title: Specific Immune Response to Phospholipase B-Like 2 Protein, a Host Cell Impurity in Lebrikizumab Clinical Material.
abstract: Host cell proteins are manufacturing process-related impurities that may co-purify with the product despite extensive efforts to optimize the purification process. The risks associated with these impurities can vary and may be patient and/or therapeutic dependent. Therefore, it is critical to monitor and control the levels of these impurities in products and their potential impact on safety and efficacy. Lebrikizumab is a humanized immunoglobulin G4 monoclonal antibody (mAb) that binds specifically to soluble interleukin 13. This mAb is currently in phase III clinical development for the treatment of asthma. Following initial phase III studies, the material used in lebrikizumab clinical trials was found to have a process-related impurity identified as Chinese hamster ovary phospholipase B-like 2 (PLBL2) which co-purified with lebrikizumab. The immunogenic potential of PLBL2 and its potential impact on the immunogenicity of lebrikizumab in clinical studies were therefore evaluated. Data from the clinical studies demonstrated that ∼90% of subjects developed a specific and measurable immune response to PLBL2. Given the high incidence of antibodies to PLBL2 as well as the comparable safety profile observed between placebo- and drug-treated subjects, no correlation between safety events and anti-PLBL2 antibodies could be made. Additionally, no impact on the incidence of anti-lebrikizumab antibodies was observed, suggesting the lack of an adjuvant effect from PLBL2. Interim analysis from ongoing phase III studies using material with substantially reduced levels of PLBL2 with patients having had longer exposure shows significantly less and dose-dependent frequency of immune responses to PLBL2.
authors.affiliation: BioAnalytical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080, USA. sallyk@gene.com.
authors.forename: Saloumeh Kadkhodayan
authors.initials: SK
authors.lastname: Fischer
authors.affiliation: BioAnalytical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Cheu
authors.affiliation: BioAnalytical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080, USA.
authors.forename: Kun
authors.initials: K
authors.lastname: Peng
authors.affiliation: BioAnalytical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080, USA.
authors.forename: John
authors.initials: J
authors.lastname: Lowe
authors.affiliation: BioAnalytical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080, USA.
authors.forename: James
authors.initials: J
authors.lastname: Araujo
authors.affiliation: Product Development Genentech Inc., South San Francisco, California, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Murray
authors.affiliation: Product Development Genentech Inc., South San Francisco, California, USA.
authors.forename: Dana
authors.initials: D
authors.lastname: McClintock
authors.affiliation: Clinical Science Respiratory Genentech Inc., South San Francisco, California, USA.
authors.forename: John
authors.initials: J
authors.lastname: Matthews
authors.affiliation: BioAnalytical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Siguenza
authors.affiliation: BioAnalytical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, California, 94080, USA.
authors.forename: An
authors.initials: A
authors.lastname: Song
mesh_terms: D000818:Animals; D000906:Antibodies / Q000097:blood*; D000911:Antibodies, Monoclonal / Q000097:blood / Q000276:immunology* / Q000627:therapeutic use; D001249:Asthma / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D016466:CHO Cells; D017326:Clinical Trials, Phase III as Topic; D006224:Cricetinae; D003412:Cricetulus; D004340:Drug Contamination; D006801:Humans; D008245:Lysophospholipase / Q000097:blood / Q000276:immunology*
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D008245:Lysophospholipase; C561806:lebrikizumab
keywords: CHO-host cell impurity; ELISA; PLB2; asthma; immune response; immunogenicity