title: Therapeutic potential and challenges of targeting receptor tyrosine kinase ROR1 with monoclonal antibodies in B-cell malignancies.
abstract: BACKGROUND
  Based on its selective cell surface expression in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), receptor tyrosine kinase ROR1 has recently emerged as a promising target for therapeutic monoclonal antibodies (mAbs). To further assess the suitability of ROR1 for targeted therapy of CLL and MCL, a panel of mAbs was generated and its therapeutic utility was investigated.
  
  
  RESULTS
  A chimeric rabbit/human Fab library was generated from immunized rabbits and selected by phage display. Chimeric rabbit/human Fab and IgG1 were investigated for their capability to bind to human and mouse ROR1, to mediate antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and internalization, and to agonize or antagonize apoptosis using primary CLL cells from untreated patients as well as MCL cell lines. A panel of mAbs demonstrated high affinity and specificity for a diverse set of epitopes that involve all three extracellular domains of ROR1, are accessible on the cell surface, and mediate internalization. The mAb with the highest affinity and slowest rate of internalization was found to be the only mAb that mediated significant, albeit weak, ADCC. None of the mAbs mediated CDC. Alone, they did not enhance or inhibit apoptosis.
  
  
  CONCLUSIONS
  Owing to its relatively low cell surface density, ROR1 may be a preferred target for armed rather than naked mAbs. Provided is a panel of fully sequenced and thoroughly characterized anti-ROR1 mAbs suitable for conversion to antibody-drug conjugates, immunotoxins, chimeric antigen receptors, and other armed mAb entities for preclinical and clinical studies.
authors.affiliation: Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Jiahui
authors.initials: J
authors.lastname: Yang
authors.forename: Sivasubramanian
authors.initials: S
authors.lastname: Baskar
authors.forename: Ka Yin
authors.initials: KY
authors.lastname: Kwong
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kennedy
authors.forename: Adrian
authors.initials: A
authors.lastname: Wiestner
authors.forename: Christoph
authors.initials: C
authors.lastname: Rader
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000920:Antibody-Dependent Cell Cytotoxicity; D017209:Apoptosis; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D008969:Molecular Sequence Data; D011817:Rabbits; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000737:chemistry / Q000276:immunology*; D017386:Sequence Homology, Amino Acid
chemical_list: D000911:Antibodies, Monoclonal; C078716:ROR1 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors