Differences in binding and effector functions between classes of TNF antagonists |
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| Authors: | Taruna Arora Rupa Padaki Ling Liu Agnes E Hamburger Aaron R Ellison Seth R Stevens James S Louie Tadahiko Kohno |
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| Institution: | 1. Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA;2. UCLA Rheumatology, 1000 Veteran Ave., Rm 32-59, Los Angeles, CA 90095-1670, USA;1. Department of Ophthalmology, Duke University, Durham, North Carolina;2. Massachusetts Eye Research and Surgery Institution, Ocular Immunology & Uveitis Foundation, Waltham, Massachusetts;3. Moorfields Eye Hospital, London, United Kingdom;4. EyePoint Pharmaceuticals, Inc., Watertown, Massachusetts;1. SuppreMol GmbH, a wholly-owned subsidiary of Baxalta Incorporated, Am Klopferspitz 19a, D-82152 Martinsried, Germany;1. Departments of Radiology, Tokyo Metropolitan Police Hospital, 4-22-1, Nakano, Nakano-ku, Tokyo, 164-0001, Japan;2. Gastroenterology (Y.S., K.O.), Tokyo Metropolitan Police Hospital, 4-22-1, Nakano, Nakano-ku, Tokyo, 164-0001, Japan;3. Department of Radiology (A.H.), Graduate School of Medicine, University of Tokyo, Tokyo, Japan;1. The Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, Warszawa, Poland;2. Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warszawa, Poland;3. Agency for Health Technology Assessment, Warszawa, Poland;4. Department of Psychiatry, Medical University of Warsaw, Warszawa, Poland;5. Department of Psychiatry, University of Michigan, Ann Arbor, USA |
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| Abstract: | There are currently two Food and Drug Administration-approved classes of biologic agents that target tumor necrosis factor-α (TNF-α): anti-TNF monoclonal antibodies (mAbs) (adalimumab and infliximab), and soluble TNF receptors (etanercept). This study examined the ability of the TNF antagonists to: (1) bind various polymorphic variants of cell surface-expressed Fc receptors (FcγRs) and the complement component C1q, and (2) mediate Ab-dependent cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC) killing of cells expressing membrane-bound TNF (mTNF) in vitro. Both mAbs and the soluble TNF receptor demonstrated low-level binding to the activating receptors FcγRI, FcγRIIa, and FcγRIIIa, and the inhibitory receptor FcγRIIb, in the absence of exogenous TNF. However, upon addition of TNF, the mAbs, but not etanercept, showed significantly increased binding, in particular to the FcγRII and FcγRIII receptors. Infliximab and adalimumab induced ADCC much more potently than etanercept. In the presence of TNF, both mAbs bound C1q in in vitro assays, but etanercept did not bind C1q under any conditions. Infliximab and adalimumab also induced CDC in cells expressing mTNF more potently than etanercept. Differences in the ability to bind ligand and mediate cell death may account for the differences in efficacy and safety of TNF antagonists. |
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