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A Novel Fusion of ALT-803 (Interleukin (IL)-15 Superagonist) with an Antibody Demonstrates Antigen-specific Antitumor Responses.
Liu, Bai; Kong, Lin; Han, Kaiping; Hong, Hao; Marcus, Warren D; Chen, Xiaoyue; Jeng, Emily K; Alter, Sarah; Zhu, Xiaoyun; Rubinstein, Mark P; Shi, Sixiang; Rhode, Peter R; Cai, Weibo; Wong, Hing C.
Afiliação
  • Liu B; From the Altor BioScience Corp., Miramar, Florida 33025.
  • Kong L; From the Altor BioScience Corp., Miramar, Florida 33025.
  • Han K; From the Altor BioScience Corp., Miramar, Florida 33025.
  • Hong H; the Departments of Radiology and Medical Physics, University of Wisconsin, Madison, Wisconsin 53706, and.
  • Marcus WD; From the Altor BioScience Corp., Miramar, Florida 33025.
  • Chen X; From the Altor BioScience Corp., Miramar, Florida 33025.
  • Jeng EK; From the Altor BioScience Corp., Miramar, Florida 33025.
  • Alter S; From the Altor BioScience Corp., Miramar, Florida 33025.
  • Zhu X; From the Altor BioScience Corp., Miramar, Florida 33025.
  • Rubinstein MP; the Departments of Surgery and Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina 29425.
  • Shi S; the Departments of Radiology and Medical Physics, University of Wisconsin, Madison, Wisconsin 53706, and.
  • Rhode PR; From the Altor BioScience Corp., Miramar, Florida 33025.
  • Cai W; the Departments of Radiology and Medical Physics, University of Wisconsin, Madison, Wisconsin 53706, and.
  • Wong HC; From the Altor BioScience Corp., Miramar, Florida 33025, hingwong@altorbioscience.com.
J Biol Chem ; 291(46): 23869-23881, 2016 Nov 11.
Article em En | MEDLINE | ID: mdl-27650494
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-2RßγC 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 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-2RßγC displayed 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Recombinantes de Fusão / Células Matadoras Naturais / Proteínas / Linfoma de Células B / Interleucina-15 / Rituximab / Imunidade Celular Limite: Animals / Female / Humans Idioma: En Revista: J Biol Chem Ano de publicação: 2016 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Recombinantes de Fusão / Células Matadoras Naturais / Proteínas / Linfoma de Células B / Interleucina-15 / Rituximab / Imunidade Celular Limite: Animals / Female / Humans Idioma: En Revista: J Biol Chem Ano de publicação: 2016 Tipo de documento: Article