JP7285537B2 - Ca ix標的nir色素及びそれらの使用 - Google Patents
Ca ix標的nir色素及びそれらの使用 Download PDFInfo
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- JP7285537B2 JP7285537B2 JP2018548414A JP2018548414A JP7285537B2 JP 7285537 B2 JP7285537 B2 JP 7285537B2 JP 2018548414 A JP2018548414 A JP 2018548414A JP 2018548414 A JP2018548414 A JP 2018548414A JP 7285537 B2 JP7285537 B2 JP 7285537B2
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Description
本特許出願は、2016年3月16日に出願された米国仮特許出願第62/309,412号に関連し、その優先権を主張し、その内容全体を参照により本開示に組み込む。
本開示は、炭酸脱水酵素9(CA IX)標的化近赤外(NIR)色素並びにそれらの治療的及び診断的使用のための方法に関する。より具体的には、本開示は、腎臓、子宮内膜、泌尿器、結腸直腸、卵巣、***、膵臓、及び食道の癌細胞、並びに多くの固形腫瘍及び関連疾患の低酸素領域等のCA IX(低酸素組織及び腫瘍の低酸素領域の広く受け入れられているマーカ)発現細胞の診断及び外科的除去(画像誘導手術)のための化合物及び方法を提供する。本開示は、化合物を製造及び使用するための方法及び組成物、化合物を組み込む方法、並びに化合物を組み込むキットを更に記載する。
B-W-X-Y-Z
式中、
BはCA IX標的化分子であり;
Wは伸長された疎水性残基であり;
Xは疎水性スペーサであり;
Yはアミノ酸スペーサであり;及び
ZはNIR色素である。
B-W-X-Y-Z
式中、
BはCA IX標的化分子であり;
Wは伸長された疎水性残基であり;
Xは疎水性スペーサであり;
Yはアミノ酸スペーサであり;
ZはNIR色素である。
B-W-X-Y-Z
式中、BはCA IX標的化分子であり;Wは伸長された疎水性残基であり、Xはスペーサであり;Yは硫黄含有側鎖基を有するアミノ酸スペーサであり;ZはNIR色素である。いくつかの実施形態では、硫黄含有側鎖基を有するアミノ酸スペーサはシステインである。いくつかの実施形態では、硫黄含有側鎖基を有するアミノ酸スペーサはメチオニンである。いくつかの実施形態では、硫黄含有側鎖基を有するアミノ酸スペーサは、チオフェノール部分を含む分子である。
B-W-X-Y-Z
式中、BはCA IX標的化分子であり;Wは伸長された疎水性残基であり、Xは疎水性スペーサであり;Yは、カルコゲン含有側鎖基を有するアミノ酸スペーサであり;ZはNIR色素である。
B-W-X-Y-Z
式中、BはCA IX標的化分子であり;Wは伸長された疎水性残基であり、Xはスペーサであり;Yは、チロシン、システイン、リシン、又はそれらの誘導体からなる群から選択されるアミノ酸であり;ZはNIR色素である。いくつかの実施形態では、Yはチロシン又はチロシン誘導体を含む。いくつかの実施形態では、Yはチロシンを含み、炭素同位体はチロシンの芳香族環上にある。いくつかの実施形態では、Yは、水素同位体を有する芳香族環を有するアミノ酸を含む。
式中:
R1は水素又はSO3Hを表し;
R2は、水素、CH3、C3H6SO3 -、C3H6SO3H又はC4H8SO3 -又はC4H8SO3H又はC3H6N+(CH3)3を表し;
R3は、炭素、場合により1つ以上の共有結合を表し;
R4は、場合により1つ以上の共有結合を有する炭素を表し;
R5は窒素、酸素、又は硫黄、あるいは無原子(芳香族環とビニル環との間の直接C-C結合)を表し;
R6は任意であり、存在する場合、芳香族置換基を表し、ビニルエーテル架橋の輝度及び安定性の増加などのスペクトル特性を向上させる。
R7は任意であり、存在する場合、芳香族アミノ酸、例えばPhe、Trp、His、又はそれらの誘導体、カチオン性アミノ酸、例えばArg、Lys、又はそれらの誘導体、アニオン性アミノ酸、例えばAsp、Glu、又はそれらの誘導体、芳香族/カチオン性/アニオン性酸又はそれらの誘導体の非天然アミノ酸を有する連結体を表し;
R8は任意であり、存在する場合、直鎖状炭素鎖、又はポリエチレングリコール連結体、カチオン性連結体、若しくはそれらの誘導体を表し;
R9は任意であり、存在する場合、Phe、Val、Leu、Ile、Trp、His、Arg、Lys、Asp、Glu、又はそれらの誘導体などの疎水性部分を表し;
R10は疎水性連結体を表し;並びに
R11は任意であり、存在する場合、F、NO2、又はそれらのような分子の結合親和性、安定性、疎水性を高める芳香族置換基を表し、R12は任意であり、存在する場合、Phe、Val、Leu、Ile、Trp、His、又はそれらの誘導体あるいは環状部分、例えばシクロヘキシル、シクロオクチル、又はそれらの誘導体等の疎水性部分を表す。
(a)生物学的組織をCA IX標的化NIR色素化合物を含む組成物と接触させる工程;
(b)組成物中の化合物が生物学的標的内に分配される時間をとる工程;
(c)化合物が吸収可能な波長の励起光で組織を照射する工程;及び
(d)化合物によって放出された光シグナルを検出する工程
を含む。
a)所与の外科部位に化合物が蓄積するのに十分な条件及び時間で、CA IX標的化NIR色素化合物を含む組成物を投与する工程;
b)赤外光を用いて化合物を視覚化するために化合物を照射する工程;並びに
c)赤外光による励起時に蛍光を発する領域の外科的切除を行う工程
を含む。
a)少なくとも1つのCA IX発現細胞へ化合物を結合可能にする時間及び条件下で、CA IX標的化NIR色素化合物のある量を、診断を必要とする被験体に投与する工程;
b)生物学的サンプル中に存在する化合物からのシグナルを測定する工程;
c)少なくとも1つのコントロールデータセットと、b)において測定されたシグナルを比較する工程であって、少なくとも1つのコントロールデータセットが、標的細胞タイプを含まない生物学的サンプルと接触した請求項1に記載の化合物からのシグナルを含む、工程;及び
d)工程c)における比較が疾患の存在を示す疾患の診断を提供する工程
を含む。
手術は米国で固形腫瘍患者の50%を治癒させるが、化学療法及び放射線療法は全ての癌患者の5%未満を治す。毎年70万人を超える患者が米国で癌手術を受け、40%の外科患者が5年以内に局所領域疾患の再発を経験する。腫瘍学分野の大きな進歩にもかかわらず、早期発見、陰性マージンを伴う原発腫瘍の外科的切除を完了するための壁を克服する方法、並びに転移性癌細胞の除去及びサテライト疾患の同定が依然として必要とされている。これらの3つの目標を達成することは、疾患のクリアランスを改善するだけでなく、術後の化学療法及び放射線に関する決定を導く。標的化されていない蛍光色素は、いくつかの腫瘍において受動的に蓄積することが示されているが、得られる腫瘍対バックグラウンド比はしばしば不十分であり、悪性組織と健康な組織との境界は規定することが困難であり得る。組織をイメージングするために、リガンド標的化蛍光色素(例えば、EC17:Folate-EDA-FITC)が使用されているが、これらの色素は、深部組織に浸透しないので有効ではなく、故に組織サンプル内のより深い組織よりも組織表面の特定細胞のみを同定している。更に、フルオレセインをベースとする色素は貯蔵寿命の安定性が低いという欠点を有する。蛍光イソチオシアネート(FITC)化合物によって形成されるチオ尿素架橋は、容易に分解し、不安定な化合物を生成する。更に、EC17はフルオレセインを使用し、これは、イメージング部位を取り囲む組織中のコラーゲンからの非特異的バックグラウンドノイズが比較的高いレベルであるという欠点を有する。更に、生物学的発色団、特にヘモグロビンによる可視光の吸収は、フルオレセインを組み込んだ色素の有用性を更に制限する。従って、従来の色素は、組織内の数ミリメートルよりも深く埋め込まれ得る腫瘍を容易に検出することができない。更に、フルオレセインからの蛍光は、低pH(pH5未満)で消光される。
B-W-X-Y-Z
式中、
BはCA IX標的化分子であり;
Wは伸長された疎水性残基であり;
Xは疎水性スペーサであり;
Yはアミノ酸スペーサであり;及び
ZはNIR色素である。
B-W-X-Y-Z
式中、BはCA IX標的化化合物であり;Wは伸長された疎水性残基であり;Xは疎水性スペーサであり;Yは硫黄含有側鎖基を有するアミノ酸スペーサであり;ZはNIR色素である。いくつかの実施形態では、硫黄含有側鎖基を有するアミノ酸スペーサはシステインである。いくつかの実施形態では、硫黄含有側鎖基を有するアミノ酸スペーサはメチオニンである。いくつかの実施形態では、硫黄含有側鎖基を有するアミノ酸スペーサは、チオフェノール部分を含む分子である。
B-W-X-Y-Z
式中、BはCA IX標的化化合物であり;Wは伸長された疎水性残基であり、Xは疎水性スペーサであり;Yは、カルコゲン含有側鎖基を有するアミノ酸スペーサであり;ZはNIR色素である。
B-W-X-Y-Z
式中、BはCA IX標的化化合物であり;Wは伸長された疎水性残基であり、Xは疎水性スペーサであり、Yは、チロシン、システイン、リシン、又はそれらの誘導体からなる群から選択されるアミノ酸であり;ZはNIR色素である。いくつかの実施形態では、Yはチロシン又はチロシン誘導体を含む。いくつかの実施形態では、Yはチロシンを含み、炭素同位体はチロシンの芳香族環上にある。いくつかの実施形態では、Yは、水素同位体を有する芳香族環を有するアミノ酸を含む。
式中:
R1は水素又はSO3Hを表し;
R2は、水素、CH3、C3H6SO3 -、C3H6SO3H又はC4H8SO3 -又はC4H8SO3H又はC3H6N+(CH3)3を表し;
R3は、炭素、場合により1以上の共有結合を表し、
R4は、場合により1以上の共有結合を有する炭素を表し;
R5は窒素、酸素、又は硫黄、あるいは無原子(芳香族環とビニル環との間の直接C-C結合)を表し;
R6は任意であり、存在する場合、芳香族置換基を表し、ビニルエーテル架橋の輝度及び安定性の増加等のスペクトル特性を向上させ;
R7は任意であり、存在する場合、芳香族アミノ酸、例えばPhe、Trp、His、又はそれらの誘導体、カチオン性アミノ酸、例えばArg、Lys、又はそれらの誘導体、アニオン性アミノ酸、例えばAsp、Glu、又はそれらの誘導体、芳香族/カチオン性/アニオン性酸又はそれらの誘導体の非天然アミノ酸を有する連結体を表し;
R8は任意であり、存在する場合、直鎖状炭素鎖、あるいはポリエチレングリコール連結体、カチオン性連結体、又はそれらの誘導体を表し;
R9は任意であり、存在する場合、Phe、Val、Leu、Ile、Trp、His、Arg、Lys、Asp、Glu、又はそれらの誘導体等の疎水性部分を表し;
R10は疎水性連結体を表し;並びに、
R11は任意であり、存在する場合、F、NO2又はそれらのような分子の結合親和性、安定性、疎水性を高める芳香族置換基を表し、
R12は任意であり、存在する場合、Phe、Val、Leu、Ile、Trp、His、又はそれらの誘導体若しくは環状部分、例えばシクロヘキシル、シクロオクチル、又はそれらの誘導体等の疎水性部分を表す。
(a)生物学的組織をCA IX標的化NIR色素化合物を含む組成物と接触させる工程;
(b)組成物中の化合物が生物学的標的内に分配される時間をとる工程;
(c)化合物が吸収可能な波長の励起光で組織を照射する工程;及び
(d)化合物によって放出された光シグナルを検出する工程
を含む。
a)所与の外科部位に化合物が蓄積するのに十分な条件及び時間で、CA IX標的化NIR色素化合物を含む組成物を投与する工程;
b)赤外光を用いて化合物を視覚化するために化合物を照射する工程;並びに
c)赤外光による励起時に蛍光を発する領域の外科的切除を行う工程;
を含む。
a)少なくとも1つのCA IX発現細胞へ化合物を結合可能にする時間及び条件下で、CA IX標的化NIR色素化合物のある量を、診断を必要とする被験体に投与する工程;
b)生物学的サンプル中に存在する化合物からのシグナルを測定する工程;
c)少なくとも1つのコントロールデータセットと、b)において測定されたシグナルを比較する工程であって、少なくとも1つのコントロールデータセットが、標的細胞タイプを含まない生物学的サンプルと接触した請求項1に記載の化合物からのシグナルを含む、工程;並びに
d)工程c)における比較が疾患の存在を示す疾患の診断を提供する工程;
を含む。
(a)生物学的組織をCA IX標的化NIR色素化合物を含む組成物と接触させる工程、
(b)組成物中の化合物が生物学的標的内に分配される時間をとる工程;
(c)化合物が吸収可能な波長の励起光で組織を照射する工程;及び
(d)化合物によって放出された光シグナルを検出する工程
を含む。
a)所与の外科部位に化合物が蓄積するのに十分な条件及び時間で、CA IX標的化NIR色素化合物を含む組成物を投与する工程;
b)赤外光を用いて化合物を視覚化するために化合物を照射する工程;及び
c)赤外光による励起時に蛍光を発する領域の外科的切除を行う工程
を含む。
a)少なくとも1つのCA IX発現細胞組織へ化合物を結合可能にする時間及び条件下で、CA IX標的化NIR色素化合物のある量を、診断を必要とする被験体に投与する工程;
b)生物学的サンプル中に存在する化合物からのシグナルを測定する工程;
c)少なくとも1つのコントロールデータセットと、b)において測定されたシグナルを比較する工程であって、少なくとも1つのコントロールデータセットが、標的細胞タイプを含まない生物学的サンプルと接触した請求項1に記載の化合物からのシグナルを含む、工程;及び
d)工程c)における比較が疾患の存在を示す疾患の診断を提供する工程
を含む。
Claims (9)
- 式B-W-X-Y-Z又はB-X-Zを有するCA IX標的化分子共役体:
式中、
Bは、W-X-Y又はXを介してNIR色素と連結されるCA IX標的化分子に由来する一価の基である;
Wは、アラニン、ロイシン、イソロイシン、バリン、プロリン、フェニルアラニン、トリプトファン、メチオニン、チロシン、アルギニン、ヒスチジン、リシン、グリシン、セリン、トレオニン、システイン、チロシン、アスパラギン、アスパラギン酸、グルタミン酸、及びグルタミンからなる群から選択される;
Xは、4級アミン側鎖を含有するアミノ酸、6-アミノヘプタン酸(SAHA)、ポリエチレングリコール(PEG)、ポリエチレンアミン(PEA)単位、N-アミノ-dPEG 2 酸;及びアリール又はアリールアルキル基を含むペプチド(ここで、前記アリール又はアリールアルキル基が6~14個の原子である。)からなる群から選択される;
Yは、アスパラギン酸、グルタミン酸、アルギニン、ヒスチジン、リシン、グリシン、セリン、トレオニン、システイン、チロシン、アスパラギン、グルタミン、アラニン、ロイシン、イソロイシン、バリン、プロリン、フェニルアラニン、トリプトファン、メチオニン、及び芳香族環上に炭素同位体を有するチロシン、フェニルアラニン-チロシン、フェニルアラニンアルギニンチロシン、並びにヒスチジン-チロシンからなる群から選択される;
ZはNIR色素に由来する一価の基である;
更に、前記CA IX標的化分子に由来する一価の基は、以下からなる群から選択される;
上記式中、nは0、1、2、又は3であり、mは0、1、2、3、4、又は5であり、pは0、1、2、又は3である。 - 以下の構造式を有する化合物又はその薬学的に許容される塩若しくはその同位体:
式中、
R19は水素又はSO3Hを表し;
R20は、水素、CH3、C3H6SO3 -、C3H6SO3H、又はC4H8SO3 -、又はC4H8SO3H、又はC3H6N+(CH3)3を表し;
R21及びR22は独立して、炭素を表し;
R23は、窒素、酸素、又は硫黄、あるいは芳香族環とビニル環との間の無原子直接C-C結合を表し;
R25は欠いているか、又はPhe、Trp、His、Arg、Lys、Asp、若しくはGluを表し;
R26は直鎖状炭素鎖又はポリエチレングリコール連結体を表し;
R27は欠いているか、又はPhe、Val、Leu、Ile、Trp、His、Arg、Lys、Asp、若しくはGluを表し;
R28はVal、Leu、Phe、Tyr、His、Trp、又はMetであり;並びに
R29は欠いているか、又はF若しくはNO2を表し;
R30は欠いているか、又はPhe、Val、Leu、Ile、Trp、His、シクロヘキシル、若しくはシクロオクチルを表す。 - 前記化合物が、500nm~900nmの間の吸収及び発光極大値を有する、請求項4又は5のいずれか1項に記載の化合物。
- 前記化合物が、近赤外波長の励起光に供されることによって、組織細胞中でのその分配後に蛍光を発するように調製される、請求項4又は5のいずれか1項に記載の化合物。
- 前記化合物が、C-SPAの結合親和性と同様の炭酸脱水酵素IXに対する結合親和性を有し、且つ腫瘍細胞への標的化に対して選択的である、請求項4又は5のいずれか1項に記載の化合物。
- 請求項4又は5のいずれか1項に記載の化合物を含むキット。
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US11555821B2 (en) | 2016-03-16 | 2023-01-17 | On Target Laboratories, Inc. | CA IX-NIR dyes and their uses |
CN111225688A (zh) * | 2017-08-22 | 2020-06-02 | 普渡研究基金会 | 靶向碳酸酐酶阳性癌症的基于fbsa的治疗和放射性成像缀合物 |
WO2019133914A1 (en) * | 2017-12-29 | 2019-07-04 | Wayne State University | Method of treatment for solid tumors containing hypoxia and/or stroma features |
WO2020131980A1 (en) * | 2018-12-19 | 2020-06-25 | Purdue Research Foundation | Carbonic anhydrase inhibitors and antibiotics against multidrug resistant bacteria |
CN110790724B (zh) * | 2019-09-20 | 2023-01-31 | 中山大学 | 一种选择性碳酸酐酶抑制剂及其合成方法和应用 |
WO2022118277A1 (en) * | 2020-12-03 | 2022-06-09 | Vilnius University | Carbonic anhydrase inhibitors synthesized on interconnecting linker chains |
EP4337265A2 (en) * | 2021-05-14 | 2024-03-20 | Purdue Research Foundation | Folate receptor-targeted conjugates with brush border membrane enzyme-cleavable linkers and methods of use in imaging and treating cancer |
WO2023081301A1 (en) * | 2021-11-05 | 2023-05-11 | On Target Laboratories, LLC | Fibroblast activation protein targeted dyes their related uses |
KR20230133319A (ko) * | 2022-02-11 | 2023-09-19 | (주)씨바이오멕스 | 탄산탈수소효소 ix를 표적으로 하는 펩타이드 리간드,이를 포함하는 펩타이드 구조체 및 이들의 용도 |
WO2024023138A2 (en) | 2022-07-28 | 2024-02-01 | Bracco Imaging Spa | Ca-ix targeting fluorescent probes |
WO2024023144A1 (en) | 2022-07-28 | 2024-02-01 | Bracco Imaging Spa | Ca-ix targeting fluorescent probes |
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IL261470A (en) | 2018-10-31 |
AU2017234681B2 (en) | 2021-07-01 |
CA3016191A1 (en) | 2017-09-21 |
KR102342319B1 (ko) | 2021-12-23 |
WO2017161197A1 (en) | 2017-09-21 |
EP3430383A1 (en) | 2019-01-23 |
WO2017161195A1 (en) | 2017-09-21 |
US10746741B2 (en) | 2020-08-18 |
MX2018011130A (es) | 2018-11-22 |
US20170285040A1 (en) | 2017-10-05 |
EP3430383A4 (en) | 2019-10-23 |
JP2019512500A (ja) | 2019-05-16 |
BR112018068142B1 (pt) | 2023-02-14 |
IL261470B (en) | 2022-05-01 |
KR20180123216A (ko) | 2018-11-15 |
BR112018068142A2 (pt) | 2019-02-12 |
CN109791107B (zh) | 2022-05-27 |
US20200174009A1 (en) | 2020-06-04 |
EP3430383B1 (en) | 2024-06-26 |
AU2017234681A1 (en) | 2018-09-27 |
CN109791107A (zh) | 2019-05-21 |
US10557854B2 (en) | 2020-02-11 |
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