A potent adjuvant effect of CD40 antibody attached to antigen

Barr, Tom A.; McCormick, Adele L.; Carlring, Jennifer; Heath, Andrew W.

doi:10.1046/j.1365-2567.2003.01634.x

Cited by 50 publications

(57 citation statements)

References 32 publications

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“…However, in the present studies, the immunized mice showed no signs of distress, and spleen size and cell counts were not increased by the immunizations (data not shown). This contrasts with the splenomegaly, septic shock-like effects and occasional mortality observed when agonistic anti-CD40 antibodies were given systemically (8,94). The most revealing experiment, however, was functional and involved separating the pScGag antigen plasmid from the pSP-D-CD40L adjuvant plasmid.…”

Section: Construction Of Expression Plasmids For 1- 2- and 4-trimermentioning

confidence: 90%

“…Agonistic anti-CD40 antibodies also act as a general vaccine adjuvant (8) and synergize with Toll-like receptor agonists to elicit profound vaccine-induced CD8 ϩ T-cell responses (4). However, these antibodies induce splenomegaly and shock-like symptoms unless used in small amounts in a single administration (8,94), which raises concerns about using agonistic anti-CD40 antibodies in humans.…”

Section: Discussionmentioning

confidence: 99%

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Multimeric Soluble CD40 Ligand and GITR Ligand as Adjuvants for Human Immunodeficiency Virus DNA Vaccines

Stone¹,

Barzee²,

Snarsky³

et al. 2006

J Virol

115

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For use in humans, human immunodeficiency virus (HIV) DNA vaccines may need to include immunostimulatory adjuvant molecules. CD40 ligand (CD40L), a member of the tumor necrosis factor (TNF) superfamily (TNFSF), is one candidate adjuvant, but it has been difficult to use because it is normally expressed as a trimeric membrane molecule. Soluble trimeric forms of CD40L have been produced, but in vitro data indicate that multimeric, many-trimer forms of soluble CD40L are more active. This multimerization requirement was evaluated in mice using plasmids that encoded either 1-trimer, 2-trimer, or 4-trimer soluble forms of CD40L. Fusion with the body of Acrp30 was used to produce the 2-trimer form, and fusion with the body of surfactant protein D was used to produce the 4-trimer form. Using plasmids for secreted HIV-1 antigens Gag and Env, soluble CD40L was active as an adjuvant in direct proportion to the valence of the trimers (1 < 2 < 4). These CD40L-augmented DNA vaccines elicited strong CD8 ؉ T-cell responses but did not elicit significant CD4 ؉ T-cell or antibody responses. To test the applicability of the multimeric fusion protein approach to other TNFSFs, a 4-trimer construct for the ligand of glucocorticoid-induced TNF family-related receptor (GITR) was also prepared. Multimeric soluble GITR ligand (GITRL) augmented the CD8 ؉ T-cell, CD4 ؉ T-cell, and antibody responses to DNA vaccination. In summary, multimeric CD40L and GITRL are new adjuvants for DNA vaccines. Plasmids for expressing multimeric TNFSF fusion proteins permit the rapid testing of TNFSF molecules in vivo.

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Section: Construction Of Expression Plasmids For 1- 2- and 4-trimermentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Multimeric Soluble CD40 Ligand and GITR Ligand as Adjuvants for Human Immunodeficiency Virus DNA Vaccines

Stone¹,

Barzee²,

Snarsky³

et al. 2006

J Virol

115

View full text Add to dashboard Cite

show abstract

“…Several studies have used agonistic anti-CD40 antibodies to activate CD40-bearing cells to enhance CD8 T-cell responses (3,4) and antitumor responses (13)(14)(15). Agonistic anti-CD40 antibodies also act as a general vaccine adjuvant (16) and synergize with Toll-like receptor agonists to augment vaccine-induced CD8 T-cell responses (17). However, these antibodies induce splenomegaly and shock-like symptoms unless used in small amounts in a single administration (15,16), which raises concerns about using systemic agonistic anti-CD40 antibodies in humans.…”

mentioning

confidence: 99%

“…Agonistic anti-CD40 antibodies also act as a general vaccine adjuvant (16) and synergize with Toll-like receptor agonists to augment vaccine-induced CD8 T-cell responses (17). However, these antibodies induce splenomegaly and shock-like symptoms unless used in small amounts in a single administration (15,16), which raises concerns about using systemic agonistic anti-CD40 antibodies in humans. Modulated local expression of CD40L at relatively lower levels by DNA or replication-defective viral vaccines could provide a safe alternative to overly potent systemic stimulation by agonistic anti-CD40 Ab or high doses of CD40L protein.…”

mentioning

confidence: 99%

CD40L-Adjuvanted DNA/Modified Vaccinia Virus Ankara Simian Immunodeficiency Virus SIV239 Vaccine Enhances SIV-Specific Humoral and Cellular Immunity and Improves Protection against a Heterologous SIVE660 Mucosal Challenge

Kwa

Lai

Gangadhara

et al. 2014

J Virol

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It remains a challenge to develop a successful human immunodeficiency virus (HIV) vaccine that is capable of preventing infection. Here, we utilized the benefits of CD40L, a costimulatory molecule that can stimulate both dendritic cells (DCs) and B cells, as an adjuvant for our simian immunodeficiency virus (SIV) DNA vaccine in rhesus macaques. We coexpressed the CD40L with our DNA/SIV vaccine such that the CD40L is anchored on the membrane of SIV virus-like particle (VLP). These CD40L containing SIV VLPs showed enhanced activation of DCs in vitro. We then tested the potential of DNA/SIV-CD40L vaccine to adjuvant the DNA prime of a DNA/modified vaccinia virus Ankara (MVA) vaccine in rhesus macaques. Our results demonstrated that the CD40L adjuvant enhanced the functional quality of anti-Env antibody response and breadth of anti-SIV CD8 and CD4 T cell responses, significantly delayed the acquisition of heterologous mucosal SIV infection, and improved viral control. Notably, the CD40L adjuvant enhanced the control of viral replication in the gut at the site of challenge that was associated with lower mucosal CD8 immune activation, one of the strong predictors of disease progression. Collectively, our results highlight the benefits of CD40L adjuvant for enhancing antiviral humoral and cellular immunity, leading to enhanced protection against a pathogenic SIV. A single adjuvant that enhances both humoral and cellular immunity is rare and thus underlines the importance and practicality of CD40L as an adjuvant for vaccines against infectious diseases, including HIV-1. IMPORTANCEDespite many advances in the field of AIDS research, an effective AIDS vaccine that can prevent infection remains elusive. CD40L is a key stimulator of dendritic cells and B cells and can therefore enhance T cell and antibody responses, but its overly potent nature can lead to adverse effects unless used in small doses. In order to modulate local expression of CD40L at relatively lower levels, we expressed CD40L in a membrane-bound form, along with SIV antigens, in a nucleic acid (DNA) vector. We tested the immunogenicity and efficacy of the CD40L-adjuvanted vaccine in macaques using a heterologous mucosal SIV infection. The CD40L-adjuvanted vaccine enhanced the functional quality of anti-Env antibody response and breadth of anti-SIV T cell responses and improved protection. These results demonstrate that VLP-membrane-bound CD40L serves as a novel adjuvant for an HIV vaccine. N ovel vaccine approaches that elicit strong humoral and cellular immunity with high functional quality will aid HIV vaccine development. Here, we utilized the benefits of CD40L, a costimulatory molecule belonging to the tumor necrosis factor superfamily (TNFSF), that can stimulate both dendritic cells (DCs) and B cells for enhancing T cell and antibody (Ab) responses (1). CD40L activates DCs and enhances the priming of the cytotoxic CD8 T cell response (2-4). CD40L also enhances the survival and differentiation of activated B cells, leading to increased germinal c...

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“…[21][22][23] Many CD40mAbs mimic the natural ligand, CD154. We showed previously that immunization of mice with low doses of anti-CD40mAb conjugated to Ag results in enhanced primary 24 and secondary Ab responses, increased IFN-␥ production, and enhanced delayed hypersensitivity responses, indicating an initiation of a Th1-like cell response. 25 It is widely known that Th1 immune responses are required for efficient tumor cell destruction; therefore, we considered the use of an anti-CD40mAb as an adjuvant might be beneficial in lymphoma Id vaccination.…”

Section: Introductionmentioning

confidence: 92%

Conjugation of lymphoma idiotype to CD40 antibody enhances lymphoma vaccine immunogenicity and antitumor effects in mice

Carlring

Szabo

Dickinson

et al. 2012

Blood

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Personalized immunotherapy of lymphoma based on tumor idiotype (Id) has shown anti-idiotype humoral immune responses in 40%-50% and cellular immune responses in 50%-75% of follicular lymphoma patients, indicating that this therapy can be clinically successful. We have developed a novel vaccine against lymphoma consisting of an anti-CD40 Ab (ADX40) chemically conjugated to the tumor idiotype A20 and tested it in a murine lymphoma model. BALB/c mice were immunized with 2 doses of immunogen alone or in conjunction with additional adjuvants before tumor challenge. ADX40-Id vaccination resulted in significantly retarded tumor growth and reduced mouse morbidity. Moreover, similar mouse survival was obtained with 2 injections of ADX40-Id as with 8 injections using the standard therapy of keyhole limpet hemocyanin Id ؉ GM-CSF. IntroductionNon-Hodgkin lymphoma (NHL) is a heterogenous group of malignancies representing approximately 4% of all cancers. Most NHLs (Ͼ 90%) are of a B-cell phenotype, and the current standard of care for these patients is a combination of chemotherapy and total B-cell ablation with an anti-CD20mAb. 1 B-cell lymphomas express a unique Ig idiotype (Id) on their surface that can be targeted for active immune therapy. 2 Id vaccines have been used in active immunization against lymphoma and have consisted of autologous Id or recombinant Id protein conjugated to keyhole limpet hemocyanin (KLH) and injected with the adjuvant GM-CSF. Vaccination with tumor-derived Id has been shown to elicit a polyclonal Ab response, as well as CD8 and CD4 T-cell recognition of Id-derived peptides presented by MHC class I and II at the tumor surface. 3,4 Studies have shown that vaccination with KLH-Id conferred protection against tumor challenge in several animal models. [5][6][7] Based on these animal studies, clinical trials in B-cell lymphoma patients were initiated. 8,9 In the first clinical trial, patients who mounted an anti-Id immune response were found to have an increase in the median time to disease progression, 8 and another study showed that patients could achieve complete molecular remission. 9 After these encouraging immunologic and clinical outcomes, randomized, double-blind, placebo-controlled phase 3 clinical trials were performed to evaluate the clinical efficacy of the KLH-Id ϩ GM-CSF vaccine. 10,11 A phase 3 trial using the personalized BiovaxID vaccine showed a statistically significant improvement in disease-free survival in vaccine versus control arms in follicular lymphoma patients in first remission. 12 The personalized MyVax vaccine (www.genitope.com) was successful in a phase 2 trial; however, a phase 3 trial showed no significant difference in the progression-free survival overall (the primary end point) of patients receiving MyVax compared with control, but did show a significant clinical effect in the immune responding group. Because the trial did not meet its primary end point, Genitope suspended the development of this vaccine. However, in a subsequent follow-up study of 91 recently dia...

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A potent adjuvant effect of CD40 antibody attached to antigen

Cited by 50 publications

References 32 publications

Multimeric Soluble CD40 Ligand and GITR Ligand as Adjuvants for Human Immunodeficiency Virus DNA Vaccines

Multimeric Soluble CD40 Ligand and GITR Ligand as Adjuvants for Human Immunodeficiency Virus DNA Vaccines

CD40L-Adjuvanted DNA/Modified Vaccinia Virus Ankara Simian Immunodeficiency Virus SIV239 Vaccine Enhances SIV-Specific Humoral and Cellular Immunity and Improves Protection against a Heterologous SIVE660 Mucosal Challenge

Conjugation of lymphoma idiotype to CD40 antibody enhances lymphoma vaccine immunogenicity and antitumor effects in mice

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