ASCO 2014：新型免疫类抗癌药物NKTR-214临床前研究结果显著
2014-06-09 MedSci MedSci原创
最近旧金山的生物技术公司Nektar公司表示公司开发的新型抗癌药NKTR－214能够明显抑制恶性肿瘤的生长并对多种恶性肿瘤都有疗效。这种药物主要是通过激活IL-2受体复合物来激活患者自身免疫系统以达到清除肿瘤细胞的效果。同时，研究人员还在乳腺癌模型EMT6以及大肠癌模型CT26上检验了NKTR-214与其他免疫药物如抗PD-1药物以及抗CTLA-4药物联合使用的疗效。结果表明联合治疗相对于单独使用
最近旧金山的生物技术公司Nektar公司表示公司开发的新型抗癌药NKTR－214能够明显抑制恶性肿瘤的生长并对多种恶性肿瘤都有疗效。这种药物主要是通过激活IL-2受体复合物来激活患者自身免疫系统以达到清除肿瘤细胞的效果。
同时，研究人员还在乳腺癌模型EMT6以及大肠癌模型CT26上检验了NKTR-214与其他免疫药物如抗PD-1药物以及抗CTLA-4药物联合使用的疗效。结果表明联合治疗相对于单独使用抗PD－1或抗CTLA－4类药物有明显改善。例如在EMT6模型中，只使用抗CTLA－4类药物或抗PD－1药物对肿瘤的抑制率进位23％，而联合用药的抑制率则达到了74％。这一研究结果被公布在本月一号在芝加哥举办的全美肿瘤学会年会（ASCO）上，摘要号3082。
Background: Durability of response is the hallmark of
immunotherapy but only a fraction of patients experience this prolonged
benefit. Recent studies suggest more patients may benefit from
combining agents with complementary immunological mechanisms. NKTR-214
is an engineered form of IL-2 that directly activates cytotoxic T cells
by targeting the IL-2 receptor beta subunit and exhibits a
pharmacokinetic profile that is more like an antibody than a cytokine.
Anti-CTLA-4 and anti-PD1 are antibodies that block negative regulation
of T cells. Here we show that combining either antibody with NKTR-214,
provides significant tumor growth inhibition in resistant mouse models.
Methods: For combination studies, BALB/c mice bearing
established CT-26 (Colon Carcinoma) or EMT6 (Mammary Carcinoma) tumors
were treated with single agent NKTR-214, murine anti-CTLA-4 antibody,
murine anti-PD-1 or the two agents in combination. Results:
NKTR-214 exhibits a plasma and tumor exposure that is 600-fold and
500-fold greater respectively, than an equivalent dose of the original
IL-2 cytokine. The optimized PK profile allows q9d dosing schedule
instead of bid; the latter being typical for cytokines. In both the
EMT-6 and the CT-26 models, the combination of NKTR-214 with anti-CTLA-4
provided 10/12 and 8/12 tumor-free animals respectively, up to 40 days
after the last dose and showed clear synergy compared to either agent
alone. The combination with anti-PD1 was also synergistic and showed
tumor regression in 5/10 animals. Single agent administration did not
show any significant tumor growth inhibition in these models. The
combinations were well tolerated with no body weight loss or other
clinical signs. Conclusions: NKTR-214 directly stimulates
cytotoxic T cells and is therefore complementary to the mechanism of
checkpoint inhibition using antibodies. The favorable pharmacokinetics
of NKTR-214 enables dosing schedules that are more like an antibody
allowing convenient combination with other antibodies. Combining
NKTR-214 mediated T cell activation with CTLA-4 or PD1 blockade is
synergistic in murine models of cancer and holds the promise for durable
responses in humans.
作者：MedSci
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