Impact of glycoengineering and antidrug antibodies on the anticancer activity of a plant-made lectin-Fc fusion protein.
Impact of glycoengineering and antidrug antibodies on the anticancer activity of a plant-made lectin-Fc fusion protein.
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DOI：
10.1111/pbi.13902
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发表时间：
2022-11
影响因子：
13.8
通讯作者：
Matoba, Nobuyuki
中科院分区：
文献类型：
--
作者：
Dent, Matthew;Mayer, Katarina L.;Garcia, Noel Verjan;Guo, Haixun;Kajiura, Hiroyuki;Fujiyama, Kazuhito;Matoba, Nobuyuki
关键词：
植物是生产糖工程单克隆抗体和抗体样分子的有效生产平台。Avaren-Fc（AvFc）是本氏烟草中产生的一种凝集素-Fc融合蛋白或凝集体，可选择性识别癌症相关的高甘露糖聚糖。在这项研究中，我们报告了AvFc糖变体的产生，该变体不含植物聚糖，包括核心α 1，3-岩藻糖和β 1，2-木糖残基。通过使用HPLC的聚糖分析证实了这些聚糖的成功去除。该变体AvFcΔXF对Fc γ受体具有显著更高的亲和力，并在针对B16 F10鼠黑色素瘤细胞的抗体依赖性细胞介导的细胞毒性（ADCC）报告基因试验中诱导更高水平的荧光素酶表达，而不诱导细胞凋亡或抑制增殖。在B16 F10侧腹肿瘤小鼠模型中，我们发现全身给予AvFcΔXF（而非缺乏Fc受体亲和力的无糖基化AvFc变体）可显著延迟肿瘤生长，表明Fc介导的效应子功能是不可或缺的。AvFcΔXF治疗还显著降低了B16 F10在静脉内激发后的肺转移，而糖结合缺陷突变体未能显示出疗效。最后，我们通过在植入肿瘤前用AvFcΔXF预处理动物，确定了抗药抗体（ADA）对体内药物活性的影响。尽管预处理诱导了显著的ADA应答，但我们发现AvFcΔXF的活性不受这些抗体存在的影响。这些结果表明，糖工程是一个强大的战略，以提高AvFc的抗肿瘤活性。当从Fc聚糖中去除核心岩藻糖残基时，植物产生的凝集体Avaren-Fc显示出增强的抗肿瘤活性。抗药物抗体似乎增强抗肿瘤功效，可能是通过lectibody的疫苗效应。
Plants are an efficient production platform for manufacturing glycoengineered monoclonal antibodies and antibody‐like molecules. Avaren‐Fc (AvFc) is a lectin‐Fc fusion protein or lectibody produced in Nicotiana benthamiana, which selectively recognizes cancer‐associated high‐mannose glycans. In this study, we report the generation of a glycovariant of AvFc that is devoid of plant glycans, including the core α1,3‐fucose and β1,2‐xylose residues. The successful removal of these glycans was confirmed by glycan analysis using HPLC. This variant, AvFcΔXF, has significantly higher affinity for Fc gamma receptors and induces higher levels of luciferase expression in an antibody‐dependent cell‐mediated cytotoxicity (ADCC) reporter assay against B16F10 murine melanoma cells without inducing apoptosis or inhibiting proliferation. In the B16F10 flank tumour mouse model, we found that systemic administration of AvFcΔXF, but not an aglycosylated AvFc variant lacking affinity for Fc receptors, significantly delayed the growth of tumours, suggesting that Fc‐mediated effector functions were integral. AvFcΔXF treatment also significantly reduced lung metastasis of B16F10 upon intravenous challenge whereas a sugar‐binding‐deficient mutant failed to show efficacy. Lastly, we determined the impact of antidrug antibodies (ADAs) on drug activity in vivo by pretreating animals with AvFcΔXF before implanting tumours. Despite a significant ADA response induced by the pretreatment, we found that the activity of AvFcΔXF was unaffected by the presence of these antibodies. These results demonstrate that glycoengineering is a powerful strategy to enhance AvFc's antitumor activity. The plant‐produced lectibody Avaren‐Fc showed enhanced antitumor activity when the core fucose residue was removed from the Fc glycan. Anti‐drug antibodies appeared to augment antitumor efficacy, possibly through the lectibody's vaccinal effect.
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影响因子：
16
作者：
Feige, Matthias J.;Groscurth, Sandra;Marcinowski, Moritz;Shimizu, Yuichiro;Kessler, Horst;Hendershot, Linda M.;Buchner, Johannes
通讯作者：
Buchner, Johannes
影响因子：
3
作者：
Ahmed, Alysia A.;Keremane, Sravya R.;Bjorkman, Pamela J.
通讯作者：
Bjorkman, Pamela J.
影响因子：
3.3
作者：
Chik, Jenny H. L.;Zhou, Jerry;Packer, Nicolle H.
通讯作者：
Packer, Nicolle H.
影响因子：
2.8
作者：
Fujiyama, K;Misaki, R;Seki, T
通讯作者：
Seki, T
影响因子：
64.5
作者：
DiLillo DJ;Ravetch JV
通讯作者：
Ravetch JV