title: The impact of Fc engineering on an anti-CD19 antibody: increased Fcgamma receptor affinity enhances B-cell clearing in nonhuman primates.
abstract: CD19, a B cell-restricted receptor critical for B-cell development, is expressed in most B-cell malignancies. The Fc-engineered anti-CD19 antibody, XmAb5574, has enhanced Fcgamma receptor (FcgammaR) binding affinity, leading to improved FcgammaR-dependent effector cell functions and antitumor activity in murine xenografts compared with the non-Fc-engineered anti-CD19 IgG1 analog. Here, we use XmAb5574 and anti-CD19 IgG1 to further dissect effector cell functions in an immune system closely homologous to that of humans, the cynomolgus monkey. XmAb5574 infusion caused an immediate and dose-related B-cell depletion in the blood (to <10% of baseline levels) concomitant with a sustained reduction of natural killer (NK) cells. NK cells had fully recovered by day 15, whereas B-cell recovery was underway by day 57. B cells in secondary lymphoid tissues were depleted (to 34%-61% of vehicle), with involuted germinal centers apparent in the spleen. Anti-CD19 IgG1 had comparable serum exposure to XmAb5574 but demonstrated no B-cell depletion and no sustained NK-cell reduction. Thus, increasing FcgammaR binding affinity dramatically increased B-cell clearing. We propose that effector cell functions, possibly those involving NK cells, mediate XmAb5574 potency in cynomolgus monkeys, and that enhancing these mechanisms should advance the treatment of B-cell malignancies in humans.
authors.affiliation: Xencor, Inc, Monrovia, CA 91016, USA. jzalevsky@xencor.com
authors.forename: Jonathan
authors.initials: J
authors.lastname: Zalevsky
authors.forename: Irene W L
authors.initials: IW
authors.lastname: Leung
authors.forename: Sher
authors.initials: S
authors.lastname: Karki
authors.forename: Seung Y
authors.initials: SY
authors.lastname: Chu
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Zhukovsky
authors.forename: John R
authors.initials: JR
authors.lastname: Desjarlais
authors.forename: David F
authors.initials: DF
authors.lastname: Carmichael
authors.forename: Chris E
authors.initials: CE
authors.lastname: Lawrence
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D018941:Antigens, CD19 / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology; D008212:Lymphocyte Depletion / Q000379:methods; D008252:Macaca fascicularis; D015202:Protein Engineering; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D018941:Antigens, CD19; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D017452:Receptors, IgG