PLGA nanoparticle-mediated delivery of tumor antigenic peptides elicits effective immune responses

Abstract Abstract 1642 Poster Board I-668 Background Tumor-derived heat shock proteins (HSPs), which bind to tumor-specific antigenic peptides, can be used for cancer immunotherapy. In this meeting, we previously reported that vaccination with mouse B-cell leukemia/lymphoma cell line, A20, -derived HSP70 (A20-HSP) against A20 cells in mice induces tumor-specific cellular immune responses (Sato et al. Blood 2001;98:1852-1857; Iuchi et al. Int J Hematol 2006;84:449-458) as well as A20-specific humoral immunity through complement dependent cell-cytotoxicities (CDCs) (Sato K et al., 2007, Blood 110:682a, Abstruct#2302). In the B-cell neoplasms, idiotype is known as one of the important tumor specific antigens which induce anti-idiotype cellular and humoral immune responses. A20-secreted monoclonal IgG (A20-Ig) and A20-idiotypic epitope peptide (A20-IP: DYWGQGTEL), which is derived from variable region of the heavy chain of the A20-Ig, are known as the A20-specific antigens (J Immunol. 2002; 168: 3983-91). Further analysis using A20-Ig and A20-IP enables to establish novel HSP70-based therapeutic strategies for B-cell neoplasms. The present study investigated whether immunization with A20-HSP induces anti-idiotypic antibodies, and also evaluated whether the antibodies showed CDCs. Methods A20 and syngeneic Balb/c mice (H-2Kd) were used in this study. HSP70 was purified from either A20 cells or healthy mouse liver tissue. A20-Ig was purified from A20 culture supernatants. After the subcutaneous immunization with A20-HSP, liver-derived HSP70 (control) to the healthy mice, the sera were harvested for the following experiments. To detect anti-A20-IP antibodies, the sera were assayed by ELISA to detect the specific IgG against A20-HSP, or A20-Ig. To confirm that immunization with A20-HSP induces anti-idiotypic antibodies, we analyzed the inhibitory effect (% inhibition) of A20-IP on the A20-HSP-mice sera reactivity against A20-HSP by preincubation of the sera with A20-IP or H-2Kd biding control peptide (mouse influenza hemagglutinin peptide: IYSTVASSL) by ELISA. To confirm that A20-HSP mice sera contains CDC type antibody directed to A20-IP, the CDC activity was determined by the trypan blue uptake of A20 cells after incubation with the complement and A20-HSP mice sera preincubated without or with A20-IP or control peptide. Results The IgG level in the A20-HSP mice against either A20-HSP or A20-Ig was significantly increased in comparison to that in control mice. % inhibition of A20-IP (45.7%) was significantly higher than that of control peptide (1.0%), indicating that almost half of IgG in the A20-HSP mice sera which reacts to A20-HSP recognizes A20-IP. The CDC activity of A20-HSP mice sera against A20 was markedly inhibited by preincubation of the sera with A20-IP but with control peptide. Conclusions: Immunization with A20-HSP70 induces anti-idiotype antibody and the antibody contributes a crucial role in eradication of A20 by CDC activity in mice. These findings enable to establish a novel and advantageous therapeutic strategy against B-cell neoplasms utilizing the anti-idiotypic antibody in HSP-based autologous tumor immunotherapy. Disclosures No relevant conflicts of interest to declare.

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Immunotherapy using heat-shock protein preparations of leukemia cells after syngeneic bone marrow transplantation in mice

Blood ◽

10.1182/blood.v98.6.1852 ◽

2001 ◽

Vol 98 (6) ◽

pp. 1852-1857 ◽

Cited By ~ 48

Author(s):

Kazuya Sato ◽

Yoshihiro Torimoto ◽

Yasuaki Tamura ◽

Motohiro Shindo ◽

Hitoshi Shinzaki ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Heat Shock ◽

T Lymphocytes ◽

Immune Responses ◽

Marrow Transplantation ◽

Leukemia Cell Line ◽

Leukemia Cells ◽

Antigenic Peptides ◽

Cd8 T Lymphocytes

Abstract Heat-shock proteins (HSPs) act as molecular chaperones binding endogenous antigenic peptides and transporting them to major histocompatibility complexes. HSPs chaperone a broad repertoire of endogenous peptides including tumor antigens. For the immunotherapy of tumors, a strategy using HSPs may be more advantageous than other procedures because the identification of each tumor-specific antigen is not necessary. In this study, the efficacy of immunotherapy against minimal residual leukemia cells using HSP preparations was evaluated. HSP70 and GP96 were purified from syngeneic leukemia cell line A20 and immunized into BALB/c mice during the reconstitution period of the immune system after syngeneic bone marrow transplantation. In this procedure, all mice not immunized were dead within 60 days of A20 inoculation, whereas the survival times of HSP-immunized mice were significantly prolonged. In addition, the depletion of either CD4+ or CD8+ T lymphocyte significantly abrogated this efficacy, indicating that both CD4+ and CD8+ T lymphocytes were required for tumor cell rejection. Moreover, the vaccination of HSPs elicited a specific response of potent CD8+ T lymphocytes cytotoxic against A20 in vitro. These observations suggest that immunization of the complex of HSPs and peptides derived from leukemia cells leads to immune responses. These immune responses are sufficient to reject minimal amounts of leukemia cells for relatively immunocompromised mice after syngeneic bone marrow transplantation.

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MCMV-based vaccine vectors expressing full-length viral proteins provide long-term humoral immune protection upon a single-shot vaccination

Cellular and Molecular Immunology ◽

10.1038/s41423-021-00814-5 ◽

2022 ◽

Author(s):

Yeonsu Kim ◽

Xiaoyan Zheng ◽

Kathrin Eschke ◽

M. Zeeshan Chaudhry ◽

Federico Bertoglio ◽

...

Keyword(s):

T Cells ◽

Immune Responses ◽

Influenza A ◽

High Morbidity ◽

Single Shot ◽

Respiratory Pathogens ◽

Antigenic Peptides ◽

Immune Protection ◽

Vaccine Vectors

AbstractGlobal pandemics caused by influenza or coronaviruses cause severe disruptions to public health and lead to high morbidity and mortality. There remains a medical need for vaccines against these pathogens. CMV (cytomegalovirus) is a β-herpesvirus that induces uniquely robust immune responses in which remarkably large populations of antigen-specific CD8+ T cells are maintained for a lifetime. Hence, CMV has been proposed and investigated as a novel vaccine vector for expressing antigenic peptides or proteins to elicit protective cellular immune responses against numerous pathogens. We generated two recombinant murine CMV (MCMV) vaccine vectors expressing hemagglutinin (HA) of influenza A virus (MCMVHA) or the spike protein of severe acute respiratory syndrome coronavirus 2 (MCMVS). A single injection of MCMVs expressing either viral protein induced potent neutralizing antibody responses, which strengthened over time. Importantly, MCMVHA-vaccinated mice were protected from illness following challenge with the influenza virus, and we excluded that this protection was due to the effects of memory T cells. Conclusively, we show here that MCMV vectors induce not only long-term cellular immunity but also humoral responses that provide long-term immune protection against clinically relevant respiratory pathogens.

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Immunoproteomic Lessons for Human Respiratory Syncytial Virus Vaccine Design

Journal of Clinical Medicine ◽

10.3390/jcm8040486 ◽

2019 ◽

Vol 8 (4) ◽

pp. 486

Author(s):

López ◽

Barriga ◽

Lorente ◽

Mir

Keyword(s):

Respiratory Syncytial Virus ◽

Immune Responses ◽

Antigen Processing ◽

Hla Class I ◽

Human Respiratory Syncytial Virus ◽

Class I ◽

Antigenic Peptides ◽

Cellular Immune Responses ◽

Syncytial Virus ◽

Cellular Immune

Accurate antiviral humoral and cellular immune responses require prior recognition of antigenic peptides presented by human leukocyte antigen (HLA) class I and II molecules on the surface of antigen-presenting cells. Both the helper and the cytotoxic immune responses are critical for the control and the clearance of human respiratory syncytial virus (HRSV) infection, which is a significant cause of morbidity and mortality in infected pediatric, immunocompromised and elderly populations. In this article we review the immunoproteomics studies which have defined the general antigen processing and presentation rules that determine both the immunoprevalence and the immunodominance of the cellular immune response to HRSV. Mass spectrometry and functional analyses have shown that the HLA class I and II cellular immune responses against HRSV are mainly focused on three viral proteins: fusion, matrix, and nucleoprotein. Thus, these studies have important implications for vaccine development against this virus, since a vaccine construct including these three relevant HRSV proteins could efficiently stimulate the major components of the adaptive immune system: humoral, helper, and cytotoxic effector immune responses.

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Development and characteristics of novel PLGA-chitosan as a new nanocarrier for pentavalent vaccine delivery

Current Pharmaceutical Biotechnology ◽

10.2174/1389201021666201218123911 ◽

2020 ◽

Vol 21 ◽

Author(s):

Zahra Alikhani ◽

Nadia Kazemi-Pour ◽

Mehdi Shafieeardestani ◽

Mojtaba Noofeli

Keyword(s):

Immune Responses ◽

Vaccine Delivery ◽

Histopathological Study ◽

Serum Samples ◽

Mtt Method ◽

Pentavalent Vaccine ◽

Notable Increase ◽

Plga Nanoparticle ◽

Cellular Immune

Background: Lately, the employment of nano-carriers has been known as an optimistic means of drug and vaccine delivery. Objective: Nano vaccines are a novel tier of vaccines that can develop humoral and cellular immune responses and can be introduced as a practical and secure nano vaccine candidate the prevention of diseases. The purpose of this study was to accomplish and use biodegradable nano-carriers for the synthesis of pentavalent vaccine and immunogenicity evaluation in the animal models. The PLGA nanoparticle was prepared and modified with chitosan nanoparticle. Nano-carrier PLGA-chitosan was loaded by the DTP-HepB-Hib antigens and confirmed by DLS, SEM, TEM and FT-IR then the in vitro loading and release were evaluated. The toxicity was assessed by the MTT method in the Hec293 cells. The antigenicity evaluation and histopathological study were conducted by injection of new nano pentavalent vaccines in the BALB/c mice and the immune response was measured in the serum samples through an indirect ELISA method. Results: Conclusions drawn from the current study exhibited the plausible ability of nano-carrier to deliver vaccine. A notable increase was shown in total IgG and IgM antibodies examined on mice vaccinated with new nano vaccines. The histopathological study in the treated mice showed no toxicity in vital organs of mice. Conclusion: The engineered vaccine delivery system showed the ability to induce robust immune responses and also the suitability features of the PLGA-chitosan as a promising carrier to improve vaccine delivery.

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MCMV based vaccine vectors expressing full-length viral proteins provide long-term humoral immune protection upon a single-shot vaccination

10.21203/rs.3.rs-566785/v1 ◽

2021 ◽

Author(s):

Luka Cicin-Sain ◽

Yeonsu Kim ◽

Xiaoyan Zheng ◽

Kathrin Eschke ◽

M. Zeeshan Chaudhry ◽

...

Keyword(s):

T Cells ◽

Immune Responses ◽

Influenza A ◽

Neutralizing Antibody ◽

Single Shot ◽

Respiratory Pathogens ◽

Antigenic Peptides ◽

Immune Protection ◽

Vaccine Vectors

Abstract Global pandemics by influenza or coronaviruses cause severe disruptions to the public health and lead to severe morbidity and mortality. Vaccines against these pathogens remain a medical need. CMV (cytomegalovirus) is a β-herpesvirus that induces uniquely robust immune responses, where outstandingly large populations of antigen-specific CD8+ T cells are maintained for a lifetime. Hence, CMV has been proposed and investigated as a novel vaccine vector expressing antigenic peptides or proteins to elicit protective cellular immune responses against numerous pathogens. We generated two recombinant murine CMV (MCMV) vaccine vectors expressing the hemagglutinin (HA) of influenza A virus (MCMVHA) or the spike protein of the severe acute respiratory syndrome coronavirus 2 (MCMVS). A single shot of MCMVs expressing either viral protein induced potent neutralizing antibody responses, which strengthened over time. Importantly, MCMVHA vaccinated mice were protected from illness following challenge with the influenza virus, and we excluded that this protection was due to effects of memory T cells. Conclusively, we show here that MCMV vectors do not only induce long-term cellular immunity, but also humoral responses that provide long-term immune protection against clinically relevant respiratory pathogens.

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Allotypic variation in antigen processing controls antigenic peptide generation from SARS-CoV-2 S1 Spike Glycoprotein

10.1101/2021.07.03.450989 ◽

2021 ◽

Author(s):

George Stamatakis ◽

Martina Samiotaki ◽

Ioannis Temponeras ◽

George Panayotou ◽

Efstratios Stratikos

Keyword(s):

Immune Responses ◽

Antigen Processing ◽

Cytotoxic T Lymphocyte ◽

Proteolytic Processing ◽

Antigenic Peptides ◽

Spike Glycoprotein ◽

Glycoprotein Precursor ◽

Intracellular Enzyme ◽

Proteomic Approach ◽

Underlying Mechanisms

Population genetic variability in immune system genes can often underlie variability in immune responses to pathogens. Cytotoxic T-lymphocytes are emerging as critical determinants of both SARS-CoV-2 infection severity and long-term immunity, either after recovery or vaccination. A hallmark of COVID-19 is its highly variable severity and breadth of immune responses between individuals. To address the underlying mechanisms behind this phenomenon we analyzed the proteolytic processing of S1 spike glycoprotein precursor antigenic peptides by 10 common allotypes of ER aminopeptidase 1 (ERAP1), a polymorphic intracellular enzyme that can regulate cytotoxic T-lymphocyte responses by generating or destroying antigenic peptides. We utilized a systematic proteomic approach that allows the concurrent analysis of hundreds of trimming reactions in parallel, thus better emulating antigen processing in the cell. While all ERAP1 allotypes were capable of producing optimal ligands for MHC class I molecules, including known SARS-CoV-2 epitopes, they presented significant differences in peptide sequences produced, suggesting allotype-dependent sequence biases. Allotype 10, previously suggested to be enzymatically deficient, was rather found to be functionally distinct from other allotypes. Our findings suggest that common ERAP1 allotypes can be a major source of heterogeneity in antigen processing and through this mechanism contribute to variable immune responses to COVID-19.

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Rational Design of PLGA Nanoparticle Vaccine Delivery Systems To Improve Immune Responses

Molecular Pharmaceutics ◽

10.1021/acs.molpharmaceut.9b00860 ◽

2019 ◽

Vol 16 (12) ◽

pp. 5000-5012 ◽

Cited By ~ 9

Author(s):

Pengfei Gu ◽

Adelijiang Wusiman ◽

Yue Zhang ◽

Zhenguang Liu ◽

Ruonan Bo ◽

...

Keyword(s):

Immune Responses ◽

Rational Design ◽

Vaccine Delivery ◽

Delivery Systems ◽

Plga Nanoparticle

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Co-delivery of anionic epitope/CpG vaccine and IDO inhibitor by self-assembled cationic liposome for combination melanoma immunotherapy

Journal of Materials Chemistry B ◽

10.1039/d1tb00256b ◽

2021 ◽

Author(s):

Qi Su ◽

Changrong Wang ◽

Huijuan Song ◽

Chuangnian Zhang ◽

Jinjian Liu ◽

...

Keyword(s):

Immune Responses ◽

Cancer Treatment ◽

Cancer Immunotherapy ◽

Cationic Liposome ◽

Antigenic Peptides ◽

Promising Strategy ◽

Self Assembled

Immunotherapy is revolutionizing cancer treatment. Vaccination of antigenic peptides has been identified as a promising strategy for cancer immunotherapy while insufficient immune responses were stimulated due to low antigenicity. Moreover,...

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