-
Frontiers in Cellular and Infection... 2022The 6-cysteine protein family is one of the most abundant surface antigens that are expressed throughout the life cycle. Many members of the 6-cysteine family have... (Review)
Review
The 6-cysteine protein family is one of the most abundant surface antigens that are expressed throughout the life cycle. Many members of the 6-cysteine family have critical roles in parasite development across the life cycle in parasite transmission, evasion of the host immune response and host cell invasion. The common feature of the family is the 6-cysteine domain, also referred to as s48/45 domain, which is conserved across Aconoidasida. This review summarizes the current approaches for recombinant expression for 6-cysteine proteins, monoclonal antibodies against 6-cysteine proteins that block transmission and the growing collection of crystal structures that provide insights into the functional domains of this protein family.
Topics: Animals; Antibodies, Blocking; Antibodies, Protozoan; Antigens, Protozoan; Cysteine; Life Cycle Stages; Malaria, Falciparum; Plasmodium; Plasmodium falciparum; Protozoan Proteins
PubMed: 35899047
DOI: 10.3389/fcimb.2022.945924 -
ACS Synthetic Biology Oct 2022Natural killer (NK) cells are a major subset of innate immune cells that are essential for host defense against pathogens and cancer. Two main classes of inhibitory NK...
Natural killer (NK) cells are a major subset of innate immune cells that are essential for host defense against pathogens and cancer. Two main classes of inhibitory NK receptors (NKR), KIR and CD94/NKG2A, play a key role in suppressing NK activity upon engagement with tumor cells or virus-infected cells, limiting their antitumor and antiviral activities. Here, we find that single-chain NKR antagonists linked to a VHH that binds the cell surface phosphatase CD45 potentiate NK and T activities to a greater extent than NKR blocking antibodies alone in vitro. We also uncovered crosstalk between NKG2A and Ly49 that collectively inhibit NK cell activation, such that CD45-NKG2A and CD45-Ly49 bispecific molecules show synergistic effects in their ability to enhance NK cell activation. The basis of the activity enhancement by CD45 ligation may reflect greater antagonism of inhibitory signaling from engagement of MHC I on target cells, combined with other mechanisms, including avidity effects, tonic signaling, antagonism of weak inhibition from engagement of MHC I on non-target cells, and possible CD45 segregation within the NK cell-target cell synapse. These results uncover a strategy for enhancing the activity of NK and T cells that may improve cancer immunotherapies.
Topics: Receptors, Natural Killer Cell; NK Cell Lectin-Like Receptor Subfamily C; Antibodies, Blocking; Receptors, Immunologic; Antigens, CD; Antiviral Agents
PubMed: 36169352
DOI: 10.1021/acssynbio.2c00337 -
Immunology Oct 2022As there are limited data of the immunogenicity of the Sinopharm/BBIBP-CorV in different populations, antibody responses against different SARS-CoV-2 variants of concern...
As there are limited data of the immunogenicity of the Sinopharm/BBIBP-CorV in different populations, antibody responses against different SARS-CoV-2 variants of concern and T cell responses, we investigated the immunogenicity of the vaccine, in individuals in Sri Lanka. SARS-CoV-2-specific antibodies were measured in 282 individuals who were seronegative at baseline, and ACE2 receptor blocking antibodies, antibodies to the receptor-binding domain (RBD) of the wild-type (WT), alpha, beta and delta variants, ex vivo and cultured IFNγ ELISpot assays, intracellular cytokine secretion assays and B cell ELISpot assays were carried out in a sub cohort of the vaccinees at 4 and 6 weeks (2 weeks after the second dose). Ninety-five percent of the vaccinees seroconverted, although the seroconversion rates were significantly lower (p < 0.001) in individuals >60 years (93.3%) compared to those who were 20-39 years (98.9%); 81.25% had ACE2 receptor blocking antibodies at 6 weeks, and there was no difference in these antibody titres in vaccine sera compared to convalescent sera (p = 0.44). Vaccinees had significantly less (p < 0.0001) antibodies to the RBD of WT and alpha, although there was no difference in antibodies to the RBD of beta and delta compared to convalescent sera; 27.7% of 46.4% of vaccinees had ex vivo IFNγ and cultured ELISpot responses respectively, and IFNγ and CD107a responses were detected by flow cytometry. Sinopharm/BBIBP-CorV appeared to induce a similar level of antibody responses against ACE2 receptor, delta and beta as seen following natural infection.
Topics: Angiotensin-Converting Enzyme 2; Antibodies, Blocking; Antibodies, Viral; Antibody Formation; COVID-19; Cytokines; Humans; Immunization, Passive; Receptors, Opioid, delta; SARS-CoV-2; Sri Lanka; COVID-19 Serotherapy
PubMed: 35758860
DOI: 10.1111/imm.13536 -
Nature Communications May 2023Cancer immunotherapy is revolutionizing oncology. The marriage of nanotechnology and immunotherapy offers a great opportunity to amplify antitumor immune response in a...
Cancer immunotherapy is revolutionizing oncology. The marriage of nanotechnology and immunotherapy offers a great opportunity to amplify antitumor immune response in a safe and effective manner. Here, electrochemically active Shewanella oneidensis MR-1 can be applied to produce FDA-approved Prussian blue nanoparticles on a large-scale. We present a mitochondria-targeting nanoplatform, MiBaMc, which consists of Prussian blue decorated bacteria membrane fragments having further modifications with chlorin e6 and triphenylphosphine. We find that MiBaMc specifically targets mitochondria and induces amplified photo-damages and immunogenic cell death of tumor cells under light irradiation. The released tumor antigens subsequently promote the maturation of dendritic cells in tumor-draining lymph nodes, eliciting T cell-mediated immune response. In two tumor-bearing mouse models using female mice, MiBaMc triggered phototherapy synergizes with anti-PDL1 blocking antibody for enhanced tumor inhibition. Collectively, the present study demonstrates biological precipitation synthetic strategy of targeted nanoparticles holds great potential for the preparation of microbial membrane-based nanoplatforms to boost antitumor immunity.
Topics: Female; Animals; Mice; Immune Checkpoint Inhibitors; Antibodies, Blocking; Ferrocyanides; Immunotherapy
PubMed: 37221237
DOI: 10.1038/s41467-023-38796-9 -
Nature Communications Jul 2023The safety and immunogenicity of a protein-based tetravalent vaccine SCTV01E that contains spike protein ectodomain (S-ECD) of Alpha, Beta, Delta and Omicron BA.1 are...
The safety and immunogenicity of a protein-based tetravalent vaccine SCTV01E that contains spike protein ectodomain (S-ECD) of Alpha, Beta, Delta and Omicron BA.1 are assessed and compared with bivalent protein vaccine SCTV01C (Alpha and Beta variants) and monovalent mRNA vaccine (NCT05323461). The primary endpoints are the geometric mean titers (GMT) of live virus neutralizing antibodies (nAb) to Delta (B.1.617.2) and Omicron BA.1 at day 28 post-injection. The secondary endpoints include the safety, day 180 GMTs against Delta and Omicron BA.1, day 28 GMTs to BA.5, and seroresponse rates of neutralizing antibodies and T cell responses at day 28 post-injection. 450 participants, comprising of 449 males and 1 female, with a median age (range) of 27 (18-62) years, are assigned to receive one booster dose of BNT162b2, 20 µg SCTV01C or 30 µg SCTV01E and completed 4-week follow-up. All SCTV01E related adverse events (AEs) are mild or moderate and no Grade ≥3 AE, serious AE or new safety concerns are identified. Day 28 GMT of live virus neutralizing antibodies and seroresponse against Omicron BA.1 and BA.5 with SCTV01E are significantly higher than those with SCTV01C and BNT162b2. These data indicate an overall neutralization superiority with tetravalent booster immunization in men.
Topics: Male; Humans; Female; Infant; BNT162 Vaccine; COVID-19; SARS-CoV-2; Antibodies, Blocking; Antibodies, Neutralizing; Antibodies, Viral
PubMed: 37422518
DOI: 10.1038/s41467-023-39766-x -
Biochemical and Biophysical Research... Jul 2017The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase involved in many cellular functions including cell growth and migration. EGFR may be activated...
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase involved in many cellular functions including cell growth and migration. EGFR may be activated by EGF family ligands such as EGF and epiregulin (EREG). EREG is overexpressed in human colon and breast cancers, implying that EREG plays roles in tumorigenesis. Although EGF family members share a receptor, it is not well known whether their signaling pathways differ. In order to investigate EREG signaling, we established the anti-EREG antibody that inhibits EGFR downstream signaling stimulated by EREG but not by EGF. While the anti-EREG antibody has little effect on cell growth, it inhibits cell adhesion of EREG-expressing autocrine cancer cell lines. Our results suggest that anti-EREG antibodies represent valuable tools for elucidating EREG-specific signaling pathways, and may serve as therapeutic candidates for the treatment of cancers.
Topics: Animals; Antibodies, Blocking; Cell Adhesion; Epiregulin; ErbB Receptors; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Signal Transduction; Structure-Activity Relationship; Tumor Cells, Cultured
PubMed: 28274874
DOI: 10.1016/j.bbrc.2017.03.006 -
Vaccine May 2023Recent work demonstrating that asymptomatic carriers of P. falciparum parasites make up a large part of the infectious reservoir highlights the need for an effective...
Recent work demonstrating that asymptomatic carriers of P. falciparum parasites make up a large part of the infectious reservoir highlights the need for an effective malaria vaccine. Given the historical challenges of vaccine development, multiple parasite stages have been targeted, including the sexual stages required for transmission. Using flow cytometry to efficiently screen for P. falciparum gamete/zygote surface reactivity, we identified 82 antibodies that bound live P. falciparum gametes/zygotes. Ten antibodies had significant transmission-reducing activity (TRA) in a standard membrane feeding assay and were subcloned along with 9 nonTRA antibodies as comparators. After subcloning, only eight of the monoclonals obtained have significant TRA. These eight TRA mAbs do not recognize epitopes present in any of the current recombinant transmission-blocking vaccine candidates, Pfs230D1M, Pfs48/45.6C, Pf47 D2 and rPfs25. One TRA mAb immunoprecipitates two surface antigens, Pfs47 and Pfs230, that are expressed by both gametocytes and gametes/zygotes. These two proteins have not previously been reported to associate and the recognition of both by a single TRA mAb suggests the Pfs47/Pfs230 complex is a new vaccine target. In total, Pfs230 was the dominant target antigen, with five of the eight TRA mAbs and 8 of 11 nonTRA gamete/zygote surface reactive mAbs interacting with Pfs230. Of the three remaining TRA mAbs, two recognized non-reduced, parasite-produced Pfs25 and one bound non-reduced, parasite-produced Pfs48/45. None of the TRA mAbs bound protein on an immunoblot of reduced gamete/zygote extract and two TRA mAbs were immunoblot negative, indicating none of the new TRA epitopes are linear. The identification of eight new TRA mAbs that bind epitopes not included in any of the constructs currently under advancement as transmission-blocking vaccine candidates may provide new targets worthy of further study.
Topics: Humans; Plasmodium falciparum; Antibodies, Blocking; Malaria, Falciparum; Epitopes; Antibodies, Protozoan; Antibodies, Monoclonal; Malaria Vaccines; Protozoan Proteins; Antigens, Protozoan
PubMed: 37100721
DOI: 10.1016/j.vaccine.2023.04.042 -
Journal of Leukocyte Biology Jul 2013It is increasingly appreciated that cancers are recognized by the immune system, and under some circumstances, the immune system may control or even eliminate tumors.... (Review)
Review
It is increasingly appreciated that cancers are recognized by the immune system, and under some circumstances, the immune system may control or even eliminate tumors. The modulation of signaling via coinhibitory or costimulatory receptors expressed on T cells has proven to be a potent way to amplify antitumor immune responses. This approach has been exploited successfully for the generation of a new class of anticancer therapies, "checkpoint-blocking" antibodies, exemplified by the recently FDA-approved agent, ipilimumab, an antibody that blocks the coinhibitory receptor CTLA-4. Capitalizing on the success of ipilimumab, agents that target a second coinhibitory receptor, PD-1, or its ligand, PD-L1, are in clinical development. Lessons learned from treating patients with CTLA-4 and PD-1 pathway-blocking antibodies will be reviewed, with a focus on concepts likely to inform the clinical development and application of agents in earlier stages of development. See related review At the bench: Preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy.
Topics: Antibodies, Blocking; CTLA-4 Antigen; Clinical Trials as Topic; Humans; Immunotherapy; Neoplasms; Programmed Cell Death 1 Receptor
PubMed: 23667165
DOI: 10.1189/jlb.1212631 -
Clinical Chemistry and Laboratory... Mar 2013Folate supplementation reduces the risk of neural tube defect (NTD) pregnancy, and folinic acid has been used to correct cerebral folate deficiency (CFD) in children... (Review)
Review
Folate supplementation reduces the risk of neural tube defect (NTD) pregnancy, and folinic acid has been used to correct cerebral folate deficiency (CFD) in children with developmental disorders. In the absence of systemic folate deficiency, the discovery of autoantibodies (AuAbs) to folate receptor α (FRα) that block the uptake of folate offers one mechanism to explain the response to folate in these disorders. The association of FRα AuAbs with pregnancy-related complications, CFD syndrome, and autism spectrum disorders and response to folate therapy is highly suggestive of the involvement of these AuAbs in the disruption of brain development and function via folate pathways. The two types of antibodies identified in the serum of patients are blocking antibody and binding antibody. The two antibodies can be measured by the specific assays described and exert their pathological effects either by functional blocking of folate transport as previously shown or hypothetically by disrupting the FR by an antigen-antibody-mediated inflammatory response. We have identified both IgG and IgM AuAbs in these conditions. The predominant antibodies in women with NTD pregnancy belong to the IgG1 and IgG2 isotype and in CFD children, the IgG1 and IgG4 isotype. This review describes the methods used to measure these AuAbs, their binding characteristics, affinity, cross-reactivity, and potential mechanisms by which folate therapy could work. Because these AuAbs are associated with various pathologies during fetal and neonatal development, early detection and intervention could prevent or reverse the consequences of exposure to these AuAbs.
Topics: Antibodies, Blocking; Antibody Affinity; Autoantibodies; Child; Child Development Disorders, Pervasive; Female; Folate Receptor 1; Folic Acid; Folic Acid Deficiency; Humans; Immunoglobulin G; Immunoglobulin Isotypes; Neural Tube Defects; Pregnancy
PubMed: 23314538
DOI: 10.1515/cclm-2012-0577 -
Vaccine Feb 2019Data on duration of protection against invasive meningococcal disease post-vaccination with the recombinant, 4-component, meningococcal serogroup B vaccine (4CMenB) are...
BACKGROUND
Data on duration of protection against invasive meningococcal disease post-vaccination with the recombinant, 4-component, meningococcal serogroup B vaccine (4CMenB) are limited. We evaluated bactericidal activity persistence in adolescents/young adults up to 7.5 years post-primary vaccination with 4CMenB, and response to a booster dose compared with vaccine-naïve controls.
METHODS
This open-label, multicenter study (NCT02446743) enrolled 15-24 year-old-previously vaccinated participants from Canada, Australia (group Primed_4y) 4 years post-priming with 4CMenB (2 doses; 0,1-month schedule), and Chile (Primed_7.5y) 7.5 years after priming with 4CMenB (2 doses; 0,1/0,2/0,6-month schedule) and vaccine-naïve participants of similar age (Naïve_4y and Naïve_7.5y groups). Primed participants received a booster dose; vaccine-naïve participants received 2 catch-up doses of 4CMenB, 1 month apart. We evaluated antibody persistence and immune responses using hSBA in terms of geometric mean titers and percentages of participants with hSBA titers ≥4, the kinetics of bactericidal activity post-booster (previously vaccinated) or post-2 doses (vaccine-naïve), and safety.
RESULTS
Antibody levels declined at 4 (Primed_4y) and 7.5 (Primed_7.5y) years post-primary vaccination, but remained higher than in vaccine-naïve participants at baseline (≤44% vs ≤ 13% [fHbp]; ≤84% vs ≤ 24% [NadA]; ≤29% vs ≤ 14% [PorA]) for all vaccine antigens except NHBA (≤81% vs ≤ 79%). One month post-booster and post-second dose, 93-100% of primed and 79-100% of vaccine-naïve participants had hSBA titers ≥4 for all antigens. Kinetics of the antibody response were similar across groups with an early robust response observed 7 days post-booster/second dose. No vaccine-related serious adverse event was reported.
CONCLUSION
For all antigens except NHBA, a higher proportion of primed participants had hSBA titers ≥4, at 4 and 7.5 years post-vaccination, compared with vaccine-naïve participants. A more robust immune response after booster compared to a first dose in vaccine-naïve individuals, showed effective priming in an adolescent/young adult population. No safety or new reactogenicity issues were identified.
Topics: Adolescent; Antibodies, Bacterial; Antibodies, Blocking; Australia; Canada; Chile; Female; Follow-Up Studies; Humans; Immunization Schedule; Immunization, Secondary; Immunogenicity, Vaccine; Kinetics; Male; Meningococcal Infections; Meningococcal Vaccines; Neisseria meningitidis, Serogroup B; Serum Bactericidal Antibody Assay; Time Factors; Young Adult
PubMed: 30691980
DOI: 10.1016/j.vaccine.2018.12.059