title: Anti-CD22 and anti-CD79b antibody-drug conjugates preferentially target proliferating B cells.
abstract: CD22 and CD79b are cell-surface receptors expressed on B-cell-derived malignancies such as non-Hodgkin's lymphoma (NHL). An anti-mitotic agent, monomethyl auristatin E, was conjugated to anti-CD22 and anti-CD79b antibodies to develop target-specific therapies for NHL. The mechanism of action (MOA) and pharmacological and pharmacokinetic (PK) profiles of these antibody-drug conjugates (ADCs) were investigated in cynomolgus monkeys.
  
  
  
  Animals were administered anti-CD22 or anti-CD79b ADCs, respective unconjugated antibodies or vehicle. Pharmacodynamic effects on total and proliferating B cells and serum PK were then assessed. Antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) of the ADCs were evaluated in vitro.
  
  
  
  Depletion of B cells was observed after administration of either ADC or the respective unconjugated antibodies. An extended duration of depletion was observed in animals administered ADCs. Similarly, preferential depletion of proliferating B cells in blood and germinal centre B cells in spleen were only observed in animals administered ADCs. Serum PK profiles of ADCs and respective unconjugated antibodies were comparable. In vitro, anti-human CD22 and anti-human CD79b antibodies showed no or only moderate ADCC activity, respectively; neither antibody had CDC activity.
  
  
  
  The findings support the proposed MOA: initial depletion of total B cells by antibody-mediated opsonization, followed by preferential, sustained depletion of proliferating B cells by the auristatin conjugate due to its anti-mitotic action. Delivering potent anti-mitotic agents to B cells via the specificity of monoclonal antibodies provides a means to eliminate pathogenic B cells in NHL with improved risk-benefit profiles over traditional chemotherapeutics.
authors.affiliation: Department of Pharmacodynamic Biomarkers, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Franklin K
authors.initials: FK
authors.lastname: Fuh
authors.affiliation: Department of Pharmacodynamic Biomarkers, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Looney
authors.affiliation: Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Dongwei
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Safety and Toxicology, Genentech, Inc., South San Francisco, CA, USA.|Denali Therapeutics, Inc., South San Francisco, CA, USA.
authors.forename: Kirsten A
authors.initials: KA
authors.lastname: Poon
authors.affiliation: Department of BioAnalytical Research and Development, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Randall C
authors.initials: RC
authors.lastname: Dere
authors.affiliation: Department of Safety Assessment, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Dimitry M
authors.initials: DM
authors.lastname: Danilenko
authors.affiliation: Department of Pharmacodynamic Biomarkers, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: McBride
authors.affiliation: Department of BioAnalytical Research and Development, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Chae
authors.initials: C
authors.lastname: Reed
authors.affiliation: Department of BioAnalytical Research and Development, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Chung
authors.affiliation: Department of Immunology Research, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Zheng
authors.affiliation: Department of Pharmacodynamic Biomarkers, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: William Rodney
authors.initials: WR
authors.lastname: Mathews
authors.affiliation: Department of Immunology Research, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Polson
authors.affiliation: Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Saileta
authors.initials: S
authors.lastname: Prabhu
authors.affiliation: Department of Pharmacodynamic Biomarkers, Genentech, Inc., South San Francisco, CA, USA.|MedImmune, Gaithersburg, MD, USA.
authors.forename: Marna
authors.initials: M
authors.lastname: Williams
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology*; D000937:Antigen-Antibody Reactions; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology; D051925:CD79 Antigens / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000276:immunology*; D013329:Structure-Activity Relationship
chemical_list: D000906:Antibodies; C497867:CD22 protein, human; D051925:CD79 Antigens; C497883:CD79B protein, human; D009842:Oligopeptides; D051918:Sialic Acid Binding Ig-like Lectin 2; C495575:monomethyl auristatin E