title: Preclinical studies on targeted delivery of multiple IFNα2b to HLA-DR in diverse hematologic cancers.
abstract: The short circulating half-life and side effects of IFNα affect its dosing schedule and efficacy. Fusion of IFNα to a tumor-targeting mAb (mAb-IFNα) can enhance potency because of increased tumor localization and improved pharmacokinetics. We used the Dock-and-Lock method to generate C2-2b-2b, a mAb-IFNα comprising tetrameric IFNα2b site-specifically linked to hL243 (humanized anti-HLA-DR). In vitro, C2-2b-2b inhibited various B-cell lymphoma leukemia and myeloma cell lines. In most cases, this immunocytokine was more effective than CD20-targeted mAb-IFNα or a mixture comprising the parental mAb and IFNα. Our findings indicate that responsiveness depends on HLA-DR expression/density and sensitivity to IFNα and hL243. C2-2b-2b induced more potent and longer-lasting IFNα signaling compared with nontargeted IFNα. Phosphorylation of STAT1 was more robust and persistent than that of STAT3, which may promote apoptosis. C2-2b-2b efficiently depleted lymphoma and myeloma cells from whole human blood but also exhibited some toxicity to B cells, monocytes, and dendritic cells. C2-2b-2b showed superior efficacy compared with nontargeting mAb-IFNα, peginterferonalfa-2a, or a combination of hL243 and IFNα, using human lymphoma and myeloma xenografts. These results suggest that C2-2b-2b should be useful in the treatment of various hematopoietic malignancies.
authors.affiliation: IBC Pharmaceuticals Inc, Morris Plains, NJ 07950, USA. erossi@immunomedics.com
authors.forename: Edmund A
authors.initials: EA
authors.lastname: Rossi
authors.forename: Diane L
authors.initials: DL
authors.lastname: Rossi
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Cardillo
authors.forename: Rhona
authors.initials: R
authors.lastname: Stein
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
authors.forename: Chien-Hsing
authors.initials: CH
authors.lastname: Chang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005260:Female; D006684:HLA-DR Antigens / Q000276:immunology*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D007938:Leukemia / Q000188:drug therapy* / Q000276:immunology; D008223:Lymphoma / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D011994:Recombinant Proteins
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D006684:HLA-DR Antigens; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins