に結合できる抗原‐結合ドメインII(ここで前記抗原‐結合ドメインI及び前記抗原‐結合ドメインIIはいずれもダイアボディタイプ結合ドメインである);
(II)第3の抗原上に存在するエピトープIIIに免疫特異的に結合できる、非ダイアボディタイプ抗原‐結合ドメインIII;並びに
(III)2つのCH2‐CH3ドメインが互いに連結することによって形成される、Fcドメイン
を備え、
前記第1の抗原、前記第2の抗原及び前記第3の抗原は同一の抗原であるか、又は独立して、前記抗原のうちの別のものと同一の若しくは異なるものである、三重特異性結合分子。 - 前記エピトープI、前記エピトープII又は前記エピトープIIIのうちの1つが細胞受容体のエピトープである、請求項1に記載の三重特異性結合分子。
- 前記エピトープI、前記エピトープII又は前記エピトープIIIのうちの1つが疾患関連抗原のエピトープである、請求項1又は2に記載の三重特異性結合分子。
- 前記疾患関連抗原が、癌細胞の表面上に配列された癌抗原である、請求項3に記載の三重特異性結合分子。
- 前記疾患関連抗原が、病原又は病原体感染細胞の表面上に配列された病原抗原である、請求項3に記載の三重特異性結合分子。
- 前記Fcドメインが、細胞の表面上に配列されたFc受容体に結合できる、請求項1〜5のいずれか1項に記載の三重特異性結合分子。
- 前記エピトープI、前記エピトープII又は前記エピトープIIIのうちの1つがCD3のエピトープであり、
前記エピトープI、前記エピトープII又は前記エピトープIIIのうちの第2のものがCD8のエピトープであり、
前記エピトープI、前記エピトープII又は前記エピトープIIIのうちの第3のものが疾患関連抗原のエピトープであり、
前記三重特異性結合分子の抗原‐結合ドメインI、II及びIIIが、細胞毒性T細胞と、疾患関連抗原を発現する細胞との協調的な結合を仲介する、請求項3〜6のいずれか1項に記載の三重特異性結合分子。 - 前記CD3、前記CD8がT細胞の表面上に配列され、
前記疾患関連抗原が癌細胞、病原又は病原体感染細胞の表面上に配列され、
前記免疫特異性結合が、前記CD3及び前記CD8並びに前記疾患関連抗原を共局在化することによって、前記疾患関連抗原配列細胞に対する前記CD8配列T細胞の活性化を促進するために十分なものである、請求項7に記載の三重特異性結合分子。 - 前記非ダイアボディタイプ結合ドメインIIIが、前記エピトープIIIに免疫特異的に結合できるFabタイプ結合ドメイン(VLIII/VHIII)を備え、
前記分子が:
(A)第1のポリペプチド鎖であって:
(I)N末端からC末端への方向に:
(1)前記3つのエピトープのうちの第1のものに結合できる免疫グロブリンの軽鎖可変ドメイン(VLI);
(2)前記3つのエピトープのうちの第2のものに結合できる免疫グロブリンの重鎖可変ドメイン(VHII);
(3)(a)第1のシステイン含有ドメイン;及びヘテロ二量体促進ドメイン;若しくは
(b)システイン含有ヘテロ二量体促進ドメイン;
(4)第2のシステイン含有ドメイン;並びに
(5)IgGのCH2及びCH3ドメイン
を備えるか、又は
(II)N末端からC末端への方向に:
(1)第1のシステイン含有ドメイン;
(2)IgGのCH2及びCH3ドメイン;
(3)前記3つのエピトープのうちの第1のものに結合できる免疫グロブリンの軽鎖可変ドメイン(VLI);
(4)前記3つのエピトープのうちの第2のものに結合できる免疫グロブリンの重鎖可変ドメイン(VHII);並びに
(5)(a)第2のシステイン含有ドメイン;及びヘテロ二量体促進ドメイン;若しくは
(b)システイン含有ヘテロ二量体促進ドメイン
を備える、第1のポリペプチド鎖;
(B)第2のポリペプチド鎖であって、N末端からC末端への方向に:
(1)前記3つのエピトープのうちの前記第2のものに結合できる免疫グロブリンの軽鎖可変ドメイン(VLII);
(2)前記3つのエピトープのうちの前記第1のものに結合できる免疫グロブリンの重鎖可変ドメイン重鎖可変ドメイン(VHI);並びに
(3)(a)第1のシステイン含有ドメイン;及びヘテロ二量体促進ドメイン;若しくは
(b)システイン含有ヘテロ二量体促進ドメイン;
を備え、前記第2のポリペプチド鎖のヘテロ二量体促進ドメインは、前記第1のポリペプチド鎖ヘテロ二量体促進ドメインに対して相補的である、第2のポリペプチド鎖;
(C)第3のポリペプチド鎖であって、N末端からC末端への方向に:
(1)前記3つのエピトープのうちの第3のものに結合できる免疫グロブリンの重鎖可変ドメイン(VHIII);並びに
(2)IgGのCH1ドメイン、システイン含有ヒンジドメイン、及びCH2‐CH3ドメイン
を備える、第3のポリペプチド鎖;並びに
(D)第4のポリペプチド鎖であって、N末端からC末端への方向に:
(1)前記3つのエピトープのうちの前記第3のものに結合できる免疫グロブリンの軽鎖可変ドメイン(VLIII);及び
(2)システイン含有軽鎖定常ドメイン(CL);
を備える、第4のポリペプチド鎖
を備え、
(i)前記VLIドメイン及び前記VHIドメインは連結して、前記エピトープIに結合できるドメインを形成し;
(ii)前記VLIIドメイン及び前記VHIIドメインは連結して、前記エピトープIIに結合できるドメインを形成し;
(iii)前記VLIIIドメイン及び前記VHIIIドメインは連結して、前記エピトープIIIに結合できるドメインを形成し;
(iv)前記第1のポリペプチド鎖の前記CH2‐CH3ドメイン及び前記第3のポリペプチド鎖の前記CH2‐CH3ドメインは連結して、Fcドメインを形成し;
(v)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、互いに対して共有結合し;
(vi)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、互いに対して共有結合し;
(vii)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、互いに対して共有結合する、請求項1〜8のいずれか1項に記載の三重特異性結合分子。 - (A)前記ヘテロ二量体促進ドメインがEコイルであり、前記相補的なヘテロ二量体促進ドメインがKコイルである;又は
(B)前記ヘテロ二量体促進ドメインがKコイルであり、前記相補的なヘテロ二量体促進ドメインがEコイルである、請求項9に記載の三重特異性結合分子。 - (A)前記第1のポリペプチド鎖及び前記第3のポリペプチド鎖の前記CH2‐CH3ドメインがそれぞれ、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連結によって形成される前記Fcドメインが正常なFcγR仲介性エフェクタ機能を呈するように、配列番号6の配列を有し;又は
(B)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ドメインがそれぞれ、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連結によって形成される前記Fcドメインが変化したFcγR仲介性エフェクタ機能を呈するように、配列番号6の配列に対して少なくとも1つのアミノ酸置換を有する、請求項9又は10に記載の三重特異性結合分子。 - 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ドメインが互いに異なっており、かつ配列番号7及び配列番号8からなる群から選択されたアミノ酸配列を有する、請求項9〜11のいずれか1項に記載の三重特異性結合分子。
- (A)前記エピトープI、前記エピトープII及び前記エピトープIIIはそれぞれ、CD3のエピトープ、CD8のエピトープ及び前記疾患関連抗原のエピトープであり;
(B)前記エピトープI、前記エピトープII及び前記エピトープIIIはそれぞれ、CD3のエピトープ、前記疾患関連抗原のエピトープ及びCD8のエピトープであり;
(C)前記エピトープI、前記エピトープII及び前記エピトープIIIはそれぞれ、CD8のエピトープ、CD3のエピトープ及び前記疾患関連抗原のエピトープであり;
(D)前記エピトープI、前記エピトープII及び前記エピトープIIIはそれぞれ、CD8のエピトープ、前記疾患関連抗原のエピトープ及びCD3のエピトープであり;
(E)前記エピトープI、前記エピトープII及び前記エピトープIIIはそれぞれ、前記疾患関連抗原のエピトープ、CD3のエピトープ及びCD8のエピトープであり;又は
(F)前記エピトープI、前記エピトープII及び前記エピトープIIIはそれぞれ、前記疾患関連抗原のエピトープ、CD8のエピトープ及びCD3のエピトープである、請求項9〜12のいずれか1項に記載の三重特異性結合分子。 - (A)CD3の前記エピトープは、抗体OKT3、M291、YTH12.5、CD3mAb1若しくはCD3mAb2によって認識されるCD3エピトープであり;又は
(B)CD8の前記エピトープは、抗体TRX2若しくはOKT8によって認識されるCD8エピトープである、請求項7〜13のいずれか1項に記載の三重特異性結合分子。 - 請求項7〜14のいずれか1項に記載の三重特異性結合分子と、薬学的に許容可能なキャリア、賦形剤又は希釈剤とを含む、医薬組成物。
- 請求項15に記載の有効量の医薬組成物を、前記医薬組成物を必要とする個体に投与するステップを含む、癌を治療する方法であって、
前記疾患関連抗原は癌抗原である、方法。 - 請求項15に記載の有効量の医薬組成物を、前記医薬組成物を必要とする個体に投与するステップを含む、病原体の存在に関連する疾患を治療する方法であって、
前記疾患関連抗原は病原体抗原である、方法。 - 抗ROR1抗体又はROR1結合性断片であって、
前記抗体は:
(A)配列番号117の配列を有するCDRL1、配列番号118の配列を有するCDRL2、及び配列番号119の配列を有するCDRL3を備える、軽鎖可変ドメイン;並びに
(B)配列番号120の配列を有するCDRH1、配列番号121の配列を有するCDRH2、及び配列番号122の配列を有するCDRH3を備える、重鎖可変ドメイン
を備える、抗ROR1抗体又はROR1結合性断片。 - 前記抗体が、配列番号51の配列を有する軽鎖可変ドメインを有する、請求項18に記載の抗ROR1抗体又はROR1結合性断片。
- 前記抗体が、配列番号52の配列を有する重鎖可変ドメインを有する、請求項18又は19に記載の抗ROR1抗体又はROR1結合性断片。
- 請求項18〜20のいずれか1項に記載のROR1結合性断片を含む、ダイアボディ、BiTe又は単鎖抗体。
- 請求項19〜21のいずれか1項に記載の抗ROR1抗体又はそのROR1結合性断片と、薬学的に許容可能なキャリア、賦形剤又は希釈剤とを含む、医薬組成物。
- 請求項22に記載の有効量の医薬組成物を、前記医薬組成物を必要とする個体に投与するステップを含む、癌を治療する方法。
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