title: The biology of MDR1-P-glycoprotein (MDR1-Pgp) in designing functional antibody drug conjugates (ADCs): the experience of gemtuzumab ozogamicin.
abstract: 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.
  
  
  OBJECTIVE
  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 calicheamicingamma1 (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.
  
  
  CONCLUSIONS
  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 Despite this set-back, the extensive recorded data and the lessons learned from gentuzumab ozogamicin recently withdrawn from the market for safety concerns helped to pave the way for next generations of clinically promising new ADCs which are currently investigated in clinical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).
authors.affiliation: Dipartimento del Farmaco, Istituto Superiore di Sanità, Rome, Italy. maurizio.cianfriglia@iss.it
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cianfriglia
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000276:immunology* / Q000502:physiology*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000375:Aging / Q000502:physiology; D000617:Aminoglycosides / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015195:Drug Design; D000079982:Gemtuzumab; D006801:Humans; D007167:Immunotherapy; D000922:Immunotoxins; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D011379:Prognosis; D012449:Safety
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000617:Aminoglycosides; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000922:Immunotoxins; D000079982:Gemtuzumab