Antibody gene therapy: an attractive approach for the treatment of cancers and other chronic diseases

Zheng, Dexian

doi:10.1038/cr.2007.13

Cited by 7 publications

(7 citation statements)

References 9 publications

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“…We chose this antibody format because it displays several advantages, as described in the literature [31]. This fragment preserves the targeting specificity of the whole mAb, it is minimally immunogenic and has superior biodistribution and blood clearance properties [31][32][33][34][35].…”

Section: Discussionmentioning

confidence: 99%

Novel humanized anti-CD3 antibodies induce a predominantly immunoregulatory profile in human peripheral blood mononuclear cells

et al. 2009

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Strategies to minimize the immunogenicity and toxicity of murine anti-CD3 antibodies (e.g. OKT3) are of special interest for organ transplantation and for the treatment of autoimmune diseases. In the present work, we have developed two humanized anti-CD3 antibodies. These molecules were shown to bind to human CD3, though less efficiently, and display less mitogenic activity than OKT3. These results prompted us to investigate whether this reduced mitogenic potential was associated with the development of anti-inflammatory properties. Indeed, in peripheral blood mononuclear cells (PBMCs), the humanized antibody versions induced a predominantly anti-inflammatory cytokine profile, in contrast with the pro-inflammatory profile induced by OKT3. Neither OKT3 nor the humanized versions induced the expression of IL-4, IL-2 or TGF-beta. Both humanized antibodies induced significantly lower production of IFN-gamma and IL-5 and slightly higher production of IL-10 than OKT3. This immunomodulatory profile was most evident by the 80-fold higher ratio of IL-10/IFN-gamma production in PBMCs cultured in the presence of the humanized antibodies, compared to those stimulated with OKT3. Furthermore, these humanized anti-CD3 antibodies induced a late FOXP3 gene expression while OKT3 led to a more transient expression of FOXP3. Taken our results, we suggest that these humanized anti-CD3 antibodies may promote the development of T cells with immunoregulatory activity.

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Section: Discussionmentioning

confidence: 99%

Novel humanized anti-CD3 antibodies induce a predominantly immunoregulatory profile in human peripheral blood mononuclear cells

et al. 2009

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“…However, there are several shortcomings that characterize antibody-based therapies, including a high-level of immune response, low specificity, low stability and solubility [79], and usually requires repetitive injections in order to achieve therapeutic/correction levels [80]. Monoclonal antibody therapies have been used successfully to treat many immune-related diseases, such as cancer and inflammatory diseases [81]. Clinical trials are ongoing for the use of mAbs in processes such as transplant rejection, rheumatoid arthritis, and prevention of viral infection [75].…”

Section: Monoclonal Antibody (Mab) Approach and Application In Disease Therapymentioning

confidence: 99%

APOE: The New Frontier in the Development of a Therapeutic Target towards Precision Medicine in Late-Onset Alzheimer’s

Yang

Kantor

Chiba‐Falek

2021

IJMS

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Alzheimer’s disease (AD) has a critical unmet medical need. The consensus around the amyloid cascade hypothesis has been guiding pre-clinical and clinical research to focus mainly on targeting beta-amyloid for treating AD. Nevertheless, the vast majority of the clinical trials have repeatedly failed, prompting the urgent need to refocus on other targets and shifting the paradigm of AD drug development towards precision medicine. One such emerging target is apolipoprotein E (APOE), identified nearly 30 years ago as one of the strongest and most reproduceable genetic risk factor for late-onset Alzheimer’s disease (LOAD). An exploration of APOE as a new therapeutic culprit has produced some very encouraging results, proving that the protein holds promise in the context of LOAD therapies. Here, we review the strategies to target APOE based on state-of-the-art technologies such as antisense oligonucleotides, monoclonal antibodies, and gene/base editing. We discuss the potential of these initiatives in advancing the development of novel precision medicine therapies to LOAD.

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“…13,18,19 A problematic limiting factor for AAV delivery of a full-length antibody has been the packaging capacity of the vector. Packaging efficiency of AAV significantly decreases once the size of the insert extends beyond B5 kb.…”

Section: Introductionmentioning

confidence: 99%

“…13,14 Nonviral forms of delivery, particularly plasmid injection/electroporation, have successfully delivered functional full-length antibodies but have not yet approached the serum antibody levels required for efficacy. 12,15,16 Recent delivery of an anti-HER2 antibody by adenovirus showed significant inhibition of tumor growth; however, expression of the antibody was relatively transient likely due to immunogenicity and levels in the serum rapidly decreased.…”

Section: Introductionmentioning

confidence: 99%

Growth inhibition of an established A431 xenograft tumor by a full-length anti-EGFR antibody following gene delivery by AAV

Wykoff-Clary

Gross

et al. 2008

Cancer Gene Ther

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Therapeutic monoclonal antibodies continue to achieve clinical success for the treatment of many different diseases, particularly cancer. However, the production and purification of antibodies continues to be a time and labor-intensive process with considerable technical challenges. Gene-based delivery of antibodies may address this, via direct production within the host that achieves therapeutic levels. In this report, we validate the feasibility that gene-based delivery is a viable approach for efficacious delivery of antibodies in the preclinical and, presumably, clinical setting. We demonstrate high and sustained in vivo expression of the murine antihuman epidermal growth factor receptor antibody 14E1 following intramuscular delivery by adeno-associated virus (AAV) 2/1. Incorporating the Furin/2A technology for monocistronic expression of both heavy and light chains, we achieved sustained serum levels of full-length 14E1 peaking over 1 mg ml À1 in athymic nude mice. In the A431 xenograft tumor model, 14E1was capable of significantly inhibiting tumor growth and prolonging survival when AAV was administered prior to tumor challenge. Furthermore, 14E1 demonstrated significant antitumor efficacy against well-established tumors (B400 mm 3 ) when AAV was administered up to 20 days after tumor challenge. Here we demonstrate for the first time growth inhibition of a well-established tumor by a full-length antibody following delivery by AAV.

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Antibody gene therapy: an attractive approach for the treatment of cancers and other chronic diseases

Cited by 7 publications

References 9 publications

Novel humanized anti-CD3 antibodies induce a predominantly immunoregulatory profile in human peripheral blood mononuclear cells

Novel humanized anti-CD3 antibodies induce a predominantly immunoregulatory profile in human peripheral blood mononuclear cells

APOE: The New Frontier in the Development of a Therapeutic Target towards Precision Medicine in Late-Onset Alzheimer’s

Growth inhibition of an established A431 xenograft tumor by a full-length anti-EGFR antibody following gene delivery by AAV

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