Pharmacologic Characterization of AMG 334, a Potent and Selective Human Monoclonal Antibody against the Calcitonin Gene-Related Peptide Receptor
Pharmacologic Characterization of AMG 334, a Potent and Selective Human Monoclonal Antibody against the Calcitonin Gene-Related Peptide Receptor
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DOI：
10.1124/jpet.115.227793
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发表时间：
2016-01-01
影响因子：
3.5
通讯作者：
Xu, Cen
中科院分区：
文献类型：
--
作者：
Shi, Licheng;Lehto, Sonya G.;Xu, Cen
阻断降钙素基因相关肽（CGRP）信号通路的治疗剂是用于偏头痛治疗的备受期待和有前途的新药类别，特别是在报道小分子CGRP受体拮抗剂对急性偏头痛治疗和偏头痛预防都有效之后。使用XenoMouse技术，我们成功制备了AMG 334，一种针对CGRP受体的全人源单克隆抗体。在此，我们发现AMG 334与[I-125]-CGRP竞争结合人CGRP受体，Ki为0.02 nM。在基于细胞的功能试验（人CGRP受体）中，AMG 334完全抑制CGRP刺激的cAMP生成，IC 50为2.3 nM，对CGRP受体的选择性是其他人降钙素家族受体（包括肾上腺髓质素、降钙素和胰淀素受体）的5000倍。AMG 334对食蟹猴（cyno）CGRP受体的效力与对人受体的效力相似，IC 50为5.7 nM，但其对犬、兔和大鼠受体的效力显著降低（>5000倍）。因此，使用辣椒素诱导的皮肤血流增加模型，在食蟹猴中评估AMG 334的体内靶向覆盖率。AMG 334在给药后第2天和第4天以剂量依赖性方式阻止辣椒素诱导的真皮血流量增加。这些结果表明AMG 334是CGRP受体的强效、选择性、完全拮抗剂，并在食蟹猴中显示出体内剂量依赖性靶向覆盖率。AMG 334目前正处于预防偏头痛的临床开发中。
Therapeutic agents that block the calcitonin gene-related peptide (CGRP) signaling pathway are a highly anticipated and promising new drug class for migraine therapy, especially after reports that small-molecule CGRP-receptor antagonists are efficacious for both acute migraine treatment and migraine prevention. Using XenoMouse technology, we successfully generated AMG 334, a fully human monoclonal antibody against the CGRP receptor. Here we show that AMG 334 competes with [I-125]-CGRP binding to the human CGRP receptor, with a K-i of 0.02 nM. AMG 334 fully inhibited CGRP-stimulated cAMP production with an IC50 of 2.3 nM in cell-based functional assays (human CGRP receptor) and was 5000-fold more selective for the CGRP receptor than other human calcitonin family receptors, including adrenomedullin, calcitonin, and amylin receptors. The potency of AMG 334 at the cynomolgus monkey (cyno) CGRP receptor was similar to that at the human receptor, with an IC50 of 5.7 nM, but its potency at dog, rabbit, and rat receptors was significantly reduced (>5000-fold). Therefore, in vivo target coverage of AMG 334 was assessed in cynos using the capsaicin-induced increase in dermal blood flow model. AMG 334 dose-dependently prevented capsaicin-induced increases in dermal blood flow on days 2 and 4 postdosing. These results indicate AMG 334 is a potent, selective, full antagonist of the CGRP receptor and show in vivo dose-dependent target coverage in cynos. AMG 334 is currently in clinical development for the prevention of migraine.