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Advances in the Assessment and Control of the Effector Functions Of PERSPECTIVES the class of receptors most relevant for the OPINION function of therapeutic antibodies. FcγRs are divided into three types — FcγRI Advances in the assessment and (CD64), FcγRII (CD32) and FcγRIII (CD16)5,6 — and have traditionally been control of the effector functions of categorized according to their affinity for specific IgG subclasses and the type of sig- nalling pathway that they trigger; that is, therapeutic antibodies whether it is inhibitory or activating6. In gen- eral, FcγRI has been considered to be a ‘high Xu-Rong Jiang, An Song, Svetlana Bergelson, Thomas Arroll, Bhavin Parekh, affinity’ receptor that binds both monomeric Kimberly May, Shan Chung, Robert Strouse, Anthony Mire-Sluis and IgG and immune complexes, whereas the Mark Schenerman affinity of FcγRII and FcγRIII for IgGs is low and intermediate, respectively5,6. Abstract | The Fc (crystallizable fragment) region of therapeutic antibodies can However, assigning affinity to the FcγRs have an important role in their safety and efficacy. Although much is known is not simple. The classification of receptor about the structure–activity relationship of antibodies and the factors that affinity as ‘high’ or ‘low’ was first introduced in early studies using cell lines and human influence Fc effector functions, a process has not yet been defined to clearly myeloma proteins with an undefined glyco- delineate how Fc functionality should be assessed and controlled during form pattern associated with the receptor antibody development and manufacturing. In this article, we summarize the molecule. FcγRI was assigned as a ‘high current knowledge of antibody Fc functionality, provide a strategy for assessing affinity’ receptor because bound radio- the effector functions of different classes of therapeutic antibodies (including labelled IgG could be detected on the surface Fc fusion proteins) and propose a path for routine testing and controls for of cells following washing; this was not pos- sible for FcγRII or FcγRIII. However, both manufacturers of antibody products. FcγRII and FcγRIII were shown to bind to immune complexes and become activated, as is the case for FcγRI. The development and manufacture of heavy chain domain combinations and Fluorescence-activated cell sorting analy- therapeutic antibodies, including Fc glycoengineering, in order to modulate sis now enables us to observe direct binding (crystallizable fragment) fusion proteins, effector functions and to optimize safety of FcRs to immune complexes. Therefore, represent a significant segment of the and efficacy3,4. the terms used to define receptor affinity are biopharmaceutical industry and have Therapeutic antibodies rely on two relative and not absolute. The use of these resulted in substantial benefits to public types of functionalities to achieve clinical terms needs to be reconsidered given that health. To date, more than 20 unconjugated efficacy: target-specific binding by the Fab it is now known that the ‘affinity’ of afuco- recombinant therapeutic antibodies (antigen-binding fragment) domain and sylated IgG1 for FcγRIIIa is greatly increased have received regulatory approval for the immune-mediated effector functions — compared with fucosylated IgG1. On the treatment of various diseases, and all of such as antibody-dependent cell-mediated other hand, if the FcγRIIIa molecule is not these antibodies are of the immunoglobulin cytotoxicity (ADCC) and complement- glycosylated at N162, there is no difference G (IgG) class1. In the 1980s, therapeutic dependent cytotoxicity (CDC)3,4 — via in the binding affinity for the different IgG antibodies were of murine origin, highly interaction of the Fc domain with glycoforms7. Both cases illustrate that over- immunogenic, suboptimal in eliciting receptors on various cell types5,6. The simplification of affinity designations can Fc effector functions and had short half- Fc portion of a therapeutic antibody may occur if the nature of the glycosylation pat- lives in humans2. These issues drove therefore have an important role in its tern of either the antibody or the receptor is the evolution of antibody technology mechanism of action through its influence not considered. and led to the development of chimeric, on either ADCC or CDC. The binding of IgG to FcγRs is a criti- humanized and human antibodies that cal step for the initiation and control of are less immunogenic, more efficient at Fc receptor and immunoglobulin categories. cell-mediated effector functions, and each promoting desired effector functions and Fc receptors (FcRs) are a group of glyco- subclass of IgG (IgG1, IgG2, IgG3 and have longer half-lives. More recently, a proteins belonging to the immunoglobulin IgG4) exhibits a distinct profile of effector new generation of therapeutic antibodies superfamily and are organized into classes, function, which is dictated by differential has been engineered, through techniques such as FcαR, FcγR and FcεR; FcγRs are binding to each of the FcγRs5,6. Whereas such as amino acid mutagenesis, altered expressed mostly on leukocytes and they are both IgG1 and IgG3 bind relatively strongly NATURE REVIEWS | DRUG DISCOVERY VOLUME 10 | FEBRUARY 2011 | 101 © 2011 Macmillan Publishers Limited. All rights reserved PERSPECTIVES Table 1 | Classification and effector function potential of FDA-approved therapeutic antibodies and Fc fusion proteins Generic name (trade Format Targets Approved Proposed Therapeutic Initial name; sponsoring indications mechanisms of antibody assessment companies) action* class of effector function potential|| Alemtuzumab Humanized IgG1κ CD52 CLL Induction of ADCC I High (Campath; Genzyme/ Bayer) Cetuximab (Erbitux; Chimeric (murine/ EGFR Metastatic Inhibition of EGFR I High ImClone/Bristol-Myers human) IgG1κ colorectal cancer, signalling; induction of Squibb/Merck–Serono) and head and neck apoptosis and ADCC; cancer sensitization of cells to chemotherapy and radiotherapy Ofatumumab Human IgG1κ CD20 CLL Induction of CDC and I High (Arzerra; Genmab/ ADCC GlaxoSmithKline) Rituximab (Rituxan; Chimeric (murine/ CD20 Non-Hodgkin’s Induction of apoptosis, I High Genentech/Roche/ human) IgG1κ lymphoma, RA and ADCC and CDC; Biogen Idec) CLL sensitization of cells to chemotherapy Trastuzumab Humanized IgG1κ HER2 HER2- Inhibition of HER2 I High (Herceptin; overexpressing signalling; induction of Genentech/Roche) breast cancer ADCC; sensitization of cells to chemotherapy Adalimumab (Humira; Human IgG1κ TNFα‡ RA, JIA, PA, CD, AS Neutralization of TNFα II Moderate Abbott) and plaque psoriasis activity Alefacept (Amevive; LFA3 ECD–Fc (IgG1) CD2 Plaque psoriasis Inhibition of II Moderate Astellas) fusion protein CD2-dependent lymphocyte activation Basiliximab (Simulect; Chimeric (murine/ CD25 Acute transplant Inhibition of IL-2- II Moderate Novartis) human) IgG1κ rejection mediated activation of lymphocytes Daclizumab (Zenapax; Humanized IgG1κ CD25 Acute transplant Inhibition of IL-2 II Moderate Roche) rejection -mediated activation of lymphocytes Efalizumab§ (Raptiva; Humanized IgG1κ CD11a Plaque psoriasis Inhibition of II Moderate Genentech) CD11a-associated leukocyte adhesion Muromonab-CD3 Mouse IgG2aκ CD3 Acute transplant Blockade of II Moderate (Orthoclone OKT3; rejection CD3-associated T cell Centocor Ortho functions Biotech) Tocilizumab (Actemra; Humanized IgG1κ IL-6R‡ RA Inhibition of IL 6R II Moderate Genentech/Roche) signalling Golimumab (Simponi; Human IgG1κ TNFα‡ RA, PA and AS Neutralization of TNFα II Moderate Centocor Ortho activity Biotech) Infliximab (Remicade; Chimeric (murine/ TNFα‡ CD, RA, PA, Neutralization of TNFα II Moderate Centocor Ortho human) IgG1κ ulcerative colitis, AS activity Biotech) and plaque psoriasis Etanercept (Enbrel; TNFR2 ECD–Fc (IgG1) TNFα‡ RA, JIA, PA, AS and Neutralization of TNFα II Low63 Amgen/Pfizer) fusion protein plaque psoriasis activity Abatacept (Orencia; CTLA4 ECD–Fc, CD80 and RA and JIA Inhibition of II Low Bristol-Myers Squibb) mutated IgG1 Fc CD86 CD80/86-dependent T cell activation Denosumab (Prolia; Human IgG2κ RANKL‡ Osteoporosis Neutralization of II Low Amgen) RANKL activity Natalizumab (Tysabri; Humanized IgG4κ α4 subunit of Multiple sclerosis Inhibition of leukocyte II Low Biogen Idec/Elan) α4β1 and α4β7 and CD adhesion mediated by integrins α4β1 and α4β7 integrins 102 | FEBRUARY 2011 | VOLUME 10 www.nature.com/reviews/drugdisc © 2011 Macmillan Publishers Limited. All rights reserved PERSPECTIVES Table 1 | (contd) Classification and effector function potential of FDA-approved therapeutic antibodies and Fc fusion proteins Panitumumab (Vectibix; Humanized IgG2κ EGFR Metastatic Inhibition of EGFR II Low Amgen) colorectal signalling; induction of carcinoma apoptosis Romiplostim (Nplate; Thrombopoietin Thrombopoietin Thrombocytopaenia Activation of II Low Amgen) receptor-binding receptor in patients thrombopoietin peptide–Fc with idiopathic receptor (aglycosylated IgG1) thrombocytopaenic fusion protein purpura Bevacizumab (Avastin; Humanized IgG1κ VEGFA Metastatic Neutralization of III Low Genentech/Roche) colorectal cancer VEGFA activity Canakinumab (Ilaris; Human IgG1κ IL 1β CAPS Neutralization of IL-1β III Low Novartis) activity Eculizumab (Soliris; Humanized IgG(2/4)κ C5 complement Paroxysmal Inhibition of cleavage III Low Alexion) protein nocturnal of C5 to C5a and C5b haemoglobinuria Omalizumab (Xolair; Humanized IgG1κ IgE Allergic asthma Inhibition of binding of III Low Genentech) IgE to FcεRI Palivizumab (Synagis; Humanized IgG1κ F protein of RSV Prevention of RSV Neutralization of
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