JP2021006531A - Bridge linkers for conjugation of cell-binding molecule - Google Patents
Bridge linkers for conjugation of cell-binding molecule Download PDFInfo
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- JP2021006531A JP2021006531A JP2020146662A JP2020146662A JP2021006531A JP 2021006531 A JP2021006531 A JP 2021006531A JP 2020146662 A JP2020146662 A JP 2020146662A JP 2020146662 A JP2020146662 A JP 2020146662A JP 2021006531 A JP2021006531 A JP 2021006531A
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Abstract
Description
本発明は、細胞結合分子上の一対のチオールの架橋連結による、化合物、特に細胞毒性剤と細胞結合分子との特異的共役に使用する新規な連結体の調製に関する。本発明はまた、先にこれらの連結体にて薬物分子を修飾し、そして細胞結合分子と反応させるか、あるいは先にこれらの連結体にて細胞結合分子を修飾し、そして薬物分子と反応させることを含む、特異的様式により、細胞結合分子−薬物分子(細胞毒性剤)共役体を調製する方法にも関する。 The present invention relates to the preparation of novel conjugates used for specific conjugation of compounds, especially cytotoxic agents and cell binding molecules, by cross-linking a pair of thiols on the cell binding molecule. The invention also first modifies the drug molecule with these conjugates and reacts with the cell binding molecule, or first modifies the cell binding molecule with these conjugates and reacts with the drug molecule. It also relates to a method of preparing a cell junction molecule-drug molecule (cytotoxic agent) conjugate in a specific manner, including the above.
伝統的な化学療法は、しばしば患者に対する全身毒性を伴っている。癌細胞の識別抗原を介した、代替的な腫瘍選択的治療アプローチを提供することができるモノクローナル抗体は、通常、単独で治療活性に十分に効果的ではない。抗体−薬物共役体(ADC)は、その名前より、抗癌剤の細胞毒性作用と組み合わた抗体の優れた標的能力を有し、正常細胞から離れて主に影響を受けず、癌細胞を標的として薬物を送達して標的化することを可能にし、よって、化学療法剤の治療指標を改善する。米国FDAによる、2011年の「Adcetris」(ブレンツキシマブ ベドチン)及び2013年の「Kadcyla」(アド−トランスツズマブ エムタンシン)の承認以来、有望な癌の標的治療として、抗体−薬物共役体(ADC)の応用が急増し、ほとんどの大手製薬会社及びバイオテクノロジー社は、このアプローチを採用している(Chari, R. et al, Angew. Chem., Int. Ed. 2014, 53, 3796-3827; Sievers, E. L. et al. Annu Rev Med. 2013, 64, 15-29; Mehrling, T. Future Oncol, 2015, 11, 549)。抗体−薬物共役体は現在、製薬会社の間で豊富な商品供給ラインを備え、商談が吹き荒れている薬剤種である。www.clinictrails.gov
によると、現在、臨床試験中のADC薬剤が50以上のADCが現在、臨床試験の様々
な段階にあり、また、前臨床前段階では更に多くあり、及び/又は世界初のヒトでのトライアルに入る用意ができており、市場は更に多くのADC薬剤が規制当局によって承認されることを望む希望に満ち溢れている。
Traditional chemotherapy is often associated with systemic toxicity to the patient. Monoclonal antibodies that can provide alternative tumor-selective therapeutic approaches via cancer cell discriminating antigens are usually not sufficiently effective in therapeutic activity on their own. Antibody-drug conjugates (ADCs), by their name, have excellent targeting capabilities for antibodies combined with the cytotoxic effects of anticancer drugs, are largely unaffected apart from normal cells, and target cancer cells. Allows delivery and targeting, thus improving the therapeutic index of chemotherapeutic agents. Since the approval of "Adcetris" (brentuximab vedotin) in 2011 and "Kadcyla" (ad-transtuzumab emtansine) in 2013 by the US FDA, antibody-drug conjugate (ADC) has been a promising targeted treatment for cancer. With the proliferation of applications, most major pharmaceutical and biotechnology companies are adopting this approach (Chari, R. et al, Angew. Chem., Int. Ed. 2014, 53, 3796-3827; Sievers, EL et al. Annu Rev Med. 2013, 64, 15-29; Mehrling, T. Future Oncol, 2015, 11, 549). Antibody-drug conjugates are currently a drug species that has abundant product supply lines among pharmaceutical companies and is in a state of turmoil. www.clinictrails.gov
According to the report, more than 50 ADCs currently in clinical trials are currently in various stages of clinical trials, and even more in preclinical stages, and / or in the world's first human trial. Ready to enter, the market is full of hope that more ADC drugs will be approved by regulators.
「Kadcyla」及び「Adcetris」を含む第一世代のADCは、抗体上の天然リジンのアミノ基又はシステインの内部鎖のチオール基と細胞毒性剤との非選択的共役によって生成される。IgG1抗体には、表面に露出した50個のリシン残基と8個のヒンジのシステイン残基があるため、この非選択的共役は、結果として抗体分子の実質的に全ての領域において任意に、細胞毒性剤と架橋連結することにより、抗体1個あたりの薬物分布(DAR)が広いADCの多様な個体群が形成される。(Wang, L., et al. 2005 Protein Sci. 14, 2436; Hamblett, K. J., et al. 2004 Clin. Cancer Res. 10, 7063)。従って、いくつかの望ましくないADCの亜個体群は、短い循環半減期、低い有効性、潜在的なオフターゲット毒性の増加、及び生体内での薬物動態の広範化に至るだろう(Hamblett, K. J. et al, Clin. Cancer Res. 2004, 10, 7063-7070; Adem, Y. T. et al, Bioconjugate Chem. 2014, 25, 656-664; Boylan, N. J. Bioconjugate Chem., 2013, 24, 1008-1016; Strop, P., et al 2013 Chem. Biol. 20, 161-167)。それに加えて、この古典的な共役は、ADCの生産におけるバッチ間の一貫性を保つのが困難であり、勤勉な製造能力が必要になる場合がある(Wakankar、mAb、2011、3、161-172)。 First-generation ADCs, including "Kadcyla" and "Adcetris," are produced by non-selective conjugation of the amino group of native lysine on the antibody or the thiol group of the internal chain of cysteine with a cytotoxic agent. Since the IgG1 antibody has 50 surface-exposed lysine residues and 8 hinged cysteine residues, this non-selective conjugation results in optionally in virtually all regions of the antibody molecule. By cross-linking with a cytotoxic agent, a diverse population of ADCs with a wide drug distribution (DAR) per antibody is formed. (Wang, L., et al. 2005 Protein Sci. 14, 2436; Hamblett, K. J., et al. 2004 Clin. Cancer Res. 10, 7063). Therefore, some unwanted ADC subpopulations will lead to short circulating half-lives, low efficacy, increased potential off-target toxicity, and widespread in vivo pharmacokinetics (Hamblett, KJ). et al, Clin. Cancer Res. 2004, 10, 7063-7070; Adem, YT et al, Bioconjugate Chem. 2014, 25, 656-664; Boylan, NJ Bioconjugate Chem., 2013, 24, 1008-1016; Strop, P., et al 2013 Chem. Biol. 20, 161-167). In addition, this classical conjugate is difficult to maintain consistency between batches in ADC production and may require diligent manufacturing capacity (Wakankar, mAb, 2011, 3, 161- 172).
従って、バイオテクノロジー企業や学術機関は、部位特異的ADC共役のための新しい信頼性の高い方法を確立することに強い焦点を当てている。これまでのところ、近年開発された、部位選択的ADCの調製のためのいくつかのアプローチがある(Panowski、S、2014、mab 6、34)。それらには、不対システイン、例えば、ジェネンテックからのTHIOMABと呼ばれる設計された反応性システイン残基の導入(Junutula, J. R., et al 2
010 Clin. Cancer Res. 16, 4769; Junutula, J. R., et al 2008 Nat Biotechnol. 26, 925-32; 米国特許8,309,300; 7,855,275; 7,521,541; 7,723,485, WO2008/141044)、ス
トレプトバーチシリウム・モバラエンストランスグルタミナーゼ(mTG)(Strop, P.,
Bioconjugate Chem., 2014, 25, 855-862; Strop, P., et al., 2013, Chem. Biol. 20,
161-167; 米国特許8871908 Rinat-Pfizer)又は微生物トランスグルタミナーゼ(MTGase)(Dennler, P., et al, 2014, Bioconjug. Chem. 25, 569-578;米国出願20130189287, Innate Pharma; 米国特許7,893,019, Bio-Ker S.r.l.(IT))により遺伝的に導
入されたグルタミンタグ、チオールフコースの導入(Dennler, P., et al, 2014 Bioconjugate Chemistry 25, 569; Okeley, N. M., et al 2013 Bioconjugate Chem. 24, 1650)、変異誘発による非天然アミノ酸の導入(Axup, J.Y., et al., 2012, Proc. Natl. Acad. Sci. 109, 16101-16106; Zimmerman, E.S., et al., 2014, Bioconjug. Chem. 25, 351-361; Wu, P., et al, 2009 Proc. Natl. Acad. Sci. 106, 3000-3005; Rabuka, D., et al, 2012 Nat. Protoc. 7, 1052-67; 米国特許8,778,631及び米国特許出願20100184135、WO2010/081110, Sutro Biopharm; WO2006/069246, 2007/059312, 米国特許 7,332,571, 7,696,312, 7,638,299 Ambrx; WO2007/130453、米国特許7,632,492及び7,829,659, Allozyne)、抗体へのセレノシステインの導入(Hofer, T., et al 2009, Biochemistry 48, 12047-12057; 米国特許8,916,159, US National Cancer Institute)、ホルミルグリシン生成酵素(FGE)による、CXPXRコンセンサス配列に位置するシステインのホルミルグリシン(FGly)への変換(Drake, P.M., et al., 2014, Bioconjug. Chem. 25, 1331-1341. Carrico; Isaac S. et al米国特許7,985,783; 8,097,701; 8,349,910、米国特
許出願20140141025、20100210543, Redwood Bioscience)、並びに、ガラクトシル及びシアリルトランスフェラーゼを用いた、グルコエンジニアリング的シアル酸の導入(Zhou, Q., et al 2014, Bioconjug. Chem., 25, 510-520、米国特許出願20140294867, Sanofi-Genzyme)が含まれる。これらの上記の方法は、ほぼ均質な製品プロファイルを生産しているが、それらは、抗体エンジニアリングプロセスと細胞培養条件の再最適化が必要である。また、ADCの製品のコストに大きな影響を与える、非天然アミノ酸の遺伝的コードのための発現収率は、通常、十分に前途有望に高いものではなかった(Tian, F., et al, 2014, Proc. Natl. Acad. Sci. U. S. A. 111, 1766-71)。加えて、システイン側鎖に共
役して得られるADCは、循環における安定性が限定的であることが示されており、これは腫瘍部位に到達する前、細胞毒性剤ペイロードの早期切断につながる(Junutula, J. R., et al 2008, Nat. Biotechnol. 26, 925-32)。
Therefore, biotechnology companies and academic institutions are strongly focused on establishing new and reliable methods for site-specific ADC conjugates. So far, there are several approaches developed in recent years for the preparation of site-selective ADCs (Panowski, S, 2014,
010 Clin. Cancer Res. 16, 4769; Junutula, JR, et al 2008 Nat Biotechnol. 26, 925-32; US Pat. No. 8,309,300; 7,855,275; 7,521,541; 7,723,485, WO2008 / 141044), Streptoverticillium mobaraens transglutaminase (MTG) (Strop, P.,
Bioconjugate Chem., 2014, 25, 855-862; Strop, P., et al., 2013, Chem. Biol. 20,
161-167; US Pat. No. 8871908 Rinat-Pfizer) or Microbial Transglutaminase (MTGase) (Dennler, P., et al, 2014, Bioconjug. Chem. 25, 569-578; US Pat. No. 20130189287, Innate Pharma; US Pat. No. 7,893,019, Introduction of the glutamine tag, thiolufcose, genetically introduced by Bio-Ker Srl (IT) (Dennler, P., et al, 2014 Bioconjugate Chemistry 25, 569; Okeley, NM, et al 2013 Bioconjugate Chem. 24, 1650), Mutation-induced introduction of unnatural amino acids (Axup, JY, et al., 2012, Proc. Natl. Acad. Sci. 109, 16101-16106; Zimmerman, ES, et al., 2014, Bioconjug. Chem. 25, 351-361; Wu, P., et al, 2009 Proc. Natl. Acad. Sci. 106, 3000-3005; Rabuka, D., et al, 2012 Nat. Protoc. 7, 1052-67; US Patent 8,778,631 and US Patent Application 20100184135, WO2010 / 081110, Sutro Biopharm; WO2006 / 069246, 2007/059312, US Patent 7,332,571, 7,696,312, 7,638,299 Ambrx; WO2007 / 130453, US Patent 7,632,492 and 7,829,659, Allozyne), Serenocysteine to antibody Introduced (Hofer, T., et al 2009, Biochemistry 48, 12047-12057; US Patent 8,916,159, US National Cancer Institute), formylglycine (FGly) of cysteine located in the CXPXR consensus sequence by formylglycine-producing enzyme (FGE). Conversion to (Drake, PM, et al., 2014, Bioconjug. Chem. 25, 1331-1341. Carrico; Is aac S. et al U.S. Pat. No. 7,985,783; 8,097,701; 8,349,910, U.S. Patent Application 20140141025, 20100210543, Redwood Bioscience), and introduction of glucoengineering sialic acid using galactosyl and sialyltransferase (Zhou, Q., et al 2014) , Bioconjug. Chem., 25, 510-520, US Patent Application 20140294867, Sanofi-Genzyme). Although these above methods produce near-homogeneous product profiles, they require an antibody engineering process and reoptimization of cell culture conditions. Also, the expression yields for the genetic coding of unnatural amino acids, which have a significant impact on the cost of ADC products, were usually not sufficiently promising (Tian, F., et al, 2014). , Proc. Natl. Acad. Sci. USA 111, 1766-71). In addition, ADCs obtained coupled to the cysteine side chain have been shown to have limited circulatory stability, leading to premature cleavage of the cytotoxic agent payload before reaching the tumor site ( Junutula, JR, et al 2008, Nat. Biotechnol. 26, 925-32).
IgG抗体の4つのサブクラスのジスルフィド結合構造は、1960年代に知られていた(Milstein C. Biochem J., 1966, 101: 338 - 351; Pink J R, Milstein C. Nature 1967, 214:92-94; Frangione B, Milstein C. Nature 1967, 216:939 - 941; Pink JR, Milstein C. Nature 1967, 216:941 -942; Frangione B, et al. Biochem J. 1968, 106,15 - 21; Frangione B, Milstein C. J Mol Biol 1968; 33:893 - 906; Edelman GM, et al. Proc Natl Acad Sci USA 1969; 63:78 -85; Frangione B, et al. Nature 196, 221:145 -148, Spiegelberg, H. L. et al Biochemistry, 1975, 10, 2157-63 )。ジスルフィド結合構造は、IgG分子の構造、安定性、及び生物学的機能にとって重要である。IgG抗体の4つのサブクラス、IgG1、IgG2、IgG3、及びIgG4の間では、各IgGは合計で12個の鎖内ジスルフィド結合を含む;各ジスルフィド結合は、個々のIgGドメインに関連付けられている。2個の重鎖は、変化可能な数、IgG1及びIgG4で2個、IgG2で4個、IgG3で11個のジスルフィド結合でヒンジ領域にて接続されている。IgG1の軽鎖は、軽鎖の最後のシステイン残基と重鎖の第5のシステイン残基との間のジスルフィド結合によって、重鎖に接続されている。しかし、IgG2、IgG3、及びIgG4については、軽鎖の最後のシステイン残基と重鎖の第3のシステイン残基との間のジスルフィド結合によって、重鎖に連結されている(Liu, H. and May, K., 2012, mAbs 4、17-23)。実験的な還元、異なるアルキル化、及びLC−MS分析によるヒトIgG1抗体中のジスルフィド結合の感受性のランクについて(Liu, H, et al An
al. Chem., 2010, 82, 5219-5226)、鎖間ジスルフィド結合は、鎖内ジスルフィド結合よりも還元の影響を受け易く、また、軽鎖と重鎖との間のジスルフィド結合は、2個の重鎖間のジスルフィド結合よりも感受性が高いものであった。また、2個の重鎖間のジスルフィド結合のうち、上流側のジスルフィド結合は、下流側のものよりも感受性が高いものであった。更に、CH2ドメインにおけるジスルフィド結合は、還元に対して最も感受性が高いものであった。VL、CL、VH、及びCH1の各ドメインにおけるジスルフィド結合は、同様で適度な感受性を有し、一方、CH3ドメインにおけるジスルフィド結合は、少なくとも還元の影響を受けやすい(Liu, H, et al Anal. Chem., 2010, 82, 5219-5226)。
The disulfide bond structures of the four subclasses of IgG antibodies were known in the 1960s (Milstein C. Biochem J., 1966, 101: 338 --351; Pink JR, Milstein C. Nature 1967, 214: 92-94; Frangione B, Milstein C. Nature 1967, 216: 939 --941; Pink JR, Milstein C. Nature 1967, 216: 941 -942; Frangione B, et al. Biochem J. 1968, 106, 15 --21; Frangione B, Milstein C. J Mol Biol 1968; 33: 893 --906; Edelman GM, et al. Proc Natl Acad Sci USA 1969; 63: 78 -85; Frangione B, et al. Nature 196, 221: 145 -148, Spiegelberg, HL et al Biochemistry, 1975, 10, 2157-63). The disulfide bond structure is important for the structure, stability, and biological function of IgG molecules. Among the four subclasses of IgG antibodies, IgG1, IgG2, IgG3, and IgG4, each IgG contains a total of 12 intrachain disulfide bonds; each disulfide bond is associated with an individual IgG domain. The two heavy chains are connected at the hinge region by disulfide bonds of variable numbers, 2 for IgG1 and IgG4, 4 for IgG2 and 11 for IgG3. The light chain of IgG1 is connected to the heavy chain by a disulfide bond between the last cysteine residue of the light chain and the fifth cysteine residue of the heavy chain. However, IgG2, IgG3, and IgG4 are linked to the heavy chain by a disulfide bond between the last cysteine residue of the light chain and the third cysteine residue of the heavy chain (Liu, H. and May, K., 2012,
al. Chem., 2010, 82, 5219-5226), interchain disulfide bonds are more susceptible to reduction than intrachain disulfide bonds, and there are two disulfide bonds between the light chain and the heavy chain. It was more sensitive than the disulfide bonds between the heavy chains of. Of the disulfide bonds between the two heavy chains, the upstream disulfide bond was more sensitive than the downstream disulfide bond. Furthermore, the disulfide bond in the CH2 domain was the most sensitive to reduction. The disulfide bonds in the VL, CL, VH, and CH1 domains have similar and moderate susceptibility, while the disulfide bonds in the CH3 domain are at least susceptible to reduction (Liu, H, et al Anal. Chem., 2010, 82, 5219-5226).
ヒトIgG1抗体における鎖間ジスルフィド結合のより多くの感受性に基づいて、複数の機関及び企業が、次世代マレイミド(NGMs)と呼ばれるブロモ又はジブロモマレイミドを使用する(Schumacher, F.F., et al 2014, Org. Biomol. Chem. 12, 7261-7269; UCL Cancer Institute);3つの炭素架橋を介してビス−アルキル試薬を適用する(Badescu, G., et al., 2014, Bioconjug. Chem. 25, 1124-1136., WO2013/190272, WO2014/064424 PolyTherics Ltd);二置換ヘテロ芳香環架橋(米国特許出願 2015/0105539, Concortis システム);又は架橋としてのジマレイミドによる(WO2014/114207)等の、天然の抗体の還元された鎖間ジスルフィド結合を再架橋することにより、化学的に特異的な共役体を得るという戦略を採用した。我々もまた、長期間、薬剤と抗体の両方を共役するために、ブロモマレイミド及びジブロモ-マレイミド連結体を使用した(WO2014/009774、PCT/IB2012/053554)。しかしながら、これらの上記の架橋連結体は、一対のジスルフィド結
合に細胞毒性剤を1個だけ共役する方法で設計されており、共役のための接近がより容易である、還元されたジスルフィド結合の数が限られているため(約2ペア)、従って、ほとんどの時間で、彼らは2未満のDAR(抗体あたりの薬剤)であるADCのみを製造している。
Based on the greater susceptibility of interchain disulfide bonds in human IgG1 antibodies, multiple institutions and companies use bromo or dibromomaleimide called next-generation maleimides (NGMs) (Schumacher, FF, et al 2014, Org. Biomol. Chem. 12, 7261-7269; UCL Cancer Institute); Applying Bis-alkyl Reagents Through Three Carbon Bridges (Badescu, G., et al., 2014, Bioconjug. Chem. 25, 1124-1136) ., WO2013 / 190272, WO2014 / 064424 PolyTherics Ltd); disubstituted heteroaromatic ring bridges (US patent application 2015/0105539, Concortis system); or reduction of natural antibodies by dimaleimide as a bridge (WO2014 / 114207). The strategy was adopted to obtain a chemically specific conjugate by recross-linking the interchain disulfide bond. We also used bromomaleimide and dibromo-maleimide conjugates for long-term conjugation of both drug and antibody (WO2014 / 009774, PCT / IB2012 / 053554). However, these cross-linked conjugates are designed by conjugating only one cytotoxic agent to a pair of disulfide bonds, which makes it easier to access for conjugation, the number of reduced disulfide bonds. Therefore, most of the time they produce only ADCs that are less than 2 DATs (drugs per antibody) due to their limited nature (about 2 pairs).
ADCの主要な問題の1つとして、最終的に腫瘍に到達する細胞毒性化合物の数又は量が限られており、3以上の好ましいDARは、ADC治療指数の改善のための多くの重要な要因であり(Epenetos, A. A. et al, Cancer Res., 1986, 46, 3183-3191; Chari, R.
V. Acc. Chem. Res., 2008, 41, 98-107, Zhao, R. Y. 2011 J. Med. Chem. 54, 3606-3623)。
One of the major problems with ADC is the limited number or amount of cytotoxic compounds that will eventually reach the tumor, and a preferred DA of 3 or more is a number of important factors for improving the ADC treatment index. (Epenetos, AA et al, Cancer Res., 1986, 46, 3183-3191; Chari, R.
V. Acc. Chem. Res., 2008, 41, 98-107, Zhao, RY 2011 J. Med. Chem. 54, 3606-3623).
従って、我々は、より高いDAR(≧4)を達成するために、TCEP及びDTTにより還元されるIgG抗体の鎖間上の、感受性の高い一対の遊離チオールの再架橋を介して、連結体あたり2以上の薬剤を共役することができる新規なジスルフィド架橋連結体を開示する。また、架橋連結体によって、特に2つの細胞毒性剤を含む架橋連結体によって到達することが困難な、他の還元されたジスルフィド結合は、共役体の末端において、酸化物、例えば、デヒドロアスコルビン酸(DHAA)又はCu(II)によって再結合(再生)することができる。要するに、本発明の架橋連結体は、簡便な方法で特定のADCの均質な製造を行うことができる。 Therefore, we per-link via recrosslinking of a pair of sensitive free thiols between the chains of TCEP and DTT-reduced IgG antibodies to achieve higher DAT (≧ 4). Disclosed is a novel disulfide cross-linked conjugate capable of conjugating two or more agents. Also, other reduced disulfide bonds that are difficult to reach by cross-linked conjugates, especially by cross-linked conjugates containing two cytotoxic agents, are at the ends of the conjugates such as oxides, such as dehydroascorbic acid It can be recombined (regenerated) with DHAA) or Cu (II). In short, the crosslinked conjugate of the present invention can produce a specific ADC in a homogeneous manner by a simple method.
本発明は、2つの薬剤と細胞結合剤(例えば、抗体)とを連結させるためのヒドラジンを含む連結体を提供する。細胞結合分子−連結体共役体の好ましい式は、以下のように表すことができる:
式中、Cbは細胞結合剤であり、Lはヒドラジン基を含む連結体であり、Drug1及びDrug2は薬物分子であり、nは1〜20の整数であり、Cbからの2つのS(硫黄)元素は架橋的にLと連結し、2以上の薬剤(架橋連結体L1つ当たり)と共有的に結合する。細胞分子−薬物共役体に連結体を適用する際の利点は以下のとおりである:a)細胞連結剤、特に抗体の、還元された一対の二硫黄と共有的に架橋(再架橋)することによって、共役体の安定性を維持する;b)細胞結合分子の特定の部位、例えば、IgG抗体の内部鎖部位、への細胞毒性剤/薬物の共役を可能にし、その結果、ADCの均質な生産をもたらす。 In the formula, Cb is a cell binding agent, L is a conjugate containing a hydrazine group, Drug 1 and Drug 2 are drug molecules, n is an integer of 1 to 20, and two Ss from Cb ( The sulfur) element is crosslinked with L and covalently associated with two or more agents (per crosslinked conjugate L). The advantages of applying a conjugate to a cell molecule-drug conjugate are as follows: a) Covalently cross-linking (re-crosslinking) with a pair of reduced disulfates of a cell-linking agent, especially an antibody. Maintains the stability of the conjugate; b) allows conjugation of the cytotoxic / drug to a specific site of the cell-binding molecule, eg, the internal chain site of an IgG antibody, resulting in homogeneous ADC. Bring production.
本発明の一態様において、前記連結体は式(I)で表される。
式中、Y1及びY2は、細胞結合剤の硫黄原子の対と反応することができる同一又は異
なる官能基である。Y1及びY2は、ジスルフィド結合、チオエーテル結合、又はチオエステル結合を形成するために、硫黄原子の対と反応することができる。Y1及びY2として好ましい官能基は、これらに限定されないが、N−ヒドロキシスクシンイミドエステル、マレイミド、ジスルフィド、ハロアセチル、エテンスルホニル、ハロゲン化アシル(酸ハライド)、アクリル(アクリロイル)、及び/又は酸無水物基である。
In the formula, Y 1 and Y 2 are the same or different functional groups capable of reacting with a pair of sulfur atoms in a cell binder. Y 1 and Y 2 can react with a pair of sulfur atoms to form a disulfide bond, thioether bond, or thioester bond. Preferred functional groups as Y 1 and Y 2 are, but are not limited to, N-hydroxysuccinimide ester, maleimide, disulfide, haloacetyl, ethensulfonyl, acyl halide (acid halide), acrylic (acryloyl), and / or acid anhydride. It is a base.
Z1及びZ2は、細胞毒性剤と反応することができる同一又は異なる官能基である。該官能基Z1又はZ2は、ジスルフィド、エーテル、エステル、チオエーテル、チオエステル、ペプチド、ヒドラゾン、カルバメート、カーボネート、アミン(二級、三級若しくは四級)、イミン、シクロヘテロアルカン、ヘテロ芳香環、アルコキシム、又はアミド結合を形成するために、細胞毒性剤と結合することができる。 Z 1 and Z 2 are the same or different functional groups capable of reacting with cytotoxic agents. The functional group Z 1 or Z 2 contains disulfide, ether, ester, thioether, thioester, peptide, hydrazone, carbamate, carbonate, amine (secondary, tertiary or quaternary), imine, cycloheteroalkoxy, heteroaromatic ring, It can be combined with a cytotoxic agent to form an alkoxy or amide bond.
R1、R2、R1、及びR4は、同じか又は異なり、且つ、不存在、炭素数1〜8の直鎖状アルキル、炭素数3〜8の分岐若しくはシクロアルキル、直鎖、分岐若しくはシクロアルケニル若しくはアルキニル、炭素数1〜8のエステル、エーテル若しくはアミド、若しくは構造式(OCH2CH2)pである(p;0〜約1000の整数)ポリエチレンオキシ単位、又はこれらの組み合わせである。 R 1 , R 2 , R 1 , and R 4 are the same or different, and are absent, linear alkyl with 1 to 8 carbon atoms, branched with 3 to 8 carbon atoms, or cycloalkyl, linear, branched. Alternatively, it is a cycloalkenyl or alkynyl, an ester having 1 to 8 carbon atoms, an ether or an amide, or a polyethylene oxy unit having a structural formula (OCH 2 CH 2 ) p (p; an integer of 0 to about 1000), or a combination thereof. ..
追加的に、R1、R2、R1、及びR4はそれぞれ、C、N、O、S、Si、及びPから選択される原子の鎖であり、好ましくは0〜500原子を有し、Y1又はY2とZ1又はZ2とを共有的に結合する。R1、R2、R1、及びR4の形成に用いられる原子は、アルキレート(alkylate)、アルキレン、アルケニレン、アルキニレン、エーテル、ポリオキシアルキレン、エステル、アミン、イミン、ポリアミン、ヒドラジン、ヒドラゾン、アミド、尿素、セミカルバジド、カルバジド、アルコキシアミン、アルコキシアミン、ウレタン、アミノ酸、ペプチド、アシルオキシアミン、若しくはヒドロキサム酸、又はそれらの組み合わせを形成するような、化学的に関連する全ての方法で結合してもよい。 Additionally, R 1 , R 2 , R 1 , and R 4 are chains of atoms selected from C, N, O, S, Si, and P, respectively, preferably having 0 to 500 atoms. , Y 1 or Y 2 and Z 1 or Z 2 are covalently coupled. The atoms used to form R 1 , R 2 , R 1 , and R 4 are alkylate, alkylene, alkenylene, alkynylene, ether, polyoxyalkylene, ester, amine, imine, polyamine, hydrazine, hydrazone, Even if bound by all chemically related methods such as forming amides, ureas, semicarbazides, carbazides, alkoxyamines, alkoxyamines, urethanes, amino acids, peptides, acyloxyamines, or hydroxamic acids, or combinations thereof. Good.
別の態様では、本発明は、式(II)の細胞結合剤−薬物共役体を提供し、これは、細胞結合分子Cbと、前記架橋連結体の末端で反応している薬剤Drug1及びDrug2を有する。
式中、Cbは、細胞結合分子を表し、抗体が好ましい。 In the formula, Cb represents a cell-binding molecule, and an antibody is preferable.
ブラケット (括弧)の内部には、一対のジスルフィド結合を介して、前記細胞結合分
子と共役された連結体−薬剤成分である。前記共役可能なチオール原子は、一般的に、TCEP及び/又はDTTによる細胞結合分子上のジスルフィド結合の対の還元から生成することができる。
Inside the bracket is a conjugate-drug component conjugate to the cell-binding molecule via a pair of disulfide bonds. The conjugatable thiol atom can generally be produced from the reduction of a pair of disulfide bonds on the cell binding molecule by TCEP and / or DTT.
「Drug1」及び「Drug2」は、同一の又は異なる細胞毒性剤/薬物を表し、ジスルフィド、チオエーテル、チオエステル、ペプチド、ヒドラゾン、エーテル、エステル、カルバメート、カーボネート、環状ヘテロalkyane、ヘテロ芳香環、アルコキシム、アミド、アルキレン、アルケニレン、アルキニレン、又は芳香族により、前記架橋連結体を介して前記細胞結合剤と連結される。 "Drug 1 " and "Drug 2 " represent the same or different cytotoxic agents / drugs, disulfide, thioether, thioester, peptide, hydrazone, ether, ester, carbamate, carbonate, cyclic heteroalkane, heteroaromatic ring, alkoxy. It is linked to the cell binding agent via the cross-linking by an ester, amide, alkylene, alkenylene, alquinylene, or aromatic.
nは1〜20である。R1、R2、R3、及びR4は、前述の式(I)に記載のものと同じである。 n is 1 to 20. R 1, R 2, R 3 , and R 4 are the same as those described in the aforementioned formula (I).
更なる態様において、本発明は、式(III)の修飾された細胞結合剤を提供するものであり、薬剤と反応し得る官能基であるZ1及びZ2を有し、また、細胞結合剤Cbは前記架橋連結体と反応する。
式中、Cb、Z1、Z2、R1、R2、R3、及びR4は、式(I)及び(II)におけるものと同じ定義である。 In the formula, Cb, Z 1 , Z 2 , R 1 , R 2 , R 3 , and R 4 have the same definitions as those in formulas (I) and (II).
更なる態様において、本発明は、式(IV)の修飾薬物を提供するものであり、式中、薬剤であるDrug1及びDrug2は、式(I)の連結体と反応し、Y1及びY2基は依然として、細胞結合分子の一対の硫黄原子と反応し得る。
式中、Y1、Y2、Drug1、Drug2、R1、R2、R3、及びR4は、式(I)及び(II)におけるものと同じ定義である。 In the formula, Y 1 , Y 2 , Drug 1 , Drug 2 , R 1 , R 2 , R 3 , and R 4 have the same definitions as those in formulas (I) and (II).
本発明は更に、前記式(II)の細胞結合分子−薬物共役体の製造方法に関し、薬剤であるDrug1及びDrug2は、前記架橋連結体を介して細胞結合分子と連結される。 The present invention further relates to the method for producing a cell-binding molecule-drug conjugate of the formula (II), wherein the drugs Drug 1 and Drag 2 are linked to the cell-binding molecule via the crosslinked conjugate.
本発明はまた、式 (III)の修飾細胞結合分子を製造する方法にも関し、前記細胞
結合分子は、式(I)の前記架橋連結体と反応している。
The present invention also relates to a method for producing a modified cell binding molecule of formula (III), wherein the cell binding molecule is reacting with the crosslinked conjugate of formula (I).
本発明はまた、式(IV)の修飾薬物の製造方法にも関し、前記薬物は式(I)の前記架橋連結体と反応している。 The present invention also relates to a method for producing a modified drug of formula (IV), wherein the drug reacts with the crosslinked conjugate of formula (I).
定義
「アルキル」とは、直鎖状又は分岐でもよい、鎖中に1〜8の炭素原子を有する脂肪族炭化水素基を意味する。「分岐」とは、直鎖状のアルキル基に1つ又は複数の低級アルキル、例えば、メチル、エチル、又はプロピル基が結合していることを指す。アルキル基の具体例としては、メチル、エチル、n−プロピル、イソプロピル、n−ブチル、t−ブチル、n−ペンチル、3−ペンチル、オクチル、ノニル、デシル、シクロペンチル、シクロヘキシル、2,2−ジメチルブチル、2,3−ジメチルブチル、2,2−ジメチルペンチル、2,3−ジメチルペンチル、3,3−ジメチルペンチル、2,3,4−トリメチルペンチル、3−メチルヘキシル、2,2−ジメチルヘキシル、2,4−ジメチルヘキシル、2,5−ジメチルヘキシル、3,5−ジメチルヘキシル、2,4−ジメチルペンチル、2−メチルヘプチル、3−メチルヘプチル、n−ヘプチル、イソヘプチル、n−オクチル、及びイソオクチルが含まれる。C1〜C8アルキル基は未置換でもよく、1つ又は複数の置換基(但し、次の置換基に制限されない)で置換されてもよい。前記置換基としては、C1〜C8アルキル、−O−(C1〜C8のアルキル)、アリール、−C(O)R’、−OC(O)R’、−C(O)OR’、−C(O)NH2、−C(O)NHR’、−C(O)N(R’)2、−NHC(O)R’、−SR’、−S(O)2R’、−S(O)R’、−OH、−ハロゲン、−N3、−NH2、−NH(R’)、−N(R’)2、及び−CNが挙げられ、尚、R’はそれぞれ独立にC1〜C8アルキル及びアリールから選択される。
Definition "Alkyl" means an aliphatic hydrocarbon group having 1 to 8 carbon atoms in the chain, which may be linear or branched. By "branching" is meant that one or more lower alkyl groups, such as methyl, ethyl, or propyl groups, are attached to a linear alkyl group. Specific examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, octyl, nonyl, decyl, cyclopentyl, cyclohexyl, 2,2-dimethylbutyl. , 2,3-Dimethylbutyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 3,3-dimethylpentyl, 2,3,4-trimethylpentyl, 3-methylhexyl, 2,2-dimethylhexyl, 2,4-Dimethylhexyl, 2,5-dimethylhexyl, 3,5-dimethylhexyl, 2,4-dimethylpentyl, 2-methylheptyl, 3-methylheptyl, n-heptyl, isoheptyl, n-octyl, and isooctyl. Is included. The C 1 to C 8 alkyl groups may be unsubstituted or substituted with one or more substituents (but not limited to the next substituent). Examples of the substituent include C 1 to C 8 alkyl, -O- (C 1 to C 8 alkyl), aryl, -C (O) R', -OC (O) R', and -C (O) OR. ', -C (O) NH 2 , -C (O) NHR', -C (O) N (R') 2 , -NHC (O) R', -SR', -S (O) 2 R' , -S (O) R', -OH, -halogen, -N 3 , -NH 2 , -NH (R'), -N (R') 2 , and -CN, and R'is They are each independently selected from C 1 -C 8 alkyl and aryl.
「ハロゲン原子」とは、フッ素、塩素、臭素、又はヨウ素原子を指し、臭素及び塩素原子が好ましい。 The "halogen atom" refers to a fluorine, chlorine, bromine, or iodine atom, preferably a bromine or chlorine atom.
「ヘテロアルキル」とは、1〜4個の炭素原子が独立して、O、S、及びNからなる群から選択されたヘテロ原子よりに置換されたC2−C8アルキルをいう。 "Heteroalkyl" refers to four independently a carbon atom, O, S, and C 2 -C 8 alkyl substituted with from heteroatoms selected from the group consisting of N.
「炭素環」(Carbocycle)は、炭素数3〜8の単環系又は炭素数7〜13の二環系の飽和又は不飽和環を指す。単環系炭素環類は、3〜6、より典型的には5又は6の環原子を有する。二環系炭素環類は、7〜12の環原子を有し、二環系[4,5]、[5,5]、[5,6]、又は[6,6]として配置されるか、あるいは9〜10の環原子を有し、二環系[5,6]又は[6,6]として配置される。代表的なC3〜C8の炭素環類(C3〜C8 carbocycles)には、シクロプロピル、シクロブチル、シクロペンチル、シクロペンタジエニル、シクロヘキシル、シクロヘキセニル、1,3−シ
クロヘキサジエニル、1,4−シクロヘキサジエニル、シクロヘプチル、1,3−シクロヘプタジエニル、1,3,5−シクロヘプタトリエニル、シクロオクチル、及びシクロオクタジエニルが含まれるが、これらに限定されない。
"Carbocycle" refers to a saturated or unsaturated ring of a monocyclic system having 3 to 8 carbon atoms or a bicyclic system having 7 to 13 carbon atoms. Monocyclic carbocycles have 3 to 6, more typically 5 or 6 ring atoms. Dicyclic carbon rings have 7-12 ring atoms and are arranged as dicyclics [4,5], [5,5], [5,6], or [6,6]. , Or have 9 to 10 ring atoms and are arranged as a bicyclic system [5,6] or [6,6]. Typical C 3 to C 8 carbon rings (C 3 to C 8 carbocycles) include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl, 1, Includes, but is not limited to, 4-cyclohexadienyl, cycloheptyl, 1,3-cyclopentadienyl, 1,3,5-cyclopentadienyl, cyclooctyl, and cyclooctadienyl.
C3〜C8炭素環(C3〜C8 carbocycle)は、3、4、5、6、7、又は8員の飽和又は不飽和非芳香族の炭素環状化合物を指す。C3〜C8炭素環は未置換のものでも置換基(ただし,次の置換基の一つ又は複数に制限されない)で置換されたものでもいい。、即ち、前記置換基としては、これらに限定されないが、−C1〜C8のアルキル、−O−(C1〜C8アルキル)、−アリール、−C(O)R’、−OC(O)R’、−C(O)OR’、−C(O)NH2、−C(O)NHR’、−C(O)N(R’)2、−NHC(O)R’、−SR’、−S(O)R’、−S(O)2R’、−OH、−ハロゲン、−N3、−NH2、−NH(R’)、−N(R’)2、及び−CNが含まれ、ここで、R’はそれぞれ独立にC1〜C8アルキル及びアリールから選択される。
C 3 -C 8 carbocycle (C 3 ~
「アルケニル」は、鎖中に2〜8の炭素原子を有し、炭素−炭素二重結合を含む、直鎖状又は分岐してもよい脂肪族炭化水素基を指す。アルケニル基には、例えば、エテニル、プロペニル、n−ブテニル、i−ブテニル、3−メチルブト−2−エニル、n−ペンテニル、ヘキシレニル、ヘプテニル、オクテニルが含まれる。 "Alkenyl" refers to a linear or optionally branched aliphatic hydrocarbon group having 2 to 8 carbon atoms in the chain and containing a carbon-carbon double bond. Alkenyl groups include, for example, ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, hexylenyl, heptenyl, octenyl.
「アルキニル」は、鎖中に2〜8の炭素原子を有し、炭素−炭素三重結合を含む、直鎖状又は分岐してもよい脂肪族炭化水素基を指す。アルキニル基には、例えば、エチニル、プロピニル、n−ブチニル、2−ブチニル、3−メチルブチニル、5−ペンチニル、n−ペンチニル、ヘキシリニル、ヘプチニル、オクチニルが含まれる。 "Alkynyl" refers to a linear or optionally branched aliphatic hydrocarbon group having 2 to 8 carbon atoms in the chain and containing a carbon-carbon triple bond. Alkynyl groups include, for example, ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, 5-pentynyl, n-pentynyl, hexylynyl, heptynyl, octynyl.
「アルキレン」は、親のアルカンの同一又は2つの異なる炭素原子から2つの水素原子を除去することにより由来する2個の1価基中心を有する、炭素数1〜18の、飽和の、直鎖状又は分岐状鎖又は環状炭化水素基を指す。典型的なアルキレン基には、メチレン(−CH2−)、1,2−エチル(−CH2CH2−)、1,3−プロピル(−CH2CH2CH2−)、1,4−ブチル(−CH2CH2CH2CH2−)等が含まれるが、これらに限定されない。 An "alkylene" is a saturated, straight chain with 1 to 18 carbon atoms, having two monovalent centers derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkane. Refers to a shaped or branched chain or cyclic hydrocarbon group. Typical alkylene groups include methylene (-CH 2- ), 1,2-ethyl (-CH 2 CH 2- ), 1,3-propyl (-CH 2 CH 2 CH 2- ), 1,4- Butyl (-CH 2 CH 2 CH 2 CH 2- ) and the like are included, but are not limited thereto.
「アルケニレン」は、親のアルケンの同一又は2つの異なる炭素原子から2つの水素原子を除去することにより由来する2個の1価基中心を有する、炭素数2〜18の、不飽和の、直鎖状又は分岐状鎖又は環状炭化水素基を指す。典型的なアルケニレン基には、1,2−エチレン(−CH=CH−)が含まれるが、これらに限定されない。 "Alkenylene" is an unsaturated, direct with 2 to 18 carbon atoms with two monovalent groups derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkene. Refers to a chain or branched chain or cyclic hydrocarbon group. Typical alkenylene groups include, but are not limited to, 1,2-ethylene (-CH = CH-).
「アルキニレン」は、親のアルキンの同一又は2つの異なる炭素原子から2つの水素原子を除去することにより由来する2個の1価基中心を有する、炭素数2〜18の、不飽和の、直鎖状又は分岐状鎖又は環状炭化水素基を指す。典型的なアルキニレン基には、アセチレン、プロパルギル、及び4−ペンチニルが含まれるが、これらに限定されない。 An "alkynylene" is an unsaturated, direct with 2 to 18 carbon atoms, having two monovalent groups derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkyne. Refers to a chain or branched chain or cyclic hydrocarbon group. Typical alkynylene groups include, but are not limited to, acetylene, propargyl, and 4-pentynyl.
「アリール」又はArは、3〜14個の炭素原子、好ましくは6〜10個の炭素原子を含む、1又は数個の環からなる芳香族又はヘテロ芳香族基を指す。「ヘテロ芳香族基」の語は、芳香族基上の1又は数個の炭素、好ましくは1、2、3、又は4個の炭素原子が、O、N、Si、Se、P、又はS、好ましくはO、S、及びNで置き換えられたものを指す。アリール又はArの語はまた、1又は数個のH原子が独立して、−R’、−ハロゲン、−OR’、又は−SR’、−NR’R’’、−N=NR’、−N=R’、−NR’R’’、−NO2、−S(O)R’、−S(O)2R’、−S(O)2OR’、−OS(O)2OR’、−PR’R’’、−P(O)R’R’’、−P(OR’)(OR’’)、−P(O)(OR’)(OR’’)、又は−OP(O)(OR’)(OR’’)により置き換
えられたものも指す。前記R’、R’’は独立して、H、アルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、アリールアルキル、カルボニル、又は薬学的塩である。
"Aryl" or Ar refers to an aromatic or heteroaromatic group consisting of one or several rings containing 3 to 14 carbon atoms, preferably 6 to 10 carbon atoms. The term "heteroaromatic group" means that one or several carbons, preferably one, two, three, or four carbon atoms on an aromatic group are O, N, Si, Se, P, or S. , Preferably those substituted with O, S, and N. The word aryl or Ar also has one or several H atoms independently, -R', -halogen, -OR', or -SR', -NR'R', -N = NR',- N = R', -NR'R', -NO 2 , -S (O) R', -S (O) 2 R', -S (O) 2 OR', -OS (O) 2 OR' , -PR'R'', -P (O) R'R'', -P (OR') (OR''), -P (O) (OR') (OR''), or -OP ( O) Refers to those replaced by (OR') (OR''). The R', R'' are independently H, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, arylalkyl, carbonyl, or pharmaceutical salts.
「複素環」(Heterocycle)は、1〜4個の環炭素原子が独立して、O、N、S、Se、B、Si、及びPの群からのヘテロ原子で置換されている環系をいう。好ましいヘテロ原子はO、N、及びSである。複素環は、The Handbook of Chemistry and Physics、第78版、CRC Press、Inc.、1997-1998、p225〜226頁に記載されており、その開示は参照により本明細書に組み込まれる。好ましい非芳香族複素環には、これらに限定されないが、エポキシ、アジリジニル、チラニル、ピロリジニル、ピラゾリジニル、イミダゾリジニル、オキシラニル、テトラヒドロフラニル、ジオキソラニル、テトラヒドロピラニル、ジオキサニル、ジオキソラニル、ピペリジル、ピペラジニル、モルホリニル、ピラニル、イミダゾリニル、ピロリニル、テトラヒドロピラニル、ジヒドロピラニル、テトラヒドロピリジル、ジヒドロピリジル、テトラヒドロピリジニル、ジヒドロチオピラニル、アゼパニル、並びにフェニル基との縮合から生じる縮合系が含まれる。 A "heterocycle" is a ring system in which 1 to 4 ring carbon atoms are independently substituted with heteroatoms from the groups O, N, S, Se, B, Si, and P. Say. Preferred heteroatoms are O, N, and S. Heterocycles are described in The Handbook of Chemistry and Physics, 78th Edition, CRC Press, Inc., 1997-1998, pp. 225-226, the disclosure of which is incorporated herein by reference. Preferred non-aromatic heterocycles include, but are not limited to, epoxies, aziridinyl, tilanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxylanyl, tetrahydrofuranyl, dioxolanyl, tetrahydropyranyl, dioxanyl, dioxolanyl, piperidyl, piperazinyl, morpholinyl, pyranyl, Includes imidazolinyl, pyrrolinyl, tetrahydropyranyl, dihydropyranyl, tetrahydropyridyl, dihydropyridyl, tetrahydropyridinyl, dihydrothiopyranyl, azepanyl, and condensation systems resulting from condensation with phenyl groups.
「ヘテロアリール」又は芳香族複素環の語は、5〜14員、好ましくは5〜10員の芳香族ヘテロ、単環式、二環式、又は多環式の環をいう。その例には、ピロリル、ピリジル、ピラゾリル、チエニル、ピリミジニル、ピラジニル、テトラゾリル、インドリル、キノリニル、プリニル、イミダゾリル、チエニル、チアゾリル、ベンゾチアゾリル、フラニル、ベンゾフラニル、1,2,4−チアジアゾリル、イソチアゾリル、トリアゾイル、テトラゾリル、イソキノリル、ベンゾチエニル、イソベンゾフリル、ピラゾリル、カルバゾリル、ベンズイミダゾリル、イソキサゾリル、ピリジル−N−オキシド、及びフェニル基との縮合から生じる縮合系が含まれる。 The term "heteroaryl" or aromatic heterocycle refers to a 5- to 14-membered, preferably 5 to 10-membered aromatic hetero, monocyclic, bicyclic, or polycyclic ring. Examples include pyrrolyl, pyridyl, pyrazolyl, thienyl, pyrimidinyl, pyrazinyl, tetrazolyl, indolyl, quinolinyl, prynyl, imidazolyl, thienyl, thiazolyl, benzothiazolyl, furanyl, benzofuranyl, 1,2,4-thiazolyl, isothiazolyl, triazoyl, tetrazolyl. , Isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, carbazolyl, benzimidazolyl, isoxazolyl, pyridyl-N-oxide, and condensation systems resulting from condensation with phenyl groups.
「アルキル」、「シクロアルキル」、「アルケニル」、「アルキニル」、「アリール」、「ヘテロアリール」、「複素環基」(heterocyclic)等には、2個の水素原子が除去されることにより形成される、対応する「アルキレン」、「シクロアルキレン」、「アルケニレン」、「アルキニレン」、「アリーレン」、「ヘテロアリーレン」、「複素環基」(heterocyclene)等をも指す。 "Alkyl", "cycloalkyl", "alkenyl", "alkynyl", "aryl", "heteroaryl", "heterocyclic" and the like are formed by removing two hydrogen atoms. It also refers to the corresponding "alkylene", "cycloalkylene", "alkenylene", "alkynylene", "arylene", "heteroarylene", "heterocyclic group" and the like.
「アリールアルキル」は、炭素原子、典型的には末端又はsp3炭素原子に結合した水素原子の1つがアリール基で置換されている、非環式アルキル基を指す。典型的なアリールアルキル基には、これらに限定されないが、ベンジル、2−フェニルエタン−1−イル、2−フェニルエテン−1−イル、ナフチルメチル、2−ナフチルエタン−1−イル、2−ナフチルエテン−1−イル、ナフトベンジル、2−ナフトフェニルエタン−1−イル等が含まれる。 "Arylalkyl", one of the carbon atoms, typically a hydrogen atom attached to a terminal or sp 3 carbon atom is substituted with an aryl group, refers to an acyclic alkyl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethane-1-yl, 2-phenylethane-1-yl, naphthylmethyl, 2-naphthylethane-1-yl, 2-naphthylethane. -1-yl, naphthobenzyl, 2-naphthophenylethane-1-yl and the like are included.
「ヘテロアリールアルキル」は、炭素原子、典型的には末端又はsp3炭素原子に結合した水素原子の1つがヘテロアリール基で置換されている、非環式アルキル基を指す。典型的なヘテロアリールアルキル基には、これらに限定されないが、2−ベンズイミダゾリルメチル、2−フリルエチル等が含まれる。 "Heteroarylalkyl" carbon atoms, typically one of the hydrogen atom attached to a terminal or sp 3 carbon atom has been substituted with a heteroaryl group refers to an acyclic alkyl group. Typical heteroarylalkyl groups include, but are not limited to, 2-benzimidazolylmethyl, 2-furylethyl and the like.
「ヒドロキシ保護基」の例には、これらに限定されないが、メトキシメチルエーテル、2−メトキシエトキシメチルエーテル、テトラヒドロピラニルエーテル、ベンジルエーテル、p−メトキシベンジルエーテル、トリメチルシリルエーテル、トリエチルシリルエーテル、トリイソプロピルシリルエーテル、t−ブチルジメチルシリルエーテル、トリフェニルメチルシリルエーテル、酢酸エステル、置換酢酸エステル、ピバロエート、ベンゾエート、メタンスルホネート、及びp−トルエンスルホネートが含まれる。 Examples of "hydroxy protective groups" include, but are not limited to, methoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ether, benzyl ether, p-methoxybenzyl ether, trimethylsilyl ether, triethylsilyl ether, triisopropylsilyl. Included are ethers, t-butyl dimethyl silyl ethers, triphenyl methyl silyl ethers, acetates, substituted acetates, pivaloates, benzoates, methanesulfonates, and p-toluenesulfonates.
「脱離基」とは、別の官能基によって置換されることができる官能基を指す。このような離脱基は、当該技術分野でよく知られており、例えば、これらに限定されないが、ハロゲン化物(例えば、塩化物、臭化物、及びヨウ化物)、メタンスルホニル(メシル)、p−トルエンスルホニル(トシル)、トリフルオロメチルスルホニル(トリフラート)、及びトリフルオロメチルスルホネートが含まれる。 "Leaving group" refers to a functional group that can be substituted by another functional group. Such leaving groups are well known in the art, such as, but not limited to, halides (eg, chlorides, bromides, and iodides), methanesulfonyl (mesyl), p-tosylsulfonyl. (Tosyl), trifluoromethylsulfonyl (triflate), and trifluoromethylsulfonate.
本明細書で以下の略語を使用することができ、以下に示された定義を有する:Boc、tert−ブトキシカルボニル;BroP、ブロモトリスピロリジノホスホニウムヘキサフルオロホスフェート;CDI、1,1’−カルボニルジイミダゾール;DCC、ジシクロヘキシルカルボジイミド;DCE、1,2−ジクロロエタン;DCM、ジクロロメタン;DIAD、アゾジカルボン酸ジイソプロピル;DIBAL−H、水素化ジイソブチルアルミニウム;DIPEA、ジイソプロピルエチルアミン;DEPC、ジエチルホスホロアニジエート;DMA、N,N−ジメチルアセトアミド;DMAP、4−(N,N−ジメチルアミノ)ピリジン;DMF、N,N−ジメチルホルムアミド;DMSO、ジメチルスルホキシド;DTT、ジチオエステル;EDC、1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド塩酸塩;ESI−MS、エレクトロスプレー質量分析;HATU、O−(7−アザベンゾトリアゾール−1−イル)−N,N,N’−N’−テトラメチルウロニウムヘキサフルオロリン酸塩;HOBt、1−ヒドロキシベンゾトリアゾール;HPLC、高圧液体クロマトグラフィー;NHS、N−ヒドロキシスクシンイミド;MMP、4−メチルモルホリン;PAB、p−アミノベンジル;PBS、リン酸緩衝生理食塩水(pH7.0〜7.5);PEG、ポリエチレングリコール;SEC、サイズ排除クロマトグラフィー;TCEP、トリス(2−カルボキシエチル)ホスフィン;TFA、トリフルオロ酢酸;THF、テトラヒドロフラン;Val、バリン。 The following abbreviations can be used herein and have the definitions given below: Boc, tert-butoxycarbonyl; BroP, bromotrispyrrolidinophosphonium hexafluorophosphate; CDI, 1,1'-carbonyldi. Imidazole; DCC, dicyclohexylcarbodiimide; DCE, 1,2-dichloroethane; DCM, dichloromethane; DIAD, diisopropyl azodicarboxylate; DIBAL-H, hydride diisobutylaluminum; DIPEA, diisopropylethylamine; DEPC, diethylphosphoroanidate; DMA, N, N-dimethylacetamide; DMAP, 4- (N, N-dimethylamino) pyridine; DMF, N, N-dimethylformamide; DMSO, dimethyl sulfoxide; DTT, dithioester; EDC, 1- (3-dimethylaminopropyl) ) -3-Ethylcarbodiimide hydrochloride; ESI-MS, electrospray mass analysis; HATU, O- (7-azabenzotriazole-1-yl) -N, N, N'-N'-tetramethyluronium hexafluoro Phosphate; HOBt, 1-hydroxybenzotriazole; HPLC, high-pressure liquid chromatography; NHS, N-hydroxysuccinimide; MMP, 4-methylmorpholin; PAB, p-aminobenzyl; PBS, phosphate-buffered physiological saline (pH 7) 0-7.5); PEG, polyethylene glycol; SEC, size exclusion chromatography; TCEP, tris (2-carboxyethyl) phosphine; TFA, trifluoroacetic acid; THF, tetrahydrofuran; Val, valine.
「薬学的に」又は「薬学的に許容される」とは、対応する化合物又は化合物組成物が適切な方法で動物又は人間に投与した際に、有害で、アレルギー又は他の有害反応を生じさせないことを指す。 "Pharmaceutically" or "pharmaceutically acceptable" means that the corresponding compound or compound composition is harmful and does not cause allergies or other adverse reactions when administered to animals or humans in an appropriate manner. Point to that.
「薬学的に許容される溶媒和物」又は「溶媒和物」は、1又は複数の溶媒分子と開示さ
れた化合物との会合を指す。薬理学的に許容される溶媒和物を形成する溶媒の例には、水、イソプロパノール、エタノール、メタノール、DMSO、酢酸エチル、酢酸、及びエタノールアミンが含まれるが、これらに限定されない。
"Pharmaceutically acceptable solvate" or "solvate" refers to the association of one or more solvent molecules with the disclosed compound. Examples of solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
薬学的に許容される補助材料は、全ての担体、希釈剤、助剤又は成形剤を含み、例えば、防腐剤、抗酸化剤、充填剤、崩壊剤、湿潤剤、乳化剤、懸濁剤、溶剤、分散性媒質、コーティング剤、抗菌剤、抗真菌剤、等張剤、吸収遅延剤等を含む。医薬分野において、活性を有する薬物成分にこれら補助材料を加えるという方法は一般的な方法である。補助材料が薬物活性成分と相容しない場合を除き、薬物成分に補助材料を加入することが妥当であるとは言える。良好な結果を得るために、活性を有する補助材料を薬物成分に加入してもよい。 Pharmaceutically acceptable auxiliary materials include all carriers, diluents, auxiliaries or molding agents, such as preservatives, antioxidants, fillers, disintegrants, wetting agents, emulsifying agents, suspending agents, solvents. , Dispersive medium, coating agent, antibacterial agent, antifungal agent, isotonic agent, absorption retardant and the like. In the pharmaceutical field, the method of adding these auxiliary materials to an active drug component is a common method. Unless the auxiliary material is incompatible with the drug active ingredient, it can be said that it is appropriate to add the auxiliary material to the drug ingredient. Active auxiliary materials may be added to the drug component for good results.
本願発明において、「薬用可能な塩」とは、本発明の化合物の塩類誘導物を指す。適当な修飾により、本願発明に係る化合物が相応の酸塩又はアルカリ塩に形成され得る。薬用可能な塩としては、常用の無毒の塩又は第四級アンモニウムを含み、これら塩は、本願発明に係る化合物と相応の無毒の無機酸又は有機酸によって調製され得る。例えば、無機酸としては、塩酸、臭化水素酸、硫酸、アミノスルホン酸、リン酸及び硝酸等を含み、有機酸としては、酢酸、プロピオ酸、コハク酸、酒石酸、クエン酸、メタンスルホン酸、ベンゼンスルホン酸、グルクロン酸、グルタミン酸、安息香酸、サリチル酸、トルエンスルホン酸、シュウ酸、フマル酸、及び乳酸等を含み、これら酸は薬学的に許容される塩に用いることが可能である。他の塩としては、トロメタモール、メグルミン、ピロールエタノー
ル等のアンモニウム塩、及びナトリウム、カリウム、カルシウム、亜鉛、マグネシウム等の金属塩を含む。
In the present invention, the "medicinal salt" refers to a salt derivative of the compound of the present invention. With appropriate modification, the compound according to the present invention can be formed into a suitable acid salt or alkali salt. Medicinal salts include commonly used non-toxic salts or quaternary ammoniums, which may be prepared with non-toxic inorganic or organic acids corresponding to the compounds according to the invention. For example, inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitrate and the like, and organic acids include acetic acid, propioic acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, etc. It contains benzenesulfonic acid, glucuronic acid, glutamic acid, benzoic acid, salicylic acid, toluenesulfonic acid, oxalic acid, fumaric acid, lactic acid and the like, and these acids can be used in pharmaceutically acceptable salts. Other salts include ammonium salts such as tromethamole, meglumin and pyrrole ethanol, and metal salts such as sodium, potassium, calcium, zinc and magnesium.
本願発明において、薬学的な塩は、従来の化学方法により、酸性又は塩基性残基を含む親化合物から製造することができる。一般的に、これらの塩は、水、有機溶媒、又は両者の混合溶媒中で、これらの化合物の遊離酸又は遊離塩基形態と化学量論的な量の適切な塩基又は酸との反応により得ることができる。非水系の反応溶媒として一般的に、エーテル、酢酸エチル、エタノール、イソプロパノール、又はアセトニトリルが好ましい。適切な塩のリストとしては、「Remington’s Pharmaceutical Sciences」,第17版.Mack Publishing Company,Easton,PA,1985,第1418頁に挙げられ、当該開示は参照として組み込まれる。 In the present invention, the pharmaceutical salt can be produced from a parent compound containing an acidic or basic residue by a conventional chemical method. Generally, these salts are obtained by reacting the free acid or free base form of these compounds with a stoichiometric amount of the appropriate base or acid in water, an organic solvent, or a mixed solvent of both. be able to. Generally, ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is preferable as the non-aqueous reaction solvent. For a list of suitable salts, see "Remington's Pharmaceutical Sciences", 17th edition. Listed in Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure is incorporated by reference.
ここで開示されている新規な共役体は、架橋連結体を用いている。いくつかの適切な架橋連結体及びその合成方法を図1から図10に示す。 The novel conjugate disclosed here uses a crosslinked conjugate. Some suitable crosslinked conjugates and methods of synthesizing them are shown in FIGS. 1-10.
架橋連結体
本発明の細胞結合分子に対する薬剤の共役体の調製と同様に、架橋連結体を得る合成経路を図1〜11に示す。架橋連結体は、3つの要素を有する:a)同一の又は独立した2つの置換基、細胞結合剤上の一対のチオールと反応することが可能であり、これらに限定されないが、N−ヒドロキシスクシンイミドエステル、マレイミド、ジスルフィド、ハロアセチル、エテンスルホニル、ハロゲン化アシル(酸ハライド)、アクリル(アクリロイル)、及び/又は酸無水物等である;b)中間の架橋が、官能基と連結するヒドラジンである;c)同一の又は独立した2つの置換基、薬剤と反応することが可能であり、これらに限定されないが、ジスルフィド、マレイミド、ハロアセチル、アルデヒド、ケトン、アジド、アミン、アルコキシアミン、及びヒドラジド等である。ヒドラジンを含む架橋連結体は、細胞結合剤及び薬剤との反応が可能な官能基の導入に続いて、酸、酸ハロゲン化物、又は酸無水物とヒドラジンとを直接縮合することにより導入することができる。これらの架橋連結体の合成は、図1〜11及び実施例の項に例示されている。
Cross-linked conjugates Similar to the preparation of drug conjugates for cell-binding molecules of the present invention, the synthetic pathways for obtaining cross-linked conjugates are shown in FIGS. The crosslinked conjugate has three elements: a) two identical or independent substituents capable of reacting with a pair of thiols on a cell binder, including but not limited to N-hydroxysuccinimide. Esters, maleimides, disulfides, haloacetyls, ethenesulfonyls, acyl halides (acid halides), acrylics (acryloyls), and / or acid anhydrides, etc .; b) Intermediate cross-linking is a hydrazine linked to a functional group; c) Two identical or independent substituents capable of reacting with the drug, including but not limited to disulfides, maleimides, haloacetyls, aldehydes, ketones, azides, amines, alkoxyamines, and hydrazides. .. A crosslinked conjugate containing hydrazine can be introduced by direct condensation of an acid, acid halide, or acid anhydride with hydrazine, following the introduction of a functional group capable of reacting with the cell binder and drug. it can. Synthesis of these crosslinked conjugates is illustrated in FIGS. 1-11 and the Section of Examples.
好ましくは、前記架橋連結体は、下記式(I)の化合物である:
式中、Y1及びY2は、ジスルフィド結合、チオエーテル結合、又はチオエステル結合を形成するために、細胞結合剤の硫黄原子の対と反応することができる同一又は異なる官能基である。Y1及びY2として好ましい官能基は、これらに限定されないが、以下に示す構造のN−ヒドロキシスクシンイミドエステル、マレイミド、ジスルフィド、ハロアセチル、ハロゲン化アシル(酸ハライド)、エテンスルホニル、アクリル(アクリロイル)、2−(トシルオキシ)アセチル、2−(メシルオキシ)アセチル、2−(ニトロフェノキシ)アセチル、2−ジニトロフェノキシ)アセチル、2−(フルオロフェノキシ)アセチル、2−(ジフルオロフェノキシ)アセチル、2−(ペンタフルオロフェノキシ)アセチル、2−(((トリフルオロメチル)スルホニル)オキシ)アセチル、及び/又は酸無水物基である。 In the formula, Y 1 and Y 2 are the same or different functional groups capable of reacting with a pair of sulfur atoms in a cell binding agent to form a disulfide bond, thioether bond, or thioester bond. Preferred functional groups as Y 1 and Y 2 are not limited to these, but N-hydroxysuccinimide ester, maleimide, disulfide, haloacetyl, acyl halide (acid halide), ethensulfonyl, acrylic (acryloyl), which have the structures shown below. 2- (tosyloxy) acetyl, 2- (mesyloxy) acetyl, 2- (nitrophenoxy) acetyl, 2-dinitrophenoxy) acetyl, 2- (fluorophenoxy) acetyl, 2- (difluorophenoxy) acetyl, 2- (pentafluoro) Phenoxy) acetyl, 2-(((trifluoromethyl) sulfonyl) oxy) acetyl, and / or acid anhydride groups.
X1はF、Cl、Br、I、又はLvである。X2はO、NH、N(R1)、又はCH2である。R5はR1、芳香環、ヘテロ芳香環、又は1個若しくは数個のH原子が独立に
、−R1、−ハロゲン、−OR1、−SR1、−NR1R2、−NO2、−S(O)R1、−S(O)2R1若しくは−COOR1で置換された芳香族基である。Lvはニトロフェノール;N−ヒドロキシスクシンイミド(NHS);フェノール;ジニトロフェノール;ペンタフルオロフェノール;テトラフルオロフェノール;ジフルオロフェノール;モノフルオロフェノール;ペンタクロロフェノール;トリフラート;イミダゾール;ジクロロフェノール;テトラクロロフェノール;1−ヒドロキシベンゾトリアゾール;トシレート;メシレート;2−エチル−5−フェニルイソキサゾリウム−3’−スルホネート;自己若しくは他の酸無水物とで形成された酸無水物(例えば、無水酢酸、無水ギ酸);又は中間体分子ペプチドカップリング反応のための、若しくはミツノブ反応のための縮合試薬により生成する中間体から選択される脱離基である。
X 1 is F, Cl, Br, I, or Lv. X 2 is O, NH, N (R 1 ), or CH 2 . R 5 is R 1, an aromatic ring, heteroaromatic ring, or to one or several H atoms are independently, -R 1, - halogen, -OR 1, -SR 1, -NR 1
Z1及びZ2は、細胞毒性剤と反応することができる同一又は異なる官能基である。前記官能基Z1及びZ2は、ジスルフィド、エーテル、エステル、チオエーテル、チオエステル、ペプチド、ヒドラゾン、カルバメート、カーボネート、アミン(二級、三級若しくは四級)、イミン、シクロヘテロアルカン、ヘテロ芳香環、アルコキシム、又はアミド結合を形成するために、細胞毒性剤と反応することができる。 Z 1 and Z 2 are the same or different functional groups capable of reacting with cytotoxic agents. The functional groups Z 1 and Z 2 include disulfide, ether, ester, thioether, thioester, peptide, hydrazone, carbamate, carbonate, amine (secondary, tertiary or quaternary), imine, cycloheteroalkoxy, heteroaromatic ring, It can react with a cytotoxic agent to form an alkoxy or amide bond.
R1、R2、R3、及びR4は、同じか又は異なり、且つ、不存在、炭素数1〜8の直鎖状アルキル、炭素数3〜8の分岐若しくはシクロアルキル、直鎖、分岐若しくはシクロアルケニル若しくはアルキニル、炭素数1〜8のエステル、エーテル若しくはアミド、若しくは構造式(OCH2CH2)pである(p;0〜約1000の整数)ポリエチレンオキシ単位、又はこれらの組み合わせである。 R 1 , R 2 , R 3 and R 4 are the same or different and are absent, linear alkyl with 1 to 8 carbon atoms, branched with 3 to 8 carbon atoms or cycloalkyl, linear, branched. Alternatively, it is a cycloalkenyl or alkynyl, an ester having 1 to 8 carbon atoms, an ether or an amide, or a polyethylene oxy unit having a structural formula (OCH 2 CH 2 ) p (p; an integer of 0 to about 1000), or a combination thereof. ..
追加的に、R1、R2、R3、及びR4はそれぞれ、C、N、O、S、Si、及びPから選択される原子の鎖であり、好ましくは0〜500原子を有し、Y1又はY2とZ1又はZ2とを共有的に結合する。R1、R2、R3、及びR4の形成に用いられる原子は、アルキレート(alkylate)、アルキレン、アルケニレン、アルキニレン、エーテル、ポリオキシアルキレン、エステル、アミン、イミン、ポリアミン、ヒドラジン、ヒドラゾン、アミド、尿素、セミカルバジド、カルバジド、アルコキシアミン、アルコキシアミン、ウレタン、アミノ酸、ペプチド、アシルオキシアミン、若しくはヒドロキサム酸、又はそれらの組み合わせを形成するような、化学的に関連する全ての方法で結合してもよい。 In addition, R 1 , R 2 , R 3 and R 4 are chains of atoms selected from C, N, O, S, Si and P, respectively, preferably having 0 to 500 atoms. , Y 1 or Y 2 and Z 1 or Z 2 are covalently coupled. The atoms used to form R 1 , R 2 , R 3 , and R 4 are alkoxylate, alkylene, alkenylene, alkynylene, ether, polyoxyalkylene, ester, amine, imine, polyamine, hydrazine, hydrazone, Even if bound by all chemically related methods such as forming amides, ureas, semicarbazides, carbazides, alkoxyamines, alkoxyamines, urethanes, amino acids, peptides, acyloxyamines, or hydroxamic acids, or combinations thereof. Good.
細胞毒性剤の連結を可能にする官能基Z1及びZ2の例には、これらに限定されないが、ジスルフィド、チオエーテル、チオエステル、ペプチド、ヒドラゾン、エステル、カルバメート、カーボネート、アルコキシム又はアミド結合を介して連結することが可能な基が挙げられる。このような官能基には、これらに限定されないが、チオール、ジスルフィド、アミノ、カルボキシ、アルデヒド、ケトン、マレイミド、ハロアセチル、ヒドラジン、アルコキシアミノ、及び/又はヒドロキシ基が含まれる。 Examples of functional groups Z 1 and Z 2 that allow ligation of cytotoxic agents include, but are not limited to, via disulfides, thioethers, thioesters, peptides, hydrazone, esters, carbamate, carbonates, alkoxys or amide bonds. Groups that can be linked together. Such functional groups include, but are not limited to, thiols, disulfides, aminos, carboxys, aldehydes, ketones, maleimides, haloacetyls, hydrazines, alkoxyaminos, and / or hydroxy groups.
薬剤/細胞毒性剤のアミンの末端と反応が可能な官能基Z1及びZ2の例としては、これらに限定されないが、N−ヒドロキシスクシンイミドエステル;p−ニトロフェニルエ
ステル;ジニトロフェニルエステル;ペンタフルオロフェニルエステル;又はテトラフルオロフェノール、ジフルオロフェノール、モノフルオロフェノール、ペンタクロロフェノール、トリフラート、イミダゾール、ジクロロフェノール、テトラクロロフェノール、1−ヒドロキシベンゾトリアゾール、トシレート、メシレート;2−エチル−5−フェニルイソキサゾリウム−3’−スルホネートで形成されたカルボン酸エステル;酢酸無水物若しくはギ酸無水物等の、形成された酸無水物;あるいは、ペプチドカップリング反応のための、又はミツノブ反応のための縮合試薬により生成する中間体とすることができる。チオールの末端と反応が可能なものとしては、これらに限定されないが、ピリジルジスルフ
ィド;ニトロピリジルジスルフィド;マレイミド;ハロ酢酸、及びカルボン酸塩化物とすることができる。ケトン又はアルデヒドの末端と反応が可能なものとしては、これらに限定されないが、アミン;アルコキシアミン;ヒドラジン;アシルオキシルアミンとすることができる。アジドの末端と反応が可能なものとしては、これらに限定されないが、アルキンとすることができる。
Examples of functional groups Z 1 and Z 2 capable of reacting with the amine terminal of the drug / cytotoxic agent are, but are not limited to, N-hydroxysuccinimide ester; p-nitrophenyl ester; dinitrophenyl ester; pentafluoro. Phenyl ester; or tetrafluorophenol, difluorophenol, monofluorophenol, pentachlorophenol, trifurate, imidazole, dichlorophenol, tetrachlorophenol, 1-hydroxybenzotriazole, tosylate, mesylate; 2-ethyl-5-phenylisoxazo A carboxylic acid ester formed with rium-3'-sulfonate; an acid anhydride formed, such as acetate or formic acid anhydride; or with a condensing reagent for a peptide coupling reaction or for a Mitsunobu reaction. It can be an intermediate to produce. Those capable of reacting with the terminal of the thiol can be, but are not limited to, pyridyl disulfide; nitropyridyl disulfide; maleimide; haloacetic acid, and carboxyl chloride. Those capable of reacting with the terminal of a ketone or aldehyde can be, but are not limited to, amine; alkoxyamine; hydrazine; acyloxylamine. Those capable of reacting with the terminal of the azide are not limited to these, but can be an alkyne.
好ましい態様において、官能基Z1及びZ2は、アミド結合を形成するための酸とアミンとの縮合により、Drug1及びDrug2と反応する。縮合試薬としては、限定されないが:EDC(N−(3−ジメチルアミノプロピル)−N’−エチルカルボジイミド)、DCC(ジシクロヘキシル−カルボジイミド)、N,N’−ジイソプロピルカルボジイミド(DIC)、N−シクロヘキシル−N’−(2−モルホリノエチル)カルボジイミドとメソ−p−トルエンスルホナート(CMC、又はCME−CDI)、1,1’−カルボニルジイミダゾール(CDI)、TBTU(O−(ベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウムテトラフルオロボラート)、N,N,N’,N’−テトラメチル−O−(1H−ベンゾトリアゾール−1−イル)ウロニウムヘキサフルオロホスファート(HBTU)、(ベンゾトリアゾール−1−イルオキシ)トリス(ジメチルアミノ)ホスホニウムヘキサフルオロホスファート(BOP)、(ベンゾトリアゾール−1−イルオキシ)トリピロリジノホスホニウムヘキサフルオロホスファート(PyBOP)、ジエチルシアノホスホネート(DEPC)、クロロ−N,N,N’,N’−テトラメチルホルムアミジニウムヘキサフルオロホスファート、1−[ビス(ジメチルアミノ)メチレン]−1H−1,2,3−トリアゾロ[4,5−b]ピリジニウム−3−オキシドヘキサフルオロホスファート(HATU)、1−[(ジメチルアミノ)(モルホリノ)メチレン]−1H−[1,2,3]トリアゾロ[4,5−b]ピリジン−1−イウム−3−オキシドヘキサフルオロホスファート(HDMA)、2−クロロ−1,3−ジメチルイミダゾリジニウムヘキサフルオロホスファート(CIP)、クロロトリピロリジノホスホニウムヘキサフルオロホスファート(PyCloP)、フルオロ−N,N,N’,N’−ビス(テトラメチレン)ホルムアミジニウムヘキサフルオロホスフェート(BTFFH)、N,N,N’,N’−テトラメチル−S−(1−オキシド−2−ピリジル)チウロニウムヘキサフルオロホスフェート、O−(2−オキソ−1(2H)ピリジル)−N,N,N’,N’−テトラメチルチウロニウムテトラフルオロボラート(TPTU)、S−(1−オキシド−2−ピリジル)−N,N,N’,N’−テトラメチルチウロニウムテトラフルオロボラート、O−[(エトキシカルボニル)シアノ−メチルエンアミノ]−N,N,N’,N’−テトラメチルウロニウムヘキサフルオロホスファート(HOTU)、(1−シアノ−2−エトキシ−2−オキソエチリデンアミノオキシ)ジメチルアミノ−モルホリノ−カルベニウムヘキサフルオロホスファート(COMU)、O−(ベンゾトリアゾール−1−イル)−N,N,N’,N’−ビス(テトラメチレン)ウロニウムヘキサフルオロホスファート(HBPyU)、N−ベンジル−N’−シクロヘキシルカルボジイミド(重合体結合と共に、あるいはなし)、ジピロリジノ(N−スクシンイミジルオキシ)−カルベニウムヘキサフルオロホスファート(HSPyU)、クロロジピロリジノカルベニウムヘキサフルオロホスファート(PyCIU)、2−クロロ−1,3−ジメチルイミダゾリニウムテトラフルオロボレート(CIB)、(ベンゾトリアゾール−1−イルオキシ)ジピペリジノカルベニウムヘキサフルオロホスファート(HBPipU)、O−(6−クロロベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウムテトラフルオロボレート(TCTU)、ブロモトリス(ジメチルアミノ)ホスホニウムヘキサフルオロホスファート(BroP)、プロピルホスホン酸無水物(PPACA、TsP(登録商標))、2−モルホリノエチルイソシアニド(MEI)、N,N,N’,N’−テトラメチル−O−(N−スクシンイミジル)ウロニウムヘキサフルオロホスファート(HSTU)、2−ブロモ−1−エチル−ピリジニウムテトラフルオロボレート(BEP)、O−[(エトキシカルボニル)シアノメチレンアミノ]−N,N,N’,N’−テトラメチルウロニウムテトラフルオロボレート(TOTU)、4−(4,6−ジメトキシ−1,
3,5−トリアジン−2−イル)−4−メチルモルホリニウムクロリド(MMTM,DMTMM)、N,N,N’,N’−テトラメチル−O−(N−スクシンイミジル)ウロニウムテトラフルオロボレート(TSTU)、O−(3,4−ジヒドロ−4−オキソ−1,2,3−ベンゾトリアジン−3−イル)−N,N,N’,N’−テトラメチルウロニウムテトラフルオロボレート(TDBTU)、1,1’−(アゾジカルボニル)ジピペリジン(ADD)、ジ−(4−クロロベンジル)アゾジカルボキシレート(DCAD)、ジ−tert−ブチル アゾジカルボキシレート(DBAD)、ジイソプロピル アゾジカルボキシレート(DIAD)、ジエチル アゾジカルボキシレート(DEAD)である。
In a preferred embodiment, the functional groups Z 1 and Z 2 react with Drug 1 and Drug 2 by condensation of an acid with an amine to form an amide bond. Condensing reagents are not limited to: EDC (N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide), DCC (dicyclohexyl-carbodiimide), N, N'-diisopropylcarbodiimide (DIC), N-cyclohexyl- N'-(2-morpholinoethyl) carbodiimide and meso-p-toluenesulfonate (CMC, or CME-CDI), 1,1'-carbonyldiimidazole (CDI), TBTU (O- (benzotriazole-1-yl) ) -N, N, N', N'-tetramethyluronium tetrafluoroborate), N, N, N', N'-tetramethyl-O- (1H-benzotriazole-1-yl) uronium hexa Fluorophosphate (HBTU), (benzotriazole-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate (BOP), (benzotriazole-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyBOP), diethyl Cyanophosphonate (DEPC), chloro-N, N, N', N'-tetramethylformamidinium hexafluorophosphate, 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4] , 5-b] Pyridinium-3-oxide hexafluorophosphate (HATU), 1-[(dimethylamino) (morpholino) methylene] -1H- [1,2,3] triazolo [4,5-b] pyridine- 1-Ium-3-oxide hexafluorophosphate (HDMA), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP), chlorotripyrrolidinophosphonium hexafluorophosphate (PyCloP), fluoro- N, N, N', N'-bis (tetramethylene) formamidinium hexafluorophosphate (BTFFH), N, N, N', N'-tetramethyl-S- (1-oxide-2-pyridyl) thi Uronium hexafluorophosphate, O- (2-oxo-1 (2H) pyridyl) -N, N, N', N'-tetramethylthiuronium tetrafluoroborate (TPTU), S- (1-oxide- 2-Pyridyl) -N, N, N', N'-Tetramethylthiuronium tetrafluoroborate, O-[(ethoxycarbonyl) cyano-methyleneamino] -N, N, N', N'-tetra Methyluronium hexafluorophosph Art (HOTU), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), O- (benzotriazole-1-yl) -N, N , N', N'-bis (tetramethylene) uronium hexafluorophosphate (HBPyU), N-benzyl-N'-cyclohexylcarbodiimide (with or without polymer bonds), dipyrrolidino (N-succinimidyloxy) )-Carbenium Hexafluorophosphate (HSPyU), Chlorodipyrrolidinocarbenium Hexafluorophosphate (PyCIU), 2-Chloro-1,3-dimethylimidazolinium tetrafluoroborate (CIB), (Benzotriazole-1) -Iloxy) Dipiperidinocarbenium hexafluorophosphate (HBPipU), O- (6-chlorobenzotriazole-1-yl) -N, N, N', N'-tetramethyluronium tetrafluoroborate (TCTU) ), Bromotris (dimethylamino) phosphonium hexafluorophosphate (BroP), propylphosphonic acid anhydride (PPACA, TsP®), 2-morpholinoethyl isocyanide (MEI), N, N, N', N'- Tetramethyl-O- (N-succinimidyl) uronium hexafluorophosphate (HSTU), 2-bromo-1-ethyl-pyridinium tetrafluoroborate (BEP), O-[(ethoxycarbonyl) cyanomethyleneamino] -N, N, N', N'-tetramethyluronium tetrafluoroborate (TOTU), 4- (4,6-dimethoxy-1,
3,5-Triazin-2-yl) -4-methylmorpholinium chloride (MMTM, DMTMM), N, N, N', N'-tetramethyl-O- (N-succinimidyl) uronium tetrafluoroborate ( TSTU), O- (3,4-dihydro-4-oxo-1,2,3-benzotriazine-3-yl) -N, N, N', N'-tetramethyluronium tetrafluoroborate (TDBTU) , 1,1'-(azodicarbonyl) dipiperidin (ADD), di- (4-chlorobenzyl) azodicarboxylate (DCAD), di-tert-butyl azodicarboxylate (DBAD), diisopropyl azodicarboxylate (DIAD), diethyl azodicarboxylate (DEAD).
好ましい態様において、R1、R2、R3、及びR4は、炭素数1〜8の直鎖状アルキル、又はジペプチドを含む、又はトリペプチド、又は構造式(OCH2CH2)pである(p;0〜100)ポリエチレンオキシ単位である。更に、R1、R2、R3、及びR4は、プロテアーゼによって開裂可能である。
In a preferred embodiment, R 1, R 2, R 3, and R 4 is a linear alkyl having 1 to 8 carbon atoms, or a dipeptide, or tripeptide, or
架橋連結体の合成の詳細例を図1〜11に示す。通常、ヒドラジンの架橋置換基は、薬剤化合物及びチオール分子と反応することができる官能基を含む連結体成分R1、R2、R3、及びR4と結合することができる。 Detailed examples of the synthesis of the crosslinked conjugate are shown in FIGS. 1 to 11. Usually, the cross-linked substituents of hydrazine can be attached to the conjugate components R 1 , R 2 , R 3 and R 4 , which contain functional groups capable of reacting with drug compounds and thiol molecules.
細胞結合剤−薬剤共役体
本発明の共役体は、以下の式で表すことができる。
式中、Cbは細胞結合分子であり、Lは連結体であり、「Drug1」及び「Drug2」は薬物分子であり、nは1〜20から整数であり、且つCbからの2個のS(硫黄)原子は、架橋的にLと連結し、架橋連結体L1個あたり2以上の薬物と共有的に接続している。 In the formula, Cb is a cell binding molecule, L is a conjugate, "Drug 1 " and "Drug 2 " are drug molecules, n is an integer from 1 to 20, and two from Cb. The S (sulfur) atom is cross-linked with L and covalently linked with two or more drugs per cross-linked L.
前記架橋連結体Lは1又は複数の連結体成分で構成されていてもよい。代表的な連結体成分には、6−マレイミドカプロイル(MC)、マレイミドプロパノイル(MP)、バリン−シトルリン(val−cit又はvc)、アラニン−フェニルアラニン(ala−phe又はaf)、p−アミノベンジルオキシカルボニル(PAB)、4−チオペンタノエート(SPP)、4−(N−マレイミドメチル)シクロヘキサン−1−カルボン酸エステル(MCC)、(4−アセチル)アミノ安息香酸(SIAB)、4−チオ−ブチレート(SPDB)、4−チオ−2−ヒドロキシスルホニル−ブチレート(2−sulfo−SPDB)、1又は複数の繰り返し単位としてエチレンオキシ(−CH2CH2O−)単位(EO又はPEO)が挙げられる。追加的な連結体成分は本発明の技術分野で公知であり、ここではその一部を記載する。 The crosslinked conjugate L may be composed of one or a plurality of conjugate components. Typical conjugate components include 6-maleimide caproyl (MC), maleimide propanoyl (MP), valine-citrulin (val-cit or vc), alanine-phenylalanine (ala-phe or af), p-amino. Phenyloxycarbonyl (PAB), 4-thiopentanoate (SPP), 4- (N-maleimidemethyl) cyclohexane-1-carboxylic acid ester (MCC), (4-acetyl) aminobenzoic acid (SIAB), 4- Thio-butylate (SPDB), 4-thio-2-hydroxysulfonyl-butylate (2-sulfo-SPDB), or ethyleneoxy (-CH 2 CH 2 O-) units (EO or PEO) as one or more repeating units Can be mentioned. Additional conjugate components are known in the art of the present invention, some of which are described herein.
連結体を含むこれらの成分の構造の例を次に示す。
好ましくは、前記共役体は、下記式(II)の化合物である:
式中、Cbは細胞結合分子、好ましくは抗体を表す。 In the formula, Cb represents a cell binding molecule, preferably an antibody.
「Drug1」及び「Drug2」は、アルキル、アルキレン、アルケニレン、アルキニレン、エーテル、ポリオキシアルキレン、エステル、アミン、イミン、ポリアミン、ヒドラジン、ヒドラゾン、アミド、尿素、セミカルバジド、カルバジド、アルコキシアミン、ウレタン、アミノ酸、ペプチド、アシルオキシルアミン、ヒドロキサム酸、ジスルフィド、チオエーテル、チオエステル、カルバメート、カーボネート、複素環、ヘテロアルキル、ヘテロ芳香環、若しくはアルコキシム結合、又はその組み合わせによって、架橋連結体を介して前記細胞結合分子と連結した、同一の又は異なる細胞毒性剤を表す。 "Drug 1 " and "Drug 2 " are alkyl, alkylene, alkenylene, alkynylene, ether, polyoxyalkylene, ester, amine, imine, polyamine, hydrazine, hydrazone, amide, urea, semicarbazide, carbazide, alkoxyamine, urethane, Amino acids, peptides, acyloxylamines, hydroxamic acids, disulfides, thioethers, thioesters, carbamate, carbonates, heterocyclics, heteroalkyls, heteroaromatic rings, or alkoxy bonds, or combinations thereof, via cross-linking molecules. Represents the same or different cytotoxic agent linked with.
ブラケット (括弧)の内部は、一対のジスルフィド結合を介して、前記細胞結合分子
と共役された連結体−薬剤成分であり、前記共役可能なチオール原子は、一般的に、TCEP及び/又はDTTによる細胞結合分子上の一対のジスルフィド結合の還元から生成することができる;
Inside the bracket is a conjugate-drug component conjugated to the cell binding molecule via a pair of disulfide bonds, and the conjugatable thiol atom is generally by TCEP and / or DTT. It can be produced from the reduction of a pair of disulfide bonds on a cell binding molecule;
nは1〜20である。R1、R2、R3、及びR4は、前述の式(I)に記載のものと同じである。 n is 1 to 20. R 1, R 2, R 3 , and R 4 are the same as those described in the aforementioned formula (I).
以下に詳述するように、「Drug1」及び「Drug2」は、多くの小分子医薬品のいずれであってもよく、チューブリシン類、カリケアマイシン類、オーリスタチン類、メイタンシノイド類、CC−1065類縁体、モルホリノ類、ドキソルビシン類、タキサン類、クリプトフィシン類、エポチロン類、及びベンゾジアゼピン二量体(例えば、ピロロベンゾジアゼピン(PBD)又はトマイマイシン)、インドリノベンゾジアゼピン類、イミダゾベンゾチアジアゼピン、又はオキサゾリジノベンゾジアゼピン類の二量体)が含まれるが、これらに限定されない。 As detailed below, "Drug 1 " and "Drug 2 " may be any of many small molecule drugs, such as tubericins, calikeamycins, auristatins, maytansinoids, CC-1065 relatives, morpholinos, doxorubicins, taxans, cryptophycins, epothilones, and benzodiazepine dimers (eg, pyrolobenzodiazepines (PBDs) or tomymycins), indolinobenzodiazepines, imidazole benzothiazepines, Alternatively, oxazolidinobenzodiazepine dimer) is included, but is not limited thereto.
共役体を合成するために、細胞結合分子は、細胞結合分子中のジスルフィド結合の還元を通じて本発明の架橋連結体により最初に修飾することができる。Z1及びZ2の反応性基を導入するために、得られた一対の遊離チオールは、例えば、DMA、DMF、エタノール、メタノール、アセトン、アセトニトリル、THF、イソプロパノール、ジオキサン、プロピレングリコール、又はエチレンジオールのような水可溶性(混和性)有機溶媒の0〜30%の添加の有無にかかわらず、pH5〜9の水性媒体において、式(I)の架橋連結体と反応することができ、ここで、反応性基は、ジスルフィド、マレイミド、ハロアセチル、アジド、1−イン、ケトン、アルデヒド、アルコキシアミノ、又はヒドラジドとすることができる。次いで、細胞毒性剤の反応性基は、適宜に修飾された細胞結合分子に反応する。例えば、ジスルフィド結合を介して連結された細胞結合剤−薬剤共役体の合成は、修飾された細胞結合剤中のジスルフィド結合と遊離チオール基を含む薬剤との間のジスルフィド交換によって達成される。チオエーテルを介して連結された細胞結合剤−薬剤共役体の合成は、マレイミド又はハロアセチル又はエチルスルホニル修飾細胞結合剤と遊離チオール基を含む薬剤との反応により達成される。酸不安定ヒドラゾンを有する共役体の合成は、当該分野で公知の方法によるカルボニル基と連結体中のヒドラジド残基との反応によって達成することができる(例えば、P. Hamann et al., Hinman, L. M., et al, Cancer Res. 53, 3336-334, 1993; B. Laguzza et al., J. Med. Chem., 32; 548-555, 1959; P. Trail et al., Cancer Res., 57; 100-105, 1997)。トリアゾール結合を有する共役体の合成は、クリックケミストリー(Huisgen環付加)を介した薬剤中の1−イン基
と連結体中のアジド残基との反応によって達成することができる(Lutz, J-F. et al, 2008, Adv. Drug Del. Rev. 60, 958-970; Sletten, E. M. et al 2011, Acc Chem. Research 44, 666-676)。
To synthesize conjugates, cell binding molecules can be first modified by the crosslinked conjugates of the invention through reduction of disulfide bonds in the cell binding molecules. To introduce the reactive groups of Z 1 and Z 2 , the resulting pair of free thiols may be, for example, DMA, DMF, ethanol, methanol, acetone, acetonitrile, THF, isopropanol, dioxane, propylene glycol, or ethylene diol. With or without the addition of 0-30% of a water-soluble (miscible) organic solvent such as, in an aqueous medium of pH 5-9, it can react with the crosslinked conjugate of formula (I), where. The reactive group can be disulfide, maleimide, haloacetyl, azide, 1-in, ketone, aldehyde, alkoxyamino, or hydrazide. The reactive group of the cytotoxic agent then reacts with the appropriately modified cell binding molecule. For example, the synthesis of a cell binding agent-drug conjugate linked via a disulfide bond is achieved by disulfide exchange between the disulfide bond in the modified cell binding agent and the drug containing the free thiol group. Synthesis of cell binder-drug conjugates linked via thioether is accomplished by reaction of maleimide or haloacetyl or ethylsulfonyl modified cell binders with drugs containing free thiol groups. Synthesis of conjugates with acid-labile hydrazone can be achieved by reaction of carbonyl groups with hydrazide residues in the conjugate by methods known in the art (eg, P. Hamann et al., Hinman, LM, et al, Cancer Res. 53, 3336-334, 1993; B. Laguzza et al., J. Med. Chem., 32; 548-555, 1959; P. Trail et al., Cancer Res., 57 100-105, 1997). Synthesis of conjugates with triazole binding can be achieved by reaction of 1-in groups in the drug with azide residues in the conjugate via click chemistry (Huisgen cycloaddition) (Lutz, JF. Et. al, 2008, Adv. Drug Del. Rev. 60, 958-970; Sletten, EM et al 2011,
あるいは、式(III)の機能性を有する修飾細胞結合分子連結体を得るために、薬剤は、細胞結合分子に共役した本発明の架橋連結体と反応することができる。例えば、チオエーテル架橋を介した細胞結合分子−薬剤共役体を得るために、チオール含有薬剤は、pH5.5〜9.0の水性緩衝液中で、マレイミド、ハロアセチル、又はエチルスルホニル置換基を有する式(III)の修飾細胞結合分子架橋連結体と反応させることができる。ジスルフィド架橋を有する共役体を得るために、チオール含有薬剤は、ピリジルジチオ残基を有する式(III)の修飾架橋連結体とジスルフィド交換をすることができる。エーテル又はチオールエーテル結合を有する修飾薬剤を得るために、水酸基又はチオール基を有する薬剤は、マイルドな塩基、例えばpH8.0〜9.5の存在下で、ハロゲン、特にカルボン酸αハライドを有する式(III)の修飾架橋連結体と反応させることができる。水酸基を含む薬剤は、エステル架橋を得るために、EDC又はDCC等の脱水剤の存在下で、カルボキシル基を有する式(I)の架橋クロス連結体と縮合させることができ、次いで、対象薬物修飾架橋連結体と細胞結合分子との共役を行う。アミド結合架橋を介した共役体を得るために、アミノ基を含む薬剤は、式(III)の細胞結合分子−架橋連結体上で、NHS、イミダゾール、ニトロフェノールのカルボキシルエステル;N−ヒドロキシスクシンイミド(NHS); フェノール;ジニトロフェノール;ペンタフルオロフェノール;テトラフルオロフェノール;ジフルオロフェノール;モノフルオロフェノール;ペンタクロロフェノール;トリフラート;イミダゾール;ジクロロフェノール;テトラクロ
ロフェノール;1−ヒドロキシベンゾトリアゾール;トシレート;メシレート;2−エチル−5−フェニルイソキサゾリウム−3’−スルホネートと縮合することができる。
Alternatively, in order to obtain a modified cell-binding molecule conjugate having the functionality of formula (III), the agent can react with the crosslinked conjugate of the invention conjugated to the cell-binding molecule. For example, to obtain a cell junction molecule-drug conjugate via thioether cross-linking, the thiol-containing drug may have a maleimide, haloacetyl, or ethylsulfonyl substituent in an aqueous buffer at pH 5.5-9.0. It can be reacted with the modified cell-binding molecule cross-linked conjugate of (III). To obtain a conjugate having a disulfide bridge, the thiol-containing agent can undergo a disulfide exchange with a modified crosslinked conjugate of formula (III) having a pyridyldithio residue. To obtain a modified agent with an ether or thiol ether bond, the agent with a hydroxyl or thiol group has a halogen, especially a carboxylic acid α-halide, in the presence of a mild base, eg pH 8.0-9.5. It can be reacted with the modified crosslinked conjugate of (III). A drug containing a hydroxyl group can be condensed with a crosslinked crosslink of formula (I) having a carboxyl group in the presence of a dehydrating agent such as EDC or DCC in order to obtain an ester crosslink, and then the target drug modification. Coupling the crosslinked conjugate with the cell-binding molecule. In order to obtain a conjugate via amide bond cross-linking, the agent containing an amino group is a carboxyl ester of NHS, imidazole, nitrophenol on the cell-binding molecule-bridge conjugate of formula (III); N-hydroxysuccinimide ( NHS); Phenol; Dinitrophenol; Pentafluorophenol; Tetrafluorophenol; Difluorophenol; Monofluorophenol; Pentachlorophenol; Triflate; Imidazole; Dichlorophenol; Tetrachlorophenol; 1-Hydroxybenzotriazole; Tosilate; Mecilate; 2- It can be condensed with ethyl-5-phenylisoxazolium-3'-sulfonate.
共役体は、標準的な生物化学方法、例えばSephadex G25又はSephacryl S300カラムによるゲルろ過、吸着クロマトグラフィー、イオン交換、又は透析によりで精製することができる、いくつかの場合では、細胞結合分子として小分子(例えば、葉酸、メラニン細胞刺激ホルモン、EGF等)を小分子薬剤で共役させた場合、クロマトグラフィー、例えばHPLC、中圧カラムクロマトグラフィー、又はイオン交換クロマトグラフィーによって精製することができる。 Conjugates can be purified by standard biochemical methods such as gel filtration, adsorption chromatography, ion exchange, or dialysis with a Sephadex G25 or Sephacryl S300 column, in some cases small as cell binding molecules. When a molecule (eg, folic acid, melanin cell stimulating hormone, EGF, etc.) is conjugated with a small molecule agent, it can be purified by chromatography, such as HPLC, medium pressure column chromatography, or ion exchange chromatography.
修飾された細胞結合剤/分子
本発明の連結体との反応により修飾された細胞結合剤は、好ましくは式(III)で表される。
式中、Cb、Z1、Z2、n、R1、R2、R3、及びR4は、式(I)及び(II)と同じ定義である。 In the formula, Cb, Z 1 , Z 2 , n, R 1 , R 2 , R 3 and R 4 have the same definitions as in formulas (I) and (II).
好ましい態様において、Z1及びZ2は、ジスルフィド置換基、マレイミド、ハロアセチル、アルコキシアミン、アジド、ケトン、アルデヒド、ヒドラジン基、N−ヒドロキシスクシンイミドエステル、又はフェノール;ジニトロフェノール;ペンタフルオロフェノール;テトラフルオロフェノール;ジフルオロフェノール;モノフルオロフェノール;ペンタクロロフェノール;トリフラート;イミダゾール;ジクロロフェノール;テトラクロロフェノール;1−ヒドロキシベンゾトリアゾール;トシレート;メシレート;2−エチル−5−フェニルイソキサゾリウム−3’−スルホネートで形成されたカルボン酸エステルである。次いで、Z1及びZ2は、チオエーテル、ヒドラゾン、アミド、アルコキシム、カルバメート、エステル、エーテル、又はジスルフィド結合によって、細胞毒性剤と反応することができる。前記修飾された細胞結合剤は、上記式(II)に記載されたものとして、式(I)の架橋連結体と細胞結合剤との反応を介して調製することができる。 In a preferred embodiment, Z 1 and Z 2 are disulfide substituents, maleimides, haloacetyls, alkoxyamines, azides, ketones, aldehydes, hydrazine groups, N-hydroxysuccinimid esters, or phenols; dinitrophenols; pentafluorophenols; tetrafluorophenols. Difluorophenol; Monofluorophenol; Pentachlorophenol; Triflate; Imidazole; Dichlorophenol; Tetrachlorophenol; 1-Hydroxybenzotriazole; Tosylate; Mecilate; 2-Ethyl-5-phenylisoxazolium-3'-sulfonate It is a formed carboxylic acid ester. Z 1 and Z 2 can then react with the cytotoxic agent by thioether, hydrazone, amide, alkoxy, carbamate, ester, ether, or disulfide bond. The modified cell binder can be prepared as described in the above formula (II) through the reaction of the crosslinked conjugate of the formula (I) with the cell binder.
細胞結合分子上の一対の遊離チオールと式(I)の架橋連結体上の官能基Y1及びY2との反応のより高い共役収率を達成するために、反応混合物へ小割合の有機共溶媒を添加することを要求してもよく、同様に、水性溶液中での式(III)の溶解性を維持するために、反応後の溶液へ添加することを要求してもよい。細胞結合剤を修飾するには、最初に、式(I)の架橋試薬(架橋連結体)を、水と混和可能な極性有機溶媒、例えばメタノール、エタノール、プロパノール等の異なるアルコール、アセトン、アセトニトリル、テトラヒドロフラン(THF)、1,4−ジオキサン、ジメチルホルムアミド(DMF)、ジメチルアセトアミド (DMA)、又はジメチルスルホキシド(DMSO)を、高濃度
、例えば1〜500mMで溶解させることができる。一方、pH5〜9.5、好ましくは6〜8.5の水性緩衝液中で濃度1〜35mg/mlで溶解した抗体等の細胞結合分子は、1〜20当量のTCEP又はDTTで20分から12時間処理される。還元後、SECクロマトグラフィー精製によりDTTを除去することができる。TCEPもまた、所望により、SECクロマトグラフィーにより除去することができ、あるいは、精製せずに次工
程反応のための反応混合物に滞留させることができる。更に、TCEP還元と同時に細胞結合分子の架橋共役を実現するために、TCEPによる抗体又はその他の細胞結合剤の還元は、式(I)の架橋連結体の存在下で行うことができる。架橋反応後、過剰に還元されたジスルフィド結合は、ジスルフィド結合を再生するために、DHAA又はCu(II)によって酸化することができ、あるいは、遊離のチオールは、N−エチルマレイミド、ヨード酢酸ナトリウム、ブロモ酢酸ナトリウム、ブロモ酢酸メチルエステル等のチオール反応性分子でキャップすることができる。
In order to achieve higher conjugation yield of the reaction with the functional groups Y 1 and Y 2 on a pair of free thiol crosslinking connection of formula (I) on the cell binding molecules, small proportion of organic co to the reaction mixture A solvent may be required to be added, and similarly, it may be required to be added to the solution after the reaction in order to maintain the solubility of formula (III) in the aqueous solution. To modify the cell binding agent, first, the cross-linking reagent (cross-linking) of formula (I) is miscible with water, such as different alcohols such as methanol, ethanol, propanol, acetone, acetonitrile, etc. Tetrahydrofuran (THF), 1,4-dioxane, dimethylformamide (DMF), dimethylacetamide (DMA), or dimethyl sulfoxide (DMSO) can be dissolved at high concentrations, such as 1-500 mM. On the other hand, cell-binding molecules such as antibodies dissolved at a concentration of 1 to 35 mg / ml in an aqueous buffer solution having a pH of 5 to 9.5, preferably 6 to 8.5 are used in 1 to 20 equivalents of TCEP or DTT for 20 minutes to 12 minutes. Time processed. After reduction, DTT can be removed by SEC chromatographic purification. TCEP can also be removed by SEC chromatography, if desired, or retained in the reaction mixture for the next step reaction without purification. Furthermore, in order to achieve cross-linking conjugation of the cell-binding molecule at the same time as TCEP reduction, the reduction of the antibody or other cell-binding agent by TCEP can be carried out in the presence of the cross-linked conjugate of formula (I). After the cross-linking reaction, the over-reduced disulfide bonds can be oxidized by DHAA or Cu (II) to regenerate the disulfide bonds, or the free thiols are N-ethylmaleimide, sodium iodoacetate, It can be capped with a thiol-reactive molecule such as sodium bromoacetate or methyl bromoacetate.
細胞結合剤の修飾のための水系溶液は、pH6〜9、好ましくは6.5〜7.5の間で緩衝され、これらのpH範囲に有用な非求核性緩衝塩を含むことができる。代表的な緩衝剤としては、リン酸塩、トリエタノールアミンHCl、HEPES、及びMOPS緩衝剤が挙げられ、更に、例えばデキストリン、ショ糖、塩(例えば、NaCl、KCl)等の追加の成分を含むことができる。還元された細胞結合分子を含む溶液中に式(I)の架橋連結体を添加した後、反応混合物を4℃〜45℃、好ましくは周囲温度でインキュベートする。反応の進行状況は、254nmでの吸収の減少又は280nmでの吸収の増加、あるいはその他の適切な波長での変化を測定することによって監視することができる。反応が完了した後、修飾細胞結合剤の単離は、常用の方法、例えば、ゲルろ過クロマトグラフィー又は吸着クロマトグラフィーにより行うことができる。 Aqueous solutions for modification of cell binders are buffered between pH 6-9, preferably 6.5-7.5 and can contain non-nucleophilic buffer salts useful in these pH ranges. Representative buffers include phosphates, triethanolamine HCl, HEPES, and MOPS buffers, which further include additional components such as, for example, dextrin, sucrose, salts (eg, NaCl, KCl). be able to. After adding the crosslinked conjugate of formula (I) to the solution containing the reduced cell binding molecule, the reaction mixture is incubated at 4 ° C. to 45 ° C., preferably ambient temperature. The progress of the reaction can be monitored by measuring a decrease in absorption at 254 nm or an increase in absorption at 280 nm, or any other change at a suitable wavelength. After the reaction is complete, isolation of the modified cell binder can be performed by conventional methods, such as gel filtration chromatography or adsorption chromatography.
修飾の程度は、UVスペクトルを介して放出されるニトロピリジンチオン、ジニトロピリジンジチオン、ピリジンチオン、カルボキシアミドピリジンジチオン、及びジカルボキシアミドピリジンジチオン基の吸光度を測定することによって評価することができる。発色団基を有しない共役体において、修飾又は共役反応は、LC−MS、好ましくはUPLC−QTOF質量分析法、又はキャピラリー電気泳動法(CEMS)により監視することができる。本明細書に記載されている架橋連結体は、適宜の置換基を有する任意の薬剤、好ましくは細胞毒性剤と反応し得る多様な官能基を有する。例えば、アミノ又はヒドロキシ置換基を有する修飾細胞結合分子は、N−ヒドロキシスクシンイミド(NHS)エステルを有する薬剤と反応することができ、チオール置換基を有する修飾細胞結合分子は、マレイミド又はハロアセチル基を有する薬剤と反応することができる。更に、カルボニル置換基(ケトン又はアルデヒド)を有する修飾細胞結合分子は、ヒドラジド又はアルキルオキシアミンを有する薬剤と反応することができる。当業者は、連結体上の利用可能な官能基の既知の反応性に基づいて、使用する連結体を容易に決定することができる。 The degree of modification can be assessed by measuring the absorbance of the nitropyridinethion, dinitropyridinedithione, pyridinethion, carboxylamidepyridinedithione, and dicarboxyamidepyridinedithione groups emitted via the UV spectrum. In conjugates without chromophores, the modification or conjugate reaction can be monitored by LC-MS, preferably UPLC-QTOF mass spectrometry, or capillary electrophoresis (CEMS). The crosslinked conjugates described herein have a variety of functional groups capable of reacting with any agent, preferably a cytotoxic agent, having the appropriate substituents. For example, a modified cell binding molecule with an amino or hydroxy substituent can react with a drug having an N-hydroxysuccinimide (NHS) ester, and a modified cell binding molecule with a thiol substituent has a maleimide or haloacetyl group. Can react with drugs. In addition, modified cell binding molecules with carbonyl substituents (ketones or aldehydes) can react with agents with hydrazides or alkyloxyamines. One of ordinary skill in the art can readily determine which conjugate to use based on the known reactivity of the available functional groups on the conjugate.
修飾された細胞毒性剤
本発明の架橋連結体との反応により修飾された細胞毒性剤は、好ましくは式(IV)で表される。
式中、Y1、Y2、Drug1、Drug2、R1、R2、R3、及びR4は、式(I)及び(II)と同じ定義である。 In the formula, Y 1 , Y 2 , Drug 1 , Drug 2 , R 1 , R 2 , R 3 , and R 4 have the same definitions as those in formulas (I) and (II).
好ましい態様において、Y1及びY2は、ジスルフィド置換基;マレイミド;ハロアセチル;カルボン酸;カルボン酸ハロゲン化物;エテンスルホニル;アクリル(アクリロイ
ル);カルボン酸無水物;N−ヒドロキシスクシンイミドエステル;又はフェノール、ジニトロフェノール、ペンタフルオロフェノール、テトラフルオロフェノール、ジフルオロフェノール、モノフルオロフェノール、ペンタクロロフェノール、トリフラート、イミダゾール、ジクロロフェノール、テトラクロロフェノール、1−ヒドロキシベンゾトリアゾール、トシレート、メシレート、2−エチル−5−フェニルイソキサゾリウム−3’−スルホネートで形成されたエステルである。
In a preferred embodiment, Y 1 and Y 2 are disulfide substituents; maleimide; haloacetyl; carboxylic acid; carboxylic acid halide; ethensulfonyl; acrylic (acryloyl); carboxylic acid anhydride; N-hydroxysuccinimide ester; or phenol, dinitro. Phenol, pentafluorophenol, tetrafluorophenol, difluorophenol, monofluorophenol, pentachlorophenol, trifurate, imidazole, dichlorophenol, tetrachlorophenol, 1-hydroxybenzotriazole, tosylate, mesylate, 2-ethyl-5-phenyliso It is an ester formed of xazolium-3'-sulfonate.
細胞結合剤の一対のチオール基と反応し得るY1及びY2基の機能性を有する式(IV)の修飾薬物を得るために、前記修飾薬物は、前記式(I)の連結体と薬剤との反応を経て調製することができる。しかしながら、チオールを含む薬剤の場合、あるいはチオエーテル、チオエステル、又はジスルフィド結合により架橋連結体を介して細胞結合分子と結合する薬剤の場合、好ましくは、Drug1又はDrug2は最初に、チオエーテル、チオエステル、又はジスルフィド結合の連結を介して、R3又はR4の成分の一部と接続するように合成されてもよい。次いで、式(IV)の架橋連結体修飾薬物を形成するために、合成されたR3−Drug1又はR4−Drug2成分がヒドラジン基に組み付けられる。 In order to obtain a modified drug of formula (IV) having the functionality of Y 1 and Y 2 groups capable of reacting with a pair of thiol groups of a cell binder, the modified drug is a conjugate and drug of the formula (I). It can be prepared through the reaction with. However, in the case of drugs containing thiols, or in the case of drugs that bind to cell-binding molecules via cross-linked conjugates via thioethers, thioesters, or disulfide bonds, preferably Drug 1 or Drug 2 is first thioether, thioester, Alternatively, it may be synthesized so as to be connected to a part of the components of R 3 or R 4 via the connection of disulfide bonds. The synthesized R 3- Drug 1 or R 4- Drug 2 component is then assembled to the hydrazine group to form the crosslinked conjugate modified drug of formula (IV).
合成例について、チオエーテル結合を有するR3−Drug1又はR4−Drug2区画を得るために、チオール含有薬剤は、中性pHの水性緩衝液中で、マレイミド置換基を有する連結体の成分R3及びR4と反応させることができ、続いて、チオエーテル結合を有する式(IV)の修飾薬物を得るために、官能基Y1及びY2を含むヒドラジン基の区画で縮合させることができる。エーテル結合を有するR3−Drug1又はR4−Drug2区画を得るために、ヒドロキシ基を担持した薬剤は、マイルドな塩基の存在下で、ハロゲン、トシレート、又はメシレートを有する連結体の成分R3及びR4と反応させることができ、続いて、チオエーテル結合を有する式(IV)の修飾薬物を得るために、官能基Y1及びY2を含むヒドラジン基の区画で縮合させることができる。エステル結合を介した式(IV)の修飾薬物を得るために、ヒドロキシ基を含む薬剤は、脱水剤、例えばEDC又はジシクロヘキシルカルボジイミド(DCC)の存在下で、カルボキシル基を有する式(I)の連結体と縮合させることができる。チオエーテル結合を有するR3−Drug1又はR4−Drug2区画を得るために、チオール含有薬剤は、マレイミド、ビニルスルホニル、又はハロアセチル基を有する連結体の成分R3及びR4と反応させることもでき、続いて、チオエーテル結合を有する式(IV)の修飾薬物を得るために、官能基Y1及びY2を含むヒドラジン基の区画で縮合させることができる。アミド結合を有する式(IV)の修飾薬物を得るために、アミノ基を有する薬剤は、同様に、式(I)の架橋連結体上のカルボキシル基と縮合させることができる。修飾薬物は、シリカゲル若しくはアルミナのカラムクロマトグラフィー、晶析、予備薄層クロマトグラフィー、イオン交換クロマトグラフィー、又はHPLC等の標準的な方法により精製することができる。 For synthetic examples, in order to obtain an R 3- Drug 1 or R 4- Drug 2 compartment with a thioether bond, the thiol-containing drug is a component R of the conjugate having a maleimide substituent in an aqueous buffer at neutral pH. 3 and can be reacted with R 4, subsequently, to obtain a modified drug of formula (IV) with a thioether bond, it can be condensed with compartment hydrazine group containing functional groups Y 1 and Y 2. To obtain an R 3- Drug 1 or R 4- Drug 2 compartment with an ether bond, the hydroxy group-carrying agent is the component R of the conjugate with halogen, tosylate, or mesylate in the presence of a mild base. 3 and can be reacted with R 4, subsequently, to obtain a modified drug of formula (IV) with a thioether bond, it can be condensed with compartment hydrazine group containing functional groups Y 1 and Y 2. In order to obtain the modified drug of formula (IV) via an ester bond, the agent containing a hydroxy group is linked to formula (I) having a carboxyl group in the presence of a dehydrating agent such as EDC or dicyclohexylcarbodiimide (DCC). Can be condensed with the body. To obtain an R 3- Drug 1 or R 4- Drug 2 compartment with a thioether bond, the thiol-containing drug can also be reacted with components R 3 and R 4 of a conjugate having a maleimide, vinylsulfonyl, or haloacetyl group. can, subsequently, to obtain a modified drug of formula (IV) with a thioether bond, it can be condensed with compartment hydrazine group containing functional groups Y 1 and Y 2. To obtain a modified drug of formula (IV) with an amide bond, the drug having an amino group can likewise be condensed with a carboxyl group on the crosslinked conjugate of formula (I). The modified drug can be purified by standard methods such as silica gel or alumina column chromatography, crystallization, preliminary thin layer chromatography, ion exchange chromatography, or HPLC.
細胞結合分子
本発明の共役体及び修飾された細胞結合分子を構成する細胞結合分子は、治療的に又は他の生物学的に修飾されようとする細胞群の残基と結合、複合化、又は反応する、現在知られている、あるいは判明する如何なる分子でもよい。
Cell-Binding Molecules The cell-binding molecules that make up the conjugates and modified cell-binding molecules of the invention bind, complex, or combine with residues of cell groups that are to be therapeutically or biologically modified. It can be any molecule that reacts, is currently known, or is known.
細胞結合分子には、大分子量タンパク質、例えば、抗体全長(ポリクローナルまたはモノクローナル)、二量体、多量体、多重特異性抗体(例えば、二重特異性抗体);一本鎖抗体;抗体断片、例えば、Fab,Fab’,F(ab’)2,Fv[Parham,J.Immunol.131,2895−2902(1983)]、Fab発現ライブラリによって得られた断片、抗イディオタイプ(anti−Id)抗体、CDR’s、二特異性抗体、三特異性抗体、癌細胞抗原、ウイルス抗原、微生物抗原、又は特異的抗原を認識し、結合し、若しくは望ましい生物活性を発現することができる、免疫系で生成したタン
パク質と免疫特異的に結合する任意の前記物のエピトープ結合断片;インターフェロン(例えば、I、II、III型);ペプチド;リンホカイン、例えば、IL−2、IL−3、IL−4、IL−5、IL−6、IL−10、GM−CSF、又はインターフェロンγ(IFN−γ);ホルモン、例えば、インスリン、TRH(甲状腺刺激ホルモン放出ホルモン)、MSH(細胞刺激ホルモン)、又はアンドロゲン、エストロゲン若しくはメラニン細胞刺激ホルモン(MSH)等のステロイドホルモン;成長因子及びコロニー刺激因子、例えば、上皮成長因子(EFG)、顆粒球マクロファージコロニー刺激因子(GM−CSF);トランスフォーミング増殖因子(TGF)、例えば、TGFα、TGFβ;インスリンおよびインスリン様成長因子(IGF−I、IGF−II)G−CSF,M−CSF、及びGM−CSF[Burgess,Immunology Today,5,155−158(1984)];ワクチン増殖因子(VGF);線維芽細胞増殖因子(FGF
);小分子量タンパク質、ポリペプチド、ペプチド、及びペプチドホルモン、例えば、ボンベシン、ガストリン、及びガストリン放出ペプチド;血小板由来増殖因子;インターロイキン及びサイトカイン、例えば、インターロイキン−2(IL−2)、インターロイキン−6(IL−6)、白血病阻害因子、顆粒球マクロファージコロニー刺激因子(GM−CSF);葉酸等のビタミン;アポタンパク質及び糖タンパク質、例えば、トランスフェリン[O’Keefe et al,J.Bio.Chem.260,932−927(1985)];レクチン等の糖結合タンパク質又はリポタンパク;細胞の栄養輸送分子;及び小分子阻害剤、例えば、前立腺特異的膜抗原(PSMA)の阻害剤、小分子チロシンキナーゼ阻害剤(TKI)、非ペプチド、または他の細胞結合分子または物質、例えば、生体活性ポリマー(Dhar,et al,Proc.Natl.Acad.Sci.2008,105,17356−61)、生物活性デンドリマー(Lee,et al,Nat.Biotechnol.2005,23,1517−26;Almutairi,et al;Proc.Natl.Acad.Sci.2009,106,685−90)、ナノ粒子(Liong,et al,ACS Nano,2008,19,1309−12;Medarova,et al,Nat.Med.2007,13,372−7;Javier,et al,Bioconjugate Chem.2008,19,1309−12)、リポソーム(Medinai,et al,Curr.Phar.Des.2004,10,2981−9)、ウイルスカプシド(Flenniken,et
al,Viruses Nanotechnol.2009,327,71−93)を含むが、これらに限定されない。
Cell-binding molecules include large molecular weight proteins such as antibody full length (polyclonal or monoclonal), dimers, multimers, multispecific antibodies (eg bispecific antibodies); single chain antibodies; antibody fragments, eg. , Fab, Fab', F (ab') 2 , Fv [Parham, J. et al. Immunol. 131,295-2902 (1983)], Fragment obtained by Fab expression library, anti-idiotype (anti-Id) antibody, CDR's, bispecific antibody, trispecific antibody, cancer cell antigen, viral antigen, An epitope-binding fragment of any of the above that immunospecifically binds to a protein produced in the immune system capable of recognizing and binding to a microbial antigen, or specific antigen, or expressing the desired biological activity; interferon (eg, interferon). , I, II, III); Peptide; phosphorus hockeyin, eg IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, GM-CSF, or interferon γ (IFN-γ) ); Hormones such as insulin, TRH (thyroid stimulating hormone releasing hormone), MSH (cell stimulating hormone), or steroid hormones such as androgen, estrogen or melanin cell stimulating hormone (MSH); growth factors and colony stimulating factors such as Epithelial growth factor (EFG), granulocyte macrophage colony stimulator (GM-CSF); transforming growth factor (TGF), such as TGFα, TGFβ; insulin and insulin-like growth factors (IGF-I, IGF-II) G- CSF, M-CSF, and GM-CSF [Burges, Immunology Today, 5,155-158 (1984)]; Vaccine Growth Factor (VGF); Fibroblast Growth Factor (FGF)
); Small molecular weight proteins, polypeptides, peptides, and peptide hormones, such as bombesin, gastrin, and gustrin-releasing peptides; platelet-derived growth factors; interleukins and cytokines, such as interleukin-2 (IL-2), interleukin. -6 (IL-6), leukemia inhibitor, granulocyte macrophage colony stimulating factor (GM-CSF); vitamins such as folic acid; apoproteins and glycoproteins, such as transferase [O'Keefe et al, J. et al. Bio. Chem. 260, 923-927 (1985)]; sugar-binding proteins such as lectin or lipoproteins; cell nutrient transport molecules; and small molecule inhibitors, such as inhibitors of prostate-specific membrane antigens (PSMA), small molecule tyrosine kinases. Inhibitors (TKIs), non-peptides, or other cell-binding molecules or substances, such as bioactive polymers (Dhar, et al, Proc. Natl. Acad. Sci. 2008, 105, 17356-61), bioactive dendrimers ( Lee, et al, Nat. Biotechnol. 2005, 23, 1517-26; Almutari, et al; Proc. Natl. Acad. Sci. 2009, 106, 685-90), nanoparticles (Ling, et al, ACS Nano, 2008, 19, 1309-12; Medalova, et al, Nat. Med. 2007, 13, 372-7; Javier, et al, Bioconjugate Protein. 2008, 19, 1309-12), liposomes (Medinai, et al, Curr) .Phar.Des.2004,10,2981-9), virus capsid (Flenniken, et.
al, Virus Nanotechnol. 2009, 327, 71-93), but not limited to these.
一般的に、適当なモノクローナル抗体が利用できれば、モノクローナル抗体は細胞表面結語分子として好ましい。抗体は、マウス、ヒト、ヒト化、キメラ、又は他の種由来のものでもよい。 In general, monoclonal antibodies are preferred as cell surface concluding molecules if suitable monoclonal antibodies are available. Antibodies may be of mouse, human, humanized, chimeric, or other species origin.
本発明で用いられる抗体の産生には、in vivo又はin vitroでの生成プロセス又はその組み合わせが含まれる。抗受容体ペプチドポリクローナル抗体の調製方法は、例えば、米国特許番号4,493,795(Nestor等)に示すように周知である。モノクローナル抗体を調製するための典型的な方法は、特定の抗原免疫化マウスから単離したマウス脾臓細胞とミエローマ細胞とを融合させるとの方法である(Kohler,G;Milstein,C.1975.Nature 256:495−497)。詳しい操作方法に関して、antibodies−A Laboratory Manual,Harlow and Lane,eds.,cold spring harbor laboratory press,new York(1988)に記載されており、ここに本明細書の一部を構成するものとして、当該文献の内容を援用する。特に、目的の抗原でマウス、ラット、ハムスター、または他の哺乳動物を免疫させる方法により、モノクローナル抗体を獲得することができ、目的の抗原として、例えば、無傷の標的細胞、標的細胞から単離された抗原、全ウイルス、弱体化した全ウイルス及びウイルスタンパク質が挙げられる。PEG6000を用いて脾臓細胞とミエローマ細胞を融合させる。融
合後得られたハイブリドーマについて、HATに対する感度を利用して、スクリーニングする。本発明の実施に有用なモノクローナル抗体を産生するハイブリドーマは、特定の標的細胞受容体との免疫反応又は受容体活性の抑制を行うことにより同定される。
The production of antibodies used in the present invention includes in vivo or in vitro production processes or combinations thereof. Methods for preparing anti-receptor peptide polyclonal antibodies are well known, for example, as shown in US Pat. No. 4,493,795 (Nestor et al.). A typical method for preparing monoclonal antibodies is to fuse mouse spleen cells isolated from specific antigen-immunized mice with myeloma cells (Kohler, G; Milstein, C. 1975. Nature). 256: 495-497). For detailed operation methods, see Antibodies-A Laboratory Manual, Harlow and Line, eds. , Cold spring harbor laboratory press, new York (1988), the contents of which are incorporated herein by reference as they form part of this specification. In particular, monoclonal antibodies can be obtained by immunizing mice, rats, hamsters, or other mammals with the antigen of interest, and as the antigen of interest, for example, isolated from intact target cells, target cells. Antigens, all viruses, all weakened viruses and viral proteins. Spleen cells and myeloma cells are fused using PEG6000. The hybridomas obtained after fusion are screened using the sensitivity to HAT. Hybridomas that produce monoclonal antibodies useful in the practice of the present invention are identified by performing an immune response with a particular target cell receptor or by suppressing receptor activity.
本願発明で用いられるモノクローナル抗体は、適切な抗原特異性を有する抗体を分泌するハイブリドーマ細胞を含む栄養培地でモノクローナルハイブリドーマ細胞の培養を開始することにより得ることができる。該培養では、ハイブリドーマ細胞が抗体を培養培地中に分泌するのに十分な時間及び条件を維持する必要がある。抗体含有培地上清を回収した後、周知の技術、例えばプロテインAアフィニティークロマトグラフィー、陰イオン交換クロマトグラフィー、陽イオン交換クロマトグラフィー、疎水性相互作用クロマトグラフィー、及び分子篩クロマトグラフィー(特に、抗原架橋プロテインAを用いたアフィニティークロマトグラフィー及び分子篩クロマトグラフィー)、遠心分離、沈殿法、又は他のタンパク質を精製するための標準的な方法により、抗体を単離することができる。 The monoclonal antibody used in the present invention can be obtained by initiating culturing of monoclonal hybridoma cells in a nutrient medium containing hybridoma cells secreting an antibody having appropriate antigen specificity. In the culture, it is necessary to maintain sufficient time and conditions for the hybridoma cells to secrete the antibody into the culture medium. After collecting the antibody-containing medium supernatant, well-known techniques such as protein A affinity chromatography, anion exchange chromatography, cation exchange chromatography, hydrophobic interaction chromatography, and molecular sieve chromatography (particularly antigen cross-linking proteins) Affinity chromatography and molecular sieve chromatography using A), centrifugation, precipitation, or standard methods for purifying other proteins can be used to isolate the antibody.
ハイブリドーマ培養に必要な培地及び人工合成培地は技術合成又は商業ルートを介して獲得することができる。そのうち、典型的な人工合成培地は、DMEM(Dulbeccoなど、Virol8:396(1959))に、4.5mg/Lのグルコース、0〜20mMのグルタミン、0〜20%のFBS、ppm量のいくつかの重金属(例えば、Cu、Mn、Fe、又はZn)又は/及び塩形態で加えた重金属、並びに消泡剤(例えば、ポリオキシエチレンポリオキシプロピレンブロック共重合体)を加えたものである。 Medium and artificial synthetic media required for hybridoma culture can be obtained via technical synthesis or commercial routes. Among them, typical artificial synthetic media are DMEM (Dulvecco et al., Virol 8: 396 (1959)) with 4.5 mg / L glucose, 0 to 20 mM glutamine, 0 to 20% FBS, and some ppm amounts. Heavy metals (eg, Cu, Mn, Fe, or Zn) and / or heavy metals added in salt form, and defoamers (eg, polyoxyethylene polyoxypropylene block copolymers) are added.
更に、細胞融合技術以外に、下記の方法によっても抗体を生成するための細胞株を構築することができる。例えば、発癌性DNAによるBリンパ球の直接的トランスフォーメーション、又は発癌性ウイルス、例えばエプスタイン−バールウイルス(EBV、ヒトヘルペスウイルス4(HHV−4)としても知られている。)若しくはカポシ肉腫関連ウイルス(KSHV)のトランスフェクションがある(詳しくは、米国特許番号4341761;4399121;4427783; 4444887; 4451570; 44669
17;4472500; 4491632; 4493890を参照)。モノクローナル抗体は、既知の方法に基づいて、抗受容体ペプチド、又は末端カルボキシル基含有ペプチドにより調製されることができる(詳しくは、Niman等Proc.Natl. Acad.
Sci. USA,80:4949−4953(1983);Geysen 等Proc.Natl. Acad. Sci. USA,82:178−182(1985); Lei等Biochemistry 34(20):6675−6688(1995)を参照)。通常
、抗受容体ポリペプチドまたはポリペプチド類似体は、モノクローナル抗体の抗受容体ポリペプチドを調製するための免疫原として、単独で、又は架橋免疫原性担体に使用することができる。
Furthermore, in addition to the cell fusion technique, a cell line for producing an antibody can also be constructed by the following method. For example, direct transformation of B lymphocytes by carcinogenic DNA, or carcinogenic viruses such as Epstein-Barr virus (EBV, also known as human herpesvirus 4 (HHV-4)) or Kaposi sarcoma-related virus. There is a transfection of (KSHV) (more specifically, US Pat. No. 4,341,761; 4399121; 4427783; 4444887; 4451570; 44669.
17; 4472500; 4491632; see 4493890). Monoclonal antibodies can be prepared with anti-receptor peptides or terminal carboxyl group-containing peptides based on known methods (see, for details, Proc. Natl. Acad.
Sci. USA, 80: 4949-4953 (1983); Geysen et al. Proc. Natl. Acad. Sci. USA, 82: 178-182 (1985); Lei et al. Biochemistry 34 (20): 6675-6688 (1995). ). Generally, anti-receptor polypeptides or polypeptide analogs can be used alone or as cross-linked immunogenic carriers as immunogens for preparing anti-receptor polypeptides for monoclonal antibodies.
本発明の結合分子としての抗体を製造するために、他の常用の製造方法もある。そのうち、特に注目されたのは、完全ヒト抗体の製造方法である。ファージディスプレイ技術は、親和性選択によって完全ヒト抗体ライブラリから、既知の抗原に特異的に結合する完全ヒト抗体を得られる。文献には、ファージディスプレイ技術そのもの、ベクトルの構築、及びライブラリのスクリーニングについて詳しい記載がある。詳しくは、Dente等 Gene.148(1):7−13(1994);Little等 Biotechnol Adv.12(3):539−55(1994);Clackson等 Nature 352:264−628(1991);Huse等 Science 246:1275−1281(1989)を参照。 There are other commonly used production methods for producing antibodies as binding molecules of the present invention. Of these, the method of producing a fully human antibody has attracted particular attention. Phage display technology provides fully human antibodies that specifically bind to known antigens from the fully human antibody library by affinity selection. The literature provides detailed information on phage display technology itself, vector construction, and library screening. For details, see Gene. Gene. 148 (1): 7-13 (1994); Little et al. Biotechnol Adv. 12 (3): 539-55 (1994); Clackson et al. Nature 352: 264-628 (1991); Huse et al. Science 246: 1275-1281 (1989).
ハイブリドーマ技術を用いて他の種(例:マウス)から得られたモノクローナル抗体について、ヒト化する必要がある。ヒト化された抗体は、人体に対する異種抗体の免疫副作用を大幅に低減することができる。そのうち、抗体のヒト化に関してよく知られている方
法は、相補性決定領域の移植及びリモデリングである。詳しくは、米国特許第5,859,205号及び第6,797,492号;Liu等,Immunol Rev.222:9−27(2008);Almagro等,Front Biosci.1;13:1619−33(2008);Lazar等,Mol Immunol.44(8):1986−98(2007);Li等 Proc.Natl.Acad.Sci.USA.103(10):3557−62(2006)を参照。前記文献の開示は参照として組み込まれる。完全ヒト抗体は、ヒト免疫グロブリン軽鎖および重鎖を大量に保有するトランスジェニックマウス、ウサギ、サルその他の哺乳動物に対し抗原免疫を行うことにより調製することができる。マウスを例に、Xenomouse(Abgenix,Inc.),HuMab−Mouse(Medarex/BMS),VelociMouse(Regeneron)がいる。詳しくは、米国特許第6,596,541号、6,207,418号、6,150,584号、6,111,166号、6,075,181号、5,922,545号、5,661,016号、5,545,806号、5,436,149号及び5,569,825号を参照。ヒトの治療の過程では、マウス抗体可変領域遺伝子及びヒト抗体定常領域遺伝子を統合して構築されたキメラ抗体がヒトの体内で産生する免疫原性は、マウス抗体よりもはるかに低くなる(Kipriyanov等,Mol Biotechnol.26:39−60(2004);Houdebine,Curr Opin
Biotechnol.13:625−9(2002))。前記文献の開示は参照として組み込まれる。さらに、抗体可変領域の部位に特異的突然変異誘発をすることにより、抗体親和性及び特異性を向上させることができる(Brannigan等,Nat Rev Mol Cell Biol.3:964−70(2002);Adams等,J.
Immunol Methods.231:249−60(1999))。抗体の定常領域を一部置き換えて、免疫エフェクター細胞との親和性を効果的に促進することによって、細胞毒性効果を増強することができる。
Monoclonal antibodies obtained from other species (eg, mice) using hybridoma technology need to be humanized. Humanized antibodies can significantly reduce the immune side effects of heterologous antibodies to the human body. Of these, well-known methods for antibody humanization are complementarity determining region transplantation and remodeling. For details, see US Pat. Nos. 5,859,205 and 6,797,492; Liu et al., Immunol Rev. 222: 9-27 (2008); Almagro et al., Front Bioscii. 1; 13: 1619-33 (2008); Lazar et al., Mol Immunol. 44 (8): 1986-98 (2007); Li et al. Proc. Natl. AutoCAD. Sci. USA. 103 (10): See 3557-62 (2006). The disclosure of the literature is incorporated as a reference. Fully human antibodies can be prepared by subjecting antigen immunization to transgenic mice, rabbits, monkeys and other mammals that carry large amounts of human immunoglobulin light and heavy chains. Examples of mice include Xenomouse (Abgenix, Inc.), HuMab-Mouse (Medarex / BMS), and VelociMouse (Regeneron). For more information, see US Pat. Nos. 6,596,541, 6,207,418, 6,150,584, 6,111,166, 6,075,181, 5,922,545,5. See 661,016, 5,545,806, 5,436,149 and 5,569,825. In the process of human treatment, the immunogenicity produced in the human body by a chimeric antibody constructed by integrating a mouse antibody variable region gene and a human antibody constant region gene is much lower than that of a mouse antibody (Kipriyanov, etc.). , Mol Biotechnol. 26: 39-60 (2004); Houdebine, Curr Opin
Biotechnol. 13: 625-9 (2002)). The disclosure of the literature is incorporated as a reference. Furthermore, antibody affinity and specificity can be improved by inducing specific mutagenesis at the site of the antibody variable region (Brannigan et al., Nat Rev Mol Cell Biol. 3: 964-70 (2002); Adams. Etc., J.
Immunol Methods. 231: 249-60 (1999)). The cytotoxic effect can be enhanced by partially replacing the constant region of the antibody to effectively promote affinity with immune effector cells.
悪性細胞抗原に対する免疫特異的抗体は、商業ルート又はいくつかの常用の技術方法、例えば化学合成又は組換え発現技術により得ることができる。同様に、悪性細胞抗原に対する免疫特異的抗体をコードするヌクレオチド配列は、GenBankデータベース又は他の類似のデータベースという商業ルート、公知文献、又はルーチンのクローニング及びシークエンシングにより得ることができる。 Immune-specific antibodies against malignant cell antigens can be obtained by commercial routes or by some commonly used techniques such as chemical synthesis or recombinant expression techniques. Similarly, nucleotide sequences encoding immune-specific antibodies against malignant cell antigens can be obtained by commercial routes, publicly known literature, or routine cloning and sequencing of the GenBank database or other similar databases.
抗体以外に、ポリペプチドまたはタンパク質は同様に結合分子として、標的細胞表面の対応する受容体又はエピトープと結合、ブロック、攻撃または他の手段によって相互作用する。これらのペプチドまたはタンパク質がエピトープまたはその対応する受容体に特異的に結合できる限り、それらは免疫グロブリンファミリーに属している必要がない。これらのポリペプチドも、ファージディスプレイ抗体と類似の技術により単離される(Szardenings,J Recept Signal Transduct Res.2003;23(4):307−49)。ランダムペプチドライブラリーから得られたペプチド断片は抗体及び抗体断片の応用と類似のものである。ポリペプチドまたはタンパク質分子が、結合分子を介していくつかの巨大分子又は媒体と接続することによってその抗原結合特異性を維持する。これら巨大分子は、これらに限られないが、アルブミン、ポリマー、リポソーム、ナノ粒子又はデンドリマーを含む。 In addition to antibodies, polypeptides or proteins also, as binding molecules, interact with the corresponding receptors or epitopes on the surface of the target cell by binding, blocking, aggression or other means. They do not have to belong to the immunoglobulin family as long as these peptides or proteins can specifically bind to the epitope or its corresponding receptor. These polypeptides are also isolated by techniques similar to phage display antibodies (Szardenings, J Recept Signal Transduct Res. 2003; 23 (4): 307-49). Peptide fragments obtained from a random peptide library are similar to antibodies and antibody fragment applications. A polypeptide or protein molecule maintains its antigen binding specificity by connecting to several macromolecules or media via binding molecules. These macromolecules include, but are not limited to, albumin, polymers, liposomes, nanoparticles or dendrimers.
癌、自己免疫性疾患、及び感染性疾患を治療するために、本発明の荷電連結体による薬物の結合に用いられる抗体には、これらに限られないが、以下を含む(この限りではない):3F8(抗GD2抗体)、アバゴボマブ(抗CA−125抗体)、アブシキシマブ(抗CD41抗体(インテグリンα−IIb))、アダリムマブ(抗TNF−α抗体)、アダリムマブ(抗EpCAM抗体、CD326)、アフェリモマブ(抗TNF−α);アフツズマブ(抗CD20抗体)、アラシズマブ ペグオル(Alacizumab pegol)(抗VEGFR2抗体)、ALD518(抗IL−6抗体)、アレムツズマブ(別名:キャンパス、
マブキャンパス、抗CD52抗体)、アルツモマブ(抗CEA抗体)、アナツモマブ(抗tag−72抗体)、アンルキンズマブ(IMA−638、抗IL−13抗体)、アポリズマブ(抗−HLA−DR抗体)、アルシツモマブ(抗CEA抗体)、アセリズマブ(抗L−セレクチン(CD62L)抗体)、アトリズマブ(Atlizumab)(別名:トシリズマ
ブ、アクテムラ、Roアクテムラ、抗IL−6受容体抗体)、アトロリムマブ(Atorolimumab)(抗アカゲザル因子抗体)、バピネオズマブ(抗β−アミロイド抗体)、バシリキシマブ(シムレクト、抗CD25(IL−2受容体α鎖)抗体)、バビツキシマブ(Bavituximab)(抗ホスファチジルセリン抗体)、ベクツモマブ(Bectumomab)(別名:LymphoScan、抗CD22抗体)、ベリムマブ(別名:BENLYSTA、LymphoStat-B、抗BAFF抗
体)、ベンラリズマブ(Benralizumab)(抗CD125抗体)、ベルチリムマブ(抗CCL11(エオタキシン−1)抗体)、ベシレソマブ(別名:Scintimun、抗CEA関連抗
原抗体)、ベバシズマブ(別名:アバスチン、抗VEGF抗体)、ビシロマブ(別名:FibriScint、抗フィブリンIIβ鎖抗体)、ビバツヅマブ(抗CD44v6抗体)、ブリナツモマブ(blinatumomab)(別名:BiTE、抗CD19抗体)、ブレンツキシマブ(Brentuximab)(cAC10、抗CD30 TNFRSF8抗体)、ブリアキヌマブ(Briakinumab)(抗IL−12、IL−23抗体)、カナキヌマブ(別名:Ilaris、抗IL−1抗体)、カンツズマブ(別名:C242、抗CanAg抗体)、カプロマブ(Capromab)、カツマキソマブ(別名:removab、抗EpCAM、抗CD3抗体)、CC49(
抗TAG−72抗体)、セデリズマブ(Cedelizumab)(抗CD4抗体)、セルトリズマ
ブペゴル(別:CIMZIA、抗TNF−α抗体)、セツキシマブ(別名:エルビタックス、IMC−C225、抗EGFR抗体)、シタツズマブ(抗EpCAM抗体)、シクスツムバム(Cixutumumab)(抗IGF−1抗体)、クレノリキシマブ(抗CD4抗体)、クリバ
ツズマブ(Clivatuzumab)(抗MUC1抗体)、コナツムマブ(Conatumumab)(抗TR
AIL−R2抗体)、CR6261(抗A型インフルエンザ赤血球凝集素抗体)、ダセツズマブ(Dacetuzumab)(抗CD40抗体)、ダクリズマブ(別名:Zenapax、抗CD25C(IL−2受容体のα鎖)抗体)、ダラツムマブ(Daratumumab)(抗CD38(サイクリックADPリボースヒドロラーゼ)抗体)、デノスマブ(別名:Prolia、抗RANKL抗体)、デツモマブ(抗B−リンパ腫細胞抗体)、ドルリモマブ、ドルキシズマブ(Dorlixizumab)、エクロメキシマブ(Ecromeximab)(抗GD3ガングリオシド抗体)、エク
リズマブ(別名:Soliris、抗C5抗体)、エドバコマブ(抗エンドトキシン抗体)、エ
ドレコロマブ(別名:Panorex、MAb17−A1、抗EpCAM抗体)、エファリズマ
ブ(別名:Raptiva、抗LFA−1(CD11a)抗体)、エファングマブ(Efungumab)(別名:Mycograb、抗Hsp90抗体)、エロツズマブ(Elotuzumab)(抗SLAMF7抗体)、エルシリモマブ(Elsilimomab)(抗IL−6抗体)、エンリモマブペゴル(抗
ICAM−1(CD54)抗体)、エピツモマブ(Epitumomab)(抗エピシアリン抗体)、エプラツズマブ(抗CD22抗体)、エルリズマブ(Erlizumab)(抗ITGB2(C
D18)抗体)、エルツマキソマブ(Ertumaxomab)(別名:Rexomun、抗HER2/neu、CD3抗体)、エタラシズマブ(別名:Abegrin、抗インテグリンαvβ3)、エク
シビビルマブ(抗B型肝炎表面抗原抗体(HBs抗体))、ファノレソマブ(Fanolesomab)(別名:NeutroSpec、抗CD15抗体)、ファラリモマブ抗体(faralimomab)(抗インターフェロン受容体抗体)、ファルレツズマブ(Farletuzumab)(抗葉酸受容体1抗体)、フェルビズマブ(Felvizumab)(RSウイルスに対する抗体)、フェザキヌマブ(Fezakinumab)(抗IL−22抗体)、フィギツムマブ(Figitumumab)(抗IGF−1受容体抗体)、フォントリズマブ(Fontolizumab)(抗IFN−γ抗体)、フォラビルマブ(Foravirumab)(抗狂犬病ウイルス糖タンパク質抗体)、フレソリムマブ(Fresolimumab)(抗T
GF−β抗体)、ガリキシマブ(Galiximab)(抗CD80抗体)、ガンテネルマブ(Gantenerumab)(抗βアミロイド抗体)、ガビリモマブ(Gavilimomab)(抗CD147(basigin
)抗体)、ゲムツズマブ(抗CD33抗体)、ギレンツシキマブ(Girentuximab)(抗炭酸脱水酵素9抗体)、グレムバツムマブ(Glembatumumab)(別名:CR011、抗GPNMB抗体)、ゴリムマブ(別名:Simponi、抗TNF−α抗体)、ゴミリキシマブ(Gomilixim
ab)(抗CD23C(IgEレセプター)抗体)、イバリズマブ(Ibalizumab)(抗CD
4抗体)、イブリツモマブ(Ibritumomab)(抗CD20抗体)、イゴボマブ(Igovomab
)(別名:Indimacis-125、抗CA−125抗体)、イムシロマブ(imciromab)(別名:Myoscint、抗心筋ミオシン抗体)、インフリキシマブ(別名:Remicade、抗TNF−α抗体)、インテツムマブ(Intetumumab)(抗CD51抗体)、イノリモマブ(Inolimomab)
(抗CD25(IL−2受容体α鎖)抗体)、イノツズマブ(Inotuzumab)(抗CD22抗体)、イピリムマブ(抗CD152抗体)、イラツムマブ(Iratumumab)(抗CD30(TNFRSF8)抗体)、ケリキシマブ(Keliximab)(抗CD4抗体)、ラベツズマブ(
別名:CEA-Cide、抗CEA抗体)、レブリキズマブ(Lebrikizumab)(抗IL−13抗体)、レマレソマブ(Lemalesomab)(抗NCA−90(顆粒球抗原)抗体)、レルデリム
マブ(Lerdelimumab)(抗TGFβ−2抗体)、レクサツムマブ(Lexatumumab)(抗T
RAIL−R2抗体)、リビビルマブ(Libivirumab)(抗B型肝炎表面抗原抗体)、リ
ンツズマブ(Lintuzumab)(抗CD33抗体)、ルカツムマブ(Lucatumumab)(抗CD
40抗体)、ルミリキシマブ(Lumiliximab)(抗CD23(IgEレセプター)抗体)
、マパツムマブ(抗TRAIL−R1抗体)、マスリモマブ(Maslimomab)(抗T細胞受容体抗体)、マツズマブ(Matuzumab)(抗EGFR抗体)、メポリズマブ(別名:Bosatria、抗IL−5抗体)、メテリムマブ(Metelimumab)(抗TGFβ−1抗体)、ミラツズマブ(Milatuzumab)(抗CD74抗体)、ミンレツモマブ(Minretumomab)(抗TA
G−72抗体)、ミツモマブ(Mitumomab)(別名;BEC−2、抗ガングリオシド抗体
−GD3)、モロリムマブ(Morolimumab)(抗アカゲザル因子抗体)、モタビズマブ(Motavizumab)(別名:Numax、抗RSウイルス抗体)、ムロモナブ(Muromonab)−CD3(別名:Orthoclone OKT3、抗CD3抗体)、ナコロマブ(Nacolomab)(抗C242抗体)、ナプツモマブ(Naptumomab)(抗5T4抗体)、ナタリズマブ(別名:Tysabri、抗イ
ンテグリンα4抗体)、ネバクマブ(Nebacumab)(抗エンドトキシン抗体)、ネシツムマブ(Necitumumab)(抗EGFR抗体)、ネレリモマブ(Nerelimomab)(抗TNF−α抗体)、ニモツズマブ(別名:Theracim、Theraloc、抗EGFR抗体)、ノフェツモマブ(Nofetumomab)、オクレリズマブ(抗CD20抗体)、オデュリモマブ(別名:Afolimomab、抗LFA−1(CD11a)抗体)、オファツムマブ(別名:Arzerra、抗CD20抗体)、オララツマブ(Olaratumab)(抗PDGF−Rα抗体)、オマリズマブ(Omalizumuba)(別名:Xolair、抗IgE Fc領域抗体)、オポルツズマブ(Oportuzumab)(抗EpCAM抗体)、オレゴボマブ(Oregovomab)(別名:OvaRex、抗CA−125抗体)、オテリキシズマブ(Otelixizumab)(抗CD3抗体)、パギバキシマブ(Pagibaximab)(抗LTA抗体)、パリビズマブ(別名:Synagis、Abbosynagis、抗RSウイルス抗
体)、パニツムマブ(別名:Vectibix、ABX−EGF、抗EGFR抗体)、パノバクマブ(Panobacumab)(抗緑膿菌抗体)、パスコリズマブ(Pascolizumab)(抗IL−4抗
体)、ペムツモマブ(Pemtumomab)(別名:Theragyn、抗MUC1抗体)、ペルツズマブ(別名:Omnitarg、2C4、抗HER2/neu抗体)、ペクセリズマブ(Pexelizumab
)(抗C5抗体)、ピンツモマブ(Pintumomab)(抗腺癌抗原抗体)、プリリキシマブ(Priliximab)(抗CD4抗体)、プリツムマブ(pritumumab)(抗ビメンチン抗体)、PRO140(抗CCR5抗体)、ラコツモマブ(racotumomab)(別名:1E10、抗(
N−グリコリルノイラミン酸(NeuGc,NGNA)−ガングリオシド(GM3)抗体)、ラフィビルマブ(Rafivirumab)(抗狂犬病ウイルス糖タンパク抗体)、ラムシルマブ(Ramucirumab)(抗VEGFR2抗体)、ラニビズマブ(別名:Lucentis、抗VEGF−
A抗体)、ラキシバクマブ(Raxibacumab)(抗炭疽菌毒素、防御抗原抗体)、レガビル
マブ(Regavirumab)(抗CMV糖タンパク質B抗体)、レスリズマブ(Reslizumab)(
抗IL−5抗体)、リロツムマブ(rilotumumab)(抗HGF抗体)、リツキシマブ(別
名:MabThera、Rituxanmab、抗CD20抗体)、ロバツムマブ(Robatumumab)(抗IG
F−1受容体抗体)、ロンタリズマブ(Rontalizumab)(抗IFN−α抗体)、ロベリズマブ(Rovelizumab)(別名:LeukArrest、抗CD11、CD18抗体)、ルプリズマブ
(Ruplizumab)(別名:Antova、抗CD154(CD40L)抗体)、サツモマブ(Satu
momab)(抗TAG−72抗体)、セビルマブ(Sevirumab)(抗CMV抗体)、シブロツズマブ(抗FAP抗体)、シファリムマブ(Sifalimumab)(抗IFN−α抗体)、シル
ツキシマブ(Siltuximab)(抗IL−6抗体)、シプリズマブ(抗CD2抗体)、(スマート)MI95(抗CD33抗体)、ソラネツマブ(solanezumab)(抗β−アミロイド
抗体)、ソネプシズマブ(Sonepcizumab)(抗スフィンゴシン−1−リン酸抗体)、ソンツズマブ(Sontuzumab)(抗エピシアリン抗体)、スタムルマブ(Stamulumab)(抗ミオスタチン抗体)、スレソマブ(sulesomab)(別名:LeukoScan、(抗NCA−90(顆粒球抗原)抗体)))、タカツズマブ(Tacatuzumab)(抗α−フェトプロテイン抗体)、タ
ドシズマブ(tadocizumab)(抗インテグリンαIIbβ3抗体)、タリズマブ(抗Ig
E抗体)、タネズマブ(tanezumab)(抗NGF抗体)、タプリツモマブ(taplitumomab
)(抗CD19抗体)、テフィバズマブ(Tefibazumab)(別名:Aurexis、抗クランピング因子A抗体)、テリモマブ(Telimomab)、テナツモマブ(Tenatumomab)(抗テネイシンC抗体)、テネリキシマブ(Teneliximab)(抗CD40抗体)、テプリズマブ(Teplizumab)(抗CD3抗体)、TGN1412(抗CD28抗体)、チシリムマブ(別名:Tremelimumab、抗CTLA−4抗体)、ティガツズマブ(Tigatuzumab)(抗TRAIL−R2抗体)、TNX−650(抗IL−13抗体)、トシリズマブ(別名Atlizumab、Actemra、RoActemra、(抗IL−6受容体抗体)、トラリズマブ(Toralizumab)(抗CD154(CD40L)抗体)、トシツモマブ(抗CD20抗体)、トラスツズマブ(別名:Herceptin、抗HER2/neu抗体)、トレメリムマブ(Tremelimumab)(抗CTLA
−4抗体)、ツコツズマブセルモロイキン(Tucotuzumab celmoleukin)(抗EpCAM抗
体)、ツビルマブ(tuvirumab)(抗B型肝炎抗体)、ウルトキサズマブ(Urtoxazumab)(抗大腸菌抗体)、ウステキヌマブ(Ustekinumab)
(別名:Stelara、抗IL−12、IL−23抗体)、バパリキシマブ(Vapaliximab)(抗AOC3(VAP−1)抗体)、ベドリズマブ(Vedolizumab)、(抗インテグリンα4
β7抗体)、ベルツズマブ(抗CD20抗体)、ベパリモマブ(Vepalimomab)(抗AO
C3(VAP−1))抗体)、ビシリズマブ(別名:Nuvion、抗CD3抗体)、ビタキシン(抗血管新生インテグリンavb3抗体)、ボロシキシマブ(Volociximab)(抗イン
テグリンα5β1)、ボツムマブ(Votumumab)(別名:HumaSPECT、抗腫瘍抗原CTAA16.88抗体)、ザルツムマブ(別名:HuMax-EGFr、(抗EGFR抗体)、ザノリムマブ(別名:HuMax-CD4、抗CD4抗体)、ジラリムマブ(Ziralimumab)(抗CD147(基本免疫グロブリン)抗体)、ゾリモマブ(zolimomab)(抗CD5抗体)、エタネルセプ
ト(登録商標「Enbrel」)、アレファセプト(Alefacept)(登録商標「Amevive」)、アバタセプト(登録商標「Orencia」)、リロナセプト(Rilonacept)(Arcalyst)、14
F7[抗IRP−2(鉄調節タンパク質2)抗体]、14G2a(Nat.Cancer Inst.から黒色腫及び固形腫瘍のための抗ガングリオシドGD2抗体)、J591(Weill Cornell Medical Schoolから前立腺癌を治療するための抗PSMA抗体、)、225.28S[黒色腫のための抗HMW−MAA(高分子量黒色腫関連抗原)抗体、Sorin Radiofarmaci S.R.L.(ミラノ、イタリア)]、COL−1(Nat. Cancer Inst.から大腸癌及び胃癌の
ための抗CEACAM3抗体、CGM1)、CYT−356(登録商標「Oncoltad」、前立腺癌)、HNK20(Ora Vax Inc.からRSウイルスのための)、ImmuRAIT(IMMUNOMEDICSから非ホジキンリンパ腫のための)、Lym−1(抗HLA−DR10抗体、Peregrine Pharmから腫瘍のため)、MAK−195F[Abbott/Knollから敗血症、毒
素ショックのための抗TNF(腫瘍壊死因子;TNFA、TNF−α;TNFSF2)抗体]、MEDI−500[別名:T10B9、MedImmune Incから移植片対宿主病のための抗CD3抗体、TRαβ(T細胞受容体α/β)、]、RING SCAN[Neoprobe Corp.から乳癌、結腸癌及び結腸直腸癌のための抗TAG72(腫瘍関連糖タンパク質72)抗体)]、Avicidin(抗EPCAM(上皮細胞接着分子)抗体)、抗TACSTD
1(腫瘍関連カルシウムシグナルトランスデューサー1)抗体、抗GA733−2(胃腸腫瘍関連タンパク質2)抗体、抗EGP−2(上皮糖タンパク質2)抗体;抗KSA抗体
;KS1/4抗原;M4S;腫瘍抗原17−1A;NeoRx Corp.から結腸癌、卵巣癌、前
立腺癌、及び非ホジキンリンパ腫のためのCD326;LYMPHOCIDE(IMMUNOMEDICS、NJ)、スマートID10(Protein Design Labs)、Oncolym(Techniclone Inc
、CA)、Allomune(BioTransplant、CA)、抗VEGF抗体(ジェネンテック、CA
);CEAcide(Immunomedics、NJ)、IMC−1C11(ImClone Systems、N
J)、並びにセツキシマブ(ImClone、NJ)が含まれるが、これらに限られない。
Antibodies used to bind drugs by the charged conjugates of the invention to treat cancer, autoimmune disorders, and infectious disorders include, but are not limited to: : 3F8 (anti-GD2 antibody), avagobomab (anti-CA-125 antibody), absiximab (anti-CD41 antibody (integrin α-IIb)), adalimumab (anti-TNF-α antibody), adalimumab (anti-EpCAM antibody, CD326), aferimomab (anti-EpCAM antibody, CD326) Anti-TNF-α); Afutuzumab (anti-CD20 antibody), Alacizumab pegol (anti-VEGFR2 antibody), ALD518 (anti-IL-6 antibody), Alemtuzumab (also known as campus,
Mabu Campus, anti-CD52 antibody), altumomab (anti-CEA antibody), anatumomab (anti-tag-72 antibody), anlucinzumab (IMA-638, anti-IL-13 antibody), apolizumab (anti-HLA-DR antibody), alcitumomab (anti-tag-72 antibody) CEA antibody), acerizumab (anti-L-selectin (CD62L) antibody), atlizumab (also known as tocilizumab, actemra, Ro actemra, anti-IL-6 receptor antibody), atorolimumab (anti-akagesal factor antibody), Bapineozumab (anti-β-amyloid antibody), bacilizumab (simlect, anti-CD25 (IL-2 receptor α chain) antibody), bavituximab (anti-phosphatidylserine antibody), belimumab (also known as LymphoScan, anti-CD22 antibody) ), Belimumab (also known as BENLYSTA, LymphoStat-B, anti-BAFF antibody), Benralizumab (anti-CD125 antibody), belimumab (anti-CCL11 (eotaxin-1) antibody), besilesomab (also known as Scintimun, anti-CEA-related antigen antibody) ), Belimumab (also known as Avastin, anti-VEGF antibody), Bicilomab (also known as FibriScint, anti-fibriIIβ chain antibody), Bibatsuzumab (anti-CD44v6 antibody), blinatumomab (also known as BiTE, anti-CD19 antibody), Brentuximab (Brentuximab) (cAC10, anti-CD30 TNFRSF8 antibody), Briakinumab (anti-IL-12, IL-23 antibody), canaquinumab (also known as Ilaris, anti-IL-1 antibody), cantuzumab (also known as C242, anti-CanAg antibody) ), Capromab, Tocilizumab (also known as removeab, anti-EpCAM, anti-CD3 antibody), CC49 (
Anti-TAG-72 antibody), Cedelizumab (anti-CD4 antibody), Celtrizumab pegol (separate: CIMZIA, anti-TNF-α antibody), cetuximab (also known as Elvitax, IMC-C225, anti-EGFR antibody), Citatuzumab (anti-EpCAM antibody), Cixutumumab (anti-IGF-1 antibody), clenoliximab (anti-CD4 antibody), Clivatuzumab (anti-MUC1 antibody), Conatumumab (anti-TR)
AIL-R2 antibody), CR6261 (anti-type A influenza hemagglutinin antibody), Dacetuzumab (anti-CD40 antibody), dacrizumab (also known as Zenapax, anti-CD25C (alpha chain of IL-2 receptor) antibody), denosumab (Daratumumab) (anti-CD38 (cyclic ADP ribose hydrolase) antibody), denosumab (also known as Prolia, anti-RANKL antibody), detumomab (anti-B-lymphoma cell antibody), dollimomab, dollixizumab, ecromeximab (anti) GD3 ganglioside antibody), eculizumab (also known as Solidis, anti-C5 antibody), edobacomab (anti-endotoxin antibody), edrecolomab (also known as Panorex, MAb17-A1, anti-EpCAM antibody), efarizumab (also known as Raptiva, anti-LFA-1 (CD11a)) ) Antibodies), Efungumab (also known as Mycograb, anti-Hsp90 antibody), Elotuzumab (anti-SLAMF7 antibody), Elsilimomab (anti-IL-6 antibody), Enlimomab pegol (anti-ICAM-1) (CD54) antibody), Epitumomab (anti-epicialin antibody), epruzumab (anti-CD22 antibody), erlizumab (anti-ITGB2 (C))
D18) antibody), Ertumaxomab (also known as Rexomun, anti-HER2 / neu, CD3 antibody), etarasizumab (also known as Abegrin, anti-integrin αvβ3), exhibivirumab (anti-hepatitis B surface antigen antibody (HBs antibody)), fanoresomab (Fanolesomab) (also known as NeutroSpec, anti-CD15 antibody), faralimomab antibody (anti-interferon receptor antibody), Farletuzumab (anti-folic
GF-β antibody), Galiximab (anti-CD80 antibody), Gantenerumab (anti-β-amyloid antibody), Gavilimomab (anti-CD147 (basigin))
) Antibodies), gemtuzumab (anti-CD33 antibody), Girentuximab (anti-carbonic anhydrase 9 antibody), Glembatumumab (also known as CR011, anti-GPNMB antibody), golimumab (also known as Simponi, anti-TNF-α antibody) , Gomilixim
ab) (anti-CD23C (IgE receptor) antibody), Ibalizumab (anti-CD)
4 antibodies), Ibritumomab (anti-CD20 antibody), Igovomab
) (Also known as Indimacis-125, anti-CA-125 antibody), imciromab (also known as Myoscint, anti-myocardial myosin antibody), infliximab (also known as Remicade, anti-TNF-α antibody), Intetumumab (anti-CD51) Antibodies), Inolimomab
(Anti-CD25 (IL-2 receptor α chain) antibody), Inotuzumab (anti-CD22 antibody), ipilimumab (anti-CD152 antibody), Iratumumab (anti-CD30 (TNFRSF8) antibody), Keliximab (Keliximab) ( Anti-CD4 antibody), labetsuzumab (
Alias: CEA-Cide, anti-CEA antibody), Lebrikizumab (anti-IL-13 antibody), Lemalesomab (anti-NCA-90 (granulocyte antigen) antibody), Lerdelimumab (anti-TGFβ-2 antibody) ), Lexatumumab (anti-T
RAIL-R2 antibody), Libivirumab (anti-hepatitis B surface antigen antibody), Lintuzumab (anti-CD33 antibody), Lucatumumab (anti-CD)
40 antibodies), Lumiliximab (anti-CD23 (IgE receptor) antibody)
, Mapatumumab (anti-TRAIL-R1 antibody), Maslimomab (anti-T cell receptor antibody), Matsuzumab (anti-EGFR antibody), mepolizumab (also known as Bosatria, anti-IL-5 antibody), Metelimumab (Anti-TGFβ-1 antibody), Milatuzumab (anti-CD74 antibody), Minretumomab (anti-TA)
G-72 antibody), Mitumomab (also known as BEC-2, anti-ganglioside antibody-GD3), Mororimumab (anti-Akagesaru factor antibody), Motavizumab (also known as Numax, anti-RS virus antibody), Muromonab-CD3 (also known as Orthoclone OKT3, anti-CD3 antibody), Nacolomab (anti-C242 antibody), Naptumomab (anti-5T4 antibody), Natalizumab (also known as Tysabri, anti-integrin α4 antibody), Neva (Nebacumab) (anti-endotoxin antibody), Necitumumab (anti-EGFR antibody), Nerelimomab (anti-TNF-α antibody), Nimotuzumab (also known as Theracim, Theraloc, anti-EGFR antibody), Nofetumomab, Ofetumomab. (Anti-CD20 antibody), Odulimomab (also known as Afolimomab, anti-LFA-1 (CD11a) antibody), Ofatumumab (also known as Arzerra, anti-CD20 antibody), Olaratumab (anti-PDGF-Rα antibody), Omalizumuba (Omalizumuba) ( Alias: Xolair, anti-IgE Fc region antibody), Oportuzumab (anti-EpCAM antibody), Oregovomab (also known as OvaRex, anti-CA-125 antibody), Otelixizumab (anti-CD3 antibody), Pagibaximab (Pagibaximab) ) (Anti-LTA antibody), Paribizumab (also known as Synagis, Abbosynagis, anti-RS virus antibody), Panitumumab (also known as Vectibix, ABX-EGF, anti-EGFR antibody), Panobakumab (anti-green pyogenic antibody), Pascolizumab (also known as anti-green pyogenic antibody) Pascolizumab (anti-IL-4 antibody), Pemtumomab (also known as Theragyn, anti-MUC1 antibody), Pertuzumab (also known as Omniarg, 2C4, anti-HER2 / neu antibody), Pexelizumab
) (Anti-C5 antibody), Pintumomab (anti-adenocarcinoma antigen antibody), Priliximab (anti-CD4 antibody), pritumumab (anti-vimentin antibody), PRO140 (anti-CCR5 antibody), racotumomab (Also known as: 1E10, anti- (
N-glycolylneuraminic acid (NeuGc, NGNA) -ganglioside (GM3) antibody), Rafivirumab (anti-rabies virus glycoprotein antibody), ramucirumab (anti-VEGFR2 antibody), ranibizumab (also known as Lucentis, anti) VEGF-
A antibody), Raxibacumab (anti-anthrax toxin, protective antigen antibody), Regavirumab (anti-CMV glycoprotein B antibody), reslizumab (Reslizumab) (
Anti-IL-5 antibody), rilotumumab (anti-HGF antibody), rituximab (also known as MabThera, Rituxanmab, anti-CD20 antibody), Robatumumab (anti-IG)
F-1 receptor antibody), Rontalizumab (anti-IFN-α antibody), Rovelizumab (also known as LeukArrest, anti-CD11, CD18 antibody), Ruprizumab (also known as Antiva, anti-CD154 (CD40L)) Antibodies), Satu
momab) (anti-TAG-72 antibody), Sevirumab (anti-CMV antibody), sibrotuzumab (anti-FAP antibody), sifalimumab (anti-IFN-α antibody), Siltuximab (anti-IL-6 antibody) , Ciprizumab (anti-CD2 antibody), (smart) MI95 (anti-CD33 antibody), solanezumab (anti-β-amyloid antibody), Sonepcizumab (anti-sphingosin-1-phosphate antibody), Sontuzumab (Sontuzumab) ( Anti-epicialin antibody), Stamulumab (anti-myostatin antibody), sulesomab (also known as LeukoScan, (anti-NCA-90 (granulocyte antigen) antibody))), Takatuzumab (anti-α-fetoprotein antibody) , Tadocizumab (anti-integrin αIIbβ3 antibody), tadocizumab (anti-Ig)
E-antibody), tanezumab (anti-NGF antibody), taplitumomab
) (Anti-CD19 antibody), Tefibazumab (also known as Aurexis, anti-clamping factor A antibody), Telimomab, Tenatumomab (anti-tenacein C antibody), Teneriximab (anti-CD40 antibody), Teplizumab (anti-CD3 antibody), TGN1412 (anti-CD28 antibody), tocilizumab (also known as Tremelimumab, anti-CTLA-4 antibody), Tigatuzumab (anti-TRAIL-R2 antibody), TNX-650 (anti-IL-13) Antibodies), tocilizumab (also known as Atlizumab, Actemra, RoActemra, (anti-IL-6 receptor antibody), tocilizumab (anti-CD154 (CD40L) antibody), tocilizumab (anti-CD20 antibody), trussutzumab (also known as Herceptin, anti-HER2) / Neu antibody), Tremelimumab (anti-CTLA)
-4 antibody), Tucotuzumab celmoleukin (anti-EpCAM antibody), tuvirumab (anti-hepatitis B antibody), Urtoxazumab (anti-E. coli antibody), Ustekinumab
(Also known as: Stellara, anti-IL-12, IL-23 antibody), Vapaliximab (anti-AOC3 (VAP-1) antibody), Vedolizumab, (anti-integrin α4)
β7 antibody), Bertzzumab (anti-CD20 antibody), Vepalimomab (anti-AO)
C3 (VAP-1)) antibody), bisirizumab (also known as Nuvion, anti-CD3 antibody), Vitaxin (anti-angiogenic integrin avb3 antibody), volociximab (anti-integrin α5β1), botumumab (also known as HumaSPECT,) Antitumor antigen CTAA16.88 antibody), saltumumab (also known as HuMax-EGFr, (anti-EGFR antibody), zanolimumab (also known as HuMax-CD4, antiCD4 antibody), Ziralimumab (anti-CD147 (basic immunoglobulin) antibody) , Zolimomab (anti-CD5 antibody), Etanelcept (registered trademark "Enbrel"), Alefacept (registered trademark "Amevive"), Avatacept (registered trademark "Orencia"), Rilonacept (Arcalyst), 14
F7 [anti-IRP-2 (iron regulatory protein 2) antibody], 14G2a (anti-ganglioside GD2 antibody for melanoma and solid tumors from Nat. Cancer Inst.), J591 (from Weill Cornell Medical School to treat prostate cancer) Anti-PSMA antibody,), 225.28S [Anti-HMW-MAA (high molecular weight melanoma-related antigen) antibody for melanoma, Sorin Radiofarmaci SRL (Milan, Italy)], COL-1 (Nat. Cancer Inst.) Anti-CEACAM3 antibody for colorectal and gastric cancer, CGM1), CYT-356 (registered trademark "Oncoltad", prostate cancer), HNK20 (for RS virus from Ora Vax Inc.), ImmuRAIT (from IMMUNOMEDICS for non-hodgkin lymphoma) For), Lym-1 (anti-HLA-DR10 antibody, for tumors from Peregrine Pharm), MAK-195F [for sepsis from Abbott / Knoll, anti-TNF for toxin shock (tumor necrosis factors; TNFA, TNF-α; TNFSF2) antibody], MEDI-500 [also known as T10B9, anti-CD3 antibody for transplanted piece-to-host disease from MedImmune Inc, TRαβ (T cell receptor α / β)], RING SCAN [from Neoprobe Corp. to cancer, Anti-TAG72 (tumor-related glycoprotein 72) antibody for colon cancer and colorectal cancer)], Avicidin (anti-EPCAM (epithelial cell adhesion molecule) antibody), anti-TACSTD
1 (tumor-related calcium signal transducer 1) antibody, anti-GA733-2 (gastrointestinal tumor-related protein 2) antibody, anti-EGP-2 (epithelial glycoprotein 2) antibody; anti-KSA antibody; KS1 / 4 antigen; M4S; tumor antigen 17-1A; CD326 for colon cancer, ovarian cancer, prostate cancer, and non-hodgkin lymphoma from NeoRx Corp.; LYMPHOCIDE (IMMUNOMEDICS, NJ), Smart ID10 (Protein Design Labs), Oncolym (Techniclone Inc)
, CA), Allomune (BioTransplant, CA), anti-VEGF antibody (Genentech, CA)
); CEAcide (Immunomedics, NJ), IMC-1C11 (ImClone Systems, NJ)
J), as well as cetuximab (ImClone, NJ), but not limited to these.
細胞結合分子/リガンドとしての他の抗体には、これらに限定されないが、以下の抗原:アミノペプチダーゼN(CD13)、アネキシンA1、B7−H3(CD276、様々な癌)、CA125(卵巣)、CA15−3(癌腫)、CA19−9(癌腫)、L6(癌腫)、ルイスY(癌腫)、ルイスX(癌腫)、α−フェトプロテイン(癌腫)、CA242(大腸直腸)、胎盤アルカリホスファターゼ(癌腫)、前立腺特異抗原(前立腺)、前立腺酸性ホスファターゼ(前立腺)、上皮成長因子(癌腫)、CD2(ホジキン病、NHLリンパ腫、多発性骨髄腫)、CD3ε(T細胞リンパ腫、肺癌、乳癌、胃癌、卵巣癌、自己免疫疾患、悪性腹水)、CD19(B細胞悪性腫瘍)、CD20(非ホジキンリンパ腫)、CD22(白血病、リンパ腫、多発性骨髄腫、全身性エリテマトーデス)、CD30(ホジキンリンパ腫)、CD33(白血病、自己免疫疾患)、CD38(多発性骨髄腫)、CD40(リンパ腫、多発性骨髄腫、白血病(CLL))、CD51(転移性黒色腫、肉腫)、CD52(白血病)、CD56(小細胞肺癌、卵巣癌、メルケル細胞癌及び液性腫瘍、多発性骨髄腫)、CD66e(癌)、CD70(転移性腎細胞癌及び非ホジキンリンパ腫)、CD74(多発性骨髄腫)、CD80(リンパ腫)、CD98(癌)、ムチン(癌腫)、CD221(固形腫瘍)、CD227(乳癌、卵巣癌)、CD262(非小細胞肺癌及び他の癌)、CD309(卵巣癌)、CD326(固形腫瘍)、CEACAM3(結腸直腸癌、胃癌)、CEACAM5(癌胎児性抗原;CEA、CD66e)(乳癌、結腸直腸癌及び肺癌)、DLL4(Δ−like−4)、EGFR(上皮成長因子受容体、種々の癌)、CTLA4(黒色腫)、CXCR4(CD184、ヘム腫瘍、固形腫瘍)、エンドグリン(CD105、固形腫瘍)、EPCAM(上皮細胞接着分子、膀胱、頭部、頸部、結腸癌、NHL前立腺癌、及び卵巣癌)、ERBB2(上皮成長因子受容体2;肺癌、乳癌、前立腺癌)、FCGR1(自己免疫疾患)、FOLR(葉酸受容体、卵巣癌)、GD2ガングリオシド(癌)、G−28G(細胞表面抗原糖脂質、黒色腫)、GD
3イディオタイプ(癌)、熱ショックタンパク質(癌)、HER1(肺癌、胃癌)、HER2(乳癌、肺癌及び卵巣癌)、HLA−DR10(NHL)、HLA−DRB(NHL、B細胞白血病)、ヒト絨毛性ゴナドトロピン(癌腫)、IGF1R(インスリン様成長因子−1受容体、固形腫瘍、血液癌)、IL−2受容体(インターロイキン−2受容体、T細胞白血病及びリンパ腫)、IL−6R(インターロイキン6受容体、多発性骨髄腫、RA、キャッスルマン病、IL6依存性腫瘍)、インテグリン(種々の癌のためのαVβ3、α5β1、α6β4、αIIβ3、α5β5、αVβ5)、MAGE−1(癌腫)、MAGE−2(癌腫)、MAGE−3(癌腫)、MAGE−4(癌腫)、抗トランスフェリン受容体(癌腫)、p97(黒色腫)、MS4A1(膜貫通4−ドメインファミリーAメンバー1、非ホジキンB細胞リンパ腫、白血病)、MUC1又はMUC1−KLH(乳癌、卵巣癌、子宮頚癌、気管支及び胃腸癌)、MUC16(CA125)(卵巣癌)、CEA(結腸)、gp100(黒色腫)、MART1(黒色腫)、MPG(黒色腫)、MS4A1(膜貫通4−ドメインファミリーAメンバー1、小細胞肺癌、NHL)、ヌクレオリン、神経癌遺伝子産物(癌腫)、P21(癌腫)、抗−(N−グルコリルノイラミン酸のパラトープ(乳癌、黒色腫癌)、PLAP様精巣アルカリホスファターゼ(卵巣癌、精巣癌)、PSMA(前立腺癌)、PSA(前立腺)、ROBO4、TAG72(腫瘍関連糖タンパク質72、白血病(AML)、胃癌、結腸直腸癌、卵巣癌)、T細胞の膜貫通タンパク質(癌)、Tie(CD202b)、TNFRSF10B(腫瘍壊死因子受容体スーパーファミリーメンバー10B、癌)、TNFRSF13B(腫瘍壊死因子受容体スーパーファミリーメンバー13B、多発性骨髄腫、NHL、他の癌、RA及びSLE)、T
PBG(栄養膜糖タンパク質、腎細胞癌)、TRAIL−R1(TNF関連アポトーシスリガンド受容体1、リンパ腫、NHL、結腸直腸癌、肺癌)、VCAM−1(CD106、黒色腫)、VEGF、VEGF−A、VEGF−2(CD309)(種々の癌)が含まれる。抗体により認識される他の腫瘍関連抗原については既に報告されている(Gerber, et al, mAbs 1:3, 247-253 (2009); Novellino et al,cancer immunol immunother. 54 (3), 187-207 (2005)Franke et al,cancer biother radiopharm. 2000, 15,459-76)。
Other antibodies as cell-binding molecules / ligands include, but are not limited to, the following antigens: aminopeptidase N (CD13), anexin A1, B7-H3 (CD276, various cancers), CA125 (ovary), CA15: -3 (cancer tumor), CA19-9 (cancer tumor), L6 (cancer tumor), Lewis Y (cancer tumor), Lewis X (cancer tumor), α-fetoprotein (cancer tumor), CA242 (colon rectal), placenta alkaline phosphatase (cancer tumor), Prostate-specific antigen (progester), prostatic acid phosphatase (progestion), epithelial growth factor (canceroma), CD2 (Hojikin's disease, NHL lymphoma, multiple myeloma), CD3ε (T-cell lymphoma, lung cancer, breast cancer, gastric cancer, ovarian cancer, Autoimmune disease, malignant ascites), CD19 (B cell malignant tumor), CD20 (non-hodgkin lymphoma), CD22 (leukemia, lymphoma, multiple myeloma, systemic erythematosus), CD30 (hodgkin lymphoma), CD33 (leukemia, self) Immune disease), CD38 (multiple myeloma), CD40 (lymphoma, multiple myeloma, leukemia (CLL)), CD51 (metastatic melanoma, sarcoma), CD52 (leukemia), CD56 (small cell lung cancer, ovarian cancer) , Mercel cell cancer and humoral tumor, multiple myeloma), CD66e (cancer), CD70 (metastatic renal cell carcinoma and non-Hodgkin lymphoma), CD74 (multiple myeloma), CD80 (lymphoma), CD98 (cancer) , Mutin (cancer tumor), CD221 (solid tumor), CD227 (breast breast cancer, ovarian cancer), CD262 (non-small cell lung cancer and other cancers), CD309 (ovarian cancer), CD326 (solid tumor), CEACAM3 (colon rectal cancer, Gastric cancer), CEACAM5 (cancer fetal antigen; CEA, CD66e) (breast breast cancer, colorectal cancer and lung cancer), DLL4 (Δ-like-4), EGFR (epithelial growth factor receptor, various cancers), CTLA4 (black tumor) ), CXCR4 (CD184, hem tumor, solid tumor), Endogrin (CD105, solid tumor), EPCAM (epithelial cell adhesion molecule, bladder, head, neck, colon cancer, NHL prostate cancer, and ovarian cancer), ERBB2 (Epithelial growth factor receptor 2; lung cancer, breast cancer, prostate cancer), FCGR1 (autoimmune disease), FOLR (folic acid receptor, ovarian cancer), GD2 ganglioside (cancer), G-28G (cell surface antigen glycolipid, black color) Tumor), GD
3 Idiotype (cancer), heat shock protein (cancer), HER1 (lung cancer, gastric cancer), HER2 (breast cancer, lung cancer and ovarian cancer), HLA-DR10 (NHL), HLA-DRB (NHL, B cell leukemia), human Villous gonadotropin (cancer tumor), IGF1R (insulin-like growth factor-1 receptor, solid tumor, hematological cancer), IL-2 receptor (interleukin-2 receptor, T-cell leukemia and lymphoma), IL-6R (inter)
PBG (Nutrition Membrane Glycoprotein, Renal Cell Carcinoma), TRAIL-R1 (TNF-Related
細胞結合剤、より好ましくは抗体は、腫瘍細胞、ウイルス感染細胞、微生物感染細胞、寄生虫感染細胞、自己免疫細胞、活性化細胞、骨髄細胞、活性化T細胞、B細胞、又はメラノサイトに対抗することができる任意の剤とすることができる。より具体的には、細胞結合剤は、以下の抗原又は受容体のいずれか1つに対して対抗することができる任意の薬剤/分子とすることができる:CD3、CD4、CD5、CD6、CD7、CD8、CD9、CD10、CD11a、CD11b、CD11c、CD12w、CD14、CD15
、CD16、CDw17、CD18、CD19、CD20、CD21、CD22、CD23、CD24、CD25、CD26、CD27、CD28、CD29、CD30、CD31、CD32、CD33、CD34、CD35、CD36、CD37、CD38、CD39、CD40、CD41、CD42、CD43、CD44、CD45、CD46、CD47、CD48、CD49b、CD49c、CD51、CD52、CD53、CD54、CD55、CD56、CD58、CD59、CD61、CD62E、CD62L、CD62P、CD63、CD66、CD68、CD69、CD70、CD72、CD74、CD79、CD79a、CD79b、CD80、CD81、CD82、CD83、CD86、CD87、CD88、CD89、CD90、CD91、CD95、CD96、CD98、CD100、CD103、CD105、CD106、CD109、CD117、CD120、CD125、CD126、CD127、CD133、CD134、CD135、CD138、CD141、CD142、CD143、CD144、CD147、CD151、CD147、CD152、CD154、CD156、CD158、CD163、CD166、CD168、CD174、CD180、CD184、CDw186、CD194、CD195、CD200、CD200a、CD200b、CD209、CD221、CD227、CD235a、CD240、CD262、CD271、CD274、CD276(B7−H3)、CD303、CD304、CD309、CD326、 4−1BB、5AC
、5T4(栄養芽細胞糖タンパク質、TPBG、5T4、Wnt活性化阻害因子1又はWAIF1)、腺癌抗原、AGS−5、AGS−22M6、アクチビン受容体様キナーゼ1、AFP、AKAP−4、ALK、αインテグリン、αvβ6、アミノペプチダーゼN、アミロイドβ、アンドロゲン受容体、アンジオポイエチン2、アンジオポイエチン3、アネキシンA1、炭疽菌トキシン防御抗原、抗トランスフェリン受容体、AOC3(VAP−1)、B7−H3、炭疽菌、BAFF(B−細胞活性化因子)、B−リンパ腫細胞、bcr−abl、ボンベシン、BORIS、C5、C242抗原、CA125(炭水化物抗原125、MUC16)、CA−IX(又はCAIX、炭酸脱水酵素9)、CALLA、CanAg、イヌIL31、炭酸脱水酵素IX、心筋ミオシン、CCL11(C−Cモチーフケモカイン11)、CCR4(CCケモカイン受容体4型、CD194)、CCR5、CD3E(イプシロン)、CEA(癌胎児性抗原)、CEACAM3、CEACAM5(癌胎児性抗原)、CFD(因子D)、Ch4D5、コレシストキニン2(CCK2R)、CLDN18(クラウディン−18)、クランピング因子A、CRIPTO、FCSF1R(コロニー刺激因子1受容体、CD115)、CSF2(コロニー刺激因子2、顆粒球マクロファージコロニー刺激因子(GM−CSF))、CTLA4(細胞傷害性Tリンパ球関連タンパク質4)、CTAA16.88腫瘍抗原、CXCR4(CD184)、CXCケモカイン受容体4型、cADPリボースヒドロラーゼ、Cyclin B1、CYP1B1、サイトメガロウイルス、サイトメガロウイルス糖タンパク質B、ダビガトラン、DLL4(デルタ様リガンド4)、DPP4(ジペプチジルペプチダーゼ4)、DR5
(デスレセプター5)、大腸菌志賀毒素2型、ED−B、EGFL7(タンパク質7含有EGF様ドメイン)、EGFR、EGFRII、EGFRvIII、エンドグリン(CD105)、エンドセリンB受容体、エンドトキシン、EpCAM(上皮細胞接着分子)、EphA2、エピシアリン、ERBB2(上皮成長因子受容体2)、ERBB3、ERG(TMPRSS2ETS融合遺伝子)、大腸菌、ETV6−AML、FAP(線維芽細胞活性化タンパク質α)、FCGR1、α−フェトプロテイン、フィブリンII、β鎖、フィブロネクチン外部ドメインB、FOLR(葉酸受容体)、葉酸受容体α、葉酸ヒドロラーゼ、Fos関連抗原1、RSウイルスのFタンパク質、Frizzled受容体、フコシルGM1、GD2ガングリオシド、G−28(細胞表面糖脂質抗原)、GD3イディオタイプ、GloboH、グリピカン3、N−グリコリルノイラミン酸、GM3、GMCSF受容体α鎖、成長分化因子8、GP100、GPNMB(膜貫通タンパク質NMB)、GUCY2C(グアニル酸シクラーゼ2C、グアニル酸シクラーゼC(GC−C)、腸グアニル酸シクラーゼ、グアニル酸シクラーゼ−C受容体、熱安定性エンテロトキシン受容体(hSTAR))、熱ショックタンパク質、血球凝集素、B型肝炎表面抗原、B型肝炎ウイルス、HER1(ヒト上皮成長因子受容体1)、HER2、HER2/neu、HER3(ERBB−3)、IgG4、HGF/SF(幹細胞増殖因子/細胞分散因子)、HHGFR、HIV−1、ヒストン複合体、HLA−DA(ヒト白血球抗原)、HLA−DR10、HLA−DRB、HMWMAA、ヒト絨毛性ゴナドトロピン、HNGF、ヒト細胞散乱因子受容体キナーゼ、HPV E6/E7、Hsp90、hTERT、ICAM−1(細胞間接着分子1)、イディオタイプ、IGF1R(IGF−1、インスリン様増殖因子1受容体)、IGHE、IFN−γ、インフルエンザ赤血球凝集素、IgE、IgE
Fc領域、IGHE、IL−1、IL−2受容体(インターロイキン2受容体)、IL−4、IL−5、IL−6、IL−6R(インターロイキン6受容体)、IL−9、IL−10、L−12、IL−13、IL−17、IL−17A、IL−20、IL−22、IL−23、IL−31RA、ILGF2(インスリン様増殖因子2)、インテグリン(α4、αIIIbβ3、αvβ3、α4β7、α5β1、α6β4、α7β7、αIIβ
3、α5β5、αvβ5)、インターフェロンγ誘導タンパク質、ITAGA2、ITGB2、KIR2D、LCK、Le、レグマイン、ルイス−Y抗原、LFA−1(リンパ球機能関連抗原1、CD11a)、LHRH、LINGO−1、リポタイコ酸、LIV1A、LMP2、LTA、MAD−CT−1、MAD−CT−2、MAGE−1、MAGE−2、MAGE−3、MAGEA1、MAGEA3、MAGEA4、MART1、MCP−1、MIF(マクロファージ遊走阻止因子又はグリコシル化阻害因子(GIF))、MS4A1(膜貫通4ドメインサブファミリーAメンバー1)、MSLN(メソテリン)、MUC1(ムチン1、細胞表面関連(MUC1)又はPolymorphic epithelial mucin(PEM))、MUC1−KLH、MUC16(CA125)、MCP1(単球走化性タンパク質1)、MelanA/MART1、ML−IAP、MPG、MS4A1(膜貫通型4ドメインサブファミリーA)、MYCN、ミエリン関連糖タンパク質、ミオスタチン、NA17、NARP−1、NCA−90(顆粒球抗原)、Nectin−4(ASG−22ME)、NGF、神経アポトーシス制御プロテイナーゼ1、NOGO−A、Notch受容体、ヌクレオリン、Neu癌遺伝子産物、NY−BR−1、NY−ESO−1、OX−40、OxLDL(酸化低密度リポタンパク質)、OY−TES1、P21、p53非変異体、P97、Page4、PAP、、抗(N−グリコリルノイラミン酸)のパラトープ、PAX3、PAX5、PCSK9、PDCD1(PD−1、プログラムされた細胞死タンパク質1、CD279)、PDGF−Rα、(血小板由来成長因子受容体α)、PDGFR−β、PDL−1、PLAC1、PLAP様精巣アルカリホスファターゼ、血小板由来成長因子受容体β、リン酸ナトリウム共輸送体、PMEL17、ポリシアル酸、プロテイナーゼ3(PR1)、前立腺癌、PS(ホスファチジルセリン)、前立腺癌細胞、緑膿菌、PSMA、PSA、PSCA、狂犬病ウイルス糖タンパク質、RHD(Rhポリペプチド1(RhPI)、CD240)、アカゲザル因子(Rhesus factor)、RANKL、PhoC,Ras変異体、RG55、ROBO
4、RSウイルス、RON、肉腫転移ブレイクポイント、SART3、スクレロスチン、SLAMF7(SLAMファミリーメンバー7)、セレクチンP、SDC1(シンデカン1)、sLe(a)、ソマトメジンC、SIP(スフィンゴシン−1−ホスフェート)、ソマトスタチン、精子タンパク質17、SSX2、STEAP1(前立腺1の6回膜貫通上皮抗原)、STEAP2、STn、TAG−22(腫瘍関連糖タンパク質72)、サバイビン、T細胞受容体、T細胞膜貫通タンパク質、TEM1(腫瘍上皮マーカー1)、TENB2、テナスシンC(TN−C)、TGF−α、TGF−β(トランスフォーミング増殖因子β)、TGF−β1、TGF−β2(トランスフォーミング増殖因子β2)、Tie(CD202b)、Tie2、TIM−1(CDX−014)、TN、TNF、TNF−α、TNFRSF8、TNFRSF10B(腫瘍壊死因子受容体スーパーファミリーメンバー10B)、TNFRSF13B(腫瘍壊死因子受容体スーパーファミリーメンバー13B)、TPBG(栄養膜糖タンパク質)、TRAIL−R1(腫瘍壊死アポトーシス誘導リガンド受容体1)、TRAILR2(細胞死受容体5(DR5))、主要関連カルシウムシグナルトランスデューサー2、MUC1の腫瘍特異的グリコシル化、TWEAK受容体、TYRP1(糖タンパク質75)、TRP−2、チロシナーゼ、VCAM−1(CD106)、VEGF、VEGF−A、VEGF−2(CD309)、VEGFR−1、VEGFR2、又はビメンチン、WT1、XAGE1、又は任意のインスリン成長因子受容体を発現する細胞、又は任意の上皮増殖因子受容体。
Cell binding agents, more preferably antibodies, counter tumor cells, virus-infected cells, microbial-infected cells, parasite-infected cells, autoimmune cells, activated cells, bone marrow cells, activated T cells, B cells, or melanocytes. It can be any agent that can. More specifically, the cell binding agent can be any drug / molecule capable of countering any one of the following antigens or receptors: CD3, CD4, CD5, CD6, CD7. , CD8, CD9, CD10, CD11a, CD11b, CD11c, CD12w, CD14, CD15
, CD16, CDw17, CD18, CD19, CD20, CD21, CD22, CD23, CD24, CD25, CD26, CD27, CD28, CD29, CD30, CD31, CD32, CD33, CD34, CD35, CD36, CD37, CD38, CD39, CD40. , CD41, CD42, CD43, CD44, CD45, CD46, CD47, CD48, CD49b, CD49c, CD51, CD52, CD53, CD54, CD55, CD56, CD58, CD59, CD61, CD62E, CD62L, CD62P, CD63, CD66, CD68. , CD69, CD70, CD72, CD74, CD79, CD79a, CD79b, CD80, CD81, CD82, CD83, CD86, CD87, CD88, CD89, CD90, CD91, CD95, CD96, CD98, CD100, CD103, CD105, CD106, CD109. , CD117, CD120, CD125, CD126, CD127, CD133, CD134, CD135, CD138, CD141, CD142, CD143, CD144, CD147, CD151, CD147, CD152, CD154, CD156, CD158, CD163, CD166, CD168, CD174, CD180. , CD184, CDw186, CD194, CD195, CD200, CD200a, CD200b, CD209, CD221, CD227, CD235a, CD240, CD262, CD271, CD274, CD276 (B7-H3), CD303, CD304, CD309, CD326, 4-1BB, 5AC
, 5T4 (nutrient blast sugar protein, TPBG, 5T4, Wnt activation inhibitor 1 or WAIF1), adenocarcinoembryonic antigen, AGS-5, AGS-22M6, actibin receptor-like kinase 1, AFP, AKAP-4, ALK, α-integrin, αvβ6, aminopeptidase N, amyloid β, androgen receptor, angiopoietin 2, angiopoietin 3, anexin A1, chemokine toxin protective antigen, anti-transferase receptor, AOC3 (VAP-1), B7-H3 , Chemokine, BAFF (B-cell activating factor), B-lymphoma cells, bcr-abl, bombesin, BORIS, C5, C242 antigen, CA125 (carbohydrate antigen 125, MUC16), CA-IX (or CAIX, carbonic acid dehydration) Enzyme 9), CALLA, CanAg, Canine IL31, Carbonide Dehydrating Enzyme IX, Myocardial Myosin, CCL11 (CC Motif Chemokine 11), CCR4 (CC Chemokine Receptor Type 4, CD194), CCR5, CD3E (Epsilon), CEA ( Carcinoembryonic antigen), CEACAM3, CEACAM5 (carcinoembryonic antigen), CFD (factor D), Ch4D5, chemokine 2 (CCK2R), CLDN18 (crowdin-18), clamping factor A, CRIPTO, FCSF1R (colony) Stimulating factor 1 receptor, CD115), CSF2 (colony stimulating factor 2, granulocyte macrophage colony stimulating factor (GM-CSF)), CTLA4 (cytotoxic T lymphocyte-related protein 4), CTAA16.88 tumor antigen, CXCR4 ( CD184), CXC chemokine receptor type 4, cADP ribose hydrolase, Cyclin B1, CYP1B1, cytomegalovirus, cytomegalovirus glycoprotein B, dabigatlan, PLL4 (delta-like ligand 4), DPP4 (zipeptidyl peptidase 4), DR5
(Death Receptor 5), Escherichia coli Shiga Toxin Type 2, ED-B, EGFL7 (Protein 7 containing EGF-like domain), EGFR, EGFRII, EGFRvIII, Endoglin (CD105), Endoserin B receptor, Endotoxin, EpCAM (Epithelial cell adhesion) Molecules), EphA2, epicialin, ERBB2 (epithelial growth factor receptor 2), ERBB3, ERG (TMPRSS2ETS fusion gene), Escherichia coli, ETV6-AML, FAP (fibroblast activation protein α), FCGR1, α-fetoprotein, fibrin II, β chain, fibronectin external domain B, FOLR (folic acid receptor), folic acid receptor α, folic acid hydrolase, Fos-related antigen 1, RS virus F protein, Frizzled receptor, fucosyl GM1, GD2 ganglioside, G-28 ( Cell surface glycolipid antigen), GD3 idiotype, GloboH, gripican 3, N-glycolylneuraminic acid, GM3, GMCS F receptor α chain, growth differentiation factor 8, GP100, GPNMB (transmembrane protein NMB), GUCY2C (guanyl) Acid cyclase 2C, guanylate cyclase C (GC-C), intestinal guanylate cyclase, guanylate cyclase-C receptor, thermostable enterotoxin receptor (hSTAR)), heat shock protein, blood cell agglutinin, hepatitis B surface Antigen, Hepatitis B virus, HER1 (human epithelial growth factor receptor 1), HER2, HER2 / neu, HER3 (ERBB-3), IgG4, HGF / SF (stem cell proliferation factor / cell dispersant), HHGFR, HIV- 1. Histon complex, HLA-DA (human leukocyte antigen), HLA-DR10, HLA-DRB, HMWMAA, human chorionic gonadotropin, HNGF, human cell scattering factor receptor kinase, HPV E6 / E7, Hsp90, hTERT, ICAM -1 (intercellular adhesion molecule 1), idiotype, IGF1R (IGF-1, insulin-
Fc region, IGHE, IL-1, IL-2 receptor (
3, α5β5, αvβ5), interferon γ-inducible protein, ITAGA2, ITGB2, KIR2D, LCK, Le, legmine, Lewis-Y antigen, LFA-1 (lymphocyte function-related antigen 1, CD11a), LHRH, LINGO-1, lipotaiko Acid, LIV1A, LMP2, LTA, MAD-CT-1, MAD-CT-2, MAGE-1, MAGE-2, MAGE-3, MAGEA1, MAGEA3, MAGEA4, MART1, MCP-1, MIF (Macrophage migrating inhibitor) Or Platelet Derived Growth Factor (GIF)), MS4A1 (Transmembrane 4 Domain Subfamily A Member 1), MSLN (Mesoterin), MUC1 (Mutin 1, Cell Surface Related (MUC1) or Polymorphic Protein Mucin (PEM)), MUC1- KLH, MUC16 (CA125), MCP1 (monosphere-migrating protein 1), MelanA / MART1, ML-IAP, MPG, MS4A1 (transmembrane 4-domain subfamily A), MYCN, myelin-related glycoprotein, myostatin, NA17 , NARP-1, NCA-90 (granulocyte antigen), Nectin-4 (ASG-22ME), NGF, nerve apoptosis control proteinase 1, NOGO-A, Notch receptor, nucleoline, Neu cancer gene product, NY-BR- 1, NY-ESO-1, OX-40, OxLDL (Oxidized Low Density Lipoprotein), OY-TES1, P21, p53 Nonvariant, P97, Page4, PAP ,, Anti (N-Glycolyl Neuramic Acid) Paratope, PAX3, PAX5, PCSK9, PDCD1 (PD-1, programmed cell death protein 1, CD279), PDGF-Rα, (platelet-derived growth factor receptor α), PDGFR-β, PDL-1, PLAC1, PLAP Like testis alkaline phosphatase, platelet-derived growth factor receptor β, sodium phosphate cotransporter, PMEL17, polysialic acid, proteinase 3 (PR1), prostate cancer, PS (phosphatidylserine), prostate cancer cells, pyogenic bacteria, PSMA, PSA, PSCA, Mad Dog Disease Virus Glycoprotein, RHD (Rh Polypeptide 1 (RhPI), CD240), Akagesaru Factor (Rhesus factor), RANKL, PhoC, Ras Variant, RG55, ROBO
4, RS virus, RON, sarcoma metastasis breakpoint, SART3, sclerostin, SLAMF7 (SLAM family member 7), selectin P, SDC1 (cindecane 1), sLe (a), somatomedin C, SIP (sphingocin-1-phosphate), Somatostatin, sperm protein 17, SSX2, STEAP1 (six transmembrane epithelial antigen of prostate 1), STEAP2, STn, TAG-22 (tumor-related glycoprotein 72), survivin, T cell receptor, T cell transmembrane protein, TEM1 ( Tumor epithelial marker 1), TENB2, tenascin C (TN-C), TGF-α, TGF-β (transforming growth factor β), TGF-β1, TGF-β2 (transforming growth factor β2), Tie (CD202b) , Tie2, TIM-1 (CDX-014), TN, TNF, TNF-α, TNFRSF8, TNFRSF10B (tumor necrosis factor receptor superfamily member 10B), TNFRSF13B (tumor necrosis factor receptor superfamily member 13B), TPBG ( (Nutrition membrane sugar protein), TRAIL-R1 (tumor necrosis apoptosis-inducing ligand receptor 1), TRAILR2 (cell death receptor 5 (DR5)), major related calcium signal transducer 2, tumor-specific glycosylation of MUC1, TWEAK acceptance Body, TYRP1 (glycoprotein 75), TRP-2, tyrosinase, VCAM-1 (CD106), VEGF, VEGF-A, VEGF-2 (CD309), VEGFR-1, VEGFR2, or Vimentin, WT1, XAGE1, or any Cells that express the insulin growth factor receptor, or any epithelial growth factor receptor.
別の特定の実施形態において、本発明の架橋連結体による細胞結合分子−薬物共役体は、癌の治療に用いられる。かかる癌は、これらに限定されるものではないが、副腎皮質癌、肛門癌、膀胱癌、脳腫瘍(成人、脳幹グリオーマ、子供、小脳星状細胞腫、脳星状細胞腫、上衣腫、髄芽腫、テント上原始神経外胚葉性および松果体腫瘍、視覚路および視床下部膠腫)、乳癌、カルチノイド腫瘍、胃腸、原発不明癌腫、子宮頸癌腫、大腸癌腫、子宮内膜癌、食道癌、肝外胆管癌、ユーイング・ファミリー腫瘍(PNET)、頭蓋外悪性胚細胞腫瘍、眼癌、眼内黒色腫、胆嚢癌、胃癌(胃)、胚細胞腫瘍、性腺外、妊娠栄養膜腫瘍、頭頸部癌、下咽頭癌、膵島細胞癌種、腎臓癌(腎細胞癌)、喉頭癌腫、白血病(急性リンパ芽球性、急性骨髄性、慢性リンパ性、慢性骨髄性、毛様細胞)、口唇および口腔癌、肝臓癌、肺癌(非小細胞、小細胞、リンパ腫(AIDS関連、中枢神経系、皮膚T細胞、ホジキン病、非ホジキン病、悪性中皮腫、黒色腫、メルケル細胞癌腫、原発不明の転移性扁平首癌、多発性骨髄腫及びその他の形質細胞腫瘍、菌状息肉腫、骨髄異形成症候群、骨髄増殖症候群、鼻咽頭癌、神経芽細胞腫、口腔癌、咽頭癌、骨肉腫、卵巣癌(上皮、生殖細胞腫瘍、低悪性ポテンシャル腫瘍)、膵臓癌(外分泌腺、膵島細胞癌)、副鼻腔および鼻腔癌、副甲状腺癌、陰茎癌、褐色細胞腫癌、下垂体癌、形質細胞腫、前立腺癌、横紋筋肉腫、直腸癌、腎細胞癌(腎癌)、腎盂及び尿管(移行細胞)、唾液腺癌、セザリー症候群、皮膚癌、皮膚癌(皮膚様T細胞リンパ腫、カポジ肉腫、黒色腫)、小腸癌、軟部組織肉腫、胃癌、精巣癌、胸腺腫(悪性)、甲状腺癌、尿道癌、子宮癌(肉腫)、子供の異常な癌、膣癌、外陰癌、ウィルムス腫瘍を含む。 In another particular embodiment, the cell binding molecule-drug conjugates of the crosslinked conjugates of the invention are used in the treatment of cancer. Such cancers are, but are not limited to, adrenocortical cancer, anal cancer, bladder cancer, brain tumor (adult, brain stem glioma, child, cerebral stellate cell tumor, brain stellate cell tumor, lining tumor, medullary bud). Tumors, primordial neuroendoblast and pine pulp tumors on the tent, visual tract and hypothalamic glioma), breast cancer, cartinoid tumors, gastrointestinal, cancer of unknown primary origin, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, Extrahepatic bile duct cancer, Ewing family tumor (PNET), extracranial malignant embryonic cell tumor, eye cancer, intraocular melanoma, bile sac cancer, gastric cancer (stomach), embryonic cell tumor, extragonadal, pregnancy nutrient membrane tumor, head and neck Cancer, hypopharyngeal cancer, pancreatic islet cell cancer type, kidney cancer (renal cell cancer), laryngeal carcinoma, leukemia (acute lymphoblastic, acute myeloid, chronic lymphocytic, chronic myeloid, hairy cells), lips and oral cavity Cancer, liver cancer, lung cancer (non-small cells, small cells, lymphoma (AIDS-related, central nervous system, skin T cells, Hodgkin's disease, non-Hodgkin's disease, malignant mesoderma, melanoma, Mercel cell carcinoma, metastasis of unknown primary origin) Flat neck cancer, multiple myeloma and other plasmacytoma, mycobacterial sarcoma, myelodystrophy syndrome, myelodystrophy syndrome, nasopharyngeal cancer, neuroblastoma, oral cancer, pharyngeal cancer, osteosarcoma, ovarian cancer (Epithelialis, germ cell tumor, low malignant potential tumor), pancreatic cancer (exocrine gland, pancreatic islet cell cancer), sinus and nasal cavity cancer, parathyroid cancer, penis cancer, brown cell tumor cancer, pituitary cancer, plasmacytoma, Prostate cancer, rhabdominal myoma, rectal cancer, renal cell cancer (renal cancer), renal pelvis and urinary tract (transitional cells), salivary adenocarcinoma, cesarly syndrome, skin cancer, skin cancer (skin-like T-cell lymphoma, capo-sarcoma, black Tumors), small bowel cancer, soft tissue sarcoma, gastric cancer, testis cancer, thoracic adenoma (malignant), thyroid cancer, urinary tract cancer, uterine cancer (sarcoma), abnormal cancer in children, vaginal cancer, genital cancer, Wilms tumor.
別の特定実施例において、本発明の架橋連結体を介した細胞結合分子−薬物共役体は、その成分と方法によって、自己免疫疾患の治療又は予防に用いることができる。該自己免疫疾患には、自己免疫性胃酸欠乏慢性活動性肝炎、急性散在性脳脊髄炎、急性出血性白質脳炎、アジソン病、無ガンマグロブリン血症、円形脱毛症、筋萎縮性側索硬化症、強直性脊椎炎、アンチ−GMB/TBM腎炎、抗リン脂質症候群、抗シンセターゼ症候群、関節炎、アトピー性アレルギー、アトピー性皮膚炎、自己免疫性再生不良性貧血、自己免疫性心筋症、自己免疫性溶血性貧血、自己免疫性肝炎、自己免疫性内耳疾患、自己免疫性リンパ球増殖症候群、自己免疫性末梢神経系疾患、自己免疫性膵炎、複数の自己免疫性内分泌障害I、II、III型、自己免疫性プロゲステロン皮膚炎、自己免疫性血小板減少性紫斑病、自己免疫性ブドウ膜炎、バーロー病/バーロー同心性硬化症、ベーチェット病、Berger病、Bickerstaff脳炎、Blau症候群、水疱性類天疱瘡、キャッ
スルマン病、シャーガス病、慢性疲労性免疫機能障害症候群、慢性炎症性脱髄性多発神経障害、慢性再発性多病巣性骨髄炎、慢性ライム病、慢性閉塞性肺疾患、アレルギー性肉芽腫性血管炎、瘢痕性類天疱瘡、セリアック病、コーガン症候群、寒冷凝集素症、補体成分C2欠損症、頭部動脈炎、クレスト症候群、クローン病(特発性炎症性腸疾患)、クッシング症候群、皮膚白血球破砕性血管炎、悪性萎縮性丘疹症、有痛脂肪症、疱疹状皮膚炎、皮膚筋炎、1型糖尿病、びまん性皮膚強皮症、心筋梗塞症、円板状紅斑性狼瘡、湿疹、子
宮内膜症、付着部炎関連関節炎、好酸球性筋膜炎、後天性表皮水疱症、結節性紅斑、特発性混合クリオグロブリン血症、エバンス症候群、進行性骨化性線維形成異常症、線維筋痛症、線維筋炎、線維化性肺胞隔炎、胃炎、消化管類天疱瘡、巨細胞性動脈炎、腎球体腎炎、グッドパスチャー症候群、バセドウ病、ギラン・バレー症候群、橋本脳症、橋本甲状腺炎、溶血性貧血、アレルギー性紫斑病、妊娠性疱疹、化膿性汗腺炎、ヒューズ症候群(抗リン脂質抗体症候群)、低ガンマグロブリン血症、特発性炎症性脱髄疾患、特発性肺線維症、特発性血小板減少性紫斑病(自己免疫性血小板減少性紫斑病)、IgA腎症(Berger病)、封入体筋炎、炎症性脱髄性多発性神経障害、間質性膀胱炎、過敏性腸症候群、若年性特発性関節炎、若年性関節リウマチ、皮膚粘膜リンパ節症候群、ランバート・イートン筋無力症候群、白血球破壊性血管炎、扁平苔癬、硬化性苔癬、リニアIgA疾患(LAD)、ルー・ゲーリッグ病(筋萎縮性側索硬化症)、狼瘡様肝炎、紅斑性狼瘡、ブラウ症候群、メニエール病、顕微鏡的多発血管炎、ミラー・フィッシャー症候群、混合結合組織病、強皮症、ミュシャ−ヤコブ病、マックル・ウェルズ症候群、多発性骨髄腫、多発性硬化症、重症筋無力症、筋炎、ナルコレプシー、視神経脊髄炎(デビック病)、神経性筋、眼瘢痕性類天疱瘡、オプソクローヌス・ミオクローヌス症候群、オード甲状腺炎、回帰性リウマチ、パンダ症候群(合併連鎖球菌感染症の児童自己免疫神経精神障害)、腫瘍小脳変性症、発作性夜間血色素尿症、パリー・ロンベルク症候群、パーソネージ-ジョー
ジア症候群、扁平部炎症、天疱瘡、尋常性天疱瘡、悪性貧血、静脈周囲性脳脊髓炎、POEMS症候群、結節性多発動脈炎、リウマチ性多発筋痛、多発性筋炎、原発性胆汁性肝硬変、原発性硬化性胆管炎、進行性炎症性神経障害、乾癬、乾癬性関節炎、壊疽性膿皮症、純赤血球無形成性貧血、ラスムッセン脳炎、レイノー病、再発性多発性軟骨炎、ライター症候群、下肢静止不能症候群、後腹膜線維症、関節リウマチ、リウマチ熱、サルコイドーシス、統合失調症、シュミット症候群、シュニッツラー症候群、強膜炎、強皮症、シェーグレン症候群、脊椎関節症、粘着性血症候群、スティル病、スティッフマン症候群はだ、亜急性細菌性心内膜炎、スザック症候群、急性熱性好中球皮膚病、シデナム舞踏病、交感性眼炎、高安動脈炎、側頭動脈炎(巨細胞性動脈炎)、トロサ・ハント症候群、横断性脊髄炎、潰瘍性大腸炎(特発性炎症性腸疾患)、未分化結合組織病、未分化脊椎関節症、血管炎、白斑、ウェゲナー肉芽腫症、ウィルソン症候群、ウェストコット−アルドリッチ症候群が含まれるが、これらに限定されない。
In another specific embodiment, the cell binding molecule-drug conjugate via the crosslinked conjugate of the present invention can be used for the treatment or prevention of autoimmune diseases by its components and methods. The autoimmune diseases include autoimmune gastric acid deficiency chronic active hepatitis, acute diffuse encephalomyelitis, acute hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, circular alopecia, and muscular atrophic lateral sclerosis. , Tonic spondylitis, anti-GMB / TBM nephritis, antiphospholipid syndrome, antisynthase syndrome, arthritis, atopic allergy, atopic dermatitis, autoimmune poor regeneration anemia, autoimmune cardiomyopathy, autoimmune Hematopoietic anemia, autoimmune hepatitis, autoimmune internal ear disease, autoimmune lymphocyte proliferation syndrome, autoimmune peripheral nervous system disease, autoimmune pancreatitis, multiple autoimmune endocrine disorders I, II, III, Autoimmune progesterone dermatitis, autoimmune thrombocytopenic purpura, autoimmune pancreatitis, Barlow's disease / Barlow concentric sclerosis, Bechet's disease, Berger's disease, Bickerstaff encephalitis, Blau syndrome, bullous vesicles, Castleman's disease, Shagas' disease, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, chronic recurrent polyfocal myelitis, chronic Lime's disease, chronic obstructive pulmonary disease, allergic granulomatous blood vessels Flame, scarring scoliosis, Celiac disease, Cogan syndrome, cold agglutinosis, complement component C2 deficiency, head arteritis, crest syndrome, Crohn's disease (idiopathic inflammatory bowel disease), Cushing syndrome, cutaneous leukocytes Fractile vasculitis, malignant atrophic scaly, painful steatosis, herpes dermatitis, dermatomyitis, type 1 diabetes, diffuse cutaneous caries, myocardial infarction, discoid erythema, eczema, intrauterine Membrane disease, adhesitis-related arthritis, eosinophilia myelitis, acquired epidermal vesicular disease, nodular erythema, idiopathic mixed cryoglobulinemia, Evans syndrome, progressive ossifying fibrosis, fibromuscularis Pain, fibromyalitis, fibrotic alveolar cystitis, gastrointestinal inflammation, gastrointestinal cystitis, giant cell artitis, nephrocyte nephritis, Good Pasture syndrome, Basedou disease, Gillan Valley syndrome, Hashimoto encephalopathy, Hashimoto thyroiditis, Hemolytic anemia, allergic purpura, gestational herpes, purulent sweat adenitis, Hughes syndrome (antiphospholipid antibody syndrome), hypogamma globulinemia, idiopathic inflammatory demyelinosis, idiopathic pulmonary fibrosis, idiopathic Thrombocytopenic purpura (autoimmune thrombocytopenic purpura), IgA nephropathy (Berger's disease), inclusion myopathy, inflammatory demyelinating polyneuropathy, interstitial cystitis, hypersensitivity bowel syndrome, juvenile Idiopathic arthritis, juvenile rheumatoid arthritis, mucocutaneous lymph node syndrome, Lambert Eaton muscle asthenia syndrome, leukocyte-destroying vasculitis, squamous lichen, sclerosing lichen, Linear Ig Disease A (LAD), Lou Gehrig's disease (muscle atrophic lateral sclerosis), scab-like hepatitis, erythematous wolf, Blau syndrome, Meniere's disease, microscopic polyangiitis, Miller-Fisher's syndrome, mixed connective tissue disease, Strong skin disease, Musha-Jakob disease, McCull Wells syndrome, multiple myeloma, multiple sclerosis, severe myasthenia, myitis, narcolepsy, optic neuromyelitis (Devik's disease), neuromuscular, eye scarring Blisters, Opsocronus myocronus syndrome, Eau de thyroiditis, recurrent rheumatism, panda syndrome (child autoimmune neuropsychiatric disorder with comorbid streptococcal infection), tumor cerebral degeneration, paroxysmal nocturnal hemochromatosis, Parry Lomberg syndrome, Personage-Georgia syndrome, squamous inflammation, vesicles, vulgaris vulgaris, malignant anemia, perivenous cerebral spondylitis, POEMS syndrome, nodular polyarteritis, rheumatic polymyopathy, polymyositis, primary biliary Liver cirrhosis, primary sclerosing cholangitis, progressive inflammatory neuropathy, psoriasis, psoriatic arthritis, necrotizing pyoderma, pure erythropoiesis anemia, Rasmussen encephalitis, Reynaud's disease, recurrent polychondritis, Reiter's syndrome , Lower limb immobility syndrome, retroperitoneal fibrosis, rheumatoid arthritis, rheumatic fever, sarcoidosis, schizophrenia, Schmidt syndrome, Schnitzler syndrome, embolitis, scleroderma, Schegren syndrome, spondylosis, sticky blood syndrome, still Disease, Stiffman syndrome, subacute bacterial endocarditis, Suzak syndrome, acute febrile neutrophil dermatosis, Sidenum butoh disease, sympathetic ophthalmitis, hyperan arteritis, temporal arteritis (giant cell artery) Flame), Trosa-Hunt syndrome, transversal myelitis, ulcerative colitis (idiopathic inflammatory bowel disease), undifferentiated connective tissue disease, undifferentiated spondyloarthritis, angiitis, leukoplakia, Wegener's granulomatosis, Wilson's syndrome , Westcott-Aldrich Syndrome, but not limited to these.
別の特定実施例において、自己免疫疾患の治療又は予防のための本発明の架橋連結体を介して共役するのに使用される結合分子には、抗エラスチン抗体;Abys抗上皮細胞抗体;抗基底膜のIV型コラーゲンタンパク質抗体;抗核抗体;抗二本鎖DNA抗体、抗一本鎖DNA抗体、抗カルジオリピン抗体IgM、IgG;抗セリアック抗体;抗リン脂質抗体IgK、IgG;抗SM抗体;抗ミトコンドリア抗体;甲状腺抗体;微粒体抗体、T細胞抗体;チログロブリン抗体、抗強皮症−70抗体(AntiSCL−70);抗ジョー抗体(Anti−Jo)、抗U1RNP抗体(Anti−U1RNP);抗La/SSB抗体;抗SSA抗体;抗SSB抗体;抗壁細胞抗体;抗ヒストン抗体;抗RNP抗体;C−ANCA;P−ANCA;抗セントロメア抗体;抗フィブリン抗体、抗GBM抗体、抗ガングリオシド抗体;抗デスモソーム糖タンパク質3コア抗体(anti−Desmogein3);抗p62抗体;抗sp100抗体;抗ミトコンドリア(M2)抗体;リウマチ因子抗体;抗MCV抗体;抗トポイソメラーゼ抗体;抗好中球細胞質(cANCA)抗体が含まれるが、これらに限定されない。 In another particular embodiment, the binding molecule used to conjugate via the cross-linking of the invention for the treatment or prevention of autoimmune disease includes anti-erastin antibody; Abys anti-epithelial cell antibody; anti-base. Membrane IV collagen protein antibody; anti-nuclear antibody; anti-double-stranded DNA antibody, anti-single-stranded DNA antibody, anti-cardiolipin antibody IgM, IgG; anti-celiac antibody; anti-phospholipid antibody IgK, IgG; anti-SM antibody; anti Mitochondrial antibody; thyroid antibody; microgranular antibody, T cell antibody; tyroglobulin antibody, anti-strong skin disease-70 antibody (AntiSCL-70); anti-Jo antibody (Anti-Jo), anti-U1RNP antibody (Anti-U1RNP); La / SSB antibody; anti-SSA antibody; anti-SSB antibody; anti-wall cell antibody; anti-histon antibody; anti-RNP antibody; C-ANCA; P-ANCA; anti-centromea antibody; anti-fibrin antibody, anti-GBM antibody, anti-ganglioside antibody; Anti-desmosome glycoprotein 3-core antibody (anti-Desmogen3); anti-p62 antibody; anti-sp100 antibody; anti-mitichotic (M2) antibody; rheumatic factor antibody; anti-MCV antibody; anti-topoisomerase antibody; anti-neutrophilase antibody (cANCEA) antibody Included, but not limited to.
いくつかの好ましい実施形態において、本発明の共役体に用いる結合分子は、自己免疫疾患に関連する活性化リンパ球によって発現された受容体又は受容体複合体と結合することができる。受容体又は受容体複合体は、例えば、免疫グロブリン遺伝子スーパーファミリーのメンバー(例えば、CD2、CD3、CD4、CD8、CD19、CD20、CD22、CD28、CD30、CD33、CD37、CD38、CD56、CD70、CD79、CD90、CD125、CD147、CD152/CTLA−4、PD−1、又はICOS)、TNF受容体スーパーファミリー(例えば、CD27、CD40、CD95/Fas、CD134/OX40、CD137/4−1BB、INF−R1、TNFR−2、RANK、TACI、BCMA、オステオプロテゲリン、Apo2/TRAIL−R1、TRAIL−R2、TRAIL−R3、TRAIL−R4、及びAPO−3)、インテグリン、サイトカイン受容体、ケモカイン受容体、主要組織適合性タンパク質、レクチン(C型、S型、若しくはI型)、又は補体調節タンパク質が挙げられる。 In some preferred embodiments, the binding molecule used in the conjugate of the invention can bind to a receptor or receptor complex expressed by activated lymphocytes associated with an autoimmune disease. The receptor or receptor complex is, for example, a member of the immunoglobulin gene superfamily (eg, CD2, CD3, CD4, CD8, CD19, CD20, CD22, CD28, CD30, CD33, CD37, CD38, CD56, CD70, CD79. , CD90, CD125, CD147, CD152 / CTLA-4, PD-1, or ICOS), TNF receptor superfamily (eg, CD27, CD40, CD95 / Fas, CD134 / OX40, CD137 / 4-1BB, INF-R1 , TNFR-2, RANK, TACI, BCMA, Osteoprotegerin, Apo2 / TRAIL-R1, TRAIL-R2, TRAIL-R3, TRAIL-R4, and APO-3), integrin, cytokine receptor, chemokine receptor, major Examples include histocompatibility proteins, lectins (C, S, or I), or receptor superfamilies.
別の具体的な実施形態において、ウイルス抗原又は細菌抗原に対して免疫特異性を有する有用な結合体は、ヒト化又はヒトモノクローナル抗体である。本文で用いられている用語の「ウイルス抗原」には、免疫応答を誘発し得る如何なるウイルスペプチド、ポリペプチドタンパク質(例えば、HIVgp120,HIVnef,RSV F糖タンパク質、インフルエンザウイルスノイラミニダーゼ、インフルエンザウイルス血球凝集素、HTLVtax、単純ヘルペスウイルス糖タンパク質(例えば、gB、gC、gD及びgE)、及びB型肝炎表面抗原)が含まれるが、これらに限定されない。本文に用いられている用語の「細菌抗原」には、免疫応答を誘発し得る如何なる微生物ペプチド、ポリペプチド、タンパク質、糖類、多糖、又は脂質分子(例えば、細菌、真菌、病原性原生動物、酵母ポリペプチド(例えば、LPS及び5/8))が含まれるが、これらに限定されない。ウイルス又は細菌感染症の治療に有用なI型抗体には、パリビズマブ(RVS感染の治療に用
いられヒト化抗呼吸器合胞体ウイルスモノクローナル抗体)、PRO542(HIV感染の治療に用いるCD4融合抗体)、Ostavir(B型肝炎ウイルスの治療に用いるヒト抗体)、PROTVIR(サイトメガロウイルスの治療に用いるヒト化抗体IgG1抗体)、抗LPS抗体が含まれるが、これらに限定されない。
In another specific embodiment, a useful conjugate having immunospecificity against a viral or bacterial antigen is a humanized or human monoclonal antibody. The term "viral antigen" used in the text refers to any viral peptide, polypeptide protein (eg, HIVgp120, HIVnef, RSVF glycoprotein, influenza virus neurominidase, influenza virus blood cell agglutinin) that can elicit an immune response. Includes, but is not limited to, HTLVtax, simple herpesvirus glycoproteins (eg, gB, gC, gD and gE), and hepatitis B surface antigens. The term "bacterial antigen" used in the text refers to any microbial peptide, polypeptide, protein, sugar, polysaccharide, or lipid molecule that can elicit an immune response (eg, bacteria, fungi, pathogenic protozoa, yeast). Polypeptides (eg, LPS and 5/8)) are included, but not limited to. Type I antibodies useful in the treatment of viral or bacterial infections include paribismab (humanized antirespiratory vesicle virus monoclonal antibody used in the treatment of RVS infection), PRO542 (CD4 fusion antibody used in the treatment of HIV infection), Ostavir (human antibody used for the treatment of hepatitis B virus), PROTVIR (humanized antibody IgG1 antibody used for the treatment of cytomegalovirus), anti-LPS antibody are included, but not limited to these.
本発明の架橋連結体によって調製された細胞結合分子−薬物共役体は、伝染性疾患の治療に用いることができる。該伝染性疾患は、アシネトバクター感染症、放線菌症、アフリカ眠り病(アフリカトリパノソーマ症)、エイズ(後天性免疫不全症候群)、アメーバ症、アナプラズマ、炭疽菌、細菌結核感染、アルゼンチン出血熱、回虫症、アスペルギルス症、アストロウイルス感染症、バベシア症、セレウス菌感染症、細菌性肺炎、細菌性膣炎、バクテロイデス感染、バランチジウム症、ベイリー線虫回虫感染症、BKウイルス感染、黒色砂毛、ブラストシスホミニス感染症、ブラストミセス、ボリビア出血熱、ボレリア感染症、ボツリヌス中毒(及び乳児ボツリヌス症)、ブラジル出血熱、ブルセラ症、バークホルデリア感染症、ブルーリ潰瘍、感染カリシウイルス(ノロウイルス、サポウイルス)、カンピロバクター感染症、カンジダ感染症(カンジダ症、鵞口瘡)、キャット・スクラッチ病、蜂巣炎、シャーガス病(アメリカトリパノソーマ症)、軟性下疳、水痘、衣原体、肺炎衣原体感染、霍乱、着色真菌症、肝吸虫病、クロストリジウム・ディフィシル感染症、コクシジオイデス症、コロラドダニ熱、風邪(急性ウイルス性鼻咽頭炎、急性鼻炎)、クロイツフェルト・ヤコブ病、クリミア−コンゴ出血熱、クリプトコッカス、クリプトスポリジウム、皮膚幼虫移行、シクロスポラ感染症、嚢虫症、サイトメガロウイルス感染、デング熱、二核アメーバ症、ジフテリア、裂頭条虫症、メジナ虫症、エボラ出血熱、包虫症、エールリヒア症、蟯虫(蟯虫感染症)、腸球菌感染症、エンテロウイルス感染症、発疹チフス、伝染性紅斑(第五病)、子供急性発疹、肥大吸虫症、片吸虫病、致死性家族性不眠症、フィラリア症、ウェルシュ菌によって引き起こされる食中毒、非寄生アメーバ感染症、フゾバクテリウム感染症、ガス壊疽(クロストリジウム筋壊死)、ジオトリクム症、ゲルストマン・ストロイスラー・シャインカー症候群、ランブル鞭毛虫症、鼻疽、
顎口虫症、淋病、鼡径部肉芽腫(ドノヴァン症)、A群連鎖球菌感染症、B群連鎖球菌感染症、インフルエンザ菌感染症、手足口病(HFMD)、ハンタウイルス肺症候群、ヘリコバクターピロリ感染、溶血性尿毒症症候群、腎症候性出血熱、A型肝炎、B型肝炎、C型肝炎、D型肝炎、E型肝炎、単純ヘルペス、ヒストプラスマ症、鉤虫感染、人間バルカンウイルス感染、人間エールリヒア症エバンス、ヒト顆粒球アナプラズマ症、ヒトメタニューモウイルス感染症、ヒト単球性エー.リキア症、ヒト乳頭腫ウイルス感染、ヒトパラインフルエンザウイルス感染、小形条虫症、インフルエンザ、イソスポーラ症、川崎病、単核(球)症、キム菌感染、クールー、ラッサ熱、レジオネラ症(在郷軍人症)、レジオネラ症(ポンティアック熱)、リーシュマニア症、ハンセン病、レプトスピラ症、リステリア症、ライム病(ライムボレリア)、リンパフィラリア症(象皮病)、リンパ球性脈絡髄膜炎、マラリア、マールブルグ出血熱、麻疹、類鼻疽(ホイットモア病)、髄膜炎、髄膜炎菌性疾患、メタゴニムス症、微胞子虫症、伝染性軟属腫、流行性耳下腺炎、発疹チフス(風土病発疹チフス)、マイコプラズマ肺炎、菌腫、ハエ病、新生児結膜炎(新生児眼炎)、クロイツフェルト・ヤコブ病(vCJD,nvCJD)、ノカルジア症、オンコセルカ症(失明性のフィラリア症)、副コクシジオイデス症(南米ブラストミセス)、肺吸虫症、パスツレラ病、アタマジラミ(アタマジラミ)、ボディシラミ病(ボディシラミ)、ケジラミ病(ケジラミ、Crarb ice)、骨盤内炎症性疾患、百日咳(Wooping cough)、疫病、肺炎球菌感染症、カリニ肺炎、肺炎、ポリオ、プレボテラ感染症、PAME、進行性多巣性白質脳症、オウム病、Q熱、狂犬病、ラット咬傷発熱、呼吸器合胞体ウイルス感染、ライノウイルス感染、リケッチア感染症、リケッチア、リフトバレー熱、ロッキー山紅斑熱、ロタウイルス感染症、風疹、サルモネラ症、SARS(重症急性呼吸器症候群)、疥癬、住血吸虫症、敗血症、下痢(赤痢)、帯状疱疹(Herpes zoster)、天然痘、スポロトリクム、ブドウ球菌食中毒、ブドウ球菌感染、線虫、梅毒、条虫症、破傷風(開口障害)、白癬性毛瘡(Barber‘s itch)、手部白癬、黒色ひこう疹、足部白癬、爪白癬、癜風、トキソカラ症(眼幼虫移行症)、トキソカラ症(内臓幼虫移行症)、トキソプラズマ症、旋毛虫、トリコモナス症、クリプトビオシス(鞭虫感染症)、肺結核症、野兎病、尿素分解尿素マイコプラズマ感染、ベネズエラウマ脳炎、ベネズエラ出血熱、ウイルス性肺炎、ウエストナイル熱、白髪根粒菌病、偽結核菌感染症、エルシニア症、黄熱病、接合菌症を含むが、これらに限定されない。
The cell-binding molecule-drug conjugate prepared by the crosslinked conjugate of the present invention can be used for the treatment of infectious diseases. The infectious diseases include asinetobacter infection, actinomycete, African sleep disease (African tripanosoma disease), AIDS (acquired immunodeficiency syndrome), amoeba disease, anaplasma, charcoal bacillus, bacterial tuberculosis infection, Argentine hemorrhagic fever, roundworm. Disease, Aspergillosis, Astrovirus infection, Babesia disease, Seleus infection, Bacterial pneumonia, Bacterial vaginal inflammation, Bacteroides infection, Valantedium disease, Bailey nematode roundworm infection, BK virus infection, Black sand hair, Blastsis Hominis infection, Blast Mrs., Bolivian hemorrhagic fever, Borrelia infection, Botulinum poisoning (and infant botulinum disease), Brazilian hemorrhagic fever, Brucella disease, Burkeholderia infection, Bruli ulcer, Infectious calicivirus (Norovirus, Sapovirus) , Campylobacter infection, Candida infection (Candida disease, scab), Cat scratch disease, Honeycombitis, Shagas disease (American tripanosoma disease), Soft scab, Water sputum, Cloth progenitor, Pneumonia Cloth progenitor infection, Disturbance, Colored fungal disease, Liver sucking Diseases, Crostridium difficile infection, Coccidiosis, Colorado tick fever, cold (acute viral nasopharyngitis, acute rhinitis), Kreuzfeld-Jakob disease, Crimea-Congo hemorrhagic fever, cryptococcus, cryptospolidium, skin larvae migration, cyclospora Infections, cysts, cytomegalovirus infections, dengue fever, dinuclear amoeba disease, diphtheria, cleft headworm disease, medina worm disease, Ebola hemorrhagic fever, cyst disease, aerrichia disease, worms (worm worm infection), enterococcal infection , Enterovirus infection, rash typhoid, infectious erythema (fifth disease), acute rash in children, hypertrophic worm disease, hemi-sucking disease, lethal familial insomnia, filariasis, food poisoning caused by Welsh bacteria, non-parasitic amoeba infection , Fuzobacterium infection, gas necrosis (Crostridium muscle necrosis), geotricum disease, Gerstmann-Stroisler-Scheinker syndrome, rumble whiplash, nasal ulcer,
Jawworm disease, gonorrhea, inguinal granulomas (Donovan disease), group A streptococcal infection, group B streptococcal infection, influenza infection, hand-foot-and-mouth disease (HFMD), huntavirus lung syndrome, helicobacter pyrori infection , Hematopoietic urinary syndrome, nephropathy hemorrhagic fever, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E, simple herpes, histoplasmosis, worm infection, human vulcan virus infection, human errichia Evans, human granulocyte anaplasmosis, human metapneumovirus infection, human monocytic A. Liquia disease, human papilloma virus infection, human parainfluenza virus infection, small streak disease, influenza, isosporosis, Kawasaki disease, mononuclear (sphere) disease, Kim fungus infection, cool, lassa fever, legionellosis (local military personnel) Disease), Legionellosis (Pontiac fever), Leishmania disease, Hansen's disease, Leptospyrosis, Listeria disease, Lime's disease (Limeborelia), Lymphophilaria (elephant skin disease), Lymphocytic choroiditis, Malaria, Marburg hemorrhagic fever, Messiah, nasal ulcer (Whitmore's disease), meningitis, meningitis fungal disease, metagonimosis, microspore disease, infectious soft gland tumor, epidemic parotid inflammation, rash typhoid (climate disease rash typhoid), mycoplasma pneumonia, Myoma, fly disease, neonatal conjunctivitis (neonatal ophthalmitis), Kreuzfeld-Jakob disease (vCJD, nvCJD), nocardiosis, oncoselka disease (blind filariasis), legionnaires' disease (South American blast Mrs.), pulmonary worm disease , Pasturella disease, Atamajirami (Atamajirami), Body shirami disease (Body shirami), Kejirami disease (Kejirami, Crabice), Pelvic inflammatory disease, Pertussis (Wooping cow), Epidemic, Pneumococcal infection, Carini pneumonia, Pneumonia Polio, Prebotera infection, PAME, progressive multifocal leukoencephalopathy, parrot disease, Q fever, mad dog disease, rat bite fever, respiratory follicles virus infection, rhinovirus infection, liquettia infection, liquettia, lift valley fever, rocky Sanko spot fever, rotavirus infection, wind rash, salmonerosis, SARS (severe acute respiratory syndrome), scab, sedation, sepsis, diarrhea (red diarrhea), herpes zoster, natural pox, sporotricum, staphylococcus. Food poisoning, staphylococcal infection, nematodes, syphilis, legionnaires' disease, rupture (opening disorder), barber's itch, tinea pedis, black leukoplakia, tinea pedis, tinea unguium, ulcer , Toxocarosis (eye larvae migration), toxocarosis (visceral larvae migration), toxoplasmosis, curly worms, trichomonas disease, cryptobiosis (whipworm infection), pulmonary tuberculosis, rabbit disease, urea-degrading ureamycoplasma infection, Includes, but is not limited to, Venezuelan encephalitis, Venezuelan hemorrhagic fever, viral pneumonia, Westnile fever, legionnaires' disease, pseudotuberculous infections, ersinia, yellow fever, and zygosity.
細胞結合分子としてより好ましくは、本願に記載された病原性株に対する抗体であり、該病原性株には、アシネトバクター・バウマニ、アクチオマイセス・イスラエリー、アクチノマイセス・オドントリチカス(Actinomyces odontolyticus)、プロピオニバクテリウム・プロピオニカス、トリパノソーマ・ブルーセイ、HIV(ヒト免疫不全ウイルス)、赤痢アメーバ、アナプラズマ属、炭疽菌、メチルスヘモリティクム(Arcanobacterium haemolyticum)、フニンウイルス、回虫、アスペルギルス、アストロウイルス科、バベシア属、セレウス菌細菌属、マルチプル・バクテリア、バクテロイデス属、結腸ポーチ繊毛虫、ベイリー回虫線虫属、BKウイルス、ピエドライア・ホルタエ(Piedraiahortae)、ブラストシスティス・ホミニス、皮炎芽生菌病、マクポ・ウイルス、ボレリア属、ボツリヌス菌、サビア、ブルセラ属、通常バークホルデリア・セパシア及び他のバークホルデリア種、マイコバクテリウム・ウルセランス、カリシウイルス科ファミリー、カンピロバクター菌、通常カンジダ・アルビカンス及び他のカンジダ種、バルトネラ・ヘンセラ菌(英:Bartonella henselae)、A群連鎖球菌及びブドウ球菌、クルーズトリパノソーマ、軟性下疳菌、水痘帯状疱疹ウイルス(VZV)、クラミジア・トラコマチス、クラミジア・ニューモニエ、コレラ菌、フォンセカエ・ペドロソイ、肝吸虫症、クロストリジウム・ディフィシレ、コクシジオイデス・イミティス、コクシジオイデス・ポサダシ、コロラドダニ熱ウイルス、ライノウイルス、コロナウイルス、クロイツフェルト・ヤコブ病・プリオン、クリミア−コンゴ出血熱ウイルス、クリプトコックス・ネオフォルマンス、クリプトスポリジウム属、猫鉤虫、共寄生虫、シクロスポラ、有鉤条虫、サイトメガロウイル
ス、デング熱ウイルス(DEN−1、DEN−2、DEN−3及びDEN−4)−フラビウイルス、双核アメーバ、コリネバクテリウム・ジフテリア、裂頭条虫属、メジナ虫(Dracunculusmedinensis)、エボラウイルス、エキノコックス属、エーリキア属、蟯虫、エンテロコッカス属、エンテロウイルス属、発疹チフス・リケッチア、パルボウイルスB19、ヒトヘルペスウイルス6型、ヒトヘルペスウイルス7型、肥大吸虫、肝蛭及び巨大肝蛭、FFIプリオン、フィラリアヘッド上科、ウェルシュ菌、フソバクテリウム、ウェルシュ菌、他のクロストリジウム属、ゲオトリクムカンジドウム、GSSプリオン、ランブル鞭毛虫(Giardia lamblia)、バークホルデリア鼻疽菌、顎口顎線虫、剛棘顎口虫、淋菌、肉芽腫菌、化膿連鎖球菌、ストレプトコッカス・アガラクティエ、インフルエンザ菌、腸内ウイルス、ほとんどのコクサッキーA型ウイ
ルス、腸内ウイルス71型、シンノンブルウイルス、ヘリコバクター・ピロリ、大腸菌O158:H7、ブニヤウイルス科、A型肝炎ウイルス、B型肝炎ウイルス、C型肝炎ウイルス、D型肝炎ウイルス、E型肝炎ウイルス、単純ヘルペスウイルス1型、単純ヘルペスウイルス2型、ヒストプラスマ・カプスラーツム、十二指腸鉤虫、アメリカ鉤虫、インフルエンザ菌、ボカ人間ウイルス、エーリキア・エウィンギ(Ehrlichia ewingii)、アナプラズマ・ファゴサイトフィルム、ヒトメタニューモウイルス、エールリッヒア・シャフェンシス、ヒトパピローマウイルス、ヒトパラインフルエンザウイルス、矮小条虫、縮小条虫、エプスタイン・バー・ウイルス、オルトミクソウイルス科、イソスポーラ・ベリ(Isospora belli)、キンゲラ・キンゲ(Kingella kingae)、肺炎桿菌、クレブシエラオツェーナ、クレブシエラリノシェレロモーティス(Klebsiellarhinoscleromotis)、クーループリオン、ラッサ熱ウイルス、レジオネラ・ニューモフィラ、レジオネラ・ニューモフィラ、リーシュマニア、ハンセン菌とマイコバクテリウム・レプロマトーシス(Mycobacterium lepromatosis)、レプトスピラ属、リステリア菌、ボレリア病及び他のボレリア種、バンクロフト糸状虫及びマレー糸状虫、リンパ球性脈絡髄膜炎ウイルス(LCMV)、プラスモジウム属(Plasmodiumgenus)、マールブルグウイルス、麻疹ウイルス、偽鼻疽菌(Burkholderia pseudomallei)、髄膜炎菌、横川吸虫、微胞子虫門、伝染性軟属腫ウイルス(MCV)、ムンプスウイルス、リケッチア・チフィ、マイコプラズマ・ニューモニエ、種々の細菌(アクチノミセトーマ)及び真菌(真菌性菌腫)、寄生ハエの幼虫の双翅目、クラミジア・トラコマチスや淋菌、vCJDプリオン、ノカルジア・アステロイデス及び他のノカルジア種、回旋糸状虫、ブラジルブラストミセス、肺吸虫およびその他の肺吸虫属、パスツレラ属、アタマジラミ、コロモジラミ、フチルス・プビス(Phthiruspubis)、百日咳菌、ペスト菌、肺炎球菌、ニューモシスチス嚢虫症、ポリオウイルス、プレボテラ属、ネグレリアのアメーバ、JCウイルス、オウム病クラミジア、コクシエラ・バーネッティ、狂犬病ウイルス、ビーズチェーン大腸菌及びラット咬傷発熱スピロヘータ、呼吸器RSウイルス、リノスポリジウム・セーベリ、ライノウイルス、リケッチア属、リケッチアダニ、リフトバレー熱ウイルス、ロッキー山紅斑熱リケッチア、ロタウイルス、風疹ウイルス、サルモネラ属、非定型肺炎コロナウイルス、疥癬ダニ、住血吸虫属、赤痢菌、水痘帯状疱疹ウイルス、大痘瘡又は小痘瘡、スポロトリックス・シェンキー、ブドウ球菌属、黄色ブドウ球菌、化膿連鎖球菌、糞線虫、梅毒スピロヘータ、条虫属、破傷風菌、白癬、トリコフィトン・トンズランス、白癬、エピデルモフィトン・フロッコースム、紅色白癬菌及び毛瘡白癬菌、紅色白癬菌、ホルテア・ウェルネッキ、白癬、マラセチア属、イヌ回虫や猫回虫、トキソプラズマ、旋毛虫、膣トリコモナス、鞭虫、結核菌、トゥーラホットフランシス細菌、ウレアプラズマ・ウレアリティカム、ベネズエラウマ脳炎ウイルス、コレラ菌、グアナリトウイルス、西ナイルウイルス、白髪胞子菌、仮性結核菌、腸炎エルシニア、黄熱病ウイルス、ケカビ目(ムコール症)と昆虫メッシュカビ(エントモフトラ症)、緑膿菌、カンピロバクター胎児(ビブリオ)、アエロモナス細菌、エドワードシエラ属.タルダ、ペスト菌、志賀赤痢菌、赤痢菌、赤痢ソンネ、ネズミチフス菌、トレポネーマ
・ペルテヌエ、トレポネーマカラテネウム、フェンセンブルグドルフェリ、ボレリア・ブ
ルグドルフェリ、レプトスピラ出血性黄疸、ニューモシスチスカリニ、ウシ流産菌、ブタ流産菌、マルタ熱菌、マイコプラズマ属、発疹チフスリケッチア、リケッチアツツツガムシ、クラミジア属、病原性真菌(アスペルギルス・フミガーツス、カンジダ・アルビカンス、ヒストプラスマカプスラーツム);原虫(赤痢アメーバ、膣トリコモナス、人トリコモナス、トリパノソーマガンビエンス、ローデシアトリパノソーマ、ドノバンリーシュマニア、リーシュマニア熱帯、リーシュマニアブラジル、ニューモシスチスカリニ肺炎、三日熱マラリア原虫、熱帯熱マラリア原虫、悪性マラリア);又は蠕虫(日本住血吸虫、マンソン住血吸虫、ビルハルツ住血吸虫と鉤虫)が含まれるが、これらに限定されない。
More preferably, as a cell-binding molecule, it is an antibody against the pathogenic strain described in the present application, and the pathogenic strain includes Acinetobacter baumani, Actiomyces islaeri, Actinomyces odonlyticus, and propionibacterium.・ Propionicas, Tripanosoma bluesei, HIV (human immunodeficiency virus), diarrhea amoeba, anaplasma genus, charcoal bacterium, methylshemolyticum (Arcanobacterium hairolyticum), funin virus, roundworm, Aspergillus, astrovirus family, Babesia genus, Seleus Bacterial Bacteria, Multiple Bacteria, Bacteroides, Colon Pouch Fiberworm, Bailey Roundworm Nematode, BK Virus, Piedraiahortae, Blastcystis Hominis, Dermatitis Sprout Disease, Macpo Virus, Borrelia, Botulinum, Savior, Brucella, usually Berkholderia sepacia and other Berkholderia species, Mycobacterium urserans, Calicivirus family, Campylobacter, usually Candida albicans and other Candida species, Bartonella Hensera (English: Bartonella henselae), Group A streptococcus and staphylococcus, cruise tripanosoma, soft hypoplasia, varicella herpes virus (VZV), chlamydia trachomatis, chlamydia pneumoniae, cholera, phonsecae pedrosoy, hepatic insectosis・ Difficile, Coccidioides imitis, Coccidioides posadashi, Colorado tick fever virus, Rhinovirus, Coronavirus, Kreuzfeld-Jakob disease ・ Prion, Crimea-Congo hemorrhagic fever virus, Cryptocox neoformance, Cryptospolidium, Cat worm , Coparasitic, cyclospora, rodent, cytomegalovirus, denfever virus (DEN-1, DEN-2, DEN-3 and DEN-4) -flavivirus, dinuclear amoeba, corynebacterium diphtheria, cleft Dracunculus medinensis, Ebola virus, Echinocox, Erikia, worm, Enterococcus, Enterovirus, rash Tihus liquettia, Parvovirus B19, human herpesvirus 6, human herpesvirus 7, hypertrophic sucking Insects, hepatic and giant hepatic worms, FFI prion, filaria head superfamily, Welsh, virus, Welsh, other genus Clostridium, Geotrichumcandidium, GSS prion, rumble lambria, Burkholderia Nasal bacillus, jaw-mouth-jaw nematode, stylus jaw-mouthworm, gonococcus, granulomatosis, purulent streptococcus, streptococcus agaractier, influenza, intestinal virus, most coxsackie type A virus, intestinal virus type 71, Shinnonburu virus, Helicobacter pylori, Escherichia coli O158: H7, Bunyavirus family, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Hepatitis D virus, Hepatitis E virus, Simple herpesvirus type 1, Simple herpesvirus Type 2, histoprasma capslatum, duodenal worm, American worm, influenza virus, boca human virus, Ehrlicia ewingii, anaplasma fagosite film, human metapneumovirus, Ehrlichia chafensis, human papillomavirus, human para Influenza virus, dwarf worm, reduced worm, Epstein bar virus, orthomixovirus family, Isospora belli, Kingella kingae, pneumonia rod, Klebsiella ozena, Klebsiella linocerero Mortis (Klebsiella rhinoscleromotis), Cooluprion, Lassa fever virus, Regionella pneumophila, Regionella pneumophila, Leishmania, Hansen and Mycobacteria lepromatosis (Mycobacterium lepromatosis, Lycobacteriaium lepromatosis, etc. Borrelia species, Bancroft filamentous worms and Murray filamentous worms, lymphocytic choriomyelitis virus (LCMV), Plasmodiumgenus, Marburg virus, measles virus, Burkholderia pseudomallei, meningitis, Yokokawa sucker, microspore phylum, infectious soft tumor virus (MCV), mumps virus, liquettia chifi, mycoplasma pneumoniae, various bacteria (actinomysetoma) and fungi (fungal myoma), parasitic fly larvae Diptera, Chlamydia tiger coma Chiss and gonococci, vCJD prion, nocardia asteroides and other nocardia species, ringworm, Brazilian blastomyces, pulmonary worms and other pulmonary worms, rickettsiae, rickettsiae, rickettsiae, ringworm, Phthirus pubis, ringworm Pest, Pneumoniae, Pneumocystis cyst, Poliovirus, Prebotera, Negrelia amoeba, JC virus, Aum chlamydia, Cocciella burnetti, Mad dog disease virus, Beadchain Escherichia coli and rat bite fever spirochete, Respiratory RS virus, Linos Polydium saveri, rhinovirus, rickettsia, rickettsia tick, rickettsia fever virus, rocky mountain erythema fever rickettsia, rotavirus, ruin virus, salmonella genus, atypical pneumonia coronavirus, ringworm tick, tinea bacillus, ringworm, Rickettsia, rickettsia, ringworm, ringworm, rickettsiae, rickettsiae, rickettsiae, rickettsiae, rickettsiae, rickettsiae, rickettsiae, rickettsiae, rickettsiae Trichophyton, Epidermophyton floccorum, Trichophyton and Trichophyton, Trichophyton tinea, Holtea Wernecki, Trichophyton, Maracetia, Canine roundworm and Cat roundworm, Toxoplasma, Trichophyton, Vaginal trichomonas, Whipworm, Tuberculosis, With Tula Hot Francis Bacteria, Ureaplasma Ureaity Cam, Venezuelan Erauma Encephalitis Virus, Cholera Bacteria, Guanalytovirus, West Nile Virus, Ringworm, Pseudo-tuberculosis, Enteritis Ersina, Yellow Fever Virus, Rickettsia (Mucorosis) Insect mesh mold (ringworm), ringworm, camppyrobacter fetal (vibrio), aeromonas bacterium, Edward Sierra. Tarda, pesto, Shiga rickettsia, ringworm, ringworm sonne, rickettsiae, treponema pertenue, treponema karateneum , Fensemburg dolferi, Borrelia burgdorferi, Leptspira hemorrhagic jaundice, Pneumocystiscarini, bovine ringworm, porcine ringworm, Martha fever, mycoplasma, rash typhos rickettsia, rickettsia, ringworm, tinea, pathogenic fungus ( Aspergillus fumigatus, Candida albicans, Histoplus macaps ratum); Protozoa (Rickettsia amoeba, Vaginal tricomonas, Human tricomonas, Tripanosoma gambience, Rhodesia tripanosoma, Donovan Leishmani A, Leishmania tropical, Leishmania Brazil, Pneumocystiscarini pneumonia, vivax malaria parasite, Plasmodium falciparum, malignant malaria); or worms (Schistosoma japonicum, Schistosoma mansson, Schistosoma haematobium and worms) , Not limited to these.
ウイルス性疾患の治療のために本発明で用いられる細胞結合リガンドとしての他の抗体は、これらに限定されないが、病原性ウイルス抗原に対する抗体が含まれ、該病原性ウイルスの例示として、これらに限定されないが、ポックスウイルス科(Poxyiridae)、ヘルペスウイルス科、アデノウイルス科、パポバウイルス科、エンテロウイルス科、ピコルナウイルス科、パルボウイルス科、レオウイルス科、レトロウイルス科、インフルエンザウイルス、パラインフルエンザウイルス、流行性耳下腺炎、麻疹、呼吸器合胞体ウイルス、風疹、アルボウイルス、ラブドウイルス、アレナウイルス科、非A/非B型肝炎ウイルス、ライノウイルス、コロナウイルス、ロタウイルス、腫瘍ウイルス[例えば、HBV(肝細胞癌)、HPV(子宮頸癌、肛門癌)、カポジ肉腫関連ヘルペスウイルス(カポジ肉腫)、EBウイルス(鼻咽頭癌、バーキットリンパ腫、原発性中枢神経系リンパ腫)、MCPyV(メルケル細胞癌)、SV40(シミアンウイルス40)、HCV(肝細胞癌)、HTLV−I(成人T細胞白血病/リンパ腫)];ウイルスによって引き起こされる免疫疾患:[例えば、ヒト免疫不全ウイルス(AIDS)]、CNSウイルス:[例えば、JCV(進行性多巣性白質脳症)、MeV(亜急性硬化性全脳炎)、LCV(リンパ球性脈絡髄膜炎)、アルボウイルス脳炎、オルトミクソウイルスウイルス科(推定)(嗜眠性脳炎)、RV(狂犬病)、水疱性口内炎、ヘルペスウイルス性髄膜炎、ラムゼイ・ハント症候群II型;ポリオウイルス(急性灰白髄炎、ポリオ後症候群)、HTLV−I(熱帯性痙性麻痺)];サイトメガロウイルス(CMV網膜炎、HSV(ヘルペス性角膜炎));心血管病ウイルス[例えばCBV(心膜炎、心筋炎)];呼吸器系/急性鼻咽頭炎/ウイルス性肺炎:[EBウイルス(EBV感染症/伝染性単核球症)、サイトメガロウイルス、SARSコロナウイルス(重症急性呼吸器系症候群)、オルトミクソウイルスウイルス科:インフルエンザウイルスA/B/C(インフルエンザ/鳥インフルエンザ)、パラミクソウイルス:ヒトパラインフルエンザウイルス(パラインフルエンザ)、RSV(ヒト呼吸器合胞体ウイルス)、hMPV];消化系ウイルス[MuV(流行性耳下腺炎)、サイトメガロウイルス(CMV性食道炎);アデノウイルス(アデノウイルス感染);ロタウイルス、ノロウイルス、アストロウイルス、コロナウイルス、HBV(B型肝炎ウイルス)、CBV、HAV(A型肝炎ウイルス)、HCV(C型肝炎ウイルス)、HDV(D型肝炎ウイルス)、HEV(E型肝炎ウイルス)、HGV(G型肝炎ウイルス)];泌尿生殖器系ウイルス[例えば、BKウイルス、MuV(流行性耳下腺炎)]が含まれる。 Other antibodies as cell binding ligands used in the present invention for the treatment of viral diseases include, but are not limited to, antibodies to pathogenic viral antigens, and are limited to these as examples of the pathogenic virus. Not, but Poxylidae, herpesvirus, adenovirus, papovavirus, enterovirus, picornavirus, parvovirus, leovirus, retrovirus, influenza virus, parainfluenza virus, epidemic Ear adenitis, measles, respiratory follicles virus, wind rash, arbovirus, rabdovirus, arenavirus family, non-A / non-B hepatitis virus, rhinovirus, coronavirus, rotavirus, tumor virus [eg, HBV ( Hepatic cell carcinoma), HPV (cervical cancer, anal cancer), Kaposi sarcoma-related herpesvirus (Kaposi sarcoma), EB virus (nasopharyngeal cancer, Berkit lymphoma, primary central nervous system lymphoma), MCPyV (Merkel cell carcinoma) , SV40 (Simian virus 40), HCV (hepatocellular carcinoma), HTLV-I (adult T-cell leukemia / lymphoma)]; Immune diseases caused by the virus: [eg, human immunodeficiency virus (AIDS)], CNS virus: [For example, JCV (progressive multifocal leukoencephalopathy), MeV (subacute sclerosing panencephalitis), LCV (lymphocytic choriomyelitis), arbovirus encephalitis, orthomyxovirus virus family (estimated) (drowsiness) Encephalitis), RV (mad dog disease), bullous stomatitis, herpesvirus meningitis, Ramsey-Hunt syndrome type II; poliovirus (acute gray-white myelitis, post-porio syndrome), HTLV-I (tropical spastic paralysis)]; Cytomegalovirus (CMV retinitis, HSV (herpes keratitis)); cardiovascular virus [eg CBV (carditis, myocarditis)]; respiratory system / acute nasopharyngitis / viral pneumonia: [EB virus (EBV infection / infectious mononuclear sphere), cytomegalovirus, SARS coronavirus (severe acute respiratory syndrome), orthomixovirus virus family: influenza virus A / B / C (influenza / bird influenza), para Mixovirus: human parainfluenza virus (parainfluenza), RSV (human respiratory vesicle virus), hMPV]; digestive system virus [MuV (epidemic parotitis), cytomegalovirus (CMV esophagitis); adeno Virus (adenovirus infection ); Rotavirus, Norovirus, Astrovirus, Coronavirus, HBV (Hepatitis B virus), CBV, HAV (Hepatitis A virus), HCV (Hepatitis C virus), HDV (Hepatitis D virus), HEV (E) Hepatitis virus), HGV (hepatitis G virus)]; urogenital system viruses [eg, BK virus, MuV (epidemic parotid inflammation)] are included.
更なる目的によれば、本願発明は、本願発明の架橋共役体を介した共役体及び薬学的に受け入れられる担体を共に含む、癌及び自己免疫疾患を治療するための医薬組成物にも関する。癌及び自己免疫疾患を治療するための方法は、インビトロ(in vitro)、インビボ(in vivo)又はエクスビボ(ex vivo)で実行することができる。インビトロ療法の例としては、目標抗原を発現しない望ましい変異体以外の全ての細胞を死滅させるため、又は所望でない抗原を表現する変異体を死滅させるための細胞培養処理を含む。エクスビボ療法の例としては、移植(HSCT)の実行に先立って造血幹細胞(HSC)を処理し、患部又は悪性細胞を殺すために、これを同一患者の体内へ戻すことを含む。例えば、癌及び自己免疫疾患の治療における自家移植に先立って、骨髄から癌細胞又はリンパ球細胞を除去するための、又は移植片対宿主病を防ぐために、移植に先立っ
て、同種異系の骨髄又は組織からT細胞及び他のリンパ細胞を除去するための臨床的エキソビボ処理は、以下により実施することができる。患者又は他の個体から骨髄細胞を獲得した後、濃度範囲が1pM〜0.1mMとなるように、本願発明の共役体を加えた血清含有培地で、37℃で30分間〜約48時間培養する。的確な濃度条件及び培養時間(=用量)は、経験豊富な臨床医によって容易に決められる。培養終了後、骨髄細胞を血清含有培地で洗浄し、静脈内注射等の既知の方法によって人体へ戻す。骨髄細胞の獲得及び再注入治療の間に、患者が他の治療(例えば、廃絶化学療法又は全身照射)を受けている場合、処理後の骨髄細胞は、標準的な医療装置を用いた液体窒素により冷凍保存される。
According to a further object, the present invention also relates to a pharmaceutical composition for treating cancer and autoimmune diseases, which comprises both a conjugate via a crosslinked conjugate of the present invention and a pharmaceutically acceptable carrier. Methods for treating cancer and autoimmune diseases can be performed in vitro, in vivo or ex vivo. Examples of in vitro therapy include cell culture treatments to kill all cells except the desired mutants that do not express the target antigen, or to kill mutants that express the unwanted antigens. Examples of exvivo therapy include treating hematopoietic stem cells (HSCs) prior to performing a transplant (HSCT) and returning them back into the same patient to kill the affected or malignant cells. For example, allogeneic bone marrow prior to transplantation to remove cancer or lymphocyte cells from the bone marrow or to prevent graft-versus-host disease prior to autologous transplantation in the treatment of cancer and autoimmune diseases. Alternatively, clinical exobibo treatment to remove T cells and other lymphocytes from the tissue can be performed as follows. After acquiring bone marrow cells from a patient or another individual, the cells are cultured at 37 ° C. for 30 minutes to about 48 hours in a serum-containing medium containing the conjugate of the present invention so that the concentration range is 1 pM to 0.1 mM. .. The exact concentration conditions and culture time (= dose) are easily determined by an experienced clinician. After completion of the culture, the bone marrow cells are washed with a serum-containing medium and returned to the human body by a known method such as intravenous injection. If the patient is receiving other treatments (eg, abolition chemotherapy or total body irradiation) during bone marrow cell acquisition and reinjection therapy, the treated bone marrow cells will be liquid nitrogen using standard medical equipment. Is stored frozen.
インビボ臨床適用において、本発明の共役薬物は、溶液の形式又は注射のために滅菌水に再溶解することができる凍結乾燥固体の形式で提供されている。適切な共役体の投与方法の例は下記のとおりである。8〜20週間にわたって、共役体を毎週1回急速静脈投与注入する。急速投与量を50〜500mLの生理食塩液に溶解させ、生理食塩液にヒト血清アルブミンを加えることができる(例えば、0.5〜5mlの濃縮ヒト血清アルブミン溶液を100mg/ml)。薬剤投与量は約50μg〜100mg/kg体重・週であり、静脈注射(毎回の注射量が10μg〜50mg/kgの範囲)である。4〜20週間の治療が終了後、患者は、第2のコースの治療を受け入れることができる。投与経路、賦形剤、希釈剤、投与量、治療期間を含め、詳細な治療方法は、経験ある外科医によって決定することができる。 For in vivo clinical applications, the conjugated drugs of the invention are provided in the form of solutions or in the form of lyophilized solids that can be redissolved in sterile water for injection. Examples of suitable conjugate administration methods are as follows. The conjugate is rapidly intravenously infused once weekly for 8-20 weeks. A rapid dose can be dissolved in 50-500 mL of saline and human serum albumin can be added to the saline (eg, 0.5-5 ml of concentrated human serum albumin solution at 100 mg / ml). The drug dose is about 50 μg to 100 mg / kg body weight / week, and is intravenous injection (the amount of each injection is in the range of 10 μg to 50 mg / kg). After 4 to 20 weeks of treatment, the patient can accept a second course of treatment. Detailed treatment methods, including routes of administration, excipients, diluents, dosages and duration of treatment, can be determined by an experienced surgeon.
インビボ又はエクスビボ法によって細胞群を選択的に死滅させることにより疾患を治療する例としては、いずれかの種類の癌、自己免疫疾患、移植拒絶反応、及び感染症(ウイルス、細菌又は寄生虫を含む)がある。 Examples of treating the disease by selectively killing the cell population in vivo or by the Exvivo method include any type of cancer, autoimmune disease, transplant rejection, and infectious diseases (including viruses, bacteria or parasites). ).
複数の要素に起因して、理想の生物学効果に必要な共役薬物の量は異なる。これら要素は、化合物の性質、有効性及び共役薬物の生物利用度、疾患の類型、患者の人種、患者の病的状態、並びに投与経路を含み、これらの要素を共同して、投与スケジュール及び投与経路が決定される。 Due to multiple factors, the amount of conjugated drug required for the ideal biological effect will vary. These factors include the nature of the compound, its efficacy and bioavailability of the conjugate drug, the type of disease, the race of the patient, the pathological condition of the patient, and the route of administration. The route of administration is determined.
一般論として、本発明の連結体を介した共役体は、0.1〜10%w/vの濃度で該共役体を含むように、生理的緩衝液に溶解した非経口投与のための製剤であってもよい。典型的な用量の範囲は、1日あたり1μg/kg体重〜0.1g/kg体重であり、好ましい用量の範囲は、1日あたり0.01mg/kg体重〜20mg/kg体重か、或いは児童用量と等価量である。好ましい薬物投与量は、例えば、疾患又は障害の進行の型及び程度、個々の患者の全体的な健康状態、選択された薬物の相対的な生物学的活性、化合物の剤形、投与様式(静脈内、筋肉内、又はその他)、選択された投与様式における薬物の薬物動態学的特性、並びに投与速度(単回注射又は連続注入)及び投与スケジュール(一定時間内に投与の頻度)等の変数に適切に依存する。 In general terms, the conjugate-mediated conjugates of the invention are formulations for parenteral administration dissolved in physiological buffer to contain the conjugate at a concentration of 0.1-10% w / v. It may be. A typical dose range is 1 μg / kg body weight to 0.1 g / kg body weight per day, and a preferred dose range is 0.01 mg / kg body weight to 20 mg / kg body weight per day, or a child dose. Is an equivalent amount. Preferred drug doses are, for example, the type and degree of progression of the disease or disorder, the overall health of the individual patient, the relative biological activity of the selected drug, the dosage form of the compound, the mode of administration (intravenous). Within, intramuscularly, or otherwise), the pharmacokinetic properties of the drug in the chosen mode of administration, and variables such as dosing rate (single or continuous infusion) and dosing schedule (frequency of dosing within a given time). Depend on properly.
本発明の連結体を介した共役体は、単位剤量で投与することもでき、ここで、「単位剤量」とは、一人の患者に投与される一回の用量を意味し、簡単で便利な包装とするで使用することができ、活性な共役体自体又は後述の薬学的に許容される組成物として物理的及び化学的に安定な単位剤量を維持している。そのため、典型的な一日投与量の範囲は、0.01〜100mg/kg体重である。一般的なガイダンスによれば、単位剤量は、1日、1週間、2週間、又は1月あたり1〜3000mgの範囲である。単位剤量として好ましくは、1mg〜500mgを週1〜4回投与することであり、更に好ましくは、10mg〜500mgを週1回投与することである。ここで与えられた共役体は、1種以上の薬学的に許容される賦形剤を医薬組成物に添加することによって調製することができる。単位剤量の薬剤は、経口投与のために、錠剤、単純カプセル又は軟カプセルとして;鼻腔内投与のために、粉末、点鼻剤、又はエアロゾルとして;あるいは、皮膚投与のために、例
えば軟膏、クリーム、ローション、ゲル、又はスプレー又は皮膚パッチとして投与されることができる。
The conjugate via the conjugate of the present invention can also be administered in unit doses, where "unit dose" means a single dose administered to a single patient and is simple. It can be used in convenient packaging and maintains a physically and chemically stable unit dose as the active conjugate itself or as a pharmaceutically acceptable composition described below. Therefore, a typical daily dose range is 0.01-100 mg / kg body weight. According to general guidance, the unit dose ranges from 1 to 3000 mg per day, 1 week, 2 weeks, or 1 month. The unit dose is preferably 1 mg to 500 mg once a week, and more preferably 10 mg to 500 mg once a week. The conjugates given herein can be prepared by adding one or more pharmaceutically acceptable excipients to the pharmaceutical composition. Unit doses of the drug are as tablets, simple capsules or soft capsules for oral administration; as powders, nasal drops, or aerosols for intranasal administration; or for skin administration, eg ointments, It can be administered as a cream, lotion, gel, or spray or skin patch.
薬物/細胞毒性剤
本発明において細胞結合分子と連結することができる薬物は、細胞毒性剤を含む小分子薬物であり、直接又は修飾後に細胞結合分子に連結することができる。ここで、「小分子薬物」は、分子量が例えば100〜1800、より好ましくは120〜1400の有機、無機又は有機金属化合物が広く用いられる。小分子薬物のより良い定義について、WO05058367A2及び米国特許第4,956,303号、並びに他の文献を参考することができ、これらはその全体が参照として組み込まれる。上記薬物には、既知の薬物及び薬物になる可能性のあるものが含まれる。
Drug / Cytotoxic Agent The drug that can be linked to a cell binding molecule in the present invention is a small molecule drug containing a cytotoxic agent and can be linked to a cell binding molecule directly or after modification. Here, as the "small molecule drug", an organic, inorganic or organometallic compound having a molecular weight of, for example, 100 to 1800, more preferably 120 to 1400 is widely used. For a better definition of small molecule drugs, WO05058367A2 and US Pat. No. 4,965,303, as well as other literature can be referenced, which are incorporated by reference in their entirety. The drugs include known drugs and potential drugs.
既知の薬物は、下記のものを含むが、この限りではない。 Known drugs include, but are not limited to:
1)化学療法剤:a)アルキル化剤:例えば、ナイトロジェンマスタード:クロラムブシル、クロルナファジン、シクロホスファミド、ダカルバジン、エストラムスチン、イホスファミド、メクロレタミン、塩酸メクロレタミンオキサイド、マンノムスチン、ミトブロニトール、メルファラン、ピポブロマン、ノベンビチン、フェネステリン、プレドニムスチン、チオテパ、トロホスファミド、ウラシルマスタード;CC−1065(アドゼレシン、カルゼレシン及びビゼレシンの合成類似体を含む。);デュオカルマイシン(合成類似体、KW−2189及びCBI−TMIを含む。);ベンゾジアゼピン二量体(例えば、ピロロベンゾジアゼピン(PBD)又はトマイマイシン、インドリノベンゾジアゼピン類、イミダゾベンゾチアヂアゼピン類、又はオキサゾリジノベンゾジアゼピン類の二量体);ニトロソ尿素化合物:(カルムスチン、ロムスチン、クロロゾトシン、フォテムスチン、ニムスチン、ラニムスチン);アルキルスルホネート(ブスルファン、トレオスル
ファン、イムプロスルファン及びピポスルファン);トリアゼン(ダカルバジン);白金含有化合物:(カルボプラチン、シスプラチン、オキサリプラチン);ベンゾドパ、カルボクオン、メツレドパ及びウレドパ等のアジリジン類;エチレンイミン類、並びにアルトレタミン、トリエチレンメラミン、トリエチレンホスホルアミド及びトリエチレンチオホスホルアミンを含むメチラメラミン類;b)植物アルカロイド:例えば、ビンカアルカロイド類:(ビンクリスチン,ビンブラスチン、ビンデシン、ビノレルビン、ナベルビン);タキソイド類:(パクリタキセル、ドセタキセル);及びこれらの類似体、メイタンシノイド類(DM1、DM2、DM3、DM4、メイタンシン、アンサマイトシン)及びこれらの類似体、クリプトフィシン類(特に、クリプトフィシン1及びクリプトフィシン8);エポチロン類、エリュテロビン類、ディスコデルモライド、ブリオスタチン類、ドロスタチン類、オーリスタチン類、チューブリシン類、セファロスタチン類;パンクラチスタチン;サルコジクチイン;スポンジスタチン;c)DNAトポイソメラーゼ阻害剤:例えば、[エピポドフィリン類:(9−アミノカンプトテシン、カンプトテシン、クリスナトール、ダウノマイシン、エトポシド、リン酸エトポシド、イリノテカン、ミトキサントロン、ノバントロン、レチノイン酸(レチノール類)、テニポシド、トポテカン、9−ニトロカンプトテシン(RFS 2000);マイトマイシン類:(マイトマイシンC))];d)代謝拮抗剤:例えば、{[抗葉酸:ジヒドロ葉酸レダクターゼ阻害剤:(メトトレキサート、トリメトレキサート、デノプテリン、プテロプテリン、アミノプテリン(4−アミノプテロイン酸)、又はその他の葉酸類似体);IMPデヒドロゲナーゼ阻害剤(ミコフェノール酸、チアゾフリン、リバビリン、EICAR);リボヌクレオチド還元酵素阻害薬(ヒドロキシウレア、デフェロキサミン)];[ピリミジン類似体:ウラシル類似体(アンシタビン、アザシチジン、6−アザウリジン、カペシタビン(ゼローダ)、カルモフール、シタラビン、ジデオキシウリジン、ドキシフルリジン、エノシタビン、5−フルオロウラシル、フロクスウリジン、ラルチトレキセド(トミュデックス));シトシン類似体:(シタラビン、シトシンアラビノシド、フルダラビン);プリン類似体:(ア
ザチオプリン、フルダラビン、メルカプトプリン、チアミプリン、チオグアニン)];フォリン酸等の葉酸補充剤};e)ホルモン療法剤:例えば、{受容体拮抗薬:[抗エストロゲン:(メゲストロール、ラロキシフェン、タモキシフェン);LHRHアゴニスト:(ゴセレリン、酢酸リュープロリド);抗アンドロゲン:(ビカルタミド、フルタミド、カルステロン、プロピオン酸ドロモスタノロン、エピチオスタノール、ゴセレリン、リュープロリド、メピチオスタン、ニルタミド、テストラクトン、トリロスタン、及び他のアンドロゲン阻害剤)];レチノイド類/三角筋:[ビタミンD3類似体:(CB1093、EB1089、KH1060、コレカルシフェロール、エルゴカルシフェロール);光線力学的療法剤:(ベルテポルフィン、フタロシアニン、光増感剤Pc4、デメトキシ−ヒポクレリンA);サイトカイン類:(インターフェロンα、インターフェロンγ、腫瘍壊死因子(TNF)、TNFドメイン含有ヒトタンパク質)]};f)キナーゼ阻害剤:例えば、BIBW2992(抗EGFR/Erb2)、イマチニブ、ゲフィチニブ、ペガプタニブ、ソラフェニブ、ダサチニブ、スニチニブ、エルロチニブ、ニロチニブ、ラパチニブ、アキシチニブ、パゾパニブ、バンデタニブ、E7080(抗VEGFR2)、ムブリチニブ、ポナチニブ(AP24534)、バフェチニブ(INNO−406)、ボスチニブ(SKI−606)、カボザンチニブ、ビスモデギブ、イニパリブ、ルキソリチニブ、CYT387、アキシチニブ、チボザニブ、ソラフェニブ、ベバシズマブ、セツキシマブ、トラスツズマブ、ラニビズマブ、パニツムマブ、イスピネシブ;g)抗生物質:例えば、エンジイン系抗生物質(例えば、カリケアマイシン類、特に、カリケアマイシンγ1、δ1、α1及びβ1、例えば、J.Med.Chem.,39(11),2103−2117(1996),Angew Chem Intl.Ed.Engl.33:183−186(1994)参照;ダイネミシンA及びデオキシダイネミシンを含むダイネミシン;エスペラミシン、ケダルシジン、C−1027、マズロペプチン、並びにネオカルジノスタチンクロモフォア及び関連する色素タンパク質エンジイン抗生物質クロモフォア、アクラシノマイシン類、アクチノマイシン、アンスラマイシン、アザセリン、ブレオマイシン類、カクチノマイシン(cactinomycin)、カラビシン(carabicin)、カルミノマイシン、カルジノフィリン;クロモマイシン類、ダクチノマイシン、ダウノルビシン、デトルビシン、6−ジアゾ−5−オキソ−L−ノルロイシン、ドキソルビシン、モルホリノ−ドキソルビシン、シアノモルホリノ−ドキソルビシン、2−ピロリノ−ドキソルビシン及びデオキシドキソルビシン、エピルビシン、イダルビシン、マルセロマイシン、マイトマイシン類、ミコフェノール酸、ノガラマイシン、オリボマイシン類、ペプロマイシン、ポトフィロマイシン、ピューロマイシン、クエラマイシン、ロドルビシン、ストレプトニグリン、ストレプトゾシン、ツベルシジン、ウベニメクス、ジノスタチン、ゾルビシン;f)その他のカテゴリー:例えば、ポリケチド(アセトゲニン類)、特にブラタシン及びブラタシノン;ゲムシタビン、エポキソミシン類(例えば、カルフィルゾミブ)、ボルテゾミブ、サリドマイド、レナリドミド、ポマリドマイド、トセドスタット、ザイブレスタット、PLX4032、STA−9090、スチムバックス(Stimuvax)、アロベクチン−7、ザイゲバ、プロベンジ、エルボイ、イソプレニル化阻害剤(例えば、ロバスタチン)、ドーパミン作動性神経毒(例えば、1−メチル−4−フェニルピリジンイオン)、細胞周期阻害剤(例えば、スタウロスポリン)、アクチノマイシン類(例えば、アクチノマイシンD、ダクチノマイシン)、ブレオマイシン類(例えば,ブレオマイシンA2、ブレオマイシンB2、ペプロマイシン)、アントラサイクリン類(例えば,ダウノルビシン、ドキソルビシン(アドリアマイシン)、イダルビシン、エピルビシン、ピラルビシン、ゾルビシン、ミトキサントロン、MDR阻害剤(例えば、ベラパミル)、Ca2+ATP阻害剤(タプシガルギン等)、ヒストン脱アセチル化酵素阻害剤(ボリノスタット、ロミデプシン、パノビノスタット、バルプロ酸、モセチノスタット(MGCD0103)、ベリノスタット、PCI−24781、エンチノスタット、SB939、レスミノスタット、ギビノスタット、AR−42、CUDC−101、スルフォラファン、トリコスタチンA);タプシガルギン、セレコキシブ、グリタゾン類、エピガロカテキンガレート、ジスルフィラム、サリノスポラミドA、抗副腎薬、例えばアミノグ
ルテチミド、ミトタン、トリロスタン;アセグラトン;アルドホスファミドクリコシド;アミノレブリン酸;アラビノシド、ベストラブシル;ビサントレン;エダトレキサート;デフォファミン、デメコルシン、ジアジコン、エルフォルニチン(DFMO)、酢酸エリプチニウム、エトクルシド、硝酸ガリウム、ガシトシン、ヒドロキシ尿素;イバンドロネート、レンチナン;ロニダミン;ミトグアゾン;モピダモール;ニトラエリン;ペントスタチン;フェナメット;ピラルビシン;ポドフィリン酸;2−エチルヒドラジド;プロカルバジン;PSK(登録商標);ラゾキサン;リゾキシン;シゾフィラン;スピロゲルマニウム;テニュアゾン酸;トリアジコン;2,2’,2’’−トリクロロトリエチルアミン;トリコテセン類(特に、T2トキシン、ベルカリンA、ロリジンA、及びアングイジン);ウレタン、siRNA、アンチセンス医薬、並びに核酸分解酵素。
1) Chemotherapeutic agent: a) Alkylating agent: For example, nitrogen mustard: chlorambucil, chlornafazine, cyclophosphamide, dacarbazine, estramstin, ifosfamide, mechlorethamine, mechlorethamine hydrochloride oxide, mannomustine, mitobronitol, mel. Faran, pipobroman, nobenbitin, phenesterin, prednimustine, thiotepa, trophosphamide, urasyl mustard; CC-1065 (including synthetic analogs of adzelesin, calzelesin and biserecin); duocarmycin (synthetic analogs, KW-2189 and CBI-TMI) ); Benzodiazepine dimers (eg, pyrolobenzodiazepine (PBD) or tomymycin, indolinobenzodiazepines, imidazole benzothiadiazepines, or oxazolidinobenzodiazepine dimers); nitrosourea compounds: (calmustin) , Romustin, chlorozotocin, fotemstin, nimustin, lanimustine); alkyl sulfonate (busulfan, treosulfan, improsulfan and piposulfan); triazene (dacarbazine); platinum-containing compounds: (carboplatin, cisplatin, oxaliplatin); benzodopa, carboquin , Aziridines such as meturedopa and uredopa; ethyleneimines, and methilamelamines including altretamine, triethylenemelamine, triethylenephosphoramide and triethylenethiophosphoramine; b) Plant alkaloids: eg, binca alkaloids: (vincristine, Binblastin, bindesin, binorerbin, navelbin); taxoids :( paclitaxel, docetaxel); and their analogs, maytansinoids (DM1, DM2, DM3, DM4, maytancin, ansamitecin) and their analogs, crypto Physins (particularly cryptophycin 1 and cryptophycin 8); epotylones, eluterobins, discodelmolides, briostatins, drostatins, auristatins, tubericins, cephalotatins; pankratisstatins; sarcodictiin Spongestatin; c) DNA topoisomerase inhibitors: eg, [epipodophyllines: (9-aminocamptothecin, camptothecin, chlormethine, daunomycin, etopocid, etopocid phosphate, irinotecan, mitoxanthro , Novantron, retinoic acid (retinols), teniposide, topotecan, 9-nitrocamptothecin (RFS 2000); mitomycins: (mitomycin C))]; d) antimetabolites: eg {[antifolic acid: dihydrofolate reductase Inhibitors: (methotrexate, trimetrexate, denopterin, pteropterin, aminopterin (4-aminopteroic acid), or other folic acid analogs); IMP dehydrogenase inhibitors (mycophenolic acid, thiazofurin, ribavirin, EICAR); ribo Nucleotide reductase inhibitors (hydroxyurea, deferroxamine)]; [pyrimidine analogs: uracil analogs (ancitabine, azacitidine, 6-azauridine, capecitabin (Xeloda), carmofur, citarabin, dideoxyuridine, doxiflulysin, enocitabine, 5-fluorouracil, Floxuridine, larcitrexed (Tomudex)); Citocin analogs: (citarabin, citocin arabinoside, fludarabin); Purine analogs: (azathiopurine, fludarabin, mercaptopurine, thiamipulin, thioguanine)]; folic acid supplementation such as phoric acid Agents}; e) Hormonal therapies: For example, {Receptor antagonists: [Antimetabolites: (Methotrexate, Laroxyphen, Tamoxyphene); LHRH agonists: (Gocerelin, Ryuprolide acetate); Antiandrogens: (Vicartamide, Flutamide, Carsterone) , Propionate dromostanolone, epithiostanol, goseleline, leuprolide, mepitiostane, niltamide, testlactone, trilostane, and other androgen inhibitors)]; retinoids / triangular muscles: [vitamin D3 analogs: (CB1093, EB1089, KH1060,) Cholecalciferol, Ergocalciferol); Photodynamic therapeutic agents: (Berteporfin, Phthalocyanin, Photosensitizer Pc4, Demethoxy-hypoclerin A); Cytocytes: (Interferon α, Interferon γ, Tumor necrosis factor (TNF), TNF domain-containing human protein)]}; f) Kinase inhibitors: eg, BIBW2992 (anti-EGFR / Erb2), imatinib, gefitinib, pegaptanib, sorafenib, dasatinib, snitinib, elrotinib, nirotinib, rapatinib, nirotinib, lapatinib, axitinib 80 (Anti-VEGFR2), Mubri Tinib, ponatinib (AP24534), bafetinib (INNO-406), bosutinib (SKI-606), cabozantinib, bismodegib, iniparib, luxolitinib, CYT387, axitinib, tibozanib, sorafenib, cetuximab, sorafenib, bevacizumab, sorafenib, bevacizumab ) Antibiotics: For example, engineered antibiotics (eg, calikeamycins, especially calikeamycin γ1, δ1, α1 and β1, eg, J. et al. Med. Chem. , 39 (11), 2103-2117 (1996), Angew Chem Intl. Ed. Engl. See 33: 183-186 (1994); Doxorubicin A and Doxorubicin, including Doxorubicin; Esperamicin, Kedarcidin, C-1027, Mazuropeptin, and Neocardinostatin Chromophore and Related Dye Proteins Endiin Antibiotics Chromophore, Aclasinomycin , Actinomycin, anthramycin, azaserin, bleomycins, cactinomycin, carabicin, carminomycin, cardinophyllin; chromomycins, doxorubicin, daunorubicin, detorbisin, 6-diazo-5 Oxo-L-norleucin, doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxidoxorubicin, epirubicin, idarubicin, marcelomycin, mitomycins, mycophenolic acid, nogalamycin, olibomycin, pepromycin, pepromycin. Mycin, puromycin, queramycin, rodorubicin, streptnigrin, streptozocin, tubersidine, ubenimex, dinostatin, sorbicin; f) Other categories: for example, polyketide (acetogenins), especially bratacin and bratacinone; gemcitabine, epoxorubicin (eg, Calfilzomib), Voltezomib, Salidamide, Lenalidemid, Pomalidemide, Tosedostat, Zybrestat, PLX4032, STA-9090, Stimuvax, Alovectin-7, Zygeba, Provenge, Elvoy, Isoprenylation inhibitor (eg) Operative neurotoxins (eg, 1-methyl-4-phenylpyridine ion), cell cycle inhibitors (eg, staurosporin), actinomycins (eg, actinomycin D, doxomycin), bleomycins (eg, eg, bleomycins) Bleomycin A2, bleomycin B2, pepromycin), anthracyclins (eg, daunorubicin, doxorubicin (adriamycin), idarubicin, epirubicin, pirarubicin, sorbicin, mitoxanthrone, MDR inhibitors (eg, verapamil), Ca 2+ ATP inhibitors (tapsigargin) Etc.), Histone deacetylase inhibitor (bolinostat, lomidepsin, panobinostat, valproic acid, etc.) Mosetinostat (MGCD0103), Verinostat, PCI-24781, Entinostat, SB939, Resminostat, Gibinostat, AR-42, CUDC-101, Sulforaphane, Tricostatin A); Tapsigargin, celecoxib, glitazones, epigalocatecin gallate, Disulfiram, salinosporamide A, anti-adrenal drugs such as aminoglutetimid, mitotane, trilostane; acegraton; aldhosphamide cricoside; aminolevulinic acid; arabinoside, bestlabsyl; bisantren; edatorexate; defofamine, demecorcin, diadicon, elfor Nitin (DFMO), elliptinium acetate, etuclucid, gallium nitrate, gasitocin, hydroxyurea; ibandronate, lentinan; ronidamine; mitoganez; mopidamole; nitraerin; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK (Registered Trademarks); razoxane; lysoxin; celecoxib; spirogermanium; tenuazonic acid; triadicon; 2,2', 2''-trichlorotriethylamine; tricotesenes (particularly T2 toxin, velcarin A, lolysin A, and anguidin); urethane , SiRNA, antisense drugs, and nucleic acid degrading enzymes.
2)抗自己免疫疾患薬:シクロスポリン、シクロスポリンA、アミノカプロン酸、アザチオプリン、ブロモクリプチン、クロラムブシル、クロロキン、シクロホスファミド、コルチコイド(例えば、ホルモン剤、ベタメタゾン、ブデソニド、フルニソリド、フルチカゾンプロピオン酸エステル、ヒドロコルチゾン、デキサメタゾン、フルオコルトダナゾール、トリアムシノロンアセトニド、ジプロピオン酸ベクロメタゾン)、デヒドロイソアンドロステロン、エタネルセプト、ヒドロキシクロロキン、インフリキシマブ、メロキシカム、メトトレキサート、モフェチル、ミコフェニレート、プレドニゾン、シロリムス、タクロリムスを含むが、これらに限定されない。 2) Anti-autoimmune disease drugs: cyclosporine, cyclosporin A, aminocaproic acid, azathioprine, bromocryptin, chlorambusyl, chloroquin, cyclophosphamide, corticoid (eg, hormonal agents, betamethasone, budesonide, flunisolide, fluticazone propionate, hydrocortisone, dexamethasone) , Fluocorticoidanazole, triamcinolone acetonide, bechromethone dipropionate), dehydroisoandrosterone, etanelcept, hydroxychloroquine, infliximab, meroxycam, methotrexate, mofetil, mycophenilate, prednisone, sirolimus, tacrolimus, but not limited to these ..
3)抗感染薬:a)アミノグリコシド類:アミカシン、アストロマイシン、ゲンタマイシン(ネチルマイシン、シソマイシン、イセパマイシン)、ハイグロマイシン、カナマイシン(アミカシン、アルベカシン、アミノデオキシカナマイシン、ジベカシン、トブラマイシン)、ネオマイシン(ネオマイシンB、パロモマイシン、リボスタマイシン)、ネチルマイシン、スペクチノマイシン、ストレプトマイシン、トブラマイシン、ベルダミシン;b)アンフェニコール類:アジダムフェニコール、クロラムフェニコール、フロルフェニコール、チアンフェニコール;c)アンサマイシン類:ゲルダナマイシン、ハービマイシン;d)カルバペネム類:ビアペネム、ドリペネム、エルタペネム、イミペネム/シラスタチン、メロペネム、パニペネム;e)セフェム類:カルバセフェム(ロラカルベフ)、セファセトリル、セファクロル、セフラジン、セファドロキシル、セファロニウム、セファロリジン、セファロチン又はセファロスポリン、セファレキシン、セファログリシン、セファマンドール、セファピリン、セファトリジン、セファザフル、セファゼドン、セファゾリン、セフブペラゾン、セフカペン、セフダロキシム、セフェピム、セフミノックス、セフォキシチン、セフプロジル、セファロスポリン、セフテゾル、セフロキシム、セフィキシム、セフジニル、セフジトレン、セフェピム、セフェタメト、セフメノキシム、セフォジジム、セフォニシド、セフォペラゾン、セホラニド、セフォタキシム、、セフォチアム、セフォゾプラン、セファレキシン、セフピミゾール、セフピラミド、セフピロム、セフポドキシム、セフプロジル、セフキノム、セフスロジン、セフタジジム、セフテラム、セフチブテン、セフチオレン、セフチゾキシム、セフタジジム、セフトリアキソン、セフロキシム、セファゾリンフラン、セファマイシン(セフォキシチン、セフォテタン、セフメタゾール)、オキサセフェム(フロモキセフ、ラタモキセフ);f)糖ペプチド類:ブレオマイシン、バンコマイシン(オリタバンシン、テラバンシン)、テイコプラニン(ダルババンシン)、ラモプラニン、キュービシン;g)グリシルサイクリン類:例えば、チゲサイクリン;h)β−ラクタマーゼ阻害剤:ペナム(スルバクタム、タゾバクタム)、クラバム(クラブラン酸);i)リンコサミド類:クリンダマイシン、リンコマイシン;j)リポペプチド類:ダプトマイシン、A54145、カルシウム依存性抗生物質(CDA);k)マクロライド類:アジスロマイシン、セスロマイシン、クラリスロマイシン、ジリスロマイシン、エリスロマイシン、フルリスロマイシン、ジョサマイシン、ケトライド(テリスロマイシン、エセスロマイシン)、ミデカマイシン、ミオカマイシン、オレアンドマイシン、リファマイシン(リファンピシンン、リファンピン、リファブチン、
リファペンチン)、ロキタマイシン、ロキシスロマイシン、スペクチノマイシン、スピラマイシン、タクロリムス(FK506)、トロレアンドマイシン、テリスロマイシンン;l)モノバクタム類:アズトレオナム、チゲモナム;M)オキサゾリジノン類:リネゾリド;N)ペニシリン類:アモキシシリン、アンピシリン(ピバンピシリン、ヘタシリン、バカンピシリン、メタンピシリン、タランピシリン)、アジドシリン、アズロシリン、ペニシリン、ベンザチンペニシリン、フェノキシベンザチンペニシリン、クロメトシリン、プロカインペニシリン、カルベニシリン(カリンダシリン)、クロキサシリン、ジクロキサシリン、セファロスポリン、フルクロキサシリン、メシリナム(ピブメシリナム)、メズロシリン、メチシリン、ナフシリン、オキサシリンナトリウム、フェネチシリン、ペニシリン、フェネチシリン、ペニシリン、ピペラシリン、プロピシリン、スルベニシリン、テモシリン、チカルシリン;o)ポリペプチド類:バシトラシン、ポリミキシンE、ポリミキシンB;p)キノロン類:アラトロフロキサシン、バロフロキサシン、シプロフロキサシン、クリナフロキサシン、ダノフロキサシン、ジフロキサシン、エノキサシン、エンロフロキサシン、オフロキサシン、ガレノキサシン、ガチフロキサシン、ゲミフロキサシン、グレパフロキサシン、Kanoトロバフロキサシン、レボフロキサシン、ロメフロキサシン、マルボフロキサシン、モキシフロキサシン、ナジフロキサシン、ノルフロキサシン、オルビフロキサシン、オフロキサシン、ペフロキサシン、トロバフロキサシン、グレパフロキサシン、シタフロキサシン、スパルフロキサシン、テマフロキサシン、トスフロキサシン、トロバフロキサシン;q)ストレプトゾトシン類:プリスチナマイシン、キヌプリスチン/ダルホプリスチン;r)スルホンアミド類:マフェニド、プロントジル、スルファセタミド、スルファメトキサゾール、スルファニルアミド、スルファサラジン、スルファフラゾール、トリメトプリム、トリメトプリム−スルファメトキサゾール(コトリモキサゾール);s)ステロイド系抗菌薬:例えば,フシジン酸;t)テトラサイクリン類:ドキシサイクリン、クロルテトラサイクリン、クロモサイクリン、デメクロサイクリン、リメサイクリン、メクロサイクリン、メタサイクリン、ミノサイクリン、オキシテトラサイクリン、ペニメピサイクリン、ロリテトラサイクリン、テトラサイクリン、グリシルサイクリン(例えば、チゲサイクリン);u)他のタイプの抗生物質:アンノナシン、アルスフェナミン、バクトプレノール阻害剤(バシトラシン)、DADAL/AR阻害剤(サイクロセリン)、ジクチオスタチン、ディスコデルモライド、エレウテロビン、エポチロン、エタンブトール、エトポシド、ファロペネム、フシジン酸、フラゾリドン、イソニアジド、ラウリマリド、メトロニダゾール、ムピロシン、マイコラクトン、NAM合成阻害剤(例えば、ホスホマイシン)、ニトロフラントイン、パクリタキセル、プラテンシマイシン、ピラジナミド、キヌプリスチン/ダルホプリスチン、リファンピン(リファンピシン)、タゾバクタムチニダゾール、ウバリシンを含むが、これらに限定されない。
3) Anti-infective agents: a) Aminoglycosides: amicacin, astromycin, gentamycin (netylmycin, cisomycin, isepamicin), hygromycin, canamycin (amicacin, albecasin, aminodeoxycanamicin, dibecasin, tobramycin), neomycin (nemycin B, paromomycin, Ribostamycin), netylmycin, spectinomycin, streptomycin, tobramycin, verdamicin; b) amphenicol: azidamphenicol, chloramphenicol, floruphenicol, thianphenicol; c) ansamycin: geldana Mycin, harbimycin; d) Carbapenems: Viapenem, Dripenem, Eltapenem, Imipenem / Silastatin, Melopenem, Panipenem; e) Cephem: Carbacephem (Loracarbef), Cepacetril, Cefchloramphenicol, Cefacetril, Cefaclorin, Cephalosporin, Cephalosporin Or cephalosporins, cephalexins, cephalosporins, cephamandols, cephapyrin, cephatridin, cefazaflu, cepazedon, cepazoline, cefbuperazone, cefcapene, cefdaloxime, cefepim, cefminox, cefoxytin, cefprodil, cephalosporins, cefprozil, cephalosporins , Cefditoren, cepepim, cefetameth, cefmenoxim, cefodidim, cefonicid, cefoperazone, cefolinide, cefotaxim, cefotiam, cefosoplan, cephalexin, cefpimisol, cefpyramid, cefpyrom Ceftadidim, ceftriaxone, ceflixim, cepazolinefuran, cephamycin (cefoxitin, cefotetan, cefmethazole), oxacephem (flomoxef, ratamoxef); f) Glycopeptides: bleomycin, bancomycin (oritavancin, teravancin), teikoplanin (dalvavancin) , Cubicin; g) Glycyrrhiclins: For example, tigecyclin; h) β-lactamase inhibitors: penum (sulbactam, tazobactam), chloramphenicol (chloramphenicol); i) lincosamides: clindamycin, lincomycin J) Rifampicins: Daptomycin, A54145, Calcium-Dependent Antibiotics (CDA); k) Macrolides: Azithromycin, Cesromycin, Clarithromycin, Dirisromycin, Erythromycin, Fururisromycin, Josamicin, Ketride (Terislo) Mycin, Erythromycin), Midecamycin, Myocamycin, Oleandomycin, Rifamycin (Rifampicin, Riphanpin, Rifabutin,
Rifapentin), lokitamycin, loxythromycin, spectinomycin, spiramycin, tachlorimus (FK506), trolleyandomycin, terrislomycin; l) monobactams: azthreonum, tigemonum; M) oxazolidinones: linezolide; N) penicillins : Amoxycillin, Ampicillin (Pivanpicillin, Hetacillin, Bacampicillin, Methanpicillin, Talampicillin), Azidocillin, Azlocillin, Penicillin, Benzatin Penicillin, Phenoxybenzatin Penicillin, Chrometocillin, Procaine Penicillin, Carbenicillin, Carbenicillin Flucloxacillin, mesylinum (pibmesillinum), mezlocillin, methicillin, naphthylin, oxacillin sodium, pheneticillin, penicillin, pheneticillin, penicillin, piperacillin, propicillin, sulbenicillin, temocillin, ticarcillin; o) Polymyxin B: P) Kinolones: Alatrofloxacin, barofloxacin, cyprofloxacin, clinafloxacin, danofloxacin, difloxacin, enoxacin, enlofloxacin, ofloxacin, galenoxacin, gachifloxacin, gemifloxacin, grepafloxacin, Kano Trovafloxacin, Levofloxacin, Romefloxacin, Malvofloxacin, Moxyfloxacin, Nadifloxacin, Norfloxacin, Orbifloxacin, Ofloxacin, Penicillin, Trovafloxacin, Grepafloxacin, Citafloxacin, Sparfloxacin, Temafloxacin , Tosfloxacin, trovafloxacin; q) Streptozotocins: pristinamycin, quinupristin / dalhopristin; r) sulfonamides: maphenide, prontozil, sulfacetamide, sulfamethoxazole, sulfanylamide, sulfasalazine, sulfafrazole, trimetoprim , Trimethoprim-sulfametoxazole (cotrimoxazole); s) Steroid antibacterial agents: eg, penicillin; t) Tetracyclins: doxicillin, chlortetracycline, chromocyclin, demecrocycline, remecyclin, mecrocycline , Metacyclin, minocyclin, oxytate Lacyclin, Penimepicycline, Loritetracycline, Tetracycline, Glycyrrhiclin (eg, Tigecycline); u) Other types of antibiotics: annonacin, arsphenamine, bactoprenol inhibitor (basitracin), DADAL / AR Inhibitors (Cycloserine), Dicthiostatin, Discodermolide, Eleuterobin, Epotiron, Etambutor, Etoposide, Faropenem, Fucidic Acid, Frazolidone, Isoniazide, Laurimalide, Metronidazole, Mupyrosine, Mycolactone, NAM Synthesis Inhibitors (eg Phosmycin) , Nitrofrantoin, paclitaxel, platensimycin, pyrazinamide, quinupristin / dalhopristin, riphanpin (riphanpicin), tazobactamtinidazole, ubaricin, but not limited to these.
4)抗ウイルス薬:a)侵入/融合阻害剤:アプラビロック、マラビロク、ビクリビロック、gp41(エンフビルチド)、PRO140、CD4(イバリズマブ);b)インテグラーゼ阻害剤:ラルテグラビル、エルビテグラビル、グロボイドナンA;c)成熟阻害剤:ベビリマット、ヴィヴィコン;d)ノイラミニダーゼ阻害剤:オセルタミビル、ザナミビル、ペラミビル;e)ヌクレオシド及びヌクレオチド:アバカビル、アシクロビル、アデフォビル、アムドキソビル、アプリシタビン、ブリブジン、シドフォビル、クレブジン、デキセルブシタビン、ジダノシン(DDI)、エルブシタビン、エムトリシタビン(FTC)、エンテカビル、ファムシクロビル、フルオロウラシル(5−FU)、3’−フルオロ置換2’,3’−デオキシヌクレオシド類似体(例えば、3’−フルオロ−2’,3’−ジデオキシチミジン(FLT)及び3’−フルオロ−2’,3’−ジデオキシグアノシン(FLG)、ホミビルセン、ガンシクロビル、イドクスウリジン、ラミブジン(3TC)、L−ヌクレオシド(例えば、β−L−チミジン、β−L−2’−デオキシシチジン)、ペンシクロビル、ラシビル、リバビリン、スタンピジン、スタブジンセット(d4T)、タリバビリン(ビラミジン)、テルビブジン、テノホビル、トリフルリジン、バラシクロビル、バルガンシクロビル、ザルシタビン(ddC)、ジドブジン(AZT);
f)非ヌクレオシド:アマンタジン、アテビリジン、カプラビリン、ジアリールピリミジン(エトラビリン、リルピビリン)、デラビルジン、ドコサノール、エミビリン、エファビレンツ、ホスカルネット(ホスホリルギ酸)、イミキモド、インターフェロンα、ロビリド、ロデノシン、メチサゾン、ネビラピン、NOV−205、ペグインターフェロンα、ポドフィロトキシン、リファンピシン、リマンタジン、レシキモド(R−848)、トロマンタジン;g)プロテアーゼ阻害剤:アンプレナビル、アタザナビル、ボセプレビル、ダルナビル、ホスアンプレナビル、インジナビル、ロピナビル、ネルフィナビル、プレコナリル、リトナビル、サキナビル、テラプレビル(VX−950)、チプラナビル;h)抗ウイルス薬の他のタイプ:アブザイム、アルビドール、カラノリドA、セラゲニン、シアノビリン−N、DAPY、没食子酸エピガロカテキン(EGCG)、ホスカルネット、グリフィスシン、タリバビリン(ビラミジン)、ヒドロキシカルバミド、KP−1461、プレコナリル、ポートマントー阻害剤、リバビリン、セリシクリブ。
4) Antiviral agents: a) Invasion / fusion inhibitors: apraviloc, maraviroc, vicribiroc, gp41 (emtricitabine), PRO140, CD4 (ibarizumab); b) integrase inhibitors: lartegravir, elvitegravir, globoidan A; c) maturation inhibition Agents: Babylimat, Vivicon; d) Neuraminidase inhibitors: Osertamivir, Zanamivir, Peramivir; e) Nucleosides and nucleotides: abacavir, acyclovir, adefobil, amdoxovir, apricitabine, bribdin, sidofovir, krebdin, dixelbusitabine, didanosine , Elbusitabine, emtricitabine (FTC), entecavir, famucyclovir, fluorouracil (5-FU), 3'-fluorosubstituted 2', 3'-deoxynucleoside analogs (eg, 3'-fluoro-2', 3'- Dideoxytimidin (FLT) and 3'-fluoro-2', 3'-dideoxyguanosine (FLG), homivirsen, gancyclovir, idoxuridine, laminuvudine (3TC), L-nucleosides (eg β-L-timidine, β- L-2'-deoxycitidine), pencyclovir, racivir, ribavirin, stampidine, stubzine set (d4T), taribavirin (viramidin), tervibdin, tenohovir, trifluidine, balaccyclovir, vulgancyclovir, zarcitabine (ddC), zidovudine (AZT) ;
f) Non-nucleosides: amantadine, atevirin, capabilin, diallylpyrimidine (etrabylin, lylpivirin), delabirdin, docosanol, emibilin, efavirentz, foscalnet (phosphorylgic acid), imikimod, interferon α, robilide, rodenosin, methisazone 205, peginterferon α, podophylrotoxin, rifampicin, limantadine, reshikimod (R-848), tromantagin; g) protease inhibitors: amprenavir, atazanavir, boceprevir, darnavir, hosamprenavir, indinavir, ropinavir, nerfinavir , Preconalil, Litonavir, Sakinavir, Terraprevir (VX-950), Tipranavir; h) Other types of antiviral agents: abzyme, albidol, caranolide A, seragenin, cyanabilin-N, DAPY, epigalocatecin (EGCG) , Hoscalnet, Griffithin, Talibavirin (Viramidine), Hydroxycarbamide, KP-1461, Preconalyl, Portmanto Inhibitor, Ribabylin, Sericicrib.
5)本発明の架橋連結体を介した共役のために用いられる薬物には、放射性同位体も含まれる。放射性同位体(放射性核種)の例として、3H、11C、14C、18F、32P、35S、64Cu、68Ga、86Y、99Tc、111In、123I、124I、125I、131I、133Xe、177Lu、211At、及び213Biが挙げられる。放射性同位体標識抗体は、受容体標的画像化実験において非常に有用であり、又は例えば抗体−薬物共役体の発明(Wu et al(2005)Nature Biotechnology 23(9):1137-1146)のように、直接に相対的標的治療に用いることができる、細胞結合分子、例えば
抗体は、前記のように、本願の架橋連結体によって結合、キレート化又は他の複雑な放射性同位元素金属結合を形成して標識することができ、この標識技術は、Current Protocols in Immunology, Volumes 1 and 2, Coligen et al, Ed. Wiley-Interscience, New York, N.Y., Pubs. (1991)に記載されている。複雑な金属錯体を生成できるキレート剤には
、DOTA、DOTP、DOTMA、DTPA、及びTETA(Macrocyclics, Dallas, Tex.)が含まれる。
5) The drugs used for conjugate via the crosslinked conjugate of the present invention also include radioactive isotopes. Examples of radioisotopes (radionuclides) are 3 H, 11 C, 14 C, 18 F, 32 P, 35 S, 64 Cu, 68 Ga, 86 Y, 99 Tc, 111 In, 123 I, 124 I, Included are 125 I, 131 I, 133 Xe, 177 Lu, 211 At, and 213 Bi. Radioisotope-labeled antibodies are very useful in receptor-targeted imaging experiments, or, for example, as in the invention of antibody-drug conjugates (Wu et al (2005) Nature Biotechnology 23 (9): 1137-1146). Cell-binding molecules, such as antibodies, which can be used directly for relative target therapy, are bound, chelated or form other complex radioisotope metal bonds by the crosslinked conjugates of the application, as described above. It can be labeled and this labeling technique is described in Current Protocols in Immunology,
6)薬学的に許容される、上記の任意の薬物の塩、酸、又は誘導体。 6) Pharmaceutically acceptable salts, acids, or derivatives of any of the above drugs.
別の実施形態において、式(II)及び(IV)の薬物は、細胞結合分子と標的細胞との相互作用の検出、監視、又は研究のために共役体を使用することができる発色団分子とすることができる。発色団分子は、UV光、蛍光光、IR光、近IR光、視覚光のようなある種の光を吸収する能力を有する化合物である;発色団分子は、黄色素胞、赤色素胞、虹色素胞、白色素胞、黒色素胞、青色素胞、及び蛍光体のクラス又はサブクラスを含み、該蛍光体は、前記蛍光体は、光で光を再放射する蛍光性化学物質;可視光伝達分子のクラス又はサブクラス;発光分子のクラス又はサブクラス;ルミネセンス分子のクラス又はサブクラス;ルシフェリン化合物のクラス又はサブクラスである。 In another embodiment, the drugs of formulas (II) and (IV) are with chromophore molecules from which conjugates can be used to detect, monitor, or study the interaction of cell binding molecules with target cells. can do. The chromophore molecule is a compound capable of absorbing certain types of light such as UV light, fluorescent light, IR light, near IR light, and visual light; the chromophore molecule is a chlorophore, a red chromatophore, Includes classes or subclasses of iridophores, white chromatophores, melanophores, blue chromatophores, and phosphors, which are fluorescent chemicals that reradiate light with light; visible light. Classes or subclasses of transducing molecules; classes or subclasses of luminescent molecules; classes or subclasses of luminescence molecules; classes or subclasses of luciferin compounds.
発色団分子は、これらに限定されないが、キサンテン誘導体(フルオレセイン、ローダミン、オレゴングリーン、エオシン、及びテキサスレッド);シアニン誘導体(シアニン、インドカルボシアニン、オキサカルボシアニン、チアカルボシアニン、及びメロシアニン);スクアレン誘導体及び環置換スクアライン(Seta、SeTau、及びSquare色素を含む);ナフタレン誘導体(ダンシル及びプロダン誘導体);クマリン誘導体;オキサジアゾール誘導体(ピリジルオキサゾール、ニトロベンゾキサジアゾール、及びベンゾオキサジアゾール);アントラセン誘導体(DRAQ5、DRAQ7、及びCyTRAK Orangeを含むアントラキノン類);ピレン誘導体(カスケードブルー等);オキサジン誘導体(ナイルレッド、ナイルブルー、クレシルバイオレット、オキサジン170等)。アクリジン誘導体(プロフラビン、アクリジンオレンジ、アクリジンイエロー等)。アリールメチン誘導体(オーラミン、クリスタルバイオレット、マラカイトグリーン)。テトラピロール誘導体(ポルフィン、フタロシアニン、ビリルビン)等の非タン
パク質有機蛍光体から選択することができる。
The chromophore molecules are, but are not limited to, xanthene derivatives (fluorescein, rhodamine, olegon green, eosin, and Texas red); cyanine derivatives (cyanine, indocarbocyanine, oxacarbosianin, thiacarbocyanin, and merocyanin); squalene. Derivatives and ring-substituted squalines (including Seta, SeTau, and Square dyes); Naphthalene derivatives (dancil and prodan derivatives); Kumarin derivatives; Oxazine derivatives (pyridyloxazole, nitrobenzoxaziazole, and benzoxaziazole) Anthracene derivatives (anthraquinones including DRAQ5, DRAQ7, and CyTRAK Orange); pyrene derivatives (cascade blue, etc.); oxazine derivatives (nile red, nile blue, cresyl violet, oxazine 170, etc.). Acridine derivatives (proflavine, acridine orange, acridine yellow, etc.). Arylmethine derivatives (auramine, crystal violet, malachite green). It can be selected from non-protein organic phosphors such as tetrapyrrole derivatives (porphyrin, phthalocyanine, bilirubin).
あるいは、発色団分子は、以下の蛍光体化合物の任意の類縁体及び誘導体から選択することができる:CF色素(Biotium)、DRAQ及びCyTRAKプローブ(Bio-Status
)、BODIPY(Invitrogen)、Alexa Fluor(Invitrogen)、DyLight Fluor(Thermo Scientific、Pierce)、Atto及びTrancy(Sigma Aldrich)、FluoProbes(Interchim)、Abberior色素(Abberior)、
DY及びMegaStokes色素(Dyomics)、SulfoCy色素(Cyandye)、HiLyte Fluor(AnaSpec)、Seta、SeTau及びSquare色素(SETA BioMedicals)、Quasar及びCal Flour色素(Biosearch Technologies)
、SureLight色素(APC、RPEPerCP、フィコビリソーム)(Columbia
Biosciences)、APC、APCXL、RPE、BPE(Phyco-Biotech)。
Alternatively, the chromophore molecule can be selected from any analog and derivative of the following fluorophore compounds: CF dye (Biotium), DRAQ and CyTRAK probe (Bio-Status).
), BODIPY (Invitrogen), Alexa Fluor (Invitrogen), DyLight Fluor (Thermo Scientific, Pierce), Atto and Trancy (Sigma Aldrich), FluorProbes (Interchim), Abberior dye (Abberior),
DY and MegaStokes dyes (Dyomics), SulfoCy dyes (Cyandye), HiLyte Fluor (AnaSpec), Seta, SeTau and Square dyes (SETA BioMedicals), Quasar and Cal Flour dyes (Biosearch Technologies)
, SureLight dye (APC, RPEPerCP, phycobilisome) (Columbia)
Biosciences), APC, APCXL, RPE, BPE (Phyco-Biotech).
本発明の連結体と反応又は共役し得る、広く使用されている蛍光体化合物の例としては、アロフィコシアニン(APC)、アミノクマリン、APC−Cy7共役体、BODIPY−FL、カスケードブルー、Cy2、Cy3、Cy3.5、Cy3B、Cy5、Cy5.5、Cy7、フルオレセイン、FluorX、ヒドロキシクマリン、リサミンローダミンB、ルシファーイエロー、メトキシクマリン、NBD、Pacific Blue、Pacific Orange、PE−Cy5共役体、PE−Cy7共役体、PerCP、R−フィコエリトリン(PE)、Red613、Seta−555−アジド、Seta−555−DBCO、Seta−555−NHS、Seta−580−NHS、Seta−680−NHS、Seta−780−NHS、Seta−APC−780、Seta−PerCP−680、Seta−R−PE−670、SeTau380−NHS、SeTau405−マレイミド、SeTau405−NHS、SeTau425−NHS、SeTau647−NHS、テキサスレッド、TRITC、TruRed、X−ローダミンが挙げられる。 Examples of widely used fluorescent compounds that can react or conjugate with the conjugates of the invention are allophicyanine (APC), aminocoumarin, APC-Cy7 conjugates, BODIPY-FL, Cascade Blue, Cy2, Cy3. , Cy3.5, Cy3B, Cy5, Cy5.5, Cy7, Fluorescein, FluorX, Hydroxycoumarin, Lisamin Rhodamine B, Lucifer Yellow, methoxycumarin, NBD, Fluorescent Blue, Pacific Orange, PE-Cy5 conjugate, PE-Cy7 Conjugates, PerCP, R-Phicoerythrin (PE), Red613, Seta-555-Azide, Seta-555-DBCO, Seta-555-NHS, Seta-580-NHS, Seta-680-NHS, Seta-780-NHS, Seta-APC-780, Seta-PerCP-680, Seta-R-PE-670, Setau380-NHS, Setau405-Maleimide, Setau405-NHS, Setau425-NHS, Setau647-NHS, Texas Red, TRITC, Trured Can be mentioned.
核酸又はタンパク質の研究のために、本発明の連結体に連結されることができる蛍光体化合物は、以下の化合物又はそれらの誘導体から選択される:7−AAD(7−アミノアクチノマイシンD、CG選択性)、アクリジンオレンジ、クロモマイシンA3、CyTRAKオレンジ(Biostatus、赤色励起暗)、DAPI、DRAQ5、DRAQ7、エチジ
ウムブロマイド、ヘキスト33258、ヘキスト33342、LDS751、ミスラマイシン、ヨウ化プロピジウム(PI)、SYTOXブルー、SYTOXグリーン、SYTOXオレンジ、チアゾールオレンジ、TO−PRO:シアニン単量体、TOTO−1、TO−PRO−1、TOTO−3、TO−PRO−3、YOseta−1、YOYO−1。細胞研究のために本発明の連結体に連結させることができる蛍光色素は、以下の化合物又はその誘導体から選択される:DCFH(2’7’ジクロロジヒドロ−フルオレセイン、酸化型)、DHR(ジヒドロローダミン123、酸化型、光が酸化を触媒する)、Fluo−3(AMエステル、pH>6)、Fluo−4(AMエステル、pH7.2)、Indo−1(AMエステル、低/高カルシウム(Ca2+))、SNARF(pH6/9)、アロフィコシアニン(APC)、AmCyan1(四量体、Clontech)、AsRed2(四量体、Clontech)、Azamiグリーン(単量体、MBL)、アズライト、B−フィコエ
リトリン(BPE)、セルリアン、CyPet、DsRed単量体(Clontech)、DsRed2(「RFP」、Clontech)、EBFP、EBFP2、ECFP、EGFP(弱二量体、Clontech)、エメラルド(弱二量体、Invitrogen)、EYFP(弱二量体、Clontech)、GFP(S65A変異体)、GFP(S65C変異体)、GFP(S65L変異体)、GFP(S65T変異体)、GFP(Y66F変異体)、GFP(Y66H変異体)、GFP(Y66W変異体)、GFPuv、HcRed1、J−Red、カチューシャ、Kusabira Orange(単量体、MBL)、mCFP、mCherry、mCit
rine、Midriishi Cyan(二量体、MBL)、mKate(TagFP6
35、単量体、Evrogen)、mKeima−Red(単量体、MBL)、mKO、mOrange、mPlum、mRaspberry、mRFP1(単量体、Tsien Lab)、mStrawberry、mTFP1、mTurquoise2、P3(フィコビリソーム複合体)、Peridinin Chlorophyll(PerCP)、R−フィコエリトリン(RPE)、T−Sapphire、TagCFP(二量体、Evrogen)、
TagGFP(二量体、Evrogen)、TagRFP(二量体、Evrogen)、TagYFP(二量体、Evrogen)、tdTomato(タンデム二量体)、トパーズ、TurboFP
602(二量体、Evrogen)、TurboFP635(二量体、Evrogen)、TurboGFP(二量体、Evrogen)、TurboRFP(二量体、Evrogen)、TurboYFP635(二量体、Evrogen)、ビーナス、天然型GFP、YPet、Zsグリーン1(四量
体、Clontech)、Zsイエロー1(四量体、Clontech)。
Fluorescent compounds that can be linked to the conjugates of the invention for the study of nucleic acids or proteins are selected from the following compounds or derivatives thereof: 7-AAD (7-aminoactinomycin D, CG). Selectivity), Acrydin Orange, Chromomycin A3, CyTRAK Orange (Biostatus, Red Excited Dark), DAPI, DRAQ5, DRAQ7, Ethidium Bromide, Hoechst 33258, Hoechst 33342, LDS751, Mythramycin, Propidium Iodide (PI), SYSTEM Blue , SYTOX Green, SYTOX Orange, Thiazol Orange, TO-PRO: Cyanine Compound, TOTO-1, TO-PRO-1, TOTO-3, TO-PRO-3, YOseta-1, YOYO-1. Fluorescent dyes that can be linked to the conjugates of the invention for cell studies are selected from the following compounds or derivatives thereof: DCFH (2'7'dichlorodihydro-fluorescein, oxidized form), DHR (dihydrorodamine). 123, oxidized form, light catalyzes oxidation), Fluo-3 (AM ester, pH> 6), Fluo-4 (AM ester, pH 7.2), Indo-1 (AM ester, low / high calcium (Ca) 2+ )), SNARF (
line, Midrisi Cyan (dimer, MBL), mKate (TagFP6)
35, monomer, Evrogen), mKeima-Red (monomer, MBL), mKO, mOrange, mPlum, mRaspbury, mRFP1 (monomer, Tsien Lab), mStrawbury, mTFP1, phycobilisome2, phycobilisome2, P3 , Peridinin Chlorophyll (PerCP), R-Phycoebilithrin (RPE), T-Sapphire, TagCFP (Dimer, Evrogen),
TagGFP (dimer, Evrogen), TagRFP (dimer, Evrogen), TagYFP (dimer, Evrogen), tdTomato (tandem dimer), topaz, TurboFP
602 (dimer, Evrogen), TurboFP635 (dimer, Evrogen), TurboGFP (dimer, Evrogen), TurboRFP (dimer, Evrogen), TurboYFP635 (dimer, Evrogen), Venus, natural GFP , YPet, Zs Green 1 (Tetramer, Clontech), Zs Yellow 1 (Tetramer, Clontech).
更に別の実施態様において、本願の架橋連結体を介して細胞結合分子と共役するのに好ましい細胞毒性剤は、チューブリシン類、メイタンシノイド類、タキサノイド類(タキサン類)、CC−1065類縁体、ダウノルビシン及びドキソルビシン化合物、ベンゾジアゼピン二量体(例えば、ピロロベンゾジアゼピン(PBD)、トマイマイシン、アントラマイシン、インドリノベンゾジアゼピン類、イミダゾベンゾチアジアゼピン、又はオキサゾリジノベンゾジアゼピン類の二量体)、カリケアマイシン類及びエンジイン類抗生物質、アクチノマイシン、アザセリン類、ブレオマイシン類、エピルビシン、タモキシフェン、イダルビシン、ドラスタチン類、オーリスタチン類(例えば、モノメチルオーリスタチンE、MMAE、MMAF、オーリスタチンPYE、オーリスタチンTP、オーリスタチン2−AQ、6−AQ、EB(AEB)、及びEFP(AEFP))、デュオカルマイシン類、チオテパ、ビンクリスチン類、ヘミアステリン類、ナズマミド類(nazumamides)、ミクロギニン類(microginins)、ラジオスミン類(radiosumins)、アルテロバクチン類(alterobactins)、ミクロスクレロデルミシン類(microsclerodermins)、テネラミド類(thenellamides)、エスペラミシン類(esperamicins)、PNU−159682、及びそれらの類縁体及び誘導体である。 In yet another embodiment, preferred cytotoxic agents for conjugating to cell binding molecules via the bridge conjugates of the present application are tubericins, maytansinoids, taxanoids (taxans), CC-1065 analogs. , Daunorbisin and doxorubicin compounds, benzodiazepine dimers (eg, pyrrolobenzodiazepine (PBD), tomymycin, anthramycin, indolinobenzodiazepines, imidazolibenzothiazepine, or oxazolidinobenzodiazepine dimers), Calicaremycin And Endiins Antibiotics, actinomycin, azaserins, bleomycins, epirubicin, tamoxyphene, idarubicin, drastatins, auristatins (eg, monomethyloristatin E, MMAE, MMAF, auristatin PYE, auristatin TP, auristatin 2-AQ, 6-AQ, EB (AEB), and EFP (AEFP)), duocalmycins, thiotepa, vincristins, hemiasterins, nazumamides, microginins, radiosumins , Alterobactins, microsclerodermins, tenellamides, esperamicins, PNU-159682, and their analogs and derivatives.
本発明の共役体に好ましい化合物であるチューブリシン類は、本技術分野で周知であり、既知の方法に基づいて天然産物から抽出するか、既知の方法で合成することができる(例えば:Balasubramanian, R.; et al. J. Med. Chem., 2009, 52, 238-240. Wipf, P.; et al. Org. Lett., 2004, 6, 4057-4060. Pando, O.; et al. J. Am. Chem. Soc., 2011, 133, 7692-7695. Reddy, J. A.; et al. Mol. Pharmaceutics, 2009, 6, 1518-1525. Raghavan, B.; et al. J. Med. Chem., 2008, 51, 1530-1533. Patterson, A. W.; et al.
J. Org. Chem., 2008, 73, 4362-4369. Pando, O.; et al. Org. Lett., 2009, 11 (24), pp 5567-5569. Wipf, P.; et al. Org. Lett., 2007, 9 (8), 1605-1607. Friestad, G. K.; Org. Lett., 2004, 6, pp 3249-3252. Hillary M. Peltier, H. M.; et al. J. Am. Chem. Soc., 2006, 128, 16018-16019. Chandrasekhar, S.; et al. J. Org. Chem., 2009, 74, 9531-9534. Liu, Y.; et al. Mol. Pharmaceutics, 2012, 9, 168-175. Friestad, G. K.; et al. Org. Lett., 2009, 11, 1095-1098. Kubicek, K.; et al., Angew Chem Int Ed Engl, 2010. 49: p. 4809-12. Chai, Y.; et al., Chem Biol, 2010, 17: 296-309. Ullrich, A.; et al., Angew Chem Int Ed Engl, 2009, 48, 4422-5. Sani, M.; et al. Angew Chem Int Ed Engl, 2007, 46, 3526-9. Domling, A.; et al., Angew Chem Int Ed Engl, 2006. 45, 7235-9. Patent applications: Zanda, M. ; et al, Can. Pat. Appl. CA 2710693 (2011). Chai, Y.; et al. Eur. Pat. Appl. 2174947 (2010), WO 2010034724. Leamon, C.; et al, WO 2010033733, WO 2009002993. Ellman, J.; et al, WO 2009134279; WO 2009012958, US appl. 20110263650, 20110021568, Matschiner, G.; et al, WO 2009095447.Vlahov, I.; et al, WO 2009055562, WO 2008112873.
Low, P.; et al, WO 2009026177. Richter, W., WO 2008138561. Kjems, J.; et al, WO
2008125116. Davis, M.; et al, WO 2008076333. Diener, J.; et al, U.S. Pat. Appl.
20070041901, WO 2006096754. Matschiner, G.; et al, WO 2006056464. Vaghefi, F.; et al, WO 2006033913. Doemling, A., Ger. Offen. DE 102004030227; WO 2004005327; WO 2004005326; WO2004005269. Stanton, M.; et al, U.S. Pat. Appl. Publ. 20040249130. Hoefle, G.; et al, Ger. Offen. DE 10254439 ; DE 10241152; DE 10008089. Leung, D.; et al, WO 2002077036. Reichenbach, H.; et al, Ger. Offen. DE 19638870; Wolfgang, R.; US 20120129779, Chen, H.,US appl. 20110027274.)。細胞結合分子と共
役するためのチューブリシン類の好ましい構造は、PCT/IB2012/053554に記載されている。
Tubericins, which are preferred compounds for the conjugates of the invention, are well known in the art and can be extracted from natural products based on known methods or synthesized by known methods (eg: Balasubramanian, R .; et al. J. Med. Chem., 2009, 52, 238-240. Wipf, P .; et al. Org. Lett., 2004, 6, 4057-4060. Pando, O .; et al. J. Am. Chem. Soc., 2011, 133, 7692-7695. Reddy, JA; et al. Mol. Pharmaceutics, 2009, 6, 1518-1525. Raghavan, B .; et al. J. Med. Chem. , 2008, 51, 1530-1533. Patterson, AW; et al.
J. Org. Chem., 2008, 73, 4362-4369. Pando, O .; et al. Org. Lett., 2009, 11 (24), pp 5567-5569. Wipf, P .; et al. Org. Lett., 2007, 9 (8), 1605-1607. Friestad, GK; Org. Lett., 2004, 6, pp 3249-3252. Hillary M. Peltier, HM; et al. J. Am. Chem. Soc. , 2006, 128, 16018-16019. Chandrasekhar, S .; et al. J. Org. Chem., 2009, 74, 9531-9534. Liu, Y .; et al. Mol. Pharmaceutics, 2012, 9, 168- 175. Friestad, GK; et al. Org. Lett., 2009, 11, 1095-1098. Kubicek, K .; et al., Angew Chem Int Ed Engl, 2010. 49: p. 4809-12. Chai, Y .; et al., Chem Biol, 2010, 17: 296-309. Ullrich, A .; et al., Angew Chem Int Ed Engl, 2009, 48, 4422-5. Sani, M .; et al. Angew Chem Int Ed Engl, 2007, 46, 3526-9. Domling, A .; et al., Angew Chem Int Ed Engl, 2006. 45, 7235-9. Patent applications: Zanda, M .; et al, Can. Pat. Appl. CA 2710693 (2011). Chai, Y .; et al. Eur. Pat. Appl. 2174947 (2010), WO 2010034724. Leamon, C .; et al, WO 2010033733, WO 2009002993. Ellman, J .; et al, WO 2009134279; WO 2009012958, US appl. 20110263650, 20110021568, Matschiner, G .; et al, WO 2009095447.Vlahov, I .; et al, WO 2009055562, WO 2008112873.
Low, P .; et al, WO 2009026177. Richter, W., WO 2008138561. Kjems, J .; et al, WO
2008125116. Davis, M .; et al, WO 2008076333. Diener, J .; et al, US Pat. Appl.
20070041901, WO 2006096754. Matschiner, G .; et al, WO 2006056464. Vaghefi, F .; et al, WO 2006033913. Doemling, A., Ger. Offen. DE 102004030227; WO 2004005327; WO 2004005326; WO2004005269. Stanton, M .; et al, US Pat. Appl. Publ. 20040249130. Hoefle, G .; et al, Ger. Offen. DE 10254439; DE 10241152; DE 10008089. Leung, D .; et al, WO 2002077036. Reichenbach, H. Et al, Ger. Offen. DE 19638870; Wolfgang, R .; US 20120129779, Chen, H., US appl. 20110027274.). Preferred structures of tubericins for conjugate with cell binding molecules are described in PCT / IB2012 / 053554.
この架橋連結体を介した抗体−チューブリシン類縁体の共役体の構造の一例として、以下のT01、T02、T03、T04、T05、T06、及びT07が挙げられる。
式中、mAbは抗体である。Z3はH、R1、OP(O)(OM1)(OM2)、OCH2OP(O)(OM1)(OM2)、OSO3M1、又はO−配糖体(グルコシド, ガラクトシド、マンノシド、グルクロノシド、アロシド、フルクトシド等)、NH−配糖体、S−配糖体若しくはCH2−配糖体である。M1及びM2は独立してH、Na、K、Ca、Mg、NH4、NR1R2R3R4である。nは1〜20である。R1、R2、R3、及びR4は、式(I)で定義されているものと同じである。 In the formula, mAb is an antibody. Z 3 is H, R 1 , OP (O) (OM 1 ) (OM 2 ), OCH 2 OP (O) (OM 1 ) (OM 2 ), OSO 3 M 1 , or O-glycoside (glucoside, galactoside, mannoside, Gurukuronoshido, Aroshido, fructosides, etc.), NH- glycosides, S- glycoside or CH 2 - is a glycoside. M 1 and M 2 are independently H, Na, K, Ca, Mg, NH 4 , NR 1 R 2 R 3 R 4 . n is 1 to 20. R 1 , R 2 , R 3 , and R 4 are the same as those defined in equation (I).
本願の細胞結合分子−薬剤共役体において好ましいカリケアマイシン及び関連するエンジイン類抗生物質は、以下の文献に記載されている。Nicolaou, K. C. et al, Science 1992, 256, 1172-1178; Proc. Natl. Acad. Sci USA. 1993, 90, 5881-5888), U.S. Patent Nos. 4,970,198; 5,053,394; 5,108,912; 5,264,586; 5,384,412; 5,606,040; 5,712,374; 5,714,586; 5,739,116; 5,770,701; 5,770,710; 5,773,001; 5,877,296; 6,015,562; 6,124,310; 8,153,768。この架橋連結体を介した抗体−カリケアマイシンアナログの共役体の構造の一例として、以下のようにC01が挙げられる。 Preferred Calicaremycin and related ediyne antibiotics in the cell-binding molecule-drug conjugates of the present application are described in the following literature. Nicolaou, KC et al, Science 1992, 256, 1172-1178; Proc. Natl. Acad. Sci USA. 1993, 90, 5881-5888), US Patent Nos. 4,970,198; 5,053,394; 5,108,912; 5,264,586; 5,384,412; 5,606,040; 5,712,374 5,714,586; 5,739,116; 5,770,701; 5,770,710; 5,773,001; 5,877,296; 6,015,562; 6,124,310; 8,153,768. As an example of the structure of the antibody-calikeamycin analog conjugate via this crosslinked conjugate, C01 can be mentioned as follows.
式中、mAbは抗体である;nは1〜20である。R1、R2、R3、及びR4は、式(I)で定義されたものと同じである。 In the formula, mAb is an antibody; n is 1-20. R 1 , R 2 , R 3 , and R 4 are the same as those defined in equation (I).
本発明で使用されることが好ましいメイタンシノール及びその類縁体を含むメイタンシノイド類は、以下の米国特許文献に記載されている。米国特許4,256,746, 4,361,650, 4,307,016, 4,294,757, 4,294,757, 4,371,533, 4,424,219, 4,331,598, 4,450,254, 4,364,866, 4,313,946, 4,315,929 4,362,663, 4,322,348, 4,371,533, 4,424,219, 5,208,020, 5,416,064, 5,208,020; 5,416,064; 6,333.410; 6,441,163; 6,716,821, 7,276,497, 7,301,019, 7,303,749, 7,368,565, 7,411,063, 7,851,432, 及び8,163,888。この架橋
連結体を介した抗体−メイタノシノイド類の共役体の構造の一例として、以下のM01が挙げられる。
Maytansinoids, including maytansinol and analogs thereof, which are preferably used in the present invention, are described in the following US patent documents. U.S. Pat. , 7,303,749, 7,368,565, 7,411,063, 7,851,432, and 8,163,888. The following M01 can be mentioned as an example of the structure of the antibody-mateanosinoid conjugate via this crosslinked conjugate.
式中、mAbは抗体である;nは1〜20である。R1、R2、R3、及びR4は、式
(I)で定義されたものと同じである。
In the formula, mAb is an antibody; n is 1-20. R 1 , R 2 , R 3 , and R 4 are the same as those defined in equation (I).
本特許の架橋連結体を介して共役させるのに好ましい、パクリタキセル(タキソール)を含む細胞毒性天然産物であるタキサン類及び半合成誘導体であるドセタキセル(タキソテール)、並びにそれらの類似体は、以下の文献に記載されている。K C. Nicolaou et al., J. Am. Chem. Soc. 117, 2409-2420, (1995); Ojima et al, J. Med. Chem. 39:3889-3896 (1996); 40:267-278 (1997); 45, 5620-5623 (2002); Ojima et al., Proc. Natl. Acad. Sci., 96:4256-4261 (1999; Kim et al., Bull. Korean Chem. Soc., 20, 1389-1390 (1999); Miller, et al. J. Med. Chem., 47, 4802-4805(2004); 米国特許番号5,475,011 5,728,849, 5,811,452; 6,340,701; 6,372,738; 6,391,913, 6.436,931; 6,589,979; 6,596,757; 6,706,708; 7,008,942; 7,186,851; 7,217,819; 7,276,499;
7,598,290; 及び7,667,054.
Taxanes, which are cytotoxic natural products containing paclitaxel (taxol) and docetaxel (taxotere), which is a semi-synthetic derivative, which are preferable for conjugation via a cross-linked conjugate of the present patent, and their analogs are described in the following documents. It is described in. K C. Nicolaou et al., J. Am. Chem. Soc. 117, 2409-2420, (1995); Ojima et al, J. Med. Chem. 39: 3889-3896 (1996); 40: 267-278 (1997); 45, 5620-5623 (2002); Ojima et al., Proc. Natl. Acad. Sci., 96: 4256-4261 (1999; Kim et al., Bull. Korean Chem. Soc., 20, 20, 1389-1390 (1999); Miller, et al. J. Med. Chem., 47, 4802-4805 (2004); US Patent No. 5,475,011 5,728,849, 5,811,452; 6,340,701; 6,372,738; 6,391,913, 6.436,931; 6,589,979; 6,596,757; 6,706,708; 7,008,942; 7,186,851; 7,217,819; 7,276,499;
7,598,290; and 7,667,054.
架橋連結体を介した抗体−タキサン類の共役体の構造の一例として、以下のTx01、Tx02、及びTx03が挙げられる。 Examples of the structure of the antibody-taxane conjugate via the crosslinked conjugate include the following Tx01, Tx02, and Tx03.
式中、mAbは抗体である;nは1〜20である。R1、R2、R3、及びR4は、式(I)で定義されたものと同じである。 In the formula, mAb is an antibody; n is 1-20. R 1 , R 2 , R 3 , and R 4 are the same as those defined in equation (I).
CC−1065類縁体及びデュオカルマイシン(Duocarmycin)類縁体もまた、本発明の架橋連結体による共役に使用するのに好ましい。CC−1065類縁体及び
デュオカルマイシ類縁体の例、並びにそれらの合成は、以下の文献に記載されている:例えば、Warpehoski, et al, J. Med. Chem. 31:590-603 (1988), D. Boger et al., J.
Org. Chem; 66; 6654-6661, 2001; 米国特許番号: 4169888, 4391904, 4671958, 4816567, 4912227, 4923990, 4952394, 4975278, 4978757, 4994578, 5037993, 5070092, 5084468, 5101038, 5117006, 5137877, 5138059, 5147786, 5187186, 5223409, 5225539, 5288514, 5324483, 5332740, 5332837, 5334528, 5403484, 5427908, 5475092, 5495009, 5530101, 5545806, 5547667, 5569825, 5571698, 5573922, 5580717, 5585089, 5585499, 5587161, 5595499, 5606017, 5622929, 5625126, 5629430, 5633425, 5641780, 5660829, 5661016, 5686237, 5693762, 5703080, 5712374, 5714586, 5739116, 5739350, 5770429,
5773001, 5773435, 5786377 5786486, 5789650, 5814318, 5846545, 5874299, 5877296,
5877397, 5885793, 5939598, 5962216, 5969108, 5985908, 6060608, 6066742, 6075181, 6103236, 6114598, 6130237, 6132722, 6143901, 6150584, 6162963, 6172197, 6180370, 6194612, 6214345, 6262271, 6281354, 6310209, 6329497, 6342480, 6486326, 6512101, 6521404, 6534660, 6544731, 6548530, 6555313, 6555693, 6566336, 6,586,618,
6593081, 6630579, 6,756,397, 6759509, 6762179, 6884869, 6897034, 6946455, 7,049,316, 7087600, 7091186, 7115573, 7129261, 7214663, 7223837, 7304032, 7329507, 7,329,760, 7,388,026, 7,655,660, 7,655,661, 7,906,545, 及び8,012,978。架橋連結体を介した抗体−CC−1065類縁体の共役体の構造の一例として、以下のCC01、CC02、及びCC03が挙げられる。
CC-1065 analogs and Duocarmycin analogs are also preferred for use in conjugation with the crosslinked conjugates of the invention. Examples of CC-1065 relatives and duocarmaisi relatives, as well as their synthesis, are described in the following literature: eg, Warpehoski, et al, J. Med. Chem. 31: 590-603 (1988). , D. Boger et al., J.
Org. Chem; 66; 6654-6661, 2001; US Patent Numbers: 4169888, 4391904, 4671958, 4816567, 4912227, 4923990, 4952394, 4975278, 4978757, 4994578, 5037993, 5070092, 5084468, 5101038, 5117006, 5137877, 5138059, 5147786, 5187186, 5223409, 5225539, 5288514, 5324483, 5332740, 5332837, 5334528, 5403484, 5427908, 5475092, 5495009, 5530101, 5545806, 5547667, 5569825, 5571698, 5573922, 5580717, 5585089, 5585499, 5587161, 5595499 5622929, 5625126, 5629430, 5633425, 5641780, 5660829, 5661016, 5686237, 5693762, 5703080, 5712374, 5714586, 5739116, 5739350, 5770429,
5773001, 5773435, 5786377 5786486, 5789650, 5814318, 5846545, 5874299, 5877296,
5877397, 5885793, 5939598, 5962216, 5969108, 5985908, 6060608, 6066742, 6075181, 6103236, 6114598, 6130237, 6132722, 6143901, 6150584, 6162963, 6172197, 6180370, 6194612, 6214345, 6262271, 6281354, 6310209, 6329497 6486326, 6512101, 6521404, 6534660, 6544731, 6548530, 6555313, 6555693, 6566336, 6,586,618,
6593081, 6630579, 6,756,397, 6759509, 6762179, 6884869, 6897034, 6946455, 7,049,316, 7087600, 7091186, 7115573, 7129261, 7214663, 7223837, 7304032, 7329507, 7,329,760, 7,388,026, 7,655,660, 7,655,661, 7,906. Examples of the structure of the conjugate of the antibody-CC-1065 analog via the crosslinked conjugate include CC01, CC02, and CC03 below.
式中、mAbは抗体である。nは1〜20である。Z4はH、PO(O)(OM1)(OM2)、SO3M1、CH2PO(OM1)(OM2)、CH3N(CH2CH2)2NC(O)−、O(CH2CH2)2NC(O)−、又は配糖体である。X3は、O、NH、NHC(O)、OC(O)、C(O)、R1、又は不存在である。M1及びM2は独立して、Na、K、H、NH4、NR1R2R3である。R1、R2、R3、及びR4は、式(I)で定義されたものと同じである。 In the formula, mAb is an antibody. n is 1 to 20. Z 4 is H, PO (O) (OM 1 ) (OM 2 ), SO 3 M 1 , CH 2 PO (OM 1 ) (OM 2 ), CH 3 N (CH 2 CH 2 ) 2 NC (O)- , O (CH 2 CH 2 ) 2 NC (O)-, or glycoside. X 3 is O, NH, NHC (O), OC (O), C (O), R 1 , or absent. M1 and M2 are independently Na, K, H, NH 4 , NR 1 R 2 R 3 . R 1 , R 2 , R 3 , and R 4 are the same as those defined in equation (I).
ダウノルビシン/ドキソルビシン類縁体もまた、本特許の架橋連結体を介した共役に好ましい。その好ましい構造及び合成方法は、以下に例示されている:Hurwitz, E., et al., Cancer Res. 35, 1175-1181 (1975);Yang, H. M., and Reisfeld, R. A., Proc. Natl. Acad. Sci. 85, 1189-1193 (1988); Pietersz, C. A., E., et al., E., et al.
," Cancer Res. 48, 926-9311 (1988); Trouet, et al., 79, 626-629 (1982); Z. Brich et al., J. Controlled Release, 19, 245-258 (1992); Chen et al., Syn. Comm., 33, 2377-2390, 2003; King et al., Bioconj. Chem., 10, 279-288, 1999; King et
al., J. Med. Chem., 45, 4336-4343, 2002; Kratz et al., J Med Chem. 45, 5523-33.
2002; Kratz et al., Biol Pharm Bull. Jan. 21, 56-61 , 1998; Lau et al., Bioorg.
Med. Chem. 3, 1305-1312, 1995; Scott et al., Bioorg. Med.l Chem. Lett. 6, 1491-1496; 1996; Watanabe et al., Tokai J. Experimental Clin. Med. 15, 327-334, 1990; Zhou et al., J. Am. Chem. Soc. 126, 15656-7, 2004; WO 01/38318; 米国特許番号5,106,951; 5,122,368; 5,146,064; 5,177,016; 5,208,323; 5,824,805; 6,146,658; 6,214,345; 7569358; 7,803,903; 8,084,586; 8,053,205。架橋連結体を介した抗体−CC−1065類縁体の共役体の構造の一例として、以下のDa01、Da02、Da03、及びDa04が挙げられる。
Daunorubicin / doxorubicin analogs are also preferred for conjugation via the cross-linked conjugate of the present patent. Its preferred structure and synthetic method are exemplified below: Hurwitz, E., et al., Cancer Res. 35, 1175-1181 (1975); Yang, HM, and Reisfeld, RA, Proc. Natl. Acad. Sci. 85, 1189-1193 (1988); Pietersz, CA, E., et al., E., et al.
, "Cancer Res. 48, 926-9311 (1988); Trouet, et al., 79, 626-629 (1982); Z. Brich et al., J. Controlled Release, 19, 245-258 (1992); Chen et al., Syn. Comm., 33, 2377-2390, 2003; King et al., Bioconj. Chem., 10, 279-288, 1999; King et al.
al., J. Med. Chem., 45, 4336-4343, 2002; Kratz et al., J Med Chem. 45, 5523-33.
2002; Kratz et al., Biol Pharm Bull. Jan. 21, 56-61, 1998; Lau et al., Bioorg.
Med. Chem. 3, 1305-1312, 1995; Scott et al., Bioorg. Med.l Chem. Lett. 6, 1491-1496; 1996; Watanabe et al., Tokai J. Experimental Clin. Med. 15, 327 -334, 1990; Zhou et al., J. Am. Chem. Soc. 126, 15656-7, 2004; WO 01/38318; US Patent No. 5,106,951; 5,122,368; 5,146,064; 5,177,016; 5,208,323; 5,824,805; 6,146,658; 6,214,345; 7569358; 7,803,903; 8,084,586; 8,053,205. Examples of the structure of the conjugate of the antibody-CC-1065 analog via the crosslinked conjugate include the following Da01, Da02, Da03, and Da04.
式中、mAbは抗体である。nは1〜20である。X3は、O、NH、NR1、NHC(O)、OC(O)、C(O)、R1、又は不存在である。R1、R2、R3、及びR4は、式(I)で定義されたものと同じである。 In the formula, mAb is an antibody. n is 1 to 20. X 3 is O, NH, NR 1 , NHC (O), OC (O), C (O), R 1 , or absent. R 1 , R 2 , R 3 , and R 4 are the same as those defined in equation (I).
オーリスタチン類(Auristatins)及びドラスタチン類(dolastatins)は、本発明の架橋連結体を介した共役に好ましい。オーリスタチン類(例えば、オーリスタチンE(AE)、オーリスタチンEB(AEB)、オーリスタチンEFP(AEFP)、モノメチルオーリスタチンE(MMAE)、モノメチルオーリスタチン(MMAF)、オーリスタチンFフェニレンジアミン(AFP)、及びMMAEのフェニルアラニン変異体)は、ドラスタチン類の合成類似体であり、以下の文献に記載されている;Int. J. Oncol. 15:367-72 (1999); Molecular Cancer Therapeutics, vol. 3, No. 8, pp. 921-932 (2004); 米国特許出願 11134826, 20060074008, 2006022925; 米国特許番号 4414205, 4753894, 4764368, 4816444, 4879278, 4943628, 4978744, 5122368, 5165923, 5169774,5286637, 5410024, 5521284, 5530097, 5554725, 5585089, 5599902, 5629197, 5635483, 5654399, 5663149, 5665860, 5708146, 5714586, 5741892, 5767236, 5767237, 5780588, 5821337, 5840699, 5965537, 6004934, 6033876, 6034065, 6048720, 6054297, 6054561, 6124431, 6143721, 6162930, 6214345, 6239104, 6323315, 6342219, 6342221, 6407213, 6569834, 6620911, 6639055, 6884869, 6913748, 7090843, 7091186, 7097840, 7098305, 7098308, 7498298, 7375078, 7462352, 7553816, 7659241, 7662387, 7745394, 7754681, 7829531, 7837980, 7837995, 7902338, 7964566, 7964567, 7851437,
7994135。架橋連結体を介した抗体−オーリスタチン類の共役体の構造の一例として、以下のAu01、Au02、Au03、Au04、及びAu05が挙げられる。
Auristatins and dolastatins are preferred for conjugation via the crosslinked conjugates of the invention. Oristatins (eg, Oristatin E (AE), Oristatin EB (AEB), Oristatin EFP (AEFP), Monomethyl Oristatin E (MMAE), Monomethyl Oristatin (MMAF), Oristatin F phenylenediamine (AFP)) , And a phenylalanine variant of MMAE) are synthetic analogs of drastatins and are described in the following literature; Int. J. Oncol. 15: 367-72 (1999); Molecular Cancer Therapeutics, vol. 3 , No. 8, pp. 921-932 (2004); US patent application 11134826, 20060074008, 2006022925; US patent number 4414205, 4753894, 4764368, 4816444, 4879278, 4943628, 4978744, 5122368, 5165923, 5169774,5286637, 5410024, 5521284, 5530097, 5554725, 5585089, 5599902, 5629197, 5635483, 5654399, 5663149, 5665860, 5708146, 5714586, 5741892, 5767236, 5767237, 5780588, 5821337, 5840699, 5965537, 6004934, 6033876, 6034065, 6048720, 6054297 6124431, 6143721, 6162930, 6214345, 6239104, 6323315, 6342219, 6342221, 6407213, 6569834, 6620911, 6639055, 6884869, 6913748, 7090843, 7091186, 7097840, 7098305, 7098308, 7498298, 7375078, 7462352, 7553816, 7659241 7745394, 7754681, 7829531, 7837980, 7837995, 7902338, 7964566, 7964567, 7851437,
7994135. Examples of the structure of antibody-auristatin conjugates via cross-linked conjugates include Au01, Au02, Au03, Au04, and Au05 below.
式中、mAbは抗体である。nは1〜20である。X3は、CH2、O、NH、NR1、NHC(O)、NHC(O)NH、C(O)、OC(O)、R1、又は不存在である。X4は、CH2、C(O)、C(O)NH、C(O)N(R1)、R1、又はC(O)Oである。R1、R2、R3、及びR4は、式(I)で定義されたものと同じである。 In the formula, mAb is an antibody. n is 1 to 20. X 3 is CH 2 , O, NH, NR 1 , NHC (O), NHC (O) NH, C (O), OC (O), R 1 , or absent. X 4 is CH 2 , C (O), C (O) NH, C (O) N (R 1 ), R 1 , or C (O) O. R 1 , R 2 , R 3 , and R 4 are the same as those defined in equation (I).
本発明の細胞毒性剤として好ましいベンゾジアゼピン二量体類(例えば、ピロロベンゾジアゼピン(PBD)又は(トマイマイシン)、インドリノベンゾジアゼピン類、イミダゾベンゾジアゼピン類、又はオキサゾリジノベンゾジアゼピン類の二量体)は、従来技術で例示されている;米国特許番号8,163,736; 8,153,627; 8,034,808; 7,834,005; 7,741,319; 7,704,924; 7,691,848; 7,678,787; 7,612,062; 7,608,615; 7,557,099; 7,528,128; 7,528,126; 7,511,032; 7,429,658; 7,407,951; 7,326,700; 7,312,210; 7,265,105; 7,202,239; 7,189,710; 7,173,026; 7,109,193; 7,067,511; 7,064,120; 7,056,913; 7,049,311; 7,022,699; 7,015,215; 6,979,684; 6,951,853; 6,884,799; 6,800,622; 6,747,144; 6,660,856; 6,608,192; 6,562,806; 6,977,254; 6,951,853; 6,909,006; 6,344,451;
5,880,122; 4,935,362; 4,764,616; 4,761,412; 4,723,007; 4,723,003; 4,683,230; 4,663,453; 4,508,647; 4,464,467; 4,427,587; 4,000,304; 米国特許出願20100203007、20100316656、20030195196。架橋連結体を介した抗体−ベンゾジアゼピン二量体類の共役体の構造の一例は、以下のPB01、PB02、PB03、PB04、PB05、PB06、PB07、PB08、及びPB09が挙げられる。
Preferred benzodiazepine dimers as the cytotoxic agents of the present invention (eg, pyrorobenzodiazepines (PBD) or (tomymycin), indolinobenzodiazepines, imidazolebenzodiazepines, or oxazolidinobenzodiazepine dimers) have been conventionally used. Illustrated in; US Pat. 7,173,026; 7,109,193; 7,067,511; 7,064,120; 7,056,913; 7,049,311; 7,022,699; 7,015,215; 6,979,684; 6,951,853; 6,884,799; 6,800,622; 6,747,144; 6,660,856; 6,608,192; 6,562,806; 6,977,254;
5,880,122; 4,935,362; 4,764,616; 4,761,412; 4,723,007; 4,723,003; 4,683,230; 4,663,453; 4,508,647; 4,464,467; 4,427,587; 4,000,304; US Patent Applications 20100203007, 20100316656, 20030195196. Examples of the structure of the conjugate of the antibody-benzodiazepine dimer via the cross-linkage include PB01, PB02, PB03, PB04, PB05, PB06, PB07, PB08, and PB09 below.
式中、mAbは抗体である;nは1〜20である。X3は、CH2、O、NH、NR1、NHC(O)、NHC(O)NH、C(O)、OC(O)、R1、又は不存在である;X4は、CH2、C(O)、C(O)NH、C(O)N(R1)、C(O)OR1、又は不存在である;R1、R2、R3、及びR4は、式(I)で定義されたものと同じである。加えて、R3及び/又はR4は不存在でもよい。 In the formula, mAb is an antibody; n is 1-20. X 3 is CH 2 , O, NH, NR 1 , NHC (O), NHC (O) NH, C (O), OC (O), R 1 , or absent; X 4 is CH 2 , C (O), C (O) NH, C (O) N (R 1 ), C (O) OR 1 , or absent; R 1 , R 2 , R 3 , and R 4 are formulas. It is the same as that defined in (I). In addition, R 3 and / or R 4 may be absent.
本発明の架橋連結体を介して共役すために用いられる薬剤/細胞毒性剤は、本発明で開示された薬剤/細胞毒性剤の任意の類縁体及び/又は誘導体でもよい。薬剤/細胞毒性剤の技術分野における当業者は、出発化合物の特異性及び/又は活性を保持する条件の下で、本願に記載された各薬剤/細胞毒性剤を修飾することができることを容易に理解する。当業者は、これらの化合物の多くは、本願に記載された薬剤/細胞毒性剤を代替することができることも理解する。従って、本発明の薬剤/細胞毒性剤は、前記各化合物の類縁体及び誘導体を含む。 The agent / cytotoxic agent used for conjugation via the crosslinked conjugate of the present invention may be any analog and / or derivative of the agent / cytotoxic agent disclosed in the present invention. Those skilled in the art of drug / cytotoxic agents will readily be able to modify each drug / cytotoxic agent described herein under conditions that retain the specificity and / or activity of the starting compound. to understand. Those skilled in the art will also appreciate that many of these compounds can replace the agents / cytotoxic agents described herein. Therefore, the agent / cytotoxic agent of the present invention includes analogs and derivatives of each of the above compounds.
明細書の上記及び続く実施例で引用された全ての文献は、その全体が明確に参照として組み込まれる。 All references cited above and in subsequent examples of the specification are expressly incorporated as references in their entirety.
以下の実施例によって、本願発明を更に説明するが、これら実施例は、本願の範囲を制限するものではない。以下の実施例に記載した細胞株は、特に説明のない限り、米国タイプカルチャーコレクション(ATCC)、ドイツ微生物細胞培養コレクション(DSMZ)、又は中国科学院の上海細胞培養研究所により特定された条件に基づいて、培地中で維持した。特に説明のない限り、細胞培養試薬は全てInvitrogen社より提供された。無水試薬は全て市販品であり、且つ窒素封入密封ボトルにで貯蔵した。他の全ての試薬及び溶媒は、最高の基準に従って購入し、更なる精製なしで使用した。分取HPLCによる分離は、Varain PreStar HPLCにより行った。NMRスペクトルは、Varian Mercury 400MHz装置により検出した。化学シフト(Δ)はppm単位とし、テトラメチルシランを標準とし、結合定数(J)の単位はHzとした。質量分析データは、Waters Acquity UPLC分離器及びAcquity TUV検出器を装備したWaters Xevo Qtof質量分析により取得した。 The invention of the present application will be further described with reference to the following examples, but these examples do not limit the scope of the present application. The cell lines described in the Examples below are based on conditions specified by the American Type Culture Collection (ATCC), the German Microbial Cell Culture Collection (DSMZ), or the Shanghai Cell Culture Laboratory of the Chinese Academy of Sciences, unless otherwise stated. And maintained in medium. Unless otherwise stated, all cell culture reagents were provided by Invitrogen. All anhydrous reagents were commercially available and stored in nitrogen-filled sealed bottles. All other reagents and solvents were purchased according to the highest standards and used without further purification. Separation by preparative HPLC was performed by Varin PreStar HPLC. The NMR spectrum was detected by a Varian Mercury 400 MHz apparatus. The chemical shift (Δ) was in ppm, tetramethylsilane was standard, and the coupling constant (J) was in Hz. Mass analysis data was acquired by Waters Xevo Qtof mass analysis equipped with a Waters Acquity UPLC separator and an Acquity TUV detector.
実施例1:3−((ベンジルオキシ)アミノ)プロパン酸tert−ブチルエステル(3)
O−ベンジルヒドロキシアミン塩酸塩(10.0g、62.7mmol)のTHF溶液(100ml)を、Et3N(15ml)及びt−ブチルアクリレート(12.1g、94.5mmol)に添加した。混合物を一晩還流し、濃縮し、SiO2カラム上でEtOAc/ヘキサン(1:4)で溶出して精製することにより、表題化合物(3)を得た(13.08g、収率83%)。1H NMR(CDCl3)7.49−7.25(m,5H),4.75(s.2H),3.20(t,J=6.4Hz,2H),2.54(t,J=6.4Hz,2H),1.49(s,9H);ESI MS m/z+ C14H21NNaO3(M+Na),計算値274.15,実測値274.20。 O- benzyl hydroxylamine hydrochloride (10.0 g, 62.7 mmol) THF solution (100ml) of was added to Et 3 N (15ml) and t- butyl acrylate (12.1 g, 94.5 mmol). The mixture was refluxed overnight, concentrated and purified by eluting with EtOAc / Hexanes (1: 4) on a SiO 2 column to give the title compound (3) (13.08 g, 83% yield). .. 1H NMR (CDCl 3 ) 7.49-7.25 (m, 5H), 4.75 (s.2H), 3.20 (t, J = 6.4Hz, 2H), 2.54 (t, J) = 6.4 Hz, 2H), 1.49 (s, 9H); ESI MS m / z + C 14 H 21 NAO 3 (M + Na), calculated value 274.15, measured value 274.20.
実施例2:3−(ヒドロキシアミノ)プロパン酸tert−ブチルエステル(4)
水素化容器中で、化合物3(13.0g、51.76mmol) のメタノール溶液(
100ml)に、Pd/C(0.85g、10%Pd、50%ウェット)を加えた。反応系を真空下で排気し、2気圧の水素ガス下に置かれた後、反応混合物を室温で一晩攪拌した。粗反応は、エタノールでリンスしたセライト(Celite)のショートパッドを通過させ、濃縮し、SiO2カラム上でメタノール/DCM(1:10〜1:5)で溶出して精製することにより、表題化合物を得た(7.25g、収率87%)。1H NMR(CDCl3)3.22(t,J=6.4Hz,2H),2.55(t,J=6.4Hz,2H),1.49(s,9H);ESI MS m/z+ C7H15NNaO3(M+Na),計算値184.10,実測値184.30。
In a hydrogenation vessel, a solution of compound 3 (13.0 g, 51.76 mmol) in methanol (
Pd / C (0.85 g, 10% Pd, 50% wet) was added to 100 ml). The reaction system was evacuated under vacuum and placed under 2 atmospheres of hydrogen gas, after which the reaction mixture was stirred at room temperature overnight. The crude reaction is carried out by passing through a short pad of Celite rinsed with ethanol, concentrating, eluting with methanol / DCM (1: 10: 5) on a SiO 2 column and purifying the title compound. Was obtained (7.25 g, yield 87%). 1H NMR (CDCl 3 ) 3.22 (t, J = 6.4Hz, 2H), 2.55 (t, J = 6.4Hz, 2H), 1.49 (s, 9H); ESI MS m / z + C 7 H 15 NNao 3 (M + Na), calculated value 184.10, measured value 184.30.
実施例3:3−((トシルオキシ)アミノ)プロパン酸tert−ブチルエステル(5)
化合物4(5.10g、31.65mmol) の DCM(50ml)及びピリジン(20ml)の混合溶液に、塩化トシル(12.05g、63.42)を4℃で添加した。添加後、混合物を室温で一晩攪拌し、SiO2カラム上でEtOAc/DCM(1:10〜1:6)で溶出して精製することにより、表題化合物を得た(8.58g、収率86%
)。1H NMR(CDCl3)7.81(s,2H),7.46(s,2H),3.22(t,J=6.4Hz,2H),2.55(t,J=6.4Hz,2H),2.41(s,3H),1.49(s,9H);ESI MS m/z+ C14H21NNaO5S(M+Na),計算値338.11,実測値338.30。
Tosyl chloride (12.05 g, 63.42) was added to a mixed solution of Compound 4 (5.10 g, 31.65 mmol) in DCM (50 ml) and pyridine (20 ml) at 4 ° C. After addition, the mixture was stirred at room temperature overnight and eluted on a SiO 2 column with EtOAc / DCM (1: 10: 6) for purification to give the title compound (8.58 g, yield). 86%
). 1H NMR (CDCl 3 ) 7.81 (s, 2H), 7.46 (s, 2H), 3.22 (t, J = 6.4Hz, 2H), 2.55 (t, J = 6.4Hz) , 2H), 2.41 (s, 3H), 1.49 (s, 9H); ESI MS m / z + C 14 H 21 NAO 5 S (M + Na), calculated value 338.11, measured value 338.30.
実施例4:3,3’−(ヒドラジン−1,2−ジイル)ジプロパン酸ジtert−ブチルエステル(7)
3−アミノプロパン酸t−ブチルエステル(6)(3.05g、21.01mmol)のTHF溶液(80ml)に、3−((トシルオキシ)アミノ)プロパン酸tert−ブチルエステル(5)(5.10g、16.18mmol)を添加した。混合物を室温で1時間攪拌し、次いで45℃で6時間撹拌した。混合物を濃縮し、SiO2カラム上でCH3OH/DCM/Et3N(1:12:0.01〜1:8:0.01)で溶出して精製することにより、表題化合物を得た(2.89g、収率62%)。ESI MS m/z+
C14H28N2NaO4(M+Na),計算値311.20,実測値311.40。
3-Aminopropanoic acid t-butyl ester (6) (3.05 g, 21.01 mmol) in THF solution (80 ml), 3-((tosyloxy) amino) propanoic acid tert-butyl ester (5) (5.10 g) , 16.18 mmol) was added. The mixture was stirred at room temperature for 1 hour and then at 45 ° C. for 6 hours. The mixture was concentrated and eluted on a SiO 2 column with CH 3 OH / DCM / Et 3 N (1: 12: 0.01 to 1: 8: 0.01) for purification to give the title compound. (2.89 g, yield 62%). ESI MS m / z +
C 14 H 28 N 2 NaO 4 (M + Na), calculated value 311.20, measured value 311.40.
実施例5:3,3’−(1,2−ビス(3−(2,5−ジオキソ−2,5−ジヒドロ−1H−ピロール−1−イル)プロパノイル)ヒドラジン−1,2−ジイル)ジプロパン酸ジtert−ブチルエステル(13)
3−マレイド−プロパン酸(1.00g、5.91mmol)のDCM溶液(50ml)に、ジ塩化オキサリル(2.70g、21.25mol)及びDMF(50μl)を添加した。この混合物を室温で2時間攪拌し、蒸発させ、DCM/トルエンで共蒸発させ、粗3−マレイド−プロパン酸塩化物を得た。化合物(7)(0.51g、1.76mmol)のDCM混合物(35ml)中に粗3−マレイド−プロパン酸塩化物を添加した。混合物を一晩攪拌し、蒸発させ、濃縮し、SiO2カラム上でEtOAc/DCM(1:15〜1:8)で溶出して精製することにより、表題化合物(13)を得た(738mg、収率71%)。ESI MS m/z+ C28H38N4NaO10(M+Na),計算値613.26,実測値613.40。
Oxalyl dichloride (2.70 g, 21.25 mol) and DMF (50 μl) were added to a DCM solution (50 ml) of 3-malade-propanoic acid (1.00 g, 5.91 mmol). The mixture was stirred at room temperature for 2 hours, evaporated and co-evaporated with DCM / toluene to give a crude 3-maleide-propanate. A crude 3-maleide-propanoate was added to a DCM mixture (35 ml) of compound (7) (0.51 g, 1.76 mmol). The mixture was stirred overnight, evaporated, concentrated and purified by eluting with EtOAc / DCM (1:15 to 1: 8) on a SiO 2 column to give the title compound (13) (738 mg,
実施例6:3,3’−(1,2−ビス(3−(2,5−ジオキソ−2,5−ジヒドロ−1H−ピロール−1−イル)プロパノイル)ヒドラジン−1,2−ジイル)ジプロパン酸(14)
化合物14(700mg、1.18mmol) のジオキサン溶液(4ml)にHCl
(1ml)を加えた。混合物を30分間攪拌し、エタノール(10ml)及びトルエン(10ml)で希釈し、エタノール(10ml)及びトルエン(10ml)共蒸発させ、更に精製せずに、次工程のための粗標記品(560mg)を得た。ESI MS m/z−
C20H21N4O10(M−H),計算値477.13,実測値477.20。
HCl in a dioxane solution (4 ml) of compound 14 (700 mg, 1.18 mmol)
(1 ml) was added. The mixture is stirred for 30 minutes, diluted with ethanol (10 ml) and toluene (10 ml), co-evaporated with ethanol (10 ml) and toluene (10 ml), and without further purification, crudely labeled (560 mg) for the next step. Got ESI MS m / z-
C 20 H 21 N 4 O 10 (MH), calculated value 477.13, measured value 477.20.
実施例7:ビス(2,5−ジオキソピロリジン−1−イル)−3,3’−(1,2−ビス(3−(2,5−ジオキソ−2,5−ジヒドロ−1H−ピロール−1−イル)プロパノイル)ヒドラジン−1,2−ジイル)ジプロパンノエート(79)
前記粗生成物(14)(〜560mg、〜1.17mmol)のDMA溶液(8ml)に、NHS(400mg、3.47mmol)及びEDC(1.01g、5.26mmol)を添加した。混合物を一晩攪拌し、蒸発させ、濃縮し、SiO2カラム上でEtOAc/DCM(1:12〜1:7)で溶出して精製することにより、表題化合物(79)を得た(520mg、収率は2ステップで65%)。ESI MS m/z+ C28H28N6NaO14(M+Na),計算値695.17,実測値695.40。 NHS (400 mg, 3.47 mmol) and EDC (1.01 g, 5.26 mmol) were added to a DMA solution (8 ml) of the crude product (14) (~ 560 mg, ~ 1.17 mmol). The mixture was stirred overnight, evaporated, concentrated and purified by eluting with EtOAc / DCM (1:12 to 1: 7) on a SiO 2 column to give the title compound (79) (520 mg, The yield is 65% in 2 steps). ESI MS m / z + C 28 H 28 N 6 NaO 14 (M + Na), calculated value 695.17, measured value 695.40.
実施例8:3−(2−(2−(2−ヒドロキシエトキシ)エトキシ)エトキシ)プロパン酸tert−ブチルエステル(84)
350mlの無水THFに、撹拌しながら80mg(0.0025mol)の金属ナトリウム及びトリエチレングリコール(84)(150.1g、1.00mol)を添加した。金属ナトリウムが完全に溶解した後、アクリル酸tert−ブチル(24ml、0.33mol)を添加した。溶液を室温で20時間撹拌し、8mLの1.0M HClで中
和した。溶媒を減圧で除去し、残渣を食塩水(250ml)に懸濁し、酢酸エチル(3×125ml)で抽出した。併せた有機層を食塩水(100ml)、次いで水(100ml)で洗浄し、硫酸ナトリウムで乾燥し、溶媒を除去した。得られた無色油状物を真空下で乾燥させ、69.78gの生成物(85)を得た(収率76%)を得た。1H NMR:1.41(s,9H),2.49(t,2H,J=6.4Hz),3.59−3.72(m,14H);ESI MS m/z− C13H25O6(M−H),計算値277.17,実測値277.20。
To 350 ml of anhydrous THF, 80 mg (0.0025 mol) of metallic sodium and triethylene glycol (84) (150.1 g, 1.00 mol) were added with stirring. After the metallic sodium was completely dissolved, tert-butyl acrylate (24 ml, 0.33 mol) was added. The solution was stirred at room temperature for 20 hours and neutralized with 8 mL of 1.0 M HCl. The solvent was removed under reduced pressure and the residue was suspended in brine (250 ml) and extracted with ethyl acetate (3 x 125 ml). The combined organic layer was washed with brine (100 ml) and then with water (100 ml) and dried over sodium sulfate to remove the solvent. The obtained colorless oil was dried under vacuum to obtain 69.78 g of product (85) (yield 76%). 1 1 H NMR: 1.41 (s, 9H), 2.49 (t, 2H, J = 6.4 Hz), 3.59-3.72 (m, 14H); ESI MS m / z-C 13 H 25 O 6 (MH), calculated value 277.17, measured value 277.20.
実施例9:3−(2−(2−(2−(トシルオキシ)エトキシ)エトキシ)エトキシ)プロパン酸tert−ブチルエステル(35)
化合物(85)(10.0g、35.95mmol)のアセトニトリル溶液(50.0ml)をピリジン(20.0ml)で処理した。塩化トシル(7.12g、37.3mmol)のアセトニトリル溶液(50ml)を、30分かけて漏斗を介して滴下することにより加えた。5時間後のTLC分析により、反応が完了したことが明らかにされた。形成したピリジン塩酸塩を濾別し、溶媒を除去した。シリカゲル上で、純粋な酢酸エチルを含む20%酢酸エチルのヘキサン溶液に溶出することにより残渣を精製し、11.2gの化合物(86)を得た(収率76%)。1H NMR:1.40(s,9H),2.40(s,3H),2.45(t,2H,J=6.4Hz),3.52−3.68(m,14H),4.11(t,2H,J=4.8Hz),7.30(d,2H,J=8.0Hz),7.75(d,2H,J=8.0Hz);ESI MS m/z+C20H33O8S(M+H),計算値433.18,実測値433.30。 An acetonitrile solution (50.0 ml) of compound (85) (10.0 g, 35.95 mmol) was treated with pyridine (20.0 ml). An acetonitrile solution (50 ml) of tosyl chloride (7.12 g, 37.3 mmol) was added by dropping through a funnel over 30 minutes. TLC analysis after 5 hours revealed that the reaction was complete. The formed pyridine hydrochloride was filtered off and the solvent was removed. The residue was purified by elution on silica gel with a hexane solution of 20% ethyl acetate containing pure ethyl acetate to give 11.2 g of compound (86) (yield 76%). 1 1 H NMR: 1.40 (s, 9H), 2.40 (s, 3H), 2.45 (t, 2H, J = 6.4Hz), 3.52-3.68 (m, 14H), 4.11 (t, 2H, J = 4.8Hz), 7.30 (d, 2H, J = 8.0Hz), 7.75 (d, 2H, J = 8.0Hz); ESI MS m / z + C 20 H 33 O 8 S (M + H), calculated value 433.18, measured value 433.30.
実施例10:3−(2−(2−(2−アジドエトキシ)エトキシ)エトキシ)プロパン酸tert−ブチルエステル(87)
50mLのDMFに、3−(2−(2−(2−(トシルオキシ)エトキシ)エトキシ)エトキシ)プロパン酸tert−ブチルエステル(86)(4.0g、9.25mmol)及びアジ化ナトリウム(0.737g、11.3mmol)を攪拌しながら加えた。反応溶液を80℃に加熱した。4時間後、TLCの分析により反応が完了したことを明らかにされた。反応溶液を室温まで冷却し、水(25mL)でクエンチした。水層を分離し、酢酸エチル(3×35mL)で抽出した。併せた有機層を無水硫酸マグネシウムで乾燥し、ろ過し、溶媒を減圧で除去した。粗アジ化物(TLCによる純度約90%)を更に精製せずに用いた。1H NMR(CDCl3):1.40(s,9H),2.45(t,2H,J=6.4Hz),3.33(t,2H,J=5.2Hz),3.53−3.66(m,12H).ESI MS m/z+C13H26N3O8(M+H),計算値304
.18,実測値304.20.
In 50 mL of DMF, 3- (2- (2- (2- (tosyloxy) ethoxy) ethoxy) ethoxy) propanoic acid tert-butyl ester (86) (4.0 g, 9.25 mmol) and sodium azide (0. 737 g (11.3 mmol) was added with stirring. The reaction solution was heated to 80 ° C. After 4 hours, TLC analysis revealed that the reaction was complete. The reaction solution was cooled to room temperature and quenched with water (25 mL). The aqueous layer was separated and extracted with ethyl acetate (3 x 35 mL). The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The crude azide (purity by TLC about 90%) was used without further purification. 1 H NMR (CDCl 3 ): 1.40 (s, 9H), 2.45 (t, 2H, J = 6.4Hz), 3.33 (t, 2H, J = 5.2Hz), 3.53 -3.66 (m, 12H). ESI MS m / z + C 13 H 26 N 3 O 8 (M + H), calculated value 304
.. 18. Measured value 304.20.
実施例11:13−アミノ−4,7,10−トリオキサドデカン酸tert−ブチルエステル(88);13−アミノ−ビス(4,7,10−トリオキサドデカン酸tert−ブチルエステル)(89)
粗アジド材料(87)(5.0g、〜14.84mmol)をエタノール(80mL)に溶解させ、300mgの10%Pd/Cを加えた。反応系を減圧し、水添反応器を介して2気圧の水素ガスの下で活発に攪拌した。反応は室温で一晩攪拌し、TLCにより出発原料が消失したことが示された。粗反応物は、エタノールでセライトリンスのショートパッドを通過した。溶媒を除去し、メタノール(5%〜15%)及び1%トリエチルアミンの塩化メチレン溶液との混合物を用いて、シリカゲル上でアミンを精製することにより、13−アミノ−4,7,10−トリオキサドデカン酸tert−ブチルエステル(88)(1.83g、収率44%、ESI MS m/z+C13H27NO5(M+H),計算値278.19,実測値278.30)及び13−アミノ−ビス(4,7,10−トリオキサドデカン酸tert−ブチルエステル)(89)(2.58g、収率32%、ESI MS m/z+C26H52NO10(M+H),計算値538.35,実測値538.40)を得た。 The crude azide material (87) (5.0 g, -14.84 mmol) was dissolved in ethanol (80 mL) and 300 mg of 10% Pd / C was added. The reaction system was depressurized and vigorously stirred under hydrogen gas at 2 atm via a hydrogenation reactor. The reaction was stirred at room temperature overnight and TLC showed that the starting material had disappeared. The crude reaction was passed through a short pad of Celite rinse with ethanol. 13-Amino-4,7,10-trioxa by removing the solvent and purifying the amine on silica gel with a mixture of methanol (5% -15%) and 1% triethylamine in methylene chloride. Dodecanoic acid tert-butyl ester (88) (1.83 g, 44% yield, ESI MS m / z + C 13 H 27 NO 5 (M + H), calculated value 278.19, measured value 278.30) and 13-amino- Bis (4,7,10-trioxadodecanoic acid tert-butyl ester) (89) (2.58 g, yield 32%, ESI MS m / z + C 26 H 52 NO 10 (M + H), calculated value 538.35, The measured value 538.40) was obtained.
実施例12:3−(2−(2−(2−アミノエトキシ)エトキシ)エトキシ)プロパン酸塩酸塩(90)
13−アミノ−4,7,10−トリオキサドデカン酸tert−ブチルエステル(88)(0.80g、2.89mmol)のジオキサン溶液(30ml)に、撹拌しながら10mlのHCl(36%)を加えた。0.5時間後、TLC分析により、反応が完了したことが確認され、反応混合物を留去し、エタノール及びエタノール/トルエンと共蒸発させて、更に精製することなく、標記生成物の塩酸塩を得た(純度>90%、0.640g、収率86%)。ESI MS m/z+C9H20NO5(M+H),計算値222.12,実測値222.20。 To a dioxane solution (30 ml) of 13-amino-4,7,10-trioxadodecanoic acid tert-butyl ester (88) (0.80 g, 2.89 mmol), add 10 ml HCl (36%) with stirring. It was. After 0.5 hours, TLC analysis confirmed that the reaction was complete, distilling off the reaction mixture and co-evaporating with ethanol and ethanol / toluene to hydrochloride the title product without further purification. Obtained (purity> 90%, 0.640 g, yield 86%). ESI MS m / z + C 9 H 20 NO 5 (M + H), calculated value 222.12, measured value 222.20.
実施例13:13−アミノ−ビス(4,7,10−トリオキサドデカン酸塩酸塩(91)
13−アミノ−ビス(4,7,10−トリオキサドデカン酸tert−ブチルエステル)(89)(1.00g,1.85mmol)のジオキサン溶液(30ml)に、撹拌しながら10mlのHCl(36%)を加えた。0.5時間後、TLC分析により、反応が完了したことが確認され、反応混合物を留去し、エタノール及びエタノール/トルエンと共蒸発させて、更に精製することなく、標記生成物の塩酸塩を得た(純度>90%、0.71g、収率91%)。ESI MS m/z+C18H36NO10(M+H),計算値426.22,実測値426.20. 10 ml HCl (36%) in a dioxane solution (30 ml) of 13-amino-bis (4,7,10-trioxadodecanoic acid tert-butyl ester) (89) (1.00 g, 1.85 mmol) with stirring. ) Was added. After 0.5 hours, TLC analysis confirmed that the reaction was complete, the reaction mixture was distilled off and co-evaporated with ethanol and ethanol / toluene to hydrochloride the title product without further purification. Obtained (purity> 90%, 0.71 g, yield 91%). ESI MS m / z + C 18 H 36 NO 10 (M + H), calculated value 426.22, measured value 426.20.
実施例14:(S)−2−(メチルアミノ)プロパン酸メイタンシノールエステル
氷/水浴上で、メイタンシノール(200mg、0.354mmol)をDMF(5ml)及びTHF(3ml)に溶解させ、DIPEA(0.3ml)、亜鉛トリフラート(380mg、1.05mmol)、及び(S)−3,4−ジメチルオキサゾリジン−2,5−ジオン(92mg、0.71mmol)を加えた。反応混合物をアルゴン雰囲気下、室温で一晩攪拌し、EtOAc(20ml)で希釈し、塩水/飽和炭酸水素ナトリウムの1:1溶液(8ml)で洗浄した。白色沈殿物を濾別し、得られた水溶液をEtOAc(2×10ml)で抽出し、有機層を食塩水で洗浄した。得られた有機層を加圧下で減少させ、C−18分取HPLC上でメタノール/水で溶出させることにより精製し(45分間でメタノール10%〜65%、φ50mm×250mm、v=80ml/min)、標記化合物を得た(156mg、収率68%)。ESI MS m/z+C32H45ClN3O9(M+H),計算値650.28,実測値650.20.
On an ice / water bath, Maytansinol (200 mg, 0.354 mmol) was dissolved in DMF (5 ml) and THF (3 ml), DIPEA (0.3 ml), zinc triflate (380 mg, 1.05 mmol), and (S). ) -3,4-Dimethyloxazolidine-2,5-dione (92 mg, 0.71 mmol) was added. The reaction mixture was stirred under an argon atmosphere overnight at room temperature, diluted with EtOAc (20 ml) and washed with a 1: 1 solution (8 ml) of brine / saturated sodium bicarbonate. The white precipitate was filtered off, the resulting aqueous solution was extracted with EtOAc (2 x 10 ml) and the organic layer was washed with brine. The obtained organic layer was reduced under pressure and purified by eluting with methanol / water on C-18 preparative HPLC (
実施例15:(2S,2S’)−2,2’−((3,3’−(1,2−ビス(3−(マレイミド)プロパノイル)ヒドラジン−1,2−ジイル)ビス(プロパノイル))ビス(メチルアザネジイル))ジプロパン酸ジメイタンシノールエステル(108)
(S)−2−(メチルアミノ)プロパン酸メイタンシノールエステル(150)(150mg、0.231mmol)及び3,3’−(1,2−ビス(3−(マレイミド)プロパノイル)ヒドラジン−1,2−ジイル)ジプロパン酸(14)(50mg、0.104mmol)のDMA溶液(10ml)にEDC(300mg、1.56mmol)を加えた。混合物を一晩攪拌し、C−18分取HPLC上でメタノール/水で溶出させることにより精製し(45分間でメタノール10%〜85%、φ20mm×250mm、v=20ml/min)、標題化合物(108)を得た(115mg、収率63%)。ESI MS m/z+C84H107Cl2N10O26(M+H),計算値1741.67,実測値1741.90. (S) -2- (Methylamino) propanoic acid mayancinol ester (150) (150 mg, 0.231 mmol) and 3,3'-(1,2-bis (3- (maleimide) propanoyl) hydrazine-1, EDC (300 mg, 1.56 mmol) was added to a DMA solution (10 ml) of 2-diyl) dipropanoic acid (14) (50 mg, 0.104 mmol). The mixture was stirred overnight and purified by elution with methanol / water on C-18 preparative HPLC (10% to 85% methanol in 45 minutes, φ20 mm × 250 mm, v = 20 ml / min) to give the title compound ( 108) was obtained (115 mg, yield 63%). ESI MS m / z + C 84 H 107 Cl 2 N 10 O 26 (M + H), calculated value 1741.67, measured value 1741.90.
実施例16:3,3’−(1,2−ビス(3−(マレイミド)プロパノイル)ヒドラジン−1,2−ジイル)ビス(N−MMAFプロパンアミド)
3,3’−(1,2−ビス(3−(マレイミド)プロパノイル)ヒドラジン−1,2−ジイル)ジプロパン酸(14)(50mg、0.104mmol)のDCM溶液(4ml)にオキサリルジクロリド(0.4ml、DCM中で2M、0.8mmol)及びDMF(10μl)を加えた。混合物を室温で2時間撹拌し、蒸発させ、DCM/トルエンで共蒸発させ、粗3,3’−(1,2−ビス(3−(マレイミド)プロパノイル)ヒドラジン−1,2−ジイル)ジプロパン酸クロリド(107)を得た。MMAF(110)(160mg、0.219mmol)のDCM溶液(5ml)に、粗酸塩化物(107)を添加した。混合物を一晩攪拌し、C−18分取HPLC上でメタノール/水で溶出させることにより精製し(45分間でメタノール10%〜85%、φ20mm×250mm、v=20ml/min)、標記化合物(111)を得た(98mg、収率49%)。ESI MS m/z+C98H149Cl2N14O24(M+H),計算値1906.08,実測値1906.50.
Oxalyl dichloride (0) in a DCM solution (4 ml) of 3,3'-(1,2-bis (3- (maleimide) propanoyl) hydrazine-1,2-diyl) dipropanoic acid (14) (50 mg, 0.104 mmol) .4 ml, 2 M in DCM, 0.8 mmol) and DMF (10 μl) were added. The mixture is stirred at room temperature for 2 hours, evaporated, co-evaporated with DCM / toluene and
実施例17:3,3’−(1,2−ビス(3−(マレイミド)プロパノイル)ヒドラジン−1,2−ジイル)ビス(N−チューブリシン類縁体のプロパンアミド)(119)
3,3’−(1,2−ビス(3−(マレイミド)プロパノイル)ヒドラジン−1,2−ジイル)ジプロパン酸(14)(50mg、0.104mmol)のDCM溶液(4ml)にオキサリルジクロリド(0.4ml、DCM中で2M、0.8mmol)及びDMF(10μl)を加えた。混合物を室温で2時間撹拌し、蒸発させ、DCM/トルエンで共蒸発させ、粗3,3’−(1,2−ビス(3−(マレイミド)プロパノイル)ヒドラジン−1,2−ジイル)ジプロパン酸クロリド(107)を得た。(4R)−4−(2−((1R,3R)−1−アセトキシ−3−((2S,3S)−N,3−ジメチル−2−((R)−1−メチルピペリジン−2−カルボキサミド)ペンタンアミド)−4−メチルペンチル)チアゾール−4−カルボキサミド)−5−(3−アミノ−4−ヒドロキシフェニル)−2−メチルペンタン酸(118)(Huang Y. et al, Med Chem. #44, 249thACS National Meetng, Denver, CO, Mar. 22-26, 2015; WO2014009774)(172mg、0.226
mmol)の DCM溶液(5ml)に、粗酸塩化物(107)を加えた。混合物を一晩
攪拌し、C−18分取HPLC上でメタノール/水で溶出させることにより精製し(45分間でメタノール10%〜80%、φ20mm×250mm、v=20ml/min)、標記化合物(119)を得た(106mg、収率52%)。ESI MS m/z+C97H139Cl2N16O24S2(M+H),計算値1975.95,実測値1976.50.
Oxalyl dichloride (0) in a DCM solution (4 ml) of 3,3'-(1,2-bis (3- (maleimide) propanoyl) hydrazine-1,2-diyl) dipropanoic acid (14) (50 mg, 0.104 mmol) .4 ml, 2 M in DCM, 0.8 mmol) and DMF (10 μl) were added. The mixture is stirred at room temperature for 2 hours, evaporated, co-evaporated with DCM / toluene and
Crude acid chloride (107) was added to a DCM solution (5 ml) of mmol). The mixture was stirred overnight and purified by elution with methanol / water on C-18 preparative HPLC (10% -80% methanol in 45 minutes, φ20 mm × 250 mm, v = 20 ml / min) and the title compound ( 119) was obtained (106 mg, yield 52%). ESI MS m / z + C 97 H 139 Cl 2 N 16 O 24 S 2 (M + H), calculated value 1975.95, measured value 1976.50.
実施例18:化合物109、112、又は120のための、化合物108、111、又は119と抗体との共役
pH6.0〜8.0で10mg/mlハーセプチンの2.0mLの混合物に、100mM NaH2PO4のPBS緩衝液0.70〜2.0mL、pH6.5〜7.5の緩衝液、TCEP(28μl、水中20mM)、及び化合物(108)、(111)、及び(119)(14μl、DMA中20mM)をそれぞれ添加した。この混合物を室温で2〜16時間インキュベートし、次いでDHAA(135μl、50mM)を添加した。室温で一晩連続インキュベートした後、G−25カラムで100mM NaH2PO4、50mM NaCl緩衝液により溶出させて混合物を精製し、13.0〜15.6mlの緩衝液中で共役体化合物(109)、(112)、及び(120)を得た。薬剤/抗体比(DAR)は、UPLC−Qtof質量スペクトルにより決定された。SEC HPLC(東ソーバイオサイエンス、Tskgel G3000SW、7.8mmID×30cm、0.5ml/min、100min)により、それらは95〜99%モノマーであり、SDS−PAGEゲルで単一のバンドが測定された。 A mixture of 2.0 mL of 10 mg / ml Herceptin at pH 6.0-8.0, PBS buffer of 100 mM NaH 2 PO 4 0.70-2.0 mL, buffer pH 6.5-7.5, TCEP ( 28 μl (20 mM in water) and compounds (108), (111), and (119) (14 μl, 20 mM in DMA) were added, respectively. The mixture was incubated at room temperature for 2-16 hours, then DHAA (135 μl, 50 mM) was added. After continuous overnight incubation at room temperature, the mixture was purified by eluting with 100 mM NaH 2 PO 4 , 50 mM NaCl buffer on a G-25 column to purify the conjugate compound (109) in 13.0-15.6 ml buffer. ), (112), and (120). The drug / antibody ratio (DAR) was determined by the UPLC-Qtof mass spectrum. By SEC HPLC (Tosoh Bioscience, Tskgel G3000SW, 7.8 mm ID x 30 cm, 0.5 ml / min, 100 min), they were 95-99% monomers and a single band was measured on an SDS-PAGE gel.
共役体(109),15.8mg(収率79%),DAR=3.90,95%モノマー;共役体(112),16.7mg(収率83%),DAR=3.95,96%モノマー;共役体(120),16.3mg(収率81%),DAR=3.96,97%モノマー。 Conjugate (109), 15.8 mg (yield 79%), DA = 3.90, 95% monomer; conjugate (112), 16.7 mg (yield 83%), DA = 3.95, 96% Monomer; conjugate (120), 16.3 mg (81% yield), DA = 3.96, 97% monomer.
実施例18:T−DM1と比較した共役体109、112、及び120のインビトロ細胞毒性評価
細胞毒性アッセイのため細胞株として、ヒト白血病細胞株HL−60、ヒト胃癌細胞株NCI−N78、及びヒト卵巣癌細胞株SKOV3を使用した。HL−60及びN87細胞のために、これらの細胞を10%FBS含有RPMI−1640で培養した。SKOV3細胞については、10%FBS含有マッコイの5A培地で培養した。アッセイを実行するために、細胞(180μl、6000細胞)を96ウェルプレートのウェルにそれぞれ加え、37℃、5%CO2で24時間インキュベートした。次いで、適切な細胞培養培地(総量、0.2mL)中で、細胞を種々の濃度の試験用化合物(20μl)で処理した。コントロールウェルは、細胞と培地を含むが、試験化合物を欠いている。プレートを37℃、5%CO2で120時間インキュベートした。MTT(5mg/ml)をウェル(20μl)に添加し、プレートを37℃で1.5時間インキュベートした。その後、培地を注意深く除去し、DMSO(180μl)を加えた。15分間振とうした後、620nmの基準フィルタを用いて490nmと570nmで吸光度を測定した。阻害率%は次の式に従って計算された:阻害率抑%=[1−(分析値−ブランク)/(コントロール−ブランク)]×100
Example 18: In vitro cytotoxicity assessment of
細胞毒性試験の結果:
3つの共役体は全て、T−DM1よりも強力であった。N87細胞に対する共役体109の特異性は93以上であり、SK−OV−3細胞に対する特異性は127以上であった。N87細胞に対する共役体112の特異性は99以上であり、SK−OV−3細胞に対する特異性は113以上であった。N87細胞に対する共役体120の特異性は105以上であり、SK−OV−3細胞に対する特異性は136以上であった。一方、N87細胞に対する共役体T−DM1の特異性は56以上であり、SK−OV−3細胞に対する特異性は84以上であった。
All three conjugates were stronger than T-DM1. The specificity of
Claims (29)
式中、
Y1及びY2は、ジスルフィド結合、チオエーテル結合、又はチオエステル結合を形成するために、細胞結合剤の硫黄原子の対と反応することができる同一又は異なる官能基であり、Y1及びY2として好ましい官能基は、以下に示す構造のN−ヒドロキシスクシンイミドエステル、マレイミド、ジスルフィド、ハロアセチル、ハロゲン化アシル(酸ハライド)、エテンスルホニル、アクリル(アクリロイル)、2−(トシルオキシ)アセチル、2−(メシルオキシ)アセチル、2−(ニトロフェノキシ)アセチル、2−ジニトロフェノキシ)アセチル、2−(フルオロフェノキシ)アセチル、2−(ジフルオロフェノキシ)アセチル、2−(ペンタフルオロフェノキシ)アセチル、2−(((トリフルオロメチル)スルホニル)オキシ)アセチル、及び/又は酸無水物基である;
式中、
X1はF、Cl、Br、I、又はLvであり;
X2はO、NH、N(R1)、又はCH2であり;
R5はR1、芳香環、ヘテロ芳香環、又は1個若しくは数個のH原子が独立に、−R1、−OR1、−SR1、−NR1R2、−NO2、−S(O)R1、−S(O)2R1若しくは−COOR1で置換された芳香族基であり;Lvはニトロフェノール、N−ヒドロキシスクシンイミド(NHS)、フェノール、ジニトロフェノール;ペンタフルオロフェノール、テトラフルオロフェノール、ジフルオロフェノール、モノフルオロフェノール、ペンタクロロフェノール、トリフラート、イミダゾール、ジクロロフェノール、テトラクロロフェノール、1−ヒドロキシベンゾトリアゾール、トシレート、メシレート、2−エチル−5−フェニルイソキサゾリウム−3’−スルホネート、自己若しくは他の酸無水物とで形成された酸無水物(例えば、無水酢酸、無水ギ酸)、又は中間体分子ペプチドカップリング反応のための、若しくはミツノブ反応のための縮合試薬により生成する中間体から選択される脱離基であり;R1及びR2の定義は以下の通りである;
Z1及びZ2は、ジスルフィド、エーテル、エステル、チオエーテル、チオエステル、ペプチド、ヒドラゾン、カルバメート、カーボネート、アミン(二級、三級若しくは四級)、イミン、シクロヘテロアルカン、ヘテロ芳香環、アルコキシム、又はアミド結合を形成するために細胞毒性剤と反応することができる同一又は異なる官能基であり;薬物/細胞障害剤のアミンの末端と反応可能なZ1及びZ2は、酸ハロゲン化物(ハロゲン化アシル);N−ヒドロキシスクシンイミドエステル;p−ニトロフェニルエステル;ジニトロフェニルエステル;ペンタフルオロフェニルエステル;又はテトラフルオロフェノール、ジフルオロフェノール、モノフルオロフェノール、フェノール、ペンタクロロフェノール、トリフラート、イミダゾール、ジクロロフェノール、テトラクロロフェノール、1−ヒドロキシベンゾトリアゾール、トシレート、メシレート、2−エチル−5−フェニルイソキサゾリウム−3’−スルホネートで形成されたエステル;又は例えば、無水酢酸、無水ギ酸で形成された酸無水物;又は中間体分子ペプチドカップリング反応のための、若しくはミツノブ反応のための縮合試薬により生成する中間体とすることができ;薬物のチオールの末端と反応可能なZ1及びZ2は、ピリジルジスルフィド、ニトロピリジルジスルフィド、マレイミド、ハロアセタート、及びカルボン酸クロリドとすることができ;薬物のケトン又はアルデヒドの末端と反応可能なZ1及びZ2は、アミン、アルコキシアミン、ヒドラジン、又はアシルオキシアミンとすることができ;薬物のアジドの末端と反応可能なZ1及びZ2は、アルキンとすることができる;
R1、R2、R3、及びR4は、同じか又は異なり、且つ、不存在、炭素数1〜8の直鎖状アルキル、炭素数3〜8の分岐若しくはシクロアルキル、直鎖、分岐若しくはシクロアルケニル若しくはアルキニル、炭素数1〜8のエステル、エーテル若しくはアミド、若しくは構造式(OCH2CH2)pである(p;0〜約1000の整数)ポリエチレンオキシ単位、又はこれらの組み合わせであり;
追加的に、R1、R2、R3、及びR4はそれぞれ、Y1又はY2とZ1又はZ2とを共有的に結合するC、N、O、S、Si、及びPから選択される原子の鎖であり、好ましくは0〜500原子を有し;R1、R2、R3、及びR4の形成に用いられる原子は、アルキレート(alkylate)、アルキレン、アルケニレン、アルキニレン、エーテル、ポリオキシアルキレン、エステル、アミン、イミン、ポリアミン、ヒドラジン、ヒドラゾン、アミド、尿素、セミカルバジド、カルバジド、アルコキシアミン、アルコキシアミン、ウレタン、アミノ酸、ペプチド、アシルオキシアミン、若しくはヒドロキサム酸、又はそれらの組み合わせを形成するような、化学的に関連する全ての方法で結合してもよい。 Crosslinked conjugate of formula (I):
During the ceremony
Y 1 and Y 2 are the same or different functional groups capable of reacting with a pair of sulfur atoms of a cell binder to form a disulfide bond, thioether bond, or thioester bond, as Y 1 and Y 2. Preferred functional groups are N-hydroxysuccinimide ester, maleimide, disulfide, haloacetyl, acyl halide (acid halide), ethensulfonyl, acrylic (acryloyl), 2- (tosyloxy) acetyl, 2- (mesyloxy) having the structures shown below. Acetyl, 2- (nitrophenoxy) acetyl, 2-dinitrophenoxy) acetyl, 2- (fluorophenoxy) acetyl, 2- (difluorophenoxy) acetyl, 2- (pentafluorophenoxy) acetyl, 2-(((trifluoromethyl) ) Hydroxyl) Oxy) Acetyl and / or acid anhydride groups;
During the ceremony
X 1 is F, Cl, Br, I, or Lv;
X 2 is O, NH, N (R 1 ), or CH 2 ;
R 5 is R 1 , aromatic ring, hetero aromatic ring, or one or several H atoms independently, -R 1 , -OR 1 , -SR 1 , -NR 1 R 2 , -NO 2 , -S. (O) R 1 , -S (O) 2 R 1 or -COOR 1 substituted aromatic group; Lv is nitrophenol, N-hydroxysuccinimide (NHS), phenol, dinitrophenol; pentafluorophenol, Tetrafluorophenol, difluorophenol, monofluorophenol, pentachlorophenol, trifurate, imidazole, dichlorophenol, tetrachlorophenol, 1-hydroxybenzotriazole, tosylate, mesylate, 2-ethyl-5-phenylisoxazolium-3' − Phenolates, acid anhydrides formed with self or other acid anhydrides (eg acetic anhydride, formic acid anhydride), or generated by condensation reagents for intermediate molecular peptide coupling reactions or for Mitsunobu reactions. It is a elimination group selected from the intermediates to be used; the definitions of R 1 and R 2 are as follows;
Z 1 and Z 2 are disulfides, ethers, esters, thioethers, thioesters, peptides, hydrazone, carbamate, carbonates, amines (secondary, tertiary or quaternary), imines, cycloheteroalkanes, heteroaromatic rings, alkoxys, etc. Alternatively, Z 1 and Z 2 which are the same or different functional groups capable of reacting with the cytotoxic agent to form an amide bond; and capable of reacting with the amine terminal of the drug / cytotoxic agent are acid halides (halogens). Acylation); N-hydroxysuccinimide ester; p-nitrophenyl ester; dinitrophenyl ester; pentafluorophenyl ester; or tetrafluorophenol, difluorophenol, monofluorophenol, phenol, pentachlorophenol, trifurate, imidazole, dichlorophenol, Esters formed of tetrachlorophenol, 1-hydroxybenzotriazole, tosylate, mesylate, 2-ethyl-5-phenylisoxazolium-3'-sulfonate; or, for example, acid anhydride formed of acetic anhydride, formicic anhydride. The product; or an intermediate produced by a condensing reagent for the molecular peptide coupling reaction or for the Mitsunobu reaction; Z 1 and Z 2 capable of reacting with the thiol end of the drug are pyridyl. It can be disulfide, nitropyridyl disulfide, maleimide, haloacetate, and carboxylic acid chloride; Z 1 and Z 2 capable of reacting with the terminal of the ketone or aldehyde of the drug can be amines, alkoxyamines, hydrazines, or acyloxyamines. Can; Z 1 and Z 2 capable of reacting with the end of the drug azide can be alkins;
R 1 , R 2 , R 3 and R 4 are the same or different and are absent, linear alkyl with 1 to 8 carbon atoms, branched with 3 to 8 carbon atoms or cycloalkyl, linear, branched. Alternatively, it is a cycloalkenyl or alkynyl, an ester having 1 to 8 carbon atoms, an ether or an amide, or a polyethylene oxy unit having a structural formula (OCH 2 CH 2 ) p (p; an integer of 0 to about 1000), or a combination thereof. ;
In addition, R 1 , R 2 , R 3 and R 4 are from C, N, O, S, Si, and P, which covalently bind Y 1 or Y 2 and Z 1 or Z 2 , respectively. a chain of atoms selected preferably have a 0-500 atoms; atoms used to form the R 1, R 2, R 3 , and R 4, alkylate (alkylate), alkylene, alkenylene, alkynylene , Ether, polyoxyalkylene, ester, amine, imine, polyamine, hydrazine, hydrazone, amide, urea, semicarbazide, carbazide, alkoxyamine, alkoxyamine, urethane, amino acid, peptide, acyloxyamine, or hydroxamic acid, or a combination thereof. It may be bound in any chemically related way, such as forming.
式中、
Cbは、細胞結合剤、好ましくは抗体を表す;
「Drug1」及び「Drug2」は、アルキル、アルキレン、アルケニレン、アルキニレン、エーテル、ポリオキシアルキレン、エステル、アミン、イミン、ポリアミン、ヒドラジン、ヒドラゾン、アミド、尿素、セミカルバジド、カルバジド、アルコキシアミン、ウレタン、アミノ酸、ペプチド、アシルオキシルアミン、ヒドロキサム酸、ジスルフィド、チオエーテル、チオエステル、カルバメート、カーボネート、複素環、ヘテロアルキル、ヘテロ芳香環、若しくはアルコキシム結合、又はその組み合わせによって、架橋連結体を介して前記細胞結合剤と連結した、同一の又は異なる細胞毒性剤/薬物を表し;
ブラケット (括弧)の内部は、対のジスルフィド結合を介して、前記細胞結合分子と
共役された連結体−薬剤成分であり、前記共役可能なチオール原子は、一般的に、TCEP及び/又はDTTによる細胞結合分子上の一対のジスルフィド結合の還元から生成することができる;
nは1〜20であり;
R1、R2、R3、及びR4は、前述の請求項1に記載のものと同じである。 Cell Binder-Drug Conjugated Compound of Formula (II):
During the ceremony
Cb represents a cell binder, preferably an antibody;
"Drug 1 " and "Drug 2 " are alkyl, alkylene, alkenylene, alkynylene, ether, polyoxyalkylene, ester, amine, imine, polyamine, hydrazine, hydrazone, amide, urea, semicarbazide, carbazide, alkoxyamine, urethane, Amino acids, peptides, acyloxylamines, hydroxamic acids, disulfides, thioethers, thioesters, carbamate, carbonates, heterocyclics, heteroalkyls, heteroaromatic rings, or alkoxy bonds, or combinations thereof, via cross-linking agents Represents the same or different cytotoxic agent / drug linked with;
Inside the bracket is a conjugate-drug component conjugated to the cell-binding molecule via a pair of disulfide bonds, and the conjugatable thiol atom is generally by TCEP and / or DTT. It can be produced from the reduction of a pair of disulfide bonds on a cell binding molecule;
n is 1 to 20;
R 1, R 2, R 3, and R 4 are the same as described in claim 1 above.
式中:
Cb、Z1、Z2、n、R1、R2、R3、及びR4は、請求項1及び2と同じ定義である。 Compound of formula (III):
During the ceremony:
Cb, Z 1 , Z 2 , n, R 1 , R 2 , R 3 , and R 4 have the same definitions as claims 1 and 2.
式中:
Y1、Y2、Drug1、Drug2、R1、R2、R3、及びR4は、請求項1及び2と同じ定義である。 Compound of formula (IV):
During the ceremony:
Y 1 , Y 2 , Drug 1 , Drug 2 , R 1 , R 2 , R 3 , and R 4 have the same definitions as claims 1 and 2.
応することができる官能基Y1、Y2、Z1、及び/又はZ2を含む連結体成分R1、R2、R3、及びR4と縮合することができる、請求項1に記載の式(I)の架橋連結体化合物。 The crosslinked hydrazine group can be introduced by direct condensation of hydrazine with an acid, acid halide, or acid anhydride, followed by the introduction of a functional group capable of reacting with a cell binding agent and a drug, usually said hydrazine. The cross-linked substituents of are the conjugate components R 1 , R 2 , R 3 , and containing the functional groups Y 1 , Y 2 , Z 1 , and / or Z 2 capable of reacting with the thiol molecule and / or the drug compound. can be condensed with R 4, crosslinked coupling compounds of formula (I) according to claim 1.
1)化学療法剤:a)アルキル化剤:ナイトロジェンマスタード:クロラムブシル、クロルナファジン、シクロホスファミド、ダカルバジン、エストラムスチン、イホスファミド、メクロレタミン、塩酸メクロレタミンオキサイド、マンノムスチン、ミトブロニトール、メルファラン、ピポブロマン、ノベンビチン、フェネステリン、プレドニムスチン、チオテパ、トロホスファミド、ウラシルマスタード;CC−1065(アドゼレシン、カルゼレシン及びビゼレシンの合成類似体を含む。);デュオカルマイシン(合成類似体、KW−2189及びCBI−TMIを含む。);ベンゾジアゼピン二量体(ピロロベンゾジアゼピン(PBD)又はトマイマイシン、インドリノベンゾジアゼピン類、イミダゾベンゾチアヂアゼピン類、又はオキサゾリジノベンゾジアゼピン類の二量体);ニトロソ尿素化合物:(カルムスチン、ロムスチン、クロロゾトシン、フォテムスチン、ニムスチン、ラニムスチン);アルキルスルホネート(ブスルファン、トレオスルファン、イムプロ
スルファン及びピポスルファン);トリアゼン(ダカルバジン);白金含有化合物:(カルボプラチン、シスプラチン、オキサリプラチン);ベンゾドパ、カルボクオン、メツレドパ及びウレドパ等のアジリジン類;エチレンイミン類、並びにアルトレタミン、トリエチレンメラミン、トリエチレンホスホルアミド及びトリエチレンチオホスホルアミンを含むメチラメラミン類;b)植物アルカロイド:ビンカアルカロイド類:(ビンクリスチン,ビンブラスチン、ビンデシン、ビノレルビン、ナベルビン); タキソイド類:(パクリタキセル、ドセタキセル);及びこれらの類似体、メイタンシノイド類(DM1、DM2、DM3、DM4、メイタンシン、アンサマイトシン)及びこれらの類似体、クリプトフィシン類(特に、クリプトフィシン1及びクリプトフィシン8);エポチロン類、エリュテロビン類、ディスコデルモライド、ブリオスタチン類、ドロスタチン類、オーリスタチン類、チューブリシン類、セファロスタチン類;パンクラチスタチン;サルコジクチイン;スポンジスタチン;c)DNAトポイソメラーゼ阻害剤:[エピポドフィリン類:(9−アミノカンプトテシン、カンプトテシン、クリスナトール、ダウノマイシン、エトポシド、リン酸エトポシド、イリノテカン、ミトキサントロン、ノバントロン、レチノイン酸(レチノール類)、テニポシド、トポテカン、9−ニトロカンプトテシン(RFS 2000);マイトマイシン類:(マイトマイシンC))];d)代謝拮抗剤:{[抗葉酸:ジヒドロ葉酸レダクターゼ阻害剤:(メトトレキサート、トリメトレキサート、デノプテリン、プテロプテリン、アミノプテリン(4−アミノプテロイン酸)、又はその他の葉酸類似体);IMPデヒドロゲナーゼ阻害剤(ミコフェノール酸、チアゾフリン、リバビリン、EICAR);リボヌクレオチド還元酵素阻害薬(ヒドロキシウレア、デフェロキサミン)];[ピリミジン類似体:ウラシル類似体(アンシタビン、アザシチジン、6−アザウリジン、カペシタビン(ゼローダ)、カルモフール、シタラビン、ジデオキシウリジン、ドキシフルリジン、エノシタビン、5−フルオロウラシル、フロクスウリジン、ラルチトレキセド(トミュデックス));シトシン類似体:(シタラビン、シトシンアラビノシド、フルダラビン);プリン類似体:(アザチオプリン、フルダラビン、メルカプトプリン、チアミプリン、チオグアニン)];フォリン酸等の葉酸補充剤};e)ホルモン療法剤:{受容体拮抗薬:[抗エストロゲン:(メゲストロール、ラロキシフェン、タモキシフェン);LHRHアゴニスト:(ゴセレリン、酢酸リュープロリド);抗アンドロゲン:(ビカルタミド、フルタミド、カルステロン、プロピオン酸ドロモスタノロン、エピチオスタノール、ゴセレリン、リュープロリド、メピチオスタン、ニルタミド、テストラクトン、トリロスタン、及び他のアンドロゲン阻害剤)];レチノイド類/三角筋:[ビタミンD3類似体:(CB1093、EB1089、KH1060、コレカルシフェロール、エルゴカルシフェロール);光線力学的療法剤:(ベルテポルフィン、フタロシアニ
ン、光増感剤Pc4、デメトキシ−ヒポクレリンA);サイトカイン類:(インターフェロンα、インターフェロンγ、腫瘍壊死因子(TNF)、TNFドメイン含有ヒトタンパク質)]};f)キナーゼ阻害剤:BIBW2992(抗EGFR/Erb2)、イマチニブ、ゲフィチニブ、ペガプタニブ、ソラフェニブ、ダサチニブ、スニチニブ、エルロチニブ、ニロチニブ、ラパチニブ、アキシチニブ、パゾパニブ、バンデタニブ、E7080(抗VEGFR2)、ムブリチニブ、ポナチニブ(AP24534)、バフェチニブ(INNO−406)、ボスチニブ(SKI−606)、カボザンチニブ、ビスモデギブ、イニパリブ、ルキソリチニブ、CYT387、アキシチニブ、チボザニブ、ソラフェニブ、ベバシズマブ、セツキシマブ、トラスツズマブ、ラニビズマブ、パニツムマブ、イスピネシブ;g)抗生物質:エンジイン系抗生物質(カリケアマイシン類、特に、カリケアマイシンγ1、δ1、α1及びβ1;ダイネミシンA及びデオキシダイネミシンを含むダイネミシン;エスペラミシン、ケダルシジン、C−1027、マズロペプチン、並びにネオカルジノスタチンクロモフォア及び関連する色素タンパク質エンジイン抗生物質クロモフォア、アクラシノマイシン類、アクチノマイシン、アンスラマイシン、アザセリン、ブレオマイシン類、カクチノマイシン(cactinomycin)、カラビシン(carabicin)、カルミノマイシン、カルジノフィリン;クロモマイシン類、ダクチノマイシン、ダウノルビシン、デトルビシン、6−ジアゾ−5−オキソ−L−ノルロイシン、ドキソルビシン、モルホリノ−ドキソルビシン、シアノモルホリノ−ドキソルビシン、2−ピロリノ−ドキソルビシン及びデオキシドキソルビシン、エピルビシン、イダルビシン、マルセロマイシン、マイトマイシン類、ミコフェノール酸、ノガラマイシン、オリボマイシン類、ペプロマイシン、ポトフィロマイシン、ピューロマイシン、クエラマイシン、ロドルビシン、ストレプトニグリン、ストレプトゾシン、ツベルシジン、ウベニメクス、ジノスタチン、ゾルビシン;f)その他のカテゴリー:ポリケチド(アセトゲニン類)、特にブラタシン及びブラタシノン;ゲムシタビン、エポキソミシン類(カルフィルゾミブ)、ボルテゾミブ、サリドマイド、レナリドミド、ポマリドマイド、トセドスタット、ザイブレスタット、PLX4032、STA−9090、スチムバックス(Stimuvax)、アロベクチン−7、ザイゲバ、プロベンジ、エルボイ、イソプレニル化阻害剤(ロバスタチン)、ドーパミン作動性神経毒(1−メチル−4−フェニルピリジンイオン)、細胞周期阻害剤(スタウロスポリン)、アクチノマイシン類(アクチノマイシンD、ダクチノマイシン)、ブレオマイシン類(例えば,ブレオマイシンA2、ブレオマイシンB2、ペプロマイシン)、アントラサイクリン類(例えば,ダウノルビシン、ドキソルビシン(アドリアマイシン)、イダルビシン、エピルビシン、ピラルビシン、ゾルビシン、ミトキサントロン、MDR阻害剤(ベラパミル)、Ca2+ATP阻害剤(タプシガルギン)、ヒストン脱アセチル化酵素阻害剤(ボリノスタット、ロミデプシン、パノビノスタット、バルプロ酸、モセチノスタット(MGCD0103)、ベリノスタット、PCI−24781、エンチノスタット、SB939、レスミノスタット、ギビノスタット、AR−42、CUDC−101、スルフォラファン、トリコスタチンA);タプシガルギン、セレコキシブ、グリタゾン類、エピガロカテキンガレート、ジスルフィラム、サリノスポラミドA、抗副腎薬、例えばアミノグルテチミド、ミトタン、トリロスタン;アセグラトン;アルドホスファミドクリコシド;アミノレブリン酸;アラビノシド、ベストラブシル;ビサントレン;エダトレキサート;デフォファミン、デメコルシン、ジアジコン、エルフォルニチン(DFMO)、酢酸エリプチニウム、エトクルシド、硝酸ガリウム、ガシトシン、ヒドロキシ尿素;イバンドロネート、レンチナン;ロニダミン;ミトグアゾン;モピダモール;ニトラエリン;ペントスタチン;フェナメット;ピラルビシン;ポドフィリン酸;2−エチルヒドラジド;プロカルバジン;PSK(登録商標);ラゾキサン;リゾキシン;シゾフィラン;スピロゲルマニウム;テニュアゾン酸;トリアジコン;2,2’,2’’−トリクロロトリエチルアミン;トリコテセン類(特に、T2トキシン、ベルカリンA、ロリジンA、及びアングイジン);ウレタン、siRNA、アンチセンス医薬、並びに核酸分解酵素;
2)抗自己免疫疾患薬:シクロスポリン、シクロスポリンA、アザチオプリン、アミノ
カプロン酸、ブロモクリプチン、クロラムブシル、クロロキン、シクロホスファミド、コルチコイド(ホルモン剤、ベタメタゾン、ブデソニド、フルニソリド、フルチカゾンプロピオン酸エステル、ヒドロコルチゾン、デキサメタゾン、フルオコルトダナゾール、トリアムシノロンアセトニド、ジプロピオン酸ベクロメタゾン)、デヒドロイソアンドロステロン、エタネルセプト、ヒドロキシクロロキン、インフリキシマブ、メロキシカム、メトトレキサート、ミコフェノール酸モフェチル、シロリムス、タクロリムス、プレドニゾン;
3)抗感染薬:a)アミノグリコシド類:アミカシン、アストロマイシン、ゲンタマイシン(ネチルマイシン、シソマイシン、イセパマイシン)、ハイグロマイシン、カナマイシン(アミカシン、アルベカシン、アミノデオキシカナマイシン、ジベカシン、トブラマイシン)、ネオマイシン(ネオマイシンB、パロモマイシン、リボスタマイシン)、ネチルマイシン, スペクチノマイシン、ストレプトマイシン、トブラマイシン、ベルダミシン;b)アンフェニコール類:アジダムフェニコール、クロラムフェニコール、フロルフェニコール、チアンフェニコール;c)アンサマイシン類:ゲルダナマイシン、ハービマイシン;d)カルバペネム類:ビアペネム、ドリペネム、エルタペネム、イミペネム/シラスタチン、メロペネム、パニペネム;e)セフェム類:カルバセフェム(ロラカルベフ)、セファセトリル、セファクロル、セフラジン、セファドロキシル、セファロニウム、セファロリジン、セファロチン又はセファロスポリン、セファレキシン、セファログリシン、セファマンドール、セファピリン、セファトリジン、セファザフル、セファゼドン、セファゾリン、セフブペラゾン、セフカペン、セフダロキシム、セフェピム、セフミノックス、セフォキシチン、セフプロジル、セファロスポリン、セフテゾル、セフロキシム、セフィキシム、セフジニル、セフジトレン、セフェピム、セフェタメト、セフメノキシム、セフォジジム、セフォニシド、セフォペラゾン、セホラニド、セフォタキシム、、セフォチアム、セフォゾプラン、セファレキシン、セフピミゾール、セフピラミド、セフピロム、セフポドキシム、セフプロジル、セフキノム、セフスロジン、セフタジジム、セフテラム、セフチブテン、セフチオレン、セフチゾキシム、セフタジジム、セフトリアキソン、セフロキシム、セファゾリンフラン、セファマイシン(セフォキシチン、セフォテタン、セフメタゾール)、オキサセフェム(フロモキセフ、ラタモキセフ);f)糖ペプチド類:ブレオマイシン、バンコマイシン(オリタバンシン、テラバンシン)、テイコプラニン(ダルババンシン)、ラモプラニン、キュービシン;g)グリシルサイクリン類:チゲサイクリン;h)β−ラクタマーゼ阻害剤:ペナム(スルバクタム、タゾバクタム)、クラバム(クラブラン酸);i)リンコサミド類:クリンダマイシン、リンコマイシン;j)リポペプチド類:ダプトマイシン、A54145、カルシウム依存性抗生物質(CDA);k)マクロライド類:アジスロマイシン、セスロマイシン、クラリスロマイシン、ジリスロマイシン、エリスロマイシン、フルリスロマイシン、ジョサマイシン、ケトライド(テリスロマイシン、エセスロマイシン)、ミデカマイシン、ミオカマイシン、オレアンドマイシン、リファマイシン(リファンピシンン、リファンピン、リファブチン、リファペンチン)、ロキタマイシン、ロキシスロマイシン、スペクチノマイシン、スピラマイシン、タクロリムス(FK506)、トロレアンドマイシン、テリスロマイシンン;l)モノバクタム類:アズトレオナム、チゲモナム;M)オキサゾリジノン類:リネゾリド;N)ペニシリン類:アモキシシリン、アンピシリン(ピバンピシリン、ヘタシリン、バカンピシリン、メタンピシリン、タランピシリン)、アジドシリン、アズロシリン、ペニシリン、ベンザチンペニシリン、フェノキシベンザチンペニシリン、クロメトシリン、プロカインペニシリン、カルベニシリン(カリンダシリン)、クロキサシリン、ジクロキサシリン、セファロスポリン、フルクロキサシリン、メシリナム(ピブメシリナム)、メズロシリン、メチシリン、ナフシリン、オキサシリンナトリウム、フェネチシリン、ペニシリン、フェネチシリン、ペニシリン、ピペラシリン、プロピシリン、スルベニシリン、テモシリン、チカルシリン;o)ポリペプチド類:バシトラシン、ポリミキシンE、ポリミキシンB; p)キノロン類:アラトロフロキサシン、バロフロキサシン、シプロフロキサシン、クリナフロキサシン、ダノフロキサシン、ジフロキサシン、エノキサシン、エンロフロキ
サシン、オフロキサシン、ガレノキサシン、ガチフロキサシン、ゲミフロキサシン、グレパフロキサシン、カノトロバフロキサシン(kanotroafloxacin)、レボフロキサシン、ロメフロキサシン、マルボフロキサシン、モキシフロキサシン、ナジフロキサシン、ノルフロキサシン、オルビフロキサシン、オフロキサシン、ペフロキサシン、トロバフロキサシン、グレパフロキサシン、シタフロキサシン、スパルフロキサシン、テマフロキサシン、トスフロキサシン、トロバフロキサシン;q)ストレプトゾトシン類:プリスチナマイシン、キヌプリスチン/ダルホプリスチン;r)スルホンアミド類:マフェニド、プロントジル、スルファセタミド、スルファメトキサゾール、スルファニルアミド、スルファサラジン、スルファフラゾール、トリメトプリム、トリメトプリム - スル
ファメトキサゾール(コトリモキサゾール);s)ステロイド系抗菌薬:例えば、フシジン酸;t)テトラサイクリン類:ドキシサイクリン、クロルテトラサイクリン、クロモサイクリン、デメクロサイクリン、リメサイクリン、メクロサイクリン、メタサイクリン、ミノサイクリン、オキシテトラサイクリン、ペニメピサイクリン、ロリテトラサイクリン、テトラサイクリン、グリシルサイクリン(チゲサイクリン);u)他のタイプの抗生物質:アンノナシン、アルスフェナミン、バクトプレノール阻害剤(バシトラシン)、DADAL/AR阻害剤(サイクロセリン)、ジクチオスタチン、ディスコデルモライド、エレウテロビン、エポチロン、エタンブトール、エトポシド、ファロペネム、フシジン酸、フラゾリドン、イソニアジド、ラウリマリド、メトロニダゾール、ムピロシン、マイコラクトン、NAM合成阻害剤(ホスホマイシン)、ニトロフラントイン、パクリタキセル、プラテンシマイシン、ピラジナミド、キヌプリスチン/ダルホプリスチン、リファンピン(リファンピシン)、タゾバクタムチニダゾール、ウバリシン;
4)抗ウイルス薬:a)侵入/融合阻害剤:アプラビロック、マラビロク、ビクリビロック、gp41(エンフビルチド)、PRO140、CD4(イバリズマブ);b)インテグラーゼ阻害剤:ラルテグラビル、エルビテグラビル、グロボイドナンA;c)成熟阻害剤:ベビリマット、ヴィヴィコン;d)ノイラミニダーゼ阻害剤:オセルタミビル、ザナミビル、ペラミビル;e)ヌクレオシド及びヌクレオチド:アバカビル、アシクロビル、アデフォビル、アムドキソビル、アプリシタビン、ブリブジン、シドフォビル、クレブジン、デキセルブシタビン、ジダノシン(DDI)、エルブシタビン、エムトリシタビン(FTC)、エンテカビル、ファムシクロビル、フルオロウラシル(5−FU)、3’−フルオロ置換2’,3’−デオキシヌクレオシド類似体(3’−フルオロ−2’,3’−ジデオキシチミジン(FLT)及び3’−フルオロ−2’,3’−ジデオキシグアノシン(FLG)、ホミビルセン、ガンシクロビル、イドクスウリジン、ラミブジン(3TC)、L−ヌクレオシド(β−L−チミジン、β−L−2’−デオキシシチジン)、ペンシクロビル、ラシビル、リバビリン、スタンピジン、スタブジンセット(d4T)、タリバビリン(ビラミジン)、テルビブジン、テノホビル、トリフルリジン、バラシクロビル、バルガンシクロビル、ザルシタビン(ddC)、ジドブジン(AZT);f)非ヌクレオシド:アマンタジン、アテビリジン、カプラビリン、ジアリールピリミジン(エトラビリン、リルピビリン)、デラビルジン、ドコサノール、エミビリン、エファビレンツ、ホスカルネット(ホスホリルギ酸)、イミキモド、インターフェロンα、ロビリド、ロデノシン、メチサゾン、ネビラピン、NOV−205、ペグインターフェロンα、ポドフィロトキシン、リファンピシン、リマンタジン、レシキモド(R−848)、トロマンタジン;g)プロテアーゼ阻害剤:アンプレナビル、アタザナビル、ボセプレビル、ダルナビル、ホスアンプレナビル、インジナビル、ロピナビル、ネルフィナビル、プレコナリル、リトナビル、サキナビル、テラプレビル(VX−950)、チプラナビル;H)抗ウイルス薬の他のタイプ:アブザイム、アルビドール、カラノリドA、セラゲニン、シアノビリン−N、DAPY、没食子酸エピガロカテキン(EGCG)、ホスカルネット、グリフィスシン、タリバビリン(ビラミジン)、ヒドロキシカルバミド、KP−1461、プレコナリル、ポートマントー阻害剤、リバビリン、セリシクリブ;
5)3H、11C、14C、18F、32P、35S、64Cu、68Ga、86Y、99Tc、111In、123I、124I、125I、131I、133Xe、177
Lu、211At、及び213Biから選択される放射性同位元素(放射性核種);
6)UV光、蛍光光、IR光、近IR光、視覚光のようなある種の光を吸収する能力を有する発色団分子;黄色素胞、赤色素胞、虹色素胞、白色素胞、黒色素胞、青色素胞、及び蛍光体のクラス又はサブクラスであって、前記蛍光体は、光で光を再放射する蛍光性化学物質、視覚的光感受性分子、発光分子、ルミネッセンス分子、ルシフェリン化合物のクラスまたはサブクラス、可視光伝達分子、発光分子、ルミネセンス分子、ルシフェリン化合物;例えば、以下の非タンパク質有機蛍光体:キサンテン誘導体(フルオレセイン、ローダミン、オレゴングリーン、エオシン、及びテキサスレッド);シアニン誘導体(シアニン、インドカルボシアニン、オキサカルボシアニン、チアカルボシアニン、及びメロシアニン);スクアレン誘導体及び環置換スクアライン(Seta、SeTau、及びSquare色素を含む);ナフタレン誘導体(ダンシル及びプロダン誘導体);クマリン誘導体;オキサジアゾール誘導体(ピリジルオキサゾール、ニトロベンゾキサジアゾール、及びベンゾオキサジアゾール);アントラセン誘導体(DRAQ5、DRAQ7、及びCyTRAK Orangeを含むアントラキノン類);ピレン誘導体(カスケードブルー等);オキサジン誘導体(ナイルレッド、ナイルブルー、クレシルバイオレット、オキサジン170等)。アクリジン誘導体(プロフラビン、アクリジンオレンジ、アクリジンイエロー等)。アリールメチン誘導体(オーラミン、クリスタルバイオレット、マラカイトグリーン)。テトラピロール誘導体(ポルフィン、フタロシアニン、ビリルビン); 以下の蛍光体化合物の任意の類縁体及び誘導体:CF色素(Biotium)、DRAQ及びCyT
RAKプローブ(Bio-Status)、BODIPY(Invitrogen)、Alexa Fluor(Invitrogen)、DyLight Fluor(Thermo Scientific、Pierce)、Att
o及びTrancy(Sigma Aldrich)、FluoProbes(Interchim)、Abberior色素(Abberior)、DY及びMegaStokes色素(Dyomics)、Sulf
oCy色素(Cyandye)、HiLyte Fluor(AnaSpec)、Seta、SeTau及びSquare色素(SETA BioMedicals)、Quasar及びCal Flour色素(Biosearch Technologies)、SureLight色素(APC、RPEPerCP、フィコビリソーム)(Columbia Biosciences)、APC、APCXL、RPE、BPE(Phyco-Biotech)、アロフィコシアニン(APC)、アミノクマリン、APC−Cy7共役
体、BODIPY−FL、カスケードブルー、Cy2、Cy3、Cy3.5、Cy3B、Cy5、Cy5.5、Cy7、フルオレセイン、FluorX、ヒドロキシクマリン、リサミンローダミンB、ルシファーイエロー、メトキシクマリン、NBD、Pacific
Blue、Pacific Orange、PE−Cy5共役体、PE−Cy7共役体、PerCP、R−フィコエリトリン(PE)、Red613、Seta−555−アジド、Seta−555−DBCO、Seta−555−NHS、Seta−580−NHS、Seta−680−NHS、Seta−780−NHS、Seta−APC−780、Seta−PerCP−680、Seta−R−PE−670、SeTau380−NHS、SeTau405−マレイミド、SeTau405−NHS、SeTau425−NHS、SeTau647−NHS、テキサスレッド、TRITC、TruRed、X−ローダミン、7−AAD(7−アミノアクチノマイシンD、CG選択性)、アクリジンオレンジ、クロモマイシンA3、CyTRAKオレンジ(Biostatus、赤色励起暗)、DA
PI、DRAQ5、DRAQ7、エチジウムブロマイド、ヘキスト33258、ヘキスト33342、LDS751、ミスラマイシン、ヨウ化プロピジウム(PI)、SYTOXブルー、SYTOXグリーン、SYTOXオレンジ、チアゾールオレンジ、TO−PRO:シアニン単量体、TOTO−1、TO−PRO−1、TOTO−3、TO−PRO−3、YOseta−1、YOYO−1。細胞研究のために本発明の連結体に連結させることができる蛍光色素は、以下の化合物又はその誘導体から選択される:DCFH(2’7’ジクロロジヒドロ−フルオレセイン、酸化型)、DHR(ジヒドロローダミン123、酸化型、光が酸化を触媒する)、Fluo−3(AMエステル、pH>6)、Fluo−4(AMエステル、pH7.2)、Indo−1(AMエステル、低/高カルシウム(Ca2+))、SNARF(pH6/9)、アロフィコシアニン(APC)、AmCyan1
(四量体、Clontech)、AsRed2(四量体、Clontech)、Azamiグリーン(単量体、MBL)、アズライト、B−フィコエリトリン(BPE)、セルリアン、CyPet、
DsRed単量体(Clontech)、DsRed2(「RFP」、Clontech)、EBFP、EBFP2、ECFP、EGFP(弱二量体、Clontech)、エメラルド(弱二量体、Invitrogen)、EYFP(弱二量体、Clontech)、GFP(S65A変異体)、GFP(S65C変異体)、GFP(S65L変異体)、GFP(S65T変異体)、GFP(Y66F変異体)、GFP(Y66H変異体)、GFP(Y66W変異体)、GFPuv、HcRed1、J−Red、カチューシャ、Kusabira Orange(単量体、MBL)
、mCFP、mCherry、mCitrine、Midriishi Cyan(二量体、MBL)、mKate(TagFP635、単量体、Evrogen)、mKeima−Red(単量体、MBL)、mKO、mOrange、mPlum、mRaspberry、mR
FP1(単量体、Tsien Lab)、mStrawberry、mTFP1、mTurquoise2、P3(フィコビリソーム複合体)、Peridinin Chlorophyll(PerCP)、R−フィコエリトリン(RPE)、T−Sapphire、TagCFP(二量体、Evrogen)、TagGFP(二量体、Evrogen)、TagRFP(二量体、Evrogen)、TagYFP(二量体、Evrogen)、tdTomato(タンデム二量体)、トパーズ、TurboFP602(二量体、Evrogen)、TurboFP63
5(二量体、Evrogen)、TurboGFP(二量体、Evrogen)、TurboRFP(二量体、Evrogen)、TurboYFP635(二量体、Evrogen)、ビーナス、天然型GFP、YPet、Zsグリーン1(四量体、Clontech)、Zsイエロー1(四量体、Clontech)。
7)薬学的に許容される、上記の任意の薬物の塩、酸、又は誘導体。 In the formulas (II) and (IV) of claims 2 and 4, Drug 1 and Drug 2 are the same or independently selected from the following:
1) Chemotherapeutic agent: a) Alkylating agent: Nitrogen mustard: Chlorambucil, chlornafazine, cyclophosphamide, dacarbazine, estramustin, ifosfamide, chlormethine, mechlorethamine hydrochloride oxide, mannomustine, mitobronitol, melfaran, Pipobroman, nobenbitin, phenesterin, predonimustine, thiotepa, trophosphamide, urasyl mustard; CC-1065 (including synthetic analogs of adzelesin, calzelesin and biserecin); duocalmycin (including synthetic analogs, KW-2189 and CBI-TMI) ); Benzodiazepine dimers (pyrrolobenzodiazepine (PBD) or tomymycin, indolinobenzodiazepines, imidazolibenzothiadiazepines, or oxazolidinobenzodiazepine dimers); nitrosourea compounds: (carmustin, romustine, chlorozotocin) , Fotemstin, nimustin, lanimustine); alkylsulfonates (busulfan, treosulfan, improsulfan and piposulfane); triazene (dacarbazine); platinum-containing compounds: (carboplatin, cisplatin, oxaliplatin); benzodopa, carboquin, meturedopa and uredopa Aziridines such as; ethyleneimines, and methilamelamines including altretamine, triethylenemelamine, triethylenephosphoramide and triethylenethiophosphoramine; b) plant alkaloids: vinca alkaloids: (vincristine, vinblastin, bindesin, binorelbin, etc. Navelbin); Taxoids: (Pacrytaxel, Dosetaxel); and their analogs, Maytansinoids (DM1, DM2, DM3, DM4, Maytancin, Ansamitocin) and their analogs, Cryptophycins (particularly cryptophytes) Physin 1 and cryptophycin 8); epotylones, erutellobins, discodelmolides, briostatins, drosstatins, auristatins, tubericins, cephalosstatins; pankratisstatin; sarcodictiin; spongestatin; c) DNA topoisomerase inhibitors: [Epipodophylline: (9-aminocamptothecin, camptothecin, chlormethine, daunomycin, etopocid, phosphate etopocid, ifosfamide, mitoxanthrone, novantron, retinoic acid (Retinols), teniposide, topotecan, 9-nitrocamptothecin (RFS 2000); mitomycins: (mitomycin C))]; d) Metabolism antagonists: {[antifolic acid: dihydrofolate reductase inhibitors: (methotrexate, trimetreki) Sate, denopterin, pteropterin, aminopterin (4-aminopteroic acid), or other folic acid analogs); IMP dehydrogenase inhibitors (mycophenolic acid, thiazofulin, ribavirin, EICAR); ribonucleotide reductase inhibitors (hydroxyurea) , Deferroxamine)]; [Pyrimidine analogs: uracil analogs (ancitabine, azacitidine, 6-azauridine, capecitabin (Xeloda), carmofur, citarabin, dideoxyuridine, doxiflulysin, enocitabine, 5-fluorouracil, floxuridine, lartitrexed) )); Citocin analogs: (citarabin, citocin arabinoside, fludarabin); purine analogs: (azathiopurine, fludarabin, mercaptopurine, thiamipulin, thioguanine)]; folic acid supplements such as phoric acid}; e) hormone therapeutic agents : {Receptor antagonist: [Anti-estrogen: (Megestrol, Laloxyphen, Tamoxyphen); LHRH agonist: (Gocerelin, leuprolide acetate); Anti-androgen: (Vicartamide, Flutamide, Calsterone, Propionate dromostanolone, Epithiostanol, Gocerelin) , Leuprolide, mepitiostan, niltamide, testlactone, trilostane, and other androgen inhibitors)]; retinoids / triangular muscles: [vitamin D3 analogs: (CB1093, EB1089, KH1060, cholecalciferol, ergocalciferol); Mechanical therapeutic agents: (verteporfin, phthalocyanine, photosensitizer Pc4, demethoxy-hypoclerin A); cytokines: (interferon α, interferon γ, tumor necrosis factor (TNF), TNF domain-containing human protein)]}; f ) Kinase inhibitors: BIBW2992 (anti-EGFR / Erb2), imatinib, gefitinib, pegaptanib, sorafenib, dasatinib, snitinib, errotinib, nirotinib, lapatinib, axitinib, rapatinib, axitinib, pazopanib, bandetanib, EG2 Buffetinib (I NNO-406), Bostinib (SKI-606), Cabozantinib, Bismodegib, Iniparib, Luxolitinib, CYT387, Axitinib, Tibozanib, Soraphenib, Bebasizumab, Setuximab, Trustuzumab, Panibizumab, Panibizumab Calicaremycins, in particular calikeamycin γ1, δ1, α1 and β1; dynemycins including dinemicin A and deoxydinemicin; esperamicin, kedalcidin, C-1027, mazulopeptin, and neocardinostatin chromophore and related pigment proteins. Endiin Antibiotics Chromophore, Aclasinomycins, Actinomycin, Anthramycin, Azaseline, Bleomycin, Cactinomycin, Carabicin, Carminomycin, Cardinophylline; Chromomycins, Doxorubicin, Daunorubicin, Detorbisin, 6-diazo-5-oxo-L-norleomycin, doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxidoxorubicin, epirubicin, idalubicin, marcelomycin, mitomycins, mycophenolic acid, nogalamycin, Oribomycins, pepromycin, potophylomycin, puromycin, queramycin, rodorubicin, streptnigrin, streptozocin, tubersidine, ubenimex, diostatin, sorbicin; f) Other categories: polyketide (acetogenins), especially bleomycin and bratacinone; gemcitabine , Epoxomicins (calfilzomib), voltezomib, salidamide, lenalidomido, pomalidemide, tosedostat, zybrestat, PLX4032, STA-9090, stimuvax, stimuvax, allovectin-7, zygeba, provenge , Dopaminergic neurotoxin (1-methyl-4-phenylpyridine ion), cell cycle inhibitor (staurosporin), actinomycins (actinomycin D, dactinomycin), bleomycins (eg, bleomycin A2, bleomycin) B2, pepromycin), anthracyclins (eg, daunorubicin, doxorubicin (a) Doriamycin), idarubicin, epirubicin, pirarubicin, sorbicin, mitoxantrone, MDR inhibitor (bellapamil), Ca2 + ATP inhibitor (tapsigargin), histone deacetylase inhibitor (vorinostat, lomidepsin, panobinostat, valproic acid, Mosetinostat (MGCD0) ), Verinostat, PCI-24781, Entinostat, SB939, Resminostat, Gibinostat, AR-42, CUDC-101, Sulforaphane, Tricostatin A); Tapsigargin, Celecoxib, Glytazones, Epigalocatecin gallate, Disulfiram, Salinosporamide A, anti-adrenal drugs such as aminoglutetimid, mitotane, trilostane; acegraton; aldphosphamide cricoside; aminolevulinic acid; arabinoside, bestlabcil; bisantren; edatrexate; defofamine, demecorcin, diadicon, elfornitin (DFMO) ), Elliptinium acetate, etuclucid, gallium nitrate, gasitocin, hydroxyurea; ibandronate, lentinan; ronidamine; mitogazone; mopidamole; nitraerin; pentostatin; phenamet; pirarubicin; podophylphosphate; 2-ethylhydrazide; procarbazine; PSK® ); Razoxane; Risoxin; Sizophyllan; Spirogermanium; Tenuazonic acid; Triadicon; 2,2', 2''-trichlorotriethylamine; Tricotesenes (particularly T2 toxin, velcarin A, loridine A, and anguidin); urethane, siRNA, Antisense drugs and nucleic acid degrading enzymes;
2) Anti-autoimmune disease drugs: cyclosporine, cyclosporin A, azathioprine, aminocaproic acid, bromocryptin, chlorambusyl, chloroquin, cyclophosphamide, corticoid (hormonal agents, betamethasone, budesonide, flunisolide, fluticazone propionate, hydrocortisone, dexamethasone, fluo) Coltdanazole, triamcinolone acetonide, vechromethasone dipropionate), dehydroisoandrosterone, etanercept, hydroxychloroquine, infliximab, meroxycam, methotrexate, mofetyl mycophenolate, silolimus, tacrolimus, prednisone;
3) Anti-infective agents: a) Aminoglycosides: amicacin, astromycin, gentamycin (netylmycin, cisomycin, isepamicin), hygromycin, canamycin (amicacin, albecasin, aminodeoxycanamicin, dibecasin, tobramycin), neomycin (nemycin B, paromomycin, Ribostamycin), netylmycin, spectinomycin, streptomycin, tobramycin, verdamicin; b) amphenicol: azidamphenicol, chloramphenicol, floruphenicol, thianphenicol; c) ansamicol: geldana Mycin, harbimycin; d) Carbapenems: Viapenem, Dripenem, Eltapenem, Imipenem / Silastatin, Melopenem, Panipenem; e) Cephem: Carbacephem (Loracarbef), Cepacetril, Cefchloramphenicol, Cefacetril, Cefaclorin, Cephalosporin, Cephalosporin Or cephalosporins, cephalexins, cephalosporins, cephamandols, cephapyrin, cephatridin, cefazaflu, cepazedon, cepazoline, cefbuperazone, cefcapene, cefdaloxime, cefepim, cefminox, cefoxytin, cefprodil, cephalosporins, cefprozil, cephalosporins , Cefditoren, cepepim, cefetameth, cefmenoxim, cefodidim, cefonicid, cefoperazone, cefolinide, cefotaxim, cefotiam, cefosoplan, cephalexin, cefpimisol, cefpyramid, cefpyrom Ceftadidim, ceftriaxone, ceflixim, cepazolinefuran, cephamycin (cefoxitin, cefotetan, cefmethazole), oxacephem (flomoxef, ratamoxef); f) Glycopeptides: bleomycin, bancomycin (oritavancin, teravancin), teikoplanin (dalvavancin) , Cubicin; g) glycylcyclins: tigecyclins; h) β-lactamase inhibitors: penum (sulbactam, tazobactam), chloramphenicol (chloramphenicol); i) lincosamides: clindamycin, lincomycin; j) Lipopeptides: daptomycin, A54145, calcium-dependent antibiotics (CDA); k) Macrolides: azithromycin, sesromycin, clarithromycin, girisromycin, erythromycin, fururisromycin, josamicin, ketride (terisromycin, ese) Thromycin), Midecamycin, Myocamycin, Oleandomycin, Rifamycin (Rifampicin, Riphanpin, Rifabutin, Rifapentin), Lokitamycin, Loxythromycin, Spectinomycin, Spiramycin, Tachlorimus (FK506), Trolleanomycin, Terislo Mycin; l) Monobactams: Azthreonum, Tigemonum; M) Oxazolidinones: Linezolide; N) Penicillins: Amoxycillin, Ampicillin (Pivanpicillin, Hetacillin, Vacampicillin, Methanpicillin, Talampicillin), Azidocillin, Azulocylin Benzatin penicillin, clometocillin, procaine penicillin, carbenicillin (calindacillin), cloxacillin, dicloxacillin, cephalosporin, flucloxacillin, mesyrinum (pibmesirinum), messulocillin, methicillin, naphthylin, oxacillin sodium, phenecillin sodium phenecillin Piperacillin, Propicillin, Sulbenicillin, Temocillin, Tikarcillin; o) Polypeptides: Basitracin, Polymyxin E, Polymyxin B; p) Kinolones: Alatrofloxacin, Barofloxacin, Ciproffloxacin, Clarithromycin, Danofoxacin, Difloxacin, Enoxacin, Enlofloxacin, Ophroxacin, Galenoxacin, Gachifloxacin, Gemifloxacin, Grepafloxacin, Kanotroafloxacin, Levofloxacin, Lomefloxacin, Malvofloxacin, Moxyfloxacin, Nadifloxacin, Norfloxacin, Floxacin, ofloxacin, pefloxacin, trovafloxacin, grepafloxacin, citafloxacin, sparfloxacin, temafloxacin, tosfloxacin, trovafloxacin; q) streptozotocins: pristinamycin, quinupristin / dalhopristin; r) Amids: Ma Phenide, Prontozil, Sulfacetamide, Sulfamethoxazole, Sulfanylamide, Sulfa salazine, Sulfafrazole, Trimethoprim, Trimethoprim-Sulfamethoxazole (cotrimoxazole); s) Antibiotic antibiotics: eg, fushidic acid; t) Tetracyclines: Doxycycline, Chlortetracycline, Chromocycline, Demecrocycline, Limecycline, Mecrocycline, Metacycline, Minocycline, Oxytetracycline, Penimepicycline, Loritetracycline, Tetracycline, Glycyrrhizyl (Tigecycline); u) Other types of antibiotics: annonacin, arsphenamine, bactoprenol inhibitor (basitracin), DADAL / AR inhibitor (cycloserine), dicthiostatin, discodelmolide, eleutellobin, epotiron, etamethoxazole, etopocid, Faropenem, fucidic acid, frazolidene, isoniazide, laurimalide, metronidazole, mupyrosine, mycolactone, NAM synthesis inhibitor (phosphomycin), nitrofurantin, paclitaxel, platencymycin, pyrazinamide, quinupristin / dalhopristin, rifampin (rifampicin), tazobactin Ubaricin;
4) Antiviral agents: a) Invasion / fusion inhibitors: apravilock, malaviloc, vicribiroc, gp41 (emtricitabine), PRO140, CD4 (ibarizumab); b) integrase inhibitors: lartegravir, erbitegrabir, globoidan A; c) maturation inhibition Agents: Babylimat, Vivicon; d) Neuraminidase inhibitors: Osertamivir, Zanamivir, Peramivir; e) Nucleosides and nucleotides: abacavir, acyclovir, adefobil, amdoxovir, apricitabine, bribdin, sidofovir, krebdin, dixelbusitabine, zidovudine , Elbusitabine, emtricitabine (FTC), entecavir, famucyclovir, fluorouracil (5-FU), 3'-fluorosubstituted 2', 3'-deoxynucleoside analogs (3'-fluoro-2', 3'-zidovudine (FLT) and 3'-fluoro-2', 3'-dideoxyguanosine (FLG), homivirsen, gancyclovir, idoxuridine, laminuvudine (3TC), L-nucleoside (β-L-thymidine, β-L-2' -Deoxycitidine), pencyclovir, racivir, ribavirin, stampidine, stubzine set (d4T), taribavirin (viramidin), tervibdin, tenohobil, trifluidine, baracyclovir, balgancyclovir, zarcitabine (ddC), zidovudine (AZT); Nucleoside: Amantadine, Atevirinin, Capravirin, Zidovudine (etrabilin, lylphibirin), delavirdin, docosanol, emibilin, efavilents, foscarnet (phosphorylgiic acid), imikimod, interferon α, robilide, rodenosin, methipin, methisazone 205 Interferon α, podophylrotoxin, rifampicin, limantadine, reshikimod (R-848), tromantadine; g) Proteoinhibitors: amprenavir, atazanavir, boceprevir, darnavir, hosamprenavir, indinavir, ropinavir, nerfinavir, pleconalyl, Litonavir, Sakinavir, Terraprevir (VX-950), Tipranavir; H) Other types of antiviral drugs: Abzyme, Albidol, Caranolide A, Seragenin, Cyanovirin-N, DAPY, Epigalocatechin (EGCG), Hoscal Net, Griffithin, Taribavirin (viramidin), hydroxycarbamide, KP-1461, pleconaril, portmanteau inhibitor, ribavirin, seliciclib;
5) 3 H, 11 C, 14 C, 18 F, 32 P, 35 S, 64 Cu, 68 Ga, 86 Y, 99 Tc, 111 In, 123 I, 124 I, 125 I, 131 I, 133 Xe, 177
Radioisotopes (radionuclides) selected from Lu, 211 At, and 213 Bi;
6) Chromatophore molecules capable of absorbing certain types of light such as UV light, fluorescent light, IR light, near IR light, and visual light; A class or subclass of melanophores, blue chromatophores, and phosphors, the phosphors being fluorescent chemicals, visually light-sensitive molecules, luminescent molecules, luminescent molecules, luciferin compounds that re-radiate light with light. Classes or subclasses, visible light transfer molecules, luminescent molecules, luminescent molecules, luciferin compounds; for example, the following non-protein organic fluorophores: xanthene derivatives (fluorescein, rhodamine, olegon green, eosin, and Texas red); cyanine derivatives ( Cyanin, indocarbocyanine, oxacarbocyanin, thiacarbocyanine, and merocyanin); squalane derivatives and ring-substituted squalines (including Seta, SeTau, and Squaree dyes); naphthalene derivatives (dancil and prodan derivatives); coumarin derivatives; oxa Diazole derivatives (pyridyl oxazole, nitrobenzoxa diazole, and benzoxa diazole); anthracene derivatives (anthraquinones including DRAQ5, DRAQ7, and CyTRAK Orange); pyrene derivatives (cascade blue, etc.); oxazine derivatives (nile red, Nile blue, cresil violet, oxazine 170, etc.). Acridine derivatives (proflavine, acridine orange, acridine yellow, etc.). Arylmethine derivatives (auramine, crystal violet, malachite green). Tetrapyrrole derivatives (porphyrin, phthalocyanine, bilirubin); any analogs and derivatives of the following fluorescent compounds: CF dyes (Biotium), DRAQ and CyT
RAK probe (Bio-Status), BODIPY (Invitrogen), Alexa Fluor (Invitrogen), DyLight Fluor (Thermo Scientific, Pierce), Att
o and Trancy (Sigma Aldrich), FluoProbes (Interchim), Abberior dye (Abberior), DY and MegaStokes dye (Dyomics), Sulfur
oCy dye (Cyandye), HiLyte Fluor (AnaSpec), Seta, SeTau and Square dye (SETA BioMedicals), Quasar and Cal Fluor dye (Biosearch Technologies), SureLight dye (APC, RPEPerCP, Phycobilisome) Co. , RPE, BPE (Phyco-Biotech), Allophycocyanin (APC), Aminocoumarin, APC-Cy7 Conjugate, BODIPY-FL, Cascade Blue, Cy2, Cy3, Cy3.5, Cy3B, Cy5, Cy5.5, Cy7, Fluorescein, FluorX, Hydroxycoumarin, Lisamin Rhodamine B, Lucifer Yellow, methoxycumarin, NBD, Pacific
Blue, Pacific Orange, PE-Cy5 conjugate, PE-Cy7 conjugate, PerCP, R-phycoerythrin (PE), Red613, Seta-555-Azide, Seta-555-DBCO, Seta-555-NHS, Seta-580- NHS, Seta-680-NHS, Seta-780-NHS, Seta-APC-780, Seta-PerCP-680, Seta-R-PE-670, Setau380-NHS, Setau405-Maleimide, Setau405-NHS, Setau425-NH SeTau647-NHS, Texas Red, TRITC, TruRed, X-Rhodamine, 7-AAD (7-aminoactinomycin D, CG selectivity), Acrydin orange, Chromomycin A3, CyTRAK orange (Biostatus, red excitation dark), DA
PI, DRAQ5, DRAQ7, ethidium bromide, Hoechst 33258, Hoechst 33342, LDS751, Mithramycin, Propidium iodide (PI), SYSTEMOX BLUE, SYNTOX Green, SYNTOX Orange, Thiazole Orange, TO-PRO: Cyanine Monomer, TOTO- 1, TO-PRO-1, TOTO-3, TO-PRO-3, YOseta-1, YOYO-1. Fluorescent dyes that can be linked to the conjugates of the invention for cell studies are selected from the following compounds or derivatives thereof: DCFH (2'7'dichlorodihydro-fluorescein, oxidized form), DHR (dihydrorhodamine). 123, Oxidized form, light catalyzes oxidation), Fluor-3 (AM ester, pH> 6), Fluor-4 (AM ester, pH 7.2), Indo-1 (AM ester, low / high calcium (Ca) 2+ )), SNARF (pH 6/9), Allophycocyanin (APC), AmCyan1
(Clontech), AsRed2 (Clontech), Azami Green (monomer, MBL), Azrite, B-Phycoerythrin (BPE), Cerulean, CyPet,
DsRed monomer (Clontech), DsRed2 ("RFP", Clontech), EBFP, EBFP2, ECFP, EGFP (weak dimer, Clontech), emerald (weak dimer, Invitrogen), EYFP (weak dimer, Clontech), GFP (S65A variant), GFP (S65C variant), GFP (S65L variant), GFP (S65T variant), GFP (Y66F variant), GFP (Y66H variant), GFP (Y66W variant) ), GFP uv , HcRed1, J-Red, Katyusha, Kusabira Orange (monomer, MBL)
, MCFP, mCherry, mCitrine, Midrisi Cyan (dimer, MBL), mKate (TagFP635, monomer, Evrogen), mKeima-Red (monomer, MBL), mKO, mOrange, mPlum, mRaspbury
FP1 (monomer, Tsien Lab), mStrawbury, mTFP1, mTurquoise2, P3 (phycobilisome complex), Peridinin Chlorophyll (PerCP), R-phycoerythrin (RPE), T-Sapphire, dimer, Tag. (Dimer, Evrogen), TagRFP (dimer, Evrogen), TagYFP (dimer, Evrogen), tdTomato (tandem dimer), Topaz, TurboFP602 (dimer, Evrogen), TurboFP63
5 (dimer, Evrogen), TurboGFP (dimer, Evrogen), TurboRFP (dimer, Evrogen), TurboYFP635 (dimer, Evrogen), Venus, natural GFP, YPet, Zs green 1 (tetramer) Body, Clontech), Zs Yellow 1 (Tetramer, Clontech).
7) Pharmaceutically acceptable salts, acids, or derivatives of any of the above drugs.
、請求項2及び3に記載の共役体化合物。 The cell binding agent / molecule is a molecule coated with an antibody, a protein, a vitamin (for example, folic acid), a peptide, a polymer micelle, a liposome, a lipoprotein drug carrier, a nanoparticle drug carrier, a dendrimer, and a cell binding ligand. The conjugate compound according to claims 2 and 3, which is selected from or a combination thereof.
4、CD15、CD16、CDw17、CD18、CD19、CD20、CD21、CD22、CD23、CD24、CD25、CD26、CD27、CD28、CD29、CD30、CD31、CD32、CD33、CD34、CD35、CD36、CD37、CD38、CD39、CD40、CD41、CD42、CD43、CD44、CD45、CD46、CD47、CD48、CD49b、CD49c、CD51、CD52、CD53、CD54、CD55、CD56、CD58、CD59、CD61、CD62E、CD62L、CD62P、CD63、CD66、CD68、CD69、CD70、CD72、CD74、CD79、CD79a、CD79b、CD80、CD81、CD82、CD83、CD86、CD87、CD88、CD89、CD90、CD91、CD95、CD96、CD98、CD100、CD103、CD105、CD106、CD109、CD117、CD120、CD125、CD126、CD127、CD133、CD134、CD135、CD138、CD141、CD142、CD143、CD144、CD147、CD151、CD147、CD152、CD154、CD156、CD158、CD163、CD166、CD168、CD174、CD180、CD184、CDw186、CD194、CD195、CD200、CD200a、CD200b、CD209、CD221、CD227、CD235a、CD240、CD262、CD271、CD274、CD276(B7−H3)、CD303、CD304、CD309、CD326、 4−1
BB、5AC、5T4(栄養芽細胞糖タンパク質、TPBG、5T4、Wnt活性化阻害因子1又はWAIF1)、腺癌抗原、AGS−5、AGS−22M6、アクチビン受容体様キナーゼ1、AFP、AKAP−4、ALK、αインテグリン、αvβ6、アミノペプチダーゼN、アミロイドβ、アンドロゲン受容体、アンジオポイエチン2、アンジオポイエチン3、アネキシンA1、炭疽菌トキシン防御抗原、抗トランスフェリン受容体、AOC3(VAP−1)、B7−H3、炭疽菌、BAFF(B−細胞活性化因子)、B−リンパ腫細胞、bcr−abl、ボンベシン、BORIS、C5、C242抗原、CA125(炭水化物抗原125、MUC16)、CA−IX(又はCAIX、炭酸脱水酵素9)、CALLA、CanAg、イヌIL31、炭酸脱水酵素IX、心筋ミオシン、CCL11(C−Cモチーフケモカイン11)、CCR4(CCケモカイン受容体4型、CD194)、CCR5、CD3E(イプシロン)、CEA(癌胎児性抗原)、CEACAM3、CEACAM5(癌胎児性抗原)、CFD(因子D)、Ch4D5、コレシストキニン2(CCK2R)、CLDN18(クラウディン−18)、クランピング因子A、CRIPTO、FCSF1R(コロニー刺激因子1受容体、CD115)、CSF2(コロニー刺激因子2、顆粒球マクロファージコロニー刺激因子(GM−CSF))、CTLA4(細胞
傷害性Tリンパ球関連タンパク質4)、CTAA16.88腫瘍抗原、CXCR4(CD184)、CXCケモカイン受容体4型、cADPリボースヒドロラーゼ、Cyclin
B1、CYP1B1、サイトメガロウイルス、サイトメガロウイルス糖タンパク質B、ダビガトラン、DLL4(デルタ様リガンド4)、DPP4(ジペプチジルペプチダーゼ4)、DR5(デスレセプター5)、大腸菌志賀毒素2型、ED−B、EGFL7(タンパク質7含有EGF様ドメイン)、EGFR、EGFRII、EGFRvIII、エンドグリン(CD105)、エンドセリンB受容体、エンドトキシン、EpCAM(上皮細胞接着分子)、EphA2、エピシアリン、ERBB2(上皮成長因子受容体2)、ERBB3、ERG(TMPRSS2ETS融合遺伝子)、大腸菌、ETV6−AML、FAP(線維芽細胞活性化タンパク質α)、FCGR1、α−フェトプロテイン、フィブリンII、β鎖、フィブロネクチン外部ドメインB、FOLR(葉酸受容体)、葉酸受容体α、葉酸ヒドロラーゼ、Fos関連抗原1、RSウイルスのFタンパク質、Frizzled受容体、フコシルGM1、GD2ガングリオシド、G−28(細胞表面糖脂質抗原)、GD3イディオタイプ、GloboH、グリピカン3、N−グリコリルノイラミン酸、GM3、GMCSF受容体α鎖、成長分化因子8、GP100、GPNMB(膜貫通タンパク質NMB)、GUCY2C(グアニル酸シクラーゼ2C、グアニル酸シクラーゼC(GC−C)、腸グアニル酸シクラーゼ、グアニル酸シクラーゼ−C受容体、熱安定性エンテロトキシン受容体(hSTAR))、熱ショックタンパク質、血球凝集素、B型肝炎表面抗原、B型肝炎ウイルス、HER1(ヒト上皮成長因子受容体1)、HER2、HER2/neu、HER3(ERBB−3)、IgG4、HGF/SF(幹細胞増殖因子/細胞分散因子)、HHGFR、HIV−1、ヒストン複合体、HLA−DA(ヒト白血球抗原)、HLA−DR10、HLA−DRB、HMWMAA、ヒト絨毛性ゴナドトロピン、HNGF、ヒト細胞散乱因子受容体キナーゼ、HPV E6/E7、Hsp90、hTERT、ICAM−1(細胞間接着分子1)、イディオタイプ、IGF1R(IGF−1、インスリン様増殖因子1受容体)、IGHE、IFN−γ、インフルエンザ赤血球凝集素、IgE、IgE Fc領域、IGHE、IL−1、IL−2受容体(インターロイキン2受容体)、IL−4、IL−5、IL−6、IL−6R(インターロイキン6受容体)、IL−9、IL−10、L−12、IL−13、IL−17、IL−17A、IL−20、IL−22、IL−23、IL−31RA、ILGF2(インスリン様増殖因子2)、インテグリン(α4、αIIIbβ3、αvβ3、α4β7、α5β1、α6β4、α7β
7、αIIβ3、α5β5、αvβ5)、インターフェロンγ誘導タンパク質、ITAGA2、ITGB2、KIR2D、LCK、Le、レグマイン、ルイス−Y抗原、LFA−1(リンパ球機能関連抗原1、CD11a)、LHRH、LINGO−1、リポタイコ酸、LIV1A、LMP2、LTA、MAD−CT−1、MAD−CT−2、MAGE−1、MAGE−2、MAGE−3、MAGEA1、MAGEA3、MAGEA4、MART1、MCP−1、MIF(マクロファージ遊走阻止因子又はグリコシル化阻害因子(GIF))、MS4A1(膜貫通4ドメインサブファミリーAメンバー1)、MSLN(メソテリン)、MUC1(ムチン1、細胞表面関連(MUC1)又はPolymorphic
epithelial mucin(PEM))、MUC1−KLH、MUC16(CA125)、MCP1(単球走化性タンパク質1)、MelanA/MART1、ML−IAP、MPG、MS4A1(膜貫通型4ドメインサブファミリーA)、MYCN、ミエリン関連糖タンパク質、ミオスタチン、NA17、NARP−1、NCA−90(顆粒球抗原)、Nectin−4(ASG−22ME)、NGF、神経アポトーシス制御プロテイナーゼ1、NOGO−A、Notch受容体、ヌクレオリン、Neu癌遺伝子産物、NY−BR−1、NY−ESO−1、OX−40、OxLDL(酸化低密度リポタンパク質)、OY−TES1、P21、p53非変異体、P97、Page4、PAP、、抗(N−グリコリルノイラミン酸)のパラトープ、PAX3、PAX5、PCSK9、PDCD1(PD−1、プログラムされた細胞死タンパク質1、CD279)、PDGF−Rα、(血小板由来成長因子受容体α)、PDGFR−β、PDL−1、PLAC1、PLAP様精巣アルカリホスファターゼ、血小板由来成長因子受容体β、リン酸ナトリウム共輸送
体、PMEL17、ポリシアル酸、プロテイナーゼ3(PR1)、前立腺癌、PS(ホスファチジルセリン)、前立腺癌細胞、緑膿菌、PSMA、PSA、PSCA、狂犬病ウイルス糖タンパク質、RHD(Rhポリペプチド1(RhPI)、CD240)、アカゲザル因子(Rhesus factor)、RANKL、PhoC,Ras変異体、RG55、ROBO4、RSウイルス、RON、肉腫転移ブレイクポイント、SART3、スクレロスチン、SLAMF7(SLAMファミリーメンバー7)、セレクチンP、SDC1(シンデカン1)、sLe(a)、ソマトメジンC、SIP(スフィンゴシン−1−ホスフェート)、ソマトスタチン、精子タンパク質17、SSX2、STEAP1(前立腺1の6回膜貫通上皮抗原)、STEAP2、STn、TAG−22(腫瘍関連糖タンパク質72)、サバイビン、T細胞受容体、T細胞膜貫通タンパク質、TEM1(腫瘍上皮マーカー1)、TENB2、テナスシンC(TN−C)、TGF−α、TGF−β(トランスフォーミング増殖因子β)、TGF−β1、TGF−β2(トランスフォーミング増殖因子β2)、Tie(CD202b)、Tie2、TIM−1(CDX−014)、TN、TNF、TNF−α、TNFRSF8、TNFRSF10B(腫瘍壊死因子受容体スーパーファミリーメンバー10B)、TNFRSF13B(腫瘍壊死因子受容体スーパーファミリーメンバー13B)、TPBG(栄養膜糖タンパク質)、TRAIL−R1(腫瘍壊死アポトーシス誘導リガンド受容体1)、TRAILR2(細胞死受容体5(DR5))、主要関連カルシウムシグナルトランスデューサー2、MUC1の腫瘍特異的グリコシル化、TWEAK受容体、TYRP1(糖タンパク質75)、TRP−2、チロシナーゼ、VCAM−1(CD106)、VEGF、VEGF−A、VEGF−2(CD309)、VEGFR−1、VEGFR2、又はビメンチン、WT1、XAGE1、又は任意のインスリン成長因子受容体を発現する細胞、又は任意の上皮増殖因子受容体。 The cell-binding molecule / agent according to claims 2, 3 and 9 may be any agent / molecule capable for any of the following antigens or receptors: CD3, CD4, CD5, CD6, CD7, CD8, CD9, CD10, CD11a, CD11b, CD11c, CD12w, CD1
4, CD15, CD16, CDw17, CD18, CD19, CD20, CD21, CD22, CD23, CD24, CD25, CD26, CD27, CD28, CD29, CD30, CD31, CD32, CD33, CD34, CD35, CD36, CD37, CD38, CD39, CD40, CD41, CD42, CD43, CD44, CD45, CD46, CD47, CD48, CD49b, CD49c, CD51, CD52, CD53, CD54, CD55, CD56, CD58, CD59, CD61, CD62E, CD62L, CD62P, CD63, CD66, CD68, CD69, CD70, CD72, CD74, CD79, CD79a, CD79b, CD80, CD81, CD82, CD83, CD86, CD87, CD88, CD89, CD90, CD91, CD95, CD96, CD98, CD100, CD103, CD105, CD106, CD109, CD117, CD120, CD125, CD126, CD127, CD133, CD134, CD135, CD138, CD141, CD142, CD143, CD144, CD147, CD151, CD147, CD152, CD154, CD156, CD158, CD163, CD166, CD168, CD174, CD180, CD184, CDw186, CD194, CD195, CD200, CD200a, CD200b, CD209, CD221, CD227, CD235a, CD240, CD262, CD271, CD274, CD276 (B7-H3), CD303, CD304, CD309, CD326, 4 -1
BB, 5AC, 5T4 (nutrient blast glycoprotein, TPBG, 5T4, Wnt activation inhibitor 1 or WAIF1), adenocarcinoembryonic antigen, AGS-5, AGS-22M6, actibin receptor-like kinase 1, AFP, AKAP-4 , ALK, α-integrine, αvβ6, aminopeptidase N, amyloid β, androgen receptor, angiopoietin 2, angiopoietin 3, anexin A1, chemokine toxin protective antigen, anti-transferase receptor, AOC3 (VAP-1), B7-H3, chemokines, BAFF (B-cell activator), B-lymphoma cells, bcr-abl, bombesin, BORIS, C5, C242 antigens, CA125 (carbohydrate antigens 125, MUC16), CA-IX (or CAIX) , Carbonide dehydration enzyme 9), CALLA, CanAg, dog IL31, carbon dioxide dehydration enzyme IX, myocardial myosin, CCL11 (CC motif chemokine 11), CCR4 (CC chemokine receptor type 4, CD194), CCR5, CD3E (epsilon) , CEA (Carcinoembryonic Antigen), CEACAM3, CEACAM5 (Carcinoembryonic Antigen), CFD (Factor D), Ch4D5, Chemokine 2 (CCK2R), CLDN18 (Claudin-18), Clamping Factor A, CRIPTO, FCSF1R (colony stimulator 1 receptor, CD115), CSF2 (colony stimulator 2, granulocyte macrophage colony stimulator (GM-CSF)), CTLA4 (cytotoxic T lymphocyte-related protein 4), CTAA 16.88 tumor antigen , CXCR4 (CD184), CXC Chemokine Receptor Type 4, cADP Ribos Hydrolase, Cyclin
B1, CYP1B1, cytomegalovirus, cytomegalovirus glycoprotein B, dabigatlan, PLL4 (delta-like ligand 4), DPP4 (dipeptidyl peptidase 4), DR5 (desceptor 5), Escherichia coli Shiga toxin type 2, ED-B, EGFL7 (protein 7-containing EGF-like domain), EGFR, EGFRII, EGFRvIII, endoglin (CD105), endoserine B receptor, endotoxin, EpCAM (epithelial cell adhesion molecule), EphA2, epicialin, ERBB2 (epithelial growth factor receptor 2) , ERBB3, ERG (TMPRSS2ETS fusion gene), Escherichia coli, ETV6-AML, FAP (fibroblast activation protein α), FCGR1, α-fetoprotein, fibrin II, β chain, fibronectin external domain B, FOLR (folic acid receptor) , Folic acid receptor α, folic acid hydrolase, Fos-related antigen 1, RS virus F protein, Frizzled receptor, fucosyl GM1, GD2 ganglioside, G-28 (cell surface glycolipid antigen), GD3 idiotype, GloboH, gripican 3, N-Glycolylneuramic acid, GM3, GMCSF receptor α chain, growth differentiation factor 8, GP100, GPNMB (transmembrane protein NMB), GUCY2C (guanylate cyclase 2C, guanylate cyclase C (GC-C), intestinal guanyl) Acid cyclase, guanylate cyclase-C receptor, thermostable enterotoxin receptor (hSTAR), heat shock protein, blood cell agglutinin, hepatitis B surface antigen, hepatitis B virus, HER1 (human epithelial growth factor receptor 1) ), HER2, HER2 / neu, HER3 (ERBB-3), IgG4, HGF / SF (stem cell proliferation factor / cell dispersant), HHGFR, HIV-1, histone complex, HLA-DA (human leukocyte antigen), HLA -DR10, HLA-DRB, HMWMAA, human chorionic gonadotropin, HNGF, human cell scattering factor receptor kinase, HPV E6 / E7, Hsp90, hTERT, ICAM-1 (intercellular adhesion molecule 1), idiotype, IGF1R (IGF) -1, insulin-like growth factor 1 receptor), IGHE, IFN-γ, influenza hemagglutinin, IgE, IgE Fc region, IGHE, IL-1, IL-2 receptor (interleukin 2 receptor), IL- 4, IL-5, IL-6, IL-6R (interleukin 6 receptor), IL -9, IL-10, L-12, IL-13, IL-17, IL-17A, IL-20, IL-22, IL-23, IL-31RA, ILGF2 (insulin-like growth factor 2), integrin ( α4, α IIIb β 3, αvβ3 , α 4 β 7, α5β1, α6β4, α7β
7, αIIβ3, α5β5, αvβ5), interferon gamma-inducing protein, ITAGA2, ITGB2, KIR2D, LCK, Le, legmine, Lewis-Y antigen, LFA-1 (lymphocyte function-related antigen 1, CD11a), LHRH, LINGO-1 , Lipoteichoic acid, LIV1A, LMP2, LTA, MAD-CT-1, MAD-CT-2, MAGE-1, MAGE-2, MAGE-3, MAGEA1, MAGEA3, MAGEA4, MART1, MCP-1, MIF (macrophage migration) Inhibitor or Glycosylation Inhibitor (GIF)), MS4A1 (Transmembrane 4 Domain Subfamily A Member 1), MSLN (Mesoterin), MUC1 (Mucin 1, Cell Surface Related (MUC1) or Polymorphic
epithelial mucin (PEM), MUC1-KLH, MUC16 (CA125), MCP1 (transforming growth factor 1), MelanA / MART1, ML-IAP, MPG, MS4A1 (transmembrane 4-domain subfamily A), MYCN , Myerin-related glycoprotein, myostatin, NA17, NARP-1, NCA-90 (granulocyte antigen), Nectin-4 (ASG-22ME), NGF, nerve apoptosis control proteinase 1, NOGO-A, Notch receptor, nucleolin, Neu cancer gene products, NY-BR-1, NY-ESO-1, OX-40, OxLDL (oxidized low density lipoprotein), OY-TES1, P21, p53 non-mutants, P97, Page4, PAP ,, anti ( N-Glycolylneuramic acid) paratope, PAX3, PAX5, PCSK9, PDCD1 (PD-1, programmed cell death protein 1, CD279), PDGF-Rα, (platelet-derived growth factor receptor α), PDGFR- β, PDL-1, PLAC1, PLAP-like testicular alkaline phosphatase, platelet-derived growth factor receptor β, sodium phosphate cotransporter, PMEL17, polysialic acid, proteinase 3 (PR1), prostate cancer, PS (phosphatidylserine), prostate Cancer cells, pyogenic bacteria, PSMA, PSA, PSCA, mad dog disease virus glycoprotein, RHD (Rh polypeptide 1 (RhPI), CD240), red squirrel factor (Rhesus factor), RANKL, PhoC, Ras mutant, RG55, ROBO4, RS virus, RON, sarcoma metastasis breakpoint, SART3, sclerostin, SLAMF7 (SLAM family member 7), selectin P, SDC1 (cindecane 1), sLe (a), somatomedin C, SIP (sphingocin-1-phosphate), somatostatin, Sperm protein 17, SSX2, STEAP1 (six transmembrane epithelial antigen of prostate 1), STEAP2, STn, TAG-22 (tumor-related glycoprotein 72), survivin, T cell receptor, T cell transmembrane protein, TEM1 (tumor epithelium) Markers 1), TENB2, Tenascin C (TN-C), TGF-α, TGF-β (Transforming Growth Factor β), TGF-β1, TGF-β2 (Transforming Growth Factor β2), Tie (CD202b), Tie2 , TIM-1 (CDX-014), TN, T NF, TNF-α, TNFRSF8, TNFRSF10B (tumor necrosis factor receptor superfamily member 10B), TNFRSF13B (tumor necrosis factor receptor superfamily member 13B), TPBG (nutrient membrane glycoprotein), TRAIL-R1 (tumor necrosis factor induction) Ligand receptor 1), TRAILR2 (cell death receptor 5 (DR5)), major related calcium signal transducer 2, tumor-specific glycosylation of MUC1, TWEAK receptor, TYRP1 (glycoprotein 75), TRP-2, tyrosinase , VCAM-1 (CD106), VEGF, VEGF-A, VEGF-2 (CD309), VEGFR-1, VEGFR2, or Vimentin, WT1, XAGE1, or any cell expressing any insulin growth factor receptor, or any Epithelial growth factor receptor.
mAbは抗体であり;
Z3はH、R1、OP(O)(OM1)(OM2)、OCH2OP(O)(OM1)(OM2)、OSO3M1、又はO−配糖体(グルコシド, ガラクトシド、マンノシド、グルクロノシド、アロシド、フルクトシド)、NH−配糖体、S−配糖体若しくはCH2−配糖体であり;
M1及びM2は独立してH、Na、K、Ca、Mg、NH4、NR1R2R3R4であり;
nは1〜20であり;
R1、R2、R3、及びR4は、請求項1で定義されているものと同じである。 "Drug 1 " and "Drug 2 " are Tubulysin analogs, and the conjugate compound of the formula (II) is preferably the following T01, T02, T03, T04, T05, T06, and T07. The conjugate compound according to claim 2, which is a structure:
mAbs are antibodies;
Z 3 is H, R 1 , OP (O) (OM 1 ) (OM 2 ), OCH 2 OP (O) (OM 1 ) (OM 2 ), OSO 3 M 1 , or O-glycoside (glucoside, galactoside, mannoside, Gurukuronoshido, Aroshido, fructosides), NH- glycosides, S- glycoside or CH 2 - be glycoside;
M 1 and M 2 are independently H, Na, K, Ca, Mg, NH 4 , NR 1 R 2 R 3 R 4 ;
n is 1 to 20;
R 1 , R 2 , R 3 , and R 4 are the same as those defined in claim 1.
式中:
mAbは抗体であり;
nは1〜20であり;
R1、R2、R3、及びR4は、請求項1で定義されているものと同じである。 The conjugate according to claim 2, wherein "Drug 1 " and "Drug 2 " are Calicheamicin analogs, and the conjugate compound of the formula (II) is preferably the structure of C01 below. Compound:
During the ceremony:
mAbs are antibodies;
n is 1 to 20;
R 1 , R 2 , R 3 , and R 4 are the same as those defined in claim 1.
式中:
mAbは抗体であり;
nは1〜20であり;
R1、R2、R3、及びR4は、請求項1で定義されているものと同じである。 The conjugate according to claim 2, wherein "Drug 1 " and "Drug 2 " are Maytansinoid analogs, and the conjugate compound of the formula (II) is preferably the structure of M01 below. Compound:
During the ceremony:
mAbs are antibodies;
n is 1 to 20;
R 1 , R 2 , R 3 , and R 4 are the same as those defined in claim 1.
式中:
mAbは抗体であり;
nは1〜20であり;
R1、R2、R3、及びR4は、請求項1で定義されているものと同じである。 The second aspect of the present invention, wherein "Drug 1 " and "Drug 2 " are taxane analogs, and the conjugated compound of the above formula (II) is preferably a structure of Tx01, Tx02, and Tx03 below. Conjugate compounds:
During the ceremony:
mAbs are antibodies;
n is 1 to 20;
R 1 , R 2 , R 3 , and R 4 are the same as those defined in claim 1.
シン類縁体であり、前記式(II)の共役体化合物が好ましくは、以下のCC01、CC02、及びCC03の構造である、請求項2に記載の共役体化合物:
式中:
mAbは抗体であり;
nは1〜20であり;
Z4はH、PO(O)(OM1)(OM2)、SO3M1、CH2PO(O)(OM1)(OM2)、CH3N(CH2CH2)2NC(O)−、O(CH2CH2)2NC(O)−、又は配糖体であり;
X3はO、NH、NR1、NHC(O)、OC(O)、CO、若しくはR1であるか、又は存在しない;
M1及びM2は独立して、Na、K、H、Ca、Mg、NH4、NR1R2R3R4で
あり;
R1、R2、R3、及びR4は、請求項1で定義されているものと同じである。 "Drug 1 " and "Drug 2 " are CC-1065 analogs and / or duocarmycin analogs, and the conjugate compound of formula (II) is preferably in the structure of CC01, CC02, and CC03 below. The conjugate compound according to claim 2:
During the ceremony:
mAbs are antibodies;
n is 1 to 20;
Z 4 is H, PO (O) (OM 1 ) (OM 2 ), SO 3 M 1 , CH 2 PO (O) (OM 1 ) (OM 2 ), CH 3 N (CH 2 CH 2 ) 2 NC ( O)-, O (CH 2 CH 2 ) 2 NC (O)-, or glycoside;
X 3 is O, NH, NR 1 , NHC (O), OC (O), CO, or R 1 or does not exist;
M 1 and M 2 are independently Na, K, H, Ca, Mg, NH 4 , NR 1 R 2 R 3 R 4 ;
R 1 , R 2 , R 3 , and R 4 are the same as those defined in claim 1.
mAbは抗体であり;
nは1〜20であり;
X3はH、O、NH、NR1、NHC(O)、OC(O)、C(O)、R1であるか、又は存在せず;
R1、R2、R3、及びR4は、請求項1で定義されているものと同じである。 According to claim 2, "Drug 1 " and "Drug 2 " are daunorubicin or doxorubicin analogs, and the conjugated compound of the above formula (II) is preferably the structure of Da01, Da02, Da03, and Da04 below. Described conjugate compound:
mAbs are antibodies;
n is 1 to 20;
X 3 is H, O, NH, NR 1 , NHC (O), OC (O), C (O), R 1 or does not exist;
R 1 , R 2 , R 3 , and R 4 are the same as those defined in claim 1.
式中:
mAbは抗体であり;
nは1〜20であり;
X3はCH2、O、NH、NR1、NHC(O)、NHC(O)NH、C(O)、OC(O)であるか、又は存在せず;
X4はCH2、C(O)、C(O)NH、C(O)N(R1)、R1、又はC(O)O
であり;
R1、R2、R3、及びR4は、請求項1で定義されているものと同じである。 "Drug 1 " and "Drug 2 " are analogs of auristatin and dolastatin, and the conjugate compound of the above formula (II) is preferably in the structure of Au01, Au02, Au03, Au04, and Au05 below. The conjugate compound according to claim 2:
During the ceremony:
mAbs are antibodies;
n is 1 to 20;
X 3 is CH 2 , O, NH, NR 1 , NHC (O), NHC (O) NH, C (O), OC (O), or does not exist;
X 4 is CH 2 , C (O), C (O) NH, C (O) N (R 1 ), R 1 , or C (O) O
Is;
R 1 , R 2 , R 3 , and R 4 are the same as those defined in claim 1.
mAbは抗体であり;
nは1〜20であり;
X3はCH2、O、NH、NR1、NHC(O)、NHC(O)NH、C(O)、OC(O)であるか、又は存在せず;
X4はCH2、C(O)、C(O)NH、C(O)N(R1)、C(O)Oであるか、又は存在せず;
R1、R2、R3、及びR4は、請求項1で定義されているものと同じであり、加えて、R3及び/又はR4は存在しなくてもよい。 "Drug 1 " and "Drug 2 " are benzodiazepine dimer analogs, and the conjugated compound of the above formula (II) is preferably the following PB01, PB02, PB03, PB04, PB05, PB06, PB07, PB08, And the conjugated compound according to claim 2, which has the structure of PB09:
mAbs are antibodies;
n is 1 to 20;
X 3 is CH 2 , O, NH, NR 1 , NHC (O), NHC (O) NH, C (O), OC (O), or does not exist;
X 4 is CH 2 , C (O), C (O) NH, C (O) N (R 1 ), C (O) O, or does not exist;
R 1, R 2, R 3, and R 4 are the same as those defined in claim 1, in addition, R 3 and / or R 4 may be absent.
ノフェン/ヒドロコドン、アダリムマブ、アファチニブ ジマレエート(Gilotrif(登録商標))、アレムツズマブ(Campath(登録商標))、アリトレチオニン(Panretin(登
録商標))、アド−トラスツズマブエム(Kadcyla(商標))、アンフェタミン混合塩(
アンフェタミン/デキストロアンフェタミン、又はadderall XR)、アナストロゾール(Arimidex(登録商標))、アリピプラゾール、アタザナビル、アテゾリズマブ(MPDL3280A)、アトルバスタチン、アキシチニブ(Inlyta(登録商標))、ベリノスタット(Beleodaq(商標))、ベバシズマブ (Avastin(登録商標))、カバジタキセル(Jevtana(登
録商標))、カボザチニブ(Cometriq(商標))、ベキサロテン(Targretin(登録商標
))、ブリナツモマブ(Blincyto(商標))、ボルテゾミブ (Velcade(登録商標))、ボスチニブ(Bosulif(登録商標))、ブレンツキマブ ベドチン(Adcetris(登録商標
))、ブデソニド、ブデソニド/ホルモテロール、ブプレノルフィン、カペシタビン、カ
ルフィルゾミブ(Kyprolis(登録商標))、セレコキシブ、セリチニブ(LDK378/Zykadia)、セツキシマブ(Erbitux(登録商標))、シクロスポリン、シナカルセット、クリゾ
チニブ (Xalkori(登録商標))、ダビガトラン、ダブラフェニブ(Tafinlar(登録商標))、ダルベポエチンα、ダルナビル、メシル酸イマチニブ(Gleevec(登録商標))、
ダサチニブ (Sprycel(登録商標))、デニロイキン ジフチトクス(Ontak(登録商標
))、デノスマブ(Xgeva(登録商標))、デパコテ(Depakote)、デキスランソプラゾ
ール、デキスメチルフェニデート、ジヌツキシマブ(Unituxin(商標))、ドキシサイクリン、デュロキセチン、エムトリシタビン/リルピビリン/フマル酸テノホビルジソプロキシル、エムトリシタビン/テノホビル/エファビレンツ、エノキサパリン、エンザルタミド(Xtandi(登録商標))、エポエチンα、エルロチニブ(Tarceva(登録商標))、
エソメプラゾール、エスゾピクロン、エタネルセプト、エベロリムス(Afinitor(登録商標))、エキセメスタン(Aromasin(登録商標))、エベロリムス(Afinitor(登録商標))、エゼチミブ、エゼチミブ/シンバスタチン、フェノフィブラート、フィルグラスチム、フィンゴリモド、プロピオン酸フルチカゾン、フルチカゾン/サルメテロール、フルベストラント(Faslodex(登録商標))、ゲフィチニブ(Iressa(登録商標))、グラチラマー、酢酸ゴセレリン(Zoladex)、イマチニブ (Gleevec)、イブリツモマブチウキ
セタン(Zevalin(登録商標))、イブルチニブ(Imbruvica(商標))、イデラリシブ(Zydelig(登録商標))、インフリキシマブ、インスリン アスパルト、インスリンデテ
ミル、インスリングラルギン、インスリンリスプロ、インターフェロンβ1a、インターフェロンβ1b、ラパチニブ(Tykerb(登録商標))、イピリムマブ (Yervoy(登録商
標))、臭化イプラトロピウム/サルブタモール、酢酸ランレオチド(Somatuline(登録商標)デポ)、レナリオミド(Revlimid (登録商標))、メシル酸レンバチニブ(Lenvima(商標))、レトロゾール(Femara(登録商標))、レボチロキシン、レボチロキシン、リドカイン、リネゾリド、リラグルチド、リスデキサムフェタミン、MEDI4736(AstraZeneca, Celgene)、メマンチン、メチルフェニデート、メトプロロール、モダフィニル、モメタゾン、ニロチニブ(Tasigna(登録商標))、ニボルマブ(Opdivo(登録
商標))、オファツムマブ(Arzerra(登録商標))、オビヌツズマブ(Gazyva(商標)
)、オラパリブ(Lynparza(商標))、オルメサルタン、オルメサルタン/ヒドロクロロチアジド、オマリズマブ、ω3脂肪酸エチルエステル、オセルタミビル、オキシコドン、パルボシクリブ(Ibrance(登録商標))、パリビズマブ、パニツムマブ(Vectibix(登
録商標))、パノビノスタット(Farydak(登録商標))、パゾパニブ(Votrient(登録
商標))、ペムブロリズマブ(Keytruda(登録商標))、ペメトレキセド(Alimta)、ペルツズマブ(Perjeta(商標))、肺炎球菌共役ワクチン、ポマリドミド(Pomalyst(登
録商標))、プレガバリン、クエチアピン、ラベプラゾール、ラジウム223塩化物(Xofigo (登録商標))、ラロキシフェン、ラルテグラビル、ラムシルマブ(Cyramza(登録商標))、ラニビズマブ、レゴラフェニブ(Stivarga(登録商標))、リツキシマブ(Rituxan(登録商標))、リバロキサバン、ロミデプシン(Istodax(登録商標))、ロスバスタチン、ルキソリチニブ(Jakafi(商標))、サルブタモール、セベラマー、シルデナフィル、シルツキシマブ(Sylvant(商標))、シタグリプチン、シタグリプチン/メト
ホルミン、ソリフェナシン、ソラフェニブ(Nexavar(登録商標))、スニチニブ(Sutent(登録商標))、タダラフィル、タモキシフェン、テラプレビル、テムシロリムス(Torisel(登録商標))、テノホビル/エムトリシタビン、テストステロンゲル、サリドマイド(Immunoprin、Talidex)、チオトロピウムブロマイド、トレミフェン(Fareston(登
録商標))、trametinib(Mekinist(登録商標))、トラスツズマブ、トレチノイン(ベサノイド(登録商標))、ウステキヌマブ、バルサルタン、バンデタニブ(Caprelsa(登録商標))、ベムラフェニブ(Zelboraf(登録商標))、ボリノスタット(Zolinza(登
録商標))、ジバフリベルセプト(Zaltrap(登録商標))、及びゾスタバックス、並び
にこれらの類縁体、誘導体、薬学的に許容される塩、これらのための担体、希釈剤若しくは賦形剤、又はこれらの組み合わせ。 The synergistic agent according to claim 28 is preferably selected from one or several of the following agents: abatacept (Orencia), abiraterone acetate (Zytiga®), acetaminophen / hydrocodon, adalimumab, Afatinib Zimareate (Gilotrif®), Alemtuzumab (Campath®), Alitrethionin (Panretin®), Ad-Trastuzumab Em (Kadcyla®), Amphetamine mixed salt (
Amphetamine / dextroamphetamine, or adderall XR), anastrozole (Arimidex®), alipiprazole, atazanavir, atezolizumab (MPDL3280A), atrubastatin, axitinib (Inlyta®), beleodaq (trademark), Bevacizumab (Avastin®), Kabazitaxel (Jevtana®), Cabozatinib (Cometriq®), Bexaloten (Targretin®), Blincyto (Blincyto), Bortezomib (Velcade®) ), Bosulif (registered trademark), Brentuximab bevacizumab (Adcetris (registered trademark)), budesonib, budesonib / formoterol, buprenorfin, capecitabin, calfilzomib (Kyprolis (registered trademark)), cetuximab, cetuximab (LDK378) (Erbitux®), Cyclosporin, Cinacalset, Cetuximab (Xalkori®), Davigatran, Dabrafenib (Tafinlar®), Dalbepoetin α, Darnavir, Imatinib Mecilate (Gleevec®),
Dasatinib (Sprycel®), Deniroykin giftitox (Ontak®), Denosumab (Xgeva®), Depakote, Dexransoprazole, Dexmethylphenidet, Unituxin®, Doxycycline , Duroxetine, Emtricitabin / Lilpivirin / Tenofovir disoproxil fumarate, Emtricitabin / Tenofovir / Efabilentz, Enozapalin, Enzalutamide (Xtandi®), Epoetin α, Erlotinib (Tarceva®),
Esomeprazole, eszopiclone, etanercept, everolimus (Afinitor®), exemethan (Aromasin®), everolimus (Afinitor®), ezetimib, ezetimib / simbatatin, phenofibrate, filgrastim, fingolimod , Propionate fluticazone, fluticazone / salmeterol, fluvestrant (Faslodex®), gefitinib (Iressa®), gratilamar, gocerelacetate (Zoladex), imatinib (Gleevec), ibritsumomabuchiuxetane (Zevalin) (Registered Trademarks)), Imbruvica (Trademark), Idelarisib (Zydelig®), Infliximab, Insulin Aspart, Insulin Detemil, Insulin Glarugin, Insulin Lispro, Interferon β1a, Interferon β1b, Lapatinib (Tykerb®) , Ipilimumab (Yervoy®), Ipratropium bromide / salbutamol, lanleotide acetate (Somatuline® depot), renariomid (Revlimid®), lembatinib mesylate (Lenvima®), Retrosol (Femara) (Registered Trademarks)), levothyroxine, levothyroxine, lidocaine, linezolide, liraglutide, lisdexamufetamine, MEDI4736 (AstraZeneca, Celgene), memantin, methylphenidate, metoprol, modafinyl, mometazone, nirotinib (registered trademark) ), Nivolumab (Opdivo®), Ofatumumab (Arzerra®), Obinutzumab (Gazyva®)
), Olaparib (Lynparza ™), olmesartan, olmesartan / hydrochlorothiazide, omalizumab, ω3 fatty acid ethyl ester, oseltamivir, oxycodon, parvocyclib (Ibrance®), paribismab, panitumumab (Vectibix®), panobix (registered trademark) (Registered Trademarks)), Pazopanib (Votrient®), Pembrolizumab (Keytruda®), Pemetrexed (Alimta), Pertuzumab (Perjeta®), Pneumococcal conjugated vaccine, Pomalyst®) , Pregavalin, Quetiapine, Labeprazole, Radium 223 Chloride (Xofigo®), Laroxyphene, Larteglavir, Ramsilumab (Cyramza®), Ranibizumab, Legorafenib (Stivarga®), Rituxan® ), Rivaroxaban, Romidepsin (Istodax®), Rosvasstatin, Luxolitinib (Jakafi®), Salbutamoll, Severamar, Sylvant®, Citagliptin, Citagliptin / Metoformin, Sorafenib (Solifenib) (Trademarks)), Snitinib (Sutent®), Tadalafil, Tamoxyphene, Terraprevir, Temcilolimus (Torisel®), Tenohovir / Emtricitabin, Testosterongel, Salidamide (Immunoprin, Talidex), Thiotropium bromide, Tremifen (Fare) Trademarks)), trametinib (Mekinist®), trastuzumab, tretinoin (vesanoid®), ustequinumab, balsartan, bandetanib (Caprelsa®), bemurafenib (Zelboraf®), bolinozat (Zolinza (registered trademark)) Registered Trademarks)), Zaltrap®, and Zostavax, and their analogs, derivatives, pharmaceutically acceptable salts, carriers, diluents or excipients for them, or A combination of these.
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US11767294B2 (en) | 2012-07-12 | 2023-09-26 | Hangzhou Dac Biotech Co., Ltd. | Conjugates of cell binding molecules with cytotoxic agents |
US11834406B2 (en) | 2012-07-12 | 2023-12-05 | Hangzhou Dac Biotech Co., Ltd. | Conjugates of cell binding molecules with cytotoxic agents |
US11873281B2 (en) | 2012-07-12 | 2024-01-16 | Hangzhou Dac Biotech Co., Ltd. | Conjugates of cell binding molecules with cytotoxic agents |
EP3862023A1 (en) * | 2020-02-05 | 2021-08-11 | Hangzhou DAC Biotech Co, Ltd | Conjugates of cell-binding molecules with cytotoxic agents |
CN114106088A (en) * | 2021-04-28 | 2022-03-01 | 联宁(苏州)生物制药有限公司 | Bromomethylpyrazine-based drug conjugates and ADCs |
CN114796204A (en) * | 2022-05-07 | 2022-07-29 | 中国人民解放军海军军医大学 | Application of ansamycin triene compound in antiviral infection medicine and preparation method |
CN117323413A (en) * | 2023-09-07 | 2024-01-02 | 中山大学附属第一医院 | Application of liraglutide in treating diabetes-related eye diseases |
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