A bispecific antibody-IFNalpha2b immunocytokine targeting CD20 and HLA-DR is highly toxic to human lymphoma and multiple myeloma cells.
The short circulating half-life and side effects of IFNα affect its dosing schedule and efficacy. Fusion of IFNα to a tumor-targeting monoclonal antibody (MAb-IFNα) can enhance potency due to increased tumor localization and improved pharmacokinetics. We report the generation and characterization of the first bispecific MAb-IFNα, designated 20-C2-2b, which comprises two copies of IFNα2b and a stabilized F(ab)(2) of hL243 (humanized anti-HLA-DR; IMMU-114) site-specifically linked to veltuzumab (humanized anti-CD20). In vitro, 20-C2-2b inhibited each of four lymphoma and eight myeloma cell lines, and was more effective than monospecific CD20-targeted MAb-IFNα or a mixture comprising the parental antibodies and IFNα in all but one (HLA-DR(-)/CD20(-)) myeloma line, suggesting that 20-C2-2b should be useful in the treatment of various hematopoietic malignancies. 20-C2-2b displayed greater cytotoxicity against KMS12-BM (CD20(+)/HLA-DR(+) myeloma) compared with monospecific MAb-IFNα, which targets only HLA-DR or CD20, indicating that all three components in 20-C2-2b could contribute to toxicity. Our findings indicate that a given cell's responsiveness to MAb-IFNα depends on its sensitivity to IFNα and the specific antibodies, as well as the expression and density of the targeted antigens.
Rossi
Edmund A
EA
IBC Pharmaceuticals, Inc., Morris Plains, New Jersey, USA.
Rossi
Diane L
DL
Stein
Rhona
R
Goldenberg
David M
DM
Chang
Chien-Hsing
CH
D018033:Antibodies, Bispecific / Q000276:immunology / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity; D018951:Antigens, CD20 / Q000276:immunology*; D006684:HLA-DR Antigens / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000276:immunology*; D008228:Lymphoma, Non-Hodgkin / Q000097:blood / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D009101:Multiple Myeloma / Q000097:blood / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000276:immunology; D011994:Recombinant Proteins
D018033:Antibodies, Bispecific; D018951:Antigens, CD20; D006684:HLA-DR Antigens; D007074:Immunoglobulin G; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins