Low doses of antigen coupled to anti-CR2 mAbs induce rapid and enduring IgG immune responses in mice and in cynomolgus monkeys

Whipple, Emily C.; Ditto, Andrew H.; Shanahan, Ryan S.; Gatesman, Jeremy; Little, Stephen F.; Taylor, Ronald P.; Lindorfer, Margaret A.

doi:10.1016/j.molimm.2006.02.032

Cited by 20 publications

(16 citation statements)

References 55 publications

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“…The antibody response was significantly higher than that from mice immunized with the control K8 scFv, indicating that the anti-CR1 scFv works as postulated and efficiently targets antigen to phagocytic cells, resulting in an increased immune response. These data are in agreement with those observed for the anti-CR1/2 whole IgG molecule coupled to ovalbumin (3) or anthrax lethal toxin (30). However, our result is superior to that reported for the anti-CR1/2 scFv derived from hybridoma 7G6, which failed to elicit a significant antibody response (24) even though the scFv was taken up and the influenza virus peptide carried on the scFv was efficiently presented by antigen-presenting cells in vitro (21).…”

Section: Discussionsupporting

confidence: 91%

“…Monoclonal immunoglobulin G (IgG) antibodies have long been used as specific targeting vehicles. A number of reports have indicated success in achieving enhanced immune responses using antibodies to complement receptor 1 (CR1) and CR2 (3,8,30), Fc receptors (1, 2), and dendritic cell DEC205 receptor (5, 6). However, there are limitations in using intact IgG as a targeting vehicle; these limitations include a weak extravascular transport ability for IgG and difficulties with expressing whole IgG by bacteria.…”

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confidence: 99%

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Expression of a Functional Single-Chain Variable-Fragment Antibody against Complement Receptor 1 inStreptococcus gordonii

Knight

Halperin

West

et al. 2008

Clin Vaccine Immunol

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Streptococcus gordonii, an oral commensal organism, is a candidate vector for oral-vaccine development. Previous studies have shown that recombinant S. gordonii expressing heterologous antigens was weakly immunogenic when delivered intranasally. In this study, antigen was specifically targeted to antigen-presenting cells (APC) in order to potentiate antigen-APC interactions and increase the humoral immune response to the antigen. To achieve this goal, a single-chain variable-fragment (scFv) antibody against complement receptor 1 (CR1) was constructed. Anti-CR1 scFv purified from Escherichia coli was able to bind to mouse mixed lymphocytes and bone marrow-derived dendritic cells. The in vivo function of the anti-CR1 scFv protein was assessed by immunizing mice intranasally with soluble scFv and determining the immune response against the hemagglutinin (HA) peptide located on the carboxy terminus of the scFv. The serum anti-HA immunoglobulin G (IgG) immune response was dose dependent; as little as 100 ng of anti-CR1 scFv induced a significant IgG immune response, while such a response was minimal when the animals were given an unrelated scFv. The anti-CR1 scFv was expressed in S. gordonii as a secreted protein, which was functional, as it bound to dendritic cells. Mice orally colonized by the anti-CR1-secreting S. gordonii produced an anti-HA IgG immune response, indicating that such an approach can be used to increase the immune response to antigens produced by this bacterium.Streptococcus gordonii is a commensal bacterium found in the oral cavities of humans. The organism is considered to be an attractive vector as a live-oral-vaccine vehicle (14,23). A number of heterologous antigens have been expressed in this organism as either secreted proteins (15, 27) or cell wall-anchored proteins (16,17,19,20,25,26). In the murine oralcolonization model, the recombinant S. gordonii was able to establish long-term colonization (16,20). However, there are difficulties in stimulating a strong protective immune response against recombinant antigens following oral colonization.Antigen targeting to immune cells has the potential to manipulate the immune system and elicit an immune response more efficiently. Monoclonal immunoglobulin G (IgG) antibodies have long been used as specific targeting vehicles. A number of reports have indicated success in achieving enhanced immune responses using antibodies to complement receptor 1 (CR1) and CR2 (3,8,30), Fc receptors (1, 2), and dendritic cell DEC205 receptor (5, 6). However, there are limitations in using intact IgG as a targeting vehicle; these limitations include a weak extravascular transport ability for IgG and difficulties with expressing whole IgG by bacteria. Single-chain variable-fragment (scFv) antibodies, however, offer a number of advantages, e.g., they can be readily produced by bacteria and can be easily engineered genetically as fusion proteins carrying polypeptide antigens. In the context of antigen targeting, scFvs against CR1 and -2 (21, 24), DEC205 (9), CD3 (31), a...

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Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 99%

Expression of a Functional Single-Chain Variable-Fragment Antibody against Complement Receptor 1 inStreptococcus gordonii

Knight

Halperin

West

et al. 2008

Clin Vaccine Immunol

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“…Addition of C3d to naive CD4 + T cells caused a modest increase in proliferation, and this increase was greatly potentiated by anti-CR2 antibodies with agonist properties (20) (Supplemental Figures 4, A and B). C3d and anti-CR2 also inhibited Treg differentiation (Supplemental Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

C3d regulates immune checkpoint blockade and enhances antitumor immunity

Platt¹,

Silva

Balin

et al. 2017

JCI Insight

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“…Mouse mAb 9H5, specific for human and mouse C3b/iC3b, was obtained by immunizing C3 knockout mice with human C3 (30). This mAb binds to Z138 cells opsonized with RTX and mouse serum and thus has a binding pattern similar to that of mAb 3E7 which binds to deposited C3b/iC3b on RTX-opsonized B cells in the presence of human serum (31).…”

Section: Antibodiesmentioning

confidence: 99%

“…IgG1 mAbs HB43 and HB57, specific for the Fc region of human IgG and for the -chain of human IgM, respectively, have been reported (25,32). F(abЈ) 2 of rat IgG2b mAb 2.4G2, specific for mouse Fc␥RII/III (33,34) were prepared as described previously (30). HD1A, anti-human CD55, was a gift from Profs.…”

Section: Antibodiesmentioning

confidence: 99%

Rituximab-CD20 Complexes Are Shaved from Z138 Mantle Cell Lymphoma Cells in Intravenous and Subcutaneous SCID Mouse Models

Williams²,

Cousar

et al. 2007

The Journal of Immunology

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Infusion of standard-dose rituximab (RTX) in chronic lymphocytic leukemia (CLL) patients promotes rapid complement activation and deposition of C3 fragments on CLL B cells. However, immediately after RTX infusions, there is substantial loss (shaving) of CD20 from circulating malignant cells. Because shaving can compromise efficacies of anticancer immunotherapeutic mAbs, we investigated whether shaving occurs in SCID mouse models. Z138 cells, a B cell line derived from human mantle cell lymphoma, were infused i.v. or s.c. The i.v. model recapitulates findings we previously reported for therapeutic RTX in CLL: i.v. infused RTX rapidly binds to Z138 cells in lungs, and binding is accompanied by deposition of C3 fragments. However, within 1 h targeted cells lose bound RTX and CD20, and these shaved cells are still demonstrable 40 h after RTX infusion. Z138 cells grow in tumors at s.c. injection sites, and infusion of large amounts of RTX (0.50 mg on each of 4 days) leads to considerable loss of CD20 from these cells. Human i.v. Ig blocked shaving, suggesting that FcγRI on cells of the mononuclear phagocytic system promote shaving. Examination of frozen tumor sections from treated mice by immunofluorescence revealed large areas of B cells devoid of CD20, with CD20 intact in adjacent areas; it is likely that RTX had opsonized Z138 cells closest to capillaries, and these cells were shaved by monocyte/macrophages. The shaving reaction occurs in neoplastic B cells in tissue and in peripheral blood, and strategies to enhance therapeutic targeting and block shaving are under development.

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Low doses of antigen coupled to anti-CR2 mAbs induce rapid and enduring IgG immune responses in mice and in cynomolgus monkeys

Cited by 20 publications

References 55 publications

Expression of a Functional Single-Chain Variable-Fragment Antibody against Complement Receptor 1 inStreptococcus gordonii

Expression of a Functional Single-Chain Variable-Fragment Antibody against Complement Receptor 1 inStreptococcus gordonii

C3d regulates immune checkpoint blockade and enhances antitumor immunity

Rituximab-CD20 Complexes Are Shaved from Z138 Mantle Cell Lymphoma Cells in Intravenous and Subcutaneous SCID Mouse Models

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