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PloS One 2020Immunogenicity is an important concern for therapeutic antibodies during drug development. By analyzing co-crystal structures of idiotypic antibodies and their...
Immunogenicity is an important concern for therapeutic antibodies during drug development. By analyzing co-crystal structures of idiotypic antibodies and their antibodies, we found that anti-idiotypic antibodies usually bind the Complementarity Determining Regions (CDR) of idiotypic antibodies. Sequence and structural features were identified for distinguishing immunogenic antibodies from non-immunogenic antibodies. For example, non-immunogenic antibodies have a significantly larger cavity volume at the CDR region and a more hydrophobic CDR-H3 loop than immunogenic antibodies. Antibodies containing no Gly at the turn of CDR-H2 loop are often immunogenic. We integrated these features together with a machine learning platform to Predict Immunogenicity for humanized and full human THerapeutic Antibodies (PITHA). This method achieved an accuracy of 83% in leave-one-out experiment for 29 therapeutic antibodies with available crystal structures. The accuracy decreased to 65% for 23 test antibodies with modeled structures, because their crystal structures were not available, and the prediction was made with modeled structures. The server of this method is accessible at http://mabmedicine.com/PITHA.
Topics: Antibodies, Monoclonal, Humanized; Antibody Formation; Crystallography, X-Ray; Drug Development; Humans; Hydrophobic and Hydrophilic Interactions; Protein Conformation
PubMed: 32866159
DOI: 10.1371/journal.pone.0238150 -
Fertility and Sterility Jul 1982Cynomolgus monkeys (Macaca fascicularis) were treated with 1.5 mg/kg dexamethasone (DEX) before (4 to 2 days) and after (0, 2, 4, and 7 days) vasectomy. Of the four...
Cynomolgus monkeys (Macaca fascicularis) were treated with 1.5 mg/kg dexamethasone (DEX) before (4 to 2 days) and after (0, 2, 4, and 7 days) vasectomy. Of the four monkeys treated with DEX, only one developed sperm antibody as measured by sperm-agglutinating and sperm-immobilizing assays. All six of the vasectomized monkeys not given DEX developed both agglutinating and immobilizing sperm antibodies. In this study, DEX given before and after vasectomy blocked sperm-agglutinating and -immobilizing antibody formation. We conclude that the major antigenic exposure to sperm responsible for sperm-agglutinating and -immobilizing antibody comes at the time of vasectomy.
Topics: Animals; Antibodies; Antibody Formation; Dexamethasone; Macaca fascicularis; Male; Spermatozoa; Sterilization Reversal; Time Factors; Vasectomy
PubMed: 7095171
DOI: 10.1016/s0015-0282(16)46402-2 -
The Journal of Experimental Medicine Aug 1949A study has been made of the relationship of antibody formation and the changes in amount of the nucleic acids in rabbit lymph nodes draining areas injected with typhoid...
A study has been made of the relationship of antibody formation and the changes in amount of the nucleic acids in rabbit lymph nodes draining areas injected with typhoid vaccine. The increase in DNA was found to parallel the increase in weight of the nodes, as might be expected from the active multiplication of cells. The peak of PNA increase occurred between the 4th and 6th days after vaccine injection when antibody formation was at its maximum. A histologic study of methyl green- and pyronine-stained sections of the nodes revealed that during the first 6 days of the experiment the cellular reaction was chiefly one of plasma cells. During the first 3 days plasmoblasts predominated; on the 5th and 6th days mature plasma cells were the prevailing cells. Most of the PNA was contained in the plasma cells. The lymphocytes began to proliferate in significant numbers on the 3rd and 4th days, and germinal centers began to appear on the 4th and 5th days. They showed their greatest activity only on the 9th day when PNA and antibody formation had passed their peaks. These results are interpreted as indicating that the plasma cell and not the lymphocyte is responsible for antibody formation.
Topics: Animals; Antibodies; Antibody Formation; Antigens; Lymph Nodes; Lymphocytes; Nucleic Acids; Plasma Cells; Rabbits
PubMed: 18136195
DOI: 10.1084/jem.90.2.157 -
Blood Aug 2019
Topics: Antibody Formation; Epitopes; Hematopoietic Stem Cell Transplantation
PubMed: 31395579
DOI: 10.1182/blood.2019002085 -
The Journal of Experimental Medicine Sep 1966Groups of rabbits were injected with either bovine serum albumin, sheep red cell stroma, or keyhole limpet hemocyanin to which 2,4-dinitrophenyl and/or p-azophenyl...
Groups of rabbits were injected with either bovine serum albumin, sheep red cell stroma, or keyhole limpet hemocyanin to which 2,4-dinitrophenyl and/or p-azophenyl arsonate groups had been coupled. Groups of animals received either doubly coupled antigen or an equivalent mixture of singly coupled antigens. Materials were injected intravenously as a solution or subcutaneously and intramuscularly in complete Freund's adjuvant. The presence of dinitrophenyl groups on the immunizing antigen could suppress, partially or completely, the antibody response to p-azophenyl arsonate when this hapten was located on the same molecule. Suppression was dependent on the ratio of haptenic groups on the molecule, appeared to be greatly affected by the method of immunization, and could be demonstrated in all three antigen systems. Partial suppression was manifested in decreased frequency and delayed appearance of the response as well as decreased maximal antibody titers. These findings appear irreconcilable with the possibility of direct clonal selection of antibody-producing cells by unprocessed antigen.
Topics: Animals; Antibody Formation; Arsenicals; Azo Compounds; Dinitrophenols; Erythrocytes; Haptens; Hemocyanins; Immunodiffusion; Mollusca; Rabbits; Serum Albumin, Bovine
PubMed: 4958801
DOI: 10.1084/jem.124.3.293 -
Brain, Behavior, and Immunity Mar 2017Cytomegalovirus (CMV) has been implicated as a factor in immunosenescence, including poor antibody response to vaccination and higher immune activation and inflammation....
Cytomegalovirus (CMV) has been implicated as a factor in immunosenescence, including poor antibody response to vaccination and higher immune activation and inflammation. Some people may be more or less vulnerable to the negative effects of CMV. The present investigation tested the effects of beta-blocker use and chronological age on the associations between CMV and immunity in adults aged 60-91 (N=98; 69% CMV seropositive) who were administered the trivalent influenza vaccine for up to 5years. Peak antibody response, corrected for baseline, and spring (persistent) antibody response, corrected for peak, were assessed, as well as beta-2 microglobulin (β2μ) and interleukin-6 (IL-6). In multi-level models with years at Level 1 and people at Level 2, CMV serostatus did not predict peak antibody response, but there was a 3-way interaction between CMV serostatus, age, and beta-blockers. Age was negatively associated with peak antibody, but only among adults who were CMV seropositive and taking beta-blockers. CMV seronegative adults who were not taking beta-blockers had the highest antibody persistence. CMV serostatus was not associated with β2μ or IL-6. Results suggest that CMV+ serostatus may negatively compromise antibody response to a greater degree than inflammatory markers in older adults. Furthermore, older adults who take beta-blockers may be more vulnerable to negative effects of age and CMV on peak antibody response, perhaps by virtue of their underlying health condition.
Topics: Adrenergic beta-Antagonists; Aged; Aged, 80 and over; Aging; Antibodies, Viral; Antibody Formation; Cytomegalovirus; Cytomegalovirus Infections; Female; Humans; Hypertension; Inflammation; Influenza Vaccines; Influenza, Human; Interleukin-6; Male; Middle Aged; Vaccination
PubMed: 27720816
DOI: 10.1016/j.bbi.2016.09.025 -
Cytokine 2010Interleukin (IL)-12 is a pivotal cytokine that strongly stimulates Th1-associated cellular immunity. It is now recognized that IL-12 also activates humoral immunity to... (Review)
Review
Interleukin (IL)-12 is a pivotal cytokine that strongly stimulates Th1-associated cellular immunity. It is now recognized that IL-12 also activates humoral immunity to both T-dependent and T-independent antigens. This has let to considerable interest in exploiting IL-12 as a vaccine adjuvant for protection against various bacterial and viral pathogens, particularly in the lung. Studies examining the efficacy of IL-12-mediated effects on protective antibody response in the mouse model are summarized in this review.
Topics: Adjuvants, Immunologic; Animals; Antibody Formation; Bacterial Infections; Bacterial Vaccines; Humans; Immunity, Cellular; Interleukin-12; Mice; Th1 Cells; Viral Vaccines; Virus Diseases
PubMed: 20650650
DOI: 10.1016/j.cyto.2010.06.011 -
Kidney International Jun 2002The T cell as a bridge between innate and adaptive immune systems: Implications for the kidney. The immune system is classically divided into innate and adaptive... (Review)
Review
The T cell as a bridge between innate and adaptive immune systems: Implications for the kidney. The immune system is classically divided into innate and adaptive components with distinct roles and functions. T cells are major components of the adaptive immune system. T cells are firmly established to mediate various immune-mediated kidney diseases and are current targets for therapy. Ischemic acute renal failure, a major cause of native kidney and allograft dysfunction, is mediated in part by inflammatory components of the innate immune system. However, recent data from experimental models in kidney as well as liver, intestine, brain and heart implicate T cells as important mediators of ischemia reperfusion injury. These data reveal new insights into the pathogenesis of ischemic acute renal failure, as well as identify novel and feasible therapeutic approaches. Furthermore, the identification of T cells as a mediator of early alloantigen-independent tissue injury demonstrates that the functional capacity of T cells spreads beyond adaptive immunity into the realm of the innate immune response.
Topics: Adaptation, Physiological; Animals; Antibody Formation; Humans; Immune System; Kidney; T-Lymphocytes
PubMed: 12028434
DOI: 10.1046/j.1523-1755.2002.00378.x -
Arthritis Research & Therapy 2004Immunosenescence is associated with a decline in both T and B lymphocyte function. Although aged individuals have normal numbers of B cells in the periphery and are... (Review)
Review
Immunosenescence is associated with a decline in both T and B lymphocyte function. Although aged individuals have normal numbers of B cells in the periphery and are capable of mounting robust humoral responses, the antibodies produced are generally of lower affinity and are less protective than those produced by young animals. Here we review multiple studies that address the mechanisms that contribute to this decline. Taken together, these studies suggest that age-associated loss of the ability to generate protective humoral immunity results in part from reduced B lymphopoiesis. As the output of new, naïve B cells declines, homeostatic pressures presumably force the filling of the peripheral B cell pool by long-lived antigen-experienced cells. Because the antibody repertoire of these cells is restricted by previous antigenic experience, they make poor quality responses to new immunologic insults.
Topics: Aging; Animals; Antibody Formation; Arthritis; Autoimmunity; B-Lymphocytes; Humans
PubMed: 15225355
DOI: 10.1186/ar1180 -
BioDrugs : Clinical Immunotherapeutics,... Jun 2017Biosimilars are highly similar versions of approved branded biologics. Unlike generics, they are not exact replicas of reference products. Minor differences between... (Review)
Review
Biosimilars are highly similar versions of approved branded biologics. Unlike generics, they are not exact replicas of reference products. Minor differences between biosimilars and reference products in some aspects are expected; likewise, biosimilar products will differ from each other. The objective of this review is to discuss the challenges associated with the development and approval of biosimilar products that are unique because of their complex structure and specialized manufacturing processes, which can impact not only efficacy but also immunogenicity and safety. Regulatory guidelines recommend a totality-of-evidence approach focused on stepwise development that involves demonstration of structural similarity and functional equivalence. Structural and functional characteristics of the proposed biosimilar are compared with the reference product; similarity of these functions forms the foundation of the biosimilar development program, including potential animal studies, a human pharmacokinetics/pharmacodynamics equivalence study, and a clinical study to confirm similar efficacy, safety, and immunogenicity. The clinical study should be performed in a sensitive population using appropriate endpoints to allow detection of any clinically meaningful differences between the biosimilar and the reference product if such differences exist. In conclusion, development of biosimilars is focused on the minimization of potential differences between the proposed biosimilar and reference product and the establishment of a robust manufacturing process to consistently produce a high-quality biosimilar product.
Topics: Animals; Antibody Formation; Biosimilar Pharmaceuticals; Delivery of Health Care; Drug Approval; Humans
PubMed: 28439817
DOI: 10.1007/s40259-017-0218-5