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The Importance of Using an Isotype Control The Importance of Using an Isotype Control White Paper What are Isotype Controls? Isotype control antibodies are essential negative controls for in vivo studies and can play an important role in standard immunoassays, such as flow cytometry and immunohistochemistry (IHC). They match the characteristics of the assay’s primary antibody (e.g. isotype, clonality), but having been raised against antigens known not to be present in common preclinical species (HEL, KLH, etc.), have no target cell/antigen specificity. This provides researchers with a suitable negative control to accurately discriminate between an antibody binding in an antigen-dependent specific manner from non-antigen dependent mAb binding due to Fc receptors (FcR) or other proteins. In the simplest terms, isotype controls help distinguish non- specific background signal from specific antibody signal. Monoclonal, subclass specific (i.e. lambda vs. kappa immunoglobulin) isotype controls provide an especially reliable method that effectively differentiates between specificity versus background in a range of drug development assays. Why is it Important to Use Isotype Controls? Structurally, all antibodies are very similar, with only a small hypervariable region determining antigen specific binding. The rest of the antibody molecule consists of Using an the constant region, where sequences are often shared by antibodies of the same “appropriate isotype. isotype control allows the true The constant regions help determine antibody mechanism of action, by coordinating determination binding to the FcR present on many cell types. FcRs are expressed on a number of different cell types in the immune system, including (but not limited to): of specific vs non-antigen • B lymphocytes specific • follicular dendritic cells binding • natural killer cells across a range • macrophages • neutrophils of in vivo “ studies and • eosinophils Immunoassays • basophils • human platelets • mast cells. The non-specific binding of antibodies to other proteins is affected by many factors, including: • high concentration • charge • hydrophobicity. 1 of 9 +1.855.827.6968 | [email protected] | www.crownbio.com How to Choose an Appropriate Isotype Control When choosing an appropriate isotype control, matching the characteristics of the primary antibody is key for accurate interpretation of study results. The main factors to consider when choosing the appropriate isotype control antibody for a study are host, isotype, conjugation, light chain, and concentration (Figure 1). Figure 1: Matching Primary Antibody Host, Isotype, Conjugation, Light Chain, and Concentration are Key Factors in Choosing an Isotype Control By matching “a range of primary antibody features, isotype controls provide an ideal negative Host Isotype control for “ precise data analysis Conjugation Light Chain Concentration Why PBS is not a Suitable Substitute for an Isotype Control While the use of PBS instead of an isotype control antibody as a negative control is not ideal, it does occur in published research. Using this non-optimal control factor can result in a range of issues during efficacy studies and immunoassays. 1. Use of PBS in Efficacy Experiments Fails to Simulate the Effects Caused by Widespread FcR Engagement Using PBS as a simplified negative control in a range of in vivo efficacy assays can result in inaccurate interpretation of results, due to performance differences observed between PBS and the isotype control. Figure 2 compares growth of the CT-26.WT syngeneic colon cancer model in the presence of PBS or rat IgG2a isotype control, with a clear difference observed between growth rates for the differing control agents. 2 of 9 +1.855.827.6968 | [email protected] | www.crownbio.com Figure 2: Performance Difference between PBS and Isotype Negative Controls in Syngeneic Tumor Studies Using PBS in place of isotype controls is “ “not advised - performance differences can result in incorrect data interpretation in in vivo studies Modest tumor inhibition can be observed with hIgG1 isotype control (Figure 3; shown for the H22 syngeneic liver cancer model). This helps to illustrate that the inhibitory effect on tumor growth of a corresponding target antibody must be compared with that of the hIgG1 isotype control, not PBS, for a correct calculation of tumor growth inhibition and a more accurate measurement of drug efficacy. 3 of 9 +1.855.827.6968 | [email protected] | www.crownbio.com Figure 3: Tumor Growth Inhibition Induced by hIgG1 compared with PBS The importance of comparison with the correct control agent is also exemplified in the Collagen Antibody-Induced Arthritis (CAIA) model shown in Figure 4. In this model, rheumatoid arthritis in BALB/c mice is induced through the administration of an athrogenic antibody followed by LPS, which can then be treated with potential new agents. In Figure 4, the model is treated with dexamethasone (with PBS control) or an anti- TNF mAb (with IgG1 isotype control). The PBS and isotype controls show a clear performance difference, which would lead to erroneous interpretation of anti-TNF mAb statistics if compared instead with a PBS control. 4 of 9 +1.855.827.6968 | [email protected] | www.crownbio.com Figure 4: Performance Difference between PBS and Isotype Negative Controls in CAIA Model Arthritis Index Scoring Scoring occurs per paw such that the total score is 16. 0 = Normal paw 1 = One toe inflamed or swollen 2 = More than one toe but not entire paw 3 = Entire paw inflamed & swollen 4 = Very inflamed and swollen paw or ankylosed paw 2. PBS Use in Flow Cytometry Experiments Does Not Mimic FcR or Protein Staining Matched “isotype In flow cytometry experiments, antibody binding to FcRs or other proteins can controls cause non-specific staining in cell types, dependent upon FcR expression. This can can mimic appear deceptively specific due to the variation in FcR expression in different tissues. Therefore, it may be useful to have matched isotype controls which can mimic this antibody staining, rather than use a non-binding PBS control. staining in flow cytometry As a result of this, in order to be useful in flow cytometry, isotype controls should experiments; ideally be the same species, heavy chain (IgA, IgG, IgD, IgE, or IgM), and light chain however, (kappa or lambda) class. For directly conjugated antibodies, isotype controls should be conjugated to the same fluorochrome at the same labelling ratio, such that an complete “ identical number of fluorescent molecules is conjugated to each antibody. matching can prove complex This is also referred to as the F:P ratio. Due to this level of complexity, researchers have different preferences regarding inclusion of isotype controls for flow cytometry. Differentially conjugated isotype controls can lead to misleading results. 3. Isotype Control Antibodies can Induce Differences in Tumor Infiltrating Lymphocyte Populations Treatment with isotype control antibodies can result in differences in tumor infiltrating lymphocyte populations, which is not observed with PBS use. This is distinct from the staining controls in flow cytometry discussed above, as animals are dosed with the isotype control, and represents an actual change in immune cell representation within the tumor itself. 5 of 9 +1.855.827.6968 | [email protected] | www.crownbio.com Figure 5 displays this occurrence for the MC38 syngeneic colon cancer model. By Day 13, treatment with isotype control, at 10mg/kg twice per week, causes an increase in CD3+ T cells, which is not observed with PBS treatment. In contrast, this effect is not seen in CT-26.WT syngeneic tumors using the same isotype control, suggesting it is highly model dependent. Therefore, these data, utilizing the correct control are critical for understanding the full response of the anti-PD-1 treated tumors. Figure 5: Isotype Controls Induce TIL Differences for Specific Time Points and Models Isotype “controls can induce TIL changes, making their use essential to understanding therapeutic antibody “ response data Immunohistochemistry Experiments also Require Appropriate Isotype Controls Isotype controls are also an ideal negative control for IHC assays. If isotype controls are not used, then they are usually swapped out for one of two options: 1. Directly staining with a secondary antibody 2. Staining with a polyclonal pool. Using a secondary antibody alone as a control instead of an isotype control antibody is disadvantageous as the secondary antibody binds directly to the sample, rather than to the Fc fragment of a primary antibody or isotype control. The secondary could also have altered binding properties in isolation compared to binding with the appropriate isotype control. Instead, ideally, the negative control used for IHC should mimic the exact concentration and isotype of the primary antibody, which is why an isotype control is the most appropriate choice. Depending upon the tissue, the antibody isotype could cause a noticeable difference due to the potentially significant interaction with resident FcRs present in different tissue sections as demonstrated in Table 1. 6 of 9 +1.855.827.6968 | [email protected] | www.crownbio.com Table 1: Binding Preferences of Mouse, Rat, and Human IgG Isotypes(1) Mouse mFcγRI mFcγRII mFcγRIII mFcγRIV IgG IgG1 No bind ++ ++ No bind IgG2a +++ + ++ +++ IgG2b ND ++ + +++ IgG3 ND No bind No bind No bind Rat IgG2a No bind ++ + + Human IgG FcγRI FcγRIIa FcγRIIb/c FcγRIIIa FcγRIIIB IgG1 +++ ++ + ++ + IgG2 No bind + + + No bind IgG3 +++ + + ++ ++ IgG4 +++ +
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