临床 KRAS(G12C) 抑制剂 AMG 510 驱动抗肿瘤免疫,Nature

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临床 KRAS(G12C) 抑制剂 AMG 510 驱动抗肿瘤免疫
Nature ( IF 50.5 ) Pub Date : 2019-10-30 , DOI: 10.1038/s41586-019-1694-1
Jude Canon ₁ , Karen Rex ₁ , Anne Y Saiki ₁ , Christopher Mohr ₁ , Keegan Cooke ₁ , Dhanashri Bagal ₂ , Kevin Gaida ₁ , Tyler Holt ₁ , Charles G Knutson ₃ , Neelima Koppada ₃ , Brian A Lanman ₁ , Jonathan Werner ₁ , Aaron S Rapaport ₂ , Tisha San Miguel ₁ , Roberto Ortiz _{3,

4} , Tao Osgood ₁ , Ji-Rong Sun ₁ , Xiaochun Zhu _{3,

5} , John D McCarter ₁ , Laurie P Volak _{3,

6} , Brett E Houk ₇ , Marwan G Fakih ₈ , Bert H O'Neil ₉ , Timothy J Price _{10,

11} , Gerald S Falchook ₁₂ , Jayesh Desai ₁₃ , James Kuo ₁₄ , Ramaswamy Govindan ₁₅ , David S Hong ₁₆ , Wenjun Ouyang ₂ , Haby Henary ₇ , Tara Arvedson ₂ , Victor J Cee ₁ , J Russell Lipford ₁

Affiliation

Amgen Research, Amgen Inc, Thousand Oaks, CA, USA.
Amgen Research, Amgen Inc, South San Francisco, CA, USA.
Amgen Research, Amgen Inc, Cambridge, MA, USA.
Pfizer, La Jolla, CA, USA.
Takeda, Cambridge, MA, USA.
Celgene, San Diego, CA, USA.
Amgen Clinical Development, Amgen Inc, Thousand Oaks, CA, USA.
City of Hope, Duarte, CA, USA.
Indiana University School of Medicine, Indianapolis, IN, USA.
The Queen Elizabeth Hospital, Woodville, South Australia, Australia.
University of Adelaide, Adelaide, South Australia, Australia.
Sarah Cannon Research Institute, Denver, CO, USA.
Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
Scientia Clinical Research, Randwick, New South Wales, Australia.
Washington University School of Medicine, St Louis, MO, USA.
The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

KRAS 是癌症中最常见的突变癌基因，编码肿瘤中的关键信号蛋白 1,2。KRAS(G12C) 突变体具有半胱氨酸残基，已被用于设计具有良好临床前活性的共价抑制剂3-5。在这里，我们优化了一系列抑制剂，使用新的结合相互作用显着提高了它们的效力和选择性。我们的努力导致了 AMG 510 的发现，据我们所知，这是临床开发中的第一个 KRAS(G12C) 抑制剂。在临床前分析中，AMG 510 治疗导致 KRASG12C 肿瘤消退，并提高了化疗和靶向药物的抗肿瘤功效。在有免疫能力的小鼠中，使用 AMG 510 进行治疗会产生促炎性肿瘤微环境，并单独或与免疫检查点抑制剂联合使用产生持久的治愈效果。治愈的小鼠拒绝同基因 KRASG12D 肿瘤的生长，这表明针对共享抗原的适应性免疫。此外，在临床试验中，AMG 510 在第一批给药队列中表现出抗肿瘤活性，并代表了对缺乏有效治疗的患者的潜在变革性疗法。用 KRAS(G12C) 抑制剂 AMG 510 治疗 KRASG12C 突变癌细胞领先对小鼠的持久反应和患者的抗肿瘤活性表明 AMG 510 可能对目前缺乏治疗的患者有效。这表明对共享抗原的适应性免疫。此外，在临床试验中，AMG 510 在第一批给药队列中表现出抗肿瘤活性，并代表了对缺乏有效治疗的患者的潜在变革性疗法。用 KRAS(G12C) 抑制剂 AMG 510 治疗 KRASG12C 突变癌细胞领先对小鼠的持久反应和患者的抗肿瘤活性表明 AMG 510 可能对目前缺乏治疗的患者有效。这表明对共享抗原的适应性免疫。此外，在临床试验中，AMG 510 在第一批给药队列中表现出抗肿瘤活性，并代表了对缺乏有效治疗的患者的潜在变革性疗法。用 KRAS(G12C) 抑制剂 AMG 510 治疗 KRASG12C 突变癌细胞领先对小鼠的持久反应和患者的抗肿瘤活性表明 AMG 510 可能对目前缺乏治疗的患者有效。

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The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity

KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours1,2. The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity3–5. Here we optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity. Our efforts have led to the discovery of AMG 510, which is, to our knowledge, the first KRAS(G12C) inhibitor in clinical development. In preclinical analyses, treatment with AMG 510 led to the regression of KRASG12C tumours and improved the anti-tumour efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG 510 resulted in a pro-inflammatory tumour microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRASG12D tumours, which suggests adaptive immunity against shared antigens. Furthermore, in clinical trials, AMG 510 demonstrated anti-tumour activity in the first dosing cohorts and represents a potentially transformative therapy for patients for whom effective treatments are lacking.Treatment of KRASG12C-mutant cancer cells with the KRAS(G12C) inhibitor AMG 510 leads to durable response in mice, and anti-tumour activity in patients suggests that AMG 510 could be effective in patients for whom treatments are currently lacking.

更新日期：2019-10-30

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