title: Potent in vitro and in vivo activity of an Fc-engineered anti-CD19 monoclonal antibody against lymphoma and leukemia.
abstract: CD19 is a pan B-cell surface receptor expressed from pro-B-cell development until its down-regulation during terminal differentiation into plasma cells. CD19 represents an attractive immunotherapy target for cancers of lymphoid origin due to its high expression levels on the vast majority of non-Hodgkin's lymphomas and some leukemias. A humanized anti-CD19 antibody with an engineered Fc domain (XmAb5574) was generated to increase binding to Fcgamma receptors on immune cells and thus increase Fc-mediated effector functions. In vitro, XmAb5574 enhanced antibody-dependent cell-mediated cytotoxicity 100-fold to 1,000-fold relative to an anti-CD19 IgG1 analogue against a broad range of B-lymphoma and leukemia cell lines. Furthermore, XmAb5574 conferred antibody-dependent cell-mediated cytotoxicity against patient-derived acute lymphoblastic leukemia and mantle cell lymphoma cells, whereas the IgG1 analogue was inactive. XmAb5574 also increased antibody-dependent cellular phagocytosis and apoptosis. In vivo, XmAb5574 significantly inhibited lymphoma growth in prophylactic and established mouse xenograft models, and showed more potent antitumor activity than its IgG1 analogue. Comparisons with a variant incapable of Fcgamma receptor binding showed that engagement of these receptors is critical for optimal antitumor efficacy. These results suggest that XmAb5574 exhibits potent tumor cytotoxicity via direct and indirect effector functions and thus warrants clinical evaluation as an immunotherapeutic for CD19(+) hematologic malignancies.
authors.affiliation: Xencor, Inc, Monrovia, California 91016, USA.
authors.forename: Holly M
authors.initials: HM
authors.lastname: Horton
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Bernett
authors.forename: Erik
authors.initials: E
authors.lastname: Pong
authors.forename: Matthias
authors.initials: M
authors.lastname: Peipp
authors.forename: Sher
authors.initials: S
authors.lastname: Karki
authors.forename: Seung Y
authors.initials: SY
authors.lastname: Chu
authors.forename: John O
authors.initials: JO
authors.lastname: Richards
authors.forename: Igor
authors.initials: I
authors.lastname: Vostiar
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Joyce
authors.forename: Roland
authors.initials: R
authors.lastname: Repp
authors.forename: John R
authors.initials: JR
authors.lastname: Desjarlais
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Zhukovsky
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000235:genetics* / Q000627:therapeutic use*; D018941:Antigens, CD19 / Q000276:immunology*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D007167:Immunotherapy; D007938:Leukemia / Q000276:immunology / Q000628:therapy*; D008223:Lymphoma / Q000276:immunology / Q000628:therapy*; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D011485:Protein Binding; D015202:Protein Engineering / Q000379:methods; D017452:Receptors, IgG / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D018941:Antigens, CD19; D000970:Antineoplastic Agents; C489017:FCGR1A protein, human; D007141:Immunoglobulin Fc Fragments; D017452:Receptors, IgG