title: The Interplay of Antigen Affinity, Internalization, and Pharmacokinetics on CD44-Positive Tumor Targeting of Monoclonal Antibodies.
abstract: Monoclonal antibodies (mAbs) offer promise as effective tumor targeting and drug delivery agents for cancer therapy. However, comparative biological and clinical characteristics of mAbs targeting the same tumor-associated antigen (TAA) often differ widely. This study examined the characteristics of mAbs that impact tumor targeting using a panel of mAb clones specific to the cancer-associated cell-surface receptor and cancer stem cell marker CD44. CD44 mAbs were screened for cell-surface binding, antigen affinity, internalization, and CD44-mediated tumor uptake by CD44-positive A549 cells. It was hypothesized that high-affinity, rapidly internalizing CD44 mAbs would result in high tumor uptake and prolonged tumor retention. Although high-affinity clones rapidly bound and were internalized by A549 cells in vitro, an intermediate-affinity clone demonstrated significantly greater tumor uptake and retention than high-affinity clones in vivo. Systemic exposure, rather than high antigen affinity or rapid internalization, best associated with tumor targeting of CD44 mAbs in A549 tumor-bearing mice.
authors.affiliation: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Marsico Hall, 125 Mason Farm Road, Chapel Hill, North Carolina 27599, United States.
authors.forename: Dylan M
authors.initials: DM
authors.lastname: Glatt
authors.affiliation: Department of Radiology, Biomedical Research Imaging Center, University of North Carolina at Chapel Hill , Marsico Hall, 125 Mason Farm Road, Chapel Hill, North Carolina 27599, United States.
authors.forename: Denis R
authors.initials: DR
authors.lastname: Beckford Vera
authors.affiliation: Department of Radiology, Biomedical Research Imaging Center, University of North Carolina at Chapel Hill , Marsico Hall, 125 Mason Farm Road, Chapel Hill, North Carolina 27599, United States.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Parrott
authors.affiliation: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Marsico Hall, 125 Mason Farm Road, Chapel Hill, North Carolina 27599, United States.
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Luft
authors.affiliation: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Marsico Hall, 125 Mason Farm Road, Chapel Hill, North Carolina 27599, United States.
authors.forename: S Rahima
authors.initials: SR
authors.lastname: Benhabbour
authors.affiliation: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Marsico Hall, 125 Mason Farm Road, Chapel Hill, North Carolina 27599, United States.
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Mumper
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D045744:Cell Line, Tumor; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D018960:Hyaluronan Receptors
keywords: 125I; A549; CD44; antibody characterization; biodistribution; cell uptake; cell-surface binding; drug delivery; mAb; screening and selection; target engagement; tumor uptake