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2016 ; 291
(46
): 23869-23881
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A Novel Fusion of ALT-803 (Interleukin (IL)-15 Superagonist) with an Antibody
Demonstrates Antigen-specific Antitumor Responses
#MMPMID27650494
Liu B
; Kong L
; Han K
; Hong H
; Marcus WD
; Chen X
; Jeng EK
; Alter S
; Zhu X
; Rubinstein MP
; Shi S
; Rhode PR
; Cai W
; Wong HC
J Biol Chem
2016[Nov]; 291
(46
): 23869-23881
PMID27650494
show ga
IL-15 and its receptor ? (IL-15R?) are co-expressed on antigen-presenting cells,
allowing transpresentation of IL-15 to immune cells bearing IL-2R??(C) and
stimulation of effector immune responses. We reported previously that the
high-affinity interactions between an IL-15 superagonist (IL-15N72D) and the
extracellular IL-15R? sushi domain (IL-15R?Su) could be exploited to create a
functional scaffold for the design of multivalent disease-targeted complexes. The
IL-15N72D·IL-15R?SuFc complex, also known as ALT-803, is a multimeric complex
constructed by fusing IL-15N72D·IL-15R?Su to the Fc domain of IgG1. ALT-803 is an
IL-15 superagonist complex that has been developed as a potent antitumor
immunotherapeutic agent and is in clinical trials. Here we describe the creation
of a novel fusion molecule, 2B8T2M, using the ALT-803 scaffold fused to four
single chains of the tumor-targeting monoclonal antibody rituximab. This molecule
displays trispecific binding activity through its recognition of the CD20
molecule on tumor cells, stimulation via IL-2R??(C) displayed on immune effector
cells, and binding to Fc? receptors on natural killer cells and macrophages.
2B8T2M activates natural killer cells to enhance antibody-dependent cellular
cytotoxicity, mediates complement-dependent cytotoxicity, and induces apoptosis
of B-lymphoma cells. Compared with rituximab, 2B8T2M exhibits significantly
stronger antitumor activity in a xenograft SCID mouse model and depletes B cells
in cynomolgus monkeys more efficiently. Thus, ALT-803 can be modified as a
functional scaffold for creating multispecific, targeted IL-15-based
immunotherapeutic agents and may serve as a novel platform to improve the
antitumor activity and clinical efficacy of therapeutic antibodies.
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