Discovery and characterization of prolactin neutralizing monoclonal antibodies for the treatment of female-prevalent pain disorders.
Discovery and characterization of prolactin neutralizing monoclonal antibodies for the treatment of female-prevalent pain disorders.
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DOI：
10.1080/19420862.2023.2254676
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发表时间：
2023-01
期刊：
影响因子：
5.3
通讯作者：
Riviere, Pierre J. M.
中科院分区：
文献类型：
--
作者：
Maciuba, Stephanie;Bowden, Gregory D.;Stratton, Harrison J.;Wisniewski, Kazimierz;Schteingart, Claudio D.;Almagro, Juan C.;Valadon, Philippe;Lowitz, Joshua;Glaser, Scott M.;Lee, Grace;Dolatyari, Mahdi;Navratilova, Edita;Porreca, Frank;Riviere, Pierre J. M.
催乳素（PRL）最近被证明可以引起雌性选择性伤害感受器敏化，并增加雌性动物的疼痛样行为。在这里，我们报告的发现和表征的一流的，人源化的PRL中和单克隆抗体（PRL单克隆抗体）。我们获得了两种有效的和选择性的PRL mAb，PL 200，031和PL 200，039。PL 200，031被改造为人IgG 1，而PL 200，039被重新格式化为人IgG 4。两种mAb均对人PRL（hPRL）具有亚纳摩尔亲和力，并对hPRL受体（hPRLR）处的hPRL信号传导产生浓度依赖性和完全抑制。这两种PRL mAb对hPRL具有选择性，因为它们不抑制其他hPRLR激动剂，如人生长激素或胎盘催乳素。它们也与非人灵长类动物PRL交叉反应，但不与啮齿类动物PRL交叉反应。此外，两种mAb在FcRn人源化小鼠中静脉内施用后均显示长清除半衰期。与其同种型一致，这些mAb仅在与Fcγ受体的结合亲和力方面存在差异，与设计预期一致。最后，PL 200，031和PL 200，039的鼠亲本mAb PL 200，019完全阻断雌性PRL人源化小鼠中的应激诱导和PRL依赖性疼痛行为，从而提供了PRL mAb在与雌性疼痛相关的机制中的体内临床前功效证明。
Prolactin (PRL) has recently been demonstrated to elicit female-selective nociceptor sensitization and increase pain-like behaviors in female animals. Here we report the discovery and characterization of first-in-class, humanized PRL neutralizing monoclonal antibodies (PRL mAbs). We obtained two potent and selective PRL mAbs, PL 200,031 and PL 200,039. PL 200,031 was engineered as human IgG1 whereas PL 200,039 was reformatted as human IgG4. Both mAbs have sub-nanomolar affinity for human PRL (hPRL) and produce concentration-dependent and complete inhibition of hPRL signaling at the hPRL receptor (hPRLR). These two PRL mAbs are selective for hPRL as they do not inhibit other hPRLR agonists such as human growth hormone or placental lactogen. They also cross-react with non-human primate PRL but not with rodent PRL. Further, both mAbs show long clearance half-lives after intravenous administration in FcRn-humanized mice. Consistent with their isotypes, these mAbs only differ in binding affinities to Fcγ receptors, as expected by design. Finally, PL 200,019, the murine parental mAb of PL 200,031 and PL 200,039, fully blocked stress-induced and PRL-dependent pain behaviors in female PRL-humanized mice, thereby providing in vivo preclinical proof-of-efficacy for PRL mAbs in mechanisms relevant to pain in females.
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影响因子：
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作者：
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