JP6723509B2 - 環状ベンジリデンアセタールリンカーを有する抗体―薬物複合体 - Google Patents
環状ベンジリデンアセタールリンカーを有する抗体―薬物複合体 Download PDFInfo
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- JP6723509B2 JP6723509B2 JP2015207621A JP2015207621A JP6723509B2 JP 6723509 B2 JP6723509 B2 JP 6723509B2 JP 2015207621 A JP2015207621 A JP 2015207621A JP 2015207621 A JP2015207621 A JP 2015207621A JP 6723509 B2 JP6723509 B2 JP 6723509B2
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Description
[1] 式(1)または式(2)で示される、環状ベンジリデンアセタールリンカーを有する抗体―薬物複合体。
Dは薬物であり;
R1およびR6はそれぞれ独立して水素原子または炭化水素基であり;
R2、R3、R4およびR5はそれぞれ独立して電子吸引性もしくは電子供与性の置換基、または水素原子であり;
s=1または2、t=0または1、かつs+t=1または2であり;
wは1〜20の整数であり;および
Z1およびZ2はそれぞれ独立して選択された2価のスペーサーである。)
−0.30≦Σσ≦1.05である、[1]の抗体―薬物複合体。
−1.71≦Σσ≦0.88である、[1]の抗体―薬物複合体。
R1およびR6はそれぞれ独立して水素原子または炭化水素基であり;
R2、R3、R4およびR5はそれぞれ独立して電子吸引性もしくは電子供与性の置換基、または水素原子であり;
X1は共有結合による薬物の連結が可能な反応性官能基であり;
s=1または2、t=0または1、かつs+t=1または2であり;
wは1〜20の整数であり;および
Z1、Z2、Z3およびZ4はそれぞれ独立して選択された2価のスペーサーである。)
R8およびR11はそれぞれ独立して水素原子または炭素数1〜5の炭化水素基であり;
R9は、ハロゲン原子を含んでいてもよい炭素数1〜10の炭化水素基であり;および
R10は塩素原子、臭素原子およびヨウ素原子からなる群より選択されるハロゲン原子である。)
R1およびR6はそれぞれ独立して水素原子または炭化水素基であり;
R2、R3、R4およびR5はそれぞれ独立して電子吸引性もしくは電子供与性の置換基、または水素原子であり;
X2は共有結合による抗体の連結が可能な反応性官能基であり;
s=1または2、t=0または1、かつs+t=1または2であり;および
Z1、Z2、Z3およびZ4はそれぞれ独立して選択された2価のスペーサーである。)
(式中、R7は水素原子またはスルホ基であり;
R8およびR11はそれぞれ独立して水素原子または炭素数1〜5の炭化水素基であり;
R9は、ハロゲン原子を含んでいてもよい炭素数1〜10の炭化水素基であり;および
R10は塩素原子、臭素原子およびヨウ素原子からなる群より選択されるハロゲン原子である。)
本明細書で使用する用語「アセタール」とは、アルデヒド類から誘導されるアセタール構造およびケトン類から誘導されるアセタール構造、即ちケタール構造の両方を意味する。
log(k/k0)=ρσ (7)
(式中、kはパラ置換およびメタ置換ベンゼン誘導体の任意の反応における速度定数または平衡定数であり、k0は上記ベンゼン誘導体が上記置換基を有さない場合、即ち置換基が水素原子である場合の速度定数または平衡定数であり、ρは反応定数であり、σは置換基定数である。)
log(k/k0)=ρ*σ*+Es (8)
(式中、kはパラ置換およびメタ置換ベンゼン誘導体の任意の反応における速度定数または平衡定数であり、k0は上記ベンゼン誘導体が上記置換基を有さない場合、即ち置換基が水素原子である場合の速度定数または平衡定数であり、ρ*は反応定数であり、σ*は置換基定数であり、Esは置換基の位置定数である。)
1991, 91, 165-195」に記載されており、置換基定数(σ)が未知の置換基については「Hammett, L. P. Chem. Rev. 1935, 17(1),
125-136」に記載の方法で測定し求めることができる。また、位置定数(Es)は「Unger, S. H.; Hansch, C. Prog. Phys. Org. Chem. 1976,
12, 91-118」に記載されている。ただし、本明細書で使用するEsは、水素原子を「0」と定義したものである。
log(k/k0)=−2.7×(0.34−0.24)=−0.27 (9)
log(k’/k)=log{(12/24)k/k}=−0.30
式を変形して
log(k’/k)=log[(k’/k0)/(k/k0)]=−0.30
log(k’/k0)−log(k/k0)=−0.30
上記式(9)を代入すると
log(k’/k0)−(−0.27)=−0.30
log(k’/k0)=−0.57 (10)
ここで、上記式(10)および式(7)を用いて置換基定数の合計(Σσ)を算出すると、下記式(11)が得られる。
log(k’/k0)=−2.7×Σσ=−0.57
Σσ=0.21 (11)
log(k”/k)=log(12k/k)=1.08
式を変形して
log(k”/k)=log[(k”/k0)/(k/k0)]=1.08
log(k”/k0)−log(k/k0)=1.08
上記式(9)を代入すると
log(k”/k0)−(−0.27)=1.08
log(k”/k0)=0.81 (12)
ここで、上記式(12)および式(7)を用いて置換基定数の合計(Σσ)を算出すると、下記式(13)が得られる。
log(k”/k0)=−2.7×Σσ=0.81
Σσ=−0.30 (13)
す限り、網羅する(Miller, K. et al. J. Immunol. 2003, 170, 4854-4861)。抗体は、マウス抗体、ヒト抗体、ヒト化抗体、キメラ抗体、または他の種由来であり得る。抗体は、特定の抗原を認識および結合することが可能な、免疫系によって生成されるタンパク質である(Janeway, C.; Travers, P.; Walport, M.; Shlomchik,
M. Immunobiology, 5th ed.; Garland Publishing: New York, 2001)。標的抗原は、一般的には、複数の抗体上にあるCDRによって認識される多数の結合部位(エピトープとも呼ばれる)を有する。異なるエピトープ特異的に結合する抗体は、異なる構造を有する。従って、ある1つの抗原は、1つよりも多くの対応する抗体を有し得る。抗体は、全長免疫グロブリン分子、または全長免疫グロブリン分子の免疫学的に活性な部分(すなわち、対象とする抗原もしくはその部分に免疫特異的に結合する抗原結合部位を含む分子)を包含する。そのような標的としては、ガン細胞、または自己免疫疾患に関連する自己免疫抗体を生成する細胞が挙げられるが、これらに限定はされない。本明細書において開示される免疫グロブリンは、任意の型(例えば、IgG、IgE、IgM、IgD、およびIgA)、クラス(例えば、IgG1、IgG2、IgG3、IgG4、IgA1、及びIgA2)またはサブクラスの免疫グロブリン分子であり得る。上記免疫グロブリンは、任意の種に由来し得る。しかし、一態様において、上記免疫グロブリンは、ヒト起源、マウス起源、またはウサギ起源である。
Alan R. Liss: New York, 1985, pp. 77-96)を含むがそれらに限定されない。そのような抗体は、IgG、IgM、IgE、IgA及びIgDを含む任意の免疫グロブリンの種類およびそれらの任意の亜種であってよい。本発明においてモノクローナル抗体を産生するハイブリドーマは、インビトロまたはインビボで培養してよい。
72-79、Olsson, L. et al. Meth. Enzymol. 1982, 92,
3-16、および米国特許第5939598号明細書および第5770429号明細書を参照)によって作成してよい。キメラモノクローナル抗体およびヒト化モノクローナル抗体などの組み換え抗体は、当分野で既知の標準的な組み換えDNA技法を用いて作ることができる(例えば、米国特許第4816567号明細書、第4816397号明細書を参照)。
1988, 85, 5879-5883及びWard,
E. S. et al. Nature 1989, 334, 544-554に記載されている)、scFv、sc-Fv-Fc、FvdsFv、ミニボディー、ダイアボディー、トライアボディー、テトラボディー、およびCDRを含み、抗体と同じ特異性を有する任意の他の分子、例えばドメイン抗体などが挙げられるが、それらに限定されない抗体のフラグメントを含む。
212-215)、BR64(Trail, P. A. et al. Cancer Research
1997, 57, 100-105)、S2C6 mAb(Francisco, J. A. et al. Cancer Res. 2000, 60, 3225-3231)などのCD40抗原に対するmAb、または米国特許出願公開第2003/0211100号明細書および第2002/0142358号明細書に開示されているようなその他の抗CD40抗体、1F6 mAbおよび2F2 mAbなどのCD70抗原に対するmAb、およびAC10(Bowen, M. A. et al. J. Immunol. 1993, 151, 5896-5906、Wahl, A. F. et al. Cancer Res. 2002, 62(13),
3736-42)またはMDX-0060(米国特許出願公開第2004/0006215号明細書)などのCD30抗原に対するmAbを含むがそれらに限定されない。
本発明の一態様では、式(1)または式(2)で示される抗体―薬物複合体は、環状ベンジリデンアセタールリンカーが結合した抗体と薬物を連結させることで合成できる。当該環状ベンジリデンアセタールリンカーが結合した抗体は、式(3)または式(4)で示される化合物である。
2nd ed.; Academic Press: San Diego, CA, 2008」、「Harris, J. M. Poly(Ethylene Glycol)
Chemistry; Plenum Press: New York, 1992」および「PEGylated Protein Drugs: Basic Science and Clinical
Applications; Veronese, F. M., Ed.; Birkhauser: Basel, Switzerland, 2009」などに記載されている反応性官能基が挙げられる。
群(I):反応相手のアミノ基と反応して共有結合を形成することが可能な官能基
下記の(a)、(b)、(c)、(d)、(e)および(f)
群(II):反応相手のチオール基と反応して共有結合を形成することが可能な官能基
下記の(a)、(b)、(c)、(d)、(e)、(f)、(g)、(h)、(i)および(j)
群(III):反応相手のアルデヒド基またはカルボキシ基と反応して共有結合を形成することが可能な官能基
下記の(g)、(k)、(l)および(m)
群(IV):反応相手のアルキニル基と反応して共有結合を形成することが可能な官能基
下記の(g)、(k)、(l)、(m)および(n)
群(V):反応相手のアジド基と反応して共有結合を形成することが可能な官能基
下記の(j)、(p)および(q)
群(VI):反応相手のハロゲン化アルキル基、アルキルスルホン酸エステルまたはアリールスルホン酸エステルと反応して共有結合を形成することが可能な官能基
下記の(o)、(g)および(k)
2nd ed.; Academic Press: San Diego, CA, 2008」に記載されている。クロスリンカーの反応性官能基の好ましい例としては、当該反応性官能基と薬物、および当該反応性官能基とX1との反応によって生じる結合が、式(1)または式(2)のZ1またはZ2に含まれるエーテル結合、エステル結合、カーボネート結合、ウレタン結合、アミド結合、チオエーテル結合、ジスルフィド結合、1H-1,2,3-トリアゾール-1,4-ジイル基、2級アミノ基もしくはこれらを含む脂肪族炭化水素基、単結合または脂肪族炭化水素基であり、具体的にはハロゲン原子、活性エステル、活性カーボネート、アルデヒド基、アミノ基、ヒドロキシ基、カルボキシ基、チオール基、マレイミド基、アルキニル基およびアジド基などが挙げられる。
本発明の別の一態様では、式(1)または式(2)で示される抗体―薬物複合体は、環状ベンジリデンアセタールリンカーが結合した薬物と抗体を連結させることで合成できる。当該環状ベンジリデンアセタールリンカーが結合した薬物は、式(5)または式(6)で示される化合物である。
2nd ed.; Academic Press: San Diego, CA, 2008」、「Harris, J. M. Poly(Ethylene Glycol) Chemistry;
Plenum Press: New York, 1992」および「PEGylated Protein Drugs: Basic Science and Clinical
Applications; Veronese, F. M., Ed.; Birkhauser: Basel, Switzerland, 2009」などに記載されている反応性官能基が挙げられる。
群(I):反応相手のアミノ基と反応して共有結合を形成することが可能な官能基
下記の(a)、(b)、(c)、(d)、(e)および(f)
群(II):反応相手のチオール基と反応して共有結合を形成することが可能な官能基
下記の(a)、(b)、(c)、(d)、(e)、(f)、(g)、(h)、(i)および(j)
群(III):反応相手のアルデヒド基またはカルボキシ基と反応して共有結合を形成することが可能な官能基
下記の(g)、(k)、(l)および(m)
群(IV):反応相手のアルキニル基と反応して共有結合を形成することが可能な官能基
下記の(g)、(k)、(l)、(m)および(n)
群(V):反応相手のアジド基と反応して共有結合を形成することが可能な官能基
下記の(j)、(p)および(q)
群(VI):反応相手のハロゲン化アルキル基、アルキルスルホン酸エステルまたはアリールスルホン酸エステルと反応して共有結合を形成することが可能な官能基
下記の(o)、(g)および(k)
2nd ed.; Academic Press: San Diego, CA, 2008」に記載されている。クロスリンカーの反応性官能基の好ましい例としては、当該反応性官能基と抗体、および当該反応性官能基とX2との反応によって生じる結合が、式(1)または式(2)のZ1またはZ2に含まれるエーテル結合、エステル結合、カーボネート結合、ウレタン結合、アミド結合、チオエーテル結合、ジスルフィド結合、1H-1,2,3-トリアゾール-1,4-ジイル基、2級アミノ基もしくはこれらを含む脂肪族炭化水素基、単結合または脂肪族炭化水素基であり、具体的にはハロゲン原子、活性エステル、活性カーボネート、アルデヒド基、アミノ基、ヒドロキシ基、カルボキシ基、チオール基、マレイミド基、アルキニル基およびアジド基などが挙げられる。
群(I):反応相手のアミノ基と反応して共有結合を形成することが可能な官能基
下記の(a)、(b)、(c)、(d)、(e)および(f)
群(II):反応相手のチオール基と反応して共有結合を形成することが可能な官能基
下記の(a)、(b)、(c)、(d)、(e)、(f)、(g)、(h)、(i)および(j)
群(III):反応相手のアルデヒド基またはカルボキシ基と反応して共有結合を形成することが可能な官能基
下記の(g)、(k)、(l)および(m)
群(IV):反応相手のアルキニル基と反応して共有結合を形成することが可能な官能基
下記の(g)、(k)、(l)、(m)および(n)
群(V):反応相手のアジド基と反応して共有結合を形成することが可能な官能基
下記の(j)、(p)および(q)
群(VI):反応相手のハロゲン化アルキル基、アルキルスルホン酸エステルまたはアリールスルホン酸エステルと反応して共有結合を形成することが可能な官能基
下記の(o)、(g)および(k)
Groups in Organic Synthesis, 4th ed.; Wiley-Interscience: New York, 2007」に記載されている。また、保護基で保護された官能基は、それぞれの保護基に適した反応条件を用いて脱保護、すなわち化学反応させることで、元の官能基を再生させることができる。したがって、本明細書では、保護基で保護されており、各種反応によって脱保護が可能な官能基は「化学反応可能な官能基」に含む。保護基の代表的な脱保護条件は前述の文献に記載されている。
温度計、窒素吹き込み管、攪拌機、Dean-stark管および冷却管を装備した200 mLの三つ口フラスコに1,2,6-ヘキサントリオール(30.0 g, 0.224 mol)、アセトンジメチルアセタール(25.6 g, 0.246 mol)およびp-トルエンスルホン酸一水和物(0.426 g, 2.24 mmol)を仕込み、80℃にてメタノールの留去を行いながら、3時間反応を行った。トリエチルアミン(0.453 g, 4.48 mmol)を加えてしばらく攪拌し、酢酸エチルで希釈後、20wt%食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、濾過後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーにて精製し、式(23)の化合物を得た。
1H-NMR(CDCl3, 内部標準TMS); δ(ppm):
1.35(3H, s, -CH 3 ),
1.41(3H, s, -CH 3 ), 1.49-1.67(6H, m, >CHCH 2 CH 2 CH 2 -),
2.07(1H, brs, -OH), 3.51(1H, t, -OCH 2CH<), 3.64(2H,
t, -CH 2 OH), 4.04(1H, dd, -OCH 2CH<),
4.07-4.10(1H, m, -OCH2CH<)
温度計、窒素吹き込み管、攪拌機および冷却管を装備した500 mLの四つ口フラスコに式(23)の化合物(20.0 g, 0.115 mol)、トリエチルアミン(23.3 g, 0.230 mol)およびトルエン(200 g)を仕込み、10℃以下に冷却した。冷却を続けながら、滴下漏斗に準備した塩化メタンスルホニル(19.8 g, 0.173 mol)を徐々に滴下した。滴下終了後、20℃で2時間反応を行った。エタノール(7.97 g, 0.173 mol)を加えてしばらく攪拌し、濾過後、有機層をイオン交換水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、濾過後、溶媒を減圧留去して式(24)の化合物を得た。
1H-NMR(CDCl3, 内部標準TMS); δ(ppm):
1.35(3H, s, -CH 3 ),
1.40(3H, s, -CH 3 ), 1.44-1.83(6H, m, >CHCH 2 CH 2 CH 2 -),
3.01(3H, s, -OSO2CH 3 ), 3.51(1H, t, -OCH 2CH<),
4.03-4.11(2H, m, -OCH 2CH<, -OCH2CH<),
4.24(2H, t, -CH 2OSO2CH3)
温度計、窒素吹き込み管、攪拌機および冷却管を装備した500 mLの四つ口フラスコに式(24)の化合物(20.0 g, 79.3 mmol)、フタルイミドカリウム(17.6 g, 95.2 mmol)および脱水ジメチルホルムアミド(200 g)を仕込み、60℃で2時間反応を行った。10℃以下に冷却し、イオン交換水(400 g)を加えてしばらく攪拌した後、酢酸エチル/ヘキサン(60/40, v/v)混合溶液で抽出した。有機層を0.2wt%炭酸カリウム水溶液で洗浄した後、無水硫酸ナトリウムで乾燥した。濾過後、溶媒を減圧留去して式(25)の化合物を得た。
1H-NMR(CDCl3, 内部標準TMS); δ(ppm):
1.34(3H, s, -CH 3 ),
1.39(3H, s, -CH 3 ), 1.44-1.75(6H, m, >CHCH 2 CH 2 CH 2 -),
3.50(1H, t, -OCH 2CH<), 3.69(2H, t, -CH 2 -phthalimide),
4.01-4.09(2H, m, -OCH 2CH<, -OCH2CH<),
7.71-7.85(4H, m, -phthalimide)
温度計、窒素吹き込み管、攪拌機および冷却管を装備した1 Lの四つ口フラスコに式(25)の化合物(15.2 g, 50.0 mmol)、p-トルエンスルホン酸一水和物(951 mg, 5.00 mmol)およびメタノール(500 mL)を仕込み、室温で4時間反応を行った。トリエチルアミン(1.01 g, 10.0 mmol)を加えてしばらく攪拌した後、溶媒を減圧留去した。残渣をクロロホルムに溶解し、イオン交換水で洗浄した後、有機層を無水硫酸ナトリウムで乾燥した。濾過後、溶媒を減圧留去して式(26)の化合物を得た。
1H-NMR(CD3CN, 内部標準TMS); δ(ppm):
1.24-1.61(6H, m,
>CHCH 2 CH 2 CH 2 -), 2.69(1H,
t, -OH), 2.75(1H, d, -OH), 3.17-3.21(1H, m, -OCH 2CH<),
3.31-3.37(1H, m, -OCH 2CH<), 3.39-3.43(1H, m, -OCH2CH<),
3.54(2H, t, -CH 2 -phthalimide), 7.67-7.75(4H, m, -phthalimide)
温度計、窒素吹き込み管、攪拌機、Dean-stark管および冷却管を装備した300 mLの三つ口フラスコに式(26)の化合物(3.87 g, 14.7 mmol)、4-ヒドロキシベンズアルデヒド(1.20 g, 9.83 mmol)、p-トルエンスルホン酸ピリジニウム(247 mg, 0.983 mmol)およびトルエン(180 g)を仕込み、副生する水をトルエンで共沸除去しながら4時間反応を行った。トリエチルアミン(199 mg, 1.97 mmol)を加えてしばらく攪拌した後、溶媒を減圧留去した。残渣をクロロホルムに溶解し、20wt%食塩水、イオン交換水の順で洗浄した後、有機層を無水硫酸ナトリウムで乾燥した。濾過後、溶媒を減圧留去して式(27)の化合物を得た。
1H-NMR(CDCl3, 内部標準TMS); δ(ppm):
1.41-1.80(6H,
m, >CHCH 2 CH 2 CH 2 -),
3.57-4.26(5H, m, -OCH 2 CH<, -CH 2 -phthalimide),
5.71(0.6H, s, >CH-), 5.82(0.4H, s, >CH-), 6.79-6.82(2H, m, arom.
H), 7.31-7.35(2H, m, arom. H), 7.70-7.86(4H, m, -phthalimide)
温度計、窒素吹き込み管、攪拌機、Dean-stark管および冷却管を装備した500 mLの三つ口フラスコにジエチレングリコール(2.12 g, 20.0 mmol)とトルエン(250g)を仕込み、水をトルエンで共沸除去した。40℃へ冷却後、トリエチルアミン(1.21 g, 12.0 mmol)を仕込み、滴下漏斗に準備した塩化メタンスルホニル(1.15 g, 10.0 mmol)を徐々に滴下した。滴下終了後、40℃で3時間反応を行った。エタノール(0.46 g, 10.0 mmol)を加えてしばらく攪拌し、濾過後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーにて精製し、式(29)の化合物を得た。
1H-NMR(CDCl3, 内部標準TMS);
δ(ppm):
3.08(3H, s,
-OSO2CH 3 ), 3.52-3.85(6H, m, -OCH 2 CH 2 -OCH 2 -),
4.37-4.39(2H, m, -CH 2 OSO2CH3)
温度計、窒素吹き込み管、攪拌機および冷却管を装備した100 mLの三つ口フラスコに式(29)の化合物(184 mg, 1.00 mmol)、式(27)の化合物(551 mg, 1.50 mmol)、炭酸カリウム(691 mg, 5.00 mmol)およびアセトニトリル(25 g)を仕込み、80℃で4時間反応を行った。濾過後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーにて精製し、式(30)の化合物を得た。
1H-NMR(CDCl3, 内部標準TMS); δ(ppm):
1.40-1.81(6H,
m, >CHCH 2 CH 2 CH 2 -),
3.52-4.25(13H, m, -OCH 2 CH 2 -, -OCH 2 CH<,
-CH 2 -phthalimide), 5.72(0.6H, s, >CH-), 5.84(0.4H,
s, >CH-), 6.89-6.91(2H, m, arom. H), 7.35-7.39(2H, m, arom.
H), 7.70-7.86(4H, m, -phthalimide)
温度計、窒素吹き込み管、攪拌機および冷却管を装備した50 mLの三つ口フラスコに式(30)の化合物(364 mg, 0.800 mmol)、メタノール(7 g)およびエチレンジアミン一水和物(1.56 g, 20.0 mmol)を仕込み、40℃にて4時間反応を行った。20wt%食塩水で希釈し、ジクロロメタンで抽出後、溶媒を減圧留去した。残渣を酢酸エチル(50 g)に溶解して無水硫酸ナトリウムで乾燥し、濾過後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーにて精製し、式(31)の化合物を得た。
1H-NMR(CD3OD, 内部標準TMS);
δ(ppm):
1.43-1.79(6H,
m, >CHCH 2 CH 2 CH 2 -),
2.77(2H, t, -CH 2 -NH2), 3.50-4.29(11H, m, -OCH 2 CH 2 -,
-OCH 2 CH<), 5.70(0.6H, s, >CH-), 5.81(0.4H,
s, >CH-), 6.93-6.98(2H, m, arom. H), 7.33-7.41(2H, m, arom.
H)
温度計、窒素吹き込み管、攪拌機および冷却管を装備した50 mLの三つ口フラスコへ式(31)の化合物(163 mg, 0.500 mmol)とアセトニトリル(10 g)を仕込み、3-マレイミドプロピオン酸 N-スクシンイミジル(160 mg, 0.600 mmol)を加えて25℃にて3時間反応を行った。濾過後、溶媒を減圧留去した。濾過後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーにて精製し、式(32)の化合物を得た。
1H-NMR(CDCl3, 内部標準TMS);
δ(ppm):
1.40-1.81(6H,
m, >CHCH 2 CH 2 CH 2 -), 2.44(2H,
t, -CH 2 CH2-maleimide), 3.27-3.37(2H, m, -CH 2 NHCO-),
3.47-4.25(13H, m, -OCH 2 CH 2 -, -OCH 2 CH<,
-CH2CH 2 -maleimide), 5.72(0.6H, s, >CH-),
5.84(0.4H, s, >CH-), 6.15(1H, brs, -NHCO-), 6.70(2H, s, -maleimide),
6.89-6.91(2H, m, arom. H), 7.35-7.39(2H, m, arom. H)
式(32)の化合物をトリエチルアミン存在下、ジクロロメタン中、N,N’-ジスクシンイミジルカーボネートと反応させることで、式(33)の化合物を得た。
1H-NMR(CDCl3, 内部標準TMS);
δ(ppm):
1.40-1.81(6H,
m, >CHCH 2 CH 2 CH 2 -),
2.44(2H, t, -CH 2 CH2-maleimide), 2.84(4H, s, -succinimide),
3.27-3.37(2H, m, -CH 2 NHCO-), 3.40-4.23(11H, m, -OCH 2 CH 2 -OCH 2 -,
-OCH 2 CH<, -CH2CH 2 -maleimide),
4.44-4.48(2H, m, -CH 2 O-COO-succinimide), 5.70(0.6H, s, >CH-),
5.82(0.4H, s, >CH-), 6.15(1H, brs, -NHCO-), 6.70(2H, s, -maleimide),
6.95-7.21(3H, m, arom. H)
3-フルオロ-4-ヒドロキシベンズアルデヒドを用いて、実施例1〜10と同様の方法にて式(34)の化合物を得た。
1H-NMR(CDCl3, 内部標準TMS); δ(ppm):
1.38-1.80(6H,
m, >CHCH 2 CH 2 CH 2 -),
3.52-4.23(11H, m, -OCH 2 CH 2 -, -OCH 2 CH<,
-CH 2 -phthalimide), 5.70(0.6H, s, >CH-), 5.82(0.4H,
s, >CH-), 6.95-7.21(3H, m, arom. H), 7.70-7.86(4H, m, -phthalimide)
2-ブロモ-5-ヒドロキシベンズアルデヒドを用いて、実施例1〜10と同様の方法にて式(35)の化合物を得た。
1H-NMR(CDCl3, 内部標準TMS); δ(ppm):
1.38-1.80(6H,
m, >CHCH 2 CH 2 CH 2 -), 3.52-4.23(11H,
m, -OCH 2 CH 2 -, -OCH 2 CH<,
-CH 2 -phthalimide), 5.70(0.6H, s, >CH-), 5.82(0.4H,
s, >CH-), 6.95-7.21(3H, m, arom. H), 7.70-7.86(4H, m, -phthalimide)
1H-NMR(CDCl3, 内部標準TMS); δ(ppm):
1.89 (2H, m, -CH 2 CH2-phthalimide),
3.19(1H, m, -OCH2CH<), 3.52-4.41(16H, m, -OCH 2 CH 2 -,
-OCH 2 CH<, -CH 2 CH2CH 2 -phthalimide),
5.34(0.8H, s, >CH-), 5.42(0.2H, s, >CH-), 6.95-7.25(3H, m, arom.
H), 7.70-7.86(4H, m, -phthalimide)
式(36)の化合物と2-ブロモ-5-ヒドロキシベンズアルデヒドを用いて、実施例5〜8と同様の方法にて式(38)の化合物を得た。
1H-NMR(CDCl3, 内部標準TMS); δ(ppm):
1.89 (2H, m, -CH 2 CH2-phthalimide),
3.19(1H, m, -OCH2CH<), 3.52-4.41(16H, m, -OCH 2 CH 2 -,
-OCH 2 CH<, -CH 2 CH2CH 2 -phthalimide),
5.61(0.8H, s, >CH-), 5.68(0.2H, s, >CH-), 6.78-7.40(3H, m, arom.
H), 7.70-7.86(4H, m, -phthalimide)
1H-NMR(CDCl3, 内部標準TMS);
δ(ppm):
1.60-1.74(4H,
m, -CH2CH 2 CH 2 CH2N3),
2.18(2H, t, -CH 2 CH2CH2CH2N3),
3.29(2H, t, -CH2CH2CH2CH 2 N3),
3.40-3.85(8H, m, -OCH 2 CH 2 -, -CONHCH 2 CH 2 -),
6.30(1H, brs, -CONH-)
実施例6と類似の方法にて、式(40)の化合物をトリエチルアミン存在下、トルエン中、塩化メタンスルホニルと反応させることで、式(41)の化合物を得た。
1H-NMR(CDCl3, 内部標準TMS);
δ(ppm):
1.60-1.74(4H,
m, -CH2CH 2 CH 2 CH2N3),
2.18(2H, t, -CH 2 CH2CH2CH2N3),
3.08(3H, s, -OSO2CH 3 ), 3.29(2H, t, -CH2CH2CH2CH 2 N3),
3.40-3.85(6H, m, -CONHCH 2 CH 2 -OCH 2 -),
4.37-4.39(2H, m, -CH 2OSO2CH3), 6.30(1H,
brs, -CH2CONH-)
3-フルオロ-4-ヒドロキシベンズアルデヒドと式(41)の化合物を用いて、実施例1〜5および7と同様の方法にて式(42)の化合物を得た。
1H-NMR(CDCl3, 内部標準TMS); δ(ppm):
1.38-1.80(10H,
m, >CHCH 2 CH 2 CH 2 -, -CH2CH 2 CH 2 CH2N3),
2.18(2H, t, -CH 2 CH2CH2CH2N3),
3.28-4.23(15H, m, -OCH 2 CH 2 -, -CH2CH2CH2CH 2 N3,
-CH2CONHCH 2 CH 2 -, -OCH 2 CH<,
-CH 2 -phthalimide), 5.70(0.6H, s, >CH-), 5.82(0.4H,
s, >CH-), 6.30(1H, brs, -CH2CONH-), 6.95-7.21(3H,
m, arom. H), 7.70-7.86(4H, m, -phthalimide)
式(42)の化合物に対して、実施例8と同様の方法にてフタルイミド基を脱保護して、式(43)の化合物を得た。
1H-NMR(CDCl3, 内部標準TMS); δ(ppm):
1.38-1.80(10H,
m, >CHCH 2 CH 2 CH 2 -, -CH2CH 2 CH 2 CH2N3),
2.18(2H, t, -CH 2 CH2CH2CH2N3),
2.77(2H, t, -CH 2 -NH2), 3.28-4.23(13H, m, -OCH 2 CH 2 -,
-CH2CH2CH2CH 2 N3,
-CH2CONHCH 2 CH 2 -, -OCH 2 CH<),
5.70(0.6H, s, >CH-), 5.82(0.4H, s, >CH-), 6.30(1H, brs, -CH2CONH-),
6.96(1H, brs, ICH2CONHCH2-), 6.95-7.21(3H, m, arom.
H)
acid])重水緩衝液は、それぞれ0.1MのMES重水溶液と0.1MのHEPES重水溶液に0.1Mの水酸化ナトリウム重水溶液を加え、「Glasoe, P. K.; Long, F. A. J. Phys. Chem.
1960, 64, 188-190」に記載されている以下の関係式に基づいて調製した。
pD=pHメーターの測定値+0.40
加水分解率(%)=[I2/(I1+I2)]×100
1H-NMR(CDCl3, 内部標準TMS); δ(ppm):
1.40-1.81(6H,
m, >CHCH 2 CH 2 CH 2 -),
3.38(3H, s, CH 3 O-), 3.52-4.25(455H, m, -(OCH 2 CH 2 )n-,
-OCH 2 CH<, -CH 2 -phthalimide),
5.72(0.6H, s, >CH-), 5.84(0.4H, s, >CH-), 6.89-6.91(2H, m, arom.
H), 7.35-7.39(2H, m, arom. H), 7.70-7.86(4H, m, -phthalimide)
GPC分析; 数平均分子量(Mn): 5462, 重量平均分子量(Mw): 5582, 多分散度(Mw/Mn): 1.022
3-フルオロ-4-ヒドロキシベンズアルデヒドを用いて、実施例1〜5および19と同様の方法にて式(46)の化合物を得た。
1H-NMR(CDCl3, 内部標準TMS); δ(ppm):
1.38-1.80(6H,
m, >CHCH 2 CH 2 CH 2 -),
3.38(3H, s, CH 3 O-), 3.52-4.23(455H, m, -(OCH 2 CH 2 )n-,
-OCH 2 CH<, -CH 2 -phthalimide),
5.70(0.6H, s, >CH-), 5.82(0.4H, s, >CH-), 6.95-7.21(3H, m, arom.
H), 7.70-7.86(4H, m, -phthalimide)
GPC分析; 数平均分子量(Mn): 5485, 重量平均分子量(Mw): 5606, 多分散度(Mw/Mn): 1.022
2-ブロモ-5-ヒドロキシベンズアルデヒドを用いて、実施例1〜5および19と同様の方法にて式(47)の化合物を得た。
1H-NMR(CDCl3, 内部標準TMS); δ(ppm):
1.38-1.80(6H,
m, >CHCH 2 CH 2 CH 2 -),
3.38(3H, s, CH 3 O-), 3.52-4.23(455H, m, -(OCH 2 CH 2 )n-,
-OCH 2 CH<, -CH 2 -phthalimide),
5.70(0.6H, s, >CH-), 5.82(0.4H, s, >CH-), 6.95-7.21(3H, m, arom.
H), 7.70-7.86(4H, m, -phthalimide)
GPC分析; 数平均分子量(Mn): 5548, 重量平均分子量(Mw): 5670, 多分散度(Mw/Mn): 1.022
式(36)の化合物と3-フルオロ-4-ヒドロキシベンズアルデヒドを用いて、実施例13および19と同様の方法にて式(48)の化合物を得た。
1H-NMR(CDCl3, 内部標準TMS); δ(ppm):
1.89 (3H, m, -CH 2 CH2-phthalimide),
3.19(1H, m, -OCH2CH<), 3.38(3H, s, CH 3 O-),
3.52-4.41(456H, m, -(OCH 2 CH 2 )n-,
-OCH 2 CH<, -CH 2 CH2CH 2 -phthalimide),
5.34(0.8H, s, >CH-), 5.42(0.2H, s, >CH-), 6.95-7.25(3H, m, arom.
H), 7.70-7.86(4H, m, -phthalimide)
GPC分析; 数平均分子量(Mn): 5498, 重量平均分子量(Mw): 5619, 多分散度(Mw/Mn): 1.022
式(36)の化合物と2-ブロモ-5-ヒドロキシベンズアルデヒドを用いて、実施例13および19と同様の方法にて式(49)の化合物を得た。
1H-NMR(CDCl3, 内部標準TMS); δ(ppm):
1.89 (3H, m, -CH 2 CH2-phthalimide),
3.19(1H, m, -OCH2CH<), 3.38(3H, s, CH 3 O-),
3.52-4.41(456H, m, -(OCH 2 CH 2 )n-,
-OCH 2 CH<, -CH 2 CH2CH 2 -phthalimide),
5.61(0.8H, s, >CH-), 5.68(0.2H, s, >CH-), 6.78-7.40(3H, m, arom.
H), 7.70-7.86(4H, m, -phthalimide)
GPC分析; 数平均分子量(Mn): 5564, 重量平均分子量(Mw): 5686, 多分散度(Mw/Mn): 1.022
式(45)、式(46)、式(47)、式(48)および式(49)の化合物(20 mg)をそれぞれpD 5.5のMES重水緩衝液(1 mL)とpD 7.4のHEPES重水緩衝液(1 mL)に溶解し、37℃の恒温槽で静置した。図1はpD 5.5、図2はpD 7.4における加水分解率の測定結果である。
文献(Doronina, S. O. et al. Nat. Biotechnot.
2003, 21, 778-784)に従って、CD30抗原に対するIgG1(Wahl, A. F. et al. Cancer Res. 2002, 62,
3736-3742)であるキメラモノクローナル抗体AC10を調製した。
式(34)の化合物のN-ヒドロキシスクシンイミジルカーボネート基に対して、ジイソプロピルエチルアミン存在下、ドキソルビシン塩酸塩(Sigma-Aldrich)を反応させ、環状ベンジリデンアセタールリンカーが結合したドキソルビシン誘導体を得た。
50 mMホウ酸ナトリウムを含むpH 8.0のPBS緩衝液中のAC10(5mg/ml)を、37℃でジチオスレイトール(DTT)(10mM)で30分間処理した。ゲルろ過(Sephadex G-25、1 mMのDTPAを含むPBS)後、5,5’-ジチオビス(2-ニトロ安息香酸)を用いるチオール測定により、抗体あたり約8つのチオールの存在を確認した。還元されたAC10に、氷冷DMSO(20 mM)に溶解した上記からのドキソルビシン誘導体(1.2モル当量/チオール)を4℃で加えた。1時間後、過剰のシステインで反応を停止させ、遠心限外ろ過、ゲルろ過(Sephadex G-25、PBS)および無菌ろ過によって抗体―薬物複合体を濃縮した。280nmおよび490nmの吸光度(ドキソルビシン吸光度)を測定して、抗体―薬物複合体の薬物保持率を測定したところ、6.8薬物/抗体を有していた。
pH6.5のPBS緩衝液(50 mMリン酸カリウム/50 mM塩化ナトリウム/2mM EDTA)中のAC10(20mg/mL)に対して、氷冷DMSO(20
mM)に溶解した7.5モル当量のジベンゾシクロオクチンN-ヒドロキシスクシンイミジルカーボネート(Sigma-Aldrich)を加えて1時間攪拌後、式(43)の化合物を加えて、さらに2時間攪拌した。続いて、文献(Angew. Chem. Int. Ed. Engl. 2003, 42, 327-332)に記載の方法で合成した(S)-(+)-カンプトテシンのp-ニトロフェニルカーボネート誘導体を氷冷DMSOに溶解(20 mM)して加え、さらに2時間攪拌した。その反応混合物を、遠心限外ろ過、ゲルろ過(Sephadex G-25、PBS)および無菌ろ過によって抗体―薬物複合体を濃縮した。280 nmおよび351 nmの吸光度(カンプトテシン吸光度)を測定して、抗体―薬物複合体の薬物保持率を測定したところ、5.2薬物/抗体を有していた。
Claims (16)
- 式(1)または式(2)で示される、環状ベンジリデンアセタールリンカーを有する抗体―薬物複合体。
(式(1)および式(2)中、
Yは抗体であり;
Dは薬物であり;
R1およびR6はそれぞれ独立して水素原子または炭化水素基であり;
R2、R3、R4およびR5はそれぞれ独立して電子吸引性もしくは電子供与性の置換基、または水素原子であり;
s=1または2、t=0または1、かつs+t=1または2であり;
wは1〜20の整数であり;および
Z1およびZ2はそれぞれ独立して選択された、エーテル結合およびアミド結合から選ばれた置換基、もしくはこれらを含む脂肪族炭化水素基、単結合または脂肪族炭化水素基からなる2価のスペーサーである。)
- s=1かつt=0であり、R2およびR5は水素原子であり、式(1)のR3、R4およびY-Z1、または式(2)のR3、R4およびD-Z1における置換基定数(σ)の合計(Σσ)が
−0.30≦Σσ≦1.05である、請求項1に記載の抗体―薬物複合体。
- s=1かつt=0であり、R2とR5との少なくとも一方が前記置換基であり、式(1)のR3、R4およびY-Z1、または式(2)のR3、R4およびD-Z1における置換基定数(σ)の合計(Σσ)が
−1.71≦Σσ≦0.88である、請求項1に記載の抗体―薬物複合体。
- s=1かつt=1、またはs=2かつt=0であり、R2およびR5は水素原子であり、式(1)のR3、R4およびY-Z1、または式(2)のR3、R4およびD-Z1における置換基定数(σ)の合計(Σσ)が−0.19≦Σσ≦0.57である、請求項1に記載の抗体―薬物複合体。
- s=1かつt=1、またはs=2かつt=0であり、R2とR5との少なくとも一方が前記置換基であり、式(1)のR3、R4およびY-Z1、または式(2)のR3、R4およびD-Z1における置換基定数(σ)の合計(Σσ)が−0.98≦Σσ≦0.48である、請求項1に記載の抗体―薬物複合体。
- 前記抗体がモノクローナル抗体、単鎖モノクローナル抗体、二重特異性抗体、または標的細胞に結合するモノクローナル抗体フラグメントである、請求項1〜5のいずれか一つの請求項に記載の抗体―薬物複合体。
- 前記抗体が表面再構成(resurfaced)モノクローナル抗体、表面再構成単鎖モノクローナル抗体、または標的細胞に結合する表面再構成モノクローナル抗体フラグメントである、請求項1〜5のいずれか一つの請求項に記載の抗体―薬物複合体。
- 前記抗体がヒトモノクローナル抗体、ヒト化モノクローナル抗体、ヒト化単鎖モノクローナル抗体、または標的細胞に結合するヒト化モノクローナル抗体フラグメントである、請求項1〜5のいずれか一つの請求項に記載の抗体―薬物複合体。
- 前記抗体がキメラ抗体、キメラ抗体フラグメント、ドメイン抗体、またはドメイン抗体フラグメントである、請求項6に記載の抗体―薬物複合体。
- 前記薬物が化学療法薬である、請求項1〜5のいずれか一つの請求項に記載の抗体―薬物複合体。
- 式(3)または式(4)で示される、環状ベンジリデンアセタールリンカーを有する化合物。
(式(3)および式(4)中、
Yは抗体であり;
R1およびR6はそれぞれ独立して水素原子または炭化水素基であり;
R2、R3、R4およびR5はそれぞれ独立して電子吸引性もしくは電子供与性の置換基、または水素原子であり;
X1は共有結合による薬物の連結が可能な反応性官能基であり;
s=1または2、t=0または1、かつs+t=1または2であり;
wは1〜20の整数であり;
および
Z1、Z2、Z3およびZ4はそれぞれ独立して選択された、エーテル結合およびアミド結合から選ばれた置換基、もしくはこれらを含む脂肪族炭化水素基、単結合または脂肪族炭化水素基からなる2価のスペーサーである。)
- X1が活性エステル基、活性カーボネート基、アルデヒド基、イソシアネート基、イソチオシアネート基、エポキシ基、マレイミド基、ビニルスルホン基、アクリル基、スルホニルオキシ基、カルボキシ基、チオール基、ジチオピリジル基、α-ハロアセチル基、アルキニル基、アリル基、ビニル基、アミノ基、オキシアミノ基、ヒドラジド基、アジド基およびヒドロキシ基よりなる群から選択される、請求項11に記載の化合物。
- 式(5)または式(6)で示される、環状ベンジリデンアセタールリンカーを有する化合物。
(式(5)および式(6)中、
Dは薬物であり;
R1およびR6はそれぞれ独立して水素原子または炭化水素基であり;
R2、R3、R4およびR5はそれぞれ独立して電子吸引性もしくは電子供与性の置換基、または水素原子であり;
X2は共有結合による抗体の連結が可能な反応性官能基であり;
s=1または2、t=0または1、かつs+t=1または2であり;および
Z1、Z2、Z3およびZ4はそれぞれ独立して選択された、エーテル結合およびアミド結合から選ばれた置換基、もしくはこれらを含む脂肪族炭化水素基、単結合または脂肪族炭化水素基からなる2価のスペーサーである。)
- X2が活性エステル基、活性カーボネート基、アルデヒド基、イソシアネート基、イソチオシアネート基、エポキシ基、マレイミド基、ビニルスルホン基、アクリル基、スルホニルオキシ基、カルボキシ基、チオール基、ジチオピリジル基、α-ハロアセチル基、アルキニル基、アリル基、ビニル基、アミノ基、オキシアミノ基、ヒドラジド基、アジド基およびヒドロキシ基よりなる群から選択される、請求項14に記載の化合物。
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