A Therapeutic Anti-VEGF Antibody with Increased Potency Independent of Pharmacokinetic Half-life
A Therapeutic Anti-VEGF Antibody with Increased Potency Independent of Pharmacokinetic Half-life
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DOI：
10.1158/0008-5472.can-09-4580
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发表时间：
2010-04-15
期刊：
影响因子：
11.2
通讯作者：
Lowman, Henry B.
中科院分区：
文献类型：
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作者：
Yeung, Yik Andy;Wu, Xiumin;Lowman, Henry B.
贝伐单抗[安维汀;抗血管内皮生长因子（VEGF）抗体]是批准用于治疗患有某些类型的结肠癌、乳腺癌和肺癌的患者的抗血管生成IgG。在这些适应症中，贝伐珠单抗每2至3周给药一次，这促使我们研究减少给药频率的方法。增加对新生儿Fc受体（FcRn）的亲和力可能会延长抗体的药代动力学半衰期，但尚未明确阐明FcRn亲和力对清除率的定量影响。为了进一步了解这种关系，我们设计了一系列具有最小氨基酸取代的抗VEGF抗体变体，并在灵长类动物中显示出一系列半衰期改善。这些结果表明，如果证明临床安全有效，贝伐珠单抗的改良版本可能通过降低给药频率和改善药物治疗依从性，为长期抗VEGF治疗的患者提供临床获益。此外，尽管由于物种特异性FcRn结合效应，变体T307 Q/N434 A在小鼠中具有与野生型相似的半衰期，但在减缓小鼠异种移植模型中某些人肿瘤系的生长方面，变体T307 Q/N434 A表现出上级的体内效力。这些结果进一步表明，除了增加全身暴露外，FcRn变体还可通过未鉴定的机制实现效价增加。Cancer Res; 70（8）; 3269-77.（C）2010年AACR。
Bevacizumab [Avastin; anti-vascular endothelial growth factor (VEGF) antibody] is an antiangiogenic IgG approved for treating patients with certain types of colon, breast, and lung cancer. In these indications, bevacizumab is administered every 2 to 3 weeks, prompting us to study ways to reduce the frequency of administration. Increasing affinity to neonatal Fc receptor (FcRn) may extend the pharmacokinetic half-life of an antibody, but the quantitative effect of FcRn affinity on clearance has not been clearly elucidated. To gain further insight into this relationship, we engineered a series of anti-VEGF antibody variants with minimal amino acid substitutions and showed a range of half-life improvements in primates. These results suggest that, if proven clinically safe and effective, a modified version of bevacizumab could potentially provide clinical benefit to patients on long-term anti-VEGF therapy through less-frequent dosing and improved compliance with drug therapy. Moreover, despite having half-life similar to that of wild-type in mice due to the species-specific FcRn binding effects, the variant T307Q/N434A exhibited superior in vivo potency in slowing the growth of certain human tumor lines in mouse xenograft models. These results further suggest that FcRn variants may achieve increased potency through unidentified mechanisms in addition to increased systemic exposure. Cancer Res; 70(8); 3269-77. (C)2010 AACR.