Angiogenesis plays an essential role in tumor growth and metastasis. Anti-angiogenic therapy has been considered effective approach to war various cancers. Although many antiangiongenic agents, especially vascular endothelial growth factor (VEGF) inhibitors, showed promising results in animal models, the efficacy in cancer patients was more modest in terms of overall survival and some vascular-related toxicities often hindered the long-term treatment. Thus, more potent and safe strategy is needed. A number of antibodies and recombinant affinity molecules are explored to find their potential therapeutic value. Our group recently developed a peptide scaffold termed ‘aptide’ that has high affinity and selectivity onto its target. Here, I describe a design and preparation of EDB and VEGF bisepcific aptide fusion proteins for potential anti-angiogenic therapy.
In chapter 2, in order to achieve more efficient therapy, I modified VEGF-trap, which is currently used in the clinic, by fusing tumor targeting ligand, an aptide targeting EDB ($APT_{EDB}$). Resulting recombinant protein, VEGF-Trap-$APT_{EDB}$ was secreted from mammalian cell, purified, and showed dual-binding activities. In addition, it showed anti-angiogenic effect and tumor-targeting ability in vitro. We expect VEGF-trap-$APT_{EDB}$ may provide more efficient and safe therapeutic value than VEGF-Trap.
In chapter 3, I described a potential anti-angiogenic platform using two aptides. Given that our VEGF-targeting aptide ($APT_{VEGF}$) had anti-angiogenic effect in choroidal and retinal neovascularization in vivo, I designed so-called bispecific aptibody for cancer therapy, by fusing on $APT_{VEGF}$ one side of human Fc of IgG and $APT_{EDB}$ on the other side for tumor targeting. It was secreted from mammalian cell, purified and examined its target binding activities and dualbinding activity. Although present study failed to show dual-binding activity, this study may provide directions for designing bispecific aptide-fusion platforms for potential cancer therapy.
Angiogenesis 는 암의 성장과 전이에서 중요한 역할을 한다. 신혈관생성의 억제는 다양한 암을 치료하는 데에 있어 효과적인 전략으로 여겨지고 있다. 비록 많은 신혈관생성 억제 약물, 특히 VEGF 억제제들이 동물 모델에서 상당한 효과를 보였지만, 실제 환자들에서는 그만큼의 효과는 보이지 못했으며, 정상조직에서의 VEGF 억제로 인한 부작용들은 이들 약물의 장기간 사용을 방해하였다. 따라서 이러한 사실들은 더욱 효과적이고 안전한 전략이 필요함을 암시하고 있다. 우리 연구팀에서는 최근 고친화력 펩타이드인 앱타이드를 개발하여 biomedical 분야에서 다양하게 응용하고 있다. 이 논문에서는 효과적인 anti-angiogenic therapy 를 위한 EDB 와 VEGF에 이중특이적인 앱타이드 융합단백질의 디자인과 생산 및 특성 분석에 대해 보고하고 있다.
