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A Novel Fusion of ALT-803 (Interleukin (IL)-15 Superagonist) with an Antibody Demonstrates Antigen-specific Antitumor Responses.


ABSTRACT: 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.

SUBMITTER: Liu B 

PROVIDER: S-EPMC5104912 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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A Novel Fusion of ALT-803 (Interleukin (IL)-15 Superagonist) with an Antibody Demonstrates Antigen-specific Antitumor Responses.

Liu Bai B   Kong Lin L   Han Kaiping K   Hong Hao H   Marcus Warren D WD   Chen Xiaoyue X   Jeng Emily K EK   Alter Sarah S   Zhu Xiaoyun X   Rubinstein Mark P MP   Shi Sixiang S   Rhode Peter R PR   Cai Weibo W   Wong Hing C HC  

The Journal of biological chemistry 20160920 46


IL-15 and its receptor α (IL-15Rα) are co-expressed on antigen-presenting cells, allowing transpresentation of IL-15 to immune cells bearing IL-2Rβγ<sub>C</sub> 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-15Rα sushi domain (IL-15RαSu) could be exploited to create a functional scaffold for the design of multivalent disease-targeted complexes. The IL-15N72D·IL-15RαSuFc co  ...[more]

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