title: Interferon-λ1 linked to a stabilized dimer of Fab potently enhances both antitumor and antiviral activities in targeted cells.
abstract: The type III interferons (IFNs), comprising IFN-λ1, IFN-λ2, and IFN-λ3, behave similarly to IFN-α in eliciting antiviral, antitumor, and immune-modulating activities. Due to their more restricted cellular targets, IFN-λs are attractive as potential alternatives to existing therapeutic regimens based on IFN-αs. We have applied the DOCK-AND-LOCK™ method to improve the anti-proliferative potency of IFN-λ1 up to 1,000-fold in targeted cancer cell lines by tethering stabilized Fab dimers, derived from hRS7 (humanized anti-Trop-2), hMN-15 (humanized anti-CEACAM6), hL243 (humanized anti-HLA-DR), and c225 (chimeric anti-EGFR), to IFN-λ1 site-specifically, resulting in novel immunocytokines designated (E1)-λ1, (15)-λ1, (C2)-λ1, and (c225)-λ1, respectively. Targeted delivery of IFN-λ1 via (15)-λ1 or (c225)-λ1 to respective antigen-expressing cells also significantly increased antiviral activity when compared with non-targeting (C2)-λ1, as demonstrated in human lung adenocarcinoma cell line A549 by (15)-λ1 against encephalomyocarditis virus (EC50 = 22.2 pM versus 223 pM), and in human hepatocarcinoma cell line Huh-7 by (c225)-λ1 against hepatitis C virus (EC50 = 0.56 pM versus 91.2 pM). These promising results, which are attributed to better localization and stronger binding of IFN-λ1 to antibody-targeted cells, together with the favorable pharmacokinetic profile of (E1)-λ1 in mice (T(1/2) = 8.6 h), support further investigation of selective prototypes as potential antiviral and antitumor therapeutic agents.
authors.affiliation: IBC Pharmaceuticals, Inc., Morris Plains, New Jersey, United States of America.
authors.forename: Donglin
authors.initials: D
authors.lastname: Liu
authors.forename: Chien-Hsing
authors.initials: CH
authors.lastname: Chang
authors.forename: Edmund A
authors.initials: EA
authors.lastname: Rossi
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Cardillo
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004591:Electrophoresis, Polyacrylamide Gel; D004686:Encephalomyocarditis virus / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D016174:Hepacivirus / Q000187:drug effects; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry*; D007372:Interferons / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D007140:Immunoglobulin Fab Fragments; D007372:Interferons