A Multicenter, Open Label, Phase I Dose Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Intravenous SAIT301 in Subjects With Advanced c-MET Positive (+) Solid Tumors Followed by Expansion in Selected Tumor Types

Mesenchymal epithelial transition factor (c-MET) is a receptor tyrosine kinase that, when engaged by its ligand hepatocyte growth factor (HGF), has been implicated in various cellular process including development as well as oncogenesis.
SAIT301 is a novel humanized monoclonal antibody targeting the alpha chain of extracellular domain of c-MET. Binding of SAIT301 to c-MET blocks HGF binding and inhibits HGF-mediated signaling. Furthermore, SAIT301 also induces efficient c-MET internalization from the cell surface and subsequent degradation, resulting in inhibition of growth of the c-MET addicted cancer cells.
The sponsor decided to enroll subjects with tumors that express c-MET (by immunohistochemistry [IHC]) for this study, as the subjects with no c-MET expression are unlikely to benefit from SAIT301 treatment.
Stage 1 of this Phase I study is designed to evaluate the safety, tolerability, pharmacokinetic (PK) profile, and anti-tumor activity of SAIT301 administered as a single IV infusion in 21 day cycles, for up to 4 cycles. Subjects without evidence of tumor progression after 4 cycles will be eligible to continue on SAIT301 treatment if there is no evidence of tumor progression for a further 4 cycles (Cycles 5 to 8). Biomarkers related to SAIT301 and/or tumor response will also be evaluated.Stage 2 will further evaluate the safety and PK profile of SAIT301 in select types of cancers. Dosing frequency may be adjusted based on the PK profile obtained during Stage 1.

开始日期2015-01-20

申办/合作机构

Samsung Medical Center

100 项与 SAIT-301 相关的临床结果

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100 项与 SAIT-301 相关的转化医学

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100 项与 SAIT-301 相关的专利（医药）

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项与 SAIT-301 相关的文献（医药）

2018-06-01·Clinical Colorectal Cancer2区 · 医学

Phase I Trial of Anti-MET Monoclonal Antibody in MET-Overexpressed Refractory Cancer

2区 · 医学

Article

作者: Park, Sungju ; Lee, Sujin ; Ahn, Hongmo ; Lim, Ho Yeong ; Park, Joon Oh ; Bok, Haesook ; Kim, Kyoung-Mee ; Kang, Won Ki ; Park, Se Hoon ; Park, Young Suk ; Lee, Jeeyun ; Kim, Seung Tae ; Ahn, Myung Ju

BACKGROUNDSamsung Advance Institute of Technology-301 (SAIT301) is a human immunoglobulin G2 antibody that can specifically target mesenchymal epithelial transition factor (c-MET). This novel antibody has higher priority over hepatocyte growth factors when binding to the Sema domain of c-MET and accelerates the internalization and degradation of c-MET, proving its powerful antitumor activities in intra- as well as extracellular areas.MATERIALS AND METHODSSAIT301 was administered intravenously once every 3 weeks in c-MET overexpressed solid tumor patients, focusing on metastatic colorectal cancer (CRC) according to common clinical phase I criteria. Dose escalation was performed according to a modified Fibonacci design, following the conventional 3+3 design. The purpose of this phase I study was to assess the safety profile, to establish the recommended dose for clinical phase II studies and to assess potential anticancer activity of the compound.RESULTSSixteen patients with a median age of 56 (range, 39-69) years were enrolled in the study. The most common adverse events were decreased appetite (50.0%), hypophosphatemia, fatigue and dizziness (25.0%, respectively), and diarrhea, blood alkaline phosphatase increased and dyspnea (18.8%, respectively). For tumor response, no patients achieved complete response. One (9.1%) CRC patient had a partial response in the 1.23 mg/kg group, 4 (36.4%) patients achieved stable disease (2 in the 0.41 mg/kg group, 2 in the 1.23 mg/kg group, 0 in the 3.69 mg/kg group, and 1 in the 8.61 mg/kg group). Because of the increase in dose-limiting toxicities (DLTs) at 8.61 mg/kg, the 3.69 mg/kg dose was considered the maximum tolerated dose and selected for further assessment in phase II.CONCLUSIONWe successfully completed a phase I trial with MET antibody in a MET-overexpressed patient population focusing on CRC, and found that the DLTs were alkaline phosphatase elevation or hypophosphatemia. The recommended dose of SAIT301 for phase II is the dose of 3.69 mg/kg.

2015-02-26·Oncogene1区 · 医学

Synthetic lethal screening reveals FGFR as one of the combinatorial targets to overcome resistance to Met-targeted therapy

1区 · 医学

Article

作者: Park, H W ; Kim, K-A ; Son, D-S ; Lee, J M ; Lee, E ; Weiner, L M ; Lee, S B ; Wang, S ; Oh, Y M ; Murray, J C ; Jeong, Y ; Song, Y-J ; Zhou, Y ; Ahn, T ; Kim, B ; Yoo, H-s ; Choi, J ; Song, P H

Met is a receptor tyrosine kinase that promotes cancer progression. In addition, Met has been implicated in resistance of tumors to various targeted therapies such as epidermal growth factor receptor inhibitors in lung cancers, and has been prioritized as a key molecular target for cancer therapy. However, the underlying mechanism of resistance to Met-targeting drugs is poorly understood. Here, we describe screening of 1310 genes to search for key regulators related to drug resistance to an anti-Met therapeutic antibody (SAIT301) by using a small interfering RNA-based synthetic lethal screening method. We found that knockdown of 69 genes in Met-amplified MKN45 cells sensitized the antitumor activity of SAIT301. Pathway analysis of these 69 genes implicated fibroblast growth factor receptor (FGFR) as a key regulator for antiproliferative effects of Met-targeting drugs. Inhibition of FGFR3 increased target cell apoptosis through the suppression of Bcl-xL expression, followed by reduced cancer cell growth in the presence of Met-targeting drugs. Treatment of cells with the FGFR inhibitors substantially restored the efficacy of SAIT301 in SAIT301-resistant cells and enhanced the efficacy in SAIT301-sensitive cells. In addition to FGFR3, integrin β3 is another potential target for combination treatment with SAIT301. Suppression of integrin β3 decreased AKT phosphorylation in SAIT301-resistant cells and restored SAIT301 responsiveness in HCC1954 cells, which are resistant to SAIT301. Gene expression analysis using CCLE database shows that cancer cells with high levels of FGFR and integrin β3 are resistant to crizotinib treatment, suggesting that FGFR and integrin β3 could be used as predictive markers for Met-targeted therapy and provide a potential therapeutic option to overcome acquired and innate resistance for the Met-targeting drugs.

2014-01-02·Oncogene1区 · 医学

Cbl-independent degradation of Met: ways to avoid agonism of bivalent Met-targeting antibody

1区 · 医学

Article

作者: Han, Y K ; Lee, S ; Jung, S ; Park, H W ; Cheong, K H ; Choi, J ; Kim, K A ; Oh, Y M ; Jeong, Y ; Lee, S B ; Song, Y-J ; Choi, H ; Kim, G W ; Kim, B ; Kim, D U ; Lee, J M ; Song, P H

The Met receptor tyrosine kinase, found to be constitutively activated in many tumors, has become a leading target for cancer therapy. Disruptions in Met downregulation have been associated with aggressive tumor progression with several therapeutic strategies addressing this aspect of Met biology. Castias B-lineage lymphoma (Cbl) E3 ligase-mediated degradation, which attenuates Met signaling via ligand-dependent Met internalization, is a major negative regulator of Met expression. It is believed that one of the mechanisms by which the therapeutic anti-Met antibodies induce cancer cell death in Met overexpressing tumors is via internalization and subsequent degradation of Met from the cell surface. However, a previously reported Met-targeting antibody demonstrated intrinsic agonistic activity while being capable of inducing Cbl-mediated degradation of Met, suggesting that Cbl-mediated degradation requires receptor activation and impedes therapeutic application. We have developed a potent and selective bivalent Met-targeting antibody (SAIT301) that invokes Met degradation using an alternative regulator LRIG1. In this report, we demonstrate that LRIG1 mediates degradation of Met by SAIT301 and this degradation does not require Met activation. Furthermore, SAIT301 was able to downregulate Met and dramatically inhibit growth of tumors with low or no Cbl expression, as well as tumors with Met exon 14 deletion that prevents Met binding to Cbl. In summary, we demonstrate the enhanced therapeutic potential of a novel tumor-inhibiting anti-Met antibody, SAIT301, which utilizes a Cbl-independent, LRIG1-mediated Met degradation pathway and thereby avoids the agonism that limits the effectiveness of previously reported anti-Met antibodies.

项与 SAIT-301 相关的新闻（医药）

2024-10-17

·药精通Bio

艾伯维cMET ADC申请上市，多款EGFRxcMET 双抗ADC已在路上，孰优孰劣？

▎追溯 9月27日，艾伯维宣布向美国食品药品监督管理局 (FDA) 提交生物制品许可申请 (BLA)，以加速批准 telisotuzumab vedotin (Teliso-V) 用于治疗先前接受过治疗的局部晚期或转移性表皮生长因子受体 (EGFR) 野生型、非鳞状非小细胞肺癌 (NSCLC) 且 cMet蛋白过表达的成年患者。该款药物属于艾伯维cMET MMAE ADC，第二代cMET topoi ADC也已迅速推进至后期临床。 BLA 申请基于2 期 LUMINOSITY 试验研究。结果显示，总人群、c-Met高表达和c-Met中等表达患者经独立中央审查（ICR）评估的总体缓解率分别为28.6%、34.6%和22.9%，中位缓解持续时间（DOR）分别为8.3个月、9.0个月和7.2个月，中位总生存期（OS）分别为14.5个月、14.6个月和14.2个月，中位无进展生存期（PFS）分别为5.7个月、5.5个月和6.0个月。 Teliso-V的安全性与之前的研究结果一致，没有发现新的安全性问题。最常见的任何级别治疗相关不良事件（TRAE）是外周感觉神经病变（30%）、外周性水肿（16%）和疲劳（14%），最常见的≥3级AE是外周感觉神经病变（7%）。三期临床也在开展之中，Teliso-V对比多西他赛二线治疗c-Met蛋白过表达、EGFR野生型晚期/转移性非鳞状NSCLC成人患者的疗效和安全性。新一代TOPOi cMET ADC，ABV-400也已推进至三期临床。迄今为止，针对cMET靶点，只有cMETxEGFR双特异性抗体Amivantamab(RYBREVANT) 获得了 FDA 的批准。先前一些被广泛研究的抗cMET抗体包括 Onartuzumab (MetMab)、Emibetuzumab (LY2875358)、Telituzumab (ABT-700)、Sym015、SAIT301 和 HLX55，都没有太好的临床进展。源于cMET单克隆抗体倾向于诱导激动活性，从而导致肿瘤细胞增殖而不是凋亡。后续迭代抗体通过构建单臂抗体来避免这种情况，从而防止受体二聚化的发生，或者通过发现和进一步铰链区设计不表现出功能性激动剂活性的单克隆抗体，如Telituzumab (ABT-700)。 Telituzumab (ABT-700)来源于Pierre Fabre开发的一款cMet拮抗型（Antagonist）抗体h224G11，在人源化后，发现有激活作用，后又根据母本鼠抗的铰链区和人IgG2铰链区进行工程化设计，多了一对二硫键。ABT-700 结合细胞 c-Met，并破坏其由 HGF 或细胞表面高密度 c-Met 诱导的二聚化和活化，不依赖于配体。大多数二价cMET单抗都有激活作用。这也是后来多数cMET抗体开发为单价的原因。来源津津药道该抗体国内到2029年专利过期，以目前的时间来看，可以使用。 cMET作为肺癌的重要布局靶点，大约 85% 的肺癌被归类为 NSCLC ，尽管治疗取得了一定进步，然而肺癌仍然是全世界男性和女性癌症相关死亡的主要原因。在大约25%的晚期 EGFR 野生型 NSCLC 患者中发现了 c-Met 蛋白过度表达，并且与这些患者的不良预后相关。这就产生一个问题，cMET单抗ADC与EGFRxcMET ADC到底谁更有优势。毫无疑问的是，在我先前的经验中，二价单抗ADC的杀伤能力以及引导内吞能力要比单价单抗ADC更为优异。但毕竟EGFRxcMET作为双抗ADC，而双抗ADC是由表达驱动的偏向性药效，也就是说如果在一个肿瘤细胞中，EGFR过表达，药效就偏向EGFR，反之则偏向cMET，二价双抗ADC在某些特定情况下还能产生协同作用，比如表达相近时。从基因层面，EGFR，cMET具有很好的相关性，但同时也存在表达差异。也就是说多数情况下，EGFRxcMET ADC并不会差于单抗cMET ADC。当然在EGFR极度不表达的情况下，只有cMET表达，cMET单抗ADC可能会优于EGFRxcMET ADC，反之亦然。从蛋白层面来看，多数情况下EGFR表达优于cMET，双抗ADC可能会更偏向于EGFR驱动药效。多年前设计EGFRxcMET ADC的理论也都是以弱化EGFR端亲和力的设计，阿斯利康也是类似设计，但目前来看几款EGFR ADC并未产生太强的靶向毒性，所以可能也未必需要太过强调EGFR作为ADC靶点的on target毒性。但不可避免的会迎来这EGFR ADC，EGFRxcMET ADC（二价），cMET ADC的差异性。EGFR ADC在多种肿瘤中可能因EGFR表达优势会占据疗效优势，而EGFRxcMET ADC在于具有广谱性和在某些肿瘤的上两者的协同作用，cMET占据的优势在于完全由cMET表达驱动，作为单价的双抗ADC会存在一定劣势。也就是说需要寻找适合的适应症来发挥这几款药物的真正优势。但开发的早，这种寻找优势的对比要求就弱很多，但开发的越晚要求越高。一如现在的TROP2 DXD面临的尴尬局面。 EGFR，cMET作为优异的靶点，都是ADC领域布局的热门。需要提醒的是，抗体并不能等同于ADC，并不是双抗ADC成功就没有必要开发双抗，也不是双抗成功了也无需开发双抗ADC，这两者的类型和作用机制完全不同。同时开发，也许更能充分的进行细分适应症的布局。 END 免责声明：本文仅作知识交流与分享及科普目的，不涉及商业宣传，不作为相关医疗指导或用药建议。文章如有侵权请联系删除。 OTC2024类器官前沿应用与3D细胞培养论坛圆满落幕，点击图片可查看会后报告，咨询OTC2025类器官论坛请联系：王晨 180 1628 8769

抗体药物偶联物临床3期

100 项与 SAIT-301 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
肿瘤	临床1期	-	Kangbuk Samsung Medical Center	-
c-met阳性实体瘤	药物发现	韩国	Samsung Medical Center	2015-01-20
实体瘤	药物发现	韩国	Samsung Medical Center	2015-01-20