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首页> 外文期刊>Istituto Superiore di Sanita. Rendiconti >The biology of MDR1-P-glycoprotein (MDR1-Pgp) in designing functional antibody drug conjugates (ADCs): the experience of gemtuzumab ozogamicin
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The biology of MDR1-P-glycoprotein (MDR1-Pgp) in designing functional antibody drug conjugates (ADCs): the experience of gemtuzumab ozogamicin

机译：MDR1-P-糖蛋白（MDR1-Pgp）在设计功能抗体药物偶联物（ADC）中的生物学：吉妥单抗ozogamicin的经验

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BACKGROUND: The treatment of cancer remains a formidable challenge owing to the difficulties in differentiating tumor cells from healthy cells to ameliorate the disease without causing intolerable toxicity to patients. In addition, the emergence of MDR1-Pgp mediated multi-drug resistance (MDR) it is a biological phenomenon that inhibits the curative potential of chemotherapeutic treatments. One way to improve the selectivity of therapeutic molecules in tumors would be to target them on the tumor site, thereby sparing normal tissues. AIMS: In this overview, we will discuss the biological factors influencing the safety and efficacy of the humanized mAb hP67.6 linked to the potent cytotoxic drug calicheamicin-gamma1 (gemtuzumab ozogamicin) that target CD33 cell surface antigen expressed on AML cells. In addition, we highlight key aspects of MDR1-Pgp biology as a platform to understand its functional role in gemtuzumab ozogamicin immunotherapy which is tightly linked to an accurate assessment of the MDR status of AML cells. DISCUSSION: Several factors may affect the efficacy and safety of immunoconjugates. These include the common issues of chemical and antibody therapeutics such as specificity, heterogeneous target antigen expression and the complex pharmacokinetics profile of conveyed antibody. Further, the delivered drug may not be sufficient for providing therapeutic benefit, since the curative cytotoxic compound may be affected by intrinsic or acquired resistance of target cells. These and other potential problems, as well as the possible ways to overcome them will be discussed in this review by examining the biological factors involved in safety and efficacy of the first in class antibody drug conjugate (ADC) gentuzumab ozogamicin. Despite this set-back, the extensive recorded data and the lessons learned from gentuzumab ozogamicin recently withdrawn from the market for safety concerns helped to pave the way for next generations of clinically promising new ADCs which are currently investigated in clinical trials and two of them, Brentuximab vedotin, and Trastuzumab emtansine (T-DM1) have been recently approved for commercial distribution in US by Food and Drug Administration (FDA).
机译：背景：由于难以将肿瘤细胞与健康细胞区分开来改善疾病而又不会对患者造成无法忍受的毒性，因此癌症的治疗仍然是一项艰巨的挑战。此外，MDR1-Pgp介导的多药耐药性（MDR）的出现是一种生物学现象，抑制了化学疗法的治疗潜力。改善肿瘤中治疗分子选择性的一种方法是将其靶向肿瘤部位，从而保留正常组织。目的：在本概述中，我们将讨论影响人源化单克隆抗体hP67.6的安全性和功效的生物学因素，所述人源化单克隆抗体hP67.6与有效的细胞毒性药物加利车霉素-gamma1（吉姆单抗ozogamicin）相关，该药物靶向AML细胞上表达的CD33细胞表面抗原。此外，我们重点介绍了MDR1-Pgp生物学的关键方面，以此为平台来了解其在吉妥单抗ozogamicin免疫疗法中的功能作用，该作用与准确评估AML细胞的MDR状态紧密相关。讨论：几个因素可能会影响免疫偶联物的功效和安全性。这些包括化学和抗体治疗的常见问题，例如特异性，异质靶抗原表达以及所输送抗体的复杂药代动力学特征。此外，所递送的药物可能不足以提供治疗益处，因为治疗性细胞毒性化合物可能受到靶细胞的固有或获得性耐药性的影响。这些和其他潜在问题，以及克服这些潜在问题的可能方法，将在本综述中通过检查与一流抗体药物偶联物（ADC）gentuzumab ozogamicin的安全性和有效性有关的生物学因素进行讨论。尽管有这样的挫折，但出于安全方面的考虑，最近从市场上撤出的gentuzumab ozogamicin的大量记录数据和经验教训，为安全起见，为目前临床试验中正在研究的下一代具有临床前景的新型ADC铺平了道路，其中两个Brentuximab vedotin和Trastuzumab emtansine（T-DM1）最近已获美国食品药品管理局（FDA）批准在美国进行商业销售。

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