Induction of anti-EGFR immune response with mimotopes identified from a phage display peptide library by panitumumab.
Induction of anti-EGFR immune response with mimotopes identified from a phage display peptide library by panitumumab.
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使用帕尼单抗从噬菌体展示肽库中鉴定出的模拟表位诱导抗 EGFR 免疫应答
DOI：
10.18632/oncotarget.12167
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发表时间：
2016-11-15
期刊：
影响因子：
--
通讯作者：
Su X
中科院分区：
文献类型：
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作者：
Wang A;Cui M;Qu H;Di J;Wang Z;Xing J;Wu F;Wu W;Wang X;Shen L;Jiang B;Su X
表皮生长因子受体（EGFR）在几种上皮肿瘤中过表达。抗EGFR人源化单克隆抗体西妥昔单抗和帕尼单抗联合化疗改善了野生型RAS肿瘤患者的预后。为了鉴定EGFR的模拟表位并开发基于模拟表位的EGFR疫苗，我们用帕尼单抗筛选了噬菌体展示肽库。分离出两个可被帕尼单抗特异性识别的EGFR模拟表位P19和P26。为了增强免疫反应，我们产生了与热休克相关蛋白70（Hsc 70）融合的P19或P26重组蛋白，并评估了Hsc 70-P19和Hsc 70-P26作为体内疫苗的功效。用Hsc 70-P19或Hsc 70-P26融合蛋白免疫刺激免疫系统产生针对肽以及EGFR的特异性抗体。此外，针对模拟表位的抗体可以诱导抗体依赖性细胞毒性（ADCC），补体依赖性细胞毒性（CDC），并抑制EGFR过表达的A431细胞的增殖。用Hsc 70-P19和Hsc 70-P26治疗显著降低BALB/c可移植肺癌模型中的肿瘤生长。尽管通过比对，噬菌体衍生肽和EGFR之间没有序列同源性，但两种肽均模拟EGFR与帕尼单抗结合的构象结构。因此，我们从噬菌体肽库中筛选出的模拟表位有望成为抗EGFR主动免疫治疗的候选疫苗。
The epidermal growth factor receptor (EGFR) is overexpressed in several epithelial tumors. Anti-EGFR humanized monoclonal antibodies, cetuximab and panitumumab, in combination with chemotherapy have improved the prognosis for patients with wild-type RAS tumors. To identify mimotopes of EGFR and develop mimotope-based EGFR vaccines, we screened a phage display peptide library with panitumumab. Two EGFR mimotopes P19 and P26, which could be recognized by panitumumab specifically, were isolated. To enhance the immune responses, we generated recombinant proteins of P19 or P26 fused to a heat-shock cognate protein 70 (Hsc70), and evaluated the efficacy of Hsc70-P19 and Hsc70-P26 as vaccines in vivo. Immunization with Hsc70-P19 or Hsc70-P26 fusion protein stimulated the immune system to produce specific antibodies against peptides as well as EGFR. Moreover, antibodies elicited against mimotopes could induce antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and inhibit the proliferation of EGFR-overexpressing A431 cells. Treatment with Hsc70-P19 and Hsc70-P26 significantly reduced tumor growth in BALB/c transplantable lung cancer models. Although there was no sequence homology between the phage-derived peptides and EGFR by alignments, both peptides mimic the conformational structure of EGFR binding to panitumumab. In conclusion, the mimotopes we identified from phage display peptide library could be promising candidate vaccines for active anti-EGFR immunotherapy against cancers.