Designing CD4 immunoadhesins for AIDS therapy

Capon, Daniel J.; Chamow, Steven M.; Mordenti, Joyce; Marsters, Scot A.; Gregory, Timothy J.; Mitsuya, Hiroaki; Byrn, Randal A.; Lucas, Cathy H.; Wurm, Florian M.; Groopman, Jerome E.; Broder, Samuel; Smith, Douglas H.

doi:10.1038/337525a0

Cited by 593 publications

(246 citation statements)

References 49 publications

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“…This protein was expected to be more efficient therapeutically than tsCR1 itself, since the tsCR1-Ig molecule is likely to have an increased half-life compared with tsCR1, due to the presence of the IgG Fc region (68,69). In addition, the IgG Fc region in the tsCR1-Ig molecules enables it to form homodimers.…”

Section: Resultsmentioning

confidence: 99%

Soluble complement receptor 1 (CD35) delivered by retrovirally infected syngeneic cells or by naked DNA injection prevents the progression of collagen-induced arthritis

Dreja¹,

Annenkov

Chernajovsky

2000

Arthritis & Rheumatism

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Objective. The complement system is important in the development of autoimmune inflammation, including rheumatoid arthritis (RA) and collagen-induced arthritis (CIA). Complement receptor 1 (CR1) is involved in regulation of complement activity. Studies on models of autoimmunity have demonstrated that soluble CR1 (sCR1) is a potent therapeutic agent. The present study was thus undertaken to investigate the feasibility of antiinflammatory gene therapy to prevent CIA by delivery of genes encoding truncated sCR1 (tsCR1) and dimeric tsCR1-Ig.Methods. Syngeneic fibroblasts or arthritogenic splenocytes, engineered to express tsCR1 using retrovirus-mediated gene transfer, were injected into DBA/1 recipients that had been immunized with bovine type II collagen (CII). In separate experiments, naked DNA containing tsCR1 and tsCR1-Ig genes was injected intramuscularly into the immunized animals. The clinical development of arthritis was monitored, anti-CII levels measured, and antigenic T cell response studied. Affinity-purified tsCR1-Ig was assayed for its inhibitory effect on the alternative complement pathway in mouse serum.Results. Treatment of CII-immunized mice with the tsCR1-expressing cells inhibited development of CIA, reduced anti-CII antibody levels, and inhibited T cell response to CII in vitro. Intramuscular injections of DNA encoding the CR1 genes prevented the progression of disease. Furthermore, compared with full-length sCR1, purified tsCR1-Ig was more active in inhibiting the murine alternative complement pathway.Conclusion. Our findings demonstrated that tsCR1 and tsCR1-Ig, when delivered via gene therapy, had a beneficial effect on autoimmune inflammation. These results indicate that targeting the complement system in RA patients may be of clinical importance.

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Section: Resultsmentioning

confidence: 99%

Soluble complement receptor 1 (CD35) delivered by retrovirally infected syngeneic cells or by naked DNA injection prevents the progression of collagen-induced arthritis

Dreja¹,

Annenkov

Chernajovsky

2000

Arthritis & Rheumatism

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“…The TNF inhibitor that we have produced and characterized finds precedent in the work of Capon et al (16) and Traunecker et al (17), who designed secreted chimeric molecules in which the binding moiety of a CD4 molecule was adjoined to an IgG heavy chain. This molecule circulated for a prolonged period of time in vivo.…”

Section: Discussionmentioning

confidence: 99%

A tumor necrosis factor (TNF) receptor-IgG heavy chain chimeric protein as a bivalent antagonist of TNF activity.

Peppel

Crawford

Beutler

1991

The Journal of Experimental Medicine

306

174

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SummaryUsing a multistep polymerase chain reaction method, we have produced a construct in which a cDNA sequence encoding the extraceUular domain of the human 55-kD tumor necrosis factor (TNF) receptor is attached to a sequence encoding the Fc portion and hinge region of a mouse IgG1 heavy chain through an oligomer encoding a thrombin-sensitive peptide linker. This construct was placed downstream from a cytomegalovirus promoter sequence, and expressed in Chinese hamster ovary cells. A secreted protein, capable of binding TNF and inactivating it, was produced by the transfected cells. Molecular characterization revealed that this soluble version of the TNF receptor was dimeric. Moreover, the protein could be quantitatively cleaved by treatment with thrombin. However, the monovalent extracellular domain prepared in this way has a greatly reduced TNF inhibitory activity compared with that of the bivalent inhibitor. Perhaps because of its high affinity for TNF, the chimeric protein is far more effective as a TNF inhibitor than are neutralizing monodonal antibodies. This molecule may prove very useful as a reagent for the antagonism and assay of TNF and lymphotoxin from diverse species in health and disease, and as a means of deciphering the exact mechanism through which TNF interacts with the 55-kD receptor.T he recent cloning of the 55-kD (1-3) and 75-kD (3-5) TNF receptors has opened the way for further studies of TNF effects and signal transduction. Moreover, it appears that truncated receptor molecules, lacking the transmembrane or cytoplasmic domains, are capable of interacting with TNF, and therefore have been isolated from urine (6, 7) and serum (2) as TNF inhibitors. We considered that derivatives of such molecules might prove useful as antagonists of TNF action in vivo, as high affinity ligands to be applied as the basis of a more sensitive assay for TNF, and as reagents to be used in defining the molecular interaction between TNF and its receptor.Unfortunately, truncated forms of the TNF receptor are highly unstable in vivo, and therefore are poor substitutes for antibodies as a means of antagonizing TNF action in living animals. The naturally occurring TNF receptor fragments are univalent and therefore have an avidity that is effectively far lower than that of a bivalent ligand. The production of large quantities of a truncated receptor by recombinant means has, in our hands, been problematic, since the protein is produced in an inactive and insoluble form in bacteria (Peppel, K., and B. Beutler, unpublished observations). This difficulty may arise from the highly cysteine-rich structure of the receptor-binding domain (1, 2). When produced in roammalian cells through recombinant techniques, the soluble receptor fragment is active, but produced at low levels, and therefore difficult to purify (Beutler, B., and T. Brown, unpublished observations).To circumvent these problems, we have engineered a chimeric protein in which the extracellular domain of the TNF receptor, which normally engages the TNF molecu...

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“…33 More importantly, previous studies have shown that IFN␥R/Fc fusion proteins have a much longer half-life in body fluids than truncated IFN␥R, 23 possibly because the larger size of immunoadhesins prevents rapid clearance in the kidney. 34 Also, dimeric IFN␥R/Fc fusion proteins can usually bind IFN␥ with greater avidity than single chain receptors, presumably because this cytokine is a homodimer. 33 For insertion into the vector, we chose heavy chain elements (part of CH1, hinge, CH2 and CH3) of the murine IgG1 isotype, instead of other isotypes, because IgG1 has a long half-life in serum and does not activate complement.…”

Section: Discussionmentioning

confidence: 99%

Prevention of autoimmune diabetes by intramuscular gene therapy with a nonviral vector encoding an interferon-gamma receptor/IgG1 fusion protein

Prud’homme

Chang

1999

Gene Ther

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We report on long-term delivery of an interferon-␥ (IFN␥) exceeding 100 ng/ml for months after treatment. These levinhibitory protein by intramuscular (i.m.) gene therapy. els are sufficient to neutralize IFN␥ in vivo, and to prevent IFN␥ is a cytokine that plays an important role in many either MDSD or cyclophosphamide (CYP)-accelerated inflammatory disorders, including autoimmune insulindiabetes in NOD mice, which are both characterized by dependent diabetes mellitus (IDDM) in NOD mice and (in systemic release of IFN␥. In these diseases gene therapy various strains) multiple low-dose streptozotocin (STZ)-considerably reduces inflammation in the islets of Langerinduced diabetes (MDSD). By cDNA insertion into plasmid hans (insulitis). Also, circulating IFN␥R/IgG1 blocked IFN␥-VICAL VR-1255 we constructed an expression vector enhanced nitric oxide production by peritoneal macroencoding a soluble IFN␥ receptor/IgG1 heavy chain (all phages. The fusion protein is constructed from nonmurine) fusion protein (IFN␥R/IgG1). This protein is immunogenic self elements, avoiding a neutralizing secreted as a homodimer and neutralizes IFN␥ in vitro. We immune response and making it suitable for prolonged show that i.m. injections of this vector as naked DNA in therapy of numerous inflammatory disorders. mice results in secretion of IFN␥R/IgG1, with serum levels

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Designing CD4 immunoadhesins for AIDS therapy

Cited by 593 publications

References 49 publications

Soluble complement receptor 1 (CD35) delivered by retrovirally infected syngeneic cells or by naked DNA injection prevents the progression of collagen-induced arthritis

Soluble complement receptor 1 (CD35) delivered by retrovirally infected syngeneic cells or by naked DNA injection prevents the progression of collagen-induced arthritis

A tumor necrosis factor (TNF) receptor-IgG heavy chain chimeric protein as a bivalent antagonist of TNF activity.

Prevention of autoimmune diabetes by intramuscular gene therapy with a nonviral vector encoding an interferon-gamma receptor/IgG1 fusion protein

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