Pourjamal Negar, Le Joncour Vadim, Vereb György, Honkamaki Cilla, Isola Jorma, Leyton Jeffrey V, Laakkonen Pirjo, Joensuu Heikki, Barok Mark
Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Laboratory of Molecular Oncology, Biomedicum, University of Helsinki, Helsinki, Finland.
Neuroscience Center, Helsinki Institute of Life Sciences (HiLIFE), University of Helsinki, Helsinki, Finland.
Transl Oncol. 2025 Mar;53:102284. doi: 10.1016/j.tranon.2025.102284. Epub 2025 Jan 20.
Most HER2-positive breast or gastric cancers eventually become resistant to the approved anti-HER2 antibody-drug conjugates (ADC) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd). Disitamab vedotin (DV) is a novel anti-HER2 ADC that binds to a different epitope on HER2 compared to trastuzumab. We assessed the efficacy of DV in breast and gastric cancer cell lines and xenografts, including tumor models resistant to T-DM1 and T-DXd. Additionally, we investigated whether combining two anti-HER2 ADCs could enhance the efficacy of the individual ADCs.
The efficacy of DV, T-DM1, and T-DXd, both as single agents and in combinations, was assessed using an AlamarBlue cell proliferation assay in HER2-positive breast and gastric cancer cell lines, including those resistant to T-DM1 and T-DXd. The efficacy of DV was evaluated also in breast and gastric cancer SCID mouse xenografts that had progressed on T-DM1 and/or T-DXd. ADC combinations were tested in breast and gastric cancer xenografts.
DV was effective in cell lines resistant to T-DM1 and/or T-DXd, and it inhibited the growth of breast and gastric cancer xenografts that had progressed on T-DM1 and/or T-DXd. The combinations of DV plus T-DM1 and DV plus T-DXd showed greater efficacy than the corresponding single agents in both breast and gastric cancer cell lines and xenografts.
DV was effective in treating breast and gastric cancer xenograft tumors resistant to T-DM1 and/or T-DXd. The combination of DV with T-DM1 or T-DXd demonstrated promising activity.
大多数HER2阳性乳腺癌或胃癌最终会对已获批的抗HER2抗体药物偶联物（ADC）曲妥珠单抗-美坦新（T-DM1）和德曲妥珠单抗（T-DXd）产生耐药。迪西他单抗维汀（DV）是一种新型抗HER2 ADC，与曲妥珠单抗相比，它与HER2上的不同表位结合。我们评估了DV在乳腺癌和胃癌细胞系及异种移植模型中的疗效，包括对T-DM1和T-DXd耐药的肿瘤模型。此外，我们研究了联合使用两种抗HER2 ADC是否能增强单个ADC的疗效。
在HER2阳性乳腺癌和胃癌细胞系中，包括对T-DM1和T-DXd耐药的细胞系，使用alamarBlue细胞增殖试验评估DV、T-DM1和T-DXd单药及联合用药的疗效。还在对T-DM1和/或T-DXd已进展的乳腺癌和胃癌SCID小鼠异种移植模型中评估DV的疗效。在乳腺癌和胃癌异种移植模型中测试ADC联合用药。
DV对T-DM1和/或T-DXd耐药的细胞系有效，并且它抑制了对T-DM1和/或T-DXd已进展的乳腺癌和胃癌异种移植瘤的生长。在乳腺癌和胃癌细胞系及异种移植模型中，DV加T-DM1和DV加T-DXd的联合用药比相应的单药显示出更高的疗效。
DV对治疗对T-DM1和/或T-DXd耐药的乳腺癌和胃癌异种移植瘤有效。DV与T-DM1或T-DXd联合显示出有前景的活性。
