Development and characterization of APRIL antagonistic monoclonal antibodies for treatment of B-cell lymphomas

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BlankDevelopment and characterization of APRIL antagonistic monoclonal

antibodies for treatment of B-cell lymphomas

1.. Marco Guadagnoli1,*,

2.. Fiona C. Kimberley1,*,

3.. Uyen Phan2,*,

4.. Cameron1,

5.. M. Vink3,

6.. Hans Rodermond1,

7.. Eldering4,

8.. Arnon P. Kater4,

9.. Hans van Eenennaam3,†, and

10.. Jan Medema1,†

+ Author Affiliations

1.. 1Laboratory of Experimental Oncology and Radiobiology (LEXOR), Center for

Experimental Molecular Medicine, Academic Medical Center (AMC), Amsterdam, The

Netherlands;

2.. 2Merck Research Laboratories, Palo Alto, CA;

3.. 3Department of Immune Therapeutics, Merck Research Laboratories, MSD, Oss,

The Netherlands; and

4.. 4Department of Experimental Immunology, AMC, Amsterdam, The Netherlands

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.