title: A Novel Fusion of ALT-803 (Interleukin (IL)-15 Superagonist) with an Antibody Demonstrates Antigen-specific Antitumor Responses.
abstract: 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-2RβγCand 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 complex, also known as ALT-803, is a multimeric complex constructed by fusing IL-15N72D·IL-15RαSu 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-2RβγCdisplayed on immune effector cells, and binding to Fcγ 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.
authors.affiliation: From the Altor BioScience Corp., Miramar, Florida 33025.
authors.forename: Bai
authors.initials: B
authors.lastname: Liu
authors.affiliation: From the Altor BioScience Corp., Miramar, Florida 33025.
authors.forename: Lin
authors.initials: L
authors.lastname: Kong
authors.affiliation: From the Altor BioScience Corp., Miramar, Florida 33025.
authors.forename: Kaiping
authors.initials: K
authors.lastname: Han
authors.affiliation: the Departments of Radiology and Medical Physics, University of Wisconsin, Madison, Wisconsin 53706, and.
authors.forename: Hao
authors.initials: H
authors.lastname: Hong
authors.affiliation: From the Altor BioScience Corp., Miramar, Florida 33025.
authors.forename: Warren D
authors.initials: WD
authors.lastname: Marcus
authors.affiliation: From the Altor BioScience Corp., Miramar, Florida 33025.
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Chen
authors.affiliation: From the Altor BioScience Corp., Miramar, Florida 33025.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Jeng
authors.affiliation: From the Altor BioScience Corp., Miramar, Florida 33025.
authors.forename: Sarah
authors.initials: S
authors.lastname: Alter
authors.affiliation: From the Altor BioScience Corp., Miramar, Florida 33025.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Zhu
authors.affiliation: the Departments of Surgery and Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Rubinstein
authors.affiliation: the Departments of Radiology and Medical Physics, University of Wisconsin, Madison, Wisconsin 53706, and.
authors.forename: Sixiang
authors.initials: S
authors.lastname: Shi
authors.affiliation: From the Altor BioScience Corp., Miramar, Florida 33025.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Rhode
authors.affiliation: the Departments of Radiology and Medical Physics, University of Wisconsin, Madison, Wisconsin 53706, and.
authors.forename: Weibo
authors.initials: W
authors.lastname: Cai
authors.affiliation: From the Altor BioScience Corp., Miramar, Florida 33025, hingwong@altorbioscience.com.
authors.forename: Hing C
authors.initials: HC
authors.lastname: Wong
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects*; D019409:Interleukin-15 / Q000819:agonists* / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D000069283:Rituximab / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C582303:ALT-803; C569274:IL15 protein, human; D019409:Interleukin-15; D011506:Proteins; D011993:Recombinant Fusion Proteins; D000069283:Rituximab
keywords: antibody; fusion protein; immunotherapy; interleukin; scaffold protein