title: Pharmacological profile of MEDI-551, a novel anti-CD19 antibody, in human CD19 transgenic mice.
abstract: B cell depletion therapy is beneficial for patients with B cell malignancies and autoimmune diseases. CD19, a transmembrane protein, is expressed on a vast majority of normal and neoplastic B cells, making it a suitable target for monoclonal antibody (MAb) mediated immunotherapy. We have developed MEDI-551, an affinity optimized and afucosylated IgG1 MAb targeting human CD19 for B cell depletion. MEDI-551 is currently under investigation in multiple clinical trials. Because MEDI-551 does not cross react with rodent and non-human primate CD19, the pharmacological characteristics of the MAb were evaluated in human CD19 transgenic mice (hCD19 Tg). Here we show that MEDI-551 potently depletes tissue and circulating B cells in hCD19 Tg mice and is more efficacious than the anti-CD19 MAb with intact fucose. The length of B cell depletion depends on MEDI-551 dose; and, B cell recovery in the circulation follows stepwise phenotypic maturation. Furthermore, intravenous (IV) and subcutaneous (SC) administration of MEDI-551 results in comparable efficacy. Lastly, the combination of MEDI-551 with the anti-CD20 MAb, rituximab, further prolongs the duration of B cell depletion. In summary, the pharmacological profile of MEDI-551 presented in hCD19 Tg mice supports further testing of MEDI-551 in clinical trials involving B cell malignancies and autoimmune diseases.
authors.affiliation: Respiratory, Inflammation and Autoimmune Research, Gaithersburg, MD, United States.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gallagher
authors.affiliation: Respiratory, Inflammation and Autoimmune Research, Gaithersburg, MD, United States.
authors.forename: Sean
authors.initials: S
authors.lastname: Turman
authors.affiliation: Respiratory, Inflammation and Autoimmune Research, Gaithersburg, MD, United States.
authors.forename: Isharat
authors.initials: I
authors.lastname: Yusuf
authors.affiliation: Translational Sciences, MedImmune LLC, Gaithersburg, MD, United States.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Akhgar
authors.affiliation: Translational Sciences, MedImmune LLC, Gaithersburg, MD, United States.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Translational Sciences, MedImmune LLC, Gaithersburg, MD, United States.
authors.forename: Lorin K
authors.initials: LK
authors.lastname: Roskos
authors.affiliation: Respiratory, Inflammation and Autoimmune Research, Gaithersburg, MD, United States.
authors.forename: Ronald
authors.initials: R
authors.lastname: Herbst
authors.affiliation: Respiratory, Inflammation and Autoimmune Research, Gaithersburg, MD, United States. Electronic address: wangy@medimmune.com.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity; D018941:Antigens, CD19 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000473:pathology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D007167:Immunotherapy / Q000379:methods*; D007279:Injections, Subcutaneous; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000069283:Rituximab / Q000494:pharmacology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018941:Antigens, CD19; C000604811:CD19 molecule, human; D000069283:Rituximab; C000609745:inebilizumab
keywords: B cell depletion; B cells; CD19; Immunotherapy; Monoclonal antibody; Pharmacodynamics; Pharmacokinetics; Transgenic mice