JP2021517584A - 増殖分化因子15アゴニスト化合物およびその使用方法 - Google Patents
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Abstract
Description
ヒトGFRAL受容体へのヒトGDF15ホモダイマーおよび例示的な化合物2のインビトロ結合パラメータは、表面プラズモン共鳴(SPR)によって決定される。GFRALのECDには、3つのCysリッチドメイン(D1、D2、およびD3)が含まれている。ヒトGDF15のホモダイマー(des−ARN配列番号1、つまり、N末端からAla、Arg、Aspを欠くGDF15)と、Fc−GDF15化合物1のホモダイマーである化合物2(配列番号2)の、HISタグ付きヒトGFRAL ECD(配列番号4)に対する親和性は、SPRによって測定できる。結合速度を表1にまとめる。
GDF15の受容体であるGFRALは、GDNF受容体ファミリーのメンバーであり、単一の膜貫通ドメインを含み、細胞内シグナル伝達ドメインを含まない。GFRALを含むGDNF受容体ファミリーのメンバーは、共受容体RETを利用して信号を変換する。GDNF受容体/RET複合体の刺激は、ERK、AKTおよびSTATリン酸化を含むシグナル伝達ネットワークを活性化することが知られている。
Maxima%=100*(x−分)/(max−分)、
ここで、分=0でありかつ刺激なしを表し、max=100でありかつ化合物の飽和用量で観察された刺激を表し、x=任意の所定の治療を表す。各化合物のEC50は、GraphPad Prismバージョン7.00の4つのパラメータのロジスティック回帰を伴う可変勾配シグモイド用量反応曲線を使用して決定される。表2の各化合物について列挙されているEC50は、以下の式を用いて各化合物の3つの独立したアッセイについてのEC50の幾何平均を生成することによって決定される。
肥満は、糖尿病およびインスリン抵抗性に関連する一般的な併存疾患である。GDF15は食物摂取を抑制し、体重減少を誘発し、グルコース恒常性を改善すると報告されている。したがって、GDF15化合物は、体重減少を誘発するための療法や、T2D、脂質異常症、NASH、および/または肥満などの状態のための療法に有効である可能性がある。化合物2を15日間の期間、雄性Sprague Dawleyラットに投与し、毎日の体重および摂食量を測定する。
体重%=(その日の体重/初期体重)X 100
体重減少、代謝、身体組成および肝脂肪変性に対する化合物2の効果を調べるために、化合物2をC57/Bl6 DIOマウスに長期的に投与する。
HOMA IR=空腹時血漿インスリン(mIUl/L)*(空腹時血糖(mmol/L)/22.5。
医薬品におけるタンパク質凝集は、全体的な生産収量を低下させ、個人に投与した場合に免疫応答を引き起こす可能性があるため、望ましくない。したがって、化合物をモノマー状態、またはこの場合は共有結合したホモダイマーに維持することが好ましい。
本発明の化合物のFc部分の独特の構造は、2つの特定の変異を有し、いずれか一方の変異のみを有するFc構築物よりも、高濃度で予想外に優れた安定性と高い溶解度を示す。単一の変異を有する2つのFcsが生成され、IgG4−FcのCH3/CH3結合が破壊され、モノマーFc構築物が作成される。最初は化合物7であり、配列番号2の173位(配列番号9の175位)に対応する完全長ヒトIgG4重鎖の405位のフェニルアラニンがグルタミンに置換された。生成された第2の単一変異体は、化合物8であって、これは、完全長ヒトIgG4重鎖の407位のチロシンがグルタミン酸で置換されたFcであり、配列番号2の175位に対応する(配列番号10の177位に対応)。デュアルFc変異体である化合物5(配列番号7)もまた生成され、化合物7と8の両方のFc変異を含む。化合物5は、追加の2つのアミノ酸APが化合物5のFc領域のN末端に存在することを除いて、化合物2と同じ配列である。化合物2、5、7および8は、モノマーIgG4Fcの形成を確実にするために、ESKYGPPCPPCP(配列番号8)のヒンジ領域を欠いている。
本発明のGDF15化合物の化学的安定性をテストするために、そのような化合物を次のバッファーに4℃で一晩透析する:10mMクエン酸、pH6(C6)、10mMクエン酸、pH7(C7)、10mM Tris、pH7.0(T7)、10mM Tris、pH8.0(T8)または1xPBS、pH7.4(PBS)。Fc−GDF15融合物の長期安定性を評価するために、1.0mg/mLタンパク質溶液をそれぞれのバッファーに4℃、25℃、40℃で4週間保存し、LMW%を分析SECによって測定する。
化合物2の薬物動態学的挙動はサルでテストされている。GDF15化合物の血漿中濃度は、Eli Lilly and Company(Indianapolis,IN)のELISA法によって決定される。サンドイッチELISAは、捕捉試薬として1または3μg/mLでコーティングされたポリクローナルヤギ抗ヒトGDF15(R&D Systems/AF957)またはモノクローナルマウス抗ヒト/霊長類GDF15抗体(R&D Systems/MAB957)を使用する。次に、GDF15化合物を、マウス抗ヒトIgG4 pFc−HRP抗体(Southern Biotech/9190−05)またはマウス抗ヒトIgG Fc−HRP抗体(Southern Biotech/9200−05)のいずれかで検出する。プレートは、テトラメチルベンジジン(TMB)基質システム(SeraCare/5120)を使用して発色され、酵素反応はTMB Stop Solution(KPL/50−85−04)でクエンチされる。
以下の核酸配列および/またはアミノ酸配列は、本開示において言及され、参照のために以下に提供される。
配列番号:1−成熟ヒトGDF15
ARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI
配列番号2−融合タンパク質
EAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFQLESRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGAPAPAPAPAPAPAPAPAPAPGGGGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI
配列番号3−リーダー配列
METDTLLLWVLLLWVPGSTG
配列番号4−人工配列
QTNNCTYLREQCLRDANGCKHAWRVMEDACNDSDPGDPCKMRNSSYCNLSIQYLVESNFQFKECLCTDDFYCTVNKLLGKKCINKSDNVKEDKFKWNLTTRSHHGFKGMWSCLEVAEACVGDVVCNAQLASYLKACSANGNPCDLKQCQAAIRFFYQNIPFNIAQMLAFCDCAQSDIPCQQSKEALHSKTCAVNMVPPPTCLSVIRSCQNDELCRRHYRTFQSKCWQRVTRKCHEDENCISTLSKQDLTCSGSDDCKAAYIDILGTVLQV QCTCRTITQSEESLCKIFQHMLHRKSCFNYPTLSNVKGMALYTRKHANKHHHHHH
配列番号5−人工配列
ERKSSVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSERKSSVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGASARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI
配列番号6−人工配列
DKTHTCPPCPAPALGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSGGGGSGGGGSNGTHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI
配列番号7−人工配列
APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFQLESRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGQGGGGQGGGGQGGGGQGGGGQGGGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI
配列番号8−Fcフラグメント
ESKYGPPCPPCP
配列番号9−人工配列
APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFQLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGQGGGGQGGGGQGGGGQGGGGQGGGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI
配列番号:10−人工配列
APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLESRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGQGGGGQGGGGQGGGGQGGGGQGGGGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI
配列番号:11−人工配列
APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFQLESRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSAPAPAPAPAPAPAPAPAPAPGGGGSGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI
配列番号12−人工配列
GGGGQGGGGQGGGGQGGGGQGGGGQ
配列番号13−人工配列
APAPAPAPAPAPAPAPAPAP
配列番号14−人工配列
GGGGS
配列番号15−人工配列
GGGG
配列番号16−人工配列
gaggccgccgggggaccatcagtcttcctgttccccccaaaacccaaggacactctcatgatctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccaggaagaccccgaggtccagttcaactggtacgtggatggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagttcaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaacggcaaggagtacaagtgcaaggtctccaacaaaggcctcccgtcctccatcgagaaaaccatctccaaagccaaagggcagccccgagagccacaggtgtacaccctgcccccatcccaggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgccgtggagtgggaaagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttccagctcgagagcaggctaaccgtggacaagagcaggtggcaggaggggaatgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacacagaagagcctctccctgtctctgggtggcggtggtggagctccagccccagctcctgctcctgcaccagcacctgcccccgctccagcacccgcacctggaggagggggcggtgaccactgtcccctggggcctggccggtgttgcagactgcatacagtccgggcctccctggaagacctgggttgggcagattgggtgctctcacctcgcgaggttcaggtgaccatgtgcattggggcttgtccctcacaatttcgcgcagctaacatgcacgcccaaatcaaaacctccctgcaccggcttaaaccggatactgttcctgctccctgctgcgtgccagcatcctacaaccccatggtgctgatccagaagacggatacaggggtgtcactgcagacctatgatgacctcctggccaaagattgccactgtatc
配列番号17−人工配列
DKTHTCPPCPAPALAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
Claims (22)
- 配列番号2を含む化合物。
- 配列番号2からなる化合物。
- 請求項1または2に記載の2つの化合物を含むホモダイマーであって、前記化合物が、第1の化合物のシステイン残基と第2の化合物のシステイン残基との間の少なくとも1つの鎖間ジスルフィド結合を介して連結されている、ホモダイマー。
- 請求項1〜3のいずれか1項に記載の化合物と、1つ以上の薬学的に許容される賦形剤とを含む、薬学的組成物。
- 患者の体重減少を誘発する方法であって、それを必要とする患者に有効量の請求項1〜3に記載の化合物または請求項4に記載の組成物を投与することを含む、方法。
- 患者の2型糖尿病を治療する方法であって、それを必要とする患者に有効量の請求項1〜3に記載の化合物または請求項4に記載の組成物を投与することを含む、方法。
- 患者の肥満を治療する方法であって、それを必要とする患者に有効量の請求項1〜3に記載の化合物または請求項4に記載の組成物を投与することを含む、方法。
- 患者のNASHを治療する方法であって、それを必要とする患者に有効量の請求項1〜3に記載の化合物または請求項4に記載の組成物を投与することを含む、方法。
- 患者の脂質異常症を治療する方法であって、それを必要とする患者に有効量の請求項1〜3に記載の化合物または請求項4に記載の組成物を投与することを含む、方法。
- 療法における使用のための、請求項1〜3のいずれか1項に記載の化合物。
- 体重減少を誘発する際の使用のための、請求項1〜3のいずれか1項に記載の化合物。
- 2型糖尿病の治療における使用のための、請求項1〜3のいずれか1項に記載の化合物。
- 肥満の治療における使用のための、請求項1〜3のいずれか1項に記載の化合物。
- 脂質異常症の治療における使用のための、請求項1〜3のいずれか1項に記載の化合物。
- NASHの治療における使用のための、請求項1〜3のいずれか1項に記載の化合物。
- 体重減少を誘発するための医薬の製造における、請求項1〜3のいずれか1項に記載の化合物の使用。
- 2型糖尿病の治療のための医薬の製造における、請求項1〜3のいずれか1項に記載の化合物の使用。
- 肥満の治療のための医薬の製造における請求項1〜3のいずれか1項に記載の化合物の使用。
- 脂質異常症の治療のための医薬の製造における請求項1〜3のいずれか1項に記載の化合物の使用。
- NASHの治療のための医薬の製造における請求項1〜3のいずれか1項に記載の化合物の使用。
- 配列番号2のアミノ酸配列を含むポリペプチドをコードするcDNA分子を含む哺乳動物細胞を、ポリペプチドが発現されるような条件下で培養し、化合物を回収することによって産生される化合物。
- 患者の体重減少を誘発する方法、2型糖尿病、肥満、NASHおよび/または脂質異常症を治療する方法であって、それを必要とする患者に有効量の請求項1〜3の化合物または請求項4の組成物を週1回投与することを含む方法。
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PCT/US2019/024756 WO2019195091A1 (en) | 2018-04-06 | 2019-03-29 | Growth differentiation factor 15 agonist compounds and methods of using the same |
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MA38873B1 (fr) | 2013-07-31 | 2018-11-30 | Amgen Inc | Constructions contenant le facteur 15 de différentiation de croissance (gdf-15) |
PE20201350A1 (es) | 2018-04-09 | 2020-11-30 | Amgen Inc | Proteinas de fusion del factor de diferenciacion de crecimiento 15 |
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WO2021076620A1 (en) | 2019-10-15 | 2021-04-22 | Eli Lilly And Company | Recombinantly engineered, lipase/esterase-deficient mammalian cell lines |
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