IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U896, Université Montpellier1, CRLC Val d'Aurelle Paul Lamarque, 208 rue des Apothicaires, Montpellier, F-34298, France.
Breast Cancer Res. 2011 Feb 4;13(1):R17. doi: 10.1186/bcr2826.
Novel adjuvant therapies are needed to prevent metastatic relapses in HER2-expressing breast cancer. Here, we tested whether trastuzumab-selected single-chain Fv (scFv) could be used to develop an anti-idiotype-based vaccine to inhibit growth of HER2-positive tumor cells in vitro and in vivo through induction of long-lasting HER-specific immunity.
BALB/c mice were immunized with anti-trastuzumab anti-idiotype (anti-Id) scFv (scFv40 and scFv69), which mimic human HER2. Their sera were assessed for the presence of HER2-specific Ab1' antibodies and for their ability to reduce viability of SK-OV-3 cells, a HER2-positive cancer cell line, in nude mice. MMTV.f.huHER2(Fo5) transgenic mice were immunized with scFv40 and scFv69 and, then, growth inhibition of spontaneous HER2-positive mammary tumors, humoral response, antibody isotype as well as splenocyte secretion of IL2 and IFN-γ were evaluated.
Adoptively-transferred sera from BALB/c mice immunized with scFv40 and scFv69 contain anti-HER2 Ab1' antibodies that can efficiently inhibit growth of SK-OV-3 cell tumors in nude mice. Similarly, prophylactic vaccination with anti-Id scFv69 fully protects virgin or primiparous FVB-MMTV.f.huHER2(Fo5) females from developing spontaneous mammary tumors. Moreover, such vaccination elicits an anti-HER2 Ab1' immune response together with a scFv69-specific Th1 response with IL2 and IFN-γ cytokine secretion.
Anti-trastuzumab anti-Id scFv69, used as a therapeutic or prophylactic vaccine, protects mice from developing HER2-positive mammary tumors by inducing both anti-HER2 Ab1' antibody production and an anti-HER2 Th2-dependent immune response. These results suggest that scFv69 could be used as an anti-Id-based vaccine for adjuvant therapy of patients with HER2-positive tumors to reverse immunological tolerance to HER2.
需要新的佐剂疗法来预防 HER2 表达型乳腺癌的转移性复发。在这里，我们测试了曲妥珠单抗选择的单链 Fv（scFv）是否可用于开发基于抗独特型的疫苗，通过诱导持久的 HER 特异性免疫来抑制体外和体内 HER2 阳性肿瘤细胞的生长。
用抗曲妥珠单抗抗独特型（抗-Id）scFv（scFv40 和 scFv69）免疫 BALB/c 小鼠，scFv40 和 scFv69 模拟人类 HER2。评估其血清中是否存在 HER2 特异性 Ab1'抗体，以及其在裸鼠中降低 HER2 阳性癌细胞系 SK-OV-3 细胞活力的能力。用 scFv40 和 scFv69 免疫 MMTV.f.huHER2（Fo5）转基因小鼠，然后评估自发 HER2 阳性乳腺肿瘤的生长抑制、体液反应、抗体同种型以及脾细胞分泌的 IL2 和 IFN-γ。
用 scFv40 和 scFv69 免疫的 BALB/c 小鼠的过继转移血清中含有可有效抑制裸鼠 SK-OV-3 细胞肿瘤生长的抗 HER2 Ab1'抗体。同样，预防性接种抗独特型 scFv69 可完全保护处女或初产 FVB-MMTV.f.huHER2（Fo5）雌性免于发生自发性乳腺肿瘤。此外，这种疫苗接种会引发抗 HER2 Ab1'免疫反应以及 scFv69 特异性 Th1 反应，伴有 IL2 和 IFN-γ细胞因子分泌。
作为治疗或预防性疫苗，抗曲妥珠单抗抗独特型 scFv69 通过诱导抗 HER2 Ab1'抗体产生和抗 HER2 Th2 依赖性免疫反应来保护小鼠免受 HER2 阳性乳腺肿瘤的发展。这些结果表明，scFv69 可用于 HER2 阳性肿瘤的辅助治疗，以逆转对 HER2 的免疫耐受，作为基于抗独特型的疫苗。
