title: Development and characterization of APRIL antagonistic monoclonal antibodies for treatment of B-cell lymphomas.
abstract: APRIL (A proliferation-inducing ligand) is a TNF family member that binds two TNF receptor family members, TACI and BCMA. It shares these receptors with the closely related TNF family member, B-cell activating factor (BAFF). Contrary to BAFF, APRIL binds heparan sulfate proteoglycans (HSPGs), which regulates cross-linking of APRIL and efficient signaling. APRIL was originally identified as a growth promoter of solid tumors, and more recent evidence defines APRIL also as an important survival factor in several human B-cell malignancies, such as chronic lymphocytic leukemia (CLL). To target APRIL therapeutically, we developed two anti-human APRIL antibodies (hAPRIL.01A and hAPRIL.03A) that block APRIL binding to BCMA and TACI. Their antagonistic properties are unique when compared with a series of commercially available monoclonal anti-human APRIL antibodies as they prevent in vitro proliferation and IgA production of APRIL-reactive B cells. In addition, they effectively impair the CLL-like phenotype of aging APRIL transgenic mice and, more importantly, block APRIL binding to human B-cell lymphomas and prevent the survival effect induced by APRIL. We therefore conclude that these antibodies have potential for further development as therapeutics to target APRIL-dependent survival in B-cell malignancies.
authors.affiliation: Laboratory of Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine, Academic Medical Center (AMC), Amsterdam, The Netherlands.
authors.forename: Marco
authors.initials: M
authors.lastname: Guadagnoli
authors.forename: Fiona C
authors.initials: FC
authors.lastname: Kimberley
authors.forename: Uyen
authors.initials: U
authors.lastname: Phan
authors.forename: Katherine
authors.initials: K
authors.lastname: Cameron
authors.forename: Paul M
authors.initials: PM
authors.lastname: Vink
authors.forename: Hans
authors.initials: H
authors.lastname: Rodermond
authors.forename: Eric
authors.initials: E
authors.lastname: Eldering
authors.forename: Arnon P
authors.initials: AP
authors.lastname: Kater
authors.forename: Hans
authors.initials: H
authors.lastname: van Eenennaam
authors.forename: Jan Paul
authors.initials: JP
authors.lastname: Medema
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use; D053301:B-Cell Maturation Antigen / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053303:Transmembrane Activator and CAML Interactor Protein / Q000276:immunology*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D053301:B-Cell Maturation Antigen; D007070:Immunoglobulin A; C114631:TNFSF13 protein, human; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13