Neutralization of Prolactin Receptor Function by Monoclonal Antibody LFA102, a Novel Potential Therapeutic for the Treatment of Breast Cancer
Neutralization of Prolactin Receptor Function by Monoclonal Antibody LFA102, a Novel Potential Therapeutic for the Treatment of Breast Cancer
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DOI：
10.1158/1535-7163.mct-12-0886
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发表时间：
2013-03-01
影响因子：
5.7
通讯作者：
Abraham, Judith A.
中科院分区：
文献类型：
--
作者：
Damiano, Jason S.;Rendahl, Katherine G.;Abraham, Judith A.
大量证据表明，多肽激素催乳素（PRL）可能通过与催乳素受体（PRLR）的相互作用而促进乳腺和前列腺肿瘤的发生。在这里，我们描述了LFA 102的生物学特性，LFA 102是一种针对PRLR胞外结构域的人源化中和性单克隆抗体。发现该抗体在体外和体内有效拮抗乳腺癌细胞中PRL诱导的信号传导，并在许多细胞系模型中阻断PRL诱导的增殖，包括自分泌/旁分泌PRL活性的实例。LFA 102的单次给药导致PRL依赖性Nb 2 -11肿瘤异种移植物的消退和显著延长的进展时间。最后，LFA 102治疗作为单一疗法显著抑制致癌物诱导的雌激素受体阳性大鼠乳腺癌模型中的PRLR信号传导以及肿瘤生长，并且当组合施用时增强芳香酶抑制剂来曲唑的功效。LFA 102的生物学特性，通过本文提出的临床前研究阐明，表明这种抗体有可能成为治疗PRL依赖性癌症的一流有效治疗药物。Mol Cancer Ther; 12（3）; 295-305.（C）2012年AACR。
Numerous lines of evidence suggest that the polypeptide hormone prolactin (PRL) may contribute to breast and prostate tumorigenesis through its interactions with the prolactin receptor (PRLR). Here, we describe the biologic properties of LFA102, a humanized neutralizing monoclonal antibody directed against the extracellular domain of PRLR. This antibody was found to effectively antagonize PRL-induced signaling in breast cancer cells in vitro and in vivo and to block PRL-induced proliferation in numerous cell line models, including examples of autocrine/paracrine PRL activity. A single administration of LFA102 resulted in regression of PRL-dependent Nb2-11 tumor xenografts and significantly prolonged time to progression. Finally, LFA102 treatment significantly inhibited PRLR signaling as well as tumor growth in a carcinogen-induced, estrogen receptor-positive rat mammary cancer model as a monotherapy and enhanced the efficacy of the aromatase inhibitor letrozole when administered in combination. The biologic properties of LFA102, elucidated by the preclinical studies presented here, suggest that this antibody has the potential to be a first-in-class, effective therapeutic for the treatment of PRL-dependent cancers. Mol Cancer Ther; 12(3); 295-305. (C)2012 AACR.