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Journal of Pharmaceutical Sciences May 2019Protein therapeutics have drastically changed the landscape of treatment for many diseases by providing a regimen that is highly specific and lacks many off-target... (Review)
Review
Protein therapeutics have drastically changed the landscape of treatment for many diseases by providing a regimen that is highly specific and lacks many off-target toxicities. The clinical utility of many therapeutic proteins has been undermined by the potential development of unwanted immune responses against the protein, limiting their efficacy and negatively impacting its safety profile. This review attempts to provide an overview of immunogenicity of therapeutic proteins, including immune mechanisms and factors influencing immunogenicity, impact of immunogenicity, preclinical screening methods, and strategies to mitigate immunogenicity.
Topics: Animals; Antibodies; Antibody Formation; Humans; Proteins
PubMed: 30599169
DOI: 10.1016/j.xphs.2018.12.014 -
Cell Jan 2020Repeated exposure to pathogens or their antigens triggers anamnestic antibody responses that are higher in magnitude and affinity than the primary response. These...
Repeated exposure to pathogens or their antigens triggers anamnestic antibody responses that are higher in magnitude and affinity than the primary response. These involve reengagement of memory B cell (MBC) clones, the diversity and specificity of which determine the breadth and effectiveness of the ensuing antibody response. Using prime-boost models in mice, we find that secondary responses are characterized by a clonality bottleneck that restricts the engagement of the large diversity of MBC clones generated by priming. Rediversification of mutated MBCs is infrequent within secondary germinal centers (GCs), which instead consist predominantly of B cells without prior GC experience or detectable clonal expansion. Few MBC clones, generally derived from higher-affinity germline precursors, account for the majority of secondary antibody responses, while most primary-derived clonal diversity is not reengaged detectably by boosting. Understanding how to counter this bottleneck may improve our ability to elicit antibodies to non-immunodominant epitopes by vaccination.
Topics: Adaptive Immunity; Animals; Antibody Formation; Antigens; B-Lymphocytes; CHO Cells; Cell Line; Cricetulus; Female; Germinal Center; Humans; Immunologic Memory; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Animal
PubMed: 31866068
DOI: 10.1016/j.cell.2019.11.032 -
MAbs 2013Knobs-into-holes is a well-validated heterodimerization technology for the third constant domain of an antibody. This technology has been used to produce a monovalent...
Knobs-into-holes is a well-validated heterodimerization technology for the third constant domain of an antibody. This technology has been used to produce a monovalent IgG for clinical development (onartuzumab) and multiple bispecific antibodies. The most advanced uses of this approach, however, have been limited to E. coli as an expression host to produce non-glycosylated antibodies. Here, we applied the technology to mammalian host expression systems to produce glycosylated, effector-function competent heterodimeric antibodies. In our mammalian host system, each arm is secreted as a heavy chain-light chain (H-L) fragment with either the knob or hole mutations to allow for preferential heterodimer formation in vitro with low levels of homodimer contaminants. Like full antibodies, the secreted H-L fragments undergo Fc glycosylation in the endoplasmic reticulum. Using a monospecific anti-CD20 antibody, we show that full antibody-dependent cell-mediated cytotoxicity (ADCC) activity can be retained in the context of a knobs-into-holes heterodimer. Because the knobs-into-holes mutations convert the Fc into an asymmetric heterodimer, this technology was further used to systematically explore asymmetric recognition of the Fc. Our results indicate that afucosylation of half the heterodimer is sufficient to produce ADCC-enhancement similar to that observed for a fully afucosylated antibody with wild-type Fc. However, the most dramatic effect on ADCC activity is observed when two carbohydrate chains are present rather than one, regardless of afucosylation state.
Topics: Animals; Antibody Formation; Antibody-Dependent Cell Cytotoxicity; CHO Cells; Cell Line; Cell Survival; Cells, Cultured; Cricetulus; Dimerization; Fucose; Glycosylation; Humans; Protein Engineering
PubMed: 23995614
DOI: 10.4161/mabs.26307 -
The AAPS Journal Jul 2014Immunogenicity is a significant concern for biologic drugs as it can affect both safety and efficacy. To date, the descriptions of product immunogenicity have varied not...
Immunogenicity is a significant concern for biologic drugs as it can affect both safety and efficacy. To date, the descriptions of product immunogenicity have varied not only due to different degrees of understanding of product immunogenicity at the time of licensing but also due to an evolving lexicon that has generated some confusion in the field. In recent years, there has been growing consensus regarding the data needed to assess product immunogenicity. Harmonization of the strategy for the elucidation of product immunogenicity by drug developers, as well as the use of defined common terminology, can benefit medical practitioners, health regulatory agencies, and ultimately the patients. Clearly, understanding the incidence, kinetics and magnitude of anti-drug antibody (ADA), its neutralizing ability, cross-reactivity with endogenous molecules or other marketed biologic drugs, and related clinical impact may enhance clinical management of patients treated with biologic drugs. To that end, the authors present terms and definitions for describing and analyzing clinical immunogenicity data and suggest approaches to data presentation, emphasizing associations of ADA development with pharmacokinetics, efficacy, and safety that are necessary to assess the clinical relevance of immunogenicity.
Topics: Antibody Formation; Guidelines as Topic; Humans; Peptides; Proteins; Terminology as Topic
PubMed: 24764037
DOI: 10.1208/s12248-014-9599-2 -
Frontiers in Immunology 2020
Topics: Antibody Formation; B-Lymphocytes; Drug Discovery; High-Throughput Nucleotide Sequencing; Humans; Vaccines
PubMed: 32714328
DOI: 10.3389/fimmu.2020.01344 -
Seminars in Immunopathology Mar 2019Vaccines are among the most impactful public health interventions, preventing millions of new infections and deaths annually worldwide. However, emerging data suggest... (Review)
Review
Vaccines are among the most impactful public health interventions, preventing millions of new infections and deaths annually worldwide. However, emerging data suggest that vaccines may not protect all populations equally. Specifically, studies analyzing variation in vaccine-induced immunity have pointed to the critical impact of genetics, the environment, nutrition, the microbiome, and sex in influencing vaccine responsiveness. The significant contribution of sex to modulating vaccine-induced immunity has gained attention over the last years. Specifically, females typically develop higher antibody responses and experience more adverse events following vaccination than males. This enhanced immune reactogenicity among females is thought to render females more resistant to infectious diseases, but conversely also contribute to higher incidence of autoimmunity among women. Dissection of mechanisms which underlie sex differences in vaccine-induced immunity has implicated hormonal, genetic, and microbiota differences across males and females. This review will highlight the importance of sex-dependent differences in vaccine-induced immunity and specifically will address the role of sex as a modulator of humoral immunity, key to long-term pathogen-specific protection.
Topics: Antibody Formation; Autoimmune Diseases; Female; Humans; Immunity, Humoral; Incidence; Infection Control; Infections; Male; Microbiota; Sex Characteristics; Vaccination; Vaccines
PubMed: 30547182
DOI: 10.1007/s00281-018-0726-5 -
MAbs 2020The origins of the various elements in the human antibody repertoire have been and still are subject to considerable uncertainty. Uncertainty in respect of whether the... (Review)
Review
The origins of the various elements in the human antibody repertoire have been and still are subject to considerable uncertainty. Uncertainty in respect of whether the various elements have always served a specific defense function or whether they were co-opted from other organismal roles to form a crude naïve repertoire that then became more complex as combinatorial mechanisms were added. Estimates of the current size of the human antibody naïve repertoire are also widely debated with numbers anywhere from 10 million members, based on experimentally derived numbers, to in excess of one thousand trillion members or more, based on the different sequences derived from theoretical combinatorial calculations. There are questions that are relevant at both ends of this number spectrum. At the lower bound it could be questioned whether this is an insufficient repertoire size to counter all the potential antigen-bearing pathogens. At the upper bound the question is rather simpler: How can any individual interrogate such an astronomical number of antibody-bearing B cells in a timeframe that is meaningful? This review evaluates the evolutionary aspects of the adaptive immune system, the calculations that lead to the large repertoire estimates, some of the experimental evidence pointing to a more restricted repertoire whose variation appears to derive from convergent 'structure and specificity features', and includes a theoretical model that seems to support it. Finally, a solution that may reconcile the size difference anomaly, which is still a hot subject of debate, is suggested.
Topics: Antibody Formation; Humans
PubMed: 32097086
DOI: 10.1080/19420862.2020.1729683 -
BioMed Research International 2014It has long been known that circulating levels of IgG and IgM antibodies are elevated in patients with essential and pregnancy-related hypertension. Recent studies... (Review)
Review
It has long been known that circulating levels of IgG and IgM antibodies are elevated in patients with essential and pregnancy-related hypertension. Recent studies indicate these antibodies target, and in many cases activate, G-protein coupled receptors and ion channels. Prominent among these protein targets are AT1 receptors, α1-adrenoceptors, β1-adrenoceptors, and L-type voltage operated Ca(2+) channels, all of which are known to play key roles in the regulation of blood pressure through modulation of vascular tone, cardiac output, and/or Na(+)/water reabsorption in the kidneys. This suggests that elevated antibody production may be a causal mechanism in at least some cases of hypertension. In this brief review, we will further describe the protein targets of the antibodies that are elevated in individuals with essential and pregnancy-related hypertension and the likely pathophysiological consequences of antibody binding to these targets. We will speculate on the potential mechanisms that underlie elevated antibody levels in hypertensive individuals and, finally, we will outline the therapeutic opportunities that could arise with a better understanding of how and why antibodies are produced in hypertension.
Topics: Animals; Antibodies; Antibody Formation; B-Lymphocytes; Humans; Hypertension
PubMed: 25050352
DOI: 10.1155/2014/504045 -
EMBO Reports Apr 2020Efficient antibody production is a crucial step during immune responses leading to pathogen clearance and neutralization. Immune synapses, contact points between T and B...
Efficient antibody production is a crucial step during immune responses leading to pathogen clearance and neutralization. Immune synapses, contact points between T and B lymphocytes in the presence of an antigen, are necessary to initiate the proliferation and differentiation of B cells in the germinal center. In this issue of EMBO Reports, Fernández-Messina et al [1] present evidence of microRNA transfer from T to B cells via exosomes during synapse formation and highlight the crucial role of these exosomes for germinal center formation and the efficient production of antigen-specific antibodies.
Topics: Antibody Formation; B-Lymphocytes; Exosomes; Germinal Center; MicroRNAs
PubMed: 32147923
DOI: 10.15252/embr.202050190 -
Cellular & Molecular Immunology Jun 2020In contrast to the previous belief that autoreactive B cells are eliminated from the normal repertoire of B cells, many autoreactive B cells actually escape clonal... (Review)
Review
In contrast to the previous belief that autoreactive B cells are eliminated from the normal repertoire of B cells, many autoreactive B cells actually escape clonal deletion and develop into mature B cells. These autoreactive B cells in healthy individuals perform some beneficial functions in the host and are homeostatically regulated by regulatory T and B cells or other mechanisms to prevent autoimmune diseases. Autoreactive B-1 cells constitutively produce polyreactive natural antibodies for tissue homeostasis. Recently, autoreactive follicular B cells were reported to participate actively in the germinal center reaction. Furthermore, the selection and usefulness of autoreactive marginal zone (MZ) B cells found in autoimmune diseases are not well understood, although the repertoire of MZ B-cell receptors (BCRs) is presumed to be biased to detect bacterial antigens. In this review, we discuss the autoreactive B-cell populations among all three major B-cell subsets and their regulation in immune responses and diseases.
Topics: Animals; Antibody Formation; B-Lymphocytes; Disease; Health; Homeostasis; Humans; Immunity
PubMed: 32382130
DOI: 10.1038/s41423-020-0445-4