Immunoglobulin Constant Region

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Mark J Selby - One of the best experts on this subject based on the ideXlab platform.

  • anti ctla 4 antibodies of igg2a isotype enhance antitumor activity through reduction of intratumoral regulatory t cells
    Cancer immunology research, 2013
    Co-Authors: Mark J Selby, John J Engelhardt, Michael Quigley, Karla A Henning, Timothy Chen, Mohan Srinivasan, Alan J. Korman
    Abstract:

    Antitumor activity of CTLA-4 antibody blockade is thought to be mediated by interfering with the negative regulation of T-effector cell (Teff) function resulting from CTLA-4 engagement by B7-ligands. In addition, a role for CTLA-4 on regulatory T cells (Treg), wherein CTLA-4 loss or inhibition results in reduced Treg function, may also contribute to antitumor responses by anti-CTLA-4 treatment. We have examined the role of the Immunoglobulin Constant Region on the antitumor activity of anti-CTLA-4 to analyze in greater detail the mechanism of action of anti-CTLA-4 antibodies. Anti-CTLA-4 antibody containing the murine Immunoglobulin G (IgG)2a Constant Region exhibits enhanced antitumor activity in subcutaneous established MC38 and CT26 colon adenocarcinoma tumor models compared with anti-CTLA-4 containing the IgG2b Constant Region. Interestingly, anti-CTLA-4 antibodies containing mouse IgG1 or a mutated mouse IgG1-D265A, which eliminates binding to all Fcγ receptors (FcγR), do not show antitumor activity in these models. Assessment of Teff and Treg populations at the tumor and in the periphery showed that anti-CTLA-4-IgG2a mediated a rapid and dramatic reduction of Tregs at the tumor site, whereas treatment with each of the isotypes expanded Tregs in the periphery. Expansion of CD8 + Teffs is observed with both the IgG2a and IgG2b anti-CTLA-4 isotypes, resulting in a superior Teff to Treg ratio for the IgG2a isotype. These data suggest that anti-CTLA-4 promotes antitumor activity by a selective reduction of intratumoral Tregs along with concomitant activation of Teffs. Cancer Immunol Res; 1(1); 32–42. ©2013 AACR .

  • role of the Immunoglobulin Constant Region in the antitumor activity of antibodies to cytotoxic t lymphocyte antigen 4 ctla 4
    Journal of Clinical Oncology, 2013
    Co-Authors: Alan J. Korman, John J Engelhardt, Karla A Henning, Timothy Chen, Vafa Shahabi, Roumyana Yordanova, Mark J Selby
    Abstract:

    9055 Background: Anti-CTLA-4 therapy enhances antitumor T-cell responses by both cell-intrinsic and cell-extrinsic mechanisms. Effector T-cell (Teff) activation is increased directly by interfering...

Alan J. Korman - One of the best experts on this subject based on the ideXlab platform.

  • anti ctla 4 antibodies of igg2a isotype enhance antitumor activity through reduction of intratumoral regulatory t cells
    Cancer immunology research, 2013
    Co-Authors: Mark J Selby, John J Engelhardt, Michael Quigley, Karla A Henning, Timothy Chen, Mohan Srinivasan, Alan J. Korman
    Abstract:

    Antitumor activity of CTLA-4 antibody blockade is thought to be mediated by interfering with the negative regulation of T-effector cell (Teff) function resulting from CTLA-4 engagement by B7-ligands. In addition, a role for CTLA-4 on regulatory T cells (Treg), wherein CTLA-4 loss or inhibition results in reduced Treg function, may also contribute to antitumor responses by anti-CTLA-4 treatment. We have examined the role of the Immunoglobulin Constant Region on the antitumor activity of anti-CTLA-4 to analyze in greater detail the mechanism of action of anti-CTLA-4 antibodies. Anti-CTLA-4 antibody containing the murine Immunoglobulin G (IgG)2a Constant Region exhibits enhanced antitumor activity in subcutaneous established MC38 and CT26 colon adenocarcinoma tumor models compared with anti-CTLA-4 containing the IgG2b Constant Region. Interestingly, anti-CTLA-4 antibodies containing mouse IgG1 or a mutated mouse IgG1-D265A, which eliminates binding to all Fcγ receptors (FcγR), do not show antitumor activity in these models. Assessment of Teff and Treg populations at the tumor and in the periphery showed that anti-CTLA-4-IgG2a mediated a rapid and dramatic reduction of Tregs at the tumor site, whereas treatment with each of the isotypes expanded Tregs in the periphery. Expansion of CD8 + Teffs is observed with both the IgG2a and IgG2b anti-CTLA-4 isotypes, resulting in a superior Teff to Treg ratio for the IgG2a isotype. These data suggest that anti-CTLA-4 promotes antitumor activity by a selective reduction of intratumoral Tregs along with concomitant activation of Teffs. Cancer Immunol Res; 1(1); 32–42. ©2013 AACR .

  • role of the Immunoglobulin Constant Region in the antitumor activity of antibodies to cytotoxic t lymphocyte antigen 4 ctla 4
    Journal of Clinical Oncology, 2013
    Co-Authors: Alan J. Korman, John J Engelhardt, Karla A Henning, Timothy Chen, Vafa Shahabi, Roumyana Yordanova, Mark J Selby
    Abstract:

    9055 Background: Anti-CTLA-4 therapy enhances antitumor T-cell responses by both cell-intrinsic and cell-extrinsic mechanisms. Effector T-cell (Teff) activation is increased directly by interfering...

Roberta Attanasio - One of the best experts on this subject based on the ideXlab platform.

  • baboon Immunoglobulin Constant Region heavy chains identification of four ighg genes
    Immunogenetics, 2002
    Co-Authors: Roberta Attanasio, Lakshmi Jayashankar, Carrie N Engleman, Franco Scinicariello
    Abstract:

    The increasing use of nonhuman primate models in biomedical research and especially in vaccine development requires the characterization of their Immunoglobulin genes and corresponding products. Therefore, we sequenced, cloned and characterized the four Immunoglobulin gamma chain Constant Region genes (IGHG) present in baboons. These four genes were designated IGHG1, IGHG2, IGHG3 and IGHG4 on the basis of sequence similarities with the four human genes encoding the IgG1, IgG2, IgG3 and IgG4 subclasses and the three known rhesus macaque IGHG genes. Specifically, the baboon IgG1, IgG2, IgG3 and IgG4 sequences exhibit 90.3%, 88.3%, 86.7% and 89.6% amino acid identity to their human counterpart. The percent of amino acid identity of baboon IgG1, IgG2 and IgG3 to the corresponding rhesus macaque sequences is 98.5, 93.1 and 94.4, respectively. Therefore, baboon and rhesus macaque IGHG genes are highly homologous to each other. The majority of differences existing between baboon and human sequences are clustered in the hinge Region, with the upper hinge being the most diverse and containing several proline residues. Similar to rhesus macaques, the hinge Regions of all baboon IGHG genes consist of a single exon, whereas in humans the IgG3 molecule is encoded by multiple exons. These results confirm the evolutionary instability of the hinge Region and indicate that functional properties associated with the hinge Regions of baboon and human IgG molecules might differ between the two species.

  • intraspecies heterogeneity of Immunoglobulin alpha chain Constant Region genes in rhesus macaques
    Immunology, 2001
    Co-Authors: Franco Scinicariello, Roberta Attanasio
    Abstract:

    Immunoglobulin A (IgA) is the major antibody class present in external secretions and is also an important component of serum Immunoglobulins. On mucosal surfaces, IgA represents a first line of defence by neutralizing invading pathogens. The number of IgA Constant-Region genes (C alpha) present in different mammalian species is variable. Immunoglobulin C alpha genes differ mainly in the sequences located in the hinge Region. IgA molecules, whose hinge Regions are remarkably similar to those of the respective human molecules, are present in hominoid primates. In this report, we show that two alleles of a single Immunoglobulin C alpha are present in rhesus macaques (Macaca mulatta). In addition, we show that intraspecies Immunoglobulin C alpha allelic polymorphism is very high in this non-human primate species. Specifically, five different hinge Regions, some of which are proline-rich, were identified from a total of eight rhesus macaque Immunoglobulin C alpha-chains. The five hinge Regions were different from those present in hominoid primates, both in length and in sequence. These results represent the first example of high levels of intraspecies Immunoglobulin Constant-Region variability and suggest that IgAs of variable structure and function may be present in rhesus macaques. As rhesus macaques are widely used as animal models for the development of vaccines for acquired immune deficiency syndrome (AIDS), the possible presence of structurally and functionally variable IgA molecules in different animals should be taken into account when designing experimental strategies to induce mucosal antibody responses to human immunodeficiency virus (HIV).

Franco Scinicariello - One of the best experts on this subject based on the ideXlab platform.

  • baboon Immunoglobulin Constant Region heavy chains identification of four ighg genes
    Immunogenetics, 2002
    Co-Authors: Roberta Attanasio, Lakshmi Jayashankar, Carrie N Engleman, Franco Scinicariello
    Abstract:

    The increasing use of nonhuman primate models in biomedical research and especially in vaccine development requires the characterization of their Immunoglobulin genes and corresponding products. Therefore, we sequenced, cloned and characterized the four Immunoglobulin gamma chain Constant Region genes (IGHG) present in baboons. These four genes were designated IGHG1, IGHG2, IGHG3 and IGHG4 on the basis of sequence similarities with the four human genes encoding the IgG1, IgG2, IgG3 and IgG4 subclasses and the three known rhesus macaque IGHG genes. Specifically, the baboon IgG1, IgG2, IgG3 and IgG4 sequences exhibit 90.3%, 88.3%, 86.7% and 89.6% amino acid identity to their human counterpart. The percent of amino acid identity of baboon IgG1, IgG2 and IgG3 to the corresponding rhesus macaque sequences is 98.5, 93.1 and 94.4, respectively. Therefore, baboon and rhesus macaque IGHG genes are highly homologous to each other. The majority of differences existing between baboon and human sequences are clustered in the hinge Region, with the upper hinge being the most diverse and containing several proline residues. Similar to rhesus macaques, the hinge Regions of all baboon IGHG genes consist of a single exon, whereas in humans the IgG3 molecule is encoded by multiple exons. These results confirm the evolutionary instability of the hinge Region and indicate that functional properties associated with the hinge Regions of baboon and human IgG molecules might differ between the two species.

  • intraspecies heterogeneity of Immunoglobulin alpha chain Constant Region genes in rhesus macaques
    Immunology, 2001
    Co-Authors: Franco Scinicariello, Roberta Attanasio
    Abstract:

    Immunoglobulin A (IgA) is the major antibody class present in external secretions and is also an important component of serum Immunoglobulins. On mucosal surfaces, IgA represents a first line of defence by neutralizing invading pathogens. The number of IgA Constant-Region genes (C alpha) present in different mammalian species is variable. Immunoglobulin C alpha genes differ mainly in the sequences located in the hinge Region. IgA molecules, whose hinge Regions are remarkably similar to those of the respective human molecules, are present in hominoid primates. In this report, we show that two alleles of a single Immunoglobulin C alpha are present in rhesus macaques (Macaca mulatta). In addition, we show that intraspecies Immunoglobulin C alpha allelic polymorphism is very high in this non-human primate species. Specifically, five different hinge Regions, some of which are proline-rich, were identified from a total of eight rhesus macaque Immunoglobulin C alpha-chains. The five hinge Regions were different from those present in hominoid primates, both in length and in sequence. These results represent the first example of high levels of intraspecies Immunoglobulin Constant-Region variability and suggest that IgAs of variable structure and function may be present in rhesus macaques. As rhesus macaques are widely used as animal models for the development of vaccines for acquired immune deficiency syndrome (AIDS), the possible presence of structurally and functionally variable IgA molecules in different animals should be taken into account when designing experimental strategies to induce mucosal antibody responses to human immunodeficiency virus (HIV).

Arturo Casadevall - One of the best experts on this subject based on the ideXlab platform.

  • The Role of the Constant Region in Antibody-Antigen Interactions: Redefining the Modular Model of Immunoglobulin Structure
    Structural Biology in Immunology, 2018
    Co-Authors: Anthony Bowen, Arturo Casadevall
    Abstract:

    Abstract Immunological canon traditionally divides Immunoglobulin molecules into a functionally distinct antigen-binding variable Region and a Constant Region that interacts with downstream components of the immune system. Recent research, along with a reexamination of earlier studies, shows that this modular model of antibody structure is incomplete. Biochemical, structural, and computational studies over the past five decades with many different antibodies illustrate an allosteric antibody model, where conformational changes in the variable Region are propagated to the Constant Region and vice versa. The Immunoglobulin Constant Region is now thought to play a major role in antibody-antigen interactions and can be viewed as another mechanism by which the immune system generates antibody diversity. While a precise structural mechanism is unclear and likely varies by the particular antibody or antibody family, the allosteric antibody model has many implications for the immune response, autoimmunity, vaccine development, and antibody engineering.

  • the Immunoglobulin Constant Region contributes to affinity and specificity
    Trends in Immunology, 2008
    Co-Authors: Marcela Torres, Arturo Casadevall
    Abstract:

    A central dogma in immunology is that antibody specificity is solely the result of variable (V)-Region interactions with an antigen. However, this view is not tenable in light of numerous reports that Constant heavy (C H ) domains can affect binding affinity and specificity and V-Region structure. Kinetic and thermodynamic proof for the occurrence of this phenomenon is now available. C H -Region effects on affinity and specificity suggest new mechanisms for generating antibody diversity and polyreactivity (multispecificity) that impact current views on idiotype regulation, autoimmunity, and B cell selection and change our understanding of vaccine responses.