Antagonism of PAMP, a potent angiogenic factor

描述（由申请人提供）： 血管生成抑制生物药物的最近临床结果已经验证了这类药物的有效性。 作为重要的抗癌剂的治疗剂。迄今为止最有前途的治疗候选物干扰VEGF的促血管生成刺激。我们在国家癌症研究所的合作者（根据CRADA）最近证明，肾上腺髓质素基因相关肽PAMP在皮摩尔浓度下表现出促血管生成活性，而VEGF和其他“经典”血管生成因子在纳摩尔浓度下介导了类似的作用。人微血管内皮细胞表达PAMP受体，并通过增加迁移和索形成对外源性PAMP的加入作出反应。 内皮细胞暴露于PAMP增加了其他血管生成因子如肾上腺髓质素、VEGF、bFGF和PDGF-C的基因表达。此外，肽片段PAMP（12-20）作为PAMP拮抗剂，在体内抑制肿瘤细胞诱导的血管生成，并减少异种移植模型中的肿瘤生长。尽管这项工作证明PAMP（12-20）可以在体内强烈抑制血管生成和肿瘤生长，但是这种新型抗血管生成分子的治疗潜力可以通过稳定其抵抗降解和肾清除而显著提高。PAMP及其衍生物在体内被脑啡肽酶快速降解。 由于脑啡肽酶仅降解<3，000道尔顿的肽，我们建议通过添加聚乙二醇链将其分子量增加至> 10，000道尔顿来稳定PAMP拮抗剂。这种方法很可能将PAMP激动剂的活性提高几个数量级，并可能导致一种新的基于抗血管生成的癌症治疗。

DESCRIPTION (provided by applicant): Recent clinical results with angiogenesis-inhibiting biopharmaceuticals have validated this class of therapeutics as important anti-cancer agents. The most promising therapeutic candidates to date interfere with proangiogenic stimulation by VEGF. Our collaborators (under a CRADA) at the National Cancer Institute have recently demonstrated that the adrenomedullin gene-related peptide, PAMP, exhibits proangiogenic activity at picomolar concentrations, whereas VEGF and other "classical" angiogenic factors mediate a comparable effect at nanomolar concentrations. Human microvascular endothelial cells express PAMP receptors and respond to exogenous addition of PAMP by increasing migration and cord formation. Exposure of endothelial cells to PAMP increases gene expression of other angiogenic factors such as adrenomedullin, VEGF, bFGF, and PDGF-C. In addition, the peptide fragment PAMP(12-20) acts as a PAMP antagonist and inhibits tumor cell-induced angiogenesis in vivo and reduces tumor growth in xenograft models. Although this work demonstrated that PAMP(12-20) can strongly inhibit both angiogenesis and tumor growth in vivo, the therapeutic potential of this novel antiangiogenic molecule could be dramatically improved by stabilizing it against degradation and renal clearance. PAMP and its derivatives are rapidly degraded in vivo by neprilysin. Because neprilysin only degrades peptides <3,000 daltons, we propose to stabilize the PAMP-antagonist by increasing its molecular weight to >10,000 daltons through the addition of a polyethylene glycol chain. This approach is likely to increase the activity of the PAMP agonist by several orders of magnitude and could lead to a novel antiangiogenesis-based cancer treatment.