Abstract
Abstract A Proliferation Inducing Ligand (APRIL) is a TNF ligand that, via its receptors TACI and BCMA, is involved in both B cell physiology as well as in proliferation and survival of malignant B cells. To target APRIL-dependent stimulation of B cell cancers, we recently produced and characterized two monoclonal antagonistic anti-human APRIL antibodies called humanAPRIL.01A (hA.01A) and humanAPRIL.03A (hA.03A). In a first biochemical assay to validate their blocking activity, hA.01A was shown to fully prevent APRIL from binding to its receptors, whereas a substantial difference was detected for hA.03A, which inhibited APRIL binding to BCMA less efficiently than hA.01A. Epitope mapping subsequently revealed that hA.01A and hA.03A bind distinct sites on APRIL, which provided a structural rationale of their different blocking activities. Importantly, this differential inhibition profile can be used to functionally dissect BCMA and TACI-dependent signals and indicated that B cell survival and IgA production are regulated differently by these receptors. Primary CLL cultures were shown to be sensitive to APRIL neutralization using hA.01A. hA.01A also inhibited hyperplasia in a transgenic mouse model reminiscent of B-CLL. Altogether, these data indicate that hA.01A is a novel tool potentially useful for the targeted treatment of B cell-derived cancers such as B-CLL and Multiple Myeloma. Citation Format: Marco Guadagnoli, Katherine Cameron, Elise Veraar, Fiona Kimberley, Andrea van Elsas, Hans van Eenennaam, Jan Paul Medema. Characterization of anti-human APRIL monoclonal antibodies capable of inhibiting APRIL-dependent B cell function and hyperproliferation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5480. doi:10.1158/1538-7445.AM2013-5480
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